Novel kinase inhibitor

Abstract

Provided are a kinase inhibitor, a preparation method therefor and a use thereof. Specifically, provided are a compound of formula (II) and a pharmaceutically acceptable salt, solvate, polymorphic substance or isomer thereof, a pharmaceutical composition comprising the compound, and a use of the compound and composition in the treatment of related diseases.

Description

A new type of kinase inhibitor

[0001] Cross-references

[0002] This application claims the patent rights of Chinese Patent Application No. 202311785897.9 filed on December 22, 2023, entitled “A Novel Kinase Inhibitor”, Chinese Patent Application No. 202410145188.2 filed on February 1, 2024, entitled “A Novel Kinase Inhibitor”, Chinese Patent Application No. 202410251564.6 filed on March 5, 2024, entitled “A Novel Kinase Inhibitor”, Chinese Patent Application No. 202410329787.X filed on March 21, 2024, and Chinese Patent Application No. 202410329787.X filed on April 22, 2024, entitled “A Novel Kinase Inhibitor”. The present invention claims priority from Chinese Patent Application No. 10488461.1, Chinese Patent Application No. 202410605099.1 filed on May 15, 2024, entitled “A Novel Kinase Inhibitor”, Chinese Patent Application No. 202410895024.1 filed on July 4, 2024, entitled “A Novel Kinase Inhibitor”, Chinese Patent Application No. 202411174428.8 filed on August 23, 2024, and Chinese Patent Application No. 202411745850.4 filed on November 29, 2024, with the entire disclosures of which are incorporated herein by reference in their entirety. Technical Field

[0003] The present invention relates to novel pyrrolopyrimidine derivatives with protein kinase inhibitory activity, preparation methods and pharmaceutical compositions thereof, and also relates to the use of such compounds and pharmaceutical compositions thereof in treating diseases associated with protein kinase. Background Art

[0004] Chromosomal rearrangements of the anaplastic lymphoma kinase (ALK) gene generate oncogenic fusion proteins, which occur in 3% to 5% of patients with non-small cell lung cancer. These fusion proteins exhibit aberrant dimerization or oligomerization, leading to constitutive ALK activation.

[0005] Fusion of ALK with the echinoderm microtubule-associated protein-like 4 (EML4) gene to form EML4-ALK has been shown to be highly oncogenic in preclinical NSCLC models. Targeting the kinase domain of EML4-ALK with small-molecule ALK inhibitors has shown clinical benefit in patients with ALK-positive NSCLC.

[0006] Three generations of ALK inhibitors have been approved to date, including first-generation (crizotinib), second-generation (alectinib, brigatinib, ceritinib), and third-generation (lorlatinib) therapies. However, resistance has emerged with these therapies. This resistance is partly due to the emergence of ALK mutations that interfere with drug binding. Crizotinib was approved in 2011 for patients with ALK-positive NSCLC, with an objective response rate of 74% in the first-line setting. However, crizotinib treatment can lead to resistance mutations in the ALK active site, such as G1269A and C1156Y, as well as mutations in the gatekeeper residue L1196M, which contribute to the development of resistance. Second-generation ALK inhibitors (alectinib, brigatinib, and ceritinib) have been approved for patients with ALK-positive NSCLC, but resistance is also prevalent due to ALK mutations, such as solvent-front mutations (e.g., G1202R), found in 33% to 37% of relapsed patients, and I1171 mutations in the hydrophobic regulatory ridge (24% to 26%). The third-generation ALK inhibitor lorlatinib is approved for patients with ALK-positive NSCLC who have previously received crizotinib and at least one other ALK inhibitor, or after first-line treatment with alectinib or ceritinib. However, 76% of plasma specimens from patients whose disease progressed after lorlatinib treatment detected ALK mutations: L1196M (38%), G1202R (28%), D1203N (24%), F1174C / L (14%), and I1171X (14%). These mutations are a mixture of single and compound mutations, with compound mutations found in 35% to 48% of treated patients. The G1202R / L1196M mutation accounts for the highest proportion of compound mutations, and currently approved ALK inhibitors have poor ALK kinase inhibition against G1202R / L1196M mutations. The reappearance of single mutations such as L1196M and G1202R may be due to the moderate efficacy of lorlatinib against these mutations (L1196M IC 50 18-30nmol / L, G1202R IC 50 Therefore, there is a need for a central nervous system (CNS) penetrant, highly potent wild-type (WT) ALK inhibitor that is not susceptible to resistance mutations arising from treatment with first-, second-, and third-generation ALK inhibitors.

[0007] This patent invents a series of novel ALK inhibitors that have strong inhibitory activity against ALK kinases with G1202R / L1196M compound mutations. Summary of the Invention

[0008] In one aspect, the present invention provides a compound of formula (II), or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof

[0009] in,

[0010] R is independently H, halogen, -CN, or C 1-4 Alkyl, or two R's are linked together to form a 3-4 membered carbon ring,

[0011] Y is -O- or -NR 10 -,

[0012] R 10 H or C 1-6 alkyl,

[0013] R1 is H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 alkenyl, or 3-6 membered cycloalkyl, said alkyl, alkenyl and cycloalkyl may be optionally substituted by halogen, -OH or -NH2, or

[0014] R1 can be optionally 10 are connected together to form a 4-8 membered heterocyclic ring, which may be optionally substituted by halogen, -CN, -OH or -NH2,

[0015] X5 is N or CR9,

[0016] R8 and R9 are each independently H, F, Cl, or ethynyl,

[0017] X4 is N and CH,

[0018] X3 is N and CH,

[0019] Ring A and Ring B are 5-6 membered aromatic rings.

[0020] R2 and R3 are each independently H, halogen, -CN, C 1-4 Alkyl, -OC 1-4 Alkyl, halogenated C 1-4 Alkyl, 3-4 membered cycloalkylmethyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclic group, or The alkyl, methyl, cycloalkyl and heterocyclic groups may be optionally substituted with halogen, -CN, -OH, -NH2, C 2-6 Alkenyl, or C 2-6 Alkynyl substitution,

[0021] R4 and R5 are each independently H, halogen, -CN, C 1-4 Alkyl, -OC 1-4Alkyl, halogenated C 1-4 alkyl, or The alkyl group may be optionally substituted with halogen, -CN, -OH, -NH2, C 2-6 Alkenyl, or C 2-6 Alkynyl substitution,

[0022] X3, R2, R3, R4, and R5 must meet the following conditions:

[0023] When X3 is CH,

[0024] At least one of R2, R3, R4 and R5 is or

[0025] R a H, halogen, C 1-6 Alkyl or halogenated C 1-6 alkyl,

[0026] R b H, halogen, C 1-6 Alkyl or halogenated C 1-6 alkyl,

[0027] R c H, halogen, C 1-6 Alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic group, 6-10 membered aryl, 5-12 membered heteroaryl, -(CO)-NH2, -(CO)-NH-C 1-6 Alkyl, -(CO)-OC 1-6 Alkyl, -(CO)-C 1-6 Alkyl, said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be optionally substituted with halogen, -OH, -NH2, -CN, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)(C 1-6 alkyl) substituted, or

[0028] R b and R c They may be optionally linked together to form a 4-8 membered carbocyclic ring or a 4-8 membered heterocyclic ring, and the carbocyclic ring and heterocyclic ring may be optionally substituted by halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, or -N(C 1-6 Alkyl)(C 1-6alkyl), said alkyl, alkenyl and alkynyl groups may be optionally substituted by halogen, -OH, -NH2, or -CN,

[0029] R d Each independently is C 1-6 alkyl.

[0030] In some embodiments, Y is -O-.

[0031] In some embodiments, R1 is H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 The alkyl, alkenyl and cycloalkyl groups may be optionally substituted by halogen, -OH or -NH2.

[0032] In some embodiments, R8 and R9 are each independently H or F.

[0033] In some embodiments, R d It is a methyl group.

[0034] In some embodiments, R2 and R3 are each independently H, halogen, -CN, C 1-4 Alkyl, -OC 1-4 Alkyl, halogenated C 1-4 Alkyl, 3-4 membered cycloalkylmethyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclic group, or The alkyl, methyl, cycloalkyl and heterocyclic groups may be optionally substituted with halogen, -CN, -OH, -NH2, C 2-6 Alkenyl, or C 2-6 Alkynyl substitution,

[0035] R4 and R5 are each independently H, halogen, -CN, C 1-4 Alkyl, -OC 1-4 Alkyl, halogenated C 1-4 alkyl, or The alkyl group may be optionally substituted with halogen, -CN, -OH, -NH2, C 2-6 Alkenyl, or C 2-6 Alkynyl substitution,

[0036] X3, R2, R3, R4, and R5 must meet the following conditions:

[0037] When X3 is CH,

[0038] At least one of R2, R3, R4 and R5 is or R a 、R band R c As defined above.

[0039] In some embodiments, R is H.

[0040] In some embodiments, R8 is F,

[0041] In some embodiments, R1 is methyl or ethyl.

[0042] In some embodiments, the present invention provides the following compounds, or pharmaceutically acceptable salts, solvates, polymorphs, or isomers thereof:

[0043] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, and optionally comprising a pharmaceutically acceptable carrier.

[0044] On the other hand, the present invention provides a method for treating an ALK-mediated disease, the method comprising administering to a subject an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, or the above-mentioned composition. In some embodiments, the ALK-mediated disease has an ALK site mutation of G1202R and / or an ALK site mutation of L1196M; preferably, the ALK-mediated disease has a compound mutation of the ALK site mutation of G1202R and the ALK site mutation of L1196M. In some embodiments, the ALK-mediated disease is ALK-positive non-small cell lung cancer, anaplastic large cell lymphoma, inflammatory myofibroblastic tumor, nasopharyngeal carcinoma, breast cancer, colorectal cancer, diffuse large B-cell lymphoma, systemic histiocytosis, or neuroblastoma.

[0045] In some embodiments of the present invention, the subject involved in the present invention is a mammal including humans.

[0046] On the other hand, the present invention provides the use of a compound of the present invention or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, or the above-mentioned composition in the preparation of a medicament for treating an ALK-mediated disease. In some embodiments, the ALK-mediated disease has an ALK site mutation of G1202R and / or an ALK site mutation of L1196M; preferably, the ALK-mediated disease has a compound mutation of the ALK site mutation of G1202R and the ALK site mutation of L1196M. In some embodiments, the ALK-mediated disease is ALK-positive non-small cell lung cancer, anaplastic large cell lymphoma, inflammatory myofibroblastic tumor, nasopharyngeal carcinoma, breast cancer, colorectal cancer, diffuse large B-cell lymphoma, systemic histiocytosis, or neuroblastoma.

[0047] Detailed Description of the Invention

[0048] Unless otherwise defined, all technical and scientific terms herein have the same meanings as commonly understood by those skilled in the art to which the subject matter of the claims pertains. Unless otherwise indicated, all patents, patent applications, and publications cited herein are incorporated herein by reference in their entirety.

[0049] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any present subject matter.

[0050] Some chemical terms

[0051] The terms "optional," "optional," or "optionally" mean that the subsequently described event or circumstance may or may not occur, and the description includes both the occurrence of the event or circumstance and the non-occurrence of the event or circumstance. For example, "optionally substituted alkyl" means "unsubstituted alkyl" or "substituted alkyl." Furthermore, an optionally substituted group may be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F), or any hierarchy between monosubstituted and fully substituted (e.g., -CH2CHF2, -CF2CH3, -CFHCHF2, etc.). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that would be sterically impossible and / or incomposable to synthesize will be introduced.

[0052] Definitions of standard chemical terms can be found in the references (including Carey and Sundberg, Advanced Organic Chemistry, 4th edition, Volume A (2000) and Volume B (2001), Plenum Press, New York). Unless otherwise indicated, conventional methods within the technical scope of the art, such as mass spectrometry, nuclear magnetic resonance, high performance liquid chromatography, infrared and ultraviolet / visible spectroscopy and pharmacological methods, are used. Unless specifically defined, the relevant terms and experimental steps and techniques in analytical chemistry, organic synthetic chemistry, and pharmaceutical and medicinal chemistry herein are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, drug preparation, formulation and delivery, and in the treatment of patients. For example, the manufacturer's instructions for use of the kit can be utilized, or reactions and purification can be carried out in a manner known in the art or in accordance with the description of the present invention. Generally, the above-mentioned techniques and methods can be implemented according to conventional methods well known in the art, based on the descriptions in the multiple summary and more specific documents cited and discussed in this specification. In this specification, groups and substituents thereof can be selected by those skilled in the art to provide stable structural moieties and compounds.

[0053] Some chemical groups named herein may be abbreviated to indicate the total number of carbon atoms. For example, C 1-6 Alkyl describes an alkyl group, as defined below, having a total of 1 to 6 carbon atoms. The total number of carbon atoms indicated in the abbreviated notation does not include the carbon atoms in possible substituents.

[0054]

[0046] The term "fused" or "fused ring," as used herein, alone or in combination, refers to a cyclic structure in which two or more rings share one or more bonds.

[0055]

[00146] The term "spiro" or "spirocycle," as used herein, alone or in combination, refers to a cyclic structure in which two or more rings share one or more atoms.

[0056] The term "alkyl" as used herein alone or as part of another component (such as a haloalkyl) refers to an optionally substituted straight chain or optionally substituted branched monovalent saturated hydrocarbon having 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, connected to the rest of the molecule by a single bond, for example, methyl, ethyl, isopropyl, n-butyl, isobutyl, n-pentyl, n-heptyl, 2-methylhexyl, n-octyl, and the like.

[0057] The term "alkenyl" as used herein, alone or in combination, refers to an optionally substituted straight chain or optionally substituted branched monovalent hydrocarbon radical having one or more C=C double bonds and having 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. The double bonds in these groups can be in cis or trans configurations and are understood to encompass both isomers. Examples include, but are not limited to, ethenyl (CH=CH2), 1-propenyl (CH2CH=CH2), isopropenyl (C(CH3)=CH2), butenyl, and 1,3-butadienyl, among others. Where alkenyl as defined herein appears in a numerical range, for example, "C2-C6 alkenyl" or "C 2-6 The term "alkenyl" refers to an alkenyl group which may be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms. The alkenyl group herein also includes the case where no numerical range is specified.

[0058] The term "alkynyl" as used herein, alone or in combination, refers to an optionally substituted linear or branched monovalent hydrocarbon radical having one or more C≡C triple bonds and having 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, and 1,3-butadiynyl. When a numerical range appears for an alkynyl group as defined herein, for example, "C2-C6 alkynyl" or "C 2-6 The term "alkynyl" refers to an alkynyl group which may be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms. The alkynyl group herein also encompasses the case where no numerical range is specified.

[0059] The term "aryl" refers to an all-carbon monocyclic or fused ring having a completely conjugated π electron system having 6-14 carbon atoms, preferably 6-12 carbon atoms, and most preferably 6 carbon atoms. Aryl can be unsubstituted or substituted with one or more substituents, examples of which include but are not limited to alkyl, alkyloxy, aryl, aralkyl, amino, halogen, hydroxyl, sulfonyl, sulfinyl, phosphoryl, and heteroalicyclic groups. Non-limiting examples of unsubstituted aryl include but are not limited to phenyl, naphthyl, and anthracenyl.

[0060] The term "heteroaryl" refers to a monocyclic or fused ring of 5-12 ring atoms, having 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms, of which 1, 2, 3 or 4 are selected from N, O, S, with the remaining ring atoms being C, and having a completely conjugated π-electron system. Heteroaryl groups may be unsubstituted or substituted, with substituents including, but not limited to, alkyl, alkyloxy, aryl, aralkyl, amino, halogen, hydroxy, cyano, nitro, carbonyl and heteroalicyclic groups. Non-limiting examples of unsubstituted heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl and triazinyl.

[0061] The term "cycloalkyl" as used herein, alone or as part of another component, refers to a stable, monovalent, non-aromatic, monocyclic or polycyclic hydrocarbon radical, containing only carbon and hydrogen atoms, which may include fused, spiro or bridged ring systems, containing 3 to 15 ring carbon atoms, preferably 3 to 10 ring carbon atoms, more preferably 3 to 8 ring carbon atoms, which may be saturated or unsaturated, and which is attached to the rest of the molecule by a single bond. Non-limiting examples of "cycloalkyl" include cyclopropyl, cyclohexyl, cyclohexanone, cyclooctyl, 1H-indenyl, decahydronaphthyl, and the like.

[0062] The terms "heterocyclyl" and "heterocycle" as used herein, alone or as part of another component, refer to a stable 3-18 membered monovalent non-aromatic ring comprising 2-12 carbon atoms and 1-6 heteroatoms selected from nitrogen, oxygen and sulfur. Unless otherwise specified, a heterocyclyl group may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may contain fused, spirocyclic or bridged ring systems, the nitrogen, carbon or sulfur atoms in the heterocyclyl group may be optionally oxidized, the nitrogen atom may be optionally quaternized, and the heterocyclyl group may be partially or fully saturated. The heterocyclyl group may be linked to the rest of the molecule via a single bond through a carbon atom or heteroatom in the ring. A heterocyclyl group containing a fused ring may contain one or more aromatic or heteroaromatic rings, as long as the atoms attached to the rest of the molecule are non-aromatic ring atoms. The heterocyclic group is preferably a stable 4-11 membered monovalent non-aromatic monocyclic or bicyclic ring containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, and more preferably a stable 4-8 membered monovalent non-aromatic monocyclic ring containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur. Non-limiting examples of heterocyclic groups include azepanyl, azetidinyl, decahydroisoquinolinyl, dihydrofuranyl, dihydroindolinyl, dioxolane, morpholinyl, 2-oxopiperidinyl, tetrahydroisoquinolinyl, trithianyl and the like.

[0063] The term "carbocycle" as used herein, alone or in combination, refers to a structure consisting of a covalently closed ring of carbon atoms, which may be saturated or partially unsaturated. A carbocycle may be formed by 3, 4, 5, 6, 7, 8, 9 or more atoms. As used herein, a "carbocycle" may be a monocyclic ring or a polycyclic ring, including spirocyclic rings, fused rings and bridged rings. The carbocycle may be arbitrarily substituted. As used herein, a "carbocycle" preferably comprises from about 5 to about 20, or from 5 to 10, or from 5 to 8, or from 5 to 6 backbone ring atoms.

[0064]

[0046] The terms "halogen," "halo," or "halide," as used herein, alone or in combination, refer to fluorine, chlorine, bromine, and iodine.

[0065] Unless otherwise specified, compounds of the present invention containing olefinic double bonds include both E and Z isomers.

[0066] It should be understood that the compounds of the present invention may contain asymmetric centers. These asymmetric centers can independently be in the R or S configuration. Some compounds of the present invention may also exhibit cis-trans isomerism, which is apparent to those skilled in the art. It should be understood that the compounds of the present invention include their individual geometric isomers and stereoisomers and mixtures thereof, including racemic mixtures. These isomers can be separated from their mixtures by implementing or modifying known methods, such as chromatography and recrystallization techniques, or they can be prepared separately from the appropriate isomers of their intermediates.

[0067] As used herein, the term "pharmaceutically acceptable salt" includes both acid-addition salts and base-addition salts.

[0068] "Pharmaceutically acceptable salts" refer to those which retain the biological effectiveness and properties of the free base of the compound, are not biologically or otherwise undesirable, and are reacted with inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, decanoic acid, hexanoic acid, octanoic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethylsulfonic acid, 2-hydroxyethanedioic acid, formic acid, Salts formed from fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphate glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1,5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, etc. "Pharmaceutically acceptable base-added salts" refer to salts that retain the biological effectiveness and properties of the free acids of the compound and are not biologically or otherwise undesirable. These salts are prepared by reacting the free acid with an inorganic base or an organic base. Salts formed by reaction with an inorganic base include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, and the like. Preferred inorganic salts are ammonium salts, sodium salts, potassium salts, calcium salts, and manganese salts.

[0069] Organic bases for forming salts include, but are not limited to, primary amines, secondary amines, tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, dimethylaminoethanol, 2-dimethylethanolamine, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrazine penicillin, choline, betaine, phenethylbenzylamine, benzathine penicillin, ethylenediamine, glucosamine, meglumine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0070] The compound of the present invention or its salt can be administered alone as an active substance, or preferably in the form of a pharmaceutical composition.

[0071] The term "pharmaceutical composition" as used herein refers to a preparation containing a compound of the present invention and a medium generally accepted in the art for delivering biologically active compounds to mammals (such as humans), including all pharmaceutically acceptable carriers.

[0072] The term "acceptable" with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.

[0073] As used herein, the term "pharmaceutically acceptable" refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention and is relatively non-toxic, that is, the substance can be administered to a subject without causing an adverse biological response or interacting in an adverse manner with any components contained in the composition.

[0074] "Pharmaceutically acceptable carrier" includes, but is not limited to, adjuvants, carriers, excipients, auxiliary agents, deodorants, diluents, preservatives, dyes / colorants, flavor enhancers, surfactants and wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that have been approved by relevant government administrative departments for use in humans and domesticated animals.

[0075] The pharmaceutical composition of the present invention can be formulated into solid, semisolid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, solutions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.

[0076] Typical routes of administration of the compounds of the present invention, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, transmucosal, enteral administration, or topical, transdermal, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration. The preferred route of administration is oral administration.

[0077] The pharmaceutical composition of the present invention can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, sugar-coated pill making methods, grinding methods, emulsification methods, freeze-drying methods, etc.

[0078] In a preferred embodiment, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with a pharmaceutically acceptable carrier well known in the art. These carriers enable the compounds of the invention to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, and the like for oral administration to a patient.

[0079] Solid oral pharmaceutical compositions can be prepared by conventional mixing, filling, or tableting methods. For example, they can be obtained by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable adjuvants if necessary, and then processing the mixture into granules to obtain a tablet or dragee core. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners, or flavoring agents. Examples include microcrystalline cellulose, glucose solution, acacia mucilage, gelatin solution, sucrose, and starch paste; talc, starch, magnesium stearate, calcium stearate, or stearic acid; lactose, sucrose, starch, mannitol, sorbitol, or dicalcium phosphate; silicon dioxide; cross-linked sodium carboxymethylcellulose, pre-gelatinized starch, sodium starch glycolate, alginic acid, corn starch, potato starch, methylcellulose, agar, carboxymethylcellulose, cross-linked polyvinyl pyrrolidone, and the like. The dragee core can optionally be coated according to methods known in conventional pharmaceutical practice, particularly with an enteric coating.

[0080] The pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms. Appropriate excipients, such as fillers, buffers or surfactants, can be used. DETAILED DESCRIPTION

[0081] The compounds of the present invention, their preparation methods and uses are described below with reference to the examples.

[0082] The following non-limiting examples are illustrative only and are not intended to limit the present invention in any way.

[0083] Unless otherwise stated, temperatures are in degrees Celsius. Reagents were purchased from commercial suppliers such as Sinopharm Chemical Reagent Beijing Co., Ltd., Alfa Aesar, or Beijing J&K Technology Co., Ltd. and were used directly without further purification unless otherwise stated.

[0084] Unless otherwise noted, the following reactions were performed at room temperature in anhydrous solvents under a positive pressure of nitrogen or argon or using a drying tube; the reaction flasks were fitted with rubber septa to facilitate the addition of substrates and reagents via syringe; and the glassware was oven-dried and / or heat-dried.

[0085] Unless otherwise specified, column chromatography purification used 200-300 mesh silica gel from Qingdao Ocean Chemical Plant; preparative thin-layer chromatography silica gel precast plates (HSGF254) produced by Yantai Institute of Chemical Industry were used; MS measurements were performed using a Thermo LCQ Fleet (ESI) liquid chromatography-mass spectrometer; and optical rotation was determined using an SGW-3 automatic polarimeter (Shanghai Shenguang Instrument Co., Ltd.).

[0086] NMR data ( 1 H NMR was performed using a Varian instrument at 400 MHz. Solvents used for NMR data included CDCl₃, CD₃OD, D₂O, and DMSO-d₆, with reference to tetramethylsilane (0.00 ppm) or residual solvent (CDCl₃: 7.26 ppm; CD₃OD: 3.31 ppm; D₂O: 4.79 ppm; d₆-DMSO: 2.50 ppm). When peak shape multiplicity is indicated, the following abbreviations are used to denote the different peak shapes: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad), dd (double of doublets), and dt (double of triplets). Coupling constants, if given, are in Hertz (Hz).

[0087] Abbreviations:

[0088] Synthesis method

[0089] General Synthesis Method A

[0090] Under nitrogen protection, at -35 ° C, isopropylmagnesium chloride tetrahydrofuran solution (2M, 1eq) was added dropwise to iodide 1 (1.05eq). Subsequently, the reaction solution was warmed to 0 ° C and the reaction was continued for 1 hour. At 0 ° C, a tetrahydrofuran solution of compound 2 (1eq) was added dropwise to the above reaction solution, and the reaction was heated to room temperature overnight. Saturated aqueous ammonium chloride solution was added to the reaction solution. The resulting mixture was extracted with ethyl acetate, and the extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by rapid silica gel column chromatography to obtain compound 3.

[0091] General Synthesis Method B

[0092] Under nitrogen protection, triethylsilane (3.0 eq) was added to a dichloromethane solution of compound 3 (1.0 eq), and then the reaction solution temperature was lowered to 0°C, and trifluoroacetic acid (4.0 eq) was slowly added dropwise. After the addition was complete, the reaction solution was warmed to room temperature and reacted overnight. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by flash silica gel column chromatography to obtain compound 4.

[0093] General Synthesis Method C

[0094] Under nitrogen, a dioxane solution of aromatic halide 5 (1.0 eq), boronic acid or boronic acid ester 6 (1.1 eq), Pd(dppf)Cl2 (0.1 eq), and cesium carbonate (2.0 eq) was heated to 80°C and reacted overnight. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by flash silica gel column chromatography to obtain compound 7.

[0095] General Synthesis Method D

[0096] Methanesulfonic anhydride (1.5 eq) was added to a dichloromethane solution of compound 8 (1.0 eq) and triethylamine (2.0 eq) at 0°C. The reaction mixture was allowed to react for 2 hours at 0°C. Saturated aqueous sodium bicarbonate was added to the reaction mixture to quench the reaction. The resulting solution was extracted with dichloromethane, and the extract was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue, 9, was used directly in the next step without further purification.

[0097] General Synthesis Method E

[0098] Under nitrogen, a solution of compound 9 (1.0 eq), compound 10 (1.2 eq), and anhydrous potassium phosphate (2.0 eq) in N,N-dimethylacetamide was heated to 65°C and stirred overnight. The reaction solution was poured into water, and the resulting aqueous solution was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash silica gel column chromatography to obtain compound 11.

[0099] General Synthesis Method F

[0100] Under nitrogen, a solution of compound 12 (1.0 eq), cataCXium A (0.2 eq), potassium pivalate (2.0 eq), and palladium acetate (0.1 eq) in tert-amyl alcohol was heated to 100°C and stirred overnight. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by flash silica gel column chromatography to obtain compound 13.

[0101] General Synthesis Method G

[0102] To a solution of compound 14 (1.0 eq) in trifluoroacetic acid was added NIS (2.5 eq), and the reaction mixture was heated to 30°C for 48 hours. The reaction mixture was concentrated under reduced pressure, and a saturated aqueous sodium bicarbonate solution was added to the resulting residue. The resulting mixture was extracted with ethyl acetate, and the extract was washed with a saturated sodium thiosulfate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography to obtain compound 15.

[0103] General Synthesis Method H

[0104] Under nitrogen, compound 17 (2.0 eq) was added to a DMF solution of compound 16 (1.0 eq), Pd(PPh3)2Cl2 (0.1 eq), triethylamine (3.0 eq), and cuprous iodide (0.2 eq). The reaction mixture was heated to 80°C overnight. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by flash silica gel column chromatography to obtain compound 18.

[0105] General Synthesis Method I

[0106] To a methanol solution of compound 19 (1.0 eq) was added anhydrous potassium carbonate (2.0 eq) at room temperature. The reaction mixture was stirred at room temperature until the reaction was complete. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash silica gel column chromatography to obtain compound 20.

[0107] General Synthesis Method J

[0108] At room temperature, trifluoroacetic acid (dichloromethane: trifluoroacetic acid = 3: 1) was added to a dichloromethane solution of compound 21 and stirred at room temperature until the reaction was complete. The reaction solution was concentrated under reduced pressure. A saturated aqueous sodium bicarbonate solution was added to the obtained residue, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by rapid silica gel column chromatography to obtain compound 22.

[0109] Example 1: (19R)-3-ethyl-5-ethynyl-16-fluoro-10,19-dimethyl-3,4,9,10,11,23-hexaaza-20-oxapentacyclo[19.3.1.0 2,6 .0 8,12 .0 13,18 ]pentacosyl-1(25),2(6),4,8(9),11,13(14),15,17,21(22),23-decen-22-amine

[0110] Step 1

[0111] At -30 ° C, to a solution of compound 1-1 (21g) in tetrahydrofuran (400mL) was slowly added dropwise isopropylmagnesium chloride furan solution (29mL, 2M), and the reaction solution was stirred at -30 ° C for 30 minutes. To the reaction solution was slowly added dropwise a solution of compound 1-2 (7.42g) in tetrahydrofuran (50mL) at -30 ° C, and the reaction solution was reacted at room temperature for 2 hours. Saturated aqueous ammonium chloride solution (400mL) was added to the reaction solution to quench the reaction. The mixture was extracted with ethyl acetate (200mL×3), the extract was washed with saturated brine (300mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to give compound 1-3 (15g).

[0112] Step: To a solution of compound 1-3 (15 g) in dichloromethane (150 mL) at 20°C, triethylsilane (15.7 g) and trifluoroacetic acid (20 g) were added, and the reaction mixture was stirred at room temperature overnight. The reaction solution was poured into a saturated aqueous sodium bicarbonate solution (300 mL), and the mixture was extracted with ethyl acetate (150 mL × 3). The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain compound 1-4 (11 g).

[0113] Step 3

[0114] Under nitrogen, a solution of compound 1-4 (8.5 g), compound 1-5 (5.3 g), anhydrous sodium carbonate (9 g), and Pd(dppf)Cl2 (7.8 g) in tetrahydrofuran / water (80 mL / 8 mL) was heated to 65°C and reacted overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1 to 1:1) to give compound 1-6 (9.6 g).

[0115] Step 4

[0116] Methanesulfonic anhydride (7.9 g) was added to a solution of compound 1-6 (7.5 g) and triethylamine (9.2 g) in dichloromethane (150 mL) at 0°C, and the reaction solution was stirred at 0°C for 1 hour. Water (200 mL) was added to the reaction solution to quench the reaction, and the mixture was extracted with dichloromethane (100 mL × 3). The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound 1-7.

[0117] Step 5

[0118] A solution of compounds 1-7 (8.4 g), 1-8 (3.9 g) and cesium carbonate (9.2 g) in N-methylpyrrolidone (20 mL) was heated to 45° C. and reacted for 3 hours. The reaction solution was poured into water (200 mL), and the mixture was extracted with ethyl acetate (100 mL×3). The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:ethyl acetate = 2:1 to 1:1) to obtain compound 1-9 (7.8 g).

[0119] Step 6

[0120] Under nitrogen, a solution of compound 1-9 (7.0 g), cataCXium A (1.2 g), potassium pivalate (5.8 g), and palladium acetate (0.37 g) in tert-amyl alcohol (140 mL) was heated to 100° C. and reacted overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:ethyl acetate = 2:1 to 1:1) to obtain compound 1-10 (3.5 g).

[0121] Step 7

[0122] To a solution of compound 1-10 (1.0 g) in trifluoroacetic acid (20 mL) was added NIS (1.34 g), and the reaction mixture was heated to 30°C for 48 hours. The reaction mixture was concentrated under reduced pressure, and a saturated aqueous sodium bicarbonate solution (100 mL) was added to the residue. The mixture was extracted with ethyl acetate (80 mL × 3), and the extract was washed with a saturated aqueous sodium thiosulfate solution (80 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 30:1) to provide compound 1-11 (720 mg).

[0123] Step 8

[0124] Under nitrogen, trimethylsilylacetylene (0.1 mL) was added to a DMF (2 mL) solution of compound 1-11 (100 mg), Pd(PPh3)2Cl2 (13 mg), triethylamine (80 μL), and cuprous iodide (7 mg), and the reaction mixture was heated to 80°C overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 40:1) to give compound 1-12 (85 mg).

[0125] Step 9

[0126] Anhydrous potassium carbonate (45 mg) was added to a solution of compound 1-12 (85 mg) in methanol (2 mL) at room temperature, and the reaction mixture was stirred at room temperature until the reaction was complete. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 40:1) to obtain the title compound. LC-MS (ESI) [M+H] + :444.2. 1 H NMR (400MHz, CDCl3), 7.52 (brs, 1H), 7.31 (dd, J=9.6Hz, 2.8Hz, 1H), 7.09 (dd, J= 8.4Hz, 5.6Hz, 1H), 7.03 (td, J=8.4Hz, 2.8Hz, 1H), 6.22 (d, J=1.6Hz, 1H), 5.24-5. 29(m,1H),5.04(s,2H),4.22(s,3H),4.04-4.13(m,2H),3.98(d,J=15.6Hz,1H),3 .31(s,1H),3.19(d,J=15.6Hz,1H),1.79(d,J=6.0Hz,3H),1.37(t,J=7.2Hz,3H).

[0127] Example 2: (19R)-3-ethyl-16-fluoro-10,19-dimethyl-5-vinyl-3,4,9,10,11,23-hexaaza-20-oxapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0128] Under nitrogen, a solution of 1-11 (100 mg), 2-1 (35 mg), Pd(dppf)Cl2 (14 mg), and anhydrous sodium carbonate (40 mg) in dioxane / water (2 ml / 0.5 mL) was heated to 80°C overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 40:1) to obtain the title compound (42 mg). LC-MS (ESI) [M+H] + :446.4. 1 H NMR(400MHz, CDCl3),7.52(s,1H),7.32(dd,J=10.0Hz,2.4Hz,1H),7.08(dd,J=8.8Hz,6.0Hz,1H),7 .02(td,J=8.0Hz,2.4Hz,1H),6.95(dd,J=18.0Hz,11.2Hz,1H),6.27(s,1H),6.19(dd,J=18.0Hz,1. 6Hz,1H),5.43(dd,J=11.2Hz,1.2Hz,1H),5.23-5.30(m,1H),4.85(s,2H),4.21(s,3H),4.03-4.18( m, 2H), 3.84 (d, J = 15.6Hz, 1H), 3.19 (d, J = 15.6Hz, 1H), 1.79 (d, J = 6.4Hz, 3H), 1.37 (t, J = 7.2Hz, 3H).

[0129] Example 3: (19R)-5-[3-(dimethylamino)prop-1-ynyl]-3-ethyl-16-fluoro-10,19-dimethyl-3,4,9,10,11,23-hexaaza-20-oxapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0130] The synthesis method of Example 3 is the same as that of Example 1. LC-MS (ESI) [M+H] + :501.3. 1H NMR(400MHz, CDCl3),7.52(d,J=1.2Hz,1H),7.32(dd,J=10.0Hz,2.4Hz,1H),7.11(dd, J=8.4Hz, 6.0Hz, 1H), 7.03(td, J=8.4Hz, 2.4Hz, 1H), 6.23 (d, J=1.2Hz, 1H), 5.24-5.29 (m,1H),4.49(s,2H),4.20(s,3H),4.06-4.15(m,2H),3.97(d,J=15.6Hz,1H),3.65(s, 2H), 3.18 (d, J = 15.6Hz, 1H), 2.48 (s, 6H), 1.79 (d, J = 6.0Hz, 3H), 1.39 (t, J = 7.2Hz, 3H).

[0131] Example 4: (19R)-3-ethyl-16-fluoro-5-(3-methoxyprop-1-ynyl)-10,19-dimethyl-3,4,9,10,11,23-hexaaza-20-oxapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0132] The synthesis method of Example 4 is the same as that of Example 1. LC-MS (ESI) [M+H] + :488.3. 1 H NMR(400MHz, CDCl3),7.45-7.56(brs,1H),7.32(dd,J=10.0Hz,2.4Hz,1H),7.11(dd, J=8.4Hz,6.0Hz,1H),7.04(td,J=8.4Hz,2.4Hz,1H),6.24(s,1H),5.22-5.31(m,1H), 4.91(s,2H),4.39-4.47(m,2H),4.21(s,3H),4.07-4.15(m,2H),3.98(d,J=15.6Hz,1 H), 3.52 (s, 3H), 3.18 (d, J = 15.6Hz, 1H), 1.80 (d, J = 6.4Hz, 3H), 1.39 (t, J = 7.2Hz, 3H).

[0133] Example 5: (19R)-5-(3-aminoprop-1-ynyl)-3-ethyl-16-fluoro-10,19-dimethyl-3,4,9,10,11,23-hexaaza-20-oxapentacyclo[19.3.1.08,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0134] Step 1

[0135] Under nitrogen, compound 17 (85 mg) was added to a solution of compound 1-11 (150 mg), Pd(PPh3)2Cl2 (25 mg), triethylamine (115 μL), and cuprous iodide (11 mg) in DMF (2 mL). The reaction mixture was then heated to 80°C overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 40:1) to afford compound 5-1 (80 mg).

[0136] Step 2

[0137] Trifluoroacetic acid (1 mL) was added to a solution of compound 5-1 (80 mg) in dichloromethane (3 mL) at room temperature, and the reaction mixture was stirred at room temperature until the reaction was complete. The reaction mixture was concentrated under reduced pressure, and a saturated aqueous sodium bicarbonate solution (30 mL) was added to the residue, and the mixture was extracted with ethyl acetate (20 mL × 3). The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 15:1) to obtain the title compound (52 mg). LC-MS (ESI) [M+H] + :473.2. 1 H NMR(400MHz, CDCl3),7.50(d,J=1.2Hz,1H),7.32(dd,J=10.0Hz,2.4Hz,1H),7.10(dd,J= 8.4Hz, 6.0Hz, 1H), 7.03 (td, J=8.4Hz, 2.4Hz, 1H), 6.21 (d, J=1.2Hz, 1H), 5.24-5.29 (m, 1 H),4.84(s,2H),4.23(s,3H),4.06-4.12(m,2H),3.95(d,J=15.6Hz,1H),3.74(s,2H),3. 17(d,J=15.6Hz,1H),1.90-2.14(brs,2H),1.79(d,J=6.0Hz,3H),1.38(t,J=7.2Hz,3H).

[0138] Example 6: 3-[(19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-3,4,9,10,11,23-hexaaza-20-oxapentacyclo[19.3.1.08,12 .0 13,18 .0 2,6 1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decen-5-yl]prop-2-yn-1-ol

[0139] The synthesis method of Example 6 is the same as that of Example 1. LC-MS (ESI) [M+H] + :474.1. 1 H NMR (400MHz, CDCl3), 7.52 (d, J=1.2Hz, 1H), 7.31 (dd, J=9.6Hz, 2.4Hz, 1H), 7.09 (dd, J= 8.4Hz,5.6Hz,1H),7.02(dd,J=8.4Hz,2.4Hz,1H),6.21(d,J=1.2Hz,1H),5.20-5.28(m,1 H),4.99(s,2H),4.57(s,2H),4.21(s,3H),4.04-4.14(m,2H),3.95(d,J=15.6Hz,1H),3. 16(d,J=15.6Hz,1H),2.56-2.96(brs,1H),1.78(d,J=6.4Hz,3H),1.36(t,J=7.2Hz,3H).

[0140] Example 7: (19R)-3-ethyl-16-fluoro-10,19-dimethyl-5-vinyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0141] The synthesis method of Example 7 is the same as that of Example 2. LC-MS (ESI) [M+H] + :445.3. 1H NMR(400MHz, CD3OD),7.54(dd,J=10.0Hz,2.8Hz,1H),7.43(s,1H),7.41(d,J=1.6Hz,1H),7.21( dd,J=8.4Hz,6.0Hz,1H),7.07(td,J=8.4Hz,2.8Hz,1H),6.89(dd,J=17.6Hz,11.6Hz,1H),6.49(d ,J=1.6Hz,1H),6.00(dd,J=17.6Hz,1.6Hz,1H),5.38-5.44(m,2H),4.02-4.19(m,2H),3.90(s,3 H), 3.75 (d, J = 16.0Hz, 1H), 2.90 (d, J = 16.0Hz, 1H), 1.80 (d, J = 6.4Hz, 3H), 1.31 (t, J = 7.2Hz, 3H).

[0142] Example 8: 3-[(3R)-24-amino-19-ethyl-6-fluoro-3,12-dimethyl-11,12,13,18,19,23-hexaaza-2-oxapentacyclo[19.3.1.0 4,9 .0 10,14 .0 16,20 1(25),4(5),6,8,10(11),13,16(20),17,21(22),23-decen-17-yl]prop-2-ynamide

[0143] The synthesis method of Example 8 is the same as that of Example 1. LC-MS (ESI) [M+H] + :487.2. 1 H NMR(400MHz, CDCl3),7.51(d,J=1.6Hz,1H),7.31(dd,J=9.6Hz,2.4Hz,1H),7. 08-7.12(m,1H),7.04(td,J=8.0Hz,2.8Hz,1H),6.18-6.25(m,2H),6.09-6.17( brs,1H),5.19-5.30(m,3H),4.21(s,3H),4.13(q,J=7.2Hz,2H),4.01(d,J=15. 6Hz, 1H), 3.19 (d, J = 15.6Hz, 1H), 1.78 (d, J = 6.0Hz, 3H), 1.40 (t, J = 7.2Hz, 3H).

[0144] Example 9: (3R)-17-(azetidin-3-ylethynyl)-19-ethyl-6-fluoro-3,12-dimethyl-11,12,13,18,19,23-hexaaza-2-oxapentacyclo[19.3.1.0 4,9 .0 10,14 .0 16,20 ]pentacosyl-1(25),4(5),6,8,10(11),13,16(20),17,21(22),23-decen-24-amine

[0145] The synthesis method of Example 9 is the same as that of Example 5. LC-MS (ESI) [M+H] + : 499.4. 1 H NMR(400MHz, CDCl3),7.50(d,J=1.6Hz,1H),7.31(dd,J=9.6Hz,2.4Hz,1H),7.12(dd,J=8.4Hz,5.6Hz,1H),7.02(dd,J=8.0Hz,2.8Hz,1H),6.21(d,J=1 .6Hz,1H),5.24-5.29(m,1H),4.60-5.18(m,4H),4.22(s,3H),3.90-4.18(m ,7H), 3.17(d,J=15.2Hz,1H), 1.78(d,J=6.0Hz,3H), 1.37(t,J=7.2Hz,3H).

[0146] Example 10: (3R)-19-ethyl-6-fluoro-3,12-dimethyl-17-(pyridin-4-ylethynyl)-11,12,13,18,19,23-hexaaza-2-oxopentacyclo[19.3.1.0 4,9 .0 10,14 .0 16,20 ]pentacosyl-1(25),4(5),6,8,10(11),13,16(20),17,21(22),23-decen-24-amine

[0147] The synthesis method of Example 10 is the same as that of Example 1. LC-MS (ESI) [M+H] + : 521.3. 1H NMR(400MHz, CDCl3),8.61(d,J=6.0Hz,2H),7.53(d,J=1.6Hz,1H),7.47(d,J=6.0Hz,2H),7 .33(dd,J=9.6Hz,2.4Hz,1H),7.14(dd,J=8.4Hz,5.6Hz,1H),7.05(td,J=8.0Hz,2.8Hz,1H) ,6.25(d,J=1.6Hz,1H),5.25-5.32(m,1H),4.90(s,2H),4.22(s,3H),4.12-4.19(m,2H),4. 02(d,J=15.6Hz,1H), 3.25(d,J=15.6Hz,1H), 1.81(d,J=6.4Hz,3H), 1.43(t,J=7.2Hz,3H).

[0148] Example 11: (3R)-19-ethyl-6-fluoro-3,12-dimethyl-17-(pyridin-3-ylethynyl)-11,12,13,18,19,23-hexaaza-2-oxapentacyclo[19.3.1.0 4,9 .0 10,14 .0 16,20 ]pentacosyl-1(25),4(5),6,8,10(11),13,16(20),17,21(22),23-decen-24-amine

[0149] The synthesis method of Example 11 is the same as that of Example 1. LC-MS (ESI) [M+H] + : 521.3. 1 H NMR(400MHz, CDCl3),8.85(s,1H),8.56(d,J=4.4Hz,1H),7.90(dt,J=8.0Hz,2.0Hz,1H),7.54 (d,J=1.2Hz,1H),7.29-7.34(m,2H),7.14(dd,J=8.4Hz,5.6Hz,1H),7.05(td,J=8.0Hz,2.8Hz ,1H),6.27(d,J=1.2Hz,1H),5.25-5.32(m,1H),4.94(s,2H),4.22(s,3H),4.12-4.18(m,2H), 4.04(d,J=15.6Hz,1H), 3.25(d,J=15.6Hz,1H), 1.80(d,J=6.8Hz,3H), 1.42(t,J=7.2Hz,3H).

[0150] Example 12: (3R)-19-ethyl-6-fluoro-3,12-dimethyl-17-[3-(methylamino)prop-1-ynyl]-11,12,13,18,19,23-hexaaza-2-oxapentacyclo[19.3.1.0 4,9 .0 10,14 .0 16,20 ]pentacosyl-1(25),4(5),6,8,10(11),13,16(20),17,21(22),23-decen-24-amine

[0151] The synthesis method of Example 12 is the same as that of Example 5. LC-MS (ESI) [M+H] + :487.3. 1 H NMR(400MHz, CD3OD),7.60(dd,J=10.4Hz,2.8Hz,1H),7.43(d,J=1.6Hz,1H),7.17( dd,J=8.4Hz,6.0Hz,1H),7.11(td,J=8.4Hz,2.8Hz,1H),6.21(d,J=1.6Hz,1H),5.34 -5.41(m,1H),4.21(s,2H),4.19(s,3H),4.03-4.18(m,2H),3.96(d,J=15.6Hz,1H), 3.21(d,J=15.6Hz,1H),2.88(s,3H),1.80(d,J=6.0Hz,3H),1.32(t,J=7.2Hz,3H).

[0152] Example 13: (3R)-19-ethyl-6-fluoro-17-(1-fluorovinyl)-3,12-dimethyl-11,12,13,18,19,23-hexaaza-2-oxopentacyclo[19.3.1.0 4,9 .0 10,14 .0 16,20 ]pentacosyl-1(25),4(5),6,8,10(11),13,16(20),17,21(22),23-decen-24-amine

[0153] The synthesis method of Example 13 is the same as that of Example 1. LC-MS (ESI) [M+H] + :464.2. 1H NMR(400MHz, CDCl3),7.52(d,J=1.2Hz,1H),7.31(dd,J=9.6Hz,2.4Hz,1H),7.10(dd,J=8.4Hz, 5.6Hz,1H),7.04(td,J=8.0Hz,2.8Hz,1H),6.29(d,J=1.2Hz,1H),5.52(dd,J=50.8Hz,3.2Hz,1 H),5.14-5.43(m,3H),5.02(dd,J=18.0Hz,3.2Hz,1H),4.22(s,3H),4.06-4.17(m,2H),3.98(d ,J=16.0Hz,1H),3.18(dd,J=16.0Hz,1.6Hz,1H),1.81(d,J=6.8Hz,3H),1.37(t,J=7.2Hz,3H).

[0154] Example 14: (3R)-17-(3,3-difluoroprop-1-en-2-yl)-19-ethyl-6-fluoro-3,12-dimethyl-11,12,13,18,19,23-hexaaza-2-oxapentacyclo[19.3.1.0 4,9 .0 10,14 .0 16,20 ]pentacosyl-1(25),4(5),6,8,10(11),13,16(20),17,21(22),23-decen-24-amine

[0155] The synthesis method of Example 14 is the same as that of Example 2. LC-MS (ESI) [M+H] + : 496.2.

[0156] Example 15: (3R)-17-(2,2-difluorovinyl)-19-ethyl-6-fluoro-3,12-dimethyl-11,12,13,18,19,23-hexaaza-2-oxapentacyclo[19.3.1.0 4,9 .0 10,14 .0 16,20 ]pentacosyl-1(25),4(5),6,8,10(11),13,16(20),17,21(22),23-decen-24-amine

[0157] The synthesis method of Example 15 is the same as that of Example 2. LC-MS (ESI) [M+H] + : 482.2.

[0158] Example 16: 3-{[(3R)-24-amino-19-ethyl-6-fluoro-3,12-dimethyl-11,12,13,18,19,23-hexaaza-2-oxapentacyclo[19.3.1.0 4,9 .0 10,14 .0 16,20 ]pentacyl-1(25),4(5),6,8,10(11),13,16(20),17,21(22),23-decen-17-yl]ethynyl}azetidin-3-ol

[0159] The synthesis method of Example 16 is the same as that of the compound of Example 5. LC-MS (ESI) [M+H] + : 515.2. 1 H NMR(400MHz, CDCl3+CD3OD),7.39(d,J=1.6Hz,1H),7.29(dd,J=9.6Hz,2.4Hz,1H), 7.09(dd,J=8.8Hz,5.6Hz,1H),7.01(td,J=8.0Hz,2.4Hz,1H),6.15(d,J=1.6Hz,1H ),5.16-5.23(m,1H),4.27-4.35(m,4H),4.17(s,3H),4.03-4.09(m,2H),3.92(d,J =15.6Hz, 1H), 3.15 (d, J = 15.6Hz, 1H), 1.75 (d, J = 6.0Hz, 3H), 1.33 (t, J = 7.2Hz, 3H).

[0160] Example 17: (3R)-17-(azetidin-3-ylidenemethyl)-19-ethyl-6-fluoro-3,12-dimethyl-11,12,13,18,19,23-hexaaza-2-oxapentacyclo[19.3.1.0 4,9 .0 10,14 .0 16,20 ]pentacosyl-1(25),4(5),6,8,10(11),13,16(20),17,21(22),23-decen-24-amine

[0161] The synthesis method of Example 17 is the same as that of Example 2. LC-MS (ESI) [M+H] + : 487.2. 1H NMR(400MHz, CDCl3),7.51(d,J=1.6Hz,1H),7.32(dd,J=10.0Hz,2.8Hz,1H),7.07(dd,J=8.4Hz, 6.0Hz,1H),7.02(td,J=8.4Hz,2.8Hz,1H),6.41-6.45(m,1H),6.24(d,J=1.6Hz,1H),5.22-5.28( m,1H),4.73-4.84(m,3H),4.56-4.67(m,2H),4.44-4.51(m,1H),4.20(s,3H),4.05(q,J=7.2Hz,2 H), 3.74 (d, J = 16.0Hz, 1H), 3.15 (d, J = 16.0Hz, 1H), 1.78 (d, J = 6.0Hz, 3H), 1.35 (t, J = 7.2Hz, 3H).

[0162] Example 18: (3R)-19-ethyl-6-fluoro-3,12-dimethyl-17-[(1-methylazetidin-3-ylidene)methyl]-11,12,13,18,19,23-hexaaza-2-oxapentacyclo[19.3.1.0 4,9 .0 10,14 .0 16,20 ]pentacosyl-1(25),4(5),6,8,10(11),13,16(20),17,21(22),23-decen-24-amine

[0163] The synthesis method of Example 18 is the same as that of Example 2. LC-MS (ESI) [M+H] + : 501.2. 1 H NMR(400MHz, CDCl3),7.50(d,J=1.6Hz,1H),7.31(dd,J=9.6Hz,2.4Hz,1H),7.06(dd,J=8.4Hz,5 .6Hz,1H),7.01(td,J=8.0Hz,2.8Hz,1H),6.42-6.45(m,1H),6.24(d,J=1.6Hz,1H),5.22-5.27(m ,1H),4.79(s,2H),4.31-4.44(m,2H),4.19(s,3H),4.18(s,2H),4.04(q,J=7.2Hz,2H),3.72(d,J =15.6Hz, 1H), 3.14 (d, J = 15.6Hz, 1H), 2.57 (s, 3H), 1.78 (d, J = 6.0Hz, 3H), 1.35 (t, J = 7.2Hz, 3H).

[0164] Example 19: (3R)-17-(1-chlorovinyl)-19-ethyl-6-fluoro-3,12-dimethyl-11,12,13,18,19,23-hexaaza-2-oxapentacyclo[19.3.1.0 4,9 .0 10,14 .0 16,20 ]pentacosyl-1(25),4(5),6,8,10(11),13,16(20),17,21(22),23-decen-24-amine

[0165] The synthesis method of Example 19 is the same as that of Example 2. LC-MS (ESI) [M+H] + : 480.3.

[0166] Example 20: (3R)-17-[(aminocyclopropyl)ethynyl]-19-ethyl-6-fluoro-3,12-dimethyl-11,12,13,18,19,23-hexaaza-2-oxapentacyclo[19.3.1.0 4,9 .0 10,14 .0 16,20 ]pentacosyl-1(25),4(5),6,8,10(11),13,16(20),17,21(22),23-decen-24-amine

[0167] The synthesis method of Example 20 is the same as that of the compound of Example 5. LC-MS (ESI) [M+H] + : 499.3. 1 H NMR (400MHz, CDCl3), 7.47 (d, J = 1.6 Hz, 1H), 7.31 (dd, J = 9.6 Hz, 2.4 Hz, 1H), 7.11 (dd, J = 8. 4Hz,5.6Hz,1H),7.02(td,J=8.0Hz,2.8Hz,1H),6.21(d,J=1.6Hz,1H),5.22-5.29(m,1H), 5.05(s,2H),4.22(s,3H),4.03-4.13(m,2H),3.91(d,J=15.6Hz,1H),3.15(d,J=15.6Hz,1 H), 2.46-2.99 (brs, 2H), 1.78 (d, J = 6.0Hz, 3H), 1.36 (t, J = 7.2Hz, 3H), 1.12-1.20 (m, 4H).

[0168] Example 21: 4-[(3R)-24-amino-19-ethyl-6-fluoro-3,12-dimethyl-11,12,13,18,19,23-hexaaza-2-oxapentacyclo[19.3.1.0 4,9 .0 10,14.0 16,20 1(25),4(5),6,8,10(11),13,16(20),17,21(22),23-decen-17-yl]-2-methylbut-3-yn-2-ol

[0169] The synthesis method of Example 21 is the same as that of Example 1. LC-MS (ESI) [M+H] + : 502.3.

[0170] Example 22: 3-{[(3R)-24-amino-19-ethyl-6-fluoro-3,12-dimethyl-11,12,13,18,19,23-hexaaza-2-oxapentacyclo[19.3.1.0 4,9 .0 10,14 .0 16,20 ]pentacosyl-1(25),4(5),6,8,10(11),13,16(20),17,21(22),23-decen-17-yl]ethynyl}oxetan-3-ol

[0171] The synthesis method of Example 22 is the same as that of Example 1. LC-MS (ESI) [M+H] + : 516.2. 1 H NMR(400MHz, CDCl3),7.53(d,J=1.6Hz,1H),7.32(dd,J=9.6Hz,2.4Hz,1H),7.09(dd,J=8 .4Hz,5.6Hz,1H),7.03(td,J=8.4Hz,2.8Hz,1H),6.21(d,J=1.6Hz,1H),5.22-5.29(m,1H) ,5.01-5.04(m,2H),4.87(s,2H),4.81-4.84(m,2H),4.21(s,3H),4.05-4.15(m,2H),3.8 9(d,J=15.6Hz,1H), 3.14(d,J=15.6Hz,1H), 1.78(d,J=6.0Hz,3H), 1.37(t,J=7.2Hz,3H).

[0172] Example 23: (3R)-19-ethyl-6-fluoro-3,12-dimethyl-17-(oxetan-3-ylethynyl)-11,12,13,18,19,23-hexaaza-2-oxopentacyclo[19.3.1.0 4,9 .0 10,14 .0 16,20 ]pentacosyl-1(25),4(5),6,8,10(11),13,16(20),17,21(22),23-decen-24-amine

[0173] The synthesis method of Example 23 is the same as that of Example 1. LC-MS (ESI) [M+H] + : 500.3. 1 H NMR(400MHz, CDCl3),7.51(d,J=1.2Hz,1H),7.32(dd,J=10.0Hz,2.8Hz,1H),7.12(dd,J= 8.4Hz,5.6Hz,1H),7.03(td,J=8.0Hz,2.8Hz,1H),6.23(d,J=1.2Hz,1H),5.24-5.30(m,1H ),4.88-4.94(m,4H),4.86(s,2H),4.23(s,3H),4.16-4.20(m,1H),4.07-4.14(m,2H),3.9 4(d,J=15.6Hz,1H), 3.18(d,J=15.6Hz,1H), 1.79(d,J=6.4Hz,3H), 1.39(t,J=7.2Hz,3H).

[0174] Example 24: (3R)-19-ethyl-6-fluoro-3,12-dimethyl-17-[(1E)-2-(pyridin-4-yl)vinyl]-11,12,13,18,19,23-hexaaza-2-oxopentacyclo[19.3.1.0 4,9 .0 10,14 .0 16,20 ]pentacosyl-1(25),4(5),6,8,10(11),13,16(20),17,21(22),23-decen-24-amine

[0175] The synthesis method of Example 24 is the same as that of Example 2. LC-MS (ESI) [M+H] + : 523.2. 1 H NMR(400MHz, CDCl3),8.32-8.82(brs,2H),7.42-7.60(m,5H),7.34(dd,J=9.6Hz, 2.8Hz, 1H), 7.11 (dd, J=8.4Hz, 5.6Hz, 1H), 7.04 (td, J=8.0Hz, 2.8Hz, 1H), 6.30 (s ,1H),5.25-5.32(m,1H),5.00(s,2H),4.22(s,3H),4.10-4.21(m,2H),3.91(d,J= 16.0Hz, 1H), 3.26 (d, J = 16.0Hz, 1H), 1.81 (d, J = 6.4Hz, 3H), 1.42 (t, J = 7.2Hz, 3H).

[0176] Example 25: (3R)-19-ethyl-6-fluoro-3,12-dimethyl-17-[(1E)-2-(pyridin-3-yl)vinyl]-11,12,13,18,19,23-hexaaza-2-oxapentacyclo[19.3.1.0 4,9 .0 10,14 .0 16,20 ]pentacosyl-1(25),4(5),6,8,10(11),13,16(20),17,21(22),23-decen-24-amine

[0177] The synthesis method of Example 25 is the same as that of Example 2. LC-MS (ESI) [M+H] + : 523.2. 1 H NMR(400MHz, CDCl3),8.80(s,1H),8.49(d,J=4.4Hz,1H),7.92(d,J=8.0Hz,1H),7.53-7.58(m,2 H),7.40(d,J=16.4Hz,1H),7.30-7.35(m,2H),7.12(dd,J=8.4Hz,5.6Hz,1H),7.04(td,J=8.0Hz, 2.8Hz,1H),6.32(d,J=1.6Hz,1H),5.25-5.32(m,1H),5.15(s,2H),4.22(s,3H),4.08-4.19(m,2 H), 3.92 (d, J = 16.0Hz, 1H), 3.25 (d, J = 16.0Hz, 1H), 1.80 (d, J = 6.4Hz, 3H), 1.41 (t, J = 7.2Hz, 3H).

[0178] Example 26: (3R)-17-(cyclopropylethynyl)-19-ethyl-6-fluoro-3,12-dimethyl-11,12,13,18,19,23-hexaaza-2-oxapentacyclo[19.3.1.0 4,9 .0 10,14 .0 16,20 ]pentacosyl-1(25),4(5),6,8,10(11),13,16(20),17,21(22),23-decen-24-amine

[0179] The synthesis method of Example 26 is the same as that of Example 1. LC-MS (ESI) [M+H] + : 484.3.

[0180] Example 27: (3R)-19-ethyl-17-ethynyl-6-fluoro-3,12-dimethyl-2-oxa-11,12,18,19,23-pentaazapentacyclo[19.3.1.04,9 .0 10,14 .0 16,20 ]pentacosyl-1(25),4(5),6,8,10(11),13,16(20),17,21(22),23-decen-24-amine

[0181] The synthesis method of Example 27 is the same as that of Example 1. LC-MS (ESI) [M+H] + : 443.2. 1 H NMR(400MHz,CD3OD),7.55(s,1H),7.53(dd,J=10.4Hz,2.8Hz,1H),7.43(s,1H ),7.19(dd,J=8.4Hz,5.6Hz,1H),7.08(td,J=8.4Hz,2.8Hz,1H),6.47(s,1H),5 .38-5.45(m,1H),4.03-4.18(m,2H),3.92(s,3H),3.86(s,1H),3.78(d,J=15. 6Hz, 1H), 2.90 (d, J = 15.6Hz, 1H), 1.81 (d, J = 6.4Hz, 3H), 1.32 (t, J = 7.2Hz, 3H).

[0182] Example 28: 3-[(3R)-24-amino-19-ethyl-6-fluoro-3,12-dimethyl-2-oxa-11,12,18,19,23-pentaazapentacyclo[19.3.1.0 4,9 .0 10,14 .0 16,20 1(25),4(5),6,8,10(11),13,16(20),17,21(22),23-decen-17-yl]prop-2-yn-1-ol

[0183] The synthesis method of Example 28 is the same as that of Example 1. LC-MS (ESI) [M+H] + : 473.4. 1H NMR(400MHz, CDCl3),7.52(d,J=1.6Hz,1H),7.40(s,1H),7.28(dd,J=10.0Hz,2.8Hz,1 H),7.10(dd,J=8.4Hz,5.6Hz,1H),6.98(td,J=8.0Hz,2.8Hz,1H),6.50(d,J=1.6Hz,1H ),5.36-5.42(m,1H),4.85(s,2H),4.56(s,2H),4.07-4.13(m,2H),3.90(s,3H),3.73( d, J=15.2Hz, 1H), 2.87 (d, J=15.2Hz, 1H), 1.78 (d, J=6.0Hz, 3H), 1.38 (t, J=7.2Hz, 3H).

[0184] Example 29: (3R)-17-(3-aminoprop-1-ynyl)-19-ethyl-6-fluoro-3,12-dimethyl-2-oxa-11,12,18,19,23-pentaazapentacyclo[19.3.1.0 4,9 .0 10,14 .0 16,20 ]pentacosyl-1(25),4(5),6,8,10(11),13,16(20),17,21(22),23-decen-24-amine

[0185] The synthesis method of Example 29 is the same as that of the compound of Example 5. LC-MS (ESI) [M+H] + : 472.3. 1 H NMR(400MHz, CDCl3),7.50(d,J=1.6Hz,1H),7.43(s,1H),7.28(dd,J=10.0Hz,2.4Hz,1H),7 .10(dd,J=8.4Hz,5.6Hz,1H),6.97(td,J=8.0Hz,2.4Hz,1H),6.49(d,J=1.6Hz,1H),5.35-5. 42(m,1H),4.92(s,2H),4.06-4.14(m,2H),3.91(s,3H),3.85(s,2H),3.72(d,J=15.6Hz,1H) ,3.26-3.63(brs,2H),2.87(d,J=15.6Hz,1H),1.76(d,J=6.4Hz,3H),1.37(t,J=7.2Hz,3H).

[0186] Example 30: (3R)-6-Fluoro-3,12-dimethyl-18-(prop-2-ynyl)-2-oxa-11,12,18,19,23-pentaazapentacyclo[19.3.1.0 4,9 .0 10,14 .0 16,20 ]pentacosyl-1(25),4(5),6,8,10(11),13,16(17),19,21(22),23-decen-24-amine

[0187] The synthesis method of Example 30 is the same as that of Example 1. LC-MS (ESI) [M+H] + : 429.3. 1 H NMR(400MHz, CDCl3),7.69(s,1H),7.65(d,J=1.2Hz,1H),7.28-7.31(m,2H),7.20-7.23(m,1H),7.08-7.13(m,1H),6.94(d,J=1.2Hz,1H),5.28 -5.35(m,1H),4.91(d,J=2.4Hz,2H),3.92(s,3H),3.76(d,J=16.0Hz,1H),3.09(d,J=16.0Hz,1H),2.57(t,J=2.4Hz,1H),1.85(d,J=6.4Hz,3H).

[0188] Example 31: (3R)-13-chloro-19-ethyl-17-ethynyl-6-fluoro-3,12-dimethyl-2-oxa-11,12,18,19,23-pentaazapentacyclo[19.3.1.0 4,9 .0 10,14 .0 16,20 ]pentacosyl-1(25),4(5),6,8,10(11),13,16(20),17,21(22),23-decen-24-amine

[0189] The synthesis method of Example 31 is the same as that of Example 1. LC-MS (ESI) [M+H] + : 477.3.

[0190] Example 32: (3R)-19-ethyl-6-fluoro-3-methyl-12-(prop-2-ynyl)-11,12,13,18,19,23-hexaaza-2-oxapentacyclo[19.3.1.0 4,9 .0 10,14 .0 16,20 ]pentacosyl-1(25),4(5),6,8,10(11),13,16(20),17,21(22),23-decen-24-amine

[0191] The synthesis method of Example 32 is the same as that of Example 1. LC-MS (ESI) [M+H] + : 444.3.

[0192] Example 33: (3R)-12-cyclopropyl-19-ethyl-17-ethynyl-6-fluoro-3-methyl-11,12,13,18,19,23-hexaaza-2-oxapentacyclo[19.3.1.0 4,9 .0 10,14 .0 16,20 ]pentacosyl-1(25),4(5),6,8,10(11),13,16(20),17,21(22),23-decen-24-amine

[0193] The synthesis method of Example 33 is the same as that of Example 1. LC-MS (ESI) [M+H] + : 444.3.

[0194] Example 34: (3R)-19-ethyl-6-fluoro-12-methyl-3-(prop-2-ynyl)-11,12,13,18,19,23-hexaaza-2-oxapentacyclo[19.3.1.0 4,9 .0 10,14 .0 16,20 ]pentacosyl-1(25),4(5),6,8,10(11),13,16(20),17,21(22),23-decen-24-amine

[0195] The synthesis method of Example 34 is the same as that of Example 1. LC-MS (ESI) [M+H] + : 444.2.

[0196] Example 35: (3R)-3,19-diethyl-6-fluoro-12-methyl-11,12,13,18,19,23-hexaaza-2-oxapentacyclo[19.3.1.0 4,9 .0 10,14 .0 16,20 ]pentacosyl-1(25),4(5),6,8,10(11),13,16(20),17,21(22),23-decen-24-amine

[0197] The synthesis method of Example 35 is the same as that of Example 1. LC-MS (ESI) [M+H] + : 434.3. 1H NMR(400MHz, DMSO),7.70(dd,J=10.4Hz,2.4Hz,1H),7.55(s,1H),7.41(d,J=1.6Hz, 1H),7.14-7.21(m,2H),6.14(s,2H),6.04(d,J=1.6Hz,1H),4.97(td,J=7.2Hz,1.6Hz ,1H),4.13(s,3H),3.92-4.02(m,2H),3.75(d,J=15.6Hz,1H),2.94(d,J=15.6Hz,1H) ,2.13-2.24(m,1H),1.94-2.04(m,1H),1.24(t,J=7.2Hz,3H),0.94(t,J=7.2Hz,3H).

[0198] Example 36: (3S)-19-ethyl-6-fluoro-12-methyl-3-(trifluoromethyl)-11,12,13,18,19,23-hexaaza-2-oxapentacyclo[19.3.1.0 4,9 .0 10,14 .0 16,20 ]pentacosyl-1(25),4(5),6,8,10(11),13,16(20),17,21(22),23-decen-24-amine

[0199] The synthesis method of Example 36 is the same as that of Example 1. LC-MS (ESI) [M+H] + : 474.2. 1 H NMR(400MHz, CDCl3),7.71(s,1H),7.58(s,1H),7.49-7.54(m,1H),7.18-7.22(m,2H),6.23(s,1H),5.47-5.52(m,1H) ,5.14(s,2H),4.24(s,3H),4.02-4.16(m,2H),3.83(d,J=15.6Hz,1H),3.16(d,J=15.6Hz,1H),1.40(t,J=7.2Hz,3H).

[0200] Example 37: (3R)-19-ethyl-17-ethynyl-6-fluoro-3,12-dimethyl-2-oxa-10,11,18,19,23-pentaazapentacyclo[19.3.1.0 4,9 .0 10,14 .0 16,20 ]pentacosyl-1(25),4(5),6,8,11,13,16(20),17,21(22),23-decen-24-amine

[0201] The synthesis method of Example 37 is the same as that of Example 1. LC-MS (ESI) [M+H] + : 443.2.

[0202] Example 38: (3R)-19-ethyl-17-ethynyl-6-fluoro-3,12-dimethyl-2,13-dioxa-11,18,19,23-tetraazapentacyclo[19.3.1.0 4,9 .0 10,14 .0 16,20 ]pentacosyl-1(25),4(5),6,8,10(14),11,16(20),17,21(22),23-decen-24-amine

[0203] The synthesis method of Example 38 is the same as that of Example 1. LC-MS (ESI) [M+H] + : 444.2. 1 H NMR (400MHz, CDCl3), 7.51 (s, 1H), 7.30 (dd, J = 9.6Hz, 2.8Hz, 1H), 7.07 (dd, J = 8. 4Hz, 5.6Hz, 1H), 6.98 (td, J=8.4Hz, 2.8Hz, 1H), 6.57 (d, J=1.2Hz, 1H), 5.39-5.4 5(m,1H),4.86(s,2H),4.07-4.17(m,2H),3.97(d,J=15.6Hz,1H),3.30(d,J=15. 6Hz, 1H), 3.29 (s, 1H), 2.49 (s, 3H), 1.80 (d, J = 6.4Hz, 3H), 1.41 (t, J = 7.2Hz, 3H).

[0204] Example 39: (3R)-19-ethyl-17-ethynyl-6-fluoro-3,12-dimethyl-2-oxa-11,18,19,23-tetraaza-13-thiapentacyclo[19.3.1.0 4,9 .0 10,14 .0 16,20 ]pentacosyl-1(25),4(5),6,8,10(14),11,16(20),17,21(22),23-decen-24-amine

[0205] The synthesis method of Example 39 is the same as that of Example 1. LC-MS (ESI) [M+H] + : 460.3. 1H NMR(400MHz,CD3OD),7.55(dd,J=10.0Hz,2.8Hz,1H),7.45(d,J=1.6Hz,1H),7. 22(dd,J=8.4Hz,6.0Hz,1H),7.08(td,J=8.4Hz,2.8Hz,1H),6.50(d,J=1.6Hz,1H ),5.23-5.30(m,1H),4.06-4.20(m,2H),4.03(d,J=16.0Hz,1H),3.89(s,1H),3. 37 (d, J = 16.0 Hz, 1H), 2.69 (s, 3H), 1.82 (d, J = 6.4 Hz, 3H), 1.33 (t, J = 7.2 Hz, 3H).

[0206] Example 40: (3R)-19-ethyl-17-ethynyl-6-fluoro-3,12-dimethyl-2,11-dioxa-13,18,19,23-tetraazapentacyclo[19.3.1.0 4,9 .0 10,14 .0 16,20 ]pentacosyl-1(25),4(5),6,8,10(14),12,16(20),17,21(22),23-decen-24-amine

[0207] The synthesis method of Example 40 is the same as that of Example 1. LC-MS (ESI) [M+H] + : 444.3. 1 H NMR(400MHz, CDCl3),7.52(d,J=1.6Hz,1H),7.32(dd,J=10.0Hz,2.8Hz,1H),7. 15(dd,J=8.4Hz,5.6Hz,1H),7.04(td,J=8.4Hz,2.8Hz,1H),6.71(d,J=1.6Hz,1H ),4.98-5.30(m,3H),4.02-4.15(m,2H),3.85(d,J=15.2Hz,1H),3.32(s,1H),3. 09(d,J=15.2Hz,1H),2.51(s,3H),1.79(d,J=6.4Hz,3H),1.37(t,J=7.2Hz,3H).

[0208] Example 41: (3R)-19-ethyl-17-ethynyl-6-fluoro-3,12-dimethyl-2-oxa-13,18,19,23-tetraaza-11-thiapentacyclo[19.3.1.0 4,9 .0 10,14 .0 16,20]pentacosyl-1(25),4(5),6,8,10(14),12,16(20),17,21(22),23-decen-24-amine

[0209] The synthesis method of Example 41 is the same as that of Example 1. LC-MS (ESI) [M+H] + : 460.3. 1 H NMR(400MHz, CDCl3),7.54(s,1H),7.27(dd,J=9.6Hz,2.8Hz,1H),7.15(dd,J=8 .4Hz,5.6Hz,1H),7.02(td,J=8.4Hz,2.8Hz,1H),6.75(s,1H),5.44-5.50(m,1H ),4.87(s,2H),4.15(q,J=7.2Hz,2H),3.92(d,J=15.2Hz,1H),3.29(s,1H),3.2 3(d,J=15.2Hz,1H),2.72(s,3H),1.74(d,J=6.4Hz,3H),1.43(t,J=7.2Hz,3H).

[0210] Example 42: (3R)-17-Chloro-19-ethyl-6,15,15-trifluoro-3,12-dimethyl-11,12,13,18,19,23-hexaaza-2-oxapentacyclo[19.3.1.0 4,9 .0 10,14 .0 16,20 ]pentacosyl-1(25),4(5),6,8,10(11),13,16(20),17,21(22),23-decen-24-amine

[0211] The synthesis method of Example 42 is the same as that of Example 1. LC-MS (ESI) [M+H] + : 490.2.

[0212] Example 43: (3R)-19-ethyl-17-ethynyl-6,15,15-trifluoro-3,12-dimethyl-2-oxa-11,12,18,19,23-pentaazapentacyclo[19.3.1.0 4,9 .0 10,14 .0 16,20 ]pentacosyl-1(25),4(5),6,8,10(11),13,16(20),17,21(22),23-decen-24-amine

[0213] The synthesis method of Example 43 is the same as that of Example 1. LC-MS (ESI) [M+H] + : 479.2.

[0214] Example 44: (3R)-17-chloro-20-ethyl-6-fluoro-3,12-dimethyl-2-oxa-11,12,19,24-tetraazapentacyclo[20.3.1.0 4,9 .0 10,14 .0 16,21 Hexadecene-1(26),4(5),6,8,10(11),13,16(17),18,20,22(23),24-undecene-25-amine

[0215] The synthesis method of Example 44 is the same as that of Example 1. LC-MS (ESI) [M+H] + :479.2.

[0216] Example 45: (19R)-3-ethyl-16-fluoro-10,19-dimethyl-5-(2-methylprop-1-enyl)-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0217] The synthesis method of compound 45-1 is the same as that of compound 1-10. Under nitrogen protection, cuprous iodide (583 mg), potassium iodide (5.64 g) and N,N'-dimethylethylenediamine (0.56 mL) were added to a solution of compound 45-1 (1.7 g) in 1,4-dioxane (35 mL). The reaction solution was heated to 135°C under microwave and reacted at this temperature for 2 hours. The reaction solution was filtered, and the resulting filtrate was concentrated under reduced pressure and purified by flash silica gel column chromatography (dichloromethane:ethyl acetate = 3:1 to 1:1) to obtain compound 45-2 (1.3 g). Example 45 was synthesized using 45-2 as the starting material by general synthesis method C. LC-MS (ESI) [M+H] + :473.3. 1H NMR(400MHz, CDCl3),7.47(d,J=1.2Hz,1H),7.28(dd,J=10.0Hz,2.8Hz,1H),7.22(s,1H),7.1 3(dd,J=8.4Hz,5.6Hz,1H),7.00(td,J=8.4Hz,2.8Hz,1H),6.56(d,J=1.2Hz,1H),6.26(s,1H), 5.36-5.43(m,1H),5.16(s,2H),4.10(q,J=7.2Hz,2H),3.90(s,3H),3.57(d,J=16.0Hz,1H),2 .86(d,J=16.0Hz,1H),2.15(s,3H),1.99(s,3H),1.78(d,J=6.0Hz,3H),1.40(t,J=7.2Hz,3H).

[0218] Example 46: (19R)-3-ethyl-16-fluoro-10,19-dimethyl-5-(prop-1-en-2-yl)-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0219] The synthesis method of Example 46 is the same as that of Example 45. LC-MS (ESI) [M+H] + :459.4. 1 H NMR(400MHz, CDCl3),7.38(s,1H),7.32(s,1H),7.28(d,J=10.0Hz,2.4Hz,1H),7.17(dd,J =8.4Hz,5.6Hz,1H),7.03(td,J=8.0Hz,2.8Hz,1H),6.62(s,1H),5.70-5.89(brs,2H),5.5 9(s,1H),5.40-5.47(m,1H),5.29(s,1H),4.04-4.16(m,2H),3.91(s,3H),3.80(d,J=16.0 Hz, 1H), 2.94 (d, J = 16.0Hz, 1H), 2.27 (s, 3H), 1.81 (d, J = 6.4Hz, 3H), 1.38 (t, J = 7.2Hz, 3H).

[0220] Example 47: (2R)-4-[(19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decen-5-yl]but-3-yn-2-ol

[0221] Under nitrogen, compound 17 (30 mg) was added to a solution of compound 45-2 (100 mg), Pd(PPh3)2Cl2 (17 mg), triethylamine (51 μL), and cuprous iodide (7 mg) in DMF (2 mL). The reaction mixture was then heated to 80°C overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 40:1) to obtain the title compound (53 mg). LC-MS (ESI) [M+H] + :487.4. 1 H NMR(400MHz, CD3OD),7.59(s,1H),7.53(dd,J=10.0Hz,2.4Hz,1H),7.43(s,1H),7.19(d, J=8.4Hz,5.6Hz,1H),7.08(td,J=8.0Hz,2.8Hz,1H),6.48(d,J=1.2Hz,1H),5.38-5.45(m ,1H),4.78(q,J=6.8Hz,1H),4.02-4.17(m,2H),3.92(s,3H),3.77(d,J=15.6Hz,1H),2.8 8(d,J=15.6Hz,1H), 1.81(d,J=6.4Hz,3H), 1.55(d,J=6.4Hz,3H), 1.31(t,J=7.2Hz,3H).

[0222] Example 48: (2S)-4-[(19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decen-5-yl]but-3-yn-2-ol

[0223] The synthesis method of Example 48 is the same as that of Example 47. LC-MS (ESI) [M+H] + :487.3. 1 H NMR(400MHz,CD3OD),7.59(s,1H),7.53(dd,J=10.0Hz,2.4Hz,1H),7.35-7.50(brs,1H), 7.18(dd,J=8.4Hz,5.6Hz,1H),7.07(td,J=8.0Hz,2.8Hz,1H),6.48(s,1H),5.39-5.44(m ,1H),4.78(q,J=6.8Hz,1H),4.02-4.17(m,2H),3.92(s,3H),3.77(d,J=15.6Hz,1H),2.8 8(d,J=15.6Hz,1H), 1.81(d,J=6.8Hz,3H), 1.56(d,J=6.4Hz,3H), 1.31(t,J=7.2Hz,3H).

[0224] Example 49: (19R)-3-ethyl-16-fluoro-10,19-dimethyl-5-(prop-1-ynyl)-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0225] The synthesis method of Example 49 is the same as that of Example 47. LC-MS (ESI) [M+H] + :487.3. 1 H NMR(400MHz, CD3OD),7.51-7.54(m,2H),7.41(d,J=1.6Hz,1H),7.18(dd,J=8.4Hz,5.6Hz,1H),7.07(td,J=8.4Hz,2.8Hz,1H),6.46(d,J=1.6Hz,1H),5.37 -5.44(m,1H),4.00-4.15(m,2H),3.92(s,3H),3.74(d,J=16.0Hz,1H),2.85( d,J=16.0Hz,1H),2.14(s,3H),1.81(d,J=6.4Hz,3H),1.30(t,J=7.2Hz,3H).

[0226] Example 50: (19R)-3-ethyl-16-fluoro-10,19-dimethyl-5-(pyrazin-2-ylethynyl)-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0227] The synthesis method of Example 50 is the same as that of Example 47. LC-MS (ESI) [M+H] + :521.3. 1 H NMR(400MHz, CD3OD),8.87(d,J=1.2Hz,1H),8.64-8.65(m,1H),8.59(d,J=2.8Hz,1H),7.63(s ,1H),7.54(dd,J=10.0Hz,2.8Hz,1H),7.41-7.52(brs,1H),7.22(dd,J=8.4Hz,6.0Hz,1H),7. 08(td,J=8.4Hz,2.8Hz,1H),6.50(s,1H),5.39-5.45(m,1H),4.09-4.24(m,2H),3.91(s,3H), 3.90(d,J=15.6Hz,1H), 2.98(d,J=15.6Hz,1H), 1.80(d,J=6.0Hz,3H), 1.36(t,J=7.2Hz,3H).

[0228] Example 51: (19R)-5-[(3S)-3-aminobut-1-ynyl]-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0229] The synthesis method of Example 51 is the same as that of Example 47. LC-MS (ESI) [M+H] + :486.3. 1H NMR(400MHz, CDCl3),7.50(d,J=2.0Hz,1H),7.40(s,1H),7.28(dd,J=10.0Hz,2.8Hz,1H),7.13(d d,J=8.4Hz,5.6Hz,1H),6.99(td,J=8.0Hz,2.8Hz,1H),6.49(d,J=2.0Hz,1H),5.40(qd,J=6.0Hz,1 .6Hz,1H),4.81(s,2H),4.07-4.13(m,2H),4.00(q,J=6.4Hz,1H),3.91(s,3H),3.74(d,J=15.6Hz ,1H),2.89(d,J=15.6Hz,1H),1.78(d,J=6.4Hz,3H),1.50(d,J=6.8Hz,3H),1.39(t,J=7.2Hz,3H).

[0230] Example 52: (19R)-5-[(3S)-3-aminobut-1-ynyl]-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0231] The synthesis method of Example 52 is the same as that of Example 47. LC-MS (ESI) [M+H] + :486.3. 1 H NMR(400MHz, CDCl3),7.50(s,2H),7.28(dd,J=10.0Hz,2.8Hz,1H),7.08-7.12(m,1H) ,6.95(td,J=8.0Hz,2.4Hz,1H),6.49(d,J=1.2Hz,1H),5.37-5.42(m,1H),4.90(s,2H) ,4.25(q,J=6.8Hz,1H),4.06-4.16(m,2H),3.92(s,3H),3.73(d,J=15.6Hz,1H),2.88( d, J=15.6Hz, 1H), 1.78 (d, J=6.4Hz, 3H), 1.65 (d, J=6.8Hz, 3H), 1.37 (t, J=7.2Hz, 3H).

[0232] Example 53: 3-ethyl-16-fluoro-10-methyl-19-(prop-2-ynyl)-3,4,9,10,11,23-hexaaza-20-oxapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0233] The synthesis method of the compound in Example 53 is the same as that of compound 45-1. LC-MS (ESI) [M+H] + :444.2. 1 H NMR(400MHz, CDCl3),7.71(s,1H),7.54(d,J=1.6Hz,1H),7.38(dd,J=9.6Hz,2.4Hz,1H),7.1 1(dd,J=8.4Hz,5.6Hz,1H),7.06(td,J=8.0Hz,2.8Hz,1H),6.27(d,J=1.6Hz,1H),5.24-5.28 (m,1H),5.04(s,2H),4.22(s,3H),4.02-4.15(m,2H),3.79(d,J=15.6Hz,1H),3.19(d,J=15. 6Hz, 1H), 3.02-3.09 (m, 1H), 2.92-2.98 (m, 1H), 2.09 (t, J = 2.4Hz, 1H), 1.38 (t, J = 7.2Hz, 3H).

[0234] Example 54: (19R)-3-Ethyl-16-fluoro-10,19-dimethyl-5-[(1-methylpyrazol-4-yl)ethynyl]-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0235] The synthesis method of Example 54 is the same as that of Example 47. LC-MS (ESI) [M+H] + :523.3. 1H NMR(400MHz, CDCl3),7.68(s,1H),7.60(s,1H),7.50(d,J=1.6Hz,1H),7.44(s,1H),7.29(dd ,J=10.0Hz,2.4Hz,1H),7.14(dd,J=8.4Hz,5.6Hz,1H),7.00(td,J=8.0Hz,2.8Hz,1H),6.54(d ,J=1.6Hz,1H),5.38-5.45(m,1H),5.07(s,2H),4.09-4.15(m,2H),3.92(s,3H),3.90(s,3H), 3.82(d,J=15.6Hz,1H), 2.93(d,J=15.6Hz,1H), 1.79(d,J=6.4Hz,3H), 1.41(t,J=6.8Hz,3H).

[0236] Example 55: (19R)-5-((1-(5,5-dimethyl-2-oxa-5-silan-1-yl)pyrazol-4-yl)ethynyl)-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0] 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0237] The synthesis method of Example 55 is the same as that of Example 47. LC-MS (ESI) [M+H] + :639.4. 1 H NMR(400MHz, CDCl3),7.81(s,1H),7.73(s,1H),7.45(s,1H),7.22-7.30(m,2H),7.17(dd,J=8 .4Hz,5.6Hz,1H),7.04(td,J=8.4Hz,2.4Hz,1H),6.62(s,1H),5.62-6.00(brs,2H),5.40-5.4 8(m,3H),4.08-4.16(m,2H),3.91(s,3H),3.86(d,J=15.6Hz,1H),3.57-3.61(m,2H),2.94(d, J=15.6Hz,1H),1.82(d,J=6.0Hz,3H),1.42(t,J=7.2Hz,3H),0.90-0.94(m,2H),-0.01(s,9H).

[0238] Example 56: (19R)-3-Ethyl-16-fluoro-5-[3-(imidazol-1-yl)prop-1-ynyl]-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0239] The synthesis method of Example 56 is the same as that of Example 47. LC-MS (ESI) [M+H] + :523.4. 1 H NMR(400MHz, CDCl3),7.92(s,1H),7.48(d,J=1.6Hz,1H),7.23-7.30(m,2H),7. 10-7.19(m,3H),7.00(td,J=8.4Hz,2.8Hz,1H),6.50(d,J=1.6Hz,1H),5.36-5. 41(m,1H),4.83-5.24(m,4H),4.11(q,J=7.2Hz,2H),3.89(s,3H),3.71(d,J=15 .6Hz, 1H), 2.91 (d, J = 15.6Hz, 1H), 1.78 (d, J = 6.0Hz, 3H), 1.40 (t, J = 7.2Hz, 3H).

[0240] Example 57: (19R)-3-ethyl-16-fluoro-10,19-dimethyl-5-(pyridin-4-ylethynyl)-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2,6 .0 8,12 .0 13,18 ]pentacosyl-1(25),2(6),4,8(9),11,13(14),15,17,21(22),23-decen-22-amine

[0241] The synthesis method of Example 57 is the same as that of Example 47. LC-MS (ESI) [M+H] + :520.4. 1H NMR(400MHz, CDCl3),8.51-8.54(m,2H),7.54(s,1H),7.45(d,J=4.8Hz,2H),7.41(s,1H) ,7.30(dd,J=9.6Hz,2.8Hz,1H),7.16(dd,J=8.4Hz,5.6Hz,1H),7.01(td,J=8.4Hz,2.8Hz, 1H),6.52(s,1H),5.38-5.45(m,1H),4.89(s,2H),4.17(q,J=7.2Hz,2H),3.91(s,3H),3.8 4(d,J=15.6Hz,1H), 2.99(d,J=15.6Hz,1H), 1.79(d,J=6.4Hz,3H), 1.43(t,J=7.2Hz,3H).

[0242] Example 58: (19R)-3-ethyl-16-fluoro-10,19-dimethyl-5-(pyridin-3-ylethynyl)-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2,6 .0 8,12 .0 13,18 ]pentacosyl-1(25),2(6),4,8(9),11,13(14),15,17,21(22),23-decen-22-amine

[0243] The synthesis method of Example 58 is the same as that of Example 47. LC-MS (ESI) [M+H] + :520.4. 1 H NMR(400MHz, CDCl3),8.83(d,J=1.2Hz,1H),8.57(dd,J=4.8Hz,1.2Hz,1H),7.87(dt,J=8.0Hz,2.0 Hz,1H),7.54(s,1H),7.44(s,1H),7.28-7.32(m,2H),7.16(dd,J=8.4Hz,5.6Hz,1H),7.00(td,J=8. 4Hz,2.4Hz,1H),6.53(d,J=1.2Hz,1H),5.38-5.45(m,1H),4.88(s,2H),4.13-4.19(m,2H),3.90(s ,3H),3.85(d,J=15.6Hz,1H),2.98(d,J=15.6Hz,1H),1.79(d,J=6.4Hz,3H),1.43(t,J=7.2Hz,3H).

[0244] Example 59: (19R)-3-ethyl-16-fluoro-5-[(1E)-3-methoxyprop-1-enyl]-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2,6 .0 8,12 .0 13,18 ]pentacosyl-1(24),2(6),4,8(9),11,13(18),14,16,21(25),22-decen-22-amine

[0245] The synthesis method of Example 59 is the same as that of Example 45. LC-MS (ESI) [M+H] + :489.3. 1 H NMR(400MHz, CDCl3),7.42-7.56(brs,1H),7.26-7.29(m,2H),7.14(dd,J=8.4Hz,5.6Hz,1H ),7.02(td,J=8.4Hz,2.4Hz,1H),6.76(dt,J=16.4Hz,1.6Hz,1H),6.55-6.62(m,2H),5.18- 5.56(m,3H),4.16(dd,J=5.6Hz,1.2Hz,2H),4.05-4.13(m,2H),3.90(s,3H),3.70(d,J=16. 0Hz, 1H), 3.44 (s, 3H), 2.93 (d, J = 16.0Hz, 1H), 1.79 (d, J = 6.0Hz, 3H), 1.39 (t, J = 7.2Hz, 3H).

[0246] Example 60: (19R)-3-ethyl-16-fluoro-10,19-dimethyl-5-(1,3-thiazol-4-ylethynyl)-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosyl-1(24),2(6),4,8(9),11,13(14),15,17,21(25),22-decen-22-amine

[0247] The synthesis method of Example 60 is the same as that of Example 47. LC-MS (ESI) [M+H] + :526.4. 1H NMR(400MHz, CDCl3),8.83(d,J=2.0Hz,1H),7.66(d,J=2.0Hz,1H),7.53(d,J=1.6Hz,1H),7.49 (s,1H),7.28(dd,J=10.0Hz,2.8Hz,1H),7.13(dd,J=8.4Hz,5.6Hz,1H),7.00(td,J=8.4Hz,2.8 Hz,1H),6.55(d,J=1.6Hz,1H),5.38-5.45(m,1H),4.95(s,2H),4.11-4.17(m,2H),3.90(d,J=1 5.6Hz, 1H), 3.89 (s, 3H), 2.95 (d, J = 15.6Hz, 1H), 1.79 (d, J = 6.4Hz, 3H), 1.41 (t, J = 7.2Hz, 3H).

[0248] Example 61: 4-[(19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decen-5-yl]-2-methylbut-3-yn-2-ol

[0249] The synthesis method of Example 61 is the same as that of Example 47. LC-MS (ESI) [M+H] + :501.4. 1 H NMR(400MHz, CDCl3),7.48(d,J=1.6Hz,1H),7.41(s,1H),7.28(dd,J=10.0Hz,2.8Hz,1 H),7.14(dd,J=8.4Hz,5.6Hz,1H),7.00(td,J=8.4Hz,2.8Hz,1H),6.53(d,J=1.6Hz,1H ),5.38-5.45(m,1H),5.20(s,2H),4.04-4.14(m,2H),3.90(s,3H),3.73(d,J=15.6Hz, 1H), 2.89 (d, J = 15.6Hz, 1H), 1.79 (d, J = 6.4Hz, 3H), 1.68 (s, 6H), 1.38 (t, J = 7.2Hz, 3H).

[0250] Example 62: (19R)-3-Ethyl-16-fluoro-5-(1H-pyrazol-4-ylethynyl)-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0251] The synthesis method of Example 62 is the same as that of Example 47. LC-MS (ESI) [M+H] + :509.4. 1 H NMR(400MHz, CDCl3),10.10-11.20(brs,1H),7.73-7.97(brs,2H),7.49(d,J=1.2Hz,1H),7 .46(s,1H),7.29(dd,J=10.0Hz,2.8Hz,1H),7.16(dd,J=8.4Hz,5.6Hz,1H),7.02(td,J=8.4 Hz,2.8Hz,1H),6.58(d,J=1.2Hz,1H),5.32-5.48(m,3H),4.10-4.16(m,2H),3.91(s,3H),3 .85(d,J=15.6Hz,1H), 2.95(d,J=15.6Hz,1H), 1.80(d,J=6.4Hz,3H), 1.42(t,J=7.2Hz,3H).

[0252] Example 63: (19R)-3-ethyl-16-fluoro-10,19-dimethyl-5-(pyridin-2-ylethynyl)-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0253] The synthesis method of Example 63 is the same as that of Example 47. LC-MS (ESI) [M+H] + :520.4. 1H NMR(400MHz, CDCl3),8.65(d,J=4.8Hz,1H),7.71(td,J=8.0Hz,2.0Hz,1H),7.62(d,J=7.6Hz,1H), 7.54(d,J=1.6Hz,1H),7.49(s,1H),7.26-7.30(m,2H),7.14(dd,J=8.4Hz,5.6Hz,1H),7.00(td,J=8 .4Hz,2.8Hz,1H),6.56(d,J=1.6Hz,1H),5.39-5.46(m,1H),4.81(s,2H),4.14-4.20(m,2H),3.94(d ,J=16.0Hz,1H),3.89(s,3H),2.97(d,J=16.0Hz,1H),1.79(d,J=6.4Hz,3H),1.44(t,J=7.2Hz,3H).

[0254] Example 64: (19R)-3-Ethyl-16-fluoro-5-(imidazo[2,3-f][1,2]pyridazin-3-ylethynyl)-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0255] The synthesis method of Example 64 is the same as that of Example 47. LC-MS (ESI) [M+H] + :560.4. 1 H NMR(400MHz, CDCl3),8.46(dd,J=4.4Hz,1.6Hz,1H),8.09(s,1H),8.01(dd,J=8.8Hz,1.6Hz,1H),7 .64(s,1H),7.56(d,J=1.6Hz,1H),7.30(dd,J=9.6Hz,2.8Hz,1H),7.12-7.16(m,2H),7.00(td,J=8. 4Hz,2.8Hz,1H),6.57(d,J=1.6Hz,1H),5.41-5.48(m,1H),4.82(s,2H),4.15-4.20(m,2H),3.93(d ,J=15.6Hz,1H),3.91(s,3H),3.00(d,J=15.6Hz,1H),1.80(d,J=6.4Hz,3H),1.43(t,J=7.2Hz,3H).

[0256] Example 65: (19R)-5-(cyclopropylethynyl)-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2,6 .0 8,12 .0 13,18 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0257] The synthesis method of Example 65 is the same as that of Example 47. LC-MS (ESI) [M+H] + :483.4. 1 H NMR(400MHz, CDCl3),7.50(d,J=1.6Hz,1H),7.41(s,1H),7.25-7.28(m,1H),7.14(dd,J=8. 4Hz, 5.6Hz, 1H), 6.99 (td, J=8.4Hz, 2.8Hz, 1H), 6.52 (d, J=1.6Hz, 1H), 5.36-5.42 (m, 1H), 5. 02-5.29(brs,2H),4.01-4.10(m,2H),3.91(s,3H),3.74(d,J=15.6Hz,1H),3.86(d,J=15.6 Hz, 1H), 1.78 (d, J = 6.0Hz, 3H), 1.49-1.55 (m, 1H), 1.34 (t, J = 7.2Hz, 3H), 0.45-0.93 (m, 4H).

[0258] Example 66: (19R)-5-(azetidin-3-ylethynyl)-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2,6 .0 8,12 .0 13,18 ]pentacosyl-1(24),2(6),4,8(9),11,13(18),14,16,21(25),22-decen-22-amine

[0259] The synthesis method of Example 66 is the same as that of Example 47. LC-MS (ESI) [M+H] + :498.4. 1H NMR(400MHz, CD3OD),7.57(s,1H),7.52(dd,J=9.6Hz,2.4Hz,1H),7.30-7.51(brs,1H),7.17(dd,J=8.4Hz,5.6Hz,1H),7.06(t,J=8.4Hz,2.4Hz,1H),6.46 (s,1H),5.37-5.43(m,1H),4.00-4.46(m,7H),3.92(s,3H),3.76(d,J=15.6H z, 1H), 2.87 (d, J = 15.6Hz, 1H), 1.79 (d, J = 6.0Hz, 3H), 1.30 (t, J = 7.2Hz, 3H).

[0260] Example 67: (19R)-3-ethyl-16-fluoro-10,19-dimethyl-5-(phenylethynyl)-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2,6 .0 8,12 .0 13,18 ]pentacosyl-1(24),2(6),4,8(9),11,13(18),14,16,21(25),22-decen-22-amine

[0261] The synthesis method of Example 67 is the same as that of Example 47. LC-MS (ESI) [M+H] + :519.4. 1 H NMR(400MHz, CD3OD),7.28-7.75(m,8H),7.22(dd,J=8.4Hz,5.6Hz,1H),7.07(td,J=8.4Hz,2.8Hz,1H),6.50(s,1H),5.39-5.45(m, 1H), 4.06-4.21 (m, 2H), 3.91 (s, 3H), 3.87 (d, J = 15.6Hz, 1H), 2.95 (d, J = 15.6Hz, 1H), 1.81 (d, J = 6.4Hz, 3H), 1.35 (t, J = 7.2Hz, 3H).

[0262] Example 68: (19R)-5-[(aminocyclopropyl)ethynyl]-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2,6 .0 8,12 .0 13,18 ]pentacosyl-1(24),2(6),4,8(9),11,13(18),14,16,21(25),22-decen-22-amine

[0263] The synthesis method of Example 68 is the same as that of Example 47. LC-MS (ESI) [M+H] + :498.4. 1 H NMR(400MHz, CDCl3),7.46(d,J=1.2Hz,1H),7.40(s,1H),7.29(dd,J=10.0Hz,2.8Hz,1H),7.14 (dd,J=8.4Hz,5.6Hz,1H),7.00(td,J=8.0Hz,2.8Hz,1H),6.53(d,J=1.2Hz,1H),5.38-5.45(m, 1H),5.16-5.36(brs,2H),4.06-4.12(m,2H),3.92(s,3H),3.72(d,J=15.6Hz,1H),2.88(d,J=1 5.6Hz, 1H), 1.80 (d, J = 6.4Hz, 3H), 1.38 (t, J = 7.2Hz, 3H), 1.22-1.27 (m, 2H), 1.11-1.16 (m, 2H).

[0264] Example 69: (19R)-5-[(aminocyclopropyl)ethynyl]-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2,6 .0 8,12 .0 13,18 ]pentacosyl-1(24),2(6),4,8(9),11,13(18),14,16,21(25),22-decen-22-amine

[0265] The synthesis method of Example 69 is the same as that of Example 47. LC-MS (ESI) [M+H] + :486.3. 1 H NMR(400MHz, CD3OD),7.57(s,1H),7.53(dd,J=10.0Hz,2.8Hz,1H),7.44(s,1H),7.20(dd,J=8.4Hz,5.6Hz,1H),7.08(td,J=8.4Hz,2.8Hz,1H),6.48(d,J=1 .6Hz,1H),5.39-5.45(m,1H),4.06-4.21(m,2H),3.92(s,3H),3.85(d,J=15.6 Hz, 1H), 2.93 (d, J = 15.6Hz, 1H), 1.81 (d, J = 6.4Hz, 3H), 1.33 (t, J = 7.2Hz, 3H).

[0266] Example 70: (19R)-5-(4-aminobut-1-ynyl)-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2,6 .0 8,12 .0 13,18 ]pentacosyl-1(24),2(6),4,8(9),11,13(14),15,17,21(25),22-decen-22-amine

[0267] The synthesis method of Example 70 is the same as that of Example 47. LC-MS (ESI) [M+H] + :486.4. 1 H NMR(400MHz, CDCl3),7.50(d,J=1.6Hz,1H),7.42(s,1H),7.28(dd,J=10.0Hz,2.8Hz,1H),7.13(dd, J=8.8Hz,6.0Hz,1H),6.99(td,J=8.0Hz,2.8Hz,1H),6.50(d,J=1.6Hz,1H),5.37-5.43(m,1H),4.82( s,2H),4.07-4.13(m,2H),3.91(s,3H),3.74(d,J=15.6Hz,1H),3.03(t,J=6.4Hz,2H),2.89(d,J=15 .6Hz,1H),2.71(t,J=6.4Hz,2H),2.16-2.42(brs,2H),1.78(d,J=6.0Hz,3H),1.38(t,J=7.2Hz,3H).

[0268] Example 71: 4-[(19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2,6 .0 8,12 .0 13,18 1(24),2(6),4,8(9),11,13(14),15,17,21(25),22-decen-5-yl]but-3-yn-1-ol

[0269] The synthesis method of Example 71 is the same as that of Example 47. LC-MS (ESI) [M+H] + :487.4. 1H NMR(400MHz, CDCl3),7.49(d,J=1.2Hz,1H),7.42(s,1H),7.28(dd,J=10.0Hz,2.4Hz,1H),7.12 (dd,J=8.4Hz,5.6Hz,1H),6.98(td,J=8.0Hz,2.8Hz,1H),6.50(d,J=1.2Hz,1H),5.36-5.43(m, 1H),4.88(s,2H),4.06-4.12(m,2H),3.90(s,3H),3.88(t,J=6.4Hz,2H),3.73(d,J=15.6Hz,1H ), 2.87 (d, J = 15.6Hz, 1H), 2.78 (t, J = 6.4Hz, 2H), 1.78 (d, J = 6.0Hz, 3H), 1.38 (t, J = 7.2Hz, 3H).

[0270] Example 72: (19R)-3-Ethyl-16-fluoro-10,19-dimethyl-5-(pyrimidin-5-ylethynyl)-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0271] The synthesis method of Example 72 is the same as that of Example 47. LC-MS (ESI) [M+H] + :521.4. 1 H NMR(400MHz, CDCl3),9.17(s,1H),8.92(s,2H),7.53(d,J=1.6Hz,1H),7.40(s,1H),7.29( dd,J=10.0Hz,2.8Hz,1H),7.17(dd,J=8.4Hz,5.6Hz,1H),7.02(td,J=8.0Hz,2.8Hz,1H),6 .56(d,J=1.6Hz,1H),5.39-5.46(m,1H),5.25(s,2H),4.13-4.19(m,2H),3.92(s,3H),3.8 4(d,J=15.6Hz,1H), 3.00(d,J=15.6Hz,1H), 1.80(d,J=6.4Hz,3H), 1.43(t,J=7.2Hz,3H).

[0272] Example 73: (19R)-3-Ethyl-16-fluoro-5-(hexahydropyridin-4-ylethynyl)-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0273] The synthesis method of Example 73 is the same as that of Example 47. LC-MS (ESI) [M+H] + :526.4. 1 H NMR(400MHz, CDCl3),7.50(d,J=1.6Hz,1H),7.40(s,1H),7.28(dd,J=10.0Hz,2.8Hz,1H),7.14(dd,J =8.4Hz,5.6Hz,1H),6.99(td,J=8.0Hz,2.8Hz,1H),6.49(d,J=1.6Hz,1H),5.37-5.43(m,1H),4.82(s, 2H),4.07-4.13(m,2H),3.91(s,3H),3.73(d,J=15.6Hz,1H),2.92-3.10(m,1H),3.15-3.20(m,2H),2. 89(d,J=15.6Hz,1H),2.76-2.84(m,2H),1.98-2.06(m,2H),1.74-1.84(m,5H),1.38(t,J=7.2Hz,3H).

[0274] Example 74: (19R)-3-Ethyl-16-fluoro-5-(1H-imidazol-4-ylethynyl)-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0275] The synthesis method of Example 74 is the same as that of Example 47. LC-MS (ESI) [M+H] + :509.4. 1H NMR(400MHz, CDCl3),11.92-12.16(brs,1H),7.68(s,1H),7.51(d,J=1.6Hz,1H),7.47(s,1H),7 .40(s,1H),7.28(dd,J=10.0Hz,2.8Hz,1H),7.13(dd,J=8.4Hz,5.6Hz,1H),7.00(td,J=8.4Hz,2 .8Hz,1H),6.56(d,J=1.6Hz,1H),5.39-5.45(m,1H),4.95(s,2H),4.11-4.17(m,2H),3.90(s,3H ), 3.86 (d, J = 15.6Hz, 1H), 1.94 (d, J = 15.6Hz, 1H), 1.79 (d, J = 6.0Hz, 3H), 1.42 (t, J = 7.2Hz, 3H).

[0276] Example 75: (19R)-3-Ethyl-16-fluoro-10,19-dimethyl-5-(tetrahydro-1H-pyrrol-2-ylethynyl)-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0277] The synthesis method of Example 75 is the same as that of Example 47. LC-MS (ESI) [M+H] + :512.4. 1 H NMR(400MHz, CD3OD),7.57(s,1H),7.54(dd,J=10.0Hz,2.8Hz,1H),7.43(s,1H),7.17(dd,J=8.4Hz,5 .6Hz,1H),7.08(td,J=8.4Hz,2.8Hz,1H),6.46(d,J=1.6Hz,1H),5.36-5.44(m,1H),4.43-4.50(m,1H) ,4.05-4.17(m,2H),3.93(s,3H),3.77(d,J=16.0Hz,1H),3.31-3.37(m,1H),3.14-3.24(m,1H),2.90( d,J=16.0Hz,1H),2.34-2.44(m,1H),1.96-2.22(m,3H),1.81(d,J=6.4Hz,3H),1.31(t,J=7.2Hz,3H).

[0278] Example 76: (19R)-3-Ethyl-16-fluoro-10,19-dimethyl-5-[(1-methylpyrrol-3-yl)ethynyl]-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosyl-1(24),2(6),4,8(9),11,13(14),15,17,21(25),22-decen-22-amine

[0279] The synthesis method of Example 76 is the same as that of Example 47. LC-MS (ESI) [M+H] + :522.4. 1 H NMR(400MHz, CDCl3),7.74(s,1H),7.49(s,1H),7.24-7.28(m,1H),7.15(dd,J=8. 4Hz,5.6Hz,1H),7.01(td,J=8.4Hz,2.8Hz,1H),6.93(s,1H),6.54(s,2H),6.35(s ,1H),5.32-5.57(m,3H),4.06-4.14(m,2H),3.90(s,3H),3.84(d,J=15.6Hz,1H), 3.66 (s, 3H), 2.91 (d, J = 15.6Hz, 1H), 1.79 (d, J = 6.0Hz, 3H), 1.36 (t, J = 7.2Hz, 3H).

[0280] Example 77: (19R)-3-Ethyl-16-fluoro-5-(1H-pyrazolo[3,4-b]pyridin-5-ylethynyl)-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2,6 .0 8,12 .0 13,18 ]pentacosyl-1(24),2(6),4,8(9),11,13(18),14,16,21(25),22-decen-22-amine

[0281] The synthesis method of Example 77 is the same as that of Example 47. LC-MS (ESI) [M+H] + :560.4. 1H NMR(400MHz,CD3OD),8.73(d,J=2.0Hz,1H),8.48(d,J=2.0Hz,1H),8.17(s,1H),7.66(s ,1H),7.55(dd,J=10.0Hz,5.6Hz,1H),7.48(s,1H),7.25(dd,J=8.4Hz,2.8Hz,1H),7.10 (td,J=8.0Hz,2.8Hz,1H),6.58(d,J=1.6Hz,1H),5.44-5.50(m,1H),4.10-4.22(m,2H), 3.90-3.94(m,4H),2.98(d,J=15.6Hz,1H),1.83(d,J=6.4Hz,3H),1.37(t,J=7.2Hz,3H).

[0282] Example 78: (19R)-3-Ethyl-16-fluoro-10,19-dimethyl-5-[(2-methyl-1,2,3-triazol-4-yl)ethynyl]-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0283] The synthesis method of Example 78 is the same as that of Example 47. LC-MS (ESI) [M+H] + :524.4. 1 H NMR (400MHz, CD3OD), 7.90 (s, 1H), 7.59 (s, 1H), 7.54 (dd, J = 10.0Hz, 2.8Hz, 1H), 7.4 0-7.52(brs,1H),7.21(dd,J=8.4Hz,5.6Hz,1H),7.08(td,J=8.4Hz,2.8Hz,1H),6.4 9(s,1H),5.39-5.45(m,1H),4.21(s,3H),4.07-4.20(m,2H),3.91(s,3H),3.83(d,J =15.6Hz, 1H), 2.94 (d, J = 15.6Hz, 1H), 1.81 (d, J = 6.0Hz, 3H), 1.34 (t, J = 7.2Hz, 3H).

[0284] Example 79: (19R)-3-ethyl-16-fluoro-10,19-dimethyl-5-(oxetan-3-ylethynyl)-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0285] The synthesis method of Example 79 is the same as that of Example 47. LC-MS (ESI) [M+H] + :499.4. 1 H NMR(400MHz, CD3OD),7.57(s,1H),7.54(dd,J=10.0Hz,2.8Hz,1H),7.43(s,1H),7.20(dd,J= 8.4Hz,5.6Hz,1H),7.08(td,J=8.4Hz,2.8Hz,1H),6.47(s,1H),5.38-5.44(m,1H),4.96(dd, J=8.8Hz,5.6Hz,2H),4.80-4.83(m,2H),4.19-4.27(m,1H),4.03-4.18(m,2H),3.92(s,3H), 3.76(d,J=15.6Hz,1H), 2.89(d,J=15.6Hz,1H), 1.81(d,J=6.4Hz,3H), 1.32(t,J=7.2Hz,3H).

[0286] Example 80: (19R)-3-Ethyl-16-fluoro-5-(hexahydropyridin-2-ylethynyl)-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0287] The synthesis method of Example 80 is the same as that of Example 47. LC-MS (ESI) [M+H] + :526.4. 1H NMR(400MHz, CD3OD),7.61(s,0.5H),7.60(s,0.5H),7.54(dd,J=1.0Hz,2.8Hz,1H),7.43(d,J=1.6Hz,1 H),7.18(dd,J=8.8Hz,6.0Hz,1H),7.08(td,J=8.4Hz,2.8Hz,1H),6.47(d,J=1.6Hz,1H),5.38-5.45(m,1 H),4.02-4.17(m,2H),3.88-3.97(m,4H),3.79(d,J=15.6Hz,1H),3.11-3.17(m,1H),2.89(d,J=15.6Hz, 1H), 2.72-2.78 (m, 1H), 1.85-2.03 (m, 2H), 1.72-1.84 (m, 4H), 1.54-1.64 (m, 3H), 1.31 (t, J = 7.6Hz, 3H).

[0288] Example 81: (19R)-5-(1,2-pyridazin-3-ylethynyl)-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0289] The synthesis method of Example 81 is the same as that of Example 47. LC-MS (ESI) [M+H] + :521.4. 1 H NMR(400MHz, CDCl3),9.17(dd,J=4.8Hz,1.6Hz,1H),7.74(dd,J=8.0Hz,1.6Hz,1H),7.47-7 .52(m,3H),7.29(dd,J=10.0Hz,2.8Hz,1H),7.16(dd.J=8.4Hz,5.6Hz,1H),7.03(td,J=8.4 Hz,2.8Hz,1H),6.63(d,J=1.2Hz,1H),5.40-5.52(m,3H),4.14-4.20(m,2H),3.98(d,J=15. 6Hz, 1H), 3.90 (s, 3H), 2.99 (d, J = 15.6Hz, 1H), 1.81 (d, J = 6.4Hz, 3H), 1.45 (t, J = 7.2Hz, 3H).

[0290] Example 82: 1-{[(19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosyl-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decen-5-yl]ethynyl}cyclohexan-1-ol

[0291] The synthesis method of Example 82 is the same as that of Example 47. LC-MS (ESI) [M+H] + :541.4. 1 H NMR(400MHz, CDCl3),7.43(s,1H),7.41(s,1H),7.28(dd,J=10.0Hz,2.8Hz,1H),7.17(dd,J =8.4Hz,5.6Hz,1H),7.04(td,J=8.4Hz,2.8Hz,1H),6.60(d,J=1.6Hz,1H),5.76-6.02(brs,2 H),5.41-5.48(m,1H),4.04-4.14(m,2H),3.91(s,3H),3.78(d,J=15.6Hz,1H),2.91(d,J=15 .6Hz,1H),2.03-2.12(m,2H),1.54-1.85(m,10H),1.39(t,J=7.2Hz,3H),1.28-1.36(m,1H).

[0292] Example 83: (19R)-5-(3,3-dimethylbut-1-ynyl)-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.08,12.013,18.02,6]pentacosyl-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decen-22-amine

[0293] The synthesis method of Example 83 is the same as that of Example 47. LC-MS (ESI) [M+H] + :499.4. 1H NMR (400MHz, CDCl3), 7.46 (s, 1H), 7.43 (s, 1H), 7.28 (d, J = 10.0Hz, 2.8Hz, 1H), 7. 17(dd,J=8.4Hz,5.6Hz,1H),7.01(td,J=8.4Hz,2.8Hz,1H),6.55(d,J=1.6Hz,1H), 5.40-5.46(m,1H),5.24-5.39(brs,2H),4.03-4.14(m,2H),3.91(s,3H),3.75(d, J=15.6Hz,1H),2.88(d,J=15.6Hz,1H),1.80(d,J=6.4Hz,3H),1.36-1.39(m,12H).

[0294] Example 84: (19R)-5-(cyclohexylethynyl)-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0295] The synthesis method of Example 84 is the same as that of Example 47. LC-MS (ESI) [M+H] + :525.4. 1 H NMR(400MHz, CDCl3),7.51(s,1H),7.43(s,1H),7.24-7.28(m,1H),7.14(dd,J=8.4Hz, 5.6Hz,1H),7.00(td,J=8.4Hz,2.8Hz,1H),6.53(d,J=1.2Hz,1H),5.30-5.44(m,3H),3. 99-4.09(m,2H),3.90(s,3H),3.75(d,J=15.6Hz,1H),2.86(d,J=15.6Hz,1H),2.63-2. 72(m,1H),1.89-1.98(m,2H),1.71-1.83(m,5H),1.52-1.65(m,3H),1.29-1.42(m,6H).

[0296] Example 85: (19R)-3-Ethyl-16-fluoro-10,19-dimethyl-5-(pyrimidin-2-ylethynyl)-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2,6 .08,12 .0 13,18 ]pentacosyl-1(24),2(6),4,8(9),11,13(18),14,16,21(25),22-decen-22-amine

[0297] The synthesis method of Example 85 is the same as that of Example 47. LC-MS (ESI) [M+H] + :521.4. 1 H NMR(400MHz,CD3OD),8.84(d,J=5.2Hz,2H),7.65(s,1H),7.55(dd,J=10.0Hz,2.8 Hz,1H),7.45-7.52(m,2H),7.23(dd,J=8.4Hz,5.6Hz,1H),7.09(td,J=8.4Hz,2.8H z,1H),6.52(s,1H),5.41-5.48(m,1H),4.08-4.23(m,2H),3.95(d,J=7.6Hz,1H), 3.91 (s, 3H), 2.98 (d, J = 15.6Hz, 1H), 1.82 (d, J = 6.4Hz, 3H), 1.36 (t, J = 7.2Hz, 3H).

[0298] Example 86: (19R)-3-Ethyl-16-fluoro-10,19-dimethyl-5-(1,3-oxazol-5-ylethynyl)-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 2,6 .0 13,18 ]pentacosyl-1(25),2(6),4,8(9),11,13(14),15,17,21(22),23-decen-22-amine

[0299] The synthesis method of Example 86 is the same as that of Example 47. LC-MS (ESI) [M+H] + :510.4. 1H NMR(400MHz, CDCl3),7.91(s,1H),7.53(d,J=1.6Hz,1H),7.41(s,1H),7.39(s,1H),7.29( dd,J=10.0Hz,2.8Hz,1H),7.14(dd,J=8.4Hz,5.6Hz,1H),7.01(td,J=8.4Hz,2.8Hz,1H),6. 54(d,J=1.6Hz,1H),5.39-5.45(m,1H),4.92(s,2H),4.16(q,J=7.2Hz,2H),3.92(s,3H),3. 82(d,J=15.6Hz,1H), 2.98(d,J=15.6Hz,1H), 1.80(d,J=6.4Hz,3H), 1.43(t,J=7.2Hz,3H).

[0300] Example 87: (19R)-3-Ethyl-16-fluoro-10,19-dimethyl-5-(3,3,3-trifluoroprop-1-ynyl)-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 2,6 .0 13,18 ]pentacosyl-1(25),2(6),4,8(9),11,13(14),15,17,21(22),23-decen-22-amine

[0301] The synthesis method of Example 87 is the same as that of Example 47. LC-MS (ESI) [M+H] + :511.3. 1 H NMR(400MHz, CDCl3),7.47-7.87(brs,1H),7.32(s,1H),7.22-7.26(m,1H),7.1 7(dd,J=8.4Hz,5.6Hz,1H),7.05(td,J=8.4Hz,2.8Hz,1H),6.60(s,1H),6.14-6 .48(brs,2H),5.32-5.44(m,1H),4.02-4.24(m,2H),3.93(s,3H),3.78(d,J=15 .6Hz, 1H), 2.97 (d, J = 15.6Hz, 1H), 1.81 (d, J = 6.4Hz, 3H), 1.40 (t, J = 7.2Hz, 3H).

[0302] Example 88: (19R)-5-(5-aminopent-1-ynyl)-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.08,12 .0 13,18 .0 2,6 ]pentacosyl-1(24),2(6),4,8(9),11,13(14),15,17,21(25),22-decen-22-amine

[0303] The synthesis method of Example 88 is the same as that of Example 47. LC-MS (ESI) [M+H] + :500.4. 1 H NMR(400MHz, CDCl3),7.44(d,J=1.6Hz,1H),7.37(s,1H),7.28(dd,J=10.0Hz,2.8Hz,1H),7.13( dd,J=8.4Hz,5.6Hz,1H),6.99(td,J=8.4Hz,2.4Hz,1H),6.51(d,J=1.6Hz,1H),5.22-5.44(m,3H ),4.03-4.09(m,2H),3.90(s,3H),3.71(d,J=15.6Hz,1H),3.21(t,J=7.2Hz,2H),2.87(d,J=15. 6Hz, 1H), 2.68 (t, J = 7.2Hz, 2H), 1.99-2.09 (m, 2H), 1.79 (d, J = 6.0Hz, 3H), 1.34 (t, J = 7.2Hz, 3H).

[0304] Example 89: 5-[(19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 1(24),2(6),4,8(9),11,13(14),15,17,21(25),22-decen-5-yl]pent-4-yn-1-ol

[0305] The synthesis method of Example 89 is the same as that of Example 47. LC-MS (ESI) [M+H] + :501.4. 1H NMR (400MHz, CDCl3), 7.49 (d, J = 1.6Hz, 1H), 7.41 (s, 1H), 7.28 (dd, J = 10.0Hz, 2.8Hz, 1H), 7.12 (dd, J = 8. 4Hz, 5.6Hz, 1H), 6.98 (td, J=8.4Hz, 2.8Hz, 1H), 6.50 (d, J=1.6Hz, 1H), 5.36-5.42 (m, 1H), 4.89 (s, 2H), 4. 06-4.12(m,2H),3.90(s,3H),3.83(t,J=6.0Hz,2H),3.73(d,J=15.6Hz,1H),2.87(d,J=15.6Hz,1H),2.6 2(t,J=7.2Hz,2H),1.96-2.22(brs,1H),1.88-1.94(m,2H),1.78(d,J=6.4Hz,3H),1.38(t,J=7.2Hz,3H).

[0306] Example 90: (19R)-3-ethyl-16-fluoro-5-(3-methoxyprop-1-ynyl)-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosyl-1(24),2(6),4,8(9),11,13(14),15,17,21(25),22-decen-22-amine

[0307] The synthesis method of Example 90 is the same as that of Example 47. LC-MS (ESI) [M+H] + :487.4. 1 H NMR(400MHz, CDCl3),7.49(d,J=1.6Hz,1H),7.41(s,1H),7.28(dd,J=10.0Hz,2.8Hz,1H), 7.13(dd,J=8.4Hz,5.6Hz,1H),7.00(td,J=8.4Hz,2.8Hz,1H),6.53(d,J=1.6Hz,1H),5.37 -5.44(m,1H),4.99(s,2H),4.42(s,2H),4.09-4.14(m,2H),3.91(s,3H),3.78(d,J=15.6H z, 1H), 3.50 (s, 3H), 2.91 (d, J = 15.6Hz, 1H), 1.79 (d, J = 6.4Hz, 3H), 1.40 (t, J = 7.2Hz, 3H).

[0308] Example 91: (19R)-3-Ethyl-16-fluoro-10,19-dimethyl-5-[(methylcyclopropyl)ethynyl]-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0309] The synthesis method of Example 91 is the same as that of Example 47. LC-MS (ESI) [M+H] + :497.4. 1 H NMR(400MHz, CDCl3),7.50(s,1H),7.41(s,1H),7.26-7.29(m,1H),7.15(dd,J=8.8Hz, 5.6Hz,1H),6.98-7.02(m,1H),6.52(s,1H),5.37-5.43(m,1H),4.78-5.02(brs,2H),4. 02-4.12(m,2H),3.92(s,3H),3.74(d,J=15.6Hz,1H),2.86(d,J=15.6Hz,1H),1.79(d,J =6.4Hz,3H),1.41(s,3H),1.36(t,J=7.2Hz,3H),1.06-1.09(m,2H),0.71-0.73(m,2H).

[0310] Example 92: (19R)-3-Ethyl-16-fluoro-10,19-dimethyl-5-[(1-methylimidazol-4-yl)ethynyl]-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0311] The synthesis method of Example 92 is the same as that of Example 47. LC-MS (ESI) [M+H] + :423.4. 1H NMR (400MHz, Acetone),8.03-8.52(m,2H),7.62(s,1H),7.53(s,1H),7.44(d,J=9.6Hz,1H),7.16-7.25(m,2H),6.45(d,J=1.2Hz,1H),5.4 0-5.46(m,1H),4.10-4.20(m,1H),3.86-4.04(m,7H),3.12-3.36(m,1H),2.58-2.74(m,1H),1.73(d,J=6.4Hz,3H),1.33(t,J=7.2Hz,3H).

[0312] Example 93: (19R)-3-Ethyl-16-fluoro-10,19-dimethyl-5-(3,4,5,6-tetrahydro-2H-pyran-4-ylethynyl)-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2,6 .0 8,12 .0 13,18 ]pentacosyl-1(24),2(6),4,8(9),11,13(18),14,16,21(25),22-decen-22-amine

[0313] The synthesis method of Example 93 is the same as that of Example 47. LC-MS (ESI) [M+H] + :527.4. 1 H NMR(400MHz, CDCl3),7.41-7.70(brs,1H),7.40(s,1H),7.25-7.28(m,1H),7.13-7.16(m,1 H),6.97-7.04(m,1H),6.51(s,1H),5.36-5.42(m,1H),5.11-5.30(brs,2H),4.03-4.14(m,2 H),3.94-4.02(m,2H),3.91(s,3H),3.74(d,J=15.6Hz,1H),3.54-3.59(m,2H),2.90-2.99( m, 1H), 2.88 (d, J = 15.6Hz, 1H), 1.93-2.02 (m, 2H), 1.74-1.89 (m, 5H), 1.34 (t, J = 7.2Hz, 3H).

[0314] Example 94: (19R)-3-Ethyl-16-fluoro-10,19-dimethyl-5-(tetrahydrofuran-3-ylethynyl)-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18.0 2,6 ]pentacosyl-1(24),2(6),4,8(9),11,13(14),15,17,21(25),22-decen-22-amine

[0315] The synthesis method of Example 94 is the same as that of Example 47. LC-MS (ESI) [M+H] + :513.4. 1 H NMR(400MHz, CDCl3),7.50(d,J=1.6Hz,1H),7.39(s,1H),7.28(dd,J=10.0Hz,2.8Hz,1H),7.14(dd,J=8 .4Hz, 6.0Hz, 1H), 6.99 (td, J=8.4Hz, 2.8Hz, 1H), 6.50 (d, J=1.6Hz, 1H), 5.37-5.44 (m, 1H), 4.87 (s, 2H), 4.07-4.15(m,3H),3.86-4.03(m,5H),3.79-3.83(m,1H),3.73(d,J=15.6Hz,1H),3.26-3.33(m,1H),2.8 9(d,J=15.6Hz,1H),2.29-2.38(m,1H),2.12-2.21(m,1H),1.78(d,J=6.0Hz,3H),1.39(t,J=7.2Hz,3H).

[0316] Example 95: (19R)-5-[(1E)-2-cyclopropylvinyl]-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosyl-1(24),2(6),4,8(9),11,13(14),15,17,21(25),22-decen-22-amine

[0317] The synthesis method of Example 95 is the same as that of Example 45. LC-MS (ESI) [M+H] + :485.4. 1H NMR(400MHz, CDCl3),7.50(d,J=1.2Hz,1H),7.27-7.30(m,2H),7.14(dd,J=8.4Hz,6.0Hz,1H),6.99(dd, J=8.4Hz,2.8Hz,1H),6.59(d,J=16.0Hz,1H),6.50(d,J=1.6Hz,1H),6.07(dd,J=16.0Hz,8.8Hz,1H),5.36 -5.42(m,1H),4.80(s,2H),4.04-4.15(m,2H),3.91(s,3H),3.62(d,J=16.0Hz,1H),2.90(d,J=16.0Hz,1H ),1.78(d,J=6.4Hz,3H),1.57-1.66(m,1H),1.37(d,J=7.2Hz,3H),0.82-0.87(m,2H),0.57-0.60(m,2H).

[0318] Example 96: (19R)-3-Ethyl-16-fluoro-10,19-dimethyl-5-[(1-methylpyrrol-2-yl)ethynyl]-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosyl-1(24),2(6),4,8(9),11,13(14),15,17,21(25),22-decen-22-amine

[0319] The synthesis method of Example 96 is the same as that of Example 47. LC-MS (ESI) [M+H] + :522.4. 1 H NMR(400MHz, CDCl3),7.78(s,1H),7.46(s,1H),7.24-7.28(m,1H),7.15(dd,J=8.4Hz,6.0 Hz,1H),7.01(td,J=8.4Hz,2.4Hz,1H),6.69-6.70(m,1H),6.53-6.56(m,2H),6.12-6.14(m ,1H),5.58(s,2H),5.35-5.41(m,1H),4.09(q,J=7.2Hz,2H),3.90(s,3H),3.82(d,J=15.6 Hz, 1H), 3.77 (s, 3H), 2.95 (d, J = 15.6Hz, 1H), 1.78 (d, J = 6.0Hz, 3H), 1.32 (t, J = 7.2Hz, 3H).

[0320] Example 97: (19R)-5-(1,2-pyridazin-4-ylethynyl)-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0321] The synthesis method of Example 97 is the same as that of Example 47. LC-MS (ESI) [M+H] + :521.4. 1 H NMR(400MHz, CDCl3),9.28(s,1H),9.20(d,J=5.2Hz,1H),7.59(dd,J=5.2Hz,2.0Hz,1H),7.54(s ,1H),7.37(s,1H),7.29(dd,J=9.6Hz,2.8Hz,1H),7.16(dd,J=8.4Hz,5.6Hz,1H),7.11(td,J=8. 4Hz,2.8Hz,1H),6.52(s,1H),5.37-5.44(m,1H),5.05(s,2H),4.17(q,J=7.2Hz,2H),3.91(s,3H ), 3.83 (d, J = 15.6Hz, 1H), 3.01 (d, J = 15.6Hz, 1H), 1.79 (d, J = 6.4Hz, 3H), 1.43 (t, J = 7.2Hz, 3H).

[0322] Example 98: (19R)-3-ethyl-16-fluoro-10,19-dimethyl-5-(1,4-oxazacyclohexan-2-ylethynyl)-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2,6 .0 8,12 .0 13,18 ]pentacosyl-1(25),2(6),4,8(9),11,13(14),15,17,21(22),23-decen-22-amine

[0323] The synthesis method of Example 98 is the same as that of Example 47. LC-MS (ESI) [M+H] + :528.4. 1H NMR(400MHz, CDCl3),7.51(s,1H),7.43(s,0.5H),7.41(s,0.5H),7.28(dd,J=10.0Hz,2.8H z,1H),7.11-7.15(m,1H),7.00(td,J=8.4Hz,2.8Hz,1H),6.51(s,1H),5.38-5.44(m,1H),4. 82(s,2H),4.64-4.71(m,1H),4.01-4.15(m,3H),3.91(s,3H),3.66-3.80(m,2H),3.26-3.30 (m,1H),3.06-3.13(m,1H),2.90-3.00(m,3H),1.79(d,J=6.0Hz,3H),1.39(t,J=7.2Hz,3H).

[0324] Example 99: (19R)-3-ethyl-16-fluoro-10,19-dimethyl-5-(1,4-oxazacyclohexan-3-ylethynyl)-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2,6 .0 8,12 .0 13,18 ]pentacosyl-1(25),2(6),4,8(9),11,13(14),15,17,21(22),23-decen-22-amine

[0325] The synthesis method of Example 99 is the same as that of Example 47. LC-MS (ESI) [M+H] + :528.4. 1 H NMR (400MHz, CDCl3), 7.50 (s, 1H), 7.46 (s, 1H), 7.28 (dd, J = 10.0Hz, 2.8Hz, 1H), 7.1 3(dd,J=8.4Hz,5.6Hz,1H),6.99(td,J=8.4Hz,2.8Hz,1H),6.50(s,1H),5.36-5.43(m ,1H),4.85(s,2H),4.07-4.14(m,2H),3.99-4.06(m,2H),3.91(s,3H),3.65-3.84(m, 4H), 3.12-3.20 (m, 1H), 2.88-2.99 (m, 2H), 1.78 (d, J = 6.0Hz, 3H), 1.37-1.41 (m, 3H).

[0326] Example 100: (19R)-3-ethyl-16-fluoro-10,19-dimethyl-5-(tetrahydrofuran-2-ylethynyl)-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosyl-1(24),2(6),4,8(9),11,13(14),15,17,21(25),22-decen-22-amine

[0327] The synthesis method of Example 100 is the same as that of Example 47. LC-MS (ESI) [M+H] + :513.4. 1 H NMR(400MHz, CDCl3),7.50(s,1H),7.43(s,0.5H),7.42(s,0.5H),7.28(dd,J=10.0Hz,2.8Hz,1H) ,7.11-7.15(m,1H),6.99(td,J=8.4Hz,2.8Hz,1H),6.51(s,1H),5.38-5.43(m,1H),4.90-4.94(m ,1H),4.85(s,2H),3.99-4.15(m,3H),3.86-3.92(m,4H),3.76(d,J=15.6Hz,1H),2.89(d,J=15.6 Hz, 1H), 2.08-2.32 (m, 2.5H), 1.90-2.04 (m, 1.5H), 1.78 (d, J = 6.0Hz, 3H), 1.38 (t, J = 7.2Hz, 3H).

[0328] Example 101: (19R)-3-ethyl-16-fluoro-10,19-dimethyl-5-[(1-methylimidazol-4-yl)ethynyl]-20-oxa-3,4,9,23-tetraaza-11-thiapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosyl-1(25),2(6),4,8(12),9,13(18),14,16,21(22),23-decen-22-amine

[0329] The synthesis method of Example 101 is the same as that of Example 47. LC-MS (ESI) [M+H] + :540.4. 1H NMR(400MHz, CD3OD+CDCl3),7.91(s,1H),7.58-7.79(brs,1H),7.23-7.26(m,2H),7.10-7.15(m,1H),7.00(td,J=8.0Hz,2.4Hz,1H),6.71(s,1H),5 .35-5.43(m,1H),4.00-4.16(m,2H),3.82-3.92(m,1H),3.75(s,3H),2.9 6-3.10(m,1H),2.64(s,3H),1.70(d,J=6.4Hz,3H),1.35(t,J=7.2Hz,3H).

[0330] Example 102: (19R)-3-Ethyl-16-fluoro-5-(4-fluorobut-1-ynyl)-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0331] The synthesis method of Example 102 is the same as that of Example 47. LC-MS (ESI) [M+H] + :489.4. 1 H NMR(400MHz, CDCl3),7.48(s,1H),7.43(s,1H),7.28(dd,J=10.0Hz,2.8Hz,1H),7.15(dd, J=8.4Hz,5.6Hz,1H),7.01(td,J=8.4Hz,2.8Hz,1H),6.57(s,1H),5.06-5.57(m,3H),4.65( dt,J=46.4Hz,6.4Hz,2H),4.06-4.12(m,2H),3.91(s,3H),3.77(d,J=15.6Hz,1H),2.94(dt ,J=20Hz,6.4Hz,2H),2.89(d,J=15.6Hz,1H),1.80(d,J=6.4Hz,3H),1.39(t,J=7.2Hz,3H).

[0332] Example 103: Bis[(19R)-3-ethyl-16-fluoro-5-[(5-methoxypyridin-2-yl)ethynyl]-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .013,18 .0 2,6 Pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decen-22-amine]

[0333] The synthesis method of Example 103 is the same as that of Example 47. LC-MS (ESI) [M+H] + :550.4. 1 H NMR(400MHz, CDCl3),8.33(d,J=3.2Hz,1H),7.56(d,J=5.2Hz,1H),7.53(s,1H),7.50(s,1H),7.2 8(dd,J=10.0Hz,2.8Hz,1H),7.19(dd,J=8.8Hz,2.8Hz,1H),7.13(dd,J=8.4Hz,5.6Hz,1H),6.99(t d,J=8.4Hz,2.8Hz,1H),6.55(s,1H),5.39-5.45(m,1H),4.88(s,2H),4.12-4.18(m,2H),3.92(d, J=15.6Hz,1H),3.88(s,6H),2.95(d,J=15.6Hz,1H),1.78(d,J=6.0Hz,3H),1.42(t,J=7.2Hz,3H).

[0334] Example 104: (19R)-5-[3-(Dimethylamino)prop-1-ynyl]-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0335] The synthesis method of Example 104 is the same as that of Example 47. LC-MS (ESI) [M+H] + :500.4. 1H NMR(400MHz, CDCl3),7.50(d,J=2.0Hz,1H),7.42(s,1H),7.29(dd,J=10.0Hz,2.8Hz,1H), 7.13(dd,J=8.4Hz,5.6Hz,1H),6.99(td,J=8.4Hz,2.8Hz,1H),6.50(d,J=2.0Hz,1H),5.38 -5.43(m,1H),4.81(s,2H),4.08-4.14(m,2H),3.90(s,3H),3.77(d,J=15.6Hz,1H),3.61( s, 2H), 2.91 (d, J = 15.6Hz, 1H), 2.41 (s, 6H), 1.78 (d, J = 6.0Hz, 3H), 1.39 (t, J = 7.2Hz, 3H).

[0336] Example 105: (19R)-3-Ethyl-16-fluoro-10,19-dimethyl-5-[3-(methylamino)prop-1-ynyl]-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0337] The synthesis method of Example 105 is the same as that of Example 47. LC-MS (ESI) [M+H] + :486.4. 1 H NMR(400MHz, CDCl3),7.45-7.56(m,2H),7.28(d,J=10.0Hz,2.8Hz,1H),7.11(dd ,J=8.4Hz,2.8Hz,1H),6.98(td,J=8.4Hz,2.8Hz,1H),6.49(s,1H),5.36-5.42(m, 1H),4.90(s,2H),4.07-4.13(m,2H),3.83-4.01(m,5H),3.73(d,J=15.6Hz,1H),2 .89(d,J=15.6Hz,1H),2.74(s,3H),1.77(d,J=6.4Hz,3H),1.38(t,J=7.2Hz,3H).

[0338] Example 106: (19R)-3-Ethyl-16-fluoro-10,19-dimethyl-5-(3,4,5,6-tetrahydro-2H-pyran-3-ylethynyl)-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0339] The synthesis method of Example 106 is the same as that of Example 47. LC-MS (ESI) [M+H] + :527.4. 1 H NMR(400MHz, CDCl3),7.40-7.56(m,2H),7.28(dd,J=10.0Hz,2.8Hz,1H),7.15(dd,J=8.4Hz,5 .6Hz,1H),7.01(td,J=8.4Hz,2.8Hz,1H),6.53(s,1H),5.38-5.45(m,1H),5.01-5.24(brs,2H ),4.03-4.14(m,3H),3.84-3.94(m,4H),3.74(d,J=15.2Hz,1H),3.46-3.56(m,2H),2.84-2.9 1(m,2H),2.15-2.23(m,1H),1.80(d,J=6.4Hz,3H),1.59-1.77(m,3H),1.39(t,J=7.2Hz,3H).

[0340] Example 107: (19R)-3-Ethyl-16-fluoro-10,19-dimethyl-5-[3-(1,4-oxazepan-4-yl)prop-1-ynyl]-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosyl-1(24),2(6),4,8(9),11,13(14),15,17,21(25),22-decen-22-amine

[0341] The synthesis method of Example 107 is the same as that of Example 47. LC-MS (ESI) [M+H] + :542.4. 1H NMR(400MHz, CDCl3),7.51(d,J=1.6Hz,1H),7.43(s,1H),7.29(dd,J=10.0Hz,2.8Hz,1H), 7.13(dd,J=8.4Hz,2.8Hz,1H),6.99(td,J=8.4Hz,2.8Hz,1H),6.50(d,J=1.6Hz,1H),5.37 -5.43(m,1H),4.83(s,2H),4.07-4.16(m,2H),3.91(s,3H),3.73-3.78(m,5H),3.65(s,2H ), 2.91 (d, J = 15.6Hz, 1H), 2.69-2.72 (m, 4H), 1.79 (d, J = 6.0Hz, 3H), 1.39 (t, J = 7.2Hz, 3H).

[0342] Example 108: (19R)-3-Ethyl-16-fluoro-10,19-dimethyl-5-[3-(4-methylpiperazin-1-yl)prop-1-ynyl]-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosyl-1(24),2(6),4,8(9),11,13(14),15,17,21(25),22-decen-22-amine

[0343] The synthesis method of Example 108 is the same as that of Example 47. LC-MS (ESI) [M+H] + :555.4. 1 H NMR(400MHz, CDCl3),7.49(d,J=2.0Hz,1H),7.45(s,1H),7.28(dd,J=10.0Hz,2.8Hz,1H) ,7.13(dd,J=8.4Hz,5.6Hz,1H),6.98(td,J=8.4Hz,2.8Hz,1H),6.49(d,J=2.0Hz,1H),5. 36-5.43(m,1H),4.83(s,2H),4.07-4.13(m,2H),3.93(s,3H),3.75(d,J=15.6Hz,1H),3. 66(s,2H),2.57-3.02(m,9H),2.48(s,3H),1.78(d,J=6.4Hz,3H),1.38(t,J=7.2Hz,3H).

[0344] Example 109: (19R)-3-ethyl-16-fluoro-10,19-dimethyl-5-(1,3-thiazol-2-ylethynyl)-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosyl-1(24),2(6),4,8(9),11,13(14),15,17,21(25),22-decen-22-amine

[0345] The synthesis method of Example 109 is the same as that of Example 47. LC-MS (ESI) [M+H] + :526.4. 1 H NMR(400MHz, CDCl3),7.90(d,J=2.8Hz,1H),7.46(s,1H),7.44(d,J=2.8Hz,1H),7.24 -7.40(m,2H),7.17(dd,J=8.4Hz,6.0Hz,1H),7.06(td,J=8.4Hz,2.8Hz,1H),6.69(s, 1H),6.21-6.52(brs,2H),5.44-5.50(m,1H),4.09-4.17(m,2H),3.95(d,J=15.6Hz,1 H), 3.90 (s, 3H), 2.97 (d, J = 15.6Hz, 1H), 1.84 (d, J = 6.4Hz, 3H), 1.45 (t, J = 7.2Hz, 3H).

[0346] Example 110: 3-[(19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2,6 .0 8,12 .0 13,18 1-(4-methylpiperazin-1-yl)prop-2-yn-1-one

[0347] The synthesis method of Example 110 is the same as that of Example 47. LC-MS (ESI) [M+H] + :569.4. 1H NMR(400MHz, CDCl3),7.51(s,1H),7.40(s,1H),7.28(dd,J=10.0Hz,2.8Hz,1H),7.13( dd,J=8.4Hz,5.6Hz,1H),7.00(td,J=8.4Hz,2.8Hz,1H),6.53(s,1H),5.38-5.44(m,1H) ,4.88(s,2H),4.13-4.19(m,2H),3.97-4.08(m,2H),3.91(s,3H),3.68-3.90(m,3H),2 .96(d,J=15.6Hz,1H),2.28-2.80(m,7H),1.79(d,J=6.4Hz,3H),1.41(t,J=7.2Hz,3H).

[0348] Example 111: 3-[(19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2,6 .0 8,12 .0 13,18 1-(1,4-oxazacyclohexan-4-yl)prop-2-yn-1-one

[0349] The synthesis method of Example 111 is the same as that of Example 47. LC-MS (ESI) [M+H] + :556.4. 1 H NMR(400MHz, CDCl3),7.48(d,J=1.6Hz,1H),7.41(s,1H),7.28(dd,J=10.0Hz,2.8Hz,1H),7.13 (dd,J=8.4Hz,5.6Hz,1H),7.02(td,J=8.4Hz,2.8Hz,1H),6.56(d,J=1.6Hz,1H),5.40-5.46(m, 1H),5.13-5.27(brs,2H),4.12-4.18(m,2H),3.88-3.93(m,5H),3.84(d,J=15.6Hz,1H),3.75- 3.77(m,2H),3.72(s,4H),2.96(d,J=15.6Hz,1H),1.80(d,J=6.4Hz,3H),1.41(t,J=6.4Hz,3H).

[0350] Example 112: (19R)-3-ethyl-16-fluoro-10,19-dimethyl-5-(3,4,5,6-tetrahydro-2H-pyran-2-ylethynyl)-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0351] The synthesis method of Example 112 is the same as that of Example 47. LC-MS (ESI) [M+H] + :527.4. 1 H NMR(400MHz, CDCl3),7.42-7.54(m,2H),7.28(d,J=10.0Hz,2.8Hz,1H),7.12-7.16(m,1H),7 .00(td,J=8.4Hz,2.8Hz,1H),6.54(s,1H),5.39-5.45(m,1H),4.96-5.20(brs,2H),4.63-4. 67(m,1H),4.04-4.16(m,3H),3.91(s,3H),3.77-3.82(m,1H),3.60-3.66(m,1H),2.90(d,J= 15.6Hz,1H),1.91-2.03(m,2H),1.79-1.90(m,4H),1.52-1.75(m,3H),1.39(t,J=7.2Hz,3H).

[0352] Example 113: (19R)-3-Ethyl-16-fluoro-5-[3-(hexahydropyridin-1-yl)prop-1-ynyl]-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosyl-1(24),2(6),4,8(9),11,13(14),15,17,21(25),22-decen-22-amine

[0353] The synthesis method of Example 113 is the same as that of Example 47. LC-MS (ESI) [M+H] + :540.4. 1H NMR(400MHz, CDCl3),7.48-7.55(brs,1H),7.46(s,1H),7.29(dd,J=10.0Hz,2.8Hz,1H),7.13(d d, J=8.8Hz, 5.6Hz, 1H), 7.00 (td, J=8.4Hz, 2.8Hz, 1H), 6.51 (s, 1H), 5.37-5.43 (m, 1H), 4.74-4. 94(brs,2H),4.07-4.16(m,2H),3.92(s,3H),3.65-3.78(m,3H),2.90(d,J=15.6Hz,1H),2.60-2 .84(m,4H),1.79(d,J=6.0Hz,3H),1.66-1.76(m,4H),1.43-1.52(m,2H),1.39(t,J=7.2Hz,3H).

[0354] Example 114: (19R)-5-[3-(4-cyclopropylpiperazin-1-yl)prop-1-ynyl]-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 2,6 .0 13,18 ]pentacosyl-1(24),2(6),4,8(9),11,13(14),15,17,21(25),22-decen-22-amine

[0355] The synthesis method of Example 114 is the same as that of Example 47. LC-MS (ESI) [M+H] + :581.4. 1 H NMR(400MHz, CDCl3),7.50(d,J=1.6Hz,1H),7.42(s,1H),7.28(dd,J=10.0Hz,2.8Hz,1H),7.12(dd,J =8.4Hz,5.6Hz,1H),6.99(td,J=8.4Hz,2.8Hz,1H),6.49(d,J=1.6Hz,1H),5.36-5.42(m,1H),4.89(s ,2H),4.05-4.14(m,2H),3.90(s,3H),3.74(d,J=15.6Hz,1H),3.64(s,2H),2.88(d,J=15.6Hz,1H),2 .60-2.84(m,8H),1.77(d,J=6.0Hz,3H),1.60-1.70(m,1H),1.37(t,J=7.2Hz,3H),0.37-0.51(m,4H).

[0356] Example 115: (19R)-3-Ethyl-16-fluoro-10,19-dimethyl-5-{[4-(trifluoromethyl)phenyl]ethynyl}-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0357] The synthesis method of Example 115 is the same as that of Example 47. LC-MS (ESI) [M+H] + :587.4. 1 H NMR(400MHz, CDCl3),7.70(d,J=8.4Hz,2H),7.63(d,J=8.4Hz,2H),7.45-7.60(brs,1H),7.44 (s,1H),7.30(dd,J=9.6Hz,2.8Hz,1H),7.17(dd,J=8.4Hz,5.6Hz,1H),7.02(td,J=8.4Hz,2.8 Hz,1H),6.55(s,1H),5.39-5.46(m,1H),4.85-5.04(brs,2H),4.12-4.21(m,2H),3.91(s,3H) ,3.86(d,J=15.6Hz,1H), 2.99(d,J=15.6Hz,1H), 1.80(d,J=6.4Hz,3H), 1.44(t,J=7.2Hz,3H).

[0358] Example 116: (19R)-3-Ethyl-16-fluoro-5-[(4-fluorophenyl)ethynyl]-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0359] The synthesis method of Example 116 is the same as that of Example 47. LC-MS (ESI) [M+H] + :537.4. 1H NMR(400MHz, CDCl3),7.50-7.63(m,3H),7.45(s,1H),7.28-7.30(m,1H),7.14-7.17(m,1H),6.96-7.10(m,3H),6.54(s,1H),5.36-5.45(m,1H ),5.02(s,2H),4.05-4.20(m,2H),3.90(s,3H),3.84(d,J=15.6Hz,1H),2.95(d,J=15.6Hz,1H),1.79(d,J=5.6Hz,3H),1.39(t,J=7.2Hz,3H).

[0360] Example 117: 3-[(19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2,6 .0 8,12 .0 13,18 1(25),2(6),4,8(9),11,13(14),15,17,21(22),23-decen-5-yl]-N-cyclopropylprop-2-ynamide

[0361] The synthesis method of Example 117 is the same as that of Example 47. LC-MS (ESI) [M+H] + :526.4. 1 H NMR (400MHz, CDCl3), 7.42 (d, J = 2.4Hz, 1H), 7.38 (s, 1H), 7.25-7.29 (m, 1H), 7.14 (dd, J = 8.4Hz, 5. 6Hz,1H),7.04(td,J=8.4Hz,2.4Hz,1H),6.60(s,1H),6.12(s,1H),5.48-5.84(brs,2H),5.40-5.4 6(m,1H),4.12(q,J=7.2Hz,2H),3.91(s,3H),3.84(d,J=15.6Hz,1H),2.93(d,J=15.6Hz,1H),2.78 -2.85(m,1H),1.81(d,J=6.4Hz,3H),1.41(t,J=7.2Hz,3H),0.84-0.89(m,2H),0.59-0.63(m,2H).

[0362] Example 118: 3-[(19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2,6.0 8,12 .0 13,18 1-(hexahydropyridin-1-yl)prop-2-yn-1-one

[0363] The synthesis method of Example 118 is the same as that of Example 47. LC-MS (ESI) [M+H] + :554.4. 1 H NMR(400MHz, CDCl3),7.48(s,1H),7.44(s,1H),7.28(dd,J=10.0Hz,2.8Hz,1H),7.13( dd,J=8.4Hz,5.6Hz,1H),7.01(td,J=8.4Hz,2.4Hz,1H),6.56(s,1H),5.40-5.45(m,1H) ,5.18(s,2H),4.08-4.21(m,2H),3.90(s,3H),3.83-3.86(m,3H),3.63-3.66(m,2H),2 .94(d,J=15.6Hz,1H),1.80(d,J=6.4Hz,3H),1.56-1.74(m,6H),1.40(t,J=7.2Hz,3H).

[0364] Example 119: (19R)-5-[(5-chloropyridin-2-yl)ethynyl]-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0365] The synthesis method of Example 119 is the same as that of Example 47. LC-MS (ESI) [M+H] + :554.3. 1H NMR(400MHz, CDCl3),8.59(d,J=2.4Hz,1H),7.69(dd,J=8.4Hz,2.4Hz,1H),7.51-7.59(m,2 H),7.46(s,1H),7.28(dd,J=10.0Hz,2.4Hz,1H),7.14(dd,J=8.4Hz,5.6Hz,1H),7.01(td,J =8.4Hz,2.4Hz,1H),6.57(s,1H),5.37-5.45(m,1H),4.82-5.22(brs,2H),4.09-4.20(m,2H ), 3.86-3.94 (m, 4H), 2.97 (d, J = 15.6Hz, 1H), 1.79 (d, J = 6.4Hz, 3H), 1.42 (t, J = 7.2Hz, 3H).

[0366] Example 120: 3-[(19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2,6 .0 8,12 .0 13,18 1(24),2(6),4,8(9),11,13(14),15,17,21(25),22-decen-5-yl]prop-2-enenitrile

[0367] The synthesis method of Example 120 is the same as that of Example 45. LC-MS (ESI) [M+H] + :469.4. 1 H NMR(400MHz, CDCl3),7.46-7.58(m,2H),7.24-7.30(m,1H),7.12-7.20(m,2H),7.04-7.09(m,1H),6.61(s,1H),6.19-6.46(m,3H),5.36-5 .46(m,1H),4.06-4.22(m,2H),3.93(s,3H),3.66(d,J=15.6Hz,1H),2.99(d,J=15.6Hz,1H),1.82(d,J=6.0Hz,3H),1.41(t,J=7.2Hz,3H).

[0368] Example 121: (19R)-3-Ethyl-16-fluoro-5-[(4-methoxyphenyl)ethynyl]-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .02,6 ]pentacosyl-1(24),2(6),4,8(9),11,13(14),15,17,21(25),22-decen-22-amine

[0369] The synthesis method of Example 121 is the same as that of Example 47. LC-MS (ESI) [M+H] + :549.4. 1 H NMR(400MHz, CD3OD+CDCl3),7.38-7.48(m,3H),7.29-7.34(m,1H),7.22(s,1H),7.11-7.14(m,1H),6.99-7.03(m,1H),6.83(d,J=8.4Hz,2H),8.6 2(s,1H),5.29-5.39(m,1H),3.96-4.12(m,2H),3.81-3.85(m,4H),3.76( s, 3H), 2.85 (d, J = 16.0Hz, 1H), 1.80 (d, J = 5.6Hz, 3H), 1.29-1.39 (m, 3H).

[0370] Example 122: 3-{[(19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosyl-1(24),2(6),4,8(9),11,13(14),15,17,21(25),22-decen-5-yl]ethynyl}oxetan-3-ol

[0371] The synthesis method of Example 122 is the same as that of Example 47. LC-MS (ESI) [M+H] + :515.4. 1H NMR(400MHz, CDCl3),7.36(s,1H),7.22-7.31(m,2H),7.10(dd,J=8.4Hz,5.6Hz,1H),6.99 (td,J=8.4Hz,2.4Hz,1H),6.49(s,1H),5.34-5.44(m,1H),5.08-5.32(brs,2H),5.00(d,J =6.8Hz,1H),4.94(d,J=6.8Hz,1H),4.83-4.85(m,2H),3.98-4.15(m,2H),3.90(s,3H),3. 63(d,J=15.6Hz,1H), 2.79(d,J=15.6Hz,1H), 1.79(d,J=5.6Hz,3H), 1.32(t,J=6.4Hz,3H).

[0372] Example 123: (19R)-3-ethyl-16-fluoro-10,19-dimethyl-5-(1,3-oxazol-4-ylethynyl)-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosyl-1(24),2(6),4,8(9),11,13(14),15,17,21(25),22-decen-22-amine

[0373] The synthesis method of Example 123 is the same as that of Example 47. LC-MS (ESI) [M+H] + :510.4. 1 H NMR(400MHz, CDCl3),7.97(s,1H),7.94(s,1H),7.47(s,1H),7.24-7.31(m,2H),7.18(dd,J=8.4Hz,5.6Hz,1H),7.09(td,J=8.4Hz,2.4Hz,1H),6.76(s ,1H),5.46-5.53(m,1H),4.02-4.17(m,2H),3.94(d,J=15.6Hz,1H),3.91(s ,3H), 2.95(d,J=15.6Hz,1H), 1.86(d,J=5.6Hz,3H), 1.43(t,J=7.2Hz,3H).

[0374] Example 124: 5-[(19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18.0 2,6 1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decen-5-yl]-2-methylpent-4-yn-2-ol

[0375] The synthesis method of Example 124 is the same as that of Example 47. LC-MS (ESI) [M+H] + :515.4. 1 H NMR(400MHz, CDCl3),7.50(d,J=1.6Hz,1H),7.42(s,1H),7.28(dd,J=10.0Hz,2.8Hz,1H),7.13 (dd,J=8.4Hz,5.6Hz,1H),6.99(td,J=8.4Hz,2.8Hz,1H),6.50(d,J=1.6Hz,1H),5.37-5.43(m,1 H),4.91(s,2H),4.05-4.15(m,2H),3.90(s,3H),3.74(d,J=15.6Hz,1H),2.90(d,J=15.6Hz,1H ), 2.71 (s, 2H), 2.06-2.20 (brs, 1H), 1.78 (d, J = 6.0Hz, 3H), 1.41 (s, 6H), 1.38 (t, J = 7.2Hz, 3H).

[0376] Example 125: (19R)-5-[(3,5-dimethoxyphenyl)ethynyl]-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0377] The synthesis method of Example 125 is the same as that of Example 47. LC-MS (ESI) [M+H] + :579.4. 1H NMR(400MHz, CDCl3),7.49-7.58(brs,1H),7.46(s,1H),7.29(dd,J=10.0Hz,2.8Hz,1H),7.16( dd,J=8.4Hz,5.6Hz,1H),7.01(td,J=8.4Hz,2.8Hz,1H),6.76(d,J=2.0Hz,2H),6.54(s,1H),6.4 8(t,J=2.0Hz,1H),5.38-5.45(m,1H),4.92(s,2H),4.11-4.16(m,2H),3.90(s,3H),3.86(d,J= 15.6Hz, 1H), 3.81 (s, 6H), 2.96 (d, J = 15.6Hz, 1H), 1.79 (d, J = 6.4Hz, 3H), 1.40 (t, J = 7.2Hz, 3H).

[0378] Example 126: 2-(4-{3-[(19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 2,6 .0 13,18 1-(24),2(6),4,8(9),11,13(14),15,17,21(25),22-decen-5-yl]prop-2-ynyl}piperazin-1-yl)ethan-1-ol

[0379] The synthesis method of Example 126 is the same as that of Example 47. LC-MS (ESI) [M+H] + :585.5. 1 H NMR(400MHz, CDCl3),7.48(d,J=1.6Hz,1H),7.42(s,1H),7.27(dd,J=10.0Hz,2.8Hz,1H),7.12(d d,J=8.4Hz,5.6Hz,1H),6.98(td,J=8.4Hz,2.8Hz,1H),6.48(d,J=1.6Hz,1H),5.35-5.42(m,1H), 4.85(s,2H),4.05-4.14(m,2H),3.91(s,3H),3.74(d,J=15.6Hz,1H),3.69(t,J=5.2Hz,2H),3.65 (s, 2H), 2.89 (d, J = 15.6Hz, 1H), 2.61-2.88 (m, 10H), 1.76 (d, J = 6.4Hz, 3H), 1.37 (t, J = 7.2Hz, 3H).

[0380] Example 127: (19R)-5-[(4-chlorophenyl)ethynyl]-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0381] The synthesis method of Example 127 is the same as that of Example 47. LC-MS (ESI) [M+H] + :553.3. 1 H NMR(400MHz, CDCl3),7.58(s,1H),7.52(d,J=8.4Hz,2H),7.44(s,1H),7.34(d,J=8.4Hz, 2H),7.26-7.31(m,1H),7.17(dd,J=8.4Hz,5.6Hz,1H),7.02(td,J=8.4Hz,2.8Hz,1H),6. 55(s,1H),5.37-5.44(m,1H),4.80-5.30(brs,2H),4.04-4.18(m,2H),3.91(s,3H),3.85 (d, J=15.6Hz, 1H), 2.96 (d, J=15.6Hz, 1H), 1.80 (d, J=6.4Hz, 3H), 1.40 (t, J=7.2Hz, 3H).

[0382] Example 128: (19R)-3-Ethyl-16-fluoro-5-(hexahydropyridin-3-ylethynyl)-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0383] The synthesis method of Example 128 is the same as that of Example 47. LC-MS (ESI) [M+H] + :526.4. 1H NMR(400MHz, CD3OD),7.53-7.56(m,2H),7.42(d,J=1.2Hz,1H),7.19(dd,J=8.4Hz,5.6Hz, 1H),7.08(td,J=8.4Hz,2.8Hz,1H),6.46(d,J=1.2Hz,1H),5.37-5.44(m,1H),4.02-4.17(m ,2H),3.92(s,3H),3.74(d,J=15.6Hz,1H),3.30-3.38(m,1H),2.82-3.11(m,5H),2.12-2. 20(m,1H),1.87-1.96(m,1H),1.74-1.85(m,4H),1.61-1.72(m,1H),1.31(t,J=7.2Hz,3H).

[0384] Example 129: (19R)-3-Ethyl-16-fluoro-5-[(5-fluoropyridin-2-yl)ethynyl]-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2,6 .0 8,12 .0 13,18 ]pentacosyl-1(25),2(6),4,8(9),11,13(14),15,17,21(22),23-decen-22-amine

[0385] The synthesis method of Example 129 is the same as that of Example 47. LC-MS (ESI) [M+H] + :538.4. 1 H NMR(400MHz, CDCl3),8.50(d,J=2.8Hz,1H),7.63(dd,J=8.8Hz,4.4Hz,1H),7.52(s,1H),7.47( s,1H),7.43(td,J=8.4Hz,2.8Hz,1H),7.29(dd,J=10.0Hz,2.8Hz,1H),7.14(dd,J=8.4Hz,5.6Hz ,1H),7.01(td,J=8.4Hz,2.8Hz,1H),6.56(s,1H),5.39-5.45(m,1H),4.97(s,2H),4.15-4.21( m, 2H), 3.89-3.94 (m, 4H), 2.97 (d, J = 15.6Hz, 1H), 1.79 (d, J = 6.4Hz, 3H), 1.43 (t, J = 7.2Hz, 3H).

[0386] Example 130: 4-[(19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2,6 .0 8,12 .0 13,18 1(24),2(6),4,8(9),11,13(18),14,16,21(25),22-decen-5-yl]-1,1,1-trifluorobut-3-yn-2-ol

[0387] The synthesis method of Example 130 is the same as that of Example 47. LC-MS (ESI) [M+H] + :541.4. 1 H NMR(400MHz, CD3OD),7.36-7.60(m,3H),7.19(dd,J=8.4Hz,6.0Hz,1H),7.08(td,J=8.4Hz,2.8Hz,1H),6.48(s,1H),5.38-5.46(m,1H),5.1 5(q,J=6.0Hz,1H),4.04-4.19(m,2H),3.92(s,3H),3.75-3.80(m,1H),2.92(d,J=15.6Hz,1H),1.81(d,J=6.4Hz,3H),1.32(t,J=7.2Hz,3H).

[0388] Example 131: 3-[(19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2,6 .0 8,12 .0 13,18 1(24),2(6),4,8(9),11,13(18),14,16,21(25),22-decen-5-yl]-N,N-dimethylprop-2-ynamide

[0389] The synthesis method of Example 131 is the same as that of Example 47. LC-MS (ESI) [M+H] + :514.3. 1H NMR(400MHz,CD3OD),7.59(s,1H),7.55(dd,J=10.0Hz,2.8Hz,1H),7.39-7.51(brs, 1H),7.21(dd,J=8.4Hz,5.6Hz,1H),7.09(td,J=8.4Hz,2.8Hz,1H),6.48(s,1H),5.3 9-5.46(m,1H),4.08-4.23(m,2H),3.92(s,3H),3.83(d,J=15.6Hz,1H),3.39(s,3H) ,3.05(s,3H),2.96(d,J=15.6Hz,1H),1.81(d,J=6.4Hz.3H),1.34(t,J=7.2Hz,3H).

[0390] Example 132: 3-[(19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2,6 .0 8,12 .0 13,18 1(24),2(6),4,8(9),11,13(18),14,16,21(25),22-decen-5-yl]-N-methylprop-2-ynamide

[0391] The synthesis method of Example 132 is the same as that of Example 47. LC-MS (ESI) [M+H] + :500.3. 1 H NMR(400MHz,CD3OD),7.56(s,1H),7.54(dd,J=10.0Hz,2.8Hz,1H),7.39-7.52(b rs,1H),7.20(dd,J=8.4Hz,6.0Hz,1H),7.08(td,J=8.4Hz,2.8Hz,1H),6.47(s,1 H),5.38-5.44(m,1H),4.06-4.20(m,2H),3.92(s,3H),3.84(d,J=15.6Hz,1H),2 .92(d,J=15.6Hz,1H),2.84(s,3H),1.81(d,J=6.4Hz,3H),1.32(t,J=7.2Hz,3H).

[0392] Example 133: (19R)-5-[(3,5-difluorophenyl)ethynyl]-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .013,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0393] The synthesis method of Example 133 is the same as that of Example 47. LC-MS (ESI) [M+H] + :555.3. 1 H NMR(400MHz, CDCl3),7.54(s,1H),7.41(s,1H),7.30(dd,J=10.0Hz,2.8Hz,1H),7.17(dd, J=8.4Hz,5.6Hz,1H),7.06-7.13(m,2H),7.02(td,J=8.4Hz,2.8Hz,1H),6.80-6.86(m,1H) ,6.55(s,1H),5.40-5.45(m,1H),4.88-5.10(brs,2H),4.13-4.18(m,2H),3.92(s,3H),3. 83(d,J=15.6Hz,1H), 2.98(d,J=15.6Hz,1H), 1.81(d,J=6.4Hz,3H), 1.43(t,J=7.2Hz,3H).

[0394] Example 134: 1-{[(19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decen-5-yl]ethynyl}cyclopropan-1-ol

[0395] The synthesis method of Example 134 is the same as that of Example 47. LC-MS (ESI) [M+H] + :499.4. 1H NMR(400MHz,CD3OD),7.57(s,1H),7.52(dd,J=10.4Hz,2.8Hz,1H),7.34-7.51(br s,1H),7.18(dd,J=8.4Hz,5.6Hz,1H),7.06(td,J=8.4Hz,2.8Hz,1H),6.47(s,1H), 5.37-5.44(m,1H),3.99-4.16(m,2H),3.92(s,3H),3.75(d,J=15.6Hz,1H),2.87( d,J=15.6Hz,1H),1.80(d,J=6.4Hz,3H),1.30(t,J=7.2Hz,3H),1.08-1.14(m,4H).

[0396] Example 135: 6-[(19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decen-5-yl]-2-methylhex-5-yn-2-ol

[0397] The synthesis method of Example 135 is the same as that of Example 47. LC-MS (ESI) [M+H] + :529.4. 1 H NMR(400MHz, CDCl3),7.50(d,J=1.2Hz,1H),7.42(s,1H),7.27(dd,J=10.4Hz,2.8Hz,1H),7.14(d d,J=8.4Hz,5.6Hz,1H),6.99(td,J=8.4Hz,2.8Hz,1H),6.51(d,J=1.2Hz,1H),5.36-5.43(m,1H),5 .00(s,2H),4.03-4.12(m,2H),3.91(s,3H),3.73(d,J=15.6Hz,1H),2.87(d,J=15.6Hz,1H),2.62( t,J=8.0Hz,2H),1.89(t,J=8.0Hz,2H),1.78(d,J=6.0Hz,3H),1.36(t,J=7.2Hz,3H),1.28(s,6H).

[0398] Example 136: 3-[(19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2,6 .0 8,12 .0 13,18 1-(3,3-difluoroazetidin-1-yl)prop-2-yn-1-one

[0399] The synthesis method of Example 136 is the same as that of Example 47. LC-MS (ESI) [M+H] + :562.4. 1 H NMR(400MHz, CDCl3),7.41(s,1H),7.36(s,1H),7.29(dd,J=10.0Hz,2.8Hz,1H),7.15(dd,J =8.4Hz,5.6Hz,1H),7.05(td,J=8.4Hz,2.8Hz,1H),6.61(s,1H),5.64-5.96(brs,2H),5.41 -5.48(m,1H),4.64-4.71(m,2H),4.44(t,J=12.0Hz,2H),4.11-4.17(m,2H),3.92(s,3H),3 .82(d,J=16.0Hz,1H), 2.96(d,J=15.6Hz,1H), 1.83(d,J=6.0Hz,3H), 1.43(t,J=7.2Hz,3H).

[0400] Example 137: (19R)-3-Ethyl-16-fluoro-10,19-dimethyl-5-[(4-methyl-1,3-thiazol-5-yl)ethynyl]-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0401] The synthesis method of Example 137 is the same as that of Example 47. LC-MS (ESI) [M+H] + :540.4. 1H NMR(400MHz, CDCl3),8.66(s,1H),7.47-7.67(brs,1H),7.43(s,1H),7.29(dd,J=10.0 Hz,2.4Hz,1H),7.15(dd,J=8.4Hz,5.6Hz,1H),7.01(td,J=8.4Hz,2.4Hz,1H),6.55(s,1 H),5.38-5.46(m,1H),5.23(s,2H),4.08-4.17(m,2H),3.91(s,3H),3.82(d,J=15.6Hz, 1H), 2.98 (d, J = 15.6Hz, 1H), 2.64 (s, 3H), 1.80 (d, J = 6.4Hz, 3H), 1.41 (t, J = 7.2Hz, 3H).

[0402] Example 138: (19R)-3-Ethyl-16-fluoro-5-[(2-methoxypyridin-3-yl)ethynyl]-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0403] The synthesis method of Example 138 is the same as that of Example 47. LC-MS (ESI) [M+H] + :550.4. 1 H NMR(400MHz, CDCl3),8.14(dd,J=5.2Hz,1.6Hz,1H),7.79(dd,J=7.6Hz,2.0Hz,1H),7.51-7.60(m,2H),7. 28(dd,J=10.0Hz,2.8Hz,1H),7.14(dd,J=8.4Hz.5.6Hz,1H),7.00(td,J=8.4Hz,2.8Hz,1H),6.90(dd,J=7 .2Hz,5.2Hz,1H),6.58(s,1H),5.40-5.48(m,1H),5.17-5.36(brs,2H),4.08-4.18(m,2H),3.98(s,3H),3 .91(s,3H),3.90(d,J=15.2Hz,1H),2.96(d,J=15.2Hz,1H),1.80(d,J=6.4Hz,3H),1.39(d,J=7.2Hz,3H).

[0404] Example 139: (19R)-3-Ethyl-16-fluoro-5-[(6-methoxypyridin-3-yl)ethynyl]-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0405] The synthesis method of Example 139 is the same as that of Example 47. LC-MS (ESI) [M+H] + :550.4. 1 H NMR(400MHz, CDCl3),8.42(d,J=2.0Hz,1H),7.74(dd,J=8.4Hz,2.0Hz,1H),7.49-7.59(brs,1H),7. 45(s,1H),7.28(dd,J=10.0Hz,2.8Hz,1H),7.16(dd,J=8.4Hz,5.6Hz,1H),7.02(td,J=8.4Hz,2.8Hz ,1H),6.75(d,J=8.4Hz,1H),6.58(s,1H),5.22-5.48(m,3H),4.08-4.18(m,2H),3.96(s,3H),3.90( s, 3H), 3.85 (d, J = 15.6Hz, 1H), 2.96 (d, J = 15.6Hz, 1H), 1.80 (d, J = 6.8Hz, 3H), 1.41 (t, J = 7.2Hz, 3H).

[0406] Example 140: (19R)-3-Ethyl-16-fluoro-10,19-dimethyl-5-[(3-methylisoxazol-5-yl)ethynyl]-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0407] The synthesis method of Example 140 is the same as that of Example 47. LC-MS (ESI) [M+H] + :523.4. 1H NMR(400MHz, CD3OD),7.40-7.65(m,3H),7.22(dd,J=8.4Hz,5.6Hz,1H),7.08(td,J=8.4Hz,2.8Hz,1H),6.67(s,1H),6.51(s,1H),5.40-5.47(m, 1H),4.09-4.22(m,2H),3.92(s,3H),3.82(d,J=15.6Hz,1H),2.98(d,J= 15.6Hz, 1H), 2.34 (s, 3H), 1.82 (d, J = 6.4Hz, 3H), 1.36 (t, J = 7.2Hz, 3H).

[0408] Example 141: 3-[(19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 2,6 .0 13,18 1-[4-(2-hydroxyethyl)piperazin-1-yl]prop-2-yn-1-one]pentacrylic acid-1-one (24), 2 (6), 4, 8 (9), 11, 13 (14), 15, 17, 21 (25), 22-decen-5-yl)-1-[4-(2-hydroxyethyl)piperazin-1-yl]prop-2-yn-1-one

[0409] The synthesis method of Example 141 is the same as that of Example 47. LC-MS (ESI) [M+H] + :598.4. 1 H NMR(400MHz, CDCl3),7.50(s,1H),7.41(s,1H),7.28(dd,J=10.0Hz,1H),7.13(dd,J=8.4Hz, 5.6Hz,1H),7.00(td,J=8.4Hz,2.8Hz,1H),6.53(d,J=1.6Hz,1H),5.39-5.45(m,1H),4.99(s ,2H),4.11-4.20(m,2H),3.97-4.00(m,2H),3.91(s,3H),3.76-3.84(m,3H),3.70-3.72(m,2 H), 2.96 (d, J = 15.6Hz, 1H), 2.58-2.74 (m, 6H), 1.79 (d, J = 6.4Hz, 3H), 1.40 (t, J = 7.2Hz, 3H).

[0410] Example 142: (19R)-3-Ethyl-16-fluoro-5-{[(3S)-tetrahydrofuran-3-yl]ethynyl}-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosyl-1(24),2(6),4,8(9),11,13(14),15,17,21(25),22-decen-22-amine

[0411] The synthesis method of Example 142 is the same as that of Example 47. LC-MS (ESI) [M+H] + :513.3. 1 H NMR(400MHz, CDCl3),7.51(s,1H),7.39(s,1H),7.28(dd,J=10.0Hz,2.8Hz,1H),7.14(dd,J=8.4Hz,5.6Hz ,1H),6.99(td,J=8.4Hz,2.8Hz,1H),6.50(d,J=1.6Hz,1H),5.37-5.43(m,1H),4.95(s,2H),4.06-4.15(m, 3H),3.95-4.01(m,1H),3.87-3.93(m,4H),3.79-3.83(m,1H),3.72(d,J=15.6Hz,1H),3.28-3.32(m,1H),2 .89(d,J=15.6Hz,1H),2.29-2.38(m,1H),2.11-2.19(m,1H),1.79(d,J=6.0Hz,3H),1.37(t,J=7.2Hz,3H).

[0412] Example 143: (19R)-3-Ethyl-16-fluoro-5-{[(3R)-1,4-oxazacyclohexan-3-yl]ethynyl}-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0413] The synthesis method of Example 143 is the same as that of Example 47. LC-MS (ESI) [M+H] + :528.4. 1H NMR(400MHz, CDCl3),7.48(s,1H),7.44(s,1H),7.28(dd,J=10.0Hz,2.8Hz,1H),7 .12(dd,J=8.4Hz,5.6Hz,1H),6.99(td,J=8.4Hz,2.8Hz,1H),6.51(s,1H),5.37(m ,1H),5.08-5.24(brs,2H),3.98-4.12(m,4H),3.90(s,1H),3.64-3.82(m,4H),3. 10-3.20(m,1H),2.86-2.98(m,2H),1.78(d,J=6.0Hz,3H),1.38(t,J=7.2Hz,3H).

[0414] Example 144: (19R)-3-Ethyl-16-fluoro-5-{[(2S)-1,4-oxazacyclohexan-2-yl]ethynyl}-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2,6 .0 8,12 .0 13,18 ]pentacosyl-1(25),2(6),4,8(9),11,13(14),15,17,21(22),23-decen-22-amine

[0415] The synthesis method of Example 144 is the same as that of Example 47. LC-MS (ESI) [M+H] + :528.4. 1 H NMR(400MHz, CDCl3),7.51(d,J=1.2Hz,1H),7.43(s,1H),7.29(dd,J=10.0Hz,2.8Hz,1H),7.13(dd,J=8.4Hz,5 .6Hz,1H),6.99(td,J=8.4Hz,2.8Hz,1H),6.51(d,J=1.2Hz,1H),5.38-5.44(m,1H),4.81(s,2H),4.66(dd,J=6. 8Hz,2.8Hz,1H),4.02-4.16(m,3H),3.91(s,3H),3.77(d,J=15.6Hz,1H),3.67-3.74(m,1H),3.27(dd,J=12.8H z, 3.2Hz, 1H), 3.09 (dd, J = 12.8Hz, 6.8Hz, 1H), 2.90-2.98 (m, 3H), 1.79 (d, J = 6.0Hz, 3H), 1.39 (t, J = 7.2Hz, 3H).

[0416] Example 145: (19R)-3-Ethyl-16-fluoro-10,19-dimethyl-5-[(1-methylhexahydropyridin-2-yl)ethynyl]-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosyl-1(24),2(6),4,8(9),11,13(14),15,17,21(25),22-decen-22-amine

[0417] The synthesis method of Example 145 is the same as that of Example 47. LC-MS (ESI) [M+H] + :540.4. 1 H NMR (400MHz, CDCl3), 7.38-7.54 (m, 2H), 7.29 (dd, J = 10.0Hz, 2.8Hz, 1H), 7.14 (dd, J = 8. 4Hz,5.6Hz,1H),6.97-7.02(m,1H),6.49-6.50(m,1H),5.38-5.45(m,1H),4.82(s,2H), 4.06-4.20(m,2H),3.85-4.03(m,4H),3.72-3.77(m,1H),2.80-2.98(m,2H),2.51-2.74 (m,4H),1.97-2.24(m,2H),1.70-1.90(m,5H),1.56-1.68(m,2H),1.39(t,J=7.2Hz,3H).

[0418] Example 146: 3-{[(19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosyl-1(24),2(6),4,8(9),11,13(14),15,17,21(25),22-decen-5-yl]ethynyl}azetidin-3-ol

[0419] The synthesis method of Example 146 is the same as that of Example 47. LC-MS (ESI) [M+H] + :514.4. 1H NMR(400MHz,CD3OD+CDCl3),7.36-7.48(m,2H),7.30(dd,J=9.6Hz,2.4Hz,1H),7.09 (dd,J=8.4Hz,5.6Hz,1H),6.99(td,J=8.4Hz,2.8Hz,1H),6.59(s,1H),5.32-5.40(m, 1H),4.33-4.37(m,2H),4.17-4.20(m,2H),3.97-4.07(m,2H),3.84(s,3H),3.74(d, J=15.6Hz, 1H), 2.83 (d, J=15.6Hz, 1H), 1.78 (d, J=6.0Hz, 3H), 1.31 (t, J=7.2Hz, 3H).

[0420] Example 147: (19R)-3-Ethyl-16-fluoro-5-(4-methoxybut-1-ynyl)-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0421] The synthesis method of Example 147 is the same as that of Example 47. LC-MS (ESI) [M+H] + :501.4. 1 H NMR(400MHz, CDCl3),7.47(s,1H),7.23-7.30(m,2H),7.19(dd,J=8.4Hz,5.6Hz,1H),7.1 0(td,J=8.4Hz,2.8Hz,1H),6.76(s,1H),5.46-5.54(m,1H),3.98-4.10(m,2H),3.92(s,3 H),3.85(d,J=15.6Hz,1H),3.65(t,J=7.2Hz,2H),3.41(s,3H),3.22-3.40(brs,2H),2.8 8(d,J=15.6Hz,1H), 2.79(t,J=7.2Hz,2H), 1.87(d,J=6.4Hz,3H), 1.40(t,J=7.2Hz,3H).

[0422] Example 148: (19R)-3-Ethyl-16-fluoro-10,19-dimethyl-5-(thien-2-ylethynyl)-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0423] The synthesis method of Example 148 is the same as that of Example 47. LC-MS (ESI) [M+H] + :525.3. 1 H NMR(400MHz, CDCl3),7.49(s,1H),7.46(s,1H),7.35(dd,J=7.6Hz,1.2Hz,1H),7.32(dd,J= 9.2Hz, 1.2Hz, 1H), 7.29 (dd, J=10.0Hz, 2.8Hz, 1H), 7.16 (dd, J=8.4Hz, 5.6Hz, 1H), 6.99-7. 04(m,2H),6.57(s,1H),5.40-5.46(m,1H),5.23(s,2H),4.11-4.17(m,2H),3.91(s,3H),3. 85(d,J=15.6Hz,1H), 2.95(d,J=15.6Hz,1H), 1.81(d,J=6.4Hz,3H), 1.42(t,J=7.2Hz,3H).

[0424] Example 149: (19R)-3-Ethyl-16-fluoro-10,19-dimethyl-5-(thien-3-ylethynyl)-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0425] The synthesis method of Example 149 is the same as that of Example 47. LC-MS (ESI) [M+H] + :525.3. 1H NMR(400MHz, CDCl3),7.59(dd,J=2.4Hz,1.2Hz,1H),7.50(s,1H),7.46(s,1H),7.28-7.33 (m,2H),7.24-7.26(m,1H),7.16(dd,J=8.4Hz,5.6Hz,1H),7.01(td,J=8.4Hz,2.8Hz,1H), 6.56(d,J=1.2Hz,1H),5.40-5.46(m,1H),5.15(s,2H),4.10-4.16(m,2H),3.90(s,3H),3. 85(d,J=15.6Hz,1H), 2.95(d,J=15.6Hz,1H), 1.80(d,J=6.4Hz,3H), 1.42(t,J=7.2Hz,3H).

[0426] Example 150: (19R)-3-Ethyl-16-fluoro-10,19-dimethyl-5-(pyrimidin-4-ylethynyl)-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2,6 .0 8,12 .0 13,18 ]pentacosyl-1(24),2(6),4,8(9),11,13(18),14,16,21(25),22-decen-22-amine

[0427] The synthesis method of Example 150 is the same as that of Example 47. LC-MS (ESI) [M+H] + :521.3. 1 H NMR(400MHz, CDCl3),9.10-9.42(brs,1H),8.58-8.97(brs,1H),7.36-7.70(m, 3H),7.23-7.30(m,1H),7.19(dd,J=8.4Hz,5.6Hz,1H),7.08(td,J=8.4Hz,2.0Hz ,1H),6.99(s,1H),5.43-5.52(m,1H),4.10-4.24(m,2H),3.97(d,J=15.6Hz,1H) ,3.91(s,3H),3.00(d,J=15.6Hz,1H),1.85(d,J=6.0Hz,3H),1.43-1.50(m,3H).

[0428] Example 151: (19R)-5-[(2-aminopyrimidin-5-yl)ethynyl]-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.08,12 .0 13,18 .0 2,6 ]pentacosyl-1(24),2(6),4,8(9),11,13(14),15,17,21(25),22-decen-22-amine

[0429] The synthesis method of Example 151 is the same as that of Example 47. LC-MS (ESI) [M+H] + :536.3. 1 H NMR(400MHz, CDCl3),8.51(s,2H),7.53(d,J=2.0Hz,1H),7.42(s,1H),7.29(dd,J=9.6Hz ,2.8Hz,1H),7.15(dd,J=8.4Hz,5.6Hz,1H),7.00(td,J=8.4Hz,2.8Hz,1H),6.53(d,J=2.0 Hz,1H),5.39-5.46(m,1H),5.33(s,2H),4.95(s,2H),4.11-4.18(m,2H),3.91(s,3H),3.8 2(d,J=15.6Hz,1H), 2.96(d,J=15.6Hz,1H), 1.79(d,J=6.4Hz,3H), 1.42(t,J=7.2Hz,3H).

[0430] Example 152: (19R)-3-ethyl-16-fluoro-10,19-dimethyl-5-[3-methyl-3-(methyldioxy- 6 -sulfanyl)but-1-ynyl]-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosyl-1(24),2(6),4,8(9),11,13(14),15,17,21(25),22-decen-22-amine

[0431] The synthesis method of Example 152 is the same as that of Example 47. LC-MS (ESI) [M+H] + :563.4. 1H NMR(400MHz, CDCl3),7.56-7.87(brs,1H),7.54(s,1H),7.24-7.27(m,1H),7.1 3(dd,J=8.4Hz,5.6Hz,1H),7.00(td,J=8.4Hz,2.8Hz,1H),6.54(s,1H),5.54(s, 2H),5.36-5.43(m,1H),4.01-4.14(m,2H),3.91(s,3H),3.71(d,J=15.6Hz,1H) ,3.12(s,3H),2.93(d,J=15.6Hz,1H),1.79-1.81(m,9H),1.33(t,J=7.2Hz,3H).

[0432] Example 153: 1-{3-[(19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosyl-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decen-5-yl]prop-2-ynyl}cyclobutan-1-ol

[0433] The synthesis method of Example 153 is the same as that of Example 47. LC-MS (ESI) [M+H] + :527.4. 1 H NMR(400MHz, CDCl3),7.51(s,1H),7.42(s,1H),7.28(d,J=10.4Hz,1H),7.11-7.14 (m,1H),6.96-7.01(m,1H),6.49(s,1H),5.34-5.44(m,1H),4.89(s,2H),4.04-4.14 (m,2H),3.89(s,3H),3.73(d,J=15.6Hz,1H),2.89(d,J=15.6Hz,1H),2.84(s,2H), 1.95-2.26(m,5H),1.78(d,J=5.2Hz,3H),1.56-1.68(m,1H),1.37(t,J=6.8Hz,3H).

[0434] Example 154: (19R)-3-Ethyl-16-fluoro-10,19-dimethyl-5-[(4-methyl-1,4-oxazacyclohexan-3-yl)ethynyl]-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.02,6 .0 8,12 .0 13,18 ]pentacosyl-1(25),2(6),4,8(9),11,13(14),15,17,21(22),23-decen-22-amine

[0435] The synthesis method of Example 154 is the same as that of Example 47. LC-MS (ESI) [M+H] + :542.3. 1 H NMR(400MHz, CDCl3),7.44-7.53(m,2H),7.28(dd,J=10.0Hz,2.8Hz,1H),7.12-7 .16(m,1H),7.00(td,J=8.4Hz,2.8Hz,1H),6.53(s,1H),5.40-5.46(m,1H),4.90 -5.12(brs,2H),3.98-4.18(m,3H),3.70-3.96(m,7H),3.48-3.68(brs,1H),2.8 2-2.97(m,2H),2.38-2.68(m,4H),1.80(d,J=6.4Hz,3H),1.39(t,J=7.2Hz,3H).

[0436] Example 155: (19R)-3-Ethyl-16-fluoro-10,19-dimethyl-5-[(4-methyl-1,4-oxazepan-2-yl)ethynyl]-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2,6 .0 8,12 .0 13,18 ]pentacosyl-1(25),2(6),4,8(9),11,13(14),15,17,21(22),23-decen-22-amine

[0437] The synthesis method of Example 155 is the same as that of Example 47. LC-MS (ESI) [M+H] + :542.4. 1H NMR(400MHz, CDCl3),7.50(s,1H),7.38-7.44(m,1H),7.28(dd,J=10.0Hz,2.8Hz,1H),7.13(d d,J=8.4Hz,5.6Hz,1H),6.97-7.03(m,1H),6.52(s,1H),5.38-5.45(m,1H),4.67-5.04(m,3H), 4.08-4.14(m,2H),4.00-4.07(m,1H),3.84-3.97(m,4H),3.77(d,J=15.2Hz,1H),2.98-3.21(m ,1H),2.91(d,J=15.2Hz,1H),2.30-2.84(m,6H),1.79(d,J=6.4Hz,3H),1.39(t,J=7.6Hz,3H).

[0438] Example 156: (19R)-3-Ethyl-16-fluoro-10,19-dimethyl-5-[3-methyl-3-(1,4-oxazepan-4-yl)but-1-ynyl]-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0439] The synthesis method of Example 156 is the same as that of Example 47. LC-MS (ESI) [M+H] + :570.4. 1 H NMR(400MHz,CD3OD),7.59(s,1H),7.53(dd,J=10.0Hz,2.8Hz,1H),7.39-7.50(brs,1H) ,7.20(dd,J=8.4Hz,5.6Hz,1H),7.08(td,J=8.4Hz,2.8Hz,1H),6.48(s,1H),5.38-5.44 (m,1H),4.02-4.18(m,2H),3.92(s,3H),3.74-3.79(m,5H),2.91(d,J=15.6Hz,1H),2.8 2-2.84(m,4H),1.81(d,J=6.4Hz,3H),1.55(s,3H),1.54(s,3H),1.31(t,J=7.2Hz,3H).

[0440] Example 157: 2-(4-{[(19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decen-5-yl]ethynyl}-1,3-thiazol-2-yl)propan-2-ol

[0441] The synthesis method of Example 157 is the same as that of Example 47. LC-MS (ESI) [M+H] + :583.4. 1 H NMR(400MHz, CD3OD),7.55-7.94(m,3H),7.54(dd,J=10.0Hz,2.4Hz,1H),7.24(dd,J=8.4Hz,5.6Hz,1H),7.10(td,J=8.4Hz,2.4Hz,1H),6.62(s, 1H),5.44-5.52(m,1H),4.07-4.24(m,2H),3.86-3.94(m,4H),2.95(d,J =15.6Hz, 1H), 1.85 (d, J = 6.4Hz, 3H), 1.64 (s, 6H), 1.34 (t, J = 7.2Hz, 3H).

[0442] Example 158: (19R)-5-(2,3-dihydro-1H-indol-7-ylethynyl)-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0443] The synthesis method of Example 158 is the same as that of Example 47. LC-MS (ESI) [M+H] + :560.4. 1H NMR(400MHz, CD3OD),7.61(s,1H),7.48(dd,J=8.4Hz,2.8Hz,1H),7.45(d,J=1.6Hz,1H),7.20(dd,J =8.4Hz,5.6Hz,1H),7.13(d,J=7.2Hz,1H),7.02-7.09(m,2H),6.63(t,J=7.6Hz,1H),6.52(d,J=1.6 Hz,1H),5.37-5.44(m,1H),4.05-4.20(m,2H),3.90(s,3H),3.86(d,J=15.6Hz,1H),3.61(t,J=8.4H z, 2H), 3.07 (t, J = 8.4Hz, 2H), 2.94 (d, J = 15.6Hz, 1H), 1.81 (d, J = 6.4Hz, 3H), 1.35 (t, J = 7.2Hz, 3H).

[0444] Example 159: 2-(5-{[(19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 2,6 .0 13,18 1(24),2(6),4,8(9),11,13(14),15,17,21(25),22-decen-5-yl]ethynyl}pyrimidin-2-yl)propan-2-ol

[0445] The synthesis method of Example 159 is the same as that of Example 47. LC-MS (ESI) [M+H] + :579.4. 1 H NMR(400MHz, CDCl3),8.90(s,2H),7.54(d,J=1.6Hz,1H),7.40(s,1H),7.30(dd,J=9.6Hz,2.8 Hz,1H),7.16(dd,J=8.4Hz,5.6Hz,1H),7.01(td,J=8.4Hz,2.8Hz,1H),6.53(d,J=1.6Hz,1H), 5.39-5.46(m,1H),4.86(s,2H),4.50(s,1H),4.18(q,J=7.2Hz,2H),3.92(s,3H),3.84(d,J=1 5.6Hz, 1H), 3.01 (d, J = 15.6Hz, 1H), 1.80 (d, J = 6.4Hz, 3H), 1.62 (s, 6H), 1.44 (t, J = 7.2Hz, 3H).

[0446] Example 160: (5-{[(19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 pentacosyl-1(24),2(6),4,8(9),11,13(14),15,17,21(25),22-decen-5-yl]ethynyl}pyrimidin-2-yl)methanol

[0447] The synthesis method of Example 160 is the same as that of Example 47. LC-MS (ESI) [M+H] + :551.4. 1 H NMR(400MHz, CDCl3),8.91(s,2H),7.53(d,J=1.6Hz,1H),7.40(s,1H),7.30(dd,J=9.6Hz,2.8Hz ,1H),7.17(dd,J=8.8Hz,6.0Hz,1H),7.01(td,J=8.4Hz,2.8Hz,1H),7.54(d,J=1.6Hz,1H),5.40 -5.46(m,1H),4.94(s,2H),4.88(s,2H),4.17(q,J=7.2Hz,2H),3.92(s,3H),3.84(d,J=15.6Hz, 1H), 3.46-3.62 (brs, 1H), 3.01 (d, J = 15.6Hz, 1H), 1.80 (d, J = 6.4Hz, 3H), 1.44 (t, J = 7.2Hz, 3H).

[0448] Example 161: (19R)-3-Ethyl-16-fluoro-10,19-dimethyl-5-(1,3-oxazol-2-ylethynyl)-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosyl-1(24),2(6),4,8(9),11,13(14),15,17,21(25),22-decen-22-amine

[0449] The synthesis method of Example 161 is the same as that of Example 47. LC-MS (ESI) [M+H] + :510.4. 1H NMR (400MHz, CD3OD), 8.04 (s, 1H), 7.59 (s, 1H), 7.53 (dd, J = 10.4Hz, 2.8Hz, 1H), 7.4 0-7.52(brs,1H),7.34(s,1H),7.20(dd,J=8.4Hz,5.6Hz,1H),7.07(td,J=8.4Hz,2. 8Hz,1H),6.48(s,1H),5.38-5.45(m,1H),4.08-4.23(m,2H),3.91(s,3H),3.83(d,J =15.6Hz, 1H), 2.97 (d, J = 15.6Hz, 1H), 1.79 (d, J = 6.0Hz, 3H), 1.35 (t, J = 7.2Hz, 3H).

[0450] Example 162: 3-{3-[(19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decen-5-yl]prop-2-ynyl}oxetan-3-ol

[0451] The synthesis method of Example 162 is the same as that of Example 47. LC-MS (ESI) [M+H] + :529.4. 1 H NMR(400MHz, CDCl3),7.45-7.57(brs,1H),7.42(s,1H),7.28(dd,J=10.0Hz,2.8Hz,1H) ,7.12(dd,J=8.4Hz,5.6Hz,1H),6.99(td,J=8.4Hz,2.8Hz,1H),6.49(s,1H),5.36-542(m ,1H),4.93(s,2H),4.64-4.71(m,4H),4.05-4.14(m,2H),3.89(s,3H),3.71(d,J=15.6Hz ,1H),3.08(s,2H),2.89(d,J=15.6Hz,1H),1.78(d,J=6.0Hz,3H),1.37(t,J=7.2Hz,3H).

[0452] Example 163: (19R)-3-Ethyl-16-fluoro-10,19-dimethyl-5-[(2-methylpyrazol-3-yl)ethynyl]-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2,6 .0 8,12 .0 13,18 ]pentacosyl-1(25),2(6),4,8(9),11,13(14),15,17,21(22),23-decen-22-amine

[0453] The synthesis method of Example 163 is the same as that of Example 47. LC-MS (ESI) [M+H] + :523.4. 1 H NMR(400MHz, CDCl3),7.52(d,J=1.6Hz,1H),7.49(d,J=2.0Hz,1H),7.42(s,1H),7.30(dd,J=9.6H z,2.8Hz,1H),7.15(dd,J=8.4Hz,6.0Hz,1H),7.01(td,J=8.4Hz,2.8Hz,1H),6.55(d,J=2.0Hz,1H) ,6.53(d,J=1.6Hz,1H),5.40-5.45(m,1H),4.98(s,2H),4.13-4.20(m,2H),4.05(s,3H),3.92(s, 3H), 3.81 (d, J = 15.6Hz, 1H), 2.99 (d, J = 15.6Hz, 1H), 1.80 (d, J = 6.8Hz, 3H), 1.43 (t, J = 7.2Hz, 3H).

[0454] Example 164: (19R)-5-{[1-(difluoromethyl)pyrazol-4-yl]ethynyl}-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0455] The synthesis method of Example 164 is the same as that of Example 47. LC-MS (ESI) [M+H] + :559.4. 1H NMR(400MHz,CD3OD),8.41(s,1H),7.93(s,1H),7.58(s,1H),7.53(dd,J=10.0Hz,2.4Hz ,1H),7.52(t,J=59.6Hz,1H),7.46(s,1H),7.19(dd,J=8.4Hz,5.6Hz,1H),7.07(td,J=8 .4Hz,2.4Hz,1H),6.50(s,1H),5.38-5.46(m,1H),4.04-4.20(m,2H),3.91(s,3H),3.82 (d, J=15.6Hz, 1H), 2.93 (d, J=15.6Hz, 1H), 1.80 (d, J=6.4Hz, 3H), 1.33 (t, J=7.2Hz, 3H).

[0456] Example 165: (19R)-3-ethyl-16-fluoro-10,19-dimethyl-9-vinyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0457] The synthesis method of Example 165 is the same as that of Example 47. LC-MS (ESI) [M+H] + :445.3. 1 H NMR(400MHz,CD3OD),7.57(s,1H),7.52(dd,J=10.0Hz,2.8Hz,1H),7.30-7.43(brs,1H),7 .15(dd,J=8.4Hz,5.6Hz,1H),7.04(td,J=8.4Hz,2.8Hz,1H),6.75(dd,J=18.4Hz,11.6Hz,1 H),6.56(s,1H),5.69-5.73(m,2H),5.56-5.61(m,1H),3.99-4.14(m,2H),3.90(s,3H),3. 82(d,J=15.6Hz,1H), 3.16(d,J=15.6Hz,1H), 1.84(d,J=6.4Hz,3H), 1.28(t,J=7.2Hz,3H).

[0458] Example 166: 1-{[(19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosyl-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decen-5-yl]ethynyl}cyclobutan-1-ol

[0459] The synthesis method of Example 166 is the same as that of Example 47. LC-MS (ESI) [M+H] + :513.4. 1 H NMR(400MHz,CD3OD),7.60(s,1H),7.43-7.56(m,2H),7.20(dd,J=8.4Hz,6.0Hz,1H ),7.08(td,J=8.4Hz,2.8Hz,1H),6.48(s,1H),5.38-5.44(m,1H),4.02-4.17(m,2H ),3.92(s,3H),3.79(d,J=15.6Hz,1H),2.90(d,J=15.6Hz,1H),2.52-2.58(m,2H), 2.32-2.41(m,2H),1.87-1.98(m,2H),1.81(d,J=6.4Hz,3H),1.30(t,J=7.2Hz,3H).

[0460] Example 167: 2-(4-{[(19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decen-5-yl]ethynyl}phenyl)propan-2-ol

[0461] The synthesis method of Example 167 is the same as that of Example 47. LC-MS (ESI) [M+H] + :577.3. 1H NMR(400MHz, CD3OD+CDCl3),7.40-7.55(m,7H),7.19(dd,J=8.4Hz,5.6Hz,1H),7.04(td,J=8.4Hz,2.8Hz,1H),6.52(s,1H),5.36-5.43(m,1H ),4.06-4.20(m,2H),3.91(s,3H),3.85(d,J=15.6Hz,1H),2.95(d,J=15.6Hz,1H),1.81(d,J=6.4Hz,3H),1.54(s,6H),1.36(t,J=7.2Hz,3H).

[0462] Example 168: 5-{[(19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2,6 .0 8,12 .0 13,18 1(24),2(6),4,8(9),11,13(18),14,16,21(25),22-decen-5-yl]ethynyl}pyridine-2-carbonitrile

[0463] The synthesis method of Example 168 is the same as that of Example 47. LC-MS (ESI) [M+H] + :545.3. 1 H NMR(400MHz,CD3OD),8.90(d,J=2.0Hz,1H),8.17(dd,J=8.0Hz,2.4Hz,1H),7.91(d,J=8.0Hz,1H), 7.60(s,1H),7.54(dd,J=10.0Hz,2.8Hz,1H),7.46(d,J=2.0Hz,1H),7.22(dd,J=8.4Hz,5.6Hz,1H), 7.08(td,J=8.4Hz,2.8Hz,1H),6.50(d,J=2.0Hz,1H),5.40-5.46(m,1H),4.10-4.22(m,2H),3.91(s ,3H),3.88(d,J=15.6Hz,1H),2.98(d,J=15.6Hz,1H),1.82(d,J=6.4Hz,3H),1.36(t,J=7.2Hz,3H).

[0464] Example 169: (19R)-5-{[dimethyl(oxyylidene)-λ 6-sulfylidene]amino}-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0465] Under nitrogen, a toluene solution (2 mL) of compound 45-2 (30 mg), compound 169-2 (10 mg), Pd2(dba)3 (5 mg), Xantphos (6 mg), and cesium carbonate (54 mg) was heated to 100°C and allowed to react overnight. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by flash silica gel column chromatography (dichloromethane:methanol = 30:1) to obtain Example 169. LC-MS (ESI) [M+H] + :510.5. 1 H NMR (400MHz, CDCl3), 7.58 (s, 1H), 7.48 (s, 1H), 7.27 (dd, J = 10.0Hz, 2.8Hz, 1H), 7.11 (dd,J=8.4Hz,6.0Hz,1H),6.97(td,J=8.4Hz,2.8Hz,1H),6.56(s,1H),5.38-5.44(m,1 H),4.85(s,2H),4.00(q,J=7.2Hz,2H),3.90(s,3H),3.67(d,J=15.6Hz,1H),3.43(s,3 H), 3.28 (s, 3H), 2.73 (d, J = 15.6Hz, 1H), 1.78 (d, J = 6.0Hz, 3H), 1.34 (t, J = 7.2Hz, 3H).

[0466] Example 170: (19R)-3-Ethyl-16-fluoro-10,19-dimethyl-5-(1,2,5-thiadiazol-3-ylethynyl)-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0467] The synthesis method of Example 170 is the same as that of Example 47. LC-MS (ESI) [M+H] +:527.3. 1 H NMR(400MHz, CDCl3),8.75(s,1H),7.46(s,1H),7.19-7.29(m,3H),7.09(td,J=8.0Hz,2.8Hz,1H),6.73(s,1H),5.46-5.54(m,1H),5.24-5. 42(brs,2H),4.09-4.16(m,2H),3.97(d,J=15.6Hz,1H),3.92(s,3H),3.00(d,J=15.6Hz,1H),1.87(d,J=6.4Hz,3H),1.46(t,J=6.8Hz,3H).

[0468] Example 171: 5-{[(19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decen-5-yl]ethynyl}-1,2-dihydropyridin-2-one

[0469] The synthesis method of Example 171 is the same as that of Example 47. LC-MS (ESI) [M+H] + :536.4. 1 H NMR(400MHz, CDCl3),12.50-13.42(brs,1H),7.71(d,J=2.4Hz,1H),7.61(dd,J=9.2Hz,2.4Hz,1H),7.53(d, J=1.6Hz,1H),7.40(s,1H),7.30(dd,J=9.6Hz,2.8Hz,1H),7.15(dd,J=8.4Hz,5.6Hz,1H),7.00(td,J=8.4Hz ,2.8Hz,1H),6.59(d,J=9.2Hz,1H),6.52(d,J=1.6Hz,1H),5.38-5.45(m,1H),4.91(s,2H),4.13-4.19(m,2H ), 3.92 (s, 3H), 3.78 (d, J = 15.6Hz, 1H), 2.96 (d, J = 15.6Hz, 1H), 1.79 (d, J = 6.4Hz, 3H), 1.42 (t, J = 7.2Hz, 3H).

[0470] Example 172: (19R)-5-[(3,3-difluorocyclobutyl)ethynyl]-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0471] The synthesis method of Example 172 is the same as that of Example 47. LC-MS (ESI) [M+H] + :533.4. 1 H NMR(400MHz, CDCl3),7.51(d,J=1.6Hz,1H),7.39(s,1H),7.29(dd,J=10.0Hz,2.8Hz,1H),7 .14(dd,J=8.4Hz,5.6Hz,1H),6.99(td,J=8.4Hz,2.8Hz,1H),6.49(d,J=1.6Hz,1H),5.37-5. 44(m,1H),4.85(s,2H),4.08-4.13(m,2H),3.91(s,3H),3.72(d,J=15.6Hz,1H),3.16-3.26 (m,1H),2.94-3.06(m,2H),2.76-2.92(m,3H),1.78(d,J=6.0Hz,3H),1.39(t,J=7.2Hz,3H).

[0472] Example 173: 5-{[(19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]penta-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decen-5-yl]ethynyl}-1-methyl-1,2-dihydropyridin-2-one

[0473] The synthesis method of Example 173 is the same as that of Example 47. LC-MS (ESI) [M+H] + :550.4. 1H NMR(400MHz, CDCl3),7.63(d,J=2.4Hz,1H),7.53(s,1H),7.48(dd,J=9.6Hz,2.4Hz,1H),7.40(s,1H) ,7.30(dd,J=9.6Hz,2.8Hz,1H),7.13(dd,J=8.4Hz,5.6Hz,1H),7.00(td,J=8.4Hz,2.8Hz,1H),6.57(d ,J=9.6Hz,1H),6.51(s,1H),5.38-5.44(m,1H),4.83(s,2H),4.14(q,J=7.2Hz,2H),3.92(s,3H),3.7 8(d,J=5.6Hz,1H),3.57(s,3H),2.95(d,J=15.6Hz,1H),1.79(d,J=6.4Hz,3H),1.42(t,J=7.2Hz,3H).

[0474] Example 174: (19R)-3-Ethyl-16-fluoro-10,19-dimethyl-5-[(1-methylpyrazol-3-yl)ethynyl]-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2,6 .0 8,12 .0 13,18 ]pentacosyl-1(25),2(6),4,8(9),11,13(14),15,17,21(22),23-decen-22-amine

[0475] The synthesis method of Example 174 is the same as that of Example 47. LC-MS (ESI) [M+H] + :523.4. 1 H NMR(400MHz, CDCl3),7.51(d,J=1.6Hz,1H),7.49(s,1H),7.35(d,J=2.4Hz,1H),7.28(dd,J=10.0 Hz,2.8Hz,1H),7.12(dd,J=8.4Hz,5.6Hz,1H),7.00(td,J=8.4Hz,2.8Hz,1H),6.57(d,J=1.6Hz,1H ),6.52(d,J=2.0Hz,1H),5.39-5.46(m,1H),4.97(s,2H),4.11-4.17(m,2H),3.94(s,3H),3.90(d, J=15.6Hz,1H),3.89(s,3H),2.93(d,J=15.6Hz,1H),1.79(d,J=6.4Hz,3H),1.42(t,J=7.2Hz,3H).

[0476] Example 175: (19R)-5-{[4-(difluoromethyl)phenyl]ethynyl}-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0477] The synthesis method of Example 175 is the same as that of Example 47. LC-MS (ESI) [M+H] + :569.4. 1 H NMR(400MHz, CD3OD),7.69(d,J=8.0Hz,2H),7.50-7.59(m,5H),7.20(dd,J=8.4Hz,5.6Hz,1H),7.05(t,J=7.6Hz,1H),6.80(t,J=56.0Hz,1H),6.48( s,1H),5.35-5.43(m,1H),4.03-4.23(m,2H),3.90(s,3H),3.86(d,J=15.6 Hz, 1H), 2.92 (d, J = 15.6Hz, 1H), 1.83 (d, J = 5.6Hz, 3H), 1.30-1.39 (m, 3H).

[0478] Example 176: 5-{[(19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decen-5-yl]ethynyl}pyridine-3-carbonitrile

[0479] The synthesis method of Example 176 is the same as that of Example 47. LC-MS (ESI) [M+H] + :545.4. 1H NMR(400MHz, CD3OD),8.99(d,J=1.6Hz,1H),8.88(d,J=2.0Hz,1H),8.40-8.42(m,1H),7.60(s ,1H),7.53(dd,J=10.0Hz,2.8Hz,1H),7.46(s,1H),7.21(dd,J=8.4Hz,5.6Hz,1H),7.07(td,J =8.4Hz,2.8Hz,1H),6.49(d,J=1.6Hz,1H),5.39-5.46(m,1H),4.08-4.24(m,2H),3.91(s,3H) ,3.87(d,J=15.6Hz,1H),2.97(d,J=15.6Hz,1H),1.81(d,J=6.4Hz,3H),1.35(t,J=7.2Hz,3H).

[0480] Example 177: 1-{3-[(19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 1(24),2(6),4,8(9),11,13(14),15,17,21(25),22-decen-5-yl]prop-2-ynyl}tetrahydropyrrol-2-one

[0481] The synthesis method of Example 177 is the same as that of Example 47. LC-MS (ESI) [M+H] + :540.4. 1 H NMR(400MHz, CDCl3),7.50(d,J=1.6Hz,1H),7.38(s,1H),7.28(dd,J=10.0Hz,2.8Hz,1H),7.13(dd,J= 8.4Hz,5.6Hz,1H),6.99(td,J=8.4Hz,2.8Hz,1H),6.51(d,J=1.6Hz,1H),5.37-5.44(m,1H),4.83(s,2H ),4.43(s,2H),4.08-4.14(m,2H),3.92(s,3H),3.73(d,J=15.6Hz,1H),3.61(t,J=7.2Hz,2H),2.90(d, J=15.6Hz,1H),2.40(t,J=8.0Hz,2H),2.04-2.12(m,2H),1.79(d,J=6.0Hz,3H),1.39(t,J=7.2Hz,3H).

[0482] Example 178: (19R)-3-Ethyl-16-fluoro-10,19-dimethyl-5-[(5-methyl-1,3,4-thiadiazacyclopentan-2-yl)ethynyl]-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosyl-1(24),2(6),4,8(9),11,13(14),15,17,21(25),22-decen-22-amine

[0483] The synthesis method of Example 178 is the same as that of Example 47. LC-MS (ESI) [M+H] + :541.3. 1 H NMR (400MHz, CDCl3), 7.53 (s, 1H), 7.43 (s, 1H), 7.29 (dd, J = 10.0Hz, 2.8Hz, 1H), 7.14 (dd,J=8.4Hz,5.6Hz,1H),7.01(td,J=8.4Hz,2.8Hz,1H),6.55(d,J=1.6Hz,1H),5.39 -5.46(m,1H),4.93(s,2H),4.18(q,J=7.2Hz,2H),3.91(s,3H),3.88(d,J=15.6Hz,1H ), 2.99 (d, J = 15.6Hz, 1H), 2.83 (s, 3H), 1.80 (d, J = 6.8Hz, 3H), 1.44 (t, J = 7.2Hz, 3H).

[0484] Example 179: 1-(4-{[(19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 1-(24),2(6),4,8(9),11,13(14),15,17,21(25),22-decen-5-yl]ethynyl}hexahydropyridin-1-yl)ethan-1-one

[0485] The synthesis method of Example 179 is the same as that of Example 47. LC-MS (ESI) [M+H] + :568.3. 1H NMR(400MHz, CDCl3),7.51(s,1H),7.37(s,1H),7.29(dd,J=10.0Hz,2.8Hz,1H),7.12-7.17(m, 1H),7.00(td,J=8.4Hz,2.8Hz,1H),6.49(s,1H),5.37-5.44(m,1H),4.87(s,2H),3.96-4.14(m, 3H),3.91(s,3H),3.70-3.80(m,2H),3.32-3.46(m,2H),2.96-3.03(m,1H),2.90(d,J=15.6Hz,1 H), 2.11 (s, 1.5H), 2.10 (s, 1.5H), 1.91-2.03 (m, 2H), 1.73-1.84 (m, 5H), 1.39 (t, J = 7.2Hz, 3H).

[0486] Example 180: (19R)-3-ethyl-16-fluoro-10,19-dimethyl-5-{[1-(methyldioxy- 6 -sulfanyl)hexahydropyridin-4-yl]ethynyl}-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 2,6 .0 13,18 ]pentacosyl-1(24),2(6),4,8(9),11,13(14),15,17,21(25),22-decen-22-amine

[0487] The synthesis method of Example 180 is the same as that of Example 47. LC-MS (ESI) [M+H] + :604.3. 1H NMR (400MHz, CDCl3), 7.50 (d, J = 1.6Hz, 1H), 7.37 (s, 1H), 7.29 (dd, J = 10.0Hz, 2.8Hz, 1H), 7.13 (dd, J = 8. 4Hz, 5.6Hz, 1H), 7.00 (td, J=8.4Hz, 2.8Hz, 1H), 6.49 (d, J=1.6Hz, 1H), 5.37-5.43 (m, 1H), 4.88 (s, 2H), 4 .08-4.14(m,2H),3.92(s,3H),3.71(d,J=15.6Hz,1H),3.52-3.59(m,2H),3.14-3.21(m,2H),2.89-2.98 (m,2H),2.78(s,3H),2.04-2.12(m,2H),1.88-1.98(m,2H),1.79(d,J=6.4Hz,3H),1.39(t,J=7.2Hz,3H).

[0488] Example 181: 4-{[(19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 1(24),2(6),4,8(9),11,13(14),15,17,21(25),22-decen-5-yl]ethynyl}cyclohexan-1-one

[0489] The synthesis method of Example 181 is the same as that of Example 47. LC-MS (ESI) [M+H] + :539.4. 1 H NMR (400MHz, CDCl3), 7.50 (d, J = 1.6Hz, 1H), 7.37 (s, 1H), 7.29 (dd, J = 10.0Hz, 2.4Hz, 1H), 7.14 (dd, J = 8.4Hz, 5. 1H NMR(400MHz,CD3OD),6Hz,1H),7.00(td,J=8.4Hz,2.4Hz,1H),6.49(d,J=1.6Hz ,1H),5.37-5.44(m,1H),4.85(s,2H),4.08-4.14(m,2H),3.91(s,3H),3.72(d,J =15.6Hz,1H),3.16-3.22(m,1H),2.91(d,J=15.6Hz,1H),2.67-2.75(m,2H),2.3 7-2.44(m,2H),2.12-2.23(m,4H),1.79(d,J=6.4Hz,3H),1.39(t,J=7.2Hz,3H).

[0490] Example 182: (19R)-3-Ethyl-9-ethynyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2,6 .0 8,12 .0 13,18 ]pentacosyl-1(24),2(6),4,8(9),11,13(14),15,17,21(25),22-decen-22-amine

[0491] The synthesis method of Example 182 is the same as that of Example 47. LC-MS (ESI) [M+H] + :443.4. 1 H NMR(400MHz, CD3OD),7.68(s,1H),7.24-7.61(m,2H),7.13(dd,J=8.4Hz,5.6Hz,1H),7.05(td,J=8.4Hz,5.6Hz,1H),6.50(s,1H),5.48-5.54(m, 1H),4.42(s,1H),4.00-4.15(m,2H),3.95(s,3H),3.77(d,J=15.6Hz,1H ), 3.09 (d, J = 15.6Hz, 1H), 1.82 (d, J = 6.0Hz, 3H), 1.30 (t, J = 7.2Hz, 3H).

[0492] Example 183: (19R)-3-Ethyl-16-fluoro-10,19-dimethyl-5-[(1-methyl-1,2,4-triazol-3-yl)ethynyl]-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2,6 .0 8,12 .0 13,18]pentacosyl-1(24),2(6),4,8(9),11,13(18),14,16,21(25),22-decen-22-amine

[0493] The synthesis method of Example 183 is the same as that of Example 47. LC-MS (ESI) [M+H] + :443.4. 1 H NMR(400MHz,CD3OD),8.48(s,1H),7.62(s,1H),7.53(dd,J=10.0Hz,2.8Hz,1H),7.46( d,J=2.0Hz,1H),7.20(dd,J=8.4Hz,5.6Hz,1H),7.08(td,J=8.4Hz,2.8Hz,1H),6.50(d ,J=2.0Hz,1H),5.40-5.46(m,1H),4.08-4.23(m,2H),3.98(s,3H),3.92(s,3H),3.86( d, J=15.6Hz, 1H), 2.96 (d, J=15.6Hz, 1H), 1.81 (d, J=6.4Hz, 3H), 1.35 (t, J=7.2Hz, 3H).

[0494] Example 184: (19R)-5-[(1,2-dimethylimidazol-4-yl)ethynyl]-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2,6 .0 8,12 .0 13,18 ]pentacosyl-1(24),2(6),4,8(9),11,13(18),14,16,21(25),22-decen-22-amine

[0495] The synthesis method of Example 184 is the same as that of Example 47. LC-MS (ESI) [M+H] + :537.4. 1H NMR(400MHz, CD3OD),7.62(s,1H),7.53(dd,J=10.0Hz,2.4Hz,1H),7.44(d,J=1.6Hz,1H),7.36(s 1H),7.18(dd,J=8.4Hz,5.6Hz,1H),7.08(td,J=8.4Hz,2.4Hz,1H),6.50(d,J=1.6Hz,1H),5.39-5.46(m,1H),4.04-4.20(m,2H),3. 92(s,3H),3.83(d,J=15.6Hz,1H),3.65(s,3H),2.91(d,J=15.6Hz,1H),2.38(s,3H),1.81(d,J=6.4Hz,3H),1.33(t,J=7.2Hz,3H).

[0496] Example 185: (19R)-3-Ethyl-16-fluoro-10,19-dimethyl-5-[(3-methylimidazol-4-yl)ethynyl]-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2,6 .0 8,12 .0 13,18 ]pentacosyl-1(24),2(6),4,8(9),11,13(18),14,16,21(25),22-decen-22-amine

[0497] The synthesis method of Example 185 is the same as that of Example 47. LC-MS (ESI) [M+H] + :523.4. 1 H NMR(400MHz,CD3OD),7.82(s,1H),7.60(s,1H),7.54(dd,J=10.0Hz,2.8Hz,1H),7.46(s, 1H),7.34-7.44(brs,1H),7.22(dd,J=8.4Hz,5.6Hz,1H),7.08(td,J=8.4Hz,2.8Hz,1H),6 .50(d,J=1.6Hz,1H),5.40-5.47(m,1H),4.10-4.21(m,2H),3.92(s,3H),3.85(s,3H),3.8 3(d,J=15.6Hz,1H), 2.97(d,J=15.6Hz,1H), 1.82(d,J=6.4Hz,3H), 1.35(t,J=7.2Hz,3H).

[0498] Example 186: (19R)-3-Ethyl-16-fluoro-10,19-dimethyl-5-[(1-methyl-1,2,3-triazol-4-yl)ethynyl]-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2,6 .0 8,12 .0 13,18 ]pentacosyl-1(24),2(6),4,8(9),11,13(18),14,16,21(25),22-decen-22-amine

[0499] The synthesis method of Example 186 is the same as that of Example 47. LC-MS (ESI) [M+H] + :524.3. 1 H NMR (400MHz, CD3OD), 8.26 (s, 1H), 7.61 (s, 1H), 7.53 (dd, J = 10.0Hz, 2.8Hz, 1H), 7. 45(d,J=1.6Hz,1H),7.19(dd,J=8.4Hz,5.6Hz,1H),7.07(td,J=8.4Hz,2.8Hz,1H),6 .50(d,J=1.6Hz,1H),5.39-5.45(m,1H),4.06-4.22(m,5H),3.92(s,3H),3.83(d,J =15.6Hz, 1H), 2.94 (d, J = 15.6Hz, 1H), 1.80 (d, J = 6.4Hz, 3H), 1.34 (t, J = 7.2Hz, 3H).

[0500] Example 187: 3-{[(19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2,6 .0 8,12 .0 13,18 1-Methylcyclobutan-1-ol

[0501] The synthesis method of Example 187 is the same as that of Example 47. LC-MS (ESI) [M+H] + :527.3. 1H NMR(400MHz, CDCl3),7.49(s,1H),7.41(s,1H),7.29(dd,J=10.0Hz,2.8Hz,1H),7.15(dd, J=8.4Hz,5.6Hz,1H),7.00(td,J=8.4Hz,2.8Hz,1H),6.52(s,1H),5.38-5.45(m,1H),4.97 (s,2H),4.06-4.16(m,2H),3.91(s,3H),3.75(d,J=15.6Hz,1H),2.81-2.91(m,2H),2.51- 2.56(m,2H),2.17-2.23(m,2H),1.79(d,J=6.4Hz,3H),1.39(t,J=7.2Hz,3H),3.40(s,3H).

[0502] Example 188: (19R)-3-Ethyl-16-fluoro-10,19-dimethyl-5-{[1-(oxetan-3-yl)pyrazol-4-yl]ethynyl}-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0503] The synthesis method of Example 188 is the same as that of Example 47. LC-MS (ESI) [M+H] + :527.3. 1 H NMR(400MHz, CDCl3),7.81(s,1H),7.78(s,1H),7.53(d,J=1.2Hz,1H),7.43(s,1H),7.29(dd,J =10.0Hz,2.8Hz,1H),7.14(dd,J=8.4Hz,5.6Hz,1H),6.99(td,J=8.4Hz,2.8Hz,1H),6.52(d,J=1 .2Hz,1H),5.38-5.49(m,2H),5.06(d,J=6.4Hz,4H),6.85(s,2H),4.11-4.16(m,2H),3.90(s,3H ), 3.81 (d, J = 15.6Hz, 1H), 2.94 (d, J = 15.6Hz, 1H), 1.78 (d, J = 6.0Hz, 3H), 1.41 (t, J = 7.2Hz, 3H).

[0504] Example 189: (19R)-5-{[3-(difluoromethyl)imidazol-4-yl]ethynyl}-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0505] The synthesis method of Example 189 is the same as that of Example 47. LC-MS (ESI) [M+H] + :559.3. 1 H NMR(400MHz,CD3OD),8.20(s,1H),7.71(t,J=58.8Hz,1H),7.57(s,1H),7.54(dd,J=10.0Hz, 2.8Hz,1H),7.50(s,1H),7.46(d,J=1.6Hz,1H),7.19(dd,J=8.4Hz,5.6Hz,1H),7.08(td,J=8 .4Hz,2.8Hz,1H),6.50(d,J=1.6Hz,1H),5.40-5.46(m,1H),4.08-4.23(m,2H),3.91(s,3H), 3.82(d,J=15.6Hz,1H), 2.96(d,J=15.6Hz,1H), 1.81(d,J=6.4Hz,3H), 1.35(t,J=7.2Hz,3H).

[0506] Example 190: (19R)-5-{[1-(difluoromethyl)imidazol-4-yl]ethynyl}-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0507] The synthesis method of Example 190 is the same as that of Example 47. LC-MS (ESI) [M+H] + :559.3. 1H NMR(400MHz,CD3OD),8.20(s,1H),7.90(d,J=1.6Hz,1H),7.62(s,1H),7.60(t,J=60.0Hz,1H ),7.53(dd,J=10.4Hz,2.8Hz,1H),7.49(s,1H),7.20(dd,J=8.4Hz,5.6Hz,1H),7.08(td,J=8 .4Hz,2.8Hz,1H),6.52(d,J=1.6Hz,1H),5.40-5.46(m,1H),4.05-4.20(m,2H),3.92(s,3H), 3.84(d,J=15.6Hz,1H), 2.93(d,J=15.6Hz,1H), 1.81(d,J=6.4Hz,3H), 1.33(t,J=7.2Hz,3H).

[0508] Example 191: (19R)-5-[(1-cyclopropylpyrazol-4-yl)ethynyl]-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0509] The synthesis method of Example 191 is the same as that of Example 47. LC-MS (ESI) [M+H] + :549.3. 1 H NMR(400MHz, CDCl3+CD3OD),7.88(s,1H),7.52-7.82(brs,2H),7.51(s,1H),7.44(dd,J=10 .0Hz, 2.8Hz, 1H), 7.17 (dd, J=8.4Hz, 5.6Hz, 1H), 7.04 (td, J=8.4Hz, 2.8Hz, 1H), 6.53 (s, 1H) ,5.36-5.42(m,1H),4.05-4.16(m,2H),3.91(s,3H),3.79(d,J=15.6Hz,1H),3.62-3.67(m,1 H), 2.91 (d, J = 15.6Hz, 1H), 1.81 (d, J = 6.4Hz, 3H), 1.35 (t, J = 7.2Hz, 3H), 1.03-1.14 (m, 4H).

[0510] Example 192: (5-{[(19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 pentacyl-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decen-5-yl]ethynyl}pyridin-2-yl)methanol

[0511] The synthesis method of Example 192 is the same as that of Example 47. LC-MS (ESI) [M+H] + :550.4. 1 H NMR(400MHz,CD3OD),8.69(d,J=2.0Hz,1H),8.04(dd,J=8.0Hz,2.0Hz,1H),7.61-7.63(m,2H),7.5 4(dd,J=10.0Hz,2.8Hz,1H),7.46(d,J=2.0Hz,1H),7.23(dd,J=8.4Hz,6.0Hz,1H),7.08(td,J=8.4 Hz,2.8Hz,1H),6.50(d,J=2.0Hz,1H),5.40-5.46(m,1H),4.73(s,2H),4.08-4.23(m,2H),3.92(s, 3H), 3.87 (d, J = 15.6Hz, 1H), 2.97 (d, J = 15.6Hz, 1H), 1.82 (d, J = 6.4Hz, 3H), 1.35 (t, J = 7.2Hz, 3H).

[0512] Example 193: N-{4-[(19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decen-5-yl]-2-methylbut-3-yn-2-yl}methanesulfonamide

[0513] The synthesis method of Example 193 is the same as that of Example 47. LC-MS (ESI) [M+H] + :578.4. 1H NMR(400MHz,CD3OD),7.72(s,1H),7.52(dd,J=10.4Hz,2.8Hz,1H),7.44(s,1H),7.19 (dd,J=8.4Hz,5.6Hz,1H),7.07(td,J=8.4Hz,2.8Hz,1H),6.49(s,1H),5.39-5.45(m, 1H),4.02-4.18(m,2H),3.92(s,3H),3.77(d,J=15.6Hz,1H),3.17(s,3H),2.89(d,J= 15.6Hz, 1H), 1.81 (d, J = 6.4Hz, 3H), 1.75 (s, 3H), 1.72 (s, 3H), 1.31 (t, J = 7.2Hz, 3H).

[0514] Example 194: (19R)-3-Ethyl-16-fluoro-10,19-dimethyl-5-{[3-(oxetan-3-yl)imidazol-4-yl]ethynyl}-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0515] The synthesis method of Example 194 is the same as that of Example 47. LC-MS (ESI) [M+H] + :565.4. 1 H NMR(400MHz, CDCl3),7.64(s,1H),7.56(d,J=1.2Hz,1H),7.53(d,J=1.2Hz,1H),7.50(s,1H),7.28(dd, J=10.0Hz, 2.8Hz, 1H), 7.12 (dd, J=8.4Hz, 5.6Hz, 1H), 6.99 (td, J=8.4Hz, 2.8Hz, 1H), 6.56 (d, J=1.6Hz, 1H),5.40-5.45(m,1H),5.25-5.33(m,1H),5.11-5.15(m,2H),4.78-4.87(m,4H),4.12-4.17(m,2H),3. 90(d,J=15.6Hz,1H),3.89(s,3H),2.94(d,J=15.6Hz,1H),1.79(d,J=6.0Hz,3H),1.42(t,J=7.2Hz,3H).

[0516] Example 195: (19R)-5-[dimethyl(oxyylidene)-λ 5 -methylphosphino]-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0517] The synthesis method of Example 195 is the same as that of Example 169. LC-MS (ESI) [M+H] + :495.3. 1 H NMR(400MHz, CDCl3),7.86(s,1H),7.48(s,1H),7.26(dd,J=10.0Hz,2.8Hz,1H),7.10( dd,J=8.4Hz,5.6Hz,1H),6.96(td,J=8.4Hz,2.8Hz,1H),6.60(d,J=1.6Hz,1H),5.44-5. 50(m,1H),4.84(s,2H),4.06-4.17(m,3H),3.88(s,3H),2.98(d,J=15.6Hz,1H),1.97( d, J=13.6Hz, 3H), 1.79 (d, J=6.4Hz, 3H), 1.76 (d, J=13.6Hz, 3H), 1.37 (t, J=7.2Hz, 3H).

[0518] Example 196: (19R)-3-Ethyl-16-fluoro-10,19-dimethyl-5-[(4-methyl-3,4,5,6-tetrahydro-2H-pyran-4-yl)ethynyl]-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosyl-1(24),2(6),4,8(9),11,13(14),15,17,21(25),22-decen-22-amine

[0519] The synthesis method of Example 196 is the same as that of Example 47. LC-MS (ESI) [M+H] + :541.4. 1H NMR(400MHz, CDCl3),7.50(d,J=1.6Hz,1H),7.40(s,1H),7.29(dd,J=10.0Hz,2.8Hz,1H),7. 16(dd,J=8.4Hz,5.6Hz,1H),7.00(td,J=8.4Hz,2.8Hz,1H),6.50(d,J=1.6Hz,1H),5.39-5.44 (m,1H),4.85(s,2H),4.07-4.16(m,2H),3.84-3.93(m,7H),3.73(d,J=15.6Hz,1H),2.92(d, J=15.6Hz,1H),1.80(d,J=6.4Hz,3H),1.58-1.70(m,4H),1.43(s,3H),1.39(t,J=7.2Hz,3H).

[0520] Example 197: 4-{[(19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 1(24),2(6),4,8(9),11,13(14),15,17,21(25),22-decen-5-yl]ethynyl}tetrahydropyran-4-carbonitrile

[0521] The synthesis method of Example 197 is the same as that of Example 47. LC-MS (ESI) [M+H] + :552.4. 1 H NMR(400MHz, CDCl3),7.52(s,1H),7.38(s,1H),7.29(dd,J=10.0Hz,2.8Hz,1H),7.15(dd ,J=8.4Hz,6.0Hz,1H),7.00(td,J=8.4Hz,2.8Hz,1H),6.50(d,J=1.2Hz,1H),5.38-5.45(m ,1H),4.76-4.96(brs,2H),4.11-4.16(m,2H),3.81-4.00(m,7H),3.71(d,J=15.6Hz,1H) ,2.95(d,J=15.6Hz,1H),2.15-2.31(m,4H),1.79(d,J=6.4Hz,3H),1.40(t,J=7.2Hz,3H).

[0522] Example 198: (19R)-3-Ethyl-16-fluoro-5-{[1-(2-methoxyethyl)imidazol-4-yl]ethynyl}-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2,6 .0 8,12 .0 13,18 ]pentacosyl-1(25),2(6),4,8(9),11,13(14),15,17,21(22),23-decen-22-amine

[0523] The synthesis method of Example 198 is the same as that of Example 47. LC-MS (ESI) [M+H] + :567.4. 1 H NMR (400 MH 1 H NMR(400MHz,CD3OD),7.50-7.55(m,2H),7.46(s,1H),7.30(s,1H),7.27(dd,J=10.0Hz,2 .8Hz,1H),7.13(dd,J=8.4Hz,6.0Hz,1H),7.01(td,J=8.4Hz,2.8Hz,1H),6.61(s,1H),5. 30-5.47(m,3H),4.04-4.15(m,4H),3.92(d,J=15.6Hz,1H),3.89(s,3H),3.64(t,J=4.8H z, 2H), 3.36 (s, 3H), 2.92 (d, J = 15.6Hz, 1H), 1.80 (d, J = 6.4Hz, 3H), 1.42 (t, J = 7.2Hz, 3H).

[0524] Example 199: (19R)-3-Ethyl-16-fluoro-5-{[1-(2-methoxyethyl)pyrazol-4-yl]ethynyl}-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2,6 .0 8,12 .0 13,18 ]pentacosyl-1(25),2(6),4,8(9),11,13(14),15,17,21(22),23-decen-22-amine

[0525] The synthesis method of Example 199 is the same as that of Example 47. LC-MS (ESI) [M+H] + :567.4. 1H NMR(400MHz, CDCl3),7.33-7.80(m,4H),7.28(dd,J=10.0Hz,2.8Hz,1H),7.15(dd,J=8.4Hz,5 .6Hz,1H),7.01(td,J=8.4Hz,2.8Hz,1H),6.56(s,1H),5.38-5.45((m,1H),4.76-5.32(brs,2 H),4.30(t,J=5.2Hz,2H),4.09-4.14(m,2H),3.91(s,3H),3.83(d,J=15.6Hz,1H),3.75(t,J= 5.2Hz, 2H), 3.35 (s, 3H), 2.93 (d, J = 15.6Hz, 1H), 1.80 (d, J = 6.4Hz, 3H), 1.40 (t, J = 7.2Hz, 3H).

[0526] Example 200: (6-{[(19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 pentacyl-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decen-5-yl]ethynyl}pyridin-2-yl)methanol

[0527] The synthesis method of Example 200 is the same as that of Example 47. LC-MS (ESI) [M+H] + :550.4. 1 H NMR(400MHz,CD3OD),7.89(t,J=8.0Hz,1H),7.65(s,1H),7.58(d,J=8.0Hz,2H),7.54(dd,J =10.0Hz,2.8Hz,1H),7.34-7.53(brs,1H),7.21(dd,J=8.8Hz,6.0Hz,1H),7.08(td,J=8.4Hz ,2.8Hz,1H),6.51(s,1H),5.40-5.46(m,1H),4.71(s,2H),4.08-4.23(m,2H),3.93(d,J=15 .6Hz, 1H), 3.91 (s, 3H), 2.95 (d, J = 15.6Hz, 1H), 1.81 (d, = 6.4Hz, 3H), 1.35 (t, J = 7.2Hz, 3H).

[0528] Example 201: 2-(6-{[(19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2,6 .0 8,12 .0 13,18 1(24),2(6),4,8(9),11,13(18),14,16,21(25),22-decen-5-yl]ethynyl}pyridin-3-yl)propan-2-ol

[0529] The synthesis method of Example 201 is the same as that of Example 47. LC-MS (ESI) [M+H] + :578.4. 1 H NMR(400MHz, CDCl3),8.76(d,J=2.0Hz,1H),7.84(dd,J=8.0Hz,2.0Hz,1H),7.58(d,J=8.0Hz,1H), 7.48-7.52(m,2H),7.28(dd,J=10.0Hz,2.8Hz,1H),7.13(dd,J=8.4Hz,5.6Hz,1H),7.00(td,J=8.4 Hz,2.8Hz,1H),6.57(d,J=1.6Hz,1H),5.39-5.45(m,1H),4.11-4.20(m,2H),3.94(d,J=15.6Hz,1H ), 3.88 (s, 3H), 2.96 (d, J = 15.6Hz, 1H), 1.79 (d, J = 6.4Hz, 3H), 1.62 (s, 6H), 1.43 (t, J = 7.2Hz, 3H).

[0530] Example 202: (6-{[(19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2,6 .0 8,12 .0 13,18 1(24),2(6),4,8(9),11,13(18),14,16,21(25),22-decen-5-yl]ethynyl}pyridin-3-yl)methanol

[0531] The synthesis method of Example 202 is the same as that of Example 47. LC-MS (ESI) [M+H] + :550.4. 1H NMR (400MHz, CD3OD), 8.62 (s, 1H), 7.96-7.99 (m, 1H), 7.78 (dd, J = 7.6Hz, 3.2Hz, 1H), 7.67 ( s,1H),7.56(dd,J=10.0Hz,2.8Hz,1H),7.50(s,1H),7.27-7.31(m,1H),7.16(td,J=8.4Hz, 2.8Hz,1H),6.80(s,1H),5.56-5.63(m,1H),4.72(s,2H),4.13-4.23(m,2H),4.01(d,J=15. 6Hz, 1H), 3.91 (s, 3H), 3.01 (d, J = 15.6Hz, 1H), 1.88 (d, J = 6.4Hz, 3H), 1.37 (t, J = 7.2Hz, 3H).

[0532] Example 203: 2-(6-{[(19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decen-5-yl]ethynyl}pyridin-2-yl)propan-2-ol

[0533] The synthesis method of Example 203 is the same as that of Example 47. LC-MS (ESI) [M+H] + :578.4. 1 H NMR(400MHz,CD3OD),7.33-7.91(m,6H),7.20-7.24(m,1H),7.06-7.10(m,1H),6.53(s,1H),5.38-5.50(m,1H),4. 05-4.26(m,2H),3.78-3.99(m,4H),2.96(d,J=14.8Hz,1H),1.82(d,J=6.0Hz,3H),1.56(s,6H),1.30-1.39(m,3H).

[0534] Example 204: (19R)-5-[(1-cyclopropylimidazol-4-yl)ethynyl]-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0535] The synthesis method of Example 204 is the same as that of Example 47. LC-MS (ESI) [M+H] + :549.4. 1 H NMR(400MHz, CD3OD),7.78(s,1H),7.61(s,1H),7.55(s,1H),7.53(dd,J=10.0Hz,2.8Hz,1H),7.44(d,J=1.6Hz,1H),7.19(dd 1 H NMR(400MHz, CDCl3),,J=8.4Hz,5.6Hz,1H),7.07(td,J=8.4Hz,2.8Hz,1H),6.50(d,J=1.6Hz,1H),5.40-5.46(m,1H),4.05-4.20(m,2H),3. 92(s,3H),3.83(d,J=15.6Hz,1H),3.50-3.56(m,1H),2.92(d,J=15.6Hz,1H),1.81(d,J=6.4Hz,3H),1.33(t,J=7.2Hz,3H),04-1.08(m,4H).

[0536] Example 205: (19R)-5-[(1-cyclopropylimidazol-5-yl)ethynyl]-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0537] The synthesis method of Example 205 is the same as that of Example 47. LC-MS (ESI) [M+H] + :549.4. 1H NMR(400MHz, CD3OD),7.77(s,1H),7.60(s,1H),7.54(dd,J=10.0Hz,2.8Hz,1H),7.46(d,J=1.6H z,1H),7.32(s,1H),7.20(dd,J=8.4Hz,5.6Hz,1H),7.07(td,J=8.4Hz,2.8Hz,1H),6.49(d,J=1. 6Hz,1H),5.40-5.46(m,1H),4.08-4.23(m,2H),3.91(s,3H),3.86(d,J=15.6Hz,1H),3.48-3.54 (m,1H),2.97(d,J=15.6Hz,1H),1.81(d,J=6.4Hz,3H),1.35(t,J=7.2Hz,3H),1.12-1.13(m,4H).

[0538] Example 206: (19R)-9-{[dimethyl(oxyylidene)-λ 6 -sulfylidene]amino}-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosyl-1(24),2(6),4,8(9),11,13(14),15,17,21(25),22-decen-22-amine

[0539] The synthesis method of Example 206 is the same as that of Example 169. LC-MS (ESI) [M+H] + :510.3. 1 H NMR(400MHz, CDCl3),7.69(s,1H),7.39(s,1H),7.25(dd,J=10.0Hz,2.8Hz,1H),7.13( dd,J=8.4Hz,5.6Hz,1H),7.00(td,J=8.4Hz,2.8Hz,1H),6.84(s,1H),5.66-5.98(brs,2 H),5.56-5.63(m,1H),4.07-4.20(m,2H),3.80(s,3H),3.71(d,J=15.6Hz,1H),3.27(s, 3H), 3.03 (d, J = 15.6Hz, 1H), 2.58 (s, 3H), 1.84 (d, J = 6.4Hz, 3H), 1.37 (t, J = 7.2Hz, 3H).

[0540] Example 207: (19R)-3-Ethyl-16-fluoro-10,19-dimethyl-5-{[1-(2,2,2-trifluoroethyl)imidazol-4-yl]ethynyl}-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2,6 .0 8,12 .0 13,18 ]pentacosyl-1(24),2(6),4,8(9),11,13(18),14,16,21(25),22-decen-22-amine

[0541] The synthesis method of Example 207 is the same as that of Example 47. LC-MS (ESI) [M+H] + :591.4. 1 H NMR (400MHz, CD3OD), 7.85 (s, 1H), 7.63 (s, 2H), 7.53 (dd, J = 10.0Hz, 2.8Hz, 1H), 7.4 5(s,1H),7.20(dd,J=8.4Hz,5.6Hz,1H),7.07(td,J=8.4Hz,2.8Hz,1H),6.50(s,1H) ,5.40-5.46(m,1H),4.95(q,J=8.8Hz,2H),4.05-4.21(m,2H),3.92(s,3H),3.85(d, J=15.6Hz, 1H), 2.93 (d, J=15.6Hz, 1H), 1.81 (d, J=6.4Hz, 3H), 1.34 (t, J=7.2Hz, 3H).

[0542] Example 208: (19R)-3-Ethyl-16-fluoro-10,19-dimethyl-5-{[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]ethynyl}-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2,6 .0 8,12 .0 13,18 ]pentacosyl-1(24),2(6),4,8(9),11,13(18),14,16,21(25),22-decen-22-amine

[0543] The synthesis method of Example 208 is the same as that of Example 47. LC-MS (ESI) [M+H] + :591.4. 1H NMR(400MHz,CD3OD),8.11(s,1H),7.81(s,1H),7.58(s,1H),7.53(dd,J=10.0Hz,2.8Hz ,1H),7.45(s,1H),7.21(dd,J=8.4Hz,5.6Hz,1H),7.07(td,J=8.4Hz,2.8Hz,1H),6.49( s,1H),5.39-5.46(m,1H),4.99(q,J=8.8Hz,2H),4.05-4.20(m,2H),3.92(s,3H),3.82( d, J=15.6Hz, 1H), 2.93 (d, J=15.6Hz, 1H), 1.81 (d, J=6.4Hz, 3H), 1.33 (t, J=7.2Hz, 3H).

[0544] Example 209: (19R)-3-Ethyl-16-fluoro-10,19-dimethyl-5-{[3-(oxetan-3-yl)imidazol-5-yl]ethynyl}-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0545] The synthesis method of Example 209 is the same as that of Example 47. LC-MS (ESI) [M+H] + :591.4. 1 H NMR(400MHz, CDCl3),7.88(s,1H),7.53(d,J=1.6Hz,1H),7.45(s,1H),7.42(s,1H),7.29(dd,J=9 .6Hz, 2.8Hz, 1H), 7.13 (dd, J=8.4Hz, 5.6Hz, 1H), 7.00 (td, J=8.4Hz, 2.8Hz, 1H), 6.51 (s, 1H), 5.56 -5.63(m,1H),5.38-5.45(m,1H),5.04-5.16(m,4H),4.84(s,2H),4.16(q,J=7.2Hz,2H),3.91(s, 3H), 3.79 (d, J = 15.6Hz, 1H), 2.97 (d, J = 15.6Hz, 1H), 1.79 (d, J = 6.4Hz, 3H), 1.43 (t, J = 7.2Hz, 3H).

[0546] Example 210: 4-{[(19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]penta-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decen-5-yl]nitrogenylidene-4λ 6 -1,4-oxathiolan-4-one

[0547] The synthesis method of Example 210 is the same as that of Example 169. LC-MS (ESI) [M+H] + :552.3. 1 H NMR(400MHz, CDCl3),7.59(s,1H),7.49(d,J=1.6Hz,1H),7.28(dd,J=10.0Hz,2.8Hz,1H),7.11(d d,J=8.4Hz,6.0Hz,1H),6.97(td,J=8.4Hz,2.8Hz,1H),6.54(d,J=1.6Hz,1H),5.36-5.43(m,1H),4 .80(s,2H),4.18-4.31(m,3H),3.95-4.12(m,4H),3.89(s,3H),3.68(d,J=15.6Hz,1H),3.44-3.5 7(m,2H),3.26-3.33(m,1H),2.74(d,J=15.6Hz,1H),1.78(d,J=6.4Hz,3H),1.31(t,J=7.2Hz,3H).

[0548] Example 211: 1-{[(19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]penta-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decen-5-yl]nitropropene}tetrahydro-1λ 6 -Thiophen-1-one

[0549] The synthesis method of Example 211 is the same as that of Example 169. LC-MS (ESI) [M+H] + :536.4. 1H NMR(400MHz, CDCl3),7.57(s,1H),7.49(s,1H),7.27(dd,J=9.6Hz,2.4Hz,1H),7.10(dd,J=8.4 Hz,5.6Hz,1H),6.96(td,J=8.4Hz,2.8Hz,1H),6.55(d,J=1.2Hz,1H),5.37-5.42(m,1H),4.79( s,2H),3.99(q,J=7.2Hz,2H),3.89(s,3H),3.79-3.86(m,1H),3.59-3.68(m,2H),3.16-3.30(m ,2H),2.72(d,J=15.2Hz,1H),2.22-2.42(m,4H),1.77(d,J=6.4Hz,3H),1.33(t,J=7.2Hz,3H).

[0550] Example 212: (19R)-3-Ethyl-16-fluoro-5-[(4-fluoro-3,4,5,6-tetrahydro-2H-pyran-4-yl)ethynyl]-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosyl-1(24),2(6),4,8(9),11,13(14),15,17,21(25),22-decen-22-amine

[0551] The synthesis method of Example 212 is the same as that of Example 47. LC-MS (ESI) [M+H] + :545.4. 1 H NMR(400MHz, CDCl3),7.51(s,1H),7.38(s,1H),7.29(dd,J=10.0Hz,2.8Hz,1H),7.15( dd,J=8.4Hz,5.6Hz,1H),7.01(td,J=8.4Hz,2.8Hz,1H),6.51(s,1H),5.37-5.45(m,1H) ,4.80-4.98(brs,2H),4.10-4.16(m,2H),3.81-4.01(m,7H),3.71(d,J=15.2Hz,1H),2 .95(d,J=15.2Hz,1H),2.13-2.33(m,4H),1.80(d,J=6.4Hz,3H),1.40(t,J=7.2Hz,3H).

[0552] Example 213: 1-(4-{[(19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2,6 .0 8,12 .0 13,18 1(24),2(6),4,8(9),11,13(18),14,16,21(25),22-decen-5-yl]ethynyl}pyrazol-1-yl)-2-methylpropan-2-ol

[0553] The synthesis method of Example 213 is the same as that of Example 47. LC-MS (ESI) [M+H] + :581.4. 1 H NMR(400MHz,CD3OD),7.96(s,1H),7.72(s,1H),7.58(s,1H),7.54(dd,J=10.0Hz,2.8Hz,1 H),7.44(d,J=1.6Hz,1H),7.21(dd,J=8.4Hz,6.0Hz,1H),7.08(td,J=8.4Hz,2.8Hz,1H),6 .50(d,J=1.6Hz,1H),5.39-5.45(m,1H),4.05-4.20(m,4H),3.92(s,3H),3.81(d,J=16.0H z, 1H), 2.92 (d, J = 16.0Hz, 1H), 1.81 (d, J = 6.4Hz, 3H), 1.34 (t, J = 7.2Hz, 3H), 1.18 (s, 6H).

[0554] Example 214: 1-(4-{[(19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2,6 .0 8,12 .0 13,18 1(24),2(6),4,8(9),11,13(18),14,16,21(25),22-decen-5-yl]ethynyl}imidazol-1-yl)-2-methylpropan-2-ol

[0555] The synthesis method of Example 214 is the same as that of Example 47. LC-MS (ESI) [M+H] + :581.4. 1H NMR(400MHz, CD3OD),7.69(d,J=1.2Hz,1H),7.63(s,1H),7.54(dd,J=10.0Hz,2.8Hz,1H),7.51(d ,J=1.2Hz,1H),7.45(d,J=1.6Hz,1H),7.20(dd,J=8.4Hz,6.0Hz,1H),7.08(td,J=8.4Hz,2.8Hz,1H ),6.51(d,J=1.6Hz,1H),5.40-5.46(m,1H),4.05-4.20(m,2H),3.99(s,2H),3.92(s,3H),3.85(d, J=15.6Hz, 1H), 2.92 (d, J=15.6Hz, 1H), 1.81 (d, J=6.4Hz, 3H), 1.33 (t, J=7.2Hz, 3H), 1.19 (s, 6H).

[0556] Example 215: (19R)-3-Ethyl-16-fluoro-10,19-dimethyl-5-{[1-(2,2,2-trifluoroethyl)imidazol-5-yl]ethynyl}-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2,6 .0 8,12 .0 13,18 ]pentacosyl-1(24),2(6),4,8(9),11,13(18),14,16,21(25),22-decen-22-amine

[0557] The synthesis method of Example 215 is the same as that of Example 47. LC-MS (ESI) [M+H] + :591.4. 1 H NMR (400MHz, CD3OD), 7.96 (s, 1H), 7.57 (s, 1H), 7.54 (dd, J = 10.0Hz, 2.8Hz, 1H), 7.46 (s,2H),7.19(dd,J=8.4Hz,6.0Hz,1H),7.09(td,J=8.4Hz,2.8Hz,1H),6.49(d,J=1.2H z,1H),5.39-5.45(m,1H),5.01-5.09(m,2H),4.09-4.24(m,2H),3.91(s,3H),3.81(d ,J=16.0Hz,1H),2.96(d,J=16.0Hz,1H),1.81(d,J=6.4Hz,3H),1.36(t,J=7.2Hz,3H).

[0558] Example 216: 1-({[(19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]penta-1(24),2(6),4,8(9),11,13(14),15,17,21(25),22-decen-5-yl]ethynyl}nitrogenylidene)-1λ 6 -Thiacyclohexan-1-one

[0559] The synthesis method of Example 216 is the same as that of Example 169. LC-MS (ESI) [M+H] + :574.4. 1 H NMR(400MHz, CDCl3),7.51(s,1H),7.38(s,1H),7.29(dd,J=10.0Hz,2.8Hz,1H),7.15(dd,J =8.4Hz,5.6Hz,1H),7.01(td,J=8.4Hz,2.8Hz,1H),6.51(s,1H),5.37-5.44(m,1H),4.78-5. 01(brs,2H),4.10-4.17(m,2H),3.81-4.01(m,7H),3.71(d,J=15.6Hz,1H),2.95(d,J=15.6 Hz, 1H), 2.14-2.32 (m, 4H), 1.80 (d, J = 6.0Hz, 3H), 1.50-1.67 (m, 2H), 1.40 (t, J = 7.2Hz, 3H).

[0560] Example 217: (19R)-5-[(6-aminopyridin-3-yl)ethynyl]-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosyl-1(24),2(6),4,8(9),11,13(14),15,17,21(25),22-decen-22-amine

[0561] The synthesis method of Example 217 is the same as that of Example 47. LC-MS (ESI) [M+H] + :534.4. 1H NMR(400MHz, CDCl3),8.33(d,J=1.6Hz,1H),7.62(dd,J=8.4Hz,2.0Hz,1H),7.52(s,1H),7.46(s,1H),7 .29(dd,J=10.0Hz,2.4Hz,1H),7.16(dd,J=8.4Hz,6.0Hz,1H),7.00(td,J=8.4Hz,2.4Hz,1H),6.55(s,1 H),6.50(d,J=8.4Hz,1H),5.39-5.46(m,1H),4.96(s,2H),4.56-4.84(brs,2H),4.10-4.17(m,2H),3.9 0 (s, 3H), 3.84 (d, J = 15.6Hz, 1H), 2.95 (d, J = 15.6Hz, 1H), 1.80 (d, J = 6.4Hz, 3H), 1.42 (t, J = 7.2Hz, 3H).

[0562] Example 218: (19R)-3-Ethyl-16-fluoro-10,19-dimethyl-5-[(5-methyl-1,3,4-oxadiazol-2-yl)ethynyl]-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0563] The synthesis method of Example 218 is the same as that of Example 47. LC-MS (ESI) [M+H] + :525.4. 1 H NMR(400MHz, CDCl3),7.51(s,1H),7.40(s,1H),7.29(dd,J=10.0Hz,2.8Hz,1H),7.14( dd,J=8.4Hz,5.6Hz,1H),7.02(td,J=8.4Hz,2.8Hz,1H),6.56(d,J=1.2Hz,1H),5.40-5. 46(m,1H),5.09-5.27(brs,2H),4.17(q,J=6.8Hz,2H),3.91(s,3H),3.85(d,J=15.6Hz, 1H), 2.99 (d, J = 15.6Hz, 1H), 2.61 (s, 3H), 1.80 (d, J = 6.4Hz, 3H), 1.44 (t, J = 7.2Hz, 3H).

[0564] Example 219: (19R)-3-Ethyl-16-fluoro-10,19-dimethyl-5-(3-methylbut-1-ynyl)-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2,6 .0 8,12 .0 13,18 ]pentacosyl-1(24),2(6),4,8(9),11,13(18),14,16,21(25),22-decen-22-amine

[0565] The synthesis method of Example 219 is the same as that of Example 47. LC-MS (ESI) [M+H] + :485.4. 1 H NMR(400MHz, CD3OD),7.51-7.54(m,2H),7.43(s,1H),7.20(dd,J=8.4Hz,5.6Hz,1H),7.08(td,J=8.4Hz,2.8Hz,1H),6.48(d,J=1.6Hz,1H),5.38-5.45(m ,1H),4.01-4.13(m,2H),3.92(s,3H),3.74(d,J=15.6Hz,1H),2.85-2.93(m, 2H), 1.81 (d, J = 6.4Hz, 3H), 1.34 (s, 3H), 1.33 (s, 3H), 1.30 (t, J = 7.2Hz, 3H).

[0566] Example 220: (19R)-5-[(2-aminopyridin-4-yl)ethynyl]-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosyl-1(24),2(6),4,8(9),11,13(14),15,17,21(25),22-decen-22-amine

[0567] The synthesis method of Example 220 is the same as that of Example 47. LC-MS (ESI) [M+H] + :535.4. 1H NMR(400MHz, CDCl3),7.93(d,J=5.6Hz,1H),7.52(d,J=1.6Hz,1H),7.38(s,1H ),7.30(dd,J=10.0Hz,2.4Hz,1H),7.16(dd,J=8.4Hz,5.6Hz,1H),7.02(td,J=8 .4Hz,2.8Hz,1H),6.82-6.84(m,2H),6.53(d,J=1.6Hz,1H),5.51-5.96(brs,2 H),5.39-5.45(m,1H),5.05(s,2H),4.12-4.20(m,2H),3.92(s,3H),3.82(d,J= 1 H NMR (400MHz, CD3OD), 15.9Hz, 1H), 2.99 (d, J = 15.6Hz, 1H), 1.80 (d, J = 6.4Hz, 3H), 1.43 (t, J = 7.2Hz, 3H).

[0568] Example 221: (19R)-5-[(2-amino-1,3-thiazol-5-yl)ethynyl]-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosyl-1(24),2(6),4,8(9),11,13(14),15,17,21(25),22-decen-22-amine

[0569] The synthesis method of Example 221 is the same as that of Example 47. LC-MS (ESI) [M+H] + :541.4. 1 H NMR(400MHz, CDCl3),7.50(d,J=1.6Hz,1H),7.42(s,1H),7.35(s,1H),7.29(dd,J=10.0Hz ,2.8Hz,1H),7.15(dd,J=8.4Hz,6.0Hz,1H),7.00(td,J=8.4Hz,2.8Hz,1H),6.54(d,J=1.6 Hz,1H),5.39-5.46(m,1H),5.15-(s,2H),5.04(s,2H),4.10-4.16(m,2H),3.92(s,3H),3. 80(d,J=15.6Hz,1H), 2.94(d,J=15.6Hz,1H), 1.80(d,J=6.4Hz,3H), 1.41(t,J=7.2Hz,3H).

[0570] Example 222: (19R)-5-[(1E)-3-ethoxyprop-1-enyl]-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosyl-1(24),2(6),4,8(9),11,13(14),15,17,21(25),22-decen-22-amine

[0571] The synthesis method of Example 222 is the same as that of Example 47. LC-MS (ESI) [M+H] + :503.4. 1 H NMR(400MHz, CDCl3),7.47(s,1H),7.27-7.30(m,2H),7.14(dd,J=8.4Hz,6.0Hz,1H),7.01(td,J=8.4Hz, 2.8Hz,1H),6.76(d,J=16.4Hz,1H),6.60(dt,J=16.4Hz,6.0Hz,1H),6.54(s,1H),5.37-5.42(m,1H),5.15 (s,2H),4.21(dd,J=6.0Hz,1.2Hz,2H),4.05-4.15(m,2H),3.90(s,3H),3.69(d,J=16.0Hz,1H),3.60(q,J =7.2Hz, 2H), 2.93 (d, J = 16.0Hz, 1H), 1.79 (d, J = 6.4Hz, 3H), 1.38 (t, J = 7.2Hz, 3H), 1.27 (t, J = 7.2Hz, 3H).

[0572] Example 223: (19R)-5-[(6-aminopyridin-2-yl)ethynyl]-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2,6 .0 8,12 .0 13,18 ]pentacosyl-1(24),2(6),4,8(9),11,13(18),14,16,21(25),22-decen-22-amine

[0573] The synthesis method of Example 223 is the same as that of Example 47. LC-MS (ESI) [M+H] + :535.4. 1H NMR(400MHz,CD3OD),7.64(s,1H),7.54(dd,J=10.0Hz,2.8Hz,1H),7.48(dd,J=8.8Hz,6.8Hz,1H), 7.45(d,J=1.6Hz,1H),7.22(dd,J=8.4Hz,6.0Hz,1H),7.08(td,J=8.4Hz,2.8Hz,1H),6.91(d,J=7.2 Hz,1H),6.60(d,J=8.4Hz,1H),6.51(d,J=1.6Hz,1H),5.40-5.46(m,1H),4.06-4.22(m,2H),3.92(s ,3H),3.91(d,J=15.6Hz,1H),2.94(d,J=15.6Hz,1H),1.82(d,J=6.4Hz,3H),1.34(t,J=7.2Hz,3H).

[0574] Example 224: (19R)-5-[(2-aminopyridin-3-yl)ethynyl]-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2,6 .0 8,12 .0 13,18 ]pentacosyl-1(24),2(6),4,8(9),11,13(18),14,16,21(25),22-decen-22-amine

[0575] The synthesis method of Example 224 is the same as that of Example 47. LC-MS (ESI) [M+H] + :535.4. 1 H NMR(400MHz, CD3OD),7.97(dd,J=5.2Hz,2.0Hz,1H),7.72(dd,J=7.6Hz,2.0Hz,1H),7.63(s,1H),7.54( dd,J=10.0Hz,2.8Hz,1H),7.46(d,J=2.0Hz,1H),7.23(dd,=8.4Hz,6.0Hz,1H),7.08(td,J=8.4Hz,2.8H z,1H),6.68(dd,J=7.6Hz,5.2Hz,1H),6.50(d,J=2.0Hz,1H),5.39-5.46(m,1H),4.10-4.23(m,2H),3.9 1(s,3H),3.87(d,J=15.6Hz,1H),2.96(d,J=15.6Hz,1H),1.82(d,J=6.4Hz,3H),1.37(t,J=7.2Hz,3H).

[0576] Example 225: (19R)-5-[(6-amino-1,2-pyridazin-3-yl)ethynyl]-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2,6 .0 8,12 .0 13,18 ]pentacosyl-1(25),2(6),4,8(9),11,13(14),15,17,21(22),23-decen-22-amine

[0577] The synthesis method of Example 225 is the same as that of Example 47. LC-MS (ESI) [M+H] + :536.4. 1 H NMR(400MHz, CDCl3),7.54(s,1H),7.51(s,1H),7.46(d,J=8.8Hz,1H),7.28(dd,J=10.4Hz,2 .8Hz,1H),7.14(dd,J=8.4Hz,6.0Hz,1H),7.00(td,J=8.4Hz,2.8Hz,1H),6.75(d,J=8.8Hz,1H ),6.57(s,1H),5.40-5.46(m,1H),4.96(s,2H),4.91(s,2H),4.13-4.19(m,2H),3.93(d,J=15 .6Hz, 1H), 3.89 (s, 3H), 2.96 (d, J = 15.6Hz, 1H), 1.79 (d, J = 6.4Hz, 3H), 1.43 (t, J = 7.2Hz, 3H).

[0578] Example 226: (19R)-5-[(5-aminopyrazin-2-yl)ethynyl]-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2,6 .0 8,12 .0 13,18 ]pentacosyl-1(25),2(6),4,8(9),11,13(14),15,17,21(22),23-decen-22-amine

[0579] The synthesis method of Example 226 is the same as that of Example 47. LC-MS (ESI) [M+H] + :536.4. 1H NMR(400MHz, CDCl3),8.31(s,1H),8.01(s,1H),7.54(s,1H),7.48(s,1H),7.29(dd,J=10 .0Hz, 2.8Hz, 1H), 7.13 (dd, J=8.4Hz, 5.6Hz, 1H), 7.00 (td, J=8.4Hz, 2.8Hz, 1H), 6.56 (s, 1 H),5.39-5.46(m,1H),4.87(s,2H),4.77(s,2H),4.16(q,J=7.2Hz,2H),3.90(d,J=15.6H z, 1H), 3.89 (s, 3H), 2.96 (d, J = 15.6Hz, 1H), 1.79 (d, J = 6.4Hz, 3H), 1.43 (t, J = 7.2Hz, 3H).

[0580] Example 227: (19R)-5-[(6-aminopyrazin-2-yl)ethynyl]-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2,6 .0 8,12 .0 13,18 ]pentacosyl-1(25),2(6),4,8(9),11,13(14),15,17,21(22),23-decen-22-amine

[0581] The synthesis method of Example 227 is the same as that of Example 47. LC-MS (ESI) [M+H] + :536.4. 1 H NMR(400MHz, CDCl3),8.20(s,1H),7.93(s,1H),7.54(d,J=1.6Hz,1H),7.45(s,1H),7.29(dd ,J=10.0Hz,2.8Hz,1H),7.14(dd,J=8.4Hz,6.0Hz,1H),7.00(td,J=8.4Hz,2.8Hz,1H),6.54(d ,J=1.6Hz,1H),5.39-5.45(m,1H),4.84(s,2H),4.71(s,2H),4.13-4.20(m,2H),3.90(s,3H), 3.89(d,J=15.6Hz,1H), 2.98(d,J=15.6Hz,1H), 1.79(d,J=6.4Hz,3H), 1.43(t,J=7.2Hz,3H).

[0582] Example 228: (19R)-5-{[diethyl(oxyylidene)-λ 6-sulfylidene]amino}-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0583] The synthesis method of Example 228 is the same as that of Example 169. LC-MS (ESI) [M+H] + :538.4. 1 H NMR(400MHz, CDCl3),7.59(s,1H),7.38-7.58(brs,1H),7.26(dd,J=10.0Hz,2.8Hz,1H),7.12(dd,J=8.4 Hz,6.0Hz,1H),6.97(td,J=8.4Hz,2.8Hz,1H),6.56(s,1H),5.37-5.42(m,1H),4.74-5.26(brs,2H),3.9 6(q,J=7.2Hz,2H),3.89(s,3H),3.69(d,J=15.6Hz,1H),3.48-3.63(m,2H),3.21-3.41(m,2H),2.71(d,J =15.6Hz, 1H), 1.78 (d, J = 6.0Hz, 3H), 1.51 (t, J = 7.2Hz, 3H), 1.46 (t, J = 7.2Hz, 3H), 1.30 (t, J = 7.2Hz, 3H).

[0584] Example 229: 1-{[(19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]penta-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decen-5-yl]nitrogenylidene-1λ 6 -Thietan-1-one

[0585] The synthesis method of Example 229 is the same as that of Example 169. LC-MS (ESI) [M+H] + :522.4. 1H NMR (400MHz, CDCl3), 7.53 (s, 1H), 7.50 (d, J = 1.2Hz, 1H), 7.27 (dd, J = 10.0Hz, 2.8Hz, 1H), 7.09 (dd, J = 8. 4Hz, 6.0Hz, 1H), 6.97 (td, J=8.4Hz, 2.8Hz, 1H), 6.56 (d, J=1.2Hz, 1H), 5.36-5.43 (m, 1H), 4.68-4.82 (m, 3 H),4.53-4.62(m,1H),4.19-4.27(m,1H),4.08-4.15(m,1H),4.00(q,J=7.2Hz,2H),3.88(s,3H),3.66(d ,J=15.6Hz,1H),2.74(d,J=15.6Hz,1H),2.28-2.46(m,2H),1.78(d,J=6.8Hz,3H),1.34(t,J=7.2Hz,3H).

[0586] Example 230: 2-{[(19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]penta-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decen-5-yl]nitrogenylidene-2λ 6 -2-thiaspiro[3.3]heptan-2-one

[0587] The synthesis method of Example 230 is the same as that of Example 169. LC-MS (ESI) [M+H] + :562.4. 1 H NMR(400MHz, CDCl3),7.48(d,J=7.1Hz,2H),7.28(d,J=2.3Hz,1H),7.09(m,1H),7.0 2-6.84(m,1H),6.56(s,1H),5.39(d,J=6.1Hz,1H),5.05(d,J=12.9Hz,1H),4.99-4. 85(m,6H),4.44(d,J=13.3Hz,1H),4.32(d,J=13.3Hz,1H),3.96(m,2H),3.88(s,3H) ,3.63(d,J=15.5Hz,1H),2.72(d,J=15.4Hz,1H),1.78(d,J=6.2Hz,3H),1.30(m,4H).

[0588] Example 231: (19R)-3-Ethyl-16-fluoro-10,19-dimethyl-5-{[1-(trifluoromethyl)pyrazol-4-yl]ethynyl}-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0589] The synthesis method of Example 231 is the same as that of Example 47. LC-MS (ESI) [M+H] + :577.4. 1 H NMR(400MHz,CD3OD),8.61(s,1H),8.06(s,1H),7.58(s,1H),7.54(dd,J=10.0Hz,2.8H z,1H),7.45(d,J=1.6Hz,1H),7.20(dd,J=8.4Hz,5.6Hz,1H),7.08(td,J=8.4Hz,2.8Hz ,1H),6.50(d,J=1.6Hz,1H),5.40-5.46(m,1H),4.08-4.20(m,2H),3.92(s,3H),3.83( d, J=16.0Hz, 1H), 2.94 (d, J=16.0Hz, 1H), 1.82 (d, J=6.4Hz, 3H), 1.34 (t, J=7.2Hz, 3H).

[0590] Example 232: (19R)-10-(Difluoromethyl)-3-ethyl-16-fluoro-5-[(1E)-3-methoxyprop-1-enyl]-19-methyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0591] The synthesis method of Example 232 is the same as that of Example 45. LC-MS (ESI) [M+H] + :525.4. 1H NMR(400MHz, CD3OD),7.81(s,1H),7.58(dd,J=10.0Hz,2.8Hz,1H),7.483(t,J=59.6Hz,1H),7.43 (s,1H),7.27(dd,J=8.4Hz,6.0Hz,1H),7.12(td,J=8.4Hz,2.8Hz,1H),6.82(d,J=16.4Hz,1H),6.5 7(dt,J=16.4Hz,6.0Hz,1H),6.34(d,J=1.6Hz,1H),5.34-5.40(m,1H),4.02-4.19(m,4H),3.80(d, J=16.0Hz,1H),3.44(s,3H),2.93(d,J=16.0Hz,1H),1.80(d,J=6.4Hz,3H),1.33(t,J=7.2Hz,3H).

[0592] Example 233: (19R)-10-(Difluoromethyl)-3-ethyl-5-ethynyl-16-fluoro-19-methyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0593] The synthesis method of Example 233 is the same as that of Example 47. LC-MS (ESI) [M+H] + :479.2. 1 H NMR(400MHz, CD3OD),7.93(s,1H),7.57(dd,J=10.0Hz,2.8Hz,1H),7.50(t,J=60 .0Hz,1H),7.45(s,1H),7.24(dd,J=8.4Hz,5.6Hz,1H),7.11(td,J=8.4Hz,2.4Hz, 1H),6.32(s,1H),5.35-5.41(m,1H),4.04-4.19(m,2H),3.89(s,1H),3.83(d,J=1 5.6Hz, 1H), 2.94 (d, J = 15.6Hz, 1H), 1.80 (d, J = 6.4Hz, 3H), 1.33 (t, J = 7.2Hz, 3H).

[0594] Example 234: (19R)-5-[(2-amino-1,3-thiazol-4-yl)ethynyl]-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosyl-1(24),2(6),4,8(9),11,13(14),15,17,21(25),22-decen-22-amine

[0595] The synthesis method of Example 234 is the same as that of Example 47. LC-MS (ESI) [M+H] + :541.4. 1 H NMR(400MHz, CDCl3),7.49-7.43(m,2H),7.28(dd,J=9.9,2.7Hz,1H),7.12(dd,J=8.5,5.8Hz,1H),7.01(td,J=8.2,2.5Hz,1H),6.85(s,1H),6 .57(d,J=1.4Hz,1H),5.48-5.26(m,5H),4.20-4.06(m,2H),3.89(s,4H),2.92(d,J=15.5Hz,1H),1.79(d,J=6.3Hz,3H),1.41(t,J=7.2Hz,3H).

[0596] Example 235: (19R)-3-Ethyl-16-fluoro-10,19-dimethyl-5-(pyrazolo[1,5-a]pyridin-5-ylethynyl)-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2,6 .0 8,12 .0 13,18 ]pentacosyl-1(24),2(6),4,8(9),11,13(18),14,16,21(25),22-decen-22-amine

[0597] The synthesis method of Example 235 is the same as that of Example 47. LC-MS (ESI) [M+H] + :559.4. 1H NMR(400MHz, CD3OD),8.55(d,J=7.2Hz,1H),8.00(d,J=2.4Hz,1H),7.94(s,1H),7.62(s,1H),7.54(dd,J=10 .0Hz,2.8Hz,1H),7.46(d,J=2.4Hz,1H),7.24(dd,J=8.4Hz,6.0Hz,1H),7.09(td,J=8.4Hz,2.8Hz,1H),7.00 (dd,J=7.2Hz,2.0Hz,1H),6.70(d,J=2.4Hz,1H),6.51(d,J=2.0Hz,1H),5.41-5.47(m,1H),4.08-4.24(m,2H ), 3.92 (s, 3H), 3.89 (d, J = 15.6Hz, 1H), 2.98 (d, J = 15.6Hz, 1H), 1.82 (d, J = 6.4Hz, 3H), 1.36 (t, J = 7.2Hz, 3H).

[0598] Example 236: (19R)-3-Ethyl-16-fluoro-5-(imidazo[1,2-a]pyridin-6-ylethynyl)-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2,6 .0 8,12 .0 13,18 ]pentacosyl-1(24),2(6),4,8(9),11,13(18),14,16,21(25),22-decen-22-amine

[0599] The synthesis method of Example 236 is the same as that of Example 47. LC-MS (ESI) [M+H] + :559.4. 1 H NMR(400MHz,CD3OD),8.83(s,1H),7.90(s,1H),7.59-7.64(m,3H),7.54(dd,J=10.0Hz ,2.8Hz,1H),7.44-7.47(m,2H),7.22(dd,J=8.4Hz,5.6Hz,1H),7.08(td,J=8.4Hz,2.8H z,1H),6.51(d,J=2.0Hz,1H),5.40-5.48(m,1H),4.08-4.24(m,2H),3.92(s,3H),3.88( d, J=15.6Hz, 1H), 2.97 (d, J=15.6Hz, 1H), 1.82 (d, J=6.4Hz, 3H), 1.36 (t, J=7.2Hz, 3H).

[0600] Example 237: (19R)-10-(difluoromethyl)-5-{[dimethyl(oxyylidene)-λ 6 -sulfylidene]amino}-3-ethyl-16-fluoro-19-methyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0601] The synthesis method of Example 237 is the same as that of Example 169. LC-MS (ESI) [M+H] + :546.4. 1 H NMR (400MHz, CD3OD), 8.12 (s, 1H), 7.55 (dd, J = 10.0Hz, 2.8Hz, 1H), 7.47 (t, J = 60.4Hz, 1H),7.40(s,1H),7.20(dd,J=8.4Hz,5.6Hz,1H),7.10(td,J=8.4Hz,2.8Hz,1H),6.35(d ,J=1.6Hz,1H),5.34-5.40(m,1H),3.91-4.06(m,2H),3.72(d,J=15.6Hz,1H),3.40(s, 3H), 3.35 (s, 3H), 2.72 (d, J = 15.6Hz, 1H), 1.80 (d, J = 6.4Hz, 3H), 1.28 (t, J = 7.2Hz, 3H).

[0602] Example 238: ({[(19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decen-5-yl]ethynyl}cyclopropyl)methanol

[0603] The synthesis method of Example 238 is the same as that of Example 47. LC-MS (ESI) [M+H] + :513.4. 1H NMR(400MHz, CD3OD),7.63(s,1H),7.52(dd,J=10.4Hz,2.8Hz,1H),7.36-7.50(brs,1H),7. 19(dd,J=8.4Hz,6.0Hz,1H),7.07(td,J=8.4Hz,2.8Hz,1H),6.47(s,1H),5.38-5.44(m,1H), 3.99-4.15(m,2H),3.92(s,3H),3.76(d,J=15.6Hz,1H),3.57-3.63(m,2H),2.86(d,J=15.6 Hz, 1H), 1.81 (d, J = 6.4Hz, 3H), 1.29 (d, J = 7.2Hz, 3H), 1.04-1.08 (m, 2H), 0.94-0.97 (m, 2H).

[0604] Example 239: (19R)-3-Ethyl-16-fluoro-10,19-dimethyl-5-[(1E)-3-(oxetan-3-yloxy)prop-1-enyl]-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosyl-1(24),2(6),4,8(9),11,13(14),15,17,21(25),22-decen-22-amine

[0605] The synthesis method of Example 239 is the same as that of Example 45. LC-MS (ESI) [M+H] + :531.4. 1H NMR(400MHz, CDCl3),7.47(s,1H),7.33-7.43(brs,1H),7.29(dd,J=10.0Hz,2.8Hz,1H),7.14(dd,J=8.4Hz,6 .0Hz,1H),7.00(td,J=8.4Hz,2.8Hz,1H),6.76(d,J=16.4Hz,1H),6.55(dt,J=16.4Hz,6.0Hz,1H),6.51(s,1H ),5.35-5.42(m,1H),5.02(s,2H),4.82-4.90(m,1H),4.77-4.81(m,2H),4.54-4.58(m,2H),4.05-4.16(m,4H ), 3.90 (s, 3H), 3.66 (d, J = 16.0Hz, 1H), 2.93 (d, J = 16.0Hz, 1H), 1.78 (d, J = 6.0Hz, 3H), 1.38 (t, J = 7.2Hz, 3H).

[0606] Example 240: 6-{[(19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 1(24),2(6),4,8(9),11,13(14),15,17,21(25),22-decen-5-yl]ethynyl}-1,2-dihydropyridin-2-one

[0607] The synthesis method of Example 240 is the same as that of Example 47. LC-MS (ESI) [M+H] + :536.4. 1 H NMR(400MHz, CDCl3),7.36-7.51(m,3H),7.29(dd,J=10.0Hz,2.8Hz,1H),7.15(d d,J=8.4Hz,6.0Hz,1H),7.05(td,J=8.4Hz,2.8Hz,1H),6.64(s,1H),6.55(d,J=7 .2Hz,1H),6.45(d,J=8.8Hz,1H),5.44-5.51(m,1H),4.02-4.20(m,2H),3.85-3. 90 (m, 4H), 2.86 (d, J = 15.6Hz, 1H), 1.84 (d, J = 6.4Hz, 3H), 1.40 (t, J = 7.2Hz, 3H).

[0608] Example 241: 4-{[(19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 1(24),2(6),4,8(9),11,13(14),15,17,21(25),22-decen-5-yl]ethynyl}-1,2-dihydropyridin-2-one

[0609] The synthesis method of Example 241 is the same as that of Example 47. LC-MS (ESI) [M+H] + :536.4. 1 H NMR(400MHz, CDCl3),12.05-12.88(brs,1H),7.42-7.58(brs,1H),7.40(s,1H),7.35(d,J=6.8Hz,1H), 7.29(dd,J=10.0Hz,2.4Hz,1H),7.19(dd,J=8.4Hz,6.0Hz,1H),7.06(td,J=8.4Hz,2.4Hz,1H),6.79(s, 1H),6.63(s,1H),6.41(d,J=6.4Hz,1H),5.87-6.29(brs,2H),5.42-5.50(m,1H),4.08-4.23(m,2H),3. 92 (s, 3H), 3.86 (d, J = 16.0Hz, 1H), 2.98 (d, J = 16.0Hz, 1H), 1.83 (d, J = 6.4Hz, 3H), 1.44 (t, J = 7.2Hz, 3H).

[0610] Example 242: 6-{[(19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosyl-1(24),2(6),4,8(9),11,13(14),15,17,21(25),22-decen-5-yl]ethynyl}-1-methyl-1,2-dihydropyridin-2-one

[0611] The synthesis method of Example 242 is the same as that of Example 47. LC-MS (ESI) [M+H] + :550.4. 1H NMR(400MHz, CD3OD),7.61(s,1H),7.54(dd,J=10.0Hz,2.8Hz,1H),7.50(dd,J=9.2Hz,7.2Hz,1H),7 .46(s,1H),7.22(dd,J=8.4Hz,6.0Hz,1H),7.07(td,J=8.4Hz,2.8Hz,1H),6.80(dd,J=6.8Hz,1.2Hz ,1H),6.62(dd,J=9.2Hz,1.2Hz,1H),6.48(d,J=1.6Hz,1H),5.39-5.46(m,1H),4.09-4.24(m,2H),3 .91(s,3H),3.82-3.85(m,4H),2.99(d,J=15.6Hz,1H),1.81(d,J=6.4Hz,3H),1.35(t,J=7.2Hz,3H).

[0612] Example 243: 4-{[(19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosyl-1(24),2(6),4,8(9),11,13(14),15,17,21(25),22-decen-5-yl]ethynyl}-1-methyl-1,2-dihydropyridin-2-one

[0613] The synthesis method of Example 243 is the same as that of Example 47. LC-MS (ESI) [M+H] + :550.4. 1 H NMR(400MHz, CD3OD),7.68(d,J=7.2Hz,1H),7.56(s,1H),7.54(dd,J=10.0Hz,2.8Hz,1H),7.4 5(d,J=1.6Hz,1H),7.23(dd,J=8.4Hz,6.0Hz,1H),7.08(td,J=8.4Hz,2.8Hz,1H),6.72(d,J=1 .6Hz,1H),6.47-6.50(m,2H),5.39-5.45(m,1H),4.08-4.23(m,2H),3.91(s,3H),3.83(d,J=1 5.6Hz, 1H), 3.58 (s, 3H), 2.96 (d, J = 15.6Hz, 1H), 1.81 (d, J = 6.4Hz, 3H), 1.35 (t, J = 7.2Hz, 3H).

[0614] Example 244: (19R)-3-Ethyl-16-fluoro-10,19-dimethyl-5-(prop-2-enyl)-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0615] The synthesis method of Example 244 is the same as that of Example 45. LC-MS (ESI) [M+H] + :459.4. 1 H NMR(400MHz, CDCl3),7.42-7.60(brs,1H),7.24-7.29(m,2H),7.13(dd,J=8.4H z,6.0Hz,1H),6.99(td,J=8.4Hz,2.8Hz,1H),6.55(s,1H),6.07-6.17(m,1H),5 .24-5.56(m,3H),5.12-5.23(m,2H),3.98-4.10(m,2H),3.90(s,3H),3.54-3.5 8(m,3H),2.88(d,J=16.0Hz,1H),1.79(d,J=6.0Hz,3H),1.31(t,J=7.2Hz,3H).

[0616] Example 245: (19R)-5-{[cyclopropyl(methyl)(oxyylidene)-λ 6 -sulfylidene]amino}-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0617] The synthesis method of Example 245 is the same as that of Example 169. LC-MS (ESI) [M+H] + :536.5. 1H NMR(400MHz, CDCl3),7.58(s,1H),7.50(s,1H),7.24-7.29(m,1H),7.11(dd,J=8.4Hz,5. 6Hz,1H),6.97(td,J=8.4Hz,2.4Hz,1H),6.55(s,1H),5.36-5.42(m,1H),4.62-4.89(brs ,2H),3.93-4.04(m,2H),3.89(s,3H),3.62(d,J=15.6Hz,1H),3.41(s,3H),2.68-2.75(m ,2H),1.78(d,J=6.0Hz,3H),1.36-1.44(m,2H),1.32(t,J=6.4Hz,3H),1.09-1.14(m,2H).

[0618] Example 246: (19R)-10-(difluoromethyl)-3-ethyl-16-fluoro-19-methyl-5-(prop-2-enyl)-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0619] The synthesis method of Example 246 is the same as that of Example 45. LC-MS (ESI) [M+H] + :495.4. 1 H NMR(400MHz, CD3OD),7.91(s,1H),7.56(dd,J=10.0Hz,2.4Hz,1H),7.47(t,J=60.0Hz,1H),7.39( d,J=1.6Hz,1H),7.24(dd,J=8.4Hz,5.6Hz,1H),7.10(td,J=8.4Hz,2.8Hz,1H),6.33(d,J=1.6Hz,1 H),6.07-6.17(m,1H),5.34-5.40(m,1H),5.13-5.21(m,2H),4.00-4.16(m,2H),3.67(d,J=16.0Hz ,1H),3.60(d,J=6.4Hz,2H),2.88(d,J=16.0Hz,1H),1.80(d,J=6.0Hz,3H),1.30(t,J=7.2Hz,3H).

[0620] Example 247: N-{4-[(19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 1(24),2(6),4,8(9),11,13(14),15,17,21(25),22-decen-5-yl]-2-methylbut-3-yn-2-yl}acetamide

[0621] The synthesis method of Example 247 is the same as that of Example 47. LC-MS (ESI) [M+H] + :542.4. 1 H NMR(400MHz, CDCl3),7.67(s,1H),7.46(s,1H),7.27(dd,J=10.0Hz,2.8Hz,1H),7.15(dd, J=8.4Hz,5.6Hz,1H),6.99(td,J=8.4Hz,2.8Hz,1H),6.57(d,J=1.6Hz,1H),5.77(s,1H),5. 26-5.52(m,3H),4.00-4.14(m,2H),3.93(s,3H),3.78(d,J=15.6Hz,1H),2.89(d,J=15.6Hz ,1H),1.96(s,3H),1.80(d,J=6.4Hz,3H),1.78(s,3H),1.76(s,3H),1.36(t,J=7.2Hz,3H).

[0622] Example 248: N-{4-[(19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 2,6 .0 13,18 1(24),2(6),4,8(9),11,13(14),15,17,21(25),22-decen-5-yl]-2-methylbut-3-yn-2-yl}propane-2-sulfonamide

[0623] The synthesis method of Example 248 is the same as that of Example 47. LC-MS (ESI) [M+H] + :606.5. 1H NMR(400MHz, CDCl3),7.70(s,1H),7.39(s,1H),7.27(dd,J=10.0Hz,2.8Hz,1H),7.16 (dd,J=8.4Hz,6.0Hz,1H),7.03(td,J=8.4Hz,2.8Hz,1H),6.64(s,1H),5.93-6.13(brs ,2H),5.44-5.48(m,1H),4.00-4.14(m,3H),3.91(s,3H),3.80(d,J=15.6Hz,1H),2.9 0(d,J=15.6Hz,1H),1.82(d,J=6.0Hz,3H),1.73-1.78(m,12H),1.38(t,J=7.2Hz,3H).

[0624] Example 249: 3-{[(19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2,6 .0 8,12 .0 13,18 1(25),2(6),4,8(9),11,13(14),15,17,21(22),23-decen-5-yl]ethynyl}-1,2-dihydropyridin-2-one

[0625] The synthesis method of Example 249 is the same as that of Example 47. LC-MS (ESI) [M+H] + :536.4. 1 H NMR (400MHz, CDCl3), 8.31 (dd, J=4.8Hz, 1.6Hz, 1H), 7.97 (dd, J=7.2Hz, 1.6Hz, 1H ),7.56(s,1H),7.46(s,1H),7.26-7.31(m,2H),7.17-7.21(m,2H),7.00(td,J=8. 4Hz,2.8Hz,1H),6.64(s,1H),5.46-5.50(m,1H),4.83(s,2H),4.13-4.26(m,3H), 3.88 (s, 3H), 3.04 (d, J = 15.6Hz, 1H), 1.81 (d, J = 6.4Hz, 3H), 1.45 (t, J = 7.2Hz, 3H).

[0626] Example 250: 2-(4-{[(19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.02,6 .0 8,12 .0 13,18 1-(25),2(6),4,8(9),11,13(14),15,17,21(22),23-decen-5-yl]ethynyl}pyrazol-1-yl)ethan-1-ol

[0627] The synthesis method of Example 250 is the same as that of Example 47. LC-MS (ESI) [M+H] + :553.4. 1 H NMR(400MHz, CDCl3),7.73(s,1H),7.70(s,1H),7.54(s,1H),7.44(s,1H),7.28(dd,J=10.0Hz,2.4H z,1H),7.15(dd,J=8.4Hz,6.0Hz,1H),7.01(td,J=8.4Hz,2.4Hz,1H),6.56(s,1H),5.37-5.45(m,1H ),4.84-5.36(brs,2H),4.27(t,J=4.8Hz,2H),4.11(q,J=7.2Hz,2H),4.03(t,J=4.8Hz,2H),3.91(s ,3H),3.82(d,J=15.6Hz,1H),2.93(d,J=15.6Hz,1H),1.80(d,J=6.4Hz,3H),1.40(t,J=7.2Hz,3H).

[0628] Example 251: 3-{[(19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2,6 .0 8,12 .0 13,18 ]pentacosyl-1(25),2(6),4,8(9),11,13(14),15,17,21(22),23-decen-5-yl]ethynyl}-1-methyl-1,2-dihydropyridin-2-one

[0629] The synthesis method of Example 251 is the same as that of Example 47. LC-MS (ESI) [M+H] + :550.4. 1H NMR(400MHz, CDCl3),7.76(s,1H),7.69(dd,J=6.8Hz,2.0Hz,1H),7.53(s,1H),7.32(dd,J=6.8Hz,2.0H z,1H),7.27(dd,J=10.0Hz,2.8Hz,1H),7.14(dd,J=8.4Hz,5.6Hz,1H),6.98(td,J=8.4Hz,2.8Hz,1H),6 .60(s,1H),6.19(t,J=7.2Hz,1H),5.44-5.49(m,1H),4.90(s,2H),4.10-4.16(m,2H),3.95(d,J=15.6H z, 1H), 3.92 (s, 3H), 3.61 (s, 3H), 2.96 (d, J = 15.6Hz, 1H), 1.80 (d, J = 6.4Hz, 3H), 1.41 (t, J = 7.2Hz, 3H).

[0630] Example 252: (5-{[(19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2,6 .0 8,12 .0 13,18 1(24),2(6),4,8(9),11,13(18),14,16,21(25),22-decen-5-yl]ethynyl}pyrazin-2-yl)methanol

[0631] The synthesis method of Example 252 is the same as that of Example 47. LC-MS (ESI) [M+H] + :551.4. 1 H NMR(400MHz,CD3OD),8.80(s,1H),8.76(s,1H),7.64(s,1H),7.54(dd,J=10.0Hz,2.8Hz,1 H),7.47(d,J=1.2Hz,1H),7.23(dd,J=8.4Hz,5.6Hz,1H),7.08(td,J=8.4Hz,2.8Hz,1H),6 .51(d,J=1.6Hz,1H),5.41-5.46(m,1H),4.80(s,2H),4.11-4.23(m,2H),3.92(d,J=15.6H z, 1H), 3.91 (s, 3H), 2.98 (d, J = 15.6Hz, 1H), 1.82 (d, J = 6.4Hz, 3H), 1.36 (t, J = 7.2Hz, 3H).

[0632] Example 253: N-{4-[(19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2,6 .0 8,12 .0 13,18 1-(25),2(6),4,8(9),11,13(14),15,17,21(22),23-decen-5-yl]-2-methylbut-3-yn-2-yl}-1-(methylamino)methaneamide

[0633] The synthesis method of Example 253 is the same as that of Example 47. LC-MS (ESI) [M+H] + :557.4. 1 H NMR(400MHz, CDCl3),7.53(s,1H),7.50(s,1H),7.28(dd,J=10.4Hz,2.8Hz,1H),7.14(dd,J=8.4 Hz,6.0Hz,1H),7.00(td,J=8.4Hz,2.8Hz,1H),6.54(d,J=1.6Hz,1H),5.03(s,2H),4.91-4.98(m, 1H),4.61(s,1H),4.07-4.13(m,2H),3.93(s,3H),3.73(d,J=15.6Hz,1H),2.92(d,J=15.6Hz,1H ), 2.78 (d, J = 4.8Hz, 3H), 1.80 (d, J = 6.4Hz, 3H), 1.74 (s, 3H), 1.72 (s, 3H), 1.39 (t, J = 7.2Hz, 3H).

[0634] Example 254: 1-({4-[(19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2,6 .0 8,12 .0 13,18 [penta-1(25),2(6),4,8(9),11,13(14),15,17,21(22),23-decen-5-yl]-2-methylbut-3-yn-2-yl}amino)-N,N-dimethylmethaneamide

[0635] The synthesis method of Example 254 is the same as that of Example 47. LC-MS (ESI) [M+H] + :571.5. 1H NMR(400MHz, CDCl3),7.76(s,1H),7.50(d,J=1.6Hz,1H),7.28(dd,J=10.0Hz,2.8Hz,1H ),7.14(dd,J=8.4Hz,6.0Hz,1H),6.98(dd,J=8.4Hz,2.8Hz,1H),6.55(d,J=2.0Hz,1H), 5.41-5.48(m,1H),4.86(s,2H),4.60(s,1H),4.04-4.14(m,2H),3.93(s,3H),3.80(d,J =15.2Hz,1H),2.87-2.91(m,7H),1.78-1.81(m,6H),1.76(s,3H),1.37(t,J=7.2Hz,3H).

[0636] Example 255: ({4-[(19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2,6 .0 8,12 .0 13,18 1(25),2(6),4,8(9),11,13(14),15,17,21(22),23-decen-5-yl]-2-methylbut-3-yn-2-yl}amino)methane methyl ester

[0637] The synthesis method of Example 255 is the same as that of Example 47. LC-MS (ESI) [M+H] + :558.4. 1 H NMR(400MHz, CDCl3),7.64(s,1H),7.56(s,1H),7.24-7.27(m,1H),7.15(dd,J=8.4Hz ,5.6Hz,1H),7.00(td,J=8.4Hz,2.8Hz,1H),6.57(s,1H),5.38-5.44(m,1H),4.99(s, 1H),3.97-4.11(m,2H),3.93(s,3H),3.79(d,J=15.6Hz,1H),3.61(s,3H),2.88(d,J= 15.6Hz, 1H), 1.80 (d, J = 6.4Hz, 3H), 1.76 (s, 3H), 1.73 (s, 3H), 1.32 (t, J = 7.2Hz, 3H).

[0638] Example 256: N-{4-[(19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 2,6 .0 13,18 ]pentacyl-1(24),2(6),4,8(9),11,13(14),15,17,21(25),22-decen-5-yl]-2-methylbut-3-yn-2-yl}cyclopropanesulfonamide

[0639] The synthesis method of Example 256 is the same as that of Example 47. LC-MS (ESI) [M+H] + :604.4. 1 H NMR(400MHz, CDCl3),7.60(s,1H),7.48(s,1H),7.27(dd,J=10.0Hz,2.8Hz,1H),7.14(dd,J=8.4Hz,6.0H z,1H),7.00(td,J=8.4Hz,2.8Hz,1H),6.56(s,1H),5.40-5.44(m,1H),5.18-5.38(brs,2H),4.79(s,1H), 4.04-4.14(m,2H),3.91(s,3H),3.75(d,J=15.6Hz,1H),2.90(d,J=15.6Hz,1H),2.79-2.86(m,1H),1.81 (s,3H),1.80(d,J=6.8Hz,3H),1.78(s,3H),1.37(t,J=7.2Hz,3H),1.21-1.28(m,2H),1.00-1.07(m,2H).

[0640] Example 257: 1,1,1-Trifluoro-N-{4-[(19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 2,6 .0 13,18 1(24),2(6),4,8(9),11,13(14),15,17,21(25),22-decen-5-yl]-2-methylbut-3-yn-2-yl}methanesulfonamide

[0641] The synthesis method of Example 257 is the same as that of Example 47. LC-MS (ESI) [M+H] + :632.6. 1H NMR(400MHz, CDCl3),7.52(s,1H),7.44(s,1H),7.28(dd,J=10.0Hz,2.8Hz,1H),7.15(dd ,J=8.4Hz,5.6Hz,1H),7.02(td,J=8.4Hz,2.8Hz,1H),6.59(d,J=1.2Hz,1H),5.60-5.78(b rs,2H),5.42-5.46(m,1H),4.01-4.16(m,2H),3.90(s,3H),3.72(d,J=15.6Hz,1H),2.88( d,J=15.6Hz,1H),1.87(s,3H),1.86(s,3H),1.82(d,J=6.0Hz,3H),1.38(t,J=7.2Hz,3H).

[0642] Example 258: 5-{[(19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 2,6 .0 13,18 pentacyl-1(24),2(6),4,8(9),11,13(14),15,17,21(25),22-decen-5-yl]ethynyl}-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridin-2-one

[0643] The synthesis method of Example 258 is the same as that of Example 47. LC-MS (ESI) [M+H] + :618.4. 1H NMR(400MHz, CDCl3),7.61(d,J=1.6Hz,1H),7.50(dd,J=9.6Hz,1.6Hz,1H),7.46(s,1H),7.40(s,1H),7.30 (dd,J=9.6Hz,2.4Hz,1H),7.16(dd,J=8.4Hz,5.6Hz,1H),7.03(td,J=8.4Hz,2.4Hz,1H),6.64(d,J=9.6Hz,1 H),6.58(d,J=1.6Hz,1H),5.50-5.76(brs,2H),5.41-5.46(m,1H),4.35-4.71(m,2H),4.04.08-4.17(m,2H ), 3.92 (s, 3H), 3.80 (d, J = 15.6Hz, 1H), 2.96 (d, = 15.6Hz, 1H), 1.81 (d, J = 6.0Hz, 3H), 1.43 (d, J = 7.2Hz, 3H).

[0644] Example 259: 3-Ethyl-16-fluoro-10-methyl-3,4,9,10,11,23,26-heptaazahexacyclo[22.3.1.0 8,12 .0 13,18 .0 19,23 .0 2,6 ]Octadecadien-1(28),2(6),4,8(9),11,13(18),14,16,24(25),26-decadien-25-amine

[0645] Step 1: Under nitrogen protection, a solution of compound 259-1 (317 mg), pinacol diboron (500 mg), potassium acetate (400 mg) and Pd(dppf)Cl2 (73 mg) in dioxane (5 mL) was heated to 90°C and stirred overnight. The resulting solution of compound 259-2 was directly used in the next reaction.

[0646] Step 2: To the solution of compound 259-2 obtained in the previous step, water (1 mL), compound 259-3 (300 mg), anhydrous sodium carbonate (200 mg), and Ruphos-Pd-G3 (100 mg) were added. The reaction mixture was heated to 100°C and stirred overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by flash silica gel column chromatography (dichloromethane:methanol = 50:1) to obtain compound 259-4 (110 mg).

[0647] Step 3: 4N hydrogen chloride dioxane solution (5 mL) was added to compound 259-4 (110 mg), and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure to obtain compound 259-5 (70 mg).

[0648] Step 4: To a solution of compound 259-5 (70 mg) in DMF (2 mL) were added compound 259-6 (44 mg) and DIEA (103 mg). The reaction mixture was heated to 60°C and stirred for 1 hour. The mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by flash silica gel column chromatography (dichloromethane:methanol = 30:1) to obtain compound 259-7 (55 mg).

[0649] Step 5: Using compound 259-7 (55 mg) as starting material, compound 259-8 (52 mg) was obtained by general synthetic method F.

[0650] Step 6: To a solution of compound 259-8 (55 mg) in ethanol (5 mL) / water (1 mL) was added ammonium chloride (40 mg) and reduced iron powder (50 mL). The reaction solution was heated to 80°C and stirred for 1.5 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash silica gel column chromatography (dichloromethane:methanol=30:1) to obtain Example 259 (12 mg). LC-MS (ESI) [M+H] + :445.5. 1 H NMR(400MHz, CDCl3),7.73(s,1H),7.62(s,1H),7.32(dd,J=10.4Hz,2.8Hz,1H),7.02(dd ,J=8.4Hz,6.0Hz,1H),6.94(td,J=8.4Hz,2.8Hz,1H),6.44(s,1H),5.20(s,2H),4.16-4. 24(m,4H),4.03-4.13(m,2H),3.80-3.86(m,1H),3.75(d,J=15.6Hz,1H),3.16(d,J=15.6 Hz, 1H), 2.42-2.51 (m, 2H), 2.14-2.25 (m, 1H), 1.93-2.11 (m, 2H), 1.42 (t, J = 7.2Hz, 3H).

[0651] Example 260: 5-Chloro-3-ethyl-16-fluoro-10-methyl-3,4,10,11,23,26-hexaazahexacyclo[22.3.1.0 8,12 .0 13,18 .0 19,23 .0 2,6]Octadecadien-1(28),2(6),4,8(9),11,13(18),14,16,24(25),26-decadien-25-amine

[0652] The synthesis method of Example 260 is the same as that of Example 259. LC-MS (ESI) [M+H] + :478.4. 1 H NMR(400MHz, CDCl3),7.58(d,J=1.6Hz,1H),7.41(s,1H),7.29(dd,J=10.4Hz,2.8Hz,1H),7.06( dd,J=8.4Hz,6.0Hz,1H),6.92(td,J=8.4Hz,2.8Hz,1H),6.67(d,J=2.0Hz,1H),5.36(s,2H),4.32 -4.36(m,1H),4.02-4.08(m,2H),3.92(s,3H),3.83-3.88(m,1H),3.60(d,J=15.6Hz,1H),2.82(d ,J=15.6Hz,1H),2.46-2.55(m,2H),2.15-2.24(m,1H),1.93-2.10(m,2H),1.41(t,J=7.2Hz,3H).

[0653] Example 261: (3R)-19-ethyl-17-ethynyl-6,8-difluoro-3,12-dimethyl-2-oxa-11,12,18,19,23-pentaazapentacyclo[19.3.1.0 4,9 .0 10,14 .0 16,20 ]pentacosyl-1(25),4(5),6,8,10(11),13,16(20),17,21(22),23-decen-24-amine

[0654] The synthesis method of Example 261 is the same as that of Example 47. LC-MS (ESI) [M+H] + :461.4. 1H NMR(400MHz, CDCl3),7.55(d,J=1.6Hz,1H),7.45(s,1H),7.11-7.14(m,1H ),6.77-6.83(m,1H),6.53(d,J=1.6Hz,1H),5.34-5.40(m,1H),4.81(s,2H ),4.10-4.16(m,2H),3.93(s,3H),3.82(d,J=15.6Hz,1H),3.29(s,1H),2. 84(dd,J=15.6Hz,1.6Hz,1H), 1.77(d,J=6.4Hz,3H), 1.41(t,J=7.2Hz,3H).

[0655] Example 262: (3R)-8-Chloro-19-ethyl-17-ethynyl-6-fluoro-3,12-dimethyl-2-oxa-11,12,18,19,23-pentaazapentacyclo[19.3.1.0 4,9 .0 10,14 .0 16,20 ]pentacosyl-1(25),4(5),6,8,10(11),13,16(20),17,21(22),23-decen-24-amine

[0656] The synthesis method of Example 262 is the same as that of Example 47. LC-MS (ESI) [M+H] + :477.4.

[0657] Example 263: (3R)-8,17-Dichloro-19-ethyl-6-fluoro-3,12-dimethyl-2-oxa-11,12,18,19,23-pentaazapentacyclo[19.3.1.0 4,9 .0 10,14 .0 16,20 ]pentacosyl-1(25),4(5),6,8,10(11),13,16(20),17,21(22),23-decen-24-amine

[0658] The synthesis method of Example 263 is the same as that of Example 47. LC-MS (ESI) [M+H] + :487.4. 1H NMR(400MHz, CDCl3),7.45(s,1H),7.41(s,1H),7.23(dd,J=8.8Hz,2.8Hz,1H),7.15(dd,J=7.6Hz,2.8Hz,1H),6.59(s,1H),5.25-5.31(m,1H), 4.90 (s, 2H), 4.10 (q, J = 7.2Hz, 2H), 3.94 (s, 3H), 3.69 (d, J = 16.0Hz, 1H), 2.76 (d, J = 16.0Hz, 1H), 1.74 (d, J = 6.0Hz, 3H), 1.40 (t, J = 6.8Hz, 3H).

[0659] Example 264: (3R)-17-Chloro-19-ethyl-8-ethynyl-6-fluoro-3,12-dimethyl-2-oxa-11,12,18,19,23-pentaazapentacyclo[19.3.1.0 4,9 .0 10,14 .0 16,20 ]pentacosyl-1(25),4(5),6,8,10(11),13,16(20),17,21(22),23-decen-24-amine

[0660] The synthesis method of Example 264 is the same as that of Example 47. LC-MS (ESI) [M+H] + :477.4.

[0661] Example 265: (3R)-19-Ethyl-17-ethynyl-6-fluoro-3,12-dimethyl-8,11,12,18,19,23-hexaaza-2-oxapentacyclo[19.3.1.0 4,9 .0 10,14 .0 16,20 ]pentacosyl-1(25),4(5),6,8,10(11),13,16(20),17,21(22),23-decen-24-amine

[0662] The synthesis method of Example 265 is the same as that of Example 47. LC-MS (ESI) [M+H] + :444.4. 1H NMR(400MHz, CDCl3),8.46(d,J=2.8Hz,1H),7.63(dd,J=9.2Hz,2.8Hz,1H),7.54(s,1H),7.46(s,1H),6.53(d,J=1.6Hz,1H),5.45-5.51(m,1H),4.8 8(s,2H),4.07-4.13(m,2H),3.94(d,J=15.6Hz,1H),3.91(s,3H),3.29(s, 1H), 2.93 (d, J = 15.6Hz, 1H), 1.83 (d, J = 6.4Hz, 3H), 1.39 (t, J = 7.2Hz, 3H).

[0663] Example 266: (3R)-24-amino-17-chloro-19-ethyl-6-fluoro-3,12-dimethyl-2-oxa-11,12,18,19,23-pentaazapentacyclo[19.3.1.0 4,9 .0 10,14 .0 16,20 ]25-1(25),4(5),6,8,10(11),13,16(20),17,21(22),23-decene-8-carbonitrile

[0664] The synthesis method of Example 266 is the same as that of Example 47. LC-MS (ESI) [M+H] + :477.3.

[0665] Example 267: (19R)-3-Ethyl-5-ethynyl-16-fluoro-19-methyl-20-oxa-3,4,9,11,23-pentaaza-10-thiapentacyclo[19.3.1.0 2,6 .0 8,12 .0 13,18 ]pentacosyl-1(24),2(6),4,8(9),11,13(14),15,17,21(25),22-decen-22-amine

[0666] The synthesis method of Example 267 is the same as that of Example 1. LC-MS (ESI) [M+H] + :447.4. 1H NMR(400MHz, CD3OD),7.61(dd,J=10.0Hz,2.4Hz,1H),7.44(d,J=1.6Hz,1H),7.32(dd,J=8.4Hz,6.0Hz,1H),7.15(td,J=8.4Hz,2.4Hz,1H),5. 83(d,J=1.6Hz,1H),5.16-5.21(m,1H),4.05-4.16(m,3H),3.74(s,1H),3.53(d,J=15.6Hz,1H),1.81(d,J=6.8Hz,3H),1.32(t,J=7.2Hz,3H).

[0667] Example 268: (19R)-3-Ethyl-5-ethynyl-16-fluoro-19-methyl-20-oxa-3,4,8,11,23-pentaazapentacyclo[19.3.1.0 2,6 .0 8,12 .0 13,18 ]pentacosyl-1(24),2(6),4,9,11,13(14),15,17,21(25),22-decen-22-amine

[0668] The synthesis method of Example 268 is the same as that of Example 1. LC-MS (ESI) [M+H] + :429.3. 1 H NMR(400MHz, CDCl3),7.16-7.68(m,5H),7.04-7.09(m,1H),5.93(s,1H),5.56-5.70(brs,1H),5.17-5.38(brs,2H),5. 04(d,J=13.2Hz,1H),4.42(d,J=14.8Hz,1H),4.14-4.19(m,2H),3.39(s,1H),1.82-1.96(m,3H),1.44(t,J=7.6Hz,3H).

[0669] Example 269: (19R)-3-Ethyl-5-ethynyl-16-fluoro-19-methyl-20-oxa-3,4,11,12,23-pentaazapentacyclo[19.3.1.0 2,6 .0 8,12 .0 13,18 ]pentacosyl-1(24),2(6),4,8(9),10,13(14),15,17,21(25),22-decen-22-amine

[0670] The synthesis method of Example 269 is the same as that of Example 1. LC-MS (ESI) [M+H] + :429.3. 1 H NMR(400MHz, CDCl3),7.66(d,J=1.6Hz,1H),7.58(s,1H),7.35(dd,J=9.2Hz,2.8Hz ,1H),7.15(dd,J=8.4Hz,5.6Hz,1H),7.05-7.10(m,1H),6.41(s,1H),6.26(s,1H), 5.28-5.33(m,1H),4.72-5.18(brs,2H),4.12-4.19(m,2H),3.99(d,J=16.0Hz,1H) ,3.30(s,1H),3.14(d,J=16.0Hz,1H),1.81(d,J=6.4Hz,3H),1.42(t,J=7.2Hz,3H).

[0671] Example 270: (19R)-3-Ethyl-5-ethynyl-16-fluoro-19-methyl-20-oxa-3,4,11,23-tetraaza-10-thiapentacyclo[19.3.1.0 2,6 .0 8,12 .0 13,18 ]pentacosyl-1(24),2(6),4,8(9),11,13(14),15,17,21(25),22-decen-22-amine

[0672] The synthesis method of Example 270 is the same as that of Example 1. LC-MS (ESI) [M+H] + :446.3. 1 H NMR(400MHz, CDCl3),8.74(d,J=1.6Hz,1H),7.53(s,1H),7.32(dd,J=10.0Hz,2.4Hz, 1H),7.11(dd,J=8.4Hz,5.6Hz,1H),7.03(td,J=8.4Hz,2.4Hz,1H),6.08(d,J=1.6Hz, 1H),5.19-5.24(m,1H),4.87(s,2H),4.11-4.16(m,2H),3.91(dd,J=15.6Hz,1.6Hz,1 H), 3.33 (s, 1H), 3.17 (d, J = 15.6Hz, 1H), 1.81 (d, J = 6.4Hz, 3H), 1.41 (t, J = 7.2Hz, 3H).

[0673] Example 271: (19R)-3-Ethyl-5-ethynyl-16-fluoro-19-methyl-10,20-dioxa-3,4,11,23-tetraazapentacyclo[19.3.1.0 2,6 .0 8,12 .0 13,18 ]pentacosyl-1(24),2(6),4,8(9),11,13(14),15,17,21(25),22-decen-22-amine

[0674] The synthesis method of Example 271 is the same as that of Example 1. LC-MS (ESI) [M+H] + :430.3. 1 H NMR(400MHz, CDCl3),8.52(d,J=1.2Hz,1H),7.56(s,1H),7.35(dd,J=9.6Hz,2.4Hz,1H ),7.16(dd,J=8.4Hz,5.6Hz,1H),7.10(td,J=8.4Hz,2.4Hz,1H),6.32(d,J=1.2Hz,1H), 5.36-5.42(m,1H),5.06-5.24(brs,2H),4.04-4.16(m,2H),3.81(dd,J=16.0Hz,1.6Hz, 1H), 3.33 (s, 1H), 2.80 (d, J = 16.0Hz, 1H), 1.81 (d, J = 6.4Hz, 3H), 1.38 (t, J = 7.2Hz, 3H).

[0675] Example 272: (20R)-3-Ethyl-5-ethynyl-17-fluoro-11,20-dimethyl-21-oxa-3,4,12,24-tetraazapentacyclo[20.3.1.0 2,6 .0 8,13 .0 14,19 Hexadecene-1(25),2(6),4,8(9),10,12,14(15),16,18,22(26),23-undecene-23-amine

[0676] The synthesis method of Example 272 is the same as that of Example 1. LC-MS (ESI) [M+H] + :454.5. 1H NMR(400MHz,CD3OD),7.96(d,J=8.0Hz,1H),7.54(dd,J=10.0Hz,2.8Hz,1H),7.45(s,1H) ,7.33(d,J=8.4Hz,1H),7.25(dd,J=8.4Hz,5.6Hz,1H),7.08(td,J=8.4Hz,2.8Hz,1H),6. 25(d,J=1.6Hz,1H),5.14-5.20(m,1H),4.12-4.22(m,2H),3.92(d,J=15.6Hz,1H),3.88( s, 1H), 3.25 (d, J = 15.6Hz, 1H), 2.54 (s, 3H), 1.85 (d, J = 6.8Hz, 3H), 1.36 (t, J = 7.2Hz, 3H).

[0677] Example 273: (20R)-3-Ethyl-5-ethynyl-17-fluoro-20-methyl-21-oxa-3,4,11,24-tetraazapentacyclo[20.3.1.0 2,6 .0 8,13 .0 14,19 Hexadecene-1(25),2(6),4,8(9),10,12,14(15),16,18,22(26),23-undecene-23-amine

[0678] The synthesis method of Example 273 is the same as that of Example 1. LC-MS (ESI) [M+H] + :440.3. 1 H NMR(400MHz, CDCl3),8.52-8.66(brs,1H),8.30-8.40(brs,1H),7.62-7.70(brs,1H),7.54(s, 1H),7.32(dd,J=10.0Hz,2.8Hz,1H),7.10(dd,J=8.4Hz,5.6Hz,1H),7.04(td,J=8.4Hz,2.8Hz, 1H),6.18(d,J=1.6Hz,1H),5.17-5.24(m,1H),4.87(s,2H),4.18(q,J=7.2Hz,2H),3.88(d,J=1 5.6Hz, 1H), 3.33 (s, 1H), 3.28 (d, J = 15.6Hz, 1H), 1.83 (d, J = 6.0Hz, 3H), 1.43 (t, J = 7.2Hz, 3H).

[0679] Example 274: (20R)-3-Ethyl-5-ethynyl-17-fluoro-20-methyl-21-oxa-3,4,10,24-tetraazapentacyclo[20.3.1.0 2,6 .0 8,13 .0 14,19 Hexadecene-1(25),2(6),4,8(9),10,12,14(15),16,18,22(26),23-undecene-23-amine

[0680] The synthesis method of Example 274 is the same as that of Example 1. LC-MS (ESI) [M+H] + :440.3. 1 H NMR(400MHz,CD3OD),8.78-8.96(brs,1H),8.38-8.48(brs,1H),7.56(dd,J=10.0Hz, 2.8Hz,1H),7.47(s,1H),7.27(s,1H),7.20(dd,J=8.4Hz,5.6Hz,1H),7.11(td,J=8.4H z,2.8Hz,1H),6.26(s,1H),5.26-5.33(m,1H),4.11-4.25(m,2H),3.98(d,J=15.6Hz,1 H), 3.94 (s, 1H), 3.29 (d, J = 15.6Hz, 1H), 1.85 (d, J = 6.4Hz, 3H), 1.36 (t, J = 7.2Hz, 3H).

[0681] Example 275: (20R)-3-Ethyl-5-ethynyl-17-fluoro-20-methyl-21-oxa-3,4,12,24-tetraazapentacyclo[20.3.1.0 2,6 .0 8,13 .0 14,19 Hexadecene-1(25),2(6),4,8(9),10,12,14(15),16,18,22(26),23-undecene-23-amine

[0682] The synthesis method of Example 275 is the same as that of Example 1. LC-MS (ESI) [M+H] + :440.3. 1H NMR(400MHz,CD3OD),8.51(dd,J=4.8Hz,0.8Hz,1H),8.11(d,J=8.0Hz,1H),7.54(dd,J=1 0.0Hz, 2.4Hz, 1H), 7.45-7.48 (m, 2H), 7.25 (dd, J=8.4Hz, 5.6Hz, 1H), 7.09 (td, J=8.4Hz, 2 .4Hz,1H),6.21(d,J=1.6Hz,1H),5.14-5.20(m,1H),4.10-4.24(m,2H),3.97(d,J=15.6H z, 1H), 3.89 (s, 1H), 3.27 (d, J = 15.6Hz, 1H), 1.84 (d, J = 6.0Hz, 3H), 1.36 (t, J = 7.2Hz, 3H).

[0683] Example 276: (20R)-3-Ethyl-5-ethynyl-17-fluoro-10,20-dimethyl-21-oxa-3,4,12,24-tetraazapentacyclo[20.3.1.0 2,6 .0 8,13 .0 14,19 Hexadecene-1(25),2(6),4,8(9),10,12,14(15),16,18,22(26),23-undecene-23-amine

[0684] The synthesis method of Example 276 is the same as that of Example 1. LC-MS (ESI) [M+H] + :454.4. 1 H NMR (400MHz, CD3OD), 8.35 (s, 1H), 7.91 (s, 1H), 7.52 (dd, J = 10.4Hz, 2.8Hz, 1H), 7.4 6(s,1H),7.23(dd,J=8.4Hz,5.6Hz,1H),7.07(td,J=8.4Hz,2.8Hz,1H),6.23(d,J=1 .6Hz,1H),5.14-5.20(m,1H),4.12-4.22(m,2H),3.94(d,J=15.6Hz,1H),3.91(s,1H ), 3.24 (d, J = 15.6Hz, 1H), 2.39 (s, 3H), 1.83 (d, J = 6.0Hz, 3H), 1.37 (t, J = 7.2Hz, 3H).

[0685] Example 277: (20R)-3-Ethyl-5-ethynyl-17-fluoro-20-methyl-21-oxa-3,4,10,12,24-pentaazapentacyclo[20.3.1.0 2,6 .08,13 .0 14,19 Hexadecene-1(25),2(6),4,8(9),10,12,14(15),16,18,22(26),23-undecene-23-amine

[0686] The synthesis method of Example 277 is the same as that of Example 1. LC-MS (ESI) [M+H] + :441.4. 1 H NMR(400MHz, CDCl3),9.15(s,1H),9.11(s,1H),7.50(s,1H),7.35(dd,J=9.6Hz ,2.4Hz,1H),7.10(dd,J=8.4Hz,5.6Hz,1H),7.05(td,J=8.4Hz,2.4Hz,1H),6.1 4(s,1H),5.12-5.29(m,3H),4.15(q,J=6.8Hz,2H),4.02(d,J=15.6Hz,1H),3.3 6(s,1H),3.29(d,J=15.6Hz,1H),1.86(d,J=6.0Hz,3H),1.41(t,J=7.2Hz,3H).

[0687] Example 278: (20R)-3-Ethyl-5-ethynyl-17-fluoro-11,20-dimethyl-21-oxa-3,4,10,12,24-pentaazapentacyclo[20.3.1.0 2,6 .0 8,13 .0 14,19 Hexadecene-1(25),2(6),4,8(9),10,12,14(15),16,18,22(26),23-undecene-23-amine

[0688] The synthesis method of Example 278 is the same as that of Example 1. LC-MS (ESI) [M+H] + :455.4.

[0689] Example 279: (20R)-3-Ethyl-5-ethynyl-17-fluoro-20-methyl-21-oxa-3,4,11,12,24-pentaazapentacyclo[20.3.1.0 2,6 .0 8,13 .0 14,19 Hexadecene-1(25),2(6),4,8(9),10,12,14(15),16,18,22(26),23-undecene-23-amine

[0690] The synthesis method of Example 279 is the same as that of Example 1. LC-MS (ESI) [M+H] + :441.3.

[0691] Example 280: (19R)-3-Ethyl-5-ethynyl-16-fluoro-19-methyl-9,20-dioxa-3,4,11,23-tetraazapentacyclo[19.3.1.0 2,6 .0 8,12 .0 13,18 ]pentacosyl-1(24),2(6),4,8(12),10,13(14),15,17,21(25),22-decen-22-amine

[0692] The synthesis method of Example 280 is the same as that of Example 1. LC-MS (ESI) [M+H] + :430.4.

[0693] Example 281: (19R)-3-Ethyl-5-ethynyl-16-fluoro-19-methyl-20-oxa-3,4,11,23-tetraaza-9-thiapentacyclo[19.3.1.0 2,6 .0 8,12 .0 13,18 ]pentacosyl-1(24),2(6),4,8(12),10,13(14),15,17,21(25),22-decen-22-amine

[0694] The synthesis method of Example 281 is the same as that of Example 1. LC-MS (ESI) [M+H] + :446.3. 1 H NMR(400MHz,CD3OD+CDCl3),8.75(s,1H),7.34-7.60(brs,1H),7.26-7.29(m,1H),7.09(dd,J=8.4Hz,5.6Hz,1H),6.98(td,J=8.4Hz,2.8Hz ,1H),6.32(s,1H),5.06-5.13(m,1H),4.01-4.11(m,3H),3.40(d,J=16.0Hz,1H),3.34(s,1H),1.75(d,J=6.4Hz,3H),1.33(t,J=7.2Hz,3H).

[0695] Example 282: (19R)-3-Ethyl-5-ethynyl-16-fluoro-19-methyl-10-(trideuteriomethyl)-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .013,18 .0 2,6 ]pentacosyl-1(24),2(6),4,8(9),11,13(14),15,17,21(25),22-decen-22-amine

[0696] The synthesis method of Example 282 is the same as that of Example 1. LC-MS (ESI) [M+H] + :446.3. 1 H NMR (400MHz, CDCl3), 7.52 (s, 1H), 7.43 (s, 1H), 7.28 (dd, J = 10.0Hz, 2.8Hz, 1H), 7.13(dd,J=8.4Hz,5.6Hz,1H),7.00(td,J=8.4Hz,2.8Hz,1H),6.52(d,J=1.2Hz,1 H),5.38-5.44(m,1H),4.87(s,2H),4.09-4.15(m,2H),3.79(d,J=15.6Hz,1H),3 .30(s,1H),2.92(d,J=15.6Hz,1H),1.79(d,J=6.4Hz,3H),1.40(t,J=7.2Hz,3H).

[0697] Example 283: (20R)-3-Ethyl-5-ethynyl-10,17-difluoro-20-methyl-21-oxa-3,4,12,24-tetraazapentacyclo[20.3.1.0 8,13 .0 14,19 .0 2,6 Hexadecene-1(25),2(6),4,8(9),10,12,14(19),15,17,22(26),23-undecene-23-amine

[0698] The synthesis method of Example 283 is the same as that of Example 1. LC-MS (ESI) [M+H] + :458.3. 1H NMR(400MHz, CDCl3),8.43(d,J=2.0Hz,1H),7.78(dd,J=9.6Hz,2.4Hz,1H),7.42-7.52(brs,1H ),7.30(dd,J=9.6Hz,2.4Hz,1H),7.12(dd,J=8.4Hz,5.6Hz,1H),7.03(td,J=8.4Hz,2.4Hz,1H), 6.23(s,1H),5.54-5.74(brs,2H),5.15-5.20(m,1H),4.16(q,J=7.2Hz,2H),3.99(d,J=15.6Hz, 1H), 3.36 (s, 1H), 3.30 (dd, J = 15.6Hz, 1.6Hz, 1H), 1.84 (d, J = 6.4Hz, 3H), 1.44 (t, J = 7.2Hz, 3H).

[0699] Example 284: (20R)-3-Ethyl-5-ethynyl-17-fluoro-11-methoxy-20-methyl-21-oxa-3,4,12,24-tetraazapentacyclo[20.3.1.0 8,13 .0 14,19 .0 2,6 Hexadecene-1(26),2(6),4,8(9),10,12,14(19),15,17,22(23),24-undecene-23-amine

[0700] The synthesis method of Example 284 is the same as that of Example 1. LC-MS (ESI) [M+H] + :470.4. 1 H NMR(400MHz, CD3OD),7.92(d,J=8.8Hz,1H),7.50(dd,J=10.0Hz,2.8Hz,1H),7.44(d,J= 2.0Hz, 1H), 7.20 (dd, J=8.4Hz, 6.0Hz, 1H), 7.05 (td, J=8.4Hz, 2.8Hz, 1H), 6.83 (d, J=8.8 Hz,1H),6.37(d,J=1.6Hz,1H),5.33-5.39(m,1H),4.10-4.20(m,2H),3.89(s,4H),3.88 (d, J=15.6Hz, 1H), 3.23 (d, J=15.6Hz, 1H), 1.86 (d, J=6.4Hz, 3H), 1.35 (t, J=7.2Hz, 3H).

[0701] Example 285: (19R)-3-(Cyclopropylmethyl)-5-ethynyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosyl-1(24),2(6),4,8(9),11,13(18),14,16,21(25),22-decen-22-amine

[0702] The synthesis method of Example 285 is the same as that of Example 1. LC-MS (ESI) [M+H] + :469.4. 1 H NMR(400MHz, CDCl3),7.50-7.74(brs,1H),7.45(s,1H),7.25-7.28(m,1H),7.15(dd,J=8.4Hz,5.6 Hz,1H),7.03(td,J=8.4Hz,2.8Hz,1H),6.60(s,1H),5.58-6.14(brs,2H),5.40-5.46(m,1H),4.08 (dd,J=14.0Hz,6.0Hz,1H),3.92(s,3H),3.80-3.87(m,2H),3.32(s,1H),2.92(d,J=15.2Hz,1H),1 .82(d,J=6.4Hz,3H),1.13-1.24(m,1H),0.42-0.56(m,2H),0.30-0.38(m,1H),0.14-0.22(m,1H).

[0703] Example 286: (19R)-5-ethynyl-16-fluoro-3-(2-methoxyethyl)-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0704] The synthesis method of Example 286 is the same as that of Example 1. LC-MS (ESI) [M+H] + :473.5. 1H NMR(400MHz, CDCl3),7.80(d,J=1.6Hz,1H),7.43(s,1H),7.28(dd,J=10.0Hz,2.4Hz,1H),7.11(dd ,J=8.4Hz,6.0Hz,1H),6.98(td,J=8.4Hz,2.4Hz,1H),6.50(d,J=1.6Hz,1H),5.36-5.41(m,1H),4. 83(s,2H),4.24-4.31(m,1H),4.08-4.14(m,1H),3.90(s,3H),3.84-3.89(m,1H),3.77(d,J=15.6H z,1H),3.70-3.75(m,1H),3.31(s,1H),3.23(s,3H),2.92(d,J=15.6Hz,1H),1.77(d,J=6.4Hz,3H).

[0705] Example 287: 2-[(19R)-22-amino-5-ethynyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decen-3-yl]ethan-1-ol

[0706] The synthesis method of Example 287 is the same as that of Example 1. LC-MS (ESI) [M+H] + :459.4. 1 H NMR(400MHz, CDCl3),7.52-7.64(brs,1H),7.41(s,1H),7.28(dd,J=10.0Hz,2.8Hz,1H) ,7.11(dd,J=8.4Hz,5.6Hz,1H),6.98(td,J=8.4Hz,2.8Hz,1H),6.49(s,1H),5.35-5.42 (m,1H),4.93(s,2H),4.22-4.28(m,1H),4.08-4.13(m,1H),3.94-4.01(m,2H),3.91(s, 3H), 3.78 (d, J = 15.6Hz, 1H), 3.31 (s, 1H), 2.92 (d, J = 15.6Hz, 1H), 1.77 (d, J = 6.4Hz, 3H).

[0707] Example 288: (19R)-5-ethynyl-16-fluoro-10,19-dimethyl-3-(1,1,1-trifluoroeth-2-yl)-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0708] The synthesis method of Example 288 is the same as that of Example 1. LC-MS (ESI) [M+H] + :497.5. 1 H NMR(400MHz, CDCl3),7.49-7.58(brs,1H),7.45(s,1H),7.29(dd,J=10.0Hz,2.4Hz,1H),2.12(dd,J=8.4Hz,6.0Hz,1H),7.00(td,J=8.4Hz,2.4Hz,1H),6.48 (s,1H),5.38-5.47(m,1H),4.87(s,2H),4.56-4.78(m,2H),3.93(s,3H),3.79 (d, J=15.6Hz, 1H), 3.35 (s, 1H), 2.95 (d, J=15.6Hz, 1H), 1.80 (d, J=6.4Hz, 3H).

[0709] Example 289: (19R)-3-(Difluoromethyl)-5-ethynyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0710] The synthesis method of Example 289 is the same as that of Example 1. LC-MS (ESI) [M+H] + :465.4. 1H NMR(400MHz, CD3OD),7.58(s,1H),7.55(dd,J=10.0Hz,2.8Hz,1H),7.49(s,1H),7.38(t,J=58.0Hz,1H),7.21(dd,J=8.4Hz,5.6Hz,1H),7.09(td,J=8.4H z,2.8Hz,1H),6.53(d,J=2.0Hz,1H),5.41-5.47(m,1H),4.03(s,1H),3.92(s ,3H),3.81(d,J=15.6HZ,1H),2.96(d,J=15.6Hz,1H),1.82(d,J=6.4Hz,3H).

[0711] Example 290: (19R)-3-(Cyclopropylmethyl)-5-ethynyl-16-fluoro-19-methyl-10-(trideuteriomethyl)-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 8,12 .0 13,18 .0 2,6 ]pentacosa-1(25),2(6),4,8(9),11,13(18),14,16,21(22),23-decene-22-amine

[0712] The synthesis method of Example 290 is the same as that of Example 1. LC-MS (ESI) [M+H] + :472.5. 1 H NMR(400MHz, CDCl3),7.61(s,1H),7.45(s,1H),7.26(dd,J=9.6Hz,2.8Hz,1H),7.13(dd,J=8.4Hz,5.6Hz,1 H),7.00(t,J=8.4Hz,2.8Hz,1H),6.54(d,J=1.2Hz,1H),5.38-5.44(m,1H),5.06-5.52(brs,2H),4.07(dd,J =14.4Hz, 6.4Hz, 1H), 3.83 (dd, J = 14.4Hz, 7.2Hz, 1H), 3.79 (d, J = 15.6Hz, 1H), 3.31 (s, 1H), 2.91 (d, J = 15.6 Hz,1H),1.79(d,J=6.4Hz,3H),1.12-1.22(m,1H),0.40-0.52(m,2H),0.26-0.32(m,1H),0.12-0.18(m,1H).

[0713] Biological activity experiments

[0714] 1. Detection of ALK complex mutant kinase inhibitory activity of compounds (IC 50 Value determination)

[0715] In this patent, the homogeneous time-resolved fluorescence (HTRF) experimental system was used to establish ALK G1202R / L1196M and ALK I1171N / D1203N Kinase activity detection platform to measure compound activity. G1202R / L1196M Reaction buffer: 50 mM HEPES, pH 7.5; 0.1 mM Na3VO4; 0.001% Tween-20; 5 mM MnCl2; 1 mM DTT; 50 nM SEB (purchased from Cisbio) and 0.01% BSA. The final concentration of ATP was 4 μM, and the final concentration of TK peptide substrate was 2 μM (purchased from Cisbio). ALK I1171N / D1203N Reaction buffer: 50 mM HEPES, pH 7.5; 0.1 mM Na₃VO₄; 0.001% Tween-20; 5 mM MnCl₂; 1 mM DTT; 10 nM SEB (Cisbio), and 0.01% BSA. The final concentration of ATP was 1 μM, and the final concentration of TK peptide substrate was 1 μM (Cisbio).

[0716] First, dilute the 10mM compound 50-fold with DMSO, then perform a 5-fold serial dilution (8 concentrations in total, including 0mM). Take 2μL of each diluted compound and add it to 48μL reaction buffer for dilution and mixing. Take 2.5μL of the diluted compound and add it to a 384-well plate (OptiPlate-384, purchased from PerkinElmer), then add 2.5μL of ATP and TK peptide substrate mixture, and then add 5μL of His-ALK G1202R / L1196M (final concentration 0.5nM) / His-ALK I1171N / D1203N (final concentration of 0.3nM), centrifuged, started the reaction, and the total reaction volume was 10μL. The 384-well plate was placed in an incubator at 23°C for 1 hour, and then 5μL ALK Antibody (purchased from Cisbio) and 5μL Streptavidin-XL665 (purchased from Cisbio) were added to stop the reaction. After incubation in the incubator for another 1 hour, the fluorescence value was read on the Envision machine (purchased from PerkinElmer) (320nm excitation, detection of 665nm and 620nm emission light, the ratio of the two is ALK G1202R / L1196M / ALK I1171N / D1203N The signal value of the compound at each concentration was measured and the activity signal of the compound on His-ALK was calculated using GraphPad Prism software. G1202R / L1196M / His-ALKG1202R / L1196M IC of enzyme inhibition 50 Value (Table 1). Data A in the table is high activity: IC 50 ≤5nM. ND means not detected.

[0717] Table 1. Effects of Example Compounds on ALK G1202R / L1196M The inhibitory effect

[0718] 2. Determination of cell proliferation inhibitory activity of compounds (IC 50 Value determination)

[0719] Baf3 EML4-ALK V1G1202R / L1196M cells and Baf3 EML4-ALK V1I1171N / D1203N cells were cultured in RPMI-1640 medium supplemented with 10% fetal bovine serum (FBS, Gibco, Brazil), 1% penicillin / streptomycin (P / S, Life Technology), and 2 μg / ml Puromycin (Solarbio). Cells were cultured in a 37°C, 5% CO2 incubator. The day before compound testing, Baf3 EML4-ALK V1G1202R / L1196M cells were plated at a density of 1000 cells / 195 μL / well in a 96-well plate (purchased from Corning), and Baf3 EML4-ALK V1I1171N / D1203N cells were plated at a density of 2000 cells / 195 μL / well in a 96-well plate. After 24 hours, the compound was diluted 3-fold with DMSO starting from 10 mM (a total of 11 concentrations), and then 4 μL of each concentration was added to 96 μL of serum-free medium for further dilution. After each concentration of the diluted compound, 5 μL was added to the cell culture plate and placed in a cell culture incubator for further culture for 3 days. After 3 days, 35 μL of Cell-Titer Glo reagent (purchased from Promega) was added directly to the culture medium. Incubate at room temperature for 5-10 minutes. The fluorescence signal value was read on the Envision machine, and the IC value of the compound for cell proliferation inhibition was calculated using GraphPadPrism software. 50 Value. (Table 2). Data A in the table is high activity: IC 50 ≤10nM.

[0720] Table 2. Effect of Example Compounds on BaF3 EML4-ALK G1202R / L1196M Inhibitory effect on cell proliferation

[0721] 3. Pharmacokinetic data Male SD rats were obtained from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd. The rats were divided into groups of 3 in each group and were orally administered a single oral gavage with the test sample suspension (5 mg / kg). The animals were fasted overnight before the experiment, and the fasting period was from 10 hours before administration to 4 hours after administration. Blood was collected at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration. After anesthesia with isoflurane using a small animal anesthesia machine, 0.3 mL of whole blood was collected through the fundus venous plexus and placed in a heparin anticoagulant tube. The sample was centrifuged at 4°C and 4000 rpm for 5 minutes. The plasma was transferred to a centrifuge tube and stored at -80°C until analysis. The sample in the plasma was extracted using a protein precipitation method, and the extract was analyzed by LC / MS / MS (Table 3).

[0722] Table 3. Pharmacokinetic data of example compounds

[0723] 4. In vivo pharmacodynamics of the example compounds in ALK mutant cell line xenograft models

[0724] The compound was prepared as a solution at a dose of 10 mL / kg in a 20% Hp-β-CD vehicle. The experimental animals used were obtained from Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd. Female BALB / c-nude mice, 6-8 weeks old. Ba / F3EML4-ALK G1202R / L1196M Mutant cells were cultured in RPMI1640 medium supplemented with 10% fetal bovine serum, 100 U / mL penicillin, 100 μg / mL streptomycin, and 2 μg / mL puromycin at 37°C in a 5% CO2 incubator. Cells were passaged twice weekly. When cell saturation reached 80%-90% and the desired number of cells was reached, cells were harvested, counted, and plated.

[0725] Place Ba / F3 EML4-ALK G1202R / L1196M Mutant cells (1×10 6 cells / 0.1 mL) were subcutaneously inoculated on the back of each mouse, and the average tumor volume reached about 150 mm 3 The mice were weighed three times a week and the tumor diameter was measured three times with a vernier caliper (Table 4). The tumor volume was calculated as follows: V = 0.5 × a × b 2, a and b represent the long diameter and short diameter of the tumor, respectively. The anti-tumor efficacy of the compound was evaluated using TGl (%) or relative tumor growth rate T / C (%). Tumor growth inhibition rate TGI (%), TGI (%) = [1-(average tumor volume of a treatment group at the end of drug administration - average tumor volume of the treatment group at the beginning of drug administration) / (average tumor volume of the solvent control group at the end of treatment - average tumor volume of the solvent control group at the beginning of treatment)] × 100%. Relative tumor growth rate T / C (%) = T RTV / C RTV ×100%(T RTV : Average RTV value of treatment group; C RTV : Average RTV of negative control group). Relative tumor volume (RTV) was calculated based on the results of tumor measurement. The calculation formula is RTV = Vt / Vo, where V0 is the tumor volume measured at the time of group administration (i.e., day 0), Vt is the tumor volume at a certain measurement, and T RTV with C RTV Data from Ba / F3 EML4-ALK G1202R / L1196M The results of the mutant cell mouse xenograft tumor model experiment showed that the compound of the present invention has the following effects on Ba / F3 EML4-ALK G1202R / L1196M It showed excellent tumor inhibitory effect and safety in mutant cell tumor models.

[0726] Table 4. Example compounds in Ba / F3 EML4-ALK G1202R / L1196M In vivo evaluation of tumor suppressor efficacy in models

Claims

1. A compound of formula (II) or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof: in, R is independently H, halogen, -CN, or C 1-4 Alkyl, or two R's are linked together to form a 3-4 membered carbon ring, Y is -O- or -NR 10 -, R 10 H or C 1-6 alkyl, R1 is H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, or 3-6 membered cycloalkyl, said alkyl, alkenyl and cycloalkyl may be optionally substituted by halogen, -OH or -NH2, or R1 may optionally be 10 are connected together to form a 4-8 membered heterocyclic ring, which may be optionally substituted by halogen, -CN, -OH or -NH2, X5 is N or CR9, R8 and R9 are each independently H, F, Cl, or ethynyl, X4 is N and CH, X3 is N and CH, Ring A and Ring B are 5-6 membered aromatic rings. R2 and R3 are each independently H, halogen, -CN, C 1-4 Alkyl, -OC 1-4 Alkyl, halogenated C 1-4 Alkyl, 3-4 membered cycloalkylmethyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclic group, or The alkyl, methyl, cycloalkyl and heterocyclic groups may be optionally substituted with halogen, -CN, -OH, -NH2, C 2-6 Alkenyl, or C 2-6 Alkynyl substitution, R4 and R5 are each independently H, halogen, -CN, C 1-4 Alkyl, -OC 1-4 Alkyl, halogenated C 1-4 alkyl, or The alkyl group may be optionally substituted with halogen, -CN, -OH, -NH2, C 2-6 Alkenyl, or C 2-6 Alkynyl substitution, X3, R2, R3, R4 and R5 must meet the following conditions: When X3 is CH, At least one of R2, R3, R4 and R5 is or R a H, halogen, C 1-6 Alkyl or halogenated C 1-6 alkyl, R b H, halogen, C 1-6 Alkyl or halogenated C 1-6 alkyl, R c H, halogen, C 1-6 alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 6-10 membered aryl, 5-12 membered heteroaryl, -(CO)-NH2, -(CO)-NH-C 1-6 Alkyl, -(CO)-OC 1-6 Alkyl, -(CO)-C 1-6 Alkyl, the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be optionally substituted with halogen, -OH, -NH2, -CN, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)(C 1-6 alkyl) substituted, or R b and R c They may be optionally linked together to form a 4-8 membered carbocyclic ring or a 4-8 membered heterocyclic ring, and the carbocyclic ring and the heterocyclic ring may be optionally substituted by halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, or -N(C 1-6 Alkyl)(C 1-6 alkyl), wherein the alkyl, alkenyl and alkynyl groups may be optionally substituted by halogen, -OH, -NH2, or -CN, R d Each independently is C 1-6 alkyl.

2. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof, wherein Y is -O-, R1 is H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, or 3-6 membered cycloalkyl, said alkyl, alkenyl and cycloalkyl may be optionally substituted by halogen, -OH or -NH2, R8 and R9 are each independently H or F.

3. The compound according to claim 2 or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof, wherein R2 and R3 are each independently H, halogen, -CN, C 1-4 Alkyl, -OC 1-4 Alkyl, halogenated C 1-4 Alkyl, 3-4 membered cycloalkylmethyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclic group, or The alkyl, methyl, cycloalkyl and heterocyclic groups may be optionally substituted with halogen, -CN, -OH, -NH2, C 2-6 Alkenyl, or C 2-6 Alkynyl substitution, R4 and R5 are each independently H, halogen, -CN, C 1-4 Alkyl, -OC 1-4 Alkyl, halogenated C 1-4 alkyl, or The alkyl group may be optionally substituted with halogen, -CN, -OH, -NH2, C 2-6 Alkenyl, or C 2-6 Alkynyl substitution, X3, R2, R3, R4 and R5 must meet the following conditions: When X3 is CH, At least one of R2, R3, R4 and R5 is or R a , R b and R c As defined in claim 1.

4. The compound according to claim 2, or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof, wherein R is H.

5. The compound according to claim 2 or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof, wherein R8 is F.

6. The compound according to claim 2 or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof, wherein R1 is methyl or ethyl.

7. The following compound or its pharmaceutically acceptable salt, solvate, polymorph, or isomer:

8. A pharmaceutical composition comprising the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, and optionally comprising a pharmaceutically acceptable carrier.

9. Use of a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, or a composition according to claim 8 in the preparation of a medicament for treating an ALK-mediated disease.

10. The use according to claim 9, wherein the ALK-mediated disease is ALK-positive non-small cell lung cancer, anaplastic large cell lymphoma, inflammatory myofibroblastic tumor, nasopharyngeal carcinoma, breast cancer, colorectal cancer, diffuse large B-cell lymphoma, systemic histiocytosis, or neuroblastoma.

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