Spiro compound, and preparation method therefor and use thereof

Abstract

A spiro compound, and a preparation method therefor and a use thereof. Specifically, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, a pharmaceutical composition comprising the compound, a preparation method therefor, and a use thereof in preparation of a drug for preventing or treating KRAS-mediated related diseases.

Description

Spirocyclic compound, preparation method and use thereof Technical Field

[0001] The present invention belongs to the field of medicine, and in particular relates to a spirocyclic compound, a preparation method thereof and uses thereof. Background Art

[0002] RAS is a guanine nucleotide-binding protein with GTPase activity that anchors to the inner side of the cell membrane. RAS proteins can transition between an inactive, GDP-bound state and an active, GTP-bound state, influencing downstream signaling pathways such as Raf, PI3K, and RalGDS, regulating protein synthesis, gene transcription, cell growth, differentiation, apoptosis, and migration.

[0003] RAS mutations lead to persistent activation of downstream signaling pathways, promoting tumor development and progression. Across all tumor types, RAS mutations primarily occur in KRAS (85%). In KRAS-mutated tumor cells, KRAS GTPase activity decreases, remaining persistently active. KRAS mutations are closely associated with the development of various cancers, including lung, pancreatic, and colorectal cancers.

[0004] Proteolysis-Targeting Chimeras (PROTAC) are bifunctional molecules whose structure consists of three parts: (1) a part that binds to the target protein substrate; (2) a part that binds to the E3 ubiquitin ligase; and (3) a chain connecting the first two parts. PROTAC can recognize the target protein and E3 ubiquitin ligase respectively, shorten the distance between the target protein and the E3 ubiquitin ligase, and induce the ubiquitination process and induce the degradation of the target protein by inducing the recruitment of the E3 ubiquitin ligase to the surface of the target protein. PROTAC has the advantages of a wide range of pharmacological activities, high target selectivity, can be used to degrade difficult-to-drug target proteins, has strong degradation efficacy, and can maintain catalytic degradation at low concentrations.

[0005] There is an urgent need in this field to develop KRAS PROTACs with novel structure, good biological activity, safety and efficacy.

[0006] SUMMARY OF THE INVENTION

[0007] The present invention provides compounds that can be used as degraders and / or inhibitors targeting the KRAS protein. The compounds of the present invention are PROTACs, one end of which can bind to the target protein, while the high-affinity VHL ligand at the other end can recruit the target protein to the E3 ubiquitin ligase, leading to ubiquitination and subsequent degradation of the KRAS protein. The compounds of the present invention can be used to treat and / or prevent cancers or diseases caused by aggregation and / or overactivation of the target protein.

[0008] In one aspect, the present invention provides a compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein the compound has the structure of Formula (I):

[0009] in,

[0010] Ring A is C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the cycloalkyl or heterocyclic group is optionally substituted by one or more selected from halogen, C 1-6 Alkyl and C 1-6 Substitution of haloalkyl groups;

[0011] Ring B is a 3-12 membered nitrogen-containing heterocyclic group;

[0012] X 1 and X 2 are each independently selected from O and N;

[0013] X 3 、X 4 and X 5 Each independently selected from CR 7 and N;

[0014] L is a covalent bond, or is selected from O, S and NR 8 ;

[0015] L 1 Selected from O, S and NR 9 ;

[0016] L 2 is a covalent bond, or is selected from C 1-6 Alkylene and halogenated C 1-6 alkylene;

[0017] L 3 is a covalent bond, or is selected from C 1-6 Alkylene and halogenated C 1-6 alkylene;

[0018] L 4 is a covalent bond, or is selected from O, NR 10 、C 1-6 Alkylene, -OC 1-6 Alkylene-, -C 1-6 Alkylene-O-, -C 1-6 Alkylene-NR 10 -、-C 1-6 Alkylene-OC 1-6 Alkylene-, C 3-6 Cycloalkyl and 3-10 membered heterocyclic groups, wherein the cycloalkyl and heterocyclic groups are optionally substituted by one or more selected from halogen, hydroxyl, cyano, C1-6 Alkyl, C 1-6 Substitution of haloalkyl groups;

[0019] L 5 Selected from -C(=O)-NR 11 -、-C 1-6 Alkylene-C(=O)-NR 11 - and 5-10 membered heteroaryl, said heteroaryl being optionally substituted by one or more selected from halogen, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Substitution of haloalkyl groups;

[0020] Each R 1 independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, -OC 3-6 Cycloalkyl and 3-6 membered heterocyclic groups;

[0021] R 2 Selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 6-10 Aryl, 3-12 membered heterocyclic group, 5-10 membered heteroaryl, -C 1-6 Alkylene-C 3-6 Cycloalkyl, -C 1-6 Alkylene-3-10 membered heterocyclic group and -C 1-6 Alkylene-5-10 membered heteroaryl, wherein the alkyl, cycloalkyl, aryl, heterocyclic and heteroaryl groups are optionally substituted by one or more selected from halogen, hydroxy, amino, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -C 1-6 Alkylene -OH, -OC 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclic group, 5-10 membered heteroaryl, -NR 12a R 12b 、-C 1-6 Alkylene-OC 1-6 Alkyl and -C(=O)-NR 12a R 12b wherein the alkyl, cycloalkyl, phenyl, heterocyclic and heteroaryl groups in the substituents are optionally further substituted with one or more halogen, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC1-6 Alkyl, -C 1-6 Alkylene -OH, -OC 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, phenyl, 3-10 membered heterocyclic group, 5-10 membered heteroaryl, -NR 12a R 12b 、-C 1-6 Alkylene-OC 1-6 Alkyl and -C(=O)-NR 12a R 12b Substituents substituted;

[0022] R 3 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-6 Cycloalkyl;

[0023] R 4a and R 4b are each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkylene -OH and C 3-6 Cycloalkyl; or

[0024] R 4a and R 4b Together with the carbon atoms connected to form C 3-6 Cycloalkyl or 3-6 membered heterocyclic group;

[0025] R 5 is selected from halogen, phenyl and 5-6 membered heteroaryl, wherein the phenyl and heteroaryl are optionally substituted by one or more selected from halogen, hydroxy, cyano, C 1-6 Alkyl and C 1-6 Substitution of haloalkyl groups;

[0026] Each R 6 are independently selected from hydrogen, halogen, hydroxyl, C 1-6 Alkyl and C 1-6 haloalkyl; or

[0027] R 5 and adjacent R 6 and the carbon atoms to which they are connected together form a benzene ring or a 5-6 membered heteroaromatic ring, wherein the benzene ring and the heteroaromatic ring are optionally substituted by one or more selected from halogen, C 1-6 Alkyl and C 1-6 Substitution of haloalkyl groups;

[0028] Each R 7 are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C3-6 Cycloalkyl, C 1-6 Alkoxy and C 1-6 Haloalkyl-O-;

[0029] R 8 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-6 Cycloalkyl;

[0030] R 9 Selected from hydrogen and C 1-6 alkyl;

[0031] R 10 Selected from hydrogen and C 1-6 alkyl;

[0032] R 11 Selected from hydrogen and C 1-6 alkyl;

[0033] R 12a and R 12b are each independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, -C 1-6 Alkylene -OH and -C 1-6 Alkylene-OC 1-6 Alkyl, or R 12a and R 12b The nitrogen to which it is connected forms a 3-6 membered nitrogen-containing heterocyclic group;

[0034] m is selected from 0, 1, 2, 3, 4, 5 and 6;

[0035] n is selected from 0, 1, 2, 3 and 4.

[0036] On the other hand, the present invention provides a pharmaceutical composition comprising a prophylactically and / or therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, and one or more pharmaceutically acceptable carriers.

[0037] In another aspect, the present invention provides a kit comprising a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention, and optionally instructions.

[0038] On the other hand, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention, or a drug kit of the present invention, which targets KRAS protein and is used to degrade KRAS protein.

[0039] On the other hand, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention, or a drug kit of the present invention, for use in preventing and / or treating KRAS-mediated related diseases.

[0040] In another aspect, the present invention provides use of a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention, or a pharmaceutical kit of the present invention in the preparation of a medicament for preventing and / or treating KRAS-mediated related diseases.

[0041] On the other hand, the present invention provides a method for preventing and / or treating KRAS-mediated related diseases, comprising administering to an individual in need thereof a preventively and / or therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention or a pharmaceutical kit of the present invention.

[0042] In another aspect, the present invention provides methods of preparing the compounds of the present invention.

[0043] Detailed Description of the Invention

[0044] definition

[0045] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as those commonly understood by those skilled in the art. References to technology used herein are intended to refer to technology commonly understood in the art, including variations of technology or substitutions of equivalent technology that would be apparent to those skilled in the art. While it is believed that the following terms are well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.

[0046] As used herein, the terms "comprises," "comprising," "having," "containing," or "involving," and variations thereof herein, are inclusive or open-ended and do not exclude additional unrecited elements or method steps.

[0047] As used herein, the term "alkyl" is defined as a straight-chain or branched saturated aliphatic hydrocarbon group. For example, as used herein, the term "C 1-6 "Alkyl" refers to a straight or branched chain group having 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl), which is optionally substituted by one or more (such as 1, 2 or 3) suitable substituents such as halogen.

[0048] As used herein, the term "alkylene" refers to a divalent saturated aliphatic hydrocarbon group derived from the corresponding "alkyl" by removing one hydrogen atom. For example, as used herein, the term "C 1-6 "Alkylene" refers to an alkylene group having 1 to 6 carbon atoms, for example methylene (-CH2-), ethylene (-CH2CH2-), isopropylene (-CH(CH3)CH2-), which is optionally substituted by one or more (such as 1, 2 or 3) suitable substituents such as halogen.

[0049] As used herein, the term "alkenyl" refers to a straight or branched aliphatic hydrocarbon group having one or more carbon-carbon double bonds. 2-6 The term "alkenyl" refers to an alkenyl group having 2 to 6 carbon atoms and one, two or three (preferably one) carbon-carbon double bonds (such as vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl or 4-methyl-3-pentenyl, etc.), which is optionally substituted by one or more (such as 1, 2 or 3) suitable substituents such as halogen.

[0050] As used herein, the term "alkynyl" refers to a straight or branched aliphatic hydrocarbon group having one or more carbon-carbon triple bonds. 2-6 The term "alkynyl" refers to an alkynyl group having 2 to 6 carbon atoms and one, two or three (preferably one) carbon-carbon triple bonds (such as ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl or 5-hexynyl, etc.), which is optionally substituted by one or more (such as 1, 2 or 3) suitable substituents such as halogen.

[0051] As used herein, the term "cycloalkyl" refers to a saturated or partially unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or cyclononyl, or a bicyclic ring, including spirocyclic, fused or bridged systems such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl or bicyclo[5.2.0]nonyl, decahydronaphthyl, etc.), which is optionally substituted with one or more (such as 1 to 3) suitable substituents. For example, the term "C 3- "6-cycloalkyl" refers to a saturated or partially unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring having 3 to 6 ring carbon atoms (for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), which is optionally substituted with one or more (such as 1, 2 or 3) suitable substituents, for example methyl-substituted cyclopropyl.

[0052] As used herein, the term "cycloalkylene" refers to a divalent group derived from a corresponding "cycloalkyl" by removing a hydrogen atom.

[0053] As used herein, the term "halo" or "halogen" group is defined to include fluorine, chlorine, bromine, or iodine.

[0054] As used herein, the term "haloalkyl" refers to an alkyl group substituted by one or more (such as 1, 2 or 3) the same or different halogen atoms. For example, the term "C 1-6 "Haloalkyl" refers to a haloalkyl group having 1 to 6 carbon atoms, for example, -CF3, -C2F5, -CHF2, -CH2F, -CH2CF3, -CH2Cl or -CH2CH2CF3.

[0055] As used herein, the term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic group (including bridged, fused or spirocyclic rings), for example, having 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms and one or more (e.g., 1, 2, 3 or 4) independently selected from N, O or S(O) in the ring. t (wherein t is 0, 1 or 2) a heteroatom, such as a 3-12 membered heterocyclyl, a 3-7 membered heterocyclyl, a 3-6 membered heterocyclyl, a 5-6 membered heterocyclyl, etc. Representative examples of heterocyclyl include, but are not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyrrolidinyl, hexahydro-1H-pyrroline, pyrrolidonyl, imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl or piperazinyl.

[0056] As used herein, the term "nitrogen-containing heterocyclic group" refers to a group containing at least one nitrogen heteroatom, optionally containing one or more (e.g., 1, 2, 3 or 4) nitrogen heterocyclic groups selected from O or S(O) t (wherein t is 0, 1 or 2) heterocyclic group containing a heteroatom, which may include nitrogen-containing monocyclic heterocyclic group or polycyclic heterocyclic group (e.g., nitrogen-containing bridged heterocyclic group, nitrogen-containing heterocyclic group, nitrogen-containing spiro heterocyclic group), such as azetidinyl, piperidinyl, etc.

[0057] As used herein, the term "heterocyclylene" refers to a divalent group obtained by removing a hydrogen atom from a corresponding "heterocyclyl".

[0058] As used herein, the term "aryl" or "aromatic ring" refers to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated π electron system. For example, the term "C 6-10 Aryl" or "C 6-10 "Aromatic ring" refers to an aromatic group containing 6 to 10 carbon atoms, such as phenyl (ring) or naphthyl (ring). The aryl group is optionally substituted by one or more (such as 1, 2 or 3) suitable substituents (for example, halogen, -OH, -CN, -NO2 or C 1-6 alkyl, etc.) substituted.

[0059] As used herein, the term "heteroaryl" or "heteroaromatic ring" refers to a monocyclic, bicyclic or tricyclic aromatic ring system containing at least one heteroatom selected from N, O and S, for example having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular containing 1, 2, 3, 4, 5, 6, 9 or 10 carbon atoms, and in each case may be benzo-fused. For example, the heteroaryl or heteroaromatic ring can be selected from thienyl (ring), furanyl (ring), pyrrolyl (ring), oxazolyl (ring), thiazolyl (ring), imidazolyl (ring), pyrazolyl (ring), isoxazolyl (ring), isothiazolyl (ring), oxadiazolyl (ring), triazolyl (ring), thiadiazolyl (ring) and the like, and benzo derivatives thereof; or pyridyl (ring), pyridazinyl (ring), pyrimidinyl (ring), pyrazinyl (ring), triazinyl (ring) and the like, and benzo derivatives thereof.

[0060] As used herein, the term "heteroarylene" refers to a divalent group derived from a corresponding "heteroaryl" by removing a hydrogen atom.

[0061] The term "substituted" means that one or more (e.g., 1, 2, 3, or 4) hydrogen atoms on the designated atom are replaced with a group selected from the indicated group, provided that the designated atom's normal valence in the present context is not exceeded and that the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0062] If a substituent is described as being "optionally substituted with," the substituent may be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as being optionally substituted with one or more of the substituents listed, one or more hydrogens on the carbon (to the extent of any hydrogens present) may be replaced, individually and / or collectively, with independently selected substituents or unsubstituted. If a nitrogen of a substituent is described as being optionally substituted with one or more of the substituents listed, one or more hydrogens on the nitrogen (to the extent of any hydrogens present) may each be replaced with an independently selected substituent or unsubstituted.

[0063] If a substituent is described as being "independently selected" from a group of groups, each substituent is selected independently of the other. Thus, each substituent may be the same as or different from another (other) substituent.

[0064] As used herein, the term "one or more" means 1 or more than 1, such as 2, 3, 4, 5, 6, 7, 8, 9 or 10, where reasonable.

[0065] Unless otherwise indicated, as used herein, the point of attachment of a substituent may be from any suitable position of the substituent.

[0066] When a bond to a substituent is shown to pass through a bond connecting two atoms in a ring, then such substituent may be bonded to any ring atom in the substitutable ring.

[0067] The present invention also includes all pharmaceutically acceptable isotopically labeled compounds which are identical to the compounds of the present invention except that one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number prevalent in nature. Examples of suitable isotopes for inclusion in the compounds of the present invention include, but are not limited to, isotopes of hydrogen (e.g., 2 H. 3 H, deuterium D, tritium T); carbon isotopes (such as 11 C. 13 C and 14 C); isotopes of chlorine (e.g. 37 Cl); isotopes of fluorine (e.g. 18 F); isotopes of iodine (such as 123 I and 125 I); isotopes of nitrogen (e.g. 13 N and 15 N); oxygen isotopes (e.g. 15 O. 17 O and 18 O); isotopes of phosphorus (such as 32 P); and sulfur isotopes (e.g. 35S). Certain isotopically labeled compounds of the invention (e.g., those incorporating radioactive isotopes) are useful in drug and / or substrate tissue distribution studies (e.g., assays). The radioactive isotope tritium (i.e., 3 H) and carbon-14 (i.e. 14 C) are particularly useful for this purpose because they are easy to incorporate and easy to detect. 11 C. 18 F. 15 O and 13 N) substitution can be used to examine substrate receptor occupancy in positron emission tomography (PET) studies. Isotopically labeled compounds of the present invention can be prepared by methods analogous to those described in the accompanying schemes and / or examples and preparations by using appropriate isotopically labeled reagents instead of the non-labeled reagents previously employed. Pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent is isotopically substituted, for example, D2O, acetone-d6 or DMSO-d6.

[0068] The term "stereoisomer" refers to an isomer formed due to at least one asymmetric center. In compounds with one or more (e.g., 1, 2, 3, or 4) asymmetric centers, racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers can be produced. Specific individual molecules can also exist as geometric isomers (cis / trans). Similarly, the compounds of the present invention can exist as mixtures of two or more structurally different forms in rapid equilibrium (commonly referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. It is understood that the scope of this application encompasses all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0069] The present invention encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be single polymorphs or mixtures of more than one polymorph in any ratio.

[0070] It should also be understood that certain compounds of the present invention may be used therapeutically in free form or, where appropriate, in the form of pharmaceutically acceptable derivatives thereof. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, solvates, metabolites, or prodrugs that, upon administration to a patient in need thereof, are capable of directly or indirectly providing a compound of the present invention or a metabolite or residue thereof. Therefore, when reference is made herein to a "compound of the present invention," such various derivative forms of the compound are also intended to be encompassed.

[0071] Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof. Suitable acid addition salts are formed from acids that form pharmaceutically acceptable salts. Suitable base addition salts are formed from bases that form pharmaceutically acceptable salts. For a review of suitable salts, see Stahl and Wermuth, "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the present invention are known to those skilled in the art.

[0072] The compounds of the present invention may exist in the form of solvates (preferably hydrates), wherein the compounds of the present invention contain a polar solvent as a structural element of the crystal lattice of the compound, in particular water, methanol or ethanol. The amount of polar solvent, in particular water, may be present in a stoichiometric or non-stoichiometric ratio.

[0073] Those skilled in the art will appreciate that not all nitrogen-containing heterocycles are capable of forming N-oxides, as nitrogen requires an available lone pair of electrons to oxidize to an oxide; those skilled in the art will recognize nitrogen-containing heterocycles that are capable of forming N-oxides. Those skilled in the art will also recognize that tertiary amines are capable of forming N-oxides. Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art and include oxidation of heterocycles and tertiary amines with peroxyacids such as peracetic acid and meta-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate, and dioxirane such as dimethyldioxirane. These methods for preparing N-oxides have been extensively described and reviewed in the literature, see for example: TL Gilchrist, Comprehensive Organic Synthesis, vol. 7, pp 748-750; AR Katritzky and AJ Boulton, Eds., Academic Press; and GWH Cheeseman and ESGWerstiuk, Advances in Heterocyclic Chemistry, vol. 22, pp 390-392, AR Katritzky and AJ Boulton, Eds., Academic Press.

[0074] Also included within the scope of the present invention are metabolites of the compounds of the invention, i.e., substances formed in vivo upon administration of the compounds of the invention. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc. of the administered compound. Thus, the present invention includes metabolites of the compounds of the invention, including compounds produced by contacting a compound of the invention with a mammal for a period of time sufficient to produce a metabolic product thereof.

[0075] The present invention further includes within its scope prodrugs of the compounds of the present invention, which are certain derivatives of the compounds of the present invention that may themselves have little or no pharmacological activity, and when administered to the body or thereon, can be converted into the compounds of the present invention having the desired activity by, for example, hydrolytic cleavage. Typically, such prodrugs will be functional group derivatives of the compounds that are readily converted into the desired therapeutically active compounds in vivo. Further information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems," Volume 14, ACS Symposium Series (T. Higuchi and V. Stella) and "Bioreversible Carriers in Drug Design," Pergamon Press, 1987 (E.B. Roche, ed., American Pharmaceutical Association). The prodrugs of the present invention can be prepared, for example, by replacing appropriate functional groups present in the compounds of the present invention with certain moieties known to those skilled in the art as "pro-moieties" (e.g., as described in "Design of Prodrugs," H. Bundgaard (Elsevier, 1985)).

[0076] The present invention also encompasses compounds of the present invention that contain protecting groups. During any process for preparing the compounds of the present invention, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules involved, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved using conventional protecting groups, for example, those described in Protective Groups in Organic Chemistry, ed. JFW McOmie, Plenum Press, 1973; and TW Greene & P.GM Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which references are incorporated herein by reference. Protecting groups can be removed at an appropriate subsequent stage using methods known in the art.

[0077] The term "about" means within ±10%, preferably within ±5%, and more preferably within ±2% of the stated numerical value.

[0078] Compound

[0079] The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof:

[0080] in,

[0081] Ring A is C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the cycloalkyl or heterocyclic group is optionally substituted by one or more selected from halogen, C 1-6 Alkyl and C 1-6 Substitution of haloalkyl groups;

[0082] Ring B is a 3-12 membered nitrogen-containing heterocyclic group;

[0083] X 1 and X 2 are each independently selected from O and N;

[0084] X 3 、X 4 and X 5 Each independently selected from CR 7 and N;

[0085] L is a covalent bond, or is selected from O, S and NR 8 ;

[0086] L 1 Selected from O, S and NR 9 ;

[0087] L 2 is a covalent bond, or is selected from C 1-6 Alkylene and halogenated C 1-6 alkylene;

[0088] L 3 is a covalent bond, or is selected from C 1-6 Alkylene and halogenated C 1-6 alkylene;

[0089] L 4 is a covalent bond, or is selected from O, NR 10 、C 1-6 Alkylene, -OC 1-6 Alkylene-, -C 1-6 Alkylene-O-, -C 1-6 Alkylene-NR 10 -、-C1-6 Alkylene-OC 1-6 Alkylene-, C 3-6 Cycloalkyl and 3-10 membered heterocyclic groups, wherein the cycloalkyl and heterocyclic groups are optionally substituted by one or more selected from halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Substitution of haloalkyl groups;

[0090] L 5 Selected from -C(=O)-NR 11 -、-C 1-6 Alkylene-C(=O)-NR 11 - and 5-10 membered heteroaryl, said heteroaryl being optionally substituted by one or more selected from halogen, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Substitution of haloalkyl groups;

[0091] Each R 1 independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, -OC 3-6 Cycloalkyl and 3-6 membered heterocyclic groups;

[0092] R 2 Selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 6-10 Aryl, 3-12 membered heterocyclic group, 5-10 membered heteroaryl, -C 1-6 Alkylene-C 3-6 Cycloalkyl, -C 1-6 Alkylene-3-10 membered heterocyclic group and -C 1-6 Alkylene-5-10 membered heteroaryl, wherein the alkyl, cycloalkyl, aryl, heterocyclic and heteroaryl groups are optionally substituted by one or more selected from halogen, hydroxy, amino, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -C 1-6 Alkylene -OH, -OC 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclic group, 5-10 membered heteroaryl, -NR 12a R 12b 、-C 1-6 Alkylene-OC 1-6 Alkyl and -C(=O)-NR 12a R 12bwherein the alkyl, cycloalkyl, phenyl, heterocyclic and heteroaryl groups in the substituents are optionally further substituted with one or more halogen, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -C 1-6 Alkylene -OH, -OC 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, phenyl, 3-10 membered heterocyclic group, 5-10 membered heteroaryl, -NR 12a R 12b 、-C 1-6 Alkylene-OC 1-6 Alkyl and -C(=O)-NR 12a R 12b Substituents substituted;

[0093] R 3 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-6 Cycloalkyl;

[0094] R 4a and R 4b are each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkylene -OH and C 3-6 Cycloalkyl; or

[0095] R 4a and R 4b Together with the carbon atoms connected to form C 3-6 Cycloalkyl or 3-6 membered heterocyclic group;

[0096] R 5 is selected from halogen, phenyl and 5-6 membered heteroaryl, wherein the phenyl and heteroaryl are optionally substituted by one or more selected from halogen, hydroxy, cyano, C 1-6 Alkyl and C 1-6 Substitution of haloalkyl groups;

[0097] Each R 6 are independently selected from hydrogen, halogen, hydroxyl, C 1-6 Alkyl and C 1-6 haloalkyl; or

[0098] R 5 and adjacent R 6 and the carbon atoms to which they are connected together form a benzene ring or a 5-6 membered heteroaromatic ring, wherein the benzene ring and the heteroaromatic ring are optionally substituted by one or more selected from halogen, C 1-6 Alkyl and C 1-6Substitution of haloalkyl groups;

[0099] Each R 7 are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy and C 1-6 Haloalkyl-O-;

[0100] R 8 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-6 Cycloalkyl;

[0101] R 9 Selected from hydrogen and C 1-6 alkyl;

[0102] R 10 Selected from hydrogen and C 1-6 alkyl;

[0103] R 11 Selected from hydrogen and C 1-6 alkyl;

[0104] R 12a and R 12b are each independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, -C 1-6 Alkylene -OH and -C 1-6 Alkylene-OC 1-6 Alkyl, or R 12a and R 12b The nitrogen to which it is connected forms a 3-6 membered nitrogen-containing heterocyclic group;

[0105] m is selected from 0, 1, 2, 3, 4, 5 and 6;

[0106] n is selected from 0, 1, 2, 3 and 4.

[0107] In some embodiments of the present invention, the compound of formula (I) has the structure of formula (II-A), formula (II-B), formula (II-C) or formula (II-D):

[0108] Among them, ring A, ring B, R 2 、R 3 、R 4a 、R 4b 、R 5 、R 6 ,L,L 1 、L 2 、L3 、L 4 、L 5 and n are as defined above.

[0109] In some embodiments of the present invention, L 1 It is -O-.

[0110] In some embodiments of the present invention, L 2 C 1-3 Alkylene.

[0111] In some embodiments of the present invention, L 2 It is -CH2-.

[0112] In some embodiments of the present invention, L 3 C 1-3 Alkylene.

[0113] In some embodiments of the present invention, L 3 It is -CH2-.

[0114] In some embodiments of the present invention, Ring A is C 3-6 Cycloalkyl.

[0115] In some embodiments of the present invention, Ring A is cyclopropyl.

[0116] In some embodiments of the present invention, L 2 C 1-3 Alkylene, L 3 C 1-3 Alkylene, Ring A is C 3-6 Cycloalkyl.

[0117] In some embodiments of the present invention, L 2 -CH2-, L 3 is -CH2-, ring A is C 3-6 Cycloalkyl.

[0118] In some embodiments of the present invention, L 2 -CH2-, L 3 is -CH2-, and ring A is cyclopropyl.

[0119] In some embodiments of the present invention, Ring B is a 4-8 membered nitrogen-containing monoheterocyclic group.

[0120] In some embodiments of the present invention, Ring B is a 4-6 membered nitrogen-containing monoheterocyclic group.

[0121] In some embodiments of the present invention, Ring B is azetidinyl or piperidinyl.

[0122] In some embodiments of the invention, Ring B is

[0123] In some embodiments of the present invention, L 4 It is a covalent bond.

[0124] In some embodiments of the present invention, L 5 It is a 5-10 membered heteroarylene group.

[0125] In some embodiments of the present invention, L 5 It is a 5-6 membered heteroarylene group.

[0126] In some embodiments of the present invention, L 5 It is a 5-6 membered nitrogen-containing heteroarylene group.

[0127] In some embodiments of the present invention, L 5 It is a triazole subunit.

[0128] In some embodiments of the present invention, L 5 for

[0129] In some embodiments of the present invention, R 3 C 1-6 alkyl.

[0130] In some embodiments of the present invention, R 3 C 3-6 alkyl.

[0131] In some embodiments of the present invention, R 3 is tert-butyl or isopropyl.

[0132] In some embodiments of the present invention, R 3 For tert-butyl.

[0133] In some embodiments of the present invention, R 3 It is isopropyl.

[0134] In some embodiments of the present invention, R 4a and R 4b are each independently selected from hydrogen, C 1-3 Alkyl, -C 1-3 Alkylene -OH and C 3-6 Cycloalkyl; or R 4a and R 4b Together with the carbon atoms connected to form C 3-6 Cycloalkyl.

[0135] In some embodiments of the present invention, R 4a and R 4b are each independently selected from hydrogen and C 1-3 Alkyl; or R4a and R 4b Together with the carbon atoms connected to form C 3-6 Cycloalkyl.

[0136] In some embodiments of the present invention, R 4a and R 4b are each independently selected from hydrogen, methyl and hydroxymethyl; or R 4a and R 4b Together with the carbon atom to which they are attached, they form a cyclopropyl or cyclobutyl group.

[0137] In some embodiments of the present invention, R 4a is selected from hydrogen and methyl, R 4b is methyl; or R 4a and R 4b Together with the carbon atom to which they are attached, they form a cyclopropyl group.

[0138] In some embodiments of the present invention, R 4a is hydrogen, R 4b It is a methyl group.

[0139] In some embodiments of the present invention, R 4a is methyl, R 4b It is a methyl group.

[0140] In some embodiments of the present invention, R 4a and R 4b Together with the carbon atom to which they are attached, they form a cyclopropyl group.

[0141] In some embodiments of the present invention, R 5 phenyl and 5-6 membered heteroaryl, wherein the phenyl and heteroaryl are optionally substituted by one or more selected from halogen, hydroxy, cyano, C 1-4 Alkyl and C 1-4 The substituents of the haloalkyl group are substituted.

[0142] In some embodiments of the present invention, R 5 is selected from phenyl and 5-6 membered heteroaryl, wherein the phenyl and heteroaryl are optionally substituted by one or more selected from halogen and C 1-4 The alkyl group is substituted with a substituent.

[0143] In some embodiments of the present invention, R 5 is selected from phenyl, thiazolyl, oxazolyl, pyrazolyl, pyrazinyl, pyridinyl and pyrimidinyl, wherein the phenyl, thiazolyl, oxazolyl, pyrazolyl, pyrazinyl, pyridinyl and pyrimidinyl are optionally substituted with one or more substituents selected from fluoro, chloro, hydroxy, cyano, methyl, ethyl, isopropyl and trifluoromethyl.

[0144] In some embodiments of the present invention, R 5is selected from phenyl, thiazolyl, pyrazinyl, pyridinyl and pyrimidinyl, wherein the phenyl, thiazolyl, pyrazinyl, pyridinyl and pyrimidinyl are optionally substituted with one or two substituents selected from fluoro, chloro and methyl.

[0145] In some embodiments of the present invention, R 5 Selected from

[0146] In some embodiments of the present invention, R 5 Selected from

[0147] In some embodiments of the present invention, R 6 is selected from hydrogen and fluorine; n is selected from 0 and 1.

[0148] In some embodiments of the invention, the fragment Selected from

[0149] In some embodiments of the present invention, L is a covalent bond, or is selected from -O- and -NR 8 -;R 8 Selected from hydrogen and C 1-3 alkyl.

[0150] In some embodiments of the present invention, L is a covalent bond, or is selected from -O-, -NH-, and -N(CH3)-.

[0151] In some embodiments of the present invention, L is a covalent bond.

[0152] In some embodiments of the present invention, L is -O-.

[0153] In some embodiments of the present invention, L is selected from -NH- and -N(CH3)-.

[0154] In some embodiments of the present invention, R 2 Selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, phenyl, 3-10 membered heterocyclic group, 5-10 membered heteroaryl, -C 1-6 Alkylene-C 3-6 Cycloalkyl, -C 1-6 Alkylene-3-10 membered heterocyclic group and -C 1-6 Alkylene-5-10 membered heteroaryl, wherein the alkyl, cycloalkyl, phenyl, heterocyclic and heteroaryl groups are optionally substituted by one or more selected from halogen, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6Alkyl, -C 1-6 Alkylene -OH, -OC 1-6 Halogenated alkyl, C 3- 6-cycloalkyl, phenyl, 3-10 membered heterocyclic group, 5-10 membered heteroaryl, -NR 12a R 12b 、-C 1-6 Alkylene-OC 1-6 Alkyl and -C(=O)-NR 12a R 12b wherein the alkyl, cycloalkyl, phenyl, heterocyclic and heteroaryl groups in the substituents are optionally further substituted with one or more halogen, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -C 1-6 Alkylene -OH, -OC 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, phenyl, 3-10 membered heterocyclic group, 5-10 membered heteroaryl, -NR 12a R 12b 、-C 1-6 Alkylene-OC 1-6 Alkyl and -C(=O)-NR 12a R 12b Substituents substituted; R 12a and R 12b are each independently selected from hydrogen, C 1- 3 alkyl, C 3-6 Cycloalkyl, -C 1-3 Alkylene -OH and -C 1-3 Alkylene-OC 1-3 Alkyl, or R 12a and R 12b The nitrogen to which it is connected forms a 3-6 membered nitrogen-containing heterocyclic group.

[0155] In some embodiments of the present invention, R 2 Selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 6-10 Aryl, 3-12 membered heterocyclic group and 5-10 membered heteroaryl, wherein the alkyl, cycloalkyl, aryl, heterocyclic group and heteroaryl are optionally substituted by one or more selected from halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -C 1-6 Alkylene -OH, -OC 1-6 Haloalkyl and -C(=O)-NR 12a R 12b substituted by a substituent.

[0156] In some embodiments of the present invention, R 2 Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, phenyl, 3-10 membered heterocyclic group, 5-10 membered heteroaryl, -C 1-6 Alkylene-C 3-6 Cycloalkyl and -C 1-6 Alkylene-3-10 membered heterocyclic group, wherein the alkyl, cycloalkyl, phenyl, heterocyclic group and heteroaryl are optionally substituted by one or more selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -C 1-6 Alkylene-OH, C 3-6 Cycloalkyl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl, -NR 12a R 12b 、-C 1-6 Alkylene-OC 1-6 Alkyl and -C(=O)-NR 12a R 12b wherein the alkyl, cycloalkyl, phenyl, heterocyclic and heteroaryl groups in the substituents are optionally further selected from 3-10 membered heterocyclic groups and -C(=O)-NR 12a R 12b Substituents substituted; R 12a and R 12b are each independently selected from hydrogen, C 1-3 Alkyl, -C 1-3 Alkylene -OH and -C 1-3 Alkylene-OC 1-3 Alkyl, or R 12a and R 12b The nitrogen to which it is connected forms a 3-6 membered nitrogen-containing heterocyclic group.

[0157] In some embodiments of the present invention, R 2 Selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, phenyl, 3-10 membered heterocyclic group and 5-10 membered heteroaryl, wherein the alkyl, cycloalkyl, phenyl, heterocyclic group and heteroaryl are optionally substituted by one or more selected from halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -C 1-6 Alkylene -OH, -OC 1-6 Haloalkyl and -C(=O)-NR 12a R 12b Substituents substituted; R12a and R 12b are each independently selected from hydrogen, C 1-3 Alkyl, C 3-6 Cycloalkyl, -C 1-3 Alkylene -OH and -C 1-3 Alkylene-OC 1-3 alkyl.

[0158] In some embodiments of the present invention, R 2 Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, phenyl, 3-10 membered heterocyclic group and 5-10 membered heteroaryl, wherein the alkyl, cycloalkyl, phenyl, heterocyclic group and heteroaryl are optionally substituted by one or more selected from halogen, amino, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -C 1-6 Alkylene -OH and -C(=O)-NR 12a R 12b Substituents substituted; R 12a and R 12b are each independently selected from hydrogen, C 1-3 Alkyl, -C 1-3 Alkylene -OH and -C 1-3 Alkylene-OC 1-3 alkyl.

[0159] In some embodiments of the present invention, R 2 Selected from hydrogen,

[0160] In some embodiments of the present invention, R 2 Selected from hydrogen,

[0161] In some embodiments of the invention, fragment-LR 2 Selected from hydrogen,

[0162] In some embodiments of the invention, fragment-LR 2 Selected from hydrogen,

[0163] In some embodiments of the present invention, the above-mentioned compound has the structure of Formula (III-A), Formula (III-B), Formula (III-C) or Formula (III-D):

[0164] Among them, ring A, ring B, R 2 、R 3 、R 4a 、R 4b 、R 5 、R 6 ,L,L 1 、L 2 、L 3 、L 4 、L 5 and n are as defined above.

[0165] In some embodiments of the present invention, the above-mentioned compound has the structure of Formula (IV-A), Formula (IV-B), Formula (IV-C) or Formula (IV-D):

[0166] Among them, ring A, ring B, R 2 、R 3 、R 4a 、R 4b 、R 5 、R 6 ,L,L 1 、L 2 、L 3 、L 4 、L 5 and n are as defined above.

[0167] The present invention encompasses compounds obtained by any combination of the various embodiments. Embodiments obtained by combining the technical features or preferred technical features in one embodiment with the technical features or preferred technical features in another embodiment are also within the scope of the present invention.

[0168] In some embodiments of the compound of Formula (I), the compound of Formula (I) is selected from:

[0169] Preparation method

[0170] The compound of formula (II-A) of the present invention can be prepared by the method shown in the following Scheme 1:

[0171] Route 1

[0172] in:

[0173] Ring A, Ring B, R 2 、R 3 、R 4a 、R 4b 、R 5 、R 6 ,L,L 1 、L 2 、L 3 、L 4 、L 5 and n is as defined above;

[0174] LG 1 LG 2 and LG 3 each independently represents a leaving group, such as a halogen, a triflate, a toluenesulfonate, or a methanesulfonate;

[0175] The method comprises the following steps:

[0176] 1) reacting compound II-A1 with compound II-A2 to obtain compound II-A3;

[0177] 2) reacting compound II-A3 with compound II-A4 to obtain compound II-A5;

[0178] 3) Compound II-A5 is reacted with 3 The reagent of the group is reacted to obtain compound II-A6;

[0179] 4) reacting compound II-A6 with compound II-A7 to obtain compound II-A8; and

[0180] 5) Compound II-A8 and compound II-A9 are subjected to a ring-closure reaction to obtain compound II-A.

[0181] The reaction in step (1) is preferably carried out in a suitable organic solvent and in the presence of a suitable base. The organic solvent may be selected from acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, tetrahydrofuran, 1,4-dioxane, and any combination thereof, preferably N,N-dimethylformamide. The base may be selected from N,N-diisopropylethylamine, triethylamine, potassium carbonate, cesium carbonate, and any combination thereof, preferably cesium carbonate. The reaction is preferably carried out at a temperature of 0°C to 100°C for 0.5 to 48 hours.

[0182] The reaction of step (2) is preferably carried out in a suitable organic solvent and in the presence of a suitable base. The organic solvent may be selected from acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, tetrahydrofuran, 1,4-dioxane and any combination thereof, preferably dimethyl sulfoxide or tetrahydrofuran. The base may be selected from N,N-diisopropylethylamine, triethylamine, sodium hydride, potassium carbonate, cesium carbonate, sodium tert-butoxide or potassium tert-butoxide, preferably N,N-diisopropylethylamine, sodium tert-butoxide or cesium carbonate. The reaction is preferably carried out at a temperature of 20°C-120°C for 2-48 hours; or the reaction of step (2) is preferably carried out in a suitable solvent and in the presence of a metal catalyst and a base. The metal catalyst can be a palladium metal catalyst, such as tris(dibenzylideneacetone)dipalladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium, methanesulfonic acid [n-butyldi(1-adamantyl)phosphine] (2-amino-1,1'-biphenyl-2-yl) palladium (II), tetrakistriphenylphosphine palladium and palladium acetate, preferably [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium. The base can be an organic base or an inorganic base, for example, selected from sodium tert-butoxide, potassium carbonate, potassium phosphate, cesium carbonate and sodium carbonate, preferably potassium carbonate. The solvent can be selected from N,N-dimethylformamide, N-methylpyrrolidone, toluene, ethanol, ethylene glycol dimethyl ether, water, 1,4-dioxane and any combination thereof, preferably a combination of 1,4-dioxane and water. The reaction is preferably carried out at a temperature of 20-120°C for 2-16 hours.

[0183] The reaction of step (3) is preferably carried out in a suitable organic solvent and in a suitable solvent containing -LG 3 The reagent containing -LG 3 The reagent for the group can be selected from methanesulfonyl chloride, methanesulfonic anhydride, p-toluenesulfonyl chloride, or trifluoromethanesulfonic anhydride, preferably methanesulfonic anhydride. The base can be selected from N,N-diisopropylethylamine or triethylamine, preferably triethylamine. The organic solvent can be selected from tetrahydrofuran, dichloromethane, toluene, 1,2-dichloroethane, and any combination thereof, preferably dichloromethane. The reaction is preferably carried out at a temperature of 0-40°C for 2-16 hours.

[0184] The reaction of step (4) is preferably carried out in a suitable organic solvent and in the presence of an inorganic base and an inorganic salt. The inorganic base may be selected from potassium carbonate or cesium carbonate, preferably potassium carbonate. The inorganic salt may be selected from potassium iodide or sodium iodide, preferably potassium iodide. The organic solvent may be selected from acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, tetrahydrofuran, 1,4-dioxane, and any combination thereof, preferably acetonitrile. The reaction is preferably carried out at a temperature of 25-100° C. for 2-16 hours.

[0185] The ring-closure reaction in step (5) is preferably carried out in a suitable organic solvent and in the presence of a suitable reagent. The organic solvent may be selected from methanol, ethanol, isopropanol, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, and any combination thereof, preferably ethanol. The reagent is a combination of ammonium acetate and sulfur powder. The reaction is preferably carried out at a temperature of 0-100° C. for 1-12 hours.

[0186] The present invention provides a second method for preparing a compound of formula (II-A), comprising the following steps:

[0187] Route 2

[0188] in:

[0189] Ring A, Ring B, R 2 、R 3 、R 4a 、R 4b 、R 5 、R 6 ,L,L 1 、L 2 、L 3 、L 4 、L 5 and n is as defined above;

[0190] LG 1 LG 2 and LG 3 each independently represents a leaving group, such as a halogen, a triflate, a toluenesulfonate, or a methanesulfonate;

[0191] The method comprises the following steps:

[0192] 1) reacting compound II-A1 with compound II-A4 to obtain compound II-A3a;

[0193] 2) reacting compound II-A3a with compound II-A2 to obtain compound II-A5;

[0194] 3) Compound II-A5 is reacted with 3 The reagent of the group is reacted to obtain compound II-A6;

[0195] 4) reacting compound II-A6 with compound II-A7 to obtain compound II-A8 and

[0196] 5) Compound II-A8 and compound II-A9 are subjected to a ring-closure reaction to obtain compound II-A.

[0197] The reaction in step (1) is preferably carried out in a suitable organic solvent and in the presence of a suitable base. The organic solvent may be selected from acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, tetrahydrofuran, 1,4-dioxane, and any combination thereof, preferably tetrahydrofuran. The base may be selected from N,N-diisopropylethylamine, triethylamine, potassium carbonate, cesium carbonate, sodium hydride, sodium tert-butoxide, or potassium tert-butoxide, preferably sodium hydride. The reaction is preferably carried out at a temperature of 0°C to 100°C for 0.5 to 48 hours.

[0198] The reaction in step (2) is preferably carried out in a suitable organic solvent and in the presence of a suitable base. The organic solvent may be selected from acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, tetrahydrofuran, 1,4-dioxane, and any combination thereof, preferably tetrahydrofuran. The base may be selected from N,N-diisopropylethylamine, triethylamine, potassium carbonate, cesium carbonate, sodium hydride, sodium tert-butoxide, or potassium tert-butoxide, preferably sodium hydride. The reaction is preferably carried out at a temperature of 0°C to 120°C for 2 to 48 hours.

[0199] The reaction of step (3) is preferably carried out in a suitable organic solvent and in a suitable solvent containing -LG 3 The reagent containing -LG 3 The reagent for the group can be selected from methanesulfonyl chloride, methanesulfonic anhydride, p-toluenesulfonyl chloride, or trifluoromethanesulfonic anhydride, preferably methanesulfonic anhydride. The base can be selected from N,N-diisopropylethylamine or triethylamine, preferably triethylamine. The organic solvent can be selected from tetrahydrofuran, dichloromethane, toluene, 1,2-dichloroethane, and any combination thereof, preferably dichloromethane. The reaction is preferably carried out at a temperature of 0-40°C for 2-16 hours.

[0200] The reaction of step (4) is preferably carried out in a suitable organic solvent and in the presence of an inorganic base and an inorganic salt. The inorganic base may be selected from potassium carbonate or cesium carbonate, preferably potassium carbonate. The inorganic salt may be selected from potassium iodide or sodium iodide, preferably potassium iodide. The organic solvent may be selected from acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, tetrahydrofuran, 1,4-dioxane, and any combination thereof, preferably acetonitrile. The reaction is preferably carried out at a temperature of 25-100° C. for 2-16 hours.

[0201] The ring-closure reaction in step (5) is preferably carried out in a suitable organic solvent and in the presence of a suitable reagent. The organic solvent may be selected from methanol, ethanol, isopropanol, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, and any combination thereof, preferably ethanol. The reagent is a combination of ammonium acetate and sulfur powder. The reaction is preferably carried out at a temperature of 0-100° C. for 1-12 hours.

[0202] The present invention provides a third method for preparing a compound of formula (II-A), comprising the following steps:

[0203] Route 3

[0204] in:

[0205] Ring A, Ring B, R 2 、R 3 、R 4a 、R 4b 、R 5 、R 6 ,L,L 1 、L 2 、L 3 、L 4 、L 5 and n is as defined above;

[0206] LG 1 LG 2 and LG 3 each independently represents a leaving group, such as a halogen, a triflate, a toluenesulfonate, or a methanesulfonate;

[0207] The method comprises the following steps:

[0208] 1) reacting compound II-A1 with compound II-A2 to obtain compound II-A3;

[0209] 2) reacting compound II-A3 with compound II-A4 to obtain compound II-A5;

[0210] 3) subjecting compound II-A5 to a ring-closure reaction with compound II-A9 to obtain compound II-A6b;

[0211] 4) subjecting compound II-A6b to a protection reaction to obtain compound II-A7b;

[0212] 5) Compound II-A7b is reacted with 3 The reaction is carried out with a reagent of the group to obtain compound II-A8b;

[0213] 6) reacting compound II-A8b with compound II-A7 to obtain compound II-A9b and

[0214] 7) Compound II-A9b is subjected to a deprotection reaction to obtain compound II-A.

[0215] The reaction in step (1) is preferably carried out in a suitable organic solvent and in the presence of a suitable base. The organic solvent may be selected from acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, tetrahydrofuran, 1,4-dioxane, and any combination thereof, preferably N,N-dimethylformamide. The base may be selected from N,N-diisopropylethylamine, triethylamine, potassium carbonate, cesium carbonate, and any combination thereof, preferably cesium carbonate. The reaction is preferably carried out at a temperature of 0°C to 100°C for 0.5 to 48 hours.

[0216] The reaction of step (2) is preferably carried out in a suitable organic solvent and in the presence of a suitable base. The organic solvent may be selected from acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, tetrahydrofuran, 1,4-dioxane and any combination thereof, preferably acetonitrile or tetrahydrofuran. The base may be selected from N,N-diisopropylethylamine, triethylamine, sodium hydride, potassium carbonate, cesium carbonate, sodium tert-butoxide or potassium tert-butoxide, preferably potassium carbonate or cesium carbonate. The reaction is preferably carried out at a temperature of 20°C-120°C for 2-48 hours or the reaction of step (2) is preferably carried out in a suitable solvent and in the presence of a metal catalyst and a base. The metal catalyst can be a palladium metal catalyst, such as tris(dibenzylideneacetone)dipalladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium, methanesulfonic acid [n-butyldi(1-adamantyl)phosphine] (2-amino-1,1'-biphenyl-2-yl) palladium (II), tetrakistriphenylphosphine palladium and palladium acetate, preferably [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium. The base can be an organic base or an inorganic base, for example, selected from sodium tert-butoxide, potassium carbonate, potassium phosphate, cesium carbonate and sodium carbonate, preferably potassium carbonate. The solvent can be selected from N,N-dimethylformamide, N-methylpyrrolidone, toluene, ethanol, ethylene glycol dimethyl ether, water, 1,4-dioxane and any combination thereof, preferably a combination of 1,4-dioxane and water. The reaction is preferably carried out at a temperature of 20-120°C for 2-16 hours.

[0217] The ring-closure reaction in step (3) is preferably carried out in a suitable organic solvent and in the presence of a suitable reagent. The organic solvent may be selected from methanol, ethanol, isopropanol, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, and any combination thereof, preferably ethanol. The reagent is a combination of ammonium acetate and sulfur powder. The reaction is preferably carried out at a temperature of 0-100° C. for 1-12 hours.

[0218] The reaction in step (4) is preferably carried out in a suitable organic solvent in the presence of N,N-dimethylformamide dimethyl acetal. The organic solvent may be selected from acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, tetrahydrofuran, 1,4-dioxane, and any combination thereof, preferably tetrahydrofuran. The reaction is preferably carried out at a temperature of 25-100° C. for 2-16 hours.

[0219] The reaction of step (5) is preferably carried out in a suitable organic solvent and in a suitable solvent containing -LG 3 The reagent containing -LG 3 The reagent for the group can be selected from methanesulfonyl chloride, methanesulfonic anhydride, p-toluenesulfonyl chloride, or trifluoromethanesulfonic anhydride, preferably methanesulfonic anhydride. The base can be selected from N,N-diisopropylethylamine or triethylamine, preferably triethylamine. The organic solvent can be selected from tetrahydrofuran, dichloromethane, toluene, 1,2-dichloroethane, and any combination thereof, preferably dichloromethane. The reaction is preferably carried out at a temperature of 0-40°C for 2-16 hours.

[0220] The reaction of step (6) is preferably carried out in a suitable organic solvent and in the presence of an inorganic base and an inorganic salt. The inorganic base may be selected from potassium carbonate or cesium carbonate, preferably potassium carbonate. The inorganic salt may be selected from potassium iodide or sodium iodide, preferably potassium iodide. The organic solvent may be selected from acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, tetrahydrofuran, 1,4-dioxane, and any combination thereof, preferably acetonitrile. The reaction is preferably carried out at a temperature of 25-100° C. for 2-16 hours.

[0221] The deprotection reaction in step (7) is preferably carried out in a suitable organic solvent and in the presence of a suitable deprotecting agent. The organic solvent may be selected from methanol, ethanol, isopropanol, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, tetrahydrofuran, and any combination thereof, preferably tetrahydrofuran. The deprotecting agent may be selected from hydrochloric acid, trifluoroacetic acid, acetic acid, and any combination thereof, preferably hydrochloric acid. The reaction is preferably carried out at a temperature of 0-100° C. for 1-12 hours.

[0222] Pharmaceutical compositions and kits

[0223] Another object of the present invention is to provide a pharmaceutical composition comprising a preventively and / or therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, and one or more pharmaceutically acceptable carriers.

[0224] Another object of the present invention is to provide a drug kit comprising a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention, and optionally instructions.

[0225] In the present invention, "pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient or vehicle that is administered together with the therapeutic agent and is suitable for contact with the tissues of humans and / or other animals without excessive toxicity, irritation, allergic response or other problems or complications corresponding to a reasonable benefit / risk ratio within the scope of reasonable medical judgment.

[0226] Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions or pharmaceutical formulations of this invention include, but are not limited to, sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.

[0227] The pharmaceutical composition may be in the form of a solid preparation, a semisolid preparation, a liquid preparation, or a gaseous preparation. Examples of solid preparations include tablets, capsules, powders, granules, or suppositories, and examples of liquid preparations include solutions, suspensions, or injections. The composition may also be in the form of liposomes, microspheres, or other dosage forms.

[0228] The pharmaceutical compositions of the present invention can act systemically and / or locally. For this purpose, they can be administered by suitable routes, for example, by injection (such as intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection, including instillation) or transdermal administration; or by oral, buccal, nasal, transmucosal, topical, in the form of ophthalmic preparations or by inhalation.

[0229] The content or dosage of the compound of the present invention in the pharmaceutical composition may be about 0.001 mg to about 1000 mg, suitably 0.01-800 mg, preferably 0.05-500 mg, more preferably 0.1-350 mg, particularly preferably 0.5-100 mg.

[0230] In some embodiments, the present invention provides a method for preparing a pharmaceutical composition of the present invention, comprising combining a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof with one or more pharmaceutically acceptable carriers.

[0231] Treatment methods and uses

[0232] Another object of the present invention is to provide a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention, for use in preventing and / or treating KRAS-mediated related diseases.

[0233] Another object of the present invention is to provide use of the compound of the present invention or its pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug, or the pharmaceutical composition of the present invention in the preparation of a medicament for preventing and / or treating KRAS-mediated related diseases.

[0234] Another object of the present invention is to provide a method for preventing and / or treating KRAS-mediated related diseases, which comprises administering to an individual in need thereof a preventively or therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention.

[0235] According to some embodiments of the present invention, the KRAS-mediated related disease is a tumor or cancer.

[0236] As used herein, the term "effective amount" refers to an amount sufficient to achieve the desired prophylactic or therapeutic effect, for example, to achieve relief of one or more symptoms associated with the disease being treated.

[0237] The dosage regimen can be adjusted to provide the optimal desired response. For example, a single bolus can be administered, several divided doses can be administered over time, or the dose can be proportionally reduced or increased as indicated by the urgency of the therapeutic situation. It is to be noted that dosage values ​​can vary with the type and severity of the condition to be alleviated and can include single or multiple doses. It is to be further understood that for any particular individual, the specific dosage regimen should be adjusted over time according to the individual's needs and the professional judgment of the person administering or supervising the administration of the composition.

[0238] The amount of the compound of the present invention administered will depend on the severity of the individual, disease or the patient's condition, the speed of administration, the disposal of the compound and the judgment of the prescribing physician for treatment. Generally speaking, effective dose is about 0.0001 to about 50mg per kg body weight per day, for example, about 0.01 to about 10mg / kg / day (single or divided administration). For 70kg people, this will add up to about 0.007mg / day to about 3500mg / day, for example, about 0.7mg / day to about 700mg / day. In some cases, it can be enough to be not higher than the dosage level of the lower limit of the aforementioned range, and in other cases, it is still possible to adopt a larger dose in the case of not causing any harmful side effects, provided that the larger dose is first divided into several smaller doses to be administered throughout the day.

[0239] The term "prevention" as used herein includes inhibition and delay of the onset of a disease, and includes not only prevention before the development of a disease but also prevention of recurrence of a disease after treatment.

[0240] The terms "treat," "treat," "treat," or "treating" as used herein means to reverse, alleviate, or eliminate the progression of the disorder or condition to which such terms apply, or one or more symptoms of such disorder or condition.

[0241] As used herein, "subject" includes humans and non-human animals. Exemplary human subjects include human subjects suffering from diseases (e.g., the diseases described herein) (referred to as patients) or normal individuals. "Non-human animals" herein include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.). Example

[0242] The embodiments of the present invention are described in detail below with reference to the examples. However, those skilled in the art will appreciate that the following examples are only used to illustrate the present invention and should not be considered as limiting the scope of the present invention.

[0243] In the examples, if the specific conditions are not specified, all experiments were carried out under conventional conditions or those recommended by the manufacturer. All reagents or instruments used, if the manufacturer is not specified, are commercially available conventional products.

[0244] The structure of the compound was determined by nuclear magnetic resonance ( 1 H NMR) and / or mass spectrometry (MS).

[0245] 1H NMR measurements were performed on a JEOL Eclipse 400 nuclear magnetometer. The solvents used were deuterated methanol (CD3OD), deuterated chloroform (CDCl3), or hexadeuterated dimethyl sulfoxide (DMSO-d6). The internal standard was tetramethylsilane (TMS). Chemical shifts (δ) were given in parts per million (ppm).

[0246] The MS measuring instrument is an Agilent (ESI) mass spectrometer, manufactured by Agilent, model: Agilent 6120B.

[0247] Reverse phase column chromatography using Agela C18 reverse phase Flash column

[0248] The preparative HPLC conditions were as follows:

[0249] (1) Instrument model: Agilent 1260; Column: Waters SunFire Prep C 18 OBD (19 mm × 150 mm × 5.0 μm); column temperature: 25°C; flow rate: 20.0 mL / min; detection wavelength: 214 nm; elution gradient: (0 min: 10% A, 90% B; 16.0 min: 90% A, 10% B); mobile phase A: acetonitrile; mobile phase B: 0.05% formic acid in water;

[0250] (2) Instrument model: Agilent 1260, chromatographic column: Waters XBridge Prep C 18 OBD (19 mm × 150 mm × 5.0 μm); column temperature: 25°C; flow rate: 20.0 mL / min; detection wavelength: 214 nm; elution gradient: (0 min: 10% A, 90% B; 16.0 min: 90% A, 10% B); mobile phase A: acetonitrile; mobile phase B: 0.05% ammonium bicarbonate aqueous solution.

[0251] Aluminum plates (20×20 cm) produced by Merck were used for thin layer chromatography silica gel plates (TLC), and the specifications used for thin layer chromatography separation and purification were GF 254 (1 mm) produced in Yantai.

[0252] The reaction is monitored by thin layer chromatography (TLC) or LC-MS; the developing solvent systems used include: dichloromethane and methanol system, n-hexane and ethyl acetate system, and petroleum ether and ethyl acetate system. The volume ratio of the solvent is adjusted according to the polarity of the compound or by adding triethylamine.

[0253] Column chromatography generally uses 200-300 mesh silica gel as a carrier. Eluent systems include: dichloromethane and methanol systems, and petroleum ether and ethyl acetate systems. The volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triethylamine can also be added for adjustment.

[0254] Unless otherwise specified, the reaction temperature was room temperature (20°C-35°C).

[0255] The reagents used in the examples were purchased from Acros Organics, Aldrich Chemical Company, Teber Chemical and other companies.

[0256] The meanings of the abbreviations used in this document are shown in the following table.

[0257] Preparation of intermediates

[0258] Intermediate Preparation Example 1: Preparation of (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0259] Step 1: Preparation of (2S,4R)-1-((S)-2-azido-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl))ethyl)pyrrolidine-2-carboxamide

[0260] (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl))ethyl)pyrrolidine-2-carboxamide (2.0 g, 4.07 mmol), 1H-imidazole-1-sulfonyl azide hydrochloride (1.35 g, 6.11 mmol), copper sulfate pentahydrate (103.81 mg, 0.407 mmol) and potassium carbonate (1.99 g, 14.26 mmol) were dissolved in methanol (20 mL) and water (10 mL) and stirred at room temperature for 2 hours. The reaction solution was concentrated, diluted with ethyl acetate (45 mL), and washed twice with saturated brine (35 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography (eluent: dichloromethane / methanol = 15 / 1, volume ratio) to give the title compound (1.43 g, yield: 73.8%).

[0261] MS m / z(ESI):471.3[M+H] + .

[0262] Step 2: Preparation of tert-butyl 4-(1-((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl))ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-1H-1,2,3-triazol-4-yl)piperidine-1-carboxylate

[0263] (2S,4R)-1-((S)-2-azido-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl))ethyl)pyrrolidine-2-carboxamide (1.43 g, 3.01 mmol) and tert-butyl 4-ethynylpiperidine-1-carboxylate (649.08 mg, 3.01 mmol) were dissolved in DMSO (30 mL) and water (3 mL). Sodium ascorbate (912.23 mg, 4.51 mmol) and copper sulfate pentahydrate (1.53 g, 6.02 mmol) were added to the system and stirred at room temperature for 12 hours. The reaction solution was diluted with ethyl acetate (100 mL), washed three times with saturated brine (50 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography (eluent: dichloromethane / methanol = 15 / 1, volume ratio) to give the title compound (1.61 g, yield: 77.9%).

[0264] MS m / z(ESI):680.5[M+H] + .

[0265] Step 3: Preparation of (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0266] Tert-butyl 4-(1-((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl))ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-1H-1,2,3-triazol-4-yl)piperidine-1-carboxylate (1.61 g, 2.34 mmol) was dissolved in 4 M hydrogen chloride in ethyl acetate (10 mL) and stirred at room temperature for 4 hours. The reaction mixture was concentrated to obtain the title compound (1.77 g, yield: 98.0%).

[0267] MS m / z(ESI):580.4[M+H] + .

[0268] Intermediate Preparation Example 2: Preparation of (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-N-((S)-1-(2'-fluoro-[1,1'-biphenyl]-4-yl)ethyl)-4-hydroxypyrrolidine-2-carboxamide

[0269] The synthetic route in Intermediate Preparation Example 1 was used to replace the first step reaction raw material (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl))ethyl)pyrrolidine-2-carboxamide with (2S,4R)-1-((2S)-2-amino-3,3-dimethylbutyryl)-N-((1S)-1-(4-(2-fluorophenyl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide to give the title compound (5.1 g, yield: 80.1%).

[0270] MS m / z(ESI):577.4[M+H] + .

[0271] Intermediate Preparation Example 3: Preparation of (S)-3-(4-chloro-6-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-2'-one

[0272] (S)-3-(4,6-Dichloropyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-2'-one (8 g, 22.8 mmol) was dissolved in DMF (80 mL). 1,1-Cyclopropane dimethanol (3.49 g, 34.2 mmol) and cesium carbonate (18.6 g, 57 mmol) were added and stirred at room temperature for 2 hours. The reaction mixture was diluted with water (300 mL) and extracted three times with ethyl acetate (100 mL). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / ethyl acetate = 3 / 1, volume ratio) to obtain the title compound (6.7 g, yield: 70.5%).

[0273] MS m / z(ESI):418.1[M+H] + .

[0274] Intermediate Preparation Example 4: Preparation of (E)-(1-((2-(3-cyano-2-((dimethylamino)methylene)amino)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-(pyrimidin-5-yloxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl methanesulfonate

[0275] Step 1: Preparation of (S)-3-(4-(((1-(hydroxymethyl)cyclopropyl)methoxy)-6-(pyrimidin-5-yloxy)pyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-2'-one

[0276] (S)-3-(4-chloro-6-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-2'-one (5.0 g, 11.99 mmol), 5-hydroxypyrimidine (1.50 g, 15.59 mmol), triethylenediamine (201.74 mg, 1.80 mmol), and potassium carbonate (1.99 g, 14.39 mmol) were suspended in acetonitrile (75 mL) and stirred at 60°C for 8 hours. The reaction mixture was cooled to room temperature and poured into water (750 mL). A solid precipitated and was filtered. The filter cake was collected and dried to give the title compound (5.4 g, 94.4% yield).

[0277] MS m / z(ESI):478.2[M+H] + .

[0278] Step 2: Preparation of (S)-2-amino-3'-(4-((1-(hydroxymethyl)cyclopropyl)methoxy)-6-(pyrimidin-5-yloxy)pyrimidin-2-yl)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-3-carbonitrile

[0279] (S)-3-(4-(((1-(hydroxymethyl)cyclopropyl)methoxy)-6-(pyrimidin-5-yloxy)pyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-2'-one (5.4 g, 11.32 mmol), ammonium acetate (3.49 g, 45.28 mmol), and sulfur (1.45 g, 45.28 mmol) were dissolved in ethanol (35 mL) and stirred at 60°C for 15 minutes. A solution of malononitrile (3.74 g, 56.6 mmol) in ethanol (20 mL) was then added dropwise, and the mixture was stirred at 80°C for 8 hours. The reaction mixture was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1, volume ratio) to give the title compound (4.3 g, yield: 68.2%).

[0280] MS m / z(ESI):558.2[M+H] + .

[0281] Step 3: Preparation of (E)-N'-(3-cyano-3'-(4-((1-(hydroxymethyl)cyclopropyl)methoxy)-6-(pyrimidin-5-yloxy)pyrimidin-2-yl)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-2-yl)-N,N-dimethylformamide

[0282] (S)-2-amino-3'-(4-((1-(hydroxymethyl)cyclopropyl)methoxy)-6-(pyrimidin-5-yloxy)pyrimidin-2-yl)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-3-carbonitrile (4.3 g, 7.7 mmol) was dissolved in tetrahydrofuran (50 mL). N,N-dimethylformamide dimethyl acetal (1.1 g, 9.24 mmol) was added and stirred at room temperature for 2 hours. The reaction mixture was concentrated to obtain the title compound (4.6 g, yield: 97.9%).

[0283] MS m / z(ESI):613.2[M+H] + .

[0284] Step 4: Preparation of (E)-(1-((2-(3-cyano-2-((dimethylamino)methylene)amino)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-(pyrimidin-5-yloxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl methanesulfonate

[0285] (E)-N'-(3-cyano-3'-(4-((1-(hydroxymethyl)cyclopropyl)methoxy)-6-(pyrimidin-5-yloxy)pyrimidin-2-yl)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-2-yl)-N,N-dimethylformamide (4.6 g, 7.5 mmol) was dissolved in dichloromethane (50 mL). N,N-diisopropylethylamine (1.94 g, 15.0 mmol) was added, followed by methanesulfonic anhydride (1.96 g, 11.25 mmol), and the mixture was reacted at 25°C for 2 hours. Water (50 mL) was added to the reaction solution, and the mixture was extracted twice with dichloromethane (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1, volume ratio) to give the title compound (4.6 g, yield: 88.8%).

[0286] MS m / z(ESI):691.3[M+H] + .

[0287] Intermediate Preparation Example 5: Preparation of (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-N-((S)-1-(4-(3-fluoropyridin-4-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide

[0288] Step 1: Preparation of tert-butyl (S)-(1-(4-(3-fluoropyridin-4-yl)phenyl)ethyl)carbamate

[0289] Tert-butyl (S)-(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)carbamate (0.5 g, 1.44 mmol) and 3-fluoro-4-bromopyridine (304.1 mg, 1.73 mmol) were dissolved in 1,4-dioxane (10 mL) and water (1 mL). Potassium carbonate (398 mg, 2.88 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (105.3 mg, 144 μmol) were added. After nitrogen was replaced three times, the mixture was stirred at 90°C for 2 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1, volume ratio) to obtain the title compound (410 mg, yield: 89.7%).

[0290] MS m / z(ESI):317.1[M+H] + .

[0291] Step 2: Preparation of (S)-1-(4-(3-fluoropyridin-4-yl)phenyl)ethan-1-amine

[0292] (S)-tert-Butyl (1-(4-(3-fluoropyridin-4-yl)phenyl)ethyl)carbamate (410 mg, 1.29 mmol) was dissolved in a 4 M solution of hydrogen chloride in dioxane (4 mL) and dichloromethane (4 mL), and the mixture was stirred at 25°C for 1 hour. The mixture was concentrated to obtain the title compound (275 mg, yield: 97.8%).

[0293] MS m / z(ESI):217.1[M+H] + .

[0294] Step 3: Preparation of tert-butyl (S)-1-((2S,4R)-2-(((S)-1-(4-(3-fluoropyridin-4-yl)phenyl)ethyl)carbamoyl)-4-hydroxypyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate

[0295] (S)-1-(4-(3-fluoropyridin-4-yl)phenyl)ethan-1-amine (275 mg, 1.27 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (722.4 mg, 1.9 mmol), and (2S,4R)-1-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylic acid (437.4 mg, 1.27 mmol) were dissolved in DMF (5 mL). N,N-Diisopropylethylamine (820.7 mg, 6.35 mmol) was added dropwise under ice-cooling, and the mixture was allowed to react at room temperature for 2 hours. The reaction solution was poured into water (30 mL) and extracted three times with ethyl acetate (10 mL). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1, volume ratio) to give the title compound (500 mg, yield: 72.8%).

[0296] MS m / z(ESI):543.3[M+H] + .

[0297] Step 4: Preparation of (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-N-(S)-1-(4-(3-fluoropyridin-4-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide

[0298] Tert-butyl (S)-1-((2S,4R)-2-(((S)-1-(4-(3-fluoropyridin-4-yl)phenyl)ethyl)carbamoyl)-4-hydroxypyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate (500 mg, 0.92 mmol) was dissolved in dichloromethane (5 mL). A 4M solution of hydrogen chloride in 1,4-dioxane (4 mL) was added and the mixture was reacted at room temperature for 2 hours. The reaction solution was concentrated to obtain the title compound (400 mg, yield: 98.0%).

[0299] MS m / z(ESI):443.2[M+H] + .

[0300] Step 5: Preparation of (2S,4R)-1-((S)-2-azido-3,3-dimethylbutanoyl)-N-((S)-1-(4-(3-fluoropyridin-4-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide

[0301] (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-N-(S)-1-(4-(3-fluoropyridin-4-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide (400 mg, 0.91 mmol), 1H-imidazole-1-sulfonyl azide hydrochloride (286.6 mg, 1.37 mmol), copper sulfate pentahydrate (22.75 mg, 0.091 mmol) and potassium carbonate (440.2 mg, 3.19 mmol) were dissolved in methanol (10 mL) and water (5 mL) and stirred at room temperature for 2 hours. The reaction solution was concentrated, diluted with ethyl acetate (15 mL), and washed twice with saturated brine (25 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1, volume ratio) to give the title compound (360 mg, yield: 85.1%).

[0302] MS m / z(ESI):469.3[M+H] + .

[0303] Step 6: Preparation of tert-butyl 4-(1-(((S)-1-((2S,4R)-2-(((S)-1-(4-(3-fluoropyridin-4-yl)phenyl)ethyl)carbamoyl)-4-hydroxypyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-1H-1,2,3-triazol-4-yl)piperidine-1-carboxylate

[0304] (2S,4R)-1-((S)-2-azido-3,3-dimethylbutanoyl)-N-((S)-1-(4-(3-fluoropyridin-4-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide (360 mg, 0.77 mmol) and tert-butyl 4-ethynylpiperidine-1-carboxylate (161 mg, 0.77 mmol) were dissolved in DMSO (10 mL) and water (1 mL). Sodium ascorbate (228.8 mg, 1.16 mmol) and copper sulfate pentahydrate (385 mg, 1.54 mmol) were added to the system and stirred at room temperature for 5 hours. The reaction solution was diluted with ethyl acetate (20 mL), washed three times with saturated brine (20 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1, volume ratio) to give the title compound (390 mg, yield: 75.0%).

[0305] MS m / z(ESI):678.4[M+H] + .

[0306] Step 7: Preparation of (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-N-((S)-1-(4-(3-fluoropyridin-4-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide

[0307] Tert-butyl 4-(1-(((S)-1-((2S,4R)-2-(((S)-1-(4-(3-fluoropyridin-4-yl)phenyl)ethyl)carbamoyl)-4-hydroxypyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-1H-1,2,3-triazol-4-yl)piperidine-1-carboxylate (0.39 g, 0.58 mmol) was dissolved in a 4 M solution of hydrogen chloride in ethyl acetate (10 mL) and stirred at room temperature for 4 hours. The reaction solution was concentrated, and the residue was diluted with ethyl acetate (10 mL). The organic phase was then washed with sodium bicarbonate solution, separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the title compound (220 mg, yield: 97.8%).

[0308] MS m / z(ESI):578.3[M+H] + .

[0309] Intermediate Preparation Example 6: Preparation of 1-(6-((1-((4-(1-((S)-1-((2S,4R)-4-hydroxy-2-(((S))-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-1H-1,2,3-triazol-4-yl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-2-((S)-2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-3-yl)pyrimidin-4-yl)-1H-pyrazole-3-carboxylic acid

[0310] Step 1: Preparation of (S)-1-(6-((1-(hydroxymethyl)cyclopropyl)methoxy)-2-(2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-3-yl)pyrimidin-4-yl)-1H-pyrazole-3-carboxylic acid methyl ester

[0311] (S)-3-(4-chloro-6-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-2'-one (1.0 g, 2.39 mmol), methyl 3-pyrazolecarboxylate (0.45 g, 3.58 mmol), and cesium carbonate (1.56 g, 4.78 mmol) were suspended in acetonitrile (20 mL) and stirred at 70°C for 12 hours. The reaction mixture was cooled to room temperature and poured into water (750 mL). A solid precipitated and was filtered. The filter cake was collected and dried to give the title compound (0.9 g, 74.4% yield).

[0312] MS m / z(ESI):508.2[M+H] + .

[0313] Step 2: Preparation of (S)-1-(6-((1-(((methylsulfonyl)oxy)methyl)cyclopropyl)methoxy)-2-(2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-3-yl)pyrimidin-4-yl)-1H-pyrazole-3-carboxylic acid methyl ester

[0314] Methyl (S)-1-(6-((1-(hydroxymethyl)cyclopropyl)methoxy)-2-(2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-3-yl)pyrimidin-4-yl)-1H-pyrazole-3-carboxylate (0.9 g, 1.77 mmol) was dissolved in dichloromethane (10 mL). N,N-diisopropylethylamine (458 mg, 3.54 mmol) was added, followed by methanesulfonic anhydride (463 mg, 2.65 mmol). The mixture was reacted at 25°C for 2 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted twice with dichloromethane (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the title compound (0.99 g, 95.2% yield).

[0315] MS m / z(ESI):586.2[M+H] + .

[0316] Step 3: Preparation of methyl 1-(6-((1-((4-(1-((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-1H-1,2,3-triazol-4-yl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-2-((S)-2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazole-7,1'-cyclohexane]-3-yl)pyrimidin-4-yl)-1H-pyrazole-3-carboxylate

[0317] (S)-1-(6-((1-(((methylsulfonyl)oxy)methyl)cyclopropyl)methoxy)-2-(2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-3-yl)pyrimidin-4-yl)-1H-pyrazole-3-carboxylic acid methyl ester (0.99 g, 1.69 mmol) was dissolved in acetonitrile (10 mL), and potassium carbonate (934 mg, 6.76 mmol) and iodine were added. To the mixture was added (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (978.5 mg, 1.69 mmol), and the mixture was stirred at 60°C for 6 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (20 mL). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1, volume ratio) to obtain the title compound (900 mg, yield: 49.7%).

[0318] MS m / z(ESI):1069.5[M+H] + .

[0319] Step 4: Preparation of 1-(6-((1-((4-(1-((S)-1-((2S,4R)-4-hydroxy-2-(((S))-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-1H-1,2,3-triazol-4-yl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-2-((S)-2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazole-7,1'-cyclohexane]-3-yl)pyrimidin-4-yl)-1H-pyrazole-3-carboxylic acid

[0320] (1-(6-((1-((4-(1-((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-1H-1,2,3-triazol-4-yl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-2-((S)-2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazole Methyl (1H-pyrazole-3-carboxylate (0.9 g, 0.84 mmol) (7,1'-cyclohexane]-3-yl)pyrimidin-4-yl)-1H-pyrazole-3-carboxylate (0.9 g, 0.84 mmol) was dissolved in methanol (10 mL) and water (10 mL). Lithium hydroxide (176.4 mg, 4.2 mmol) was added and stirred at room temperature for 6 hours. The reaction mixture was concentrated, diluted with water (10 mL), and the pH was adjusted to 5 with 2M hydrochloric acid solution. The precipitated solid was filtered, and the filter cake was dried to obtain the title compound (804 mg, 90.5% yield).

[0321] MS m / z(ESI):1055.5[M+H] + .

[0322] Intermediate Preparation Example 7: Preparation of (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-4-hydroxy-N-((S)-1-(4-(pyrimidin-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0323] The synthetic route in Intermediate Preparation Example 5 was adopted, and the starting material in the first step, 3-fluoro-4-bromopyridine, was replaced with 5-bromopyrimidine to obtain the title compound (150 mg, yield: 75.3%).

[0324] MS m / z(ESI):561.3[M+H] + .

[0325] Intermediate Preparation Example 8: Preparation of (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-4-hydroxy-N-((S)-1-(4-(pyrazin-2-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0326] The synthetic route in Intermediate Preparation Example 5 was adopted, and the raw material in the first step, 3-fluoro-4-bromopyridine, was replaced with 2-chloropyrazine to obtain the title compound (100 mg, yield: 70.2%).

[0327] MS m / z(ESI):561.3[M+H]+ .

[0328] Intermediate Preparation Example 9: Preparation of (2S,4R)-1-((S)-2-(4-(azetidin-3-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0329] Using the synthetic route in Intermediate Preparation Example 1, the second step reaction raw material 4-ethynylpiperidine-1-carboxylic acid tert-butyl ester was replaced with 3-ethynylazetidine-1-carboxylic acid tert-butyl ester to obtain the title compound (95 mg, yield: 93.0%).

[0330] MS m / z(ESI):552.3[M+H] + .

[0331] Intermediate Preparation Example 10: Preparation of (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-4-hydroxy-N-((S)-1-(4-(3-methylpyridin-2-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0332] The synthetic route in Intermediate Preparation Example 5 was used to replace the first step reaction raw material 4-bromo-3-fluoropyridine with 2-bromo-3-methylpyridine to obtain the title compound (35 mg, yield: 96.0%).

[0333] MS m / z(ESI):574.3[M+H] + .

[0334] Intermediate Preparation Example 11: Preparation of ((2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-4-hydroxy-N-((S)-1-(4-(pyridin-4-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0335] The synthetic route in Intermediate Preparation Example 5 was adopted, and the starting material in the first step, 4-bromo-3-fluoropyridine, was replaced with 4-bromopyridine to obtain the title compound (95 mg, yield: 95.6%).

[0336] MS m / z(ESI):560.3[M+H] + .

[0337] Intermediate Preparation Example 12: Preparation of (2S,4R)-N-((S)-1-(4-(3-chloropyridin-4-yl)phenyl)ethyl)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0338] The synthetic route in Intermediate Preparation Example 5 was adopted, and the starting material in the first step, 4-bromo-3-fluoropyridine, was replaced with 4-bromo-3-chloropyridine to obtain the title compound (150 mg, yield: 97.4%).

[0339] MS m / z(ESI):594.3[M+H] + .

[0340] Intermediate Preparation Example 13: Preparation of (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-4-hydroxy-N-((S)-1-(4-(5-methylpyrimidin-4-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0341] The synthetic route in Intermediate Preparation Example 5 was adopted, and the starting material in the first step, 4-bromo-3-fluoropyridine, was replaced with 4-bromo-5-methylpyrimidine to obtain the title compound (60 mg, yield: 94.6%).

[0342] MS m / z(ESI):575.3[M+H] + .

[0343] Intermediate Preparation Example 14: Preparation of (2S,4R)-N-((S)-1-(4-(4-chloropyridin-3-yl)phenyl)ethyl)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0344] The synthetic route in Intermediate Preparation Example 5 was adopted, and the starting material in the first step, 4-bromo-3-fluoropyridine, was replaced with 3-bromo-4-chloropyridine to obtain the title compound (160 mg, yield: 97.9%).

[0345] MS m / z(ESI):594.3[M+H] + .

[0346] Intermediate Preparation Example 15: Preparation of (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-4-hydroxy-N-(2-(4-(4-methylthiazol-5-yl)phenyl)propan-2-yl)pyrrolidine-2-carboxamide

[0347] Using the synthetic route in Intermediate Preparation Example 1, the first step reaction raw material (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl))ethyl)pyrrolidine-2-carboxamide was replaced with (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-(2-(4-(4-methylthiazol-5-yl)phenyl)propan-2-yl)pyrrolidine-2-carboxamide to obtain the title compound (88 mg, yield: 67.3%).

[0348] MS m / z(ESI):594.3[M+H] + .

[0349] Intermediate Preparation Example 16: Preparation of (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-4-hydroxy-N-(1-(4-(4-methylthiazol-5-yl)phenyl)cyclopropyl)pyrrolidine-2-carboxamide

[0350] Using the synthetic route in Intermediate Preparation Example 1, the first step reaction raw material (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl))ethyl)pyrrolidine-2-carboxamide was replaced with (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-(1-(4-(4-methylthiazol-5-yl)phenyl)cyclopropyl)pyrrolidine-2-carboxamide to give the title compound (150 mg, yield: 87.1%).

[0351] MS m / z(ESI):592.3[M+H] + .

[0352] Intermediate Preparation Example 17: Preparation of (2S,4R)-N-((S)-1-(4-(3-chloropyridin-2-yl)phenyl)ethyl)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0353] The synthetic route in Intermediate Preparation Example 5 was adopted, and the starting material in the first step, 4-bromo-3-fluoropyridine, was replaced with 2-bromo-3-chloropyridine to obtain the title compound (310.4 mg, yield: 97.8%).

[0354] MS m / z(ESI):594.3[M+H] + .

[0355] Intermediate Preparation Example 18: Preparation of (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-4-hydroxy-N-((S)-1-(4-(3-methylpyridin-4-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0356] The synthetic route in Intermediate Preparation Example 5 was adopted, and the starting material in the first step, 4-bromo-3-fluoropyridine, was replaced with 4-bromo-3-methylpyridine to obtain the title compound (176.3 mg, yield: 70.1%).

[0357] MS m / z(ESI):574.3[M+H] + .

[0358] Intermediate Preparation Example 19: Preparation of (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylpyrimidin-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0359] The synthetic route in Intermediate Preparation Example 5 was used to replace the first step reaction raw material 4-bromo-3-fluoropyridine with 5-bromo-4-methylpyrimidine to obtain the title compound (50 mg, yield: 46.5%).

[0360] MS m / z(ESI):575.3[M+H] + .

[0361] Intermediate Preparation Example 20: Preparation of (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-N-((S)-1-(4-(3-fluoropyridin-2-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide

[0362] The synthetic route in Intermediate Preparation Example 5 was adopted, and the starting material in the first step, 4-bromo-3-fluoropyridine, was replaced with 2-bromo-3-fluoropyridine to obtain the title compound (60 mg, yield: 80.1%).

[0363] MS m / z(ESI):578.4[M+H] + .

[0364] Intermediate Preparation Example 21: Preparation of (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-4-hydroxy-N-((S)-1-(4-(pyridin-2-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0365] The synthetic route in Intermediate Preparation Example 5 was adopted, and the starting material in the first step, 4-bromo-3-fluoropyridine, was replaced with 2-bromopyridine to obtain the title compound (35 mg, yield: 61.5%).

[0366] MS m / z(ESI):560.5[M+H] + .

[0367] Intermediate Preparation Example 22: Preparation of (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-4-hydroxy-N-((S)-1-(4-(pyridin-3-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0368] The synthetic route in Intermediate Preparation Example 5 was adopted, and the starting material in the first step, 4-bromo-3-fluoropyridine, was replaced with 3-bromopyridine to obtain the title compound (140 mg, yield: 97.0%).

[0369] MS m / z(ESI):560.3[M+H] + .

[0370] Intermediate Preparation Example 23: Preparation of (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-4-hydroxy-N-((S)-1-(4-(pyrimidin-2-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0371] The synthetic route in Intermediate Preparation Example 5 was adopted, and the starting material in the first step, 4-bromo-3-fluoropyridine, was replaced with 2-bromopyrimidine to obtain the title compound (350 mg, yield: 98.2%).

[0372] MS m / z(ESI):560.3[M+H] + .

[0373] Intermediate Preparation Example 24: Preparation of (1-(2-methoxyethyl)-1H-pyrazol-3-yl)boronic acid

[0374] 3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (500 mg, 2.55 mmol) and 1-bromo-2-methoxyethane (538 mg, 3.83 mmol) were dissolved in N,N-dimethylformamide (5 mL). Cesium carbonate (1.68 g, 5.10 mmol) and potassium iodide (855 mg, 5.10 mmol) were added and reacted at 80°C for 2 hours. The reaction solution was cooled to room temperature and filtered. The filtrate was purified by reverse-phase column chromatography (eluent: pure water / acetonitrile = 1 / 9, volume ratio) to obtain the title compound (400 mg, yield: 91.3%).

[0375] MS m / z(ESI):171.2[M+H] + .

[0376] Intermediate Preparation Example 25: Preparation of 5-cyclopropylpyridin-3-ol

[0377] 5-Bromopyridin-3-ol (500 mg, 2.87 mmol) was dissolved in 1.4-dioxane (5 mL) and water (0.5 mL). Cyclopropylboronic acid (1.23 g, 14.37 mmol), potassium phosphate (2.44 g, 11.49 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (25 mg, 0.03 mmol) were added sequentially. The mixture was stirred at 80°C for 5 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 1, volume ratio) to obtain the title compound (270 mg, yield: 70.1%).

[0378] MS m / z(ESI):136.1[M+H] + .

[0379] Intermediate Preparation Example 26: Preparation of N-isopropyl-2-(1H-pyrazol-3-yl)acetamide

[0380] 2-(1H-pyrazol-3-yl)acetic acid (1.0 g, 7.94 mmol) and isopropylamine (938 mg, 15.88 mmol) were dissolved in dichloromethane (20 mL). 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (712 mg, 15.88 mmol), 1-hydroxybenzotriazole (2.28 g, 11.91 mmol), and N,N-diisopropylethylamine (5.13 g, 39.71 mmol) were added sequentially, and the mixture was stirred at 25°C for 3 hours. The reaction mixture was washed once with saturated sodium bicarbonate solution (20 mL) and once with saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 1, volume ratio) to obtain the title compound (398 mg, yield: 30.2%).

[0381] MS m / z(ESI):168.3[M+H] + .

[0382] Intermediate Preparation Example 27: Preparation of (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-N-((S)-1-(3-fluoro-4-(4-methylthiazol-5-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide

[0383] Step 1: Preparation of (R)-N-(4-bromo-3-fluorobenzylidene)-2-methylpropane-2-sulfenamide

[0384] 4-Bromo-3-fluorobenzaldehyde (2.0 g, 9.75 mmol) was dissolved in 1.2-dichloroethane (20 mL). (R)-2-methylpropane-2-sulfenamide (1.79 g, 14.63 mmol) and copper sulfate pentahydrate (3.69 g, 14.63 mmol) were added sequentially. The mixture was reacted at 60°C for 12 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 5 / 1, volume ratio) to obtain the title compound (2.75 g, yield: 91.1%).

[0385] MS m / z(ESI):306.1[M+H] + .

[0386] Step 2: Preparation of (R)-N-((S)-1-(4-bromo-3-fluorophenyl)ethyl)-2-methylpropane-2-sulfenamide

[0387] (R)-N-(4-bromo-3-fluorobenzylidene)-2-methylpropane-2-sulfenamide (2.75 g, 8.98 mmol) was dissolved in dichloromethane (50 mL), cooled to -50°C, and a 1 M solution of methylmagnesium bromide in tetrahydrofuran (27 mL) was added dropwise. The mixture was allowed to react at -50°C for 3 hours. The reaction mixture was warmed to 0°C and quenched with saturated ammonium chloride solution (30 mL). The layers were separated, and the organic layer was washed with saturated brine (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 1, volume ratio) to obtain the title compound (1.9 g, yield: 64.9%).

[0388] MS m / z(ESI):322.4[M+H] + .

[0389] Step 3: Preparation of (R)-2-methyl-N-[(S)-1-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]propane-2-sulfenamide

[0390] (R)-N-((S)-1-(4-bromo-3-fluorophenyl)ethyl)-2-methylpropane-2-sulfenamide (1.9 g, 5.84 mmol) was dissolved in 1.4-dioxane (30 mL). Bis(pinacolato)diboron (2.25 g, 8.76 mmol), potassium phosphate (4.95 g, 23.35 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (481 mg, 0.58 mmol) were added sequentially. The mixture was stirred at 90°C for 6 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 2 / 1, volume ratio) to obtain the title compound (1.4 g, yield: 64.2%).

[0391] MS m / z(ESI):370.3[M+H] + .

[0392] Step 4: Preparation of (R)-2-methyl-N-[(S)-1-[3-fluoro-4-(4-methylthiazol-5-yl)phenyl]ethyl]propane-2-sulfenamide

[0393] (R)-2-Methyl-N-[(S)-1-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]propane-2-sulfenamide (1.4 g, 3.75 mmol) was dissolved in 1.4-dioxane (20 mL) and water (2 mL). 5-Bromo-4-methylthiazole (1.01 g, 5.63 mmol), potassium phosphate (2.41 g, 11.26 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (310 mg, 0.37 mmol) were added sequentially, and the mixture was stirred at 90°C for 6 hours. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 3, volume ratio) to give the title compound (860 mg, yield: 66.6%).

[0394] MS m / z(ESI):341.2[M+H] + .

[0395] Step 5: Preparation of (S)-1-[3-fluoro-4-(4-methylthiazol-5-yl)phenyl]ethylamine

[0396] (R)-2-Methyl-N-[(S)-1-[3-fluoro-4-(4-methylthiazol-5-yl)phenyl]ethyl]propane-2-sulfenamide (860 mg, 2.50 mmol) was dissolved in anhydrous methanol (10 mL). A 4 M solution of hydrogen chloride in 1,4-dioxane (5 mL) was added and stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain the title compound (590 mg, yield: 85.63%).

[0397] MS m / z(ESI):237.1[M+H] + .

[0398] Step 6: Preparation of tert-butyl ((S)-1-((2S,4R)-2-(((S)-1-(3-fluoro-4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl))-4-hydroxypyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate

[0399] (S)-1-[3-Fluoro-4-(4-methylthiazol-5-yl)phenyl]ethanamine (300 mg, 1.26 mmol) was dissolved in N,N-dimethylformamide (10 mL). (2S,4R)-4-hydroxy-1-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoyl]pyrrolidine-2-carboxylic acid (525 mg, 1.51 mmol), N,N-diisopropylethylamine (656 mg, 5.03 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (724 mg, 1.89 mmol) were added sequentially. The mixture was stirred at 25°C for 2 hours. The reaction mixture was purified by reverse-phase column chromatography (eluent: pure water / acetonitrile = 1 / 1, volume ratio) to obtain the title compound (550 mg, yield: 74.1%).

[0400] MS m / z(ESI):563.2[M+H] + .

[0401] Step 7: Preparation of (2S,4R)-4-hydroxy-1-[(S)-2-amino-3,3-dimethylbutyryl]-N-[(S)-1-[3-fluoro-4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide

[0402] Tert-butyl ((S)-1-((2S,4R)-2-(((S)-1-(3-fluoro-4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl))4-hydroxypyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate (550 mg, 0.96 mmol) was dissolved in ethyl acetate (10 mL). A 4 M solution of hydrogen chloride in 1,4-dioxane (5 mL) was added, and the mixture was stirred at 25°C for 3 hours. The reaction mixture was concentrated under reduced pressure to obtain the title compound (320 mg, yield: 98.4%).

[0403] MS m / z(ESI):463.3[M+H] + .

[0404] Step 8: Preparation of (2S,4R)-4-hydroxy-1-[(S)-2-azido-3,3-dimethylbutanoyl]-N-[(S)-1-[3-fluoro-4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide

[0405] (2S,4R)-4-Hydroxy-1-[(S)-2-amino-3,3-dimethylbutanoyl]-N-[(S)-1-[3-fluoro-4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (320 mg, 0.63 mmol) was dissolved in anhydrous methanol (10 mL) and water (2 mL). 1H-imidazole-1-sulfonyl azide hydrochloride (220 mg, 1.04 mmol), copper sulfate pentahydrate (18 mg, 96.2 μmol), and anhydrous potassium carbonate (290 mg, 2.08 mmol) were added sequentially. The mixture was reacted at 25°C for 2 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1, volume ratio) to obtain the title compound (320 mg, yield: 93.7%).

[0406] MS m / z(ESI):489.4[M+H] + .

[0407] Step 9: Preparation of tert-butyl 4-[1-[(S)-2,2-dimethyl-1-[(2S,4R)-4-hydroxy-2-[[(S)-1-[3]-fluoro-4-(4-methylthiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]propyl]triazol-4-yl]piperidine-1-carboxylate

[0408] (2S,4R)-4-Hydroxy-1-[(S)-2-azido-3,3-dimethylbutanoyl]-N-[(S)-1-[3-fluoro-4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (320 mg, 0.65 mmol) was dissolved in dimethyl sulfoxide (5 mL) and water (0.5 mL). 4-Ethynylpiperidine-1-carboxylic acid tert-butyl ester (137 mg, 0.65 mmol), sodium ascorbate (260 mg, 1.30 mmol), and copper sulfate pentahydrate (327 mg, 1.30 mmol) were added sequentially. The mixture was reacted at 25°C for 2 hours. The reaction solution was filtered and purified by reverse-phase column chromatography (eluent: pure water / acetonitrile = 1 / 2, volume ratio) to obtain the title compound (420 mg, 91.9% yield).

[0409] MS m / z(ESI):698.5[M+H] + .

[0410] Step 10: Preparation of (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-N-((S)-1-(3-fluoro-4-(4-methylthiazol-5-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide

[0411] Tert-butyl 4-[1-[(S)-2,2-dimethyl-1-[(2S,4R)-4-hydroxy-2-[[(S)-1-[3]-fluoro-4-(4-methylthiazol-5-yl)phenyl]ethyl]carbamoyl]pyrrolidine-1-carbonyl]propyl]triazol-4-yl]piperidine-1-carboxylate (420 mg, 0.60 mmol) was dissolved in ethyl acetate (10 mL). A 4 M solution of hydrochloric acid in 1.4-dioxane (5 mL) was added, and the mixture was stirred at 25°C for 3 hours. The reaction mixture was concentrated under reduced pressure to obtain the title compound (350 mg, yield: 97.3%).

[0412] MS m / z(ESI):598.1[M+H] + .

[0413] Intermediate Preparation Example 28: Preparation of (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-N-((S)-1-(2-fluoro-4-(4-methylthiazol-5-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide

[0414] The synthetic route in Intermediate Preparation Example 27 was adopted, and the raw material in the first step, 4-bromo-3-fluorobenzaldehyde, was replaced with 4-bromo-2-fluorobenzaldehyde to obtain the title compound (300 mg, yield: 98.1%).

[0415] MS m / z(ESI):598.1[M+H] + .

[0416] Intermediate Preparation Example 29: Preparation of (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-4-hydroxy-N-((S)-1-(4-(3-methylpyrazin-2-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0417] The synthetic route in Intermediate Preparation Example 5 was adopted, and the starting material in the first step, 4-bromo-3-fluoropyridine, was replaced with 2-bromo-3-methylpyrazine to obtain the title compound (32 mg, yield: 36.8%).

[0418] MS m / z(ESI):575[M+H] + .

[0419] Intermediate Preparation Example 30: Preparation of (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-4-hydroxy-N-((S)-1-(4-(2-methylpyridin-3-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0420] The synthetic route in Intermediate Preparation Example 5 was used to replace the first step reaction raw material 4-bromo-3-fluoropyridine with 3-bromo-2-methylpyridine to obtain the title compound (76 mg, yield: 64.4%).

[0421] MS m / z(ESI):574[M+H] + .

[0422] Intermediate Preparation Example 31: Preparation of (2S,4R)-N-((S)-1-(4-(2-chloropyridin-3-yl)phenyl)ethyl)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-4-hydroxypyrrolidine-2-carboxamide

[0423] The synthetic route in Intermediate Preparation Example 5 was adopted, and the starting material in the first step, 4-bromo-3-fluoropyridine, was replaced with 3-bromo-2-chloropyridine to obtain the title compound (82 mg, yield: 35.5%).

[0424] MS m / z(ESI):594[M+H] + .

[0425] Intermediate Preparation Example 32: Preparation of (2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0426] Step 1: Preparation of tert-butyl (2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-carboxylate

[0427] (2S,4R)-1-tert-Butoxycarbonyl-4-hydroxy-pyrrolidine-2-carboxylic acid (294 mg, 1.27 mmol), (1S)-1-[4-(4-methylthiazol-5-yl)phenyl]ethanamine hydrochloride (324 mg, 1.27 mmol), and N,N-diisopropylethylamine (411 mg, 3.18 mmol) were dissolved in N,N-dimethylacetamide (6 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (628 mg, 1.65 mmol) was added. The gas was replaced with nitrogen, and the reaction was stirred at 25°C for 6 hours. The reaction solution was diluted with ethyl acetate (20 mL) and washed once with saturated brine (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 15 / 1, volume ratio) to give the title compound (507 mg, yield: 92.5%).

[0428] MS m / z(ESI):432.1[M+H] + .

[0429] Step 2: Preparation of (2S,4R)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0430] Tert-butyl (2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-carboxylate (507 mg, 1.17 mmol) was dissolved in a 4M solution of hydrogen chloride in ethyl acetate (3 mL) and stirred at 25°C for 2 hours. The reaction mixture was concentrated to obtain the title compound (432 mg, 99.9% yield).

[0431] MS m / z(ESI):332.1[M+H] + .

[0432] Step 3: Preparation of tert-butyl ((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin)-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate

[0433] N-tert-Butyloxycarbonyl-L-valine (255 mg, 1.17 mmol), (2S,4R)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (432 mg, 1.17 mmol), and N,N-diisopropylethylamine (380 mg, 2.94 mmol) were dissolved in N,N-dimethylacetamide (5 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (581 mg, 1.53 mmol) was added. The atmosphere was replaced with nitrogen three times, and the reaction was stirred at 25°C for 12 hours. The reaction solution was diluted with ethyl acetate (20 mL), washed twice with saturated brine (10 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 15 / 1, volume ratio) to give the title compound (472 mg, yield: 75.7%).

[0434] MS m / z(ESI):531.2[M+H] + .

[0435] Step 4: Preparation of (2S,4R)-1-(L-valyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0436] Tert-butyl ((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate (472 mg, 890 μmol) was dissolved in a 4 M solution of hydrogen chloride in ethyl acetate (3 mL) and stirred at 25°C for 5 hours. The reaction mixture was concentrated to obtain the title compound (414 mg, 99.6% yield).

[0437] MS m / z(ESI):431.2[M+H] + .

[0438] Step 5: Preparation of (2S,4R)-1-((S)-2-azido-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0439] (2S,4R)-1-(L-valyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (414 mg, 886 μmol) and potassium carbonate (429 mg, 3.10 mmol) were dissolved in methanol (10 mL). Water (10 mL) was added and stirred for 3 minutes. 1H-imidazole-1-sulfonyl azide hydrochloride (279 mg, 1.33 mmol) and copper sulfate pentahydrate (22 mg, 89 μmol) were added and the reaction was stirred at 25 °C for 2 hours. The reaction solution was diluted with ethyl acetate (20 mL) and washed twice with saturated brine (15 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1, volume ratio) to give the title compound (197 mg, yield: 48.8%).

[0440] MS m / z(ESI):457.1[M+H] + .

[0441] Step 6: Preparation of tert-butyl 4-(1-((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl))ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)-1H-1,2,3-triazol-4-yl)piperidine-1-carboxylate

[0442] (2S,4R)-1-((S)-2-azido-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (197 mg, 431 μmol) and N-tert-butoxycarbonyl-4-ethynylpiperidine (90 mg, 431 μmol) were dissolved in dimethyl sulfoxide (4 mL) and water (0.4 mL). Sodium ascorbate (128 mg, 647 μmol) and copper sulfate pentahydrate (215 mg, 862 μmol) were added to the system, and the reaction was stirred at 25 ° C for 12 hours. The reaction solution was diluted with ethyl acetate (20 mL), washed three times with saturated brine (10 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 15 / 1, volume ratio) to give the title compound (138 mg, yield: 48.0%).

[0443] MS m / z(ESI):666.3[M+H] + .

[0444] Step 7: Preparation of (2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0445] Tert-butyl 4-(1-((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl))ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)-1H-1,2,3-triazol-4-yl)piperidine-1-carboxylate (138 mg, 207 μmol) was dissolved in a 4M solution of hydrogen chloride in ethyl acetate (1 mL) and stirred at 25°C for 5 hours. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate (10 mL). The organic phase was then washed with sodium bicarbonate solution, separated, and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the title compound (123 mg, yield: 98.8%).

[0446] MS m / z(ESI):566.3[M+H] + .

[0447] Intermediate Preparation Example 33: Preparation of N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazole-3-carboxamide

[0448] 1H-pyrazole-3-carboxylic acid (200 mg, 1.79 mmol) and 2-((tert-butyldimethylsilyl)oxy)ethylamine (343 mg, 1.96 mmol) were dissolved in DMF (5 mL). 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.02 g, 2.69 mmol) and N,N-diisopropylethylamine (461.8 mg, 3.58 mmol) were added sequentially, and the mixture was stirred at 25°C for 3 hours. The reaction mixture was diluted with ethyl acetate (20 mL), washed once with saturated sodium bicarbonate solution (10 mL) and once with saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 15 / 1, volume ratio) to obtain the title compound (150 mg, yield: 31.1%).

[0449] MS m / z(ESI):270.1[M+H] + .

[0450] Synthesis Example

[0451] Example 1: Preparation of (2S,4R)-1-((S)-2-(4-(1-(((2-(S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-(2-methoxyethoxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 3)

[0452] Step 1: Preparation of (S)-3-(4-chloro-6-(2-methoxyethoxy)pyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-2'-one

[0453] (S)-3-(4,6-Dichloropyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-2'-one (300 mg, 0.84 mmol) and 2-methoxyethanol (97 mg, 1.26 mmol) were dissolved in N,N-dimethylformamide (3 mL). Anhydrous cesium carbonate (555 mg, 1.69 mmol) was added and stirred at 25°C for 2 hours. The solid was filtered off, and the filtrate was purified by reverse-phase column chromatography (eluent: pure water / acetonitrile = 1 / 1, volume ratio) to obtain the title compound (250 mg, yield: 74.9%).

[0454] MS m / z(ESI):392.2[M+H] + .

[0455] Step 2: Preparation of (S)-3-(4-((1-(hydroxymethyl)cyclopropyl)methoxy)-6-(2-methoxyethoxy)pyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-2'-one

[0456] 1,1-Cyclopropane dimethanol (98 mg, 0.95 mmol) was dissolved in tetrahydrofuran (3 mL), and sodium hydride (38 mg, 0.95 mmol) was added. The mixture was stirred at 25°C for 0.5 hour. (S)-3-(4-chloro-6-(2-methoxyethoxy)pyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-2'-one (250 mg, 0.63 mmol) was added, and the mixture was stirred at 25°C for 2 hours. The reaction was quenched with water (0.5 mL), and the quenched reaction solution was dried over anhydrous sodium sulfate. The solid was filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 1, volume ratio) to provide the title compound (95 mg, yield: 32.5%).

[0457] MS m / z(ESI):458.5[M+H] + .

[0458] Step 3: Preparation of (S)-(1-(((6-(2-methoxyethoxy)-2-(2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-3-yl)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl methanesulfonate

[0459] (S)-3-(4-((1-(hydroxymethyl)cyclopropyl)methoxy)-6-(2-methoxyethoxy)pyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-2'-one (95 mg, 207.6 μmol) was dissolved in dichloromethane (2 mL). N,N-diisopropylethylamine (53.7 mg, 415.2 μmol) was added, followed by methanesulfonic anhydride (54.2 mg, 311.4 μmol). The mixture was reacted at 25°C for 12 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted twice with dichloromethane (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the title compound (100 mg, 90.1% yield).

[0460] MS m / z(ESI):536.2[M+H] + .

[0461] Step 4: Preparation of (2S,4R)-4-hydroxy-1-((S)-2-(4-(1-(1-(((6-(2-methoxyethoxy))-2-((S)-2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexyl]-3-yl)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-N-(S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0462] (S)-(1-((6-methoxy-2-(2-oxo-5,6-dihydro-4H-spiro)[benzo[d]isoxazol-7,1-cyclohexane]-3-yl)pyrimidin-4-yl)oxymethyl)cyclopropyl)methyl methanesulfonate (50 mg, 93.3 μmol) was dissolved in acetonitrile (2 mL), and potassium carbonate (25.8 mg, 187 μmol) and potassium iodide (15.5 mg, 93 To the reaction mixture was added (54.2 mg, 93.3 μmol) of (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (54.2 mg, 93.3 μmol), and the mixture was stirred at 60°C for 6 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (10 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1, volume ratio) to obtain the title compound (50 mg, yield: 52.6%).

[0463] MS m / z(ESI):1019.5[M+H] + .

[0464] Step 5: Preparation of (2S,4R)-1-((S)-2-(4-(1-(((2-(S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-(2-methoxyethoxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0465] (2S,4R)-4-hydroxy-1-((S)-2-(4-(1-(1-(((6-(2-methoxyethoxy))-2-((S)-2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexyl]-3-yl)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-N-(S) 1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (50 mg, 49.1 μmol), ammonium acetate (15.1 mg, 196.3 μmol), and sulfur (6.3 mg, 196.3 μmol) were dissolved in ethanol (2 mL) and stirred at 60°C for 15 minutes. A solution of malononitrile (16.1 mg, 245.5 μmol) in ethanol (1 mL) was then added dropwise, and the mixture was stirred at 80°C for 5 hours. The reaction mixture was filtered, the filtrate was concentrated, and the residue was purified by HPLC (Condition 1) to obtain the title compound (11 mg, yield: 19.5%).

[0466] MS m / z(ESI):1099.5[M+H] + .

[0467] 1 H-NMR (400MHz, DMSO-d6) δ8.99(s,1H),8.53(d,J=8.0Hz,1H),8.27(s,1H),8.00(s,1H),7.44(d,J= 8.0Hz,2H),7.37(d,J=8.0Hz,2H),6.96(s,2H),6.36(s,1H),5.44(s,1H),5.15(s,1H),4.91(t,J=4. 0Hz,1H),4.50-4.27(m,7H),3.68-3.60(m,4H),3.34(s,3H),3.09-2.98(m,4H),2.68-2.63(m,3H),2 .46-2.30(m,2H),2.06-1.52(m,18H),1.37(d,J=8.0Hz,2H),0.96(s,9H),0.67(s,2H),0.43(s,2H).

[0468] Example 2: Preparation of (2S,4R)-1-((S)-2-(4-(1-((((2-(S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-(piperidin-4-yloxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 22)

[0469] Step 1: Preparation of tert-butyl (S)-4-((6-chloro-2-(2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-3-yl)pyrimidin-4-yl)oxy)piperidine-1-carboxylate

[0470] (S)-3-(4,6-Dichloropyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-2'-one (300 mg, 0.84 mmol) and tert-butyl 4-hydroxypiperidine-1-carboxylate (253 mg, 1.26 mmol) were dissolved in N,N-dimethylformamide (3 mL). Anhydrous cesium carbonate (555 mg, 1.69 mmol) was added and stirred at 25°C for 2 hours. The solid was filtered off, and the filtrate was purified by reverse-phase column chromatography (eluent: pure water / acetonitrile = 1 / 1, volume ratio) to obtain the title compound (150 mg, yield: 34.1%).

[0471] MS m / z(ESI):517.2[M+H] + .

[0472] Step 2: Preparation of tert-butyl (S)-4-((6-(((1-(hydroxymethyl)cyclopropyl)methoxy)-2-(2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexyl]-3-yl)pyrimidin-4-yl)oxy)piperidine-1-carboxylate

[0473] 1,1-Cyclopropane dimethanol (44.4 mg, 0.44 mmol) was dissolved in tetrahydrofuran (3 mL), and sodium hydride (26.4 mg, 0.44 mmol) was added. The mixture was stirred at 25°C for 0.5 hour. (S)-3-(4-chloro-6-(2-methoxyethoxy)pyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-2'-one (150 mg, 0.29 mmol) was added, and the mixture was stirred at 25°C for 2 hours. The reaction was quenched with water (0.2 mL), and the quenched reaction solution was dried over anhydrous sodium sulfate. The solid was filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 1, volume ratio) to provide the title compound (60 mg, yield: 35.5%).

[0474] MS m / z(ESI):583.3[M+H] + .

[0475] Step 3: Preparation of tert-butyl (S)-4-((6-((1-(((methylsulfonyl)oxy)methyl)cyclopropyl)methoxy)-2-(2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazole-7,1'-cyclohexane]-3-yl)pyrimidin-4-yl)oxy)piperidine-1-carboxylate

[0476] To the mixture of tert-butyl (S)-4-((6-(((1-(hydroxymethyl)cyclopropyl)methoxy)-2-(2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexyl]-3-yl)pyrimidin-4-yl)oxy)piperidine-1-carboxylate (60 mg, 103 μmol) was dissolved in dichloromethane (3 mL), and N,N-diisopropylethylamine (26.6 mg, 206 μmol) and methanesulfonic anhydride (26.9 mg, 154.5 μmol) were added sequentially. The mixture was reacted at 25°C for 12 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted twice with dichloromethane (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the title compound (65 mg, yield: 95.6%).

[0477] MS m / z(ESI):661.3[M+H] + .

[0478] Step 4: Preparation of tert-butyl 4-((6-((1-((4-(1-(S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-1H-1,2,3-triazol-4-yl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-2-((S)-2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexyl]-3-yl)pyrimidin-4-yl)oxy)piperidine-1-carboxylate

[0479] (S)-(1-((6-methoxy-2-(2-oxo-5,6-dihydro-4H-spiro)[benzo[d]isoxazol-7,1-cyclohexane]-3-yl)pyrimidin-4-yl)oxymethyl)cyclopropyl)methyl methanesulfonate (65 mg, 98.3 μmol) was dissolved in acetonitrile (2 mL), and potassium carbonate (27.2 mg, 196.6 μmol) and potassium iodide (16.3 mg) were added. , 98.3 μmol) and (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (57 mg, 98.3 μmol) were added and stirred at 60°C for 6 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (10 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1, volume ratio) to obtain the title compound (55 mg, yield: 49.1%).

[0480] MS m / z(ESI):1144.5[M+H] + .

[0481] Step 5: Preparation of tert-butyl 4-((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-((1-((4-(1-(S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-1H-1,2,3-triazol-4-yl)piperidin-1-yl)methyl)cyclopropyl)methoxy)pyrimidin-4-yl)oxy)piperidine-1-carboxylate

[0482] 4-((6-((1-((4-(1-(S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-1H-1,2,3-triazol-4-yl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-2-((S)-2'-oxo-5,6-dihydro-4H-spiro[benzo[ Tert-butyl (d-isoxazol-7,1'-cyclohexyl)-3-yl)pyrimidin-4-yl)oxy)piperidine-1-carboxylate (55 mg, 48.1 μmol), ammonium acetate (14.8 mg, 192.4 μmol), and sulfur (6.2 mg, 192.4 μmol) were dissolved in ethanol (2 mL) and stirred at 60°C for 15 minutes. A solution of malononitrile (15.8 mg, 240.5 μmol) in ethanol (2 mL) was then added dropwise, and the mixture was stirred at 80°C for 5 hours. The reaction mixture was filtered, the filtrate was concentrated, and the residue was purified by HPLC (Condition 1) to obtain the title compound (18 mg, yield: 30.6%).

[0483] MS m / z(ESI):1224.5[M+H] + .

[0484] Step 6: Preparation of (2S,4R)-1-((S)-2-(4-(1-((((2-(S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-(piperidin-4-yloxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0485] 4-((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-((1-((4-(1-(S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)amino tert-Butyl (18 mg, 14.7 μmol) (methyl)-1,2,3-dimethyl-1-oxobutan-2-yl (3,3-dimethyl-1-oxobutan-2-yl (4,4 ...

[0486] MS m / z(ESI):1124.5[M+H] + .

[0487] 1 H-NMR (400MHz, DMSO-d6) δ8.99(s,1H),8.53(d,J=8.0Hz,1H),8.27(s,1H),8.00(s,1H),7.44(d,J=8.0H z,2H),7.37(d,J=8.0Hz,2H),6.97(s,2H),6.37(s,1H),5.44(s,1H),5.20(s,1H),4.91(t,J=4.0Hz,1H), 4.42-4.27(m,4H),3.67-3.60(m,3H),3.08-2.83(m,6H),2.64-2.60(m,2H),2.54-2.51(m,2H),2.49(s,3 H), 2.46-2.30 (m, 3H), 2.20-1.61 (m, 21H), 1.37 (d, J = 8.0Hz, 2H), 0.95 (s, 9H), 0.67 (s, 2H), 0.43 (s, 2H).

[0488] Example 3: Preparation of (2S,4R)-1-((S)-2-(4-(1-(((2-(S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-cyclopropylpyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 21)

[0489] Step 1: Preparation of (S)-3-(4-cyclopropyl-6-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-2'-one

[0490] (S)-3-(4-chloro-6-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexyl]-2'-one (100 mg, 239 μmol) and cyclopropylboronic acid (61.2 mg, 717 μmol) were dissolved in 1,4-dioxane (5 mL). Cesium carbonate (233.6 mg, 717 μmol) and Pd(dppf)Cl2 (17.5 mg, 23.9 μmol) were added. The atmosphere was purged with nitrogen three times and stirred at 95°C for 12 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1, volume ratio) to obtain the title compound (54 mg, yield: 53.2%).

[0491] MS m / z(ESI):424.2[M+H] + .

[0492] Step 2: Preparation of (S)-(1-(((6-cyclopropyl-2-(2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-3-yl)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl methanesulfonate

[0493] (S)-3-(4-cyclopropyl-6-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-2'-one (54 mg, 127 μmol) was dissolved in dichloromethane (2 mL). N,N-diisopropylethylamine (32.9 mg, 254 μmol) was added, followed by methanesulfonic anhydride (33.1 mg, 190.5 μmol). The mixture was reacted at 25°C for 12 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted twice with dichloromethane (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the title compound (60 mg, 94.0% yield).

[0494] MS m / z(ESI):502.1[M+H] + .

[0495] Step 3: Preparation of (2S,4R)-1-((S)-2-(4-(1-(((6-cyclopropyl-2-(S)-2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexanone]-3-yl)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-(S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0496] (S)-(1-(((6-cyclopropyl-2-(2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-3-yl)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl methanesulfonate (60 mg, 120 μmol) was dissolved in acetonitrile (2 mL), and potassium carbonate (49.7 mg, 360 μmol), potassium iodide (19.9 mg, 4 μmol) and ethanol (500 μmol) were added. The reaction mixture was stirred at 60°C for 6 hours. Water (10 mL) was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate (10 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1, volume ratio) to obtain the title compound (55 mg, yield: 46.6%).

[0497] MS m / z(ESI):985.5[M+H]+ .

[0498] Step 4: Preparation of (2S,4R)-1-((S)-2-(4-(1-(((2-(S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-cyclopropylpyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0499] (2S,4R)-1-((S)-2-(4-(1-(((6-cyclopropyl-2-(S)-2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexanone]-3-yl)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-(S)-1-(4 (4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (55 mg, 55.8 μmol), ammonium acetate (17.2 mg, 223.2 μmol), and sulfur (7.1 mg, 223.2 μmol) were dissolved in ethanol (1 mL) and stirred at 60°C for 15 minutes. A solution of malononitrile (18.4 mg, 279 μmol) in ethanol (2 mL) was then added dropwise, and the mixture was stirred at 80°C for 5 hours. The reaction mixture was filtered, the filtrate was concentrated, and the residue was purified by HPLC (Condition 1) to obtain the title compound (10 mg, yield: 16.8%).

[0500] MS m / z(ESI):1065.5[M+H] + .

[0501] 1H-NMR (400MHz, DMSO-d6) δ8.99(s,1H),8.53(d,J=8.0Hz,1H),8.27(s,1H),8.00(s,1H),7.44(d,J=8.0H z,2H),7.37(d,J=8.0Hz,2H),6.95(d,J=8.0Hz,3H),5.43(s,1H),5.14(s,1H),4.91(t,J=4.0Hz,1H),4. 42-4.27(m,4H),3.67-3.63(m,2H),3.09-2.98(m,3H),2.54-2.51(m,4H),2.49(s,3H),2.34-2.30(m,2H ),2.04-1.60(m,17H),1.37(d,J=4.0Hz,2H),1.06-1.04(m,4H),0.96(s,9H),0.68(s,2H),0.43(s,2H).

[0502] Example 4: Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-(((R)-tetrahydrofuran-3-yl)oxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 15)

[0503] The synthetic route in Example 1 was used to replace the first step reaction raw material 2-methoxyethanol with (R)-tetrahydrofuran-3-ol to obtain the title compound (5 mg, yield: 10.2%).

[0504] MS m / z(ESI):1111.5[M+H] + .

[0505] 1H-NMR (400MHz, DMSO-d6) δ8.99(s,1H),8.52(d,J=8.0Hz,1H),8.27(s,1H),8.00(s,1H),7.44(d,J=8.0 Hz,2H),7.37(d,J=8.0Hz,2H),6.96(s,2H),6.37(s,1H),5.60(s,1H),5.44(s,1H),5.15(s,1H),4.91(t ,J=4.0Hz,1H),4.44-4.29(m,4H),3.93-3.63(m,7H),3.03-2.97(m,4H),2.53-2.51(m,2H),2.49(s,3H ),2.32-2.26(m,3H),2.15-1.50(m,17H),1.37(d,J=4.0Hz,2H),0.96(s,9H),0.67(s,2H),0.43(s,2H).

[0506] Example 5: Preparation of (2S,4R)-1-((S)-2-(4-(1-(((2-(((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-(3-(dimethylamino)azetidin-1-yl)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-(((S)-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 17)

[0507] Step 1: Preparation of (S)-3-(4-(3-(dimethylamino)azetidin-1-yl)-6-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-2'-one

[0508] (S)-3-(4-chloro-6-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexyl]-2'-one (100 mg, 239 μmol) was dissolved in dimethyl sulfoxide (5 mL). N,N-diisopropylethylamine (123.6 mg, 956 μmol) and N,N-dimethylazetidin-3-amine hydrochloride (65.3 mg, 478 μmol) were added. The atmosphere was replaced with nitrogen three times and the mixture was stirred at 95°C for 18 hours. The reaction mixture was cooled to room temperature, water (10 mL) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (10 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 15 / 1, volume ratio) to give the title compound (75 mg, yield: 65.2%).

[0509] MS m / z(ESI):482.3[M+H] + .

[0510] Step 2: Preparation of (S)-(1-(((6-(3-(dimethylamino)azetidin-1-yl)-2-(2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexyl]-3-yl)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl methanesulfonate

[0511] (S)-3-(4-(3-(dimethylamino)azetidin-1-yl)-6-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-2'-one (75 mg, 156 μmol) was dissolved in dichloromethane (2 mL). N,N-diisopropylethylamine (60.5 mg, 468 μmol) and methanesulfonic anhydride (40.7 mg, 234 μmol) were added sequentially and reacted at 25°C for 12 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted twice with dichloromethane (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the title compound (80 mg, yield: 91.8%).

[0512] MS m / z(ESI):560.2[M+H] + .

[0513] Step 3: Preparation of (2S,4R)-1-((S)-2-(4-(1-(1-(((6-(3-(dimethylamino)azetidin-1-yl))-2-((S)-2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexyl]-3-yl)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-(S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0514] (S)-(1-(((6-(3-(dimethylamino)azetidin-1-yl)-2-(2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexyl]-3-yl)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl methanesulfonate (80 mg, 143 μmol) was dissolved in acetonitrile (2 mL), and potassium carbonate (59.3 mg, 429 μmol) and iodine were added. The reaction mixture was stirred at 60°C for 6 hours in the presence of potassium chloride (23.7 mg, 143 μmol) and (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (82.9 mg, 143 μmol). Water (10 mL) was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate (10 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1, volume ratio) to obtain the title compound (75 mg, yield: 50.3%).

[0515] MS m / z(ESI):1043.5[M+H] + .

[0516] Step 4: Preparation of (2S,4R)-1-((S)-2-(4-(1-(((2-(((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-(3-(dimethylamino)azetidin-1-yl)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-(((S)-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0517] (2S,4R)-1-((S)-2-(4-(1-(1-(((6-(3-(dimethylamino)azetidin-1-yl))-2-((S)-2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexyl]-3-yl)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-( ... (S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (75 mg, 71.9 μmol), ammonium acetate (22.1 mg, 287.6 μmol), and sulfur (9.2 mg, 287.6 μmol) were dissolved in ethanol (1 mL) and stirred at 60°C for 15 minutes. A solution of malononitrile (23.7 mg, 359.5 μmol) in ethanol (2 mL) was then added dropwise, and the mixture was stirred at 80°C for 5 hours. The reaction mixture was filtered, the filtrate was concentrated, and the residue was purified by HPLC (Condition 2) to obtain the title compound (20 mg, yield: 24.8%).

[0518] MS m / z(ESI):1123.5[M+H] + .

[0519] 1 H-NMR (400MHz, DMSO-d6) δ8.99(s,1H),8.53(d,J=7.6Hz,1H),7.98(d,J=16.8Hz,1H),7.44(d,J=7.6Hz,2H),7.37(d,J=7.6Hz,2H),6. 95(s,2H),5.72(s,1H),5.44(s,1H),5.25-5.12(m,1H),4.97-4.85(m,1H),4.43(t,J=8.4Hz,1H),4.24(dd,J=32.4,10.4Hz,4H),4.06( t,J=8.4Hz,2H),3.82(t,J=6.8Hz,2H),3.56-3.72(m,2H),3.21(t,J=6.0Hz,1H),3.01(d,J=14.4Hz,4H),2.71-2.51(m,5H),2.46(s,3H ),2.36-2.27(m,2H),2.12(s,6H),2.11-1.71(m,9H),1.48-1.70(m,2H),1.38(d,J=7.2Hz,3H),0.96(s,9H),0.64(s,2H),0.40(s,2H).

[0520] Example 6: Preparation of (2S,4R)-1-((S)-2-(4-(1-(((2-(S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-((R)-3-methylpiperazin-1-yl)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 20)

[0521] Step 1: Preparation of tert-butyl (R)-4-(6-((1-(hydroxymethyl)cyclopropyl)methoxy)-2-((S)-2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-3-yl)pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate

[0522] (S)-3-(4-chloro-6-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexyl]-2'-one (100 mg, 239 μmol) was dissolved in dimethyl sulfoxide (5 mL), and N,N-diisopropylethylamine (123.6 mg, 956 μmol) and (R)-tert-butyl 2-methylpiperazine-1-carboxylate (95.6 mg, 478 μmol) were added. The atmosphere was replaced with nitrogen three times and the mixture was stirred at 95°C for 18 hours. The reaction mixture was cooled to room temperature, water (10 mL) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (10 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1, volume ratio) to give the title compound (88 mg, yield: 63.2%).

[0523] MS m / z(ESI):582.3[M+H] + .

[0524] Step 2: Preparation of tert-butyl (R)-2-methyl-4-(6-((1-(((methylsulfonyl)oxy)methyl)cyclopropyl)methoxy)-2-(((S)-2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-3-yl)pyrimidin-4-yl)piperazine-1-carboxylate

[0525] Tert-butyl (R)-4-(6-((1-(hydroxymethyl)cyclopropyl)methoxy)-2-((S)-2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-3-yl)pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate (88 mg, 151 μmol) was dissolved in dichloromethane (2 mL). N,N-diisopropylethylamine (58.5 mg, 453 μmol) and methanesulfonic anhydride (39.4 mg, 226.5 μmol) were added sequentially, and the mixture was reacted at 25°C for 12 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted twice with dichloromethane (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the title compound (95 mg, 95% yield).

[0526] MS m / z(ESI):660.2[M+H] + .

[0527] Step 3: Preparation of tert-butyl (R)-4-(6-((1-((4-(1-(S)-1-((2S,4R)-4-hydroxy-2-(((S)-1,4-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-1H-1,2,3-triazol-4-yl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-2-((S)-2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexyl]-3-yl)pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate

[0528] (R)-tert-Butyl 2-methyl-4-(6-((1-(((methylsulfonyl)oxy)methyl)cyclopropyl)methoxy)-2-(((S)-2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-3-yl)pyrimidin-4-yl)piperazine-1-carboxylate (95 mg, 144 μmol) was dissolved in acetonitrile (2 mL), potassium carbonate (59.7 mg, 432 μmol) and potassium iodide (23.9 mg, 144 μmol) were added, and (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)- The reaction mixture was stirred at 60°C for 6 hours with the addition of 1H-(1,2,3-triazol-1-yl)butyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (83.5 mg, 144 μmol). Water (10 mL) was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate (10 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1, volume ratio) to obtain the title compound (80 mg, yield: 48.6%).

[0529] MS m / z(ESI):1143.6[M+H] + .

[0530] Step 4: Preparation of (R)-tert-butyl 4-(2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-((1-((4-(1-(S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-1H-1,2,3-triazol-4-yl)piperidin-1-yl)methyl)cyclopropyl)methoxy)pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate

[0531] (2S,4R)-1-((S)-2-(4-(1-(1-(((6-(3-(dimethylamino)azetidin-1-yl))-2-((S)-2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexyl]-3-yl)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4- Hydroxy-N-(S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (80 mg, 70 μmol), ammonium acetate (21.6 mg, 280 μmol), and sulfur (9.0 mg, 280 μmol) were dissolved in ethanol (2 mL) and stirred at 60°C for 15 minutes. A solution of malononitrile (23.1 mg, 350 μmol) in ethanol (1 mL) was then added dropwise, and the mixture was stirred at 80°C for 5 hours. The reaction mixture was filtered, the filtrate was concentrated, and the residue was purified by HPLC to obtain the title compound (15 mg, yield: 17.5%).

[0532] MS m / z(ESI):1223.6[M+H] + .

[0533] Step 5: Preparation of (2S,4R)-1-((S)-2-(4-(1-(((2-(S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-((R)-3-methylpiperazin-1-yl)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0534] (R)-4-(2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-((1-((4-(1-(S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)amino tert-Butyl 2-methylpiperazine-1-carboxylate (15 mg, 12.3 μmol) was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (0.5 mL) was added. The mixture was stirred at 25°C for 3 hours. The reaction mixture was adjusted to pH 8 with aqueous sodium bicarbonate and extracted three times with ethyl acetate (10 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (Condition 2) to obtain the title compound (3 mg, yield: 21.7%).

[0535] MS m / z(ESI):1123.5[M+H] + .

[0536] 1 H-NMR (400MHz, DMSO-d6) δ8.99(s,1H),8.53(d,J=7.6Hz,1H),7.98(d,J=16.8Hz,1H),7.44(d,J=7.6Hz,2H),7.37(d,J=7.6 Hz,2H),6.95(s,2H),5.72(s,1H),5.44(s,1H),5.25-5.12(m,1H),4.91(t,J=6.8Hz,1H),4.42(t,J=8.4Hz,1H),4.36-4.24 (m,4H),3.70-3.53(m,1H),3.47-3.19(m,2H),3.16-2.95(m,6H),2.67-2.54(m,1H),2.46(d,J=1.6Hz,3H),2.29-2.03(m,4 H), 2.02-1.86 (m, 9H), 1.87-1.71 (m, 7H), 1.59-1.38 (m, 6H), 1.28 (d, J = 6.4Hz, 3H), 0.97 (s, 9H), 0.67 (s, 2H), 0.43 (s, 2H).

[0537] Example 7: Preparation of (2S,4R)-1-((S)-2-(4-(1-((S)-(2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol-3-yl)-6-methoxypyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-N-((S)-1-(2-fluoro-[1,1-biphenyl]-4-yl)ethyl)-4-hydroxypyrrolidine-2-carboxamide (Compound 1)

[0538] Step 1: Preparation of (S)-3-(4-chloro-6-methoxypyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-2'-one

[0539] Dissolve (S)-3-(4,6-dichloropyridin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1-cyclohexane]-2-one (200.0 mg, 539.4 μmol) in tetrahydrofuran (2 mL), add sodium methoxide (97.1 mg, 539.4 μmol), and stir at 25°C for 3 hours. Dilute with ethyl acetate (15 mL), wash the organic phase with water (15 mL), dry, and concentrate to obtain the title compound (160 mg, yield: 85.3%).

[0540] MS m / z(ESI):348.1[M+H] + .

[0541] Step 2: Preparation of (S)-3-(4-((1-(hydroxymethyl)cyclopropyl)methoxy)-6-methoxypyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-2'-one

[0542] (S)-3-(4-chloro-6-methoxypyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1-cyclohexane]-2-one (160 mg, 464.4 μmol) was dissolved in tetrahydrofuran (2 mL), and sodium hydride (55.72 mg, 1.39 mmol) was added. The mixture was stirred at 25°C for 3 hours. Water (10 mL) was slowly added to the reaction solution, which was then extracted three times with ethyl acetate (10 mL). The organic phases were combined, washed once with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1, volume ratio) to provide the title compound (80 mg, yield: 39.6%).

[0543] MS m / z(ESI):414.2[M+H] + .

[0544] Step 3: Preparation of (S)-(1-((6-methoxy-2-(2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-3-yl)pyrimidin-4-yl)oxymethyl)cyclopropyl)methyl methanesulfonate

[0545] (S)-3-(4-((1-(hydroxymethyl)cyclopropyl)methoxy)-6-methoxypyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-2'-one (80 mg, 193.5 μmol) was dissolved in dichloromethane (2 mL). N,N-diisopropylethylamine (50.0 mg, 387.0 μmol) and methanesulfonic anhydride (50.6 mg, 290.2 μmol) were added and reacted at 25°C for 12 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted twice with dichloromethane (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the title compound (100 mg, yield: 99.9%).

[0546] MS m / z(ESI):492.2[M+H] + .

[0547] Step 4: Preparation of (2S,4R)-N-(S)-1-(2-fluoro-[1,1-biphenyl]-4-yl)ethyl)-4-hydroxy-1-(S)-2-(4-(1-(6-methoxy-2-(S)-2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-3-yl)pyrimidin-4-yl)oxy)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)pyrrolidine-2-carboxamide

[0548] (S)-(1-((6-methoxy-2-(2'-oxo-5,6-dihydro-4H-spiro)[benzo[d]isoxazol-7,1'-cyclohexane]-3-yl)pyrimidin-4-yl)oxymethyl)cyclopropyl)methyl methanesulfonate (50 mg, 96.6 μmol) was dissolved in acetonitrile (2 mL), and potassium carbonate (49.2 mg, 338.2 μmol) and potassium iodide (18.6 mg, The reaction mixture was stirred at 60°C for 6 hours. Water (10 mL) was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate (10 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1, volume ratio) to obtain the title compound (50 mg, yield: 50.5%).

[0549] MS m / z(ESI):972.5[M+H] + .

[0550] Step 5: Preparation of (2S,4R)-1-((S)-2-(4-(1-((S)-(2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol-3-yl)-6-methoxypyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-N-((S)-1-(2-fluoro-[1,1-biphenyl]-4-yl)ethyl)-4-hydroxypyrrolidine-2-carboxamide

[0551] (2S,4R)-N-(S)-1-(2-fluoro-[1,1-biphenyl]-4-yl)ethyl)-4-hydroxy-1-(S)-2-(4-(1-(6-methoxy-2-(S)-2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-3-yl)pyrimidin-4-yl)oxy)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl) (-3,3-dimethylbutanoyl)pyrrolidine-2-carboxamide (50 mg, 48.86 μmol), ammonium acetate (15.1 mg, 195.4 μmol), and sulfur (6.3 mg, 195.4 μmol) were dissolved in ethanol (1 mL) and stirred at 60°C for 15 minutes. A solution of malononitrile (16.1 mg, 244.3 μmol) in ethanol (2 mL) was then added dropwise, and the mixture was stirred at 80°C for 5 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by HPLC (Condition 1) to obtain the title compound (11 mg, yield: 19.5%).

[0552] MS m / z(ESI):1051.5[M+H] + .

[0553] 1 H-NMR (400MHz, DMSO-d6) δ8.53(d,J=7.6Hz,1H),8.27(s,1H),8.00(s,1H),7.50(d,J=8.4Hz,3H),7.44-7.35(m,3H),7.30 (d,J=5.2Hz,2H),6.97(s,2H),6.35(s,1H),5.44(s,1H),4.92(t,J=7.2Hz,1H),4.43(t,J=8.4Hz,1H),4.37(d,J=10.8Hz, 1H),4.33-4.23(m,2H),3.95(s,3H),3.72-3.60(m,3H),3.10(d,J=15.6Hz,1H),2.96(d,J=14.4Hz,3H),2.64-2.60(m,1H) ,2.32-2.25(m,3H),2.13-1.72(m,13H),1.67-1.50(m,2H),1.39(d,J=6.8Hz,3H),0.97(s,9H),0.43(s,2H),0.67(s,2H).

[0554] Example 8: Preparation of (2S,4R)-1-((S)-2-(4-(1-(((2-(S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-methoxypyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 2)

[0555] Using the synthetic route in Example 7, the fourth step reaction raw material (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-N-((S)-1-(2'-fluoro-[1,1'-biphenyl]-4-yl)ethyl)-4-hydroxypyrrolidine-2-carboxamide was replaced with (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide to give the title compound (3 mg, yield: 9.2%).

[0556] MS m / z(ESI):1055.4[M+H] + .

[0557] 1H-NMR (400MHz, DMSO-d6) δ8.99(s,1H),8.52(d,J=7.6Hz,1H),7.99(s,1H),7.47-7.42(m,2H),7.41-7.34(m,2H),6.96(s, 2H),6.35(s,1H),5.44(s,1H),5.15(d,J=3.6Hz,1H),4.90(t,J=7.2Hz,1H),4.48-4.33(m,2H),4.30(d,J=9.2Hz,2H),3.95 (s,3H),3.75-3.52(m,2H),3.10(d,J=13.2Hz,1H),2.98(s,2H),2.73-2.53(m,2H),2.46(s,3H),2.41-2.19(m,4H),2.13-1 .70(m,11H),1.67-1.49(m,4H),1.37(d,J=7.2Hz,2H),1.30-1.17(m,1H),0.95(d,J=4.0Hz,9H),0.68(s,2H),0.43(s,2H).

[0558] Example 9: Preparation of (2S,4R)-1-((S)-2-(4-(1-(((2-(S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 5)

[0559] The synthetic route in Example 1 was used to replace the first step reaction raw material 2-methoxyethanol with tetrahydro-2H-pyran-4-ol to obtain the title compound (7 mg, yield: 18.6%).

[0560] MS m / z(ESI):1125.5[M+H] + .

[0561] 1H-NMR (400MHz, DMSO-d6) δ8.99(s,1H),8.52(d,J=7.6Hz,1H),7.99(d,J=2.4Hz,1H),7.44(d,J=6.8Hz,2H),7.42-7.32(m,2H),6.96(s,2H),6 .36(s,1H),5.44(s,1H),5.25(t,J=8.4Hz,1H),5.15(d,J=3.6Hz,1H),4.90(t,J=7.2Hz,1H),4.42(t,J=8.4Hz,1H),4.38-4.24(m,4H),3.93- 3.82(m,2H),3.73-3.57(m,2H),3.53-3.43(m,2H),3.11-2.91(m,4H), 2.70-2.56(m,2H),2.54(d,J=4.4Hz,2H),2.46(s,3H),2.34-2.27(m,2 H),2.13-2.00(m,6H),1.88-181(m,8H),1.66-1.56(m,2H),1.54-1.39 (m,1H),1.37(d,J=6.8Hz,3H),0.95(s,9H),0.42(s,2H),0.67(s,2H).

[0562] Example 10: Preparation of (2S,4R)-1-((S)-2-(4-(1-((2-(S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3-yl)-6-(pyrimidin-5-yloxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 11)

[0563] Step 1: Preparation of (S)-3-(4-chloro-6-(pyrimidin-5-yloxy)pyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-2'-one

[0564] (S)-3-(4,6-Dichloropyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-2'-one (300 mg, 0.84 mmol) and 5-hydroxypyrimidine (120.9 mg, 1.26 mmol) were dissolved in N,N-dimethylformamide (3 mL). Anhydrous cesium carbonate (555 mg, 1.69 mmol) was added, and the mixture was stirred at 25°C for 2 hours. The solid was filtered off, and the filtrate was purified by reverse-phase column chromatography (eluent: pure water / acetonitrile = 1 / 1, volume ratio) to obtain the title compound (200 mg, yield: 57%).

[0565] MS m / z(ESI):412.1[M+H] + .

[0566] Step 2: Preparation of (S)-3-(4-(((1-(hydroxymethyl)cyclopropyl)methoxy)-6-(pyrimidin-5-yloxy)pyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-2'-one

[0567] 1,1-Cyclopropane dimethanol (74.5 mg, 0.73 mmol) was dissolved in tetrahydrofuran (3 mL), and sodium hydride (43.8 mg, 0.73 mmol) was added. The mixture was stirred at 25°C for 0.5 hour. (S)-3-(4-chloro-6-(pyrimidin-5-yloxy)pyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-2'-one (200 mg, 0.49 mmol) was added, and the mixture was stirred at 25°C for 2 hours. The reaction was quenched with water (0.5 mL), and the quenched reaction solution was dried over anhydrous sodium sulfate. The solid was filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 1, volume ratio) to provide the title compound (95 mg, yield: 40.9%).

[0568] MS m / z(ESI):478.2[M+H] + .

[0569] Step 3: Preparation of (S)-(1-(((2-(2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexanone]-3-yl)-6-(pyrimidin-5-yloxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl methanesulfonate

[0570] (S)-3-(4-(((1-(hydroxymethyl)cyclopropyl)methoxy)-6-(pyrimidin-5-yloxy)pyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-2'-one (95 mg, 199 μmol) was dissolved in dichloromethane (2 mL). N,N-diisopropylethylamine (77 mg, 596 μmol) was added, followed by methanesulfonic anhydride (51.9 mg, 298.5 μmol). The mixture was reacted at 25°C for 12 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted twice with dichloromethane (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the title compound (105 mg, yield: 94.6%).

[0571] MS m / z(ESI):556.2[M+H] + .

[0572] Step 4: Preparation of (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(1-(((2-(S)-2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexanone]-3-yl)-6-(pyrimidin-5-yloxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-4-hydroxy-N-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0573] (S)-(1-(((2-(2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexanone]-3-yl)-6-(pyrimidin-5-yloxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl methanesulfonate (105 mg, 188.8 μmol) was dissolved in acetonitrile (5 mL), and potassium carbonate (78.3 mg, 566.4 μmol), potassium iodide (31 The reaction mixture was stirred at 60°C for 6 hours. Water (10 mL) was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate (10 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1, volume ratio) to obtain the title compound (80 mg, yield: 40.8%).

[0574] MS m / z(ESI):1039.5[M+H] + .

[0575] Step 5: Preparation of (2S,4R)-1-((S)-2-(4-(1-((2-(S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3-yl)-6-(pyrimidin-5-yloxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0576] (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(1-(((2-(S)-2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexanone]-3-yl)-6-(pyrimidin-5-yloxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-4-hydroxy-N-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrimidin-5-yloxy)-1H-1,2,3-triazol-1-yl)butanoyl)-4-hydroxy-N-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrimidin-4-yl Pyrrolidine-2-carboxamide (80 mg, 77 μmol), ammonium acetate (23.7 mg, 308 μmol), and sulfur (9.9 mg, 308 μmol) were dissolved in ethanol (2 mL) and stirred at 60°C for 15 minutes. A solution of malononitrile (25.4 mg, 385 μmol) in ethanol (1 mL) was then added dropwise, and the mixture was stirred at 80°C for 5 hours. The reaction mixture was filtered, the filtrate was concentrated, and the residue was purified by HPLC (Condition 2) to obtain the title compound (20 mg, yield: 23.3%).

[0577] MS m / z(ESI):1119.5[M+H] + .

[0578] 1H-NMR(400MHz DMSO-d6)δ9.14(d,J=1.6Hz,1H),8.99(s,1H),8.91(s,2H),8.52(d,J=7.6Hz,1H),8.00(d,J=2.4Hz,1H),7.50-7.42(m,2H), 7.41-7.30(m,2H),6.94(s,2H),6.79(s,1H),5.44(s,1H),5.15(d,J=3.6Hz,1H),4.90(t,J=7.2Hz,1H),4.49-4.33(m,3H),4 .29(s,1H),3.73-3.54(m,2H),2.99(s,2H),2.73-2.55(m,2H),2.46(s,3H),2.41-2.30(m,2H),2.29-2.17(m,1H),2.12-1.9 2(m,3H),1.93-1.85(m,5H),1.85-1.70(m,5H),1.70-1.48(m,3H),1.42-1.34(m,3H),0.95(s,9H),0.71(s,2H),0.46(s,2H).

[0579] Example 11: Preparation of 1-(2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-((1-((4-(1-((S)-1-((2S,4R)-4-hydroxy-2-(((S))-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-1H-1,2,3-triazol-4-yl)piperidin-1-yl)methyl)cyclopropyl)methoxy)pyrimidin-4-yl)-N-(2-methoxyethyl)-1H-pyrazole-3-carboxamide (Compound 6)

[0580] Step 1: Preparation of (S)-1-(6-((1-(hydroxymethyl)cyclopropyl)methoxy)-2-(2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexyl]-3-yl)pyrimidin-4-yl)-N-(2-methoxyethyl)-1H-pyrazole-3-carboxamide

[0581] (S)-3-(4-chloro-6-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-2'-one (100 mg, 239 μmol) was dissolved in tetrahydrofuran (5 mL). Cesium carbonate (116.6 mg, 358.5 μmol) and N-(2-methoxyethyl)-1H-pyrazole-3-carboxamide (60.6 mg, 358.5 μmol) were added. The atmosphere was replaced with nitrogen three times and the mixture was stirred at 70°C for 2 hours. The reaction mixture was cooled to room temperature, water (10 mL) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (10 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 15 / 1, volume ratio) to give the title compound (50 mg, yield: 37.9%).

[0582] MS m / z(ESI):551.2[M+H] + .

[0583] Step 2: Preparation of (S)-(1-(((6-(3-((2-methoxyethyl)carbamoyl)-1H-pyrazol-1-yl)-2-(2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-3-yl)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl methanesulfonate

[0584] (S)-1-(6-((1-(hydroxymethyl)cyclopropyl)methoxy)-2-(2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexyl]-3-yl)pyrimidin-4-yl)-N-(2-methoxyethyl)-1H-pyrazole-3-carboxamide (50 mg, 90.7 μmol) was dissolved in dichloromethane (2 mL). N,N-diisopropylethylamine (35.2 mg, 272 μmol) and methanesulfonic anhydride (23.7 mg, 136.1 μmol) were added sequentially, and the mixture was reacted at 25°C for 12 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted twice with dichloromethane (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the title compound (56 mg, yield: 98.2%).

[0585] MS m / z(ESI):629.2[M+H] + .

[0586] Step 3: Preparation of 1-(6-((1-((4-(1-(S)-1-((2S,4R)-4-hydroxy-2-(((S)-1,4-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-1H-1,2,3-triazol-4-yl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-2-((S)-2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazole-7,1'-cyclohexyl]-3-yl)pyrimidin-4-yl)-N-(2-methoxyethyl)-1H-pyrazole-3-carboxamide

[0587] (S)-(1-(((6-(3-((2-methoxyethyl)carbamoyl)-1H-pyrazol-1-yl)-2-(2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-3-yl)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl methanesulfonate (56 mg, 89 μmol) was dissolved in acetonitrile (2 mL) and potassium carbonate (36.9 mg, 267 μmol) was added. mol), potassium iodide (14.8 mg, 89 μmol), and (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (51.6 mg, 89 μmol) were stirred at 60°C for 6 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (10 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1, volume ratio) to obtain the title compound (60 mg, yield: 60.6%).

[0588] MS m / z(ESI):1112.5[M+H] + .

[0589] Step 4: Preparation of 1-(2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-3'-yl)-6-((1-((4-(1-((S)-1-((2S,4R)-4-hydroxy-2-(((S))-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-1H-1,2,3-triazol-4-yl)piperidin-1-yl)methyl)cyclopropyl)methoxy)pyrimidin-4-yl)-N-(2-methoxyethyl)-1H-pyrazole-3-carboxamide

[0590] 1-(6-((1-((4-(1-(S)-1-((2S,4R)-4-hydroxy-2-(((S)-1,4-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-1H-1,2,3-triazol-4-yl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-2-((S)-2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazole [7,1'-cyclohexyl]-3-yl)pyrimidin-4-yl)-N-(2-methoxyethyl)-1H-pyrazole-3-carboxamide (60 mg, 53.9 μmol), ammonium acetate (16.6 mg, 215.8 μmol), and sulfur (6.9 mg, 215.8 μmol) were dissolved in ethanol (2 mL) and stirred at 60°C for 15 minutes. A solution of malononitrile (17.8 mg, 269.5 μmol) in ethanol (1 mL) was then added dropwise, and the mixture was stirred at 80°C for 5 hours. The reaction mixture was filtered, the filtrate was concentrated, and the residue was purified by high-performance liquid chromatography (Condition 1) to obtain the title compound (7 mg, yield: 10.9%).

[0591] MS m / z(ESI):1192.5[M+H] + .

[0592] 1H-NMR (400MHz, CD3OD) δ8.87-8.83(m,2H),8.02(d,J=6.4Hz,1H),7.46-7.35(m,5H),6.97(t,J=2.4Hz ,1H),5.47(s,1H),5.02-4.89(m,2H),4.62-4.42(m,5H),3.86-3.69(m,2H),3.59(s,3H),3.39(s,3H), 3.34(s,1H),3.18-3.13(m,2H),2.92-2.84(m,1H),2.79-2.59(m,3H),2.48(s,3H),2.19-2.07(m,5H) ,2.06-1.90(m,11H),1.73-1.62(m,3H),1.50(d,J=7.2Hz,2H),1.04(s,9H),0.77(s,2H),0.55(s,2H).

[0593] Example 12: Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-(thiazol-2-yloxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 13)

[0594] Step 1: Preparation of (S)-3-(4-((1-(hydroxymethyl)cyclopropyl)methoxy)-6-(thiazol-2-yloxy)pyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]]isoxazol-7,1'-cyclohexane]-2'-one

[0595] (S)-3-(4-chloro-6-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-2'-one (120 mg, 0.27 mmol) and 2-thiazolol (37 mg, 0.35 mmol) were dissolved in tetrahydrofuran (3 mL), and sodium tert-butoxide (40 mg, 0.41 mmol) was added. The mixture was reacted at 80°C for 12 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (10 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 1, volume ratio) to provide the title compound (60 mg, yield: 45.1%).

[0596] MS m / z(ESI):483.3[M+H] + .

[0597] Step 2: Preparation of (S)-(1-(((2-(2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-3-yl)-6-(thiazol-2-yloxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl methanesulfonate

[0598] (S)-3-(4-((1-(hydroxymethyl)cyclopropyl)methoxy)-6-(thiazol-2-yloxy)pyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]]isoxazol-7,1'-cyclohexane]-2'-one (60 mg, 124 μmol) was dissolved in dichloromethane (2 mL). N,N-diisopropylethylamine (48 mg, 372 μmol) and methanesulfonic anhydride (32.4 mg, 186 μmol) were added sequentially. The mixture was reacted at 25°C for 12 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted twice with dichloromethane (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the title compound (69 mg, yield: 98.8%).

[0599] MS m / z(ESI):561.3[M+H] + .

[0600] Step 3: Preparation of (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(1-((1-(((2-((S)-2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-3-yl)-6-(thiazol-2-yloxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0601] (S)-(1-(((2-(2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-3-yl)-6-(thiazol-2-yloxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl methanesulfonate (69 mg, 123 μmol) was dissolved in acetonitrile (2 mL), and potassium carbonate (51 mg, 369 μmol) and potassium iodide (20. The reaction mixture was stirred at 60°C for 6 hours. Water (10 mL) was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate (10 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1, volume ratio) to obtain the title compound (50 mg, yield: 38.9%).

[0602] MS m / z(ESI):1044.6[M+H] + .

[0603] Step 4: Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-2-amino-3-cyano-5',6,6'),7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-(thiazol-2-yloxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0604] (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(1-((1-(((2-((S)-2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-3-yl)-6-(thiazol-2-yloxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-4-hydroxy-N-((S)- 1-(4-(4-Methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (50 mg, 47.9 μmol), ammonium acetate (14.7 mg, 191.6 μmol), and sulfur (6.1 mg, 191.6 μmol) were dissolved in ethanol (0.5 mL) and stirred at 60°C for 15 minutes. A solution of malononitrile (15.8 mg, 239.5 μmol) in ethanol (1 mL) was then added dropwise, and the mixture was stirred at 80°C for 5 hours. The reaction mixture was filtered, the filtrate was concentrated, and the residue was purified by HPLC (Condition 1) to obtain the title compound (10 mg, yield: 17.6%).

[0605] MS m / z(ESI):1124.6[M+H] + .

[0606] 1 H-NMR (400MHz, DMSO-d6) δ8.99(s,1H),8.53(d,J=8.0Hz,1H),8.01(s,1H),7.80(d,J=8.0Hz,1H),7.63(s,1H),7.45(d,J=8.0 Hz,2H),7.38(d,J=8.0Hz,2H),6.97(s,2H),6.82(d,J=4.0Hz,1H),5.44(s,1H),5.16(d,J=4.0Hz,1H),4.91(t,J=8.0Hz,1H),4 .47-4.38(m,4H),4.29(s,1H),3.70-3.60(m,3H),3.09(dd,J=16.0,4.0Hz,2H),2.72-2.62(m,2H),2.56-2.54(m,1H),2.46(s ,3H),2.34-2.32(m,1H),2.09-1.73(m,14H),1.69-1.55(m,3H),1.38(d,J=8.0Hz,3H),0.96(s,9H),0.68(s,2H),0.44(s,2H).

[0607] Example 13: Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 7)

[0608] Step 1: Preparation of (S)-3-(4-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-2'-one

[0609] Dissolve (S)-3-(4-chloro-6-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-2'-one (200 mg, 478.6 μmol) in tetrahydrofuran (5 mL) and water (0.5 mL). Add palladium acetate (19.9 mg, 86.15 μmol) and potassium fluoride (51 mg, 861.48 μmol). Slowly add a solution of polymethylhydrosiloxane (205.4 mg, 904.6 μmol) in tetrahydrofuran (1 mL) dropwise. Stir at 25°C for 1 hour. To the reaction solution was added aqueous sodium bicarbonate solution (5 mL), extracted three times with ethyl acetate (5 mL), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1, volume ratio) to give the title compound (165 mg, yield: 60.4%).

[0610] MS m / z(ESI):384.2[M+H] + .

[0611] Step 2: Preparation of (S)-(1-(((2-(2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-3-yl)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl methanesulfonate

[0612] (S)-3-(4-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-2'-one (96.6 mg, 251.9 μmol) was dissolved in dichloromethane (5 mL), followed by the addition of methanesulfonic anhydride (63.2 mg, 362.8 μmol) and N,N-diisopropylethylamine (62.5 mg, 483.8 μmol). The mixture was stirred at 25°C for 2 hours. Water (15 mL) was added to the reaction mixture, and the mixture was extracted three times with dichloromethane (10 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the title compound (92.8 mg, 84% yield).

[0613] MS m / z(ESI):462.1[M+H] + .

[0614] Step 3: Preparation of (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(1-((1-(((2-((S)-2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-3-yl)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0615] (S)-(1-(((2-(2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-3-yl)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl methanesulfonate (92.8 mg, 210 μmol) and (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1, To a solution of (116.6 mg, 210 μmol) in acetonitrile (5 mL) was added potassium carbonate (87 mg, 630 μmol) and potassium iodide (34.8 mg, 210 μmol), and the mixture was stirred at 60°C for 6 hours. Water (10 mL) was added to the reaction solution, which was then extracted three times with ethyl acetate (10 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1, volume ratio) to obtain the title compound (128.4 mg, yield: 64.8%).

[0616] MS m / z(ESI):945.5[M+H] + .

[0617] Step 4: Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0618] (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(1-((1-(((2-((S)-2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-3-yl)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-4-hydroxy-N-((S)-1-(4- (4-Methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (18 mg, 18.1 μmol) was dissolved in ethanol (3 mL), and ammonium acetate (5.7 mg, 72.4 μmol) and sulfur (2.32 mg, 72.4 μmol) were added. The mixture was stirred at 60°C for 0.5 hour, followed by the dropwise addition of a solution of malononitrile (6 mg, 90.5 μmol) in ethanol (0.5 mL). The temperature was raised to 80°C and stirred for 3 hours. Water (5 mL) was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate (5 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by HPLC (Condition 2) to obtain the title compound (7 mg, yield: 35.8%).

[0619] MS m / z(ESI):1025.5[M+H] + .

[0620] 1H-NMR (400MHz, CD3OD) δ8.87(d,J=2.4Hz,1H),8.59-8.51(m,1H),8.04(d,J=6.4Hz,1H),7.49-7.33(m, 4H),6.89(d,J=5.6Hz,1H),5.48(s,1H),5.06-4.99(m,2H),4.65-4.40(m,5H),3.85-3.82(m,1H),3.72( t,J=6.4Hz,3H),3.21-3.16(m,3H),2.85-2.72(m,2H),2.67-2.55(m,2H),2.48-2.44(m,4H),2.13-1.9 5(m,9H),1.90-1.85(m,3H),1.73(s,2H),1.51(d,J=7.2Hz,2H),1.05(s,9H),0.74(s,2H),0.53(s,2H).

[0621] Example 14: Preparation of (2S,4R)-1-((S)-2-(4-(1-(((2-(S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-((1-(dimethylamino)cyclopropyl)methoxy)pyrimidin-4-yl)oxy)methyl)cyclopropylmethyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 16)

[0622] The synthetic route in Example 1 was used to replace the first step reaction raw material 2-methoxyethanol with (1-(dimethylamino)cyclopropyl)methanol to obtain the title compound (15 mg, yield: 27.9%).

[0623] MS m / z(ESI):1138.5[M+H] + .

[0624] 1H-NMR (400MHz, DMSO-d6) δ8.99(s,1H),8.52(d,J=7.6Hz,1H),7.99(d,J=3.2Hz,1H),7.44(d,J=8.0Hz,2H),7.37( d,J=7.6Hz,2H),6.96(s,2H),6.32(s,1H),5.44(s,1H),5.21-5.08(m,1H),4.91(t,J=4.0Hz,1H),4.53-4.32(m,4H ),4.28(t,J=8.0Hz,2H),3.73-3.52(m,3H),3.12-2.87(m,4H),2.72-2.57(m,2H),2.46(s,3H),2.35(s,9H),2.13- 1.70(m,13H),1.69-1.49(m,2H),1.38(d,J=7.2Hz,3H),0.96(s,9H),0.75-0.64(m,4H),0.60(s,2H),0.43(s,2H).

[0625] Example 15: Preparation of (2S,4R)-1-((S)-2-(4-(1-((2-(S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-((R)-3,4-dimethylpiperazin-1-yl)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 23)

[0626] The synthetic route in Example 3 was used to replace the first step reaction raw material cyclopropylboronic acid with trimethylcyclotriboroxine to obtain the title compound (30 mg, yield: 39.6%).

[0627] MS m / z(ESI):1039.5[M+H] + .

[0628] 1H NMR(400MHz, DMSO-d6)δ8.99(s,1H).8.52(d,J=7.6Hz,1H),7.98(d,J=16.0Hz,1H),7.53-7.41(m,2H),7.40-7 .32(m,2H),6.92(d,J=12.0Hz,3H),5.44(s,1H),5.22-5.12(m,1H),4.91(t,J=7.2Hz,1H),4.42(t,J=8.4Hz,2H ),4.37-4.20(m,2H),3.80-3.53(m,2H),3.14-2.83(m,3H),2.72-2.50(m,3H),2.45(d,J=4.8Hz,6H),2.40-2.1 3(m,3H),2.10-1.69(m,13H),1.68-1.45(m,3H),1.37(d,J=7.2Hz,3H),0.95(s,9H),0.69(s,2H),0.44(s,2H).

[0629] Example 16: Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-(pyrimidin-5-ylamino)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 25)

[0630] The synthetic route in Example 12 was used to replace the first step reaction raw material 2-thiazolol with 5-aminopyrimidine to obtain the title compound (3 mg, yield: 18.6%).

[0631] MS m / z(ESI):1118.5[M+H] + .

[0632] 1H-NMR (400MHz, DMSO-d6) δ9.99(s,1H),9.18(s,2H),8.99(s,1H),8.82(d,J=2.4Hz,1H),8.52(d,J=7.6Hz,1H),8.00(s,1H),7.49-7.41(m ,2H),7.36(d,J=8.4Hz,2H),6.96(s,2H),6.21(s,1H),5.44(s,1H),5.16(s,1H),4.90(t,J=6.8Hz,1H),4.43(t,J=8.4Hz,2H),4.27(d,J=1 1.6Hz,2H),3.72-3.55(m,2H),3.00(dd,J=25.2,12.0Hz,3H),2.71-2.55(m,2H),2.46(s,3H),2.40-2.22(m,2H),2.13-1.69(m,10H),1.6 2-1.53(m,2H),1.37(d,J=6.8Hz,3H),1.23(s,5H),1.11-1.01(m,1H),0.94(d,J=6.0Hz,9H),0.89-0.81(m,1H),0.68(s,2H),0.44(s,2H).

[0633] Example 17: Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 26)

[0634] The synthetic route in Example 3 was used to replace the first step reaction raw material cyclopropylboronic acid with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole to obtain the title compound (10 mg, yield: 13.3%).

[0635] MS m / z(ESI):1105.5[M+H] + .

[0636] 1H-NMR (400MHz, DMSO-d6) δ8.99(s,1H),8.52(d,J=7.6Hz,1H),8.45(s,1H),8.18(s,1H),7.97(d,J=16.8Hz,1H),7.47-7.42(m,2H ),7.38-7.33(m,2H),7.26(s,1H),6.97(s,2H),5.43(s,1H),5.15(d,J=3.6Hz,1H),4.90(t,J=7.2Hz,1H),4.49-4.25(m,4H),3.92 (s,3H),3.73-3.55(m,2H),3.18-2.93(m,3H),2.74-2.51(m,5H),2.46(s,3H),2.35(s,2H),2.13-1.94(m,5H),1.88(d,J=5.6Hz, 6H),1.81-1.70(m,1H),1.72-1.55(m,2H),1.44(dd,J=7.2,6.8Hz,3H),1.28-1.21(m,1H),0.94(s,9H),0.71(s,2H),0.47(s,2H).

[0637] Example 18: Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-(((R)-2,2-dimethylazetidin-3-yl)oxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 27)

[0638] Using the synthetic route in Example 2, the first step reaction raw material 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester was replaced with (R)-3-hydroxy-2,2-dimethylazetidin-1-carboxylic acid tert-butyl ester to obtain the title compound (2.47 mg, yield: 3.6%).

[0639] MS m / z(ESI):1124.5[M+H] + .

[0640] 1H-NMR(400MHz,CD3OD)δ8.87(d,J=2.4Hz,1H),8.03(d,J=9.2Hz,1H),7.47-7 .33(m,4H),5.49(s,1H),5.01(t,J=7.2Hz,1H),4.87-4.77(m,1H),4.53(dd, J=9.2,7.6Hz,1H),4.43(s,1H),4.35-4.13(m,3H),3.83(dd,J=11.2,3.6Hz, 2H),3.78-3.65(m,1H),3.43-3.59(m,1H),3.34(s,3H),3.09(s,1H),2.87-2 .67(m,2H),2.63-2.60(m,2H),2.47(d,J=4.0Hz,3H),2.39(d,J=5.6Hz,1H), 2.25-2.10(m,1H),2.09(d,J=12.0Hz,1H),2.03(t,J=7.6Hz,3H),2.00-1.94 (m,3H),1.90(d,J=18.4Hz,1H),1.82-1.60(m,3H),1.51(d,J=7.2Hz,2H),1. 34-1.24(m,10H),1.05(s,9H),0.93-0.85(m,1H),0.68(s,2H),0.50(s,2H).

[0641] Example 19: Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-(2,6-diazaspiro[3.4]octan-6-yl)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 28)

[0642] The synthetic route in Example 6 was used to replace the first step reaction raw material (R)-2-methylpiperazine-1-carboxylic acid tert-butyl ester with 2,6-diazaspiro[3.4]octyl-2-carboxylic acid tert-butyl ester to obtain the title compound (18 mg, yield: 53.8%).

[0643] MS m / z(ESI):1135.5[M+H] + .

[0644] 1 H-NMR (400MHz, DMSO-d6) δ8.99(s,1H),8.54(d,J=7.6Hz,1H),8.35(s,1H),7.98(d,J=16.4Hz,1H),7.40(dd ,J=12.4,7.6Hz,4H),6.95(s,2H),5.77(s,1H),5.44(s,1H),5.01-4.76(m,1H),4.42(t,J=8.4Hz,1H),4.33 -4.15(m,3H),4.03-3.74(m,4H),3.72-3.19(m,8H),3.05(d,J=11.6Hz,3H),2.64(t,J=11.2Hz,1H),2.46(s ,4H),2.28(d,J=8.4Hz,3H),2.13-1.44(m,17H),1.42-1.18(m,3H),0.96(s,9H),0.64(s,2H),0.41(s,2H).

[0645] Example 20: Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-(2-methoxyethoxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-N-((S)-1-(2'-fluoro-[1,1'-biphenyl]-4-yl)ethyl)-4-hydroxypyrrolidine-2-carboxamide (Compound 4)

[0646] Using the synthetic route in Example 1, the raw material for the fourth step reaction, (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide, was replaced with (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-N-((S)-1-(2'-fluoro-[1,1'-biphenyl]-4-yl)ethyl)-4-hydroxypyrrolidine-2-carboxamide to give the title compound (21 mg, yield: 30.8%).

[0647] MS m / z(ESI):1096.7[M+H] + .

[0648] 1 H-NMR (400MHz, DMSO-d6) δ8.53(d,J=8.0Hz,1H),8.01(s,1H),7.53-7.48(m,3H),7.44-7.36(m,3H),7.33-7.27(m,2 H),6.36(s,1H),5.51(s,1H),5.44(s,1H),5.15(s,1H),4.92(t,J=8.0Hz,1H),4.52-4.46(m,2H),4.43(t,J=8.0Hz,1 H),4.39-4.34(m,2H),4.31-4.25(m,2H),3.68-3.60(m,4H),3.29(s,3H),3.09-3.11(m,4H),2.67-2.59(m,3H),2.5 1-2.49(m,1H),2.39-2.31(m,2H),2.10-1.73(m,15H),1.39(d,J=4.0Hz,3H),0.96(s,9H),0.68(s,2H),0.44(s,2H).

[0649] Example 21: Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-(((S)-tetrahydrofuran-3-yl))oxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 9)

[0650] The synthetic route in Example 1 was used to replace the first step reaction raw material 2-methoxyethanol with (S)-tetrahydrofuran-3-ol to obtain the title compound (19 mg, yield: 13.9%).

[0651] MS m / z(ESI):1111.6[M+H] + .

[0652] 1H-NMR (400MHz, DMSO-d6) δ8.99(s,1H),8.53(d,J=8.0Hz,1H),8.00(s,1H),7.47(d,J=8.0Hz,2H),7.36(d,J=8.0H z,2H),6.96(s,1H),6.36(s,1H),5.62-5.58(m,1H),5.44(s,1H),5.16(d,J=4.0Hz,1H),4.91(t,J=8.0Hz,1H),4. 44-4.26(m,4H),3.93-3.75(m,4H),3.69-3.60(m,2H),3.09-2.98(m,4H),2.69-2.61(m,3H),2.46(s,3H),2.35-2 .25(m,2H),2.09-1.72(m,15H),1.66-1.56(m,3H),1.38(d,J=8.0Hz,3H),0.96(s,9H),0.68(s,2H),0.44(s,2H).

[0653] Example 22: Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(((6-((2-oxaspiro[3.3]hept-6-yl)oxy)-2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 14)

[0654] The synthetic route in Example 1 was used to replace the first step reaction raw material 2-methoxyethanol with 2-oxaspiro[3.3]heptan-6-ol to obtain the title compound (11 mg, yield: 16.2%).

[0655] MS m / z(ESI):1137.5[M+H] + .

[0656] 1H-NMR (400MHz, DMSO-d6) δ8.99(s,1H),8.53(d,J=8.0Hz,1H),7.99(s,1H),7.46(d,J=8.0Hz,2H),7.36(d,J=8.0Hz ,2H),6.96(s,2H),6.29(s,1H),5.44(s,1H),5.04(t,J=4.0Hz,1H),4.91(t,J=8.0Hz,1H),4.62(s,2H),4.54(s,2H) ,4.44-4.26(m,4H),3.70-3.55(m,2H),3.06-2.94(m,4H),2.81-2.76(m,2H),2.67-2.62(m,2H),2.46(s,3H),2.33 -2.25(m,4H),2.10-1.72(m,15H),1.64-1.51(m,3H),1.38(d,J=8.0Hz,3H),0.96(s,9H),0.68(s,2H),0.44(s,2H).

[0657] Example 23: Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-morpholinyl)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4)-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 10)

[0658] The synthetic route in Example 5 was used to replace the starting material N,N-dimethylazetidin-3-amine in the first step with morpholine to obtain the title compound (20 mg, yield: 29.3%).

[0659] MS m / z(ESI):1110.6[M+H] + .

[0660] 1H-NMR (400MHz, DMSO-d6) δ8.99(s,1H),8.52(d,J=8.0Hz,1H),8.07(s,1H),7.46(d,J=8.0Hz,2H),7.38 (d,J=8.0Hz,2H),6.95(s,1H),6.29(s,1H),5.46(s,1H),5.17(d,J=4.0Hz,1H),4.91(t,J=8.0Hz,2H),4 .42(t,J=8.0Hz,1H),4.31-4.24(m,3H),3.71-3.58(m,10H),3.32(s,3H),3.05-2.99(m,2H),2.62-2.54 (m,2H),2.46(s,3H),2.11-1.72(m,16H),1.38(d,J=8.0Hz,3H),0.96(s,9H),0.68(s,2H),0.44(s,2H).

[0661] Example 24: Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-(methyl-((R)-pyrrolidin-3-yl)amino)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 12)

[0662] Using the synthetic route of Example 6, the first step reaction raw material (R)-2-methylpiperazine-1-carboxylic acid tert-butyl ester was replaced with (R)-3-(methylamino)pyrrolidine-1-carboxylic acid tert-butyl ester to obtain the title compound (20 mg, yield: 29.3%).

[0663] MS m / z(ESI):1123.6[M+H] + .

[0664] 1H-NMR (400MHz, DMSO-d6) δ8.88(s,1H),8.53(s,1H),8.09(s,1H),7.46(d,J=8.0H z,4H),6.01(s,1H),5.51(s,1H),5.04-4.97(m,2H),4.55-4.43(m,4H),3.84-3.4 8(m,13H),3.22-3.15(m,6H),2.90-2.73(m,4H),2.63-2.57(m,2H),2.48(s,3H), 2.14-1.92(m,15H),1.52(d,J=8.0Hz,3H),1.06(s,9H),0.79(s,2H),0.62(s,2H).

[0665] Example 25: Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 18)

[0666] Using the synthetic route in Example 6, the first step reaction raw material (R)-2-methylpiperazine-1-carboxylic acid tert-butyl ester was replaced with 3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester to obtain the title compound (31 mg, yield: 16.3%).

[0667] MS m / z(ESI):1135.6[M+H] + .

[0668] 1H-NMR (400MHz, DMSO-d6) δ8.99(s,1H),8.53(d,J=8.0Hz,1H),8.19(s,1H),8.01(s,1H),7.45(d,J=8.0Hz,2H), 7.37(d,J=8.0Hz,2H),6.95(s,2H),6.08(s,1H),5.44(s,1H),4.91(t,J=8.0Hz,1H),4.42(t,J=8.0Hz,1H),4.30 -4.20(m,4H),3.70-3.55(m,4H),3.08-2.95(m,4H),2.89(d,J=12.0Hz,2H),2.69-2.61(m,3H),2.46(s,3H),2. 34(s,2H),2.10-1.72(m,20H),1.68-1.60(m,2H),1.38(d,J=8.0Hz,3H),0.96(s,9H),0.65(s,2H),0.42(s,2H).

[0669] Example 26: Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-(1,4-oxazepan-4-yl)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 8)

[0670] The synthetic route in Example 5 was used to replace the first step reaction raw material N,N-dimethylazetidin-3-amine with 1,4-oxazepane to obtain the title compound (15.4 mg, yield: 53.0%).

[0671] MS m / z(ESI):1124.4[M+H] + .

[0672] 1H-NMR (400MHz, DMSO-d6) δ8.99(s,1H),8.53(d,J=7.6Hz,1H),8.00(s,1H),7.46-7.42(m,2H),7.36(dd,J=8.4,4.0Hz,2H),6.96(s, 2H),6.04(s,1H),5.44(s,1H),5.16(d,J=3.6Hz,1H),4.93-4.87(m,1H),4.42(t,J=8.4Hz,1H),4.30-4.22(m,3H),3.70(d,J=10.0Hz ,3H),3.68-3.65(m,1H),3.63-3.59(m,3H),3.01(dd,J=12.4,2.0Hz,3H),2.63-2.53(m,3H),2.45(s,3H),2.32(dd,J=3.6,1.6Hz,2H ), 2.10-1.79(m,17H),1.75(dd,J=9.2,4.0Hz,2H),1.67-1.57(m,2H),1.37(d,J=7.2Hz,3H),0.95(s,9H),0.65(s,2H),0.41(s,2H).

[0673] Example 27: Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-(piperazin-1-yl)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 19)

[0674] The synthetic route in Example 6 was used to replace the raw material in the first step (R)-2-methylpiperazine-1-carboxylic acid tert-butyl ester with tert-butyl 1-piperazinecarboxylate to obtain the title compound (4.0 mg, yield: 42.3%).

[0675] MS m / z(ESI):1109.4[M+H] + .

[0676] 1H-NMR (400MHz, DMSO-d6) δ8.99(s,1H),8.53(d,J=7.6Hz,1H),8.28(s,1H),8.00(s,1H),7.44(d,J=8.4Hz,2H),7.36(d,J=8.4 Hz,2H),6.95(s,2H),6.12(s,1H),5.43(s,1H),4.93-4.87(m,1H),4.42(t,J=8.4Hz,1H),4.29(dd,J=6.0,4.0Hz,2H),4.21(d, J=10.4Hz,1H),3.70-3.62(m,4H),3.57(s,3H),3.05-2.94(m,4H),2.78(s,4H),2.66-2.52(m,2H),2.45(s,3H),2.33-2.31(m ,1H),2.11-1.85(m,11H),1.84-1.72(m,5H),1.67-1.57(m,2H),1.37(d,J=7.2Hz,3H),0.95(s,9H),0.64(s,2H),0.40(s,2H).

[0677] Example 28: Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-(pyridin-3-yloxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 24)

[0678] The synthetic route in Example 10 was used to replace the raw material 5-hydroxypyrimidine in the first step with 3-hydroxypyridine to obtain the title compound (1.82 mg, yield: 9.4%).

[0679] MS m / z(ESI):1118.4[M+H] + .

[0680] 1H-NMR(400MHz,DMSO-d6)δ8.88(d,J=3.2Hz,1H),8.52(s,1H),8.47(d,J=4.0Hz,1H), 8.06-8.03(m,1H),7.79-7.76(m,1H),7.56(dd,J=8.4,4.8Hz,1H),7.45(dd,J=10.0,3 .6Hz,4H),7.39(dd,J=21.6,5.6Hz,1H),6.50(s,1H),5.49(d,J=2.4Hz,1H),5.03(dd, J=14.0,7.2Hz,1H),4.54(dd,J=9.2,8.0Hz,1H),4.47(s,2H),4.44(s,1H),3.84(dd,J =11.2,3.6Hz,1H),3.73(d,J=11.2Hz,1H),3.18-3.15(m,1H),2.78-2.71(m,1H),2.60 -2.54(m,3H),2.48(s,3H),2.47(s,1H),2.45(d,J=2.8Hz,2H),2.33(dd,J=11.2,5.6H z,2H),2.22-2.08(m,4H),2.03-1.91(m,9H),1.80-1.72(m,3H),1.63(d,J=7.2Hz,1H) ,1.51(d,J=7.2Hz,3H),1.29(s,1H),1.05(d,J=3.6Hz,9H),0.74(s,2H),0.52(s,2H).

[0681] Example 29: Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-(((R)-pyrrolidin-3-yl)oxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 29)

[0682] The synthetic route in Example 2 was used to replace the first step reaction raw material 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester with (S)-1-N-tert-butyloxycarbonyl-3-hydroxypyrrolidine to obtain the title compound (2.47 mg, yield: 3.6%).

[0683] MS m / z(ESI):1110.5[M+H] + .

[0684] 1 H-NMR (400MHz, DMSO-d6) δ8.99(s,1H),8.53(d,J=4.0Hz,1H),8.27(s,1H),8.00(s,1H),7.44(d,J=8.0Hz,2H) ,7.36(d,J=8.4Hz,2H),6.96(s,2H),6.32(s,1H),5.51(s,1H),5.44(s,1H),4.92(t,J=4.0Hz,1H),4.42(d,J=8 .0Hz,1H),4.35-4.27(m,3H),3.63-3.37(m,4H),3.05-2.98(m,8H),2.66-2.52(m,2H),2.45(s,3H),2.33-2.3 1(m,2H),2.15-1.85(m,15H),1.67-1.47(m,3H),1.37(d,J=4.0Hz,3H),0.96(s,9H),0.67(s,2H),0.43(s,2H).

[0685] Example 30: (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-3'-yl)-6-(3-(1-(tetrahydro-2H-pyran-4-yl)-1H-1,2 Preparation of ((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 112)

[0686] Step 1: Preparation of (S)-3-(4-(3-bromo-1H-pyrazol-1-yl)-6-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-2'-one

[0687] (S)-3-(4-chloro-6-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexyl]-2'-one (200 mg, 478 μmol) was dissolved in acetonitrile (5 mL), and cesium carbonate (311.8 mg, 957 μmol) and 3-bromopyrazole (105.4 mg, 717 μmol) were added. The mixture was stirred at 70°C for 6 hours. The reaction mixture was cooled to room temperature, and water (10 mL) was added. The mixture was extracted three times with ethyl acetate (10 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1, volume ratio) to obtain the title compound (218 mg, yield: 86.2%).

[0688] MS m / z(ESI):528.1[M+H] + .

[0689] Step 2: Preparation of (S)-3-(4-((1-(hydroxymethyl)cyclopropyl)methoxy)-6-(3-((trimethylsilyl)ethynyl)-1H-pyrazol-1-yl)pyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-2'-one

[0690] (S)-3-(4-(3-bromo-1H-pyrazol-1-yl)-6-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-2'-one (218 mg, 413 μmol) was dissolved in DMF (5 mL). Trimethylsilylacetylene (202.7 mg, 2.06 mmol), bistriphenylphosphine palladium dichloride (28.9 mg, 41.3 μmol), cuprous iodide (15.7 mg, 82.6 μmol), and triethylamine (417.9 mg, 4.13 mmol) were added sequentially. The atmosphere was purged with nitrogen three times and the reaction was carried out at 80°C for 12 h. Water (10 mL) was added to the reaction solution, and the mixture was extracted twice with dichloromethane (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1, volume ratio) to give the title compound (187 mg, yield: 83.1%).

[0691] MS m / z(ESI):546.2[M+H] + .

[0692] Step 3: Preparation of (S)-3-(4-(3-ethynyl-1H-pyrazol-1-yl)-6-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-2'-one

[0693] (S)-3-(4-((1-(hydroxymethyl)cyclopropyl)methoxy)-6-(3-((trimethylsilyl)ethynyl)-1H-pyrazol-1-yl)pyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-2'-one (187 mg, 342 μmol) was dissolved in dichloromethane (6 mL) and methanol (3 mL). Potassium carbonate (189.3 mg, 1.37 mmol) was added and stirred at room temperature for 2 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted three times with dichloromethane (10 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (80 mg, yield: 49.4%).

[0694] MS m / z(ESI):474.2[M+H] + .

[0695] Step 4: Preparation of (S)-3-(4-((1-(hydroxymethyl)cyclopropyl)methoxy)-6-(3-(1-(tetrahydro-2H-pyran-4-yl)-1H-1,2,3-triazol-4-yl)-1H-pyrazol-1-yl)pyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-2'-one

[0696] (S)-3-(4-(3-ethynyl-1H-pyrazol-1-yl)-6-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-2'-one (80 mg, 169 μmol) and 4-azidotetrahydropyran (21.5 mg, 169 μmol) were dissolved in DMSO (3 mL) and water (0.3 mL). Sodium ascorbate (66.9 mg, 338 μmol) and copper sulfate pentahydrate (105.6 mg, 422.5 μmol) were added to the system and stirred at room temperature for 4 hours. The reaction solution was diluted with ethyl acetate (10 mL), washed three times with saturated brine (10 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography (eluent: ethyl acetate) to give the title compound (30 mg, yield: 29.4%).

[0697] MS m / z(ESI):601.3[M+H] + .

[0698] Step 5: Preparation of (S)-(1-(((2-(2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazole-7,1'-cyclohexane]-3-yl)-6-(3-(1-(tetrahydro-2H-pyran-4-yl)-1H-1,2,3-triazol-4-yl)-1H-pyrazol-1-yl)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl methanesulfonate

[0699] (S)-3-(4-((1-(hydroxymethyl)cyclopropyl)methoxy)-6-(3-(1-(tetrahydro-2H-pyran-4-yl)-1H-1,2,3-triazol-4-yl)-1H-pyrazol-1-yl)pyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-2'-one (30 mg, 50 μmol) was dissolved in dichloromethane (3 mL). N,N-Diisopropylethylamine (129 mg, 100 μmol) was added, followed by methanesulfonic anhydride (13.1 mg, 75 μmol), and the mixture was reacted at 25°C for 2 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted twice with dichloromethane (5 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the title compound (30 mg, yield: 88.5%).

[0700] MS m / z(ESI):679.3[M+H] + .

[0701] Step 6: Preparation of (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(1-((1-(((2-((S)-2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-3-yl)-6-(3-(1-(tetrahydro-2H-pyran-4-yl)-1H-1,2,3-triazol-4-yl)-1H-pyrazol-1-yl)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0702] (S)-(1-(((2-(2'-Oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-3-yl)-6-(3-(1-(tetrahydro-2H-pyran-4-yl)-1H-1,2,3-triazol-4-yl)-1H-pyrazol-1-yl)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl methanesulfonate (30 mg, 44.2 μmol) was dissolved in acetonitrile (3 mL) and potassium carbonate (12.2 To the reaction mixture was added (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (25.5 mg, 44.2 μmol), and the mixture was stirred at 60°C for 6 hours. Water (5 mL) was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate (5 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1, volume ratio) to obtain the title compound (28 mg, yield: 54.6%).

[0703] MS m / z(ESI):1162.5[M+H] + .

[0704] Step 7: Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-(3-(1-(tetrahydro-2H-pyran-4-yl)-1H-1,2,3-triazol-4-yl)-1H-pyrazol-1-yl)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0705] (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(1-((1-(((2-((S)-2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-3-yl)-6-(3-(1-(tetrahydro-2H-pyran-4-yl)-1H-1,2,3-triazol-4-yl)-1H-pyrazol-1-yl)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl A mixture of 4-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (28 mg, 32.5 μmol), ammonium acetate (10 mg, 130 μmol), and sulfur (4.2 mg, 130 μmol) was dissolved in ethanol (2 mL) and stirred at 60°C for 15 minutes. A solution of malononitrile (10.8 mg, 163.8 μmol) in ethanol (1 mL) was then added dropwise, and the mixture was stirred at 80°C for 6 hours. The reaction mixture was filtered, the filtrate was concentrated, and the residue was purified by high-performance liquid chromatography (Condition 2) to obtain the title compound (6 mg, yield: 20.1%).

[0706] MS m / z(ESI):1242.5[M+H] + .

[0707] 1 H-NMR (400MHz, DMSO-d6) δ8.99(s,1H),8.77(s,1H),8.67(d,J=4.0Hz,1H),8.51(d,J=8.0Hz,1H),7.99(s,1H),7.44(t,J =4.0Hz,2H),7.36(d,J=4.0Hz,2H),7.27(s,1H),7.04(t,J=4.0Hz,1H),6.96(s,2H),5.42(s,1H),5.14(s,1H),4.92-4.8 3(m,3H),4.51-4.39(m,3H),4.28(s,1H),4.01(d,J=8.0Hz,2H),3.68-3.51(m,4H),3.19-3.01(m,3H),2.73-2.67(m,2H) ,2.50-2.32(m,6H),2.11-1.86(m,17H),1.61-1.50(m,3H),1.36(d,J=8.0Hz,3H),0.93(s,9H),0.74(s,2H),0.47(s,2H).

[0708] Example 31: Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-(pyrimidin-5-yloxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(3-fluoropyridin-4-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide (Compound 82)

[0709] Step 1: Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-3-cyano-2-(((E)-(dimethylamino)))methylene)amino)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-(pyrimidin-5-yloxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(3-fluoropyridin-4-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide

[0710] (E)-(1-((2-(3-cyano-2-((dimethylamino)methylene)amino)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-(pyrimidin-5-yloxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl methanesulfonate (100 mg, 145 μmol) was dissolved in acetonitrile (3 mL) and potassium carbonate (40 mL) was added. The reaction mixture was stirred at 60°C for 6 hours. Water (10 mL) was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate (10 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1, volume ratio) to obtain the title compound (100 mg, yield: 58.8%).

[0711] MS m / z(ESI):1172.5[M+H] + .

[0712] Step 2: Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-(pyrimidin-5-yloxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(3-fluoropyridin-4-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide

[0713] (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-3-cyano-2-(((E)-(dimethylamino)))methylene)amino)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-(pyrimidin-5-yloxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3- Triazol-1-yl)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(3-fluoropyridin-4-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide (100 mg, 85.3 μmol) was dissolved in tetrahydrofuran (1 mL), and 2 M hydrochloric acid solution (1 mL) was added. The mixture was stirred at 65° C. for 3 hours. The reaction solution was concentrated and the residue was purified by HPLC (Condition 2) to give the title compound (45 mg, yield: 47.2%).

[0714] MS m / z(ESI):1117.5[M+H] + .

[0715] 1H-NMR (400MHz, DMSO-d6) δ9.14(s,1H),8.91(s,2H),8.66(d,J=4.0Hz,1H),8.49(d,J=4.0Hz,1H),8.01(s,1 H),7.64-7.61(m,3H),7.43(d,J=12.0Hz,2H),6.94(s,2H),6.79(s,1H),5.44(s,1H),5.15(d,J=4.0Hz,1H), 4.93(t,J=8.0Hz,1H),4.45-4.36(m,3H),4.29(s,1H),3.69-3.60(m,2H),3.31(t,J=8.0Hz,2H),2.70-2.58( m,2H),2.49-2.33(m,2H),2.10-1.51(m,19H),1.38(d,J=8.0Hz,3H),0.96(s,9H),0.71(s,2H),0.46(s,2H).

[0716] Example 32: Preparation of 1-(2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-((1-((4-(1-((S)-1-((2S,4R)-4-hydroxy-2-(((S))-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-1H-1,2,3-triazol-4-yl)piperidin-1-yl)methyl)cyclopropyl)methoxy)pyrimidin-4-yl)-N-methyl-1H-pyrazole-3-carboxamide (Compound 107)

[0717] Step 1: Preparation of 1-(6-((1-((4-(1-((S)-1-((2S,4R)-4-hydroxy-2-(((S))-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-1H-1,2,3-triazol-4-yl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-2-((S)-2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazole-7,1'-cyclohexane]-3-yl)pyrimidin-4-yl)-N-methyl-1H-pyrazole-3-carboxamide

[0718] Methylamine hydrochloride (6.7 mg, 99.6 μmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (18.9 mg, 49.8 μmol) and 1-(6-((1-((4-(1-((S)-1-((2S,4R)-4-hydroxy-2-(((S))-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-1- oxobutan-2-yl) methylamine hydrochloride (6.7 mg, 99.6 μmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (18.9 mg, 49.8 μmol) and 1-(6-((1-((4-(1-((S)-1-((2S,4R)-4-hydroxy-2-(((S))-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl) methylamine hydrochloride (6.7 mg, 99.6 μmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (18.9 mg, 49.8 μmol) and 1-(6-((1-((4-(1-((S)-1-((2S,4R)-4-hydroxy-2-(((S))-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl To the solution of (35 mg, 33.2 μmol) of 2-((S)-2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazole-7,1'-cyclohexane]-3-yl)pyrimidin-4-yl)-1H-pyrazole-3-carboxylic acid (35 mg, 33.2 μmol) in DMF (2 mL), N,N-diisopropylethylamine (25.7 mg, 199.2 μmol) was added dropwise under ice-cooling, followed by reaction at room temperature for 2 hours. The reaction mixture was poured into water (5 mL) and extracted three times with ethyl acetate (5 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1, volume ratio) to give the title compound (22 mg, yield: 61.9%).

[0719] MS m / z(ESI):1068.5[M+H] + .

[0720] Step 2: Preparation of 1-(2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-((1-((4-(1-((S)-1-((2S,4R)-4-hydroxy-2-(((S))-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-1H-1,2,3-triazol-4-yl)piperidin-1-yl)methyl)cyclopropyl)methoxy)pyrimidin-4-yl)-N-methyl-1H-pyrazole-3-carboxamide

[0721] 1-(6-((1-((4-(1-((S)-1-((2S,4R)-4-hydroxy-2-(((S))-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-1H-1,2,3-triazol-4-yl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-2-((S)-2'-oxo-5,6-dihydro-4H-spiro[benzo[ d]-isoxazole-7,1'-cyclohexane-3-yl)pyrimidin-4-yl)-N-methyl-1H-pyrazole-3-carboxamide (22 mg, 20.6 μmol), ammonium acetate (6.4 mg, 82.4 μmol), and sulfur (2.6 mg, 82.4 μmol) were dissolved in ethanol (1 mL) and stirred at 60°C for 15 minutes. A solution of malononitrile (6.8 mg, 103 μmol) in ethanol (0.5 mL) was then added dropwise, and the mixture was stirred at 80°C for 6 hours. The reaction mixture was filtered, the filtrate was concentrated, and the residue was purified by HPLC (Condition 2) to obtain the title compound (5 mg, yield: 21.2%).

[0722] MS m / z(ESI):1148.5[M+H] + .

[0723] 1 H-NMR (400MHz, DMSO-d6) δ8.99(s,1H),8.63(d,J=4.0Hz,1H),8.56(d,J=8.0Hz,1H),8.50(d,J=8.0Hz,1H),7.98(s,1H) ,7.47-7.43(m,3H),7.36(d,J=8.0Hz,2H),6.94(s,2H),5.44(s,1H),5.13(d,J=4.0Hz,1H),4.90(t,J=8.0Hz,1H),4.51- 4.39(m,4H),4.29(s,1H),3.68-3.60(m,3H),3.17-3.13(m,2H),3.05-2.96(m,3H),2.81(d,J=4.0Hz,3H),2.71-2.67(m ,1H),2.58-2.51(m,2H),2.45(s,3H),2.06-1.50(m,16H),1.38(d,J=8.0Hz,3H),0.95(s,9H),0.74(s,2H),0.47(s,2H).

[0724] Example 33: Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-((5-methoxypyridin-3-yl)oxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 103)

[0725] Using the synthetic route in Example 11, the first step reaction raw material N-(2-methoxyethyl)-1H-pyrazole-3-carboxamide was replaced with 5-methoxypyridin-3-ol to obtain the title compound (6 mg, yield: 11.2%).

[0726] MS m / z(ESI):1148.5[M+H] + .

[0727] 1 H-NMR (400MHz, DMSO-d6) δ8.99(s,1H),8.52(d,J=8.0Hz,1H),8.26(d,J=4.0Hz,1H),8.16(d,J=4.0Hz,1H),7.49 -7.43(m,3H),7.43(d,J=8.0Hz,2H),6.96(s,2H),6.92(s,1H),5.44(s,1H),5.16(d,J=4.0Hz,1H),4.91(t,J=8.0 Hz,1H),4.44-4.34(m,3H),4.29(s,1H),3.84(s,3H),3.69-3.61(m,2H),3.03-2.96(m,2H),2.68-2.59(m,2H),2 .49(s,4H),2.33-2.25(m,4H),2.10-1.51(m,17H),1.37(d,J=8.0Hz,3H),0.96(s,9H),0.70(s,2H),0.45(s,2H).

[0728] Example 34: Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-(pyrimidin-5-yloxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(pyrimidin-5-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide (Compound 85)

[0729] Using the synthetic route in Example 31, the first step reaction raw material (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-N-((S)-1-(4-(3-fluoropyridin-4-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide was replaced with (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-4-hydroxy-N-((S)-1-(4-(pyrimidin-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide to obtain the title compound (36 mg, yield: 45.7%).

[0730] MS m / z(ESI):1100.5[M+H] + .

[0731] 1 H-NMR (400MHz, DMSO-d6) δ9.18(s,1H),9.13(d,J=4.0Hz,3H),8.91(s,2H),8.53(d,J=4.0Hz,1H),8.01(s,1H ),7.75(d,J=4.0Hz,2H),7.43(d,J=4.0Hz,2H),6.94(s,2H),6.79(s,1H),5.44(s,1H),5.14(d,J=4.0Hz,1H) ,4.93(t,J=8.0Hz,1H),4.45-4.36(m,3H),4.28(s,1H),3.68-3.60(m,2H),3.01(t,J=8.0Hz,2H),2.68-2.59 (m,2H),2.49-2.32(m,2H),2.10-1.51(m,19H),1.38(d,J=8.0Hz,3H),0.96(s,9H),0.71(s,2H),0.46(s,2H).

[0732] Example 35: Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-(pyrimidin-5-yloxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(pyrazin-2-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide (Compound 90)

[0733] Using the synthetic route in Example 31, the first step reaction raw material (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-N-((S)-1-(4-(3-fluoropyridin-4-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide was replaced with (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-4-hydroxy-N-((S)-1-(4-(pyrazin-2-yl)phenyl)ethyl)pyrrolidine-2-carboxamide to give the title compound (40 mg, yield: 50.3%).

[0734] MS m / z(ESI):1100.5[M+H] + .

[0735] 1H-NMR (400MHz, DMSO-d6) δ9.24(s,1H),9.14(s,1H),8.91(s,2H),8.71(d,J=4.0Hz,1H),8.60(d,J=4.0Hz,1H),8.54( d,J=4.0Hz,1H),8.08(d,J=8.0Hz,2H),8.01(s,1H),7.44(d,J=4.0Hz,2H),6.94(s,2H),6.79(s,1H),5.44(s,1H),5.1 5(d,J=4.0Hz,1H),4.94(t,J=8.0Hz,1H),4.45-4.39(m,3H),4.29(s,1H),3.66-3.60(m,2H),3.01(t,J=8.0Hz,2H),2. 69-2.59(m,2H),2.49-2.37(m,2H),2.10-1.63(m,19H),1.38(d,J=8.0Hz,3H),0.94(s,9H),0.71(s,2H),0.46(s,2H).

[0736] Example 36: Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-((5-fluoropyridin-3-yl)oxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 102)

[0737] Using the synthetic route in Example 11, the first step reaction raw material N-(2-methoxyethyl)-1H-pyrazole-3-carboxamide was replaced with 5-fluoropyridin-3-ol to obtain the title compound (2 mg, yield: 3.1%).

[0738] MS m / z(ESI):1136.5[M+H] + .

[0739] 1H-NMR (400MHz, CD3OD) δ8.78(d,J=3.2Hz,1H),8.33(dd,J=6.4,2.4Hz,2H),7.95(d,J=8.8Hz,1H),7.63(dd,J=9.2 ,2.4Hz,1H),7.40-7.22(m,4H),6.45(d,J=1.2Hz,1H),5.39(s,1H),4.93(t,J=7.2Hz,1H),4.48-4.28(m,4H),3.74 (dd,J=11.2,3.6Hz,1H),3.67-3.57(m,1H),3.07(d,J=6.8Hz,2H),2.80-2.43(m,3H),2.38(d,J=5.2Hz,3H),2.34- 2.22(m,1H),2.17-2.04(m,2H),2.01-1.57(m,16H),1.47(d,J=7.2Hz,3H),0.96(s,9H),0.66(s,2H),0.45(s,2H).

[0740] Example 37: Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-((6-methylpyridin-3-yl)oxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 104)

[0741] Using the synthetic route in Example 11, the first step reaction raw material N-(2-methoxyethyl)-1H-pyrazole-3-carboxamide was replaced with 6-methylpyridin-3-ol to obtain the title compound (20 mg, yield: 23.2%).

[0742] MS m / z(ESI):1132.5[M+H] + .

[0743] 1H-NMR (400MHz, DMSO-d6) δ8.99(d,J=1.6Hz,1H),8.52(d,J=7.6Hz,1H),8.39(d,J=2.8Hz,1H),8.00(s,1H),7.63 (dd,J=8.4,2.8Hz,1H),7.48-7.33(m,5H),6.94(s,2H),6.57(d,J=2.0Hz,1H),5.44(s,1H),5.15(d,J=3.6Hz,1H) ,4.92(t,J=7.2Hz,1H),4.51-4.24(m,5H),3.72-3.52(m,2H),2.99(s,2H),2.70-2.52(m,3H),2.46(s,3H),2.39- 2.17(m,5H),2.12-1.84(m,7H),1.85-1.55(m,9H),1.44(d,J=7.2Hz,3H),0.95(s,9H),0.69(s,2H),0.44(s,2H).

[0744] Example 38: Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-((6-chloropyridin-3-yl)oxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 105)

[0745] Using the synthetic route in Example 11, the first step reaction raw material N-(2-methoxyethyl)-1H-pyrazole-3-carboxamide was replaced with 6-chloropyridin-3-ol to obtain the title compound (8 mg, yield: 10.6%).

[0746] MS m / z(ESI):1152.4[M+H] + .

[0747] 1H-NMR (400MHz, DMSO-d6) δ8.99(s,1H),8.52(d,J=7.6Hz,1H),8.45(d,J=2.8Hz,1H),8.00(s,1H),7.89(dd,J=8.4,2.8Hz,1 H),7.66(d,J=8.4Hz,1H),7.44(d,J=8.4Hz,2H),7.39-7.33(m,2H),6.95(s,2H),6.70(s,1H),5.44(s,1H),5.16(d,J=3.6Hz ,1H),4.91(t,J=7.2Hz,1H),4.50-4.32(m,3H),4.29(s,1H),3.72-3.55(m,2H),3.00(d,J=12.8Hz,2H),2.70-2.53(m,2H), 2.46(s,3H),2.38-2.18(m,3H),2.13-1.45(m,16H),1.42-1.29(m,4H),1.22(s,1H),0.95(s,9H),0.70(s,2H),0.45(s,2H).

[0748] Example 39: Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-(pyrimidin-5-yloxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 68)

[0749] Using the synthetic route in Example 31, the first step reaction raw material (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-N-((S)-1-(4-(3-fluoropyridin-4-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide was replaced with (2S,4R)-1-((S)-2-(4-(azetidin-3-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide to give the title compound (3 mg, yield: 3.9%).

[0750] MS m / z(ESI):1091.4[M+H] + .

[0751] 1 H-NMR (400MHz, DMSO-d6) δ9.15(s,1H),8.99(s,1H),8.92(s,2H),8.52(d,J=7.6Hz,1H),8.20(d,J=8.4Hz,1H),7.44(d,J=8 .0Hz,2H),7.37(d,J=8.0Hz,2H),6.95(s,2H),6.79(s,1H),5.45(s,1H),5.18(d,J=16.8Hz,1H),4.92(t,J=7.2Hz,1H),4.4 2(t,J=8.4Hz,1H),4.31(d,J=16.0Hz,3H),3.81-3.55(m,6H),3.14(d,J=6.4Hz,2H),2.46(d,J=2.4Hz,4H),2.32-2.14(m,2 H),2.12-2.04(m,1H),2.02-1.87(m,2H),1.88-1.61(m,9H),1.45(d,J=7.2Hz,3H),0.96(s,9H),0.59(s,2H),0.46(s,2H).

[0752] Example 40: Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-(pyrimidin-5-yloxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(3-methylpyridin-2-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 76)

[0753] Using the synthetic route in Example 31, the first step reaction raw material (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-N-((S)-1-(4-(3-fluoropyridin-4-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide was replaced with (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-4-hydroxy-N-((S)-1-(4-(3-methylpyridin-2-yl)phenyl)ethyl)pyrrolidine-2-carboxamide to give the title compound (6 mg, yield: 15.7%).

[0754] MS m / z(ESI):1113.5[M+H] + .

[0755] 1 H-NMR (400MHz, DMSO-d6) δ9.14(s,1H),8.91(d,J=1.2Hz,2H),8.52(d,J=7.6H z,1H),8.49-8.43(m,1H),7.99(d,J=15.6Hz,1H),7.71(d,J=7.2Hz,1H),7.54 -7.46(m,2H),7.38-7.31(m,2H),7.28(dd,J=7.6,4.8Hz,1H),6.94(s,2H),6. 78(s,1H),5.44(s,1H),5.11(dd,J=12.0,3.2Hz,1H),4.95(t,J=7.2Hz,1H),4. 50-4.34(m,3H),4.30(s,1H),3.75-3.51(m,2H),2.99(s,2H),2.71-2.58(m,2 H),2.61-2.52(m,5H),2.33(s,5H),2.31-2.17(m,1H),2.08(s,2H),2.07-1.94 (m,2H),1.90(dd,J=10.8,4.4Hz,3H),1.78(d,J=10.0Hz,3H),1.65(t,J=8.0H z,2H),1.57-1.36(m,3H),1.24(s,1H),0.95(s,9H),0.71(s,2H),0.46(s,2H).

[0756] Example 41: Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-(pyrimidin-5-yloxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(pyridin-4-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 81)

[0757] Using the synthetic route in Example 31, the first step reaction raw material (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-N-((S)-1-(4-(3-fluoropyridin-4-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide was replaced with (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-4-hydroxy-N-((S)-1-(4-(pyridin-4-yl)phenyl)ethyl)pyrrolidine-2-carboxamide to give the title compound (17 mg, yield: 15.8%).

[0758] MS m / z(ESI):1099.5[M+H] + .

[0759] 1H-NMR (400MHz, DMSO-d6) δ9.14(d,J=1.6Hz,1H),8.91(s,2H),8.65-8.60(m,2H),8.53(d,J=7.6Hz,1H),7.98(d,J=8.0 Hz,1H),7.79-7.72(m,2H),7.71-7.67(m,2H),7.44-7.39(m,2H),6.94(s,2H),6.78(s,1H),5.44(s,1H),5.11(dd,J=16 .0,3.2Hz,1H),4.93(t,J=7.2Hz,1H),4.46-4.34(m,3H),4.28(s,1H),3.72-3.56(m,2H),2.99(s,2H),2.71-2.59(m,1 H),2.60-2.50(m,4H),2.41-2.15(m,3H),2.12-1.84(m,9H),1.83-1.34(m,7H),0.95(s,9H),0.71(s,2H),0.46(s,2H).

[0760] Example 42: Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-(pyrimidin-5-yloxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(3-chloropyridin-4-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide (Compound 83)

[0761] Using the synthetic route in Example 31, the first step reaction raw material (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-N-((S)-1-(4-(3-fluoropyridin-4-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide was replaced with (2S,4R)-N-((S)-1-(4-(3-chloropyridin-4-yl)phenyl)ethyl)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-4-hydroxypyrrolidine-2-carboxamide (140 mg, yield: 44.5%).

[0762] MS m / z(ESI):1133.5[M+H] + .

[0763] 1 H-NMR (400MHz, CD3OD) δ9.06(s,1H),9.06(s,1H),8.83(s,2H),8.63(d,J=4.0Hz,1H),8.50(d,J=4.8Hz,1H),8 .04(d,J=8.4Hz,1H),7.61-7.36(m,5H),6.59(s,1H),5.49(s,1H),5.05(t,J=7.2Hz,1H),4.88-4.78(m,1H),4 .59-4.37(m,4H),3.84(dd,J=11.2,3.6Hz,1H),3.78-3.68(m,1H),3.59-3.44(m,1H),3.23-3.09(m,2H),2.75 (s,1H),2.67-2.29(m,6H),2.25-1.67(m,13H),1.58(d,J=7.2Hz,3H),1.05(s,9H),0.74(s,2H),0.53(s,2H).

[0764] Example 43: Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-(pyrimidin-5-yloxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(5-methylpyrimidin-4-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 89)

[0765] Using the synthetic route in Example 31, the first step reaction raw material (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-N-((S)-1-(4-(3-fluoropyridin-4-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide was replaced with (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-4-hydroxy-N-((S)-1-(4-(5-methylpyrimidin-4-yl)phenyl)ethyl)pyrrolidine-2-carboxamide to give the title compound (19 mg, yield: 33.2%).

[0766] MS m / z(ESI):1114.5[M+H]+ .

[0767] 1 H-NMR (400MHz, DMSO-d6) δ9.14(s,1H),9.07(s,1H),8.91(s,2H),8.72(s,1H),8.55(d,J=7.6Hz,1H),7.99(d,J=6. 8Hz,1H),7.71-7.54(m,2H),7.48-7.28(m,2H),6.94(s,2H),6.79(s,1H),5.44(s,1H),5.28-5.10(m,1H),4.96(t, J=7.2Hz,1H),4.52-4.31(m,3H),4.29(s,1H),3.73-3.52(m,2H),2.99(s,2H),2.71-2.51(m,4H),2.40-1.83(m,16 H),1.79(t,J=11.6Hz,4H),1.70-1.55(m,2H),1.47(dd,J=56.8,7.2Hz,3H),0.95(s,9H),0.71(s,2H),0.46(s,2H).

[0768] Example 44: Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-(pyrimidin-5-yloxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-chloropyridin-3-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide (Compound 79)

[0769] The synthetic route in Example 31 was used to replace the first step reaction raw material (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-N-((S)-1-(4-(3-fluoropyridin-4-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide with (2S,4R)-N-((S)-1-(4-(4-chloropyridin-3-yl)phenyl)ethyl)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-4-hydroxypyrrolidine-2-carboxamide (40 mg, yield: 46.6%).

[0770] MS m / z(ESI):1133.5[M+H] + .

[0771] 1 H-NMR (400MHz, DMSO-d6) δ9.14(d,J=1.2Hz,1H),8.91(d,J=1.2Hz,2H),8.62-8.45(m,3H),7.99(d,J=16.0Hz,1H ),7.67(d,J=5.2Hz,1H),7.53-7.36(m,4H),6.94(s,2H),6.78(s,1H),5.44(s,1H),5.23-5.11(m,1H),4.96(t,J= 7.2Hz,1H),4.50-4.34(m,3H),4.30(s,1H),3.75-3.54(m,2H),2.98(d,J=13.2Hz,2H),2.72-2.50(m,5H),2.43-2 .17(m,4H),2.13-1.73(m,12H),1.63-1.51(m,2H),1.47(d,J=7.2Hz,3H),0.95(s,9H),0.71(s,2H),0.46(s,2H).

[0772] Example 45: Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-(((R)-pyrrolidin-3-yl)oxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 46)

[0773] Using the synthetic route in Example 2, the first step reaction raw material 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester was replaced with (R)-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester to obtain the title compound (4 mg, yield: 24.5%).

[0774] MS m / z(ESI):1110.5[M+H] + .

[0775] 1H-NMR(400MHz,CD3OD)δ8.88(s,1H),8.16(d,J=3.2Hz,1H),7.49-7.37(m,4H),6.32(s,1H),5.87(s,1H), 5.56(d,J=5.2Hz,1H),5.04-5.02(m,2H),4.63-4.51(m,2H),4.46-4.36(m,2H),4.12-4.07(m,1H),3.87-3 .81(m,4H),3.65(d,J=4.0Hz,2H),3.56-3.47(m,5H),3.19-3.10(m,4H),2.83-2.77(m,2H),2.66-2.56(m, 2H),2.53-2.38(m,6H),2.23-1.97(m,13H),1.53(d,J=7.2Hz,3H),1.08(s,9H),0.73(s,2H),0.47(s,2H).

[0776] Example 46: Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-(pyrimidin-5-yloxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-N-((S)-1-(2'-fluoro-[1,1'-biphenyl]-4-yl)ethyl)-4-hydroxypyrrolidine-2-carboxamide (Compound 72)

[0777] Using the synthetic route in Example 31, the first step reaction raw material (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-N-((S)-1-(4-(3-fluoropyridin-4-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide was replaced with (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-N-((S)-1-(2'-fluoro-[1,1'-biphenyl]-4-yl)ethyl)-4-hydroxypyrrolidine-2-carboxamide to give the title compound (7 mg, yield: 18.5%).

[0778] MS m / z(ESI):1116.5[M+H] + .

[0779] 1 H-NMR (400MHz, DMSO-d6) δ9.14 (s, 1H), 8.91 (s, 2H), 8.52 (d, J = 7.6Hz, 1H), 8.01 (s, 1H), 7.54-7. 26(m,8H),6.94(s,2H),6.78(s,1H),5.44(s,1H),5.16(d,J=3.6Hz,1H),4.97-4.87(m,1H),4.48- 4.26(m,4H),3.71-3.58(m,2H),3.00(s,2H),2.65-2.58(m,2H),2.42-2.14(m,4H),2.10-1.72(m ,13H),1.72-1.56(m,3H),1.42-1.32(m,3H),1.22(s,1H),0.96(s,9H),0.71(s,2H),0.46(s,2H).

[0780] Example 47: Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-(pyrimidin-5-yloxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-(2-(4-(4-methylthiazol-5-yl)phenyl)propan-2-yl)pyrrolidine-2-carboxamide (Compound 71)

[0781] Using the synthetic route in Example 31, the first step reaction raw material (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butyryl)-N-((S)-1-(4-(3-fluoropyridin-4-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide was replaced with (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butyryl)-4-hydroxy-N-(2-(4-(4-methylthiazol-5-yl)phenyl)propan-2-yl)pyrrolidine-2-carboxamide to obtain the title compound (7 mg, yield: 22.7%).

[0782] MS m / z(ESI):1133.5[M+H] + .

[0783] 1H-NMR(400MHz,DMSO-d6)δ9.14(s,1H),8.96-8.90(m,3H),8.39(s,1H),8.06(s,1H),7.52(d ,J=8.0Hz,2H),7.37(t,J=7.2Hz,2H),6.94(s,2H),6.78(s,1H),5.42(s,1H),5.16(d,J=3.2 Hz,1H),4.60-4.29(m,4H),3.69-3.60(m,3H),3.00(s,2H),2.66(s,2H),2.45-2.43(m,3H), 2.34(s,2H),2.24-1.72(m,16H),1.70-1.49(m,8H),0.94(s,9H),0.70(s,2H),0.45(s,2H).

[0784] Example 48: Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-((4-methylpyridin-3-yl)oxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 97)

[0785] Using the synthetic route in Example 11, the first step reaction raw material N-(2-methoxyethyl)-1H-pyrazole-3-carboxamide was replaced with 4-methylpyridin-3-ol to obtain the title compound (7 mg, yield: 23.2%).

[0786] MS m / z(ESI):1132.5[M+H] + .

[0787] 1H-NMR (400MHz, DMSO-d6) δ8.99 (s, 1H), 8.52 (d, J = 7.6Hz, 1H), 8.41-8.29 (m, 2H), 7.98 (s, 1H), 7.45-7 .36(m,5H),6.92(s,2H),6.62(s,1H),5.44(s,1H),5.20-4.90(m,2H),4.49-4.26(m,4H),3.73-3.57( m,3H),2.99(s,2H),2.69-2.59(m,2H),2.46-2.42(m,4H),2.34(s,2H),2.14(s,3H),2.10-1.88(m,7H ),1.83-1.70(m,6H),1.65-1.51(m,4H),1.37(d,J=6.8Hz,3H),0.95(s,9H),0.70(s,2H),0.45(s,2H).

[0788] Example 49: Preparation of 1-(2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-((1-((4-(1-((S)-1-((2S,4R)-4-hydroxy-2-(((S))-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-1H-1,2,3-triazol-4-yl)piperidin-1-yl)methyl)cyclopropyl)methoxy)pyrimidin-4-yl)-N,N-dimethyl-1H-pyrazole-3-carboxamide (Compound 108)

[0789] The synthetic route in Example 32 was used to replace the first step reaction raw material methylamine hydrochloride with dimethylamine hydrochloride to obtain the title compound (8 mg, yield: 32.4%).

[0790] MS m / z(ESI):1162.5[M+H] + .

[0791] 1H-NMR (400MHz, DMSO-d6) δ8.99(s,1H),8.65(d,J=2.4Hz,1H),8.52(d,J=7.6Hz,1H),7.98-7.94(m,1H),7.44(d,J=8.0Hz ,2H),7.36(d,J=8.0Hz,2H),7.26(s,1H),6.98(s,2H),6.90(d,J=2.4Hz,1H),5.43(s,1H),5.19-5.15(m,1H),4.92-4.88( m,1H),4.53-4.27(m,4H),3.68-3.60(m,4H),3.29(s,4H),3.03(s,5H),2.73-2.67(m,2H),2.46(s,3H),2.40-2.32(m,2H ),2.08-2.01(m,7H),1.90-1.80(m,6H),1.67-1.50(m,3H),1.37(d,J=6.8Hz,3H),0.94(s,9H),0.73(s,2H),0.46(s,2H).

[0792] Example 50: Preparation of 1-(2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-((1-((4-(1-((S)-1-((2S,4R)-4-hydroxy-2-(((S))-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-1H-1,2,3-triazol-4-yl)piperidin-1-yl)methyl)cyclopropyl)methoxy)pyrimidin-4-yl)-N-isopropyl-1H-pyrazole-3-carboxamide (Compound 109)

[0793] Using the synthetic route in Example 32, the first step reaction raw material methylamine hydrochloride was replaced by isopropylamine to obtain the title compound (8 mg, yield: 19.7%).

[0794] MS m / z(ESI):1176.5[M+H] + .

[0795] 1H-NMR (400MHz, DMSO-d6) δ8.99(s,1H),8.62(d,J=2.4Hz,1H),8.52(d,J=7.6Hz,1H),8.31(d,J=8.4Hz,1H),7. 99-7.95(m,1H),7.57(s,1H),7.45-7.36(m,4H),6.99-6.94(m,2H),5.43(s,1H),5.19-5.16(m,1H),4.98-4.8 4(m,1H),4.59-4.09(m,5H),3.69-3.54(m,2H),3.17-2.97(m,4H),2.79-2.54(m,4H),2.46(s,3H),2.41-2.32 (m,2H),2.20-1.55(m,17H),1.37(d,J=6.8Hz,3H),1.23-1.20(m,5H),0.95(s,9H),0.74(s,2H),0.47(s,2H).

[0796] Example 51: Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-(pyrimidin-5-yloxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(3-chloropyridin-2-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide (Compound 75)

[0797] Using the synthetic route in Example 31, the first step reaction raw material (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-N-((S)-1-(4-(3-fluoropyridin-4-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide was replaced with (2S,4R)-N-((S)-1-(4-(3-chloropyridin-2-yl)phenyl)ethyl)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-4-hydroxypyrrolidine-2-carboxamide to give the title compound (8 mg, yield: 27.6%).

[0798] MS m / z(ESI):1133.5[M+H] + .

[0799] 1 H-NMR(400MHz,CD3OD)δ9.08(s,1H),8.83(s,2H),8.54-8.52(m,1H),8.08-7.98(m,2H), 7.63-7.59(m,2H),7.51-7.30(m,3H),6.62(s,1H),5.50(d,J=6.4Hz,2H),5.10-4.98(m, 2H),4.75-4.29(m,6H),3.89-3.44(m,2H),2.84(s,1H),2.62-2.56(m,4H),2.44-2.28(m ,2H),2.25-1.63(m,14H),1.53(d,J=7.2Hz,3H),1.06(s,9H),0.81(s,2H),0.62(s,2H).

[0800] Example 52: Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-(pyrimidin-5-yloxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(3-methylpyridin-4-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 84)

[0801] Using the synthetic route in Example 31, the first step reaction raw material (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-N-((S)-1-(4-(3-fluoropyridin-4-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide was replaced with (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-4-hydroxy-N-((S)-1-(4-(3-methylpyridin-4-yl)phenyl)ethyl)pyrrolidine-2-carboxamide to give the title compound (8 mg, yield: 36.9%).

[0802] MS m / z(ESI):1113.5[M+H] + .

[0803] 1H-NMR(400MHz,CD3OD)δ9.06(s,1H),8.83(s,2H),8.47-8.34(m,2H),8.0 5(s,1H),7.50-7.21(m,5H),6.59(s,1H),4.61-4.44(m,6H),3.85-3.66( m,3H),3.16-3.13m,2H),2.75-2.71(m,1H),2.67-2.12(m,14H),1.92-1. 62(m,10H),1.53(d,J=7.2Hz,3H),1.05(s,9H),0.74(s,2H),0.53(s,2H).

[0804] Example 53: Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-(pyrimidin-5-yloxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylpyrimidin-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 86)

[0805] Using the synthetic route in Example 31, the first step reaction raw material (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-N-((S)-1-(4-(3-fluoropyridin-4-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide was replaced with (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylpyrimidin-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide to give the title compound (14 mg, yield: 32.8%).

[0806] MS m / z(ESI):1114.5[M+H] + .

[0807] 1H-NMR(400MHz,CD3OD)δ9.06(s,1H),8.98(d,J=3.6Hz,1H),8.83(s,2H),8.54(d,J=4.8Hz,1H),8.05-8 .03(m,1H),7.49-7.38(m,4H),6.59(s,1H),5.49(s,1H),5.07-5.05(m,1H),4.64-4.42(m,5H),3.87-3. 65(m,2H),3.16-3.13(m,2H),2.77-2.71(m,1H),2.67-2.55(m,3H),2.52-2.42(m,5H),2.19-2.08(m,3H ),2.06-1.83(m,10H),1.78-1.72(m,3H),1.53(d,J=7.2Hz,3H),1.05(s,9H),0.74(s,2H),0.52(s,2H).

[0808] Example 54: Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-(pyrimidin-5-yloxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(3-fluoropyridin-2-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide (Compound 74)

[0809] Using the synthetic route in Example 31, the first step reaction raw material (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-N-((S)-1-(4-(3-fluoropyridin-4-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide was replaced with (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-N-((S,1-(4-(3-fluoropyridin-2-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide to give the title compound (12.8 mg, yield: 18.8%).

[0810] MS m / z(ESI):1117.6[M+H] + .

[0811] 1H-NMR (400MHz, DMSO-d6) δ9.15 (s, 1H), 8.91 (s, 2H), 8.55 (d, J = 8.0Hz, 2H), 8.02 (s, 1H), 7.88-7.82 (m ,3H),7.49-7.45(m,1H),7.43(d,J=8.0Hz,2H),6.94(s,2H),6.76(s,1H),5.44(s,1H),5.18(s,1H),4. 93(t,J=8.0Hz,1H),4.45-4.36(m,3H),4.30(s,1H),3.67-3.54(m,3H),3.01-3.03(m,3H),2.57(s,1H) ,2.38-2.33(m,3H),2.08-1.59(m,15H),1.40(d,J=8.0Hz,3H),0.96(s,9H),0.72(s,2H),0.47(s,2H).

[0812] Example 55: Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-(pyrimidin-5-yloxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(pyridin-2-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 73)

[0813] Using the synthetic route in Example 31, the first step reaction raw material (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-N-((S)-1-(4-(3-fluoropyridin-4-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide was replaced with (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-4-hydroxy-N-((S)-1-(4-(pyridin-2-yl)phenyl)ethyl)pyrrolidine-2-carboxamide to give the title compound (3.4 mg, yield: 6.9%).

[0814] MS m / z(ESI):1099.4[M+H] + .

[0815] 1H-NMR (400MHz, DMSO-d6) δ9.15(s,1H),8.91(s,2H),8.65(d,J=8.0Hz,1H),8.53(d,J=8.0Hz,1H),8.05-8.01(m,3H),7 .94(d,J=8.0Hz,1H),7.89-7.85(m,1H),7.40(d,J=8.0Hz,2H),7.36-7.32(m,1H),6.94(s,2H),6.78(s,1H),5.44(s,1H ),5.16(d,J=4.0Hz,1H),4.93(t,J=8.0Hz,1H),4.45-4.36(m,3H),4.30(s,1H),3.70-3.60(m,2H),3.01-3.03(m,2H),2 .67-2.65(m,1H),2.38-2.21(m,4H),2.08-1.59(m,18H),1.40(d,J=8.0Hz,3H),0.96(s,9H),0.71(s,2H),0.46(s,2H).

[0816] Example 56: Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-(pyrimidin-5-yloxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(pyridin-3-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 77)

[0817] Using the synthetic route in Example 31, the first step reaction raw material (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-N-((S)-1-(4-(3-fluoropyridin-4-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide was replaced with (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-4-hydroxy-N-((S)-1-(4-(pyridin-3-yl)phenyl)ethyl)pyrrolidine-2-carboxamide to give the title compound (37 mg, yield: 38.4%).

[0818] MS m / z(ESI):1099.5[M+H] + .

[0819] 1 H-NMR (400MHz, DMSO-d6) δ9.15(s,1H),8.91(s,2H),8.88(d,J=4.0Hz,1H),8.56(d,J=8.0Hz,1H),8.53(d,J=8.0Hz,1H),8.0 7(d,J=8.0Hz,1H),8.01(s,1H),7.68(d,J=8.0Hz,2H),7.49-7.46(m,1H),7.40(d,J=8.0Hz,2H),6.94(s,2H),6.78(s,1H),5 .44(s,1H),5.16(d,J=4.0Hz,1H),4.93(t,J=8.0Hz,1H),4.45-4.36(m,3H),4.30(s,1H),3.70-3.60(m,2H),3.01-3.03(m,2 H),2.67-2.65(m,1H),2.38-2.21(m,4H),2.08-1.59(m,18H),1.40(d,J=8.0Hz,3H),0.96(s,9H),0.71(s,2H),0.46(s,2H).

[0820] Example 57: Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-(pyrimidin-5-yloxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(pyrimidin-2-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 87)

[0821] Using the synthetic route in Example 31, the first step reaction raw material (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-N-((S)-1-(4-(3-fluoropyridin-4-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide was replaced with (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-4-hydroxy-N-((S)-1-(4-(pyrimidin-2-yl)phenyl)ethyl)pyrrolidine-2-carboxamide to give the title compound (9.2 mg, yield: 19.1%).

[0822] MS m / z(ESI):1100.5[M+H] + .

[0823] 1 H-NMR (400MHz, DMSO-d6) δ9.14(s,1H),8.91(s,2H),8.89(d,J=4.0Hz,2H),8.55(d,J=8.0Hz,2H),8.34( d,J=4.0Hz,2H),8.01(s,1H),7.44-7.42(m,3H),6.94(s,2H),6.78(s,1H),5.44(s,1H),5.18(s,1H),4.9 3(t,J=8.0Hz,1H),4.45-4.36(m,3H),4.30(s,1H),3.67-3.54(m,2H),3.01-3.03(m,2H),2.67-2.62(m,1 H),2.38-2.33(m,3H),2.08-1.59(m,18H),1.40(d,J=8.0Hz,3H),0.96(s,9H),0.72(s,2H),0.47(s,2H).

[0824] Example 58: Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-((5-chloropyridin-3-yl)oxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 101)

[0825] Using the synthetic route in Example 11, the first step reaction raw material N-(2-methoxyethyl)-1H-pyrazole-3-carboxamide was replaced with 5-chloropyridin-3-ol to obtain the title compound (41 mg, yield: 18.9%).

[0826] MS m / z(ESI):1152.6[M+H] + .

[0827] 1H-NMR (400MHz, DMSO-d6) δ8.99(s,1H),8.61(d,J=2.0Hz,1H),8.57(d,J=2.0Hz,1H),8.52(d,J=8.0Hz,1H),8.15(t ,J=2.0Hz,1H),8.02(s,1H),7.47-7.41(m,2H),7.39-7.34(m,2H),6.94(s,2H),6.73(s,1H),5.44(s,1H),5.15(d,J =3.2Hz,1H),4.94-4.88(m,1H),4.45-4.34(m,3H),4.29(s,1H),3.72-3.54(m,3H),3.04(s,2H),2.68-2.57(m,3H) ,2.46(s,4H),2.30-2.23(m,2H),2.09-1.64(m,16H),1.37(d,J=8.0Hz,3H),0.96(s,9H),0.72(s,2H),0.48(s,2H).

[0828] Example 59: Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-((6-methoxypyridin-3-yl)oxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 106)

[0829] Using the synthetic route in Example 11, the first step reaction raw material N-(2-methoxyethyl)-1H-pyrazole-3-carboxamide was replaced with 6-methoxypyridin-3-ol to obtain the title compound (15 mg, yield: 9.5%).

[0830] MS m / z(ESI):1148.6[M+H] + .

[0831] 1H-NMR (400MHz, DMSO-d6) δ8.99(s,1H),8.52(d,J=8.0Hz,1H),8.13(d,J=2.8Hz,1H),8.01(s,1H),7.70(d,J=8.8Hz ,1H),7.44(d,J=8.0Hz,2H),7.37(d,J=8.0Hz,2H),6.94(d,J=4.0Hz,2H),6.55(s,1H),5.44(s,1H),5.16(d,J=3.2H z,1H),4.93-4.88(m,1H),4.47-4.25(m,4H),3.88(s,3H),3.72-3.54(m,3H),3.02-2.88(m,3H),2.68-2.63(m,2H) ,2.46(s,3H),2.38-2.33(m,2H),2.10-1.56(m,18H),1.37(d,J=8.0Hz,3H),0.95(s,9H),0.70(s,2H),0.45(s,2H).

[0832] Example 60: Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-((5-cyclopropylpyridin-3-yl)oxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 115)

[0833] Using the synthetic route in Example 11, the first step reaction raw material N-(2-methoxyethyl)-1H-pyrazole-3-carboxamide was replaced with 5-cyclopropylpyridin-3-ol to obtain the title compound (15 mg, yield: 13.8%).

[0834] MS m / z(ESI):1158.5[M+H] + .

[0835] 1H-NMR (400MHz, DMSO-d6) δ8.99(s,1H),8.53(d,J=8.0Hz,1H),8.35(d,J=2.0Hz,1H),8.29(d,J=2.0Hz,1H),8.00(s,1H),7. 46-7.41(m,3H),7.37(d,J=8.0Hz,2H),6.95(s,2H),6.60(s,1H),5.44(s,1H),5.16(d,J=4.0Hz,1H),4.94-4.88(m,1H),4. 44-4.37(m,3H),4.29(s,1H),3.70-3.59(m,2H),2.99(s,2H),2.68-2.61(m,1H),2.46(s,3H),2.33(s,2H),2.25-2.18(m,1 H),2.07-1.59(m,20H),1.37(d,J=8.0Hz,3H),1.04-1.00(m,2H),0.95(s,9H),0.81-0.76(m,2H),0.70(s,2H),0.44(s,2H).

[0836] Example 61: Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-((4-aminophenoxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 34)

[0837] Step 1: Preparation of tert-butyl (S)-(4-((6-((1-(hydroxymethyl)cyclopropyl)methoxy)-2-(2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-3-yl)pyrimidin-4-yl)oxy)phenyl)carbamate

[0838] (S)-3-(4-chloro-6-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-2'-one (200 mg, 454.67 μmol) was dissolved in acetonitrile (5 mL). Tert-butyl N-(4-hydroxyphenyl)carbamate (144 mg, 682.01 μmol) and cesium carbonate (300 mg, 909.34 μmol) were added sequentially. The mixture was reacted at 80°C for 2 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1, volume ratio) to obtain the title compound (240 mg, yield: 88.4%).

[0839] MS m / z(ESI):591.4[M+H] + .

[0840] Step 2: Preparation of (S)-(1-(((6-(4-((tert-Butoxycarbonyl)amino)phenoxy)-2-(2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-3-yl)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl methanesulfonate

[0841] Tert-butyl (S)-(4-((6-((1-(hydroxymethyl)cyclopropyl)methoxy)-2-(2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-3-yl)pyrimidin-4-yl)oxy)phenyl)carbamate (240 mg, 402.26 μmol) was dissolved in dichloromethane (5 mL). N,N-diisopropylethylamine (157 mg, 1.21 mmol) and methanesulfonic anhydride (106 mg, 603.39 μmol) were added sequentially, and the mixture was reacted at 25°C for 2 hours. Saturated brine was added to the reaction solution, the layers were separated, the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (250 mg, yield: 92.0%).

[0842] MS m / z(ESI):669.3[M+H] + .

[0843] Step 3: Preparation of tert-butyl (4-((6-((1-((4-(1-((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-1H-1,2,3-triazol-4-yl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-2-((S)-2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-3-yl)pyrimidin-4-yl)oxy)phenyl)carbamate

[0844] (S)-(1-(((6-(4-((tert-Butoxycarbonyl)amino)phenoxy)-2-(2'-oxo-5,6-dihydro-4H-spiro[benzo[d]isoxazol-7,1'-cyclohexane]-3-yl)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl methanesulfonate (250 mg, 370.09 μmol) was dissolved in acetonitrile (5 mL), and potassium carbonate (206 mg, 1.48 mmol) and iodine were added. To the mixture was added (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (296 mg, 518.13 μmol), and the mixture was stirred at 60°C for 6 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (10 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1, volume ratio) to obtain the title compound (250 mg, yield: 58.03%).

[0845] MS m / z(ESI):1152.7[M+H] + .

[0846] Step 4: Preparation of tert-butyl (4-((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-((1-((4-(1-((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-1H-1,2,3-triazol-4-yl)piperidin-1-yl)methyl)cyclopropyl)methoxy)pyrimidin-4-yl)oxy)phenyl)carbamate

[0847] (4-((6-((1-((4-(1-((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-1H-1,2,3-triazol-4-yl)piperidin-1-yl)methyl)cyclopropyl)methoxy)-2-((S)-2'-oxo-5,6-dihydro-4H-spiro[benzo[ Tert-butyl [d]isoxazol-7,1'-cyclohexane-3-yl)pyrimidin-4-yl)oxy)phenyl)carbamate (250 mg, 214.77 μmol), ammonium acetate (66 mg, 859.07 μmol), and sulfur (27 mg, 859.07 μmol) were dissolved in ethanol (5 mL) and stirred at 60°C for 15 minutes. A solution of malononitrile (71 mg, 1.07 mmol) in ethanol (1 mL) was then added dropwise, and the mixture was stirred at 80°C for 5 hours. The reaction mixture was filtered, the filtrate was concentrated, and the residue was purified by high-performance liquid chromatography to obtain the title compound (120 mg, yield: 44.9%).

[0848] MS m / z(ESI):1232.6[M+H] + .

[0849] Step 5: Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-((4-aminophenoxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0850] (4-((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-((1-((4-(1-((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl) Tert-butyl (120 mg, 96.4 μmol) (amino)-1H-1,2,3-triazol-4-yl (1,2-dimethyl-1-oxobutan-2-yl, 1,2-dimethyl-2-nitropropane-1-yl, 1,2-dimethyl-1-nitropropane-2-yl, 1,2-dimethyl-2-nitropropane-1-yl, 1,2-dimethyl-1-nitropropane-2-yl, 1,2-dimethyl-2-nitropropane-1-yl, 1,2-dimethyl-2 ...2-yl,

[0851] MS m / z(ESI):1132.2[M+H] + .

[0852] 1 H-NMR (400MHz, DMSO-d6) δ8.99(s,1H),8.52(d,J=8.0Hz,1H),8.00(s,1H),7.44(d,J=8.0Hz,2H),7.37(d,J=8 .0Hz,2H),6.95(s,2H),6.88(d,J=8.8Hz,2H),6.61(d,J=8.8Hz,2H),6.12(s,1H),5.44(s,1H),5.15(s,2H),4. 94-4.88(m,1H),4.45-4.27(m,5H),3.69-3.54(m,3H),2.99(s,2H),2.89-2.78(m,2H),2.69-2.58(m,2H),2.4 6(s,3H),2.35-2.30(m,2H),2.07-1.68(m,16H),1.37(d,J=8.0Hz,3H),0.96(s,9H),0.67(s,2H),0.42(s,2H).

[0853] Example 62: Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-((3-methyl-1H-pyrazol-1-yl)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 37)

[0854] Using the synthetic route in Example 11, the first step reaction raw material N-(2-methoxyethyl)-1H-pyrazole-3-carboxamide was replaced with 3-methyl-1H-pyrazole to obtain the title compound (1.6 mg, yield: 2.7%).

[0855] MS m / z(ESI):1105.8[M+H] + .

[0856] 1 H-NMR (400MHz, CD3OD) δ8.90(s,1H),8.67(d,J=8.0Hz,1H),8.63(d,J=4.0Hz,1H),8.19-8.16(m,1H),7.47-7.40(m,4H),7.24(s ,1H),6.46-6.41(m,1H),5.57-5.53(m,1H),5.06-5.01(m,1H),4.84(d,J=8.0Hz,1H),4.77(d,J=12.0Hz,1H),4.72-4.63(m,1H), 4.58-4.53(m,1H),4.45(s,1H),4.39(d,J=12.0,1H),3.99-3.75(m,4H),3.49-3.39(m,2H),3.27-3.21(m,2H),2.89-2.80(m,2H) ,2.65-2.57(m,2H),2.48(s,3H),2.37(s,3H),2.22-1.96(m,15H),1.52(d,J=8.0Hz,3H),1.08(s,9H),0.94(s,2H),0.54(s,2H).

[0857] Example 63: Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-(3-(2-(isopropylamino)-2-oxoethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 113)

[0858] Using the synthetic route in Example 11, the first step reaction raw material N-(2-methoxyethyl)-1H-pyrazole-3-carboxamide was replaced with N-isopropyl-2-(1H-pyrazol-3-yl)acetamide to obtain the title compound (4.3 mg, yield: 7.9%).

[0859] MS m / z(ESI):1190.6[M+H] + .

[0860] 1 H-NMR (400MHz, DMSO-d6) δ8.99(s,1H),8.56-8.46(m,2H),8.03(d,J=8.0Hz,1H),7.99(s,1H),7.47-7.42(m,2H),7.36(d,J=8.0Hz ,2H),7.12(s,1H),6.97(s,2H),6.55(d,J=2.0Hz,1H),5.43(s,1H),5.15(d,J=4.0Hz,1H),4.93-4.87(m,1H),4.43(t,J=8.0Hz,3H ),4.29(s,1H),3.89-3.80(m,1H),3.68-3.59(m,2H),3.51(s,2H),3.13(d,J=12.0Hz,1H),3.00(s,2H),2.70-2.61(m,2H),2.46(s ,3H),2.37-2.32(m,2H),2.19-1.53(m,18H),1.37(d,J=8.0Hz,3H),1.07(d,J=8.0Hz,6H),0.90(s,9H),0.72(s,2H),0.45(s,2H).

[0861] Example 64: Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-(1-(2-methoxyethyl)-1H-pyrazol-3-yl)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 41)

[0862] The synthetic route in Example 3 was used to replace the first step reaction raw material cyclopropylboronic acid with (1-(2-methoxyethyl)-1H-pyrazol-3-yl)boronic acid to obtain the title compound (4 mg, yield: 3.7%).

[0863] MS m / z(ESI):1149.5[M+H] + .

[0864] 1 H-NMR (400MHz, DMSO-d6) δ8.99(s,1H),8.51(d,J=8.0Hz,1H),8.04(s,1H),7.89(d,J=2.0Hz,1H),7.48-7.42(m,2H), 7.37(d,J=8.0Hz,2H),7.29(s,1H),6.96(s,1H),6.92(d,J=2.0Hz,1H),5.44(s,1H),5.15(d,J=4.0Hz,1H),4.94-4.8 8(m,1H),4.47-4.33(m,5H),4.29(s,1H),3.78-3.73(m,2H),3.70-3.60(m,3H),3.25(s,3H),2.72-2.62(m,2H),2.54 (s,2H),2.46(s,3H),2.17-1.58(m,19H),1.37(d,J=8.0Hz,3H),1.23(s,2H),0.96(s,9H),0.78(s,2H),0.54(s,2H).

[0865] Example 65: Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-(pyrimidin-5-yloxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-N-((S)-1-(3-fluoro-4-(4-methylthiazol-5-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide (Compound 96)

[0866] Using the synthetic route in Example 31, the first step reaction raw material (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butyryl)-N-((S)-1-(4-(3-fluoropyridin-4-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide was replaced with (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butyryl)-N-((S)-1-(3-fluoro-4-(4-methylthiazol-5-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide to give the title compound (21 mg, yield: 31.1%).

[0867] MS m / z(ESI):1137.4[M+H] + .

[0868] 1 H-NMR(400MHz,DMSO-d6)δ9.15(s,1H),9.11(s,1H),8.91(s,2H),8.56(d,J=8.0Hz,1H),8.00(s,1H), 7.45(t,J=8.0,1H),7.29-7.19(m,2H),6.94(s,2H),6.79(s,1H),5.44(s,1H),5.17(t,J=8.0Hz,1H), 4.96-4.90(m,1H),4.44-4.36(m,3H),4.30(s,1H),3.70-3.55(m,2H),2.99(s,2H),2.67-2.57(m,2H) ,2.37-2.25(m,6H),2.08-1.61(m,18H),1.38(d,J=8.0Hz,3H),0.95(s,9H),0.71(s,2H),0.46(s,2H).

[0869] Example 66: Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-(pyrimidin-5-yloxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-N-((S)-1-(2-fluoro-4-(4-methylthiazol-5-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide (Compound 95)

[0870] Using the synthetic route in Example 31, the first step reaction raw material (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-N-((S)-1-(4-(3-fluoropyridin-4-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide was replaced with (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-N-((S)-1-(2-fluoro-4-(4-methylthiazol-5-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide to obtain the title compound (22 mg, yield: 38.4%).

[0871] MS m / z(ESI):1137.4[M+H] + .

[0872] 1 H-NMR(400MHz,DMSO-d6)δ9.15(s,1H),9.11(s,1H),8.91(s,2H),8.56(d,J=8.0Hz,1H),8.00(s,1H), 7.45(t,J=8.0Hz,1H),7.29-7.19(m,2H),6.94(s,2H),6.79(s,1H),5.44(s,1H),5.17(t,J=8.0Hz,1H) ,4.96-4.90(m,1H),4.44-4.36(m,3H),4.30(s,1H),3.70-3.55(m,2H),2.99(s,2H),2.67-2.57(m,2H) ,2.37-2.25(m,6H),2.08-1.61(m,18H),1.38(d,J=8.0Hz,3H),0.95(s,9H),0.71(s,2H),0.46(s,2H).

[0873] Example 67: Preparation of (2S,4R)-1-((S)-2-(4-(1-(((2-(S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-(3-aminophenoxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S-5-methyl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 35)

[0874] Using the synthetic route in Example 61, the first step reaction raw material N-(4-hydroxyphenyl)carbamic acid tert-butyl ester was replaced with N-(3-hydroxyphenyl)carbamic acid tert-butyl ester to obtain the title compound (3.5 mg, yield: 3.3%).

[0875] MS m / z(ESI):1132.5[M+H] + .

[0876] 1 H-NMR(400MHz,DMSO-d6)δ8.98(s,1H),8.52(d,J=7.6Hz,1H),8.00(s,1H),7.44 (dd,J=8.0,4.4Hz,2H),7.38-7.33(m,2H),7.07(t,J=8.0Hz,1H),6.95(s,2H),6 .49(dd,J=8.0,1.2Hz,1H),6.37(t,J=2.0Hz,1H),6.31(d,J=8.0Hz,1H),6.21(d ,J=4.0Hz,1H),5.76(s,3H),5.43(s,1H),5.34(s,2H),5.15(d,J=3.6Hz,1H),4.9 4-4.88(m,1H),4.45-4.36(m,2H),4.30(d,J=10.8Hz,2H),3.65(d,J=7.6Hz,2H) ,3.01-2.93(m,2H),2.88-2.81(m,1H),2.64-2.58(m,1H),2.45(s,3H),2.31-2.2 9(m,1H),2.09-1.96(m,5H),1.91-1.77(m,8H),1.76-1.72(m,1H),1.64-1.55(m ,2H),1.37(d,J=6.8Hz,3H),1.23(s,1H),0.95(s,9H),0.67(s,2H),0.42(s,2H).

[0877] Example 68: Preparation of 1-(2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-(1-((4-(1-(S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-1H-1,2,3-triazol-4-yl)piperidin-1-yl)methyl)cyclopropyl)methoxy)pyrimidin-4-yl)-N-(2-hydroxyethyl)-1H-pyrazole-3-carboxamide (Compound 36)

[0878] Using the synthetic route in Example 61, the first step reaction raw material N-(4-hydroxyphenyl)carbamic acid tert-butyl ester was replaced with N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazole-3-carboxamide to obtain the title compound (11.3 mg, yield: 13.6%).

[0879] MS m / z(ESI):1178.5[M+H] + .

[0880] 1 H-NMR (400MHz, DMSO-d6) δ8.98(s,1H),8.63(d,J=2.0Hz,1H),8.52(d,J=7.2Hz,2H),7.97(d,J=15.6Hz,1H),7.49(s,1H),7.43(d,J=8.0Hz,2H),7.36 (d,J=7.6Hz,2H),6.99-6.95(m,2H),5.43(s,1H),5.17(t,J=5.2Hz,1H),4. 94-4.86(m,1H),4.83(t,J=5.2Hz,1H),4.58-4.34(m,3H),4.29(s,1H),3.6 4(dd,J=25.6,9.6Hz,2H),3.56-3.51(m,2H),3.15(d,J=13.6Hz,2H),3.01 (s,2H),2.77-2.53(m,4H),2.45(s,3H),2.42-2.29(m,2H),2.02(dd,J=16. 0,8.0Hz,6H),1.94-1.80(m,6H),1.80-1.70(m,2H),1.62(s,2H),1.51(d,J =6.8Hz,1H),1.36(d,J=6.8Hz,3H),0.94(s,9H),0.74(s,2H),0.48(s,2H).

[0881] Example 69: Preparation of (2S,4R)-1-((S)-2-(4-(1-(((2-(S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-((5-methylpyridin-3-yl)oxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 100)

[0882] Using the synthetic route in Example 11, the first step reaction raw material N-(2-methoxyethyl)-1H-pyrazole-3-carboxamide was replaced with 5-methyl-3-hydroxypyridine to obtain the title compound (50.1 mg, yield: 32.1%).

[0883] MS m / z(ESI):1132.5[M+H] + .

[0884] 1H-NMR (400MHz, DMSO-d6) δ8.98 (s, 1H), 8.52 (d, J = 7.6Hz, 1H), 8.37-8.33 (m, 2H ),8.00(s,1H),7.62(s,1H),7.44(d,J=8.0Hz,2H),7.36(d,J=8.0Hz,2H),6.94 (s,2H),6.60(s,1H),5.43(s,1H),5.16(d,J=3.2Hz,1H),4.95-4.86(m,1H),4. 45-4.35(m,3H),4.29(s,1H),3.70-3.59(m,2H),2.97(d,J=9.6Hz,2H),2.69-2. 59(m,2H),2.59-2.55(m,1H),2.45(s,3H),2.34(s,5H),2.27-2.20(m,1H),2.0 8(t,J=6.0Hz,1H),2.03(d,J=3.6Hz,1H),2.00(s,1H),1.98-1.95(m,1H),1.88( d,J=12.4Hz,4H),1.82(s,1H),1.79(s,2H),1.76(d,J=2.4Hz,2H),1.63(dd,J= 13.2,7.6Hz,3H),1.37(d,J=6.8Hz,3H),0.95(s,9H),0.69(s,2H),0.44(s,2H).

[0885] Example 70: Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-((4-methoxypyridin-3-yl)oxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 99)

[0886] Using the synthetic route in Example 11, the first step reaction raw material N-(2-methoxyethyl)-1H-pyrazole-3-carboxamide was replaced with 3-hydroxy-4-methoxypyridine to obtain the title compound (29 mg, yield: 33.4%).

[0887] MS m / z(ESI):1148.5[M+H] + .

[0888] 1 H-NMR (400MHz, DMSO-d6) δ8.98(s,1H),8.54(d,J=7.6Hz,1H),8.42(d,J=5.6Hz,1H),8.36(s,1H),8.00(s,1H),7.44(d,J=8.4Hz,2H),7.36(d, J=8.0Hz,2H),7.27(d,J=5.6Hz,1H),6.94(s,2H),6.60(s,1H),5.43(s,1H),5.16(d,J=3.6Hz,1H),4.91(t,J=6.8Hz,1H),4.42(t,J=8.4Hz,1H) ,4.38-4.32(m,2H),4.29(s,1H),3.79(s,3H),3.70-3.59(m,2H),2.99 (s,2H),2.68-2.61(m,1H),2.45(s,3H),2.33(s,2H),2.16-1.96(m,5H) ,1.95-1.85(m,4H),1.82-1.72(m,6H),1.70(d,J=2.8Hz,1H),1.67-1.5 6(m,3H),1.37(d,J=7.2Hz,3H),0.95(s,9H),0.69(s,2H),0.44(s,2H).

[0889] Example 71: Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-((4-chloropyridin-3-yl)oxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 98)

[0890] Using the synthetic route in Example 11, the first step reaction raw material N-(2-methoxyethyl)-1H-pyrazole-3-carboxamide was replaced with 3-hydroxy-4-chloropyridine to obtain the title compound (8.15 mg, yield: 20.7%).

[0891] MS m / z(ESI):1152.4[M+H] + .

[0892] 1H-NMR (400MHz, DMSO-d6) δ8.98(s,1H),8.68(s,1H),8.52(d,J=5.2Hz,2H),8.00(s,1H),7.78(d,J=5.2Hz,1H),7.44(d,J=8.4Hz,2H),7.36(d,J=8. 0Hz,2H),6.93(s,2H),6.80(s,1H),5.43(s,1H),5.15(d,J=3.6Hz,1H),4 .91(t,J=6.8Hz,1H),4.41(dd,J=16.4,8.0Hz,3H),4.29(s,1H),3.70-3.5 7(m,2H),3.04-2.95(m,2H),2.66-2.59(m,2H),2.45(s,3H),2.40(dd,J= 9.2,8.0Hz,1H),2.33(d,J=4.8Hz,2H),2.17-1.97(m,5H),1.91(dd,J=16. 4,6.8Hz,4H),1.76(t,J=8.8Hz,5H),1.70(dd,J=5.2,2.8Hz,1H),1.67-1 .57(m,3H),1.37(d,J=7.2Hz,3H),0.95(s,9H),0.71(s,2H),0.45(s,2H).

[0893] Example 72: Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-(pyrimidin-5-yloxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(3-methylpyrazin-2-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 91)

[0894] Using the synthetic route in Example 31, the first step reaction raw material (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-N-((S)-1-(4-(3-fluoropyridin-4-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide was replaced with (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-4-hydroxy-N-((S)-1-(4-(3-methylpyrazin-2-yl)phenyl)ethyl)pyrrolidine-2-carboxamide to give the title compound (1.20 mg, yield: 18.2%).

[0895] MS m / z(ESI):1114.5[M+H] + .

[0896] 1 H-NMR (400MHz, CD3OD) δ9.10(s,1H),8.84(d,J=2.0Hz,2H),8.48(d,J=8.8Hz,2H),8.12(d,J=7.2Hz,1H),7.56(t,J=8.4Hz,2H),7.45(d,J=8.0H z,2H),6.66(s,1H),5.54(s,1H),5.08(t,J=7.2Hz,1H),4.62(s,2H),4. 57(dd,J=9.2,7.6Hz,1H),4.43-4.33(m,1H),3.88-3.76(m,1H),3.59-3 .50(m,1H),3.06-2.93(m,2H),2.62-2.55(m,5H),2.54-2.48(m,1H),2. 37-2.15(m,4H),2.00(dd,J=10.4,3.6Hz,9H),1.87-1.81(m,4H),1.79- 1.69(m,1H),1.66(d,J=7.2Hz,1H),1.54(d,J=7.2Hz,2H),1.39-1.34(m ,1H),1.30(t,J=7.2,3.2Hz,1H),1.08(s,9H),0.93(s,2H),0.77(s,2H).

[0897] Example 73: Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-(pyrimidin-5-yloxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(2-methylpyridin-3-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 80)

[0898] Using the synthetic route in Example 31, the first step reaction raw material (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-N-((S)-1-(4-(3-fluoropyridin-4-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide was replaced with (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-4-hydroxy-N-((S)-1-(4-(2-methylpyridin-3-yl)phenyl)ethyl)pyrrolidine-2-carboxamide to give the title compound (5.60 mg, yield: 38.3%).

[0899] MS m / z(ESI):1113.5[M+H] + .

[0900] 1H-NMR (400MHz, CD3OD) δ9.06 (s, 1H), 8.84 (s, 2H), 8.40 (d, J = 2.4Hz, 1H), 8.07-8.03 (m, 1H), 7.64 (dd, J = 7.6, 1.6Hz, 1H), 7. 40(d,J=8.0Hz,2H),7.35-7.30(m,3H),6.60(d,J=3.6Hz,1H),5.49(s,1H),4.49(s,1H),4.45(s,1H),3.66(s,3H),3.18-3.1 5(m,1H),2.79-2.71(m,1H),2.66-2.54(m,3H),2.46(s,3H),2.42-2.35(m,2H),2.24-2.15(m,2H),2.02(dd,J=13.2,8.0Hz, 6H),1.96-1.90(m,4H),1.82-1.70(m,8H),1.53(d,J=7.2Hz,2H),1.34-1.28(m,1H),1.06(s,9H),0.75(s,2H),0.54(s,2H).

[0901] Example 74: Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-(pyrimidin-5-yloxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(2-chloropyridin-3-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide (Compound 78)

[0902] Using the synthetic route in Example 31, the first step reaction raw material (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-N-((S)-1-(4-(3-fluoropyridin-4-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide was replaced with (2S,4R)-N-((S)-1-(4-(2-chloropyridin-3-yl)phenyl)ethyl)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-4-hydroxypyrrolidine-2-carboxamide to give the title compound (3.50 mg, yield: 18.9%).

[0903] MS m / z(ESI):1133.4[M+H] + .

[0904] 1 H-NMR (400MHz, DMSO-d6) δ9.14(s,1H),8.91(s,2H),8.54(d,J=7.6Hz,1H),8.43(d,J=4.8Hz,1H),8.01(s,1H),7.87(d,J=7.6Hz,1H),7.52(dd ,J=7.6,4.8Hz,1H),7.47-7.42(m,2H),7.38(dd,J=8.4,4.4Hz,2H),6.94(s,2H),6.79(s,1H),5.44(s,1H),5.16(d,J=3.6Hz,1H),4.99-4.90( m,1H),4.47-4.34(m,3H),4.30(s,1H),3.72-3.59(m,2H),3.04-2.94( m,2H),2.66-2.60(m,1H),2.60-2.54(m,1H),2.37-2.31(m,2H),2.29-2 .20(m,1H),2.07-1.85(m,9H),1.78(dd,J=10.0,3.2Hz,5H),1.69-1.5 6(m,3H),1.39(d,J=7.2Hz,3H),0.96(s,9H),0.71(s,2H),0.46(s,2H).

[0905] Example 75: Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-(3-(pyrrolidine-1-carbonyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 110)

[0906] The synthetic route in Example 32 was used to replace the first step reaction raw material methylamine hydrochloride with tetrahydropyrrole to obtain the title compound (5.12 mg, yield: 16.1%).

[0907] MS m / z(ESI):1188.5[M+H] + .

[0908] 1 H-NMR (400MHz, DMSO-d6) δ8.98 (s, 1H), 8.64 (d, J = 2.8Hz, 1H), 8.51 (d, J = 7.6 Hz,1H),7.97(s,1H),7.44(dd,J=8.0,3.6Hz,2H),7.36(d,J=8.4Hz,2H),7.28 (s,1H),6.96(dd,J=6.0,3.6Hz,3H),5.42(s,1H),5.15(d,J=3.6Hz,1H),4.90 (t,J=6.8Hz,1H),4.52-4.38(m,3H),4.28(s,1H),3.94(t,J=6.8Hz,2H),3.62 (t,J=12.0Hz,1H),3.52(t,J=6.8Hz,2H),3.15(dd,J=16.8,3.6Hz,1H),3.00( t,J=10.8Hz,2H),2.76-2.68(m,1H),2.64-2.59(m,1H),2.45(s,3H),2.36(s, 2H),2.11-1.95(m,8H),1.89(dd,J=13.2,6.4Hz,11H),1.78-1.71(m,1H),1.6 3-1.49(m,3H),1.36(d,J=7.2Hz,3H),0.93(s,9H),0.73(s,2H),0.46(s,2H).

[0909] Example 76: Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-(3-(morpholine-4-carbonyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 111)

[0910] The synthetic route in Example 32 was used to replace the first step reaction raw material methylamine hydrochloride with morpholine to obtain the title compound (14.07 mg, yield: 30.2%).

[0911] MS m / z(ESI):1204.5[M+H] + .

[0912] 1 H-NMR (400MHz, DMSO-d6) δ8.98(s,1H),8.66(d,J=2.8Hz,1H),8.51(d,J=7.6Hz,1H),7.97(s,1H),7.44(d,J=8.0Hz,2H),7.36(d,J=8.4Hz,2H),7.2 7(s,1H),6.97(s,2H),6.92(d,J=2.8Hz,1H),5.42(s,1H),5.15(d,J=3.6H z,1H),4.92-4.87(m,1H),4.50(d,J=10.8Hz,1H),4.42(dd,J=14.0,6.0Hz ,2H),4.28(s,1H),3.96-3.92(m,2H),3.67(s,6H),3.03-2.95(m,2H),2.7 3-2.59(m,4H),2.45(s,3H),2.35(d,J=5.6Hz,1H),2.06(dd,J=13.2,7.2H z,3H),2.02-1.95(m,5H),1.87-181(m,7H),1.63-1.49(m,3H),1.36(d,J= 7.2Hz, 3H), 1.05 (t, J = 7.2Hz, 1H), 0.94 (s, 9H), 0.73 (s, 2H), 0.46 (s, 2H).

[0913] Example 77: Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 38)

[0914] The synthetic route in Example 3 was used to replace the first step reaction raw material cyclopropylboronic acid with 1-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole to obtain the title compound (2.8 mg, yield: 7.7%).

[0915] MS m / z(ESI):1149.5[M+H] + .

[0916] 1 H-NMR (400MHz, DMSO-d6) δ8.99(s,1H),8.52(d,J=7.6Hz,1H),8.46(s,1H),8.21(s,1H),8.00(d,J=2.0Hz,1H),7.45-7.42(m,2H),7.36(d,J=8.0Hz ,2H),7.28(s,1H),6.97(s,2H),5.43(s,1H),5.15(d,J=3.6Hz,1H),4.93- 4.88(m,1H),4.44-4.38(m,2H),4.34(dd,J=9.2,4.0Hz,3H),4.28(d,J=0. 8Hz,1H),3.72(t,J=5.2Hz,2H),3.69-3.59(m,2H),3.24(s,3H),3.14(dd, J=15.6,4.0Hz,1H),3.00(d,J=4.4Hz,2H),2.55-2.52(m,1H),2.45(s,3H) ,2.36(s,1H),2.09-1.81(m,15H),1.79-1.71(m,2H),1.68-1.59(m,2H),1 .37(d,J=6.8Hz,3H),1.23(s,1H),0.95(s,9H),0.71(s,2H),0.45(s,2H).

[0917] Example 78: Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-(1-methyl-1H-pyrazol-3-yl)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 40)

[0918] The synthetic route in Example 3 was used to replace the first step reaction raw material cyclopropylboronic acid with 1-methylpyrazole-3-boronic acid pinacol ester to obtain the title compound (16.8 mg, yield: 32.1%).

[0919] MS m / z(ESI):1105.4[M+H] + .

[0920] 1H-NMR (400MHz, DMSO-d6) δ8.98(s,1H),8.52(d,J=7.6Hz,1H),7.98(s,1H),7.86(d,J=2.0Hz,1H),7.45-7.42(m,2H),7.36(d,J=8.0 Hz,2H),7.26(s,1H),6.97(s,2H),6.91(d,J=2.0Hz,1H),5.43(s,1H),5.15(d,J=3.6Hz,1H),4.91(t,J=7.2Hz,1H),4.45-4.36(m,3H ),4.28(s,1H),3.95(s,3H),3.70-3.59(m,2H),3.16(dd,J=15.6,3.2Hz,1H),3.00(t,J=10.4Hz,2H),2.74-2.58(m,4H),2.45(s,3H) ,2.34(dd,J=12.0,5.2Hz,2H),2.07-1.81(m,14H),1.66-1.56(m,2H),1.37(d,J=6.8Hz,3H),0.94(s,9H),0.71(s,2H),0.44(s,2H).

[0921] Example 79: Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-(pyrimidin-5-yloxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 69)

[0922] Using the synthetic route in Example 31, the first step reaction raw material (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-N-((S)-1-(4-(3-fluoropyridin-4-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide was replaced with (2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide to give the title compound (3.20 mg, yield: 4.9%).

[0923] MS m / z(ESI):1105.5[M+H] + .

[0924] 1 H-NMR(400MHz,DMSO-d6)δ9.14(s,1H),8.98(s,1H),8.91(s,2H),8.51(d,J =7.6Hz,1H),7.92(s,1H),7.44(d,J=8.0Hz,2H),7.35(d,J=8.0Hz,2H),6.9 3(s,1H),6.77(s,1H),5.19(dd,J=8.4,7.2Hz,2H),4.92-4.87(m,1H),4.41 -4.34(m,3H),4.32-4.28(m,1H),3.75(dd,J=10.8,4.0Hz,1H),3.63(dd,J= 10.8,1.2Hz,1H),3.02-2.96(m,2H),2.45(s,3H),2.08-1.94(m,6H),1.92- 1.84(m,4H),1.83-1.73(m,6H),1.66-1.55(m,3H),1.36(d,J=6.8Hz,3H),1 .23(s,3H),1.08-1.04(m,1H),1.02(d,J=6.4Hz,3H),0.95(dd,J=6.0,3.2H z, 1H), 0.88-0.82 (m, 1H), 0.70 (s, 2H), 0.61 (d, J = 6.4Hz, 3H), 0.45 (s, 2H).

[0925] Example 80: Preparation of (2S,4R)-1-((S)-2-(4-(1-((1-(((2-((S)-2-amino-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazol]-3'-yl)-6-(pyrimidin-5-yloxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-(1-(4-(4-methylthiazol-5-yl)phenyl)cyclopropyl)pyrrolidine-2-carboxamide (Compound 70)

[0926] Using the synthetic route in Example 31, the first step reaction raw material (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-N-((S)-1-(4-(3-fluoropyridin-4-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide was replaced with (2S,4R)-1-((S)-3,3-dimethyl-2-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)butanoyl)-4-hydroxy-N-(1-(4-(4-methylthiazol-5-yl)phenyl)cyclopropyl)pyrrolidine-2-carboxamide to give the title compound (1.90 mg, yield: 6.1%).

[0927] MS m / z(ESI):1131.5[M+H] + .

[0928] 1 H-NMR(400MHz,DMSO-d6)δ9.14(s,1H),8.95(s,1H),8.90(s,3H),8.05(s,1H),7.33(d,J=8.4Hz,4H),6.9 4(s,2H),6.78(s,1H),5.44(s,1H),5.18(d,J=3.6Hz,1H),4.42-4.35(m,4H),3.73(dd,J=10.8,3.6Hz,1H ),3.63(d,J=10.8Hz,1H),3.02-2.96(m,2H),2.43(s,3H),2.33(d,J=3.2Hz,2H),2.05-1.96(m,4H),1.91 -1.73(m,10H),1.71-1.57(m,4H),1.23(s,4H),1.21-1.11(m,3H),0.94(s,9H),0.70(s,2H),0.45(s,2H).

[0929] Biological Examples:

[0930] Experimental Example 1: Compound degradation test of KRAS-G12D protein in cells

[0931] ●Test system and parameters:

[0932] Cells: Human colon cancer cell line GP2D

[0933] Protein quantification: Pierce TM BCA Protein Assay Kit (Thermofisher)

[0934] Protein electrophoresis: Electrophoresis tank (Thermo) 180V constant voltage electrophoresis

[0935] Protein transfer: transfer tank (BIO-RAD) 300mA constant flow transfer

[0936] ●Test steps

[0937] (1) Compound-treated cells

[0938] The cells were plated in six-well plates with 1.5 × 10 cells per well. 6 Cells were cultured overnight and treated with compounds (at concentrations of 0, 50, and 500 nM) for 24 h.

[0939] (2) Sample processing

[0940] 1) Discard the culture medium and add 2 ml of PBS to wash the cells. Discard the wash buffer and add an appropriate amount of lysis buffer (CST, 9803). Lyse the cells on ice for 30 minutes. Centrifuge at 12,000 rpm for 10 minutes at 4°C and remove the supernatant.

[0941] 2) Referring to the BCA kit instructions, prepare 40 μL of the standard protein concentration (2 mg / mL) and lysate in a 1:1 gradient dilution to 1, 0.5, 0.25, 0.125, and 0.0625 mg / mL. Add 10 μL of the sample supernatant dilution and the standard protein dilution to each well of a 96-well plate. Add 200 μL of a 50:1 mixture of reagents A and B to each well. Incubate at 37°C with shaking for 30 minutes, then measure the OD at 562 nm. Fit the standard curve, calculate the sample concentration based on the curve, and adjust the samples to the same concentration.

[0942] 3) Add 5X SDS loading buffer (Biyuntian, P0015L) to the sample and denature the protein at 100°C for 10 minutes.

[0943] (3) Protein separation, transfer, and development

[0944] 1) Protein samples were separated by electrophoresis at 180 V using NuPAGE 4-12% gradient protein precast gels (Thermofisher). The gels were transferred to membranes using a transfer tank at 4°C and 300 mA for 90 minutes and blocked with 5% skim milk powder for 1 hour.

[0945] 2) Use Ras (G12D mutation-specific) antibody (CST, 14429) and α-Tubulin antibody (CST, 2125S) diluted according to the antibody instructions and incubated with the membrane overnight at 4°C. Wash three times with TBST, 10 minutes each. Use goat anti-rabbit HRP secondary antibody (CST, 7074) diluted according to the antibody instructions and incubated with the membrane for 1 hour at room temperature. Wash three times with TBST, 10 minutes each.

[0946] 3) The membrane was immersed in ECL luminescent solution (Millipore\WBKLS0500) and the fluorescence signal was collected using a Bio-rad gel imager.

[0947] Data processing

[0948] The result images were quantified using Image J software, and the degradation rate of KRAS G12D protein was calculated by comparing with the control group without compound addition. The calculation formula is as follows:

[0949] Degradation rate (%) = (1-(experimental group KRAS-G12D gray level / experimental group α-Tubulin gray level) / (control group KRAS-G12D gray level / control group α-Tubulin gray level)) × 100%

[0950] Test results

[0951] The degradation effect of the compound on KRAS G12D protein in GP2D cells was determined according to the above method. The results are shown in Table 1-1.

[0952] Table 1-1. Degradation rate of KRAS G12D protein by compounds

[0953] ●Test conclusion

[0954] The compound of the present invention exhibits a strong degradation effect on KRAS G12D protein in GP2D cells.

[0955] Test Example 2: Cell proliferation inhibitory activity test of compounds

[0956] ●Test system and procedures

[0957] AsPC-1, GP2D, H358, SK-CO-1, and MKN1 cells were cultured in monolayers in vitro using the following culture conditions: AsPC-1, H358, and MKN1 cells were cultured in RPMI1640 medium supplemented with 10% fetal bovine serum (FBS); GP2D cells were cultured in DMEM medium supplemented with 10% FBS; and SK-CO-1 cells were cultured in MEM medium supplemented with 10% FBS supplemented with 1% non-essential amino acids and 1 mM sodium pyruvate. The cells were cultured in a 37°C CO2 incubator. 2,000 cells were plated per well in 96-well flat-bottom cell culture plates and cultured overnight. The following day, compound dilutions were added. Compounds were diluted to a maximum concentration of 100 μM, and a 4-fold gradient was constructed over nine concentration points. DMSO was used as a control. The final DMSO concentration in the cell culture medium was 1%.

[0958] The compounds were incubated with AsPC-1 cells, GP2D cells, SK-CO-1 cells, H358 cells, and MKN1 cells in a carbon dioxide incubator at 37°C for 5 days, and then the relative chemiluminescence units (RLU) were read using the CellCounting-LiteTM 2.0 reagent (Nanjing Novozymes) in the chemiluminescence detection mode of a microplate reader.

[0959] Data processing

[0960] The percentage inhibition rate of compounds at different concentrations was calculated according to the following formula:

[0961] Percent inhibition rate = (1-(chemiluminescent signal value of the test compound-chemiluminescent signal value of the blank control) / (chemiluminescent signal value of the negative control-chemiluminescent signal value of the blank control))*100%. Graphpad 7.0 was used to fit the curve according to the four-parameter model to calculate the half-maximal inhibitory concentration (IC) of the compound. 50 ).

[0962] Test results

[0963] The proliferation inhibitory activity of the compounds on KRAS mutant cells was determined according to the above method. The results are shown in Table 2-1, Table 2-2 and Table 2-3.

[0964] Table 2-1. Effects of Compounds on KRAS G12D Proliferation inhibitory activity of mutant cells (AsPC-1)

[0965] Table 2-2. Effects of Compounds on KRAS G12D Proliferation inhibitory activity of mutant cells (GP2D)

[0966] Table 2-3. Effects of Compounds on KRAS G12V Proliferation inhibitory activity of mutant cells (SK-CO-1)

[0967] ●Test conclusion

[0968] The compound of the present invention exhibits strong proliferation inhibition activity on KRAS mutant cells.

[0969] The above embodiments do not limit the scope of the present invention in any way. In addition to those described herein, various modifications of the present invention will be apparent to those skilled in the art based on the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in this application (including all patents, patent applications, journal articles, books and any other disclosures) is incorporated herein by reference in its entirety.

Claims

A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein the compound has the structure of formula (I): in, Ring A is C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the cycloalkyl or heterocyclic group is optionally substituted by one or more selected from halogen, C 1-6 Alkyl and C 1-6 Substitution of haloalkyl groups; Ring B is a 3-12 membered nitrogen-containing heterocyclic group; X 1 and X 2 are each independently selected from O and N; X 3 、X 4 and X 5 Each independently selected from CR 7 and N; L is a covalent bond, or is selected from O, S and NR 8 ; L 1 Selected from O, S and NR 9 ; L 2 is a covalent bond, or is selected from C 1-6 Alkylene and halogenated C 1-6 alkylene; L 3 is a covalent bond, or is selected from C 1-6 Alkylene and halogenated C 1-6 alkylene; L 4 is a covalent bond, or is selected from O, NR 10 、C 1-6 Alkylene, -OC 1-6 Alkylene-, -C 1-6 Alkylene-O-, -C 1-6 Alkylene-NR 10 -、-C 1-6 Alkylene-OC 1-6 Alkylene-, C 3-6 Cycloalkyl and 3-10 membered heterocyclic groups, wherein the cycloalkyl and heterocyclic groups are optionally substituted by one or more selected from halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Substitution of haloalkyl groups; L 5 Selected from -C(=O)-NR 11 -、-C 1-6 Alkylene-C(=O)-NR 11 - and 5-10 membered heteroaryl, said heteroaryl being optionally substituted by one or more selected from halogen, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Substitution of haloalkyl groups; Each R 1 independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, -OC 3-6 Cycloalkyl and 3-6 membered heterocyclic groups; R 2 Selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 6-10 Aryl, 3-12 membered heterocyclic group, 5-10 membered heteroaryl, -C 1-6 Alkylene-C 3-6 Cycloalkyl, -C 1-6 Alkylene-3-10 membered heterocyclic group and -C 1-6 Alkylene-5-10 membered heteroaryl, wherein the alkyl, cycloalkyl, aryl, heterocyclic and heteroaryl groups are optionally substituted by one or more selected from halogen, hydroxy, amino, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -C 1-6 Alkylene -OH, -OC 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclic group, 5-10 membered heteroaryl, -NR 12a R 12b 、-C 1-6 Alkylene-OC 1-6 Alkyl and -C(=O)-NR 12a R 12b wherein the alkyl, cycloalkyl, phenyl, heterocyclic and heteroaryl groups in the substituents are optionally further substituted with one or more halogen, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -C 1-6 Alkylene -OH, -OC 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, phenyl, 3-10 membered heterocyclic group, 5-10 membered heteroaryl, -NR 12a R 12b 、-C 1-6 Alkylene-OC 1-6 Alkyl and -C(=O)-NR 12a R 12b Substituents substituted; Preferably, R 2 Selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 6-10 Aryl, 3-12 membered heterocyclic group and 5-10 membered heteroaryl, wherein the alkyl, cycloalkyl, aryl, heterocyclic group and heteroaryl are optionally substituted by one or more selected from halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -C 1-6 Alkylene -OH, -OC 1-6 Haloalkyl and -C(=O)-NR 12a R 12b Substituents substituted; R 3 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-6 Cycloalkyl; R 4a and R 4b are each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkylene -OH and C 3-6 Cycloalkyl; or R 4a and R 4b Together with the carbon atoms connected to form C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; R 5 is selected from halogen, phenyl and 5-6 membered heteroaryl, wherein the phenyl and heteroaryl are optionally substituted by one or more selected from halogen, hydroxy, cyano, C 1-6 Alkyl and C 1-6 Substitution of haloalkyl groups; Each R 6 are independently selected from hydrogen, halogen, hydroxyl, C 1-6 Alkyl and C 1-6 haloalkyl; or R 5 and adjacent R 6 and the carbon atoms to which they are connected together form a benzene ring or a 5-6 membered heteroaromatic ring, wherein the benzene ring and the heteroaromatic ring are optionally substituted by one or more selected from halogen, C 1-6 Alkyl and C 1-6 Substitution of haloalkyl groups; Each R 7 are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy and C 1-6 Haloalkyl-O-; R 8 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-6 Cycloalkyl; R 9 Selected from hydrogen and C 1-6 alkyl; R 10 Selected from hydrogen and C 1-6 alkyl; R 11 Selected from hydrogen and C 1-6 alkyl; R 12a and R 12b are each independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, -C 1-6 Alkylene -OH and -C 1-6 Alkylene-OC 1-6 Alkyl, or R 12a and R 12b The nitrogen to which it is connected forms a 3-6 membered nitrogen-containing heterocyclic group; m is selected from 0, 1, 2, 3, 4, 5 and 6; n is selected from 0, 1, 2, 3 and 4. The compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, wherein the compound has the structure of Formula (II-A), Formula (II-B), Formula (II-C) or Formula (II-D): Among them, ring A, ring B, R 2 、R 3 、R 4a 、R 4b 、R 5 、R 6 ,L,L 1 、L 2 、L 3 、L 4 、L 5 and n as defined in claim 1. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, wherein L 1 It is -O-. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, wherein: L 2 C 1-3 Alkylene, L 3 C 1-3 Alkylene, Ring A is C 3-6 Cycloalkyl; Preferably, L 2 -CH2-, L 3 is -CH2-, ring A is C 3-6 Cycloalkyl; More preferably, L 2 -CH2-, L 3 is -CH2-, and ring A is cyclopropyl. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, wherein: Ring B is a 4-8 membered nitrogen-containing monoheterocyclic group; Preferably, ring B is a 4-6 membered nitrogen-containing monoheterocyclic group; Preferably, ring B is azetidinyl or piperidinyl; More preferably, ring B is The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, wherein L 4 It is a covalent bond. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, wherein: L 5 is a 5-10 membered heteroarylene group; Preferably, L 5 is a 5-6 membered heteroarylene group; Preferably, L 5 is a 5-6 membered nitrogen-containing heteroarylene group; Preferably, L 5 It is a triazole subunit; More preferably, L 5 for The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, wherein: R 3 C 1-6 alkyl; Preferably, R 3 C 3-6 alkyl; Preferably, R 3 is tert-butyl or isopropyl. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, wherein: R 4a and R 4b are each independently selected from hydrogen, C 1-3 Alkyl, -C 1-3 Alkylene -OH and C 3-6 Cycloalkyl; or R 4a and R 4b Together with the carbon atoms connected to form C 3-6 Cycloalkyl; Preferably, R 4a and R 4b are each independently selected from hydrogen and C 1-3 Alkyl; or R 4a and R 4b Together with the carbon atoms connected to form C 3-6 Cycloalkyl; Preferably, R 4a and R 4b are each independently selected from hydrogen, methyl and hydroxymethyl; or R 4a and R 4b Together with the carbon atom to which they are attached, they form a cyclopropyl or cyclobutyl group; More preferably, R 4a is selected from hydrogen and methyl, R 4b is methyl; or R 4a and R 4b Together with the carbon atom to which they are attached, they form a cyclopropyl group. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, wherein: R 5 phenyl and 5-6 membered heteroaryl, wherein the phenyl and heteroaryl are optionally substituted by one or more selected from halogen, hydroxy, cyano, C 1-4 Alkyl and C 1-4 Substitution of haloalkyl groups; Preferably, R 5 is selected from phenyl and 5-6 membered heteroaryl, wherein the phenyl and heteroaryl are optionally substituted by one or more selected from halogen and C 1-4 Substitution of alkyl groups; Preferably, R 5 is selected from phenyl, thiazolyl, oxazolyl, pyrazolyl, pyrazinyl, pyridinyl and pyrimidinyl, wherein the phenyl, thiazolyl, oxazolyl, pyrazolyl, pyrazinyl, pyridinyl and pyrimidinyl are optionally substituted with one or more substituents selected from fluoro, chloro, hydroxy, cyano, methyl, ethyl, isopropyl and trifluoromethyl; Preferably, R 5 is selected from phenyl, thiazolyl, pyrazinyl, pyridinyl and pyrimidinyl, wherein the phenyl, thiazolyl, pyrazinyl, pyridinyl and pyrimidinyl are optionally substituted with one or two substituents selected from fluoro, chloro and methyl; Preferably, R 5 Selected from The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, wherein: R 6 selected from hydrogen and fluorine; n is selected from 0 and 1; Preferably, the fragment Selected from The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, wherein: L is a covalent bond, or selected from -O- and -NR 8 -; R 8 Selected from hydrogen and C 1-3 alkyl. Preferably, L is a covalent bond, or is selected from -O-, -NH- and -N(CH3)-. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, wherein: R 2 Selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, phenyl, 3-10 membered heterocyclic group, 5-10 membered heteroaryl, -C 1-6 Alkylene-C 3-6 Cycloalkyl, -C 1-6 Alkylene-3-10 membered heterocyclic group and -C 1-6 Alkylene-5-10 membered heteroaryl, wherein the alkyl, cycloalkyl, phenyl, heterocyclic and heteroaryl groups are optionally substituted by one or more selected from halogen, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -C 1-6 Alkylene -OH, -OC 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, phenyl, 3-10 membered heterocyclic group, 5-10 membered heteroaryl, -NR 12a R 12b 、-C 1-6 Alkylene-OC 1-6 Alkyl and -C(=O)-NR 12a R 12b wherein the alkyl, cycloalkyl, phenyl, heterocyclic and heteroaryl groups in the substituents are optionally further substituted with one or more halogen, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -C 1-6 Alkylene -OH, -OC 1- 6 haloalkyl, C 3-6 Cycloalkyl, phenyl, 3-10 membered heterocyclic group, 5-10 membered heteroaryl, -NR 12a R 12b 、-C 1-6 Alkylene-OC 1-6 Alkyl and -C(=O)-NR 12a R 12b Substituents substituted; R 12a and R 12b are each independently selected from hydrogen, C 1-3 Alkyl, C 3-6 Cycloalkyl, -C 1-3 Alkylene -OH and -C 1-3 Alkylene-OC 1-3 Alkyl, or R 12a and R 12b The nitrogen to which it is connected forms a 3-6 membered nitrogen-containing heterocyclic group; Preferably, R 2 Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, phenyl, 3-10 membered heterocyclic group, 5-10 membered heteroaryl, -C 1- 6-alkylene-C 3-6 Cycloalkyl and -C 1-6 Alkylene-3-10 membered heterocyclic group, wherein the alkyl, cycloalkyl, phenyl, heterocyclic group and heteroaryl are optionally substituted by one or more selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -C 1-6 Alkylene-OH, C 3-6 Cycloalkyl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl, -NR 12a R 12b 、-C 1-6 Alkylene-OC 1-6 Alkyl and -C(=O)-NR 12a R 12b wherein the alkyl, cycloalkyl, phenyl, heterocyclic and heteroaryl groups in the substituents are optionally further selected from 3-10 membered heterocyclic groups and -C(=O)-NR 12a R 12b Substituents substituted; R 12a and R 12b are each independently selected from hydrogen, C 1-3 Alkyl, -C 1-3 Alkylene -OH and -C 1-3 Alkylene-OC 1-3 Alkyl, or R 12a and R 12b The nitrogen to which it is connected forms a 3-6 membered nitrogen-containing heterocyclic group; Preferably, R 2 Selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, phenyl, 3-10 membered heterocyclic group and 5-10 membered heteroaryl, wherein the alkyl, cycloalkyl, phenyl, heterocyclic group and heteroaryl are optionally substituted by one or more selected from halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -C 1-6 Alkylene -OH, -OC 1-6 Haloalkyl and -C(=O)-NR 12a R 12b Substituents substituted; R 12a and R 12b are each independently selected from hydrogen, C 1-3 Alkyl, C 3-6 Cycloalkyl, -C 1-3 Alkylene -OH and -C 1-3 Alkylene-OC 1-3 alkyl; Preferably, R 2 Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, phenyl, 3-10 membered heterocyclic group and 5-10 membered heteroaryl, wherein the alkyl, cycloalkyl, phenyl, heterocyclic group and heteroaryl are optionally substituted by one or more selected from halogen, amino, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -C 1-6 Alkylene -OH and -C(=O)-NR 12a R 12b Substituents substituted; R 12a and R 12b are each independently selected from hydrogen, C 1-3 Alkyl, -C 1-3 Alkylene -OH and -C 1-3 Alkylene-OC 1-3 alkyl; Preferably, R 2 Selected from hydrogen, Preferably, fragment-LR 2 Selected from hydrogen, A compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein the compound has a structure of Formula (III-A), Formula (III-B), Formula (III-C), or Formula (III-D): Among them, ring A, ring B, R 2 、R 3 、R 4a 、R 4b 、R 5 、R 6 ,L,L 1 , L 2 , L 3 , L 4 , L 5 and n is as defined in any one of claims 1 to 13; Preferably, the compound has the structure of Formula (IV-A), Formula (IV-B), Formula (IV-C) or Formula (IV-D): Among them, ring A, ring B, R 2 、R 3 、R 4a 、R 4b 、R 5 、R 6 ,L,L 1 , L 2 , L 3 , L 4 , L 5 and n is as defined in any one of claims 1-13. The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein the compound is selected from: A pharmaceutical composition comprising a prophylactically and / or therapeutically effective amount of a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, and one or more pharmaceutically acceptable carriers. Use of the compound according to any one of claims 1 to 15 or its pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug, or the pharmaceutical composition according to claim 16 in the preparation of a medicament for preventing and / or treating KRAS-mediated related diseases such as tumors or cancer. The method for preparing the compound of formula (II-A) is shown in Scheme 1: Route 1 Among them, ring A, ring B, R 2 、R 3 、R 4a 、R 4b 、R 5 、R 6 ,L,L 1 , L 2 , L 3 , L 4 , L 5 and n is as defined in any one of claims 1 to 15; LG 1 LG 2 and LG 3 each independently represents a leaving group, such as a halogen, a triflate, a toluenesulfonate, or a methanesulfonate; The method comprises the following steps: 1) reacting compound II-A1 with compound II-A2 to obtain compound II-A3; 2) reacting compound II-A3 with compound II-A4 to obtain compound II-A5; 3) Compound II-A5 is reacted with 3 The reagent of the group is reacted to obtain compound II-A6; 4) reacting compound II-A6 with compound II-A7 to obtain compound II-A8; and 5) subjecting compound II-A8 to a ring-closure reaction with compound II-A9 to obtain compound II-A; Alternatively, the method is as shown in Route 2: Route 2 Among them, ring A, ring B, R 2 、R 3 、R 4a 、R 4b 、R 5 、R 6 ,L,L 1 , L 2 , L 3 , L 4 , L 5 and n is as defined in any one of claims 1 to 15; LG 1 LG 2 and LG 3 each independently represents a leaving group, such as a halogen, a triflate, a toluenesulfonate, or a methanesulfonate; The method comprises the following steps: 1) reacting compound II-A1 with compound II-A4 to obtain compound II-A3a; 2) reacting compound II-A3a with compound II-A2 to obtain compound II-A5; 3) Compound II-A5 is reacted with 3 The reagent of the group is reacted to obtain compound II-A6; 4) reacting compound II-A6 with compound II-A7 to obtain compound II-A8; and 5) Compound II-A8 and compound II-A9 are subjected to a ring-closure reaction to obtain compound II-A. Alternatively, the method is as shown in Route 3: Route 3 in: Ring A, Ring B, R 2 、R 3 、R 4a 、R 4b 、R 5 、R 6 ,L,L 1 , L 2 , L 3 , L 4 , L 5 and n is as defined in any one of claims 1 to 15; LG 1 LG 2 and LG 3 each independently represents a leaving group, such as a halogen, a triflate, a toluenesulfonate, or a methanesulfonate; The method comprises the following steps: 1) reacting compound II-A1 with compound II-A2 to obtain compound II-A3; 2) reacting compound II-A3 with compound II-A4 to obtain compound II-A5; 3) subjecting compound II-A5 to a ring-closure reaction with compound II-A9 to obtain compound II-A6b; 4) subjecting compound II-A6b to a protection reaction to obtain compound II-A7b; 5) Compound II-A7b is reacted with 3 The reaction is carried out with a reagent of the group to obtain compound II-A8b; 6) reacting compound II-A8b with compound II-A7 to obtain compound II-A9b; and 7) Compound II-A9b is subjected to a deprotection reaction to obtain compound II-A.

Images