Tricyclic compounds for the treatment of cancer

Abstract

The present invention relates to compounds of formula (I), wherein R1 to R4, A1, A2, M and L are as described herein, and their pharmaceutically acceptable salt thereof, and compositions including the compounds and methods of using the compounds.

Description

[0001] Case 38378 Tricyclic 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 (RAFRBD), 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-BRAFRBDherein). 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), (I), wherein 1 R is , 1-oxo-2,7-diazaspiro[4.4]nonanyl substituted by C2-6alkynylcarbonyl, or 5-oxo-2,6-diazaspiro[3.4]octanyl substituted by (dihaloC1-6alkyl)carbonyl, C2- 6alkenylcarbonyl, C2-6alkynylcarbonyl or haloC2-6alkenylcarbonyl; wherein R5is C1-6alkyl; R6is C3-7cycloalkyl substituted by haloC2-6alkynyl, piperidyl once or twice substituted by substituents independently selected from (dihaloC1-6alkyl)carbonyl, C2-6alkenylcarbonyl, C2- 6alkynylcarbonyl, halogen and haloC2-6alkenylcarbonyl, or pyrrolidinyl substituted by (dihaloC1-6alkyl)carbonyl, C2- 6alkenylcarbonyl, C2-6alkynylcarbonyl or morpholinoC2- 6alkynylcarbonyl; R2is C1-6alkyl; R3is H, morpholino, (haloC1-6alkyl)piperazinyl or C1-6alkylpiperazinyl; R4is C1-6alkoxyC1-6alkyl; A1is hydroxyphenylene or thiazolylene; A2is C1-6alkylene; M is O or CH2; L is C1-6alkylene or haloC1-6alkylene; 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, G12D, G12V or G13C. In one embodiment, the compound of current invention had good pharmacokinetic properties comparing with the reference compounds. 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. BRIEF DESCRIPTION OF THE FIGURE Figure 1. X-ray crystallographic analysis of Intermediate A3. Figure 2. X-ray crystallographic analysis of Intermediate A4. DETAILED DESCRIPTION OF THE INVENTION DEFINITIONS The term “C1-6alkyl” 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 “C1-6alkylene” 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 “C2-6alkenyl” 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 “C2-6alkynyl” denotes a monovalent linear or branched saturated hydrocarbon group of 2 to 6 carbon atoms comprising one, two or three triple bonds. In particular embodiments alkynyl has from 2 to 4 carbon atoms comprising one or two triple bonds. Examples of C2-6alkynyl include ethynyl, propynyl, prop-2-ynyl, isopropynyl, and n-butynyl. The term “halogen” and “halo” are used interchangeably herein and denote fluoro, chloro, bromo, or iodo. The term “haloC1-6alkyl” denotes a C1-6alkyl group wherein at least one of the hydrogen atoms of the C1-6alkyl group have been replaced by same or different halogen atoms. Examples of haloC1-6alkyl include fluoro, difluoro- or chloro(fluoro)-methyl, -ethyl or -propyl, for example fluoromethyl, difluoropropyl, difluoromethyl, difluoroethyl, chloro(fluoro)methyl, trifluoroethyl, or trifluoromethyl. The term “haloC1-6alkylene” denotes a C1-6alkylene group wherein at least one of the hydrogen atoms of the C1-6alkylene group have been replaced by same or different halogen atoms. Examples of haloC1-6alkylene include fluoro, difluoro- or chloro(fluoro)-methylene, - ethylene or -propylene, for example fluoromethylene, difluoromethylene, fluoroethylene, difluoroethylene, fluoropropylene, difluoropropylene or chloro(fluoro)methylene. The term “dihaloC1-6alkyl” denotes a C1-6alkyl group wherein two of the hydrogen atoms of the C1-6alkyl group have been replaced by same or different halogen atoms. Examples of dihaloC1-6alkyl include, difluoro- or chloro(fluoro)-methyl, -ethyl or -propyl, for example difluoropropyl, difluoromethyl, difluoroethyl or chloro(fluoro)methyl. The term “haloC2-6alkenyl” denotes a C2-6alkenyl group wherein at least one of the hydrogen atoms of the C2-6alkenyl group have been replaced by same or different halogen atoms. The term “haloC2-6alkynyl” denotes a C2-6alkynyl group wherein at least one of the hydrogen atoms of the C2-6alkynyl 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 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 1 R is , 1-oxo-2,7-diazaspiro[4.4]nonanyl substituted by C2-6alkynylcarbonyl, or 5-oxo-2,6-diazaspiro[3.4]octanyl substituted by (dihaloC1-6alkyl)carbonyl, C2- 6alkenylcarbonyl, C2-6alkynylcarbonyl or haloC2-6alkenylcarbonyl; wherein R5is C1-6alkyl; R6is C3-7cycloalkyl substituted by haloC2-6alkynyl, piperidyl once or twice substituted by substituents independently selected from (dihaloC1-6alkyl)carbonyl, C2-6alkenylcarbonyl, C2- 6alkynylcarbonyl, halogen and haloC2-6alkenylcarbonyl, or pyrrolidinyl substituted by (dihaloC1-6alkyl)carbonyl, C2- 6alkenylcarbonyl, C2-6alkynylcarbonyl or morpholinoC2- 6alkynylcarbonyl; R2is C1-6alkyl; R3is H, morpholino, (haloC1-6alkyl)piperazinyl or C1-6alkylpiperazinyl; R4is C1-6alkoxyC1-6alkyl; A1is hydroxyphenylene or thiazolylene; A2is C1-6alkylene; M is O or CH2; L is C1-6alkylene or haloC1-6alkylene; or a pharmaceutically acceptable salt thereof. Another embodiment of present invention is (ii) a compound of formula (Ia), wherein 1 R is , 1-oxo-2,7-diazaspiro[4.4]nonanyl substituted by C2-6alkynylcarbonyl, or 5-oxo-2,6-diazaspiro[3.4]octanyl substituted by (dihaloC1-6alkyl)carbonyl, C2- 6alkenylcarbonyl, C2-6alkynylcarbonyl or haloC2-6alkenylcarbonyl; wherein R5is C1-6alkyl; R6is C3-7cycloalkyl substituted by haloC2-6alkynyl, piperidyl once or twice substituted by substituents independently selected from (dihaloC1-6alkyl)carbonyl, C2-6alkenylcarbonyl, C2- 6alkynylcarbonyl, halogen and haloC2-6alkenylcarbonyl, or pyrrolidinyl substituted by (dihaloC1-6alkyl)carbonyl, C2- 6alkenylcarbonyl, C2-6alkynylcarbonyl or morpholinoC2- 6alkynylcarbonyl; R2is C1-6alkyl; R3is H, morpholino, (haloC1-6alkyl)piperazinyl or C1-6alkylpiperazinyl; R4is C1-6alkoxyC1-6alkyl; A1is hydroxyphenylene or thiazolylene; A2is C1-6alkylene; M is O or CH2; L is C1-6alkylene or haloC1-6alkylene; 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 R1is , wherein R5is C1-6alkyl; R6is piperidyl twice substituted by substituents independently selected from (dihaloC1-6alkyl)carbonyl, C2-6alkenylcarbonyl, halogen and haloC2- 6alkenylcarbonyl. 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 R1is , wherein R5is C1-6alkyl; R6is piperidyl substituted by halogen and another substituent selected from (dihaloC1-6alkyl)carbonyl, C2-6alkenylcarbonyl and haloC2- 6alkenylcarbonyl. 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 , wherein R5is methyl; R6is 4- fluoro-1-prop-2-enoyl-4-piperidyl, 4-fluoro-1-(2-fluoroprop-2-enoyl)-4-piperidyl, 4-fluoro-1-(2- chloro-2-fluoro-acetyl)-4-piperidyl or 4-fluoro-1-prop-2-enoyl-4-piperidyl. 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 R2is 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 R3is morpholino or C1-6alkylpiperazinyl. 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 R3is morpholino or 4-methylpiperazin-1-yl. 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 R4is 1- methoxyethyl. 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 A1is , wherein bond “a” connects to tricyclic ring. 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 A2is dimethylmethylene. 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 M is O. 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 L is C1- 6alkylene. 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 L is ethylene. A further embodiment of present invention is (xv) a compound of formula (I) or (Ia), according to any one of (i) or (ii), R1 is , wherein R5is C1-6alkyl; R6is piperidyl substituted by halogen and another substituent selected from (dihaloC1-6alkyl)carbonyl, C2-6alkenylcarbonyl and haloC2-6alkenylcarbonyl; R2is C1-6alkyl; R3is morpholino or C1-6alkylpiperazinyl; R4is C1-6alkoxyC1-6alkyl; A1is , wherein bond “a” connects to tricyclic ring; A2is C1-6alkylene; M is O; L is C1-6alkylene; or a pharmaceutically acceptable salt thereof. Another embodiment of present invention is (xvi) a compound of formula (I) or (Ia), according to (xv), wherein 1 R is , wherein R5is methyl; R6is 4-fluoro-1-prop-2-enoyl-4-piperidyl, 4- fluoro-1-(2-fluoroprop-2-enoyl)-4-piperidyl, 4-fluoro-1-[(2R)-2-chloro-2-fluoro- acetyl]-4-piperidyl or 4-fluoro-1-prop-2-enoyl-4-piperidyl; R2is isopropyl; R3is morpholino or 4-methylpiperazin-1-yl; R4is (1S)-1-methoxyethyl; A1is , wherein bond “a” connects to tricyclic ring; A2is dimethylmethylene; M is O; L is ethylene; or a pharmaceutically acceptable salt thereof. Another embodiment of present invention is (xvii) a compound of formula (I) or (Ia) selected from the following: (3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(20S,26S)-30-hydroxy-(13M)-13-[2- [(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-19,25-dioxo-7,18-dioxa-12,24,33- triazahexacyclo[26.3.1.12,6.120,24.04,14.05,12]tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaen- 26-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide; (3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(19S,25S)-29-hydroxy-(12M)-12-[2- [(1S)-1-methoxyethyl]-3-pyridyl]-15,15-dimethyl-18,24-dioxo-7,17-dioxa-11,23,32- triazahexacyclo[25.3.1.12,6.119,23.04,13.05,11]tritriaconta-1(30),2,4,6(33),12,27(31),28-heptaen-25- yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide; 1-[(2R)-2-chloro-2-fluoro-acetyl]-4-fluoro-N-[(1S)-1-[[(19S,25S)-29-hydroxy-(12M)-12- [2-[(1S)-1-methoxyethyl]-3-pyridyl]-15,15-dimethyl-18,24-dioxo-7,17-dioxa-11,23,32- triazahexacyclo[25.3.1.12,6.119,23.04,13.05,11]tritriaconta-1(30),2,4,6(33),12,27(31),28-heptaen-25- yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide; (3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(18S,24S)-28-hydroxy-(11M)-11-[(3R)- 2-[(1S)-1-methoxyethyl]-2,3-dihydropyridin-3-yl]-14,14-dimethyl-17,23-dioxo-16-oxa-10,22,31- triazahexacyclo[24.3.1.12,6.118,22.04,12.05,10]dotriaconta-1(29),2,4,6(32),11,26(30),27-heptaen-24- yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide; (3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(18S,24S)-28-hydroxy-(11M)-11-[2- [(1S)-1-methoxyethyl]-3-pyridyl]-14,14-dimethyl-17,23-dioxo-7,16-dioxa-10,22,31- triazahexacyclo[24.3.1.12,6.118,22.04,12.05,10]dotriaconta-1(29),2,4,6(32),11,26(30),27-heptaen-24- yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide; (3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia- 9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26- hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide; (2S)-2-[2-[(2R)-2-chloro-2-fluoro-acetyl]-5-oxo-2,6-diazaspiro[3.4]octan-6-yl]-N- [(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3- pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7- yl]-3-methyl-butanamide; (2S)-2-(2-but-2-ynoyl-5-oxo-2,6-diazaspiro[3.4]octan-6-yl)-N-[(7S,13S)-(20M)-20-[2- [(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14- dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaen-7-yl]-3-methyl-butanamide; (2S)-2-[2-[(2R)-2-chloro-2-fluoro-acetyl]-5-oxo-2,6-diazaspiro[3.4]octan-6-yl]-N- [(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14- dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaen-7-yl]-3-methyl-butanamide; (2S)-2-(2-but-2-ynoyl-5-oxo-2,6-diazaspiro[3.4]octan-6-yl)-N-[(7S,13S)-(20M)-20-[2- [(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia- 9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26- hexaen-7-yl]-3-methyl-butanamide; (2S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17- dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7- yl]-3-methyl-2-(5-oxo-2-prop-2-enoyl-2,6-diazaspiro[3.4]octan-6-yl)butanamide; (3S)-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]- 17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7- yl]carbamoyl]-2-methyl-propyl]-N-methyl-1-(4-morpholinobut-2-ynoyl)pyrrolidine-3- carboxamide; (2S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin- 1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7- yl]-3-methyl-2-(5-oxo-2-prop-2-enoyl-2,6-diazaspiro[3.4]octan-6-yl)butanamide; (2S)-2-(2-but-2-ynoyl-5-oxo-2,6-diazaspiro[3.4]octan-6-yl)-N-[(7S,13S)-(20M)-20-[2- [(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15- oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaen-7-yl]-3-methyl-butanamide; 4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3- pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7- yl]carbamoyl]-2-methyl-propyl]-N-methyl-1-prop-2-enoyl-piperidine-4-carboxamide; 1-but-2-ynoyl-4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5- morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7- yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide; cis-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]- 17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7- yl]carbamoyl]-2-methyl-propyl]-N-methyl-3-(3,3,3-trifluoroprop-1- ynyl)cyclobutanecarboxamide; 1-[(2R)-2-chloro-2-fluoro-acetyl]-4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7- yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide; (2S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3- pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7- yl]-3-methyl-2-(5-oxo-2-prop-2-enoyl-2,6-diazaspiro[3.4]octan-6-yl)butanamide; (2S)-2-[2-[(2R)-2-chloro-2-fluoro-acetyl]-5-oxo-2,6-diazaspiro[3.4]octan-6-yl]-N- [(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17- dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7- yl]-3-methyl-butanamide; cis-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)- 3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7- yl]carbamoyl]-2-methyl-propyl]-N-methyl-3-(3,3,3-trifluoroprop-1- ynyl)cyclobutanecarboxamide; (2S)-2-[2-(2-fluoroprop-2-enoyl)-5-oxo-2,6-diazaspiro[3.4]octan-6-yl]-N-[(7S,13S)-(20M)- 20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4- thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaen-7-yl]-3-methyl-butanamide; cis-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2- trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7- yl]carbamoyl]-2-methyl-propyl]-N-methyl-3-(3,3,3-trifluoroprop-1- ynyl)cyclobutanecarboxamide; 4-fluoro-1-(2-fluoroprop-2-enoyl)-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7- yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide; 1-but-2-ynoyl-4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7- yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide; 4-fluoro-1-(2-fluoroprop-2-enoyl)-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia- 9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26- hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide; 1-[(2R)-2-chloro-2-fluoro-acetyl]-4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia- 9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26- hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide; 1-[(2R)-2-chloro-2-fluoro-acetyl]-4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia- 9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26- hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide; 4-fluoro-1-(2-fluoroprop-2-enoyl)-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia- 9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26- hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide; 1-but-2-ynoyl-4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5- morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7- yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide; 1-[(2R)-2-chloro-2-fluoro-acetyl]-4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4- thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4- carboxamide; 4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1- yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7- yl]carbamoyl]-2-methyl-propyl]-N-methyl-1-prop-2-enoyl-piperidine-4-carboxamide; 1-but-2-ynoyl-4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7- yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide; (3R)-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]- 17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7- yl]carbamoyl]-2-methyl-propyl]-N-methyl-1-prop-2-enoyl-pyrrolidine-3-carboxamide; (3R)-1-but-2-ynoyl-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5- morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7- yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide; 4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1- yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7- yl]carbamoyl]-2-methyl-propyl]-N-methyl-1-prop-2-enoyl-piperidine-4-carboxamide; (2S)-2-[(5R)-7-but-2-ynoyl-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-N-[(7S,13S)-(20M)-20- [2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15- oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaen-7-yl]-3-methyl-butanamide; 4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3- pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7- yl]carbamoyl]-2-methyl-propyl]-N-methyl-1-prop-2-enoyl-piperidine-4-carboxamide; N-[(1S)-1-[[(7S,13S)-23,23-difluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7- yl]carbamoyl]-2-methyl-propyl]-4-fluoro-N-methyl-1-prop-2-enoyl-piperidine-4-carboxamide; N-[(1S)-1-[[(7S,13S)-23,23-difluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3- pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7- yl]carbamoyl]-2-methyl-propyl]-4-fluoro-1-(2-fluoroprop-2-enoyl)-N-methyl-piperidine-4- carboxamide; 1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(7S,13S)-23,23-difluoro-(20M)-20-[2-[(1S)- 1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(29),2,5(31),19,25,27-hexaen-7- yl]carbamoyl]-2-methyl-propyl]-4-fluoro-N-methyl-piperidine-4-carboxamide; N-[(1S)-1-[[(7S,13S)-23,23-difluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3- pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7- yl]carbamoyl]-2-methyl-propyl]-4-fluoro-N-methyl-1-prop-2-enoyl-piperidine-4-carboxamide; 1-but-2-ynoyl-N-[(1S)-1-[[(7S,13S)-23,23-difluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5- morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7- yl]carbamoyl]-2-methyl-propyl]-4-fluoro-N-methyl-piperidine-4-carboxamide; 4-fluoro-1-(2-fluoroprop-2-enoyl)-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4- thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4- carboxamide; 4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3- pyridyl]-17,17,23,23-tetramethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7- yl]carbamoyl]-2-methyl-propyl]-N-methyl-1-prop-2-enoyl-piperidine-4-carboxamide; 4-fluoro-N-[(1S)-1-[[(7S,13S,22S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3- pyridyl]-17,17,22-trimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7- yl]carbamoyl]-2-methyl-propyl]-N-methyl-1-prop-2-enoyl-piperidine-4-carboxamide; and 4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3- pyridyl]-17,17,23,23-tetramethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(29),2,5(31),19,25,27-hexaen-7- yl]carbamoyl]-2-methyl-propyl]-N-methyl-1-prop-2-enoyl-piperidine-4-carboxamide; or a pharmaceutically acceptable salt thereof. Another embodiment of present invention is related to (xviii) a process for the preparation of a compound according to any one of (i) to (xvii) comprising the following step: a) coupling reaction between compound of formula (II), presence of a coupling reagent and a base to form the compound of formula (I); b) coupling reaction between compound of formula (VI),

[0002] the presence of a coupling reagent and a base to form the compound of formula (VIII), c) coupling reaction between compound of formula (XI),

[0003] (XII), in the presence of a coupling reagent and a base to form the compound of formula (XIII), wherein Q is unsubstituted or substituted piperidinylene or pyrrolidinylene; T is dihaloC1- 6alkyl, C2-6alkenyl, C2-6alkynyl, haloC2-6alkenyl or morpholinoC2-6alkynyl; R1to R6, A1, A2, M and L are defined as in any one of claims 1 to 16; the coupling reagent in step a) to c) is T3P, HATU, PyBOP or EDCI / HOBt; the base in step a) to c) is TEA, DIEPA or DMAP. Another embodiment of present invention is (xix) a compound or pharmaceutically acceptable salt according to any one of (i) to (xvii) for use as therapeutically active substance. Another embodiment of present invention is (xx) a pharmaceutical composition comprising a compound in accordance with any one of (i) to (xvii) and a pharmaceutically acceptable excipient. Another embodiment of present invention is (xxi) the use of a compound according to any one of (i) to (xvii) for treating a KRAS G12C protein-related disease. Another embodiment of present invention is (xxii) the use of a compound according to any one of (i) to (xvii) for treating a KRAS G12C, G12D and G12V protein-related disease. Another embodiment of present invention is (xxiii) the use of a compound according to any one of (i) to (xvii) for inhibiting RAS interaction with downstream effectors, wherein the downstream effectors are RAF and PI3K. Another embodiment of present invention is (xxiv) the use of a compound according to any one of (i) to (xvii) for inhibiting the propagating oncogenic MAPK and PI3K signaling. Another embodiment of present invention is (xxv) the use of a compound according to any one of (i) to (xvii) 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 (xxvi) the use of a compound according to any one of (i) to (xvii) 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 (xxvii) a compound or pharmaceutically acceptable salt according to any one of (i) to (xvii) 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) the use of a compound according to any one of (i) to (xvii) 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 (xxix) 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 (xvii). Another embodiment of present invention is (xxx) a compound or pharmaceutically acceptable salt according to any one of (i) to (xvii), when manufactured according to a process of (xviii). 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 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, R1to R6, M and L and A1and A2are 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) and (Ia) are shown below. Scheme 1 Compound of formula II was synthesized according to the procedure described in Intermediate A to R. 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. Scheme 2 wherein PG is a protecting group, such as Boc and Cbz. Compound of formula (V) can be obtained by a coupling reaction between acid (IV) and compound of formula (II) with coupling reagent(s), such as T3P, HATU, PyBOP or EDCI / HOBt, in the presence of a base, such TEA, DIEPA or DMAP. Deprotection of compound of formula (V) can afford compound of formula (VI) in the presence of an acid, such as TFA, or under hydrogenation condition with a catalyst, such as Pd / C and Pd(OH)2 / C. Compound of formula (VIII) can be obtained by a coupling reaction between acid (VII) and acid (VI) with coupling reagent(s), such as T3P, HATU, PyBOP and EDCI / HOBt, in the presence of a base, such as TEA, DIEPA and DMAP. Scheme 3 wherein PG is a protecting group, such as Boc and Cbz; T is dihaloC1-6alkyl, C2-6alkenyl, C2-6alkynyl, haloC2-6alkenyl or morpholinoC2-6alkynyl; Q is unsubstituted or substituted piperidinylene or pyrrolidinylene. Compound of formula (X) can be obtained by a coupling reaction using acid (IX), compound of formula (VI) and coupling reagent(s), such as T3P, HATU, PyBOP or EDCI / HOBt, in the presence of a base, such TEA, DIEPA or DMAP. Deprotection of compound of formula (X) can afford compound of formula (XI) in the presence of an acid, such as TFA, or under hydrogenation condition with a catalyst, such as Pd / C and Pd(OH)2 / C. Compound of formula (XIII) can be obtained by a coupling reaction between acid (XII) and compound of formula (XI) 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. 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), presence of a coupling reagent and a base to form the compound of formula (I); b) coupling reaction between compound of formula (VI), the presence of a coupling reagent and a base to form the compound of formula (VIII), c) coupling reaction between compound of formula (XI), (XII), in the presence of a coupling reagent and a base to form the compound of formula wherein in step a), b) and c) the coupling reagent can be, for example, T3P, HATU, PyBOP or EDCI / HOBt; the base can be, for example, TEA, DIEPA or DMAP. 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 CuI copper(I) iodide DIEPA: N, N-diethylpropylamine DMAP: 4-Dimethylaminopyridine DMF: dimethyl formamide 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 [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 MTDA Dimethylketene methyl trimethylsilyl acetal NMM N-Methylmorpholine NaBH(OAc)3 Sodium triacetoxyborohydride NBS N-Bromosuccinimide NIS N-iodosuccinimide 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 TBAF Tetrabutylammonium fluoride TEA: triethylamine TFA: trifluoroacetic acid THF: tetrahydrofuran 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 XBridgeTMPrep-C18 (5 µm, OBDTM 30 × 100 mm) column, SunFireTMPrep-C18 (5 µm, OBDTM30 × 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 (WatersTMAlliance 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 A1 (2S)-2-(2-tert-butoxycarbonyl-5-oxo-2,6-diazaspiro[3.4]octan-6-yl)-3-methyl-butanoic acid The compound was prepared according to the following scheme:A1-gIntermediate A1 Step 1: preparation of tert-butyl 3-allyl-3-cyano-azetidine-1-carboxylate (compound A1-b) To a solution of tert-butyl 3-cyanoazetidine-1-carboxylate (compound A1-a, 10.0 g, 54.88 mmol) in THF (100 mL) was added LDA (60.3 mL, 60.37 mmol) dropwise at -70 °C under nitrogen atmosphere. After being stirred at -70 °C for 0.5 h, the reaction mixture was added with allyl bromide (7.9 g, 65.85 mmol). The mixture was stirred at 16 °C for another 1 h, then concentrated in vacuo and the residue was purified by column chromatography (EtOAc in PE: 3%-10%) to afford tert-butyl 3-allyl-3-cyano-azetidine-1-carboxylate (compound A1-b, 12.5 g) as light yellow oil.1H NMR (400 MHz, CHLOROFORM-d) δ 5.90 - 5.70 (m, 1 H), 5.32 (s, 1 H), 5.28 (d, J = 5.2 Hz, 1 H), 4.23 (d, J = 8.8 Hz, 2 H), 3.86 (d, J = 8.8 Hz, 2 H), 2.63 (d, J = 7.2 Hz, 2 H), 1.45 (s, 9 H) ppm. Step 2: 3-allyl-1-tert-butoxycarbonyl-azetidine-3-carboxylic acid (compound A1-c) A mixture of tert-butyl 3-allyl-3-cyano-azetidine-1-carboxylate (compound A1-b, 12.5 g, 56.24 mmol) and potassium hydroxide (12.6 g, 224.94 mmol) in ethanol (60 mL) and water (60 mL) was stirred at 100 °C for 16 hrs. After the reaction was completed, the pH of the reaction mixture was acidified by HCl (1 M) aq. to pH=3. The reaction mixture was extracted with EtOAc (120 mL, three times). The combined organic layer was washed with brine (300 mL), dried over Na2SO4, filtered and concentrated in vacuo to afford 3-allyl-1-tert-butoxycarbonyl- azetidine-3-carboxylic acid (compound A1-c, 14.0 g) as a white solid. MS calc’d 242.1 (MH+), measured 186.2 (M-C4H8+H+). Step 3: O1-tert-butyl O3-methyl 3-allylazetidine-1,3-dicarboxylate (compound A1-d) To a mixture of 3-allyl-1-tert-butoxycarbonyl-azetidine-3-carboxylic acid (compound A1-c, 8.0 g, 33.16 mmol) in DMF (80 mL) was added potassium carbonate (13.7 g, 99.47 mmol) followed by iodomethane (9.4 g, 66.31 mmol). After being stirred at 20 °C for 2 hrs, the reaction mixture was poured into water (400 mL) and the resulting mixture was extracted with EtOAc (100 mL, three times). The combined organic layer was washed with brine (300 mL), dried over Na2SO4, filtered and concentrated in vacuo to afford O1-tert-butyl O3-methyl 3-allylazetidine- 1,3-dicarboxylate (compound A1-d, 7.3 g) as yellow oil.1H NMR (400 MHz, CHLOROFORM- d) δ = 5.80 - 5.60 (m, 1 H), 5.19 - 5.14 (m, 1 H), 5.12 (s, 1 H), 4.16 (d, J = 8.8 Hz, 2 H), 3.82 - 3.69 (m, 5 H), 2.63 (d, J = 7.2 Hz, 2 H), 1.44 (s, 9 H) ppm. Step 4: O1-tert-butyl O3-methyl 3-(2-oxoethyl)azetidine-1,3-dicarboxylate (compound A1-e) To a mixture of O1-tert-butyl O3-methyl 3-allylazetidine-1,3-dicarboxylate (compound A1-d, 2 g, 7.83 mmol) in 1,4-dioxane (20 mL) and water (20 mL) was added 2,6-Lutidine (1.8 mL, 15.67 mmol) and K2OsO4 (144.3 mg, 0.39 mmol). After being stirred at 16 °C for 15 minutes, the reaction mixture was added with sodium metaperiodate (6.7 g, 31.33 mmol) and stirred for another 1 h, then poured into water (120 mL) and the resulting mixture was extracted with EtOAc (40 mL, three times). The combined organic layer was washed with sat. Na2SO3 (60 mL), brine (60 mL), dried over Na2SO4, filtered and concentrated in vacuo to afford O1-tert- butyl O3-methyl 3-(2-oxoethyl)azetidine-1,3-dicarboxylate (compound A1-e, 2.8 g) as yellow oil. MS calc’d 258.1 (MH+), measured 202.1 (M-C4H8+H+). Step 5: O1-tert-butyl O3-methyl 3-[2-[[(1S)-1-benzyloxycarbonyl-2-methyl- propyl]amino]ethyl]azetidine-1,3-dicarboxylate (compound A1-f) To a mixture of L-valine benzyl ester hydrochloride (3.2 g, 13.06 mmol) and O1-tert-butyl O3-methyl 3-(2-oxoethyl)azetidine-1,3-dicarboxylate (compound A1-e, 2.8 g, 10.88 mmol) in methanol (50 mL) was added zinc chloride (1.8 g, 13.06 mmol). After being stirred at 16 °C for 0.5 h, the reaction mixture was added with sodium cyanoborohydride (1.4 g, 21.77 mmol) and the resulting mixture was stirred for another 1 h. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography (EtOAc in PE: 30% - 50%) to afford O1-tert-butyl O3-methyl 3-[2-[[(1S)-1-benzyloxycarbonyl-2-methyl- propyl]amino]ethyl]azetidine-1,3-dicarboxylate (compound A1-f, 2.2 g,) as colorless oil. MS calc’d 449.3 (MH+), measured 449.3 (MH+). Step 6: tert-butyl 6-[(1S)-1-benzyloxycarbonyl-2-methyl-propyl]-5-oxo-2,6- diazaspiro[3.4]octane-2-carboxylate (compound A1-g) To a mixture of 4-dimethylaminopyridine (544.7 mg, 4.46 mmol), DIEA (7.7 mL, 44.59 mmol) and O1-tert-butyl O3-methyl 3-[2-[[(1S)-1-benzyloxycarbonyl-2-methyl- propyl]amino]ethyl]azetidine-1,3-dicarboxylate (compound A1-f, 2.0 g, 4.46 mmol) in toluene (2 mL) was stirred at 100 °C for 20 hrs. After the reaction was completed, the reaction mixture was concentrated in vacuo and the residue was dissolved in EtOAc (60 mL). The resulting solution was washed with HCl aq. (1 M, 60 mL), then brine (60 mL), dried over Na2SO4, filtered. The filtrate was concentrated in vacuo to afford tert-butyl 6-[(1S)-1-benzyloxycarbonyl-2- methyl-propyl]-5-oxo-2,6-diazaspiro[3.4]octane-2-carboxylate (compound A1-g, 1.5 g) as a white solid. MS calc’d 417.2 (MH+), measured 361.2 (M-C4H8+H+). Step 7: (2S)-2-(2-tert-butoxycarbonyl-5-oxo-2,6-diazaspiro[3.4]octan-6-yl)-3-methyl- butanoic acid (intermediate A1) A mixture of tert-butyl 6-[(1S)-1-benzyloxycarbonyl-2-methyl-propyl]-5-oxo-2,6- diazaspiro[3.4]octane-2-carboxylate (compound A1-g, 1.5 g, 3.6 mmol) and Pd on activated carbon (150.0 mg) in methanol (20 mL) was stirred under H2 balloon at 16 °C for 2 hrs. The reaction mixture was filtered and the filtrate was concentrated in vacuo to afford (2S)-2-(2-tert- butoxycarbonyl-5-oxo-2,6-diazaspiro[3.4]octan-6-yl)-3-methyl-butanoic acid (intermediate A1, 920.0 mg) as a white solid. MS calc’d 327.2 (MH+), measured 271.2 (M-C4H8+H+). Intermediate A2 cis-(2S)-3-methyl-2-[methyl-[3-(3,3,3-trifluoroprop-1- ynyl)cyclobutanecarbonyl]amino]butanoic acid The compound was prepared according to the following scheme: Step 1: Preparation of methyl 3-(methoxymethylene)cyclobutanecarboxylate (compound A2-b) To a solution of (methoxymethyl)triphenylphosphonium chloride (267.5 g, 780.46 mmol) in THF (1.6 L) was added potassium tert-butoxide (87.6 g, 780.46 mmol) slowly at 0 °C and warmed to 20 °C. Methyl 3-oxocyclobutanecarboxylate (compound A2-a, 50.0 g, 390.23 mmol) was added to the reaction mixture after 1.5 hrs. After being stirred at 70 °C for 3 hrs, the reaction mixture was concentrated under vacuum to give the residue. A mixed solution of PE in EtOAc (10:1, 1.1 L) was added to the residue. After being stirred at 20 °C for 0.5 h, the suspension was filtered and the filtrate was concentrated under vacuum to give a residue. The residue was purified by column chromatography to afford methyl 3- (methoxymethylene)cyclobutanecarboxylate (compound A2-b, 18.0 g) as yellow oil.1H NMR (400 MHz, CHLOROFORM-d) δ = 5.85 - 5.79 (m, 1 H), 3.70 (s, 3 H), 3.60 (s, 3 H), 3.29 - 3.09 (m, 1 H), 3.01 - 2.90 (m, 2H), 2.89 - 2.71 (m, 2 H) ppm. Step 2: Preparation of methyl 3-formylcyclobutanecarboxylate (compound A2-c) To a solution of methyl 3-(methoxymethylene)cyclobutanecarboxylate (compound A2-b, 26.0 g, 166.47 mmol) in DCM (300 mL) and water (30 mL) was added TFA (26.0 mL). The reaction mixture was stirred at 20 °C for 3 hrs. After the reaction was completed, the reaction mixture was added with H2O (600 mL) then extracted with DCM (100 mL, three times). The organic layer was washed with brine (500 mL), dried over Na2SO4, filtered and concentrated under vacuum to give methyl 3-formylcyclobutanecarboxylate (compound A2-c, 18.0 g, 126.63 mmol) as yellow oil.1H NMR (400 MHz, CHLOROFORM-d) δ = 9.84 - 9.52 (m, 1H), 3.75 - 3.63 (m, 3H), 3.32 - 3.20 (m, 1H), 3.18 - 3.07 (m, 1H), 2.67- 2.38 (m, 4H) ppm. Step 3: Preparation of methyl 3-ethynylcyclobutanecarboxylate (compound A2-d) To a solution of methyl 3-formylcyclobutanecarboxylate (compound A2-c, 10.0 g, 70.35 mmol) in methanol (120 mL) was cooled to 0 °C and then dimethyl (1-diazo-2- oxopropyl)phosphonate (21.0 g, 109.31 mmol) and potassium carbonate (20.0 g, 144.71 mmol) were added to the reaction mixture. After being stirred at 20 °C for 3 hrs, the reaction mixture was added with H2O (150 mL) and then extracted with PE (60 mL, twice). The combined organic layer was washed with brine (80 mL), dried over Na2SO4, filtered and concentrated under vacuum to give a residue. The residue was purified by column chromatography (EtOAc in PE: 0 % to 25 %) to give methyl 3-ethynylcyclobutanecarboxylate (compound A2-d, 6.0 g) as colorless oil.1H NMR (400 MHz, CHLOROFORM-d) δ = 3.75 - 3.62 (m, 3H), 3.42 - 3.21 (m, 1H), 3.07 - 2.89 (m, 1H), 2.65 - 2.33 (m, 4H), 2.23 - 2.17 (m, 1H) ppm. Step 4: Preparation of 3-ethynylcyclobutanecarboxylic acid (compound A2-e) To a solution of methyl 3-ethynylcyclobutanecarboxylate (compound A2-d, 6.0 g, 43.43 mmol) in THF (10 mL) and water (30 mL) was added lithium hydroxide (3.6 g, 86.86 mmol) at 0 °C and then the solution was stirred at 20 °C for 3 hrs. After the reaction was completed, the reaction mixture was concentrated under vacuum to remove THF then added with H2O (60 mL) and extracted with MTBE (30 mL). The MTBE phase was discarded and the pH of the aqueous phase was acidified to pH=5 with HCl aq. (1 N, 60 mL) and it was extracted with EtOAc (60 mL, three times). The combined organic layer was washed with brine (80 mL), dried over Na2SO4, filtered and concentrated under vacuum to afford 3-ethynylcyclobutanecarboxylic acid (compound A2-e, 3.8 g) as colorless oil.1H NMR (400 MHz, CHLOROFORM-d) δ = 12.14 - 9.87 (m, 1 H), 3.36 - 3.15 (m, 1 H), 3.10 - 2.95 (m, 1 H), 2.68 - 2.53 (m, 2 H), 2.51 - 2.35 (m, 2 H), 2.22 (dd, J = 15.2, 2.4 Hz, 1 H) ppm. Step 5: Preparation of cis-tert-butyl (2S)-2-[(3-ethynylcyclobutanecarbonyl)-methyl- amino]-3-methyl-butanoate (compound A2-f) To a solution of 3-ethynylcyclobutanecarboxylic acid (compound A2-e, 3.8 g, 30.61 mmol) in DMF (50 mL) was added DIEA (19.0 mL, 114.96 mmol), HATU (14.3 g, 37.48 mmol). After being stirred at 0 °C for 10 min, tert-butyl (2S)-3-methyl-2-(methylamino)butanoate (5.7 g, 30.44 mmol) was added to the reaction mixture. The reaction mixture was stirred at 0 °C for another 1 h. After the reaction was completed, the reaction mixture was added with H2O (120 mL) then extracted with EtOAc (40 mL, three times). The combined organic layer was washed with brine (60 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 %) and prep- HPLC (column: Welch Ultimate XB-CN 250 × 50 × 10 µm; mobile phase: Hexane-EtOH (0.1% FA); B%: 1 % - 20 %, 15 min) to afford cis-tert-butyl (2S)-2-[(3-ethynylcyclobutanecarbonyl)- methyl-amino]-3-methyl-butanoate (compound A2-f, faster eluted, 3 g) as yellow oil. MS calc’d 294.2 (MH+), measured 294.1 (MH+).1H NMR (400 MHz, CHLOROFORM-d) δ = 4.80 (d, J = 10.4 Hz, 0.5 H), 3.58 (d, J = 10.8 Hz, 0.5 H), 3.27 - 3.11 (m, 1 H), 3.01 - 2.91 (m, 1 H), 2.87 (d, J = 6.8 Hz, 3 H), 2.59 - 2.40 (m, 4 H), 2.25 - 2.12 (m, 2 H), 1.45 (s, 9 H), 1.00 (dd, J = 14.4, 6.4 Hz, 3 H), 0.84 (dd, J = 6.8, 1.2 Hz, 3 H) ppm. Stereochemistry of compound A2-f was confirmed by 2D-NMR. Step 6: Preparation of cis-tert-butyl (2S)-3-methyl-2-[methyl-[3-(3,3,3-trifluoroprop-1- ynyl)cyclobutanecarbonyl]amino]butanoate (compound A2-g) A suspension of CuI (408.9 mg, 2.15 mmol), K2CO3 (593.5 mg, 4.29 mmol) and TMEDA (249.5 mg, 2.15 mmol) in DMF (10 mL) was stirred at 25 °C under argon atmosphere for 20 min. TMSCF3 (407.1 mg, 2.86 mmol) was added to the reaction and the reaction mixture was stirred for 10 min under argon atmosphere. A solution of TMSCF3 (407.1 mg, 2.86 mmol) and cis-tert- butyl (2S)-2-[(3-ethynylcyclobutanecarbonyl)-methyl-amino]-3-methyl-butanoate (compound A2-f, 420.0 mg, 1.43 mmol) in DMF (10 mL) was added to the reaction. The reaction mixture was stirred at 0 °C for 30 min and allowed to warm to 25 °C. After being stirred at 25 °C for another 12 hrs, the reaction mixture was added with H2O (30 mL) then extracted with EtOAc (10 mL, three times). The combined organic layer was washed with brine (50 mL) and dried over Na2SO4, filtered and concentrated under vacuum to give a residue. The residue was purified by reversed-phase chromatography and prep-HPLC to afford cis-tert-butyl (2S)-3-methyl-2- [methyl-[3-(3,3,3-trifluoroprop-1-ynyl)cyclobutanecarbonyl]amino]butanoate (compound A2-g, 80.0 mg) as yellow oil. MS calc’d 362.2 (MH+), measured 362.1 (MH+).1H NMR (400 MHz, CHLOROFORM-d) δ = 4.80 (d, J =10.0 Hz, 0.5 H), 3.62 - 3.46 (m, 1.5 H), 3.28 - 3.13 (m, 1 H), 2.89 (d, J = 4.4 Hz, 3 H), 2.82 - 2.67 (m, 2 H), 2.48 - 2.38 (m, 2 H), 2.29 - 2.15 (m, 1 H), 1.46 (d, J = 2.8 Hz, 9 H), 1.05 - 0.98 (m, 3 H), 0.85 (d, J = 6.8 Hz, 3 H) ppm. Step 7: Preparation of cis-(2S)-3-methyl-2-[methyl-[3-(3,3,3-trifluoroprop-1- ynyl)cyclobutanecarbonyl]amino]butanoic acid (Intermediate A2) To a solution of cis-tert-butyl (2S)-3-methyl-2-[methyl-[3-(3,3,3-trifluoroprop-1- ynyl)cyclobutanecarbonyl]amino]butanoate (compound A2-g, 80.0 mg, 0.22 mmol) in DCM (1 mL) was added TFA (1.0 mL) and the mixture was stirred at 20 °C for 1 h. After the reaction was completed, the reaction mixture was concentrated under vacuum to afford cis-(2S)-3- methyl-2-[methyl-[3-(3,3,3-trifluoroprop-1-ynyl)cyclobutanecarbonyl]amino]butanoic acid (Intermediate A2, 80.0 mg) as yellow oil, which was used directly in the next step. MS calc’d 306.0 (MH+), measured 306.0 (MH+). Intermediate A3 and Intermediate A4 (2S)-2-[(5R)-7-tert-butoxycarbonyl-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-3-methyl-butanoic acid (intermediate A3) and (2S)-2-[(5S)-7-tert-butoxycarbonyl-1-oxo-2,7- diazaspiro[4.4]nonan-2-yl]-3-methyl-butanoic acid (intermediate A4) intermediate A3intermediate A4 The compound was prepared according to the following scheme:intermediate A3intermediate A4Step 1: Preparation of O1-tert-butyl O3-methyl 3-allylpyrrolidine-1,3-dicarboxylate (compound A3-b) To a solution of O1-tert-butyl O3-methyl pyrrolidine-1,3-dicarboxylate (compound A3-a, 5.0 g, 21.8 mmol) in THF (60 mL) was added LDA (12 mL, 24 mmol) dropwise at -70 °C under nitrogen atmosphere. After being stirred for 0.5 h, allyl bromide (2.9 g, 23.99 mmol) was added slowly. After the reaction was completed, the reaction mixture was poured into sat. NH4Cl aq. (100 mL) and extracted with EtOAc (70 mL, twice). The combined organic layer was washed with brine (70 mL ), dried over Na2SO4, filtered and concentrated under vacuum to give a residue, which was purified by silica gel column to afford O1-tert-butyl O3-methyl 3- allylpyrrolidine-1,3-dicarboxylate (compound A3-b, 2.91 g) as colorless oil. Step 2: Preparation of O1-tert-butyl O3-methyl 3-(2-oxoethyl)pyrrolidine-1,3- dicarboxylate (compound A3-c) To the mixture of O1-tert-butyl O3-methyl 3-allylpyrrolidine-1,3-dicarboxylate (compound A3-b, 2.1 g, 7.8 mmol) in 1,4-dioxane (60 mL) and water (6 mL) was added 2,6- Lutidine (1.8 mL, 15.6 mmol) and K2OsO4 (0.1 g, 0.39 mmol) in one portion at 0 °C. After being stirred at 0 °C for 15 min, sodium metaperiodate (6.6 g, 31.19 mmol) was added portion-wise at 0 °C. The resulting mixture was warmed to 20 °C and stirred for another 6 hrs. After the reaction was completed, it was quenched with saturated Na2S2O3 aqueous solution (100 mL) and the reaction mixture was extracted with EtOAc (50 mL, three times). The combined organic layer was washed with brine (50 mL), dried with anhydrous Na2SO4, filtered and concentrated under vacuum to afford O1-tert-butyl O3-methyl 3-(2-oxoethyl)pyrrolidine-1,3-dicarboxylate (compound A3-c, 2.1 g) as yellow oil, which was used in the next step directly. Step 3: Preparation of O1-tert-butyl O3-methyl 3-[2-[[(1S)-1-benzyloxycarbonyl-2- methyl-propyl]amino]ethyl]pyrrolidine-1,3-dicarboxylate (compound A3-d) To the mixture of O1-tert-butyl O3-methyl 3-(2-oxoethyl)pyrrolidine-1,3-dicarboxylate (compound A3-c, 2.1 g, 7.74 mmol) and benzyl (2S)-2-amino-3-methyl-butanoate (1.6 g, 7.74 mmol) in methanol (20 mL) was added zinc chloride (1.05 g, 7.74 mmol) in one portion at 0 °C. After being stirred at 0 °C for 1 h, to the mixture was added sodium cyanoborohydride (0.97 g, 15.48 mmol) at 0 °C. The resulting mixture was stirred at 0 °C for another 2 hrs. After the reaction was completed, the mixture was poured into saturated NH4Cl aqueous solution (40 mL) at 0 °C and extracted with EtOAc (50 mL, three times). The combined organic layer was washed with brine (30 mL, four times), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue, which was purified by silica gel column to afford O1-tert-butyl O3-methyl 3-[2-[[(1S)-1-benzyloxycarbonyl-2-methyl-propyl]amino]ethyl]pyrrolidine-1,3- dicarboxylate (compound A3-d, 2.2 g) as yellow oil. MS calc’d 463.3 (MH+), measured 463.2 (MH+). Step 4: Preparation of tert-butyl (5R)-2-[(1S)-1-benzyloxycarbonyl-2-methyl-propyl]- 1-oxo-2,7-diazaspiro[4.4]nonane-7-carboxylate (compound A3-e) and tert-butyl (5S)-2- [(1S)-1-benzyloxycarbonyl-2-methyl-propyl]-1-oxo-2,7-diazaspiro[4.4]nonane-7- carboxylate (compound A3-f). To the mixture of O1-tert-butyl O3-methyl 3-[2-[[(1S)-1-benzyloxycarbonyl-2-methyl- propyl]amino]ethyl]pyrrolidine-1,3-dicarboxylate (compound A3-d, 2.1 g, 4.54 mmol) in toluene (20 mL) was added DIEA (7.9 mL, 45.4 mmol) and DMAP (0.6 g, 4.54 mmol) in one portion. The mixture was heated to 80 °C and stirred for 16 hrs. After the reaction was completed, the mixture was poured into water (30 mL) and extracted with EtOAc (30 mL, three times). The combined organic layer was washed with brine (30 mL), dried with anhydrous Na2SO4, filtered and concentrated under vacuum to give a residue, which was purified by reversed phase flash column and the eluent was concentrated under vacuum. The residue was further separated by prep-SFC to afford tert-butyl (5R)-2-[(1S)-1-benzyloxycarbonyl-2-methyl-propyl]-1-oxo-2,7- diazaspiro[4.4]nonane-7-carboxylate (compound A3-e, faster eluted, 521 mg) and tert-butyl (5S)-2-[(1S)-1-benzyloxycarbonyl-2-methyl-propyl]-1-oxo-2,7-diazaspiro[4.4]nonane-7- carboxylate (compound A3-f, slower eluted, 525 mg). MS calc’d 453.3 (MNa+), measured 453.2 (MNa+). SFC conditions: Instrument: SFC 150 Mgm; Column: Chiralpak IG-350×4.6mm I.D., 3um. Mobile phase: A for CO2 Phase B for MEOH (0.05%DEA); Gradient elution: 40%B in A; Flow rate: 3mL / min; Detector: DAD; Back pressure: 100 bar; Column temperature: 35℃. Step 5: Preparation of (2S)-2-[(5R)-7-tert-butoxycarbonyl-1-oxo-2,7- diazaspiro[4.4]nonan-2-yl]-3-methyl-butanoic acid (Intermediate A3). To a solution of tert-butyl (5R)-2-[(1S)-1-benzyloxycarbonyl-2-methyl-propyl]-1-oxo-2,7- diazaspiro[4.4]nonane-7-carboxylate (compound A3-e, 120 mg, 0.28 mmol) in toluene (2 mL) was added wet palladium (12 mg, 10% wt. on activated carbon). The mixture was degassed and purged with hydrogen for 3 times. The reaction mixture was heated to 35 °C and stirred for 3 hrs under hydrogen atmosphere. After the reaction was completed, the solution was filtered and the filtrate was concentrated in vacuo to give (2S)-2-[(5R)-7-tert-butoxycarbonyl-1-oxo-2,7- diazaspiro[4.4]nonan-2-yl]-3-methyl-butanoic acid (Intermediate A3, 94 mg) as a white solid. MS calc’d 363.2 (MNa+), measured 363.1 (MNa+). X-ray crystallographic analysis of intermediate A3 Absolute configuration structure of intermediate A3 was confirmed by X-ray crystallographic analysis of its single crystal. (Figure 1) Step 6: Preparation of (2S)-2-[(5S)-7-tert-butoxycarbonyl-1-oxo-2,7- diazaspiro[4.4]nonan-2-yl]-3-methyl-butanoic acid (intermediate A4). To a solution of tert-butyl (5S)-2-[(1S)-1-benzyloxycarbonyl-2-methyl-propyl]-1-oxo-2,7- diazaspiro[4.4]nonane-7-carboxylate (compound A3-f, 120 mg, 0.28 mmol) in toluene (2 mL) was added wet palladium (12 mg, 10% wt. on activated carbon). The mixture was degassed and purged with hydrogen for 3 times. The mixture was heated to 35 °C and stirred for 3 h under hydrogen atmosphere. After the reaction was completed, the solution was filtered and the filtrate was concentrated in vacuo to afford (2S)-2-[(5S)-7-tert-butoxycarbonyl-1-oxo-2,7- diazaspiro[4.4]nonan-2-yl]-3-methyl-butanoic acid (intermediate A4, 79 mg) as a white solid.MS calc’d 363.2 (MNa+), measured 363.1 (MNa+). X-ray crystallographic analysis of intermediate A4 Absolute configuration structure of intermediate A4 was confirmed by X-ray crystallographic analysis of its single crystal. (Figure 2) Intermediate B1 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 B1-b) To a solution of L-M-tyrosine (compound B1-a, 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 B1-b, 6.2 g) as a yellow solid.1H NMR (400 MHz, CD3OD) δ = 7.18 (t, J = 8.0 Hz, 1H), 6.78 - 6.66 (m, 3H), 4.29 (t, J = 6.4 Hz, 1H), 3.82 (s, 3H), 3.23 - 3.05 (m, 2H). Step 2: Preparation of methyl (2S)-2-(tert-butoxycarbonylamino)-3-(3- hydroxyphenyl)propanoate (compound B1-c) To a solution of methyl (2S)-2-amino-3-(3-hydroxyphenyl)propanoate (compound B1-b, 32.0 g, 138.1 mmol) in THF (80 mL) and water (20 mL) was 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, 3 times). The combined organic phase was washed with 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 B1-c, 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 B1-d) To a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-(3- hydroxyphenyl)propanoate (compound B1-c, 40.0 g, 135.4 mmol) and 1H-imidazole (27.6 g, 406.3 mmol) in DMF (400 mL) was added triisopropylsilyl chloride (39.1 g, 203.1 mmol) dropwise at 0 °C. After being stirred for 12 hrs at 25 °C, the mixture was diluted with water (250 mL) at 0 °C and extracted with ethyl acetate (200 mL, 3 times). The combined organic phase was washed with brine (80 mL, four 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 B1-d, 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 B1-e) To a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-(3- triisopropylsilyloxyphenyl)propanoate (compound B1-d, 15.0 g, 33.2 mmol), 4,4'-di-tert-butyl- 2,2'-bipyridine (2.6 g, 9.9 mmol) and bis(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 B1-e, 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 B1-f) 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 B1-e, 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 hour, 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, 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 B1-f, 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 B1) 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 B1-f, 8.0 g, 14.1 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (5.6 g, 14.9 mmol) 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 B1-g, 2.6 g, 14.9 mmol) was added. The resulting mixture was stirred at 20 °C for 1.5 hrs, then diluted with water (200 mL) and extracted with EtOAc (100 mL, twice). 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 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 B1, 7.8 g) as yellow oil. MS: calc’d 690 (MH+), measured 690.4 (MH+). Intermediate B2 Methyl (3S)-1-[(2S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)- propanoyl]hexahydropyridazine-3-carboxylate The intermediate B2 was prepared according to the following scheme:

[0004] B2-h Intermediate B2 Step 1: Preparation of (4-bromothiazol-2-yl)methanol (compound B2-b) To a solution of 4-bromothiazole-2-carboxaldehyde (compound B2-a, 6.0 g, 31.25 mmol) in methanol (70 mL) was added sodium borohydride (1.7 g, 46.87 mmol) at 0 °C. The mixture was stirred at 25 °C for 1 hour. The reaction was quenched with water (300 mL) at 0 °C and the reaction mixture was extracted by ethyl acetate (200 mL, three times). The combined organic phase was washed with 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 B2-b, 6g) as colorless oil. Step 2: Preparation of 4-bromo-2-(bromomethyl)thiazole (compound B2-c) To a solution of (4-bromothiazol-2-yl)methanol (compound B2-b, 6.0 g, 30.92 mmol) in DCM (80 mL) was added CBr4 (15.4 g, 46.38 mmol) and triphenylphosphine (12.1 g, 46.38 mmol) at 0 °C. After being stirred at 25 °C for 1 hour, the mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel column, eluted with ethyl acetate in petroleum ether = 0~10% to afford (4-bromothiazol-2-yl)methanol (compound B2-c, 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 B2-e) To a mixture of (R)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine (compound B2-d, 4.3 g, 23.45 mmol) in THF (60 mL) was added n-butyllithium (10 mL, 25.22 mmol, 2.5 M) at - 78 °C slowly. After addition, the mixture was stirred for 0.5 hour at -78 °C.4-bromo-2- (bromomethyl)thiazole (compound B2-c, 5.4 g, 21.02 mmol) was added into above mixture at - 78 °C which was stirred for another 1 hour. The reaction was quenched with saturated solution of NH4Cl (100 mL) and the reaction mixture was 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 under vacuum. The residue was purified by reversed- phase chromatography to afford 4-bromo-2-[[(2S,5R)-5-isopropyl-3,6-dimethoxy-2,5- dihydropyrazin-2-yl]methyl]thiazole (compound B2-e, 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 B2-f) To a solution of 4-bromo-2-[[(2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2- yl]methyl]thiazole (compound B2-e, 3.6 g, 10 mmol) in ACN (20 mL) was added hydrochloric acid (66.6 mL, 0.3 M). The mixture was stirred at 25 °C for 2 hours. The mixture was basified by saturated 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 B2-f, 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 B2-g) To a solution of methyl (2S)-2-amino-3-(4-bromothiazol-2-yl)propanoate (compound B2-f, 3.1 g, 11.69 mmol) in DCM (40 mL) were added triethylamine (2.9 g, 29.23 mmol) and (Boc)2O (3.8 g, 17.54 mmol). After being 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 B2-g, 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 B2-h) To a solution of methyl (2S)-3-(4-bromothiazol-2-yl)-2-(tert- butoxycarbonylamino)propanoate (compound B2-g, 3.2 g, 8.76 mmol) in THF (30 mL), methanol (2 mL) and water (10 mL) was added lithium hydroxide (0.4 mL, 43.81 mmol). After being stirred at 25 °C for 1 hour, the reaction mixture was acidified by 1 M 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 B2-h, 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 (Intermediate B2) To a solution of (2S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)propanoic acid (compound B2-h, 3.1 g, 8.83 mmol) in DCM (50 mL) was added methyl (3S)- hexahydropyridazine-3-carboxylate;hydrochloride (compound B1-g, 2.4 g, 13.24 mmol), EDCI (3.4 g, 17.65 mmol), 1-Hydroxybenzotriazole (238.5 mg, 1.77 mmol) and NMM (9.92 mL, 88.26 mmol) at 0 °C. After being stirred at 25 °C for 1 hour, the reaction mixture was 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 B2, 2.4 g). MS calc’d 477(MH+), measured 476.9 (MH+). Intermediate C1 Benzyl 4-[5-ethynyl-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate The compound C1 was prepared according to the following scheme: Step 1: Preparation of benzyl 4-[5-bromo-6-[(1S)-1-methoxyethyl]-3- pyridyl]piperazine-1-carboxylate (compound C1-b) To a solution of 3-bromo-5-iodo-2-[(1S)-1-methoxyethyl]pyridine (compound C1-a, 660 mg, 1.9 mmol, CAS 2641451-76-3, PBWZ170, PharmaBlock (Nanjing) R&D Co. Ltd) and 1- Cbz-piperazine (compound C1-b, 425.1 mg, 1.9 mmol) in toluene (10 mL) 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). After being stirred at 100 °C for 12 hrs under N2 protection, the mixture was filtered and then 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 C1-b, 740 mg) as a yellow solid. MS calc’d 434.1 (MH+), measured 434.1 (MH+). Step 2: Preparation of benzyl 4-[6-[(1S)-1-methoxyethyl]-5-(2-trimethylsilylethynyl)-3- pyridyl]piperazine-1-carboxylate (compound C1-a) To a solution of benzyl 4-[5-bromo-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1- carboxylate (compound C1-b, 33.0 g, 75.98 mmol) in DMF (1 L) was added trimethylsilylacetylene (85.9 mL, 607.83 mmol), Pd(PPh3)2Cl2 (5.3 g, 7.6 mmol), CuI (1.5 g, 7.6 mmol) and TEA (52.9 mL, 379.9 mmol) under a nitrogen atmosphere. The reaction mixture was degassed with nitrogen for three times and then it was stirred at 100 °C for 12 hrs. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered and the filtrate was added with H2O (3 L). The reaction mixture was extracted with EtOAc (1 L, three times). The combined organic layer was washed with brine (3 L), dried over Na2SO4, filtered and concentrated under vacuum to give a residue, which was purified by column chromatography to afford benzyl 4-[6-[(1S)-1-methoxyethyl]-5-(2-trimethylsilylethynyl)-3-pyridyl]piperazine-1- carboxylate (compound C1-c, 21.0 g) as a yellow solid. MS calc’d 452.2 (MH+), measured 452.2 (MH+). Step 3: Preparation of benzyl 4-[5-ethynyl-6-[(1S)-1-methoxyethyl]-3- pyridyl]piperazine-1-carboxylate (intermediate D1) To a solution of benzyl 4-[6-[(1S)-1-methoxyethyl]-5-(2-trimethylsilylethynyl)-3- pyridyl]piperazine-1-carboxylate (compound C1-c, 31 g, 68.6 mmol) in Methanol (500 mL) was added potassium fluoride (8.1 g, 139.8 mmol) at 0 °C. 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, which was purified by column chromatography to afford benzyl 4-[5-ethynyl-6-[(1S)-1- methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (intermediate C1, 25 g) as a brown solid. MS calc’d 380.2 (MH+), measured 380.2 (MH+). Intermediate C2 4-[5-ethynyl-6-[(1S)-1-methoxyethyl]-3-pyridyl]morpholine The title compound was prepared in analogy to the preparation of Intermediate C1 by using morpholine instead of 1-Cbz-piperazine. Intermediate C3 1-[5-ethynyl-6-[(1S)-1-methoxyethyl]-3-pyridyl]-4-(2,2,2-trifluoroethyl)piperazine The title compound was prepared in analogy to the preparation of Intermediate C1 by using 1-(2,2,2-trifluoroethyl)piperazine instead of 1-Cbz-piperazine. Intermediate C4 3-ethynyl-2-[(1S)-1-methoxyethyl]pyridine The title compound was prepared in analogy to the preparation of Intermediate C1 by using 3-bromo-2-[(1S)-1-methoxyethyl]pyridine (CAS 2641451-44-5, PBU8238, PharmaBlock (Nanjing) R&D Co. Ltd) instead of benzyl 4-[5-bromo-6-[(1S)-1-methoxyethyl]-3- pyridyl]piperazine-1-carboxylate (compound C1-b). Intermediate D1 6-bromo-8-iodo-1,2,3,4-tetrahydroquinoline The compound was prepared according to the following scheme: D1-a D1To a solution of 6-bromo-1,2,3,4-tetrahydroquinoline (compound D1-a, 40.0 g, 188.6 mmol) in DMF (1.3 L) was added NIS (42.4 g, 188.6 mmol) portion-wise at 0 °C. After being stirred for 2 h at 25 °C, the reaction mixture was poured into water (4 L) and extracted with EtOAc (2 L, three times). The combined organic layer was washed with brine (2 L, three times), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to give a residue. The residue was purified by reversed phase chromatography to give 6-bromo-8-iodo-1,2,3,4- tetrahydroquinoline (Intermediate D1, 37 g) as a brown gum. MS calc’d 337.9 (MH+), measured 338.0 (MH+). Intermediate D2 7-bromo-5-iodo-3,4-dihydro-2H-1,4-benzoxazine The compound was prepared according to the following scheme: p-toluenesulfonyl chloride silver sulfate TEA,DCM I2, EtOH D2-a D2-b D2-c D2-d D2-e D2 Step 1: Preparation of (2-amino-5-bromo-phenyl) 4-methylbenzenesulfonate (compound D2-b) To a solution of 2-amino-5-bromophenol (compound D2-a, 75.0 g, 398.89 mmol) and TEA (66.7 mL, 478.67 mmol) in DCM (1.5 L) was added p-toluenesulfonyl chloride (83.6 g, 438.78 mmol). After being stirred at 25 °C for 1 h, the reaction was quenched with sat. NaHCO3 aq. (400 mL) and EtOAc (500 mL, three times). The organic layer was washed with brine (200 mL), dried over Na2SO4, filtered and concentrated under vacuum to afford crude (2-amino-5-bromo- phenyl) 4-methylbenzenesulfonate (compound D2-b, 146.5 g) as a dark brown solid, which was used in the next step without purification. MS calc’d 342 (MH+), measured 342 (MH+). Step 2: Preparation of (2-amino-5-bromo-3-iodo-phenyl) 4-methylbenzenesulfonate (compound D2-c) To a solution of (2-amino-5-bromo-phenyl) 4-methylbenzenesulfonate (compound D2-b, 146.5 g, 428.1 mmol) in ethanol (1.5 L) was added silver sulfate (133.5 g, 428.1 mmol) and iodine (108.7 g, 428.1 mmol). After being stirred at 25 °C for 12 hrs, the reaction was quenched by sat. NaHCO3 aq. (400 mL) and EtOAc (500 mL, three times). The organic layer was washed with brine (200 mL), dried over Na2SO4, filtered and concentrated under vacuum to afford (2- amino-5-bromo-3-iodo-phenyl) 4-methylbenzenesulfonate (compound D2-c, 210.0 g) as a dark brown solid, which was used directly in the next step without purification. MS calc’d 467.8 (MH+), measured 467.8 (MH+). Step 3: Preparation of 2-amino-5-bromo-3-iodo-phenol (compound D2-d) To a solution of (2-amino-5-bromo-3-iodo-phenyl) 4-methylbenzenesulfonate (compound D2-c, 210.0 g, 448.62 mmol) in ethanol (1.5 L) and THF (500 mL) was added sodium hydroxide (62.8 g, 1570.18 mmol). The mixture was heated to reflux for 1 h. After being cooled to room temperature, the reaction mixture was concentrated under vacuum to give a residue. The residue was neutralized until pH = 7 by using 6 N HCl, and then extracted with EtOAc (1 L, twice). The combined organic layer was dried over Na2SO4, filtered and concentrated under vacuum to give a residue. The crude product was purified by column chromatography to afford 2-amino-5- bromo-3-iodo-phenol (compound D2-d, 120.0 g) as a dark brown solid. MS calc’d 313.9 (MH+), measured 313.9 (MH+). Step 4: Preparation of 7-bromo-5-iodo-4H-1,4-benzoxazin-3-one (compound D2-e) To a solution of 2-amino-5-bromo-3-iodo-phenol (compound D2-d, 50.0 g, 159.28 mmol) and potassium carbonate (33.0 g, 238.91 mmol) in DMF (2 L) was added chloroacetyl chloride (19.0 mL, 238.91 mmol). After being stirred at 25 °C for 12 hrs, the reaction mixture was concentrated under vacuum to give a residue. The residue was poured into H2O (1 L), and extracted with EtOAc (1 L, three times). The organic layer was washed with brine (1.5 L, twice), dried over Na2SO4, filtered and concentrated under vacuum to give a residue. The crude product was triturated with MTBE (100 mL) at 25 °C for 30 min. The suspension was filtered, the filter cake was collected to afford 7-bromo-5-iodo-4H-1,4-benzoxazin-3-one (compound D2-e, 175.0 g) as a dark brown solid. MS calc’d 353.9 (MH+), measured 353.9 (MH+). Step 5: Preparation of 7-bromo-5-iodo-3,4-dihydro-2H-1,4-benzoxazine (Intermediate D2) To a stirred solution of 7-bromo-5-iodo-4H-1,4-benzoxazin-3-one (compound D2-e, 20.0 g, 56.51 mmol) in THF (500 mL) under N2 atmosphere was added borane tetrahydrofuran complex solution (113.0 mL, 113.01 mmol) at 0°C. After being stirred at 80 °C for 1 h, the mixture was cooled to room temperature, followed by addition of MeOH (100 mL). The mixture was poured into H2O (100 mL), extracted with EtOAc (200 mL, three times). The organic layer was washed with brine (100 mL, twice), dried over Na2SO4, filtered and concentrated under vacuum to give a residue. The crude product was purified by column chromatography to afford 7-bromo-5-iodo- 3,4-dihydro-2H-1,4-benzoxazine (intermediate D2, 17.6 g) as a pink solid. MS calc’d 340.0 (MH+), measured 340.0(MH+).1H NMR (400 MHz, DMSO-d6) δ = 7.31 (d, J = 2.4 Hz, 1H), 6.88 (d, J = 2.4 Hz, 1H), 5.42 (br s, 1H), 4.07 (t, J = 4.4 Hz, 2H), 3.38 - 3.33 (m, 2H). Intermediate D3 6-bromo-3,3-difluoro-8-iodo-2,4-dihydro-1H-quinoline The compound was prepared according to the following scheme: Step 1: Preparation of 3,3-difluoro-1H-quinoline-2,4-dione (compound D3-b) To a solution of 1H-quinoline-2,4-dione (compound D3-a, 8.0 g, 49.64 mmol) and potassium carbonate (13.7 g, 99.28 mmol) in ACN (160 mL) and water (80 mL) was added Selectfluor (40.0 g, 112.91 mmol) at 0 °C. After being stirred at 25 °C for 1 h, the reaction mixture was concentrated in vacuo and the residue was filtered. The filtrate was added to water (1 L). The resultant mixture was extracted with EtOAc (400 mL, three times). The combined organic layer was washed with brine (400 mL, twice), dried over Na2SO4, filtered and concentrated in vacuo to afford 3,3-difluoro-1H-quinoline-2,4-dione (compound D3-b, 46.0 g) as a yellow solid.1H NMR (400 MHz, CHLOROFORM-d) δ = 9.77 (s, 1H), 8.22 - 7.94 (m, 1H), 7.81 - 7.64 (m, 1H), 7.33 - 7.28 (m, 1H), 7.17 (d, J = 8.0 Hz, 1H). Step 2: Preparation of 3,3-difluoro-2,4-dihydro-1H-quinolin-4-ol (compound D3-c) To a solution of 3,3-difluoro-1H-quinoline-2,4-dione (compound D3-b, 69.0 g, 350.01 mmol) in THF (700 mL) was added borane-tetrahydrofuran complex (700.0 mL, 700.0 mmol) at 0 °C. After being stirred at 25 °C for 16 hrs, the reaction was quenched with MeOH (500 mL) at 0 °C dropwise, and then concentrated in vacuo to afford 3,3-difluoro-2,4-dihydro-1H-quinolin-4- ol (compound D3-c, 64.8 g) as yellow oil. MS calc’d 185.1 (MH+), measured 168.0, (M-OH+H+). Step 3: Preparation of 3,3-difluoro-2,4-dihydro-1H-quinoline (compound D3-d) To a solution of 3,3-difluoro-2,4-dihydro-1H-quinolin-4-ol (compound D3-c, 64.8 g, 349.95 mmol) in Et3SiH (206.8 mL, 1.29 mol) was added TFA (405.4 mL, 5.26 mol) at 0 °C. After being stirred at 25 °C for 16 hrs, the reaction mixture was concentrated in vacuo and adjusted to pH=8 by adding sat. NaHCO3 aq., extracted with EtOAc (1 L, twice). The combined organic layer was washed by brine (1.6 L), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue, which was purified by silica gel column chromatography to afford 3,3-difluoro-2,4-dihydro-1H-quinoline (compound D3-d, 45.0 g) as a yellow solid. MS calc’d 170.1 (MH+), measured 170.0 (MH+). Step 4: Preparation of 6-bromo-3,3-difluoro-2,4-dihydro-1H-quinoline (compound D3-e) To a solution of 3,3-difluoro-2,4-dihydro-1H-quinoline (compound D3-d, 50.0 g, 295.56 mmol) in DMF (800 mL) was added NBS (50.0 g, 280.92 mmol) at 0 °C. After being stirred at 0 °C for 1 h, the mixture was poured into water (1200 mL) and the resulting mixture was extracted with EtOAc (800 mL, three times). The combined organic layer was washed with brine (1 L, three times), dried over Na2SO4, filtered and concentrated in vacuo, which was purified by column chromatography to afford 6-bromo-3,3-difluoro-2,4-dihydro-1H-quinoline (compound D3-e, 57.0 g) as a yellow solid. MS calc’d 248.0 (MH+), measured 247.9 (MH+). Step 5: Preparation of 6-bromo-3,3-difluoro-8-iodo-2,4-dihydro-1H-quinoline (Intermediate D3) To a solution of 6-bromo-3,3-difluoro-2,4-dihydro-1H-quinoline (compound D3-e, 49.0 g, 197.52 mmol) in DMF (700 mL) was added NIS (48.9 g, 217.28 mmol) at 0 °C. After being stirred at 0 °C for 5 hrs, the reaction mixture was poured into water (1.2 L) and the resultant mixture was extracted with EtOAc (650 mL, three times). The combined organic layer was washed with brine (1 L, three times), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography to afford 6-bromo-3,3-difluoro-8-iodo-2,4- dihydro-1H-quinoline (intermediate D3, 68.0 g) as a white solid. MS calc’d 373.9 (MH+), measured 373.9 (MH+). Intermediate D4 7-bromo-5-iodo-2,2-dimethyl-3,4-dihydro-1,4-benzoxazine The title compound was prepared in analogy to the preparation of Intermediate D2 by using ethyl 2-bromo-2-methyl-propanoate instead of chloroacetyl chloride. Intermediate D5 7-bromo-5-iodo-3-methyl-3,4-dihydro-2H-1,4-benzoxazine The compound was prepared according to the following scheme: Step 1: Preparation of 7-bromo-5-iodo-3-methyl-2H-1,4-benzoxazine (compound D5-a) To a solution of 2-amino-5-bromo-3-iodo-phenol (compound D2-d, 18 g, 57.34 mmol) in acetone (300 mL) was added potassium carbonate (15.8 g, 114.68 mmol) and chloroacetone (10.6 g, 114.68 mmol). After being stirred at 25 °C for 18 hrs, the reaction mixture was poured into EtOAc (200 mL) / water (400 mL), and layers were separated. The aqueous phase was extracted with EtOAc (200 mL, twice). The combined organic layer was washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give a residue. The residue was purified by flash chromatography to give 7-bromo-5-iodo-3-methyl-2H-1,4-benzoxazine (compound D5-a, 20 g) as light brown solid. MS calc’d 351.9 (MH+), measured 351.9 (MH+). Step 2: Preparation of 7-bromo-5-iodo-3-methyl-3,4-dihydro-2H-1,4-benzoxazine (Intermediate D5) To a solution of 7-bromo-5-iodo-3-methyl-2H-1,4-benzoxazine (compound D5-a, 20.0 g, 60 mmol) in TFA (1 L, 12.98 mmol) was added sodium cyanoborohydride (17 g, 270 mmol) and then stirred at 25 °C for 2 hrs. The mixture was slowly added to NaOH aq. (150 mL, 2M) and then extracted with EtOAc (100 mL, twice). The organic layer was washed with water, brine, dried over sodium sulfate, filtered, concentrated under vacuum to give a residue. The residue was purified by silica gel chromatography to afford 7-bromo-5-iodo-3-methyl-3,4-dihydro-2H-1,4- benzoxazine (Intermediate D5, 14.6 g) as brown thick oil. MS calc’d 353.9 (MH+), measured 353.9 (MH+). Intermediate D6 9-bromo-7-iodo-3,4,5,6-tetrahydro-2H-1,6-benzoxazocine The compound was prepared according to the following scheme: D6-e Intermediate D6 Step 1: Preparation of tert-butyl N-(4-bromo-2-hydroxy-phenyl)carbamate (compound D6-b) To a solution of 2-amino-5-bromophenol (compound D6-a, 15.0 g, 79.77 mmol) in anhydrous DCM (80 mL) was added (Boc)2O (26.1g, 119.67 mmol) and TEA (22.2 mL, 159.57 mmol). After being stirred at 25 ℃ for 15 hrs, EtOAc (450 mL) and water (450 mL) were added in to the reaction. The layers were separated, and the aqueous phase was extracted with EtOAc (450 mL, twice). The combined organic layer was washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give a residue. The residue was purified by column chromatography to afford tert-butyl N-(4-bromo-2-hydroxy-phenyl)carbamate (compound D6-b, 11.85 g) as a yellow solid. MS calc’d 288.0 (MH+), measured 231.6 (M- C4H8+H+). Step 2: Preparation of tert-butyl N-[4-bromo-2-[3-(1,3-dioxolan-2- yl)propoxy]phenyl]carbamate (compound D6-d) To a solution of tert-butyl N-(4-bromo-2-hydroxy-phenyl)carbamate (compound D6-b, 10.0 g, 34.71 mmol) in anhydrous DMF (150 mL) at 25 ℃ was added 2-(3-bromopropyl)-1,3- dioxolane (compound D6-c, 13.5 g, 69.44 mmol) and TEA (14.51 mL, 104.12 mmol). The mixture was then heated to 90 ℃ and stirred for another 15 hrs. After the reaction was completed, EtOAc (300 mL) and water (200 mL) were added to previous mixture and layers were separated. The aqueous phase was extracted with EtOAc (250 mL, twice). The combined organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give a residue. The residue was purified by column chromatography to afford tert-butyl N-[4-bromo- 2-[3-(1,3-dioxolan-2-yl)propoxy]phenyl]carbamate (compound D6-d, 12.6 g ) as yellow oil. MS calc’d 402.0 (MH+), measured 423.8 (MNa+). Step 3: Preparation of 9-bromo-3,4,5,6-tetrahydro-2H-1,6-benzoxazocine (compound D6-e) To a solution of tert-butyl N-[4-bromo-2-[3-(1,3-dioxolan-2-yl)propoxy]phenyl]carbamate (compound D6-d, 7.1 g, 17.65 mmol) in DCM (500 mL) at 0 ℃ was added TFA (125 mL) via syringe dropwise over 5 min under nitrogen atmosphere. After being stirred at 25 ℃ for 1h, triethylsilane (10.3 g, 88.25 mmol) was added to the reaction and then it was stirred at 25 ℃ for another 4 hrs. After the reaction was completed, the mixture was concentrated under vacuum to get a residue. EtOAc (500 mL) and sat. NaHCO3 aq. solution (500 mL) were added to the residue and the layers were separated. The aqueous phase was extracted with EtOAc (500 mL, twice). The combined organic layer was washed with brine (400 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give a residue. The residue was purified by column chromatograph to afford 9-bromo-3,4,5,6-tetrahydro-2H-1,6-benzoxazocine (compound D6-e, 2.9 g) as an orange solid. MS calc’d 242.0 (MH+), measured 242.0 (MH+). Step 4: Preparation of 9-bromo-7-iodo-3,4,5,6-tetrahydro-2H-1,6-benzoxazocine (intermediate D6) To a solution of 9-bromo-3,4,5,6-tetrahydro-2H-1,6-benzoxazocine (compound D6-e, 2.8 g, 11.56 mmol) in acetic acid (100 mL) was added NIS (3.9 g, 17.35 mmol) slowly. The mixture was stirred for 15 hours at 25 ℃. After the reaction was completed, the mixture was concentrated in vacuo. The residue was purified by reversed phase chromatography to afford 9- bromo-7-iodo-3,4,5,6-tetrahydro-2H-1,6-benzoxazocine (intermediate D6, 1.2 g ) as a brown solid. MS calc’d 367.9 (MH+), measured 367.9 (MH+). Intermediate D7 8-bromo-6-iodo-2,3,4,5-tetrahydro-1,5-benzoxazepine The title compound was prepared in analogy to the preparation of Intermediate D6 by using 2-(2-bromoethyl)-1,3-dioxolane instead of 2-(3-bromopropyl)-1,3-dioxolane (compound D6-c). Intermediate D8 6-bromo-8-iodo-3,3-dimethyl-2,4-dihydro-1H-quinoline The title compound was prepared in analogy to the preparation of Intermediate D1 by using 6-bromo-3,3-dimethyl-2,4-dihydro-1H-quinoline instead of 6-bromo-1,2,3,4- tetrahydroquinoline (compound D1-a). Intermediate E

[0005] (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]- 17,17-dimethyl-15-oxa-4-thia-9,21,30,31- 2,5 9,13 19,27 21,26 tetrazahexacyclo[23.3.1.1 .1 .0 .0 ]hentriaconta-1(28),2,5(31),19,25(29),26-hexaene- 8,14-dione The compound was prepared according to the following scheme: Intermediate E Step 1: Preparation of benzyl 4-[5-[2-(6-bromo-1,2,3,4-tetrahydroquinolin-8- yl)ethynyl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound E1). To a solution of benzyl 4-[6-[(1S)-1-methoxyethyl]-5-(2-trimethylsilylethynyl)-3- pyridyl]piperazine-1-carboxylate (Intermediate C1, 26.1 g, 68.8 mmol) in DMF (400 mL) were added 6-bromo-8-iodo-1,2,3,4-tetrahydroquinoline (Intermediate D1, 23.3 g, 68.8 mmol), TEA (47.9 mL, 343.92 mmol), CuI (0.3 mL, 6.88 mmol), and Pd(PPh3)2Cl2 (4.8 g, 6.88 mmol). The reaction mixture was degassed and purged with nitrogen for three times and then it was stirred at 25 °C for 12 hrs. After the reaction was completed, the reaction mixture was poured into water (1.4 L), and extracted with EtOAc (800 mL, three times). The combined organic layer was washed with brine (800 mL, four times), dried over Na2SO4, filtered and concentrated under vacuum to give a residue, which was purified by column chromatography to afford benzyl 4-[5- [2-(6-bromo-1,2,3,4-tetrahydroquinolin-8-yl)ethynyl]-6-[(1S)-1-methoxyethyl]-3- pyridyl]piperazine-1-carboxylate (compound E1, 30.0 g) as a yellow solid. MS calc’d 589.2 (MH+), measured 589.2(MH+). Step 2: Preparation of benzyl 4-[5-(6-bromo-1-azatricyclo[6.3.1.04,12]dodeca- 2,4,6,8(12)-tetraen-2-yl)-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound E2). To a solution of benzyl 4-[5-[2-(6-bromo-1,2,3,4-tetrahydroquinolin-8-yl)ethynyl]-6-[(1S)- 1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound E1, 27.0 g, 45.8 mmol) in DMF (270 mL) was added PdCl2 (1.6 g, 9.16 mmol) in one portion. The reaction mixture was degassed under vacuum, flashed with nitrogen for three times and then heated to 70 °C for 16 hrs. After being cooled to the room temperature, the mixture was poured into water (800 mL), and extracted with EtOAc (300 mL, three times). The combined organic layer was washed with brine (300 mL, three times), dried over Na2SO4, filtered and concentrated under vacuum to give a residue, which was purified by column chromatography to afford benzyl 4-[5-(6-bromo-1- azatricyclo[6.3.1.04,12]dodeca-2,4,6,8(12)-tetraen-2-yl)-6-[(1S)-1-methoxyethyl]-3- pyridyl]piperazine-1-carboxylate (compound E2, 19.2 g) as a yellow solid. MS calc’d 589.2 (MH+), measured 589.2 (MH+). Step 3: Preparation of benzyl 4-[5-(6-bromo-3-formyl-1-azatricyclo[6.3.1.04,12]dodeca- 2,4,6,8(12)-tetraen-2-yl)-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound E3). Phosphorus oxychloride (30.4 mL, 325.69 mmol) was added into DMF (350 mL) dropwise slowly at 0°C. After being stirred at 0 °C for 0.5 h, the reaction mixture was added with a solution of benzyl 4-[5-(6-bromo-1-azatricyclo[6.3.1.04,12]dodeca-2,4,6,8(12)-tetraen-2-yl)-6- [(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound E2, 19.2 g, 32.57 mmol) in DMF (150 mL) dropwise at 0 ºC. The reaction mixture was heated to 45 °C, and then stirred for another 1 h. The reaction was quenched with sat. NaHCO3 aq. solution (1.5 L), extracted with EtOAc (500 mL, three times). The organic phase was washed with brine (500 mL, three times), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to give a residue. The residue was purified by column chromatography to afford benzyl 4-[5-(6-bromo-3-formyl-1- azatricyclo[6.3.1.04,12]dodeca-2,4,6,8(12)-tetraen-2-yl)-6-[(1S)-1-methoxyethyl]-3- pyridyl]piperazine-1-carboxylate (compound E3, 14.6 g) as a yellow solid. MS calc’d 616.9 (MH+), measured 617.2 (MH+). Step 4: Preparation of benzyl 4-[5-[6-bromo-3-(1-hydroxy-3-methoxy-2,2-dimethyl-3- 4,12 oxo-propyl)-1-azatricyclo[6.3.1.0 ]dodeca-2,4,6,8(12)-tetraen-2-yl]-6-[(1S)-1- methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound E4) To a solution of methyl isobutyrate (13.4 g, 131.17 mmol) in THF (150 mL) was added LDA (65.58 mL, 131.17 mmol) dropwise at -70 °C under nitrogen atmosphere. After being stirred for 0.5 h, the reaction mixture was added with a solution of benzyl 4-[5-(6-bromo-3- formyl-1-azatricyclo[6.3.1.04,12]dodeca-2,4,6,8(12)-tetraen-2-yl)-6-[(1S)-1-methoxyethyl]-3- pyridyl]piperazine-1-carboxylate (compound E3, 13.5 g, 21.86 mmol) in THF (50 mL) dropwise at -70 °C. The reaction mixture was then allowed warm up to room temperature and stirred for 1 h. After the reaction was completed, the mixture was quenched with sat. NH4Cl (600 mL) aqueous solution and extracted with EtOAc (200 mL, three times). The organic phase was washed with brine (500 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to give a residue. The residue was purified by column chromatography to afford benzyl 4-[5-[6-bromo-3-(1-hydroxy-3-methoxy-2,2-dimethyl-3-oxo-propyl)-1- 4,12 azatricyclo[6.3.1.0 ]dodeca-2,4,6,8(12)-tetraen-2-yl]-6-[(1S)-1-methoxyethyl]-3- pyridyl]piperazine-1-carboxylate (compound E4, 14.01 g) as a yellow gum. MS calc’d 719.3 (MH+), measured 719.2 (MH+). Step 5: Preparation of benzyl 4-[5-[6-bromo-3-(3-methoxy-2,2-dimethyl-3-oxo- propyl)-1-azatricyclo[6.3.1.04,12]dodeca-2,4,6,8(12)-tetraen-2-yl]-6-[(1S)-1-methoxyethyl]-3- pyridyl]piperazine-1-carboxylate (compound E5) To a solution of benzyl 4-[5-(6-bromo-3-formyl-1-azatricyclo[6.3.1.04,12]dodeca- 2,4,6,8(12)-tetraen-2-yl)-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound E4, 14.0 g, 19.45 mmol) and Et3SiH (18.1 g, 155.63 mmol) in DCM (280 mL) was added TFA (57.8 mL, 778.15 mmol) at 0 °C. After being stirred at 25°C for 12 hrs, the reaction mixture was concentrated under vacuum to give a residue, which was diluted with sat. NaHCO3 aq. until pH=9 and extracted with EtOAc (300 mL, three times). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under vacuum to give a residue. The residue was purified by column to afford benzyl 4-[5-[6-bromo-3-(3-methoxy-2,2-dimethyl-3- oxo-propyl)-1-azatricyclo[6.3.1.04,12]dodeca-2,4,6,8(12)-tetraen-2-yl]-6-[(1S)-1-methoxyethyl]- 3-pyridyl]piperazine-1-carboxylate (compound E5, 14 g) as a yellow gum. MS calc’d 703.2 (MH+), measured 703.2 (MH+). Step 6: Preparation of benzyl 4-[(5M)-5-[6-bromo-3-(3-hydroxy-2,2-dimethyl-propyl)- 1-azatricyclo[6.3.1.04,12]dodeca-2,4,6,8(12)-tetraen-2-yl]-6-[(1S)-1-methoxyethyl]-3- pyridyl]piperazine-1-carboxylate (compound E6) To a solution of benzyl 4-[5-[6-bromo-3-(3-methoxy-2,2-dimethyl-3-oxo-propyl)-1- azatricyclo[6.3.1.04,12]dodeca-2,4,6,8(12)-tetraen-2-yl]-6-[(1S)-1-methoxyethyl]-3- pyridyl]piperazine-1-carboxylate (compound E5, 14.0 g, 19.9 mmol) in THF (150 mL) was added lithium borohydride (99.48 mL, 198.96 mmol) dropwise under N2 at 0°C. After being stirred at 20 °C for 15 hrs, the reaction was quenched by sat. NH4Cl aq. (600 mL) at 0 °C and the resultant mixture was extracted with EtOAc (100mL, three times). The combined organic layer was washed with brine (200 mL), dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography to afford benzyl 4-[(5M)-5-[6- bromo-3-(3-hydroxy-2,2-dimethyl-propyl)-1-azatricyclo[6.3.1.04,12]dodeca-2,4,6,8(12)-tetraen-2- yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound E6, 7 g, faster eluted) as a yellow solid. MS calc’d 675.3 (MH+), measured 675.2 (MH+). Step 7: Preparation of benzyl 4-[(5M)-5-[3-(3-hydroxy-2,2-dimethyl-propyl)-6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-azatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7- tetraen-2-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound E7) To a solution of benzyl 4-[(5M)-5-[6-bromo-3-(3-hydroxy-2,2-dimethyl-propyl)-1- azatricyclo[6.3.1.04,12]dodeca-2,4,6,8(12)-tetraen-2-yl]-6-[(1S)-1-methoxyethyl]-3- pyridyl]piperazine-1-carboxylate (compound E6, 7.0 g, 10.36 mmol) and bis(pinacolato)diboron (3.95 g, 15.54 mmol) in toluene (140 mL) was added KOAc (2.56 g, 26.05 mmol) and Pd(dppf)Cl2 (760.87 mg, 1.04 mmol). The mixture was degassed, purged with nitrogen for three times and stirred at 75 °C for 16 hrs. After being cooled to the room temperature, the reaction mixture was filtered and concentrated under vacuum to give a residue. The residue was purified by column chromatography to afford benzyl 4-[(5M)-5-[3-(3-hydroxy-2,2-dimethyl-propyl)-6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-azatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7- tetraen-2-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound E7, 7.3 g) as a yellow solid.MS calc’d 723.4 (MH+), measured 723.4 (MH+). Step 8: Preparation of methyl (3S)-1-[(2S)-3-[4-[(2M)-2-[5-(4- benzyloxycarbonylpiperazin-1-yl)-2-[(1S)-1-methoxyethyl]-3-pyridyl]-3-(3-hydroxy-2,2- dimethyl-propyl)-1-azatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-6-yl]thiazol-2-yl]-2- (tert-butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylate (compound E8) To a solution of benzyl 4-[(5M)-5-[3-(3-hydroxy-2,2-dimethyl-propyl)-6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1-azatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]- 6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound E7, 6.8 g, 9.41 mmol) and methyl (3S)-1-[(2S)-3-(4-bromothiazol-2-yl)-2-(tert- butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylate (Intermediate B2, 4.94 g, 10.35 mmol) in toluene (90 mL) / 1,4-dioxane (30 mL) / water (30 mL) was added K3PO4 (5.0 g, 23.52 mmol) and Pd(dtbpf)Cl2 (613.2 mg, 0.94 mmol) in one portion. The mixture was degassed, purged with nitrogen for three times and then stirred at 70 °C for 15 hrs. After being cooled to room temperature, the reaction mixture was filtered and the filtrate was concentrated under vacuum to give a residue. The residue was purified by column chromatography to afford methyl (3S)-1-[(2S)-3-[4-[(2M)-2-[5-(4-benzyloxycarbonylpiperazin-1-yl)-2-[(1S)-1-methoxyethyl]-3- pyridyl]-3-(3-hydroxy-2,2-dimethyl-propyl)-1-azatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen- 6-yl]thiazol-2-yl]-2-(tert-butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylate (compound E8, 8.1 g) as a yellow solid. MS calc’d 993.7 (MH+), measured 993.7 (MH+). Step 9: Preparation of (3S)-1-[(2S)-3-[4-[(2M)-2-[5-(4-benzyloxycarbonylpiperazin-1- yl)-2-[(1S)-1-methoxyethyl]-3-pyridyl]-3-(3-hydroxy-2,2-dimethyl-propyl)-1- azatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-6-yl]thiazol-2-yl]-2-(tert- butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylic acid (compound E9) To the mixture of methyl (3S)-1-[(2S)-3-[4-[(2M)-2-[5-(4-benzyloxycarbonylpiperazin-1- yl)-2-[(1S)-1-methoxyethyl]-3-pyridyl]-3-(3-hydroxy-2,2-dimethyl-propyl)-1- azatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-6-yl]thiazol-2-yl]-2-(tert- butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylate (compound E8, 8.1 g, 8.16 mmol) in DCE (160 mL) was added trimethyltin hydroxide (5.9 g, 32.62 mmol) in one portion. After being stirred at 60 °C for 16 hrs, the reaction mixture was poured into water (200 mL) and extracted with EtOAc (100 mL, three times). The combined organic layer was washed with brine (200 mL), dried over anhydrous Na2SO4, filtered. The filtrate was concentrated under vacuum to afford (3S)-1-[(2S)-3-[4-[(2M)-2-[5-(4-benzyloxycarbonylpiperazin-1-yl)-2-[(1S)-1- methoxyethyl]-3-pyridyl]-3-(3-hydroxy-2,2-dimethyl-propyl)-1-azatricyclo[6.3.1.04,12]dodeca- 2,4(12),5,7-tetraen-6-yl]thiazol-2-yl]-2-(tert- butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylic acid (compound E9, 7.9 g) as a brown solid. MS calc’d 979.5 (MH+), measured 979.5 (MH+). Step 10: Preparation of benzyl 4-[(5M)-5-[(7S,13S)-7-(tert-butoxycarbonylamino)- 17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen- 20-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound E10) To a solution of (3S)-1-[(2S)-3-[4-[(2M)-2-[5-(4-benzyloxycarbonylpiperazin-1-yl)-2- [(1S)-1-methoxyethyl]-3-pyridyl]-3-(3-hydroxy-2,2-dimethyl-propyl)-1- azatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-6-yl]thiazol-2-yl]-2-(tert- butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylic acid (compound E9, 6.8 g, 6.94 mmol) in DCM (700 mL) was added DIEA (24.2 mL, 138.89 mmol), EDCI (19.97 g, 104.17 mmol) and HOBt (2.35 g, 17.36 mmol) at 0°C. After being stirred at 30 °C for 15 hrs, the reaction mixture was poured into water (500 mL), and extracted with EtOAc (300 mL, three times). The combined organic layer was washed with brine (300 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under vacuum to give a residue, which was purified by silica column to afford benzyl 4-[(5M)-5-[(7S,13S)-7-(tert-butoxycarbonylamino)-17,17- dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-20- yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound E10, 5.6 g) as a yellow solid. MS calc’d 961.5 (MH+), measured 961.5 (MH+). Step 11: Preparation of tert-butyl N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5- (4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen- 7-yl]carbamate (compound E11) To a solution of benzyl 4-[(5M)-5-[(7S,13S)-7-(tert-butoxycarbonylamino)-17,17- dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-20- yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound E10, 5.6 g, 5.83 mmol) and formaldehyde (1.89 g, 23.3 mmol) in methanol (150 mL) was added Pd(OH)2 on activated carbon (3.0 g, 2.91 mmol) under nitrogen atmosphere. The reaction mixture was degassed and purged with H2 for three times and then it was stirred at 35 °C for 15 hrs under H2 (15psi). After being cooled to room temperature, the reaction mixture was filtered and the filtrate was concentrated under vacuum to give a residue. EtOAc (50 mL) and water (50 mL) were added into the residue and the layers were separated. The aqueous phase was extracted with EtOAc (50 mL, twice). The combined organic layer was washed with brine (60 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under vacuum to give tert-butyl N-[(7S,13S)- (20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14- dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamate (compound E11, 3.9 g) as a yellow solid which was used in the next step without further purification. MS calc’d 841.5 (MH+), measured 841.4 (MH+). Step 12: Preparation of (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaene- 8,14-dione (Intermediate E) To a solution of tert-butyl N-[(7S,13S)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin- 1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7- yl]carbamate (compound E11, 3.9 g, 4.6 mmol) in DCM (30 mL) was added TFA (15.0 mL) in one portion. After being stirred at 25°C for 1 h, the mixture was poured into water (100 mL) and extracted with EtOAc (200 mL). The organic phase was washed with water (50 mL, twice). The combined aqueous phase was basified with sat. NaHCO3 aq. until pH = 9 and extracted with EtOAc (100 mL, three times). The combined organic layer was washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to afford (7S,13S)-7- amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17- dimethyl-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate E, 2.95 g) as a yellow solid. MS calc’d 741.5 (MH+), measured 741.4 (MH+). Intermediate F (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17- dimethyl-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaene-8,14-dione The title compound was prepared in analogy to the preparation of Intermediate E by using 4-[5-ethynyl-6-[(1S)-1-methoxyethyl]-3-pyridyl]morpholine (Intermediate C2) instead of benzyl 4-[5-ethynyl-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (Intermediate C1). Intermediate G (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1- yl]-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26- hexaene-8,14-dione The compound was prepared according to the following scheme: Intermediate G Step 1: Preparation of tert-butyl N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5- piperazin-1-yl-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen- 7-yl]carbamate (compound G1) To a solution of benzyl 4-[(5M)-5-[(7S,13S)-7-(tert-butoxycarbonylamino)-17,17- dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-20- yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound E10, 400.0 mg, 0.42 mmol) in EtOAc (8 mL) was added Pd / C on activated carbon (200.0 mg) under nitrogen atmosphere. The mixture was degassed and purged with H2 for three times and then stirred at 25 °C for 48 hrs under H2 (15psi). The reaction mixture was filtered and the filtrate was concentrated under vacuum to give tert-butyl N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5- piperazin-1-yl-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7- yl]carbamate (compound G1, 320.0 mg) as an off-white solid, which was used in the next step without further purification. MS calc’d 827.6 (MH+), measured 827.4 (MH+). Step 2: Preparation of tert-butyl N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4- (2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia- 9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamate (compound G2). To a solution of tert-butyl N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-piperazin-1- yl-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7- yl]carbamate (compound G1, 290.0 mg, 0.35 mmol) in THF (6 mL) was added TEA (0.15 mL, 1.05 mmol) and CF3CH2OTf (162.8 mg, 0.7 mmol). After being stirred at 60 °C for 15 hrs, the reaction mixture was concentrated under vacuum to give a residue. The residue was purified by silica gel column to afford tert-butyl N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4- (2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia- 9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26- hexaen-7-yl]carbamate (compound G2, 230.0 mg) as a white solid. MS calc’d 909.4 (MH+), measured 909.4 (MH+). Step 3: Preparation of (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4- (2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaene- 8,14-dione (intermediate G). To a solution of tert-butyl N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2- trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7- yl]carbamate (compound G2, 230.0 mg, 0.25 mmol) in DCM (2 mL) was added TFA (2 mL). After being stirred at 20 °C for 1 h, sat. NaHCO3 solution (40 mL) was added into the reaction mixture and it was extracted with EtOAc (50 mL, three times). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated under vacuum to afford (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5- [4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaene- 8,14-dione (intermediate G, 200.0 mg) as a yellow solid which was used in the next step without further purification. MS calc’d 809.4 (MH+), measured 809.4 (MH+). Intermediate H (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]- 17,17-dimethyl-15,24-dioxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaene- 8,14-dione The title compound was prepared in analogy to the preparation of Intermediate E by using 7-bromo-5-iodo-3,4-dihydro-2H-1,4-benzoxazine (Intermediate D2) instead of 6-bromo-8-iodo- 1,2,3,4-tetrahydroquinoline (Intermediate D1). Intermediate I (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17- dimethyl-15,24-dioxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaene- 8,14-dione The title compound was prepared in analogy to the preparation of Intermediate E by using 4-[5-ethynyl-6-[(1S)-1-methoxyethyl]-3-pyridyl]morpholine (Intermediate C2) and 7-bromo-5- iodo-3,4-dihydro-2H-1,4-benzoxazine (Intermediate D2) instead of benzyl 4-[5-ethynyl-6-[(1S)- 1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (Intermediate C1) and 6-bromo-8-iodo- 1,2,3,4-tetrahydroquinoline (Intermediate D1). Intermediate J (7S,13S)-7-amino-23,23-difluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin- 1-yl)-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaene- 8,14-dione The title compound was prepared in analogy to the preparation of Intermediate E by using 6-bromo-3,3-difluoro-8-iodo-2,4-dihydro-1H-quinoline (Intermediate D3) instead of 6-bromo-8- iodo-1,2,3,4-tetrahydroquinoline (Intermediate D1). Intermediate K (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17,23,23- tetramethyl-15,24-dioxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaene- 8,14-dione The title compound was prepared in analogy to the preparation of Intermediate E by using 7-bromo-5-iodo-2,2-dimethyl-3,4-dihydro-1,4-benzoxazine (Intermediate D4) and 4-[5-ethynyl- 6-[(1S)-1-methoxyethyl]-3-pyridyl]morpholine (Intermediate C2) instead of 6-bromo-8-iodo- 1,2,3,4-tetrahydroquinoline (intermediate D1) and benzyl 4-[5-ethynyl-6-[(1S)-1-methoxyethyl]- 3-pyridyl]piperazine-1-carboxylate (Intermediate C1). Intermediate L (7S,13S,22S)-7-amino-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17,22- trimethyl-15,24-dioxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaene- 8,14-dione The title compound was prepared in analogy to the preparation of Intermediate E by using 7-bromo-5-iodo-3-methyl-3,4-dihydro-2H-1,4-benzoxazine (Intermediate D5) and 4-[5-ethynyl- 6-[(1S)-1-methoxyethyl]-3-pyridyl]morpholine (Intermediate C2) instead of 6-bromo-8-iodo- 1,2,3,4-tetrahydroquinoline (intermediate D1) and benzyl 4-[5-ethynyl-6-[(1S)-1-methoxyethyl]- 3-pyridyl]piperazine-1-carboxylate (Intermediate C1). Intermediate M (7S,13S)-7-amino-23,23-difluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3- pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaene- 8,14-dione The title compound was prepared in analogy to the preparation of Intermediate E by using 6-bromo-3,3-difluoro-8-iodo-2,4-dihydro-1H-quinoline (Intermediate D3) and 4-[5-ethynyl-6- [(1S)-1-methoxyethyl]-3-pyridyl]morpholine (Intermediate C2) instead of 6-bromo-8-iodo- 1,2,3,4-tetrahydroquinoline (intermediate D1) and benzyl 4-[5-ethynyl-6-[(1S)-1-methoxyethyl]- 3-pyridyl]piperazine-1-carboxylate (Intermediate C1). Intermediate N (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16- dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.12,6.120,24.04,14.05,12]tetratriaconta- 1(31),2,4,6(34),13,28(32),29-heptaene-19,25-dione The compound was prepared according to the following scheme: intermediate N Step 1: Preparation of tert-butyl N-[(20S,26S)-30-hydroxy-(13M)-13-[2-[(1S)-1- methoxyethyl]-3-pyridyl]-16,16-dimethyl-19,25-dioxo-7,18-dioxa-12,24,33- triazahexacyclo[26.3.1.12,6.120,24.04,14.05,12]tetratriaconta-1(31),2,4,6(34),13,28(32),29- heptaen-26-yl]carbamate (compound N-b) To a solution of tert-butyl N-[(20S,26S)-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]- 16,16-dimethyl-19,25-dioxo-30-triisopropylsilyloxy-7,18-dioxa-12,24,33- triazahexacyclo[26.3.1.12,6.120,24.04,14.05,12]tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaen- 26-yl]carbamate (compound N-a), 16.0 mg, 0.02 mmol) in THF (4 mL) was added TBAF (20 µL, 0.02 mmol, 1M in THF). After being stirred at 0 °C for 0.5 h, the mixture was concentrated in vacuo to get a residue. The residue was poured into water (10 mL) and extracted with EtOAc (8 mL, three times). The combined organic phase was washed with brine (5mL), dried over sodium sulfate, filtered and concentrated under vacuum to afford tert-butyl N-[(20S,26S)-30-hydroxy- (13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-19,25-dioxo-7,18-dioxa- 12,24,33-triazahexacyclo[26.3.1.12,6.120,24.04,14.05,12]tetratriaconta-1(31),2,4,6(34),13,28(32),29- heptaen-26-yl]carbamate (compound N-b, 12.0 mg) as yellow oil, which was used in the next step without purification. MS calc’d 782.4 (MH+), measured 782.4 (MH+). Step 2: Preparation of (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1- methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33- triazahexacyclo[26.3.1.12,6.120,24.04,14.05,12]tetratriaconta-1(31),2,4,6(34),13,28(32),29- heptaene-19,25-dione (Intermediate N) To a solution of tert-butyl N-[(20S,26S)-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]- 3-pyridyl]-16,16-dimethyl-19,25-dioxo-7,18-dioxa-12,24,33- triazahexacyclo[26.3.1.12,6.120,24.04,14.05,12]tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaen- 26-yl]carbamate (compound N-b, 12 mg, 0.015 mmol) in DCM (2.5 mL) was added TFA (0.5 mL). The mixture was stirred at 20 °C for 1.5 hrs. After the reaction was completed, the mixture was concentrated in vacuo to get a residue. The residue was purified by reversed phase chromatography to afford (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]- 3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33- triazahexacyclo[26.3.1.12,6.120,24.04,14.05,12]tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaene- 19,25-dione (Intermediate N), 10.0 mg) as yellow solid. MS calc’d 682.4 (MH+), measured 682.4 (MH+). The title compound N-a was prepared in analogy to the preparation of compound E10 by using 9-bromo-7-iodo-3,4,5,6-tetrahydro-2H-1,6-benzoxazocine (intermediate D6) and 3- ethynyl-2-[(1S)-1-methoxyethyl]pyridine (Intermediate C4) instead of 6-bromo-8-iodo-1,2,3,4- tetrahydroquinoline (intermediate D1) and benzyl 4-[5-ethynyl-6-[(1S)-1-methoxyethyl]-3- pyridyl]piperazine-1-carboxylate (Intermediate C1). Intermediate O (19S,25S)-25-amino-29-hydroxy-(12M)-12-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-15,15- dimethyl-7,17-dioxa-11,23,32-triazahexacyclo[25.3.1.12,6.119,23.04,13.05,11]tritriaconta- 1(30),2,4,6(33),12,27(31),28-heptaene-18,24-dione The title compound was prepared in analogy to the preparation of Intermediate N by using 8-bromo-6-iodo-2,3,4,5-tetrahydro-1,5-benzoxazepine (Intermediate D7) instead of 9-bromo-7- iodo-3,4,5,6-tetrahydro-2H-1,6-benzoxazocine (intermediate D6). Intermediate P (18S,24S)-24-amino-28-hydroxy-(11M)-11-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-14,14- dimethyl-16-oxa-10,22,31-triazahexacyclo[24.3.1.12,6.118,22.04,12.05,10]dotriaconta- 1(29),2,4,6(32),11,26(30),27-heptaene-17,23-dione The title compound was prepared in analogy to the preparation of Intermediate N by using 6-bromo-8-iodo-1,2,3,4-tetrahydroquinoline (intermediate D1) instead of and 9-bromo-7-iodo- 3,4,5,6-tetrahydro-2H-1,6-benzoxazocine (intermediate D6). Intermediate Q (18S,24S)-24-amino-28-hydroxy-(11M)-11-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-14,14- dimethyl-7,16-dioxa-10,22,31-triazahexacyclo[24.3.1.12,6.118,22.04,12.05,10]dotriaconta- 1(29),2,4,6(32),11,26(30),27-heptaene-17,23-dione The title compound was prepared in analogy to the preparation of Intermediate N by using 7-bromo-5-iodo-3,4-dihydro-2H-1,4-benzoxazine (intermediate D2) instead of and 9-bromo-7- iodo-3,4,5,6-tetrahydro-2H-1,6-benzoxazocine (intermediate D6). Intermediate R (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]- 17,17,23,23-tetramethyl-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaene- 8,14-dione The title compound was prepared in analogy to the preparation of Intermediate E by using 6-bromo-8-iodo-3,3-dimethyl-2,4-dihydro-1H-quinoline (Intermediate D8) instead of 6-bromo- 8-iodo-1,2,3,4-tetrahydroquinoline (Intermediate D1). Example 1 (3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(20S,26S)-30-hydroxy-(13M)-13-[2-[(1S)- 1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-19,25-dioxo-7,18-dioxa-12,24,33- triazahexacyclo[26.3.1.12,6.120,24.04,14.05,12]tetratriaconta-1(31),2,4,6(34),13,28(32),29- heptaen-26-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide The compound was prepared according to the following scheme: 1g Example 1 Step 2: Preparation of tert-butyl N-[(1S)-1-[[(20S,26S)-30-hydroxy-(13M)-13-[2-[(1S)- 1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-19,25-dioxo-7,18-dioxa-12,24,33- triazahexacyclo[26.3.1.12,6.120,24.04,14.05,12]tetratriaconta-1(31),2,4,6(34),13,28(32),29- heptaen-26-yl]carbamoyl]-2-methyl-propyl]-N-methyl-carbamate (compound 1c) To a solution of DIEA (70 µL, 0.41 mmol, 3.0 eq) and Boc-N-Me-Val-OH (compound 1b, 30.4 mg, 0.15 mmol) in DMF (2.5 mL) was added HATU (63.1 mg, 0.17 mmol). After being stirred for 10 min, the reaction mixture was added with a solution of (20S,26S)-26-amino-30- hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33- triazahexacyclo[26.3.1.12,6.120,24.04,14.05,12]tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaene- 19,25-dione (intermediate N) (110.0 mg, 0.14 mmol) in DMF (2.5 mL). The resulting mixture was stirred at 20 °C for 2 h. After the reaction was completed, the reaction mixture was purified by Prep-HPLC to afford tert-butyl N-[(1S)-1-[[(20S,26S)-30-hydroxy-(13M)-13-[2-[(1S)-1- methoxyethyl]-3-pyridyl]-16,16-dimethyl-19,25-dioxo-7,18-dioxa-12,24,33- triazahexacyclo[26.3.1.12,6.120,24.04,14.05,12]tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaen- 26-yl]carbamoyl]-2-methyl-propyl]-N-methyl-carbamate (compound 1c, 115 mg) as a yellow solid. MS calc’d 895.5 (MH+), measured 895.5 (MH+). Step 2: Preparation of (2S)-N-[(20S,26S)-30-hydroxy-(13M)-13-[2-[(1S)-1- methoxyethyl]-3-pyridyl]-16,16-dimethyl-19,25-dioxo-7,18-dioxa-12,24,33- triazahexacyclo[26.3.1.12,6.120,24.04,14.05,12]tetratriaconta-1(31),2,4,6(34),13,28(32),29- heptaen-26-yl]-3-methyl-2-(methylamino)butanamide(compound 1d) To a solution of tert-butyl N-[(1S)-1-[[(20S,26S)-30-hydroxy-(13M)-13-[2-[(1S)-1- methoxyethyl]-3-pyridyl]-16,16-dimethyl-19,25-dioxo-7,18-dioxa-12,24,33- triazahexacyclo[26.3.1.12,6.120,24.04,14.05,12]tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaen- 26-yl]carbamoyl]-2-methyl-propyl]-N-methyl-carbamate (compound 1c,115 mg, 0.13 mmol) in DCM (8 mL) was added TFA (2.0 mL, 2 mmol) at 0°C. After being stirred at 20 °C for 1 h, the reaction mixture was concentrated in vacuo and diluted with sat. NaHCO3 (10 mL), extracted with EtOAc (20 mL, three times). The combined organic layer was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated in vacuo to afford (2S)-N-[(20S,26S)-30-hydroxy- (13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-19,25-dioxo-7,18-dioxa- 12,24,33-triazahexacyclo[26.3.1.12,6.120,24.04,14.05,12]tetratriaconta-1(31),2,4,6(34),13,28(32),29- heptaen-26-yl]-3-methyl-2-(methylamino)butanamide(compound 1d, 95.0 mg) as a yellow solid. MS calc’d 795.4 (MH+), measured 795.4 (MH+). Step 3: Preparation of tert-butyl (3S)-3-[[(1S)-1-[[(20S,26S)-30-hydroxy-(13M)-13-[2- [(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-19,25-dioxo-7,18-dioxa-12,24,33- triazahexacyclo[26.3.1.12,6.120,24.04,14.05,12]tetratriaconta-1(31),2,4,6(34),13,28(32),29- heptaen-26-yl]carbamoyl]-2-methyl-propyl]-methyl-carbamoyl]pyrrolidine-1-carboxylate (compound 1f) To a solution of (3S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (compound 1e, 59.6 mg, 0.28 mmol), DIEA (0.1 mL, 0.55 mmol) and HATU (115.75 mg, 0.3 mmol) in DMF (2 mL) was added (2S)-N-[(20S,26S)-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]- 16,16-dimethyl-19,25-dioxo-7,18-dioxa-12,24,33- triazahexacyclo[26.3.1.12,6.120,24.04,14.05,12]tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaen- 26-yl]-3-methyl-2-(methylamino)butanamide(compound 1d, 110.0 mg, 0.14 mmol). After being stirred at 20 °C for 1 h, the reaction mixture was concentrated under vacuum to get a residue. The residue was purified by reversed phase chromatography to afford tert-butyl (3S)-3-[[(1S)-1- [[(20S,26S)-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-19,25- dioxo-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.12,6.120,24.04,14.05,12]tetratriaconta- 1(31),2,4,6(34),13,28(32),29-heptaen-26-yl]carbamoyl]-2-methyl-propyl]-methyl- carbamoyl]pyrrolidine-1-carboxylate (compound 1f, 95.0 mg) as a yellow solid. MS calc’d 992.5 (MH+), measured 892.5 (M-Boc+H+). Step 4: Preparation of (3S)-N-[(1S)-1-[[(20S,26S)-30-hydroxy-(13M)-13-[2-[(1S)-1- methoxyethyl]-3-pyridyl]-16,16-dimethyl-19,25-dioxo-7,18-dioxa-12,24,33- triazahexacyclo[26.3.1.12,6.120,24.04,14.05,12]tetratriaconta-1(31),2,4,6(34),13,28(32),29- heptaen-26-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide (compound 1g) To a solution of tert-butyl (3S)-3-[[(1S)-1-[[(20S,26S)-30-hydroxy-(13M)-13-[2-[(1S)-1- methoxyethyl]-3-pyridyl]-16,16-dimethyl-19,25-dioxo-7,18-dioxa-12,24,33- triazahexacyclo[26.3.1.12,6.120,24.04,14.05,12]tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaen- 26-yl]carbamoyl]-2-methyl-propyl]-methyl-carbamoyl]pyrrolidine-1-carboxylate (compound 1f, 95.0 mg, 0.1 mmol) in DCM (8 mL) was added TFA (2.0 mL, 11.48 mmol). The reaction mixture was stirred at 20 °C for 0.5 h. The mixture was concentrated in vacuo and diluted with sat.NaHCO3 (10 mL), extracted with EtOAc (20 mL, three times). The combined organic layer was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated in vacuo to afford (3S)-N-[(1S)-1-[[(20S,26S)-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16- dimethyl-19,25-dioxo-7,18-dioxa-12,24,33- triazahexacyclo[26.3.1.12,6.120,24.04,14.05,12]tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaen- 26-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide (compound 1g, 65.0 mg) as a yellow solid. MS calc’d 892.5 (MH+), measured 446.9 (M / 2+H+). Step 5: Preparation of (3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(20S,26S)-30- hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-19,25-dioxo-7,18- dioxa-12,24,33-triazahexacyclo[26.3.1.12,6.120,24.04,14.05,12]tetratriaconta- 1(31),2,4,6(34),13,28(32),29-heptaen-26-yl]carbamoyl]-2-methyl-propyl]-N-methyl- pyrrolidine-3-carboxamide (Example 1) To a solution of (2R)-2-chloro-2-fluoro-acetic acid (compound 1h, 13.8 mg, 0.12 mmol), (3S)-N-[(1S)-1-[[(20S,26S)-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16- dimethyl-19,25-dioxo-7,18-dioxa-12,24,33- triazahexacyclo[26.3.1.12,6.120,24.04,14.05,12]tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaen- 26-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide (compound 1g, 55.0 mg, 0.06 mmol) in DMF (1 mL) was added DIEA (30 µL, 0.18 mmol,) and HATU (52.7 mg, 0.14 mmol) at 0°C. The mixture was stirred at 20 °C for 2 h. EtOAc (20 mL) and water (20 mL) were added into the reaction mixture 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, and concentrated under vacuum to give a residue. The residue was purified by prep-HPLC to afford (3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(20S,26S)- 30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-19,25-dioxo-7,18- dioxa-12,24,33-triazahexacyclo[26.3.1.12,6.120,24.04,14.05,12]tetratriaconta- 1(31),2,4,6(34),13,28(32),29-heptaen-26-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine- 3-carboxamide (Example 1, 15.9 mg) as a yellow solid. MS calc’d 986.5 (MH+), measured 986.5 (MH+).1H NMR (400 MHz, METHANOL-d4) δ = 8.87 - 8.82 (m, 1H), 8.61 - 8.51 (m, 1H), 8.17 - 8.09 (m, 1H), 7.97 - 7.85 (m, 1H), 7.82 - 7.70 (m, 1H), 7.60 - 7.48 (m, 1H), 7.33 - 7.25 (m, 1H), 7.09 - 7.01 (m, 1H), 6.76 - 6.26 (m, 1H), 4.75 - 4.70 (m, 1H), 4.53 - 4.42 (m, 1H), 4.37 - 4.16 (m, 1H), 3.90 - 3.83 (m, 2H), 3.81 - 3.75 (m, 2H), 3.68 - 3.63 (m, 1H), 3.60 - 3.54 (m, 1H), 3.28 - 3.25 (m, 1H), 3.21 - 3.17 (m, 3H), 3.16 - 3.11 (m, 1H), 3.10 - 3.00 (m, 2H), 2.97 - 2.92 (m, 1H), 2.89 (s, 1H), 2.88 - 2.85 (m, 1H), 2.42 - 2.24 (m, 1H), 2.23 - 2.18 (m, 1H), 1.89 - 1.79 (m, 1H), 1.69 - 1.65 (m, 5H), 1.54 - 1.50 (m, 4H), 1.46 - 1.39 (m, 2H) 1.38 - 1.26 (m, 5H), 1.09 - 1.00 (m, 3H), 0.99 - 0.89 (m, 5H), 0.88 - 0.86 (m, 2H), 0.84 - 0.82 (m, 2H), 0.79 - 0.74 (m, 3H). Example 2 (3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(19S,25S)-29-hydroxy-(12M)-12-[2-[(1S)- 1-methoxyethyl]-3-pyridyl]-15,15-dimethyl-18,24-dioxo-7,17-dioxa-11,23,32- triazahexacyclo[25.3.1.12,6.119,23.04,13.05,11]tritriaconta-1(30),2,4,6(33),12,27(31),28-heptaen- 25-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide The title compound was prepared in analogy to the preparation of Example 1 by using (19S,25S)-25-amino-29-hydroxy-(12M)-12-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-15,15-dimethyl- 7,17-dioxa-11,23,32-triazahexacyclo[25.3.1.12,6.119,23.04,13.05,11]tritriaconta- 1(30),2,4,6(33),12,27(31),28-heptaene-18,24-dione (intermediate O) instead of (20S,26S)-26- amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa- 12,24,33-triazahexacyclo[26.3.1.12,6.120,24.04,14.05,12]tetratriaconta-1(31),2,4,6(34),13,28(32),29- heptaene-19,25-dione (intermediate N). Example 2 (15.9 mg) was obtained as a yellow solid. MS calc’d 972.4 (MH+), measured 972.4 (MH+).1H NMR (400 MHz, METHANOL-d4) δ = 8.89 - 8.79 (m, 1H), 8.33 - 8.21 (m, 1H), 7.92 - 7.81 (m, 1H), 7.75 - 7.66 (m, 1H), 7.47 - 7.36 (m, 1H), 7.29 - 7.13 (m, 1H), 7.11 - 6.98 (m, 1H), 6.93 - 6.71 (m, 1H), 6.54 - 6.44 (m, 1H), 5.66 - 5.53 (m, 1H), 4.72 (d, J = 11.1 Hz, 1H), 4.61 - 4.38 (m, 3H), 4.15 - 4.04 (m, 1H), 4.03 - 3.91 (m, 1H), 3.90 - 3.75 (m, 3H), 3.74 - 3.63 (m, 3H), 3.62 - 3.43 (m, 3H), 3.15 - 3.04 (m, 1H), 2.96 - 2.91 (m, 3H), 2.84 - 2.73 (m, 2H), 2.44 - 2.26 (m, 3H), 2.22 - 2.17 (m, 1H), 2.14 - 2.00 (m, 2H), 1.98 - 1.87 (m, 1H), 1.82 - 1.57 (m, 2H), 1.51 - 1.47 (m, 3H), 1.40 - 1.23 (m, 5H), 0.99 - 0.90 (m, 3H), 0.87 - 0.78 (m, 6H), 0.76 - 0.63 (m, 3H). Example 3 1-[(2R)-2-chloro-2-fluoro-acetyl]-4-fluoro-N-[(1S)-1-[[(19S,25S)-29-hydroxy-(12M)-12-[2- [(1S)-1-methoxyethyl]-3-pyridyl]-15,15-dimethyl-18,24-dioxo-7,17-dioxa-11,23,32- triazahexacyclo[25.3.1.12,6.119,23.04,13.05,11]tritriaconta-1(30),2,4,6(33),12,27(31),28-heptaen- 25-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide The title compound was prepared in analogy to the preparation of Example 1 by using (19S,25S)-25-amino-29-hydroxy-(12M)-12-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-15,15-dimethyl- 7,17-dioxa-11,23,32-triazahexacyclo[25.3.1.12,6.119,23.04,13.05,11]tritriaconta- 1(30),2,4,6(33),12,27(31),28-heptaene-18,24-dione (intermediate O) and 1-tert-butoxycarbonyl- 4-fluoro-piperidine-4-carboxylic acid instead of (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2- [(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33- triazahexacyclo[26.3.1.12,6.120,24.04,14.05,12]tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaene- 19,25-dione (intermediate N) and (3S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (compound 1e). Example 3 (2.4 mg) was obtained as a yellow solid. MS calc’d 1004.4 (MH+), measured 1004.5 (MH+). Example 4 (3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(18S,24S)-28-hydroxy-(11M)-11-[(3R)-2- [(1S)-1-methoxyethyl]-2,3-dihydropyridin-3-yl]-14,14-dimethyl-17,23-dioxo-16-oxa- 10,22,31-triazahexacyclo[24.3.1.12,6.118,22.04,12.05,10]dotriaconta-1(29),2,4,6(32),11,26(30),27- heptaen-24-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide The title compound was prepared in analogy to the preparation of Example 1 by using (18S,24S)-24-amino-28-hydroxy-(11M)-11-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-14,14-dimethyl- 16-oxa-10,22,31-triazahexacyclo[24.3.1.12,6.118,22.04,12.05,10]dotriaconta- 1(29),2,4,6(32),11,26(30),27-heptaene-17,23-dione (intermediate P) instead of (20S,26S)-26- amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa- 12,24,33-triazahexacyclo[26.3.1.12,6.120,24.04,14.05,12]tetratriaconta-1(31),2,4,6(34),13,28(32),29- heptaene-19,25-dione (intermediate N). Example 4 (10.9 mg) was obtained as a yellow solid. MS calc’d 956.4 (MH+), measured 956.4 (MH+).1H NMR (400 MHz, METHANOL-d4) δ = 8.87 - 8.80 (m, 1H), 8.32 - 8.15 (m, 1H), 7.91 - 7.79 (m, 2H), 7.37 (d, J = 13.6 Hz, 2H), 7.08 - 6.99 (m, 1H), 6.89 - 6.70 (m, 1H), 6.59 - 6.42 (m, 1H), 5.67 - 5.46 (m, 1H), 4.77 - 4.65 (m, 1H), 4.59 - 4.41 (m, 2H), 3.99 (d, J = 10.4 Hz, 1H), 3.93 - 3.81 (m, 3H), 3.81 - 3.65 (m, 5H), 3.57 - 3.49 (m, 1H), 3.28 - 3.19 (m, 1H), 3.13 - 3.03 (m, 3H), 3.02 - 2.81 (m, 6H), 2.79 - 2.71 (m, 2H), 2.37 - 2.23 (m, 3H), 2.20 - 2.06 (m, 3H), 2.05 - 1.90 (m, 2H), 1.75 - 1.58 (m, 2H), 1.50 (d, J = 6.4 Hz, 3H), 0.96 - 0.72 (m, 12H). Example 5 (3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(18S,24S)-28-hydroxy-(11M)-11-[2-[(1S)- 1-methoxyethyl]-3-pyridyl]-14,14-dimethyl-17,23-dioxo-7,16-dioxa-10,22,31- triazahexacyclo[24.3.1.12,6.118,22.04,12.05,10]dotriaconta-1(29),2,4,6(32),11,26(30),27-heptaen- 24-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide The title compound was prepared in analogy to the preparation of Example 1 by using (18S,24S)-24-amino-28-hydroxy-(11M)-11-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-14,14-dimethyl- 7,16-dioxa-10,22,31-triazahexacyclo[24.3.1.12,6.118,22.04,12.05,10]dotriaconta- 1(29),2,4,6(32),11,26(30),27-heptaene-17,23-dione (intermediate Q) instead of (20S,26S)-26- amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa- 12,24,33-triazahexacyclo[26.3.1.12,6.120,24.04,14.05,12]tetratriaconta-1(31),2,4,6(34),13,28(32),29- heptaene-19,25-dione (intermediate N). Example 5 (10.3 mg) was obtained as a white solid. MS calc’d 958.4 (MH+), measured 958.4 (MH+).1H NMR (400 MHz, METHANOL-d4) δ = 8.78 (d, J = 4.0Hz, 1H), 8.14 - 8.02 (m, 1H), 7.74 - 7.65 (m, 1H), 7.64 - 7.56 (m, 1H), 7.33 (s, 1H), 7.08 - 6.85 (m, 3H), 6.64 - 6.43 (m, 1H), 5.63 - 5.51 (m, 1H), 4.61 - 4.58 (m, 2H), 4.49 - 4.40 (m, 1H), 4.25 - 3.93 (m, 2H), 3.85 - 3.77 (m, 3H), 3.76 - 3.69 (m, 3H), 3.67 - 3.52 (m, 2H), 3.06 - 3.00 (m, 1H), 2.98 - 2.93 (m, 3H), 2.92 - 2.89 (m, 1H), 2.88 - 2.82 (m, 1H), 2.80 (s, 3H), 2.38 - 2.12 (m, 4H), 1.97 - 1.92 (m, 1H), 1.83 - 1.70 (m, 1H), 1.68 - 1.55 (m, 2H), 1.50 (d, J = 6.0Hz, 3H), 1.41 - 1.25 (m, 2H), 1.19 - 1.06 (m, 1H), 1.00 - 0.92 (m, 3H), 0.91 (s, 3H), 0.87 - 0.82 (m, 3H), 0.56 - 0.68 (m, 3H). Example 6 (3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4- thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine- 3-carboxamide

[0006] 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]-5-(4-methylpiperazin-1-yl)-3-pyridyl]- 17,17-dimethyl-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaene- 8,14-dione (intermediate E) instead of (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1- methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33- triazahexacyclo[26.3.1.12,6.120,24.04,14.05,12]tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaene- 19,25-dione (intermediate N). Example 6 (11.5 mg) was obtained as a yellow solid. MS calc’d 1045.5 (MH+), measured 1045.5 (MH+).1H NMR (400 MHz, METHANOL-d4) δ = 8.50 - 8.45 (m, 1H), 8.42 - 8.34 (m, 1H), 7.54 - 7.39 (m, 3H), 6.94 - 6.72 (m, 1H), 5.83 - 5.55 (m, 1H), 4.49 - 4.39 (m, 2H), 4.31 - 4.12 (m, 3H), 3.83 - 3.72 (m, 5H), 3.64 - 3.52 (m, 4H), 3.41 - 3.34 (m, 5H), 3.12 - 3.06 (m, 4H), 3.00 - 2.96 (m, 4H), 2.89 - 2.67 (m, 2H), 2.63 - 2.54 (m, 1H), 2.39 - 2.14 (m, 7H), 2.11 - 2.03 (m, 1H), 1.98 - 1.90 (m, 1H), 1.85 - 1.73 (m, 1H), 1.70 - 1.53 (m, 2H), 1.47 - 1.43 (m, 3H), 1.35 - 1.26 (m, 4H), 1.01 - 0.92 (m, 6H), 0.89 - 0.84 (m, 3H), 0.60 - 0.50 (m, 3H). Example 7 (2S)-2-[2-[(2R)-2-chloro-2-fluoro-acetyl]-5-oxo-2,6-diazaspiro[3.4]octan-6-yl]-N-[(7S,13S)- (20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]- 17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen- 7-yl]-3-methyl-butanamide The compound was prepared according to the following scheme: Step 1: Preparation of tert-butyl 6-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14- dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-5-oxo-2,6- diazaspiro[3.4]octane-2-carboxylate (compound 7a) To a solution of (2S)-2-(2-tert-butoxycarbonyl-5-oxo-2,6-diazaspiro[3.4]octan-6-yl)-3- methyl-butanoic acid (intermediate A1, 50.0 mg, 0.15 mmol) in DMF (1 mL) was added DIEA (110 µL, 0.62 mmol), HATU (60.0 mg, 0.16 mmol), and (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-15-oxa-4- thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (intermediate G, 50.0 mg, 0.06 mmol). The mixture was stirred at 25 °C for 1 h. The reaction mixture was poured into water (40 mL), and extracted with EtOAc (20 mL, three times). The combined organic layer was washed with brine (30 mL, three times), dried over Na2SO4, filtered and concentrated under vacuum to give a residue which was purified by column chromatography to afford tert-butyl 6-[(1S)-1-[[(7S,13S)- (20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17- dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7- yl]carbamoyl]-2-methyl-propyl]-5-oxo-2,6-diazaspiro[3.4]octane-2-carboxylate (compound 7a, 50.0 mg) as an off-white solid. MS calc’d 1117.5 (MH+), measured 1117.5 (MH+). Step 2: Preparation of (2S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4- (2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia- 9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaen-7-yl]-3-methyl-2-(5-oxo-2,6-diazaspiro[3.4]octan-6- yl)butanamide (compound 7b) To a solution of tert-butyl 6-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4- (2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia- 9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26- hexaen-7-yl]carbamoyl]-2-methyl-propyl]-5-oxo-2,6-diazaspiro[3.4]octane-2-carboxylate (compound 7a, 50.0 mg, 0.04 mmol) in DCM (0.5 mL) was added TFA (0.5 mL, 6.49 mmol), and the mixture was stirred at 25 °C for 1 h. After the reaction was completed, sat. NaHCO3 aq. (40 mL) was added to the reaction mixture and the mixture was extracted with EtOAc (30 mL, three times). The combined organic layer was washed by brine (30 mL), dried over Na2SO4, filtered and concentrated under vacuum to afford (2S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo- 15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaen-7-yl]-3-methyl-2-(5-oxo-2,6-diazaspiro[3.4]octan-6- yl)butanamide (compound 7b, 45.0 mg) as an off-white solid which was used in the next step without further purification. MS calc’d 1017.5 (MH+), measured 1017.7 (MH+). Step 3: Preparation of (2S)-2-[2-[(2R)-2-chloro-2-fluoro-acetyl]-5-oxo-2,6- diazaspiro[3.4]octan-6-yl]-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2- trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia- 9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaen-7-yl]-3-methyl-butanamide (Example 7) To a solution of (2S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2- trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7- yl]-3-methyl-2-(5-oxo-2,6-diazaspiro[3.4]octan-6-yl)butanamide (compound 7b, 45.0 mg, 0.04 mmol) in DMF (1 mL) was added DIEA (80 µL, 0.46 mmol), (2R)-2-chloro-2-fluoro-acetic acid (compound 1h, 26.3 mg, 0.23 mmol) and T3P (146.3 mg, 0.23 mmol), and the mixture was stirred at 25 °C for 1 h. After the reaction was completed, 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, three times), dried over Na2SO4, filtered and concentrated under vacuum to give a residue which was purified by Prep-HPLC to afford (2S)-2-[2-[(2R)-2-chloro- 2-fluoro-acetyl]-5-oxo-2,6-diazaspiro[3.4]octan-6-yl]-N-[(7S,13S)-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo- 15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaen-7-yl]-3-methyl-butanamide (Example 7, 12.3 mg) as a yellow solid. MS calc’d 1111.5 (MH+), measured 1111.5 (MH+).1H NMR (400 MHz, Methanol-d4) δ = 8.47 - 8.34 (m, 2H), 7.78 - 7.72 (m, 1H), 7.56 - 7.41 (m, 2H), 6.76 - 6.58 (m, 1H), 5.83 - 5.71 (m, 1H), 4.57 - 4.50 (m, 1H), 4.44 - 4.29 (m, 3H), 4.26 - 4.04 (m, 3H), 3.80 - 3.62 (m, 3H), 3.52 - 3.36 (m, 10H), 3.29 - 3.24 (m, 1H), 3.23 - 2.96 (m, 6H), 2.92 - 2.85 (m, 4H), 2.83 - 2.76 (m, 1H), 2.71 - 2.62 (m, 1H), 2.41 - 2.28 (m, 3H), 2.24 - 2.15 (m, 3H), 1.99 - 1.90 (m, 1H), 1.86 - 1.72 (m, 1H), 1.67 - 1.56 (m, 1H), 1.47 (d, J = 6.4 Hz, 3H), 1.36 - 1.26 (m, 1H), 1.03 - 0.96 (m, 6H), 0.87 (dd, J = 2.0, 6.4 Hz, 3H), 0.63 - 0.56 (m, 3H). Example 8 (2S)-2-(2-but-2-ynoyl-5-oxo-2,6-diazaspiro[3.4]octan-6-yl)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14- dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaen-7-yl]-3-methyl-butanamide The title compound was prepared in analogy to the preparation of Example 7 by using but- 2-ynoic acid instead of (2R)-2-chloro-2-fluoro-acetic acid (compound 1h). Example 8 (38 mg) was obtained as a yellow solid. MS calc’d 1083.5 (MH+), measured 1083.6 (MH+).1H NMR (400 MHz, Methanol-d4) δ = 8.44 (s, 1H), 8.36 (s, 1H), 7.91 - 7.84 (m, 1H), 7.54 - 7.44 (m, 2H), 5.82 - 5.71 (m, 1H), 4.60 - 4.52 (m, 1H), 4.44 - 4.36 (m, 2H), 4.35 - 4.29 (m, 1H), 4.27 - 4.09 (m, 4H), 3.97 - 3.91 (m, 1H), 3.81 - 3.71 (m, 2H), 3.71 - 3.63 (m, 1H), 3.54 - 3.46 (m, 5H), 3.46 - 3.36 (m, 5H), 3.27 - 3.07 (m, 5H), 3.05 - 2.96 (m, 1H), 2.91 - 2.85 (m, 4H), 2.84 - 2.74 (m, 1H), 2.72 - 2.64 (m, 1H), 2.37 - 2.28 (m, 3H), 2.25 - 2.15 (m, 3H), 2.03 (d, J = 4.4 Hz, 3H), 1.98 - 1.90 (m, 1H), 1.84 - 1.73 (m, 1H), 1.68 - 1.56 (m, 1H), 1.48 (d, J = 6.4 Hz, 3H), 1.04 - 0.96 (m, 6H), 0.89 - 0.84 (m, 3H), 0.61 (s, 3H). Example 9 (2S)-2-[2-[(2R)-2-chloro-2-fluoro-acetyl]-5-oxo-2,6-diazaspiro[3.4]octan-6-yl]-N-[(7S,13S)- (20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15- oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaen-7-yl]-3-methyl-butanamide The title compound was prepared in analogy to the preparation of Example 7 by using (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl- 15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (intermediate F) instead of (7S,13S)-7-amino- (20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17- dimethyl-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26- hexaene-8,14-dione (intermediate G). Example 9 (30.1 mg) was obtained as a yellow solid. MS calc’d 1030.4 (MH+), measured 1030.5 (MH+).1H NMR (400 MHz, METHANOL-d4) δ = 8.44 (s, 1 H) 8.36 (d, J=2.40 Hz, 1 H),7.85 (d, J = 2.4 Hz, 1 H), 7.55 - 7.43 (m, 2 H), 6.68 (dd, J = 49.2, 2.4 Hz, 1 H), 5.85 - 5.71 (m, 1 H), 4.62 - 4.51 (m, 2 H), 4.47 - 4.01 (m, 8 H), 3.87 (t, J = 4.8 Hz, 4 H), 3.82 - 3.72 (m, 2 H), 3.71 - 3.62 (m, 1 H), 3.60 - 3.48 (m, 1 H), 3.46 - 3.37 (m, 8 H), 3.29 - 3.24 (m, 1 H), 3.16 – 2.97 (m, 3 H), 2.85 - 2.65 (m, 2 H), 2.43 - 2.28 (m, 3 H), 2.27 - 2.15 (m, 3 H), 2.00 – 1.91 (m, 1 H), 1.89 - 1.71 (m, 1 H), 1.69 - 1.55 (m, 1 H), 1.48 (d, J=6.4 Hz, 3 H), 1.05 – 0.95 (m, 6 H), 0.87 (dd, J=6.80, 2.80 Hz, 3 H), 0.62 (d, J=4.0 Hz, 3 H). Example 10 (2S)-2-(2-but-2-ynoyl-5-oxo-2,6-diazaspiro[3.4]octan-6-yl)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia- 9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaen-7-yl]-3-methyl-butanamide The title compound was prepared in analogy to the preparation of Example 7 by using (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl- 15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (intermediate F) and but-2-ynoic acid instead of (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]- 3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26- hexaene-8,14-dione (intermediate G) and (2R)-2-chloro-2-fluoro-acetic acid (compound 1h). Example 10 (43.6 mg) was obtained as a yellow solid. MS calc’d 1002.5 (MH+), measured 1002.5 (MH+).1H NMR (400 MHz, METHANOL-d4) δ = 8.44 (s, 1H), 8.40 - 8.33 (m, 1H), 7.85 (dd, J = 5.6, 3.2 Hz, 1H), 7.52 (d, J = 10.8 Hz, 1H), 7.46 (d, J = 2.0 Hz, 1H), 5.82 - 5.73 (m, 1H), 4.61 - 4.52 (m, 1H), 4.47 - 4.37 (m, 2H), 4.33 (d, J = 11.2 Hz, 1H), 4.28 - 4.10 (m, 4H), 4.01 - 3.94 (m, 1H), 3.87 (t, J = 4.80 Hz, 4H), 3.82 - 3.73 (m, 2H), 3.71 - 3.61 (m, 1H), 3.60-3.48 (m, 1H), 3.47 - 3.38 (m, 9H), 3.29-3.24 (m, 1H), 3.17 – 2.98 (m, 3H), 2.86 - 2.75 (m, 1H), 2.74 - 2.63 (m, 1H), 2.41 - 2.28 (m, 3H), 2.26 - 2.12 (m, 3H), 2.04 (d, J = 4.0 Hz, 3H), 2.00 – 1.90 (m, 1H), 1.88 - 1.72 (m, 1H), 1.70 - 1.56 (m, 1H), 1.49 (d, J = 6.00 Hz, 3H), 1.06 – 0.96 (m, 6H), 0.88 (d, J = 6.4 Hz, 3H), 0.61 (s, 3H). Example 11 (2S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17- dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen- 7-yl]-3-methyl-2-(5-oxo-2-prop-2-enoyl-2,6-diazaspiro[3.4]octan-6-yl)butanamide The title compound was prepared in analogy to the preparation of Example 7 by using (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl- 15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (intermediate F) and acrylic acid instead of (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]- 3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26- hexaene-8,14-dione (intermediate G) and (2R)-2-chloro-2-fluoro-acetic acid (compound 1h). Example 11 (21.6 mg) was obtained as a yellow solid. MS calc’d 990.5 (MH+), measured 990.5 (MH+).1H NMR (400 MHz, METHANOL-d4) δ = 8.44 (s, 1H), 8.37 (s, 1H), 7.81 - 7.71 (m, 1H), 7.53 (d, J = 18.8 Hz, 1H), 7.46 (d, J = 6.4 Hz, 1H), 6.41 - 6.26 (m, 2H), 5.81 - 5.74 (m, 2H), 4.57 - 4.13 (m, 9H), 4.02 (d, J = 10.0 Hz, 1H), 3.86 (t, J = 4.4 Hz, 4H), 3.81 - 3.47 (m, 5H), 3.45 - 3.38 (m, 9H), 3.14 - 3.01 (m, 3H), 2.84 - 2.76 (m, 1H), 2.71 - 2.63 (m, 1H), 2.42 - 2.31 (m, 3H), 2.25 - 2.16 (m, 3H), 1.95 - 1.60 (m, 3H), 1.48 (d, J = 6.4 Hz, 3H), 1.02 - 0.98 (m, 5H), 0.89 - 0.85 (m, 3H), 0.63 - 0.56 (m, 3H). Example 12 (3S)-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]- 17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen- 7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-1-(4-morpholinobut-2-ynoyl)pyrrolidine-3- carboxamide 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]-5-morpholino-3-pyridyl]-17,17-dimethyl- 15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (intermediate F) and 4-morpholinobut-2-ynoic acid (CAS 38346-95-1, SY291865-5g, Accela ChemBio Co., Ltd.) instead of (20S,26S)-26- amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa- 12,24,33-triazahexacyclo[26.3.1.12,6.120,24.04,14.05,12]tetratriaconta-1(31),2,4,6(34),13,28(32),29- heptaene-19,25-dione (intermediate N) and (2R)-2-chloro-2-fluoro-acetic acid (compound 1h). Example 12 (29.1 mg) was obtained as a yellow solid. MS calc’d 1089.6 (MH+), measured 1089.6 (MH+).1H NMR (400 MHz, Methanol-d4) δ = 8.63 - 8.43 (m, 1H), 8.37 (s, 1H), 7.83 - 7.62 (m, 1H), 7.51 (d, J = 10.4 Hz, 1H), 7.45 (d, J = 7.6 Hz, 1H), 5.81 - 5.60 (m, 1H), 4.82 – 4.77(m, 3H), 4.57 - 4.49 (m, 1H), 4.45 - 4.39 (m, 1H), 4.34 - 4.08 (m, 4H), 4.07 - 3.90 (m, 4H), 3.90 - 3.84 (m, 5H), 3.84 - 3.78 (m, 2H), 3.76 (s, 2H), 3.72 - 3.57 (m, 5H), 3.46 - 3.37 (m, 8H), 3.15 - 3.08 (m, 5H), 3.05 - 2.97 (m, 2H), 2.85 - 2.76 (m, 1H), 2.69 - 2.61 (m, 1H), 2.37 - 2.18 (m, 6H), 1.99 - 1.92 (m, 1H), 1.86 – 1.76(m, 1H), 1.69 - 1.60 (m, 1H), 1.52 - 1.44 (m, 3H), 1.09 - 0.97 (m, 6H), 0.94 - 0.85 (m, 3H), 0.67 - 0.52 (m, 3H). Example 13 (2S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1- yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen- 7-yl]-3-methyl-2-(5-oxo-2-prop-2-enoyl-2,6-diazaspiro[3.4]octan-6-yl)butanamide The title compound was prepared in analogy to the preparation of Example 7 by using acrylic acid instead of (2R)-2-chloro-2-fluoro-acetic acid (compound 1h). Example 13 (9.5 mg) was obtained as a yellow solid. MS calc’d 1071.5 (MH+), measured 1071.5 (MH+).1H NMR (400 MHz, METHANOL-d4) δ = 8.45 (s, 1H), 8.36 (s, 1H), 7.91 (d, J = 2.4 Hz, 1H), 7.57 - 7.46 (m, 2H), 6.40 - 6.24 (m, 2H), 5.82 - 5.74 (m, 2H), 4.60 - 4.53 (m, 1H), 4.51 - 4.39 (m, 2H), 4.33 - 4.31 (m, 1H), 4.30 - 4.21 (m, 3H), 4.15 - 4.09 (m, 1H), 4.01 (d, J = 10.0 Hz, 1H), 3.81 - 3.73 (m, 2H), 3.70 - 3.63 (m, 1H), 3.53 - 3.49 (m, 4H), 3.45 (d, J = 5.6 Hz, 3H), 3.40 (s, 1H), 3.29 - 3.24 (m, 1H), 3.22 - 3.14 (m, 3H), 3.13 - 3.09 (m, 1H), 3.08 - 3.02 (m, 1H), 2.91 - 2.87 (m, 4H), 2.83 - 2.76 (m, 1H), 2.72 - 2.66 (m, 1H), 2.40 - 2.30 (m, 3H), 2.25 - 2.17 (m, 3H), 1.98 - 1.91 (m, 1H), 1.85 - 1.74 (m, 1H), 1.66 - 1.58 (m, 1H), 1.49 (d, J = 6.4 Hz, 3H), 1.37 - 1.27 (m, 2H), 1.03 - 0.97 (m, 6H), 0.87 (d, J = 6.4 Hz, 3H), 0.62 (d, J = 6.0 Hz, 3H). Example 14

[0007] (2S)-2-(2-but-2-ynoyl-5-oxo-2,6-diazaspiro[3.4]octan-6-yl)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4- thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaen-7-yl]-3-methyl-butanamide The title compound was prepared in analogy to the preparation of Example 7 by using (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]- 17,17-dimethyl-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (intermediate E) and but-2-ynoic acid instead of (7S,13S)-7-amino-(20M)-20-[2- [(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-15- oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (intermediate G) and (2R)-2-chloro-2-fluoro- acetic acid (compound 1h). Example 14 (21 mg) was obtained as a yellow solid. MS calc’d 1015.5 (MH+), measured 1015.5 (MH+).1H NMR (400 MHz, METHANOL-d4) δ = 8.48 (d, J = 2.8 Hz, 1H), 8.41 (s, 1H), 7.62 (t, J = 3.2 Hz, 1H), 7.51 (d, J = 12.0 Hz, 1H), 7.44 (s, 1H), 5.80 - 5.68 (m, 1H), 4.52 - 4.47 (m, 1H), 4.44 - 4.38 (m, 2H), 4.35 - 4.31 (m, 1H) 4.30 - 4.11 (m, 5H) 3.97 (d, J = 10.0 Hz, 1H), 3.81 - 3.67 (m, 3H), 3.64 - 3.49 (m, 4H), 3.48 - 3.33 (m, 8H), 3.14 - 3.07 (m, 2H), 3.02 - 2.95 (m, 4H), 2.84 - 2.77 (m, 1H), 2.64 - 2.56 (m, 1H), 2.42 - 2.10 (m, 7H), 2.04 (d, J = 4.4 Hz, 3H), 1.98 - 1.92 (m, 1H), 1.84 - 1.74 (m, 1H), 1.66 - 1.57 (m, 1H), 1.46 (d, J = 6.4 Hz, 3H), 1.37 - 1.24 (m, 1H), 1.03 - 0.96 (m, 6 H), 0.87 (d, J = 6.4 Hz, 3H), 0.55 (s, 3H). Example 15 4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]- 17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen- 7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-1-prop-2-enoyl-piperidine-4-carboxamide 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]-5-morpholino-3-pyridyl]-17,17-dimethyl- 15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (intermediate F), 1-tert-butoxycarbonyl-4- fluoro-piperidine-4-carboxylic acid and acrylic acid instead of (20S,26S)-26-amino-30-hydroxy- (13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33- triazahexacyclo[26.3.1.12,6.120,24.04,14.05,12]tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaene- 19,25-dione (intermediate N), (3S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (compound 1e) and (2R)-2-chloro-2-fluoro-acetic acid (compound 1h). Example 15 (13.4 mg) was obtained as a yellow solid. MS calc’d 1024.5 (MH+), measured 1024.5 (MH+).1H NMR (400 MHz, METHANOL-d4) δ = 8.43 (s, 1H), 8.37 (d, J = 2.8 Hz, 1H), 7.85 (s, 1H), 7.56 - 7.38 (m, 2H), 7.09 - 6.62 (m, 1H), 6.25 (d, J = 17.2 Hz, 1H), 6.09 - 5.44 (m, 2H), 4.73 (d, J = 11.2 Hz, 1H), 4.58 - 4.52 (m, 1H), 4.49 - 4.34 (m, 2H), 4.28 - 4.18 (m, 1H), 4.17 - 4.03 (m, 2H), 3.86 (t, J = 4.4 Hz, 4H), 3.81 - 3.71 (m, 2H), 3.71 - 3.63 (m, 1H), 3.56 - 3.47 (m, 1H), 3.46 - 3.33 (m, 8H), 3.29 - 3.23 (m, 1H), 3.18 (br d, J = 5.2 Hz, 3H), 3.15 - 3.07 (m, 2H), 3.04 - 3.00 (m, 1H), 2.86 - 2.74 (m, 1H), 2.69 (d, J = 14.0 Hz, 1H), 2.41 - 2.09 (m, 8H), 1.99 - 1.90 (m, 1H), 1.84 - 1.72 (m, 1H), 1.66 - 1.58 (m, 1H), 1.48 (d, J = 6.4 Hz, 3H), 1.40 - 1.26 (m, 2H), 1.02 - 0.96 (m, 5H), 0.95 - 0.86 (m, 3H), 0.61 (s, 3H). Example 16 1-but-2-ynoyl-4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5- morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen- 7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide The title compound was prepared in analogy to the preparation of Example 1 by using (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl- 15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (intermediate F), 1-tert-butoxycarbonyl-4- fluoro-piperidine-4-carboxylic acid and but-2-ynoic acid instead of (20S,26S)-26-amino-30- hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33- triazahexacyclo[26.3.1.12,6.120,24.04,14.05,12]tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaene- 19,25-dione (intermediate N), (3S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (compound 1e) and (2R)-2-chloro-2-fluoro-acetic acid (compound 1h). Example 16 (11.2 mg) was obtained as a yellow solid. MS calc’d 1036.5 (MH+), measured 1036.4 (MH+),1H NMR(400 MHz, METHANOL-d4) δ = 8.43 (s, 1H), 8.37 (d, J = 2.8 Hz, 1H), 7.86 - 7.76 (m, 1H), 7.52- 7.44 (m, 2H), 5.88 - 5.64 (m, 1H), 4.77 - 4.68 (m, 1H), 4.56 - 4.51 (m, 1H), 4.45 - 4.31 (m, 3H), 4.26 - 4.20 (m, 1H), 4.18 - 4.10 (m, 1H), 3.86 (t, J = 4.8 Hz, 4H), 3.80 - 3.73 (m, 2H), 3.70 - 3.63 (m, 1H), 3.60 - 3.51 (m, 1H), 3.44 - 3.40 (m, 7H), 3.35 (s, 1H), 3.28 - 3.21 (m, 1H), 3.18 (t, J = 5.2 Hz, 3H), 3.11 - 3.00 (m, 3H), 2.86 - 2.76 (m, 1H), 2.73 - 2.64 (m, 1H), 2.31 - 2.10 (m, 7H), 2.06 (d, J = 4.0 Hz, 3H), 1.98 - 1.91 (m, 1H), 1.85 - 1.75 (m, 1H), 1.66 - 1.59 (m, 1H), 1.48 (d, J = 6.4 Hz, 3H), 1.35 - 1.28 (m, 3H), 1.02 - 0.97 (m, 5H), 0.91 - 0.85 (m, 3H), 0.68 - 0.54 (m, 3H). Example 17 cis-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17- dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen- 7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-3-(3,3,3-trifluoroprop-1- ynyl)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]-5-morpholino-3-pyridyl]-17,17-dimethyl- 15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (intermediate F) and cis-(2S)-3-methyl-2- [methyl-[3-(3,3,3-trifluoroprop-1-ynyl)cyclobutanecarbonyl]amino]butanoic acid (Intermediate A2) instead of (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]- 16,16-dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.12,6.120,24.04,14.05,12]tetratriaconta- 1(31),2,4,6(34),13,28(32),29-heptaene-19,25-dione (intermediate N) and Boc-N-Me-Val-OH (compound 1b). Example 17 (21.4 mg) was obtained as a yellow solid. MS calc’d 1015.5 (MH+), measured 1015.5 (MH+),1H NMR (400 MHz, METHANOL-d4) δ = 8.44 (s, 1H), 8.36 (d, J = 2.8 Hz, 1H), 7.90 - 7.84 (m, 1H), 7.47 - 7.41 (m, 2H), 5.79 - 5.71 (m, 1H), 4.94 - 4.90 (m, 1H), 4.75 (d, J = 11.2 Hz, 1H), 4.60 - 4.51 (m, 1H), 4.47 - 4.36 (m, 1H), 4.28 - 4.19 (m, 1H), 4.18 - 4.09 (m, 1H), 3.86 (t, J = 4.8 Hz, 4H), 3.81 - 3.74 (m, 2H), 3.70 - 3.64 (m, 1H), 3.54 - 3.47 (m, 1H), 3.45 - 3.43 (m, 5H), 3.39 - 3.34 (m, 1H), 3.28 - 3.24 (m, 1H), 3.15 - 3.07 (m, 2H), 3.05 - 2.98 (m, 1H), 2.96 - 2.91 (m, 3H), 2.84 - 2.75 (m, 1H), 2.73 - 2.62 (m, 3H), 2.56 - 2.38 (m, 2H), 2.35 - 2.29 (m, 1H), 2.25 - 2.16 (m, 3H), 1.99 - 1.91 (m, 1H), 1.85 - 1.74 (m, 1H), 1.61 (dd, J = 3.6, 12.4 Hz, 1H), 1.48 (d, J = 6.0 Hz, 3H), 1.36 - 1.27 (m, 2H), 1.06 - 0.96 (m, 6H), 0.85 (d, J = 6.4 Hz, 3H), 0.66 - 0.57 (m, 3H) Example 18 1-[(2R)-2-chloro-2-fluoro-acetyl]-4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia- 9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine- 4-carboxamide The title compound was prepared in analogy to the preparation of Example 1 by using (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl- 15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (intermediate F) and 1-tert-butoxycarbonyl-4- fluoro-piperidine-4-carboxylic acid instead of (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2- [(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33- triazahexacyclo[26.3.1.12,6.120,24.04,14.05,12]tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaene- 19,25-dione (intermediate N) and (3S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (compound 1e). Example 18 (11.2 mg) was obtained as a yellow solid. MS calc’d 1064.5 (MH+), measured 1064.7 (MH+).1H NMR (400 MHz, METHANOL-d4) δ = 8.44 (s, 1H), 8.37 (d, J = 3.2 Hz, 1H), 7.88 - 7.77 (m, 1H), 7.51 - 7.43 (m, 2H), 7.12 - 6.92 (m, 1H), 5.85 - 5.67 (m, 1H), 4.78 - 4.66 (m, 1H), 4.54 (t, J = 6.4 Hz, 1H), 4.46 - 4.38 (m, 1H), 4.37 - 4.28 (m, 1H), 4.26 - 4.18 (m, 1H), 4.17 - 4.08 (m, 1H), 3.86 (t, J = 4.8 Hz, 4H), 3.80 - 3.73 (m, 2H), 3.71 - 3.64 (m, 1H), 3.56 - 3.47 (m, 1H), 3.45 - 3.40 (m, 7H), 3.38 - 3.34 (m, 1H), 3.27 - 3.22 (m, 1H), 3.17 (t, J = 5.6 Hz, 3H), 3.11 - 3.08 (m, 1H), 3.06 - 2.97 (m, 2H), 2.87 - 2.77 (m, 1H), 2.73 - 2.65 (m, 1H), 2.41 - 2.11 (m, 8H), 2.09 - 1.89 (m, 2H), 1.83 - 1.73 (m, 1H), 1.66 - 1.58 (m, 1H), 1.48 (d, J = 6.4 Hz, 3H), 1.34 - 1.28 (m, 1H), 1.23 - 1.04 (m, 1H), 1.01 - 0.96 (m, 5H), 0.91 - 0.83 (m, 3H), 0.68 - 0.56 (m, 3H). Example 19 (2S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]- 17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen- 7-yl]-3-methyl-2-(5-oxo-2-prop-2-enoyl-2,6-diazaspiro[3.4]octan-6-yl)butanamide The title compound was prepared in analogy to the preparation of Example 7 by using (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]- 17,17-dimethyl-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaene- 8,14-dione (intermediate E) and acrylic acid instead of (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-15-oxa-4- thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (intermediate G) and (2R)-2-chloro-2-fluoro- acetic acid (compound 1h). Example 19 (5.2 mg) was obtained as a yellow solid. MS calc’d 1003.5 (MH+), measured 1003.8 (MH+).1H NMR (400 MHz, METHANOL-d4) δ = 8.48 (d, J = 2.4 Hz, 1H), 8.41 (s, 1H), 7.56 - 7.49 (m, 2H), 7.43 (d, J = 6.4 Hz, 1H), 6.41 - 6.26 (m, 2H), 5.78 (dd, J = 2.0, 10.0 Hz, 1H), 5.76 - 5.66 (m, 1H), 4.85 - 4.82 (m, 1H), 4.55 - 4.36 (m, 4H), 4.34 (d, J = 10.8 Hz, 1H), 4.31 - 4.16 (m, 5H), 4.05 - 4.01 (m, 1H), 3.76 (s, 2H), 3.62 - 3.50 (m, 4H), 3.46 - 3.42 (m, 2H), 3.39 (d, J = 6.0 Hz, 5H), 3.16 - 3.05 (m, 3H), 3.02 - 2.97 (m, 4H), 2.83 - 2.77 (m, 1H), 2.59 (dd, J = 7.2, 14.0 Hz, 1H), 2.40 - 2.34 (m, 2H), 2.33 - 2.27 (m, 1H), 2.26 - 2.18 (m, 3H), 1.96 (d, J = 14.8 Hz, 1H), 1.86 - 1.76 (m, 1H), 1.67 - 1.60 (m, 1H), 1.46 (d, J = 6.4 Hz, 3H), 1.34 - 1.29 (m, 1H), 1.02 - 0.97 (m, 6H), 0.90 - 0.86 (m, 3H), 0.54 (d, J = 4.8 Hz, 3H). Example 20 (2S)-2-[2-[(2R)-2-chloro-2-fluoro-acetyl]-5-oxo-2,6-diazaspiro[3.4]octan-6-yl]-N-[(7S,13S)- (20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl- 8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen- 7-yl]-3-methyl-butanamide The title compound was prepared in analogy to the preparation of Example 7 by using (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]- 17,17-dimethyl-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaene- 8,14-dione (intermediate E) instead (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4- (2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26- hexaene-8,14-dione (intermediate G). Example 19 (2.0 mg) was obtained as a yellow solid. MS calc’d 1043.5 (MH+), measured 1043.8 (MH+).1H NMR (400 MHz, METHANOL-d4) δ = 8.47 (d, J = 2.8 Hz, 1H), 8.40 (s, 1H), 7.54 - 7.46 (m, 2H), 7.42 (d, J = 10.0 Hz, 1H), 6.76 - 6.61 (m, 1H), 5.80 - 5.69 (m, 1H), 4.61 - 4.56 (m, 1H), 4.51 - 4.42 (m, 2H), 4.41 - 4.37 (m, 1H), 4.35 - 4.32 (m, 1H), 4.31 - 4.22 (m, 3H), 4.10 - 4.05 (m, 1H), 3.76 (s, 2H), 3.62 - 3.50 (m, 4H), 3.45 - 3.42 (m, 2H), 3.38 (d, J = 4.8 Hz, 4H), 3.15 - 3.05 (m, 3H), 2.99 (s, 3H), 2.84 - 2.77 (m, 1H), 2.63 - 2.56 (m, 1H), 2.43 - 2.37 (m, 2H), 2.36 - 2.24 (m, 2H), 2.24 - 2.17 (m, 3H), 2.07 - 1.91 (m, 2H), 1.85 - 1.76 (m, 1H), 1.62 (dd, J = 4.0, 13.2 Hz, 1H), 1.45 (d, J = 6.0 Hz, 3H), 1.35 - 1.28 (m, 4H), 1.02 - 0.96 (m, 6H), 0.88 (dd, J = 2.4, 6.0 Hz, 3H), 0.54 (d, J = 2.8 Hz, 3H). Example 21 cis-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3- pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen- 7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-3-(3,3,3-trifluoroprop-1- ynyl)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]-5-(4-methylpiperazin-1-yl)-3-pyridyl]- 17,17-dimethyl-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaene- 8,14-dione (intermediate E) and cis-(2S)-3-methyl-2-[methyl-[3-(3,3,3-trifluoroprop-1- ynyl)cyclobutanecarbonyl]amino]butanoic acid (Intermediate A2) instead of (20S,26S)-26- amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa- 12,24,33-triazahexacyclo[26.3.1.12,6.120,24.04,14.05,12]tetratriaconta-1(31),2,4,6(34),13,28(32),29- heptaene-19,25-dione (intermediate N) and Boc-N-Me-Val-OH (compound 1b). Example 21 (22.0 mg) was obtained as yellow solid. MS calc’d 1028.5 (MH+), measured 1028.4 (MH+).1H NMR (400 MHz, METHANOL-d4) δ = 8.48 (d, J = 2.8 Hz, 1H), 8.41 (s, 1H), 7.63 - 7.55 (m, 1H), 7.49 - 7.43 (m, 1H), 7.42 - 7.38 (m, 1H), 5.80 - 5.67 (m, 1H), 4.75 (d, J = 10.8 Hz, 1H), 4.48 (q, J = 6.0 Hz, 1H), 4.42 (d, J = 11.6 Hz, 1H), 4.27 - 4.18 (m, 2H), 4.12 - 3.96 (m, 1H), 3.75 (s, 2H), 3.63 - 3.55 (m, 2H), 3.55 - 3.47 (m, 2H), 3.46 - 3.42 (m, 1H), 3.41 - 3.37 (m, 4H), 3.29 - 3.18 (m, 3H), 3.13 - 3.06 (m, 2H), 2.98 (s, 4H), 2.96 - 2.94 (m, 1H), 2.93 (s, 2H), 2.79 (dt, J = 3.2, 12.8 Hz, 1H), 2.70 - 2.58 (m, 3H), 2.54 - 2.42 (m, 2H), 2.39 - 2.14 (m, 5H), 1.95 (d, J = 13.2 Hz, 1H), 1.85 - 1.73 (m, 1H), 1.67 - 1.56 (m, 1H), 1.46 (d, J = 6.0 Hz, 3H), 1.36 - 1.25 (m, 2H), 1.05 - 0.96 (m, 6H), 0.85 (d, J = 6.8 Hz, 3H), 0.55 (s, 3H). Example 22 (2S)-2-[2-(2-fluoroprop-2-enoyl)-5-oxo-2,6-diazaspiro[3.4]octan-6-yl]-N-[(7S,13S)-(20M)- 20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4- thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaen-7-yl]-3-methyl-butanamide The title compound was prepared in analogy to the preparation of Example 7 by using (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl- 15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (intermediate F) and 2-fluoroprop-2-enoic acid instead of (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2- trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26- hexaene-8,14-dione (intermediate G) and (2R)-2-chloro-2-fluoro-acetic acid (compound 1h). Example 22 (19.7 mg) was obtained as a yellow solid. MS calc’d 1008.5 (MH+), measured 1008.7 (MH+).1H NMR (400 MHz, Methanol-d4) δ = 8.43 (s, 1H), 8.36 (d, J = 2.4 Hz, 1H), 7.82 - 7.76（m, 1H), 7.55 - 7.43 (m, 2H), 5.81 - 5.74 (m, 1H), 5.66 - 5.51 (m, 1H), 5.28 - 5.21(m, 1H), 4.64 - 4.59 (m, 1H), 4.57 - 4.52 (m, 1H), 4.45 - 4.39 (m, 2H), 4.33 (d, J = 11.2 Hz, 1H), 4.30 - 4.23 (m, 2H), 4.18 - 4.12 (m, 1H), 4.05 (d, J = 10.4 Hz, 1H), 3.87 (t, J = 4.4 Hz, 4H), 3.80 - 3.73(m, 2H), 3.69 - 3.64 (m, 1H), 3.58 - 3.46 (m, 2H), 3.43 (d, J = 4.0 Hz, 5H), 3.41 (s, 3H), 3.29 - 3.25 (m, 1H), 3.16 - 3.11(m, 1H), 3.10 - 3.07 (m, 1H), 3.06 - 2.99 (m, 1H), 2.84 - 2.77 (m, 1H), 2.71 - 2.65 (m, 1H), 2.40 - 2.36 (m, 2H), 2.34 - 2.30 (m, 1H), 2.24 - 2.16 (m, 3H), 1.99 - 1.92 (m, 1H), 1.84 - 1.77 (m,1H), 1.68 - 1.60 (m, 1H), 1.48 (d, J = 6.4 Hz, 3H), 1.02 - 0.98 (m, 6H), 0.87 (dd, J = 3.2, 6.8 Hz, 3H), 0.63 - 0.58 (m, 3H). Example 23 cis-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2- trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia- 9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-3-(3,3,3- trifluoroprop-1-ynyl)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]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]- 3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26- hexaene-8,14-dione (intermediate G) and cis-(2S)-3-methyl-2-[methyl-[3-(3,3,3-trifluoroprop-1- ynyl)cyclobutanecarbonyl]amino]butanoic acid (Intermediate A2) instead of (20S,26S)-26- amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa- 12,24,33-triazahexacyclo[26.3.1.12,6.120,24.04,14.05,12]tetratriaconta-1(31),2,4,6(34),13,28(32),29- heptaene-19,25-dione (intermediate N) and Boc-N-Me-Val-OH (compound 1b). Example 23 (38.4 mg) was obtained as a yellow solid. MS calc’d 1096.5 (MH+), measured 1096.5 (MH+).1H NMR (400 MHz, METHANOL-d4) δ = 8.43 (s, 1H), 8.36 (d, J = 2.8 Hz, 1H), 7.80 (d, J = 2.8 Hz, 1H), 7.47 - 7.40 (m, 2H), 5.82 - 5.71 (m, 1H), 4.75 (d, J = 10.8 Hz, 1H), 4.53 (q, J = 6.0 Hz, 1H), 4.45 - 4.38 (m, 1H), 4.23 (dd, J = 3.2, 12.0 Hz, 1H), 4.18 - 4.11 (m, 1H), 3.78 - 3.73 (m, 2H), 3.70 - 3.65 (m, 1H), 3.61 (q, J = 7.2 Hz, 1H), 3.49 - 3.46 (m, 4H), 3.44 - 3.41 (m, 3H), 3.28 - 3.25 (m, 1H), 3.19 - 3.07 (m, 4H), 3.04 - 2.99 (m 1H), 2.97 - 2.93 (m, 1H), 2.92 (s, 2H), 2.88 (t, J = 4.8 Hz, 4H), 2.83 - 2.76 (m, 1H), 2.71 - 2.60 (m, 3H), 2.54 - 2.41 (m, 2H), 2.39 - 2.24 (m, 2H), 2.24 - 2.13 (m, 3H), 1.99 - 1.91 (m, 1H), 1.86 - 1.75 (m, 1H), 1.67 - 1.58 (m, 1H), 1.47 (d, J = 6.4 Hz, 3H), 1.34 - 1.24 (m, 1H), 1.18 (t, J = 7.2 Hz, 1H), 1.08 - 1.02 (m, 1H), 1.01 - 0.96 (m, 4H), 0.88 - 0.83 (m, 3H), 0.65 - 0.57 (m, 3H). Example 24 4-fluoro-1-(2-fluoroprop-2-enoyl)-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]- 5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen- 7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide The title compound was prepared in analogy to the preparation of Example 1 by using (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl- 15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (intermediate F), 1-tert-butoxycarbonyl-4- fluoro-piperidine-4-carboxylic acid and 2-fluoroprop-2-enoic acid instead of (20S,26S)-26- amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa- 12,24,33-triazahexacyclo[26.3.1.12,6.120,24.04,14.05,12]tetratriaconta-1(31),2,4,6(34),13,28(32),29- heptaene-19,25-dione (intermediate N), (3S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (compound 1e) and (2R)-2-chloro-2-fluoro-acetic acid (compound 1h). Example 24 (36.5 mg) was obtained as a yellow solid. MS calc’d 1042.5 (MH+), measured 1042.4 (MH+).1H NMR (400 MHz, METHANOL-d4) δ = 8.43 (s, 1H), 8.37 (d, J = 2.8 Hz, 1H), 7.80 (s, 1H), 7.47 (br d, J = 15.2 Hz, 2H), 5.86 - 5.71 (m, 1H), 5.33 - 5.25 (m, 1H), 5.25 - 5.16 (m, 1H), 4.73 (d, J = 11.2 Hz, 1H), 4.53 (q, J = 5.6 Hz, 1H), 4.42 (br d, J = 13.6 Hz, 1H), 4.23 (dd, J = 2.8, 12.0 Hz, 1H), 4.17 - 4.11 (m, 1H), 3.86 (t, J = 4.8 Hz, 4H), 3.77 (d, J = 2.4 Hz, 1H), 3.70 - 3.64 (m, 1H), 3.61 (q, J = 6.0 Hz, 3H), 3.43 - 3.39 (m, 7H), 3.28 - 3.23 (m, 1H), 3.18 (d, J = 5.2 Hz, 2H), 3.15 - 3.07 (m, 2H), 3.05 - 3.01 (m, 1H), 2.85 - 2.76 (m, 1H), 2.72 - 2.65 (m, 1H), 2.36 - 2.24 (m, 3H), 2.24 - 2.15 (m, 4H), 1.99 - 1.91 (m, 1H), 1.85 - 1.74 (m, 1H), 1.68 - 1.59 (m, 1H), 1.48 (d, J = 6.0 Hz, 3H), 1.35 - 1.28 (m, 2H), 1.18 (t, J = 7.2 Hz, 4H), 1.01 - 0.96 (m, 5H), 0.92 - 0.84 (m, 3H), 0.61 (s, 3H). Example 25 1-but-2-ynoyl-4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen- 7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide The title compound was prepared in analogy to the preparation of Example 1 by using (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]- 17,17-dimethyl-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaene- 8,14-dione (intermediate E), 1-tert-butoxycarbonyl-4-fluoro-piperidine-4-carboxylic acid and but-2-ynoic acid instead of (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1- methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33- triazahexacyclo[26.3.1.12,6.120,24.04,14.05,12]tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaene- 19,25-dione (intermediate N), (3S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (compound 1e) and (2R)-2-chloro-2-fluoro-acetic acid (compound 1h). Example 25 (49.7 mg) was obtained as a yellow solid. MS calc’d 1049.5 (MH+), measured 1049.8 (MH+).1H NMR (400 MHz, Methanol-d4) δ = 8.48 (s, 1H), 8.40 (s, 1H), 7.68 - 7.46 (m, 2H), 7.44 - 7.40 (m, 1H), 5.81 - 5.71 (m, 1H), 4.80 - 4.75 (m, 1H), 4.74 - 4.69 (m, 1H), 4.49 - 4.31 (m, 4H), 4.29 - 4.11 (m, 3H), 3.79 - 3.68 (m, 3H), 3.63 - 3.54 (m, 3H), 3.53 - 3.41 (m, 3H), 3.40 - 3.34 (m, 5H), 3.20 - 3.16 (m, 3H), 3.15 - 3.12 (m, 1H), 3.11 - 3.04 (m, 2H), 2.99 (s, 5H), 2.84 - 2.75 (m, 1H), 2.65 - 2.56 (m, 1H), 2.36 - 2.24 (m, 3H), 2.22 - 2.09 (m, 5H), 2.06 (d, J = 4.0 Hz, 3H), 1.98 - 1.91 (m, 1H), 1.83 - 1.73 (m, 1H), 1.67 - 1.58 (m, 1H), 1.46 (d, J = 6.0 Hz, 3H), 0.97 (s, 6H), 0.90 - 0.83 (m, 3H), 0.55 (s, 3H). Example 26 4-fluoro-1-(2-fluoroprop-2-enoyl)-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]- 5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen- 7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide The title compound was prepared in analogy to the preparation of Example 1 by using (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]- 17,17-dimethyl-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaene- 8,14-dione (intermediate E), 1-tert-butoxycarbonyl-4-fluoro-piperidine-4-carboxylic acid and 2- fluoroprop-2-enoic acid instead of (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1- methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33- triazahexacyclo[26.3.1.12,6.120,24.04,14.05,12]tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaene- 19,25-dione (intermediate N), (3S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (compound 1e) and (2R)-2-chloro-2-fluoro-acetic acid (compound 1h). Example 26 (34.7 mg) was obtained as a yellow solid. MS calc’d 1055.5 (MH+), measured 1055.6 (MH+).1H NMR (400 MHz, Methanol-d4) δ = 8.47 (s, 1H), 8.41 - 8.38 (m, 1H), 7.59 - 7.43 (m, 2H), 7.43 - 7.38 (m, 1H), 5.82 - 5.68 (m, 1H), 5.33 - 5.26 (m, 1H), 5.24 - 5.16 (m, 1H), 4.79 (s, 1H), 4.75 - 4.71 (m, 1H), 4.48 - 4.39 (m, 2H), 4.28 - 4.15 (m, 3H), 4.09 - 3.90 (m, 2H), 3.78 - 3.74 (m, 2H), 3.63 - 3.52 (m, 3H), 3.50 - 3.40 (m, 3H), 3.39 - 3.35 (m, 4H), 3.29 - 3.24 (m, 2H), 3.21 - 3.16 (m, 3H), 3.15 – 3.11(m, 1H), 3.11 - 3.04 (m, 2H), 3.04 - 2.93 (m, 5H), 2.84 - 2.75(m, 1H), 2.60 ( d, J = 13.6 Hz, 1H), 2.37 - 2.26 (m, 3H), 2.25 - 2.11 (m, 5H), 1.99 - 1.90(m, 1H), 1.84 - 1.74 (m, 1H), 1.69 - 1.58 (m, 1H), 1.48 - 1.42 (m, 3H), 1.02 - 0.93 (m, 6H), 0.92 - 0.83(m, 3H), 0.55 (s, 3H). Example 27 1-[(2R)-2-chloro-2-fluoro-acetyl]-4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4- thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine- 4-carboxamide 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]-5-(4-methylpiperazin-1-yl)-3-pyridyl]- 17,17-dimethyl-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaene- 8,14-dione (intermediate E) and 1-tert-butoxycarbonyl-4-fluoro-piperidine-4-carboxylic acid instead of (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]- 16,16-dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.12,6.120,24.04,14.05,12]tetratriaconta- 1(31),2,4,6(34),13,28(32),29-heptaene-19,25-dione (intermediate N) and (3S)-1-tert- butoxycarbonylpyrrolidine-3-carboxylic acid (compound 1e). Example 27 (44.98 mg) was obtained as a yellow solid. MS calc’d 1077.5 (MH+), measured 1077.5 (MH+).1H NMR (400 MHz, Methanol-d4) δ = 8.48 (s, 1H), 8.40 (s, 1H), 7.48 (s, 1H), 7.45 - 7.40 (m, 1H), 7.12 - 6.91 (m, 1H), 5.81 - 5.71 (m, 1H), 4.79 - 4.66 (m, 2H), 4.57 - 4.29 (m, 4H), 4.26 - 4.18 (m, 2H), 3.99 - 3.85 (m, 2H), 3.82 - 3.69 (m, 3H), 3.64 - 3.50 (m, 4H), 3.41 - 3.34 (m, 5H), 3.23 - 3.16 (m, 4H), 3.12 - 3.05 (m, 2H), 3.03 - 2.95 (m, 5H), 2.85 - 2.77 (m, 1H), 2.65 - 2.57 (m, 1H), 2.45 - 2.24 (m, 4H), 2.23 - 2.07 (m, 5H), 1.99 - 1.92 (m, 1H), 1.85 - 1.73 (m, 1H), 1.67 - 1.58 (m, 1H), 1.48 - 1.44 (m, 3H), 1.00 - 0.94 (m, 7H), 0.88 (d, J = 6.0 Hz, 3H), 0.61 - 0.53 (m, 3H). Example 28 1-[(2R)-2-chloro-2-fluoro-acetyl]-4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia- 9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine- 4-carboxamide The title compound was prepared in analogy to the preparation of Example 1 by using (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl- 15,24-dioxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (intermediate I) and 1-tert-butoxycarbonyl-4- fluoro-piperidine-4-carboxylic acid instead of (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2- [(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33- triazahexacyclo[26.3.1.12,6.120,24.04,14.05,12]tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaene- 19,25-dione (intermediate N) and (3S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (compound 1e). Example 28 (22.2 mg) was obtained as a yellow solid. MS calc’d 1066.4 (MH+); measured 1066.4 (MH+).1H NMR (400 MHz, METHANOL-d4) δ = 8.41 (br s, 1H), 8.26 (s, 1H), 7.91 (br s, 1H), 7.47 (br d, J = 4.8 Hz, 1H), 7.19 - 6.97 (m, 2H), 5.79 - 5.65 (m, 1H), 4.76 - 4.70 (m, 1H), 4.69 - 4.57 (m, 3H), 4.47 - 4.31 (m, 2H), 4.31 - 4.20 (m, 2H),3.92 - 3.75 (m, 8H), 3.45 (br d, J = 4.5 Hz, 8H), 3.35 - 3.31 (m, 2H), 3.25 - 3.13 (m, 5H), 3.07 (br s, 1H), 2.86 - 2.75 (m, 1H), 2.73 - 2.64 (m, 1H), 2.50 - 2.04 (m, 6H), 2.02 - 1.91 (m, 1H), 1.87 - 1.73 (m, 1H), 1.70 - 1.57 (m, 1H), 1.55 - 1.48 (m, 3H),1.10 - 1.04 (m, 3H), 1.02 - 0.94 (m, 3H), 0.89 (br d, J = 6.3 Hz, 2H), 0.61 (br d, J = 6.4 Hz, 3H). Example 29 4-fluoro-1-(2-fluoroprop-2-enoyl)-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]- 5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen- 7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide The title compound was prepared in analogy to the preparation of Example 1 by using (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl- 15,24-dioxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (intermediate I), 1-tert-butoxycarbonyl-4-fluoro- piperidine-4-carboxylic acid and 2-fluoroprop-2-enoic acid instead of (20S,26S)-26-amino-30- hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33- triazahexacyclo[26.3.1.12,6.120,24.04,14.05,12]tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaene- 19,25-dione (intermediate N), (3S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (compound 1e) and (2R)-2-chloro-2-fluoro-acetic acid (compound 1h). Example 29 (22 mg) was obtained as a light yellow solid. MS calc’d 1044.5 (MH+), measured 1044.7 (MH+).1H NMR (400 MHz, δ = 8.37 (d, J = 2.8 Hz, 1H), 8.23 (s, 1H), 7.74 (br s, 1H), 7.48 (br s, 1H), 7.12 (s, 1H), 5.79 - 5.71 (m, 1H), 5.32 - 5.26 (m, 1H), 5.25 - 5.18 (m, 1H), 4.76 - 4.72 (m, 1H), 4.65 - 4.57 (m, 3H), 4.42 (br dd, J = 1.9, 11.7 Hz, 1H), 4.27 (td, J = 3.6, 12.0 Hz, 2H), 3.89 - 3.84 (m, 4H), 3.83 - 3.78 (m, 1H), 3.76 (s, 2H), 3.48 (br s, 2H), 3.44 - 3.37 (m, 9H), 3.19 (br d, J = 5.6 Hz, 3H), 3.13 (br s, 1H), 3.02 (s, 1H), 2.84 - 2.75 (m, 1H), 2.68 - 2.62 (m, 1H), 2.40 - 2.11 (m, 7H), 1.99 - 1.92 (m, 1H), 1.86 - 1.76 (m, 1H), 1.68 - 1.59 (m, 1H), 1.48 (d, J = 6.4 Hz, 3H), 1.03 (s, 3H), 1.00 - 0.95 (m, 3H), 0.88 (br d, J = 6.6 Hz, 3H), 0.58 (s, 3H). Example 30 1-but-2-ynoyl-4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5- morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen- 7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide The title compound was prepared in analogy to the preparation of Example 1 by using (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl- 15,24-dioxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (intermediate I), 1-tert-butoxycarbonyl-4-fluoro- piperidine-4-carboxylic acid and but-2-ynoic acid instead of (20S,26S)-26-amino-30-hydroxy- (13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33- triazahexacyclo[26.3.1.12,6.120,24.04,14.05,12]tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaene- 19,25-dione (intermediate N), (3S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (compound 1e) and (2R)-2-chloro-2-fluoro-acetic acid (compound 1h). Example 30 (17.7 mg) was obtained as a light yellow solid. MS calc’d 1038.5 (MH+), measured 1038.8 (MH+).1H 8.37 (d, J = 2.8 Hz, 1H), 8.23 (s, 1H), 7.80 (dd, J = 2.6, 7.0 Hz, 1H), 7.48 (d, J = 4.3 Hz, 1H), 7.13 (d, J = 3.6 Hz, 1H), 5.80 - 5.69 (m, 1H), 4.72 (br d, J = 11.0 Hz, 1H), 4.59 (br d, J = 6.1 Hz, 3H), 4.45 - 4.30 (m, 4H), 4.28 - 4.22 (m, 2H), 3.88 - 3.84 (m, 4H), 3.83 - 3.78 (m, 1H), 3.76 (s, 2H), 3.61 - 3.46 (m, 2H), 3.46 - 3.37 (m, 9H), 3.18 (dd, J = 2.6, 5.5 Hz, 3H), 3.15 - 3.11 (m, 1H), 3.06 - 2.95 (m, 1H), 2.84 - 2.75 (m, 1H), 2.69 - 2.62 (m, 1H), 2.33 - 2.08 (m, 7H), 1.99 - 1.92 (m, 1H), 1.87 - 1.77 (m, 1H), 1.67 - 1.57 (m, 1H), 1.50 - 1.46 (m, 3H), 1.05 - 1.01 (m, 3H), 1.00 - 0.94 (m, 3H), 0.88 (br d, J = 6.6 Hz, 3H), 0.58 (br s, 3H). Example 31 1-[(2R)-2-chloro-2-fluoro-acetyl]-4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24- dioxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine- 4-carboxamide 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]-5-(4-methylpiperazin-1-yl)-3-pyridyl]- 17,17-dimethyl-15,24-dioxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaene- 8,14-dione (intermediate H) and 1-tert-butoxycarbonyl-4-fluoro-piperidine-4-carboxylic acid instead of (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]- 16,16-dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.12,6.120,24.04,14.05,12]tetratriaconta- 1(31),2,4,6(34),13,28(32),29-heptaene-19,25-dione (intermediate N) and (3S)-1-tert- butoxycarbonylpyrrolidine-3-carboxylic acid (compound 1e). Example 31 (33.5 mg) was obtained as a light yellow solid. MS calc’d 1079.5 (MH+), measured 1079.8 (MH+).1H NMR (400 MHz, METHANOL-d4) δ = 8.23 (s, 1H), 7.68 (s, 1H), 7.49 (d, J = 3.2 Hz, 1H), 7.14 (d, J = 10 Hz, 1H), 7.00 (s, 1H), 5.75 - 5.71 (m, 1H), 4.79 - 4.70 (m, 1H), 4.66 - 4.54 (m, 3H), 4.45 - 4.25 (m, 4H), 4.10 (br s, 3H), 3.81 - 3.74 (m, 3H), 3.70 - 3.47 (m, 4H), 3.46 - 3.37 (m, 5H), 3.28 - 3.14 (m, 6H), 3.10 - 2.90 (m, 4H), 2.86 - 2.75 (m, 1H), 2.67 - 2.57 (m, 1H), 2.05 (s, 6H), 2.02 - 1.93 (m, 1H), 1.88 - 1.75 (m, 1H), 1.71 - 1.57 (m, 1H), 1.53 - 1.43 (m, 3H), 1.42 - 1.23 (m, 1H), 1.22 - 0.79 (m, 10H), 0.64 - 0.48 (m, 3H). Example 32 4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1- yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen- 7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-1-prop-2-enoyl-piperidine-4-carboxamide 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]-5-(4-methylpiperazin-1-yl)-3-pyridyl]- 17,17-dimethyl-15,24-dioxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaene- 8,14-dione (intermediate H), 1-tert-butoxycarbonyl-4-fluoro-piperidine-4-carboxylic acid and acrylic acid instead of (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3- pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33- triazahexacyclo[26.3.1.12,6.120,24.04,14.05,12]tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaene- 19,25-dione (intermediate N), (3S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (compound 1e) and (2R)-2-chloro-2-fluoro-acetic acid (compound 1h). Example 32 (18.9 mg) was obtained as a light yellow solid. MS calc’d 1039.5 (MH+), measured 1039.5 (MH+).1H δ = 8.50 (d, J = 2.8 Hz, 1H), 8.24 - 8.17 (m, 1H), 7.70 - 7.59 (m, 1H), 7.52 - 7.44 (m, 1H), 7.15 - 7.06 (m, 1H), 6.89 - 6.77 (m, 1H), 6.29 - 6.20 (m, 1H), 5.81 - 5.75 (m, 1H), 5.75 - 5.66 (m, 1H), 4.76 - 4.69 (m, 1H), 4.67 - 4.59 (m, 2H), 4.55 (br d, J = 6.3 Hz, 1H), 4.48 - 4.38 (m, 2H), 4.33 - 4.25 (m, 2H), 4.19 - 3.90 (m, 3H), 3.80 - 3.66 (m, 4H), 3.53 (br s, 3H), 3.45 - 3.34 (m, 6H), 3.22 - 3.12 (m, 5H), 3.04 - 2.94 (m, 4H), 2.84 - 2.75 (m, 1H), 2.65 - 2.54 (m, 1H), 2.42 - 2.02 (m, 7H), 2.00 - 1.93 (m, 1H), 1.87 - 1.76 (m, 1H), 1.68 - 1.59 (m, 1H), 1.49 - 1.43 (m, 3H), 1.05 - 1.00 (m, 3H), 0.99 - 0.94 (m, 3H), 0.92 - 0.81 (m, 3H), 0.53 (s, 3H). Example 33 1-but-2-ynoyl-4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen- 7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide The title compound was prepared in analogy to the preparation of Example 1 by using (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]- 17,17-dimethyl-15,24-dioxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaene- 8,14-dione (intermediate H), 1-tert-butoxycarbonyl-4-fluoro-piperidine-4-carboxylic acid and but-2-ynoic acid instead of (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1- methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33- triazahexacyclo[26.3.1.12,6.120,24.04,14.05,12]tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaene- 19,25-dione (intermediate N), (3S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (compound 1e) and (2R)-2-chloro-2-fluoro-acetic acid (compound 1h). Example 33 (25.1 mg) was obtained as a light yellow solid. MS calc’d 1051.5 (MH+), measured 1051.8 (MH+).1H δ = 8.49 (s, 1H), 8.20 (s, 1H), 7.67 - 7.60 (m, 1H), 7.50 - 7.45 (m, 1H), 7.13 - 7.08 (m, 1H), 5.79 - 5.61 (m, 1H), 4.76 - 4.68 (m, 1H), 4.67 - 4.58 (m, 2H), 4.54 (d, J = 6.4 Hz, 1H), 4.48 - 4.21 (m, 6H), 3.79 - 3.73 (m, 3H), 3.52 (br s, 3H), 3.47 - 3.35 (m, 6H), 3.19 (br d, J = 5.4 Hz, 6H), 3.04 - 2.94 (m, 4H), 2.86 - 2.75 (m, 1H), 2.63 - 2.55 (m, 1H), 2.38 - 2.11 (m, 6H), 2.09 - 2.00 (m, 4H), 1.99 - 1.92 (m, 1H), 1.87 - 1.75 (m, 1H), 1.68 - 1.58 (m, 1H), 1.49 - 1.43 (m, 3H), 1.22 - 1.12 (m, 1H), 1.02 (s, 6H), 0.92 - 0.81 (m, 3H), 0.53 (s, 3H). Example 34 (3R)-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]- 17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen- 7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-1-prop-2-enoyl-pyrrolidine-3-carboxamide 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]-5-morpholino-3-pyridyl]-17,17-dimethyl- 15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (intermediate F) and acrylic acid instead of (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl- 7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.12,6.120,24.04,14.05,12]tetratriaconta- 1(31),2,4,6(34),13,28(32),29-heptaene-19,25-dione (intermediate N) and (2R)-2-chloro-2-fluoro- acetic acid (compound 1h). Example 34 (41.0 mg) was obtained as a yellow solid. MS calc’d 992.5 (MH+), measured 992.5 (MH+).1H NMR (400 MHz, METHANOL-d4) δ = 8.46 - 8.35 (m, 2H), 7.74 (s, 1H), 7.55 - 7.41 (m, 2H), 7.00 - 6.84 (m, 1H), 6.68 - 6.55 (m, 1H), 6.35 - 6.24 (m, 1H), 5.85 - 5.67 (m, 2H), 4.83 - 4.75 (m, 1H), 4.57 - 4.48 (m, 1H), 4.44 - 4.39 (m, 1H), 4.29 - 4.12 (m, 2H), 3.87 - 3.79 (m, 7H), 3.78 - 3.73 (m, 2H), 3.69 - 3.56 (m, 3H), 3.44 - 3.38 (m, 7H), 3.28 - 3.21 (m, 1H), 3.14 - 3.06 (m, 5H), 3.03 - 2.99 (m, 1H), 2.84 - 2.73 (m, 1H), 2.71 - 2.60 (m, 1H), 2.34 - 2.18 (m, 5H), 2.00 - 1.88 (m, 1H), 1.85 - 1.72 (m, 1H), 1.67 - 1.55 (m, 1H), 1.47 (d, J = 6.4 Hz, 3H), 1.03 - 0.95 (m, 7H), 0.91 - 0.80 (d, J = 6.4 Hz, 3H), 0.65 - 0.54 (m, 3H). Example 35 (3R)-1-but-2-ynoyl-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino- 3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen- 7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide 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]-5-morpholino-3-pyridyl]-17,17-dimethyl- 15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (intermediate F) and but-2-ynoic acid instead of (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl- 7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.12,6.120,24.04,14.05,12]tetratriaconta- 1(31),2,4,6(34),13,28(32),29-heptaene-19,25-dione (intermediate N) and (2R)-2-chloro-2-fluoro- acetic acid (compound 1h). Example 35 (12.9 mg) was obtained as a yellow solid. MS calc’d 1004.5 (MH+), measured 1004.6 (MH+).1H NMR (400 MHz, METHANOL-d4) δ = 8.43 (s,1H), 8.37 (s, 1H), 7.84 - 7.72 (m, 1H), 7.50 (d, J = 3.2 Hz, 1H), 7.45 (s, 1H), 5.84 - 4.61 (m, 1H), 4.83 - 4.77 (m, 1H), 4.59 - 4.49 (m, 1H), 4.44 - 4.39 (m, 1H), 4.30 - 4.22 (m, 1H), 4.20 - 4.13 (m, 1H), 3.99 - 3.90 (m, 1H), 3.88 - 3.84 (m, 4H), 3.82 - 3.79 (m, 1H), 3.79 - 3.69 (m, 4H), 3.68 - 3.55 (m, 3H), 3.45 - 3.39 (m, 7H), 3.28 - 3.21 (m, 1H), 3.14 - 3.00 (m, 6H), 2.84 - 2.74 (m, 1H), 2.65 (d, J = 14.8 Hz, 1H), 2.33 - 2.13 (m, 6H), 2.08 - 2.02 (m, 2H), 1.98 - 1.91 (m, 2H), 1.85 - 1.75 (m, 1H), 1.67 - 1.57 (m, 1H), 1.48 (d, J = 6.4 Hz, 3H), 1.02 - 0.96 (m, 6H), 0.91 - 0.81 (m, 3H), 0.65 - 0.55 (m, 3H). Example 36 4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1- yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen- 7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-1-prop-2-enoyl-piperidine-4-carboxamide 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]-5-(4-methylpiperazin-1-yl)-3-pyridyl]- 17,17-dimethyl-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaene- 8,14-dione (intermediate E), 1-tert-butoxycarbonyl-4-fluoro-piperidine-4-carboxylic acid and acrylic acid instead of (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3- pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33- triazahexacyclo[26.3.1.12,6.120,24.04,14.05,12]tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaene- 19,25-dione (intermediate N), (3S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (compound 1e) and (2R)-2-chloro-2-fluoro-acetic acid (compound 1h). Example 36 (24.5 mg) was obtained as a yellow solid. MS calc’d 1037.5 (MH+), measured 1037.6 (MH+).1H NMR (400 MHz, Methanol-d4) δ = 8.47 (d, J = 2.8 Hz, 1H), 8.40 (s, 1H), 7.51 - 7.40 (m, 3H), 6.87 - 6.77 (m, 1H), 6.25 (d, J = 16.8 Hz, 1H), 5.81 - 5.72 (m, 2H), 4.73 (d, J = 11.2 Hz, 1H), 4.49 - 4.40 (m, 3H), 4.27 - 4.20 (m, 2H), 4.08 (s, 2H), 3.83 - 3.73 (m, 3H), 3.63 - 3.52 (m, 4H), 3.44 - 3.35 (m, 7H), 3.27 - 3.18 (m, 5H), 3.14 - 3.04 (m, 3H), 2.99 (s, 4H), 2.84 - 2.77(m, 1H), 2.59 (d, J = 14.4 Hz, 1H), 2.35 - 2.26 (m, 3H), 2.24 - 2.13(m, 5H), 1.99 - 1.92(m, 1H), 1.85 - 1.77 (m, 1H), 1.68 - 1.60 (m, 1H), 1.45 (d, J = 6.0 Hz, 3H), 1.01 - 0.95 (m, 6H), 0.88 (d, J = 6.4 Hz, 3H), 0.54 (s, 3H). Example 37 (2S)-2-[(5R)-7-but-2-ynoyl-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-N-[(7S,13S)-(20M)-20-[2- [(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15- oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaen-7-yl]-3-methyl-butanamide The title compound was prepared in analogy to the preparation of Example 7 by using (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]- 17,17-dimethyl-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaene- 8,14-dione (intermediate E), (2S)-2-[(5R)-7-tert-butoxycarbonyl-1-oxo-2,7- diazaspiro[4.4]nonan-2-yl]-3-methyl-butanoic acid (intermediate A3) and but-2-ynoic acid instead of (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2- trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26- hexaene-8,14-dione (intermediate G), (2S)-2-(2-tert-butoxycarbonyl-5-oxo-2,6- diazaspiro[3.4]octan-6-yl)-3-methyl-butanoic acid (intermediate A1) and (2R)-2-chloro-2-fluoro- acetic acid (compound 1h). Example 37 (11.1 mg) was obtained as a yellow solid. MS calc’d 1029.5 (MH+), measured 1029.7 (MH+).1H NMR (400 MHz, Methanol-d4) δ = 8.47 (d, J = 2.4 Hz, 1H), 8.40 (s, 1H), 7.53 - 7.45 (m, 2H), 7.42 (s, 1H), 5.75 (t, J = 7.8 Hz, 1H), 4.49 - 4.37 (m, 2H), 4.34 - 4.20 (m, 3H), 4.02 - 3.84 (m, 2H), 3.80 - 3.35 (m, 18H), 3.28 - 3.23 (m, 1H), 3.13 - 3.05 (m, 2H), 2.99 (s, 4H), 2.87 - 2.74 (m, 1H), 2.65 - 2.53 (m, 1H), 2.36 - 2.14 (m, 5H), 2.09 - 2.02 (m, 5H), 2.00 - 1.90 (m, 2H), 1.86 - 1.73 (m, 1H), 1.69 - 1.55 (m, 1H), 1.45 (d, J = 6.0 Hz, 3H), 1.18 (t, J = 7.2 Hz, 1H), 1.03 - 0.95 (m, 6H), 0.89 (t, J = 6.4 Hz, 3H), 0.54 (s, 3H). Example 38 4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]- 17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen- 7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-1-prop-2-enoyl-piperidine-4-carboxamide 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]-5-morpholino-3-pyridyl]-17,17-dimethyl- 15,24-dioxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (intermediate I), 1-tert-butoxycarbonyl-4-fluoro- piperidine-4-carboxylic acid and acrylic acid instead of (20S,26S)-26-amino-30-hydroxy-(13M)- 13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33- triazahexacyclo[26.3.1.12,6.120,24.04,14.05,12]tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaene- 19,25-dione (intermediate N), (3S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (compound 1e) and (2R)-2-chloro-2-fluoro-acetic acid (compound 1h). Example 38 (11.3 mg) was obtained as a light yellow solid. MS calc’d 1026.5 (MH+), measured 1026.4 (MH+).1H NMR (400 MHz, METHANOL-d4) δ = 8.38 (d, J = 2.4 Hz, 1H), 8.28 - 8.18 (m, 1H), 7.84 (s, 1H), 7.49 (d, J = 10.9 Hz, 1H), 7.13 (dd, J = 2.8, 5.9 Hz, 1H), 6.83 (dd, J = 10.5, 16.6 Hz, 1H), 6.25 (d, J = 16.9 Hz, 1H), 5.92 - 5.65 (m, 2H), 4.73 (d, J = 11.0 Hz, 1H), 4.69 - 4.57 (m, 3H), 4.49 - 4.39 (m, 2H), 4.25 (t, J = 11.6 Hz, 2H), 4.16 - 4.02 (m, 1H), 3.89 - 3.84 (m, 4H), 3.82 - 3.72 (m, 3H), 3.58 - 3.49 (m, 1H), 3.46 - 3.37 (m, 8H), 3.22 - 3.15 (m, 4H), 3.09 - 2.95 (m, 1H), 2.84 - 2.73 (m, 1H), 2.72 - 2.63 (m, 1H), 2.29 - 2.10 (m, 5H), 1.94 (s, 1H), 1.89 - 1.73 (m, 1H), 1.70 - 1.55 (m, 1H), 1.49 (d, J = 6.3 Hz, 3H), 1.39 - 1.28 (m, 1H), 1.31 (t, J = 7.4 Hz, 1H), 1.04 (s, 3H), 0.98 (d, J = 6.3 Hz, 3H), 0.88 (d, J = 6.5 Hz, 3H), 0.59 (s, 3H). Example 39 N-[(1S)-1-[[(7S,13S)-23,23-difluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen- 7-yl]carbamoyl]-2-methyl-propyl]-4-fluoro-N-methyl-1-prop-2-enoyl-piperidine-4- carboxamide The title compound was prepared in analogy to the preparation of Example 1 by using (7S,13S)-7-amino-23,23-difluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1- yl)-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaene- 8,14-dione (intermediate J), 1-tert-butoxycarbonyl-4-fluoro-piperidine-4-carboxylic acid and acrylic acid instead of (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3- pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.12,6.120,24.04,14.05,12]tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaene-19,25-dione (intermediate N), (3S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (compound 1e) and (2R)-2-chloro-2-fluoro-acetic acid (compound 1h). Example 39 (23.1 mg) was obtained as a yellow solid. MS calc’d 1073.5 (MH+), measured 1073.5 (MH+).1H NMR (400 MHz, METHANOL-d4) δ = 8.52 (d, J = 2.8 Hz, 2H), 7.56 (d, J = 4.0 Hz, 2H), 6.82 (dd, J = 10.8, 16.8 Hz, 1H), 6.25 (d, J = 16.8 Hz, 1H), 5.86 - 5.66 (m, 2H), 4.83 - 4.79 (m, 1H), 4.73 (d, J = 11.2 Hz, 1H), 4.59 - 4.38 (m, 4H), 4.29 - 4.22 (m, 1H), 4.12 - 4.06 (m, 1H), 4.02 - 3.82 (m, 2H), 3.80 - 3.73 (m, 2H), 3.70 - 3.46 (m, 6H), 3.45 - 3.42 (m, 1H), 3.41 - 3.36 (m, 4H), 3.36 - 3.32 (m, 1H), 3.30 - 3.22 (m, 2H), 3.19 (d, J = 5.2 Hz, 3H), 3.14 - 3.09 (m, 1H), 3.07 - 2.89 (m, 4H), 2.85 - 2.76 (m, 1H), 2.66 - 2.56 (m, 1H), 2.35 - 2.09 (m, 6H), 2.00 - 1.92 (m, 1H), 1.86 - 1.74 (m, 1H), 1.68 - 1.58 (m, 1H), 1.47 (d, J = 6.0 Hz, 3H), 1.34 - 1.28 (m, 1H), 1.06 - 0.93 (m, 6H), 0.93 - 0.82 (m, 3H), 0.57 (s, 3H). Example 40 N-[(1S)-1-[[(7S,13S)-23,23-difluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3- pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen- 7-yl]carbamoyl]-2-methyl-propyl]-4-fluoro-1-(2-fluoroprop-2-enoyl)-N-methyl-piperidine- 4-carboxamide The title compound was prepared in analogy to the preparation of Example 1 by using (7S,13S)-7-amino-23,23-difluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]- 17,17-dimethyl-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaene- 8,14-dione (intermediate M), 1-tert-butoxycarbonyl-4-fluoro-piperidine-4-carboxylic acid and 2- fluoroprop-2-enoic acid instead of (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1- methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33- triazahexacyclo[26.3.1.12,6.120,24.04,14.05,12]tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaene- 19,25-dione (intermediate N), (3S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (compound 1e) and (2R)-2-chloro-2-fluoro-acetic acid (compound 1h). Example 40 (17.8 mg) was obtained as a yellow solid. MS calc’d 1078.5 (MH+), measured 1078.5 (MH+).1H NMR (400 MHz, METHANOL-d4) δ = 8.54 (s, 1H), 8.41 (d, J = 2.8 Hz, 1H), 7.84 (s, 1H), 7.58 (d, J = 16.4 Hz, 2H), 5.84 - 5.73 (m, 1H), 5.32 - 5.26 (m, 1H), 5.24 - 5.17 (m, 1H), 4.72 (d, J = 11.2 Hz, 1H), 4.60 - 4.54 (m, 1H), 4.52 - 4.40 (m, 2H), 4.24 (dd, J = 3.2, 12.0 Hz, 1H), 4.10 - 3.96 (m, 2H), 3.88 – 3.84 (m, 4H), 3.82 - 3.72 (m, 2H), 3.69 - 3.51 (m, 3H), 3.44 - 3.42 (m, 6H), 3.40 - 3.36 (m, 1H), 3.30 - 3.21 (m, 2H), 3.18 (d, J = 5.2 Hz, 3H), 3.13 - 3.07 (m, 1H), 2.84 - 2.76 (m, 1H), 2.75 - 2.67 (m, 1H), 2.33 - 2.13 (m, 6H), 1.99 - 1.91 (m, 1H), 1.84 - 1.73 (m, 1H), 1.68 - 1.59 (m, 1H), 1.50 (d, J = 6.4 Hz, 3H), 1.37 - 1.25 (m, 1H), 1.12 - 1.04 (m, 1H), 1.03 - 0.94 (m, 6H), 0.87 (d, J = 6.8 Hz, 3H), 0.63 (s, 3H). Example 41 1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(7S,13S)-23,23-difluoro-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia- 9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(29),2,5(31),19,25,27- hexaen-7-yl]carbamoyl]-2-methyl-propyl]-4-fluoro-N-methyl-piperidine-4-carboxamide The title compound was prepared in analogy to the preparation of Example 1 by using (7S,13S)-7-amino-23,23-difluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]- 17,17-dimethyl-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaene- 8,14-dione (intermediate M) and 1-tert-butoxycarbonyl-4-fluoro-piperidine-4-carboxylic acid instead of (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]- 16,16-dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.12,6.120,24.04,14.05,12]tetratriaconta- 1(31),2,4,6(34),13,28(32),29-heptaene-19,25-dione (intermediate N) and (3S)-1-tert- butoxycarbonylpyrrolidine-3-carboxylic acid (compound 1e). Example 41 (13.7 mg) was obtained as a yellow solid. MS calc’d 1100.4 (MH+), measured 1100.5 (MH+).1H NMR (400 MHz, METHANOL-d4) δ = 8.54 (s, 1H), 8.44 - 8.39 (m, 1H), 7.90 - 7.80 (m, 1H), 7.65 - 7.53 (m, 2H), 7.13 - 6.92 (m, 1H), 5.85 - 5.71 (m, 1H), 4.77 - 4.66 (m, 1H), 4.61 - 4.54 (m, 1H), 4.52 - 4.39 (m, 2H), 4.38 - 4.29 (m, 1H), 4.28 - 4.19 (m, 1H), 4.10 - 3.90 (m, 2H), 3.88 - 3.84 (m, 4H), 3.82 - 3.72 (m, 2H), 3.71 - 3.57 (m, 2H), 3.55 - 3.50 (m, 1H), 3.44 - 3.41 (m, 6H), 3.40 - 3.33 (m, 1H), 3.28 - 3.23 (m, 1H), 3.20 - 3.15 (m, 3H), 3.14 - 3.06 (m, 1H), 2.84 - 2.66 (m, 2H), 2.42 - 2.09 (m, 6H), 1.97 - 1.91 (m, 1H), 1.83 - 1.73 (m, 1H), 1.67 - 1.58 (m, 1H), 1.50 (d, J = 6.0 Hz, 3H), 1.42 - 1.22 (m, 1H), 1.14 - 1.04 (m, 1H), 1.03 - 0.93 (m, 6H), 0.87 (d, J = 6.8 Hz, 3H), 0.70 - 0.56 (m, 3H). Example 42 N-[(1S)-1-[[(7S,13S)-23,23-difluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3- pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen- 7-yl]carbamoyl]-2-methyl-propyl]-4-fluoro-N-methyl-1-prop-2-enoyl-piperidine-4- carboxamide The title compound was prepared in analogy to the preparation of Example 1 by using (7S,13S)-7-amino-23,23-difluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]- 17,17-dimethyl-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaene- 8,14-dione (intermediate M), 1-tert-butoxycarbonyl-4-fluoro-piperidine-4-carboxylic acid and acrylic acid instead of (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3- pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33- triazahexacyclo[26.3.1.12,6.120,24.04,14.05,12]tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaene- 19,25-dione (intermediate N), (3S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (compound 1e) and (2R)-2-chloro-2-fluoro-acetic acid (compound 1h). Example 42 (10 mg) was obtained as a yellow solid. MS calc’d 1060.5 (MH+), measured 1060.8 (MH+).1H NMR (400 MHz, METHANOL-d4) δ = 8.54 (s, 1H), 8.41 (d, J = 2.8 Hz, 1H), 7.87 (s, 1H), 7.64 - 7.55 (m, 2H), 6.87 - 6.77 (m, 1H), 6.25 (d, J = 16.8 Hz, 1H), 5.83 - 5.72 (m, 2H), 4.72 (d, J = 11.2 Hz, 1H), 4.61 - 4.56 (m, 1H), 4.51 - 4.38 (m, 3H), 4.28 - 4.21 (m, 1H), 4.12 - 3.99 (m, 2H), 3.86 (t, J = 4.8 Hz, 4H), 3.82 - 3.73 (m, 2H), 3.70 - 3.63 (m, 1H), 3.58 - 3.53 (m, 1H), 3.44 (s, 7H), 3.27 - 3.23 (m, 1H), 3.18 (d, J = 5.2 Hz, 3H), 3.15 - 3.08 (m, 1H), 3.04 - 2.98 (m, 1H), 2.86 - 2.76 (m, 1H), 2.74 - 2.66 (m, 1H), 2.31 - 2.14 (m, 5H), 2.00 - 1.91 (m, 1H), 1.86 - 1.73 (m, 1H), 1.68 - 1.58 (m, 1H), 1.50 (d, J = 6.4 Hz, 3H), 1.40 - 1.33 (m, 3H), 1.02 (s, 3H), 0.98 (d, J = 6.4 Hz, 3H), 0.92 - 0.83 (m, 3H), 0.63 (s, 3H). Example 43 1-but-2-ynoyl-N-[(1S)-1-[[(7S,13S)-23,23-difluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5- morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen- 7-yl]carbamoyl]-2-methyl-propyl]-4-fluoro-N-methyl-piperidine-4-carboxamide The title compound was prepared in analogy to the preparation of Example 1 by using (7S,13S)-7-amino-23,23-difluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]- 17,17-dimethyl-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaene- 8,14-dione (intermediate M), 1-tert-butoxycarbonyl-4-fluoro-piperidine-4-carboxylic acid and but-2-ynoic acid instead of (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1- methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33- triazahexacyclo[26.3.1.12,6.120,24.04,14.05,12]tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaene- 19,25-dione (intermediate N), (3S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (compound 1e) and (2R)-2-chloro-2-fluoro-acetic acid (compound 1h). Example 43 (18.1 mg) was obtained as a yellow solid. MS calc’d 1072.5 (MH+), measured 1072.7 (MH+).1H NMR (400 MHz, METHANOL-d4) δ = 8.55 (s, 1H), 8.41 (d, J = 2.8 Hz, 1H), 7.90 - 7.85 (m, 1H), 7.61 (d, J = 3.2 Hz, 1H), 7.57 (d, J = 4.0 Hz, 1H), 5.83 - 5.73 (m, 1H), 4.72 (d, J = 11.2 Hz, 1H), 4.61 - 4.55 (m, 1H), 4.48 - 4.30 (m, 4H), 4.28 - 4.20 (m, 1H), 4.08 - 3.98 (m, 1H), 3.88 - 3.84 (m, 4H), 3.81 - 3.72 (m, 2H), 3.68 - 3.54 (m, 3H), 3.47 - 3.40 (m, 8H), 3.29 - 3.23 (m, 1H), 3.18 (t, J = 5.2 Hz, 3H), 3.13 - 3.08 (m, 1H), 3.07 - 2.93 (m, 1H), 2.85 - 2.76 (m, 1H), 2.74 - 2.66 (m, 1H), 2.33 - 2.10 (m, 6H), 2.06 (d, J = 6.8 Hz, 3H), 1.99 - 1.92 (m, 1H), 1.84 - 1.74 (m, 1H), 1.68 - 1.59 (m, 1H), 1.50 (d, J = 6.4 Hz, 3H), 1.05 - 1.00 (m, 3H), 0.98 (d, J = 6.4 Hz, 3H), 0.88 (d, J = 6.4 Hz, 3H), 0.67 - 0.59 (m, 3H). Example 44 4-fluoro-1-(2-fluoroprop-2-enoyl)-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]- 5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia- 9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine- 4-carboxamide The title compound was prepared in analogy to the preparation of Example 1 by using (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]- 17,17-dimethyl-15,24-dioxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaene- 8,14-dione (intermediate H), 1-tert-butoxycarbonyl-4-fluoro-piperidine-4-carboxylic acid and 2- fluoroprop-2-enoic acid instead of (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1- methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33- triazahexacyclo[26.3.1.12,6.120,24.04,14.05,12]tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaene- 19,25-dione (intermediate N), (3S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (compound 1e) and (2R)-2-chloro-2-fluoro-acetic acid (compound 1h). Example 44 (36.0 mg) was obtained as a light yellow solid. MS calc’d 1057.5 (MH+), measured 1057.6 (MH+).1H NMR (400 MHz, METHANOL-d4) δ = 8.48 (d, J = 2.8 Hz, 1H), 8.25 - 8.15 (m, 1H), 7.62 - 7.41 (m, 2H), 7.10 (s, 1H), 5.78 - 5.67 (m, 1H), 5.34 - 5.15 (m, 2H), 4.78 - 4.72 (m, 1H), 4.64 - 4.57 (m, 2H), 4.52 (q, J = 5.9 Hz, 1H), 4.42 (d, J = 11.1 Hz, 1H), 4.36 - 4.23 (m, 3H), 4.12 - 3.98 (m, 2H), 3.84 - 3.69 (m, 4H), 3.64 - 3.54 (m, 2H), 3.46 - 3.36 (m, 6H), 3.27 - 3.10 (m, 8H), 3.04 - 2.96 (m, 4H), 2.85 - 2.75 (m, 1H), 2.63 - 2.54 (m, 1H), 2.36 - 2.14 (m, 6H), 1.99 - 1.92 (m, 1H), 1.89 - 1.76 (m, 1H), 1.62 (d t, J = 8.9, 12.6 Hz, 1H), 1.46 (d, J = 6.1 Hz, 3H), 1.04 - 0.93 (m, 6H), 0.88 (d, J = 6.5 Hz, 3H), 0.52 (s, 3H). Example 45 4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]- 17,17,23,23-tetramethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen- 7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-1-prop-2-enoyl-piperidine-4-carboxamide 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]-5-morpholino-3-pyridyl]-17,17,23,23- tetramethyl-15,24-dioxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaene- 8,14-dione (intermediate K), 1-tert-butoxycarbonyl-4-fluoro-piperidine-4-carboxylic acid and acrylic acid instead of (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3- pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33- triazahexacyclo[26.3.1.12,6.120,24.04,14.05,12]tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaene- 19,25-dione (intermediate N), (3S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (compound 1e) and (2R)-2-chloro-2-fluoro-acetic acid (compound 1h). Example 45 (4.2 mg) was obtained as a yellow solid. MS calc’d 1054.5 (MH+), measured 1054.8 (MH+),1H NMR (400 MHz, Methanol-d4) δ = 8.48 - 8.40 (m, 1H), 8.38 (d, J = 2.8 Hz, 1H), 8.22 (s, 1H), 7.74 - 7.68 (m, 1H), 7.47 (d, J = 11.6 Hz, 1H), 7.12 - 7.06 (m, 1H), 6.88 - 6.78 (m, 1H), 6.25 (dd, J = 1.6 Hz, 16.4 Hz, 1H), 5.85 - 5.73 (m, 2H), 4.72 (d, J = 11.6 Hz, 1H), 4.69 - 4.63 (m, 1H), 4.50 - 4.38 (m, 2H), 4.25 (d, J = 11.6 Hz, 1H), 4.14 - 4.03 (m, 1H), 3.98 (d, J = 12.4 Hz, 1H), 3.86 (t, J = 4.4 Hz, 3H), 3.82 - 3.76 (m, 2H), 3.63 (d, J = 8.0 Hz, 1H), 3.59 - 3.47 (m, 1H), 3.43 - 3.38 (m, 6H), 3.19 (d, J = 5.2 Hz, 3H), 3.13 - 3.07 (m, 1H), 3.04 - 2.97 (m, 1H), 2.90 - 2.82 (m, 1H), 2.81 - 2.75 (m, 1H), 2.71 - 2.65 (m, 1H), 2.36 - 2.24 (m, 2H), 2.22 - 2.17 (m, 2H), 2.15 - 2.02 (m, 2H), 1.98 - 1.91 (m, 1H), 1.85 - 1.72 (m, 1H), 1.71 - 1.57 (m, 2H), 1.50 (t, J = 7.6 Hz, 6H), 1.35 (s, 4H), 0.99 (t, J = 9.2 Hz, 6H), 0.88 (d, J = 6.4 Hz, 3H), 0.65 (s, 3H). Example 46 4-fluoro-N-[(1S)-1-[[(7S,13S,22S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3- pyridyl]-17,17,22-trimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen- 7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-1-prop-2-enoyl-piperidine-4-carboxamide The title compound was prepared in analogy to the preparation of Example 1 by using (7S,13S,22S)-7-amino-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17,22- trimethyl-15,24-dioxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaene- 8,14-dione (intermediate L), 1-tert-butoxycarbonyl-4-fluoro-piperidine-4-carboxylic acid and acrylic acid instead of (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3- pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33- triazahexacyclo[26.3.1.12,6.120,24.04,14.05,12]tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaene- 19,25-dione (intermediate N), (3S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (compound 1e) and (2R)-2-chloro-2-fluoro-acetic acid (compound 1h). Example 46 (3.2 mg) was obtained as a white solid. MS calc’d 1040.5 (MH+), measured 1040.9 (MH+).1H NMR (400 MHz, Methanol-d4) δ = 8.41 (d, J = 2.8 Hz, 1H), 8.29 (d, J = 5.6 Hz, 1H), 7.42 - 7.35 (m, 2H), 7.08 (d, J = 17.6 Hz, 1H), 6.85 - 6.75 (m, 1H), 6.40 - 6.30 (m, 1H), 6.24 (dd, J = 16.8 Hz, J = 6.4 Hz, 1H), 5.84 - 5.73 (m, 1H), 4.59 (d, J = 11.2 Hz, 1H), 4.51 - 4.46 (m, 1H), 4.43 - 4.35 (m, 5H), 3.86 (t, J = 4.4 Hz, 4H), 3.80 (s, 1H), 3.16 (d, J = 15.2 Hz, 2H), 3.08 - 3.04 (m, 5H), 3.00 - 2.93 (m, 1H), 2.86 - 2.77 (m, 1H), 2.43 - 2.33 (m, 1H), 2.26 - 2.14 (m, 4H), 2.07 - 1.97 (m, 4H), 1.89 - 1.76 (m, 3H), 1.59 (d, J = 6.4 Hz, 4H), 1.29 (s, 6H), 1.16 (d, J = 6.8 Hz, 3H), 0.96 (s, 4H), 0.90 (t, J = 6.8 Hz, 3H), 0.83 (d, J = 5.6 Hz, 2H), 0.52 (s, 3H), 0.10 (s, 1H). Example 47 4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]- 17,17,23,23-tetramethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(29),2,5(31),19,25,27-hexaen-7- yl]carbamoyl]-2-methyl-propyl]-N-methyl-1-prop-2-enoyl-piperidine-4-carboxamide 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]-5-morpholino-3-pyridyl]-17,17,23,23-tetramethyl- 15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (intermediate R), 1-tert-butoxycarbonyl-4- fluoro-piperidine-4-carboxylic acid and acrylic acid instead of (20S,26S)-26-amino-30-hydroxy- (13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33- triazahexacyclo[26.3.1.12,6.120,24.04,14.05,12]tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaene- 19,25-dione (intermediate N), (3S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (compound 1e) and (2R)-2-chloro-2-fluoro-acetic acid (compound 1h). Example 47 (5.9 mg) was obtained as a white solid. MS calc’d 1052.5 (MH+), measured 1052.9 (MH+),1H NMR (500 MHz, METHANOL-d4) δ = 8.40 (br d, J = 2.9 Hz, 2H), 7.52 - 7.44 (m, 1H), 7.44 - 7.36 (m, 1H), 7.21 (d, J = 2.6 Hz, 1H), 6.87 - 6.77 (m, 1H), 6.29 - 6.20 (m, 1H), 5.79 (dd, J = 1.8, 10.7 Hz, 1H), 4.74 - 4.70 (m, 1H), 4.66 - 4.53 (m, 3H), 4.49 - 4.39 (m, 3H), 4.27 - 4.19 (m, 1H), 4.14 - 4.04 (m, 1H), 3.87 - 3.84 (m, 4H), 3.82 - 3.72 (m, 3H), 3.58 - 3.50 (m, 1H), 3.39 (br s, 2H), 3.22 - 3.16 (m, 3H), 3.05 - 2.97 (m, 2H), 2.95 - 2.87 (m, 2H), 2.85 - 2.77 (m, 2H), 2.76 - 2.71 (m, 1H), 2.69 - 2.63 (m, 1H), 2.35 - 2.25 (m, 2H), 2.18 (br s, 3H), 2.03 (s, 1H), 1.97 - 1.91 (m, 1H), 1.83 - 1.71 (m, 1H), 1.67 - 1.55 (m, 2H), 1.49 - 1.42 (m, 3H), 1.34 - 1.23 (m, 3H), 1.13 (s, 3H), 1.00 - 0.96 (m, 3H), 0.94 - 0.91 (m, 3H), 0.90 - 0.83 (m, 6H), 0.64 - 0.55 (m, 3H). BIOLOGICAL EXAMPLE Example 48 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) G12D IC50 (µM) G12V IC50 (µM) Example 1 0.049 5.079 5.535 Example 2 0.049 5.779 5.557 Example 3 0.019 1.621 1.881 Example 4 0.013 0.597 0.318 Example 5 0.020 6.406 2.508 Example 6 0.003 2.753 4.650 Example 7 0.004 >10 >10 Example 8 0.022 2.357 1.959 Example 9 0.004 >10 >10 Example 10 0.015 2.762 2.840 Example 11 0.030 1.045 0.690 Example 12 0.026 2.528 2.772 Example 13 0.041 0.918 0.670 Example 14 0.073 4.040 4.046 Example 15 0.003 2.977 2.669 Example 16 0.003 2.498 0.951 Example 17 0.015 >10 >10 Example 18 0.002 0.036 0.029 Example 19 0.057 2.879 2.334 Example 20 0.008 6.765 >10 Example 21 0.018 3.202 1.247 Example 22 0.027 4.499 5.793 Example 23 0.033 >1 >1 Example 24 0.024 >1 *0.153 Example 25 0.010 >1 >1 Example 26 0.029 >1 0.248 Example 27 0.002 0.292 0.107 Example 28 0.003 >1 0.505 Example 30 0.020 >1 >1 Example 31 0.003 >1 >1 Example 32 0.006 >1 >1 Example 33 0.016 >1 >1 Example 34 0.019 >1 >1 Example 35 0.020 >1 >1 Example 36 0.003 >1 >1 Example 37 0.022 >1 >1 Example 38 0.003 >1 >1 Example 39 0.010 >1 >1 Example 41 0.008 0.016 0.026 Example 42 0.011 >1 >1 Example 43 0.021 >1 >1 Example 45 0.022 >1 >1 Example 46 0.038 >1 0.427 Example 47 0.045 >1 >1 Example 49 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- BRAFRBDwere 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) G12D IC50 (μM) G12V IC50 (μM) Example 1 0.036 >10 >10 Example 2 0.018 >10 >10 Example 3 0.173 >10 >10 Example 4 0.006 1.878 0.164 Example 5 0.016 3.910 0.445 Example 6 0.066 >10 >10 Example 7 0.081 >10 >10 Example 9 0.064 >10 >10 Example 11 0.080 >10 >10 Example 12 0.059 >10 >10 Example 13 0.097 6.847 >10 Example 15 0.087 >10 >10 Example 16 0.242 >10 >10 Example 17 0.111 >10 >10 Example 18 0.079 >10 >10 Example 19 0.147 >10 >10 Example 20 0.236 >10 >10 Example 21 0.079 >10 >10 Example 25 0.091 >10 >10 Example 27 0.083 >10 >10 Example 30 0.322 0.406 0.479 Example 31 0.188 >10 >10 Example 32 0.115 >10 >10 Example 33 0.250 >10 >10 Example 34 1.039 >10 >10 Example 36 0.131 >10 >10 Example 37 0.325 >10 >10 Example 38 0.120 >10 >10 Example 39 0.553 >10 >10 Example 44 0.292 >10 >10 Example 46 0.091 0.811 1.161 Example 50 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) G12D IC50(µM) G12V IC50(µM) Example 1 0.311 >10 >10 Example 2 0.036 5.180 2.077 Example 3 0.017 >10 >10 Example 4 0.009 0.803 0.571 Example 5 0.071 5.200 1.596 Example 6 0.012 >10 1.645 Example 7 0.022 >10 >10 Example 8 0.024 >10 >10 Example 9 0.016 >10 >10 Example 10 0.020 >10 9.762 Example 11 0.032 >10 >10 Example 12 0.010 >10 6.226 Example 13 0.007 5.650 >10 Example 14 0.030 >10 5.438 Example 15 0.002 >10 0.036 Example 16 0.010 >10 0.042 Example 17 0.024 >10 2.353 Example 18 0.001 >10 0.023 Example 19 0.075 >10 >10 Example 20 0.019 0.062 0.038 Example 21 0.007 >10 0.104 Example 22 0.029 >10 0.081 Example 23 0.014 >1 >1 Example 24 0.014 0.502 0.035 Example 25 0.004 >1 0.045 Example 26 0.015 0.210 0.042 Example 27 0.002 0.713 0.115 Example 28 0.003 0.595 0.045 Example 29 0.014 0.887 0.023 Example 30 0.005 >1 0.027 Example 31 0.005 >1 0.056 Example 32 0.005 >1 0.061 Example 33 0.016 >1 0.069 Example 34 0.017 >1 0.311 Example 35 0.033 >1 0.439 Example 36 0.003 >1 0.040 Example 37 0.040 >1 >1 Example 38 0.004 >1 0.018 Example 39 0.007 >1 0.635 Example 40 0.053 >1 0.212 Example 41 0.006 >1 0.614 Example 42 0.005 >1 0.374 Example 43 0.014 >1 0.190 Example 44 0.029 >1 0.047 Example 45 0.014 >1 0.321 Example 46 0.019 >1 0.208 Example 47 0.021 >1 >1

Claims

CLAIMS 1. A compound of formula (I),wherein 1R is , 1-oxo-2,7-diazaspiro[4.4]nonanyl substituted by C2-6alkynylcarbonyl, or 5-oxo-2,6-diazaspiro[3.4]octanyl substituted by (dihaloC1-6alkyl)carbonyl, C2- 6alkenylcarbonyl, C2-6alkynylcarbonyl or haloC2-6alkenylcarbonyl; wherein R5is C1-6alkyl; R6is C3-7cycloalkyl substituted by haloC2-6alkynyl, piperidyl once or twice substituted by substituents independently selected from (dihaloC1-6alkyl)carbonyl, C2-6alkenylcarbonyl, C2- 6alkynylcarbonyl, halogen and haloC2-6alkenylcarbonyl, or pyrrolidinyl substituted by (dihaloC1-6alkyl)carbonyl, C2- 6alkenylcarbonyl, C2-6alkynylcarbonyl or morpholinoC2- 6alkynylcarbonyl; R2is C1-6alkyl; R3is H, morpholino, (haloC1-6alkyl)piperazinyl or C1-6alkylpiperazinyl; R4is C1-6alkoxyC1-6alkyl; A1is hydroxyphenylene or thiazolylene; A2is C1-6alkylene;M is O or CH2; L is C1-6alkylene or haloC1-6alkylene; or a pharmaceutically acceptable salt thereof.

2. A compound of formula (Ia),wherein 1R is , 1-oxo-2,7-diazaspiro[4.4]nonanyl substituted by C2-6alkynylcarbonyl, or 5-oxo-2,6-diazaspiro[3.4]octanyl substituted by (dihaloC1-6alkyl)carbonyl, C2- 6alkenylcarbonyl, C2-6alkynylcarbonyl or haloC2-6alkenylcarbonyl; wherein R5is C1-6alkyl; R6is C3-7cycloalkyl substituted by haloC2-6alkynyl, piperidyl once or twice substituted by substituents independently selected from (dihaloC1-6alkyl)carbonyl, C2-6alkenylcarbonyl, C2- 6alkynylcarbonyl, halogen and haloC2-6alkenylcarbonyl, or pyrrolidinyl substituted by (dihaloC1-6alkyl)carbonyl, C2- 6alkenylcarbonyl, C2-6alkynylcarbonyl or morpholinoC2- 6alkynylcarbonyl; R2is C1-6alkyl; R3is H, morpholino, (haloC1-6alkyl)piperazinyl or C1-6alkylpiperazinyl;R4is C1-6alkoxyC1-6alkyl; A1is hydroxyphenylene or thiazolylene; A2is C1-6alkylene; M is O or CH2; L is C1-6alkylene or haloC1-6alkylene; or a pharmaceutically acceptable salt thereof.

3. A compound according to claim 1 or 2, wherein R1is , wherein R5is C1- 6alkyl; R6is piperidyl twice substituted by substituents independently selected from (dihaloC1- 6alkyl)carbonyl, C2-6alkenylcarbonyl, halogen and haloC2-6alkenylcarbonyl. compound according to any one of claims 1-3, wherein R14. A is , wherein R5is C1-6alkyl; R6is piperidyl substituted by halogen and another substituent selected from (dihaloC1-6alkyl)carbonyl, C2-6alkenylcarbonyl and haloC2-6alkenylcarbonyl.

5. A compound according to any one of claims 1-4, wherein, wherein R5is methyl; R6is 4-fluoro-1-prop-2-enoyl-4-piperidyl, 4-fluoro-1-(2-fluoroprop-2-enoyl)-4- piperidyl, 4-fluoro-1-(2-chloro-2-fluoro-acetyl)-4-piperidyl or 4-fluoro-1-prop-2-enoyl-4- piperidyl.

6. A compound according to any one of claims 1-5, wherein R2is isopropyl.

7. A compound according to any one of claims 1-6, wherein R3is morpholino or C1- 6alkylpiperazinyl.

8. A compound according to any one of claims 1-7, wherein R3is morpholino or 4- methylpiperazin-1-yl.

9. A compound according to any one of claims 1-8, wherein R4is 1-methoxyethyl.

10. A compound according to any one of claims 1-9, wherein A1is, wherein bond “a” connects to tricyclic ring.

11. A compound according to any one of claims 1-10, wherein A2is dimethylmethylene.

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

13. A compound according to any one of claims 1-12, wherein L is C1-6alkylene.

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

15. A compound according to claim 1 or 2, wherein R1is , wherein R5is C1-6alkyl; R6is piperidyl substituted by halogen and another substituent selected from (dihaloC1-6alkyl)carbonyl, C2-6alkenylcarbonyl and haloC2-6alkenylcarbonyl; R2is C1-6alkyl; R3is morpholino or C1-6alkylpiperazinyl; R4is C1-6alkoxyC1-6alkyl;A1is , wherein bond “a” connects to tricyclic ring; A2is C1-6alkylene; M is O; L is C1-6alkylene; or a pharmaceutically acceptable salt thereof.

16. A compound according to claim 15, wherein R1is , wherein R5is methyl; R6is 4-fluoro-1-prop-2-enoyl-4-piperidyl, 4- fluoro-1-(2-fluoroprop-2-enoyl)-4-piperidyl, 4-fluoro-1-[(2R)-2-chloro-2-fluoro- acetyl]-4-piperidyl or 4-fluoro-1-prop-2-enoyl-4-piperidyl; R2is isopropyl; R3is morpholino or 4-methylpiperazin-1-yl; R4is (1S)-1-methoxyethyl; A1is, wherein bond “a” connects to tricyclic ring; A2is dimethylmethylene; M is O; L is ethylene; or a pharmaceutically acceptable salt thereof.

17. A compound selected from: (3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(20S,26S)-30-hydroxy-(13M)-13-[2- [(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-19,25-dioxo-7,18-dioxa-12,24,33- triazahexacyclo[26.3.1.12,6.120,24.04,14.05,12]tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaen- 26-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide;(3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(19S,25S)-29-hydroxy-(12M)-12-[2- [(1S)-1-methoxyethyl]-3-pyridyl]-15,15-dimethyl-18,24-dioxo-7,17-dioxa-11,23,32- triazahexacyclo[25.3.1.12,6.119,23.04,13.05,11]tritriaconta-1(30),2,4,6(33),12,27(31),28-heptaen-25- yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide; 1-[(2R)-2-chloro-2-fluoro-acetyl]-4-fluoro-N-[(1S)-1-[[(19S,25S)-29-hydroxy-(12M)-12- [2-[(1S)-1-methoxyethyl]-3-pyridyl]-15,15-dimethyl-18,24-dioxo-7,17-dioxa-11,23,32- triazahexacyclo[25.3.1.12,6.119,23.04,13.05,11]tritriaconta-1(30),2,4,6(33),12,27(31),28-heptaen-25- yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide; (3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(18S,24S)-28-hydroxy-(11M)-11-[(3R)- 2-[(1S)-1-methoxyethyl]-2,3-dihydropyridin-3-yl]-14,14-dimethyl-17,23-dioxo-16-oxa-10,22,31- triazahexacyclo[24.3.1.12,6.118,22.04,12.05,10]dotriaconta-1(29),2,4,6(32),11,26(30),27-heptaen-24- yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide; (3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(18S,24S)-28-hydroxy-(11M)-11-[2- [(1S)-1-methoxyethyl]-3-pyridyl]-14,14-dimethyl-17,23-dioxo-7,16-dioxa-10,22,31- triazahexacyclo[24.3.1.12,6.118,22.04,12.05,10]dotriaconta-1(29),2,4,6(32),11,26(30),27-heptaen-24- yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide; (3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia- 9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26- hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide; (2S)-2-[2-[(2R)-2-chloro-2-fluoro-acetyl]-5-oxo-2,6-diazaspiro[3.4]octan-6-yl]-N- [(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3- pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7- yl]-3-methyl-butanamide; (2S)-2-(2-but-2-ynoyl-5-oxo-2,6-diazaspiro[3.4]octan-6-yl)-N-[(7S,13S)-(20M)-20-[2- [(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14- dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaen-7-yl]-3-methyl-butanamide; (2S)-2-[2-[(2R)-2-chloro-2-fluoro-acetyl]-5-oxo-2,6-diazaspiro[3.4]octan-6-yl]-N- [(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14- dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaen-7-yl]-3-methyl-butanamide;(2S)-2-(2-but-2-ynoyl-5-oxo-2,6-diazaspiro[3.4]octan-6-yl)-N-[(7S,13S)-(20M)-20-[2- [(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia- 9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26- hexaen-7-yl]-3-methyl-butanamide; (2S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17- dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7- yl]-3-methyl-2-(5-oxo-2-prop-2-enoyl-2,6-diazaspiro[3.4]octan-6-yl)butanamide; (3S)-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]- 17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7- yl]carbamoyl]-2-methyl-propyl]-N-methyl-1-(4-morpholinobut-2-ynoyl)pyrrolidine-3- carboxamide; (2S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin- 1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7- yl]-3-methyl-2-(5-oxo-2-prop-2-enoyl-2,6-diazaspiro[3.4]octan-6-yl)butanamide; (2S)-2-(2-but-2-ynoyl-5-oxo-2,6-diazaspiro[3.4]octan-6-yl)-N-[(7S,13S)-(20M)-20-[2- [(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15- oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaen-7-yl]-3-methyl-butanamide; 4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3- pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7- yl]carbamoyl]-2-methyl-propyl]-N-methyl-1-prop-2-enoyl-piperidine-4-carboxamide; 1-but-2-ynoyl-4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5- morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7- yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide; cis-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]- 17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-3-(3,3,3-trifluoroprop-1- ynyl)cyclobutanecarboxamide; 1-[(2R)-2-chloro-2-fluoro-acetyl]-4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7- yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide; (2S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3- pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7- yl]-3-methyl-2-(5-oxo-2-prop-2-enoyl-2,6-diazaspiro[3.4]octan-6-yl)butanamide; (2S)-2-[2-[(2R)-2-chloro-2-fluoro-acetyl]-5-oxo-2,6-diazaspiro[3.4]octan-6-yl]-N- [(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17- dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7- yl]-3-methyl-butanamide; cis-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)- 3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7- yl]carbamoyl]-2-methyl-propyl]-N-methyl-3-(3,3,3-trifluoroprop-1- ynyl)cyclobutanecarboxamide; (2S)-2-[2-(2-fluoroprop-2-enoyl)-5-oxo-2,6-diazaspiro[3.4]octan-6-yl]-N-[(7S,13S)-(20M)- 20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4- thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaen-7-yl]-3-methyl-butanamide; cis-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2- trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7- yl]carbamoyl]-2-methyl-propyl]-N-methyl-3-(3,3,3-trifluoroprop-1- ynyl)cyclobutanecarboxamide; 4-fluoro-1-(2-fluoroprop-2-enoyl)-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7- yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide;1-but-2-ynoyl-4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7- yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide; 4-fluoro-1-(2-fluoroprop-2-enoyl)-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia- 9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26- hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide; 1-[(2R)-2-chloro-2-fluoro-acetyl]-4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia- 9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26- hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide; 1-[(2R)-2-chloro-2-fluoro-acetyl]-4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia- 9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26- hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide; 4-fluoro-1-(2-fluoroprop-2-enoyl)-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia- 9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26- hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide; 1-but-2-ynoyl-4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5- morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7- yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide; 1-[(2R)-2-chloro-2-fluoro-acetyl]-4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4- thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4- carboxamide; 4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1- yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7- yl]carbamoyl]-2-methyl-propyl]-N-methyl-1-prop-2-enoyl-piperidine-4-carboxamide;1-but-2-ynoyl-4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7- yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide; (3R)-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]- 17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7- yl]carbamoyl]-2-methyl-propyl]-N-methyl-1-prop-2-enoyl-pyrrolidine-3-carboxamide; (3R)-1-but-2-ynoyl-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5- morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7- yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide; 4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1- yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7- yl]carbamoyl]-2-methyl-propyl]-N-methyl-1-prop-2-enoyl-piperidine-4-carboxamide; (2S)-2-[(5R)-7-but-2-ynoyl-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-N-[(7S,13S)-(20M)-20- [2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15- oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaen-7-yl]-3-methyl-butanamide; 4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3- pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7- yl]carbamoyl]-2-methyl-propyl]-N-methyl-1-prop-2-enoyl-piperidine-4-carboxamide; N-[(1S)-1-[[(7S,13S)-23,23-difluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7- yl]carbamoyl]-2-methyl-propyl]-4-fluoro-N-methyl-1-prop-2-enoyl-piperidine-4-carboxamide; N-[(1S)-1-[[(7S,13S)-23,23-difluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3- pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7- yl]carbamoyl]-2-methyl-propyl]-4-fluoro-1-(2-fluoroprop-2-enoyl)-N-methyl-piperidine-4- carboxamide;1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(7S,13S)-23,23-difluoro-(20M)-20-[2-[(1S)- 1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(29),2,5(31),19,25,27-hexaen-7- yl]carbamoyl]-2-methyl-propyl]-4-fluoro-N-methyl-piperidine-4-carboxamide; N-[(1S)-1-[[(7S,13S)-23,23-difluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3- pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7- yl]carbamoyl]-2-methyl-propyl]-4-fluoro-N-methyl-1-prop-2-enoyl-piperidine-4-carboxamide; 1-but-2-ynoyl-N-[(1S)-1-[[(7S,13S)-23,23-difluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5- morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7- yl]carbamoyl]-2-methyl-propyl]-4-fluoro-N-methyl-piperidine-4-carboxamide; 4-fluoro-1-(2-fluoroprop-2-enoyl)-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4- thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4- carboxamide; 4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3- pyridyl]-17,17,23,23-tetramethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7- yl]carbamoyl]-2-methyl-propyl]-N-methyl-1-prop-2-enoyl-piperidine-4-carboxamide; 4-fluoro-N-[(1S)-1-[[(7S,13S,22S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3- pyridyl]-17,17,22-trimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7- yl]carbamoyl]-2-methyl-propyl]-N-methyl-1-prop-2-enoyl-piperidine-4-carboxamide; and 4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3- pyridyl]-17,17,23,23-tetramethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(29),2,5(31),19,25,27-hexaen-7- yl]carbamoyl]-2-methyl-propyl]-N-methyl-1-prop-2-enoyl-piperidine-4-carboxamide; or a pharmaceutically acceptable salt thereof.

18. A process for the preparation of a compound according to any one of claims 1 to 17 comprising any of the following steps:a) coupling reaction between compound of formula (II),presence of a coupling reagent and a base to form the compound of formula (I); b) coupling reaction between compound of formula (VI),the presence of a coupling reagent and a base to form the compound of formula (VIII),c) coupling reaction between compound of formula (XI),(XII), in the presence of a coupling reagent and a base to form the compound of formula (XIII),wherein Q is unsubstituted or substituted piperidinylene or pyrrolidinylene; T is dihaloC1- 6alkyl, C2-6alkenyl, C2-6alkynyl, haloC2-6alkenyl or morpholinoC2-6alkynyl; R1to R6, A1, A2, M and L are defined as in any one of claims 1 to 16; the coupling reagent in step a) to c) is T3P, HATU, PyBOP or EDCI / HOBt; the base in step a) to c) is TEA, DIEPA or DMAP.

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

20. A pharmaceutical composition comprising a compound in accordance with any one of claims 1 to 17 and a pharmaceutically acceptable excipient.

21. The use of a compound according to any one of claims 1 to 17 for treating a KRAS G12C protein-related disease.

22. The use of a compound according to any one of claims 1 to 17 for treating a KRAS G12C, G12D and G12V protein-related disease.

23. The use of a compound according to any one of claims 1 to 17 for inhibiting RAS interaction with downstream effectors, wherein the downstream effectors are RAF and PI3K.

24. The use of a compound according to any one of claims 1 to 17 for inhibiting the propagating oncogenic MAPK and PI3K signaling.

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

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

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

29. 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 17.

30. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 17, when manufactured according to a process of claim 18.

31. The invention as hereinbefore described.

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