Tricyclic compounds for treatment of cancer

Abstract

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

Description

[0001] The present application relates to organic compounds useful for therapy and / or prophylaxis in a mammal, and in particular to inhibition of KRAS mutants useful for the treatment of cancer. TECHNICAL FIELD

[0002] RAS is one of the best known proto-oncogenes. Approximately 30% of human cancers harbor mutations in three most prominent members (KRAS, HRAS and NRAS), making them the most common oncogenic drivers. KRAS mutations are often associated with poor prognosis, especially in colorectal, pancreatic, lung cancers. As the most frequently mutated RAS isoform, KRAS has been extensively studied over the past few years. Among the most common KRAS alleles (including G12D, G12V, G12C, G13D, G12R, G12A, G12S, Q61H, etc.), G12C, G12D and G12V account for more than half of all K-RAS driven cancers (including colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC), lung adenocarcinoma (LUAD)). Notably, KRAS wild-type amplifications are also found in about 7% of all KRAS-altered cancers (ovarian, esophageal and gastric, uterine), ranking second to alterations in the front line.

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

[0004] The KRAS protein switches between inactive and active forms 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) involved in catalyzing the exchange of GDP for GTP, thereby enhancing the intrinsic GTPase activity or accelerating RAS-mediated GTP hydrolysis. In response to extracellular stimuli, inactive RAS-GDP is converted to active RAS-GTP, which directly binds to the RAF RAS-binding domain (RAFRBD ) binds, thereby recruiting the RAF kinase family from the cytoplasm to the cell membrane, where they dimerize and become active. Active RAF then phosphorylates its downstream mitogen-activated protein kinase (MEK) and extracellular signal-regulated kinase (ERK) in a series of phosphorylation reactions and propagates growth signals. Among the RAF protein kinase family (three known isoforms ARAF, BRAF, CRAF / RAF1), BRAF mutations are most frequent and still the most potent activators of MEK. Although individual RAS and RAF family members exhibit different binding preferences, all RAFs have a conserved RBD for forward transmission of MAPK signaling, frequently used to characterize KRAS inhibition (e.g. KRAS-BRAF RBD ). For KRAS, mutations at positions 12, 13, 61, and 146 shift toward active KRAS forms by impairing nucleotide hydrolysis or activating nucleotide exchange, leading to MAPK pathway over-activation that drives tumorigenesis.

[0005] Despite its well-recognized importance in cancer malignancies, past sustained efforts have failed to develop approved therapies for KRAS mutant cancers, until recently, when the first selective drug AMG510 was rapidly approved as a second-line treatment for KRAS G12C-driven non-small cell lung cancer (NSCLC). However, after about 6 months of treatment, clinical acquired resistance to KRAS G12C inhibitors emerged dramatically as the disease progressed. All mutations converge to re-activate RAS-MAPK signaling, with secondary RAS mutants having been observed at oncogenic hotspots (e.g. G12 / G13 / Q61) and within the switch II pocket (e.g. H95, R68, and Y96); moreover, over 85% of cancers still lack novel agents in all KRAS mutant or wild-type amplification-driven cancers. Altogether, both the myriad of escape mechanisms and the variety of oncogenic alleles highlight the urgent medical need for additional KRAS therapies. Accordingly, we invented an oral compound that targets and inhibits KRAS alleles for the treatment of KRAS mutant-driven cancers. SUMMARY

[0006] The present invention relates to novel compounds having the formula (I),

[0007] (I),

[0008] wherein

[0009] R1 for ,

[0010] via C 2-6 Alkyne carbonyl-substituted 1-oxo-2,7-diazaspiro[4.4]nonyl, or

[0011] (Dihalogenated C) 1-6 alkyl)carbonyl, C 2-6 alkenyl carbonyl, C 2-6 alkynyl carbonyl or halogenated C 2-6 Alkenyl carbonyl-substituted 5-oxo-2,6-diazaspiro[3,4]octyl;

[0012] Where R 5 C 1-6 alkyl;

[0013] R 6 For halogenated C 2-6 alkynyl-substituted C 3-7 cycloalkyl,

[0014] Independently selected from (dihalogenated C) 1-6 alkyl)carbonyl, C 2-6 alkenyl carbonyl, C 2-6 Alkyne carbonyl, halogen and halogenated C 2-6 The substituent of the alkenyl carbonyl group replaces the piperidinyl group once or twice, or

[0015] (Dihalogenated C) 1-6 alkyl)carbonyl, C 2-6 alkenyl carbonyl, C 2-6 alkynyl carbonyl or morpholino C 2-6 Acynyl carbonyl-substituted pyrrolidinyl groups;

[0016] R 2 C 1-6 alkyl;

[0017] R 3 H, morpholino, (halogenated C) 1-6 alkyl)piperazine or C 1-6 alkylpiperazine group;

[0018] R 4 C 1-6 Alkoxy C 1-6 alkyl;

[0019] A 1 It is a hydroxyphenylene group or an imidazolidinyl group;

[0020] A 2 C 1-6 Alkylene;

[0021] M is O or CH2;

[0022] L is C 1-6 alkylene or haloC 1-6 alkylene;

[0023] or pharmaceutically acceptable salts thereof.

[0024] The present application also relates to their manufacture, medicaments based on the compounds according to the application and their production, and the use of the compounds of the formula (I) or (Ia) as KRAS inhibitors.

[0025] The compounds of the formula (I) or (Ia) show good KRAS inhibition for G12C, G12D, G12V or G13C. In one embodiment, the compounds of the present application have good pharmacokinetic properties compared to reference compounds. In another embodiment, the compounds of the present application show superior cancer cell inhibition and human hepatocyte stability. In addition, the compounds of the formula (I) or (Ia) also show good or improved cytotoxicity and solubility characteristics. BRIEF DESCRIPTION OF DRAWINGS

[0026] Figure 1. X-ray crystallographic analysis of intermediate A3.

[0027] Figure 2. X-ray crystallographic analysis of intermediate A4. DETAILED DESCRIPTION

[0028] DEFINITIONS

[0029] The term "C 1-6 alkyl" denotes a saturated, straight-chain or branched alkyl group containing 1 to 6, in particular 1 to 4 carbon atoms, for example methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl and the like. In particular, the "C 1-6 alkyl" group is methyl, ethyl and n-propyl.

[0030] The term "(C 1-6 )alkylene" denotes a straight-chain or branched saturated divalent hydrocarbon group of 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon group of 3 to 6 carbon atoms. Examples of (C 1-6 )alkylene groups include methylene, ethylene, propylene, 2-methylpropylene, butylene, 2- ethylbutylene, pentylene, hexylene.

[0031] The term "C 2-6 alkenyl" denotes a monovalent straight-chain or branched hydrocarbon group of 2 to 6 carbon atoms with at least one double bond. In particular embodiments, the alkenyl group has 2 to 4 carbon atoms and at least one double bond. C2-6 Examples of alkenyl groups include ethenyl (or vinyl), propenyl, prop-2-enyl, isopropenyl, n-butenyl, and isobutenyl.

[0032] The term "C 2-6 Alkynyl" denotes a monovalent straight-chain or branched saturated hydrocarbon group of 2 to 6 carbon atoms, including one, two or three triple bonds. In particular embodiments, alkynyl has 2 to 4 carbon atoms, including one or two triple bonds. C 2-6 Examples of alkynyl groups include ethynyl, propynyl, prop-2-ynyl, isopropynyl, and n-butynyl.

[0033] The terms "halogen" and "halo" are used interchangeably herein to denote fluorine, chlorine, bromine, or iodine.

[0034] The term "haloC 1-6 Alkyl" denotes a C 1-6 alkyl group, wherein the C 1-6 at least one of the hydrogen atoms of the alkyl group has been replaced by the same or different halogen atom. HaloC 1-6 Examples of alkyl groups include fluoro, difluoro- or chloro(fluoro)-methyl, -ethyl or -propyl, such as fluoromethyl, difluoropropyl, difluoromethyl, difluoroethyl, chloro(fluoro)methyl, trifluoroethyl or trifluoromethyl.

[0035] The term "haloC 1-6 Alkylene" denotes a C 1-6 alkylene group, wherein the C 1-6 at least one of the hydrogen atoms of the alkylene group has been replaced by the same or different halogen atom. HaloC 1-6 Examples of alkylene groups include fluoro, difluoro- or chloro(fluoro)-methylene, -ethylene or -propylene, such as fluoromethylene, difluoromethylene, fluoroethylene, difluoroethylene, fluoropropylene, difluoropropylene or chloro(fluoro)methylene.

[0036] The term "di-haloC 1-6 Alkyl" denotes a C 1-6 alkyl group, wherein the C 1-6 two of the hydrogen atoms of the alkyl group have been replaced by the same or different halogen atom. Di-haloC 1-6 Examples of alkyl groups include difluoro- or chloro(fluoro)-methyl, -ethyl or -propyl, such as difluoropropyl, difluoromethyl, difluoroethyl or chloro(fluoro)methyl.

[0037] The term "haloC 2-6 Alkenyl" denotes a C 2-6 alkenyl group, wherein the C 2-6at least one of the hydrogen atoms of the alkenyl group has been replaced by the same or different halogen atom.

[0038] The term "halo-C 2-6 "alkynyl" denotes a monovalent unsaturated aliphatic hydrocarbon group 2-6 "alkynyl" denotes a monovalent unsaturated aliphatic hydrocarbon group 2-6 at least one of the hydrogen atoms of the alkynyl group has been replaced by the same or different halogen atom.

[0039] The term "C 3-7 "Cycloalkyl" denotes a monovalent saturated monocyclic or bicyclic hydrocarbon group of 3 to 7 ring carbon atoms. Bicyclic means consisting of two saturated carbocyclic rings having one or more common carbon atoms. Examples of monocyclic cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Examples of bicyclic cycloalkyl groups are bicyclo[1.1.0]butanyl, bicyclo[2.2.1]heptan-2-yl, bicyclo[1.1.1]pentan-1-yl or bicyclo[2.2.2]octan-2-yl.

[0040] The term "thiazolyl" denotes a monovalent thiazole group.

[0041] The term "2,2-propylenyl" denotes .

[0042] The term "protecting group" denotes a group that selectively blocks a functional group, rendering the blocked functional group chemically unreactive, in the presence of other functional groups. Protecting groups can be removed at an appropriate point during a synthetic sequence. Exemplary protecting groups are amino-protecting groups, carboxyl-protecting groups, or hydroxyl-protecting groups.

[0043] The term "pharmaceutically acceptable salt" denotes those salts which are not biologically or otherwise undesirable. "Pharmaceutically acceptable salt" includes both acid and base addition salts.

[0044] "Pharmaceutically acceptable acid addition salt" refers to those salts which are, in essence, salts of inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid and the like, as well as salts of organic acids such as aliphatic, alicyclic, aromatic, araliphatic, heterocyclic, formic and sulfonic classes of organic acids such as formic, acetic, propionic, glycolic, gluconic, lactic, pyruvic, oxalic, malic, maleic, malonic, succinic, fumaric, tartaric, citric, aspartic, ascorbic, glutamic, anthranilic, benzoic, cinnamic, mandelic, embonic, phenylacetic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, and salicylic acid and the like.

[0045] The term "pharmaceutically acceptable base addition salt" refers to those salts which are in contact 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 include 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, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine and polyamine resins.

[0046] The term "pharmacologically active metabolite" refers to 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 can alter their physical properties and biological effects. These metabolic transformations, which usually affect the polarity of the compounds of the application, alter the way in which drugs are distributed within the body and excreted from it. In some cases, however, drug metabolism is necessary for therapeutic effect.

[0047] The term "therapeutically effective amount" means an amount of a compound or molecule of the application, when administered to a subject, that (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 depend on the compound, the disease state being treated, the severity of the disease state, the age and relative health of the subject, the route and form of administration, the judgment of the attending medical or veterinary practitioner, and other factors.

[0048] The term "pharmaceutical composition" means a mixture or solution of a therapeutically effective amount of an active pharmaceutical ingredient together with a pharmaceutically acceptable excipient that is administered to a mammal, such as a human, in need thereof.

[0049] The terms "pharmaceutically acceptable excipient," "pharmaceutically acceptable carrier," and "therapeutically inert excipient" can be used interchangeably and refer to any pharmaceutically acceptable ingredient in a pharmaceutical composition that does not have therapeutic activity and is non-toxic to the subject(s) to whom the pharmaceutical composition is administered, such as a disintegrant, a binder, a filler, a solvent, a buffer, a tonicity agent, a stabilizer, an antioxidant, a surfactant, a vehicle, a diluent, or a lubricant used in formulating pharmaceutical products.

[0050] KRAS inhibitor

[0051] The present application relates to (i) a compound of formula (I),

[0052] (I),

[0053] wherein

[0054] R 1 is ,

[0055] C 2-6 alkynylcarbonyl-substituted 1-oxo-2,7-diazaspiro[4.4]nonanyl, or

[0056] (di-halo C 1-6 alkyl)carbonyl, C 2-6 alkenylcarbonyl, C 2-6 alkynylcarbonyl, or halo C 2-6 alkenylcarbonyl-substituted 5-oxo-2,6-diazaspiro[3.4]octanyl;

[0057] wherein R 5 is C 1-6 alkyl;

[0058] R 6 is C 2-6 alkyl-substituted C 3-7 cycloalkyl,

[0059] substituted once or twice by substituents independently selected from (di-halo C 1-6 alkyl)carbonyl, C 2-6 alkenylcarbonyl, C 2-6 alkynylcarbonyl, halo, and halo C 2-6 alkenylcarbonyl, or

[0060] (di-halo C 1-6 alkyl)carbonyl, C 2-6 alkenylcarbonyl, C 2-6 alkynylcarbonyl, or morpholino C 2-6 alkynylcarbonyl-substituted pyrrolidinyl;

[0061] R 2 is C 1-6 alkyl;

[0062] R 3 is H, morpholino, (halo C 1-6 alkyl)piperazinyl, or C 1-6 alkylpiperazinyl;

[0063] R 4 is C 1-6 alkoxy C 1-6 alkyl;

[0064] A 1 is hydroxyphenylene or thiazolylene;

[0065] A 2 For C 1-6 alkylene;

[0066] M is O or CH2;

[0067] L is C 1-6 alkylene or haloC 1-6 alkylene;

[0068] or a pharmaceutically acceptable salt thereof.

[0069] Another embodiment of the present application is (ii) a compound of formula (Ia),

[0070] (Ia),

[0071] wherein

[0072] R 1 is ,

[0073] substituted by C 2-6 alkynylcarbonyl, or

[0074] substituted once or twice by substituents independently selected from (dihaloC 1-6 alkyl)carbonyl, C 2-6 alkenylcarbonyl, C 2-6 alkynylcarbonyl or haloC 2-6 alkenylcarbonyl;

[0075] wherein R 5 is C 1-6 alkyl;

[0076] R 6 is C 2-6 cycloalkyl substituted by haloC 3-7 alkyl,

[0077] substituted once or twice by substituents independently selected from (dihaloC 1-6 alkyl)carbonyl, C 2-6 alkenylcarbonyl, C 2-6 alkynylcarbonyl, halo and haloC 2-6 alkenylcarbonyl, or

[0078] substituted by (dihaloC 1-6 alkyl)carbonyl, C 2-6 alkenylcarbonyl, C 2-6 alkynylcarbonyl or morpholinoC 2-6 alkynylcarbonyl;

[0079] R 2for C 1-6 alkyl;

[0080] R 3 is H, morpholino, (haloC 1-6 alkyl)piperazinyl or C 1-6 alkylpiperazinyl;

[0081] R 4 is C 1-6 alkoxyC 1-6 alkyl;

[0082] A 1 is hydroxyphenylene or thiazolylene;

[0083] A 2 is C 1-6 alkylene;

[0084] M is O or CH2;

[0085] L is C 1-6 alkylene or haloC 1-6 alkylene;

[0086] or a pharmaceutically acceptable salt thereof.

[0087] A further embodiment of the present application is (iii) a compound of formula (I) or (la) according to (i) or (ii), or a pharmaceutically acceptable salt thereof, wherein R 1 is wherein R 5 is C 1-6 alkyl; R 6 is piperidinyl which is substituted twice with substituents independently selected from (dihaloC 1-6 alkyl)carbonyl, C 2-6 alkenylcarbonyl, halogen and haloC 2-6 alkenylcarbonyl.

[0088] A further embodiment of the present application is (iv) a compound of formula (I) or (la) according to any one of (i) to (iii), or a pharmaceutically acceptable salt thereof, wherein R 1 is wherein R 5 is C 1-6 alkyl; R 6 is piperidinyl which is substituted with halogen and a further substituent selected from (dihaloC 1-6 alkyl)carbonyl, C 2-6 alkenylcarbonyl and haloC 2-6 alkenylcarbonyl.

[0089] A further embodiment of the present application is (v) a compound of formula (I) or (la) according to any one of (i) to (iv), or a pharmaceutically acceptable salt thereof, wherein R 1 is wherein R 5 is methyl; R 6 is 4-fluoro-1-prop-2-enoyl-4-piperidinyl, 4-fluoro-1-(2-fluoroprop-2-enoyl)-4- piperidinyl, 4-fluoro-1-(2-chloro-2-fluoro-acetyl)-4-piperidinyl or 4-fluoro-1-prop-2- enoyl-4-piperidinyl.

[0090] A further embodiment of the present application is (vi) a compound of formula (I) or (la) according to any one of (i) to (v), or a pharmaceutically acceptable salt thereof, wherein R 2 is isopropyl.

[0091] A further embodiment of the present application is (vii) a compound of formula (I) or (la) according to any one of (i) to (vi), or a pharmaceutically acceptable salt thereof, wherein R 3 is morpholino or C 1-6 alkylpiperazinyl.

[0092] A further embodiment of the present application is (viii) a compound of formula (I) or (la) according to any one of (i) to (vii), or a pharmaceutically acceptable salt thereof, wherein R 3 is morpholino or 4-methylpiperazin-1-yl.

[0093] A further embodiment of the present application is (ix) a compound of formula (I) or (la) according to any one of (i) to (xviii), or a pharmaceutically acceptable salt thereof, wherein R 4 is 1-methoxyethyl.

[0094] A further embodiment of the present application is (x) a compound of formula (I) or (la) according to any one of (i) to (ix), or a pharmaceutically acceptable salt thereof, wherein A 1 is wherein the bond "a" is attached to the tricyclic ring.

[0095] A further embodiment of the present application is (xi) a compound of formula (I) or (la) according to any one of (i) to (x), or a pharmaceutically acceptable salt thereof, wherein A 2 is 2,2-propylene.

[0096] A further embodiment of the application is (xii) a compound of formula (I) or (la) according to any one of (i) to (xi), or a pharmaceutically acceptable salt thereof, wherein M is O.

[0097] A further embodiment of the application is (xiii) a compound of formula (I) or (la) according to any one of (i) to (xii), or a pharmaceutically acceptable salt thereof, wherein L is C 1-6 alkylene.

[0098] A further embodiment of the application is (xiv) a compound of formula (I) or (la) according to any one of (i) to (xiii), or a pharmaceutically acceptable salt thereof, wherein L is ethylene.

[0099] A further embodiment of the application is (xv) a compound of formula (I) or (la) according to any one of (i) or (ii),

[0100] R 1 is wherein R 5 is C 1-6 alkyl; R 6 is piperidinyl substituted with halo and a further substituent selected from (dihaloC 1-6 alkyl)carbonyl, C 2-6 alkenylcarbonyl and haloC 2-6 alkenylcarbonyl;

[0101] R 2 is C 1-6 alkyl;

[0102] R 3 is morpholino or C 1-6 alkylpiperazinyl;

[0103] R 4 is C 1-6 alkoxyC 1-6 alkyl;

[0104] A 1 is wherein the bond "a" is attached to the tricyclic ring;

[0105] A 2 is C 1-6 alkylene;

[0106] M is O;

[0107] L is C 1-6 alkylene;

[0108] Or its medicinal salt.

[0109] Another embodiment of the present invention is (xvi) a compound of formula (I) or (Ia) according to (xv), wherein

[0110] R 1 for , where R 5 Methyl; R 6 It is 4-fluoro-1-prop-2-enoyl-4-piperidinyl, 4-fluoro-1-(2-fluoroprop-2-enoyl)-4-piperidinyl, 4-fluoro-1-[(2R)-2-chloro-2-fluoro-acetyl]-4-piperidinyl or 4-fluoro-1-prop-2-enoyl-4-piperidinyl;

[0111] R 2 It is isopropyl;

[0112] R 3 It is morpholino or 4-methylpiperazin-1-yl;

[0113] R 4 It is (1S)-1-methoxyethyl;

[0114] A 1 for The key "a" is connected to the three rings;

[0115] A 2 It is 2,2-propylidene;

[0116] M is O;

[0117] L represents ethylene;

[0118] Or its medicinal salt.

[0119] Another embodiment of the present invention is (xvii) a compound of formula (I) or (Ia) selected from the following:

[0120] (3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(20S,26S)-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-19,25-dioxo-7,18-dioxa-12,24,33-triazahexane[26.3.1.1] 2,6 .1 20,24 .0 4,14 .0 5,12[34-carbon-1(31),2,4,6(34),13,28(32),29-heptaen-26-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide;

[0121] (3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(19S,25S)-29-hydroxy-(12M)-12-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-15,15-dimethyl-18,24-dioxo-7,17-dioxa-11,23,32-triazahexane[25.3.1.1] 2,6 .1 19,23 .0 4,13 .0 5,11 [30),2,4,6(33),12,27(31),28-heptaen-25-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide;

[0122] 1-[(2R)-2-chloro-2-fluoro-acetyl]-4-fluoro-N-[(1S)-1-[[(19S,25S)-29-hydroxy-(12M)-12-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-15,15-dimethyl-18,24-dioxo-7,17-dioxa-11,23,32-triazahexane[25.3.1.1] 2,6 .1 19,23 .0 4,13 .0 5,11 [30),2,4,6(33),12,27(31),28-heptaen-25-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide;

[0123] (3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(18S,24S)-28-hydroxy-(11M)-11-[(3R)-2-[(1S)-1-methoxyethyl]-2,3-dihydropyridin-3-yl]-14,14-dimethyl-17,23-dioxo-16-oxa-10,22,31-triazahexane[24.3.1.1] 2,6 .1 18,22 .0 4,12 .0 5,10 [32-carbon-1(29),2,4,6(32),11,26(30),27-heptaen-24-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide;

[0124] (3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(18S,24S)-28-hydroxy- (11M)-11-[2-[(1S)-1-methoxy-ethyl]-3-pyridinyl]-14,14-dimethyl-17,23-dioxo- 7,16-dioxa-10,22,31-triazahexacyclo[24.3.1.1 2,6 .1 18,22 .0 4,12 .0 5,10 ]tridocosan-1(29),2,4,6(32),11,26(30),27-heptaen-24-yl]carbamoyl]-2-methyl- propyl]-N-methyl-pyrrolidine-3-carboxamide;

[0125] (3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1- methoxy-ethyl]-5-(4-methyl-piperazin-1-yl)-3-pyridinyl]-17,17-dimethyl-8,14- dioxo-15-oxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]tridocosan-1(29),2,4,6(32),11,26(30),27-heptaen-24-yl]carbamoyl]-2-methyl- propyl]-N-methyl-pyrrolidine-3-carboxamide;

[0126] (2S)-2-[2-[(2R)-2-chloro-2-fluoro-acetyl]-5-oxo-2,6-diazaspiro[3.4]oct-6-yl]-N- [(7S,13S)-(20M)-20-[2-[(1S)-1-methoxy-ethyl]-5-[4-(2,2,2-trifluoro-ethyl)- piperazin-1-yl]-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]tridocosan-1(29),2,4,6(32),11,26(30),27-heptaen-24-yl]carbamoyl]-2-methyl- propyl]-N-methyl-pyrrolidine-3-carboxamide;

[0127] (2S)-2-(2-but-2-ynoyl-5-oxo-2,6-diazaspiro[3.4]oct-6-yl)-N-[(7S,13S)-(20M)-20-[2- [(1 S)-1 -methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1 -yl]-3-pyridyl]- 17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31 -tetraazahexacyclo[23.3.1.1 2,5 .1 9, 13 .0 19,27 .0 21,26 ]triaconta-1 (28),2,5(31 ),19,25(29),26-hexaen-7-yl]-3-methyl-butyramide;

[0128] (2S)-2-[2-[(2R)-2-chloro-2-fluoro-acetyl]-5-oxo-2,6-diazaspiro[3.4]oct-6-yl]-N-[(7S,13S)-(20M)-20-[2-[(1 S)-1 -methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl- 8,14-dioxo-15-oxa-4-thia-9,21,30,31 -tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]triaconta-1 (28),2,5(31 ),19,25(29),26-hexaen-7-yl]-3-methyl-butyramide;

[0129] (2S)-2-(2-but-2-ynoyl-5-oxo-2,6-diazaspiro[3.4]oct-6-yl)-N-[(7S,13S)-(20M)-20-[2- [(1 S)-1 -methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15- oxa-4-thia-9,21,30,31 -tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]triaconta-1 (28),2,5(31 ),19,25(29),26-hexaen-7-yl]-3-methyl-butyramide;

[0130] (2S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridinyl]- 17, 17-dimethyl-8, 14-dioxo-15-oxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1 2,5 .1 9 ,13 .0 19,27 .0 21,26 ]triaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]-3-methyl-2-(5-oxo-2-prop-2- enoyl-2,6-diazaspiro[3.4]octan-6-yl)butanamide;

[0131] (3S)-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3- pyridinyl]-17, 17-dimethyl-8, 14-dioxo-15-oxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]triaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N- methyl-1-(4-morpholinobutan-2-ynoyl)pyrrolidine-3-carboxamide;

[0132] (2S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin- 1-yl]-3-pyridinyl]-17, 17-dimethyl-8, 14-dioxo-15-oxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]triaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]-3-methyl-2-(5-oxo-2-prop-2- enoyl-2,6-diazaspiro[3.4]octan-6-yl)butanamide;

[0133] (2S)-2-(2-but-2-ynoyl-5-oxo-2,6-diazaspiro[3.4]oct-6-yl)-N-[(7S,13S)-(20M)-20-[2- [(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridinyl]-17,17-dimethyl-8,14- dioxo-15-oxa-4-thia-9,21,30,31 -tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]triaconta-1 (28), 2, 5(31), 19, 25(29), 26-hexaen-7-yl]-3-methyl-butyramide;

[0134] 4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3- pyridinyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31 -tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]triaconta-1 (28), 2, 5(31), 19, 25(29), 26-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N- methyl-1-prop-2-enoyl-piperidine-4-carboxamide;

[0135] 1-but-2-ynoyl-4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5- morpholino-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31 - tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]triaconta-1 (28), 2, 5(31), 19, 25(29), 26-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N- methyl-1-prop-2-enoyl-piperidine-4-carboxamide;

[0136] cis-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3- pyridinyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31 -tetraazahexacyclo[23.3.1.1 2,5 .19,13 .0 19,27 .0 21,26 [C31-1(28),2,5(31),19,25(29),26-hexene-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-3-(3,3,3-trifluoroprop-1-ynyl)cyclobutanecarboxamide;

[0137] 1-[(2R)-2-chloro-2-fluoro-acetyl]-4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 [C31-1(28),2,5(31),19,25(29),26-hexene-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide;

[0138] (2S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 [C31-1(28),2,5(31),19,25(29),26-hexen-7-yl]-3-methyl-2-(5-oxo-2-prop-2-enoyl-2,6-diazaspiro[3.4]octane-6-yl)butyramide;

[0139] (2S)-2-[2-[(2R)-2-chloro-2-fluoro-acetyl]-5-oxo-2,6-diazaspiro[3.4]octane-6-yl]-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1] 2,5 .1 9, 13 .0 19,27 .0 21,26(2S)-2-[2-(2-fluoroprop-2-enoyl)-5-oxo-2,6-diazaspiro[3.4]octan-6-yl]-N-[(7S,13S)- (20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridinyl]-17,17-dimethyl-8,14-dioxo- 15-oxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1

[0140] (2S)-2-[2-(2-fluoroprop-2-enoyl)-5-oxo-2,6-diazaspiro[3.4]octan-6-yl]-N-[(7S,13S)- (20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridinyl]-17,17-dimethyl-8,14-dioxo- 15-oxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 (2S)-2-[2-(2-fluoroprop-2-enoyl)-5-oxo-2,6-diazaspiro[3.4]octan-6-yl]-N-[(7S,13S)- (20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridinyl]-17,17-dimethyl-8,14-dioxo- 15-oxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1

[0141] (2S)-2-[2-(2-fluoroprop-2-enoyl)-5-oxo-2,6-diazaspiro[3.4]octan-6-yl]-N-[(7S,13S)- (20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridinyl]-17,17-dimethyl-8,14-dioxo- 15-oxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 (2S)-2-[2-(2-fluoroprop-2-enoyl)-5-oxo-2,6-diazaspiro[3.4]octan-6-yl]-N-[(7S,13S)- (20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridinyl]-17,17-dimethyl-8,14-dioxo- 15-oxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1

[0142] (2S)-2-[2-(2-fluoroprop-2-enoyl)-5-oxo-2,6-diazaspiro[3.4]octan-6-yl]-N-[(7S,13S)- (20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridinyl]-17,17-dimethyl-8,14-dioxo- 15-oxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 (2S)-2-[2-(2-fluoroprop-2-enoyl)-5-oxo-2,6-diazaspiro[3.4]octan-6-yl]-N-[(7S,13S)- (20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridinyl]-17,17-dimethyl-8,14-dioxo- 15-oxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1

[0143] 4-fluoro- 1 -(2-fluoroprop-2-enoyl)-N-[(1 S)-1 -[[(7S,13S)-(20M)-20-[2-[(1 S)-1 - methoxyethyl]-5-(4-methylpiperazin-1 -yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4- thia-9,21,30,31 -tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]thirty-one carbon-1 (28),2,5(31 ),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl- propyl]-N-methyl-piperidine-4-carboxamide;

[0144] 1 -but-2-ynoyl-4-fluoro-N-[(1 S)-1 -[[(7S,13S)-(20M)-20-[2-[(1 S)-1 -methoxyethyl]-5-(4- methylpiperazin-1 -yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31 - tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]thirty-one carbon-1 (28),2,5(31 ),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl- propyl]-N-methyl-piperidine-4-carboxamide;

[0145] 4-fluoro- 1 -(2-fluoroprop-2-enoyl)-N-[(1 S)-1 -[[(7S,13S)-(20M)-20-[2-[(1 S)-1 - methoxyethyl]-5-(4-methylpiperazin-1 -yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4- thia-9,21,30,31 -tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]thirty-one carbon-1 (28),2,5(31 ),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl- propyl]-N-methyl-piperidine-4-carboxamide;

[0146] 1-[(2R)-2-chloro-2-fluoro-acetyl]-4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 [C31-1(28),2,5(31),19,25(29),26-hexene-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide;

[0147] 1-[(2R)-2-chloro-2-fluoro-acetyl]-4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 [C31-1(28),2,5(31),19,25(29),26-hexene-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide;

[0148] 4-Fluoro-1-(2-fluoroprop-2-enoyl)-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 [C31-1(28),2,5(31),19,25(29),26-hexene-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide;

[0149] 1 -But-2-ynoyl-4-fluoro-N-[(1 S)-1 -[[(7S,13S)-(20M)-20-[2-[(1 S)-1 - methoxyethyl]-5-morpholino-3-pyridinyl]-17,17-dimethyl-8,14-dioxo- 15,24-dioxa-4-thia-9,21,30,31 -tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]thirty-one carbon-1 (28),2,5(31 ),19,25(29),26-hexaen-7-yl]carbamoyl]-2- methyl-propyl]-N-methyl-piperidine-4-carboxamide;

[0150] 1 -But-2-ynoyl-4-fluoro-N-[(1 S)-1 -[[(7S,13S)-(20M)-20-[2-[(1 S)-1 - methoxyethyl]-5-morpholino-3-pyridinyl]-17,17-dimethyl-8,14-dioxo- 15,24-dioxa-4-thia-9,21,30,31 -tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]thirty-one carbon-1 (28),2,5(31 ),19,25(29),26-hexaen-7-yl]carbamoyl]-2- methyl-propyl]-N-methyl-piperidine-4-carboxamide;

[0151] 1 -But-2-ynoyl-4-fluoro-N-[(1 S)-1 -[[(7S,13S)-(20M)-20-[2-[(1 S)-1 - methoxyethyl]-5-morpholino-3-pyridinyl]-17,17-dimethyl-8,14-dioxo- 15,24-dioxa-4-thia-9,21,30,31 -tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]thirty-one carbon-1 (28),2,5(31 ),19,25(29),26-hexaen-7-yl]carbamoyl]-2- methyl-propyl]-N-methyl-piperidine-4-carboxamide;

[0152] 1 -But-2-ynoyl-4-fluoro-N-[(1 S)-1 -[[(7S,13S)-(20M)-20-[2-[(1 S)-1 -methoxyethyl]-5-(4- methylpiperazin-1 -yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia- 9,21,30,31 -tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]thirty-one carbon-1 (28), 2, 5(31), 19, 25(29), 26-hexaen-7-yl]carbamoyl]-2- methyl-propyl]-N-methyl-piperidine-4-carboxamide;

[0153] (3R)-N-[(1 S)-1 -[[(7S,13S)-(20M)-20-[2-[(1 S)-1 -methoxyethyl]-5-morpholino-3- pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31 -tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]thirty-one carbon-1 (28), 2, 5(31), 19, 25(29), 26-hexaen-7-yl]carbamoyl]-2- methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide;

[0154] (3R)-1 -But-2-ynoyl-N-[(1 S)-1 -[[(7S,13S)-(20M)-20-[2-[(1 S)-1 -methoxyethyl]-5- morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31 - tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]thirty-one carbon-1 (28), 2, 5(31), 19, 25(29), 26-hexaen-7-yl]carbamoyl]-2- methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide;

[0155] 4-Fluoro-N-[(1 S)-1 -[[(7S,13S)-(20M)-20-[2-[(1 S)-1 -methoxyethyl]-5-(4- methylpiperazin-1 -yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia- 9,21,30,31 -tetraazahexacyclo[23.3.1.12,5 .1 9,13 .0 19,27 .0 21,26 ]triaconta-1(28),2,5(31),19,25(29),26-hexen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-1-prop-2-enoyl-piperidine-4-carboxamide;

[0156] (2S)-2-[(5R)-7-but-2-ynoyl-1-oxo-2,7-diazaspiro[4.4]non-2-yl]-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21 ,26 ]triaconta-1(28),2,5(31),19,25(29),26-hexen-7-yl]-3-methyl-butyramide;

[0157] 4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]triaconta-1(28),2,5(31),19,25(29),26-hexen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-1-prop-2-enoyl-piperidine-4-carboxamide;

[0158] N-[(1S)-1-[[(7S,13S)-23,23-difluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26N-[(1 S)-1 -[[7S, 13S)-23,23-difluoro-(20M)-20-[2-[(1 S)-1 -methoxyethyl]-5- morpholino-3-pyridinyl]-17, 17-dimethyl-8, 14-dioxo-15-oxa-4-thia-9,21,30,31 - tetraazahexacyclo[23.3.1.1

[0159] N-[(1 S)-1 -[[7S, 13S)-23,23-difluoro-(20M)-20-[2-[(1 S)-1 -methoxyethyl]-5- morpholino-3-pyridinyl]-17, 17-dimethyl-8, 14-dioxo-15-oxa-4-thia-9,21,30,31 - tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 N-[(1 S)-1 -[[7S, 13S)-23,23-difluoro-(20M)-20-[2-[(1 S)-1 -methoxyethyl]-5- morpholino-3-pyridinyl]-17, 17-dimethyl-8, 14-dioxo-15-oxa-4-thia-9,21,30,31 - tetraazahexacyclo[23.3.1.1

[0160] N-[(1 S)-1 -[[7S, 13S)-23,23-difluoro-(20M)-20-[2-[(1 S)-1 -methoxyethyl]-5- morpholino-3-pyridinyl]-17, 17-dimethyl-8, 14-dioxo-15-oxa-4-thia-9,21,30,31 - tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 N-[(1 S)-1 -[[7S, 13S)-23,23-difluoro-(20M)-20-[2-[(1 S)-1 -methoxyethyl]-5- morpholino-3-pyridinyl]-17, 17-dimethyl-8, 14-dioxo-15-oxa-4-thia-9,21,30,31 - tetraazahexacyclo[23.3.1.1

[0161] N-[(1 S)-1 -[[7S, 13S)-23,23-difluoro-(20M)-20-[2-[(1 S)-1 -methoxyethyl]-5- morpholino-3-pyridinyl]-17, 17-dimethyl-8, 14-dioxo-15-oxa-4-thia-9,21,30,31 - tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 N-[(1 S)-1 -[[7S, 13S)-23,23-difluoro-(20M)-20-[2-[(1 S)-1 -methoxyethyl]-5- morpholino-3-pyridinyl]-17, 17-dimethyl-8, 14-dioxo-15-oxa-4-thia-9,21,30,31 - tetraazahexacyclo[23.3.1.1

[0162] 1-But-2-ynyl-N-[(1S)-1-[[(7S,13S)-23,23-difluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 [C31-1(28),2,5(31),19,25(29),26-hexene-7-yl]carbamoyl]-2-methyl-propyl]-4-fluoro-N-methyl-piperidine-4-carboxamide;

[0163] 4-Fluoro-1-(2-fluoroprop-2-enoyl)-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 [C31-1(28),2,5(31),19,25(29),26-hexene-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide;

[0164] 4-Fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17,23,23-tetramethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 [C31-1(28),2,5(31),19,25(29),26-hexene-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-1-prop-2-enoyl-piperidine-4-carboxamide;

[0165] 4-fluoro-N-[(1S)-1-[[(7S,13S,22S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridinyl]- 17, 17, 22-trimethyl-8, 14-dioxo-15, 24-dioxa-4-thia-9, 21, 30, 31-tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]triaconta-1(28), 2, 5(31), 19, 25(29), 26-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-1-prop-2- enoyl-piperidine-4-carboxamide; and

[0166] 4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridinyl]- 17, 17, 23, 23-tetramethyl-8, 14-dioxo-15-oxa-4-thia-9, 21, 30, 31-tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]triaconta-1(29), 2, 5(31), 19, 25, 27-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-1-prop-2- enoyl-piperidine-4-carboxamide;

[0167] or a pharmaceutically acceptable salt thereof.

[0168] Another embodiment of the present application relates to (xviii) a process for preparing a compound according to any one of (i) to (xvii), the process comprising the following steps:

[0169] a) coupling between a compound of formula (II),

[0170] (II) and an acid (III), (III) in the presence of a coupling reagent and a base to form the compound of formula (I);

[0171] b) coupling between a compound of formula (VI),

[0172] (VI) and an acid (VII), (VII) in the presence of a coupling reagent and a base to form a compound of formula (VIII), (VIII).

[0173] c) coupling a compound of formula (XI),

[0174] (XI) with an acid (XII), (XII) in the presence of a coupling reagent and a base to form a compound of formula (XIII), (XIII);

[0175] wherein Q is unsubstituted or substituted piperidinylene or pyrrolidinylene; T is dihaloC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, haloC 2-6 alkenyl or morpholinoC 2-6 alkynyl; R 1 to R 6 , A 1 , A 2 , M and L are as defined in any one of claims 1 to 16; the coupling reagent in steps a) to c) is T3P, HATU, PyBOP or EDCI / HOBt; the base in steps a) to c) is TEA, DIEPA or DMAP.

[0176] Another embodiment of the present application is (xix) a compound or pharmaceutically acceptable salt according to any one of (i) to (xvii) for use as a therapeutic active substance.

[0177] Another embodiment of the present application is (xx) a pharmaceutical composition comprising a compound according to any one of (i) to (xvii), and a pharmaceutically acceptable excipient.

[0178] Another embodiment of the present application is (xxi) the use of a compound according to any one of (i) to (xvii) for the treatment of a KRAS G12C protein related disease.

[0179] Another embodiment of the present application is (xxii) the use of a compound according to any one of (i) to (xvii) for the treatment of a KRAS G12C, G12D and G12V protein related disease.

[0180] Another embodiment of the present application is (xxiii) the use of a compound according to any one of (i) to (xvii) for the inhibition of the interaction of RAS with downstream effectors, wherein the downstream effectors are RAF and PI3K.

[0181] Another embodiment of the application is (xxiv) the use of a compound according to any one of (i) to (xvii) for the inhibition of propagating oncogenic MAPK and PI3K signaling.

[0182] Another embodiment of the application is (xxv) the use of a compound according to any one of (i) to (xvii) for the treatment or prophylaxis of a KRAS mutation- driven cancer, wherein the cancer is selected from pancreatic cancer, colorectal cancer, lung cancer, esophageal cancer, gallbladder cancer, melanoma, ovarian cancer, and endometrial cancer.

[0183] Another embodiment of the application is (xxvi) the use of a compound according to any one of (i) to (xvii) for the treatment or prophylaxis of a KRAS mutation- driven cancer, wherein the cancer is selected from pancreatic adenocarcinoma, colorectal cancer, and non-small cell lung cancer.

[0184] Another embodiment of the application is (xxvii) a compound or pharmaceutically acceptable salt according to any one of (i) to (xvii) for use in the treatment or prophylaxis of a KRAS mutation-driven cancer, wherein the cancer is selected from pancreatic adenocarcinoma, colorectal cancer, and non-small cell lung cancer.

[0185] Another embodiment of the application is (xxviii) the use of a compound according to any one of (i) to (xvii) for the manufacture of a medicament for the treatment or prophylaxis of a KRAS mutation-driven cancer, wherein the cancer is selected from pancreatic adenocarcinoma, colorectal cancer, and non-small cell lung cancer.

[0186] Another embodiment of the application is (xxix) a method for the treatment or prophylaxis of a KRAS mutation-driven cancer, wherein the cancer is selected from pancreatic adenocarcinoma, colorectal cancer, and non-small cell lung cancer, comprising administering a therapeutically effective amount of a compound as defined in any one of (i) to (xvii).

[0187] Another embodiment of the application is (xxx) a compound or pharmaceutically acceptable salt according to any one of (i) to (xvii), when manufactured according to a process of (xviii).

[0188] Pharmaceutical compositions and administration

[0189] Another embodiment provides pharmaceutical compositions or medicaments containing a compound of the application and a therapeutically inert carrier, diluent or excipient, as well as methods of using the compounds of the application to prepare such compositions and medicaments. In one example, a compound of Formula (I) can be formulated into galenical administration forms by mixing at ambient temperature with the physiologically acceptable carrier, i.e., carrier that does not produce an immune response in a recipient at the doses and concentrations employed, and in the desired purity. The pH of the formulation depends mainly on the particular use and concentration of the compound but is preferably in the range of 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, a compound of Formula (I) is sterile. The compounds can be stored, for example, as solid or amorphous compositions, as lyophilized formulations or as aqueous solutions.

[0190] The 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 part of the body to be treated, 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 the interaction of mutant RAS (e.g., KRASG12C) with RAF, thereby blocking oncogenic MAPK signaling. For example, the amount can be below the amount that is toxic to normal cells or the mammal as a whole.

[0191] In one example, a pharmaceutically effective amount of a compound of the application administered parenterally per dose will be in the range of from about 0.1 to 1000 mg / kg of patient body weight per day, 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 will preferably contain from about 1 to about 1000 mg of a compound of the application.

[0192] The compounds of the application can be administered by any suitable mode of administration, 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.

[0193] The compounds of the application can be administered in any convenient administration form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, creams, patches, etc. Such compositions can include conventional ingredients of a pharmaceutical formulation, e.g., diluents, carriers, pH adjusting agents, sweeteners, fillers, and other active agents.

[0194] The usual formulations are prepared by mixing a compound of the application 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., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th ed., Lippincott, Williams & Wilkins, Philadelphia, 2004; Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems . Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Remington: The Science and Practice of Pharmacy . Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients . Chicago, Pharmaceutical Press, 2005. The formulations can also 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 application or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).

[0195] An example of a suitable oral dosage form is a tablet comprising about 1 to 1000 mg of a compound of the application 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 components are first mixed together and then mixed with a PVP solution. The resulting composition can be dried, granulated, mixed with magnesium stearate, and compressed to tablet form using conventional equipment. An example of an aerosol formulation can be prepared by dissolving a compound of the application (e.g., 5 mg to 400 mg) in a suitable buffer solution (e.g., a phosphate buffer) with a permeation enhancer (e.g., a salt such as sodium chloride) if desired. The solution can be filtered, e.g., using a 0.2 micron filter, to remove impurities and contaminants.

[0196] Accordingly, embodiments include a pharmaceutical composition comprising a compound of Formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof. Further embodiments include a pharmaceutical composition comprising a compound of Formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0197] Another embodiment includes a pharmaceutical composition comprising a compound of Formula (I) for use in treating a mutant KRAS driven cancer. Another embodiment includes a pharmaceutical composition comprising a compound of Formula (I) for use in treating a mutant KRAS driven cancer.

[0198] The following compositions A and B illustrate typical compositions of the present application, but are merely representative thereof.

[0199] Composition A

[0200] The compounds of the present application can be used as active ingredients in the production of tablets of the following composition in a manner known per se:

[0201] Each tablet

[0202] Active ingredient 200 mg

[0203] Microcrystalline cellulose 155 mg

[0204] Corn starch 25 mg

[0205] Talc 25 mg

[0206] Hydroxypropyl methylcellulose 20 mg

[0207] 425 mg

[0208] Composition B

[0209] The compounds of the present application can be used as active ingredients in the production of capsules of the following composition in a manner known per se:

[0210] Each capsule

[0211] Active ingredient 100.0 mg

[0212] Corn starch 20.0 mg

[0213] Lactose 95.0 mg

[0214] Talc 4.5 mg

[0215] Magnesium stearate 0.5 mg

[0216] 220.0 mg

[0217] Indications and methods of treatment

[0218] The compounds of the present application induce a new binding pocket in KRAS by driving the formation of a high-affinity tri-complex between the KRAS protein and the ubiquitously expressed cyclophilin A (CYP A), which inhibits the interaction of KRAS with downstream effectors such as RAF and PI3K. Thus, the compounds of the present application can be used to inhibit the propagating oncogenic MAPK and PI3K signaling, reducing cell, particularly cancer cell, proliferation. The compounds of the present application can be used to terminate RAS signaling in cells expressing RAS mutations, particularly KRAS mutations, driven pancreatic cancer, colorectal cancer, lung cancer, esophageal cancer, gallbladder cancer, melanoma, ovarian cancer, endometrial cancer, etc. Alternatively, the compounds of the present application can be used to terminate RAS signaling in malignant solid tumors, where the oncogenic effect of KRAS mutations is potentiated by the dysregulation or mutation of the effector pathways of MAPK, PI3K-AKT-mTOR (mammalian target of rapamycin) driven signaling, etc., which compounds are used in targeted therapy of pancreatic adenocarcinoma, colorectal cancer, non-small cell lung cancer, etc.

[0219] 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, a tautomer, or a pharmaceutically acceptable salt thereof.

[0220] Synthesis

[0221] The compounds of the present application can be prepared by any conventional means. Suitable methods for synthesizing these compounds and their starting materials are provided in the following schemes and examples. Unless otherwise indicated, all substituents, particularly R 1 to R 6 , M and L and A 1 and A 2 are as defined above. Furthermore, unless explicitly otherwise stated, all reactions, reaction conditions, abbreviations and symbols have the meanings that would be conventionally understood by a person of ordinary skill in the art of organic chemistry.

[0222] General synthetic routes for preparing compounds of Formula (I) and (Ia) are shown below.

[0223] Scheme 1

[0224]

[0225] Compounds of formula II are synthesized according to the procedures described in intermediates A to R. Compounds of formula (I) can be obtained by a coupling reaction between an acid (III) and a compound of formula (II) in the presence of a base such as TEA, DIEPA and DMAP with one or more coupling reagents such as T3P, HATU, PyBOP and EDCI / HOBt.

[0226] Scheme 2

[0227]

[0228] wherein PG is a protecting group such as Boc and Cbz.

[0229] Compounds of formula (V) can be obtained by a coupling reaction between an acid (IV) and a compound of formula (II) in the presence of a base such as TEA, DIEPA or DMAP with one or more coupling reagents such as T3P, HATU, PyBOP or EDCI / HOBt. Deprotection of compounds of formula (V) can provide compounds of formula (VI) in the presence of an acid such as TFA, or under hydrogenation conditions with a catalyst such as Pd / C and Pd(OH)2 / C. Compounds of formula (VIII) can be obtained by a coupling reaction between an acid (VII) and an acid (VI) in the presence of a base such as TEA, DIEPA and DMAP with one or more coupling reagents such as T3P, HATU, PyBOP and EDCI / HOBt.

[0230] Scheme 3

[0231]

[0232] wherein PG is a protecting group such as Boc and Cbz; T is a dihaloC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, haloC 2-6 alkenyl or morpholinoC 2-6 alkynyl; Q is unsubstituted or substituted piperidinylene or pyrrolidinylene.

[0233] The compound of formula (X) can be obtained by a coupling reaction between the acid (IX), the compound of formula (VI) and one or more coupling reagents such as T3P, HATU, PyBOP or EDCI / HOBt in the presence of a base such as TEA, DIEPA or DMAP. Deprotection of the compound of formula (X) can provide the compound of formula (XI) in the presence of an acid such as TFA, or under hydrogenation conditions with a catalyst such as Pd / C and Pd(OH)2 / C. The compound of formula (XIII) can be obtained by a coupling reaction between the acid (XII) and the compound of formula (XI) with a coupling reagent such as T3P, HATU, PyBOP or EDCI / HOBt in the presence of a base such as TEA, DIEPA or DMAP.

[0234] The compounds of the application can be obtained as a mixture of diastereomers or enantiomers, which can be separated by methods well known in the art, for example, (chiral) HPLC or SFC. In another embodiment, the compound of formula (I) can be obtained according to the above scheme using the corresponding chiral starting materials.

[0235] The present application also relates to a process for preparing a compound of formula (I), comprising the steps of:

[0236] a) subjecting a compound of formula (II),

[0237] to a coupling reaction with an acid (III), (III) in the presence of a coupling reagent and a base, to form said compound of formula (I);

[0238] b) subjecting a compound of formula (VI),

[0239] to a coupling reaction with an acid (VII), (VII) in the presence of a coupling reagent and a base, to form a compound of formula (VIII), (VIII);

[0240] c) subjecting a compound of formula (XI),

[0241] to a coupling reaction with an acid (XII), (XII) in the presence of a coupling reagent and a base, to form a compound of formula (XIII), (XIII);

[0242] wherein

[0243] In steps a), b) and c), the coupling reagent can be, for example, T3P, HATU, PyBOP or EDCI / HOBt; the base can be, for example, TEA, DIEPA or DMAP.

[0244] The compounds of formula (I) or (Ia) produced according to the above process are also an object of the present application.

[0245] Examples

[0246] The present application will be more fully understood by reference to the following examples. They should not, however, be construed as limiting the scope of the application.

[0247] Abbreviations

[0248] The present application will be more fully understood by reference to the following examples. They should not, however, be construed as limiting the scope of the application.

[0249] The abbreviations used herein are as follows:

[0250] ACN acetonitrile

[0251] aq. aqueous

[0252] Boc-N-Me-Val-OH N-(tert-butoxycarbonyl)-N-methyl-L-valine

[0253] (Boc)20 di-tert-butyl dicarbonate

[0254] (R)-binap (R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl

[0255] CDCl3: deuterated chloroform

[0256] CD3OD: deuterated methanol

[0257] CuI copper(I) iodide

[0258] DIEPA: N,N-diisopropylamine

[0259] DMAP: 4-dimethylaminopyridine

[0260] DMF: dimethylformamide

[0261] DMSO: dimethyl sulfoxide

[0262] EDCI: N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride

[0263] EtOAc or EA: ethyl acetate

[0264] FRET fluorescence resonance energy transfer

[0265] HATU: (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate)

[0266] hr: hour(s)

[0267] HPLC: high performance liquid chromatography

[0268] HOBt: N-hydroxybenzotriazole

[0269] [Ir(OMe)(COD)]2 (1,5-cyclooctadiene) (methoxy)iridium(I) dimer

[0270] LDA lithium diisopropylamide

[0271] MS: (ESI): mass spectrometry (electrospray ionization)

[0272] min(s): minute(s)

[0273] MTBE methyl tert-butyl ether

[0274] MTDA dimethyl ketene methyltrimethylsilyl acetal

[0275] NMM N-methylmorpholine

[0276] NaBH(OAc)3 sodium triacetoxyborohydride

[0277] NBS N-bromosuccinimide

[0278] NIS N-iodosuccinimide

[0279] NMR: nuclear magnetic resonance

[0280] NMO 4-methylmorpholine N-oxide

[0281] obsd. observed

[0282] Pd(dppf)Cl2 [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium(II)

[0283] Pd(dtbpf)Cl2 [1,1'-bis(di-tert-butylphosphino)ferrocene] dichloropalladium(II)

[0284] prep-HPLC preparative high performance liquid chromatography

[0285] PyBOP: benzotriazol-1- yloxytrispyrrolidino phosphonium hexafluorophosphate

[0286] RT or rt: room temperature

[0287] sat. saturation

[0288] Selective fluorine reagent 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octanebis(tetrafluoroborate)

[0289] SFC Supercritical Fluid Chromatography

[0290] TBAF tetrabutylammonium fluoride

[0291] TEA: Triethylamine

[0292] TFA: Trifluoroacetic acid

[0293] THF: Tetrahydrofuran

[0294] TMEDA Tetramethylethylenediamine

[0295] TMSCF3 Trifluoromethyltrimethylsilane

[0296] T3P: Propylphosphonic anhydride

[0297] General experimental conditions

[0298] Purify intermediates and final compounds using rapid chromatography using one of the following instruments: i) Biotage SP1 system and Quad 12 / 25 Cartridge module; ii) ISCO combi-flash chromatograph. Silica gel brand and pore size: i) KP-SIL 60 Å, particle size: 40-60 µm; ii) CAS Registry Number: 63231-67-4, particle size: 47-60 µm silica gel; iii) ZCX from Qingdao Ocean Chemical Co., Ltd., pore size: 200-300 or 300-400.

[0299] Intermediates and the final compound were purified by preparative HPLC on a reversed-phase column using an XBridge column. TM Prep-C18 (5 µm, OBDTM 30 × 100 mm) column, SunFire TM Prep-C18 (5 µm, OBD) TM30 × 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, detectors: Micromass ZQ and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water; acetonitrile and 0.1% FA in water, or acetonitrile and 0.1% TFA in water). Alternatively, use the 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).

[0300] For chiral separation of SFC, intermediates were separated by chiral columns (Daicel chiralpak IC, 5 µm, 30 × 250 mm), AS (10 µm, 30 × 250 mm), or AD (10 µm, 30 × 250 mm), using a Mettler Toledo Multigram III system SFC, a Waters 80Q preparative SFC, or a Thar 80 preparative SFC. The solvent system was CO2 and IPA (0.5% TEA in IPA) or CO2 and MeOH (0.1% NH3∙H2O in MeOH). The back pressure was 100 bar, and the detection UV was 254 nm or 220 nm.

[0301] Using LC / MS (Waters TM The LC / MS spectra of the compounds were obtained using an Alliance 2795-Micromass ZQ, Shimadzu Alliance2020-Micromass ZQ, or Agilent Alliance 6110-Micromass ZQ. The LC / MS conditions were as follows (run time 3 or 1.5 minutes):

[0302] Acidic conditions I: A: 0.1% TFA solution in H2O; B: 0.1% TFA solution in acetonitrile;

[0303] Acidic conditions II: A: 0.0375% TFA in H2O; B: 0.01875% TFA in acetonitrile;

[0304] Basic conditions I: A: 0.1% NH3H2O in H2O; B: acetonitrile;

[0305] Basic conditions II: A: 0.025% NH3H2O in H2O; B: acetonitrile;

[0306] Neutral conditions: A: H2O; B: acetonitrile.

[0307] Mass spectrometry (MS): Typically only ions representing the parent mass are reported, and the mass ions quoted are positive mass ions (MH) unless otherwise stated. + .

[0308] NMR spectra were obtained using a Bruker Avance 400 MHz or 500 MHz.

[0309] Microwave assisted reactions were performed in a Biotage Initiator Sixty microwave synthesizer. All reactions involving air sensitive reagents were performed under an argon or nitrogen atmosphere. Reagents were purchased from commercial suppliers as received and without further purification unless otherwise stated.

[0310] Preparative examples

[0311] The following examples are intended to illustrate the meaning of the present application but by no means represent a restriction of the meaning of the present application:

[0312] Preparation of intermediates

[0313] Intermediate A1

[0314] (2S)-2-(2-tert-Butoxycarbonyl-5-oxo-2,6-diazaspiro[3.4]octan-6-yl)-3-methyl- butanoic acid

[0315]

[0316] The compounds were prepared according to the following schemes:

[0317]

[0318] Step 1: Preparation of 3-allyl-3-cyano-azetidine-1-carboxylic acid tert-butyl ester (Compound A1-b)

[0319] To a solution of tert-butyl 3-cyanoazetidine-l-carboxylate (Compound Al-a, 10.0 g, 54.88 mmol) in THF (100 mL) was added LDA (60.3 mL, 60.37 mmol) dropwise at -70 °C under nitrogen atmosphere. After stirring at -70 °C for 0.5 h, to the reaction mixture was added allyl bromide (7.9 g, 65.85 mmol). The mixture was stirred at 16 °C for another 1 h, then concentrated in vacuum, and the residue was purified by column chromatography (EtOAc in PE: 3% to 10%) to give tert-butyl 3-allyl-3-cyano-azetidine-l-carboxylate (Compound Al-b, 12.5 g) as a light yellow oil. 1 H NMR (400 MHz, chloroform-d) δ 5.90 - 5.70 (m, 1 H), 5.32 (s, 1 H), 5.28 (d, J = 5.2 Hz, 1 H), 4.23 (d, J = 8.8 Hz, 2 H), 3.86 (d, J = 8.8 Hz, 2 H), 2.63 (d, J = 7.2 Hz, 2 H), 1.45 (s, 9 H) ppm.

[0320] Step 2: tert-Butyl 3-allyl-l-tert-butoxycarbonyl-azetidine-3-carboxylate (Compound Al-c)

[0321] A mixture of tert-butyl 3-allyl-3-cyano-azetidine-l-carboxylate (Compound Al-b, 12.5 g, 56.24 mmol) and potassium hydroxide (12.6 g, 224.94 mmol) in ethanol (60 mL) and water (60 mL) was stirred at 100 °C for 16 hours. After the reaction was completed, the pH of the reaction mixture was acidified to pH = 3 by aqueous HC1 (1 M). The reaction mixture was extracted with EtOAc (120 mL) three times. The combined organic layers were washed with brine (300 mL), dried over Na2S04, filtered and concentrated in vacuum to give tert-butyl 3-allyl-l-tert-butoxycarbonyl-azetidine-3-carboxylate (Compound Al-c, 14.0 g) as a white solid. MS calc 242.1 (MH + ); found 186.2 (M-C4H8+H + ).

[0322] Step 3: O1-tert-Butyl 03-methyl 3-allylazetidine-l,3-dicarboxylate (Compound Al-d)

[0323] To a mixture of 3-allyl-l-tert-butoxycarbonyl-azetidine-3-carboxylic acid (Compound Al-c, 8.0 g, 33.16 mmol) in DMF (80 mL) was added potassium carbonate (13.7 g, 99.47 mmol) followed by iodomethane (9.4 g, 66.31 mmol). After stirring at 20 °C for 2 h, the reaction mixture was poured into water (400 mL) and the resulting mixture was extracted with EtOAc (100 mL) three times. The combined organic layers were washed with brine (300 mL), dried over Na2S04, filtered and concentrated in vacuo to give O1-tert-butyl O3-methyl 3-allylazetidine-l,3-dicarboxylate (Compound Al-d, 7.3 g) as a yellow oil. 1 H NMR (400 MHz, chloroform-d) δ 5.80 - 5.60 (m, 1 H), 5.19 - 5.14 (m, 1 H), 5.12 (s, 1 H), 4.16 (d, J = 8.8 Hz, 2 H), 3.82 - 3.69 (m, 5 H), 2.63 (d, J = 7.2 Hz, 2 H), 1.44 (s, 9 H) ppm.

[0324] Step 4: O1-tert-Butyl O3-methyl 3-(2-oxoethyl)azetidine-l,3-dicarboxylate (Compound Al-e)

[0325] To a mixture of O1-tert-buty1 O3-methyl 3-allylazetidin-l,3-dicarboxylate (Compound A1-d, 2 g, 7.83 mmol) in 1,4-dioxane (20 mL) and water (20 mL) was added 2,6-dimethylpyridine (1.8 mL, 15.67 mmol) and K2OsO4(144.3 mg, 0.39 mmol). After stirring at 16 °C for 15 min, sodium metaperiodate (6.7 g, 31.33 mmol) was added to the reaction mixture and stirred for another 1 h, then poured into water (120 mL), and the resulting mixture was extracted with EtOAc (40 mL) three times. The combined organic layers were washed with saturated Na2SO3(60 mL), brine (60 mL), dried over Na2SO4, filtered and concentrated in vacuo to give O1-tert-buty1 O3-methyl 3-(2-oxoethyl)azetidin-l,3-dicarboxylate (Compound A1-e, 2.8 g) as a yellow oil. MS calculated for 258.1 (MH + ) ; found 202.1 (M-C4H8+H + ).

[0326] Step 5: O1-tert-Butyl O3-methyl 3-[2-[[(1S)-1-benzyloxycarbonyl-2-methyl- propyl]amino]ethyl]azetidin-1,3-dicarboxylate (Compound A1-f)

[0327] To a mixture of L-valine benzyl ester hydrochloride (3.2 g, 13.06 mmol) and O1-tert-buty1 O3-methyl 3-(2-oxoethyl)azetidin-l,3-dicarboxylate (Compound A1-e, 2.8 g, 10.88 mmol) in methanol (50 mL) was added zinc chloride (1.8 g, 13.06 mmol). After stirring at 16 °C for 0.5 h, sodium cyanoborohydride (1.4 g, 21.77 mmol) was added to the reaction mixture, and the resulting mixture was stirred for another 1 h. The reaction mixture was concentrated in vacuo, and the residue was purified by column chromatography (EtOAc in PE: 30% to 50%) to give O1-tert-buty1 O3-methyl 3-[2-[[(1S)-1-benzyloxycarbonyl-2-methyl- propyl]amino]ethyl]azetidin-1,3-dicarboxylate (Compound A1-f, 2.2 g) as a colorless oil. MS calculated for 449.3 (MH + ) ; found 449.3 (MH + ).

[0328] Step 6: tert-Butyl 6-[(1S)-1-benzyloxycarbonyl-2-methyl-propyl]-5-oxo-2,6- diazaspiro[3.4]octane-2-carboxylate (Compound A1-g)

[0329] A mixture of 4-dimethylaminopyridine (544.7 mg, 4.46 mmol), DIEA (7.7 mL, 44.59 mmol), and O1-tert-butyl O3-methyl 3-[2-[[(1S)-1-benzyloxycarbonyl-2-methyl- propyl]amino]ethyl]azetidine-1,3-dicarboxylate (Compound A1-f, 2.0 g, 4.46 mmol) in toluene (2 mL) was stirred at 100 °C for 20 hours. After the reaction was completed, the reaction mixture was concentrated in vacuo and the residue was dissolved in EtOAc (60 mL). The resulting solution was washed with aqueous HC1 (1 M, 60 mL), then washed with brine (60 mL), dried over Na2S04, filtered. The filtrate was concentrated in vacuo to give tert-butyl 6-[(1S)-1-benzyloxycarbonyl-2-methyl-propyl]-5-oxo-2,6- diazaspiro[3.4]octane-2-carboxylate (Compound A1-g, 1.5 g) as a white solid. MS calc’d 417.2 (MH + ) ; measured 361.2 (M-C4H8+H + ).

[0330] Step 7: (2S)-2-(2-tert-Butoxycarbonyl-5-oxo-2,6-diazaspiro[3.4]octan-6-yl)-3-methyl- butyric acid (Intermediate A1)

[0331] A mixture of tert-butyl 6-[(1S)-1-benzyloxycarbonyl-2-methyl-propyl]-5-oxo-2,6- diazaspiro[3.4]octane-2-carboxylate (Compound A1-g, 1.5 g, 3.6 mmol) and Pd on activated carbon (150.0 mg) in methanol (20 mL) was stirred under a balloon of H2 at 16 °C for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give (2S)-2-(2-tert-butoxycarbonyl-5-oxo-2,6-diazaspiro[3.4]octan-6-yl)-3-methyl- butyric acid (Intermediate A1, 920.0 mg) as a white solid. MS calc’d 327.2 (MH + ) ; measured 271.2 (M-C4H8+H + ).

[0332] Intermediate A2

[0333] cis-(2S)-3-methyl-2-[methyl-[3-(3,3,3-trifluoroprop-1-ynyl)cyclobutane- carbonyl]amino]butyric acid

[0334]

[0335] The compound was prepared according to the following scheme:

[0336]

[0337] Step 1: Preparation of methyl 3-(methoxymethylene)cyclobutane carboxylate (Compound A2-b)

[0338] To a solution of (methoxymethyl)triphenylphosphonium chloride (267.5 g, 780.46 mmol) in THF (1.6 L) was added potassium tert-butoxide (87.6 g, 780.46 mmol) slowly at 0 °C and warmed to 20 °C. After 1.5 hours, methyl 3-oxocyclobutane carboxylate (Compound A2-a, 50.0 g, 390.23 mmol) was added to the reaction mixture. After stirring at 70 °C for 3 hours, the reaction mixture was concentrated under vacuum to give a residue. A mixed solution of PE in EtOAc (10:1, 1.1 L) was added to the residue. After stirring at 20 °C for 0.5 hours, the suspension was filtered and the filtrate was concentrated under vacuum to give a residue. The residue was purified by column chromatography to give methyl 3-(methoxymethylene)cyclobutane carboxylate (Compound A2-b, 18.0 g) as a yellow oil. 1 H NMR (400 MHz, chloroform-d) δ = 5.85 - 5.79 (m, 1 H), 3.70 (s, 3 H), 3.60 (s, 3 H), 3.29 - 3.09 (m, 1H), 3.01 - 2.90 (m, 2H), 2.89 - 2.71 (m, 2 H) ppm.

[0339] Step 2: Preparation of methyl 3-formylcyclobutane carboxylate (Compound A2-c)

[0340] To a solution of methyl 3-(methoxymethylene)cyclobutane carboxylate (Compound A2-b, 26.0 g, 166.47 mmol) in DCM (300 mL) and water (30 mL) was added TFA (26.0 mL). The reaction mixture was stirred at 20 °C for 3 hours. After the reaction was completed, to the reaction mixture was added H2O (600 mL), then extracted with DCM (100 mL, three times). The organic layer was washed with brine (500 mL), dried over Na2SO4, filtered and concentrated under vacuum to give methyl 3-formylcyclobutane carboxylate (Compound A2-c, 18.0 g, 126.63 mmol) as a yellow oil. 1 H NMR (400 MHz, Chloroform-d) δ = 9.84 - 9.52 (m, 1H), 3.75 - 3.63 (m, 3H), 3.32 - 3.20 (m, 1H), 3.18 - 3.07 (m, 1H), 2.67- 2.38 (m, 4H) ppm.

[0341] Step 3: Preparation of methyl 3-ethynylcyclobutane carboxylate (Compound A2-d)

[0342] A solution of methyl 3-formylcyclobutane carboxylate (Compound A2-c, 10.0 g, 70.35 mmol) in methanol (120 mL) was cooled to 0 °C and then (1-diazo-2-oxopropyl)dimethyl phosphate (21.0 g, 109.31 mmol) and potassium carbonate (20.0 g, 144.71 mmol) were added to the reaction mixture. After stirring at 20 °C for 3 hours, to the reaction mixture was added H2O (150 mL), and then extracted with PE (60 mL, twice). The combined organic layer was washed with brine (80 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give a residue. The residue was purified by column chromatography (EtOAc in PE: 0% to 25%) to give methyl 3-ethynylcyclobutane carboxylate (Compound A2-d, 6.0 g) as a colorless oil. 1 H NMR (400 MHz, Chloroform-d) δ = 3.75 - 3.62 (m, 3H), 3.42 - 3.21 (m, 1H), 3.07 - 2.89 (m, 1H), 2.65 - 2.33 (m, 4H), 2.23- 2.17 (m, 1H) ppm.

[0343] Step 4: Preparation of 3-ethynylcyclobutane carboxylic acid (Compound A2-e)

[0344] To a solution of methyl 3-ethynylcyclobutane carboxylate (Compound A2-d, 6.0 g, 43.43 mmol) in THF (10 mL) and water (30 mL) was added lithium hydroxide (3.6 g, 86.86 mmol) at 0 °C, and then the solution was stirred at 20 °C for 3 hours. After the reaction was completed, the reaction mixture was concentrated under vacuum to remove THF, then H2O (60 mL) was added and extracted with MTBE (30 mL). The MTBE phase was discarded and the aqueous phase was acidified to pH = 5 with aqueous HC1 (1 N, 60 mL), and extracted with EtOAc (60 mL, three times). The combined organic layers were washed with brine (80 mL), dried over Na2S04, filtered and concentrated under vacuum to give 3-ethynylcyclobutane carboxylic acid (Compound A2-e, 3.8 g) as a colorless oil. 1 H NMR (400 MHz, Chloroform-d) δ = 12.14 - 9.87 (m, 1 H), 3.36 - 3.15 (m, 1 H), 3.10 - 2.95 (m, 1 H), 2.68 - 2.53 (m, 2 H), 2.51 - 2.35 (m, 2 H), 2.22 (dd, J = 15.2, 2.4 Hz, 1 H) ppm.

[0345] Step 5: Preparation of cis-(2S)-2-[(3-ethynylcyclobutane carbonyl)-methyl- amino]-3-methyl-butyric acid tert-butyl ester (Compound A2-f)

[0346] To a solution of 3-ethynylcyclobutane carboxylic acid (compound A2-e, 3.8 g, 30.61 mmol) in DMF (50 mL) was added DIEA (19.0 mL, 114.96 mmol), HATU (14.3 g, 37.48 mmol). After stirring at 0 °C for 10 min, tert-butyl (2S)-3-methyl-2-(methylamino)butanoate (5.7 g, 30.44 mmol) was added to the reaction mixture. The reaction mixture was stirred at 0 °C for another 1 h. After the reaction was completed, H2O (120 mL) was added to the reaction mixture, which was then extracted with EtOAc (40 mL, three times). The combined organic layers were washed with brine (60 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give a residue. The residue was purified by column chromatography (EtOAc in PE: 9% - 16%) and preparative HPLC (column: Welch Ultimate XB-CN 250 x 50 x 10 pm; mobile phase: hexanes-EtOH (0.1% FA); B%: 1% to 20%, 15 min) to give tert-butyl cis-(2S)-2-[(3-ethynylcyclobutane carbonyl)-methyl-amino]-3-methyl- butanoate (compound A2-f, faster elution, 3 g) as a yellow oil. MS calculated 294.2 (MH + ) ; found 294.1 (MH + ). 1 H NMR (400 MHz, chloroform-d) δ =4.80 (d, J = 10.4 Hz, 0.5 H), 3.58 (d, J = 10.8 Hz, 0.5 H), 3.27 - 3.11 (m, 1H), 3.01 - 2.91 (m, 1 H), 2.87 (d, J = 6.8 Hz, 3 H), 2.59 - 2.40 (m, 4 H), 2.25 - 2.12 (m, 2 H), 1.45 (s, 9 H), 1.00 (dd, J = 14.4, 6.4 Hz, 3 H), 0.84 (dd, J = 6.8, 1.2 Hz, 3 H) ppm. The stereochemistry of compound A2-f was confirmed by 2D-NMR.

[0347] Step 6: Preparation of tert-butyl cis-(2S)-3-methyl-2-[methyl-[3-(3,3,3- trifluoroprop-1-ynyl)cyclobutane carbonyl]amino]butanoate (compound A2-g)

[0348] A suspension of Cul (408.9 mg, 2.15 mmol), K2CO3(593.5 mg, 4.29 mmol), and TMEDA (249.5 mg, 2.15 mmol) in DMF (10 mL) was stirred under an argon atmosphere at 25 °C for 20 minutes. A solution of TMSCF3(407.1 mg, 2.86 mmol) and cis-(2S)-2-[(3-ethynylcyclobutanecarbonyl)-methyl- amino]-3-methyl-butyric acid tert-butyl ester (Compound A2-f, 420.0 mg, 1.43 mmol) in DMF (10 mL) was added to the reaction. The reaction mixture was stirred at 0 °C for 30 minutes and allowed to warm to 25 °C. After stirring at 25 °C for an additional 12 hours, H2O (30 mL) was added to the reaction mixture, which was then extracted with EtOAc (10 mL, three times). The combined organic layers were washed with brine (50 mL), and dried over Na2SO4, filtered, and concentrated under vacuum to give a residue. The residue was purified by reverse phase chromatography and preparative HPLC to give cis-(2S)-3-methyl-2-[methyl-[3-(3,3,3-trifluoroprop-1-ynyl)cyclobanecarbonyl]amino]butyric acid tert-butyl ester (Compound A2-g, 80.0 mg) as a yellow oil. MS calculated 362.2 (MH + ) ; found 362.1 (MH + ). 1 H NMR (400 MHz, chloroform-d) δ =4.80 (d, J =10.0 Hz, 0.5 H), 3.62 - 3.46 (m, 1.5 H), 3.28 - 3.13 (m, 1 H), 2.89 (d, J = 4.4 Hz, 3 H), 2.82 - 2.67 (m, 2 H), 2.48 - 2.38 (m, 2 H), 2.29 - 2.15 (m, 1 H), 1.46 (d, J = 2.8 Hz, 9 H), 1.05 - 0.98 (m, 3 H), 0.85 (d, J = 6.8 Hz, 3 H) ppm.

[0349] Step 7: Preparation of cis-(2S)-3-methyl-2-[methyl-[3-(3,3,3-trifluoroprop-1-ynyl)cyclobutanecarbonyl]amino]butyric acid (Intermediate A2)

[0350] To a solution of cis-(2S)-3-methyl-2-[methyl-[3-(3,3,3-trifluoroprop-1-ynyl)cyclobutane- carbonyl]amino]butyric acid tert-butyl ester (Compound A2-g, 80.0 mg, 0.22 mmol) in DCM (1 mL) was added TFA (1.0 mL) and the mixture was stirred at 20 °C for 1 hour. After the reaction was completed, the reaction mixture was concentrated under vacuum to give cis-(2S)-3-methyl-2-[methyl-[3-(3,3,3-trifluoroprop-1-ynyl)cyclobutane- carbonyl]amino]butyric acid (Intermediate A2, 80.0 mg) as a yellow oil, which was used directly for the next step. MS calculated 306.0 (MH + ) ; found 306.0 (MH + ).

[0351] Intermediate A3 and Intermediate A4

[0352] (2S)-2-[(5R)-7-tert-butoxycarbonyl-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-3-methyl- butyric acid (Intermediate A3) and (2S)-2-[(5S)-7-tert-butoxycarbonyl-1-oxo-2,7-diazaspiro[4.4]nonan- 2-yl]-3-methyl-butyric acid (Intermediate A4)

[0353]

[0354] The compounds were prepared according to the following scheme:

[0355]

[0356] Step 1: Preparation of O1-tert-butyl O3-methyl 3-allyl pyrrolidine-1,3-dicarboxylate (Compound A3-b)

[0357] To a solution of O1-tert-butyl O3-methyl pyrrolidine-1,3-dicarboxylate (Compound A3-a, 5.0 g, 21.8 mmol) in THF (60 mL) was added LDA (12 mL, 24 mmol) dropwise at -70 °C under nitrogen atmosphere. After stirring for 0.5 h, propenyl bromide (2.9 g, 23.99 mmol) was added slowly. After completion of the reaction, the reaction mixture was poured into saturated aqueous NH4Cl solution (100 mL) and extracted with EtOAc (70 mL, twice). The combined organic layers were washed with brine (70 mL), dried over Na2SO4, filtered and concentrated under vacuum to get a residue which was purified by silica gel column to get O1-tert-butyl O3-methyl 3-allyl pyrrolidine-1,3-dicarboxylate (Compound A3-b, 2.91 g) as colorless oil.

[0358] Step 2: Preparation of O1-tert-butyl O3-methyl 3-(2-oxoethyl) pyrrolidine-1,3-dicarboxylate (Compound A3-c)

[0359] To a mixture of O1-tert-butyl O3-methyl 3-allyl pyrrolidine-1,3-dicarboxylate (Compound A3-b, 2.1 g, 7.8 mmol) in 1,4-dioxane (60 mL) and water (6 mL) was added 2,6-dimethylpyridine (1.8 mL, 15.6 mmol) and K2OsO4(0.1 g, 0.39 mmol) in one portion at 0 °C. After stirring for 15 min at 0 °C, sodium metaperiodate (6.6 g, 31.19 mmol) was added portion wise at 0 °C. The resulting mixture was allowed to warm to 20 °C and stirred for another 6 h. After completion of the reaction, it was quenched with saturated aqueous Na2S2O3 solution (100 mL) and the reaction mixture was extracted with EtOAc (50 mL, thrice). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to get O1-tert-butyl O3-methyl 3-(2-oxoethyl) pyrrolidine-1,3-dicarboxylate (Compound A3-c, 2.1 g) as yellow oil which was used directly for the next step.

[0360] Step 3: Preparation of O1-tert-butyl O3-methyl 3-[2-[[(1S)-1-benzyloxycarbonyl-2-methyl- propyl]amino]ethyl]pyrrolidine-1,3-dicarboxylate (Compound A3-d)

[0361] To a mixture of O1-tert-butyl O3-methyl 3-(2-oxoethyl)pyrrolidine-1,3-dicarboxylate (Compound A3-c, 2.1 g, 7.74 mmol) and (2S)-2-amino-3-methyl-benzyl butanoate (1.6 g, 7.74 mmol) in methanol (20 mL) was added zinc chloride (1.05 g, 7.74 mmol) in one portion at 0 °C. After stirring at 0 °C for 1 h, sodium cyanoborohydride (0.97 g, 15.48 mmol) was added to the mixture at 0 °C. The resulting mixture was stirred at 0 °C for another 2 h. After the reaction was complete, the mixture was poured into saturated aqueous NH4Cl solution (40 mL) at 0 °C, and extracted with EtOAc (50 mL, three times). The combined organic layers were washed with brine (30 mL, four times), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue, which was purified by silica gel column to give O1-tert-butyl O3-methyl 3-[2-[[(1S)-1-benzyloxycarbonyl-2-methyl-propyl]amino]ethyl]pyrrolidine-1,3-dicarboxylate (Compound A3-d, 2.2 g) as a yellow oil. MS calculated for 463.3 (MH + ) ; found 463.2 (MH + ).

[0362] Step 4: Preparation of (5R)-2-[(1S)-1-benzyloxycarbonyl-2-methyl-propyl]-1-oxo-2,7-diazaspiro[4.4]nonane-7-carboxylic acid tert-butyl ester (Compound A3-e) and (5S)-2-[(1S)-1-benzyloxycarbonyl-2-methyl-propyl]-1-oxo-2,7-diazaspiro[4.4]nonane-7-carboxylic acid tert-butyl ester (Compound A3-f).

[0363] To a mixture of O1-tert-buty1 O3-methyl 3-[2-[[(1S)-1-benzyloxycarbonyl-2- methyl-propyl]amino]ethyl]pyrrolidine-1,3-dicarboxylate (Compound A3-d, 2.1 g, 4.54 mmol) in toluene (20 mL) was added DIEA (7.9 mL, 45.4 mmol) and DMAP (0.6 g, 4.54 mmol) in one portion. The mixture was heated to 80 °C and stirred for 16 hours. After the reaction was completed, the mixture was poured into water (30 mL) and extracted with EtOAc (30 mL) three times. The combined organic layer was washed with brine (30 mL), dried over anhydrous Na2S04, filtered, and concentrated under vacuum to give a residue, which was purified by reverse phase flash column and the eluent was concentrated under vacuum. The residue was further separated by preparative SFC to give (5R)-2-[(1S)-1-benzyloxycarbonyl-2-methyl-propyl]-1-oxo-2,7- diazaspiro[4.4]nonane-7-carboxylic acid tert-butyl ester (Compound A3-e, faster elution, 521 mg) and (5S)-2-[(1S)-1-benzyloxycarbonyl-2-methyl-propyl]-1-oxo-2,7- diazaspiro[4.4]nonane-7-carboxylic acid tert-butyl ester (Compound A3-f, slower elution, 525 mg). MS calculated for 453.3 (MNa + ) ; found 453.2 (MNa + ).

[0364] SFC conditions: Instrument: SFC 150 Mgm; Column: Chiralpak IG-3 50 x 4.6 mm I.D., 3um. Mobile phase: A is C02, Phase B is MEOH (0.05% DEA); Gradient elution: 40% B in A; Flow rate: 3 mL / min; Detector: DAD; Back pressure: 100 bar; Column temperature: 35 °C.

[0365] Step 5: Preparation of (2S)-2-[(5R)-7-tert-butoxycarbonyl-1-oxo-2,7- diazaspiro[4.4]nonan-2-yl]-3-methyl-butyric acid (Intermediate A3).

[0366] To a solution of (5R)-2-[(1S)-1-benzyloxycarbonyl-2-methyl-propyl]-1-oxo- 2,7-diazaspiro[4.4]nonane-7-carboxylic acid tert-butyl ester (Compound A3-e, 120 mg, 0.28 mmol) in toluene (2 mL) was added wet palladium (12 mg, 10% wt, on activated carbon). The mixture was degassed and purged with hydrogen gas 3 times. The reaction mixture was heated to 35 °C and stirred under hydrogen atmosphere for 3 hours. After completion of the reaction, the solution was filtered and the filtrate was concentrated in vacuum to give (2S)-2-[(5R)-7-tert-butoxycarbonyl-1-oxo-2,7- diazaspiro[4.4]nonan-2-yl]-3-methyl-butyric acid (Intermediate A3, 94 mg) as a white solid. MS calculated for C20H33N2O5(MNa + ) 363.1 (MNa + ).

[0367] X-ray crystallographic analysis of Intermediate A3

[0368] The absolute configuration of Intermediate A3 was confirmed by X-ray crystallographic analysis of its single crystal. (Figure 1)

[0369] Step 6: Preparation of (2S)-2-[(5S)-7-tert-butoxycarbonyl-1-oxo-2,7- diazaspiro[4.4]nonan-2-yl]-3-methyl-butyric acid (Intermediate A4).

[0370] To a solution of (5S)-2-[(1S)-1-benzyloxycarbonyl-2-methyl-propyl]-1-oxo- 2,7-diazaspiro[4.4]nonane-7-carboxylic acid tert-butyl ester (Compound A3-f, 120 mg, 0.28 mmol) in toluene (2 mL) was added wet palladium (12 mg, 10% wt, on activated carbon). The mixture was degassed and purged with hydrogen gas 3 times. The mixture was heated to 35 °C and stirred under hydrogen for 3 h. After completion of the reaction, the solution was filtered and the filtrate was concentrated in vacuum to give (2S)-2-[(5S)-7-tert-butoxycarbonyl-1-oxo-2,7- diazaspiro[4.4]nonan-2-yl]-3-methyl-butyric acid (Intermediate A4, 79 mg) as a white solid. MS calculated for C20H33N2O5(MNa + ) 363.1 (MNa + ).

[0371] X-ray crystallographic analysis of Intermediate A4

[0372] The absolute configuration of intermediate A4 was confirmed by X-ray crystallographic analysis of its single crystal. (Figure 2)

[0373] Intermediate B1

[0374] (3S)-1-[(2S)-2-(tert-Butoxycarbonylamino)-3-[3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-5-triisopropylsiloxyl-phenyl]propionyl]hexahydropyridazine-3- carboxylic acid methyl ester

[0375]

[0376] Intermediate B was prepared according to the following scheme:

[0377]

[0378] Step 1: Preparation of (2S)-2-amino-3-(3-hydroxyphenyl)propanoic acid methyl ester (Compound B1-b)

[0379] To a solution of L-M-tyrosine (Compound B1-a, 5.0 g, 27.6 mmol) in methanol (80 mL) was added sulfuryl chloride (10 mL, 137.9 mmol). The mixture was stirred at 60 °C for 12 hours. The reaction mixture was cooled to 20 °C and concentrated in vacuo to give (2S)-2-amino-3-(3-hydroxyphenyl)propanoic acid methyl ester (Compound B1-b, 6.2 g) as a yellow solid. 1 H NMR (400 MHz, CD3OD) δ = 7.18 (t, J = 8.0 Hz, 1H), 6.78- 6.66 (m, 3H), 4.29 (t, J = 6.4 Hz, 1H), 3.82 (s, 3H), 3.23 - 3.05 (m, 2H).

[0380] Step 2: Preparation of (2S)-2-(tert-butoxycarbonylamino)-3-(3-hydroxyphenyl)propanoic acid methyl ester (Compound B1-c)

[0381] To a solution of (2S)-2-amino-3-(3-hydroxyphenyl)propanoic acid methyl ester (Compound B1-b, 32.0 g, 138.1 mmol) in THF (80 mL) and water (20 mL) was added sodium bicarbonate (40.6 g, 483.4 mmol) followed by di-tert-butyl dicarbonate (33.1 g, 151.9 mmol) at 20 °C. The mixture was stirred at 20 °C for 12 h. The mixture was diluted with water (100 mL) and acidified with 1 M aqueous HC1 until pH = 5. The mixture was extracted with ethyl acetate (100 mL) for 3 times. The combined organic phase was washed with brine (80 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to give (2S)-2-(tert-butoxycarbonylamino)-3-(3-hydroxyphenyl)propanoic acid methyl ester (Compound B1-c, 40 g) as a colorless gum. MS: calc’d 318 (MNa + ); meas’d 318.3 (MNa + ).

[0382] Step 3: Preparation of (2S)-2-(tert-butoxycarbonylamino)-3-(3- triisopropylsilyloxyphenyl)propanoic acid methyl ester (Compound B1-d)

[0383] To a solution of (2S)-2-(tert-butoxycarbonylamino)-3-(3-hydroxyphenyl)propanoic acid methyl ester (Compound B1-c, 40.0 g, 135.4 mmol) and 1H-imidazole (27.6 g, 406.3 mmol) in DMF (400 mL) was added triisopropylsilyl chloride (39.1 g, 203.1 mmol) dropwise at 0 °C. After stirring at 25 °C for 12 h, the mixture was diluted with water (250 mL) and extracted with ethyl acetate (200 mL, 3 times) at 0 °C. The combined organic phase was washed with brine (80 mL) for 4 times, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to give a residue. The residue was purified by silica gel chromatography (EA / PE: 0 to 20%) to give (2S)-2-(tert-butoxycarbonylamino)-3-(3-triisopropylsilyloxyphenyl)propanoic acid methyl ester (Compound B1-d, 60 g) as a yellow oil. MS: calc’d 474 (MNa + ); meas’d 474.2 (MNa + ).

[0384] Step 4: Preparation of (2S)-2-(tert-butoxycarbonylamino)-3-[3-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-5-triisopropylsilxyoxy-phenyl]propionic acid methyl ester (Compound B1 -e)

[0385] To a solution of (2S)-2-(tert-butoxycarbonylamino)-3-(3- triisopropylsilxyoxyphenyl)propionic acid methyl ester (Compound B1 -d, 15.0 g, 33.2 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (2.6 g, 9.9 mmol) and bis(pinacolato)diboron (12.6 g, 49.8 mmol) in hexane (200 mL) was added [lr(OMe)(COD)]2(2.2 g, 3.3 mmol). The mixture was degassed and purged with N2three times. The resulting mixture was stirred at 70 °C for 12 hours. The reaction mixture was then cooled to 20 °C, diluted with petroleum ether (100 mL) and filtered. The filtrate was concentrated in vacuo to give a residue which was purified by silica gel chromatography (EA / PE: 0 to 20%) to give (2S)-2-(tert-butoxycarbonylamino)-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5- triisopropylsilxyoxy-phenyl]propionic acid methyl ester (Compound B1 -e, 21 g) as a yellow oil. MS: calc. 600 (MNa + ) ; found 600.3 (MNa + ).

[0386] Step 5: Preparation of (2S)-2-(tert-butoxycarbonylamino)-3-[3-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-5-triisopropylsilxyoxy-phenyl]propionic acid (Compound B1 -f)

[0387] To a solution of (2S)-2-(tert-butoxycarbonylamino)-3-[3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-5-triisopropylsilanyloxy-phenyl]propionic acid methyl ester (Compound B1 -e, 40.0 g, 69.2 mmol) in methanol (300 mL) was added a solution of lithium hydroxide (3.2 mL, 346.2 mmol) in water (100 mL). After stirring at 20 °C for 1 h, the reaction mixture was diluted with water (200 mL) and the MeOH was removed under vacuum. The resulting mixture was acidified with 1 M aqueous HC1 until pH = 5. The resulting mixture was extracted with EtOAc (250 mL) 3 times. The organic phase was washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuum to give (2S)-2-(tert-butoxycarbonylamino)-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5- triisopropylsilanyloxy-phenyl]propanoic acid (Compound B1 -f, 33 g) as a white solid. MS: calc. 586 (MNa + ) ; found 586.3 (MNa + ).

[0388] Step 6: Preparation of (3S)-1 -[(2S)-2-(tert-butoxycarbonylamino)-3-[3-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-5-triisopropylsilanyloxy-phenyl]propanoyl]hexahydropyridazine-3- carboxylic acid methyl ester (Intermediate B1 )

[0389] To a solution of (2S)-2-(tert-butoxycarbonylamino)-3-[3-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-5-triisopropylsilanyloxy-phenyl]propionic acid (Compound B1 -f, 8.0 g, 14.1 mmol) and O-(7-azabenzotriazol-1 -yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (5.6 g, 14.9 mmol) in DMF (100 mL) was added N,N-diisopropylethylamine (6.4 g, 49.6 mmol). The mixture was stirred at 0 °C for 10 minutes. Then (3S)-methyl hexahydropyridazine-3-carboxylate hydrochloride (Compound B1 -g, 2.6 g, 14.9 mmol) was added. The resulting mixture was stirred at 20 °C for 1.5 hours, then diluted with water (200 mL) and extracted with EtOAc (100 mL, twice). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography to give (3S)-1 -[(2S)-2-(tert- butoxycarbonylamino)-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5- triisopropylsilanyloxy-phenyl]propanoyl]methyl hexahydropyridazine-3-carboxylate (Intermediate B1, 7.8 g) as a yellow oil. MS: calc’d 690 (MH + ); measured 690.4 (MH + ).

[0390] Intermediate B2

[0391] (3S)-1 -[(2S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)- propanoyl]methyl hexahydropyridazine-3-carboxylate

[0392]

[0393] Intermediate B2 was prepared according to the following scheme:

[0394]

[0395] Step 1 : Preparation of (4-bromothiazol-2-yl)methanol (Compound B2-b)

[0396] To a solution of 4-bromothiazole-2-carbaldehyde (compound B2-a, 6.0 g, 31.25 mmol) in methanol (70 mL) was added sodium borohydride (1.7 g, 46.87 mmol) at 0 °C. The mixture was stirred at 25 °C for 1 h. The reaction was quenched with water (300 mL) at 0 °C and the reaction mixture was extracted with ethyl acetate (200 mL, thrice). The combined organic phase was washed with brine (150 mL, twice), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under vacuum to give (4-bromothiazol-2-yl)methanol (compound B2-b, 6 g) as a colorless oil.

[0397] Step 2: Preparation of 4-bromo-2-(bromomethyl)thiazole (compound B2-c)

[0398] To a solution of (4-bromothiazol-2-yl)methanol (compound B2-b, 6.0 g, 30.92 mmol) in DCM (80 mL) was added CBr4(15.4 g, 46.38 mmol) and triphenylphosphine (12.1 g, 46.38 mmol) at 0 °C. After stirring at 25 °C for 1 h, the mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel column with ethyl acetate in petroleum ether (0 to 10%) as eluent to give (4-bromothiazol-2-yl)methanol (compound B2-c, 6.0 g) as a yellow oil. MS calculated 255.9 (MH + ) ; found 255.9 (MH + ).

[0399] Step 3: Preparation of 4-bromo-2-[[(2S,5R)-5-isopropyl-3,6-dimethoxy-2,5- dihydropyrazin-2-yl]methyl]thiazole (compound B2-e)

[0400] To a mixture of (R)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine (compound B2-d, 4.3 g, 23.45 mmol) in THF (60 mL), n-butyllithium (10 mL, 25.22 mmol, 2.5 M) was slowly added at -78 °C. After addition, the mixture was stirred at -78 °C for 0.5 h. To the above mixture, 4-bromo-2-(bromomethyl)thiazole (compound B2-c, 5.4 g, 21.02 mmol) was added at -78 °C, and the mixture was stirred for another 1 h. The reaction was quenched with saturated NH4Cl solution (100 mL), and the reaction mixture was extracted with EtOAc (100 mL, twice). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The residue was purified by reversed-phase chromatography to give 4-bromo-2-[[(2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2-yl]methyl]thiazole (compound B2-e, 3.6 g), a yellow oil. MS calculated value 360 ​​(MH). + ); Measured value 359.9 (MH) + ).

[0401] Step 4: Preparation of (2S)-2-amino-3-(4-bromothiazol-2-yl)propionate (compound B2-f)

[0402] Hydrochloric acid (66.6 mL, 0.3 M) was added to a solution of 4-bromo-2-[[(2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2-yl]methyl]thiazole (compound B2-e, 3.6 g, 10 mmol) in ACN (20 mL). The mixture was stirred at 25 °C for 2 h. The mixture was alkalized with saturated NaHCO3 solution until pH = 8. The mixture was extracted twice with EtOAc (80 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to give methyl (2S)-2-amino-3-(4-bromothiazol-2-yl)propionate (compound B2-f, 3.1 g) as a yellow oil. MS calculated value 264.9 (MH) + ); Measured value 264.9 (MH) + ).

[0403] Step 5: Preparation of methyl (2S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)propionate (compound B2-g)

[0404] To a solution of (2S)-2-amino-3-(4-bromothiazol-2-yl)propionic acid methyl ester (Compound B2-f, 3.1 g, 11.69 mmol) in DCM (40 mL) was added triethylamine (2.9 g, 29.23 mmol) and (Boc)20 (3.8 g, 17.54 mmol). After stirring at 30 °C for 12 h, the mixture was concentrated under vacuum. The residue was purified by silica gel column eluted with ethyl acetate in petroleum ether (0 to 30%) to give (2S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)propionic acid methyl ester (Compound B2-g, 3.2 g) as a yellow oil. MS calculated for C14H19BrN2O4(MNa + ) 386.9 (MNa + ).

[0405] Step 6: Preparation of (2S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)- propionic acid (Compound B2-h)

[0406] To a solution of (2S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)propionic acid methyl ester (Compound B2-g, 3.2 g, 8.76 mmol) in THF (30 mL), methanol (2 mL) and water (10 mL) was added lithium hydroxide (0.4 mL, 43.81 mmol). After stirring at 25 °C for 1 h, the reaction mixture was acidified with 1 M HC1 solution until pH = 5. The mixture was extracted with EtOAc (40 mL) twice. The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to give (2S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)propionic acid (Compound B2-h, 3.1 g) as a yellow oil. MS calculated for C13H17BrN2O4(MNa + ) 372.9 (MNa + ).

[0407] Step 7: Preparation of (3S)-1-[(2S)-3-(4-bromothiazol-2-yl)-2-(tert- butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylic acid methyl ester (Intermediate B2)

[0408] To a solution of (2S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)propanoic acid (Compound B2-h, 3.1 g, 8.83 mmol) in DCM (50 mL) was added (3S)-methyl hexahydropyridazine-3-carboxylate; hydrochloride (Compound B1-g, 2.4 g, 13.24 mmol), EDCI (3.4 g, 17.65 mmol), 1-hydroxybenzotriazole (238.5 mg, 1.77 mmol) and NMM (9.92 mL, 88.26 mmol) at 0 °C. After stirring at 25 °C for 1 h, the reaction mixture was diluted with water (60 mL) and extracted with EtOAc (60 mL, three times). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel column and eluted with ethyl acetate in petroleum ether (10% to 30%) to give (3S)-methyl 1-[(2S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylate (Intermediate B2, 2.4 g). MS calculated for C21H29BrN4O5(MH+) 517.1, found 517.1 (MH + ). +

[0409] Intermediate C1

[0410] 4-[5-ethynyl-6-[(1S)-1-methoxyethyl]-3-pyridinyl]piperazine-1-carboxylic acid benzyl ester

[0411]

[0412] Compound C1 was prepared according to the following scheme:

[0413]

[0414] Step 1: Preparation of 4-[5-bromo-6-[(1S)-1-methoxyethyl]-3-pyridinyl]piperazine-1-carboxylic acid benzyl ester (Compound C1-b)

[0415] ​To a solution of 3-bromo-5-iodo-2-[(1S)-1-methoxyethyl]pyridine (compound C1-a, 660 mg, 1.9 mmol, CAS 2641451-76-3, PBWZ170, PharmaBlock (Nanjing) R&D Co. Ltd) and 1-Cbz-piperazine (compound C1-b, 425.1 mg, 1.9 mmol) in toluene (10 mL) was added cesium carbonate (1.6 g, 4.83 mmol), (R)-BINAP (60.1 mg, 0.1 mmol) and palladium(II) acetate (43.3 mg, 0.19 mmol). After stirring at 100 °C for 12 hours under N2protection, the mixture was filtered, and then the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (EA / PE: 0 to 50%) to give 4-[5-bromo-6-[(1S)-1-methoxyethyl]-3-pyridyl]benzyl piperazine-1-carboxylate (compound C1-b, 740 mg) as a yellow solid. MS calculated 434.1 (MH + ) ; found 434.1 (MH + ).

[0416] Step 2: Preparation of 4-[6-[(1S)-1-methoxyethyl]-5-(2-trimethylsilylethynyl)-3-pyridyl]benzyl piperazine-1-carboxylate (compound C1-a)

[0417] To a solution of 4-[5-bromo-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1- carboxylate benzyl ester (Compound C1-b, 33.0 g, 75.98 mmol) in DMF (1 L) was added trimethylsilyl acetylene (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 nitrogen atmosphere. The reaction mixture was degassed with nitrogen three times and then the reaction mixture was stirred at 100 °C for 12 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered and to the filtrate was added H2O (3 L). The reaction mixture was extracted with EtOAc (1 L, three times). The combined organic layer was washed with brine (3 L), dried over Na2SO4, filtered and concentrated under vacuum to get a residue which was purified by column chromatography to get 4-[6-[(1S)-1-methoxyethyl]-5-(2-trimethylsilyl ethynyl)-3-pyridyl]piperazine-1-carboxylate benzyl ester (Compound C1-c, 21.0 g) as a yellow solid. MS calculated for C28H39N4O4Si 452.2 (MH + ); found 452.2 (MH + ).

[0418] Step 3: Preparation of 4-[5-ethynyl-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1- carboxylate benzyl ester (Intermediate D1)

[0419] To a solution of 4-[6-[(1S)-1-methoxyethyl]-5-(2-trimethylsilyl ethynyl)-3-pyridyl]piperazine-1-carboxylate benzyl ester (Compound C1-c, 31 g, 68.6 mmol) in methanol (500 mL) was added potassium fluoride (8.1 g, 139.8 mmol) at 0 °C. The mixture was stirred at 20 °C for 1 hour. After completion of the reaction, the reaction mixture was concentrated under vacuum to get a residue which was purified by column chromatography to get 4-[5-ethynyl-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate benzyl ester (Intermediate C1, 25 g) as a brown solid. MS calculated for C22H25N4O3 380.2 (MH + ); found 380.2 (MH + ).

[0420] Intermediate C2

[0421] 4-[5-ethynyl-6-[(1S)-1-methoxyethyl]-3-pyridyl]morpholine

[0422]

[0423] The title compound was prepared in analogy to the preparation of Intermediate C1 by using morpholine instead of 1-Cbz-piperazine.

[0424] Intermediate C3

[0425] 1-[5-ethynyl-6-[(1S)-1-methoxyethyl]-3-pyridyl]-4-(2,2,2-trifluoroethyl)piperazine

[0426]

[0427] The title compound was prepared in analogy to the preparation of Intermediate C1 by using 1-(2,2,2-trifluoroethyl)piperazine instead of 1-Cbz-piperazine.

[0428] Intermediate C4

[0429] 3-ethynyl-2-[(1S)-1-methoxyethyl]pyridine

[0430]

[0431] The title compound was prepared in analogy to the preparation of Intermediate C1 by using 3-bromo-2-[(1S)-1-methoxyethyl]pyridine (CAS 2641451-44-5, PBU8238, PharmaBlock (Nanjing) R&D Co. Ltd) instead of 4-[5-bromo-6-[(1S)-1-methoxyethyl]-3-pyridyl]benzyl piperazine-1-carboxylate (Compound C1-b).

[0432] Intermediate D1

[0433] 6-bromo-8-iodo-1,2,3,4-tetrahydroquinoline

[0434]

[0435] The compound was prepared according to the following scheme:

[0436]

[0437] To a solution of 6-bromo-l,2,3,4-tetrahydroquinoline (compound Dl-a, 40.0 g, 188.6 mmol) in DMF (1.3 L) was added NIS (42.4 g, 188.6 mmol) in portions at 0 °C. After stirring at 25 °C for 2 h, the reaction mixture was poured into water (4 L) and extracted with EtOAc (2 L, three times). The combined organic layers were washed with brine (2 L, three times), dried over anhydrous Na2S04, filtered, and concentrated under vacuum to give a residue. The residue was purified by reverse phase chromatography to give 6-bromo-8-iodo-l,2,3,4-tetrahydroquinoline (Intermediate Dl, 37 g) as a brown gum. MS calculated 337.9 (MH + ); measured 338.0 (MH + ).

[0438] Intermediate D2

[0439] 7-bromo-5-iodo-3,4-dihydro-2H-l,4-benzoxazine

[0440]

[0441] The compound was prepared according to the following scheme:

[0442]

[0443] Step 1: Preparation of (2-amino-5-bromo-phenyl) 4-methylbenzenesulfonate (compound D2-b)

[0444] To a solution of 2-amino-5-bromophenol (compound D2-a, 75.0 g, 398.89 mmol) and TEA (66.7 mL, 478.67 mmol) in DCM (1.5 L) was added p-toluenesulfonyl chloride (83.6 g, 438.78 mmol). After stirring at 25 °C for 1 h, the reaction was quenched with saturated aqueous NaHC03solution (400 mL) and EtOAc (500 mL, three times). The organic layer was washed with brine (200 mL), dried over Na2S04, filtered, and concentrated under vacuum to give crude (2-amino-5-bromo-phenyl) 4-methylbenzenesulfonate (compound D2-b, 146.5 g) as a dark brown solid, which was used in the next step without purification. MS calculated 342 (MH + ); measured 342 (MH + ).

[0445] Step 2: Preparation of (2-amino-5-bromo-3-iodo-phenyl) 4-methylbenzenesulfonate (Compound D2-c)

[0446] To a solution of (2-amino-5-bromo-phenyl) 4-methylbenzenesulfonate (Compound D2-b, 146.5 g, 428.1 mmol) in ethanol (1.5 L) was added silver sulfate (133.5 g, 428.1 mmol) and iodine (108.7 g, 428.1 mmol). After stirring at 25 °C for 12 h, the reaction was quenched by saturated aqueous NaHC03solution (400 mL) and EtOAc (500 mL, three times). The organic layer was washed with brine (200 mL), dried over Na2S04, filtered and concentrated under vacuum to give (2-amino-5-bromo-3-iodo-phenyl) 4-methylbenzenesulfonate (Compound D2-c, 210.0 g) as a dark brown solid, which was used directly in the next step without purification. MS calculated 467.8 (MH + ) ; found 467.8 (MH + ).

[0447] Step 3: Preparation of 2-amino-5-bromo-3-iodo-phenol (Compound D2-d)

[0448] To a solution of (2-amino-5-bromo-3-iodo-phenyl) 4-methylbenzenesulfonate (Compound D2-c, 210.0 g, 448.62 mmol) in ethanol (1.5 L) and THF (500 mL) was added sodium hydroxide (62.8 g, 1570.18 mmol). The mixture was heated to reflux for 1 h. After cooling to room temperature, the reaction mixture was concentrated under vacuum to give a residue. The residue was neutralized by using 6 N HC1 until pH = 7, and then extracted with EtOAc (1 L, twice). The combined organic layers were dried over Na2S04, filtered and concentrated under vacuum to give a residue. The crude product was purified by column chromatography to give 2-amino-5-bromo-3-iodo-phenol (Compound D2-d, 120.0 g) as a dark brown solid. MS calculated 313.9 (MH + ) ; found 313.9 (MH + ).

[0449] Step 4: Preparation of 7-bromo-5-iodo-4H-l,4-benzoxazin-3-one (Compound D2-e)

[0450] To a solution of 2-amino-5-bromo-3-iodo-phenol (compound D2-d, 50.0 g, 159.28 mmol) and potassium carbonate (33.0 g, 238.91 mmol) in DMF (2 L) was added chloroacetyl chloride (19.0 mL, 238.91 mmol). After stirring at 25 °C for 12 h, the reaction mixture was concentrated under vacuum to give a residue. The residue was poured into H2O (1 L) and extracted with EtOAc (1 L, three times). The organic layer was washed with brine (1.5 L, twice), dried over Na2S04, filtered and concentrated under vacuum to give a residue. The crude product was triturated with MTBE (100 mL) at 25 °C for 30 min. The suspension was filtered, and the filter cake was collected to give 7-bromo-5-iodo-4H-l,4-benzoxazin-3-one (compound D2-e, 175.0 g) as a dark brown solid. MS calculated 353.9 (MH + ) ; found 353.9 (MH + ).

[0451] Step 5: Preparation of 7-bromo-5-iodo-3,4-dihydro-2H-l,4-benzoxazine (Intermediate D2)

[0452] To a stirred solution of 7-bromo-5-iodo-4H-l,4-benzoxazin-3-one (compound D2-e, 20.0 g, 56.51 mmol) in THF (500 mL) was added borane tetrahydrofuran complex solution (113.0 mL, 113.01 mmol) at 0 °C under N2 atmosphere. After stirring at 80 °C for 1 h, the mixture was cooled to room temperature, followed by the addition of MeOH (100 mL). The mixture was poured into H2O (100 mL) and extracted with EtOAc (200 mL, three times). The organic layer was washed with brine (100 mL, twice), dried over Na2S04, filtered and concentrated under vacuum to give a residue. The crude product was purified by column chromatography to give 7-bromo-5-iodo-3,4-dihydro-2H-l,4-benzoxazine (Intermediate D2, 17.6 g) as a pink solid. MS calculated 340.0 (MH + ) ; found 340.0 (MH + ). 1H NMR (400 MHz, DMSO-d6) δ = 7.31 (d, J = 2.4 Hz, 1H), 6.88 (d, J = 2.4 Hz, 1H), 5.42 (br s, 1H),4.07 (t, J = 4.4 Hz, 2H), 3.38 - 3.33 (m, 2H).

[0453] Intermediate D3

[0454] 6-bromo-3,3-difluoro-8-iodo-2,4-dihydro-lH-quinoline

[0455]

[0456] The compound was prepared according to the following scheme:

[0457]

[0458] Step 1: Preparation of 3,3-difluoro-lH-quinoline-2,4-dione (Compound D3-b)

[0459] To a solution of lH-quinoline-2,4-dione (Compound D3-a, 8.0 g, 49.64 mmol) and potassium carbonate (13.7 g, 99.28 mmol) in ACN (160 mL) and water (80 mL) was added Selectfluor (40.0 g, 112.91 mmol) at 0 °C. After stirring at 25 °C for 1 h, the reaction mixture was concentrated in vacuo and the residue was filtered. The filtrate was added to water (1 L). The resulting mixture was extracted with EtOAc (400 mL, thrice). The combined organic layers were washed with brine (400 mL, twice), dried over Na2S04, filtered and concentrated in vacuo to give 3,3-difluoro-lH-quinoline-2,4-dione (Compound D3-b, 46.0 g) as a yellow solid. 1 H NMR (400 MHz, Chloroform-d) δ = 9.77 (s, 1H), 8.22 - 7.94 (m, 1H), 7.81 - 7.64 (m, 1H), 7.33 - 7.28 (m, 1H), 7.17 (d, J = 8.0 Hz, 1H).

[0460] Step 2: Preparation of 3,3-difluoro-2,4-dihydro-lH-quinolin-4-ol (Compound D3-c)

[0461] To a solution of 3,3-difluoro-lH-quinoline-2,4-dione (compound D3-b, 69.0 g, 350.01 mmol) in THF (700 mL) was added borane-tetrahydrofuran complex (700.0 mL, 700.0 mmol) at 0 °C. After stirring at 25 °C for 16 h, the reaction was quenched with MeOH (500 mL) dropwise at 0 °C, and then concentrated in vacuo to give 3,3-difluoro-2,4-dihydro-lH-quinolin-4-ol (compound D3-c, 64.8 g) as a yellow oil. MS calculated 185.1 (MH + ) ; found 168.0 (M-OH+H + ).

[0462] Step 3: Preparation of 3,3-difluoro-2,4-dihydro-lH-quinoline (compound D3-d)

[0463] To a solution of 3,3-difluoro-2,4-dihydro-lH-quinolin-4-ol (compound D3-c, 64.8 g, 349.95 mmol) in Et3SiH (206.8 mL, 1.29 mol) was added TFA (405.4 mL, 5.26 mol) at 0 °C. After stirring at 25 °C for 16 h, the reaction mixture was concentrated in vacuo and adjusted to pH = 8 by adding saturated aqueous NaHC03solution, extracted with EtOAc (1 L, twice). The combined organic layers were washed with brine (1.6 L), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue, which was purified by silica gel column chromatography to give 3,3-difluoro-2,4-dihydro-lH-quinoline (compound D3-d, 45.0 g) as a yellow solid. MS calculated 170.1 (MH + ) ; found 170.0 (MH + ).

[0464] Step 4: Preparation of 6-bromo-3,3-difluoro-2,4-dihydro-lH-quinoline (compound D3-e)

[0465] To a solution of 3,3-difluoro-2,4-dihydro-lH-quinoline (compound D3-d, 50.0 g, 295.56 mmol) in DMF (800 mL) was added NBS (50.0 g, 280.92 mmol) at 0 °C. After stirring at 0 °C for 1 h, the mixture was poured into water (1200 mL) and the resulting mixture was extracted with EtOAc (800 mL, thrice). The combined organic layers were washed with brine (1 L, thrice), dried over Na2S04, filtered and concentrated in vacuo which was purified by column chromatography to give 6-bromo-3,3-difluoro-2,4-dihydro-lH-quinoline (compound D3-e, 57.0 g) as a yellow solid. MS calculated for C8H6BrF2N 248.0 (MH + ) ; found 247.9 (MH + ).

[0466] Step 5: Preparation of 6-bromo-3,3-difluoro-8-iodo-2,4-dihydro-lH-quinoline (Intermediate D3)

[0467] To a solution of 6-bromo-3,3-difluoro-2,4-dihydro-lH-quinoline (compound D3-e, 49.0 g, 197.52 mmol) in DMF (700 mL) was added NIS (48.9 g, 217.28 mmol) at 0 °C. After stirring at 0 °C for 5 h, the reaction mixture was poured into water (1.2 L) and the resulting mixture was extracted with EtOAc (650 mL, thrice). The combined organic layers were washed with brine (1 L, thrice), dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by column chromatography to give 6-bromo-3,3-difluoro-8-iodo-2,4-dihydro-lH-quinoline (Intermediate D3, 68.0 g) as a white solid. MS calculated for C8H6Br2F2N 373.9 (MH + ) ; found 373.9 (MH + ).

[0468] Intermediate D4

[0469] 7-bromo-5-iodo-2,2-dimethyl-3,4-dihydro-l,4-benzoxazine

[0470]

[0471] The title compound was prepared in analogy to the preparation of Intermediate D2 by using 2-bromo-2-methyl-propionic acid ethyl ester instead of chloroacetyl chloride.

[0472] Intermediate D5

[0473] 7-bromo-5-iodo-3-methyl-3,4-dihydro-2H-l,4-benzoxazine

[0474]

[0475] The compound was prepared according to the following scheme:

[0476]

[0477] Step 1: Preparation of 7-bromo-5-iodo-3-methyl-2H-l,4-benzoxazine (Compound D5-a)

[0478] To a solution of 2-amino-5-bromo-3-iodo-phenol (Compound D2-d, 18 g, 57.34 mmol) in acetone (300 mL) was added potassium carbonate (15.8 g, 114.68 mmol) and chloroacetone (10.6 g, 114.68 mmol). After stirring at 25 °C for 18 h, the reaction mixture was poured into EtOAc (200 mL) / water (400 mL) and the layers were separated. The aqueous phase was extracted with EtOAc (200 mL, twice). The combined organic layers were washed with brine (300 mL), dried over Na2S04, filtered, and concentrated under vacuum to give a residue. The residue was purified by flash chromatography to give 7-bromo-5-iodo-3-methyl-2H-l,4-benzoxazine (Compound D5-a, 20 g) as a light brown solid. MS calculated 351.9 (MH + ); measured 351.9 (MH + ).

[0479] Step 2: Preparation of 7-bromo-5-iodo-3-methyl-3,4-dihydro-2H-l,4-benzoxazine (Intermediate D5)

[0480] To a solution of 7-bromo-5-iodo-3-methyl-2H-l,4-benzoxazine (Compound D5-a, 20.0 g, 60 mmol) in TFA (1 L, 12.98 mmol) was added sodium cyanoborohydride (17 g, 270 mmol) and then stirred at 25 °C for 2 hours. The mixture was slowly added to aqueous NaOH (150 mL, 2M) and then extracted with EtOAc (100 mL, twice). The organic layer was washed with water, brine, dried over sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by silica gel chromatography to give 7-bromo-5-iodo-3-methyl-3,4-dihydro-2H-l,4-benzoxazine (Intermediate D5, 14.6 g) as a brown thick oil. MS calc’d 353.9 (MH + ) ; found 353.9 (MH + ).

[0481] Intermediate D6

[0482] 9-bromo-7-iodo-3,4,5,6-tetrahydro-2H-l,6-benzoxazepine

[0483]

[0484] The compound was prepared according to the following scheme:

[0485]

[0486] Step 1: Preparation of tert-butyl N-(4-bromo-2-hydroxy-phenyl)carbamate (Compound D6-b)

[0487] To a solution of 2-amino-5-bromophenol (Compound D6-a, 15.0 g, 79.77 mmol) in anhydrous DCM (80 mL) was added (Boc)20 (26.1 g, 119.67 mmol) and TEA (22.2 mL, 159.57 mmol). After stirring at 25 °C for 15 hours, EtOAc (450 mL) and water (450 mL) were added to the reaction. The layers were separated and the aqueous phase was extracted with EtOAc (450 mL, twice). The combined organic layers were washed with brine (200 mL), dried over Na2S04, filtered and concentrated under vacuum to give a residue. The residue was purified by column chromatography to give tert-butyl N-(4-bromo-2-hydroxy-phenyl)carbamate (Compound D6-b, 11.85 g) as a yellow solid. MS calc’d 288.0 (MH +) ; found 231.6 (M-C4H8+H + ).

[0488] Step 2: Preparation of tert-butyl N-[4-bromo-2-[3-(l,3-dioxolan-2- yl)propoxy]phenyl]carbamate (Compound D6-d)

[0489] To a solution of tert-butyl N-(4-bromo-2-hydroxy-phenyl)carbamate (Compound D6-b, 10.0 g, 34.71 mmol) in anhydrous DMF (150 mL) was added 2-(3-bromopropyl)-l,3-dioxolane (Compound D6-c, 13.5 g, 69.44 mmol) and TEA (14.51 mL, 104.12 mmol) at 25 °C. The mixture was then heated to 90 °C and stirred for another 15 h. After the reaction was completed, EtOAc (300 mL) and water (200 mL) were added to the previous mixture and the layers were separated. The aqueous phase was extracted with EtOAc (250 mL, twice). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give a residue. The residue was purified by column chromatography to give tert-butyl N-[4-bromo-2-[3-(l,3-dioxolan-2-yl)propoxy]phenyl]carbamate (Compound D6-d, 12.6 g) as a yellow oil. MS calculated for 402.0 (MH + ), found 423.8 (MNa + ).

[0490] Step 3: Preparation of 9-bromo-3,4,5,6-tetrahydro-2H-l,6-benzoxazepine (Compound D6-e)

[0491] To a solution of tert-butyl N-[4-bromo-2-[3-(1,3-dioxolan-2-yl)propoxy]phenyl]carbamate (Compound D6-d, 7.1 g, 17.65 mmol) in DCM (500 mL) was added TFA (125 mL) dropwise via syringe at 0 °C under nitrogen atmosphere. After stirring at 25 °C for 1 h, triethylsilane (10.3 g, 88.25 mmol) was added to the reaction and then stirred at 25 °C for another 4 h. After the reaction was completed, the mixture was concentrated under vacuum to give a residue. EtOAc (500 mL) and saturated aqueous NaHCO3 solution (500 mL) were added to the residue and the layers were separated. The aqueous phase was extracted with EtOAc (500 mL, twice). The combined organic layers were washed with brine (400 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give a residue. The residue was purified by column chromatography to give 9-bromo-3,4,5,6-tetrahydro-2H-1,6-benzoxazepine (Compound D6-e, 2.9 g) as an orange solid. MS calculated for C9H10BrNO 242.0 (MH + ); measured 242.0 (MH + ).

[0492] Step 4: Preparation of 9-bromo-7-iodo-3,4,5,6-tetrahydro-2H-1,6-benzoxazepine (Intermediate D6)

[0493] To a solution of 9-bromo-3,4,5,6-tetrahydro-2H-1,6-benzoxazepine (Compound D6-e, 2.8 g, 11.56 mmol) in acetic acid (100 mL) was slowly added NIS (3.9 g, 17.35 mmol). The mixture was stirred at 25 °C for 15 h. After the reaction was completed, the mixture was concentrated in vacuum. The residue was purified by reverse phase column chromatography to give 9-bromo-7-iodo-3,4,5,6-tetrahydro-2H-1,6-benzoxazepine (Intermediate D6, 1.2 g) as a brown solid. MS calculated for C9H9BrI NO 367.9 (MH + ); measured 367.9 (MH + ).

[0494] Intermediate D7

[0495] 8-bromo-6-iodo-2,3,4,5-tetrahydro-1,5-benzoxazepine

[0496]

[0497] The title compound is prepared in analogy to the preparation of intermediate D6 by using 2-(2-bromoethyl)-1,3-dioxolane instead of 2-(3-bromopropyl)-1,3-dioxolane (compound D6-c).

[0498] Intermediate D8

[0499] 6-bromo-8-iodo-3,3-dimethyl-2,4-dihydro-1 H-quinoline

[0500]

[0501] The title compound is prepared in analogy to the preparation of intermediate D1 by using 6-bromo-3,3-dimethyl-2,4-dihydro-1 H-quinoline instead of 6-bromo-1,2,3,4-tetrahydroquinoline (compound D1 -a).

[0502] Intermediate E

[0503] (7S,13S)-7-amino-(20M)-20-[2-[(1 S)-1 -methoxyethyl]-5-(4-methylpiperazin-1 -yl)-3- pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31 -tetraazahexacyclo[23.3.1.1 2,5 .1 9, 13 .0 19,27 .0 21,26 ]thirty-one carbon-1 (28),2,5(31 ),19,25(29),26-hexaene-8,14-dione

[0504]

[0505] The compounds are prepared according to the following schemes:

[0506]

[0507]

[0508]

[0509] Step 1 : Preparation of 4-[5-[2-(6-bromo-1,2,3,4-tetrahydroquinolin-8-yl)ethynyl]-6-[(1 S)-1 - methoxyethyl]-3-pyridyl]piperazine-1 -carboxylic acid benzyl ester (compound E1 ).

[0510] To a solution of 4-[6-[(1S)-1-methoxyethyl]-5-(2-trimethylsilylethynyl)-3- pyridyl]piperazine-1-carboxylic acid benzyl ester (Intermediate C1, 26.1 g, 68.8 mmol) in DMF (400 mL) was added 6-bromo-8-iodo-1,2,3,4-tetrahydroquinoline (Intermediate D1, 23.3 g, 68.8 mmol), TEA (47.9 mL, 343.92 mmol), CuI (0.3 mL, 6.88 mmol) and Pd(PPh3)2Cl2(4.8 g, 6.88 mmol). The reaction mixture was degassed and purged with nitrogen three times, and then the reaction mixture was stirred at 25 °C for 12 hours. 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 layers were washed with brine (800 mL, four times), dried over Na2SO4, filtered and concentrated under vacuum to give a residue, which was purified by column chromatography to give 4-[5-[2-(6-bromo-1,2,3,4-tetrahydroquinolin-8-yl)ethynyl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylic acid benzyl ester (Compound E1, 30.0 g) as a yellow solid. MS calculated for C39H45BrN4O4(MH+) 689.2 (MH + ) found 689.2 (MH + ).

[0511] Step 2: Preparation of 4-[5-(6-bromo-1-azatricyclo[6.3.1.0 4,12 ]dodeca-2,4,6,8(12)-tetraen-2-yl)-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylic acid benzyl ester (Compound E2).

[0512] To a solution of 4-[5-[2-(6-bromo-l,2,3,4-tetrahydroquinolin-8-yl)ethynyl]-6-[(lS)-l- methoxyethyl]-3-pyridyl]piperazine-l-carboxylic acid benzyl ester (Compound El, 27.0 g, 45.8 mmol) in DMF (270 mL) was added PdCl2(1.6 g, 9.16 mmol) in one portion. The reaction mixture was degassed under vacuum, flashed with nitrogen three times, and then heated to 70 °C for 16 h. After cooling to room temperature, the mixture was poured into water (800 mL) and extracted with EtOAc (300 mL, three times). The combined organic layers were washed with brine (300 mL, three times), dried over Na2SO4, filtered, and concentrated under vacuum to give a residue, which was purified by column chromatography to give 4-[5-(6-bromo- 1 -azatricyclo[6.3.1.0 4,12 ]dodeca-2,4,6,8(12)-tetraen-2-yl)-6-[(lS)-l-methoxyethyl]-3-pyridyl]piperazine-l- carboxylic acid benzyl ester (Compound E2, 19.2 g). MS calculated 589.2 (MH + ) ; found 589.2 (MH +

[0513] Step 3: Preparation of 4-[5-(6-bromo-3-formyl-l-azatricyclo[6.3.1.0 4,12 ]dodeca-2,4,6,8(12)-tetraen-2-yl)-6-[(lS)-l-methoxyethyl]-3-pyridyl]piperazine-l- carboxylic acid benzyl ester (Compound E3).

[0514] Phosphorus oxychloride (30.4 mL, 325.69 mmol) was slowly added dropwise to DMF (350 mL) at 0 °C. After stirring at 0 °C for 0.5 h, 4-[5-(6-bromo-l-azatricyclo[6.3.1.0 4,12 ​A solution of 1,2-(1S)-2,4,6,8(12)-tetraen-2-yl)-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylic acid benzyl ester (compound E2, 19.2 g, 32.57 mmol) in DMF (150 mL). The reaction mixture was heated to 45 °C and then stirred for 1 h. The reaction was quenched with saturated aqueous NaHCO3 solution (1.5 L) and extracted with EtOAc (500 mL, three times). The organic phase was washed with brine (500 mL, three times), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give a residue. The residue was purified by column chromatography to give a yellow solid of 4-[5-(6-bromo-3-formyl-1-azatricyclic[6.3.1.0] 4,12 [1S-2,4,6,8(12)-tetraen-2-yl)-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylic acid benzyl ester (compound E3, 14.6 g). MS calculated value 616.9 (MH) + ); Measured value 617.2 (MH) + ).

[0515] Step 4: 4-[5-[6-bromo-3-(1-hydroxy-3-methoxy-2,2-dimethyl-3-oxopropyl)-1-azatricyclo[6.3.1.0] 4,12 Preparation of 2,4,6,8(12)-tetraen-2-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylic acid benzyl ester (compound E4)

[0516] Under a nitrogen atmosphere, at -70°C, LDA (65.58 mL, 131.17 mmol) was added dropwise to a solution of methyl isobutyrate (13.4 g, 131.17 mmol) in THF (150 mL). After stirring for 0.5 h, 4-[5-(6-bromo-3-formyl-1-azatricyclo[6.3.1.0]) was added dropwise to the reaction mixture. 4,12A solution of benzyl 4-[5-[6-bromo-3-(1-hydroxy-3-methoxy-2,2-dimethyl-3- oxopropyl)-1-azatricyclo[6.3.1.0 4,12 ]dec-2,4,6,8(12)-tetraen-2-yl]-6-[(1S)-1-methoxyethyl]-3-pyridinyl]piperazine-1- carboxylate (Compound E4, 14.01 g). MS calculated 719.3 (MH + ); measured 719.2 (MH + ).

[0517] Step 5: Preparation of benzyl 4-[5-[6-bromo-3-(3-methoxy-2,2-dimethyl-3-oxo- propyl)-1-azatricyclo[6.3.1.0 4,12 ]dec-2,4,6,8(12)-tetraen-2-yl]-6-[(1S)-1-methoxyethyl]-3-pyridinyl]piperazine-1- carboxylate (Compound E5)

[0518] To a solution of benzyl 4-[5-[6-bromo-3-(3-methoxy-2,2-dimethyl-3-oxo-propyl)-1- azatricyclo[6.3.1.0 4,12To a solution of benzyl 4-[5-[6-bromo-3-(3-methoxy-2,2-dimethyl-3-oxo- propyl)-1 -azatricyclo[6.3.1.0 4,12 ]dodeca-2,4,6,8(12)-tetraen-2-yl]-6-[(1S)-1 -methoxyethyl]-3-pyridinyl]piperazine-1 - carboxylate (Compound E5, 14 g). MS calculated 703.2 (MH + ) ; measured 703.2 (MH + ).

[0519] Step 6: Preparation of 4-[(5M)-5-[6-bromo-3-(3-hydroxy-2,2-dimethyl-propyl)-1 - azatricyclo[6.3.1.0 4 ,12 ]dodeca-2,4,6,8(12)-tetraen-2-yl]-6-[(1S)-1 -methoxyethyl]-3-pyridinyl]piperazine-1 - carboxylate (Compound E6)

[0520] To a solution of benzyl 4-[5-[6-bromo-3-(3-methoxy-2,2-dimethyl-3-oxo- propyl)-1 -azatricyclo[6.3.1.0 4,12To a solution of benzyl [6-[(1S)-1-methoxyethyl]-3-pyridinyl]-4-[(5M)-5-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(3-hydroxy-2,2-dimethyl- propyl)-1-azatricyclo[6.3.1.0 4,12 ]dodeca-2,4,6,8(12)-tetraen-2-yl]-6-[(1S)-1-methoxyethyl]-3-pyridinyl]piperazine-1- carboxylate (Compound E6, 7 g, faster eluting). MS calculated 675.3 (MH + ) ; measured 675.2 (MH + ).

[0521] Step 7: Preparation of benzyl [6-[(1S)-1-methoxyethyl]-3-pyridinyl]-4-[(5M)-5-[3-(3- hydroxy-2,2-dimethyl-propyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1- azatricyclo[6.3.1.0 4,12 ]dodeca-2,4(12),5,7-tetraen-2-yl]-6-[(1S)-1-methoxyethyl]-3-pyridinyl]piperazine-1- carboxylate (Compound E7)

[0522] To a solution of benzyl [6-[(1S)-1-methoxyethyl]-3-pyridinyl]-4-[(5M)-5-[6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(3-hydroxy-2,2-dimethyl-propyl)-1- azatricyclo[6.3.1.0 4,12To a solution of [3-(3-hydroxy-2,2-dimethyl-propyl)-6-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1-azatricyclo[6.3.1.0 4,12 ]dodeca-2,4(12),5,7-tetraen-2-yl]-6-[(1S)-1-methoxyethyl]-3-pyridinyl]piperazine-1- carboxylate (Compound E7, 7.3 g). MS calculated 723.4 (MH + ) ; found 723.4 (MH + ).

[0523] Step 8: Preparation of methyl (3S)-1-[(2S)-3-[4-[(2M)-2-[5-(4-benzyloxy-carbonylpiperazin-1- yl)-2-[(1S)-1-methoxyethyl]-3-pyridinyl]-3-(3-hydroxy-2,2-dimethyl-propyl)-1- azatricyclo[6.3.1.0 4,12 ]dodeca-2,4(12),5,7-tetraen-6-yl]thiazol-2-yl]-2-(tert-butoxycarbonylamino)propionyl] hexahydropyridazine-3-carboxylate (Compound E8)

[0524] To a solution of [3-(3-hydroxy-2,2-dimethyl-propyl)-6-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1-azatricyclo[6.3.1.0 4,12[Dodecyl-2,4(12),5,7-tetraen-2-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylic acid benzyl ester (compound E7, 6.8 g, 9.41 mmol) and (3S)-1-[(2S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)propionyl]hexahydropyridazine-3-carboxylic acid methyl ester (intermediate B2, 4.94 g, 10.35 mmol) were added in a single step to a solution of toluene (90 mL) / 1,4-dioxane (30 mL) / water (30 mL) with K3PO4 (5.0 g, 23.52 mmol) and Pd(dtbpf)Cl2 (613.2 mg, 0.94 mmol). The mixture was degassed, purged three times with nitrogen, and then stirred at 70 °C for 15 hours. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated under vacuum to obtain a residue. The residue was purified by column chromatography to give (3S)-1-[(2S)-3-[4-[(2M)-2-[5-(4-benzyloxycarbonylpiperazin-1-yl)-2-[(1S)-1-methoxyethyl]-3-pyridyl]-3-(3-hydroxy-2,2-dimethyl-propyl)-1-azatricyclo[6.3.1.0] as a yellow solid. 4,12 Methyl hexahydropyridazine-3-carboxylate (compound E8, 8.1 g). MS calculated value 993.7 (MH). + ); Measured value 993.7 (MH) + ).

[0525] Step 9: (3S)-1-[(2S)-3-[4-[(2M)-2-[5-(4-benzyloxycarbonylpiperazin-1-yl)-2-[(1S)-1-methoxyethyl]-3-pyridyl]-3-(3-hydroxy-2,2-dimethyl-propyl)-1-azatricyclo[6.3.1.0] 4,12 Preparation of [dodecano-2,4(12),5,7-tetraen-6-yl]thiazolyl]-2-(tert-butoxycarbonylamino)propionyl]hexahydropyridazine-3-carboxylic acid (compound E9)

[0526] To (3S)-1-[(2S)-3-[4-[(2M)-2-[5-(4-benzyloxycarbonylpiperazin-1-yl)-2-[(1S)-1-methoxyethyl]-3-pyridyl]-3-(3-hydroxy-2,2-dimethyl-propyl)-1-azatricyclo[6.3.1.0] 4,12Methyl hexahydropyridazine-3-carboxylate (compound E8, 8.1 g, 8.16 mmol) was added in a single addition of trimethyltin hydroxide (5.9 g, 32.62 mmol) to a mixture in a DCE (160 mL). After stirring at 60 °C for 16 hours, the reaction mixture was poured into water (200 mL) and extracted with EtOAc (100 mL, three times). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under vacuum to obtain (3S)-1-[(2S)-3-[4-[(2M)-2-[5-(4-benzyloxycarbonylpiperazin-1-yl)-2-[(1S)-1-methoxyethyl]-3-pyridyl]-3-(3-hydroxy-2,2-dimethyl-propyl)-1-azatricyclo[6.3.1.0], a brown solid. 4,12 [Dodeca-2,4(12),5,7-tetraen-6-yl]thiazolyl]-2-(tert-butoxycarbonylamino)propionyl]hexahydropyridazine-3-carboxylic acid (Compound E9, 7.9 g). MS calculated value 979.5 (MH). + ); Measured value 979.5 (MH) + ).

[0527] Step 10: 4-[(5M)-5-[(7S,13S)-7-(tert-butoxycarbonylamino)-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 Preparation of Benzyl Piperazine-1(28),2,5(31),19,25(29),26-hexen-20-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound E10)

[0528] At 0 °C, to (3S)-1-[(2S)-3-[4-[(2M)-2-[5-(4-benzyloxycarbonylpiperazin-1-yl)-2-[(1S)-1-methoxyethyl]-3-pyridyl]-3-(3-hydroxy-2,2-dimethyl-propyl)-1-azatricyclo[6.3.1.0] 4 ,12To a solution of [5M]-5-[(7S,13S)-7-(tert-butoxycarbonylamino)-17,17- dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]triaconta-l(28),2,5(31),19,25(29),26-hexaen-20-yl]-6-[(lS)-l- methoxyethyl]-3-pyridinyl]piperazine-l-carboxylic acid benzyl ester (Compound E10, 5.6 g). MS calculated 961.5 (MH + ) ; measured 961.5 (MH + ).

[0529] Step 11: Preparation of tert-butyl N-[(7S,13S)-(20M)-20-[2-[(lS)-l- methoxyethyl]-5-(4-methylpiperazin-l-yl)-3-pyridinyl]-17,17-dimethyl-8,14-dioxo- 15-oxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]triaconta-l(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamate (Compound El 1)

[0530] To a solution of [5M]-5-[(7S,13S)-7-(tert-butoxycarbonylamino)-17,17- dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.12,5 .1 9,13 .0 19,27 .0 21 ,26 A solution of benzyl [(7S, 13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridinyl]-6-[(1S)-1-methoxyethyl]-3-pyridinyl]piperazine-1- carboxylate (Compound E10, 5.6 g, 5.83 mmol) and formaldehyde (1.89 g, 23.3 mmol) in methanol (150 mL) was added with Pd(OH)2on charcoal (3.0 g, 2.91 mmol). The reaction mixture was degassed and purged with H2three times, and then the reaction mixture was stirred at 35 °C under H2(15 psi) for 15 hours. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated under vacuum to give a residue. EtOAc (50 mL) and water (50 mL) were added to the residue, and the layers were separated. The aqueous phase was extracted with EtOAc (50 mL, twice). The combined organic layers were washed with brine (60 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under vacuum to give N-[(7S, 13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3- pyridinyl]-6-[(1S)-1-methoxyethyl]-3-pyridinyl]-7,7-dimethyl-15-oxa-4-thia-9,21,30,31- tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 tert-Butyl [(7S, 13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3- pyridinyl]-6-[(1S)-1-methoxyethyl]-3-pyridinyl]carbamate (Compound E11, 3.9 g) was used in the next step without further purification. MS calcd 841.5 (MH + ); found 841.4 (MH + ).

[0531] Step 12: (7S, 13S)-7-Amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1- yl)-3-pyridinyl]-17, 17-dimethyl-15-oxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26Preparation of triaconta-l(28),2,5(31), 19,25(29),26-hexaen-8,14-dione (Intermediate E)

[0532] To a solution of tert-butyl (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridinyl]-17,17-dimethyl-15-oxa-4- thia-9,21,30,31-tetraazahexacyclo[23.3.1.1 2, 5 .1 9,13 .0 19,27 .0 21,26 ]triaconta-l(28),2,5(31),19,25(29),26-hexen-7-yl]carbamate (Compound E11, 3.9 g, 4.6 mmol) in DCM (30 mL) was added TFA (15.0 mL) in one portion. After stirring at 25 °C for 1 h, the mixture was poured into water (100 mL) and extracted with EtOAc (200 mL). The organic phase was washed with water (50 mL, twice). The combined aqueous phases were basified with saturated aqueous NaHC03solution until pH = 9 and extracted with EtOAc (100 mL, three times). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2S04, filtered and concentrated under vacuum to give (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridinyl]-17,17-dimethyl-15-oxa-4- thia-9,21,30,31-tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]triaconta-l(28),2,5(31),19,25(29),26-hexaen-8,14-dione (Intermediate E, 2.95 g). MS calculated 741.5 (MH + ); measured 741.4 (MH + ).

[0533] Intermediate F

[0534] (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridinyl]-17,17-dimethyl-15-oxa-4- thia-9,21,30,31-tetraazahexacyclo[23.3.1.12,5 .1 9,13 .0 19,27 .0 21,26 ]triaconta-l(28),2,5(31),19,25(29),26-hexaen-8,14-dione

[0535]

[0536] The title compound was prepared in analogy to the preparation of intermediate E by using 4-[5-ethynyl-6-[(lS)-l-methoxyethyl]-3-pyridyl]morpholine (intermediate C2) instead of 4-[5-ethynyl-6-[(lS)-l-methoxyethyl]-3-pyridyl]piperazin-l-yl- benzylate (intermediate CI).

[0537] Intermediate G

[0538] (7S,13S)-7-amino-(20M)-20-[2-[(lS)-l-methoxyethyl]-5-[4-(2,2,2- trifluoroethyl)piperazin-l-yl]-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31- tetraazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]triaconta-l(28),2,5(31),19,25(29),26- hexaen-8,14-dione

[0539]

[0540] The compound was prepared according to the following scheme:

[0541]

[0542] Step 1 : N-[(7S,13S)-(20M)-20-[2-[(lS)-l-methoxyethyl]-5-piperazin-l-yl-3- pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1 2, 5 .1 9,13 .0 19,27 .0 21,26 ]triaconta-l(28),2,5(31),19,25(29),26-hexaen-8,14-dione

[0543] To a solution of N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2- trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia- 9,21,30,31-tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21 ,26 ]tritriaconta-1(28),2,5(31),19,25(29),26-hexaen-20-yl]-6-[(1S)-1- methoxyethyl]-3-pyridyl]piperazine-1-carboxylic acid benzyl ester (Compound E10, 400.0 mg, 0.42 mmol) in EtOAc (8 mL) was added Pd / C on charcoal (200.0 mg). The mixture was degassed and purged with H2 three times and then stirred at 25 °C under H2 (15 psi) for 48 hours. The reaction mixture was filtered and the filtrate was concentrated under vacuum to give N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-piperazin-1-yl-3- pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1 2,5 .1 9 ,13 .0 19,27 .0 21,26 ]tritriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]tert-butyl carbamate (Compound G1, 320.0 mg) which was used in the next step without further purification. MS calculated 827.6 (MH + ); measured 827.4 (MH + ).

[0544] Step 2: Preparation of N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2- trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia- 9,21,30,31-tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]tritriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]tert-butyl carbamate (Compound G2).

[0545] To a solution of tert-butyl N-[(7S,13S)-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-piperazin-1-yl-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4- thia-9,21,30,31-tetraazahexacyclo[23.3.1.1 2,5 .1 9 ,13 .0 19,27 .0 21,26 ]tritriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamate (Compound G1, 290.0 mg, 0.35 mmol) in THF (6 mL) was added TEA (0.15 mL, 1.05 mmol) and CF3CH2OTf (162.8 mg, 0.7 mmol). After stirring at 60 °C for 15 hours, the reaction mixture was concentrated under vacuum to give a residue. The residue was purified by silica gel column to give tert-butyl N-[(7S,13S)-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14- dioxo-15-oxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1 2,5 .1 9, 13 .0 19,27 .0 21,26 ]tritriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamate (Compound G2, 230.0 mg). MS calculated 909.4 (MH + ); measured 909.4 (MH + ).

[0546] Step 3: Preparation of tert-butyl N-[(7S,13S)-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-15-oxa- 4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]tritriaconta-1(28),2,5(31),19,25(29),26-hexaen-8,14-dione (Intermediate G).

[0547] To a solution of tert-butyl N-[(7S,13S)-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl- 8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]tritriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamate (Compound G2, 230.0 mg, 0.25 mmol) in DCM (2 mL) was added TFA (2 mL). After stirring at 20 °C for 1 h, saturated NaHCO3solution (40 mL) was added to the reaction mixture and the reaction mixture was extracted with EtOAc (50 mL, three times). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated under vacuum to give (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2- trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31- tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]tritriaconta-1(28),2,5(31),19,25(29),26-hexaen-8,14-dione (Intermediate G, 200.0 mg) was used in the next step without further purification. MS calculated 809.4 (MH + ); measured 809.4 (MH + ).

[0548] Intermediate H

[0549] (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3- pyridyl]-17,17-dimethyl-15,24-dioxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1 2, 5 .1 9,13 .0 19,27 .0 21,26thirty-one carbon-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione

[0550]

[0551] The title compound is prepared in analogy to the preparation of intermediate E by using 7-bromo-5-iodo-3,4-dihydro-2H-1,4-benzoxazine (intermediate D2) instead of 6-bromo-8-iodo-1,2,3,4-tetrahydroquinoline (intermediate D1).

[0552] Intermediate I

[0553] (7S,13S)-7-amino-23,23-difluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31 - tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19, 27 .0 21,26 thirty-one carbon-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione

[0554]

[0555] The title compound is prepared in analogy to the preparation of intermediate E by using 4-[5-ethynyl-6-[(1S)-1-methoxyethyl]-3-pyridyl]morpholine (intermediate C2) and 7-bromo-5-iodo-3,4-dihydro-2H-1,4-benzoxazine (intermediate D2) instead of benzyl 4-[5-ethynyl-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1- carboxylate (intermediate C1 ) and 6-bromo-8-iodo-1,2,3,4-tetrahydroquinoline (intermediate D1 ).

[0556] Intermediate J

[0557] (7S,13S)-7-amino-23,23-difluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31 - tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26Hexacos-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione

[0558]

[0559] The title compound is prepared in analogy to the preparation of intermediate E by using 6-bromo-3,3-difluoro-8-iodo-2,4-dihydro-1 H-quinoline (intermediate D3) instead of 6-bromo-8-iodo-1,2,3,4-tetrahydroquinoline (intermediate D1 ).

[0560] Intermediate K

[0561] (7S,13S)-7-amino-(20M)-20-[2-[(1 S)-1 -methoxyethyl]-5-morpholino-3-pyridyl]- 17,17,23,23-tetramethyl-15,24-dioxa-4-thia-9,21,30,31 -tetraazahexacyclo[23.3.1 2,5 .1 9, 13 .0 19,27 .0 21,26 Hexacos-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione

[0562]

[0563] The title compound is prepared in analogy to the preparation of intermediate E by using 7-bromo-5-iodo-2,2-dimethyl-3,4-dihydro-1,4-benzoxazine (intermediate D4) and 4-[5-ethynyl-6-[(1 S)-1 -methoxyethyl]-3-pyridyl]morpholine (intermediate C2) instead of 6-bromo-8-iodo-1,2,3,4-tetrahydroquinoline (intermediate D1 ) and 4-[5-ethynyl-6-[(1 S)-1 -methoxyethyl]-3-pyridyl]piperazine-1 -carboxylic acid benzyl ester (intermediate C1 ).

[0564] Intermediate L

[0565] (7S,13S,22S)-7-amino-20-[2-[(1 S)-1 -methoxyethyl]-5-morpholino-3-pyridyl]- 17,17,22-trimethyl-15,24-dioxa-4-thia-9,21,30,31 -tetraazahexacyclo[23.3.1 2,5 .1 9,13 .0 19, 27 .0 21,26Hexacos-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione

[0566]

[0567] The title compound is prepared in analogy to the preparation of intermediate E by using 6-bromo-3,3-difluoro-8-iodo-2,4-dihydro-lH-quinoline (intermediate D3) and 4-[5-ethynyl-6-[(lS)-l-methoxyethyl]-3-pyridyl]morpholine (intermediate C2) instead of 6-bromo-8-iodo-l,2,3,4-tetrahydroquinoline (intermediate Dl) and 4-[5-ethynyl-6-[(lS)-l-methoxyethyl]-3-pyridyl]piperazine-l-carboxylic acid benzyl ester (intermediate Cl).

[0568] Intermediate M

[0569] (20S,26S)-26-Amino-30-hydroxy-(13M)-13-[2-[(lS)-l-methoxyethyl]-3-pyridyl]- 16,16-dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.13 2,5 .1 9, 13 .0 19,27 .0 21,26 Hexacos-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione

[0570]

[0571] The title compound is prepared in analogy to the preparation of intermediate E by using 6-bromo-3,3-difluoro-8-iodo-2,4-dihydro-lH-quinoline (intermediate D3) and 4-[5-ethynyl-6-[(lS)-l-methoxyethyl]-3-pyridyl]morpholine (intermediate C2) instead of 6-bromo-8-iodo-l,2,3,4-tetrahydroquinoline (intermediate Dl) and 4-[5-ethynyl-6-[(lS)-l-methoxyethyl]-3-pyridyl]piperazine-l-carboxylic acid benzyl ester (intermediate Cl).

[0572] Intermediate N

[0573] (20S,26S)-26-Amino-30-hydroxy-(13M)-13-[2-[(lS)-l-methoxyethyl]-3-pyridyl]- 16,16-dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.13 2,6 .120,24 .0 4,14 .0 5,12 ]tricosa-1(31),2,4,6(34),13,28(32),29-heptaen-19,25-dione

[0574]

[0575] The compounds were prepared according to the following schemes:

[0576]

[0577] Step 1: tert-butyl N-[(20S,26S)-30-hydroxy-(13M)-13-[2-[(1S)-1- methoxyethyl]-3-pyridinyl]-16,16-dimethyl-19,25-dioxo-7,18-dioxa-12,24,33- triazahexacyclo[26.3.1.13,8.017,11]tritriaconta-1(31),2,4,6(34),13,28(32),29- heptaen-26-yl]carbamate (Compound N-b) 2,6 .1 20 ,24 .0 4,14 .0 5,12 ]tricosa-1(31),2,4,6(34),13,28(32),29-heptaen-19,25-dione

[0578] To a solution of N-[(20S,26S)-(13M)-13-[2-[(1S)-1-methoxyethyl]-3- pyridinyl]-16,16-dimethyl-19,25-dioxo-30-triisopropylsilanyloxy-7,18-dioxa- 12,24,33-triazahexacyclo[26.3.1.13,8.017,11]tritriaconta-1(31),2,4,6(34),13,28(32),29- heptaen-26-yl]carbamate (Compound N-b) (0.050 g, 0.058 mmol) in THF (0.5 mL) was added TBAF (0.5 mL, 0.5 mmol, 1 M in THF). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic extracts were dried over Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC (C18 column, 10-90% CH3CN in H2O with 0.1% TFA) to give Compound N-c (0.030 g, 0.038 mmol, 66% yield). LCMS (ES+): m / z 1023.5 (M+H). 2,6 .1 20,24 .0 4,14 .0 5,12A solution of tert-butyl [thirty-four-carbA- 1 (31), 2, 4, 6(34), 13, 28(32), 29- heptaen-26-yl]carbamate (Compound N-a, 16.0 mg, 0.02 mmol) in THF (4 mL) was added TBAF (20 μL, 0.02 mmol, 1M in THF). After stirring at 0 °C for 0.5 h, the mixture was concentrated in vacuo to give a residue. The residue was poured into water (10 mL) and extracted with EtOAc (8 mL, three times). The combined organic phase was washed with brine (5 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give N-[(20S,26S)-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridinyl]- 16,16-dimethyl-19,25-dioxo-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.13 2,6 .1 20,24 .0 4,14 .0 5,12 ]tert-butyl [thirty-four-carbA- 1 (31), 2, 4, 6(34), 13, 28(32), 29-heptaen-26-yl]carbamate (Compound N-b, 12.0 mg) was used in the next step without purification. MS calc 782.4 (MH + ); found 782.4 (MH + ).

[0579] Step 2: (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3- pyridinyl]-16,16-dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.13 2,6 .1 20,24 .0 4,14 .0 5,12 Preparation of thirty-four-carbA- 1 (31), 2, 4, 6(34), 13, 28(32), 29-heptaen-19,25- dione (Intermediate N)

[0580] To a solution of N-[(20S,26S)-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3- pyridinyl]-16,16-dimethyl-19,25-dioxo-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.13 2,6 .1 20,24 .0 4, 14 .0 5,12A solution of tert-butyl [tricosa-1(31),2,4,6(34),13,28(32),29-heptaen-26-yl]carbamate (Compound N-b, 12 mg, 0.015 mmol) in DCM (2.5 mL) was added TFA (0.5 mL). The mixture was stirred at 20 °C for 1.5 hours. After the reaction was completed, the mixture was concentrated in vacuo to give a residue. The residue was purified by reverse phase chromatography to give (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridinyl]-16,16-dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.13 2,6 .1 20,24 .0 4,14 .0 5,12 ]tricosa-1(31),2,4,6(34),13,28(32),29-heptaen-19,25-dione (Intermediate N, 10.0 mg). MS calculated 682.4 (MH + ); measured 682.4 (MH + ).

[0581] The title compound N-a was prepared in analogy to the preparation of Compound E10 by using 9-bromo-7-iodo-3,4,5,6-tetrahydro-2H-1,6-benzoxazepine (Intermediate D6) and 3-ethynyl-2-[(1S)-1-methoxyethyl]pyridine (Intermediate C4) instead of 6-bromo-8-iodo-1,2,3,4-tetrahydroquinoline (Intermediate D1) and benzyl 4-[5-ethynyl-6-[(1S)-1-methoxyethyl]-3-pyridinyl]piperazine-1-carboxylate (Intermediate C1).

[0582] Intermediate O

[0583] (19S,25S)-25-amino-29-hydroxy-(12M)-12-[2-[(1S)-1-methoxyethyl]-3-pyridinyl]-15,15-dimethyl-7,17-dioxa-11,23,32-triazahexacyclo[25.3.1.13 2,6 .1 19,23 .0 4,13 .0 5,11 ]tricosa-1(31),2,4,6(34),13,28(32),29-heptaen-19,25-dione

[0584]

[0585] The title compound is prepared in analogy to the preparation of Intermediate N by using 8-bromo-6-iodo-2,3,4,5-tetrahydro-l,5-oxazepine (Intermediate D7) instead of 9-bromo-7-iodo-3,4,5,6-tetrahydro-2H-l,6-benzoxazepine (Intermediate D6).

[0586] Intermediate P

[0587] (18S,24S)-24-amino-28-hydroxy-(l lM)-l l-[2-[(lS)-l-methoxyethyl]-3- pyridinyl]-14,14-dimethyl-7,16-dioxa-10,22,31-triazahexacyclo[24.3.1.13 2,6 .1 18,22 .0 4,12 .0 5,10 ]thirtytwo- 1(29),2,4,6(32), 11,26(30),27-heptaen-17,23-dione

[0588]

[0589] The title compound is prepared in analogy to the preparation of Intermediate N by using 6-bromo-8-iodo-l,2,3,4-tetrahydroquinoline (Intermediate Dl) instead of 9-bromo-7-iodo-3,4,5,6-tetrahydro-2H-l,6-benzoxazepine (Intermediate D6).

[0590] Intermediate Q

[0591] (18S,24S)-24-amino-28-hydroxy-(l lM)-l l-[2-[(lS)-l-methoxyethyl]-3- pyridinyl]-14,14-dimethyl-7,16-dioxa-10,22,31-triazahexacyclo[24.3.1.13 2,6 .1 18,22 .0 4,12 .0 5,10 ]thirtytwo- 1(29),2,4,6(32), 11,26(30),27-heptaen-17,23-dione

[0592]

[0593] The title compound is prepared in analogy to the preparation of Intermediate N by using 7-bromo-5-iodo-3,4-dihydro-2H-l,4-benzoxazine (Intermediate D2) instead of 9-bromo-7-iodo-3,4,5,6-tetrahydro-2H-l,6-benzoxazepine (Intermediate D6).

[0594] Intermediate R

[0595] (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]- 17,17,23,23-tetramethyl-15-oxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1 2, 5 .1 9,13 .0 19,27 .0 21,26 ]thirty-one-carb-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione

[0596]

[0597] The title compound is prepared in analogy to the preparation of intermediate E by using 6-bromo-8-iodo-3,3-dimethyl-2,4-dihydro-1H-quinoline (intermediate D8) instead of 6-bromo-8-iodo-1,2,3,4-tetrahydroquinoline (intermediate D1).

[0598] Example 1

[0599] (3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(20S,26S)-30-hydroxy-(13M)-13-[2-[(1S)-1- methoxyethyl]-3-pyridyl]-16,16-dimethyl-19,25-dioxo-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 ]thirty-one-carb-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione

[0600]

[0601] The compounds are prepared according to the following scheme:

[0602]

[0603] Step 2: N-[(1S)-1-[[(20S,26S)-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16- dimethyl-19,25-dioxo-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 ]tert-Butyl [N-[(1S)-1-[[(20S,26S)-30-hydroxy-(13M)-13-[2-[(1S)-1- methoxyethyl]-3-pyridinyl]-16,16-dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1

[0604] To a solution of DIEA (70 μL, 0.41 mmol, 3.0 equiv) and Boc-N-Me-Val-OH (Compound lb, 30.4 mg, 0.15 mmol) in DMF (2.5 mL) was added HATU (63.1 mg, 0.17 mmol). After stirring for 10 min, (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridinyl]-16,16-dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20 ,24 .0 4,14 .0 5,12 ]tert-Butyl [N-[(1S)-1-[[(20S,26S)-30-hydroxy-(13M)-13-[2-[(1S)-1- methoxyethyl]-3-pyridinyl]-16,16-dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 ]tert-Butyl [N-[(1S)-1-[[(20S,26S)-30-hydroxy-(13M)-13-[2-[(1S)-1- methoxyethyl]-3-pyridinyl]-16,16-dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 + ) 895.5 (MH + ).

[0605] Step 2: (2S)-N-[(20S,26S)-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-19,25-dioxo-7,18-dioxa-12,24,33-triazahexane[26.3.1.1] 2, 6 .1 20,24 .0 4,14 .0 5,12 Preparation of 34-carbon-1(31),2,4,6(34),13,28(32),29-heptaen-26-yl]-3-methyl-2-(methylamino)butyramide (compound 1d)

[0606] At 0 °C, N-[(1S)-1-[[(20S,26S)-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-19,25-dioxo-7,18-dioxa-12,24,33-triazahexane[26.3.1.1] 2,6 .1 20,24 .0 4,14 .0 5,12 [34-C-1(31),2,4,6(34),13,28(32),29-Heptaeno-26-yl]carbamoyl]-2-methyl-propyl]-N-methyl-carbamate tert-butyl ester (compound 1c, 115 mg, 0.13 mmol) was added to a solution of TFA (2.0 mL, 2 mmol) in DCM (8 mL). After stirring at 20 °C for 1 hour, the reaction mixture was concentrated under vacuum and diluted with saturated NaHCO3 (10 mL), and extracted with EtOAc (20 mL, three times). The combined organic layers were washed with brine (10 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum to give a yellow solid (2S)-N-[(20S,26S)-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-19,25-dioxo-7,18-dioxa-12,24,33-triazahexane[26.3.1.1]. 2,6 .1 20,24 .0 4 ,14 .0 5,12 [[C34-1(31),2,4,6(34),13,28(32),29-heptaen-26-yl]-3-methyl-2-(methylamino)butyramide (Compound 1d, 95.0 mg). MS calculated value 795.4 (MH)]+ ) ; found 795.4 (MH + ).

[0607] Step 3: Preparation of tert-butyl (3S)-3-[[(1S)-1-[[(20S,26S)-30-hydroxy- (13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridinyl]-16,16-dimethyl-19,25-dioxo-7,18- dioxaa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 ]tritriaconta-1(31),2,4,6(34),13,28(32),29-heptaen-26-yl]carbamoyl]-2- methyl-propyl]-methyl-carbamoyl]pyrrolidine-1-carboxylate (Compound 1f)

[0608] To a solution of (3S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (Compound 1e, 59.6 mg, 0.28 mmol), DIEA (0.1 mL, 0.55 mmol), and HATU (115.75 mg, 0.3 mmol) in DMF (2 mL) was added (2S)-N-[(20S,26S)-30-hydroxy- (13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridinyl]-16,16-dimethyl-19,25-dioxo-7,18- dioxaa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 ]tritriaconta-1(31),2,4,6(34),13,28(32),29-heptaen-26-yl]-3-methyl-2- (methylamino)butanamide (Compound 1d, 110.0 mg, 0.14 mmol). After stirring at 20 °C for 1 h, the reaction mixture was concentrated under vacuum to give a residue. The residue was purified by reverse phase chromatography to give (3S)-3-[[(1S)-1-[[(20S,26S)-30-hydroxy- (13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridinyl]-16,16-dimethyl-19,25-dioxo-7,18- dioxaa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12[34-C-1(31),2,4,6(34),13,28(32),29-heptaen-26-yl]carbamoyl]-2-methyl-propyl]-methyl-carbamoyl]pyrrolidine-1-carboxylic acid tert-butyl ester (compound 1f, 95.0 mg). MS calculated value 992.5 (MH) + The measured value was 892.5 (M-Boc+H). + ).

[0609] Step 4: (3S)-N-[(1S)-1-[[(20S,26S)-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-19,25-dioxo-7,18-dioxa-12,24,33-triazahexane[26.3.1.1] 2,6 .1 20,24 .0 4,14 .0 5,12 Preparation of 1 g of compound [34-carbon-1(31),2,4,6(34),13,28(32),29-heptaen-26-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide]

[0610] To (3S)-3-[[(1S)-1-[[(20S,26S)-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-19,25-dioxo-7,18-dioxa-12,24,33-triazahexane[26.3.1.1] 2,6 .1 20,24 .0 4,14 .0 5,12To a solution of tert-butyl [(3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-2-methyl- pyrrolidin-1-yl]-carbamic acid (20S,26S)-30-hydroxy-13-(2-[(1S)-1-methoxy- ethyl]-3-pyridinyl)-16,16-dimethyl-19,25-dioxo-7,18-dioxa-12,24,33-triaza- hexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 ]heptatriaconta-1(31),2,4,6(34),13,28(32),29-heptaen-26-yl]carbamoyl]-2- methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide (Compound 1g, 65.0 mg). MS calculated 892.5 (MH + ), measured 446.9 (M / 2+H + ).

[0611] Step 5: (3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(20S,26S)-30-hydroxy- (13M)-13-[2-[(1S)-1-methoxy-ethyl]-3-pyridinyl]-16,16-dimethyl-19,25-dioxo- 7,18-dioxa-12,24,33-triaza-hexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 ]heptatriaconta-1(31),2,4,6(34),13,28(32),29-heptaen-26-yl]carbamoyl]-2- methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide (Example 1)

[0612] To a solution of (2R)-2-chloro-2-fluoro-acetic acid (Compound 1h, 13.8 mg, 0.12 mmol), (3S)-N-[(1S)-1-[[(20S,26S)-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3- pyridinyl]-16,16-dimethyl-19,25-dioxo-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5 ,12 ]tritriaconta-1(31),2,4,6(34),13,28(32),29-heptaen-26-yl]carbamoyl]-2-methyl- propyl]-N-methyl-pyrrolidine-3-carboxamide (Compound 1g, 55.0 mg, 0.06 mmol) in DMF (1 mL) was added DIEA (30 μL, 0.18 mmol) and HATU (52.7 mg, 0.14 mmol). The mixture was stirred at 20 °C for 2 hours. EtOAc (20 mL) and water (20 mL) were added to the reaction mixture and the layers were separated. The aqueous phase was extracted with EtOAc (10 mL, twice). The combined organic layers were washed with brine (10 mL), dried over Na2SO4 and concentrated under vacuum to give a residue. The residue was purified by preparative HPLC to give (3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(20S,26S)-30-hydroxy- (13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridinyl]-16,16-dimethyl-19,25-dioxo-7,18- dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 ]tritriaconta-1(31),2,4,6(34),13,28(32),29-heptaen-26-yl]carbamoyl]-2-methyl- propyl]-N-methyl-pyrrolidine-3-carboxamide (Example 1, 15.9 mg). MS calc'd 986.5 (MH + ), found 986.5 (MH + ). 1H NMR (400 MHz, Methanol-d4) δ = 8.87 - 8.82 (m, 1H), 8.61 - 8.51 (m, 1H), 8.17 - 8.09 (m, 1H), 7.97 - 7.85 (m, 1H), 7.82 - 7.70 (m, 1H), 7.60 - 7.48 (m, 1H), 7.33 - 7.25 (m, 1H), 7.09 - 7.01 (m, 1H), 6.76 - 6.26 (m, 1H), 4.75 - 4.70 (m, 1H), 4.53 - 4.42 (m, 1H), 4.37 - 4.16 (m, 1H), 3.90 - 3.83 (m, 2H), 3.81 - 3.75 (m, 2H), 3.68 - 3.63 (m, 1H), 3.60 - 3.54 (m, 1H), 3.28 - 3.25 (m, 1H), 3.21 - 3.17 (m, 3H), 3.16 - 3.11 (m, 1H), 3.10 - 3.00 (m, 2H), 2.97 - 2.92 (m, 1H), 2.89 (s, 1H), 2.88 - 2.85 (m, 1H), 2.42 - 2.24 (m, 1H), 2.23 - 2.18 (m, 1H), 1.89 - 1.79 (m, 1H), 1.69 - 1.65 (m, 5H), 1.54 - 1.50 (m, 4H), 1.46 - 1.39 (m, 2H) 1.38 - 1.26 (m, 5H), 1.09 - 1.00 (m, 3H), 0.99 - 0.89 (m, 5H), 0.88 - 0.86 (m, 2H), 0.84 - 0.82 (m, 2H), 0.79 - 0.74 (m, 3H).

[0613] Example 2

[0614] (3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(19S,25S)-29-hydroxy-(12M)-12-[2-[(1S)-1-methoxy-ethyl]-3-pyridinyl]-15,15-dimethyl-18,24-dioxo-7,17-dioxaa-11,23,32-triazahexacyclo[25.3.1.1 2,6 .1 19,23 .0 4,13 .0 5,11[33-carbonyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide

[0615]

[0616] Example 1 using (19S,25S)-25-amino-29-hydroxy-(12M)-12-[2-[(1S)-1- methoxyethyl]-3-pyridinyl]-15,15-dimethyl-7,17-dioxa-11,23,32-triazahexacyclo[25.3.1.1 2,6 .1 19,23 .0 4,13 .0 5,11 Example 1 using (19S,25S)-25-amino-29-hydroxy-(12M)-12-[2-[(1S)-1- methoxyethyl]-3-pyridinyl]-15,15-dimethyl-7,17-dioxa-11,23,32-triazahexacyclo[25.3.1.1 2,6 .1 20,24 .0 4, 14 .0 5,12 Example 1 using (19S,25S)-25-amino-29-hydroxy-(12M)-12-[2-[(1S)-1- methoxyethyl]-3-pyridinyl]-15,15-dimethyl-7,17-dioxa-11,23,32-triazahexacyclo[25.3.1.1 + ); measure 972.4 (MH +) δ = 8.89 - 8.79 (m, 1H), 8.33 - 8.21 (m, 1H), 7.92 - 7.81 (m, 1H), 7.75 - 7.66 (m, 1H), 7.47 - 7.36 (m, 1H), 7.29 - 7.13 (m, 1H), 7.11 - 6.98 (m, 1H), 6.93 - 6.71 (m, 1H), 6.54 - 6.44 (m, 1H), 5.66 - 5.53 (m, 1H), 4.72 (d, J = 11.1 Hz, 1H), 4.61 - 4.38 (m, 3H), 4.15 - 4.04 (m, 1H), 4.03 - 3.91 (m, 1H), 3.90 - 3.75 (m, 3H), 3.74 - 3.63 (m, 3H), 3.62 - 3.43 (m, 3H), 3.15 - 3.04 (m, 1H), 2.96 - 2.91 (m, 3H), 2.84 - 2.73 (m, 2H), 2.44 - 2.26 (m, 3H), 2.22 - 2.17 (m, 1H), 2.14 - 2.00 (m, 2H), 1.98 - 1.87 (m, 1H), 1.82 - 1.57 (m, 2H), 1.51 - 1.47 (m, 3H), 1.40 - 1.23 (m, 5H), 0.99 - 0.90 (m, 3H), 0.87 - 0.78 (m, 6H), 0.76 - 0.63 (m, 3H).

[0617] Example 3

[0618] 1-[(2R)-2-chloro-2-fluoro-acetyl]-4-fluoro-N-[(1S)-1-[[(19S,25S)-29-hydroxy- (12M)-12-[2-[(1S)-1-methoxy-ethyl]-3-pyridinyl]-15,15-dimethyl-18,24-dioxo-7,17- dioxa-11,23,32-triazahexacyclo[25.3.1.1 2,6 .1 19,23 .0 4,13 .0 5,11 ]tritriaconta-1 (30),2,4,6(33),12,27(31),28-heptaen-25-yl]carbamoyl]-2-methyl- propyl]-N-methyl-piperidine-4-carboxamide

[0619]

[0620] The title compound is prepared in analogy to the preparation of Example 1 by using (19S,25S)-25-amino-29-hydroxy-(12M)-12-[2-[(1S)-1-methoxyethyl]-3- pyridyl]-15,15-dimethyl-7,17-dioxa-11,23,32-triazahexacyclo[25.3.1.13 2,6 .1 19,23 .0 4,13 .0 5,11 ]tritriaconta-1(30),2,4,6(33),12,27(31),28-heptaen-18,24-dione (Intermediate O) and (3S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (Compound 1e) instead of (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3- pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.13 2,6 .1 20,24 .0 4,14 .0 5,12 ]tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaen-19,25-dione (Intermediate N) and (3S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (Compound 1e). Example 3 (2.4 mg) is obtained as a yellow solid. MS calculated 1004.4 (MH + ); measured 1004.5 (MH + ).

[0621] Example 4

[0622] (3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(18S,24S)-28-hydroxy-(11M)-11- [(3R)-2-[(1S)-1-methoxyethyl]-2,3-dihydropyridin-3-yl]-14,14-dimethyl-17,23- dioxo-16-oxa-10,22,31-triazahexacyclo[24.3.1.13 2,6 .1 18,22 .0 4,12 .0 5,10 ]dodeca-1(28),2,4,6(29),11,26(30),27-heptaen-24-yl]carbamoyl]-2-methyl- propyl]-N-methyl-pyrrolidine-3-carboxamide

[0623]

[0624] The title compound is prepared in analogy to the preparation of Example 1 by using (18S,24S)-24-amino-28-hydroxy-(11M)-11-[2-[(1S)-1-methoxyethyl]-3- pyridyl]-14,14-dimethyl-16-oxa-10,22,31-triazahexacyclo[24.3.1.1 2,6 .1 18,22 .0 4,12 .0 5,10 ]tricyclo-1(29),2,4,6(32),11,26(30),27-heptadeca-17,23-dione (Intermediate P) instead of (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1- methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4, 14 .0 5,12 ]tetracyclo-1(31),2,4,6(34),13,28(32),29-hepta-19,25-dione (Intermediate N). Example 4 is obtained as a yellow solid (10.9 mg). MS calculated 956.4 (MH + ); measured 956.4 (MH +) ppm.1H NMR (400 MHz, Methanol-d4) δ = 8.87 - 8.80 (m, 1H), 8.32 - 8.15 (m, 1H), 7.91 - 7.79 (m, 2H), 7.37 (d, J = 13.6 Hz, 2H), 7.08 - 6.99 (m, 1H), 6.89 - 6.70 (m, 1H), 6.59 - 6.42 (m, 1H), 5.67 - 5.46 (m, 1H), 4.77 - 4.65 (m, 1H), 4.59 - 4.41 (m, 2H), 3.99 (d, J = 10.4 Hz, 1H), 3.93 - 3.81 (m, 3H), 3.81 - 3.65 (m, 5H), 3.57 - 3.49 (m, 1H), 3.28 - 3.19 (m, 1H), 3.13 - 3.03 (m, 3H), 3.02 - 2.81 (m, 6H), 2.79 - 2.71 (m, 2H), 2.37 - 2.23 (m, 3H), 2.20 - 2.06 (m, 3H), 2.05 - 1.90 (m, 2H), 1.75 - 1.58 (m, 2H), 1.50 (d, J = 6.4 Hz, 3H), 0.96 - 0.72 (m, 12H).

[0625] Example 5

[0626] (3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(18S,24S)-28-hydroxy- (11M)-11-[2-[(1S)-1-methoxy-ethyl]-3-pyridinyl]-14,14-dimethyl-17,23-dioxo-7,16- dioxa-10,22,31-triazahexacyclo[24.3.1.1 2,6 .1 18,22 .0 4,12 .0 5,10 ]tridocosane-1(29),2,4,6(32),11,26(30),27-heptaen-24-yl]carbamoyl]-2-methyl- propyl]-N-methyl-pyrrolidine-3-carboxamide

[0627]

[0628] The title compound is prepared in analogy to the preparation of Example 1 by using (18S,24S)-24-amino-28-hydroxy-(11M)-11-[2-[(1S)-1-methoxyethyl]-3- pyridyl]-14,14-dimethyl-7,16-dioxa-10,22,31-triazahexacyclo[24.3.1.1 2,6 .1 18,22 .0 4,12 .0 5,10 ]tritriaconta-1(29),2,4,6(32),11,26(30),27-heptaen-17,23-dione (Intermediate Q) instead of (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1- methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4, 14 .0 5,12 ]tetratetraconta-1(31),2,4,6(34),13,28(32),29-heptaen-19,25-dione (Intermediate N). Example 5 is obtained as a white solid (10.3 mg). MS calc. 958.4 (MH + ); measured 958.4 (MH +) δ = 8.78 (d, J = 4.0 Hz, 1H), 8.14 - 8.02 (m, 1H), 7.74 - 7.65 (m, 1H), 7.64 - 7.56 (m, 1H), 7.33 (s, 1H), 7.08 - 6.85 (m, 3H), 6.64 - 6.43 (m, 1H), 5.63 - 5.51 (m, 1H), 4.61 - 4.58 (m, 2H), 4.49- 4.40 (m, 1H), 4.25 - 3.93 (m, 2H), 3.85 - 3.77 (m, 3H), 3.76 - 3.69 (m,3H), 3.67 - 3.52 (m, 2H), 3.06 - 3.00 (m, 1H), 2.98 - 2.93 (m, 3H), 2.92 -2.89 (m, 1H), 2.88 - 2.82 (m, 1H), 2.80 (s, 3H), 2.38 - 2.12 (m, 4H), 1.97 -1.92 (m, 1H), 1.83 - 1.70 (m, 1H), 1.68 - 1.55 (m, 2H), 1.50 (d, J = 6.0Hz, 3H), 1.41 - 1.25 (m, 2H), 1.19 - 1.06 (m, 1H), 1.00 - 0.92 (m, 3H), 0.91 (s, 3H), 0.87 - 0.82 (m, 3H), 0.56 - 0.68 (m, 3H).

[0629] Example 6

[0630] (3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1- methoxy-ethyl]-5-(4-methyl-piperazin-1-yl)-3-pyridinyl]-17,17-dimethyl-8,14-dioxo- 15-oxa-4-thia-9,21,30,31 -tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]tritriaconta-1 (28),2,5(31),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl- propyl]-N-methyl-pyrrolidine-3-carboxamide

[0631]

[0632] The title compound is prepared in analogy to the preparation of Example 1 by using (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3- pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]tricyclohexaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate E) instead of (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1- methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20 ,24 .0 4,14 .0 5,12 ]tetracyclohexaconta-1(31),2,4,6(34),13,28(32),29-heptaene-19,25-dione (Intermediate N). Example 6 is obtained as a yellow solid (11.5 mg). MS calculated 1045.5 (MH + ) for C64H89N10O8; measured 1045.5 (MH +) δ = 8.50 - 8.45 (m, 1H), 8.42 - 8.34 (m, 1H), 7.54 - 7.39 (m, 3H), 6.94 - 6.72 (m, 1H), 5.83 - 5.55 (m, 1H), 4.49- 4.39 (m, 2H), 4.31 - 4.12 (m, 3H), 3.83 - 3.72 (m, 5H), 3.64 - 3.52 (m, 4H), 3.41 - 3.34 (m, 5H), 3.12 - 3.06 (m, 4H), 3.00 - 2.96 (m, 4H), 2.89 - 2.67 (m, 2H), 2.63 - 2.54 (m, 1H), 2.39 - 2.14 (m, 7H), 2.11 - 2.03 (m, 1H), 1.98 - 1.90 (m, 1H), 1.85 - 1.73 (m, 1H), 1.70 - 1.53 (m, 2H), 1.47 - 1.43 (m, 3H), 1.35 - 1.26 (m, 4H), 1.01 - 0.92 (m, 6H), 0.89 - 0.84 (m, 3H), 0.60- 0.50 (m, 3H).

[0633] Example 7

[0634] (2S)-2-[2-[(2R)-2-chloro-2-fluoro-acetyl]-5-oxo-2,6-diazaspiro[3.4]octan-6-yl]-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxy-ethyl]-5-[4-(2,2,2-trifluoro-ethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]tritriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]-3-methyl-butyramide

[0635]

[0636] The compounds were prepared according to the following schemes:

[0637]

[0638] Step 1: Preparation of tert-butyl 6-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14- dioxo-15-oxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]thria- 1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-5-oxo-2,6- diazaspiro[3.4]octane-2-carboxylate (Compound 7a) 2,5 .1 9,13 .0 19,27 .0 21,26 Step 1: Preparation of tert-butyl 6-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14- dioxo-15-oxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]thria- 1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-5-oxo-2,6- diazaspiro[3.4]octane-2-carboxylate (Compound 7a)

[0639] To a solution of (2S)-2-(2-tert-butoxycarbonyl-5-oxo-2,6-diazaspiro[3.4]octan-6-yl)-3- methyl-butyric acid (Intermediate Al, 50.0 mg, 0.15 mmol) in DMF (1 mL) was added DIEA (110 µL, 0.62 mmol), HATU (60.0 mg, 0.16 mmol) and (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-15-oxa-4- thia-9,21,30,31-tetraazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]tria-1(28),2,5(31),19,25(29), 26-hexaen-8,14-dione (Intermediate G, 50.0 mg, 0.06 mmol). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was poured into water (40 mL) and extracted with EtOAc (20 mL, three times). The combined organic layers were washed with brine (30 mL, three times), dried over Na2SO4 and concentrated under vacuum to give a residue which was purified by column chromatography to give 6-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo- 15-oxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]tria-1(28),2,5(31),19, 25(29),26-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-5-oxo-2,6-diazaspiro[3.4]octane-2- carboxylic acid tert-butyl ester (Compound 7a) as an off-white solid. 2,5 .1 9,13 .0 19,27 .021,26 ]triaconta-l(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl- propyl]-5-oxo-2,6-diazaspiro[3.4]octane-2-carboxylic acid tert-butyl ester (Compound 7a, 50.0 mg). MS calculated 1117.5 (MH + ); measured 1117.5 (MH + ).

[0640] Step 2: (2S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2- trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4- thia-9,21,30,31-tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]triaconta-l(28),2,5(31),19,25(29),26-hexaen-7-yl]-3-methyl-2-(5-oxo-2,6- diazaspiro[3.4]octan-6-yl)butanamide (Compound 7b)

[0641] To 6-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2- trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4- thia-9,21,30,31-tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26To a solution of tert-butyl [(2S)-2-methyl-3-oxo-2-(5-oxo-2,6-diazaspiro[3.4]oct- 6-yl)propyl]carbamate (Compound 7a, 50.0 mg, 0.04 mmol) in DCM (0.5 mL) was added TFA (0.5 mL, 6.49 mmol), and the mixture was stirred at 25 °C for 1 h. After the reaction was completed, saturated aqueous NaHCO3 (40 mL) was added to the reaction mixture and the mixture was extracted with EtOAc (30 mL, three times). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give (2S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2- trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]triaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]-3-methyl-2-(5-oxo-2,6-diazaspiro[3.4]octan-6- yl)butanamide (Compound 7b, 45.0 mg) was used in the next step without further purification. MS calculated 1017.5 (MH + ); measured 1017.7 (MH + ).

[0642] Step 3: (2S)-2-[2-[(2R)-2-chloro-2-fluoro-acetyl]-5-oxo-2,6-diazaspiro[3.4]octan-6-yl]-N-[(7S,13S)- (20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17- dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 Preparation of [(2S)-2-methyl-3-oxo-2-(5-oxo-2,6-diazaspiro[3.4]oct-6-yl)propyl]carbamate (Compound 7a)

[0643] To (2S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 [[C28,2,5(31),19,25(29),26-hexen-7-yl]-3-methyl-2-(5-oxo-2,6-diazaspiro[3.4]octane-6-yl)butyramide (compound 7b, 45.0 mg, 0.04 mmol)) was added to a solution of DIEA (80 µL, 0.46 mmol), (2R)-2-chloro-2-fluoroacetic acid (compound 1h, 26.3 mg, 0.23 mmol), and T3P (146.3 mg, 0.23 mmol) in DMF (1 mL), and the mixture was stirred at 25 °C for 1 hour. After the reaction was complete, the reaction mixture was poured into water (20 mL) and extracted with EtOAc (20 mL, three times). The combined organic layers were washed with brine (30 mL, three times), dried over Na2SO4, filtered, and concentrated under vacuum to obtain the residue, which was purified by preparative HPLC to obtain a yellow solid (2S)-2-[2-[(2R)-2-chloro-2-fluoro-acetyl]-5-oxo-2,6-diazaspiro[3.4]octane-6-yl]-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1] 2,5 .1 9,13 .0 19, 27 .0 21,26 [C31-1(28),2,5(31),19,25(29),26-hexene-7-yl]-3-methylbutyramide (Example 7, 12.3 mg). MS calculated value 1111.5 (MH) + ); Measured value 1111.5 (MH) + ). 1H NMR (400 MHz, Methanol-d4) δ = 8.47 - 8.34 (m, 2H), 7.78 - 7.72 (m, 1H), 7.56 - 7.41 (m, 2H), 6.76 - 6.58 (m, 1H), 5.83 - 5.71 (m, 1H), 4.57 - 4.50 (m, 1H), 4.44 - 4.29 (m, 3H), 4.26 - 4.04 (m, 3H), 3.80 - 3.62 (m, 3H), 3.52 - 3.36 (m, 10H), 3.29 - 3.24 (m, 1H), 3.23 - 2.96 (m, 6H), 2.92 - 2.85 (m, 4H), 2.83 - 2.76 (m, 1H), 2.71 - 2.62 (m, 1H), 2.41 - 2.28 (m, 3H), 2.24 - 2.15 (m, 3H), 1.99 - 1.90 (m, 1H), 1.86 - 1.72 (m, 1H), 1.67 - 1.56 (m, 1H), 1.47 (d, J = 6.4 Hz, 3H), 1.36 - 1.26 (m, 1H), 1.03 - 0.96 (m, 6H), 0.87 (dd, J = 2.0, 6.4 Hz, 3H), 0.63 - 0.56 (m, 3H).

[0644] Example 8

[0645] (2S)-2-(2-But-2-ynoyl-5-oxo-2,6-diazaspiro[3.4]octan-6-yl)-N-[(7S,13S)-(20M)-20-[2- [(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17- dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1 2,5 .1 9, 13 .0 19,27 .0 21,26 ]thirty-one-carb-1(28),2,5(31),19,25(29),26-hexaen-7-yl]-3-methyl-butyramide

[0646]

[0647] The title compound was prepared in analogy to the preparation of Example 7 by using but-2-ynoic acid instead of (2R)-2-chloro-2-fluoro-acetic acid (compound 1h). Example 8 (38 mg) was obtained as a yellow solid. MS calculated 1083.5 (MH + ); found 1083.6 (MH + ). 1 H NMR (400 MHz, Methanol-d4) δ = 8.44 (s, 1H), 8.36 (s, 1H), 7.91 - 7.84 (m, 1H), 7.54 - 7.44 (m, 2H), 5.82 - 5.71 (m, 1H), 4.60 - 4.52 (m, 1H), 4.44 - 4.36 (m, 2H), 4.35 - 4.29 (m, 1H), 4.27 - 4.09 (m, 4H), 3.97 - 3.91 (m, 1H), 3.81 - 3.71 (m, 2H), 3.71 - 3.63 (m, 1H), 3.54 - 3.46 (m, 5H), 3.46 - 3.36 (m, 5H), 3.27 - 3.07 (m, 5H), 3.05 - 2.96 (m, 1H), 2.91 - 2.85 (m, 4H), 2.84 - 2.74 (m, 1H), 2.72 - 2.64 (m, 1H), 2.37 - 2.28 (m, 3H), 2.25 - 2.15 (m, 3H), 2.03 (d, J = 4.4 Hz, 3H), 1.98 - 1.90 (m, 1H), 1.84 - 1.73 (m, 1H), 1.68 - 1.56 (m, 1H), 1.48 (d, J = 6.4 Hz, 3H), 1.04 - 0.96 (m, 6H), 0.89 - 0.84 (m, 3H), 0.61 (s, 3H).

[0648] Example 9

[0649] (2S)-2-[2-[(2R)-2-chloro-2-fluoro-acetyl]-5-oxo-2,6-diazaspiro[3.4]octan-6-yl]-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxy-ethyl]-5-morpholino-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1 2,5 .19,13 .0 19,27 .0 21,26 [C31-1(28),2,5(31),19,25(29),26-hexene-7-yl]-3-methyl-butanamide]

[0650]

[0651] Similar to the preparation in Example 7, this was achieved by using (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 The title compound was prepared by substituting (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hexacarbon-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (intermediate G) with 31-carbon-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (intermediate G). Example 9 (30.1 mg) was obtained as a yellow solid. MS calculated value: 1030.4 (MH). + ); Measured value 1030.5 (MH) + ). 1H NMR (400 MHz, Methanol-d4) δ = 8.44 (s, 1 H) 8.36 (d, J = 2.40 Hz, 1 H), 7.85 (d, J = 2.4 Hz, 1 H), 7.55 - 7.43 (m, 2 H), 6.68 (dd, J = 49.2, 2.4 Hz, 1 H), 5.85 - 5.71 (m, 1 H), 4.62 - 4.51 (m, 2 H), 4.47 - 4.01 (m, 8 H), 3.87 (t, J = 4.8 Hz, 4 H), 3.82 - 3.72 (m, 2 H), 3.71 - 3.62 (m, 1 H), 3.60 - 3.48 (m, 1 H), 3.46 - 3.37 (m, 8 H), 3.29 - 3.24 (m, 1 H), 3.16 - 2.97 (m, 3 H), 2.85 - 2.65 (m, 2 H), 2.43 - 2.28 (m, 3 H), 2.27 - 2.15 (m, 3 H), 2.00 - 1.91 (m, 1 H), 1.89 - 1.71 (m, 1 H), 1.69 - 1.55 (m, 1 H), 1.48 (d, J = 6.4 Hz, 3 H), 1.05 - 0.95 (m, 6 H), 0.87 (dd, J = 6.80, 2.80 Hz, 3 H), 0.62 (d, J = 4.0 Hz, 3 H).

[0652] Example 10

[0653] (2S)-2-(2-but-2-ynoyl-5-oxo-2,6-diazaspiro[3.4]octan-6-yl)-N-[(7S,13S)-(20M)-20-[2- [(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4- thia-9,21,30,31 -tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]thirty-one-carb-1(28),2,5(31),19,25(29),26-hexaen-7-yl]-3-methyl-butyramide

[0654]

[0655] Similar to the preparation in Example 7, this was achieved by using (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 [Tyrocarbon-1(28),2,5(31),19,25(29),26-hexane-8,14-dione (intermediate F) and butyryl-2-alkynyl acid substitutes for (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl] The title compound was prepared from -15-oxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]tetrate-1(28),2,5(31),19,25(29),26-hexane-8,14-dione (intermediate G) and (2R)-2-chloro-2-fluoroacetic acid (compound 1h). Example 10 (43.6 mg) was obtained as a yellow solid. MS calculated value 1002.5 (MH) + ); Measured value 1002.5 (MH) + ). 1H NMR (400 MHz, methanol-d4) δ = 8.44 (s, 1H), 8.40 - 8.33 (m, 1H), 7.85 (dd, J = 5.6, 3.2 Hz, 1H), 7.52 (d, J = 10.8 Hz, 1H), 7.46 (d, J = 2.0 Hz,1H), 5.82 - 5.73 (m, 1H), 4.61 - 4.52 (m, 1H), 4.47 - 4.37 (m, 2H), 4.33 (d,J = 11.2 Hz, 1H), 4.28 - 4.10 (m, 4H), 4.01 - 3.94 (m, 1H), 3.87 (t, J = 4.80Hz, 4H), 3.82 - 3.73 (m, 2H), 3.71 - 3.61 (m, 1H), 3.60-3.48 (m, 1H), 3.47 -3.38 (m, 9H), 3.29-3.24 (m, 1H), 3.17 - 2.98 (m, 3H), 2.86 - 2.75 (m, 1H), 2.74 - 2.63 (m, 1H), 2.41 - 2.28 (m, 3H), 2.26 - 2.12 (m, 3H), 2.04 (d, J =4.0 Hz, 3H), 2.00 - 1.90 (m, 1H), 1.88 - 1.72 (m, 1H), 1.70 - 1.56 (m, 1H), 1.49 (d, J = 6.00 Hz, 3H), 1.06 – 0.96 (m, 6H), 0.88 (d, J = 6.4 Hz, 3H), 0.61 (s, 3H).

[0656] Example 11

[0657] (2S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9 ,13 .0 19,27 .0 21,26[C31-1(28),2,5(31),19,25(29),26-hexen-7-yl]-3-methyl-2-(5-oxo-2-prop-2-enoyl-2,6-diazaspiro[3.4]octane-6-yl)butyramide

[0658]

[0659] Similar to the preparation in Example 7, this was achieved by using (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 [Tyrocarbon-1(28),2,5(31),19,25(29),26-hexane-8,14-dione (intermediate F) and acrylic acid-substituted (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-1] The title compound was prepared from 5-oxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]tetrate-1(28),2,5(31),19,25(29),26-hexaen-8,14-dione (intermediate G) and (2R)-2-chloro-2-fluoroacetic acid (compound 1h). Example 11 (21.6 mg) was obtained as a yellow solid. MS calculated value 990.5 (MH) + ); Measured value 990.5 (MH) + ). 1HNMR (400 MHz, Methanol-d4) δ = 8.44 (s, 1H), 8.37 (s, 1H), 7.81 - 7.71 (m, 1H), 7.53 (d, J = 18.8 Hz, 1H), 7.46 (d, J = 6.4 Hz, 1H), 6.41 - 6.26 (m, 2H), 5.81 - 5.74 (m, 2H), 4.57 - 4.13 (m, 9H), 4.02 (d, J = 10.0 Hz, 1H), 3.86 (t, J = 4.4 Hz, 4H), 3.81 - 3.47 (m, 5H), 3.45 - 3.38 (m, 9H), 3.14 - 3.01 (m, 3H), 2.84 - 2.76 (m, 1H), 2.71 - 2.63 (m, 1H), 2.42 - 2.31 (m, 3H), 2.25 - 2.16 (m, 3H), 1.95 - 1.60 (m, 3H), 1.48 (d, J = 6.4 Hz, 3H), 1.02 - 0.98 (m, 5H), 0.89 - 0.85 (m, 3H), 0.63 - 0.56 (m, 3H).

[0660] Example 12

[0661] (3S)-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3- pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]tritriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl- propyl]-N-methyl-1-(4-morpholinobut-2-ynoyl)pyrrolidine-3-carboxamide

[0662]

[0663] Example 1 using (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3- pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.12,5 .1 9,13 .0 19,27 .0 21,26 ]triaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate F) and 4-morpholinobut-2-ynoic acid (CAS 38346-95-1, SY291865-5g, Accela ChemBio Co., Ltd.) in place of (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1- methoxyethyl]-3-pyridinyl]-16,16-dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 ]tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaene-19,25-dione (Intermediate N) and (2R)-2-chloro-2-fluoro-acetic acid (Compound 1h) to prepare the title compound. Example 12 (29.1 mg) was obtained as a yellow solid. MS calculated 1089.6 (MH + ); measured 1089.6 (MH + ). 1H NMR (400 MHz, methanol-d4) δ = 8.63 - 8.43(m, 1H), 8.37 (s, 1H), 7.83 - 7.62 (m, 1H), 7.51 (d, J = 10.4 Hz, 1H), 7.45(d, J = 7.6 Hz, 1H), 5.81 - 5.60 (m, 1H), 4.82 - 4.77 (m, 3H), 4.57 - 4.49 (m,1H), 4.45 - 4.39 (m, 1H), 4.34 - 4.08 (m, 4H), 4.07 - 3.90 (m, 4H), 3.90 -3.84 (m, 5H), 3.84 - 3.78 (m, 2H), 3.76 (s, 2H), 3.72 - 3.57 (m, 5H), 3.46 -3.37 (m, 8H), 3.15 - 3.08 (m, 5H), 3.05 - 2.97 (m, 2H), 2.85 - 2.76 (m, 1H),2.69 - 2.61 (m, 1H), 2.37 - 2.18 (m, 6H), 1.99 - 1.92 (m, 1H), 1.86 - 1.76(m,1H), 1.69 - 1.60 (m, 1H), 1.52 - 1.44 (m, 3H), 1.09 - 0.97 (m, 6H), 0.94 -0.85 (m, 3H), 0.67 - 0.52 (m, 3H).

[0664] Example 13

[0665] (2S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 [C31-1(28),2,5(31),19,25(29),26-hexen-7-yl]-3-methyl-2-(5-oxo-2-prop-2-enoyl-2,6-diazaspiro[3.4]octane-6-yl)butyramide

[0666]

[0667] Similar to the preparation in Example 7, the title compound was prepared by substituting acrylic acid for (2R)-2-chloro-2-fluoro-acetic acid (compound 1h). Example 13 (9.5 mg) was obtained as a yellow solid. MS calculated value 1071.5 (MH) + ); Measured value 1071.5 (MH) + ). 1 H NMR (400 MHz, methanol-d4) δ = 8.45 (s, 1H), 8.36 (s, 1H), 7.91 (d, J = 2.4 Hz, 1H), 7.57 - 7.46 (m, 2H), 6.40 - 6.24 (m, 2H), 5.82 -5.74 (m, 2H), 4.60 - 4.53 (m, 1H), 4.51 - 4.39 (m, 2H), 4.33 - 4.31 (m, 1H), 4.30 - 4.21 (m, 3H), 4.15 - 4.09 (m, 1H), 4.01 (d, J = 10.0 Hz, 1H), 3.81 -3.73 (m, 2H), 3.70 - 3.63 (m, 1H), 3.53 - 3.49 (m, 4H), 3.45 (d, J = 5.6 Hz,3H), 3.40 (s, 1H), 3.29 - 3.24 (m, 1H), 3.22 - 3.14 (m, 3H), 3.13 - 3.09 (m,1H), 3.08 - 3.02 (m, 1H), 2.91 - 2.87 (m, 4H), 2.83 - 2.76 (m, 1H), 2.72 -2.66 (m, 1H), 2.40 - 2.30 (m, 3H), 2.25 - 2.17 (m, 3H), 1.98 - 1.91 (m, 1H),1.85 - 1.74 (m, 1H), 1.66 - 1.58 (m, 1H), 1.49 (d, J = 6.4 Hz, 3H), 1.37 -1.27 (m, 2H), 1.03 - 0.97 (m, 6H), 0.87 (d, J = 6.4 Hz, 3H), 0.62 (d, J = 6.0Hz, 3H).

[0668] Example 14

[0669] (2S)-2-(2-but-2-ynoyl-5-oxo-2,6-diazaspiro[3.4]octan-6-yl)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia- 9,21,30,31-tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]triaconta-1(28),2,5(31),19,25(29),26-hexene-7-yl]-3-methyl-butyramide

[0670]

[0671] The title compound was prepared in analogy to the preparation of Example 7 by using (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3- pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]triaconta-1(28),2,5(31),19,25(29),26-hexene-8,14-dione (Intermediate E) and but-2-ynoic acid instead of (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2- trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31- tetraazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]triaconta-1(28),2,5(31),19,25(29),26- hexene-8,14-dione (Intermediate G) and (2R)-2-chloro-2-fluoro-acetic acid (Compound 1h). Example 14 (21 mg) was obtained as a yellow solid. MS calculated 1015.5 (MH + ); measured 1015.5 (MH +) δ = 8.48 (d, J = 2.8 Hz, 1H), 8.41 (s, 1H), 7.62 (t, J = 3.2 Hz, 1H), 7.51 (d, J = 12.0 Hz, 1H), 7.44 (s, 1H), 5.80 - 5.68 (m, 1H), 4.52 - 4.47 (m, 1H), 4.44 - 4.38 (m, 2H), 4.35 - 4.31 (m, 1H) 4.30 - 4.11 (m, 5H) 3.97 (d, J = 10.0 Hz, 1H), 3.81 - 3.67 (m, 3H), 3.64 - 3.49 (m, 4H), 3.48 - 3.33 (m, 8H), 3.14 - 3.07 (m, 2H), 3.02 - 2.95 (m, 4H), 2.84 - 2.77 (m, 1H), 2.64 - 2.56 (m, 1H), 2.42 - 2.10 (m, 7H), 2.04 (d, J = 4.4 Hz, 3H), 1.98 - 1.92 (m, 1H), 1.84 - 1.74 (m, 1H), 1.66 - 1.57 (m, 1H), 1.46 (d, J = 6.4 Hz, 3H), 1.37 - 1.24 (m, 1H), 1.03 - 0.96 (m, 6 H), 0.87 (d, J = 6.4 Hz, 3H), 0.55 (s, 3H).

[0672] Example 15

[0673] 4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3- pyridinyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]tritriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N- methyl-1-prop-2-enoyl-piperidine-4-carboxamide

[0674]

[0675] The title compound was prepared in analogy to the preparation of Example 1 by using (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3- pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]tritriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate F), 1-tert-butoxycarbonyl-4-fluoro-piperidine-4-carboxylic acid and acrylic acid instead of (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1- methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 ]tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaene-19,25-dione (Intermediate N), (3S)-1-tert-butoxycarbonyl-pyrrolidine-3-carboxylic acid (Compound 1e) and (2R)-2-chloro-2-fluoro-acetic acid (Compound 1h). Example 15 (13.4 mg) was obtained as a yellow solid. MS calculated 1024.5 (MH + ), measured 1024.5 (MH + ). 1H NMR (400 MHz, Methanol-d4) δ = 8.43 (s, 1H), 8.37 (d, J = 2.8 Hz, 1H), 7.85 (s, 1H), 7.56 - 7.38 (m, 2H), 7.09 - 6.62 (m, 1H), 6.25 (d, J = 17.2 Hz, 1H), 6.09 - 5.44 (m, 2H), 4.73 (d, J = 11.2 Hz, 1H), 4.58 - 4.52 (m, 1H), 4.49 - 4.34 (m, 2H), 4.28 - 4.18 (m, 1H), 4.17 - 4.03 (m, 2H), 3.86 (t, J = 4.4 Hz, 4H), 3.81 - 3.71 (m, 2H), 3.71 - 3.63 (m, 1H), 3.56 - 3.47 (m, 1H), 3.46 - 3.33 (m, 8H), 3.29 - 3.23 (m, 1H), 3.18 (br d, J = 5.2 Hz, 3H), 3.15 - 3.07 (m, 2H), 3.04 - 3.00 (m, 1H), 2.86 - 2.74 (m, 1H), 2.69 (d, J = 14.0 Hz, 1H), 2.41 - 2.09 (m, 8H), 1.99 - 1.90 (m, 1H), 1.84 - 1.72 (m, 1H), 1.66 - 1.58 (m, 1H), 1.48 (d, J = 6.4 Hz, 3H), 1.40 - 1.26 (m, 2H), 1.02 - 0.96 (m, 5H), 0.95 - 0.86 (m, 3H), 0.61 (s, 3H).

[0676] Example 16

[0677] 1 -But-2-ynoyl-4-fluoro-N-[(1 S)-1 -[[(7S,13S)-(20M)-20-[2-[(1 S)-1 -methoxyethyl]-5- morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31 - tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26[31.1] Triaconta-1(30),2,4,6(31),13,28(29),29-hexaen-19,25-dione (Intermediate N), (3S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (Compound 1e), and (2R)-2-chloro-2-fluoro-acetic acid (Compound 1h) to prepare the title compound. Example 16 (11.2 mg) was obtained as a yellow solid. MS calculated 1036.5 (MH

[0678]

[0679] Example 1, by using (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5- morpholino-3-pyridinyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ] triaconta-1(30),2,4,6(31),13,28(29),29-hexaen-19,25-dione (Intermediate N), (3S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (Compound 1e), and (2R)-2-chloro-2-fluoro-acetic acid (Compound 1h) to prepare the title compound. Example 16 (11.2 mg) was obtained as a yellow solid. MS calculated 1036.5 (MH 2,6 .1 20,24 .0 4,14 .0 5,12 ] triaconta-1(30),2,4,6(31),13,28(29),29-hexaen-19,25-dione (Intermediate N), (3S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (Compound 1e), and (2R)-2-chloro-2-fluoro-acetic acid (Compound 1h) to prepare the title compound. Example 16 (11.2 mg) was obtained as a yellow solid. MS calculated 1036.5 (MH + ), measured 1036.4 (MH + , 1H NMR (400 MHz, Methanol-d4) δ = 8.43 (s, 1H), 8.37 (d, J = 2.8 Hz, 1H), 7.86 - 7.76 (m, 1H), 7.52 -7.44 (m, 2H), 5.88 - 5.64 (m, 1H), 4.77 - 4.68 (m, 1H), 4.56 - 4.51 (m, 1H),4.45 - 4.31 (m, 3H), 4.26 - 4.20 (m, 1H), 4.18 - 4.10 (m, 1H), 3.86 (t, J =4.8 Hz, 4H), 3.80 - 3.73 (m, 2H), 3.70 - 3.63 (m, 1H), 3.60 - 3.51 (m, 1H),3.44 - 3.40 (m, 7H), 3.35 (s, 1H), 3.28 - 3.21 (m, 1H), 3.18 (t, J = 5.2 Hz,3H), 3.11 - 3.00 (m, 3H), 2.86 - 2.76 (m, 1H), 2.73 - 2.64 (m, 1H), 2.31 -2.10 (m, 7H), 2.06 (d, J = 4.0 Hz, 3H), 1.98 - 1.91 (m, 1H), 1.85 - 1.75 (m,1H), 1.66 - 1.59 (m, 1H), 1.48 (d, J = 6.4 Hz, 3H), 1.35 - 1.28 (m, 3H), 1.02- 0.97 (m, 5H), 0.91 - 0.85 (m, 3H), 0.68 - 0.54 (m, 3H).

[0680] Example 17

[0681] cis-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3- pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]thirtyone-1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-3-(3,3,3-trifluoroprop-1-ynyl)cyclobutane carboxamide

[0682]

[0683] The title compound was prepared in analogy to the preparation of Example 1 by using (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3- pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]tritriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate F) and cis-(2S)-3-methyl-2-[methyl-[3-(3,3,3-trifluoroprop-1-ynyl)cyclobutanecarbonyl]amino]butanoic acid (Intermediate A2) instead of (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1- methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20, 24 .0 4,14 .0 5,12 ]tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaene-19,25-dione (Intermediate N) and Boc-N-Me-Val-OH (Compound 1b). Example 17 (21.4 mg) was obtained as a yellow solid. MS calculated 1015.5 (MH + ), measured 1015.5 (MH + ), 1H NMR (400 MHz, Methanol-d4) δ 8.44 (s, 1H), 8.36 (d, J = 2.8 Hz, 1H), 7.90 - 7.84 (m, 1H), 7.47 - 7.41 (m, 2H), 5.79 - 5.71 (m, 1H), 4.94 - 4.90 (m, 1H), 4.75 (d, J = 11.2 Hz, 1H), 4.60 - 4.51 (m, 1H), 4.47 - 4.36 (m, 1H), 4.28 - 4.19 (m, 1H), 4.18 - 4.09 (m, 1H), 3.86 (t, J = 4.8 Hz, 4H), 3.81 - 3.74 (m, 2H), 3.70 - 3.64 (m, 1H), 3.54 - 3.47 (m, 1H), 3.45 - 3.43 (m, 5H), 3.39 - 3.34 (m, 1H), 3.28 - 3.24 (m, 1H), 3.15 - 3.07 (m, 2H), 3.05 - 2.98 (m, 1H), 2.96 - 2.91 (m, 3H), 2.84 - 2.75 (m, 1H), 2.73 - 2.62 (m, 3H), 2.56 - 2.38 (m, 2H), 2.35 - 2.29 (m, 1H), 2.25 - 2.16 (m, 3H), 1.99 - 1.91 (m, 1H), 1.85 - 1.74 (m, 1H), 1.61 (dd, J = 3.6, 12.4 Hz, 1H), 1.48 (d, J = 6.0 Hz, 3H), 1.36 - 1.27 (m, 2H), 1.06 - 0.96 (m, 6H), 0.85 (d, J = 6.4 Hz, 3H), 0.66 - 0.57 (m, 3H)

[0684] Example 18

[0685] 1-[(2R)-2-chloro-2-fluoro-acetyl]-4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1- methoxy-ethyl]-5-morpholino-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4- thia-9,21,30,31-tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27.0 21,26 [[C31-1(28),2,5(31),19,25(29),26-hexene-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide]

[0686]

[0687] Similar to the preparation in Example 1, this was achieved by using (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 [Trin-1(28),2,5(31),19,25(29),26-hexane-8,14-dione (intermediate F) and 1-tert-butoxycarbonyl-4-fluoro-piperidine-4-carboxylic acid substitutes for (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33-triazahexane[26.3.1.1] 2,6 .1 20,24 .0 4,14 .0 5,12 The title compound was prepared from 34-carbon-1(31),2,4,6(34),13,28(32),29-heptaen-19,25-dione (intermediate N) and (3S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (compound 1e). Example 18 (11.2 mg) was obtained as a yellow solid. MS calculated value 1064.5 (MH) + ); Measured value 1064.7 (MH) + ). 1H NMR (400 MHz, methanol-d4) δ = 8.44 (s, 1H), 8.37 (d, J = 3.2 Hz,1H), 7.88 - 7.77 (m, 1H), 7.51 - 7.43 (m, 2H), 7.12 - 6.92 (m, 1H), 5.85 -5.67 (m, 1H), 4.78 - 4.66 (m, 1H), 4.54 (t, J = 6.4 Hz, 1H), 4.46 - 4.38 (m,1H), 4.37 - 4.28 (m, 1H), 4.26 - 4.18 (m, 1H), 4.17 - 4.08 (m, 1H), 3.86 (t,J = 4.8 Hz, 4H), 3.80 - 3.73 (m, 2H), 3.71 - 3.64 (m, 1H), 3.56 - 3.47 (m,1H), 3.45 - 3.40 (m, 7H), 3.38 - 3.34 (m, 1H), 3.27 - 3.22 (m, 1H), 3.17 (t,J = 5.6 Hz, 3H), 3.11 - 3.08 (m, 1H), 3.06 - 2.97 (m, 2H), 2.87 - 2.77 (m,1H), 2.73 - 2.65 (m, 1H), 2.41 - 2.11 (m, 8H), 2.09 - 1.89 (m, 2H), 1.83 -1.73 (m, 1H), 1.66 - 1.58 (m, 1H), 1.48 (d, J = 6.4 Hz, 3H), 1.34 - 1.28 (m,1H), 1.23 - 1.04 (m, 1H), 1.01 - 0.96 (m, 5H), 0.91 - 0.83 (m, 3H), 0.68 -0.56 (m, 3H).

[0688] Example 19

[0689] (2S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26[C31-1(28),2,5(31),19,25(29),26-hexen-7-yl]-3-methyl-2-(5-oxo-2-prop-2-enoyl-2,6-diazaspiro[3.4]octane-6-yl)butyramide]

[0690]

[0691] Similar to the preparation in Example 7, this was achieved by using (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 [Tyrocarbon-1(28),2,5(31),19,25(29),26-hexane-8,14-dione (intermediate E) and acrylic acid-substituted (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-1] The title compound was prepared from 5-oxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]tetrate-1(28),2,5(31),19,25(29),26-hexane-8,14-dione (intermediate G) and (2R)-2-chloro-2-fluoroacetic acid (compound 1h). Example 19 (5.2 mg) was obtained as a yellow solid. MS calculated value 1003.5 (MH) + ); Measured value 1003.8 (MH) + ). 1H NMR (400 MHz, Methanol-d4) δ = 8.48 (d, J = 2.4 Hz, 1H), 8.41 (s, 1H), 7.56 - 7.49 (m, 2H), 7.43 (d, J = 6.4 Hz, 1H), 6.41 - 6.26 (m, 2H), 5.78 (dd, J = 2.0, 10.0 Hz, 1H), 5.76 - 5.66 (m, 1H), 4.85 - 4.82 (m, 1H), 4.55 - 4.36 (m, 4H), 4.34 (d, J = 10.8 Hz, 1H), 4.31 - 4.16 (m, 5H), 4.05 - 4.01 (m, 1H), 3.76 (s, 2H), 3.62 - 3.50 (m, 4H), 3.46 - 3.42 (m, 2H), 3.39 (d, J = 6.0 Hz, 5H), 3.16 - 3.05 (m, 3H), 3.02 - 2.97 (m, 4H), 2.83 - 2.77 (m, 1H), 2.59 (dd, J = 7.2, 14.0 Hz, 1H), 2.40 - 2.34 (m, 2H), 2.33 - 2.27 (m, 1H), 2.26 - 2.18 (m, 3H), 1.96 (d, J = 14.8 Hz, 1H), 1.86 - 1.76 (m, 1H), 1.67 - 1.60 (m, 1H), 1.46 (d, J = 6.4 Hz, 3H), 1.34 - 1.29 (m, 1H), 1.02 - 0.97 (m, 6H), 0.90 - 0.86 (m, 3H), 0.54 (d, J = 4.8 Hz, 3H).

[0692] Example 20

[0693] (2S)-2-[2-[(2R)-2-chloro-2-fluoro-acetyl]-5-oxo-2,6-diazaspiro[3.4]octan-6-yl]-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxy-ethyl]-5-(4-methyl-piperazin-1-yl)-3-pyridyl]- 17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1 2,5 .1 9, 13 .0 19,27 .021,26 [C31-1(28),2,5(31),19,25(29),26-hexene-7-yl]-3-methyl-butanamide]

[0694]

[0695] Similar to the preparation in Example 7, this was achieved by using (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 The title compound was prepared by substituting (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hexacarbon-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (intermediate G) with 31-carbon-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (intermediate G). Example 19 (2.0 mg) was obtained as a yellow solid. MS calculated value: 1043.5 (MH). + ); Measured value 1043.8 (MH) + ). 1H NMR (400 MHz, Methanol-d4) δ = 8.47 (d, J = 2.8 Hz, 1H), 8.40 (s, 1H), 7.54 - 7.46 (m, 2H), 7.42 (d, J = 10.0 Hz, 1H), 6.76 - 6.61 (m, 1H), 5.80 - 5.69 (m, 1H), 4.61 - 4.56 (m, 1H), 4.51 - 4.42 (m, 2H), 4.41 - 4.37 (m, 1H), 4.35 - 4.32 (m, 1H), 4.31 - 4.22 (m, 3H), 4.10 - 4.05 (m, 1H), 3.76 (s, 2H), 3.62 - 3.50 (m, 4H), 3.45 - 3.42 (m, 2H), 3.38 (d, J = 4.8 Hz, 4H), 3.15 - 3.05 (m, 3H), 2.99 (s, 3H), 2.84 - 2.77 (m, 1H), 2.63 - 2.56 (m, 1H), 2.43 - 2.37 (m, 2H), 2.36 - 2.24 (m, 2H), 2.24 - 2.17 (m, 3H), 2.07 - 1.91 (m, 2H), 1.85 - 1.76 (m, 1H), 1.62 (dd, J = 4.0, 13.2 Hz, 1H), 1.45 (d, J = 6.0 Hz, 3H), 1.35 - 1.28 (m, 4H), 1.02 - 0.96 (m, 6H), 0.88 (dd, J = 2.4, 6.0 Hz, 3H), 0.54 (d, J = 2.8 Hz, 3H).

[0696] Example 21

[0697] cis-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3- pyridyl]-17, 17-dimethyl-8, 14-dioxo-15-oxa-4-thia-9, 21, 30, 31 - tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26[3-(3,3,3-trifluoroprop-1-ynyl)cyclobutyl]carbonyl]-2-methyl-propyl]-N-methyl-3-(3,3,3-trifluoroprop-1-ynyl)cyclobutane carboxamide

[0698]

[0699] Example 1 using (7S, 13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31- tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 Example 1 using (7S, 13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31- tetraazahexacyclo[23.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 Example 1 using (7S, 13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31- tetraazahexacyclo[23.3.1.1 + ); Measurement: 1028.4 (MH + ). 1H NMR (400 MHz, Methanol-d4) δ = 8.48 (d, J = 2.8 Hz, 1H), 8.41 (s, 1H), 7.63 - 7.55 (m, 1H), 7.49 - 7.43 (m, 1H), 7.42 - 7.38 (m, 1H), 5.80 - 5.67 (m, 1H), 4.75 (d, J = 10.8 Hz, 1H), 4.48 (q, J = 6.0 Hz, 1H), 4.42 (d, J = 11.6 Hz, 1H), 4.27 - 4.18 (m, 2H), 4.12 - 3.96 (m, 1H), 3.75 (s, 2H), 3.63 - 3.55 (m, 2H), 3.55 - 3.47 (m, 2H), 3.46 - 3.42 (m, 1H), 3.41 - 3.37 (m, 4H), 3.29 - 3.18 (m, 3H), 3.13 - 3.06 (m, 2H), 2.98 (s, 4H), 2.96 - 2.94 (m, 1H), 2.93 (s, 2H), 2.79 (dt, J = 3.2, 12.8 Hz, 1H), 2.70 - 2.58 (m, 3H), 2.54 - 2.42 (m, 2H), 2.39 - 2.14 (m, 5H), 1.95 (d, J = 13.2 Hz, 1H), 1.85 - 1.73 (m, 1H), 1.67 - 1.56 (m, 1H), 1.46 (d, J = 6.0 Hz, 3H), 1.36 - 1.25 (m, 2H), 1.05 - 0.96 (m, 6H), 0.85 (d, J = 6.8 Hz, 3H), 0.55 (s, 3H).

[0700] Example 22

[0701] (2S)-2-[2-(2-fluoroprop-2-enoyl)-5-oxo-2,6-diazaspiro[3.4]octan-6-yl]-N-[(7S,13S)- (20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14- dioxy-15-oxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26[C31-1(28),2,5(31),19,25(29),26-hexene-7-yl]-3-methyl-butanamide]

[0702]

[0703] Similar to the preparation in Example 7, this was achieved by using (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 [Tyrocarbon-1(28),2,5(31),19,25(29),26-hexane-8,14-dione (intermediate F) and 2-fluoropropionic-2-enoic acid substitutes for (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl] The title compound was prepared by reacting 15-oxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]tetrate-1(28),2,5(31),19,25(29),26-hexaen-8,14-dione (intermediate G) and (2R)-2-chloro-2-fluoroacetic acid (compound 1h). Example 22 (19.7 mg) was obtained as a yellow solid. MS calculated value 1008.5 (MH) + ); Measured value 1008.7 (MH) + ). 1H NMR (400 MHz, Methanol-d4) δ = 8.43 (s, 1H), 8.36 (d, J = 2.4 Hz, 1H), 7.82 - 7.76 (m, 1H), 7.55 - 7.43 (m, 2H), 5.81 - 5.74 (m, 1H), 5.66 - 5.51 (m, 1H), 5.28 - 5.21 (m, 1H), 4.64 - 4.59 (m, 1H), 4.57 - 4.52 (m, 1H), 4.45 - 4.39 (m, 2H), 4.33 (d, J = 11.2 Hz, 1H), 4.30 - 4.23 (m, 2H), 4.18 - 4.12 (m, 1H), 4.05 (d, J = 10.4 Hz, 1H), 3.87 (t, J = 4.4 Hz, 4H), 3.80 - 3.73 (m, 2H), 3.69 - 3.64 (m, 1H), 3.58 - 3.46 (m, 2H), 3.43 (d, J = 4.0 Hz, 5H), 3.41 (s, 3H), 3.29 - 3.25 (m, 1H), 3.16 - 3.11 (m, 1H), 3.10 - 3.07 (m, 1H), 3.06 - 2.99 (m, 1H), 2.84 - 2.77 (m, 1H), 2.71 - 2.65 (m, 1H), 2.40 - 2.36 (m, 2H), 2.34 - 2.30 (m, 1H), 2.24 - 2.16 (m, 3H), 1.99 - 1.92 (m, 1H), 1.84 - 1.77 (m, 1H), 1.68 - 1.60 (m, 1H), 1.48 (d, J = 6.4 Hz, 3H), 1.02 - 0.98 (m, 6H), 0.87 (dd, J = 3.2, 6.8 Hz, 3H), 0.63 - 0.58 (m, 3H).

[0704] Example 23

[0705] cis-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2- trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4- thia-9,21,30,31-tetraazahexacyclo[23.3.1.12,5 .1 9,13 .0 19,27 .0 21,26 ]triaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl- propyl]-N-methyl-3-(3,3,3-trifluoroprop-1-ynyl)cyclobutane carboxamide

[0706]

[0707] The title compound was prepared in analogy to the preparation of Example 1 by using (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2- trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31- tetraazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]triaconta-1(28),2,5(31),19,25(29),26- hexaen-8,14-dione (Intermediate G) and cis-(2S)-3-methyl-2-[methyl-[3-(3,3,3- trifluoroprop-1-ynyl)cyclobutane carboxyl]amino]butanoic acid (Intermediate A2) instead of (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3- pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.13,8.19,23.020,27]triaconta- 1(30),2,5(31),19,25(29),26-hexaen-8,14-dione (Intermediate A) and Boc-N-Me-Val-OH (Compound 1b). Example 23 (38.4 mg) was obtained as a yellow solid. MS calculated 1096.5 (MH+) ; found 1096.5 (MH+). 2,6 .1 20,24 .0 4,14 .0 5,12 ]tetratriaconta-1(32),2,4,6(34),13,28(32),29-heptaen-19,25-dione (Intermediate N) and Boc-N-Me-Val-OH (Compound 1b). Example 23 (38.4 mg) was obtained as a yellow solid. MS calculated 1096.5 (MH+) ; found 1096.5 (MH+). + ) ; found 1096.5 (MH+). + 1 ​HNMR (400 MHz, methanol-d4) δ = 8.43 (s, 1H), 8.36 (d, J = 2.8 Hz, 1H), 7.80 (d, J= 2.8 Hz, 1H), 7.47 - 7.40 (m, 2H), 5.82 - 5.71 (m, 1H), 4.75 (d, J = 10.8Hz, 1H), 4.53 (q, J = 6.0 Hz, 1H), 4.45 - 4.38 (m, 1H), 4.23 (dd, J = 3.2,12.0 Hz, 1H), 4.18 - 4.11 (m, 1H), 3.78 - 3.73 (m, 2H), 3.70 - 3.65 (m, 1H), 3.61 (q, J = 7.2 Hz, 1H), 3.49 - 3.46 (m, 4H), 3.44 - 3.41 (m, 3H), 3.28 -3.25 (m, 1H), 3.19 - 3.07 (m, 4H), 3.04 - 2.99 (m 1H), 2.97 - 2.93 (m, 1H), 2.92 (s, 2H), 2.88 (t, J = 4.8 Hz, 4H), 2.83 - 2.76 (m, 1H), 2.71 - 2.60 (m,3H), 2.54 - 2.41 (m, 2H), 2.39 - 2.24 (m, 2H), 2.24 - 2.13 (m, 3H), 1.99 -1.91 (m, 1H), 1.86 - 1.75 (m, 1H), 1.67 - 1.58 (m, 1H), 1.47 (d, J = 6.4 Hz,3H), 1.34 - 1.24 (m, 1H), 1.18 (t, J = 7.2 Hz, 1H), 1.08 - 1.02 (m, 1H), 1.01 - 0.96 (m, 4H), 0.88 - 0.83 (m, 3H), 0.65 - 0.57 (m, 3H).

[0708] Example 24

[0709] 4-Fluoro-1-(2-fluoroprop-2-enoyl)-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1]2,5 .1 9,13 .0 19,27 .0 21,26 ]thirty-one-carb-1(28),2,5(31),19,25(29),26-hexene-7-yl]carbamoyl]-2-methyl- propyl]-N-methyl-piperidine-4-carboxamide

[0710]

[0711] Prepared in analogy to Example 1 by using (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31- tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]thirty-one-carb-1(28),2,5(31),19,25(29),26-hexene-7-yl]carbamoyl]-2-methyl- propyl]-N-methyl-piperidine-4-carboxamide 2,6 .1 20,24 .0 4,14 .0 5,12 ]thirty-one-carb-1(28),2,5(31),19,25(29),26-hexene-7-yl]carbamoyl]-2-methyl- propyl]-N-methyl-piperidine-4-carboxamide + ); measured 1042.4 (MH + ). 1H NMR (400 MHz, methanol-d4) δ = 8.43 (s, 1H), 8.37 (d, J = 2.8 Hz, 1H), 7.80 (s, 1H), 7.47 (br d, J =15.2 Hz, 2H), 5.86 - 5.71 (m, 1H), 5.33 - 5.25 (m, 1H), 5.25 - 5.16 (m, 1H), 4.73 (d, J = 11.2 Hz, 1H), 4.53 (q, J = 5.6 Hz, 1H), 4.42 (br d, J = 13.6 Hz,1H), 4.23 (dd, J = 2.8, 12.0 Hz, 1H), 4.17 - 4.11 (m, 1H), 3.86 (t, J = 4.8Hz, 4H), 3.77 (d, J = 2.4 Hz, 1H), 3.70 - 3.64 (m, 1H), 3.61 (q, J = 6.0 Hz,3H), 3.43 - 3.39 (m, 7H), 3.28 - 3.23 (m, 1H), 3.18 (d, J = 5.2 Hz, 2H), 3.15- 3.07 (m, 2H), 3.05 - 3.01 (m, 1H), 2.85 - 2.76 (m, 1H), 2.72 - 2.65 (m,1H), 2.36 - 2.24 (m, 3H), 2.24 - 2.15 (m, 4H), 1.99 - 1.91 (m, 1H), 1.85 -1.74 (m, 1H), 1.68 - 1.59 (m, 1H), 1.48 (d, J = 6.0 Hz, 3H), 1.35 - 1.28 (m,2H), 1.18 (t, J = 7.2 Hz, 4H), 1.01 - 0.96 (m, 5H), 0.92 - 0.84 (m, 3H), 0.61 (s, 3H).

[0712] Example 25

[0713] 1-But-2-ynyl-4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1] 2,5 .19,13 .0 19,27 .0 21,26 ]triaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl- propyl]-N-methyl-piperidine-4-carboxamide

[0714]

[0715] Prepared in analogy to Example 1 by using (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-15-oxa-4- thia-9,21,30,31-tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]triaconta-1(28),2,5(31),19,25(29),26-hexaen-8,14-dione (Intermediate E), 1-tert- butoxycarbonyl-4-fluoro-piperidine-4-carboxylic acid and but-2-ynoic acid in place of (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3- pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 ]tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaen-19,25-dione (Intermediate N), (3S)-1-tert-butoxycarbonyl-pyrrolidine-3-carboxylic acid (Compound 1e) and (2R)-2-chloro-2-fluoro-acetic acid (Compound 1h) to give the title compound. Example 25 (49.7 mg) was obtained as a yellow solid. MS calculated 1049.5 (MH + ); measured 1049.8 (MH + ). 1H NMR (400MHz, Methanol-d4) δ = 8.48 (s, 1H), 8.40 (s, 1H), 7.68 - 7.46 (m, 2H), 7.44 -7.40 (m, 1H), 5.81 - 5.71 (m, 1H), 4.80 - 4.75 (m, 1H), 4.74 - 4.69 (m, 1H),4.49 - 4.31 (m, 4H), 4.29 - 4.11 (m, 3H), 3.79 - 3.68 (m, 3H), 3.63 - 3.54(m, 3H), 3.53 - 3.41 (m, 3H), 3.40 - 3.34 (m, 5H), 3.20 - 3.16 (m, 3H), 3.15- 3.12 (m, 1H), 3.11 - 3.04 (m, 2H), 2.99 (s, 5H), 2.84 - 2.75 (m, 1H), 2.65- 2.56 (m, 1H), 2.36 - 2.24 (m, 3H), 2.22 - 2.09 (m, 5H), 2.06 (d, J = 4.0Hz, 3H), 1.98 - 1.91 (m, 1H), 1.83 - 1.73 (m, 1H), 1.67 - 1.58 (m, 1H), 1.46(d, J = 6.0 Hz, 3H), 0.97 (s, 6H), 0.90 - 0.83 (m, 3H), 0.55 (s, 3H).

[0716] Example 26

[0717] 4-fluoro-1-(2-fluoroprop-2-enoyl)-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa- 4-thia-9,21,30,31 -tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]thirty-one carbon-1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl- propyl]-N-methyl-piperidine-4-carboxamide

[0718]

[0719] The title compound was prepared in analogy to the preparation of Example 1 by using (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1 -methoxyethyl]-5-(4-methylpiperazin-1 -yl)-3- pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31 -tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]tritriaconta-1 (28),2,5(31 ),19,25(29),26-hexaene-8,14-dione (Intermediate E), 1 -tert-butoxycarbonyl-4-fluoro-piperidine-4-carboxylic acid and 2-fluoroprop-2-enoic acid in place of (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1 - methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33-triaza- hexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 ]tetratriaconta-1 (31 ),2,4,6(34),13,28(32),29-heptaene-19,25-dione (Intermediate N), (3S)-1 -tert-butoxycarbonylpyrrolidine-3-carboxylic acid (Compound 1 e) and (2R)-2-chloro-2-fluoro-acetic acid (Compound 1 h). Example 26 (34.7 mg) was obtained as a yellow solid. MS calculated 1055.5 (MH + ); measured 1055.6 (MH + ). 1H NMR (400 MHz, Methanol-d4) δ 8.47 (s, 1H), 8.41 - 8.38 (m, 1H), 7.59 - 7.43 (m, 2H), 7.43 - 7.38 (m, 1H), 5.82 - 5.68 (m, 1H), 5.33 - 5.26 (m, 1H), 5.24 - 5.16 (m, 1H), 4.79 (s, 1H), 4.75 - 4.71 (m, 1H), 4.48 - 4.39 (m, 2H), 4.28 - 4.15 (m, 3H), 4.09 - 3.90 (m, 2H), 3.78 - 3.74 (m, 2H), 3.63 - 3.52 (m, 3H), 3.50 - 3.40 (m, 3H), 3.39 - 3.35 (m, 4H), 3.29 - 3.24 (m, 2H), 3.21 - 3.16 (m, 3H), 3.15 - 3.11 (m, 1H), 3.11 - 3.04 (m, 2H), 3.04 - 2.93 (m, 5H), 2.84 - 2.75 (m, 1H), 2.60 (d, J = 13.6 Hz, 1H), 2.37 - 2.26 (m, 3H), 2.25 - 2.11 (m, 5H), 1.99 - 1.90 (m, 1H), 1.84 - 1.74 (m, 1H), 1.69 - 1.58 (m, 1H), 1.48 - 1.42 (m, 3H), 1.02 - 0.93 (m, 6H), 0.92 - 0.83 (m, 3H), 0.55 (s, 3H).

[0720] Example 27

[0721] 1-[(2R)-2-chloro-2-fluoro-acetyl]-4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1- methoxy-ethyl]-5-(4-methyl-piperazin-1-yl)-3-pyridinyl]-17,17-dimethyl-8,14-dioxo- 15-oxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26[triaconta- 1 (28), 2, 5(31), 19, 25(29), 26-hexaen-7-yl] carbamoyl] -2-methyl- propyl] -N-methyl-piperidine-4-carboxamide

[0722]

[0723] Example 1 using (7S, 13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-17, 17-dimethyl-15-oxa-4-thia-9,21,30,31- tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 Example 1 using (7S, 13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-17, 17-dimethyl-15-oxa-4-thia-9,21,30,31- tetraazahexacyclo[23.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 Example 1 using (7S, 13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-17, 17-dimethyl-15-oxa-4-thia-9,21,30,31- tetraazahexacyclo[23.3.1.1 + ; measured 1077.5 (MH + ). 1H NMR (400 MHz, Methanol-d4) δ = 8.48 (s, 1H), 8.40 (s, 1H), 7.48 (s, 1H), 7.45 - 7.40 (m, 1H), 7.12 - 6.91 (m, 1H), 5.81 - 5.71 (m, 1H), 4.79 - 4.66 (m, 2H), 4.57 - 4.29 (m, 4H), 4.26 - 4.18 (m, 2H), 3.99 - 3.85 (m, 2H), 3.82 - 3.69 (m, 3H), 3.64 - 3.50 (m, 4H), 3.41 - 3.34 (m, 5H), 3.23 - 3.16 (m, 4H), 3.12 - 3.05 (m, 2H), 3.03 - 2.95 (m, 5H), 2.85 - 2.77 (m, 1H), 2.65 - 2.57 (m, 1H), 2.45 - 2.24 (m, 4H), 2.23 - 2.07 (m, 5H), 1.99 - 1.92 (m, 1H), 1.85 - 1.73 (m, 1H), 1.67 - 1.58 (m, 1H), 1.48 - 1.44 (m, 3H), 1.00 - 0.94 (m, 7H), 0.88 (d, J = 6.0 Hz, 3H), 0.61 - 0.53 (m, 3H).

[0724] Example 28

[0725] 1-[(2R)-2-chloro-2-fluoro-acetyl]-4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1- methoxy-ethyl]-5-morpholino-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4- thia-9,21,30,31-tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]thirty-one carbon-1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl- propyl]-N-methyl-piperidine-4-carboxamide

[0726]

[0727] Similar to the preparation in Example 1, this was achieved by using (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 [Trin-1(28),2,5(31),19,25(29),26-hexane-8,14-dione (intermediate I) and 1-tert-butoxycarbonyl-4-fluoro-piperidine-4-carboxylic acid replacing (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33-triazahexane[26.3.1.1] 2,6 .1 20,24 .0 4,14 .0 5,12 The title compound was prepared from 34-carbon-1(31),2,4,6(34),13,28(32),29-heptaen-19,25-dione (intermediate N) and (3S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (compound 1e). Example 28 (22.2 mg) was obtained as a yellow solid. MS calculated value 1066.4 (MH) + ); Measured value 1066.4 (MH) + ). 1H NMR (400 MHz, Methanol-d4) δ = 8.41 (br s, 1H), 8.26 (s, 1H), 7.91 (br s, 1H), 7.47 (br d, J = 4.8 Hz, 1H), 7.19 - 6.97 (m, 2H), 5.79 - 5.65 (m, 1H), 4.76 - 4.70 (m, 1H), 4.69 - 4.57 (m, 3H), 4.47 - 4.31 (m, 2H), 4.31 - 4.20 (m, 2H), 3.92 - 3.75 (m, 8H), 3.45 (br d, J = 4.5 Hz, 8H), 3.35 - 3.31 (m, 2H), 3.25 - 3.13 (m, 5H), 3.07 (br s, 1H), 2.86 - 2.75 (m, 1H), 2.73 - 2.64 (m, 1H), 2.50 - 2.04 (m, 6H), 2.02 - 1.91 (m, 1H), 1.87 - 1.73 (m, 1H), 1.70 - 1.57 (m, 1H), 1.55 - 1.48 (m, 3H), 1.10 - 1.04 (m, 3H), 1.02 - 0.94 (m, 3H), 0.89 (br d, J = 6.3 Hz, 2H), 0.61 (br d, J = 6.4 Hz, 3H).

[0728] Example 29

[0729] 4-fluoro-1-(2-fluoroprop-2-enoyl)-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-morpholino-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4- thia-9,21,30,31 -tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]thirty-one carbon-1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl- propyl]-N-methyl-piperidine-4-carboxamide

[0730]

[0731] The title compound was prepared in analogy to the preparation of Example 1 by using (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3- pyridyl]-17,17-dimethyl-15,24-dioxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]tritriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate I), 1-tert-butoxycarbonyl-4-fluoro-piperidine-4-carboxylic acid and 2-fluoro-prop-2-enoic acid in place of (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1- methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 ]tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaene-19,25-dione (Intermediate N), (3S)-1-tert-butoxycarbonyl-pyrrolidine-3-carboxylic acid (Compound 1e) and (2R)-2-chloro-2-fluoro-acetic acid (Compound 1h). Example 29 (22 mg) was obtained as a light yellow solid. MS calculated for 1044.5 (MH + ); measured 1044.7 (MH + ). 1H NMR (400 MHz, Methanol-d4) δ 8.37 (d, J = 2.8 Hz, 1H), 8.23 (s, 1H), 7.74 (br s, 1H), 7.48 (br s, 1H), 7.12 (s, 1H), 5.79 - 5.71 (m, 1H), 5.32 - 5.26 (m, 1H), 5.25 - 5.18 (m, 1H), 4.76 - 4.72 (m, 1H), 4.65 - 4.57 (m, 3H), 4.42 (br dd, J = 1.9, 11.7 Hz, 1H), 4.27 (td, J = 3.6, 12.0 Hz, 2H), 3.89 - 3.84 (m, 4H), 3.83 - 3.78 (m, 1H), 3.76 (s, 2H), 3.48 (br s, 2H), 3.44 - 3.37 (m, 9H), 3.19 (br d, J = 5.6 Hz, 3H), 3.13 (br s, 1H), 3.02 (s, 1H), 2.84 - 2.75 (m, 1H), 2.68 - 2.62 (m, 1H), 2.40 - 2.11 (m, 7H), 1.99 - 1.92 (m, 1H), 1.86 - 1.76 (m, 1H), 1.68 - 1.59 (m, 1H), 1.48 (d, J = 6.4 Hz, 3H), 1.03 (s, 3H), 1.00 - 0.95 (m, 3H), 0.88 (br d, J = 6.6 Hz, 3H), 0.58 (s, 3H).

[0732] Example 30

[0733] 1 -But-2-ynoyl-4-fluoro-N-[(1 S)-1 -[[(7S,13S)-(20M)-20-[2-[(1 S)-1 -methoxyethyl]-5- morpholino-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31 - tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]thirty-one carbon-1 (28),2,5(31 ),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl- propyl]-N-methyl-piperidine-4-carboxamide

[0734]

[0735] The title compound was prepared in analogy to the preparation of Example 1 by using (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3- pyridyl]-17,17-dimethyl-15,24-dioxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]tritriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate I), 1-tert-butoxycarbonyl-4-fluoro-piperidine-4-carboxylic acid and but-2-ynoic acid in place of (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1- methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 ]tetraconta-1(31),2,4,6(34),13,28(32),29-heptaene-19,25-dione (Intermediate N), (3S)-1-tert-butoxycarbonyl-pyrrolidine-3-carboxylic acid (Compound 1e) and (2R)-2-chloro-2-fluoro-acetic acid (Compound 1h). Example 30 (17.7 mg) was obtained as a light yellow solid. MS calculated 1038.5 (MH + ); measured 1038.8 (MH + ). 1H NMR (400 MHz, Methanol-d4) δ = 8.37 (d, J = 2.8 Hz, 1H), 8.23 (s, 1H), 7.80 (dd, J = 2.6, 7.0 Hz, 1H), 7.48 (d, J = 4.3 Hz, 1H), 7.13 (d, J = 3.6 Hz, 1H), 5.80 - 5.69 (m, 1H), 4.72 (br d, J = 11.0 Hz, 1H), 4.59 (br d, J = 6.1 Hz, 3H), 4.45 - 4.30 (m, 4H), 4.28 - 4.22 (m, 2H), 3.88 - 3.84 (m, 4H), 3.83 - 3.78 (m, 1H), 3.76 (s, 2H), 3.61 - 3.46 (m, 2H), 3.46 - 3.37 (m, 9H), 3.18 (dd, J = 2.6, 5.5 Hz, 3H), 3.15 - 3.11 (m, 1H), 3.06 - 2.95 (m, 1H), 2.84 - 2.75 (m, 1H), 2.69 - 2.62 (m, 1H), 2.33 - 2.08 (m, 7H), 1.99 - 1.92 (m, 1H), 1.87 - 1.77 (m, 1H), 1.67 - 1.57 (m, 1H), 1.50 - 1.46 (m, 3H), 1.05 - 1.01 (m, 3H), 1.00 - 0.94 (m, 3H), 0.88 (br d, J = 6.6 Hz, 3H), 0.58 (br s, 3H).

[0736] Example 31

[0737] 1-[(2R)-2-chloro-2-fluoro-acetyl]-4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1- methoxy-ethyl]-5-(4-methyl-piperazin-1-yl)-3-pyridinyl]-17,17-dimethyl-8,14-dioxo- 15,24-dioxa-4-thia-9,21,30,31 -tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26[31.1.1.1.1

[0738]

[0739] Example 31 was prepared in analogy to the preparation of Example 1 by using (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3- pyridyl]-17,17-dimethyl-15,24-dioxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]tricosa-1(28),2,5(31),19,25(29),26-hexaen-8,14-dione (Intermediate H) and (3S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (Compound 1e) in place of (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3- pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 ]tetracosa-1(31),2,4,6(34),13,28(32),29-heptaen-19,25-dione (Intermediate N) and (3S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (Compound 1e) in place of (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3- pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 + ; measured 1079.8 (MH + ). 1H NMR (400 MHz, Methanol-d4) δ = 8.23 (s, 1H), 7.68 (s, 1H), 7.49 (d, J = 3.2 Hz, 1H), 7.14 (d, J = 10 Hz, 1H), 7.00 (s, 1H), 5.75 - 5.71 (m, 1H), 4.79 - 4.70 (m, 1H), 4.66 - 4.54 (m, 3H), 4.45 - 4.25 (m, 4H), 4.10 (br s, 3H), 3.81 - 3.74 (m, 3H), 3.70 - 3.47 (m, 4H), 3.46 - 3.37 (m, 5H), 3.28 - 3.14 (m, 6H), 3.10 - 2.90 (m, 4H), 2.86 - 2.75 (m, 1H), 2.67 - 2.57 (m, 1H), 2.05 (s, 6H), 2.02 - 1.93 (m, 1H), 1.88 - 1.75 (m, 1H), 1.71 - 1.57 (m, 1H), 1.53 - 1.43 (m, 3H), 1.42 - 1.23 (m, 1H), 1.22 - 0.79 (m, 10H), 0.64 - 0.48 (m, 3H).

[0740] Example 32

[0741] 4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4- thia-9,21,30,31 -tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]tritriaconta-1 (28),2,5(31),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl- propyl]-N-methyl-1-prop-2-enoyl-piperidine-4-carboxamide

[0742]

[0743] The title compound was prepared in analogy to the preparation of Example 1 by using (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3- pyridyl]-17,17-dimethyl-15,24-dioxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]tritriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate H), 1-tert-butoxycarbonyl-4-fluoro-piperidine-4-carboxylic acid and acrylic acid in place of (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]- 16,16-dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.13 2,6 .1 20,24 .0 4,14 .0 5,12 ]tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaene-19,25-dione (Intermediate N), (3S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (Compound 1e) and (2R)-2-chloro-2-fluoro-acetic acid (Compound 1h). Example 32 (18.9 mg) was obtained as a light yellow solid. MS calculated 1039.5 (MH + ); measured 1039.5 (MH + ). 1H NMR (400 MHz, Methanol-d4) δ 8.50 (d, J = 2.8 Hz, 1H), 8.24 - 8.17 (m, 1H), 7.70 - 7.59 (m, 1H), 7.52 - 7.44 (m, 1H), 7.15 - 7.06 (m, 1H), 6.89 - 6.77 (m, 1H), 6.29 - 6.20 (m, 1H), 5.81 - 5.75 (m, 1H), 5.75 - 5.66 (m, 1H), 4.76 - 4.69 (m, 1H), 4.67 - 4.59 (m, 2H), 4.55 (br d, J = 6.3 Hz, 1H), 4.48 - 4.38 (m, 2H), 4.33 - 4.25 (m, 2H), 4.19 - 3.90 (m, 3H), 3.80 - 3.66 (m, 4H), 3.53 (br s, 3H), 3.45 - 3.34 (m, 6H), 3.22 - 3.12 (m, 5H), 3.04 - 2.94 (m, 4H), 2.84 - 2.75 (m, 1H), 2.65 - 2.54 (m, 1H), 2.42 - 2.02 (m, 7H), 2.00 - 1.93 (m, 1H), 1.87 - 1.76 (m, 1H), 1.68 - 1.59 (m, 1H), 1.49 - 1.43 (m, 3H), 1.05 - 1.00 (m, 3H), 0.99 - 0.94 (m, 3H), 0.92 - 0.81 (m, 3H), 0.53 (s, 3H).

[0744] Example 33

[0745] 1 -But-2-ynoyl-4-fluoro-N-[(1 S)-1 -[[(7S,13S)-(20M)-20-[2-[(1 S)-1 -methoxyethyl]-5-(4- methylpiperazin-1 -yl)-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia- 9,21,30,31 -tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]thirtyonecarbon-1 (28),2,5(31),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl- propyl]-N-methyl-piperidine-4-carboxamide

[0746]

[0747] The title compound is prepared in analogy to the preparation of Example 1 by using (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3- pyridyl]-17,17-dimethyl-15,24-dioxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]tritriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate H), 1-tert-butoxycarbonyl-4-fluoro-piperidine-4-carboxylic acid and but-2-ynoic acid in place of (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1- methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 ]tetraconta-1(31),2,4,6(34),13,28(32),29-heptaene-19,25-dione (Intermediate N), (3S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (Compound 1e) and (2R)-2-chloro-2-fluoro-acetic acid (Compound 1h). Example 33 (25.1 mg) is obtained as a light yellow solid. MS calculated 1051.5 (MH + ); measured 1051.8 (MH + ). 1HNMR (400 MHz, methanol-d4) δ = 8.49 (s, 1H), 8.20 (s, 1H), 7.67 - 7.60 (m, 1H), 7.50 - 7.45 (m, 1H), 7.13 - 7.08 (m, 1H), 5.79 - 5.61 (m, 1H), 4.76 - 4.68(m, 1H), 4.67 - 4.58 (m, 2H), 4.54 (d, J = 6.4 Hz, 1H), 4.48 - 4.21 (m, 6H), 3.79 - 3.73 (m, 3H), 3.52 (br s, 3H), 3.47 - 3.35 (m, 6H), 3.19 (br d, J =5.4 Hz, 6H), 3.04 - 2.94 (m, 4H), 2.86 - 2.75 (m, 1H), 2.63 - 2.55 (m, 1H), 2.38 - 2.11 (m, 6H), 2.09 - 2.00 (m, 4H), 1.99 - 1.92 (m, 1H), 1.87 - 1.75(m, 1H), 1.68 - 1.58 (m, 1H), 1.49 - 1.43 (m, 3H), 1.22 - 1.12 (m, 1H), 1.02(s, 6H), 0.92 - 0.81 (m, 3H), 0.53 (s, 3H).

[0748] Example 34

[0749] (3R)-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 [C31-1(28),2,5(31),19,25(29),26-hexen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-1-prop-2-enoyl-pyrrolidine-3-carboxamide]

[0750]

[0751] Example 1, by using (7S, 13S)-7-amino-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31- tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]triaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate F) and acrylic acid in place of (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1- methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20, 24 .0 4,14 .0 5,12 ]tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaene-19,25-dione (Intermediate N) and (2R)-2-chloro-2-fluoro-acetic acid (Compound 1h) to prepare the title compound. Example 34 (41.0 mg) was obtained as a yellow solid. MS calculated for C58H73C12F2N8O10(MH+) 992.5 (MH + ); measured 992.5 (MH + ). 1H NMR (400 MHz, Methanol-d4) δ 8.46 - 8.35 (m, 2H), 7.74 (s, 1H), 7.55 - 7.41 (m, 2H), 7.00 - 6.84 (m, 1H), 6.68 - 6.55 (m, 1H), 6.35 - 6.24 (m, 1H), 5.85 - 5.67 (m, 2H), 4.83 - 4.75 (m, 1H), 4.57 - 4.48 (m, 1H), 4.44 - 4.39 (m, 1H), 4.29 - 4.12 (m, 2H), 3.87 - 3.79 (m, 7H), 3.78 - 3.73 (m, 2H), 3.69 - 3.56 (m, 3H), 3.44 - 3.38 (m, 7H), 3.28 - 3.21 (m, 1H), 3.14 - 3.06 (m, 5H), 3.03 - 2.99 (m, 1H), 2.84 - 2.73 (m, 1H), 2.71 - 2.60 (m, 1H), 2.34 - 2.18 (m, 5H), 2.00 - 1.88 (m, 1H), 1.85 - 1.72 (m, 1H), 1.67 - 1.55 (m, 1H), 1.47 (d, J = 6.4 Hz, 3H), 1.03 - 0.95 (m, 7H), 0.91 - 0.80 (d, J = 6.4 Hz, 3H), 0.65 - 0.54 (m, 3H).

[0752] Example 35

[0753] (3R)-1 -but-2-ynoyl-N-[(1 S)-1 -[[(7S,13S)-(20M)-20-[2-[(1 S)-1 -methoxyethyl]-5- morpholino-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31 - tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]thirty-one carbon-1 (28),2,5(31 ),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl- propyl]-N-methyl-pyrrolidine-3-carboxamide

[0754]

[0755] The title compound was prepared in analogy to the preparation of Example 1 by using (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3- pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]tritriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate F) and but-2-ynoic acid instead of (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1- methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20 ,24 .0 4,14 .0 5,12 ]tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaene-19,25-dione (Intermediate N) and (2R)-2-chloro-2-fluoro-acetic acid (Compound 1h). Example 35 (12.9 mg) was obtained as a yellow solid. MS calculated for C58H73C12F2N8O10(MH+) 1004.5 (MH + ); measured 1004.6 (MH + ). 1H NMR (400 MHz, Methanol-d4) δ 8.43 (s, 1H), 8.37 (s, 1H), 7.84 - 7.72 (m, 1H), 7.50 (d, J = 3.2 Hz, 1H), 7.45 (s, 1H), 5.84 - 4.61 (m, 1H), 4.83 - 4.77 (m, 1H), 4.59 - 4.49 (m, 1H), 4.44 - 4.39 (m, 1H), 4.30 - 4.22 (m, 1H), 4.20 - 4.13 (m, 1H), 3.99 - 3.90 (m, 1H), 3.88 - 3.84 (m, 4H), 3.82 - 3.79 (m, 1H), 3.79 - 3.69 (m, 4H), 3.68 - 3.55 (m, 3H), 3.45 - 3.39 (m, 7H), 3.28 - 3.21 (m, 1H), 3.14 - 3.00 (m, 6H), 2.84 - 2.74 (m, 1H), 2.65 (d, J = 14.8 Hz, 1H), 2.33 - 2.13 (m, 6H), 2.08 - 2.02 (m, 2H), 1.98 - 1.91 (m, 2H), 1.85 - 1.75 (m, 1H), 1.67 - 1.57 (m, 1H), 1.48 (d, J = 6.4 Hz, 3H), 1.02 - 0.96 (m, 6H), 0.91 - 0.81 (m, 3H), 0.65 - 0.55 (m, 3H).

[0756] Example 36

[0757] 4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]thirty-one-carb-1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl- propyl]-N-methyl-1-prop-2-enoyl-piperidine-4-carboxamide

[0758]

[0759] The title compound was prepared in analogy to the preparation of Example 1 by using (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1 -methoxyethyl]-5-(4-methylpiperazin-1 -yl)-3- pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31 -tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]tritriaconta-1 (28),2,5(31 ),19,25(29),26-hexaene-8,14-dione (Intermediate E), 1 -tert-butoxycarbonyl-4-fluoro-piperidine-4-carboxylic acid and acrylic acid in place of (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1 -methoxyethyl]-3- pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 ]tetratriaconta-1 (31 ),2,4,6(34),13,28(32),29-heptaene-19,25-dione (Intermediate N), (3S)-1 -tert-butoxycarbonylpyrrolidine-3-carboxylic acid (Compound 1 e) and (2R)-2-chloro-2-fluoro-acetic acid (Compound 1 h). Example 36 (24.5 mg) was obtained as a yellow solid. MS calculated 1037.5 (MH + ); measured 1037.6 (MH + ). 1H NMR (400MHz, Methanol-d4) δ = 8.47 (d, J = 2.8 Hz, 1H), 8.40 (s, 1H), 7.51 - 7.40 (m, 3H), 6.87 - 6.77 (m, 1H), 6.25 (d, J = 16.8 Hz, 1H), 5.81 - 5.72 (m, 2H), 4.73 (d, J = 11.2 Hz, 1H), 4.49 - 4.40 (m, 3H), 4.27 - 4.20 (m, 2H), 4.08 (s, 2H), 3.83 - 3.73 (m, 3H), 3.63 - 3.52 (m, 4H), 3.44 - 3.35 (m, 7H), 3.27 - 3.18 (m, 5H), 3.14 - 3.04 (m, 3H), 2.99 (s, 4H), 2.84 - 2.77 (m, 1H), 2.59 (d, J = 14.4 Hz, 1H), 2.35 - 2.26 (m, 3H), 2.24 - 2.13 (m, 5H), 1.99 - 1.92 (m, 1H), 1.85 - 1.77 (m, 1H), 1.68 - 1.60 (m, 1H), 1.45 (d, J = 6.0 Hz, 3H), 1.01 - 0.95 (m, 6H), 0.88 (d, J = 6.4 Hz, 3H), 0.54 (s, 3H).

[0760] Example 37

[0761] (2S)-2-[(5R)-7-but-2-ynoyl-l-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-N-[(7S,13S)- (20M)-20-[2-[(lS)-l-methoxyethyl]-5-(4-methylpiperazin-l-yl)-3-pyridinyl]- 17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21 ,26 ]thirty-one-carb-1(28),2,5(31),19,25(29),26-hexaen-7-yl]-3-methyl-butyramide

[0762]

[0763] Similar to the preparation in Example 7, this was achieved by using (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 [C31-1(28),2,5(31),19,25(29),26-hexane-8,14-dione (intermediate E), (2S)-2-[(5R)-7-tert-butoxycarbonyl-1-oxo-2,7-diazaspiro[4.4]nonane-2-yl]-3-methyl-butyric acid (intermediate A3) and but-2-alkynyl acid substitutes for (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-di] The title compound was prepared by reacting methyl-15-oxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.12,5.19,13.019,27.021,26]tetratec-1(28),2,5(31),19,25(29),26-hexaden-8,14-dione (intermediate G), (2S)-2-(2-tert-butoxycarbonyl-5-oxo-2,6-diazaspiro[3.4]octane-6-yl)-3-methyl-butyric acid (intermediate A1) and (2R)-2-chloro-2-fluoro-acetic acid (compound 1h). Example 37 (11.1 mg) was obtained as a yellow solid. MS calculated value 1029.5 (MH) + ); Measured value 1029.7 (MH) + ). 1H NMR (400 MHz, Methanol-d4) δ = 8.47 (d, J = 2.4 Hz, 1H), 8.40 (s, 1H), 7.53 - 7.45 (m, 2H), 7.42 (s, 1H), 5.75 (t, J = 7.8 Hz, 1H), 4.49 - 4.37 (m, 2H), 4.34 - 4.20 (m, 3H), 4.02 - 3.84 (m, 2H), 3.80 - 3.35 (m, 18H), 3.28 - 3.23 (m, 1H), 3.13 - 3.05 (m, 2H), 2.99 (s, 4H), 2.87 - 2.74 (m, 1H), 2.65 - 2.53 (m, 1H), 2.36 - 2.14 (m, 5H), 2.09 - 2.02 (m, 5H), 2.00 - 1.90 (m, 2H), 1.86 - 1.73 (m, 1H), 1.69 - 1.55 (m, 1H), 1.45 (d, J = 6.0 Hz, 3H), 1.18 (t, J = 7.2 Hz, 1H), 1.03 - 0.95 (m, 6H), 0.89 (t, J = 6.4 Hz, 3H), 0.54 (s, 3H).

[0764] Example 38

[0765] 4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3- pyridinyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]trihentacos-1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N- methyl-1-prop-2-enoyl-piperidine-4-carboxamide

[0766]

[0767] The title compound was prepared in analogy to the preparation of Example 1 by using (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1 -methoxyethyl]-5-morpholino-3- pyridyl]-17,17-dimethyl-15,24-dioxa-4-thia-9,21,30,31 -tetraazahexacyclo[23.3.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]tritriaconta-1 (28),2,5(31 ),19,25(29),26-hexaene-8,14-dione (Intermediate I), 1 -tert-butoxycarbonyl-4-fluoro-piperidine-4-carboxylic acid and acrylic acid instead of (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1 - methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33-triaza- hexacyclo[26.3.1 2,6 .1 20,24 .0 4,14 .0 5,12 ]tetratriaconta-1 (31 ),2,4,6(34),13,28(32),29-heptaene-19,25-dione (Intermediate N), (3S)-1 -tert-butoxycarbonyl-pyrrolidine-3-carboxylic acid (Compound 1 e) and (2R)-2-chloro-2-fluoro-acetic acid (Compound 1 h). Example 38 (1 1.3 mg) was obtained as a light yellow solid. MS calculated 1026.5 (MH + ); measured 1026.4 (MH + ). 1H NMR (400 MHz, Methanol-d4) δ = 8.38 (d, J = 2.4 Hz, 1H), 8.28 - 8.18 (m, 1H), 7.84 (s, 1H), 7.49 (d, J = 10.9 Hz, 1H), 7.13 (dd, J = 2.8, 5.9 Hz, 1H), 6.83 (dd, J = 10.5, 16.6 Hz, 1H), 6.25 (d, J = 16.9 Hz, 1H), 5.92 - 5.65 (m, 2H), 4.73 (d, J = 11.0 Hz, 1H), 4.69 - 4.57 (m, 3H), 4.49 - 4.39 (m, 2H), 4.25 (t, J = 11.6 Hz, 2H), 4.16 - 4.02 (m, 1H), 3.89 - 3.84 (m, 4H), 3.82 - 3.72 (m, 3H), 3.58 - 3.49 (m, 1H), 3.46 - 3.37 (m, 8H), 3.22 - 3.15 (m, 4H), 3.09 - 2.95 (m, 1H), 2.84 - 2.73 (m, 1H), 2.72 - 2.63 (m, 1H), 2.29 - 2.10 (m, 5H), 1.94 (s, 1H), 1.89 - 1.73 (m, 1H), 1.70 - 1.55 (m, 1H), 1.49 (d, J = 6.3 Hz, 3H), 1.39 - 1.28 (m, 1H), 1.31 (t, J = 7.4 Hz, 1H), 1.04 (s, 3H), 0.98 (d, J = 6.3 Hz, 3H), 0.88 (d, J = 6.5 Hz, 3H), 0.59 (s, 3H).

[0768] Example 39

[0769] N-[(1S)-1-[[(7S,13S)-23,23-difluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26[31.1.1.1.1]thirty-one-carb-1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-4-fluoro-N-methyl-1-prop-2-enoyl-piperidine-4-carboxamide

[0770]

[0771] Prepared in analogy to Example 1 by using (7S,13S)-7-amino-23,23-difluoro-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31- tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]thirty-one-carb-1(28),2,5(31),19,25(29),26-hexaen-8,14-dione (Intermediate J), 1-tert-butoxycarbonyl-4-fluoro-piperidine-4-carboxylic acid and acrylic acid in place of (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 ]thirty-one-carb-1(28),2,5(31),19,25(29),26-hexaen-8,14-dione (Intermediate J), 1-tert-butoxycarbonyl-4-fluoro-piperidine-4-carboxylic acid and acrylic acid in place of (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 + ); measured 1073.5 (MH + ). 1H NMR (400 MHz, Methanol-d4) δ 8.52 (d, J = 2.8 Hz, 2H), 7.56 (d, J = 4.0 Hz, 2H), 6.82 (dd, J = 10.8, 16.8 Hz, 1H), 6.25 (d, J = 16.8 Hz, 1H), 5.86 - 5.66 (m, 2H), 4.83 - 4.79 (m, 1H), 4.73 (d, J = 11.2 Hz, 1H), 4.59 - 4.38 (m, 4H), 4.29 - 4.22 (m, 1H), 4.12 - 4.06 (m, 1H), 4.02 - 3.82 (m, 2H), 3.80 - 3.73 (m, 2H), 3.70 - 3.46 (m, 6H), 3.45 - 3.42 (m, 1H), 3.41 - 3.36 (m, 4H), 3.36 - 3.32 (m, 1H), 3.30 - 3.22 (m, 2H), 3.19 (d, J = 5.2 Hz, 3H), 3.14 - 3.09 (m, 1H), 3.07 - 2.89 (m, 4H), 2.85 - 2.76 (m, 1H), 2.66 - 2.56 (m, 1H), 2.35 - 2.09 (m, 6H), 2.00 - 1.92 (m, 1H), 1.86 - 1.74 (m, 1H), 1.68 - 1.58 (m, 1H), 1.47 (d, J = 6.0 Hz, 3H), 1.34 - 1.28 (m, 1H), 1.06 - 0.93 (m, 6H), 0.93 - 0.82 (m, 3H), 0.57 (s, 3H).

[0772] Example 40

[0773] N-[(1S)-1-[[(7S,13S)-23,23-difluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3- pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26[3-(7S, 13S)-7-amino-23,23-difluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5- morpholino-3-pyridinyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1

[0774]

[0775] Example 1 using (7S, 13S)-7-amino-23,23-difluoro-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-morpholino-3-pyridinyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31- tetraazahexacyclo[23.3.1.1 2,5 9,13 19,27 21,26 Example 1 using (7S, 13S)-7-amino-23,23-difluoro-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-morpholino-3-pyridinyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31- tetraazahexacyclo[23.3.1.1 2,6 20,24 4,14 5,12 Example 1 using (7S, 13S)-7-amino-23,23-difluoro-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-morpholino-3-pyridinyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31- tetraazahexacyclo[23.3.1.1 + + 1 ​​​​​​​​H NMR (400 MHz, Methanol-d4) δ 8.54 (s, 1H), 8.41 (d, J = 2.8 Hz, 1H), 7.84 (s, 1H), 7.58 (d, J = 16.4 Hz, 2H), 5.84 - 5.73 (m, 1H), 5.32 - 5.26 (m, 1H), 5.24 - 5.17 (m, 1H), 4.72 (d, J = 11.2 Hz, 1H), 4.60 - 4.54 (m, 1H), 4.52 - 4.40 (m, 2H), 4.24 (dd, J = 3.2, 12.0 Hz, 1H), 4.10 - 3.96 (m, 2H), 3.88 – 3.84 (m, 4H), 3.82 - 3.72 (m, 2H), 3.69 - 3.51 (m, 3H), 3.44 - 3.42 (m, 6H), 3.40 - 3.36 (m, 1H), 3.30 - 3.21 (m, 2H), 3.18 (d, J = 5.2 Hz, 3H), 3.13 - 3.07 (m, 1H), 2.84 - 2.76 (m, 1H), 2.75 - 2.67 (m, 1H), 2.33 - 2.13 (m, 6H), 1.99 - 1.91 (m, 1H), 1.84 - 1.73 (m, 1H), 1.68 - 1.59 (m, 1H), 1.50 (d, J = 6.4 Hz, 3H), 1.37 - 1.25 (m, 1H), 1.12 - 1.04 (m, 1H), 1.03 - 0.94 (m, 6H), 0.87 (d, J = 6.8 Hz, 3H), 0.63 (s, 3H).

[0776] Example 41

[0777] 1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(7S,13S)-23,23-difluoro-(20M)-20-[2-[(1S)-1-methoxy-ethyl]-5-morpholino-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26[triaconta- 1 (29), 2, 5(31), 19, 25, 27-hexen-7-yl] carbamoyl] -2-methyl- propyl] -4-fluoro-N-methyl-piperidine-4-carboxamide

[0778]

[0779] The title compound is prepared in analogy to the preparation of Example 1 by using (7S, 13S)-7-amino-23, 23-difluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5- morpholino-3-piperidyl]-17, 17-dimethyl-15-oxa-4-thia-9, 21, 30, 31-tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]triaconta- 1 (28), 2, 5(31), 19, 25(29), 26-hexaen-8, 14-dione (Intermediate M) and (3S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (Compound 1e) instead of (20S, 26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3- piperidyl]-16, 16-dimethyl-7, 18-dioxa-12, 24, 33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 ]tetratriaconta- 1 (31), 2, 4, 6(34), 13, 28(32), 29-heptaen-19, 25-dione (Intermediate N) and (3S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (Compound 1e) instead of (20S, 26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1-methoxyethyl]-3- piperidyl]-16, 16-dimethyl-7, 18-dioxa-12, 24, 33-triazahexacyclo[26.3.1.1 + ) 1100.5 (MH + ). 1H NMR (400 MHz, Methanol-d4) δ = 8.54 (s, 1H), 8.44 - 8.39 (m, 1H), 7.90 - 7.80 (m, 1H), 7.65 - 7.53 (m, 2H), 7.13 - 6.92 (m, 1H), 5.85 - 5.71 (m, 1H), 4.77 - 4.66 (m, 1H), 4.61 - 4.54 (m, 1H), 4.52 - 4.39 (m, 2H), 4.38 - 4.29 (m, 1H), 4.28 - 4.19 (m, 1H), 4.10 - 3.90 (m, 2H), 3.88 - 3.84 (m, 4H), 3.82 - 3.72 (m, 2H), 3.71 - 3.57 (m, 2H), 3.55 - 3.50 (m, 1H), 3.44 - 3.41 (m, 6H), 3.40 - 3.33 (m, 1H), 3.28 - 3.23 (m, 1H), 3.20 - 3.15 (m, 3H), 3.14 - 3.06 (m, 1H), 2.84 - 2.66 (m, 2H), 2.42 - 2.09 (m, 6H), 1.97 - 1.91 (m, 1H), 1.83 - 1.73 (m, 1H), 1.67 - 1.58 (m, 1H), 1.50 (d, J = 6.0 Hz, 3H), 1.42 - 1.22 (m, 1H), 1.14 - 1.04 (m, 1H), 1.03 - 0.93 (m, 6H), 0.87 (d, J = 6.8 Hz, 3H), 0.70 - 0.56 (m, 3H).

[0780] Example 42

[0781] N-[(1S)-1-[[(7S,13S)-23,23-difluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3- pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26[31.1.1.1.1]thirty-one-carb-1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-4-fluoro-N-methyl-1-prop-2-enoyl-piperidine-4-carboxamide

[0782]

[0783] Example 1 using (7S,13S)-7-amino-23,23-difluoro-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-morpholino-3-pyridinyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31- tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 Example 1 using (7S,13S)-7-amino-23,23-difluoro-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-morpholino-3-pyridinyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31- tetraazahexacyclo[23.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 Example 1 using (7S,13S)-7-amino-23,23-difluoro-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-morpholino-3-pyridinyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31- tetraazahexacyclo[23.3.1.1 + ); found 1060.8 (MH + ) 1060.8 (MH 1H NMR (400 MHz, Methanol-d4) δ = 8.54 (s, 1H), 8.41 (d, J = 2.8 Hz, 1H), 7.87 (s, 1H), 7.64 - 7.55 (m, 2H), 6.87 - 6.77 (m, 1H), 6.25 (d, J = 16.8 Hz, 1H), 5.83 - 5.72 (m, 2H), 4.72 (d, J = 11.2 Hz, 1H), 4.61 - 4.56 (m, 1H), 4.51 - 4.38 (m, 3H), 4.28 - 4.21 (m, 1H), 4.12 - 3.99 (m, 2H), 3.86 (t, J = 4.8 Hz, 4H), 3.82 - 3.73 (m, 2H), 3.70 - 3.63 (m, 1H), 3.58 - 3.53 (m, 1H), 3.44 (s, 7H), 3.27 - 3.23 (m, 1H), 3.18 (d, J = 5.2 Hz, 3H), 3.15 - 3.08 (m, 1H), 3.04 - 2.98 (m, 1H), 2.86 - 2.76 (m, 1H), 2.74 - 2.66 (m, 1H), 2.31 - 2.14 (m, 5H), 2.00 - 1.91 (m, 1H), 1.86 - 1.73 (m, 1H), 1.68 - 1.58 (m, 1H), 1.50 (d, J = 6.4 Hz, 3H), 1.40 - 1.33 (m, 3H), 1.02 (s, 3H), 0.98 (d, J = 6.4 Hz, 3H), 0.92 - 0.83 (m, 3H), 0.63 (s, 3H).

[0784] Example 43

[0785] 1 -But-2-ynoyl-N-[(1 S)-1 -[[(7S,13S)-23,23-difluoro-(20M)-20-[2-[(1 S)-1 - methoxyethyl]-5-morpholino-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4- thia-9,21,30,31 -tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26[31.1.1.1.1

[0786]

[0787] Example 1 using (7S, 13S)-7-amino-23,23-difluoro-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-morpholino-3-pyridinyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31- tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 Example 1 using (7S, 13S)-7-amino-23,23-difluoro-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-morpholino-3-pyridinyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31- tetraazahexacyclo[23.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 Example 1 using (7S, 13S)-7-amino-23,23-difluoro-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-morpholino-3-pyridinyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31- tetraazahexacyclo[23.3.1.1 + ); measure 1072.7 (MH + ). 1H NMR (400MHz, Methanol-d4) δ = 8.55 (s, 1H), 8.41 (d, J = 2.8 Hz, 1H), 7.90 - 7.85 (m, 1H), 7.61 (d, J = 3.2 Hz, 1H), 7.57 (d, J = 4.0 Hz, 1H), 5.83 - 5.73 (m, 1H), 4.72 (d, J = 11.2 Hz, 1H), 4.61 - 4.55 (m, 1H), 4.48 - 4.30 (m, 4H), 4.28 - 4.20 (m, 1H), 4.08 - 3.98 (m, 1H), 3.88 - 3.84 (m, 4H), 3.81 - 3.72 (m, 2H), 3.68 - 3.54 (m, 3H), 3.47 - 3.40 (m, 8H), 3.29 - 3.23 (m, 1H), 3.18 (t, J = 5.2 Hz, 3H), 3.13 - 3.08 (m, 1H), 3.07 - 2.93 (m, 1H), 2.85 - 2.76 (m, 1H), 2.74 - 2.66 (m, 1H), 2.33 - 2.10 (m, 6H), 2.06 (d, J = 6.8 Hz, 3H), 1.99 - 1.92 (m, 1H), 1.84 - 1.74 (m, 1H), 1.68 - 1.59 (m, 1H), 1.50 (d, J = 6.4 Hz, 3H), 1.05 - 1.00 (m, 3H), 0.98 (d, J = 6.4 Hz, 3H), 0.88 (d, J = 6.4 Hz, 3H), 0.67 - 0.59 (m, 3H).

[0788] Example 44

[0789] 4-fluoro-1-(2-fluoroprop-2-enoyl)-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo- 15,24-dioxa-4-thia-9,21,30,31 -tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26[31.0] Triaconta-1(30),2,5(31), 19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl- propyl]-N-methyl-piperidine-4-carboxamide

[0790]

[0791] Example 1 using (7S, 13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-15,24-dioxa-4-thia-9,21,30,31- tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 Example 1 using (7S, 13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-15,24-dioxa-4-thia-9,21,30,31- tetraazahexacyclo[23.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 Example 1 using (7S, 13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-15,24-dioxa-4-thia-9,21,30,31- tetraazahexacyclo[23.3.1.1 + .1 + .0 1HNMR (400 MHz, Methanol-d4) δ = 8.48 (d, J = 2.8 Hz, 1H), 8.25 - 8.15 (m, 1H), 7.62 - 7.41 (m, 2H), 7.10 (s, 1H), 5.78 - 5.67 (m, 1H), 5.34 - 5.15 (m, 2H), 4.78 - 4.72 (m, 1H), 4.64 - 4.57 (m, 2H), 4.52 (q, J = 5.9 Hz, 1H), 4.42 (d, J = 11.1 Hz, 1H), 4.36 - 4.23 (m, 3H), 4.12 - 3.98 (m, 2H), 3.84 - 3.69 (m, 4H), 3.64 - 3.54 (m, 2H), 3.46 - 3.36 (m, 6H), 3.27 - 3.10 (m, 8H), 3.04 - 2.96 (m, 4H), 2.85 - 2.75 (m, 1H), 2.63 - 2.54 (m, 1H), 2.36 - 2.14 (m, 6H), 1.99 - 1.92 (m, 1H), 1.89 - 1.76 (m, 1H), 1.62 (d t, J = 8.9, 12.6 Hz, 1H), 1.46 (d, J = 6.1 Hz, 3H), 1.04 - 0.93 (m, 6H), 0.88 (d, J = 6.5 Hz, 3H), 0.52 (s, 3H).

[0792] Example 45

[0793] 4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3- pyridyl]-17,17,23,23-tetramethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31- tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]thirty-one-carb-1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl- propyl]-N-methyl-1-prop-2-enoyl-piperidine-4-carboxamide

[0794]

[0795] Example 1 using (7S, 13S)-7-amino-(20M)-20-[2-[(1S)-1 -methoxyethyl]-5- morpholino-3-pyridyl]-17, 17, 23, 23-tetramethyl-15, 24-dioxa-4-thia-9, 21, 30, 31 - tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]triaconta-1(28), 2, 5(31), 19, 25(29), 26-hexaene-8, 14-dione (Intermediate K), 1-tert-butoxycarbonyl-4-fluoro-piperidine-4-carboxylic acid and acrylic acid in place of (20S, 26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1 -methoxyethyl]-3- pyridyl]-16, 16-dimethyl-7, 18-dioxa-12, 24, 33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 ]tetratriaconta-1(31), 2, 4, 6(34), 13, 28(32), 29-heptaene-19, 25-dione (Intermediate N), (3S)-1-tert-butoxycarbonyl-pyrrolidine-3-carboxylic acid (Compound 1e) and (2R)-2-chloro-2-fluoro-acetic acid (Compound 1h) to make the title compound. Example 45 (4.2 mg) was obtained as a yellow solid. MS calculated 1054.5 (MH + ), measured 1054.8 (MH + ), 1H NMR (400 MHz, Methanol-d4) δ 8.48 - 8.40 (m, 1H), 8.38 (d, J = 2.8 Hz, 1H), 8.22 (s, 1H), 7.74 - 7.68 (m, 1H), 7.47 (d, J = 11.6 Hz, 1H), 7.12 - 7.06 (m, 1H), 6.88 - 6.78 (m, 1H), 6.25 (dd, J = 1.6 Hz, 16.4 Hz, 1H), 5.85 - 5.73 (m, 2H), 4.72 (d, J = 11.6 Hz, 1H), 4.69 - 4.63 (m, 1H), 4.50 - 4.38 (m, 2H), 4.25 (d, J = 11.6 Hz, 1H), 4.14 - 4.03 (m, 1H), 3.98 (d, J = 12.4 Hz, 1H), 3.86 (t, J = 4.4 Hz, 3H), 3.82 - 3.76 (m, 2H), 3.63 (d, J = 8.0 Hz, 1H), 3.59 - 3.47 (m, 1H), 3.43 - 3.38 (m, 6H), 3.19 (d, J = 5.2 Hz, 3H), 3.13 - 3.07 (m, 1H), 3.04 - 2.97 (m, 1H), 2.90 - 2.82 (m, 1H), 2.81 - 2.75 (m, 1H), 2.71 - 2.65 (m, 1H), 2.36 - 2.24 (m, 2H), 2.22 - 2.17 (m, 2H), 2.15 - 2.02 (m, 2H), 1.98 - 1.91 (m, 1H), 1.85 - 1.72 (m, 1H), 1.71 - 1.57 (m, 2H), 1.50 (t, J = 7.6 Hz, 6H), 1.35 (s, 4H), 0.99 (t, J = 9.2 Hz, 6H), 0.88 (d, J = 6.4 Hz, 3H), 0.65 (s, 3H).

[0796] Example 46

[0797] 4-fluoro-N-[(1S)-1-[[(7S,13S,22S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridinyl]- 17,17,22-trimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]tritriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-1-prop-2-enoyl-piperidine-4-carboxamide

[0798]

[0799] Example 46 was prepared in analogy to the preparation of Example 1 by using (7S,13S,22S)-7-amino-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridinyl]-17,17,22-trimethyl- 15,24-dioxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]tritriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-1-prop-2-enoyl-piperidine-4-carboxamide 2,6 .1 20,24 .0 4,14 .0 5,12 ]tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaen-19,25-dione (Intermediate N), (3S)-1-tert-butoxycarbonyl-pyrrolidine-3-carboxylic acid (Compound 1e) and (2R)-2-chloro-2-fluoro-acetic acid (Compound 1h). Example 46 was obtained as a white solid (3.2 mg). MS calculated 1040.5 (MH + ); measured 1040.9 (MH +) δ = 8.41 (d, J = 2.8 Hz, 1H), 8.29 (d, J = 5.6 Hz, 1H), 7.42 - 7.35 (m, 2H), 7.08 (d, J = 17.6 Hz, 1H), 6.85 - 6.75 (m, 1H), 6.40 - 6.30 (m, 1H), 6.24 (dd, J = 16.8 Hz, J = 6.4 Hz, 1H), 5.84 - 5.73 (m, 1H), 4.59 (d, J = 11.2 Hz, 1H), 4.51 - 4.46 (m, 1H), 4.43 - 4.35 (m, 5H), 3.86 (t, J = 4.4 Hz, 4H), 3.80 (s, 1H), 3.16 (d, J = 15.2 Hz, 2H), 3.08 - 3.04 (m, 5H), 3.00 - 2.93 (m, 1H), 2.86 - 2.77 (m, 1H), 2.43 - 2.33 (m, 1H), 2.26 - 2.14 (m, 4H), 2.07 - 1.97 (m, 4H), 1.89 - 1.76 (m, 3H), 1.59 (d, J = 6.4 Hz, 4H), 1.29 (s, 6H), 1.16 (d, J = 6.8 Hz, 3H), 0.96 (s, 4H), 0.90 (t, J = 6.8 Hz, 3H), 0.83 (d, J = 5.6 Hz, 2H), 0.52 (s, 3H), 0.10 (s, 1H).

[0800] Example 47

[0801] 4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3- pyridinyl]-17,17,23,23-tetramethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]trihentriaconta-1(29),2,5(31),19,25,27-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N- methyl-1-prop-2-enoyl-piperidine-4-carboxamide

[0802]

[0803] The title compound was prepared in analogy to the preparation of Example 1 by using (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3- pyridyl]-17,17,23,23-tetramethyl-15-oxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]tritriaconta-1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate R), 1-tert-butoxycarbonyl-4-fluoro-piperidine-4-carboxylic acid and acrylic acid in place of (20S,26S)-26-amino-30-hydroxy-(13M)-13-[2-[(1S)-1- methoxyethyl]-3-pyridyl]-16,16-dimethyl-7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 ]tetratriaconta-1(31),2,4,6(34),13,28(32),29-heptaene-19,25-dione (Intermediate N), (3S)-1-tert-butoxycarbonyl-pyrrolidine-3-carboxylic acid (Compound 1e) and (2R)-2-chloro-2-fluoro-acetic acid (Compound 1h). Example 47 was obtained as a white solid (5.9 mg). MS calculated 1052.5 (MH + ), measured 1052.9 (MH + , 1H NMR (500 MHz, Methanol-d4) δ = 8.40 (br d, J = 2.9 Hz, 2H), 7.52 - 7.44 (m, 1H), 7.44 - 7.36 (m, 1H), 7.21 (d, J = 2.6 Hz, 1H), 6.87 - 6.77 (m, 1H), 6.29 - 6.20 (m, 1H), 5.79 (dd, J = 1.8, 10.7 Hz, 1H), 4.74 - 4.70 (m, 1H), 4.66 - 4.53 (m, 3H), 4.49 - 4.39 (m, 3H), 4.27 - 4.19 (m, 1H), 4.14 - 4.04 (m, 1H), 3.87 - 3.84 (m, 4H), 3.82 - 3.72 (m, 3H), 3.58 - 3.50 (m, 1H), 3.39 (br s, 2H), 3.22 - 3.16 (m, 3H), 3.05 - 2.97 (m, 2H), 2.95 - 2.87 (m, 2H), 2.85 - 2.77 (m, 2H), 2.76 - 2.71 (m, 1H), 2.69 - 2.63 (m, 1H), 2.35 - 2.25 (m, 2H), 2.18 (br s, 3H), 2.03 (s, 1H), 1.97 - 1.91 (m, 1H), 1.83 - 1.71 (m, 1H), 1.67 - 1.55 (m, 2H), 1.49 - 1.42 (m, 3H), 1.34 - 1.23 (m, 3H), 1.13 (s, 3H), 1.00 - 0.96 (m, 3H), 0.94 - 0.91 (m, 3H), 0.90 - 0.83 (m, 6H), 0.64 - 0.55 (m, 3H).

[0804] Biological Examples

[0805] Example 48

[0806] Cell Viability Assay

[0807] The purpose of this cell assay is to determine the effect of the test compound on the proliferation of human cancer cell lines NCI-H358 (ATCC-CRL5807) cells, AGS (ATCC-CRL-1739) cells, SW620 (ATCC-CCL-227) over a 3-day treatment period by quantifying the amount of NADPH present at the endpoint using the Cell Counting Kit-8.

[0808] Cells were seeded at 5,000 cells / well (NCI-H358), 2,000 cells / well (AGS) and 2,000 cells / well (SW620) in 96-well assay plates (Corning-3699) and incubated overnight. On the day of the assay, diluted compounds were added at a final concentration of 0.5% DMSO. After 72 hours of incubation, one-tenth volume of Cell Counting Kit 8 (Dnjindo-CK04) was added to each well. After 2 hours of incubation, the signal was read using EnVision (OD450 minus OD650). IC 50 Determined by fitting a 4-parameter S-shaped concentration response model.

[0809] Table 1. Activity of Examples and compounds of the invention in the KRAS cell viability assay

[0810]

[0811] Example 49

[0812] KRAS-BRAF interaction assay with CYPA (500 nM)

[0813] In this example, TR-FRET was also used to measure compound or compound-CYPA dependent disruption of the KRAS G12C-BRAF complex. This protocol was also used to measure the disruption of KRAS G12D or KRAS G12V binding to BRAF by compounds of the application, respectively. In wells of a 384-well assay plate were mixed at final concentrations of 50 nM, 6.25 nM and 1 nM, respectively. Compounds were present in the plate wells in a 16-point 3-fold dilution series starting from a final concentration of 10 µM and incubated for 3 hours. Then a mixture of MAb anti-6His-XL665 (Cisbio, 61HISXLB) and Mab anti-GST-TB Acceptor (Cisbio, 61GSTTLB) was added at final concentrations of 6.67 nM and 0.21 nM, respectively, and the plate was incubated for a further 1.5 hours. The TR-FRET signal was read on a PHERstar FSX microplate reader (Ex 320 nm, Em 665 / 615 nm). Compounds that promote disruption of the KRAS-BRAF complex were identified as compounds that caused a decrease in the TR-FRET ratio compared to DMSO control wells. RBD In wells of a 384-well assay plate were mixed at final concentrations of 50 nM, 6.25 nM and 1 nM, respectively. Compounds were present in the plate wells in a 16-point 3-fold dilution series starting from a final concentration of 10 µM and incubated for 3 hours. Then a mixture of MAb anti-6His-XL665 (Cisbio, 61HISXLB) and Mab anti-GST-TB Acceptor (Cisbio, 61GSTTLB) was added at final concentrations of 6.67 nM and 0.21 nM, respectively, and the plate was incubated for a further 1.5 hours. The TR-FRET signal was read on a PHERstar FSX microplate reader (Ex 320 nm, Em 665 / 615 nm). Compounds that promote disruption of the KRAS-BRAF complex were identified as compounds that caused a decrease in the TR-FRET ratio compared to DMSO control wells.

[0814] Table 2. Activity of examples and compounds of the application in the KRAS-BRAF interaction assay with CYPA (500 nM)

[0815]

[0816] Example 50

[0817] pERK inhibition assay

[0818] This assay aims to measure the ability of the tested compounds to inhibit ERK phosphorylation, downstream signaling of KRAS G12C in NCI-H358 cells, KRAS G12D in AGS cells, and KRAS G12V in SW620. NCI-H358 (ATCC-CRL5807) cells, AGS (ATCC-CRL-1739) cells, SW620 (ATCC-CCL-227) cells were grown and maintained using RPMI-1640 medium (Thermo Fisher Scientific) containing 10% fetal bovine serum and 1% penicillin / streptomycin. One day prior to compound addition, cells were plated in tissue culture treated 96-well plates (Corning-3699) at a density of 30,000 cells / well, 20,000 cells / well, 30,000 cells / well (for NCI-H358, AGS, and SW620, respectively) and allowed to attach overnight. Diluted compounds were then added at a final concentration of 0.5% DMSO. After 4 hours of incubation, the medium was removed, 100 μL of 4% formaldehyde was added, and the assay plates were incubated at room temperature for 20 minutes. The plates were then washed once with phosphate buffered saline (PBS) and permeabilized with 100 μL of cold methanol for 10 minutes. Non-specific antibodies bound to the plates were blocked using 50 μL of 1X BSA blocking buffer (Thermo-37520, diluted 10X in phosphate buffered saline (PBST)) for at least 1 hour at room temperature.

[0819] The amount of phosphor-ERK was determined using an antibody specific for the phosphorylated form of ERK. The primary antibody (pERK, CST-4370, Cell Signaling Technology) was diluted 1:300 in blocking buffer with 50µL aliquoted to each well and incubated overnight at 4°C. The cells were washed five times with PBST for 5 minutes. The secondary antibody (HRP-linked anti-rabbit IgG, CST-7074, Cell Signaling Technology) was diluted 1:1000 in blocking buffer and 50 µL was added to each well and incubated at room temperature for 1-2 hours. The cells were washed 5 times with PBST for 5 minutes, 100μL of TMB ELISA substrate (abcam-ab171523) was added, and gently shaken for 20 minutes. 50μL of stop solution (abcam-ab171529) was added and then the signal (OD450) was read using an EnVision.

[0820] IC 50 Determined by fitting a 4-parameter S-shaped concentration response model.

[0821] Table 3. Activity of examples and compounds of the invention in the KRAS pERK inhibition assay

[0822]

Claims

1. A compound of formula (I), (I)， wherein R 1 For , C 2-6 1 -oxo-2,7-diazaspiro[4.4]nonanyl, or (dihaloC 1-6 alkyl)carbonyl, C 2-6 alkenylcarbonyl, C 2-6 alkynylcarbonyl or haloC 2-6 alkenylcarbonyl substituted 5-oxo-2,6-diazaspiro[3.4]octanyl; wherein R 5 is C 1-6 alkyl; R 6 halo-substituted C 2-6 alkynyl-substituted C 3-7 cycloalkyl, alkyl)carbonyl, C 1-6 alkenylcarbonyl, C 2-6 alkenylcarbonyl, C 2-6 alkynylcarbonyl, halogen and haloC 2-6 alkenylcarbonyl, C alkenylcarbonyl, C (dihaloC 1-6 alkyl)carbonyl, C 2-6 alkenylcarbonyl, C 2-6 alkynylcarbonyl or morpholino C 2-6 pyrrolidinyl substituted with alkynylcarbonyl; R 2 For C 1-6 alkyl; R 3 H, morpholino, (haloC 1-6 alkyl)piperazinyl or C 1-6 alkylpiperazinyl; R 4 For C 1-6 Alkoxy C 1-6 Alkyl; A 1 is hydroxyphenylene or thiazolylene; A 2 For C 1-6 alkylene; M is O or CH2; L is C 1-6 alkylene or haloC 1-6 alkylene; or a pharmaceutically acceptable salt thereof.

2. A compound of formula (la), (Ia), wherein R 1 For , C 2-6 1 -oxo-2,7-diazaspiro[4.4]nonanyl, or (dihaloC 1-6 alkyl)carbonyl, C 2-6 alkenylcarbonyl, C 2-6 alkynylcarbonyl or haloC 2-6 alkenylcarbonyl substituted 5-oxo-2,6-diazaspiro[3.4]octanyl; wherein R 5 is C 1-6 alkyl; R 6 halo-substituted C 2-6 alkynyl-substituted C 3-7 cycloalkyl, alkyl)carbonyl, C 1-6 alkyl)carbonyl, C 2-6 alkyl)carbonyl, C 2-6 alkyl)carbonyl, C 2-6 alkyl)carbonyl, C (dihaloC 1-6 alkyl)carbonyl, C 2-6 alkenylcarbonyl, C 2-6 alkynylcarbonyl or morpholino C 2-6 pyrrolidinyl substituted with alkynylcarbonyl; R 2 For C 1-6 alkyl; R 3 R is H, morpholino, (haloC 1-6 alkyl)piperazinyl or C 1-6 alkylpiperazinyl; R 4 For C 1-6 Alkoxy C 1-6 Alkyl; A 1 is hydroxyphenylene or thiazolylene; A 2 For C 1-6 alkylene; M is O or CH2; L is C 1-6 alkylene or haloC 1-6 alkylene; or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 or 2, wherein R 1 is wherein R 5 is C 1-6 alkyl; R 6 is piperidinyl substituted twice with substituents independently selected from (dihaloC 1-6 alkyl)carbonyl, C 2-6 alkenylcarbonyl, halo, and haloC 2-6 alkenylcarbonyl.

4. The compound according to any one of claims 1 to 3, wherein R 1 is wherein R 5 is C 1-6 alkyl; R 6 is piperidinyl substituted with halo and a further substituent selected from (dihaloC 1-6 alkyl)carbonyl, C 2-6 alkenylcarbonyl and haloC 2-6 alkenylcarbonyl.

5. The compound according to any one of claims 1 to 4, wherein R 1 is wherein R 5 is methyl; R 6 is 4-fluoro-1-prop-2-enoyl-4-piperidinyl, 4-fluoro-1-(2-fluoroprop-2-enoyl)-4- piperidinyl, 4-fluoro-1-(2-chloro-2-fluoro-acetyl)-4-piperidinyl or 4-fluoro-1-prop-2- enoyl-4-piperidinyl.

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

7. The compound according to any one of claims 1 to 6, wherein R 3 is morpholino or C 1-6 alkylpiperazinyl.

8. The compound according to any one of claims 1 to 7, wherein R 3 is morpholino or 4-methylpiperazin-1-yl.

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

10. The compound of any one of claims 1 to 9, wherein A 1 is wherein the bond "a" is connected to the tricyclic ring.

11. The compound according to any one of claims 1 to 10, wherein A 2 is 2,2-propylene.

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

13. The compound of any one of claims 1 to 12, wherein L is C 1-6 alkylene.

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

15. The compound according to claim 1 or 2, wherein R 1 For wherein R 5 is C 1-6 alkyl; R 6 is piperidinyl substituted with halo and another substituent selected from (dihaloC 1-6 alkyl)carbonyl, C 2-6 alkenylcarbonyl and haloC 2-6 alkenylcarbonyl; R 2 For C 1-6 alkyl; R 3 Morpholine or C 1-6 alkylpiperazine group; R 4 For C 1-6 Alkoxy C 1-6 Alkyl; A 1 For wherein the bond "a" is connected to the tricyclic ring; A 2 For C 1-6 alkylene; M is O; L is C 1-6 alkylene; or a pharmaceutically acceptable salt thereof.

16. The compound according to claim 15, wherein R 1 For wherein R 5 is methyl; R 6 is 4-fluoro-1-prop-2-enoyl-4-piperidyl, 4-fluoro-1-(2-fluoroprop-2-enoyl)-4- piperidyl, 4-fluoro-1-[(2R)-2-chloro-2-fluoro-acetyl]-4-piperidyl or 4-fluoro-1-prop-2- enoyl-4-piperidyl; R 2 is isopropyl; R 3 is morpholino or 4-methylpiperazin-1-yl; R 4 is (1S)-1-methoxyethyl; A 1 For wherein the bond "a" is connected to the tricyclic ring; A 2 is 2,2-propylene; M is O; L is ethylene; or a pharmaceutically acceptable salt thereof.

17. A compound selected from: (3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(2OS,26S)-30-hydroxy- (13M)-13-[2-[(1S)-1-methoxy-ethyl]-3-pyridinyl]-16,16-dimethyl-19,25-dioxo- 7,18-dioxa-12,24,33-triazahexacyclo[26.3.1.1 2,6 .1 20,24 .0 4,14 .0 5,12 ]tricosa-1(31),2,4,6(34),13,28(32),29-heptaen-26-yl]carbamoyl]-2-methyl- propyl]-N-methyl-pyrrolidine-3-carboxamide; (3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(19S,25S)-29-hydroxy- (12M)-12-[2-[(1S)-1-methoxy-ethyl]-3-pyridinyl]-15,15-dimethyl-18,24-dioxo- 7,17-dioxa-11,23,32-triazahexacyclo[25.3.1.1 2,6 .1 19,23 .0 4,13 .0 5,11 ]tricosa-1(30),2,4,6(33),12,27(31),28-heptaen-25-yl]carbamoyl]-2-methyl- propyl]-N-methyl-pyrrolidine-3-carboxamide; 1 -[(2R)-2-chloro-2-fluoro-acetyl]-4-fluoro-N-[(1 S)-1 -[[(19S,25S)-29-hydroxy- (12M)-12-[2-[(1 S)-1 -methoxy-ethyl]-3-pyridinyl]-15,15-dimethyl-18,24-dioxo- 7,17-dioxa-11,23,32-triazahexacyclo[25.3.1.1 2,6 .1 19,23 .0 4,13 .0 5,11 ]tricosa-1 (30),2,4,6(33),12,27(31 ),28-heptaen-25-yl]carbamoyl]-2-methyl- propyl]-N-methyl-piperidine-4-carboxamide; (3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1 S)-1 -[[(18S,24S)-28-hydroxy- (11M)-11-[(3R)-2-[(1 S)-1 -methoxy-ethyl]-2,3-dihydro-pyridin-3-yl]-14,14- dimethyl-17,23-dioxo-16-oxa-10,22,31-triazahexacyclo[24.3.1.1 2,6 .1 18,22 .0 4,12 .0 5,10 ]thirty-two carbon-1(29),2,4,6(32),11,26(30),27-heptaen-24-yl]carbamoyl]-2- methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide; (3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(18S,24S)-28-hydroxy- (11M)-11-[2-[(1S)-1-methoxy-ethyl]-3-pyridinyl]-14,14-dimethyl-17,23-dioxo- 7,16-dioxa-10,22,31-triazahexacyclo[24.3.1.1 2,6 .1 18,22 .0 4,12 .0 5,10 ]thirty-two carbon-1(29),2,4,6(32),11,26(30),27-heptaen-24-yl]carbamoyl]-2- methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide; (3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1- methoxy-ethyl]-5-(4-methyl-piperazin-1-yl)-3-pyridinyl]-17,17-dimethyl-8,14-dioxo- 15-oxa-4-thia-9,21,30,31 -tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]triaconta-1 (28),2,5(31 ),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N- methyl-pyrrolidine-3-carboxamide; (2S)-2-[2-[(2R)-2-chloro-2-fluoro-acetyl]-5-oxo-2,6-diazaspiro[3.4]oct-6-yl]-N-[(7S,13S)- (20M)-20-[2-[(1S)-1-methoxy-ethyl]-5-[4-(2,2,2-trifluoro-ethyl)piperazin-1-yl]-3- pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]tritriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]-3-methyl-butyramide; (2S)-2-(2-but-2-ynoyl-5-oxo-2,6-diazaspiro[3.4]octan-6-yl)-N-[(7S,13S)-(20M)-20-[2- [(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17- dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1 2,5 .1 9, 13 .0 19,27 .0 21,26 ]triaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]-3-methyl-butyramide; (2S)-2-[2-[(2R)-2-chloro-2-fluoro-acetyl]-5-oxo-2,6-diazaspiro[3.4]oct-6-yl]-N-[(7S,13S)- (20M)-20-[2-[(1S)-1-methoxy-ethyl]-5-morpholino-3-pyridinyl]-17,17-dimethyl-8,14-dioxo- 15-oxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]triaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]-3-methyl-butyramide; (2S)-2-(2-but-2-ynoyl-5-oxo-2,6-diazaspiro[3.4]oct-6-yl)-N-[(7S,13S)-(20M)-20-[2- [(1S)-1-methoxyethyl]-5-morpholino-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-15-oxa- 4-thia-9,21,30,31 -tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]triaconta-1 (28),2,5(31 ),19,25(29),26-hexaen-7-yl]-3-methyl-butyramide; (2S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1 -methoxyethyl]-5-morpholino-3-pyridinyl]- 17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31 -tetraazahexacyclo[23.3.1.1 2,5 .1 9, 13 .0 19,27 .0 21,26 ]triaconta-1 (28),2,5(31 ),19,25(29),26-hexaen-7-yl]-3-methyl-2-(5-oxo-2-prop-2- enoyl-2,6-diazaspiro[3.4]octan-6-yl)butanamide; (3S)-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3- pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31 -tetraazahexacyclo[23.3.1.1 2, 5 .1 9,13 .0 19,27 .0 21,26 ]triaconta-1 (28),2,5(31 ),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N- methyl-1 -(4-morpholinobut-2-ynoyl)pyrrolidine-3-carboxamide; (2S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]trithiacyclohexadecane-7-yl]-3-methyl-2-(5-oxo-2-prop-2-enoyl-2,6-diazaspiro[3.4]oct-6-yl)butanamide; (2S)-2-(2-but-2-ynoyl-5-oxo-2,6-diazaspiro[3.4]oct-6-yl)-N-[(7S,13S)-(20M)-20-[2- [(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14- dioxy-15-oxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]triaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]-3-methyl-butyramide; 4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3- pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1 2, 5 .1 9,13 .0 19,27 .0 21,26 ]triaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N- methyl-1-prop-2-enoyl-piperidine-4-carboxamide; 1 -But-2-ynoyl-4-fluoro-N-[(1 S)-1 -[[(7S,13S)-(20M)-20-[2-[(1 S)-1 - methoxyethyl]-5-morpholino-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4- thia-9,21,30,31 -tetraazahexacyclo[23.3.1.1 1 2,5 .1 9,13 .0 19,27 .0 21,26 ]thirty-one carbon-1 (28),2,5(31 ),19,25(29),26-hexaen-7-yl]carbamoyl]-2- methyl-propyl]-N-methyl-piperidine-4-carboxamide; cis-N-[(1 S)-1 -[[(7S,13S)-(20M)-20-[2-[(1 S)-1 -methoxyethyl]-5-morpholino-3- pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31 -tetraazahexacyclo[23.3.1.1 2, 5 .1 9,13 .0 19,27 .0 21,26 ]triaconta-1 (28),2,5(31 ),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl- propyl]-N-methyl-3-(3,3,3-trifluoroprop-1 -ynyl)cyclobutane carboxamide; 1-[(2R)-2-chloro-2-fluoro-acetyl]-4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 [C31-1(28),2,5(31),19,25(29),26-hexene-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide; (2S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3- pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1 2 ,5 .1 9,13 .0 19,27 .0 21,26 ]triaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]-3-methyl-2-(5-oxo-2-prop-2-enoyl-2,6- diazaspiro[3.4]octan-6-yl)butanamide; (2S)-2-[2-[(2R)-2-chloro-2-fluoro-acetyl]-5-oxo-2,6-diazaspiro[3.4]oct-6-yl]-N-[(7S,13S)- (20M)-20-[2-[(1S)-1-methoxy-ethyl]-5-(4-methyl-piperazin-1-yl)-3-pyridyl]-17,17-dimethyl- 8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1 2,5 .1 9, 13 .0 19,27 .0 21,26 ]triaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]-3-methyl-butyramide; cis-N-[(1 S)-1 -[[(7S,13S)-(20M)-20-[2-[(1 S)-1 -methoxyethyl]-5-(4- methylpiperazin-1 -yl)-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia- 9,21,30,31 -tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]triaconta-1 (28),2,5(31 ),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl- propyl]-N-methyl-3-(3,3,3-trifluoroprop-1 -ynyl)cyclobutane carboxamide; (2S)-2-[2-(2-fluoroprop-2-enoyl)-5-oxo-2,6-diazaspiro[3.4]oct-6-yl]-N-[(7S,13S)- (20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14- dioxy-15-oxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]tritriaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]-3-methyl-butyramide; cis-N-[(1 S)-1 -[[(7S,13S)-(20M)-20-[2-[(1 S)-1 -methoxyethyl]-5-[4-(2,2,2- trifluoroethyl)piperazin-1 -yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4- thia-9,21,30,31 -tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]triaconta-1 (28),2,5(31 ),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl- propyl]-N-methyl-3-(3,3,3-trifluoroprop-1 -ynyl)cyclobutane carboxamide; 4-fluoro-1 -(2-fluoroprop-2-enoyl)-N-[(1 S)-1 -[[(7S,13S)-(20M)-20-[2-[(1 S)-1 - methoxyethyl]-5-morpholino-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4- thia-9,21,30,31 -tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]thirty-one carbon-1 (28),2,5(31 ),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl- propyl]-N-methyl-piperidine-4-carboxamide; 1 -But-2-ynoyl-4-fluoro-N-[(1 S)-1 -[[(7S,13S)-(20M)-20-[2-[(1 S)-1 - methoxyethyl]-5-(4-methylpiperazin-1 -yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo- 15-oxa-4-thia-9,21,30,31 -tetraazahexacyclo[23.3.1.1 1 2,5 .1 9,13 .0 19,27 .0 21,26 ]thirty-one carbon-1 (28),2,5(31 ),19,25(29),26-hexaen-7-yl]carbamoyl]-2- methyl-propyl]-N-methyl-piperidine-4-carboxamide; 4-Fluoro-1-(2-fluoroprop-2-enoyl)-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 [C31-1(28),2,5(31),19,25(29),26-hexene-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide; 1 -[(2R)-2-chloro-2-fluoro-acetyl]-4-fluoro-N-[(1 S)-1 -[[(7S,13S)-(20M)-20-[2-[(1 S)-1 - methoxyethyl]-5-(4-methylpiperazin-1 -yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4- thia-9,21,30,31 -tetraazahexacyclo[23.3.1.1 1 2,5 .1 9,13 .0 19,27 .0 21,26 ]triaconta-1 (28),2,5(31 ),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4- carboxamide; 1 -[(2R)-2-chloro-2-fluoro-acetyl]-4-fluoro-N-[(1 S)-1 -[[(7S,13S)-(20M)-20-[2-[(1 S)-1 - methoxyethyl]-5-morpholino-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4- thia-9,21,30,31 -tetraazahexacyclo[23.3.1.1 1 2,5 .1 9,13 .0 19,27 .0 21,26 ]thirty-one carbon-1 (28),2,5(31 ),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl- propyl]-N-methyl-piperidine-4-carboxamide; 4-fluoro-1 -(2-fluoroprop-2-enoyl)-N-[(1 S)-1 -[[(7S,13S)-(20M)-20-[2-[(1 S)-1 - methoxyethyl]-5-morpholino-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4- thia-9,21,30,31 -tetraazahexacyclo[23.3.1.1 1 2,5 .1 9,13 .0 19,27 .0 21,26 ]thirty-one carbon-1 (28),2,5(31 ),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl- propyl]-N-methyl-piperidine-4-carboxamide; 1 -But-2-ynoyl-4-fluoro-N-[(1 S)-1 -[[(7S,13S)-(20M)-20-[2-[(1 S)-1 - methoxyethyl]-5-morpholino-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-15,24- dioxa-4-thia-9,21,30,31 -tetraazahexacyclo[23.3.1.1 1 2,5 .1 9,13 .0 19,27 .0 21,26 ]thirty-one carbon-1 (28),2,5(31 ),19,25(29),26-hexaen-7-yl]carbamoyl]-2- methyl-propyl]-N-methyl-piperidine-4-carboxamide; 1-[(2R)-2-chloro-2-fluoro-acetyl]-4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 [C31-1(28),2,5(31),19,25(29),26-hexene-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide; 4-fluoro-N-[(1 S)-1 -[[(7S,13S)-(20M)-20-[2-[(1 S)-1 -methoxyethyl]-5-(4- methylpiperazin-1 -yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia- 9,21,30,31 -tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]triaconta-1 (28),2,5(31 ),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl- propyl]-N-methyl-1 -prop-2-enoyl-piperidine-4-carboxamide; 1-But-2-ynyl-4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 [C31-1(28),2,5(31),19,25(29),26-hexene-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide; (3R)-N-[(1 S)-1 -[[(7S,13S)-(20M)-20-[2-[(1 S)-1 -methoxyethyl]-5-morpholino-3- pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31 - tetraazahexacyclo[23.3.1.1 2, 5 .1 9,13 .0 19,27 .0 21,26 ]thirty-one carbon-1 (28),2,5(31 ),19,25(29),26-hexaen-7-yl]carbamoyl]-2- methyl-propyl]-N-methyl-1 -prop-2-enoyl-pyrrolidine-3-carboxamide; (3R)-1 -but-2-ynoyl-N-[(1 S)-1 -[[(7S,13S)-(20M)-20-[2-[(1 S)-1 - methoxyethyl]-5-morpholino-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4- thia-9,21,30,31 -tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]thirty-one carbon-1 (28),2,5(31 ),19,25(29),26-hexaen-7-yl]carbamoyl]-2- methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide; 4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia- 9,21,30,31 -tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]triaconta-1 (28),2,5(31 ),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl- propyl]-N-methyl-1 -prop-2-enoyl-piperidine-4-carboxamide; (2S)-2-[(5R)-7-but-2-ynoyl-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-N-[(7S,13S)- (20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]- 17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21 ,26 ]triaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]-3-methyl-butyramide; 4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3- pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]triaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N- methyl-1-prop-2-enoyl-piperidine-4-carboxamide; N-[(1 S)-1 -[[(7S,13S)-23,23-difluoro-(20M)-20-[2-[(1 S)-1 -methoxyethyl]-5-(4- methylpiperazin-1 -yl)-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia- 9,21,30,31 -tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]triaconta-1 (28),2,5(31 ),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl- propyl]-4-fluoro-N-methyl-1 -prop-2-enoyl-piperidine-4-carboxamide; N-[(1S)-1-[[(7S,13S)-23,23-difluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 [C31-1(28),2,5(31),19,25(29),26-hexene-7-yl]carbamoyl]-2-methyl-propyl]-4-fluoro-1-(2-fluoroprop-2-enoyl)-N-methyl-piperidine-4-carboxamide; 1 -[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1 S)-1 -[[(7S,13S)-23,23-difluoro-(20M)-20- [2-[(1 S)-1 -methoxy-ethyl]-5-morpholino-3-pyridinyl]-17,17-dimethyl-8,14-dioxo- 15-oxa-4-thia-9,21,30,31 -tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]triaconta-1 (29),2,5(31 ),19,25,27-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-4- fluoro-N-methyl-piperidine-4-carboxamide; N-[(1S)-1-[[(7S,13S)-23,23-difluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 [C31-1(28),2,5(31),19,25(29),26-hexene-7-yl]carbamoyl]-2-methyl-propyl]-4-fluoro-N-methyl-1-prop-2-enoyl-piperidine-4-carboxamide; 1 -But-2-ynoyl-N-[(1 S)-1 -[[(7S,13S)-23,23-difluoro-(20M)-20-[2-[(1 S)-1 - methoxyethyl]-5-morpholino-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4- thia-9,21,30,31 -tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]thirty-one carbon-1 (28),2,5(31 ),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl- propyl]-4-fluoro-N-methyl-piperidine-4-carboxamide; 4-fluoro-1 -(2-fluoroprop-2-enoyl)-N-[(1 S)-1 -[[(7S,13S)-(20M)-20-[2-[(1 S)-1 - methoxyethyl]-5-(4-methylpiperazin-1 -yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo- 15,24-dioxa-4-thia-9,21,30,31 -tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]thirty-one carbon-1 (28),2,5(31 ),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl- propyl]-N-methyl-piperidine-4-carboxamide; 4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3- pyridyl]-17,17,23,23-tetramethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31- tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]triaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N- methyl-1-prop-2-enoyl-piperidine-4-carboxamide; 4-fluoro-N-[(1S)-1-[[(7S,13S,22S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridinyl]- 17,17,22-trimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]triaconta-1(28),2,5(31),19,25(29),26-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-1-propan-2-enoyl-piperidine-4-carboxamide; and 4-fluoro-N-[(1 S)-1 -[[(7S,13S)-(20M)-20-[2-[(1 S)-1 -methoxyethyl]-5-morpholino-3- pyridyl]-17,17,23,23-tetramethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31 - tetraazahexacyclo[23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]thirty-one carbon-1 (29),2,5(31 ),19,25,27-hexaen-7-yl]carbamoyl]-2-methyl- propyl]-N-methyl-1 -prop-2-enoyl-piperidine-4-carboxamide; or a pharmaceutically acceptable salt thereof.

18. A process for preparing a compound according to any one of claims 1 to 17, comprising any one of the following steps: a) reacting a compound of formula (II), (II) with an acid (III), (III) in the presence of a coupling reagent and a base to form a compound of formula (I); b) reacting a compound of formula (VI), (VII) in the presence of a coupling reagent and a base to form a compound of formula (VIII), (VII) in the presence of a coupling reagent and a base to form a compound of formula (VIII), (VIII); c) reacting a compound of formula (XI), (XI) with an acid (XII), (XII) in the presence of a coupling reagent and a base to form a compound of formula (XIII), (XIII); wherein Q is unsubstituted or substituted piperidinylene or pyrrolidinylene; T is dihaloC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, haloC 2-6 alkenyl, or morpholinoC 2-6 alkynyl; R 1 to R 6 , A 1 , A 2 , M and L are as defined in any one of claims 1 to 16; the coupling reagent in steps a) to c) is T3P, HATU, PyBOP, or EDCI / HOBt; the base in steps a) to c) is TEA, DIEPA, or DMAP.

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

20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 17, and a pharmaceutically acceptable excipient.

21. Use of a compound according to any one of claims 1 to 17 for the treatment of a KRAS G12C protein related disease.

22. Use of a compound according to any one of claims 1 to 17 for the treatment of a KRAS G12C, KRAS G12D and KRAS G12V protein related disease.

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

24. Use of a compound according to any one of claims 1 to 17 for inhibiting propagated oncogenic MAPK and PI3K signaling.

25. Use of a compound according to any one of claims 1 to 17 for the treatment or prevention of a KRAS mutation driven cancer, wherein the cancer is selected from the group consisting of pancreatic cancer, colorectal cancer, lung cancer, esophageal cancer, gallbladder cancer, melanoma, ovarian cancer and endometrial cancer.

26. Use of a compound according to any one of claims 1 to 17 for the treatment or prevention of a KRAS mutation driven cancer, wherein the cancer is selected from the group consisting of pancreatic adenocarcinoma, colorectal cancer and non-small cell lung cancer.

27. A compound or a pharmaceutically acceptable salt according to any one of claims 1 to 17 for use in the treatment or prevention of a KRAS mutation driven cancer, wherein the cancer is selected from the group consisting of pancreatic adenocarcinoma, colorectal cancer and non-small cell lung cancer.

28. Use of a compound as described in any one of claims 1-17 for the manufacture of a medicament for the treatment or prevention of a KRAS mutationally driven cancer, wherein the cancer is selected from pancreatic adenocarcinoma, colorectal cancer, and non-small cell lung cancer.

29. A method for the treatment or prevention of a KRAS mutationally driven cancer, wherein the cancer is selected from pancreatic adenocarcinoma, colorectal cancer, and non-small cell lung cancer, comprising administering a therapeutically effective amount of a compound as defined in any one of claims 1-17.

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

31. The application as described herein.

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