Tricyclic compounds for the treatment of cancer

Abstract

The present invention relates to a compound of formula (Ib), TIFF2026506637000237.tif69170, R 1 ~R 3 wherein M and L are as described herein, as well as their pharmaceutically acceptable salts, enantiomers and diastereomers, and compositions comprising and methods of using said compounds.

Description

[Technical Field]

[0001] The present invention relates to organic compounds useful for the treatment and / or prophylaxis in mammals, particularly the inhibition of mutant KRAS, which is useful for treating cancer. [Background technology]

[0002] FIELD OF THE INVENTION RAS is one of the most well-known proto-oncogenes. Approximately 30% of human cancers contain mutations in its three most notable members, KRAS, HRAS, and NRAS, making them the most common oncogenic drivers. KRAS mutations are generally associated with poor prognosis, particularly in colorectal, pancreatic, and lung cancers. As the most frequently mutated RAS isoform, KRAS has been intensively studied over the past few years. Among the most commonly occurring KRAS alleles (including G12D, G12V, G12C, G13D, G12R, G12A, G12S, and Q61H), G12C, G12D, and G12V account for more than half of all KRAS-driven cancers across colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC), and lung adenocarcinoma (LUAD). Also notably, wild-type KRAS amplification is found in approximately 7% of all KRAS-altered cancers (ovarian, esophagogastric, and uterine), ranking among the most common mutations.

[0003] All RAS proteins belong to the small GTPase family, which hydrolyzes GTP to GDP. KRAS is structurally divided into an effector-binding lobe, followed by an allosteric lobe, and a carboxy-terminal region responsible for membrane anchoring. The effector lobe contains the P-loop, switch I, and switch II regions. The switch I / II loop plays an important 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] The KRAS protein switches from an inactive to an active form via binding to GTP or 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), which are involved in catalyzing the exchange of GDP for GTP, enhancing intrinsic GTPase activity, or accelerating RAS-mediated GTP hydrolysis. Inactive RAS-GDP is released by the RAF RAS-binding domain (RAF) in response to extracellular stimuli. RBD), which directly binds to RAS-GTP, recruiting the RAF kinase family from the cytoplasm to the membrane, where it dimerizes and becomes active. Activated RAF then propagates growth signals through a series of phosphorylation reactions on its downstream mitogen-activated protein kinases (MEKs) and extracellular signal-regulated kinases (ERKs). 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 exhibit distinct binding preferences, all RAFs possess a conserved RBD for forward transduction of MAPK signaling, which is frequently used to characterize KRAS inhibition (e.g., the KRAS-BRAF complex described herein). RBD For KRAS, mutations at positions 12, 13, 61, and 146 result in a shift to an active KRAS form by impairing nucleotide hydrolysis or activating nucleotide exchange, resulting in overactivation of the MAPK pathway, leading to tumorigenesis.

[0005] Despite its well-recognized importance in cancer malignancy, ongoing efforts have failed to develop approved therapies for KRAS mutant cancers until recently, with the first-line drug AMG510 being rapidly approved as second-line treatment in KRAS G12C-driven non-small cell lung cancer (NSCLC). Nevertheless, clinically acquired resistance to KRAS G12C inhibitors emerges rigorously with disease progression after approximately 6 months of treatment. Secondary RAS mutations at oncogenic hotspots (e.g., G12 / G13 / Q61) and within the switch II pocket (e.g., H95, R68, and Y96) have been observed, with all of these mutations converging to reactivate RAS-MAPK signaling. Furthermore, over 85% of all KRAS mutant or wild-type amplification-driven cancers still lack novel therapeutics. Collectively, both the myriad escape mechanisms and the variety of oncogenic alleles highlight the urgent medical need for additional RAS treatments. Therefore, the inventors have invented oral compounds that target and inhibit RAS alleles for the treatment of RAS mutant-driven cancers. Summary of the Invention

[0006] Summary of the Invention The present invention relates to novel compounds of formula (Ib) TIFF2026506637000002.tif69170 formula, R 1 is 2-oxabicyclo[2.1.1]hexanyl, 3-oxabicyclo[3.1.0]hexanyl, 6-bicyclo[3.1.0]hexanyl substituted twice with halogen, 6-Tricyclo[3.1.1.0 3,6 ]heptanyl, C 1~6 Alkyl, C 1~6 Alkylpyridinyl, C 1~6 Alkylpyrimidinyl, C 1~6 Alkyltetrazolyl, C 3~7 Cycloalkyl, HaloC 1~6C substituted once, twice or three times with substituents independently selected from alkyl, halogen, halophenyl, hydroxy, phenyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl and thiazolyl 3~7 cycloalkyl, or is tetrahydropyranyl; R 2 is 1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazinyl, 3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazinyl, morpholinyl, or Unsubstituted or C 1~6 Alkoxy C 1~6 Alkyl, C 1~6 Alkyl, C 3~7 Cycloalkyl, HaloC 1~6 Alkyl, Hydroxy C 1~6 Alkyl, morpholinyl C 1~6 Alkyl, oxetanyl, oxopyrrolidinyl C 1~6 Alkyl and tetrahydrofuranyloxy C 1~6 piperazinyl substituted with substituents independently selected from alkyl; R 3 is H or a halogen; M is C 1~6 alkylene or O; L is C 1~6 Alkylene, Hydroxy C 1~6 Alkylene or HaloC 1~6 is alkylene, The present invention relates to a compound, or a pharmaceutically acceptable salt, enantiomer, and diastereomer thereof.

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

[0008] The compounds of formula (I), (Ia), (Ib) or (Ic) showed good KRAS inhibition against G12C, G12D and G12V.

[0009] In another embodiment, the compounds of the present invention have significantly improved single-dose pharmacokinetic (PK) properties compared to the reference compound, suggesting that the compounds of the present invention are more suitable for the treatment of RAS-mutated cancers as oral therapeutic active ingredients in the clinic (Example 128).

[0010] In another embodiment, compounds of the present invention exhibited excellent human hepatocyte stability, which is advantageous for improving the in vivo performance of the compounds, such as dose reduction, enhanced exposure, and extended half-life (Example 129).

[0011] In another embodiment, compounds of the present invention exhibited reduced inhibitory effects on the hERG potassium channel compared to a reference compound, suggesting that compounds of the present invention may reduce concerns regarding cardiovascular toxicity associated with hERG channel blockade (Example 138).

[0012] In another embodiment, compounds of the present invention exhibit better selectivity compared to reference compounds over WT KRAS / HRAS / NRAS, potentially demonstrating improved tolerability and safety profiles (Example 132).

[0013] In another embodiment, compounds of the invention consistently exhibit more potent antiproliferative activity across a 119 cell panel that was significantly differentiated from the reference compound-treated group, potentially leading to more robust antitumor responses in the clinic (Example 131).

[0014] In another embodiment, compounds of the invention exhibit longer and more sustained pathway inhibition over the treatment period, demonstrating significantly enhanced antitumor activity compared to reference compounds, potentially leading to more durable antitumor responses in the clinic (Example 130).

[0015] In another embodiment, the compounds of the present invention exhibited much higher binding affinity to CYPA and significantly lower dissociation rates, demonstrating greater stability of the formed CYPA-compound binary complex. This result is consistent with the smaller potency shift observed in Example 24 in the washout assay of Example 140, which further suggests a more sustained inhibition of cell proliferation, which may be advantageous for achieving sustained efficacy in the clinic (Examples 139 and 140).

[0016] Furthermore, the compounds of the present invention showed superior tumor growth inhibition (TGI) in a brain metastasis intracranial model, improved toxicity and solubility profiles, and avoided the generation of undesirable or toxic metabolites in vivo compared to reference compounds. [Brief explanation of the drawings]

[0017] [Figure 1] Absolute configuration of compound F6 in the form of (2S,3S)-2,3-bis[(4-methylbenzoyl)oxy]butanedioic acid salt acetonitrile solvate. [Figure 2] Bioluminescence signal changes and body weight changes after administration of vehicle or test article to female BALB / c nude mice bearing NCI-H1373-luc intracranial tumors. Data points represent the mean ± SEM. [Figure 3] Figure 2. Photographs of tumor bioluminescence in each group. [Figure 4] DUSP6 express levels in brain samples from the NCI-H1373-luc intracranial tumor model in Figure 2. All data were analyzed using Prism GraphPad software. *** indicates p<0.001. Error bars represent the standard error of the mean (SEM). [Figure 5]DUSP6 expresses levels in tumor samples from the SHP77 xenograft model. The difference in DUSP6 inhibition relative to the EX24 group was determined to be statistically significant relative to the A122 group at both 48 and 72 hours post-administration by two-tailed t-test. * indicates p<0.05. Error bars represent the standard error of the mean (SEM). All data were analyzed using Prism GraphPad software. [Figure 6] Tumor volume and body weight changes after administration of vehicle or test article to female CB-17 SCID mice bearing SHP-77 SCLC tumors. Data points represent mean ± SEM. Tumor volumes on day 14 for the EX24 group were determined to be statistically significant compared to the A122 group by two-tailed t-test. * indicates P<0.05. po: oral administration; QD: once daily. [Figure 7] Scatter plot of IC50 values ​​for the RAS-intoxicated cell panel (n=119) from Table 3. The median IC50 for the EX24 group (0.95 nM) was determined to be statistically significant relative to the median IC50 for the A122 group (1.90 nM) by a two-tailed t-test. **** indicates P<0.0001. DETAILED DESCRIPTION OF THE INVENTION

[0018] Detailed Description of the Invention definition "C 1~6 The term "alkyl" refers to saturated straight or branched chain alkyl groups containing 1 to 6, especially 1 to 4, carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, etc. 1~6 "Alkyl" groups are methyl, ethyl, and n-propyl.

[0019] "C 1~6 The term "alkylene" means a linear saturated divalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon radical of 3 to 6 carbon atoms. 1~6Examples of alkylene groups include methylene, ethylene, propylene, 2-methylpropylene, butylene, 2-ethylbutylene, pentylene, and hexylene.

[0020] The terms "halogen" and "halo" are used interchangeably herein and refer to fluoro, chloro, bromo, or iodo.

[0021] "Haro C 1~6 The term "alkyl" refers to 1~6 C in which at least one of the hydrogen atoms of the alkyl group is replaced by the same or different halogen atom, in particular a fluoro atom. 1~6 means an alkyl group. Examples of haloalkyl include monofluoro-, difluoro- or trifluoro-methyl, -ethyl or -propyl, such as 3,3,3-trifluoropropyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, fluoromethyl or trifluoromethyl.

[0022] "Haro C 1~6 The term "alkylene" refers to 1~6 C in which at least one hydrogen atom of the alkylene group is replaced by the same or different halogen atom 1~6 represents an alkylene group.

[0023] The term "halophenyl" means a phenyl group in which at least one of the hydrogen atoms of the phenyl group has been replaced by the same or different halogen atom.

[0024] "C 3-7The term "cycloalkyl" means a monovalent saturated monocyclic or bicyclic hydrocarbon radical of 3 to 7 ring carbon atoms. Bicyclic means consisting of two saturated carbocyclic 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.

[0025] The terms "cis" and "trans" refer to the relative stereochemistry of molecules or moieties. For example: intermediate R1 as a trans isomer is TIFF2026506637000003.tif27170. The method of indicating relative stereochemistry also applies to the final compound.

[0026] Those skilled in the art will recognize that the following structures of compounds of formula (Ia) and (Ia') are equivalent, particularly with respect to the chiral centers. TIFF2026506637000004.tif70170

[0027] The term "pharmaceutically acceptable salt" means a salt that is not biologically or otherwise undesirable. Pharmaceutically acceptable salts include both acid and base addition salts.

[0028] The term "pharmaceutically acceptable acid addition salt" refers to a pharmaceutically acceptable salt formed with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and the like, and an organic acid selected from the aliphatic, alicyclic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid.

[0029] 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 salt, potassium salt, ammonium salt, calcium salt, magnesium salt, iron salt, zinc salt, copper salt, manganese salt, and aluminum salt. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines, including natural substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperidine, N-ethylpiperidine, and polyamine resins.

[0030] The term "pharmaceutically active metabolite" refers to a pharmacologically active product produced through metabolism in the body of a particular compound or its salt. 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 compounds of the present invention and alter how the drug is distributed in and excreted from the body. However, in some cases, drug metabolism is required for therapeutic effect.

[0031] The term "therapeutically effective amount" means an amount of a compound or molecule of the invention that, when administered to a subject, will (i) treat or prevent a particular disease, condition, or disorder, (ii) reduce, ameliorate, or eliminate one or more symptoms of a particular disease, condition, or disorder, or (iii) prevent or delay the onset of one or more symptoms of a particular disease, condition, or disorder, as described herein. A therapeutically effective amount will vary depending on the compound, the condition being treated, the severity of the disease being treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending physician or veterinarian, and other factors.

[0032] The term "pharmaceutical composition" means a mixture or solution containing a therapeutically effective amount of an active ingredient together with pharmaceutically acceptable excipients, for administration to a mammal, e.g., a human, in need thereof.

[0033] The terms "pharmaceutically acceptable excipient," "pharmaceutically acceptable carrier," and "therapeutically inactive excipient" can be used interchangeably and refer to any pharmaceutically acceptable ingredient in a pharmaceutical composition that has no therapeutic activity and is non-toxic to a subject to which it is administered, such as a disintegrant, binder, filler, solvent, buffer, tonicity agent, stabilizer, antioxidant, surfactant, carrier, diluent, or lubricant used in formulating a pharmaceutical product.

[0034] KRAS inhibitors The present invention relates to (i') a compound of formula (Ib), TIFF2026506637000005.tif69170 formula, R 1 is 2-oxabicyclo[2.1.1]hexanyl, 3-oxabicyclo[3.1.0]hexanyl, 6-bicyclo[3.1.0]hexanyl substituted twice with halogen, 6-Tricyclo[3.1.1.0 3,6 ]heptanyl, C 1~6 Alkyl, C 1~6 Alkylpyridinyl, C 1~6 Alkylpyrimidinyl, C 1~6 Alkyltetrazolyl, C 3~7 Cycloalkyl, HaloC 1~6 C substituted once, twice or three times with substituents independently selected from alkyl, halogen, halophenyl, hydroxy, phenyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl and thiazolyl 3~7 cycloalkyl, or is tetrahydropyranyl; R 2 is 1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazinyl, 3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazinyl, morpholinyl, or Unsubstituted or C 1~6 Alkoxy C 1~6 Alkyl, C 1~6 Alkyl, C 3~7 Cycloalkyl, HaloC 1~6 Alkyl, Hydroxy C 1~6 Alkyl, morpholinyl C 1~6 Alkyl, oxetanyl, oxopyrrolidinyl C 1~6 Alkyl and tetrahydrofuranyloxy C 1~6 piperazinyl substituted with substituents independently selected from alkyl; R 3 is H or a halogen; M is C 1~6alkylene or O; L is C 1~6 Alkylene, Hydroxy C 1~6 Alkylene or HaloC 1~6 is alkylene, The present invention relates to a compound, or a pharmaceutically acceptable salt, enantiomer, and diastereomer thereof.

[0035] Another embodiment of the present invention is (ii') a compound of formula (Ic) TIFF2026506637000006.tif66170 formula, R 1 is 2-oxabicyclo[2.1.1]hexanyl, 3-oxabicyclo[3.1.0]hexanyl, 6-bicyclo[3.1.0]hexanyl substituted twice with halogen, 6-Tricyclo[3.1.1.0 3,6 ]heptanyl, C 1~6 Alkyl, C 1~6 Alkylpyridinyl, C 1~6 Alkylpyrimidinyl, C 1~6 Alkyltetrazolyl, C 3~7 Cycloalkyl, HaloC 1~6 C substituted once, twice or three times with substituents independently selected from alkyl, halogen, halophenyl, hydroxy, phenyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl and thiazolyl 3~7 cycloalkyl, or is tetrahydropyranyl; R 2 is 1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazinyl, 3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazinyl, morpholinyl, or Unsubstituted or C 1~6 Alkoxy C 1~6 Alkyl, C 1~6 Alkyl, C 3~7 Cycloalkyl, HaloC1~6 Alkyl, Hydroxy C 1~6 Alkyl, morpholinyl C 1~6 Alkyl, oxetanyl, oxopyrrolidinyl C 1~6 Alkyl and tetrahydrofuranyloxy C 1~6 piperazinyl substituted with substituents independently selected from alkyl; R 3 is H or a halogen; M is C 1~6 alkylene or O; L is C 1~6 Alkylene, Hydroxy C 1~6 Alkylene or HaloC 1~6 is alkylene, or a pharmaceutically acceptable salt, enantiomer, or diastereomer thereof.

[0036] A further embodiment of the present invention is a compound of formula (Ib) or (Ic) according to (iii')(i') or (ii'), or pharmaceutically acceptable salts, enantiomers and diastereomers thereof, wherein R 1 is C 1~6 C substituted once or twice with substituents independently selected from alkyl and pyridinyl 3~7 It is cycloalkyl.

[0037] A further embodiment of the present invention is a compound of formula (Ib) or (Ic), or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, according to any one of (iv')(i') to (iii'), wherein R 1 is cyclopropyl substituted once by pyridyl or twice by methyl.

[0038] A further embodiment of the present invention is a compound of formula (Ib) or (Ic), or a pharmaceutically acceptable salt, enantiomer, or diastereomer thereof, according to any one of (v')(i') to (iv'), wherein R 1is 2,3-dimethyl-cyclopropyl or 2-(3-pyridinyl)cyclopropyl.

[0039] A further embodiment of the present invention is a compound of formula (Ib) or (Ic), or a pharmaceutically acceptable salt, enantiomer, or diastereomer thereof, according to any one of (vi')(i') to (v'), wherein R 2 is morpholinyl or C 1~6 It is an alkylpiperazinyl.

[0040] A further embodiment of the present invention is a compound of formula (Ib) or (Ic), or a pharmaceutically acceptable salt, enantiomer, or diastereomer thereof, according to any one of (vii')(i') to (vi'), wherein R 2 is morpholinyl or 4-methylpiperazin-1-yl.

[0041] A further embodiment of the present invention is a compound of formula (Ib) or (Ic) according to any one of (i') to (vii'), or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, wherein M is C 1~6 It is alkylene.

[0042] A further embodiment of the present invention is a compound of formula (Ib) or (Ic), or a pharmaceutically acceptable salt, enantiomer, or diastereomer thereof, according to any one of (ix')(i') to (viii'), wherein M is CH2.

[0043] A further embodiment of the present invention is a compound of formula (Ib) or (Ic), or a pharmaceutically acceptable salt, enantiomer, or diastereomer thereof, according to any one of (x'), (i'), to (ix'), wherein L is ethylene or difluoroethylene.

[0044] A further embodiment of the present invention is a compound of formula (Ib) or (Ic), or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, according to any one of (xi')(i') to (x'), wherein L is TIFF2026506637000007.tif22170, and bond "a" connects to M.

[0045] A further embodiment of the present invention is a compound of formula (Ib) or (Ic) according to any one of (xii')(i') to (xi'), wherein: R 1 But C 1~6 C substituted once or twice with substituents independently selected from alkyl and pyridinyl 3~7 is cycloalkyl; R 2 but morpholinyl or C 1~6 alkylpiperazinyl; R 3 is H; M is C 1~6 is alkylene; L is C 1~6 Alkylene or HaloC 1~6 is alkylene, or a pharmaceutically acceptable salt, enantiomer, or diastereomer thereof.

[0046] A further embodiment of the present invention is a compound of formula (Ib) or (Ic) according to any one of (xiii') (i') to (xii'), wherein: R 1 is 2,3-dimethyl-cyclopropyl or 2-(3-pyridinyl)cyclopropyl; R 2 is morpholinyl or 4-methylpiperazin-1-yl; R 3 is H; M is CH2; L, TIFF2026506637000008.tif22170, wherein bond "a" connects to M; or a pharmaceutically acceptable salt, enantiomer, or diastereomer thereof.

[0047] The present invention provides (i) a compound of formula (I): TIFF2026506637000009.tif70170In the formula, R 1 2-oxabicyclo[2.1.1]hexanyl, 3-oxabicyclo[3.1.0]hexanyl, 6-bicyclo[3.1.0]hexanyl substituted twice with halogen, 6-Tricyclo[3.1.1.0 3,6 ]heptanyl, C 1~6 Alkyl, C 1~6 Alkyltetrazolyl, C 3~7 Cycloalkyl, HaloC 1~6 C substituted once, twice or three times with substituents independently selected from alkyl, halogen, halophenyl, hydroxy, phenyl, pyridazinyl, pyridinyl, and pyrimidinyl 3~7 cycloalkyl, or is tetrahydropyranyl; R 2 However, 1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazinyl, 3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazinyl, morpholinyl, (haloC 1~6 alkyl)piperazinyl or C 1~6 alkylpiperazinyl; M is C 1~6 alkylene or O; L is C 1~6 Alkylene or HaloC 1~6 is alkylene, The present invention relates to a compound, or a pharmaceutically acceptable salt, enantiomer, and diastereomer thereof.

[0048] Another embodiment of the present invention is (ii) a compound of formula (Ia): TIFF2026506637000010.tif69170 formula, R 1 2-oxabicyclo[2.1.1]hexanyl, 3-oxabicyclo[3.1.0]hexanyl, 6-bicyclo[3.1.0]hexanyl substituted twice with halogen, 6-Tricyclo[3.1.1.0 3,6 ]heptanyl, C 1~6 Alkyl, C 1~6 Alkyltetrazolyl, C 3~7 Cycloalkyl, HaloC 1~6 C substituted once, twice or three times with substituents independently selected from alkyl, halogen, halophenyl, hydroxy, phenyl, pyridazinyl, pyridinyl, and pyrimidinyl 3~7 cycloalkyl, or is tetrahydropyranyl; R 2 However, 1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazinyl, 3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazinyl, morpholinyl, (haloC 1~6 alkyl)piperazinyl or C 1~6 alkylpiperazinyl; M is C 1~6 alkylene or O; L is C 1~6 Alkylene or HaloC 1~6 is alkylene, or a pharmaceutically acceptable salt, enantiomer, or diastereomer thereof.

[0049] A further embodiment of the present invention is a compound of formula (I) or (Ia) according to (iii)(i) or (ii), or pharmaceutically acceptable salts, enantiomers and diastereomers thereof, wherein R 1 is C 1~6 C substituted once or twice with substituents independently selected from alkyl and pyridinyl 3~7It is cycloalkyl.

[0050] A further embodiment of the present invention is (iv) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, enantiomer, or diastereomer thereof, according to any one of formulas (i) to (iii), wherein R 1 is cyclopropyl substituted once by pyridyl or twice by methyl.

[0051] A further embodiment of the present invention is (v) a compound of formula (I) or (Ia) according to any one of formulas (i) to (iv), wherein R 1 is 2,3-dimethyl-cyclopropyl or 2-(3-pyridinyl)cyclopropyl.

[0052] A further embodiment of the present invention is (vi) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, enantiomer, or diastereomer thereof, according to any one of formulas (i) to (v), wherein R 2 is morpholinyl or C 1~6 It is an alkylpiperazinyl.

[0053] A further embodiment of the present invention is a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, enantiomer, or diastereomer thereof, according to any one of (vii)(i) to (vi), wherein R 2 is morpholinyl or 4-methylpiperazin-1-yl.

[0054] A further embodiment of the present invention is a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, enantiomer, or diastereomer thereof, according to any one of (viii)(i) to (vii), wherein M is C 1~6 It is alkylene.

[0055] A further embodiment of the present invention is a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, enantiomer, or diastereomer thereof, according to any one of (ix)(i) to (viii), wherein M is CH.

[0056] A further embodiment of the present invention is a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, enantiomer, or diastereomer thereof, according to any one of (x)(i) to (ix), wherein L is ethylene or difluoroethylene.

[0057] A further embodiment of the present invention is a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, enantiomer, or diastereomer thereof, according to any one of (xi)(i) to (x), wherein L is TIFF2026506637000011.tif22170, and bond "a" connects to M.

[0058] A further embodiment of the present invention is (xii) a compound of formula (I) or (Ia) according to any one of (i) to (xi), R 1 But C 1~6 C substituted once or twice with substituents independently selected from alkyl and pyridinyl 3~7 is cycloalkyl; R 2 but morpholinyl or C 1~6 alkylpiperazinyl; M is C 1~6 is alkylene; L is C 1~6 Alkylene or HaloC 1~6 is alkylene, or a pharmaceutically acceptable salt, enantiomer, or diastereomer thereof.

[0059] A further embodiment of the present invention is a compound of formula (I) or (Ia) according to any one of (xiii) (i) to (xii), R1 is 2,3-dimethyl-cyclopropyl or 2-(3-pyridinyl)cyclopropyl; R 2 is morpholinyl or 4-methylpiperazin-1-yl; M is CH2; L, TIFF2026506637000012.tif22170, wherein bond "a" connects to M; or a pharmaceutically acceptable salt, enantiomer, or diastereomer thereof.

[0060] In a more particular embodiment, the present invention provides a compound of formula (I'): TIFF2026506637000013.tif47170In the formula, R 1 , R 2 is as previously defined herein; or a pharmaceutically acceptable salt, enantiomer, or diastereomer thereof.

[0061] In a more particular embodiment, the present invention provides a compound of formula (I'): TIFF2026506637000014.tif47170 formula, R 1 is 2,3-dimethyl-cyclopropyl or 2-(3-pyridinyl)cyclopropyl; R 2 is morpholinyl or 4-methylpiperazin-1-yl; or a pharmaceutically acceptable salt, enantiomer, or diastereomer thereof.

[0062] In a more particular embodiment, the present invention provides a compound of formula (I'a): TIFF2026506637000015.tif47170In the formula, R 1 , R 2 is as previously defined herein; or a pharmaceutically acceptable salt, enantiomer, or diastereomer thereof.

[0063] In a more particular embodiment, the present invention provides a compound of formula (I'a): TIFF2026506637000016.tif47170 formula, R 1 is 2,3-dimethyl-cyclopropyl or 2-(3-pyridinyl)cyclopropyl; R 2 is morpholinyl or 4-methylpiperazin-1-yl; or a pharmaceutically acceptable salt, enantiomer, or diastereomer thereof.

[0064] Another embodiment of the present invention is (xiv') the following: (1S,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]-2-methyl-cyclopropanecarboxamide; (1S,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]-2-methyl-cyclopropanecarboxamide; (1S,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]-2-methyl-cyclopropanecarboxamide; (1S,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-15,24-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]-2-methyl-cyclopropanecarboxamide; (1S,2S)-2-(Difluoromethyl)-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]cyclopropanecarboxamide; (1S,5R,6r)-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[23.3.1.12,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]-3-oxabicyclo[3.1.0]hexane-6-carboxamide; (1S,2S)-N-[(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]-2-methyl-cyclopropanecarboxamide; (1S,2S)-2-(Difluoromethyl)-N-[(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]cyclopropanecarboxamide; (1S,5R,6r)-N-[(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]-3-oxabicyclo[3.1.0]hexane-6-carboxamide; (1S,2S)-2-(Difluoromethyl)-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-15,24-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]cyclopropanecarboxamide; (1S,5R,6r)-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-15,24-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]-3-oxabicyclo[3.1.0]hexane-6-carboxamide; (1S,5R,6r)-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-oxabicyclo[3.1.0]hexane-6-carboxamide; (1S,2S)-2-(Difluoromethyl)-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]cyclopropanecarboxamide; (1S,5R,6r)-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-oxabicyclo[3.1.0]hexane-6-carboxamide; (1R,2S)-2-Cyclopropyl-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]cyclopropanecarboxamide; (1S,2S)-N-[(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]-2-methyl-cyclopropanecarboxamide; (1S,2S)-N-[(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]-2-methyl-cyclopropanecarboxamide; 2,2-Difluoro-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]-1-methyl-cyclopropanecarboxamide; (1S,2S)-2-(Difluoromethyl)-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]cyclopropanecarboxamide; (1S,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]-2-phenyl-cyclopropanecarboxamide; (1r,2R,3S)-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]-2,3-dimethyl-cyclopropanecarboxamide; (1S,2S)-N-[(7S,13S)-(20M)-20-[5-[(9aS)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-2-[(1S)-1-methoxyethyl]-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]-2-methyl-cyclopropanecarboxamide; (1R,2R)-2-(2-fluorophenyl)-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]cyclopropanecarboxamide; (1S,2S)-2-(2-fluorophenyl)-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]cyclopropanecarboxamide; (1S,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]-2-(2-pyridyl)cyclopropanecarboxamide; (1S,2S)-N-[(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(29),2,5(31),19,25,27-hexaen-7-yl]-2-(difluoromethyl)cyclopropanecarboxamide; (1S,2R)-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]-2-methyl-cyclopropanecarboxamide; (1S,2S)-2-(Difluoromethyl)-N-[(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]cyclopropanecarboxamide; (1S,5R,6r)-N-[(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]-3-oxabicyclo[3.1.0]hexane-6-carboxamide; (1R,2S)-2-Cyclopropyl-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(29),2,5(31),19,25,27-hexaen-7-yl]cyclopropanecarboxamide; (1S,2S)-N-[(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[23.3.1.12,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]-2-methyl-cyclopropanecarboxamide; (1S,5R,6r)-N-[(7S,13S)-(20M)-20-[5-[(9aS)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-2-[(1S)-1-methoxyethyl]-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-oxabicyclo[3.1.0]hexane-6-carboxamide; (1S,2S)-N-[(7S,13S)-(20M)-20-[5-[(9aS)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-2-[(1S)-1-methoxyethyl]-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]-2-(difluoromethyl)cyclopropanecarboxamide; (1R,5S,6s)-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-oxabicyclo[3.1.0]hexane-6-carboxamide; (1S,2S)-N-[(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(29),2,5(31),19,25,27-hexaen-7-yl]-2-phenyl-cyclopropanecarboxamide; (1S,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-15,24-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(29),2,5(31),19,25,27-hexaen-7-yl]-2-phenyl-cyclopropanecarboxamide; (1r,2S,3R)-N-[(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]-2,3-dimethyl-cyclopropanecarboxamide; (1S,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(29),2,5(31),19,25,27-hexaen-7-yl]-2-phenyl-cyclopropanecarboxamide; (1S,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]-2-pyrimidin-5-yl-cyclopropanecarboxamide; (1S,5R)-3,3-Difluoro-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]bicyclo[3.1.0]hexane-6-carboxamide; (1S,2S)-N-[(7S,13S)-(20M)-20-[5-[(9aR)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-2-[(1S)-1-methoxyethyl]-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]-2-methyl-cyclopropanecarboxamide; (1S,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]-2-pyrimidin-4-yl-cyclopropanecarboxamide; (1S,2S)-N-[(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(29),2,5(31),19,25,27-hexaen-7-yl]-2-phenyl-cyclopropanecarboxamide; (1R,5S,6s)-N-[(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]-3-oxabicyclo[3.1.0]hexane-6-carboxamide; (1S,2S)-N-[(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]-2-methyl-cyclopropanecarboxamide; 2,2-Difluoro-N-[(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(29),2,5(31),19,25,27-hexaen-7-yl]-1-methyl-cyclopropanecarboxamide; N-[(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[23.3.1.12,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(29),2,5(31),19,25,27-hexaen-7-yl]-1,2-dimethyl-cyclopropanecarboxamide; (1S,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]-2-(3-pyridyl)cyclopropanecarboxamide; (1S,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]-2-(4-pyridyl)cyclopropanecarboxamide; (1R,2R)-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]-2-(4-pyridyl)cyclopropanecarboxamide; 2-(4-Fluorophenyl)-N-[(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(29),2,5(31),19,25,27-hexaen-7-yl]cyclopropanecarboxamide; (1S,5R,6r)-N-[(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]-3-oxabicyclo[3.1.0]hexane-6-carboxamide; (1r,2R,3S)-N-[(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]-2,3-dimethyl-cyclopropanecarboxamide; (1S,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]-2-pyridazin-3-yl-cyclopropanecarboxamide; (1R,2S)-2-Cyclopropyl-N-[(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(29),2,5(31),19,25,27-hexaen-7-yl]cyclopropanecarboxamide; 3,3-Difluoro-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]cyclopentanecarboxamide; 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 .19,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]-2-oxabicyclo[2.1.1]hexane-1-carboxamide; (1S,2S)-N-[(7S,13S)-23,23-difluoro-(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]-2-methyl-cyclopropanecarboxamide; (1r,2R,3S)-N-[(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(29),2,5(31),19,25,27-hexaen-7-yl]-2,3-dimethyl-cyclopropanecarboxamide; (1r,2S,3R)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-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(28),2,5(31),19,25(29),26-hexaen-7-yl]-2,3-dimethyl-cyclopropanecarboxamide; trans-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(29),2,5(31),19,25,27-hexaen-7-yl]-4-(1-methyltetrazol-5-yl)cyclohexanecarboxamide; trans-4-Hydroxy-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]-4-methyl-cyclohexanecarboxamide; 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]tricyclo[3.1.1.0 3,6 ]heptane-6-carboxamide; (1r,2S,3R)-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]-2,3-dimethyl-cyclopropanecarboxamide; (1S,2S)-N-[(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]-2-methyl-cyclopropanecarboxamide; (1r,2S,3R)-N-[(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]-2,3-dimethyl-cyclopropanecarboxamide; 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]tetrahydropyran-4-carboxamide; (1S,2S)-N-[(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]-2-phenyl-cyclopropanecarboxamide; (1S,2S)-N-[(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]-2-phenyl-cyclopropanecarboxamide; (1S,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]-2-pyrimidin-2-yl-cyclopropanecarboxamide; (1R,2R)-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 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]-2-pyrimidin-2-yl-cyclopropanecarboxamide; (1r,2S,3R)-N-[(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(29),2,5(31),19,25,27-hexaen-7-yl]-2,3-dimethyl-cyclopropanecarboxamide; (1r,2S,3R)-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-15,24-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]-2,3-dimethyl-cyclopropanecarboxamide; (1r,2R,3S)-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]-2,3-dimethyl-cyclopropanecarboxamide; (1r,2S,3R)-N-[(7S,13S)-23,23-difluoro-(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]-2,3-dimethyl-cyclopropanecarboxamide; (1S,2S)-N-[(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]-2-pyrimidin-5-yl-cyclopropanecarboxamide; (1S,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]-2-(3-pyridyl)cyclopropanecarboxamide; (1S,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]-2-(3-pyridyl)cyclopropanecarboxamide; (1S,2S)-N-[(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]-2-(3-pyridyl)cyclopropanecarboxamide; (1S,2S)-N-[(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]-2-(3-pyridyl)cyclopropanecarboxamide; (1S,2S)-N-[(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]-2-pyrimidin-5-yl-cyclopropanecarboxamide; (1S,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]-2-pyrimidin-5-yl-cyclopropanecarboxamide; (1S,2S)-N-[(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]-2-pyrimidin-5-yl-cyclopropanecarboxamide; (1S,2S)-N-[(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]-2-(3-pyridyl)cyclopropanecarboxamide; (1S,2S)-N-[(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]-2-(3-pyridyl)cyclopropanecarboxamide; (1S,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-15,24-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]-2-(3-pyridyl)cyclopropanecarboxamide; (1S,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]-2-pyrazin-2-yl-cyclopropanecarboxamide; (1r,2R,3S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,25-dioxa-4-thia-9,21,31,32-tetrazahexacyclo[24.3.1.1 2,5 .1 9,13 .0 19,28 .0 21,27 ]dotriaconta-1(29),2,5(32),19,26(30),27-hexaen-7-yl]-2,3-dimethyl-cyclopropanecarboxamide; (1r,2S,3R)-N-[(7S,13S)-(20M)-20-[5-[(9aR)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-2-[(1S)-1-methoxyethyl]-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]-2,3-dimethyl-cyclopropanecarboxamide; (1S,2S)-N-[(7S,13S)-(20M)-20-[5-[(9aR)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-2-[(1S)-1-methoxyethyl]-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]-2-(3-pyridyl)cyclopropanecarboxamide; (1S,2S)-N-[(7S,13S)-(20M)-20-[5-[(9aR)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-2-[(1S)-1-methoxyethyl]-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]-2-pyrimidin-5-yl-cyclopropanecarboxamide; (1S,2S)-N-[(7S,13S)-(20M)-20-[5-[(9aS)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-2-[(1S)-1-methoxyethyl]-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]-2-(3-pyridyl)cyclopropanecarboxamide; (1S,2S)-N-[(7S,13S)-(20M)-20-[5-[(9aS)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-2-[(1S)-1-methoxyethyl]-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]-2-pyrimidin-5-yl-cyclopropanecarboxamide; (1r,2R,3S)-N-[(7S,13S)-(20M)-20-[5-(4-cyclopropylpiperazin-1-yl)-2-[(1S)-1-methoxyethyl]-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]-2,3-dimethyl-cyclopropanecarboxamide; (1r,2R,3S)-N-[(7S,13S,23S)-23-hydroxy-(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]-2,3-dimethyl-cyclopropanecarboxamide; (1r,2R,3S)-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 ]Hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]-2,3-dimethyl-cyclopropanecarboxamide; (1r,2R,3S)-N-[(7S,13S)-20-[5-[4-(2,2-difluoroethyl)piperazin-1-yl]-2-[(1S)-1-methoxyethyl]-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]-2,3-dimethyl-cyclopropanecarboxamide; (1r,2R,3S)-N-[(7S,13S)-(20M)-20-[5-[4-(2-fluoroethyl)piperazin-1-yl]-2-[(1S)-1-methoxyethyl]-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]-2,3-dimethyl-cyclopropanecarboxamide; (1r,2R,3S)-N-[(7S,13S)-(20M)-20-[5-[4-(3-hydroxypropyl)piperazin-1-yl]-2-[(1S)-1-methoxyethyl]-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]-2,3-dimethyl-cyclopropanecarboxamide; (1R,2R)-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]-2-(4-methylpyrimidin-5-yl)cyclopropanecarboxamide; (1r,2R,3S)-N-[(7S,13S)-(20M)-20-[5-(4-ethylpiperazin-1-yl)-2-[(1S)-1-methoxyethyl]-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]-2,3-dimethyl-cyclopropanecarboxamide; (1R,2R)-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]-2-thiazol-4-yl-cyclopropanecarboxamide; (1r,2S,3R)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2-methoxyethyl)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]-2,3-dimethyl-cyclopropanecarboxamide; (1R,2R)-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]-2-(2-methyl-3-pyridyl)cyclopropanecarboxamide; (1r,2R,3S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-tetrahydropyran-4-ylpiperazin-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]-2,3-dimethyl-cyclopropanecarboxamide; (1r,2R,3S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(oxetan-3-yl)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]-2,3-dimethyl-cyclopropanecarboxamide; (1r,2S,3R)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-[[(2S)-morpholin-2-yl]methyl]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]-2,3-dimethyl-cyclopropanecarboxamide; (1R,2R)-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]-2-(5-methyl-3-pyridyl)cyclopropanecarboxamide; (1r,2R,3S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-[2-(2-oxopyrrolidin-1-yl)ethyl]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]-2,3-dimethyl-cyclopropanecarboxamide; (1r,2R,3S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2-tetrahydrofuran-3-yloxyethyl)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]-2,3-dimethyl-cyclopropanecarboxamide; (1r,2R,3S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(3-methoxy-3-methyl-butyl)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]-2,3-dimethyl-cyclopropanecarboxamide; (1r,2S,3R)-N-[(7S,13S)-29-fluoro-(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]-2,3-dimethyl-cyclopropanecarboxamide; (1S,2S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17,22,22-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]-2-methyl-cyclopropanecarboxamide; (1r,2R,3S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,31,32-tetrazahexacyclo[24.3.1.1 2,5 .1 9,13 .0 19,28 .0 21,27 ]dotriaconta-1(29),2,5(32),19,26(30),27-hexaen-7-yl]-2,3-dimethyl-cyclopropanecarboxamide; and (1r,2R,3S)-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-9,21,32,33-tetrazahexacyclo[25.3.1.1 2,5 .1 9,13 .0 19,29 .0 21,28 ]tritriaconta-1(30),2,5(33),19,27(31),28-hexaen-7-yl]-2,3-dimethyl-cyclopropanecarboxamide or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

[0065] A further embodiment of the present invention is (xv'): TIFF2026506637000017.tif191170TIFF2026506637000018.tif131170, or a pharmaceutically acceptable salt, enantiomer, or diastereomer thereof.

[0066] Another embodiment of the present invention is a process for the preparation of a compound according to any one of (xvi)(i) to (xiii) and (xv'), comprising the steps of: a) reacting a compound of formula (II) with a coupling agent and a base TIFF2026506637000019.tif56170 and acid (III), TIFF2026506637000020.tif20170 to form a compound of formula (Ib), In the formula, R 1 , R 2 M and L are as described in any one of (i) to (xiii); the coupling reagent is T3P, HATU, PyBOP, or EDCI / HOBt; and the base is TEA, DIEPA, or DMAP.

[0067] Another embodiment of the present invention is a method for preparing a compound according to any one of (xvi')(i') to (xv'), comprising the steps of: a) in the presence of a coupling reagent and a base, a compound of formula (IIb): TIFF2026506637000021.tif66170 Acid (III), TIFF2026506637000022.tif20170 to form a compound of formula (Ib), In the formula, R 1 , R 2 M and L are as described in any one of (i') to (xiii'); the coupling reagent is T3P, HATU, PyBOP, or EDCI / HOBt; and the base is TEA, DIEPA, or DMAP.

[0068] Another embodiment of the present invention is (xvii') a compound or pharmaceutically acceptable salt according to any one of (i') to (xv') or (i) to (xiii) for use as a therapeutically active substance.

[0069] Another embodiment of the present invention is (xviii') a pharmaceutical composition comprising a compound according to any one of (i')-(xv') or (i)-(xiii) and a pharmaceutically acceptable excipient.

[0070] Another embodiment of the present invention is (xix') the use of a compound according to any one of (i') to (xv') or (i) to (xiii) for treating a KRAS G12C protein-associated disease.

[0071] Another embodiment of the present invention is (xx') the use of a compound according to any one of (i') to (xv') or (i) to (xiii) for treating a KRAS G12C, G12D and G12V protein-associated disease.

[0072] Another embodiment of the present invention is (xxi') the use of a compound according to any one of (i') to (xv') or (i) to (xiii) for inhibiting RAS interaction with downstream effectors, wherein the downstream effectors are RAF and PI3K.

[0073] Another embodiment of the present invention is (xxii') the use of a compound according to any one of (i') to (xv') or (i) to (xiii) for inhibiting proliferating oncogene MAPK and PI3K signaling.

[0074] Another embodiment of the present invention is (xxiii') use of a compound according to any one of (i') to (xv') or (i) to (xiii) for the treatment or prevention of cancer in a subject in need thereof, wherein the cancer comprises a first RAS mutation that is G12C and a second RAS mutation at a position selected from the group consisting of V8A, V9Y, S17E, A59T, T58I, D69P, M72I, S65W, R68S, D92R, H95N, Y96D, Q99W and F156L.

[0075] Another embodiment of the present invention is (xxiv') use of a compound according to any one of (i') to (xv') or (i) to (xiii) for the preparation of a medicament for treating or preventing cancer in a subject in need thereof, wherein the cancer comprises a first RAS mutation that is G12C and a second RAS mutation at a position selected from the group consisting of V8A, V9Y, S17E, A59T, T58I, D69P, M72I, S65W, R68S, D92R, H95N, Y96D, Q99W and F156L.

[0076] Another embodiment of the present invention is (xxv') the use of a compound according to any one of (i')-(xv') or (i)-(xiii) for the treatment or prevention of a 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.

[0077] Another embodiment of the present invention is (xxvi') the use of a compound according to any one of (i') to (xv') or (i) to (xiii) for the treatment or prevention of a KRAS mutation-driven cancer, wherein the cancer is selected from pancreatic adenocarcinoma, colorectal cancer, and non-small cell lung cancer.

[0078] Another embodiment of the present invention is (xxvii') the use of a compound according to any one of (i') to (xv') or (i) to (xiii) for the treatment or prevention of a primary central nervous system (CNS) tumor with an RAS mutation or a RAS-driven cancer with brain metastasis, wherein the CNS tumor is a primary melanocytic tumor of the CNS with an NRAS mutation; and the cancer is selected from pancreatic adenocarcinoma, colorectal cancer, and non-small cell lung cancer.

[0079] Another embodiment of the present invention is (xxviii') the use of a compound described in any one of (i') to (xv') or (i) to (xiii) for the treatment or prevention of a primary central nervous system (CNS) tumor with an RAS mutation or a RAS-driven cancer with brain metastases, wherein the CNS tumor is a primary melanocytic tumor of the CNS with an NRAS mutation; and the cancer is non-small cell lung cancer.

[0080] Another embodiment of the present invention is (xxix') a compound or pharmaceutically acceptable salt according to any one of (i') to (xv') or (i) to (xiii) for the treatment or prevention of KRAS mutation-driven cancer, wherein the cancer is selected from pancreatic adenocarcinoma, colorectal cancer, and non-small cell lung cancer.

[0081] Another embodiment of the present invention is (xxx') the use of a compound according to any one of (i') to (xv') or (i) to (xiii) for the preparation of a medicament for the treatment or prevention of KRAS mutation-driven cancer, wherein the cancer is selected from pancreatic adenocarcinoma, colorectal cancer and non-small cell lung cancer.

[0082] Another embodiment of the present invention is (xxxi') a method for treating or preventing a KRAS mutation-driven cancer, wherein the cancer is selected from pancreatic adenocarcinoma, colorectal cancer, and non-small cell lung cancer, the method comprising administering a therapeutically effective amount of a compound described in any one of (i') to (xv') or (i) to (xiii).

[0083] Another embodiment of the present invention is a compound or pharmaceutically acceptable salt according to any one of (i')-(xv') or (i)-(xiii) when prepared according to the process of (xxxii')(xvi) or (xvi').

[0084] Pharmaceutical Compositions and Administration In another embodiment, pharmaceutical compositions or medicaments containing a compound of the present invention and a therapeutically inert carrier, diluent, or excipient, as well as methods of using the compounds of the present invention to prepare such compositions and medicaments, are provided. In one example, a compound of Formula I can be formulated into a galenical dosage form by mixing it at ambient temperature, at an appropriate pH and with the desired purity, with a physiologically acceptable carrier, i.e., a carrier that is non-toxic to recipients at the dosage and concentration used. The pH of the formulation will depend primarily on the particular application and the concentration of the compound, but is preferably anywhere from about 3 to about 8. In one example, a compound of Formula (I) is formulated in acetate buffer at pH 5. In another embodiment, the compound of Formula (I) is sterile. The compound can be stored, for example, as a solid or amorphous composition, as a lyophilized formulation, or as an aqueous solution.

[0085] The composition is formulated, dosed and administered in a manner consistent with good medical practice.The factors that should be considered in this regard include the specific disease that is treated, the specific mammal that is treated, the clinical condition of individual patients, the cause of the disorder, the delivery site of the drug, the method of administration, the administration schedule and other factors that are known to medical professionals.The "effective amount" of the compound that is administered is determined by such considerations, and is the minimum amount that is required to inhibit the interaction between mutant RAS (for example, KRAS G12C) and RAF and block oncogenic MAPK signal transduction.For example, this amount may be below the amount that is toxic to normal cells or the whole mammal.

[0086] In one example, a pharmaceutically effective amount of a compound of the invention administered parenterally per dose ranges from about 0.1 to 1000 mg / kg, or about 0.1 to 1000 mg per kg of patient body weight per day, with a typical initial range of compound used being 0.3 to 15 mg / kg / day. In another embodiment, an oral dosage unit, such as a tablet or capsule, preferably contains from about 1 to about 1000 mg of a compound of the invention.

[0087] The compounds of the present invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural, and intranasal, and, if desired for localized treatment, intralesional administration. Parenteral administration includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

[0088] The compounds of the present invention may be administered in any convenient dosage form, such as, for example, tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain ingredients conventional in pharmaceutical preparations, such as diluents, carriers, pH adjusters, sweeteners, fillers, and additional active agents.

[0089] Typical preparation is prepared by mixing the compound of the present invention with carrier or excipient.Suitable carrier and excipient are well known to those skilled in the art, and are described in detail in, 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 include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, fragrances, flavorings, diluents, and other known additives to provide proper presentation of the drug (i.e., a compound of the present invention or a pharmaceutical composition thereof) or to aid in the manufacture of a pharmaceutical composition (i.e., a medicament).

[0090] An example of a suitable oral dosage form is a tablet containing approximately 1-1000 mg of a compound of the present invention formulated with approximately 1-1000 mg of anhydrous lactose, approximately 1-1000 mg of croscarmellose sodium, approximately 1-1000 mg of polyvinylpyrrolidone (PVP) K30, and approximately 1-1000 mg of magnesium stearate. The powdered ingredients are first blended 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 aerosol formulation can be prepared by dissolving, for example, 5-400 mg of a compound of the present invention in a suitable buffer solution, such as phosphate buffer, and adding an isotonicity agent (e.g., a salt such as sodium chloride) if desired. The solution may be filtered, for example, using a 0.2 micron filter, to remove impurities and contaminants.

[0091] Thus, one embodiment includes a pharmaceutical composition comprising a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof. A further embodiment includes a pharmaceutical composition comprising a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier or excipient.

[0092] Another embodiment includes a pharmaceutical composition comprising a compound of formula (I) for use in treating mutant KRAS-driven cancers.Another embodiment includes a pharmaceutical composition comprising a compound of formula (I) for use in treating mutant KRAS-driven cancers.

[0093] Compositions A and B below show typical compositions of the present invention and serve merely as representative thereof.

[0094] Composition A The compounds of the invention can be used in a manner known per se as the active ingredient for producing tablets of the following composition: per tablet Active ingredient 200mg Microcrystalline cellulose 155mg Cornstarch 25mg Talc 25mg Hydroxypropyl methylcellulose 20mg 425mg

[0095] Composition B The compounds of the invention can be used in a manner known per se as active ingredients for the manufacture of capsules of the following composition: Per capsule Active ingredient 100.0mg Cornstarch 20.0mg Lactose 95.0mg Talc 4.5mg Magnesium stearate 0.5mg 220.0mg

[0096] Indications and Treatment Methods The compounds of the present invention induce a new binding pocket in KRAS by driving the formation of a high-affinity ternary complex between the KRAS protein and the widely expressed cyclophilin A (CYPA), which inhibits KRAS interaction with downstream effectors such as RAF and PI3K. Therefore, the compounds of the present invention are useful for inhibiting proliferative 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 oncogenic role of KRAS mutations is enhanced by dysregulation or mutation of effector pathways such as MAPK, PI3K-AKT, and mTOR (mammalian target of rapamycin)-driven signaling, for targeted therapy in pancreatic adenocarcinoma, colorectal cancer, and non-small cell lung cancer.

[0097] Another embodiment includes a method of treating or preventing cancer in a mammal in need thereof, 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.

[0098] synthesis The compounds of the present invention can be prepared by any conventional means. Suitable methods for synthesizing these compounds and their starting materials are provided in the following schemes and examples. All substituents, particularly R 1 , R 2 , M and L are as defined above unless otherwise specified. Furthermore, unless otherwise specified, all reactions, reaction conditions, abbreviations and symbols have meanings well known to those skilled in the art of organic chemistry.

[0099] A general synthetic route for preparing compounds of formula (I) or (Ia) is shown below. TIFF2026506637000023.tif66170

[0100] Compounds of formula Ib were synthesized according to the procedures described in Intermediates B to V. Compounds of formula (Ib) can be obtained by coupling reaction between acid (III) and compounds of formula (IIb) using coupling reagents such as T3P, HATU, PyBOP and EDCI / HOBt in the presence of bases such as TEA, DIEPA and DMAP.

[0101] The compounds of the present invention can be obtained as mixtures of diastereomers or enantiomers that can be separated by methods well known in the art, such as (chiral) HPLC or SFC. In another embodiment, the compounds of formula (Ia) and (Ic) can be obtained according to the above scheme by using the corresponding chiral starting materials.

[0102] The present invention also relates to a process for the preparation of compounds of formula (I), (Ia), (Ib) and (Ic) comprising the steps of: a) reacting a compound of formula (IIb) with a coupling agent and a base TIFF2026506637000024.tif66170 and acid (III), coupling reaction of TIFF2026506637000025.tif20170 to form a compound of formula (Ib), In step a), the coupling reagent may be, for example, T3P, HATU, PyBOP or EDCI / HOBt; the base may be, for example, TEA, DIEPA or DMAP.

[0103] Compounds of formula (I), (Ia), (Ib) and (Ic) when prepared according to the above processes are also an object of the present invention. [Example]

[0104] The present invention will be more fully understood by reference to the following examples, which should not, however, be construed as limiting the scope of the invention.

[0105] Abbreviation The present invention will be more fully understood by reference to the following examples, which should not, however, be construed as limiting the scope of the invention.

[0106] The abbreviations used herein are as follows: ACN Acetonitrile aq. Water-based Ad2nBuP-Pd-G3 [(di(1-adamantyl)-butylphosphine)-2-(2'-amino-1,1'-biphenyl)]methanesulfonate palladium(II) (Boc)2O di-tert-butyl dicarbonate (R)-binap (R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl CDCl3: deuterated chloroform CuI Copper(I) iodide DIEPA: N,N-diethylpropylamine DMAP: 4-dimethylaminopyridine EDCI: N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride EtOAc 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 LDA: lithium diisopropylamide MS: (ESI): Mass spectrometry (electrospray ionization) min(s) minutes MTBE Methyl tert-butyl ether NMI 1-methylimidazole NMM N-methylmorpholine NBS N-Bromosuccinimide NIS N-iodosuccinimide NMR: nuclear magnetic resonance obsd. Actual measurement 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: Benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate RT or rt: room temperature sat. saturation Selectfluor 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) SFC: Supercritical Fluid Chromatography TCFH: [chloro(dimethylamino)methylene]-dimethyl-ammonium; hexafluorophosphate TEA: Triethylamine TFA: Trifluoroacetic acid T3P: Propylphosphonic anhydride

[0107] General experimental conditions Intermediates and final compounds were purified by flash chromatography using one of the following instruments: i) a Biotage SP1 system and Quad 12 / 25 cartridge module; ii) an ISCO Combi-Flash chromatography system. Silica gel brand and pore size: i) KP-SIL 60Å, particle size: 40–60 μm; ii) CAS Registry Number: Silica Gel: 63231-67-4, particle size: 47–60 micron silica gel; iii) ZCX from Qingdao Haiyang Chemical Co., Ltd., pore size: 200–300 or 300–400.

[0108] Intermediates and final compounds were purified by preparative HPLC on reversed-phase columns using XBridge™ Prep-C18 (5 μm, OBD™ 30 × 100 mm), SunFire™ Prep-C18 (5 μm, OBD™ 30 × 100 mm), Phenomenex Synergi-C18 (10 μm, 25 × 150 mm), or Phenomenex Gemini-C18 (10 μm, 25 × 150 mm) columns on a Waters AutoP purification system (sample manager 2767, pump 2525, detectors: Micromass ZQ and UV 2487, solvent systems: acetonitrile and 0.1% ammonium hydroxide in water; acetonitrile and 0.1% FA in water; or acetonitrile and 0.1% TFA in water). Alternatively, a Gilson-281 purification system (Pump 322, Detector: UV 156, Solvent system: acetonitrile and 0.05% aqueous ammonium hydroxide; acetonitrile and 0.225% aqueous FA; acetonitrile and 0.05% aqueous HCl; acetonitrile and 0.075% aqueous TFA; or acetonitrile and water) was used.

[0109] For SFC chiral separations, intermediates were separated by chiral columns (Daicel chiralpak IC, 5 μm, 30 × 250 mm), AS (10 μm, 30 × 250 mm), or AD (10 μm, 30 × 250 mm) on a Mettler Toledo Multigram III system SFC, Waters 80Q preparative SFC, or Thar80 preparative SFC, solvent system: CO2 and IPA (0.5% TEA in IPA) or CO2 and MeOH (0.1% NH3·H2O in MeOH), back pressure 100 bar, UV detection at 254 or 220 nm.

[0110] 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) under the following LC / MS conditions (run 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 condition I: A: 0.1% NH3·H2O in H2O; B: acetonitrile; Basic conditions II: 0.025% NH3·H2O in H2O; B: acetonitrile; Neutral conditions: A: H2O; B: acetonitrile. Mass spectra (MS): Generally, only ions representing the parent mass are reported, and unless otherwise stated, the mass ions quoted are positive mass ions (M−H). + is.

[0111] NMR spectra were obtained using a Bruker Avance 400 MHz or 500 MHz.

[0112] Microwave-assisted reactions were performed on a Biotage Initiator Sixty microwave synthesizer. All reactions involving air-sensitive reagents were carried out under an argon or nitrogen atmosphere. Reagents were used as received from commercial suppliers without further purification unless otherwise noted.

[0113] Preparation example The following examples are intended to illustrate the meaning of the present invention but do not in any way represent a limitation within the meaning of the present invention.

[0114] Preparation of intermediates Intermediate B Methyl (3S)-1-[(2S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylate TIFF2026506637000026.tif56170 Intermediate B was prepared according to the following scheme: TIFF2026506637000027.tif152170

[0115] Step 1: Preparation of (4-bromothiazol-2-yl)methanol (Compound B2) To a solution of 4-bromothiazole-2-carboxaldehyde (compound B1, 6.0 g, 31.25 mmol) in methanol (70 mL) was added sodium borohydride (1.7 g, 46.87 mmol) at 0° C. The mixture was stirred at 25° C. for 1 hour. The reaction 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 in vacuo to give (4-bromothiazol-2-yl)methanol (compound B2, 6 g) as a colorless oil.

[0116] Step 2: Preparation of 4-bromo-2-(bromomethyl)thiazole (Compound B3) To a solution of (4-bromothiazol-2-yl)methanol (compound B2, 6.0 g, 30.92 mmol) in DCM (80 mL) at 0 °C, CBr (15.4 g, 46.38 mmol) and triphenylphosphine (12.1 g, 46.38 mmol) were added. After stirring at 25 °C for 1 h, the mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified on a silica gel column eluted with ethyl acetate in petroleum ether (0-10%) to give 4-bromo-2-(bromomethyl)thiazole (compound B3, 6.0 g) as a yellow oil. MS calculated 255.9 (MH + ), measured value 255.9 (MH + ).

[0117] Step 3: Preparation of 4-bromo-2-[[(2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2-yl]methyl]thiazole (Compound B5) To a mixture of (2R)-2-isopropyl-3,6-dimethoxy-2.5-dihydropyrazine (compound B4, 4.3 g, 23.45 mmol) in THF (60 mL) was slowly added n-butyllithium (10 mL, 25.22 mmol, 2.5 M) at −78° C. After the addition, the mixture was stirred at −78° C. for 0.5 h. 4-Bromo-2-(bromomethyl)thiazole (compound B3, 5.4 g, 21.02 mmol) was added to the above mixture at −78° C., which was stirred for an additional 1 h. The reaction was quenched with a saturated solution of NH4Cl (100 mL), and the reaction mixture was extracted with EtOAc (100 mL, 2 times). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was purified by reverse phase chromatography to give 4-bromo-2-[[(2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2-yl]methyl]thiazole (compound B5, 3.6 g) as a yellow oil. MS calculated 360 (MH + ), measured value 359.9 (MH + ).

[0118] Step 4: Preparation of methyl (2S)-2-amino-3-(4-bromothiazol-2-yl)propanoate (Compound B6) To a solution of 4-bromo-2-[[(2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2-yl]methyl]thiazole (compound B5, 3.6 g, 10 mmol) in ACN (20 mL) was added hydrochloric acid (66.6 mL, 0.3 M). The mixture was stirred at 25 °C for 2 hours. The mixture was basified with a saturated aqueous solution of NaHCO to pH = 8. The mixture was extracted with EtOAc (80 mL, 6 times). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to give methyl (2S)-2-amino-3-(4-bromothiazol-2-yl)propanoate (compound B6, 3.1 g) as a yellow oil. MS calculated 264.9 (MH+ ), measured value 264.9 (MH + ).

[0119] Step 5: Preparation of methyl (2S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)propanoate (Compound B7) To a solution of methyl (2S)-2-amino-3-(4-bromothiazol-2-yl)propanoate (compound B6, 3.1 g, 11.69 mmol) in DCM (40 mL) was added TEA (2.9 g, 29.23 mmol) and (Boc)2O (3.8 g, 17.54 mmol). After stirring at 30 °C for 12 h, the mixture was concentrated in vacuo. The residue was purified on a silica gel column eluted with ethyl acetate in petroleum ether (0-30%) to give methyl (2S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)propanoate (compound B7, 3.2 g) as a yellow oil. MS calculated 387 (Mn + ), measured value 386.9 (MNa + ).

[0120] Step 6: Preparation of (2S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)-propanoic acid (compound B8) To a solution of methyl (2S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)propanoate (compound B7, 3.2 g, 8.76 mmol) in THF (30 mL), methanol (2 mL), and water (10 mL) was added lithium hydroxide (0.4 mL, 43.81 mmol). After stirring at 25 °C for 1 hour, the reaction mixture was acidified with a 1 M solution of HCl to pH = 5. The mixture was extracted with EtOAc (40 mL, twice). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to give (2S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)propanoic acid (compound B8, 3.1 g) as a yellow oil. MS calculated 373 (MNa + ), measured value 372.9 (MNa+ ).

[0121] Step 7: Preparation of methyl (3S)-1-[(2S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylate (Intermediate B) To a solution of (2S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)propanoic acid (compound B8, 3.1 g, 8.83 mmol) in DCM (50 mL) was added methyl (3S)-hexahydropyridazine-3-carboxylate hydrochloride (compound B9, 2.4 g, 13.24 mmol), EDCI (3.4 g, 17.65 mmol), 1-hydroxybenzotriazole (238.5 mg, 1.77 mmol), and NMM (9.92 mL, 88.26 mmol) at 0 °C. After stirring at 25 °C for 1 h, the reaction mixture was diluted with water (60 mL) and extracted with EtOAc (60 mL, 3 times). The combined organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was purified on a silica gel column, eluting with ethyl acetate in petroleum ether (10-30%) to give methyl (3S)-1-[(2S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylate (Intermediate B, 2.4 g). MS calculated 477 (MH + ), measured value 476.9 (MH + ).

[0122] Intermediate C1 Benzyl 4-[5-bromo-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate TIFF2026506637000028.tif44170 Compound C1 was prepared according to the following scheme: TIFF2026506637000029.tif96170

[0123] Step 1: Preparation of benzyl 4-[5-bromo-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (Compound A5) To a solution of 3-bromo-5-iodo-2-[(1S)-1-methoxyethyl]pyridine (Compound A3, 660 mg, 1.9 mmol, CAS 2641451-76-3, PBWZ170, PharmaBlock (Nanjing) R&D Co. Ltd.) and 1-Cbz-piperazine (Compound A4, 425.1 mg, 1.9 mmol) in toluene (10 mL) was added 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). After stirring at 100 °C under N protection for 12 hours, the mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (EA / PE: 0-50%) to give 4-[5-bromo-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound A5, 740 mg) as a yellow solid. MS calculated: 434.1 (MH + ), measured value 434.1 (MH + ).

[0124] 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 A5, 33.0 g, 75.98 mmol) in DMF (1 L), trimethylsilylacetylene (85.9 mL, 607.83 mmol), Pd(PPh)Cl (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 mixture was degassed with nitrogen three times and then stirred at 100 °C for 12 h. After the reaction was complete, the reaction mixture was cooled to room temperature, filtered, and HO (3 L) was added to the filtrate. The reaction mixture was extracted with EtOAc (1 L, 3 times). The combined organic layers were washed with brine (3 L), dried over NaSO, filtered, and concentrated in vacuo to give a residue that was purified by column chromatography to give benzyl 4-[6-[(1S)-1-methoxyethyl]-5-(2-trimethylsilylethynyl)-3-pyridyl]piperazine-1-carboxylate (compound C1-a, 21.0 g) as a yellow solid. MS calculated 452.2 (MH + ), measured value 452.2 (MH + ).

[0125] Step 3: Preparation of benzyl 4-[5-ethynyl-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (Intermediate C1) To a solution of benzyl 4-[6-[(1S)-1-methoxyethyl]-5-(2-trimethylsilylethynyl)-3-pyridyl]piperazine-1-carboxylate (compound C1-a, 31 g, 68.6 mmol) in methanol (500 mL) was added potassium fluoride (8.1 g, 139.8 mmol) at 0 °C. The mixture was stirred at 20 °C for 1 hour. After the reaction was completed, the reaction mixture was concentrated in vacuo to give a residue, which was purified by column chromatography to give benzyl 4-[5-ethynyl-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (intermediate C1, 25 g) as a brown solid. MS calculated 380.2 (MH + ), measured value 380.2 (MH + ).

[0126] Intermediate C2 4-[5-bromo-6-[(1S)-1-methoxyethyl]-3-pyridyl]morpholine TIFF2026506637000030.tif371701-The title compound was prepared in a manner similar to the preparation of intermediate C1 by using morpholine instead of Cbz-piperazine (compound A4).

[0127] Intermediate C3 1-[5-ethynyl-6-[(1S)-1-methoxyethyl]-3-pyridyl]-4-(2,2,2-trifluoroethyl)piperazine TIFF2026506637000031.tif441701-The title compound was prepared in a manner similar to the preparation of intermediate C1 by using 1-(2,2,2-trifluoroethyl)piperazine instead of Cbz-piperazine (compound A4).

[0128] Intermediate C4 (9aS)-8-[5-ethynyl-6-[(1S)-1-methoxyethyl]-3-pyridyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazine The title compound was prepared in a manner similar to that of intermediate C1 by using (9aS)-1,3,4,6,7,8,9,9a-octahydropyrazino[2,1-c][1,4]oxazine instead of TIFF2026506637000032.tif441701-Cbz-piperazine (compound A4).

[0129] Intermediate C5 (9aR)-2-[5-ethynyl-6-[(1S)-1-methoxyethyl]-3-pyridyl]-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazine The title compound was prepared in a manner similar to that of intermediate C1 by using (9aR)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine instead of TIFF2026506637000033.tif441701-Cbz-piperazine (compound A4).

[0130] Intermediate D1 6-Bromo-8-iodo-1,2,3,4-tetrahydroquinoline TIFF2026506637000034.tif25170This compound was prepared according to the following scheme: TIFF2026506637000035.tif30170

[0131] To a solution of 6-bromo-1,2,3,4-tetrahydroquinoline (compound D1-a, 40.0 g, 188.6 mmol) in DMF (1.3 L) was added NIS (42.4 g, 188.6 mmol) portionwise at 0 °C. After stirring at 25 °C for 2 h, the reaction mixture was poured into water (4 L) and extracted with EtOAc (2 L, 3 times). The combined organic layers were washed with brine (2 L, 3 times), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give a residue. The residue was purified by reverse-phase chromatography to give 6-bromo-8-iodo-1,2,3,4-tetrahydroquinoline (intermediate D1, 37 g) as a brown gum. MS calculated 337.9 (MH + ), measured value 338.0 (MH + ).

[0132] Intermediate D2 7-Bromo-5-iodo-3,4-dihydro-2H-1,4-benzoxazine TIFF2026506637000036.tif26170This compound was prepared according to the following scheme: TIFF2026506637000037.tif70170

[0133] Step 1: Preparation of (2-amino-5-bromo-phenyl) 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) was added p-toluenesulfonyl chloride (83.6 g, 438.78 mmol). After stirring at 25 °C for 1 h, the reaction was quenched with saturated aqueous NaHCO (400 mL) and extracted with EtOAc (500 mL, 3 times). The organic layer was washed with brine (200 mL), dried over NaSO, filtered, and concentrated in vacuo to give crude (2-amino-5-bromo-phenyl) 4-methylbenzenesulfonate (compound D2-b, 146.5 g) as a dark brown solid, which was used in the next step without purification. MS calculated 342 (MH + ), measured value 342 (MH + ).

[0134] Step 2: Preparation of (2-amino-5-bromo-3-iodo-phenyl) 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) was added silver sulfate (133.5 g, 428.1 mmol) and iodine (108.7 g, 428.1 mmol). After stirring at 25 °C for 12 h, the reaction was quenched with saturated aqueous NaHCO (400 mL) and EtOAc (500 mL, 3 times). The organic layer was washed with brine (200 mL), dried over NaSO, filtered, and concentrated in vacuo to give (2-amino-5-bromo-3-iodo-phenyl) 4-methylbenzenesulfonate (compound D2-c, 210.0 g) as a dark brown solid, which was used in the next step without purification. MS calculated 467.8 (MH + ), measured value 467.8(MH + ).

[0135] Step 3: Preparation of 2-amino-5-bromo-3-iodo-phenol (compound D2-d) To a solution of (2-amino-5-bromo-3-iodo-phenyl) 4-methylbenzenesulfonate (compound D2-c, 210.0 g, 448.62 mmol) in ethanol (1.5 L) and THF (500 mL) was added sodium hydroxide (62.8 g, 1570.18 mmol). The mixture was heated to reflux for 1 h. After cooling to room temperature, the reaction mixture was concentrated in vacuo to give a residue. The residue was neutralized to pH = 7 by using 6 N HCl and extracted with EtOAc (1 L, twice). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to give a residue. The crude product was purified by column chromatography to give 2-amino-5-bromo-3-iodo-phenol (compound D2-d, 120.0 g) as a dark brown solid. MS calculated 313.9 (MH + ), measured value 313.9 (MH + ).

[0136] Step 4: Preparation of 7-bromo-5-iodo-4H-1,4-benzoxazin-3-one (compound D2-e) To a solution of 2-amino-5-bromo-3-iodo-phenol (compound D2-d, 50.0 g, 159.28 mmol) and potassium carbonate (33.0 g, 238.91 mmol) in DMF (2 L) was added chloroacetyl chloride (19.0 mL, 238.91 mmol). After stirring at 25 °C for 12 h, the reaction mixture was concentrated in vacuo to give a residue. The residue was poured into HO (1 L) and extracted with EtOAc (1 L, 3 times). The organic layer was washed with brine (1.5 L, 2 times), dried over NaSO, filtered, and concentrated in vacuo to give a residue. The crude product was triturated with MTBE (100 mL) at 25 °C for 30 min. The suspension was filtered and the collected solid was collected to give 7-bromo-5-iodo-4H-1,4-benzoxazin-3-one (compound D2-e, 175.0 g) as a dark brown solid. MS calculated 353.9 (MH + ), measured value 353.9 (MH + ).

[0137] Step 5: Preparation of 7-bromo-5-iodo-3,4-dihydro-2H-1,4-benzoxazine (Intermediate D2) To a stirred solution of 7-bromo-5-iodo-4H-1,4-benzoxazin-3-one (compound D2-e, 20.0 g, 56.51 mmol) in THF (500 mL) under a N atmosphere was added borane tetrahydrofuran complex solution (113.0 mL, 113.01 mmol) at 0 °C. After stirring at 80 °C for 1 h, the mixture was cooled to room temperature, and then MeOH (100 mL) was added. The mixture was poured into HO (100 mL) and extracted with EtOAc (200 mL, 3 times). The organic layer was washed with brine (100 mL, 2 times), dried over NaSO, filtered, and concentrated in vacuo to give a residue. The crude product was purified by column chromatography to give 7-bromo-5-iodo-3,4-dihydro-2H-1,4-benzoxazine (intermediate D2, 17.6 g) as a pink solid. MS calculated value 340.0 (MH + ), measured value 340.0 (MH + ). 1 H NMR(400MHz,DMSO-d6)δ=7.31(d,J=2.4Hz,1H),6.88(d,J=2.4Hz,1H),5.42(br s,1H),4.07(t,J=4.4Hz,2H),3.38-3.33(m,2H).

[0138] Intermediate D3 6-Bromo-3,3-difluoro-8-iodo-2,4-dihydro-1H-quinoline TIFF2026506637000038.tif28170This compound was prepared according to the following scheme: TIFF2026506637000039.tif64170

[0139] Step 1: Preparation of 3,3-difluoro-1H-quinoline-2,4-dione (compound D3-b) 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) was added Selectfluor (40.0 g, 112.91 mmol) at 0 °C. After stirring at 25 °C for 1 h, the reaction mixture was concentrated in vacuo, and the residue was filtered. The filtrate was added to water (1 L). The resulting mixture was extracted with EtOAc (400 mL, 3 times). The combined organic layers were washed with brine (400 mL, 2 times), dried over NaSO, filtered, and concentrated in vacuo to give 3,3-difluoro-1H-quinoline-2,4-dione (compound D3-b, 46.0 g) as a yellow solid. 1 H NMR(400MHz,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=8.0Hz,1H). Step 2: Preparation of 3,3-fluoro-2,4-dihydro-1H-quinolin-4-ol (compound D3-c)

[0140] To 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 added borane-tetrahydrofuran complex (700.0 mL, 700.0 mmol) at 0 °C. After stirring at 25 °C for 16 h, the reaction was quenched dropwise with MeOH (500 mL) at 0 °C and then concentrated in vacuo to give 3,3-difluoro-2,4-dihydro-1H-quinolin-4-ol (compound D3-c, 64.8 g) as a yellow oil. MS calculated 185.1 (MH + ), measured value 168.0 (M-OH+H + ).

[0141] 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-quinolin-4-ol (compound D3-c, 64.8 g, 349.95 mmol) in EtSiH (206.8 mL, 1.29 mol) was added TFA (405.4 mL, 5.26 mol) at 0 °C. After stirring at 25 °C for 16 h, the reaction mixture was concentrated in vacuo, adjusted to pH = 8 by adding saturated aqueous NaHCO solution, and extracted with EtOAc (1 L, twice). The combined organic layers were washed with brine (1.6 L), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a residue that was purified by silica gel column chromatography to give 3,3-difluoro-2,4-dihydro-1H-quinoline (compound D3-d, 45.0 g) as a yellow solid. MS calculated 170.1 (MH + ), measured value 170.0 (MH + ).

[0142] 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) was added NBS (50.0 g, 280.92 mmol) at 0 °C. After stirring at 0 °C for 1 h, the reaction mixture was poured into water (1200 mL), and the resulting mixture was extracted with EtOAc (800 mL, 3 times). The combined organic layers were washed with brine (1 L, 3 times), dried over Na SO , filtered, and concentrated in vacuo, which was purified by column chromatography to give 6-bromo-3,3-difluoro-2,4-dihydro-1H-quinoline (compound D3-e, 57.0 g) as a yellow solid. MS calculated 248.0 (MH + ), measured value 247.9 (MH + ).

[0143] 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) was added NIS (48.9 g, 217.28 mmol) at 0 °C. After stirring at 0 °C for 5 h, the reaction mixture was poured into water (1.2 L), and the resulting mixture was extracted with EtOAc (650 mL, 3 times). The combined organic layers were washed with brine (1000 mL, 3 times), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography to give 6-bromo-3,3-difluoro-8-iodo-2,4-dihydro-1H-phosphorus (intermediate D3, 68.0 g) as a white solid. MS calculated 373.9 (MH + ), measured value 373.9 (MH + ).

[0144] Intermediate D4 7-Bromo-5-iodo-2,2-dimethyl-3,4-dihydro-1,4-benzoxazine TIFF2026506637000040.tif30170 The title compound was prepared in a manner similar to the preparation of intermediate D2 by using ethyl 2-bromo-2-methyl-propane instead of chloroacetyl chloride.

[0145] Intermediate D5 7-Bromo-5-iodo-3-methyl-3,4-dihydro-2H-1,4-benzoxazine TIFF2026506637000041.tif24170This compound was prepared according to the following scheme: TIFF2026506637000042.tif36170

[0146] 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-iodo-phenol (compound D2-d, 18 g, 57.34 mmol) in acetone (300 mL) was added potassium carbonate (15.8 g, 114.68 mmol) and chloroacetone (10.6 g, 114.68 mmol). After stirring at 25 °C for 18 h, the reaction mixture was poured into EtOAc (200 mL) / water (400 mL) and the layers were separated. The aqueous phase was extracted with EtOAc (200 mL, twice). The combined organic layers were washed with brine (300 mL), dried over NaSO, filtered, and concentrated in vacuo to give a residue. The residue was purified by flash chromatography to give 7-bromo-5-iodo-3-methyl-2H-1,4-benzoxazine (compound D5-a, 20 g) as a light brown solid. MS calculated 351.9 (MH + ), measured value 351.9 (MH + ).

[0147] Step 2: Preparation of 7-bromo-5-iodo-3-methyl-3,4-dihydro-2H-1,4-benzoxazine (Intermediate D5) 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) was added sodium cyanoborohydride (17 g, 270 mmol), followed by stirring at 25° C. for 2 hours. The mixture was slowly added to aqueous NaOH (150 mL, 2 M) and then extracted with EtOAc (100 mL, twice). The combined organic layers were washed with water and brine, dried over sodium sulfate, and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography to give 7-bromo-5-iodo-3-methyl-3,4-dihydro-2H-1,4-benzoxazine (intermediate D5, 14.6 g) as a thick brown oil. MS calculated 353.9 (MH + ), measured value 353.9 (MH + ).

[0148] Intermediate D6 6-Bromo-8-iodo-3,3-dimethyl-2,4-dihydro-1H-quinoline TIFF2026506637000043.tif25170 The title compound was prepared in a manner similar to 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).

[0149] Intermediate D7 8-Bromo-6-iodo-2,3,4,5-tetrahydro-1,5-benzoxazepine TIFF2026506637000044.tif24170This compound was prepared according to the following scheme: TIFF2026506637000045.tif36170

[0150] Step 1: Preparation of 4-bromo-2-[2-(1,3-dioxolan-2-yl)ethoxy]-6-iodo-aniline (compound D7-b). To a solution of 2-amino-5-bromo-3-iodo-phenol (compound D2-d, 3.5 g, 11.05 mmol) in anhydrous DMF (80 mL) at 25 °C, 2-(2-bromoethyl)-1,3-dioxolane (compound D7-a, 4.0 g, 22.11 mmol) and K2CO3 (4.6 g, 33.16 mmol) were added. After stirring at 25 °C for 15 h, EtOAc (100 mL) / water (100 mL) was added to the reaction mixture and the layers were separated. The aqueous phase was extracted with EtOAc (100 mL, 2 times). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give a residue. The residue was purified by flash chromatography to give 4-bromo-2-[2-(1,3-dioxolan-2-yl)ethoxy]-6-iodo-aniline (compound D7-b, 3.3 g) as a yellow solid. MS calculated 414.0 (MH + ), measured value 414.0 (MH + ).

[0151] Step 2: Preparation of 8-bromo-6-iodo-2,3,4,5-tetrahydro-1,5-benzoxazepine (Intermediate D7). To a solution of 4-bromo-2-[2-(1,3-dioxolan-2-yl)ethoxy]-6-iodo-aniline (compound D7-b, 3.3 g, 7.97 mmol) in DCM (24 mL) at 0 °C was added TFA (6.0 mL) dropwise over 1 minute via syringe under a nitrogen atmosphere. After stirring at 25 °C for 60 minutes, triethylsilane (4.63 g, 39.78 mmol) was added to the reaction mixture and stirred at 25 °C for an additional 14 hours. After the reaction was complete, the mixture was concentrated in vacuo to give a residue. The resulting residue was diluted with saturated aqueous NaHCO (50 mL) and extracted with EtOAc (20 mL, 3 times). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a residue which was purified by column chromatography to give 8-bromo-6-iodo-2,3,4,5-tetrahydro-1,5-benzoxazepine (compound D7, 1.98 g) as a brown oil. MS calculated 353.9 (MH + ), measured value 354.0 (MH + ).

[0152] Intermediate D9 6-Bromo-8-iodo-1,2,3,4-tetrahydroquinolin-3-ol TIFF2026506637000046.tif23170 The title compound was prepared in a manner similar to the preparation of intermediate D3 by using 1,2,3,4-tetrahydroquinolin-3-ol instead of 3,3-difluoro-2,4-dihydro-1H-quinoline (compound D3-d).

[0153] Intermediate D10 6-Bromo-5-fluoro-8-iodo-1,2,3,4-tetrahydroquinoline TIFF2026506637000047.tif28170This compound was prepared according to the following scheme: TIFF2026506637000048.tif76170

[0154] Step 1: Preparation of methyl (E)-3-(2-fluoro-6-nitro-phenyl)prop-2-enoate (compound D10-b). To a mixture of 2-bromo-1-fluoro-3-nitro-benzene (compound D10-a, 14.2 g, 64.55 mmol) and methyl acrylate (9 g, 104.31 mmol) in NMP (150 mL), N,N-dicyclohexylmethylamine (37.8 g, 193.64 mmol), tetrabutylammonium chloride (1.8 g, 6.45 mmol), and Pd(dtbpf)Cl (4.21 g, 6.45 mmol) were added in one portion. The mixture was purged under vacuum and degassed with nitrogen three times, then stirred at 80 °C for 12 h. After the reaction was complete, the reaction mixture was cooled to room temperature and poured into water (300 mL). The mixture was extracted with EtOAc (100 mL, three times). The combined organic layers were washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give a residue. The residue was purified by column chromatography (PE: EtOAc = 1: 0 to 3: 1) to give methyl (E)-3-(2-fluoro-6-nitro-phenyl) prop-2-enoate (compound D10-b, 6.21 g) as a yellow solid. 1 H NMR(400MHz,CHLOROFORM-d)δ=7.80(d,J=8.0Hz,1H),7.72(d,J=16.4Hz,1H),7.50( dt,J=5.2,8.4Hz,1H),7.46-7.39(m,1H),6.54(dd,J=2.0,16.4Hz,1H),3.85(s,3H).

[0155] Step 2: Preparation of 5-fluoro-3,4-dihydro-1H-quinolin-2-one (compound D10-c). To a mixture of methyl (E)-3-(2-fluoro-6-nitrophenyl)prop-2-enoate (compound D10-b, 6.0 g, 26.65 mmol) in methanol (60 mL) was added Pd on activated carbon (2.8 g, 2.66 mmol) under an Ar atmosphere. The reaction mixture was degassed and purged with Ar three times, then degassed and purged with hydrogen three times. The mixture was stirred under a hydrogen atmosphere (15 Psi) at 60 °C for 16 h. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated in vacuo to give 5-fluoro-3,4-dihydro-1H-quinolin-2-one (compound D10-c, 4.37 g) as an off-white solid. MS calculated 166.1 (MH + ), measured value 166.2 (MH + ).

[0156] Step 3: Preparation of 5-fluoro-1,2,3,4-tetrahydroquinoline (compound D10-d). To a solution of 5-fluoro-3,4-dihydro-1H-quinolin-2-one (compound D10-c, 4.0 g, 24.22 mmol) in THF (80 mL) was slowly added borane-tetrahydrofuran complex (48 mL, 48.44 mmol, 1 M) under a nitrogen atmosphere at 0 °C. After stirring at 25 °C for 12 h, the reaction was quenched by the dropwise addition of MeOH (100 mL) at 0 °C and stirred for 30 min. The mixture was then concentrated in vacuo to remove most of the solvent, followed by the addition of water (100 mL) and extraction with EtOAc (30 mL, 3 times). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a residue that was purified by column chromatography to give 5-fluoro-1,2,3,4-tetrahydroquinoline (compound D10-d, 3.74 g) as a yellow oil. MS calculated value 152.1 (MH + ), measured value 152.0 (MH + ).

[0157] Step 4: Preparation of 6-bromo-5-fluoro-1,2,3,4-tetrahydroquinoline (compound D10-e). To a solution of 5-fluoro-1,2,3,4-tetrahydroquinoline (compound D10-d, 3.5 g, 23.42 mmol) in DMF (60 mL) was added NBS (4.2 g, 23.42 mmol) slowly at 0 °C. The mixture was stirred at 0 °C for 0.25 h. After the reaction was completed, the mixture was poured into water (30 mL) and extracted with EtOAc (100 mL, 3 times). The combined organic layers were washed with brine (100 mL, 3 times), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a residue that was purified by column chromatography to give 6-bromo-5-fluoro-1,2,3,4-tetrahydroquinoline (compound D10-e, 4.0 g) as a yellow oil. MS calculated 230.0 (MH + ), measured value 230.2 (MH + ).

[0158] Step 5: Preparation of 6-bromo-5-fluoro-8-iodo-1,2,3,4-tetrahydroquinoline (Intermediate D10).

[0159] To a solution of 6-bromo-5-fluoro-1,2,3,4-tetrahydroquinoline (compound D10-e, 3.5 g, 15.21 mmol) in DMF (50 mL) cooled to -10 °C, TFA (3.5 mL, 45.64 mmol) was added, followed by a solution of NIS (3.6 g, 15.97 mmol) in ACN (20 mL) / DMF (20 mL). The reaction solution was stirred for an additional 30 minutes under a nitrogen atmosphere. The reaction mixture was quenched by the slow addition of saturated NaSO solution (100 mL) under stirring. The reaction mixture was then poured into water (300 mL), and the mixture was extracted with EtOAc (100 mL, 3 times). The combined organic layers were washed with brine (100 mL, 5 times), dried over NaSO, filtered, and concentrated in vacuo to give a residue that was purified by column chromatography to give 6-bromo-5-fluoro-8-iodo-1,2,3,4-tetrahydroquinoline (compound D10, 5.77 g) as a white solid. MS calculated 355.9 (MH + ), measured value 356.0 (MH + ).

[0160] 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 ]Hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione TIFF2026506637000049.tif57170This compound was prepared according to the following scheme: TIFF2026506637000050.tif213170TIFF2026506637000051.tif94170

[0161] Step 1: Preparation of benzyl 4-[5-[2-(6-bromo-1,2,3,4-tetrahydroquinolin-8-yl)ethynyl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (Compound E1). To a solution of benzyl 4-[5-ethynyl-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (Intermediate C1, 26.1 g, 68.8 mmol) in DMF (400 mL) was added 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 (1.3 g, 6.88 mmol), and Pd(PPh)Cl (4.8 g, 6.88 mmol). The reaction mixture was degassed and purged with nitrogen three times, then stirred at 25 °C for 12 h. After the reaction was complete, the reaction mixture was poured into water (1.4 L) and extracted with EtOAc (800 mL, three times). The combined organic layers were washed with brine (800 mL, 4 times), dried over NaSO, filtered, and concentrated in vacuo to give a residue that was purified by column chromatography to give benzyl 4-[5-[2-(6-bromo-1,2,3,4-tetrahydroquinolin-8-yl)ethynyl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (Compound E1, 30.0 g) as a yellow solid. MS calculated 589.2 (MH + ), measured value 589.2 (MH + ).

[0162] 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). To a solution of benzyl 4-[5-[2-(6-bromo-1,2,3,4-tetrahydroquinolin-8-yl)ethynyl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (Compound E1, 27.0 g, 45.8 mmol) in DMF (270 mL) was added PdCl (1.6 g, 9.16 mmol) in one portion. The reaction mixture was degassed under vacuum and flushed with nitrogen three times, then heated to 70 °C for 16 h. After cooling to room temperature, the mixture was poured into water (800 mL) and extracted with EtOAc (300 mL, three times). The combined organic layers were washed with brine (300 mL, 3 times), dried over Na2SO4, filtered, and concentrated in vacuo to give a residue which was purified by column chromatography to give 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, 19.2 g) was obtained as a yellow solid. MS calculated 589.2 (MH + ), measured value 589.2 (MH + ).

[0163] 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 h, the reaction mixture was treated with benzyl 4-[5-(6-bromo-1-azatricyclo[6.3.1.0]-methyl-2-(2-methyl-4-oxo-1-methylpropional]-2-methylpropional]-4-(2-methylpropional) ... 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) was added dropwise at 0 °C. The reaction mixture was heated to 45 °C and stirred for an additional 1 h. The reaction was quenched with saturated aqueous NaHCO (1.5 L) and extracted with EtOAc (500 mL, 3 times). The organic layer was washed with brine (500 mL, 3 times), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give a residue. The residue was purified by column chromatography to give 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, 14.6 g) was obtained as a yellow solid. MS calculated 616.9 (MH + ), measured value 617.2 (MH + ).

[0164] Step 4: Benzyl 4-[5-[6-bromo-3-(1-hydroxy-3-methoxy-2,2-dimethyl-3-oxo-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 E4) To a solution of methyl isobutyrate (13.4 g, 131.17 mmol) in THF (150 mL) was added LDA (65.58 mL, 131.17 mmol) dropwise under a nitrogen atmosphere at −70° C. After stirring for 0.5 h, the reaction mixture was treated with benzyl 4-[5-(6-bromo-3-formyl-1-azatricyclo[6.3.1.0]-methyl-2-(2-methyl-4-oxo-1-methylpropional]-2-methylpropional]-2-methylpropional]-2-methylpropional in THF (50 mL). 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) 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 aqueous NH4Cl (600 mL) and extracted with EtOAc (200 mL, 3 times). The organic layer was washed with brine (500 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give a residue. The residue was purified by column chromatography to give benzyl 4-[5-[6-bromo-3-(1-hydroxy-3-methoxy-2,2-dimethyl-3-oxo-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 E4, 14.01 g) was obtained as a yellow solid. MS calculated 719.3 (MH + ), measured value 719.2 (MH + ).

[0165] Step 5: Preparation of benzyl 4-[5-[6-bromo-3-(3-methoxy-2,2-dimethyl-3-oxo-propyl)-1-azatricyclo[6.3.1.04,12]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-(1-hydroxy-3-methoxy-2,2-dimethyl-3-oxo-propyl)-1-azatricyclo[6.3.1.0 in DCM (280 mL)] 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 EtSiH (18.1 g, 155.63 mmol) was added TFA (57.8 mL, 778.15 mmol) at 0 °C. After stirring at 25 °C for 12 h, the reaction mixture was concentrated in vacuo to give a residue, which was diluted with aqueous NaHCO to pH = 9 and extracted with EtOAc (300 mL, 3 times). The combined organic phase was dried over anhydrous NaSO, filtered, and concentrated in vacuo to give a residue. The residue was purified by column to give benzyl 4-[5-[6-bromo-3-(3-methoxy-2,2-dimethyl-3-oxo-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 E5, 14 g) was obtained as a yellow solid. MS calculated 703.2 (MH + ), measured value 703.2 (MH + ).

[0166] 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-oxo-propyl)-1-azatricyclo[6.3.1.0] in THF (150 mL) 4,12To a solution of [(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound E5, 14.0 g, 19.9 mmol) was added lithium borohydride (99.48 mL, 198.96 mmol) dropwise under N at 0 °C. After stirring at 20 °C for 15 h, the reaction was quenched with saturated aqueous NH Cl (600 mL) at 0 °C, and the resulting mixture was extracted with EtOAc (100 mL, 3 times). The combined organic layers were washed with brine (200 mL), dried over Na SO , filtered, and concentrated in vacuo to give a residue. The residue was purified by column chromatography to give 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, 7 g, faster eluting) was obtained as a yellow oil. MS calculated 675.3 (MH + ), measured value 675.2 (MH + ).

[0167] Step 7: Benzyl 4-[(5M)-5-[3-(3-hydroxy-2,2-dimethyl-propyl)-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) Benzyl 4-[(5M)-5-[6-bromo-3-(3-hydroxy-2,2-dimethyl-propyl)-1-azatricyclo[6.3.1.0] in toluene (140 mL) 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)diboron (3.95 g, 15.54 mmol) was added KOAc (2.56 g, 26.05 mmol) and Pd(dppf)Cl (760.87 mg, 1.04 mmol). The mixture was degassed and purged with nitrogen three times and stirred at 75 °C for 16 h. After cooling to room temperature, the reaction mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography to give benzyl 4-[(5M)-5-[3-(3-hydroxy-2,2-dimethyl-propyl)-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, 7.3 g) was obtained as a yellow solid. MS calculated 723.4 (MH + ), measured value 723.4 (MH + ).

[0168] 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-dimethyl-propyl)-1-azatricyclo[6.3.1.0 4,12 Preparation of ]dodeca-2,4(12),5,7-tetraen-6-yl]thiazol-2-yl]-2-(tert-butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylate (compound E8) Benzyl 4-[(5M)-5-[3-(3-hydroxy-2,2-dimethyl-propyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-azatricyclo[6.3.1.0] in toluene (90 mL) / 1,4-dioxane (30 mL) / water (30 mL) 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-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylate (Intermediate B, 4.9 g, 10.35 mmol), KPO (5.0 g, 23.52 mmol) and Pd(dtbpf)Cl (613.2 mg, 0.94 mmol) were added in one portion. The mixture was degassed and purged with nitrogen three times, then stirred at 70 °C for 15 h. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated in vacuo to give a residue, which was purified by column chromatography to give methyl (3S)-1-[(2S)-3-[4-[(2M)-2-[5-(4-benzyloxycarbonylpiperazin-1-yl)-2-[(1S)-1-methoxyethyl]-3-pyridyl]-3-(3-hydroxy-2,2-dimethyl-propyl)-1-azatricyclo[6.3.1.0 4,12 ]dodeca-2,4(12),5,7-tetraen-6-yl]thiazol-2-yl]-2-(tert-butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylate (compound E8, 8.1 g) was obtained as a yellow solid. MS calculated 993.7 (MH + ), measured value 993.7 (MH + ).

[0169] 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-dimethyl-propyl)-1-azatricyclo[6.3.1.0 4,12 Preparation of ]dodeca-2,4(12),5,7-tetraen-6-yl]thiazol-2-yl]-2-(tert-butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylic acid (compound E9) Methyl (3S)-1-[(2S)-3-[4-[(2M)-2-[5-(4-benzyloxycarbonylpiperazin-1-yl)-2-[(1S)-1-methoxyethyl]-3-pyridyl]-3-(3-hydroxy-2,2-dimethyl-propyl)-1-azatricyclo[6.3.1.0] in DCE (160 mL) 4,12 To a mixture of [dodeca-2,4(12),5,7-tetraen-6-yl]thiazol-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 in one portion. After stirring at 60 °C for 16 h, the reaction mixture was poured into water (200 mL) and extracted with EtOAc (100 mL, 3 times). The combined organic layers were washed with brine (200 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated under vacuum to give (3S)-1-[(2S)-3-[4-[(2M)-2-[5-(4-benzyloxycarbonylpiperazin-1-yl)-2-[(1S)-1-methoxyethyl]-3-pyridyl]-3-(3-hydroxy-2,2-dimethyl-propyl)-1-azatricyclo[6.3.1.0 4,12 ]dodeca-2,4(12),5,7-tetraen-6-yl]thiazol-2-yl]-2-(tert-butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylic acid (compound E9, 7.9 g) was obtained as a brown solid. MS calculated 979.5 (MH + ), measured value 979.5 (MH + ).

[0170] 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-dimethyl-propyl)-1-azatricyclo[6.3.1.0] in DCM (700 mL) 4,12 To a solution of [dodeca-2,4(12),5,7-tetraen-6-yl]thiazol-2-yl]-2-(tert-butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylic acid (Compound E9, 6.8 g, 6.94 mmol), DIEA (24.2 mL, 138.89 mmol), EDCI (19.9 g, 104.17 mmol), and HOBt (2.4 g, 17.36 mmol) were added at 0 °C. After stirring at 30 °C for 15 h, the reaction mixture was poured into water (500 mL) and extracted with EtOAc (300 mL, 3 times). The combined organic layers were washed with brine (300 mL), dried over Na SO , and filtered. The filtrate was concentrated under vacuum to give a residue, which was purified by silica column to give 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, 5.6 g) was obtained as a yellow solid. MS calculated 961.5 (MH + ), measured value 961.5 (MH + ).

[0171] 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) 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 (1.9 g, 23.3 mmol) was added Pd(OH)2 on activated carbon (3.0 g, 2.91 mmol) under a nitrogen atmosphere. The reaction mixture was degassed and purged with H2 three times, then stirred under H2 (15 psi) at 35 °C for 15 min. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated in vacuo to give a residue. EtOAc (50 mL) and water (50 mL) were added to the residue, and the layers were separated. The aqueous phase was extracted with EtOAc (50 mL, twice). The combined organic layers were washed with brine (60 mL), dried over NaSO, and filtered. The filtrate was concentrated in vacuo to give 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 .19,13 .0 19,27 .0 21,26 ]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamate (compound E11, 3.9 g) was obtained as a yellow solid, which was used in the next step without further purification. MS calculated 841.5 (MH + ), measured value 841.4 (MH + ).

[0172] 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) 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 21,26To 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) was added TFA (15.0 mL) in one portion. After stirring at 25 °C for 1 h, the mixture was poured into water (100 mL) and extracted with EtOAc (200 mL). The organic phase was washed with water (50 mL, 2 times). The combined aqueous phase was basified with saturated aqueous NaHCO3 to pH = 9 and extracted with EtOAc (100 mL, 3 times). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give (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, 2.95 g) was obtained as a yellow solid. MS calculated 741.5 (MH + ), measured value 741.4 (MH + ).

[0173] 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 ]Hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione TIFF2026506637000052.tif64170This compound was prepared according to the following scheme: TIFF2026506637000053.tif252170

[0174] Step 1: Preparation of 4-[5-[2-(6-bromo-1,2,3,4-tetrahydroquinolin-8-yl)ethynyl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]morpholine (Compound F1). To a solution of 4-[5-ethynyl-6-[(1S)-1-methoxyethyl]-3-pyridyl]morpholine (Intermediate C2, 27.6 g, 112.06 mmol) in DMF (650 mL) was added 6-bromo-8-iodo-1,2,3,4-tetrahydroquinoline (Intermediate D1, 37.9 g, 112.14 mmol), TEA (78 mL, 560.73 mmol), CuI (2.14 g, 11.24 mmol), and Pd(PPh)Cl (7.9 g, 11.24 mmol). The reaction mixture was degassed and purged with nitrogen three times, then stirred at 25 °C for 12 h. After the reaction was complete, the reaction mixture was poured into water (1.4 L) and extracted with EtOAc (800 mL, three times). The combined organic layers were washed with brine (800 mL, 4 times), dried over NaSO, filtered, and concentrated in vacuo to give a residue that was purified by column chromatography to give 4-[5-[2-(6-bromo-1,2,3,4-tetrahydroquinolin-8-yl)ethynyl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]morpholine (compound F1, 33.0 g) as a yellow solid. MS calculated 456.1 (MH + ), measured value 456.1 (MH + ).

[0175] Step 2: 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]morpholine (Compound F2). To a solution of 4-[5-[2-(6-bromo-1,2,3,4-tetrahydroquinolin-8-yl)ethynyl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]morpholine (compound F1, 33.0 g, 72.31 mmol) in DMF (400 mL) was added PdCl (2.6 g, 14.46 mmol) in one portion. The reaction mixture was degassed under vacuum, flushed with nitrogen three times, and then heated to 60 °C for 15 h. After cooling to room temperature, the mixture was poured into water (800 mL) and extracted with EtOAc (500 mL, three times). The combined organic layers were washed with brine (400 mL, three times), dried over NaSO, filtered, and concentrated under vacuum to give a residue that was purified by column chromatography to give 4-[5-(6-bromo-1-azatricyclo[6.3.1.0]H NMR (CDCl) δ 1.04-1.04 (Hz ... 4,12 ]dodeca-2,4,6,8(12)-tetraen-2-yl)-6-[(1S)-1-methoxyethyl]-3-pyridyl]morpholine (compound F2, 25.0 g) was obtained as a yellow solid. MS calculated 456.1 (MH + ), measured value 456.1 (MH + ).

[0176] Step 3: 6-Bromo-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-1-azatricyclo[6.3.1.0 4,12 ]Preparation of dodeca-2,4,6,8(12)-tetraene-3-carbaldehyde (compound F3). Phosphorus oxychloride (51.1 mL, 547.83 mmol) was slowly added dropwise to DMF (500 mL) at 0° C. After stirring at 0° C. for 0.5 h, the reaction mixture was treated with 4-[5-(6-bromo-1-azatricyclo[6.3.1.0]-methyl-2-(2-methyl-4-oxo-1-methylpropional]-2-methylpropional]-2-methylpropional]-2-methylpropional in DMF (375 mL). 4,12A solution of 6-bromo-2-[2-[(1S)-1-methoxyethyl]-3-pyridyl]morpholine (compound F2, 25.0 g, 54.78 mmol) was added dropwise at 0 °C. The reaction mixture was heated to 45 °C and stirred for an additional 1.5 h. The reaction was quenched with saturated aqueous NaHCO (1.5 L) and extracted with EtOAc (1 L, 3 times). The organic layer was washed with brine (600 mL, 3 times), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give a residue. The residue was purified by column chromatography to give 6-bromo-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-1-azatricyclo[6.3.1.0]. 4,12 ]dodeca-2,4,6,8(12)-tetraene-3-carbaldehyde (compound F3, 20.0 g) was obtained as a yellow solid. MS calculated 484.1 (MH + ), measured value 484.1 (MH + ).

[0177] Step 4: Methyl 3-[6-bromo-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-1-azatricyclo[6.3.1.0 4,12 Preparation of ]dodeca-2,4,6,8(12)-tetraen-3-yl]-3-hydroxy-2,2-dimethyl-propanoate (compound F4) To a solution of methyl isobutyrate (25.3 g, 247.72 mmol) in THF (700 mL) was added LDA (123.8 mL, 247.73 mmol) dropwise under a nitrogen atmosphere at −70° C. After stirring for 0.5 h, the reaction mixture was treated with 6-bromo-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-1-azatricyclo[6.3.1.0] in THF (200 mL). 4,12A solution of ]dodeca-2,4,6,8(12)-tetraene-3-carbaldehyde (compound F3, 20.0 g, 41.29 mmol) 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 aqueous NH4Cl (1 L) and extracted with EtOAc (800 mL, 3 times). The organic layer was washed with brine (500 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give a residue. The residue was purified by column chromatography to give methyl 3-[6-bromo-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-1-azatricyclo[6.3.1.0 4,12 ]dodeca-2,4,6,8(12)-tetraen-3-yl]-3-hydroxy-2,2-dimethyl-propanoate (compound F4, 20 g) was obtained as a yellow solid. MS calculated 586.2 (MH + ), measured value 586.2 (MH + ).

[0178] Step 5: Methyl 3-[6-bromo-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-1-azatricyclo[6.3.1.0 4,12 Preparation of ]dodeca-2,4,6,8(12)-tetraen-3-yl]-2,2-dimethyl-propanoate (compound F5) Methyl 3-[6-bromo-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-1-azatricyclo[6.3.1.0] in DCM (550 mL) 4,12To a solution of ]dodeca-2,4,6,8(12)-tetraen-3-yl]-3-hydroxy-2,2-dimethyl-propanoate (compound F4, 20 g, 34.1 mmol) and EtSiH (31.7 g, 272.87 mmol) was added TFA (110.0 mL, 1480.88 mmol) at 0 °C. After stirring at 25 °C for 12 hours, the reaction mixture was concentrated in vacuo to give a residue, which was diluted with aqueous NaHCO to pH = 9 and extracted with EtOAc (500 mL, 3 times). The combined organic phase was dried over anhydrous NaSO, filtered, and concentrated in vacuo to give a residue. The residue was purified by column chromatography to give methyl 3-[6-bromo-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-1-azatricyclo[6.3.1.0 4,12 ]dodeca-2,4,6,8(12)-tetraen-3-yl]-2,2-dimethyl-propanoate (compound F5, 17 g) was obtained as a yellow solid. MS calculated 570.2 (MH + ), measured value 570.2 (MH + ).

[0179] Step 6: 3-[6-bromo-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-1-azatricyclo[6.3.1.0 4,12 Preparation of ]dodeca-2,4,6,8(12)-tetraen-3-yl]-2,2-dimethyl-propan-1-ol (compound F6) Methyl 3-[6-bromo-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-1-azatricyclo[6.3.1.0] in THF (370 mL) 4,12To a solution of ]dodeca-2,4,6,8(12)-tetraen-3-yl]-2,2-dimethyl-propanoate (compound F5, 17 g, 29.8 mmol) was added lithium borohydride (7.8 g, 358.03 mmol) under N at 0 °C. After stirring at 25 °C for 15 h, the reaction was quenched with saturated aqueous NH Cl (500 mL) at 0 °C, and the resulting mixture was extracted with EtOAc (600 mL, 3 times). The combined organic layers were washed with brine (200 mL), dried over Na SO , filtered, and concentrated in vacuo to give a residue. The residue was purified by column chromatography to give 3-[6-bromo-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-1-azatricyclo[6.3.1.0]. 4,12 ]dodeca-2,4,6,8(12)-tetraen-3-yl]-2,2-dimethyl-propan-1-ol (compound F6, 7.9 g, faster eluting) was obtained as a yellow solid. MS calculated 542.2 (MH + ), measured value 542.2 (MH + ).

[0180] X-ray crystallography of compound F6 The absolute configuration of compound F6 was confirmed by X-ray crystallography of its (2S,3S)-2,3-bis[(4-methylbenzoyl)oxy]butanedioate acetonitrile solvate (Figure 1). TIFF2026506637000054.tif52170

[0181] Step 7: 3-[(2M)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-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-3-yl]-2,2-dimethyl-propan-1-ol (compound F7) 3-[6-bromo-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-1-azatricyclo[6.3.1.0] in toluene (130 mL) 4,12To a solution of ]dodeca-2,4,6,8(12)-tetraen-3-yl]-2,2-dimethyl-propan-1-ol (compound F6, 7.3 g, 13.46 mmol), bis(pinacolato)diboron (5.1 g, 20.2 mmol), KOAc (3.3 g, 33.63 mmol), and Pd(dppf)Cl (993.0 mg, 1.36 mmol) were added. The mixture was degassed and purged with nitrogen three times and stirred at 90 °C for 12 h. After cooling to room temperature, the reaction mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography to give 3-[(2M)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-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-3-yl]-2,2-dimethyl-propan-1-ol (compound F7, 7.14 g) was obtained as a yellow solid. MS calculated 590.4 (MH + ), measured value 590.4 (MH + ).

[0182] Step 8: Methyl (3S)-1-[(2S)-2-(tert-butoxycarbonylamino)-3-[4-[3-(3-hydroxy-2,2-dimethyl-propyl)-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-1-azatricyclo[6.3.1.0 4,12 Preparation of ]dodeca-2,4(12),5,7-tetraen-6-yl]thiazol-2-yl]propanoyl]hexahydropyridazine-3-carboxylate (compound F8) 3-[(2M)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-azatricyclo[6.3.1.0] in toluene (90 mL) / 1,4-dioxane (30 mL) / water (30 mL). 4,12To a solution of ]dodeca-2,4(12),5,7-tetraen-3-yl]-2,2-dimethyl-propan-1-ol (Compound F7, 7.14 g, 12.11 mmol) and methyl (3S)-1-[(2S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylate (Intermediate B, 4.8 g, 10.1 mmol), KPO (5.4 g, 25.3 mmol) and Pd(dtbpf)Cl (1.3 g, 2.03 mmol) were added in one portion. The mixture was degassed and purged with nitrogen three times, then stirred at 70 °C for 12 h. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography to give (3S)-1-[(2S)-2-(tert-butoxycarbonylamino)-3-[4-[3-(3-hydroxy-2,2-dimethyl-propyl)-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-1-azatricyclo[6.3.1.0 4,12 ]dodeca-2,4(12),5,7-tetraen-6-yl]thiazol-2-yl]propanoyl]hexahydropyridazine-3-carboxylate (compound F8, 7.9 g) was obtained as a yellow solid. MS calculated 860.4 (MH + ), measured value 860.4 (MH + ).

[0183] Step 9: (3S)-1-[(2S)-2-(tert-butoxycarbonylamino)-3-[4-[3-(3-hydroxy-2,2-dimethyl-propyl)-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-1-azatricyclo[6.3.1.0 4,12 Preparation of ]dodeca-2,4(12),5,7-tetraen-6-yl]thiazol-2-yl]propanoyl]hexahydropyridazine-3-carboxylic acid (compound F9) Methyl (3S)-1-[(2S)-2-(tert-butoxycarbonylamino)-3-[4-[3-(3-hydroxy-2,2-dimethyl-propyl)-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-1-azatricyclo[6.3.1.0] in DCE (180 mL) 4,12 To a mixture of [dodeca-2,4(12),5,7-tetraen-6-yl]thiazol-2-yl]propanoyl]hexahydropyridazine-3-carboxylate (compound F8, 7.9 g, 9.19 mmol), trimethyltin hydroxide (8.3 g, 45.99 mmol) was added in one portion. After stirring at 60 °C for 15 h, the reaction mixture was poured into water (80 mL) and extracted with EtOAc (200 mL, 3 times). The combined organic layers were washed with brine (200 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated under vacuum to give (3S)-1-[(2S)-2-(tert-butoxycarbonylamino)-3-[4-[3-(3-hydroxy-2,2-dimethyl-propyl)-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-1-azatricyclo[6.3.1.0 4,12 ]dodeca-2,4(12),5,7-tetraen-6-yl]thiazol-2-yl]propanoyl]hexahydropyridazine-3-carboxylic acid (compound F9, 7.5 g) was obtained as a yellow solid. MS calculated 846.4 (MH + ), measured value 846.4 (MH + ).

[0184] Step 10: tert-Butyl 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 Preparation of ]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamate (compound F10) (3S)-1-[(2S)-2-(tert-butoxycarbonylamino)-3-[4-[3-(3-hydroxy-2,2-dimethyl-propyl)-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-1-azatricyclo[6.3.1.0] in DCM (1.5 L) 4,12 To a solution of [dodeca-2,4(12),5,7-tetraen-6-yl]thiazol-2-yl]propanoyl]hexahydropyridazine-3-carboxylic acid (compound F9, 7.5 g, 8.86 mmol), DIEA (22.9 g, 177.38 mmol), EDCI (25.6 g, 133.61 mmol), and HOBt (3.0 g, 22.2 mmol) were added at 0 °C. After stirring at 25 °C for 12 h, the reaction mixture was poured into water (200 mL) and extracted with EtOAc (300 mL, 3 times). The combined organic layers were washed with brine (300 mL), dried over Na SO , and then filtered. The filtrate was concentrated under vacuum to give a residue, which was purified by column chromatography to give tert-butyl 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]carbamate (compound F10, 5.9 g) was obtained as a yellow solid. MS calculated 828.4 (MH + ), measured value 828.4 (MH + ).

[0185] Step 11: (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]Preparation of Hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate F) tert-Butyl 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 To a solution of ]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamate (compound F10, 1.0 g, 1.21 mmol) was added TFA (3.5 mL) in one portion. After stirring at 25 °C for 1 h, the mixture was poured into water (50 mL) and extracted with EtOAc (20 mL). The organic phase was washed with water (50 mL, 2 times). The combined aqueous phase was basified with saturated aqueous NaHCO3 to pH = 9 and extracted with EtOAc (100 mL, 3 times). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give (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, 760 mg) was obtained as a yellow solid. MS calculated 741.4 (MH + ), measured value 741.4 (MH + ).

[0186] 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]hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione TIFF2026506637000055.tif63170This compound was prepared according to the following scheme: TIFF2026506637000056.tif89170

[0187] 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) 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 21,26To 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) was added Pd / C on activated carbon (200.0 mg) under a nitrogen atmosphere. The mixture was degassed and purged with H2 three times, then stirred under H2 (15 psi) at 25 °C for 48 min. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give 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 ]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, which was used in the next step without further purification. MS calculated 827.6 (MH + ), measured value 827.4 (MH + ).

[0188] 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). 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) was added TEA (0.15 mL, 1.05 mmol) and CF3CH2OTf (162.8 mg, 0.7 mmol). After stirring at 60 °C for 15 h, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by silica gel column to give 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 calculated 909.4 (MH + ), measured value 909.4 (MH + ).

[0189] 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 21,26] Preparation of hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione a (intermediate G). 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) was added TFA (2 mL). After stirring at 20 °C for 1 h, saturated NaHCO solution (40 mL) was added to the reaction mixture, which was then extracted with EtOAc (50 mL, 3 times). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum to give (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, which was used in the next step without further purification. MS calculated 809.4 (MH + ), measured value 809.4 (MH + ).

[0190] 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 ]Hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione TIFF2026506637000057.tif56170 The title compound was prepared in a manner similar to that 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).

[0191] Intermediate I (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-15,24-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 The title compound was prepared in a manner similar to that of Intermediate E by using 1-[5-ethynyl-6-[(1S)-1-methoxyethyl]-3-pyridyl]-4-(2,2,2-trifluoroethyl)piperazine (Intermediate C3) 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]piperazine-1-carboxylate (Intermediate C1) and 6-bromo-8-iodo-1,2,3,4-tetrahydroquinoline (Intermediate D1).

[0192] Intermediate J (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 The title compound was prepared in a manner similar to that 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]piperazine-1-carboxylate (Intermediate C1) and 6-bromo-8-iodo-1,2,3,4-tetrahydroquinoline (Intermediate D1).

[0193] Intermediate K (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 TIFF2026506637000060.tif70170 The title compound was prepared in a manner similar to that 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 (Compound D1).

[0194] Intermediate L (7S,13S)-(20M)-20-[5-[(9aS)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-2-[(1S)-1-methoxyethyl]-3-pyridyl]-7-amino-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 The title compound was prepared in a manner similar to that of Intermediate E by using (9aS)-8-[5-ethynyl-6-[(1S)-1-methoxyethyl]-3-pyridyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazine (Intermediate C4) instead of benzyl 4-[5-ethynyl-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (Intermediate C1).

[0195] Intermediate L2 (7S,13S)-(20M)-20-[5-[(9aR)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-2-[(1S)-1-methoxyethyl]-3-pyridyl]-7-amino-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 The title compound was prepared in a manner similar to that of Intermediate L by using (9aR)-2-[5-ethynyl-6-[(1S)-1-methoxyethyl]-3-pyridyl]-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazine (Intermediate C5) instead of (9aS)-8-[5-ethynyl-6-[(1S)-1-methoxyethyl]-3-pyridyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazine (Intermediate C4).

[0196] Intermediate M (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 The title compound was prepared in a manner similar to that 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 (Compound D1) and benzyl 4-[5-ethynyl-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (Intermediate C1).

[0197] Intermediate N (7S,13S,22S)-7-amino-(20M)-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 The title compound was prepared in a manner similar to that for 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 (Compound D1) and benzyl 4-[5-ethynyl-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (Intermediate C1).

[0198] Intermediate O (7S,13S)-7-amino-23,23-difluoro-(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 The title compound was prepared in a manner similar to that of Intermediate E by using 6-bromo-3,3-difluoro-8-iodo-2,4-dihydro-1H-quinoline (Intermediate D3) and 1-[5-ethynyl-6-[(1S)-1-methoxyethyl]-3-pyridyl]-4-(2,2,2-trifluoroethyl)piperazine (Intermediate C3) 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).

[0199] Intermediate P (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-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 ]Hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione TIFF2026506637000066.tif56170 The title compound was prepared in a manner similar to that of Intermediate E by using 6-bromo-8-iodo-3,3-dimethyl-2,4-dihydro-1H-quinoline (Intermediate D6) instead of 6-bromo-8-iodo-1,2,3,4-tetrahydroquinoline (Intermediate D1).

[0200] Intermediate Q (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 The title compound was prepared in a manner similar to that 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 (Compound D1) and benzyl 4-[5-ethynyl-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (Intermediate C1).

[0201] Intermediate R1 trans-2-pyrimidin-5-ylcyclopropanecarboxylic acid TIFF2026506637000068.tif22170This compound was prepared according to the following scheme: TIFF2026506637000069.tif40170

[0202] Step 1: trans-ethyl 2-pyrimidin-5-ylcyclopropanecarboxylate (Compound R1-c) To a solution of 5-bromopyrimidine (compound R1-a, 200.0 mg, 1.26 mmol), potassium (trans-2-(ethoxycarbonyl)cyclopropyl)trifluoroborate (compound R1-b, 276.8 mg, 1.26 mmol) in toluene / water (3 mL / 0.3 mL) was added Cs2CO3 (819.7 mg, 2.52 mmol), Ad2nBuP-Pd-G3 (45.8 mg, 0.06 mmol). After stirring at 90 °C for 16 h, the reaction mixture was cooled to room temperature. EtOAc (10 mL) and water (10 mL) were added to the reaction mixture, and the layers were separated. The aqueous phase was extracted with EtOAc (10 mL, twice). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give a residue. The residue was purified by reverse-phase chromatography to give trans-ethyl 2-pyrimidin-5-ylcyclopropanecarboxylate (compound R1-c, 100.0 mg) as a yellow oil. MS calculated 193.1 (MH + ), measured value 193.1 (MH + ).

[0203] Step 2: trans-2-pyrimidin-5-ylcyclopropanecarboxylic acid (intermediate R1) To a solution of trans-ethyl 2-pyrimidin-5-ylcyclopropanecarboxylate (compound R1-c, 85.0 mg, 0.44 mmol) in ethanol (1 mL) was added aqueous NaOH (1 M, 0.5 mL, 0.53 mmol). After stirring at 30 °C for 16 h, the reaction mixture was acidified with a 1 M solution of HCl to pH = 5. The mixture was directly concentrated and purified by reverse-phase chromatography to give trans-2-pyrimidin-5-ylcyclopropanecarboxylic acid (intermediate R1, 50.0 mg) as a white solid. MS calculated 165.1 (MH + ), measured value 165.1 (MH + ).

[0204] Intermediate R2 trans-2-pyridazin-3-ylcyclopropanecarboxylic acid TIFF2026506637000070.tif19170 The title compound was prepared in a manner similar to the preparation of intermediate R1 by using 3-bromopyridazine instead of 5-bromopyrimidine (compound R1-a).

[0205] Intermediate R3 2-Pyrimidin-4-ylcyclopropanecarboxylic acid TIFF2026506637000071.tif23170This compound was prepared according to the following scheme: TIFF2026506637000072.tif84170

[0206] Step 1: Ethyl (E)-3-pyrimidin-4-ylprop-2-enoate (Compound R3-c) To a stirred solution of pyrimidine-4-carboxaldehyde (compound R3-a, 400.0 mg, 3.7 mmol) and triethylphosphonoacetate (compound R3-b, 829.6 mg, 3.7 mmol) in THF (10 mL) was added sodium hydride (177.6 mg, 7.4 mmol, 60% dispersion in mineral oil) at 0 °C. After stirring the reaction mixture at 0 °C for 2 h, the reaction was quenched with HO (5 mL) at the same temperature. The mixture was diluted with HO (10 mL) and extracted with EA (20 mL, 3 times). The combined organic layers were washed with brine (30 mL), dried over NaSO, filtered, and concentrated in vacuo to give a residue. The residue was purified by flash chromatography to give (E)-3-pyrimidin-4-ylprop-2-enoate (compound R3-c, 530.0 mg) as a white solid. MS calculated value 179.1 (MH + ), measured value 179.1 (MH + ).

[0207] Step 2: Ethyl 2-pyrimidin-4-ylcyclopropanecarboxylate (Compound R3-d) To a solution of trimethylsulfoxonium iodide (2.2 g, 9.76 mmol) in DMSO (3 mL) was added sodium hydride (156.3 mg, 6.51 mmol, 60% dispersion in mineral oil) at 0 °C. After stirring at room temperature for 20 minutes under N2, a solution of ethyl (E)-3-pyrimidin-4-ylprop-2-enoate (compound R3-c, 580.0 mg, 3.25 mmol) in THF (3 mL) was added to the reaction mixture. After stirring at room temperature for 1 hour, EtOAc (10 mL) and water (10 mL) were added to the reaction mixture, and the layers were separated. The aqueous phase was extracted with EtOAc (10 mL, twice). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give a residue. The residue was purified by flash chromatography to give ethyl 2-pyrimidin-4-ylcyclopropanecarboxylate (compound R3-d, 220.0 mg) as a white solid. MS calculated 193.1 (MH + ), measured value 193.1 (MH + ).

[0208] Step 3: 2-Pyrimidin-4-ylcyclopropanecarboxylic acid (Intermediate R3) To a solution of ethyl 2-pyrimidin-4-ylcyclopropanecarboxylate (compound R3-d, 150.0 mg, 0.78 mmol) in ethanol (3 mL) was added aqueous NaOH (1 M, 0.9 mL, 0.9 mmol). After stirring at 30 °C for 16 h, the reaction mixture was acidified with a 1 M solution of HCl to pH = 5. The mixture was directly concentrated and purified by reverse-phase chromatography to give 2-pyrimidin-4-ylcyclopropanecarboxylic acid (intermediate R3, 55.0 mg) as a white solid. MS calculated 165.1 (MH + ), measured value 165.1 (MH + ).

[0209] Intermediate R4 trans-2-(4-pyridyl)cyclopropanecarboxylic acid TIFF2026506637000073.tif19170 The title compound was prepared in a manner similar to the preparation of intermediate R1 by using 4-bromopyridine instead of 5-bromopyrimidine (compound R1-a).

[0210] Intermediate R5 2-Pyrimidin-2-ylcyclopropanecarboxylic acid TIFF2026506637000074.tif22170 The title compound was prepared in a manner similar to the preparation of intermediate R3 by using pyrimidine-2-carbaldehyde instead of pyrimidine-4-carboxaldehyde (compound R3-a).

[0211] Intermediate R6 trans-(1S,2S)-2-pyrazin-2-ylcyclopropanecarboxylic acid TIFF2026506637000075.tif201705-The title compound was prepared in a manner similar to the preparation of intermediate R1 by using 2-bromopyrazine instead of bromopyrimidine (compound R1-a).

[0212] Intermediate R7 trans-(1S,2S)-2-(4-methylpyrimidin-5-yl)cyclopropanecarboxylic acid TIFF2026506637000076.tif20170 The title compound was prepared in a manner similar to the preparation of intermediate R1 by using 5-bromo-4-methyl-pyrimidine instead of 5-bromopyrimidine (compound R1-a).

[0213] Intermediate R8 trans-(1S,2S)-2-thiazol-4-ylcyclopropanecarboxylic acid TIFF2026506637000077.tif201705-The title compound was prepared in a manner similar to the preparation of intermediate R1 by using 4-bromothiazole instead of bromopyrimidine (compound R1-a).

[0214] Intermediate R9 trans-(1S,2S)-2-(2-methyl-3-pyridyl)cyclopropanecarboxylic acid TIFF2026506637000078.tif21170 The title compound was prepared in a manner similar to the preparation of intermediate R1 by using 3-bromo-2-methyl-pyridine instead of 5-bromopyrimidine (compound R1-a).

[0215] Intermediate R10 trans-(1S,2S)-2-(5-methyl-3-pyridyl)cyclopropanecarboxylic acid TIFF2026506637000079.tif20170 The title compound was prepared in a manner similar to the preparation of intermediate R1 by using 3-bromo-5-methyl-pyridine instead of 5-bromopyrimidine (compound R1-a).

[0216] Intermediate S (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-15,25-dioxa-4-thia-9,21,31,32-tetrazahexacyclo[24.3.1.1 2,5 .1 9,13 .0 19,28 .0 21,27 ]dotriaconta-1(29),2,5(32),19,26(30),27-hexaene-8,14-dione TIFF2026506637000080.tif67170 The title compound was prepared in a manner similar to that of Intermediate E by using 8-bromo-6-iodo-2,3,4,5-tetrahydro-1,5-benzoxazepine (Intermediate D7) instead of 6-bromo-8-iodo-1,2,3,4-tetrahydroquinoline (Intermediate D1).

[0217] Intermediate T (7S,13S)-7-amino-23-benzyloxy-(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 TIFF2026506637000081.tif73170This compound was prepared according to the following scheme: TIFF2026506637000082.tif255170

[0218] Step 1: Preparation of 6-bromo-8-[2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]ethynyl]-1,2,3,4-tetrahydroquinolin-3-ol (Compound T1). A suspension of 2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]ethynyl-trimethyl-silane (1.8 g, 5.65 mmol), 6-bromo-8-iodo-1,2,3,4-tetrahydroquinolin-3-ol (Intermediate D9, 2 g, 5.65 mmol), EtN (1.71 g, 2.35 mL, 16.89 mmol), copper(I) iodide (107.3 mg, 0.56 mmol), and CsF (858.2 mg, 5.65 mmol) in THF (21 mL) was stirred at room temperature under a nitrogen atmosphere for 12 hours. After the reaction was complete, the reaction mixture was filtered. The collected solid was washed with EtOAc (40 mL). The combined filtrate was washed with brine (10 mL), dried over NaSO, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography to give 6-bromo-8-[2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]ethynyl]-1,2,3,4-tetrahydroquinolin-3-ol (compound T1, 1.7 g) as a pale yellow solid. MS calculated 472.1 (MH + ), measured value 472.1 (MH + ).

[0219] Step 2: 6-Bromo-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-1-azatricyclo[6.3.1.0 4,12 ] Preparation of dodeca-2,4,6,8(12)-tetraen-10-ol (compound T2). A solution of palladium(II) chloride (60 mg, 340.83 μmol) in DMF (25 mL) was stirred at 70° C. under a nitrogen atmosphere for 15 min. A solution of 6-bromo-8-[2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]ethynyl]-1,2,3,4-tetrahydroquinolin-3-ol (compound T1, 1610 mg, 3.41 mmol) in DMF (25 mL) was added to the reaction mixture. After stirring for an additional 18 h, water was added to the reaction mixture, which was then extracted with EA (100 mL, 3 times). The combined organic layers were concentrated and then purified by reverse-phase chromatography to give 6-bromo-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-1-azatricyclo[6.3.1.0]. 4,12 ] Dodeca-2,4,6,8(12)-tetraen-10-ol (compound T2, 970 mg) was obtained as an orange foam. MS calculated 472.1 (MH + ), measured value 472.1 (MH + ).

[0220] Step 3: 4-[5-(10-benzyloxy-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]morpholine (Compound T3). 6-Bromo-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-1-azatricyclo[6.3.1.0] in DMF (24 mL) 4,12To a suspension of ]dodeca-2,4,6,8(12)-tetraen-10-ol (compound T2, 970 mg, 1.95 mmol), NaH (60%, 156 mg, 3.9 mmol) was added at room temperature under a nitrogen atmosphere. After stirring at room temperature for 1 h, the reaction mixture was cooled to 0 °C, and benzyl bromide (667 mg, 464 μL, 3.9 mmol) was added. The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was cooled to 0 °C, and then the reaction was quenched with saturated aqueous NH4Cl (20 mL). EA (40 mL) was added to the reaction mixture, and the aqueous phase was extracted with EA (40 mL, 3 times). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography to give 4-[5-(10-benzyloxy-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]morpholine (compound T3, 1 g) was obtained as an orange solid. MS calculated 562.1 (MH + ), measured value 562.1 (MH + ).

[0221] Step 4: 10-benzyloxy-6-bromo-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-1-azatricyclo[6.3.1.0 4,12 ]Preparation of dodeca-2,4,6,8(12)-tetraene-3-carbaldehyde (compound T4) Phosphorus oxychloride (1 mL, 10.73 mmol) was added to DMF (10 mL) at 0° C. under a nitrogen atmosphere. After stirring at 0° C. for 0.5 h, the reaction mixture was treated with 4-[5-(10-benzyloxy-6-bromo-1-azatricyclo[6.3.1.0]-methyl-2-methyl-4-(4-methyl-2-methyl-4 ... 4,12A solution of 10-benzyloxy-6-bromo-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-1-azatricyclo[6.3.1.0]-2,4,6,8(12)-tetraen-2-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]morpholine (Compound T3, 1 g, 1.78 mmol) was added dropwise under a nitrogen atmosphere. After stirring at room temperature for 2 hours, the reaction mixture was poured into saturated aqueous NaHCO3 solution (30 mL) cooled to 0 °C and then extracted with EA (30 mL, 3 times). The combined organic layer was washed with brine (10 mL), dried over Na2SO4, and concentrated in vacuo to give a residue. The resulting residue was purified by silica gel chromatography to give 10-benzyloxy-6-bromo-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-1-azatricyclo[6.3.1.0]-2,4,6,8(12)-tetraen-2-yl]-6 ... 4,12 ]dodeca-2,4,6,8(12)-tetraene-3-carbaldehyde (compound T4, 900 mg, 77.16%) was obtained as an orange solid. MS calculated 590.2 (MH + ), measured value 590.2 (MH + ).

[0222] Step 5: [10-benzyloxy-6-bromo-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-1-azatricyclo[6.3.1.0 4,12 Preparation of ]dodeca-2,4,6,8(12)-tetraen-3-yl]methanol (Compound T5) 10-Benzyloxy-6-bromo-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-1-azatricyclo[6.3.1.0] in MeOH (20 mL) 4,12 To a solution of ]dodeca-2,4,6,8(12)-tetraene-3-carbaldehyde (compound T4, 900 mg, 1.37 mmol) was added NaBH4 (103.8 mg, 2.74 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The solvent was removed in vacuo to give a residue. The residue was purified by silica gel chromatography to give [10-benzyloxy-6-bromo-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-1-azatricyclo[6.3.1.0 4,12]dodeca-2,4,6,8(12)-tetraen-3-yl]methanol (compound T5, 740 mg) was obtained as a pale yellow oil. MS calculated 592.2 (MH + ), measured value 592.2 (MH + ).

[0223] Step 6: Methyl 3-[10-benzyloxy-6-bromo-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-1-azatricyclo[6.3.1.0 4,12 Preparation of ]dodeca-2,4,6,8(12)-tetraen-3-yl]-2,2-dimethyl-propanoate (compound T6) 1-Methoxy-1-(trimethylsiloxy)-2-methyl-1-propene (653.1 mg, 759.41 μL, 3.75 mmol) and [10-benzyloxy-6-bromo-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-1-azatricyclo[6.3.1.0] in DCM (10 mL) 4,12 A solution of ]dodeca-2,4,6,8(12)-tetraen-3-yl]methanol (compound T5, 740 mg, 1.25 mmol) was stirred at room temperature for 15 minutes. Magnesium perchlorate (557.5 mg, 2.5 mmol) was added to the reaction mixture, which was then stirred for an additional 12 hours. The reaction was quenched with saturated aqueous NaHCO3 (10 mL) and DCM (30 mL). The organic layer was washed with water (3 mL, 3 times), brine (3 mL), dried over Na2SO4, and concentrated in vacuo to give a residue. The resulting residue was purified by silica gel chromatography to give methyl 3-[10-benzyloxy-6-bromo-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-1-azatricyclo[6.3.1.0]. 4,12 ]dodeca-2,4,6,8(12)-tetraen-3-yl]-2,2-dimethyl-propanoate (compound T6, 560 mg) was obtained as a pale yellow oil. MS calculated 676.2 (MH + ), measured value 676.2 (MH + ).

[0224] Step 7: 3-[10-benzyloxy-6-bromo-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-1-azatricyclo[6.3.1.0 4,12 Preparation of ]dodeca-2,4,6,8(12)-tetraen-3-yl]-2,2-dimethyl-propan-1-ol (compound T7) Methyl 3-[10-benzyloxy-6-bromo-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-1-azatricyclo[6.3.1.0] in THF (5 mL) 4,12 To a solution of ]dodeca-2,4,6,8(12)-tetraen-3-yl]-2,2-dimethyl-propanoate (compound T6, 560 mg, 0.828 mmol) was added 2 M LiBH (827 μL, 1.66 mmol) dropwise under N at 0 °C. After stirring at room temperature for 15 h, the reaction was quenched with saturated aqueous NH Cl (10 mL) at 0 °C, and the resulting mixture was extracted with EtOAc (10 mL, 3 times). The combined organic layers were washed with brine (20 mL), dried over Na SO , filtered, and concentrated in vacuo to give a residue. The residue was purified by column chromatography to give 3-[10-benzyloxy-6-bromo-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-1-azatricyclo[6.3.1.0]. 4,12 ]dodeca-2,4,6,8(12)-tetraen-3-yl]-2,2-dimethyl-propan-1-ol (compound T7, 525 mg) was obtained as a pale yellow oil. MS calculated 648.2 (MH + ), measured value 648.2 (MH + ).

[0225] Step 8: 3-[10-benzyloxy-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-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-3-yl]-2,2-dimethyl-propan-1-ol (compound T8) 3-[10-benzyloxy-6-bromo-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-1-azatricyclo[6.3.1.0] in 1,4-dioxane (6 mL) 4,12 To a solution of ]dodeca-2,4,6,8(12)-tetraen-3-yl]-2,2-dimethyl-propan-1-ol (compound T7, 525 mg, 809.4 μmol), bis(pinacolato)diboron (246.6 mg, 971.28 μmol), and KOAc (198 mg, 2.02 mmol) was added Pd(dppf)Cl (66 mg, 80.94 μmol). The mixture was degassed and purged under a nitrogen atmosphere three times, and the mixture was stirred at 90 °C for 2 h. After the reaction was complete, the mixture was cooled to room temperature and then filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by silica column chromatography to give 3-[10-benzyloxy-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-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-3-yl]-2,2-dimethyl-propan-1-ol (compound T8, 525 mg, 93.24%) was obtained as a pale yellow oil. MS calculated 696.4 (MH + ), measured value 696.4 (MH + ).

[0226] Step 9: Methyl (3S)-1-[(2S)-3-[4-[10-benzyloxy-3-(3-hydroxy-2,2-dimethyl-propyl)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-1-azatricyclo[6.3.1.0 4,12 Preparation of ]dodeca-2,4(12),5,7-tetraen-6-yl]thiazol-2-yl]-2-(tert-butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylate (compound T9) 3-[10-benzyloxy-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-azatricyclo[6.3.1.0] in 1,4-dioxane (7 mL) / water (2 mL) 4,12 To a solution of ]dodeca-2,4(12),5,7-tetraen-3-yl]-2,2-dimethyl-propan-1-ol (Compound T8, 525 mg, 754.65 μmol) and methyl (3S)-1-[(2S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylate (Intermediate B, 342 mg, 716.91 μmol), KPO (400 mg, 1.89 mmol) and Pd(dtbpf)Cl (49 mg, 75.46 μmol) were added in one portion. The mixture was degassed and purged with nitrogen three times, then stirred at 70 °C for 15 h. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under vacuum to give the crude product methyl (3S)-1-[(2S)-3-[4-[10-benzyloxy-3-(3-hydroxy-2,2-dimethyl-propyl)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-1-azatricyclo[6.3.1.0 4,12 ]dodeca-2,4(12),5,7-tetraen-6-yl]thiazol-2-yl]-2-(tert-butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylate (compound T9, 700 mg) was obtained as a black oil, which was used in the next step without purification. MS calculated 966.5 (MH + ), measured value 966.5 (MH + ).

[0227] Step 10: (3S)-1-[(2S)-3-[4-[10-benzyloxy-3-(3-hydroxy-2,2-dimethyl-propyl)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-1-azatricyclo[6.3.1.0 4,12Preparation of ]dodeca-2,4(12),5,7-tetraen-6-yl]thiazol-2-yl]-2-(tert-butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylic acid (compound T10) Methyl (3S)-1-[(2S)-3-[4-[10-benzyloxy-3-(3-hydroxy-2,2-dimethyl-propyl)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-1-azatricyclo[6.3.1.0] in MeOH (10 mL) / THF (10 mL) 4,12 To a solution of [(3S)-1-[(2S)-3-[4-[10-benzyloxy-3-(3-hydroxy-2,2-dimethyl-propyl)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-1-azatricyclo[6.3.1.0 methyl]-2-(tert-butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylate (Compound T9, 700 mg, 0.725 mmol) was added 2 M LiOH (2 mL, 4 mmol) and then stirred at room temperature for 2 hours. The reaction mixture was acidified to pH = 5 with a 1 M solution of HCl and then extracted with EtOAc (40 mL, 3 times). The combined organic layers were concentrated and then purified by reverse phase chromatography to give (3S)-1-[(2S)-3-[4-[10-benzyloxy-3-(3-hydroxy-2,2-dimethyl-propyl)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-1-azatricyclo[6.3.1.0 methyl]-2-(tert-butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylate (Compound T9, 700 mg, 0.725 mmol). 4,12 ]dodeca-2,4(12),5,7-tetraen-6-yl]thiazol-2-yl]-2-(tert-butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylic acid (compound T10, 433 mg) was obtained as a pale yellow powder. MS calculated 952.5 (MH + ), measured value 952.5 (MH + ).

[0228] Step 11: tert-butyl N-[(7S,13S)-23-benzyloxy-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 .19,13 .0 19,27 .0 21,26 Preparation of ]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamate (compound T11) A solution of TCFH (229.8 mg, 819.18 μmol) and NMI (269 mg, 261 μL, 3.28 mmol) in MeCN (103 mL) was stirred at room temperature for 15 min. (3S)-1-[(2S)-3-[4-[10-benzyloxy-3-(3-hydroxy-2,2-dimethylpropyl)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-1-azatricyclo[6.3.1.0]] in acetonitrile (51 mL) was added. 4,12 Another solution of N-[(7S,13S)-23-benzyloxy-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]carbamate (compound T11, 514 mg) was obtained as a light brown oil. MS calculated 934.4 (MH + ), measured value 934.4 (MH + ).

[0229] Step 12: (7S,13S)-7-amino-23-benzyloxy-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 ]Preparation of Hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate T) tert-Butyl N-[(7S,13S)-23-benzyloxy-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 To a solution of ]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamate (Compound T11, 300 mg, 321.15 μmol) was added TFA (2 mL), and the mixture was stirred at 20° C. for 1 hour. After the reaction was complete, the reaction mixture was concentrated under vacuum to give (7S,13S)-7-amino-23-benzyloxy-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 T, 300 mg) was obtained as a pale yellow oil. MS calculated 834.4 (MH + ), measured value 834.4 (MH + ).

[0230] Intermediate U (7S,13S)-7-amino-29-fluoro-(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 TIFF2026506637000083.tif67170 The title compound was prepared in a manner similar to that of Intermediate E by using 6-bromo-5-fluoro-8-iodo-1,2,3,4-tetrahydroquinoline (Intermediate D10) instead of 6-bromo-8-iodo-1,2,3,4-tetrahydroquinoline (Intermediate D1).

[0231] Intermediate V Benzyl 4-[(5M)-5-[(7S,13S)-7-(tert-butoxycarbonylamino)-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-20-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate TIFF2026506637000084.tif66170 The title compound was prepared in a manner similar to that of Intermediate E10 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).

[0232] Example 1 (1S,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]-2-methyl-cyclopropanecarboxamide TIFF2026506637000085.tif72170(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 To a solution of hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate F, 32.13 mg, 0.12 mmol) and (1S,2S)-2-methylcyclopropanecarboxylic acid (33.0 mg, 0.33 mmol) was added DIEA (85.0 mg, 0.66 mmol) and T3P (67.0 mg, 0.11 mmol) at 0 °C. After stirring at 20 °C for 1 h, the reaction mixture was diluted with water (15 mL) and extracted with EtOAc (15 mL, 3 times). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC to give Example 1 (26.6 mg) as a yellow solid. MS calculated 810.4 (MH + ), measured value 810.4 (MH + ). 1H NMR(400MHz,METHANOL-d4)δ=8.42(s,1H),8.36(d,J=2.8Hz,1H),7.86(d,J=2.4Hz,1H),7.50(s,1H),7.45(s,1H),5.83-5. 77(m,1H),4.59-4.38(m,1H),4.21-4.17(m,1H),4.16-4.08(m,1H),3.86(t,J=4.8Hz,4H),3.81-3.59(m,3H),3.50-3.32(m ,8H),3.29-3.22(m,2H),3.19-2.94(m,4H),2.86-2.60(m,2H),2.43-2.07(m,3H),2.01-1.86(m,1H),1.83-1.53(m,2H),1. 50-1.43(m,4H),1.31-1.17(m,1H),1.12(d,J=6.0Hz,3H),1.09-1.02(m,2H),0.99(s,3H),0.66-0.63(m,1H),0.62(s,3H).

[0233] Example 2 (1S,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]-2-methyl-cyclopropanecarboxamide TIFF2026506637000086.tif58170

[0234] (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) was replaced with (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 ] The title compound was prepared in a manner similar to that of Example 1 by using hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate E). Example 2 (16.2 mg) was obtained as a yellow solid. MS calculated 823.4 (MH + ), measured value 823.4 (MH + ). 1 H NMR(400MHz,Methanol-d4)δ=8.49(d,J=2.8Hz,1H),8.39(s,1H),7.67(s,1H),7.49(s,1H),7.43(s,1H),5.83-5.73(m,1H),4.85-4. 77(m,1H),4.54-4.40(m,2H),4.25-4.16(m,2H),3.85-3.67(m,3H),3.66-3.57(m,2H),3.46-3.33(m,6H),3.30-3.22(m,2H),3.18-2. 92(m,7H),2.82-2.71(m,1H),2.67-2.58(m,1H),2.39-2.25(m,1H),2.23-2.13(m,2H),1.98-1.89(m,1H),1.84-1.69(m,1H),1.66-1 .53(m,1H),1.51-1.43(m,4H),1.37-1.15(m,2H),1.14-1.10(m,3H),1.09-1.04(m,1H),0.98(s,3H),0.67-0.61(m,1H),0.56(s,3H).

[0235] Example 3 (1S,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]-2-methyl-cyclopropanecarboxamide TIFF2026506637000087.tif60170(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) was replaced with (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 ] The title compound was prepared in a manner similar to that of Example 1 by using hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate G). Example 3 (27.6 mg) was obtained as a yellow solid. MS calculated 891.4 (MH + ), measured value 891.4 (MH + ). 1H NMR(400MHz,Methanol-d4)δ=8.42(s,1H),8.37(d,J=2.8Hz,1H),7.83(d,J=2.8Hz,1H),7.50(s,1H),7.45(s,1H),5.85-5.75(m,1H),4.5 6-4.48(m,1H),4.47-4.39(m,1H),4.22(dd,J=3.2,11.8Hz,1H),4.17-4.09(m,1H),3.81-3.72(m,2H),3.70-3.62(m,1H),3.51-3.46(m,4H) ),3.42(s,3H),3.30-2.95(m,7H),2.90-2.85(m,4H),2.81-2.65(m,2H),2.39-2.27(m,1H),2.24-2.13(m,2H),1.98-1.89(m,1H),1.82-1. 67(m,1H),1.66-1.52(m,1H),1.49-1.43(m,4H),1.27-1.18(m,1H),1 .14-1.10(m,3H),1.09-1.04(m,1H),1.00(s,3H),0.67-0.58(m,4H).

[0236] Example 5 (1S,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-15,24-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]-2-methyl-cyclopropanecarboxamide TIFF2026506637000088.tif64170(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 .019,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (intermediate F) was replaced with (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-15,24-dioxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ] The title compound was prepared in a manner similar to that of Example 1 by using hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate I). Example 5 (22.11 mg) was obtained as a pale yellow solid. MS calculated 893.4 (MH + ), measured value 893.4 (MH + ). 1 H NMR(400MHz,DMSO-d6)δ=8.52(d,J=8.8Hz,1H),8.44(d,J=2.7Hz,1H),8.12(s,1H),7.74(s,1H),7.18(d,J=2.8Hz,1H),7.15(s,1H),5 .55(t,J=9.0Hz,1H),5.04(d,J=12.1Hz,1H),4.68-4.54(m,2H),4.35-4.15(m,4H),3.74-3.67(m,1H),3.62-3.56(m,2H),3.28-3.25( m,4H),3.23(s,3H),3.19-3.07(m,1H),3.03-2.84(m,1H),2.83-2.69(m,5H),2.43(s,1H),2.14-2.08(m,1H),1.87-1.71(m,2H),1.56 -1.43(m,2H),1.33(d,J=6.1Hz,3H),1.23(s,1H),1.08-1.01(m,6H),0.94(s,3H),0.87-0.82(m,1H),0.58-0.48(m,1H),0.38(s,3H).

[0237] Example 6 (1S,2S)-2-(Difluoromethyl)-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]cyclopropanecarboxamide The title compound was prepared in a manner similar to that of Example 1, except that (1S,2S)-2-(dihydromethyl)cyclopropanecarboxylic acid was used instead of (1S,2S)-2-methylcyclopropanecarboxylic acid. Example 6 (34.9 mg) was obtained as a yellow solid. MS calculated 846.4 (MH + ), measured value 846.4 (MH + ). 1 H NMR(400MHz,METHANOL-d4)δ=8.42(s,1H),8.36(d,J=2.80Hz,1H),7.82(d,J=2.80Hz,1H),7.51(s,1H),7.45(s,1H) ,5.96-5.64(m,2H),4.53(q,J=6.40Hz,1H),4.47-4.38(m,1H),4.24-4.09(m,2H),3.87(t,J=4.80Hz,4H),3.81-3.64 (m,3H),3.44-3.38(m,8H),3.17-2.94(m,3H),2.83-2.67(m,2H),2.38-2.26(m,1H),2.25-2.11(m,2H),2.09-2.00( m,2H),1.98-1.88(m,1H),1.84-1.69(m,2H),1.67-1.54(m,1H),1.48(d,J=6.40Hz,3H),1.21-1.07(m,2H),0.99(s,3 H),0.62(s,3H).

[0238] Example 7 (1S,5R,6r)-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-oxabicyclo[3.1.0]hexane-6-carboxamide The title compound was prepared in a manner similar to that of Example 1, except that (1S,5R,6r)-3-oxabicyclo[3.1.0]hexane-6-carboxylic acid was used instead of (1S,2S)-2-methylcyclopropanecarboxylic acid. Example 7 (29.3 mg) was obtained as a yellow solid. MS calculated 838.4 (MH + ), measured value 838.4 (MH + ). 1 H NMR(400MHz,DMSO-d6)δ=8.56(d,J=8.8Hz,1H),8.44(d,J=2.8Hz,1H),8.34(s,1H),7.71(s,1H),7 .45(s,1H),7.34(s,1H),5.58(t,J=8.80Hz,1H),5.07(d,J=12.4Hz,1H),4.39-4.31(m,1H),4.27- 4.13(m,3H),3.85-3.72(m,8H),3.29-3.24(m,7H),3.17-2.84(m,6H),2.81-2.70(m,1H),2.29-2. 04(m,4H),1.97-1.71(m,5H),1.67-1.41(m,3H),1.35(d,J=6.40Hz,3H),0.92(s,3H),0.43(s,3H).

[0239] Example 8 (1S,2S)-N-[(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]-2-methyl-cyclopropanecarboxamide TIFF2026506637000091.tif49170(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) was replaced with (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 ] The title compound was prepared in a manner similar to that of Example 1 by using hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate J). Example 8 (20 mg) was obtained as a pale yellow solid. MS calculated 812.4 (MH + ), measured value 812.4 (MH + ). 1H NMR(400MHz,ACETONITRILE-d3)δ=8.38(d,J=2.9Hz,1H),8.20(s,1H),7.44(s,1H),7.29(d,J=2.8Hz,1H),7.15-7.06(m,2H),5.67(t,J=8.9Hz,1H) ,4.67-4.56(m,2H),4.48(d,J=6.2Hz,1H),4.45-4.18(m,4H),3.89-3.79 (m,4H),3.78-3.63(m,3H),3.40-3.25(m,8H),3.20-3.09(m,1H),3.04(br d,J=14.3Hz,1H),2.77-2.65(m,1H),2.58(br d,J=14.3Hz,1H),1.91(br d,J=12.6Hz,1H),1.85-1.74(m,1H),1.62-1.51(m,1H),1.44-1.36(m,4H),1.29(br d,J=6.0Hz,1H),1.21-1.15(m,1H),1.13-1.08(m,3H),1.04-0.95(m,4H),0.66-0.58(m,1H),0.51(s,3H).

[0240] Example 9 (1S,2S)-2-(Difluoromethyl)-N-[(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]cyclopropanecarboxamide TIFF2026506637000092.tif50170(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 .021,26 ]hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (intermediate F) and (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]] instead of (1S,2S)-2-methylcyclopropanecarboxylic acid. 2,5 .1 9,13 .0 19,27 .0 21,26 ] The title compound was prepared in a manner similar to that of Example 1 by using hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate J) and (1S,2S)-2-(difluoromethyl)cyclopropanecarboxylic acid. Example 9 (6 mg) was obtained as a pale yellow solid. MS calculated 848.4 (MH + ), measured value 848.4 (MH + ). 1 H NMR(400MHz,ACETONITRILE-d3)δ=8.29(d,J=3.0Hz,1H),8.22(d,J=0.8Hz,1H),7.54 (d,J=3.0Hz,1H),7.45(s,1H),7.33-7.26(m,1H),7.13(d,J=1.0Hz,1H),5.80-5.48(m ,2H),4.65-4.55(m,3H),4.53-4.35(m,1H),4.37-4.32(m,1H),4.29-4.21(m,2H),3. 85-3.79(m,5H),3.72(d,J=6.8Hz,2H),3.41-3.31(m,8H),3.20-3.11(m,1H),3.03(br d,J=14.3Hz,1H),2.73(br d,J=3.0Hz,1H),2.65(br d,J=14.3Hz,1H),1.83-1.74(m,2H),1.63-1.52(m,1H),1.41(d,J=6.3Hz,3H),1.32-1.25(m,3H),1.12(br s,2H),1.01(s,3H),0.58(s,3H).

[0241] Example 10 (1S,5R,6r)-N-[(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]-3-oxabicyclo[3.1.0]hexane-6-carboxamide TIFF2026506637000093.tif67170(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 (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]] instead of (1S,2S)-2-methylcyclopropanecarboxylic acid. 2,5 .1 9,13 .0 19,27 .0 21,26 The title compound was prepared in a manner similar to that of Example 1 by using ]hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate J) and (1S,5R,6r)-3-oxabicyclo[3.1.0]hexane-6-carboxylic acid. Example 10 (5.2 mg) was obtained as a pale yellow solid. MS calculated 840.4 (MH + ), measured value 840.4 (MH + ). 1H NMR(400MHz,ACETONITRILE-d3)δ=8.34(d,J=3.0Hz,1H),8.21(s,1H),7.45(s,1H),7.41(d,J=2.8Hz,1H),7.12(d,J=1 .0Hz,2H),5.92-5.63(m,2H),4.67-4.58(m,2H),4.53(d,J=6.3Hz,1H),4.45-4.37(m,1H),4.35-4.28(m,2H),4.22(br d,J=3.0Hz,1H),3.88(s,2H),3.85-3.79(m,4H),3.76(s,1H),3.74-3.66(m,4H),3.39-3.29(m,8H),3.17-3.10(m,1H),3.04(d,J= 14.5Hz,1H),2.75-2.68(m,1H),2.64-2.60(m,1H),2.03(s,1H),2.01-1.99(m,1H),1.94-1.87(m,1H),1.84-1.73(m,1H),1.56(br t,J=3.3Hz,2H),1.41(d,J=6.3Hz,3H),1.00(s,3H),0.55(s,3H).

[0242] Example 11 (1S,2S)-2-(Difluoromethyl)-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-15,24-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]cyclopropanecarboxamide TIFF2026506637000094.tif73170(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 .19,13 .0 19,27 .0 21,26 ]hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (intermediate F) 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-15,24-dioxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1]] instead of (1S,2S)-2-methylcyclopropanecarboxylic acid. 2,5 .1 9,13 .0 19,27 .0 21,26 The title compound was prepared in a manner similar to that of Example 1 by using hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate I) and (1S,2S)-2-(difluoromethyl)cyclopropanecarboxylic acid. Example 11 (22.1 mg) was obtained as a pale yellow solid. MS calculated 929.4 (MH + ), measured value 929.4 (MH + ). 1 H NMR(400MHz,ACETONITRILE-d3)δ=8.40(d,J=2.8Hz,1H),8.17(s,1H),7.41(s,1H),7.22-7.16(m,1H),7.15-7.11(m,1H) ,7.07-7.03(m,1H),5.77-5.66(m,1H),4.66-4.52(m,2H),4.44-4.34(m,3H),4.33-4.18(m,2H),3.76-3.63(m,3H),3.37( d,J=15.5Hz,1H),3.30-3.24(m,7H),3.19-3.06(m,4H),3.00(d,J=15.0Hz,1H),2.83-2.79(m,4H),2.74-2.63(m,2H),2.5 8-2.49(m,2H),1.79-1.76(m,2H),1.60-1.52(m,2H),1.37(d,J=6.1Hz,3H),1.13-1.06(m,2H),0.96(s,3H),0.47(s,3H).

[0243] Example 12 (1S,5R,6r)-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-15,24-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]-3-oxabicyclo[3.1.0]hexane-6-carboxamide TIFF2026506637000095.tif67170(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 (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-15,24-dioxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1]] instead of (1S,2S)-2-methylcyclopropanecarboxylic acid. 2,5 .1 9,13 .0 19,27 .0 21,26 The title compound was prepared in a manner similar to that of Example 1 by using ]hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate I) and (1S,5R,6r)-3-oxabicyclo[3.1.0]hexane-6-carboxylic acid. Example 12 (13.4 mg) was obtained as a white solid. MS calculated 921.4 (MH+ ), measured value 921.4 (MH + ). 1 H NMR(400MHz,ACETONITRILE-d3)δ=8.44-8.37(m,1H),8.20-8.14(m,1H),7.44-7.38(m,1H),7.16-7.12(m,1H),7.06(d,J=1.0Hz,1H),7.02 -6.97(m,1H),5.71-5.60(m,1H),4.61-4.52(m,2H),4.40-4.36(m,2H ),4.30-4.19(m,2H),3.89-3.82(m,2H),3.75-3.66(m,4H),3.41-3.32 (m,2H),3.30-3.24(m,7H),3.17-3.05(m,4H),3.00(d,J=13.9Hz,1H),2.83-2.79(m,4H),2.74-2.65(m,2H),2.56-2.52(m,1H),2.00(s,1H) ),1.78-1.75(m,1H),1.55-1.50(m,2H),1.37(d,J=6.1Hz,3H),1.30-1.26(m,1H),1.00-0.93(m,3H),0.92-0.87(m,1H),0.51-0.41(m,3H).

[0244] Example 13 (1S,5R,6r)-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-oxabicyclo[3.1.0]hexane-6-carboxamide TIFF2026506637000096.tif65170(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 (1S,2S)-2-methylcyclopropanecarboxylic acid were replaced with (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 The title compound was prepared in a manner similar to that of Example 1 by using ]hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate G) and (1S,5R,6r)-3-oxabicyclo[3.1.0]hexane-6-carboxylic acid. Example 13 (11.9 mg) was obtained as a yellow solid. MS calculated 919.4 (MH + ), measured value 919.4 (MH + ). 1H NMR(400MHz,METHANOL-d4)δ=8.45-8.33(m,2H),7.84-7.83(m,1H),7.54-7.43(m,2H),5.81(d,J=8.4Hz,1H),4. 52(d,J=6.4Hz,1H),4.43(d,J=1.6Hz,1H),4.25-4.17(m,1H),4.17-4.08(m,1H),3.92(t,J=8.8Hz,2H),3.81-3. 67(m,5H),3.52-3.38(m,8H),3.25-2.99(m,6H),2.91-2.85(m,4H),2.82-2.66(m,2H),2.37-2.15(m,3H),2.13- 2.04(m,2H),1.98-1.88(m,1H),1.81-1.57(m,3H),1.48(d,J=6.0Hz,3H),1.05-0.95(m,3H),0.66-0.57(m,3H).

[0245] Example 14 (1S,2S)-2-(Difluoromethyl)-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]cyclopropanecarboxamide TIFF2026506637000097.tif67170

[0246] (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 (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] instead of (1S,2S)-2-methylcyclopropanecarboxylic acid. 2,5 .1 9,13 .0 19,27 .0 21,26 ] The title compound was prepared in a manner similar to that of Example 1 by using hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate E) and (1S,2S)-2-(difluoromethyl)cyclopropanecarboxylic acid. Example 14 (28.7 mg) was obtained as a yellow solid. MS calculated 859.4 (MH + ), measured value 859.5 (MH + ). 1 H NMR(400MHz,METHANOL-d4)δ=8.47(d,J=2.8Hz,1H),8.38(s,1H),7.51-7.47(m,2H),7.41(s,1H),5.82-5.79(m,2H),4.44(m,2H), 4.26-4.19(m,2H),4.12-4.02(m,1H),3.80-3.68(m,3H),3.65-3.49(m,2H),3.45-3.40(m,2H),3.38-3.33(m,5H),3.29-3.26(m,1H) ),3.15-3.01(m,3H),3.01-2.97(m,4H),2.73-2.81(m,1H),2.64-2.57(m,1H),2.35-2.26(m,1H),2.21-2.14(m,2H),2.12-1.94(m ,2H),1.83-1.73(m,2H),1.66-1.58(m,1H),1.45(d,J=6.0Hz,3H),1.34-1.28(m,1H),1.18-1.09(m,2H),0.96(s,3H),0.55(s,3H).

[0247] Example 15 (1S,5R,6r)-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-oxabicyclo[3.1.0]hexane-6-carboxamide TIFF2026506637000098.tif63170(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 (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] instead of (1S,2S)-2-methylcyclopropanecarboxylic acid. 2,5 .1 9,13 .0 19,27 .0 21,26 The title compound was prepared in a manner similar to that of Example 1 by using ]hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate E) and (1S,5R,6r)-3-oxabicyclo[3.1.0]hexane-6-carboxylic acid. Example 15 (26.8 mg) was obtained as a yellow solid. MS calculated 851.4 (MH + ), measured value 851.4 (MH + ). 1H NMR(400MHz,Methanol-d4)δ=8.48(d,J=2.8Hz,1H),8.39(s,1H),7.59(d,J=2 .8Hz,1H),7.50(s,1H),7.43(s,1H),5.77(d,J=8.0Hz,1H),4.90-4.88(m,1H) ,4.50-4.41(m,2H),4.25-4.18(m,2H),4.14-4.01(m,1H),3.99-3.86(m,3H), 3.81-3.70(m,5H),3.66-3.52(m,3H),3.45-3.39(m,2H),3.38(s,3H),3.28-3 .24(m,1H),3.14-3.07(m,2H),2.99(s,4H),2.81-2.74(m,1H),2.62(d,J=14. 4Hz,1H),2.36-2.27(m,1H),2.21-2.14(m,2H),2.12-2.09(m,1H),2.08-2.04 (m,1H),1.97-1.90(m,1H),1.82-1.73(m,1H),1.69(t,J=2.8Hz,1H),1.65-1. 57(m,1H),1.46(d,J=6.4Hz,3H),1.39-1.25(m,1H),0.97(s,3H),0.56(s,3H).

[0248] Example 16 (1R,2S)-2-Cyclopropyl-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]cyclopropanecarboxamide TIFF2026506637000099.tif73170(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 (1S,2S)-2-methylcyclopropanecarboxylic acid (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]) instead of the concentration. 2,5 .1 9,13 .0 19,27 .0 21,26 ] The title compound was prepared in a manner similar to that of Example 1 by using hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate E) and (1R,2S)-2-cyclopropylcyclopropanecarboxylic acid. Example 16 (8 mg) was obtained as a yellow solid. MS calculated 849.4 (MH + ), measured value 849.4 (MH + ). 1H NMR(400MHz,METHANOL-d4)δ=8.48(d,J=3.2Hz,1H),8.39(d,J=2.4Hz,1H),7.63(d,J=2.8Hz,1H),7.50(d,J=8.0Hz,1H),7.43(d,J=2.8Hz,1H), 5.77(d,J=8.4Hz,1H),4.53-4.39(m,2H),4.28-4.05(m,3H),3.83-3.66 (m,3H),3.65-3.50(m,3H),3.47-3.34(m,6H),3.29-3.24(m,1H),3.15- 2.93(m,7H),2.82-2.72(m,1H),2.61(d,J=14.4Hz,1H),2.38-2.27(m,1 H),2.23-2.13(m,2H),1.98-1.90(m,1H),1.83-1.70(m,1H),1.66-1.54 (m,2H),1.46(d,J=6.4Hz,3H),1.33-1.28(m,1H),1.09-0.71(m,6H),0. 71-0.63(m,1H),0.61-0.50(m,3H),049-0.39(m,2H),0.20-0.13(m,2H).

[0249] Example 17 (1S,2S)-N-[(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]-2-methyl-cyclopropanecarboxamide TIFF2026506637000100.tif69170(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 .019,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (intermediate F) was replaced with (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 ] The title compound was prepared in a manner similar to that of Example 1 by using hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate H). Example 17 (4.8 mg) was obtained as a white solid. MS calculated 825.4 (MH + ), measured value 825.4 (MH + ). 1 H NMR(400MHz,ACETONITRILE-d3)δ=8.42(d,J=3.0Hz,1H),8.24-8.10(m,1H),7.46-7.37(m,1H),7.14(d,J=3.1Hz,1H),7.08-6.94(m,2 H),5.64(s,1H),4.67-4.53(m,2H),4.52-4.34(m,3H),4.31-4.15(m,2H),3.77-3.61(m,3H),3.60-3.44(m,1H),3.40(s,5H),3.26(s, 3H),3.17-3.07(m,1H),3.05-2.97(m,1H),2.95-2.85(m,4H),2.73-2.63(m,2H),2.55(s,4H),1.77(td,J=2.6,4.9Hz,1H),1.59-1.47 (m,2H),1.37(d,J=6.1Hz,3H),1.30-1.25(m,1H),1.19-1.13(m,1H),1.10-1.06(m,3H),0.97(s,3H),0.63-0.56(m,1H),0.46(s,3H).

[0250] Example 18 (1S,2S)-N-[(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]-2-methyl-cyclopropanecarboxamide TIFF2026506637000101.tif57170(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) was replaced with (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 ] The title compound was prepared in a manner similar to that of Example 1 by using hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate K). Example 18 (11.2 mg) was obtained as a yellow solid. MS calculated 859.4 (MH + ), measured value 859.4 (MH + ). 1H NMR(400MHz,Methanol-d4)δ=8.55-8.46(m,2H),7.56(s,2H),7.53(d,J=2.8Hz,1H),5.82-5.73(m,1H),4.63-4.38(m,3H),4.24(dd, J=11.6,2.8Hz,1H),4.18-3.85(m,3H),3.82-3.68(m,3H),3.68-3.45(m,5H),3.45-3.39(m,2H),3.37(s,3H),3.30-3.24(m,2H),3.1 4-3.08(m,1H),2.98(s,3H),2.82-2.72(m,1H),2.65-2.57(m,1H),2.23-2.12(m,1H),2.01-1.87(m,1H),1.85-1.71(m,1H),1.68-1. 54(m,1H),1.52-1.45(m,4H),1.28-1.18(m,1H),1.16-1.11(m,3H),1.09-1.04(m,1H),0.98(s,3H),0.67-0.61(m,1H),0.56(s,3H).

[0251] Example 19 2,2-Difluoro-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]-1-methyl-cyclopropanecarboxamide TIFF2026506637000102.tif64170(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 (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] instead of (1S,2S)-2-methylcyclopropanecarboxylic acid. 2,5 .1 9,13 .0 19,27 .0 21,26 ] The title compound was prepared in a manner similar to that of Example 1 by using hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate E) and 2,2-difluoro-1-methyl-cyclopropanecarboxylic acid. Example 19 (11 mg) was obtained as a yellow solid. MS calculated 859.4 (MH + ), measured value 859.6 (MH + ). 1 H NMR(400MHz,METHANOL-d4)δ=8.49(d,J=2.8Hz,1H),8.39(d,J=6.4Hz,1H),7.6 6-7.57(m,1H),7.53-7.47(m,1H),7.43(s,1H),5.85-5.70(m,1H),4.53-4.46(m 1H),4.42(d,J=12.4Hz,1H),4.29-4.18(m,2H),4.15-4.04(m,1H),3.77-3.73(m,2H),3.66-3.52(m, 3H),3.47-3.39(m,6H),3.38-3.33(m,3H),3.15-3.08(m,2H),3.01-2.95(m,4H),2.82-2.73(m,1H), 2.59(d,J=14.4Hz,1H),2.34-2.26(m,1H),2.23-2.14(m,2H),2.13-2.02(m,1H),1.98-1.90(m,1H), 1.85-1.73(m,1H),1.57(s,4H),1.46(d,J=6.4Hz,3H),1.41-1.28(m,2H),0.99(s,3H),0.54(s,3H).

[0252] Example 21 (1S,2S)-2-(Difluoromethyl)-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]cyclopropanecarboxamide TIFF2026506637000103.tif72170(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 (1S,2S)-2-methylcyclopropanecarboxylic acid were replaced with (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 ] The title compound was prepared in a manner similar to that of Example 1 by using hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate G) and (1S,2S)-2-(difluoromethyl)cyclopropanecarboxylic acid. Example 21 (7.3 mg) was obtained as a yellow solid. MS calculated 927.4 (MH + ), measured value 927.4 (MH+ ). 1 H NMR(400MHz,METHANOL-d4)δ=8.42(s,1H),8.37(d,J=2.8Hz,1H),7.80(d,J=2.8Hz,1H),7.50(s,1H),7.45(s,1H),5.94-5.66(m,2H),4.54-4.48(m,1) H),4.42(d,J=11.6Hz,1H),4.21(dd,J=2.8,12.4Hz,1H),4.16-4.10(m,1H) ,3.80-3.72(m,2H),3.49-3.45(m,4H),3.42-3.40(m,3H),3.29-3.23(m,1H ),3.21-3.11(m,3H),3.11-3.00(m,3H),2.89-2.85(m,4H),2.81-2.74(m, 1H),2.73-2.67(m,1H),2.36-2.29(m,1H),2.21-2.13(m,2H),2.07-2.02(m ,1H),1.95-1.89(m,1H),1.81-1.72(m,2H),1.65-1.57(m,1H),1.47(d,J=6 .4Hz,3H),1.30-1.27(m,1H),1.16-1.08(m,2H),0.99(s,3H),0.62(s,3H).

[0253] Example 22 (1S,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]-2-phenyl-cyclopropanecarboxamide TIFF2026506637000104.tif56170(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 (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] instead of (1S,2S)-2-methylcyclopropanecarboxylic acid. 2,5 .1 9,13 .0 19,27 .0 21,26 ] The title compound was prepared in a manner similar to that of Example 1 by using hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate E) and (1S,2S)-2-phenylcyclopropanecarboxylic acid. Example 22 (21.7 mg) was obtained as a yellow solid. MS calculated 885.4 (MH + ), measured value 885.4 (MH + ). 1H NMR(400MHz,Methanol-d4)δ=8.48(d,J=2.8Hz,1H),8.40(s,1H),7.58(d,J=2 .8Hz,1H),7.51(s,1H),7.43(s,1H),7.29-7.24(m,2H),7.20-7.13(m,3H),5. 82(d,J=7.2Hz,1H),4.92-4.87(m,1H),4.50-4.40(m,2H),4.26-4.19(m,2H), 4.15-3.81(m,2H),3.76(d,J=1.6Hz,2H),3.65-3.51(m,3H),3.45-3.40(m,2H ),3.38(s,3H),3.29-3.22(m,2H),3.18-3.05(m,3H),2.99(s,4H),2.82-2.75 (m,1H),2.62(d,J=14.0Hz,1H),2.38-2.30(m,2H),2.23-2.15(m,2H),2.08-2 .04(m,1H),1.97-1.91(m,1H),1.81-1.72(m,1H),1.66-1.58(m,1H),1.54-1. 49(m,1H),1.46(d,J=6.4Hz,3H),1.32-1.28(m,1H),0.97(s,3H),0.56(s,3H).

[0254] Example 24 (1r,2R,3S)-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]-2,3-dimethyl-cyclopropanecarboxamide TIFF2026506637000105.tif63170(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 (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] instead of (1S,2S)-2-methylcyclopropanecarboxylic acid. 2,5 .1 9,13 .0 19,27 .0 21,26 The title compound was prepared in a manner similar to that of Example 1 by using hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate E) and (1r,2S,3R)-2,3-dimethylcyclopropanecarboxylic acid (CAS 34669-51-7). Example 24 (7.3 mg) was obtained as a white solid. MS calculated 837.4 (MH + ), measured value 837.4 (MH + ). 1H NMR(400MHz,Methanol-d4)δ=8.33-8.25(m,2H),7.37(s,1H),7.29(s,1H),7.17(d,J=2.8Hz,1H),5.72-5.64(m,1H),4.47(br s,2H),4.36-4.24(m,2H),4.17-4.08(m,2H),3.66-3.62(m,2H),3.54-3.45(m,1H), 3.34-3.26(m,5H),3.18-3.13(m,1H),3.02-2.85(m,3H),2.73-2.61(m,5H),2.50(br d,J=14.3Hz,1H),2.38(s,3H),2.25-2.15(m,1H),2.12-2.02(m,2H),1.82(br d,J=13.3Hz,1H),1.71-1.58(m,1H),1.49(dq,J=3.6,12.5Hz,1H),1.36-1.31(m, 3H),1.30-1.21(m,2H),1.08-0.94(m,8H),0.86-0.81(m,3H),0.46-0.40(m,3H).

[0255] Example 25 (1S,2S)-N-[(7S,13S)-(20M)-20-[5-[(9aS)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-2-[(1S)-1-methoxyethyl]-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]-2-methyl-cyclopropanecarboxamide TIFF2026506637000106.tif54170(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 .019,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (intermediate F) was replaced with (7S,13S)-(20M)-20-[5-[(9aS)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-2-[(1S)-1-methoxyethyl]-3-pyridyl]-7-amino-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 ] The title compound was prepared in a manner similar to that of Example 1 by using hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate L). Example 25 (35.4 mg) was obtained as a yellow solid. MS calculated 865.4 (MH + ), measured value 865.5 (MH + ). 1H NMR(400MHz,METHANOL-d4)δ=8.48(s,1H),8.39(s,1H),7.71-7.59(m,1H),7 .50(s,1H),7.43(s,1H),5.77(d,J=8.4Hz,1H),4.51-4.40(m,2H),4.31-4.1 5(m,3H),4.11-3.92(m,4H),3.89-3.84(m,1H),3.84-3.68(m,3H),3.67-3.5 8(m,4H),3.51-3.45(m,1H),3.43-3.40(m,1H),3.39-3.29(m,3H),3.27-3.1 9(m,1H),3.17-3.05(m,3H),3.05-2.94(m,2H),2.81-2.72(m,1H),2.61-2.4 3(m,1H),2.37-2.28(m,1H),2.17-1.98(m,2H),1.94-1.88(m,1H),1.82-1.7 3(m,1H),1.66-1.56(m,1H),1.50-1.45(m,4H),1.27-1.19(m,1H),1.12(d,J =6.0Hz,3H),1.10-1.01(m,1H),0.98(s,3H),0.66-0.61(m,1H),0.56(s,3H).

[0256] Example 28 and Example 29 (1R,2R)-2-(2-fluorophenyl)-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]cyclopropanecarboxamide and (1S,2S)-2-(2-fluorophenyl)-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]cyclopropanecarboxamide TIFF2026506637000107.tif63170(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 (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] instead of (1S,2S)-2-methylcyclopropanecarboxylic acid. 2,5 .1 9,13 .0 19,27 .0 21,26 ] The title compound was prepared in a manner similar to that of Example 1 by using hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (intermediate E) and trans-2-(2-fluorophenyl)cyclopropanecarboxylic acid, and then purified by prep-HPLC and SFC. SFC conditions: Instrument: SFC 150 Mgm; Column: TCI Chiral MB-S 250 x 30 mm I.D., 5 μm. Mobile phase: A for CO2 and B for IPA (0.1% NH3H2O); Gradient: B 35%; Flow rate: 80 mL / min; Back pressure: 100 bar; Column temperature: 35 °C.

[0257] Example 28 (4.8 mg, SFC, slow elution) was obtained as a yellow solid. MS calculated 903.4 (MH + ), measured value 903.4 (MH + ). 1 H NMR(400MHz,Methanol-d4)δ=8.47(d,J=3.2Hz,1H),8.40(s,1H),7.52-7.48(m,2H),7.42(s,1H),7.26-7.20(m,1H),7.14-7.04(m, 3H),5.87-5.81(m,1H),4.48-4.42(m,2H),4.28-3.97(m,4H),3.76(s,3H),3.62-3.55(m,2H),3.46-3.41(m,2H),3.39-3.37(m,3H) ,3.28-3.25(m,1H),3.13-3.08(m,2H),2.99(s,5H),2.82-2.75(m,1H),2.61-2.52(m,2H),2.35-2.28(m,1H),2.27-2.00(m,4H),1. 97-1.91(m,1H),1.82-1.73(m,1H),1.65-1.58(m,1H),1.50-1.43(m,4H),1.42-1.23(m,2H),1.00-0.95(m,3H),0.57-0.51(m,3H).

[0258] Example 29 (5.3 mg, SFC, faster eluting) was obtained as a white solid. MS calculated 903.4 (MH + ), measured value 903.4 (MH + ). 1H NMR(400MHz,Methanol-d4)δ=8.47-8.39(m,2H),7.56-7.49(m,1H),7.46-7.39(m,1H),7.30-7.20(m,2H),7.19-7.02(m,3H),5.93-5.83(m,1) H),4.73-4.50(m,6H),4.47-4.36(m,1H),4.31-4.21(m,1H),3.80-3.5 7(m,3H),3.51-3.41(m,1H),3.32-3.27(m,3H),3.17-2.97(m,2H),2.8 6-2.75(m,1H),2.70-2.60(m,4H),2.58-2.51(m,1H),2.41-2.29(m,3H) ),2.25-2.12(m,3H),1.98-1.90(m,1H),1.84-1.69(m,1H),1.66-1.58 (m,1H),1.56-1.50(m,1H),1.48-1.41(m,3H),1.38-1.34(m,1H),1.33 -1.27(m,3H),1.00-0.94(m,3H),0.93-0.84(m,1H),0.61-0.50(m,3H).

[0259] Example 30 (1S,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]-2-(2-pyridyl)cyclopropanecarboxamide TIFF2026506637000108.tif72170(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 (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] instead of (1S,2S)-2-methylcyclopropanecarboxylic acid. 2,5 .1 9,13 .0 19,27 .0 21,26 ] The title compound was prepared in a manner similar to that of Example 1 by using hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (intermediate E) and trans-2-(2-pyridyl)cyclopropanecarboxylic acid, and then purified by prep-HPLC and SFC. SFC conditions: Instrument: SFC 150 Mgm; Column: TCI Chiral MB-S 250 x 30 mm I.D., 5 μm. Mobile phase: A for CO2 and B for IPA (0.1% NH3H2O); Gradient: B 35%; Flow rate: 80 mL / min; Back pressure: 100 bar; Column temperature: 35 °C.

[0260] Example 30 (3.2 mg, SFC, faster eluting) was obtained as a yellow solid. MS calculated 886.4 (MH + ), measured value 886.4 (MH + ). 1H NMR(400MHz,Methanol-d4)δ=8.33-8.26(m,3H),7.64-7.56(m,1H),7.41-7.37(m,1H),7.31-7.28(m,1H),7.25-7.21(m,1H),7 .16-7.13(m,1H),7.13-7.07(m,1H),5.76-5.68(m,1H),4.53-4.42(m,6H),4.34-4.25(m,2H),4.16-4.09(m,2H),3.69-3.63(m ,2H),3.54-3.47(m,1H),3.35-3.29(m,1H),3.04-2.89(m,3H),2.73-2.62(m,1H),2.57-2.48(m,5H),2.44-2.37(m,1H),2.28- 2.17(m,5H),2.14-2.03(m,2H),1.86-1.79(m,1H),1.71-1.42(m,5H),1.37-1.32(m,3H),0.89-0.75(m,4H),0.49-0.41(m,3H).

[0261] Example 31 (1S,2S)-N-[(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(29),2,5(31),19,25,27-hexaen-7-yl]-2-(difluoromethyl)cyclopropanecarboxamide TIFF2026506637000109.tif66170(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 (1S,2S)-2-methylcyclopropanecarboxylic acid were replaced with (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 ] The title compound was prepared in a manner similar to that of Example 1 by using hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate K) and (1S,2S)-2-(difluoromethyl)cyclopropanecarboxylic acid. Example 31 (5.1 mg) was obtained as a yellow solid. MS calculated 895.4 (MH + ), measured value 895.4 (MH + ). 1 H NMR(400MHz,METHANOL-d4)δ=8.51-8.48(m,2H),7.58-7.55(m,2H),7.39(d,J=2.8Hz,1H),5.84-5.65(m,2H),4.61-4.55(m,1H),4.49-4. 41(m,2H),4.25(dd,J=2.8,12.0Hz,1H),4.10-3.99(m,2H),3.94-3.86(m,1H),3.81-3.68(m,3H),3.66-3.56(m,3H),3.53-3.40(m,3H),3. 35(s,4H),3.28(s,1H),3.14-3.11(m,1H),2.99(s,3H),2.82-2.76(m ,1H),2.62-2.56(m,1H),2.21-2.15(m,1H),2.08-2.03(m,1H),1.97- 1.92(m,1H),1.83-1.74(m,2H),1.65-1.59(m,1H),1.46(d,J=6.0Hz,3H),1.32-1.28(m,1H),1.19-1.10(m,2H),0.97(s,3H),0.55(s,3H).

[0262] Example 33 (1S,2R)-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]-2-methyl-cyclopropanecarboxamide TIFF2026506637000110.tif55170(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 (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] instead of (1S,2S)-2-methylcyclopropanecarboxylic acid. 2,5 .1 9,13 .0 19,27 .0 21,26 ] The title compound was prepared in a manner similar to that of Example 1 by using hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate E) and (1S,2R)-2-methylcyclopropanecarboxylic acid. Example 33 (12.5 mg) was obtained as a white solid. MS calculated 824.4 (MH + ), measured value 824.4 (MH + ). 1H NMR(400MHz,METHANOL-d4)δ=8.40-8.36(m,1H),8.32-8.28(m,1H),7.46-7.43(m ,1H),7.42-7.38(m,1H),7.35-7.30(m,1H),5.71-5.66(m,1H),4.40-4.35(m,1H) ,4.34-4.28(m,1H),4.18-4.07(m,2H),4.03-3.85(m,1H),3.72-3.55(m,3H),3.5 4-3.45(m,2H),3.40-3.35(m,1H),3.34-3.31(m,1H),3.31-3.24(m,6H),3.17(br d,J=8.8Hz,2H),3.04-2.97(m,2H),2.93-2.87(m,4H),2.72-2.63(m,1H),2.52- 2.47(m,1H),2.27-2.16(m,1H),2.13-2.04(m,2H),1.89-1.81(m,1H),1.75-1.61 (m,2H),1.56-1.45(m,1H),1.39-1.33(m,3H),1.21-1.13(m,1H),1.02-0.98(m, 3H),0.89-0.86(m,3H),0.86-0.80(m,1H),0.76-0.70(m,1H),0.47-0.42(m,3H).

[0263] Example 34 (1S,2S)-2-(Difluoromethyl)-N-[(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]cyclopropanecarboxamide TIFF2026506637000111.tif65170(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 (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]] instead of (1S,2S)-2-methylcyclopropanecarboxylic acid. 2,5 .1 9,13 .0 19,27 .0 21,26 The title compound was prepared in a manner similar to that of Example 1 by using hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate H) and (1S,2S)-2-(difluoromethyl)cyclopropanecarboxylic acid. Example 34 (38.2 mg) was obtained as a pale yellow solid. MS calculated 861.4 (MH + ), measured value 861.4 (MH + ). 1H NMR(400MHz,METHANOL-d4)δ=8.48(d,J=2.9Hz,1H),8.24-8.15(m,1H),7.61-7.52(m,1H),7.49(s,1H),7.10(s,1H),5.99-5.62(m,2H),4.6 6-4.57(m,2H),4.51(q,J=6.3Hz,1H),4.43(d,J=12.5Hz,1H),4.33-4.23(m,2H),4.18-3.89(m,2H),3.80-3.64(m,4H),3.63-3.49(m,2H),3 .47-3.35(m,6H),3.29-3.23(m,2H),3.16-3.10(m,1H),2.99(s,3H), 2.83-2.72(m,1H),2.59(d,J=14.5Hz,1H),2.25-2.16(m,1H),2.09-2. 02(m,1H),1.95(d,J=12.6Hz,1H),1.87-1.71(m,2H),1.68-1.55(m,1H ),1.46(d,J=6.3Hz,3H),1.21-1.08(m,2H),1.00(s,3H),0.53(s,3H).

[0264] Example 35 (1S,5R,6r)-N-[(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]-3-oxabicyclo[3.1.0]hexane-6-carboxamide TIFF2026506637000112.tif62170(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 .019,27 .0 21,26 ]hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (intermediate F) and (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]] instead of (1S,2S)-2-methylcyclopropanecarboxylic acid. 2,5 .1 9,13 .0 19,27 .0 21,26 The title compound was prepared in a manner similar to that of Example 1 by using ]hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate H) and (1S,5R,6r)-3-oxabicyclo[3.1.0]hexane-6-carboxylic acid. Example 35 (42.0 mg) was obtained as a pale yellow solid. MS calculated 853.4 (MH + ), measured value 853.4 (MH + ). 1H NMR(400MHz,METHANOL-d4)δ=8.48(d,J=2.8Hz,1H),8.19(s,1H),7.51-7.48(m,2H),7.09(d,J=0.9Hz,1H),5.73(d,J=7.6Hz,1H),4.64-4.57(m,2H), 4.52-4.40(m,2H),4.35-4.23(m,2H),3.99-3.98(m,1H),4.21-3.97(m,1H ),3.93(d,J=8.6,11.6Hz,2H),3.80-3.67(m,6H),3.58(d,J=6.0Hz,2H),3. 45-3.34(m,6H),3.30-3.19(m,4H),3.12(d,J=14.3Hz,1H),2.78(t,J=2.8 ,13.0Hz,1H),2.58(d,J=14.5Hz,1H),2.26-2.16(m,1H),2.14-2.09(m,1H) ,2.09-1.99(m,2H),1.99-1.91(m,1H),1.87-1.73(m,1H),1.69(t,J=3.1H z,1H),1.67-1.55(m,1H),1.46(d,J=6.1Hz,3H),1.00(s,3H),0.52(s,3H).

[0265] Example 37 (1R,2S)-2-Cyclopropyl-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(29),2,5(31),19,25,27-hexaen-7-yl]cyclopropanecarboxamide The title compound was prepared in a manner similar to that of Example 1, except that (1R,2S)-2-cyclopropylcyclopropanecarboxylic acid was used instead of (1S,2S)-2-methylcyclopropanecarboxylic acid. Example 37 (23.1 mg) was obtained as a yellow solid. MS calculated 836.4 (MH +), measured value 836.6 (MH + ). 1 H NMR(400MHz,METHANOL-d4)δ=8.41(d,J=2.4Hz,1H),8.37(d,J=2.8Hz,1H),7.73(d, J=2.4Hz,1H),7.50(d,J=8.4Hz,1H),7.44(d,J=4.0Hz,1H),5.80(d,J=7.2Hz,1H),4. 55-4.48(m,1H),4.42(d,J=13.2Hz,1H),4.25-4.18(m,1H),4.18-4.11(m,1H),3.86( t,J=4.8Hz,4H),3.75(d,J=6.4Hz,2H),3.70-3.64(m,1H),3.61(d,J=6.8Hz,1H),3.4 2-3.37(m,8H),3.28-3.23(m,1H),3.11-3.03(m,2H),2.81-2.72(m,1H),2.71-2.64 (m,1H),2.22-2.14(m,2H),1.97-1.89(m,1H),1.80-1.70(m,1H),1.64-1.54(m,2H), 1.47(d,J=6.0Hz,3H),1.34-1.29(m,1H),1.20-1.16(m,1H),1.01-0.94(m,4H),0.91 -0.86(m,1H),0.70-0.64(m,1H),0.60(s,3H),0.49-0.39(m,2H),0.20-0.14(m,2H).

[0266] Example 38 (1S,2S)-N-[(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]-2-methyl-cyclopropanecarboxamide TIFF2026506637000114.tif60170(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) was replaced with (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 ] The title compound was prepared in a manner similar to that of Example 1 by using hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate M). Example 38 (8.3 mg) was obtained as a white solid. MS calculated 840.4 (MH + ), measured value 840.4 (MH + ). 1H NMR(400MHz,METHANOL-d4)δ=8.37(d,J=2.8Hz,1H),8.21(s,1H),7.75(s,1H),7.48(s,1H),7.08(s,1H) ),5.82-5.80(m,1H),4.74-4.60(m,1H),4.50-4.38(m,1H),4.28-4.16(m,1H),4.03-3.92(d,J=12.4Hz 1H),3.90-3.82(t,J=4.8,5H),3.81-3.74(s,2H),3.64(d,J=12.4Hz,1H),3.42-3.38(m,7H), 3.14-3.01(m,1H),2.83-2.73(m,1H),2.69(d,J=14.3Hz,1H),2.20(m,1H),2.01-1.88(m,1H), 1.81-1.69(m,1H),1.68-1.56(m,1H),1.53-1.48(m,6H),1.48-1.44(m,1H),1.35(s,3H),1.31 -1.18(m,2H),1.12(d,J=6.0Hz,3H),1.09-1.03(m,1H),1.02-0.97(s,3H),0.69-0.60(m,4H).

[0267] Example 40 (1S,5R,6r)-N-[(7S,13S)-(20M)-20-[5-[(9aS)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-2-[(1S)-1-methoxyethyl]-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-oxabicyclo[3.1.0]hexane-6-carboxamide TIFF2026506637000115.tif57170(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 (1S,2S)-2-methylcyclopropanecarboxylic acid were replaced with (7S,13S)-(20M)-20-[5-[(9aS)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-2-[(1S)-1-methoxyethyl]-3-pyridyl]-7-amino-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 The title compound was prepared in a manner similar to that of Example 1 by using ]hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate L) and (1S,5R,6r)-3-oxabicyclo[3.1.0]hexane-6-carboxylic acid. Example 40 (17.1 mg) was obtained as a yellow solid. MS calculated 893.4 (MH + ), measured value 893.4 (MH + ). 1H NMR(400MHz,Methanol-d4)δ=8.49(d,J=2.8Hz,1H),8.40(s,1H),7.54-7.50(m ,2H),7.44(s,1H),5.78(d,J=8.0Hz,1H),4.87-4.83(m,1H),4.49-4.42(m,2H) ,4.28-4.20(m,2H),4.16-4.05(m,4H),3.98-3.92(m,2H),3.90-3.83(m,1H),3 .80-3.74(m,4H),3.65-3.57(m,4H),3.53-3.48(m,1H),3.46-3.40(m,2H),3.3 9(s,3H),3.29-3.25(m,1H),3.15-3.08(m,2H),3.05-2.90(m,2H),2.84-2.76( m,1H),2.61(d,J=14.0Hz,1H),2.37-2.29(m,1H),2.24-2.17(m,2H),2.15-2.0 7(m,2H),1.99-1.91(m,1H),1.85-1.75(m,1H),1.71(t,J=3.2Hz,1H),1.66-1. 57(m,1H),1.47(d,J=6.0Hz,3H),1.38-1.28(m,1H),0.98(s,3H),0.57(s,3H).

[0268] Example 41 (1S,2S)-N-[(7S,13S)-(20M)-20-[5-[(9aS)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-2-[(1S)-1-methoxyethyl]-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]-2-(difluoromethyl)cyclopropanecarboxamide TIFF2026506637000116.tif60170(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 (1S,2S)-2-methylcyclopropanecarboxylic acid were replaced with (7S,13S)-(20M)-20-[5-[(9aS)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-2-[(1S)-1-methoxyethyl]-3-pyridyl]-7-amino-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 The title compound was prepared in a manner similar to that of Example 1 by using hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate L) and (1S,2S)-2-(difluoromethyl)cyclopropanecarboxylic acid. Example 41 (16.4 mg) was obtained as a yellow solid. MS calculated 901.4 (MH + ), measured value 901.4 (MH + ). 1H NMR(400MHz,Methanol-d4)δ=8.47(d,J=2.8Hz,1H),8.39(s,1H),7.52-7.49(m,2H),7.42(s,1H),5.96-5.66(m,2H),4.85-4.81(m,1H),4.47-4.4 0(m,2H),4.26-4.19(m,2H),4.14-4.04(m,4H),3.89-3.83(m,1H),3.78- 3.73(m,2H),3.64-3.56(m,4H),3.53-3.43(m,2H),3.43-3.38(m,2H),3.3 7(s,3H),3.27-3.25(m,1H),3.12-3.05(m,2H),3.02-2.90(m,2H),2.82- 2.74(m,1H),2.60(d,J=14.4Hz,1H),2.35-2.28(m,1H),2.21-2.14(m,2H ),2.08-2.04(m,1H),1.97-1.91(m,1H),1.82-1.74(m,2H),1.65-1.56(m ,1H),1.45(d,J=6.0Hz,3H),1.19-1.10(m,2H),0.96(s,3H),0.55(s,3H).

[0269] Example 42 (1R,5S,6s)-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-oxabicyclo[3.1.0]hexane-6-carboxamide TIFF2026506637000117.tif69170(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 .19,13 .0 19,27 .0 21,26 ]hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (intermediate F) and (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] instead of (1S,2S)-2-methylcyclopropanecarboxylic acid. 2,5 .1 9,13 .0 19,27 .0 21,26 The title compound was prepared in a manner similar to that of Example 1 by using ]hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate E) and (1R,5S,6s)-3-oxabicyclo[3.1.0]hexane-6-carboxylic acid. Example 42 (9 mg) was obtained as a white solid. MS calculated 851.4 (MH + ), measured value 851.6 (MH + ). 1 H NMR(400MHz,METHANOL-d4)δ=8.48(br s,1H),8.39(s,1H),7.56(br s,1H),7.49(s,1H),7.41(s,1H),5.78(br d,J=7.0Hz,1H),4.51-4.38(m,2H),4.29-4.14(m,2H),3.90(br d,J=12.3Hz,3H),3.82-3.67(m,5H),3.66-3.54(m,3H),3.36(s,7H),3.28-3.22(m, 1H),3.17-3.02(m,3H),2.97(s,4H),2.83-2.71(m,1H),2.69-2.56(m,1H),2.17(br d,J=12.0Hz,3H),2.12-2.01(m,2H),1.98-1.85(m,1H),1.83-1.54(m,3H),1.45(d,J=6.1Hz,3H),0.96(s,3H),0.55(s,3H).

[0270] Example 43 (1S,2S)-N-[(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(29),2,5(31),19,25,27-hexaen-7-yl]-2-phenyl-cyclopropanecarboxamide TIFF2026506637000118.tif60170(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 (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]] instead of (1S,2S)-2-methylcyclopropanecarboxylic acid. 2,5 .1 9,13 .0 19,27 .0 21,26 The title compound was prepared in a manner similar to that of Example 1 by using hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate J) and (1S,2S)-2-phenylcyclopropanecarboxylic acid. Example 43 (14.54 mg) was obtained as a pale yellow solid. MS calculated 874.4 (MH + ), measured value 874.4 (MH + ). 1H NMR(400MHz,METHANOL-d4)δ=8.37(d,J=3.0Hz,1H),8.23(s,1H),7.81(br d,J=0.9Hz,1H),7.51(s,1H),7.29-7.25(m,2H),7.19(d,J=7.5Hz,1H),7.16-7.13(m,3H),5.81(br d,J=7.8Hz,1H),4.68-4.55(m,4H),4.45-4.40(m,1H),4.26(br d,J=8.4Hz,2H),3.91-3.84(m,5H),3.77(d,J=3.8Hz,2H),3.43(s,5H),3.40(br s,3H),3.17-3.13(m,1H),2.67(br d,J=14.1Hz,1H),2.39-2.32(m,1H),2.20(br d,J=12.6Hz,1H),2.06-2.02(m,1H),1.99-1.91(m,1H),1.85-1.73(m,1H),1.69- 1.59(m,1H),1.49(d,J=6.1Hz,4H),1.33-1.28(m,2H),1.03(s,3H),0.59(s,3H).

[0271] Example 44 (1S,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-15,24-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(29),2,5(31),19,25,27-hexaen-7-yl]-2-phenyl-cyclopropanecarboxamide TIFF2026506637000119.tif70170(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 .019,27 .0 21,26 ]hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (intermediate F) 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-15,24-dioxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1]] instead of (1S,2S)-2-methylcyclopropanecarboxylic acid. 2,5 .1 9,13 .0 19,27 .0 21,26 The title compound was prepared in a manner similar to that of Example 1 by using hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate I) and (1S,2S)-2-phenylcyclopropanecarboxylic acid. Example 44 (21.3 mg) was obtained as a pale yellow solid. MS calculated 955.4 (MH + ), measured value 955.4 (MH + ). 1H NMR(400MHz,METHANOL-d4)δ=8.37(d,J=2.8Hz,1H),8.22(s,1H),7.66(d,J=2.9Hz,1H),7.50(s,1H),7 .29-7.25(m,2H),7.19(d,J=7.3Hz,1H),7.14(d,J=7.4Hz,2H),7.12(s,1H),5.84-5.78(m,1H),4.61(br d,J=3.9Hz,2H),4.54(br d,J=6.3Hz,1H),4.43(br d,J=10.5Hz,1H),4.26(dd,J=2.6,12.1Hz,2H),3.76(s,3H),3.44(dt,5H),3.40(s,3H),3.28-3.22(m,1H),3.19-3.11(m,3H),2.88(br t,J=4.8Hz,4H),2.79(dt,J=2.9,13.0Hz,1H),2.65(d,J=14.6Hz,1H),2.39-2 .32(m,1H),2.24-2.17(m,1H),2.09-2.04(m,1H),1.99-1.91(m,1H),1.78(br d,J=11.9Hz,1H),1.62(br dd,J=3.9,12.2Hz,1H),1.54-1.50(m,1H),1.47(d,J=6.3Hz,3H),1.33-1.28(m,1H),1.02(s,3H),0.57(s,3H).

[0272] Example 45 (1r,2S,3R)-N-[(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]-2,3-dimethyl-cyclopropanecarboxamide TIFF2026506637000120.tif62170(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 (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]] instead of (1S,2S)-2-methylcyclopropanecarboxylic acid. 2,5 .1 9,13 .0 19,27 .0 21,26 The title compound was prepared in a manner similar to that of Example 1 by using hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate H) and (1r,2S,3R)-2,3-dimethylcyclopropanecarboxylic acid. Example 45 (32.0 mg) was obtained as a pale yellow solid. MS calculated 839.4 (MH + ), measured value 839.4 (MH + ). 1H NMR(400MHz,METHANOL-d4)δ=8.47(d,J=2.8Hz,1H),8.19(s,1H),7.56-7.44(m,2H),7.09(d,J=1.0Hz,1H),5.73(d,J=7.5Hz,1H),4. 86-4.83(m,1H),4.66-4.57(m,2H),4.51-4.39(m,2H),4.37-4.23(m,2H),4.04(d,J=2.9Hz,2H),3.79-3.69(m,3H),3.61(d,J=7.0Hz, 2H),3.37(s,4H),3.28-3.08(m,4H),2.99(s,3H),2.82-2.72(m,1H),2.62-2.53(m,1H),2.20(d,J=2.8,12.8Hz,1H),2.00-1.91(m,1H) ),1.86-1.72(m,1H),1.68-1.55(m,1H),1.45(d,J=6.3Hz,3H),1.42-1.27(m,3H),1.19-1.09(m,7H),1.04-0.96(m,3H),0.52(s,3H).

[0273] Example 46 (1S,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(29),2,5(31),19,25,27-hexaen-7-yl]-2-phenyl-cyclopropanecarboxamide The title compound was prepared in a manner similar to that of Example 1, except that (1S,2S)-2-phenylcyclopropanecarboxylic acid was used instead of (1S,2S)-2-methylcyclopropanecarboxylic acid. Example 46 (8 mg) was obtained as a yellow solid. MS calculated 872.4 (MH + ), measured value 872.6 (MH + ). 1H NMR(400MHz,METHANOL-d4)δ=8.38(s,2H),7.49(s,1H),7.40(s,1H),7.30-7.23(m,3H),7.21-7.12(m,3H),5.92-5.74(m,1H),4. 45-4.37(m,2H),4.28-4.21(m,2H),3.86(t,J=4.4Hz,4H),3.76(s,2H),3.62-3.56(m,1H),3.46-3.42(m,1H),3.14-2.97(m,4H), 2.82-2.74(m,1H),2.65-2.59(m,1H),2.39-2.29(m,2H),2.23-2.16(m,2H),2.08-2.03(m,1H),1.96-1.90(m,1H),1.80-1.72(m, 1H),1.67-1.54(m,2H),1.54-1.49(m,1H),1.44(d,J=6.0Hz,3H),1.34-1.27(m,6H),0.96(s,3H),0.92-0.87(m,1H),0.55(s,3H).

[0274] Example 47 (1S,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]-2-pyrimidin-5-yl-cyclopropanecarboxamide TIFF2026506637000122.tif77170(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 (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] instead of (1S,2S)-2-methylcyclopropanecarboxylic acid. 2,5 .1 9,13 .0 19,27 .0 21,26 ] The title compound was prepared in the same manner as in Example 1 by using hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (intermediate E) and trans-2-pyrimidin-5-ylcyclopropanecarboxylic acid (intermediate R1), and then purified by prep-HPLC and SFC. SFC conditions: Column: DAICEL CHIRALPAK IC (250 mm x 30 mm, 10 μm); Conditions: CO₂-EtOH (0.1% NH₃H₂O); Start: 70% B, End: 70% B; Gradient time (min): 6.8, Hold: 100% B; Flow rate (mL / min): 100.

[0275] Example 47 (13 mg, SFC, faster eluting) was obtained as a yellow solid. MS calculated 887.4 (MH + ), measured value 887.6 (MH + ). 1H NMR(400MHz,METHANOL-d4)δ=8.91(s,1H),8.60-8.50(s,2H),8.38-8.24(d,J= 30Hz,2H),7.45-7.37(s,1H),7.33-7.25(d,J=11.2Hz,2H),5.75-5.66(m,1H),4 .36-4.30(m,2H),4.16-4.11(m,2H),4.03-3.97(m,1H),3.68-3.64(s,2H),3.4 9-3.43(m,2H),3.39-3.35(m,1H),3.34-3.31(s,1H),3.23-3.22(m,1H),3.04-2 .95(m,3H),2.90-2.86(s,4H),2.74-2.65(m,1H),2.52-2.39(m,2H),2.34-2.2 7(m,1H),2.25-2.16(m,1H),2.13-2.08(m,4H),1.88-1.82(m,1H),1.71-1.64(m ,1H),1.56-1.51(m,2H),1.36-1.31(d,J=6.4Hz,4H),1.28-1.24(d,J=6.8Hz,2 H),1.20-1.18(s,2H),0.88-0.83(s,3H),0.82-0.77(m,1H),0.47-0.40(s,3H).

[0276] Example 48 (1S,5R)-3,3-Difluoro-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]bicyclo[3.1.0]hexane-6-carboxamide TIFF2026506637000123.tif67170(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 (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] instead of (1S,2S)-2-methylcyclopropanecarboxylic acid. 2,5 .1 9,13 .0 19,27 .0 21,26 The title compound was prepared in a manner similar to that of Example 1 by using ]hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate E) and (1S,5R)-3,3-difluorobicyclo[3.1.0]hexane-6-carboxylic acid. Example 48 (18.1 mg) was obtained as a yellow solid. MS calculated 885.4 (MH + ), measured value 885.6 (MH + ). 1H NMR(400MHz,Methanol-d4)δ=8.47(d,J=2.8Hz,1H),8.38(s,1H),7.52-7.48(m,2H),7.42(s,1H),5.77-5.71(m,1H),4.89 (s,1H),4.48-4.40(m,2H),4.26-4.19(m,2H),4.17-3.85(m,2H),3.75(s,2H),3.67-3.52(m,3H),3.37(s,3H),3.28-3.24( m,1H),3.12-3.06(m,2H),2.99(s,4H),2.81-2.73(m,1H),2.60(d,J=14.4Hz,1H),2.57-2.40(m,3H),2.33-2.14(m,6H),1. 97-1.83(m,4H),1.82-1.73(m,2H),1.64-1.57(m,1H),1.45(d,J=6.0Hz,3H),1.34-1.29(m,1H),0.96(s,3H),0.55(s,3H).

[0277] Example 49 (1S,2S)-N-[(7S,13S)-(20M)-20-[5-[(9aR)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-2-[(1S)-1-methoxyethyl]-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]-2-methyl-cyclopropanecarboxamide TIFF2026506637000124.tif65170(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) was replaced with (7S,13S)-(20M)-20-[5-[(9aR)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-2-[(1S)-1-methoxyethyl]-3-pyridyl]-7-amino-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 ] The title compound was prepared in a manner similar to that of Example 1 by using hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate L2). Example 49 (29.8 mg) was obtained as a yellow solid. MS calculated 863.5 (MH + ), measured value 863.6 (MH + ). 1 H NMR(400MHz,Methanol-d4)δ=8.50(d,J=2.8Hz,1H),8.39(s,1H),7.66(s,1 H),7.50(s,1H),7.43(s,1H),5.79-5.74(m,1H),4.52-4.47(m,1H),4.43(d, J=10.8Hz,1H),4.23(dd,J=3.0,12.0Hz,1H),4.21-4.07(m,3H),3.78-3.72 (m,2H),3.64-3.52(m,3H),3.39(s,5H),3.36-3.33(m,1H),3.30-3.22(m,2H ),3.14-3.06(m,3H),3.04-2.95(m,2H),2.81-2.73(m,1H),2.61(d,J=14.4 Hz,1H),2.37-2.28(m,1H),2.22-2.14(m,2H),2.07-1.92(m,4H),1.87-1.74 (m,2H),1.68-1.56(m,3H),1.51-1.45(m,4H),1.27-1.20(m,1H),1.12(d,J= 6.0Hz,3H),1.09-1.05(m,1H),0.98(s,3H),0.66-0.61(m,1H),0.56(s,3H).

[0278] Example 50 (1S,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]-2-pyrimidin-4-yl-cyclopropanecarboxamide TIFF2026506637000125.tif71170(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 (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] instead of (1S,2S)-2-methylcyclopropanecarboxylic acid. 2,5 .1 9,13 .0 19,27 .0 21,26 ] The title compound was prepared in a similar manner to the preparation of Example 1 by using hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (intermediate E) and 2-pyrimidin-4-ylcyclopropanecarboxylic acid (intermediate R3), and then purified by prep-HPLC and SFC. SFC conditions: Column: Chiralpak IG-3 50 x 4.6 mm ID, 3 um; Mobile phase: Phase A for CO2, Phase B for EtOH + ACN (0.05% DEA); Gradient elution: 60% EtOH + ACN (0.05% DEA) in CO2, Flow rate: 3 mL / min; Detector: PDA; Column temperature: 35°C; Back pressure: 100 bar

[0279] Example 50 (16.9 mg, SFC, faster eluting) was obtained as a white solid. MS calculated 887.4 (MH + ), measured value 887.5 (MH + ). 1 H NMR(400MHz,METHANOL-d4)δ=8.89(s,1H),8.54-8.43(d,J=5.2Hz 1H),8.35-8.23(m,2H),7.44-7.38(d,J=4.4Hz,1H),7.35(s,1H),7.28(s,1H),7.19-7.14(d,J=2.4Hz,1H),5.81-5.69(d,J=8.8Hz,1 H),4.37-4.23(m,2H),4.18-4.07(m,2H),4.03-3.96(m,3H),3.60(s,2H),3.52-3.45(m,1H), 3.27(s,3H),2.98-2.90(m,2H),2.63(s,3H),2.55-2.48(m,1H),2.42-2.39(m,1H),2.36-2.2 8(m,3H),2.13-2.07(m,3H),1.87-1.80(m,1H),1.71-1.59(m,1H),1.56-1.46(m,3H),1.30-1 .35(d,J=6.0Hz,3H),1.27(s,2H),1.25(s,2H),1.19(s,3H),0.85(s,3H),0.49-0.39(m,3H).

[0280] Example 51 (1S,2S)-N-[(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 .019,27 .0 21,26 ]Hentriaconta-1(29),2,5(31),19,25,27-hexaen-7-yl]-2-phenyl-cyclopropanecarboxamide TIFF2026506637000126.tif55170

[0281] (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 (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]] instead of (1S,2S)-2-methylcyclopropanecarboxylic acid. 2,5 .1 9,13 .0 19,27 .0 21,26 The title compound was prepared in a manner similar to that of Example 1 by using hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate H) and (1S,2S)-2-phenylcyclopropanecarboxylic acid. Example 51 (19.1 mg) was obtained as a pale yellow solid. MS calculated 887.4 (MH + ), measured value 887.4 (MH + ). 1H NMR(400MHz,METHANOL-d4)δ=8.49(d,J=2.4Hz,1H),8.21(s,1H),7.64(d,J=2.6Hz,1H),7.50(s,1H),7.31-7.22(m,1H),7.39-7.00(m,5H),5.78(d ,J=8.5Hz,1H),4.64-4.52(m,3H),4.42(d,J=11.8Hz,1H),4.34-4.24(m,2 H),4.21-3.92(m,2H),3.76(s,4H),3.68-3.52(m,2H),3.44-3.37(m,6H), 3.28-3.21(m,2H),3.14(d,J=14.6Hz,1H),2.98(s,3H),2.78(d,J=2.6Hz ,1H),2.60(d,J=14.3Hz,1H),2.35(d,J=2.8,6.1Hz,1H),2.21(d,J=10.0H z,1H),2.09-2.03(m,1H),1.99-1.89(m,1H),1.85-1.73(m,1H),1.66-1.5 6(m,1H),1.54-1.45(m,4H),1.32-1.26(m,1H),1.02(s,3H),0.54(s,3H).

[0282] Example 52 (1R,5S,6s)-N-[(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]-3-oxabicyclo[3.1.0]hexane-6-carboxamide TIFF2026506637000127.tif68170(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[23.3.1.12,5 .1 9,13 .0 19,27 .0 21,26 ]hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (intermediate F) and (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]] instead of (1S,2S)-2-methylcyclopropanecarboxylic acid. 2,5 .1 9,13 .0 19,27 .0 21,26 The title compound was prepared in a manner similar to that of Example 1 by using ]hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate H) and (1R,5S,6s)-3-oxabicyclo[3.1.0]hexane-6-carboxylic acid. Example 52 (28.2 mg) was obtained as a pale yellow solid. MS calculated 853.4 (MH + ), measured value 853.4 (MH + ). 1H NMR(400MHz,METHANOL-d4)δ=8.51(d,J=2.8Hz,1H),8.22(s,1H),7.68-7.57(m,1H),7.51(s,1H),7.12(s,1H),5.75(d,J=8.3Hz,1H),4.71-4.5 9(m,2H),4.54(q,J=5.9Hz,1H),4.49-4.41(m,1H),4.38-4.25(m,2H),4 .24-4.01(m,2H),4.00-3.86(m,3H),3.84-3.71(m,6H),3.70-3.54(m,2H ),3.52-3.38(m,6H),3.28(d,J=5.8Hz,1H),3.17-3.12(m,1H),3.01(s, 3H),2.84-2.75(m,1H),2.68-2.55(m,1H),2.29-2.18(m,1H),2.16-2.0 5(m,2H),2.02-1.92(m,1H),1.89-1.75(m,1H),1.71(t,J=3.1Hz,1H),1 .64(d,J=3.2,12.7Hz,1H),1.55-1.44(m,3H),1.03(s,3H),0.55(s,3H).

[0283] Example 53 (1S,2S)-N-[(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]-2-methyl-cyclopropanecarboxamide TIFF2026506637000128.tif63170

[0284] (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) was replaced with (7S,13S,22S)-7-amino-(20M)-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 ] The title compound was prepared in a manner similar to that of Example 1 by using hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate N). Example 53 (11 mg) was obtained as a white solid. MS calculated 826.4 (MH + ), measured value 826.4 (MH + ). 1H NMR(400MHz,METHANOL-d4)δ=8.44-8.41(d,J=2.8Hz,1H),8.26(s,1H),7.44-7.40(m,2H),7.09-7.05(m,1H),6.38(t,J=6.8Hz,1H),4 .52-4.36(m,5H),3.92-3.85(m,5H),3.83-3.76(m,2H),3.38-3.35(m,1H),3.31-3.24(m,4H),3.20-3.15(d,J=8.4Hz,1H),3.10-3.05 (m,3H),2.80-2.71(m,1H),2.43-2.36(d,J=14.8Hz,1H),1.79-1.67(m,2H),1.63-1.58(m,3H),1.53-1.44(m,1H),1.42-1.29(m,3H), 1.26-1.20(m,1H),1.19-1.15(d,6.8Hz,3H),1.13-1.08(m,3H),1.05-0.98(m,1H),0.97-0.91(m,3H),0.60-0.54(m,2H),0.53(s,2H).

[0285] Example 54 2,2-Difluoro-N-[(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(29),2,5(31),19,25,27-hexaen-7-yl]-1-methyl-cyclopropanecarboxamide TIFF2026506637000129.tif66170(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 (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]] instead of (1S,2S)-2-methylcyclopropanecarboxylic acid. 2,5 .1 9,13 .0 19,27 .0 21,26 ] The title compound was prepared in a manner similar to that of Example 1 by using hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate H) and 2,2-difluoro-1-methyl-cyclopropanecarboxylic acid. Example 54 (34 mg) was obtained as a pale yellow solid. MS calculated 861.4 (MH + ), measured value 861.4 (MH + ). 1 H NMR(400MHz,METHANOL-d4)δ=8.55-8.46(m,1H),8.20(br d,J=6.1Hz,1H),7.62(br s,1H),7.49(s,1H),7.10(s,1H),5.88-5.63(m,1H),4.67-4.50(m,4H),4.43(br d,J=11.1Hz,1H),4.36-4.23(m,2H),4.20-3.89(m,2H),3.78-3.69(m,3H),3.67-3.52(m,2H),3.40(s,7H),3.16(br d,J=14.4Hz,2H),2.99(s,3H),2.85-2.73(m,1H),2.58(br d,J=14.0Hz,1H),2.23(br d,J=11.4Hz,1H),2.15-1.90(m,2H),1.89-1.73(m,1H),1.69-1.54(m,4H),1.52-1.36(m,4H),1.02(s,3H),0.52(s,3H).

[0286] Example 55 N-[(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(29),2,5(31),19,25,27-hexaen-7-yl]-1,2-dimethyl-cyclopropanecarboxamide TIFF2026506637000130.tif69170(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 (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]] instead of (1S,2S)-2-methylcyclopropanecarboxylic acid. 2,5 .1 9,13 .0 19,27 .0 21,26 The title compound was prepared in a manner similar to that of Example 1 by using hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate H) and 1,2-dimethylcyclopropanecarboxylic acid. Example 55 (19.8 mg) was obtained as a pale yellow solid. MS calculated 839.4 (MH + ), measured value 839.4 (MH + ). 1H NMR(400MHz,METHANOL-d4)δ=8.57(s,1H),8.26(s,1H),7.66(s,1H),7.52(s,1H),7.16(s,1H),5.80-5.65(m,1H) ,4.74-4.46(m,4H),4.46-4.38(m,1H),4.37-4.22(m,2H),4.20-3.91(m,2H),3.75(s,4H),3.68-3.53(m,2H),3.52 -3.34(m,8H),3.21-3.08(m,2H),2.84-2.71(m,1H),2.64-2.50(m,1H),2.31-2.15(m,1H),2.03-1.91(m,1H),1.89 -1.75(m,1H),1.65-1.54(m,1H),1.49-1.24(m,9H),1.16(t,J=5.3Hz,3H),1.02(s,3H),0.52(s,3H),0.32(s,1H).

[0287] Example 56 (1S,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]-2-(3-pyridyl)cyclopropanecarboxamide TIFF2026506637000131.tif56170(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 (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] instead of (1S,2S)-2-methylcyclopropanecarboxylic acid. 2,5 .1 9,13 .0 19,27 .0 21,26 The title compound was prepared in a manner similar to that of Example 1 by using hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate E) and (1S,2S)-2-(3-pyridyl)cyclopropanecarboxylic acid. Example 56 (11.6 mg) was obtained as a yellow solid. MS calculated 886.4 (MH + ), measured value 886.6 (MH + ). 1 H NMR(400MHz,Methanol-d4)δ=8.78(s,1H),8.68(d,J=5.2Hz,1H),8.48(d,J=3.2Hz,1H),8.40(s,1H),8.33(d,J=7.6Hz,1H),7.96(dd,J=8.0,6.0Hz, 1H),7.55-7.49(m,2H),7.43(s,1H),5.86-5.76(m,1H),4.89(s,1H),4.48 -4.41(m,2H),4.27-4.19(m,2H),4.17-3.88(m,2H),3.76(s,3H),3.70-3. 55(m,3H),3.51-3.42(m,3H),3.37(s,3H),3.28-3.24(m,1H),3.14-3.07( m,2H),2.99(s,4H),2.84-2.76(m,1H),2.66-2.57(m,2H),2.34-2.16(m,4 H),1.99-1.92(m,1H),1.86-1.75(m,1H),1.74-1.69(m,1H),1.67-1.59(m ,1H),1.58-1.54(m,1H),1.46(d,J=6.4Hz,3H),0.97(s,3H),0.56(s,3H).

[0288] Example 57 and Example 58 (1S,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]-2-(4-pyridyl)cyclopropanecarboxamide and (1R,2R)-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]-2-(4-pyridyl)cyclopropanecarboxamide TIFF2026506637000132.tif73170

[0289] (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 (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] instead of (1S,2S)-2-methylcyclopropanecarboxylic acid. 2,5 .1 9,13 .0 19,27 .0 21,26 ] The title compound was prepared in a manner similar to that of Example 1 by using hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (intermediate E) and trans-2-(4-pyridyl)cyclopropanecarboxylic acid (intermediate R4), and then purified by prep-HPLC and SFC. SFC conditions: Column: DAICEL CHIRALCEL OJ (250 mm x 30 mm, 10 μm); Condition: CO₂-EtOH (0.1% NH₃H₂O); Start: B 30 min, End: 30 min; Gradient time (min): 4 min, Hold: 100% B; Flow rate (mL / min): 120

[0290] Example 57 (6.5 mg, SFC, faster eluting) was obtained as a white solid. MS calculated 886.4 (MH + ), measured value 886.4 (MH + ). 1H NMR(400MHz,Methanol-d4)δ=8.43-8.35(m,4H),7.49(s,J=2.0Hz,1H),7.40(s,1H),7.28-7.19(m,3H),5.81(d,J=8.8Hz,1H), 4.45-4.35(m,2H),4.27-4.18(m,2H),3.75(s,2H),3.64-3.54(m,1H),3.43(d,J=15.2Hz,1H),3.38-3.34(m,2H),3.29-3.20(m, 2H),3.14-2.91(m,4H),2.78(t,J=12.8Hz,1H),2.67-2.60(m,5H),2.40-2.35(m,4H),2.32-2.25(m,1H),2.23-2.13(m,3H),1.9 8-1.89(m,1H),1.80-1.69(m,1H),1.66-1.57(m,2H),1.43(d,J=6.0Hz,4H),1.38-1.22(m,2H),1.03-0.82(m,4H),0.55(s,3H).

[0291] In Example 58 (7.6 mg, SFC, soluble in water), a white solid was obtained. MS calculated value: 886.4 (MH + ), measured value 886.4 (MH + ). 1H NMR(400MHz,Methanol-d4)δ=8.45-8.35(m,4H),7.48(s,1H),7.39(s,1H),7.33-7.27(m,1H),7.25(d,J=5.2Hz,2H),5.84(d,J= 9.2Hz,1H),4.47-4.34(m,2H),4.28-4.19(m,2H),3.76(s,2H),3.64-3.54(m,1H),3.49-3.41(m,4H),3.27-3.22(m,1H),3.13-2. 97(m,4H),2.95-2.90(m,2H),2.82-2.75(m,1H),2.64-2.51(m,4H),2.46-2.38(m,1H),2.34-2.26(m,1H),2.23-2.16(m,3H),1. 99-1.89(m,1H),1.83-1.72(m,1H),1.69-1.49(m,4H),1.44(d,J=6.0Hz,4H),1.36-1.21(m,2H),1.03-0.93(m,4H),0.54(s,3H).

[0292] Example 59 2-(4-Fluorophenyl)-N-[(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(29),2,5(31),19,25,27-hexaen-7-yl]cyclopropanecarboxamide TIFF2026506637000133.tif78170(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 (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]] instead of (1S,2S)-2-methylcyclopropanecarboxylic acid. 2,5 .1 9,13 .0 19,27 .0 21,26 The title compound was prepared in a manner similar to that of Example 1 by using hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate H) and 2-(4-fluorophenyl)cyclopropanecarboxylic acid. Example 59 (37.8 mg) was obtained as a pale yellow solid. MS calculated 905.4 (MH + ), measured value 905.5 (MH + ). 1 H NMR(400MHz,METHANOL-d4)δ=8.50(d,J=2.8Hz,1H),8.28(s,1H),7.72(s,1H),7.49 (d,J=3.4Hz,1H),7.24-6.97(m,5H),5.86-5.72(m,1H),4.71-4.51(m,3H),4.43(br d,J=12.4Hz,1H),4.34-4.22(m,2H),4.21-3.85(m,2H),3.76(s,3H),3.63-3.55(m,1H),3.46-3.36(m,6H),3.29-3.21(m,2H),3.14(br d,J=14.8Hz,1H),2.98(s,3H),2.78(br t,J=12.4Hz,1H),2.60(br d,J=14.3Hz,1H),2.44-2.31(m,1H),2.21(br d,J=10.9Hz,1H),2.01-1.90(m,2H),1.81-1.16(m,9H),1.01(s,3H),0.54(s,3H).

[0293] Example 60 (1S,5R,6r)-N-[(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]-3-oxabicyclo[3.1.0]hexane-6-carboxamide TIFF2026506637000134.tif70170(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 (1S,2S)-2-methylcyclopropanecarboxylic acid were replaced with (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 The title compound was prepared in a manner similar to that of Example 1 by using ]hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate K) and (1S,5R,6r)-3-oxabicyclo[3.1.0]hexane-6-carboxylic acid. Example 60 (19.3 mg) was obtained as a white solid. MS calculated 887.4 (MH + ), measured value 887.4 (MH +), 1 H NMR(400MHz,Methanol-d4)δ=8.48(s,1H),8.43(d,J=2.8Hz,1H),7.57-7.51(m,2H),7.28-7.24(m,1H),5.80-5.72(m,1H),4.67-4.55(m,1H) ),4.45-4.39(m,2H),4.24(dd,J=3.2,12.0Hz,1H),3.98-3.87(m,3H),3.78-3.70(m,4H),3.67-3.45(m,3H),3.40-3.33(m,6H),3.29-3.22( m,1H),3.11-3.04(m,1H),2.81-2.72(m,1H),2.70-2.65(m,4H),2.64 -2.58(m,1H),2.39(s,3H),2.21-2.15(m,1H),2.12-2.03(m,2H),1.97 -1.89(m,1H),1.82-1.72(m,1H),1.70-1.68(m,1H),1.65-1.56(m,1H),1.44(d,J=6.0Hz,3H),1.29(s,1H),0.98-0.94(m,3H),0.55(s,3H).

[0294] Example 61 (1r,2R,3S)-N-[(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]-2,3-dimethyl-cyclopropanecarboxamide TIFF2026506637000135.tif62170(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 .019,27 .0 21,26 ]hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (intermediate F) and (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]] instead of (1S,2S)-2-methylcyclopropanecarboxylic acid. 2,5 .1 9,13 .0 19,27 .0 21,26 ] The title compound was prepared in a manner similar to that of Example 1 by using hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate M) and (1r,2R,3S)-2,3-dimethylcyclopropanecarboxylic acid. Example 61 (18 mg) was obtained as a white solid. MS calculated 854.4 (MH + ), measured value 854.5 (MH + ). 1H NMR(400MHz,Methanol-d4)δ=8.45-8.36(d,J=3.2Hz,1H),8.25-8.20(s,1H),7.85 -7.77(d,J=2.8Hz,1H),7.53-7.46(s,1H),7.15-7.8(s,1H),5.86-5.79(d,J=6.8H z,1H),4.74-4.64(d,J=6.4Hz,1H),4.49-4.40(d,J=11.6Hz,1H),4.37-4.20(dd,J =3.2Hz,12Hz,1H),4.03-3.93(d,J=12.4Hz,1H),3.91-3.84(t,J=4.8Hz,5H),3.84 -3.79(s,2H),3.73-3.62(d,J=12.4Hz,1H),3.47-3.43(s,3H),3.41-3.37(m,1H), 3.30-3.24(m,1H),3.12-3.05(d,J=13.6Hz,1H),2.85-2.67(m,2H),2.21-2.21(dd ,J=2Hz,13.2Hz,1H),1.98-1.89(d,J=11.6Hz,1H),1.81-1.60(m,2H),1.57-1.49( m,7H),1.45-1.29(m,6H),1.20-1.11(m,8H),1.05-0.95(s,3H),0.72-0.68(s,3H).

[0295] Example 63 (1S,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]-2-pyridazin-3-yl-cyclopropanecarboxamide TIFF2026506637000136.tif76170(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 (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] instead of (1S,2S)-2-methylcyclopropanecarboxylic acid. 2,5 .1 9,13 .0 19,27 .0 21,26 ] The title compound was prepared in a manner similar to that of Example 1 by using hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate E) and trans-2-pyridazin-3-ylcyclopropanecarboxylic acid (Intermediate R2). Example 63 (6.0 mg) was obtained as a yellow solid. MS calculated 887.4 (MH + ), measured value 887.5 (MH + ). 1H NMR(400MHz,Methanol-d4)δ=9.10-9.04(m,1H),8.53-8.46(m,1H),8.44-8.36(m,1H),7.77-7.66(m,2H),7.60(d,J=2.8Hz,1H),7.50(s,1H),7. 43(s,1H),5.87-5.81(m,1H),4.49-4.39(m,2H),4.26-4.16(m,2H),3.7 8-3.72(m,2H),3.67-3.58(m,2H),3.48-3.39(m,3H),3.39-3.35(m,4H), 3.28-3.23(m,1H),3.16-3.04(m,3H),3.02-2.97(m,4H),2.87-2.74(m, 2H),2.74-2.67(m,1H),2.66-2.60(m,1H),2.59-2.53(m,1H),2.38-2.26 (m,1H),2.24-2.13(m,2H),1.99-1.90(m,1H),1.81-1.58(m,4H),1.50( d,J=6.4Hz,4H),1.35-1.28(m,1H),1.05-0.96(m,3H),0.64-0.57(m,3H)

[0296] Example 64 (1R,2S)-2-Cyclopropyl-N-[(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(29),2,5(31),19,25,27-hexaen-7-yl]cyclopropanecarboxamide TIFF2026506637000137.tif69170(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 .019,27 .0 21,26 ]hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (intermediate F) and (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]] instead of (1S,2S)-2-methylcyclopropanecarboxylic acid. 2,5 .1 9,13 .0 19,27 .0 21,26 ] The title compound was prepared in a manner similar to that of Example 1 by using hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate H) and (1R,2S)-2-cyclopropylcyclopropanecarboxylic acid. Example 64 (45.0 mg) was obtained as a pale yellow solid. MS calculated 851.4 (MH + ), measured value 851.4 (MH + ). 1H NMR(400MHz,METHANOL-d4)δ=8.29(d,J=2.6Hz,1H),8.01(d,J=3.0Hz,1H),7.35(d ,J=2.8Hz,1H),7.28(d,J=8.0Hz,1H),6.90(d,J=3.3Hz,1H),5.57(d,J=8.8Hz,1H), 4.56(s,3H),4.46-4.37(m,2H),4.32(q,J=6.5Hz,1H),4.24(d,J=13.3Hz,1H),4.14 -4.04(m,2H),3.62-3.46(m,4H),3.39-3.22(m,4H),3.18(d,J=1.5Hz,4H),3.07(d, J=5.9Hz,1H),2.93(d,J=12.6Hz,1H),2.79(s,3H),2.64-2.52(m,1H),2.39(d,J=14 .5Hz,1H),2.06-1.95(m,1H),1.80-1.71(m,1H),1.68-1.52(m,1H),1.48-1.35(m,2 H),1.27(d,J=6.1Hz,3H),1.16-1.07(m,1H),0.85-0.74(m,4H),0.73-0.65(m,1H), 0.48(dd,J=7.0Hz,11.0Hz,1H),0.34(s,3H),0.29-0.17(m,2H),0.05-0.09(m,2H).

[0297] Example 65 3,3-Difluoro-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]cyclopentanecarboxamide TIFF2026506637000138.tif70170(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 (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] instead of (1S,2S)-2-methylcyclopropanecarboxylic acid. 2,5 .1 9,13 .0 19,27 .0 21,26 ] The title compound was prepared in a manner similar to that of Example 1 by using hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate E) and 3,3-difluorocyclopentanecarboxylic acid. Example 65 (13.9 mg) was obtained as a pale yellow solid. MS calculated 873.4 (MH + ), measured value 873.5 (MH + ). 1H NMR(400MHz,METHANOL-d4)δ=8.49-8.42(m,1H),8.36(d,J=2.5Hz,1H),8.29(s,1H),7.39(s,1H),7.34-7.30(m,2H),5.65(br t,J=8.1Hz,1H),4.36-4.29(m,2H),4.15(br d,J=10.4Hz,2H),3.66(s,2H),3.54-3.43(m,3H),3.31(br s,2H),3.27(s,4H),3.18-3.13(m,2H),3.05-2.94(m,4H),2.89(s,4H),2.74-2.64(m,1H),2.48(br d,J=14.6Hz,1H),2.31-2.17(m,3H),2.14-2.05(m,3H),2.03-1.81(m,4H),1.74-1.63(m,1 H),1.58-1.49(m,1H),1.34(d,J=6.1Hz,3H),1.24-1.17(m,1H),0.87(s,3H),0.43(s,3H).

[0298] Example 66 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]-2-oxabicyclo[2.1.1]hexane-1-carboxamide TIFF2026506637000139.tif53170(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 (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] instead of (1S,2S)-2-methylcyclopropanecarboxylic acid. 2,5 .1 9,13 .0 19,27 .0 21,26 The title compound was prepared in a manner similar to that of Example 1 by using ]hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate E) and 2-oxabicyclo[2.1.1]hexane-1-carboxylic acid. Example 66 (13.4 mg) was obtained as a white solid. MS calculated 851.4 (MH + ), measured value 851.5 (MH + ). 1 H NMR(400MHz,METHANOL-d4)δ=8.36(br s,1H),8.30(br s,1H),7.46(br s,1H),7.38(d,J=3.1Hz,1H),7.32(br s,1H),5.86-5.76(m,1H),4.39-4.30(m,2H),4.18-4.05(m,3H),3.88-3.81(m,2H),3.67(br s,2H),3.55-3.47(m,3H),3.34-3.30(m,2H),3.29-3.25(m,5H),3.04-2.94(m,3H),2.89(br d,J=3.1Hz,5H),2.69(br t,J=12.7Hz,1H),2.52(br d,J=14.4Hz,1H),2.26-2.18(m,1H),2.15-2.02(m,4H),1.90-1.81(m,1H),1.73-1.64(m,1H),1.63-1.48(m,4H),1.40-1.33(m,3H),1.19(br s,1H),0.86(br s,3H),0.47(br s,3H).

[0299] Example 67 (1S,2S)-N-[(7S,13S)-23,23-difluoro-(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]-2-methyl-cyclopropanecarboxamide TIFF2026506637000140.tif60170(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) was replaced with (7S,13S)-7-amino-23,23-difluoro-(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 ] The title compound was prepared in a manner similar to that of Example 1 by using hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate O). Example 67 (22.8 mg) was obtained as a yellow solid. MS calculated 927.4 (MH + ), measured value 927.6 (MH + ), 1H NMR(400MHz,METHANOL-d4)δ=8.51(s,1H),8.40(d,J=2.8Hz,1H),7.65(d,J=2.8Hz,1H),7.60-7.54(m,2H),5.79(dd,J=1.2,8.8Hz,1H ),4.57-4.38(m,3H),4.23(dd,J=3.2,12.0Hz,1H),4.06-3.94(m,1H),3.82-3.48(m,5H),3.47-3.43(m,4H),3.39(s,3H),3.29-3.24( m,1H),3.21-3.08(m,3H),2.91-2.85(m,4H),2.82-2.73(m,1H),2.71-2.64(m,1H),2.21-2.13(m,1H),1.98-1.89(m,1H),1.82-1.70( m,1H),1.65-1.55(m,1H),1.50-1.45(m,4H),1.27-1.18(m,1H),1.15-1.10(m,3H),1.09-1.04(m,1H),1.00(s,3H),0.67-0.56(m,4H).

[0300] Example 68 (1r,2R,3S)-N-[(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(29),2,5(31),19,25,27-hexaen-7-yl]-2,3-dimethyl-cyclopropanecarboxamide TIFF2026506637000141.tif65170(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 (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]] instead of (1S,2S)-2-methylcyclopropanecarboxylic acid. 2,5 .1 9,13 .0 19,27 .0 21,26 ] The title compound was prepared in a manner similar to that of Example 1 by using hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate J) and (1r,2S,3R)-2,3-dimethylcyclopropanecarboxylic acid. Example 68 (50 mg) was obtained as a yellow solid. MS calculated 826.4 (MH + ), measured value 826.6 (MH + ). 1 H NMR(400MHz,METHANOL-d4)δ=8.41(d,J=2.6Hz,1H),8.24(s,1H),7.90(d,J=2.8Hz,1H),7.48(s,1H),7.14(s,1H),5.77(br d,J=8.4Hz,1H),4.71-4.52(m,3H),4.45-4.40(m,1H),4.25(br d,J=9.0Hz,2H),3.91-3.80(m,5H),3.76(br d,J=5.9Hz,2H),3.42(s,7H),3.37(s,1H),3.30-3.21(m,1H),3.16(br d,J=14.4Hz,1H),2.80-2.62(m,2H),2.26-2.12(m,1H),1.99-1.86(m,1H),1.85-1.68(m,1H),1.65- 1.55(m,1H),1.50(d,J=6.3Hz,3H),1.43-1.29(m,2H),1.20-1.10(m,7H),1.04(s,3H),0.60(s,3H).

[0301] Example 69 (1r,2S,3R)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-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(28),2,5(31),19,25(29),26-hexaen-7-yl]-2,3-dimethyl-cyclopropanecarboxamide TIFF2026506637000142.tif72170(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 (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17,23,23-tetramethyl-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1]] instead of (1S,2S)-2-methylcyclopropanecarboxylic acid. 2,5 .1 9,13 .0 19,27 .0 21,26 ] The title compound was prepared in a manner similar to that of Example 1 by using hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate P) and (1r,2S,3R)-2,3-dimethylcyclopropanecarboxylic acid. Example 69 (6 mg) was obtained as a white solid. MS calculated 865.5 (MH + ), measured value 865.5 (MH + ). 1H NMR(400MHz,METHANOL-d4)δ=8.49(br d,J=2.4Hz,1H),8.41(s,1H),7.52(d,J=2.6Hz,1H),7.49(s,1H),7.41(s,1H),5.83(dd,J=1.9,8.4Hz ,1H),4.57-4.47(m,2H),4.45-4.35(m,1H),4.24-4.15(m,1H),3.84-3.74(m,3H),3.67-3.34(m,8H), 3.29-3.21(m,2H),3.08-3.00(m,1H),2.99-2.95(m,3H),2.94-2.87(m,1H),2.81-2.71(m,2H),2.70- 2.62(m,1H),2.17-2.06(m,1H),1.95-1.84(m,1H),1.76-1.68(m,1H),1.66(d,J=7.0Hz,3H),1.60(br s,1H),1.47(d,J=6.1Hz,3H),1.42-1.27(m,3H),1.17-1.10(m,9H),0.92(s,3H),0.88-0.84(m,3H),0.61(s,3H).

[0302] Example 70 trans-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(29),2,5(31),19,25,27-hexaen-7-yl]-4-(1-methyltetrazol-5-yl)cyclohexanecarboxamide TIFF2026506637000143.tif75170(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 (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] instead of (1S,2S)-2-methylcyclopropanecarboxylic acid. 2,5 .1 9,13 .0 19,27 .0 21,26 ] The title compound was prepared in a manner similar to that of Example 1 by using hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate E) and trans-4-(1-methyltetrazol-5-yl)cyclohexanecarboxylic acid. Example 70 (8 mg) was obtained as a white solid. MS calculated 933.5 (MH+), found 933.5 (MH+). 1 H NMR(400MHz,METHANOL-d4)δ=8.44-8.35(m,2H),7.46(s,1H),7.38(s,1H),7.26(d,J=2.9Hz,1H),5.85-5.66(m,1H),4.48-4.34(m,2H) ),4.30-4.21(m,2H),4.04(s,3H),3.80-3.69(m,2H),3.62-3.51(m,1H),3.47-3.40(m,1H),3.40-3.35(m,4H),3.35-3.32(m,3H),3.2 8-3.22(m,1H),3.15-2.90(m,4H),2.86-2.70(m,4H),2.65(s,1H),2.59(d,J=14.4Hz,1H),2.52-2.47(m,1H),2.44(s,3H),2.35-2.23 (m,1H),2.23-2.13(m,2H),2.12-1.98(m,4H),1.98-1.86(m,1H),1.84-1.55(m,6H),1.43(d,J=6.1Hz,3H),0.96(s,3H),0.52(s,3H).

[0303] Example 71 trans-4-Hydroxy-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]-4-methyl-cyclohexanecarboxamide TIFF2026506637000144.tif61170(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 (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] instead of (1S,2S)-2-methylcyclopropanecarboxylic acid. 2,5 .1 9,13 .0 19,27 .0 21,26 The title compound was prepared in a manner similar to that of Example 1 by using hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate E) and trans-4-hydroxy-4-methyl-cyclohexanecarboxylic acid. Example 71 (12.3 mg) was obtained as a white solid. MS calculated 881.5 (MH + ), measured value 881.5 (MH + ). 1H NMR(400MHz,METHANOL-d4)δ=8.34-8.26(m,2H),7.37(s,1H),7.29(s,1H),7.15(d,J=2.8Hz,1H),5.64(br d,J=8.3Hz,1H),4.47(br s,1H),4.35-4.25(m,2H),4.15(br dd,J=2.6,11.9Hz,2H),3.65(s,2H),3.57-3.42(m,2H),3.30-3.26(m,4H),3.24(s,2H) ),3.18-3.12(m,1H),3.03-2.94(m,2H),2.93-2.83(m,1H),2.71-2.61(m,5H),2.49(br d,J=14.4Hz,1H),2.33(s,3H),2.30-2.14(m,3H),2.13-2.05(m,2H),1.87-1.79(m,2H),1.76-1.68(m,2H),1.67- 1.61(m,2H),1.58-1.49(m,3H),1.47-1.39(m,2H),1.33(d,J=6.1Hz,3H),1.14(s,3H),0.86(s,3H),0.43(s,3H).

[0304] Example 72 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]tricyclo[3.1.1.0 3,6 ]heptane-6-carboxamide TIFF2026506637000145.tif46170(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 .019,27 .0 21,26 ]hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (intermediate F) and (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] instead of (1S,2S)-2-methylcyclopropanecarboxylic acid. 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 tricyclo[3.1.1.0 3,6 The title compound was prepared in a manner similar to that of Example 1 by using 1-heptane-6-carboxylic acid. Example 72 (6.7 mg) was obtained as a white solid. MS calculated 861.4 (MH + ), measured value 861.4 (MH + ). 1 H NMR(400MHz,METHANOL-d4)δ=8.29(s,2H),7.37(s,1H),7.29(s,1H),7.15(s,1H),5.71(dd,J=2.8,6.8Hz,1H),4.47(s,1H),4.37-4.25(m,2H),4. 18-4.10(m,2H),3.66(s,2H),3.52-3.43(m,1H),3.34-3.30(m,2H),3.24 (s,5H),3.09-3.02(m,3H),3.01-2.86(m,6H),2.73-2.65(m,1H),2.61(br s,3H),2.50(br d,J=14.5Hz,1H),2.31(s,3H),2.17(br d,J=11.3Hz,4H),2.13-2.05(m,2H),1.88-1.81(m,1H),1.72-1.63(m,1H),1.57-1.46(m ,1H),1.35-1.31(m,3H),1.24-1.13(m,1H),0.86(s,3H),0.82-0.68(m,1H),0.43(s,3H).

[0305] Example 73 (1r,2S,3R)-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]-2,3-dimethyl-cyclopropanecarboxamide The title compound was prepared in a manner similar to that of Example 1, except that (1r,2S,3R)-2,3-dimethylcyclopropanecarboxylic acid was used instead of (1S,2S)-2-methylcyclopropanecarboxylic acid. Example 73 (28 mg) was obtained as a yellow solid. MS calculated 824.4 (MH + ), measured value 824.6 (MH + ). 1 H NMR(400MHz,Methanol-d4)δ=8.42(s,1H),8.36(d,J=2.8Hz,1H),7.89-7.83(m,1H),7.51(s,1H),7.45(s,1H),5.84-5.78(m,1H),4.5 8-4.50(m,1H),4.43(d,J=11.6Hz,1H),4.25-4.17(m,1H),4.16-4.09(m,1H),3.86(t,J=4.4Hz,4H),3.79-3.72(m,2H),3.71-3.65(m,1 H),3.43(s,7H),3.38(s,1H),3.29-3.22(m,1H),3.14-3.01(m,3H),2.80-2.67(m,2H),2.37-2.29(m,1H),2.23-2.12(m,2H),1.97-1.8 8(m,1H),1.80-1.69(m,1H),1.65-1.55(m,1H),1.48(d,J=6.4Hz,3H),1.40-1.32(m,2H),1.17-1.11(m,7H),0.99(s,3H),0.62(s,3H).

[0306] Example 75 (1S,2S)-N-[(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]-2-methyl-cyclopropanecarboxamide TIFF2026506637000147.tif60170(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) was replaced with (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 ] The title compound was prepared in a manner similar to that of Example 1 by using hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate Q). Example 75 (19.5 mg) was obtained as a yellow solid. MS calculated 846.4 (MH + ), measured value 846.4 (MH + ). 1H NMR(400MHz,METHANOL-d4)δ=8.52(s,1H),8.40(d,J=2.8Hz,1H),7.77(s,1H),7.58(d,J=7.2Hz,2H),5.80(d,J=8.4Hz,1H ),4.57-4.41(m,3H),4.22(d,J=8.8Hz,1H),4.04(d,J=14.4Hz,1H),3.86(d,J=4.4Hz,4H),3.82-3.71(m,2H),3.69-3.47( m,3H),3.45-3.39(m,8H),3.26(d,J=8.8Hz,1H),3.11(d,J=15.2Hz,1H),2.82-2.67(m,2H),2.17(d,J=11.6Hz,1H),1.94( d,J=12.8Hz,1H),1.75(s,1H),1.61(d,J=15.2Hz,1H),1.49(d,J=6.4Hz,3H),1.23-1.03(m,6H),1.01(s,3H),0.62(s,3H).

[0307] Example 76 (1r,2S,3R)-N-[(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]-2,3-dimethyl-cyclopropanecarboxamide TIFF2026506637000148.tif59170

[0308] (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 (1S,2S)-2-methylcyclopropanecarboxylic acid were replaced with (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 ] The title compound was prepared in a manner similar to that of Example 1 by using hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate Q) and (1r,2S,3R)-2,3-dimethylcyclopropanecarboxylic acid. Example 76 (16.7 mg) was obtained as a yellow solid. MS calculated 860.4 (MH + ), measured value 860.4 (MH + ). 1 H NMR(400MHz,METHANOL-d4)δ=8.52(s,1H),8.40(d,J=3.2Hz,1H),7.66(s,1H),7.59-7.56(m,2H),5.79(d,J=7.6Hz,1H),4.56-4.49(m,2H),4 .46-4.40(m,1H),4.25-4.20(m,1H),4.05-3.95(m,1H),3.86(t,J=4.4 Hz,4H),3.81-3.77(m,1H),3.74-3.70(m,1H),3.69-3.58(m,2H),3.57 -3.48(m,1H),3.41-3.37(m,7H),3.28-3.23(m,1H),3.10(d,J=14.4Hz,1H),2.81-2.73(m,1H),2.68(d,J=14.4Hz,1H),2.21-2.14(m,1H),1. 97-1.89(m,1H),1.81-1.70(m,1H),1.64-1.56(m,1H),1.48(d,J=6.4H z,3H),1.40-1.33(m,2H),1.16-1.11(m,7H),1.00(s,3H),0.61(s,3H).

[0309] Example 77 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]tetrahydropyran-4-carboxamide TIFF2026506637000149.tif59170(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 (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] instead of (1S,2S)-2-methylcyclopropanecarboxylic acid. 2,5 .1 9,13 .0 19,27 .0 21,26 ] The title compound was prepared in a manner similar to that of Example 1 by using hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate E) and tetrahydropyran-4-carboxylic acid. Example 77 (11.4 mg) was obtained as a pale yellow solid. MS calculated 853.4 (MH + ), measured value 853.5 (MH + ). 1H NMR(400MHz,METHANOL-d4)δ=8.37(d,J=2.9Hz,1H),8.30(s,1H),7.44(d,J=2.9Hz,1H),7.39(s,1H),7.32(s,1H),5.65(br d,J=7.5Hz,1H),4.46-4.29(m,2H),4.18-4.08(m,2H),3.89(tdd,J=3.3,7.0,10.8Hz,3H),3.66(s ,2H),3.59-3.33(m,7H),3.32-3.26(m,5H),3.19-3.13(m,2H),3.05-2.96(m,2H),2.89(s,4H),2.7 2-2.64(m,1H),2.57-2.46(m,2H),2.26-2.17(m,1H),2.13-2.04(m,2H),1.88-1.80(m,1H),1.75-1 .68(m,3H),1.67-1.60(m,2H),1.57-1.47(m,2H),1.36(d,J=6.1Hz,3H),0.88(s,3H),0.45(s,3H).

[0310] Example 78 (1S,2S)-N-[(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]-2-phenyl-cyclopropanecarboxamide TIFF2026506637000150.tif74170(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 (1S,2S)-2-methylcyclopropanecarboxylic acid were replaced with (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 ] The title compound was prepared in a manner similar to that of Example 1 by using hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate K) and (1S,2S)-2-phenylcyclopropanecarboxylic acid. Example 78 (25.9 mg) was obtained as a yellow solid. MS calculated 921.4 (MH + ), measured value 921.6 (MH + ). 1H NMR(400MHz,Methanol-d4)δ=8.53-8.48(m,2H),7.61-7.55(m,2H),7.42(d, J=2.8Hz,1H),7.30-7.24(m,2H),7.21-7.12(m,3H),5.85-5.78(m,1H),4.87- 4.85(m,1H),4.63-4.53(m,1H),4.51-4.39(m,2H),4.25(dd,J=12.0,2.8Hz,1 H),4.18-3.83(m,3H),3.81-3.72(m,2H),3.68-3.44(m,5H),3.41(s,1H),3.3 5(s,5H),3.26(d,J=8.8Hz,1H),3.13-3.08(m,1H),2.99(s,3H),2.83-2.75( m,1H),2.60(d,J=15.2Hz,1H),2.39-2.33(m,1H),2.22-2.15(m,1H),2.08-2. 03(m,1H),1.97-1.91(m,1H),1.82-1.71(m,1H),1.68-1.59(m,1H),1.54-1.4 9(m,1H),1.47(d,J=6.4Hz,3H),1.32-1.28(m,1H),0.97(s,3H),0.56(s,3H).

[0311] Example 79 (1S,2S)-N-[(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]-2-phenyl-cyclopropanecarboxamide TIFF2026506637000151.tif66170(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[23.3.1.12,5 .1 9,13 .0 19,27 .0 21,26 ]hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (intermediate F) and (1S,2S)-2-methylcyclopropanecarboxylic acid were replaced with (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 ] The title compound was prepared in a manner similar to that of Example 1 by using hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate Q) and (1S,2S)-2-phenylcyclopropanecarboxylic acid. Example 79 (20 mg) was obtained as a yellow solid. MS calculated 908.4 (MH + ), measured value 908.6 (MH + ). 1H NMR(400MHz,Methanol-d4)δ=8.54(s,1H),8.40(d,J=2.8Hz,1H),7.78(d,J= 2.8Hz,1H),7.60-7.58(m,2H),7.28-7.24(m,2H),7.18-7.13(m,3H),5.87-5. 83(m,1H),4.88-4.85(m,1H),4.55(d,J=6.4Hz,1H),4.51-4.40(m,2H),4.23( dd,J=12.0,2.8Hz,1H),4.07-3.99(m,1H),3.87(t,J=4.8Hz,4H),3.77(d,J=1 7.6Hz,2H),3.65-3.52(m,2H),3.43-3.40(m,7H),3.30-3.24(m,1H),3.13-3. 07(m,1H),2.83-2.76(m,1H),2.71(d,J=14.0Hz,1H),2.38-2.34(m,1H),2.20 -2.14(m,1H),2.08-2.03(m,1H),1.96-1.91(m,1H),1.81-1.72(m,1H),1.68- 1.52(m,2H),1.51-1.49(m,3H),1.32-1.27(m,1H),1.01(s,3H),0.63(s,3H).

[0312] Example 80 and Example 81 (1S,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]-2-pyrimidin-2-yl-cyclopropanecarboxamide and (1R,2R)-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[23.3.1.12,5 .1 9,13 .0 19,27 .0 21,26 ]Hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]-2-pyrimidin-2-yl-cyclopropanecarboxamide TIFF2026506637000152.tif76170

[0313] (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 (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] instead of (1S,2S)-2-methylcyclopropanecarboxylic acid. 2,5 .1 9,13 .0 19,27 .0 21,26 ] The title compound was prepared in the same manner as in Example 1 by using hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (intermediate E) and 2-pyrimidin-2-ylcyclopropanecarboxylic acid (intermediate R5), and then purified by prep-HPLC and SFC. SFC conditions: Column: DAICEL CHIRALCEL IG (250 mm x 30 mm, 10 μm); Condition: CO₂-EtOH (0.1% NH₃H₂O); Start: B 75°C, End: 75°C, Gradient time (min): 3.3 min, Hold: 100% B; Flow rate (mL / min): 100.

[0314] Example 80 (13.4 mg, SFC, faster eluting) was obtained as a white solid. MS calculated 887.4 (MH + ), measured value 887.4 (MH + ). 1 H NMR(400MHz,Methanol-d4)δ=8.67(d,J=4.8Hz,2H),8.44(s,1H),8.38(s,1H),7.46(s,1H),7.39(s,1H),7.33(s,1H),7.30(t,J=5.0 Hz,1H),5.81(d,J=8.4Hz,1H),4.45-4.39(m,2H),4.26-4.21(m,2H),3.76(s,2H),3.58-3.49(m,5H),3.43(m,1H),3.39(s,1H),3.26- 3.21(m,2H),3.13-3.04(m,2H),3.01-2.93(m,1H),2.81(s,5H),2.71-2.65(m,1H),2.59(m,1H),2.50-2.44(m,1H),2.34-2.26(m,1H) ,2.21-2.15(m,2H),1.96-1.91(m,1H),1.77(m,1H),1.64-1.54(m,4H),1.44(d,J=6.8Hz,3H),1.29(s,3H),0.95(s,3H),0.55(s,3H).

[0315] Example 81 (7.6 mg, SFC, slow elution) was obtained as a white solid. MS calculated 887.4 (MH + ), measured value 887.4 (MH + ). 1H NMR(400MHz,Methanol-d4)δ=8.65(d,J=4.8Hz,2H),8.41-8.37(m,2H),8.37(s,2H),7.30-7.24(m,2H),5.84(d, J=8.8Hz,1H),4.44-4.35(m,2H),4.28-4.20(m,2H),3.76(s,2H),3.64-3.56(m,1H),3.49-3.35(m,4H),3.25(m,1 H),3.15-2.94(m,4H),2.81-2.74(m,1H),2.69-2.61(m,6H),2.49(m,2H),2.37(s,3H),2.34-2.13(m,4H),1.95- 1.89(m,1H),1.73(s,1H),1.63-1.57(m,3H),1.44(d,J=6.0Hz,3H),1.32-1.28(m,1H),0.95(s,3H),0.55(s,3H).

[0316] Example 83 (1r,2S,3R)-N-[(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(29),2,5(31),19,25,27-hexaen-7-yl]-2,3-dimethyl-cyclopropanecarboxamide TIFF2026506637000153.tif72170(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 (1S,2S)-2-methylcyclopropanecarboxylic acid were replaced with (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 ] The title compound was prepared in a manner similar to that of Example 1 by using hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate K) and (1r,2S,3R)-2,3-dimethylcyclopropanecarboxylic acid. Example 83 (16 mg) was obtained as a yellow solid. MS calculated 873.4 (MH + ), measured value 873.6 (MH + ). 1 H NMR(400MHz,Methanol-d4)δ=8.52-8.48(m,2H),7.58-7.55(m,2H),7.48(d,J=2.8Hz,1H),5.80-5.74(m,1H),4.91-4.87(m,1H),4.5 8-4.41(m,3H),4.24(dd,J=12.0,3.2Hz,1H),4.13-3.86(m,3H),3.82-3.68(m,3H),3.68-3.53(m,4H),3.45-3.38(m,2H),3.36(s,3H) ),3.27-3.24(m,1H),3.11(d,J=14.4Hz,1H),2.99(s,3H),2.81-2.74(m,1H),2.60(d,J=14.4Hz,1H),2.20-2.14(m,1H),1.97-1.91( m,1H),1.82-1.73(m,1H),1.66-1.58(m,1H),1.47(d,J=6.4Hz,3H),1.40-1.33(m,2H),1.19-1.09(m,8H),0.98(s,3H),0.56(s,3H).

[0317] Example 85 (1r,2S,3R)-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-15,24-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]-2,3-dimethyl-cyclopropanecarboxamide TIFF2026506637000154.tif77170(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 (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-15,24-dioxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1]] instead of (1S,2S)-2-methylcyclopropanecarboxylic acid. 2,5 .1 9,13 .0 19,27 .0 21,26 The title compound was prepared in a manner similar to that of Example 1 by using hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate I) and (1r,2S,3R)-2,3-dimethylcyclopropanecarboxylic acid. Example 85 (22.2 mg) was obtained as a yellow solid. MS calculated 907.4 (MH + ), measured value 907.5 (MH+ ). 1 H NMR(400MHz,METHANOL-d4...

Claims

1. A compound of formula (Ib) During the ceremony, R １ is 2-oxabicyclo[2.1.1]hexanyl, 3-oxabicyclo[3.1.0]hexanyl, 6-bicyclo[3.1.0]hexanyl substituted twice with halogen, 6-tricyclo[3.1.1.0 ３，６ ]heptanyl, C １～６ Alkyl, C １～６ Alkylpyridinyl, C １～６ Alkylpyrimidinyl, C １～６ Alkyltetrazolyl, C ３～７ Cycloalkyl, haloC １～６ C substituted once, twice or three times with substituents independently selected from alkyl, halogen, halophenyl, hydroxy, phenyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl and thiazolyl ３～７ cycloalkyl, or tetrahydropyranyl; R ２ is 1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazinyl, 3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazinyl, morpholinyl, or unsubstituted or C １～６ Alkoxy C １～６ Alkyl, C １～６ Alkyl, C ３～７ Cycloalkyl, haloC １～６ Alkyl, hydroxy C １～６ Alkyl, morpholinyl C １～６ Alkyl, oxetanyl, oxopyrrolidinyl C １～６ Alkyl and tetrahydrofuranyloxy C １～６ piperazinyl substituted with substituents independently selected from alkyl; R ３ is H or a halogen; M is C １～６ alkylene or O; L is C １～６ Alkylene, Hydroxy C １～６ Alkylene or haloC １～６ is alkylene, The compound, or a pharmaceutically acceptable salt thereof.

2. A compound of formula (Ic) During the ceremony, R １ is 2-oxabicyclo[2.1.1]hexanyl, 3-oxabicyclo[3.1.0]hexanyl, 6-bicyclo[3.1.0]hexanyl substituted twice with halogen, 6-tricyclo[3.1.1.0 ３，６ ]heptanyl, C １～６ Alkyl, C １～６ Alkylpyridinyl, C １～６ Alkylpyrimidinyl, C １～６ Alkyltetrazolyl, C ３～７ Cycloalkyl, haloC １～６ C substituted once, twice or three times with substituents independently selected from alkyl, halogen, halophenyl, hydroxy, phenyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl and thiazolyl ３～７ cycloalkyl, or tetrahydropyranyl; R ２ is 1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazinyl, 3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazinyl, morpholinyl, or unsubstituted or C １～６ Alkoxy C １～６ Alkyl, C １～６ Alkyl, C ３～７ Cycloalkyl, haloC １～６ Alkyl, hydroxy C １～６ Alkyl, morpholinyl C １～６ Alkyl, oxetanyl, oxopyrrolidinyl C １～６ Alkyl and tetrahydrofuranyloxy C １～６ piperazinyl substituted with substituents independently selected from alkyl; R ３ is H or a halogen; M is C １～６ alkylene or O; L is C １～６ Alkylene, Hydroxy C １～６ Alkylene or haloC １～６ is alkylene, The compound, or a pharmaceutically acceptable salt thereof.

3. R １ But C １～６ C substituted once or twice with substituents independently selected from alkyl and pyridinyl ３～７ 3. The compound of claim 1 or 2, which is cycloalkyl.

4. R １ The compound of any one of claims 1 to 3, wherein is cyclopropyl substituted once with pyridinyl or twice with methyl.

5. R １ The compound of any one of claims 1 to 4, wherein is 2,3-dimethyl-cyclopropyl or 2-(3-pyridinyl)cyclopropyl.

6. R ２ is morpholinyl or C １～６ The compound of any one of claims 1 to 5, which is alkylpiperazinyl.

7. R ２ The compound of any one of claims 1 to 6, wherein is morpholinyl or 4-methylpiperazin-1-yl.

8. M is C １～６ The compound of any one of claims 1 to 7, which is alkylene.

9. M is CH ２ The compound according to any one of claims 1 to 8, wherein

10. The compound of any one of claims 1 to 9, wherein L is ethylene or difluoroethylene.

11. L, 11. The compound of any one of claims 1 to 10, wherein bond "a" is connected to M.

12. R １ But C １～６ C substituted once or twice with substituents independently selected from alkyl and pyridinyl ３～７ is cycloalkyl; R ２ is morpholinyl or C １～６ alkylpiperazinyl; R ３ is H; M is C １～６ alkylene; L is C １～６ Alkylene or haloC １～６ is alkylene, 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof.

13. R １ is 2,3-dimethyl-cyclopropyl or 2-(3-pyridinyl)cyclopropyl; R ２ is morpholinyl or 4-methylpiperazin-1-yl; R ３ is H; M is CH ２ and L, where bond "a" connects to M.

13. The compound of claim 12, or a pharmaceutically acceptable salt thereof.

14. (1S,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]-2-methyl-cyclopropanecarboxamide; (1S,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]-2-methyl-cyclopropanecarboxamide; (1S,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]-2-methyl-cyclopropanecarboxamide; (1S,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-15,24-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]-2-methyl-cyclopropanecarboxamide; (1S,2S)-2-(Difluoromethyl)-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]cyclopropanecarboxamide; (1S,5R,6r)-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-oxabicyclo[3.1.0]hexane-6-carboxamide; (1S,2S)-N-[(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]-2-methyl-cyclopropanecarboxamide; (1S,2S)-2-(Difluoromethyl)-N-[(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]cyclopropanecarboxamide; (1S,5R,6r)-N-[(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]-3-oxabicyclo[3.1.0]hexane-6-carboxamide; (1S,2S)-2-(Difluoromethyl)-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-15,24-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]cyclopropanecarboxamide; (1S,5R,6r)-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-15,24-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]-3-oxabicyclo[3.1.0]hexane-6-carboxamide; (1S,5R,6r)-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-oxabicyclo[3.1.0]hexane-6-carboxamide; (1S,2S)-2-(Difluoromethyl)-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]cyclopropanecarboxamide; (1S,5R,6r)-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-oxabicyclo[3.1.0]hexane-6-carboxamide; (1R,2S)-2-Cyclopropyl-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]cyclopropanecarboxamide; (1S,2S)-N-[(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]-2-methyl-cyclopropanecarboxamide; (1S,2S)-N-[(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]-2-methyl-cyclopropanecarboxamide; 2,2-Difluoro-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]-1-methyl-cyclopropanecarboxamide; (1S,2S)-2-(Difluoromethyl)-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]cyclopropanecarboxamide; (1S,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]-2-phenyl-cyclopropanecarboxamide; (1r,2R,3S)-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]-2,3-dimethyl-cyclopropanecarboxamide; (1S,2S)-N-[(7S,13S)-(20M)-20-[5-[(9aS)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-2-[(1S)-1-methoxyethyl]-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]-2-methyl-cyclopropanecarboxamide; (1R,2R)-2-(2-fluorophenyl)-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]cyclopropanecarboxamide; (1S,2S)-2-(2-fluorophenyl)-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]cyclopropanecarboxamide; (1S,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]-2-(2-pyridyl)cyclopropanecarboxamide; (1S,2S)-N-[(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(29),2,5(31),19,25,27-hexaen-7-yl]-2-(difluoromethyl)cyclopropanecarboxamide; (1S,2R)-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]-2-methyl-cyclopropanecarboxamide; (1S,2S)-2-(Difluoromethyl)-N-[(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]cyclopropanecarboxamide; (1S,5R,6r)-N-[(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]-3-oxabicyclo[3.1.0]hexane-6-carboxamide; (1R,2S)-2-Cyclopropyl-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(29),2,5(31),19,25,27-hexaen-7-yl]cyclopropanecarboxamide; (1S,2S)-N-[(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]-2-methyl-cyclopropanecarboxamide; (1S,5R,6r)-N-[(7S,13S)-(20M)-20-[5-[(9aS)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-2-[(1S)-1-methoxyethyl]-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-oxabicyclo[3.1.0]hexane-6-carboxamide; (1S,2S)-N-[(7S,13S)-(20M)-20-[5-[(9aS)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-2-[(1S)-1-methoxyethyl]-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]-2-(difluoromethyl)cyclopropanecarboxamide; (1R,5S,6s)-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-oxabicyclo[3.1.0]hexane-6-carboxamide; (1S,2S)-N-[(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(29),2,5(31),19,25,27-hexaen-7-yl]-2-phenyl-cyclopropanecarboxamide; (1S,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-15,24-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(29),2,5(31),19,25,27-hexaen-7-yl]-2-phenyl-cyclopropanecarboxamide; (1r,2S,3R)-N-[(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]-2,3-dimethyl-cyclopropanecarboxamide; (1S,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(29),2,5(31),19,25,27-hexaen-7-yl]-2-phenyl-cyclopropanecarboxamide; (1S,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]-2-pyrimidin-5-yl-cyclopropanecarboxamide; (1S,5R)-3,3-Difluoro-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]bicyclo[3.1.0]hexane-6-carboxamide; (1S,2S)-N-[(7S,13S)-(20M)-20-[5-[(9aR)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-2-[(1S)-1-methoxyethyl]-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]-2-methyl-cyclopropanecarboxamide; (1S,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]-2-pyrimidin-4-yl-cyclopropanecarboxamide; (1S,2S)-N-[(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(29),2,5(31),19,25,27-hexaen-7-yl]-2-phenyl-cyclopropanecarboxamide; (1R,5S,6s)-N-[(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]-3-oxabicyclo[3.1.0]hexane-6-carboxamide; (1S,2S)-N-[(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]-2-methyl-cyclopropanecarboxamide; 2,2-Difluoro-N-[(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(29),2,5(31),19,25,27-hexaen-7-yl]-1-methyl-cyclopropanecarboxamide; N-[(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(29),2,5(31),19,25,27-hexaen-7-yl]-1,2-dimethyl-cyclopropanecarboxamide; (1S,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]-2-(3-pyridyl)cyclopropanecarboxamide; (1S,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]-2-(4-pyridyl)cyclopropanecarboxamide; (1R,2R)-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]-2-(4-pyridyl)cyclopropanecarboxamide; 2-(4-Fluorophenyl)-N-[(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(29),2,5(31),19,25,27-hexaen-7-yl]cyclopropanecarboxamide; (1S,5R,6r)-N-[(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]-3-oxabicyclo[3.1.0]hexane-6-carboxamide; (1r,2R,3S)-N-[(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]-2,3-dimethyl-cyclopropanecarboxamide; (1S,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]-2-pyridazin-3-yl-cyclopropanecarboxamide; (1R,2S)-2-Cyclopropyl-N-[(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(29),2,5(31),19,25,27-hexaen-7-yl]cyclopropanecarboxamide; 3,3-Difluoro-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]cyclopentanecarboxamide; 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]-2-oxabicyclo[2.1.1]hexane-1-carboxamide; (1S,2S)-N-[(7S,13S)-23,23-difluoro-(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]-2-methyl-cyclopropanecarboxamide; (1r,2R,3S)-N-[(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(29),2,5(31),19,25,27-hexaen-7-yl]-2,3-dimethyl-cyclopropanecarboxamide; (1r,2S,3R)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-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(28),2,5(31),19,25(29),26-hexaen-7-yl]-2,3-dimethyl-cyclopropanecarboxamide; trans-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(29),2,5(31),19,25,27-hexaen-7-yl]-4-(1-methyltetrazol-5-yl)cyclohexanecarboxamide; trans-4-hydroxy-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]-4-methyl-cyclohexanecarboxamide; 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]tricyclo[3.1.1.0 ３，６ ]heptane-6-carboxamide; (1r,2S,3R)-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]-2,3-dimethyl-cyclopropanecarboxamide; (1S,2S)-N-[(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]-2-methyl-cyclopropanecarboxamide; (1r,2S,3R)-N-[(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]-2,3-dimethyl-cyclopropanecarboxamide; 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]tetrahydropyran-4-carboxamide; (1S,2S)-N-[(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]-2-phenyl-cyclopropanecarboxamide; (1S,2S)-N-[(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]-2-phenyl-cyclopropanecarboxamide; (1S,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]-2-pyrimidin-2-yl-cyclopropanecarboxamide; (1R,2R)-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 ２１，２６ ]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]-2-pyrimidin-2-yl-cyclopropanecarboxamide; (1r,2S,3R)-N-[(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(29),2,5(31),19,25,27-hexaen-7-yl]-2,3-dimethyl-cyclopropanecarboxamide; (1r,2S,3R)-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-15,24-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]-2,3-dimethyl-cyclopropanecarboxamide; (1r,2R,3S)-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]-2,3-dimethyl-cyclopropanecarboxamide; (1r,2S,3R)-N-[(7S,13S)-23,23-difluoro-(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]-2,3-dimethyl-cyclopropanecarboxamide; (1S,2S)-N-[(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]-2-pyrimidin-5-yl-cyclopropanecarboxamide; (1S,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]-2-(3-pyridyl)cyclopropanecarboxamide; (1S,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]-2-(3-pyridyl)cyclopropanecarboxamide; (1S,2S)-N-[(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]-2-(3-pyridyl)cyclopropanecarboxamide; (1S,2S)-N-[(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]-2-(3-pyridyl)cyclopropanecarboxamide; (1S,2S)-N-[(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]-2-pyrimidin-5-yl-cyclopropanecarboxamide; (1S,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]-2-pyrimidin-5-yl-cyclopropanecarboxamide; (1S,2S)-N-[(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]-2-pyrimidin-5-yl-cyclopropanecarboxamide; (1S,2S)-N-[(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]-2-(3-pyridyl)cyclopropanecarboxamide; (1S,2S)-N-[(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]-2-(3-pyridyl)cyclopropanecarboxamide; (1S,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-15,24-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]-2-(3-pyridyl)cyclopropanecarboxamide; (1S,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]-2-pyrazin-2-yl-cyclopropanecarboxamide; (1r,2R,3S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,25-dioxa-4-thia-9,21,31,32-tetrazahexacyclo[24.3.1.1 ２，５ .1 ９，１３ .0 １９，２８ .0 ２１，２７ ]dotriaconta-1(29),2,5(32),19,26(30),27-hexaen-7-yl]-2,3-dimethyl-cyclopropanecarboxamide; (1r,2S,3R)-N-[(7S,13S)-(20M)-20-[5-[(9aR)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-2-[(1S)-1-methoxyethyl]-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]-2,3-dimethyl-cyclopropanecarboxamide; (1S,2S)-N-[(7S,13S)-(20M)-20-[5-[(9aR)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-2-[(1S)-1-methoxyethyl]-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]-2-(3-pyridyl)cyclopropanecarboxamide; (1S,2S)-N-[(7S,13S)-(20M)-20-[5-[(9aR)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-2-[(1S)-1-methoxyethyl]-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]-2-pyrimidin-5-yl-cyclopropanecarboxamide; (1S,2S)-N-[(7S,13S)-(20M)-20-[5-[(9aS)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-2-[(1S)-1-methoxyethyl]-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]-2-(3-pyridyl)cyclopropanecarboxamide; (1S,2S)-N-[(7S,13S)-(20M)-20-[5-[(9aS)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-2-[(1S)-1-methoxyethyl]-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]-2-pyrimidin-5-yl-cyclopropanecarboxamide; (1r,2R,3S)-N-[(7S,13S)-(20M)-20-[5-(4-cyclopropylpiperazin-1-yl)-2-[(1S)-1-methoxyethyl]-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]-2,3-dimethyl-cyclopropanecarboxamide; (1r,2R,3S)-N-[(7S,13S,23S)-23-hydroxy-(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]-2,3-dimethyl-cyclopropanecarboxamide; (1r,2R,3S)-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 ]Hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]-2,3-dimethyl-cyclopropanecarboxamide; (1r,2R,3S)-N-[(7S,13S)-20-[5-[4-(2,2-difluoroethyl)piperazin-1-yl]-2-[(1S)-1-methoxyethyl]-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]-2,3-dimethyl-cyclopropanecarboxamide; (1r,2R,3S)-N-[(7S,13S)-(20M)-20-[5-[4-(2-fluoroethyl)piperazin-1-yl]-2-[(1S)-1-methoxyethyl]-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]-2,3-dimethyl-cyclopropanecarboxamide; (1r,2R,3S)-N-[(7S,13S)-(20M)-20-[5-[4-(3-hydroxypropyl)piperazin-1-yl]-2-[(1S)-1-methoxyethyl]-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]-2,3-dimethyl-cyclopropanecarboxamide; (1R,2R)-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]-2-(4-methylpyrimidin-5-yl)cyclopropanecarboxamide; (1r,2R,3S)-N-[(7S,13S)-(20M)-20-[5-(4-ethylpiperazin-1-yl)-2-[(1S)-1-methoxyethyl]-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]-2,3-dimethyl-cyclopropanecarboxamide; (1R,2R)-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]-2-thiazol-4-yl-cyclopropanecarboxamide; (1r,2S,3R)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2-methoxyethyl)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]-2,3-dimethyl-cyclopropanecarboxamide; (1R,2R)-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]-2-(2-methyl-3-pyridyl)cyclopropanecarboxamide; (1r,2R,3S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-tetrahydropyran-4-ylpiperazin-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]-2,3-dimethyl-cyclopropanecarboxamide; (1r,2R,3S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(oxetan-3-yl)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]-2,3-dimethyl-cyclopropanecarboxamide; (1r,2S,3R)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-[[(2S)-morpholin-2-yl]methyl]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]-2,3-dimethyl-cyclopropanecarboxamide; (1R,2R)-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]-2-(5-methyl-3-pyridyl)cyclopropanecarboxamide; (1r,2R,3S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-[2-(2-oxopyrrolidin-1-yl)ethyl]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]-2,3-dimethyl-cyclopropanecarboxamide; (1r,2R,3S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2-tetrahydrofuran-3-yloxyethyl)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]-2,3-dimethyl-cyclopropanecarboxamide; (1r,2R,3S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(3-methoxy-3-methyl-butyl)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]-2,3-dimethyl-cyclopropanecarboxamide; (1r,2S,3R)-N-[(7S,13S)-29-fluoro-(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]-2,3-dimethyl-cyclopropanecarboxamide; (1S,2S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17,22,22-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]-2-methyl-cyclopropanecarboxamide; (1r,2R,3S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,31,32-tetrazahexacyclo[24.3.1.1 ２，５ .1 ９，１３ .0 １９，２８ .0 ２１，２７ ]dotriaconta-1(29),2,5(32),19,26(30),27-hexaen-7-yl]-2,3-dimethyl-cyclopropanecarboxamide; and (1r,2R,3S)-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-9,21,32,33-tetrazahexacyclo[25.3.1.1 ２，５ .1 ９，１３ .0 １９，２９ .0 ２１，２８ ]tritriaconta-1(30),2,5(33),19,27(31),28-hexaen-7-yl]-2,3-dimethyl-cyclopropanecarboxamide or a pharmaceutically acceptable salt thereof.

15. A compound selected from the following: or a pharmaceutically acceptable salt thereof.

16. a) in the presence of a coupling reagent and a base, a compound of formula (IIb): and acid (III), to form said compound of formula (Ib), In the formula, R １ , R ２ , M and L are as defined in any one of claims 1 to 13; and the coupling reagent is T ３ 16. A process for the preparation of a compound according to any one of claims 1 to 15, wherein the base is TEA, DIEPA or DMAP.

17. 16. A compound or a pharmaceutically acceptable salt according to any one of claims 1 to 15 for use as a therapeutically active substance.

18. A pharmaceutical composition comprising a compound according to any one of claims 1 to 15 and a pharmaceutically acceptable excipient.

19. Use of a compound according to any one of claims 1 to 15 for treating a KRAS G12C protein-related disease.

20. Use of a compound according to any one of claims 1 to 15 for treating KRAS G12C, G12D and G12V protein-associated diseases.

21. Use of a compound according to any one of claims 1 to 15 for inhibiting RAS interaction with downstream effectors, wherein said downstream effectors are RAF and PI3K.

22. Use of a compound according to any one of claims 1 to 15 for inhibiting proliferating oncogenic MAPK and PI3K signalling.

23. 16. Use of a compound of any one of claims 1 to 15 for the treatment or prevention of cancer in a subject in need thereof, wherein the cancer comprises a first RAS mutation that is G12C and a second RAS mutation at a position selected from the group consisting of V8A, V9Y, S17E, A59T, T58I, D69P, M72I, S65W, R68S, D92R, H95N, Y96D, Q99W and F156L.

24. 16. Use of a compound of any one of claims 1 to 15 for the preparation of a medicament for the treatment or prevention of cancer in a subject in need thereof, wherein the cancer comprises a first RAS mutation that is G12C and a second RAS mutation at a position selected from the group consisting of V8A, V9Y, S17E, A59T, T58I, D69P, M72I, S65W, R68S, D92R, H95N, Y96D, Q99W and F156L.

25. 16. Use of a compound according to any one of claims 1 to 15 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. 16. Use of a compound according to any one of claims 1 to 15 for the treatment or prevention of KRAS mutation-driven cancer, wherein said cancer is selected from pancreatic adenocarcinoma, colorectal cancer, and non-small cell lung cancer.

27. 16. Use of a compound according to any one of claims 1 to 15 for the treatment or prevention of a primary central nervous system (CNS) tumor with a RAS mutation or a RAS-driven cancer with brain metastasis, wherein the CNS tumor is a primary melanocytic tumor of the CNS with an NRAS mutation; and the cancer is selected from pancreatic adenocarcinoma, colorectal cancer, and non-small cell lung cancer.

28. 16. Use of a compound according to any one of claims 1 to 15 for the treatment or prevention of a primary central nervous system (CNS) tumor with a RAS mutation or a RAS-driven cancer with brain metastasis, wherein the CNS tumor is a primary melanocytic tumor of the CNS with an NRAS mutation; and the cancer is non-small cell lung cancer.

29. 16. The compound or pharmaceutically acceptable salt of any one of claims 1 to 15, 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.

30. 20. Use of a compound according to any one of claims 1 to 15 for the preparation of a medicament for the treatment or prevention of KRAS mutation-driven cancer, wherein the cancer is selected from pancreatic adenocarcinoma, colorectal cancer, and non-small cell lung cancer.

31. 16. A method for the treatment or prevention of KRAS mutation-driven cancer, wherein said cancer is selected from pancreatic adenocarcinoma, colorectal cancer, and non-small cell lung cancer, said method comprising administering a therapeutically effective amount of a compound of any one of claims 1 to 15.

32. 17. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 15 when produced according to the method of claim 16.

33. 10. The invention as hereinbefore described.

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