Haloindole macrocyclic compounds for the treatment of cancer

Abstract

The present invention relates to a compound of formula (I) TIFF2025519199000148.tif73170(wherein R 1 ~R 7 , A 1 and A 2 are as described herein), and pharmaceutically acceptable salts thereof, as well as compositions containing the compound and methods of using the compound.

Description

Technical Field

[0001] The present invention relates to organic compounds useful for treatment and / or prevention in mammals, particularly to the inhibition of KRAS G12C useful for treating cancer.

Background Art

[0002] RAS is one of the most well-known oncogenes. Approximately 30% of human cancers contain mutations in three of the most notable members, KRAS, HRAS, and NRAS, making them the most common cancer drivers. KRAS mutations are generally associated with poor prognosis, particularly in colorectal cancer, pancreatic cancer, and lung cancer. As the most frequently mutated RAS isoform, KRAS has been intensively studied in the past few years. Among the most commonly occurring KRAS alleles (including G12D, G12V, G12C, G13D, G12R, G12A, G12S, Q61H, etc.), G12C, G12D, and G12V represent more than half of all K-RAS-driven cancers across colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC), and lung adenocarcinoma (LUAD). Notably, KRAS wild-type amplification is also seen in approximately 7% of all KRAS-altered cancers (ovary, esophagogastric, uterus) and ranks among the top alterations.

[0003] All RAS proteins belong to the protein family of small GTPases that hydrolyze 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 form to an active form via binding to GTP and GDP, respectively. Under physiological conditions, the transition between these two states is regulated by guanine nucleotide exchange factors (GEFs), such as Son Of Sevenless Homolog 1 (SOS1), or GTPase-activating proteins (GAPs) that catalyze the exchange of GDP for GTP, enhance the intrinsic GTPase activity, or promote RAS-mediated GTP hydrolysis. In response to extracellular stimuli, inactive RAS-GDP is converted to active RAS-GTP that directly binds to the RAF RAS-binding domain (RAF RBD ), recruits the RAF kinase family from the cytoplasm to the membrane, where it dimerizes and becomes active. Subsequently, activated RAF performs a series of phosphorylation reactions on its downstream mitogen-activated protein kinases (MEK) and extracellular signal-regulated kinases (ERK), propagating the growth signal. Among the RAF family of protein kinases (three known isoforms ARAF, BRAF, CRAF / RAF1), BRAF is the most frequently mutated and remains the most potent activator of MEK. Despite revealing different binding preferences for individual RAS and RAF family members, all RAFs have a conserved RBD for the forward transmission of MAPK signaling, which is frequently used to characterize KRAS inhibition (e.g., KRAS-BRAF in this specification RBD ). In the case of KRAS, mutations at positions 12, 13, 61, and 146 result in a shift to the active KRAS form by impairing nucleotide hydrolysis or activating nucleotide exchange, leading to hyperactivation of the MAPK pathway that culminates in tumorigenesis.

[0005] Despite its well-recognized importance in cancer malignancy, past continuous efforts have not been able to develop an approved therapy for KRAS mutant cancers until recently, and the first-choice drug AMG510 was rapidly approved as a second-line treatment in KRAS G12C-driven non-small cell lung cancer (NSCLC). Nevertheless, clinically acquired resistance to KRAS G12C inhibitors strictly appears with disease progression after about 6 months of treatment. All mutations converge to reactivate RAS-MAPK signaling, and secondary RAS mutants in cancer hotspots (e.g., G12 / G13 / Q61) and within the switch II pocket (e.g., H95, R68, and Y96) have been observed. Furthermore, more than 85% of all KRAS mutant or wild-type amplified-driven cancers still lack novel drugs. In summary, both numerous escape mechanisms and various cancer alleles highlight the urgent medical need for further KRAS therapies. Thus, the inventors have invented an oral compound that targets and inhibits KRAS alleles for the treatment of KRAS mutant-driven cancers.

SUMMARY OF THE INVENTION

[0006] The present invention relates to a novel compound of formula (I), TIFF2025519199000002.tif73170wherein, R 1 is TIFF2025519199000003.tif291701-oxo-2,7-diazaspiro[4.4]nonanyl substituted with (dihaloC 1-6 alkyl)carbonyl, (dihaloC 1-6 alkyl)carbonyl, (dihaloC 1-6 alkyl)carbonyl, (dihaloC 1-6 alkyl)carbonyl, (dihaloC 1-65-oxo-2,6-diazaspiro[3.5]nonanyl substituted with (alkyl)carbonyl, (dihaloC 1-6 6-oxo-2,7-diazaspiro[4.5]decanil substituted with (alkyl)carbonyl, or (dihaloC 1-6 azetidinyl oxyC substituted with (alkyl)carbonyl 1-6 is alkyl; wherein R 8 is C 1-6 alkyl; R 9 is halogen and piperidinyl disubstituted with (dihaloC 1-6 (alkyl)carbonyl, or pyrrolidinyl substituted with (dihaloC 1-6 (alkyl)carbonyl; R 2 is C 1-6 alkyl; R 3 is H, C 1-6 alkyl or halogen; R 4 is H or halogen; R 5 is C 1-6 alkyl or haloC 1-6 alkyl; R 6 is C 1-6 alkoxyC 1-6 alkyl; R 7 is morpholinyl, (haloC 1-6 (alkyl)piperazinyl or C 1-6 alkylpiperazinyl; A 1 is thiazolylene or phenylene substituted with hydroxy; A 2 is C 1-6 alkylene; provided that R 3 and R 4 are not simultaneously H, relates to a compound or a pharmaceutically acceptable salt thereof.

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

[0008] The compounds of formula (I) or (Ia) show good KRAS inhibition against G12C, G12D and G12V. In another embodiment, the compounds of the invention showed excellent cancer cell inhibition and human hepatocyte stability. Furthermore, the compounds of formula (I) or (Ia) also show good or improved cytotoxicity and solubility profiles. Furthermore, the compounds of the invention addressed the problem of GSH toxicity compared to the reference compounds. BRIEF DESCRIPTION OF THE DRAWINGS

[0009]

Figure 1

Figure 2

Figure 3

[0010] Definitions The term "C 1-6 alkyl" refers to a saturated straight-chain or branched-chain alkyl group containing 1 to 6, especially 1 to 4 carbon atoms, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl and the like. Certain "C 1-6 alkyl" groups are methyl, ethyl, and n-propyl.

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

[0012] The terms "halogen" and "halo" are used interchangeably herein and denote fluoro, chloro, bromo, or iodo.

[0013] The term "haloindole" denotes an indole in which one or more hydrogen atoms are replaced by the same or different halogen atoms.

[0014] "Dihalo C 1-6 alkyl" denotes a C 1-6 alkyl group in which two hydrogen atoms of the C 1-6 alkyl group are replaced by the same or different halogen atoms. Examples of dihalo C 1-6 alkyl include difluoro or chloro(fluoro)-methyl, -ethyl or -propyl, especially difluoropropyl, difluoromethyl, difluoroethyl or chloro(fluoro)methyl.

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

[0016] The term "phenylene" denotes a divalent phenyl group.

[0017] The term "piperidinylene" denotes a divalent piperidinyl group.

[0018] The term "pyrrolidinylene" denotes a divalent pyrrolidinyl group.

[0019] The term "thiazolylene" denotes a divalent thiazolyl group.

[0020] The term "oxo" refers to the divalent oxygen atom =O.

[0021] The term "azetidinyl oxy" refers to azetidinyl -O-.

[0022] The term "dimethylmethylene" refers to TIFF2025519199000004.tif15170.

[0023] The term "protecting group" refers to a group that selectively blocks a reaction site in a polyfunctional compound so that a chemical reaction can be carried out selectively at another unprotected reaction site in the meaning customarily associated with synthetic chemistry. The protecting group can be removed at an appropriate point. Exemplary protecting groups are amino protecting groups, carboxy protecting groups, or hydroxy protecting groups.

[0024] One of ordinary skill in the art will understand that the following structures of the compounds of formula (Ia) and (Ia') are identical, especially with respect to the chiral centers. TIFF2025519199000005.tif126170

[0025] The term "pharmaceutically acceptable salt" means a salt that is not biologically or otherwise undesirable. Pharmaceutically acceptable salts include both acid addition salts and base addition salts.

[0026] The term "pharmaceutically acceptable acid addition salts" refers to pharmaceutically acceptable salts formed from organic acids selected from aliphatic, alicyclic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and 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.

[0027] The term "pharmaceutically acceptable base addition salts" means pharmaceutically acceptable salts formed with organic or inorganic bases. Examples of acceptable inorganic bases include sodium salts, potassium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, and aluminum salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include primary, secondary, and tertiary amines, salts of substituted amines, such as natural substituted amines, cyclic amines, and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperidine, piperidine, N-ethylpiperidine, and polyamine resins.

[0028] The term "pharmaceutically active metabolite" refers to a pharmacologically active product produced through the metabolism in vivo of a specific compound or its salt. After entering the body, most drugs serve as substrates for chemical reactions that can change their physical properties and biological effects. These metabolic conversions usually affect the polarity of the compounds of the present invention and change the way the drugs are distributed in and excreted from the body. However, in some cases, drug metabolism is required for a therapeutic effect.

[0029] The term "therapeutically effective amount" refers to an amount of a compound or molecule of the present invention that, when administered to a subject, (i) treats or prevents a specific disease, symptom, or disorder, (ii) attenuates, alleviates, or eliminates one or more symptoms of a specific disease, symptom, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a specific disease, symptom, or disorder described herein. The therapeutically effective amount will vary depending on the compound, the condition of the disease 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.

[0030] The term "pharmaceutical composition" refers to a mixture or solution containing a therapeutically effective amount of an active pharmaceutical ingredient together with pharmaceutically acceptable additives, which is administered to a mammal, such as a human in need thereof.

[0031] The terms "pharmaceutically acceptable additive", "pharmaceutically acceptable carrier", and "therapeutically inert additive" are used interchangeably and refer to any pharmaceutically acceptable component that has no therapeutic activity and is non-toxic to the subject being administered and is used in the formulation of a medicament, such as a disintegrant, binder, filler, solvent, buffer, isotonic agent, stabilizer, antioxidant, surfactant, carrier, diluent, or lubricant.

[0032] Inhibitor of KRAS The present invention relates to (i) a compound of formula (I), wherein TIFF2025519199000006.tif73170 wherein, R 1 is TIFF2025519199000007.tif29170(Di halo C 1-6 alkyl) carbonyl substituted 1 - oxo - 2,7 - diazaspiro[4.4]nonanyl, (Di halo C 1-6 alkyl) carbonyl substituted 1 - oxo - 2,8 - diazaspiro[4.5]decanyl, (Di halo C 1-6 alkyl) carbonyl substituted 1 - oxo - 2,9 - diazaspiro[5.5]undecanyl, (Di halo C 1-6 alkyl) carbonyl substituted 5 - oxo - 2,6 - diazaspiro[3.4]octanyl, (Di halo C 1-6 alkyl) carbonyl substituted 5 - oxo - 2,6 - diazaspiro[3.5]nonanyl, (Di halo C 1-6 alkyl) carbonyl substituted 6 - oxo - 2,7 - diazaspiro[4.5]decanyl, or (Di halo C 1-6 alkyl) carbonyl substituted azetidinyl oxy C 1-6 alkyl; wherein, R 8 is 1-6 alkyl; R 9 is halogen and piperidinyl twice substituted with (di halo C 1-6 alkyl) carbonyl, or pyrrolidinyl substituted with (di halo C 1-6 alkyl) carbonyl; R 2 is 1-6 alkyl; R 3 is H, C 1-6 alkyl or halogen; R 4 is H or halogen; R 5 is 1-6 alkyl or halo C1-6 is alkyl; R 6 is C 1-6 alkoxy C 1-6 is alkyl; R 7 is morpholinyl, (halo C 1-6 alkyl)piperazinyl or C 1-6 alkylpiperazinyl; A 1 is thiazolylene or phenylene substituted with hydroxy; A 2 is C 1-6 is alkylene; provided that R 3 and R 4 are not simultaneously H, relates to a compound, or a pharmaceutically acceptable salt thereof.

[0033] Another embodiment of the present invention is a compound of formula (Ia), TIFF2025519199000008.tif73170wherein, R 1 is TIFF2025519199000009.tif291701-oxo-2,7-diazaspiro[4.4]nonanyl substituted with (dihalo C 1-6 alkyl)carbonyl, (dihalo C 1-6 alkyl)carbonyl-substituted 1-oxo-2,8-diazaspiro[4.5]decanyl, (dihalo C 1-6 alkyl)carbonyl-substituted 1-oxo-2,9-diazaspiro[5.5]undecanyl, (dihalo C 1-6 alkyl)carbonyl-substituted 5-oxo-2,6-diazaspiro[3.4]octanyl, (dihalo C 1-6 alkyl)carbonyl-substituted 5-oxo-2,6-diazaspiro[3.5]nonanyl, (dihalo C 1-66-oxo-2,7-diazaspiro[4.5]decan-1-yl substituted with (alkyl)carbonyl, or (dihaloC 1-6 azetidinyl oxyC substituted with (alkyl)carbonyl 1-6 alkyl; wherein R 8 is C 1-6 alkyl; R 9 is halogen and piperidinyl disubstituted with (dihaloC 1-6 alkyl)carbonyl, or pyrrolidinyl substituted with (dihaloC 1-6 alkyl)carbonyl; R 2 is C 1-6 alkyl; R 3 is H, C 1-6 alkyl or halogen; R 4 is H or halogen; R 5 is C 1-6 alkyl or haloC 1-6 alkyl; R 6 is C 1-6 alkoxyC 1-6 alkyl; R 7 is morpholinyl, (haloC 1-6 alkyl)piperazinyl or C 1-6 alkylpiperazinyl; A 1 is thiazolylene or phenylene substituted with hydroxy; A 2 is C 1-6 alkylene; provided that R 3 and R 4 are not simultaneously H, a compound, or a pharmaceutically acceptable salt thereof.

[0034] A further embodiment of the present invention is a compound of formula (I) or (Ia) according to (iii) (i) or (ii), or a pharmaceutically acceptable salt thereof, wherein R 1 is TIFF2025519199000010.tif29170 1-oxo-2,7-diazaspiro[4.4]nonanyl substituted with (dihaloC 1-6 alkyl)carbonyl, (dihaloC 1-6 alkyl)carbonyl-substituted 1-oxo-2,8-diazaspiro[4.5]decan-2-yl, (dihaloC 1-6 alkyl)carbonyl-substituted 1-oxo-2,9-diazaspiro[5.5]undecan-2-yl, or (dihaloC 1-6 alkyl)carbonyl-substituted 5-oxo-2,6-diazaspiro[3.4]octan-2-yl; wherein R 8 is 1-6 alkyl; R 9 is piperidinyl disubstituted with halogen and (dihaloC 1-6 alkyl)carbonyl, or pyrrolidinyl substituted with (dihaloC 1-6 alkyl)carbonyl. A further embodiment of the present invention is a compound of formula (I) or (Ia) according to any one of (iv) (i) to (iii), or a pharmaceutically acceptable salt thereof, wherein R 1 is TIFF2025519199000011.tif29170 1-oxo-2,7-diazaspiro[4.4]nonan-2-yl substituted with chloro(fluoro)acetyl, 1-oxo-2,8-diazaspiro[4.5]decan-2-yl substituted with chloro(fluoro)acetyl, 1-oxo-2,9-diazaspiro[5.5]undecan-2-yl substituted with chloro(fluoro)acetyl, or It is 5-oxo-2,6-diazaspiro[3.4]octan-6-yl substituted with chloro(fluoro)acetyl; wherein R 8 is methyl; R 9 is piperidinyl disubstituted with fluoro and chloro(fluoro)acetyl, or pyrrolidinyl substituted with chloro(fluoro)acetyl.

[0035] A further embodiment of the present invention is a compound of formula (I) or (Ia) according to any one of (v)(i)-(iv), wherein R 1 is (5R)-7-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl, (5S)-7-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl, 8-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,8-diazaspiro[4.5]decane-2-yl, 9-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,9-diazaspiro[5.5]undecane-2-yl, 2-[(2R)-2-chloro-2-fluoro-acetyl]-5-oxo-2,6-diazaspiro[3.4]octan-6-yl, 1-[(2R)-2-chloro-2-fluoro-acetyl]-4-fluoro-4-piperidinyl or 1-[(2R)-2-chloro-2-fluoro-acetyl]pyrrolidin-3-yl.

[0036] A further embodiment of the present invention is (vi) a compound of formula (I) or (Ia) according to any one of (i)-(v), or a pharmaceutically acceptable salt thereof, wherein R 2 is isopropyl.

[0037] A further embodiment of the present invention is (vii) a compound of formula (I) or (Ia) according to any one of (i)-(vi), or a pharmaceutically acceptable salt thereof, wherein R 3 is H, methyl or fluoro.

[0038] A further embodiment of the present invention is a compound of formula (I) or (Ia) according to any one of (i) to (vii) or a pharmaceutically acceptable salt thereof, wherein (viii) R 3 is fluoro.

[0039] A further embodiment of the present invention is a compound of formula (I) or (Ia) according to any one of (i) to (viii) or a pharmaceutically acceptable salt thereof, wherein (ix) R 4 is H or fluoro.

[0040] A further embodiment of the present invention is a compound of formula (I) or (Ia) according to any one of (i) to (ix) or a pharmaceutically acceptable salt thereof, wherein (x) R 4 is H.

[0041] A further embodiment of the present invention is a compound of formula (I) or (Ia) according to any one of (i) to (x) or a pharmaceutically acceptable salt thereof, wherein (xi) R 5 is ethyl or 2,2,2-trifluoroethyl.

[0042] A further embodiment of the present invention is a compound of formula (I) or (Ia) according to any one of (i) to (xi) or a pharmaceutically acceptable salt thereof, wherein (xii) is 1-methoxyethyl.

[0043] A further embodiment of the present invention is a compound of formula (I) or (Ia) according to any one of (i) to (xii) or a pharmaceutically acceptable salt thereof, wherein (xiii) R 7 is morpholinyl, 4-(2,2,2-trifluoroethyl)piperazin-1-yl or 4-methylpiperazin-1-yl.

[0044] A further embodiment of the present invention is a compound of formula (I) or (Ia) according to any one of (i) to (xiii) or a pharmaceutically acceptable salt thereof, wherein (xiv) A 1 is TIFF2025519199000012.tif20170, and is a compound of formula (I) or (Ia) according to any one of (i) to (xiii) or a pharmaceutically acceptable salt thereof, wherein the linking "a" is attached to the indole ring.

[0045] A further embodiment of the present invention is (xv) A 2 is dimethylmethylene, and is a compound of formula (I) or (Ia) according to any one of (i) to (xiv) or a pharmaceutically acceptable salt thereof.

[0046] Another embodiment of the present invention is a compound of formula (I) or (Ia) according to (xvi) (i) or (ii), wherein R 1 is 1-oxo-2,7-diazaspiro[4.4]nonanyl substituted with TIFF2025519199000013.tif29170 (dihalo C 1-6 alkyl)carbonyl, (dihalo C 1-6 alkyl)carbonyl-substituted 1-oxo-2,8-diazaspiro[4.5]decanyl, (dihalo C 1-6 alkyl)carbonyl-substituted 1-oxo-2,9-diazaspiro[5.5]undecanyl, or (dihalo C 1-6 alkyl)carbonyl-substituted 5-oxo-2,6-diazaspiro[3.4]octanyl; wherein R 8 is C 1-6 alkyl; R 9 is piperidinyl disubstituted with halogen and (dihalo C 1-6 alkyl)carbonyl, or pyrrolidinyl substituted with (dihalo C 1-6 alkyl)carbonyl; R 2 is C 1-6 alkyl; R 3 is halogen; R 4is H; R 5 is C 1-6 alkyl or halo C 1-6 alkyl; R 6 is C 1-6 alkoxy C 1-6 alkyl; R 7 is morpholinyl, (halo C 1-6 alkyl) piperazinyl or C 1-6 alkyl piperazinyl; A 1 is TIFF2025519199000014.tif20170, and the bond "a" is attached to the indole ring; A 2 is C 1-6 alkylene, a compound, or a pharmaceutically acceptable salt thereof.

[0047] Another embodiment of the present invention is a compound of formula (I) or (Ia) according to (xvii)(xvi), wherein R 1 is (5R)-7-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl, (5S)-7-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl, 8-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,8-diazaspiro[4.5]decane-2-yl, 9-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,9-diazaspiro[5.5]undecane-2-yl, 2-[(2R)-2-chloro-2-fluoro-acetyl]-5-oxo-2,6-diazaspiro[3.4]octane-6-yl, 1-[(2R)-2-chloro-2-fluoro-acetyl]-4-fluoro-4-piperidinyl or 1-[(2R)-2-chloro-2-fluoro-acetyl]pyrrolidin-3-yl; R 2 is isopropyl; R 3 is fluoro; R 4 is H; R 5 is ethyl or 2,2,2-trifluoroethyl; R 6 is (1S)-1-methoxyethyl; R 7 is morpholinyl, 4-(2,2,2-trifluoroethyl)piperazin-1-yl or 4-methylpiperazin-1-yl; A 1 is TIFF2025519199000015.tif20170, and the bond "a" is attached to the indole ring; A 2 is dimethylmethylene, a compound, or a pharmaceutically acceptable salt thereof.

[0048] Another embodiment of the present invention is a compound of formula (I) or (Ia) selected from (xviii) the following: (3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(7S,13S)-25-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaene-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide; (3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide; (3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17,24-trimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide; (2S)-2-[(5R)-7-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butanamide; (2S)-2-[(5S)-7-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butanamide; (2S)-2-[9-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,9-diazaspiro[5.5]undecan-2-yl]-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butanamide; (3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(8S,14S)-25-fluoro-4-hydroxy-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-18,18-dimethyl-9,15-dioxo-22-(2,2,2-trifluoroethyl)-16-oxa-10,22,28-triazapentacyclo[18.5.2.1 2,6 .1 10,14 .023,27 Nonacosa-1(26),2,4,6(29),20,23(27),24-heptaen-8-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide; 1-[(2R)-2-chloro-2-fluoro-acetyl]-4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17,24-trimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide; 1-[(2R)-2-chloro-2-fluoro-acetyl]-4-fluoro-N-[(1S)-1-[[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide; (2S)-2-[2-[(2R)-2-chloro-2-fluoro-acetyl]-5-oxo-2,6-diazaspiro[3.5]nonan-6-yl]-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butanamide; (2R)-2-[[1-[(2R)-2-chloro-2-fluoro-acetyl]azetidin-3-yl]oxymethyl]-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butanamide; (2S)-2-[[1-[(2R)-2-chloro-2-fluoro-acetyl]azetidin-3-yl]oxymethyl]-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butanamide; (2S)-2-[8-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,8-diazaspiro[4.5]decane-2-yl]-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butanamide; (2S)-2-[(5S)-2-[(2R)-2-chloro-2-fluoro-acetyl]-6-oxo-2,7-diazaspiro[4.5]decane-7-yl]-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butanamide; (2S)-2-[(5R)-2-[(2R)-2-chloro-2-fluoro-acetyl]-6-oxo-2,7-diazaspiro[4.5]decane-7-yl]-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butanamide; (2S)-2-[9-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,9-diazaspiro[5.5]undecan-2-yl]-N-[(7S,13S)-25-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butanamide; (2S)-2-[(5R)-2-[(2S)-2-chloro-2-fluoro-acetyl]-6-oxo-2,7-diazaspiro[4.5]decane-7-yl]-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butanamide; (2S)-2-[(5S)-2-[(2S)-2-chloro-2-fluoro-acetyl]-6-oxo-2,7-diazaspiro[4.5]decane-7-yl]-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .022,26 Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butanamide; (3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide; (2S)-2-[2-[(2R)-2-chloro-2-fluoro-acetyl]-5-oxo-2,6-diazaspiro[3.4]octan-6-yl]-N-[(7S,13S)-24-fluoro-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butanamide; (3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .022,26 Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide; (3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(8S,14S)-26-fluoro-4-hydroxy-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-18,18-dimethyl-9,15-dioxo-22-(2,2,2-trifluoroethyl)-16-oxa-10,22,28-triazapentacyclo[18.5.2.1 2,6 .1 10,14 .0 23,27 Nonacosa-1(26),2,4,6(29),20,23(27),24-heptaen-8-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide; (2S)-2-[8-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,8-diazaspiro[4.5]decane-2-yl]-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butanamide; (2S)-2-[2-[(2R)-2-chloro-2-fluoro-acetyl]-5-oxo-2,6-diazaspiro[3.4]octane-6-yl]-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.12,5 .1 9,13 .0 22,26 Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butanamide; (2S)-2-[(5R)-7-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butanamide; (2S)-2-[(5S)-7-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butanamide; (3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .022,26 Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide; (3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(7S,13S)-21-ethyl-24-fluoro-(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-9,21,27,28-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide; 1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-4-fluoro-N-methyl-piperidine-4-carboxamide; (2S)-2-[(5R)-7-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-N-[(7S,13S)-21-ethyl-24-fluoro-(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-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butanamide; (2S)-2-[(5S)-7-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-N-[(7S,13S)-21-ethyl-24-fluoro-(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-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butanamide; (2S)-2-[9-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,9-diazaspiro[5.5]undecan-2-yl]-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butanamide; (2S)-2-[2-[(2R)-2-chloro-2-fluoro-acetyl]-5-oxo-2,6-diazaspiro[3.4]octan-6-yl]-N-[(7S,13S)-21-ethyl-24-fluoro-(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-9,21,27,28-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butanamide; (2S)-2-[8-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,8-diazaspiro[4.5]decane-2-yl]-N-[(7S,13S)-21-ethyl-24-fluoro-(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-9,21,27,28-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butanamide; (2R)-2-[[1-[(2R)-2-chloro-2-fluoro-acetyl]azetidin-3-yl]oxymethyl]-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butanamide; (2S)-2-[[1-[(2R)-2-chloro-2-fluoro-acetyl]azetidin-3-yl]oxymethyl]-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butanamide; (2S)-2-[9-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,9-diazaspiro[5.5]undecan-2-yl]-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butanamide; (2S)-2-[(5R)-7-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-N-[(7S,13S)-24-fluoro-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .19,13 .0 22,26 Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butanamide; (2S)-2-[(5S)-7-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butanamide; 1-[(2R)-2-chloro-2-fluoro-acetyl]-4-fluoro-N-[(1S)-1-[[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide; (2S)-2-[2-[(2R)-2-chloro-2-fluoro-acetyl]-5-oxo-2,6-diazaspiro[3.4]octan-6-yl]-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butanamide; (2S)-2-[8-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,8-diazaspiro[4.5]decane-2-yl]-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butanamide; (2S)-2-[9-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,9-diazaspiro[5.5]undecane-2-yl]-N-[(7S,13S)-21-ethyl-24-fluoro-(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-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butanamide; 1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(7S,13S)-21-ethyl-24-fluoro-(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-9,21,27,28-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-4-fluoro-N-methyl-piperidine-4-carboxamide; (2S)-2-[8-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,8-diazaspiro[4.5]decane-2-yl]-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butanamide; (2S)-2-[(5S)-7-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,7-diazaspiro[4.4]nonane-2-yl]-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butanamide; (2S)-2-[(5R)-7-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butanamide; (2S)-2-[2-[(2R)-2-chloro-2-fluoro-acetyl]-5-oxo-2,6-diazaspiro[3.4]octan-6-yl]-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butanamide; 1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-4-fluoro-N-methyl-piperidine-4-carboxamide; (3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide; (2S)-2-[(5S)-7-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butanamide; and (2S)-2-[2-[(2R)-2-chloro-2-fluoro-acetyl]-5-oxo-2,6-diazaspiro[3.4]octan-6-yl]-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .19,13 .0 22,26 [[ID=]], - octacosa-1(25),2,5(28),19,22(26),23 - hexaen-7-yl - 3 - methyl - butanamide; or a pharmaceutically acceptable salt thereof.

[0049] Another embodiment of the present invention relates to a compound having the structure (xix) below: TIFF2025519199000016.tif83170.

[0050] Another embodiment of the present invention is a process for preparing a compound according to any one of (xx) (i) to (xix), comprising any of the following steps: a) A coupling reaction of a compound of formula (II), TIFF2025519199000017.tif54170 (II) and an acid (III), TIFF2025519199000018.tif23170 (III) in the presence of a coupling reagent and a base to form a compound of formula (I); b) A coupling reaction of a compound of formula (VI), TIFF2025519199000019.tif73170 and an acid (VII), TIFF2025519199000020.tif16170 (VII) in the presence of a coupling reagent and a base to form a compound of formula (VIII), TIFF2025519199000021.tif73170; c) A coupling reaction of a compound of formula (XI), TIFF2025519199000022.tif73170 and an acid (XII), TIFF2025519199000023.tif16170 (XII) in the presence of a coupling reagent and a base to form a compound of formula (XIII), TIFF2025519199000024.tif73170. In the formula, Q is unsubstituted or substituted piperidinylene or pyrrolidinylene; T is dihalo C 1-6 alkyl; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , A 1 and A 2 are defined in the same manner as any one of (i) to (xvii); the coupling reagent in steps a) to c) is T3P, HATU, PyBOP or EDCI / HOBt; the base in steps a) to c) is TEA, DIEPA or DMAP, relating to the process.

[0051] Another embodiment of the present invention is a compound or pharmaceutically acceptable salt according to any one of (i) to (xix) for use as a therapeutic active substance.

[0052] Another embodiment of the present invention relates to a pharmaceutical composition comprising a compound according to any one of (i) to (xix) and a pharmaceutically acceptable additive.

[0053] Another embodiment of the present invention is the use of a compound according to any one of (i) to (xix) for treating a KRAS G12C protein-related disease.

[0054] Another embodiment of the present invention is the use of a compound according to any one of (i) to (xix) for treating a disease related to KRAS G12C, G12D and G12V proteins.

[0055] Another embodiment of the present invention is the use of a compound according to any one of (i) to (xix) for inhibiting the RAS interaction with downstream effectors, wherein the downstream effectors are RAF and PI3K.

[0056] Another embodiment of the present invention is the use of a compound according to any one of (i) to (xix) for inhibiting propagating cancerous MAPK and PI3K signaling.

[0057] Another embodiment of the present invention is the use of a compound according to any one of (i) to (xix) for the treatment or prevention of KRAS mutant-driven cancer, wherein the cancer is selected from pancreatic cancer, colorectal cancer, lung cancer, esophageal cancer, gallbladder cancer, melanoma, ovarian cancer and endometrial cancer.

[0058] Another embodiment of the present invention is the use of a compound according to any one of (i) to (xix) for the treatment or prevention of KRAS mutant-driven cancer, wherein the cancer is selected from pancreatic adenocarcinoma, colorectal cancer and non-small cell lung cancer.

[0059] Another embodiment of the present invention is a compound according to any one of (i) to (xix) or a pharmaceutically acceptable salt thereof for the treatment or prevention of KRAS mutant-driven cancer, wherein the cancer is selected from pancreatic adenocarcinoma, colorectal cancer and non-small cell lung cancer.

[0060] Another embodiment of the present invention is the use of a compound according to any one of (i) to (xix) for the preparation of a medicament for the treatment or prevention of KRAS mutant-driven cancer, wherein the cancer is selected from pancreatic adenocarcinoma, colorectal cancer and non-small cell lung cancer.

[0061] Another embodiment of the present invention is a method for the treatment or prevention of KRAS mutant-driven cancer, comprising administering a therapeutically effective amount of a compound as defined in any one of (i) to (xix), wherein the cancer is selected from pancreatic adenocarcinoma, colorectal cancer and non-small cell lung cancer.

[0062] Another embodiment of the present invention is a compound according to any one of (i) to (xix) or a pharmaceutically acceptable salt thereof when produced according to the process of (xx).

[0063] Pharmaceutical Compositions and Administration Another embodiment provides a pharmaceutical composition or medicament containing a compound of the present invention and a therapeutically inactive carrier, diluent or additive, and a method of using the compound of the present invention for preparing such compositions and medicaments. In one example, a compound of formula (I) can be formulated into a crude drug dosage form by mixing it with a physiologically acceptable carrier, i.e., a carrier that is non-toxic to the recipient at the dosage and concentration used, at ambient temperature, at an appropriate pH, and at the desired degree of purity. The pH of the formulation mainly depends on the specific use and the concentration of the compound, but is preferably somewhere in the range of about 3 to about 8. In one example, a compound of formula (I) is formulated in an acetate buffer at pH 5. In another embodiment, a 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.

[0064] The compositions are formulated, dosed, and administered in a manner consistent with good medical practice. Factors to be considered in this regard include the specific disorder being treated, the specific mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of drug delivery, the method of administration, the dosing schedule, and other factors known to medical practitioners. The "effective amount" of the compound administered is governed by such considerations and is the minimum amount necessary to inhibit the interaction between mutant RAS (e.g., KRAS G12C) and RAF and block oncogenic MAPK signaling. For example, such an amount may be below an amount that is toxic to normal cells or to the mammal as a whole.

[0065] In one example, the pharmaceutically effective amount of the compound of the present invention administered parenterally per dose ranges from about 0.1 to 1000 mg / kg of the patient's body weight per day, or from about 0.1 to 1000 mg / kg of the patient's body weight per day, and a typical initial range of the compound used is 0.3 to 15 mg / kg / day. In another embodiment, oral unit dosage forms such as tablets and capsules preferably contain about 1 to about 1000 mg of the compound of the present invention.

[0066] The compounds of the present invention can be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intralung, intradermal, intrathecal and epidural, as well as intranasal, and, if desired for local treatment, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

[0067] The compounds of the present invention can be administered in any convenient dosage form, such as tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions can contain ingredients conventional in pharmaceutical formulations, such as diluents, carriers, pH adjusters, sweeteners, bulking agents and additional active agents.

[0068] Typical formulations are prepared by mixing the compounds of the present invention with carriers or additives. Suitable carriers and additives are well known to those skilled in the art and are described in detail, for example, in Ansel, Howard C., et al., Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. The formulations can also contain one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifying agents, flow promoters, processing aids, colorants, sweeteners, flavors, fragrances, diluents and other known additives to provide an attractive appearance for the drug (i.e., the compound of the present invention or its pharmaceutical composition) or to assist in the manufacture of the pharmaceutical product (i.e., the medicine).

[0069] Examples of suitable oral dosage forms are tablets containing from about 1 to 1000 mg of anhydrous lactose, from about 1 to 1000 mg of croscarmellose sodium, from about 1 to 1000 mg of polyvinylpyrrolidone (PVP) K30, and from about 1 to 1000 mg of magnesium stearate, and from about 1 to 1000 mg of the compound of the present invention. The powdered components are first mixed together and then mixed with a solution of PVP. The resulting composition can be dried, granulated, mixed with magnesium stearate, and compressed into tablet form using conventional equipment. Examples of aerosol formulations can be prepared by dissolving, for example, 5 to 400 mg of the compound of the present invention in a suitable buffer solution, such as a phosphate buffer, and adding salts, such as sodium chloride, as an isotonic agent, if desired. The solution can be filtered, for example, using a 0.2 micron filter to remove impurities and contaminants.

[0070] Accordingly, one embodiment includes a pharmaceutical composition comprising a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof. In a further embodiment, it includes a pharmaceutical composition comprising a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or additive.

[0071] Another embodiment includes a pharmaceutical composition comprising a compound of formula (I) for use in the treatment of mutant KRAS-driven cancer. Another embodiment includes a pharmaceutical composition comprising a compound of formula (I) for use in the treatment of mutant KRAS-driven cancer.

[0072] The following Examples A and B illustrate typical compositions of the present invention, but serve merely as representatives thereof.

[0073] Example A The compound of the present invention can be used as an active ingredient in a manner known per se to produce tablets of the following composition. Per tablet Active ingredient 200 mg Microcrystalline cellulose 155 mg Corn starch 25 mg Talc 25 mg Hydroxypropylmethylcellulose 20 mg 425 mg

[0074] Example B The compounds of the present invention can be used as active ingredients in a manner known per se for producing capsules of the following composition. Per capsule Active ingredient 100.0 mg Corn starch 20.0 mg Lactose 95.0 mg Talc 4.5 mg Magnesium stearate 0.5 mg 220.0 mg

[0075] Indications and treatment methods The compounds of the present invention drive the formation of a high-affinity ternary complex between the KRAS protein and cyclophilin A (CYPA), which is widely expressed, thereby inducing a new binding pocket in KRAS, which inhibits the interaction of KRAS with downstream effectors such as RAF and PI3K. Therefore, the compounds of the present invention are useful for inhibiting propagating cancerous MAPK and PI3K signaling and reducing cell proliferation, particularly cancer cells. The compounds of the present invention are useful for terminating RAS signaling in cells expressing RAS mutations, such as pancreatic cancer, colorectal cancer, lung cancer, esophageal cancer, gallbladder cancer, melanoma ovarian cancer, endometrial cancer, etc., driven by KRAS mutations. Alternatively, the compounds of the present invention are useful for terminating RAS signaling in malignant solid tumors, and the cancerous role of KRAS mutations is enhanced by dysregulation or mutation of effector pathways such as signaling driven by MAPK, PI3K-AKT-mTOR (mammalian target of rapamycin), and is useful for targeted therapy in pancreatic adenocarcinoma, colorectal cancer, non-small cell lung cancer, etc.

[0076] 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), stereoisomer, tautomer, prodrug, or a pharmaceutically acceptable salt thereof.

[0077] Synthesis The compounds of the present invention can be prepared by any conventional means. Suitable processes for synthesizing these compounds as well as their starting materials are shown in the following schemes and examples. All substituents, especially R 1 ~R 7 , A 1 and A 2 are as defined above, unless otherwise indicated. Further, unless otherwise explicitly stated, all reactions, reaction conditions, abbreviations and symbols have meanings well-known to those skilled in the art of organic chemistry.

[0078] A general synthetic route for preparing the compounds of formula (I) is shown below. Scheme 1 TIFF2025519199000025.tif53170 The compounds of formula II were synthesized according to the procedures described for intermediates A - L. The compounds of formula (I) can be obtained by a coupling reaction between an acid (III) and a compound of formula (II) using a coupling reagent(s) such as T3P, HATU, PyBOP and EDCI / HOBt in the presence of a base such as TEA, DIEPA and DMAP. Scheme 2 TIFF2025519199000026.tif124170 wherein PG is a protecting group such as Boc or Cbz.

[0079] Alternatively, the compound of formula (V) can be obtained by a coupling reaction between acid (IV) and the compound of formula (II) using a coupling reagent(s) such as T3P, HATU, PyBOP or EDCI / HOBt in the presence of a base such as TEA, DIEPA and DMAP. Deprotection of the compound of formula (V) can give the compound of formula (VI) in the presence of an acid such as TFA or under hydrogenation conditions using a catalyst such as Pd / C and Pd(OH)2 / C. The compound of formula (VIII) can be obtained by a coupling reaction between acid (VII) and the compound of formula (VI) using a coupling reagent(s) such as T3P, HATU, PyBOP and EDCI / HOBt in the presence of a base such as TEA, DIEPA and DMAP. Scheme 3 TIFF2025519199000027.tif130170 wherein PG is a protecting group such as Boc and Cbz; T is dihalo C 1-6 is alkyl; Q is unsubstituted or substituted piperidinylene or pyrrolidinylene.

[0080] Alternatively, the compound of formula (X) can be obtained by a coupling reaction using acid (IX), the compound of formula (VI), and a coupling reagent(s) such as T3P, HATU, PyBOP or EDCI / HOBt in the presence of a base such as TEA, DIEPA or DMAP. Deprotection of the compound of formula (X) can give the compound of formula (XI) in the presence of an acid such as TFA or under hydrogenation conditions using a catalyst such as Pd / C and Pd(OH)2 / C. The compound of formula (XIII) can be obtained by a coupling reaction between acid (XII) and the compound of formula (XI) using a coupling reagent(s) such as T3P, HATU, PyBOP and EDCI / HOBt in the presence of a base such as TEA, DIEPA and DMAP.

[0081] The compounds of the present invention can be obtained as mixtures of diastereomers or enantiomers, which can be separated by methods well known in the art, such as (chiral) HPLC or SFC. In another embodiment, the compounds of formula (I) can be obtained according to the above scheme by using the corresponding chiral starting materials.

[0082] The present invention also relates to a process for preparing a compound of formula (I), comprising any of the following steps: a) a coupling reaction of a compound of formula (II), TIFF2025519199000028.tif54170 (II) and an acid (III), TIFF2025519199000029.tif23170 (III) in the presence of a coupling reagent and a base to form a compound of formula (I); b) a coupling reaction of a compound of formula (VI), TIFF2025519199000030.tif73170 and an acid (VII), TIFF2025519199000031.tif16170 (VII) in the presence of a coupling reagent and a base to form a compound of formula (VIII), TIFF2025519199000032.tif73170; c) a coupling reaction of a compound of formula (XI), TIFF2025519199000033.tif73170 and an acid (XII), TIFF2025519199000034.tif16170 (XII) in the presence of a coupling reagent and a base to form a compound of formula (XIII), TIFF2025519199000035.tif73170, wherein in steps a), b) and c), the coupling reagent can be, for example, T3P, HATU, PyBOP or EDCI / HOBt; the base can be, for example, TEA, DIEPA or DMAP; T is dihalo C 1-6It relates to a preparation process, where R is alkyl; and Q is unsubstituted or substituted piperidinylene or pyrrolidinylene.

[0083] Compounds of formula (I) or (Ia) when produced according to the above process are also an object of the present invention.

Examples

[0084] The present invention will be more fully understood by reference to the following examples. However, these examples should not be construed as limiting the scope of the present invention.

[0085] Abbreviations The present invention will be more fully understood by reference to the following examples. However, these examples should not be construed as limiting the scope of the present invention.

[0086] The abbreviations used in this specification are as follows: ACN Acetonitrile aq. Aqueous solution Boc-N-Me-Val-OH N-(tert-Butoxycarbonyl)-N-methyl-L-valine (Boc)2O Di-tert-butyl dicarbonate (R)-binap (R)-(+)-2,2’-Bis(diphenylphosphino)-1,1’-binaphthyl CDCl3: Deuterochloroform CD3OD: Deuteromethanol COMU (1-Cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate DIEPA: N,N-Diethylpropylamine DIBAL-H Diisobutylaluminum hydride DMAP: 4-Dimethylaminopyridine DMF: Dimethylformamide DMSO: Dimethyl sulfoxide 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): Hour HPLC: High performance liquid chromatography HOBt: N-Hydroxybenzotriazole H-VAL-OTBU HCl: (S)-tert-Butyl 2-amino-3-methylbutanoate hydrochloride [Ir(OMe)(COD)]2: (1,5-Cyclooctadiene)(methoxy)iridium(I) dimer LDA: Lithium diisopropylamide MS:(ESI): Mass spectrometry (electron spray ionization) min(s): Minute NMM: N-Methylmorpholine NMR: Nuclear magnetic resonance NMO: 4-Methylmorpholine N-oxide obsd.: Observed value Pd(dppf)Cl2: [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(dtbpf)Cl2: [1,1'-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) prep-HPLC: Preparative high performance liquid chromatography PyBOP: Benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate RT or rt: Room temperature sat.: Saturated SFC: Supercritical fluid chromatography TEA: Triethylamine TFA: Trifluoroacetic acid THF: Tetrahydrofuran TEA: Triethylamine T3P: Propylphosphonic anhydride

[0087] General experimental conditions Intermediates and final compounds were purified using the following equipment: i) Biotage SP1 system and Quad12 / 25 cartridge module, ii) ISCO combi-flash chromatography equipment, silica gel brand and pore size: i) KP-SIL 60Å, particle size: 40 - 60μm; ii) CAS registration number: silica gel: 63231-67-4, particle size: 47 - 60 micron silica gel; iii) ZCX manufactured by Qingdao Haiyang Chemical Co., Ltd., pore: 200 - 300 or 300 - 400.

[0088] Intermediates and final compounds were purified by preparative HPLC on a reverse-phase column using XBridge™ Prep-C18 (5μm, OBD™ 30×100mm) column, SunFire™ Prep-C18 (5μm, OBD™ 30×100mm) column, Phenomenex Synergi-C18 (10μm, 25×150mm) or Phenomenex Gemini-C18 (10μm, 25×150mm). Waters AutoP purification system (sample manager 2767, pump 2525, detectors: Micromass ZQ and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water; acetonitrile and 0.1% FA in water or acetonitrile and 0.1% TFA in water), or Gilson-281 purification system (pump 322, detector: UV156, solvent system: acetonitrile and 0.05% ammonium hydroxide in water; acetonitrile and 0.225% FA in water; acetonitrile and 0.05% HCl in water; acetonitrile and 0.075% TFA in water; or acetonitrile and water), by Prep-HPLC on a reverse-phase column.

[0089] For SFC chiral separation, the intermediate was separated by a chiral column (Daicel chiralpak IC, 5 μm, 30 × 250 mm), AS (10 μm, 30 × 250 mm) or AD (10 μm, 30 × 250 mm) using a Mettler Toledo Multigram III system SFC, Waters 80Q preparative SFC or Thar 80 preparative SFC, solvent system: CO2 and IPA (0.5% TEA in IPA) or CO2 and MeOH (0.1% NH3·H2O in MeOH), back pressure 100 bar, detection UV@254 or 220 nm.

[0090] The LC / MS spectra of the compounds were obtained using LC / MS (Waters™ Alliance 2795 - Micromass ZQ, Shimadzu Alliance 2020 - Micromass ZQ or Agilent Alliance 6110 - Micromass ZQ), and the LC / MS conditions were as follows (run time 3 minutes or 1.5 minutes): Acidic condition I: A: 0.1% TFA in H2O; B: 0.1% TFA in acetonitrile; Acidic condition 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 condition II: A: 0.025% NH3·H2O in H2O; B: acetonitrile; Neutral condition: A: H2O; B: acetonitrile. Mass spectrum (MS): Generally, only ions indicating the parent mass are reported, and unless otherwise stated, the mass ions cited are the positive mass ions (MH) + is. The NMR spectra were obtained using a Bruker Avance 400 MHz.

[0091] The microwave-assisted reactions were carried out on a Biotage Initiator Sixty microwave synthesizer. All reactions involving air-sensitive reagents were conducted under an argon or nitrogen atmosphere. Reagents were used as received from commercial suppliers without further purification, unless otherwise specified.

[0092] Preparation Example Preparation of Intermediates Intermediate A 1-[6-[(1S)-1-Methoxyethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]-4-methyl-piperazine TIFF2025519199000036.tif52170Title Intermediate A was prepared according to the following scheme. TIFF2025519199000037.tif125170

[0093] Step 1: Preparation of 3-bromo-2-[(1S)-1-methoxyethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (Compound A2) To a solution of 3-bromo-2-[(1S)-1-methoxyethyl]pyridine (Compound A1, 2.0 g, 9.26 mmol) and bis(pinacolato)diboron (3.5 g, 13.9 mmol) in THF (30 mL) were added 4,4'-di-tert-butyl-2,2'-bipyridine (372.7 mg, 1.39 mmol) and [Ir(OMe)(COD)]2 (306.3 mg, 0.460 mmol). The mixture was stirred at 75 °C for 16 h under N2 protection. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (EA / PE: 0 - 20%) to give 3-bromo-2-[(1S)-1-methoxyethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (Compound A2, 2.4 g) as a yellow oil. 11H NMR (400 MHz, CDCl3) δ ppm 8.91 (d, J = 1.4 Hz, 1H), 8.21 (d, J = 1.4 Hz, 1H), 4.95 (q, J = 6.5 Hz, 1H), 3.30 (s, 3H), 1.49 (d, J = 6.5 Hz, 3H), 1.35 (s, 12H).

[0094] Step 2: Preparation of 3-bromo-5-iodo-2-[(1S)-1-methoxyethyl]pyridine (Compound A3) To a solution of 3-bromo-2-[(1S)-1-methoxyethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (Compound A2, 2.5 g, 7.3 mmol) in ACN (40 mL) was added N-iodosuccinimide (4.1 g, 18.27 mmol). The mixture was stirred at 90 °C for 40 h under N2 protection. The reaction was quenched with a saturated solution of Na2SO3 (40 mL), and the reaction mixture was extracted with EtOAc (30 mL, 2 times). The combined organic layers were washed with brine (50 mL), filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (EA / PE: 0 - 20%) to give 3-bromo-5-iodo-2-[(1S)-1-methoxyethyl]pyridine (Compound A3, 660 mg) as a yellow oil. MS calculated value 342 (MH + ), measured value 341.8 (MH + ).

[0095] Step 3: Preparation of benzyl 4-[5-bromo-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (Intermediate A5) A solution of 3-bromo-5-iodo-2-[(1S)-1-methoxyethyl]pyridine (Compound A3, 660 mg, 1.9 mmol) and 1-Cbz-piperazine (Compound A4, 425.1 mg, 1.9 mmol) in toluene (10 mL) was added with cesium carbonate (1.6 g, 4.83 mmol), (R)-BINAP (60.1 mg, 0.1 mmol) and palladium(II) acetate (43.3 mg, 0.19 mmol). The mixture was stirred at 100 °C for 12 h under N2 protection. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (EA / PE: 0~50%) to obtain benzyl 4-[5-bromo-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (Intermediate A5, 740 mg) as a yellow solid. MS calculated value 434.1 (MH + ), measured value 434.1 (MH + ).

[0096] Step 4: Preparation of 1-[6-[(1S)-1-methoxyethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]-4-methyl-piperazine (Intermediate A) To a solution of benzyl 4-[5-bromo-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (Intermediate A5, 740 mg, 1.7 mmol) and bis(pinacolato)diboron (519.2 mg, 2.04 mmol) in toluene (12 mL) were added KOAc (418.0 mg, 4.26 mmol) and Pd(dppf)Cl2 (124.7 mg, 0.170 mmol). The reaction mixture was stirred at 90 °C for 12 h under N2 protection. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column to obtain 1-[6-[(1S)-1-methoxyethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]-4-methyl-piperazine (Intermediate A, 470 mg) as a brown solid. MS calculated value 482.3 (MH + ), measured value 482.2 (MH + ).

[0097] Intermediate B Methyl (3S)-1-[(2S)-2-(tert-butoxycarbonylamino)-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-triisopropylsilyloxy-phenyl]propanoyl]hexahydropyridazine-3-carboxylate TIFF2025519199000038.tif47170 Intermediate B was prepared according to the following scheme. TIFF2025519199000039.tif145170

[0098] Step 1: Preparation of methyl (2S)-2-amino-3-(3-hydroxyphenyl)propanoate (Compound B2) Thionyl chloride (10 mL, 137.9 mmol) was added to a solution of L-M-tyrosine (Compound B1, 5.0 g, 27.6 mmol) in methanol (80 mL). The mixture was stirred at 60 °C for 12 h. The reaction mixture was cooled to 20 °C and concentrated in vacuo to give methyl (2S)-2-amino-3-(3-hydroxyphenyl)propanoate (Compound B2, 6.2 g) as a yellow solid. 1 H NMR (400 MHz, CD3OD) δ ppm 7.18 (t, J = 8.0 Hz, 1H), 6.78 - 6.66 (m, 3H), 4.29 (t, J = 6.4 Hz, 1H), 3.82 (s, 3H), 3.23 - 3.05 (m, 2H).

[0099] Step 2: Preparation of methyl (2S)-2-(tert-butoxycarbonylamino)-3-(3-hydroxyphenyl)propanoate (Compound B3) A solution of methyl (2S)-2-amino-3-(3-hydroxyphenyl)propanoate (Compound B2, 32.0 g, 138.1 mmol) in THF (80 mL) and water (20 mL) was added with sodium bicarbonate (40.6 g, 483.4 mmol), followed by the addition of di-t-butyl dicarbonate (33.1 g, 151.9 mmol) at 20 °C. The mixture was stirred at 20 °C for 12 h. The mixture was diluted with water (100 mL) and acidified with 1 M aqueous HCl until pH = 5. The mixture was extracted with ethyl acetate (100 mL, 3 times). The combined organic phases were washed with brine (80 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to give methyl (2S)-2-(tert-butoxycarbonylamino)-3-(3-hydroxyphenyl)propanoate (Compound B3, 40 g) as a colorless gum. MS: calculated value 318 (MNa + ), measured value 318.3 (MNa + ).

[0100] Step 3: Preparation of methyl (2S)-2-(tert-butoxycarbonylamino)-3-(3-triisopropylsilyloxyphenyl)propanoate (Compound B4) To a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-(3-hydroxyphenyl)propanoate (Compound B3, 40.0 g, 135.4 mmol) and 1H-imidazole (27.6 g, 406.3 mmol) in DMF (400 mL) was added dropwise triisopropylsilyl chloride (39.1 g, 203.1 mmol) at 0 °C. After stirring at 25 °C for 12 h, the mixture was diluted with water (250 mL) at 0 °C and extracted with ethyl acetate (200 mL, 3 times). The combined organic phases were washed with brine (80 mL, 4 times), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to give a residue. The residue was purified by silica gel chromatography (EA / PE: 0 - 20%) to give methyl (2S)-2-(tert-butoxycarbonylamino)-3-(3-triisopropylsilyloxyphenyl)propanoate (Compound B4, 60 g) as a yellow oil. MS: calculated value 474 (MNa +) Measured value 474.2 (MNa + ).

[0101] Step 4: Preparation of Methyl (2S)-2-(tert-butoxycarbonylamino)-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-triisopropylsilyloxy-phenyl]propanoate (Compound B5) To a solution of Methyl (2S)-2-(tert-butoxycarbonylamino)-3-(3-triisopropylsilyloxyphenyl)propanoate (Compound B4, 15.0 g, 33.2 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (2.6 g, 9.9 mmol) and bis(pinacolato)diboron (12.6 g, 49.8 mmol) in hexane (200 mL) was added [Ir(OMe)(COD)]2 (2.2 g, 3.3 mmol). The mixture was degassed and purged three times with N2. The resulting mixture was stirred at 70 °C for 12 h. The reaction mixture was then cooled to 20 °C, diluted with petroleum ether (100 mL) and filtered. The filtrate was concentrated in vacuo to give a residue, which was purified by silica gel chromatography (EA / PE: 0 - 20%) to give Methyl (2S)-2-(tert-butoxycarbonylamino)-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-triisopropylsilyloxy-phenyl]propanoate (Compound B5, 21 g) as a yellow oil. MS: Calculated 600 (MNa + ) Measured value 600.3 (MNa + ).

[0102] Step 5: Preparation of (2S)-2-(tert-butoxycarbonylamino)-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-triisopropylsilyloxy-phenyl]propanoic acid (Compound B6) A solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-triisopropylsilyloxy-phenyl]propanoate (Compound B5, 40.0 g, 69.2 mmol) in methanol (300 mL) was added to a solution of lithium hydroxide (3.2 mL, 346.2 mmol) in water (100 mL). After stirring at 20 °C for 1 hour, the reaction mixture was diluted with water (200 mL) and MeOH was removed under vacuum. The resulting mixture was acidified with 1 M aqueous HCl to pH = 5. The resulting mixture was extracted with EtOAc (250 mL, 3 times). The organic phase was washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to give (2S)-2-(tert-butoxycarbonylamino)-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-triisopropylsilyloxy-phenyl]propanoic acid (Compound B6, 33 g) as a white solid. MS: calculated 586 (MNa + ), found 586.3 (MNa + ).

[0103] Step 6: Preparation of methyl (3S)-1-[(2S)-2-(tert-butoxycarbonylamino)-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-triisopropylsilyloxy-phenyl]propanoyl]hexahydropyridazine-3-carboxylate (Intermediate B) (2S)-2-(tert-Butoxycarbonylamino)-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-triisopropylsilyloxy-phenyl]propanoic acid (Compound B6, 8.0 g, 14.1 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (5.6 g, 14.9 mmol) in DMF (100 mL) were added N,N-diisopropylethylamine (6.4 g, 49.6 mmol). The mixture was stirred at 0 °C for 10 minutes. Then, methyl (3S)-hexahydropyridazine-3-carboxylate hydrochloride (Compound B7, 2.6 g, 14.9 mmol) was added. The resulting mixture was stirred at 20 °C for 1.5 hours. The mixture was diluted with water (200 mL) and extracted with EtOAc (100 mL, 2 times). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography to give methyl (3S)-1-[(2S)-2-(tert-butoxycarbonylamino)-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-triisopropylsilyloxy-phenyl]propanoyl]hexahydropyridazine-3-carboxylate (Intermediate B, 7.8 g) as a yellow oil. MS: Calcd 690 (MH + ), Found 690.4 (MH + ).

[0104] Intermediate C Methyl (3S)-1-[(2S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylate TIFF2025519199000040.tif52170 Intermediate C was prepared according to the following scheme. TIFF2025519199000041.tif143170

[0105] Step 1: Preparation of (4-bromothiazol-2-yl)methanol (Compound C2) To a solution of 4-bromothiazole-2-carboxaldehyde (6.0 g, 31.25 mmol) in methanol (70 mL), sodium borohydride (1.7 g, 46.87 mmol) was added at 0 °C. The mixture was stirred at 25 °C for 1 h. 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 under vacuum to give (4-bromothiazol-2-yl)methanol (Compound C2, 6 g) as a colorless oil.

[0106] Step 2: Preparation of 4-bromo-2-(bromomethyl)thiazole (Compound C3) To a solution of (4-bromothiazol-2-yl)methanol (Compound C2, 6.0 g, 30.92 mmol) in DCM (80 mL), CBr4 (15.4 g, 46.38 mmol) and triphenylphosphine (12.1 g, 46.38 mmol) were added at 0 °C. After stirring at 25 °C for 1 h, the mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel column eluting with ethyl acetate in petroleum ether = 0 - 10% to give (4-bromothiazol-2-yl)methyl bromide (Compound C3, 6.0 g) as a yellow oil. MS calculated value 255.9 (MH + )、measured value 255.9 (MH + ).

[0107] Step 3: Preparation of 4-bromo-2-[[(2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2-yl]methyl]thiazole (Compound C5) A mixture of (R)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine (Compound C4, 4.3 g, 23.45 mmol) in THF (60 mL) was slowly added with 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 C3, 5.4 g, 21.02 mmol) was added to the above mixture at -78 °C and the mixture 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 under vacuum. 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 C5, 3.6 g) as a yellow oil. MS calculated value 360 (MH + ), measured value 359.9 (MH + ).

[0108] Step 4: Preparation of methyl (2S)-2-amino-3-(4-bromothiazol-2-yl)propanoate (Compound C6) Hydrochloric acid (66.6 mL, 0.3 M) was added to a solution of 4-bromo-2-[[(2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2-yl]methyl]thiazole (Compound C5, 3.6 g, 10 mmol) in ACN (20 mL). The mixture was stirred at 25 °C for 2 h. The mixture was basified to pH = 8 with a saturated solution of NaHCO3. 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 under vacuum to give methyl (2S)-2-amino-3-(4-bromothiazol-2-yl)propanoate (Compound C6, 3.1 g) as a yellow oil. MS calculated value 264.9 (MH + ), measured value 264.9 (MH + ).

[0109] Step 5: Preparation of Methyl (2S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)propanoate (Compound C7) A solution of methyl (2S)-2-amino-3-(4-bromothiazol-2-yl)propanoate (Compound C6 、 3.1 g, 11.69 mmol) in DCM (40 mL) was added with triethylamine (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 under vacuum. The residue was purified by silica gel column, eluting with ethyl acetate in petroleum ether = 0 - 30% to obtain methyl (2S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)propanoate (Compound C7, 3.2 g) as a yellow oil. MS calculated value 387 (MNa + ), measured value 386.9 (MNa + ).

[0110] Step 6: Preparation of (2S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)propanoic acid (Compound C8) To a solution of methyl (2S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)propanoate (Compound C7, 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 h, the reaction mixture was acidified with 1 M HCl solution until pH = 5. The mixture was extracted with EtOAc (40 mL, 2 times). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to obtain (2S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)propanoic acid (Compound C8, 3.1 g) as a yellow oil. MS calculated value 373 (MNa + ), measured value 372.9 (MNa + ).

[0111] Step 7: Preparation of Methyl (3S)-1-[(2S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylate (Intermediate C) To a solution of (2S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)propanoic acid (Compound C8, 3.1 g, 8.83 mmol) in DCM (50 mL) were added methyl (3S)-hexahydropyridazine-3-carboxylate; hydrochloride (Compound C9, 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 layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column, 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 C, 2.4 g). MS calculated value 477 (MH + ), measured value 476.9 (MH + ).

[0112] Intermediate D (7S,13S)-7-Amino-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaene 8,14-dione TIFF2025519199000042.tif56170 The intermediate D was prepared according to the following scheme. TIFF2025519199000043.tif191170 TIFF2025519199000044.tif208170

[0113] Step 1: Preparation of 1-(5-bromo-6-fluoro-1H-indol-3-yl)-3-((tert-butyldiphenylsilyl) oxy)-2,2-dimethylpropan-1-one (Compound D3) To a mixture of 3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropanoyl chloride (Compound D1, 35.0 g, 116.8 mmol) in DCM (400 mL) at 0 °C, a solution of SnCl4 (97.2 mL, 121.5 mmol) was slowly added. After stirring at -40 °C for 0.5 h, 5-bromo-6-fluoro-1H-indole (Compound D2, 25.0 g, 116.8 mmol) in DCM (200 mL) was added dropwise and the mixture was stirred at -40 °C for 15 min. After completion of the reaction, it was quenched with saturated aqueous NaHCO3 (800 mL) and the reaction mixture was extracted with EtOAc (900 mL, 2 times). The combined organic layers were washed with brine (700 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was triturated with a solution (100 mL, petroleum ether:ethyl acetate = 8:1) and filtered. Drying the filter cake in vacuo gave 1-(5-bromo-6-fluoro-1H-indol-3-yl)-3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropan-1-one (Compound D3, 50.0 g) as a yellow solid. MS calculated value 552.1 (MH + )), measured value 552.1 (MH + ).

[0114] Step 2: Preparation of [3-(5-bromo-6-fluoro-1H-indol-3-yl)-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (Compound D4) A mixture of 1-(5-bromo-6-fluoro-1H-indol-3-yl)-3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropan-1-one (Compound D3, 50.0 g, 90.49 mmol) in THF (600 mL) was added dropwise with LiBH4 (48.4 mL, 193.49 mmol, 4 M in THF) at 0 °C. The mixture was stirred at 70 °C for 24 h under a nitrogen atmosphere. After the reaction was completed, it was quenched by slowly adding water (600 mL) at 0 °C, and the reaction mixture was extracted with EtOAc (600 mL, 2 times). The combined organic layers were washed with brine (600 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica column chromatography (EtOAc in PE = 20% - 33%) to obtain [3-(5-bromo-6-fluoro-1H-indol-3-yl)-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (Compound D4, 46.0 g) as a white solid. MS calculated value 538.1 (MH + ), measured value 538.2 (MH + ).

[0115] Step 3: Preparation of [3-(5-bromo-6-fluoro-2-iodo-1H-indol-3-yl)-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (Compound D5) [3-(5-Bromo-6-fluoro-1H-indol-3-yl)-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (Compound D4, 35.4 g, 65.73 mmol) and iodine (18.4 g, 72.3 mmol) in a mixture of THF (400 mL), silver trifluoromethanesulfonate (20.3 g, 78.88 mmol) was added at 0 °C. The mixture was stirred at 0 °C for 10 minutes. After the reaction was completed, it was quenched with saturated aqueous Na2SO3 (400 mL) and EtOAc (400 mL), and the reaction mixture was filtered. The organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica column chromatography (EtOAc in PE = 0% - 2.5%) to give [3-(5-bromo-6-fluoro-2-iodo-1H-indol-3-yl)-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (Compound D5, 43.0 g) as a yellow solid. MS calculated value 664.0 (MH + ), measured value 664.1 (MH + ).

[0116] Step 4: Preparation of benzyl 4-[5-[5-bromo-3-[3-[tert-butyl(diphenyl)silyl]oxy-2,2-dimethyl-propyl]-6-fluoro-1H-indol-2-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (Compound D6) A mixture of [3-(5-bromo-6-fluoro-2-iodo-1H-indol-3-yl)-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (Compound D5, 16.7 g, 25.13 mmol) and benzyl 4-[6-[(1S)-1-methoxyethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]piperazine-1-carboxylate (Intermediate A, 16.7 g, 34.69 mmol) in a mixed solution of 1,4-dioxane (270 mL) / toluene (90 mL) / water (90 mL) was added with potassium phosphate (15.7 g, 73.92 mmol) and Pd(dppf)Cl2 (920 mg, 1.26 mmol). The mixture was stirred at 70 °C for 12 h under a nitrogen atmosphere. After the reaction was completed, the mixture was filtered and concentrated in vacuo. The residue was purified by silica column chromatography (EtOAc in PE = 20% - 50%) to obtain 4-[5-[5-bromo-3-[3-[tert-butyl(diphenyl)silyl]oxy-2,2-dimethyl-propyl]-6-fluoro-1H-indol-2-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (Compound D6, 19.5 g) as a white solid. MS calculated value 891.3 (MH + ), measured value 891.3 (MH + ).

[0117] Step 5: Preparation of benzyl 4-[(5M)-5-[5-bromo-3-[3-[tert-butyl(diphenyl)silyl]oxy-2,2-dimethyl-propyl]-6-fluoro-1-(2,2,2-trifluoroethyl)indol-2-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (Compound D7) 4-[5-[5-Bromo-3-[3-[tert-butyl(diphenyl)silyl]oxy-2,2-dimethyl-propyl]-6-fluoro-1H-indol-2-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (Compound D6, 14.5 g, 16.26 mmol) and Cs2CO3 (15.9 g, 48.77 mmol) in DMF (200 mL) were added dropwise with 2,2,2-trifluoroethyl trifluoromethanesulfonate (37.7 g, 162.56 mmol) at 0 °C, and the mixture was stirred at 20 °C for 12 hours. After the reaction was completed, EtOAc (70 mL) and water (100 mL) were added, and the layers were separated. The aqueous phase was extracted with EtOAc (70 mL, 2 times). The combined organic layers were washed with brine (100 mL, 4 times), dried over Na2SO4, filtered, and concentrated under vacuum to obtain a residue. Purification of the residue by silica column chromatography gave benzyl 4-[(5M)-5-[5-bromo-3-[3-[tert-butyl(diphenyl)silyl]oxy-2,2-dimethyl-propyl]-6-fluoro-1-(2,2,2-trifluoroethyl)indol-2-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (Compound D7, 8.0 g, peak 1, eluting faster) as a yellow oil. MS calculated value 973.3 (MH + ), measured value 973.2 (MH + ).

[0118] Step 6: Preparation of benzyl 4-[(5M)-5-[5-bromo-6-fluoro-3-(3-hydroxy-2,2-dimethylpropyl)-1-(2,2,2-trifluoroethyl)indol-2-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (Compound D8) Benzyl 4-[(5M)-5-[5-bromo-3-[3-[tert-butyl(diphenyl)silyl]oxy-2,2-dimethyl-propyl]-6-fluoro-1-(2,2,2-trifluoroethyl)indol-2-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (Compound D7, 10.5 g, 10.78 mmol) in DMF (130 mL) was added cesium fluoride (8.2 g, 53.9 mmol), and the mixture was stirred at 60 °C for 24 h. After the reaction was complete, EtOAc (100 mL) and water (100 mL) were added and the layers were separated. The aqueous phase was extracted with EtOAc (100 mL, 2 times). The combined organic layers were washed with brine (80 mL, 3 times), dried over Na2SO4, filtered, and concentrated under vacuum to give a residue. The residue was purified by silica column chromatography (EtOAc in PE = 25% - 66%) to give benzyl 4-[(5M)-5-[5-bromo-6-fluoro-3-(3-hydroxy-2,2-dimethylpropyl)-1-(2,2,2-trifluoroethyl)indol-2-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (Compound D8, 6.5 g) as a yellow solid. MS calcd 735.2 (MH + ), found 735.1 (MH + ).

[0119] Step 7: Preparation of benzyl 4-[(5M)-5-[6-fluoro-3-(3-hydroxy-2,2-dimethylpropyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)indol-2-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (Compound D9) A solution of benzyl 4-[(5M)-5-[5-bromo-6-fluoro-3-(3-hydroxy-2,2-dimethylpropyl)-1-(2,2,2-trifluoroethyl)indol-2-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (Compound D8, 5.4 g), bis(pinacolato)diboron (2.8 g, 11.01 mmol) and potassium acetate (1.2 mL, 18.35 mmol) in toluene (70 mL) was added with Pd(dppf)Cl2 (537.1 mg, 0.73 mmol). The mixture was degassed and purged three times with a nitrogen atmosphere, and the mixture was stirred at 90 °C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to obtain a residue. The residue was purified by silica column chromatography (EtOAc in PE = 25% - 66%) to give benzyl 4-[(5M)-5-[6-fluoro-3-(3-hydroxy-2,2-dimethylpropyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)indol-2-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (Compound D9, 5.2 g) as a yellow oil. MS calculated value 783.3 (MH + ), measured value 783.3 (MH + ).

[0120] Step 8: Preparation of methyl (3S)-1-[(2S)-3-[4-[(2M)-2-[5-(4-benzyloxycarbonylpiperazin-1-yl)-2-[(1S)-1-methoxyethyl]-3-pyridyl]-6-fluoro-3-(3-hydroxy-2,2-dimethylpropyl)-1-(2,2,2-trifluoroethyl)indol-5-yl]thiazol-2-yl]-2-(tert-butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylate (Compound D10) (3S)-1-[(2S)-3-(4-Bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylate (Intermediate C, 2.7 g, 5.69 mmol), benzyl 4-[(5M)-5-[6-fluoro-3-(3-hydroxy-2,2-dimethylpropyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)indol-2-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (Compound D9, 4.9 g, 6.32 mmol) in toluene (60 mL) / 1,4-dioxane (20 mL) / water (20 mL), under a nitrogen atmosphere, K3PO4 (3.4 g, 15.81 mmol) and Pd(dtbpf)Cl2 (412.2 mg, 0.63 mmol) were added. The mixture was stirred at 70 °C for 12 h. After the reaction was completed, the mixture was concentrated in vacuo to give a residue. The residue was purified by silica column (EtOAc in PE = 10% - 75%) to give methyl (3S)-1-[(2S)-3-[4-[(2M)-2-[5-(4-benzyloxycarbonylpiperazin-1-yl)-2-[(1S)-1-methoxyethyl]-3-pyridyl]-6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-1-(2,2,2-trifluoroethyl)indol-5-yl]thiazol-2-yl]-2-(tert-butoxycarbonylamino)-propanoyl]hexahydropyridazine-3-carboxylate (Compound D10, 3.6 g) as a brown solid. MS calculated 1053.4 (MH + ), found 1053.3 (MH + ).

[0121] Step 9: Preparation of (3S)-1-[(2S)-3-[4-[(2M)-2-[5-(4-Benzyloxycarbonylpiperazin-1-yl)-2-[(1S)-1-methoxyethyl]-3-pyridyl]-6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-1-(2,2,2-trifluoroethyl)indol-5-yl]thiazol-2-yl]-2-(tert-butoxycarbonylamino)-propanoyl]hexahydropyridazine-3-carboxylic acid (Compound D11) To a solution of methyl (3S)-1-[(2S)-3-[4-[(2M)-2-[5-(4-benzyloxycarbonylpiperazin-1-yl)-2-[(1S)-1-methoxyethyl]-3-pyridyl]-6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-1-(2,2,2-trifluoroethyl)indol-5-yl]thiazol-2-yl]-2-(tert-butoxycarbonylamino)-propanoyl]-hexahydropyridazine-3-carboxylate (Compound D10, 3.6 g, 3.42 mmol) in DCE (50 mL) was added trimethylstannanol (2.4 g, 13.67 mmol), and the mixture was stirred at 60 °C for 12 h. After completion of the reaction, EtOAc (80 mL) and water (60 mL) were added, and the layers were separated. The aqueous phase was extracted with EtOAc (80 mL, 2 times). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give (3S)-1-[(2S)-3-[4-[(2M)-2-[5-(4-benzyloxycarbonylpiperazin-1-yl)-2-[(1S)-1-methoxyethyl]-3-pyridyl]-6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-1-(2,2,2-trifluoroethyl)indol-5-yl]thiazol-2-yl]-2-(tert-butoxycarbonylamino)-propanoyl]hexahydropyridazine-3-carboxylic acid (Compound D11, 4.3 g) as a brown solid. MS calculated value 1039.4 (MH + +), measured value 1039.2 (MH + +).

[0122] Step 10: Preparation of Benzyl 4-[5-[(7S,13S)-7-(tert-Butoxycarbonylamino)-24-fluoro-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-(20M)-20-yl]-6-[(1S)-1-methoxyethyl)-3-pyridyl]piperazine-1-carboxylate (Compound D12) (3S)-1-[(2S)-3-[4-[(2M)-2-[5-(4-Benzyloxycarbonylpiperazin-1-yl)-2-[(1S)-1-methoxyethyl]-3-pyridyl]-6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-1-(2,2,2-trifluoroethyl)indol-5-yl]thiazol-2-yl]-2-(tert-butoxycarbonylamino)-propanoyl]hexahydropyridazine-3-carboxylic acid (Compound D11, 4.3 g, 4.14 mmol) in DCM (430 mL) was added with DIEA (14.4 mL, 82.76 mmol), EDCI (11.9 g, 62.07 mmol) and 1-hydroxybenzotriazole (1.4 g, 10.35 mmol) at 0 °C. The mixture was stirred at 15 °C for 12 h. After the reaction was completed, the mixture was concentrated in vacuo, then diluted with water (80 mL) and extracted with EtOAc (80 mL, twice). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica column chromatography (EtOAc in PE = 25% - 66%) to give benzyl 4-[5-[(7S,13S)-7-(tert-butoxycarbonylamino)-24-fluoro-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26Octacosa-1(25),2,5(28),19,22(26),23-hexaen-(20M)-20-yl]-6-[(1S)-1-methoxyethyl)-3-pyridyl]piperazine-1-carboxylate (Compound D12, 3.1 g) was obtained as a yellow rubber. MS calculated value 1021.4 (MH + ), measured value 1021.2 (MH + ).

[0123] Step 11: Preparation of tert-butyl N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamate (Compound D13) Benzyl 4-[5-[(7S,13S)-7-(tert-butoxycarbonylamino)-24-fluoro-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26Octacosa-1(25),2,5(28),19,22(26),23-hexaene-(20M)-20-yl]-6-[(1S)-1-methoxyethyl)-3-pyridyl]piperazine-1-carboxylate (Compound D12, 3.1 g, 3.04 mmol) and aqueous formaldehyde solution (775.0 mg, 9.55 mmol) in methanol (150 mL) were added Pd(OH)2 on activated carbon (2.79 g, 3.97 mmol). The mixture was degassed and purged three times with H2. The mixture was hydrogenated at 30 °C for 18 h. After the reaction was completed, the mixture was filtered and the filtrate was concentrated in vacuo to give tert-butyl N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamate (Compound D13, 2.6 g) was obtained as a brown solid. MS calculated value 901.3 (MH + ), measured value 901.3 (MH + ).

[0124] Step 12: (7S,13S)-7-amino-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 Preparation of octacosa-1(25),2,5(28),19,22(26),23-hexaene 8,14-dione (Intermediate D) tert-Butyl N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamate (Compound D13, 2.6 g, 2.89 mmol) in DCM (18 mL), TFA (14.0 mL, 181.72 mmol) was added. The mixture was stirred at 15 °C for 0.5 h. After completion of the reaction, the mixture was concentrated in vacuo, diluted with saturated NaHCO3 solution (30 mL), and extracted with EtOAc (30 mL, 3 times). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give (7S,13S)-7-amino-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-8,14-dione (Intermediate D, 2.0 g) was obtained as a yellow solid and used directly in the next step. MS calculated 801.3 (MH + ), found 801.2 (MH + ).

[0125] Intermediate E (7S,13S)-7-Amino-25-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione TIFF2025519199000045.tif57170In the same manner as the preparation of Intermediate D, the title compound was prepared using 5-bromo-4-fluoro-1H-indole instead of 5-bromo-6-fluoro-1H-indole (Compound D2).

[0126] Intermediate F (7S,13S)-7-Amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17,24-trimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione TIFF2025519199000046.tif58170In the same manner as the preparation of Intermediate D, the title compound was prepared using 5-bromo-6-methyl-1H-indole instead of 5-bromo-6-fluoro-1H-indole (Compound D2).

[0127] Intermediate G (8S,14S)-8-Amino-25-fluoro-4-hydroxy-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-18,18-dimethyl-22-(2,2,2-trifluoroethyl)-16-oxa-10,22,28-triazapentacyclo[18.5.2.12,6 .1 10,14 .0 23,27 Nonacosa-1(26),2,4,6(29),20,23(27),24-heptaen-9,15-dione Compound intermediate G was prepared according to the following scheme for TIFF2025519199000047.tif63170. TIFF2025519199000048.tif163170

[0128] Step 1: Preparation of methyl (3S)-1-[(2S)-3-[3-[(2M)-2-[5-(4-benzyloxycarbonylpiperazin-1-yl)-2-[(1S)-1-methoxyethyl]-3-pyridyl]-6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-1-(2,2,2-trifluoroethyl)indol-5-yl]-5-triisopropylsilyloxy-phenyl]-2-(tert-butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylate (Compound G1) Benzyl 4-[(5M)-5-[5-bromo-1-ethyl-6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)indol-2-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (Compound D8, 950.0 mg, 1.29 mmol) and methyl (3S)-1-[(2S)-2-(tert-butoxycarbonylamino)-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-triisopropylsilyloxy-phenyl]propanoyl]hexahydropyridazine-3-carboxylate (Intermediate B, 1.07 g, 1.55 mmol) in 1,4-dioxane (25 mL) and water (5 mL) were treated with sodium carbonate (342.2 mg, 3.23 mmol) and Pd(dtbpf)Cl2 (84.2 mg, 0.13 mmol). The mixture was stirred at 85 °C for 12 h under a nitrogen atmosphere. After completion of the reaction, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by reverse-phase flash column and concentrated in vacuo to give methyl (3S)-1-[(2S)-3-[3-[(2M)-2-[5-(4-benzyloxycarbonylpiperazin-1-yl)-2-[(1S)-1-methoxyethyl]-3-pyridyl]-6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-1-(2,2,2-trifluoroethyl)indol-5-yl]-5-triisopropylsilyloxy-phenyl]-2-(tert-butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylate (Compound G1, 1.3 g) as a brown solid. MS calcd 1218.6 (MH + ) 1218.5 (MH + ).

[0129] Step 2: Preparation of (3S)-1-[(2S)-3-[3-[(2M)-2-[5-(4-Benzyloxycarbonylpiperazin-1-yl)-2-[(1S)-1-methoxyethyl]-3-pyridyl]-6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-1-(2,2,2-trifluoroethyl)indol-5-yl]-5-triisopropylsilyloxy-phenyl]-2-(tert-butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylic acid (Compound G2) To a mixture of methyl (3S)-1-[(2S)-3-[3-[(2M)-2-[5-(4-benzyloxycarbonylpiperazin-1-yl)-2-[(1S)-1-methoxyethyl]-3-pyridyl]-6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-1-(2,2,2-trifluoroethyl)indol-5-yl]-5-triisopropylsilyloxy-phenyl]-2-(tert-butoxycarbonylamino)-propanoyl]hexahydropyridazine-3-carboxylate (Compound G1, 1.1 g, 0.9 mmol) in DCE (20 mL) was added Me3SnOH (652.9 mg, 3.61 mmol). The mixture was stirred at 60 °C for 12 h. After the reaction was completed, the mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL, 2 times). The combined organic layers were washed with brine (150 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give (3S)-1-[(2S)-3-[3-[(2M)-2-[5-(4-benzyloxycarbonylpiperazin-1-yl)-2-[(1S)-1-methoxyethyl]-3-pyridyl]-6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-1-(2,2,2-trifluoroethyl)indol-5-yl]-5-triisopropylsilyloxy-phenyl]-2-(tert-butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylic acid (Compound G2, 1.5 g) as a yellow solid, which was used directly in the next step. MS calculated 1204.6 (MH + +), found 1204.5 (MH + +).

[0130] Step 3: Preparation of Benzyl 4-[5-[(8S,14S)-8-(tert-Butoxycarbonylamino)-25-fluoro-18,18-dimethyl-9,15-dioxo-22-(2,2,2-trifluoroethyl)-4-triisopropylsilyloxy-16-oxa-10,22,28-triazapentacyclo[18.5.2.1 2,6 .1 10,14 .0 23,27 nonacosa-1(26),2,4,6(29),20,23(27),24-heptaen-(21M)-21-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (Compound G3) (3S)-1-[(2S)-3-[3-[(2M)-2-[5-(4-Benzyloxycarbonylpiperazin-1-yl)-2-[(1S-1-methoxyethyl]-3-pyridyl]-6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-1-(2,2,2-trifluoroethyl)indol-5-yl]-5-triisopropylsilyloxy-phenyl]-2-(tert-butoxycarbonylamino)-propanoyl]hexahydropyridazine-3-carboxylic acid (Compound G2, 1.5 g, 1.25 mmol) in a mixture of DCM (150 mL), DIEA (4.4 mL, 24.95 mmol), EDCI (3.6 g, 18.71 mmol) and HOBt (421.4 mg, 3.12 mmol) were added at 0 °C. After stirring at 15 °C for 12 hours, the reaction mixture was concentrated in vacuo, diluted with water (50 mL), and extracted with EtOAc (50 mL, 3 times). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (EtOAc in PE = 25% - 50%) to give Benzyl 4-[5-[(8S,14S)-8-(tert-Butoxycarbonylamino)-25-fluoro-18,18-dimethyl-9,15-dioxo-22-(2,2,2-trifluoroethyl)-4-triisopropylsilyloxy-16-oxa-10,22,28-triazapentacyclo[18.5.2.1 2,6 .1 10,14 .0 23,27Nonaosa-1(26),2,4,6(29),20,23(27),24-heptaene-(21M)-21-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (Compound G3, 1.1 g) was obtained as a yellow solid. MS calculated value 1186.4 (MH + ), measured value 1186.5 (MH + ).

[0131] Step 4: Preparation of tert-butyl N-[(8S,14S)-25-fluoro-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-18,18-dimethyl-9,15-dioxo-22-(2,2,2-trifluoroethyl)-4-triisopropylsilyloxy-16-oxa-10,22,28-triazapentacyclo[18.5.2.1 2,6 .1 10,14 .0 23,27 nonaosa-1(26),2,4,6(29),20,23(27),24-heptaen-8-yl]carbamate (Compound G4) Benzyl 4-[5-[(8S,14S)-8-(tert-butoxycarbonylamino)-25-fluoro-18,18-dimethyl-9,15-dioxo-22-(2,2,2-trifluoroethyl)-4-triisopropylsilyloxy-16-oxa-10,22,28-triazapentacyclo[18.5.2.1 2,6 .1 10,14 .0 23,27Nonacosa-1(26),2,4,6(29),20,23(27),24-heptaen-(21M)-21-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (Compound G3, 890.0 mg, 0.75 mmol) and formaldehyde (182.6 mg, 2.25 mmol) in methanol (15 mL), Pd(OH)2 on activated carbon (700.0 mg, 1.0 mmol) was added. The mixture was degassed and purged with H2 three times. The mixture was hydrogenated at 30 °C for 18 h. The mixture was filtered and the filtrate was concentrated in vacuo to give tert-butyl N-[(8S,14S)-25-fluoro-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-18,18-dimethyl-9,15-dioxo-22-(2,2,2-trifluoroethyl)-4-triisopropylsilyloxy-16-oxa-10,22,28-triazapentacyclo[18.5.2.1 2,6 .1 10,14 .0 23,27 Nonacosa-1(26),2,4,6(29),20,23(27),24-heptaen-8-yl]carbamate (Compound G4, 780.0 mg) was obtained as a colorless gum and used directly in the next step. MS calculated 1066.5 (MH + ), found 1066.7 (MH + ).

[0132] Step 5: Preparation of tert-butyl N-[(8S,14S)-25-fluoro-4-hydroxy-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-18,18-dimethyl-9,15-dioxo-22-(2,2,2-trifluoroethyl)-16-oxa-10,22,28-triazapentacyclo[18.5.2.1 2,6 .1 10,14 .0 23,27 Nonacosa-1(26),2,4,6(29),20,23(27),24-heptaen-8-yl]carbamate (Compound G5) tert-Butyl N-[(8S,14S)-25-fluoro-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-18,18-dimethyl-9,15-dioxo-22-(2,2,2-trifluoroethyl)-4-triisopropylsilyloxy-16-oxa-10,22,28-triazapentacyclo[18.5.2.1 2,6 .1 10,14 .0 23,27 nonacosa-1(26),2,4,6(29),20,23(27),24-heptaen-8-yl]carbamate (Compound G4, 780.0 mg, 0.73 mmol) in THF (10 mL), tetrabutylammonium fluoride (0.8 mL, 0.8 mmol, 1 M in THF) was added at 0 °C. After stirring at 0 °C for 0.5 h, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL, 3 times). The combined organic layers were washed with brine (30 mL, 2 times), dried over Na2SO4, filtered, and concentrated in vacuo to give tert-Butyl N-[(8S,14S)-25-fluoro-4-hydroxy-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-18,18-dimethyl-9,15-dioxo-22-(2,2,2-trifluoroethyl)-16-oxa-10,22,28-triazapentacyclo[18.5.2.1 2,6 .1 10,14 .0 23,27 nonacosa-1(26),2,4,6(29),20,23(27),24-heptaen-8-yl]carbamate (Compound G5, 700.0 mg, 0.77 mmol) as a yellow solid, which was used directly in the next step. MS calculated 910.4 (MH + ), found 910.7 (MH + ).

[0133] Step 6: Preparation of (8S,14S)-8-amino-25-fluoro-4-hydroxy-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-18,18-dimethyl-22-(2,2,2-trifluoroethyl)-16-oxa-10,22,28-triazapentacyclo[18.5.2.1 2,6 .1 10,14 .0 23,27 nonacosa-1(26),2,4,6(29),20,23(27),24-heptaene-9,15-dione (Intermediate G) A mixture of tert-butyl N-[(8S,14S)-25-fluoro-4-hydroxy-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-18,18-dimethyl-9,15-dioxo-22-(2,2,2-trifluoroethyl)-16-oxa-10,22,28-triazapentacyclo[18.5.2.1 2,6 .1 10,14 .0 23,27 nonacosa-1(26),2,4,6(29),20,23(27),24-heptaen-8-yl]carbamate (Compound G5, 700.0 mg, 0.77 mmol) in DCM (10 mL) was added TFA (6.0 mL, 77.88 mmol). After stirring at 15 °C for 0.5 h, the reaction mixture was concentrated in vacuo, diluted with saturated NaHCO3 (15 mL), and extracted with EtOAc (50 mL, 2 times). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give (8S,14S)-8-amino-25-fluoro-4-hydroxy-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-18,18-dimethyl-22-(2,2,2-trifluoroethyl)-16-oxa-10,22,28-triazapentacyclo[18.5.2.1 2,6 .1 10,14 .0 23,27Nonacosa-1(26),2,4,6(29),20,23(27),24-heptaen-9,15-dione (Intermediate G, 600.0 mg) was obtained as a yellow solid and used directly in the next step. MS calculated value 810.3 (MH + ), measured value 810.4 (MH + ).

[0134] Intermediate H (7S,13S)-7-Amino-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaene 8,14-dione TIFF2025519199000049.tif The title compound was prepared in the same manner as Intermediate D by using iodoethane instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate.

[0135] Intermediate I (7S,13S)-7-Amino-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaene 8,14-dione TIFF2025519199000050.tif51170

[0136] The compound was prepared according to the following scheme. TIFF2025519199000051.tif247170

[0137] Step 1: Preparation of 4-[5-bromo-6-[(1S)-1-methoxyethyl]-3-pyridyl]morpholine (Compound I2) To a mixture of 3-bromo-5-iodo-2-[(1S)-1-methoxyethyl]pyridine (Compound I1, 3.4 g, 9.94 mmol) and morpholine (0.9 g, 9.94 mmol) in toluene (50 mL), cesium carbonate (8.1 g, 24.87 mmol), (R)-binap (0.3 g, 0.5 mmol) and palladium(II) acetate (0.1 g, 0.5 mmol) were added. The mixture was stirred at 100 °C for 12 h under a nitrogen atmosphere. After the reaction was completed, the mixture was filtered and concentrated in vacuo. The residue was purified by column chromatography (EtOAc in PE = 10% - 25%) to give 4-[5-bromo-6-[(1S)-1-methoxyethyl]-3-pyridyl]morpholine (Compound I2, 2100.0 mg) as a colorless oil. MS calculated value 301.1 (MH + ), measured value 301.1 (MH + ).

[0138] Step 2: Preparation of 4-[6-[(1S)-1-methoxyethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]morpholine (Compound I3) A mixture of 4-[5-bromo-6-[(1S)-1-methoxyethyl]-3-pyridyl]morpholine (Compound I2, 2.1 g, 6.97 mmol) and bis(pinacolato)diboron (2.1 g, 8.37 mmol) in 1,4-dioxane (25 mL) was added with KOAc (1.7 g, 17.43 mmol) and Pd(dppf)Cl2 (0.2 g, 0.35 mmol). The mixture was stirred at 90 °C for 12 h under a nitrogen atmosphere. After the reaction was completed, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (EtOAc in PE = 10% - 25%) to obtain 4-[6-[(1S)-1-methoxyethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]morpholine (Compound I3, 1100.0 mg) as a brown solid. MS calculated value 349.2 (MH + ), measured value 349.2 (MH + ).

[0139] Step 3: Preparation of [3-[5-bromo-6-fluoro-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-1H-indol-3-yl]-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (Compound I4) A mixture of [3-(5-bromo-6-fluoro-2-iodo-1H-indol-3-yl)-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (Compound D6, 1.9 g, 2.94 mmol) and 4-[6-[(1S)-1-methoxyethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]morpholine (Compound I3, 1.0 g, 2.94 mmol) in 1,4-dioxane (25 mL) and water (5 mL) was added with potassium phosphate (1.8 g, 8.64 mmol) and Pd(dppf)Cl2 (0.22 g, 0.29 mmol). The mixture was stirred at 70 °C for 12 h under a nitrogen atmosphere. After the reaction was completed, the reaction mixture was filtered, the filtrate was diluted with water (50 mL), and extracted with EtOAc (100 mL, 3 times). The combined organic phases were washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the residue by column chromatography gave [3-[5-bromo-6-fluoro-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-1H-indol-3-yl]-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (Compound I4, 1.4 g) as a yellow gum. MS calculated value 758.2 (MH + ), measured value 758.2 (MH + ).

[0140] Step 4: Preparation of [3-[5-bromo-6-fluoro-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-1-(2,2,2-trifluoroethyl)indol-3-yl]-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (Compound I5) [3-[5-Bromo-6-fluoro-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-1H-indol-3-yl]-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (Compound I4, 1.4 g, 1.89 mmol) and cesium carbonate (1.8 g, 5.67 mmol) in DMF (30 mL) were added dropwise with 2,2,2-trifluoroethyl trifluoromethanesulfonate (4.4 g, 18.9 mmol) at 0 °C, and the mixture was stirred at 30 °C for 16 h. After the reaction was completed, EtOAc (200 mL) and water (200 mL) were added, and the layers were separated. The aqueous phase was extracted with EtOAc (100 mL, twice). The combined organic layers were washed with brine (100 mL, three times), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (EtOAc in PE = 25% - 66%) to give [3-[5-bromo-6-fluoro-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-1-(2,2,2-trifluoroethyl)indol-3-yl]-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (Compound I5, 800.0 mg, Peak 1, eluting faster) as a brown solid. MS calculated value 840.1 (MH + ), measured value 840.1 (MH + ).

[0141] Step 5: Preparation of 3-[5-bromo-6-fluoro-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-1-(2,2,2-trifluoroethyl)indol-3-yl]-2,2-dimethyl-propan-1-ol (Compound I6) [3-[5-Bromo-6-fluoro-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-1-(2,2,2-trifluoroethyl)indol-3-yl]-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (Compound I5, 0.8 g, 0.95 mmol) in DMF (10 mL) was added cesium fluoride (0.7 g, 4.93 mmol), and the mixture was stirred at 60 °C for 15 h. After the reaction was completed, the reaction mixture was cooled to room temperature. EtOAc (70 mL) and water (100 mL) were added, and the layers were separated. The aqueous phase was extracted with EtOAc (70 mL, 2 times). The combined organic layers were washed with brine (80 mL, 4 times), dried over Na2SO4, filtered, and concentrated under vacuum to obtain a residue. The residue was purified by column chromatography (EtOAc in PE = 10% - 66%) to give 3-[5-bromo-6-fluoro-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-1-(2,2,2-trifluoroethyl)indol-3-yl]-2,2-dimethyl-propan-1-ol (Compound I6, 430.0 mg) as a yellow gum. MS calculated value 602.1 (MH + ), measured value 602.2 (MH + ).

[0142] Step 6: Preparation of 3-[6-Fluoro-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)indol-3-yl]-2,2-dimethyl-propan-1-ol (Compound I7)3-[5-Bromo-6-fluoro-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-1-(2,2,2-trifluoroethyl)indol-3-yl]-2,2-dimethyl-propan-1-ol (Compound I6, 430.0 mg, 0.71 mmol) and bis(pinacolato)diboron (199.3 mg, 0.79 mmol) in toluene (5 mL) were added with potassium acetate (0.1 mL, 1.78 mmol) and Pd(dppf)Cl2 (52.2 mg, 0.07 mmol), and the mixture was degassed for 2 minutes by bubbling nitrogen, and then the mixture was stirred at 90 °C for 15 hours under a nitrogen atmosphere. After the reaction was completed, the reaction mixture was filtered, and the filtrate was concentrated in vacuo to obtain a residue. The residue was purified by column chromatography (EtOAc in PE = 10% - 66%) to give 3-[6-fluoro-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)indol-3-yl]-2,2-dimethyl-propan-1-ol (Compound I7, 390.0 mg) as a colorless gum. MS calculated value 650.3 (MH + ), measured value 650.3 (MH + ).

[0143] Step 7: Preparation of methyl (3S)-1-[(2S)-2-(tert-butoxycarbonylamino)-3-[4-[6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-1-(2,2,2-trifluoroethyl)indol-5-yl]thiazol-2-yl]propanoyl]hexahydropyridazine-3-carboxylate (Compound I8) In toluene (4 mL), 1,4-dioxane (1.3 mL) and water (1.3 mL), to a mixture of 3-[6-fluoro-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)indol-3-yl]-2,2-dimethyl-propan-1-ol (Compound I7, 390.0 mg, 0.6 mmol) and methyl (3S)-1-[(2S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylate (Intermediate C, 291.6 mg, 0.61 mmol), K3PO4 (320.06 mg, 1.51 mmol) and Pd(dtbpf)Cl2 (39.1 mg, 0.06 mmol) were added. The mixture was stirred at 70 °C for 12 h under a nitrogen atmosphere. After the reaction was completed, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (EtOAc in PE = 10% - 75%) to give (3S)-1-[(2S)-2-(tert-butoxycarbonylamino)-3-[4-[6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-1-(2,2,2-trifluoroethyl)indol-5-yl]thiazol-2-yl]propanoyl]hexahydropyridazine-3-carboxylate (Compound I8, 200.0 mg) as a brown solid. MS calculated value 920.3 (MH + ), measured value 920.3 (MH + ).

[0144] Step 8: Preparation of (3S)-1-[(2S)-2-(tert-butoxycarbonylamino)-3-[4-[6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-1-(2,2,2-trifluoroethyl)indol-5-yl]thiazol-2-yl]propanoyl]hexahydropyridazine-3-carboxylic acid (Compound I9) A solution of methyl (3S)-1-[(2S)-2-(tert-butoxycarbonylamino)-3-[4-[6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-1-(2,2,2-trifluoroethyl)indol-5-yl]thiazol-2-yl]propanoyl]hexahydropyridazine-3-carboxylate (Compound I8, 170.0 mg, 0.18 mmol) in DCE (4 mL) was added trimethylstannanol (133.6 mg, 0.74 mmol). The mixture was stirred at 60 °C for 15 h. After the reaction was completed, the reaction mixture was cooled to room temperature. The reaction mixture was concentrated, then EtOAc (40 mL) and water (50 mL) were added and the layers were separated. The aqueous phase was extracted with EtOAc (50 mL, 2 times). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give (3S)-1-[(2S)-2-(tert-butoxycarbonylamino)-3-[4-[6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-1-(2,2,2-trifluoroethyl)indol-5-yl]thiazol-2-yl]propanoyl]hexahydropyridazine-3-carboxylic acid (Compound I9, 160.0 mg) as a yellow solid. MS calculated 906.3 (MH + ), found 906.3 (MH + ).

[0145] Step 9: tert-Butyl N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26Preparation of [[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]]octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamate (Compound I10) (3S)-1-[(2S)-2-(tert-Butoxycarbonylamino)-3-[4-[6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-1-(2,2,2-trifluoroethyl)indol-5-yl]thiazol-2-yl]propanoyl]hexahydropyridazine-3-carboxylic acid (Compound I9, 160.0 mg, 0.18 mmol) in DCM (15 mL) was added with EDCI (507.8 mg, 2.65 mmol) and DIEA (0.6 mL, 3.53 mmol), then HOBt (59.6 mg, 0.44 mmol) was added at 0 °C, and then the mixture was stirred at 20 °C for 15 h. After the reaction was completed, EtOAc (50 mL) and water (80 mL) were added, and the layers were separated. The aqueous phase was extracted with EtOAc (50 mL, 2 times). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain a residue. The residue was purified by column chromatography (EtOAc in PE = 25% - 66%) to give tert-butyl N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamate (Compound I10, 130.0 mg) was obtained as an off-white solid. MS calculated value 888.3 (MH + )), measured value 888.3 (MH + ).

[0146] Project 10: (7S,13S)-7-Amino-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 Preparation of octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate I) A solution of tert-butyl N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamate (Compound I10, 130.0 mg, 0.15 mmol) was added to TFA (0.6 mL, 8.27 mmol), and the mixture was stirred at 20 °C for 1 hour. After the reaction was completed, saturated NaHCO3 solution (40 mL) was added, and the mixture was extracted with EtOAc (50 mL, 3 times). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give (7S,13S)-7-amino-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate I, 105.0 mg) was obtained as a yellow solid. MS calculated value 788.3 (MH + ), measured value 788.3 (MH+ )。

[0147] Intermediate J (7S,13S)-7-Amino-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione TIFF2025519199000052.tif57170

[0148] By using 1-(2,2,2-trifluoroethyl)piperazine instead of morpholine, the title compound was prepared in the same manner as the preparation of Intermediate I.

[0149] Intermediate K (8S,14S)-8-Amino-26-fluoro-4-hydroxy-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-18,18-dimethyl-22-(2,2,2-trifluoroethyl)-16-oxa-10,22,28-triazapentacyclo[18.5.2.1 2,6 .1 10,14 .0 23,27 nonacosa-1(26),2,4,6(29),20,23(27),24-heptaene-9,15-dione The title compound TIFF2025519199000053.tif52170 was prepared by using benzyl 4-[(5M)-5-[5-bromo-4-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-1-(2,2,2-trifluoroethyl)indol-2-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (Compound K8) instead of benzyl 4-[(5M)-5-[5-bromo-1-ethyl-6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)indol-2-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (Compound D8) in the same manner as the preparation of Intermediate G.

[0150] Benzyl 4-[(5M)-5-[5-bromo-4-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-1-(2,2,2-trifluoroethyl)indol-2-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (Compound K8) was prepared by using 5-bromo-4-fluoro-1H-indole instead of 5-bromo-6-fluoro-1H-indole (Compound D2) in the same manner as the preparation of benzyl 4-[(5M)-5-[5-bromo-1-ethyl-6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)indol-2-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (Compound D8).

[0151] Intermediate L

[0152] (7S,13S)-7-amino-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazine-1-yl]-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26Octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione TIFF2025519199000054.tif57170The title compound was prepared in the same manner as Intermediate I by using 1-(2,2,2-trifluoroethyl)piperazine and iodoethane instead of morpholine and 2,2,2-trifluoroethyl trifluoromethanesulfonate.

[0153] Intermediate M (7S,13S)-7-amino-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo-[17.5.2.1 2,5 .1 9,13 .0 22,26 Octacosa-1(25),2,5(28),19,22(26),23-hexaene 8,14-dione TIFF2025519199000055.tif160170TIFF2025519199000056.tif201170

[0154] Step 1: Preparation of [3-[5-bromo-1-ethyl-6-fluoro-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]indol-3-yl]-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (Compound M1) [3-[5-Bromo-6-fluoro-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-1H-indol-3-yl]-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (Compound I4, 15 g, 19.77 mmol) in DMF (300 mL) was added with Cs2CO3 (19.3 g, 59.3 mmol) and iodoethane (6.16 g, 39.53 mmol) at 0 °C. After stirring at 20 °C for 16 h, the reaction mixture was poured into water (200 mL) and extracted with EtOAc (200 mL, 3 times). The combined organic layers were washed with brine (10 mL, 3 times), dried over Na2SO4, filtered, and concentrated under vacuum to give a residue. Purification of the residue by column chromatography gave [3-[5-bromo-1-ethyl-6-fluoro-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]indol-3-yl]-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (Compound M1, 14.7 g) as a yellow oil. MS calculated value 786.3 (MH + ), measured value 786.4 (MH + ).

[0155] Step 2: Preparation of 3-[5-bromo-1-ethyl-6-fluoro-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]indol-3-yl]-2,2-dimethyl-propan-1-ol (Compound M2) and 3-[5-bromo-1-ethyl-6-fluoro-(2P)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]indol-3-yl]-2,2-dimethyl-propan-1-ol (Compound M3) [3-[5-Bromo-1-ethyl-6-fluoro-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]indol-3-yl]-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (Compound M1, 14.7 g, 18.68 mmol) in DMF (160 mL) was added cesium fluoride (14.2 g, 93.41 mmol). The mixture was stirred at 60 °C for 48 h. After cooling to room temperature, EtOAc (300 mL) and water (300 mL) were added to the reaction mixture and the layers were separated. The aqueous phase was extracted with EtOAc (200 mL, 3 times). The combined organic layers were washed with brine (200 mL, 4 times), dried over Na2SO4, filtered, and concentrated in vacuo to give a residue. Purification of the residue by column chromatography gave 3-[5-bromo-1-ethyl-6-fluoro-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]indol-3-yl]-2,2-dimethyl-propan-1-ol (Compound M2, 6 g, eluting faster) as a colorless foam and 3-[5-bromo-1-ethyl-6-fluoro-(2P)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]indol-3-yl]-2,2-dimethyl-propan-1-ol (Compound M3, 4.5 g, eluting slower) as a colorless foam. Compound M2: MS calcd 548.2 (MH + ), found 548.2 (MH + ). 1 H NMR (400 MHz, methanol-d4) δ = 8.41 (d, J = 2.4 Hz, 1H), 7.92 (d, J = 6.8 Hz, 1H), 7.37 - 7.33 (m, 2H), 4.58 (s, 1H), 4.05 - 3.98 (m, 2H), 3.87 - 3.82 (m, 5H), 3.27 - 3.23 (m, 4H), 3.15 - 3.13 (m, 1H), 3.00 (s, 3H), 2.75 - 2.71 (m, 1H), 2.24 - 2.22 (m, 1H), 1.42 (d, J = 6.4 Hz, 3H), 1.22 (t, J = 7.2 Hz, 3H), 0.76 (s, 3H), 0.76 (s, 3H).

[0156] X-ray crystal structure analysis of Compound M2 The absolute configuration structure of compound M2 was confirmed by X-ray crystallographic analysis of its single crystal. (Figure 3). Step 3: Preparation of 3-[1-Ethyl-6-fluoro-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indol-3-yl]-2,2-dimethyl-propan-1-ol (Compound M4) To a solution of 3-[5-Bromo-1-ethyl-6-fluoro-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]indol-3-yl]-2,2-dimethyl-propan-1-ol (Compound M2, 6 g, 10.94 mmol) and bis(pinacolato)diboron (4.2 g, 16.41 mmol) in toluene (60 mL) were added potassium acetate (2.7 g, 27.35 mmol) and Pd(dppf)Cl2 (0.8 g, 1.09 mmol). The reaction mixture was degassed by bubbling nitrogen for 5 minutes and then stirred at 90 °C for 15 hours. 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 3-[1-Ethyl-6-fluoro-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indol-3-yl]-2,2-dimethyl-propan-1-ol (Compound M4, 4.5 g) as a colorless gum. MS calculated value 596.4 (MH + ), measured value 596.4 (MH + ).

[0157] Step 4: Preparation of Methyl (3S)-1-[(2S)-2-(tert-butoxycarbonylamino)-3-[4-[1-ethyl-6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]indol-5-yl]thiazol-2-yl]propanoyl]hexahydropyridazine-3-carboxylate (Compound M5) In toluene (45 mL), 1,4-dioxane (15 mL) and water (15 mL), to a mixture of 3-[1-ethyl-6-fluoro-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indol-3-yl]-2,2-dimethyl-propan-1-ol (Compound M4, 4.5 g, 7.56 mmol) and methyl (3S)-1-[(2S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylate (Intermediate C, 3.6 g, 7.56 mmol) were added K3PO4 (4.0 g, 18.89 mmol) and Pd(dtbpf)Cl2 (492.5 mg, 0.75 mmol). The mixture was stirred at 70 °C for 12 h under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give a residue. Purification of the residue by column chromatography gave methyl (3S)-1-[(2S)-2-(tert-butoxycarbonylamino)-3-[4-[1-ethyl-6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]indol-5-yl]thiazol-2-yl]propanoyl]hexahydropyridazine-3-carboxylate (Compound M5, 3.8 g) as a colorless gum. MS calculated 866.4 (MH + ), found 866.4 (MH + ).

[0158] Step 5: Preparation of (3S)-1-[(2S)-2-(tert-butoxycarbonylamino)-3-[4-[1-ethyl-6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]indol-5-yl]thiazol-2-yl]propanoyl]hexahydropyridazine-3-carboxylic acid (Compound M6) To a mixture of DCE (76 mL) and methyl (3S)-1-[(2S)-2-(tert-butoxycarbonylamino)-3-[4-[1-ethyl-6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]indol-5-yl]thiazol-2-yl]propanoyl]hexahydropyridazine-3-carboxylate (Compound M5, 3.8 g, 4.39 mmol), Me3SnOH (3.2 g, 17.55 mmol) was added. The mixture was stirred at 60 °C for 48 h. The reaction mixture was concentrated under vacuum to give a residue. EtOAc (200 mL) and water (100 mL) were added to the residue and the layers were separated. The aqueous phase was extracted with EtOAc (150 mL, 2 times). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give (3S)-1-[(2S)-2-(tert-butoxycarbonylamino)-3-[4-[1-ethyl-6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]indol-5-yl]thiazol-2-yl]propanoyl]hexahydropyridazine-3-carboxylic acid (Compound M6, 3.7 g) as a brown solid. MS calculated 852.4 (MH + ), found 852.4 (MH + ).

[0159] Step 6: Preparation of tert-butyl N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaene-7-yl]carbamate (Compound M7) (3S)-1-[(2S)-2-(tert-Butoxycarbonylamino)-3-[4-[1-Ethyl-6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]indol-5-yl]thiazol-2-yl]propanoyl]hexahydropyridazine-3-carboxylic acid (Compound M6, 2.5 g, 2.93 mmol) in a mixture of DCM (250 mL), DIEA (7.58 mL, 58.68 mmol), EDCI (8.4 g, 44.01 mmol) and HOBt (991.2 mg, 0.91 mmol) were added at 0 °C. After stirring at 20 °C for 12 h, the reaction mixture was poured into water (100 mL) and extracted with EtOAc (100 mL, 3 times). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under vacuum to give a residue, which was purified by column chromatography to give tert-butyl N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaene-7-yl]carbamate (Compound M7, 1.2 g) was obtained as a yellow oil. MS calculated value 834.4 (MH + ), measured value 834.4 (MH + ).

[0160] Step 7: (7S,13S)-7-Amino-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26Preparation of Octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate M) In DCM (12 mL), tert-butyl N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 To a solution of [Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamate (Compound M7, 1.2 g, 1.44 mmol) in TFA (6.0 mL) was added. The mixture was stirred at 20 °C for 3 hours. After the reaction was complete, the reaction mixture was concentrated under vacuum to obtain a residue. Saturated aqueous NaHCO3 (60 mL) was added, and the mixture was extracted with EtOAc (80 mL, 3 times). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give (7S,13S)-7-amino-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 Octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate M, 1 g) was obtained as a yellow solid. MS calculated value 734.3 (MH + ), measured value 734.3 (MH + ).

[0161] Intermediate N (7S,13S)-7-Amino-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .19,13 .0 22,26 Octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione TIFF2025519199000057.tif57170 In the same manner as the preparation of Intermediate I, 2-[(1S)-1-methoxyethyl]-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (Compound N1) was used in place of 4-[6-[(1S)-1-methoxyethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]morpholine (Compound I3) to prepare the title compound.

[0162] Compound N1 was prepared in the same manner as the preparation of Intermediate A, using 3-bromo-2-[(1S)-1-methoxyethyl]pyridine (Compound A1) in place of benzyl 4-[5-bromo-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (Intermediate A5).

[0163] Example 1 (3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(7S,13S)-25-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide TIFF2025519199000058.tif62170 The compound was prepared according to the following scheme. TIFF2025519199000059.tif187170

[0164] Project 1: tert-Butyl N-[(1S)-1-[[(7S,13S)-25-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-carbamate (Compound 1B) Preparation. (7S,13S)-7-Amino-25-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26To a solution of octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate E, 150.0 mg, 0.19 mmol) in DMF (1.5 mL) was added a solution of BOC-N-ME-VAL-OH (Compound 1A, 75.0 mg, 0.32 mmol), DIEA (0.1 mL, 0.58 mmol) and HATU (120.0 mg, 0.32 mmol) in DMF (1.5 mL) at 0 °C, and the mixture was stirred at 20 °C for 1 h. After the reaction was complete, the reaction mixture was poured into water (30 mL) and extracted with EtOAc (20 mL, 3 times). The combined organic layers were washed with brine (30 mL, 3 times), dried over Na2SO4, filtered, concentrated under vacuum to give a residue, which was purified by preparative HPLC. The eluent was concentrated in vacuo to give tert-butyl N-[(1S)-1-[[(7S,13S)-25-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-carbamate (Compound 1B, 150.0 mg) as a yellow solid. MS calculated value 1014.5 (MH + ), measured value 1014.5 (MH + ).

[0165] Step 2: (2S)-N-[(7S,13S)-25-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26Preparation of [[(Z)-N-[(7S,13S)-25-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.111,15.022,26.027,31]henicosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-2-(methylamino)butanamide (Compound 1C)]] A solution of tert-butyl N-[(1S)-1-[[(7S,13S)-25-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-carbamate (Compound 1B, 100.0 mg, 0.1 mmol) in DCM (1 mL) was treated with TFA (1.0 mL) and the mixture was stirred at 20 °C for 2 h. After completion of the reaction, the reaction mixture was concentrated under vacuum to give a residue. Saturated aqueous NaHCO3 (20 mL) was added and the mixture was extracted with EtOAc (20 mL, 3×). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give (2S)-N-[(7S,13S)-25-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-2-(methylamino)butanamide (Compound 1C, 90.0 mg) was obtained as a yellow solid. MS calcd for 914.4 (MH + +), found 914.4 (MH + +).

[0166] Step 3: tert-Butyl (3S)-3-[[(1S)-1-[[(7S,13S)-25-Fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-methyl-carbamoyl]pyrrolidine-1-carboxylate (Compound 1E) Preparation (2S)-N-[(7S,13S)-25-Fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26A solution of [[(7S,13S)-25-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-2-(methylamino)butanamide (Compound 1C, 90.0 mg, 0.1 mmol) in DMF (1.5 mL) was added with a solution of (S)-1-Boc-pyrrolidine-3-carboxylic acid (Compound 1D, 31.9 mg, 0.15 mmol), DIEA (0.1 mL, 0.33 mmol), and HATU (57.2 mg, 0.15 mmol) at 0 °C, and then the mixture was stirred at 20 °C for 1 h. After the reaction was completed, the reaction mixture was poured into water (20 mL) and extracted with EtOAc (20 mL, 3 times). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain a residue, which was purified by preparative-HPLC to give tert-butyl (3S)-3-[[(1S)-1-[[(7S,13S)-25-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1

[0167] Step 4: (3S)-N-[(1S)-1-[[(7S,13S)-25-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-methyl-carbamoyl]pyrrolidine-1-carboxylate (Compound 1E, 40.0 mg) as a yellow solid. MS calculated value 1111.5 (MH + +), measured value 1111.6 (MH + +).22,26 Preparation of [[(7S,13S)-25-fluoro-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.111,15.02,6.122,26.123,25]octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide (Compound 1F) tert-Butyl (3S)-3-[[(1S)-1-[[(7S,13S)-25-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.111,15.02,6.122,26.123,25]octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-methyl-carbamoyl]pyrrolidine-1-carboxylate (Compound 1E, 40.0 mg, 0.04 mmol) in DCM (1 mL) was added with TFA (0.3 mL), and the mixture was stirred at 20 °C for 1 h. After the reaction was completed, the reaction mixture was concentrated under vacuum to obtain a residue. Saturated aqueous NaHCO3 (20 mL) was added, and the mixture was extracted with EtOAc (15 mL, 3 times). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give (3S)-N-[(1S)-1-[[(7S,13S)-25-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.111,15.02,6.122,26.123,25]octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide (Compound 1F, 25.0 mg) was obtained as a yellow solid. MS calculated value 1011.4 (MH 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-methyl-carbamoyl]pyrrolidine-1-carboxylate (Compound 1E, 40.0 mg, 0.04 mmol) in DCM (1 mL) was added with TFA (0.3 mL), and the mixture was stirred at 20 °C for 1 h. After the reaction was completed, the reaction mixture was concentrated under vacuum to obtain a residue. Saturated aqueous NaHCO3 (20 mL) was added, and the mixture was extracted with EtOAc (15 mL, 3 times). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give (3S)-N-[(1S)-1-[[(7S,13S)-25-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.111,15.02,6.122,26.123,25]octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide (Compound 1F, 25.0 mg) was obtained as a yellow solid. MS calculated value 1011.4 (MH 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide (Compound 1F, 25.0 mg) was obtained as a yellow solid. MS calculated value 1011.4 (MH +) Measurement value 1011.4 (MH + )

[0168] Step 5: (3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(7S,13S)-25-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide (Preparation of Example 1) (2R)-2-chloro-2-fluoro-acetic acid (23.0 mg, 0.2 mmol), (3S)-N-[(1S)-1-[[(7S,13S)-25-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26A solution of [[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(7S,13S)-25-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide (Compound 1F, 25.0 mg, 0.02 mmol) and DIEA (0.1 mL, 0.77 mmol) in DMF (2 mL) was added T3P (130.0 mg, 0.2 mmol) at 0 °C and the mixture was stirred at 20 °C for 1 h. After completion of the reaction, the reaction mixture was poured into water (20 mL) and extracted with EtOAc (20 mL, 3 times). The combined organic layers were washed with brine (30 mL, 3 times), dried over Na2SO4, filtered and concentrated under vacuum to give a residue which was purified by preparative HPLC to give [[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(7S,13S)-25-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 + ) (3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(7S,13S)-25-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 + . 1 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide (Example 1, 9.4 mg) was obtained as a white solid. MS calculated 1105.4 (MH + ), found 1105.8 (MH + ). 11H NMR (400 MHz, methanol-d4) δ = 8.52 (d, J = 2.8 Hz, 1H), 7.59 - 7.41 (m, 4H), 7.01 - 6.70 (m, 1H), 5.97 - 5.85 (m, 1H), 5.22 - 5.04 (m, 1H), 4.68 - 4.63 (m, 1H), 4.43 - 4.35 (m, 1H), 4.11 - 3.91 (m, 3H), 3.81 - 3.48 (m, 13H), 3.44 - 3.39 (m, 1H), 3.28 - 3.24 (m, 1H), 3.23 - 3.11 (m, 6H), 3.05 - 2.97 (m, 4H), 2.92 - 2.80 (m, 1H), 2.66 - 2.55 (m, 1H), 2.39 - 1.97 (m, 4H), 1.71 - 1.60 (m, 1H), 1.46 (d, J = 6.4 Hz, 3H), 1.35 - 1.27 (m, 2H), 1.18 (t, J = 7.2 Hz, 3H), 0.98 - 0.79 (m, 9H), 0.67 - 0.57 (m, 2H) ppm.

[0169] Example 2 (3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide TIFF2025519199000060.tif67170

[0170] In the same manner as the preparation of Example 1, (7S,13S)-7-amino-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo-[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-8,14-dione (Intermediate D) was used instead of (7S,13S)-7-amino-25-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-8,14-dione (Intermediate E) to prepare the title compound. Example 2 (39.0 mg) was obtained as a white solid. MS calculated value 1105.4 (MH + ), measured value 1105.6 (MH + ). 11H NMR (400 MHz, methanol-d4) δ = 8.68 (d, J = 7.6 Hz, 1H), 8.57 - 8.49 (m, 1H), 7.79 - 7.66 (m, 1H), 7.56 - 7.43 (m, 2H), 6.95 - 6.72 (m, 1H), 5.83 - 5.61 (m, 1H), 5.30 - 5.10 (m, 1H), 4.96 - 4.88 (m, 3H), 4.82 (dd, J = 11.2, 3.6 Hz, 1H), 4.52 - 4.36 (m, 1H), 4.29 - 4.17 (m, 2H), 4.15 - 3.93 (m, 2H), 3.90 - 3.67 (m, 6H), 3.66 - 3.55 (m, 2H), 3.55 - 3.41 (m, 2H), 3.36 (d, J = 2.8 Hz, 3H), 3.34 - 3.32 (m, 1H), 3.30 - 3.23 (m, 2H), 3.19 - 3.14 (m, 1H), 3.14 - 3.09 (m, 3H), 3.03 - 2.96 (m, 3H), 2.89 - 2.74 (m, 1H), 2.63 - 2.50 (m, 1H), 2.45 - 2.21 (m, 3H), 2.20 - 1.91 (m, 2H), 1.90 - 1.75 (m, 1H), 1.72 - 1.57 (m, 1H), 1.45 (d, J = 6.4 Hz, 3H), 1.11 - 0.98 (m, 3H), 0.98 - 0.94 (m, 3H), 0.94 - 0.84 (m, 3H), 0.54 - 0.34 (m, 3H) ppm.

[0171] Example 3 (3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17,24-trimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide TIFF2025519199000061.tif68170

[0172] In the same manner as the preparation of Example 1, (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17,24-trimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo-[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate F) was used instead of (7S,13S)-7-amino-25-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate E) to prepare the title compound. Example 3 (4.7 mg) was obtained as a white solid. MS calculated value 1101.5 (MH + ), measured value 1101.6 (MH + ). 11H NMR (400 MHz, methanol-d4) δ = 8.52 - 8.47 (m, 1H), 8.15 - 7.98 (m, 1H), 7.54 - 7.37 (m, 3H), 6.95 - 6.70 (m, 1H), 5.85 - 5.75 (m, 1H), 5.35 - 5.07 (m, 2H), 4.78 - 4.67 (m, 1H), 4.50 - 4.38 (m, 1H), 4.25 - 4.14 (m, 1H), 4.12 - 3.95 (m, 2H), 3.91 - 3.55 (m, 10H), 3.50 - 3.07 (m, 5H), 3.00 (s, 3H), 2.79 - 2.64 (m, 1H), 2.62 - 2.43 (m, 4H), 2.40 - 2.12 (m, 4H), 2.10 - 1.84 (m, 3H), 1.72 - 1.49 (m, 3H), 1.47 - 1.41 (m, 3H), 1.39 - 1.32 (m, 2H), 1.29 - 1.23 (m, 3H), 0.98 - 0.95 (m, 3H), 0.95 - 0.91 (m, 3H), 0.88 - 0.84 (m, 3H), 0.43 - 0.36 (m, 3H) ppm.

[0173] Examples 4 and 5 (2S)-2-[(5R)-7-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butanamide (Example 4) TIFF2025519199000062.tif73170 (Example 4) (2S)-2-[(5S)-7-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butanamide (Example 5) TIFF2025519199000063.tif63170 (Example 5)

[0174] Example 4 was prepared according to the following scheme. TIFF2025519199000064.tif94170

[0175] Step 1: tert-butyl (5S)-2-[(1S)-1-[[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-1-oxo-2,7-diazaspiro[4.4]nonane-7-carboxylate (Compound 4A) Preparation (2S)-2-[(5S)-7-tert-Butoxycarbonyl-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-3-methyl-butanoic acid (Compound 4f2, 85.0 mg, 0.25 mmol) in DMF (3 mL) was added with HATU (94.9 mg, 0.25 mmol) and DIEA (0.1 mL, 0.37 mmol). After stirring at 20 °C for 0.2 h, (7S,13S)-7-amino-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate D, 100.0 mg, 0.12 mmol) was added. The reaction mixture was stirred at 20 °C for an additional 2 h. After completion of the reaction, the reaction mixture was directly purified by reverse-phase flash column, and the eluent was concentrated under vacuum to remove ACN. The aqueous layer was neutralized with NaHCO3 and extracted with EtOAc (10 mL, 3 times). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give tert-butyl (5S)-2-[(1S)-1-[[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-1-oxo-2,7-diazaspiro[4.4]nonane-7-carboxylate (Compound 4A, 120.0 mg) as a yellow solid. MS calculated value 1123.6 (MH + ), measured value 1123.6 (MH+ )。

[0176] Project 2: (2S)-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-2-[(5R)-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]butanamide (Compound 4B) Preparation tert-Butyl (5S)-2-[(1S)-1-[[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26A solution of [[ID=]], 2,5 .1 9,13 .0 22,26 octa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-2-[(5R)-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]butanamide (Compound 4B, 120.0 mg) was obtained as a yellow solid. MS calculated value 1023.5 (MH + ), measured value 1023.5 (MH + ).

[0177] Step 3: (2S)-2-[(5R)-7-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .19,13 .0 22,26 Preparation of [[(7S,13S)-24-fluoro-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1]]-N-[(7S,13S)-24-fluoro-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 (2S)-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 Preparation of [[(7S,13S)-24-fluoro-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1]]-N-[(7S,13S)-24-fluoro-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26+ )、Measured value 1117.4 (MH + )。1H NMR (400 MHz, methanol-d4) δ: 8.68 (d, J = 7.2 Hz, 1H), 8.50 (d, J = 2.8 Hz, 1H), 7.82 - 7.69 (m, 1H), 7.52 - 7.45 (m, 2H), 6.95 - 6.72 (m, 1H), 5.72 - 5.65 (m, 1H), 5.21 - 5.14 (m, 1H), 4.46 - 4.38 (m, 1H), 4.37 - 4.31 (m, 1H), 4.27 - 4.20 (m, 2H), 4.16 - 3.97 (m, 2H), 3.97 - 3.88 (m, 1H), 3.88 - 3.72 (m, 4H), 3.72 - 3.54 (m, 6H), 3.53 - 3.44 (m, 3H), 3.35 (d, J = 4.2 Hz, 2H), 3.19 - 3.13 (m, 2H), 3.00 (s, 3H), 2.86 - 2.78 (m, 1H), 2.62 - 2.51 (m, 1H), 2.34 - 2.19 (m, 3H), 2.18 - 2.07 (m, 3H), 2.06 - 1.93 (m, 2H), 1.89 - 1.77 (m, 1H), 1.69 - 1.60 (m, 1H), 1.45 (d, J = 6.0 Hz, 3H), 1.37 - 1.26 (m, 2H), 1.03 - 0.96 (m, 6H), 0.93 - 0.89 (m, 3H), 0.46 - 0.40 (m, 3H) ppm.

[0178] Example 5 was prepared in the same manner as the preparation of Example 4, using (2S)-2-[(5R)-7-tert-butoxycarbonyl-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-3-methyl-butyric acid (Compound 4f1) instead of (2S)-2-[(5S)-7-tert-butoxycarbonyl-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-3-methyl-butyric acid (Compound 4f2). Example 5 (44 mg) was obtained as a white solid. MS calculated value 1117.4 (MH + )、Measured value 1117.4 (MH + )。 1 + [Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butanamide (Example 4, 54.4 mg) was obtained as a yellow solid. MS calculated value 1117.4 (MH)、Measured value 1117.4 (MH + )。1H NMR (400 MHz, methanol-d4) δ: 8.68 (d, J = 7.2 Hz, 1H), 8.50 (d, J = 2.8 Hz, 1H), 7.82 - 7.69 (m, 1H), 7.52 - 7.45 (m, 2H), 6.95 - 6.72 (m, 1H), 5.72 - 5.65 (m, 1H), 5.21 - 5.14 (m, 1H), 4.46 - 4.38 (m, 1H), 4.37 - 4.31 (m, 1H), 4.27 - 4.20 (m, 2H), 4.16 - 3.97 (m, 2H), 3.97 - 3.88 (m, 1H), 3.88 - 3.72 (m, 4H), 3.72 - 3.54 (m, 6H), 3.53 - 3.44 (m, 3H), 3.35 (d, J = 4.2 Hz, 2H), 3.19 - 3.13 (m, 2H), 3.00 (s, 3H), 2.86 - 2.78 (m, 1H), 2.62 - 2.51 (m, 1H), 2.34 - 2.19 (m, 3H), 2.18 - 2.07 (m, 3H), 2.06 - 1.93 (m, 2H), 1.89 - 1.77 (m, 1H), 1.69 - 1.60 (m, 1H), 1.45 (d, J = 6.0 Hz, 3H), 1.37 - 1.26 (m, 2H), 1.03 - 0.96 (m, 6H), 0.93 - 0.89 (m, 3H), 0.46 - 0.40 (m, 3H) ppm.

[0178] Example 5 was prepared in the same manner as the preparation of Example 4, using (2S)-2-[(5R)-7-tert-butoxycarbonyl-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-3-methyl-butyric acid (Compound 4f1) instead of (2S)-2-[(5S)-7-tert-butoxycarbonyl-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-3-methyl-butyric acid (Compound 4f2). Example 5 (44 mg) was obtained as a white solid. MS calculated value 1117.4 (MH + )、Measured value 1117.4 (MH + )。 1 ​​​​​​​​​​​​1H NMR (400 MHz, methanol-d4) δ = 8.74 - 8.68 (m, 1H), 8.56 - 8.50 (m, 1H), 7.76 - 7.69 (m, 1H), 7.62 - 7.56 (m, 1H), 7.54 - 7.47 (m, 1H), 6.96 - 6.73 (m, 1H), 5.75 - 5.64 (m, 1H), 5.20 (dd, J = 8.4, 16.4 Hz, 1H), 4.46 - 4.40 (m, 1H), 4.35 (dd, J = 4.8, 11.1 Hz, 1H), 4.31 - 4.19 (m, 2H), 4.18 - 4.02 (m, 2H), 3.95 (dd, J = 4.9, 10.1 Hz, 1H), 3.85 - 3.72 (m, 4H), 3.71 - 3.61 (m, 3H), 3.56 - 3.42 (m, 4H), 3.38 (s, 4H), 3.27 (dd, J = 5.1, 10.0 Hz, 2H), 3.21 - 3.14 (m, 1H), 3.21 - 3.12 (m, 1H), 3.01 (s, 3H), 2.90 - 2.79 (m, 1H), 2.60 (d, J = 14.5 Hz, 1H), 2.33 - 2.20 (m, 3H), 2.17 - 2.05 (m, 3H), 2.02 - 1.92 (m, 1H), 1.90 - 1.78 (m, 1H), 1.76 - 1.60 (m, 1H), 1.48 (d, J = 6.1 Hz, 3H), 1.37 - 1.30 (m, 1H), 1.06 - 0.99 (m, 6H), 0.95 - 0.87 (m, 3H), 0.47 (s, 3H) ppm.

[0179] Compounds 4f1 and 4f2 were prepared according to the following scheme. TIFF2025519199000065.tif145170

[0180] Step 1: Preparation of 1-(tert-butyl) 3-methyl 3-allyl pyrrolidine-1,3-dicarboxylate (Compound 4b) To a solution of 1-(tert-butyl) 3-methylpyrrolidine-1,3-dicarboxylate (Compound 4a, 5.0 g, 21.8 mmol) in THF (60 mL) was added dropwise LDA (12 mL, 24 mmol) at -70 °C under a nitrogen atmosphere. After stirring for 0.5 h, allyl bromide (2.9 g, 23.99 mmol) was slowly added. After the reaction was completed, the reaction mixture was poured into saturated NH4Cl solution (100 mL) and extracted with EtOAc (70 mL, twice). The combined organic layers were washed with brine (70 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain a residue, which was purified by silica gel column to give 1-(tert-butyl) 3-methyl 3-allylpyrrolidine-1,3-dicarboxylate (Compound 4b, 2.91 g) as a colorless oil.

[0181] Step 2: Preparation of 1-(tert-butyl) 3-methyl 3-(2-oxoethyl)pyrrolidine-1,3-dicarboxylate (Compound 4c) To a mixture of 1-(tert-butyl) 3-methyl 3-allylpyrrolidine-1,3-dicarboxylate (Compound 4b, 2.1 g, 7.8 mmol) in 1,4-dioxane (60 mL) and water (6 mL) were added 2,6-lutidine (1.8 mL, 15.6 mmol) and K2OsO4 (0.1 g, 0.39 mmol) at 0 °C all at once. After stirring at 0 °C for 15 min, sodium metaperiodate (6.6 g, 31.19 mmol) was added portionwise at 0 °C. The resulting mixture was warmed to 20 °C and stirred for an additional 6 h. After the reaction was completed, it was quenched with saturated aqueous Na2S2O3 (100 mL), and the reaction mixture was extracted with EtOAc (50 mL, three times). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give 1-(tert-butyl) 3-methyl 3-(2-oxoethyl)pyrrolidine-1,3-dicarboxylate (Compound 4c, 2.1 g) as a yellow oil, which was used directly in the next step.

[0182] Step 3: Preparation of 1-(tert-butyl) 3-methyl 3-(2-(((S)-1-(benzyloxy)-3-methyl-1-oxobutan-2-yl)amino)ethyl)pyrrolidine-1,3-dicarboxylate (Compound 4d) To a mixture of 1-(tert-butyl) 3-methyl 3-(2-oxoethyl)pyrrolidine-1,3-dicarboxylate (Compound 4c, 2.1 g, 7.74 mmol) and benzyl (2S)-2-amino-3-methyl-butanoate (1.6 g, 7.74 mmol) in methanol (20 mL), zinc chloride (1.05 g, 7.74 mmol) was added at once at 0 °C. After stirring at 0 °C for 1 h, sodium cyanoborohydride (0.97 g, 15.48 mmol) was added to the mixture at 0 °C. The resulting mixture was stirred at 0 °C for an additional 2 h. After completion of the reaction, the mixture was poured into a saturated aqueous NH4Cl solution (40 mL) at 0 °C and extracted with EtOAc (50 mL, 3 times). The combined organic layers were washed with brine (30 mL, 4 times), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a residue, which was purified by silica gel column chromatography to afford 1-(tert-butyl) 3-methyl 3-(2-(((S)-1-(benzyloxy)-3-methyl-1-oxobutan-2-yl)amino)ethyl)pyrrolidine-1,3-dicarboxylate (Compound 4d, 2.2 g) as a yellow oil. MS calculated value 463.3 (MH + ), measured value 463.2 (MH + ).

[0183] Step 4: Preparation of tert-butyl 7-((S)-1-(benzyloxy)-3-methyl-1-oxobutan-2-yl)-6-oxo-2,7-diazaspiro[4.4]nonane-2-carboxylate (Compounds 4e 1 and 4e 2) A mixture of 1-(tert-butyl) 3-methyl 3-(2-(((S)-1-(benzyloxy)-3-methyl-1-oxobutan-2-yl)amino)ethyl)pyrrolidine-1,3-dicarboxylate (Compound 4d, 2.1 g, 4.54 mmol) in toluene (20 mL) was added with DIEA (7.9 mL, 45.4 mmol) and DMAP (0.6 g, 4.54 mmol) at once. The mixture was heated to 80 °C and stirred for 16 h. After the reaction was completed, the mixture was poured into water (30 mL) and extracted with EtOAc (30 mL, 3 times). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain a residue, which was purified by reverse-phase flash column and the eluent was concentrated under vacuum. Further separation of the residue by preparative SFC gave tert-butyl 7-((S)-1-(benzyloxy)-3-methyl-1-oxobutan-2-yl)-6-oxo-2,7-diazaspiro[4.4]nonane-2-carboxylate (Compound 4e 1, eluting faster, 521 mg, Compound 4e 2, eluting slower, 525 mg). MS calculated value 453.3 (MNa + ), measured value 453.2 (MNa + ).

[0184] Step 5: Preparation of (2S)-2-[(5R)-7-tert-butoxycarbonyl-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-3-methyl-butanoic acid (Compound 4f1) A solution of tert-butyl (R)-7-((S)-1-(benzyloxy)-3-methyl-1-oxobutan-2-yl)-6-oxo-2,7-diazaspiro[4.4]nonane-2-carboxylate (Compound 4e1, 120 mg, 0.28 mmol) in toluene (2 mL) was added with wet palladium (12 mg, 10 wt% on activated carbon). The mixture was degassed and purged with hydrogen three times. The reaction mixture was heated to 35 °C and stirred under a hydrogen atmosphere for 3 hours. After the reaction was completed, the solution was filtered and the filtrate was concentrated in vacuo to give (2S)-2-[(5R)-7-tert-butoxycarbonyl-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-3-methyl-butanoic acid (Compound 4f1, 94 mg) as a white solid. MS calculated value 363.2 (MNa + ), measured value 363.1 (MNa + ).

[0185] X-ray crystal analysis of Compound 4f1 The absolute configuration structure of Compound 4f1 was confirmed by X-ray crystal analysis of its single crystal. (Figure 1)

[0186] Step 6: Preparation of (2S)-2-[(5S)-7-tert-butoxycarbonyl-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-3-methyl-butanoic acid (Compound 4f2) A solution of tert-butyl (S)-7-((S)-1-(benzyloxy)-3-methyl-1-oxobutan-2-yl)-6-oxo-2,7-diazaspiro[4.4]nonane-2-carboxylate (Compound 4e 2, 120 mg, 0.28 mmol) in toluene (2 mL) was added with wet palladium (12 mg, 10 wt% on activated carbon). The mixture was degassed and purged with hydrogen three times. The mixture was heated to 35 °C and stirred under a hydrogen atmosphere for 3 hours. After the reaction was completed, the solution was filtered and the filtrate was concentrated in vacuo to give (2S)-2-[(5S)-7-tert-butoxycarbonyl-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-3-methyl-butanoic acid (Compound 4f2, 79 mg) as a white solid. MS calculated value 363.2 (MNa + ), measured value 363.1 (MNa+ )。

[0187] X-ray crystal analysis of compound 4f2 The absolute configuration structure of compound 4f2 was confirmed by X-ray crystal analysis of its single crystal. (Figure 2)

[0188] Example 6 (2S)-2-[9-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,9-diazaspiro[5.5]undecane-2-yl]-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butanamide TIFF2025519199000066.tif72170Example 6 was prepared according to the following scheme. TIFF2025519199000067.tif133170

[0189] Step 1: Preparation of tert-butyl 2-[(1S)-1-[[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-1-oxo-2,9-diazaspiro[5.5]undecane-9-carboxylate (Compound 6K) (2S)-2-(9-tert-Butoxycarbonyl-1-oxo-2,9-diazaspiro[5.5]undecan-2-yl)-3-methyl-butanoic acid (Compound 6J, 138.0 mg, 0.37 mmol) in DMF (2 mL) was added with DIEA (0.2 mL, 0.94 mmol) and HATU (106.8 mg, 0.28 mmol). After stirring at 20 °C for 10 minutes, a solution of (7S,13S)-7-amino-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate D, 150.0 mg, 0.19 mmol) in DMF (2 mL) was added, and the reaction mixture was stirred at 20 °C for 50 minutes. After the reaction was completed, the reaction mixture was added to water (20 mL) and extracted with EtOAc (20 mL, 3 times). The combined organic layers were washed with brine (20 mL, 3 times), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain a residue, which was purified by reverse-phase flash column to give tert-butyl 2-[(1S)-1-[[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaene-7-yl]carbamoyl]-2-methyl-propyl]-1-oxo-2,9-diazaspiro[5.5]undecane-9-carboxylate (Compound 6K, 125.0 mg) as a yellow solid. MS calculated value 1151.6 (MH +) Measurement value 1151.8 (MH + )。

[0190] Step 2: (2S)-N-[(7S,13S)-24-Fluoro-(20M)-20-[2-[(1S)-1-Methoxyethyl]-5-(4-Methylpiperazin-1-yl)-3-pyridyl]-17,17-Dimethyl-8,14-Dioxo-21-(2,2,2-Trifluoroethyl)-15-Oxa-4-Thia-9,21,27,28-Tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 Octacosa-1(25),2,5(28),19,22(26),23-Hexaene-7-yl]-3-Methyl-2-(1-Oxo-2,9-Diazaspiro[5.5]Undecane-2-yl)Butanamide (Compound 6L) Preparation tert-Butyl 2-[(1S)-1-[[(7S,13S)-24-Fluoro-(20M)-20-[2-[(1S)-1-Methoxyethyl]-5-(4-Methylpiperazin-1-yl)-3-pyridyl]-17,17-Dimethyl-8,14-Dioxo-21-(2,2,2-Trifluoroethyl)-15-Oxa-4-Thia-9,21,27,28-Tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26A solution of [[ID=]], 2,5 .1 9,13 .0 22,26 -[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 + )-carbamoyl]-2-methyl-propyl]-1-oxo-2,9-diazaspiro[5.5]undecane-9-carboxylate (Compound 6K, 125.0 mg, 0.11 mmol) was added to TFA (0.6 mL, 7.73 mmol). The mixture was stirred at 20 °C for 0.5 h. After completion of the reaction, the reaction mixture was added to saturated aqueous NaHCO3 (20 mL) and extracted with EtOAc (20 mL, 3 times). The combined organic layers were washed with brine (20 mL, 3 times), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give (2S)-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 + ).

[0191] Step 3: (2S)-2-[9-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,9-diazaspiro[5.5]undecane-2-yl]-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26Preparation of [[(7S,13S)-24-fluoro-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.111,15]henicosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methylbutanamide (Example 6) (2S)-N-[(7S,13S)-24-Fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 (7S,13S)-24-Fluoro-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.111,15]henicosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-2-(1-oxo-2,9-diazaspiro[5.5]undecan-2-yl)butanamide (Compound 6L, 110.0 mg, 0.1 mmol) and (R)-2-chloro-2-fluoroacetic acid (58.8 mg, 0.52 mmol) in DMF (3 mL) were added with DIEA (0.1 mL, 0.52 mmol) and T3P (99.9 mg, 0.16 mmol) at 0 °C. The mixture was stirred at 20 °C for 1 h. After the reaction was completed, the reaction mixture was poured into water (40 mL) and extracted with EtOAc (20 mL, 3 times). The combined organic layers were washed with brine (20 mL, 3 times), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum to obtain a residue, which was purified by preparative HPLC to give (2S)-2-[9-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,9-diazaspiro[5.5]undecan-2-yl]-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26+ Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butanamide (Example 6, 17.7 mg) was obtained as a white solid. MS calculated value 1145.5 (MH + ), measured value 1145.3 (MH 1 ).

[0192] Compound 6J was prepared according to the following scheme. TIFF2025519199000068.tif119170

[0193] Step 1: Preparation of O1-tert-butyl O4-methyl 4-but-3-enylpiperidine-1,4-dicarboxylate (Compound 6C) ​​​​​​​​​​​A solution of O1-tert-butyl O4-methyl piperidine-1,4-dicarboxylate (Compound 6A, 5.0 g, 20.55 mmol) in THF (80 mL) was added with LDA (11.3 mL, 22.61 mmol) at -70 °C under a nitrogen atmosphere. After stirring for 0.5 h, 4-bromobut-1-ene (Compound 6B, 3.0 g, 22.61 mmol) was added to the reaction mixture, and the resulting mixture was warmed to 20 °C and further stirred for 2.5 h. After the reaction was completed, it was quenched by adding saturated aqueous NH4Cl solution at 0 °C, and the reaction mixture was extracted with EtOAc (50 mL, 2 times). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum to obtain a residue, which was purified by column chromatography (EtOAc in PE = 5% - 30%) to obtain O1-tert-butyl O4-methyl 4-but-3-enyl piperidine-1,4-dicarboxylate (Compound 6C, 4.13 g) as a yellow oil. 1 H NMR(400MHz,CHLOROFORM-d)δ 5.69-5.81(m,1H),4.91-5.06(m,2H),3.87(d,J=14.0Hz,2H),3.71(s,3H),2.92-2.82(m,2H),2.11(d,J=13.6Hz,2H),2.00-1.92(m,2H),1.63-1.58(m,2H),1.45(s,9H),1.40-1.32(m,2H)ppm.

[0194] Step 2: Preparation of O1-tert-butyl O4-methyl 4-(3-oxopropyl)piperidine-1,4-dicarboxylate (Compound 6D) A mixture of O1-tert-butyl O4-methyl 4-but-3-enylpiperidine-1,4-dicarboxylate (Compound 6C, 1.9 g, 6.49 mmol) in 1,4-dioxane (40 mL) and water (4 mL) was added with 2,6-lutidine (1.5 mL, 12.98 mmol) and potassium osmate(VI) dihydrate (119.5 mg, 0.32 mmol) at 0 °C. After stirring at 0 °C for 15 minutes, sodium metaperiodate (5.6 g, 25.96 mmol) was added to the reaction mixture at 0 °C, and the resulting mixture was warmed to 20 °C and stirred for 3 hours. After the reaction was completed, the reaction mixture was extracted with EtOAc (20 mL, 3 times) and washed with a saturated aqueous Na2SO3 solution (20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain O1-tert-butyl O4-methyl 4-(3-oxopropyl)piperidine-1,4-dicarboxylate (Compound 6D, 2.0 g) as a yellow oil. MS calculated value 200.2 (M - Boc + H + ), measured value 200.1 (M - Boc + H + ).

[0195] Step 3: Preparation of O1-tert-butyl O4-methyl 4-[3-[[(1S)-1-tert-butoxycarbonyl-2-methyl-propyl]amino]propyl]piperidine-1,4-dicarboxylate (Compound 6F) A mixture of O1-tert-butyl O4-methyl 4-(3-oxopropyl)piperidine-1,4-dicarboxylate (Compound 6D, 1.0 g, 3.34 mmol) and Boc-N-Me-Val-OH (770.5 mg, 3.67 mmol) in methanol (20 mL) was added zinc chloride (500.7 mg, 3.67 mmol) at 0 °C. After stirring at 0 °C for 0.5 h, sodium cyanoborohydride (272.8 mg, 4.34 mmol) was added to the reaction mixture at 0 °C, and the resulting mixture was warmed to 20 °C and stirred for an additional 1 h. After the reaction was complete, it was quenched with saturated aqueous NH4Cl (20 mL), and the reaction mixture was extracted with EtOAc (20 mL, 3 times). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give a residue, which was purified by column chromatography (EtOAc in PE = 10% - 30%) to give O1-tert-butyl O4-methyl 4-[3-[[(1S)-1-tert-butoxycarbonyl-2-methyl-propyl]amino]propyl]piperidine-1,4-dicarboxylate (Compound 6F, 1.1 g) as a yellow oil. MS calculated value 457.3 (MH + ), measured value 457.2 (MH + ).

[0196] Step 4: Preparation of lithium; 1-tert-butoxycarbonyl-4-[3-[[(1S)-1-tert-butoxycarbonyl-2-methyl-propyl]amino]propyl]piperidine-4-carboxylate (Compound 6G) O1-tert-Butyl O4-methyl 4-[3-[[(1S)-1-tert-butoxycarbonyl-2-methyl-propyl]amino]propyl]piperidine-1,4-dicarboxylate (Compound 6F, 400.0 mg, 0.88 mmol) in a mixture of methanol (6 mL), THF (0.6 mL) and water (0.6 mL) was added lithium hydroxide monohydrate (367.6 mg, 8.76 mmol). The resulting mixture was heated to 60 °C and stirred for 12 hours. After the reaction was complete, the reaction mixture was cooled to 20 °C and concentrated under vacuum to give lithium; 1-tert-butoxycarbonyl 4-[3-[[(1S)-1-tert-butoxycarbonyl-2-methyl-propyl]amino]propyl]piperidine-4-carboxylate (Compound 6G, 392.0 mg) as a white solid. MS calculated value 443.3 (M-Li+H + ), measured value 443.2 (M-Li+H + ).

[0197] Step 5: Preparation of tert-butyl 2-[(1S)-1-tert-butoxycarbonyl-2-methyl-propyl]-1-oxo-2,9-diazaspiro[5.5]undecane-9-carboxylate (Compound 6H) Lithium in DMF (8 mL); To a mixture of 1-tert-butoxycarbonyl-4-[3-[[(1S)-1-tert-butoxycarbonyl-2-methyl-propyl]amino]propyl]piperidine-4-carboxylate (392.0 mg, 0.87 mmol) in DMF (8 mL), DIEA (0.5 mL, 2.62 mmol) and COMU (673.7 mg, 1.57 mmol) were added at 0 °C. The mixture was stirred at 20 °C for 1 h. After the reaction was completed, the reaction mixture was poured into water (80 mL) and extracted with EtOAc (20 mL, 3 times). The combined organic layers were washed with brine (20 mL, 3 times), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain a residue, which was purified by column chromatography (EtOAc in PE = 5% - 25%) to give tert-butyl 2-[(1S)-1-tert-butoxycarbonyl-2-methyl-propyl]-1-oxo-2,9-diazaspiro[5.5]undecane-9-carboxylate (Compound 6H, 200.0 mg) as a yellow oil. MS calculated value 425.3 (MH + ), measured value 425.3 (MH + ).

[0198] Step 6: Preparation of (2S)-3-methyl-2-(1-oxo-2,9-diazaspiro[5.5]undecan-2-yl)butanoic acid (Compound 6I) To a solution of tert-butyl 2-[(1S)-1-tert-butoxycarbonyl-2-methyl-propyl]-1-oxo-2,9-diazaspiro[5.5]undecane-9-carboxylate (Compound 6H, 200.0 mg, 0.47 mmol) in DCM (1.5 mL), trifluoroacetic acid (1.0 mL, 12.98 mmol) was added. The mixture was stirred at 20 °C for 1 h. After the reaction was completed, the mixture was concentrated under vacuum to give (2S)-3-methyl-2-(1-oxo-2,9-diazaspiro[5.5]undecan-2-yl)butanoic acid (Compound 6I, 180.0 mg, TFA salt) as a colorless oil. MS calculated value 269.2 (MH + ), measured value 269.2 (MH + ).

[0199] Step 7: Preparation of (2S)-2-(9-tert-butoxycarbonyl-1-oxo-2,9-diazaspiro[5.5]undecan-2-yl)-3-methyl-butanoic acid (Compound 6J) (2S))-3-methyl-2-(1-oxo-2,9-diazaspiro[5.5]undecan-2-yl)butanoic acid (Compound 6I, 180.0 mg, 0.47 mmol, TFA salt) in THF (3 mL) and water (3 mL) was added sodium carbonate (99.8 mg, 0.94 mmol) and di-tert-butyl dicarbonate (123.3 mg, 0.56 mmol). The mixture was stirred at 20 °C for 1 hour. After the reaction was complete, the mixture was concentrated under vacuum to give a residue, which was purified by reverse phase flash column to give (2S)-2-(9-tert-butoxycarbonyl-1-oxo-2,9-diazaspiro[5.5]undecan-2-yl)-3-methyl-butanoic acid (Compound 6J, 400.0 mg) as an off-white solid. MS calculated value 367.2 (MH + ), measured value 367.2 (MH + ).

[0200] Example 8 (3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(8S,14S)-25-fluoro-4-hydroxy-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-18,18-dimethyl-9,15-dioxo-22-(2,2,2-trifluoroethyl)-16-oxa-10,22,28-triazapentacyclo[18.5.2.1 2,6 .1 10,14 .0 23,27 nonacosa-1(26),2,4,6(29),20,23(27),24-heptaene-8-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide TIFF2025519199000069.tif72170

[0201] In the same manner as the preparation of Example 1, (8S,14S)-8-amino-25-fluoro-4-hydroxy-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-18,18-dimethyl-22-(2,2,2-trifluoroethyl)-16-oxa-10,22,28-triazapentacyclo[18.5.2.1 2,6 .1 10,14 .0 23,27 nonacosa-1(26),2,4,6(29),20,23(27),24-heptaene-9,15-dione (Intermediate G) was used instead of (7S,13S)-7-amino-25-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate E) to prepare the title compound. Example 8 (21.6 mg) was obtained as a white solid. MS calculated value 1114.5 (MH + ), measured value 1114.8 (MH + ). 11H NMR (400 MHz, methanol-d4) δ = 8.43 (d, J = 2.4 Hz, 1H), 7.62 (dd, J = 10.8, 7.2 Hz, 1H), 7.55 - 7.53 (m, 2H), 7.29 (s, 1H), 7.26 - 7.20 (m, 1H), 6.96 - 6.90 (m, 1H), 6.65 - 6.55 (m, 1H), 5.65 - 5.49 (m, 1H), 4.97 - 4.68 (m, 2H), 4.67 - 4.62 (m, 1H), 4.46 - 4.38 (m, 1H), 4.20 - 4.12 (m, 1H), 4.00 - 3.87 (m, 1H), 3.82 - 3.61 (m, 6H), 3.59 - 3.43 (m, 5H), 3.38 - 3.32 (m, 2H), 3.25 - 3.11 (m, 1H), 3.04 (s, 2H), 2.99 - 2.96 (m, 1H), 2.93 (s, 4H), 2.90 - 2.65 (m, 3H), 2.63 - 2.47 (m, 2H), 2.39 - 2.11 (m, 3H), 2.10 - 1.95 (m, 2H), 1.89 - 1.79 (m, 1H), 1.58 - 1.27 (m, 6H), 1.03 - 0.92 (m, 6H), 0.91 - 0.84 (m, 1H), 0.83 - 0.75 (m, 3H), 0.47 - 0.32 (m, 3H) ppm.

[0202] Example 9 1-[(2R)-2-chloro-2-fluoro-acetyl]-4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17,24-trimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide TIFF2025519199000070.tif61170

[0203] In the same manner as the preparation of Example 1, 1-tert-butoxycarbonyl-4-fluoro-piperidine-4-carboxylic acid and (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17,24-trimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate F) was used instead of (S)-1-Boc-pyrrolidine-3-carboxylic acid (Compound 1D) and (7S,13S)-7-amino-25-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate E) to prepare the title compound. Example 9 (2.7 mg) was obtained as a white solid. MS calculated value 1133.5 (MH + ), measured value 1133.5 (MH + ). 11H NMR (400 MHz, methanol-d4) δ = 8.49 - 8.36 (m, 1H), 8.03 (d, J = 13.6 Hz, 1H), 7.58 - 7.39 (m, 3H), 7.12 - 6.94 (m, 1H), 5.90 - 5.77 (m, 1H), 5.26 - 5.11 (m, 1H), 4.73 - 4.61 (m, 1H), 4.52 - 4.31 (m, 2H), 4.21 (m, 1H), 4.14 - 3.84 (m, 4H), 3.75 - 3.49 (m, 3H), 3.26 - 3.07 (m, 10H), 3.00 (s, 4H), 2.52 (m, 6H), 2.15 (m, 8H), 1.97 - 1.82 (m, 1H), 1.71 - 1.50 (m, 2H), 1.45 (m, 3H), 1.36 - 1.24 (m, 3H), 1.02 - 0.87 (m, 9H), 0.39 (s, 3H) ppm.

[0204] Example 10 1-[(2R)-2-chloro-2-fluoro-acetyl]-4-fluoro-N-[(1S)-1-[[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide TIFF2025519199000071.tif56170

[0205] In the same manner as the preparation of Example 1, 1-tert-butoxycarbonyl-4-fluoro-piperidine-4-carboxylic acid and (7S,13S)-7-amino-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate D) was used in place of (S)-1-Boc-pyrrolidine-3-carboxylic acid (Compound 1D) and (7S,13S)-7-amino-25-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate E) to prepare the title compound. Example 10 (17.5 mg) was obtained as a yellow solid. MS calculated value 1137.5 (MH + ), measured value 1137.5 (MH + ), 11H NMR (400 MHz, methanol-d4) δ = 8.74 - 8.68 (m, 1H), 8.54 - 8.51 (m, 1H), 7.74 - 7.70 (m, 1H), 7.57 - 7.47 (m, 2H), 7.15 - 6.97 (m, 1H), 5.75 - 5.64 (m, 1H), 5.26 - 5.12 (m, 1H), 4.83 - 4.73 (m, 1H), 4.51 - 4.32 (m, 2H), 4.29 - 4.21 (m, 2H), 4.20 - 3.89 (m, 3H), 3.88 - 3.62 (m, 5H), 3.60 - 3.43 (m, 4H), 3.40 - 3.36 (m, 4H), 3.26 - 3.22 (m, 4H), 3.04 - 3.00 (m, 4H), 2.89 - 2.81 (m, 1H), 2.64 - 2.56 (m, 1H), 2.39 - 2.15 (m, 6H), 1.98 - 1.95 (m, 1H), 1.89 - 1.78 (m, 1H), 1.73 - 1.59 (m, 1H), 1.50 - 1.43 (m, 4H), 1.38 - 1.28 (m, 1H), 1.04 - 0.97 (m, 6H), 0.95 - 0.88 (m, 3H), 0.51 - 0.41 (m, 3H) ppm.

[0206] Example 11 (2S)-2-[2-[(2R)-2-chloro-2-fluoro-acetyl]-5-oxo-2,6-diazaspiro[3.5]nonan-6-yl]-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butanamide TIFF2025519199000072.tif71170

[0207] In the same manner as the preparation of Example 6, the title compound was prepared by using (2S)-2-(2-tert-butoxycarbonyl-5-oxo-2,6-diazaspiro[3.5]nonan-6-yl)-3-methyl-butanoic acid (Compound 11J) instead of (2S)-2-(9-tert-butoxycarbonyl-1-oxo-2,9-diazaspiro[5.5]undecan-2-yl)-3-methyl-butanoic acid (Compound 6J). Example 11 (6.6 mg) was obtained as a white solid. MS calculated value 1117.4 (MH + ), measured value 1117.5 (MH + ). 1 H NMR (400 MHz, methanol-d4) δ = 8.68 (d, J = 7.3 Hz, 1H), 8.50 (d, J = 2.8 Hz, 1H), 7.72 (dd, J = 2.4, 15.6 Hz, 1H), 7.50 - 7.45 (m, 2H), 6.79 - 6.60 (m, 1H), 5.72 - 5.64 (m, 1H), 5.21 - 5.10 (m, 3H), 4.44 (br s, 2H), 4.21 (br d, J = 5.6 Hz, 3H), 4.05 - 3.86 (m, 3H), 3.79 (br d, J = 11.2 Hz, 1H), 3.74 - 3.61 (m, 4H), 3.57 - 3.40 (m, 8H), 3.35 (br s, 2H), 3.15 (br d, J = 14.8 Hz, 3H), 3.00 (s, 3H), 2.83 (br t, J = 11.6 Hz, 1H), 2.62 - 2.50 (m, 1H), 2.20 (br s, 3H), 1.99 - 1.94 (m, 1H), 1.83 (br s, 3H), 1.64 (br dd, J = 4.0, 12.0 Hz, 1H), 1.44 (d, J = 6.0 Hz, 3H), 1.00 (br dd, J = 2.8, 6.4 Hz, 3H), 0.97 (s, 3H), 0.89 (br d, J = 6.4 Hz, 3H), 0.44 (s, 3H) ppm.

[0208] Compound 11J was prepared according to the following scheme. TIFF2025519199000073.tif152170

[0209] Step 1: Preparation of tert-butyl 3-but-3-enyl-3-cyano-azetidine-1-carboxylate (Compound 11B) To a solution of tert-butyl 3-cyanoazetidine-1-carboxylate (Compound 11A, 5.0 g, 27.44 mmol) cooled to -70 °C in THF (50 mL) was added lithium bis(trimethylsilyl)amide (30.1 mL, 30.18 mmol) dropwise under a nitrogen atmosphere. After stirring for 0.5 h, 4-bromo-1-butene (4.4 g, 32.93 mmol) was slowly added to the reaction mixture at -70 °C. The mixture was warmed to 20 °C and stirred for 3 h. After completion of the reaction, it was quenched with saturated NH4Cl (200 mL), and the reaction mixture was extracted with EtOAc (50 mL, 3 times). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain a residue, which was purified by column chromatography (EtOAc in PE = 5% - 30%) to give tert-butyl 3-but-3-enyl-3-cyano-azetidine-1-carboxylate (Compound 11B, 5.4 g) as a yellow oil. MS calculated value 237.2 (MH + ), measured value 181.6 (M - C4H8 + H + ).

[0210] Step 2: Preparation of 3-but-3-enyl-1-tert-butoxycarbonyl-azetidine-3-carboxylic acid (Compound 11C) To a mixture of tert-butyl 3-but-3-enyl-3-cyano-azetidine-1-carboxylate (Compound 11B, 5.4 g, 22.85 mmol) in ethanol (60 mL) and water (60 mL) was added potassium hydroxide (5.1 g, 91.41 mmol) all at once. The mixture was heated at 80 °C for 16 h. After completion of the reaction, the pH of the reaction mixture was adjusted to pH = 3 with 1N HCl aqueous solution, and this was extracted with EtOAc (50 mL, 3 times). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give 3-but-3-enyl-1-tert-butoxycarbonyl-azetidine-3-carboxylic acid (Compound 11C, 6.31 g) as a yellow oil. MS calculated value 256.2 (MH + ), measured value 200.3 (M - C4H8 + H + ).

[0211] Step 3: Preparation of O1-tert-butyl O3-methyl 3-but-3-enylazetidine-1,3-dicarboxylate (Compound 11D) To a mixture of 3-but-3-enyl-1-tert-butoxycarbonyl-azetidine-3-carboxylic acid (Compound 11C, 6.3 g, 24.72 mmol) in DMF (60 mL) were added potassium carbonate (10.2 g, 74.15 mmol) and iodomethane (7.0 g, 49.43 mmol) all at once. The mixture was stirred at 20 °C for 2 hours. After the reaction was completed, the mixture was poured into water (150 mL) and extracted with EtOAc (70 mL, 3 times). The combined organic layers were washed with brine (70 mL, 3 times), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (EtOAc in PE = 5% - 30%) to obtain O1-tert-butyl O3-methyl 3-but-3-enylazetidine-1,3-dicarboxylate (Compound 11D, 3.76 g) as a yellow oil. MS calculated value 270.2 (MH + ), measured value 214.3 (M - C4H8 + H + ).

[0212] Step 4: Preparation of O1-tert-butyl O3-methyl 3-(3-oxopropyl)azetidine-1,3-dicarboxylate (Compound 11E) A mixture of O1-tert-butyl O3-methyl 3-but-3-enyl azetidine-1,3-dicarboxylate (Compound 11D, 3.7 g, 13.96 mmol) in 1,4-dioxane (100 mL) and water (10 mL) was added with 2,6-lutidine (3.2 mL, 27.92 mmol) and potassium osmate(VI) dihydrate (0.3 g, 0.7 mmol) at 0 °C all at once. After stirring at 0 °C for 15 minutes, sodium metaperiodate (11.9 g, 55.84 mmol) was added to the reaction mixture, and the resulting mixture was warmed to 20 °C and stirred for an additional 3 hours. After the reaction was complete, the reaction was quenched by adding saturated aqueous Na2SO3 (200 mL), and the reaction mixture was extracted with EtOAc (100 mL, 3 times). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give O1-tert-butyl O3-methyl 3-(3-oxopropyl)azetidine-1,3-dicarboxylate (Compound 11E, 3.8 g) as a yellow oil. MS calculated value 272.2 (MH + ), measured value 216.3 (M-C4H8+H + ).

[0213] Step 5: Preparation of O1-tert-butyl O3-methyl 3-[3-[[(1S)-1-tert-butoxycarbonyl-2-methyl-propyl]amino]propyl]azetidine-1,3-dicarboxylate (Compound 11F) A mixture of tert-butyl L-valinate hydrochloride (1.8 g, 10.5 mmol) and O1-tert-butyl O3-methyl 3-(3-oxopropyl)azetidine-1,3-dicarboxylate (Compound 11E, 1.9 g, 7.0 mmol) in methanol (20 mL) was added zinc chloride (1.4 g, 10.5 mmol) at 0 °C all at once. After stirring at 20 °C for 0.5 h, sodium cyanoborohydride (0.9 g, 14.01 mmol) was added to the reaction mixture at 0 °C, and the resulting mixture was stirred at 20 °C for an additional 1 h. After completion of the reaction, it was quenched by the addition of saturated NH4Cl aqueous solution (100 mL), and the reaction mixture was extracted with EtOAc (50 mL, 3 times). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain a residue, which was purified by column chromatography (EtOAc in PE = 10% - 30%) to give O1-tert-butyl O3-methyl 3-[3-[[(1S)-1-tert-butoxycarbonyl-2-methyl-propyl]amino]propyl]azetidine-1,3-dicarboxylate (Compound 11F, 1.2 g) as a yellow oil. MS calculated value 429.3 (MH + ), measured value 429.4 (MH + ).

[0214] Step 6: Preparation of lithium; 1-tert-butoxycarbonyl-3-[3-[[(1S)-1-tert-butoxycarbonyl-2-methyl-propyl]amino]propyl]azetidine-3-carboxylate (Compound 11G) O1-tert-butyl O3-methyl 3-[3-[[(1S)-1-tert-butoxycarbonyl-2-methyl-propyl]amino]propyl]azetidine-1,3-dicarboxylate (Compound 11F, 1.2 g, 2.8 mmol) in a mixture of methanol (30 mL), water (3 mL) and THF (3 mL) was added lithium hydroxide monohydrate (1.2 g, 28.0 mmol). The mixture was then heated to 60 °C and stirred for 12 h. After completion of the reaction, the reaction mixture was concentrated under vacuum to give lithium; 1-tert-butoxycarbonyl-3-[3-[[(1S)-1-tert-butoxycarbonyl-2-methyl-propyl]amino]propyl]azetidine-3-carboxylate (Compound 11G, 2.3 g) as a yellow solid. MS calculated value 421.8 (MH + ), measured value 415.2 (M-Li+H + ).

[0215] Step 7: Preparation of tert-butyl 6-[(1S)-1-tert-butoxycarbonyl-2-methyl-propyl]-5-oxo-2,6-diazaspiro[3.5]nonane-2-carboxylate (Compound 11H) Lithium in DMF (30 mL); To 1-tert-butoxycarbonyl-3-[3-[[(1S)-1-tert-butoxycarbonyl-2-methyl-propyl]amino]propyl]azetidine-3-carboxylate (Compound 11G, 2.0 g, 2.41 mmol), DIEA (2.1 mL, 12.06 mmol) and COMU (2.0 g, 4.82 mmol) were added at 0 °C all at once. Then the reaction mixture was warmed to 20 °C and stirred for 1 h. After the reaction was complete, the mixture was poured into water (100 mL) and extracted with EtOAc (50 mL, 3 times). The combined organic layers were washed with brine (50 mL, 3 times), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give a residue, which was purified by column chromatography (EtOAc in PE = 20% - 30%) to give tert-butyl 6-[(1S)-1-tert-1-tert-butoxycarbonyl-2-methyl-propyl]-5-oxo-2,6-diazaspiro[3.5]nonane-2-carboxylate (Compound 11H, 512.0 mg) as a yellow solid. MS calculated value 397.3 (MH + ), measured value 419.4 (MH + ).

[0216] Step 8: Preparation of (2S)-3-methyl-2-(5-oxo-2,6-diazaspiro[3.5]nonan-6-yl)butanoic acid (Compound 11I) To a solution of tert-butyl 6-[(1S)-1-tert-1-tert-butoxycarbonyl-2-methyl-propyl]-5-oxo-2,6-diazaspiro[3.5]nonane-2-carboxylate (Compound 11H, 512.0 mg, 1.29 mmol) in DCM (3 mL), TFA (3.0 mL, 38.94 mmol) was added. The mixture was stirred at 20 °C for 2 h. After the reaction was complete, the mixture was concentrated under vacuum to give (2S)-3-methyl-2-(5-oxo-2,6-diazaspiro[3.5]nonan-6-yl)butanoic acid (Compound 11I, 301.0 mg) as a yellow oil as the TFA salt. MS calculated value 241.2 (MH + ), measured value 241.5 (MH + ).

[0217] Step 9: Preparation of (2S)-2-(2-tert-butoxycarbonyl-5-oxo-2,6-diazaspiro[3.5]nonan-6-yl)-3-methyl-butanoic acid (Compound 11J) To a mixture of (2S)-3-methyl-2-(5-oxo-2,6-diazaspiro[3.5]nonan-6-yl)butanoic acid (Compound 11I, 301.0 mg, 1.25 mmol) in THF (12 mL) were added di-tert-butyl dicarbonate (326.9 mg, 1.5 mmol) and sodium carbonate (661.6 mg, 6.24 mmol) at once, and the mixture was stirred at 20 °C for 2 h. After the reaction was completed, the mixture was filtered through a filter, and the filtrate was concentrated under vacuum. The obtained residue was purified by preparative HPLC to give (2S)-2-(2-tert-butoxycarbonyl-5-oxo-2,6-diazaspiro[3.5]nonan-6-yl)-3-methyl-butanoic acid (Compound 11J, 303.0 mg) as a colorless gum. MS calculated value 341.2 (MH + +), measured value 363.2 (MH + +).

[0218] Example 13 (2R)-2-[[1-[(2R)-2-chloro-2-fluoro-acetyl]azetidin-3-yl]oxymethyl]-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo-[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaene-7-yl]-3-methyl-butanamide TIFF2025519199000074.tif57170 The compound was prepared according to the following scheme. TIFF2025519199000075.tif234170

[0219] Project 1: Preparation of Ethyl 3-Hydroxy-3-Methyl-2-Methylene-Butanoate (Compound 13C) DIBAL-H (152.9 mL, 152.91 mmol) was added dropwise to a solution of NMO (23.8 g, 203.87 mmol) in THF (500 mL) at 0 °C. After stirring at 0 °C for 30 minutes, ethyl prop-2-ynoate (Compound 13A, 10 g, 101.94 mmol) was added dropwise to the reaction mixture at 0 °C. After further stirring at 0 °C for 1 hour, acetone (Compound 13B, 5.9 g, 101.94 mmol) and boron trifluoride etherate (12.9 mL, 101.94 mmol) were added to the reaction mixture, and the resulting mixture was stirred at room temperature for 18 hours. The reaction was worked up by adding EA (100 mL). The organic layer was washed with HCl (1 N, 37.5 mL), saturated NaHCO3 (10 mL), and water (10 mL), then dried over Na2SO4 and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (PE:EA = 10:1) to give ethyl 3-hydroxy-3-methyl-2-methylene-butanoate (Compound 13C, 4.8 g) as a colorless oil. 1 H NMR (400 MHz, chloroform-d) δ = 6.14 (s, 1H), 5.83 - 5.70 (m, 1H), 4.23 (q, J = 7.3 Hz, 2H), 3.93 (br s, 1H), 1.49 - 1.37 (m, 6H), 1.31 (t, J = 7.1 Hz, 3H) ppm.

[0220] Project 2: Preparation of Ethyl 2-(Bromomethyl)-3-Methyl-But-2-enoate (Compound 13D) To a solution of ethyl 3-hydroxy-3-methyl-2-methylene-butanoate (Compound 13C, 4.8 g, 30.34 mmol) in THF (100 mL) was added dropwise a solution of phosphorus tribromide (4.9 g, 18.21 mmol) at 0 °C. After stirring at 15 °C for 2.5 h, the reaction mixture was poured into ice water at 0 °C, and the aqueous layer was extracted with EA (10 mL). The organic layer was washed with brine, dried over Na2SO4, concentrated to give a crude product, which was purified by silica gel chromatography (petroleum / EtOAc = 20 / 1 to 10 / 1) to give ethyl 2-(bromomethyl)-3-methyl-but-2-enoate (Compound 13D, 5.3 g) as a colorless oil. 1 H NMR (400 MHz, chloroform-d) δ = 4.30 (s, 2H), 4.24 (d, J = 7.2 Hz, 2H), 2.15 (s, 3H), 1.97 (s, 3H), 1.32 (t, J = 7.2 Hz, 3H) ppm.

[0221] Step 3: Preparation of benzyl 3-(2-ethoxycarbonyl-3-methyl-but-2-enoxy)azetidine-1-carboxylate (Compound 13F) To a mixture of benzyl 3-hydroxyazetidine-1-carboxylate (Compound 13E, 625.0 mg, 3.02 mmol), tetrabutylammonium iodide (116.0 mg, 0.31 mmol) and sodium hydroxide (267.8 mg, 6.7 mmol) in water (2 mL) and THF (4 mL) was added ethyl 2-(bromomethyl)-3-methyl-but-2-enoate (Compound 13D, 1.0 g, 4.52 mmol) at 0 °C. After stirring at 10 °C for 16 h, the reaction mixture was diluted with water (5 mL), and the resulting mixture was extracted with EA (10 mL, 2 times). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum / EtOAc = 20 / 1 to 10 / 1) to give benzyl 3-(2-ethoxycarbonyl-3-methyl-but-2-enoxy)azetidine-1-carboxylate (Compound 13F, 590.0 mg) as a colorless oil. MS calculated value 348.1 (MH + ), measured value 348.1 (MH + ).

[0222] Step 4: Preparation of tert-butyl 3-(2-ethoxycarbonyl-3-methyl-butoxy)azetidine-1-carboxylate (Compound 13G) To a solution of benzyl 3-(2-ethoxycarbonyl-3-methyl-but-2-enoxy)azetidine-1-carboxylate (Compound 13F, 950.0 mg, 2.73 mmol) in methanol (25 mL), Pd / C (240.0 mg, 0.26 mmol) was added at 15 °C under N2. The reaction mixture was purged with H2 and stirred at 50 °C for 2 h under a H2 atmosphere. The reaction mixture was filtered through a filter, and the filter cake was washed with methanol (30 mL). The combined filtrates were concentrated under vacuum, and the resulting residue was purified by silica gel chromatography (petroleum / EtOAc = 10 / 1 - 5 / 1) to give tert-butyl 3-(2-ethoxycarbonyl-3-methyl-butoxy)azetidine-1-carboxylate (Compound 13G, 700.0 mg) as a colorless oil. 1 H NMR (400 MHz, chloroform-d) δ = 4.25 - 4.11 (m, 3H), 4.08 - 3.99 (m, 2H), 3.80 (dd, J = 4.3, 9.4 Hz, 2H), 3.61 - 3.46 (m, 2H), 2.45 (ddd, J = 4.9, 7.3, 9.5 Hz, 1H), 1.97 - 1.86 (m, 1H), 1.43 (s, 9H), 1.31 - 1.24 (m, 3H), 0.99 - 0.90 (m, 6H) ppm.

[0223] Step 5: Preparation of 2-[(1-tert-butoxycarbonylazetidin-3-yl)oxymethyl]-3-methyl-butanoic acid (Compound 13H) To a mixture of tert-butyl 3-(2-ethoxycarbonyl-3-methyl-butoxy)azetidine-1-carboxylate (Compound 13G, 350.0 mg, 1.11 mmol) in methanol (6 mL) was added an aqueous NaOH solution (1 N, 6.0 mL, 6.0 mmol). After stirring at 50 °C for 16 h, the reaction mixture was concentrated under vacuum. The resulting residue was diluted with water (10 mL), the pH of the reaction mixture was adjusted to pH = 5 with 1 N aqueous HCl solution, and then the reaction mixture was extracted with EA (30 mL, 2 times). The combined organic layers were washed with brine (50 mL), dried (Na2SO4), and concentrated under vacuum to give a crude product. The crude product was purified by silica gel chromatography (petroleum / EtOAc = 5 / 1 to 3 / 1) to give 2-[(1-tert-butoxycarbonylazetidin-3-yl)oxymethyl]-3-methyl-butanoic acid (Compound 13H, 200.0 mg) as a colorless oil. 1 H NMR (400 MHz, chloroform-d) δ = 4.22 (tt, J = 4.3, 6.4 Hz, 1H), 4.10 - 4.03 (m, 2H), 3.83 (dd, J = 4.3, 9.7 Hz, 2H), 3.63 - 3.48 (m, 2H), 2.50 (ddd, J = 4.8, 7.1, 9.2 Hz, 1H), 1.99 (qd, J = 6.8, 13.7 Hz, 1H), 1.44 (s, 9H), 0.99 (dd, J = 2.9, 6.8 Hz, 6H) ppm.

[0224] Step 6: tert-Butyl 3-[(2R)-2-[[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-3-methyl-butoxy]azetidine-1-carboxylate (Compound 13I) and tert-butyl 3-[(2S)-2-[[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 Preparation of ]octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-3-methyl-butoxy]azetidine-1-carboxylate (Compound 13J) (7S,13S)-7-amino-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26A solution of octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (intermediate D, 225.0 mg, 0.28 mmol) and 2-[(1-tert-butoxycarbonylazetidin-3-yl)oxymethyl]-3-methyl-butanoic acid (compound 13H, 104.9 mg, 0.37 mmol) in DMF (2.5 mL) was added with DIEA (0.2 mL, 0.84 mmol) and HATU (213.6 mg, 0.56 mmol) at 0 °C. After stirring for 1 hour by the method of Seto et al., the reaction mixture was diluted with water (3 mL) and extracted with EtOAc (8 mL, twice). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC to give tert-butyl 3-[(2R)-2-[[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-3-methyl-butoxy]azetidine-1-carboxylate (compound 13I, eluting faster, 45.0 mg) as a pale yellow solid, and tert-butyl 3-[(2S)-2-[[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26+ )、measured value 1070.6 (MH + ).

[0225] Step 7: Preparation of (2R)-2-(azetidin-3-yloxymethyl)-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butanamide (Compound 13K) In DCM (0.5 mL), tert-butyl 3-[(2R)-2-[[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 It should be noted that the original text seems to be a bit fragmented and might have some formatting or chemical formula-related inaccuracies. The translation is done as accurately as possible based on the provided text.​​​​​​​​A solution of [[(7S,13S)-24-fluoro-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]-octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-3-methyl-butoxy]azetidine-1-carboxylate (Compound 13I, 45.0 mg, 0.04 mmol) was treated with TFA (0.2 mL) at 0 °C, and then the mixture was stirred at 15 °C for 0.5 h. The reaction mixture was concentrated under vacuum to give (2R)-2-(azetidin-3-yloxymethyl)-N- 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butanamide; 2,2,2-trifluoroacetic acid (Compound 13K, 40.0 mg) as a yellow oil. MS calculated 970.4 (MH + ), found 970.4 (MH + ).

[0226] Step 8: Preparation of (2R)-2-[[1-[(2R)-2-chloro-2-fluoro-acetyl]azetidin-3-yl]oxymethyl]-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]-octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butanamide (Example 13) 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butanamide (Example 13) (2R)-2-(azetidin-3-yloxymethyl)-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butanamide; To a solution of 2,2,2-trifluoroacetic acid (Compound 13K, 40.0 mg, 0.04 mmol) in DMF (0.2 mL) were added DIEA (0.1 mL, 0.74 mmol), T3P (469.6 mg, 0.74 mmol) and (2R)-2-chloro-2-fluoro-acetic acid (Compound 13L, 83.0 mg, 0.74 mmol) at 0 °C. After stirring at 20 °C for 1 hour, the reaction mixture was concentrated under vacuum and the resulting residue was purified by preparative HPLC to give (2R)-2-[[1-[(2R)-2-chloro-2-fluoroacetyl]azetidin-3-yl]oxymethyl]-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo-[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butanamide (Example 13, 22.6 mg) was obtained as a white solid. MS calculated value 1064.5 (MH + ), measured value 1064.5 (MH + ). 11H NMR (400 MHz, chloroform-d) δ = 8.65 (br d, J = 6.8 Hz, 2H), 7.64 (dd, J = 1.9, 4.9 Hz, 1H), 7.26 - 7.20 (m, 1H), 7.14 (br d, J = 11.9 Hz, 1H), 6.77 - 6.67 (m, 1H), 6.41 - 6.22 (m, 1H), 5.89 (br t, J = 8.1 Hz, 1H), 4.95 (br dd, J = 9.0, 16.5 Hz, 1H), 4.65 - 4.48 (m, 3H), 4.46 - 4.21 (m, 6H), 4.17 - 4.09 (m, 1H), 3.86 (br d, J = 11.1 Hz, 2H), 3.74 - 3.69 (m, 3H), 3.60 - 3.55 (m, 2H), 3.52 - 3.45 (m, 2H), 3.36 (s, 3H), 3.15 - 3.09 (m, 2H), 2.94 - 2.87 (m, 3H), 2.75 - 2.67 (m, 1H), 2.47 - 2.34 (m, 1H), 2.30 - 2.21 (m, 2H), 2.04 - 1.94 (m, 4H), 1.88 - 1.79 (m, 1H), 1.70 - 1.54 (m, 2H), 1.50 (d, J = 6.1 Hz, 3H), 1.30 - 1.20 (m, 1H), 1.02 (dd, J = 4.6, 6.3 Hz, 6H), 0.97 (s, 3H), 0.45 (s, 3H) ppm.

[0227] Example 14 (2S)-2-[[1-[(2R)-2-chloro-2-fluoro-acetyl]azetidin-3-yl]oxymethyl]-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butanamide TIFF2025519199000076.tif68170

[0228] The title compound was prepared in the same manner as in the preparation of Example 13, using tert-butyl 3-[(2S)-2-[[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-3-methyl-butoxy]azetidine-1-carboxylate (Compound 13J) in place of tert-butyl 3-[(2R)-2-[[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-3-methyl-butoxy]azetidine-1-carboxylate (Compound 13I). Example 14 (38.0 mg) was obtained as a white solid. MS calculated value 1064.5 (MH + ), measured value 1064.5 (MH + ). 11H NMR (400 MHz, chloroform-d) δ = 8.72 (br s, 1H), 8.66 (d, J = 7.4 Hz, 1H), 7.65 (s, 1H), 7.14 (d, J = 12.0 Hz, 1H), 6.80 - 6.72 (m, 1H), 6.39 - 6.23 (m, 1H), 5.97 - 5.86 (m, 1H), 5.01 - 4.83 (m, 2H), 4.60 - 4.49 (m, 5H), 4.36 - 4.22 (m, 6H), 4.05 - 3.93 (m, 2H), 3.87 (br d, J = 10.4 Hz, 1H), 3.73 - 3.68 (m, 2H), 3.64 - 3.53 (m, 4H), 3.45 (s, 1H), 3.36 (s, 3H), 3.20 - 3.00 (m, 4H), 2.93 (br s, 3H), 2.73 (br t, J = 13.2 Hz, 1H), 2.43 (br d, J = 14.1 Hz, 1H), 2.30 - 2.20 (m, 2H), 2.04 - 1.96 (m, 2H), 1.85 - 1.78 (m, 1H), 1.69 - 1.62 (m, 1H), 1.51 (d, J = 6.1 Hz, 3H), 1.06 (br dd, J = 3.0, 6.6 Hz, 3H), 1.03 - 1.00 (m, 3H), 0.96 (br s, 3H), 0.46 (s, 3H) ppm.

[0229] Example 15 (2S)-2-[8-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,8-diazaspiro[4.5]decane-2-yl]-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butanamide TIFF2025519199000077.tif57170

[0230] In the same manner as the preparation of Example 6, the title compound was prepared by using (2S)-2-(8-tert-butoxycarbonyl-1-oxo-2,8-diazaspiro[4.5]decan-2-yl)-3-methyl-butanoic acid (Compound 15F) instead of (2S)-2-(9-tert-butoxycarbonyl-1-oxo-2,9-diazaspiro[5.5]undecan-2-yl)-3-methyl-butanoic acid (Compound 6J). Example 15 (56.8 mg) was obtained as a white solid. MS calculated value 1131.5 (MH + ), measured value 1131.5 (MH + ). 1 H NMR (400 MHz, methanol-d4) δ = 8.86 (d, J = 7.2 Hz, 1H), 8.68 (d, J = 7.6 Hz, 1H), 8.50 (d, J = 2.8 Hz, 1H), 7.71 (s, 1H), 7.50 - 7.46 (m, 1H), 7.13 - 6.92 (m, 1H), 5.68 (br s, 1H), 5.20 - 5.13 (m, 1H), 4.41 (d, J = 14.1 Hz, 1H), 4.36 - 4.21 (m, 4H), 4.20 - 3.85 (m, 4H), 3.82 - 3.68 (m, 3H), 3.61 (d, J = 7.3 Hz, 4H), 3.46 (d, J = 14.4 Hz, 4H), 3.36 - 3.35 (m, 2H), 3.24 - 3.08 (m, 4H), 3.00 (s, 3H), 2.90 - 2.78 (m, 1H), 2.57 (d, J = 14.4 Hz, 1H), 2.28 - 2.17 (m, 2H), 2.08 (s, 2H), 1.96 (d, J = 12.8 Hz, 2H), 1.88 - 1.77 (m, 2H), 1.76 - 1.52 (m, 4H), 1.45 (d, J = 6.0 Hz, 3H), 1.00 (d, J = 6.4 Hz, 3H), 0.97 (s, 3H), 0.92 - 0.84 (m, 3H), 0.44 (s, 3H) ppm.

[0231] Compound 15F was prepared according to the following scheme. TIFF2025519199000078.tif86170

[0232] Step 1: Preparation of O1-tert-butyl O4-methyl 4-allylpiperidine-1,4-dicarboxylate (Compound 15B) A solution of O1-tert-butyl O4-methylpiperidine-1,4-dicarboxylate (Compound 15A, 10.0 g, 41.1 mmol) in THF (100 mL) was added dropwise with LDA (22.6 mL, 45.21 mmol) at -70 °C under a nitrogen atmosphere. After stirring for 0.5 h, allyl bromide (5.5 g, 45.21 mmol) was added to the reaction mixture at -70 °C, and then the reaction mixture was warmed to 15 °C and stirred for 2 h. After the reaction was completed, it was quenched with saturated aqueous NH4Cl solution (300 mL), and the reaction mixture was extracted with EtOAc (100 mL, 3 times). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (EtOAc in PE = 5% - 30%) to obtain O1-tert-butyl O4-methyl 4-allylpiperidine-1,4-dicarboxylate (Compound 15B, 10.8 g) as a yellow oil. MS calculated value 284.2 (MH + ), measured value 228.2 (M - C4H8 + H + ).

[0233] Step 2: Preparation of O1-tert-butyl O4-methyl 4-(2-oxoethyl)piperidine-1,4-dicarboxylate (Compound 15C) To a mixture of O1-tert-butyl O4-methyl 4-allylpiperidine-1,4-dicarboxylate (Compound 15B, 6.0 g, 21.17 mmol) in 1,4-dioxane (200 mL) and water (20 mL) were added 2,6-lutidine (4.9 mL, 42.35 mmol) and potassium osmate(VI) dihydrate (0.4 g, 1.06 mmol) at 0 °C all at once. After stirring at 0 °C for 15 minutes, sodium metaperiodate (18.1 g, 84.7 mmol) was added portionwise to the reaction mixture at 0 °C, and the resulting mixture was warmed to 20 °C and stirred for 2 hours. The reaction was quenched with saturated aqueous Na2SO3 solution (200 mL), and the reaction mixture was extracted with EtOAc (100 mL, 3 times). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give O1-tert-butyl O4-methyl 4-(2-oxoethyl)piperidine-1,4-dicarboxylate (Compound 15C, 6.0 g) as a yellow oil. MS calculated 286.2 (MH + ), found 186.2 (M-C5H8O2+H + ).

[0234] Step 3: Preparation of O1-tert-butyl O4-methyl 4-[2-[[(1S)-1-benzyloxycarbonyl-2-methyl-propyl)amino]ethyl]piperidine-1,4-dicarboxylate (Compound 15D) A mixture of benzyl (2S)-2-amino-3-methyl-butanoate hydrochloride (2.2 g, 10.51 mmol) and O1-tert-butyl O4-methyl 4-(2-oxoethyl)piperidine-1,4-dicarboxylate (Compound 15C, 2.0 g, 7.01 mmol) in methanol (30 mL) was added with zinc chloride (1.4 g, 10.51 mmol) at 0 °C. After stirring at 0 °C for 0.5 h, sodium cyanoborohydride (0.9 g, 14.02 mmol) was added to the reaction mixture. After further stirring at 20 °C for 1 h, the reaction was quenched with saturated aqueous NH4Cl solution (100 mL), and the reaction mixture was extracted with EtOAc (50 mL, 3 times). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain a residue, which was purified by column chromatography (EtOAc in PE = 10% - 30%) to give O1-tert-butyl O4-methyl 4-[2-[[(1S)-1-benzyloxycarbonyl-2-methyl-propyl)amino]ethyl]piperidine-1,4-dicarboxylate (Compound 15D, 2.46 g) as a yellow oil. MS calculated value 477.3 (MH + ), measured value 477.3 (MH + ).

[0235] Step 4: Preparation of tert-butyl 2-[(1S)-1-benzyloxycarbonyl-2-methyl-propyl]-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (Compound 15E) To a mixture of 1-(tert-butyl) 4-methyl (S)-4-(2-((1-(benzyloxy)-3-methyl-1-oxobutan-2-yl)amino)ethyl)piperidine-1,4-dicarboxylate (Compound 15D, 1.2 g, 2.52 mmol) in toluene (20 mL), DIEA (4.4 mL, 25.18 mmol) and DMAP (0.3 g, 2.52 mmol) were added. The reaction mixture was heated to 100 °C and stirred for 30 h. After completion of the reaction, the reaction mixture was poured into water (30 mL) and extracted with EtOAc (30 mL, 3 times). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by reverse-phase column to give tert-butyl 2-[(1S)-1-benzyloxycarbonyl-2-methyl-propyl]-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (Compound 15E, 586.0 mg) as a yellow oil. MS calculated value 445.3 (MH + ), measured value 467.4 (MH + ).

[0236] Step 5: Preparation of (2S)-2-(8-tert-butoxycarbonyl-1-oxo-2,8-diazaspiro[4.5]decane-2-yl)-3-methyl-butanoic acid (Compound 15F) To a solution of tert-butyl 2-[(1S)-1-benzyloxycarbonyl-2-methyl-propyl]-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (Compound 15E, 500.0 mg) in toluene (20 mL), palladium on wet activated carbon (50.0 mg, 10% wt) was added. The mixture was degassed and purged with H2 three times. The mixture was hydrogenated at 35 °C. The reaction solution was filtered and the filter cake was washed with DMF (100 mL). The combined filtrate was concentrated in vacuo to give (2S)-2-(8-tert-butoxycarbonyl-1-oxo-2,8-diazaspiro[4.5]decane-2-yl)-3-methyl-butanoic acid (Compound 15F, 144.0 mg) as a white solid. MS calculated value 355.2 (MH + ), measured value 377.1 (MH + ).

[0237] Example 16 and Example 18 (2S)-2-[(5S)-2-[(2R)-2-chloro-2-fluoro-acetyl]-6-oxo-2,7-diazaspiro[4.5]decane-7-yl]-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butanamide (Example 16) and (2S)-2-[(5R)-2-[(2R)-2-chloro-2-fluoro-acetyl]-6-oxo-2,7-diazaspiro[4.5]decane-7-yl]-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butanamide (Example 18) TIFF2025519199000079.tif124170

[0238] In the same manner as the preparation of Example 6, the title compound was prepared by using (2S)-2-[(5S)-2-tert-butoxycarbonyl-6-oxo-2,7-diazaspiro[4.5]decan-7-yl]-3-methyl-butanoic acid (Compound 16o1) instead of (2S)-2-(9-tert-butoxycarbonyl-1-oxo-2,9-diazaspiro[5.5]undecan-2-yl)-3-methyl-butanoic acid (Compound 6J). Example 16 (14.0 mg) was obtained as a white solid. MS calculated value 1131.5 (MH + ), measured value 1131.4 (MH + ). 1 H NMR (400 MHz, methanol-d4) δ = 8.69 (dd, J = 2.0, 7.6 Hz, 1H), 8.50 (d, J = 2.8 Hz, 1H), 7.80 - 7.70 (m, 1H), 7.51 - 7.45 (m, 2H), 6.91 - 6.73 (m, 1H), 5.72 - 5.64 (m, 1H), 5.23 - 5.13 (m, 2H), 4.42 (d, J = 12.0 Hz, 1H), 4.27 - 4.20 (m, 2H), 4.10 - 4.00 (m, 3H), 3.93 - 3.82 (m, 2H), 3.79 - 3.69 (m, 3H), 3.66 - 3.56 (m, 3H), 3.52 - 3.43 (m, 4H), 3.36 - 3.34 (m, 4H), 3.19 - 3.12 (m, 2H), 3.00 (s, 3H), 2.87 - 2.79 (m, 1H), 2.60 - 2.53 (m, 1H), 2.52 - 2.41 (m, 1H), 2.39 - 2.18 (m, 3H), 2.07 - 1.81 (m, 8H), 1.68 - 1.61 (m, 1H), 1.45 (d, J = 6.0 Hz, 3H), 1.00 - 0.96 (m, 6H), 0.90 (d, J = 6.4 Hz, 3H), 0.47 - 0.41 (m, 3H) ppm.

[0239] In the same manner as the preparation of Example 6, the title compound was prepared by using (2S)-2-[(5R)-2-tert-butoxycarbonyl-6-oxo-2,7-diazaspiro[4.5]decan-7-yl]-3-methyl-butanoic acid (Compound 16o 2) instead of (2S)-2-(9-tert-butoxycarbonyl-1-oxo-2,9-diazaspiro[5.5]undecan-2-yl)-3-methyl-butanoic acid (Compound 6J). Example 18 (25.6 mg) was obtained as a white solid. MS calculated value 1131.4 (MH + ), measured value 1131.5 (MH + ). 1 H NMR (400 MHz, methanol-d4) δ = 8.68 (d, J = 7.6 Hz, 1H), 8.50 (d, J = 2.8 Hz, 1H), 7.74 - 7.71 (m, 1H), 7.50 - 7.45 (m, 2H), 6.91 - 6.76 (m, 1H), 5.72 - 5.65 (m, 1H), 5.24 - 5.11 (m, 2H), 4.83 - 4.79 (m, 3H), 4.47 - 4.18 (m, 2H), 4.12 - 3.87 (m, 3H), 3.81 - 3.60 (m, 6H), 3.56 - 3.44 (m, 3H), 3.41 - 3.33 (m, 6H), 3.26 - 3.12 (m, 3H), 3.00 (s, 3H), 2.87 - 2.78 (m, 1H), 2.26 - 2.46 (m, 2H), 2.39 - 2.19 (m, 2H), 2.05 - 1.79 (m, 7H), 1.71 - 1.60 (m, 1H), 1.44 (d, J = 6.4 Hz, 3H), 1.02 - 0.95 (m, 6H), 0.90 (d, J = 6.4 Hz, 3H), 0.44 (s, 3H) ppm.

[0240] Compounds 16o1 and 16o2 were prepared according to the following scheme. TIFF2025519199000080.tif196170

[0241] Step 1: Preparation of 1-(tert-butyl) 3-methyl 3-(but-3-en-1-yl)pyrrolidine-1,3-dicarboxylate (Compound 16c) To a solution of 1-(tert-butyl) 3-methylpyrrolidine-1,3-dicarboxylate (Compound 16a, 25.0 g, 109.04 mmol) in THF (300 mL) was added LDA (59.9 mL, 119.95 mmol) at -70 °C under a nitrogen atmosphere. After stirring for 0.5 h, 4-bromo-1-butene (Compound 16b, 16.1 g, 119.95 mmol) was added to the reaction mixture. After stirring at 20 °C for 2.5 h, the reaction was quenched with saturated NH4Cl (100 mL), and the reaction mixture was extracted with EtOAc (150 mL, 2 times). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain a residue, which was purified by silica gel column (EtOAc in PE = 0% - 5%) to give 1-(tert-butyl) 3-methyl 3-(but-3-en-1-yl)pyrrolidine-1,3-dicarboxylate (Compound 16c, 13.2 g) as a yellow oil. 1 H NMR (400 MHz, methanol-d4) δ = 5.83 - 5.73 (m, 1H), 5.05 - 4.93 (m, 2H), 3.84 (d, J = 10.8 Hz, 1H), 3.71 (s, 3H), 3.46 - 3.37 (m, 1H), 3.29 - 3.11 (m, 2H), 2.40 - 2.32 (m, 1H), 2.01 - 1.91 (m, 2H), 1.90 - 1.74 (m, 3H), 1.46 (d, J = 3.2 Hz, 9H) ppm.

[0242] Step 2: Preparation of methyl 3-(but-3-en-1-yl)pyrrolidine-3-carboxylate (Compound 16d) To a solution of 1-(tert-butyl) 3-methyl 3-(but-3-en-1-yl)pyrrolidine-1,3-dicarboxylate (Compound 16c, 13.2 g, 46.58 mmol) in 1,4-dioxane (50 mL) was added HCl solution (50.0 mL, 4 M in dioxane). After stirring at 20 °C for 0.5 h, the reaction mixture was concentrated under vacuum to give methyl 3-(but-3-en-1-yl)pyrrolidine-3-carboxylate hydrochloride (Compound 16d, 10.2 g) as a yellow oil.

[0243] Step 3: Preparation of Methyl 3-(but-3-en-1-yl)-1-tritylpyrrolidine-3-carboxylate (Compound 16e) To a solution of methyl 3-(but-3-en-1-yl)pyrrolidine-3-carboxylate hydrochloride (Compound 16d, 3.0 g, 13.65 mmol) in ACN (70 mL) were added trityl chloride (3.81 g, 13.65 mmol) and potassium carbonate (4.72 g, 34.14 mmol). The mixture was stirred at 20 °C for 12 h. After completion of the reaction, the mixture was poured into water (100 mL) and extracted with EtOAc (30 mL, 3 times). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a residue, which was purified by silica gel column (EtOAc in PE = 0% - 5%) to afford methyl 3-(but-3-en-1-yl)-1-tritylpyrrolidine-3-carboxylate (Compound 16e, 1.3 g) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ = 7.48 - 7.45 (m, 6H), 7.26 - 7.23 (m, 6H), 7.15 (t, J = 7.2 Hz, 3H), 5.78 - 5.68 (m, 1H), 5.00 - 4.89 (m, 2H), 3.74 (s, 3H), 3.00 (d, J = 9.6 Hz, 1H), 2.61 - 2.55 (m, 1H), 2.43 - 2.35 (m, 1H), 2.20 - 2.14 (m, 1H), 2.03 (s, 1H), 1.98 - 1.83 (m, 2H), 1.82 - 1.61 (m, 2H), 1.52 - 1.45 (m, 1H) ppm.

[0244] Step 4: Preparation of Methyl 3-(3-oxopropyl)-1-tritylpyrrolidine-3-carboxylate (Compound 16f) A solution of methyl 3-(but-3-en-1-yl)-1-tritylpyrrolidin-3-carboxylate (Compound 16e, 660 mg, 1.55 mmol) in THF (20 mL) and water (10 mL) was added with potassium osmate(VI) (5 mg, 0.02 mmol) and sodium periodate (663 mg, 3.1 mmol). The reaction mixture was stirred at 20 °C for 2 h. After the reaction was completed, it was quenched with saturated aqueous NH4Cl, and the reaction mixture was extracted with EtOAc (50 mL, 2 times). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain a residue, which was purified by silica gel column (EtOAc in PE = 0% - 5%) to give methyl 3-(3-oxopropyl)-1-tritylpyrrolidin-3-carboxylate (Compound 16f, 300 mg) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ = 9.75 - 9.69 (m, 1H), 7.52 - 7.48 (m, 6H), 7.29 (t, J = 4.0 Hz, 6H), 7.19 (t, J = 7.2 Hz, 3H), 3.77 (s, 3H), 3.05 (d, J = 9.2 Hz, 1H), 2.67 - 2.57 (m, 1H), 2.47 - 2.31 (m, 3H), 2.29 - 2.21 (m, 1H), 2.04 - 1.87 (m, 2H), 1.62 - 1.43 (m, 2H) ppm.

[0245] Step 5: Preparation of methyl 3-(3-(((S)-1-(tert-butoxy)-3-methyl-1-oxobutan-2-yl)amino)propyl)-1-tritylpyrrolidin-3-carboxylate (Compound 16h) A mixture of methyl 3-(3-oxopropyl)-1-tritylpyrrolidine-3-carboxylate (Compound 16f, 550.0 mg, 1.29 mmol), H-VAL-OTBU HCl (Compound 16g, 296.7 mg, 1.42 mmol) and zinc chloride (192.8 mg, 1.42 mmol) in methanol (6 mL) was added with sodium cyanoborohydride (88.9 mg, 1.42 mmol) at 0 °C. The mixture was stirred at 25 °C for 2 h. After the reaction was completed, water (30 mL) was added to the reaction mixture. The resulting mixture was concentrated under vacuum. The obtained suspension was diluted with water (40 mL) and extracted with EtOAc (30 mL, twice). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain a residue, which was purified by column chromatography (EtOAc in PE = 0% - 10%) to give methyl 3-(3-(((S)-1-(tert-butoxy)-3-methyl-1-oxobutan-2-yl)amino)propyl)-1-tritylpyrrolidine-3-carboxylate (Compound 16h, 510 mg) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ = 7.47 (d, J = 8.0 Hz, 6H), 7.28 - 7.27 (m, 1H), 7.27 - 7.23 (m, 5H), 7.18 - 7.13 (m, 3H), 3.78 - 3.73 (m, 3H), 3.05 (t, J = 8.4 Hz, 1H), 2.79 (dd, J = 2.4, 6.0 Hz, 1H), 2.67 - 2.59 (m, 1H), 2.55 - 2.49 (m, 1H), 2.43 - 2.31 (m, 2H), 2.14 - 2.09 (m, 1H), 1.99 - 1.94 (m, 1H), 1.88 - 1.82 (m, 1H), 1.68 - 1.64 (m, 3H), 1.60 - 1.55 (m, 2H), 1.48 - 1.45 (m, 9H), 1.37 - 1.33 (m, 1H), 0.94 - 0.90 (m, 6H) ppm.

[0246] Step 6: Preparation of 3-(3-(((S)-1-(tert-butoxy)-3-methyl-1-oxobutan-2-yl)amino)propyl)-1-tritylpyrrolidine-3-carboxylic acid (Compound 16i) A solution of methyl 3-(3-(((S)-1-(tert-butoxy)-3-methyl-1-oxobutan-2-yl)amino)propyl)-1-tritylpyrrolidine-3-carboxylate (Compound 16h, 510 mg, 0.8 mmol) in methanol (6 mL), water (0.6 mL) and THF (0.6 mL) was added lithium hydroxide monohydrate (336 mg, 8 mmol). The mixture was stirred at 60 °C for 12 h. After the reaction was completed, the mixture was diluted with water (20 mL), neutralized with 1 M aqueous HCl, and extracted with EtOAc (20 mL, 2 times). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give 3-(3-(((S)-1-(tert-butoxy)-3-methyl-1-oxobutan-2-yl)amino)propyl)-1-tritylpyrrolidine-3-carboxylic acid (Compound 16i, 440 mg) as a white gum. 1 H NMR (400 MHz, CDCl3) δ = 7.46 (d, J = 8.0 Hz, 6H), 7.26 - 7.19 (m, 6H), 7.16 - 7.10 (m, 3H), 3.10 - 2.86 (m, 4H), 2.54 - 2.45 (m, 2H), 2.37 - 2.22 (m, 2H), 2.18 - 2.10 (m, 1H), 2.04 - 1.97 (m, 1H), 1.68 - 1.54 (m, 2H), 1.49 - 1.44 (m, 9H), 1.41 - 1.35 (m, 2H), 0.99 - 0.89 (m, 6H) ppm.

[0247] Step 7: Preparation of tert-butyl (2S)-3-methyl-2-(6-oxo-2-trityl-2,7-diazaspiro[4.5]decane-7-yl)butanoate (Compound 16j) To a solution of 3-(3-(((S)-1-(tert-butoxy)-3-methyl-1-oxobutan-2-yl)amino)propyl)-1-tritylpyrrolidine-3-carboxylic acid (Compound 16i, 440 mg, 0.77 mmol) in DMF (5 mL) were added DIEA (0.67 mL, 3.85 mmol) and COMU (594 mg, 1.39 mmol) at 0 °C. The mixture was stirred at 20 °C for 1 h. After completion of the reaction, the reaction mixture was poured into water (20 mL) and extracted with EtOAc (20 mL, twice). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a residue, which was purified by silica gel column (EtOAc in PE = 0% - 10%) to afford tert-butyl (2S)-3-methyl-2-(6-oxo-2-trityl-2,7-diazaspiro[4.5]decane-7-yl)butanoate (Compound 16j, 420 mg) as a yellow oil. MS calculated value 553.3 (MH + ), measured value 553.2 (MH + ).

[0248] Step 8: Preparation of (2S)-3-methyl-2-(6-oxo-2,7-diazaspiro[4.5]decane-7-yl)butanoic acid (Compound 16k) To a solution of tert-butyl (2S)-3-methyl-2-(6-oxo-2-trityl-2,7-diazaspiro[4.5]decane-7-yl)butanoate (Compound 16j, 550 mg, 1 mmol) in DCM (3 mL) was added TFA (3.0 mL). The mixture was stirred at 20 °C for 12 h. After completion of the reaction, the mixture was concentrated under vacuum to give a residue, which was dissolved in water (10 mL) and the aqueous phase was washed with EtOAc (20 mL, twice). The aqueous phase was concentrated under vacuum to afford (2S)-3-methyl-2-(6-oxo-2,7-diazaspiro[4.5]decane-7-yl)butanoic acid (Compound 16k, 365 mg) in the form of TFA salt as a colorless oil. MS calculated value 255.2 (MH + ), measured value 255.2 (MH + ).

[0249] Step 9: Preparation of (2S)-2-(2-(tert-Butoxycarbonyl)-6-oxo-2,7-diazaspiro[4.5]decane-7-yl)-3-methylbutanoic acid (Compound 16l). To a solution of (2S)-3-methyl-2-(6-oxo-2,7-diazaspiro[4.5]decane-7-yl)butanoic acid (Compound 16k, 365 mg, 0.99 mmol) in the TFA salt form in THF (10 mL) and water (10 mL) were added sodium carbonate (210 mg, 1.98 mmol) and di-tert-butyl dicarbonate (259 mg, 1.19 mmol). The mixture was stirred at 20 °C for 2 hours. After completion of the reaction, the mixture was neutralized with 1 M aqueous HCl, and the reaction mixture was extracted with EtOAc (20 mL, 2 times). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum to give (2S)-2-(2-(tert-butoxycarbonyl)-6-oxo-2,7-diazaspiro[4.5]decane-7-yl)-3-methylbutanoic acid (Compound 16l, 350 mg) as a white solid.

[0250] Step 10: Preparation of tert-butyl (5S)-7-[(1S)-1-tert-butoxycarbonyl-2-methyl-propyl]-6-oxo-2,7-diazaspiro[4.5]decane-2-carboxylate (Compound 16m1) and tert-butyl (5R)-7-[(1S)-1-tert-butoxycarbonyl-2-methyl-propyl]-6-oxo-2,7-diazaspiro[4.5]decane-2-carboxylate (Compound 16m2). tert-Butyl 7-[(1S)-1-tert-butoxycarbonyl-2-methyl-propyl]-6-oxo-2,7-diazaspiro[4.5]decane-2-carboxylate (Compound 16l, 680.0 mg, 1.66 mmol) was separated by SFC (regis (S,S) whelk-O1 (250 mm, twice 5 mm×10 um), mobile phase: (0.1% NH3H2O) IPA, B%: 15%-15%, 4.4 min) to give tert-butyl (5S)-7-[(1S)-1-tert-butoxycarbonyl-2-methyl-propyl]-6-oxo-2,7-diazaspiro[4.5]decane-2-carboxylate (Compound 16m1, 245.0 mg, eluting faster) as a yellow oil, and tert-butyl (5R)-7-[(1S)-1-tert-butoxycarbonyl-2-methyl-propyl]-6-oxo-2,7-diazaspiro[4.5]decane-2-carboxylate (Compound 16m2, 223.0 mg, eluting slower) as a yellow oil. MS calculated value 411.3 (MH + ), measured value 411.3 (MH + ).

[0251] Step 11: Preparation of (2S)-3-methyl-2-[(5S)-6-oxo-2,7-diazaspiro[4.5]decane-7-yl]butanoic acid (Compound 16n1) To a solution of tert-butyl (5S)-7-[(1S)-1-tert-butoxycarbonyl-2-methyl-propyl]-6-oxo-2,7-diazaspiro[4.5]decane-2-carboxylate (Compound 16m1, 245.0 mg, 0.6 mmol) in DCM (1 mL) was added TFA (1.0 mL, 12.98 mmol). The mixture was stirred at 20 °C for 1 h. After completion of the reaction, the mixture was concentrated under vacuum to give (2S)-3-methyl-2-[(5S)-6-oxo-2,7-diazaspiro[4.5]decane-7-yl]butanoic acid (Compound 16n1, 219.0 mg, TFA salt) as a colorless liquid, which was used directly in the next step. MS calculated value 255.2 (MH + ), measured value 255.2 (MH + ).

[0252] Step 12: Preparation of (2S)-2-[(5S)-2-tert-butoxycarbonyl-6-oxo-2,7-diazaspiro[4.5]decan-7-yl]-3-methyl-butyric acid (Compound 16o1) (2S)-3-Methyl-2-[(5S)-6-oxo-2,7-diazaspiro[4.5]decan-7-yl]butyric acid (Compound 16n1, 219.0 mg, 0.59 mmol) in a solution of THF (2 mL) and water (2 mL) was added with sodium carbonate (189.05 mg, 1.78 mmol) and di-tert-butyl dicarbonate (155.71 mg, 0.71 mmol). The mixture was stirred at 20 °C for 1 hour. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated under vacuum to obtain a residue, which was purified by reverse-phase flash column to give (2S)-2-[(5S)-2-tert-butoxycarbonyl-6-oxo-2,7-diazaspiro[4.5]decan-7-yl]-3-methyl-butyric acid (Compound 16o1, 200.0 mg) as a white solid. MS calculated value 353.2 (MH + ), measured value 353.0 (MH + ).

[0253] Step 13: Preparation of (2S)-3-Methyl-2-[(5R)-6-oxo-2,7-diazaspiro[4.5]decan-7-yl]butyric acid (Compound 16n2) To a solution of tert-butyl (5R)-7-[(1S)-1-tert-butoxycarbonyl-2-methyl-propyl]-6-oxo-2,7-diazaspiro[4.5]decan-2-carboxylate (Compound 16m2, 223.0 mg, 0.54 mmol) in DCM (1.5 mL) was added TFA (1.5 mL, 19.47 mmol). The mixture was stirred at 20 °C for 1 hour. After the reaction was completed, the mixture was concentrated under vacuum to obtain (2S)-3-Methyl-2-[(5S)-6-oxo-2,7-diazaspiro[4.5]decan-7-yl]butyric acid (Compound 16n2, 200.0 mg, TFA salt) as a colorless liquid, which was used directly in the next step. MS calculated value 255.2 (MH + ), measured value 255.1 (MH + ).

[0254] Process 14: Preparation of (2S)-2-[(5R)-2-tert-butoxycarbonyl-6-oxo-2,7-diazaspiro[4.5]decane-7-yl]-3-methyl-butanoic acid (Compound 16o2) (2S)-3-methyl-2-[(5R)-6-oxo-2,7-diazaspiro[4.5]decane-7-yl]butanoic acid (Compound 16n2, 200.0 mg, 0.54 mmol) in a solution of THF (2 mL) and water (2 mL) was added with sodium carbonate (115.1 mg, 1.09 mmol) and di-tert-butyl dicarbonate (142.2 mg, 0.65 mmol). The mixture was stirred at 20 °C for 1 hour. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated under vacuum to obtain a residue, which was purified by reverse-phase flash column to obtain (2S)-2-[(5R)-2-tert-butoxycarbonyl-6-oxo-2,7-diazaspiro[4.5]decane-7-yl]-3-methyl-butanoic acid (Compound 16o2, 150.0 mg) as a white solid. MS calculated value 355.2 (MH + ), measured value 377.2 (MH + ).

[0255] Example 20 (2S)-2-[9-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,9-diazaspiro[5.5]undecane-2-yl]-N-[(7S,13S)-25-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaene-7-yl]-3-methyl-butanamide TIFF2025519199000081.tif61170

[0256] In the same manner as in the preparation of Example 6, (7S,13S)-7-amino-25-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo-[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-8,14-dione (Intermediate E) was used in place of (7S,13S)-7-amino-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-8,14-dione (Intermediate D) to prepare the title compound. Example 20 (6.1 mg) was obtained as a white solid. MS calculated value 1145.5 (MH + ), measured value 1145.5 (MH + ). 1 H NMR (400 MHz, methanol-d4) δ = 8.52 (s, 1H), 7.61 - 7.45 (m, 4H), 7.09 - 6.91 (m, 1H), 5.97 - 5.84 (m, 1H), 5.24 - 5.06 (m, 3H), 4.69 - 4.56 (m, 0.5H), 4.44 - 4.33 (m, 0.5H), 4.20 - 3.96 (m, 3H), 3.90 - 3.40 (m, 10H), 3.27 - 3.10 (m, 12H), 3.00 (s, 3H), 2.95 - 2.75 (m, 1H), 2.71 - 2.53 (m, 1H), 2.25 - 2.04 (m, 2H), 2.00 - 1.79 (m, 4H), 1.72 - 1.53 (m, 3H), 1.44 (d, J = 6.0 Hz, 3H), 1.37 - 1.19 (m, 2H), 0.94 (d, J = 6.0 Hz, 3H), 0.89 - 0.73 (m, 7H), 0.71 - 0.53 (m, 3H) ppm.

[0257] Example 22 and Example 23 (2S)-2-[(5R)-2-[(2S)-2-chloro-2-fluoro-acetyl]-6-oxo-2,7-diazaspiro[4.5]decane-7-yl]-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butanamide (Example 22) and (2S)-2-[(5S)-2-[(2S)-2-chloro-2-fluoro-acetyl]-6-oxo-2,7-diazaspiro[4.5]decane-7-yl]-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butanamide (Example 23) TIFF2025519199000082.tif150170

[0258] The title compound was prepared in the same manner as in the preparation of Example 6, using (2S)-2-chloro-2-fluoro-acetic acid, (2S)-2-[(5S)-2-tert-butoxycarbonyl-6-oxo-2,7-diazaspiro[4.5]decane-7-yl]-3-methyl-butanoic acid (Compound 16o1), and (7S,13S)-7-amino-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate H), (2R)-2-chloro-2-fluoro-acetic acid, (2S)-2-(9-tert-butoxycarbonyl-1-oxo-2,9-diazaspiro[5.5]undecane-2-yl)-3-methyl-butanoic acid (Compound 6J), and (7S,13S)-7-amino-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate D) instead. Example 22 (4.1 mg) was obtained as a white solid. MS calculated value 1077 (MH + ), measured value 1077 (MH + ). 1HNMR (400 MHz, DMSO-d6) δ 9.98 - 10.20 (m, 1H), 8.42 - 8.62 (m, 2H), 8.10 - 8.34 (m, 1H), 7.71 (d, J = 2.50 Hz, 1H), 7.57 (d, J = 13.01 Hz, 1H), 7.39 (br s, 1H), 7.15 (d, J = 10.01 Hz, 1H), 7.00 - 7.07 (m, 1H), 5.41 - 5.54 (m, 1H), 5.18 (br dd, J = 19.51, 11.88 Hz, 1H), 4.81 (br dd, J = 12.88, 11.38 Hz, 1H), 4.23 - 4.28 (m, 2H), 4.13 (br s, 5H), 3.57 (br s, 3H), 3.34 - 3.34 (m, 3H), 2.82 - 2.94 (m, 3H), 2.66 - 2.81 (m, 7H), 2.41 (br s, 1H), 2.31 - 2.34 (m, 3H), 2.21 (br d, J = 6.88 Hz, 1H), 1.69 - 1.88 (m, 7H), 1.50 (br s, 1H), 1.33 (d, J = 6.13 Hz, 3H), 1.18 - 1.26 (m, 3H), 0.84 - 0.98 (m, 11H), 0.80 (br t, J = 7.32 Hz, 3H), 0.35 (s, 3H) ppm.

[0259] Example 23 was prepared in the same manner as Example 6, using (2S)-2-chloro-2-fluoro-acetic acid, (2S)-2-[(5R)-2-tert-butoxycarbonyl-6-oxo-2,7-diazaspiro[4.5]decane-7-yl]-3-methyl-butanoic acid (Compound 16o 2), and (7S,13S)-7-amino-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26Octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate H) was used in place of octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate D) and prepared by using (2R)-2-chloro-2-fluoro-acetic acid, (2S)-2-(9-tert-butoxycarbonyl-1-oxo-2,9-diazaspiro[5.5]undecan-2-yl)-3-methyl-butanoic acid (Compound 6J) and (7S,13S)-7-amino-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 Octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate D) and was prepared as a white solid (2.2 mg). MS calculated value 1077 (MH + ), measured value 1077 (MH + ). 1 H NMR (400 MHz, methanol-d4) δ ppm 8.66 (d, J = 7.50 Hz, 1H), 8.47 (d, J = 2.88 Hz, 1H), 7.66 (br d, J = 7.13 Hz, 1H), 7.45 (d, J = 2.75 Hz, 1H), 7.33 - 7.36 (m, 1H), 6.73 - 6.94 (m, 1H), 5.32 - 5.38 (m, 2H), 4.37 - 4.53 (m, 2H), 4.09 - 4.30 (m, 5H), 3.68 - 3.81 (m, 4H), 3.61 (br d, J = 7.00 Hz, 4H), 3.04 (q, J = 7.75 Hz, 4H), 2.94 (br s, 3H), 2.77 - 2.87 (m, 2H), 2.54 - 2.66 (m, 2H), 2.16 - 2.22 (m, 3H), 2.01 - 2.05 (m, 3H), 1.88 (br s, 2H), 1.63 (dt, J = 15.26, 4.31 Hz, 8H), 1.43 (d, J = 6.25 Hz, 3H), 0.89 - 1.00 (m, 15H), 0.49 (br d, J = 2.63 Hz, 3H).

[0260] Example 24 (3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide TIFF2025519199000083.tif64170

[0261] In the same manner as the preparation of Example 1, (7S,13S)-7-amino-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo-[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-8,14-dione (Intermediate I) was used in place of (7S,13S)-7-amino-25-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-8,14-dione (Intermediate E) to prepare the title compound. Example 24 (18.9 mg) was obtained as a white solid. MS calculated value 1092.4 (MH + ), measured value 1092.5 (MH+ )。 1 1H NMR (400 MHz, methanol-d4) δ = 8.79 - 8.66 (m, 1H), 8.60 - 8.35 (m, 1H), 7.81 - 7.67 (m, 2H), 7.57 - 7.42 (m, 1H), 6.94 - 6.72 (m, 1H), 5.76 - 5.61 (m, 1H), 5.33 - 5.10 (m, 1H), 4.80 - 4.60 (m, 2H), 4.43 - 4.10 (m, 3H), 3.88 - 3.52 (m, 12H), 3.43 - 3.36 (m, 8H), 3.11 - 2.99 (m, 4H), 2.85 - 2.81 (m, 1H), 2.68 - 2.64 (m, 1H), 2.34 - 2.21 (m, 4H), 1.95 - 1.61 (m, 3H), 1.48 - 1.47 (m, 3H), 1.07 - 0.81 (m, 9H), 0.60 - 0.42 (m, 3H) ppm.

[0262] Example 25 (2S)-2-[2-[(2R)-2-chloro-2-fluoro-acetyl]-5-oxo-2,6-diazaspiro[3.4]octan-6-yl]-N-[(7S,13S)-24-fluoro-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butanamide TIFF2025519199000084.tif63170

[0263] In the same manner as the preparation of Example 6, the title compound was prepared by using (2S)-2-(8-tert-butoxycarbonyl-1-oxo-2,8-diazaspiro[4.5]decan-2-yl)-3-methyl-butanoic acid (Compound 25H) instead of (2S)-2-(9-tert-butoxycarbonyl-1-oxo-2,9-diazaspiro[5.5]undecan-2-yl)-3-methyl-butanoic acid (Compound 6J). Example 25 (20.8 mg) was obtained as a white solid. MS calculated value 1103.4 (MH + ), measured value 1103.7 (MH + ). 1 H NMR (400 MHz, methanol-d4) δ = 8.96 (d, J = 8.4 Hz, 1H), 8.68 (d, J = 7.6 Hz, 1H), 8.50 (d, J = 2.8 Hz, 1H), 7.72 (dd, J = 2.4, 17.6 Hz, 1H), 7.54 - 7.41 (m, 2H), 6.80 - 6.61 (m, 1H), 5.72 - 5.60 (m, 1H), 5.21 - 5.14 (m, 1H), 4.65 - 4.55 (m, 1H), 4.45 - 4.38 (m, 2H), 4.38 - 4.28 (m, 2H), 4.26 - 4.19 (m, 2H), 4.16 - 4.00 (m, 3H), 3.81 - 3.67 (m, 3H), 3.66 - 3.53 (m, 3H), 3.51 - 3.39 (m, 4H), 3.35 (s, 3H), 3.25 - 3.10 (m, 3H), 3.00 (s, 3H), 2.89 - 2.78 (m, 1H), 2.60 - 2.52 (m, 1H), 2.47 - 2.36 (m, 2H), 2.28 - 2.19 (m, 2H), 1.99 - 1.92 (m, 1H), 1.89 - 1.78 (m, 1H), 1.70 - 1.59 (m, 1H), 1.44 (d, J = 6.0 Hz, 3H), 1.01 (dd, J = 3.6, 6.4 Hz, 3H), 0.97 (s, 3H), 0.92 - 0.86 (m, 3H), 0.43 (s, 3H) ppm.

[0264] Compound 25H was prepared according to the following scheme. TIFF2025519199000085.tif109170

[0265] Project 1: tert-Butyl 3-allyl-3-cyano-azetidine-1-carboxylate (Compound 25B) To a solution of tert-butyl 3-cyanoazetidine-1-carboxylate (Compound 25A, 10.0 g, 54.88 mmol) in THF (100 mL) was added LDA (60.3 mL, 60.37 mmol) dropwise at -70 °C under a nitrogen atmosphere. After stirring at -70 °C for 0.5 h, allyl bromide (7.9 g, 65.85 mmol) was added to the reaction mixture. The mixture was stirred at 16 °C for an additional 1 h and then concentrated in vacuo. The residue was purified by column chromatography (EtOAc in PE: 3% - 10%) to give tert-butyl 3-allyl-3-cyano-azetidine-1-carboxylate (Compound 25B, 12.5 g) as a pale yellow oil. 1 H NMR (400 MHz, chloroform-d) δ 5.90 - 5.70 (m, 1H), 5.32 (s, 1H), 5.28 (d, J = 5.2 Hz, 1H), 4.23 (d, J = 8.8 Hz, 2H), 3.86 (d, J = 8.8 Hz, 2H), 2.63 (d, J = 7.2 Hz, 2H), 1.45 (s, 9H) ppm.

[0266] Project 2: 3-Allyl-1-tert-butoxycarbonyl-azetidine-3-carboxylic acid (Compound 25C) A mixture of tert-butyl 3-allyl-3-cyano-azetidine-1-carboxylate (Compound 25B, 12.5 g, 56.24 mmol) and potassium hydroxide (12.6 g, 224.94 mmol) in ethanol (60 mL) and water (60 mL) was stirred at 100 °C for 16 h. After the reaction was complete, the pH of the reaction mixture was acidified to pH = 3 with aqueous HCl (1 M). The reaction mixture was extracted with EtOAc (120 mL, 3 times). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give 3-allyl-1-tert-butoxycarbonyl-azetidine-3-carboxylic acid (Compound 25C, 14.0 g) as a white solid. MS calculated value 241.1 (MH + ), measured value 186.2 (M - C4H8 + H + ).

[0267] Step 3: O1-tert-butyl O3-methyl 3-allylazetidine-1,3-dicarboxylate (Compound 25D) To a mixture of 3-allyl-1-tert-butoxycarbonyl-azetidine-3-carboxylic acid (Compound 25C, 8.0 g, 33.16 mmol) in DMF (80 mL) was added potassium carbonate (13.7 g, 99.47 mmol), followed by iodomethane (9.4 g, 66.31 mmol). After stirring at 20 °C for 2 h, the reaction mixture was poured into water (400 mL), and the resulting mixture was extracted with EtOAc (100 mL, 3 times). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give O1-tert-butyl O3-methyl 3-allylazetidine-1,3-dicarboxylate (Compound 25D, 7.3 g) as a yellow oil. 1 H NMR (400 MHz, chloroform-d) δ 5.80 - 5.60 (m, 1H), 5.19 - 5.14 (m, 1H), 5.12 (s, 1H), 4.16 (d, J = 8.8 Hz, 2H), 3.82 - 3.69 (m, 5H), 2.63 (d, J = 7.2 Hz, 2H), 1.44 (s, 9H) ppm.

[0268] Step 4: O1-tert-butyl O3-methyl 3-(2-oxoethyl)azetidine-1,3-dicarboxylate (Compound 25E) To a mixture of O1-tert-butyl O3-methyl 3-allylazetidine-1,3-dicarboxylate (Compound 25D, 2 g, 7.83 mmol) in 1,4-dioxane (20 mL) and water (20 mL) were added 2,6-lutidine (1.8 mL, 15.67 mmol) and K2OsO4 (144.3 mg, 0.39 mmol). After stirring at 16 °C for 15 minutes, sodium metaperiodate (6702.2 mg, 31.33 mmol) was added to the reaction mixture, and the mixture was stirred for an additional 1 hour, then poured into water (120 mL), and the resulting mixture was extracted with EtOAc (40 mL, 3 times). The combined organic layers were washed with saturated Na2SO3 (60 mL), brine (60 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give O1-tert-butyl O3-methyl 3-(2-oxoethyl)azetidine-1,3-dicarboxylate (Compound 25E, 2.8 g) as a yellow oil. MS calculated 257.1 (MH + ), found 202.1 (M-C4H8+H + ).

[0269] Step 5: O1-tert-butyl O3-methyl 3-[2-[[(1S)-1-benzyloxycarbonyl-2-methyl-propyl]amino]ethyl]azetidine-1,3-dicarboxylate (Compound 25F) A mixture of L-valine benzyl ester hydrochloride (3.2 g, 13.06 mmol) and O1-tert-butyl O3-methyl 3-(2-oxoethyl)azetidine-1,3-dicarboxylate (Compound 25E, 2.8 g, 10.88 mmol) in methanol (50 mL) was added zinc chloride (1.8 g, 13.06 mmol). After stirring at 16 °C for 0.5 h, sodium cyanoborohydride (1.4 g, 21.77 mmol) was added to the reaction mixture and the resulting mixture was stirred for an additional 1 h. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography (EtOAc in PE: 30%-50%) to give O1-tert-butyl O3-methyl 3-[2-[[(1S)-1-benzyloxycarbonyl-2-methyl-propyl]amino]ethyl]azetidine-1,3-dicarboxylate (Compound 25F, 2.2 g,) as a colorless oil. MS calculated 449.3 (MH + ), found 449.3 (MH + ).

[0270] Step 6: tert-Butyl 6-[(1S)-1-benzyloxycarbonyl-2-methyl-propyl]-5-oxo-2,6-diazaspiro[3.4]octane-2-carboxylate (Compound 25G) 4-Dimethylaminopyridine (544.7 mg, 4.46 mmol), DIEA (7.7 mL, 44.59 mmol) and a mixture of O1-tert-butyl O3-methyl 3-[2-[[(1S)-1-benzyloxycarbonyl-2-methyl-propyl]amino]ethyl]azetidine-1,3-dicarboxylate (Compound 25F, 2.0 g, 4.46 mmol) in toluene (2 mL) were stirred at 100 °C for 20 h. After the reaction was completed, the reaction mixture was concentrated in vacuo and the residue was dissolved in EtOAc (60 mL). The resulting solution was washed with aqueous HCl (1 M, 60 mL), then brine (60 mL), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to give tert-butyl 6-[(1S)-1-benzyloxycarbonyl-2-methyl-propyl]-5-oxo-2,6-diazaspiro[3.4]octane-2-carboxylate (Compound 25G, 1.5 g) as a white solid. MS calculated 417.2 (MH + ), found 361.2 (M-C4H8+H + ).

[0271] Step 7: (2S)-2-(2-tert-Butoxycarbonyl-5-oxo-2,6-diazaspiro[3.4]octan-6-yl)-3-methyl-butanoic acid (Compound 25H) A mixture of tert-butyl 6-[(1S)-1-benzyloxycarbonyl-2-methyl-propyl]-5-oxo-2,6-diazaspiro[3.4]octane-2-carboxylate (Compound 25G, 1.5 g, 3.6 mmol) and Pd on activated carbon (150.0 mg) in methanol (20 mL) was stirred at 16 °C for 2 h under a H2 balloon. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give (2S)-2-(2-tert-butoxycarbonyl-5-oxo-2,6-diazaspiro[3.4]octan-6-yl)-3-methyl-butanoic acid (Compound 25H, 920.0 mg) as a white solid. MS calculated 327.2 (MH + ), found 271.2 (M-C4H8+H + ).

[0272] Example 26 (3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide TIFF2025519199000086.tif63170

[0273] In the same manner as in the preparation of Example 1, (7S,13S)-7-amino-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-8,14-dione (Intermediate J) was prepared from (7S,13S)-7-amino-25-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26The title compound was prepared by using instead of octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate E). Example 26 (14.6 mg) was obtained as a white solid. MS calculated value 1173.4 (MH + ), measured value 1173.7 (MH + ). 1 H NMR (400 MHz, methanol-d4) δ = 8.72 - 8.68 (m, 1H), 8.42 (d, J = 2.4 Hz, 1H), 7.77 - 7.68 m, 1H), 7.57 - 7.45 (m, 2H), 6.93 - 6.76 (m, 1H), 5.81 - 5.63 (m, 1H), 5.27 - 5.11 (m, 1H), 4.96 - 4.93 (m, 1H), 4.88 - 4.79 (m, 2H), 4.47 - 4.38 (m, 1H), 4.28 - 4.18 (m, 2H), 3.88 - 3.53 (m, 7H), 3.47 - 3.34 (m, 8H), 3.30 - 3.24 (m, 1H), 3.23 - 3.07 (m, 6H), 2.92 - 2.80 (m, 5H), 2.70 - 2.56 (m, 1H), 2.40 - 2.06 (m, 4H), 2.00 - 1.91 (m, 1H), 1.88 - 1.74 (m, 1H), 1.69 - 1.57 (m, 1H), 1.49 - 1.41 (m, 3H), 1.01 - 0.97 (m, 5H), 0.92 - 0.82 (m, 3H), 0.53 - 0.42 (m, 3H) ppm.

[0274] Example 27 (3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(8S,14S)-26-fluoro-4-hydroxy-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-18,18-dimethyl-9,15-dioxo-22-(2,2,2-trifluoroethyl)-16-oxa-10,22,28-triazapentacyclo[18.5.2.1 2,6 .1 10,14 .0 23,27 nonacosa-1(26),2,4,6(29),20,23(27),24-heptaene-8-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide TIFF2025519199000087.tif59170

[0275] In the same manner as the preparation of Example 1, (8S,14S)-8-amino-26-fluoro-4-hydroxy-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-18,18-dimethyl-22-(2,2,2-trifluoroethyl)-16-oxa-10,22,28-triazapentacyclo[18.5.2.1 2,6 .1 10,14 .0 23,27 nonacosa-1(26),2,4,6(29),20,23(27),24-heptaene-9,15-dione (Intermediate K) was used instead of (7S,13S)-7-amino-25-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate E) to prepare the title compound. Example 27 (5.2 mg) was obtained as a white solid. MS calculated value 1114.5 (MH + ), measured value 1114.6 (MH + ), 11H NMR (400 MHz, methanol-d4) δ: 8.50 (d, J = 2.8 Hz, 1H), 8.21 - 8.10 (m, 1H), 7.51 (s, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.42 - 7.36 (m, 1H), 7.14 - 7.06 (m, 1H), 6.89 - 6.86 (m, 1H), 5.34 (t, J = 4.4 Hz, 1H), 4.69 (d, J = 10.8 Hz, 1H), 4.43 - 4.34 (m, 0.5H), 4.27 - 4.17 (m, 0.5H), 4.14 - 3.95 (m, 1H), 3.79 - 3.56 (m, 6H), 3.23 (s, 2H), 3.02 (d, J = 14 Hz, 6H), 2.91 - 2.78 (m, 2H), 2.78 - 2.56 (m, 2H), 2.19 (t, J = 7.6 Hz, 2H), 2.06 - 2.01 (m, 3H), 1.88 - 1.77 (m, 1H), 1.64 - 1.56 (m, 1H), 1.50 - 1.46 (m, 3H), 1.44 (d, J = 1.6 Hz, 1H), 1.34 - 1.29 (m, 10H), 1.18 (t, J = 6.8 Hz, 2H), 0.97 - 0.87 (m, 8H), 0.86 - 0.82 (m, 3H), 0.41 (s, 3H) ppm.

[0276] Example 28 (2S)-2-[8-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,8-diazaspiro[4.5]decane-2-yl]-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaene-7-yl]-3-methyl-butanamide TIFF2025519199000088.tif52170

[0277] The title compound was prepared in the same manner as in the preparation of Example 6, using (2S)-2-(8-tert-butoxycarbonyl-1-oxo-2,8-diazaspiro[4.5]decane-2-yl)-3-methyl-butanoic acid (Compound 15F) and (7S,13S)-7-amino-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate H) in place of (2S)-2-(9-tert-butoxycarbonyl-1-oxo-2,9-diazaspiro[5.5]undecane-2-yl)-3-methyl-butanoic acid (Compound 6J) and (7S,13S)-7-amino-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate D). Example 28 (11.7 mg) was obtained as a white solid. MS calculated value 1077.5 (MH + ), measured value 1077.5 (MH + ). 11H NMR (400 MHz, methanol-d4) δ 8.64 (d, J = 7.7 Hz, 1H), 8.43 (d, J = 1.7 Hz, 1H), 7.66 (s, 1H), 7.43 (d, J = 2.2 Hz, 1H), 7.30 (d, J = 12.3 Hz, 1H), 7.13 - 6.92 (m, 1H), 5.69 - 5.53 (m, 2H), 5.51 - 5.36 (m, 1H), 4.58 (s, 11H), 4.54 - 4.23 (m, 1H), 4.22 - 3.80 (m, 1H), 3.78 - 3.46 (m, 3H), 2.75 - 2.59 (m, 5H), 2.44 - 2.30 (m, 5H), 2.29 - 2.19 (m, 2H), 2.18 - 2.05 (m, 3H), 2.03 - 1.74 (m, 6H), 1.70 - 1.55 (m, 3H), 1.30 - 1.15 (m, 7H), 1.03 - 0.94 (m, 7H), 0.90 (dd, J = 2.6, 6.5 Hz, 3H), 0.61 (s, 3H) ppm.

[0278] Example 29 (2S)-2-[2-[(2R)-2-chloro-2-fluoro-acetyl]-5-oxo-2,6-diazaspiro[3.4]octan-6-yl]-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaene-7-yl]-3-methyl-butanamide TIFF2025519199000089.tif57170

[0279] The title compound was prepared in the same manner as in the preparation of Example 6, using (2S)-2-(2-tert-butoxycarbonyl-5-oxo-2,6-diazaspiro[3.4]octan-6-yl)-3-methyl-butanoic acid (Compound 25H) and (7S,13S)-7-amino-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate H) instead of (2S)-2-(9-tert-butoxycarbonyl-1-oxo-2,9-diazaspiro[5.5]undecan-2-yl)-3-methyl-butanoic acid (Compound 6J) and (7S,13S)-7-amino-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate D). Example 29 (63.2 mg) was obtained as a yellow solid. MS calculated value 1049.5 (MH + ), measured value 1049.5 (MH + ). 11H NMR (400 MHz, Methanol-d4) δ = 8.76 - 8.63 (m, 1H), 8.58 - 8.45 (m, 1H), 7.78 - 7.56 (m, 2H), 7.44 - 7.30 (m, 1H), 6.82 - 6.59 (m, 1H), 5.83 - 5.67 (m, 1H), 4.65 - 4.53 (m, 1H), 4.50 - 3.99 (m, 11H), 3.88 - 3.67 (m, 3H), 3.61 - 3.47 (m, 3H), 3.47 - 3.42 (m, 3H), 3.41 - 3.35 (m, 4H), 3.32 - 3.22 (m, 2H), 3.11 - 3.04 (m, 1H), 3.01 (s, 3H), 2.90 - 2.78 (m, 1H), 2.69 - 2.60 (m, 1H), 2.45 - 2.35 (m, 2H), 2.31 - 2.16 (m, 2H), 2.03 - 1.92 (m, 1H), 1.90 - 1.75 (m, 1H), 1.72 - 1.58 (m, 1H), 1.52 - 1.41 (m, 3H), 1.08 - 0.98 (m, 6H), 0.96 (s, 3H), 0.89 (dd, J = 2.8, 6.4 Hz, 3H), 0.62 - 0.43 (m, 3H) ppm.

[0280] Examples 30 and 31 (2S)-2-[(5R)-7-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butanamide (Example 30) TIFF2025519199000090.tif62170 (Example 30)

[0281] (2S)-2-[(5S)-7-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butanamide (Example 31) TIFF2025519199000091.tif62170 (Example 31)

[0282] Example 30 was prepared in the same manner as in the preparation of Example 4, (7S,13S)-7-amino-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate H) was used instead of (7S,13S)-7-amino-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate D) and was prepared. Example 30 (42.4 mg) was obtained as a yellow solid. MS calculated value 1063.5 (MH+ ) Measurement value 1063.5 (MH + ). 1 H NMR (400 MHz, methanol-d4) δ 8.72 - 8.65 (m, 1H), 8.56 - 8.45 (m, 1H), 7.78 - 7.73 (m, 0.5H), 7.70 - 7.64 (m, 0.5H), 7.63 - 7.57 (m, 1H), 7.41 - 7.31 (m, 1H), 6.95 - 6.71 (m, 1H), 5.82 - 5.67 (m, 1H), 4.51 - 4.02 (m, 8H), 3.99 - 3.90 (m, 1H), 3.88 - 3.70 (m, 5H), 3.69 - 3.56 (m, 4H), 3.52 - 3.43 (m, 3H), 3.37 (d, J = 6.4 Hz, 4H), 3.30 - 3.23 (m, 2H), 3.13 - 3.05 (m, 1H), 3.01 (s, 3H), 2.88 - 2.79 (m, 1H), 2.69 - 2.57 (m, 1H), 2.36 - 2.18 (m, 3H), 2.18 - 2.04 (m, 3H), 2.01 - 1.96 (m, 1H), 1.88 - 1.76 (m, 1H), 1.71 - 1.59 (m, 1H), 1.46 (d, J = 6.0 Hz, 3H), 1.05 - 0.94 (m, 9H), 0.94 - 0.89 (d, J = 6.6 Hz, 3H), 0.58 - 0.41 (m, 3H) ppm.

[0283] Example 31 was prepared in the same manner as Example 4, (2S)-2-[(5R)-7-tert-butoxycarbonyl-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-3-methyl-butanoic acid (Compound 4f1) and (7S,13S)-7-amino-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26Octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (intermediate H) was prepared by using it instead of octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (intermediate D). Example 31 (56.7 mg) was obtained as a yellow solid. MS calculated value 1063.5 (MH 2,5 .1 9,13 .0 22,26 ), measured value 1063.5 (MH + ). + 1 HNMR (400 MHz, methanol-d4) δ = 8.67 (d, J = 7.6 Hz, 1H), 8.48 (d, J = 2.8 Hz, 1H), 7.65 (s, 1H), 7.57 (s, 1H), 7.34 (d, J = 12.8 Hz, 1H), 6.94 - 6.73 (m, 1H), 5.75 (t, J = 8.8 Hz, 1H), 4.45 - 4.37 (m, 1H), 4.36 - 4.29 (m, 2H), 4.28 - 4.08 (m, 4H), 4.07 - 3.97 (m, 1H), 3.97 - 3.87 (m, 1H), 3.85 - 3.72 (m, 4H), 3.71 - 3.63 (m, 2H), 3.63 - 3.41 (m, 7H), 3.34 (s, 3H), 3.30 - 3.23 (m, 2H), 3.07 - 3.02 (m, 1H), 3.00 (s, 3H), 2.87 - 2.77 (m, 1H), 2.69 - 2.57 (m, 1H), 2.33 - 2.15 (m, 3H), 2.14 - 2.03 (m, 3H), 1.97 - 1.91 (m, 1H), 1.84 - 1.72 (m, 1H), 1.69 - 1.57 (m, 1H), 1.44 (d, J = 6.0 Hz, 3H), 1.03 - 0.92 (m, 9H), 0.89 (d, J = 6.8 Hz, 3H), 0.51 (s, 3H) ppm.​

[0284] Example 32 (3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide TIFF2025519199000092.tif57170

[0285] In the same manner as in the preparation of Example 1, (7S,13S)-7-amino-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-8,14-dione (Intermediate H) was used to react with (7S,13S)-7-amino-25-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26The title compound was prepared by using instead of octacosa-1(25),2,5(28),19,22(26),23-hexaen-8,14-dione (Intermediate E). Example 32 (36.7 mg) was obtained as a yellow solid. MS calculated value 1051.4 (MH + ), measured value 1051.6 (MH + ). 1 H NMR (400 MHz, MeOD) δ 8.67 (d, J = 7.6 Hz, 1H), 8.49 (d, J = 2.8 Hz, 1H), 7.73 - 7.59 (m, 2H), 7.34 (d, J = 12.8 Hz, 1H), 6.96 - 6.70 (m, 1H), 5.82 - 5.61 (m, 1H), 5.00 - 4.90 (m, 2H), 4.83 - 4.77 (m, 1H), 4.49 - 4.38 (m, 1H), 4.37 - 4.05 (m, 5H), 4.00 - 3.89 (m, 1H), 3.89 - 3.47 (m, 10H), 3.47 - 3.39 (m, 2H), 3.36 (d, J = 4.8 Hz, 3H), 3.28 - 3.22 (m, 1H), 3.15 - 3.07 (m, 3H), 3.06 - 3.02 (m, 1H), 3.00 (s, 3H), 2.89 - 2.76 (m, 1H), 2.69 - 2.56 (m, 1H), 2.42 - 2.01 (m, 4H), 2.00 - 1.90 (m, 1H), 1.89 - 1.73 (m, 1H), 1.71 - 1.56 (m, 1H), 1.44 (d, J = 6.4 Hz, 3H), 1.25 - 0.96 (m, 6H), 0.96 - 0.92 (m, 3H), 0.92 - 0.82 (m, 3H), 0.61 - 0.39 (m, 3H) ppm.

[0286] Example 33 (3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(7S,13S)-21-ethyl-24-fluoro-(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-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide TIFF2025519199000093.tif61170

[0287] In the same manner as the preparation of Example 1, (7S,13S)-7-amino-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 Octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate L) was used instead of (7S,13S)-7-amino-25-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 By using Octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate E) instead, the title compound was prepared. Example 33 (45.2 mg) was obtained as a yellow solid. MS calculated value 1119.5 (MH + ), measured value 1119.7 (MH + ). 11H NMR (400 MHz, methanol-d4) δ = 8.73 - 8.65 (m, 1H), 8.38 (s, 1H), 7.94 - 7.86 (m, 1H), 7.72 - 7.62 (m, 1H), 7.37 (d, J = 12.6 Hz, 1H), 6.94 - 6.72 (m, 1H), 5.83 - 5.69 (m, 1H), 4.84 - 4.76 (m, 1H), 4.47 - 4.19 (m, 3H), 4.17 - 3.92 (m, 2H), 3.89 - 3.62 (m, 6H), 3.61 - 3.53 (m, 1H), 3.51 - 3.46 (m, 4H), 3.43 - 3.37 (m, 3H), 3.28 - 3.13 (m, 3H), 3.10 - 3.03 (m, 3H), 2.93 - 2.87 (m, 4H), 2.86 - 2.66 (m, 2H), 2.42 - 2.11 (m, 4H), 2.00 - 1.90 (m, 1H), 1.86 - 1.73 (m, 1H), 1.71 - 1.57 (m, 1H), 1.46 (d, J = 6.4 Hz, 3H), 1.36 - 1.27 (m, 1H), 1.14 - 0.78 (m, 13H), 0.69 - 0.54 (m, 3H) ppm.

[0288] Example 34 1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-4-fluoro-N-methyl-piperidine-4-carboxamide TIFF2025519199000094.tif57170

[0289] In the same manner as the preparation of Example 1, 1-tert-butoxycarbonyl-4-fluoro-piperidine-4-carboxylic acid and (7S,13S)-7-amino-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate H) was used in place of (S)-1-Boc-pyrrolidine-3-carboxylic acid (Compound 1D) and (7S,13S)-7-amino-25-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate E) to prepare the title compound. Example 34 (12.9 mg) was obtained as a yellow solid. MS calculated value 1083.5 (MH + ), measured value 1083.6 (MH + ), 11H NMR (400 MHz, methanol-d4) δ = 8.65 (d, J = 7.6 Hz, 1H), 8.48 (d, J = 2.4 Hz, 1H), 7.64 (s, 1H), 7.54 (s, 1H), 7.34 (d, J = 12.4 Hz, 1H), 7.11 - 6.95 (m, 1H), 5.78 - 5.71 (m, 1H), 4.47 - 4.37 (m, 2H), 4.35 - 4.23 (m, 2H), 4.22 - 4.07 (m, 4H), 4.00 - 3.88 (m, 2H), 3.80 - 3.69 (m, 3H), 3.68 - 3.57 (m, 2H), 3.54 - 3.41 (m, 4H), 3.34 (s, 3H), 3.20 (t, J = 4.8 Hz, 4H), 3.14 - 3.05 (m, 2H), 3.03 - 2.95 (m, 5H), 2.86 - 2.79 (m, 1H), 2.65 - 2.57 (m, 1H), 2.32 - 2.13 (m, 5H), 2.03 - 1.90 (m, 2H), 1.84 - 1.77 (m, 1H), 1.68 - 1.59 (m, 1H), 1.44 (d, J = 6.0 Hz, 3H), 1.29 - 1.09 (m, 2H), 1.00 - 0.97 (m, 3H), 0.93 (s, 3H), 0.91 - 0.86 (m, 3H), 0.50 (d, J = 5.2 Hz, 3H).

[0290] Example 35 and Example 38 (2S)-2-[(5R)-7-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-N-[(7S,13S)-21-ethyl-24-fluoro-(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-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butanamide (Example 35) TIFF2025519199000095.tif61170 (Example 35)

[0291] (2S)-2-[(5S)-7-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-N-[(7S,13S)-21-ethyl-24-fluoro-(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-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butanamide (Example 38) TIFF2025519199000096.tif61170 (Example 38)

[0292] Example 35 was prepared in the same manner as Example 4, (7S,13S)-7-amino-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-8,14-dione (Intermediate L) was combined with (7S,13S)-7-amino-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26Prepared by using in place of octacosa-1(25),2,5(28),19,22(26),23-hexaen-8,14-dione (Intermediate D). Example 35 (21.1 mg) was obtained as a yellow solid. MS calculated value 1131.5 (MH + ), measured value 1131.6 (MH + ). 1 H NMR (400 MHz, methanol-d4) δ 8.71 (dd, J = 2.4, 7.6 Hz, 1H), 8.38 (t, J = 2.4 Hz, 1H), 7.87 - 7.81 (m, 1H), 7.76 - 7.62 (m, 1H), 7.37 (dd, J = 2.8, 12.6 Hz, 1H), 6.92 - 6.69 (m, 1H), 5.84 - 5.71 (m, 1H), 4.45 - 4.12 (m, 5H), 4.10 - 4.00 (m, 1H), 3.96 - 3.69 (m, 5H), 3.60 - 3.54 (m, 2H), 3.51 - 3.42 (m, 6H), 3.41 - 3.37 (m, 3H), 3.26 - 3.12 (m, 3H), 3.09 - 2.96 (m, 1H), 2.93 - 2.87 (m, 4H), 2.85 - 2.66 (m, 2H), 2.34 - 2.15 (m, 3H), 2.12 - 1.93 (m, 4H), 1.86 - 1.73 (m, 1H), 1.71 - 1.57 (m, 1H), 1.45 (d, J = 6.4 Hz, 3H), 1.04 - 0.95 (m, 9H), 0.89 (d, J = 6.8 Hz, 3H), 0.58 (d, J = 12.8 Hz, 3H).

[0293] Example 38 was prepared in the same manner as the preparation of Example 4, (2S)-2-[(5R)-7-tert-butoxycarbonyl-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-3-methyl-butanoic acid (Compound 4f1) and (7S,13S)-7-amino-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26Octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate I) was used instead of (2S)-2-[(5S)-7-tert-butoxycarbonyl-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-3-methyl-butanoic acid (Compound 4f2) and (7S,13S)-7-amino-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 Octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate D) was prepared by using instead. Example 38 (26.1 mg) was obtained as a yellow solid. MS calculated value 1131.5 (MH + ), measured value 1131.7 (MH + ). 1HNMR (400 MHz, methanol-d4) δ = 8.88 - 8.81 (m, 1H), 8.71 (d, J = 7.6 Hz, 1H), 8.38 (d, J = 2.0 Hz, 1H), 7.96 - 7.87 (m, 1H), 7.67 - 7.64 (m, 1H), 7.37 (d, J = 12.4 Hz, 1H), 6.91 - 6.75 (m, 1H), 5.84 - 5.79 (m, 1H), 4.46 - 4.36 (m, 2H), 4.33 - 4.25 (m, 2H), 4.18 - 4.12 (m, 1H), 4.08 - 3.84 (m, 2H), 3.81 - 3.43 (m, 4H), 3.69 - 3.61 (m, 2H), 3.52 - 3.48 (m, 5H), 3.40 (s, 3H), 3.23 - 3.15 (m, 3H), 3.03 - 2.97 (m, 1H), 2.91 - 2.88 (m, 4H), 2.83 - 2.73 (m, 2H), 2.27 - 2.15 (m, 3H), 2.11 - 2.04 (m, 3H), 2.00 - 1.91 (m, 2H), 1.85 - 1.76 (m, 1H), 1.70 - 1.61 (m, 1H), 1.46 (d, J = 6.4 Hz, 3H), 1.04 - 0.99 (m, 5H), 0.96 (s, 3H), 0.89 (d, J = 6.8 Hz, 3H), 0.61 (s, 3H) ppm.

[0294] Example 36 (2S)-2-[9-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,9-diazaspiro[5.5]undecan-2-yl]-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaene-7-yl]-3-methyl-butanamide TIFF2025519199000097.tif62170

[0295] In the same manner as the preparation of Example 6, (7S,13S)-7-amino-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate H) was used in place of (7S,13S)-7-amino-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate D) to prepare the title compound. Example 36 (27.5 mg) was obtained as a yellow solid. MS calculated value 1091.5 (MH + ), measured value 1091.5 (MH + ). 11H NMR (400 MHz, methanol-d4) δ = 8.67 (d, J = 7.6 Hz, 1H), 8.48 (d, J = 2.8 Hz, 1H), 7.67 (d, J = 2.4 Hz, 1H), 7.61 - 7.51 (m, 1H), 7.34 (d, J = 12.8 Hz, 1H), 7.15 - 6.85 (m, 1H), 5.80 - 5.68 (m, 1H), 4.86 - 4.76 (m, 1H), 4.47 - 4.36 (m, 1H), 4.35 - 4.05 (m, 6H), 3.97 - 3.86 (m, 1H), 3.83 - 3.67 (m, 3H), 3.66 - 3.51 (m, 2H), 3.50 - 3.40 (m, 4H), 3.34 (s, 3H), 3.30 - 3.09 (m, 4H), 3.07 - 3.01 (m, 1H), 3.00 (s, 3H), 2.88 - 2.76 (m, 1H), 2.68 - 2.56 (m, 1H), 2.33 - 2.08 (m, 4H), 1.97 - 1.75 (m, 6H), 1.68 - 1.57 (m, 3H), 1.44 (d, J = 6.0 Hz, 3H), 1.37 - 1.24 (m, 2H), 1.01 - 0.90 (m, 9H), 0.87 (d, J = 6.4 Hz, 3H), 0.51 (s, 3H) ppm.

[0296] Example 37 (2S)-2-[2-[(2R)-2-chloro-2-fluoro-acetyl]-5-oxo-2,6-diazaspiro[3.4]octan-6-yl]-N-[(7S,13S)-21-ethyl-24-fluoro-(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-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaene-7-yl]-3-methyl-butanamide TIFF2025519199000098.tif57170

[0297] The title compound was prepared in the same manner as in the preparation of Example 6, using (2S)-2-(2-tert-butoxycarbonyl-5-oxo-2,6-diazaspiro[3.4]octan-6-yl)-3-methyl-butyric acid (Compound 25H) and (7S,13S)-7-amino-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate L) in place of (2S)-2-(9-tert-butoxycarbonyl-1-oxo-2,9-diazaspiro[5.5]undecan-2-yl)-3-methyl-butyric acid (Compound 6J) and (7S,13S)-7-amino-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate D). Example 37 (32.1 mg) was obtained as a yellow solid. MS calculated value 1117.5 (MH + ), measured value 1117.5 (MH + ). 11H NMR (400 MHz, methanol-d4) δ = 8.69 (d, J = 7.6 Hz, 1H), 8.38 (d, J = 2.4 Hz, 1H), 7.74 (s, 1H), 7.66 (dd, J = 4.0 Hz, 24.4 Hz, 1H), 7.35 (d, J = 12.8 Hz, 1H), 6.68 (d, J = 57.6 Hz, 1H), 5.78 (s, 1H), 4.57 (t, J = 5.6 Hz, 1H), 4.45 - 4.22 (m, 6H), 4.19 - 4.11 (m, 1H), 4.11 - 4.01 (m, 2H), 3.82 - 3.68 (m, 2H), 3.45 (s, 6H), 3.37 (d, J = 6.8 Hz, 4H), 3.22 - 3.12 (m, 2H), 3.07 - 2.97 (m, 1H), 2.88 (s, 4H), 2.76 - 2.66 (m, 2H), 2.38 (s, 2H), 2.26 - 2.13 (m, 2H), 1.99 - 1.92 (m, 1H), 1.86 - 1.74 (m, 1H), 1.69 - 1.61 (m, 1H), 1.45 (d, J = 6.4 Hz, 3H), 1.34 - 1.23 (m, 1H), 1.05 - 0.98 (m, 6H), 0.95 (s, 3H), 0.87 (dd, J = 2.4 Hz, 6.4 Hz, 3H), 0.57 (s, 3H) ppm.

[0298] Example 39 (2S)-2-[8-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,8-diazaspiro[4.5]decane-2-yl]-N-[(7S,13S)-21-ethyl-24-fluoro-(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-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butanamide TIFF2025519199000099.tif61170

[0299] The title compound was prepared in the same manner as in the preparation of Example 6, (2S)-2-(8-tert-butoxycarbonyl-1-oxo-2,8-diazaspiro[4.5]decane-2-yl)-3-methyl-butanoic acid (Compound 15F) and (7S,13S)-7-amino-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate L) was used instead of (2S)-2-(9-tert-butoxycarbonyl-1-oxo-2,9-diazaspiro[5.5]undecane-2-yl)-3-methyl-butanoic acid (Compound 6J) and (7S,13S)-7-amino-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate D). Example 39 (22.9 mg) was obtained as a yellow solid. MS calculated value 1145.5 (MH + ), measured value 1145.5 (MH + ). 11H NMR (400 MHz, methanol-d4) δ = 8.85 - 8.77 (m, 1H), 8.69 (d, J = 7.6 Hz, 1H), 8.39 (d, J = 2.8 Hz, 1H), 7.72 - 7.64 (m, 2H), 7.37 - 7.33 (m, 1H), 7.09 - 6.93 (m, 1H), 5.83 - 5.74 (m, 1H), 4.46 - 4.37 (m, 1H), 4.34 - 4.24 (m, 4H), 4.18 - 4.14 (m, 1H), 4.11 - 4.04 (m, 1H), 3.96 - 3.89 (m, 1H), 3.80 - 3.71 (m, 2H), 3.64 - 3.50 (m, 2H), 3.45 - 3.41 (m, 5H), 3.36 (s, 3H), 3.20 - 3.13 (m, 4H), 3.04 - 2.98 (m, 1H), 2.90 - 2.86 (m, 4H), 2.83 - 2.78 (m, 1H), 2.73 - 2.68 (m, 1H), 2.25 - 2.16 (m, 2H), 2.06 - 2.01 (m, 2H), 1.97 - 1.76 (m, 5H), 1.68 - 1.53 (m, 3H), 1.44 (d, J = 6.4 Hz, 3H), 1.02 - 0.98 (m, 5H), 0.95 (s, 3H), 0.89 - 0.86 (m, 3H), 0.57 (s, 3H) ppm.

[0300] Example 40 (2R)-2-[[1-[(2R)-2-chloro-2-fluoro-acetyl]azetidin-3-yl]oxymethyl]-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butanamide TIFF2025519199000100.tif56170

[0301] In the same manner as the preparation of Example 13, (7S,13S)-7-amino-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate H) was used instead of (7S,13S)-7-amino-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate D) to prepare the title compound. Example 40 (26.2 mg) was obtained as a yellow solid. MS calculated value 1010.5 (MH + ), measured value 1010.4 (MH + ). 11H NMR (400 MHz, methanol-d4) δ = 8.66 (t, J = 7.8 Hz, 1H), 8.50 (d, J = 2.4 Hz, 1H), 7.72 (br s, 1H), 7.63 (t, J = 2.9 Hz, 1H), 7.34 (dd, J = 2.9, 12.6 Hz, 1H), 6.69 - 6.44 (m, 1H), 5.83 (br t, J = 7.5 Hz, 1H), 5.01 - 4.92 (m, 1H), 4.63 - 3.86 (m, 11H), 3.84 - 3.65 (m, 3H), 3.64 - 3.53 (m, 3H), 3.45 (br d, J = 15.2 Hz, 3H), 3.36 (br d, J = 3.4 Hz, 3H), 3.31 - 3.22 (m, 3H), 3.10 - 2.94 (m, 4H), 2.81 (br t, J = 12.4 Hz, 1H), 2.65 (br t, J = 13.4 Hz, 1H), 2.52 - 2.37 (m, 1H), 2.19 (br d, J = 12.2 Hz, 1H), 1.96 (br d, J = 12.8 Hz, 1H), 1.90 - 1.71 (m, 2H), 1.70 - 1.54 (m, 1H), 1.45 (d, J = 6.2 Hz, 3H), 1.17 - 0.77 (m, 12H), 0.54 (br d, J = 9.3 Hz, 3H) ppm.

[0302] Example 41 (2S)-2-[[1-[(2R)-2-chloro-2-fluoro-acetyl]azetidin-3-yl]oxymethyl]-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaene-7-yl]-3-methyl-butanamide TIFF2025519199000101.tif56170

[0303] The title compound was prepared in the same manner as in the preparation of Example 13, using tert-butyl 3-[(2S)-2-[[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-3-methyl-butoxy]azetidine-1-carboxylate, Compound 40B) in place of tert-butyl 3-[(2R)-2-[[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 -octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-3-methyl-butoxy]azetidine-1-carboxylate (Compound 13I). Example 41 (32.9 mg) was obtained as a yellow solid. MS calculated value 1010.5 (MH + ), measured value 1010.4 (MH + ). 11H NMR (400 MHz, methanol-d4) δ = 8.68 (d, J = 7.4 Hz, 1H), 8.51 (d, J = 2.8 Hz, 1H), 7.80 (d, J = 2.8 Hz, 1H), 7.65 (d, J = 2.4 Hz, 1H), 7.35 (d, J = 12.6 Hz, 1H), 6.75 - 6.53 (m, 1H), 5.86 (br d, J = 7.1 Hz, 1H), 5.03 - 4.92 (m, 1H), 4.54 - 4.01 (m, 11H), 4.01 - 3.83 (m, 2H), 3.81 - 3.66 (m, 3H), 3.66 - 3.50 (m, 4H), 3.50 - 3.38 (m, 3H), 3.36 (s, 3H), 3.02 (br s, 1H), 2.99 (s, 3H), 2.86 - 2.74 (m, 1H), 2.74 - 2.62 (m, 1H), 2.48 - 2.34 (m, 1H), 2.17 (br d, J = 12.1 Hz, 1H), 2.00 - 1.85 (m, 2H), 1.83 - 1.70 (m, 1H), 1.68 - 1.55 (m, 1H), 1.45 (d, J = 6.3 Hz, 3H), 1.09 - 0.85 (m, 12H), 0.57 (s, 3H) ppm.

[0304] Compound 40B was prepared in the same manner as Compound 13J, (7S,13S)-7-amino-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate H) with (7S,13S)-7-amino-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26Prepared by using instead of octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate D).

[0305] Example 42 (2S)-2-[9-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,9-diazaspiro[5.5]undecan-2-yl]-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butanamide TIFF2025519199000102.tif64170

[0306] In the same manner as the preparation of Example 6, (7S,13S)-7-amino-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate J) was used in (7S,13S)-7-amino-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5.1 9,13 .0 22,26 By using instead of octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate D), the title compound was prepared. Example 42 (7.8 mg) was obtained as a yellow solid. MS calculated value 1213.5 (MH + ), measured value 1213.4 (MH + ). 1 H NMR (400 MHz, methanol-d4) δ = 8.70 (d, J = 7.6 Hz, 1H), 8.42 (d, J = 2.8 Hz, 1H), 7.74 - 7.67 (m, 1H), 7.52 - 7.41 (m, 2H), 7.13 - 6.87 (m, 1H), 5.75 - 5.65 (m, 1H), 5.20 - 5.11 (m, 1H), 4.81 - 4.78 (m, 1H), 4.48 - 4.34 (m, 1H), 4.25 - 4.05 (m, 3H), 3.98 - 3.65 (m, 3H), 3.52 - 3.33 (m, 11H), 3.30 - 3.09 (m, 6H), 2.91 - 2.78 (m, 5H), 2.68 - 2.57 (m, 1H), 2.32 - 2.06 (m, 4H), 2.00 - 1.77 (m, 6H), 1.70 - 1.57 (m, 3H), 1.44 (d, J = 6.0 Hz, 3H), 1.03 - 0.92 (m, 6H), 0.90 - 0.84 (m, 3H), 0.47 (s, 3H) ppm.

[0307] Example 43 and Example 45 (2S)-2-[(5R)-7-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-N-[(7S,13S)-24-fluoro-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butanamide (Example 43) TIFF2025519199000103.tif67170 (Example 43)

[0308] (2S)-2-[(5S)-7-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butanamide (Example 45) TIFF2025519199000104.tif66170 (Example 45)

[0309] Example 43 was prepared in the same manner as Example 4, (7S,13S)-7-amino-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-8,14-dione (Intermediate J) was reacted with (7S,13S)-7-amino-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .022,26 Prepared by using in place of octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate D). Example 43 (43.9 mg) was obtained as a yellow solid. MS calculated value 1185.4 (MH + ), measured value 1185.5 (MH + ). 1 H NMR (400 MHz, methanol-d4) δ 8.82 - 8.71 (m, 1H), 8.44 (br s, 1H), 7.84 - 7.66 (m, 1H), 7.56 - 7.45 (m, 2H), 6.96 - 6.71 (m, 1H), 5.77 - 5.65 (m, 1H), 5.26 - 5.16 (m, 1H), 4.49 - 4.33 (m, 2H), 4.31 - 4.19 (m, 2H), 4.07 - 3.69 (m, 5H), 3.66 - 3.55 (m, 2H), 3.54 - 3.34 (m, 10H), 3.25 - 3.12 (m, 3H), 2.96 - 2.78 (m, 5H), 2.72 - 2.57 (m, 1H), 2.40 - 2.17 (m, 3H), 2.16 - 1.92 (m, 4H), 1.91 - 1.76 (m, 1H), 1.75 - 1.57 (m, 1H), 1.53 - 1.41 (m, 3H), 1.38 - 1.14 (m, 1H), 1.06 - 0.97 (m, 6H), 0.94 - 0.86 (m, 3H), 0.59 - 0.42 (m, 3H) ppm.

[0310] Example 45 was prepared in the same manner as in the preparation of Example 4 from (2S)-2-[(5R)-7-tert-butoxycarbonyl-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-3-methyl-butanoic acid (Compound 4f1) and (7S,13S)-7-amino-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26Octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate J) was used in place of octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate D) to prepare (2S)-2-[(5S)-7-tert-butoxycarbonyl-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-3-methyl-butanoic acid (Compound 4f2) and (7S,13S)-7-amino-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 Octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate D) was prepared by using it instead. Example 45 (24.2 mg) was obtained as a white solid. MS calculated value 1185.4 (MH + ), measured value 1185.5 (MH + ). 1 HNMR (400 MHz, methanol-d4) δ = 8.70 (d, J = 7.6 Hz, 1H), 8.42 (d, J = 2.8 Hz, 1H), 7.71 (t, J = 2.4 Hz, 1H), 7.57 (s, 1H), 7.48 (d, J = 12.8 Hz, 1H), 6.84 (dd, J = 10.8 Hz, 48.8 Hz, 1H), 5.72 (s, 1H), 5.24 - 5.21 (m, 2H), 4.48 - 4.18 (m, 3H), 3.82 - 3.68 (m, 4H), 3.68 - 3.55 (m, 2H), 3.55 - 3.44 (m, 3H), 3.42 (d, J = 3.6 Hz, 4H), 3.37 (s, 3H), 3.30 - 3.08 (m, 5H), 2.89 (t, J = 4.8 Hz, 4H), 2.86 - 2.77 (m, 1H), 2.64 (d, J = 14.4 Hz, 1H), 2.32 - 2.15 (m, 3H), 2.14 - 2.01 (m, 3H), 1.98 - 1.90 (m, 1H), 1.88 - 1.74 (m, 1H), 1.69 - 1.57 (m, 1H), 1.45 (d, J = 6.4 Hz, 3H), 1.01 (d, J = 6.4 Hz, 3H), 0.99 (s, 3H), 0.90 (d, J = 6.4 Hz, 3H), 0.49 (s, 3H) ppm.

[0311] Example 44 1-[(2R)-2-chloro-2-fluoro-acetyl]-4-fluoro-N-[(1S)-1-[[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide TIFF2025519199000105.tif62170

[0312] In the same manner as in the preparation of Example 1, 1-tert-butoxycarbonyl-4-fluoro-piperidine-4-carboxylic acid and (7S,13S)-7-amino-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate J) were used with (S)-1-Boc-pyrrolidine-3-carboxylic acid (Compound 1D) and (7S,13S)-7-amino-25-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5.1 9,13 .0 22,26 By using instead of octacosa-1(25),2,5(28),19,22(26),23-hexaen-8,14-dione (Intermediate E), the title compound was prepared. Example 44 (18.4 mg) was obtained as an off-white solid. MS calculated value 1205.4 (MH + ), measured value 1205.6 (MH + ), 1 H NMR (400 MHz, methanol-d4) δ = 8.69 (d, J = 7.2 Hz, 1H), 8.42 (d, J = 2.8 Hz, 1H), 7.69 (s, 1H), 7.58 - 7.51 (m, 1H), 7.48 (d, J = 12.4 Hz, 1H), 7.11 - 6.97 (m, 1H), 5.74 - 5.68 (m, 1H), 5.24 - 5.10 (m, 2H), 4.75 (d, J = 11.2 Hz, 1H), 4.46 - 4.34 (m, 2H), 4.27 - 4.16 (m, 2H), 4.00 - 3.88 (m, 1H), 3.81 - 3.69 (m, 2H), 3.57 - 3.49 (m, 1H), 3.47 - 3.38 (m, 5H), 3.37 (s, 3H), 3.22 - 3.17 (m, 4H), 3.16 - 3.12 (m, 2H), 3.10 - 3.01 (m, 1H), 2.88 (t, J = 4.4 Hz, 5H), 2.84 - 2.77 (m, 1H), 2.68 - 2.59 (m, 1H), 2.35 - 2.15 (m, 6H), 1.99 - 1.93 (m, 1H).1.88 - 1.77 (m, 1H), 1.69 - 1.59 (m, 1H), 1.45 (d, J = 6.0 Hz, 3H), 1.00 - 0.95 (m, 6H), 0.89 (d, J = 6.4 Hz, 3H), 0.48 (d, J = 5.6 Hz, 3H).

[0313] Example 46 (2S)-2-[2-[(2R)-2-chloro-2-fluoro-acetyl]-5-oxo-2,6-diazaspiro[3.4]octan-6-yl]-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butanamide TIFF2025519199000106.tif66170

[0314] The title compound was prepared in the same manner as in Example 6 from (2S)-2-(2-tert-butoxycarbonyl-5-oxo-2,6-diazaspiro[3.4]octan-6-yl)-3-methyl-butyric acid (Compound 25H) and (7S,13S)-7-amino-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26Octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate J) was used in place of octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate D) to prepare (2S)-2-(9-tert-butoxycarbonyl-1-oxo-2,9-diazaspiro[5.5]undecan-2-yl)-3-methyl-butanoic acid (Compound 6J) and (7S,13S)-7-amino-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 Octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate D) to give Example 46 (17.0 mg) as an off-white solid. MS calculated 1171.4 (MH + ), found 1171.5 (MH + ). 11H NMR (400 MHz, methanol-d4) δ = 8.72 (d, J = 7.6 Hz, 1H), 8.42 (d, J = 2.4 Hz, 1H), 7.74 (d, J = 2.4 Hz, 1H), 7.70 (d, J = 2.0 Hz, 1H), 7.50 (d, J = 12.4 Hz, 1H), 6.69 (dd, J = 1.6 Hz, 48.8 Hz, 1H), 5.74 - 5.69 (m, 1H), 4.44 - 4.21 (m, 5H), 3.84 - 3.67 (m, 2H), 3.59 - 3.52 (m, 1H), 3.46 (s, 6H), 3.40 (d, J = 1.2 Hz, 3H), 3.24 - 3.14 (m, 3H), 3.14 - 3.08 (m, 1H), 2.90 (t, J = 5.2 Hz, 4H), 2.85 - 2.77 (m, 1H), 2.71 - 2.61 (m, 1H), 2.44 - 2.36 (m, 2H), 2.27 - 2.14 (m, 2H), 2.01 - 1.90 (m, 1H), 1.90 - 1.71 (m, 1H), 1.70 - 1.55 (m, 1H), 1.47 (d, J = 6.4 Hz, 3H), 1.25 (s, 2H), 1.20 (s, 3H), 1.02 - 0.96 (m, 6H), 0.88 (dd, J = 3.2 Hz, 6.4 Hz, 3H), 0.51 (s, 3H) ppm.

[0315] Example 47 (2S)-2-[8-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,8-diazaspiro[4.5]decane-2-yl]-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butanamide TIFF2025519199000107.tif61170

[0316] The title compound was prepared in the same manner as in the preparation of Example 6, using (2S)-2-(8-tert-butoxycarbonyl-1-oxo-2,8-diazaspiro[4.5]decane-2-yl)-3-methyl-butanoic acid (Compound 15F) and (7S,13S)-7-amino-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate J) in place of (2S)-2-(9-tert-butoxycarbonyl-1-oxo-2,9-diazaspiro[5.5]undecane-2-yl)-3-methyl-butanoic acid (Compound 6J) and (7S,13S)-7-amino-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate D). Example 47 (21.1 mg) was obtained as a white solid. MS calculated value 1199.5 (MH + ), measured value 1199.4 (MH + ), 11H NMR (400 MHz, methanol-d4) δ = 8.86 - 8.79 (m, 1H), 8.69 (d, J = 7.2 Hz, 1H), 8.44 - 8.40 (m, 1H), 7.69 (s, 1H), 7.51 - 7.43 (m, 2H), 7.12 - 6.90 (m, 1H), 5.69 (s, 1H), 5.22 - 5.11 (m, 1H), 4.44 - 4.37 (m, 1H), 4.34 - 4.19 (m, 4H), 3.99 - 3.87 (m, 1H), 3.81 - 3.68 (m, 2H), 3.62 - 3.58 (m, 1H), 3.49 - 3.42 (m, 2H), 3.41 - 3.37 (m, 4H), 3.35 (s, 3H), 3.28 - 3.23 (m, 1H), 3.20 - 3.09 (m, 4H), 2.90 - 2.86 (m, 4H), 2.84 - 2.78 (m, 1H), 2.62 (d, J = 14.4 Hz, 1H), 2.26 - 2.19 (m, 2H), 2.10 - 2.02 (m, 2H), 2.00 - 1.90 (m, 2H), 1.87 - 1.76 (m, 2H), 1.70 - 1.53 (m, 3H), 1.44 (d, J = 6.0 Hz, 3H), 1.18 (t, J = 7.2 Hz, 1H), 1.03 - 0.96 (m, 6H), 0.88 (d, J = 5.6 Hz, 3H), 0.47 (s, 3H) ppm.

[0317] Example 48 (2S)-2-[9-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,9-diazaspiro[5.5]undecan-2-yl]-N-[(7S,13S)-21-ethyl-24-fluoro-(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-9,21,27,28-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaene-7-yl]-3-methyl-butanamide TIFF2025519199000108.tif64170

[0318] In the same manner as the preparation of Example 6, (7S,13S)-7-amino-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-8,14-dione (Intermediate L) was used instead of (7S,13S)-7-amino-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-8,14-dione (Intermediate E) to prepare the title compound. Example 48 (10 mg) was obtained as a yellow solid. MS calculated value 1159.5 (MH + ), measured value 1159.5 (MH + ). 11H NMR (400 MHz, methanol-d4) δ = 8.69 (d, J = 7.6 Hz, 1H), 8.40 (d, J = 2.8 Hz, 1H), 7.68 - 7.64 (m, 1H), 7.63 - 7.57 (m, 1H), 7.35 (d, J = 12.8 Hz, 1H), 7.11 - 6.87 (m, 1H), 5.82 - 5.71 (m, 1H), 4.82 - 4.75 (m, 2H), 4.45 - 4.38 (m, 1H), 4.36 - 4.29 (m, 1H), 4.27 - 4.03 (m, 4H), 3.97 - 3.81 (m, 1H), 3.79 - 3.70 (m, 2H), 3.47 - 3.42 (m, 6H), 3.36 (s, 3H), 3.30 - 3.12 (m, 5H), 3.08 - 2.96 (m, 1H), 2.92 - 2.79 (m, 5H), 2.73 - 2.64 (m, 1H), 2.32 - 2.06 (m, 4H), 2.00 - 1.90 (m, 1H), 1.90 - 1.72 (m, 5H), 1.68 - 1.55 (m, 3H), 1.44 (d, J = 6.4 Hz, 3H), 1.05 - 0.94 (m, 9H), 0.89 - 0.82 (m, 3H), 0.55 (s, 3H) ppm.

[0319] Example 49 1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(7S,13S)-21-ethyl-24-fluoro-(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-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-4-fluoro-N-methyl-piperidine-4-carboxamide TIFF2025519199000109.tif57170

[0320] In the same manner as the preparation of Example 1, 1-tert-butoxycarbonyl-4-fluoro-piperidine-4-carboxylic acid and (7S,13S)-7-amino-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate L) was used in place of (S)-1-Boc-pyrrolidine-3-carboxylic acid (Compound 1D) and (7S,13S)-7-amino-25-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate E) to prepare the title compound. Example 49 (25.1 mg) was obtained as a yellow solid. MS calculated value 1151.5 (MH + ), measured value 1151.5 (MH + ), 11H NMR (400 MHz, methanol-d4) δ = 8.70 (d, J = 7.6 Hz, 1H), 8.39 (d, J = 2.8 Hz, 1H), 7.85 - 7.78 (m, 1H), 7.67 - 7.60 (m, 1H), 7.36 (d, J = 12.4 Hz, 1H), 7.11 - 6.94 (d, J = 49.2 Hz, 1H), 5.89 - 5.69 (m, 1H), 4.77 - 4.67 (m, 1H), 4.46 - 4.32 (m, 3H), 4.30 - 4.21 (m, 1H), 4.18 - 4.12 (m, 1H), 4.10 - 4.00 (m, 1H), 3.96 - 3.86 (m, 1H), 3.81 - 3.71 (m, 2H), 3.51 - 3.43 (m, 5H), 3.43 - 3.34 (m, 4H), 3.28 - 3.13 (m, 7H), 3.03 - 2.98 (m, 1H), 2.92 - 2.87 (m, 4H), 2.86 - 2.78 (m, 1H), 2.76 - 2.66 (m, 1H), 2.36 - 2.08 (m, 6H), 1.99 - 1.90 (m, 1H), 1.85 - 1.71 (m, 1H), 1.70 - 1.58 (m, 1H), 1.45 (d, J = 6.4 Hz, 3H), 1.04 - 0.93 (m, 9H), 0.91 - 0.80 (m, 3H), 0.65 - 1.53 m, 3H) ppm.

[0321] Example 50 (2S)-2-[8-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,8-diazaspiro[4.5]decane-2-yl]-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaene-7-yl]-3-methyl-butanamide TIFF2025519199000110.tif53170

[0322] The title compound was prepared in the same manner as in the preparation of Example 6, (2S)-2-(8-tert-butoxycarbonyl-1-oxo-2,8-diazaspiro[4.5]decane-2-yl)-3-methyl-butanoic acid (Compound 15F) and (7S,13S)-7-amino-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo-[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate M) was used instead of (2S)-2-(9-tert-butoxycarbonyl-1-oxo-2,9-diazaspiro[5.5]undecane-2-yl)-3-methyl-butanoic acid (Compound 6J) and (7S,13S)-7-amino-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate D). Example 50 (51.8 mg) was obtained as a yellow solid. MS calculated value 1064.5 (MH + ), measured value 1064.3 (MH + ), 11H NMR (400 MHz, chloroform-d) δ = 8.99 (br s, 1H), 8.66 - 8.64 (d, J = 7.5 Hz, 1H), 7.60 - 7.58 (dd, J = 1.8, 8.4 Hz, 1H), 7.45 - 7.41 (dd, J = 2.3, 16.1 Hz, 1H), 7.32 - 7.30 (br d, J = 8.9 Hz, 0.5H), 7.19 - 7.18 (br d, J = 8.8 Hz, 0.5H), 7.14 - 7.11 (d, J = 12.3 Hz, 1H), 6.57 - 6.54 (m, 0.5H), 6.40 - 6.28 (m, 0.5H), 5.81 (td, J = 9.2, 13.9 Hz, 1H), 4.66 - 4.52 (m, 1H), 4.40 (q, J = 6.4 Hz, 1H), 4.31 - 4.22 (m, 1H), 4.19 - 4.03 (m, 5H), 3.92 (br t, J = 4.5 Hz, 4H), 3.83 (br d, J = 11.2 Hz, 1H), 3.69 (br d, J = 11.1 Hz, 1H), 3.62 - 3.54 (m, 8H), 3.45 - 3.36 (m, 9H), 3.21 - 3.07 (m, 2H), 2.78 - 2.65 (m, 1H), 2.50 - 2.30 (m, 2H), 2.22 (br d, J = 12.0 Hz, 1H), 2.00 - 1.96 (m, 2H), 1.92 - 1.76 (m, 1H), 1.61 (br d, J = 10.1 Hz, 2H), 1.55 - 1.54 (d, J = 6.4 Hz, 3H), 1.06 - 0.93 (m, 9H), 0.89 - 0.87 (dd, J = 2.4, 6.4 Hz, 3H), 0.49 (s, 3H) ppm.

[0323] Examples 51 and 53 (2S)-2-[(5S)-7-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butanamide (Example 51) TIFF2025519199000111.tif63170 (Example 51)

[0324] (2S)-2-[(5R)-7-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butanamide (Example 53) TIFF2025519199000112.tif62170 (Example 53)

[0325] Example 51 was prepared in the same manner as in Example 4, (2S)-2-[(5R)-7-tert-butoxycarbonyl-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-3-methyl-butyric acid (Compound 4f1) and (7S,13S)-7-amino-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo-[17.5.2.1 2,5 .1 9,13 .0 22,26Octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate M) was used in place of (2S)-2-[(5S)-7-tert-butoxycarbonyl-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-3-methyl-butanoic acid (Compound 4f2) and (7S,13S)-7-amino-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 Octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate D) was prepared by using in its place. Example 51 (21.4 mg) was obtained as a yellow solid. MS calculated value 1050.4 (MH + ), measured value 1050.4 (MH + ). 11H NMR (400 MHz, methanol-d4) δ = 8.70 (d, J = 7.6 Hz, 1H), 8.39 (d, J = 2.8 Hz, 1H), 7.89 (dd, J = 2.8, 9.6 Hz, 1H), 7.65 (s, 1H), 7.38 (d, J = 12.8 Hz, 1H), 8.90 - 6.74 (m, 1H), 5.79 (d, J = 9.2 Hz, 1H), 4.44 - 4.37 (m, 2H), 4.33 - 4.24 (m, 2H), 4.18 - 4.12 (m, 1H), 4.08 - 4.00 (m, 1H), 3.87 (t, J = 4.4 Hz, 4H), 3.81 - 3.70 (m, 4H), 3.68 - 3.63 (m, 1H), 3.58 - 3.54 (m, 1H), 3.51 - 3.47 (m, 1H), 3.45 - 3.41 (m, 5H), 3.40 (s, 3H), 3.29 - 3.23 (m, 1H), 3.02 (d, J = 14.4 Hz, 1H), 2.86 - 2.71 (m, 2H), 2.28 - 2.15 (m, 3H), 2.09 - 2.00 (m, 3H), 1.98 - 1.93 (m, 1H), 1.84 - 1.75 (m, 1H), 1.68 - 1.60 (m, 1H), 1.46 (d, J = 6.4 Hz, 3H), 1.34 - 1.28 (m, 1H), 1.04 - 0.99 (m, 6H), 0.97 (s, 3H), 0.88 (d, J = 6.4 Hz, 3H), 0.60 (s, 3H).

[0326] Example 53 was prepared in the same manner as in Example 4, (7S,13S)-7-amino-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo-[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate M) was used to react with (7S,13S)-7-amino-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5.1 9,13 .0 22,26 It was prepared by using instead of octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate D). Example 53 (28.8 mg) was obtained as a yellow solid. MS calculated value 1050.4 (MH + ), measured value 1050.5 (MH + ). 1 H NMR (400 MHz, methanol-d4) δ = 8.88 - 8.87 (m, 1H), 8.72 - 8.68 (m, 1H), 8.38 (t, J = 2.4 Hz, 1H), 7.80 (t, J = 2.8 Hz, 1H), 7.74 - 7.64 (m, 1H), 7.39 - 7.34 (m, 1H), 6.91 - 6.69 (m, 1H), 5.81 - 5.73 (m, 1H), 4.45 - 4.36 (m, 2H), 4.34 - 4.30 (m, 1H), 4.29 - 4.23 (m, 1H), 4.21 - 4.13 (m, 1H), 4.11 - 4.02 (m, 1H), 3.93 - 3.85 (m, 5H), 3.81 - 3.72 (m, 4H), 3.63 - 3.51 (m, 3H), 3.49 - 3.43 (m, 2H), 3.42 - 3.38 (m, 7H), 3.09 - 2.99 (m 1H), 2.87 - 2.78 (m, 1H), 2.70 (t, J = 14.0 Hz, 1H), 2.33 - 2.25 (m, 1H), 2.24 - 2.16 (m, 2H), 2.12 - 2.06 (m, 2H), 2.02 - 1.91 (m, 2H), 1.85 - 1.76 (m, 1H), 1.70 - 1.61 (m, 1H), 1.46 (d, J = 6.4 Hz, 3H), 1.04 - 0.98 (m, 6H), 0.97 - 0.96 (m, 2H), 0.89 (d, J = 6.8 Hz, 3H), 0.61 - 0.55 (m, 3H).

[0327] Example 52 (2S)-2-[2-[(2R)-2-chloro-2-fluoro-acetyl]-5-oxo-2,6-diazaspiro[3.4]octan-6-yl]-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butanamide TIFF2025519199000113.tif54170

[0328] The title compound was prepared in the same manner as in Example 6 from (2S)-2-(2-tert-butoxycarbonyl-5-oxo-2,6-diazaspiro[3.4]octan-6-yl)-3-methyl-butyric acid (Compound 25H) and (7S,13S)-7-amino-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 octacosa-1(25),2,5(28),19,22(26),23-hexaen-8,14-dione (Intermediate M), (2S)-2-(9-tert-butoxycarbonyl-1-oxo-2,9-diazaspiro[5.5]undecane-2-y...

Claims

1. A compound of formula (I), During the ceremony, R １ teeth, (Jiharo C １－６ 1-oxo-2,7-diazaspiro[4.4]nonanyl substituted with alkyl)carbonyl, (Jiharo C １－６ 1-oxo-2,8-diazaspiro[4.5]decanyl substituted with alkyl)carbonyl, (Jiharo C １－６ 1-oxo-2,9-diazaspiro[5.5]undecanyl substituted with alkyl)carbonyl, (Jiharo C １－６ 5-oxo-2,6-diazaspiro[3.4]octanyl substituted with alkyl)carbonyl, (Jiharo C １－６ 5-oxo-2,6-diazaspiro[3.5]nonanyl substituted with alkyl)carbonyl, (Jiharo C １－６ 6-oxo-2,7-diazaspiro[4.5]decanyl substituted with alkyl)carbonyl, or (dihalo C １－６ alkyl)carbonyl-substituted azetidinyl oxy C １－６ alkyl; R ８ C １－６ It is alkyl; R ９ is halogen and (dihalo C １－６ Piperidinyl double-substituted with alkyl carbonyl, or (dihalo C １－６ It is a pyrrolidinyl substituted with an alkyl carbonyl; R ２ C １－６ It is alkyl; R ３ H, C １－６ It is an alkyl or halogen; R ４ is H or a halogen; R ５ C １－６ Alkyl or Halo C １－６ It is alkyl; R ６ C １－６ Alkoxy C １－６ It is alkyl; R ７ is morpholinyl, (halo C １－６ Alkyl)piperazinyl or C １－６ It is an alkylpiperazinyl; A １ is hydroxylated thiazolyene or phenylene; A ２ C １－６ It is alkylene; However, R ３ and R ４ It is not H at the same time. A compound, or a pharmaceutically acceptable salt thereof.

2. A compound of formula (Ia), During the ceremony, R １ teeth, (Jiharo C １－６ 1-oxo-2,7-diazaspiro[4.4]nonanyl substituted with alkyl)carbonyl, (Jiharo C １－６ 1-oxo-2,8-diazaspiro[4.5]decanyl substituted with alkyl)carbonyl, (Jiharo C １－６ 1-oxo-2,9-diazaspiro[5.5]undecanyl substituted with alkyl)carbonyl, (Jiharo C １－６ 5-oxo-2,6-diazaspiro[3.4]octanyl substituted with alkyl)carbonyl, (Jiharo C １－６ 5-oxo-2,6-diazaspiro[3.5]nonanyl substituted with alkyl)carbonyl, (Jiharo C １－６ 6-oxo-2,7-diazaspiro[4.5]decanyl substituted with alkyl)carbonyl, or (Jiharo C １－６ Azetidinyl oxy C substituted with alkyl carbonyl １－６ It is alkyl; R ８ C １－６ It is alkyl; R ９ is halogen and (dihalo C １－６ Piperidinyl double-substituted with alkyl carbonyl, or (dihalo C １－６ It is a pyrrolidinyl substituted with an alkyl carbonyl; R ２ C １－６ It is alkyl; R ３ H, C １－６ It is an alkyl or halogen; R ４ is H or a halogen; R ５ C １－６ Alkyl or Halo C １－６ It is alkyl; R ６ C １－６ Alkoxy C １－６ It is alkyl; R ７ is morpholinyl, (halo C １－６ Alkyl)piperazinyl or C １－６ It is an alkylpiperazinyl; A １ is hydroxylated thiazolyene or phenylene; A ２ C １－６ It is alkylene; However, R ３ and R ４ It is not H at the same time. A compound, or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1, R １ teeth, (Jiharo C １－６ 1-oxo-2,7-diazaspiro[4.4]nonanyl substituted with alkyl)carbonyl, (Jiharo C １－６ 1-oxo-2,8-diazaspiro[4.5]decanyl substituted with alkyl)carbonyl, (Jiharo C １－６ 1-oxo-2,9-diazaspiro[5.5]undecanyl substituted with alkyl)carbonyl, or (Jiharo C １－６ It is 5-oxo-2,6-diazaspiro[3.4]octanyl substituted with an alkyl)carbonyl; R ８ C １－６ It is alkyl; R ９ is halogen and (dihalo C １－６ Piperidinyl double-substituted with alkyl carbonyl, or (dihalo C １－６ A compound that is a pyrrolidinyl substituted with an alkyl carbonyl group.

4. The compound according to claim 1, R １ teeth, 1-oxo-2,7-diazaspiro[4.4]nonan-2-yl substituted with chloro(fluoro)acetyl, 1-oxo-2,8-diazaspiro[4.5]decane-2-yl substituted with chloro(fluoro)acetyl, 1-oxo-2,9-diazaspiro[5.5]undecane-2-yl substituted with chloro(fluoro)acetyl, or It is 5-oxo-2,6-diazaspiro[3.4]octan-6-yl substituted with chloro(fluoro)acetyl; R ８ It is methyl; R ９ This compound is a piperidinyl compound that is double-substituted with fluoro and chloro(fluoro)acetyl, or a pyrrolidinyl compound that is substituted with chloro(fluoro)acetyl.

5. R １ However, (5R)-7-[(2R)-2-chloro-2-fluoroacetyl]-1-oxo-2,7-diazaspiro[4.4]nonane-2-yl, (5S)-7-[(2R)-2-chloro-2-fluoroacetyl]-1-oxo-2,7-diazaspiro[4.4]nonane-2-yl, 8-[(2R)-2-chloro-2-fluoroacetyl]-1-oxo-2,8-diazaspiro[4.5]decane-2-yl, 9-[(2R)-2-chloro-2 The compound according to claim 1, wherein the compound is -fluoroacetyl]-1-oxo-2,9-diazaspiro[5.5]undecane-2-yl, 2-[(2R)-2-chloro-2-fluoroacetyl]-5-oxo-2,6-diazaspiro[3.4]octan-6-yl, 1-[(2R)-2-chloro-2-fluoroacetyl]-4-fluoro-4-piperidinyl, or 1-[(2R)-2-chloro-2-fluoroacetyl]pyrrolidine-3-yl.

6. R ２ The compound according to claim 1, wherein isopropyl.

7. R ３ The compound according to claim 1, wherein the compound is H, methyl, or fluoro.

8. R ３ The compound according to claim 1, wherein is fluoro.

9. R ４ The compound according to claim 1, wherein the compound is H or fluoro.

10. R ４ The compound according to claim 1, wherein is H.

11. R ５ The compound according to claim 1, wherein the compound is ethyl or 2,2,2-trifluoroethyl.

12. R ６ The compound according to claim 1, wherein is 1-methoxyethyl.

13. R ７ The compound according to claim 1, wherein the compound is morpholinyl, 4-(2,2,2-trifluoroethyl)piperazine-1-yl, or 4-methylpiperazine-1-yl.

14. A １ but The compound according to claim 1, wherein bond "a" is bonded to the indole ring.

15. A ２ The compound according to claim 1, wherein A is dimethylmethylene.

16. The compound according to claim 1, R １ teeth, (Jiharo C １－６ 1-oxo-2,7-diazaspiro[4.4]nonanyl substituted with alkyl)carbonyl, (Jiharo C １－６ 1-oxo-2,8-diazaspiro[4.5]decanyl substituted with alkyl)carbonyl, (Jiharo C １－６ 1-oxo-2,9-diazaspiro[5.5]undecanyl substituted with alkyl)carbonyl, or (Jiharo C １－６ It is 5-oxo-2,6-diazaspiro[3.4]octanyl substituted with an alkyl)carbonyl; R ８ is C １－６ alkyl; R ９ is halogen and (dihalo C １－６ Piperidinyl double-substituted with alkyl carbonyl, or (dihalo C １－６ It is a pyrrolidinyl substituted with an alkyl carbonyl; R ２ C １－６ It is alkyl; R ３ It is a halogen; R ４ H is; R ５ C １－６ Alkyl or Halo C １－６ It is alkyl; R ６ C １－６ Alkoxy C １－６ It is alkyl; R ７ is morpholinyl, (halo C １－６ Alkyl)piperazinyl or C １－６ It is an alkylpiperazinyl; A １ teeth The bond "a" is attached to the indole ring; A ２ C １－６ It is alkylene. A compound, or a pharmaceutically acceptable salt thereof.

17. The compound according to claim 16, R １ However, (5R)-7-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,7-diazaspiro[4.4]nonane-2-yl, (5S)-7-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,7-diazaspiro[4.4]nonane-2-yl, 8-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,8-diazaspiro[4.5]decane-2-yl, 9-[(2R)-2 [-chloro-2-fluoro-acetyl]-1-oxo-2,9-diazaspiro[5.5]undecane-2-yl, 2-[(2R)-2-chloro-2-fluoro-acetyl]-5-oxo-2,6-diazaspiro[3.4]octan-6-yl, 1-[(2R)-2-chloro-2-fluoro-acetyl]-4-fluoro-4-piperidinyl or 1-[(2R)-2-chloro-2-fluoro-acetyl]pyrrolidine-3-yl; R ２ However, it is isopropyl; R ３ However, it is fluoro; R ４ However, it is H; R ５ However, it is ethyl or 2,2,2-trifluoroethyl; R ６ However, it is (1S)-1-methoxyethyl; R ７ However, these are morpholinyl, 4-(2,2,2-trifluoroethyl)piperazine-1-yl, or 4-methylpiperazine-1-yl; A １ but The bond "a" is attached to the indole ring; A ２ However, it is dimethylmethylene. A compound, or a pharmaceutically acceptable salt thereof.

18. below: (3S)-1-[(2R)-2-chloro-2-fluoroacetyl]-N-[(1S)-1-[[(7S,13S)-25-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazine-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 ２，５ 1. ９，１３ . 0 ２２，２６ Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide; (3S)-1-[(2R)-2-chloro-2-fluoroacetyl]-N-[(1S)-1-[[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazine-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 ２，５ 1. ９，１３ . 0 ２２，２６ Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide; (3S)-1-[(2R)-2-chloro-2-fluoroacetyl]-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazine-1-yl)-3-pyridyl]-17,17,24-trimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 ２，５ 1. ９，１３ . 0 ２２，２６ Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide; (2S)-2-[(5R)-7-[(2R)-2-chloro-2-fluoroacetyl]-1-oxo-2,7-diazaspiro[4.4]nonane-2-yl]-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazine-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 ２，５ 1. ９，１３ . 0 ２２，２６ Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methylbutanamide; (2S)-2-[(5S)-7-[(2R)-2-chloro-2-fluoroacetyl]-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazine-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 ２，５ 1. ９，１３ . 0 ２２，２６ Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methylbutanamide; (2S)-2-[9-[(2R)-2-chloro-2-fluoroacetyl]-1-oxo-2,9-diazaspiro[5.5]undecane-2-yl]-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazine-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 ２，５ 1. ９，１３ . 0 ２２，２６ Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methylbutanamide; (3S)-1-[(2R)-2-chloro-2-fluoroacetyl]-N-[(1S)-1-[[(8S,14S)-25-fluoro-4-hydroxy-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazine-1-yl)-3-pyridyl]-18,18-dimethyl-9,15-dioxo-22-(2,2,2-trifluoroethyl)-16-oxa-10,22,28-triazapentacyclo[18.5.2.1 ２，６ 1. １０，１４ . 0 ２３，２７ ]nonacosa-1(26),2,4,6(29),20,23(27),24-heptaen-8-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide; 1-[(2R)-2-chloro-2-fluoroacetyl]-4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazine-1-yl)-3-pyridyl]-17,17,24-trimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 ２，５ 1. ９，１３ . 0 ２２，２６ Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide; 1-[(2R)-2-chloro-2-fluoroacetyl]-4-fluoro-N-[(1S)-1-[[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazine-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 ２，５ 1. ９，１３ . 0 ２２，２６ Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide; (2S)-2-[2-[(2R)-2-chloro-2-fluoroacetyl]-5-oxo-2,6-diazaspiro[3.5]nonane-6-yl]-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazine-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 ２，５ 1. ９，１３ . 0 ２２，２６ Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methylbutanamide; (2R)-2-[[1-[(2R)-2-chloro-2-fluoro-acetyl]azetidine-3-yl]oxymethyl]-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazine-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 ２，５ 1. ９，１３ . 0 ２２，２６ Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methylbutanamide; (2S)-2-[[1-[(2R)-2-chloro-2-fluoro-acetyl]azetidine-3-yl]oxymethyl]-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazine-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 ２，５ 1. ９，１３ . 0 ２２，２６ Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methylbutanamide; (2S)-2-[8-[(2R)-2-chloro-2-fluoroacetyl]-1-oxo-2,8-diazaspiro[4.5]decane-2-yl]-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazine-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 ２，５ 1. ９，１３ . 0 ２２，２６ Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methylbutanamide; (2S)-2-[(5S)-2-[(2R)-2-chloro-2-fluoroacetyl]-6-oxo-2,7-diazaspiro[4.5]decane-7-yl]-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazine-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 ２，５ 1. ９，１３ . 0 ２２，２６ Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methylbutanamide; (2S)-2-[(5R)-2-[(2R)-2-chloro-2-fluoroacetyl]-6-oxo-2,7-diazaspiro[4.5]decane-7-yl]-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazine-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 ２，５ 1. ９，１３ . 0 ２２，２６ Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methylbutanamide; (2S)-2-[9-[(2R)-2-chloro-2-fluoroacetyl]-1-oxo-2,9-diazaspiro[5.5]undecane-2-yl]-N-[(7S,13S)-25-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazine-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 ２，５ 1. ９，１３ . 0 ２２，２６ Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methylbutanamide; (2S)-2-[(5R)-2-[(2S)-2-chloro-2-fluoroacetyl]-6-oxo-2,7-diazaspiro[4.5]decane-7-yl]-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazine-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 ２，５ 1. ９，１３ . 0 ２２，２６ Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methylbutanamide; (2S)-2-[(5S)-2-[(2S)-2-chloro-2-fluoroacetyl]-6-oxo-2,7-diazaspiro[4.5]decane-7-yl]-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazine-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 ２，５ 1. ９，１３ . 0 ２２，２６ Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methylbutanamide; (3S)-1-[(2R)-2-chloro-2-fluoroacetyl]-N-[(1S)-1-[[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 ２，５ 1. ９，１３ . 0 ２２，２６ Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide; (2S)-2-[2-[(2R)-2-chloro-2-fluoroacetyl]-5-oxo-2,6-diazaspiro[3.4]octan-6-yl]-N-[(7S,13S)-24-fluoro-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazine-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 ２，５ 1. ９，１３ . 0 ２２，２６ Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methylbutanamide; (3S)-1-[(2R)-2-chloro-2-fluoroacetyl]-N-[(1S)-1-[[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazine-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 ２，５ 1. ９，１３ . 0 ２２，２６ Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide; (3S)-1-[(2R)-2-chloro-2-fluoroacetyl]-N-[(1S)-1-[[(8S,14S)-26-fluoro-4-hydroxy-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazine-1-yl)-3-pyridyl]-18,18-dimethyl-9,15-dioxo-22-(2,2,2-trifluoroethyl)-16-oxa-10,22,28-triazapentacyclo[18.5.2.1 ２，６ 1. １０，１４ . 0 ２３，２７ ]nonacosa-1(26),2,4,6(29),20,23(27),24-heptaen-8-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide; (2S)-2-[8-[(2R)-2-chloro-2-fluoroacetyl]-1-oxo-2,8-diazaspiro[4.5]decane-2-yl]-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazine-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 ２，５ 1. ９，１３ . 0 ２２，２６ Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methylbutanamide; (2S)-2-[2-[(2R)-2-chloro-2-fluoroacetyl]-5-oxo-2,6-diazaspiro[3.4]octan-6-yl]-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazine-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 ２，５ 1. ９，１３ . 0 ２２，２６ Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methylbutanamide; (2S)-2-[(5R)-7-[(2R)-2-chloro-2-fluoroacetyl]-1-oxo-2,7-diazaspiro[4.4]nonane-2-yl]-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazine-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 ２，５ 1. ９，１３ . 0 ２２，２６ Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methylbutanamide; (2S)-2-[(5S)-7-[(2R)-2-chloro-2-fluoroacetyl]-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazine-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 ２，５ 1. ９，１３ . 0 ２２，２６ Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methylbutanamide; (3S)-1-[(2R)-2-chloro-2-fluoroacetyl]-N-[(1S)-1-[[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazine-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 ２，５ 1. ９，１３ . 0 ２２，２６ Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide; (3S)-1-[(2R)-2-chloro-2-fluoroacetyl]-N-[(1S)-1-[[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazine-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 ２，５ 1. ９，１３ . 0 ２２，２６ Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide; 1-[(2R)-2-chloro-2-fluoroacetyl]-N-[(1S)-1-[[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazine-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 ２，５ 1. ９，１３ . 0 ２２，２６ Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-4-fluoro-N-methyl-piperidine-4-carboxamide; (2S)-2-[(5R)-7-[(2R)-2-chloro-2-fluoroacetyl]-1-oxo-2,7-diazaspiro[4.4]nonane-2-yl]-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazine-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 ２，５ 1. ９，１３ . 0 ２２，２６ Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methylbutanamide; (2S)-2-[(5S)-7-[(2R)-2-chloro-2-fluoroacetyl]-1-oxo-2,7-diazaspiro[4.4]nonane-2-yl]-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazine-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 ２，５ 1. ９，１３ . 0 ２２，２６ Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methylbutanamide; (2S)-2-[9-[(2R)-2-chloro-2-fluoroacetyl]-1-oxo-2,9-diazaspiro[5.5]undecane-2-yl]-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazine-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 ２，５ 1. ９，１３ . 0 ２２，２６ Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methylbutanamide; (2S)-2-[2-[(2R)-2-chloro-2-fluoroacetyl]-5-oxo-2,6-diazaspiro[3.4]octan-6-yl]-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazine-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 ２，５ 1. ９，１３ . 0 ２２，２６ Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methylbutanamide; (2S)-2-[8-[(2R)-2-chloro-2-fluoroacetyl]-1-oxo-2,8-diazaspiro[4.5]decane-2-yl]-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazine-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 ２，５ 1. ９，１３ . 0 ２２，２６ Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methylbutanamide; (2R)-2-[[1-[(2R)-2-chloro-2-fluoro-acetyl]azetidine-3-yl]oxymethyl]-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazine-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 ２，５ 1. ９，１３ . 0 ２２，２６ Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methylbutanamide; (2S)-2-[[1-[(2R)-2-chloro-2-fluoro-acetyl]azetidine-3-yl]oxymethyl]-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazine-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 ２，５ 1. ９，１３ . 0 ２２，２６ Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methylbutanamide; (2S)-2-[9-[(2R)-2-chloro-2-fluoroacetyl]-1-oxo-2,9-diazaspiro[5.5]undecane-2-yl]-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazine-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 ２，５ 1. ９，１３ . 0 ２２，２６ Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methylbutanamide; (2S)-2-[(5R)-7-[(2R)-2-chloro-2-fluoroacetyl]-1-oxo-2,7-diazaspiro[4.4]nonane-2-yl]-N-[(7S,13S)-24-fluoro-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazine-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 ２，５ 1. ９，１３ . 0 ２２，２６ Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methylbutanamide; (2S)-2-[(5S)-7-[(2R)-2-chloro-2-fluoroacetyl]-1-oxo-2,7-diazaspiro[4.4]nonane-2-yl]-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazine-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 ２，５ 1. ９，１３ . 0 ２２，２６ Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methylbutanamide; 1-[(2R)-2-chloro-2-fluoroacetyl]-4-fluoro-N-[(1S)-1-[[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazine-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 ２，５ 1. ９，１３ . 0 ２２，２６ Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide; (2S)-2-[2-[(2R)-2-chloro-2-fluoroacetyl]-5-oxo-2,6-diazaspiro[3.4]octan-6-yl]-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazine-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 ２，５ 1. ９，１３ . 0 ２２，２６ Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methylbutanamide; (2S)-2-[8-[(2R)-2-chloro-2-fluoroacetyl]-1-oxo-2,8-diazaspiro[4.5]decane-2-yl]-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazine-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 ２，５ 1. ９，１３ . 0 ２２，２６ Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methylbutanamide; (2S)-2-[9-[(2R)-2-chloro-2-fluoroacetyl]-1-oxo-2,9-diazaspiro[5.5]undecane-2-yl]-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazine-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 ２，５ 1. ９，１３ . 0 ２２，２６ Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methylbutanamide; 1-[(2R)-2-chloro-2-fluoroacetyl]-N-[(1S)-1-[[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazine-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 ２，５ 1. ９，１３ . 0 ２２，２６ Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-4-fluoro-N-methyl-piperidine-4-carboxamide; (2S)-2-[8-[(2R)-2-chloro-2-fluoroacetyl]-1-oxo-2,8-diazaspiro[4.5]decane-2-yl]-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 ２，５ 1. ９，１３ . 0 ２２，２６ Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methylbutanamide; (2S)-2-[(5S)-7-[(2R)-2-chloro-2-fluoroacetyl]-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 ２，５ 1. ９，１３ . 0 ２２，２６ Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methylbutanamide; (2S)-2-[(5R)-7-[(2R)-2-chloro-2-fluoroacetyl]-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 ２，５ 1. ９，１３ . 0 ２２，２６ Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methylbutanamide; (2S)-2-[2-[(2R)-2-chloro-2-fluoroacetyl]-5-oxo-2,6-diazaspiro[3.4]octan-6-yl]-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 ２，５ 1. ９，１３ . 0 ２２，２６ Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methylbutanamide; 1-[(2R)-2-chloro-2-fluoroacetyl]-N-[(1S)-1-[[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 ２，５ 1. ９，１３ . 0 ２２，２６ Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-4-fluoro-N-methyl-piperidine-4-carboxamide; (3S)-1-[(2R)-2-chloro-2-fluoroacetyl]-N-[(1S)-1-[[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 ２，５ 1. ９，１３ . 0 ２２，２６ Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide; (2S)-2-[(5S)-7-[(2R)-2-chloro-2-fluoroacetyl]-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 ２，５ 1. ９，１３ . 0 ２２，２６ Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methylbutanamide; and (2S)-2-[2-[(2R)-2-chloro-2-fluoroacetyl]-5-oxo-2,6-diazaspiro[3.4]octan-6-yl]-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 ２，５ 1. ９，１３ . 0 ２２，２６ Octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methylbutanamide A compound selected from, or a pharmaceutically acceptable salt thereof.

19. The following structure: A compound having the following properties.

20. A method for preparing a compound according to any one of claims 1 to 19, comprising the following steps: a) Compound of formula (II), (II) and acids (III), (III) The step of carrying out a coupling reaction in the presence of a coupling reagent and a base to form the compound of formula (I); b) Compound of formula (VI), and acid (VII), The coupling reaction of (VII) in the presence of a coupling reagent and a base is performed to obtain formula (VIII), The process of forming the compound; c) Compound of formula (XI), and acid (XII), The coupling reaction of (XII) in the presence of a coupling reagent and a base is performed to obtain equation (XIII), The process of forming the compound Includes any of the following: In the formula, Q is an unsubstituted or substituted piperidinylene or pyrrolidinylene; T is a dihalo C １－６ It is alkyl; R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ A １ and A ２ is defined as in any one of claims 1 to 17; the coupling reagent in steps a) to c) is T ３ A method wherein the base is P, HATU, PyBOP, or EDCI / HOBt; and the base in steps a) to c) is TEA, DIEPA, or DMAP.

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

22. A pharmaceutical composition comprising a compound according to any one of claims 1 to 19 and a pharmaceutically acceptable additive.

23. Use of a compound according to any one of claims 1 to 19 for the treatment of KRAS G12C protein-related disorders.

24. Use of a compound according to any one of claims 1 to 19 for the treatment of KRAS G12C, G12D, and G12V protein-related disorders.

25. Use of a compound according to any one of claims 1 to 19 for inhibiting RAS interaction with a downstream effector, wherein the downstream effector is RAF and PI3K.

26. Use of a compound according to any one of claims 1 to 19 to inhibit the propagation of cancerous MAPK and PI3K signaling.

27. Use of a compound according to any one of claims 1 to 19 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.

28. Use of a compound according to any one of claims 1 to 19 for the treatment or prevention of KRAS mutation-driven cancer, wherein the cancer is selected from pancreatic adenocarcinoma, colorectal cancer and non-small cell lung cancer.

29. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 19 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. Use of a compound according to any one of claims 1 to 19 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. A method for treating or preventing KRAS mutation-driven cancer, wherein the cancer is selected from pancreatic adenocarcinoma, colorectal cancer, and non-small cell lung cancer, and the method comprises administering a therapeutically effective amount of any one of claims 1 to 19.

32. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 19, as produced according to the method of claim 20.

33. The invention as previously described herein.

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