Macrocyclic compounds for the treatment of cancer

Abstract

The present invention relates to compounds of formula (I), wherein R1 to R5, A1 to A4 are as described herein, and their pharmaceutically acceptable salt, enantiomers and diastereomers thereof, and compositions including the compounds and methods of using the compounds.

Description

[0001] Case 39390 Macrocyclic 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 cancer. 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, G12V represent more than half of all KRAS-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 characterizing 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 emerging rigorously with disease progresses after around 6 months 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 myriads of escape mechanisms and various oncogenic alleles highlight the urgent medical need for additional RAS therapies. As such, we invented oral compounds that target and inhibit RAS alleles for the treatment of RAS mutant driven cancers. SUMMARY OF THE INVENTION The present invention relates to novel compounds of formula (I), wherein R1is 3-oxabicyclo[3.1.0]hexanyl, or C3-7cycloalkyl substituted once or twice by the substituents independently selected from a group consisting of C1-6alkyl, haloC1-6alkyl, C1-6alkylpyrimidinyl, C3-7cycloalkyl, phenyl, pyridyl and pyrimidinyl; R2is morpholino or C1-6alkylpiperazinyl; R3is C1-6alkoxyC1-6alkyl; R4is C1-6alkyl and R5is H, or R4and R5together with the atoms they are attached to form a 6- or 7-membered heterocycle ring; A1is 2,3-diazabicyclo[3.1.1]heptanylene, 2,3-diazabicyclo[3.2.1]octanylene, 2,3-diazabicyclo[4.1.0]heptanylene, 3,4-diazabicyclo[4.1.0]heptanylene which is unsubstituted, or substituted once, twice or three times by the substituents independently selected from a group consisting of C1-6alkyl and halogen, 3,4-diazabicyclo[4.2.0]octanylene, 5,6-diazaspiro[2.5]octanylene, halo-1,2,3,6-tetrahydropyridazinylene, or 7-oxa-2,3-diazabicyclo[3.3.1]nonanylene; A2is C1-6alkylene; A3is thiazolylene or hydroxyphenylene; A4is C1-6alkylene or C3-7cycloalkylene; or a pharmaceutically acceptable salt, enantiomers and diastereomers thereof. The invention also relates to their manufacturing 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) showed good KRAS inhibition for G12C, G12D and G12V. 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 divalent C1-6alkyl. Examples of C1-6alkylene groups include methylene, ethylene, propylene, 2-methylpropylene, butylene, 2-ethylbutylene, pentylene, hexylene. The term “C1-6alkoxy” denotes C1-6alkyl-O-. 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 alkynyl 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 has been replaced by same or different halogen atoms, particularly fluoro atoms. Examples of haloalkyl include monofluoro-, difluoro- or trifluoro-methyl, -ethyl or -propyl, for example 3,3,3-trifluoropropyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, fluoromethyl, or trifluoromethyl. The term “haloC1-6alkylene” denotes a divalent haloC1-6alkyl. 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 of 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 “C3-7cycloalkylene” denotes a divalent C3-7cycloalkyl. The term “thiazolylene” denotes a divalent thiazolyl. The term “hydroxyphenylene” denotes a divalent hydroxyphenyl. The term “hexahydropyridazinylene” denotes a divalent hexahydropyridazinyl. The term “2,3-diazabicyclo[3.1.1]heptanylene” denotes a divalent 2,3- diazabicyclo[3.1.1]heptanyl. The term “2,3-diazabicyclo[3.2.1]octanylene” denotes a divalent 2,3- diazabicyclo[3.2.1]octanyl. The term “2,3-diazabicyclo[4.1.0]heptanylene” denotes a divalent 2,3- diazabicyclo[4.1.0]heptanyl. The term “3,4-diazabicyclo[4.1.0]heptanylene” denotes a divalent 3,4- diazabicyclo[4.1.0]heptanyl. The term “3,4-diazabicyclo[4.2.0]octanylene” denotes a divalent 3,4- diazabicyclo[4.2.0]octanyl. The term “5,6-diazaspiro[2.5]octanylene” denotes a divalent 5,6-diazaspiro[2.5]octanyl. The term “halo-1,2,3,6-tetrahydropyridazinylene” denotes a divalent 1,2,3,6- tetrahydropyridazinyl, wherein at least one of the hydrogen atoms of the 1,2,3,6- tetrahydropyridazinylene group has been replaced by same or different halogen atoms, particularly fluoro atom. The terms “heterocyclic group”, “heterocyclic”, “heterocycle”, “heterocyclyl”, or “heterocyclo” are used interchangeably and refer to any mono-, bi-, tricyclic, spiro or bridged, saturated, partially saturated or unsaturated, non-aromatic ring system, having 3 to 20 ring atoms, where the ring atoms are carbon, and at least one atom in the ring or ring system is a heteroatom selected from nitrogen, sulfur, oxygen or silicon. If any ring atom of a cyclic system is a heteroatom, that system is a heterocycle, regardless of the point of attachment of the cyclic system to the rest of the molecule. In one example, heterocyclyl includes 3-11 ring atoms (“members”) and includes monocycles, bicycles, tricycles, spiro, and bridged ring systems, wherein the ring atoms are carbon, where at least one atom in the ring or ring system is a heteroatom selected from nitrogen, sulfur, oxygen or silicon. In other examples, heterocyclyl includes 4-10 or 5-10 ring atoms. In one example, heterocyclyl includes 1 to 4 heteroatoms. In one example, heterocyclyl includes 1 to 3 heteroatoms. In another example, heterocyclyl includes 3- to 7-membered monocycles having 1-2, 1-3 or 1-4 heteroatoms selected from nitrogen, sulfur, oxygen or silicon. In another example, heterocyclyl includes 4- to 6-membered monocycles having 1-2, 1-3 or 1-4 heteroatoms selected from nitrogen, sulfur, oxygen or silicon. In another example, heterocyclyl includes 3-membered monocycles. In another example, heterocyclyl includes 4-membered monocycles. In another example, heterocyclyl includes 5-6 membered monocycles. In some embodiments, a heterocycloalkyl includes at least one nitrogen. In one example, the heterocyclyl group includes 0 to 3 double bonds. Any nitrogen or sulfur heteroatom may optionally be oxidized (e.g., NO, SO, SO2), and any nitrogen heteroatom may optionally be quaternized (e.g., [NR4]+Cl-, [NR4]+OH-). Examples of heterocycles include, but not limited to, oxiranyl, aziridinyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, 1,2-dithietanyl, 1,3- dithietanyl, pyrrolidinyl, dihydro-1H-pyrrolyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothienyl, tetrahydrothienyl, imidazolidinyl, piperidinyl, piperazinyl, isoquinolinyl, tetrahydroisoquinolinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, dihydropyranyl, tetrahydropyranyl, hexahydrothiopyranyl, hexahydropyrimidinyl, oxazinanyl, thiazinanyl, thioxanyl, homopiperazinyl, homopiperidinyl, azepanyl, oxepanyl, thiepanyl, oxazepinyl, oxazepanyl, diazepanyl, 1,4-diazepanyl, diazepinyl, thiazepinyl, thiazepanyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl, 1,1-dioxoisothiazolidinonyl, 1,1-dioxoisothiazolyl, oxazolidinonyl, imidazolidinonyl, 4,5,6,7-tetrahydro[2H]indazolyl, tetrahydrobenzoimidazolyl, 4,5,6,7-tetrahydrobenzo[d]imidazolyl, thiazinyl, oxazinyl, thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, oxathiazinyl, thiatriazinyl, oxatriazinyl, dithiadiazinyl, imidazolinyl, dihydropyrimidyl, tetrahydropyrimidyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, thiapyranyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl, pyrimidinonyl, pyrimidindionyl, pyrimidin-2,4-dionyl, piperazinonyl, piperazindionyl and pyrazolidinylimidazolinyl. 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 R1is 3-oxabicyclo[3.1.0]hexanyl, or C3-7cycloalkyl substituted once or twice by the substituents independently selected from a group consisting of C1-6alkyl, haloC1-6alkyl, C1-6alkylpyrimidinyl, C3-7cycloalkyl, phenyl, pyridyl and pyrimidinyl; R2is morpholino or C1-6alkylpiperazinyl; R3is C1-6alkoxyC1-6alkyl; R4is C1-6alkyl and R5is H, or R4and R5together with the atoms they are attached to form a 6- or 7-membered heterocycle ring; A1is 2,3-diazabicyclo[3.1.1]heptanylene, 2,3-diazabicyclo[3.2.1]octanylene, 2,3-diazabicyclo[4.1.0]heptanylene, 3,4-diazabicyclo[4.1.0]heptanylene which is unsubstituted, or substituted once, twice or three times by the substituents independently selected from a group consisting of C1-6alkyl and halogen, 3,4-diazabicyclo[4.2.0]octanylene, 5,6-diazaspiro[2.5]octanylene, halo-1,2,3,6-tetrahydropyridazinylene, or 7-oxa-2,3-diazabicyclo[3.3.1]nonanylene; A2is C1-6alkylene; A3is thiazolylene or hydroxyphenylene; A4is C1-6alkylene or C3-7cycloalkylene; or a pharmaceutically acceptable salt, enantiomers and diastereomers thereof. Another embodiment of present invention is (ii) a compound of formula (Ia), wherein R1is 3-oxabicyclo[3.1.0]hexanyl, or C3-7cycloalkyl substituted once or twice by the substituents independently selected from a group consisting of C1-6alkyl, haloC1-6alkyl, C1-6alkylpyrimidinyl, C3- 7cycloalkyl, phenyl, pyridyl and pyrimidinyl; R2is morpholino or C1-6alkylpiperazinyl; R3is C1-6alkoxyC1-6alkyl; R4is C1-6alkyl and R5is H, or R4and R5together with the atoms they are attached to form a 6- or 7-membered heterocycle ring; A1is 2,3-diazabicyclo[3.1.1]heptanylene, 2,3-diazabicyclo[3.2.1]octanylene, 2,3-diazabicyclo[4.1.0]heptanylene, 3,4-diazabicyclo[4.1.0]heptanylene which is unsubstituted, or substituted once, twice or three times by the substituents independently selected from a group consisting of C1-6alkyl and halogen, 3,4-diazabicyclo[4.2.0]octanylene, 5,6-diazaspiro[2.5]octanylene, halo-1,2,3,6-tetrahydropyridazinylene, or 7-oxa-2,3-diazabicyclo[3.3.1]nonanylene; A2is C1-6alkylene; A3is thiazolylene or hydroxyphenylene; A4is C1-6alkylene or C3-7cycloalkylene; or a pharmaceutically acceptable salt, enantiomers and diastereomers 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, enantiomers and diastereomers thereof, wherein R1is C3-7cycloalkyl substituted once or twice by the substituents independently selected from a group consisting of C1-6alkyl, haloC1-6alkyl, C1-6alkylpyrimidinyl, pyridyl and pyrimidinyl. 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, enantiomers and diastereomers thereof, wherein R1is cyclopropyl substituted once or twice by the substituents independently selected from a group consisting of methyl, difluoromethyl, methylpyrimidinyl, pyridyl and pyrimidinyl. A further embodiment of present invention is (v) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, enantiomers and diastereomers thereof, according to any one of (i) to (iv), wherein R1is 2-(2-methylpyrimidin-5-yl)cyclopropyl, 2-(3-pyridyl)cyclopropyl, 2,3- dimethyl-cyclopropyl, 2-difluoromethyl-cyclopropyl or 2-pyrimidin-5-yl-cyclopropyl. A further embodiment of present invention is (vi) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, enantiomers and diastereomers thereof, according to any one of (i) to (v), wherein R2is morpholino or 4-methylpiperazin-1-yl. A further embodiment of present invention is (vii) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, enantiomers and diastereomers thereof, according to any one of (i) to (vi), wherein R3is 1-methoxyethyl. A further embodiment of present invention is (viii) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, enantiomers and diastereomers thereof, according to any one of (i) to (vii), w wherein R4is ethyl and R5is H. A further embodiment of present invention is (ix) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, enantiomers and diastereomers thereof, according to any one of (i) to (viii), wherein A1is 2,3-diazabicyclo[3.2.1]octanylene. A further embodiment of present invention is (x) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, enantiomers and diastereomers thereof, according to any one of (i) to (ix), wherein A further embodiment of present invention is (xi) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, enantiomers and diastereomers thereof, according to any one of (i) to (x), wherein A3is thiazolylene. A further embodiment of present invention is (xii) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, enantiomers and diastereomers thereof, according to any one of (i) to (xi), wherein A4is methylene. A further embodiment of present invention is (xiii) a compound of formula (I) or (Ia), according to any one of (i) to (xii), wherein R1is C3-7cycloalkyl substituted once or twice by the substituents independently selected from a group consisting of C1-6alkyl, haloC1-6alkyl, C1-6alkylpyrimidinyl, pyridyl and pyrimidinyl; R2is morpholino or C1-6alkylpiperazinyl; R3is C1-6alkoxyC1-6alkyl; R4is C1-6alkyl; R5is H; A1is 2,3-diazabicyclo[3.2.1]octanylene; A2is C1-6alkylene; A3is thiazolylene; A4is C1-6alkylene; or a pharmaceutically acceptable salt, enantiomers and diastereomers thereof. A further embodiment of present invention is (xiv) a compound of formula (I) or (Ia), according to any one of (i) to (xiii), wherein R1is 2-(2-methylpyrimidin-5-yl)cyclopropyl, 2-(3-pyridyl)cyclopropyl, 2,3-dimethyl- cyclopropyl, 2-difluoromethyl-cyclopropyl or 2-pyrimidin-5-yl-cyclopropyl; R2is morpholino or 4-methylpiperazin-1-yl; R3is 1-methoxyethyl; R4is ethyl; R5is H; A1is 2,3-diazabicyclo[3.2.1]octanylene; A3is thiazolylene; A4is methylene; or a pharmaceutically acceptable salt, enantiomers and diastereomers thereof. The present invention relates to (i’) a compound of formula (I), wherein R1is 3-oxabicyclo[3.1.0]hexanyl, or C3-7cycloalkyl substituted once or twice by the substituents independently selected from a group consisting of C1-6alkyl, haloC1-6alkyl, C1-6alkylpyrimidinyl, C3- 7cycloalkyl, phenyl, pyridyl and pyrimidinyl; R2is morpholino, C1-6alkylpiperazinyl, (1,1-dioxo-1,4-thiazinanyl)C2-6alkynyl, (1,4- oxazepanyl)C2-6alkynyl, azetidinylC2-6alkynyl or morpholinoC2-6alkynyl; R3is C1-6alkoxyC1-6alkyl or C1-6alkyl; R4is C1-6alkyl and R5is H; or R4and R5together with the atoms they are attached to form a 6- or 7-membered heterocycle ring, wherein R4is C1-6alkylene or haloC1-6alkylene, R5is C1-6alkylene or O; A1is hexahydropyridazinylene, 2,3-diazabicyclo[3.1.1]heptanylene, 2,3-diazabicyclo[3.2.1]octanylene, 2,3-diazabicyclo[4.1.0]heptanylene, 3,4-diazabicyclo[4.1.0]heptanylene which is unsubstituted, or substituted once, twice or three times by the substituents independently selected from a group consisting of C1-6alkyl and halogen, 3,4-diazabicyclo[4.2.0]octanylene, 5,6-diazaspiro[2.5]octanylene, halo-1,2,3,6-tetrahydropyridazinylene, or 7-oxa-2,3-diazabicyclo[3.3.1]nonanylene; A2is C1-6alkylene; A3is thiazolylene or hydroxyphenylene; A4is C1-6alkylene or C3-7cycloalkylene; or a pharmaceutically acceptable salt, enantiomers and diastereomers thereof. Another embodiment of present invention is (ii’) a compound of formula (Ia), wherein R1is 3-oxabicyclo[3.1.0]hexanyl, or C3-7cycloalkyl substituted once or twice by the substituents independently selected from a group consisting of C1-6alkyl, haloC1-6alkyl, C1-6alkylpyrimidinyl, C3- 7cycloalkyl, phenyl, pyridyl and pyrimidinyl; R2is morpholino, C1-6alkylpiperazinyl, (1,1-dioxo-1,4-thiazinanyl)C2-6alkynyl, (1,4- oxazepanyl)C2-6alkynyl, azetidinylC2-6alkynyl or morpholinoC2-6alkynyl; R3is C1-6alkoxyC1-6alkyl or C1-6alkyl; R4is C1-6alkyl and R5is H; or R4and R5together with the atoms they are attached to form a 6- or 7-membered heterocycle ring, wherein R4is C1-6alkylene or haloC1-6alkylene, R5is C1-6alkylene or O; A1is hexahydropyridazinylene, 2,3-diazabicyclo[3.1.1]heptanylene, 2,3-diazabicyclo[3.2.1]octanylene, 2,3-diazabicyclo[4.1.0]heptanylene, 3,4-diazabicyclo[4.1.0]heptanylene which is unsubstituted, or substituted once, twice or three times by the substituents independently selected from a group consisting of C1-6alkyl and halogen, 3,4-diazabicyclo[4.2.0]octanylene, 5,6-diazaspiro[2.5]octanylene, halo-1,2,3,6-tetrahydropyridazinylene, or 7-oxa-2,3-diazabicyclo[3.3.1]nonanylene; A2is C1-6alkylene; A3is thiazolylene or hydroxyphenylene; A4is C1-6alkylene or C3-7cycloalkylene; or a pharmaceutically acceptable salt, enantiomers and diastereomers 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, enantiomers and diastereomers thereof, wherein R1is C3-7cycloalkyl substituted once or twice by the substituents independently selected from a group consisting of C1-6alkyl, haloC1-6alkyl, C1-6alkylpyrimidinyl, pyridyl and pyrimidinyl. 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, enantiomers and diastereomers thereof, wherein R1is cyclopropyl substituted once or twice by the substituents independently selected from a group consisting of methyl, difluoromethyl, methylpyrimidinyl, pyridyl and pyrimidinyl. A further embodiment of present invention is (v’) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, enantiomers and diastereomers thereof, according to any one of (i’) to (iv’), wherein R1is 2-(2-methylpyrimidin-5-yl)cyclopropyl, 2-(3-pyridyl)cyclopropyl, 2,3- dimethyl-cyclopropyl, 2-difluoromethyl-cyclopropyl or 2-pyrimidin-5-yl-cyclopropyl. A further embodiment of present invention is (vi’) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, enantiomers and diastereomers thereof, according to any one of (i’) to (v’), wherein R2is morpholino or 4-methylpiperazin-1-yl. A further embodiment of present invention is (vii’) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, enantiomers and diastereomers thereof, according to any one of (i’) to (vi’), wherein R3is 1-methoxyethyl. A further embodiment of present invention is (viii’) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, enantiomers and diastereomers thereof, according to any one of (i’) to (vii’), w wherein R4is ethyl and R5is H. A further embodiment of present invention is (ix’) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, enantiomers and diastereomers thereof, according to any one of (i’) to (viii’), wherein R4and R5together with the atoms they are attached to form a 6- or 7- membered heterocycle ring; wherein R4is ethylene, propylene or difluoroethylene; R5is methylene or O. A further embodiment of present invention is (x’) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, enantiomers and diastereomers thereof, according to any one of (i’) to (ix’), wherein A1is 2,3-diazabicyclo[3.2.1]octanylene. A further embodiment of present invention is (xi’) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, enantiomers and diastereomers thereof, according to any one of (i’) to (x’), wherein A further embodiment of present invention is (xii’) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, enantiomers and diastereomers thereof, according to any one of (i’) to (xi’), wherein A3is thiazolylene. A further embodiment of present invention is (xiii’) a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, enantiomers and diastereomers thereof, according to any one of (i’) to (xi’), wherein A4is methylene. A further embodiment of present invention is (xiv’) a compound of formula (I) or (Ia), according to any one of (i’) to (xiii’), wherein R1is C3-7cycloalkyl substituted once or twice by the substituents independently selected from a group consisting of C1-6alkyl, haloC1-6alkyl, C1-6alkylpyrimidinyl, pyridyl and pyrimidinyl; R2is morpholino or C1-6alkylpiperazinyl; R3is C1-6alkoxyC1-6alkyl; R4is C1-6alkyl; R5is H; or R4and R5together with the atoms they are attached to form a 6- or 7-membered heterocycle ring, wherein R4is C1-6alkylene or haloC1-6alkylene, R5is C1-6alkylene or O; A1is 2,3-diazabicyclo[3.2.1]octanylene; A2is C1-6alkylene; A3is thiazolylene; A4is C1-6alkylene; or a pharmaceutically acceptable salt, enantiomers and diastereomers thereof. A further embodiment of present invention is (xv’) a compound of formula (I) or (Ia), according to any one of (i’) to (xiv’), wherein R1is 2-(2-methylpyrimidin-5-yl)cyclopropyl, 2-(3-pyridyl)cyclopropyl, 2,3-dimethyl- cyclopropyl, 2-difluoromethyl-cyclopropyl or 2-pyrimidin-5-yl-cyclopropyl; R2is morpholino or 4-methylpiperazin-1-yl; R3is 1-methoxyethyl; R4is ethyl; R5is H; or R4and R5together with the atoms they are attached to form a 6- or 7-membered heterocycle ring; wherein R4is ethylene, propylene or difluoroethylene; R5is methylene or O; A1is 2,3-diazabicyclo[3.2.1]octanylene; A3is thiazolylene; A4is methylene; or a pharmaceutically acceptable salt, enantiomers and diastereomers thereof. Another embodiment of present invention is (xvi) a compound of formula (I) or (Ia) selected from the following: (1S,2S)-N-[(7S,11R,14S)-22-ethyl-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-18,18-dimethyl-8,15-dioxo-16-oxa-4-thia-9,22,29,30- tetrazahexacyclo[18.5.2.12,5.19,14.111,14.023,27]triaconta-1(26),2,5(30),20,23(27),24-hexaen-7-yl]- 2-(2-methylpyrimidin-5-yl)cyclopropanecarboxamide; (1R,2R)-N-[(7S,11R,14S)-22-ethyl-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-18,18-dimethyl-8,15-dioxo-16-oxa-4-thia-9,22,29,30- tetrazahexacyclo[18.5.2.12,5.19,14.111,14.023,27]triaconta-1(26),2,5(30),20,23(27),24-hexaen-7-yl]- 2-(2-methylpyrimidin-5-yl)cyclopropanecarboxamide; (1S,2S)-N-[(7S)-21-ethyl-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]- 17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,29,30- tetrazahexacyclo[17.5.2.210,13.12,5.19,13.022,26]triaconta-1(25),2,5(30),19,22(26),23-hexaen-7-yl]- 2-(2-pyridyl)cyclopropanecarboxamide; (2R,3S)-N-[(7S)-21-ethyl-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]- 17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,29,30- tetrazahexacyclo[17.5.2.210,13.12,5.19,13.022,26]triaconta-1(25),2,5(30),19,22(26),23-hexaen-7-yl]- 2,3-dimethyl-cyclopropanecarboxamide; (1S,2S)-N-[(7S,11R,14S)-22-ethyl-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-18,18-dimethyl-8,15-dioxo-16-oxa-4-thia-9,22,29,30- tetrazahexacyclo[18.5.2.12,5.19,14.111,14.023,27]triaconta-1(25),2,5(30),20,23,26-hexaen-7-yl]-2- pyrimidin-5-yl-cyclopropanecarboxamide; (2S,3R)-N-[(7S,11R,15R)-23-ethyl-(22M)-22-[2-[(1S)-1-methoxyethyl]-5-morpholino-3- pyridyl]-19,19-dimethyl-8,16-dioxo-13,17-dioxa-4-thia-9,23,30,31- tetrazahexacyclo[19.5.2.12,5.19,15.111,15.024,28]hentriaconta-1(27),2,5(31),21,24(28),25-hexaen-7- yl]-2,3-dimethyl-cyclopropanecarboxamide; (1S,2S)-N-[(7S,11R,14S)-22-ethyl-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-18,18-dimethyl-8,15-dioxo-16-oxa-4-thia-9,22,29,30- tetrazahexacyclo[18.5.2.12,5.19,14.111,14.023,27]triaconta-1(26),2,5(30),20,23(27),24-hexaen-7-yl]- 2-(3-pyridyl)cyclopropanecarboxamide; (2R,3S)-N-[(1S,23S,27R)-(8M)-8-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3- pyridyl]-5,5-dimethyl-2,24-dioxo-3,12-dioxa-20-thia-9,25,30,32- tetrazaheptacyclo[23.4.1.11,27.113,17.118,21.07,15.09,14]tritriaconta-7,13,15,17(33),18,21(32)-hexaen- 23-yl]-2,3-dimethyl-cyclopropanecarboxamide; (1S,2S)-N-[(1S,23S,27R)-(8M)-8-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3- pyridyl]-5,5-dimethyl-2,24-dioxo-3,12-dioxa-20-thia-9,25,30,32- tetrazaheptacyclo[23.4.1.11,27.113,17.118,21.07,15.09,14]tritriaconta-7,13,15,17(33),18,21(32)-hexaen- 23-yl]-2-methyl-cyclopropanecarboxamide; N-[(7S,11R,14S)-22-ethyl-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)- 3-pyridyl]-18,18-dimethyl-8,15-dioxo-16-oxa-4-thia-9,22,29,30- tetrazahexacyclo[18.5.2.12,5.19,14.111,14.023,27]triaconta-1(26),2,5(30),20,23(27),24-hexaen-7-yl]- 1,2-dimethyl-cyclopropanecarboxamide; (1R,2S)-2-cyclopropyl-N-[(7S,11R,14S)-22-ethyl-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-18,18-dimethyl-8,15-dioxo-16-oxa-4-thia-9,22,29,30- tetrazahexacyclo[18.5.2.12,5.19,14.111,14.023,27]triaconta-1(26),2,5(30),20,23(27),24-hexaen-7- yl]cyclopropanecarboxamide; (1R,2S)-N-[(7S,11R,14S)-22-ethyl-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-18,18-dimethyl-8,15-dioxo-16-oxa-4-thia-9,22,29,30- tetrazahexacyclo[18.5.2.12,5.19,14.111,14.023,27]triaconta-1(26),2,5(30),20,23(27),24-hexaen-7-yl]- 2-phenyl-cyclopropanecarboxamide; (1S,2S)-N-[(7S,11R,14S)-22-ethyl-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-18,18-dimethyl-8,15-dioxo-16-oxa-4-thia-9,22,29,30- tetrazahexacyclo[18.5.2.12,5.19,14.111,14.023,27]triaconta-1(26),2,5(30),20,23(27),24-hexaen-7-yl]- 2-phenyl-cyclopropanecarboxamide; (1S,2S)-N-[(1S,23S,27R)-(8M)-8-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3- pyridyl]-5,5-dimethyl-2,24-dioxo-3-oxa-20-thia-9,25,30,32- tetrazaheptacyclo[23.4.1.11,27.113,17.118,21.07,15.09,14]tritriaconta-7,13,15,17(33),18,21(32)-hexaen- 23-yl]-2-methyl-cyclopropanecarboxamide; (1R,5S)-N-[(7S,11R,14S)-22-ethyl-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-morpholino-3- pyridyl]-18,18-dimethyl-8,15-dioxo-16-oxa-4-thia-9,22,29,30- tetrazahexacyclo[18.5.2.12,5.19,14.111,14.023,27]triaconta-1(26),2,5(30),20,23(27),24-hexaen-7-yl]- 3-oxabicyclo[3.1.0]hexane-6-carboxamide; (1S,2R)-N-[(7S,11R,14S)-22-ethyl-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-18,18-dimethyl-8,15-dioxo-16-oxa-4-thia-9,22,29,30- tetrazahexacyclo[18.5.2.12,5.19,14.111,14.023,27]triaconta-1(26),2,5(30),20,23(27),24-hexaen-7-yl]- 2-phenyl-cyclopropanecarboxamide; (1R,2R)-N-[(7S,11R,14S)-22-ethyl-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-18,18-dimethyl-8,15-dioxo-16-oxa-4-thia-9,22,29,30- tetrazahexacyclo[18.5.2.12,5.19,14.111,14.023,27]triaconta-1(26),2,5(30),20,23(27),24-hexaen-7-yl]- 2-phenyl-cyclopropanecarboxamide; (1R,5S)-N-[(7S,11R,14S)-22-ethyl-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-18,18-dimethyl-8,15-dioxo-16-oxa-4-thia-9,22,29,30- tetrazahexacyclo[18.5.2.12,5.19,14.111,14.023,27]triaconta-1(26),2,5(30),20,23(27),24-hexaen-7-yl]- 3-oxabicyclo[3.1.0]hexane-6-carboxamide; (2R,3S)-N-[(7S,11R,14S)-22-ethyl-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-18,18-dimethyl-8,15-dioxo-16-oxa-4-thia-9,22,29,30- tetrazahexacyclo[18.5.2.12,5.19,14.111,14.023,27]triaconta-1(26),2,5(30),20,23(27),24-hexaen-7-yl]- 2,3-dimethyl-cyclopropanecarboxamide; (2R,3S)-N-[(7S,11R,14S)-22-ethyl-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-morpholino-3- pyridyl]-18,18-dimethyl-8,15-dioxo-16-oxa-4-thia-9,22,29,30- tetrazahexacyclo[18.5.2.12,5.19,14.111,14.023,27]triaconta-1(26),2,5(30),20,23(27),24-hexaen-7-yl]- 2,3-dimethyl-cyclopropanecarboxamide; (1S,2S)-2-(difluoromethyl)-N-[(7S,11R,14S)-22-ethyl-(21M)-21-[2-[(1S)-1-methoxyethyl]- 5-morpholino-3-pyridyl]-18,18-dimethyl-8,15-dioxo-16-oxa-4-thia-9,22,29,30- tetrazahexacyclo[18.5.2.12,5.19,14.111,14.023,27]triaconta-1(26),2,5(30),20,23(27),24-hexaen-7- yl]cyclopropanecarboxamide; (1S,5R)-N-[(7S,11R,14S)-22-ethyl-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-morpholino-3- pyridyl]-18,18-dimethyl-8,15-dioxo-16-oxa-4-thia-9,22,29,30- tetrazahexacyclo[18.5.2.12,5.19,14.111,14.023,27]triaconta-1(26),2,5(30),20,23(27),24-hexaen-7-yl]- 3-oxabicyclo[3.1.0]hexane-6-carboxamide; (1S,5R)-N-[(7S,11R,14S)-22-ethyl-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-18,18-dimethyl-8,15-dioxo-16-oxa-4-thia-9,22,29,30- tetrazahexacyclo[18.5.2.12,5.19,14.111,14.023,27]triaconta-1(26),2,5(30),20,23(27),24-hexaen-7-yl]- 3-oxabicyclo[3.1.0]hexane-6-carboxamide; (1S,2S)-2-(difluoromethyl)-N-[(7S,11R,14S)-22-ethyl-(21M)-21-[2-[(1S)-1-methoxyethyl]- 5-(4-methylpiperazin-1-yl)-3-pyridyl]-18,18-dimethyl-8,15-dioxo-16-oxa-4-thia-9,22,29,30- tetrazahexacyclo[18.5.2.12,5.19,14.111,14.023,27]triaconta-1(26),2,5(30),20,23(27),24-hexaen-7- yl]cyclopropanecarboxamide; (1S,2S)-N-[(7S,11R,14S)-22-ethyl-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-18,18-dimethyl-8,15-dioxo-16-oxa-4-thia-9,22,29,30- tetrazahexacyclo[18.5.2.12,5.19,14.111,14.023,27]triaconta-1(26),2,5(30),20,23(27),24-hexaen-7-yl]- 2-methyl-cyclopropanecarboxamide; (1S,2S)-N-[(7S)-21-ethyl-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]- 17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,29,30- tetrazahexacyclo[17.5.2.210,13.12,5.19,13.022,26]triaconta-1(25),2,5(30),19,22(26),23-hexaen-7-yl]- 2-methyl-cyclopropanecarboxamide; (1S,2S)-N-[(7S,11R,14S)-22-ethyl-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-morpholino-3- pyridyl]-18,18-dimethyl-8,15-dioxo-16-oxa-4-thia-9,22,29,30- tetrazahexacyclo[18.5.2.12,5.19,14.111,14.023,27]triaconta-1(26),2,5(30),20,23(27),24-hexaen-7-yl]- 2-methyl-cyclopropanecarboxamide; (1S,2S)-N-[(7S)-22-ethyl-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]- 18,18-dimethyl-8,15-dioxo-16-oxa-4-thia-9,22,28,29- tetrazahexacyclo[18.5.2.12,5.19,14.012,14.023,27]nonacosa-1(26),2,5(29),20,23(27),24-hexaen-7-yl]- 2-methyl-cyclopropanecarboxamide; (2S,3R)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3- pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,32- 2,5 9,13 10,12 19,27 21,26 tetrazaheptacyclo[23.3.1.1 .1 .1 .0 .0 ]dotriaconta-1(29),2,5(32),19,25,27-hexaen-7- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(7S,13R)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3- pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,32- 2,5 9,13 10,12 19,27 21,26 tetrazaheptacyclo[23.3.1.1 .1 .1 .0 .0 ]dotriaconta-1(29),2,5(32),19,25,27-hexaen-7- yl]-2,3-dimethyl-cyclopropanecarboxamide; and (2S,3R)-N-[(7S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3- pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,32- 2,5 9,13 10,12 19,27 21,26 tetrazaheptacyclo[23.3.1.1 .1 .1 .0 .0 ]dotriaconta-1(29),2,5(32),19,25,27-hexaen-7- yl]-2,3-dimethyl-cyclopropanecarboxamide; or a pharmaceutically acceptable salt, enantiomers and diastereomers thereof. Another embodiment of present invention is (xvii) a compound of formula (I) or (Ia) selected from the following: (2R,3S)-N-[(7S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3- pyridyl]-17,17-dimethyl-8,14-dioxo-spiro[15-oxa-4-thia-9,21,30,32- tetrazaheptacyclo[23.3.1.12,5.19,13.110,12.019,27.021,26]dotriaconta-1(29),2,5(32),19,25,27-hexaene- 6,1'-cyclopropane]-7-yl]-2,3-dimethyl-cyclopropanecarboxamide; (2R,3S)-N-[(7S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3- pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,32- tetrazaheptacyclo[23.3.1.12,5.19,13.110,12.019,27.021,26]dotriaconta-1(29),2,5(32),19,25,27-hexaen-7- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2R,3S)-N-[(7S)-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-9,21,30,32- tetrazaheptacyclo[23.3.1.12,5.19,13.110,12.019,27.021,26]dotriaconta-1(29),2,5(32),19,25,27-hexaen-7- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2R,3S)-N-[(3S,26S,28R)-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)- 3-pyridyl]-21,21-dimethyl-2,24-dioxo-23-oxa-6-thia-1,17,30,32- tetrazaheptacyclo[23.4.1.15,8.19,13.011,19.012,17.026,28]dotriaconta-5(32),7,9(31),10,12,18-hexaen-3- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2R,3S)-N-[(3S,26S,28R)-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)- 3-pyridyl]-21,21-dimethyl-2,24-dioxo-14,23-dioxa-6-thia-1,17,30,32- tetrazaheptacyclo[23.4.1.15,8.19,13.011,19.012,17.026,28]dotriaconta-5(32),7,9(31),10,12,18-hexaen-3- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2R,3S)-N-[(3S,26S,28R)-15,15-difluoro-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-21,21-dimethyl-2,24-dioxo-23-oxa-6-thia-1,17,30,32- tetrazaheptacyclo[23.4.1.15,8.19,13.011,19.012,17.026,28]dotriaconta-5(32),7,9(31),10,12,18-hexaen-3- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(3S,27S,29R)-(19M)-19-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)- 3-pyridyl]-22,22-dimethyl-2,25-dioxo-14,24-dioxa-6-thia-1,18,31,33- tetrazaheptacyclo[24.4.1.15,8.19,13.011,20.012,18.027,29]tritriaconta-5(33),7,9(32),10,12,19-hexaen-3- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2R,3S)-N-[(3S,26R,28S)-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)- 3-pyridyl]-21,21-dimethyl-2,24-dioxo-23-oxa-6-thia-1,17,30,32- tetrazaheptacyclo[23.4.1.15,8.19,13.011,19.012,17.026,28]dotriaconta-5(32),7,9(31),10,12,18-hexaen-3- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2R,3S)-N-[(3S,26R,28S)-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)- 3-pyridyl]-21,21-dimethyl-2,24-dioxo-14,23-dioxa-6-thia-1,17,30,32- tetrazaheptacyclo[23.4.1.15,8.19,13.011,19.012,17.026,28]dotriaconta-5(32),7,9(31),10,12,18-hexaen-3- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2R,3S)-N-[(3S,26R,28S)-15,15-difluoro-(18M)18-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-21,21-dimethyl-2,24-dioxo-23-oxa-6-thia-1,17,30,32- tetrazaheptacyclo[23.4.1.15,8.19,13.011,19.012,17.026,28]dotriaconta-5(32),7,9(31),10,12,18-hexaen-3- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(3S,27R,29S)-(19M)-19-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)- 3-pyridyl]-22,22-dimethyl-2,25-dioxo-14,24-dioxa-6-thia-1,18,31,33- tetrazaheptacyclo[24.4.1.15,8.19,13.011,20.012,18.027,29]tritriaconta-5(33),7,9(32),10,12,19-hexaen-3- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2R,3S)-N-[(7S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3- pyridyl]-17,17-dimethyl-8,14-dioxo-spiro[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-hexaene-12,1'- cyclopropane]-7-yl]-2,3-dimethyl-cyclopropanecarboxamide; (2R,3S)-N-[(7S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3- pyridyl]-17,17-dimethyl-8,14-dioxo-spiro[15,24-dioxa-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-hexaene-12,1'- cyclopropane]-7-yl]-2,3-dimethyl-cyclopropanecarboxamide; (2R,3S)-N-[(7S)-23,23-difluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin- 1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-spiro[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-hexaene-12,1'- cyclopropane]-7-yl]-2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(7S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3- pyridyl]-17,17-dimethyl-8,14-dioxo-spiro[15,25-dioxa-4-thia-9,21,31,32- tetrazahexacyclo[24.3.1.12,5.19,13.019,28.021,27]dotriaconta-1(30),2,5(32),19,26,28-hexaene-12,1'- cyclopropane]-7-yl]-2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(3S,26R,28S)-27,27-difluoro-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-21,21-dimethyl-2,24-dioxo-23-oxa-6-thia-1,17,30,32- tetrazaheptacyclo[23.4.1.15,8.19,13.011,19.012,17.026,28]dotriaconta-5(32),7,9(31),10,12,18-hexaen-3- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(3S,26R,28S)-27,27-difluoro-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-21,21-dimethyl-2,24-dioxo-14,23-dioxa-6-thia-1,17,30,32- tetrazaheptacyclo[23.4.1.15,8.19,13.011,19.012,17.026,28]dotriaconta-5(32),7,9(31),10,12,18-hexaen-3- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-2,3-dimethyl-N-[(3S,26R,28S)-15,15,27,27-tetrafluoro-(18M)-18-[2-[(1S)-1- methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-21,21-dimethyl-2,24-dioxo-23-oxa-6-thia- 1,17,30,32-tetrazaheptacyclo[23.4.1.15,8.19,13.011,19.012,17.026,28]dotriaconta- 5(32),7,9(31),10,12,18-hexaen-3-yl]cyclopropanecarboxamide; (2R,3S)-N-[(3S,27R,29S)-28,28-difluoro-(19M)-19-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-22,22-dimethyl-2,25-dioxo-14,24-dioxa-6-thia-1,18,31,33- tetrazaheptacyclo[24.4.1.15,8.19,13.011,20.012,18.027,29]tritriaconta-5(33),7,9(32),10,12,19-hexaen-3- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(3S,26S,28R)-27,27-difluoro-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-21,21-dimethyl-2,24-dioxo-23-oxa-6-thia-1,17,30,32- tetrazaheptacyclo[23.4.1.15,8.19,13.011,19.012,17.026,28]dotriaconta-5(32),7,9(31),10,12,18-hexaen-3- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(3S,28R)-27,27-difluoro-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-21,21-dimethyl-2,24-dioxo-14,23-dioxa-6-thia-1,17,30,32- tetrazaheptacyclo[23.4.1.15,8.19,13.011,19.012,17.026,28]dotriaconta-5(32),7,9(31),10,12,18-hexaen-3- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-2,3-dimethyl-N-[(3S,26S,28R)-15,15,27,27-tetrafluoro-(18M)-18-[2-[(1S)-1- methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-21,21-dimethyl-2,24-dioxo-23-oxa-6-thia- 1,17,30,32-tetrazaheptacyclo[23.4.1.15,8.19,13.011,19.012,17.026,28]dotriaconta- 5(32),7,9(31),10,12,18-hexaen-3-yl]cyclopropanecarboxamide; (2R,3S)-N-[(3S,27S,29R)-28,28-difluoro-(19M)-19-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-22,22-dimethyl-2,25-dioxo-14,24-dioxa-6-thia-1,18,31,33- tetrazaheptacyclo[24.4.1.15,8.19,13.011,20.012,18.027,29]tritriaconta-5(33),7,9(32),10,12,19-hexaen-3- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2R,3S)-N-[(3S,25S,26R,29S)-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1- yl)-3-pyridyl]-21,21-dimethyl-2,24-dioxo-23-oxa-6-thia-1,17,31,33- tetrazaheptacyclo[23.5.1.15,8.19,13.011,19.012,17.026,29]tritriaconta-5(33),7,9(32),10,12,18-hexaen-3- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2R,3S)-N-[(3S,25S,26R,29S)-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1- yl)-3-pyridyl]-21,21-dimethyl-2,24-dioxo-14,23-dioxa-6-thia-1,17,31,33- tetrazaheptacyclo[23.5.1.15,8.19,13.011,19.012,17.026,29]tritriaconta-5(33),7,9(32),10,12,18-hexaen-3- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2R,3S)-N-[(3S,25S,26R,29S)-15,15-difluoro-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-21,21-dimethyl-2,24-dioxo-23-oxa-6-thia-1,17,31,33- tetrazaheptacyclo[23.5.1.15,8.19,13.011,19.012,17.026,29]tritriaconta-5(33),7,9(32),10,12,18-hexaen-3- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(3S,26S,27R,30S)-(19M)-19-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1- yl)-3-pyridyl]-22,22-dimethyl-2,25-dioxo-14,24-dioxa-6-thia-1,18,32,34- tetrazaheptacyclo[24.5.1.15,8.19,13.011,20.012,18.027,30]tetratriaconta-5(34),7,9(33),10,12,19-hexaen- 3-yl]-2,3-dimethyl-cyclopropanecarboxamide; (2R,3S)-N-[(3S,25S,26S,29R)-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1- yl)-3-pyridyl]-21,21-dimethyl-2,24-dioxo-23-oxa-6-thia-1,17,31,33- tetrazaheptacyclo[23.5.1.15,8.19,13.011,19.012,17.026,29]tritriaconta-5(33),7,9(32),10,12,18-hexaen-3- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2R,3S)-N-[(3S,25S,26S,29R)-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1- yl)-3-pyridyl]-21,21-dimethyl-2,24-dioxo-14,23-dioxa-6-thia-1,17,31,33- tetrazaheptacyclo[23.5.1.15,8.19,13.011,19.012,17.026,29]tritriaconta-5(33),7,9(32),10,12,18-hexaen-3- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2R,3S)-N-[(3S,25S,26S,29R)-15,15-difluoro-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-21,21-dimethyl-2,24-dioxo-23-oxa-6-thia-1,17,31,33- tetrazaheptacyclo[23.5.1.15,8.19,13.011,19.012,17.026,29]tritriaconta-5(33),7,9(32),10,12,18-hexaen-3- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(3S,26S,27S,30R)-(19M)-19-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1- yl)-3-pyridyl]-22,22-dimethyl-2,25-dioxo-14,24-dioxa-6-thia-1,18,32,34- tetrazaheptacyclo[24.5.1.15,8.19,13.011,20.012,18.027,30]tetratriaconta-5(34),7,9(33),10,12,19-hexaen- 3-yl]-2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(3S,26R,28S)-27,27-difluoro-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-21,21,26-trimethyl-2,24-dioxo-23-oxa-6-thia-1,17,30,32- tetrazaheptacyclo[23.4.1.15,8.19,13.011,19.012,17.026,28]dotriaconta-5(32),7,9(31),10,12,18-hexaen-3- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2R,3S)-N-[(3S,26R,28S)-27,27-difluoro-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-21,21,26-trimethyl-2,24-dioxo-14,23-dioxa-6-thia-1,17,30,32- tetrazaheptacyclo[23.4.1.15,8.19,13.011,19.012,17.026,28]dotriaconta-5(32),7,9(31),10,12,18-hexaen-3- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(3S,26R,28S)-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)- 3-pyridyl]-21,21,26-trimethyl-2,24-dioxo-23-oxa-6-thia-1,17,30,32- tetrazaheptacyclo[23.4.1.15,8.19,13.011,19.012,17.026,28]dotriaconta-5(32),7,9(31),10,12,18-hexaen-3- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2R,3S)-N-[(3S,26R,28S)-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)- 3-pyridyl]-21,21,26-trimethyl-2,24-dioxo-14,23-dioxa-6-thia-1,17,30,32- tetrazaheptacyclo[23.4.1.15,8.19,13.011,19.012,17.026,28]dotriaconta-5(32),7,9(31),10,12,18-hexaen-3- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(3S,26S,28R)-27,27-difluoro-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-21,21,26-trimethyl-2,24-dioxo-23-oxa-6-thia-1,17,30,32- tetrazaheptacyclo[23.4.1.15,8.19,13.011,19.012,17.026,28]dotriaconta-5(32),7,9(31),10,12,18-hexaen-3- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(3S,26S,28R)-27,27-difluoro-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-21,21,26-trimethyl-2,24-dioxo-14,23-dioxa-6-thia-1,17,30,32- tetrazaheptacyclo[23.4.1.15,8.19,13.011,19.012,17.026,28]dotriaconta-5(32),7,9(31),10,12,18-hexaen-3- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(3S,26S,28R)-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)- 3-pyridyl]-21,21,26-trimethyl-2,24-dioxo-23-oxa-6-thia-1,17,30,32- tetrazaheptacyclo[23.4.1.15,8.19,13.011,19.012,17.026,28]dotriaconta-5(32),7,9(31),10,12,18-hexaen-3- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(3S,26S,28R)-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)- 3-pyridyl]-21,21,26-trimethyl-2,24-dioxo-14,23-dioxa-6-thia-1,17,30,32- tetrazaheptacyclo[23.4.1.15,8.19,13.011,19.012,17.026,28]dotriaconta-5(32),7,9(31),10,12,18-hexaen-3- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(7S)-11-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)- 3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(29),2,5(31),11,19,25,27-heptaen-7- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(7S)-11-fluoro-(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(29),2,5(31),11,19,25,27-heptaen-7- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(3S,26R,28S)-27,27-difluoro-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-21,21-dimethyl-2,24-dioxo-spiro[23-oxa-6-thia-1,17,30,32- tetrazaheptacyclo[23.4.1.15,8.19,13.011,19.012,17.026,28]dotriaconta-5(32),7,9(31),10,12,18-hexaene- 4,1'-cyclobutane]-3-yl]-2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(3S,26R,28S)-27,27-difluoro-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-21,21-dimethyl-2,24-dioxo-spiro[14,23-dioxa-6-thia- 1,17,30,32-tetrazaheptacyclo[23.4.1.15,8.19,13.011,19.012,17.026,28]dotriaconta- 5(32),7,9(31),10,12,18-hexaene-4,1'-cyclobutane]-3-yl]-2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(3S,26R,28S)-27,27-difluoro-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-21,21-dimethyl-2,24-dioxo-spiro[23-oxa-6-thia-1,17,30,32- tetrazaheptacyclo[23.4.1.15,8.19,13.011,19.012,17.026,28]dotriaconta-5(32),7,9(31),10,12,18-hexaene- 4,1'-cyclopropane]-3-yl]-2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(3S,26R,28S)-27,27-difluoro-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-21,21-dimethyl-2,24-dioxo-spiro[14,23-dioxa-6-thia- 1,17,30,32-tetrazaheptacyclo[23.4.1.15,8.19,13.011,19.012,17.026,28]dotriaconta- 5(32),7,9(31),10,12,18-hexaene-4,1'-cyclopropane]-3-yl]-2,3-dimethyl- cyclopropanecarboxamide; (2S,3R)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3- pyridyl]-17,17-dimethyl-8,14-dioxo-15-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]- 2,3-dimethyl-cyclopropanecarboxamide; (2R,3S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[3-(1,4-oxazepan-4-yl)prop-1- ynyl]-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]- 2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(7S,13S)-(20M)-20-[5-[3-(azetidin-1-yl)prop-1-ynyl]-2-[(1S)-1-methoxyethyl]- 3-pyridyl]-17,17-dimethyl-8,14-dioxo-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(29),2,5(31),19,25,27-hexaen-7-yl]- 2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(7S,13S)-(20M)-20-[5-[3-(1,1-dioxo-1,4-thiazinan-4-yl)prop-1-ynyl]-2-[(1S)-1- methoxyethyl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-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(29),2,5(31),19,25,27-hexaen-7-yl]- 2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(3-morpholinoprop-1-ynyl)-3- pyridyl]-17,17-dimethyl-8,14-dioxo-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(29),2,5(31),19,25,27-hexaen-7-yl]- 2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(7S,13S)-23,23-difluoro-(20M)-20-[2-isopropyl-5-[3-(1,4-oxazepan-4-yl)prop- 1-ynyl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-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(29),2,5(31),19,25,27-hexaen-7-yl]- 2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(7S,13S)-23,23-difluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[3-(1,4- oxazepan-4-yl)prop-1-ynyl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-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(29),2,5(31),19,25,27-hexaen-7-yl]- 2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(7S,13S)-(20M)-20-[5-[3-(azetidin-1-yl)prop-1-ynyl]-2-[(1S)-1-methoxyethyl]- 3-pyridyl]-23,23-difluoro-17,17-dimethyl-8,14-dioxo-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(29),2,5(31),19,25,27-hexaen-7-yl]- 2,3-dimethyl-cyclopropanecarboxamide; (2R,3S)-N-[(7S,13S)-(20M)-20-[5-[3-(1,1-dioxo-1,4-thiazinan-4-yl)prop-1-ynyl]-2-[(1S)-1- methoxyethyl]-3-pyridyl]-23,23-difluoro-17,17-dimethyl-8,14-dioxo-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(29),2,5(31),19,25,27-hexaen-7-yl]- 2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(7S,13S)-23,23-difluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(3- morpholinoprop-1-ynyl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-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(29),2,5(31),19,25,27-hexaen-7-yl]- 2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(7S,13S)-(20M)-20-[2-isopropyl-5-[3-(1,4-oxazepan-4-yl)prop-1-ynyl]-3- pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31- 2,5 9,13 19,27 21,26 tetrazahexacyclo[23.3.1.1 .1 .0 .0 ]hentriaconta-1(29),2,5(31),19,25,27-hexaen-7-yl]- 2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[3-(1,4-oxazepan-4-yl)prop-1- ynyl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31- 2,5 9,13 19,27 21,26 tetrazahexacyclo[23.3.1.1 .1 .0 .0 ]hentriaconta-1(29),2,5(31),19,25,27-hexaen-7-yl]- 2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(7S,13S)-(20M)-20-[5-[3-(azetidin-1-yl)prop-1-ynyl]-2-[(1S)-1-methoxyethyl]- 3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31- 2,5 9,13 19,27 21,26 tetrazahexacyclo[23.3.1.1 .1 .0 .0 ]hentriaconta-1(29),2,5(31),19,25,27-hexaen-7-yl]- 2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(7S,13S)-(20M)-20-[5-[3-(1,1-dioxo-1,4-thiazinan-4-yl)prop-1-ynyl]-2-[(1S)-1- methoxyethyl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31- 2,5 9,13 19,27 21,26 tetrazahexacyclo[23.3.1.1 .1 .0 .0 ]hentriaconta-1(29),2,5(31),19,25,27-hexaen-7-yl]- 2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(3-morpholinoprop-1-ynyl)-3- pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31- 2,5 9,13 19,27 21,26 tetrazahexacyclo[23.3.1.1 .1 .0 .0 ]hentriaconta-1(29),2,5(31),19,25,27-hexaen-7-yl]- 2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(7S,13S)-(20M)-20-[2-isopropyl-5-[3-(1,4-oxazepan-4-yl)prop-1-ynyl]-3- pyridyl]-17,17-dimethyl-8,14-dioxo-15,25-dioxa-4-thia-9,21,31,32- 2,5 9,13 19,28 21,27 tetrazahexacyclo[24.3.1.1 .1 .0 .0 ]dotriaconta-1(30),2,5(32),19,26,28-hexaen-7-yl]- 2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[3-(1,4-oxazepan-4-yl)prop-1- ynyl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,25-dioxa-4-thia-9,21,31,32- 2,5 9,13 19,28 21,27 tetrazahexacyclo[24.3.1.1 .1 .0 .0 ]dotriaconta-1(30),2,5(32),19,26,28-hexaen-7-yl]- 2,3-dimethyl-cyclopropanecarboxamide; (2R,3S)-N-[(7S,13S)-(20M)-20-[5-[3-(azetidin-1-yl)prop-1-ynyl]-2-[(1S)-1-methoxyethyl]- 3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,25-dioxa-4-thia-9,21,31,32- 2,5 9,13 19,28 21,27 tetrazahexacyclo[24.3.1.1 .1 .0 .0 ]dotriaconta-1(30),2,5(32),19,26,28-hexaen-7-yl]- 2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(7S,13S)-(20M)-20-[5-[3-(1,1-dioxo-1,4-thiazinan-4-yl)prop-1-ynyl]-2-[(1S)-1- methoxyethyl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,25-dioxa-4-thia-9,21,31,32- 2,5 9,13 19,28 21,27 tetrazahexacyclo[24.3.1.1 .1 .0 .0 ]dotriaconta-1(30),2,5(32),19,26,28-hexaen-7-yl]- 2,3-dimethyl-cyclopropanecarboxamide; (2R,3S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(3-morpholinoprop-1-ynyl)-3- pyridyl]-17,17-dimethyl-8,14-dioxo-15,25-dioxa-4-thia-9,21,31,32- 2,5 9,13 19,28 21,27 tetrazahexacyclo[24.3.1.1 .1 .0 .0 ]dotriaconta-1(30),2,5(32),19,26,28-hexaen-7-yl]- 2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(7S,13S)-(20M)-20-[2-isopropyl-5-[3-(1,4-oxazepan-4-yl)prop-1-ynyl]-3- pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,32- 2,5 9,13 10,12 19,27 21,26 tetrazaheptacyclo[23.3.1.1 .1 .1 .0 .0 ]dotriaconta-1(29),2,5(32),19,25,27-hexaen-7- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[3-(1,4-oxazepan-4-yl)prop-1- ynyl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,32- 2,5 9,13 10,12 19,27 21,26 tetrazaheptacyclo[23.3.1.1 .1 .1 .0 .0 ]dotriaconta-1(29),2,5(32),19,25,27-hexaen-7- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(7S,13S)-(20M)-20-[5-[3-(azetidin-1-yl)prop-1-ynyl]-2-[(1S)-1-methoxyethyl]- 3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,32- 2,5 9,13 10,12 19,27 21,26 tetrazaheptacyclo[23.3.1.1 .1 .1 .0 .0 ]dotriaconta-1(29),2,5(32),19,25,27-hexaen-7- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(7S,13S)-(20M)-20-[5-[3-(1,1-dioxo-1,4-thiazinan-4-yl)prop-1-ynyl]-2-[(1S)-1- methoxyethyl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,32- 2,5 9,13 10,12 19,27 21,26 tetrazaheptacyclo[23.3.1.1 .1 .1 .0 .0 ]dotriaconta-1(29),2,5(32),19,25,27-hexaen-7- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(3-morpholinoprop-1-ynyl)-3- pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,32- 2,5 9,13 10,12 19,27 21,26 tetrazaheptacyclo[23.3.1.1 .1 .1 .0 .0 ]dotriaconta-1(29),2,5(32),19,25,27-hexaen-7- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(7S,13S)-23,23-difluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[3-(1,4- oxazepan-4-yl)prop-1-ynyl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,32- 2,5 9,13 10,12 19,27 21,26 tetrazaheptacyclo[23.3.1.1 .1 .1 .0 .0 ]dotriaconta-1(29),2,5(32),19,25,27-hexaen-7- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(7S,13S)-(20M)-20-[5-[3-(azetidin-1-yl)prop-1-ynyl]-2-[(1S)-1-methoxyethyl]- 3-pyridyl]-23,23-difluoro-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,32- 2,5 9,13 10,12 19,27 21,26 tetrazaheptacyclo[23.3.1.1 .1 .1 .0 .0 ]dotriaconta-1(29),2,5(32),19,25,27-hexaen-7- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(7S,13S)-(20M)-20-[5-[3-(1,1-dioxo-1,4-thiazinan-4-yl)prop-1-ynyl]-2-[(1S)-1- methoxyethyl]-3-pyridyl]-23,23-difluoro-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,32- 2,5 9,13 10,12 19,27 21,26 tetrazaheptacyclo[23.3.1.1 .1 .1 .0 .0 ]dotriaconta-1(29),2,5(32),19,25,27-hexaen-7- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(7S,13S)-23,23-difluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(3- morpholinoprop-1-ynyl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,32- 2,5 9,13 10,12 19,27 21,26 tetrazaheptacyclo[23.3.1.1 .1 .1 .0 .0 ]dotriaconta-1(29),2,5(32),19,25,27-hexaen-7- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[3-(1,4-oxazepan-4-yl)prop-1- ynyl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,32- 2,5 9,13 10,12 19,27 21,26 tetrazaheptacyclo[23.3.1.1 .1 .1 .0 .0 ]dotriaconta-1(29),2,5(32),19,25,27-hexaen-7- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(7S,13S)-(20M)-20-[5-[3-(azetidin-1-yl)prop-1-ynyl]-2-[(1S)-1-methoxyethyl]- 3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,32- 2,5 9,13 10,12 19,27 21,26 tetrazaheptacyclo[23.3.1.1 .1 .1 .0 .0 ]dotriaconta-1(29),2,5(32),19,25,27-hexaen-7- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(7S,13S)-(20M)-20-[5-[3-(1,1-dioxo-1,4-thiazinan-4-yl)prop-1-ynyl]-2-[(1S)-1- methoxyethyl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,32- 2,5 9,13 10,12 19,27 21,26 tetrazaheptacyclo[23.3.1.1 .1 .1 .0 .0 ]dotriaconta-1(29),2,5(32),19,25,27-hexaen-7- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(3-morpholinoprop-1-ynyl)-3- pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,32- 2,5 9,13 10,12 19,27 21,26 tetrazaheptacyclo[23.3.1.1 .1 .1 .0 .0 ]dotriaconta-1(29),2,5(32),19,25,27-hexaen-7- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[3-(1,4-oxazepan-4-yl)prop-1- ynyl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,25-dioxa-4-thia-9,21,31,33- 2,5 9,13 10,12 19,28 21,27 tetrazaheptacyclo[24.3.1.1 .1 .1 .0 .0 ]tritriaconta-1(30),2,5(33),19,26,28-hexaen-7- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2R,3S)-N-[(7S,13S)-(20M)-20-[5-[3-(azetidin-1-yl)prop-1-ynyl]-2-[(1S)-1-methoxyethyl]- 3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,25-dioxa-4-thia-9,21,31,33- 2,5 9,13 10,12 19,28 21,27 tetrazaheptacyclo[24.3.1.1 .1 .1 .0 .0 ]tritriaconta-1(30),2,5(33),19,26,28-hexaen-7- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(7S,13S)-(20M)-20-[5-[3-(1,1-dioxo-1,4-thiazinan-4-yl)prop-1-ynyl]-2-[(1S)-1- methoxyethyl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,25-dioxa-4-thia-9,21,31,33- 2,5 9,13 10,12 19,28 21,27 tetrazaheptacyclo[24.3.1.1 .1 .1 .0 .0 ]tritriaconta-1(30),2,5(33),19,26,28-hexaen-7- yl]-2,3-dimethyl-cyclopropanecarboxamide; and (2R,3S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(3-morpholinoprop-1-ynyl)-3- pyridyl]-17,17-dimethyl-8,14-dioxo-15,25-dioxa-4-thia-9,21,31,33- 2,5 9,13 10,12 19,28 21,27 tetrazaheptacyclo[24.3.1.1 .1 .1 .0 .0 ]tritriaconta-1(30),2,5(33),19,26,28-hexaen-7- yl]-2,3-dimethyl-cyclopropanecarboxamide; or a pharmaceutically acceptable salt, enantiomers and diastereomers 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 (xvi) and (i’) to (xvii’) comprising the following step: a) coupling reaction between compound of formula (II), (III), in the presence of a coupling reagent and a base to form the compound of formula (I); wherein R1to R5, A1to A4are defined as in any one of (i) to (xiv) or (i’) to (xv’); the coupling reagent is T3P, HATU, PyBOP or EDCI / HOBt; the base 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 (xvi) and (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 (xvi) and (i’) to (xvii’) and a pharmaceutically acceptable excipient. Another embodiment of the present invention is (xxi) the use of a compound according to any one of (i) to (xvi) and (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 (xvi) and (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 (xvi) and (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 (xvi) and (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 (xvi) and (i’) to (xvii’) for the treatment or prophylaxis of cancers in a subject in need thereof, wherein the cancer comprises a first RAS mutation that is G12C and a second RAS mutation at a position selected from the group consisting of V8A, V9Y, S17E, A59T, T58I, D69P, M72I, S65W, R68S, D92R, H95N, Y96D, Q99W and F156L. Another embodiment of present invention is (xxvi) the use of a compound according to any one of (i) to (xvi) and (i’) to (xvii’) for the preparation of a medicament for the treatment or prophylaxis of cancers in a subject in need thereof, wherein the cancer comprises a first RAS mutation that is G12C and a second RAS mutation at a position selected from the group consisting of V8A, V9Y, S17E, A59T, T58I, D69P, M72I, S65W, R68S, D92R, H95N, Y96D, Q99W and F156L. Another embodiment of present invention is (xxvii) the use of a compound according to any one of (i) to (xvi) and (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 (xxviii) the use of a compound according to any one of (i) to (xvi) and (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 (xxix) the use of a compound according to any one of (i) to (xvi) and (i’) to (xvii’) for the treatment or prophylaxis of primary central nervous system (CNS) tumors harboring RAS mutations or RAS driven cancers with brain metastases; wherein the CNS tumor is primary melanocytic tumors of the CNS harboring NRAS mutation; wherein the cancer is selected from pancreatic adenocarcinoma, colorectal cancer, non-small cell lung cancer. Another embodiment of present invention is (xxx) the use of a compound according to any one of (i) to (xvi) and (i’) to (xvii’) for the treatment or prophylaxis of primary central nervous system (CNS) tumors harboring RAS mutations or RAS driven cancers with brain metastases; wherein the CNS tumor is primary melanocytic tumors of the CNS harboring NRAS mutation; wherein the cancer is non-small cell lung cancer. Another embodiment of present invention is (xxxi) a compound or pharmaceutically acceptable salt according to any one of (i) to (xvi) and (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 (xxxii) the use of a compound according to any one of (i) to (xvi) and (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 (xxxiii) 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 (xvi) and (i’) to (xvii’). Another embodiment of present invention is (xxxiv) a compound or pharmaceutically acceptable salt according to any one of (i) to (xvi) and (i’) to (xvii’), when manufactured according to a process of (xvii). 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 amounts may be below the amount that is toxic to normal cells, or the mammal as a whole. In one example, the pharmaceutically effective amount of the compound of the invention administered parenterally per dose will be in the range of about 0.1 to 1000 mg / kg, alternatively about 0.1 to 1000 mg / kg of patient body weight per day, with the typical initial range of compound used being 0.3 to 15 mg / kg / day. In another embodiment, oral unit dosage forms, such as tablets and capsules, preferably contain from about 1 to about 1000 mg of the compound of the invention. The compounds of the invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural and intranasal, and, if desired for local treatment, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. The compounds of the present invention may be administered in any convenient administrative form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain components conventional in pharmaceutical preparations, e.g., diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents. A typical formulation is prepared by mixing a compound of the present invention and a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, e.g., Ansel, Howard C., et al., Ansel’s Pharmaceutical Dosage Forms and Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. The formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament). An example of a suitable oral dosage form is a tablet containing about 1 to 1000 mg of the compound of the invention compounded with about 1 to 1000 mg anhydrous lactose, about 1 to 1000 mg sodium croscarmellose, about 1 to 1000 mg polyvinylpyrrolidone (PVP) K30, and about 1 to 1000 mg magnesium stearate. The powdered ingredients are first mixed together and then mixed with a solution of the PVP. The resulting composition can be dried, granulated, mixed with the magnesium stearate and compressed to tablet form using conventional equipment. An example of an aerosol formulation can be prepared by dissolving the compound, for example 5 to 400mg, of the invention in a suitable buffer solution, e.g. a phosphate buffer, adding a tonicifier, e.g. a salt such sodium chloride, if desired. The solution may be filtered, e.g., using a 0.2 micron filter, to remove impurities and contaminants. An embodiment, therefore, includes a pharmaceutical composition comprising a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof. In a further embodiment includes a pharmaceutical composition comprising a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or excipient. Another embodiment includes a pharmaceutical composition comprising a compound of formula (I) for use in the treatment of mutant KRAS-driven cancers. Another embodiment includes a pharmaceutical composition comprising a compound of Formula (I) for use in the treatment of mutant KRAS-driven cancers. The following composition A and B illustrate typical compositions of the present invention but serve merely as representative thereof. Composition A A compound of the present invention can be used in a manner known per se as the active ingredient for the production of tablets of the following composition: Per tablet Active ingredient 200 mg Microcrystalline cellulose 155 mg Corn starch 25 mg Talc 25 mg Hydroxypropylmethylcellulose 20 mg 425 mg Composition B A compound of the present invention can be used in a manner known per se as the active ingredient for the production of capsules of the following composition: Per capsule Active ingredient 100.0 mg Corn starch 20.0 mg Lactose 95.0 mg Talc 4.5 mg Magnesium stearate 0.5 mg 220.0 mg INDICATIONS AND METHODS OF TREATMENT The compounds of the invention induce a new binding pocket in KRAS by driving formation of a high affinity tri-complex between KRAS protein and the widely expressed cyclophilin A (CYPA), which inhibit KRAS interaction with downstream effectors, such as RAF and PI3K. Accordingly, the compounds of the invention are useful for inhibiting the propagating oncogenic MAPK and PI3K signaling, reducing cell proliferation, in particular cancer cells. Compounds of the invention are useful for termination of RAS signaling in cells that express RAS mutants, 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 R5, A1to A4are 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 route for preparing the compound of formula (I) is shown below. Scheme 1 Compound of formula II was synthesized according to the procedure described in Intermediate A1 to J. Compound of formula (I) can be obtained by a coupling reaction between acid (III) and compound of formula (II) with coupling reagent(s), such as T3P, HATU, PyBOP and EDCI / HOBt, in the presence of a base, such as TEA, DIEPA and DMAP. Compounds of this invention can be obtained as mixtures of diastereomers or enantiomers, which can be separated by methods well known in the art, e.g. (chiral) HPLC or SFC. In another embodiment, the compound of formula (I) can be obtained according to the 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 the following step: a) coupling reaction between compound of formula (II), , , (III), in the presence of a coupling reagent and a base to form the compound of formula (I); wherein in step a) the coupling reagent can be, for example, T3P, HATU, PyBOP or EDCI / HOBt; the base can be, for example, TEA, DIEPA or DMAP. A compound of formula (I) 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)2O Di-tert-butyldicarbonate (R)-binap (R)-(+)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl CDCl3: deuterated chloroform CD3OD deuterated methanol DIEPA N, N-diethylpropylamine DMF dimethyl formamide DMSO dimethyl sulfoxide 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 LDA Lithium diisopropylamide MS: (ESI) mass spectroscopy (electron spray ionization) min(s) minute(s) NMR nuclear magnetic resonance 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 RT or rt room temperature sat. saturated SFC supercritical fluid chromatography TBAF Tetrabutylammonium fluoride TEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuran 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: CO2and IPA (0.5% TEA in IPA) or CO2and 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 for Intermediate Intermediate A1 Benzyl (1S,5R)-2,3-diazabicyclo[3.2.1]octane-1-carboxylate The compound was prepared according to the following scheme: Step 1: Preparation of 3-methoxycarbonylcyclopentanecarboxylic acid (compound A1-b) To a solution of dimethyl cyclopentane-1,3-dicarboxylate (compound A1-a, 259.0 g, 1.4 mol) in Methanol (2 L) was added sodium hydroxide (55.6 g, 1.4 mol). The reaction was stirred at 25 °C for 18 hrs. The other batch (203 g) was combined with the mixture and then worked up. The reaction mixture was diluted with ice water (1 L) and adjusted pH=1~2 by adding 1M HCl aq. and then concentrated in vacuo. The residue mixture was extracted with EA (800 mL, three times). The combined organic layer was washed with brine (1 L, twice), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluted with PE / EA (PE / EA = 5: 1) to give 3- methoxycarbonylcyclopentanecarboxylic acid (compound A1-b, 280.0 g) as light yellow oil. MS calc’d 173.1 (MH+), measured 155.0 (M-H2O+H+). Step 2: Preparation of methyl 3-(hydroxymethyl)cyclopentanecarboxylate (compound A1-c) A solution of 3-methoxycarbonylcyclopentanecarboxylic acid (compound A1-b, 120.0 g, 696.9 mmol) in THF (1 L) was cooled to -20 °C and then added with BH3•Me2S (80.2 mL, 801.4 mmol) dropwise. The reaction was stirred at 25 °C for 12 hrs. The other two batches (160 g) were combined and worked up altogether. The reaction was quenched by adding MeOH (200 mL) and stirred for 1 h. The reaction mixture was concentrated in vacuo at 25 °C to give a residue. The residue was washed by added HCl aq. (0.5 N), and extracted with EA (500 mL, three times). The combined organic layer was dried over Na2SO4, concentrated and purified by silica gel column to give methyl 3-(hydroxymethyl)cyclopentanecarboxylate (compound A1-c, 245 g) as colorless oil. MS calc’d 159.0 (MH+), measured 159.0 (MH+). Step 3: Preparation of methyl 3-[ butyl(dimethyl)silyl]oxymethyl]cyclopentanecarboxylate (compound A1-d) A solution of methyl 3-(hydroxymethyl)cyclopentanecarboxylate (compound A1-c, 72.0 g, 455.15 mmol) and DIEA (124.4 mL, 910.3 mmol) in DCM (1 L) was cooled to 0 °C. The reaction mixture was added with tert-butyldimethylsilyl trifluoromethanesulfonate (144.4 g, 546.18 mmol) dropwise slowly and stirred at 20 °C for 12 hrs. The other two batches (200 g) were combined with mixture and worked up. The reaction mixture was concentrated in vacuo and purified by silica gel column to afford methyl 3-[[tert- butyl(dimethyl)silyl]oxymethyl]cyclopentanecarboxylate (compound A1-d, 230.0 g) as colorless oil. MS calc’d 273.2 (MH+), measured 273.2 (MH+). Step 4: Preparation of methyl 1-[tert-butoxycarbonyl-(tert- butoxycarbonylamino)amino]-3-[[tert- butyl(dimethyl)silyl]oxymethyl]cyclopentanecarboxylate (compound A1-e) To a solution of methyl 3-[[tert-butyl(dimethyl)silyl]oxymethyl]cyclopentanecarboxylate (compound A1-d, 10.0 g, 36.7 mmol) in THF (100 mL) which cooled to -60°C, was added with LDA (2M in THF, 27.5 mL, 55.05 mmol) dropwise. The reaction solution was stirred at -40~-50 °C for 1 h. The reaction mixture was cooled to -70 °C and then added with a solution of di-tert- butyl azodicarboxylate (12.7 g, 55.05 mmol) in THF (40 mL). The solution was stirred at 20 °C, slowly warmed to 20 °C in 3 hrs. The other four batches (100 g) were combined and worked up altogether. The reaction was quenched by adding aq. NH4Cl (50 mL) and the solution was extracted with EA (1 L, three times). The combined organic layer was washed with brine (1 L, twice), dried over Na2SO4 and concentrated to give crude product in vacuo. The crude product was purified by column chromatography to give methyl 1-[tert-butoxycarbonyl-(tert- butoxycarbonylamino)amino]-3-[[tert-butyl(dimethyl)silyl]oxymethyl]cyclopentanecarboxylate (compound A1-e, 200 g) as light yellow oil. MS calc’d 503.4 (MH+), measured 503.4 (MH+). Step 5: Preparation of methyl 1-[tert-butoxycarbonyl-(tert- butoxycarbonylamino)amino]-3-(hydroxymethyl)cyclopentanecarboxylate (compound A1-f) To a solution of methyl 1-[tert-butoxycarbonyl-(tert-butoxycarbonylamino)amino]-3-[[tert- butyl(dimethyl)silyl]oxymethyl]cyclopentanecarboxylate (compound A1-e, 10 g) in Methanol (200 mL) at 70 °C was added KF (11.6 g, 198.92 mmol). The solution was stirred at 70 °C for 30 hrs. The other 4 batches (40 g) were combined and worked up altogether. The reaction solution was concentrated in vacuo and diluted with EA. The solid was filtered, and filtrate was concentrated under vacuum to give yellow oil. The oil was purified by silica gel column (PE / EA=5 / 1~1 / 1) to give methyl 1-[tert-butoxycarbonyl-(tert-butoxycarbonylamino)amino]-3- (hydroxymethyl)cyclopentanecarboxylate (compound A1-f, 34.7 g) as light yellow gum. MS calc’d 389.2 (MH+), measured 389.2 (MH+). Step 6: Preparation of methyl 1-[tert-butoxycarbonyl-(tert- butoxycarbonylamino)amino]-3-(ethylsulfonyloxymethyl)cyclopentanecarboxylate (compound A1-g) To a solution of methyl 1-[tert-butoxycarbonyl-(tert-butoxycarbonylamino)amino]-3- (hydroxymethyl)cyclopentanecarboxylate (compound A1-f, 4.7 g, 12.1 mmol) in DCM (95 mL) was added TEA (8.4 mL, 60.5 mmol). The solution was cooled to 0 °C. Ethanesulfonyl chloride (2.3 mL, 24.2 mmol) was added dropwise at 0 °C. The mixture was stirred at 0 °C for 2 hrs. The other 6 batches (30 g) were combined and worked up altogether. The reaction solution was quenched by ice-water (1 L) at 0 °C and extracted with DCM (100 mL, three times). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column to give methyl 1-[tert-butoxycarbonyl-(tert- butoxycarbonylamino)amino]-3-(ethylsulfonyloxymethyl)cyclopentanecarboxylate (compound A1-g, 43 g) as light yellow oil. MS calc’d 481.2 (MH+), measured 481.3 (MH+). Step 7: Preparation of O2,O3-ditert-butyl O1-methyl 2,3-diazabicyclo[3.2.1]octane- 1,2,3-tricarboxylate (compound A1-h) To a solution of methyl 1-[tert-butoxycarbonyl-(tert-butoxycarbonylamino)amino]-3- (ethylsulfonyloxymethyl)cyclopentanecarboxylate (compound A1-g, 9.0 g, 18.73 mmol) in THF (180 mL) cooled to 0°C was added with TBAF (22.5 mL, 22.5 mmol). The solution was stirred at 25 °C for 2 hrs. The other 5 batches (34g) were combined and worked up altogether. The reaction mixture was poured into ice water (1.5 L). The mixture was concentrated in vacuo. The residue was extracted with EtOAc (500 mL, three times). The combined organic layer was washed with brine (500 mL), dried over Na2SO4 and concentrated to give crude product. The crude was purified by silica gel chromatography to give O2,O3-ditert-butyl O1-methyl 2,3- diazabicyclo[3.2.1]octane-1,2,3-tricarboxylate (compound A1-h, 11.5 g) as yellow oil. MS calc’d 371.2 (MH+), measured 371.3 (MH+). Step 8: Preparation of 2,3-bis(tert-butoxycarbonyl)-2,3-diazabicyclo[3.2.1]octane-1- carboxylic acid (compound A1-i) To a solution of O2,O3-ditert-butyl O1-methyl 2,3-diazabicyclo[3.2.1]octane-1,2,3- tricarboxylate (compound A1-h, 4.8 g, 12.96 mmol) in 1,4-dioxane (140 mL) was added KOH aq. (2N, 134.4 mL, 268.8 mmol) at 0°C. The mixture was stirred at 80 °C for 15 hrs. The other 2 batches (10 g) were combined and worked up altogether. The reaction was concentrated in vacuo. The residue was diluted with ice-water and adjusted pH=4 by adding 1N HCl and extracted with EA (40 mL, three times). The combined organic layer was washed with brine (50 mL), dried over Na2SO4and concentrated in vacuo to give a residue, which was purified by silica gel chromatography to give 2,3-bis(tert-butoxycarbonyl)-2,3-diazabicyclo[3.2.1]octane-1-carboxylic acid (compound A1-i, 10.0 g, 28.06 mmol) as a white solid. MS calc’d 357.2 (MH+), measured 201.1 (M-156+H+). Step 9: Preparation of O1-benzyl O2,O3-ditert-butyl (1S,5R)-2,3- diazabicyclo[3.2.1]octane-1,2,3-tricarboxylate (compound A1-j) To a mixture of 2,3-bis(tert-butoxycarbonyl)-2,3-diazabicyclo[3.2.1]octane-1-carboxylic acid (compound A1-i, 10.0 g, 28.06 mmol), K2CO3(11.6 g, 84.17 mmol) and NaI (4.2 g, 28.06 mmol) in DMF (150 mL) was added with benzyl bromide (4.4 mL, 36.47 mmol). The mixture was stirred at 40 °C for 15 hrs. The reaction was diluted with ice-water and extracted with EA (80 mL, three times). The combined organic layer was washed with brine (150 mL), dried over Na2SO4and concentrated in vacuo to give crude product. The crude product was purified by silica gel chromatography to give product as a white solid. The product was purified by SFC (Column: Chiralpak AD-350×4.6mm I.D.,3µm;Mobile phase: Phase A for CO2, and Phase B for IPA(0.05%DEA); Gradient elution: IPA(0.05%DEA) in CO2from 5% to 40%; Flow rate:3mL / min; Detector: PDA; Colum Temp:35C; Back Pressure:100Bar) to afford O1-benzyl O2,O3-ditert-butyl (1S,5R)-2,3-diazabicyclo[3.2.1]octane-1,2,3-tricarboxylate (compound A1-j, 5.0 g) (slower eluted) as light yellow oil. MS calc’d 447.2 (MH+), measured 291.3 (M -156+H+). Step 10: Preparation of benzyl (1S,5R)-2,3-diazabicyclo[3.2.1]octane-1-carboxylate (Intermediate A1) To a solution of O1-benzyl O2,O3-ditert-butyl (1S,5R)-2,3-diazabicyclo[3.2.1]octane-1,2,3- tricarboxylate (compound A1-j, 5.0 g, 11.2 mmol) in DCM (35 mL) was cooled to 0°C. TFA (12.5 mL) was added dropwise to the solution at 0°C. The reaction was stirred at 25 °C for 1 h. The reaction was concentrated in vacuo. The residue was dissolved in DCM (20 mL) and concentrated in vacuo. This procedure repeated three times to afford benzyl (1S,5R)-2,3- diazabicyclo[3.2.1]octane-1-carboxylate (Intermediate A1, 4 g) as light yellow oil, which was used in the next step without further purification. MS calc’d 247.1 (MH+), measured 247.3 (MH+). Intermediate A2 Benzyl 2,3-diazabicyclo[2.2.2]octane-1-carboxylate The title compound was prepared in analogy to the preparation of Intermediate A1 by using methyl 4-hydroxycyclohexanecarboxylate instead of methyl 3- (hydroxymethyl)cyclopentanecarboxylate (compound A1-c). Intermediate A3 Benzyl (1R,5R)-7-oxa-2,3-diazabicyclo[3.3.1]nonane-1-carboxylate The title compound was prepared in analogy to the preparation of Intermediate A1 by using methyl 5-(benzyloxymethyl)tetrahydropyran-3-carboxylate instead of methyl 3-[[tert- butyl(dimethyl)silyl]oxymethyl]cyclopentanecarboxylate (compound A1-d). Intermediate B1 Benzyl (1S,5R)-3-[(2S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)propanoyl]- 2,3-diazabicyclo[3.2.1]octane-1-carboxylate The compound was prepared according to the following scheme:

[0002] B1-h Intermediate B1 Step 1: Preparation of (4-bromothiazol-2-yl)methanol (compound B1-b) To a solution of 4-bromothiazole-2-carboxaldehyde (compound B1-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 in vacuo to afford (4-bromothiazol-2-yl)methanol (compound B1-b, 6g) as colorless oil. Step 2: Preparation of 4-bromo-2-(bromomethyl)thiazole (compound B1-c) To a solution of (4-bromothiazol-2-yl)methanol (compound B1-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 in vacuo. 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 B1-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 B1-e) To a mixture of (R)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine (compound B1-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 B1-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 in vacuo. 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 B1-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 B1-f) To a solution of 4-bromo-2-[[(2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2- yl]methyl]thiazole (compound B1-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 in vacuo to afford methyl (2S)-2-amino-3-(4-bromothiazol-2- yl)propanoate (compound B1-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 B1-g) To a solution of methyl (2S)-2-amino-3-(4-bromothiazol-2-yl)propanoate (compound B1-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 in vacuo. 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 B1-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 B1-h) To a solution of methyl (2S)-3-(4-bromothiazol-2-yl)-2-(tert- butoxycarbonylamino)propanoate (compound B1-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 in vacuo to afford (2S)-3-(4-bromothiazol-2-yl)-2-(tert- butoxycarbonylamino)propanoic acid (compound B1-h, 3.1 g) as yellow oil. MS calc’d 373(MNa+), measured 372.9 (MNa+). Step 7: Preparation of benzyl (1S,5R)-3-[(2S)-3-(4-bromothiazol-2-yl)-2-(tert- butoxycarbonylamino)propanoyl]-2,3-diazabicyclo[3.2.1]octane-1-carboxylate (Intermediate B1) To a solution of (2S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)propanoic acid (compound B1-h, 3.5 g, 10.11 mmol) and benzyl (1S,5R)-2,3-diazabicyclo[3.2.1]octane-1- carboxylate (Intermediate A1, 4.0 g, 11.12 mmol) in DMF (100 mL) was added DIEA (17.1 mL, 101.08 mmol) at 0 °C. The reaction was stirred at 0 °C for 10min. T3P (13.3 g, 28.92 mmol) was added to the mixture at 0 °C. After being stirred at 25 °C for 2 h, the reaction was poured into ice water (50 mL), then extracted with EA (150 mL, three times). The combined organic layer was washed with 300 mL brine, dried over Na2SO4and concentrated in vacuo to give crude product. The crude product was purified by silica gel chromatography to give benzyl (1S,5R)-3-[(2S)-3- (4-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)propanoyl]-2,3-diazabicyclo[3.2.1]octane-1- carboxylate (Intermediate B1, 5.0 g) as a light yellow solid. MS calc’d 579.1.1 (MH+), measured 579.2 (MH+). Intermediate B2 Benzyl 3-[(2S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)propanoyl]-2,3- diazabicyclo[2.2.2]octane-1-carboxylate The title compound was prepared in analogy to the preparation for Intermediate B1 by using Benzyl 2,3-diazabicyclo[2.2.2]octane-1-carboxylate (Intermediate A2) instead of benzyl (1S,5R)- 2,3-diazabicyclo[3.2.1]octane-1-carboxylate (Intermediate A1). Intermediate B3 Benzyl (1R,5R)-3-[(2S)-2-amino-3-(4-bromothiazol-2-yl)propanoyl]-7-oxa-2,3- diazabicyclo[3.3.1]nonane-1-carboxylate The title compound was prepared in analogy to the preparation of Intermediate B1 by using benzyl (1R,5R)-7-oxa-2,3-diazabicyclo[3.3.1]nonane-1-carboxylate (Intermediate A3) instead of benzyl (1S,5R)-2,3-diazabicyclo[3.2.1]octane-1-carboxylate (Intermediate A1). Intermediate B4 Benzyl (1R,5R)-3-[(2S)-2-amino-3-(4-bromothiazol-2-yl)propanoyl]-7-oxa-2,3- diazabicyclo[3.3.1]nonane-1-carboxylate The title compound was prepared in analogy to the preparation of Intermediate B1 by using methyl 2,3-diazabicyclo[4.1.0]heptane-1-carboxylate instead of benzyl (1S,5R)-2,3- diazabicyclo[3.2.1]octane-1-carboxylate (Intermediate A1). Intermediate B5 Methyl 2-[(2S)-2-amino-3-(4-bromothiazol-2-yl)propanoyl]-2,3-diazabicyclo[3.1.1]heptane- 4-carboxylate The title compound was prepared in analogy to the preparation of Intermediate B1 by using methyl 2,3-diazabicyclo[3.1.1]heptane-4-carboxylate (CAS # 3034241-36-3) instead of benzyl (1S,5R)-2,3-diazabicyclo[3.2.1]octane-1-carboxylate (Intermediate A1). Intermediate C1 -[1-ethyl-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-5-(4,4,5,5-tetramethyl-,3,2-dioxaborolan-2-yl)indol-3-yl]-2,2-dimethyl-propan-1-ol The compound was prepared according to the following scheme:

[0003] Step 1: Preparation of 4-[5-bromo-6-[(1S)-1-methoxyethyl]-3-pyridyl]morpholine (compound C1-b) To a mixture of 3-bromo-5-iodo-2-[(1S)-1-methoxyethyl]pyridine (compound C1-a, CAS: 2641451-76-3, 10.0 g, 29.24 mmol) and morpholine (2.5 g, 29.24 mmol) in Toluene (165 mL) were added cesium carbonate (19.1 g, 58.48 mmol), (R)-binap (0.9 g, 1.46 mmol) and palladium (II) acetate (0.33 g, 1.46 mmol). The mixture was stirred at 100 °C for 12 hrs under nitrogen atmosphere. The other 2 batches (20 g) were combined and worked up altogether. The mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography to give 4-[5-bromo-6-[(1S)-1-methoxyethyl]-3-pyridyl]morpholine (compound C1-b, 23.6 g) as yellow oil. MS calc’d 301.0 (MH+), measured 301.0 (MH+). Step 2: Preparation of 4-[6-[(1S)-1-methoxyethyl]-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-3-pyridyl]morpholine (compound C1-c) To a mixture of 4-[5-bromo-6-[(1S)-1-methoxyethyl]-3-pyridyl]morpholine (compound C1- b, 5.0 g, 16.6 mmol) and bis(pinacolato)diboron (16.9 g, 66.41 mmol) in Toluene (50 mL) were added KOAc (3.26 g, 33.2 mmol) and [1,1- bis(diphenylphosphino)ferrocene]palladium,(ii)chloride (0.7 g, 0.83 mmol). The mixture was stirred at 90 °C for 12 h under nitrogen atmosphere. The mixture was filtered, and the filtrate was concentrated in vacuo to give the crude product. The residue was purified by silica gel chromatography to give 4-[6-[(1S)-1-methoxyethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-3-pyridyl]morpholine (compound C1-c, 3.0 g) as a brown solid. MS calc’d 349.2 (MH+), measured 349.2 (MH+). Step 3: Preparation of [3-[5-bromo-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3- pyridyl]-1H-indol-3-yl]-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (compound C1-e) To a mixture of [3-(5-bromo-2-iodo-1H-indol-3-yl)-2,2-dimethyl-propoxy]-tert-butyl- diphenyl-silane (compound C1-d, 4.2 g, 6.46 mmol), 4-[6-[(1S)-1-methoxyethyl]-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]morpholine (compound C1-c, 3.0 g, 6.46 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (472.7 mg, 0.65 mmol) in 1,4- dioxane (50 mL) was added potassium phosphate (4.1 g, 19.29 mmol). The mixture was stirred at 70 °C for 12 hrs under nitrogen atmosphere. The reaction mixture was extracted with EA (20 mL, twice). The combined organic phase was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography to afford [3-[5-bromo-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-1H-indol-3-yl]-2,2- dimethyl-propoxy]-tert-butyl-diphenyl-silane (compound C1-e, 5.9 g) as brown oil. MS calc’d 740.3 (MH+), measured 740.3 (M H+). Step 4: Preparation of [3-[5-bromo-1-ethyl-2-[2-[(1S)-1-methoxyethyl]-5-morpholino- 3-pyridyl]indol-3-yl]-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (compound C1-f) To the mixture of [3-[5-bromo-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-1H- indol-3-yl]-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (compound C1-e, 5.6 g, 7.56 mmol) in Toluene (92.5 mL) was added Et3BnNCl (3.4 g, 15.12 mmol) and KOH (1.06 g, 18.9 mmol) and cooled to 0 °C. The reaction mixture was added with iodoethane (1.5 mL, 18.9 mmol) dropwise at 0 °C. After being stirred at 25 °C for 0.5 h, the reaction mixture was cooled to room temperature. EtOAc (80 mL) and water (50 mL) were added to the reaction mixture and layers were separated. The aqueous phase was extracted with EtOAc (30 mL, twice). The organic layer was washed with brine (60 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography to give [3-[5-bromo-1-ethyl-2-[2- [(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]indol-3-yl]-2,2-dimethyl-propoxy]-tert-butyl- diphenyl-silane (compound C1-f, 5 g) as dark brown oil. MS calc’d 768.3 (MH+), measured 768.3 (MH+). Step 5: Preparation of 3-[5-bromo-1-ethyl-(2M)-2-[2-[(1S)-1-methoxyethyl]-5- morpholino-3-pyridyl]indol-3-yl]-2,2-dimethyl-propan-1-ol (compound C1-g) To a mixture of [3-[5-bromo-1-ethyl-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3- pyridyl]indol-3-yl]-2,2-dimethyl-propoxy]-tert-butyl-diphenyl-silane (compound C1-f, 5.0 g, 6.5 mmol) in DMF (50 mL) was added cesium fluoride (4.9 g, 32.51 mmol). The mixture was stirred at 80 °C for 16 hrs. The mixture was diluted with water (100 mL), extracted with EtOAc (80 mL, three times). The combined organic layer was washed with brine (150 mL, three times), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography to afford 3-[5-bromo-1-ethyl-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3- pyridyl]indol-3-yl]-2,2-dimethyl-propan-1-ol (compound C1-g, faster eluted, 3.6 g) as dark brown oil. MS calc’d 530.2 (MH+), measured 530.3 (MH+). Step 6: Preparation of 3-[1-ethyl-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3- pyridyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indol-3-yl]-2,2-dimethyl-propan-1- ol (Intermediate C1) To a solution of 3-[5-bromo-1-ethyl-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3- pyridyl]indol-3-yl]-2,2-dimethyl-propan-1-ol (compound C1-g, 3.3 g, 6.22 mmol) and bis(pinacolato)diboron (6.3 g, 24.88 mmol) in toluene (40 mL) was added potassium acetate (1.5 g, 15.55 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.5 g, 0.62 mmol). The reaction mixture was stirred at 90 °C for 2 hrs under nitrogen atmosphere. The reaction mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography to give 3-[1-ethyl-(2M)-2-[2-[(1S)-1-methoxyethyl]-5- morpholino-3-pyridyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indol-3-yl]-2,2-dimethyl- propan-1-ol (Intermediate C1, 3.67 g) as a yellow solid. MS calc’d 578.4 (MH+), measured 578.4 (MH+). Intermediate C2 3-[1-ethyl-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)indol-3-yl]-2,2-dimethyl-propan-1-ol The compound was prepared according to the following scheme: To a mixture of benzyl 4-[(5M)-5-[1-ethyl-3-(3-hydroxy-2,2-dimethyl-propyl)-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)indol-2-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine- 1-carboxylate (compound C2-a, 9.0 g, 12.66 mmol) and formaldehyde (20.5 g, 253.27 mmol) in Methanol (180.9 mL) was added Pd(OH)2 / C on activated carbon (6.6 g). The mixture was degassed and purged with hydrogen three times. The mixture was stirred at 30 °C for 18 hrs under hydrogen atmosphere (15 psi). The mixture was filtered and washed with MeOH. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography to give 3-[1-ethyl-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)indol-3-yl]-2,2-dimethyl-propan-1-ol (Intermediate C2, 5.8 g) as a light yellow solid. MS calc’d 591.4 (MH+), measured 591.4 (MH+). The compound C2-a was prepared in analogy to the preparation of Intermediate C1 by using benzyl piperazine-1-carboxylate instead of morpholine. Intermediate C3 3-[(2M)-2-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-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-3- yl]-2,2-dimethyl-propan-1-ol The compound was prepared according to the following scheme:

[0004] Step 1: Preparation of benzyl 4-[5-bromo-6-[(1S)-1-methoxyethyl]-3- pyridyl]piperazine-1-carboxylate (compound C3-b) To a solution of 3-bromo-5-iodo-2-[(1S)-1-methoxyethyl]pyridine (compound C3-a, 660 mg, 1.9 mmol, CAS 2641451-76-3, PBWZ170, PharmaBlock (Nanjing) R&D Co. Ltd) and 1- Cbz-piperazine (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 in vacuo. 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 C3-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 C3-c) To a solution of benzyl 4-[5-bromo-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1- carboxylate (compound C3-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 in vacuo 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 C3-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 C3-d) To a solution of benzyl 4-[6-[(1S)-1-methoxyethyl]-5-(2-trimethylsilylethynyl)-3- pyridyl]piperazine-1-carboxylate (compound C3-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 in vacuo 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 (compound C3-d, 25 g) as a brown solid. MS calc’d 380.2 (MH+), measured 380.2 (MH+). Step 4: 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 C3-f). To a solution of benzyl 4-[5-ethynyl-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1- carboxylate (compound C3-d, 26.1 g, 68.8 mmol) in DMF (400 mL) were added 6-bromo-8- iodo-1,2,3,4-tetrahydroquinoline (compound C3-e, 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 in vacuo 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 C3-f, 30.0 g) as a yellow solid. MS calc’d 589.2 (MH+), measured 589.2(MH+). Step 5: 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 C3-g). 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 C3-f, 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 in vacuo, 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 in vacuo 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 C3-g, 19.2 g) as a yellow solid. MS calc’d 589.2 (MH+), measured 589.2 (MH+). Step 6: 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 C3-h). 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 C3-g, 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 in vacuo 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 C3-h, 14.6 g) as a yellow solid. MS calc’d 616.9 (MH+), measured 617.2 (MH+). Step 7: Preparation of benzyl 4-[5-[6-bromo-3-(1-hydroxy-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 C3-i) 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 C3-h, 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 with anhydrous Na2SO4, filtered and concentrated in vacuo 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-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 C3-i, 14.01 g) as a yellow gum. MS calc’d 719.3 (MH+), measured 719.2 (MH+). Step 8: 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 C3-j) To a solution of benzyl 4-[5-[6-bromo-3-(1-hydroxy-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 C3-i, 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 in vacuo to give a residue, which was diluted with sat. NaHCO3aq. until pH=9 and extracted with EtOAc (300 mL, three times). The combined organic layer was dried with anhydrous Na2SO4, filtered and concentrated in vacuo 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 C3-j, 14 g) as a yellow gum. MS calc’d 703.2 (MH+), measured 703.2 (MH+). Step 9: 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 C3-k) 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 C3-j, 14.0 g, 19.9 mmol) in THF (150 mL) was added lithium borohydride (99.48 mL, 198.96 mmol) dropwise under N2at 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 C3-k, 7 g, faster eluted) as a yellow solid. MS calc’d 675.3 (MH+), measured 675.2 (MH+). Step 10: 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 C3-l) 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 C3-k, 7.0 g, 10.36 mmol) and bis(pinacolato)diboron (3.9 g, 15.54 mmol) in toluene (140 mL) was added KOAc (2.6 g, 26.05 mmol) and Pd(dppf)Cl2 (760.8 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 in vacuo 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 C3-l, 7.3 g) as a yellow solid.MS calc’d 723.4 (MH+), measured 723.4 (MH+). Step 11: Preparation of 3-[2-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3- pyridyl]-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-3-yl]-2,2-dimethyl-propan-1-ol (Intermediate C3) To a mixture 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 C3-l, 7.3 g, 10.8 mmol) and formaldehyde (20.5 g, 253.27 mmol) in Methanol (180.91 mL) was added Pd(OH)2 / C on activated carbon (6.7 g). The mixture was degassed and purged with hydrogen three times. The mixture was stirred at 30 °C for 18 hrs under hydrogen atmosphere (15 psi). The mixture was filtered, and washed with MeOH. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography to give 3-[2-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-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-3-yl]-2,2-dimethyl-propan-1-ol (Intermediate C3, 4.8 g) as a light yellow solid. MS calc’d 603.4 (MH+), measured 603.4 (MH+). Intermediate D (7S,11R,14S)-7-amino-22-ethyl-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-morpholino-3- pyridyl]-18,18-dimethyl-16-oxa-4-thia-9,22,29,30- tetrazahexacyclo[18.5.2.12,5.19,14.111,14.023,27]triaconta-1(26),2,5(30),20,23(27),24-hexaene-8,15- dione (Intermediate D) The compound was prepared according to the following scheme:Intermediate DStep 1: Preparation of benzyl (1S,5R)-3-[(2S)-2-(tert-butoxycarbonylamino)-3-[4-[1- ethyl-3-(3-hydroxy-2,2-dimethyl-propyl)-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3- pyridyl]indol-5-yl]thiazol-2-yl]propanoyl]-2,3-diazabicyclo[3.2.1]octane-1-carboxylate (compound D1) To a solution of 3-[1-ethyl-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indol-3-yl]-2,2-dimethyl-propan-1-ol (Intermediate C1, 1.8g, 2.58mmol) and benzyl (1S,5R)-3-[(2S)-3-(4-bromothiazol-2-yl)-2-(tert- butoxycarbonylamino)propanoyl]-2,3-diazabicyclo[3.2.1]octane-1-carboxylate (Intermediate B1, 1.65 g, 2.84 mmol) in Toluene (30 mL) / 1,4-dioxane (9 mL) / Water (9 mL) were added K3PO4 (1.4 g, 6.46 mmol) and Pd(dtbpf)Cl2 (168.4 mg, 0.26 mmol). The mixture was stirred at 70 °C for 12 hrs under nitrogen atmosphere. The reaction mixture was added water and extracted with EA (20 mL, three times). The combined organic layer was dried over Na2SO4and concentrated to give crude product. The residue was purified by silica gel chromatography to give benzyl (1S,5R)-3-[(2S)-2-(tert-butoxycarbonylamino)-3-[4-[1-ethyl-3-(3-hydroxy-2,2-dimethyl-propyl)- (2M)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]indol-5-yl]thiazol-2-yl]propanoyl]- 2,3-diazabicyclo[3.2.1]octane-1-carboxylate (compound D1,1.28 g) as a light brown solid. MS calc’d 950.5 (MH+), measured 950.5 (MH+). Step 2: Preparation of (1S,5R)-3-[(2S)-2-(tert-butoxycarbonylamino)-3-[4-[1-ethyl-3- (3-hydroxy-2,2-dimethyl-propyl)-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3- pyridyl]indol-5-yl]thiazol-2-yl]propanoyl]-2,3-diazabicyclo[3.2.1]octane-1-carboxylic acid (compound D2) To a solution benzyl (1S,5R)-3-[(2S)-2-(tert-butoxycarbonylamino)-3-[4-[1-ethyl-3-(3- hydroxy-2,2-dimethyl-propyl)-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]indol- 5-yl]thiazol-2-yl]propanoyl]-2,3-diazabicyclo[3.2.1]octane-1-carboxylate (compound D1, 1.1 g, 1.16 mmol) in methanol (100 mL) was added Pd / C on activated carbon (500.0 mg) under nitrogen atmosphere. After being stirred at 25 °C for 3 hrs, the mixture was filtered, washed with MeCN. The filtrate was concentrated in vacuo to give (1S,5R)-3-[(2S)-2-(tert- butoxycarbonylamino)-3-[4-[1-ethyl-3-(3-hydroxy-2,2-dimethyl-propyl)-(2M)-2-[2-[(1S)-1- methoxyethyl]-5-morpholino-3-pyridyl]indol-5-yl]thiazol-2-yl]propanoyl]-2,3- diazabicyclo[3.2.1]octane-1-carboxylic acid (compound D2, 1.1 g) as a light yellow solid. MS calc’d 860.0 (MH+), measured 860.5 (MH+). Step 3: Preparation of tert-butyl N-[(7S,11R,14S)-22-ethyl-(21M)-21-[2-[(1S)-1- methoxyethyl]-5-morpholino-3-pyridyl]-18,18-dimethyl-8,15-dioxo-16-oxa-4-thia- 9,22,29,30-tetrazahexacyclo[18.5.2.12,5.19,14.111,14.023,27]triaconta-1(26),2,5(30),20,23(27),24- hexaen-7-yl]carbamate (compound D3) To a solution of (1S,5R)-3-[(2S)-2-(tert-butoxycarbonylamino)-3-[4-[1-ethyl-3-(3-hydroxy- 2,2-dimethyl-propyl)-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]indol-5- yl]thiazol-2-yl]propanoyl]-2,3-diazabicyclo[3.2.1]octane-1-carboxylic acid (compound D2, 200.0 mg, 0.23 mmol) in DCM (20 mL) was added DIEA (901.6 mg, 6.98 mmol) and HATU (795.7 mg, 2.09 mmol) at 0 °C. The reaction was stirred at 0 °C for 15 min., 1H-imidazole (237.5 mg, 3.49 mmol) was added. After being stirred at 25 °C for 1 h, the reaction mixture was concentrated under reduced pressure to remove the solvent, extracted with EA (30 mL, twice), dried over Na2SO4 and concentrated to give crude product. The crude was purified by silica gel chromatography to give tert-butyl N-[(7S,11R,14S)-22-ethyl-(21M)-21-[2-[(1S)-1- methoxyethyl]-5-morpholino-3-pyridyl]-18,18-dimethyl-8,15-dioxo-16-oxa-4-thia-9,22,29,30- tetrazahexacyclo[18.5.2.12,5.19,14.111,14.023,27]triaconta-1(26),2,5(30),20,23(27),24-hexaen-7- yl]carbamate (compound D3, 190 mg) as a light yellow solid. MS calc’d 842.4 (MH+), measured 842.4 (MH+). Step 4: Preparation of (7S,11R,14S)-7-amino-22-ethyl-(21M)-21-[2-[(1S)-1- methoxyethyl]-5-morpholino-3-pyridyl]-18,18-dimethyl-16-oxa-4-thia-9,22,29,30- tetrazahexacyclo[18.5.2.12,5.19,14.111,14.023,27]triaconta-1(26),2,5(30),20,23(27),24-hexaene- 8,15-dione (Intermediate D) To a solution of tert-butyl N-[(7S,11R,14S)-22-ethyl-(21M)-21-[2-[(1S)-1-methoxyethyl]-5- morpholino-3-pyridyl]-18,18-dimethyl-8,15-dioxo-16-oxa-4-thia-9,22,29,30- tetrazahexacyclo[18.5.2.12,5.19,14.111,14.023,27]triaconta-1(26),2,5(30),20,23(27),24-hexaen-7- yl]carbamate (compound D3, 190.0 mg, 0.23 mmol) in DCM (5 mL) was added TFA (1.0 mL) at 0 °C. The reaction was stirred at 25 °C for 1 h, and then concentrated. The reaction mixture was quenched with 10 mL sat. NaHCO3aq., extracted with EA (30 mL, twice). The combined organic layer was dried over Na2SO4 and concentrated to give (7S,11R,14S)-7-amino-22-ethyl- (21M)-21-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-18,18-dimethyl-16-oxa-4-thia- 9,22,29,30-tetrazahexacyclo[18.5.2.12,5.19,14.111,14.023,27]triaconta-1(26),2,5(30),20,23(27),24- hexaene-8,15-dione (Intermediate D, 200 mg) as a light yellow solid. MS calc’d 741.9 (MH+), measured 742.3 (MH+). Intermediate E (7S,11R,14S)-7-amino-22-ethyl-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1- yl)-3-pyridyl]-18,18-dimethyl-16-oxa-4-thia-9,22,29,30- tetrazahexacyclo[18.5.2.12,5.19,14.111,14.023,27]triaconta-1(26),2,5(30),20,23(27),24-hexaene-8,15- dione (Intermediate E) The title compound was prepared in analogy to the preparation of Intermediate D by using 3-[1-ethyl-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)indol-3-yl]-2,2-dimethyl-propan-1-ol (Intermediate C2) instead of 3-[1-ethyl-(2M)-2-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)indol-3-yl]-2,2-dimethyl-propan-1-ol (Intermediate C1). Intermediate F

[0005] (7S)-7-amino-21-ethyl-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17- dimethyl-15-oxa-4-thia-9,21,29,30-tetrazahexacyclo[17.5.2.210,13.12,5.19,13.022,26]triaconta- 1(25),2,5(30),19,22(26),23-hexaene-8,14-dione The title compound was prepared in analogy to the preparation of Intermediate D by using benzyl 3-[(2S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)propanoyl]-2,3- diazabicyclo[2.2.2]octane-1-carboxylate (Intermediate B2) instead of benzyl (1S,5R)-3-[(2S)-3- (4-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)propanoyl]-2,3-diazabicyclo[3.2.1]octane-1- carboxylate (Intermediate B1). Intermediate G

[0006] (7S,11R,15R)-7-amino-23-ethyl-(22M)-22-[2-[(1S)-1-methoxyethyl]-5-morpholino-3- pyridyl]-19,19-dimethyl-13,17-dioxa-4-thia-9,23,30,31- tetrazahexacyclo[19.5.2.12,5.19,15.111,15.024,28]hentriaconta-1(27),2,5(31),21,24(28),25-hexaene- 8,16-dione The title compound was prepared in analogy to the preparation of Intermediate D by using benzyl (1R,5R)-3-[(2S)-2-amino-3-(4-bromothiazol-2-yl)propanoyl]-7-oxa-2,3- diazabicyclo[3.3.1]nonane-1-carboxylate (Intermediate B3) instead of benzyl (1S,5R)-3-[(2S)-3- (4-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)propanoyl]-2,3-diazabicyclo[3.2.1]octane-1- carboxylate (Intermediate B1). Intermediate H

[0007] (1S,23S,27R)-23-amino-(8M)-8-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3- pyridyl]-5,5-dimethyl-3-oxa-20-thia-9,25,30,32- tetrazaheptacyclo[23.4.1.11,27.113,17.118,21.07,15.09,14]tritriaconta-7,13,15,17(33),18,21(32)- hexaene-2,24-dione The title compound was prepared in analogy to the preparation of Intermediate D by using 3-[2-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-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-3-yl]-2,2-dimethyl- propan-1-ol (Intermediate C3) instead of 3-[1-ethyl-(2M)-2-[2-[(1S)-1-methoxyethyl]-5- morpholino-3-pyridyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indol-3-yl]-2,2-dimethyl- propan-1-ol (Intermediate C1). Intermediate I

[0008] (1S,23S,27R)-23-amino-(8M)-8-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3- pyridyl]-5,5-dimethyl-3,12-dioxa-20-thia-9,25,30,32- tetrazaheptacyclo[23.4.1.11,27.113,17.118,21.07,15.09,14]tritriaconta-7,13,15,17(33),18,21(32)- hexaene-2,24-dione The title compound was prepared in analogy to the preparation of Intermediate H by using 7-bromo-5-iodo-3,4-dihydro-2H-1,4-benzoxazine instead of 6-bromo-8-iodo-1,2,3,4- tetrahydroquinoline. Intermediate J (7S)-7-amino-22-ethyl-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-18,18- dimethyl-16-oxa-4-thia-9,22,28,29-tetrazahexacyclo[18.5.2.12,5.19,14.012,14.023,27]nonacosa- 1(26),2,5(29),20,23(27),24-hexaene-8,15-dione The title compound was prepared in analogy to the preparation of Intermediate D by using methyl 3-[(2S)-2-amino-3-(4-bromothiazol-2-yl)propanoyl]-2,3-diazabicyclo[4.1.0]heptane-1- carboxylate (Intermediate B4) instead of benzyl (1S,5R)-3-[(2S)-3-(4-bromothiazol-2-yl)-2-(tert- butoxycarbonylamino)propanoyl]-2,3-diazabicyclo[3.2.1]octane-1-carboxylate (Intermediate B1). Intermediate K (7S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]- 17,17-dimethyl-15-oxa-4-thia-9,21,30,32- 2,5 9,13 10,12 19,27 21,26 tetrazaheptacyclo[23.3.1.1 .1 .1 .0 .0 ]dotriaconta-1(29),2,5(32),19,25,27- hexaene-8,14-dione The title compound was prepared in analogy to the preparation of Intermediate D by using methyl 2-[(2S)-2-amino-3-(4-bromothiazol-2-yl)propanoyl]-2,3-diazabicyclo[3.1.1]heptane-4- carboxylate (intermediate B5) and 3-[2-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3- pyridyl]-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-3-yl]-2,2-dimethyl-propan-1-ol (Intermediate C3) instead of benzyl (1S,5R)- 3-[(2S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)propanoyl]-2,3- diazabicyclo[3.2.1]octane-1-carboxylate (intermediate B1) and 3-[1-ethyl-(2M)-2-[2-[(1S)-1- methoxyethyl]-5-morpholino-3-pyridyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indol-3- yl]-2,2-dimethyl-propan-1-ol (Intermediate C1). Example 1-1 and 1-2 (1S,2S)-N-[(7S,11R,14S)-22-ethyl-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin- 1-yl)-3-pyridyl]-18,18-dimethyl-8,15-dioxo-16-oxa-4-thia-9,22,29,30- tetrazahexacyclo[18.5.2.12,5.19,14.111,14.023,27]triaconta-1(26),2,5(30),20,23(27),24-hexaen-7-yl]- 2-(2-methylpyrimidin-5-yl)cyclopropanecarboxamide and (1R,2R)-N-[(7S,11R,14S)-22- ethyl-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-18,18- dimethyl-8,15-dioxo-16-oxa-4-thia-9,22,29,30- tetrazahexacyclo[18.5.2.12,5.19,14.111,14.023,27]triaconta-1(26),2,5(30),20,23(27),24-hexaen-7-yl]- 2-(2-methylpyrimidin-5-yl)cyclopropanecarboxamide To a solution of (1R)-2-(2-methylpyrimidin-5-yl)cyclopropanecarboxylic acid (6.0 mg, 0.33 mmol) in N,N-dimethylformamide (0.2 mL) was added HATU (18.9 mg, 49.67 µmol,) and DIEA (17 µL, 99.34 µmol) and the mixture was stirred at 20 °C for 10 min. (7S,11R,14S)-7- amino-22-ethyl-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]- 18,18-dimethyl-16-oxa-4-thia-9,22,29,30-tetrazahexacyclo[18.5.2.12,5.19,14.111,14.023,27]triaconta- 1(26),2,5(30),20,23(27),24-hexaene-8,15-dione (Intermediate E, 25 mg, 33.11 µmol) was added to the reaction and stirred at rt for 2 hrs. After the reaction was completed, the reaction mixture was concentrated in vacuo and then purified by prep-HPLC and SFC to afford (1R,2R)-N- [(7S,11R,14S)-22-ethyl-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3- pyridyl]-18,18-dimethyl-8,15-dioxo-16-oxa-4-thia-9,22,29,30- tetrazahexacyclo[18.5.2.12,5.19,14.111,14.023,27]triaconta-1(26),2,5(30),20,23(27),24-hexaen-7-yl]- 2-(2-methylpyrimidin-5-yl)cyclopropanecarboxamide (Example 1-2, 5 mg) as white powder and (1S,2S)-N-[(7S,11R,14S)-22-ethyl-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-18,18-dimethyl-8,15-dioxo-16-oxa-4-thia-9,22,29,30- tetrazahexacyclo[18.5.2.12,5.19,14.111,14.023,27]triaconta-1(26),2,5(30),20,23(27),24-hexaen-7-yl]- 2-(2-methylpyrimidin-5-yl)cyclopropanecarboxamide (Example 1-1, 5.8 mg) as white powder. Instrument: SFC 150 Mgm. Column: GS Ethyl Pyridine Ⅱ, 50×20 mm I.D., 5µm Mobile phase: A for CO2 and B for ethanol (0.1% NH3H2O);Gradient: B 15%;Flow rate: 80 mL / min; Back pressure: 100bar.Column temperature: 35℃. Example 1-1 (5.8 mg, SFC, slower eluted) was obtained as a white solid. MS calc’d 915.5 (MH+), measured 915.5 (MH+).1H NMR (400 MHz, METHANOL-d4) δ 8.45 - 8.42 (m, 2H), 8.37 - 8.34 (m, 2H), 7.59 (dd, J = 1.5, 8.5 Hz, 1H), 7.43 - 7.34 (m, 3H), 5.89 (br d, J = 7.3 Hz, 1H), 5.26 - 5.20 (m, 1H), 4.19 - 4.06 (m, 3H), 4.05 - 3.88 (m, 2H), 3.80 - 3.74 (m, 1H), 3.71 - 3.66 (m, 1H), 3.49 - 3.44 (m, 2H), 3.36 - 3.31 (m, 1H), 3.15 (s, 4H), 2.86 (br d, J = 12.4 Hz, 1H), 2.69 (br d, J = 13.0 Hz, 3H), 2.56 - 2.53 (m, 3H), 2.51 - 2.46 (m, 2H), 2.27 - 2.21 (m, 1H), 2.13 - 2.07 (m, 1H), 2.02 - 1.97 (m, 1H), 1.95 - 1.88 (m, 2H), 1.87 - 1.81 (m, 2H), 1.57 - 1.51 (m, 2H), 1.50 - 1.41 (m, 2H), 1.35 - 1.32 (m, 3H), 1.17 - 1.16 (m, 1H), 1.12 - 1.11 (m, 1H), 1.06 (d, J = 6.3 Hz, 1H), 0.95 (t, J = 7.1 Hz, 3H), 0.82. Example 1-2 (5.0 mg, SFC, faster eluted) was obtained as a white solid. MS calc’d 915.5 (MH+), measured 915.5 (MH+).1H NMR (400 MHz, METHANOL-d4) δ 8.40 (s, 2H), 8.37 (d, J = 0.9 Hz, 1H), 8.32 (d, J = 2.8 Hz, 1H), 7.57 (dd, J = 1.5, 8.6 Hz, 1H), 7.40 - 7.38 (m, 1H), 7.35 (d, J = 7.8 Hz, 1H), 7.26 (d, J = 2.9 Hz, 1H), 5.97 (dd, J = 1.6, 8.1 Hz, 1H), 5.27 - 5.19 (m, 1H), 4.15 - 4.09 (m, 2H), 4.05 - 3.96 (m, 2H), 3.77 (d, J = 10.5 Hz, 1H), 3.73 - 3.67 (m, 1H), 3.46 (dd, J = 1.8, 15.1 Hz, 1H), 3.30 - 3.26 (m, 4H), 3.15 - 3.11 (m, 3H), 2.90 - 2.84 (m, 1H), 2.82 - 2.80 (m, 1H), 2.75 - 2.70 (m, 1H), 2.66 - 2.60 (m, 4H), 2.57 - 2.54 (m, 3H), 2.49 - 2.46 (m, 1H), 2.35 - 2.31 (m, 3H), 2.28 - 2.22 (m, 1H), 2.12 - 2.07 (m, 1H), 2.02 - 1.97 (m, 1H), 1.96 - 1.90 (m, 2H), 1.84 - 1.81 (m, 1H), 1.35 - 1.32 (m, 3H), 1.12 (s, 2H), 1.06 (d, J = 6.3 Hz, 2H), 0.99 - 0.93 (m, 3H), 0.81 - 0.78 (m, 1H), 0.72 (s, 3H), 0.51 (s, 2H). The following compounds were prepared in analogy to the preparation of Example 1-1 and Example 1-2. Table 1. Compound list Example MS measured (MH+) and Compound name and structures NO. NMR MS measured (MH+): 887.4 NMR:1H NMR (400 MHz, METHANOL-d4) δ = 8.54 - 8.49 (m, 2H), 8.36 (d, J = 1.9 Hz, 1H), 8.32 (d, J = 2.9 Hz, 1H), 8.30 (dd, J = 1.4, 5.0 Hz, 1H), 7.62 - 7.58 (m, 1H), 7.55 (dd, J = 1.6, 8.6 Hz, 1H), 7.41 - 7.37 (m, 2H), 7.36 - 7.31 (m, 2H), 5.98 - 5.92 (m, 1H), 4.23 (br s,1H), 4.10 - 4.02 (m, 1H), 1-3 4.01 - 3.96 (m, 2H), 3.88 - 3.82 (m, 2H), 3.77 (t, J = 4.8 Hz, (1S,2S)-N-[(7S)-21-ethyl-(20M)-20-[2-[(1S)-1- 4H), 3.40 - 3.33 (m, 1H), 3.16 methoxyethyl]-5-morpholino-3-pyridyl]-17,17- (br d, J = 8.0 Hz, 3H), 3.04 - dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,29,30- 2.98 (m, 1H), 2.97 (s, 3H), 2.39 tetrazahexacyclo[17.5.2.210,13.12,5.19,13.022,26]triac - 2.30 (m, 2H), 2.09 - 1.91 (m, onta-1(25),2,5(30),19,22(26),23-hexaen-7-yl]-2- 4H), 1.90 - 1.79 (m, 2H), 1.76 - (2-pyridyl)cyclopropanecarboxamide 1.60 (m, 4H), 1.43 (td, J = 4.9, 9.5 Hz, 1H), 1.35 - 1.31 (m, 3H), 1.24 - 1.18 (m, 1H), 1.13 (t, J = 7.1 Hz, 3H), 0.75 (s, 3H), 0.59 (s, 3H).

[0009] MS measured (MH+): 838.5 NMR:1H NMR (500 MHz, METHANOL-d4) δ = 8.60 (s, 1H), 8.41 (d, J = 2.7 Hz, 1H), 7.66 (br dd, J = 1.5, 8.5 Hz, 1H), 7.55 (br s, 1H), 7.51 - 7.45 (m, 2H), 6.08 - 5.90 (m, 1H), 4.35 - 4.29 (m, 1H), 4.23 - 4.14 (m, 1H), 4.13 - 4.02 (m, 2H), 4.00 - 3.90 (m, 2H), 3.87 (br t, J-4 (2R,3S)-N-[(7S)-21-ethyl-(20M)-20-[2-[(1S)-1- = 4.7 Hz, 4H), 3.46 - 3.39 (m, methoxyethyl]-5-morpholino-3-pyridyl]-17,17- 1H), 3.37 - 3.33 (m, 2H), 3.29 - dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,29,30- 3.23 (m, 1H), 3.11 (s, 3H), 3.08 tetrazahexacyclo[17.5.2.210,13.12,5.19,13.022,26]triac - 3.02 (m, 1H), 2.50 - 2.41 (m, onta-1(25),2,5(30),19,22(26),23-hexaen-7-yl]- 1H), 2.17 - 2.04 (m, 2H), 2.01 - 2,3-dimethyl-cyclopropanecarboxamide 1.88 (m, 2H), 1.86 - 1.69 (m, 4H), 1.43 (br d, J = 6.4 Hz, 3H), 1.35 - 1.28 (m, 3H), 1.22 (s, 3H), 1.17 - 1.11 (m, 1H), 1.11 - 1.02 (m, 7H), 0.85 (s, 3H), 0.70 (s, 3H). MS measured (MH+): 901.5 NMR:1H NMR (400 MHz, METHANOL-d4) δ = 9.00 (s, 1H), 8.64 (s, 2H), 8.50 - 8.48 (m, 2H), 7.71 (dd, J = 1.6, 8.4 Hz, 1H), 7.62 (d, J = 2.8 Hz,-5 1H), 7.53 (s, 1H), 7.50 (d, J = 8.4 Hz, 1H), 6.04 - 5.98 (m, 1H), 4.30 - 4.24 (m, 2H), 4.21 - (1S,2S)-N-[(7S,11R,14S)-22-ethyl-(21M)-21-[2- 4.17 (m, 1H), 4.14 - 4.07 (m, [(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1- 2H), 4.04 - 3.98 (m, 1H), 3.89 - yl)-3-pyridyl]-18,18-dimethyl-8,15-dioxo-16- 3.78 (m, 3H), 3.61 - 3.53 (m, oxa-4-thia-9,22,29,30- 3H), 3.48 - 3.40 (m, 2H), 3.28 tetrazahexacyclo[18.5.2.12,5.19,14.111,14.023,27]triac (s, 3H), 3.00 (s, 3H), 2.98 - 2.94 onta-1(25),2,5(30),20,23,26-hexaen-7-yl]-2- (m, 1H), 2.90 - 2.77 (m, 2H), pyrimidin-5-yl-cyclopropanecarboxamide 2.61 - 2.56 (m, 2H), 2.54 - 2.49 (m, 1H), 2.40 - 2.36 (m, 1H), 2.16 - 2.12 (m, 1H), 2.01 - 1.97 (m, 1H), 1.95 - 1.92 (m, 2H), 1.68 - 1.63 (m, 1H), 1.59 - 1.55 (m, 1H), 1.45 (d, J = 6.4 Hz, 3H), 1.43 - 1.38 (m, 2H), 1.34 - 1.29 (m, 1H), 1.06 (t, J = 7.2 Hz, 3H), 0.83 (s, 3H), 0.62 (s, 3H). MS measured (MH+): 854.4 NMR:1H NMR (400 MHz, METHANOL-d4) δ = 8.50 (s, 1H), 8.40 (br d, J = 2.5 Hz, 1H), 7.90 (br d, J = 2.0 Hz, 1H), 7.80 (br d, J = 9.1 Hz, 1H), 7.60 - 7.52 (m, 2H),5.86 (br d, J = 9.3 Hz, 1H), 5.78 - 5.58 (m, 1H),4.64 (br d, J = 12.8 Hz,-6 1H), 4.47 (br d, J = 6.3 Hz, 1H), (2R,3S)-N-[(7S,11S,15S)-23-ethyl-(22M)-22-[2- 4.43 - 4.34 (m, 1H), 4.29 (br d, [(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]- J = 11.5 Hz, 1H),4.11 (br d, J = 19,19-dimethyl-8,16-dioxo-13,17-dioxa-4-thia- 11.4 Hz, 2H), 3.98 - 3.75 (m, 9,23,30,31- 9H),3.45 (s, 6H), 3.27 - 3.01 (m, tetrazahexacyclo[19.5.2.12,5.19,15.111,15.024,28]hentr 4H), 2.74 - 2.64 (m, 1H),2.24 - iaconta-1(27),2,5(31),21,24(28),25-hexaen-7-yl]- 2.10 (m, 3H),1.48 (br d, J = 6.3 2,3-dimethyl-cyclopropanecarboxamide Hz, 3H),1.35-1.30 (m, 3H), 1.17 - 1.11 (m, 7H), 1.01 (br s, 3H), 0.96 (s, 3H), 0.54 (br s, 3H). MS measured (MH+): 900.5 NMR:1H NMR (400 MHz, METHANOL-d4) δ = 8.78 - 8.73 (m, 1H), 8.69 - 8.63 (m, 1H), 8.52 - 8.46 (m, 2H), 8.33 - 8.27 (m, 1H), 7.97 - 7.90 (m, 1H), 7.76 - 7.68 (m, 1H), 7.67 - 7.63 (m, 1H), 7.54 - 7.49 (m, (1S,2S)-N-[(7S,11R,14S)-22-ethyl-(21M)-21-[2- 2H), 6.11 - 5.88 (m, 1H), 4.33 - [(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1- 4.23 (m, 2H), 4.19 (br dd, J = yl)-3-pyridyl]-18,1 2.6, 12.5 Hz, 1H), 4.12 - 3.98-7 8-dimethyl-8,15-dioxo-16- oxa-4-thia-9,22,29,30- (m, 2H), 3.90 - 3.85 (m, 1H), tetrazahexacyclo[18.5.2.12,5.19,14.111,14.023,27]triac 3.81 - 3.77 (m, 1H), 3.67 - 3.54 onta-1(26),2,5(30),20,23(27),24-hexaen-7-yl]-2- (m, 3H), 3.50 - 3.39 (m, 2H), (3-pyridyl)cyclopropanecarboxamide 3.28 (s, 3H), 3.25 - 3.17 (m, 1H), 3.04 - 2.93 (m, 5H), 2.91 - 2.76 (m, 2H), 2.64 - 2.45 (m, 4H), 2.25 - 2.15 (m, 1H), 2.11 - 1.87 (m, 4H), 1.70 - 1.59 (m, 2H), 1.51 - 1.31 (m, 5H), 0.96 (s, 3H), 0.90 - 0.77 (m, 3H), 0.63 (s, 3H). MS measured (MH+): 865.5 NMR:1H NMR (400 MHz, METHANOL- d4) δ = 8.52 - 8.45 (m, 1H), 8.11 (s, 1H), 7.79 - 7.48 (m, 1H), 7.47 - 7.40 (m,-8 1H), 7.12 - 7.00 (m, 1H), 5.86 (d, J = 7.9 Hz, 1H), 4.64 - 4.54 (m, 2H), 4.53 - 4.43 (m, 1H), 4.37 - 4.27 (m, 1H), 4.22 - 4.14 (m, 1H), 4.13 - 3.90 (m, 2H), 3.89 - 3.68 (m, 4H), 3.65 - 3.57 (2R,3S)-N-[(1S,23S,27R)-(8M)-8-[2-[(1S)-1- (m, 1H), 3.54 - 3.45 (m, 2H), methoxyethyl]-5-(4-methylpiperazin-1-yl)-3- 3.34 (s, 3H), 3.28 - 3.11 (m, pyridyl]-5,5-dimethyl-2,24-dioxo-3,12-dioxa-20- 3H), 3.06 (d, J = 15.0 Hz, 1H), thia-9,25,30,32- 3.01 - 2.99 (m, 3H), 2.96 - 2.92 tetrazaheptacyclo[23.4.1.11,27.113,17.118,21.07,15.09,14(m, 1H), 2.84 - 2.49 (m, 4H), ]tritriaconta-7,13,15,17(33),18,21(32)-hexaen-23- 2.06 - 1.89 (m, 3H), 1.73 - 1.61 yl]-2,3-dimethyl-cyclopropanecarboxamide (m, 1H), 1.51 - 1.44 (m, 3H), 1.41 - 1.26 (m, 3H), 1.16 - 1.09 (m, 7H), 0.96 - 0.89 (m, 3H), 0.55 (s, 3H). MS measured (MH+): 851.5 NMR:1H NMR (400 MHz, METHANOL- d4) δ = 8.68 - 8.45 (m, 1H), 8.11 - 8.01 (m, 1H), 7.55 (d, J = 2.8 Hz, 1H), 7.47 - 7.41 (m, 1H), 7.01 (s, 1H), 5.86 (d, J = 8.3 Hz, 1H), 4.66 - 4.55 (m, 2H), 4.50 (q, J = 6.5 Hz, 1H), 4.35 - 4.27 (m, 1H), 4.21 - 4.15 (m, 1H), 4.13 - 3.92 (m, 2H), 3.82 - 3.70 (m,-9 3H), 3.68 - 3.55 (m, 2H), 3.53 - (1S,2S)-N-[(1S,23S,27R)-(8M)-8-[2-[(1S)-1- 3.47 (m, 2H), 3.35 (s, 3H), 3.27 methoxyethyl]-5-(4-methylpiperazin-1-yl)-3- (d, J = 6.6 Hz, 1H), 3.10 - 3.03 pyridyl]-5,5-dimethyl-2,24-dioxo-3,12-dioxa-20- (m, 1H), 3.01 - 2.98 (m, 3H), thia-9,25,30,32- 1,27 13,17 18,21 72.97 - 2.92 (m, 1H), 2.79 - 2.54 tetrazaheptacyclo[23.4.1.1 .1 .1 .0,15.09,14(m, 4H), 2.11 - 1.85 (m, 4H), ]tritriaconta-7,13,15,17(33),18,21(32)-hexaen-23- 1.72 - 1.63 (m, 1H), 1.37 (d, J = yl]-2-methyl-cyclopropanecarboxamide 3.4, 6.9 Hz, 1H), 1.52 - 1.28 (m, 4H), 1.34 - 1.27 (m, 1H), 1.24 - 1.15 (m, 1H), 1.10 (d, J = 5.9 Hz, 3H), 1.03 (td, J = 4.3, 8.6 Hz, 1H), 0.93 (s, 3H), 0.64 - 0.52 (m, 4H). MS measured (MH+): 851.5 NMR:1H NMR (400 MHz, METHANOL-d4) δ = 8.51 - 8.43 (m, 2H), 7.76 - 7.55 (m, 2H), 7.53 - 7.48 (m, 2H), 5.91 (s, 1H), 4.30 - 4.22 (m, 2H), 4.20 - 3.95 (m, 5H), 3.87 - 3.76 (m, 2H), 3.70 - 3.57 (m, 3H), 3.54 - 3.43 (m, 3H), 3.28 - 3.27 (m, 2H), 3.17 - 3.12 (m, 1H),-10 3.03 - 2.91 (m, 6H), 2.80 - 2.70 (m, 1H), 2.67 - 2.52 (m, 3H), N-[(7S,11R,14S)-22-ethyl-(21M)-21-[2-[(1S)-1- 2.12 - 1.98 (m, 2H), 1.96 - 1.88 methoxyethyl]-5-(4-methylpiperazin-1-yl)-3- (m, 2H), 1.71 - 1.63 (m, 1H), pyridyl]-18,18-dimethyl-8,15-dioxo-16-oxa-4- 1.45 - 1.41 (m, 3H), 1.38 - 1.29 thia-9,22,29,30- (m, 5H), 1.12 (d, J = 6.1 Hz, tetrazahexacyclo[18.5.2.12,5.19,14.111,14.023,27]triac 2H), 1.05 - 0.94 (m, 3H), 0.89 - onta-1(26),2,5(30),20,23(27),24-hexaen-7-yl]- 0.70 (m, 3H), 0.59 (d, J = 12.8 1,2-dimethyl-cyclopropanecarboxamide Hz, 3H), 0.28 (d, J = 2.6, 3.2 Hz, 1H). MS measured (MH+): 863.5 NMR:1H NMR (400 MHz, METHANOL-d4) δ = 8.50 - 8.42 (m, 2H), 7.78 - 7.67 (m, 1H), 7.60 (br d, J = 1.9 Hz, 1H), 7.53 - 7.48 (m, 2H), 5.95 (d, J =-11 9.8 Hz, 1H), 4.32 - 4.22 (m, 2H), 4.21 - 3.99 (m, 4H), 3.89 - 3.80 (m, 2H), 3.66 - 3.47 (m, (1R,2S)-2-cyclopropyl-N-[(7S,11R,14S)-22-ethyl- 4H), 3.44 - 3.39 (m, 1H), 3.29 - (21M)-21-[2-[(1S)-1-methoxyethyl]-5-(4- 3.29 (m, 2H), 3.20 - 3.12 (m, methylpiperazin-1-yl)-3-pyridyl]-18,18-dimethyl- 1H), 3.00 (s, 4H), 2.97 - 2.89 8,15-dioxo-16-oxa-4-thia-9,22,29,30- (m, 2H), 2.74 (d, J = 14.0 Hz, tetrazahexacyclo[18.5.2.12,5.19,14.111,14.023,27]triac 1H), 2.63 - 2.47 (m, 3H), 2.06 - onta-1(26),2,5(30),20,23(27),24-hexaen-7- 1.86 (m, 4H), 1.68 - 1.62 (m, yl]cyclopropanecarboxamide 1H), 1.52 (td, J = 3.9, 8.1 Hz, 1H), 1.46 - 1.42 (m, 3H), 1.34 - 1.23 (m, 2H), 1.03 (t, J = 6.8 Hz, 3H), 1.00 - 0.87 (m, 2H), 0.84 (s, 3H), 0.65 - 0.55 (m, 4H), 0.46 - 0.38 (m, 2H), 0.14 (d, J = 4.0 Hz, 2H). MS measured (MH+): 899.9 NMR:1H NMR (400 MHz, METHANOL-d4) δ = 8.49 (d, J = 2.5 Hz, 1H), 8.44 - 8.35 (m, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.64 - 7.59 (m, 1H), 7.53 - 7.44 (m, 2H), 7.39 - 7.19 (m, 1H), 6.97 (br t, J = 7.6 Hz, 1H), 7.09 (br d, J = 7.3 Hz, 2H), 6.87 - (1R,2S)-N-[(7S,11R,14S)-22-ethyl-(21M)-21-[2- 6.80 (m, 1H), 5.67 (br d, J = 8.4 [(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1- Hz, 1H), 4.33 - 4.21 (m, 2H),-12 yl)-3-pyridyl]-18,18-dimethyl-8,15-dioxo-16- 4.21 - 3.91 (m, 4H), 3.87 - 3.83 oxa-4-thia-9,22,29,30- (m, 1H), 3.75 (br d, J = 10.8 Hz, tetrazahexacyclo[18.5.2.12,5.19,14.111,14.023,27]triac 1H), 3.64 - 3.58 (m, 1H), 3.51 - onta-1(26),2,5(30),20,23(27),24-hexaen-7-yl]-2- 3.34 (m, 4H), 3.27 - 3.26 (m, phenyl-cyclopropanecarboxamide 2H), 3.20 - 3.09 (m, 2H), 3.04 - 2.95 (m, 4H), 2.88 (br d, J = 12.4 Hz, 1H), 2.78 (br s, 1H), 2.61 - 2.32 (m, 4H), 2.22 - 2.14 (m, 1H), 2.09 - 1.74 (m, 4H), 1.65 - 1.51 (m, 2H), 1.47 - 1.39 (m, 3H), 1.36 - 1.14 (m, 2H), 1.08 (br t, J = 6.9 Hz, 3H), 0.80 (s, 3H), 0.61 (s, 3H)。 MS measured (MH+): 899.6 NMR:1H NMR (400 MHz, METHANOL-d4) δ = 8.51 - 8.42 (m, 2H), 7.65 - 7.59 (m, 1H), 7.71 (br d, J = 8.0 Hz, 1H), 7.55 - 7.46 (m, 2H), 7.29 - 7.23 (m, 2H), 7.19 - 7.10 (m, 3H), 6.03 - 5.92 (m, 1H), 4.37 - 4.23 (m, 2H), 4.22 - 3.97 (m, 4H), (1S,2S)-N-[(7S,11R,14S)-22-ethyl-(21M)-21-[2- 3.89 - 3.78 (m, 2H), 3.67 - 3.46-13 [(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1- (m, 4H), 3.41 - 3.37 (m, 1H), yl)-3-pyridyl]-18,18-dimethyl-8,15-dioxo-16- 3.29 ( s, 2H), 3.25 - 3.12 (m, oxa-4-thia-9,22,29,30- 2H), 3.02 - 2.96 (m, 4H), 2.96 - tetrazahexacyclo[18.5.2.12,5.19,14.111,14.023,27]triac 2.90 (m, 1H), 2.77 (d, J = 1.8, onta-1(26),2,5(30),20,23(27),24-hexaen-7-yl]-2- 12.8 Hz, 1H), 2.67 - 2.42 (m, phenyl-cyclopropanecarboxamide 3H), 2.34 - 2.24 (m, 1H), 2.12 - 1.80 (m, 5H), 1.68 - 1.60 (m, 1H), 1.50 - 1.40 (m, 4H), 1.38 - 1.17 (m, 2H), 1.05 (t, J = 6.8 Hz, 3H), 0.84 (s, 3H), 0.61 (s, 3H). MS measured (MH+): 849.7 NMR:1H NMR (400 MHz, METHANOL-d4) δ = 8.49 (d, J = 2.8 Hz, 1H), 8.26 (s, 1H), 7.61 (d, J = 2.8 Hz, 1H), 7.46-14 (s, 1H), 7.41 (s, 1H), 5.93 (d, J = 8.4 Hz, 1H), 4.44 (q, J = 6.4 Hz, 1H), 4.22 - 4.10 (m, 3H), 3.85 - 3.77 (m, 2H), 3.69 - 3.59 (m, 3H), 3.55 - 3.45 (m, 3H), 3.33 (s, 3H), 3.27 - 3.24 (m, (1S,2S)-N-[(1S,23S,27R)-(8M)-8-[2-[(1S)-1- 1H), 3.14 - 3.02 (m, 3H), 2.99 methoxyethyl]-5-(4-methylpiperazin-1-yl)-3- (s, 3H), 2.98 - 2.91 (m, 3H), pyridyl]-5,5-dimethyl-2,24-dioxo-3-oxa-20-thia- 2.66 - 2.55 (m, 3H), 2.31 - 2.26 9,25,30,32- (m, 1H), 2.22 - 2.17 (m, 1H), tetrazaheptacyclo[23.4.1.11,27.113,17.118,21.07,15.09,142.02 - 1.97 (m, 1H), 1.95 - 1.89 ]tritriaconta-7,13,15,17(33),18,21(32)-hexaen-23- (m, 2H), 1.69 - 1.63 (m, 1H), yl]-2-methyl-cyclopropanecarboxamide 1.47 (d, J = 6.0 Hz, 3H), 1.44 - 1.40 (m, 1H), 1.36 - 1.26 (m, 3H), 1.20 - 1.16 (m, 1H), 1.12 - 1.09 (m, 3H), 1.04 - 1.00 (m, 1H), 0.88 (s, 3H), 0.61 (s, 3H). MS measured (MH+): 852.1 NMR:1H NMR (400 MHz, METHANOL-d4) δ = 8.52 - 8.37 (m, 2H), 7.72 (br d, J = 8.4 Hz, 2H), 7.54 - 7.48 (m, 2H), 6.10 - 5.21 (m, 1H), 4.34 - 4.22 (m, 2H), 4.08 - 4.00 (m, 1H), 3.82 (s, 8H), 3.74 - 3.67 (m, 2H), 3.64 - 3.59 (m, 1H), 3.45 --15 (1R,5S)-N-[(7S,11R,14S)-22-ethyl-(21M)-21-[2- 3.36 (m, 5H), 3.26 - 3.07 (m, [(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]- 3H), 2.99 - 2.74 (m, 3H), 2.60 - 18,18-dimethyl-8,15-dioxo-16-oxa-4-thia- 2.47 (m, 2H), 2.03 (s, 2H), 1.93 9,22,29,30- (d, J = 5.1 Hz, 2H), 1.69 - 1.59 tetrazahexacyclo[18.5.2.12,5.19,14.111,14.023,27]triac (m, 2H), 1.45 (d, J = 6.3 Hz, onta-1(26),2,5(30),20,23(27),24-hexaen-7-yl]-3- 2H), 1.41 - 1.35 (m, 2H), 1.34 - oxabicyclo[3.1.0]hexane-6-carboxamide 1.29 (m, 1H), 1.20 - 1.08 (m, 4H), 0.80 (s, 3H), 0.73 - 0.66 (m, 3H). MS measured (MH+): 899.5 NMR:1H NMR (400 MHz, METHANOL-d4) δ = 8.53 - 8.38 (m, 2H), 7.84 - 7.53 (m, 2H), 7.52 - 7.41 (m, 2H), 7.27 - 7.18 (m, 5H), 5.97 - 5.29 (m, 1H), 4.37 - 4.20 (m, 2H), 4.17 - 4.07 (m, 2H), 4.03 (br s, 1H), 3.86 - 3.73 (m, 2H), 3.51 - 3.43 (1S,2R)-N-[(7S,11R,14S)-22-ethyl-(21M)-21-[2- (m, 2H), 3.28 (s, 3H), 3.14 (br-16 [(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1- d, J = 6.6 Hz, 2H), 3.05 - 2.95 yl)-3-pyridyl]-18,18-dimethyl-8,15-dioxo-16- (m, 4H), 2.85 - 2.73 (m, 2H), oxa-4-thia-9,22,29,30- 2.67 - 2.56 (m, 1H), 2.54 - 2.48 tetrazahexacyclo[18.5.2.12,5.19,14.111,14.023,27]triac (m, 2H), 2.39 - 2.28 (m, 1H), onta-1(26),2,5(30),20,23(27),24-hexaen-7-yl]-2- 2.18 - 2.03 (m, 2H), 1.99 - 1.76 phenyl-cyclopropanecarboxamide (m, 3H), 1.68 (br s, 3H), 1.39 (br d, J = 6.3 Hz, 3H), 1.37 - 1.28 (m, 3H), 1.20 (br s, 1H), 1.10 - 0.98 (m, 3H), 0.94 - 0.70 (m, 3H), 0.70 - 0.52 (m, 3H). MS measured (MH+): 899.5 NMR:1H NMR (400 MHz, METHANOL-d4) δ = 8.54 - 8.41 (m, 2H), 7.70 (dd, J = 1.4, 8.6 Hz, 1H), 7.60 (d, J = 2.8 Hz, 1H), 7.52 - 7.45 (m, 2H), 7.26-19 (t, J = 7.6 Hz, 2H), 7.20 - 7.09 (m, 3H), 6.06 - 5.27 (m, 1H), 4.40 - 4.24 (m, 2H), 4.22 - 3.94 (1R,2R)-N-[(7S,11R,14S)-22-ethyl-(21M)-21-[2- (m, 4H), 3.87 - 3.78 (m, 2H), [(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1- 3.67 - 3.45 (m, 4H), 3.43 - 3.37 yl)-3-pyridyl]-18,18-dimethyl-8,15-dioxo-16- (m, 1H), 3.30 - 3.29 (m, 2H), oxa-4-thia-9,22,29,30- 3.28 - 3.18 (m, 2H), 3.00 (s, tetrazahexacyclo[18.5.2.12,5.19,14.111,14.023,27]triac 4H), 2.96 - 2.91 (m, 1H), 2.75 onta-1(26),2,5(30),20,23(27),24-hexaen-7-yl]-2- (br d, J = 14.5 Hz, 1H), 2.66 - phenyl-cyclopropanecarboxamide 2.46 (m, 3H), 2.39 - 2.29 (m, 1H), 2.16 - 1.84 (m, 5H), 1.73 - 1.61 (m, 1H), 1.48 - 1.40 (m, 4H), 1.36 - 1.20 (m, 2H), 1.08 - 0.97 (m, 3H), 0.84 (s, 3H), 0.64 - 0.55 (m, 3H). MS measured (MH+): 865.5 NMR:1H NMR (400 MHz, METHANOL-d4) δ = 8.54 - 8.45 (m, 2H), 7.78 - 7.59 (m, 2H), 7.53 - 7.48 (m, 2H), 5.99 (d, J = 7.1 Hz, 1H), 4.37 - 4.23 (m, 2H), 4.21 - 4.15 (m, 1H), 4.15 - 3.93 (m, 3H), 3.90 - 3.84 (m, 3H), 3.82 - 3.77 (m, 1H), 3.74 - 3.69 (m, 2H), 3.66 - 3.41-20 (1R,5S)-N-[(7S,11R,14S)-22-ethyl-(21M)-21-[2- (m, 5H), 3.30 - 3.29 (m, 2H), [(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1- 3.28 - 3.14 (m, 2H), 3.06 - 2.98 yl)-3-pyridyl]-18,18-dimethyl-8,15-dioxo-16- (m, 4H), 2.95 (d, J = 12.4 Hz, oxa-4-thia-9,22,29,30- 2,5 9,1H), 2.91 - 2.75 (m, 2H), 2.58 tetrazahexacyclo[18.5.2.1 .114.111,14.023,27]triac (s, 1H), 2.54 - 2.42 (m, 1H), onta-1(26),2,5(30),20,23(27),24-hexaen-7-yl]-3- 2.14 - 1.87 (m, 6H), 1.68 - 1.59 oxabicyclo[3.1.0]hexane-6-carboxamide (m, 2H), 1.47 - 1.39 (m, 3H), 1.32 (t, J = 7.3 Hz, 1H), 1.09 - 0.99 (m, 3H), 0.84 (s, 3H), 0.68 - 0.61 (m, 3H). MS measured (MH+): 851.5 NMR:1H NMR (400 MHz, METHANOL-d4) δ = 8.53 - 8.45 (m, 2H), 7.76 - 7.67 (m, 2H), 7.55 - 7.49 (t, J = 7.2 Hz, 2H), 6.16 - 5.94 (m, 1H), 4.33 - 4.24 (m, 2H), 4.20-4.09 (m, 1H), 4.08 - 4.04 (m, 1H), 3.93 - 3.85 (m, 1H), 3.85 - 3.72 (m, 2H), 3.64 - 3.59 (m, 1H), 3.55 --21 (2R,3S)-N-[(7S,11R,14S)-22-ethyl-(21M)-21-[2- 3.46 (m, 2H), 3.24 - 3.19 (m, [(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1- 2H), 3.02-2.98 (s, 3H), 2.90 - yl)-3-pyridyl]-18,18-dimethyl-8,15-dioxo-16- 2.74 (m, 2H), 2.64 - 2.53 (m, oxa-4-thia-9,22,29,30- 2H), 1.97-1.93 (m, 2H), 1.76 - tetrazahexacyclo[18.5.2.12,5.19,14.111,14.023,27]triac 1.58 (m, 4H), 1.49-1.43 (m, onta-1(26),2,5(30),20,23(27),24-hexaen-7-yl]- 3H), 1.40 - 1.35 (m, 4H), 1.34- 2,3-dimethyl-cyclopropanecarboxamide 1.28 (m, 3H), 1.12 - 1.08 (m, 5H), 1.08-1.02 (m, 6H), 0.88 - 0.80 (d, J = 1.6 Hz, 3H), 0.66- 0.60 (d, J = 14.0 Hz, 3H). MS measured (MH+): 838.4 NMR:1H NMR (400 MHz, METHANOL-d4) δ = 8.49 - 8.36 (m, 2H), 7.72 - 7.65 (m, 1H), 7.52 - 7.43 (m, 2H), 7.38 (d, J = 2.5 Hz, 1H), 5.99 - 5.92-22 (m, 1H), 4.26 - 4.06 (m, 4H), 3.91 - 3.83 (m, 5H), 3.80 - 3.76 (m, 1H), 3.75 - 3.68 (m, 3H), 3.58 - 3.45 (m, 2H), 3.26 - 3.19 (2R,3S)-N-[(7S,11R,14S)-22-ethyl-(21M)-21-[2- (m, 2H), 2.77 (d, J = 15.0 Hz, [(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]- 1H), 2.65 - 2.45 (m, 3H), 2.09 - 18,18-dimethyl-8,15-dioxo-16-oxa-4-thia- 1.86 (m, 4H), 1.65 - 1.57 (m, 9,22,29,30- tetrazahexacyclo[18.5.2.12,5.19,14.111,14.023,27]triac 1H), 1.43 (d, J = 6.1 Hz, 4H), onta-1(26),2,5(30),20,23(27),24-hexaen-7-yl]- 1.34 - 1.29 (m, 3H), 1.17 - 0.95 2,3-dimethyl-cyclopropanecarboxamide (m, 11H), 0.90 - 0.76 (m, 3H), 0.63 - 0.53 (m, 3H). MS measured (MH+): 860.4 NMR:1H NMR (400 MHz, ACETONITRILE-d3) δ = 8.58 (br d, J = 8.3 Hz, 1H), 8.48 - 8.34 (m, 1H), 7.92 - 7.72 (m, 1H), 7.69 - 7.62 (m, 1H), 7.57 - 7.51 (m, 1H), 7.50 - 7.45 (m, 1H), 7.30 - 7.23 (m, 1H), 6.01 - 5.85 (m, 1H), 5.80 - 5.55 (m, 1H), 5.2-4.82 (m, 1H), 4.38 - (1S,2S)-2-(difluoromethyl)-N-[(7S,11R,14S)-22- 4.21 (m, 2H), 4.20 - 4.11 (m,-24 ethyl-(21M)-21-[2-[(1S)-1-methoxyethyl]-5- 1H), 4.10 - 4.02 (m, 1H), 3.94 - morpholino-3-pyridyl]-18,18-dimethyl-8,15- 3.87 (m, 1H), 3.86 - 3.80 (m, dioxo-16-oxa-4-thia-9,22,29,30- 5H), 3.74 (d, J = 10.9 Hz, 1H), tetrazahexacyclo[18.5.2.12,5.19,14.111,14.023,27]triac 3.58 - 3.53 (m, 1H), 3.40 - 3.32 onta-1(26),2,5(30),20,23(27),24-hexaen-7- (m, 5H), 3.31 (s, 5H), 3.27 (s, yl]cyclopropanecarboxamide 2H), 3.20 - 3.14 (m, 1H), 3.01 (s, 1H), 2.93 - 2.86 (m, 1H), 2.81 (br d, J = 8.8 Hz, 1H), 1.99 (s, 2H), 1.45 - 1.39 (m, 3H), 1.35 - 1.31 (m, 1H), 1.11 - 1.01(m, 4H), 0.94 (s, 1H), 0.88 - 0.59 (m, 6H). MS measured (MH+): 852.4 NMR:1H NMR (400 MHz, ACETONITRILE-d3) δ = 8.52 (s, 1H), 8.44 - 8.30 (m, 1H), 7.83 - 7.68 (m, 1H), 7.64 - 7.53 (m, 1H), 7.53 - 7.49 (m, 1H), 7.47 - 7.42 (m, 1H), 7.06 - 6.99 (m, 1H), 5.28 - 4.73 (m, 1H), 4.36 - 4.17 (m, 2H), 4.16 - 4.03 (m, 2H), 3.83 - 3.78 (m, 7H), 3.72 - 3.62 (m, 3H), 3.57 - 3.48-25 (1S,5R)-N-[(7S,11R,14S)-22-ethyl-(21M)-21-[2- (m, 3H), 3.35 - 3.29 (m, 5H), [(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]- 3.23 - 3.22 (m, 2H), 3.16 - 3.10 18,18-dimethyl-8,15-dioxo-16-oxa-4-thia- (m, 1H), 2.98 - 2.93 (m, 1H), 9,22,29,30- hexacyclo[18.5.2.12,5.19,142.88 - 2.75 (m, 2H), 2.12 - 2.06 tetraza .111,14.023,27]triac (m, 2H), 1.85 - 1.75 (m, 2H), onta-1(26),2,5(30),20,23(27),24-hexaen-7-yl]-3- 1.60 - 1.55 (m, 1H), 1.50 - 1.43 oxabicyclo[3.1.0]hexane-6-carboxamide (m, 1H), 1.41 - 1.36 (m, 3H), 1.32 - 1.28 (m, 1H), 1.14 - 1.09 (m, 2H), 1.06 - 1.02 (m, 2H), 0.92 - 0.88 (m, 1H), 0.86 - 0.58 (m, 6H). MS measured (MH+): 865.4 NMR:1H NMR (400 MHz, METHANOL-d4) δ = 8.53 (s, 1H), 8.49 (d, J = 2.9 Hz, 1H), 7.86 (d, J = 2.9 Hz, 1H), 7.74-26 (d, J = 1.4, 8.7 Hz, 1H), 7.54 - 7.51 (m, 2H), 6.04 (d, J = 6.6 Hz, 1H), 4.35 - 4.27 (m, 2H), 4.21 (d, J = 3.0, 12.8 Hz, 2H), 4.10 - 4.00 (m, 2H), 3.90 (d, J = 1.4, 8.8 Hz, 4H), 3.85 - 3.81 (m, (1S,5R)-N-[(7S,11R,14S)-22-ethyl-(21M)-21-[2- 1H), 3.73 (dd, J = 2.4, 4.5, 8.4 [(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1- Hz, 3H), 3.55 (dd, J = 2.1, 15.1 yl)-3-pyridyl]-18,18-dimethyl-8,15-dioxo-16- Hz, 2H), 3.11 (s, 1H), 3.02 (s, oxa-4-thia-9,22,29,30- 4H), 2.97 (d, J = 12.0 Hz, 1H), tetrazahexacyclo[18.5.2.12,5.19,14.111,14.023,27]triac 2.86 (s, 2H), 2.64 - 2.55 (m, onta-1(26),2,5(30),20,23(27),24-hexaen-7-yl]-3- 2H), 2.49 - 2.39 (m, 1H), 2.23 - oxabicyclo[3.1.0]hexane-6-carboxamide 2.10 (m, 1H), 2.08 - 2.04 (m, 2H), 2.04 - 1.91 (m, 3H), 1.63 (t, J = 3.2 Hz, 2H), 1.47 (d, J = 6.3 Hz, 3H), 1.42 (d, J = 6.4 Hz, 1H), 1.38 - 1.32 (m, 1H), 1.29 (t, J = 2.9, 7.3 Hz, 1H), 1.22 - 1.15 (m, 1H), 1.10 (t, J = 7.1 Hz, 3H), 0.86 (s, 3H), 0.71 - 0.69 (m, 3H). MS measured (MH+): 873.4 NMR:1H NMR (400 MHz, METHANOL-d4) δ = 8.50 - 8.46 (m, 2H), 7.70 (d, J = 1.5, 8.5 Hz, 1H), 7.63 (d, J = 3.0 Hz, 1H), 7.52 (s, 1H), 7.51 - 7.48 (m, 1H), 6.00 (d, J = 1.5, 8.0 Hz, 1H), 5.77 (d, J = 4.0 Hz, 1H), 4.32 - 4.23 (m, 2H),-27 4.19 (d, J = 3.0, 12.3 Hz, 1H), 4.09 (d, J = 7.1, 14.9 Hz, 2H), 3.87 - 3.78 (m, 2H), 3.61 (1S,2S)-2-(difluoromethyl)-N-[(7S,11R,14S)-22- (d, J = 1.5, 8.5 Hz, 1H), 3.58 - ethyl-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-(4- 3.51 (m, 2H), 3.41 - 3.37 (m, methylpiperazin-1-yl)-3-pyridyl]-18,18-dimethyl- 4H), 3.28 (s, 3H), 3.00 (s, 4H), 8,15-dioxo-16-oxa-4-thia-9,22,29,30- 2.95 (d, J = 12.5 Hz, 1H), 2.90 tetrazahexacyclo[18.5.2.12,5.19,14.111,14.023,27]triac (d, J = 14.3 Hz, 1H), 2.81 - onta-1(26),2,5(30),20,23(27),24-hexaen-7- 2.73 (m, 1H), 2.61 - 2.47 (m, yl]cyclopropanecarboxamide 3H), 1.99 (td, J = 4.4, 8.9 Hz, 2H), 1.94 - 1.90 (m, 2H), 1.77 - 1.63 (m, 2H), 1.44 (d, J = 6.3 Hz, 3H), 1.41 (s, 1H), 1.32 (d, J = 2.8 Hz, 1H), 1.15 - 1.08 (m, 1H), 1.05 (t, J = 7.1 Hz, 4H), 0.83 (s, 3H), 0.60 (s, 3H). MS measured (MH+): 837.5 NMR:1H NMR (400 MHz, METHANOL-d4) δ = 8.51 (s, 1H), 8.46 (s, 1H), 8.02 - 7.88 (m, 1H), 7.72 (d, J = 9.8 Hz, 1H), 7.53 - 7.50 (m, 2H), 6.02 (d, J = 7.1 Hz, 1H), 4.35 - 4.27 (m, 2H), 4.23 - 4.17 (m, 2H), 4.07 - 3.95 (m, 2H), 3.93 - 3.76 (m, 3H), 3.73 - 3.59 (m, 3H), 3.56 - 3.48 (m, 2H), 3.13 (s,-29 1H), 3.00 (s, 3H), 2.95 (d, J = (1S,2S)-N-[(7S,11R,14S)-22-ethyl-(21M)-21-[2- 11.6 Hz, 1H), 2.85 (s, 2H), 2.62 [(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1- - 2.51 (m, 2H), 2.47 - 2.36 (m, yl)-3-pyridyl]-18,18-dimethyl-8,15-dioxo-16- 1H), 1.95 - 1.90 (m, 2H), 1.68 - oxa-4-thia-9,22,29,30- 1.61 (m, 1H), 1.45 (d, J = 6.3 tetrazahexacyclo[18.5.2.12,5.19,14.111,14.023,27]triac Hz, 3H), 1.42 - 1.37 (m, 2H), onta-1(26),2,5(30),20,23(27),24-hexaen-7-yl]-2- 1.36 - 1.27 (m, 2H), 1.22 - 1.17 methyl-cyclopropanecarboxamide (m, 1H), 1.12 - 1.03 (m, 7H), 1.04 - 0.97 (m, 2H), 0.85 (s, 3H), 0.73 - 0.68 (m, 3H), 0.61 - 0.53 (m, 1H). MS measured (MH+): 824.4 NMR:1H NMR (400 MHz, ACETONITRILE-d3) δ = 8.45 - 8.30 (m, 2H), 7.75 - 7.59 (m, 1H), 7.56 - 7.34 (m, 4H), 7.09 (br d, J = 9.0 Hz, 1H), 5.95-5.20 (s, 1H), 4.81 (s, 1H),4.39 - 3.90 (m, 4H), 3.89 - 3.75 (m, 5H), 3.74 - 3.41 (m, 2H), 3.37 - 3.09-30 (m, 7H),2.97 (s, 1H),2.93 - 2.63 (m, 2H), 2.61 - 2.42 (m, 3H), (1S,2S)-N-[(7S)-21-ethyl-(20M)-20-[2-[(1S)-1- 2.16 - 2.03 (m, 2H), 1.95 - 1.89 methoxyethyl]-5-morpholino-3-pyridyl]-17,17- (m, 1H), 1.87 - 1.78 (m, 1H), dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,29,30- 1.68 - 1.52 (m, 1H), 1.39 (d, J = tetrazahexacyclo[17.5.2.210,13.12,5.19,13.022,26]triac 6.2 Hz, 2H),1.33- 1.18 (m, onta-1(25),2,5(30),19,22(26),23-hexaen-7-yl]-2- 5H),1.14- 1.00 (m, 4H) 0.93 (s, methyl-cyclopropanecarboxamide 2H), 0.84 (s, 2H), 0.66 - 0.54 (m, 3H). MS measured (MH+): 824.4 NMR:1H NMR (400 MHz, ACETONITRILE-d3) δ = 8.45 - 8.30 (m, 2H), 7.75 - 7.59 (m, 1H), 7.56 - 7.34 (m, 4H), 7.09 (br d, J = 9.0 Hz, 1H),5.95-5.20 (s, 1H), 4.81 (s, 1H),4.39 - 3.90-31 (m, 4H), 3.89 - 3.75 (m, 5H), 3.74 - 3.41 (m, 2H), 3.37 - 3.09 (m, 7H),2.97 (s, 1H),2.93 - 2.63 (m, 2H), 2.61 - 2.42 (m, 3H), 2.16 - 2.03 (m, 2H), 1.95 - 1.89 (1S,2S)-N-[(7S,11R,14S)-22-ethyl-(21M)-21-[2- (m, 1H), 1.87 - 1.78 (m, [(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]- 1H),1.68 - 1.52 (m, 1H), 1.39 18,18-dimethyl-8,15-dioxo-16-oxa-4-thia- (d, J = 6.2 Hz, 2H),1.33- 1.18 9,22,29,30- (m, 5H),1.14- 1.00 (m, 4H) 0.93 tetrazahexacyclo[18.5.2.12,5.19,14.111,14.023,27]triac (s, 2H), 0.84 (s, 2H), 0.66 - 0.54 onta-1(26),2,5(30),20,23(27),24-hexaen-7-yl]-2- (m, 3H). methyl-cyclopropanecarboxamide MS measured (MH+): 810.4 NMR:1H NMR (400 MHz, ACETONITRILE- d3) δ = 8.41 (br d, J = 2.7 Hz, 1H), 8.34 - 8.29 (m, 1H), 7.83 - 7.74 (m, 1H), 7.55 - 7.46 (m, 2H), 7.41 (m, 1H), 7.22 - 6.92 (m, 1H),5.36 - 4.89 (m, 1H), 4.16 - 4.03 (m, 2H), 3.94-3.76 (m,-33 5H), 3.58 - 3.29 (m, 2H),3.28- 3.17 (m, 5H),3.16 - 3.02 (m, (1S,2S)-N-[(7S)-22-ethyl-(21M)-21-[2-[(1S)-1- 1H),3.00 - 2.89 (m, 3H), 2.85 - methoxyethyl]-5-morpholino-3-pyridyl]-18,18- 2.75 (m, 1H),2.49 - 2.36 (m, dimethyl-8,15-dioxo-16-oxa-4-thia-9,22,28,29- 3H), 2.16 - 2.07 (m, 1H),1.85 - tetrazahexacyclo[18.5.2.12,5.19,14.012,14.023,27]nona 1.65 (m, 2H),1.56 - 1.35 (m, cosa-1(26),2,5(29),20,23(27),24-hexaen-7-yl]-2- 4H),1.35 -1.15(m, 6H), 1.13 - methyl-cyclopropanecarboxamide 1.03 (m, 3H),1.02 - 0.82 (m, 2H), 0.81 - 0.64 (m, 6H), 0.62 - 0.48 (m, 1H). MS measured (MH+): 849.4 NMR:1H NMR (400 MHz, METHANOL-d4) δ = 8.51 - 8.47 (m, 1H), 8.28 (s, 1H), 7.60 (d, J = 2.8 Hz, 1H), 7.52 - 7.41-34 (m, 2H), 5.60 - 5.52 (m, 1H), 4.66 - 4.63 (m, 1H), 4.52 - 4.45 (m, 1H), 4.22 - 4.16 (m, 1H), 4.02 - 3.91 (m, 1H), 3.82 - 3.53 (m, 6H), 3.50 - 3.41 (m, 2H), (2S,3R)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1- 3.41 - 3.33 (m, 5H), 3.30 - 3.23 methoxyethyl]-5-(4-methylpiperazin-1-yl)-3- (m, 2H), 3.14 - 3.07 (m, 2H), pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4- 3.06 - 3.03 (m, 1H), 3.01 - 2.93 thia-9,21,30,32- (m, 4H), 2.75 - 2.52 (m, 3H), 2,5 9,13 10,12 19,27 21,26 tetrazaheptacyclo[23.3.1.1 .1 .1 .0 .0 2.49 - 2.41 (m, 1H), 2.36 - 2.27 ]dotriaconta-1(29),2,5(32),19,25,27-hexaen-7-yl]- (m, 1H), 2.22 - 2.14 (m, 2H), 2,3-dimethyl-cyclopropanecarboxamide 1.60 - 1.50 (m, 1H), 1.48 - 1.45 (m, 3H), 1.44 - 1.33 (m, 2H), 1.20 - 1.10 (m, 7H), 1.09 - 1.03 (m, 1H), 0.96 - 0.88 (m, 3H), 0.55 (s, 2H). MS measured (MH+): 849.4 NMR:1H NMR (400 MHz, METHANOL-d4) δ = 8.50 (d, J = 3.2 Hz, 1H), 8.28 (s, 1H), 7.72 (d, J = 2.4 Hz, 1H), 7.48 - 7.40 (m, 2H), 6.08 - 6.00 (m, 1H), 4.66 - 4.60 (m, 1H), 4.51 (s, 1H), 4.22 - 4.18 (m, 1H), 4.02 - 3.88 (m, 4H), 3.80 - 3.76 (m, 1H), 3.66 - 3.59 (m, 2H),-35 (2S,3R)-N-[(7S,13R)-(20M)-20-[2-[(1S)-1- 3.52 - 3.44 (m, 2H), 3.38 - 3.33 methoxyethyl]-5-(4-methylpiperazin-1-yl)-3- (m, 3H), 3.15 - 3.11 (m, 1H), pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4- 3.09 - 3.03 (m, 3H), 3.02 - 2.99 thia-9,21,30,32- (m, 6H), 2.72 - 2.66 (m, 1H), 2,5 9,13 10,12 19,27 21,26 tetrazaheptacyclo[23.3.1.1 .1 .1 .0 .0 2.55 - 2.42 (m, 2H), 2.37 - 2.22 ]dotriaconta-1(29),2,5(32),19,25,27-hexaen-7-yl]- (m, 3H), 2.21 - 2.17 (m, 1H), 2,3-dimethyl-cyclopropanecarboxamide 1.85 - 1.77 (m, 1H), 1.49 - 1.44 (m, 3H), 1.37 - 1.29 (m, 2H), 1.15 - 1.04 (m, 8H), 0.87 (s, 3H), 0.71 - 0.65 (m, 3H). MS measured (MH+): 849.4 1-36 (2S,3R)-N-[(7S)-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-(4-methylpiperazin-1-yl)-3- pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4- thia-9,21,30,32- 2,5 9,13 10,12 19,27 21,26 tetrazaheptacyclo[23.3.1.1 .1 .1 .0 .0 ]dotriaconta-1(29),2,5(32),19,25,27-hexaen-7-yl]- 2,3-dimethyl-cyclopropanecarboxamide The following compounds can be prepared in analogy to the preparation of Example 1-1 and Example 1-2. Table 2. Compound list Exampl Compound name and structures e NO. 2-4 (2R,3S)-N-[(7S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3- pyridyl]-17,17-dimethyl-8,14-dioxo-spiro[15-oxa-4-thia-9,21,30,32- tetrazaheptacyclo[23.3.1.12,5.19,13.110,12.019,27.021,26]dotriaconta-1(29),2,5(32),19,25,27- hexaene-6,1'-cyclopropane]-7-yl]-2,3-dimethyl-cyclopropanecarboxamide -5 (2R,3S)-N-[(7S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3- pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,32- tetrazaheptacyclo[23.3.1.12,5.19,13.110,12.019,27.021,26]dotriaconta-1(29),2,5(32),19,25,27- hexaen-7-yl]-2,3-dimethyl-cyclopropanecarboxamide -6 (2R,3S)-N-[(7S)-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- 9,21,30,32-tetrazaheptacyclo[23.3.1.12,5.19,13.110,12.019,27.021,26]dotriaconta- 1(29),2,5(32),19,25,27-hexaen-7-yl]-2,3-dimethyl-cyclopropanecarboxamide -7 (2R,3S)-N-[(3S,26S,28R)-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1- yl)-3-pyridyl]-21,21-dimethyl-2,24-dioxo-23-oxa-6-thia-1,17,30,32- tetrazaheptacyclo[23.4.1.15,8.19,13.011,19.012,17.026,28]dotriaconta-5(32),7,9(31),10,12,18- hexaen-3-yl]-2,3-dimethyl-cyclopropanecarboxamide -8 (2R,3S)-N-[(3S,26S,28R)-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1- yl)-3-pyridyl]-21,21-dimethyl-2,24-dioxo-14,23-dioxa-6-thia-1,17,30,32- tetrazaheptacyclo[23.4.1.15,8.19,13.011,19.012,17.026,28]dotriaconta-5(32),7,9(31),10,12,18- hexaen-3-yl]-2,3-dimethyl-cyclopropanecarboxamide -9 (2R,3S)-N-[(3S,26S,28R)-15,15-difluoro-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-21,21-dimethyl-2,24-dioxo-23-oxa-6-thia- 1,17,30,32-tetrazaheptacyclo[23.4.1.15,8.19,13.011,19.012,17.026,28]dotriaconta- 5(32),7,9(31),10,12,18-hexaen-3-yl]-2,3-dimethyl-cyclopropanecarboxamide -10 (2S,3R)-N-[(3S,27S,29R)-(19M)-19-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1- yl)-3-pyridyl]-22,22-dimethyl-2,25-dioxo-14,24-dioxa-6-thia-1,18,31,33- tetrazaheptacyclo[24.4.1.15,8.19,13.011,20.012,18.027,29]tritriaconta-5(33),7,9(32),10,12,19- hexaen-3-yl]-2,3-dimethyl-cyclopropanecarboxamide -11 (2R,3S)-N-[(3S,26R,28S)-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1- yl)-3-pyridyl]-21,21-dimethyl-2,24-dioxo-23-oxa-6-thia-1,17,30,32- tetrazaheptacyclo[23.4.1.15,8.19,13.011,19.012,17.026,28]dotriaconta-5(32),7,9(31),10,12,18- hexaen-3-yl]-2,3-dimethyl-cyclopropanecarboxamide -12 (2R,3S)-N-[(3S,26R,28S)-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1- yl)-3-pyridyl]-21,21-dimethyl-2,24-dioxo-14,23-dioxa-6-thia-1,17,30,32- tetrazaheptacyclo[23.4.1.15,8.19,13.011,19.012,17.026,28]dotriaconta-5(32),7,9(31),10,12,18- hexaen-3-yl]-2,3-dimethyl-cyclopropanecarboxamide -13 (2R,3S)-N-[(3S,26R,28S)-15,15-difluoro-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-21,21-dimethyl-2,24-dioxo-23-oxa-6-thia- 1,17,30,32-tetrazaheptacyclo[23.4.1.15,8.19,13.011,19.012,17.026,28]dotriaconta- 5(32),7,9(31),10,12,18-hexaen-3-yl]-2,3-dimethyl-cyclopropanecarboxamide -14 (2S,3R)-N-[(3S,27R,29S)-(19M)-19-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1- yl)-3-pyridyl]-22,22-dimethyl-2,25-dioxo-14,24-dioxa-6-thia-1,18,31,33- tetrazaheptacyclo[24.4.1.15,8.19,13.011,20.012,18.027,29][24.4.1.15,8.19,13.011,20.012,18.027,29]tr itriaconta-5(33),7,9(32),10,12,19-hexaen-3-yl]-2,3-dimethyl- cyclopropanecarboxamide -15 (2R,3S)-N-[(7S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3- pyridyl]-17,17-dimethyl-8,14-dioxo-spiro[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- hexaene-12,1'-cyclopropane]-7-yl]-2,3-dimethyl-cyclopropanecarboxamide -16 (2R,3S)-N-[(7S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3- pyridyl]-17,17-dimethyl-8,14-dioxo-spiro[15,24-dioxa-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- hexaene-12,1'-cyclopropane]-7-yl]-2,3-dimethyl-cyclopropanecarboxamide -17 (2R,3S)-N-[(7S)-23,23-difluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-spiro[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-hexaene-12,1'-cyclopropane]-7-yl]-2,3-dimethyl- cyclopropanecarboxamide -18 (2S,3R)-N-[(7S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3- pyridyl]-17,17-dimethyl-8,14-dioxo-spiro[15,25-dioxa-4-thia-9,21,31,32- tetrazahexacyclo[24.3.1.12,5.19,13.019,28.021,27]dotriaconta-1(30),2,5(32),19,26,28- hexaene-12,1'-cyclopropane]-7-yl]-2,3-dimethyl-cyclopropanecarboxamide -19 (2S,3R)-N-[(3S,26R,28S)-27,27-difluoro-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-21,21-dimethyl-2,24-dioxo-23-oxa-6-thia- 1,17,30,32-tetrazaheptacyclo[23.4.1.15,8.19,13.011,19.012,17.026,28]dotriaconta- 5(32),7,9(31),10,12,18-hexaen-3-yl]-2,3-dimethyl-cyclopropanecarboxamide -20 (2S,3R)-N-[(3S,26R,28S)-27,27-difluoro-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-21,21-dimethyl-2,24-dioxo-14,23-dioxa-6-thia- 1,17,30,32-tetrazaheptacyclo[23.4.1.15,8.19,13.011,19.012,17.026,28]dotriaconta- 5(32),7,9(31),10,12,18-hexaen-3-yl]-2,3-dimethyl-cyclopropanecarboxamide -21 (2S,3R)-2,3-dimethyl-N-[(3S,26R,28S)-15,15,27,27-tetrafluoro-(18M)-18-[2-[(1S)-1- methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-21,21-dimethyl-2,24-dioxo-23- oxa-6-thia-1,17,30,32-tetrazaheptacyclo[23.4.1.15,8.19,13.011,19.012,17.026,28]dotriaconta- 5(32),7,9(31),10,12,18-hexaen-3-yl]cyclopropanecarboxamide -22 (2R,3S)-N-[(3S,27R,29S)-28,28-difluoro-(19M)-19-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-22,22-dimethyl-2,25-dioxo-14,24-dioxa-6-thia- 1,18,31,33-tetrazaheptacyclo[24.4.1.15,8.19,13.011,20.012,18.027,29]tritriaconta- 5(33),7,9(32),10,12,19-hexaen-3-yl]-2,3-dimethyl-cyclopropanecarboxamide -23 (2S,3R)-N-[(3S,26S,28R)-27,27-difluoro-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-21,21-dimethyl-2,24-dioxo-23-oxa-6-thia- 1,17,30,32-tetrazaheptacyclo[23.4.1.15,8.19,13.011,19.012,17.026,28]dotriaconta- 5(32),7,9(31),10,12,18-hexaen-3-yl]-2,3-dimethyl-cyclopropanecarboxamide -24 (2S,3R)-N-[(3S,28R)-27,27-difluoro-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-21,21-dimethyl-2,24-dioxo-14,23-dioxa-6-thia- 1,17,30,32-tetrazaheptacyclo[23.4.1.15,8.19,13.011,19.012,17.026,28]dotriaconta- 5(32),7,9(31),10,12,18-hexaen-3-yl]-2,3-dimethyl-cyclopropanecarboxamide -25 (2S,3R)-2,3-dimethyl-N-[(3S,26S,28R)-15,15,27,27-tetrafluoro-(18M)-18-[2-[(1S)-1- methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-21,21-dimethyl-2,24-dioxo-23- oxa-6-thia-1,17,30,32-tetrazaheptacyclo[23.4.1.15,8.19,13.011,19.012,17.026,28]dotriaconta- 5(32),7,9(31),10,12,18-hexaen-3-yl]cyclopropanecarboxamide -26 (2R,3S)-N-[(3S,27S,29R)-28,28-difluoro-(19M)-19-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-22,22-dimethyl-2,25-dioxo-14,24-dioxa-6-thia- 1,18,31,33-tetrazaheptacyclo[24.4.1.15,8.19,13.011,20.012,18.027,29]tritriaconta- 5(33),7,9(32),10,12,19-hexaen-3-yl]-2,3-dimethyl-cyclopropanecarboxamide -27 (2R,3S)-N-[(3S,25S,26R,29S)-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-21,21-dimethyl-2,24-dioxo-23-oxa-6-thia- 1,17,31,33-tetrazaheptacyclo[23.5.1.15,8.19,13.011,19.012,17.026,29]tritriaconta- 5(33),7,9(32),10,12,18-hexaen-3-yl]-2,3-dimethyl-cyclopropanecarboxamide -28 (2R,3S)-N-[(3S,25S,26R,29S)-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-21,21-dimethyl-2,24-dioxo-14,23-dioxa-6-thia- 1,17,31,33-tetrazaheptacyclo[23.5.1.15,8.19,13.011,19.012,17.026,29]tritriaconta- 5(33),7,9(32),10,12,18-hexaen-3-yl]-2,3-dimethyl-cyclopropanecarboxamide -29 (2R,3S)-N-[(3S,25S,26R,29S)-15,15-difluoro-(18M)-18-[2-[(1S)-1-methoxyethyl]-5- (4-methylpiperazin-1-yl)-3-pyridyl]-21,21-dimethyl-2,24-dioxo-23-oxa-6-thia- 1,17,31,33-tetrazaheptacyclo[23.5.1.15,8.19,13.011,19.012,17.026,29]tritriaconta- 5(33),7,9(32),10,12,18-hexaen-3-yl]-2,3-dimethyl-cyclopropanecarboxamide -30 (2S,3R)-N-[(3S,26S,27R,30S)-(19M)-19-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-22,22-dimethyl-2,25-dioxo-14,24-dioxa-6-thia- 1,18,32,34-tetrazaheptacyclo[24.5.1.15,8.19,13.011,20.012,18.027,30]tetratriaconta- 5(34),7,9(33),10,12,19-hexaen-3-yl]-2,3-dimethyl-cyclopropanecarboxamide -31 (2R,3S)-N-[(3S,25S,26S,29R)-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-21,21-dimethyl-2,24-dioxo-23-oxa-6-thia- 1,17,31,33-tetrazaheptacyclo[23.5.1.15,8.19,13.011,19.012,17.026,29]tritriaconta- 5(33),7,9(32),10,12,18-hexaen-3-yl]-2,3-dimethyl-cyclopropanecarboxamide -32 (2R,3S)-N-[(3S,25S,26S,29R)-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-21,21-dimethyl-2,24-dioxo-14,23-dioxa-6-thia- 1,17,31,33-tetrazaheptacyclo[23.5.1.15,8.19,13.011,19.012,17.026,29]tritriaconta- 5(33),7,9(32),10,12,18-hexaen-3-yl]-2,3-dimethyl-cyclopropanecarboxamide -33 (2R,3S)-N-[(3S,25S,26S,29R)-15,15-difluoro-(18M)-18-[2-[(1S)-1-methoxyethyl]-5- (4-methylpiperazin-1-yl)-3-pyridyl]-21,21-dimethyl-2,24-dioxo-23-oxa-6-thia- 1,17,31,33-tetrazaheptacyclo[23.5.1.15,8.19,13.011,19.012,17.026,29]tritriaconta- 5(33),7,9(32),10,12,18-hexaen-3-yl]-2,3-dimethyl-cyclopropanecarboxamide -34 (2S,3R)-N-[(3S,26S,27S,30R)-(19M)-19-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-22,22-dimethyl-2,25-dioxo-14,24-dioxa-6-thia- 1,18,32,34-tetrazaheptacyclo[24.5.1.15,8.19,13.011,20.012,18.027,30]tetratriaconta- 5(34),7,9(33),10,12,19-hexaen-3-yl]-2,3-dimethyl-cyclopropanecarboxamide -35 (2S,3R)-N-[(3S,26R,28S)-27,27-difluoro-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-21,21,26-trimethyl-2,24-dioxo-23-oxa-6-thia- 1,17,30,32-tetrazaheptacyclo[23.4.1.15,8.19,13.011,19.012,17.026,28]dotriaconta- 5(32),7,9(31),10,12,18-hexaen-3-yl]-2,3-dimethyl-cyclopropanecarboxamide -36 (2R,3S)-N-[(3S,26R,28S)-27,27-difluoro-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-21,21,26-trimethyl-2,24-dioxo-14,23-dioxa-6-thia- 1,17,30,32-tetrazaheptacyclo[23.4.1.15,8.19,13.011,19.012,17.026,28]dotriaconta- 5(32),7,9(31),10,12,18-hexaen-3-yl]-2,3-dimethyl-cyclopropanecarboxamide -37 (2S,3R)-N-[(3S,26R,28S)-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1- yl)-3-pyridyl]-21,21,26-trimethyl-2,24-dioxo-23-oxa-6-thia-1,17,30,32- tetrazaheptacyclo[23.4.1.15,8.19,13.011,19.012,17.026,28]dotriaconta-5(32),7,9(31),10,12,18- hexaen-3-yl]-2,3-dimethyl-cyclopropanecarboxamide -38 (2R,3S)-N-[(3S,26R,28S)-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1- yl)-3-pyridyl]-21,21,26-trimethyl-2,24-dioxo-14,23-dioxa-6-thia-1,17,30,32- tetrazaheptacyclo[23.4.1.15,8.19,13.011,19.012,17.026,28]dotriaconta-5(32),7,9(31),10,12,18- hexaen-3-yl]-2,3-dimethyl-cyclopropanecarboxamide -39 (2S,3R)-N-[(3S,26S,28R)-27,27-difluoro-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-21,21,26-trimethyl-2,24-dioxo-23-oxa-6-thia- 1,17,30,32-tetrazaheptacyclo[23.4.1.15,8.19,13.011,19.012,17.026,28]dotriaconta- 5(32),7,9(31),10,12,18-hexaen-3-yl]-2,3-dimethyl-cyclopropanecarboxamide -40 (2S,3R)-N-[(3S,26S,28R)-27,27-difluoro-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-21,21,26-trimethyl-2,24-dioxo-14,23-dioxa-6-thia- 1,17,30,32-tetrazaheptacyclo[23.4.1.15,8.19,13.011,19.012,17.026,28]dotriaconta- 5(32),7,9(31),10,12,18-hexaen-3-yl]-2,3-dimethyl-cyclopropanecarboxamide -41 (2S,3R)-N-[(3S,26S,28R)-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1- yl)-3-pyridyl]-21,21,26-trimethyl-2,24-dioxo-23-oxa-6-thia-1,17,30,32- tetrazaheptacyclo[23.4.1.15,8.19,13.011,19.012,17.026,28]dotriaconta-5(32),7,9(31),10,12,18- hexaen-3-yl]-2,3-dimethyl-cyclopropanecarboxamide -42 (2S,3R)-N-[(3S,26S,28R)-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1- yl)-3-pyridyl]-21,21,26-trimethyl-2,24-dioxo-14,23-dioxa-6-thia-1,17,30,32- tetrazaheptacyclo[23.4.1.15,8.19,13.011,19.012,17.026,28]dotriaconta-5(32),7,9(31),10,12,18- hexaen-3-yl]-2,3-dimethyl-cyclopropanecarboxamide -43 (2S,3R)-N-[(7S)-11-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin- 1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(29),2,5(31),11,19,25,27- heptaen-7-yl]-2,3-dimethyl-cyclopropanecarboxamide -44 (2S,3R)-N-[(7S)-11-fluoro-(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(29),2,5(31),11,19,25,27- heptaen-7-yl]-2,3-dimethyl-cyclopropanecarboxamide -45 (2S,3R)-N-[(3S,26R,28S)-27,27-difluoro-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-21,21-dimethyl-2,24-dioxo-spiro[23-oxa-6-thia- 1,17,30,32-tetrazaheptacyclo[23.4.1.15,8.19,13.011,19.012,17.026,28]dotriaconta- 5(32),7,9(31),10,12,18-hexaene-4,1'-cyclobutane]-3-yl]-2,3-dimethyl- cyclopropanecarboxamide -46 (2S,3R)-N-[(3S,26R,28S)-27,27-difluoro-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-21,21-dimethyl-2,24-dioxo-spiro[14,23-dioxa-6- thia-1,17,30,32-tetrazaheptacyclo[23.4.1.15,8.19,13.011,19.012,17.026,28]dotriaconta- 5(32),7,9(31),10,12,18-hexaene-4,1'-cyclobutane]-3-yl]-2,3-dimethyl- cyclopropanecarboxamide -47 (2S,3R)-N-[(3S,26R,28S)-27,27-difluoro-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-21,21-dimethyl-2,24-dioxo-spiro[23-oxa-6-thia- 1,17,30,32-tetrazaheptacyclo[23.4.1.15,8.19,13.011,19.012,17.026,28]dotriaconta- 5(32),7,9(31),10,12,18-hexaene-4,1'-cyclopropane]-3-yl]-2,3-dimethyl- cyclopropanecarboxamide -48 (2S,3R)-N-[(3S,26R,28S)-27,27-difluoro-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-21,21-dimethyl-2,24-dioxo-spiro[14,23-dioxa-6- thia-1,17,30,32-tetrazaheptacyclo[23.4.1.15,8.19,13.011,19.012,17.026,28]dotriaconta- 5(32),7,9(31),10,12,18-hexaene-4,1'-cyclopropane]-3-yl]-2,3-dimethyl- cyclopropanecarboxamide -49 (2S,3R)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)- 3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-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]-2,3-dimethyl-cyclopropanecarboxamide -50 (2R,3S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[3-(1,4-oxazepan-4- yl)prop-1-ynyl]-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]-2,3-dimethyl-cyclopropanecarboxamide -51 (2S,3R)-N-[(7S,13S)-(20M)-20-[5-[3-(azetidin-1-yl)prop-1-ynyl]-2-[(1S)-1- methoxyethyl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-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(29),2,5(31),19,25,27- hexaen-7-yl]-2,3-dimethyl-cyclopropanecarboxamide -52 (2S,3R)-N-[(7S,13S)-(20M)-20-[5-[3-(1,1-dioxo-1,4-thiazinan-4-yl)prop-1-ynyl]-2- [(1S)-1-methoxyethyl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia- 2,5 9,13 19,27 21,26 9,21,30,31-tetrazahexacyclo[23.3.1.1 .1 .0 .0 ]hentriaconta- 1(29),2,5(31),19,25,27-hexaen-7-yl]-2,3-dimethyl-cyclopropanecarboxamide -53 (2S,3R)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(3-morpholinoprop-1- ynyl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-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(29),2,5(31),19,25,27- hexaen-7-yl]-2,3-dimethyl-cyclopropanecarboxamide

[0010] .54 (2S,3R)-N-[(7S,13S)-23,23-difluoro-(20M)-20-[2-isopropyl-5-[3-(1,4-oxazepan-4- yl)prop-1-ynyl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-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(29),2,5(31),19,25,27- hexaen-7-yl]-2,3-dimethyl-cyclopropanecarboxamide -55 (2S,3R)-N-[(7S,13S)-23,23-difluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[3-(1,4- oxazepan-4-yl)prop-1-ynyl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia- 2,5 9,13 19,27 21,26 9,21,30,31-tetrazahexacyclo[23.3.1.1 .1 .0 .0 ]hentriaconta- 1(29),2,5(31),19,25,27-hexaen-7-yl]-2,3-dimethyl-cyclopropanecarboxamide -56 (2S,3R)-N-[(7S,13S)-(20M)-20-[5-[3-(azetidin-1-yl)prop-1-ynyl]-2-[(1S)-1- methoxyethyl]-3-pyridyl]-23,23-difluoro-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia- 2,5 9,13 19,27 21,26 9,21,30,31-tetrazahexacyclo[23.3.1.1 .1 .0 .0 ]hentriaconta- 1(29),2,5(31),19,25,27-hexaen-7-yl]-2,3-dimethyl-cyclopropanecarboxamide -57 (2R,3S)-N-[(7S,13S)-(20M)-20-[5-[3-(1,1-dioxo-1,4-thiazinan-4-yl)prop-1-ynyl]-2- [(1S)-1-methoxyethyl]-3-pyridyl]-23,23-difluoro-17,17-dimethyl-8,14-dioxo-15-oxa- 2,5 9,13 19,27 21,26 4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.1 .1 .0 .0 ]hentriaconta- 1(29),2,5(31),19,25,27-hexaen-7-yl]-2,3-dimethyl-cyclopropanecarboxamide -58 (2S,3R)-N-[(7S,13S)-23,23-difluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(3- morpholinoprop-1-ynyl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia- 2,5 9,13 19,27 21,26 9,21,30,31-tetrazahexacyclo[23.3.1.1 .1 .0 .0 ]hentriaconta- 1(29),2,5(31),19,25,27-hexaen-7-yl]-2,3-dimethyl-cyclopropanecarboxamide

[0011] -59 (2S,3R)-N-[(7S,13S)-(20M)-20-[2-isopropyl-5-[3-(1,4-oxazepan-4-yl)prop-1-ynyl]-3- pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31- 2,5 9,13 19,27 21,26 tetrazahexacyclo[23.3.1.1 .1 .0 .0 ]hentriaconta-1(29),2,5(31),19,25,27- hexaen-7-yl]-2,3-dimethyl-cyclopropanecarboxamide -60 (2S,3R)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[3-(1,4-oxazepan-4- yl)prop-1-ynyl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31- 2,5 9,13 19,27 21,26 tetrazahexacyclo[23.3.1.1 .1 .0 .0 ]hentriaconta-1(29),2,5(31),19,25,27- hexaen-7-yl]-2,3-dimethyl-cyclopropanecarboxamide -61 (2S,3R)-N-[(7S,13S)-(20M)-20-[5-[3-(azetidin-1-yl)prop-1-ynyl]-2-[(1S)-1- methoxyethyl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31- 2,5 9,13 19,27 21,26 tetrazahexacyclo[23.3.1.1 .1 .0 .0 ]hentriaconta-1(29),2,5(31),19,25,27- hexaen-7-yl]-2,3-dimethyl-cyclopropanecarboxamide

[0012] -62 (2S,3R)-N-[(7S,13S)-(20M)-20-[5-[3-(1,1-dioxo-1,4-thiazinan-4-yl)prop-1-ynyl]-2- [(1S)-1-methoxyethyl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia- 2,5 9,13 19,27 21,26 9,21,30,31-tetrazahexacyclo[23.3.1.1 .1 .0 .0 ]hentriaconta- 1(29),2,5(31),19,25,27-hexaen-7-yl]-2,3-dimethyl-cyclopropanecarboxamide -63 (2S,3R)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(3-morpholinoprop-1- ynyl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31- 2,5 9,13 19,27 21,26 tetrazahexacyclo[23.3.1.1 .1 .0 .0 ]hentriaconta-1(29),2,5(31),19,25,27- hexaen-7-yl]-2,3-dimethyl-cyclopropanecarboxamide -64 (2S,3R)-N-[(7S,13S)-(20M)-20-[2-isopropyl-5-[3-(1,4-oxazepan-4-yl)prop-1-ynyl]-3- pyridyl]-17,17-dimethyl-8,14-dioxo-15,25-dioxa-4-thia-9,21,31,32- 2,5 9,13 19,28 21,27 tetrazahexacyclo[24.3.1.1 .1 .0 .0 ]dotriaconta-1(30),2,5(32),19,26,28- hexaen-7-yl]-2,3-dimethyl-cyclopropanecarboxamide -65 (2S,3R)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[3-(1,4-oxazepan-4- yl)prop-1-ynyl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,25-dioxa-4-thia-9,21,31,32- 2,5 9,13 19,28 21,27 tetrazahexacyclo[24.3.1.1 .1 .0 .0 ]dotriaconta-1(30),2,5(32),19,26,28- hexaen-7-yl]-2,3-dimethyl-cyclopropanecarboxamide -66 (2R,3S)-N-[(7S,13S)-(20M)-20-[5-[3-(azetidin-1-yl)prop-1-ynyl]-2-[(1S)-1- methoxyethyl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,25-dioxa-4-thia-9,21,31,32- 2,5 9,13 19,28 21,27 tetrazahexacyclo[24.3.1.1 .1 .0 .0 ]dotriaconta-1(30),2,5(32),19,26,28- hexaen-7-yl]-2,3-dimethyl-cyclopropanecarboxamide

[0013] (2R,3S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(3-morpholinoprop-1- ynyl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,25-dioxa-4-thia-9,21,31,32- 2,5 9,13 19,28 21,27 tetrazahexacyclo[24.3.1.1 .1 .0 .0 ]dotriaconta-1(30),2,5(32),19,26,28- hexaen-7-yl]-2,3-dimethyl-cyclopropanecarboxamide -69 (2S,3R)-N-[(7S,13S)-(20M)-20-[2-isopropyl-5-[3-(1,4-oxazepan-4-yl)prop-1-ynyl]-3- pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,32- 2,5 9,13 10,12 19,27 21,26 tetrazaheptacyclo[23.3.1.1 .1 .1 .0 .0 ]dotriaconta-1(29),2,5(32),19,25,27- hexaen-7-yl]-2,3-dimethyl-cyclopropanecarboxamide

[0014] -70 (2S,3R)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[3-(1,4-oxazepan-4- yl)prop-1-ynyl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,32- 2,5 9,13 10,12 19,27 21,26 tetrazaheptacyclo[23.3.1.1 .1 .1 .0 .0 ]dotriaconta-1(29),2,5(32),19,25,27- hexaen-7-yl]-2,3-dimethyl-cyclopropanecarboxamide -71 (2S,3R)-N-[(7S,13S)-(20M)-20-[5-[3-(azetidin-1-yl)prop-1-ynyl]-2-[(1S)-1- methoxyethyl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,32- 2,5 9,13 10,12 19,27 21,26 tetrazaheptacyclo[23.3.1.1 .1 .1 .0 .0 ]dotriaconta-1(29),2,5(32),19,25,27- hexaen-7-yl]-2,3-dimethyl-cyclopropanecarboxamide -72 (2S,3R)-N-[(7S,13S)-(20M)-20-[5-[3-(1,1-dioxo-1,4-thiazinan-4-yl)prop-1-ynyl]-2- [(1S)-1-methoxyethyl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia- 2,5 9,13 10,12 19,27 21,26 9,21,30,32-tetrazaheptacyclo[23.3.1.1 .1 .1 .0 .0 ]dotriaconta- 1(29),2,5(32),19,25,27-hexaen-7-yl]-2,3-dimethyl-cyclopropanecarboxamide -73 (2S,3R)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(3-morpholinoprop-1- ynyl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,32- 2,5 9,13 10,12 19,27 21,26 tetrazaheptacyclo[23.3.1.1 .1 .1 .0 .0 ]dotriaconta-1(29),2,5(32),19,25,27- hexaen-7-yl]-2,3-dimethyl-cyclopropanecarboxamide -74 (2S,3R)-N-[(7S,13S)-23,23-difluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[3-(1,4- oxazepan-4-yl)prop-1-ynyl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia- 2,5 9,13 10,12 19,27 21,26 9,21,30,32-tetrazaheptacyclo[23.3.1.1 .1 .1 .0 .0 ]dotriaconta- 1(29),2,5(32),19,25,27-hexaen-7-yl]-2,3-dimethyl-cyclopropanecarboxamide -75 (2S,3R)-N-[(7S,13S)-(20M)-20-[5-[3-(azetidin-1-yl)prop-1-ynyl]-2-[(1S)-1- methoxyethyl]-3-pyridyl]-23,23-difluoro-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia- 2,5 9,13 10,12 19,27 21,26 9,21,30,32-tetrazaheptacyclo[23.3.1.1 .1 .1 .0 .0 ]dotriaconta- 1(29),2,5(32),19,25,27-hexaen-7-yl]-2,3-dimethyl-cyclopropanecarboxamide -76 (2S,3R)-N-[(7S,13S)-(20M)-20-[5-[3-(1,1-dioxo-1,4-thiazinan-4-yl)prop-1-ynyl]-2- [(1S)-1-methoxyethyl]-3-pyridyl]-23,23-difluoro-17,17-dimethyl-8,14-dioxo-15-oxa- 2,5 9,13 10,12 19,27 21,26 4-thia-9,21,30,32-tetrazaheptacyclo[23.3.1.1 .1 .1 .0 .0 ]dotriaconta- 1(29),2,5(32),19,25,27-hexaen-7-yl]-2,3-dimethyl-cyclopropanecarboxamide

[0015] -77 (2S,3R)-N-[(7S,13S)-23,23-difluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(3- morpholinoprop-1-ynyl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia- 2,5 9,13 10,12 19,27 21,26 9,21,30,32-tetrazaheptacyclo[23.3.1.1 .1 .1 .0 .0 ]dotriaconta- 1(29),2,5(32),19,25,27-hexaen-7-yl]-2,3-dimethyl-cyclopropanecarboxamide -78 (2S,3R)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[3-(1,4-oxazepan-4- yl)prop-1-ynyl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,32- 2,5 9,13 10,12 19,27 21,26 tetrazaheptacyclo[23.3.1.1 .1 .1 .0 .0 ]dotriaconta-1(29),2,5(32),19,25,27- hexaen-7-yl]-2,3-dimethyl-cyclopropanecarboxamide -79 (2S,3R)-N-[(7S,13S)-(20M)-20-[5-[3-(azetidin-1-yl)prop-1-ynyl]-2-[(1S)-1- methoxyethyl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,32- 2,5 9,13 10,12 19,27 21,26 tetrazaheptacyclo[23.3.1.1 .1 .1 .0 .0 ]dotriaconta-1(29),2,5(32),19,25,27- hexaen-7-yl]-2,3-dimethyl-cyclopropanecarboxamide -80 (2S,3R)-N-[(7S,13S)-(20M)-20-[5-[3-(1,1-dioxo-1,4-thiazinan-4-yl)prop-1-ynyl]-2- [(1S)-1-methoxyethyl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia- 2,5 9,13 10,12 19,27 21,26 9,21,30,32-tetrazaheptacyclo[23.3.1.1 .1 .1 .0 .0 ]dotriaconta- 1(29),2,5(32),19,25,27-hexaen-7-yl]-2,3-dimethyl-cyclopropanecarboxamide -81 (2S,3R)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(3-morpholinoprop-1- ynyl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,32- 2,5 9,13 10,12 19,27 21,26 tetrazaheptacyclo[23.3.1.1 .1 .1 .0 .0 ]dotriaconta-1(29),2,5(32),19,25,27- hexaen-7-yl]-2,3-dimethyl-cyclopropanecarboxamide

[0016] -82 (2S,3R)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[3-(1,4-oxazepan-4- yl)prop-1-ynyl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,25-dioxa-4-thia-9,21,31,33- 2,5 9,13 10,12 19,28 21,27 tetrazaheptacyclo[24.3.1.1 .1 .1 .0 .0 ]tritriaconta-1(30),2,5(33),19,26,28- hexaen-7-yl]-2,3-dimethyl-cyclopropanecarboxamide -83 (2R,3S)-N-[(7S,13S)-(20M)-20-[5-[3-(azetidin-1-yl)prop-1-ynyl]-2-[(1S)-1- methoxyethyl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,25-dioxa-4-thia-9,21,31,33- 2,5 9,13 10,12 19,28 21,27 tetrazaheptacyclo[24.3.1.1 .1 .1 .0 .0 ]tritriaconta-1(30),2,5(33),19,26,28- hexaen-7-yl]-2,3-dimethyl-cyclopropanecarboxamide -84 (2S,3R)-N-[(7S,13S)-(20M)-20-[5-[3-(1,1-dioxo-1,4-thiazinan-4-yl)prop-1-ynyl]-2- [(1S)-1-methoxyethyl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,25-dioxa-4-thia- 2,5 9,13 10,12 19,28 21,27 9,21,31,33-tetrazaheptacyclo[24.3.1.1 .1 .1 .0 .0 ]tritriaconta- 1(30),2,5(33),19,26,28-hexaen-7-yl]-2,3-dimethyl-cyclopropanecarboxamide

[0017] 2-85 (2R,3S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(3-morpholinoprop-1- ynyl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,25-dioxa-4-thia-9,21,31,33- 2,5 9,13 10,12 19,28 21,27 tetrazaheptacyclo[24.3.1.1 .1 .1 .0 .0 ]tritriaconta-1(30),2,5(33),19,26,28- hexaen-7-yl]-2,3-dimethyl-cyclopropanecarboxamide BIOLOGICAL EXAMPLE Example 3 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 3. 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) 1-1 0.018 0.094 0.018 1-2 0.086 0.317 0.142 1-3 0.194 0.665 0.298 1-4 0.350 0.683 0.331 1-5 0.013 0.055 0.012 1-6 0.041 0.097 0.056 1-7 0.013 0.056 0.016 1-8 0.093 0.109 0.103 1-9 0.096 0.303 0.113 1-10 0.017 0.070 0.029 1-11 0.016 0.059 0.029 1-13 0.029 0.487 0.041 1-14 0.117 - 0.152 1-15 0.021 0.080 0.044 1-16 0.374 - - 1-19 0.011 0.086 0.013 1-20 0.034 0.121 0.051 1-21 0.091 0.435 0.134 1-22 0.039 0.348 0.049 1-24 0.028 0.538 0.048 1-25 0.036 0.294 0.048 1-26 0.017 0.102 0.030 1-27 0.031 0.142 0.048 1-29 0.024 0.396 0.037 1-30 0.574 - 0.827 1-31 0.037 0.297 0.054 1-34 0.022 0.230 0.025

Claims

CLAIMS 1. A compound of formula (I),wherein R1is 3-oxabicyclo[3.1.0]hexanyl, or C3-7cycloalkyl substituted once or twice by the substituents independently selected from a group consisting of C1-6alkyl, haloC1-6alkyl, C1-6alkylpyrimidinyl, C3- 7cycloalkyl, phenyl, pyridyl and pyrimidinyl; R2is morpholino, C1-6alkylpiperazinyl, (1,1-dioxo-1,4-thiazinanyl)C2-6alkynyl, (1,4- oxazepanyl)C2-6alkynyl, azetidinylC2-6alkynyl or morpholinoC2-6alkynyl; R3is C1-6alkoxyC1-6alkyl or C1-6alkyl; R4is C1-6alkyl and R5is H; or R4and R5together with the atoms they are attached to form a 6- or 7-membered heterocycle ring, wherein R4is C1-6alkylene or haloC1-6alkylene, R5is C1-6alkylene or O; A1is hexahydropyridazinylene, 2,3-diazabicyclo[3.1.1]heptanylene, 2,3-diazabicyclo[3.2.1]octanylene, 2,3-diazabicyclo[4.1.0]heptanylene, 3,4-diazabicyclo[4.1.0]heptanylene which is unsubstituted, or substituted once, twice or three times by the substituents independently selected from a group consisting of C1-6alkyl and halogen, 3,4-diazabicyclo[4.2.0]octanylene, 5,6-diazaspiro[2.5]octanylene, halo-1,2,3,6-tetrahydropyridazinylene, or7-oxa-2,3-diazabicyclo[3.3.1]nonanylene; A2is C1-6alkylene; A3is thiazolylene or hydroxyphenylene; A4is C1-6alkylene or C3-7cycloalkylene; or a pharmaceutically acceptable salt thereof.

2. A compound of formula (Ia),wherein R1is 3-oxabicyclo[3.1.0]hexanyl, or C3-7cycloalkyl substituted once or twice by the substituents independently selected from a group consisting of C1-6alkyl, haloC1-6alkyl, C1-6alkylpyrimidinyl, C3- 7cycloalkyl, phenyl, pyridyl and pyrimidinyl; R2is morpholino, C1-6alkylpiperazinyl, (1,1-dioxo-1,4-thiazinanyl)C2-6alkynyl, (1,4- oxazepanyl)C2-6alkynyl, azetidinylC2-6alkynyl or morpholinoC2-6alkynyl; R3is C1-6alkoxyC1-6alkyl or C1-6alkyl; R4is C1-6alkyl and R5is H; or R4and R5together with the atoms they are attached to form a 6- or 7-membered heterocycle ring, wherein R4is C1-6alkylene or haloC1-6alkylene, R5is C1-6alkylene or O; A1is hexahydropyridazinylene, 2,3-diazabicyclo[3.1.1]heptanylene, 2,3-diazabicyclo[3.2.1]octanylene, 2,3-diazabicyclo[4.1.0]heptanylene,3,4-diazabicyclo[4.1.0]heptanylene which is unsubstituted, or substituted once, twice or three times by the substituents independently selected from a group consisting of C1-6alkyl and halogen, 3,4-diazabicyclo[4.2.0]octanylene, 5,6-diazaspiro[2.5]octanylene, halo-1,2,3,6-tetrahydropyridazinylene, or 7-oxa-2,3-diazabicyclo[3.3.1]nonanylene; A2is C1-6alkylene; A3is thiazolylene or hydroxyphenylene; A4is C1-6alkylene or C3-7cycloalkylene; or a pharmaceutically acceptable salt thereof.

3. A compound according to claim 1 or 2, wherein R1is C3-7cycloalkyl substituted once or twice by the substituents independently selected from a group consisting of C1-6alkyl, haloC1-6alkyl, C1-6alkylpyrimidinyl, pyridyl and pyrimidinyl.

4. A compound according to any one of claims 1-3, wherein R1is cyclopropyl substituted once or twice by the substituents independently selected from a group consisting of methyl, difluoromethyl, methylpyrimidinyl, pyridyl and pyrimidinyl.

5. A compound according to any one of claims 1-4, wherein R1is 2-(2-methylpyrimidin-5- yl)cyclopropyl, 2-(3-pyridyl)cyclopropyl, 2,3-dimethyl-cyclopropyl, 2-difluoromethyl- cyclopropyl or 2-pyrimidin-5-yl-cyclopropyl.

6. A compound according to any one of claims 1-5, wherein R2is morpholino or 4- methylpiperazin-1-yl.

7. A compound according to any one of claims 1-6, wherein R3is 1-methoxyethyl.

8. A compound according to any one of claims 1-7, wherein R4is ethyl and R5is H.

9. A compound according to any one of claims 1-7, wherein R4and R5together with the atoms they are attached to form a 6- or 7-membered heterocycle ring; wherein R4is ethylene, propylene or difluoroethylene; R5is methylene or O.

10. A compound according to any one of claims 1-8, wherein A1is 2,3- diazabicyclo[3.2.1]octanylene.

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

12. A compound according to any one of claims 1-11, wherein A3is thiazolylene.

13. A compound according to any one of claims 1-12, wherein A4is methylene.

14. A compound according to claim 1 or 2, wherein R1is C3-7cycloalkyl substituted once or twice by the substituents independently selected from a group consisting of C1-6alkyl, haloC1-6alkyl, C1-6alkylpyrimidinyl, pyridyl and pyrimidinyl; R2is morpholino or C1-6alkylpiperazinyl; R3is C1-6alkoxyC1-6alkyl; R4is C1-6alkyl; R5is H; or R4and R5together with the atoms they are attached to form a 6- or 7-membered heterocycle ring, wherein R4is C1-6alkylene or haloC1-6alkylene, R5is C1-6alkylene or O; A1is 2,3-diazabicyclo[3.2.1]octanylene; A2is C1-6alkylene; A3is thiazolylene; A4is C1-6alkylene; or a pharmaceutically acceptable salt thereof.

15. A compound according to claim 14, wherein R1is 2-(2-methylpyrimidin-5-yl)cyclopropyl, 2-(3-pyridyl)cyclopropyl, 2,3-dimethyl- cyclopropyl, 2-difluoromethyl-cyclopropyl or 2-pyrimidin-5-yl-cyclopropyl;R2is morpholino or 4-methylpiperazin-1-yl; R3is 1-methoxyethyl; R4is ethyl; R5is H; or R4and R5together with the atoms they are attached to form a 6- or 7-membered heterocycle ring; wherein R4is ethylene, propylene or difluoroethylene; R5is methylene or O; A1is 2,3-diazabicyclo[3.2.1]octanylene;A3is thiazolylene; A4is methylene; or a pharmaceutically acceptable salt thereof.

16. A compound selected from: (1S,2S)-N-[(7S,11R,14S)-22-ethyl-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-18,18-dimethyl-8,15-dioxo-16-oxa-4-thia-9,22,29,30- tetrazahexacyclo[18.5.2.12,5.19,14.111,14.023,27]triaconta-1(26),2,5(30),20,23(27),24-hexaen-7-yl]- 2-(2-methylpyrimidin-5-yl)cyclopropanecarboxamide; (1R,2R)-N-[(7S,11R,14S)-22-ethyl-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-18,18-dimethyl-8,15-dioxo-16-oxa-4-thia-9,22,29,30- tetrazahexacyclo[18.5.2.12,5.19,14.111,14.023,27]triaconta-1(26),2,5(30),20,23(27),24-hexaen-7-yl]- 2-(2-methylpyrimidin-5-yl)cyclopropanecarboxamide; (1S,2S)-N-[(7S)-21-ethyl-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]- 17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,29,30- tetrazahexacyclo[17.5.2.210,13.12,5.19,13.022,26]triaconta-1(25),2,5(30),19,22(26),23-hexaen-7-yl]- 2-(2-pyridyl)cyclopropanecarboxamide; (2R,3S)-N-[(7S)-21-ethyl-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]- 17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,29,30- tetrazahexacyclo[17.5.2.210,13.12,5.19,13.022,26]triaconta-1(25),2,5(30),19,22(26),23-hexaen-7-yl]- 2,3-dimethyl-cyclopropanecarboxamide; (1S,2S)-N-[(7S,11R,14S)-22-ethyl-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-18,18-dimethyl-8,15-dioxo-16-oxa-4-thia-9,22,29,30-tetrazahexacyclo[18.5.2.12,5.19,14.111,14.023,27]triaconta-1(25),2,5(30),20,23,26-hexaen-7-yl]-2- pyrimidin-5-yl-cyclopropanecarboxamide; (2S,3R)-N-[(7S,11R,15R)-23-ethyl-(22M)-22-[2-[(1S)-1-methoxyethyl]-5-morpholino-3- pyridyl]-19,19-dimethyl-8,16-dioxo-13,17-dioxa-4-thia-9,23,30,31- tetrazahexacyclo[19.5.2.12,5.19,15.111,15.024,28]hentriaconta-1(27),2,5(31),21,24(28),25-hexaen-7- yl]-2,3-dimethyl-cyclopropanecarboxamide; (1S,2S)-N-[(7S,11R,14S)-22-ethyl-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-18,18-dimethyl-8,15-dioxo-16-oxa-4-thia-9,22,29,30- tetrazahexacyclo[18.5.2.12,5.19,14.111,14.023,27]triaconta-1(26),2,5(30),20,23(27),24-hexaen-7-yl]- 2-(3-pyridyl)cyclopropanecarboxamide; (2R,3S)-N-[(1S,23S,27R)-(8M)-8-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3- pyridyl]-5,5-dimethyl-2,24-dioxo-3,12-dioxa-20-thia-9,25,30,32- tetrazaheptacyclo[23.4.1.11,27.113,17.118,21.07,15.09,14]tritriaconta-7,13,15,17(33),18,21(32)-hexaen- 23-yl]-2,3-dimethyl-cyclopropanecarboxamide; (1S,2S)-N-[(1S,23S,27R)-(8M)-8-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3- pyridyl]-5,5-dimethyl-2,24-dioxo-3,12-dioxa-20-thia-9,25,30,32- tetrazaheptacyclo[23.4.1.11,27.113,17.118,21.07,15.09,14]tritriaconta-7,13,15,17(33),18,21(32)-hexaen- 23-yl]-2-methyl-cyclopropanecarboxamide; N-[(7S,11R,14S)-22-ethyl-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)- 3-pyridyl]-18,18-dimethyl-8,15-dioxo-16-oxa-4-thia-9,22,29,30- tetrazahexacyclo[18.5.2.12,5.19,14.111,14.023,27]triaconta-1(26),2,5(30),20,23(27),24-hexaen-7-yl]- 1,2-dimethyl-cyclopropanecarboxamide; (1R,2S)-2-cyclopropyl-N-[(7S,11R,14S)-22-ethyl-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-18,18-dimethyl-8,15-dioxo-16-oxa-4-thia-9,22,29,30- tetrazahexacyclo[18.5.2.12,5.19,14.111,14.023,27]triaconta-1(26),2,5(30),20,23(27),24-hexaen-7- yl]cyclopropanecarboxamide; (1R,2S)-N-[(7S,11R,14S)-22-ethyl-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-18,18-dimethyl-8,15-dioxo-16-oxa-4-thia-9,22,29,30- tetrazahexacyclo[18.5.2.12,5.19,14.111,14.023,27]triaconta-1(26),2,5(30),20,23(27),24-hexaen-7-yl]- 2-phenyl-cyclopropanecarboxamide; (1S,2S)-N-[(7S,11R,14S)-22-ethyl-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-18,18-dimethyl-8,15-dioxo-16-oxa-4-thia-9,22,29,30-tetrazahexacyclo[18.5.2.12,5.19,14.111,14.023,27]triaconta-1(26),2,5(30),20,23(27),24-hexaen-7-yl]- 2-phenyl-cyclopropanecarboxamide; (1S,2S)-N-[(1S,23S,27R)-(8M)-8-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3- pyridyl]-5,5-dimethyl-2,24-dioxo-3-oxa-20-thia-9,25,30,32- tetrazaheptacyclo[23.4.1.11,27.113,17.118,21.07,15.09,14]tritriaconta-7,13,15,17(33),18,21(32)-hexaen- 23-yl]-2-methyl-cyclopropanecarboxamide; (1R,5S)-N-[(7S,11R,14S)-22-ethyl-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-morpholino-3- pyridyl]-18,18-dimethyl-8,15-dioxo-16-oxa-4-thia-9,22,29,30- tetrazahexacyclo[18.5.2.12,5.19,14.111,14.023,27]triaconta-1(26),2,5(30),20,23(27),24-hexaen-7-yl]- 3-oxabicyclo[3.1.0]hexane-6-carboxamide; (1S,2R)-N-[(7S,11R,14S)-22-ethyl-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-18,18-dimethyl-8,15-dioxo-16-oxa-4-thia-9,22,29,30- tetrazahexacyclo[18.5.2.12,5.19,14.111,14.023,27]triaconta-1(26),2,5(30),20,23(27),24-hexaen-7-yl]- 2-phenyl-cyclopropanecarboxamide; (1R,2R)-N-[(7S,11R,14S)-22-ethyl-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-18,18-dimethyl-8,15-dioxo-16-oxa-4-thia-9,22,29,30- tetrazahexacyclo[18.5.2.12,5.19,14.111,14.023,27]triaconta-1(26),2,5(30),20,23(27),24-hexaen-7-yl]- 2-phenyl-cyclopropanecarboxamide; (1R,5S)-N-[(7S,11R,14S)-22-ethyl-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-18,18-dimethyl-8,15-dioxo-16-oxa-4-thia-9,22,29,30- tetrazahexacyclo[18.5.2.12,5.19,14.111,14.023,27]triaconta-1(26),2,5(30),20,23(27),24-hexaen-7-yl]- 3-oxabicyclo[3.1.0]hexane-6-carboxamide; (2R,3S)-N-[(7S,11R,14S)-22-ethyl-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-18,18-dimethyl-8,15-dioxo-16-oxa-4-thia-9,22,29,30- tetrazahexacyclo[18.5.2.12,5.19,14.111,14.023,27]triaconta-1(26),2,5(30),20,23(27),24-hexaen-7-yl]- 2,3-dimethyl-cyclopropanecarboxamide; (2R,3S)-N-[(7S,11R,14S)-22-ethyl-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-morpholino-3- pyridyl]-18,18-dimethyl-8,15-dioxo-16-oxa-4-thia-9,22,29,30- tetrazahexacyclo[18.5.2.12,5.19,14.111,14.023,27]triaconta-1(26),2,5(30),20,23(27),24-hexaen-7-yl]- 2,3-dimethyl-cyclopropanecarboxamide; (1S,2S)-2-(difluoromethyl)-N-[(7S,11R,14S)-22-ethyl-(21M)-21-[2-[(1S)-1-methoxyethyl]- 5-morpholino-3-pyridyl]-18,18-dimethyl-8,15-dioxo-16-oxa-4-thia-9,22,29,30-tetrazahexacyclo[18.5.2.12,5.19,14.111,14.023,27]triaconta-1(26),2,5(30),20,23(27),24-hexaen-7- yl]cyclopropanecarboxamide; (1S,5R)-N-[(7S,11R,14S)-22-ethyl-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-morpholino-3- pyridyl]-18,18-dimethyl-8,15-dioxo-16-oxa-4-thia-9,22,29,30- tetrazahexacyclo[18.5.2.12,5.19,14.111,14.023,27]triaconta-1(26),2,5(30),20,23(27),24-hexaen-7-yl]- 3-oxabicyclo[3.1.0]hexane-6-carboxamide; (1S,5R)-N-[(7S,11R,14S)-22-ethyl-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-18,18-dimethyl-8,15-dioxo-16-oxa-4-thia-9,22,29,30- tetrazahexacyclo[18.5.2.12,5.19,14.111,14.023,27]triaconta-1(26),2,5(30),20,23(27),24-hexaen-7-yl]- 3-oxabicyclo[3.1.0]hexane-6-carboxamide; (1S,2S)-2-(difluoromethyl)-N-[(7S,11R,14S)-22-ethyl-(21M)-21-[2-[(1S)-1-methoxyethyl]- 5-(4-methylpiperazin-1-yl)-3-pyridyl]-18,18-dimethyl-8,15-dioxo-16-oxa-4-thia-9,22,29,30- tetrazahexacyclo[18.5.2.12,5.19,14.111,14.023,27]triaconta-1(26),2,5(30),20,23(27),24-hexaen-7- yl]cyclopropanecarboxamide; (1S,2S)-N-[(7S,11R,14S)-22-ethyl-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-18,18-dimethyl-8,15-dioxo-16-oxa-4-thia-9,22,29,30- tetrazahexacyclo[18.5.2.12,5.19,14.111,14.023,27]triaconta-1(26),2,5(30),20,23(27),24-hexaen-7-yl]- 2-methyl-cyclopropanecarboxamide; (1S,2S)-N-[(7S)-21-ethyl-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]- 17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,29,30- tetrazahexacyclo[17.5.2.210,13.12,5.19,13.022,26]triaconta-1(25),2,5(30),19,22(26),23-hexaen-7-yl]- 2-methyl-cyclopropanecarboxamide; (1S,2S)-N-[(7S,11R,14S)-22-ethyl-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-morpholino-3- pyridyl]-18,18-dimethyl-8,15-dioxo-16-oxa-4-thia-9,22,29,30- tetrazahexacyclo[18.5.2.12,5.19,14.111,14.023,27]triaconta-1(26),2,5(30),20,23(27),24-hexaen-7-yl]- 2-methyl-cyclopropanecarboxamide; (1S,2S)-N-[(7S)-22-ethyl-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]- 18,18-dimethyl-8,15-dioxo-16-oxa-4-thia-9,22,28,29- tetrazahexacyclo[18.5.2.12,5.19,14.012,14.023,27]nonacosa-1(26),2,5(29),20,23(27),24-hexaen-7-yl]- 2-methyl-cyclopropanecarboxamide; (2S,3R)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3- pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,32-2,5 9,13 10,12 19,27 21,26 tetrazaheptacyclo[23.3.1.1 .1 .1 .0 .0 ]dotriaconta-1(29),2,5(32),19,25,27-hexaen-7- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(7S,13R)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3- pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,32- 2,5 9,13 10,12 19,27 21,26 tetrazaheptacyclo[23.3.1.1 .1 .1 .0 .0 ]dotriaconta-1(29),2,5(32),19,25,27-hexaen-7- yl]-2,3-dimethyl-cyclopropanecarboxamide; and (2S,3R)-N-[(7S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3- pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,32- 2,5 9,13 10,12 19,27 21,26 tetrazaheptacyclo[23.3.1.1 .1 .1 .0 .0 ]dotriaconta-1(29),2,5(32),19,25,27-hexaen-7- yl]-2,3-dimethyl-cyclopropanecarboxamide; or a pharmaceutically acceptable salt thereof.

17. A compound selected from: (2R,3S)-N-[(7S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3- pyridyl]-17,17-dimethyl-8,14-dioxo-spiro[15-oxa-4-thia-9,21,30,32- tetrazaheptacyclo[23.3.1.12,5.19,13.110,12.019,27.021,26]dotriaconta-1(29),2,5(32),19,25,27-hexaene- 6,1'-cyclopropane]-7-yl]-2,3-dimethyl-cyclopropanecarboxamide; (2R,3S)-N-[(7S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3- pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,32- tetrazaheptacyclo[23.3.1.12,5.19,13.110,12.019,27.021,26]dotriaconta-1(29),2,5(32),19,25,27-hexaen-7- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2R,3S)-N-[(7S)-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-9,21,30,32- tetrazaheptacyclo[23.3.1.12,5.19,13.110,12.019,27.021,26]dotriaconta-1(29),2,5(32),19,25,27-hexaen-7- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2R,3S)-N-[(3S,26S,28R)-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)- 3-pyridyl]-21,21-dimethyl-2,24-dioxo-23-oxa-6-thia-1,17,30,32- tetrazaheptacyclo[23.4.1.15,8.19,13.011,19.012,17.026,28]dotriaconta-5(32),7,9(31),10,12,18-hexaen-3- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2R,3S)-N-[(3S,26S,28R)-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)- 3-pyridyl]-21,21-dimethyl-2,24-dioxo-14,23-dioxa-6-thia-1,17,30,32- tetrazaheptacyclo[23.4.1.15,8.19,13.011,19.012,17.026,28]dotriaconta-5(32),7,9(31),10,12,18-hexaen-3- yl]-2,3-dimethyl-cyclopropanecarboxamide;(2R,3S)-N-[(3S,26S,28R)-15,15-difluoro-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-21,21-dimethyl-2,24-dioxo-23-oxa-6-thia-1,17,30,32- tetrazaheptacyclo[23.4.1.15,8.19,13.011,19.012,17.026,28]dotriaconta-5(32),7,9(31),10,12,18-hexaen-3- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(3S,27S,29R)-(19M)-19-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)- 3-pyridyl]-22,22-dimethyl-2,25-dioxo-14,24-dioxa-6-thia-1,18,31,33- tetrazaheptacyclo[24.4.1.15,8.19,13.011,20.012,18.027,29]tritriaconta-5(33),7,9(32),10,12,19-hexaen-3- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2R,3S)-N-[(3S,26R,28S)-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)- 3-pyridyl]-21,21-dimethyl-2,24-dioxo-23-oxa-6-thia-1,17,30,32- tetrazaheptacyclo[23.4.1.15,8.19,13.011,19.012,17.026,28]dotriaconta-5(32),7,9(31),10,12,18-hexaen-3- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2R,3S)-N-[(3S,26R,28S)-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)- 3-pyridyl]-21,21-dimethyl-2,24-dioxo-14,23-dioxa-6-thia-1,17,30,32- tetrazaheptacyclo[23.4.1.15,8.19,13.011,19.012,17.026,28]dotriaconta-5(32),7,9(31),10,12,18-hexaen-3- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2R,3S)-N-[(3S,26R,28S)-15,15-difluoro-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-21,21-dimethyl-2,24-dioxo-23-oxa-6-thia-1,17,30,32- tetrazaheptacyclo[23.4.1.15,8.19,13.011,19.012,17.026,28]dotriaconta-5(32),7,9(31),10,12,18-hexaen-3- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(3S,27R,29S)-(19M)-19-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)- 3-pyridyl]-22,22-dimethyl-2,25-dioxo-14,24-dioxa-6-thia-1,18,31,33- tetrazaheptacyclo[24.4.1.15,8.19,13.011,20.012,18.027,29]tritriaconta-5(33),7,9(32),10,12,19-hexaen-3- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2R,3S)-N-[(7S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3- pyridyl]-17,17-dimethyl-8,14-dioxo-spiro[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-hexaene-12,1'- cyclopropane]-7-yl]-2,3-dimethyl-cyclopropanecarboxamide; (2R,3S)-N-[(7S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3- pyridyl]-17,17-dimethyl-8,14-dioxo-spiro[15,24-dioxa-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-hexaene-12,1'- cyclopropane]-7-yl]-2,3-dimethyl-cyclopropanecarboxamide;(2R,3S)-N-[(7S)-23,23-difluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin- 1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-spiro[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-hexaene-12,1'- cyclopropane]-7-yl]-2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(7S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3- pyridyl]-17,17-dimethyl-8,14-dioxo-spiro[15,25-dioxa-4-thia-9,21,31,32- tetrazahexacyclo[24.3.1.12,5.19,13.019,28.021,27]dotriaconta-1(30),2,5(32),19,26,28-hexaene-12,1'- cyclopropane]-7-yl]-2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(3S,26R,28S)-27,27-difluoro-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-21,21-dimethyl-2,24-dioxo-23-oxa-6-thia-1,17,30,32- tetrazaheptacyclo[23.4.1.15,8.19,13.011,19.012,17.026,28]dotriaconta-5(32),7,9(31),10,12,18-hexaen-3- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(3S,26R,28S)-27,27-difluoro-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-21,21-dimethyl-2,24-dioxo-14,23-dioxa-6-thia-1,17,30,32- tetrazaheptacyclo[23.4.1.15,8.19,13.011,19.012,17.026,28]dotriaconta-5(32),7,9(31),10,12,18-hexaen-3- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-2,3-dimethyl-N-[(3S,26R,28S)-15,15,27,27-tetrafluoro-(18M)-18-[2-[(1S)-1- methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-21,21-dimethyl-2,24-dioxo-23-oxa-6-thia- 1,17,30,32-tetrazaheptacyclo[23.4.1.15,8.19,13.011,19.012,17.026,28]dotriaconta- 5(32),7,9(31),10,12,18-hexaen-3-yl]cyclopropanecarboxamide; (2R,3S)-N-[(3S,27R,29S)-28,28-difluoro-(19M)-19-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-22,22-dimethyl-2,25-dioxo-14,24-dioxa-6-thia-1,18,31,33- tetrazaheptacyclo[24.4.1.15,8.19,13.011,20.012,18.027,29]tritriaconta-5(33),7,9(32),10,12,19-hexaen-3- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(3S,26S,28R)-27,27-difluoro-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-21,21-dimethyl-2,24-dioxo-23-oxa-6-thia-1,17,30,32- tetrazaheptacyclo[23.4.1.15,8.19,13.011,19.012,17.026,28]dotriaconta-5(32),7,9(31),10,12,18-hexaen-3- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(3S,28R)-27,27-difluoro-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-21,21-dimethyl-2,24-dioxo-14,23-dioxa-6-thia-1,17,30,32- tetrazaheptacyclo[23.4.1.15,8.19,13.011,19.012,17.026,28]dotriaconta-5(32),7,9(31),10,12,18-hexaen-3- yl]-2,3-dimethyl-cyclopropanecarboxamide;(2S,3R)-2,3-dimethyl-N-[(3S,26S,28R)-15,15,27,27-tetrafluoro-(18M)-18-[2-[(1S)-1- methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-21,21-dimethyl-2,24-dioxo-23-oxa-6-thia- 1,17,30,32-tetrazaheptacyclo[23.4.1.15,8.19,13.011,19.012,17.026,28]dotriaconta- 5(32),7,9(31),10,12,18-hexaen-3-yl]cyclopropanecarboxamide; (2R,3S)-N-[(3S,27S,29R)-28,28-difluoro-(19M)-19-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-22,22-dimethyl-2,25-dioxo-14,24-dioxa-6-thia-1,18,31,33- tetrazaheptacyclo[24.4.1.15,8.19,13.011,20.012,18.027,29]tritriaconta-5(33),7,9(32),10,12,19-hexaen-3- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2R,3S)-N-[(3S,25S,26R,29S)-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1- yl)-3-pyridyl]-21,21-dimethyl-2,24-dioxo-23-oxa-6-thia-1,17,31,33- tetrazaheptacyclo[23.5.1.15,8.19,13.011,19.012,17.026,29]tritriaconta-5(33),7,9(32),10,12,18-hexaen-3- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2R,3S)-N-[(3S,25S,26R,29S)-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1- yl)-3-pyridyl]-21,21-dimethyl-2,24-dioxo-14,23-dioxa-6-thia-1,17,31,33- tetrazaheptacyclo[23.5.1.15,8.19,13.011,19.012,17.026,29]tritriaconta-5(33),7,9(32),10,12,18-hexaen-3- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2R,3S)-N-[(3S,25S,26R,29S)-15,15-difluoro-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-21,21-dimethyl-2,24-dioxo-23-oxa-6-thia-1,17,31,33- tetrazaheptacyclo[23.5.1.15,8.19,13.011,19.012,17.026,29]tritriaconta-5(33),7,9(32),10,12,18-hexaen-3- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(3S,26S,27R,30S)-(19M)-19-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1- yl)-3-pyridyl]-22,22-dimethyl-2,25-dioxo-14,24-dioxa-6-thia-1,18,32,34- tetrazaheptacyclo[24.5.1.15,8.19,13.011,20.012,18.027,30]tetratriaconta-5(34),7,9(33),10,12,19-hexaen- 3-yl]-2,3-dimethyl-cyclopropanecarboxamide; (2R,3S)-N-[(3S,25S,26S,29R)-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1- yl)-3-pyridyl]-21,21-dimethyl-2,24-dioxo-23-oxa-6-thia-1,17,31,33- tetrazaheptacyclo[23.5.1.15,8.19,13.011,19.012,17.026,29]tritriaconta-5(33),7,9(32),10,12,18-hexaen-3- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2R,3S)-N-[(3S,25S,26S,29R)-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1- yl)-3-pyridyl]-21,21-dimethyl-2,24-dioxo-14,23-dioxa-6-thia-1,17,31,33- tetrazaheptacyclo[23.5.1.15,8.19,13.011,19.012,17.026,29]tritriaconta-5(33),7,9(32),10,12,18-hexaen-3- yl]-2,3-dimethyl-cyclopropanecarboxamide;(2R,3S)-N-[(3S,25S,26S,29R)-15,15-difluoro-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-21,21-dimethyl-2,24-dioxo-23-oxa-6-thia-1,17,31,33- tetrazaheptacyclo[23.5.1.15,8.19,13.011,19.012,17.026,29]tritriaconta-5(33),7,9(32),10,12,18-hexaen-3- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(3S,26S,27S,30R)-(19M)-19-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1- yl)-3-pyridyl]-22,22-dimethyl-2,25-dioxo-14,24-dioxa-6-thia-1,18,32,34- tetrazaheptacyclo[24.5.1.15,8.19,13.011,20.012,18.027,30]tetratriaconta-5(34),7,9(33),10,12,19-hexaen- 3-yl]-2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(3S,26R,28S)-27,27-difluoro-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-21,21,26-trimethyl-2,24-dioxo-23-oxa-6-thia-1,17,30,32- tetrazaheptacyclo[23.4.1.15,8.19,13.011,19.012,17.026,28]dotriaconta-5(32),7,9(31),10,12,18-hexaen-3- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2R,3S)-N-[(3S,26R,28S)-27,27-difluoro-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-21,21,26-trimethyl-2,24-dioxo-14,23-dioxa-6-thia-1,17,30,32- tetrazaheptacyclo[23.4.1.15,8.19,13.011,19.012,17.026,28]dotriaconta-5(32),7,9(31),10,12,18-hexaen-3- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(3S,26R,28S)-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)- 3-pyridyl]-21,21,26-trimethyl-2,24-dioxo-23-oxa-6-thia-1,17,30,32- tetrazaheptacyclo[23.4.1.15,8.19,13.011,19.012,17.026,28]dotriaconta-5(32),7,9(31),10,12,18-hexaen-3- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2R,3S)-N-[(3S,26R,28S)-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)- 3-pyridyl]-21,21,26-trimethyl-2,24-dioxo-14,23-dioxa-6-thia-1,17,30,32- tetrazaheptacyclo[23.4.1.15,8.19,13.011,19.012,17.026,28]dotriaconta-5(32),7,9(31),10,12,18-hexaen-3- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(3S,26S,28R)-27,27-difluoro-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-21,21,26-trimethyl-2,24-dioxo-23-oxa-6-thia-1,17,30,32- tetrazaheptacyclo[23.4.1.15,8.19,13.011,19.012,17.026,28]dotriaconta-5(32),7,9(31),10,12,18-hexaen-3- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(3S,26S,28R)-27,27-difluoro-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-21,21,26-trimethyl-2,24-dioxo-14,23-dioxa-6-thia-1,17,30,32- tetrazaheptacyclo[23.4.1.15,8.19,13.011,19.012,17.026,28]dotriaconta-5(32),7,9(31),10,12,18-hexaen-3- yl]-2,3-dimethyl-cyclopropanecarboxamide;(2S,3R)-N-[(3S,26S,28R)-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)- 3-pyridyl]-21,21,26-trimethyl-2,24-dioxo-23-oxa-6-thia-1,17,30,32- tetrazaheptacyclo[23.4.1.15,8.19,13.011,19.012,17.026,28]dotriaconta-5(32),7,9(31),10,12,18-hexaen-3- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(3S,26S,28R)-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)- 3-pyridyl]-21,21,26-trimethyl-2,24-dioxo-14,23-dioxa-6-thia-1,17,30,32- tetrazaheptacyclo[23.4.1.15,8.19,13.011,19.012,17.026,28]dotriaconta-5(32),7,9(31),10,12,18-hexaen-3- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(7S)-11-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)- 3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(29),2,5(31),11,19,25,27-heptaen-7- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(7S)-11-fluoro-(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(29),2,5(31),11,19,25,27-heptaen-7- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(3S,26R,28S)-27,27-difluoro-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-21,21-dimethyl-2,24-dioxo-spiro[23-oxa-6-thia-1,17,30,32- tetrazaheptacyclo[23.4.1.15,8.19,13.011,19.012,17.026,28]dotriaconta-5(32),7,9(31),10,12,18-hexaene- 4,1'-cyclobutane]-3-yl]-2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(3S,26R,28S)-27,27-difluoro-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-21,21-dimethyl-2,24-dioxo-spiro[14,23-dioxa-6-thia- 1,17,30,32-tetrazaheptacyclo[23.4.1.15,8.19,13.011,19.012,17.026,28]dotriaconta- 5(32),7,9(31),10,12,18-hexaene-4,1'-cyclobutane]-3-yl]-2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(3S,26R,28S)-27,27-difluoro-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-21,21-dimethyl-2,24-dioxo-spiro[23-oxa-6-thia-1,17,30,32- tetrazaheptacyclo[23.4.1.15,8.19,13.011,19.012,17.026,28]dotriaconta-5(32),7,9(31),10,12,18-hexaene- 4,1'-cyclopropane]-3-yl]-2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(3S,26R,28S)-27,27-difluoro-(18M)-18-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-21,21-dimethyl-2,24-dioxo-spiro[14,23-dioxa-6-thia- 1,17,30,32-tetrazaheptacyclo[23.4.1.15,8.19,13.011,19.012,17.026,28]dotriaconta- 5(32),7,9(31),10,12,18-hexaene-4,1'-cyclopropane]-3-yl]-2,3-dimethyl- cyclopropanecarboxamide;(2S,3R)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3- pyridyl]-17,17-dimethyl-8,14-dioxo-15-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]- 2,3-dimethyl-cyclopropanecarboxamide; (2R,3S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[3-(1,4-oxazepan-4-yl)prop-1- ynyl]-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]- 2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(7S,13S)-(20M)-20-[5-[3-(azetidin-1-yl)prop-1-ynyl]-2-[(1S)-1-methoxyethyl]- 3-pyridyl]-17,17-dimethyl-8,14-dioxo-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(29),2,5(31),19,25,27-hexaen-7-yl]- 2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(7S,13S)-(20M)-20-[5-[3-(1,1-dioxo-1,4-thiazinan-4-yl)prop-1-ynyl]-2-[(1S)-1- methoxyethyl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-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(29),2,5(31),19,25,27-hexaen-7-yl]- 2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(3-morpholinoprop-1-ynyl)-3- pyridyl]-17,17-dimethyl-8,14-dioxo-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(29),2,5(31),19,25,27-hexaen-7-yl]- 2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(7S,13S)-23,23-difluoro-(20M)-20-[2-isopropyl-5-[3-(1,4-oxazepan-4-yl)prop- 1-ynyl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-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(29),2,5(31),19,25,27-hexaen-7-yl]- 2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(7S,13S)-23,23-difluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[3-(1,4- oxazepan-4-yl)prop-1-ynyl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-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(29),2,5(31),19,25,27-hexaen-7-yl]- 2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(7S,13S)-(20M)-20-[5-[3-(azetidin-1-yl)prop-1-ynyl]-2-[(1S)-1-methoxyethyl]- 3-pyridyl]-23,23-difluoro-17,17-dimethyl-8,14-dioxo-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(29),2,5(31),19,25,27-hexaen-7-yl]- 2,3-dimethyl-cyclopropanecarboxamide;(2R,3S)-N-[(7S,13S)-(20M)-20-[5-[3-(1,1-dioxo-1,4-thiazinan-4-yl)prop-1-ynyl]-2-[(1S)-1- methoxyethyl]-3-pyridyl]-23,23-difluoro-17,17-dimethyl-8,14-dioxo-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(29),2,5(31),19,25,27-hexaen-7-yl]- 2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(7S,13S)-23,23-difluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(3- morpholinoprop-1-ynyl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-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(29),2,5(31),19,25,27-hexaen-7-yl]- 2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(7S,13S)-(20M)-20-[2-isopropyl-5-[3-(1,4-oxazepan-4-yl)prop-1-ynyl]-3- pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31- 2,5 9,13 19,27 21,26 tetrazahexacyclo[23.3.1.1 .1 .0 .0 ]hentriaconta-1(29),2,5(31),19,25,27-hexaen-7-yl]- 2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[3-(1,4-oxazepan-4-yl)prop-1- ynyl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31- 2,5 9,13 19,27 21,26 tetrazahexacyclo[23.3.1.1 .1 .0 .0 ]hentriaconta-1(29),2,5(31),19,25,27-hexaen-7-yl]- 2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(7S,13S)-(20M)-20-[5-[3-(azetidin-1-yl)prop-1-ynyl]-2-[(1S)-1-methoxyethyl]- 3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31- 2,5 9,13 19,27 21,26 tetrazahexacyclo[23.3.1.1 .1 .0 .0 ]hentriaconta-1(29),2,5(31),19,25,27-hexaen-7-yl]- 2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(7S,13S)-(20M)-20-[5-[3-(1,1-dioxo-1,4-thiazinan-4-yl)prop-1-ynyl]-2-[(1S)-1- methoxyethyl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31- 2,5 9,13 19,27 21,26 tetrazahexacyclo[23.3.1.1 .1 .0 .0 ]hentriaconta-1(29),2,5(31),19,25,27-hexaen-7-yl]- 2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(3-morpholinoprop-1-ynyl)-3- pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31- 2,5 9,13 19,27 21,26 tetrazahexacyclo[23.3.1.1 .1 .0 .0 ]hentriaconta-1(29),2,5(31),19,25,27-hexaen-7-yl]- 2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(7S,13S)-(20M)-20-[2-isopropyl-5-[3-(1,4-oxazepan-4-yl)prop-1-ynyl]-3- pyridyl]-17,17-dimethyl-8,14-dioxo-15,25-dioxa-4-thia-9,21,31,32- 2,5 9,13 19,28 21,27 tetrazahexacyclo[24.3.1.1 .1 .0 .0 ]dotriaconta-1(30),2,5(32),19,26,28-hexaen-7-yl]- 2,3-dimethyl-cyclopropanecarboxamide;(2S,3R)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[3-(1,4-oxazepan-4-yl)prop-1- ynyl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,25-dioxa-4-thia-9,21,31,32- 2,5 9,13 19,28 21,27 tetrazahexacyclo[24.3.1.1 .1 .0 .0 ]dotriaconta-1(30),2,5(32),19,26,28-hexaen-7-yl]- 2,3-dimethyl-cyclopropanecarboxamide; (2R,3S)-N-[(7S,13S)-(20M)-20-[5-[3-(azetidin-1-yl)prop-1-ynyl]-2-[(1S)-1-methoxyethyl]- 3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,25-dioxa-4-thia-9,21,31,32- 2,5 9,13 19,28 21,27 tetrazahexacyclo[24.3.1.1 .1 .0 .0 ]dotriaconta-1(30),2,5(32),19,26,28-hexaen-7-yl]- 2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(7S,13S)-(20M)-20-[5-[3-(1,1-dioxo-1,4-thiazinan-4-yl)prop-1-ynyl]-2-[(1S)-1- methoxyethyl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,25-dioxa-4-thia-9,21,31,32- 2,5 9,13 19,28 21,27 tetrazahexacyclo[24.3.1.1 .1 .0 .0 ]dotriaconta-1(30),2,5(32),19,26,28-hexaen-7-yl]- 2,3-dimethyl-cyclopropanecarboxamide; (2R,3S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(3-morpholinoprop-1-ynyl)-3- pyridyl]-17,17-dimethyl-8,14-dioxo-15,25-dioxa-4-thia-9,21,31,32- 2,5 9,13 19,28 21,27 tetrazahexacyclo[24.3.1.1 .1 .0 .0 ]dotriaconta-1(30),2,5(32),19,26,28-hexaen-7-yl]- 2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(7S,13S)-(20M)-20-[2-isopropyl-5-[3-(1,4-oxazepan-4-yl)prop-1-ynyl]-3- pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,32- 2,5 9,13 10,12 19,27 21,26 tetrazaheptacyclo[23.3.1.1 .1 .1 .0 .0 ]dotriaconta-1(29),2,5(32),19,25,27-hexaen-7- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[3-(1,4-oxazepan-4-yl)prop-1- ynyl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,32- 2,5 9,13 10,12 19,27 21,26 tetrazaheptacyclo[23.3.1.1 .1 .1 .0 .0 ]dotriaconta-1(29),2,5(32),19,25,27-hexaen-7- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(7S,13S)-(20M)-20-[5-[3-(azetidin-1-yl)prop-1-ynyl]-2-[(1S)-1-methoxyethyl]- 3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,32- 2,5 9,13 10,12 19,27 21,26 tetrazaheptacyclo[23.3.1.1 .1 .1 .0 .0 ]dotriaconta-1(29),2,5(32),19,25,27-hexaen-7- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(7S,13S)-(20M)-20-[5-[3-(1,1-dioxo-1,4-thiazinan-4-yl)prop-1-ynyl]-2-[(1S)-1- methoxyethyl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,32- 2,5 9,13 10,12 19,27 21,26 tetrazaheptacyclo[23.3.1.1 .1 .1 .0 .0 ]dotriaconta-1(29),2,5(32),19,25,27-hexaen-7- yl]-2,3-dimethyl-cyclopropanecarboxamide;(2S,3R)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(3-morpholinoprop-1-ynyl)-3- pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,32- 2,5 9,13 10,12 19,27 21,26 tetrazaheptacyclo[23.3.1.1 .1 .1 .0 .0 ]dotriaconta-1(29),2,5(32),19,25,27-hexaen-7- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(7S,13S)-23,23-difluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[3-(1,4- oxazepan-4-yl)prop-1-ynyl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,32- 2,5 9,13 10,12 19,27 21,26 tetrazaheptacyclo[23.3.1.1 .1 .1 .0 .0 ]dotriaconta-1(29),2,5(32),19,25,27-hexaen-7- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(7S,13S)-(20M)-20-[5-[3-(azetidin-1-yl)prop-1-ynyl]-2-[(1S)-1-methoxyethyl]- 3-pyridyl]-23,23-difluoro-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,32- 2,5 9,13 10,12 19,27 21,26 tetrazaheptacyclo[23.3.1.1 .1 .1 .0 .0 ]dotriaconta-1(29),2,5(32),19,25,27-hexaen-7- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(7S,13S)-(20M)-20-[5-[3-(1,1-dioxo-1,4-thiazinan-4-yl)prop-1-ynyl]-2-[(1S)-1- methoxyethyl]-3-pyridyl]-23,23-difluoro-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,32- 2,5 9,13 10,12 19,27 21,26 tetrazaheptacyclo[23.3.1.1 .1 .1 .0 .0 ]dotriaconta-1(29),2,5(32),19,25,27-hexaen-7- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(7S,13S)-23,23-difluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(3- morpholinoprop-1-ynyl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,32- 2,5 9,13 10,12 19,27 21,26 tetrazaheptacyclo[23.3.1.1 .1 .1 .0 .0 ]dotriaconta-1(29),2,5(32),19,25,27-hexaen-7- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[3-(1,4-oxazepan-4-yl)prop-1- ynyl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,32- 2,5 9,13 10,12 19,27 21,26 tetrazaheptacyclo[23.3.1.1 .1 .1 .0 .0 ]dotriaconta-1(29),2,5(32),19,25,27-hexaen-7- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(7S,13S)-(20M)-20-[5-[3-(azetidin-1-yl)prop-1-ynyl]-2-[(1S)-1-methoxyethyl]- 3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,32- 2,5 9,13 10,12 19,27 21,26 tetrazaheptacyclo[23.3.1.1 .1 .1 .0 .0 ]dotriaconta-1(29),2,5(32),19,25,27-hexaen-7- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(7S,13S)-(20M)-20-[5-[3-(1,1-dioxo-1,4-thiazinan-4-yl)prop-1-ynyl]-2-[(1S)-1- methoxyethyl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,32- 2,5 9,13 10,12 19,27 21,26 tetrazaheptacyclo[23.3.1.1 .1 .1 .0 .0 ]dotriaconta-1(29),2,5(32),19,25,27-hexaen-7- yl]-2,3-dimethyl-cyclopropanecarboxamide;(2S,3R)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(3-morpholinoprop-1-ynyl)-3- pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,32- 2,5 9,13 10,12 19,27 21,26 tetrazaheptacyclo[23.3.1.1 .1 .1 .0 .0 ]dotriaconta-1(29),2,5(32),19,25,27-hexaen-7- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[3-(1,4-oxazepan-4-yl)prop-1- ynyl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,25-dioxa-4-thia-9,21,31,33- 2,5 9,13 10,12 19,28 21,27 tetrazaheptacyclo[24.3.1.1 .1 .1 .0 .0 ]tritriaconta-1(30),2,5(33),19,26,28-hexaen-7- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2R,3S)-N-[(7S,13S)-(20M)-20-[5-[3-(azetidin-1-yl)prop-1-ynyl]-2-[(1S)-1-methoxyethyl]- 3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,25-dioxa-4-thia-9,21,31,33- 2,5 9,13 10,12 19,28 21,27 tetrazaheptacyclo[24.3.1.1 .1 .1 .0 .0 ]tritriaconta-1(30),2,5(33),19,26,28-hexaen-7- yl]-2,3-dimethyl-cyclopropanecarboxamide; (2S,3R)-N-[(7S,13S)-(20M)-20-[5-[3-(1,1-dioxo-1,4-thiazinan-4-yl)prop-1-ynyl]-2-[(1S)-1- methoxyethyl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,25-dioxa-4-thia-9,21,31,33- 2,5 9,13 10,12 19,28 21,27 tetrazaheptacyclo[24.3.1.1 .1 .1 .0 .0 ]tritriaconta-1(30),2,5(33),19,26,28-hexaen-7- yl]-2,3-dimethyl-cyclopropanecarboxamide; and (2R,3S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(3-morpholinoprop-1-ynyl)-3- pyridyl]-17,17-dimethyl-8,14-dioxo-15,25-dioxa-4-thia-9,21,31,33- 2,5 9,13 10,12 19,28 21,27 tetrazaheptacyclo[24.3.1.1 .1 .1 .0 .0 ]tritriaconta-1(30),2,5(33),19,26,28-hexaen-7- yl]-2,3-dimethyl-cyclopropanecarboxamide; 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 the following step: a) coupling reaction between compound of formula (II),(III), in the presence of a coupling reagent and a base to form the compound of formula (I); wherein R1to R5, A1to A4are defined as in any one of claims 1 to 14; the coupling reagent is T3P, HATU, PyBOP or EDCI / HOBt; the base 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 cancers in a subject in need thereof, wherein the cancer comprises a first RAS mutation that is G12C and a second RAS mutation at a position selected from the groupconsisting of V8A, V9Y, S17E, A59T, T58I, D69P, M72I, S65W, R68S, D92R, H95N, Y96D, Q99W and F156L.

26. 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 cancers in a subject in need thereof, wherein the cancer comprises a first RAS mutation that is G12C and a second RAS mutation at a position selected from the group consisting of V8A, V9Y, S17E, A59T, T58I, D69P, M72I, S65W, R68S, D92R, H95N, Y96D, Q99W and F156L.

27. 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.

28. 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.

29. The use of a compound according to any one of claims 1 to 17 for the treatment or prophylaxis of primary central nervous system (CNS) tumors harboring RAS mutations or RAS driven cancers with brain metastases; wherein the CNS tumor is primary melanocytic tumors of the CNS harboring NRAS mutation; wherein the cancer is selected from pancreatic adenocarcinoma, colorectal cancer, non-small cell lung cancer.

30. The use of a compound according to any one of claims 1 to 17 for the treatment or prophylaxis of primary central nervous system (CNS) tumors harboring RAS mutations or RAS driven cancers with brain metastases; wherein the CNS tumor is primary melanocytic tumors of the CNS harboring NRAS mutation; wherein the cancer is non-small cell lung cancer.

31. 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.

32. 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.

33. 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.

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

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