Sulfonyl vinyl compounds for the treatment of cancer

Abstract

The present invention provides a compound of formula (I), 1 ~R 7 , A 1 and A 2 as described herein), and pharmaceutically acceptable salts thereof, as well as compositions comprising and methods of using said compounds.

Description

[Technical Field]

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

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

[0003] All RAS proteins belong to the small GTPase family, which hydrolyzes GTP to GDP. KRAS is structurally divided into an effector-binding lobe, followed by an allosteric lobe, and a carboxy-terminal region responsible for membrane anchoring. The effector lobe contains the P-loop, switch I, and switch II regions. The switch I / II loop plays an important role in KRAS downstream signaling by mediating protein-protein interactions with effector proteins, including RAF in the mitogen-activated protein kinase (MAPK) pathway or PI3K in the phosphatidylinositol 3-kinase (PI3K) / protein kinase B (AKT) pathway.

[0004] The KRAS protein switches from an inactive to an active form via binding to GTP 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), which are involved in catalyzing the exchange of GDP for GTP, enhancing intrinsic GTPase activity, or accelerating RAS-mediated GTP hydrolysis. Inactive RAS-GDP is released by the RAF RAS-binding domain (RAF) in response to extracellular stimuli. RBD ), which directly binds to RAS-GTP, recruiting the RAF kinase family from the cytoplasm to the membrane, where it dimerizes and becomes active. Activated RAF then performs a series of phosphorylation reactions on its downstream mitogen-activated protein kinase (MEK) and extracellular signal-regulated kinase (ERK), propagating growth signals. Of the RAF family of protein kinases (three known isoforms: ARAF, BRAF, and CRAF / RAF1), BRAF is the most frequently mutated and remains the most potent activator of MEK. Although individual RAS and RAF family members exhibit distinct binding preferences, all RAFs possess a conserved RBD for forward transduction of MAPK signaling, which is frequently used to characterize KRAS inhibition (e.g., the KRAS-BRAF complex described herein). RBD For KRAS, mutations at positions 12, 13, 61, and 146 result in a shift to an active KRAS form by impairing nucleotide hydrolysis or activating nucleotide exchange, resulting in overactivation of the MAPK pathway, leading to tumorigenesis.

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

[0006] The present invention relates to novel compounds of formula (I) [ka] (In the formula, R 1 teeth, [ka] and R 8 is C 1-6 is alkyl, R 9 is ((C 1-6 Alkylsulfonyl)halo C 2-6 alkenyl)azetidinyl, ((C 1-6 Alkylsulfonyl)halo C 2-6 Alkenyl)C 3-7 Cycloalkyl, (C 1-6 Alkyl Sulfonyl C 2-6alkenyl)azetidinyl, (C 1-6 Alkyl Sulfonyl C 2-6 Alkenyl)C 3-7 Cycloalkyl or (C 1-6 Alkyl Sulfonyl C 2-6 alkenyl)piperidinyl, R 2 is C 1~6 is alkyl, R 3 is H or a halogen, R 4 is H, R 5 is C 1-6 Alkyl or haloC 1-6 is alkyl, R 6 is C 1-6 Alkoxy C 1-6 is alkyl, R 7 H, morpholinyl, (haloC 1-6 alkyl)piperazinyl or C 1-6 alkylpiperazinyl, A 1 is thiazolylene, phenylene, or hydroxyphenylene; A 2 is C 1-6 alkylene), 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 their production, and to the use of those compounds of formula (I) or (Ia) as inhibitors of KRAS.

[0008] The compounds of formula (I) or (Ia) show good KRAS inhibition against G12C. In another embodiment, the compounds of the present invention show good cancer cell inhibition and human stem cell stability. Furthermore, the compounds of formula (I) or (Ia) also show good or improved cytotoxicity and solubility profiles. Furthermore, the compounds of the present invention have good pharmacokinetic properties compared to reference compounds. [Brief explanation of the drawings]

[0009] [Figure 1] X-ray crystallography of intermediate A. [Figure 2] X-ray crystallographic analysis of compound Q5. DETAILED DESCRIPTION OF THE INVENTION

[0010] definition "C 1-6 The term "alkyl" refers to saturated straight or branched chain alkyl groups containing 1 to 6, especially 1 to 4, carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, etc. 1-6 "Alkyl" groups are methyl, ethyl, and n-propyl.

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

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

[0013] The terms "halogen" and "halo" are used interchangeably herein and refer to fluoro, chloro, bromo, or iodo.

[0014] "Haro C2-6 The term "alkenyl" refers to 1-6 At least one hydrogen atom of the alkenyl group is replaced by the same or different halogen atom 1-6 This represents an alkenyl group.

[0015] "C 3-7 The term "cycloalkyl" means a monovalent saturated monocyclic or bicyclic hydrocarbon radical of 3 to 7 ring carbon atoms. Bicyclic means consisting of two saturated carbocyclic rings having one or more carbon atoms in common. Examples of monocyclic cycloalkyls are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. Examples of bicyclic cycloalkyls are bicyclo[1.1.0]butyl, bicyclo[2.2.1]heptanyl, bicyclo[1.1.1]pentanyl, or bicyclo[2.2.2]octanyl.

[0016] The term "thiazolylene" means a divalent thiazolyl group.

[0017] The term "dimethylmethylene" [ka] means.

[0018] The term "protecting group" refers to a group that selectively blocks a reactive site in a polyfunctional compound so that a chemical reaction, in the sense commonly associated with synthetic chemistry, can be carried out selectively at an otherwise unprotected reactive site. The protecting group can be removed at an appropriate point. Exemplary protecting groups are amino-, carboxy-, or hydroxy-protecting groups.

[0019] Those skilled in the art will recognize that the following structures of compounds of formula (I) and (I') are equivalent, particularly with respect to the chiral centers. [ka] (I') [ka] (I)

[0020] The term "pharmaceutically acceptable salt" means a salt that is not biologically or otherwise undesirable. Pharmaceutically acceptable salts include both acid and base addition salts.

[0021] The term "pharmaceutically acceptable acid addition salt" refers to a pharmaceutically acceptable salt formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and the like, and organic acids selected from the aliphatic, alicyclic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids, such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid.

[0022] The term "pharmaceutically acceptable base addition salt" refers to a pharmaceutically acceptable salt formed with an organic or inorganic base. Examples of acceptable inorganic bases include sodium salts, potassium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, and aluminum salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines, including natural substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperidine, N-ethylpiperidine, and polyamine resins.

[0023] The term "pharmaceutically active metabolite" refers to a pharmacologically active product produced through metabolism in the body of a particular compound or its salt. After entering the body, most drugs become substrates for chemical reactions that can alter their physical properties and biological effects. These metabolic transformations usually affect the polarity of the compounds of the present invention and change how the drug is distributed in and excreted from the body. However, in some cases, drug metabolism is required for therapeutic effect.

[0024] The term "therapeutically effective amount" refers to an amount of a compound or molecule of the invention that, when administered to a subject, (i) treats or prevents a particular disease, condition, or disorder, (ii) reduces, ameliorate, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. A therapeutically effective amount will vary depending on the compound, the disease state being treated, the severity of the disease being treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending physician or veterinarian, and other factors.

[0025] The term "pharmaceutical composition" refers to a mixture or solution containing a therapeutically effective amount of an active pharmaceutical ingredient together with pharmaceutically acceptable excipients, for administration to a mammal, e.g., a human in need thereof.

[0026] The terms "pharmaceutically acceptable excipient," "pharmaceutically acceptable carrier," and "therapeutically inactive excipient" can be used interchangeably and refer to any pharmaceutically acceptable ingredient in a pharmaceutical composition that has no therapeutic activity and is non-toxic to a subject to which it is administered, such as a disintegrant, binder, filler, solvent, buffer, isotonicity agent, stabilizer, antioxidant, surfactant, carrier, diluent, or lubricant used in formulating a drug product.

[0027] KRAS inhibitors The present invention relates to a compound of formula (I): [ka] (In the formula, R 1 teeth, [ka] and R 8 is C 1-6 is alkyl, R 9 is ((C 1-6 Alkylsulfonyl)halo C 2-6 alkenyl)azetidinyl, ((C 1-6 Alkylsulfonyl)halo C 2-6 Alkenyl)C 3-7 Cycloalkyl, (C 1-6 Alkyl Sulfonyl C 2-6 alkenyl)azetidinyl, (C 1-6 Alkyl Sulfonyl C 2-6 Alkenyl)C 3-7 Cycloalkyl or (C 1-6 Alkyl Sulfonyl C 2-6 alkenyl)piperidinyl, R 2 is C 1~6 is alkyl, R 3 is H or a halogen, R 4 is H, R 5 is C 1-6 Alkyl or haloC 1-6 is alkyl, R 6 is C 1-6 Alkoxy C 1-6 is alkyl, R 7 H, morpholinyl, (haloC 1-6 alkyl)piperazinyl or C 1-6 alkylpiperazinyl, A 1 is thiazolylene, phenylene, or hydroxyphenylene; A 2 is C 1-6 alkylene), or a pharmaceutically acceptable salt thereof.

[0028] Another embodiment of the present invention is a compound of formula (Ia): [ka] (In the formula, R 1 teeth, [ka] and R 8 is C 1-6 is alkyl, R 9 is ((C 1-6 Alkylsulfonyl)halo C 2-6 alkenyl)azetidinyl, ((C 1-6 Alkylsulfonyl)halo C 2-6 Alkenyl)C 3-7 Cycloalkyl, (C 1-6 Alkyl Sulfonyl C 2-6 alkenyl)azetidinyl, (C 1-6 Alkyl Sulfonyl C 2-6 Alkenyl)C 3-7 Cycloalkyl or (C 1-6 Alkyl Sulfonyl C 2-6 alkenyl)piperidinyl, R 2 is C 1~6 is alkyl, R 3 is H or a halogen, R 4 is H, R 5 is C 1-6 Alkyl or haloC 1-6 is alkyl, R 6 is C 1-6 Alkoxy C 1-6 is alkyl, R 7H, morpholinyl, (haloC 1-6 alkyl)piperazinyl or C 1-6 alkylpiperazinyl, A 1 is thiazolylene, phenylene, or hydroxyphenylene; A 2 is C 1-6 alkylene), or a pharmaceutically acceptable salt thereof.

[0029] 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 teeth, [ka] and R 8 is C 1-6 alkyl, and R 9 is (C 1-6 Alkyl Sulfonyl C 2-6 alkenyl)azetidinyl or (C 1-6 Alkyl Sulfonyl C 2-6 Alkenyl)C 3-7 It is cycloalkyl.

[0030] A further embodiment of the present invention is (iv) a compound of formula (I) or (Ia) according to any one of (i) to (iii), or a pharmaceutically acceptable salt thereof, wherein R 1 teeth, [ka] and R 8 is methyl and R 9 is 3-(2-methylsulfonylvinyl)azetidin-1-yl or 3-(2-methylsulfonylvinyl)cyclobutyl.

[0031] A further embodiment of the present invention is a compound of formula (I) or (Ia) according to any one of (v)(i) to (iv), wherein R1 is methyl-[3-[(E)-2-methylsulfonylvinyl]azetidine-1-carbonyl]amino or methyl-[3-[(E)-2-methylsulfonylvinyl]cyclobutanecarbonyl]amino.

[0032] A further embodiment of the present invention is (vi) a compound of formula (I) or (Ia) according to any one of (i) to (v), or a pharmaceutically acceptable salt thereof, wherein R 2 is isopropyl.

[0033] A further embodiment of the present invention is (vii) a compound of formula (I) or (Ia) according to any one of (i) to (vi) or a pharmaceutically acceptable salt thereof, wherein R 3 is H or fluoro.

[0034] A further embodiment of the present invention is (viii) a compound of formula (I) or (Ia) according to any one of (i) to (vii) or a pharmaceutically acceptable salt thereof, wherein R 3 is fluoro.

[0035] A further embodiment of the present invention is a compound of formula (I) or (Ia) according to any one of (ix)(i) to (xviii), or a pharmaceutically acceptable salt thereof, wherein R 4 is H.

[0036] A further embodiment of the present invention is a compound of formula (I) or (Ia) according to any one of (x)(i) to (ix), or a pharmaceutically acceptable salt thereof, wherein R 5 is ethyl or 2,2,2-trifluoroethyl.

[0037] A further embodiment of the present invention is (xi) a compound of formula (I) or (Ia) according to any one of (i) to (x), or a pharmaceutically acceptable salt thereof, wherein R 6 is 1-methoxyethyl.

[0038] A further embodiment of the present invention is (xii) a compound of formula (I) or (Ia) according to any one of (i) to (xi), or a pharmaceutically acceptable salt thereof, wherein R 7 is C 1-6 It is alkylpiperazinyl or morpholinyl.

[0039] A further embodiment of the present invention is (xiii) a compound of formula (I) or (Ia) according to any one of (i) to (xii), or a pharmaceutically acceptable salt thereof, wherein R 7 is 4-methylpiperazin-1-yl or morpholinyl.

[0040] 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 A 1 teeth, [ka] or [ka] and bond "a" is attached to the indole ring.

[0041] A further embodiment of the present invention is a compound of formula (I) or (Ia) according to any one of (i) to (xiv), or a pharmaceutically acceptable salt thereof, wherein A 2 is dimethylmethylene.

[0042] Another embodiment of the present invention is a compound of formula (I) or (Ia) according to (xvi)(i) or (ii), wherein: R 1 teeth, [ka] and R 8 is C 1-6 alkyl, and R 9 is (C1-6 Alkyl Sulfonyl C 2-6 alkenyl)azetidinyl or (C 1-6 Alkyl Sulfonyl C 2-6 Alkenyl)C 3-7 is cycloalkyl, R 2 is C 1-6 is alkyl, R 3 is a halogen, R 4 is H, R 5 is C 1-6 Alkyl or haloC 1-6 is alkyl, R 6 is C 1-6 Alkoxy C 1-6 is alkyl, R 7 is C 1-6 alkylpiperazinyl or morpholinyl, A 1 teeth, [ka] or [ka] and bond "a" is attached to the indole ring, A 2 is C 1-6 alkylene), or a pharmaceutically acceptable salt thereof.

[0043] A further embodiment of the present invention is a compound of formula (I) or (Ia) according to (xvii)(xvi), wherein: R 1 is methyl-[3-[(E)-2-methylsulfonylvinyl]azetidine-1-carbonyl]amino or methyl-[3-[(E)-2-methylsulfonylvinyl]cyclobutanecarbonyl]amino, R 2 is isopropyl, R 3is fluoro, R 4 is H, R 5 is ethyl or 2,2,2-trifluoroethyl, R 6 is (1S)-1-methoxyethyl, R 7 is 4-methylpiperazin-1-yl or morpholinyl, A 1 teeth, [ka] or [ka] and bond "a" is attached to the indole ring, A 2 is dimethylmethylene), or a pharmaceutically acceptable salt thereof.

[0044] Another embodiment of the present invention is a compound represented by the formula (xviii): N-[(1S)-1-[[(8S,14S)-22-ethyl-4-hydroxy-(21M)-21-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-18,18-dimethyl-9,15-dioxo-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-3-[(E)-2-methylsulfonylvinyl]cyclobutanecarboxamide; N-[(1S)-1-[[(8S,14S)-22-ethyl-(21M)-21-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-18,18-dimethyl-9,15-dioxo-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-3-[(E)-2-methylsulfonylvinyl]cyclobutanecarboxamide; trans-N-[(1S)-1-[[(8S,14S)-22-ethyl-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-18,18-dimethyl-9,15-dioxo-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-3-[(E)-2-methylsulfonylvinyl]cyclobutanecarboxamide; trans-N-[(1S)-1-[[(8S,14S)-22-ethyl-4-hydroxy-(21M)-21-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-18,18-dimethyl-9,15-dioxo-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-3-[(E)-2-methylsulfonylvinyl]cyclobutanecarboxamide; trans-N-[(1S)-1-[[(7S,13S)-21-ethyl-(20M)-20-[2-[(1S)-1-methoxyethyl]-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-3-[(E)-2-methylsulfonylvinyl]cyclobutanecarboxamide; N-[(1S)-1-[[(7S,13S)-21-ethyl-(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-3-[(E)-2-methylsulfonylvinyl]cyclobutanecarboxamide; N-[(1S)-1-[[(7S,13S)-(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-3-[(E)-2-methylsulfonylvinyl]cyclobutanecarboxamide; N-[(1S)-1-[[(8S,14S)-22-ethyl-4-hydroxy-(21M)-21-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-18,18-dimethyl-9,15-dioxo-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-3-[(E)-2-methylsulfonylvinyl]azetidine-1-carboxamide; N-[(1S)-1-[[(8S,14S)-22-ethyl-4-hydroxy-(21M)-21-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-18,18-dimethyl-9,15-dioxo-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-4-[(E)-2-methylsulfonylvinyl]piperazine-1-carboxamide; trans-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-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-3-[(E)-2-methylsulfonylvinyl]cyclobutanecarboxamide; trans-N-[(1S)-1-[[(8S,14S)-22-ethyl-4-hydroxy-(21M)-21-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-18,18-dimethyl-9,15-dioxo-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]-3-[(E)-2-fluoro-2-methylsulfonyl-vinyl]-N-methyl-cyclobutanecarboxamide; cis-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-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-3-[(E)-2-methylsulfonylvinyl]cyclobutanecarboxamide; trans-N-[(1S)-1-[[(8S,14S)-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-3-[(E)-2-methylsulfonylvinyl]cyclobutanecarboxamide; 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]-3-[(E)-2-fluoro-2-methylsulfonyl-vinyl]-N-methyl-azetidine-1-carboxamide; 3-[(E)-2-Fluoro-2-methylsulfonyl-vinyl]-N-[(1S)-1-[[(7S,13S)-(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-azetidine-1-carboxamide; 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-3-[(E)-2-methylsulfonylvinyl]azetidine-1-carboxamide; 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-3-[(E)-2-methylsulfonylvinyl]azetidine-1-carboxamide; trans-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-3-[(E)-2-methylsulfonylvinyl]cyclobutanecarboxamide; and 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]-3-[(E)-2-fluoro-2-methylsulfonyl-vinyl]-N-methyl-azetidine-1-carboxamide or a pharmaceutically acceptable salt thereof.

[0045] Another embodiment of the present invention is a process for preparing a compound according to any one of (xix)(i) to (xviii), comprising any of the following steps: a) a compound of formula (II), [ka] and acid (III), [ka] and a coupling reaction in the presence of a coupling reagent and a base to form the compound of formula (I). Including, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , A 1 and A 2 is as defined in any one of (i) to (xvii), the coupling reagent is T3P, HATU, PyBOP or EDCI / HOBt, and the base is TEA, DIEPA or DMAP.

[0046] Another embodiment of the present invention is (xx) a compound or a pharmaceutically acceptable salt according to any one of (i) to (xviii) for use as a therapeutically active substance.

[0047] Another embodiment of the present invention is (xxi) a pharmaceutical composition comprising a compound according to any one of (i) to (xviii) and a pharmaceutically acceptable excipient.

[0048] Another embodiment of the present invention is (xxii) use of a compound according to any one of (i) to (xviii) for treating a KRAS G12C protein-associated disease.

[0049] Another embodiment of the present invention is (xxiii) the use of a compound according to any one of (i) to (xviii) for treating a KRAS G12C, G12D and G12V protein-associated disease.

[0050] Another embodiment of the present invention is (xxiv) the use of a compound according to any one of (i) to (xviii) for inhibiting RAS interaction with downstream effectors, wherein the downstream effectors are RAF and PI3K.

[0051] Another embodiment of the present invention is (xxv) the use of a compound according to any one of (i) to (xviii) for inhibiting proliferating oncogenic MAPK and PI3K signaling.

[0052] Another embodiment of the present invention is (xxvi) the use of a compound according to any one of (i) to (xviii) 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.

[0053] Another embodiment of the present invention is (xxvii) the use of a compound according to any one of (i) to (xv) for the treatment or prevention of a KRAS mutation-driven cancer, wherein the cancer is selected from pancreatic adenocarcinoma, colorectal cancer, and non-small cell lung cancer.

[0054] Another embodiment of the present invention is (xxviii) a compound or a pharmaceutically acceptable salt thereof according to any one of (i) to (xviii) 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.

[0055] Another embodiment of the present invention is (xxix) the use of a compound according to any one of (i) to (xviii) for the preparation of a medicament for the treatment or prevention of a KRAS mutation-driven cancer, wherein the cancer is selected from pancreatic adenocarcinoma, colorectal cancer, and non-small cell lung cancer.

[0056] Another embodiment of the present invention is (xxx) a method for treating or preventing a KRAS mutation-driven cancer, wherein the cancer is selected from pancreatic adenocarcinoma, colorectal cancer, and non-small cell lung cancer, and the method comprises administering a therapeutically effective amount of a compound defined in any one of (i) to (xviii).

[0057] Another embodiment of the present invention is a compound or a pharmaceutically acceptable salt according to any one of (i) to (xviii) when prepared according to the process of (xxxi)(xix).

[0058] Pharmaceutical Compositions and Administration Another embodiment provides pharmaceutical compositions or medicaments containing a compound of the present invention and a therapeutically inert carrier, diluent, or excipient, as well as methods of using the compounds of the present invention to prepare such compositions and medicaments. In one example, a compound of Formula (I) can be formulated into a galenic dosage form by mixing it at ambient temperature, at an appropriate pH, and to the desired degree of purity with a physiologically acceptable carrier, i.e., a carrier that is nontoxic to recipients at the dosage and concentration used. The pH of the formulation will depend primarily on the particular application and the concentration of the compound, but is preferably in the range of about 3 to about 8. In one example, a compound of Formula (I) is formulated in acetate buffer at pH 5. In another embodiment, the compound of Formula (I) is sterile. The compound can be stored, for example, as a solid or amorphous composition, as a lyophilized formulation, or as an aqueous solution.

[0059] The composition is formulated, dosed, and administered in a manner consistent with good medical practice.The factors to be considered in this regard include the specific disorder to be treated, the specific mammal to be treated, the clinical symptoms of individual patients, the cause of the disorder, the delivery site of the drug, the method of administration, the administration schedule, and other factors known to medical professionals.The "effective amount" of the compound to be administered is governed by such considerations, and is the minimum amount required to inhibit the interaction between mutant RAS (for example, KRAS G12C) and RAF, and block oncogenic MAPK signal transduction.For example, this amount may be below the amount that is toxic to normal cells or the whole mammal.

[0060] In one example, a pharmaceutically effective amount of a compound of the invention administered parenterally per dose ranges from about 0.1 to 1000 mg / kg, or about 0.1 to 1000 mg per kg of patient body weight per day, with a typical initial range of compound used being 0.3 to 15 mg / kg / day. In another embodiment, an oral dosage unit, such as a tablet or capsule, preferably contains from about 1 to about 1000 mg of a compound of the invention.

[0061] 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, intrapulmonary, intradermal, intrathecal and epidural, and intranasal, and, if desired for localized treatment, intralesional administration. Parenteral administration includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

[0062] The compounds of the present invention may be administered in any convenient dosage form, such as tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain components conventional in pharmaceutical preparations, such as diluents, carriers, pH adjusters, sweeteners, fillers, and additional active agents.

[0063] Typical preparation is prepared by mixing the compound of the present invention with carrier or excipient.Suitable carrier and excipient are well known to those skilled in the art, and are described in detail in, for example, Ansel, Howard C. et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems.Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al., Remington: The Science and Practice of Pharmacy.Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients.Chicago, Pharmaceutical Press, 2005. The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricating agents, emulsifying agents, suspending agents, preservatives, antioxidants, opacifying agents, glidants, processing aids, colorants, sweeteners, flavors, flavorings, diluents, and other known additives to present the drug (i.e., a compound of the present invention or a pharmaceutical composition thereof) aesthetically or to aid in the manufacture of a pharmaceutical product (i.e., a medicament).

[0064] An example of a suitable oral dosage form is a tablet containing approximately 1-1000 mg of a compound of the present invention formulated with approximately 1-1000 mg of anhydrous lactose, approximately 1-1000 mg of croscarmellose sodium, approximately 1-1000 mg of polyvinylpyrrolidone (PVP) K30, and approximately 1-1000 mg of magnesium stearate. The powdered ingredients are first blended and then mixed with a solution of PVP. The resulting composition can be dried, granulated, mixed with magnesium stearate, and compressed into tablet form using conventional equipment. An example aerosol formulation can be prepared by dissolving, for example, 5-400 mg of a compound of the present invention in a suitable buffer solution, such as phosphate buffer, and adding an isotonicity agent (e.g., a salt such as sodium chloride) if desired. The solution may be filtered, for example, using a 0.2 micron filter, to remove impurities and contaminants.

[0065] Thus, one embodiment includes a pharmaceutical composition comprising a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof. A further embodiment includes a pharmaceutical composition comprising a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or excipient.

[0066] Another embodiment includes a pharmaceutical composition comprising a compound of formula (I) for use in treating mutant KRAS-driven cancers.Another embodiment includes a pharmaceutical composition comprising a compound of formula (I) for use in treating mutant KRAS-driven cancers.

[0067] Compositions A and B below show typical compositions of the present invention and serve merely as representative thereof.

[0068] Composition A The compounds of the present invention can be used in a manner known per se as active ingredients to prepare tablets of the following composition: Per tablet Active ingredient 200mg Microcrystalline cellulose 155mg Cornstarch 25mg Talc 25mg Hydroxypropyl methylcellulose 20mg 425mg

[0069] Composition B The compounds of the present invention can be used as active ingredients in a manner known per se to prepare capsules of the following composition: Per capsule Active ingredient 100.0mg Cornstarch 20.0mg Lactose 95.0mg Talc 4.5mg Magnesium stearate 0.5mg 220.0mg

[0070] Indications and Treatment Methods The compounds of the present invention induce a new binding pocket in KRAS by promoting the formation of a high-affinity ternary complex between the KRAS protein and the widely expressed cyclophilin A (CYPA), which inhibits KRAS interaction with downstream effectors such as RAF and PI3K. Therefore, the compounds of the present invention are useful for inhibiting proliferative oncogenic MAPK and PI3K signaling and reducing cell proliferation, particularly in cancer cells. The compounds of the present invention are useful for terminating RAS signaling in cells expressing RAS mutants, such as KRAS mutation-driven pancreatic cancer, colorectal cancer, lung cancer, esophageal cancer, gallbladder cancer, melanoma, ovarian cancer, and endometrial cancer. Alternatively, the compounds of the present invention are useful for terminating RAS signaling in malignant solid tumors where the oncogenic role of KRAS mutations is enhanced by dysregulation or mutation of effector pathways such as MAPK, PI3K-AKT, and mTOR (mammalian target of rapamycin)-driven signaling, for targeted therapy in pancreatic adenocarcinoma, colorectal cancer, and non-small cell lung cancer.

[0071] Another embodiment includes a method of treating or preventing cancer in a mammal in need thereof, the method comprising administering to the mammal a therapeutically effective amount of a compound of Formula (I), a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

[0072] synthesis The compounds of the present invention can be prepared by any conventional means. Suitable methods for synthesizing these compounds and their starting materials are shown in the following schemes and examples. All substituents, particularly R 1 ~R 7 , A 1 and A 2 are as defined above unless otherwise indicated. Furthermore, unless otherwise specified, all reactions, reaction conditions, abbreviations and symbols have meanings well known to one skilled in the art of organic chemistry.

[0073] A general synthetic route for preparing compounds of formula (I) is shown below. Scheme 1 [ka]

[0074] Compounds of formula II were synthesized according to the procedures described in Intermediates A to H. Compounds of formula (I) can be obtained by coupling reaction of acid (III) with compounds of formula (II) and coupling reagents such as T3P, HATU, PyBOP and EDCI / HOBt in the presence of bases such as TEA, DIEPA and DMAP.

[0075] The compounds of the present invention can be obtained as mixtures of diastereomers or enantiomers that can be separated by methods well known in the art, such as (chiral) HPLC or SFC. In another embodiment, the compounds of formula (I) can be obtained according to the above scheme by using the corresponding chiral starting materials.

[0076] The compounds of the present invention may be obtained as mixtures of diastereomers or enantiomers that can be separated by methods well known in the art, such as (chiral) HPLC or SFC. In another embodiment, the compounds of formula (I) may be obtained according to the above scheme by using the corresponding chiral starting materials.

[0077] The present invention also provides a process for preparing a compound of formula (I), comprising the steps of: a) a compound of formula (II), [ka] and acid (III), [ka] and in the presence of a coupling reagent and a base, to form a compound of formula (I). Including, In step a), the coupling reagent may be, for example, T3P, HATU, PyBOP or EDCI / HOBt, and the base may be, for example, TEA, DIEPA or DMAP.

[0078] Compounds of formula (I) or (Ia) when prepared according to the above processes are also an object of the present invention. [Example]

[0079] The present invention will be more fully understood by reference to the following examples, which should not, however, be construed as limiting the scope of the invention.

[0080] Abbreviation The present invention will be more fully understood by reference to the following examples, which should not, however, be construed as limiting the scope of the invention.

[0081] The abbreviations used herein 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: deuterated chloroform CD3OD: deuterated methanol COMU:(1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate DIEPA: N,N-diethylpropylamine DIBAL-H Diisobutylaluminum hydride DMAP: 4-dimethylaminopyridine DMF: dimethylformamide DMP: 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one 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): time 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 (electrospray ionization) min(s): minutes MTBE: Methyl tert-butyl ether NMM: N-methylmorpholine NMR: nuclear magnetic resonance NMO: 4-methylmorpholine N-oxide obsd.: Actual measurement Pd(dppf)Cl2: [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(dtbpf)Cl2: [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) prep-HPLC: preparative high-performance liquid chromatography PyBOP: benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate RT or rt: room temperature sat.: saturation selectfluor: 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane Bis(tetrafluoroborate) SFC: Supercritical Fluid Chromatography TEA: Triethylamine TFA: Trifluoroacetic acid THF: tetrahydrofuran TEA: Trimethylamine TMEDA: Tetramethylethylenediamine TMSCF3: Trifluoromethyltrimethylsilane T3P: Propylphosphonic anhydride

[0082] General experimental conditions Intermediates and final compounds were purified by flash chromatography using one of the following instruments: i) a Biotage SP1 system and Quad 12 / 25 cartridge module; ii) an ISCO Combi-Flash chromatography system. Silica gel brand and pore size: i) KP-SIL 60Å, particle size: 40-60 μm; ii) CAS Registry Number: Silica Gel: 63231-67-4, particle size: 47-60 micron; iii) ZCX from Qingdao Haiyang Chemical Co., Ltd., pore size: 200-300 or 300-400.

[0083] Intermediates and final compounds were synthesized using XBridge ( 商標 ) Prep-C18 (5 μm, OBD™ 30 × 100 mm) column, SunFire ( 商標 ) Prep-C18 (5 μm, OBD ( 商標 Purification was performed by preparative HPLC on a reversed-phase column using a Phenomenex Synergi-C18 (10 μm, 25 × 150 mm) or Phenomenex Gemini-C18 (10 μm, 25 × 150 mm) column. Purification was performed using a Waters AutoP purification system (sample manager 2767, pump 2525, detectors: Micromass ZQ and UV2487, solvent systems: acetonitrile and 0.1% ammonium hydroxide in water; acetonitrile and 0.1% FA in water; or acetonitrile and 0.1% TFA in water) or a Gilson-281 purification system (pump 322, detector: UV156, solvent systems: 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).

[0084] For SFC chiral separations, intermediates were separated by chiral columns (Daicel chiralpak IC, 5 μm, 30 × 250 mm), AS (10 μm, 30 × 250 mm), or AD (10 μm, 30 × 250 mm) on a Mettler Toledo Multigram III system SFC, Waters 80Q preparative SFC, or Thar80 preparative SFC, solvent systems: CO2 and IPA (0.5% TEA in IPA) or CO2 and MeOH (0.1% NH3·H2O in MeOH), back pressure 100 bar, and UV detection at 254 or 220 nm.

[0085] LC / MS spectra of the compounds were obtained using LC / MS (Waters (商標) Acquisition was performed using an 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 conditions I: A: 0.1% TFA in H2O; B: 0.1% TFA in acetonitrile; Acidic conditions II: A: 0.0375% TFA in H2O; B: 0.01875% TFA in acetonitrile; Basic condition I: A: 0.1% NH3·H2O in H2O; B: acetonitrile; Basic conditions II: A: 0.025% NH3·H2O in H2O; B: acetonitrile; Neutral conditions: A: H2O; B: acetonitrile.

[0086] Mass spectra (MS): Generally, only ions representing the parent mass are reported, and unless otherwise stated, the mass ions quoted are positive mass ions (M−H). + is.

[0087] NMR spectra were obtained using a Bruker Avance 400 MHz or 500 MHz.

[0088] Microwave-assisted reactions were performed on a Biotage Initiator Sixty microwave synthesizer. All reactions involving air-sensitive reagents were carried out under an argon or nitrogen atmosphere. Reagents were used as received from commercial suppliers without further purification unless otherwise stated.

[0089] Preparation example The following examples are intended to illustrate the meaning of the present invention but do not in any way represent a limitation within the meaning of the present invention.

[0090] Preparation of intermediates Intermediate A 3-[5-Bromo-1-ethyl-(2M)-2-[2-[(1S)-1-methoxyethyl]-3-pyridyl]indol-3-yl]-2,2-dimethyl-propan-1-ol [ka] The title intermediate A was prepared according to the following scheme. [ka] [ka]

[0091] Preparation of 2-[(1S)-1-methoxyethyl]-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (Compound A12) To a mixture of 3-bromo-2-[(1S)-1-methoxyethyl]pyridine (compound A11, 40.0 g, 185.1 mmol) and bis(pinacolato)diboron (56.4 g, 222.1 mmol) in 1,4-dioxane (500 mL) was added KOAc (23.1 mL, 370.2 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (6.7 g, 9.2 mmol). The mixture was stirred at 100 °C under N protection for 5 hours. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (EA / PE: 0-50%) to give 2-[(1S)-1-methoxyethyl]-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (compound A12, 55 g) as a dark brown oil. MS: calculated 264 (MH + ), measured value 264.1 (MH + ).

[0092] Step 1: Preparation of methyl 3-[tert-butyl(diphenyl)silyl]oxy-2,2-dimethyl-propanoate (Compound A2) To a solution of methyl 3-hydroxy-2,2-dimethylpropanoate (compound A1, 110.0 g, 832.3 mmol) and imidazole (169.9 g, 2.5 mol) in THF (1.5 L) was added tert-butylchlorodiphenylsilane (256.5 mL, 998.7 mmol) at 0 °C. The mixture was stirred at 0 °C for 2 h. The mixture was diluted with petroleum ether (1.0 L) and filtered. The collected solid was washed twice with petroleum ether (150 mL). The combined filtrate was concentrated under vacuum to give a residue. The residue was purified by silica gel chromatography (EA / PE: 0-50%) to give methyl 3-[tert-butyl(diphenyl)silyl]oxy-2,2-dimethylpropanoate (compound A2, 220 g) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ ppm 7.68-7.63(m,4H),7.44-7.36(m,6H),3.69(s,3H),3.65(s,2H),1.21(s,6H),1.04(s,9H).

[0093] Step 2: Preparation of 3-[tert-butyl(diphenyl)silyl]oxy-2,2-dimethyl-propanoic acid (Compound A3) To a solution of methyl 3-[tert-butyl(diphenyl)silyl]oxy-2,2-dimethyl-propanoate (compound A2, 110.0 g, 296.8 mmol) in ethanol (1200 mL) was added a solution of potassium hydroxide (43.2 g, 770.2 mmol) in ethanol (500 mL). The mixture was stirred at 90° C. for 5 hours, then concentrated in vacuo to remove EtOH and diluted with ice water (1000 mL). The mixture was acidified with a 1 M aqueous solution of HCl to pH = 3. The aqueous phase was extracted twice with EtOAc (600 mL). The combined organic layers were washed with brine (400 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo. The residue was triturated with petroleum ether (300 mL) to give 3-[tert-butyl(diphenyl)silyl]oxy-2,2-dimethyl-propanoic acid (compound A3, 80 g) as a white solid. 1 H NMR (400 MHz, CDCl3) δ ppm 7.70-7.65 (m, 4H), 7.47-7.38 (m, 6H), 3.67 (s, 2H), 1.25 (s, 6H), 1.05 (s, 9H).

[0094] Step 3: Preparation of 3-[tert-butyl(diphenyl)silyl]oxy-2,2-dimethyl-propanoyl chloride (Compound A4) To a solution of 3-[tert-butyl(diphenyl)silyl]oxy-2,2-dimethyl-propanoic acid (Compound A3, 163.0 g, 457.1 mmol) in DMF (166.8 mg, 2.3 mmol) and DCM (50 mL) was added thionyl chloride (265.6 mL, 3657 mmol). The mixture was stirred at 50° C. for 12 hours and then concentrated in vacuo to give 3-[tert-butyl(diphenyl)silyl]oxy-2,2-dimethyl-propanoyl chloride (Compound A4, 171.4 g) as a yellow oil, which was used in the next step without further purification.

[0095] Step 4: Preparation of 1-(5-bromo-1H-indol-3-yl)-3-[tert-butyl(diphenyl)silyl]oxy-2,2-dimethyl-propan-1-one (Compound A5) To a mixture of 3-[tert-butyl(diphenyl)silyl]oxy-2,2-dimethyl-propanoyl chloride (compound A4, 52.5 g, 140 mmol) in DCM (350 ml) was added a solution of SnCl4 (140 mL, 140 mmol, 1 M in DCM) slowly at 0 °C. The mixture was stirred at -10 °C for 0.5 h. Then, 5-bromoindole (27.4 g, 140 mmol) in DCM (150 mL) was added dropwise. After the addition, the mixture was stirred at -10 °C for 15 min. The mixture was then stirred at 0 °C for 15 min. ℃ The mixture was diluted with saturated aqueous NaHCO3 (1000 mL) at rt, and then extracted twice with EtOAc (800 mL). The combined organic layers were washed with brine (600 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo. The residue was triturated with EtOAc (100 mL) to give 1-(5-bromo-1H-indol-3-yl)-3-[tert-butyl(diphenyl)silyl]oxy-2,2-dimethyl-propan-1-one (compound A5, 40 g) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ ppm 8.68(s,1H),8.60(br.s,1H),7.67(d,J=2.8 Hz,1H),7.54-7.48(m,4H),7.42-7.35(m,3H),7.32-7.25(m,5H),3.90(s,2H),1.42(s,6H),0.96(s,9H).

[0096] Step 5: Preparation of [3-(5-bromo-1H-indol-3-yl)-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (compound A6) To a solution of 1-(5-bromo-1h-indol-3-yl)-3-[tert-butyl(diphenyl)silyl]oxy-2,2-dimethyl-propan-1-one (compound A5, 20.0 g, 37.4 mmol) in THF (250 mL), LiBH (28.1 mL, 112.2 mmol) was added under N protection at 0 °C. The mixture was stirred at 60 °C for 12 h. Upon completion of the reaction, the reaction mixture was cooled to 25 °C. ℃ The mixture was cooled to rt and quenched with MeOH (20 mL). The mixture was then diluted with EtOAc (300 mL) and washed with brine (250 mL). The organic layer was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated in vacuo. The residue was dissolved in DCM (250 mL) and cooled to 10° C. To this was added diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (3.7 g, 14.9 mmol) and p-toluenesulfonic acid monohydrate (356.7 mg, 1.8 mmol). After stirring at 10° C. for 2 hours, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (EA / PE: 0-50%) to give [3-(5-bromo-1H-indol-3-yl)-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (compound A6, 17.2 g) as a colorless oil. 1 H NMR(400 MHz,CDCl3)δ 8.00(s,1H),7.75(s,1H),7.74-7.65(m,4H),7.47-7.36(m,6H),7.26-7.19(m,2H),6.89(d,J=2.0 Hz, 1H), 3.40 (s, 2H), 2.73 (s, 2H), 1.15 (s, 9H), 0.89 (s, 6H).

[0097] Step 6: Preparation of [3-(5-bromo-2-iodo-1H-indol-3-yl)-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (compound A7) To a solution of [3-(5-bromo-1H-indol-3-yl)-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (compound A6, 41.2 g, 79.1 mmol) and iodine (20.1 g, 79.1 mmol) in THF (500 mL) was added silver trifluoromethanesulfonate (24.4 g, 94.9 mmol). After stirring at 25 °C for 1 h, the mixture was quenched with a saturated aqueous solution of Na SO (400 mL) and extracted with EtOAc (500 mL). The organic layer was washed with brine (400 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (EA / PE: 0-20%) to give [3-(5-bromo-2-iodo-1H-indol-3-yl)-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (compound A7, 46 g) as a yellow solid. 1 H NMR(400 MHz, CDCl3)δ ppm 8.07(s,1H),7.75-7.67(m,5H),7.46-7.37(m,6H),7.26-7.15(m,2H),3.49(s,2H),2.70(s,2H),1.15(s,9H),0.94(s,6H). MS: Calculated value 646 (MH + ), measured value 645.9 (MH + ).

[0098] Step 7: Preparation of [3-[5-bromo-2-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-1H-indol-3-yl]-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (compound A8) To a solution of [3-(5-bromo-2-iodo-1H-indol-3-yl)-2,2-dimethylpropoxy]-tert-butyl-diphenyl-silane (Compound A7, 18 g, 27.8 mmol) and 2-[(1S)-1-methoxyethyl]-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (Compound A12, 10.9 g, 41.7 mmol) in 1,4-dioxane (200 mL) and water (30 mL) was added potassium carbonate (9.6 g, 69.6 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.02 g, 1.4 mmol). The mixture was stirred at 80 °C for 12 h under N2. The mixture was cooled to 20 °C, diluted with EtOAc (200 mL), and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (EA / PE: 0-20%) to give [3-[5-bromo-2-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-1H-indol-3-yl]-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (compound A8, 10 g) as a brown oil. 1 H NMR(400MHz,CDCl3)δ ppm 9.31(s,1H),8.32(dd,J=4.4,0.8 Hz,1H),7.83-7.76(m,2H),7.64-7.58(m,4H),7.46-7.34(m,7H),7.32-7.29(m,1H),7.26-7.23(m,1H),4.52(q,J=6.4 Hz,1H),3.34(s,3H),3.33-3.27(m,2H),2.90-2.80(m,2H),1.41(d,J=6.4 Hz,3H),1.07(s,9H),0.64(s,3H),0.59(s,3H). MS: Calculated value 657 (MH + ), measured value 657.0 (MH + ).

[0099] Step 8: Preparation of [3-[5-bromo-1-ethyl-2-[2-[(1S)-1-methoxyethyl]-3-pyridyl]indol-3-yl]-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (Compound A9) To a solution of [3-[5-bromo-2-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-1H-indol-3-yl]-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (compound A8, 36.0 g, 54.9 mmol) in DMF (300 mL) was added cesium carbonate (35.7 g, 109.8 mmol) and iodoethane (8.7 mL, 109.8 mmol) at 0° C. After stirring at 25° C. for 12 h, the mixture was diluted with water (1000 mL) and extracted with EtOAc (500 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give [3-[5-bromo-1-ethyl-2-[2-[(1S)-1-methoxyethyl]-3-pyridyl]indol-3-yl]-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (compound A9, 32 g) as a brown oil. MS: calculated 685 (MH + ), measured value 685.0 (MH + ).

[0100] Step 9: Preparation of 3-[5-bromo-1-ethyl-(2M)-2-[2-[(1S)-1-methoxyethyl]-3-pyridyl]indol-3-yl]-2,2-dimethyl-propan-1-ol (Intermediate A) To a solution of [3-[5-bromo-1-ethyl-2-[2-[(1S)-1-methoxyethyl]-3-pyridyl]indol-3-yl]-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (compound A9, 32.0 g, 46.8 mmol) in THF (200 mL) was added tetrabutylammonium fluoride (280.7 mL, 280.7 mmol, 1 M in THF). After stirring at 50° C. for 12 hours, the mixture was diluted with water (500 mL) and extracted with EtOAc (300 mL). The combined organic layer was washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (EA / PE: 0-20%) to give 3-[5-bromo-1-ethyl-(2M)-2-[2-[(1S)-1-methoxyethyl]-3-pyridyl]indol-3-yl]-2,2-dimethyl-propan-1-ol (Intermediate A, 7.4 g, fast elution) as a yellow gum and 3-[5-bromo-1-ethyl-(2P)-2-[2-[(1S)-1-methoxyethyl]-3-pyridyl]indol-3-yl]-2,2-dimethyl-propan-1-ol (Compound A10, 5.6 g, slow elution) as a yellow solid. Intermediate A: 1 H NMR(400mhz,cdcl3)δppm 8.83(dd,J=4.8,2.0Hz,1H),7.90(d,J=1.6Hz,1H),7.69(dd,J=7.6,1.6Hz,1H),7.39-7.32(m,2 H),7.26-7.23(m,1H),4.12-4.07(m,1H),4.03-3.95(m,1H),3.92-3.81(m,1H),3.27(dd,J=24.8 10.4Hz,2H),3.07(s,3H),2.74(d,J=14.0Hz,1H),2.26(d,J=14.0Hz,1H),1 .60-1.52(m,1H),1.48(d,J=6.4Hz,3H),1.19(t,J=7.2Hz,3H),0.77(s,6H). MS: Calculated value 445 (MH + ), measured value 445.1 (MH + ).

[0101] X-ray crystallography of intermediate A The absolute configuration of intermediate A was confirmed by X-ray crystallography of its single crystal (Figure 1).

[0102] Intermediate B Methyl (3S)-1-[(2S)-2-(tert-butoxycarbonylamino)-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-triisopropylsilyloxyphenyl]propanoyl]hexahydropyridazine-3-carboxylate [ka] Intermediate B was prepared according to the following scheme: [ka]

[0103] Step 1: Preparation of methyl (2S)-2-amino-3-(3-hydroxyphenyl)propanoate (Compound B2) To a solution of LM-tyrosine (Compound B1, 5.0 g, 27.6 mmol) in methanol (80 mL) was added thionyl chloride (10 mL, 137.9 mmol). The mixture was stirred at 60° C. for 12 hours. 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).

[0104] Step 2: Preparation of methyl (2S)-2-(tert-butoxycarbonylamino)-3-(3-hydroxyphenyl)propanoate (Compound B3) To 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 sodium bicarbonate (40.6 g, 483.4 mmol), followed by di-t-butyl dicarbonate (33.1 g, 151.9 mmol) at 20° C. The mixture was stirred at 20° C. for 12 hours. The mixture was diluted with water (100 mL) and acidified with a 1 M aqueous solution of HCl to pH = 5. The mixture was extracted three times with ethyl acetate (100 mL). The combined organic phases were washed with brine (80 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to give methyl (2S)-2-(tert-butoxycarbonylamino)-3-(3-hydroxyphenyl)propanoate (Compound B3, 40 g) as a colorless gum. MS: Calculated 318 (MNa + ), measured value 318.3 (MNa + ).

[0105] 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 triisopropylsilyl chloride (39.1 g, 203.1 mmol) dropwise at 0 °C. ℃ After stirring at RT for 12 h, the mixture was diluted with water (250 mL) at 0 °C and extracted three times with ethyl acetate (200 mL). The combined organic phase was washed four times with brine (80 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo 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 474 (MNa +), measured value 474.2 (MNa + ).

[0106] 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 g, 3.3 mmol). The mixture was degassed and purged with N three times. 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 (Mn + ), measured value 600.3 (MNa + ).

[0107] 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) To 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 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 in vacuo. The resulting mixture was acidified with a 1 M aqueous solution of HCl to pH = 5. The resulting mixture was extracted three times with EtOAc (250 mL). 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 (Mn + ), measured value 586.3 (MNa + ).

[0108] 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) To a solution 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, 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) was 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 twice with EtOAc (100 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (EA / PE: 0-20%) 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: calculated 690 (MH + ), measured value 690.4 (MH + ).

[0109] Intermediate C (8S,14S)-8-amino-22-ethyl-4-hydroxy-(21M)-21-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-18,18-dimethyl-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 [ka] Intermediate C was prepared according to the following scheme: [ka]

[0110] Step 1: Preparation of methyl (3S)-1-[(2S)-2-(tert-butoxycarbonylamino)-3-[3-[1-ethyl-3-(3-hydroxy-2,2-dimethyl-propyl)-(2M)-2-[2-[(1S)-1-methoxyethyl]-3-pyridyl]indol-5-yl]-5-triisopropylsilyloxy-phenyl]propanoyl]hexahydropyridazine-3-carboxylate (Compound C1) To a mixture 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, 1.1 g, 1.6 mmol) and 3-[5-bromo-1-ethyl-(2M)-2-[2-[(1S)-1-methoxyethyl]-3-pyridyl]indol-3-yl]-2,2-dimethyl-propan-1-ol (Intermediate A, 356.9 mg, 3.3 mmol) in 1,4-dioxane (12 mL) and water (1.2 mL) was added Pd(dtbpf)Cl (87.7 mg, 0.13 mmol). The mixture was degassed and purged with N2 three times. The resulting mixture was stirred at 85 °C for 12 h. The reaction mixture was cooled to 20 °C and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (EA / PE: 0-50%) to give methyl (3S)-1-[(2S)-2-(tert-butoxycarbonylamino)-3-[3-[1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-(2M)-2-[2-[(1S)-1-methoxyethyl]-3-pyridyl]indol-5-yl]-5-triisopropylsilyloxy-phenyl]propanoyl]hexahydropyridazine-3-carboxylate (Compound C1, 750 mg) as a yellow oil. MS: calculated 928 (MH +), measured value 928.3 (MH + ).

[0111] Step 2: Preparation of (3S)-1-[(2S)-2-(tert-butoxycarbonylamino)-3-[3-[1-ethyl-3-(3-hydroxy-2,2-dimethyl-propyl)-(2M)-2-[2-[(1S)-1-methoxyethyl]-3-pyridyl]indol-5-yl]-5-triisopropylsilyloxy-phenyl]propanoyl]hexahydropyridazine-3-carboxylic acid (Compound C2) To a solution of methyl (3S)-1-[(2S)-2-(tert-butoxycarbonylamino)-3-[3-[1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-(2M)-2-[2-[(1S)-1-methoxyethyl]-3-pyridyl]indol-5-yl]-5-triisopropylsilyloxy-phenyl]propanoyl]hexahydropyridazine-3-carboxylate (Compound C1, 750.0 mg, 0.7 mmol) in DCE (12 mL) was added trimethyltin hydroxide (519.5 mg, 2.8 mmol). The mixture was stirred at 60 °C for 12 hours. The mixture was added to water (40 mL) and extracted three times with ethyl acetate (50 mL). The combined organic phase was washed with brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give (3S)-1-[(2S)-2-(tert-butoxycarbonylamino)-3-[3-[1-ethyl-3-(3-hydroxy-2,2-dimethyl-propyl)-(2M)-2-[2-[(1S)-1-methoxyethyl]-3-pyridyl]indol-5-yl]-5-triisopropylsilyloxy-phenyl]propanoyl]hexahydropyridazine-3-carboxylic acid (compound C2, 650 mg) as a yellow solid. MS: calculated 914 (MH + ), measured value 914.5 (MH + ).

[0112] Step 3: tert-Butyl N-[(8S,14S)-22-ethyl-(21M)-21-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-18,18 dimethyl-9,15 dioxo-4-triisopropylsilyloxy-16-oxa-10,22,28 triazapentacyclo[18.5.2.1 2,6 .1 10,14 .0 23,27 Preparation of ]nonacosa-1(26),2,4,6(29),20,23(27),24 heptaen-8-yl]carbamic acid (compound C3) To a solution of (3S)-1-[(2S)-2-(tert-butoxycarbonylamino)-3-[3-[1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-(2M)-2-[2-[(1S)-1-methoxyethyl]-3-pyridyl]indol-5-yl]-5-triisopropylsilyloxyphenyl]propanoyl]hexahydropyridazine-3-carboxylic acid (Compound C2, 650.0 mg, 0.7 mmol) in DCM (10 mL) was added DIEA (1.4 g, 11.3 mmol), EDCI (1.9 g, 10.6 mmol), followed by HOBT (240.1 mg, 1.8 mmol) at 0° C. The mixture was stirred at 20° C. for 12 hours. The mixture was poured into water (40 mL) and extracted three times with EtOAc (30 mL). The combined organic phase was washed with brine (40 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (EA / PE: 0-50%) to give tert-butyl N-[(8S,14S)-22-ethyl-(21M)-21-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-18,18 dimethyl-9,15 dioxo-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 C3, 530 mg) was obtained as a yellow oil. MS: calculated 896 (MH + ), measured value 896.2 (MH + ).

[0113] Step 4: tert-Butyl N-[(8S,14S)-22-ethyl-4-hydroxy-(21M)-21-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-18,18 dimethyl-9,15-dioxo-16-oxa-10,22,28 triazapentacyclo[18.5.2.1 2,6 .1 10,14 .0 23,27 Preparation of ]nonacosa-1(26),2,4,6(29),20,23(27),24 heptaen-8-yl]carbamic acid (compound C4) tert-Butyl N-[(8S,14S)-22-ethyl-(21M)-21-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-18,18 dimethyl-9,15-dioxo-4-triisopropylsilyloxy-16-oxa-10,22,28-triazapentacyclo[18.5.2.1 2,6 .1 10,14 .0 23,27 To a solution of ]nonacosa-1(26),2,4,6(29),20,23(27),24-heptaen-8-yl]carbamate (compound C3, 480.0 mg, 0.5 mmol) in THF (5 mL) was added TBAF (0.6 mL, 0.6 mmol, 1.0 M in THF) at 0° C. After stirring at 0° C. for 0.5 h, the reaction mixture was diluted with water (30 mL) and extracted three times with EtOAc (40 mL). The combined organic phases were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give tert-butyl N-[(8S,14S)-22-ethyl-4-hydroxy-(21M)-21-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-18,18-dimethyl-9,15-dioxo-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 C4, 390 mg) was obtained as a colorless gum. MS: calculated 740 (MH + ), measured value 740.2 (MH + ).

[0114] Step 5: (8S,14S)-8-amino-22-ethyl-4-hydroxy-(21M)-21-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-18,18-dimethyl-16-oxa-10,22,28-triazapentacyclo[18.5.2.1 2,6 .1 10,14 .0 23,27 ]Preparation of nonacosa-1(26),2,4,6(29),20,23(27),24-heptaene-9,15-dione (intermediate C) tert-Butyl N-[(8S,14S)-22-ethyl-4-hydroxy-(21M)-21-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-18,18-dimethyl-9,15-dioxo-16-oxa-10,22,28-triazapentacyclo[18.5.2.1 2,6 .1 10,14 .0 23,27 To a solution of ]nonacosa-1(26),2,4,6(29),20,23(27),24-heptaen-8-yl]carbamate (compound C4, 430.0 mg, 0.6 mmol) in DCM (4 mL) was added TFA (0.8 mL). After stirring at 20 °C for 1 h, the reaction mixture was diluted with a saturated aqueous solution of NaHCO3 (40 mL) and extracted three times with EtOAc (60 mL). The combined organic phases were washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give (8S,14S)-8-amino-22-ethyl-4-hydroxy-(21M)-21-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-18,18-dimethyl-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 C, 330 mg) was obtained as a yellow solid. MS: calculated 640 (MH + ), measured value 640.3 (MH + ). 1H NMR(400Mhz,CD3OD)δ ppm 8.72-8.71(m,1H),7.89(d,J=7.6Hz,1H),7.81(s,1H),7.55-7.44(m,3H),7.11(s,1H),6.92(s,1H),6.60(s,1H),4.7 5(t,J=7.2Hz,1H),4.60(br.s,1H),4.41(d,J=12.8Hz,1H),4.35-4.20(m,2H),4.14-4.05(m,1H),3.62(d,J=10.8Hz,1 H),3.49(d,J=10.8Hz,1H),3.26(s,2H),3.13-3.00(m,1H),2.89-2.84(m,1H),2.81-2.78(m,3H),2.66-2.62(m,1H), 2.05-2.00(m,1H),1.82-1.80(m,1H),1.51-1.46(m,5H),1.02(t,J=6.8Hz,3H),0.86-0.82(m,3H),0.59-0.56(m,3H).

[0115] Intermediate D Benzyl 4-[(5M)-5-[5-bromo-1-ethyl-3-(3-hydroxy-2,2-dimethyl-propyl)indol-2-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate [ka] The title compound was prepared in a manner similar to that used to prepare intermediate A, except that 1-[6-[(1S)-1-methoxyethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]-4-methyl-piperazine (compound D5) was used instead of 2-[(1S)-1-methoxyethyl]-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (compound A12).

[0116] Compound D5 was prepared according to the following scheme: [ka]

[0117] Step 1: Preparation of 3-bromo-2-[(1S)-1-methoxyethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (Compound D1) To a solution of 3-bromo-2-[(1S)-1-methoxyethyl]pyridine (compound A11, 2.0 g, 9.26 mmol) and bis(pinacolato)diboron (3.5 g, 13.9 mmol) in THF (30 mL) was added 4,4'-di-tert-butyl-2,2'-bipyridine (372.7 mg, 1.39 mmol) and [Ir(OMe)(COD)] (306.3 mg, 0.460 mmol). The mixture was stirred at 75 °C under N protection for 16 h. 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 D1, 2.4 g) as a yellow oil. 1 H NMR(400 MHz, CDCl3)δ ppm 8.91(d,J=1.4 Hz,1 H),8.21(d,J=1.4 Hz,1 H),4.95(q,J=6.5 Hz,1 H),3.30(s,3 H),1.49(d,J=6.5 Hz,3 H),1.35(s,12 H).

[0118] Step 2: Preparation of 3-bromo-5-iodo-2-[(1S)-1-methoxyethyl]pyridine (Compound D2) To a solution of 3-bromo-2-[(1S)-1-methoxyethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (compound D1, 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 under N protection for 40 h. The reaction was quenched with a saturated solution of NaSO (40 mL), and the reaction mixture was extracted with EtOAc (30 mL, twice). The combined organic layers were washed with brine (50 mL), filtered, and the filtrate was concentrated 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 D2, 660 mg) as a yellow oil. MS calculated 342 (MH + ), measured value 341.8 (MH + ).

[0119] Step 3: Preparation of benzyl 4-[5-bromo-6-[([(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (Compound D4) To a solution of 3-bromo-5-iodo-2-[(1S)-1-methoxyethyl]pyridine (Compound D2, 660 mg, 1.9 mmol) and 1-Cbz-piperazine (Compound D3, 425.1 mg, 1.9 mmol) in toluene (10 mL) was added cesium carbonate (1.6 g, 4.83 mmol), (R)-BINAP (60.1 mg, 0.1 mmol), and palladium(II) acetate (43.3 mg, 0.19 mmol). The mixture was stirred at 100 °C under N protection for 12 h. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (EA / PE: 0-50%) to give benzyl 4-[5-bromo-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound D4, 740 mg) as a yellow solid. MS calculated: 434.1 (MH + ), measured value 434.1 (MH + ).

[0120] 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 (Compound D5) To a solution of benzyl 4-[5-bromo-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (Compound D4, 740 mg, 1.7 mmol) and bis(pinacolato)diboron (519.2 mg, 2.04 mmol) in toluene (12 mL) was added KOAc (418.0 mg, 4.26 mmol) and Pd(dppf)Cl (124.7 mg, 0.170 mmol). The reaction mixture was stirred at 90 °C under a N atmosphere for 12 hours. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column to give 1-[6-[(1S)-1-methoxyethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]-4-methyl-piperazine (compound D5, 470 mg) as a brown solid. MS calculated 482.3 (MH + ), measured value 482.2 (MH + ).

[0121] Intermediate E Methyl (3S)-1-[(2S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylate [ka] Intermediate E was prepared according to the following scheme: [ka]

[0122] Step 1: Preparation of (4-bromothiazol-2-yl)methanol (Compound E2) To a solution of 4-bromothiazole-2-carboxaldehyde (6.0 g, 31.25 mmol) in methanol (70 mL) was added sodium borohydride (1.77 g, 46.87 mmol) at 0° C. The mixture was stirred at 25° C. for 1 hour. The reaction mixture was quenched with water (300 mL) at 0° C. and extracted with ethyl acetate (200 mL, 3 times). The combined organic phase was washed with brine (150 mL, 2 times), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to give (4-bromothiazol-2-yl)methanol (compound E2, 6 g) as a colorless oil.

[0123] Step 2: Preparation of 4-bromo-2-(bromomethyl)thiazole (Compound E3) To a solution of (4-bromothiazol-2-yl)methanol (compound E2, 6.0 g, 30.92 mmol) in DCM (80 mL) was added CBr4 (15.38 g, 46.38 mmol) and triphenylphosphine (12.16 g, 46.38 mmol) at 0 °C. ℃ After stirring at rt for 1 h, the mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified on a silica gel column eluted with 0-10% ethyl acetate in petroleum ether to give (4-bromothiazol-2-yl)methanol (compound E3, 6.0 g) as a yellow oil. MS calculated 255.9 (MH + ), measured value 255.9 (MH + ).

[0124] Step 3: Preparation of 4-bromo-2-[[(2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2-yl]methyl]thiazole (Compound E5) To a mixture of (R)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine (compound E4, 4.32 g, 23.45 mmol) in THF (60 mL), n-butyllithium (10 mL, 25.22 mmol, 2.5 M) was added slowly at −78° C., and the mixture was stirred at −78° C. for 0.5 h. 4-Bromo-2-(bromomethyl)thiazole (compound E3, 5.4 g, 21.02 mmol) was added to the mixture at −78° C., which was stirred for another 1 h. The mixture was quenched with a saturated aqueous solution of NH4Cl (100 mL) and extracted with EtOAc (100 mL, twice). The combined organic layer was washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by reverse-phase chromatography, eluting with HO containing ACN (0.01% FA) from 0 to 60% to give 4-bromo-2-[[(2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2-yl]methyl]thiazole (compound E5, 3.6 g) as a yellow oil. MS calculated 360 (MH + ), measured value 359.9 (MH + ).

[0125] Step 4: Preparation of methyl (2S)-2-amino-3-(4-bromothiazol-2-yl)propanoate (Compound E6) To a solution of 4-bromo-2-[[(2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2-yl]methyl]thiazole (compound E5, 3.6 g, 10 mmol) in ACN (20 mL) was added hydrochloric acid (66.62 mL, 0.3 M). The mixture was stirred at 25 °C for 2 hours. The mixture was basified with a saturated aqueous solution of NaHCO to pH = 8. The mixture was extracted with EtOAc (80 mL, 6 times). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to give methyl (2S)-2-amino-3-(4-bromothiazol-2-yl)propanoate (compound E6, 3.1 g) as a yellow oil. MS calculated 264.9 (MH + ), measured value 264.9 (MH + ).

[0126] Step 5: Preparation of methyl (2S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)propanoate (Compound E7) To a solution of methyl (2S)-2-amino-3-(4-bromothiazol-2-yl)propanoate (compound E6, 3.1 g, 11.69 mmol) in DCM (40 mL) was added triethylamine (2.96 g, 29.23 mmol) and (Boc)2O (3.83 g, 17.54 mmol). The mixture was stirred at 30 °C for 12 h. The mixture was concentrated in vacuo. The residue was purified on a silica gel column eluted with 0 to 30% ethyl acetate in petroleum ether to give methyl (2S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)propanoate (compound E7, 3.2 g) as a yellow oil. MS calculated 387 (Mn + ), measured value 386.9 (MNa + ).

[0127] Step 6: Preparation of (2S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)propanoic acid (compound E8) To a solution of methyl (2S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)propanoate (compound E7, 3.2 g, 8.76 mmol) in THF (30 mL), methanol (2 mL), and water (10 mL) was added lithium hydroxide (0.41 mL, 43.81 mmol). The mixture was stirred at 25° C. for 1 hour. The mixture was acidified with 1 M aqueous HCl to pH=5. The mixture was extracted with EtOAc (40 mL, twice). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to give (2S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)propanoic acid (compound E8, 3.1 g) as a yellow oil. MS calculated 373 (MNa + ), measured value 372.9 (MNa + ).

[0128] Step 7: Preparation of methyl (3S)-1-[(2S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylate (E) To a solution of (2S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)propanoic acid (compound E8, 3.1 g, 8.83 mmol) in DCM (50 mL) was added methyl (3S)-hexahydropyridazine-3-carboxylate hydrochloride (compound E9, 2.39 g, 13.24 mmol), EDCI (3.38 g, 17.65 mmol), 1-hydroxybenzotriazole (238.53 mg, 1.77 mmol), and NMM (9.92 mL, 88.26 mmol) at 0° C. The mixture was stirred at 25° C. for 1 hour, then diluted with water (60 mL) and extracted with EtOAc (60 mL, 3 times). The combined organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was purified on a silica gel column and eluted with 10-30% ethyl acetate in petroleum ether to give methyl (3S)-1-[(2S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylate (Intermediate E, 2.4 g). MS calculated 477 (MH + ), measured value 476.9 (MH + ).

[0129] Intermediate F Methyl (3S)-1-[(2S)-3-(3-bromophenyl)-2-(tert-butoxycarbonylamino)propanoyl]-hexahydropyridazine-3-carboxylate [ka] Similar to the preparation of intermediate E, by using methyl (2S)-2-amino-3-(3-bromophenyl)propanoate, Preparation of methyl (2S)-2-amino-3-(4-bromothiazol-2-yl)propanoate (Compound E6).

[0130] intermediate G (7S,13S)-7-amino-21-ethyl-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17dimethyl-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-8,14dione [ka] Compound intermediate G was prepared according to the following scheme. [ka]

[0131] Step 1: Preparation of benzyl 4-[(5M)-5-[1-ethyl-3-(3-hydroxy-2,2-dimethyl-propyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indol-2-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (Compound G3) To a solution of benzyl 4-[(5M)-5-[5-bromo-1-ethyl-3-(3-hydroxy-2,2-dimethyl-propyl)indol-2-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (Intermediate D, 110.0 mg, 0.17 mmol) and bis(pinacolato)diboron (46.3 mg, 0.18 mmol) in toluene (4 mL) was added KOAc (40.67 mg, 0.4 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (12.13 mg, 0.02 mmol). After stirring at 90 °C for 12 h under N protection, the mixture was concentrated in vacuo. The residue was purified on a silica gel column and eluted with ethyl acetate in petroleum ether (30-60%) to give benzyl 4-[(5M)-5-[1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indol-2-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound G3, 100 mg) as a yellow oil. MS calculated 711 (MH + ), measured value 711.1 (MH + ).

[0132] Step 2: Benzyl 4-[(5M)-5-[(7S,13S)-7-(tert-butoxycarbonylamino)-21-ethyl-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 Preparation of ]octacosa-1(25),2,5(28),19,22(26),23-hexaen-20-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (Compound G1) 3-[(5M)-5-Bromo-1-ethyl-2-[2-[(1S)-1-methoxyethyl]-3-pyridyl]indol-3-yl]-2,2-dimethyl-propan-1-ol (Intermediate A) 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) instead of 4-[(5M)-5-[1-ethyl-3-(3 Compound G1 was prepared similarly to the preparation of intermediate C by using [(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indol-2-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound G3) and methyl (3S)-1-[(2S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylate (intermediate E).

[0133] Step 3: tert-Butyl N-[(7S,13S)-21-ethyl-(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 Preparation of ]octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamate (compound G2) Benzyl 4-[(5M)-5-[(7S,13S)-7-(tert-butoxycarbonylamino)-21-ethyl-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 22,26To a solution of [(1S)-octacosa-1(25),2,5(28),19,22(26),23-hexaen-20-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (Compound G1, 35.0 mg, 0.04 mmol) in methanol (5 mL) was added Pd(OH)2 / C (20 mg). The mixture was degassed and purged with H2 three times. After stirring under a H2 balloon at 25 °C for 3 h, the mixture was filtered, and the filtrate was concentrated in vacuo to give the intermediate (20 mg) as a white solid. To a solution of this intermediate (20.0 mg) in methanol (1 mL) was added acetic acid (5.04 mg, 0.08 mmol). After stirring at 25° C. for 15 minutes, formaldehyde (5 mg, 0.06 mmol) and NaBHCN (2.1 mg, 0.03 mmol) were added to the mixture, which was then stirred for an additional 45 minutes. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by reverse-phase chromatography to give tert-butyl N-[(7S,13S)-21-ethyl-(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]carbamate (compound G2, 17 mg). MS calculated: 829 (MH + ), measured value 829.1 (MH + ).

[0134] Step 4: (7S,13S)-7-amino-21-ethyl-(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 ]Preparation of octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (intermediate G) tert-Butyl N-[(7S,13S)-21-ethyl-(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 To a mixture of octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamate (Compound G2, 17.0 mg, 0.02 mmol) in DCM (5 mL) was added TFA (1.0 mL). After stirring at 30 °C for 1 h, the mixture was concentrated in vacuo, diluted with saturated NaHCO solution (10 mL), and extracted with EtOAc. The combined organic layers were washed with brine (15 mL), filtered, concentrated in vacuo, and purified to give (7S,13S)-7-amino-21-ethyl-(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 G, 10 mg) was obtained as a yellow oil. MS calculated 729 (MH + ), measured value 729.2 (MH + ).

[0135] Intermediate H (7S,13S)-7-amino-21-ethyl-(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 .1 9,13 .0 22,26 ]Octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione [ka] The title intermediate was prepared similarly to the preparation of intermediate G by using 3-[5-bromo-1-ethyl-(2M)-2-[2-[(1S)-1-methoxyethyl]-3-pyridyl]indol-3-yl]-2,2-dimethyl-propan-1-ol (intermediate A) instead of benzyl 4-[5-[5-bromo-1-ethyl-3-(3-hydroxy-2,2-dimethyl-propyl)indol-2-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (intermediate D).

[0136] Intermediate I (8S,14S)-8-amino-22-ethyl-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-18,18-dimethyl-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 [ka] The title intermediate was prepared similarly to the preparation of intermediate G by using methyl (3S)-1-[(2S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylate (intermediate E) instead of methyl (3S)-1-[(2S)-3-(3-bromophenyl)-2-(tert-butoxycarbonylamino)propanoyl]-hexahydropyridazine-3-carboxylate (intermediate F).

[0137] Intermediate J (8S,14S)-8-amino-22-ethyl-(21M)-21-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-18,18-dimethyl-16-oxa-10,22,28-triazapentacyclo[18.5.2.1 2,6 .110,14 .0 23,27 ]Nonacosa-1(26),2,4,6(29),20,23(27),24-heptaene-9,15-dione [ka] Analogously to the preparation of intermediate C, 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) and 3-[5-bromo-1-ethyl-(2M)-2-[2-[(1S)-1-methoxyethyl]-3-pyridyl]indol-3-yl]-2,2dimethyl-propan-1-ol (intermediate A) The title intermediate was prepared by using 3-[1-ethyl-(2M)-2-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indol-3-yl]-2,2-dimethyl-propan-1-ol (Intermediate J1) and methyl (3S)-1-[(2S)-3-(3-bromophenyl)-2-(tert-butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylate (Intermediate F) instead of

[0138] Compound J1 was prepared in a manner similar to the preparation of intermediate G3, by using 3-[5-bromo-1-ethyl-(2M)-2-[2-[(1S)-1-methoxyethyl]-3-pyridyl]indol-3-yl]-2,2-dimethyl-propan-1-ol (intermediate A) instead of benzyl 4-[(5M)-5-[5-bromo-1-ethyl-3-(3-hydroxy-2,2-dimethyl-propyl)indol-2-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (intermediate D).

[0139] Intermediate K (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-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 K) [ka] The title compound was prepared similarly to the preparation of intermediate H by using 2,2,2-trifluoroethyl trifluoromethanesulfonate instead of iodoethane.

[0140] Intermediate L (7S,13S)-7-amino-(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 K) [ka] The title compound was prepared similarly to the preparation of intermediate G, using 2,2,2-trifluoroethyl trifluoromethanesulfonate instead of iodoethane.

[0141] Intermediate M (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 [ka] The title intermediate M was prepared according to the following scheme. [ka] [ka]

[0142] Step 1: 1-(5-bromo-6-fluoro-1H-indol-3-yl)-3-((tert-butyldiphenylsilyl) Preparation of (oxy)-2,2-dimethylpropan-1-one (compound M3) To a mixture of 3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropanoyl chloride (compound M1, 35.0 g, 116.8 mmol) in DCM (400 mL) was added a solution of SnCl (121.2 mL, 121.5 mmol, 1 M in DCM) slowly at 0 °C. After stirring at −40 °C for 0.5 h, 5-bromo-6-fluoro-1H-indole (compound M2, 25.0 g, 116.8 mmol) in DCM (200 mL) was added dropwise to the mixture, which was stirred at −40 °C for an additional 15 min. After completion of the reaction, it was quenched with saturated aqueous NaHCO (800 mL), and the reaction mixture was extracted with EtOAc (900 mL, twice). The combined organic layers were washed with brine (700 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was triturated with a solution (100 mL, petroleum ether:ethyl acetate = 8:1) and filtered. The collected solid was dried in vacuo to give 1-(5-bromo-6-fluoro-1H-indol-3-yl)-3-((tertbutyldiphenylsilyl)oxy)-2,2-dimethylpropan-1-one (compound M3, 50.0 g) as a yellow solid. MS calculated 552.1 (MH + ), measured value 552.1 (MH + ).

[0143] Step 2: Preparation of [3-(5-bromo-6-iodo-1H-indol-3-yl)-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (compound M4) To a mixture of 1-(5-bromo-6-fluoro-1H-indol-3-yl)-3-((tertbutyldiphenylsilyl)oxy)-2,2-dimethylpropan-1-one (compound M3, 50.0 g, 90.49 mmol) in THF (600 mL) was added LiBH (48.4 mL, 193.49 mmol, 4 M in THF) dropwise at 0 °C. The mixture was stirred at 70 °C under a nitrogen atmosphere for 24 hours. After completion of the reaction, the reaction was quenched by slowly adding water (600 mL) at 0 °C, and the reaction mixture was extracted with EtOAc (600 mL, twice). The combined organic layers were washed with brine (600 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica column chromatography (20% to 33% EtOAc in PE) to give [3-(5-bromo-6-fluoro-1H-indol-3-yl)-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (compound M4, 46.0 g) as a white solid. MS calculated 538.1 (MH + ), measured value 538.2 (MH + ).

[0144] Step 3: Preparation of [3-(5-bromo-6-fluoro-2-iodo-1H-indol-3-yl)-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (compound M5) To a mixture of [3-(5-bromo-6-fluoro-1H-indol-3-yl)-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (compound M4, 35.4 g, 65.73 mmol) and iodine (18.4 g, 72.3 mmol) in THF (400 mL) was added silver trifluoromethanesulfonate (20.3 g, 78.88 mmol) at 0° C. The mixture was stirred at 0° C. for 10 minutes. After the reaction was complete, it was quenched with saturated aqueous NaSO (400 mL) and EtOAc (400 mL), and the reaction mixture was filtered. The organic layer was washed with brine (100 mL), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica column chromatography (0% to 2.5% EtOAc in PE) to give [3-(5-bromo-6-fluoro-2-iodo-1H-indol-3-yl)-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (compound M5, 43.0 g) as a yellow solid. MS calculated 664.0 (MH + ), measured value 664.1 (MH + ).

[0145] 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 M6) To a mixture of [3-(5-bromo-6-fluoro-2-iodo-1H-indol-3-yl)-2,2-dimethylpropoxy]-tert-butyl-diphenyl-silane (compound M5, 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 (compound D5, 16.7 g, 34.69 mmol) in 1,4-dioxane (270 mL) / toluene (90 mL) / water (90 mL) was added potassium phosphate (15.7 g, 73.92 mmol) and Pd(dppf)Cl (920 mg, 1.26 mmol). The mixture was stirred at 70 °C under a nitrogen atmosphere for 12 hours. After the reaction was completed, the mixture was filtered and concentrated in vacuo. The residue was purified by silica column chromatography (20% to 50% EtOAc in PE) to give 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 M6, 19.5 g) as a white solid. MS calculated 891.3 (MH + ), measured value 891.3 (MH + ).

[0146] 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 M7) To a solution of 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 M6, 14.5 g, 16.26 mmol) and CsCO (15.9 g, 48.77 mmol) in DMF (200 mL), 2,2,2-trifluoroethyl trifluoromethanesulfonate (37.7 g, 162.56 mmol) was added dropwise at 0 °C, and the mixture was stirred at 20 °C for 12 h. After the reaction was complete, EtOAc (70 mL) and water (100 mL) were added, and the layers were separated. The aqueous phase was extracted with EtOAc (70 mL, twice). The combined organic layers were washed with brine (100 mL, 4 times), dried over NaSO, filtered, and concentrated in vacuo to give a residue. The residue was purified by silica column chromatography to give 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 M7, 8.0 g, PEAK 1) as a yellow oil. MS calculated 973.3 (MH + ), measured value 973.2 (MH + ).

[0147] Step 6: Preparation of benzyl 4-[(5M)-5-[5-bromo-6-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 M8) To a solution of benzyl 4-[(5M)-5-[5-bromo-3-[3-[tert-butyl(diphenyl)silyl]oxy-2,2-dimethylpropyl]-6-fluoro-1-(2,2,2-trifluoroethyl)indol-2-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound M7, 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 Na SO , filtered, and concentrated in vacuo to give a residue. The residue was purified by silica column chromatography (25% to 66% EtOAc in PE) to give benzyl 4-[(5M)-5-[5-bromo-6-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 M8, 6.5 g) as a yellow solid. MS calculated 735.2 (MH + ), measured value 735.1 (MH + ).

[0148] Step 7: Preparation of benzyl 4-[(5M)-5-[6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-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 M9) To a solution of benzyl 4-[(5M)-5-[5-bromo-6-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 M8, 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 Pd(dppf)Cl (537.1 mg, 0.73 mmol). The mixture was degassed and purged with nitrogen three times, and the mixture was stirred at 90 °C for 12 h. After completion of the reaction, the mixture was cooled to room temperature. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give a residue, which was purified by silica column chromatography (25% to 66% EtOAc in PE) 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 M9, 5.2 g) as a yellow oil. MS calculated 783.3 (MH + ), measured value 783.3 (MH + ).

[0149] 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-dimethyl-propyl)-1-(2,2,2-trifluoroethyl)indol-5-yl]thiazol-2-yl]-2-(tert-butoxycarbonylamino)-propanoyl]hexahydropyridazine-3-carboxylate (Compound C10) Methyl (3S)-1-[(2S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylate (Intermediate E, 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, To a mixture of [(2,2-trifluoroethyl)indol-2-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (Compound M9, 4.9 g, 6.32 mmol) in toluene (60 mL), 1,4-dioxane (20 mL), and water (20 mL) was added KPO (3.4 g, 15.81 mmol) and Pd(dtbpf)Cl (412.2 mg, 0.63 mmol) under a nitrogen atmosphere. The mixture was stirred at 70 °C for 12 hours. After the reaction was complete, the mixture was concentrated in vacuo to give a residue. The residue was purified by silica column (10% to 75% EtOAc in PE) 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 M10, 3.6 g) as a brown solid. MS calculated 1053.4 (MH + ), measured value 1053.3 (MH + ).

[0150] 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 M11) 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 M10, 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 hours. After the reaction was complete, EtOAc (80 mL) and water (60 mL) were added, and the layers were separated. The aqueous phase was extracted with EtOAc (80 mL, 2 times). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo 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 M11, 4.3 g) as a brown solid. MS calculated 1039.4 (MH + ), measured value 1039.2 (MH + ).

[0151] Step 10: 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-tetraazapentacyclo[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-(20M)-20-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound M12) To a mixture 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 M11, 4.3 g, 4.14 mmol) in DCM (430 mL) was added 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 hours. After the reaction was complete, 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% to 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 22,26]octacosa-1(25),2,5(28),19,22(26),23-hexaen-(20M)-20-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound M12, 3.1 g) was obtained as a yellow gum. MS calculated 1021.4 (MH + ), measured value 1021.2 (MH + ).

[0152] Step 11: 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 Preparation of ]octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamate (compound M13) 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-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26To a mixture of [(1S)-octacosa-1(25),2,5(28),19,22(26),23-hexaen-(20M)-20-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound M12, 3.1 g, 3.04 mmol) and aqueous formaldehyde (775.0 mg, 9.55 mmol) was added Pd(OH)2 on activated carbon (2.79 g, 3.97 mmol). The mixture was degassed and purged with H2 three times. The mixture was hydrogenated at 30 °C for 18 h. After the reaction was complete, 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 M13, 2.6 g) was obtained as a brown solid. MS calculated 901.3 (MH + ), measured value 901.3 (MH + ).

[0153] 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-tetraazapentacyclo[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 M) 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 To a mixture of 2.6 g (2.89 mmol) of octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamate (compound M13) in 18 mL of DCM was added 14.0 mL of TFA (181.72 mmol). 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 NaHCO (30 mL), and extracted with EtOAc (30 mL, 3 times). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, concentrated in vacuo, and purified to afford (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 M, 2.0 g) was obtained as a yellow solid, which was used directly in the next step. MS calculated 801.3 (MH + ), measured value 801.2 (MH + ).

[0154] Intermediate N (8S,14S)-8-amino-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-heptaene-9,15-dione (intermediate N) [ka] The title compound was prepared in a manner similar to that used to prepare intermediate C, by using 3-[5-bromo-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-1-(2,2,2-trifluoroethyl)indol-3-yl]-2,2-dimethyl-propan-1-ol (compound N1) instead of 3-[5-bromo-1-ethyl-(2M)-2-[2-[(1S)-1-methoxyethyl]-3-pyridyl]indol-3-yl]-2,2-dimethyl-propan-1-ol (intermediate A).

[0155] Compound N1 was prepared similarly to the preparation of intermediate D by using 1-methylpiperazine and 2,2,2-trifluoroethyl trifluoromethanesulfonate instead of 1-Cbz-piperazine (compound D3) and iodoethane.

[0156] Intermediate O (7S,13S)-7-amino-(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 O) [ka] By using 3-[5-bromo-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-1-(2,2,2-trifluoroethyl)indol-3-yl]-2,2-dimethyl-propan-1-ol (compound N1), similar to the preparation of intermediate C,

[0157] Intermediate P (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 ] The title compound was prepared in place of octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione. [ka] This compound was prepared according to the following scheme. [ka] [ka]

[0158] Step 1: Preparation of 1-[5-bromo-6-[(1S)-1-methoxyethyl]-3-pyridyl]-4-(2,2,2-trifluoroethyl)piperazine (Compound P2). To a mixture of 3-bromo-5-iodo-2-[(1S)-1-methoxyethyl]pyridine (compound D2, 2.03 g, 5.95 mmol) and 1-(2,2,2-trifluoroethyl)piperazine (compound P1, 1.0 g, 5.95 mmol) in toluene (15 mL) was added CsCO (4.85 g, 14.88 mmol), (R)-binap (92.6 mg, 0.15 mmol), and Pd(OAc) (66.8 mg, 0.3 mmol). The reaction mixture was degassed and purged with nitrogen three times, and the mixture was stirred under a nitrogen atmosphere at 100 °C for 12 h. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography to give 1-[5-bromo-6-[(1S)-1-methoxyethyl]-3-pyridyl]-4-(2,2,2-trifluoroethyl)piperazine (compound E2, 2.0 g) as a yellow oil. MS calculated 382.2 (MH + ), measured value 382.1 (MH + )

[0159] Step 2: 1-[6-[(1S)-1-Methoxyethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]-4-(2,2,2-trifluoroethyl)piperazine (compound P3). To a solution of 1-[5-bromo-6-[(1S)-1-methoxyethyl]-3-pyridyl]-4-(2,2,2-trifluoroethyl)piperazine (Compound P2, 3.2 g, 8.37 mmol), bis(pinacolato)diboron (3.19 g, 12.56 mmol), and KOAc (2.1 g, 20.93 mmol) in toluene (50 mL) was added Pd(dppf)Cl (306.3 mg, 0.42 mmol). The mixture was degassed and purged with nitrogen three times, and the mixture was stirred under a nitrogen atmosphere at 90 °C for 12 h. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated in vacuo to give a residue that was purified by reverse-phase column chromatography to give 1-[6-[(1S)-1-methoxyethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]-4-(2,2,2-trifluoroethyl)piperazine (Compound P3, 1.9 g) as a yellow gum. MS calculated 430.2 (MH + ), measured value 348.4 (M-C6H 10 +H + ).

[0160] Step 3: Preparation of [3-[5-bromo-6-fluoro-2-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-1H-indol-3-yl]-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (compound P4). To a solution of 1-[6-[(1S)-1-methoxyethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]-4-(2,2,2-trifluoroethyl)piperazine (compound P3, 1.9 g, 4.41 mmol), [3-(5-bromo-6-fluoro-2-iodo-1H-indol-3-yl)-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (compound M5, 2.1 g, 3.15 mmol) in 1,4-dioxane (24 mL), water (8 mL), and toluene (8 mL) was added KPO (2.1 g, 9.5 mmol) and Pd(dppf)Cl (231 mg, 0.37 mmol). The mixture was degassed by bubbling nitrogen through for 2 minutes, and the reaction mixture was stirred at 70°C for 12 hours. After cooling to room temperature, the reaction mixture was filtered. The filtrate was concentrated in vacuo to give a residue, which was purified by column chromatography (30%-60% EtOAc in PE) to give [3-[5-bromo-6-fluoro-2-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-1H-indol-3-yl]-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (compound P4, 960.0 mg) as a yellow gum. MS calculated 839.3 (MH + ), measured value 839.3 (MH + )

[0161] Step 4: Preparation of [3-[5-bromo-6-fluoro-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-1-(2,2,2-trifluoroethyl)indol-3-yl]-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (compound P5). To a solution of [3-[5-bromo-6-fluoro-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-1H-indol-3-yl]-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (compound P4, 1 g, 1.14 mmol) in DMF (35 mL) was added CsCO (1.1 g, 3.44 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (2.7 g, 11.63 mmol) at 0° C. After stirring at 20° C. for 15 h, the reaction mixture was poured into water (100 mL) and extracted with EtOAc (50 mL, 3 times). The combined organics were washed with brine (50 mL, 3 times), dried over Na2SO4, filtered, and concentrated in vacuo to give a residue that was purified by column chromatography (EtOAc in PE: 30%-40%) to give [3-[5-bromo-6-fluoro-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-1-(2,2,2-trifluoroethyl)indol-3-yl]-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (compound P5, 640.0 mg, 0.69 mmol) as a white solid. MS calculated 921.3 (MH + ), measured value 921.4 (MH + ).

[0162] Step 5: Preparation of 3-[5-bromo-6-fluoro-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-1-(2,2,2-trifluoroethyl)indol-3-yl]-2,2-dimethyl-propan-1-ol (compound P6). To a solution of [3-[5-bromo-6-fluoro-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-1-(2,2,2-trifluoroethyl)indol-3-yl]-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (compound P5, 640.0 mg, 0.69 mmol) in DMF (7 mL) was added cesium fluoride (421.8 mg, 2.78 mmol). The mixture was stirred at 60 °C for 16 hours. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated in vacuo to give a residue, which was purified by column chromatography (30%-60% EtOAc in PE) to give 3-[5-bromo-6-fluoro-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-1-(2,2,2-trifluoroethyl)indol-3-yl]-2,2-dimethyl-propan-1-ol (compound P6, 360.0 mg) as a yellow oil. MS calculated 683.2 (MH + ), measured value 683.1 (MH + ).

[0163] Step 6: Preparation of 3-[5-bromo-6-fluoro-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-1-(2,2,2-trifluoroethyl)indol-3-yl]-2,2-dimethyl-propan-1-ol (compound P7). To a solution of 3-[5-bromo-6-fluoro-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-1-(2,2,2-trifluoroethyl)indol-3-yl]-2,2-dimethyl-propan-1-ol (compound P6, 360.0 mg, 0.53 mmol), bis(pinacolato)diboron (200.6 mg, 0.79 mmol) in toluene (6 mL) was added potassium acetate (0.08 mL, 1.32 mmol) and Pd(dppf)Cl (40 mg, 0.1 mmol). The reaction mixture was degassed by bubbling nitrogen for 5 minutes and then stirred at 80 °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 that was purified by column chromatography (30% to 50% EtOAc in PE) to give 3-[5-bromo-6-fluoro-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-1-(2,2,2-trifluoroethyl)indol-3-yl]-2,2-dimethyl-propan-1-ol (compound P7, 300.0 mg) as a yellow gum. MS calculated 731.4 (MH + ), measured value 731.4 (MH + ).

[0164] 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-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-1-(2,2,2-trifluoroethyl)indol-5-yl]thiazol-2-yl]propanoyl]hexahydropyridazine-3-carboxylate (Compound P8). 3-[5-bromo-6-fluoro-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-1-(2,2,2-trifluoroethyl)indol-3-yl]-2,2-dimethyl-propan-1-ol (compound P7, 0.3 g, 0.41 mmol) and methyl (3S)-1-[(2S)-3-(4-bromothiazol- To a mixture of [(2-(tert-butoxycarbonyl-2-yl)-2-(tert-butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylate (Intermediate E, 196.7 mg, 0.41 mmol) in toluene (3 mL), 1,4-dioxane (1 mL), and water (1 mL) was added KPO (221.3 mg, 1.04 mmol) and Pd(dtbpf)Cl (27.05 mg, 0.04 mmol). The mixture was stirred at 70 °C under a nitrogen atmosphere for 12 h. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated in vacuo to give a residue that was purified by column chromatography (EtOAc in PE: 60% to 80%) to give methyl (3S)-1-[(2S)-2-(tert-butoxycarbonylamino)-3-[4-[6-fluoro-3-(3-hydroxy-2,2-dimethylpropyl)-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-1-(2,2,2-trifluoroethyl)indol-5-yl]thiazol-2-yl]propanoyl]hexahydropyridazine-3-carboxylate (compound P8, 200.0 mg) as a yellow gum. MS calculated 1001.4 (MH + ), measured value 1001.4 (MH + ).

[0165] 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-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-1-(2,2,2-trifluoroethyl)indol-5-yl]thiazol-2-yl]propanoyl]hexahydropyridazine-3-carboxylic acid (Compound P9). To a mixture 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-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-1-(2,2,2-trifluoroethyl)indol-5-yl]thiazol-2-yl]propanoyl]hexahydropyridazine-3-carboxylate (Compound P8, 200.0 mg, 0.2 mmol) in DCE (5 mL) was added MeSnOH (200.0 mg, 1.11 mmol). The mixture was stirred at 60 °C for 12 hours. The reaction mixture was concentrated in vacuo to give a residue. EtOAc (10 mL) and water (10 mL) were added to the residue, and the layers were separated. The aqueous phase was extracted with EtOAc (15 mL, 2 times). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo 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-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-1-(2,2,2-trifluoroethyl)indol-5-yl]thiazol-2-yl]propanoyl]hexahydropyridazine-3-carboxylic acid (Compound P9, 188.0 mg) as a brown solid. MS calculated value 987.4 (MH + ), measured value 987.4 (MH + ).

[0166] Step 9: tert-Butyl 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-tetraazapentacyclo[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]carbamate (compound P10). To a mixture of (3S)-1-[(2S)-2-(tert-butoxycarbonylamino)-3-[4-[6-fluoro-3-(3-hydroxy-2,2-dimethylpropyl)-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-1-(2,2,2-trifluoroethyl)indol-5-yl]thiazol-2-yl]propanoyl]hexahydropyridazine-3-carboxylic acid (Compound P9, 188.0 mg, 0.19 mmol) in DCM (20 mL) was added DIEA (0.7 mL, 3.81 mmol), EDCI (550.0 mg, 2.87 mmol), and HOBt (65.0 mg, 0.48 mmol) at 0 °C. After stirring at 20°C for 12 hours, the reaction mixture was poured into water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over NaSO, filtered, and concentrated in vacuo to give a residue, which was purified by column chromatography (50% to 70% EtOAc in PE) to give tert-butyl 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 .022,26 ]octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamate (compound P10, 110.0 mg) was obtained as a yellow solid. MS calculated 969.4 (MH + ), measured value 969.5 (MH + ).

[0167] Step 10: (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-tetraazapentacyclo[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 P). tert-Butyl 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-tetraazapentacyclo[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-hexaen-7-yl]carbamate (Compound P10, 110.0 mg, 0.11 mmol) was added TFA (1.0 mL, 12.98 mmol). The mixture was stirred at 20 °C for 1 hour. After the reaction was complete, the reaction mixture was concentrated in vacuo to give 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 in vacuo to give (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 P, 98.0 mg) was obtained as a yellow solid. MS calculated: 869.4 (MH + ), measured value 869.2 (MH + ).

[0168] Intermediate Q (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 [ka] [ka] [ka]

[0169] Step 1: Preparation of 4-[5-bromo-6-[(1S)-1-methoxyethyl]-3-pyridyl]morpholine (Compound Q1) To a mixture of 3-bromo-5-iodo-2-[(1S)-1-methoxyethyl]pyridine (Compound D2, 30 g, 87.73 mmol) and morpholine (7.6 g, 87.73 mmol) in toluene (450 mL) was added CsCO (57.2 g, 175.45 mmol), (R)-binap (2.7 g, 4.39 mmol), and Pd(OAc) (0.98 g, 4.39 mmol). The reaction mixture was degassed and purged with nitrogen three times, and the mixture was stirred at 90 °C under a nitrogen atmosphere for 12 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 4-[5-bromo-6-[(1S)-1-methoxyethyl]-3-pyridyl]morpholine (Compound Q1, 21 g) as a yellow oil. MS calculated value 301.1 (MH + ), measured value 301.1 (MH + ).

[0170] 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 Q2) To a solution of 4-[5-bromo-6-[(1S)-1-methoxyethyl]-3-pyridyl]morpholine (Compound Q1, 21 g, 63.3 mmol), bis(pinacolato)diboron (24.0 g, 94.63 mmol), and KOAc (13.6 g, 138.79 mmol) in toluene (500 mL) was added Pd(dppf)Cl (4.4 g, 6.31 mmol). The mixture was degassed and purged with nitrogen three times, and the mixture was stirred under a nitrogen atmosphere at 90 °C for 12 h. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give the crude product 4-[6-[(1S)-1-methoxyethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]morpholine (compound Q2, 45 g) as a yellow gum, which was used in the next step without further purification. MS calculated 349.2 (MH + ), measured value 349.2 (MH + ).

[0171] 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 Q3) To a solution of 4-[6-[(1S)-1-methoxyethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]morpholine (Compound Q2, 40.6 g, 46.65 mmol), [3-(5-bromo-6-fluoro-2-iodo-1H-indol-3-yl)-2,2-dimethylpropoxy]-tert-butyl-diphenyl-silane (Compound M5, 31 g, 46.65 mmol) in 1,4-dioxane (420 mL) and water (80 mL) was added KPO (29.7 g, 2.33 mmol) and Pd(dppf)Cl (1.7 g, 0.29 mmol). The mixture was degassed by bubbling nitrogen through for 2 minutes, and the reaction mixture was stirred at 90 °C for 18 hours. After cooling to room temperature, the reaction mixture was extracted with EA (200 mL, 3 times). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography to give [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 Q3, 17.2 g) as a yellow oil. MS calculated 758.3 (MH + ), measured value 758.3 (MH + ).

[0172] Step 4: 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 Q4) To a solution 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 Q3, 15 g, 19.77 mmol) in DMF (300 mL) was added CsCO (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 x 3). The combined organic layers were washed with brine (10 mL, 3 times), dried over NaSO, filtered, and concentrated in vacuo to give a residue that was purified by column chromatography to give [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 Q4, 14.7 g) as a yellow oil. MS calculated 786.3 (MH + ), measured value 786.4 (MH + ).

[0173] Step 5: 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 Q5) 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 Q6) 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-propoxy]-tert-butyl-diphenyl-silane (compound Q4, 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 Na SO , filtered, and concentrated in vacuo to give a residue. The residue was purified by column chromatography to give 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 Q5, 6 g, fast elution) 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 Q6, 4.5 g, slow elution) as a colorless foam. Compound Q5: MS calculated 548.2 (MH + ), measured value 548.2 (MH + ). 1 H NMR(400MHz,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).

[0174] X-ray crystallography of compound Q5 The absolute configuration of compound Q5 was confirmed by single-crystal X-ray crystallography (Figure 2).

[0175] Step 6: 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 Q7) 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 Q5, 6 g, 10.94 mmol), bis(pinacolato)diboron (4.2 g, 16.41 mmol) in toluene (60 mL) was added potassium acetate (2.7 g, 27.35 mmol) and Pd(dppf)Cl (0.8 g, 1.09 mmol). The reaction mixture was degassed by bubbling nitrogen through 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 which 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 Q7, 4.5 g) as a colorless gum. MS calculated 596.4 (MH + ), measured value 596.4 (MH + ).

[0176] Step 7: 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 Q8) 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 Q7, 4.5 g, 7.56 mmol) and methyl (3S)-1-[(2S)-3-(4-bromothiazole To a mixture of [(2-(tert-butoxycarbonylamino)propanoyl)hexahydropyridazine-3-carboxylate (Intermediate E, 3.6 g, 7.56 mmol) in toluene (45 mL), 1,4-dioxane (15 mL), and water (15 mL) was added KPO (4.0 g, 18.89 mmol) and Pd(dtbpf)Cl (492.5 mg, 0.75 mmol). The mixture was stirred at 70 °C under a nitrogen atmosphere for 12 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 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 Q8, 3.8 g) as a colorless gum. MS calculated 866.4 (MH + ), measured value 866.4 (MH + ).

[0177] Step 8: 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 Q9) To a mixture 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 Q8, 3.8 g, 4.39 mmol) in DCE (76 mL) was added MeSnOH (3.2 g, 17.55 mmol). The mixture was stirred at 60 °C for 48 h. The reaction mixture was concentrated in vacuo 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 phase was washed with brine (200 mL), dried over NaSO, filtered, and concentrated in vacuo 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 Q9, 3.7 g) as a brown solid. MS calculated 852.4 (MH + ), measured value 852.4 (MH + ).

[0178] Step 9: 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-tetraazapentacyclo[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]carbamate (compound Q10) To a mixture 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 Q9, 2.5 g, 2.93 mmol) in DCM (250 mL) was added DIEA (7.58 ml, 58.68 mmol), EDCI (8.4 g, 44.01 mmol) and HOBt (991.2 mg, 0.91 mmol) at 0° C. After stirring at 20° C. for 12 hours, the reaction mixture was poured into water (100 mL) and extracted with EtOAc (100 mL, 3×). The combined organic layers were washed with brine (30 mL), dried over NaSO, filtered, and concentrated in vacuo to give a residue that 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-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]carbamate (compound Q10, 1.2 g) was obtained as a yellow oil. MS calculated 834.4 (MH + ), measured value 834.4 (MH + ).

[0179] Step 10: (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 ]Preparation of octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (intermediate Q) 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-tetraazapentacyclo[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 Q10, 1.2 g, 1.44 mmol) was added TFA (6.0 mL). The mixture was stirred at 20 °C for 3 hours. After the reaction was complete, the reaction mixture was concentrated in vacuo to give 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-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 Q, 1 g) was obtained as a yellow solid. MS calculated 734.3 (MH + ), measured value 734.3 (MH+ ).

[0180] Example 1 N-[(1S)-1-[[(8S,14S)-22-ethyl-4-hydroxy-(21M)-21-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-18,18-dimethyl-9,15-dioxo-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-3-[(E)-2-methylsulfonylvinyl]cyclobutanecarboxamide; [ka] This compound was prepared according to the following scheme. [ka]

[0181] Step 1: Preparation of tert-butyl (2S)-2-[[3-(methoxymethylene)cyclobutanecarbonyl]-methyl-amino]-3-methyl-butanoate (Compound 1B) To a solution of 3-(methoxymethylene)cyclobutanecarboxylic acid (compound 1A, 200.0 mg, 1.41 mmol) in DMF (5 mL) was added HATU (641.9 mg, 1.69 mmol) and DIEA (272.7 mg, 2.11 mmol) at 0 °C. After stirring at 0 °C for 20 minutes, tert-butyl (2S)-3-methyl-2-(methylamino)butanoate (316.2 mg, 1.69 mmol) was added to the reaction mixture, which was then stirred at 25 °C for an additional 1.5 hours. After the reaction was complete, the reaction mixture was purified by reverse-phase column chromatography to give tert-butyl (2S)-2-[[3-(methoxymethylene)cyclobutanecarbonyl]-methyl-amino]-3-methyl-butanoate (compound 1B, 210.0 mg) as a colorless oil. MS calculated 312.2 (MH +), measured value 312.2 (MH + ).

[0182] Step 2: Preparation of tert-butyl (2S)-2-[(3-formylcyclobutanecarbonyl)-methyl-amino]-3-methyl-butanoate (Compound 1C) To a solution of tert-butyl (2s)-2-[[3-(methoxymethylene)cyclobutanecarbonyl]-methyl-amino]-3-methyl-butanoate (Compound 1B, 200.0 mg, 0.64 mmol) in DCM (15 mL) and water (1.5 mL) was added TFA (0.5 mL) dropwise at 0° C. The reaction mixture was stirred at 25° C. for 2.5 hours. After the reaction was complete, it was concentrated in vacuo, and then EtOAc (20 mL) and water (20 mL) were added, and the layers were separated. The aqueous phase was extracted with EtOAc (10 mL, twice). The combined organic layers were washed with brine (10 mL), dried over NaSO, filtered, and concentrated in vacuo to give tert-butyl (2S)-2-[(3-formylcyclobutanecarbonyl)-methyl-amino]-3-methyl-butanoate (Compound 1C, 130.0 mg) as a colorless oil, which was used directly in the next step. MS calculated 298.2 (MH + ), measured value 320.3, (MNa + ).

[0183] Step 3: Preparation of tert-butyl (2S)-3-methyl-2-[methyl-[3-[(E)-2-methylsulfonylvinyl]cyclobutanecarbonyl]amino]butanoate (Compound 1E) A solution of diethyl methylsulfonylmethylphosphonate (Compound 1D, 77.4 mg, 0.34 mmol) in THF (2 mL) was added to a suspension of NaH (20.2 mg, 0.5 mmol) in THF (3 mL) at 0° C. After stirring at 0° C. for 0.5 h, tert-butyl (2S)-2-[(3-formylcyclobutanecarbonyl)-methyl-amino]-3-methyl-butanoate (Compound 1C, 100.0 mg, 0.34 mmol) was added to the reaction mixture and stirred at room temperature for 4 h. After the reaction was complete, the reaction mixture was extracted with EtOAc (20 mL, twice). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was purified by reverse-phase column chromatography to give tert-butyl (2S)-3-methyl-2-[methyl-[3-[(E)-2-methylsulfonylvinyl]-cyclobutanecarbonyl]amino]butanoate (compound 1E, 90 mg) as a yellow oil. MS calculated 374.2 (MH + ), measured value 374.3 (MH + ).

[0184] Step 4: Preparation of (2S)-3-methyl-2-[methyl-[3-[(E)-2-methylsulfonylvinyl]cyclobutanecarbonyl]amino]butanoic acid (Compound 1F) To a solution of tert-butyl (2S)-3-methyl-2-[methyl-[3-[(E)-2-methylsulfonylvinyl]cyclobutanecarbonyl]amino]butanoate (Compound 1E, 90 mg, 0.24 mmol) in DCM (2 mL) was added TFA (3.0 mL) at 0° C. After stirring at 25° C. for 1 hour, the reaction mixture was concentrated in vacuo to give a residue, which was purified by reverse-phase column chromatography to give (2S)-3-methyl-2-[methyl-[3-[(E)-2-methylsulfonylvinyl]cyclobutanecarbonyl]amino]butanoic acid (Compound 1F, 70.0 mg) as a yellow oil. MS calculated 318.2 (MH + ), measured value 318.2 (MH + ).

[0185] Step 5: N-[(1S)-1-[[(8S,14S)-22-ethyl-4-hydroxy-(21M)-21-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-18,18-dimethyl-9,15-dioxo-16-oxa-10,22,28-triazapentacyclo[18.5.2.1 2,6 .1 10,14 .0 23,27 Preparation of ]nonacosa-1(26),2,4,6(29),20,23(27),24-heptaen-8-yl]carbamoyl]-2-methyl-propyl]-N-methyl-3-[(E)-2-methylsulfonylvinyl]cyclobutanecarboxamide (Example 1) To a solution of (2S)-3-methyl-2-[methyl-[3-[(E)-2-methylsulfonylvinyl]cyclobutanecarbonyl]amino]butanoic acid (Compound 1F, 17.8 mg, 0.06 mmol) in DCM (3 mL) was added HATU (26.7 mg, 0.07 mmol) and DIPEA (18.2 mg, 0.14 mmol). After stirring for 10 min, the reaction mixture was converted to (8S,14S)-8-amino-22-ethyl-4-hydroxy-(21M)-21-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-18,18-dimethyl-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 C, 30.0 mg, 0.05 mmol) was added. After stirring at 25 °C for 2 h, the reaction mixture was purified by preparative HPLC to give N-[(1S)-1-[[(8S,14S)-22-ethyl-4-hydroxy-(21M)-21-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-18,18-dimethyl-9,15-dioxo-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-3-[(E)-2-methylsulfonylvinyl]cyclobutanecarboxamide (Example 1, 15.6 mg) was obtained as a yellow solid. MS calculated 939.5 (MH + ), measured value 939.5 (MH + ). 1 H NMR(400 MHz,METHANOL-d4)δ=8.84-8.53(m,1H), 8.28-8.21(m,1H), 8.17-8.10(m,1H), 8.09 -7.98(m,1H), 7.76-7.68(m,1H), 7.57-7.48(m,1H), 7.39-7.30(m,1H), 7.12-6.92(m ,1H), 6.65-6.52(m,1H), 5.64-5.07(m,1H), 4.68-4.57(m,1H), 4.50-4.31(m,2H), 4 .29-4.14(m,1H), 4.05-3.84(m,1H), 3.86-3.62(m,1H), 3.79-3.67(m,1H), 3.65-3.5 4(m,1H), 3.30-3.12(m,2H), 3.09-2.97(m,7H), 2.94-2.83(m,2H), 2.82-2.70(m,1H ), 2.68-2.60(m,1H), 2.58-2.51(m,1H), 2.50-2.39(m,1H), 2.37-2.06(m,4H), 1.88- 1.74(m,1H), 1.61-1.51(m,2H), 1.51-1.41(m,4H), 1.34-1.20(m,1H), 1.17-1.01(m, 4H), 0.94-0.86(m,1H), 0.86-0.79(m,6H), 0.78-0.71(m,4H), 0.71-0.59(m,3H)ppm.

[0186] Example 2 N-[(1S)-1-[[(8S,14S)-22-ethyl-(21M)-21-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-18,18-dimethyl-9,15-dioxo-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-3-[(E)-2-methylsulfonylvinyl]cyclobutanecarboxamide [ka] Analogously to the preparation of Example 1, (8S,14S)-8-amino-22-ethyl-4-hydroxy-(21M)-21-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-18,18-dimethyl-16-oxa-10,22,28-triazapentacyclo[18.5.2.1 2,6 .1 10,14 .0 23,27 ] Instead of nonacosa-1(26),2,4,6(29),20,23(27),24-heptaene-9,15-dione (intermediate C), (8S,14S)-8-amino-22-ethyl-(21M)-21-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-18,18-dimethyl-16-oxa-10,22,28-triazapentacyclo[18.5.2.1 2,6 .1 10,14 .0 23,27 The title compound was prepared by using nonacosa-1(26),2,4,6(29),20,23(27),24-heptaene-9,15-dione (Intermediate J). Example 2 (6.4 mg) was obtained as a yellow solid. MS calculated 923.5 (MH + ), measured value 923.5 (MH + ). 1H NMR(400MHz,Methanol-d4)δ=8.84-8.76(m,1H), 8.28-8.21(m,1H), 8.17-8.09(m, 1H), 8.09-8.04(m,1H), 7.98-7.91(m,1H), 7.76-7.68(m,2H), ,7.59-7.51(m,1H), 7 .37-7.25(m,1H), 7.13-7.05(m,1H), 7.00-6.92(m,1H), 6.69-6.55(m,1H), 5.65-5 .52(m,1H), 4.38-4.17(m,1H), 4.09-3.88(m,1H), 3.86-3.62(m,3H), 3.27-3.24(m, 3H), 3.23-3.17(m,2H), 3.15-3.11(m,1H), 2.96-2.93(m,1H), 2.92-2.86(m,2H), 2 .86-2.83(m,1H), 2.81-2.75(m,2H), 2.74-2.63(m,2H), 2.55-2.41(m,2H), 2.20-2. 02(m,3H), 1.97-1.86(m,1H), 1.78-1.54(m,2H), 1.51-1.41(m,4H), 1.34-1.25(m,1 H), 1.16-1.01(m,4H), 0.98-0.86(m,3H), 0.86-0.75(m,8H), 0.73-0.58(m,4H)ppm.

[0187] Example 3 trans-N-[(1S)-1-[[(8S,14S)-22-ethyl-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-18,18-dimethyl-9,15-dioxo-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-3-[(E)-2-methylsulfonylvinyl]cyclobutanecarboxamide [ka] Analogously to the preparation of Example 1, (8S,14S)-8-amino-22-ethyl-4-hydroxy-(21M)-21-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-18,18-dimethyl-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 C) and tert-butyl(2S)-2-[(3-formylcyclobutanecarbonyl)-methyl-amino]-3-methyl-butanoate (compound 1C), (8S,14S)-8-amino-22-ethyl-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-18,18-dimethyl-16-oxa-10,22,28-triazapentacyclo[18.5.2.1 2,6 .1 10,14 .0 23,27 The title compound was prepared by using ]-nonacosa-1(26),2,4,6(29),20,23(27),24-heptaene-9,15-dione (Intermediate I) and trans-tert-butyl (2S)-2-[(3-formylcyclobutanecarbonyl)-methyl-amino]-3-methyl-butanoate (Compound 3D). Example 3 (6.0 mg) was obtained as a white solid. MS calculated 1021.6 (MH + ), measured value 1021.7(MH + ). 1H NMR(400MHz,Methanol-d4)δ=8.49(d,J=2.8Hz,1H), 8.06-7.97(m,2H), 7.90(s, 1H), 7.69-7.65(m,1H), 7.63-7.57(m,2H), 7.55-7.52(m,1H), 7.34-7.28(m,1H) , 7.20-7.14(m,1H), 6.98-6.58(m,1H), 5.78-5.98(m,1H), 4.30-4.17(m,2H), 4. 12-4.01(m,2H), 3.81-3.77(m,1H), 3.69-3.57(m,5H), 3.50-3.37(m,2H), 3.24- 3.15(m,5H), 3.02-3.00(m,4H), 2.99-2.97(m,3H), 2.94-2.85(m,5H), 2.83(s,1) H), 2.79-2.71(m,2H), 2.53-2.47(m,1H), 2.38-2.21(m,2H), 2.16-2.07(m,2H), 1.93-1.87(m,1H), 1.68-1.54(m,2H), 1.45(d,J=6.4Hz,3H), 1.32-1.26(m,1H), 1.20-1.16(m,2H), 1.13-1.07(m,3H), 0.86-0.79(m,9H), 0.75-0.66(m,4H)ppm.

[0188] Compound 3D was prepared according to the following scheme: [ka]

[0189] Step 1: Preparation of methyl trans-methyl 3-[[(1S)-1-tert-butoxycarbonyl-2-methyl-propyl]-methyl-carbamoyl]cyclobutanecarboxylate (Compound 3B) To a mixture of trans-3-methoxycarbonylcyclobutanecarboxylic acid (compound 3A, 5.0 g, 31.62 mmol) in DMF (80 mL) was added DIEA (13.7 mL, 79.04 mmol) and HATU (14.4 g, 37.94 mmol) at 0 °C. After stirring at room temperature for 0.5 h, tert-butyl (2S)-3-methyl-2-(methylamino)butanoate (5.9 g, 31.62 mmol) was added to the reaction. The reaction mixture was stirred at 20 °C for 1 h. After the reaction was complete, the reaction mixture was diluted with water (80 mL) and extracted with EtOAc (80 mL, 3 times). The combined organic layers were washed with brine (150 mL, 3 times), dried over Na SO , filtered, and concentrated in vacuo. The residue was purified by column chromatography (10% to 25% EtOAc in PE) to give trans-methyl 3-[[(1S)-1-tert-butoxycarbonyl-2-methyl-propyl]-methyl-carbamoyl]cyclobutanecarboxylate (compound 3B, 10.0 g) as a yellow oil. MS calculated 328.2 (MH + ), measured value 328.3 (MH + ).

[0190] Step 2: Preparation of trans-tert-butyl (2S)-2-[[3-(hydroxymethyl)cyclobutanecarbonyl]-methyl-amino]-3-methyl-butanoate (Compound 3C) To a mixture of trans-methyl 3-[[(1S)-1-tert-butoxycarbonyl-2-methyl-propyl]-methyl-carbamoyl]cyclobutanecarboxylate (Compound 3B, 10.0 g, 30.54 mmol) in THF (100 mL) under a nitrogen atmosphere was added lithium borohydride (20.0 mL, 4 M in THF, 80.0 mmol) dropwise at 0° C. After stirring at room temperature for 48 h, the reaction was quenched with HO (300 mL) and extracted with EtOAc (300 mL, 2 times). The combined organic layers were washed with brine (300 mL), dried over NaSO, filtered, and concentrated in vacuo to give trans-tert-butyl (2S)-2-[[3-(hydroxymethyl)cyclobutanecarbonyl]-methyl-amino]-3-methyl-butanoate (compound 3C, 8.0 g, 26.72 mmol) as a colorless oil. MS calculated 300.2 (MH + ), measured value 300.3 (MH + ).

[0191] Step 3: Preparation of trans-tert-butyl (2S)-2-[(3-formylcyclobutanecarbonyl)-methyl-amino]-3-methyl-butanoate (Compound 3D) To a mixture of trans-tert-butyl (2S)-2-[[3-(hydroxymethyl)cyclobutanecarbonyl]-methyl-amino]-3-methyl-butanoate (Compound 3C, 7.0 g, 23.38 mmol) in DCM (100 mL) was added DMP (19.8 g, 46.76 mmol) at 0 °C. After stirring at 20 °C for 2 h, the mixture was concentrated in vacuo to give a residue, which was purified by column chromatography (5% to 10% EtOAc in PE) to give trans-tert-butyl (2S)-2-[(3-formylcyclobutanecarbonyl)-methyl-amino]-3-methyl-butanoate (Compound 3D, 6.8 g) as a yellow oil. MS calculated 298.2 (MH + ), measured value 298.2 (MH + ); 1H NMR(400 MHz,CDCl3)δ=9.85(dd,J=6,0.8 Hz,1H), 4.86-4.77(m,0.5H), 3.62-3.53(m,0.5H), 3.50-3.09(m,2H), 2.97-2.82(m,3H), 2.71-2.42(m,4H), 2.26-2.17(m,1H), 1.45(s,9H), 1.05-0.97(m,3H), 0.89-0.81(m,3H).

[0192] Example 4 trans-N-[(1S)-1-[[(8S,14S)-22-ethyl-4-hydroxy-(21M)-21-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-18,18-dimethyl-9,15-dioxo-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-3-[(E)-2-methylsulfonylvinyl]cyclobutanecarboxamide [ka] The title compound was prepared in a manner similar to that of Example 1, except that trans-tert-butyl (2S)-2-[(3-formylcyclobutanecarbonyl)-methyl-amino]-3-methyl-butanoate (Compound 3D) was used instead of tert-butyl (2S)-2-[(3-formylcyclobutanecarbonyl)-methyl-amino]-3-methyl-butanoate (Compound 1C). Example 4 (5.1 mg) was obtained as a yellow solid. MS calculated 939.5 (MH + ), measured value 939.7 (MH + ).

[0193] Example 5 trans-N-[(1S)-1-[[(7S,13S)-21-ethyl-(20M)-20-[2-[(1S)-1-methoxyethyl]-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-3-[(E)-2-methylsulfonylvinyl]cyclobutanecarboxamide [ka] Analogously to the preparation of Example 1, (8S,14S)-8-amino-22-ethyl-4-hydroxy-(21M)-21-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-18,18-dimethyl-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 C) and tert-butyl(2S)-2-[(3-formylcyclobutanecarbonyl)-methyl-amino]-3-methyl-butanoate (compound 1C), (7S,13S)-7-amino-21-ethyl-(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 .1 9,13 .0 22,26 The title compound was prepared by using octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate H) and trans-tert-butyl (2S)-2-[(3-formylcyclobutanecarbonyl)-methyl-amino]-3-methyl-butanoate (Compound 3D). Example 5 (115.8 mg) was obtained as a yellow solid. MS calculated 930.4 (MH +), measured value 930.4 (MH + ). 1 H NMR(400MHz,Methanol-d4)δ=8.82(dd,J=5.2,1.6 Hz,1H), 8.60(s,1H), 8.21-8.16(m,1H), 7.80-7.72(m,2H), 7.58-7.50(m,2H), 7.20-7.03(m,1H), 6.70-6.60(m,1 H), 5.94-5.72(m,1H), 4.84-4.76(m,1H), 4.52-4.45(m,1H), 4.44-4.30(m,2H), 4.25-4.18(m,1H), 4.11-4.02(m,1 H), 3.73(s,2H), 3.53-3.27(m,5H), 3.30-3.20(m,2H), 3.11-3.03(m,1H), 3.03-2.95(m,4H), 2.91(s,1H), 2.84(s, 1H), 2.81-2.57(m,4H), 2.35-2.15(m,4H), 1.97-1.90(m,1H), 1.83-1.72(m,1H), 1.66-1.56(m,1H), 1.47(d,J=6.0 Hz,3H), 1.04-0.92(m,9H), 0.89-0.83(m,3H), 0.52(s,3H)ppm.

[0194] Example 6 N-[(1S)-1-[[(7S,13S)-21-ethyl-(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-3-[(E)-2-methylsulfonylvinyl]cyclobutanecarboxamide [ka] Analogously to the preparation of Example 1, (8S,14S)-8-amino-22-ethyl-4-hydroxy-(21M)-21-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-18,18-dimethyl-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 C), instead of (7S,13S)-7-amino-21-ethyl-(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 The title compound was prepared by using octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate G). Example 6 (66.8 mg) was obtained as a yellow solid. MS calculated 1028.5 (MH + ), measured value 1028.7(MH + ). 1H NMR(400MHz,Methanol-d4)δ=8.60-8.54(m,1H), 8.48(d,J=2.8 Hz,1H), 7.74-7.69(m,1H), 7.65-7.60(m,1H), 7.58-7.46(m,2H), 7.17-7.06(m,0.5H), 6.69-6.60(m,0.5H), 5. 79-5.65(m,1H), 4.82-4.75(m,1H), 4.45-4.37(m,1H), 4.36-4.19(m,3H), 4.18-3.84(m,3H), 3.78-3.68(m,3H), 3.63-3.38(m,5H), 3.38-3.34(m,3H), 3.30-3.20(m,6H), 3.14-3.06(m,2H), 3.03-2.90(m,9H), 2.83-2.75(m,1H) ), 2.66-2.52(m,2H), 2.33-2.14(m,3H), 1.99-1.89(m,1H), 1.84-1.72(m,1H), 1.69-1.54(m,1H), 1.43(d,J=6.0 Hz,3H), 1.12-0.89(m,9H), 0.89-0.79(m,3H), 0.56-0.41(m,3H)ppm.

[0195] Example 7 N-[(1S)-1-[[(7S,13S)-(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-3-[(E)-2-methylsulfonylvinyl]cyclobutanecarboxamide [ka] Analogously to the preparation of Example 1, (8S,14S)-8-amino-22-ethyl-4-hydroxy-(21M)-21-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-18,18-dimethyl-16-oxa-10,22,28-triazapentacyclo[18.5.2.1 2,6 .1 10,14 .0 23,27 ] Instead of nonacosa-1(26),2,4,6(29),20,23(27),24-heptaene-9,15-dione (intermediate C), (7S,13S)-7-amino-21-ethyl-(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 The title compound was prepared by using octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate L). Example 7 (25.7 mg) was obtained as an off-white solid. MS calculated 1082.5 (MH + ), measured value 1082.7(MH + ). 1H NMR(400MHz,Methanol-d4)δ=8.61-8.56(m,1H), 8.52-8.47(m,1H), 7.80-7.73(m,1H), 7.66-7.56(m,2H), 7.54-7.49(m,1H), 7.16- 7.05(m,0.5H), 6.69-6.62(m,0.5H), 5.74-5.62(m,1H), 4.82-4.77(m,1H), 4.45-4.37(m,1H), 4.29-4.19(m,2H), 4.02-3.91(m,1H) , 3.78-3.71(m,3H), 3.71-3.67(m,3H), 3.63-3.41(m,5H), 3.36-3.34(m,3H), 3.20-3.03(m,5H), 3.00-2.97(m,5H), 2.95-2.90(m,4 H), 2.83-2.77(m,1H), 2.66-2.51(m,2H), 2.29-2.19(m,3H), 2.01-1.89(m,1H), 1.88-1.75(m,1H), 1.69-1.55(m,1H), 1.44(d,J=6.4 Hz,3H), 1.01-0.96(m,7H), 0.90-0.83(m,5H), 0.42(s,3H)ppm.

[0196] Example 8 N-[(1S)-1-[[(8S,14S)-22-ethyl-4-hydroxy-(21M)-21-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-18,18-dimethyl-9,15-dioxo-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-3-[(E)-2-methylsulfonylvinyl]azetidine-1-carboxamide [ka] The title compound was prepared in a similar manner to the preparation of Example 1, except that tert-butyl (2S)-3-methyl-2-[methyl-[3-[(E)-2-methylsulfonylvinyl]azetidine-1-carbonyl]amino]butanoate (Compound 8D) was used instead of tert-butyl (2S)-2-[(3-formylcyclobutanecarbonyl)-methyl-amino]-3-methyl-butanoate (Compound 1C). Example 8 (12.5 mg) was obtained as a yellow solid. MS calculated 940.5 (MH + ), measured value 940.5 (MH + ). 1 H NMR(400MHz,Methanol-d4)δ=8.79(d,J=3.2Hz,1H), 8.15-8.09(m,1H), 8.07-7.98(m,1H), 7.73-7.67(m,1H), 7.65-7 .57(m,1H), 7.54-7.51(m,1H), 7.44-7.36(m,1H), 7.18-7.09(m,1H), 7.08-7.01(m,1H), 6.82-6.72(m,1H), 6.63-6.53 (m,1H), 5.69-5.59(m,1H), 4.52-4.39(m,1H), 4.36-4.27(m,3H), 4.21(d,J=11.2Hz,1H), 4.05-3.85(m,3H), 3.81-3.7 5(m,1H), 3.72-3.66(m,1H), 3.58-3.50(m,1H), 3.27(d,J=2.8Hz,3H), 3.03-2.97(m,4H), 2.97-2.93(m,1H), 2.77(s,2) h)2.68(s,2H), 2.16-2.05(m,2H), 1.94-1.85(m,1H), 1.61(d,J=7.2Hz,1H), 1.48-1.45(m,4H), 1.35-1.28(m,4H), 1.07(t,J=6.4Hz,3H), 0.94-0.89(m,3H), 0.88-0.83(m,6H), 0.69(s,3H)ppm.

[0197] Compound 8D was prepared according to the following scheme: [ka]

[0198] Step 1: Preparation of tert-butyl 3-[(E)-2-methylsulfonylvinyl]azetidine-1-carboxylate (Compound 8B) To a solution of diethyl methylsulfonylmethylphosphonate (683.6 mg, 2.97 mmol) in THF (10 mL) was added sodium hydride (215.9 mg, 5.4 mmol, 60% in mineral oil) at 0° C. under a nitrogen atmosphere. After stirring at 0° C. for 10 minutes, tert-butyl 3-formylazetidine-1-carboxylate (compound 8A, 500.0 mg, 2.7 mmol) was added to the reaction mixture. The reaction mixture was stirred at 0° C. for an additional 0.5 hours. After the reaction was complete, it was quenched with water (50 mL) and extracted with EtOAc (50 mL, twice). The combined organic layers were washed with brine (80 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography (25% to 50% EtOAc in PE) to give tert-butyl 3-[(E)-2-methylsulfonylvinyl]azetidine-1-carboxylate (compound 8B, 500.0 mg) as a colorless oil. MS calculated 262.1 (MH + ), measured value 205.7 (M-C4H9+H + )

[0199] Step 2: Preparation of 3-[(E)-2-methylsulfonylvinyl]azetidine (Compound 8C) To a solution of tert-butyl 3-[(E)-2-methylsulfonylvinyl]azetidine-1-carboxylate (compound 8B, 450.0 mg, 1.72 mmol) in DCM (10 mL) was added TFA (4 mL). The reaction mixture was stirred at 20° C. for 0.5 h. After completion of the reaction, the reaction mixture was concentrated in vacuo to give 3-[(E)-2-methylsulfonylvinyl]azetidine; 2,2,2-trifluoroacetic acid (compound 8C, 550.0 mg, crude) as a yellow gum. MS calculated 162.1 (MH + ), measured value 162.1 (MH + ).

[0200] Step 3: Preparation of tert-butyl (2S)-3-methyl-2-[methyl-[3-[(E)-2-methylsulfonylvinyl]azetidine-1-carbonyl]amino]butanoate (Compound 8D) To a solution of tert-butyl (2S)-3-methyl-2-(methylamino)butanoate (680.4 mg, 3.63 mmol) in DCM (10 mL) was added DIEA (593.6 mg, 4.59 mmol) and triphosgene (400.0 mg, 1.35 mmol) at 0° C. After stirring at 0° C. for 0.5 h, a mixture of 3-[(E)-2-methylsulfonylvinyl]azetidine (compound 8C, 1.0 g, 3.63 mmol, TFA salt) and DIEA (1.3 g, 10.33 mmol) in DCM (10 mL) was added at 0° C. After stirring at 20°C for an additional hour, the reaction was quenched with saturated NaHCO3 (30 mL), extracted with DCM (10 mL, 2 times), washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give a residue. The residue was purified by column chromatography (EtOAc in PE: 9%, -16%) to give tert-butyl (2S)-3-methyl-2-[methyl-[3-[(E)-2-methylsulfonylvinyl]azetidine-1-carbonyl]amino]butanoate (compound 8D, 380.0 mg) as a colorless oil. MS calculated 375.2 (MH + ), measured value 375.2 (MH + ).

[0201] Example 9 N-[(1S)-1-[[(8S,14S)-22-ethyl-4-hydroxy-(21M)-21-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-18,18-dimethyl-9,15-dioxo-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-4-[(E)-2-methylsulfonylvinyl]piperazine-1-carboxamide [ka] The title compound was prepared in a similar manner to the preparation of Example 1, except that tert-butyl (2S)-3-methyl-2-[methyl-[4-[(E)-2-methylsulfonylvinyl]piperidine-1-carbonyl]amino]butanoate (Compound 9D) was used instead of tert-butyl (2S)-2-[(3-formylcyclobutanecarbonyl)-methyl-amino]-3-methyl-butanoate (Compound 1C). Example 10 (1.3 mg) was obtained as a yellow solid. MS calculated 968.5 (MH + ), measured value 968.5 (MH + ). 1 H NMR(400MHz,Methanol-d4)δ=8.74(d,J=4.0Hz,1H), 8.05-7.98(m,1H), 7.90(d,J=8.0Hz,1H), 7.62-7.36(m,6H), 7.06-7.02(m,1H), 6.92-6.85(m, 1H), 6.66-6.61(m,1H), 6.49-6.42(m,1H), 5.71-5.61(m,1H), 4.59(s,2H) ), 4.49-4.42(m,1H), 4.33-4.20(m,2H), 4.07-4.00(m,1H), 3.95-3.91(m, 1H), 3.84-3.75(m,3H), 3.24-3.20(m,3H), 3.02-2.98(m,3H), 2.95-2.85 (m,2H), 2.82-2.76(m,2H), 2.70-2.66(m,2H), 2.15-2.11(m,1H), 1.91-1. 82(m,3H), 1.71-1.56(m,4H), 1.46(d,J=6.0Hz,3H), 1.33-1.28(m,3H), 1. 09-1.03(m,4H), 0.92-0.86(m,6H), 0.84-0.80(m,3H), 0.70-0.61(m,3H).

[0202] Compound 9D was prepared similarly to the preparation of compound 8D by substituting tert-butyl 4-formylpiperidine-1-carboxylate (compound 9A) for tert-butyl 3-formylazetidine-1-carboxylate (compound 8A).

[0203] Example 10 trans-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-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-3-[(E)-2-methylsulfonylvinyl]cyclobutanecarboxamide [ka] Analogously to the preparation of Example 1, (8S,14S)-8-amino-22-ethyl-4-hydroxy-(21M)-21-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-18,18-dimethyl-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 C) and tert-butyl(2S)-2-[(3-formylcyclobutanecarbonyl)-methyl-amino]-3-methyl-butanoate (compound 1C), (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-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 octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate K) and trans-tert-butyl (2S)-2-[(3-formylcyclobutanecarbonyl)-methyl-amino]-3-methyl-butanoate (Compound 3D). Example 10 (45.9 mg) was obtained as an off-white solid. MS calculated 984.4 (MH + ), measured value 984.4 (MH + ). 1 H NMR(400MHz,Methanol-d4)δ=8.83(dd,J=4.8,1.2 Hz,1H), 8.62(s,1H), 8.11(d,J=7.2 Hz,1H), 7.83-7.71(m,2H), 7.67-7.53(m,2H), 7.16-7.05(m,1H), 6.76-6.56(m,1H), 5.81-5.64(m,1H), 5.29-5.14(m,1 H), 4.86-4.73(m,2H), 4.48-4.32(m,2H), 4.30-4.18(m,1H), 3.83-3.69(m,2H), 3.63-3.46(m,1H), 3.46-3.36(m,4H), 3. 30-3.20(m,2H), 3.17-3.07(m,1H), 3.03-2.99(m,3H), 2.98-2.92(m,1H), 2.92-2.89(m,2H), 2.87-2.72(m,1H), 2.70-2. 59(m,2H), 2.58-2.39(m,1H), 2.39-2.15(m,4H), 2.00-1.88(m,1H), 1.85-1.70(m,1H), 1.68-1.55(m,1H), 1.47(d,J=6.0 Hz,3H), 1.13-0.97(m,3H), 0.97(s,3H), 0.90-0.82(m,3H), 0.51-0.39(m,3H)ppm.

[0204] Example 11 trans-N-[(1S)-1-[[(8S,14S)-22-ethyl-4-hydroxy-(21M)-21-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-18,18-dimethyl-9,15-dioxo-16-oxa-10,22,28-triazapentacyclo[18.5.2.1 2,6 .110,14 .0 23,27 ]Nonacosa-1(26),2,4,6(29),20,23(27),24-heptaen-8-yl]carbamoyl]-2-methyl-propyl]-3-[(E)-2-fluoro-2-methylsulfonyl-vinyl]-N-methyl-cyclobutanecarboxamide [ka] The title compound was prepared in a similar manner to the preparation of Example 1, except that trans-tert-butyl (2S)-2-[(3-formylcyclobutanecarbonyl)-methyl-amino]-3-methyl-butanoate (Compound 3D) and 1-[ethoxy-[fluoro(methylsulfonyl)methyl]phosphoryl]oxyethane (Compound 11A) were used instead of tert-butyl (2S)-2-[(3-formylcyclobutanecarbonyl)-methyl-amino]-3-methyl-butanoate (Compound 1C) and diethylmethylsulfonylmethylphosphonate (Compound 1D). Example 11 (2.8 mg) was obtained as a white solid. MS calculated 957.5 (MH + ), measured value 957.5 (MH + ). 1 H NMR(400MHz,CDCl3)δ=8.89-8.80(m,1H), 8.05-7.40(m,5H), 7.24-6.67(m,3H), 6.50-6.10(m,1H), 5.73-5.55(m,1H), 5.21-4.13(m,5H) , 4.06-3.24(m,9H), 3.19-2.49(m,14H), 2.40-1.76(m,9H), 1.54-1.48(m,3H), 1.34-1.24(m,1H), 1.14-0.79(m,11H), 0.55-0.45(m,2H).

[0205] Compound 11A was prepared according to the following scheme: [ka] Preparation of 1-[ethoxy-[fluoro(methylsulfonyl)methyl]phosphoryl]oxyethane (compound 11A) To a solution of diethyl methylsulfonylmethylphosphonate (compound 1D, 500.0 mg, 2.17 mmol) in THF (28 mL) was added LiHMDS (2.61 mL, 2.61 mmol) at −60° C. After stirring at −60° C. for 0.5 h, selectfluor (923.3 mg, 2.61 mmol) was added to the reaction mixture. The reaction mixture was stirred at −60° C. for an additional 2 h. The reaction mixture was stirred at −20° C. for an additional 2 h. After stirring at 0° C. for an additional 2 h, the reaction was quenched by the addition of water (20 mL), then diluted with water (100 mL), and extracted with EtOAc (50 mL, 4 times). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and concentrated in vacuo to give 1-[ethoxy-[fluoro(methylsulfonyl)methyl]phosphoryl]oxyethane (compound 11A, 490.0 mg) as a yellow oil, which was used in the next step. 1 H NMR (400 MHz, CDCl3) δ = 5.30-5.10 (m, 1H), 4.40-4.20 (m, 4H), 3.24-3.17 (m, 3H), 1.45-1.36 (m, 6H).

[0206] Example 12 cis-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-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-3-[(E)-2-methylsulfonylvinyl]cyclobutanecarboxamide [ka] Analogously to the preparation of Example 1, (8S,14S)-8-amino-22-ethyl-4-hydroxy-(21M)-21-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-18,18-dimethyl-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 C) and tert-butyl (2S)-2-[(3-formylcyclobutanecarbonyl)-methyl-amino]-3-methyl-butanoate (compound 1C), (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-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 The title compound was prepared by using octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate K) and cis-tert-butyl (2S)-2-[(3-formylcyclobutanecarbonyl)-methyl-amino]-3-methyl-butanoate (Compound 12D). Example 12 (4.0 mg) was obtained as an off-white solid. MS calculated 984.4 (MH + ), measured value 984.4 (MH + ). 1H NMR(400MHz,Methanol-d4)δ=8.78(dd,J=4.8,1.6 Hz,1H), 8.62-8.46(m,1H), 7.95(d,J=7.6 Hz,1H), 7.86-7.75(m,1H), 7.71-7.57(m,3H), 7.04-6.84(m,1H), 6.68-6.48(m,1H), 5.77-5.62(m,1H), 5.29- 5.13(m,1H), 4.83-4.74(m,1H), 4.46-4.36(m,1H), 4.36-4.22(m,2H), 3.93-3.65(m,3H), 3.65-3.50(m,1H), 3. 50-3.40(m,2H), 3.40-3.35(m,3H), 3.28-3.19(m,1H), 3.19-3.05(m,2H), 3.03-2.86(m,6H), 2.86-2.75(m,1H) , 2.65-2.35(m,3H), 2.32-2.13(m,3H), 2.00-1.89(m,1H), 1.87-1.74(m,1H), 1.69-1.56(m,1H), 1.46(d,J=6.0 Hz,3H), 1.23-1.04(m,1H), 1.01-0.93(m,5H), 0.91-0.79(m,3H), 0.49-0.35(m,3H)ppm.

[0207] Compound 12D was prepared in the same manner as Compound 3D, except that cis-3-methoxycarbonylcyclobutanecarboxylic acid (Compound 12A) was used instead of trans-3-methoxycarbonylcyclobutanecarboxylic acid (Compound 3A).

[0208] Example 13 trans-N-[(1S)-1-[[(8S,14S)-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-3-[(E)-2-methylsulfonylvinyl]cyclobutanecarboxamide [ka] Analogously to the preparation of Example 1, (8S,14S)-8-amino-22-ethyl-4-hydroxy-(21M)-21-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-18,18-dimethyl-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 C) and tert-butyl (2S)-2-[(3-formylcyclobutanecarbonyl)-methyl-amino]-3-methyl-butanoate (compound 1C), (8S,14S)-8-amino-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 The title compound was prepared by using ]nonacosa-1(26),2,4,6(29),20,23(27),24-heptaene-9,15-dione (Intermediate N) and trans-tert-butyl (2S)-2-[(3-formylcyclobutanecarbonyl)-methyl-amino]-3-methyl-butanoate (Compound 3D). Example 13 (7.3 mg) was obtained as a white solid. MS calculated 1091.5 (MH + ), measured value 1091.5 (MH + ). 1H NMR(400MHz,CHLOROFORM-d)δ=8.43(d,J=2.8Hz,1H), 8.00(s,1H), 7.60(s,2H), 7.34(s,1H), 7.28(s,1H), 7.03(s,1H), 6.55(s,1H), 5.62-5.52(m,1H) ), 5.17-5.04(m,1H), 4.77-4.56(m,1H), 4.43(d,J=12.8Hz,1H), 4.12(d,J= 6.0Hz,1H), 3.81-3.51(m,3H), 3.36(s,4H), 3.25(s,3H), 3.21-3.06(m,1H) , 3.00(s,3H), 2.98-2.88(m,3H), 2.81(s,2H), 2.78-2.71(m,2H), 2.68(s,4 H), 2.64-2.51(m,2H), 2.39(s,3H), 2.31-2.11(m,4H), 1.95-1.86(m,1H), 1 .77-1.67(m,1H), 1.67-1.54(m,2H), 1.53-1.46(m,1H), 1.43(d,J=6.0Hz,3 H), 1.29(s,6H), 1.01-0.92(m,6H), 0.83(d,J=6.4Hz,3H), 0.52(s,3H)ppm.

[0209] Example 14 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]-3-[(E)-2-fluoro-2-methylsulfonyl-vinyl]-N-methyl-azetidine-1-carboxamide [ka] Analogously to the preparation of Example 1, (8S,14S)-8-amino-22-ethyl-4-hydroxy-(21M)-21-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-18,18-dimethyl-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 C) and tert-butyl (2S)-2-[(3-formylcyclobutanecarbonyl)-methyl-amino]-3-methyl-butanoate (carbonyl 1C), 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-tetrapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 The title compound was prepared by using octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate M) and tert-butyl (2S)-2-[[3-[(E)-2-fluoro-2-methylsulfonyl-vinyl]azetidine-1-carbonyl]-methyl-amino]-3-methyl-butanoate (Compound 14D). Example 14 (23.5 mg) was obtained as a yellow solid. MS calculated 1119.5 (MH + ), measured value 1119.5 (MH + ). 1H NMR(400 MHz,CDCl3)δ=8.66(d,J=7.2 Hz,1H),8.49(d,J=2.6 Hz,1H),7.63(s,1H),7.18-7.05(m,2H),6.52-6.33(m,1H),5.86-5.76(m,1H),5.75-5.55(m, 1H),5.12-4.76(m,2H),4.71-4.42(m,3H),4.37-4.09(m,4H),4.05-3.95(m,1H),3.90-3.65( m,3H),3.62-3.35(m,1H),3.36-3.24(m,7H),3.18-3.05(m,4H),3.03-2.95(m,2H),2.88-2.8 2(m,3H),2.78-2.56(m,5H),2.49-2.17(m,6H),2.00-1.90(m,1H),1.86-1.77(m,1H),1.59(br s,1H),1.47-1.45(m,3H),0.99-0.89(m,9H),0.43(s,3H)ppm.

[0210] Compound 14D was prepared in a similar manner to the preparation of compound 8D, by substituting 1-[ethoxy-[fluoro(methylsulfonyl)methyl]phosphoryl]oxyethane (compound 11A) for diethyl methylsulfonylmethylphosphonate (compound 1D).

[0211] Example 15 3-[(E)-2-Fluoro-2-methylsulfonyl-vinyl]-N-[(1S)-1-[[(7S,13S)-(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-azetidine-1-carboxamide [ka] Analogously to the preparation of Example 1, (8S,14S)-8-amino-22-ethyl-4-hydroxy-(21M)-21-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-18,18-dimethyl-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 C) and tert-butyl (2S)-2-[(3-formylcyclobutanecarbonyl)-methyl-amino]-3-methyl-butanoate (compound 1C), 3-[(E)-2-fluoro-2-methylsulfonyl-vinyl]-N-[(1S)-1-[[(7S,13S)-(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 The title compound was prepared by using ]octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-n-methyl-azetidine-1-carboxamide (Intermediate O) and tert-butyl (2S)-2-[[3-[(E)-2-fluoro-2-methylsulfonyl-vinyl]azetidine-1-carbonyl]-methyl-amino]-3-methyl-butanoate (Compound 14D). Example 15 (10.1 mg) was obtained as a white solid. MS calculated 1088.4 (MH + ), measured value 1088.5 (MH + ). 1H NMR(400 MHz,CDCl3)δ=8.59(s,1H),8.47(d,J=2.8 Hz,1H),7.65(br d,J=7.2 Hz,1H),7.43-7.30(m,3H),7.11(s,1H),6.37-6.22(m,1H),5.86-5.77(m,1H),5.74-5.57(m,1H),5.53-5.32(m,1H),5.14-4.82(m,1 H),4.74-4.43(m,3H),4.33-4.12(m,3H),4.06-3.97(m,1H),3.94-3.86(m,4H),3.85-3.79(m,1H),3.78-3.71(m,1H),3.50-3.42(m, 1H),3.36(s,2H),3.32-3.10(m,3H),3.18-3.06(m,3H),3.03-2.98(m,1H),2.90-2.82(m,2H),2.78-2.62(m,2H),2.51-2.42(m,1H), 2.33-2.19(m,2H),2.05-1.91(m,1H),1.85-1.73(m,1H),1.50-1.42(m,3H),1.35-1.24(m,5H),1.06-0.86(m,10H),0.42(s,3H)ppm.

[0212] Compound 14D was prepared in a manner similar to that used to prepare compound 8D, by substituting 1-[ethoxy-[fluoro(methylsulfonyl)methyl]phosphoryl]oxyethane (compound 11A) for diethyl methylsulfonylmethylphosphonate (compound 1D).

[0213] Example 16 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-3-[(E)-2-methylsulfonylvinyl]azetidine-1-carboxamide [ka] Analogously to the preparation of Example 1, (8S,14S)-8-amino-22-ethyl-4-hydroxy-(21M)-21-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-18,18-dimethyl-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 C) and tert-butyl (2S)-2-[(3-formylcyclobutanecarbonyl)-methyl-amino]-3-methyl-butanoate (compound 1C), (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 The title compound was prepared by using octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate M) and tert-butyl (2S)-3-methyl-2-[methyl-[3-[(E)-2-methylsulfonylvinyl]azetidine-1-carbonyl]amino]butanoate (Compound 8D). Example 16 (25.5 mg) was obtained as a white solid. MS calculated 1101.4 (MH + ), measured value 1101.5 (MH + ). 1H NMR(400MHz,CHLOROFORM-d)δ=8.66(d,J=7.5 Hz,1H), 8.48(d,J=2.8 Hz,1H), 7.65(s,1H), 7.23-7.08(m,3H), 6.51(d,J=14.8 Hz,1H), 5.80(t,J=9.0 Hz,1H), 5.13-4.94(m,1H), 4.66-4.38(m,3H), 4.32-4.21(m,1H), 4.21-4.13(m,3H), 4.12-4.05(m,1H), 4.01(d,J=12.2 Hz,1H), 3.90-3.80(m,2H), 3.71(d,J=11.2 Hz,1H), 3.58-3.49(m,1H), 3.43(d,J=14.8 Hz,1H), 3.34(s,7H), 3.19-3.06(m,2H), 3.00(s,3H), 2.85(s,3H), 2.71(s,5H), 2.46(s, 1H), 2.44(s,3H), 2.35-2.17(m,2H), 2.03-1.92(m,2H), 1.66-1.53(m,2H), 1.46(d,J=6.1 Hz,3H), 0.98-0.90(m,9H), 0.42(s,3H)ppm.

[0214] Example 17 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-3-[(E)-2-methylsulfonylvinyl]azetidine-1-carboxamide [ka] Analogously to the preparation of Example 1, (8S,14S)-8-amino-22-ethyl-4-hydroxy-(21M)-21-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-18,18-dimethyl-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 C) and tert-butyl(2S)-2-[(3-formylcyclobutanecarbonyl)-methyl-amino]-3-methyl-butanoate (compound 1C), (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 The title compound was prepared by using octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate Q) and tert-butyl (2S)-3-methyl-2-[methyl-[3-[(E)-2-methylsulfonylvinyl]azetidine-1-carbonyl]amino]butanoate (Compound 8D). Example 17 (16.1 mg) was obtained as a white solid. MS calculated 1034.4 (MH + ), measured value 1034.5 (MH + ). 1H NMR(400MHz,CHLOROFORM-d)δ=8.64(d,J=7.6Hz,1H), 8.53-8.46(m,1H), 7.6 1(d,J=2.0Hz,1H), 7.19(d,J=8.2,15.0Hz,1H), 7.12-7.04(m,2H), 6.51(d,J= 15.2Hz,1H), 5.81(t,J=9.4Hz,1H), 4.64-4.53(m,1H), 4.44(t,J=8.5Hz,1H) , 4.34-3.98(m,9H), 3.92-3.89(m,4H), 3.87-3.81(m,2H), 3.71(d,J=11.1Hz, 1H), 3.59-3.49(m,1H), 3.43(d,J=14.9Hz,1H), 3.38(s,3H), 3.26-3.22(m,4 H), 3.17-3.06(m,2H), 3.00(s,3H), 2.85(s,3H), 2.73-2.64(m,1H), 2.45(d,J) =14.2Hz,1H), 2.32-2.17(m,2H), 2.02(s,1H), 1.99-1.92(m,1H), 1.60(d,J= 3.4,12.4Hz,1H), 1.45(d,J=6.1Hz,3h), 0.99-0.90(m,12H), 0.44(s,3H)ppm.

[0215] Example 18 trans-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-3-[(E)-2-methylsulfonylvinyl]cyclobutanecarboxamide [ka] Analogously to the preparation of Example 1, (8S,14S)-8-amino-22-ethyl-4-hydroxy-(21M)-21-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-18,18-dimethyl-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 C) and tert-butyl (2S)-2-[(3-formylcyclobutanecarbonyl)-methyl-amino]-3-methyl-butanoate (compound 1C), (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 The title compound was prepared by using octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate P) and trans-tert-butyl (2S)-2-[(3-formylcyclobutanecarbonyl)-methyl-amino]-3-methyl-butanoate (Compound 3D). Example 18 (40.8 mg) was obtained as an off-white solid. MS calculated 1168.5 (MH + ), measured value 1168.5 (MH + ). 1H NMR(400 MHz,Methanol-d4)δ=8.70(d,J=7.2Hz,1H), 8.42(d,J=2.8Hz,1H), 7.67(d,J=2.4Hz,1H), 7.60(d,J=2.4Hz,1H), 7.48(d,j=12.4 hz,1H), 7.20-7.04(m,1H), 6.69-6.59(m,1H), 5.78-5.75(m,1H), 5.29-5.09(m,1H), 4.84-4.74(m,2H), 4.48-4.37(m,1H), 4.29 -4.16(m,2H), 3.83-3.76(m,1H), 3.74-3.68(m,1H), 3.62-3.50(m,1H), 3.49-3.38(m,5H), 3.37(s,3H), 3.29-3.20(m,2H), 3.20- 3.04(m,3H), 3.04-2.93(m,4H), 2.92(s,2H), 2.88(t,J=4.8Hz,4H), 2.86-2.78(m,1H), 2.73-2.40(m,3H), 2.39-2.16(m,4H), 2. 03-1.91(m,1H), 1.89-1.72(m,1H), 1.72-1.56(m,1H), 1.45(d,J=6.0Hz,3H), 1.09-0.95(m,6H), 0.92-0.83(m,3H), 0.50(s,3H).

[0216] Example 19 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]-3-[(E)-2-fluoro-2-methylsulfonyl-vinyl]-N-methyl-azetidine-1-carboxamide [ka] Analogously to the preparation of Example 1, (8S,14S)-8-amino-22-ethyl-4-hydroxy-(21M)-21-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-18,18-dimethyl-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 C) and tert-butyl (2S)-2-[(3-formylcyclobutanecarbonyl)-methyl-amino]-3-methyl-butanoate (compound 1C), 3-[(E)-2-fluoro-2-methylsulfonyl-vinyl]-n-[(1S)-1-[[(7S,13S)-(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 The title compound was prepared by using ]octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-n-methyl-azetidine-1-carboxamide (Intermediate Q) and tert-butyl (2S)-2-[[3-[(E)-2-fluoro-2-methylsulfonyl-vinyl]azetidine-1-carbonyl]-methyl-amino]-3-methyl-butanoate (Compound 14D). Example 19 (1.6 mg) was obtained as a white solid. MS calculated 1052.5 (MH + ), measured value 1052.5 (MH + ). 1H NMR(400 MHz,Methanol-d4)δ=8.67(d,J=7.6 Hz,1H),8.39(d,J=2.8 Hz,1H),8.35(d,J=9.2 Hz,1H),7.67(d,J=2.2 Hz,1H),7.55(br d,J=3.6 Hz,1H),7.38-7.28(m,1H),6.61-6.43(m,1H),5.86-5.73(m,1H),4.96-4.91( m,2H),4.82(s,2H),4.47-4.35(m,2H),4.34-4.11(m,7H),3.96(dd,J=6.0,7.8 Hz,1H),3.92-3.84(m,5H),3.80-3.69(m,2H),3.50-3.45(m,1H),3.37-3.34(m,1H),3.28-3.22(m,1H),3.16(s,3 H),3.14-2.93(m,2H),2.89-2.79(m,4H),2.74-2.62(m,1H),2.25-2.14(m,2H),2.20-1.90(m,1H),1.80(d,J=12.2 Hz,1H),1.70-1.53(m,1H),1.47-1.41(m,3H),1.02-0.98(m,3H),0.97-0.92(m,6H),0.91-0.89(m,3H),0.58-0.48(m,3H)ppm.

[0217] Biological Examples Example 20 Cell viability assay The purpose of this cell assay was to determine the effect of test compounds on the proliferation of human cancer cell lines NCI-H358 (ATCC-CRL5807), AGS (ATCC-CRL-1739), and SW620 (ATCC-CCL-227) over a 3-day treatment period by quantifying the amount of NADPH present at the endpoint using the Cell Counting Kit-8.

[0218] Cells were seeded into 96-well assay plates (Corning-3699) at 5,000 cells / well (NCI-H358), 2,000 cells / well (AGS), or 2,000 cells / well (SW620) and incubated overnight. Then, on the day of the assay, diluted compounds were added to a final concentration of 0.5% DMSO. After 72 hours of incubation, one-tenth the volume of Cell Counting Kit 8 (DnJindo-CK04) was added to each well. After 2 hours of incubation, the signal (OD450 minus OD650) was read using EnVision. IC 50 was determined by fitting a four-parameter sigmoidal concentration-response model. [Table 1]

[0219] Example 21 Interaction assay between CYPA (500 nM) and KRAS-BRAF In this example, TR-FRET was also used to measure compound- or compound-CYPA-dependent disruption of the KRAS G12C-BRAF complex. This protocol was also used to measure disruption of KRAS G12D or KRAS G12V binding to BRAF by compounds of the present invention. Untagged CYPA, GMPPNP-loaded 6His-KRAS protein, and GST-BRAF were assayed in assay buffer containing 25 mM HEPES pH=7.4 (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid, Thermo, 15630080), 0.002% Tween 20, 0.1% BSA, 100 mM NaCl, 5 mM MgCl2, and 10 μM GMPPNP (guanosine 5'-[β,γ-imido]triphosphate trisodium salt hydrate, Sigma, G0635). RBDThe compounds were mixed in wells of a 384-well assay plate at final concentrations of 50 nM, 6.25 nM, and 1 nM, respectively. Compounds were added to the plate wells as a 16-point, 3-fold dilution series starting at a final concentration of 10 μM and incubated for 3 hours. A mixture of MAb anti-6His-XL665 (Cisbio, 61HISXLB) and MAb anti-GST-TB cryptate (Cisbio, 61GSTTLB) was then added at final concentrations of 6.67 nM and 0.21 nM, respectively, and the plate was incubated for an additional 1.5 hours. TR-FRET signals were read on a PHERstar FSX microplate reader (Ex 320 nm, Em 665 / 615 nm). Compounds that promote disruption of the KRAS-BRAF complex were identified as those that induce a decrease in the TR-FRET ratio compared to DMSO control wells. [Table 2]

[0220] Example 22 pERK inhibition assay This assay measures the ability of test compounds to inhibit downstream signaling of ERK phosphorylation: KRAS G12C in NCI-H358 cells, KRAS G12D in AGS cells, and KRAS G12V in SW620 cells. NCI-H358 (ATCC-CRL5807), AGS (ATCC-CRL-1739), and SW620 (ATCC-CCL-227) cells were all grown and maintained in RPMI-1640 medium (Thermo Fisher Scientific) containing 10% fetal bovine serum and 1% penicillin / streptomycin. The day before compound addition, cells were plated into tissue-culture-treated 96-well plates (Corning-3699) at densities of 30,000, 20,000, and 30,000 cells / well for NCI-H358, AGS, and SW620, respectively, and allowed to adhere overnight. The diluted compounds were then added to a final concentration of 0.5% DMSO. After 4 hours of incubation, the medium was removed, 100 μL of 4% formaldehyde was added, and the assay plate was incubated at room temperature for 20 minutes. The plate was then washed once with phosphate-buffered saline (PBS) and permeabilized with 100 μL of chilled methanol for 10 minutes. Nonspecific antibody binding to the plate was blocked with 50 μL of 1× BSA blocking buffer (Thermo-37520, diluted 10-fold with phosphate-buffered saline Tween (PBST)) for at least 1 hour at room temperature.

[0221] The amount of phosphorylated ERK was determined using an antibody specific for the phosphorylated form of ERK. The primary antibody (pERK, CST-4370, Cell Signaling Technology) was diluted 1:300 in blocking buffer, and 50 μL was aliquoted into each well and incubated overnight at 4°C. The cells were washed five times for 5 minutes with PBST. The secondary antibody (HRP-conjugated anti-rabbit IgG, CST-7074, Cell Signaling Technology) was diluted 1:1000 in blocking buffer, and 50 μL was added to each well and incubated at room temperature for 1–2 hours. The cells were washed five times for 5 minutes with PBST, and 100 μL of TMB ELISA substrate (abcam-ab171523) was added and gently shaken for 20 minutes. 50 μL of stop solution (abcam-ab171529) was added, and the signal (OD450) was then read by EnVision.

[0222] I C 50 was determined by fitting a four-parameter sigmoidal concentration-response model. [Table 3]

Claims

1. A compound of formula (I), 【Chemistry 1】 (In the formula, R １ teeth, 【Chemistry 2】 and R ８ is C １－６ is alkyl, R ９ is ((C １－６ Alkylsulfonyl)halo C ２－６ alkenyl)azetidinyl, ((C １－６ Alkylsulfonyl)halo C ２－６ alkenyl)C ３－７ cycloalkyl, (C １－６ Alkylsulfonyl C ２－６ alkenyl)azetidinyl, (C １－６ Alkylsulfonyl C ２－６ alkenyl)C ３－７ cycloalkyl or (C １－６ Alkylsulfonyl C ２－６ alkenyl)piperidinyl, R ２ is C １～６ is alkyl, R ３ is H or a halogen, R ４ is H, R ５ is C １－６ Alkyl or halo C １－６ is alkyl, R ６ is C １－６ Alkoxy C １－６ is alkyl, R ７ is H, morpholinyl, (haloC １－６ alkyl)piperazinyl or C １－６ alkylpiperazinyl, A １ is thiazolylene, phenylene, or hydroxyphenylene; A ２ is C １－６ alkylene), or a pharmaceutically acceptable salt thereof.

2. A compound of formula (Ia), 【Transformation 3】 (In the formula, R １ teeth, 【Chemistry 4】 and R ８ is C １－６ is alkyl, R ９ is ((C １－６ Alkylsulfonyl)halo C ２－６ alkenyl)azetidinyl, ((C １－６ Alkylsulfonyl)halo C ２－６ alkenyl)C ３－７ cycloalkyl, (C １－６ Alkylsulfonyl C ２－６ alkenyl)azetidinyl, (C １－６ Alkylsulfonyl C ２－６ alkenyl)C ３－７ cycloalkyl or (C １－６ Alkylsulfonyl C ２－６ alkenyl)piperidinyl, R ２ is C １～６ is alkyl, R ３ is H or a halogen, R ４ is H, R ５ is C １－６ Alkyl or halo C １－６ is alkyl, R ６ is C １－６ Alkoxy C １－６ is alkyl, R ７ is H, morpholinyl, (haloC １－６ alkyl)piperazinyl or C １－６ alkylpiperazinyl, A １ is thiazolylene, phenylene, or hydroxyphenylene; A ２ is C １－６ alkylene), or a pharmaceutically acceptable salt thereof.

3. R １ but, 【Transformation 5】 and R ８ But C １－６ alkyl, and R ９ However, (C １－６ Alkylsulfonyl C ２－６ alkenyl)azetidinyl or (C １－６ Alkylsulfonyl C ２－６ alkenyl)C ３－７ 3. The compound of claim 1 or 2, which is cycloalkyl.

4. R １ but, 【Transformation 6】 and R ８ is methyl, and R ９ The compound according to any one of claims 1 to 3, wherein is 3-(2-methylsulfonylvinyl)azetidin-1-yl or 3-(2-methylsulfonylvinyl)cyclobutyl.

5. R １ is methyl-[3-[(E)-2-methylsulfonylvinyl]azetidine-1-carbonyl]amino or methyl-[3-[(E)-2-methylsulfonylvinyl]cyclobutanecarbonyl]amino.

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

7. R ３ The compound of any one of claims 1 to 6, wherein is H or fluoro.

8. R ３ The compound of any one of claims 1 to 7, wherein is fluoro.

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

10. R ５ The compound according to any one of claims 1 to 9, wherein is ethyl or 2,2,2-trifluoroethyl.

11. R ６ The compound of any one of claims 1 to 10, wherein is 1-methoxyethyl.

12. R ７ But C １－６ The compound of any one of claims 1 to 11, which is alkylpiperazinyl or morpholinyl.

13. R ７ The compound of any one of claims 1 to 12, wherein is 4-methylpiperazin-1-yl or morpholinyl.

14. A １ but, 【Transformation 7】 or 【Transformation 8】 and bond "a" is attached to the indole ring.

15. A ２ The compound according to any one of claims 1 to 14, wherein is dimethylmethylene.

16. R １ but, 【Chemistry 9】 and R ８ is C １－６ alkyl, and R ９ is (C １－６ Alkylsulfonyl C ２－６ alkenyl)azetidinyl or (C １－６ Alkylsulfonyl C ２－６ alkenyl)C ３－７ is cycloalkyl, R ２ But C １－６ is alkyl, R ３ is a halogen, R ４ is H, R ５ But C １－６ Alkyl or halo C １－６ is alkyl, R ６ But C １－６ Alkoxy C １－６ is alkyl, R ７ But C １－６ alkylpiperazinyl or morpholinyl, A １ but, 【Chemistry 10】 or 【Chemistry 11】 and bond "a" is attached to the indole ring; A ２ But C １－６ The compound of claim 1 or 2, which is alkylene. or a pharmaceutically acceptable salt thereof.

17. R １ is methyl-[3-[(E)-2-methylsulfonylvinyl]azetidine-1-carbonyl]amino or methyl-[3-[(E)-2-methylsulfonylvinyl]cyclobutanecarbonyl]amino, R ２ is isopropyl, R ３ But it is fluoro, R ４ is H, R ５ is ethyl or 2,2,2-trifluoroethyl, R ６ is (1S)-1-methoxyethyl, R ７ is 4-methylpiperazin-1-yl or morpholinyl; A １ but, 【Chemistry 12】 or 【Chemistry 13】 and bond "a" is attached to the indole ring; A ２ is dimethylmethylene or a pharmaceutically acceptable salt thereof.

18. N-[(1S)-1-[[(8S,14S)-22-ethyl-4-hydroxy-(21M)-21-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-18,18-dimethyl-9,15-dioxo-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-3-[(E)-2-methylsulfonylvinyl]cyclobutanecarboxamide; N-[(1S)-1-[[(8S,14S)-22-ethyl-(21M)-21-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-18,18-dimethyl-9,15-dioxo-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-3-[(E)-2-methylsulfonylvinyl]cyclobutanecarboxamide; trans-N-[(1S)-1-[[(8S,14S)-22-ethyl-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-18,18-dimethyl-9,15-dioxo-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-3-[(E)-2-methylsulfonylvinyl]cyclobutanecarboxamide; trans-N-[(1S)-1-[[(8S,14S)-22-ethyl-4-hydroxy-(21M)-21-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-18,18-dimethyl-9,15-dioxo-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-3-[(E)-2-methylsulfonylvinyl]cyclobutanecarboxamide; trans-N-[(1S)-1-[[(7S,13S)-21-ethyl-(20M)-20-[2-[(1S)-1-methoxyethyl]-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-3-[(E)-2-methylsulfonylvinyl]cyclobutanecarboxamide; N-[(1S)-1-[[(7S,13S)-21-ethyl-(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-3-[(E)-2-methylsulfonylvinyl]cyclobutanecarboxamide; N-[(1S)-1-[[(7S,13S)-(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-3-[(E)-2-methylsulfonylvinyl]cyclobutanecarboxamide; N-[(1S)-1-[[(8S,14S)-22-ethyl-4-hydroxy-(21M)-21-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-18,18-dimethyl-9,15-dioxo-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-3-[(E)-2-methylsulfonylvinyl]azetidine-1-carboxamide; N-[(1S)-1-[[(8S,14S)-22-ethyl-4-hydroxy-(21M)-21-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-18,18-dimethyl-9,15-dioxo-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-4-[(E)-2-methylsulfonylvinyl]piperazine-1-carboxamide; trans-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-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-3-[(E)-2-methylsulfonylvinyl]cyclobutanecarboxamide; trans-N-[(1S)-1-[[(8S,14S)-22-ethyl-4-hydroxy-(21M)-21-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-18,18-dimethyl-9,15-dioxo-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]-3-[(E)-2-fluoro-2-methylsulfonyl-vinyl]-N-methyl-cyclobutanecarboxamide; cis-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-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-3-[(E)-2-methylsulfonylvinyl]cyclobutanecarboxamide; trans-N-[(1S)-1-[[(8S,14S)-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-3-[(E)-2-methylsulfonylvinyl]cyclobutanecarboxamide; 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]-3-[(E)-2-fluoro-2-methylsulfonyl-vinyl]-N-methyl-azetidine-1-carboxamide; 3-[(E)-2-Fluoro-2-methylsulfonyl-vinyl]-N-[(1S)-1-[[(7S,13S)-(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-azetidine-1-carboxamide; 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-3-[(E)-2-methylsulfonylvinyl]azetidine-1-carboxamide; 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-3-[(E)-2-methylsulfonylvinyl]azetidine-1-carboxamide; trans-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-3-[(E)-2-methylsulfonylvinyl]cyclobutanecarboxamide; and 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]-3-[(E)-2-fluoro-2-methylsulfonyl-vinyl]-N-methyl-azetidine-1-carboxamide 1. A compound selected from:

19. A process for preparing a compound according to any one of claims 1 to 18, comprising any of the following steps: a) a compound of formula (II), 【Chemistry 14】 and acid (III), 【Chemistry 15】 and a coupling reaction in the presence of a coupling reagent and a base to form the compound of formula (I). Including, R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , A １ and A ２ is as defined in any one of claims 1 to 17, and the coupling reagent is T ３ P, HATU, PyBOP or EDCI / HOBt, and said base is TEA, DIEPA or DMAP.

20. 19. A compound or a pharmaceutically acceptable salt according to any one of claims 1 to 18 for use as a therapeutically active substance.

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

22. Use of a compound according to any one of claims 1 to 18 for treating a KRAS G12C protein-related disease.

23. Use of a compound according to any one of claims 1 to 18 for treating KRAS G12C, G12D and G12V protein-associated diseases.

24. Use of a compound according to any one of claims 1 to 18 for inhibiting RAS interaction with downstream effectors, wherein said downstream effectors are RAF and PI3K.

25. Use of a compound according to any one of claims 1 to 18 for inhibiting propagating oncogenic MAPK and PI3K signalling.

26. 20. Use of a compound according to any one of claims 1 to 18 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.

27. 20. Use of a compound according to any one of claims 1 to 18 for the treatment or prevention of KRAS mutation-driven cancer, wherein the cancer is selected from pancreatic adenocarcinoma, colorectal cancer, and non-small cell lung cancer.

28. 20. The compound or pharmaceutically acceptable salt of any one of claims 1 to 18, 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. 20. Use of a compound according to any one of claims 1 to 18 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.

30. 20. A method for the treatment or prevention of KRAS mutation-driven cancer, wherein said cancer is selected from pancreatic adenocarcinoma, colorectal cancer, and non-small cell lung cancer, said method comprising administering a therapeutically effective amount of a compound of any one of claims 1 to 18.

31. 20. A compound or a pharmaceutically acceptable salt according to any one of claims 1 to 18 when produced according to the process of claim 19.

32. The invention as hereinbefore described.

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