Tricyclic compounds for cancer treatment

Abstract

The present invention relates to a compound of formula (I), TIFF2026515652000156.tif69170 (in the formula, R 1 ~R 4 , A 1 , A 2 The present invention relates to compounds (where M and L are as described herein), pharmaceutically acceptable salts thereof, compositions comprising the compounds, and methods for using the compounds.

Description

[Technical Field]

[0001] This invention relates to organic compounds useful for the treatment and / or prevention in mammals, particularly to the inhibition of KRAS variants useful for treating cancer. [Background technology]

[0002] Field of Invention RAS is one of the best-known proto-oncogenes. Approximately 30% of human cancers contain mutations in three of its most notable members, KRAS, HRAS, and NRAS, making them the most common cancer drivers. KRAS mutations are generally associated with poor prognosis, particularly in colorectal cancer, pancreatic cancer, and lung cancer. As the most frequently mutated RAS isoform, KRAS has been studied intensively in recent years. Among the most commonly occurring 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 across colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC), and lung adenocarcinoma (LUAD). Furthermore, it is noteworthy that KRAS wild-type amplification is found in approximately 7% of all KRAS-associated cancers (ovarian, esophageal, gastric, and uterine), ranking among the most significant mutations.

[0003] All RAS proteins belong to a family of small GTPase proteins that hydrolyze GTP to GDP. KRAS is structurally divided into an effector-binding lobe, a subsequent allosteric lobe, and a carboxy-terminal region responsible for membrane fixation. The effector lobe includes the P-loop, switch I, and switch II regions. The switch I / II loop plays a crucial role in KRAS downstream 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 from inactive to 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 Son of Sevenless Homolog 1 (SOS1), or GTPase-activating proteins (GAPs) involved in catalyzing the exchange of GDP to GTP, enhancing intrinsic GTPase activity, or promoting RAS-mediated GTP hydrolysis. In response to extracellular stimuli, inactive RAS-GDP is converted to the RAF-RAS binding domain (RAF RBD It is converted to active RAS-GTP, which directly binds to () and recruits the RAF kinase family from the cytoplasm to the membrane, where it dimerizes and becomes active. Subsequently, activated RAF carries out a series of phosphorylation reactions on its downstream mitogen-activated protein kinase (MEK) and extracellular signal-regulated kinase (ERK), propagating the proliferation signal. Of the RAF family of protein kinases (three known isoforms: ARAF, BRAF, and CRAF / RAF1), BRAF is the most frequently mutated and remains the most potent activator of MEK. Although individual RAS and RAF family members have revealed different binding preferences, all RAFs have a conserved RBD for forward transmission of MAPK signaling, which is frequently used to characterize KRAS inhibition (e.g., KRAS-BRAF as described herein). RBD In the case of KRAS, mutations at positions 12, 13, 61, and 146 lead to a shift to the active KRAS morphology by impairing nucleotide hydrolysis or activating nucleotide exchange, resulting in hyperactivation of the MAPK pathway leading to tumorigenesis.

[0005] Despite its well-recognized importance in cancer malignancy, past continuous efforts have not been able to develop an approved therapy for KRAS mutant cancers until recently, and the first-choice drug AMG510 was rapidly approved as a second-line therapy in KRAS G12C-driven non-small cell lung cancer (NSCLC). Nevertheless, clinically acquired resistance to KRAS G12C inhibitors strictly appears with disease progression after about 6 months of treatment. Secondary RAS mutants in cancer hotspots (e.g., G12 / G13 / Q61) and within the switch II pocket (e.g., H95, R68, and Y96) have been observed where all mutations converge to reactivate RAS-MAPK signaling. Furthermore, more than 85% of all KRAS mutant or wild-type amplified-driven cancers still lack new drugs. In summary, both numerous escape mechanisms and various cancer alleles highlight the urgent medical need for further KRAS therapies. Therefore, the inventors have invented an oral compound that targets and inhibits KRAS alleles for the treatment of KRAS mutant-driven cancers. [[ID=​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​C2-6 Alkynyl-substituted C 3-7 Cycloalkyl, (Jihar C 1-6 Alkyl)carbonyl, C 2-6 Alkenylcarbonyl, C 2-6 Alkynylcarbonyl, halogen and halo C 2-6 Piperidyls that are substituted once or twice with substituents independently selected from alkenylcarbonyls, or (Jihar C 1-6 Alkyl)carbonyl, C 2-6 Alkenylcarbonyl, C 2-6 Alkinylcarbonyl or Morpholino C 2-6 It is a pyrrolidinyl substituted with an alkynylcarbonyl; R 2 C 1-6 It is alkyl; R 3 H, Morpholino, (Halo C 1-6 Alkyl)piperazinyl or C 1-6 It is alkylpiperazinyl; R 4 C 1-6 Alkoxy C 1-6 It is alkyl; A 1 These are hydroxyphenylene or thiazoylene; A 2 C 1-6 It is alkylene; M is either O or CH2; L is C 1-6 Alkylene or Halo C 1-6 A compound that is alkylene; or relating to a pharmaceutically acceptable salt thereof.

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

[0008] Compounds of formula (I) or (Ia) exhibit good KRAS inhibition against G12C, G12D, G12V, or G13C. In one embodiment, the compounds of the present invention had better pharmacokinetic properties compared to the reference compound. In another embodiment, the compounds of the present invention showed excellent cancer cell inhibition and human stem cell stability. Furthermore, compounds of formula (I) or (Ia) also exhibit good or improved cytotoxicity and solubility profiles. [Brief explanation of the drawing]

[0009] [Figure 1] X-ray crystallography of intermediate A3. [Figure 2] X-ray crystallography of intermediate A4. [Modes for carrying out the invention]

[0010] Detailed description of the invention definition "C 1-6 The term "alkyl" refers to saturated linear or branched alkyl groups containing 1 to 6 carbon atoms, particularly 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, etc. 1-6 The alkyl groups are methyl, ethyl, and n-propyl.

[0011] "C 1-6 The term "alkylene" refers to a linear or branched saturated divalent hydrocarbon group consisting of 1 to 6 carbon atoms, or a bibranched saturated divalent hydrocarbon group consisting of 3 to 6 carbon atoms. 1-6 Examples of alkylene groups include methylene, ethylene, propylene, 2-methylpropylene, butylene, 2-ethylbutylene, pentylene, and hexylene.

[0012] "C 2-6The term "alkenyl" refers to a monovalent linear or branched hydrocarbon group consisting of 2 to 6 carbon atoms having at least one double bond. In certain embodiments, an alkenyl has 2 to 4 carbon atoms having at least one double bond. 2-6 Examples of alkenyls include ethenyl (or vinyl), propenyl, propa-2-enyl, isopropenyl, n-butenyl, and iso-butenyl.

[0013] "C 2-6 The term "alkynyl" refers to a monovalent linear or branched saturated hydrocarbon group consisting of 2 to 6 carbon atoms, containing one, two, or three triple bonds. In certain embodiments, an alkynyl has 2 to 4 carbon atoms, containing one or two triple bonds. 2-6 Examples of alkynyls include ethynyl, propynyl, propa-2-inyl, isopropynyl, and n-butynyl.

[0014] The terms "halogen" and "halo" are used interchangeably herein and mean fluoro, chloro, bromo, or iodine.

[0015] "HaroC 1-6 The term "alkyl" is C 1-6 C in which at least one hydrogen atom of the alkyl group is replaced by the same or a different halogen atom. 1-6 It means alkyl group. Halo C 1-6 Examples of alkyl groups include fluoromethyl, difluoromethyl, or chloro(fluoro)methyl, -ethyl, or -propyl, such as fluoromethyl, difluoropropyl, difluoromethyl, difluoroethyl, chloro(fluoro)methyl, trifluoroethyl, or trifluoromethyl.

[0016] "HaroC 1-6 The term "alkylene" is C 1-6 C 1-6 This refers to an alkylene group. 1-6Examples of alkylenes include fluoro, difluoro, or chloro(fluoro)methylene, -ethylene, or -propylene, such as fluoromethylene, difluoromethylene, fluoroethylene, difluoroethylene, fluoropropylene, difluoropropylene, or chloro(fluoro)methylene.

[0017] "Jihar C 1-6 The term "alkyl" is C 1-6 C in which two hydrogen atoms of the alkyl group are replaced by the same or different halogen atoms. 1-6 It means alkyl group. Dihalo C 1-6 Examples of alkyl groups include difluoro- or chloro(fluoro)-methyl, -ethyl, or -propyl, such as difluoropropyl, difluoromethyl, difluoroethyl, or chloro(fluoro)methyl.

[0018] "HaroC 2-6 The term "Alkenil" is C 2-6 C in which at least one hydrogen atom of the alkenyl group is replaced by the same or a different halogen atom. 2-6 This refers to the alkenyl group.

[0019] "HaroC 2-6 The term "alkinyl" is C 2-6 C in which at least one hydrogen atom of the alkynyl group is replaced by the same or a different halogen atom. 2-6 This refers to an alkynyl group.

[0020] "C 3-7The term "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 carbon atoms in common. Examples of monocyclic cycloalkyls are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. Examples of bicyclic cycloalkyls are bicyclo[1.1.0]butyl, bicyclo[2.2.1]heptanyl, bicyclo[1.1.1]pentanyl, or bicyclo[2.2.2]octanyl.

[0021] The term "thiazolylen" refers to a divalent thiazolyl group.

[0022] The term "dimethylmethylene" is, This means TIFF2026515652000004.tif17170.

[0023] The term "protecting group" refers to a group that selectively blocks a reaction site in a polyfunctional compound so that the chemical reaction can selectively proceed at another unprotected reaction site, in the sense conventionally related in synthetic chemistry. Protecting groups can be removed at appropriate points. Exemplary protecting groups are amino protecting groups, carboxy protecting groups, or hydroxy protecting groups.

[0024] The term "pharmaceutically acceptable salt" refers to a salt that is not biologically or otherwise undesirable. Pharmacopoecitable salts include both acid addition salts and base addition salts.

[0025] The term "pharmaceutically acceptable acid addition salt" means a pharmaceutically acceptable salt formed from an organic acid selected from an aliphatic, alicyclic, aromatic, aryl-containing aliphatic, heterocyclic, carboxylic acid, and sulfonic acid group, such as an inorganic acid including hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, and phosphoric acid, as well as an organic acid including 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, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid.

[0026] The term "pharmaceutically acceptable base addition salt" refers to a pharmaceutically acceptable salt formed with an organic or inorganic base. Examples of acceptable inorganic bases include sodium salts, potassium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, and aluminum salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines and substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydravamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperidine, piperidine, N-ethylpiperidine, and polyamine resins.

[0027] The term "pharmaceutically active metabolite" refers to pharmacologically active products produced through the metabolism of a particular compound or a salt thereof in the body. After entering the body, most drugs become substrates for chemical reactions that can alter their physical properties and biological effects. These metabolic transformations typically affect the polarity of the compound in the present invention and change how the drug is distributed within and excreted from the body. However, in some cases, the metabolism of a drug is necessary for its therapeutic effect.

[0028] The term "therapeutic dose" means the amount of the compound or molecule of the present invention, when administered to a subject, that (i) treat or prevent a particular disease, symptom, or disorder; (ii) reduce, alleviate, or eliminate one or more symptoms of a particular disease, symptom, or disorder; or (iii) prevent or delay the onset of one or more symptoms of a particular disease, symptom, or disorder as described herein. The therapeutic dose may vary depending on the compound, the state of the disease being treated, the severity of the disease being treated, the age and relative health status of the subject, the route and form of administration, the judgment of the attending physician or veterinarian, and other factors.

[0029] The term "pharmaceutical composition" means a mixture or solution containing a therapeutically effective amount of an active pharmaceutical ingredient together with pharmaceutically acceptable additives, which is administered to a mammal, for example, a human being in need.

[0030] The terms “pharmaceutically acceptable additive,” “pharmaceutically acceptable carrier,” and “therapeutically inactive additive” are interchangeable and refer to any pharmaceutically acceptable component in a pharmaceutical composition that is non-therapeutic and non-toxic to the target of administration, used in the formulation of pharmaceutical products, such as disintegrants, binders, fillers, solvents, buffers, isotonic agents, stabilizers, antioxidants, surfactants, carriers, diluents, or lubricants.

[0031] KRAS inhibitors The present invention relates to (i) a compound of formula (I), TIFF2026515652000005.tif69170 formula, R 1 teeth, TIFF2026515652000006.tif30170C 2-6 1-oxo-2,7-diazaspiro[4.4]nonanyl substituted with alkynylcarbonyl, or (Jihar C 1-6 Alkyl)carbonyl, C 2-6 Alkenylcarbonyl, C 2-6 Alkynylcarbonyl or Halo C 2-6 It is a 5-oxo-2,6-diazaspiro[3.4]octanyl substituted with an alkenylcarbonyl; Here, R 5 C 1-6 It is alkyl; R 6 , Haro C2-6 Alkynyl-substituted C 3-7 Cycloalkyl, (Jihar C 1-6 Alkyl)carbonyl, C 2-6 Alkenylcarbonyl, C 2-6 Alkynylcarbonyl, halogen and halo C 2-6 Piperidyls that are substituted once or twice with substituents independently selected from alkenylcarbonyls, or (Jihar C 1-6 Alkyl)carbonyl, C 2-6 Alkenylcarbonyl, C 2-6 Alkinylcarbonyl or Morpholino C 2-6 It is a pyrrolidinyl substituted with an alkynylcarbonyl; R 2 C 1-6 It is alkyl; R 3 H, Morpholino, (Halo C 1-6 Alkyl)piperazinyl or C 1-6 It is alkylpiperazinyl; R 4 C 1-6 Alkoxy C 1-6 It is alkyl; A 1is hydroxyphenylene or thiazolylene; A 2 is C 1-6 alkylene; M is O or CH2; L is C 1-6 alkylene or halo C 1-6 alkylene, a compound; or a pharmaceutically acceptable salt thereof.

[0032] Another embodiment of the present invention is a compound of (ii) formula (Ia), TIFF2026515652000007.tif69170wherein, R 1 is TIFF2026515652000008.tif30170C 2-6 1-oxo-2,7-diazaspiro[4.4]nonanyl substituted with alkynylcarbonyl, or (dihalo C 1-6 alkyl)carbonyl, C 2-6 alkenylcarbonyl, C 2-6 alkynylcarbonyl or halo C 2-6 alkenylcarbonyl substituted 5-oxo-2,6-diazaspiro[3.4]octanyl; where R 5 is C 1-6 alkyl; R 6 is halo C2-6 alkynyl substituted C 3-7 cycloalkyl, (dihalo C 1-6 alkyl)carbonyl, C 2-6 alkenylcarbonyl, C 2-6 alkynylcarbonyl, halogen and halo C 2-6 alkenylcarbonyl independently selected from the substituents substituted one or two times piperidyl, or (dihalo C 1-6 alkyl)carbonyl, C 2-6 alkenylcarbonyl, C 2-6 alkynylcarbonyl or morpholino C2-6 It is a pyrrolidinyl substituted with an alkynylcarbonyl; R 2 C 1-6 It is alkyl; R 3 H, Morpholino, (Halo C 1-6 Alkyl)piperazinyl or C 1-6 It is alkylpiperazinyl; R 4 C 1-6 Alkoxy C 1-6 It is alkyl; A 1 These are hydroxyphenylene or thiazoylene; A 2 C 1-6 It is alkylene; M is either O or CH2; L is C 1-6 Alkylene or Halo C 1-6 A compound that is alkylene; or a pharmaceutically acceptable salt thereof.

[0033] Further embodiments of the present invention include compounds of formula (I) or (Ia) according to (iii)(i) or (ii), or pharmaceutically acceptable salts thereof, TIFF2026515652000009.tif30170, R 5 is C 1-6 It is alkyl; R 6 (Jiharo C 1-6 Alkyl)carbonyl, C 2-6 Alkenylcarbonyl, halogen and halo C 2-6 A compound that is a piperidyl double-substituted with substituents independently selected from an alkenylcarbonyl, or a pharmaceutically acceptable salt thereof.

[0034] Further embodiments of the present invention include compounds of formula (I) or (Ia) described in any one of (iv)(i) to (iii), or pharmaceutically acceptable salts thereof, TIFF2026515652000010.tif30170, R5 is C 1-6 It is alkyl; R 6 is halogen and (dihalo C 1-6 Alkyl)carbonyl, C 2-6 Alkenylcarbonyl and Halo C 2-6 A compound that is piperidyl substituted with another substituent selected from alkenylcarbonyls, or a pharmaceutically acceptable salt thereof.

[0035] Further embodiments of the present invention are compounds of formula (I) or (Ia) as described in any one of (v)(i) to (iv), TIFF2026515652000011.tif30170, R 5 is methyl; R 6 These are compounds that are 4-fluoro-1-propa-2-enoyl-4-piperidyl, 4-fluoro-1-(2-fluoropropa-2-enoyl)-4-piperidyl, 4-fluoro-1-(2-chloro-2-fluoroacetyl)-4-piperidyl, or 4-fluoro-1-propa-2-enoyl-4-piperidyl.

[0036] Further embodiments of the present invention include (vi)R 2 However, it is an isopropyl compound of formula (I) or (Ia) described in any one of (i) to (v), or a pharmaceutically acceptable salt thereof.

[0037] Further embodiments of the present invention include (vii)R 3 is morpholino or C 1-6 The alkylpiperazinyl compound of formula (I) or (Ia) described in any one of (i) to (vi), or a pharmaceutically acceptable salt thereof.

[0038] Further embodiments of the present invention include (viii)R 3 The compound of formula (I) or (Ia) described in any one of (i) to (vii), wherein is morpholino or 4-methylpiperazin-1-yl, or a pharmaceutically acceptable salt thereof.

[0039] Further embodiments of the present invention are (ix)R 4 The compound of formula (I) or (Ia) described in any one of (i) to (xviii), wherein is 1-methoxyethyl, or a pharmaceutically acceptable salt thereof.

[0040] Further embodiments of the present invention include: TIFF2026515652000012.tif22170 A compound of formula (I) or (Ia) described in any one of (i) to (ix), in which bond "a" is bonded to a tricyclic ring, or a pharmaceutically acceptable salt thereof.

[0041] Further embodiments of the present invention include (xi)A 2 However, it is dimethylmethylene, a compound of formula (I) or (Ia) described in any one of (i) to (x), or a pharmaceutically acceptable salt thereof.

[0042] Further embodiments of the present invention are compounds of formula (I) or (Ia) described in any one of (i) to (xi), wherein (xii)M is O, or pharmaceutically acceptable salts thereof.

[0043] A further embodiment of the present invention is (xiii) L is C 1-6 It is an alkylene, a compound of formula (I) or (Ia) described in any one of (i) to (xii), or a pharmaceutically acceptable salt thereof.

[0044] Further embodiments of the present invention are compounds of formula (I) or (Ia) described in any one of (i) to (xiii), wherein (xiv)L is ethylene, or pharmaceutically acceptable salts thereof.

[0045] Further embodiments of the present invention are compounds of formula (I) or (Ia) as described in either (xv)(i) or (ii), TIFF2026515652000013.tif30170, R 5 is C 1-6 It is alkyl; R 6 is halogen and (dihalo C1-6 Alkyl)carbonyl, C 2-6 Alkenylcarbonyl and Halo C 2-6 It is a piperidyl substituted with another substituent selected from alkenylcarbonyl; R 2 C 1-6 It is alkyl; R 3 is morpholino or C 1-6 It is alkylpiperazinyl; R 4 C 1-6 Alkoxy C 1-6 It is alkyl; TIFF2026515652000014.tif22170 The bond "a" is bonded to a tricyclic ring; A 2 C 1-6 It is alkylene; M is O; L is C 1-6 A compound that is alkylene; or a pharmaceutically acceptable salt thereof.

[0046] Another embodiment of the present invention is a compound of formula (I) or (Ia) by (xvi)(xv), wherein, The file is TIFF2026515652000015.tif30170, and in the formula, R 5 is methyl; R 6 These are 4-fluoro-1-propa-2-enoyl-4-piperidyl, 4-fluoro-1-(2-fluoropropa-2-enoyl)-4-piperidyl, 4-fluoro-1-[(2R)-2-chloro-2-fluoroacetyl]-4-piperidyl, or 4-fluoro-1-propa-2-enoyl-4-piperidyl; R 2 It is isopropyl; R 3 It is morpholino or 4-methylpiperazine-1-yl; R 4 is (1S)-1-methoxyethyl; The file is TIFF2026515652000016.tif22170, and bond "a" is bonded to a tricyclic ring; A 2 It is dimethylmethylene; M is O; L is ethylene, a compound; or a pharmaceutically acceptable salt thereof.

[0047] Another embodiment of the present invention is a compound of formula (I) or (Ia) selected from (xvii) below.

[0048] (3S)-1-[(2R)-2-chloro-2-fluoroacetyl]-N-[(1S)-1-[[(20S,26S)-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-19,25-dioxo-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 Tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaen-26-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide; (3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(19S,25S)-29-hydroxy-(12M)-12-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-15,15-dimethyl-18,24-dioxo-7,17-dioxa-11,23,32-triazahexacyclo[25.3.1.1 2,6 .1 19,23 .0 4,13 .0 5,11 Tritriaconta-1(30),2,4,6(33),12,27(31),28-heptaen-25-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide; 1-[(2R)-2-chloro-2-fluoro-acetyl]-4-fluoro-N-[(1S)-1-[[(19S,25S)-29-hydroxy-(12M)-12-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-15,15-dimethyl-18,24-dioxo-7,17-dioxa-11,23,32-triazahexacyclo[25.3.1.1 2,6 .1 19,23 .0 4,13 .0 5,11 Tritriaconta-1(30),2,4,6(33),12,27(31),28-heptaen-25-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide; (3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(18S,24S)-28-hydroxy-(11M)-11-[(3R)-2-[(1S)-1-methoxyethyl]-2,3-dihydropyridine-3-yl]-14,14-dimethyl-17,23-dioxo-16-oxa-10,22,31-triazahexacyclo[24.3.1.1 2,6 .1 18,22 .0 4,12 .0 5,10 ]dotriaconta-1(29),2,4,6(32),11,26(30),27-heptaen-24-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide; (3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(18S,24S)-28-hydroxy-(11M)-11-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-14,14-dimethyl-17,23-dioxo-7,16-dioxa-10,22,31-triazahexacyclo[24.3.1.1 2,6 .1 18,22 .0 4,12 .0 5,10 Dotriaconta-1(29),2,4,6(32),11,26(30),27-heptaen-24-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide; (3S)-1-[(2R)-2-chloro-2-fluoroacetyl]-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide; (2S)-2-[2-[(2R)-2-chloro-2-fluoroacetyl]-5-oxo-2,6-diazaspiro[3.4]octan-6-yl]-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazine-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]-3-methylbutanamide; (2S)-2-(2-buta-2-inoyl-5-oxo-2,6-diazaspiro[3.4]octan-6-yl)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]-3-methylbutanamide; (2S)-2-[2-[(2R)-2-chloro-2-fluoroacetyl]-5-oxo-2,6-diazaspiro[3.4]octan-6-yl]-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]-3-methylbutanamide; (2S)-2-(2-buta-2-inoyl-5-oxo-2,6-diazaspiro[3.4]octan-6-yl)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]-3-methylbutanamide; (2S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]-3-methyl-2-(5-oxo-2-propa-2-enoyl-2,6-diazaspiro[3,4]octan-6-yl)butanamide; (3S)-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-1-(4-morpholinbuta-2-inoyl)pyrrolidine-3-carboxamide; (2S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]-3-methyl-2-(5-oxo-2-propa-2-enoyl-2,6-diazaspiro[3,4]octan-6-yl)butanamide; (2S)-2-(2-buta-2-inoyl-5-oxo-2,6-diazaspiro[3.4]octan-6-yl)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazine-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]-3-methylbutanamide; 4-Fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-1-propa-2-enoylpiperidine-4-carboxamide; 1-Buta-2-inoyl-4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide; cis-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-3-(3,3,3-trifluoropropane-1-inyl)cyclobutanecarboxamide; 1-[(2R)-2-chloro-2-fluoro-acetyl]-4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide; (2S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]-3-methyl-2-(5-oxo-2-propa-2-enoyl-2,6-diazaspiro[3,4]octan-6-yl)butanamide; (2S)-2-[2-[(2R)-2-chloro-2-fluoroacetyl]-5-oxo-2,6-diazaspiro[3.4]octan-6-yl]-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazine-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]-3-methylbutanamide; cis-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-3-(3,3,3-trifluoropropane-1-inyl)cyclobutanecarboxamide; (2S)-2-[2-(2-fluoropropanenoyl)-5-oxo-2,6-diazaspiro[3.4]octan-6-yl]-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]-3-methylbutanamide; cis-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-3-(3,3,3-trifluoropropane-1-inyl)cyclobutanecarboxamide; 4-Fluoro-1-(2-fluoropropa-2-enoyl)-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide; 1-Buta-2-inoyl-4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide; 4-Fluoro-1-(2-fluoropropanenoyl)-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide; 1-[(2R)-2-chloro-2-fluoroacetyl]-4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazine-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide; 1-[(2R)-2-chloro-2-fluoroacetyl]-4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide; 4-Fluoro-1-(2-fluoropropa-2-enoyl)-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide; 1-Buta-2-inoyl-4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide; 1-[(2R)-2-chloro-2-fluoroacetyl]-4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide; 4-Fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-1-propa-2-enoylpiperidine-4-carboxamide; 1-Buta-2-inoyl-4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide; (3R)-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-1-propa-2-enoyl-pyrrolidine-3-carboxamide; (3R)-1-buta-2-inoyl-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide; 4-Fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-1-propa-2-enoylpiperidine-4-carboxamide; (2S)-2-[(5R)-7-buta-2-inoyl-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazine-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]-3-methylbutanamide; 4-Fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-1-propa-2-enoylpiperidine-4-carboxamide; N-[(1S)-1-[[(7S,13S)-23,23-difluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]carbamoyl]-2-methyl-propyl]-4-fluoro-N-methyl-1-propa-2-enoylpiperidine-4-carboxamide; N-[(1S)-1-[[(7S,13S)-23,23-difluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]carbamoyl]-2-methyl-propyl]-4-fluoro-1-(2-fluoropropane-2-enoyl)-N-methyl-piperidine-4-carboxamide; 1-[(2R)-2-chloro-2-fluoroacetyl]-N-[(1S)-1-[[(7S,13S)-23,23-difluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 Hentriaconta-1(29),2,5(31),19,25,27-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-4-fluoro-N-methyl-piperidine-4-carboxamide; N-[(1S)-1-[[(7S,13S)-23,23-difluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]carbamoyl]-2-methyl-propyl]-4-fluoro-N-methyl-1-propa-2-enoylpiperidine-4-carboxamide; 1-Buta-2-inoyl-N-[(1S)-1-[[(7S,13S)-23,23-difluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]carbamoyl]-2-methyl-propyl]-4-fluoro-N-methyl-piperidine-4-carboxamide; 4-Fluoro-1-(2-fluoropropanenoyl)-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide; 4-Fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17,23,23-tetramethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-1-propa-2-enoylpiperidine-4-carboxamide; 4-Fluoro-N-[(1S)-1-[[(7S,13S,22S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17,22-trimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-1-propa-2-enoylpiperidine-4-carboxamide; and 4-Fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17,23,23-tetramethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(29),2,5(31),19,25,27-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-1-propa-2-enoylpiperidine-4-carboxamide; or a pharmaceutically acceptable salt thereof.

[0049] Another embodiment of the present invention relates to a method for preparing any one of the compounds described in (xviii)(i) to (xvii), the following steps: a) Compound of formula (II), TIFF2026515652000017.tif56170 and Acid(III), A step of coupling TIFF2026515652000018.tif28170 in the presence of a coupling reagent and a base to form a compound of formula (I); b) Compound of formula (VI), TIFF2026515652000019.tif57170 and Acid (VII), TIFF2026515652000020.tif20170 The coupling reaction is carried out in the presence of a coupling reagent and a base to form the compound of formula (VIII), The process of forming TIFF2026515652000021.tif57170; c) Compound of formula (XI), TIFF2026515652000022.tif56170 and Acid (XII), TIFF2026515652000023.tif20170 The coupling reaction is carried out in the presence of a coupling reagent and a base to form the compound of formula (XIII). The process of forming TIFF2026515652000024.tif56170 includes, In the formula, Q is an unsubstituted or substituted piperidinylene or pyrrolidinylene; T is a dihalo C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinil, Halo C 2-6 Alkenyl or Morpholino C 2-6 It is alkinyl; R 1 ~R 6 , A 1 , A 2M and L are defined as in any one of claims 1 to 16; the coupling reagent in steps a) to c) is T3P, HATU, PyBOP, or EDCI / HOBt; and the base in steps a) to c) is TEA, DIEPA, or DMAP.

[0050] Another embodiment of the present invention is (xix) a compound or pharmaceutically acceptable salt described in any one of (i) to (xvii) for use as a therapeutic active substance.

[0051] Another embodiment of the present invention is a pharmaceutical composition comprising a compound described in any one of (xx)(i) to (xvii) and a pharmaceutically acceptable additive.

[0052] Another embodiment of the present invention is the use of any one of the compounds described in (i) to (xvii) for the treatment of (xxi)KRAS G12C protein-related disorders.

[0053] Another embodiment of the present invention is the use of any one of the compounds described in (i) to (xvii) for the treatment of (xxii)KRAS G12C, G12D, and G12V protein-related disorders.

[0054] Another embodiment of the present invention is the use of any one of the compounds described in (i) to (xvii) for inhibiting RAS interaction with a downstream effector, wherein the downstream effector is RAF and PI3K.

[0055] Another embodiment of the present invention is the use of any one of the compounds described in (i) to (xvii) to inhibit the propagation of cancerous MAPK and PI3K signaling.

[0056] Another embodiment of the present invention is the use of any one of the compounds described in (i) to (xvii) 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.

[0057] Another embodiment of the present invention is the use of any one of the compounds described in (i) to (xvii) 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.

[0058] Another embodiment of the present invention is a compound or pharmaceutically acceptable salt of any one of (i) to (xvii) for the treatment or prevention of KRAS mutation-driven cancer, selected from pancreatic adenocarcinoma, colorectal cancer, and non-small cell lung cancer.

[0059] Another embodiment of the present invention is the use of any one of the compounds described in (i) to (xvii) for the preparation of a pharmacopoeia 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.

[0060] Another embodiment of the present invention is a method for treating or prophylactic KRAS mutation-driven cancer, wherein (xxix) cancer is selected from pancreatic adenocarcinoma, colorectal cancer and non-small cell lung cancer, and the method comprises administering a therapeutically effective dose of any one of (i) to (xvii).

[0061] Another embodiment of the present invention is a compound or pharmaceutically acceptable salt described in any one of (i) to (xvii) as prepared according to the method of (xxx)(xviii).

[0062] Pharmaceutical composition and administration Another embodiment provides a pharmaceutical composition or pharmaceutically acceptable

[0063] The composition is formulated, administered, and given in a manner consistent with good medical practice. Factors to consider in this regard include the specific disorder being treated, the specific mammal being treated, the individual patient's clinical symptoms, the cause of the disorder, the site of drug delivery, the method of administration, the administration schedule, and other factors known to the healthcare professional. The “effective dose” of the compound to be administered is governed by such considerations and is the minimum amount required to inhibit the interaction between a variant RAS (e.g., KRAS G12C) and RAF and block cancerous MAPK signaling. For example, such a dose may be below the amount that is toxic to normal cells or the entire mammal.

[0064] In one example, the pharmaceutically effective dose of the compound of the present invention administered parenterally per dose is in the range of about 0.1 to 1000 mg / kg, or about 0.1 to 1000 mg / kg patient body weight / day, and the typical initial range of the compound used is 0.3 to 15 mg / kg / day. In another embodiment, the oral unit dosage form, such as tablets and capsules, preferably contains about 1 to about 1000 mg of the compound of the present invention.

[0065] The compounds of the present invention may be administered by any suitable means, including orally, topically (including buccal and sublingual), rectally, vaginally, percutaneously, parenterally, subcutaneously, intraperitoneally, intrapulmonaryly, intradermally, intrathecally, and epidurally, as well as intranasally, and, if desired for topical treatment, intrafocal administration. Parenteral administration includes intramuscular, intravenous, intra-arterial, intraperitoneal, or subcutaneous administration.

[0066] The compounds of the present invention can be administered in any convenient dosage form, such as tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, and patches. Such compositions may contain common components in pharmaceutical preparations, such as diluents, carriers, pH adjusters, sweeteners, fillers, and further active agents.

[0067] Typical formulations are prepared by mixing the compound of the present invention with a carrier or additive. Suitable carriers and additives are well known to those skilled in the art and are described in detail, for example, 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, smoothing agents, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, flow enhancers, processing aids, colorants, sweeteners, flavorings, diluents, and other known additives for providing a drug (i.e., the compound of the present invention or its pharmaceutical composition) in an appealing manner or for assisting in the manufacture of a pharmaceutical product (i.e., a pharmaceutical).

[0068] A suitable example of an oral dosage form is a tablet containing about 1 to 1000 mg of the compound of the present invention, comprising 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 components are first mixed together, and then mixed with a solution of PVP. The resulting composition can be dried, granulated, mixed with magnesium stearate, and compressed into tablet form using conventional equipment. An example of an aerosol formulation can be prepared, for example, by dissolving 5 to 400 mg of the compound of the present invention in a suitable buffer solution, such as phosphate buffer, and optionally adding an isotonic agent (e.g., a salt such as sodium chloride). The solution may be filtered, for example, using a 0.2 micron filter, to remove impurities and contaminants.

[0069] Accordingly, one embodiment includes a pharmaceutical composition comprising a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. Further embodiments include a pharmaceutical composition comprising a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or additive.

[0070] Another embodiment includes a pharmaceutical composition comprising a compound of formula (I) for use in the treatment of mutant KRAS-driven cancer.

[0071] The following compositions A and B represent typical compositions of the present invention, but serve only as representative examples.

[0072] Composition A The compounds of the present invention can be used in a manner known to the extent of their own as active ingredients to produce tablets having the following compositions.

[0073] per tablet Active ingredient 200mg Microcrystalline cellulose 155mg Corn starch 25mg Talc 25mg Hydroxypropyl methylcellulose 20 mg 425mg

[0074] Composition B The compounds of the present invention can be used in a manner known to the present invention as active ingredients to produce capsules having the following compositions.

[0075] per capsule Active ingredient: 100.0 mg Corn starch 20.0 mg Lactose 95.0 mg Talc 4.5mg Magnesium stearate 0.5 mg 220.0 mg

[0076] Indications and treatment methods The compounds of the present invention induce a novel binding pocket in KRAS by driving the formation of a high-affinity triplicate between the KRAS protein and widely expressed cyclophyllin A (CYPA), thereby inhibiting KRAS interactions with downstream effectors such as RAF and PI3K. Therefore, the compounds of the present invention are useful in inhibiting propagating oncogenic MAPK and PI3K signaling and reducing cell proliferation, particularly in cancer cells. The compounds of the present invention are useful for terminating RAS signaling in cells expressing RAS mutants, such as KRAS mutation-driven pancreatic cancer, colorectal cancer, lung cancer, esophageal cancer, gallbladder cancer, melanoma, ovarian cancer, and endometrial cancer. Alternatively, the compounds of the present invention are useful for terminating RAS signaling in malignant solid tumors where the role of the KRAS mutation in oncogenes is enhanced by dysregulation or mutations in effector pathways as MAPK, PI3K-AKT-mTOR (mammalian target of rapamycin) driven signaling, for targeted therapy in pancreatic adenocarcinoma, colorectal cancer, non-small cell lung cancer, etc.

[0077] Another embodiment includes a method for treating or preventing cancer in a mammal requiring such treatment, the method comprising administering to the mammal a therapeutically effective amount of a compound of formula (I), a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

[0078] synthesis The compounds of the present invention can be prepared by any conventional means. Preferred methods for synthesizing these compounds and their starting materials are provided in the following scheme and examples. All substituents, in particular, R 1 ~R 6 , M and L and A 1 and A 2 Unless otherwise specified, the above provisions apply. Furthermore, unless otherwise specified, all reactions, reaction conditions, abbreviations, and symbols have meanings familiar to those skilled in the art of organic chemistry.

[0079] The following are general synthetic routes for preparing the compounds of formulas (I) and (Ia).

[0080] Scheme 1 TIFF2026515652000025.tif57170

[0081] The compound of formula II was synthesized according to the procedure described in intermediates A to R. The compound of formula (I) can be obtained by a coupling reaction of acid (III) and the compound of formula (II) with a coupling reagent such as T3P, HATU, PyBOP, and EDCI / HOBt in the presence of a base such as TEA, DIEPA, and DMAP.

[0082] Scheme 2 In formula TIFF2026515652000026.tif127170, PG is a protecting group, such as Boc and Cbz.

[0083] The compound of formula (V) can be obtained by a coupling reaction between acid (IV) and the compound of formula (II) using a coupling reagent(s) such as T3P, HATU, PyBOP, or EDCI / HOBt, in the presence of a base such as TEA, DIEPA, and DMAP. By deprotecting the compound of formula (V), the compound of formula (VI) can be obtained in the presence of an acid such as TFA, or under hydrogenation conditions using a catalyst such as Pd / C and Pd(OH)2 / C. The compound of formula (VIII) can be obtained by a coupling reaction between acid (VII) and acid (VI) using a coupling reagent(s) such as T3P, HATU, PyBOP, and EDCI / HOBt, in the presence of a base such as TEA, DIEPA, and DMAP.

[0084] Scheme 3 In formula TIFF2026515652000027.tif132170, PG is a protecting group, e.g., Boc and Cbz; T is a dihalo C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinil, Halo C 2-6 Alkenyl or Morpholino C 2-6 It is an alkynyl; Q is an unsubstituted or substituted piperidinylene or pyrrolidinylene.

[0085] Compounds of formula (X) can be obtained by a coupling reaction using acid (IX), compound (VI), and coupling reagents (multiple) such as T3P, HATU, PyBOP, or EDCI / HOBt, in the presence of a base such as TEA, DIEPA, or DMAP. Compounds of formula (XI) can be obtained by deprotection of compound (X) in the presence of an acid such as TFA, or under hydrogenation conditions using catalysts such as Pd / C and Pd(OH)2 / C. Compounds of formula (XIII) can be obtained by a coupling reaction between acid (XII) and compound (XI) using coupling reagents (multiple) such as T3P, HATU, PyBOP, and EDCI / HOBt, in the presence of a base such as TEA, DIEPA, or DMAP.

[0086] The compounds of the present invention can be obtained as a mixture of diastereomers or enantiomers, which can be separated by methods well known in the art, such as (chiral) HPLC or SFC. In another embodiment, the compound of formula (I) can be obtained according to the scheme described above by using the corresponding chiral starting material.

[0087] The present invention also relates to a method for preparing a compound of formula (I), comprising the following steps: a) Compound of formula (II), TIFF2026515652000028.tif56170 and Acid(III), A step of coupling TIFF2026515652000029.tif28170 in the presence of a coupling reagent and a base to form a compound of formula (I); b) Compound of formula (VI), TIFF2026515652000030.tif57170 and Acid (VII), TIFF2026515652000031.tif20170 The coupling reaction is carried out in the presence of a coupling reagent and a base to obtain the compound of formula (VIII), The process of forming TIFF2026515652000032.tif57170; c) Compound of formula (XI), TIFF2026515652000033.tif56170 and Acid (XII), TIFF2026515652000034.tif20170 The coupling reaction is carried out in the presence of a coupling reagent and a base to obtain the compound of formula (XIII). The process of forming TIFF2026515652000035.tif56170 includes, During the ceremony, In steps a), b), and c), the coupling reagent may be, for example, T3P, HATU, PyBOP, or EDCI / HOBt; the base may be, for example, TEA, DIEPA, or DMAP.

[0088] Compounds of formula (I) or (Ia) produced according to the method described above are also objects of the present invention. [Examples]

[0089] The present invention will be better understood by referring to the following embodiments. However, these embodiments should not be construed as limiting the scope of the invention.

[0090] Abbreviation The present invention will be better understood by referring to the following embodiments. However, these embodiments should not be construed as limiting the scope of the invention.

[0091] The abbreviations used in this specification are as follows: ACN Acetonitrile aq.Aqueous solution Boc-N-Me-Val-OH N-(tert-butoxycarbonyl)-N-methyl-L-valine (Boc)2O di-tert-butyl dicarbonate (R)-binap (R)-(+)-2,2'-bis(diphenylphosphin)-1,1'-binaphthyl CDCl3: Deuterated chloroform CD3OD: Deuterated methanol CuI Copper(I) iodide DIEPA: N,N-diethylpropylamine DMAP: 4-dimethylaminopyridine DMF: Dimethylformamide DMSO: Dimethyl sulfoxide EDCI: N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride methoxy or EA: ethyl acetate FRET fluorescence resonance energy transfer HATU: (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-]b]pyridinium 3-oxide hexafluorophosphate) hr(s): time HPLC: High-Performance Liquid Chromatography HOBt: N-hydroxybenzotriazole [Ir(OMe)(COD)]2(1,5-cyclooctadiene)(methoxy)iridium(I) dimer LDA Lithium Diisopropylamide MS (ESI): Mass Spectrometry (Electron Spray Ionization) min(s) minutes MTBE methyl tert-butyl ether MTDA (Dimethylketene Methyltrimethylsilyl Acetal) NMM (N-methylmorpholine) NaBH(OAc)3 Sodium borotriacetoxyhydride NBS N-bromosuccinimide NIS N-iodosuccinimide NMR: nuclear magnetic resonance NMO 4-methylmorpholine N-oxide obsd. Measured value Pd(dppf)Cl2[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(dtbpf)Cl2[1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) Prep-HPLC: Preparative High-Performance Liquid Chromatography PyBOP: Benzotriazole-1-yloxytripyrrolidinophosphonium hexafluorophosphate RT or rt: Room temperature sat. saturation Selectfluor 1-Chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanbis(tetrafluoroborate) SFC Supercritical Fluid Chromatography TBAF Tetrabutylammonium Fluoride TEA: Triethylamine TFA: Trifluoroacetic acid THF: Tetrahydrofuran TMEDA Tetramethylethylenediamine TMSCF3 Trifluoromethyltrimethylsilane T3P: Propylphosphonic anhydride

[0092] General experimental conditions The intermediate and final compounds were purified by flash chromatography using one of the following instruments: i) Biotage SP1 system and Quad 12 / 25 cartridge module, ii) ISCO combi-flash chromatography instrument. Silica gel brands and pore sizes: i) KP-SIL 60Å, particle size: 40-60 μm; ii) CAS registry number: silica gel: 63231-67-4, particle size: 47-60 microns; iii) ZCX from Qingdao Haiyang Chemical Co., Ltd, pore size: 200-300 or 300-400.

[0093] The intermediates and final compounds were purified by preparative HPLC using XBridge® Prep-C18 (5 μm, OBD® 30 × 100 mm) columns, SunFire® Prep-C18 (5 μm, OBD® 30 × 100 mm) columns, or reverse-phase columns using Phenomenex Synergi-C18 (10 μm, 25 × 150 mm) or Phenomenex Gemini-C18 (10 μm, 25 × 150 mm). The samples were purified by preparative HPLC on a reversed-phase column using either a Waters AutoP purification system (Sample Manager 2767, Pump 2525, Detectors: Micromass ZQ and UV2487, Solvents: Acetonitrile and 0.1% ammonium hydroxide aqueous solution; Acetonitrile and 0.1% FA aqueous solution or Acetonitrile and 0.1% TFA aqueous solution) or a Gilson-281 purification system (Pump 322, Detector: UV156, Solvents: Acetonitrile and 0.05% ammonium hydroxide aqueous solution; Acetonitrile and 0.225% FA aqueous solution; Acetonitrile and 0.05% HCl aqueous solution; Acetonitrile and 0.075% TFA aqueous solution; or Acetonitrile and water).

[0094] For SFC chiral separation, intermediates were separated using chiral columns (Daicel chiralpak IC, 5 μm, 30 × 250 mm), AS (10 μm, 30 × 250 mm), or AD (10 μm, 30 × 250 mm) with a Mettler Toledo Multigram III system SFC, Waters 80Q preparative SFC, or Thar 80 preparative SFC, solvent system: CO2 and IPA (0.5% TEA in IPA) or CO2 and MeOH (0.1% NH3·H2O in MeOH), back pressure of 100 bar, and detection UV at 254 or 220 nm.

[0095] The LC / MS spectra of the compounds were obtained using LC / MS (Waters® Alliance 2795-Micromass ZQ, Shimadzu Alliance 2020-Micromass ZQ, or Agilent Alliance 6110-Micromass ZQ), with the following LC / MS conditions (trial time 3 minutes or 1.5 minutes). Acidic conditions I: A: 0.1% TFA in H2O; B: 0.1% TFA in acetonitrile; Acidic conditions II: A: 0.0375% TFA in H2O; B: 0.01875% TFA in acetonitrile; Basic conditions I: A: 0.1% NH3·H2O in H2O; B: Acetonitrile; Basic conditions II: A: 0.025% NH3·H2O in H2O; B: Acetonitrile; Neutral conditions: A: H2O; B: Acetonitrile. Mass spectra (MS): Generally, only ions showing the primary mass are reported, and unless otherwise stated, the cited mass ions are positive mass ions (MH). + That is the case.

[0096] NMR spectra were acquired using a Bruker Avance 400MHz or 500MHz.

[0097] Microwave-assisted reactions were carried out using a Biotage Initiator Sixty microwave synthesizer. All reactions involving air-sensitive reagents were performed under an argon or nitrogen atmosphere. Unless otherwise specified, reagents were used as received from commercial suppliers without further purification.

[0098] Preparation Examples The following examples are intended to illustrate the meaning of the present invention, but are not intended to represent the meaning of the present invention. This does not represent a limitation within a specific range.

[0099] Preparation of intermediates Intermediate A1 (2S)-2-(2-tert-butoxycarbonyl-5-oxo-2,6-diazaspiro[3,4]octan-6-yl)-3-methylbutanoic acid TIFF2026515652000036.tif29170

[0100] The compound was prepared according to the following scheme: JPEG2026515652000037.jpg112170

[0101] Step 1: Preparation of tert-butyl 3-allyl-3-cyano-azetidine-1-carboxylate (compound A1-b) To a solution of tert-butyl 3-cyanoazetidine-1-carboxylate (compound A1-a, 10.0 g, 54.88 mmol) in THF (100 mL), LDA (60.3 mL, 60.37 mmol) was added dropwise at -70°C under a nitrogen atmosphere. After stirring at -70°C for 0.5 hours, allyl bromide (7.9 g, 65.85 mmol) was added to the reaction mixture. The mixture was stirred further at 16°C for 1 hour, then concentrated under vacuum, and the residue was purified by column chromatography (HCl in PE: 3%-10%) to obtain tert-butyl 3-allyl-3-cyanoazetidine-1-carboxylate (compound A1-b, 12.5 g) as a pale yellow oil. 1H NMR (400 MHz, chloroform-d)δ 5.90-5.70(m,1 H),5.32(s,1 H),5.28(d,J=5.2 Hz,1 H),4.23(d,J=8.8 Hz,2 H),3.86(d,J=8.8 Hz,2 H),2.63(d,J=7.2 Hz,2 H),1.45(s,9 H)ppm.

[0102] Step 2: 3-Allyl-1-tert-butoxycarbonylazetidine-3-carboxylic acid (compound A1-c) A mixture of tert-butyl-3-allyl-3-cyano-azetidine-1-carboxylate (compound A1-b, 12.5 g, 56.24 mmol) and potassium hydroxide (12.6 g, 224.94 mmol) in ethanol (60 mL) and water (60 mL) was stirred at 100°C for 16 hours. After the reaction was complete, the pH of the reaction mixture was acidified to pH=3 with HCl (1 M) aqueous solution. The reaction mixture was extracted with ELISA (120 mL, 3 times). The combined organic layer was washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain 3-allyl-1-tert-butoxycarbonyl-azetidine-3-carboxylic acid (compound A1-c, 14.0 g) as a white solid. MS calculation value 242.1 (MH) + ), measured value 186.2 (M-C4H8+H + ).

[0103] Step 3: O1-tert-butyl O3-methyl3-allylazetidine-1,3-dicarboxylate (compound A1-d) To a mixture of 3-allyl-1-tert-butoxycarbonylazetidine-3-carboxylic acid (compound A1-c, 8.0 g, 33.16 mmol) in DMF (80 mL), potassium carbonate (13.7 g, 99.47 mmol) was added, followed by iodomethane (9.4 g, 66.31 mmol). After stirring at 20°C for 2 hours, the reaction mixture was poured into water (400 mL), and the resulting mixture was extracted with ELISA (100 mL, 3 times). The combined organic layer was washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain O1-tert-butylO3-methyl3-allylazetidine-1,3-dicarboxylate (compound A1-d, 7.3 g) as a yellow oil. 1 ¹H NMR (400 MHz, chloroform-d): δ = 5.80–5.60 (m, 1 H), 5.19–5.14 (m, 1 H), 5.12 (s, 1 H), 4.16 (d, J=8.8 Hz, 2 H), 3.82–3.69 (m, 5 H), 2.63 (d, J=7.2 Hz, 2 H), 1.44 (s, 9 H) ppm.

[0104] Step 4: O1-tert-butyl O3-methyl 3-(2-oxoethyl)azetidine-1,3-dicarboxylate (compound A1-e) To a mixture of O1-tert-butylO3-methyl3-allylazetidine-1,3-dicarboxylate (compound A1-d, 2g, 7.83 mmol) in 1,4-dioxane (20 mL) and water (20 mL), 2,6-lutidine (1.8 mL, 15.67 mmol) and K2OsO4 (144.3 mg, 0.39 mmol) were added. After stirring at 16°C for 15 minutes, sodium metaperiodate (6.7 g, 31.33 mmol) was added to the reaction mixture, and the mixture was stirred for a further 1 hour. Then, it was poured into water (120 mL), and the resulting mixture was extracted with phenylethylamine (40 mL, 3 times). The combined organic layers were washed with saturated Na2SO3 (60 mL) and brine (60 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain O1-tert-butylO3-methyl3-(2-oxoethyl)azetidine-1,3-dicarboxylate (compound A1-e, 2.8 g) as a yellow oil. MS calculation value: 258.1 (MH)+ ), measured value 202.1 (M-C4H8+H + ).

[0105] Step 5: O1-tert-butyl O3-methyl 3-[2-[[(1S)-1-benzyloxycarbonyl-2-methyl-propyl]amino]ethyl]azetidine-1,3-dicarboxylate (compound A1-f) Zinc chloride (1.8 g, 13.06 mmol) was added to a mixture of L-valine benzyl hydrochloride (3.2 g, 13.06 mmol) and O1-tert-butyl O3-methyl 3-(2-oxoethyl)azetidine-1,3-dicarboxylate (compound A1-e, 2.8 g, 10.88 mmol) in methanol (50 mL). After stirring at 16 °C for 0.5 hours, sodium cyanoborohydride (1.4 g, 21.77 mmol) was added to the reaction mixture, and the resulting mixture was stirred for a further 1 hour. The reaction mixture was concentrated under vacuum, and the residue was purified by column chromatography (SiO2 in PE: 30%-50%) to obtain O1-tert-butylO3-methyl3-[2-[[(1S)-1-benzyloxycarbonyl-2-methyl-propyl]amino]ethyl]azetidine-1,3-dicarboxylate (compound A1-f, 2.2g) as a colorless oil. MS calculation value: 449.3 (MH) + ), measured value 449.3 (MH) + ).

[0106] Step 6: tert-butyl 6-[(1S)-1-benzyloxycarbonyl-2-methyl-propyl]-5-oxo-2,6-diazaspiro[3.4]octane-2-carboxylate (compound A1-g) A mixture of 4-dimethylaminopyridine (544.7 mg, 4.46 mmol), DIEA (7.7 mL, 44.59 mmol), and O1-tert-butylO3-methyl3-[2-[[(1S)-1-benzyloxycarbonyl-2-methyl-propyl]amino]ethyl]azetidine-1,3-dicarboxylate (compound A1-f, 2.0 g, 4.46 mmol) in toluene (2 mL) was stirred at 100 °C for 20 hours. After the reaction was complete, the reaction mixture was concentrated under vacuum, and the residue was dissolved in ELISA (60 mL). The resulting solution was washed with aqueous HCl (1 M, 60 mL), then with brine (60 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under vacuum to obtain tert-butyl 6-[(1S)-1-benzyloxycarbonyl-2-methyl-propyl]-5-oxo-2,6-diazaspiro[3.4]octane-2-carboxylate (compound A1-g, 1.5g) as a white solid. MS calculation value: 417.2 (MH) + ), measured value 361.2 (M-C4H8+H + ).

[0107] Step 7: (2S)-2-(2-tert-butoxycarbonyl-5-oxo-2,6-diazaspiro[3,4]octan-6-yl)-3-methylbutanoic acid (intermediate A1) A mixture of tert-butyl 6-[(1S)-1-benzyloxycarbonyl-2-methyl-propyl]-5-oxo-2,6-diazaspiro[3.4]octane-2-carboxylate (compound A1-g, 1.5g, 3.6 mmol) and activated carbon-supported Pd (150.0 mg) in methanol (20 mL) was stirred under an H2 balloon at 16°C for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under vacuum to obtain (2S)-2-(2-tert-butoxycarbonyl-5-oxo-2,6-diazaspiro[3.4]octane-6-yl)-3-methyl-butanoic acid (intermediate A1, 920.0 mg) as a white solid. MS calculation value: 327.2 (MH) + ), measured value 271.2 (M-C4H8+H + ).

[0108] Intermediate A2 cis-(2S)-3-methyl-2-[methyl-[3-(3,3,3-trifluoropropane-1-inyl)cyclobutanecarbonyl]amino]butanoic acid TIFF2026515652000038.tif38170

[0109] The compound was prepared according to the following scheme: TIFF2026515652000039.tif176170

[0110] Step 1: Preparation of methyl 3-(methoxymethylene)cyclobutane carboxylate (compound A2-b) Potassium tert-butoxide (87.6 g, 780.46 mmol) was slowly added at 0°C to a solution of (methoxymethyl)triphenylphosphonium chloride (267.5 g, 780.46 mmol) in THF (1.6 L), and the mixture was heated to 20°C. Methyl 3-oxocyclobutane carboxylate (compound A2-a, 50.0 g, 390.23 mmol) was added to the reaction mixture after 1.5 hours. After stirring at 70°C for 3 hours, the reaction mixture was concentrated under vacuum to obtain the residue. A mixed solution of PE in ethyl phosphate (10:1, 1.1 L) was added to the residue. After stirring at 20°C for 0.5 hours, the suspension was filtered, and the filtrate was concentrated under vacuum to obtain the residue. The residue was purified by column chromatography to obtain methyl 3-(methoxymethylene)cyclobutane carboxylate (compound A2-b, 18.0 g) as a yellow oil. 1 ¹H NMR (400 MHz, chloroform-d): δ = 5.85–5.79 (m, 1 H), 3.70 (s, 3 H), 3.60 (s, 3 H), 3.29–3.09 (m, 1 H), 3.01–2.90 (m, 2 H), 2.89–2.71 (m, 2 H) ppm.

[0111] Step 2: Preparation of methyl 3-formylcyclobutane carboxylate (compound A2-c) To a solution of methyl 3-(methoxymethylene)cyclobutane carboxylate (compound A2-b, 26.0 g, 166.47 mmol) in DCM (300 mL) / water (30 mL), TFA (26.0 mL) was added. The reaction mixture was stirred at 20 °C for 3 hours. After the reaction was complete, H₂O (600 mL) was added to the reaction mixture, and then extracted with DCM (100 mL, 3 times). The organic layer was washed with brine (500 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum to obtain methyl 3-formylcyclobutane carboxylate (compound A2-c, 18.0 g, 126.63 mmol) as a yellow oil. 1 ¹H NMR (400 MHz, chloroform-d): δ = 9.84-9.52 (m, 1H), 3.75-3.63 (m, 3H), 3.32-3.20 (m, 1H), 3.18-3.07 (m, 1H), 2.67-2.38 (m, 4H) ppm.

[0112] Step 3: Preparation of methyl 3-ethynylcyclobutane carboxylate (compound A2-d) A methanol (120 mL) solution of methyl 3-formylcyclobutane carboxylate (compound A2-c, 10.0 g, 70.35 mmol) was cooled to 0°C, and dimethyl (1-diazo-2-oxopropyl)phosphonate (21.0 g, 109.31 mmol) and potassium carbonate (20.0 g, 144.71 mmol) were added to the reaction mixture. After stirring at 20°C for 3 hours, H2O (150 mL) was added to the reaction mixture, and then it was extracted with PE (60 mL, twice). The combined organic layer was washed with brine (80 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain the residue. The residue was purified by column chromatography (SiO in PE: 0%~25%) to obtain methyl 3-ethynylcyclobutane carboxylate (compound A2-d, 6.0 g) as a colorless oil. 1 ¹H NMR (400 MHz, chloroform-d): δ = 3.75-3.62 (m,3H), 3.42-3.21 (m,1H), 3.07-2.89 (m,1H), 2.65-2.33 (m,4H), 2.23-2.17 (m,1H) ppm.

[0113] Step 4: Preparation of 3-ethynylcyclobutanecarboxylic acid (compound A2-e) A solution of methyl 3-ethynylcyclobutane carboxylate (compound A2-d, 6.0 g, 43.43 mmol) in THF (10 mL) and water (30 mL) was mixed with lithium hydroxide (3.6 g, 86.86 mmol) at 0°C, and the solution was stirred at 20°C for 3 hours. After the reaction was complete, the reaction mixture was concentrated under vacuum to remove the THF, then H2O (60 mL) was added and the mixture was extracted with MTBE (30 mL). The MTBE phase was discarded, and the pH of the aqueous phase was acidified to pH=5 with aqueous HCl (1 N, 60 mL), and extracted with ELISA (60 mL, 3 times). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain 3-ethynylcyclobutanecarboxylic acid (compound A2-e, 3.8 g) as a colorless oil. 1 ¹H NMR (400 MHz, chloroform-d): δ = 12.14–9.87 (m, 1 H), 3.36–3.15 (m, 1 H), 3.10–2.95 (m, 1 H), 2.68–2.53 (m, 2 H), 2.51–2.35 (m, 2 H), 2.22 (dd, J=15.2, 2.4 Hz, 1 H) ppm.

[0114] Step 5: Preparation of cis-tert-butyl(2S)-2-[(3-ethynylcyclobutanecarbonyl)-methyl-amino]-3-methyl-butanoate (compound A2-f) To a solution of 3-ethynylcyclobutanecarboxylic acid (compound A2-e, 3.8 g, 30.61 mmol) in DMF (50 mL), DIEA (19.0 mL, 114.96 mmol) and HATU (14.3 g, 37.48 mmol) were added. After stirring at 0°C for 10 minutes, tert-butyl(2S)-3-methyl-2-(methylamino)butanoate (5.7 g, 30.44 mmol) was added to the reaction mixture. The reaction mixture was stirred at 0°C for a further 1 hour. After the reaction was complete, H2O (120 mL) was added to the reaction mixture, and then extracted with ELISA (40 mL, 3 times). The combined organic layers were washed with brine (60 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain the residue. The residue was purified by column chromatography (SiO in PE: 9%-16%) and preparative HPLC (column: Welch Ultimate XB-CN 250×50×10 μm; mobile phase: hexane-EtOH (0.1% FA); B%: 1%-20%, 15 min) to obtain cis-tert-butyl(2S)-2-[(3-ethynylcyclobutanecarbonyl)-methyl-amino]-3-methyl-butanoate (compound A2-f, faster elution, 3 g) as a yellow oily substance. MS calculation value: 294.2 (MH) + ), measured value 294.1 (MH) + ). 1 ¹H NMR (400 MHz, chloroform-d): δ = 4.80 (d, J = 10.4 Hz, 0.5 H), 3.58 (d, J = 10.8 Hz, 0.5 H), 3.27-3.11 (m, 1 H), 3.01-2.91 (m, 1 H), 2.87 (d, J = 6.8 Hz, 3 H), 2.59-2.40 (m, 4 H), 2.25-2.12 (m, 2 H), 1.45 (s, 9 H), 1.00 (dd, J = 14.4, 6.4 Hz, 3 H), 0.84 (dd, J = 6.8, 1.2 Hz, 3 H) ppm. The stereochemistry of compound A2-f was confirmed by 2D-NMR.

[0115] Step 6: Preparation of cis-tert-butyl(2S)-3-methyl-2-[methyl-[3-(3,3,3-trifluoropropane-1-inyl)cyclobutanecarbonyl]amino]butanoate (compound A2-g) A suspension of CuI (408.9 mg, 2.15 mmol), K2CO3 (593.5 mg, 4.29 mmol), and TMEDA (249.5 mg, 2.15 mmol) in DMF (10 mL) was stirred under an argon atmosphere at 25°C for 20 minutes. TMSCF3 (407.1 mg, 2.86 mmol) was added to the reaction mixture, and the reaction mixture was stirred under an argon atmosphere for 10 minutes. A solution of TMSCF3 (407.1 mg, 2.86 mmol) and cis-tert-butyl(2S)-2-[(3-ethynylcyclobutanecarbonyl)-methyl-amino]-3-methyl-butanoate (compound A2-f, 420.0 mg, 1.43 mmol) in DMF (10 mL) was added to the reaction mixture. The reaction mixture was stirred at 0°C for 30 minutes and then heated to 25°C. After stirring at 25°C for a further 12 hours, H2O (30 mL) was added to the reaction mixture, and then it was extracted with siRNA (10 mL, 3 times). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain the residue. The residue was purified by reverse-phase chromatography and preparative HPLC to obtain cis-tert-butyl(2S)-3-methyl-2-[methyl-[3-(3,3,3-trifluoropropane-1-inyl)cyclobutanecarbonyl]amino]butanoate (compound A2-g, 80.0 mg) as a yellow oil. MS calculation value: 362.2 (MH) + ), measured value 362.1 (MH) + ). 1 H NMR(400 MHz,chloroform-d)δ=4.80(d,J=10.0 Hz,0.5 H),3.62-3.46(m,1.5 H),3.28-3.13(m,1 H),2.89(d,J=4.4 Hz,3 H),2.82-2.67(m,2 H),2.48-2.38(m,2 H),2.29-2.15(m,1 H),1.46(d,J=2.8 Hz,9 H),1.05-0.98(m,3 H),0.85(d,J=6.8 Hz,3 H)ppm.

[0116] Step 7: Preparation of cis-(2S)-3-methyl-2-[methyl-[3-(3,3,3-trifluoropropane-1-inyl)cyclobutanecarbonyl]amino]butanoic acid (intermediate A2) To a solution of cis-tert-butyl(2S)-3-methyl-2-[methyl-[3-(3,3,3-trifluoropropa-1-inyl)cyclobutanecarbonyl]amino]butanoate (compound A2-g, 80.0 mg, 0.22 mmol) in DCM (1 mL), TFA (1.0 mL) was added, and the mixture was stirred at 20°C for 1 hour. After the reaction was complete, the reaction mixture was concentrated under vacuum to obtain cis-(2S)-3-methyl-2-[methyl-[3-(3,3,3-trifluoropropa-1-inyl)cyclobutanecarbonyl]amino]butanoic acid (intermediate A2, 80.0 mg) as a yellow oil, which was used directly in the next step. MS calculation value: 306.0 (MH) + ), measured value 306.0 (MH) + ).

[0117] Intermediate A3 and Intermediate A4 (2S)-2-[(5R)-7-tert-butoxycarbonyl-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-3-methylbutanoic acid (intermediate A3) and (2S)-2-[(5S)-7-tert-butoxycarbonyl-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-3-methylbutanoic acid (intermediate A4) JPEG2026515652000040.jpg39170

[0118] The compound was prepared according to the following scheme: JPEG2026515652000041.jpg113170

[0119] Step 1: Preparation of O1-tert-butyl O3-methyl3-allylpyrrolidine-1,3-dicarboxylate (compound A3-b) To a solution of O1-tert-butylO3-methylpyrrolidine-1,3-dicarboxylate (compound A3-a, 5.0 g, 21.8 mmol) in THF (60 mL), LDA (12 mL, 24 mmol) was added dropwise at -70°C under a nitrogen atmosphere. After stirring for 0.5 hours, allyl bromide (2.9 g, 23.99 mmol) was slowly added. After the reaction was complete, the reaction mixture was poured into saturated NH4Cl aqueous solution (100 mL) and extracted with siRNA (70 mL, twice). The combined organic layer was washed with brine (70 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain a residue. This residue was purified by silica gel column chromatography to obtain O1-tert-butylO3-methyl3-allylpyrrolidine-1,3-dicarboxylate (compound A3-b, 2.91 g) as a colorless oil.

[0120] Step 2: Preparation of O1-tert-butyl O3-methyl 3-(2-oxoethyl)pyrrolidine-1,3-dicarboxylate (compound A3-c) To a mixture of O1-tert-butylO3-methyl3-allylpyrrolidine-1,3-dicarboxylate (compound A3-b, 2.1 g, 7.8 mmol) in 1,4-dioxane (60 mL) and water (6 mL), 2,6-lutidine (1.8 mL, 15.6 mmol) and K2OsO4 (0.1 g, 0.39 mmol) were added all at once at 0°C. After stirring at 0°C for 15 minutes, sodium metaperiodate (6.6 g, 31.19 mmol) was added gradually at 0°C. The resulting mixture was heated to 20°C and stirred for a further 6 hours. After the reaction was complete, the mixture was quenched with saturated Na2S2O3 aqueous solution (100 mL), and the reaction mixture was extracted with ELISA (50 mL, 3 times). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain O1-tert-butylO3-methyl3-(2-oxoethyl)pyrrolidine-1,3-dicarboxylate (compound A3-c, 2.1 g) as a yellow oil, which was used directly in the next step.

[0121] Step 3: Preparation of O1-tert-butyl O3-methyl 3-[2-[[(1S)-1-benzyloxycarbonyl-2-methyl-propyl]amino]ethyl]pyrrolidine-1,3-dicarboxylate (compound A3-d) To a mixture of O1-tert-butylO3-methyl3-(2-oxoethyl)pyrrolidine-1,3-dicarboxylate (compound A3-c, 2.1 g, 7.74 mmol) and benzyl(2S)-2-amino-3-methyl-butanoate (1.6 g, 7.74 mmol) in methanol (20 mL), zinc chloride (1.05 g, 7.74 mmol) was added all at once at 0°C. After stirring at 0°C for 1 hour, sodium borohydride cyanohydride (0.97 g, 15.48 mmol) was added to the mixture at 0°C. The resulting mixture was stirred for a further 2 hours at 0°C. After the reaction was complete, the mixture was poured into a saturated aqueous solution of NH4Cl at 0°C (40 mL) and extracted with ELISA (50 mL, 3 times). The combined organic layers were washed with brine (30 mL, 4 times), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the residue. This residue was purified by silica gel column chromatography to obtain O1-tert-butylO3-methyl3-[2-[[(1S)-1-benzyloxycarbonyl-2-methyl-propyl]amino]ethyl]pyrrolidine-1,3-dicarboxylate (compound A3-d, 2.2 g) as a yellow oil. MS calculation value: 463.3 (MH) + ), measured value 463.2 (MH) + ).

[0122] Step 4: Preparation of tert-butyl(5R)-2-[(1S)-1-benzyloxycarbonyl-2-methyl-propyl]-1-oxo-2,7-diazaspiro[4.4]nonane-7-carboxylate (compound A3-e) and tert-butyl(5S)-2-[(1S)-1-benzyloxycarbonyl-2-methyl-propyl]-1-oxo-2,7-diazaspiro[4.4]nonane-7-carboxylate (compound A3-f). To a mixture of O1-tert-butylO3-methyl3-[2-[[(1S)-1-benzyloxycarbonyl-2-methyl-propyl]amino]ethyl]pyrrolidine-1,3-dicarboxylate (compound A3-d, 2.1 g, 4.54 mmol) in toluene (20 mL), DIEA (7.9 mL, 45.4 mmol) and DMAP (0.6 g, 4.54 mmol) were added in one step. The mixture was heated to 80°C and stirred for 16 hours. After the reaction was complete, the mixture was poured into water (30 mL) and extracted with ELISA (30 mL, 3 times). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain the residue, which was purified by reverse-phase flash column, and the eluent was concentrated under vacuum. The residue was further separated by prep-SFC to obtain tert-butyl(5R)-2-[(1S)-1-benzyloxycarbonyl-2-methyl-propyl]-1-oxo-2,7-diazaspiro[4.4]nonane-7-carboxylate (compound A3-e, faster elution, 521 mg) and tert-butyl(5S)-2-[(1S)-1-benzyloxycarbonyl-2-methyl-propyl]-1-oxo-2,7-diazaspiro[4.4]nonane-7-carboxylate (compound A3-f, slower elution, 525 mg). MS calculation value 453.3 (MNa + ), measured value 453.2 (MNa + ).

[0123] SFC conditions: Equipment: SFC 150 Mgm; Column: Chiralpak IG-3 50×4.6mm ID, 3um. Mobile phase: Phase A for CO2, Phase B for MEOH (0.05% DEA); Gradient elution: 40% B in A; Flow rate: 3 mL / min; Detector: DAD; Back pressure: 100 bar; Column temperature: 35°C.

[0124] Step 5: Preparation of (2S)-2-[(5R)-7-tert-butoxycarbonyl-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-3-methylbutanoic acid (intermediate A3) To a solution of tert-butyl(5R)-2-[(1S)-1-benzyloxycarbonyl-2-methylpropyl]-1-oxo-2,7-diazaspiro[4.4]nonane-7-carboxylate (compound A3-e, 120 mg, 0.28 mmol) in toluene (2 mL), wet palladium (12 mg, 10 wt%) on activated carbon was added. The mixture was degassed and purged three times with hydrogen. The reaction mixture was heated to 35°C and stirred under a hydrogen atmosphere for 3 hours. After the reaction was complete, the solution was filtered, and the filtrate was concentrated under vacuum to obtain (2S)-2-[(5R)-7-tert-butoxycarbonyl-1-oxo-2,7-diazaspiro[4.4]nonane-2-yl]-3-methylbutanoic acid (intermediate A3, 94 mg) as a white solid. MS calculation value 363.2 (MNa + ), measured value 363.1 (MNa + ).

[0125] X-ray crystallography of intermediate A3 The absolute configuration structure of intermediate A3 was confirmed by X-ray crystallography of its single crystal. (Figure 1)

[0126] Step 6: Preparation of (2S)-2-[(5S)-7-tert-butoxycarbonyl-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-3-methylbutanoic acid (intermediate A4). To a solution of tert-butyl(5S)-2-[(1S)-1-benzyloxycarbonyl-2-methylpropyl]-1-oxo-2,7-diazaspiro[4.4]nonane-7-carboxylate (compound A3-f, 120 mg, 0.28 mmol) in toluene (2 mL), wet palladium (12 mg, 10 wt%) on activated carbon was added. The mixture was degassed and purged three times with hydrogen. The mixture was heated to 35°C and stirred under a hydrogen atmosphere for 3 hours. After the reaction was complete, the solution was filtered, and the filtrate was concentrated under vacuum to obtain (2S)-2-[(5S)-7-tert-butoxycarbonyl-1-oxo-2,7-diazaspiro[4.4]nonane-2-yl]-3-methylbutanoic acid (intermediate A4, 79 mg) as a white solid. MS calculation value 363.2 (MNa + ), measured value 363.1 (MNa +).

[0127] X-ray crystallography of intermediate A4 The absolute configuration structure of intermediate A4 was confirmed by X-ray crystallography of its single crystal. (Figure 2)

[0128] Intermediate B1 Methyl(3S)-1-[(2S)-2-(tert-butoxycarbonylamino)-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-triisopropylsilyloxyphenyl]propanoyl]hexahydropyridazine-3-carboxylate TIFF2026515652000042.tif51170

[0129] Intermediate B was prepared according to the following scheme: JPEG2026515652000043.jpg137170

[0130] Step 1: Preparation of methyl(2S)-2-amino-3-(3-hydroxyphenyl)propanoate (compound B1-b) To a solution of LM-tyrosine (compound B1-a, 5.0 g, 27.6 mmol) in methanol (80 mL), thionyl chloride (10 mL, 137.9 mmol) was added. The mixture was stirred at 60°C for 12 hours. The reaction mixture was cooled to 20°C and concentrated under vacuum to obtain methyl(2S)-2-amino-3-(3-hydroxyphenyl)propanoate (compound B1-b, 6.2 g) as a yellow solid. 1 H NMR(400 MHz,CD3OD)δ=7.18(t,J=8.0 Hz,1H),6.78-6.66(m,3H),4.29(t,J=6.4 Hz,1H),3.82(s,3H),3.23-3.05(m,2H).

[0131] Step 2: Preparation of methyl(2S)-2-(tert-butoxycarbonylamino)-3-(3-hydroxyphenyl)propanoate (compound B1-c) A solution of methyl(2S)-2-amino-3-(3-hydroxyphenyl)propanoate (compound B1-b, 32.0 g, 138.1 mmol) in THF (80 mL) and water (20 mL) was prepared by adding sodium bicarbonate (40.6 g, 483.4 mmol), followed by the addition of di-t-butyl dicarbonate (33.1 g, 151.9 mmol) at 20°C. The mixture was stirred at 20°C for 12 hours. The mixture was diluted with water (100 mL) and acidified with 1 M aqueous solution of HCl to pH=5. The mixture was extracted with ethyl acetate (100 mL, 3 times). The combined organic phases were washed with brine (80 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to obtain methyl(2S)-2-(tert-butoxycarbonylamino)-3-(3-hydroxyphenyl)propanoate (compound B1-c 40 g) as a colorless rubber. MS: Calculated value 318 (MNa + ), measured value 318.3 (MNa + ).

[0132] Step 3: Preparation of methyl(2S)-2-(tert-butoxycarbonylamino)-3-(3-triisopropylsilyloxyphenyl)propanoate (compound B1-d) To a solution of methyl(2S)-2-(tert-butoxycarbonylamino)-3-(3-hydroxyphenyl)propanoate (compound B1-c, 40.0 g, 135.4 mmol) and 1H-imidazole (27.6 g, 406.3 mmol) in DMF (400 mL), triisopropylsilyl chloride (39.1 g, 203.1 mmol) was added dropwise at 0°C. After stirring at 25°C for 12 hours, the mixture was diluted with water (250 mL) at 0°C and extracted with ethyl acetate (200 mL, 3 times). The combined organic phase was washed with brine (80 mL, 4 times), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to obtain the residue. The residue was purified by silica gel chromatography (EA / PE: 0-20%) to obtain methyl(2S)-2-(tert-butoxycarbonylamino)-3-(3-triisopropylsilyloxyphenyl)propanoate (compound B1-d, 60g) as a yellow oil. MS: Calculated value 474 (MNa +), measured value 474.2 (MNa + ).

[0133] Step 4: Preparation of methyl(2S)-2-(tert-butoxycarbonylamino)-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-triisopropylsilyloxyphenyl]propanoate (compound B1-e) [Ir(OMe)(COD)]2 (2.2 g, 3.3 mmol) was added to a solution of methyl(2S)-2-(tert-butoxycarbonylamino)-3-(3-triisopropylsilyloxyphenyl)propanoate (compound B1-d, 15.0 g, 33.2 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (2.6 g, 9.9 mmol), and bis(pinacolate)diborone (12.6 g, 49.8 mmol) in hexane (200 mL). The mixture was degassed and purged three times with N2. The resulting mixture was stirred at 70°C for 12 hours. The reaction mixture was then cooled to 20°C, diluted with petroleum ether (100 mL), and filtered. The filtrate was concentrated under vacuum to obtain a residue, which was purified by silica gel chromatography (EA / PE: 0-20%) to obtain methyl(2S)-2-(tert-butoxycarbonylamino)-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-triisopropylsilyloxyphenyl]propanoate (compound B1-e, 21g) as a yellow oily substance. MS: Calculated value 600 (MNa + ), measured value 600.3 (MNa + ).

[0134] Step 5: Preparation of (2S)-2-(tert-butoxycarbonylamino)-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-triisopropylsilyloxyphenyl]propanoic acid (compound B1-f) A solution of methyl(2S)-2-(tert-butoxycarbonylamino)-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-triisopropylsilyloxyphenyl]propanoate (compound B1-e, 40.0 g, 69.2 mmol) in methanol (300 mL) was added to a solution of lithium hydroxide (3.2 mL, 346.2 mmol) in water (100 mL). After stirring at 20°C for 1 hour, the reaction mixture was diluted with water (200 mL), and the MeOH was removed under vacuum. The resulting mixture was acidified with a 1 M aqueous solution of HCl to pH=5. The resulting mixture was extracted with ELISA (250 mL, 3 times). The organic phase was washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to obtain (2S)-2-(tert-butoxycarbonylamino)-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-triisopropylsilyloxyphenyl]propanoic acid (compound B1-f, 33 g) as a white solid. MS: Calculated value 586 (MNa + ), measured value 586.3 (MNa + ).

[0135] Step 6: Preparation of methyl(3S)-1-[(2S)-2-(tert-butoxycarbonylamino)-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-triisopropylsilyloxyphenyl]propanoyl]hexahydropyridazine-3-carboxylate (intermediate B1) (2S)-2-(tert-butoxycarbonylamino)-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-triisopropylsilyloxyphenyl]propanoic acid (compound B1-f, 8.0 g, 14.1 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (5.6 g, 14.9 mmol) were dissolved in DMF (100 mL) and N,N-diisopropylethylamine (6.4 g, 49.6 mmol) was added. The mixture was stirred at 0°C for 10 minutes. Methyl(3S)-hexahydropyridazine-3-carboxylate hydrochloride (compound B1-g, 2.6 g, 14.9 mmol) was then added. The resulting mixture was stirred at 20°C for 1.5 hours, then diluted with water (200 mL) and extracted with ethyl acetate (100 mL, twice). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography to obtain methyl(3S)-1-[(2S)-2-(tert-butoxycarbonylamino)-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-triisopropylsilyloxyphenyl]propanoyl]hexahydropyridazine-3-carboxylate (intermediate B1, 7.8 g) as a yellow oil. MS: Calculated value 690 (MH) + ), measured value 690.4 (MH) + ).

[0136] Intermediate B2 Methyl(3S)-1-[(2S)-3-(4-bromothiazole-2-yl)-2-(tert-butoxycarbonylamino)-propanoyl]hexahydropyridazine-3-carboxylate TIFF2026515652000044.tif56170

[0137] Intermediate B2 was prepared according to the following scheme: JPEG2026515652000045.jpg140170

[0138] Step 1: Preparation of (4-bromothiazole-2-yl)methanol (compound B2-b) To a solution of 4-bromothiazole-2-carboxyaldehyde (compound B2-a, 6.0 g, 31.25 mmol) in methanol (70 mL), sodium borohydride (1.7 g, 46.87 mmol) was added at 0°C. The mixture was stirred at 25°C for 1 hour. The reaction product was quenched with water (300 mL) at 0°C, and the reaction mixture was extracted with ethyl acetate (200 mL, 3 times). The combined organic phases were washed with brine (150 mL, 2 times), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to obtain (4-bromothiazole-2-yl)methanol (compound B2-b, 6 g) as a colorless oil.

[0139] Step 2: Preparation of 4-bromo-2-(bromomethyl)thiazole (compound B2-c) To a solution of (4-bromothiazole-2-yl)methanol (compound B2-b, 6.0 g, 30.92 mmol) in DCM (80 mL), CBr4 (15.4 g, 46.38 mmol) and triphenylphosphine (12.1 g, 46.38 mmol) were added at 0°C. 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, and eluted with ethyl acetate in petroleum ether (0-10%) to obtain (4-bromothiazole-2-yl)methanol (compound B2-c, 6.0 g) as a yellow oily substance. MS calculation value: 255.9 (MH) + ), measured value 255.9 (MH) + ).

[0140] Step 3: Preparation of 4-bromo-2-[[(2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine-2-yl]methyl]thiazole (compound B2-e) To a mixture of (R)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine (compound B2-d, 4.3 g, 23.45 mmol) in THF (60 mL), n-butyllithium (10 mL, 25.22 mmol, 2.5 M) was slowly added at -78 °C. After addition, the mixture was stirred at -78 °C for 0.5 hours. 4-bromo-2-(bromomethyl)thiazole (compound B2-c, 5.4 g, 21.02 mmol) was added to the above mixture at -78 °C, and the mixture was stirred for a further 1 hour. The reaction product was quenched with a saturated solution of NH4Cl (100 mL), and the reaction mixture was extracted with ELISA (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 reverse-phase chromatography to obtain 4-bromo-2-[[(2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine-2-yl]methyl]thiazole (compound B2-e, 3.6 g) as a yellow oil. MS calculation value: 360 (MH) + ), measured value 359.9 (MH) + ).

[0141] Step 4: Preparation of methyl(2S)-2-amino-3-(4-bromothiazole-2-yl)propanoate (compound B2-f) A solution of 4-bromo-2-[[(2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine-2-yl]methyl]thiazole (compound B2-e, 3.6 g, 10 mmol) in ACN (20 mL) was mixed with hydrochloric acid (66.6 mL, 0.3 M). The mixture was stirred at 25 °C for 2 hours. The mixture was basicized with a saturated solution of NaHCO3 until the pH was 8. The mixture was extracted with ethyl acetate (80 mL, 6 times). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to obtain methyl(2S)-2-amino-3-(4-bromothiazole-2-yl)propanoate (compound B2-f, 3.1 g) as a yellow oil. MS calculation value: 264.9 (MH) + ), measured value 264.9 (MH) + ).

[0142] Step 5: Preparation of methyl(2S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)propanoate (compound B2-g) To a solution of methyl(2S)-2-amino-3-(4-bromothiazole-2-yl)propanoate (compound B2-f, 3.1 g, 11.69 mmol) in DCM (40 mL), triethylamine (2.9 g, 29.23 mmol) and (Boc)2O (3.8 g, 17.54 mmol) were added. After stirring at 30°C for 12 hours, the mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography and eluted with ethyl acetate (0-30%) in petroleum ether to obtain methyl(2S)-3-(4-bromothiazole-2-yl)-2-(tert-butoxycarbonylamino)propanoate (compound B2-g, 3.2 g) as a yellow oil. MS calculation value: 387 (MNa + ), measured value 386.9 (MNa + ).

[0143] Step 6: Preparation of (2S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)-propanoic acid (compound B2-h) A solution of methyl(2S)-3-(4-bromothiazole-2-yl)-2-(tert-butoxycarbonylamino)propanoate (compound B2-g, 3.2g, 8.76 mmol) was added to 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 the pH was 5. The mixture was extracted with ELISA (40 mL, twice). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to obtain (2S)-3-(4-bromothiazole-2-yl)-2-(tert-butoxycarbonylamino)propanoic acid (compound B2-h, 3.1 g) as a yellow oil. MS calculation value: 373 (MNa + ), measured value 372.9 (MNa + ).

[0144] Step 7: Preparation of methyl(3S)-1-[(2S)-3-(4-bromothiazole-2-yl)-2-(tert-butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylate (intermediate B2) To a solution of (2S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)propanoic acid (compound B2-h, 3.1 g, 8.83 mmol) in DCM (50 mL), methyl(3S)-hexahydropyridazine-3-carboxylate hydrochloride (compound B1-g, 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) were added at 0°C. After stirring at 25°C for 1 hour, the reaction mixture was diluted with water (60 mL) and extracted with ethyl acetate (60 mL, 3 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 obtain methyl (3S)-1-[(2S)-3-(4-bromothiazole-2-yl)-2-(tert-butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylate (intermediate B2, 2.4 g). MS calculation value: 477 (MH) + ), measured value 476.9 (MH) + ).

[0145] Intermediate C1 Benzyl 4-[5-ethynyl-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate TIFF2026515652000046.tif44170

[0146] Compound C1 was prepared according to the following scheme. TIFF2026515652000047.tif93170

[0147] Step 1: Preparation of benzyl 4-[5-bromo-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound C1-b) To a solution of 3-bromo-5-iodo-2-[(1S)-1-methoxyethyl]pyridine (compound C1-a, 660 mg, 1.9 mmol, CAS 2641451-76-3, PBWZ170, PharmaBlock (Nanjing) R&D Co. Ltd) and 1-Cbz-piperazine (compound C1-b, 425.1 mg, 1.9 mmol) in toluene (10 mL), 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) were added. After stirring at 100°C for 12 hours under N2 protection, the mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (EA / PE: 0-50%) to obtain benzyl 4-[5-bromo-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound C1-b, 740 mg) as a yellow solid. MS calculation value: 434.1 (MH) + ), measured value 434.1 (MH) + ).

[0148] Step 2: Preparation of benzyl 4-[6-[(1S)-1-methoxyethyl]-5-(2-trimethylsilylethynyl)-3-pyridyl]piperazine-1-carboxylate (compound C1-a) To a solution of benzyl 4-[5-bromo-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound C1-b, 33.0 g, 75.98 mmol) in DMF (1 L), trimethylsilylacetylene (85.9 mL, 607.83 mmol), Pd(PPh3)2Cl2 (5.3 g, 7.6 mmol), CuI (1.5 g, 7.6 mmol), and TEA (52.9 mL, 379.9 mmol) were added under a nitrogen atmosphere. The reaction mixture was degassed three times with nitrogen, and then stirred at 100°C for 12 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, filtered, and H2O (3 L) was added to the filtrate. The reaction mixture was extracted with RINKAN (1 L, three times). The combined organic layers were washed with brine (3 L), dried over Na2SO4, filtered, and concentrated under vacuum to obtain a residue. This residue was purified by column chromatography to obtain benzyl 4-[6-[(1S)-1-methoxyethyl]-5-(2-trimethylsilylethynyl)-3-pyridyl]piperazine-1-carboxylate (compound C1-c, 21.0 g) as a yellow solid. MS calculation value: 452.2 (MH) + ), measured value 452.2 (MH) + ).

[0149] Step 3: Preparation of benzyl 4-[5-ethynyl-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (intermediate D1) To a solution of benzyl 4-[6-[(1S)-1-methoxyethyl]-5-(2-trimethylsilylethynyl)-3-pyridyl]piperazine-1-carboxylate (compound C1-c, 31 g, 68.6 mmol) in methanol (500 mL), potassium fluoride (8.1 g, 139.8 mmol) was added at 0°C. The mixture was stirred at 20°C for 1 hour. After the reaction was complete, the reaction mixture was concentrated under vacuum to obtain a residue, which was purified by column chromatography to obtain benzyl 4-[5-ethynyl-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (intermediate C1, 25 g) as a brown solid. MS calculation value: 380.2 (MH) + ), measured value 380.2 (MH) +).

[0150] Intermediate C2 4-[5-ethynyl-6-[(1S)-1-methoxyethyl]-3-pyridyl]morpholine TIFF2026515652000048.tif37170

[0151] The title compound was prepared in the same manner as the preparation of intermediate C1, by using morpholine instead of 1-Cbz-piperazine.

[0152] Intermediate C3 1-[5-ethynyl-6-[(1S)-1-methoxyethyl]-3-pyridyl]-4-(2,2,2-trifluoroethyl)piperazine TIFF2026515652000049.tif44170

[0153] The title compound was prepared in the same manner as the preparation of intermediate C1, by using 1-(2,2,2-trifluoroethyl)piperazine instead of 1-Cbz-piperazine.

[0154] Intermediate C4 3-Ethynyl-2-[(1S)-1-methoxyethyl]pyridine TIFF2026515652000050.tif32170

[0155] The title compound was prepared in the same manner as the preparation of intermediate C1 by using 3-bromo-2-[(1S)-1-methoxyethyl]pyridine (CAS 2641451-44-5, PBU8238, PharmaBlock (Nanjing) R&D Co. Ltd.) instead of benzyl 4-[5-bromo-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound C1-b).

[0156] Intermediate D1 6-Bromo-8-iodo-1,2,3,4-tetrahydroquinoline TIFF2026515652000051.tif25170

[0157] The compound was prepared according to the following scheme: TIFF2026515652000052.tif341706-bromo-1,2,3,4-tetrahydroquinoline (compound D1-a, 40.0 g, 188.6 mmol) was dissolved in DMF (1.3 L) and NIS (42.4 g, 188.6 mmol) was gradually added at 0°C. After stirring at 25°C for 2 hours, the reaction mixture was poured into water (4 L) and extracted with ELISA (2 L, 3 times). The combined organic layer was washed with brine (2 L, 3 times), dried on anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain the residue. The residue was purified by reverse-phase chromatography to obtain 6-bromo-8-iodo-1,2,3,4-tetrahydroquinoline (intermediate D1, 37 g) as a brown, rubbery substance. MS calculation value 337.9 (MH) + ), measured value 338.0 (MH) + ).

[0158] Intermediate D2 7-Bromo-5-iodo-3,4-dihydro-2H-1,4-benzoxazine TIFF2026515652000053.tif26170

[0159] The compound was prepared according to the following scheme: JPEG2026515652000054.jpg71170

[0160] Step 1: Preparation of (2-amino-5-bromophenyl)4-methylbenzenesulfonate (compound D2-b) To a solution of 2-amino-5-bromophenol (compound D2-a, 75.0 g, 398.89 mmol) and TEA (66.7 mL, 478.67 mmol) in DCM (1.5 L), p-toluenesulfonyl chloride (83.6 g, 438.78 mmol) was added. After stirring at 25°C for 1 hour, the reaction mixture was quenched with saturated NaHCO3 aqueous solution (400 mL) and siRNA (500 mL, 3 times). The organic layer was washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain crude (2-amino-5-bromophenyl)4-methylbenzenesulfonate (compound D2-b, 146.5 g) as a dark brown solid, which was used in the next step without purification. MS calculation value: 342 (MH) + ), measured value 342 (MH) + ).

[0161] Step 2: Preparation of (2-amino-5-bromo-3-iodophenyl)4-methylbenzenesulfonate (compound D2-c) To a solution of (2-amino-5-bromo-phenyl)4-methylbenzenesulfonate (compound D2-b, 146.5 g, 428.1 mmol) in ethanol (1.5 L), silver sulfate (133.5 g, 428.1 mmol) and iodine (108.7 g, 428.1 mmol) were added. After stirring at 25°C for 12 hours, the reaction mixture was quenched with saturated aqueous solution of NaHCO3 (400 mL) and siRNA (500 mL, 3 times). The organic layer was washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain (2-amino-5-bromo-3-iodophenyl)4-methylbenzenesulfonate (compound D2-c, 210.0 g) as a dark brown solid, which was used in the next step without purification. MS calculation value: 467.8 (MH) + ), measured value 467.8 (MH) + ).

[0162] Step 3: Preparation of 2-amino-5-bromo-3-iodophenol (compound D2-d) Sodium hydroxide (62.8 g, 1570.18 mmol) was added to a solution of (2-amino-5-bromo-3-iodophenyl)4-methylbenzenesulfonate (compound D2-c, 210.0 g, 448.62 mmol) in ethanol (1.5 L) and THF (500 mL). The mixture was heated under reflux for 1 hour. After cooling to room temperature, the reaction mixture was concentrated under vacuum to obtain the residue. The residue was neutralized with 6N HCl to pH=7 and then extracted with siRNA (1 L, twice). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to obtain the residue. The crude product was purified by column chromatography to obtain 2-amino-5-bromo-3-iodophenol (compound D2-d, 120.0 g) as a dark brown solid. MS calculation value: 313.9 (MH) + ), measured value 313.9 (MH) + ).

[0163] Step 4: Preparation of 7-bromo-5-iodo-4H-1,4-benzoxazine-3-one (compound D2-e) Chloroacetyl chloride (19.0 mL, 238.91 mmol) was added to a solution of 2-amino-5-bromo-3-iodophenol (compound D2-d, 50.0 g, 159.28 mmol) and potassium carbonate (33.0 g, 238.91 mmol) in DMF (2 L). After stirring at 25°C for 12 hours, the reaction mixture was concentrated under vacuum to obtain a residue. The residue was poured into H2O (1 L) and extracted with siRNA (1 L, 3 times). The organic layer was washed with brine (1.5 L, 2 times), dried over Na2SO4, filtered, and concentrated under vacuum to obtain a residue. The crude product was macerated with MTBE (100 mL) at 25°C for 30 minutes. The suspension was filtered, and the filter cake was collected, yielding 7-bromo-5-iodo-4H-1,4-benzoxazine-3-one (compound D2-e, 175.0 g) as a dark brown solid. MS calculation value: 353.9 (MH) + ), measured value 353.9 (MH) + ).

[0164] Step 5: Preparation of 7-bromo-5-iodo-3,4-dihydro-2H-1,4-benzoxazine (intermediate D2) A boranetetrahydrofuran complex solution (113.0 mL, 113.01 mmol) was added at 0°C to a stirred solution of 7-bromo-5-iodo-4H-1,4-benzoxazine-3-one (compound D2-e, 20.0 g, 56.51 mmol) in THF (500 mL) under an N2 atmosphere. After stirring at 80°C for 1 hour, the mixture was cooled to room temperature, followed by the addition of MeOH (100 mL). The mixture was poured into H2O (100 mL) and extracted with siRNA (200 mL, 3 times). The organic layer was washed with brine (100 mL, 2 times), dried over Na2SO4, filtered, and concentrated under vacuum to obtain the residue. The crude product was purified by column chromatography to obtain 7-bromo-5-iodo-3,4-dihydro-2H-1,4-benzoxazine (intermediate D2, 17.6 g) as a pink solid. MS calculation value 340.0 (MH) + ), measured value 340.0 (MH) + ). 1 H NMR(400 MHz,DMSO-d6)δ=7.31(d,J=2.4 Hz,1H),6.88(d,J=2.4 Hz,1H),5.42(br s,1H),4.07(t,J=4.4 Hz,2H),3.38-3.33(m,2H).

[0165] Intermediate D3 6-Bromo-3,3-difluoro-8-iodo-2,4-dihydro-1H-quinoline TIFF2026515652000055.tif28170

[0166] The compound was prepared according to the following scheme: JPEG2026515652000056.jpg65170

[0167] Step 1: Preparation of 3,3-difluoro-1H-quinoline-2,4-dione (compound D3-b) Selectfluor (40.0 g, 112.91 mmol) was added at 0°C to a solution of 1H-quinoline-2,4-dione (compound D3-a, 8.0 g, 49.64 mmol) and potassium carbonate (13.7 g, 99.28 mmol) in ACN (160 mL) and water (80 mL). After stirring at 25°C for 1 hour, the reaction mixture was concentrated under vacuum, and the residue was filtered. The filtrate was added to water (1 L). The resulting mixture was extracted with ELISA (400 mL, 3 times). The combined organic layer was washed with brine (400 mL, 2 times), dried over Na2SO4, filtered, and concentrated under vacuum to obtain 3,3-difluoro-1H-quinoline-2,4-dione (compound D3-b, 46.0 g) as a yellow solid. 1 ¹H NMR (400 MHz, chloroform-d): δ = 9.77 (s, 1H), 8.22-7.94 (m, 1H), 7.81-7.64 (m, 1H), 7.33-7.28 (m, 1H), 7.17 (d, J = 8.0 Hz, 1H).

[0168] Step 2: Preparation of 3,3-difluoro-2,4-dihydro-1H-quinoline-4-ol (compound D3-c) A solution of 3,3-difluoro-1H-quinoline-2,4-dione (compound D3-b, 69.0 g, 350.01 mmol) in THF (700 mL) was mixed with borane-tetrahydrofuran complex (700.0 mL, 700.0 mmol) at 0°C. After stirring at 25°C for 16 hours, the reaction mixture was quenched by dropwise addition of MeOH (500 mL) at 0°C, and then concentrated under vacuum to obtain 3,3-difluoro-2,4-dihydro-1H-quinoline-4-ol (compound D3-c, 64.8 g) as a yellow oil. MS calculation value: 185.1 (MH) + ), measured value 168.0 (M-OH+H + ).

[0169] Step 3: Preparation of 3,3-difluoro-2,4-dihydro-1H-quinoline (compound D3-d) To a solution of 3,3-difluoro-2,4-dihydro-1H-quinoline-4-ol (compound D3-c, 64.8 g, 349.95 mmol) in Et3SiH (206.8 mL, 1.29 mol), TFA (405.4 mL, 5.26 mol) was added at 0°C. After stirring at 25°C for 16 hours, the reaction mixture was concentrated under vacuum, and the pH was adjusted to 8 by adding saturated NaHCO3 aqueous solution. The mixture was extracted with ELISA (1 L, twice). The combined organic layers were washed with brine (1.6 L), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain a residue. This residue was purified by silica gel column chromatography to obtain 3,3-difluoro-2,4-dihydro-1H-quinoline (compound D3-d, 45.0 g) as a yellow solid. MS calculation value: 170.1 (MH) + ), measured value 170.0 (MH) + ).

[0170] Step 4: Preparation of 6-bromo-3,3-difluoro-2,4-dihydro-1H-quinoline (compound D3-e) To a solution of 3,3-difluoro-2,4-dihydro-1H-quinoline (compound D3-d, 50.0 g, 295.56 mmol) in DMF (800 mL), NBS (50.0 g, 280.92 mmol) was added at 0°C. After stirring at 0°C for 1 hour, the reaction mixture was poured into water (1200 mL), and the resulting mixture was extracted with siRNA (800 mL, 3 times). The combined organic layer was washed with brine (1 L, 3 times), dried over Na2SO4, filtered, concentrated under vacuum, and purified by column chromatography to obtain 6-bromo-3,3-difluoro-2,4-dihydro-1H-quinoline (compound D3-e, 57.0 g) as a yellow solid. MS calculation value: 248.0 (MH) + ), measured value 247.9 (MH) + ).

[0171] Step 5: Preparation of 6-bromo-3,3-difluoro-8-iodo-2,4-dihydro-1H-quinoline (intermediate D3) To a solution of 6-bromo-3,3-difluoro-2,4-dihydro-1H-quinoline (compound D3-e, 49.0 g, 197.52 mmol) in DMF (700 mL), NIS (48.9 g, 217.28 mmol) was added at 0°C. After stirring at 0°C for 5 hours, the reaction mixture was poured into water (1.2 L), and the resulting mixture was extracted with ELISA (650 mL, 3 times). The combined organic layer was washed with brine (1 L, 3 times), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography to obtain 6-bromo-3,3-difluoro-8-iodo-2,4-dihydro-1H-quinoline (intermediate D3, 68.0 g) as a white solid. MS calculation value: 373.9 (MH) + ), measured value 373.9 (MH) + ).

[0172] Intermediate D4 7-Bromo-5-iodo-2,2-dimethyl-3,4-dihydro-1,4-benzoxazine TIFF2026515652000057.tif27170

[0173] The title compound was prepared in the same manner as the preparation of intermediate D2, by using ethyl 2-bromo-2-methyl-propanoate instead of chloroacetyl chloride.

[0174] Intermediate D5 7-Bromo-5-iodo-3-methyl-3,4-dihydro-2H-1,4-benzoxazine TIFF2026515652000058.tif24170

[0175] The compound was prepared according to the following scheme: TIFF2026515652000059.tif33170

[0176] Step 1: Preparation of 7-bromo-5-iodo-3-methyl-2H-1,4-benzoxazine (compound D5-a) To a solution of 2-amino-5-bromo-3-iodophenol (compound D2-d, 18 g, 57.34 mmol) in acetone (300 mL), potassium carbonate (15.8 g, 114.68 mmol) and chloroacetone (10.6 g, 114.68 mmol) were added. After stirring at 25°C for 18 hours, the reaction mixture was poured into siRNA (200 mL) / water (400 mL), and the layers were separated. The aqueous phase was extracted with siRNA (200 mL, twice). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain the residue. The residue was purified by flash chromatography to obtain 7-bromo-5-iodo-3-methyl-2H-1,4-benzoxazine (compound D5-a, 20 g) as a light brown solid. MS calculation value: 351.9 (MH) + ), measured value 351.9 (MH) + ).

[0177] Step 2: Preparation of 7-bromo-5-iodo-3-methyl-3,4-dihydro-2H-1,4-benzoxazine (intermediate D5)

[0178] To a solution of 7-bromo-5-iodo-3-methyl-2H-1,4-benzoxazine (compound D5-a, 20.0 g, 60 mmol) in TFA (1 L, 12.98 mmol), sodium borohydride (17 g, 270 mmol) was added, and the mixture was stirred at 25°C for 2 hours. The mixture was slowly added to an aqueous solution of NaOH (150 mL, 2 M), and then extracted with siRNA (100 mL, twice). The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered, and concentrated under vacuum to obtain the residue. The residue was purified by silica gel chromatography to obtain 7-bromo-5-iodo-3-methyl-3,4-dihydro-2H-1,4-benzoxazine (intermediate D5, 14.6 g) as a brown, concentrated oil. MS calculation value: 353.9 (MH) + ), measured value 353.9 (MH) + ).

[0179] Intermediate D6 9-Bromo-7-iodo-3,4,5,6-tetrahydro-2H-1,6-benzoxazosine TIFF2026515652000060.tif38170

[0180] The compound was prepared according to the following scheme: JPEG2026515652000061.jpg78170

[0181] Step 1: Preparation of tert-butyl N-(4-bromo-2-hydroxyphenyl)carbamate (compound D6-b) To a solution of 2-amino-5-bromophenol (compound D6-a, 15.0 g, 79.77 mmol) in anhydrous DCM (80 mL), (Boc)2O (26.1 g, 119.67 mmol) and TEA (22.2 mL, 159.57 mmol) were added. After stirring at 25°C for 15 hours, siRNA (450 mL) and water (450 mL) were added to the reaction mixture. The layers were separated, and the aqueous phase was extracted with siRNA (450 mL, twice). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain the residue. Purification of the residue by column chromatography yielded tert-butyl N-(4-bromo-2-hydroxyphenyl)carbamate (compound D6-b, 11.85 g) as a yellow solid. MS calculation value: 288.0 (MH) + ), measured value 231.6 (M-C4H8+H + ).

[0182] Step 2: Preparation of tert-butyl N-[4-bromo-2-[3-(1,3-dioxolan-2-yl)propoxy]phenyl]carbamate (compound D6-d) To a solution of tert-butyl N-(4-bromo-2-hydroxyphenyl)carbamate (compound D6-b, 10.0 g, 34.71 mmol) in anhydrous DMF (150 mL), 2-(3-bromopropyl)-1,3-dioxolane (compound D6-c, 13.5 g, 69.44 mmol) and TEA (14.51 mL, 104.12 mmol) were added at 25°C. The mixture was then heated to 90°C and stirred for a further 15 hours. After the reaction was complete, ELISA (300 mL) and water (200 mL) were added to the previous mixture, and the layers were separated. The aqueous phase was extracted with ELISA (250 mL, twice). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain the residue. Purification of the residue by column chromatography yielded tert-butyl N-[4-bromo-2-[3-(1,3-dioxolan-2-yl)propoxy]phenyl]carbamate (compound D6-d, 12.6g) as a yellow oily substance. MS calculation value: 402.0 (MH) + ), measured value 423.8 (MNa + ).

[0183] Step 3: Preparation of 9-bromo-3,4,5,6-tetrahydro-2H-1,6-benzoxazosine (compound D6-e) To a solution of tert-butyl N-[4-bromo-2-[3-(1,3-dioxolan-2-yl)propoxy]phenyl]carbamate (compound D6-d, 7.1 g, 17.65 mmol) in 500 mL of DCM at 0°C, 125 mL of TFA was added dropwise over 5 minutes under a nitrogen atmosphere using a syringe. After stirring at 25°C for 1 hour, triethylsilane (10.3 g, 88.25 mmol) was added to the reaction mixture, and the mixture was then stirred at 25°C for a further 4 hours. After the reaction was complete, the mixture was concentrated under vacuum to obtain the residue. 500 mL of toluene and 500 mL of saturated aqueous NaHCO3 solution were added to the residue, and the layers were separated. The aqueous phase was extracted with toluene (500 mL, twice). The combined organic layers were washed with brine (400 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain the residue. The residue was purified by column chromatography to obtain 9-bromo-3,4,5,6-tetrahydro-2H-1,6-benzoxazosine (compound D6-e, 2.9 g) as an orange solid. MS calculation value: 242.0 (MH) + ), measured value 242.0 (MH) + ).

[0184] Step 4: Preparation of 9-bromo-7-iodo-3,4,5,6-tetrahydro-2H-1,6-benzoxazosine (intermediate D6) To a solution of 9-bromo-3,4,5,6-tetrahydro-2H-1,6-benzoxazosine (compound D6-e, 2.8 g, 11.56 mmol) in acetic acid (100 mL), NIS (3.9 g, 17.35 mmol) was slowly added. The mixture was stirred at 25°C for 15 hours. After the reaction was complete, the mixture was concentrated under vacuum. The residue was purified by reverse-phase chromatography to obtain 9-bromo-7-iodo-3,4,5,6-tetrahydro-2H-1,6-benzoxazosine (intermediate D6, 1.2 g) as a brown solid. MS calculation value: 367.9 (MH) + ), measured value 367.9 (MH) + ).

[0185] Intermediate D7 8-Bromo-6-iodo-2,3,4,5-tetrahydro-1,5-benzoxazepine TIFF2026515652000062.tif25170

[0186] The title compound was prepared in the same manner as the preparation of intermediate D6 by using 2-(2-bromoethyl)-1,3-dioxolane instead of 2-(3-bromopropyl)-1,3-dioxolane (compound D6-c).

[0187] Intermediate D8 6-Bromo-8-iodo-3,3-dimethyl-2,4-dihydro-1H-quinoline TIFF2026515652000063.tif25170

[0188] The title compound was prepared in the same manner as the preparation of intermediate D1, by using 6-bromo-3,3-dimethyl-2,4-dihydro-1H-quinoline instead of 6-bromo-1,2,3,4-tetrahydroquinoline (compound D1-a).

[0189] Intermediate E (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriakonta-1(28),2,5(31),19,25(29),26-Hexaene-8,14-Zione TIFF2026515652000064.tif57170

[0190] The compound was prepared according to the following scheme: JPEG2026515652000065.jpg219170JPEG2026515652000066.jpg97170

[0191] Step 1: Preparation of benzyl 4-[5-[2-(6-bromo-1,2,3,4-tetrahydroquinoline-8-yl)ethynyl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound E1). To a solution of benzyl 4-[6-[(1S)-1-methoxyethyl]-5-(2-trimethylsilylethynyl)-3-pyridyl]piperazine-1-carboxylate (intermediate C1, 26.1 g, 68.8 mmol) in DMF (400 mL), 6-bromo-8-iodo-1,2,3,4-tetrahydroquinoline (intermediate D1, 23.3 g, 68.8 mmol), TEA (47.9 mL, 343.92 mmol), CuI (0.3 mL, 6.88 mmol), and Pd(PPh3)2Cl2 (4.8 g, 6.88 mmol) were added. The reaction mixture was degassed, purged three times with nitrogen, and then stirred at 25°C for 12 hours. After the reaction was complete, the reaction mixture was poured into water (1.4 L) and extracted with RINKAN (800 mL, three times). The combined organic layers were washed with brine (800 mL, 4 times), dried over Na2SO4, filtered, and concentrated under vacuum to obtain a residue. This residue was purified by column chromatography to obtain benzyl 4-[5-[2-(6-bromo-1,2,3,4-tetrahydroquinoline-8-yl)ethynyl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound E1, 30.0 g) as a yellow solid. MS calculation value: 589.2 (MH) + ), measured value 589.2 (MH) + ).

[0192] Step 2: Benzyl 4-[5-(6-bromo-1-azatricyclo[6.3.1.0 4,12 Preparation of dodeca-2,4,6,8(12)-tetraen-2-yl)-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound E2). A solution of benzyl 4-[5-[2-(6-bromo-1,2,3,4-tetrahydroquinoline-8-yl)ethynyl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound E1, 27.0 g, 45.8 mmol) was added in one go to DMF (270 mL), to which PdCl2 (1.6 g, 9.16 mmol) was added. The reaction mixture was degassed under vacuum, flushed three times with nitrogen, and then heated at 70°C for 16 hours. After cooling to room temperature, the mixture was poured into water (800 mL) and extracted with ELISA (300 mL, three times). The combined organic layers were washed with brine (300 mL, 3 times), dried over Na2SO4, filtered, and concentrated under vacuum to obtain the residue, which was then purified by column chromatography to obtain benzyl 4-[5-(6-bromo-1-azatricyclo[6.3.1.0 4,12 Dodeca-2,4,6,8(12)-tetraen-2-yl)-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound E2, 19.2g) was obtained as a yellow solid. MS calculation value 589.2 (MH) + ), measured value 589.2 (MH) + ).

[0193] Step 3: Benzyl 4-[5-(6-bromo-3-formyl-1-azatricyclo[6.3.1.0 4,12 Preparation of dodeca-2,4,6,8(12)-tetraen-2-yl)-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound E3). Phosphorus oxychloride (30.4 mL, 325.69 mmol) was slowly added dropwise to DMF (350 mL) at 0°C. After stirring at 0°C for 0.5 hours, benzyl 4-[5-(6-bromo-1-azatricyclo[6.3.1.0 4,12A solution of ]dodeca-2,4,6,8(12)-tetraen-2-yl)-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound E2, 19.2 g, 32.57 mmol) in DMF (150 mL) was added dropwise at 0°C. The reaction mixture was heated to 45°C and then stirred for a further 1 hour. The reaction mixture was quenched with saturated aqueous NaHCO3 (1.5 L) and extracted with ethylacetate (500 mL, 3 times). The organic layer was washed with brine (500 mL, 3 times), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain the residue. The residue was purified by column chromatography to obtain benzyl 4-[5-(6-bromo-3-formyl-1-azatricyclo[6.3.1.0 4,12 Dodeca-2,4,6,8(12)-tetraen-2-yl)-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound E3, 14.6g) was obtained as a yellow solid. MS calculation value: 616.9 (MH) + ), measured value 617.2 (MH) + ).

[0194] Step 4: Benzyl 4-[5-[6-bromo-3-(1-hydroxy-3-methoxy-2,2-dimethyl-3-oxopropyl)-1-azatricyclo[6.3.1.0 4,12 Preparation of dodeca-2,4,6,8(12)-tetraen-2-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound E4) To a solution of methyl isobutyrate (13.4 g, 131.17 mmol) in THF (150 mL), LDA (65.58 mL, 131.17 mmol) was added dropwise at -70°C under a nitrogen atmosphere. After stirring for 0.5 hours, benzyl 4-[5-(6-bromo-3-formyl-1-azatricyclo[6.3.1.0 4,12A solution of ]dodeca-2,4,6,8(12)-tetraen-2-yl)-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound E3, 13.5 g, 21.86 mmol) in THF (50 mL) was added dropwise at -70°C. The reaction mixture was then warmed to room temperature and stirred for 1 hour. After the reaction was complete, the mixture was quenched with saturated NH4Cl (600 mL) aqueous solution and extracted with  (200 mL, 3 times). The organic layer was washed with brine (500 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain the residue. The residue was purified by column chromatography to obtain benzyl 4-[5-[6-bromo-3-(1-hydroxy-3-methoxy-2,2-dimethyl-3-oxopropyl)-1-azatricyclo[6.3.1.0 4,12 Dodeca-2,4,6,8(12)-tetraen-2-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound E4, 14.01 g) was obtained as a yellow, rubbery substance. MS calculation value: 719.3 (MH) + ), measured value 719.2 (MH) + ).

[0195] Step 5: Benzyl 4-[5-[6-bromo-3-(3-methoxy-2,2-dimethyl-3-oxopropyl)-1-azatricyclo[6.3.1.0 4,12 Preparation of dodeca-2,4,6,8(12)-tetraen-2-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound E5) Benzyl 4-[5-(6-bromo-3-formyl-1-azatricyclo[6.3.1.0 4,12To a solution of dodeca-2,4,6,8(12)-tetraen-2-yl)-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound E4, 14.0 g, 19.45 mmol) and Et3SiH (18.1 g, 155.63 mmol) in DCM (280 mL), TFA (57.8 mL, 778.15 mmol) was added at 0°C. After stirring at 25°C for 12 hours, the reaction mixture was concentrated under vacuum to obtain a residue, which was diluted with saturated NaHCO3 aqueous solution to pH=9 and extracted with ELISA (300 mL, 3 times). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain a residue. The residue was purified by column chromatography to obtain benzyl 4-[5-[6-bromo-3-(3-methoxy-2,2-dimethyl-3-oxopropyl)-1-azatricyclo[6.3.1.0 4,12 Dodeca-2,4,6,8(12)-tetraen-2-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound E5, 14g) was obtained as a yellow, rubbery substance. MS calculation value: 703.2 (MH) + ), measured value 703.2 (MH) + ).

[0196] Step 6: Benzyl 4-[(5M)-5-[6-bromo-3-(3-hydroxy-2,2-dimethyl-propyl)-1-azatricyclo[6.3.1.0 4,12 Preparation of dodeca-2,4,6,8(12)-tetraen-2-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound E6) Benzyl 4-[5-[6-bromo-3-(3-methoxy-2,2-dimethyl-3-oxopropyl)-1-azatricyclo[6.3.1.0 4,12To a solution of ]dodeca-2,4,6,8(12)-tetraen-2-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound E5, 14.0 g, 19.9 mmol) in THF (150 mL), lithium borohydride (99.48 mL, 198.96 mmol) was added dropwise under N2 at 0°C. After stirring at 20°C for 15 hours, the reaction mixture was quenched at 0°C with saturated NH4Cl aqueous solution (600 mL), and the resulting mixture was extracted with ELISA (100 mL, 3 times). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain the residue. The residue was purified by column chromatography to obtain benzyl 4-[(5M)-5-[6-bromo-3-(3-hydroxy-2,2-dimethyl-propyl)-1-azatricyclo[6.3.1.0 4,12 Dodeca-2,4,6,8(12)-tetraen-2-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound E6, 7g, faster elution) was obtained as a yellow solid. MS calculation value 675.3 (MH) + ), measured value 675.2 (MH) + ).

[0197] Step 7: Benzyl 4-[(5M)-5-[3-(3-hydroxy-2,2-dimethylpropyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-azatricyclo[6.3.1.0 4,12 Preparation of dodeca-2,4(12),5,7-tetraen-2-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound E7) In toluene (140 mL), benzyl 4-[(5M)-5-[6-bromo-3-(3-hydroxy-2,2-dimethyl-propyl)-1-azatricyclo[6.3.1.0 4,12To a solution of dodeca-2,4,6,8(12)-tetraen-2-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound E6, 7.0 g, 10.36 mmol) and bis(pinacolato)diborone (3.95 g, 15.54 mmol), KOAc (2.56 g, 26.05 mmol) and Pd(dppf)Cl2 (760.87 mg, 1.04 mmol) were added. The mixture was degassed, purged three times with nitrogen, and stirred at 75°C for 16 hours. After cooling to room temperature, the reaction mixture was filtered and concentrated under vacuum to obtain the residue. The residue was purified by column chromatography to obtain benzyl 4-[(5M)-5-[3-(3-hydroxy-2,2-dimethylpropyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-azatricyclo[6.3.1.0 4,12 Dodeca-2,4(12),5,7-tetraen-2-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound E7, 7.3g) was obtained as a yellow solid. MS calculation value 723.4 (MH) + ), measured value 723.4 (MH) + ).

[0198] Step 8: Methyl(3S)-1-[(2S)-3-[4-[(2M)-2-[5-(4-benzyloxycarbonylpiperazin-1-yl)-2-[(1S)-1-methoxyethyl]-3-pyridyl]-3-(3-hydroxy-2,2-dimethylpropyl)-1-azatricyclo[6.3.1.0 4,12 Preparation of Dodeca-2,4(12),5,7-Tetraen-6-yl]thiazole-2-yl]-2-(tert-butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylate (compound E8) Toluene (90 mL) / 1,4-Dioxane (30 mL) / Water (30 mL) contains benzyl 4-[(5M)-5-[3-(3-hydroxy-2,2-dimethylpropyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-azatricyclo[6.3.1.0 4,12To a solution of ]dodeca-2,4(12),5,7-tetraen-2-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound E7, 6.8 g, 9.41 mmol) and methyl(3S)-1-[(2S)-3-(4-bromothiazole-2-yl)-2-(tert-butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylate (intermediate B2, 4.94 g, 10.35 mmol), K3PO4 (5.0 g, 23.52 mmol) and Pd(dtbpf)Cl2 (613.2 mg, 0.94 mmol) were added in one step. The mixture was degassed, purged three times with nitrogen, and then stirred at 70°C for 15 hours. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated under vacuum to obtain the residue. The residue was purified by column chromatography to obtain methyl(3S)-1-[(2S)-3-[4-[(2M)-2-[5-(4-benzyloxycarbonylpiperazin-1-yl)-2-[(1S)-1-methoxyethyl]-3-pyridyl]-3-(3-hydroxy-2,2-dimethylpropyl)-1-azatricyclo[6.3.1.0 4,12 Dodeca-2,4(12),5,7-tetraen-6-yl]thiazole-2-yl]-2-(tert-butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylate (compound E8, 8.1g) was obtained as a yellow solid. MS calculation value 993.7 (MH) + ), measured value 993.7 (MH) + ).

[0199] Step 9: (3S)-1-[(2S)-3-[4-[(2M)-2-[5-(4-benzyloxycarbonylpiperazin-1-yl)-2-[(1S)-1-methoxyethyl]-3-pyridyl]-3-(3-hydroxy-2,2-dimethylpropyl)-1-azatricyclo[6.3.1.0 4,12 Preparation of dodeca-2,4(12),5,7-tetraen-6-yl]thiazole-2-yl]-2-(tert-butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylic acid (compound E9) DCE (160mL) contains methyl(3S)-1-[(2S)-3-[4-[(2M)-2-[5-(4-benzyloxycarbonylpiperazin-1-yl)-2-[(1S)-1-methoxyethyl]-3-pyridyl]-3-(3-hydroxy-2,2-dimethylpropyl)-1-azatricyclo[6.3.1.0 4,12 To a mixture of dodeca-2,4(12),5,7-tetraen-6-yl]thiazole-2-yl]-2-(tert-butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylate (compound E8, 8.1 g, 8.16 mmol), trimethyltin hydroxide (5.9 g, 32.62 mmol) was added all at once. After stirring at 60°C for 16 hours, the reaction mixture was poured into water (200 mL) and extracted with ethyl acetate (100 mL, 3 times). The combined organic layer was washed with brine (200 mL), dried on anhydrous sodium 2 SO4, and filtered. The filtrate was concentrated under vacuum to obtain (3S)-1-[(2S)-3-[4-[(2M)-2-[5-(4-benzyloxycarbonylpiperazin-1-yl)-2-[(1S)-1-methoxyethyl]-3-pyridyl]-3-(3-hydroxy-2,2-dimethylpropyl)-1-azatricyclo[6.3.1.0 4,12 Dodeca-2,4(12),5,7-tetraen-6-yl]thiazole-2-yl]-2-(tert-butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylic acid (compound E9, 7.9g) was obtained as a brown solid. MS calculation value 979.5 (MH) + ), measured value 979.5 (MH) + ).

[0200] Step 10: Benzyl 4-[(5M)-5-[(7S,13S)-7-(tert-butoxycarbonylamino)-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26Preparation of ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-20-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound E10) (3S)-1-[(2S)-3-[4-[(2M)-2-[5-(4-benzyloxycarbonylpiperazin-1-yl)-2-[(1S)-1-methoxyethyl]-3-pyridyl]-3-(3-hydroxy-2,2-dimethylpropyl)-1-azatricyclo[6.3.1.0 4,12 To a solution of [dodeca-2,4(12),5,7-tetraen-6-yl]thiazole-2-yl]-2-(tert-butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylic acid (compound E9, 6.8 g, 6.94 mmol) in DCM (700 mL), DIEA (24.2 mL, 138.89 mmol), EDCI (19.97 g, 104.17 mmol), and HOBt (2.35 g, 17.36 mmol) were added at 0°C. After stirring at 30°C for 15 hours, the reaction mixture was poured into water (500 mL) and extracted with ethyl acetate (300 mL, 3 times). The combined organic layer was washed with brine (300 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under vacuum to obtain the residue, which was then purified by silica column chromatography to obtain benzyl 4-[(5M)-5-[(7S,13S)-7-(tert-butoxycarbonylamino)-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 [Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-20-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound E10, 5.6g) was obtained as a yellow solid. MS calculation value 961.5 (MH) + ), measured value 961.5 (MH) + ).

[0201] Step 11: tert-butyl N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 Preparation of ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]carbamate (compound E11) In methanol (150 mL), benzyl 4-[(5M)-5-[(7S,13S)-7-(tert-butoxycarbonylamino)-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 To a solution of ]Hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-20-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound E10, 5.6 g, 5.83 mmol) and formaldehyde (1.89 g, 23.3 mmol), Pd(OH)2 (3.0 g, 2.91 mmol) was added on activated carbon under a nitrogen atmosphere. The reaction mixture was degassed, purged three times with H2, and then stirred at 35°C (15 psi) under H2 for 15 hours. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated under vacuum to obtain a residue. Depositphotos (50 mL) and water (50 mL) were added to this residue, and the layers were separated. The aqueous phase was extracted with Depositphotos (50 mL, twice). The combined organic layers were washed with brine (60 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under vacuum to obtain tert-butylN-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5 .1 9,13 .0 19,27 .0 21,26 Hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamate (compound E11, 3.9g) was obtained as a yellow solid and used in the next step without further purification. MS calculation value 841.5 (MH) + ), measured value 841.4 (MH) + ).

[0202] Step 12: (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 Preparation of Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaene-8,14-dione (intermediate E) DCM (30mL) contains tert-butyl N-[(7S,13S)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26To a solution of ]Hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamate (compound E11, 3.9 g, 4.6 mmol), TFA (15.0 mL) was added all at once. After stirring at 25°C for 1 hour, the mixture was poured into water (100 mL) and extracted with Depositphotos (200 mL). The organic phase was washed with water (50 mL, twice). The combined aqueous phase was basicized to pH=9 with saturated NaHCO3 aqueous solution and extracted with Depositphotos (100 mL, three times). Wash the combined organic layers with brine (200 mL), dry with anhydrous Na2SO4, filter, and concentrate under vacuum to obtain (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 Hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-zione (intermediate E, 2.95g) was obtained as a yellow solid. MS calculation value 741.5 (MH) + ), measured value 741.4 (MH) + ).

[0203] Intermediate F (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriakonta-1(28),2,5(31),19,25(29),26-Hexaene-8,14-Zione TIFF2026515652000067.tif60170

[0204] The title compound was prepared in the same manner as the preparation of intermediate E by using 4-[5-ethynyl-6-[(1S)-1-methoxyethyl]-3-pyridyl]morpholine (intermediate C2) instead of benzyl 4-[5-ethynyl-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (intermediate C1).

[0205] intermediate G (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]henthriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione TIFF2026515652000068.tif55170

[0206] The compound was prepared according to the following scheme: JPEG2026515652000069.jpg128170

[0207] Step 1: tert-butyl N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-piperazin-1-yl-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 Preparation of ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]carbamate (compound G1) Ether (8 mL) contains benzyl 4-[(5M)-5-[(7S,13S)-7-(tert-butoxycarbonylamino)-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5 .1 9,13 .0 19,27 .0 21,26 To a solution of ]Hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-20-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound E10, 400.0 mg, 0.42 mmol), Pd / C (200.0 mg) was added on activated carbon under a nitrogen atmosphere. The mixture was degassed, purged three times with H2, and then stirred at 25°C for 48 hours under H2 (15 psi). The reaction mixture was filtered, and the filtrate was concentrated under vacuum to obtain tert-butylN-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-piperazin-1-yl-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 Hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamate (compound G1, 320.0 mg) was obtained as an off-white solid and used in the next step without further purification. MS calculation value 827.6 (MH) + ), measured value 827.4 (MH) + ).

[0208] Step 2: tert-butyl N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 Preparation of ]Hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamate (compound G2). THF (6 mL) contains tert-butyl N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-piperazin-1-yl-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 To a solution of ]Hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamate (compound G1, 290.0 mg, 0.35 mmol), TEA (0.15 mL, 1.05 mmol) and CF3CH2OTf (162.8 mg, 0.7 mmol) were added. After stirring at 60°C for 15 hours, the reaction mixture was concentrated under vacuum to obtain the residue. The residue was purified by silica gel column chromatography to obtain tert-butyl N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 Hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamate (compound G2, 230.0 mg) was obtained as a white solid. MS calculation value 909.4 (MH) + ), measured value 909.4 (MH) + ).

[0209] Step 3: (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26Preparation of Hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (intermediate G). In DCM (2 mL), tert-butyl N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 To a solution of ]Hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamate (compound G2, 230.0 mg, 0.25 mmol), TFA (2 mL) was added. After stirring at 20°C for 1 hour, saturated NaHCO3 solution (40 mL) was added to the reaction mixture, and this was extracted with  (50 mL, 3 times). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum to obtain (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 Hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (intermediate G, 200.0 mg) was obtained as a yellow solid and used in the next step without further purification. MS calculation value 809.4 (MH) + ), measured value 809.4 (MH) + ).

[0210] Intermediate H (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-15,24-dioxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriakonta-1(28),2,5(31),19,25(29),26-Hexaene-8,14-Zione TIFF2026515652000070.tif56170

[0211] The title compound was prepared in the same manner as the preparation of intermediate E, by using 7-bromo-5-iodo-3,4-dihydro-2H-1,4-benzoxazine (intermediate D2) instead of 6-bromo-8-iodo-1,2,3,4-tetrahydroquinoline (intermediate D1).

[0212] Intermediate I (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-15,24-dioxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriakonta-1(28),2,5(31),19,25(29),26-Hexaene-8,14-Zione TIFF2026515652000071.tif53170

[0213] The title compound was prepared in the same manner as the preparation of intermediate E, by using 4-[5-ethynyl-6-[(1S)-1-methoxyethyl]-3-pyridyl]morpholine (intermediate C2) and 7-bromo-5-iodo-3,4-dihydro-2H-1,4-benzoxazine (intermediate D2) instead of benzyl 4-[5-ethynyl-6-[(1S)-1-methoxyethyl]-3-pyridyl]morpholine (intermediate C2) and 6-bromo-8-iodo-1,2,3,4-tetrahydroquinoline (intermediate D1).

[0214] Intermediate J (7S,13S)-7-amino-23,23-difluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriakonta-1(28),2,5(31),19,25(29),26-Hexaene-8,14-Zione TIFF2026515652000072.tif58170

[0215] The title compound was prepared in the same manner as the preparation of intermediate E, by using 6-bromo-3,3-difluoro-8-iodo-2,4-dihydro-1H-quinoline (intermediate D3) instead of 6-bromo-8-iodo-1,2,3,4-tetrahydroquinoline (intermediate D1).

[0216] Intermediate K (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17,23,23-tetramethyl-15,24-dioxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26]Hentriakonta-1(28),2,5(31),19,25(29),26-Hexaene-8,14-Zione TIFF2026515652000073.tif54170

[0217] The title compound was prepared in the same manner as the preparation of intermediate E, by using 7-bromo-5-iodo-2,2-dimethyl-3,4-dihydro-1,4-benzoxazine (intermediate D4) and 4-[5-ethynyl-6-[(1S)-1-methoxyethyl]-3-pyridyl]morpholine (intermediate C2) instead of 6-bromo-8-iodo-1,2,3,4-tetrahydroquinoline (intermediate D1) and benzyl 4-[5-ethynyl-6-[(1S)-1-methoxyethyl]-3-pyridyl]morpholine (intermediate C2) instead of benzyl 4-[5-ethynyl-6-[(1S)-1-methoxyethyl]-3-pyridyl]morpholine (intermediate C2).

[0218] Intermediate L (7S,13S,22S)-7-amino-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17,22-trimethyl-15,24-dioxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriakonta-1(28),2,5(31),19,25(29),26-Hexaene-8,14-Zione TIFF2026515652000074.tif54170

[0219] The title compound was prepared in the same manner as the preparation of intermediate E, by using 7-bromo-5-iodo-3-methyl-3,4-dihydro-2H-1,4-benzoxazine (intermediate D5) and 4-[5-ethynyl-6-[(1S)-1-methoxyethyl]-3-pyridyl]morpholine (intermediate C2) instead of 6-bromo-8-iodo-1,2,3,4-tetrahydroquinoline (intermediate D1) and benzyl 4-[5-ethynyl-6-[(1S)-1-methoxyethyl]-3-pyridyl]morpholine (intermediate C2) instead of benzyl 4-[5-ethynyl-6-[(1S)-1-methoxyethyl]-3-pyridyl]morpholine (intermediate C2).

[0220] Intermediate M (7S,13S)-7-amino-23,23-difluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriakonta-1(28),2,5(31),19,25(29),26-Hexaene-8,14-Zione TIFF2026515652000075.tif54170

[0221] The title compound was prepared in the same manner as the preparation of intermediate E, by using 6-bromo-3,3-difluoro-8-iodo-2,4-dihydro-1H-quinoline (intermediate D3) and 4-[5-ethynyl-6-[(1S)-1-methoxyethyl]-3-pyridyl]morpholine (intermediate C2) instead of 6-bromo-8-iodo-1,2,3,4-tetrahydroquinoline (intermediate D1) and benzyl 4-[5-ethynyl-6-[(1S)-1-methoxyethyl]-3-pyridyl]morpholine (intermediate C2).

[0222] Intermediate N (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 Tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaene-19,25-zion TIFF2026515652000076.tif55170

[0223] The compound was prepared according to the following scheme: JPEG2026515652000077.jpg108170

[0224] Step 1: tert-butyl N-[(20S,26S)-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-19,25-dioxo-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 Preparation of tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaen-26-yl]carbamate (compound Nb) tert-butyl N-[(20S,26S)-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-19,25-dioxo-30-triisopropylsilyloxy-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 A solution of tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaen-26-yl]carbamate (compound Na, 16.0 mg, 0.02 mmol) in THF (4 mL) was mixed with TBAF (20 μL, 0.02 mmol, 1 M in THF). After stirring at 0°C for 0.5 hours, the mixture was concentrated under vacuum to obtain a residue. The residue was poured into water (10 mL) and extracted with RINKAN (8 mL, 3 times). The combined organic phases were washed with brine (5 mL), dried with sodium sulfate, filtered, and concentrated under vacuum to obtain tert-butyl N-[(20S,26S)-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-19,25-dioxo-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12Tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaen-26-yl]carbamate (compound Nb, 12.0 mg) was obtained as a yellow oily substance and used in the next step without purification. MS calculation value 782.4 (MH) + ), measured value 782.4 (MH) + ).

[0225] Step 2: (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 Preparation of tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaene-19,25-dione (intermediate N) tert-butyl N-[(20S,26S)-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-19,25-dioxo-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 A solution of tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaen-26-yl]carbamate (compound Nb, 12 mg, 0.015 mmol) in DCM (2.5 mL) was mixed with TFA (0.5 mL). The mixture was stirred at 20°C for 1.5 hours. After the reaction was complete, the mixture was concentrated under vacuum to obtain the residue. The residue was purified by reverse-phase chromatography to obtain (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12Tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaene-19,25-dione (intermediate N, 10.0 mg) was obtained as a yellow solid. MS calculation value: 682.4 (MH) + ), measured value 682.4 (MH) + ).

[0226] The title compound Na was prepared in the same manner as the preparation of compound E10, by using 9-bromo-7-iodo-3,4,5,6-tetrahydro-2H-1,6-benzoxazosine (intermediate D6) and 3-ethynyl-2-[(1S)-1-methoxyethyl]pyridine (intermediate C4) instead of 6-bromo-8-iodo-1,2,3,4-tetrahydroquinoline (intermediate D1) and benzyl 4-[5-ethynyl-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (intermediate C1).

[0227] Intermediate O (19S,25S)-25-amino-29-hydroxy-(12M)-12-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-15,15-dimethyl-7,17-dioxa-11,23,32-triazahexacyclo[25.3.1.1 2,6 .1 19,23 .0 4,13 .0 5,11 Tritriaconta-1(30),2,4,6(33),12,27(31),28-heptaene-18,24-zion TIFF2026515652000078.tif58170

[0228] The title compound was prepared by using 8-bromo-6-iodo-2,3,4,5-tetrahydro-1,5-benzoxazepine (intermediate D7) instead of 9-bromo-7-iodo-3,4,5,6-tetrahydro-2H-1,6-benzoxazosine (intermediate D6), similar to the preparation of intermediate N.

[0229] Intermediate P (18S,24S)-24-amino-28-hydroxy-(11M)-11-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-14,14-dimethyl-16-oxa-10,22,31-triazahexacyclo[24.3.1.1 2,6 .1 18,22 .0 4,12 .0 5,10 ] Dotriaconta-1(29),2,4,6(32),11,26(30),27-Heptaen-17,23-Zeon TIFF2026515652000079.tif57170

[0230] The title compound was prepared by using 6-bromo-8-iodo-1,2,3,4-tetrahydroquinoline (intermediate D1) instead of 9-bromo-7-iodo-3,4,5,6-tetrahydro-2H-1,6-benzoxazosine (intermediate D6), similar to the preparation of intermediate N.

[0231] Intermediate Q (18S,24S)-24-amino-28-hydroxy-(11M)-11-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-14,14-dimethyl-7,16-dioxa-10,22,31-triazahexacyclo[24.3.1.1 2,6 .1 18,22 .0 4,12 .0 5,10 ] Dotriaconta-1(29),2,4,6(32),11,26(30),27-Heptaen-17,23-Zeon TIFF2026515652000080.tif52170

[0232] The title compound was prepared by using 7-bromo-5-iodo-3,4-dihydro-2H-1,4-benzoxazine (intermediate D2) instead of 9-bromo-7-iodo-3,4,5,6-tetrahydro-2H-1,6-benzoxazosine (intermediate D6), similar to the preparation of intermediate N.

[0233] Intermediate R (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazine-1-yl)-3-pyridyl]-17,17,23,23-tetramethyl-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriakonta-1(28),2,5(31),19,25(29),26-Hexaene-8,14-Zione TIFF2026515652000081.tif56170

[0234] The title compound was prepared in the same manner as the preparation of intermediate E, by using 6-bromo-8-iodo-3,3-dimethyl-2,4-dihydro-1H-quinoline (intermediate D8) instead of 6-bromo-8-iodo-1,2,3,4-tetrahydroquinoline (intermediate D1).

[0235] Example 1 (3S)-1-[(2R)-2-chloro-2-fluoroacetyl]-N-[(1S)-1-[[(20S,26S)-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-19,25-dioxo-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 Tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaen-26-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide TIFF2026515652000082.tif56170

[0236] The compound was prepared according to the following scheme: JPEG2026515652000083.jpg164170

[0237] Step 2: tert-butyl N-[(1S)-1-[[(20S,26S)-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-19,25-dioxo-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 Preparation of tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaen-26-yl]carbamoyl]-2-methyl-propyl]-N-methyl-carbamate (compound 1c) HATU (63.1 mg, 0.17 mmol) was added to a solution of DIEA (70 μL, 0.41 mmol, 3.0 equivalents) and Boc-N-Me-Val-OH (compound 1b, 30.4 mg, 0.15 mmol) in DMF (2.5 mL). After stirring for 10 minutes, (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 A solution of tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaene-19,25-dione (intermediate N) (110.0 mg, 0.14 mmol) in DMF (2.5 mL) was added. The resulting mixture was stirred at 20°C for 2 hours. After the reaction was complete, the reaction mixture was purified by preparative HPLC and tert-butylN-[(1S)-1-[[(20S,26S)-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-19,25-dioxo-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12Tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaen-26-yl]carbamoyl]-2-methyl-propyl]-N-methyl-carbamate (compound 1c, 115 mg) was obtained as a yellow solid. MS calculation value 895.5 (MH) + ), measured value 895.5 (MH) + ).

[0238] Step 2: (2S)-N-[(20S,26S)-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-19,25-dioxo-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 Preparation of tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaen-26-yl]-3-methyl-2-(methylamino)butanamide (compound 1d) tert-butyl N-[(1S)-1-[[(20S,26S)-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-19,25-dioxo-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12To a solution of tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaen-26-yl]carbamoyl]-2-methyl-propyl]-N-methyl-carbamate (compound 1c, 115 mg, 0.13 mmol) in DCM (8 mL), TFA (2.0 mL, 2 mmol) was added at 0°C. After stirring at 20°C for 1 hour, the reaction mixture was concentrated under vacuum, diluted with saturated NaHCO3 (10 mL), and extracted with Depositphotos (20 mL, 3 times). Wash the combined organic layers with brine (10 mL), dry with Na2SO4, filter, and concentrate under vacuum to obtain (2S)-N-[(20S,26S)-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-19,25-dioxo-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 Tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaen-26-yl]-3-methyl-2-(methylamino)butanamide (compound 1d, 95.0 mg) was obtained as a yellow solid. MS calculation value: 795.4 (MH) + ), measured value 795.4 (MH) + ).

[0239] Step 3: tert-butyl(3S)-3-[[(1S)-1-[[(20S,26S)-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-19,25-dioxo-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 Preparation of tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaen-26-yl]carbamoyl]-2-methyl-propyl]-methylcarbamoyl]pyrrolidine-1-carboxylate (compound 1f) (3S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (compound 1e, 59.6 mg, 0.28 mmol), DIEA (0.1 mL, 0.55 mmol), and HATU (115.75 mg, 0.3 mmol) are dissolved in DMF (2 mL) and (2S)-N-[(20S,26S)-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-19,25-dioxo-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 Tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaen-26-yl]-3-methyl-2-(methylamino)butanamide (compound 1d, 110.0 mg, 0.14 mmol) was added. After stirring at 20°C for 1 hour, the reaction mixture was concentrated under vacuum to obtain the residue. The residue was purified by reverse-phase chromatography to obtain tert-butyl(3S)-3-[[(1S)-1-[[(20S,26S)-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-19,25-dioxo-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 Tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaen-26-yl]carbamoyl]-2-methyl-propyl]-methyl-carbamoyl]pyrrolidine-1-carboxylate (compound 1f, 95.0 mg) was obtained as a yellow solid. MS calculation value 992.5 (MH) + ), measured value 892.5 (M-Boc+H + ).

[0240] Step 4: (3S)-N-[(1S)-1-[[(20S,26S)-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-19,25-dioxo-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 Preparation of tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaen-26-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide (1 g of compound) tert-butyl(3S)-3-[[(1S)-1-[[(20S,26S)-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-19,25-dioxo-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 To a solution of tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaen-26-yl]carbamoyl]-2-methyl-propyl]-methyl-carbamoyl]pyrrolidine-1-carboxylate (compound 1f, 95.0 mg, 0.1 mmol) in DCM (8 mL), TFA (2.0 mL, 11.48 mmol) was added. The reaction mixture was stirred at 20°C for 0.5 hours. The mixture was concentrated under vacuum, diluted with saturated NaHCO3 (10 mL), and extracted with Âr (20 mL, 3 times). Wash the combined organic layers with brine (10 mL), dry with Na2SO4, filter, and concentrate under vacuum to obtain (3S)-N-[(1S)-1-[[(20S,26S)-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-19,25-dioxo-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12Tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaen-26-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide (compound 1g, 65.0mg) was obtained as a yellow solid. MS calculation value 892.5 (MH) + ), measured value 446.9 (M / 2+H + ).

[0241] Step 5: (3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(20S,26S)-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-19,25-dioxo-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 Preparation of tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaen-26-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide (Example 1) (2R)-2-chloro-2-fluoroacetic acid (compound 1h, 13.8 mg, 0.12 mmol), (3S)-N-[(1S)-1-[[(20S,26S)-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-19,25-dioxo-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12To a solution of tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaen-26-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide (compound 1 g, 55.0 mg, 0.06 mmol) in DMF (1 mL), DIEA (30 μL, 0.18 mmol) and HATU (52.7 mg, 0.14 mmol) were added at 0°C. The mixture was stirred at 20°C for 2 hours. Depositphotos (20 mL) and water (20 mL) were added to the reaction mixture, and the layers were separated. The aqueous phase was extracted with Depositphotos (10 mL, twice). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, and concentrated under vacuum to obtain the residue. The residue was purified by preparative HPLC, and (3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(20S,26S)-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-19,25-dioxo-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 Tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaen-26-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide (Example 1, 15.9 mg) was obtained as a yellow solid. MS calculation value 986.5 (MH) + ), measured value 986.5 (MH) + ). 1¹H NMR (400 MHz, methanol-d4) δ = 8.87-8.82 (m, 1H), 8.61-8.51 (m, 1H), 8.17-8.09 (m, 1H), 7.97-7.85 (m, 1H), 7.82-7.70 (m, 1H), 7.60-7.48 (m, 1H), 7.33-7.25 (m, 1H), 7.09-7.01 (m, 1H) ,6.76-6.26(m,1H),4.75-4.70(m,1H),4.53-4.42(m,1H),4.37-4.16(m,1H),3.90-3 .83(m,2H),3.81-3.75(m,2H),3.68-3.63(m,1H),3.60-3.54(m,1H),3.28-3.25(m,1 H),3.21-3.17(m,3H),3.16-3.11(m,1H),3.10-3.00(m,2H),2.97-2.92(m,1H),2.89 (s,1H),2.88-2.85(m,1H),2.42-2.24(m,1H),2.23-2.18(m,1H),1.89-1.79(m,1H), 1.69-1.65(m,5H),1.54-1.50(m,4H),1.46-1.39(m,2H)1.38-1.26(m,5H),1.09-1.0 0(m,3H),0.99-0.89(m,5H),0.88-0.86(m,2H),0.84-0.82(m,2H),0.79-0.74(m,3H).

[0242] Example 2 (3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(19S,25S)-29-hydroxy-(12M)-12-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-15,15-dimethyl-18,24-dioxo-7,17-dioxa-11,23,32-triazahexacyclo[25.3.1.1 2,6 .1 19,23 .0 4,13 .0 5,11 [Tritriaconta-1(30),2,4,6(33),12,27(31),28-heptaen-25-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide The compound described in TIFF2026515652000084.tif48170 was prepared in the same manner as in Example 1: (19S,25S)-25-amino-29-hydroxy-(12M)-12-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-15,15-dimethyl-7,17-dioxa-11,23,32-triazahexacyclo[25.3.1.1 2,6 .1 19,23 .0 4,13 .0 5,11 ]Tritriaconta-1(30),2,4,6(33),12,27(31),28-heptaene-18,24-dione (intermediate O) is converted to (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 It was prepared by using tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaene-19,25-dione (intermediate N) as a substitute. Example 2 (15.9 mg) was obtained as a yellow solid. MS calculation value 972.4 (MH) + ), measured value 972.4 (MH) +). ¹H NMR (400 MHz, methanol-d4) δ=8.89-8.79(m,¹H),8.33-8.21(m,¹H),7.92-7.81(m,¹H),7.75-7.66(m,¹H),7.47-7.36(m,¹H),7.29-7.13(m,¹H),7.11-6.98(m,¹H),6.93-6.71(m,¹H),6.54-6.44(m,¹H),5.66-5.53(m,¹H),4.72(d,J=11.1 Hz,1H),4.61-4.38(m,3H),4.15-4.04(m,1H),4.03-3.91(m,1H),3.90-3.75(m,3H),3.74-3 .63(m,3H),3.62-3.43(m,3H),3.15-3.04(m,1H),2.96-2.91(m,3H),2.84-2.73(m,2H),2.44 -2.26(m,3H),2.22-2.17(m,1H),2.14-2.00(m,2H),1.98-1.87(m,1H),1.82-1.57(m,2H),1. 51-1.47(m,3H),1.40-1.23(m,5H),0.99-0.90(m,3H),0.87-0.78(m,6H),0.76-0.63(m,3H).

[0243] Example 3 1-[(2R)-2-chloro-2-fluoro-acetyl]-4-fluoro-N-[(1S)-1-[[(19S,25S)-29-hydroxy-(12M)-12-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-15,15-dimethyl-18,24-dioxo-7,17-dioxa-11,23,32-triazahexacyclo[25.3.1.1 2,6 .1 19,23 .0 4,13 .0 5,11 [Tritriaconta-1(30),2,4,6(33),12,27(31),28-heptaen-25-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide The compound described in TIFF2026515652000085.tif48170 was prepared in the same manner as in Example 1: (19S,25S)-25-amino-29-hydroxy-(12M)-12-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-15,15-dimethyl-7,17-dioxa-11,23,32-triazahexacyclo[25.3.1.1 2,6 .1 19,23 .0 4,13 .0 5,11 ]Tritriaconta-1(30),2,4,6(33),12,27(31),28-heptaene-18,24-dione (intermediate O) and 1-tert-butoxycarbonyl-4-fluoropiperidine-4-carboxylic acid are (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 This was prepared by using tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaene-19,25-dione (intermediate N) and (3S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (compound 1e) as substitutes. Example 3 (2.4 mg) was obtained as a yellow solid. MS calculation value 1004.4 (MH) + ), measured value 1004.5 (MH) + ).

[0244] Example 4 (3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(18S,24S)-28-hydroxy-(11M)-11-[(3R)-2-[(1S)-1-methoxyethyl]-2,3-dihydropyridine-3-yl]-14,14-dimethyl-17,23-dioxo-16-oxa-10,22,31-triazahexacyclo[24.3.1.1 2,6 .1 18,22 .0 4,12 .0 5,10]dotriaconta-1(29),2,4,6(32),11,26(30),27-heptaen-24-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide The compound described in TIFF2026515652000086.tif43170 was prepared in the same manner as in Example 1: (18S,24S)-24-amino-28-hydroxy-(11M)-11-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-14,14-dimethyl-16-oxa-10,22,31-triazahexacyclo[24.3.1.1 2,6 .1 18,22 .0 4,12 .0 5,10 ]dotriaconta-1(29),2,4,6(32),11,26(30),27-heptaene-17,23-dione (intermediate P) is converted to 20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 It was prepared by using tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaene-19,25-dione (intermediate N) as a substitute. Example 4 (10.9 mg) was obtained as a yellow solid. MS calculation value 956.4 (MH) + ), measured value 956.4 (MH) +). 1H NMR (400 MHz, methanol-d4) δ=8.87-8.80(m,1H),8.32-8.15(m,1H),7.91-7.79(m,2H),7.37(d,J=13.6 Hz,2H),7.08-6.99(m,1H),6.89-6.70(m,1H),6.59-6.42(m,1H),5.67-5.46(m,1H),4.77-4.65(m,1H),4.59-4.41(m,2H),3.99(d,J=10.4 Hz,1H),3.93-3.81(m,3H),3.81-3.65(m,5H),3.57-3.49(m,1H),3.28-3.19(m,1H),3.13-3.03(m,3H),3.02-2.81( m,6H),2.79-2.71(m,2H),2.37-2.23(m,3H),2.20-2.06(m,3H),2.05-1.90(m,2H),1.75-1.58(m,2H),1.50(d,J=6.4 Hz,3H),0.96-0.72(m,12H).

[0245] Example 5 (3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(18S,24S)-28-hydroxy-(11M)-11-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-14,14-dimethyl-17,23-dioxo-7,16-dioxa-10,22,31-triazahexacyclo[24.3.1.1 2,6 .1 18,22 .0 4,12 .0 5,10 Dotriaconta-1(29),2,4,6(32),11,26(30),27-heptaen-24-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide The compound described in TIFF2026515652000087.tif49170 was prepared in the same manner as in Example 1: (18S,24S)-24-amino-28-hydroxy-(11M)-11-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-14,14-dimethyl-7,16-dioxa-10,22,31-triazahexacyclo[24.3.1.1 2,6 .1 18,22 .04,12 .0 5,10 ]dotriaconta-1(29),2,4,6(32),11,26(30),27-heptaene-17,23-dione (intermediate Q) is converted to (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 It was prepared by using tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaene-19,25-dione (intermediate N) as a substitute. Example 5 (10.3 mg) was obtained as a white solid. MS calculation value 958.4 (MH) + ), measured value 958.4 (MH) + ). 1H NMR(400 MHz, methanol-d4)δ=8.78(d,J=4.0Hz,1H),8.14-8.02(m,1H),7.74-7.65(m,1H),7.64-7.56(m,1H),7.33(s,1H),7.08-6.85(m,3H),6.64-6.43(m, 1H),5.63-5.51(m,1H),4.61-4.58(m,2H),4.49-4.40(m,1H),4.25-3.93 (m,2H),3.85-3.77(m,3H),3.76-3.69(m,3H),3.67-3.52(m,2H),3.06-3 .00(m,1H),2.98-2.93(m,3H),2.92-2.89(m,1H),2.88-2.82(m,1H),2. 80(s,3H),2.38-2.12(m,4H),1.97-1.92(m,1H),1.83-1.70(m,1H),1.68 -1.55(m,2H),1.50(d,J=6.0Hz,3H),1.41-1.25(m,2H),1.19-1.06(m,1H ),1.00-0.92(m,3H),0.91(s,3H),0.87-0.82(m,3H),0.56-0.68(m,3H).

[0246] Example 6 (3S)-1-[(2R)-2-chloro-2-fluoroacetyl]-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide The compound described in TIFF2026515652000088.tif54170 was prepared in the same manner as in Example 1: (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaene-8,14-dione (intermediate E) is converted to (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 It was prepared by using tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaene-19,25-dione (intermediate N) as a substitute. Example 6 (11.5 mg) was obtained as a yellow solid. MS calculation value 1045.5 (MH) + ), measured value 1045.5 (MH) +). 1H NMR(400 MHz, methanol-d4)δ=8.50-8.45(m,1H),8.42-8.34(m,1H),7.54-7.39(m,3H),6.94-6.72(m,1H),5.83-5.55(m,1H),4.49 -4.39(m,2H),4.31-4.12(m,3H),3.83-3.72(m,5H),3.64-3.52(m,4H),3.41-3.34(m,5H),3.12-3.06(m,4H),3.00-2.9 6(m,4H),2.89-2.67(m,2H),2.63-2.54(m,1H),2.39-2.14(m,7H),2.11-2.03(m,1H),1.98-1.90(m,1H),1.85-1.73(m, 1H),1.70-1.53(m,2H),1.47-1.43(m,3H),1.35-1.26(m,4H),1.01-0.92(m,6H),0.89-0.84(m,3H),0.60-0.50(m,3H).

[0247] Example 7 (2S)-2-[2-[(2R)-2-chloro-2-fluoroacetyl]-5-oxo-2,6-diazaspiro[3.4]octan-6-yl]-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazine-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]-3-methyl-butanamide The compound TIFF2026515652000089.tif58170 was prepared according to the following scheme: JPEG2026515652000090.jpg142170

[0248] Step 1: tert-butyl6-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 Preparation of ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]carbamoyl]-2-methyl-propyl]-5-oxo-2,6-diazaspiro[3.4]octane-2-carboxylate (compound 7a) (2S)-2-(2-tert-butoxycarbonyl-5-oxo-2,6-diazaspiro[3.4]octan-6-yl)-3-methylbutanoic acid (intermediate A1, 50.0 mg, 0.15 mmol) in DMF (1 mL) is mixed with DIEA (110 μL, 0.62 mmol), HATU (60.0 mg, 0.16 mmol), and (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5 -[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]henthriaconta-1(28),2,5(31),19,25(29),26-hexaen-8,14-dione (intermediate G, 50.0 mg, 0.06 mmol) was added. The mixture was stirred at 25°C for 1 hour. The reaction mixture was poured into water (40 mL) and extracted with ELISA (20 mL, 3 times). The combined organic layers were washed with brine (30 mL, 3 times), dried on Na2SO4, filtered, and concentrated under vacuum to obtain the residue, which was then purified by column chromatography to obtain tert-butyl6-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 [Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]carbamoyl]-2-methyl-propyl]-5-oxo-2,6-diazaspiro[3.4]octane-2-carboxylate (compound 7a, 50.0 mg) was obtained as a grayish-white solid. MS calculation value 1117.5 (MH) + ), measured value 1117.5 (MH) + ).

[0249] Step 2: (2S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 Preparation of ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]-3-methyl-2-(5-oxo-2,6-diazaspiro[3.4]octan-6-yl)butanamide (compound 7b) tert-butyl6-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 To a solution of ]Hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-5-oxo-2,6-diazaspiro[3.4]octan-2-carboxylate (compound 7a, 50.0 mg, 0.04 mmol) in DCM (0.5 mL), TFA (0.5 mL, 6.49 mmol) was added, and the mixture was stirred at 25°C for 1 hour. After the reaction was complete, saturated NaHCO3 aqueous solution (40 mL) was added to the reaction mixture, and the mixture was extracted with  (30 mL, 3 times). The combined organic layers were washed with brine (30 mL), dried on Na2SO4, filtered, and concentrated under vacuum to obtain (2S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]-3-methyl-2-(5-oxo-2,6-diazaspiro[3,4]octan-6-yl)butanamide (compound 7b, 45.0 mg) was obtained as a grayish-white solid and was used in the next step without further purification. MS calculation value 1017.5 (MH) + ), measured value 1017.7 (MH) + ).

[0250] Step 3: (2S)-2-[2-[(2R)-2-chloro-2-fluoroacetyl]-5-oxo-2,6-diazaspiro[3.4]octan-6-yl]-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 Preparation of Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]-3-methylbutanamide (Example 7) (2S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26To a solution of ]Hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]-3-methyl-2-(5-oxo-2,6-diazaspiro[3.4]octan-6-yl)butanamide (compound 7b, 45.0 mg, 0.04 mmol) in DMF (1 mL), DIEA (80 μL, 0.46 mmol), (2R)-2-chloro-2-fluoroacetic acid (compound 1h, 26.3 mg, 0.23 mmol) and T3P (146.3 mg, 0.23 mmol) were added, and the mixture was stirred at 25°C for 1 hour. After the reaction was complete, the reaction mixture was poured into water (20 mL) and extracted with ELISA (20 mL, 3 times). The combined organic layers were washed with brine (30 mL, 3 times), dried over Na2SO4, filtered, concentrated under reduced pressure to obtain a residue, which was purified by preparative HPLC to obtain (2S)-2-[2-[(2R)-2-chloro-2-fluoroacetyl]-5-oxo-2,6-diazaspiro[3.4]octan-6-yl]-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 Hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]-3-methyl-butanamide (Example 7, 12.3 mg) was obtained as a yellow solid. MS calculation value 1111.5 (MH) + ), measured value 1111.5 (MH) + ). 1H NMR(400 MHz, methanol-d4)δ=8.47-8.34(m,2H),7.78-7.72(m,1H),7.56-7.41(m,2H),6.76-6.58(m,1H),5.83-5.7 1(m,1H),4.57-4.50(m,1H),4.44-4.29(m,3H),4.26-4.04(m,3H),3.80-3.62(m,3H),3.52-3.36(m,10H ),3.29-3.24(m,1H),3.23-2.96(m,6H),2.92-2.85(m,4H),2.83-2.76(m,1H),2.71-2.62(m,1H),2.41- 2.28(m,3H),2.24-2.15(m,3H),1.99-1.90(m,1H),1.86-1.72(m,1H),1.67-1.56(m,1H),1.47(d,J=6.4 Hz,3H),1.36-1.26(m,1H),1.03-0.96(m,6H),0.87(dd,J=2.0,6.4 Hz,3H),0.63-0.56(m,3H).

[0251] Example 8 (2S)-2-(2-buta-2-inoyl-5-oxo-2,6-diazaspiro[3.4]octan-6-yl)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]-3-methyl-butanamide The title compound was prepared in the same manner as in Example 7 by using buta-2-ic acid instead of (2R)-2-chloro-2-fluoroacetic acid (compound 1h). Example 8 (38 mg) was obtained as a yellow solid. MS calculation value 1083.5 (MH) + ), measured value 1083.6 (MH) +). 1 ¹H NMR (400 MHz, methanol-d4) δ = 8.44 (s, 1H), 8.36 (s, 1H), 7.91-7.84 (m, 1H), 7.54-7.44 (m, 2H), 5.82-5.71 (m, 1H), 4.60-4.52 (m, 1H), 4.44-4.36 (m, 2H), 4.35-4.29 (m, 1H), 4.27-4.09 (m, 4H), 3.97-3.91 (m, 1H), 3.81-3.71 (m ,2H),3.71-3.63(m,1H),3.54-3.46(m,5H),3.46-3.36(m,5H),3.27-3.07(m,5H),3.05-2.96(m,1H),2.9 1-2.85(m,4H),2.84-2.74(m,1H),2.72-2.64(m,1H),2.37-2.28(m,3H),2.25-2.15(m,3H),2.03(d,J=4.4 Hz,3H),1.98-1.90(m,1H),1.84-1.73(m,1H),1.68-1.56(m,1H),1.48(d,J=6.4 Hz,3H),1.04-0.96(m,6H),0.89-0.84(m,3H),0.61(s,3H).

[0252] Example 9 (2S)-2-[2-[(2R)-2-chloro-2-fluoroacetyl]-5-oxo-2,6-diazaspiro[3.4]octan-6-yl]-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]-3-methyl-butanamide The compound described in TIFF2026515652000092.tif57170 was prepared in the same manner as in Example 7: (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 This was prepared by using ]henthriaconta-1(28),2,5(31),19,25(29),26-hexaen-8,14-dione (intermediate F) instead of (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]henthriaconta-1(28),2,5(31),19,25(29),26-hexaen-8,14-dione (intermediate G). Example 9 (30.1 mg) was obtained as a yellow solid. MS calculation value: 1030.4 (MH) + ), measured value 1030.5 (MH) + ). 1H NMR (400 MHz, methanol-d4)δ=8.44(s,1 H)8.36(d,J=2.40 Hz,1 H),7.85(d,J=2.4 Hz,1 H),7.55-7.43(m,2 H),6.68(dd,J=49.2,2.4 Hz,1 H),5.85-5.71(m,1 H),4.62-4.51(m,2 H),4.47-4.01(m,8 H),3.87(t,J=4.8 Hz,4 H),3.82-3.72(m,2 H),3.71-3.62(m,1 H),3.60-3.48(m,1 H),3.46-3.37(m,8 H),3.29-3.24(m,1 H),3.16-2.97(m,3 H),2.85-2.65(m,2 H),2.43-2.28(m,3 H),2.27-2.15(m,3 H),2.00-1.91(m,1 H),1.89-1.71(m,1 H),1.69-1.55(m,1 H),1.48(d,J=6.4 Hz,3 H),1.05-0.95(m,6 H),0.87(dd,J=6.80,2.80 Hz,3 H),0.62(d,J=4.0 Hz,3 H).

[0253] Example 10 (2S)-2-(2-buta-2-inoyl-5-oxo-2,6-diazaspiro[3.4]octan-6-yl)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]-3-methyl-butanamide The compound described in TIFF2026515652000093.tif58170 was prepared in the same manner as in Example 7: (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-8,14-dione (intermediate F) and buta-2-ic acid (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-15- It was prepared by using oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]henthriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (intermediate G) and (2R)-2-chloro-2-fluoroacetic acid (compound 1h) as substitutes. Example 10 (43.6 mg) was obtained as a yellow solid. MS calculation value 1002.5 (MH) + ), measured value 1002.5 (MH) + ). 1H NMR (400 MHz, methanol-d4) δ=8.44(s,1H),8.40-8.33(m,1H),7.85(dd,J=5.6,3.2 Hz,1H),7.52(d,J=10.8 Hz,1H),7.46(d,J=2.0 Hz,1H),5.82-5.73(m,1H),4.61-4.52(m,1H),4.47-4.37(m,2H),4.33(d,J=11.2 Hz,1H),4.28-4.10(m,4H),4.01-3.94(m,1H),3.87(t,J=4.80 Hz,4H),3.82-3.73(m,2H),3.71-3.61(m,1H),3.60-3.48(m,1H),3.47-3.38(m,9H),3.29-3.24(m,1H),3. 17-2.98(m,3H),2.86-2.75(m,1H),2.74-2.63(m,1H),2.41-2.28(m,3H),2.26-2.12(m,3H),2.04(d,J=4.0 Hz,3H),2.00-1.90(m,1H),1.88-1.72(m,1H),1.70-1.56(m,1H),1.49(d,J=6.00 Hz,3H),1.06-0.96(m,6H),0.88(d,J=6.4 Hz,3H),0.61(s,3H).

[0254] Example 11 (2S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]-3-methyl-2-(5-oxo-2-propa-2-enoyl-2,6-diazaspiro[3,4]octan-6-yl)butanamide TIFF2026515652000094.tif56170 The title compound was prepared in the same manner as in the preparation of Example 7, (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-8,14-dione (Intermediate F) and acrylic acid were used instead of (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-8,14-dione (Intermediate G) and (2R)-2-chloro-2-fluoro-acetic acid (Compound 1h). Example 11 (21.6 mg) was obtained as a yellow solid. MS calculated value 990.5 (MH + ), measured value 990.5 (MH + ). 11H NMR (400 MHz, methanol-d4) δ = 8.44 (s, 1H), 8.37 (s, 1H), 7.81 - 7.71 (m, 1H), 7.53 (d, J = 18.8 Hz, 1H), 7.46 (d, J = 6.4 Hz, 1H), 6.41 - 6.26 (m, 2H), 5.81 - 5.74 (m, 2H), 4.57 - 4.13 (m, 9H), 4.02 (d, J = 10.0 Hz, 1H), 3.86 (t, J = 4.4 Hz, 4H), 3.81 - 3.47 (m, 5H), 3.45 - 3.38 (m, 9H), 3.14 - 3.01 (m, 3H), 2.84 - 2.76 (m, 1H), 2.71 - 2.63 (m, 1H), 2.42 - 2.31 (m, 3H), 2.25 - 2.16 (m, 3H), 1.95 - 1.60 (m, 3H), 1.48 (d, J = 6.4 Hz, 3H), 1.02 - 0.98 (m, 5H), 0.89 - 0.85 (m, 3H), 0.63 - 0.56 (m, 3H).

[0255] Example 12 (3S)-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraazacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-1-(4-morpholinobut-2-inoyl)pyrrolidine-3-carboxamide TIFF2026515652000095.tif5 The title compound was prepared in the same manner as in Example 1 from (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31-tetraazacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaene-8,14-dione (intermediate F) and 4-Molfolinbuta-2-ic acid (CAS 38346-95-1,SY291865-5g,Accela ChemBio Co.,Ltd.) are (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 It was prepared by using tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaene-19,25-dione (intermediate N) and (2R)-2-chloro-2-fluoroacetic acid (compound 1h) as substitutes. Example 12 (29.1 mg) was obtained as a yellow solid. MS calculation value 1089.6 (MH) + ), measured value 1089.6 (MH) + ). 1 ¹H NMR (400 MHz, methanol-d4) δ = 8.63-8.43 (m, 1H), 8.37 (s, 1H), 7.83-7.62 (m, 1H), 7.51 (d, J=10.4 Hz, 1H), 7.45 (d, J=7.6 Hz,1H),5.81-5.60(m,1H),4.82-4.77(m,3H),4.57-4.49(m,1H),4.45-4.39(m,1H),4.34-4.08(m,4H),4.07- 3.90(m,4H),3.90-3.84(m,5H),3.84-3.78(m,2H),3.76(s,2H),3.72-3.57(m,5H),3.46-3.37(m,8H),3.15-3. 08(m,5H),3.05-2.97(m,2H),2.85-2.76(m,1H),2.69-2.61(m,1H),2.37-2.18(m,6H),1.99-1.92(m,1H),1.8 6-1.76(m,1H),1.69-1.60(m,1H),1.52-1.44(m,3H),1.09-0.97(m,6H),0.94-0.85(m,3H),0.67-0.52(m,3H).

[0256] Example 13 (2S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]-3-methyl-2-(5-oxo-2-propa-2-enoyl-2,6-diazaspiro[3,4]octan-6-yl)butanamide The title compound was prepared in the same manner as in Example 7 by using acrylic acid instead of (2R)-2-chloro-2-fluoroacetic acid (compound 1h). Example 13 (9.5 mg) was obtained as a yellow solid. MS calculation value 1071.5 (MH) + ), measured value 1071.5 (MH) + ). 1H NMR (400 MHz, methanol-d4) δ=8.45(s,1H),8.36(s,1H),7.91(d,J=2.4 Hz,1H),7.57-7.46(m,2H),6.40-6.24(m,2H),5.82-5.74(m,2H),4.60-4.53(m,1H),4.5 1-4.39(m,2H),4.33-4.31(m,1H),4.30-4.21(m,3H),4.15-4.09(m,1H),4.01(d,J=10.0 Hz,1H),3.81-3.73(m,2H),3.70-3.63(m,1H),3.53-3.49(m,4H),3.45(d,J=5.6 Hz,3H),3.40(s,1H),3.29-3.24(m,1H),3.22-3.14(m,3H),3.13-3.09(m,1H),3.08-3.02(m,1H),2.91-2.87(m,4H),2.83-2.76(m,1 H),2.72-2.66(m,1H),2.40-2.30(m,3H),2.25-2.17(m,3H),1.98-1.91(m,1H),1.85-1.74(m,1H),1.66-1.58(m,1H),1.49(d,J=6.4 Hz,3H),1.37-1.27(m,2H),1.03-0.97(m,6H),0.87(d,J=6.4 Hz,3H),0.62(d,J=6.0 Hz,3H).

[0257] Example 14 (2S)-2-(2-buta-2-inoyl-5-oxo-2,6-diazaspiro[3.4]octan-6-yl)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazine-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]-3-methyl-butanamide The compound described in TIFF2026515652000097.tif60170 was prepared in the same manner as in Example 7: (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-8,14-dione (intermediate E) and buta-2-ic acid (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-15- It was prepared by using oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]henthriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (intermediate G) and (2R)-2-chloro-2-fluoroacetic acid (compound 1h) as substitutes. Example 14 (21 mg) was obtained as a yellow solid. MS calculation value 1015.5 (MH) + ), measured value 1015.5 (MH) +). 1H NMR (400 MHz, methanol-d4) δ=8.48(d,J=2.8 Hz,1H),8.41(s,1H),7.62(t,J=3.2 Hz,1H),7.51(d,J=12.0 Hz,1H),7.44(s,1H),5.80-5.68(m,1H),4.52-4.47(m,1H),4.44-4.38(m,2H),4.35-4.31(m,1H)4.30-4.11(m,5H)3.97(d,J=10.0 Hz,1H),3.81-3.67(m,3H),3.64-3.49(m,4H),3.48-3.33(m,8H),3.14-3.07(m,2H),3. 02-2.95(m,4H),2.84-2.77(m,1H),2.64-2.56(m,1H),2.42-2.10(m,7H),2.04(d,J=4.4 Hz,3H),1.98-1.92(m,1H),1.84-1.74(m,1H),1.66-1.57(m,1H),1.46(d,J=6.4 Hz,3H),1.37-1.24(m,1H),1.03-0.96(m,6 H),0.87(d,J=6.4 Hz,3H),0.55(s,3H).

[0258] Example 15 4-Fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-1-propa-2-enoylpiperidine-4-carboxamide The compound described in TIFF2026515652000098.tif51170 was prepared in the same manner as in Example 1: (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaene-8,14-dione (intermediate F), 1-tert-butoxycarbonyl-4-fluoropiperidine-4-carboxylic acid and acrylic acid, (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 This was prepared by substituting tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaene-19,25-dione (intermediate N), (3S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (compound 1e), and (2R)-2-chloro-2-fluoroacetic acid (compound 1h). Example 15 (13.4 mg) was obtained as a yellow solid. MS calculation value 1024.5 (MH) + ), measured value 1024.5 (MH) + ). 1H NMR (400 MHz, methanol-d4) δ=8.43(s,1H),8.37(d,J=2.8 Hz,1H),7.85(s,1H),7.56-7.38(m,2H),7.09-6.62(m,1H),6.25(d,J=17.2 Hz,1H),6.09-5.44(m,2H),4.73(d,J=11.2 Hz,1H),4.58-4.52(m,1H),4.49-4.34(m,2H),4.28-4.18(m,1H),4.17-4.03(m,2H),3.86(t,J=4.4 Hz,4H),3.81-3.71(m,2H),3.71-3.63(m,1H),3.56-3.47(m,1H),3.46-3.33(m,8H),3.29-3.23(m,1H),3.18(br d,J=5.2 Hz,3H),3.15-3.07(m,2H),3.04-3.00(m,1H),2.86-2.74(m,1H),2.69(d,J=14.0 Hz,1H),2.41-2.09(m,8H),1.99-1.90(m,1H),1.84-1.72(m,1H),1.66-1.58(m,1H),1.48(d,J=6.4 Hz,3H),1.40-1.26(m,2H),1.02-0.96(m,5H),0.95-0.86(m,3H),0.61(s,3H).

[0259] Example 16 1-Buta-2-inoyl-4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide The compound described in TIFF2026515652000099.tif51170 was prepared in the same manner as in Example 1: (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaene-8,14-dione (intermediate F), 1-tert-butoxycarbonyl-4-fluoropiperidine-4-carboxylic acid and buta-2-ic acid, (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 This was prepared by using tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaene-19,25-dione (intermediate N), (3S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (compound 1e), and (2R)-2-chloro-2-fluoroacetic acid (compound 1h) as substitutes. Example 16 (11.2 mg) was obtained as a yellow solid. MS calculation value 1036.5 (MH). + ), measured value 1036.4 (MH) + ), 1¹H NMR (400 MHz, methanol-d4) δ=8.43 (s, 1H), 8.37 (d, J=2.8 Hz, 1H), 7.86-7.76 (m, 1H), 7.52-7.44 (m, 2H), 5.88-5.64 (m, 1H), 4.77-4.68 (m, 1H), 4.56-4.51 (m, 1H), 4.45-4.31 (m, 3H), 4.26-4.20 (m, 1H), 4.18-4.10 (m, 1H), 3.86 (t, J=4.8 Hz,4H),3.80-3.73(m,2H),3.70-3.63(m,1H),3.60-3.51(m,1H),3.44-3.40(m,7H),3.35(s,1H),3.28-3.21(m,1H),3.18(t,J=5.2 Hz,3H),3.11-3.00(m,3H),2.86-2.76(m,1H),2.73-2.64(m,1H),2.31-2.10(m,7H),2.06(d,J=4.0 Hz,3H),1.98-1.91(m,1H),1.85-1.75(m,1H),1.66-1.59(m,1H),1.48(d,J=6.4 Hz,3H),1.35-1.28(m,3H),1.02-0.97(m,5H),0.91-0.85(m,3H),0.68-0.54(m,3H).

[0260] Example 17 cis-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-3-(3,3,3-trifluoropropane-1-inyl)cyclobutanecarboxamide The title compound of TIFF2026515652000100.tif55170 was prepared in the same manner as in the preparation of Example 1, (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate F) and cis-(2S)-3-methyl-2-[methyl-[3-(3,3,3-trifluoroprop-1-ynyl)cyclobutanecarbonyl]amino]butanoic acid (Intermediate A2) were used instead of (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaene-19,25-dione (Intermediate N) and Boc-N-Me-Val-OH (Compound 1b). Example 17 (21.4 mg) was obtained as a yellow solid. MS calculated value 1015.5 (MH + ), measured value 1015.5 (MH + ), 1H NMR (400 MHz, methanol-d4) δ=8.44(s,1H),8.36(d,J=2.8 Hz,1H),7.90-7.84(m,1H),7.47-7.41(m,2H),5.79-5.71(m,1H),4.94-4.90(m,1H),4.75(d,J=11.2 Hz,1H),4.60-4.51(m,1H),4.47-4.36(m,1H),4.28-4.19(m,1H),4.18-4.09(m,1H),3.86(t,J=4.8 Hz,4H),3.81-3.74(m,2H),3.70-3.64(m,1H),3.54-3.47(m,1H),3.45-3.43(m,5H) ,3.39-3.34(m,1H),3.28-3.24(m,1H),3.15-3.07(m,2H),3.05-2.98(m,1H),2.96- 2.91(m,3H),2.84-2.75(m,1H),2.73-2.62(m,3H),2.56-2.38(m,2H),2.35-2.29(m ,1H),2.25-2.16(m,3H),1.99-1.91(m,1H),1.85-1.74(m,1H),1.61(dd,J=3.6,12.4 Hz,1H),1.48(d,J=6.0 Hz,3H),1.36-1.27(m,2H),1.06-0.96(m,6H),0.85(d,J=6.4 Hz,3H),0.66-0.57(m,3H)

[0261] Example 18 1-[(2R)-2-chloro-2-fluoro-acetyl]-4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide The compound described in TIFF2026515652000101.tif56170 was prepared in the same manner as in Example 1: (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (intermediate F) and 1-tert-butoxycarbonyl-4-fluoropiperidine-4-carboxylic acid are (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 This was prepared by using tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaene-19,25-dione (intermediate N) and (3S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (compound 1e) as substitutes. Example 18 (11.2 mg) was obtained as a yellow solid. MS calculation value 1064.5 (MH) + ), measured value 1064.7 (MH) + ). 1H NMR (400 MHz, methanol-d4) δ=8.44(s,1H),8.37(d,J=3.2 Hz,1H),7.88-7.77(m,1H),7.51-7.43(m,2H),7.12-6.92(m,1H),5.85-5.67(m,1H),4.78-4.66(m,1H),4.54(t,J=6.4 Hz,1H),4.46-4.38(m,1H),4.37-4.28(m,1H),4.26-4.18(m,1H),4.17-4.08(m,1H),3.86(t,J=4.8 Hz,4H),3.80-3.73(m,2H),3.71-3.64(m,1H),3.56-3.47(m,1H),3.45-3.40(m,7H),3.38-3.34(m,1H),3.27-3.22(m,1H),3.17(t,J=5.6 Hz,3H),3.11-3.08(m,1H),3.06-2.97(m,2H),2.87-2.77(m,1H),2.73-2.65(m,1H),2. 41-2.11(m,8H),2.09-1.89(m,2H),1.83-1.73(m,1H),1.66-1.58(m,1H),1.48(d,J=6.4 Hz,3H),1.34-1.28(m,1H),1.23-1.04(m,1H),1.01-0.96(m,5H),0.91-0.83(m,3H),0.68-0.56(m,3H).

[0262] Example 19 (2S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]-3-methyl-2-(5-oxo-2-propa-2-enoyl-2,6-diazaspiro[3,4]octan-6-yl)butanamide The compound described in TIFF2026515652000102.tif53170 was prepared in the same manner as in Example 7: (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-8,14-dione (intermediate E) and acrylic acid (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazine-1-yl]-3-pyridyl]-17,17-dimethyl-15-ol It was prepared by using xa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]henthriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (intermediate G) and (2R)-2-chloro-2-fluoroacetic acid (compound 1h) as substitutes. Example 19 (5.2 mg) was obtained as a yellow solid. MS calculation value 1003.5 (MH) + ), measured value 1003.8 (MH) + ). 1H NMR (400 MHz, methanol-d4) δ=8.48(d,J=2.4 Hz,1H),8.41(s,1H),7.56-7.49(m,2H),7.43(d,J=6.4 Hz,1H),6.41-6.26(m,2H),5.78(dd,J=2.0,10.0 Hz,1H),5.76-5.66(m,1H),4.85-4.82(m,1H),4.55-4.36(m,4H),4.34(d,J=10.8 Hz,1H),4.31-4.16(m,5H),4.05-4.01(m,1H),3.76(s,2H),3.62-3.50(m,4H),3.46-3.42(m,2H),3.39(d,J=6.0 Hz,5H),3.16-3.05(m,3H),3.02-2.97(m,4H),2.83-2.77(m,1H),2.59(dd,J=7.2,14.0 Hz,1H),2.40-2.34(m,2H),2.33-2.27(m,1H),2.26-2.18(m,3H),1.96(d,J=14.8 Hz,1H),1.86-1.76(m,1H),1.67-1.60(m,1H),1.46(d,J=6.4 Hz,3H),1.34-1.29(m,1H),1.02-0.97(m,6H),0.90-0.86(m,3H),0.54(d,J=4.8 Hz,3H).

[0263] Example 20 (2S)-2-[2-[(2R)-2-chloro-2-fluoroacetyl]-5-oxo-2,6-diazaspiro[3.4]octan-6-yl]-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazine-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]-3-methyl-butanamide The title compound was prepared in the same manner as in Example 7: (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 This was prepared by using ]henthriaconta-1(28),2,5(31),19,25(29),26-hexaen-8,14-dione (intermediate E) in place of (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]henthriaconta-1(28),2,5(31),19,25(29),26-hexaen-8,14-dione (intermediate G). Example 19 (2.0 mg) was obtained as a yellow solid. MS calculation value: 1043.5 (MH) + ), measured value 1043.8 (MH) + ). 1¹H NMR (400 MHz, methanol-d4) δ=8.47 (d, J=2.8 Hz, 1H), 8.40 (s, 1H), 7.54-7.46 (m, 2H), 7.42 (d, J=10.0 Hz,1H),6.76-6.61(m,1H),5.80-5.69(m,1H),4.61-4.56(m,1H),4.51-4.42(m,2H),4.41-4.37(m,1H),4.35-4.3 2(m,1H),4.31-4.22(m,3H),4.10-4.05(m,1H),3.76(s,2H),3.62-3.50(m,4H),3.45-3.42(m,2H),3.38(d,J=4.8 Hz,4H),3.15-3.05(m,3H),2.99(s,3H),2.84-2.77(m,1H),2.63-2.56(m,1H),2.43-2.37(m,2H), 2.36-2.24(m,2H),2.24-2.17(m,3H),2.07-1.91(m,2H),1.85-1.76(m,1H),1.62(dd,J=4.0,13.2 Hz,1H),1.45(d,J=6.0 Hz,3H),1.35-1.28(m,4H),1.02-0.96(m,6H),0.88(dd,J=2.4,6.0 Hz,3H),0.54(d,J=2.8 Hz, 3H).

[0264] Example 21 cis-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-3-(3,3,3-trifluoropropane-1-inyl)cyclobutanecarboxamide The compound described in TIFF2026515652000104.tif57170 was prepared in the same manner as in Example 1: (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaene-8,14-dione (intermediate E) and cis-(2S)-3-methyl-2-[methyl-[3-(3,3,3-trifluoropropane-1-inyl)cyclobutanecarbonyl]amino]butanoic acid (intermediate A2) are (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 It was prepared by using tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaene-19,25-dione (intermediate N) and Boc-N-Me-Val-OH (compound 1b) as substitutes. Example 21 (22.0 mg) was obtained as a yellow solid. MS calculation value 1028.5 (MH) + ), measured value 1028.4 (MH) + ). 1¹H NMR (400 MHz, methanol-d4) δ=8.48 (d, J=2.8 Hz, 1H), 8.41 (s, 1H), 7.63-7.55 (m, 1H), 7.49-7.43 (m, 1H), 7.42-7.38 (m, 1H), 5.80-5.67 (m, 1H), 4.75 (d, J=10.8 Hz, 1H), 4.48 (q, J=6.0 Hz, 1H), 4.42 (d, J=11.6 Hz,1H),4.27-4.18(m,2H),4.12-3.96(m,1H),3.75(s,2H),3.63-3.55(m,2H),3.55-3.47(m,2H),3.46-3.42(m,1H),3.4 1-3.37(m,4H),3.29-3.18(m,3H),3.13-3.06(m,2H),2.98(s,4H),2.96-2.94(m,1H),2.93(s,2H),2.79(dt,J=3.2,12.8 Hz,1H),2.70-2.58(m,3H),2.54-2.42(m,2H),2.39-2.14(m,5H),1.95(d,J=13.2 Hz,1H),1.85-1.73(m,1H),1.67-1.56(m,1H),1.46(d,J=6.0 Hz,3H),1.36-1.25(m,2H),1.05-0.96(m,6H),0.85(d,J=6.8 Hz,3H),0.55(s,3H).

[0265] Example 22 (2S)-2-[2-(2-fluoropropanenoyl)-5-oxo-2,6-diazaspiro[3.4]octan-6-yl]-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]-3-methyl-butanamide The compound described in TIFF2026515652000105.tif56170 was prepared in the same manner as in Example 7: (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-8,14-dione (intermediate F) and 2-fluoropropane-2-enoic acid (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl It was prepared by using -15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]henthriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (intermediate G) and (2R)-2-chloro-2-fluoroacetic acid (compound 1h) as substitutes. Example 22 (19.7 mg) was obtained as a yellow solid. MS calculation value 1008.5 (MH) + ), measured value 1008.7 (MH) + ). 1H NMR (400 MHz, methanol-d4) δ=8.43(s,1H),8.36(d,J=2.4 Hz,1H),7.82-7.76(m,1H),7.55-7.43(m,2H),5.81-5.74(m,1H),5.66-5.51(m,1H),5.2 8-5.21(m,1H),4.64-4.59(m,1H),4.57-4.52(m,1H),4.45-4.39(m,2H),4.33(d,J=11.2 Hz,1H),4.30-4.23(m,2H),4.18-4.12(m,1H),4.05(d,J=10.4 Hz,1H),3.87(t,J=4.4 Hz,4H),3.80-3.73(m,2H),3.69-3.64(m,1H),3.58-3.46(m,2H),3.43(d,J=4.0 Hz,5H),3.41(s,3H),3.29-3.25(m,1H),3.16-3.11(m,1H),3.10-3.07(m,1H),3.06-2.99(m,1H),2.84-2.77(m,1H),2.71-2.65(m,1 H),2.40-2.36(m,2H),2.34-2.30(m,1H),2.24-2.16(m,3H),1.99-1.92(m,1H),1.84-1.77(m,1H),1.68-1.60(m,1H),1.48(d,J=6.4 Hz,3H),1.02-0.98(m,6H),0.87(dd,J=3.2,6.8 Hz, 3H), 0.63-0.58 (m, 3H).

[0266] Example 23 cis-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-3-(3,3,3-trifluoropropane-1-inyl)cyclobutanecarboxamide The title compound was prepared in the same manner as in Example 1: (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]henthriaconta-1(28),2, 5(31),19,25(29),26-Hexaene-8,14-dione (intermediate G) and cis-(2S)-3-methyl-2-[methyl-[3-(3,3,3-trifluoropropane-1-inyl)cyclobutanecarbonyl]amino]butanoic acid (intermediate A2) are converted to (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 It was prepared by using tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaene-19,25-dione (intermediate N) and Boc-N-Me-Val-OH (compound 1b) as substitutes. Example 23 (38.4 mg) was obtained as a yellow solid. MS calculation value 1096.5 (MH) + ), measured value 1096.5 (MH) + ). 1H NMR (400 MHz, methanol-d4)δ=8.43(s,1H),8.36(d,J=2.8 Hz,1H),7.80(d,J=2.8 Hz,1H),7.47-7.40(m,2H),5.82-5.71(m,1H),4.75(d,J=10.8 Hz,1H),4.53(q,J=6.0 Hz,1H),4.45-4.38(m,1H),4.23(dd,J=3.2,12.0 Hz,1H),4.18-4.11(m,1H),3.78-3.73(m,2H),3.70-3.65(m,1H),3.61(q,J=7.2 Hz,1H),3.49-3.46(m,4H),3.44-3.41(m,3H),3.28-3.25(m,1H),3.19-3.07(m,4H),3.04-2.99(m 1H),2.97-2.93(m,1H),2.92(s,2H),2.88(t,J=4.8 Hz,4H),2.83-2.76(m,1H),2.71-2.60(m,3H),2.54-2.41(m,2H),2.39-2.24(m,2H),2. 24-2.13(m,3H),1.99-1.91(m,1H),1.86-1.75(m,1H),1.67-1.58(m,1H),1.47(d,J=6.4 Hz,3H),1.34-1.24(m,1H),1.18(t,J=7.2 Hz,1H),1.08-1.02(m,1H),1.01-0.96(m,4H),0.88-0.83(m,3H),0.65-0.57(m,3H).

[0267] Example 24 4-Fluoro-1-(2-fluoropropa-2-enoyl)-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide The compound described in TIFF2026515652000107.tif60170 was prepared in the same manner as in Example 1: (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaene-8,14-dione (intermediate F), 1-tert-butoxycarbonyl-4-fluoropiperidine-4-carboxylic acid and 2-fluoropropa-2-enoic acid are (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 This was prepared by using tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaene-19,25-dione (intermediate N), (3S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (compound 1e), and (2R)-2-chloro-2-fluoroacetic acid (compound 1h) as substitutes. Example 24 (36.5 mg) was obtained as a yellow solid. MS calculation value 1042.5 (MH) + ), measured value 1042.4 (MH) + ). 1H NMR (400 MHz, methanol-d4) δ=8.43(s,1H),8.37(d,J=2.8 Hz,1H),7.80(s,1H),7.47(br d,J=15.2 Hz,2H),5.86-5.71(m,1H),5.33-5.25(m,1H),5.25-5.16(m,1H),4.73(d,J=11.2 Hz,1H),4.53(q,J=5.6 Hz,1H),4.42(br d,J=13.6 Hz,1H),4.23(dd,J=2.8,12.0 Hz,1H),4.17-4.11(m,1H),3.86(t,J=4.8 Hz,4H),3.77(d,J=2.4 Hz,1H),3.70-3.64(m,1H),3.61(q,J=6.0 Hz,3H),3.43-3.39(m,7H),3.28-3.23(m,1H),3.18(d,J=5.2 Hz,2H),3.15-3.07(m,2H),3.05-3.01(m,1H),2.85-2.76(m,1H),2.72-2.65(m,1H),2.36-2.24( m,3H),2.24-2.15(m,4H),1.99-1.91(m,1H),1.85-1.74(m,1H),1.68-1.59(m,1H),1.48(d,J=6.0 Hz,3H),1.35-1.28(m,2H),1.18(t,J=7.2 Hz,4H),1.01-0.96(m,5H),0.92-0.84(m,3H),0.61(s,3H).

[0268] Example 25 1-Buta-2-inoyl-4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide The title compound was prepared in the same manner as in Example 1: (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaene-8,14-dione (intermediate E), 1-tert-butoxycarbonyl-4-fluoropiperidine-4-carboxylic acid and buta-2-ic acid, (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 This was prepared by using tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaene-19,25-dione (intermediate N), (3S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (compound 1e), and (2R)-2-chloro-2-fluoroacetic acid (compound 1h) as substitutes. Example 25 (49.7 mg) was obtained as a yellow solid. MS calculation value 1049.5 (MH) + ), measured value 1049.8 (MH) + ). 1¹H NMR (400 MHz, methanol-d4) δ = 8.48 (s, 1H), 8.40 (s, 1H), 7.68-7.46 (m, 2H), 7.44-7.40 (m, 1H), 5.81-5.71 (m, 1H), 4.80-4.75 (m, 1H), 4.74-4.69 (m, 1H), 4.49-4.31 (m, 4H), 4.29-4.11 (m, 3H), 3.79-3.68 (m, 3H), 3.63-3.54 (m,3H),3.53-3.41(m,3H),3.40-3.34(m,5H),3.20-3.16(m,3H),3.15-3.12(m,1H),3.11-3.04(m,2H), 2.99(s,5H),2.84-2.75(m,1H),2.65-2.56(m,1H),2.36-2.24(m,3H),2.22-2.09(m,5H),2.06(d,J=4.0 Hz,3H),1.98-1.91(m,1H),1.83-1.73(m,1H),1.67-1.58(m,1H),1.46(d,J=6.0 Hz,3H),0.97(s,6H),0.90-0.83(m,3H),0.55(s,3H).

[0269] Example 26 4-Fluoro-1-(2-fluoropropanenoyl)-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide The compound described in TIFF2026515652000109.tif61170 was prepared in the same manner as in Example 1: (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (intermediate E), 1-tert-butoxycarbonyl-4-fluoropiperidine-4-carboxylic acid and 2-fluoropropa-2-enoic acid, (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 This was prepared by using tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaene-19,25-dione (intermediate N), (3S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (compound 1e), and (2R)-2-chloro-2-fluoroacetic acid (compound 1h) as substitutes. Example 26 (34.7 mg) was obtained as a yellow solid. MS calculation value 1055.5 (MH) + ), measured value 1055.6 (MH) + ). 1¹H NMR (400 MHz, methanol-d4) δ = 8.47 (s, 1H), 8.41-8.38 (m, 1H), 7.59-7.43 (m, 2H), 7.43-7.38 (m, 1H), 5.82-5.68 (m, 1H), 5.33-5.26 (m, 1H), 5.24-5.16 (m, 1H), 4.79 (s, 1H), 4.75-4.71 (m, 1H), 4.48-4.39 (m, 2H), 4.28-4.15 (m, 3H), 4.09 -3.90(m,2H),3.78-3.74(m,2H),3.63-3.52(m,3H),3.50-3.40(m,3H),3.39-3.35(m,4H),3.29-3.24(m,2H), 3.21-3.16(m,3H),3.15-3.11(m,1H),3.11-3.04(m,2H),3.04-2.93(m,5H),2.84-2.75(m,1H),2.60(d,J=13.6 Hz,1H),2.37-2.26(m,3H),2.25-2.11(m,5H),1.99-1.90(m,1H),1.84-1.74(m,1H),1. 69-1.58(m,1H),1.48-1.42(m,3H),1.02-0.93(m,6H),0.92-0.83(m,3H),0.55(s,3H).

[0270] Example 27 1-[(2R)-2-chloro-2-fluoroacetyl]-4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazine-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide The compound described in TIFF2026515652000110.tif56170 was prepared in the same manner as in Example 1: (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (intermediate E) and 1-tert-butoxycarbonyl-4-fluoropiperidine-4-carboxylic acid are (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 It was prepared by using tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaene-19,25-dione (intermediate N) and (3S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (compound 1e) as substitutes. Example 27 (44.98 mg) was obtained as a yellow solid. MS calculation value 1077.5 (MH) + ), measured value 1077.5 (MH) + ). 1H NMR(400 MHz, methanol-d4)δ=8.48(s,1H),8.40(s,1H),7.48(s,1H),7.45-7.40(m,1H),7.12-6.91(m,1H),5.81-5.71(m,1H),4.79-4. 66(m,2H),4.57-4.29(m,4H),4.26-4.18(m,2H),3.99-3.85(m,2H),3.82-3.69(m,3H),3.64-3.50(m,4H),3.41-3.34(m,5H) ),3.23-3.16(m,4H),3.12-3.05(m,2H),3.03-2.95(m,5H),2.85-2.77(m,1H),2.65-2.57(m,1H),2.45-2.24(m,4H),2.23- 2.07(m,5H),1.99-1.92(m,1H),1.85-1.73(m,1H),1.67-1.58(m,1H),1.48-1.44(m,3H),1.00-0.94(m,7H),0.88(d,J=6.0 Hz,3H),0.61-0.53(m,3H).

[0271] Example 28 1-[(2R)-2-chloro-2-fluoroacetyl]-4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide The compound described in TIFF2026515652000111.tif57170 was prepared in the same manner as in Example 1: (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-15,24-dioxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (intermediate I) and 1-tert-butoxycarbonyl-4-fluoropiperidine-4-carboxylic acid are (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 It was prepared by using tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaene-19,25-dione (intermediate N) and (3S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (compound 1e) as substitutes. Example 28 (22.2 mg) was obtained as a yellow solid. MS calculation value 1066.4 (MH) + ); Measured value 1066.4 (MH) + ). 1 H NMR (400 MHz, methanol-d4) δ=8.41(br s,1H),8.26(s,1H),7.91(br s,1H),7.47(br d,J=4.8 Hz,1H),7.19-6.97(m,2H),5.79-5.65(m,1H),4.76-4.70(m,1H),4.69-4.5 7(m,3H),4.47-4.31(m,2H),4.31-4.20(m,2H),3.92-3.75(m,8H),3.45(br d,J=4.5 Hz,8H),3.35-3.31(m,2H),3.25-3.13(m,5H),3.07(br s,1H),2.86-2.75(m,1H),2.73-2.64(m,1H),2.50-2.04(m,6H),2.02-1.91(m,1H),1.87-1.7 3(m,1H),1.70-1.57(m,1H),1.55-1.48(m,3H),1.10-1.04(m,3H),1.02-0.94(m,3H),0.89(br d,J=6.3 Hz,2H),0.61(br d,J=6.4 Hz,3H).

[0272] Example 29 4-Fluoro-1-(2-fluoropropa-2-enoyl)-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide The compound described in TIFF2026515652000112.tif56170 was prepared in the same manner as in Example 1: (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-15,24-dioxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaene-8,14-dione (intermediate I), 1-tert-butoxycarbonyl-4-fluoropiperidine-4-carboxylic acid and 2-fluoropropa-2-enoic acid are (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12This was prepared by using tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaene-19,25-dione (intermediate N), (3S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (compound 1e), and (2R)-2-chloro-2-fluoroacetic acid (compound 1h) as substitutes. Example 29 (22 mg) was obtained as a pale yellow solid. MS calculation value 1044.5 (MH) + ), measured value 1044.7 (MH) + ). 1 H NMR (400 MHz, methanol-d4) δ=8.37(d,J=2.8 Hz,1H),8.23(s,1H),7.74(br s,1H),7.48(br s,1H),7.12(s,1H),5.79-5.71(m,1H),5.32-5.26(m,1H),5.25-5.18(m,1H),4.76-4.72(m,1H),4.65-4.57(m,3H),4.42(br dd,J=1.9,11.7 Hz,1H),4.27(td,J=3.6,12.0 Hz,2H),3.89-3.84(m,4H),3.83-3.78(m,1H),3.76(s,2H),3.48(br s,2H),3.44-3.37(m,9H),3.19(br d,J=5.6 Hz,3H),3.13(br s,1H),3.02(s,1H),2.84-2.75(m,1H),2.68-2.62(m,1H),2.40-2.11(m,7 H),1.99-1.92(m,1H),1.86-1.76(m,1H),1.68-1.59(m,1H),1.48(d,J=6.4 Hz,3H),1.03(s,3H),1.00-0.95(m,3H),0.88(br d,J=6.6 Hz,3H),0.58(s,3H).

[0273] Example 30 1-Buta-2-inoyl-4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .19,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide The compound described in TIFF2026515652000113.tif57170 was prepared in the same manner as in Example 1: (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-15,24-dioxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaene-8,14-dione (intermediate I), 1-tert-butoxycarbonyl-4-fluoropiperidine-4-carboxylic acid and buta-2-ic acid, (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 This was prepared by using tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaene-19,25-dione (intermediate N), (3S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (compound 1e), and (2R)-2-chloro-2-fluoroacetic acid (compound 1h) as substitutes. Example 30 (17.7 mg) was obtained as a pale yellow solid. MS calculation value 1038.5 (MH). + ), measured value 1038.8 (MH) + ). 1H NMR (400 MHz, methanol-d4) δ=8.37(d,J=2.8 Hz,1H),8.23(s,1H),7.80(dd,J=2.6,7.0 Hz,1H),7.48(d,J=4.3 Hz,1H),7.13(d,J=3.6 Hz,1H),5.80-5.69(m,1H),4.72(br d,J=11.0 Hz,1H),4.59(br d,J=6.1 Hz,3H),4.45-4.30(m,4H),4.28-4.22(m,2H),3.88-3.84(m,4H),3.83-3.78( m,1H),3.76(s,2H),3.61-3.46(m,2H),3.46-3.37(m,9H),3.18(dd,J=2.6,5.5 Hz,3H),3.15-3.11(m,1H),3.06-2.95(m,1H),2.84-2.75(m,1H),2.69-2.62(m,1H),2.33-2.08(m,7H),1.99-1.9 2(m,1H),1.87-1.77(m,1H),1.67-1.57(m,1H),1.50-1.46(m,3H),1.05-1.01(m,3H),1.00-0.94(m,3H),0.88(br d,J=6.6 Hz,3H),0.58(br s,3H).

[0274] Example 31 1-[(2R)-2-chloro-2-fluoroacetyl]-4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide The compound described in TIFF2026515652000114.tif55170 was prepared in the same manner as in Example 1: (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-15,24-dioxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (intermediate H) and 1-tert-butoxycarbonyl-4-fluoropiperidine-4-carboxylic acid are (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 It was prepared by using tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaene-19,25-dione (intermediate N) and (3S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (compound 1e) as substitutes. Example 31 (33.5 mg) was obtained as a pale yellow solid. MS calculation value 1079.5 (MH) + ), measured value 1079.8 (MH) + ). 1¹H NMR (400 MHz, methanol-d4) δ = 8.23 ​​(s, 1H), 7.68 (s, 1H), 7.49 (d, J = 3.2 Hz, 1H), 7.14 (d, J = 10 Hz, 1H), 7.00 (s, 1H), 5.75-5.71 (m, 1H), 4.79-4.70 (m, 1H), 4.66-4.54 (m, 3H), 4.45-4.25 (m, 4H), 4.10 (br s,3H),3.81-3.74(m,3H),3.70-3.47(m,4H),3.46-3.37(m,5H),3.28-3 .14(m,6H),3.10-2.90(m,4H),2.86-2.75(m,1H),2.67-2.57(m,1H),2.0 5(s,6H),2.02-1.93(m,1H),1.88-1.75(m,1H),1.71-1.57(m,1H),1.53 -1.43(m,3H),1.42-1.23(m,1H),1.22-0.79(m,10H),0.64-0.48(m,3H).

[0275] Example 32 4-Fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-1-propa-2-enoylpiperidine-4-carboxamide The compound described in TIFF2026515652000115.tif55170 was prepared in the same manner as in Example 1: (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-15,24-dioxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13.0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaene-8,14-dione (intermediate H), 1-tert-butoxycarbonyl-4-fluoropiperidine-4-carboxylic acid and acrylic acid, (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 This was prepared by using tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaene-19,25-dione (intermediate N), (3S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (compound 1e), and (2R)-2-chloro-2-fluoroacetic acid (compound 1h) as substitutes. Example 32 (18.9 mg) was obtained as a pale yellow solid. MS calculation value 1039.5 (MH) + ), measured value 1039.5 (MH) + ). 1H NMR (400 MHz, methanol-d4) δ=8.50(d,J=2.8 Hz,1H),8.24-8.17(m,1H),7.70-7.59(m,1H),7.52-7.44(m,1H),7.15-7.06(m,1H),6.89-6.77(m,1H), 6.29-6.20(m,1H),5.81-5.75(m,1H),5.75-5.66(m,1H),4.76-4.69(m,1H),4.67-4.59(m,2H),4.55(br d,J=6.3 Hz,1H),4.48-4.38(m,2H),4.33-4.25(m,2H),4.19-3.90(m,3H),3.80-3.66(m,4H),3.53(br s,3H),3.45-3.34(m,6H),3.22-3.12(m,5H),3.04-2.94(m,4H),2.84-2.75(m,1H),2.65-2.54(m,1H),2.42-2.02(m,7H),2.00-1.93( m,1H),1.87-1.76(m,1H),1.68-1.59(m,1H),1.49-1.43(m,3H),1.05-1.00(m,3H),0.99-0.94(m,3H),0.92-0.81(m,3H),0.53(s,3H).

[0276] Example 33 1-Buta-2-inoyl-4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide The title compound was prepared in the same manner as in Example 1: (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-15,24-dioxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaene-8,14-dione (intermediate H), 1-tert-butoxycarbonyl-4-fluoropiperidine-4-carboxylic acid and buta-2-ic acid, (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 This was prepared by using tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaene-19,25-dione (intermediate N), (3S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (compound 1e), and (2R)-2-chloro-2-fluoroacetic acid (compound 1h) as substitutes. Example 33 (25.1 mg) was obtained as a pale yellow solid. MS calculation value 1051.5 (MH) + ), measured value 1051.8 (MH) + ). 1H NMR(400 MHz, methanol-d4)δ=8.49(s,1H),8.20(s,1H),7.67-7.60(m,1H),7.50-7.45(m,1H),7.1 3-7.08(m,1H),5.79-5.61(m,1H),4.76-4.68(m,1H),4.67-4.58(m,2H),4.54(d,J=6.4 Hz,1H),4.48-4.21(m,6H),3.79-3.73(m,3H),3.52(br s,3H),3.47-3.35(m,6H),3.19(br d,J=5.4 Hz,6H),3.04-2.94(m,4H),2.86-2.75(m,1H),2.63-2.55(m,1H),2.38-2.11(m,6H),2.09-2.00(m,4H),1.99-1.92(m,1H) ,1.87-1.75(m,1H),1.68-1.58(m,1H),1.49-1.43(m,3H),1.22-1.12(m,1H),1.02(s,6H),0.92-0.81(m,3H),0.53(s,3H).

[0277] Example 34 (3R)-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-1-propa-2-enoyl-pyrrolidine-3-carboxamide The compound described in TIFF2026515652000117.tif56170 was prepared in the same manner as in Example 1: (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13.0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaene-8,14-dione (intermediate F) and acrylic acid are (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 It was prepared by using tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaene-19,25-dione (intermediate N) and (2R)-2-chloro-2-fluoroacetic acid (compound 1h) as substitutes. Example 34 (41.0 mg) was obtained as a yellow solid. MS calculation value 992.5 (MH) + ), measured value 992.5 (MH) + ). 1 H NMR(400 MHz, methanol-d4)δ=8.46-8.35(m,2H),7.74(s,1H),7.55-7.41(m,2H),7.00-6.84(m,1H),6.68-6.55(m,1H),6.35-6.24(m ,1H),5.85-5.67(m,2H),4.83-4.75(m,1H),4.57-4.48(m,1H),4.44-4.39(m,1H),4.29-4.12(m,2H),3.87-3.79(m,7H),3 .78-3.73(m,2H),3.69-3.56(m,3H),3.44-3.38(m,7H),3.28-3.21(m,1H),3.14-3.06(m,5H),3.03-2.99(m,1H),2.84-2 .73(m,1H),2.71-2.60(m,1H),2.34-2.18(m,5H),2.00-1.88(m,1H),1.85-1.72(m,1H),1.67-1.55(m,1H),1.47(d,J=6.4 Hz,3H),1.03-0.95(m,7H),0.91-0.80(d,J=6.4 Hz,3H),0.65-0.54(m,3H).

[0278] Example 35 (3R)-1-buta-2-inoyl-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide The compound described in TIFF2026515652000118.tif63170 was prepared in the same manner as in Example 1: (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaene-8,14-dione (intermediate F) and buta-2-ic acid are (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 It was prepared by using tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaene-19,25-dione (intermediate N) and (2R)-2-chloro-2-fluoroacetic acid (compound 1h) as substitutes. Example 35 (12.9 mg) was obtained as a yellow solid. MS calculation value 1004.5 (MH) + ), measured value 1004.6 (MH) + ). 1¹H NMR (400 MHz, methanol-d4) δ=8.43(s,1H),8.37(s,1H),7.84-7.72(m,1H),7.50(d,J=3.2 Hz,1H),7.45(s,1H),5.84-4.61(m,1H),4.83-4.77(m,1H),4.59-4.49(m,1H),4.44-4.39(m,1H),4.30-4.22(m,1H),4.20-4.13(m,1H),3.99-3.90(m,1H),3.88- 3.84(m,4H),3.82-3.79(m,1H),3.79-3.69(m,4H),3.68-3.55(m,3H),3.45-3.39 (m,7H),3.28-3.21(m,1H),3.14-3.00(m,6H),2.84-2.74(m,1H),2.65(d,J=14.8 Hz,1H),2.33-2.13(m,6H),2.08-2.02(m,2H),1.98-1.91(m,2H),1.85-1.75(m,1H),1.67-1.57(m,1H),1.48(d,J=6.4 Hz,3H),1.02-0.96(m,6H),0.91-0.81(m,3H),0.65-0.55(m,3H).

[0279] Example 36 4-Fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-1-propa-2-enoylpiperidine-4-carboxamide The compound described in TIFF2026515652000119.tif58170 was prepared in the same manner as in Example 1: (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaene-8,14-dione (intermediate E), 1-tert-butoxycarbonyl-4-fluoropiperidine-4-carboxylic acid and acrylic acid, (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 This was prepared by using tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaene-19,25-dione (intermediate N), (3S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (compound 1e), and (2R)-2-chloro-2-fluoroacetic acid (compound 1h) as substitutes. Example 36 (24.5 mg) was obtained as a yellow solid. MS calculation value 1037.5 (MH). + ), measured value 1037.6 (MH) + ). 1¹H NMR (400 MHz, methanol-d4) δ=8.47 (d, J=2.8 Hz, 1H), 8.40 (s, 1H), 7.51-7.40 (m, 3H), 6.87-6.77 (m, 1H), 6.25 (d, J=16.8 Hz, 1H), 5.81-5.72 (m, 2H), 4.73 (d, J=11.2 Hz,1H),4.49-4.40(m,3H),4.27-4.20(m,2H),4.08(s,2H),3.83-3.73(m,3H),3.63-3.52(m,4H),3.4 4-3.35(m,7H),3.27-3.18(m,5H),3.14-3.04(m,3H),2.99(s,4H),2.84-2.77(m,1H),2.59(d,J=14.4 Hz,1H),2.35-2.26(m,3H),2.24-2.13(m,5H),1.99-1.92(m,1H),1.85-1.77(m,1H),1.68-1.60(m,1H),1.45(d,J=6.0 Hz,3H),1.01-0.95(m,6H),0.88(d,J=6.4 Hz,3H),0.54(s,3H).

[0280] Example 37 (2S)-2-[(5R)-7-buta-2-inoyl-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazine-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]-3-methyl-butanamide The compound described in TIFF2026515652000120.tif49170 was prepared in the same manner as in Example 7: (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-8,14-dione (intermediate E), (2S)-2-[(5R)-7-tert-butoxycarbonyl-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-3-methylbutanoic acid (intermediate A3) and buta-2-ic acid, (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazine-1-yl]-3-pyridyl]-17,17-dimethyl- It was prepared by using 15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]henthriaconta-1(28),2,5(31),19,25(29),26-hexaen-8,14-dione (intermediate G), (2S)-2-(2-tert-butoxycarbonyl-5-oxo-2,6-diazaspiro[3.4]octan-6-yl)-3-methylbutanoic acid (intermediate A1) and (2R)-2-chloro-2-fluoroacetic acid (compound 1h) as substitutes. Example 37 (11.1 mg) was obtained as a yellow solid. MS calculation value 1029.5 (MH) + ), measured value 1029.7 (MH) + ). 1¹H NMR (400 MHz, methanol-d4) δ=8.47 (d, J=2.4 Hz, 1H), 8.40 (s, 1H), 7.53-7.45 (m, 2H), 7.42 (s, 1H), 5.75 (t, J=7.8 Hz,1H),4.49-4.37(m,2H),4.34-4.20(m,3H),4.02-3.84(m,2H),3.80 -3.35(m,18H),3.28-3.23(m,1H),3.13-3.05(m,2H),2.99(s,4H),2.87 -2.74(m,1H),2.65-2.53(m,1H),2.36-2.14(m,5H),2.09-2.02(m,5H), 2.00-1.90(m,2H),1.86-1.73(m,1H),1.69-1.55(m,1H),1.45(d,J=6.0 Hz,3H),1.18(t,J=7.2 Hz,1H),1.03-0.95(m,6H),0.89(t,J=6.4 Hz,3H),0.54(s,3H).

[0281] Example 38 4-Fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-1-propa-2-enoylpiperidine-4-carboxamide The compound described in TIFF2026515652000121.tif49170 was prepared in the same manner as in Example 1: (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-15,24-dioxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .021,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaene-8,14-dione (intermediate I), 1-tert-butoxycarbonyl-4-fluoropiperidine-4-carboxylic acid and acrylic acid, (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 This was prepared by using tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaene-19,25-dione (intermediate N), (3S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (compound 1e), and (2R)-2-chloro-2-fluoroacetic acid (compound 1h) as substitutes. Example 38 (11.3 mg) was obtained as a pale yellow solid. MS calculation value 1026.5 (MH) + ), measured value 1026.4 (MH) + ). 1H NMR (400 MHz, methanol-d4) δ=8.38(d,J=2.4 Hz,1H),8.28-8.18(m,1H),7.84(s,1H),7.49(d,J=10.9 Hz,1H),7.13(dd,J=2.8,5.9 Hz,1H),6.83(dd,J=10.5,16.6 Hz,1H),6.25(d,J=16.9 Hz,1H),5.92-5.65(m,2H),4.73(d,J=11.0 Hz,1H),4.69-4.57(m,3H),4.49-4.39(m,2H),4.25(t,J=11.6 Hz,2H),4.16-4.02(m,1H),3.89-3.84(m,4H),3.82-3.72(m,3H),3.58-3.49(m,1H),3.46-3.37(m,8H),3.22-3.15(m,4H),3.09-2.9 5(m,1H),2.84-2.73(m,1H),2.72-2.63(m,1H),2.29-2.10(m,5H),1.94(s,1H),1.89-1.73(m,1H),1.70-1.55(m,1H),1.49(d,J=6.3 Hz,3H),1.39-1.28(m,1H),1.31(t,J=7.4 Hz,1H),1.04(s,3H),0.98(d,J=6.3 Hz,3H),0.88(d,J=6.5 Hz,3H),0.59(s,3H).

[0282] Example 39 N-[(1S)-1-[[(7S,13S)-23,23-difluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]carbamoyl]-2-methyl-propyl]-4-fluoro-N-methyl-1-propa-2-enoylpiperidine-4-carboxamide The compound described in TIFF2026515652000122.tif56170 was prepared in the same manner as in Example 1: (7S,13S)-7-amino-23,23-difluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaene-8,14-dione (intermediate J), ​​1-tert-butoxycarbonyl-4-fluoropiperidine-4-carboxylic acid and acrylic acid, (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 This was prepared by using tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaene-19,25-dione (intermediate N), (3S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (compound 1e), and (2R)-2-chloro-2-fluoroacetic acid (compound 1h) as substitutes. Example 39 (23.1 mg) was obtained as a yellow solid. MS calculation value 1073.5 (MH). + ), measured value 1073.5 (MH) + ). 1H NMR (400 MHz, methanol-d4) δ=8.52(d,J=2.8 Hz,2H),7.56(d,J=4.0 Hz,2H),6.82(dd,J=10.8,16.8 Hz,1H),6.25(d,J=16.8 Hz,1H),5.86-5.66(m,2H),4.83-4.79(m,1H),4.73(d,J=11.2 Hz,1H),4.59-4.38(m,4H),4.29-4.22(m,1H),4.12-4.06(m,1H),4.02-3.82(m,2H),3.80-3.73(m,2H),3. 70-3.46(m,6H),3.45-3.42(m,1H),3.41-3.36(m,4H),3.36-3.32(m,1H),3.30-3.22(m,2H),3.19(d,J=5.2 Hz,3H),3.14-3.09(m,1H),3.07-2.89(m,4H),2.85-2.76(m,1H),2.66-2.56(m,1H),2. 35-2.09(m,6H),2.00-1.92(m,1H),1.86-1.74(m,1H),1.68-1.58(m,1H),1.47(d,J=6.0 Hz,3H),1.34-1.28(m,1H),1.06-0.93(m,6H),0.93-0.82(m,3H),0.57(s,3H).

[0283] Example 40 N-[(1S)-1-[[(7S,13S)-23,23-difluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]carbamoyl]-2-methyl-propyl]-4-fluoro-1-(2-fluoropropane-2-enoyl)-N-methyl-piperidine-4-carboxamide The compound described in TIFF2026515652000123.tif53170 was prepared in the same manner as in Example 1: (7S,13S)-7-amino-23,23-difluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (intermediate M), 1-tert-butoxycarbonyl-4-fluoropiperidine-4-carboxylic acid and 2-fluoropropa-2-enoic acid are (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 This was prepared by using tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaene-19,25-dione (intermediate N), (3S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (compound 1e), and (2R)-2-chloro-2-fluoroacetic acid (compound 1h) as substitutes. Example 40 (17.8 mg) was obtained as a yellow solid. MS calculation value 1078.5 (MH) + ), measured value 1078.5 (MH) + ). 1H NMR (400 MHz, methanol-d4) δ=8.54(s,1H),8.41(d,J=2.8 Hz,1H),7.84(s,1H),7.58(d,J=16.4 Hz,2H),5.84-5.73(m,1H),5.32-5.26(m,1H),5.24-5.17(m,1H),4.72(d,J=11.2 Hz,1H),4.60-4.54(m,1H),4.52-4.40(m,2H),4.24(dd,J=3.2,12.0 Hz,1H),4.10-3.96(m,2H),3.88-3.84(m,4H),3.82-3.72(m,2H),3.69-3.51( m,3H),3.44-3.42(m,6H),3.40-3.36(m,1H),3.30-3.21(m,2H),3.18(d,J=5.2 Hz,3H),3.13-3.07(m,1H),2.84-2.76(m,1H),2.75-2.67(m,1H),2.33-2.13( m,6H),1.99-1.91(m,1H),1.84-1.73(m,1H),1.68-1.59(m,1H),1.50(d,J=6.4 Hz,3H),1.37-1.25(m,1H),1.12-1.04(m,1H),1.03-0.94(m,6H),0.87(d,J=6.8 Hz,3H),0.63(s,3H).

[0284] Example 41 1-[(2R)-2-chloro-2-fluoroacetyl]-N-[(1S)-1-[[(7S,13S)-23,23-difluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 Hentriaconta-1(29),2,5(31),19,25,27-Hexaen-7-yl]carbamoyl]-2-methyl-propyl]-4-fluoro-N-methyl-piperidine-4-carboxamide The compound described in TIFF2026515652000124.tif56170 was prepared in the same manner as in Example 1: (7S,13S)-7-amino-23,23-difluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (intermediate M) and 1-tert-butoxycarbonyl-4-fluoropiperidine-4-carboxylic acid are used to obtain (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 This was prepared by using tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaene-19,25-dione (intermediate N) and (3S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (compound 1e) as substitutes. Example 41 (13.7 mg) was obtained as a yellow solid. MS calculation value 1100.4 (MH) + ), measured value 1100.5 (MH) + ). 1H NMR(400 MHz, methanol-d4)δ=8.54(s,1H),8.44-8.39(m,1H),7.90-7.80(m,1H),7.65-7.53(m,2H),7.13-6.92(m,1H),5.85-5.71(m,1H),4.7 7-4.66(m,1H),4.61-4.54(m,1H),4.52-4.39(m,2H),4.38-4.29(m,1H),4.28-4.19(m,1H),4.10-3.90(m,2H),3.88-3.84(m,4H),3 .82-3.72(m,2H),3.71-3.57(m,2H),3.55-3.50(m,1H),3.44-3.41(m,6H),3.40-3.33(m,1H),3.28-3.23(m,1H),3.20-3.15(m,3H) ),3.14-3.06(m,1H),2.84-2.66(m,2H),2.42-2.09(m,6H),1.97-1.91(m,1H),1.83-1.73(m,1H),1.67-1.58(m,1H),1.50(d,J=6.0 Hz,3H),1.42-1.22(m,1H),1.14-1.04(m,1H),1.03-0.93(m,6H),0.87(d,J=6.8 Hz,3H),0.70-0.56(m,3H).

[0285] Example 42 N-[(1S)-1-[[(7S,13S)-23,23-difluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]carbamoyl]-2-methyl-propyl]-4-fluoro-N-methyl-1-propa-2-enoylpiperidine-4-carboxamide The compound described in TIFF2026515652000125.tif52170 was prepared in the same manner as in Example 1: (7S,13S)-7-amino-23,23-difluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaene-8,14-dione (intermediate M), 1-tert-butoxycarbonyl-4-fluoropiperidine-4-carboxylic acid and acrylic acid, (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 This was prepared by using tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaene-19,25-dione (intermediate N), (3S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (compound 1e), and (2R)-2-chloro-2-fluoroacetic acid (compound 1h) as substitutes. Example 42 (10 mg) was obtained as a yellow solid. MS calculation value 1060.5 (MH) + ), measured value 1060.8 (MH) + ). 1H NMR (400 MHz, methanol-d4) δ=8.54(s,1H),8.41(d,J=2.8 Hz,1H),7.87(s,1H),7.64-7.55(m,2H),6.87-6.77(m,1H),6.25(d,J=16.8 Hz,1H),5.83-5.72(m,2H),4.72(d,J=11.2 Hz,1H),4.61-4.56(m,1H),4.51-4.38(m,3H),4.28-4.21(m,1H),4.12-3.99(m,2H),3.86(t,J=4.8 Hz,4H),3.82-3.73(m,2H),3.70-3.63(m,1H),3.58-3.53(m,1H),3.44(s,7H),3.27-3.23(m,1H),3.18(d,J=5.2 Hz,3H),3.15-3.08(m,1H),3.04-2.98(m,1H),2.86-2.76(m,1H),2.74-2.66(m,1H),2. 31-2.14(m,5H),2.00-1.91(m,1H),1.86-1.73(m,1H),1.68-1.58(m,1H),1.50(d,J=6.4 Hz,3H),1.40-1.33(m,3H),1.02(s,3H),0.98(d,J=6.4 Hz,3H),0.92-0.83(m,3H),0.63(s,3H).

[0286] Example 43 1-Buta-2-inoyl-N-[(1S)-1-[[(7S,13S)-23,23-difluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]carbamoyl]-2-methyl-propyl]-4-fluoro-N-methyl-piperidine-4-carboxamide The compound described in TIFF2026515652000126.tif57170 was prepared in the same manner as in Example 1: (7S,13S)-7-amino-23,23-difluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaene-8,14-dione (intermediate M), 1-tert-butoxycarbonyl-4-fluoropiperidine-4-carboxylic acid and buta-2-ic acid, (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 This was prepared by using tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaene-19,25-dione (intermediate N), (3S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (compound 1e), and (2R)-2-chloro-2-fluoroacetic acid (compound 1h) as substitutes. Example 43 (18.1 mg) was obtained as a yellow solid. MS calculation value 1072.5 (MH). + ), measured value 1072.7 (MH) + ). 1¹H NMR (400 MHz, methanol-d4) δ = 8.55 (s, 1H), 8.41 (d, J = 2.8 Hz, 1H), 7.90-7.85 (m, 1H), 7.61 (d, J = 3.2 Hz, 1H), 7.57 (d, J = 4.0 Hz, 1H), 5.83-5.73 (m, 1H), 4.72 (d, J = 11.2 Hz,1H),4.61-4.55(m,1H),4.48-4.30(m,4H),4.28-4.20(m,1H),4.08-3.98(m,1H),3.88-3.84( m,4H),3.81-3.72(m,2H),3.68-3.54(m,3H),3.47-3.40(m,8H),3.29-3.23(m,1H),3.18(t,J=5.2 Hz,3H),3.13-3.08(m,1H),3.07-2.93(m,1H),2.85-2.76(m,1H),2.74-2.66(m,1H),2.33-2.10(m,6H),2.06(d,J=6.8 Hz,3H),1.99-1.92(m,1H),1.84-1.74(m,1H),1.68-1.59(m,1H),1.50(d,J=6.4 Hz,3H),1.05-1.00(m,3H),0.98(d,J=6.4 Hz,3H),0.88(d,J=6.4 Hz,3H),0.67-0.59(m,3H).

[0287] Example 44 4-Fluoro-1-(2-fluoropropanenoyl)-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide The compound described in TIFF2026515652000127.tif57170 was prepared in the same manner as in Example 1: (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-15,24-dioxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (intermediate H), 1-tert-butoxycarbonyl-4-fluoropiperidine-4-carboxylic acid and 2-fluoropropa-2-enoic acid, (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 This was prepared by using tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaene-19,25-dione (intermediate N), (3S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (compound 1e), and (2R)-2-chloro-2-fluoroacetic acid (compound 1h) as substitutes. Example 44 (36.0 mg) was obtained as a pale yellow solid. MS calculation value 1057.5 (MH). + ), measured value 1057.6 (MH) + ). 1¹H NMR (400 MHz, methanol-d4) δ=8.48 (d, J=2.8 Hz, 1H), 8.25-8.15 (m, 1H), 7.62-7.41 (m, 2H), 7.10 (s, 1H), 5.78-5.67 (m, 1H), 5.34-5.15 (m, 2H), 4.78-4.72 (m, 1H), 4.64-4.57 (m, 2H), 4.52 (q, J=5.9 Hz, 1H), 4.42 (d, J=11.1 Hz,1H),4.36-4.23(m,3H),4.12-3.98(m,2H),3.84-3.69(m,4H),3.64-3.54(m,2H),3.46-3.36(m,6H),3.27-3.10(m,8H),3.04- 2.96(m,4H),2.85-2.75(m,1H),2.63-2.54(m,1H),2.36-2.14(m,6H),1.99-1.92(m,1H),1.89-1.76(m,1H),1.62(dt,J=8.9,12.6 Hz,1H),1.46(d,J=6.1 Hz,3H),1.04-0.93(m,6H),0.88(d,J=6.5 Hz,3H),0.52(s,3H).

[0288] Example 45 4-Fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17,23,23-tetramethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-1-propa-2-enoylpiperidine-4-carboxamide The compound described in TIFF2026515652000128.tif54170 was prepared in the same manner as in Example 1: (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17,23,23-tetramethyl-15,24-dioxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaene-8,14-dione (intermediate K), 1-tert-butoxycarbonyl-4-fluoropiperidine-4-carboxylic acid and acrylic acid, (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 This was prepared by using tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaene-19,25-dione (intermediate N), (3S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (compound 1e), and (2R)-2-chloro-2-fluoroacetic acid (compound 1h) as substitutes. Example 45 (4.2 mg) was obtained as a yellow solid. MS calculation value 1054.5 (MH) + ), measured value 1054.8 (MH) + ), 1H NMR (400 MHz, methanol-d4)δ=8.48-8.40(m,1H),8.38(d,J=2.8 Hz,1H),8.22(s,1H),7.74-7.68(m,1H),7.47(d,J=11.6 Hz,1H),7.12-7.06(m,1H),6.88-6.78(m,1H),6.25(dd,J=1.6 Hz,16.4 Hz,1H),5.85-5.73(m,2H),4.72(d,J=11.6 Hz,1H),4.69-4.63(m,1H),4.50-4.38(m,2H),4.25(d,J=11.6 Hz,1H),4.14-4.03(m,1H),3.98(d,J=12.4 Hz,1H),3.86(t,J=4.4 Hz,3H),3.82-3.76(m,2H),3.63(d,J=8.0 Hz,1H),3.59-3.47(m,1H),3.43-3.38(m,6H),3.19(d,J=5.2 Hz,3H),3.13-3.07(m,1H),3.04-2.97(m,1H),2.90-2.82(m,1H),2.81-2.75(m,1H),2.71-2.65(m,1H),2.36-2.24( m,2H),2.22-2.17(m,2H),2.15-2.02(m,2H),1.98-1.91(m,1H),1.85-1.72(m,1H),1.71-1.57(m,2H),1.50(t,J=7.6 Hz,6H),1.35(s,4H),0.99(t,J=9.2 Hz,6H),0.88(d,J=6.4 Hz,3H),0.65(s,3H).

[0289] Example 46 4-Fluoro-N-[(1S)-1-[[(7S,13S,22S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17,22-trimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-1-propa-2-enoylpiperidine-4-carboxamide The compound described in TIFF2026515652000129.tif50170 was prepared in the same manner as in Example 1: (7S,13S,22S)-7-amino-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17,22-trimethyl-15,24-dioxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaene-8,14-dione (intermediate L), 1-tert-butoxycarbonyl-4-fluoropiperidine-4-carboxylic acid and acrylic acid, (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 This was prepared by using tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaene-19,25-dione (intermediate N), (3S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (compound 1e), and (2R)-2-chloro-2-fluoroacetic acid (compound 1h) as substitutes. Example 46 (3.2 mg) was obtained as a white solid. MS calculation value 1040.5 (MH) + ), measured value 1040.9 (MH) +). 1H NMR (400 MHz, methanol-d4) δ=8.41(d,J=2.8 Hz,1H),8.29(d,J=5.6 Hz,1H),7.42-7.35(m,2H),7.08(d,J=17.6 Hz,1H),6.85-6.75(m,1H),6.40-6.30(m,1H),6.24(dd,J=16.8 Hz,J=6.4 Hz,1H),5.84-5.73(m,1H),4.59(d,J=11.2 Hz,1H),4.51-4.46(m,1H),4.43-4.35(m,5H),3.86(t,J=4.4 Hz,4H),3.80(s,1H),3.16(d,J=15.2 Hz,2H),3.08-3.04(m,5H),3.00-2.93(m,1H),2.86-2.77(m,1H),2.43-2.33( m,1H),2.26-2.14(m,4H),2.07-1.97(m,4H),1.89-1.76(m,3H),1.59(d,J=6.4 Hz,4H),1.29(s,6H),1.16(d,J=6.8 Hz,3H),0.96(s,4H),0.90(t,J=6.8 Hz,3H),0.83(d,J=5.6 Hz,2H),0.52(s,3H),0.10(s,1H).

[0290] Example 47 4-Fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17,23,23-tetramethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(29),2,5(31),19,25,27-Hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-1-propa-2-enoylpiperidine-4-carboxamide The compound described in TIFF2026515652000130.tif56170 was prepared in the same manner as in Example 1: (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17,23,23-tetramethyl-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-Hexaene-8,14-dione (intermediate R), 1-tert-butoxycarbonyl-4-fluoropiperidine-4-carboxylic acid and acrylic acid, (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 This was prepared by using tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaene-19,25-dione (intermediate N), (3S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (compound 1e), and (2R)-2-chloro-2-fluoroacetic acid (compound 1h) as substitutes. Example 47 (5.9 mg) was obtained as a white solid. MS calculation value 1052.5 (MH) + ), measured value 1052.9 (MH) + ), 1¹H NMR (500 MHz, methanol-d4) δ=8.40 (br d, J=2.9 Hz, 2H), 7.52-7.44 (m, 1H), 7.44-7.36 (m, 1H), 7.21 (d, J=2.6 Hz, 1H), 6.87-6.77 (m, 1H), 6.29-6.20 (m, 1H), 5.79 (dd, J=1.8, 10.7 Hz,1H),4.74-4.70(m,1H),4.66-4.53(m,3H),4.49-4.39(m,3H),4.27-4.19(m,1H), 4.14-4.04(m,1H),3.87-3.84(m,4H),3.82-3.72(m,3H),3.58-3.50(m,1H),3.39(br s,2H),3.22-3.16(m,3H),3.05-2.97(m,2H),2.95-2.87(m,2H),2.85-2.7 7(m,2H),2.76-2.71(m,1H),2.69-2.63(m,1H),2.35-2.25(m,2H),2.18(br s,3H),2.03(s,1H),1.97-1.91(m,1H),1.83-1.71(m,1H),1.67-1.55(m,2H),1.49-1.42(m,3H),1.34- 1.23(m,3H),1.13(s,3H),1.00-0.96(m,3H),0.94-0.91(m,3H),0.90-0.83(m,6H),0.64-0.55(m,3H).

[0291] Biological examples Example 48 Cell viability assay The objective of this cell assay was to determine the effect of the test compound on the proliferation of human cancer cell lines NCI-H358 (ATCC-CRL5807), AGS (ATCC-CRL-1739), and SW620 (ATCC-CCL-227) over a 3-day treatment period by quantifying the amount of NADPH present at the endpoint using Cell Counting Kit-8.

[0292] Cells were seeded at 5,000 cells / well (NCI-H358), 2,000 cells / well (AGS), and 2,000 cells / well (SW620) in 96-well assay plates (Corning-3699) and incubated overnight. Then, on the day of the assay, diluted compounds were added at a final concentration of 0.5% DMSO. After 72 hours of incubation, one-tenth the volume of cell counting kit 8 (Dnjindo-CK04) was added to each well. After 2 hours of incubation, the signals (OD450-OD650) were read using EnVision. IC 50 This was determined by fitting a four-parameter sigmoid concentration response model. [Table 1] TIFF2026515652000132.tif54170

[0293] Example 49 Interaction assay between CYPA (500 nM) and KRAS-BRAF In this example, TR-FRET was also used to measure compound- or compound-CYPA-dependent disruption of the KRAS G12C-BRAF complex. This protocol was also used to measure the disruption of binding of KRAS G12D or KRAS G12V to BRAF by the compounds of the present invention, respectively. Tagless CYPA, GMPPNP-loaded 6His-KRAS protein, and GST-BRAF were measured in an assay buffer containing 25 mM HEPES PH=7.4 (4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid, Thermo, 15630080), 0.002% Tween20, 0.1% BSA, 100 mM NaCl, 5 mM MgCl2, and 10 μM GMPPNP (guanosine 5'-[β,γ-imide] trisodium triphosphate hydrate, Sigma, G0635). RBDThe compounds were mixed in the wells of a 384-well assay plate at final concentrations of 50 nM, 6.25 nM, and 1 nM, respectively. The compounds were introduced into the plate wells as a 16-point 3-fold dilution series starting at a final concentration of 10 μM and incubated for 3 hours. Then, mixtures of MAb anti-6His-XL665 (Cisbio, 61HISXLB) and Mab anti-GST-TB cryptotate (Cisbio, 61GSTTLB) were added at final concentrations of 6.67 nM and 0.21 nM, respectively, and the plate was incubated for a further 1.5 hours. The TR-FRET signal was read using a PHERstar FSX microplate reader (Ex320 nm, Em 665 / 615 nm). Compounds that promote the disruption of the KRAS-BRAF complex were identified as those that induced a decrease in the TR-FRET ratio compared to the DMSO control well. [Table 2]

[0294] Example 50 pERK Inhibition Assay This assay was designed to measure the ability of test compounds to inhibit ERK phosphorylation, downstream signaling of KRAS G12C in NCI-H358 cells, KRAS G12D in AGS cells, and KRAS G12V in SW620 cells. NCI-H358 (ATCC-CRL5807), AGS (ATCC-CRL-1739), and SW620 (ATCC-CCL-227) cells were all grown and maintained in RPMI-1640 medium (Thermo Fisher Scientific) containing 10% fetal bovine serum and 1% penicillin / streptomycin. The day before compound addition, NCI-H358, AGS, and SW620 cells were seeded in tissue culture-treated 96-well plates (Corning-3699) at densities of 30,000 cells / well, 20,000 cells / well, and 30,000 cells / well, respectively, and allowed to adhere overnight. Next, the diluted compound was added to a final concentration of 0.5% DMSO. After 4 hours of incubation, the 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 permeabilized with 100 μL of chilled methanol for 10 minutes. Nonspecific antibody binding to the plate was blocked at room temperature for at least 1 hour using 50 μL of 1× BSA blocking buffer (Thermo-37520, 10-fold dilution with phosphate-buffered saline Tween (PBST)).

[0295] 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 with blocking buffer, 50 μL was aliquoted into each well, and incubated overnight at 4°C. Cells were washed five times with PBST for 5 minutes each. The secondary antibody (HRP-conjugated anti-rabbit IgG, CST-7074, Cell Signaling Technology) was diluted 1:1000 with blocking buffer, 50 μL was added to each well, and incubated at room temperature for 1-2 hours. Cells were washed five times with PBST for 5 minutes each, 100 μL of TMB ELISA substrate (abcam-ab171523) was added, and the cells were gently shaken for 20 minutes. 50 μL of stop solution (abcam-ab171529) was added, and the signal (OD450) was read by EnVision.

[0296] I C 50 This was determined by fitting a four-parameter sigmoid concentration response model. [Table 3] TIFF2026515652000135.tif74170

Claims

1. A compound of formula (I), During the ceremony, R １ teeth, C ２－６ 1-oxo-2,7-diazaspiro[4.4]nonanyl substituted with alkynylcarbonyl, or (Jiharo C １－６ Alkyl)carbonyl, C ２－６ Alkenylcarbonyl, C ２－６ Alkynylcarbonyl or Halo C ２－６ It is a 5-oxo-2,6-diazaspiro[3.4]octanyl substituted with an alkenylcarbonyl; Here, R ５ C １－６ It is alkyl; R ６ is halo C ２－６ cycloalkyl substituted with alkynyl, ３－７ cycloalkyl, (Jiharo C １－６ Alkyl)carbonyl, C ２－６ Alkenylcarbonyl, C ２－６ Alkynylcarbonyl, halogen and halo C ２－６ Piperidyls that are substituted once or twice with substituents independently selected from alkenylcarbonyls, or (Jiharo C １－６ Alkyl)carbonyl, C ２－６ Alkenylcarbonyl, C ２－６ Alkinylcarbonyl or Morpholino C ２－６ It is a pyrrolidinyl substituted with an alkynylcarbonyl; R ２ C １－６ It is alkyl; R ３ H, Morpholino, (Halo C １－６ Alkyl)piperazinyl or C １－６ It is an alkylpiperazinyl; R ４ C １－６ Alkoxy C １－６ It is alkyl; A １ These are hydroxyphenylene or thiazoylene; A ２ C １－６ It is alkylene; M is O or CH ２ And; L is C １－６ Alkylene or Halo C １－６ A compound that is alkylene; or a pharmaceutically acceptable salt thereof.

2. A compound of formula (Ia), During the ceremony, R １ teeth, C ２－６ 1-oxo-2,7-diazaspiro[4.4]nonanyl substituted with alkynylcarbonyl, or (Jiharo C １－６ Alkyl)carbonyl, C ２－６ Alkenylcarbonyl, C ２－６ Alkynylcarbonyl or Halo C ２－６ It is a 5-oxo-2,6-diazaspiro[3.4]octanyl substituted with an alkenylcarbonyl; Here, R ５ C １－６ It is alkyl; R ６ Hello C ２－６ C substituted with alkynyl ３－７ Cycloalkyl, (Jiharo C １－６ Alkyl)carbonyl, C ２－６ Alkenylcarbonyl, C ２－６ Alkynylcarbonyl, halogen and halo C ２－６ Piperidyls that are substituted once or twice with substituents independently selected from alkenylcarbonyls, or (Jiharo C １－６ Alkyl)carbonyl, C ２－６ Alkenylcarbonyl, C ２－６ Alkinylcarbonyl or Morpholino C ２－６ It is a pyrrolidinyl substituted with an alkynylcarbonyl; R ２ C １－６ It is alkyl; R ３ H, Morpholino, (Halo C １－６ Alkyl)piperazinyl or C １－６ It is an alkylpiperazinyl; R ４ C １－６ Alkoxy C １－６ It is alkyl; A １ These are hydroxyphenylene or thiazoylene; A ２ C １－６ It is alkylene; M is O or CH ２ And; L is C １－６ Alkylene or Halo C １－６ A compound that is alkylene; or a pharmaceutically acceptable salt thereof.

3. R １ but R ５ is C １－６ It is alkyl; R ６ (Jiharo C １－６ Alkyl)carbonyl, C ２－６ Alkenylcarbonyl, halogen and halo C ２－６ The compound according to claim 1 or 2, wherein piperidyl is twice substituted with substituents independently selected from an alkenylcarbonyl.

4. R １ but R ５ is C １－６ It is alkyl; R ６ is halogen and (dihalo C １－６ Alkyl)carbonyl, C ２－６ Alkenylcarbonyl and Halo C ２－６ The compound according to any one of claims 1 to 3, wherein piperidyl is substituted with another substituent selected from alkenylcarbonyl.

5. R １ but R ５ is methyl; R ６ The compound according to any one of claims 1 to 4, wherein is 4-fluoro-1-propa-2-enoyl-4-piperidyl, 4-fluoro-1-(2-fluoropropa-2-enoyl)-4-piperidyl, 4-fluoro-1-(2-chloro-2-fluoroacetyl)-4-piperidyl, or 4-fluoro-1-propa-2-enoyl-4-piperidyl.

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

7. R ３ is morpholino or C １－６ A compound according to any one of claims 1 to 6, wherein the compound is an alkylpiperazinyl.

8. R ３ The compound according to any one of claims 1 to 7, wherein is morpholino or 4-methylpiperazine-1-yl.

9. R ４ The compound according to any one of claims 1 to 8, wherein is 1-methoxyethyl.

10. A １ but The compound according to any one of claims 1 to 9, wherein bond "a" is bonded to a tricyclic ring.

11. A ２ The compound according to any one of claims 1 to 10, wherein A is dimethylmethylene.

12. The compound according to any one of claims 1 to 11, wherein M is O.

13. L is C １－６ The compound according to any one of claims 1 to 12, which is an alkylene.

14. The compound according to any one of claims 1 to 13, wherein L is ethylene.

15. A compound according to claim 1 or 2, R １ but R ５ is C １－６ alkyl; R ６ is piperidyl substituted with halogen and another substituent selected from (dihalo C １－６ alkyl)carbonyl, C ２－６ alkenylcarbonyl and halo C ２－６ alkenylcarbonyl; R ２ However, C １－６ It is alkyl; R ３ However, morpholino or C １－６ It is an alkylpiperazinyl; R ４ However, C １－６ Alkoxy C １－６ It is alkyl; A １ but Bond "a" is bonded to a triring; A ２ However, C １－６ It is alkylene; M is O; L is C １－６ A compound that is alkylene; or a pharmaceutically acceptable salt thereof.

16. The compound according to claim 15, R １ but R ５ is methyl; R ６ These are 4-fluoro-1-propa-2-enoyl-4-piperidyl, 4-fluoro-1-(2-fluoropropa-2-enoyl)-4-piperidyl, 4-fluoro-1-[(2R)-2-chloro-2-fluoroacetyl]-4-piperidyl, or 4-fluoro-1-propa-2-enoyl-4-piperidyl; R ２ However, it is isopropyl; R ３ However, it is morpholino or 4-methylpiperazine-1-yl; R ４ However, it is (1S)-1-methoxyethyl; A １ but Bond "a" is bonded to a triring; A ２ However, it is dimethylmethylene; M is O; A compound in which L is ethylene; or a pharmaceutically acceptable salt thereof.

17. The following compounds can be selected: (3S)-1-[(2R)-2-chloro-2-fluoroacetyl]-N-[(1S)-1-[[(20S,26S)-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-19,25-dioxo-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 ２，６ 1. ２０，２４ . 0 ４，１４ . 0 ５，１２ ]Tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaen-26-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide; (3S)-1-[(2R)-2-chloro-2-fluoroacetyl]-N-[(1S)-1-[[(19S,25S)-29-hydroxy-(12M)-12-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-15,15-dimethyl-18,24-dioxo-7,17-dioxa-11,23,32-triazahexacyclo[25.3.1.1 ２，６ 1. １９，２３ . 0 ４，１３ . 0 ５，１１ ]Tritriaconta-1(30),2,4,6(33),12,27(31),28-heptaen-25-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide; 1-[(2R)-2-chloro-2-fluoroacetyl]-4-fluoro-N-[(1S)-1-[[(19S,25S)-29-hydroxy-(12M)-12-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-15,15-dimethyl-18,24-dioxo-7,17-dioxa-11,23,32-triazahexacyclo[25.3.1.1 ２，６ 1. １９，２３ . 0 ４，１３ . 0 ５，１１ ]Tritriaconta-1(30),2,4,6(33),12,27(31),28-heptaen-25-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide; (3S)-1-[(2R)-2-chloro-2-fluoroacetyl]-N-[(1S)-1-[[(18S,24S)-28-hydroxy-(11M)-11-[(3R)-2-[(1S)-1-methoxyethyl]-2,3-dihydropyridine-3-yl]-14,14-dimethyl-17,23-dioxo-16-oxa-10,22,31-triazahexacyclo[24.3.1.1 ２，６ 1. １８，２２ . 0 ４，１２ . 0 ５，１０ ]dotriaconta-1(29),2,4,6(32),11,26(30),27-heptaen-24-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide; (3S)-1-[(2R)-2-chloro-2-fluoroacetyl]-N-[(1S)-1-[[(18S,24S)-28-hydroxy-(11M)-11-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-14,14-dimethyl-17,23-dioxo-7,16-dioxa-10,22,31-triazahexacyclo[24.3.1.1 ２，６ 1. １８，２２ . 0 ４，１２ . 0 ５，１０ Dotriaconta-1(29),2,4,6(32),11,26(30),27-heptaen-24-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide; (3S)-1-[(2R)-2-chloro-2-fluoroacetyl]-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazine-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 ２，５ 1. ９，１３ . 0 １９，２７ . 0 ２１，２６ ]Hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide; (2S)-2-[2-[(2R)-2-chloro-2-fluoroacetyl]-5-oxo-2,6-diazaspiro[3.4]octan-6-yl]-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazine-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 ２，５ 1. ９，１３ . 0 １９，２７ . 0 ２１，２６ ]Hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]-3-methylbutanamide; (2S)-2-(2-buta-2-inoyl-5-oxo-2,6-diazaspiro[3.4]octan-6-yl)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazine-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 ２，５ 1. ９，１３ . 0 １９，２７ . 0 ２１，２６ ]Hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]-3-methylbutanamide; (2S)-2-[2-[(2R)-2-chloro-2-fluoroacetyl]-5-oxo-2,6-diazaspiro[3.4]octan-6-yl]-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 ２，５ 1. ９，１３ . 0 １９，２７ . 0 ２１，２６ ]Hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]-3-methylbutanamide; (2S)-2-(2-buta-2-inoyl-5-oxo-2,6-diazaspiro[3.4]octan-6-yl)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 ２，５ 1. ９，１３ . 0 １９，２７ . 0 ２１，２６ ]Hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]-3-methylbutanamide; (2S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 ２，５ 1. ９，１３ . 0 １９，２７ . 0 ２１，２６ ]Hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]-3-methyl-2-(5-oxo-2-propa-2-enoyl-2,6-diazaspiro[3.4]octan-6-yl)butanamide; (3S)-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 ２，５ 1. ９，１３ . 0 １９，２７ . 0 ２１，２６ ]Hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-1-(4-morpholinbuta-2-inoyl)pyrrolidine-3-carboxamide; (2S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazine-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 ２，５ 1. ９，１３ . 0 １９，２７ . 0 ２１，２６ ]Hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]-3-methyl-2-(5-oxo-2-propa-2-enoyl-2,6-diazaspiro[3.4]octan-6-yl)butanamide; (2S)-2-(2-buta-2-inoyl-5-oxo-2,6-diazaspiro[3.4]octan-6-yl)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazine-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 ２，５ 1. ９，１３ . 0 １９，２７ . 0 ２１，２６ ]Hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]-3-methylbutanamide; 4-Fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 ２，５ 1. ９，１３ . 0 １９，２７ . 0 ２１，２６ ]Hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-1-propa-2-enoylpiperidine-4-carboxamide; 1-Buta-2-inoyl-4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 ２，５ 1. ９，１３ . 0 １９，２７ . 0 ２１，２６ ]Hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide; cis-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 ２，５ 1. ９，１３ . 0 １９，２７ . 0 ２１，２６ ]Hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-3-(3,3,3-trifluoropropane-1-inyl)cyclobutanecarboxamide; 1-[(2R)-2-chloro-2-fluoroacetyl]-4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 ２，５ 1. ９，１３ . 0 １９，２７ . 0 ２１，２６ ]Hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide; (2S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazine-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 ２，５ 1. ９，１３ . 0 １９，２７ . 0 ２１，２６ ]Hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]-3-methyl-2-(5-oxo-2-propa-2-enoyl-2,6-diazaspiro[3.4]octan-6-yl)butanamide; (2S)-2-[2-[(2R)-2-chloro-2-fluoroacetyl]-5-oxo-2,6-diazaspiro[3.4]octan-6-yl]-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazine-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 ２，５ 1. ９，１３ . 0 １９，２７ . 0 ２１，２６ ]Hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]-3-methylbutanamide; cis-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazine-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 ２，５ 1. ９，１３ . 0 １９，２７ . 0 ２１，２６ ]Hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-3-(3,3,3-trifluoropropane-1-inyl)cyclobutanecarboxamide; (2S)-2-[2-(2-fluoropropanenoyl)-5-oxo-2,6-diazaspiro[3.4]octan-6-yl]-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 ２，５ 1. ９，１３ . 0 １９，２７ . 0 ２１，２６ ]Hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]-3-methylbutanamide; cis-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazine-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 ２，５ 1. ９，１３ . 0 １９，２７ . 0 ２１，２６ ]Hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-3-(3,3,3-trifluoropropane-1-inyl)cyclobutanecarboxamide; 4-Fluoro-1-(2-Fluoropropa-2-enoyl)-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 ２，５ 1. ９，１３ . 0 １９，２７ . 0 ２１，２６ ]Hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide; 1-Buta-2-inoyl-4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazine-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 ２，５ 1. ９，１３ . 0 １９，２７ . 0 ２１，２６ ]Hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide; 4-Fluoro-1-(2-Fluoropropane-2-enoyl)-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazine-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 ２，５ 1. ９，１３ . 0 １９，２７ . 0 ２１，２６ ]Hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide; 1-[(2R)-2-chloro-2-fluoroacetyl]-4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazine-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 ２，５ 1. ９，１３ . 0 １９，２７ . 0 ２１，２６ ]Hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide; 1-[(2R)-2-chloro-2-fluoro-acetyl]-4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 ２，５ 1. ９，１３ . 0 １９，２７ . 0 ２１，２６ ]Hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide; 4-Fluoro-1-(2-Fluoropropa-2-enoyl)-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 ２，５ 1. ９，１３ . 0 １９，２７ . 0 ２１，２６ ]Hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide; 1-Buta-2-inoyl-4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 ２，５ 1. ９，１３ . 0 １９，２７ . 0 ２１，２６ ]Hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide; 1-[(2R)-2-chloro-2-fluoroacetyl]-4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazine-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 ２，５ 1. ９，１３ . 0 １９，２７ . 0 ２１，２６ ]Hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide; 4-Fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazine-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 ２，５ 1. ９，１３ . 0 １９，２７ . 0 ２１，２６ ]Hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-1-propa-2-enoylpiperidine-4-carboxamide; 1-Buta-2-inoyl-4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazine-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 ２，５ 1. ９，１３ . 0 １９，２７ . 0 ２１，２６ ]Hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide; (3R)-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 ２，５ 1. ９，１３ . 0 １９，２７ . 0 ２１，２６ ]Hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-1-propa-2-enoyl-pyrrolidine-3-carboxamide; (3R)-1-buta-2-inoyl-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 ２，５ 1. ９，１３ . 0 １９，２７ . 0 ２１，２６ ]Hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide; 4-Fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazine-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 ２，５ 1. ９，１３ . 0 １９，２７ . 0 ２１，２６ ]Hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-1-propa-2-enoylpiperidine-4-carboxamide; (2S)-2-[(5R)-7-buta-2-inoyl-1-oxo-2,7-diazaspiro[4.4]nonane-2-yl]-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazine-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 ２，５ 1. ９，１３ . 0 １９，２７ . 0 ２１，２６ ]Hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]-3-methylbutanamide; 4-Fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 ２，５ 1. ９，１３ . 0 １９，２７ . 0 ２１，２６ ]Hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-1-propa-2-enoylpiperidine-4-carboxamide; N-[(1S)-1-[[(7S,13S)-23,23-difluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazine-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 ２，５ 1. ９，１３ . 0 １９，２７ . 0 ２１，２６ ]Hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-4-fluoro-N-methyl-1-propa-2-enoylpiperidine-4-carboxamide; N-[(1S)-1-[[(7S,13S)-23,23-difluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 ２，５ 1. ９，１３ . 0 １９，２７ . 0 ２１，２６ ]Hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-4-fluoro-1-(2-fluoropropane-2-enoyl)-N-methyl-piperidine-4-carboxamide; 1-[(2R)-2-chloro-2-fluoroacetyl]-N-[(1S)-1-[[(7S,13S)-23,23-difluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 ２，５ 1. ９，１３ . 0 １９，２７ . 0 ２１，２６ ]Hentriaconta-1(29),2,5(31),19,25,27-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-4-fluoro-N-methyl-piperidine-4-carboxamide; N-[(1S)-1-[[(7S,13S)-23,23-difluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 ２，５ 1. ９，１３ . 0 １９，２７ . 0 ２１，２６ ]Hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-4-fluoro-N-methyl-1-propa-2-enoylpiperidine-4-carboxamide; 1-Buta-2-inoyl-N-[(1S)-1-[[(7S,13S)-23,23-difluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 ２，５ 1. ９，１３ . 0 １９，２７ . 0 ２１，２６ ]Hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-4-fluoro-N-methyl-piperidine-4-carboxamide; 4-Fluoro-1-(2-Fluoropropane-2-enoyl)-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazine-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 ２，５ 1. ９，１３ . 0 １９，２７ . 0 ２１，２６ ]Hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide; 4-Fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17,23,23-tetramethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 ２，５ 1. ９，１３ . 0 １９，２７ . 0 ２１，２６ ]Hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-1-propa-2-enoylpiperidine-4-carboxamide; 4-Fluoro-N-[(1S)-1-[[(7S,13S,22S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17,22-trimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 ２，５ 1. ９，１３ . 0 １９，２７ . 0 ２１，２６ ]Hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-1-propa-2-enoylpiperidine-4-carboxamide; and 4-Fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17,23,23-tetramethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 ２，５ 1. ９，１３ . 0 １９，２７ . 0 ２１，２６ ]Hentriaconta-1(29),2,5(31),19,25,27-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-1-propa-2-enoylpiperidine-4-carboxamide; or a pharmaceutically acceptable salt thereof.

18. A method for preparing a compound according to any one of claims 1 to 17, comprising the following steps: a) Compound of formula (II), acid (III), A step of forming a compound of formula (I) by carrying out a coupling reaction in the presence of a coupling reagent and a base; b) Compound of formula (VI), and acid (VII), The coupling reaction is carried out in the presence of a coupling reagent and a base to obtain the compound of formula (VIII). The process of forming; c) Compound of formula (XI), Acid (XII), The coupling reaction is carried out in the presence of a coupling reagent and a base to obtain the compound of formula (XIII). The process of forming; Includes any of the following: In the formula, Q is an unsubstituted or substituted piperidinylene or pyrrolidinylene; T is a dihalo C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinil, Halo C ２－６ Alkenyl or Morpholino C ２－６ It is alkinyl; R １ ~R ６ A １ A ２ , M and L are defined as in any one of claims 1 to 16; the coupling reagent in steps a) to c) is T ３ A method wherein the base is P, HATU, PyBOP, or EDCI / HOBt; and the base in steps a) to c) is TEA, DIEPA, or DMAP.

19. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 17 for use as a therapeutically active substance.

20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 17 and a pharmaceutically acceptable additive.

21. Use of a compound according to any one of claims 1 to 17 for the treatment of KRAS G12C protein-related disorders.

22. Use of a compound according to any one of claims 1 to 17 for the treatment of KRAS G12C, G12D, and G12V protein-related disorders.

23. Use of a compound according to any one of claims 1 to 17 for inhibiting RAS interaction with a downstream effector, wherein the downstream effector is RAF and PI3K.

24. Use of a compound according to any one of claims 1 to 17 for inhibiting the propagation of cancerous MAPK and PI3K signaling.

25. Use of a compound according to any one of claims 1 to 17 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.

26. Use of a compound according to any one of claims 1 to 17 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.

27. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 17 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.

28. Use of a compound according to any one of claims 1 to 17 for preparing 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.

29. 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, and the method comprises administering a therapeutically effective amount of any one of claims 1 to 17.

30. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 17, as produced according to the method of claim 18.

31. The invention as previously described herein.

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