EP4649081A1

EP4649081A1 - Sulfonylvinyl compounds for the treatment of cancer

Info

Publication number: EP4649081A1
Application number: EP24701099.4A
Authority: EP
Inventors: Jianguo Chen; Haixia Liu; Hong Shen; Weixing Zhang; Dan Zhao; Wei Zhu
Original assignee: F Hoffmann La Roche AG
Current assignee: F Hoffmann La Roche AG
Priority date: 2023-01-13
Filing date: 2024-01-11
Publication date: 2025-11-19
Also published as: CN120530119A; WO2024149819A1; JP2026504029A

Abstract

The present invention relates to compounds of formula (I), wherein R¹ to R⁷, A¹ and A² are as described herein, and their pharmaceutically acceptable salt thereof, and compositions including the compounds and methods of using the compounds.

Description

Case 38188 Sulfonylvinyl compounds for the treatment of cancer The present invention relates to organic compounds useful for therapy and/or prophylaxis in a mammal, and in particular to inhibition of KRAS mutant useful for treating cancers. FIELD OF THE INVENTION RAS is one of the most well-known proto-oncogenes. Approximately 30% of human cancers contain mutations in three most notable members, KRAS, HRAS, and NRAS, making them the most prevalent oncogenic drivers. KRAS mutations are generally associated with poor prognosis especially in colorectal cancer, pancreatic cancer, lung cancers. As the most frequently mutated RAS isoform, KRAS has been intensively studied in the past years. Among the most commonly occurring KRAS alleles (including G12D, G12V, G12C, G13D, G12R, G12A, G12S, Q61H, etc), G12C, G12D and G12V represent more than half of all K-RAS-driven cancers across colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC), lung adenocarcinoma (LUAD). Of note, KRAS wild-type amplifications are also found in around 7% of all KRAS-altered cancers (ovarian, esophagogastric, uterine), ranking among the top alterations. All RAS proteins belong to a protein family of small GTPases that hydrolyze GTP to GDP. KRAS is structurally divided into an effector binding lobe followed by the allosteric lobe and a carboxy-terminal region that is responsible for membrane anchoring. The effector lobe comprises the P-loop, switch I, and switch II regions. The switch I/II loops play a critical role in KRAS downstream signaling through mediating protein–protein interactions with effector proteins that include RAF in the mitogen-activated protein kinase (MAPK) pathway or PI3K in the phosphatidylinositol 3‑kinase (PI3K)/protein kinase B (AKT) pathway. KRAS protein switches between 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) that involve catalyzing the exchange of GDP for GTP, potentiating intrinsic GTPase activity or accelerating RAS-mediated GTP hydrolysis. In response to extracellular stimuli, the inactive RAS-GDP is converted to active RAS-GTP which directly binds to RAF RAS binding domains (RAF^RBD), recruiting RAF kinase family from cytoplasm to membranes, where they dimerize and become active. The activated RAF subsequently carries out a chain of phosphorylation reactions to its downstream Mitogen- activated protein kinase (MEK) and extracellular signal-regulated kinase (ERK), and propagates the growth signal. Of the RAF family of protein kinases (three known isoforms ARAF, BRAF, CRAF/RAF1), BRAF is most frequently mutated and remains the most potent activator of MEK. Despite that individual RAS and RAF family members revealed distinct binding preferences, all RAFs possess the conserved RBD for forward transmission of MAPK singnaling, frequently used for characterize KRAS inhibition (e.g. KRAS-BRAF^RBD herein). For KRAS, mutations at positions 12, 13, 61, and 146 lead to a shift toward the active KRAS form through impairing nucleotide hydrolysis or activating nucleotide exchange, leading to hyper-activation of the MAPK pathway that results in tumorigenesis. Despite its well-recognized importance in cancer malignancy, continuous efforts in the past failed to develop approved therapies for KRAS mutant cancer until recently, the first selective drug AMG510 has fast approval as second line treatment in KRAS G12C driven non-small cell lung cancer (NSCLC). Nevertheless, the clinical acquired resistance to KRAS G12C inhibitors emerge rigorously with disease progresses after around 6 month of treatment. All of the mutations converge to reactivate RAS–MAPK signaling, with secondary RAS mutants at oncogenic hotspots (e.g. G12/G13/Q61) and within the switch II pocket (e.g. H95, R68, and Y96) have been observed; moreover, over 85% of all KRAS-mutated or wild-type amplified driven cancers still lack novel agents. Altogether, both the myriad of escape mechanism and various oncogenic alleles, highlight the urgent medical need for additional KRAS therapies. As such, we invented oral compounds that target and inhibit KRAS alleles for the treatment of KRAS mutant driven cancers. SUMMARY OF THE INVENTION The present invention relates to novel compounds of formula (I),

wherein R⁸ is C_1-6alkyl; R⁹ is ((C_1-6alkylsulfonyl)haloC_2-6alkenyl)azetidinyl, ((C_1- 6alkylsulfonyl)haloC2-6alkenyl)C3-7cycloalkyl, (C1-6alkylsulfonylC2- 6alkenyl)azetidinyl, (C1-6alkylsulfonylC2-6alkenyl)C3-7cycloalkyl or (C_1-6alkylsulfonylC_2-6alkenyl)piperidinyl; R² is C1-6alkyl; R³ is H or halogen; R⁴ is H; R⁵ is C_1-6alkyl or haloC_1-6alkyl; R⁶ is C1-6alkoxyC1-6alkyl; R⁷ is H, morpholinyl, (haloC1-6alkyl)piperazinyl or C1-6alkylpiperazinyl; A¹ is thiazolylene, phenylene or hydroxyphenylene; A² is C1-6alkylene; or a pharmaceutically acceptable salt thereof. The invention also relates to their manufacture, medicaments based on a compound in accordance with the invention and their production as well as the use of compounds of formula (I) or (Ia) thereof as inhibitor of KRAS. The compounds of formula (I) or (Ia) show good KRAS inhibition for G12C. In another embodiment, the compounds of this invention showed superior cancer cell inhibition and human hepatocyte stability. In addition, the compounds of formula (I) or (Ia) also show good or improved cytotoxicity and solubility profiles. Furthermore, the compound of current invention had good pharmacokinetic properties comparing with the reference compounds. BRIEF DESCRIPTION OF THE FIGURE Figure 1. X-ray crystallographic analysis of Intermediate A. Figure 2. X-ray crystallographic analysis of compound Q5. DETAILED DESCRIPTION OF THE INVENTION DEFINITIONS The term “C_1-6alkyl” denotes a saturated, linear or branched chain alkyl group containing 1 to 6, particularly 1 to 4 carbon atoms, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl and the like. Particular “C1-6alkyl” groups are methyl, ethyl and n-propyl. The term “C_1-6alkylene” denotes a linear or branched saturated divalent hydrocarbon group of 1 to 6 carbon atoms or a divalent branched saturated divalent hydrocarbon group of 3 to 6 carbon atoms. Examples of C1-6alkylene groups include methylene, ethylene, propylene, 2- methylpropylene, butylene, 2-ethylbutylene, pentylene, hexylene. The term “C_2-6alkenyl” denotes a monovalent linear or branched hydrocarbon group of 2 to 6 carbon atoms with at least one double bond. In particular embodiments, alkenyl has 2 to 4 carbon atoms with at least one double bond. Examples of C2-6alkenyl include ethenyl (or vinyl), propenyl, prop-2-enyl, isopropenyl, n-butenyl, and iso-butenyl. The term “halogen” and “halo” are used interchangeably herein and denote fluoro, chloro, bromo, or iodo. The term “haloC_2-6alkenyl” denotes a C_1-6alkenyl group wherein at least one of the hydrogen atoms of the C_1-6alkenyl group have been replaced by same or different halogen atoms. The term “C3-7cycloalkyl” denotes a monovalent saturated monocyclic or bicyclic hydrocarbon group of 3 to 7 ring carbon atoms. Bicyclic means consisting of two saturated carbocycles having one or more carbon atoms in common. Examples for monocyclic cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Examples for bicyclic cycloalkyl are bicyclo[1.1.0]butyl, bicyclo[2.2.1]heptanyl, bicyclo[1.1.1]pentanyl, or bicyclo[2.2.2]octanyl. The term “thiazolylene” denotes a divalent thiazolyl group. The term “dimethylmethylene” denotes . The term “protecting group” denotes the group which selectively blocks a reactive site in a multifunctional compound such that a chemical reaction can be carried out selectively at another unprotected reactive site in the meaning conventionally associated with it in synthetic chemistry. Protecting groups can be removed at the appropriate point. Exemplary protecting groups are amino-protecting groups, carboxy-protecting groups or hydroxy-protecting groups. The skilled of the art would understand that the following structures of compounds of formula (I) and (I’) are equal especially for the chiral centers: The term “pharmaceutically acceptable salts” denotes salts which are not biologically or otherwise undesirable. Pharmaceutically acceptable salts include both acid and base addition salts. The term “pharmaceutically acceptable acid addition salt” denotes those pharmaceutically acceptable salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and organic acids selected from aliphatic, cycloaliphatic, 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, maloneic 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 salicyclic acid. The term “pharmaceutically acceptable base addition salt” denotes those pharmaceutically acceptable salts formed with an organic or inorganic base. Examples of acceptable inorganic bases include sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Salts derived from pharmaceutically acceptable organic nontoxic bases includes salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperizine, piperidine, N-ethylpiperidine, and polyamine resins. The term “A pharmaceutically active metabolite” denotes a pharmacologically active product produced through metabolism in the body of a specified compound or salt thereof. After entry into the body, most drugs are substrates for chemical reactions that may change their physical properties and biologic effects. These metabolic conversions, which usually affect the polarity of the compounds of the invention, alter the way in which drugs are distributed in and excreted from the body. However, in some cases, metabolism of a drug is required for therapeutic effect. The term “therapeutically effective amount” denotes an amount of a compound or molecule of the present invention that, when administered to a subject, (i) treats or prevents the particular disease, condition or disorder, (ii) attenuates, ameliorates or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition or disorder described herein. The therapeutically effective amount will vary depending on the compound, the disease state being treated, the severity of the disease treated, the age and relative health of the subject, the route and form of administration, the judgement of the attending medical or veterinary practitioner, and other factors. The term “pharmaceutical composition” denotes a mixture or solution comprising a therapeutically effective amount of an active pharmaceutical ingredient together with pharmaceutically acceptable excipients to be administered to a mammal, e.g., a human in need thereof. The terms “pharmaceutically acceptable excipient”, “pharmaceutically acceptable carrier” and “therapeutically inert excipient” can be used interchangeably and denote any pharmaceutically acceptable ingredient in a pharmaceutical composition having no therapeutic activity and being non-toxic to the subject administered, such as disintegrators, binders, fillers, solvents, buffers, tonicity agents, stabilizers, antioxidants, surfactants, carriers, diluents or lubricants used in formulating pharmaceutical products. INHIBITOR OF KRAS The present invention relates to (i) a compound of formula (I), wherein R⁸ is C1-6alkyl; R⁹ is ((C1-6alkylsulfonyl)haloC2-6alkenyl)azetidinyl, ((C1- 6alkylsulfonyl)haloC_2-6alkenyl)C_3-7cycloalkyl, (C_1-6alkylsulfonylC_2- ₆alkenyl)azetidinyl, (C_1-6alkylsulfonylC_2-6alkenyl)C_3-7cycloalkyl or (C1-6alkylsulfonylC2-6alkenyl)piperidinyl; R² is C1-6alkyl; R³ is H or halogen; R⁴ is H; R⁵ is C1-6alkyl or haloC1-6alkyl; R⁶ is C_1-6alkoxyC_1-6alkyl; R⁷ is H, morpholinyl, (haloC_1-6alkyl)piperazinyl or C_1-6alkylpiperazinyl; A¹ is thiazolylene, phenylene or hydroxyphenylene; A² is C_1-6alkylene; or a pharmaceutically acceptable salt thereof. Another embodiment of present invention is (ii) a compound of formula (Ia), wherein R⁸ is C1-6alkyl; R⁹ is ((C1-6alkylsulfonyl)haloC2-6alkenyl)azetidinyl, ((C1- 6alkylsulfonyl)haloC_2-6alkenyl)C_3-7cycloalkyl, (C_1-6alkylsulfonylC_2- 6alkenyl)azetidinyl, (C1-6alkylsulfonylC2-6alkenyl)C3-7cycloalkyl or (C1-6alkylsulfonylC2-6alkenyl)piperidinyl; R² is C_1-6alkyl; R³ is H or halogen; R⁴ is H; R⁵ is C1-6alkyl or haloC1-6alkyl; R⁶ is C_1-6alkoxyC_1-6alkyl; R⁷ is H, morpholinyl, (haloC1-6alkyl)piperazinyl or C1-6alkylpiperazinyl; A¹ is thiazolylene, phenylene or hydroxyphenylene; A² is C_1-6alkylene; or a pharmaceutically acceptable salt thereof. A further embodiment of present invention is (iii) a compound of formula (I) or (Ia) according to (i) or (ii), or a pharmaceutically acceptable salt thereof, wherein R¹ is ; wherein R⁸ is C1-6alkyl; R⁹ is (C1-6alkylsulfonylC2-6alkenyl)azetidinyl or (C1- 6alkylsulfonylC2-6alkenyl)C3-7cycloalkyl. A further embodiment of 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 R¹ is ; wherein R⁸ is methyl; R⁹ is 3-(2-methylsulfonylvinyl)azetidin-1-yl or 3-(2- methylsulfonylvinyl)cyclobutyl. A further embodiment of present invention is (v) a compound of formula (I) or (Ia) according to any one of (i) to (iv), wherein R¹ is methyl-[3-[(E)-2-methylsulfonylvinyl]azetidine- 1-carbonyl]amino or methyl-[3-[(E)-2-methylsulfonylvinyl]cyclobutanecarbonyl]amino. A further embodiment of present invention is (vi) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (v), wherein R² is isopropyl. A further embodiment of present invention is (vii) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (vi), wherein R³ is H or fluoro. A further embodiment of present invention is (viii) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (vii), wherein R³ is fluoro. A further embodiment of present invention is (ix) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (xviii), wherein R⁴ is H. A further embodiment of present invention is (x) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (ix), wherein R⁵ is ethyl or 2,2,2-trifluoroethyl. A further embodiment of present invention is (xi) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (x), wherein R⁶ is 1- methoxyethyl. A further embodiment of present invention is (xii) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (xi), wherein R⁷ is C_1- 6alkylpiperazinyl or morpholinyl. A further embodiment of present invention is (xiii) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (xii), wherein R⁷ is 4- methylpiperazin-1-yl or morpholinyl. A further embodiment of present invention is (xiv) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (xiii), wherein A¹ is ; wherein bond “a” connects to indole ring. A further embodiment of present invention is (xv) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, according to any one of (i) to (xiv), wherein A² is dimethylmethylene. Another embodiment of present invention is (xvi) a compound of formula (I) or (Ia), , according to (i) or (ii), wherein R¹ is ; wherein R⁸ is C_1-6alkyl; R⁹ is (C_1-6alkylsulfonylC_2- 6alkenyl)azetidinyl or (C1-6alkylsulfonylC2-6alkenyl)C3-7cycloalkyl; R² is C_1-6alkyl; R³ is halogen; R⁴ is H; R⁵ is C1-6alkyl or haloC1-6alkyl; R⁶ is C_1-6alkoxyC_1-6alkyl; R⁷ is C1-6alkylpiperazinyl or morpholinyl; or a pharmaceutically acceptable salt thereof. Another embodiment of present invention is (xvii) a compound of formula (I) or (Ia), , according to (xvi), wherein R¹ is methyl-[3-[(E)-2-methylsulfonylvinyl]azetidine-1-carbonyl]amino or methyl-[3-[(E)- 2-methylsulfonylvinyl]cyclobutanecarbonyl]amino; R² is isopropyl; R³ is fluoro; R⁴ is H; R⁵ is ethyl or 2,2,2-trifluoroethyl; R⁶ is (1S)-1-methoxyethyl; R⁷ is 4-methylpiperazin-1-yl or morpholinyl; A¹ is ; wherein bond “a” connects to indole ring; A² is dimethylmethylene; or a pharmaceutically acceptable salt thereof. Another embodiment of present invention is (xviii) a compound of formula (I) or (Ia) selected from the following: N-[(1S)-1-[[(8S,14S)-22-ethyl-4-hydroxy-(21M)-21-[2-[(1S)-1-methoxyethyl]-3-pyridyl]- 2,6 10,14 23,27 18,18-dimethyl-9,15-dioxo-16-oxa-10,22,28-triazapentacyclo[18.5.2.1 .1 .0 ]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- 2,6 10,14 23,27 dimethyl-9,15-dioxo-16-oxa-10,22,28-triazapentacyclo[18.5.2.1 .1 .0 ]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- 2,6 10,14 23,27 triazapentacyclo[18.5.2.1 .1 .0 ]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- 2,6 10,14 23,27 [18.5.2.1 .1 .0 ]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- 2,5 9,13 22,26 dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 .1 .0 ]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- 2,5 9,13 22,26 tetrazapentacyclo[17.5.2.1 .1 .0 ]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- 2,5 9,13 22,26 tetrazapentacyclo[17.5.2.1 .1 .0 ]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]- 2,6 10,14 23,27 18,18-dimethyl-9,15-dioxo-16-oxa-10,22,28-triazapentacyclo[18.5.2.1 .1 .0 ]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]- 2,6 10,14 23,27 18,18-dimethyl-9,15-dioxo-16-oxa-10,22,28-triazapentacyclo[18.5.2.1 .1 .0 ]nonacosa- 1(26),2,4,6(29),20,23(27),24-heptaen-8-yl]carbamoyl]-2-methyl-propyl]-N-methyl-4-[(E)-2- methylsulfonylvinyl]piperidine-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- 2,5 9,13 22,26 tetrazapentacyclo[17.5.2.1 .1 .0 ]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- 2,6 10,14 23,27 triazapentacyclo[18.5.2.1 .1 .0 ]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- 2,5 9,13 22,26 tetrazapentacyclo[17.5.2.1 .1 .0 ]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- 2,6 10,14 23,27 10,22,28-triazapentacyclo[18.5.2.1 .1 .0 ]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- 2,5 9,13 22,26 tetrazapentacyclo[17.5.2.1 .1 .0 ]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- 2,5 9,13 22,26 oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 .1 .0 ]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- 2,5 9,13 22,26 tetrazapentacyclo[17.5.2.1 .1 .0 ]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- 2,5 9,13 22,26 tetrazapentacyclo[17.5.2.1 .1 .0 ]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- 2,5 9,13 22,26 oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 .1 .0 ]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- 2,5 9,13 22,26 tetrazapentacyclo[17.5.2.1 .1 .0 ]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. Another embodiment of present invention is related to (xix) a process for the preparation of a compound according to any one of (i) to (xviii) comprising the following step: a) coupling reaction between compound of formula (II), the presence of a coupling reagent and a base to form the compound of formula (I); wherein R¹, R², R³, R⁴ , R⁵, R⁶, R⁷, A¹ and A² are defined as in any one of (i) to (xvii); the coupling reagent is T3P, HATU, PyBOP or EDCI/HOBt; the base is TEA, DIEPA or DMAP. Another embodiment of present invention is (xx) a compound or pharmaceutically acceptable salt according to any one of (i) to (xviii) for use as therapeutically active substance. Another embodiment of present invention is (xxi) a pharmaceutical composition comprising a compound in accordance with any one of (i) to (xviii) and a pharmaceutically acceptable excipient. Another embodiment of present invention is (xxii) the use of a compound according to any one of (i) to (xviii) for treating a KRAS G12C protein-related disease. Another embodiment of 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-related disease. Another embodiment of 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. Another embodiment of present invention is (xxv) the use of a compound according to any one of (i) to (xviii) for inhibiting the propagating oncogenic MAPK and PI3K signaling. Another embodiment of present invention is (xxvi) the use of a compound according to any one of (i) to (xviii) for the treatment or prophylaxis of KRAS mutation driven cancers, wherein the cancer is selected from pancreatic cancer, colorectal cancer, lung cancer, esophageal cancer, gallbladder cancer, melanoma ovarian cancer and endometrial cancer. Another embodiment of present invention is (xxvii) the use of a compound according to any one of (i) to (xv) for the treatment or prophylaxis of KRAS mutation driven cancers, wherein the cancer is selected from pancreatic adenocarcinoma, colorectal cancer and non-small cell lung cancer. Another embodiment of present invention is (xxviii) a compound or pharmaceutically acceptable salt according to any one of (i) to (xviii) for the treatment or prophylaxis of KRAS mutation driven cancers, wherein the cancer is selected from pancreatic adenocarcinoma, colorectal cancer and non-small cell lung cancer. Another embodiment of 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 prophylaxis of KRAS mutation driven cancers, wherein the cancer is selected from pancreatic adenocarcinoma, colorectal cancer and non-small cell lung cancer. Another embodiment of present invention is (xxx) a method for the treatment or prophylaxis of KRAS mutation driven cancers, wherein the cancer is selected from pancreatic adenocarcinoma, colorectal cancer and non-small cell lung cancer, which method comprises administering a therapeutically effective amount of a compound as defined in any one of (i) to (xviii). Another embodiment of present invention is (xxxi) a compound or pharmaceutically acceptable salt according to any one of (i) to (xviii), when manufactured according to a process of (xix). PHARMACEUTICAL COMPOSITIONS AND ADMINISTRATION Another embodiment provides pharmaceutical compositions or medicaments containing the compounds of the invention and a therapeutically inert carrier, diluent or excipient, as well as methods of using the compounds of the invention to prepare such compositions and medicaments. In one example, compounds of formula (I) may be formulated by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers, i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed into a galenical administration form. The pH of the formulation depends mainly on the particular use and the concentration of compound, but preferably ranges anywhere from about 3 to about 8. In one example, a compound of formula (I) is formulated in an acetate buffer, at pH 5. In another embodiment, the compounds of formula (I) are sterile. The compound may be stored, for example, as a solid or amorphous composition, as a lyophilized formulation or as an aqueous solution. Compositions are formulated, dosed, and administered in a fashion consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners. The “effective amount” of the compound to be administered will be governed by such considerations, and is the minimum amount necessary to inhibit mutant RAS (e.g. KRAS G12C) interaction with RAF, blocking the oncogenic MAPK signaling. For example, such amount may be below the amount that is toxic to normal cells, or the mammal as a whole. In one example, the pharmaceutically effective amount of the compound of the invention administered parenterally per dose will be in the range of about 0.1 to 1000 mg/kg, alternatively about 0.1 to 1000 mg/kg of patient body weight per day, with the typical initial range of compound used being 0.3 to 15 mg/kg/day. In another embodiment, oral unit dosage forms, such as tablets and capsules, preferably contain from about 1 to about 1000 mg of the compound of the invention. The compounds of the invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural and intranasal, and, if desired for local treatment, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. The compounds of the present invention may be administered in any convenient administrative form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain components conventional in pharmaceutical preparations, e.g., diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents. A typical formulation is prepared by mixing a compound of the present invention and a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, e.g., Ansel, Howard C., et al., Ansel’s Pharmaceutical Dosage Forms and Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. The formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament). An example of a suitable oral dosage form is a tablet containing about 1 to 1000 mg of the compound of the invention compounded with about 1 to 1000 mg anhydrous lactose, about 1 to 1000 mg sodium croscarmellose, about 1 to 1000 mg polyvinylpyrrolidone (PVP) K30, and about 1 to 1000 mg magnesium stearate. The powdered ingredients are first mixed together and then mixed with a solution of the PVP. The resulting composition can be dried, granulated, mixed with the magnesium stearate and compressed to tablet form using conventional equipment. An example of an aerosol formulation can be prepared by dissolving the compound, for example 5 to 400mg, of the invention in a suitable buffer solution, e.g. a phosphate buffer, adding a tonicifier, e.g. a salt such sodium chloride, if desired. The solution may be filtered, e.g., using a 0.2 micron filter, to remove impurities and contaminants. An embodiment, therefore, includes a pharmaceutical composition comprising a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof. In 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. Another embodiment includes a pharmaceutical composition comprising a compound of formula (I) for use in the treatment of mutant KRAS-driven cancers. Another embodiment includes a pharmaceutical composition comprising a compound of Formula (I) for use in the treatment of mutant KRAS-driven cancers. The following composition A and B illustrate typical compositions of the present invention, but serve merely as representative thereof. Composition A A compound of the present invention can be used in a manner known per se as the active ingredient for the production of tablets of the following composition: Per tablet Active ingredient 200 mg Microcrystalline cellulose 155 mg Corn starch 25 mg Talc 25 mg Hydroxypropylmethylcellulose 20 mg 425 mg Composition B A compound of the present invention can be used in a manner known per se as the active ingredient for the production of capsules of the following composition: Per capsule Active ingredient 100.0 mg Corn starch 20.0 mg Lactose 95.0 mg Talc 4.5 mg Magnesium stearate 0.5 mg 220.0 mg INDICATIONS AND METHODS OF TREATMENT The compounds of the invention induce a new binding pocket in KRAS by driving formation of a high affinity tri-complex between KRAS protein and the widely expressed cyclophilin A (CYPA), which inhibit KRAS interaction with downstream effectors, such as RAF and PI3K. Accordingly, the compounds of the invention are useful for inhibiting the propagating oncogenic MAPK and PI3K signaling, reducing cell proliferation, in particular cancer cells. Compounds of the invention are useful for termination of RAS signaling in cells that express RAS mutant, e.g. KRAS mutation driven pancreatic cancer, colorectal cancer, lung cancer, esophageal cancer, gallbladder cancer, melanoma ovarian cancer, endometrial cancer, etc. Alternatively, compounds of the invention are useful for termination of RAS signaling in malignant solid tumor where the oncogenic role of KRAS mutation is reinforced by dysregulation or mutation of effector pathways as MAPK, PI3K-AKT-mTOR (Mammalian target of rapamycin) driven signaling, for targeted therapy in pancreatic adenocarcinoma, colorectal cancer, non-small cell lung cancer, etc. Another embodiment includes a method of treating or preventing cancer in a mammal in need of such treatment, wherein the method comprises administering to said mammal a therapeutically effective amount of a compound of formula (I), a stereoisomer, tautomer or pharmaceutically acceptable salt thereof. SYNTHESIS The compounds of the present invention can be prepared by any conventional means. Suitable processes for synthesizing these compounds as well as their starting materials are provided in the schemes below and in the examples. All substituents, in particular, R¹ to R⁷, A¹ and A² are as defined above unless otherwise indicated. Furthermore, and unless explicitly otherwise stated, all reactions, reaction conditions, abbreviations and symbols have the meanings well known to a person of ordinary skill in organic chemistry. General synthetic routes for preparing the compound of formula (I) are shown below. Scheme 1 Compound of formula II was synthesized according to the procedure described in Intermediate A to H. Compound of formula (I) can be obtained by a coupling reaction between acid (III) and compound of formula (II) with coupling reagent(s), such as T3P, HATU, PyBOP and EDCI/HOBt, in the presence of a base, such as TEA, DIEPA and DMAP. Compounds of this invention can be obtained as mixtures of diastereomers or enantiomers, which can be separated by methods well known in the art, e.g. (chiral) HPLC or SFC. In another embodiment, compound of formula (I) can be obtained according to above scheme by using corresponding chiral starting materials. Compounds of this invention can be obtained as mixtures of diastereomers or enantiomers, which can be separated by methods well known in the art, e.g. (chiral) HPLC or SFC. In another embodiment, compound of formula (I) can be obtained according to above scheme by using corresponding chiral starting materials. This invention also relates to a process for the preparation of a compound of formula (I) comprising following step: a) coupling reaction between compound of formula (II),

in the presence of a coupling reagent and a base to form the compound of formula (I); wherein in step a) the coupling reagent can be, for example, T3P, HATU, PyBOP or EDCI/HOBt; the base can be, for example, TEA, DIEPA or DMAP. A compound of formula (I) or (Ia) when manufactured according to the above process is also an object of the invention. EXAMPLES The invention will be more fully understood by reference to the following examples. They should not, however, be construed as limiting the scope of the invention. ABBREVIATIONS The invention will be more fully understood by reference to the following examples. They should not, however, be construed as limiting the scope of the invention. Abbreviations used herein are as follows: ACN: acetonitrile aq.: Aqueous Boc-N-Me-Val-OH: N-(tert-Butoxycarbonyl)-N-methyl-L-valine (Boc)₂O: Di-tert-butyldicarbonate (R)-binap: (R)-(+)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl CDCl3: deuterated chloroform CD₃OD: deuterated methanol COMU: (1-Cyano-2-ethoxy-2- oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate DIEPA: N, N-diethylpropylamine DIBAL-H Diisobutylaluminium hydride DMAP: 4-Dimethylaminopyridine DMF: dimethyl formamide 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-oxid hexafluorophosphate) hr(s): hour(s) 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 spectroscopy (electron spray ionization) min(s): minute(s) MTBE: Methyl tert-butyl ether NMM: N-Methylmorpholine NMR: nuclear magnetic resonance NMO: 4-Methylmorpholine N-oxide obsd.: Observed Pd(dppf)Cl₂: [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(dtbpf)Cl₂ : [1,1′-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) prep-HPLC: preparative high performance liquid chromatography PyBOP: benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate RT or rt: room temperature sat.: saturated 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 GENERAL EXPERIMENTAL CONDITIONS Intermediates and final compounds were purified by flash chromatography using one of the following instruments: i) Biotage SP1 system and the Quad 12/25 Cartridge module. ii) ISCO combi-flash chromatography instrument. Silica gel brand and pore size: i) KP-SIL 60 Å, particle size: 40-60 µm; ii) CAS registry NO: Silica Gel: 63231-67-4, particle size: 47-60 micron silica gel; iii) ZCX from Qingdao Haiyang Chemical Co., Ltd, pore: 200-300 or 300-400. Intermediates and final compounds were purified by preparative HPLC on reversed phase column using XBridge^TM Prep-C18 (5 µm, OBDTM 30 × 100 mm) column, SunFire^TM Prep-C18 (5 µm, OBD^TM 30 × 100 mm) column, Phenomenex Synergi-C18 (10 µm, 25 × 150 mm) or Phenomenex Gemini-C18 (10 µm, 25 × 150 mm). Waters AutoP purification System (Sample Manager 2767, Pump 2525, Detector: Micromass ZQ and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water; acetonitrile and 0.1% FA in water or acetonitrile and 0.1% TFA in water). Or Gilson-281 purification System (Pump 322, Detector: UV 156, solvent system: acetonitrile and 0.05% ammonium hydroxide in water; acetonitrile and 0.225% FA in water; acetonitrile and 0.05% HCl in water; acetonitrile and 0.075% TFA in water; or acetonitrile and water). For SFC chiral separation, intermediates were separated by chiral column (Daicel chiralpak IC, 5 µm, 30 × 250 mm), AS (10 µm, 30 × 250 mm) or AD (10 µm, 30 × 250 mm) using Mettler Toledo Multigram III system SFC, Waters 80Q preparative SFC or Thar 80 preparative SFC, solvent system: CO₂ and IPA (0.5% TEA in IPA) or CO₂ and MeOH (0.1% NH₃∙H₂O in MeOH), back pressure 100bar, detection UV@ 254 or 220 nm. LC/MS spectra of compounds were obtained using a LC/MS (Waters^TM Alliance 2795- Micromass ZQ, Shimadzu Alliance 2020-Micromass ZQ or Agilent Alliance 6110-Micromass ZQ), LC/MS conditions were as follows (running time 3 or 1.5 mins): Acidic condition I: A: 0.1% TFA in H2O; B: 0.1% TFA in acetonitrile; Acidic condition II: A: 0.0375% TFA in H₂O; B: 0.01875% TFA in acetonitrile; Basic condition I: A: 0.1% NH3·H2O in H2O; B: acetonitrile; Basic condition II: A: 0.025% NH3·H2O in H2O; B: acetonitrile; Neutral condition: A: H₂O; B: acetonitrile. Mass spectra (MS): generally only ions which indicate the parent mass are reported, and unless otherwise stated the mass ion quoted is the positive mass ion (MH)⁺. NMR Spectra were obtained using Bruker Avance 400 MHz or 500MHz. The microwave assisted reactions were carried out in a Biotage Initiator Sixty microwave synthesizer. All reactions involving air-sensitive reagents were performed under an argon or nitrogen atmosphere. Reagents were used as received from commercial suppliers without further purification unless otherwise noted. PREPARATIVE EXAMPLES The following examples are intended to illustrate the meaning of the present invention but should by no means represent a limitation within the meaning of the present invention: Preparation of Intermediate Intermediate A 3-[5-bromo-1-ethyl-(2M)-2-[2-[(1S)-1-methoxyethyl]-3-pyridyl]indol-3-yl]-2,2-dimethyl- propan-1-ol The title intermediate A was prepared according to the following scheme: A¹¹ _A12 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, 222.1mmol) 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 for 5 hrs under N2 protection. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (EA/PE: 0- 50%) to afford 2-[(1S)-1-methoxyethyl]-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (compound A12, 55 g) as dark brown oil. MS: calc’d 264 (MH⁺), measured 264.1 (MH⁺). 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 hrs. The mixture was diluted with petroleum ether (1.0 L) and filtered. The collected solid was washed with petroleum ether (150 mL) for 2 times. The combined filtrate was concentrated under vacuum to give a residue. The residue was purified by silica gel chromatography (EA/PE: 0-50%) to afford methyl 3-[tert-butyl(diphenyl)silyl]oxy-2,2-dimethyl-propanoate (compound A2, 220 g) as colorless (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). 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 hrs, then concentrated under vacuum to remove EtOH, and diluted with ice water (1000 mL). The mixture was acidified by 1 M aq. solution of HCl until pH=3. The aqueous phase was extracted with EtOAc (600 mL) for 2 times. The combined organic layer was washed with brine (400 mL), dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated under vacuum. The residue was triturated with petroleum ether (300 mL) to afford 3-[tert-butyl(diphenyl)silyl]oxy- 2,2-dimethyl-propanoic acid (compound A3, 80 g) as a white 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). 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, 457.1mmol) 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 hrs, then concentrated under vacuum to afford 3-[tert-butyl(diphenyl)silyl]oxy-2,2-dimethyl-propanoyl chloride (compound A4, 171.4 g) as yellow oil and it was used in the next step without further purification. 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 slowly added a solution of SnCl4 (140 mL, 140 mmol, 1M in DCM) at 0 °C. The mixture was stirred at -10 °C for 0.5 hour. Then 5- bromoindole (27.4 g, 140 mmol) in DCM (150 mL) was added dropwise. After addition, the mixture was stirred at -10 °C for 15 min. The mixture was diluted with sat. aq. solution NaHCO3 (1000 mL) at 0 ^oC, then extracted with EtOAc (800 mL) for 2 times. The combined organic layer was washed with brine (600 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was triturated in EtOAc (100 mL) to afford 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.¹H 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). 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) was added LiBH4 (28.1mL, 112.2 mmol) at 0 °C under N₂ protection. The mixture was stirred at 60 °C for 12 hrs. Once the reaction was finished, the reaction was cooled to 25 ^oC and quenched with MeOH (20 mL). Then the mixture was diluted with EtOAc (300 mL) and washed with brine (250 mL). The organic layer was dried over anhydrous sodium sulfate, then filtered. The filtrate was concentrated under vacuum. The residue was dissolved in DCM (250 mL) and cooled to 10 °C, to which 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) were added. After being stirred at 10 °C for 2 hrs, the mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (EA/PE: 0-50%) to afford [3-(5-bromo-1H-indol-3-yl)-2,2- dimethyl-propoxy]-tert-butyl-diphenyl-silane (compound A6, 17.2 g,) as colorless oil.¹H 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). 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 being stirred at 25 °C for 1 hr, the mixture was quenched with sat. aq. solution of Na2SO3 (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 under vacuum. The residue was purified by silica gel chromatography (EA/PE: 0-20%) to afford [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.¹H 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: calc’d 646 (MH⁺), measured 645.9 (MH⁺). 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-dimethyl-propoxy]-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) were added potassium carbonate (9.6 g, 69.6 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.02g, 1.4 mmol). The mixture was stirred at 80 °C for 12 hrs 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 afford [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 brown oil.¹H 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: calc’d 657 (MH⁺), measured 657.0 (MH⁺). 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) were added cesium carbonate (35.7 g, 109.8 mmol) and iodoethane (8.7 mL, 109.8 mmol) at 0 °C. After being stirred at 25 °C for 12 hrs, the mixture was diluted with water (1000 mL) and extracted with EtOAc (500 mL). The combined organic layer was washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford [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 brown oil. MS: calc’d 685 (MH⁺), measured 685.0 (MH⁺). 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 being stirred at 50 °C for 12 hrs, 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 under vacuum. The residue was purified by silica gel chromatography (EA/PE: 0-20%) to afford 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, faster eluted) 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, slower eluted) as a yellow solid. Intermediate A: ¹H NMR (400MHz, CDCl3) δ ppm 8.83 (dd, J = 4.8, 2.0 Hz, 1H), 7.90 (d, J = 1.6 Hz, 1H), 7.69 (dd, J = 7.6, 1.6 Hz, 1H), 7.39 - 7.32 (m, 2H), 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 = 24.810.4 Hz, 2H), 3.07 (s, 3H), 2.74 (d, J = 14.0 Hz, 1H), 2.26 (d, J = 14.0 Hz, 1H), 1.60 – 1.52 (m, 1H), 1.48 (d, J = 6.4 Hz, 3H), 1.19 (t, J = 7.2 Hz, 3H), 0.77 (s, 6H). MS: calc’d 445 (MH⁺), measured 445.1 (MH⁺). X-ray crystallographic analysis of Intermediate A Absolute configuration structure of intermediate A was confirmed by X-ray crystallographic analysis of its single crystal. (Figure 1) Intermediate B Methyl (3S)-1-[(2S)-2-(tert-butoxycarbonylamino)-3-[3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-5-triisopropylsilyloxy-phenyl]propanoyl]hexahydropyridazine-3- carboxylate The intermediate B was prepared according to the following scheme: Step 1: Preparation of methyl (2S)-2-amino-3-(3-hydroxyphenyl)propanoate (compound B2) To a solution of L-M-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 hrs. The reaction mixture was cooled to 20°C and concentrated in vacuo to afford methyl (2S)-2-amino-3- (3-hydroxyphenyl)propanoate (compound B2, 6.2 g) as a yellow solid.¹H 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). 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-butyldicarbonate (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 by 1 M aq. solution of HCl until the pH=5. The mixture was extracted with ethyl acetate (100 mL) for 3 times. The combined organic phase was washed by brine (80 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under vacuum to afford methyl (2S)-2-(tert- butoxycarbonylamino)-3-(3-hydroxyphenyl)propanoate (compound B3, 40 g) as colorless gum. MS: calc’d 318 (MNa⁺), measured 318.3 (MNa⁺). 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 being stirred for 12 hrs at 25 ^oC, the mixture was diluted with water (250 mL) at 0°C and extracted with ethyl acetate (200 mL) for 3 times. The combined organic phase was washed by brine (80 mL) for 4 times, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under vacuum to give a residue. The residue was purified by silica gel chromatography (EA/PE: 0-20%) to afford methyl (2S)-2-(tert-butoxycarbonylamino)-3-(3- triisopropylsilyloxyphenyl)propanoate (compound B4, 60 g) as yellow oil. MS: calc’d 474 (MNa⁺), measured 474.2 (MNa⁺). Step 4: Preparation of methyl (2S)-2-(tert-butoxycarbonylamino)-3-[3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-5-triisopropylsilyloxy-phenyl]propanoate (compound B5) To a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-(3- triisopropylsilyloxyphenyl)propanoate (compound B4, 15.0 g, 33.2 mmol), 4,4'-di-tert-butyl- 2,2'-bipyridine (2.6 g, 9.9 mmol) and bis(pinacolato)diboron (12.6 g, 49.8 mmol) in hexane (200 mL) was added [Ir(OMe)(COD)]2 (2.2 g, 3.3 mmol). The mixture was degassed and purged with N₂ for 3 times. The resulting mixture was stirred at 70°C for 12 hrs. Then the reaction mixture was 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 afford 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 yellow oil. MS: calc’d 600 (MNa⁺), measured 600.3 (MNa⁺). 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 being stirred at 20°C for 1 hr, the reaction mixture was diluted with water (200 mL) and MeOH was removed under vacuum. The resulting mixture was acidified by 1 M aq. solution of HCl until the pH=5. The resulting mixture was extracted with EtOAc (250 mL) for 3 times. The organic phase was washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo to afford (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: calc’d 586 (MNa⁺), measured 586.3 (MNa⁺). 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 min. Then methyl (3S)-hexahydropyridazine-3-carboxylate hydrochloride salt (compound B7, 2.6 g, 14.9 mmol) was added. The resulting mixture was stirred at 20°C for 1.5 hrs. The mixture was diluted with water (200 mL) and extracted with EtOAc (100 mL) for 2 times. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, filtrated and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (EA/PE: 0-20%) to afford 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 yellow oil. MS: calc’d 690 (MH⁺), measured 690.4 (MH⁺). Intermediate C (8S,14S)-8-amino-22-ethyl-4-hydroxy-(21M)-21-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-18,18- 2,6 10,14 23,27 dimethyl-16-oxa-10,22,28-triazapentacyclo[18.5.2.1 .1 .0 ]nonacosa- 1(26),2,4,6(29),20,23(27),24-heptaene-9,15-dione The intermediate C was prepared according to the following scheme: C 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)Cl2 (87.7 mg, 0.13 mmol). The mixture was degassed and purged with N2 for 3 times. The resulting mixture was stirred at 85°C for 12 hrs. The reaction mixture was cooled to 20°C and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (EA/PE: 0-50%) to afford 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, 750 mg) as a yellow oil. MS: calc’d 928 (MH⁺), measured 928.3 (MH⁺). 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-dimethyl-propyl)-(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 hrs. The mixture was added into water (40 mL) and extracted with ethyl acetate (50 mL) for 3 times. The combined organic phase was washed by brine (40 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford (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: calc’d 914 (MH⁺), measured 914.5 (MH⁺). Step 3: Preparation of 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- 2,6 10,14 23,27 triazapentacyclo[18.5.2.1 .1 .0 ]nonacosa-1(26),2,4,6(29),20,23(27),24-heptaen-8- yl]carbamate (compound C3) To a solution 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, 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 hrs. The mixture was poured into water (40 mL) and exacted with EtOAc (30 mL) for 3 times. The combined organic phase was washed by brine (40mL), dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (EA/PE: 0-50%) to afford 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- 2,6 10,14 23,27 triazapentacyclo[18.5.2.1 .1 .0 ]nonacosa-1(26),2,4,6(29),20,23(27),24-heptaen-8- yl]carbamate (compound C3, 530 mg) as yellow oil. MS: calc’d 896 (MH⁺), measured 896.2 (MH⁺). Step 4: Preparation of 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- 2,6 10,14 23,27 triazapentacyclo[18.5.2.1 .1 .0 ]nonacosa-1(26),2,4,6(29),20,23(27),24-heptaen-8- yl]carbamate (compound C4) To a solution of 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- 2,6 10,14 23,27 triazapentacyclo[18.5.2.1 .1 .0 ]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 being stirred at 0 °C for 0.5 hr, the reaction mixture was diluted with water (30 mL) and exacted with EtOAc (40 mL) for 3 times. The combined organic phase was washed by brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum to afford 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- 2,6 10,14 23,27 triazapentacyclo[18.5.2.1 .1 .0 ]nonacosa-1(26),2,4,6(29),20,23(27),24-heptaen-8- yl]carbamate (compound C4, 390 mg) as colorless gum. MS: calc’d 740 (MH⁺), measured 740.2 (MH⁺). Step 5: Preparation of (8S,14S)-8-amino-22-ethyl-4-hydroxy-(21M)-21-[2-[(1S)-1- methoxyethyl]-3-pyridyl]-18,18-dimethyl-16-oxa-10,22,28- 2,6 10,14 23,27 triazapentacyclo[18.5.2.1 .1 .0 ]nonacosa-1(26),2,4,6(29),20,23(27),24-heptaene-9,15- dione (intermediate C) To a solution of 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- 2,6 10,14 23,27 triazapentacyclo[18.5.2.1 .1 .0 ]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 being stirred at 20 °C for 1 h, the reaction mixture was diluted with saturated aqueous solution of NaHCO3 (40 mL) and extracted with EtOAc (60 mL) for 3 times. The combined organic phase was washed by brine (30mL), dried over sodium sulfate, filtered and concentrated under vacuum to afford (8S,14S)-8-amino-22-ethyl-4-hydroxy-(21M)-21-[2-[(1S)-1- methoxyethyl]-3-pyridyl]-18,18-dimethyl-16-oxa-10,22,28- 2,6 10,14 23,27 triazapentacyclo[18.5.2.1 .1 .0 ]nonacosa-1(26),2,4,6(29),20,23(27),24-heptaene-9,15- dione (intermediate C, 330 mg) as yellow solid. MS: calc’d 640 (MH⁺), measured 640.3 (MH⁺). ¹H NMR (400MHz, CD3OD) δ ppm 8.72 - 8.71 (m, 1H), 7.89 (d, J = 7.6 Hz, 1H), 7.81 (s, 1H), 7.55 - 7.44 (m, 3H), 7.11 (s, 1H), 6.92 (s, 1H), 6.60 (s, 1H), 4.75 (t, J = 7.2 Hz, 1H), 4.60 (br. s, 1H), 4.41 (d, J = 12.8 Hz, 1H), 4.35 - 4.20 (m, 2H), 4.14 - 4.05 (m, 1H), 3.62 (d, J = 10.8 Hz, 1H), 3.49 (d, J = 10.8 Hz, 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 = 6.8 Hz, 3H), 0.86 - 0.82 (m, 3H), 0.59 - 0.56 (m, 3H). 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 The title compound was prepared in analogy to the preparation of Intermediate A by using 1-[6-[(1S)-1-methoxyethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]-4- methyl-piperazine (compound D5) instead of 2-[(1S)-1-methoxyethyl]-3-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)pyridine (compound A12). The compound D5 was prepared according to the following scheme: ^{D4 D5} 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) were added 4,4'-di-tert- butyl-2,2'-bipyridin (372.7 mg, 1.39 mmol) and [Ir(OMe)(COD)]2 (306.3 mg, 0.460 mmol). The mixture was stirred at 75 °C for 16 hours under N₂ protection. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (EA/PE: 0-20%) to afford 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 yellow oil.¹H 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). 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 for 40 hrs under N₂ protection. The reaction was quenched with saturated solution of Na2SO3 (40 mL) and the reaction mixture was extracted with EtOAc (30 mL, twice). The combined organic layer was washed with brine (50 mL), filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (EA/PE: 0-20%) to afford 3-bromo-5-iodo-2-[(1S)-1- methoxyethyl]pyridine (compound D2, 660 mg) as yellow oil. MS calc’d 342 (MH⁺), measured 341.8 (MH⁺). 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) were 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 for 12 hours under N₂ protection. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (EA/PE: 0-50%) to afford benzyl 4-[5-bromo-6-[(1S)- 1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound D4, 740 mg) as a yellow solid. MS calc’d 434.1 (MH⁺), measured 434.1 (MH⁺). 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) were added KOAc (418.0 mg, 4.26 mmol) and Pd(dppf)Cl2 (124.7 mg, 0.170 mmol). The reaction mixture was stirred at 90 °C for 12 hrs under N₂ protection. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column to afford 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 calc’d 482.3 (MH⁺), measured 482.2 (MH⁺). Intermediate E Methyl (3S)-1-[(2S)-3-(4-bromothiazol-2-yl)-2-(tert- butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylate The intermediate E was prepared according to the following scheme: 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 by ethyl acetate (200 mL, three times). The combined organic phase was washed by brine (150 mL, twice), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under vacuum to afford (4-bromothiazol-2-yl)methanol (compound E2, 6g) as colorless oil. 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 being stirred at 25^oC for 1 hour, the mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel column, eluted with ethyl acetate in petroleum ether = 0~10% to afford (4-bromothiazol-2-yl)methanol (compound E3, 6.0 g) as yellow oil. MS calc’d 255.9 (MH⁺), measured 255.9 (MH⁺). 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) was added n-butyllithium (10 mL, 25.22 mmol, 2.5 M) at -78 °C slowly, then the mixture was stirred for 0.5 hour at -78 °C.4-bromo-2-(bromomethyl)thiazole (compound E3, 5.4 g, 21.02 mmol) was added into above mixture at -78 °C which was stirred for another 1 hour. The mixture was quenched with 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 reversed-phase chromatography, eluted with ACN in H₂O (0.01% FA) = 0~60% to afford 4-bromo-2-[[(2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2- yl]methyl]thiazole (compound E5, 3.6 g) as yellow oil. MS calc’d 360(MH⁺), measured 359.9 (MH⁺). 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 by saturated aquesou solution of NaHCO₃ until pH=8. The mixture was extracted with EtOAc (80 mL, six times). The combined organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under vacuum to afford methyl (2S)-2-amino-3-(4- bromothiazol-2-yl)propanoate (compound E6, 3.1 g) as yellow oil. MS calc’d 264.9(MH⁺), measured 264.9 (MH⁺). 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) were added triethylamine (2.96, 29.23 mmol) and (Boc)2O (3.83 g, 17.54 mmol). The mixture was stirred at 30 °C for 12 hours. The mixture was concentrated under vacuum. The residue was purified by silica gel column, eluted with ethyl acetate in petroleum ether = 0~30% to afford methyl (2S)-3-(4-bromothiazol-2-yl)-2-(tert- butoxycarbonylamino)propanoate (compound E7, 3.2 g) as yellow oil. MS calc’d 387(MNa⁺), measured 386.9 (MNa⁺). 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) and 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 by 1 M aqueous solution of HCl until pH=5. The mixture was extracted with EtOAc (40 mL, twice). The combined organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under vacuum to afford (2S)-3-(4-bromothiazol-2-yl)-2-(tert- butoxycarbonylamino)propanoic acid (compound E8, 3.1 g) as yellow oil. MS calc’d 373(MNa⁺), measured 372.9 (MNa⁺). 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, three times). The combined organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel column and eluted with ethyl acetate in petroleum ether = 10~30% to afford methyl (3S)-1-[(2S)-3-(4-bromothiazol-2-yl)-2- (tert-butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylate (intermediate E, 2.4 g). MS calc’d 477(MH⁺), measured 476.9 (MH⁺). Intermediate F Methyl (3S)-1-[(2S)-3-(3-bromophenyl)-2-(tert-butoxycarbonylamino)propanoyl]- hexahydropyridazine-3-carboxylate The title intermediate was prepared in analogy to the preparation of Intermediate E by using methyl (2S)-2-amino-3-(3-bromophenyl)propanoate instead of methyl (2S)-2-amino-3-(4-bromothiazol-2-yl)propanoate (compound E6). Intermediate G (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- 2,5 9,13 22,26 tetrazapentacyclo[17.5.2.1 .1 .0 ]octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14- dione The compound intermediate G was prepared according to the following scheme: 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-[ -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, 0.02mmol). After being stirred at 90 °C for 12 hours under N2 protection, the mixture was concentrated under vacuum. The residue was purified by silica gel column, eluted with ethyl acetate in petroleum ether (30~60%) to afford 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, 100 mg) as yellow oil. MS calc’d 711(MH⁺), measured 711.1 (MH⁺). Step 2: Preparation of 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- 2,5 9,13 22,26 tetrazapentacyclo[17.5.2.1 .1 .0 ]octacosa-1(25),2,5(28),19,22(26),23-hexaen-20-yl]-6- [(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound G1) Compound G1 was prepared in analogy to the preparation of Intermediate C by using 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) and methyl (3S)-1-[(2S)-3-(4-bromothiazol-2-yl)-2-(tert- butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylate (Intermediate E) instead of 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). Step 3: Preparation of 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- 2,5 9,13 22,26 thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 .1 .0 ]octacosa-1(25),2,5(28),19,22(26),23- hexaen-7-yl]carbamate (compound G2) To a solution of benzyl 4-[(5M)-5-[(7S,13S)-7-(tert-butoxycarbonylamino)-21-ethyl-17,17- 2,5 9,13 22,26 dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 .1 .0 ]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 being stirred at 25 °C for 3 hours under H₂ balloon, the mixture was filtered and the filtrate was concentrated in vacuo to afford 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 being stirred at 25 °C for 15 min, the mixture was added formaldehyde (5 mg, 0.06 mmol) and NaBH₃CN (2.1 mg, 0.03 mmol) , then stirred for another 45 min. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by reversed phase chromatography to afford 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- 2,5 9,13 22,26 tetrazapentacyclo[17.5.2.1 .1 .0 ]octacosa-1(25),2,5(28),19,22(26),23-hexaen-7- yl]carbamate (compound G2, 17 mg). MS calc’d 829 (MH⁺), measured 829.1 (MH⁺). Step 4: Preparation 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- 2,5 9,13 22,26 tetrazapentacyclo[17.5.2.1 .1 .0 ]octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14- dione (intermediate G) To a mixture of 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- 2,5 9,13 22,26 tetrazapentacyclo[17.5.2.1 .1 .0 ]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 being stirred at 30 °C for 1 hour, the mixture was concentrated under vacuum and diluted with saturated NaHCO₃ solution (10 mL), extracted with EtOAc. The combined organic layer was washed with brine (15 mL), filtered and concentrated under vacuum to afford (7S,13S)-7- amino-21-ethyl-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]- 2,5 9,13 22,26 17,17-dimethyl-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 .1 .0 ]octacosa- 1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (intermediate G, 10 mg) as yellow oil. MS calc’d 729(MH⁺), measured 729.2 (MH⁺). Intermediate H (7S,13S)-7-amino-21-ethyl-(20M)-20-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-17,17-dimethyl- 2,5 9,13 22,26 15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 .1 .0 ]octacosa- 1(25),2,5(28),19,22(26),23-hexaene-8,14-dione The title intermediate was prepared in analogy 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). Intermediate I (8S,14S)-8-amino-22-ethyl-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3- 2,6 10,14 23,27 pyridyl]-18,18-dimethyl-16-oxa-10,22,28-triazapentacyclo[18.5.2.1 .1 .0 ]-nonacosa- 1(26),2,4,6(29),20,23(27),24-heptaene-9,15-dione The title intermediate was prepared in analogy to the preparation of Intermediate G by using Methyl (3S)-1-[(2S)-3-(3-bromophenyl)-2-(tert-butoxycarbonylamino)propanoyl]- hexahydropyridazine-3-carboxylate (intermediate F) instead of Methyl (3S)-1-[(2S)-3-(4- bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylate (intermediate E). Intermediate J (8S,14S)-8-amino-22-ethyl-(21M)-21-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-18,18-dimethyl- 2,6 10,14 23,27 16-oxa-10,22,28-triazapentacyclo[18.5.2.1 .1 .0 ]nonacosa- 1(26),2,4,6(29),20,23(27),24-heptaene-9,15-dione The title intermediate was prepared in analogy to the preparation of Intermediate C 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 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]-2,2-dimethyl-propan-1-ol (Intermediate A). Compound J1 was prepared in analogy 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). Intermediate K (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-17,17-dimethyl-21-(2,2,2- 2,5 9,13 22,26 trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 .1 .0 ]octacosa- 1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate K) The title compound was prepared in analogy to the preparation of Intermediate H by using 2,2,2-trifluoroethyl trifluoromethanesulfonate instead of iodoethane. 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- 2,5 9,13 22,26 tetrazapentacyclo[17.5.2.1 .1 .0 ]octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14- dione (Intermediate K) The title compound was prepared in analogy to the preparation of Intermediate G by using 2,2,2-trifluoroethyl trifluoromethanesulfonate instead of iodoethane. 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- 2,5 9,13 22,26 tetrazapentacyclo[17.5.2.1 .1 .0 ]octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14- dione The title intermediate M was prepared according to the following scheme: M13 intermediate M Step 1: Preparation of 1-(5-bromo-6-fluoro-1H-indol-3-yl)-3-((tert-butyldiphenylsilyl) 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) at 0 °C was added a solution of SnCl₄ (121.2 mL, 121.5 mmol, 1M in DCM) slowly. After being stirred at -40 °C for 0.5 hour, 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 another 15 min. After the reaction was completed, it was quenched with sat.NaHCO₃ aq. (800 mL), and the reaction mixture was extracted with EtOAc (900 mL, twice). The combined organic layer was washed with brine (700 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was triturated with the solution (100 mL, Petroleum ether: Ethyl acetate = 8:1) and filtered. The collected solid was dried in vacuo to afford 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 calc’d 552.1 (MH⁺), measured 552.1 (MH⁺). Step 2: Preparation of [3-(5-bromo-6-fluoro-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 LiBH₄ (48.4 mL, 193.49 mmol, 4 M in THF) dropwise at 0 °C. The mixture was stirred at 70 °C for 24 hrs under nitrogen atmosphere. After the reaction was completed, it was quenched by addition of water (600 mL) at 0 °C slowly and the reaction mixture was extracted with EtOAc (600 mL, twice). The combined organic layer was washed with brine (600 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica column chromatography (EtOAc in PE = 20% ~ 33%) to afford [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 calc’d 538.1 (MH⁺), measured 538.2 (MH⁺). 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 min. After the reaction was completed, it was quenched by sat. Na2SO3 aq. (400 mL) and EtOAc (400 mL) and the reaction mixture was filtered. The organic layer was washed with brine (100 mL), dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica column chromatography (EtOAc in PE = 0% ~ 2.5%) to afford [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 calc’d 664.0 (MH⁺), measured 664.1 (MH⁺). 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-dimethyl-propoxy]-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 a mixed solution of 1,4-dioxane (270 mL)/Toluene (90 mL) /water (90 mL) were added potassium phosphate (15.7 g, 73.92 mmol) and Pd(dppf)Cl2 (920 mg, 1.26 mmol). The mixture was stirred at 70 °C for 12 hrs under nitrogen atmosphere. After the reaction was completed, the mixture was filtered and concentrated in vacuo. The residue was purified by silica column chromatography (EtOAc in PE = 20% ~ 50%) to afford 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 calc’d 891.3 (MH⁺), measured 891.3 (MH⁺). 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 Cs₂CO₃ (15.9 g, 48.77 mmol) in DMF (200 mL) was added 2,2,2- trifluoroethyl trifluoromethanesulfonate (37.7 g, 162.56 mmol) dropwise at 0 °C, and the mixture was stirred at 20 °C for 12 hrs. After the reaction was completed, EtOAc (70 mL) and water (100 mL) were added and the layers were separated. The aqueous phase was extracted with EtOAc (70 mL, twice). Combined organic layer was washed with brine (100 mL, four times), dried over Na2SO4, filtered, and concentrated under vacuum to give a residue. The residue was purified by silica column chromatography to afford 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 yellow oil. MS calc’d 973.3 (MH⁺), measured 973.2 (MH⁺). 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- dimethyl-propyl]-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 hrs. After the reaction was completed, EtOAc (100 mL) and water (100 mL) were added and the layers were separated. The aqueous phase was extracted with EtOAc (100 mL, twice). The combined organic layer was washed with brine (80 mL, three times), dried over Na2SO4, filtered, and concentrated under vacuum to give a residue. The residue was purified by silica column chromatography (EtOAc in PE = 25% ~ 66%) to afford 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 calc’d 735.2 (MH⁺), measured 735.1 (MH⁺). 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)Cl₂ (537.1 mg, 0.73 mmol). The mixture was degassed and purged with nitrogen atmosphere for three times and the mixture was stirred at 90 °C for 12 hrs. After the reaction was completed, the mixture was cooled to room temperature. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give a residue, which was purified by silica column chromatography (EtOAc in PE = 25% ~ 66%) to afford 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, 5.2 g) as yellow oil. MS calc’d 783.3 (MH⁺), measured 783.3 (MH⁺). 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) To a mixture of 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-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, 4.9 g, 6.32 mmol) in toluene (60 mL)/1,4-dioxane (20 mL) / water (20 mL) were added K3PO4 (3.4 g, 15.81 mmol) and Pd(dtbpf)Cl₂ (412.2 mg, 0.63 mmol) under nitrogen atmosphere. The mixture was stirred at 70 °C for 12 hrs. After the reaction was completed, the mixture was concentrated in vacuo to give a residue. The residue was purified by silica column (EtOAc in PE = 10% ~ 75%) to afford 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 calc’d 1053.4 (MH⁺), measured 1053.3 (MH⁺). 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]hexahy- dropyridazine-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 hrs. After the reaction was completed, EtOAc (80 mL) and water (60 mL) were added and the layers were separated. The aqueous phase was extracted with EtOAc (80 mL, twice). The combined organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give (3S)-1-[(2S)-3-[4-[(2M)-2-[5-(4-benzyloxycarbonylpiperazin-1-yl)-2- [(1S)-1-methoxyethyl]-3-pyridyl]-6-fluoro-3-(3-hydroxy-2,2-dimethyl-propyl)-1-(2,2,2- trifluoroethyl)indol-5-yl]thiazol-2-yl]-2-(tert-butoxycarbonylamino)propanoyl]hexahy- dropyridazine-3-carboxylic acid (compound M11, 4.3 g) as a brown solid. MS calc’d 1039.4 (MH⁺), measured 1039.2 (MH⁺). Step 10: Preparation of benzyl 4-[5-[(7S,13S)-7-(tert-butoxycarbonylamino)-24- fluoro-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28- 2,5 9,13 22,26 tetrazapentacyclo[17.5.2.1 .1 .0 ]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]hexahy- dropyridazine-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 hrs. After the reaction was completed, the mixture was concentrated in vacuo, then diluted with water (80 mL), extracted with EtOAc (80 mL, twice). The combined organic layer was washed with brine (80 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica column chromatography (EtOAc in PE = 25% ~ 66%) to afford benzyl 4-[5-[(7S,13S)-7-(tert- butoxycarbonylamino)-24-fluoro-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4- 2,5 9,13 22,26 thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 .1 .0 ]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) as yellow gum. MS calc’d 1021.4 (MH⁺), measured 1021.2 (MH⁺). Step 11: Preparation of tert-butyl N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2- 2,5 9,13 22,26 trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 .1 .0 ]octacosa- 1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamate (compound M13) To a mixture of benzyl 4-[5-[(7S,13S)-7-(tert-butoxycarbonylamino)-24-fluoro-17,17- dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28- 2,5 9,13 22,26 tetrazapentacyclo[17.5.2.1 .1 .0 ]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 formaldehyde aqueous (775.0 mg, 9.55 mmol) in methanol (150 mL) 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 hrs. After the reaction was completed, the mixture was filtered and the filtrate was concentrated in vacuo to afford 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- 2,5 9,13 22,26 tetrazapentacyclo[17.5.2.1 .1 .0 ]octacosa-1(25),2,5(28),19,22(26),23-hexaen-7- yl]carbamate (compound M13, 2.6 g) as a brown solid. MS calc’d 901.3 (MH⁺), measured 901.3 (MH⁺). Step 12: Preparation 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- 2,5 9,13 22,26 trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 .1 .0 ]octacosa- 1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (intermediate M) To a mixture of tert-butyl N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4- 2,5 9,13 22,26 thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 .1 .0 ]octacosa-1(25),2,5(28),19,22(26),23- hexaen-7-yl]carbamate (compound M13, 2.6 g, 2.89 mmol) in DCM (18 mL) was added TFA (14.0 mL, 181.72 mmol). The mixture was stirred at 15 °C for 0.5 h. After the reaction was completed, the mixture was concentrated in vacuo and diluted with sat. NaHCO₃ (30 mL), extracted with EtOAc (30 mL, three times). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo 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- 2,5 9,13 22,26 tetrazapentacyclo[17.5.2.1 .1 .0 ]octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (intermediate M, 2.0 g) as a yellow solid, which was used directly in the next step. MS calc’d 801.3 (MH⁺), measured 801.2 (MH⁺). 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- 2,6 10,14 23,27 triazapentacyclo[18.5.2.1 .1 .0 ]nonacosa-1(26),2,4,6(29),20,23(27),24-heptaene-9,15- dione (Intermediate N) The title compound was prepared in analogy to the preparation of 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). The compound N1 was prepared in analogy 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. 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- 2,5 9,13 22,26 tetrazapentacyclo[17.5.2.1 .1 .0 ]octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14- dione (Intermediate O) The title compound was prepared in analogy to the preparation of 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 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- 2,5 9,13 22,26 thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 .1 .0 ]octacosa-1(25),2,5(28),19,22(26),23- hexaene-8,14-dione

The compound was prepared according to the following scheme:

P10 P 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) were added Cs2CO3 (4.85 g, 14.88 mmol), (R)-binap (92.6 mg, 0.15 mmol) and Pd(OAc)2 (66.8 mg, 0.3 mmol). The reaction mixture was degassed and purged with nitrogen for 3 times and the mixture was stirred at 100 °C for 12 hrs under nitrogen atmosphere. After being cooled 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 1-[5-bromo-6- [(1S)-1-methoxyethyl]-3-pyridyl]-4-(2,2,2-trifluoroethyl)piperazine (compound E2, 2.0 g) as yellow oil. MS calc’d 382.2 (MH⁺), measured 382.1 (MH⁺) 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)Cl2 (306.3 mg, 0.42 mmol). The mixture was degassed and purged with nitrogen for 3 times and the mixture was stirred at 90 °C for 12 hrs under nitrogen atmosphere. After being cooled to the room temperature, the reaction mixture was filtered, the filtrate was concentrated in vacuo to give a residue, which was purified by reversed phase column to afford 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 calc’d 430.2 (MH⁺), measured 348.4 (M-C₆H₁₀+H⁺). 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 K3PO4 (2.1 g, 9.5 mmol) and Pd(dppf)Cl2 (231 mg, 0.37 mmol). The mixture was degassed by bubbling nitrogen for 2 min, and the reaction mixture was stirred at 70 °C for 12 hrs. After being cooled to room temperature, the reaction mixture was filtered. The filtrate was concentrated in vacuo to give a residue, which was purified by column chromatography (EtOAc in PE : 30% - 60%) to afford [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 calc’d 839.3 (MH⁺), measured 839.3 (MH⁺) 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 Cs2CO3 (1.1 g, 3.44 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (2.7 g, 11.63 mmol) at 0 °C. After being stirred at 20 °C for 15 hrs, the reaction mixture was poured into water (100 mL), and extracted with EtOAc (50 mL, three times). The combined organic was washed with brine (50 mL, three times), dried over Na2SO4, filtered and concentrated under vacuum to give a residue which was purified by column chromatography (EtOAc in PE: 30% - 40%) to afford [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 calc’d 921.3 (MH⁺), measured 921.4 (MH⁺). 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 hrs. After being cooled 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 (EtOAc in PE : 30% - 60%) to afford 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 yellow oil. MS calc’d 683.2 (MH⁺), measured 683.1 (MH⁺). 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)Cl₂ (40 mg, 0.1 mmol). The reaction mixture was degassed by bubbling nitrogen for 5 min then stirred at 80 °C for 15 hrs. After being cooled 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 (EtOAc in PE : 30% - 50%) to afford 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 yellow gum. MS calc’d 731.4 (MH⁺), measured 731.4 (MH⁺). 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). To a mixture 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, 0.3 g, 0.41 mmol) and methyl (3S)-1-[(2S)-3-(4-bromothiazol-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) were added K₃PO₄ (221.3 mg, 1.04 mmol) and Pd(dtbpf)Cl₂ (27.05 mg, 0.04 mmol). The mixture was stirred at 70 °C for 12 hrs under nitrogen atmosphere. After being cooled 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 (EtOAc in PE : 60% - 80%) to afford 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) as yellow gum. MS calc’d 1001.4 (MH⁺), measured 1001.4 (MH⁺). 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 Me₃SnOH (200.0 mg, 1.11 mmol). The mixture was stirred at 60 °C for 12 hrs. The reaction mixture was concentrated under vacuum 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, twice). The combined organic layer was washed with brine (20 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum to afford (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 calc’d 987.4 (MH⁺), measured 987.4 (MH⁺). Step 9: Preparation of 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- 2,5 9,13 22,26 tetrazapentacyclo[17.5.2.1 .1 .0 ]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-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, 0.19 mmol) in DCM (20 mL) were 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 being stirred at 20 °C for 12 hrs, the reaction mixture was poured into water (20 mL) and extracted with EtOAc (20 mL, three times). The combined organic layer was washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under vacuum to give a residue which was purified by column chromatography (EtOAc in PE : 50% - 70%) to afford 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- 2,5 9,13 22,26 tetrazapentacyclo[17.5.2.1 .1 .0 ]octacosa-1(25),2,5(28),19,22(26),23-hexaen-7- yl]carbamate (compound P10, 110.0 mg) as a yellow solid. MS calc’d 969.4 (MH⁺), measured 969.5 (MH⁺). Step 10: Preparation of (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- 2,5 9,13 22,26 (2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 .1 .0 ]- octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate P). To a solution of 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- 2,5 9,13 22,26 trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 .1 .0 ]octacosa- 1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamate (compound P10, 110.0 mg, 0.11 mmol) in DCM (1 mL) was added TFA (1.0 mL, 12.98 mmol). The mixture was stirred at 20 °C for 1 h. After the reaction was completed, the reaction mixture was concentrated under vacuum to give a residue. Sat. NaHCO3 aq. (20 mL) was added and the mixture was extracted with EtOAc (15 mL, three times). The combined organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford (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- 2,5 9,13 22,26 tetrazapentacyclo[17.5.2.1 .1 .0 ]-octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14- dione (Intermediate P, 98.0 mg) as a yellow solid. MS calc’d 869.4 (MH⁺), measured 869.2 (MH⁺). 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-tetrazapentacyclo- 2,5 9,13 22,26 [17.5.2.1 .1 .0 ]octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione

Step 1: Preparation of 4-[5-bromo-6-[(1S)-1-methoxyethyl]-3-pyridyl]morpholine 5 (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) were added Cs₂CO₃ (57.2 g, 175.45 mmol), (R)-binap (2.7 g, 4.39 mmol) and Pd(OAc)2 (0.98 g, 4.39 mmol). The reaction mixture was degassed and purged with nitrogen for 3 times and the mixture was stirred at 90 °C for 12 hrs under nitrogen atmosphere. After being cooled 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 afford 4-[5-bromo-6-[(1S)-1-methoxyethyl]-3- pyridyl]morpholine (compound Q1, 21 g) as yellow oil. MS calc’d 301.1 (MH⁺), measured 301.1 (MH⁺). 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)Cl2 (4.4 g, 6.31 mmol). The mixture was degassed and purged with nitrogen for 3 times and the mixture was stirred at 90 °C for 12 hrs under nitrogen atmosphere. After being cooled to the room temperature, the reaction mixture was filtered, the filtrate was concentrated in vacuo to give 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 calc’d 349.2 (MH⁺), measured 349.2 (MH⁺). 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-dimethyl-propoxy]-tert-butyl-diphenyl-silane (compound M5, 31 g, 46.65 mmol) in 1,4-dioxane (420 mL) and water (80 mL) was added K3PO4 (29.7 g, 2.33 mmol) and Pd(dppf)Cl₂ (1.7 g, 0.29 mmol). The mixture was degassed by bubbling nitrogen for 2 min, and the reaction mixture was stirred at 90 °C for 18 hrs. After being cooled to room temperature, the reaction mixture was extracted with EA (200 mL, three times). The combined organic layer was 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 afford [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 yellow oil. MS calc’d 758.3 (MH⁺), measured 758.3 (MH⁺). 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 Cs2CO3 (19.3 g, 59.3 mmol) and iodoethane (6.16 g, 39.53 mmol) at 0 °C. After being stirred at 20 °C for 16 hrs, the reaction mixture was poured into water (200 mL), and extracted with EtOAc (200 mL, three times). The combined organic layer was washed with brine (10 mL, three times), dried over Na2SO4, filtered and concentrated under vacuum to give a residue, which was purified by column chromatography to afford [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 yellow oil. MS calc’d 786.3 (MH⁺), measured 786.4 (MH⁺). 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 hrs. After being cooled to room temperature, the reaction mixture were added with EtOAc (300 mL) and water (300 mL) and the layers were separated. The aqueous phase was extracted with EtOAc (200 mL, three times). The combined organic layer was washed with brine (200 mL, four times), dried over Na₂SO₄, filtered, and concentrated under vacuum to give a residue. The residue was purified by column chromatography to afford 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, faster eluted) 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, slower eluted) as a colorless foam. Compound Q5: MS calc’d 548.2 (MH⁺), measured 548.2 (MH⁺).¹H 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). X-ray crystallographic analysis of compound Q5 Absolute configuration structure of compound Q5 was confirmed by X-ray crystallographic analysis of its single crystal. (Figure 2). 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)Cl₂ (0.8 g, 1.09 mmol). The reaction mixture was degassed by bubbling nitrogen for 5 min then stirred at 90 °C for 15 hrs. After being cooled 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 afford 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 calc’d 596.4 (MH⁺), measured 596.4 (MH⁺). 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) To a mixture of 3-[1-ethyl-6-fluoro-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3- pyridyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indol-3-yl]-2,2-dimethyl-propan-1-ol (compound Q7, 4.5 g, 7.56 mmol) and methyl (3S)-1-[(2S)-3-(4-bromothiazol-2-yl)-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) were added K3PO4 (4.0 g, 18.89 mmol) and Pd(dtbpf)Cl₂ (492.5 mg, 0.75 mmol). The mixture was stirred at 70 °C for 12 hrs under nitrogen atmosphere. After being cooled 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 afford 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 colorless gum. MS calc’d 866.4 (MH⁺), measured 866.4 (MH⁺). 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 Me3SnOH (3.2 g, 17.55 mmol). The mixture was stirred at 60 °C for 48 hrs. The reaction mixture was concentrated under vacuum to give a residue. EtOAc (200 mL) and water (100 mL) were added to the residue and the layers were separated. The aqueous phase was extracted with EtOAc (150 mL, twice). The combined organic layer was washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated under vacuum to afford (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 calc’d 852.4 (MH⁺), measured 852.4 (MH⁺). Step 9: Preparation of tert-butyl N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia- 2,5 9,13 22,26 9,21,27,28-tetrazapentacyclo[17.5.2.1 .1 .0 ]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) were 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 being stirred at 20 °C for 12 hrs, the reaction mixture was poured into water (100 mL) and extracted with EtOAc (100 mL, three times). The combined organic layer was washed with brine (30 mL), dried over Na₂SO₄, filtered and concentrated under vacuum to give a residue which was purified by column chromatography to afford 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- 2,5 9,13 22,26 tetrazapentacyclo[17.5.2.1 .1 .0 ]octacosa-1(25),2,5(28),19,22(26),23-hexaen-7- yl]carbamate (compound Q10, 1.2 g) as a yellow oil. MS calc’d 834.4 (MH⁺), measured 834.4 (MH⁺). Step 10: Preparation of (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- 2,5 9,13 22,26 tetrazapentacyclo[17.5.2.1 .1 .0 ]octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14- dione (Intermediate Q) To a solution of tert-butyl N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28- 2,5 9,13 22,26 tetrazapentacyclo[17.5.2.1 .1 .0 ]octacosa-1(25),2,5(28),19,22(26),23-hexaen-7- yl]carbamate (compound Q10, 1.2 g, 1.44 mmol) in DCM (12 mL) was added TFA (6.0 mL). The mixture was stirred at 20 °C for 3 hrs. After the reaction was completed, the reaction mixture was concentrated under vacuum to give a residue. Sat. NaHCO₃ aq. (60 mL) was added and the mixture was extracted with EtOAc (80 mL, three times). The combined organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford (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- 2,5 9,13 22,26 tetrazapentacyclo[17.5.2.1 .1 .0 ]octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate Q, 1 g) as a yellow solid. MS calc’d 734.3 (MH⁺), measured 734.3 (MH⁺). 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- 2,6 10,14 23,27 triazapentacyclo[18.5.2.1 .1 .0 ]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 The compound was prepared according to the following scheme: Example 1 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) at 0 °C was added HATU (641.9 mg, 1.69 mmol) and DIEA (272.7 mg, 2.11 mmol). After being stirred at 0 °C for 20 min, the reaction mixture was added with tert-butyl (2S)-3-methyl-2-(methylamino)butanoate (316.2 mg, 1.69 mmol) and then it was stirred at 25 °C for another 1.5 hrs. After the reaction was completed, the reaction mixture was purified by reversed phase column to afford tert-butyl (2S)-2-[[3- (methoxymethylene)cyclobutanecarbonyl]-methyl-amino]-3-methyl-butanoate (compound 1B, 210.0 mg) as colorless oil. MS calc’d 312.2 (MH⁺), measured 312.2 (MH⁺). 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 dropwise with TFA (0.5 mL) slowly at 0 °C. The reaction mixture was stirred at 25 °C for 2.5 hrs. After the reaction was completed, it was concentrated under vacuum , 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 layer was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum to afford tert-butyl (2S)-2-[(3-formylcyclobutanecarbonyl)-methyl-amino]-3-methyl-butanoate (compound 1C, 130.0 mg) as colorless oil which was used directly in the next step. MS calc’d 298.2 (MH⁺), measured 320.3, (MNa⁺). 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 being stirred at 0 °C for 0.5 h, the reaction was added with tert-butyl (2S)-2-[(3- formylcyclobutanecarbonyl)-methyl-amino]-3-methyl-butanoate (compound 1C, 100.0 mg, 0.34 mmol) and stirred at rt for 4 hrs. After the reaction was completed, the reaction mixture was extracted with EtOAc (20 mL, twice). The combined organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. The residue was purified by reversed phase column to afford tert-butyl (2S)-3-methyl-2-[methyl-[3-[(E)-2- methylsulfonylvinyl]-cyclobutanecarbonyl]amino]butanoate (compound 1E, 90 mg) as yellow oil. MS calc’d 374.2 (MH⁺), measured 374.3 (MH⁺). 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 being stirred at 25 °C for 1 h, the reaction mixture was concentrated under vacuum to get a residue, which was purified by reversed phase column to afford (2S)-3-methyl-2-[methyl-[3-[(E)-2- methylsulfonylvinyl]cyclobutanecarbonyl]amino]butanoic acid (compound 1F, 70.0 mg) as yellow oil. MS calc’d 318.2 (MH⁺), measured 318.2 (MH⁺). Step 5: Preparation of 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- 2,6 10,14 23,27 triazapentacyclo[18.5.2.1 .1 .0 ]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 being stirred for 10 min, the reaction was added with (8S,14S)-8-amino-22-ethyl-4- hydroxy-(21M)-21-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-18,18-dimethyl-16-oxa-10,22,28- 2,6 10,14 23,27 triazapentacyclo[18.5.2.1 .1 .0 ]nonacosa-1(26),2,4,6(29),20,23(27),24-heptaene-9,15- dione (Intermediate C, 30.0 mg, 0.05 mmol). After being stirred at 25 °C for 2 hrs, the reaction mixture was purified by prep-HPLC to afford 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- 2,6 10,14 23,27 triazapentacyclo[18.5.2.1 .1 .0 ]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) as a yellow solid. MS calc’d 939.5 (MH⁺), measured 939.5 (MH⁺).¹H 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 - 3.54 (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. Example 2 N-[(1S)-1-[[(8S,14S)-22-ethyl-(21M)-21-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-18,18-dimethyl- 2,6 10,14 23,27 9,15-dioxo-16-oxa-10,22,28-triazapentacyclo[18.5.2.1 .1 .0 ]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 The title compound was prepared in analogy to the preparation of Example 1 by using (8S,14S)-8-amino-22-ethyl-(21M)-21-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-18,18-dimethyl-16- 2,6 10,14 23,27 oxa-10,22,28-triazapentacyclo[18.5.2.1 .1 .0 ]nonacosa-1(26),2,4,6(29),20,23(27),24- heptaene-9,15-dione (Intermediate J) instead of (8S,14S)-8-amino-22-ethyl-4-hydroxy-(21M)- 21-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-18,18-dimethyl-16-oxa-10,22,28- 2,6 10,14 23,27 triazapentacyclo[18.5.2.1 .1 .0 ]nonacosa-1(26),2,4,6(29),20,23(27),24-heptaene-9,15- dione (Intermediate C). Example 2 (6.4 mg) was obtained as a yellow solid. MS calc’d 923.5 (MH⁺), measured 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, 1H), 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. 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- 2,6 10,14 23,27 triazapentacyclo[18.5.2.1 .1 .0 ]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 The title compound was prepared in analogy to the preparation of Example 1 by using (8S,14S)-8-amino-22-ethyl-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3- 2,6 10,14 23,27 pyridyl]-18,18-dimethyl-16-oxa-10,22,28-triazapentacyclo[18.5.2.1 .1 .0 ]-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) instead of (8S,14S)-8-amino-22-ethyl-4-hydroxy-(21M)-21-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-18,18- 2,6 10,14 23,27 dimethyl-16-oxa-10,22,28-triazapentacyclo[18.5.2.1 .1 .0 ]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). Example 3 (6.0 mg) was obtained as a white solid. MS calc’d 1021.6 (MH⁺), measured 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, 1H), 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. The compound 3D was prepared according to the following scheme: 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) were added DIEA (13.7 mL, 79.04 mmol) and HATU (14.4 g, 37.94 mmol) at 0 °C. After being stirred at rt for 0.5 h, the reaction was added with tert-butyl (2S)-3-methyl-2-(methylamino)butanoate (5.9 g, 31.62 mmol). The reaction mixture was stirred at 20 °C for 1 h. After the reaction was completed, the reaction mixture was diluted with water (80 mL), extracted with EtOAc (80 mL, three times). The combined organic layer was washed with brine (150 mL, three times), dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by column chromatography (EtOAc in PE=10%~25%) to afford trans- methyl 3-[[(1S)-1-tert-butoxycarbonyl-2-methyl-propyl]-methyl- carbamoyl]cyclobutanecarboxylate (compound 3B, 10.0 g) as yellow oil. MS calc’d 328.2 (MH⁺), measured 328.3 (MH⁺). 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) was added lithium borohydride (20.0 mL, 4 M in THF, 80.0 mmol) dropwise at 0 °C under nitrogen atmosphere. After being stirred at rt for 48 hrs, the reaction was quenched with H₂O (300 mL), extracted with EtOAc (300 mL, twice). The combined organic layer was washed with brine (300 mL), dried over Na2SO4, filtered and concentrated in vacuo to afford trans-tert-butyl (2S)-2-[[3- (hydroxymethyl)cyclobutanecarbonyl]-methyl-amino]-3-methyl-butanoate(compound 3C, 8.0 g, 26.72 mmol) as colorless oil. MS calc’d 300.2 (MH⁺), measured 300.3 (MH⁺). 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 being stirred at 20 °C for 2 h, the mixture was concentrated in vacuo to get a residue, which was purified by column chromatography (EtOAc in PE=5%~10%) to afford trans-tert-butyl (2S)-2-[(3-formylcyclobutanecarbonyl)-methyl-amino]- 3-methyl-butanoate (compound 3D, 6.8 g) as yellow oil. MS calc’d 298.2 (MH⁺), measured 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). 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- 2,6 10,14 23,27 [18.5.2.1 .1 .0 ]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 The title compound was prepared in analogy to the preparation of Example 1 by using trans-tert-butyl (2S)-2-[(3-formylcyclobutanecarbonyl)-methyl-amino]-3-methyl-butanoate (compound 3D) 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 calc’d 939.5 (MH⁺), measured 939.7 (MH⁺). 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- 2,5 9,13 22,26 tetrazapentacyclo[17.5.2.1 .1 .0 ]octacosa-1(25),2,5(28),19,22(26),23-hexaen-7- yl]carbamoyl]-2-methyl-propyl]-N-methyl-3-[(E)-2- methylsulfonylvinyl]cyclobutanecarboxamide The title compound was prepared in analogy to the preparation of Example 1 by using (7S,13S)-7-amino-21-ethyl-(20M)-20-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-17,17-dimethyl-15- 2,5 9,13 22,26 oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 .1 .0 ]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) instead of (8S,14S)-8-amino-22-ethyl-4-hydroxy-(21M)-21-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-18,18- 2,6 10,14 23,27 dimethyl-16-oxa-10,22,28-triazapentacyclo[18.5.2.1 .1 .0 ]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). Example 5 (115.8 mg) was obtained as a yellow solid. MS calc’d 930.4 (MH⁺), measured 930.4 (MH⁺).¹H 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, 1H), 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, 1H), 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, 9 H), 0.89 - 0.83 (m, 3H), 0.52 (s, 3H) ppm. 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- 2,5 9,13 22,26 tetrazapentacyclo[17.5.2.1 .1 .0 ]octacosa-1(25),2,5(28),19,22(26),23-hexaen-7- yl]carbamoyl]-2-methyl-propyl]-N-methyl-3-[(E)-2- methylsulfonylvinyl]cyclobutanecarboxamide The title compound was prepared in analogy to the preparation of Example 1 by using (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- 2,5 9,13 22,26 tetrazapentacyclo[17.5.2.1 .1 .0 ]octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate G) instead of (8S,14S)-8-amino-22-ethyl-4-hydroxy-(21M)-21-[2-[(1S)-1- methoxyethyl]-3-pyridyl]-18,18-dimethyl-16-oxa-10,22,28- 2,6 10,14 23,27 triazapentacyclo[18.5.2.1 .1 .0 ]nonacosa-1(26),2,4,6(29),20,23(27),24-heptaene-9,15- dione (Intermediate C). Example 6 (66.8 mg) was obtained as a yellow solid. MS calc’d 1028.5 (MH⁺), measured 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. 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- 2,5 9,13 22,26 tetrazapentacyclo[17.5.2.1 .1 .0 ]octacosa-1(25),2,5(28),19,22(26),23-hexaen-7- yl]carbamoyl]-2-methyl-propyl]-N-methyl-3-[(E)-2- methylsulfonylvinyl]cyclobutanecarboxamide The title compound was prepared in analogy to the preparation of Example 1 by using (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- 2,5 9,13 22,26 tetrazapentacyclo[17.5.2.1 .1 .0 ]octacosa-1(25),2,5(28),19,22(26),23-hexaene-8,14-dione (Intermediate L) instead of (8S,14S)-8-amino-22-ethyl-4-hydroxy-(21M)-21-[2-[(1S)-1- methoxyethyl]-3-pyridyl]-18,18-dimethyl-16-oxa-10,22,28- 2,6 10,14 23,27 triazapentacyclo[18.5.2.1 .1 .0 ]nonacosa-1(26),2,4,6(29),20,23(27),24-heptaene-9,15- dione (Intermediate C). Example 7 (25.7 mg) was obtained as an off-white solid. MS calc’d 1082.5 (MH⁺), measured 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, 4H), 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. 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- 2,6 10,14 23,27 triazapentacyclo[18.5.2.1 .1 .0 ]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 The title compound was prepared in analogy to the preparation of Example 1 by using tert- butyl (2S)-3-methyl-2-[methyl-[3-[(E)-2-methylsulfonylvinyl]azetidine-1- carbonyl]amino]butanoate (compound 8D) 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 calc’d 940.5 (MH⁺), measured 940.5 (MH⁺).¹H NMR (400MHz, Methanol-d4) δ = 8.79 (d, J = 3.2 Hz, 1 H), 8.15 - 8.09 (m, 1 H), 8.07 - 7.98 (m, 1 H), 7.73 - 7.67 (m, 1 H), 7.65 - 7.57 (m, 1 H), 7.54 - 7.51 (m, 1 H), 7.44 - 7.36 (m, 1 H), 7.18 - 7.09 (m, 1 H), 7.08 - 7.01 (m, 1 H), 6.82 - 6.72 (m, 1 H), 6.63 - 6.53 (m, 1 H), 5.69 - 5.59 (m, 1 H), 4.52 - 4.39 (m, 1 H), 4.36 - 4.27 (m, 3 H), 4.21 (d, J = 11.2 Hz, 1 H), 4.05 - 3.85 (m, 3 H), 3.81 - 3.75 (m, 1 H), 3.72 - 3.66 (m, 1 H), 3.58 - 3.50 (m, 1 H), 3.27 (d, J = 2.8 Hz, 3 H), 3.03 - 2.97 (m, 4 H), 2.97 - 2.93 (m, 1 H), 2.77 (s, 2 H) 2.68 (s, 2 H), 2.16 - 2.05 (m, 2 H), 1.94 - 1.85 (m, 1 H), 1.61 (d, J = 7.2 Hz, 1 H), 1.48 - 1.45 (m, 4 H), 1.35 - 1.28 (m, 4 H), 1.07 (t, J = 6.4 Hz, 3 H), 0.94 - 0.89 (m, 3 H), 0.88 - 0.83 (m, 6 H), 0.69 (s, 3 H) ppm. The compound 8D was prepared according to the following scheme: 8D 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 nitrogen atmosphere. After being stirred at 0 °C for 10 min, the reaction mixture was added with tert-butyl 3-formylazetidine-1-carboxylate (compound 8A, 500.0 mg, 2.7 mmol). The reaction mixture was stirred at 0 °C for another 0.5 h. After the reaction was completed, it was quenched with water (50 mL) and extracted with EtOAc (50 mL, twice). The combined organic layer was washed with brine (80 mL), dried over sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography (EtOAc in PE 25% - 50%) to afford tert-butyl 3-[(E)-2-methylsulfonylvinyl]azetidine-1-carboxylate (compound 8B, 500.0 mg) as a colorless oil. MS calc’d 262.1 (MH⁺), measured 205.7 (M-C₄H₉+H⁺) 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 the reaction was completed, the reaction mixture was concentrated under vacuum to afford 3-[(E)-2-methylsulfonylvinyl]azetidine;2,2,2- trifluoroacetic acid (compound 8C, 550.0 mg, crude) as yellow gum. MS calc’d 162.1 (MH⁺), measured 162.1 (MH⁺). 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 being stirred at 0 °C for 0.5 h, the reaction was added with 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) at 0 °C. After being stirred at 20 °C for another 1 h, the reaction was quenched with sat. NaHCO3 aq. (30 mL) and extracted with DCM (10 mL, twice), washed with brine (15 mL), dried over Na₂SO₄, filtered and concentrated under vacuum to give a residue. The residue was purified by column chromatography (EtOAc in PE: 9% - 16%) to afford tert-butyl (2S)-3-methyl-2-[methyl-[3-[(E)-2-methylsulfonylvinyl]azetidine-1- carbonyl]amino]butanoate (compound 8D, 380.0 mg) as colorless oil. MS calc’d 375.2 (MH⁺), measured 375.2 (MH⁺). 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- 2,6 10,14 23,27 triazapentacyclo[18.5.2.1 .1 .0 ]nonacosa-1(26),2,4,6(29),20,23(27),24-heptaen-8- yl]carbamoyl]-2-methyl-propyl]-N-methyl-4-[(E)-2-methylsulfonylvinyl]piperidine-1- carboxamide The title compound was prepared in analogy to the preparation of Example 1 by using tert- butyl (2S)-3-methyl-2-[methyl-[4-[(E)-2-methylsulfonylvinyl]piperidine-1- carbonyl]amino]butanoate (compound 9D) 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 calc’d 968.5 (MH⁺), measured 968.5 (MH⁺).¹H 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). The compound 9D was prepared in analogy to the preparation of compound 8D by using tert-butyl 4-formylpiperidine-1-carboxylate (compound 9A) instead of tert-butyl 3- formylazetidine-1-carboxylate (compound 8A). 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- 2,5 9,13 22,26 tetrazapentacyclo[17.5.2.1 .1 .0 ]octacosa-1(25),2,5(28),19,22(26),23-hexaen-7- yl]carbamoyl]-2-methyl-propyl]-N-methyl-3-[(E)-2- methylsulfonylvinyl]cyclobutanecarboxamide The title compound was prepared in analogy to the preparation of Example 1 by using (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-17,17-dimethyl-21-(2,2,2- 2,5 9,13 22,26 trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 .1 .0 ]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) instead of (8S,14S)-8-amino-22-ethyl-4-hydroxy-(21M)-21-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-18,18- 2,6 10,14 23,27 dimethyl-16-oxa-10,22,28-triazapentacyclo[18.5.2.1 .1 .0 ]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). Example 10 (45.9 mg) was obtained as an off-white solid. MS calc’d 984.4 (MH⁺), measured 984.4 (MH⁺).¹H 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, 1H), 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. 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- 2,6 10,14 23,27 triazapentacyclo[18.5.2.1 .1 .0 ]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 The title compound was prepared in analogy to the preparation of Example 1 by using trans-tert-butyl (2S)-2-[(3-formylcyclobutanecarbonyl)-methyl-amino]-3-methyl-butanoate (compound 3D) and 1-[ethoxy-[fluoro(methylsulfonyl)methyl]phosphoryl]oxyethane (compound 11A) instead of tert-butyl (2S)-2-[(3-formylcyclobutanecarbonyl)-methyl-amino]-3-methyl- butanoate (compound 1C) and diethyl methylsulfonylmethylphosphonate (compound 1D). Example 11 (2.8 mg) was obtained as a white solid. MS calc’d 957.5 (MH⁺), measured 957.5 (MH⁺).¹H 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). The compound 11A was prepared according to the following scheme: SelectFlur, LiHMDS 1^{D 11A} Preparation of 1-[ethoxy-[fluoro(methylsulfonyl)methyl]phosphoryl]oxyethane (compound 11A) To the 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 being stirred at -60 °C for 0.5 h, the reaction mixture was added with selectfluor (923.3 mg, 2.61 mmol). The reaction mixture was stirred at -60 °C for another 2 hrs. The reaction mixture was stirred at -20 °C for another 2 hrs. After being stirred at 0 °C for another 2 hrs, the reaction was quenched by addition of water (20 mL), then diluted with water (100 mL) and extracted with EtOAc (50 mL, four times). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under vacuum to afford 1-[ethoxy- [fluoro(methylsulfonyl)methyl]phosphoryl]oxyethane (compound 11A, 490.0 mg) as yellow oil, which was used in the next step.¹H 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). 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- 2,5 9,13 22,26 tetrazapentacyclo[17.5.2.1 .1 .0 ]octacosa-1(25),2,5(28),19,22(26),23-hexaen-7- yl]carbamoyl]-2-methyl-propyl]-N-methyl-3-[(E)-2- methylsulfonylvinyl]cyclobutanecarboxamide The title compound was prepared in analogy to the preparation of Example 1 by using (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-17,17-dimethyl-21-(2,2,2- 2,5 9,13 22,26 trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 .1 .0 ]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) instead of (8S,14S)-8-amino-22-ethyl-4-hydroxy-(21M)-21-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-18,18- 2,6 10,14 23,27 dimethyl-16-oxa-10,22,28-triazapentacyclo[18.5.2.1 .1 .0 ]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). Example 12 (4.0 mg) was obtained as an off-white solid. MS calc’d 984.4 (MH⁺), measured 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. The compound 12D was prepared in analogy to the preparation of compound 3D by using cis-3-methoxycarbonylcyclobutanecarboxylic acid (compound 12A) instead of trans-3- methoxycarbonylcyclobutanecarboxylic acid (compound 3A). 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- 2,6 10,14 23,27 oxa-10,22,28-triazapentacyclo[18.5.2.1 .1 .0 ]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 The title compound was prepared in analogy to the preparation of Example 1 by using (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- 2,6 10,14 23,27 triazapentacyclo[18.5.2.1 .1 .0 ]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) instead of (8S,14S)-8-amino-22-ethyl-4-hydroxy- (21M)-21-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-18,18-dimethyl-16-oxa-10,22,28- 2,6 10,14 23,27 triazapentacyclo[18.5.2.1 .1 .0 ]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). Example 13 (7.3 mg) was obtained as a white solid. MS calc’d 1091.5 (MH⁺), measured 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, 4H), 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, 3H), 1.29 (s, 6H), 1.01 - 0.92 (m, 6H), 0.83 (d, J = 6.4Hz, 3H), 0.52 (s, 3H) ppm. 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- 2,5 9,13 22,26 tetrazapentacyclo[17.5.2.1 .1 .0 ]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 The title compound was prepared in analogy to the preparation of Example 1 by using (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- 2,5 9,13 22,26 tetrazapentacyclo[17.5.2.1 .1 .0 ]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) instead of (8S,14S)-8-amino-22- ethyl-4-hydroxy-(21M)-21-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-18,18-dimethyl-16-oxa- 2,6 10,14 23,27 10,22,28-triazapentacyclo[18.5.2.1 .1 .0 ]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). Example 14 (23.5 mg) was obtained as a yellow solid. MS calc’d 1119.5 (MH⁺), measured 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 - 2.82 (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. The compound 14D was prepared in analogy to the preparation of compound 8D by using 1-[ethoxy-[fluoro(methylsulfonyl)methyl]phosphoryl]oxyethane (compound 11A) instead of diethyl methylsulfonylmethylphosphonate (compound 1D) 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- 2,5 9,13 22,26 trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 .1 .0 ]octacosa- 1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-azetidine-1- carboxamide The title compound was prepared in analogy to the preparation of Example 1 by using 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- 2,5 9,13 22,26 9,21,27,28-tetrazapentacyclo[17.5.2.1 .1 .0 ]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) instead of (8S,14S)-8-amino-22-ethyl-4-hydroxy-(21M)-21- [2-[(1S)-1-methoxyethyl]-3-pyridyl]-18,18-dimethyl-16-oxa-10,22,28- 2,6 10,14 23,27 triazapentacyclo[18.5.2.1 .1 .0 ]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). Example 15 (10.1 mg) was obtained as a white solid. MS calc’d 1088.4 (MH⁺), measured 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, 1H), 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. The compound 14D was prepared in analogy to the preparation of compound 8D by using 1-[ethoxy-[fluoro(methylsulfonyl)methyl]phosphoryl]oxyethane (compound 11A) instead of diethyl methylsulfonylmethylphosphonate (compound 1D) 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- 2,5 9,13 22,26 tetrazapentacyclo[17.5.2.1 .1 .0 ]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 The title compound was prepared in analogy to the preparation of Example 1 by using (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- 2,5 9,13 22,26 tetrazapentacyclo[17.5.2.1 .1 .0 ]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) instead of (8S,14S)- 8-amino-22-ethyl-4-hydroxy-(21M)-21-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-18,18-dimethyl-16- 2,6 10,14 23,27 oxa-10,22,28-triazapentacyclo[18.5.2.1 .1 .0 ]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). Example 16 (25.5 mg) was obtained as a white solid. MS calc’d 1101.4 (MH⁺), measured 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. 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- 2,5 9,13 22,26 tetrazapentacyclo[17.5.2.1 .1 .0 ]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 The title compound was prepared in analogy to the preparation of Example 1 by using (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- 2,5 9,13 22,26 [17.5.2.1 .1 .0 ]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) instead of (8S,14S)-8-amino-22-ethyl-4-hydroxy- (21M)-21-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-18,18-dimethyl-16-oxa-10,22,28- 2,6 10,14 23,27 triazapentacyclo[18.5.2.1 .1 .0 ]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). Example 17 (16.1 mg) was obtained as a white solid. MS calc’d 1034.4 (MH⁺), measured 1034.5 (MH⁺).¹H NMR (400MHz, CHLOROFORM-d) δ = 8.64 (d, J = 7.6 Hz, 1H), 8.53 - 8.46 (m, 1H), 7.61 (d, J = 2.0 Hz, 1H), 7.19 (d, J = 8.2, 15.0 Hz, 1H), 7.12 - 7.04 (m, 2H), 6.51 (d, J = 15.2 Hz, 1H), 5.81 (t, J = 9.4 Hz, 1H), 4.64 - 4.53 (m, 1H), 4.44 (t, J = 8.5 Hz, 1H), 4.34 - 3.98 (m, 9H), 3.92 - 3.89 (m, 4H), 3.87 - 3.81 (m, 2H), 3.71 (d, J = 11.1 Hz, 1H), 3.59 - 3.49 (m, 1H), 3.43 (d, J = 14.9 Hz, 1H), 3.38 (s, 3H), 3.26 - 3.22 (m, 4H), 3.17 - 3.06 (m, 2H), 3.00 (s, 3H), 2.85 (s, 3H), 2.73 - 2.64 (m, 1H), 2.45 (d, J = 14.2 Hz, 1H), 2.32 - 2.17 (m, 2H), 2.02 (s, 1H), 1.99 - 1.92 (m, 1H), 1.60 (d, J = 3.4, 12.4 Hz, 1H), 1.45 (d, J = 6.1 Hz, 3H), 0.99 - 0.90 (m, 12H), 0.44 (s, 3H) ppm. 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- 2,5 9,13 22,26 trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 .1 .0 ]octacosa- 1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-3-[(E)-2- methylsulfonylvinyl]cyclobutanecarboxamide The title compound was prepared in analogy to the preparation of Example 1 by using (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- 2,5 9,13 22,26 9,21,27,28-tetrazapentacyclo[17.5.2.1 .1 .0 ]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) instead of (8S,14S)-8-amino-22-ethyl-4-hydroxy- (21M)-21-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-18,18-dimethyl-16-oxa-10,22,28- 2,6 10,14 23,27 triazapentacyclo[18.5.2.1 .1 .0 ]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). Example 18 (40.8 mg) was obtained as an-off white solid. MS calc’d 1168.5 (MH⁺), measured 1168.5 (MH⁺).¹H NMR (400 MHz, Methanol-d4) δ = 8.70 (d, J = 7.2 Hz, 1H), 8.42 (d, J = 2.8 Hz, 1H), 7.67 (d, J = 2.4 Hz, 1H), 7.60 (d, J = 2.4 Hz, 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 = 4.8 Hz, 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 = 6.0 Hz, 3H), 1.09 - 0.95 (m, 6H), 0.92 - 0.83 (m, 3H), 0.50 (s, 3H). 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- 2,5 9,13 22,26 tetrazapentacyclo[17.5.2.1 .1 .0 ]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 The title compound was prepared in analogy to the preparation of Example 1 by using 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- 2,5 9,13 22,26 9,21,27,28-tetrazapentacyclo[17.5.2.1 .1 .0 ]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) instead of (8S,14S)-8-amino-22-ethyl-4-hydroxy-(21M)-21- [2-[(1S)-1-methoxyethyl]-3-pyridyl]-18,18-dimethyl-16-oxa-10,22,28- 2,6 10,14 23,27 triazapentacyclo[18.5.2.1 .1 .0 ]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). Example 19 (1.6 mg) was obtained as a white solid. MS calc’d 1052.5 (MH⁺), measured 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, 3H), 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. BIOLOGICAL EXAMPLE Example 20 Cell viability assay The purpose of this cellular assay was to determine the effects of test compounds on the proliferation of human cancer cell lines NCI-H358 (ATCC-CRL5807) cells, AGS (ATCC-CRL- 1739) cells, SW620 (ATCC-CCL-227) over a 3-day treatment period by quantifying the amount of NADPH present at endpoint using Cell Counting Kit-8. Cells were seeded at 5,000 cells/well (NCI-H358), 2,000 cells/well (AGS) 2,000 cells/well (SW620) in 96-well assay plates (Corning-3699) and incubated overnight. On the day of the assay, diluted compounds were then added in a final concentration of 0.5% DMSO. After 72 hrs incubation, a tenth of the volume of cell counting kit 8(DnJindo-CK04) was added into each well. Read the signal (OD450 minus OD650) using EnVision after 2 hrs incubation. IC₅₀ was determined by fitting a 4-parameter sigmoidal concentration response model. Table 1. Activity of Examples and Compounds of present invention in KRAS Cell viability assay Example G12C IC50 (μM) Example 1 0.005 Example 2 0.038 Example 3 0.071 Example 4 0.001 Example 5 0.033 Example 6 0.004 Example 7 0.003 Example 8 0.005 Example 9 0.020 Example 10 0.019 Example 11 0.003 Example 12 0.017 Example 13 0.002 Example 16 0.002 Example 17 0.002 Example 18 ^0.003 Example 19 0.027 Example 21 KRAS-BRAF with CYPA (500 nM) interaction assay In this example, TR-FRET was also used to measure the 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 a compound of the invention, respectively. In assay buffer containing 25mM HEPES PH=7.4 (4-(2-hydroxyethyl)- 1-piperazineethanesulfonic acid, Thermo, 15630080), 0.002% Tween20, 0.1% BSA, 100mM NaCl, 5mM MgCl2, 10 µM GMPPNP (Guanosine 5′-[β,γ-imido]triphosphate trisodium salt hydrate, Sigma, G0635), tagless CYPA, GMPPNP loaded 6His-KRAS proteins, and GST- BRAF^RBD were mixed in a well of a 384-well assay plate at final concentrations of 50 nM, 6.25 nM and 1nM, respectively. Compound was present in 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 a final concentration of 6.67 nM and 0.21 nM, respectively, and the plate was incubated for an additional 1.5 hours. TR-FRET signal was read on a PHERstar FSX microplate reader (Ex320 nm, Em 665/615 nm). Compounds that facilitate disruption of the KRAS-BRAF complex were identified as those eliciting a decrease in the TR-FRET ratio relative to DMSO control wells. Table 2. Activity of Examples and Compounds of present invention in KRAS-BRAF with CYPA (500 nM) interaction assay Example G12C IC₅₀ (μM) E_{xample 4} ^0.001 E_{xample 5} ^0.268 E_{xample 6} ^0.029 E_{xample 7} ^0.034 E_{xample 8} ^0.004 E_{xample 10} ^0.061 E_{xample 11} ^0.008 E_{xample 12} ^0.038 E_{xample 13} ^0.001 E_{xample 14} ^0.050 E_{xample 15} ^0.002 E_{xample 16} ^0.008 E_{xample 17} ^0.022 _{Example 18} ^0.129 E_{xample 19} ^0.101 Example 22 pERK inhibition assay This assay is to measure the ability of test compounds in inhibiting the phosphorylation of ERK, the downstream signaling of KRAS G12C in NCI-H358 cells, KRAS G12D in AGS cells, and KRAS G12V in SW620. NCI-H358 (ATCC-CRL5807) cells, AGS (ATCC-CRL-1739) cells, SW620 (ATCC-CCL-227) cells were all grown and maintained using RPMI-1640 medium (Thermo Fisher Scientific) with 10% fetal bovine serum and 1% penicillin/streptomycin. On the day prior to compound addition, cells were plated in tissue culture-treated 96 well plates (Corning-3699) at a density of 30,000 cell/well, 20,000 cell/well, 30,000 cell/well for NCI-H358, AGS and SW620 respectively, and allowed for attachment overnight. Diluted compounds were then added in 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 plates were incubated at room temperature for 20 minutes. The plates were then washed once with phosphate buffered saline (PBS), and permeabilized with 100 µL of chilled methanol for 10 minutes. Non-specific antibody binding to the plates was blocked using 50 µL 1X BSA blocking buffer (Thermo-37520, 10-fold dilution by Phosphate-Buffered Saline Tween (PBST) for at least 1 hour at room temperature. The amount of phosphor-ERK was determined using an antibody specific for phosphorylated form of ERK. Primary antibody (pERK, CST-4370, Cell Signaling Technology) was diluted 1:300 in blocking buffer, with 50 µL aliquoted to each well, and incubated overnight at 4 ℃. Cells was washed five times for 5 minutes with PBST. Secondary antibody (HRP-linked 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 1-2 hrs at room temperature. Cells was washed 5 times for 5 minutes with PBST, 100µL TMB ELISA substrate (abcam-ab171523) were added and gently shake for 20 minutes.50µL stop solution (abcam-ab171529) were added, and then read the signal (OD450) by EnVision. IC₅₀ was determined by fitting a 4-parameter sigmoidal concentration response model. Table 3. Activity of Examples and Compounds of present invention in KRAS pERK inhibition assay Example G12C IC50 (μM) _{Example 1} ^0.010 _{Example 2} ^0.091 _{Example 3} ^0.184 _{Example 4} ^0.002 _{Example 5} ^0.088 _{Example 6} ^0.005 _{Example 7} ^0.003 _{Example 8} ^0.016 _{Example 9} ^0.073 _{Example 10} ^0.020 _{Example 11} ^0.007 _{Example 12} ^0.017 _{Example 13} ^0.004 Example 14 0.006 Example 15 0.002 Example 16 0.007 Example 17 0.008 Example 18 0.001 _{Example 19} ^0.079

Claims

CLAIMS 1. A compound of formula (I), wherein R⁸ is C1-6alkyl; R⁹ is ((C1-6alkylsulfonyl)haloC2-6alkenyl)azetidinyl, ((C1- 6alkylsulfonyl)haloC_2-6alkenyl)C_3-7cycloalkyl, (C_1-6alkylsulfonylC_2- 6alkenyl)azetidinyl, (C1-6alkylsulfonylC2-6alkenyl)C3-7cycloalkyl or (C1-6alkylsulfonylC2-6alkenyl)piperidinyl; R² is C_1-6alkyl; R³ is H or halogen; R⁴ is H; R⁵ is C1-6alkyl or haloC1-6alkyl; R⁶ is C_1-6alkoxyC_1-6alkyl; R⁷ is H, morpholinyl, (haloC1-6alkyl)piperazinyl or C1-6alkylpiperazinyl; A¹ is thiazolylene, phenylene or hydroxyphenylene; A² is C_1-6alkylene; or a pharmaceutically acceptable salt thereof. 2. A compound of formula (Ia), wherein R⁸ is C_1-6alkyl; R⁹ is ((C_1-6alkylsulfonyl)haloC_2-6alkenyl)azetidinyl, ((C_1- 6alkylsulfonyl)haloC2-6alkenyl)C3-7cycloalkyl, (C1-6alkylsulfonylC2- 6alkenyl)azetidinyl, (C1-6alkylsulfonylC2-6alkenyl)C3-7cycloalkyl or (C_1-6alkylsulfonylC_2-6alkenyl)piperidinyl; R² is C1-6alkyl; R³ is H or halogen; R⁴ is H; R⁵ is C_1-6alkyl or haloC_1-6alkyl; R⁶ is C1-6alkoxyC1-6alkyl; R⁷ is H, morpholinyl, (haloC1-6alkyl)piperazinyl or C1-6alkylpiperazinyl; A¹ is thiazolylene, phenylene or hydroxyphenylene; A² is C1-6alkylene; or a pharmaceutically acceptable salt thereof. 3. A compound according to claim 1 or 2, wherein R¹ is ; wherein R⁸ is C1- 6alkyl; R⁹ is (C1-6alkylsulfonylC2-6alkenyl)azetidinyl or (C1-6alkylsulfonylC2-6alkenyl)C3- ₇cycloalkyl. 4. A compound according to any one of claims 1-3, wherein R¹ is ; wherein R⁸ is methyl; R⁹ is 3-(2-methylsulfonylvinyl)azetidin-1-yl or 3-(2-methylsulfonylvinyl)cyclobutyl. 5. A compound according to any one of claims 1-4, wherein R¹ is methyl-[3-[(E)-2- methylsulfonylvinyl]azetidine-1-carbonyl]amino or methyl-[3-[(E)-2- methylsulfonylvinyl]cyclobutanecarbonyl]amino. 6. A compound according to any one of claims 1-5, wherein R² is isopropyl. 7. A compound according to any one of claims 1-6, wherein R³ is H or fluoro. 8. A compound according to any one of claims 1-7, wherein R³ is fluoro. 9. A compound according to any one of claims 1-8, wherein R⁴ is H. 10. A compound according to any one of claims 1-9, wherein R⁵ is ethyl or 2,2,2-trifluoroethyl. 11. A compound according to any one of claims 1-10, wherein R⁶ is 1-methoxyethyl. 12. A compound according to any one of claims 1-11, wherein R⁷ is C_1-6alkylpiperazinyl or morpholinyl. 13. A compound according to any one of claims 1-12, wherein R⁷ is 4-methylpiperazin-1-yl or morpholinyl. 14. A compound according to any one of claims 1-13, wherein A¹ is ; wherein bond “a” connects to indole ring. 15. A compound according to any one of claims 1-14, wherein A² is dimethylmethylene. 16. A compound according to claim 1 or 2, wherein R¹ is ; wherein R⁸ is C1-6alkyl; R⁹ is (C1-6alkylsulfonylC2- 6alkenyl)azetidinyl or (C_1-6alkylsulfonylC_2-6alkenyl)C_3-7cycloalkyl; R² is C1-6alkyl; R³ is halogen; R⁴ is H; R⁵ is C1-6alkyl or haloC1-6alkyl; R⁶ is C1-6alkoxyC1-6alkyl; R⁷ is C_1-6alkylpiperazinyl or morpholinyl; A¹ is , wherein bond “a” connects to indole ring; A² is C_1-6alkylene; or a pharmaceutically acceptable salt thereof. 17. A compound according to claim 16, wherein R¹ is methyl-[3-[(E)-2-methylsulfonylvinyl]azetidine-1-carbonyl]amino or methyl-[3-[(E)- 2-methylsulfonylvinyl]cyclobutanecarbonyl]amino; R² is isopropyl; R³ is fluoro; R⁴ is H; R⁵ is ethyl or 2,2,2-trifluoroethyl; R⁶ is (1S)-1-methoxyethyl; R⁷ is 4-methylpiperazin-1-yl or morpholinyl; wherein bond “a” connects to indole ring; A² is dimethylmethylene; or a pharmaceutically acceptable salt thereof. 18. A compound selected from: N-[(1S)-1-[[(8S,14S)-22-ethyl-4-hydroxy-(21M)-21-[2-[(1S)-1-methoxyethyl]-3-pyridyl]- 2,6 10,14 23,27 18,18-dimethyl-9,15-dioxo-16-oxa-10,22,28-triazapentacyclo[18.5.2.1 .1 .0 ]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- 2,6 10,14 23,27 dimethyl-9,15-dioxo-16-oxa-10,22,28-triazapentacyclo[18.5.2.1 .1 .0 ]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- 2,6 10,14 23,27 triazapentacyclo[18.5.2.1 .1 .0 ]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- 2,6 10,14 23,27 [18.5.2.1 .1 .0 ]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- 2,5 9,13 22,26 dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 .1 .0 ]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- 2,5 9,13 22,26 tetrazapentacyclo[17.5.2.1 .1 .0 ]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- 2,5 9,13 22,26 tetrazapentacyclo[17.5.2.1 .1 .0 ]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]- 2,6 10,14 23,27 18,18-dimethyl-9,15-dioxo-16-oxa-10,22,28-triazapentacyclo[18.5.2.1 .1 .0 ]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]- 2,6 10,14 23,27 18,18-dimethyl-9,15-dioxo-16-oxa-10,22,28-triazapentacyclo[18.5.2.1 .1 .0 ]nonacosa- 1(26),2,4,6(29),20,23(27),24-heptaen-8-yl]carbamoyl]-2-methyl-propyl]-N-methyl-4-[(E)-2- methylsulfonylvinyl]piperidine-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- 2,5 9,13 22,26 tetrazapentacyclo[17.5.2.1 .1 .0 ]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- 2,6 10,14 23,27 triazapentacyclo[18.5.2.1 .1 .0 ]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- 2,5 9,13 22,26 tetrazapentacyclo[17.5.2.1 .1 .0 ]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- 2,6 10,14 23,27 10,22,28-triazapentacyclo[18.5.2.1 .1 .0 ]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- 2,5 9,13 22,26 tetrazapentacyclo[17.5.2.1 .1 .0 ]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- 2,5 9,13 22,26 oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 .1 .0 ]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- 2,5 9,13 22,26 tetrazapentacyclo[17.5.2.1 .1 .0 ]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- 2,5 9,13 22,26 tetrazapentacyclo[17.5.2.1 .1 .0 ]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- 2,5 9,13 22,26 oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1 .1 .0 ]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- 2,5 9,13 22,26 tetrazapentacyclo[17.5.2.1 .1 .0 ]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. 19. A process for the preparation of a compound according to any one of claims 1 to 18 comprising any of the following steps: a) coupling reaction between compound of formula (II), in the presence of a coupling reagent and a base to form the compound of formula (I); wherein R¹, R², R³, R⁴ , R⁵, R⁶, R⁷, A¹ and A² are defined as in any one of claims 1 to 17; the coupling reagent is T3P, HATU, PyBOP or EDCI/HOBt; the base is TEA, DIEPA or DMAP. 20. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 18 for use as therapeutically active substance. 21. A pharmaceutical composition comprising a compound in accordance with any one of claims 1 to 18 and a pharmaceutically acceptable excipient. 22. The use of a compound according to any one of claims 1 to 18 for treating a KRAS G12C protein-related disease. 23. The use of a compound according to any one of claims 1 to 18 for treating a KRAS G12C, G12D and G12V protein-related disease. 24. The use of a compound according to any one of claims 1 to 18 for inhibiting RAS interaction with downstream effectors, wherein the downstream effectors are RAF and PI3K. 25. The use of a compound according to any one of claims 1 to 18 for inhibiting the propagating oncogenic MAPK and PI3K signaling. 26. The use of a compound according to any one of claims 1 to 18 for the treatment or prophylaxis of KRAS mutation driven cancers, wherein the cancer is selected from pancreatic cancer, colorectal cancer, lung cancer, esophageal cancer, gallbladder cancer, melanoma ovarian cancer and endometrial cancer. 27. The use of a compound according to any one of claims 1 to 18 for the treatment or prophylaxis of KRAS mutation driven cancers, wherein the cancer is selected from pancreatic adenocarcinoma, colorectal cancer and non-small cell lung cancer. 28. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 18 for the treatment or prophylaxis of KRAS mutation driven cancers, wherein the cancer is selected from pancreatic adenocarcinoma, colorectal cancer and non-small cell lung cancer. 29. The use of a compound according to any one of claims 1 to 18 for the preparation of a medicament for the treatment or prophylaxis of KRAS mutation driven cancers, wherein the cancer is selected from pancreatic adenocarcinoma, colorectal cancer and non-small cell lung cancer. 30. A method for the treatment or prophylaxis of KRAS mutation driven cancers, wherein the cancer is selected from pancreatic adenocarcinoma, colorectal cancer and non-small cell lung cancer, which method comprises administering a therapeutically effective amount of a compound as defined in any one of claims 1 to 18. 31. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 18, when manufactured according to a process of claim 19. 32. The invention as hereinbefore described.