Spiro compound, preparation method therefor and use thereof

Abstract

The present invention relates to a spiro compound, 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 same, a preparation method therefor, and a use thereof in the preparation of drugs for preventing or treating KRAS-mediated related diseases.

Description

Spirocyclic compounds, methods of making and uses thereof

[0001] Cross-reference to related applications

[0002] This application is based on and claims priority to CN application No. 202410890471.8, filed on July 4, 2024, and CN application No. 202411978204.2, filed on December 31, 2024, the contents of all of which are incorporated herein by reference in their entirety. TECHNICAL FIELD

[0003] The present application belongs to the field of medicine, and specifically relates to a class of spiro compounds, a preparation method thereof and a use thereof. BACKGROUND

[0004] RAS is a guanine nucleotide-binding protein with GTPase activity, which has an anchoring function on the inner side of the cell membrane. RAS protein can switch between the inactive state of GDP binding and the active state of GTP binding, affecting downstream Raf, PI3K and RalGDS, and other multiple signaling pathways, and regulating protein synthesis, gene transcription, cell growth, differentiation, apoptosis and migration, etc.

[0005] RAS mutation can cause persistent activation of downstream signaling pathways, promoting the occurrence and development of tumors, and RAS mutation mainly occurs in KRAS (about 85%). In KRAS mutant tumor cells, the GTPase activity of KRAS decreases, thereby persistently maintaining in the activated state. KRAS mutation is closely related to the occurrence of lung cancer, pancreatic cancer and colorectal cancer and other cancers.

[0006] Proteolysis-targeting chimeras (PROTAC) is a bifunctional molecule, which has three parts in its structure: (1) a part that binds to the substrate of the target protein; (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, induce the recruitment of E3 ubiquitin ligase to the surface of the target protein, trigger the ubiquitination process and induce the degradation of the target protein. PROTAC has the advantages of wide pharmacological activity, high target selectivity, being applicable to the degradation of difficult-to-drug target proteins, strong degradation efficiency, and maintaining catalytic degradation at low concentrations.

[0007] There is an urgent need in the art to develop KRAS PROTAC with novel structure, good biological activity, safety and effectiveness.

[0008] SUMMARY

[0009] The present invention provides compounds useful as degraders and / or inhibitors of a targeted KRAS protein. The compounds of the present invention belong to the class of PROTACs, one end of which can bind to the target protein, while the high-affinity Cereblon (CRBN) ligand on the other end can recruit the target protein to 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 cancer or a disorder caused by aggregation and / or over-activation of the target protein.

[0010] 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, the compound having the structure of Formula (I):

[0011] wherein,

[0012] Ring A is C 3-6 cycloalkyl or 3-6 membered heterocyclyl, optionally substituted with one or more substituents selected from halogen, C 1-6 alkyl and C 1-6 haloalkyl;

[0013] Ring B is 3-12 membered nitrogen-containing heterocyclyl;

[0014] Ring E is C 6-10 aryl, 5-12 membered heteroaryl, or 3-12 membered heterocyclyl, optionally substituted with one or more substituents selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, oxo (O=), -O-C 1- 6alkyl, -O-C 1-6 haloalkyl and -O-C 3-6 cycloalkyl;

[0015] X 1 and X 2 are each independently selected from O and N;

[0016] X 3 , X 4 and X 5 are each independently selected from CR 3 and N;

[0017] X 6 is selected from CH and N;

[0018] L is a covalent bond, or is selected from O, S and NR 4 ;

[0019] L 1 is selected from O, S and NR 5 ;

[0020] L 2 is selected from C 1-6 alkylene and haloC 1-6 alkylene;

[0021] L 3 is selected from C 1-6 alkylene and haloC 1-6 alkylene;

[0022] L 4 is a covalent bond, or is selected from O, NR 6 , C 1-6 alkylene, -O-C 1-6 alkylene-, -C 1-6 alkylene-O-, -C 1-6 alkylene-O-C 1-6 alkylene-, -C(=O)-, -C(=O)-C 1-6 alkylene- and a 3-12 membered heterocyclyl group, which heterocyclyl group is optionally substituted with one or more substituents selected from halogen, hydroxy, cyano, C 1-6 alkyl, C 1-6 haloalkyl;

[0023] L 5 is a covalent bond, or is selected from O, NR 7 , C 1-6 alkylene, -O-C 1-6 alkylene-, -C 1-6 alkylene-O-, -C 1-6 alkylene-O-C 1-6 alkylene-, -C(=O)-, -C(=O)-C 1-6 alkylene- and a 3-12 membered heterocyclyl group, which heterocyclyl group is optionally substituted with one or more substituents selected from halogen, hydroxy, cyano, C 1-6 alkyl, C 1-6 haloalkyl;

[0024] L 6 is a covalent bond, or is selected from O, NR 8 and -C(=O)-NR 9 -;

[0025] each R 1 is independently selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl and a 3-6 membered heterocyclyl group;

[0026] R 2 is selected from hydrogen, halogen, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10aryl, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, -C 1-6 alkylene-C 3-6 cycloalkyl, -C 1-6 alkylene-3-12 membered heterocyclyl, and -C 1-6 alkylene-5-10 membered heteroaryl, which alkyl, alkylene, cycloalkyl, aryl, heterocyclyl, and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, -O-C 1-6 alkyl, -C 1-6 alkylene-OH, -NR 10a R 10b , -C 1-6 alkylene-O-C 1-6 alkyl, and -O-C 1-6 haloalkyl;

[0027] each R 3 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, and -O-C 1-6 haloalkyl;

[0028] R 4 is selected from the group consisting of hydrogen and C 1-6 alkyl; 1-6 haloalkyl, and C 3-6 cycloalkyl;

[0029] R 5 is selected from the group consisting of hydrogen and C 1-6 alkyl;

[0030] R 6 is selected from the group consisting of hydrogen and C 1-6 alkyl;

[0031] R 7 is selected from the group consisting of hydrogen and C 1-6 alkyl;

[0032] R 8 is selected from the group consisting of hydrogen and C 1-6 alkyl;

[0033] R 9 is selected from the group consisting of hydrogen and C 1-6 alkyl;

[0034] R 10a and R 10b are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, -C1-6 alkylene-OH and -C 1- 6alkylene-O-C 1-6 alkyl, or R 10a and R 10b together with the N to which they are attached form a 3-6 membered nitrogen containing heterocyclyl;

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

[0036] In another aspect, the present application provides a pharmaceutical composition comprising a prophylactically and / or therapeutically effective amount of a compound of the present application 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 application provides a kit comprising a compound of the present application 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 application.

[0038] In another aspect, the present application provides a compound of the present application 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 application, or a kit of the present application, which targets KRAS protein and is used for degrading KRAS protein.

[0039] In another aspect, the present application provides a compound of the present application 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 application, or a kit of the present application, which is used for preventing and / or treating a KRAS-mediated related disease.

[0040] In another aspect, the present application provides use of a compound of the present application 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 application, or a kit of the present application, in the manufacture of a medicament for preventing and / or treating a KRAS-mediated related disease.

[0041] In another aspect, the present application provides a method of preventing and / or treating a KRAS-mediated related disease, comprising administering to a subject in need thereof a prophylactically and / or therapeutically effective amount of a compound of the present application 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 application, or a kit of the present application.

[0042] In another aspect, the present application provides methods of making the compounds of the present application.

[0043] DETAILED DESCRIPTION

[0044] DEFINITIONS

[0045] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. Reference herein to technical terms used herein is intended to refer to the technical terms as commonly understood by those skilled in the art, including variations or substitutions of techniques that are apparent to those skilled in the art. Although the following terms are believed to be well understood by one of ordinary skill in the art, the following definitions are set forth to better clarify the application.

[0046] As used herein, the terms "comprise", "comprising", "have", "having", "include", "including", "contain", "containing", or "involve", and other variations thereof, 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 or branched chain saturated aliphatic hydrocarbon group. For example, as used herein, the term "C 1-6 alkyl" and "C 1-3 alkyl" refer to straight or branched chain groups having 1 to 6 carbon atoms and 1 to 3 carbon atoms, respectively (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, or n-hexyl), which are optionally substituted with 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 resulting from the removal of one hydrogen atom from the corresponding "alkyl" group. For example, as used herein, the term "C 1-6 alkylene" and "C 1-3 alkylene" refer to alkylene groups having 1 to 6 carbon atoms and 1-3 carbon atoms, respectively, such as methylene (-CH2-), ethylene (-CH2CH2-), i-propylene (-CH(CH3)CH2-), which are optionally substituted with 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 chain aliphatic hydrocarbon group having one or more carbon-carbon double bonds. For example, the term "C 2-6"Alkenyl" refers to an alkenyl group having from 2 to 6 carbon atoms and one, two, or three (preferably one) carbon-carbon double bonds (such as ethenyl, 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, and the like), which is optionally substituted with 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-chain or branched aliphatic hydrocarbon group having one or more carbon-carbon triple bonds. For example, the term "C 2-6 "Alkynyl" refers to an alkynyl group having from 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, and the like), which is optionally substituted with 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., monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or cyclononyl, or bicyclic, including spiro, fused, or bridged systems, such as bicyclo[l.l.l]pentyl, bicyclo[2.2.l]heptyl, bicyclo[3.2.l]octyl, or bicyclo[5.2.0]nonyl, decahydronaphthyl, and the like), 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 from 3 to 6 ring-forming carbon atoms (e.g., 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 "cycloalkyl" refers to a saturated or partially unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or cyclononyl, or bicyclic, including spiro, fused, or bridged systems, such as bicyclo[l.l.l]pentyl, bicyclo[2.2.l]heptyl, bicyclo[3.2.l]octyl, or bicyclo[5.2.0]nonyl, decahydronaphthyl, and the like), which is optionally substituted with one or more (such as 1 to 3) suitable substituents. For example, the term "C

[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 with one or more (such as 1, 2, or 3) same or different halogen atoms. For example, the term "C 1-6 "Haloalkyl" and "C 1-3Haloalkyl" refers to a haloalkyl group having 1 to 6 carbon atoms and 1 to 3 carbon atoms, for example -CF3, -C2F5, -CHF2, -CH2F, -CH2CF3, -CH2C1, or -CH2CH2CF3.

[0055] As used herein, the term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic ring group (including bridged, fused, or spiro ring systems), e.g., having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms in the ring, e.g., having 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms and one or more (e.g., 1, 2, 3, or 4) heteroatoms independently selected from N, O, or S(O)t(where t is 0, 1, or 2), e.g., 3-12 membered heterocyclyl, 3-8 membered heterocyclyl, 5-12 membered heterocyclyl, 6-12 membered heterocyclyl, 6-10 membered heterocyclyl, 7-12 membered heterocyclyl, 3-7 membered heterocyclyl, 3-6 membered heterocyclyl, 5-6 membered heterocyclyl, 4-8 membered heterocyclyl, etc. Representative examples of heterocyclyl groups (e.g., 3-12 membered heterocyclyl, 4-8 membered heterocyclyl, 6-10 membered heterocyclyl, 5-6 membered heterocyclyl, 3-6 membered heterocyclyl, 3-6 membered nitrogen-containing heterocyclyl, 3-8 membered nitrogen-containing monocyclic heterocyclyl, 5-12 membered nitrogen-containing bridged heterocyclyl, 6-12 membered nitrogen-containing fused heterocyclyl, 7-12 membered nitrogen-containing spiro heterocyclyl, 4-8 membered nitrogen-containing heterocyclyl, 3-12 membered nitrogen-containing heterocyclyl) include, but are not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, or piperazinyl. The ring system in a heterocyclyl group can be a fused, bridged, or spiro system. That is, a heterocyclyl group can be a monocyclic heterocyclyl group, a bridged heterocyclyl group, a fused heterocyclyl group, or a spiro heterocyclyl group. For example, a heterocyclyl group (e.g., 3-12 membered heterocyclyl or 6-10 membered heterocyclyl) of the present application also includes fused ring structures of a heterocyclyl group with a heterocyclyl group, a cycloalkyl group, an aryl group, or a heteroaryl group, including, but not limited to, heterocyclyl fused heterocyclyl, cycloalkyl fused heterocyclyl, aryl fused heterocyclyl, heteroaryl fused heterocyclyl, e.g., 4-7 membered (mono)cyclyl fused 4-7 membered (mono)cyclyl, phenyl fused 4-7 membered (mono)cyclyl (e.g., phenyl fused 5-6 membered (mono)cyclyl), 5-6 membered (mono)heteroaryl fused 4-7 membered (mono)cyclyl, examples of which include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzoimidazolyl, etc. 4-7 (mono)cycloalkyl fused 4-7 membered (mono)cyclyl, phenyl fused 4-7 membered (mono)cyclyl (e.g., phenyl fused 5-6 membered (mono)cyclyl), 5-6 membered (mono)heteroaryl fused 4-7 membered (mono)cyclyl, examples of which include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzoimidazolyl, etc.

[0056] A heterocyclyl group can also be a nitrogen-containing heterocyclyl group, an oxygen-containing heterocyclyl group, or a sulfur-containing heterocyclyl group, etc.

[0057] As used herein, the term "nitrogen-containing heterocyclyl" refers to a heterocyclyl group containing at least one N heteroatom, optionally containing one or more (e.g., 1, 2, 3, or 4) heteroatoms selected from O or S(O)t(where t is 0, 1, or 2), which can include a nitrogen-containing monocyclic heterocyclyl group or a polycyclic heterocyclyl group (e.g., a nitrogen-containing bridged heterocyclyl group, a nitrogen-containing fused heterocyclyl group, a nitrogen-containing spiroheterocyclyl group).

[0058] As used herein, the term "heterocyclyl" refers to a saturated or unsaturated ring radical having from 3 to 12 ring members, preferably 4 to 8 ring members, which contains one or more (e.g., 1, 2, 3, or 4) heteroatoms selected from O, S(O)t(where t is 0, 1, or 2), or N. The term "heterocyclyl" includes a nitrogen-containing heterocyclyl group.

[0059] The term "3-12 membered heterocyclyl" includes 4-8 membered heterocyclyl, 5-6 membered heterocyclyl, 6-10 membered heterocyclyl, 4-8 membered nitrogen-containing heterocyclyl, 3-12 membered nitrogen-containing heterocyclyl, and the like.

[0060] Examples of the term "4-8 membered heterocyclyl" include: and the like.

[0061] The term "6-10 membered heterocyclyl" includes phenylfused 5-6 membered heterocyclyl, and the like. Examples of the term "phenylfused 5-6 membered heterocyclyl" include and the like.

[0062] The term "3-12 membered nitrogen-containing heterocyclyl" includes 3-8 membered nitrogen-containing monocyclic heterocyclyl, 5-12 membered nitrogen-containing bridged heterocyclyl, 6-12 membered nitrogen-containing fused heterocyclyl, and 7-12 membered nitrogen-containing spiroheterocyclyl, and the like.

[0063] Examples of the term "3-8 membered nitrogen-containing monocyclic heterocyclyl" or "4-8 membered nitrogen-containing heterocyclyl" include aziridinyl, azetidinyl, tetrahydropyrrolizinyl, hexahydro-lH-pyrroline, pyrrolidinonyl, pyrrolidinedionyl, imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl, and the like, for example and the like.

[0064] Examples of the term "5-12 membered nitrogen-containing bridged heterocyclyl" include: and the like.

[0065] Examples of the term "6-12 membered nitrogen-containing fused heterocyclyl" include: and the like.

[0066] Examples of the term "7-12 membered nitrogen-containing spiroheterocyclyl" include: and the like.

[0067] As used herein, the term "aryl" or "aromatic ring" refers to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated pi-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 with 1 or more (such as 1, 2, or 3) suitable substituents (e.g., halogen, -OH, -CN, -NO2, or C 1-6 alkyl, etc.).

[0068] 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 3, 4, 5, 6, 7, 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 additionally in each case 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, as well as their benzo derivatives; or pyridyl (ring), pyridazinyl (ring), pyrimidinyl (ring), pyrazinyl (ring), triazinyl (ring), and the like, as well as their benzo derivatives or annelated rings formed by their fusion to one another.

[0069] The term "5-12 membered heteroaryl" includes "6-10 membered heteroaryl", "6-9 membered heteroaryl", 5-10 membered heteroaryl, and the like.

[0070] Examples of the term "6-10 membered heteroaryl" or "6-9 membered heteroaryl" include 6 membered heteroaryl, benzo derivatives of 5-6 membered heteroaryl, and annelated rings formed by the fusion of 5-6 membered heteroaryl to 5-6 membered heteroaryl, and the like, for example

[0071] The term "5-10 membered heteroaryl" includes 5-7 membered heteroaryl, benzo derivatives of 5-6 membered heteroaryl, and annelated rings formed by the fusion of 5-6 membered heteroaryl to 5-6 membered heteroaryl, and the like.

[0072] Examples of the term "5-7 membered heteroaryl" or "5-6 membered heteroaryl" include thienyl (ring), furanyl (ring), pyrrolyl (ring), oxazolyl (ring), thiazolyl (ring), imidazolyl (ring), pyrazolyl (ring), isoxazolyl (ring), isothiazolyl (ring), oxadiazolyl (ring), triazolyl (ring), thiadiazolyl (ring), pyridyl (ring), pyridazinyl (ring), pyrimidinyl (ring), pyrazinyl (ring), triazinyl (ring), and the like, for example and the like.

[0073] The term "6-membered heteroaryl" includes pyridyl (ring), pyridazinyl (ring), pyrimidinyl (ring), pyrazinyl (ring), triazinyl (ring), and the like.

[0074] As used herein, the term "heteroarylene" refers to a divalent radical resulting from the removal of two hydrogen atoms from a "heteroaryl" group.

[0075] The term "substituted" means that one or more (e.g., 1, 2, 3, or 4) hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency 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.

[0076] If a substituent is described as "optionally substituted" then the substituent can be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as optionally substituted with a member of a group of substituents, then one or more hydrogens on the carbon (to the extent there are any hydrogens present) can be replaced with a substituent independently selected from the indicated group or none. If a nitrogen of a substituent is described as optionally substituted with a member of a group of substituents, then one or more hydrogens on the nitrogen (to the extent there are any hydrogens present) can each be replaced with a substituent independently selected from the indicated group or none.

[0077] If a substituent is described as "independently selected from" a group of substituents, then each substituent is selected independently from the other. Thus, each substituent can be the same or different from the other substituent(s).

[0078] As used herein, the term "one or more" means 1 or more than 1, e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10, under reasonable conditions.

[0079] Unless indicated, as used herein, the point of attachment of a substituent can be from any suitable position on the substituent.

[0080] When the bond of a substituent is shown to be through a bond connecting two atoms in a ring, then such substituent can be bonded to either atom in the ring that can be substituted.

[0081] A wavy line as used herein refers to the point of attachment of a group. When a group has two points of attachment, the direction of attachment is not limited unless specifically defined. For example, when ring E is , it can indicate that the left end of the group is attached to L 5 and the right end is attached to L 6 , it can indicate that the left end of the group is attached to L 6 and the right end is attached to L 5Connect. And so on.

[0082] In some embodiments, when a group has two connection sites, they are connected in order of position and orientation of the group in the general formula. For example, in some embodiments, when ring E is... When this is the case, it indicates that the left end of the group is connected to L. 5 Connect, right end to L 6 connect.

[0083] This invention also includes all pharmaceutically acceptable isotopically labeled compounds that are identical to the compounds of this invention, except that one or more atoms are replaced by atoms having the same atomic number but with an atomic mass or mass number different from the dominant atomic mass or mass number in nature. Examples of isotopes suitable for inclusion in the compounds of this invention include, but are not limited to, isotopes of hydrogen (e.g., 2 H, 3 H, deuterium (D), tritium (T); carbon isotopes (e.g., H, deuterium (D), tritium (T)); 11 C 13 C and 14 C); isotopes of chlorine (e.g.) 37 Cl); isotopes of fluorine (e.g., Cl); 18 F); isotopes of iodine (e.g., F); 123 I and 125 I); nitrogen isotopes (e.g.) 13 N and 15 N); isotopes of oxygen (e.g., N); 15 O、 17 O and 18 O); isotopes of phosphorus (e.g., O); phosphorus isotopes ... 32 P); and isotopes of sulfur (e.g. 35 S). Certain isotope-labeled compounds of the present invention (e.g., those doped with radioactive isotopes) can be used in drug and / or substrate tissue distribution studies (e.g., analysis). Radioactive isotope tritium (i.e. 3 H) and carbon-14 (i.e. 14 C) It is particularly suitable for this purpose due to its ease of incorporation and detection. Using positron-emitting isotopes (e.g.) 11 C 18 F, 15 O and 13 Substitution of N) can be used in positron emission tomography (PET) studies to examine substrate acceptor occupancy. The isotopically labeled compounds of the present invention can be prepared by methods similar to those described in the accompanying routes and / or examples and preparations, by using a suitable isotopically labeled reagent instead of the previously used unlabeled reagent. Pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent can be isotopically substituted, for example, D2O, acetone-d6, or DMSO-d6.

[0084] The term "stereoisomers" denotes isomers that have the same molecular formula but different structures, due to the difference in the configuration of one or more asymmetric centers. In compounds with one or more (e.g. 1, 2, 3, or 4) asymmetric centers, they can produce racemic mixtures, single enantiomers, mixtures of diastereomers, and individual diastereomers. A particular individual molecule can also exist as geometric isomers (cis / trans). Similarly, the compounds of the present application can exist as mixtures of two or more structurally distinct forms in rapid equilibrium (often referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, and the like. It is to be understood that the scope of the 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%).

[0085] The present application encompasses all possible crystalline forms or polymorphs of the compounds of the present application, which can be a single polymorph or a mixture of more than one polymorph in any proportion.

[0086] It is also to be understood that certain compounds of the present application can exist in free form for treatment, or, where appropriate, in the form of a pharmaceutically acceptable derivative thereof. In the present application, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, solvates, metabolites, or prodrugs, which, upon administration to a patient in need thereof, are capable of providing, directly or indirectly, a compound of the present application or a metabolite or residue thereof. Accordingly, as referenced herein, reference to "a compound of the present application" is intended to encompass all such derivative forms of the compound.

[0087] Pharmaceutically acceptable salts of the compounds of the present application include acid addition salts and base addition salts. Suitable acid addition salts are formed from acids which form pharmaceutically acceptable salts. Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts. A review of suitable salts can be found in "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of compounds of the present application are known to those skilled in the art.

[0088] The compounds of the present application can exist in the form of solvates (preferably hydrates), wherein the compound of the present application contains a polar solvent, in particular, for example, water, methanol or ethanol, as a structural element of the crystal lattice of the compound. The amount of polar solvent, in particular water, can be present in stoichiometric or non-stoichiometric amounts.

[0089] One skilled in the art will appreciate that not all nitrogen-containing heterocycles are capable of forming N-oxides since nitrogen requires an available lone pair of electrons to oxidize to an oxide; one skilled in the art will recognize which nitrogen-containing heterocycles are capable of forming N-oxides. One 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 the heterocycle or tertiary amine with peroxy acids such as peroxyacetic acid and meta-chloroperoxybenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate and dioxiranes such as dimethyldioxirane. These methods for preparing N-oxides have been extensively described and reviewed in the literature, see for example: T. L. Gilchrist, Comprehensive Organic Synthesis, vol. 7, pp 748-750; A. R. Katritzky and A. J. Boulton, Eds., Academic Press; and G. W. H. Cheeseman and E. S. G. Werstiuk, Advances in Heterocyclic Chemistry, vol. 22, pp 390-392, A. R. Katritzky and A. J. Boulton, Eds., Academic Press.

[0090] Also included within the scope of the application are metabolites of the compounds of the application, i.e., substances formed in vivo upon administration of a compound of the application. Such products can result, for example, from the oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic cleavage, and the like, of the administered compound. Accordingly, the present application includes metabolites of compounds of the application, whether prepared by the methods of the application or otherwise prepared. Metabolite identification and characterization are well known in the art.

[0091] The present application further includes within its scope prodrugs of the compounds of the application, which are certain derivatives of the compounds of the application that have less or no pharmacological activity as such but, when administered into or onto the body, are converted into the compounds of the application having the desired activity, for example, by hydrolytic cleavage. Such prodrugs are typically functionally-derivatized with moieties which are readily cleaved in vivo. For example, see "Pro-drugs as Novel Delivery Systems", Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and "Bioreversible Carriers in Drug Design," Pergamon Press, 1987 (ed. E. B. Roche, American Pharmaceutical Association). Prodrugs of the application can be prepared using methods known to those of ordinary skill in the art (e.g., as described in "Design of Prodrugs", H. Bundgaard (Elsevier, 1985) as the replacement of appropriate functionalities in the compounds of the application 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)).

[0092] The present application also encompasses compounds of the present application that contain protecting groups. During any of the processes for preparation of the compounds of the present application, it can be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules concerned, as well as to protect any of the molecules concerned, thereby forming a chemically protected form of a compound of the present application. This can be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which are incorporated herein by reference. The protecting groups can be removed at a suitable subsequent stage using methods known from the art.

[0093] Unless specifically indicated otherwise, the numerical values in the present application are modified by the term "about". The term "about" means within ±20% of the stated value, preferably within ±10%, more preferably within ±5%, and even more preferably within ±2%.

[0094] Compounds

[0095] The present application provides a compound of Formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof:

[0096] wherein,

[0097] Ring A is C 3-6 cycloalkyl or 3-6 membered heterocyclyl, optionally substituted with one or more substituents selected from halo, C 1-6 alkyl and C 1-6 haloalkyl;

[0098] Ring B is 3-12 membered nitrogen-containing heterocyclyl;

[0099] Ring E is C 6-10 aryl, 5-12 membered heteroaryl or 3-12 membered heterocyclyl, optionally substituted with one or more substituents selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, oxo, -O-C 1-6 alkyl, -O-C 1-6 haloalkyl and -O-C 3-6 cycloalkyl;

[0100] X 1 and X 2 are each independently selected from O and N;

[0101] X 3 , X 4 and X 5 are each independently selected from CR 3 and N;

[0102] X 6 is selected from CH and N;

[0103] L is a covalent bond, or is selected from O, S and NR 4 ;

[0104] L 1 is selected from O, S and NR 5 ;

[0105] L 2 is selected from C 1-6 alkylene and haloC 1-6 alkylene;

[0106] L 3 is selected from C 1-6 alkylene and haloC 1-6 alkylene;

[0107] L 4It is a covalent bond, or selected from O, NR 6 C 1-6 Alkylene, -OC 1-6 alkylene-, -C 1-6 Alkylene -O-, -C 1-6 Alkylene-OC 1-6 Alkylene-, -C(=O)-, -C(=O)-C 1-6 Alkylene and 3-12 membered heterocyclic groups, wherein the heterocyclic group is optionally surrounded by one or more groups selected from halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Substituents of haloalkyl groups;

[0108] L 5 It is a covalent bond, or selected from O, NR 7 C 1-6 Alkylene, -OC 1-6 alkylene-, -C 1-6 Alkylene -O-, -C 1-6 Alkylene-OC 1-6 Alkylene-, -C(=O)-, -C(=O)-C 1-6 Alkylene and 3-12 membered heterocyclic groups, wherein the heterocyclic group is optionally surrounded by one or more groups selected from halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Substituents of haloalkyl groups;

[0109] L 6 It is a covalent bond, or selected from O, NR 8 and -C(=O)-NR 9 -;

[0110] Each R 1 Independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl groups and 3-6 membered heterocyclic groups;

[0111] R 2 Selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 3-6 cycloalkyl, C 6-10 Aryl, 3-12 membered heterocyclic, 5-10 membered heteroaryl, -C 1-6 Alkylene-C 3-6 cycloalkyl, -C 1-6 alkylene-3-12-membered heterocyclic groups and -C 1-6 Alkylene-5-10-membered heteroaryl, wherein the alkyl, alkylene, cycloalkyl, aryl, heterocyclic, and heteroaryl groups are optionally selected from one or more halogens, hydroxyl groups, amino groups, cyano groups, C6 groups, and C7 groups. 1-6 Alkyl, C 3-6 cycloalkyl, C1-6 Halogenated alkyl groups, -OC 1-6 Alkyl, -C 1-6 alkylene-OH, -NR 10a R 10b -C 1-6 Alkylene-OC 1-6 Alkyl and -OC 1-6 Substituents of haloalkyl groups;

[0112] Each R 3 Independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy and -OC 1-6 Halogenated alkyl groups;

[0113] R 4 Selected from hydrogen and C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 3-6 cycloalkyl;

[0114] R 5 Selected from hydrogen and C 1-6 alkyl;

[0115] R 6 Selected from hydrogen and C 1-6 alkyl;

[0116] R 7 Selected from hydrogen and C 1-6 alkyl;

[0117] R 8 Selected from hydrogen and C 1-6 alkyl;

[0118] R 9 Selected from hydrogen and C 1-6 alkyl;

[0119] R 10a and R 10b Each is independently selected from hydrogen and C. 1-6 Alkyl, C 3-6 cycloalkyl, -C 1-6 alkylene -OH and -C 1- 6-alkylene-OC 1-6 Alkyl, or R 10a and R 10b Together with the N connected to it, it forms a 3-6 member nitrogen-containing heterocyclic group;

[0120] m is selected from 0, 1, 2, 3, and 4.

[0121] In some implementations of formula (I),

[0122] Ring A is C 3-6 cycloalkyl or 3-6 membered heterocyclyl, optionally substituted with one or more substituents selected from halo, C 1-6 alkyl and C 1-6 haloalkyl;

[0123] Ring B is 3-12 membered nitrogen-containing heterocyclyl;

[0124] Ring E is C 6-10 aryl, 5-12 membered heteroaryl or 3-12 membered heterocyclyl, optionally substituted with one or more substituents selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, oxo, -O-C 1-6 alkyl, -O-C 1-6 haloalkyl and -O-C 3-6 cycloalkyl;

[0125] X 1 and X 2 are each independently selected from O and N;

[0126] X 3 , X 4 and X 5 are each independently selected from CR 3 and N;

[0127] X 6 is selected from CH and N;

[0128] L is a covalent bond, or is selected from O, S and NR 4 ;

[0129] L 1 is selected from O, S and NR 5 ;

[0130] L 2 is selected from C 1-6 alkylene and haloC 1-6 alkylene;

[0131] L 3 is selected from C 1-6 alkylene and haloC 1-6 alkylene;

[0132] L 4 is a covalent bond, or is selected from O, NR 6 , C 1-6 alkylene, -O-C 1-6 alkylene-, -C 1-6 alkylene-O-, -C 1-6 alkylene-O-C1-6 alkylene-, -C(=0)-, -C(=0)-C 1-6 alkylene- and 3-12 membered heterocyclyl, which is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 haloalkyl;

[0133] L 5 is a covalent bond, or is selected from the group consisting of O, NR 7 , C 1-6 alkylene, -0-C 1-6 alkylene-, -C 1-6 alkylene-0-, -C 1-6 alkylene-0-C 1-6 alkylene-, -C(=0)-, -C(=0)-C 1-6 alkylene- and 3-12 membered heterocyclyl, which is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 haloalkyl;

[0134] L 6 is a covalent bond, or is selected from the group consisting of NR 8 and -C(=0)-NR 9 -;

[0135] each R 1 is independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl and 3-6 membered heterocyclyl;

[0136] R 2 is selected from the group consisting of hydrogen, halogen, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, -C 1-6 alkylene-C 3-6 cycloalkyl, -C 1-6 alkylene-3-12 membered heterocyclyl and -C 1-6 alkylene-5-10 membered heteroaryl, which alkyl, alkylene, cycloalkyl, aryl, heterocyclyl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 1-6 haloalkyl, -0-C 1-6 alkyl, -C 1-6 alkylene-OH, -NR 10a R 10b , -C 1-6 alkylene-0-C 1-6 alkyl and -0-C1-6 Substituents of haloalkyl groups;

[0137] Each R 3 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy and -OC 1-6 Halogenated alkyl groups;

[0138] R 4 Selected from hydrogen and C 1-6 Alkyl, C 1-6 Halogenated alkyl and C 3-6 cycloalkyl;

[0139] R 5 Selected from hydrogen and C 1-6 alkyl;

[0140] R 6 Selected from hydrogen and C 1-6 alkyl;

[0141] R 7 Selected from hydrogen and C 1-6 alkyl;

[0142] R 8 Selected from hydrogen and C 1-6 alkyl;

[0143] R 9 Selected from hydrogen and C 1-6 alkyl;

[0144] R 10a and R 10b Each is independently selected from hydrogen and C. 1-6 Alkyl, C 3-6 cycloalkyl, -C 1-6 alkylene -OH and -C 1- 6-alkylene-OC 1-6 Alkyl, or R 10a and R 10b Together with the N connected to it, it forms a 3-6 member nitrogen-containing heterocyclic group;

[0145] m is selected from 0, 1, 2, 3, and 4.

[0146] In some embodiments of the present invention, R 1 It is hydrogen.

[0147] In some embodiments of the present invention, m is 0.

[0148] In some embodiments of the present invention, X 1 For O, X 2 Let N be the number of elements in the array.

[0149] In some embodiments of the application, X 1 is N, X 2 is O.

[0150] In some embodiments of the application, X 3 is N, X 4 is N, X 5 is CH.

[0151] In some embodiments of the application, X 3 is CH, X 4 is N, X 5 is N.

[0152] In some embodiments of the application, the compound of formula (I) above has the structure of formula (II-A), formula (II-B), formula (II-C), or formula (II-D):

[0153] wherein ring A, ring B, ring E, R 2 , L, L 1 , L 2 , L 3 , L 4 , L 5 , L 6 and X 6 are as defined above.

[0154] In some embodiments of the application, L 1 is -O-.

[0155] In some embodiments of the application, L 2 is C 1-3 alkylene.

[0156] In some embodiments of the application, L 2 is -CH2-.

[0157] In some embodiments of the application, L 3 is C 1-3 alkylene.

[0158] In some embodiments of the application, L 3 is -CH2-.

[0159] In some embodiments of the application, ring A is C 3-6 cycloalkyl, optionally substituted with one or more substituents selected from halogen.

[0160] In some embodiments of the application, ring A is C 3-6 cycloalkyl, optionally substituted with one or more fluorine atoms.

[0161] In some embodiments of the application, ring A is C 3-6 cycloalkyl.

[0162] In some embodiments of the application, ring A is selected from cyclopropyl, cyclobutyl, cyclopentyl,

[0163] In some embodiments of the application, ring A is cyclopropyl.

[0164] In some embodiments of the application, L 2 is C 1-3 alkylene, L 3 is C 1-3 alkylene, ring A is C 3- 6 cycloalkyl optionally substituted with one or more substituents selected from halogen.

[0165] In some embodiments of the application, L 2 is C 1-3 alkylene, L 3 is C 1-3 alkylene, ring A is C 3- 6 cycloalkyl.

[0166] In some embodiments of the application, L 2 is -CH2-, L 3 is -CH2-, ring A is C 3-6 6 cycloalkyl optionally substituted with one or more substituents selected from halogen.

[0167] In some embodiments of the application, L 2 is -CH2-, L 3 is -CH2-, ring A is C 3-6 cycloalkyl.

[0168] In some embodiments of the application, L 2 is -CH2-, L 3 is -CH2-, ring A is selected from cyclopropyl, cyclobutyl, cyclopentyl,

[0169] In some embodiments of the application, L 2 is -CH2-, L 3 is -CH2-, ring A is cyclopropyl.

[0170] In some embodiments of the application, ring B is selected from 3-8 membered nitrogen-containing mono heterocyclyl, 5-12 membered nitrogen-containing bridged heterocyclyl, 6-12 membered nitrogen-containing fused heterocyclyl, and 7-12 membered nitrogen-containing spiro heterocyclyl.

[0171] In some embodiments of the application, ring B is

[0172] In some embodiments of the application, ring B is

[0173] In some embodiments of the application, ring B is

[0174] In some embodiments of the application, ring B is

[0175] In some embodiments of the application, ring B is

[0176] In some embodiments of the application, L 4 is a covalent bond, or is selected from O, C 1-3 alkylene, -C(=O)-C 1- alkylene, and 4-8 membered nitrogen-containing heterocyclyl.

[0177] In some embodiments of the application, L 4 is a covalent bond, or is selected from C 1-3 alkylene, -C(=O)-C 1-3 alkylene, and 4-8 membered nitrogen-containing heterocyclyl.

[0178] In some embodiments of the application, L 4 is a covalent bond, or is selected from O, -CH2-, -C(=O)-CH2-,

[0179] In some embodiments of the application, L 4 is a covalent bond, or is selected from -CH2-, -C(=O)-CH2-,

[0180] In some embodiments of the application, L 5 is a covalent bond, or is selected from -C(=O)- and 4-8 membered nitrogen-containing heterocyclyl.

[0181] In some embodiments of the application, L 5 is a covalent bond, or is selected from -C(=O)-,

[0182] In some embodiments of the application, L 5is a covalent bond, or is selected from -C(=O)- and

[0183] In some embodiments of the application, the fragment -L 4 -L 5 - is selected from: a covalent bond, -O-, -C(=O)-,

[0184] In some embodiments of the application, the fragment -L 4 -L 5 - is selected from: a covalent bond, -C(=O)-,

[0185] In some embodiments of the application, the ring E is C 6-10 aryl, 6-10 membered heteroaryl or 6-10 membered heterocyclyl, said phenyl, heteroaryl and heterocyclyl being optionally substituted with one or more substituents selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, oxo, -O-C 1-6 alkyl, -O-C 1-6 haloalkyl and -O-C 3-6 cycloalkyl.

[0186] In some embodiments of the application, the ring E is phenyl, 6-9 membered heteroaryl or phenyl fused 5-6 membered heterocyclyl, said phenyl, heteroaryl and heterocyclyl being optionally substituted with one or more substituents selected from halogen, C 1-3 alkyl, C 1-3 haloalkyl, oxo and -O-C 1-3 alkyl.

[0187] In some embodiments of the application, the ring E is phenyl, 6-9 membered heteroaryl or phenyl fused 5-6 membered heterocyclyl, said phenyl, heteroaryl and heterocyclyl being optionally substituted with one or more substituents selected from halogen, C 1-3 alkyl, oxo and -O-C 1-3 alkyl.

[0188] In some embodiments of the application, the ring E is phenyl, 6-9 membered heteroaryl or phenyl fused 5-6 membered heterocyclyl, said phenyl, heteroaryl and heterocyclyl being optionally substituted with one or more substituents selected from halogen, C 1-3 alkyl, C 1-3 haloalkyl and oxo.

[0189] In some embodiments of the application, the ring E is phenyl, 6-9 membered heteroaryl or phenyl fused 5-6 membered heterocyclyl, said phenyl, heteroaryl and heterocyclyl being optionally substituted with one or more substituents selected from halogen, C1-3 alkyl and oxo.

[0190] In some embodiments of the application, ring E is selected from

[0191] In some embodiments of the application, ring E is selected from

[0192] In some embodiments of the application, ring E is selected from

[0193] In some embodiments of the application, ring E is selected from

[0194] In some embodiments of the application, ring B is -L 4 -L 5 - is a covalent bond, and ring E is

[0195] In some embodiments of the application, ring B is -L 4 -L 5 - is a covalent bond, and ring E is

[0196] In some embodiments of the application, L 6 is a covalent bond, or is selected from NR 8 and -C(=0)-NR 9 -.

[0197] In some embodiments of the application, R 8 is selected from hydrogen and C 1-3 alkyl.

[0198] In some embodiments of the application, R 9 is selected from hydrogen and C 1-3 alkyl.

[0199] In some embodiments of the application, L 6 is a covalent bond, O or NR 8 .

[0200] In some embodiments of the application, L 6 is a covalent bond or NR 8 .

[0201] In some embodiments of the application, R 8 is selected from hydrogen and C1-3 alkyl.

[0202] In some embodiments of the present invention, L 6 It is a covalent bond, O or NH.

[0203] In some embodiments of the present invention, L 6 It is a covalent bond or NH.

[0204] In some embodiments of the present invention, fragments Selected from:

[0205] In some embodiments of the present invention, fragments Selected from:

[0206] In some embodiments of the present invention, fragments Selected from:

[0207] In some embodiments of the present invention, fragments Selected from:

[0208] In some embodiments of the present invention, L is a covalent bond, or is selected from O and NR. 4 .

[0209] In some embodiments of the present invention, R 4 Selected from hydrogen and C 1-3 alkyl.

[0210] In some embodiments of the present invention, L is a covalent bond, O, or NH.

[0211] In some embodiments of the present invention, L represents a covalent bond or O.

[0212] In some embodiments of the present invention, L is O.

[0213] In some embodiments of the present invention, R 2 Selected from hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, C 6-10 Aryl, 4-8 membered heterocyclic, 5-7 membered heteroaryl, -C 1-6 Alkylene-C 3-6 cycloalkyl, -C 1-6 alkylene-4-8-membered heterocyclic groups and -C 1-6alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, -O-C 1-6 alkyl, -C 1-6 alkylene-OH, -NR 10a R 10b , -C 1-6 alkylene-O-C 1-6 alkyl and -O-C 1-6 haloalkyl. 1-6 alkyl, C 1-6 haloalkyl, -O-C 1-6 alkyl, -C 1-6 alkylene-OH, -NR 10a R 10b , -C 1-6 alkylene-O-C 1-6 alkyl and -O-C 1-6 haloalkyl. 10a and R 10b are each independently selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, -C 1-6 alkylene-OH and -C 1-6 alkylene-O-C 1-6 alkyl.

[0214] In some embodiments of the application, R 2 is selected from C 1-6 alkyl and 5-7 membered heteroaryl, which alkyl and heteroaryl are optionally substituted with one or more substituents selected from halo, hydroxy, amino, cyano, C 1-6 alkyl, C 1-6 haloalkyl, -O-C 1-6 alkyl, -C 1-6 alkylene-OH, -C 1-6 alkylene-O-C 1-6 alkyl and -O-C 1-6 haloalkyl.

[0215] In some embodiments of the application, R 2 is selected from hydrogen,

[0216] In some embodiments of the application, R 2 is selected from hydrogen,

[0217] In some embodiments of the application, R 2 is selected from hydrogen,

[0218] In some embodiments of the application, R 2 is selected from

[0219] In some embodiments of the application, the fragment -L-R 2 is selected from hydrogen,

[0220] In some embodiments of the application, the fragment -L-R 2 is selected from hydrogen,

[0221] In some embodiments of the application, the fragment -L-R 2 is selected from hydrogen,

[0222] In some embodiments of the application, the fragment -L-R 2 is selected from

[0223] In some embodiments of the application, the above compounds have the structure of Formula (III-A), Formula (III-B), Formula (III-C), or Formula (III-D):

[0224] wherein ring A, ring B, ring E, R 2 , L, L 1 , L 2 , L 3 , L 4 , L 5 , L 6 and X 6 are as defined above.

[0225] The present application encompasses compounds resulting from any combination of the various embodiments. Embodiments resulting from the combination of a technical feature or preferred technical feature in one embodiment with a technical feature or preferred technical feature in another embodiment are also within the scope of the present application.

[0226] In some embodiments of the compound of Formula (I), the compound of Formula (I) is selected from: Advantages

[0227] The compound provided by the present disclosure can achieve at least one of the following technical effects:

[0228] (1) can target KRAS protein;

[0229] (2) can effectively degrade or inhibit KRAS protein (such as KRAS mutant protein, for example KRAS-G12D, etc.);

[0230] (3) can effectively inhibit the proliferation of KRAS mutant cells;

[0231] (4) excellent physicochemical properties (such as solubility, physical and / or chemical stability);

[0232] (5) excellent pharmacokinetic properties (such as good bioavailability, appropriate half-life and duration of action);

[0233] (6) excellent safety (lower toxicity and / or fewer side effects, wider therapeutic window), etc.

[0234] Preparation method

[0235] The compound of formula (II-A) of the present application can be prepared by the method shown in Route 1 as follows:

[0236] Route 1

[0237] wherein:

[0238] ring A, ring B, ring E, R 2 , L, L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , and X 6 are as defined above;

[0239] LG 1 , LG 2 , and LG 3 each independently represents a leaving group, for example halogen, triflate, tosylate or mesylate; or,

[0240] when L 3 is C 1-3 alkylene, LG 3with L 3 and LG 3 together form a carbonyl group;

[0241] The method comprises the following steps:

[0242] (1) reacting compound II-A1 with compound II-A2 to obtain compound II-A3;

[0243] (2) reacting compound II-A3 with compound II-A4 to obtain compound II-A5; or, subjecting compound II-A3 to a dehalogenation reaction to obtain compound II-A5;

[0244] (3) subjecting compound II-A5 to a ring closure reaction with compound II-A5a to obtain compound II-A6;

[0245] (4) subjecting compound II-A6 to an upper protection reaction to obtain compound II-A7;

[0246] (5) reacting compound II-A7 with a reagent containing a -LG 3 group to obtain compound II-A8; or, subjecting compound II-A7 to an oxidation reaction to obtain compound II-A8;

[0247] (6) reacting compound II-A8 with compound II-A9 to obtain compound II-A10, and

[0248] (7) subjecting compound II-A10 to a deprotection reaction to obtain compound II-A.

[0249] The reaction of step (1) is preferably carried out in a suitable organic solvent and in the presence of a suitable base. The organic solvent can 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 can 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 0-100°C for 0.5-48 hours.

[0250] The reaction of above step (2) is preferably carried out in a suitable organic solvent and in the presence of a suitable base. The organic solvent can be selected from acetonitrile, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, tetrahydrofuran, 1,4-dioxane and any combination thereof, preferably acetonitrile or tetrahydrofuran. The base can 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 in the range of 20 °C to 120 °C for 2 to 48 hours. Alternatively, the reaction of above 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, for example selected from tris(dibenzylideneacetone)dipalladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium, [n-butyldi(1-adamantyl)phosphine]methanesulfonic acid (2-amino-1,1'-biphenyl-2-yl)palladium(II), tetrakis(triphenylphosphine)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 in the range of 20 °C to 120 °C for 2 to 16 hours. Alternatively, the reaction of above step (2) is preferably carried out in a suitable solvent and in the presence of a metal catalyst, a base and a suitable reagent. The metal catalyst is a palladium metal catalyst, for example selected from tris(dibenzylideneacetone)dipalladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium, [n-butyldi(1-adamantyl)phosphine]methanesulfonic acid (2-amino-1,1'-biphenyl-2-yl)palladium(II), tetrakis(triphenylphosphine)palladium and palladium acetate, preferably palladium acetate. The base can be an organic base or an inorganic base, for example selected from potassium fluoride, potassium carbonate, potassium phosphate, cesium fluoride, cesium carbonate and sodium carbonate, preferably potassium fluoride. The suitable reagent is polymethylhydrosiloxane. The solvent can be selected from tetrahydrofuran, ethanol, ethylene glycol dimethyl ether, water, 1,4-dioxane and any combination thereof, preferably a combination of tetrahydrofuran and water. The reaction is preferably carried out at a temperature in the range of 0 °C to 100 °C for 0.5 to 16 hours.

[0251] The ring-closing reaction in step (3) above 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 may be selected from morpholine, ammonium acetate, diethylamine, triethylamine, L-proline, sulfur powder, and any combination thereof, preferably a combination of ammonium acetate and sulfur powder. The reaction is preferably carried out at a temperature of 0-100°C for 1-20 hours, for example, 1-12 hours.

[0252] The reaction in step (4) above is preferably carried out in a suitable organic solvent and 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.

[0253] The reaction in step (5) above is preferably carried out in a suitable organic solvent and contains -LG. 3 The process is carried out in the presence of a reagent containing the -LG group and a base. 3 The reagent for the functional 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, or any combination thereof, preferably dichloromethane. The reaction is preferably carried out at a temperature of 0-40°C for 2-16 hours. Alternatively, the reaction in step (5) above is preferably carried out in a suitable organic solvent and in the presence of an oxidizing agent. The oxidizing agent can be selected from Des Martin oxidant, pyridine chlorochromate, or pyridine dichromate, preferably Des Martin oxidant. The organic solvent can be selected from tetrahydrofuran, dichloromethane, toluene, 1,2-dichloroethane, or any combination thereof, preferably dichloromethane. The reaction is preferably carried out at a temperature of 0-40°C for 2-16 hours.

[0254] The reaction of above 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 can be selected from potassium carbonate or cesium carbonate, preferably potassium carbonate. The inorganic salt can be selected from potassium iodide or sodium iodide, preferably potassium iodide. The organic solvent can be selected from acetonitrile, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, tetrahydrofuran, 1,4-dioxane and any combination thereof, preferably acetonitrile. The reaction is preferably carried out at a temperature in the range of 25-100 °C for 2-16 hours. Alternatively, the reaction of above step (6) is preferably carried out in a suitable organic solvent and in the presence of a suitable reducing agent and a suitable reagent. The organic solvent can be selected from dichloromethane, tetrahydrofuran, acetonitrile, methanol, N,N-dimethylformamide, dimethylsulfoxide, isopropanol and any combination thereof, preferably dimethylsulfoxide. The reducing agent can be selected from sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride and 2-methylpyridine borane, preferably sodium triacetoxyborohydride. The suitable reagent can be selected from tetraethyl orthotitanate, tetraisopropyl orthotitanate, acetic acid and formic acid, preferably tetraethyl orthotitanate. The reaction is preferably carried out at a temperature in the range of 0-90 °C for 1-12 hours.

[0255] The deprotection reaction of above step (7) is preferably carried out in a suitable organic solvent and in the presence of a suitable deprotecting reagent. The organic solvent can be selected from methanol, ethanol, isopropanol, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, tetrahydrofuran and any combination thereof, preferably tetrahydrofuran. The deprotecting reagent can 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 in the range of 0-100 °C for 1-12 hours.

[0256] when L 4 is a covalent bond and L 5 is -C(=O)-, the compound of formula (II-A) of the present application can be prepared by the method shown in Scheme 2 as follows:

[0257] Scheme 2

[0258] wherein:

[0259] ring A, ring B, ring E, R 2 , L, L 1 , L 2 , L 3 , L 6 and X 6 are as defined above;

[0260] LG 1 , LG 2 and LG 3each independently represents a leaving group, for example, halogen, triflate, tosylate or mesylate; or,

[0261] when L 3 is C 1-3 alkylene, LG 3 and the carbon to which L 3 G 3 are attached together form a carbonyl group;

[0262] PG 1 represents a protecting group, for example, an alkoxycarbonyl amino protecting group such as carbobenzyloxy (Cbz), tert-butoxycarbonyl (Boc), formyloxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), meth(o)xy carbonyl; an acyl amino protecting group such as phthaloyl (Pht), p-toluenesulfonyl (Tos), trifluoroacetyl (Tfa), o-(p)-nitrobenzenesulfonyl (Ns), pivaloyl, benzoyl, tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, allyloxycarbonyl, trichloroethoxycarbonyl, trimethylsilylethoxycarbonyl, carbobenzyloxy, p-methylbenzenesulfonyl, p-nitrobenzenesulfonyl, trifluoroacetyl, methoxy carbonyl, or ethoxy carbonyl; an alkyl amino protecting group such as trityl (Trt), 2,4-dimethoxybenzyl (Dmb), 4-methoxybenzyl (PMB), benzyl (Bn), preferably carbobenzyloxy (Cbz), tert-butoxycarbonyl (Boc) or benzyl;

[0263] The method comprises the following steps:

[0264] (1) reacting compound II-A1 with compound II-A2 to obtain compound II-A3;

[0265] (2) reacting compound II-A3 with compound II-A4 to obtain compound II-A5;

[0266] (3) ring-closing reaction of compound II-A5 with compound II-A5a to obtain compound II-A6;

[0267] (4) performing a protection reaction on compound II-A6 to obtain compound II-A7;

[0268] (5) performing an oxidation reaction on compound II-A7 to obtain compound II-A8;

[0269] (6) reacting compound II-A8 with compound II-A9a to obtain compound II-A10a;

[0270] (7) performing a deprotection reaction on compound II-A10a to obtain compound II-A11a;

[0271] (8) reacting compound II-A11a with compound II-A12a to give compound II-A10, and

[0272] (9) subjecting compound II-A10 to a deprotection reaction to give compound II-A.

[0273] The reaction of step (1) above is preferably carried out in a suitable organic solvent and in the presence of a suitable base. The organic solvent can be selected from the group consisting of acetonitrile, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, tetrahydrofuran, 1,4-dioxane, and any combination thereof, preferably N,N-dimethylformamide. The base can be selected from the group consisting of N,N-diisopropylethylamine, triethylamine, potassium carbonate, cesium carbonate, and any combination thereof, preferably cesium carbonate. The reaction is preferably carried out at a temperature ranging from 0 °C to 100 °C for 0.5 to 48 hours.

[0274] The reaction of step (2) above is preferably carried out in a suitable organic solvent and in the presence of a suitable base. The organic solvent can be selected from the group consisting of acetonitrile, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, tetrahydrofuran, 1,4-dioxane, and any combination thereof, preferably acetonitrile or tetrahydrofuran. The base can be selected from the group consisting of 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 ranging from 20 °C to 120 °C for 2 to 48 hours.

[0275] The ring closure reaction of step (3) above is preferably carried out in a suitable organic solvent and in the presence of a suitable reagent. The organic solvent can be selected from the group consisting of methanol, ethanol, isopropanol, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, dimethylsulfoxide, and any combination thereof, preferably ethanol. The reagent can be selected from the group consisting of morpholine, ammonium acetate, diethylamine, triethylamine, L-proline, sulfur powder, and any combination thereof, preferably a combination of ammonium acetate and sulfur powder. The reaction is preferably carried out at a temperature ranging from 0 °C to 100 °C for 1 to 12 hours.

[0276] The reaction of step (4) above is preferably carried out in a suitable organic solvent and in the presence of N,N-dimethylformamide dimethyl acetal. The organic solvent can be selected from the group consisting of acetonitrile, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, tetrahydrofuran, 1,4-dioxane, and any combination thereof, preferably tetrahydrofuran. The reaction is preferably carried out at a temperature ranging from 25 °C to 100 °C for 2 to 16 hours.

[0277] The reaction of above mentioned step (5) is preferably carried out in a suitable organic solvent and in the presence of an oxidizing agent. The oxidizing agent can be selected from the group consisting of Dess-Martin periodinane, pyridinium chlorochromate or pyridinium dichromate, preferably Dess-Martin periodinane. The organic solvent can be selected from the group consisting of tetrahydrofuran, dichloromethane, toluene, 1,2-dichloroethane and any combination thereof, preferably dichloromethane. The reaction is preferably carried out at a temperature in the range of 0-40 °C for a period of 2-16 hours.

[0278] The reaction of above mentioned step (6) is preferably carried out in a suitable organic solvent and in the presence of a suitable reducing agent. The organic solvent can be selected from the group consisting of dichloromethane, tetrahydrofuran, acetonitrile, methanol, N,N-dimethylformamide, dimethylsulfoxide, isopropanol and any combination thereof, preferably dichloromethane. The reducing agent can be selected from the group consisting of sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride and 2-methylpyridine borane, preferably sodium triacetoxyborohydride. The reaction is preferably carried out at a temperature in the range of 0-90 °C for a period of 1-12 hours.

[0279] The deprotection reaction of above mentioned step (7) is preferably carried out in a suitable organic solvent and in the presence of a suitable deprotecting agent. The organic solvent can be selected from the group consisting of methanol, ethanol, isopropanol, dichloromethane, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, tetrahydrofuran and any combination thereof, preferably dichloromethane. The deprotecting agent can be selected from the group consisting of hydrochloric acid, trifluoroacetic acid, acetic acid and any combination thereof, preferably trifluoroacetic acid. The reaction is preferably carried out at a temperature in the range of 0-100 °C for a period of 1-12 hours.

[0280] The reaction of above mentioned step (8) is preferably carried out in a suitable organic solvent and in the presence of a suitable organic base and a condensing agent. The organic solvent can be selected from the group consisting of dichloromethane, tetrahydrofuran, acetonitrile, N,N-dimethylformamide and any combination thereof, preferably N,N-dimethylformamide. The organic base can be selected from the group consisting of N,N-diisopropylethylamine, triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, preferably N,N-diisopropylethylamine. The condensing agent can be selected from the group consisting of 2-(7-azabenzotriazolyl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, 1-hydroxybenzotriazole, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N-hydroxy-7-azabenzotriazol, dicyclohexylcarbodiimide and any combination thereof, preferably 2-(7-azabenzotriazolyl)-N,N,N',N'-tetramethyluronium hexafluorophosphate. The reaction is preferably carried out at a temperature in the range of 0-60 °C for a period of 1-12 hours.

[0281] The deprotection reaction of step (9) above is preferably carried out in a suitable organic solvent and in the presence of a suitable deprotecting reagent. The organic solvent can be selected from the group consisting of methanol, ethanol, isopropanol, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, tetrahydrofuran and any combination thereof, preferably tetrahydrofuran. The deprotecting reagent can be selected from the group consisting of hydrochloric acid, trifluoroacetic acid, acetic acid and any combination thereof, preferably hydrochloric acid. The reaction is preferably carried out at a temperature between 0-100 °C for 1-12 hours.

[0282] The compounds of formula (II-B), (II-C) or (II-D) of the present application can be prepared according to the methods as shown in Scheme 1 or 2 above.

[0283] Intermediates

[0284] In some embodiments, the present application provides a compound represented by Formula II-A1, II-A2, II-A3, II-A5, II-A6, II-A7, II-A8, II-A9, II-A9a, II-A10, II-A10a, II-A11a, II-A12a, or a salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound thereof,

[0285] wherein ring A, ring B, ring E, R 2 , L, L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , X 6 , PG 1 , LG 1 , LG 2 , and LG 3 are as defined above.

[0286] The compounds represented by Formula II-A1, II-A2, II-A3, II-A5, II-A6, II-A7, II-A8, II-A9, II-A9a, II-A10, II-A10a, II-A11a, II-A12a, or a salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound thereof above can be used to prepare a compound represented by the general formula herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof.

[0287] Pharmaceutical compositions and kits

[0288] Another object of the present application is to provide a pharmaceutical composition comprising a prophylactically and / or therapeutically effective amount of a compound of the present application 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.

[0289] Another object of the present application is to provide a pharmaceutical kit comprising a compound of the present application 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 application.

[0290] In some embodiments, the pharmaceutical kit further comprises instructions for administering a compound of the present application 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 application.

[0291] In the present application, "pharmaceutically acceptable carrier" means a diluent, adjuvant, excipient or vehicle with which a therapeutic agent is administered and which is appropriate for use in contact with the tissues of humans and / or other animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit / risk ratio as defined within the scope of sound medical judgment.

[0292] The pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions or medicaments of the present application include, but are not limited to, sterile liquids, such as water and oils, including those of

[0293] The pharmaceutical composition can be, for example, in the form of a solid preparation, a semi-solid preparation, a liquid preparation or a gaseous preparation, etc. The solid preparation is, for example, a tablet, a capsule, a powder, a granule or a suppository, etc., and the liquid preparation is, for example, a solution, a suspension or an injection. The composition can also be in the form of a liposome, a microsphere, etc.

[0294] The pharmaceutical composition of the present application can act systemically and / or locally. For this purpose, they can be administered by a suitable route, such as by injection (e.g., intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection, including drip infusion) or transdermally; or by oral, buccal, nasal, transmucosal, topical, in the form of an ophthalmic preparation or by inhalation.

[0295] The content or amount of the compound of the present application in the pharmaceutical composition can 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, and particularly preferably 0.5-100 mg.

[0296] In some embodiments, the present application provides a method of preparing a pharmaceutical composition of the present application, comprising combining a compound of the present application 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.

[0297] Methods of treatment and uses

[0298] It is another object of the present application to provide a compound of the present application 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 application, for use in the prevention and / or treatment of a disease, in particular a KRAS-mediated related disease.

[0299] It is another object of the present application to provide the use of a compound of the present application 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 application, for the manufacture of a medicament, in particular for the manufacture of a medicament for the prevention and / or treatment of a KRAS-mediated related disease.

[0300] It is another object of the present application to provide a method of preventing and / or treating a KRAS-mediated related disease, comprising administering to an individual in need thereof a prophylactically or therapeutically effective amount of a compound of the present application 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 application.

[0301] According to some embodiments of the present application, the KRAS-mediated related disease is a tumor or a cancer. In some embodiments, the tumor or cancer is selected from lung cancer, pancreatic cancer, colorectal cancer, and gastric cancer.

[0302] In some embodiments, the tumor or cancer is associated with KRAS G12D mutation, KRAS G12DV mutation, and / or KRAS G13D mutation.

[0303] The term "effective amount" as used herein refers to an amount that is sufficient to achieve the desired prophylactic or therapeutic effect, e.g., an amount that achieves the alleviation of one or more symptoms associated with the disease to be treated.

[0304] The dosing regimen can be adjusted to provide the optimal required response. For example, a single bolus injection can be administered, several fractions can be administered over time, or the dose can be proportionally reduced or increased as indicated by the urgency of the treatment situation. It should be noted that dosage values ​​can vary depending on the type and severity of the condition to be alleviated, and may include single or multiple doses. To further understand, for any given individual, the specific dosing regimen should be adjusted over time based on individual needs and the professional judgment of the person administering the composition or supervising its administration.

[0305] The amount of the compounds of the present invention administered will depend on the individual being treated, the severity of the condition or illness, the rate of administration, the disposal of the compounds, and the prescribing physician's judgment. Generally, the effective dose is from about 0.0001 to about 50 mg per kg of body weight per day, for example, from about 0.01 to about 10 mg / kg / day (single or divided doses). For a 70 kg person, this would total from about 0.007 mg / day to about 3500 mg / day, for example, from about 0.7 mg / day to about 700 mg / day. In some cases, dose levels not exceeding the lower limit of the foregoing range may be sufficient, while in other cases, larger doses may still be used without causing any harmful side effects, provided that the larger dose is first divided into several smaller doses administered throughout the day.

[0306] As used in this article, the term "prevention" includes suppressing and delaying the onset of disease, and includes not only prevention before the development of disease, but also prevention of recurrence of disease after treatment.

[0307] As used in this article, the term “treatment” means to reverse, alleviate or eliminate the progression of one or more symptoms of a condition or illness to which such term is applied.

[0308] As used herein, “individual” includes both human and non-human animals. Exemplary human individuals include human individuals suffering from a disease (such as the disease described herein) (referred to as patients) or normal individuals. In this invention, “non-human animals” includes 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

[0309] The embodiments of the present invention will be described in detail below with reference to examples. However, those skilled in the art will understand that the following examples are for illustrative purposes only and should not be considered as limiting the scope of the present invention.

[0310] Unless otherwise specified in the examples, all procedures were performed under standard conditions or conditions recommended by the manufacturer. Reagents or instruments whose manufacturers are not specified are all commercially available products.

[0311] The structure of the compound was determined by nuclear magnetic resonance (H NMR) and / or mass spectrometry (MS). 1 H NMR) and / or mass spectrometry (MS).

[0312] 1 The measuring instrument of H NMR was JEOL Eclipse 400 nuclear magnetic instrument, the measuring solvent was deuterated methanol (CD3OD), deuterated chloroform (CDCl3) or hexadeuterated dimethyl sulfoxide (DMSO-d6), the internal standard was tetramethylsilane (TMS), and the chemical shift (δ) was given in units of parts per million (ppm).

[0313] The measuring instrument of MS was Agilent (ESI) mass spectrometer, manufacturer: Agilent, model: Agilent 6120B.

[0314] The reverse phase column chromatography used Agela C18 reverse phase Flash column

[0315] The preparation high performance liquid chromatography condition was as follows:

[0316] (1) Instrument model: Agilent 1260; chromatographic column: Waters SunFire Prep C 18 OBD (19mm x 150mm x 5.0μm); column temperature: 25℃; flow rate: 20.0mL / min; detection wavelength: 214nm; elution gradient: (0min: 10% A, 90% B; 16.0min: 90% A, 10% B); mobile phase A: acetonitrile; mobile phase B: 0.05% formic acid aqueous solution;

[0317] (2) Instrument model: Agilent 1260, chromatographic column: Waters XBridge Prep C 18 OBD (19mm x 150mm x 5.0μm); column temperature: 25℃; flow rate: 20.0mL / min; detection wavelength: 214nm; elution gradient: (0min: 10% A, 90% B; 16.0min: 90% A, 10% B); mobile phase A: acetonitrile; mobile phase B: 0.05% ammonium bicarbonate aqueous solution.

[0318] The thin layer chromatography silica gel plate (TLC) used aluminum plate (20 x 20cm) produced by Merck, and the specification used for thin layer chromatography separation and purification was GF 254 (1mm) produced by Yantai.

[0319] The monitoring of the reaction was carried out by thin layer chromatography (TLC) or LC-MS; the developing solvent systems used included: dichloromethane and methanol system, n-hexane and ethyl acetate system, and petroleum ether and ethyl acetate system, the volume ratio of the solvents was adjusted according to the different polarity of the compounds or adjusted by adding triethylamine, etc.

[0320] Column chromatography generally used 200-300 mesh silica gel as the carrier. The eluent system includes: dichloromethane and methanol system, and petroleum ether and ethyl acetate system, the volume ratio of the solvents is adjusted according to the different polarity of the compounds, or a small amount of triethylamine can also be added for adjustment.

[0321] Unless otherwise specified, the reaction temperature is room temperature (20-35°C).

[0322] The reagents used in the examples were purchased from Acros Organics, Aldrich Chemical Company, and TCI Chemicals, etc.

[0323] The abbreviations appearing in this text have the meanings indicated in the following table.

[0324] The following preparation examples are only exemplary, and other compounds of the present application can be synthesized similarly with reference to the following preparation examples.

[0325] Preparation of intermediates

[0326] Preparation Example 1: Preparation of (S)-(1-((2-(3-cyano-2-((dimethylamino)methylene)amino)-5',6,6',7- tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-3'-yl)-6-(pyrimidin-5-yloxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)methanesulfonate

[0327] First step: Preparation of (S)-3-(4-chloro-6-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazole-7,1'-cyclohexan]-2'-one

[0328] (S)-3-(4,6-dichloropyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazole-7,1'- cyclohexan]-2'-one (8 g, 22.8 mmol) was dissolved in DMF (80 mL), 1,1- cyclopropanedimethanol (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 solution was diluted with water (300 mL), extracted with ethyl acetate (100 mL) three times, 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, by volume) to obtain the title compound (6.7 g, yield: 70.5%).

[0329] MS m / z (ESI): 418.1 [M+H] + .

[0330] Second step: Preparation of (S)-3-(4-(((1-(hydroxymethyl)cyclopropyl)methoxy)-6- (pyrimidin-5-yloxy)pyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazole-7,1'- cyclohexan]-2'-one

[0331] (S)-3-(4-chloro-6-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrimidin-2-yl)-5,6- dihydro-4H-spiro[benzo[d]isoxazole-7,1'-cyclohexan]-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 solution was cooled to room temperature, poured into water (750 mL), and a solid was precipitated, filtered, the filter cake was collected and dried to obtain the title compound (5.4 g, yield: 94.4%).

[0332] MS m / z (ESI): 478.2 [M+H] + .

[0333] Third step: 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

[0334] (S)-3-(4-(((1-(hydroxymethyl)cyclopropyl)methoxy)-6-(pyrimidin-5-yloxy)pyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazole-7,1'-cyclohexanone]-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), stirred at 60 °C for 15 minutes, then a solution of malononitrile (3.74 g, 56.6 mmol) in ethanol (20 mL) was added dropwise, and stirred at 80 °C for 8 hours. The reaction solution 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 obtain the title compound (4.3 g, yield: 68.2%).

[0335] MS m / z (ESI): 558.2 [M+H] + .

[0336] Fourth step: Preparation of (S)-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-dimethylformamidine

[0337] (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 solution was concentrated to obtain the title compound (4.6 g, yield: 97.9%).

[0338] MS m / z (ESI): 613.2 [M+H] + .

[0339] Fifth step: Preparation of (S)-(1-((2-(3-cyano-2-((dimethylamino)methylene)amino)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-3'-yl)-6-(pyrimidin-5-yloxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl methanesulfonate

[0340] (S)-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-dimethylformamidine (4.6 g, 7.5 mmol) was dissolved in dichloromethane (50 mL), and N,N-diisopropyl ethylamine (1.94 g, 15.0 mmol) and methanesulfonic anhydride (1.96 g, 11.25 mmol) were added sequentially, and the reaction was allowed to proceed at 25°C for 2 hours. Water (50 mL) was added to the reaction mixture, which was extracted twice with dichloromethane (50 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1, by volume) to obtain the title compound (4.6 g, yield: 88.8%).

[0341] MS m / z (ESI): 691.3 [M+H] + .

[0342] Intermediate Preparation Example 2: Preparation of (S)-(1-(((2-(3-cyano-2-(((dimethylamino)methylene)amino)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-3'-yl)-6-methoxy-pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl methanesulfonate

[0343] Using the synthetic route in Intermediate Preparation Example 1, the second step reaction raw material 5-hydroxypyrimidine was replaced with sodium methoxide to obtain the title compound (203 mg, yield: 55.1%).

[0344] MS m / z (ESI): 627.2 [M+H] + .

[0345] Intermediate Preparation Example 3: Preparation of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-1-methyl-1H-indazole

[0346] First Step: Preparation of 6-bromo-3-iodo-1-methyl-1H-indazole

[0347] A mixture of 6-bromo-3-iodo-lH-indazole (10 g, 30.97 mmol) and potassium hydroxide (2.11 g, 37.16 mmol) was mixed in acetone (100 mL), iodomethane (11.1 g, 77.42 mmol) was added slowly, and the reaction was allowed to proceed at 25 °C for 16 hours. The solid was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane / ethyl acetate = 5 / 1, volume ratio) to obtain the title compound (8.0 g, yield: 75.9%).

[0348] MS m / z (ESI): 337.3 [M+H] + .

[0349] Second Step: Preparation of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-l- methyl-lH-indazole

[0350] A mixture of 6-bromo-3-iodo-l-methyl-lH-indazole (8 g, 23.5 mmol) and 2,6- bis(benzyloxy)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (9.91 g, 23.5 mmol) was dissolved in tetrahydrofuran (150 mL) and water (15 mL), and [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (1.74 g, 2.35 mmol) and cesium carbonate (19.34 g, 58.76 mmol) were added. The mixture was replaced with nitrogen three times, and the reaction was allowed to proceed at 70 °C for 16 hours. The solid was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane / ethyl acetate = 5 / 1, volume ratio) to obtain the title compound (8.3 g, yield: 69.9%).

[0351] MS m / z (ESI): 500.3 [M+H] + .

[0352] Intermediate Preparation Example 4: Preparation of 3-(l-methyl-6-(piperidin-4-yl)- lH-indazol-3-yl)piperidine-2,6-dione

[0353] First Step: Preparation of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-l- methyl-lH-indazol-6-yl)-3,6-dihydropyridine-l(2H)-carboxylate

[0354] To a solution of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-1-methyl-1H-indazole (2 g, 3.96 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.47 g, 4.75 mmol) in 1.4-dioxane (50 mL) and water (5 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (287 mg, 0.39 mmol) and anhydrous potassium carbonate (1.64 g, 11.87 mmol), and nitrogen was replaced for three times. The reaction was carried out at 90 °C for 12 hours. The solid was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3 / 1, volume ratio) to obtain the title compound (2.4 g, yield: 99.6%).

[0355] MS m / z (ESI): 603.2 [M+H] + .

[0356] Second Step: Preparation of 4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidine-1-carboxylic acid tert-butyl ester

[0357] To a solution of 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (2.4 g, 3.94 mmol) in anhydrous methanol (80 mL) was added 10% palladium carbon (500 mg), and the reaction was carried out at 25 °C for 12 hours under a hydrogen atmosphere. The solid was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the title compound (1.6 g, yield: 94.2%).

[0358] MS m / z (ESI): 427.3 [M+H] + .

[0359] Third Step: Preparation of 3-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)piperidine-2,6-dione

[0360] To a solution of 4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidine-1-carboxylic acid tert-butyl ester (500 mg, 1.16 mmol) in dichloromethane (5 mL) was added 4M hydrogen chloride solution in 1,4-dioxane (3 mL), and the reaction was carried out at 25 °C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the title compound (420 mg, yield: 98.7%).

[0361] MS m / z (ESI): 327.1 [M+H] + .

[0362] Intermediate Preparation Example 5: Preparation of 3-(1-methyl-6-(3,9-diazaspiro[5.5]undecan-3-yl)-1H-indazol-3-yl)piperidine-2,6-dione

[0363] First Step: Preparation of tert-butyl 9-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-6-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate

[0364] tert-Butyl 9-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-6-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (620 mg, 910.9 μmol) was dissolved in anhydrous methanol (20 mL), and 10% palladium carbon (200 mg) was added, and the reaction was carried out under a hydrogen atmosphere at 25 °C for 12 hours. The solid was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the title compound (360 mg, yield: 78.9%).

[0365] MS m / z (ESI): 496.3 [M+H] + .

[0366] Second Step: Preparation of tert-butyl 9-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate

[0367] tert-Butyl 9-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-6-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (620 mg, 910.9 μmol) was dissolved in anhydrous methanol (20 mL), and 10% palladium carbon (200 mg) was added, and the reaction was carried out under a hydrogen atmosphere at 25 °C for 12 hours. The solid was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the title compound (360 mg, yield: 78.9%).

[0368] MS m / z (ESI): 496.3 [M+H] + .

[0369] Step 3: Preparation of 3-(1-methyl-6-(3,9-diazaspiro[5.5]undecan-3-yl)-1H-indazol-3- yl)piperidine-2,6-dione

[0370] tert-Butyl 9-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)-3,9-diazaspiro[5.5]undecane- 3-carboxylate (150 mg, 299.63 μmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, and the reaction was allowed to react at 25 °C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the title compound (130 mg, yield: 85.1%).

[0371] MS m / z (ESI): 396.6 [M+H] + .

[0372] Intermediate Preparation Example 6: Preparation of 3-(6-(1-(7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-1- methyl-1H-indazol-3-yl)piperidine-2,6-dione

[0373] Step 1: Preparation of tert-butyl 2-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1- yl)-7-azaspiro[3.5]nonane-7-carboxylate

[0374] tert-Butyl 3-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)piperidine-2,6-dione (300 mg, 818.51 μmol) and tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (594 mg, 2.46 μmol) were dissolved in DMF (5 mL), 2 drops of glacial acetic acid were added, and the reaction was allowed to react at 25 °C for 5 hours. Sodium cyanoborohydride (104 mg, 1.64 μmol) was added, and the reaction was allowed to react at 25 °C for 5 hours. The reaction solution was purified by reverse phase column chromatography (eluent: pure water / acetonitrile = 1 / 1, by volume) to obtain the title compound (420 mg, yield: 92.4%).

[0375] MS m / z (ESI): 550.2 [M+H] + .

[0376] Step 2: Preparation of 3-(6-(1-(7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine- 2,6-dione

[0377] tert-Butyl 2-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1- yl)acetate (200 mg, 360.19 pmol) was dissolved in dichloromethane (5 mL), 4M hydrogen chloride solution in 1,4-dioxane (3 mL) was added, and the reaction was allowed to proceed at 25 °C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the title compound (160 mg, yield: 90.4%).

[0378] MS m / z (ESI): 450.3 [M+H] + .

[0379] Preparation of Intermediate: 3-(1-methyl-6-(1-(2-oxo-2-(piperazin-1-yl)ethyl)piperidin-4-yl)-1H- indazol-3-yl)piperidine-2,6-dione

[0380] First Step: Preparation of tert-butyl 2-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6- yl)piperidin-1-yl)acetate

[0381] tert-Butyl 3-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)piperidine-2,6-dione (420 mg, 1.15 mmol) was dissolved in DMF (5 mL), and tert-butyl bromoacetate (339 mg, 1.72 mmol) and triethylamine (293 mg, 2.86 mmol) were added sequentially, and the reaction was allowed to proceed at 25 °C for 16 hours. The reaction solution was purified by reverse phase column chromatography (eluent: water (containing 0.05% formic acid) / acetonitrile = 2 / 1 by volume) to obtain the title compound (290 mg, yield: 56.8%).

[0382] MS m / z (ESI): 441.2 [M+H] + .

[0383] Second Step: Preparation of 2-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1- yl)acetic acid

[0384] tert-Butyl 2-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)acetate (270 mg, 606.76 pmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, and the reaction was allowed to proceed at 25 °C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the title compound (300 mg, yield: 98.2%).

[0385] MS m / z (ESI): 385.3 [M+H]+ .

[0386] Step 3: Preparation of tert-butyl 4-(2-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6- yl)piperidin-1-yl)acetyl)piperazine-1-carboxylate

[0387] tert-Butyl 4-(2-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1- yl)acetyl)piperazine-1-carboxylate (350 mg, 626.96 pmol) was dissolved in dichloromethane (5 mL), 4M hydrogen chloride solution in 1,4-dioxane (3 mL) was added, and the reaction was allowed to proceed at 25 °C for 2 hours. The reaction was concentrated under reduced pressure to obtain the title compound (305 mg, yield: 98.4%).

[0388] MS m / z (ESI): 553.5 [M+H] + .

[0389] Step 4: Preparation of 3-(1-methyl-6-(1-(2-oxo-2-(piperazin-1-yl)ethyl)piperidin-4-yl)-1H- indazol-3-yl)piperidine-2,6-dione

[0390] tert-Butyl 4-(2-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1- yl)acetyl)piperazine-1-carboxylate (350 mg, 626.96 pmol) was dissolved in dichloromethane (5 mL), 4M hydrogen chloride solution in 1,4-dioxane (3 mL) was added, and the reaction was allowed to proceed at 25 °C for 2 hours. The reaction was concentrated under reduced pressure to obtain the title compound (305 mg, yield: 98.4%).

[0391] MS m / z (ESI): 453.4 [M+H] + .

[0392] Intermediate Preparation Example 8: Preparation of 3-(5-([1,4’-Bipiperidin]-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione

[0393] Step 1: Preparation of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3,6- dihydropyridine-1(2H)-carboxylate

[0394] Under nitrogen protection, 3-(5-bromo-l-oxo-isoindolin-2-yl)piperidine-2,6-dione (1.9 g, 5.88 mmol), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-l- carboxylic acid tert-butyl ester (5.45 g, 17.64 mmol), 1,1'-bis(diphenylphosphino) ferroecium dichloropalladium (476.6 mg, 588.0 μmol) and potassium phosphate (2.49 g, 11.76 mmol) were dissolved in DMF (20 mL) and reacted in a microwave at 100 °C for 4 hours. The reaction solution was diluted with ethyl acetate (100 mL), washed with saturated brine (50 mL) three times, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (eluent: dichloromethane / methanol = 15 / 1, volume ratio) to obtain the title compound (1.66 g, yield: 66.3%).

[0395] MS m / z (ESI): 426.2 [M+H] + .

[0396] Second Step: Preparation of 4-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5- yl)piperidine-l-carboxylic acid tert-butyl ester

[0397] 4-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)-3,6-dihydropyridine-l(2H)- carboxylic acid tert-butyl ester (1.66 g, 3.90 mmol) was dissolved in methanol (30 mL), 10% palladium carbon (475.23 mg) was added to the system, and stirred at 25 °C for 12 hours under a hydrogen atmosphere. The reaction solution was filtered through celite, the filter cake was rinsed with methanol three times, the filtrate was concentrated, and the residue was separated and purified by silica gel column chromatography (eluent: dichloromethane / methanol = 15 / 1, volume ratio) to obtain the title compound (1.9 g, yield: 99.5%).

[0398] MS m / z (ESI): 428.2 [M+H] + .

[0399] Third Step: Preparation of 3-(l-oxo-5-(piperidin-4-yl)isoindolin-2-yl)piperidine- 2,6-dione

[0400] 4-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)piperidine-l-carboxylic acid tert-butyl ester (1.9 g, 4.44 mmol) was dissolved in 4M hydrogen chloride solution in 1,4-dioxane (6 mL) and stirred at 25 °C for 12 hours. The reaction solution was concentrated to obtain the title compound (0.95 g, yield: 58.8%).

[0401] MS m / z (ESI): 328.2 [M+H] + .

[0402] Fourth Step: Preparation of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)-[1,4’-bipiperidine]-1’-carboxylate

[0403] 3-(1-oxo-5-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione (95 mg, 261.11 μmol), acetic acid (31.33 mg, 522.21 μmol) were dissolved in DMF (2 mL), benzyl 4- oxopiperidine-1-carboxylate (182.72 mg, 783.32 μmol) was added, stirred at 25 °C for 30 min, sodium triacetoxyborohydride (221.35 mg, 1.04 mmol) was added, reacted at 25 °C for 16 h. The reaction solution was purified by reverse phase column chromatography (eluent: water (containing 0.05% formic acid) / acetonitrile = 3 / 7, volume ratio) to obtain the title compound (90 mg, yield 60.12%).

[0404] MS m / z (ESI): 511.3 [M+H] + .

[0405] Fifth Step: Preparation of 3-(5-([1,4’-bipiperidine]-4-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione

[0406] Tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-[1,4’- bipiperidine]-1’-carboxylate (90 mg, 174.49 μmol) was dissolved in 4M hydrogen chloride solution in 1,4-dioxane (1 mL) and dichloromethane (1 mL), stirred at 25 °C for 2 h. The reaction solution was concentrated to obtain the title compound (76 mg, yield: 97.4%).

[0407] MS m / z (ESI): 411.3 [M+H] + .

[0408] Intermediate Preparation Example 9: Preparation of 3-(5-(1-(7-azaspiro[3.5]nonan-2- yl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0409] First Step: Preparation of tert-butyl 2-(4-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)piperidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate

[0410] To a solution of 3-(1-oxo-5-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione (95 mg, 261.11 μmol) and acetic acid (31.33 mg, 522.21 μmol) in DMF (2 mL) was added tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (218.47 mg, 783.32 μmol) and stirred at room temperature for 30 min. Sodium triacetoxyborohydride (223.35 mg, 1.04 mmol) was added and the reaction was stirred at 25 °C for 16 h. The reaction was purified by reverse phase column chromatography (eluent: water (containing 0.05% formic acid) / acetonitrile = 3 / 7, volume ratio) to give the title compound (76 mg, yield: 52.9%).

[0411] MS m / z (ESI): 551.3 [M+H] + .

[0412] Second Step: Preparation of 3-(5-(1-(7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione

[0413] To a solution of tert-butyl 2-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-1- yl)-7-azaspiro[3.5]nonane-7-carboxylate (76 mg, 143.82 μmol) in 4 M hydrogen chloride in 1,4-dioxane (1 mL) and dichloromethane (1 mL) was stirred at 25 °C for 2 h. The reaction was concentrated to give the title compound (66.5 mg, yield: 93.6%).

[0414] MS m / z (ESI): 451.3 [M+H] + .

[0415] Intermediate Preparation Example 10: Preparation of 3-(1-oxo-5-(1-(2-oxo-2-(piperazin-1- yl)ethyl)piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione

[0416] First Step: Preparation of 2-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-1- yl)acetic acid

[0417] To a solution of 3-(1-oxo-5-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione (95 mg, 261.11 μmol) and acetic acid (31.33 mg, 522.21 μmol) in DMF (2 mL) was added glyoxylic acid (58.0 mg, 783.32 μmol) and stirred at 25 °C for 0.5 h, then sodium triacetoxyborohydride (221.35 mg, 1.04 mmol) was added and stirred at 25 °C for 16 h. The reaction was purified by reverse phase column chromatography (eluent: water (containing 0.05% formic acid) / acetonitrile = 1 / 9, volume ratio) to give the title compound (35 mg, yield: 34.8%).

[0418] MS m / z (ESI): 386.2 [M+H] + .

[0419] Step 2: Preparation of tert-butyl 4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)piperidin-1-yl)acetyl)piperazine-1-carboxylate

[0420] To a solution of 2-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-1-yl)acetic acid (35 mg, 90.81 μmol), N,N-diisopropylethylamine (35.21 mg, 272.44 μmol) and tert-butyl piperazine-1-carboxylate (33.83 mg, 181.62 μmol) in DMF (2 mL) was added 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (51.77 mg, 136.22 μmol) and reacted at 25 °C for 3 h. The reaction was diluted with ethyl acetate (30 mL), washed with saturated brine (10 mL) three times, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (eluent: dichloromethane / methanol = 15 / 1, volume ratio) to give the title compound (31.5 mg, yield: 62.7%).

[0421] MS m / z (ESI): 554.3 [M+H] + .

[0422] Step 3: Preparation of 3-(1-oxo-5-(1-(2-oxo-2-(piperazin-1-yl)ethyl)piperidin-4-yl)isoindolin-2- yl)piperidine-2,6-dione

[0423] tert-Butyl 4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-1- yl)acetyl)piperazine-1-carboxylate (31.5 mg, 56.90 μmol) was dissolved in dichloromethane (1 mL), 4M hydrogen chloride solution in 1,4-dioxane (1 mL) was added, stirred at 25°C for 2 hours, the reaction solution was concentrated to obtain the title compound (24.5 mg, yield: 87.9%).

[0424] MS m / z (ESI): 454.3 [M+H] + .

[0425] Intermediate Preparation Example 11: Preparation of 3-(1-oxo-5-(3,9-diazaspiro[5.5]undecan-3- yl)isoindolin-2-yl)piperidine-2,6-dione

[0426] First Step: Preparation of tert-butyl 9-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3,9- diazaspiro[5.5]undecane-3-carboxylate

[0427] tert-Butyl 3-(5-bromo-1-oxo-isoindolin-2-yl)piperidine-2,6-dione (475 mg, 1.47 mmol), tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (560.85 mg, 2.20 mmol), dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridinyl)palladium(II) (116.23 mg, 146.99 μmol) and cesium carbonate (1.44 g, 4.41 mmol) were added to 1,4-dioxane (2 mL), stirred uniformly, replaced with nitrogen three times, stirred at 100°C for 3 hours in a microwave, the reaction solution was cooled to room temperature, the reaction solution was diluted with dichloromethane (20 mL) and 5% acetic acid aqueous solution (20 mL), washed twice with saturated brine (35 mL), the organic phase was dried with anhydrous sodium sulfate, filtered, concentrated, the residue was separated and purified by silica gel column chromatography (eluent: dichloromethane / methanol = 15 / 1, volume ratio) to obtain the title compound (152 mg, yield: 20.8%).

[0428] MS m / z (ESI): 497.3 [M+H] + .

[0429] Second Step: Preparation of 3-(1-oxo-5-(3,9-diazaspiro[5.5]undecan-3-yl)isoindolin-2-yl)piperidine- 2,6-dione

[0430] tert-Butyl 9-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (76 mg, 153.04 μmol) was dissolved in dichloromethane (1 mL), 4M hydrogen chloride solution in 1,4-dioxane (1 mL) was added, and the reaction was allowed to react at 25°C for 2 hours. The reaction solution was concentrated to obtain the title compound (59 mg, yield: 97.2%).

[0431] MS m / z (ESI): 397.2 [M+H]+.

[0432] Intermediate Preparation Example 12: Preparation of 3-(6-([1,4'-bipiperidinyl]-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione

[0433] Using the synthetic route in Intermediate Preparation Example 6, the first step reaction material 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl ester was replaced with 4-oxopiperidine-1-carboxylate tert-butyl ester to obtain the title compound (175 mg, yield: 73.5%).

[0434] MS m / z (ESI): 409.2 [M+H] + .

[0435] Intermediate Preparation Example 13: Preparation of 3-(1-oxo-5-(1-(piperidin-4-ylmethyl)piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione:

[0436] Using the synthetic route in Intermediate Preparation Example 9, the first step reaction material 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl ester was replaced with 1-tert-butoxycarbonylpiperidine-4-carbaldehyde to obtain the title compound (69 mg, yield: 97.8%).

[0437] MS m / z (ESI): 425.2 [M+H] + .

[0438] Intermediate Preparation Example 14: Preparation of (S)-N'-(3-cyano-3'-(4-((1- formylcyclopropyl)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-dimethylformamidine

[0439] (S)-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-dimethylformamidine (3g, 4.9 mmol) was dissolved in dichloromethane (30 mL), and Dess-Martin oxidizing agent (3.12 g, 7.35 mmol) was added, and stirred at room temperature for 4 hours. The reaction solution was diluted with water (50 mL), extracted with dichloromethane (50 mL) three times, 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 / 2, by volume) to obtain the title compound (2.3 g, yield: 76.9%).

[0440] MS m / z (ESI): 611.3 [M+H] + .

[0441] Preparation Example 15: Preparation of (S)-(1-(((2-(3-cyano-2-(((dimethylamino)methylene)amino)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-3'-yl)-6-((4-methylpyrimidin-5-yl)oxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl methanesulfonate

[0442] Using the synthetic route in Preparation Example 1, the raw material 5-hydroxypyrimidine in the second step was replaced with 5-hydroxy-4-methylpyrimidine to obtain the title compound (160 mg, yield: 62.3%).

[0443] MS m / z (ESI): 705.2 [M+H] + .

[0444] Preparation Example 16: Preparation of (S)-(1-(((2-(3-cyano-2-(((dimethylamino)methylene)amino)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-3'-yl)-6-((4,6-dimethylpyrimidin-5-yl)oxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl methanesulfonate

[0445] Using the synthetic route in Preparation Example 1, the raw material 5-hydroxypyrimidine in the second step was replaced with 4,6-dimethyl-5-hydroxypyrimidine to obtain the title compound (101 mg, yield: 77.3%).

[0446] MS m / z (ESI): 719.2 [M+H] + .

[0447] Preparation of Intermediate: 3-(5-fluoro-l-methyl-6-(3,9-diazaspiro[5.5]undecan-3-yl)-lH-indazol-3-yl)piperidine-2,6-dione

[0448] The first step reaction material 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-5-fluoro-l-methyl-lH-indazole in the synthetic route in the intermediate preparation example 5 was replaced by 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-5-fluoro-l-methyl-lH-indazole to obtain the title compound (2.01 g, yield: 65.2%).

[0449] MS m / z (ESI): 414.2 [M+H] + .

[0450] Preparation of Intermediate: 3-(5-fluoro-l-methyl-6-(3,9-diazaspiro[5.5]undecan-3-yl)-lH-indazol-3-yl)piperidine-2,6-dione

[0451] First step: Preparation of tert-butyl 9-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-l-methyl-lH-indazol-6-yl)-3-azaspiro[5.5]undec-8-ene-3-carboxylate

[0452] 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-l-methyl-lH-indazole (300 mg, 0.6 mmol) and tert-butyl 9-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3-azaspiro[5.5]undec-9-ene-3-carboxylate (294 mg, 0.78 mmol) were dissolved in 1,4-dioxane (8 mL) and water (2 mL), Pd(dppf)Cl2(22 mg, 30 μmol) and potassium carbonate (249 mg, 1.8 mmol) were added successively, replaced with nitrogen for three times, and reacted at 95 °C for 12 hours. The solid was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1, by volume) to obtain the title compound (302 mg, yield: 74.9%).

[0453] 4MS m / z (ESI): 671.5 [M+H] + .

[0454] Step 2: Preparation of tert-butyl 9-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)-3- azaspiro[5.5]undecane-3-carboxylate

[0455] Tert-butyl 9-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-6-yl)-3- azaspiro[5.5]undec-8-ene-3-carboxylate (302 mg, 450 pmol) was dissolved in anhydrous methanol (10 mL), 10% palladium carbon (100 mg) was added, and the reaction was stirred at 25 °C for 12 hours under hydrogen atmosphere. The solid was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (210 mg, yield: 94.2%).

[0456] MS m / z (ESI): 495.3 [M+H] + .

[0457] Step 3: Preparation of 3-(1-methyl-6-(3-azaspiro[5.5]undecan-9-yl)-1H-indazol-3-yl)piperidine- 2,6-dione

[0458] Tert-butyl 9-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)-3-azaspiro[5.5]undecane-3- carboxylate (210 mg, 424 pmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added, and the reaction was stirred at 25 °C for 2 hours. The reaction was concentrated under reduced pressure to give the title compound (143 mg, yield: 85.1%).

[0459] MS m / z (ESI): 395.3 [M+H] + .

[0460] Intermediate Preparation Example 19: Preparation of (S)-N'-(3-cyano-3'-(4-((1- formylcyclopropyl)methoxy)-6-methylpyrimidin-2-yl)-5',6,6',7-tetrahydro-4'H,5H- spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-2-yl)-N,N-dimethylformamidine

[0461] Step 1: Preparation of (S)-3-(4-((1-(hydroxymethyl)cyclopropyl)methoxy)-6-methylpyrimidin-2- yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazole-7,1'-cyclohexan]-2'-one

[0462] (S)-3-(4-chloro-6-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrimidin-2-yl)-5,6- dihydro-4H-spiro[benzo[d]isoxazole-7,1 '-cyclohexan]-2'-one (620 mg, 1.47 mmol) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxabornane (370 mg, 2.94 mmol) were dissolved in 1,4-dioxane (20 mL) and water (5 mL), Pd(dppf)Cl2(108 mg, 146 μmol) and anhydrous cesium carbonate (1.2 g, 3.67 mmol) were added, and the reaction was carried out at 90 °C for 3 hours. The reaction was reduced to room temperature, and the solid was removed by filtration, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 2, volume ratio) to obtain the title compound (400 mg, yield: 67.8%).

[0463] MS m / z (ESI): 398.2 [M+H] + .

[0464] Second step: Preparation of (S)-2-amino-3'-(4-((1-(hydroxymethyl)cyclopropyl)methoxy)-6-methylpyrimidin-2-yl)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-3-carbonitrile

[0465] (S)-3-(4-((1-(hydroxymethyl)cyclopropyl)methoxy)-6-methylpyrimidin-2-yl)-5,6- dihydro-4H-spiro[benzo[d]isoxazole-7,1 '-cyclohexan]-2'-one (400 mg, 996 μmol) was dissolved in ethanol (15 mL), ammonium acetate (307 mg, 3.99 mmol) and sulfur (127 mg, 3.99 mmol) were added, and the reaction was carried out at 60 °C for 30 minutes, and a solution of malononitrile (330 mg, 4.98 mmol) in ethanol (5 mL) was added, and the reaction was carried out at 80 °C for 12 hours. The reaction was reduced to room temperature, and the solid was removed by filtration, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1, volume ratio) to obtain the title compound (480 mg, yield: 99.8%).

[0466] MS m / z (ESI): 478.2 [M+H] + .

[0467] Step 3: Preparation of (S)-N'-(3-cyano-3'-(4-((1-(hydroxymethyl)cyclopropyl)methoxy)-6-methylpyrimidin-2-yl)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-2-yl)-N,N-dimethylformamidine

[0468] (S)-2-amino-3'-(4-((1-(hydroxymethyl)cyclopropyl)methoxy)-6-methylpyrimidin-2-yl)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-3-carbonitrile (480 mg, 995 μmol) was dissolved in tetrahydrofuran (10 mL), N,N-dimethylformamide dimethyl acetal (240 mg, 1.99 mmol) was added, and the mixture was reacted at 25°C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane / ethyl acetate = 1 / 2 by volume) to obtain the title compound (470 mg, yield: 87.7%).

[0469] MS m / z (ESI): 533.2 [M+H] + .

[0470] Step 4: Preparation of (S)-N'-(3-cyano-3'-(4-((1-formylcyclopropyl)methoxy)-6-methylpyrimidin-2-yl)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-2-yl)-N,N-dimethylformamidine

[0471] (S)-N'-(3-cyano-3'-(4-((1-(hydroxymethyl)cyclopropyl)methoxy)-6-methylpyrimidin-2-yl)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-2-yl)-N,N-dimethylformamidine (100 mg, 185 μmol) was dissolved in dichloromethane (5 mL), the system was cooled to 0°C, and Dess-Martin oxidizing agent (120 mg, 278 μmol) was added, and the mixture was reacted at 0°C for 2 hours. The solid was removed from the reaction solution, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane / ethyl acetate = 1 / 2 by volume) to obtain the title compound (95 mg, yield: 95.3%).

[0472] MS m / z (ESI): 531.2 [M+H] + .

[0473] Intermediate Preparation Example 20: Preparation of 3-(6-(1-(2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione

[0474] The synthetic route in Intermediate Preparation Example 6 was adopted, and the first step reaction raw material 2-oxo-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester was replaced by 6-oxo-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester to obtain the title compound (250 mg, yield: 97.4%).

[0475] MS m / z (ESI): 422.3 [M+H] + .

[0476] Intermediate Preparation Example 21: Preparation of 3-(1-methyl-6-(4-(piperazin-1-ylmethyl)piperidin-1-yl)-1H-indazol-3-yl)piperidine-2,6-dione

[0477] First step: Preparation of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-(4-(dimethoxymethyl)piperidin-1-yl)-1-methyl-1H-indazole

[0478] 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-1-methyl-1H-indazole (780 mg, 1.54 mmol) and 4-(dimethoxymethyl)piperidine (250 mg, 1.54 mmol) were dissolved in anhydrous toluene (15 mL), and 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl-2-yl) palladium(II) (130 mg, 154 μmol) and anhydrous cesium carbonate (1.02 g, 3.09 mmol) were added in turn, replaced with nitrogen for three times, and reacted at 100°C for 12 hours. The reaction was reduced to room temperature, and the solid was removed by filtration, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1, by volume) to obtain the title compound (530 mg, yield: 58.7%).

[0479] MS m / z (ESI): 579.2 [M+H] + .

[0480] Second step: Preparation of 1-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-6-yl)piperidine-4-carbaldehyde

[0481] Dissolve 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-(4-(dimethoxymethyl)piperidin-1-yl)-1- methyl-1H-indazole (530 mg, 906 μmol) in dichloromethane (5 mL), add 4M hydrogen chloride solution in 1,4-dioxane (2.5 mL), and react at 25°C for 5 hours. Concentrate the reaction solution under reduced pressure to obtain the title compound (516 mg, yield: 99.0%).

[0482] MS m / z (ESI): 533.3 [M+H] +

[0483] Third Step: Preparation of 4-((1-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-4-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester

[0484] Dissolve 1-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-6-yl)piperidine-4-carbaldehyde (516 mg, 897 μmol) and piperazine-1-carboxylic acid tert-butyl ester (506 mg, 2.69 mmol) in dichloromethane (15 mL), add 2 drops of acetic acid, and react at 25°C for 1 hour. Add sodium triacetoxyborohydride (575 mg, 2.68 mmol) and react at 25°C for 5 hours. Add saturated aqueous sodium bicarbonate solution (10 mL) to the reaction solution, separate the layers, dry the organic layer over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Purify the residue by silica gel column chromatography (eluent: dichloromethane / ethyl acetate = 1 / 4 by volume) to obtain the title compound (380 mg, yield: 59.6%).

[0485] MS m / z (ESI): 703.5 [M+H] + .

[0486] Fourth Step: Preparation of 4-((1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-4-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester

[0487] Dissolve 4-((1-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-4-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester (380 mg, 535 μmol) in tetrahydrofuran (20 mL), add 10% palladium-carbon (50 mg), and react at 25°C for 12 hours under a hydrogen atmosphere. Filter the reaction solution to remove the solids, and concentrate the filtrate under reduced pressure to obtain the title compound (190 mg, yield: 66.9%).

[0488] MS m / z (ESI): 525.4 [M+H]+ .

[0489] Step 5: Preparation of 3-(1-methyl-6-(4-(piperazin-1-ylmethyl)piperidin-1-yl)-1H- indazol-3-yl)piperidine-2,6-dione

[0490] tert-Butyl 4-((1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-4- yl)methyl)piperazine-1-carboxylate (190 mg, 358 µmol) was dissolved in dichloromethane (5 mL), 4M hydrogen chloride solution in 1,4-dioxane (1.0 mL) was added, and the reaction was allowed to react at 25°C for 5 hours. The reaction solution was concentrated under reduced pressure to obtain the title compound (165 mg, yield: 98.8%).

[0491] MS m / z (ESI): 425.3 [M+H] + .

[0492] Intermediate Preparation Example 22: Preparation of 3-(6-(1-(3-azaspiro[5.5]undecan-9-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione

[0493] Using the synthetic route in Intermediate Preparation Example 6, the first step reaction material tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate was replaced with tert-butyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate to obtain the title compound (250 mg, yield: 90.6%).

[0494] MS m / z (ESI): 478.3 [M+H] + .

[0495] Intermediate Preparation Example 23: Preparation of 3-(6-(1-(2-azaspiro[3.5]nonan-7-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione

[0496] Using the synthetic route in Intermediate Preparation Example 6, the first step reaction material tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate was replaced with tert-butyl 7-oxo-2-azaspiro[3.5]nonane-2-carboxylate to obtain the title compound (160 mg, yield: 99.5%).

[0497] MS m / z (ESI): 450.2 [M+H] + .

[0498] Intermediate Preparation 24: Preparation of 3-(3-(3,9-diazaspiro[5.5]undecan-3- yl)phenyl)piperidine-2,6-dione

[0499] First Step: Preparation of 2,6-bis(benzyloxy)-3-(3-bromophenyl)pyridine

[0500] Dissolve 1-bromo-3-iodobenzene (1.00 g, 3.50 mmol) and 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.48 g, 3.50 mmol) in tetrahydrofuran (200 mL) and water (20 mL), and sequentially add Pd(dppf)Cl2(260 mg, 350 µmol) and anhydrous cesium carbonate (2.88 g, 8.75 mmol), and react at 70 °C for 12 hours. The reaction solution is reduced to room temperature, and the solid is removed by filtration, and the filtrate is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20 / 1, by volume) to obtain the title compound (1.50 g, yield: 95.0%).

[0501] MS m / z (ESI): 446.3 [M+H] + .

[0502] Second Step: Preparation of tert-butyl 9-(3-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-3,9- diazaspiro[5.5]undecane-3-carboxylate

[0503] Dissolve 2,6-bis(benzyloxy)-3-(3-bromophenyl)pyridine (1.50 g, 3.33 mmol) and tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (855 mg, 3.33 mmol) in anhydrous toluene (30 mL), and sequentially add tris(dibenzylideneacetone)dipalladium (310 mg, 333 µmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (468 mg, 333 µmol), and sodium tert-butoxide (970 mg, 9.99 mmol), and react at 90 °C for 12 hours. The reaction solution is reduced to room temperature, and the solid is removed by filtration, and the filtrate is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1, by volume) to obtain the title compound (1.50 g, yield: 95.0%).

[0504] MS m / z (ESI): 620.4 [M+H] + .

[0505] Third Step: Preparation of tert-butyl 9-(3-(2,6-dioxopiperidin-3-yl)phenyl)-3,9- diazaspiro[5.5]undecane-3-carboxylate

[0506] tert-Butyl 9-(3-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-3,9-diazaspiro[5.5]undecane-3- carboxylate (500 mg, 798 pmol) was dissolved in tetrahydrofuran (20 mL), 10% palladium carbon (50 mg) was added, and the reaction was carried out under a hydrogen atmosphere at 25 °C for 12 hours. The reaction solution was filtered to remove the solids, and the filtrate was concentrated under reduced pressure to obtain the title compound (300 mg, yield: 84.2%).

[0507] MS m / z (ESI): 442.3 [M+H] + .

[0508] Fourth Step: Preparation of 3-(3-(3,9-diazaspiro[5.5]undecan-3-yl)phenyl)piperidine-2,6- dione

[0509] tert-Butyl 9-(3-(2,6-dioxopiperidin-3-yl)phenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (300 mg, 672 pmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (2 mL) was added, and the reaction was carried out at 25 °C for 3 hours. The reaction solution was concentrated under reduced pressure to obtain the title compound (300 mg, yield: 96.9%).

[0510] MS m / z (ESI): 342.2 [M+H] + .

[0511] Intermediate Preparation Example 25: Preparation of 3-(2-oxo-6-(3,9-diazaspiro[5.5]undecan-3- yl)benzo[d]oxazol-3(2H)-yl)piperidine-2,6-dione

[0512] First Step: Preparation of tert-Butyl 9-(3-hydroxy-4-nitrophenyl)-3,9-diazaspiro[5.5]undecane-3- carboxylate

[0513] 5-Fluoro-2-nitrophenol (1.00 g, 6.30 mmol) and tert-butyl 3,9-diazaspiro[5.5]undecanoate (1.94 g, 7.56 mmol) were dissolved in dimethyl sulfoxide (20 mL), N,N-diisopropylethylamine (2.47 g, 18.91 mmol) was added, and the reaction was carried out at 110 °C for 3 hours. The reaction solution was allowed to cool to room temperature, ethyl acetate (50 mL) and saturated brine (50 mL) were added to the reaction system, the organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1 by volume) to obtain the title compound (2.30 g, yield: 92.3%).

[0514] MS m / z (ESI): 392.2 [M+H] + .

[0515] Second Step: Preparation of tert-butyl 9-(4-amino-3-hydroxyphenyl)-3,9- diazaspiro[5.5]undecane-3-carboxylate

[0516] tert-Butyl 9-(3-hydroxy-4-nitrophenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (2.30 g, 5.82 mmol) was dissolved in glacial acetic acid (30 mL), zinc powder (9.60 g, 11.64 mmol) was added, and the reaction was allowed to proceed at 25°C for 12 hours. Ethyl acetate (100 mL) and water (100 mL) were added to the reaction liquid, and the solid was removed by filtration. The filtrate was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. To the residue was added a mixed solvent of n-hexane / ethyl acetate = 50 / 1 (30 mL), and the mixture was stirred at room temperature for 1 hour. The solid was collected by filtration, and the filter cake was dried to obtain the title compound (1.90 g, yield: 90.3%).

[0517] MS m / z (ESI): 362.2 [M+H] + .

[0518] Third Step: Preparation of tert-butyl 9-(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-3,9- diazaspiro[5.5]undecane-3-carboxylate

[0519] tert-Butyl 9-(4-amino-3-hydroxyphenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (1.00 g, 2.74 mmol) was dissolved in ethyl acetate (30 mL), and N,N-diisopropylethylamine (715 mg, 5.48 mmol) and N,N'-carbonyldiimidazole (672 mg, 4.11 mmol) were sequentially added. The reaction was allowed to proceed at 25°C for 12 hours. The reaction liquid was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: petroleum ether / ethyl acetate = 1 / 2, by volume) to obtain the title compound (900 mg, yield: 83.9%).

[0520] MS m / z (ESI): 388.2 [M+H] + .

[0521] Fourth Step: Preparation of tert-butyl 9-(3-(2,6-dioxopiperidin-3-yl)-2-oxo-2,3- dihydrobenzo[d]oxazol-6-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate

[0522] tert-Butyl 9-(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-3,9-diazaspiro[5.5]undecane-3- carboxylate (300 mg, 766 μmol) and 3-bromopiperidine-2,6-dione (300 mg, 1.53 mmol) were dissolved in N,N-dimethylformamide (5 mL), and anhydrous potassium carbonate (215 mg, 1.53 mmol) was added, and the reaction was allowed to proceed at 70°C for 2 hours. The reaction was allowed to stand at room temperature, and ethyl acetate (50 mL) and saturated brine (20 mL) were added to the reaction, and the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / ethyl acetate = 1 / 1, by volume) to obtain the title compound (150 mg, yield: 38.8%).

[0523] MS m / z (ESI): 499.3 [M+H] + .

[0524] Fifth step: Preparation of 3-(2-oxo-6-(3,9-diazaspiro[5.5]undecan-3-yl)benzo[d]oxazol-3(2H)- yl)piperidine-2,6-dione

[0525] tert-Butyl 9-(3-(2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-3,9- diazaspiro[5.5]undecane-3-carboxylate (150 mg, 297 μmol) was dissolved in dichloromethane (5 mL), and 4M hydrogen chloride solution in 1,4-dioxane (1.0 mL) was added, and the reaction was allowed to proceed at 25°C for 5 hours. The reaction was concentrated under reduced pressure to obtain the title compound (130 mg, yield: 99.3%).

[0526] MS m / z (ESI): 399.2 [M+H] + .

[0527] Intermediate Preparation Example 26: Preparation of 3-(1-ethyl-5-fluoro-6-(3,9-diazaspiro[5.5]undecan-3-yl)-1H-indazol-3-yl)piperidine-2,6-dione

[0528] First step: Preparation of 6-bromo-1-ethyl-5-fluoro-3-iodo-1H-indazole

[0529] To a solution of 6-bromo-5-fluoro-3-iodo-1H-indazole (1.00 g, 2.93 mmol) in acetone (20 mL) was added potassium hydroxide (200 mg, 3.52 mmol) and iodoethane (1.16 g, 7.33 mmol) successively, and the mixture was stirred at 25 °C for 12 h. Ethyl acetate (50 mL) and water (20 mL) were added to the reaction mixture, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: petroleum ether / ethyl acetate = 7 / 1, by volume) to give the title compound (560 mg, yield: 51.2%).

[0530] MS m / z (ESI): 368.9 [M+H] + .

[0531] Second Step: Preparation of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-1-ethyl-5-fluoro-1H-indazole

[0532] To a solution of 6-bromo-1-ethyl-5-fluoro-3-iodo-1H-indazole (560 mg, 1.50 mmol) and 2,6-dibenzyloxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (635 mg, 1.50 mmol) in tetrahydrofuran (20 mL) and water (2 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (110 mg, 150 µmol) and anhydrous cesium carbonate (990 mg, 3.00 mmol) successively, and the mixture was stirred at 70 °C for 12 h. The reaction mixture was allowed to cool to room temperature, and the solid was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: petroleum ether / ethyl acetate = 7 / 1, by volume) to give the title compound (610 mg, yield: 75.4%).

[0533] MS m / z (ESI): 532.1 [M+H] + .

[0534] Third Step: Preparation of tert-butyl 9-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-ethyl-5-fluoro-1H-indazol-6-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate

[0535] To a solution of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-1-ethyl-5-fluoro-1H- indazole (610 mg, 1.13 mmol) and tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (437 mg, 1.70 mmol) in anhydrous toluene (15 mL) were added successively tris(dibenzylideneacetone)dipalladium (105 mg, 113 μmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'- biphenyl (53 mg, 113 μmol) and sodium tert-butoxide (330 mg, 3.40 mmol), and the mixture was purged with nitrogen three times. The reaction was stirred at 90 °C for 12 h. The reaction was cooled to room temperature, filtered to remove the solid, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: petroleum ether / ethyl acetate = 1 / 1, by volume) to give the title compound (400 mg, yield: 49.4%).

[0536] MS m / z (ESI): 706.4 [M+H] + .

[0537] Fourth step: Preparation of tert-butyl 9-(3-(2,6-dioxopiperidin-3-yl)-1-ethyl-5-fluoro-1H- indazol-6-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate

[0538] To a solution of tert-butyl 9-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-ethyl-5-fluoro-1H- indazol-6-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (400 mg, 561 μmol) in tetrahydrofuran (20 mL) was added 10% palladium on carbon (50 mg), and the mixture was stirred at 25 °C for 12 h under a hydrogen atmosphere. The reaction was filtered to remove the solid, and the filtrate was concentrated under reduced pressure to give the title compound (290 mg, yield: 96.9%).

[0539] MS m / z (ESI): 528.3 [M+H] + .

[0540] Fifth step: Preparation of 3-(1-ethyl-5-fluoro-6-(3,9-diazaspiro[5.5]undecan-3-yl)-1H- indazol-3-yl)piperidine-2,6-dione

[0541] tert-Butyl 9-(3-(2,6-dioxopiperidin-3-yl)-1-ethyl-5-fluoro-1H-indazol-6-yl)-3,9- diazaspiro [5.5] undecane-3-carboxylate (290 mg, 544 mmol) was dissolved in dichloromethane (10 mL), 4M hydrogen chloride solution in 1,4-dioxane (2 mL,) was added, and the reaction was allowed to proceed at 25 °C for 5 hours. The reaction was concentrated under reduced pressure to obtain the title compound (250 mg, yield: 98.0%).

[0542] MS m / z (ESI): 428.4 [M+H] + .

[0543] Intermediate Preparation Example 27: Preparation of 3-(2,6-difluoro-4-(3,9- diazaspiro [5.5] undecan-3-yl) phenyl) piperidine-2,6-dione

[0544] First Step: Preparation of 2,6-bis(benzyloxy)-3-(4-bromo-2,6-difluorophenyl) pyridine

[0545] 5-Bromo-1,3-difluoro-2-iodobenzene (630 mg, 1.98 mmol) and 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (824 mg, 1.98 mmol) were mixed in 1,4-dioxane (10 mL), and Pd(dppf)Cl2(140.5 mg, 188.2 umol) and cesium carbonate (1.88 g, 5.64 mmol) were added in turn. Nitrogen was replaced three times, and the reaction was allowed to proceed at 80 °C for 16 hours. The solid was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 8 / 1, by volume) to obtain the title compound (476 mg, yield: 50%).

[0546] MS m / z (ESI): 482.1 [M+H] + .

[0547] Second Step: Preparation of tert-Butyl 9-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5- difluorophenyl)-3,9-diazaspiro [5.5] undecane-3-carboxylate

[0548] A mixture of 2,6-bis(benzyloxy)-3-(4-bromo-2,6-difluorophenyl)pyridine (476 mg, 986.9 pmol) and tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (376.5 mg, 1.48 mmol) was mixed in toluene (10 mL), and tris(dibenzylideneacetone)dipalladium (90.4 mg, 98.7 pmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (46.1 mg, 98.7 pmol) and sodium tert-butoxide (284.5 mg, 2.96 mmol) were added successively. The flask was purged with nitrogen three times, and the reaction was carried out at 90 °C for 12 h. The solid was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: petroleum ether / ethyl acetate = 1 / 1, volume ratio) to give the title compound (386 mg, yield: 59.7%).

[0549] MS m / z (ESI): 656.3 [M+H] + .

[0550] Third Step: Preparation of tert-butyl 9-(4-(2,6-dioxopiperidin-3-yl)-3,5- difluorophenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate

[0551] Tert-butyl 9-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)-3,9- diazaspiro[5.5]undecane-3-carboxylate (386 mg, 588.6 pmol) was dissolved in tetrahydrofuran (10 mL), and 10% palladium-carbon (50 mg) was added. The reaction was carried out at 25 °C for 16 h under a hydrogen atmosphere. The solid was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (250 mg, yield: 89%).

[0552] MS m / z (ESI): 478.2 [M+H] + .

[0553] Fourth Step: Preparation of 3-(2,6-difluoro-4-(3,9-diazaspiro[5.5]undecan-3- yl)phenyl)piperidine-2,6-dione

[0554] Tert-butyl 9-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (250 mg, 523.5 pmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (2 mL) was added. The reaction was carried out at 25 °C for 2 h. The reaction solution was directly concentrated under reduced pressure to give the title compound (178 mg, yield: 90%).

[0555] MS m / z (ESI): 378.2 [M+H] +.

[0556] Intermediate Preparation Example 28: Preparation of (S)-(1-(((2-(3-cyano-2-(((dimethylamino)methylene)amino)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-3'-yl)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl methanesulfonate

[0557] First Step: Preparation of (S)-3-(4-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazole-7,1'-cyclohexan]-2'-one

[0558] (S)-3-(4-chloro-6-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazole-7,1'-cyclohexan]-2'-one (400 mg, 957.2 μmol) was dissolved in tetrahydrofuran (10 mL) and water (1 mL), palladium acetate (39.8 mg, 172.3 μmol) and potassium fluoride (102 mg, 1.72 mmol) were added, and then a tetrahydrofuran solution (1 mL) of polymethylhydrosiloxane (410.8 mg, 1.8 mmol) was slowly added dropwise. Stirring was carried out at 25 °C for 1 hour. An aqueous sodium bicarbonate solution (10 mL) was added to the reaction solution, and extraction was carried out three times with ethyl acetate (10 mL), the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1, by volume) to obtain the title compound (330 mg, yield: 60.4%).

[0559] MS m / z (ESI): 384.2 [M+H] + .

[0560] Second Step: Preparation of (S)-2-amino-3'-(4-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrimidin-2-yl)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-3-carbonitrile

[0561] (S)-3-(4-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrimidin-2-yl)-5,6-dihydro-4H- spiro[benzo[d]isoxazole-7,1 '-cyclohexan]-2'-one (330 mg, 817.6 pmol) was dissolved in ethanol (5 mL), ammonium acetate (192.9 mg, 2.45 mmol) and sulfur (80.1 mg, 2.45 mmol) were added, stirred at 60 °C for 0.5 hours, then acetaldehyde (220.5 mg, 3.27 mmol) in ethanol (2 mL) was added dropwise, warmed to 80 °C and stirred for 12 hours. The reaction was cooled to room temperature, water (10 mL) was added to dilute the reaction, extracted with ethyl acetate (10 mL) three times, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / ethyl acetate = 1 / 1, volume ratio) to obtain the title compound (215.5 mg, yield: 56.9%).

[0562] MS m / z (ESI): 464.2 [M+H] + .

[0563] Third step: Preparation of (S)-N'-(3-cyano-3'-(4-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrimidin-2-yl)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-2-yl)-N,N-dimethylformamidine

[0564] (S)-2-amino-3'-(4-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrimidin-2-yl)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-3-carbonitrile (215.5 mg, 464.89 pmol) was dissolved in tetrahydrofuran (5 mL), N,N-dimethylformamide dimethyl acetal (110.8 mg, 929.8 pmol) was added, and stirred at 25 °C for 2 hours. Water (10 mL) was added to the reaction, extracted with ethyl acetate (10 mL) three times, the organic phase was washed with saturated brine (10 mL), the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / ethyl acetate = 2 / 1, volume ratio) to obtain the title compound (220 mg, yield: 91.2%).

[0565] MS m / z (ESI): 519.2 [M+H] + .

[0566] Fourth Step: Preparation of (S)-(1-(((2-(3-cyano-2-(((dimethylamino) methylene)amino)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-3'-yl)-6-((4-methylpyridin-3-yl)oxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl methanesulfonate

[0567] (S)-N'-(3-cyano-3'-(4-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrimidin-2-yl)-5',6,6',7- tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-2-yl)-N,N-dimethylformamidine (220 mg, 424.2 µmol) was dissolved in dichloromethane (5 mL), then methanesulfonic anhydride (110.8 mg, 636.3 µmol) and N,N-diisopropylethylamine (109.6 mg, 848.4 µmol) were added, and stirred at 25°C for 2 hours. Water (10 mL) was added to the reaction solution, extracted with dichloromethane (10 mL) three times, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (217 mg, yield: 85.8%).

[0568] MS m / z (ESI): 597.2 [M+H] + .

[0569] Intermediate Preparation Example 29: Preparation of (S)-(1-(((2-(3-cyano-2-(((dimethylamino)methylene)amino)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-3'-yl)-6-((4-methylpyridin-3-yl)oxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl methanesulfonate

[0570] Using the synthetic route in Intermediate Preparation Example 1, the raw material 5-hydroxypyrimidine in the second step was replaced with 4-methylpyridin-3-ol to obtain the title compound (220 mg, yield: 93.1%).

[0571] MS m / z (ESI): 704.2 [M+H] + .

[0572] Intermediate Preparation Example 30: Preparation of 3-(4-((3-azaspiro[5.5]undecan-9-yl)oxy)phenyl)piperidine-2,6-dione

[0573] First Step: Preparation of tert-butyl 9-hydroxy-3-azaspiro[5.5]undecanoate

[0574] tert-Butyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate (400 mg, 1.42 mmol) was dissolved in ethanol (10 mL), sodium borohydride (104.66 mg, 2.84 mmol) was added, and the reaction was allowed to react at 25°C for 2 hours. To the reaction solution, saturated aqueous ammonium chloride solution (10 mL) was added to quench, and extracted with ethyl acetate (10 mL) three times, and 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 (340 mg, yield: 84%).

[0575] MS m / z (ESI): 270.2 [M+H] + .

[0576] Second Step: Preparation of tert-Butyl 9-(4-iodophenoxy)-3-azaspiro[5.5]undecane-3- carboxylate

[0577] tert-Butyl 9-hydroxy-3-azaspiro[5.5]undecane-3-carboxylate (340 mg, 1.2 mmol) and 4-iodophenol (277 mg, 1.2 mmol) were dissolved in tetrahydrofuran (5 mL), and diisopropyl azodicarboxylate (275 mg, 1.32 mmol) and triphenylphosphine (481 mg, 1.8 mmol) were added, and stirred at 25°C for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1, by volume) to obtain the title compound (110 mg, yield: 18.5%).

[0578] MS m / z (ESI): 472.1 [M+H] + .

[0579] Third Step: Preparation of tert-Butyl 9-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenoxy)-3- azaspiro[5.5]undecane-3-carboxylate

[0580] tert-Butyl 9-(4-iodophenoxy)-3-azaspiro[5.5]undecane-3-carboxylate (100 mg, 210 µmol) and 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (115.1 mg, 273 µmol) were mixed in tetrahydrofuran (5 mL) and water (0.5 mL), and Pd(dppf)Cl2 (15.5 mg, 21 µmol) and cesium carbonate (172.8 mg, 525 µmol) were sequentially added. Nitrogen was replaced three times, and the reaction was allowed to react at 80°C for 16 hours. The solid was removed by filtration, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1, by volume) to obtain the title compound (105 mg, yield: 74.8%).

[0581] MS m / z (ESI): 635.3 [M+H] + .

[0582] Fourth Step: Preparation of tert-butyl 9-(4-(2,6-dioxopiperidin-3-yl)phenoxy)-3- azaspiro[5.5]undecane-3-carboxylate

[0583] tert-Butyl 9-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenoxy)-3-azaspiro[5.5]undecane-3- carboxylate (105 mg, 157.1 umol) was dissolved in tetrahydrofuran (5 mL), 10% palladium on carbon (10 mg) was added, and the reaction was stirred under hydrogen atmosphere at 25 °C for 16 hours. The solid was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (63 mg, yield: 88%).

[0584] MS m / z (ESI): 457.2 [M+H] + .

[0585] Fifth Step: Preparation of 3-(4-((3-azaspiro[5.5]undecan-9-yl)oxy)phenyl)piperidine-2,6- dione

[0586] tert-Butyl 9-(4-(2,6-dioxopiperidin-3-yl)phenoxy)-3-azaspiro[5.5]undecane-3-carboxylate (63 mg, 138 μmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added, and the reaction was stirred at 25 °C for 2 hours. The reaction was directly concentrated under reduced pressure to give the title compound (44 mg, yield: 90%).

[0587] MS m / z (ESI): 357.2 [M+H] + .

[0588] Intermediate Preparation Example 31: Preparation of methyl (1-(((6-((8-oxabicyclo[3.2.1]octan-3- yl)oxy)-2-((S)-3-cyano-2-(dimethylamino)methylidene)amino)-5',6,6',7-tetrahydro-4'H,5H- spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-3'-yl)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl) methanesulfonate

[0589] Using the synthetic route in Intermediate Preparation Example 1, the second step reaction starting material 5-hydroxypyrimidine was replaced with 8-oxabicyclo[3.2.1]octan-3-ol to give the title compound (26 mg, yield: 92%).

[0590] MS m / z (ESI): 723.2 [M+H]+ .

[0591] Intermediate Preparation Example 32: Preparation of 1-(6-(1-(7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0592] First Step: Preparation of tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[0593] tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (70 mg, 156.29 µmol) was dissolved in methanol (3 mL), 10% palladium carbon (20 mg) was added to the system, and the mixture was stirred at 25 °C for 12 hours under a hydrogen atmosphere. The reaction solution was filtered through celite, the filter cake was rinsed with methanol for 2-3 times, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 15 / 1, volume ratio) to obtain the title compound (50 mg, yield: 74.8%).

[0594] MS m / z (ESI): 426.2 [M+H] + .

[0595] Second Step: Preparation of tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidine-1-carboxylate

[0596] tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (70 mg, 156.29 µmol) was dissolved in methanol (3 mL), 10% palladium carbon (20 mg) was added to the system, and the mixture was stirred at 25 °C for 12 hours under a hydrogen atmosphere. The reaction solution was filtered through celite, the filter cake was rinsed with methanol for 2-3 times, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 15 / 1, volume ratio) to obtain the title compound (50 mg, yield: 74.8%).

[0597] MS m / z (ESI): 428.2 [M+H] + .

[0598] Step 3: Preparation of 1-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

[0599] tert-Butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidine- 1-carboxylate (50 mg, 116.96 pmol) was dissolved in 4 M hydrogen chloride in 1,4-dioxane (2 mL) and stirred at 25 °C for 12 h. The reaction was concentrated to give the title compound (40. mg, yield: 94%).

[0600] MS m / z (ESI): 328.2 [M+H] + .

[0601] Step 4: Preparation of tert-Butyl 2-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl- 1H-indazol-6-yl)piperidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate

[0602] 1-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (40 mg, 122.18 pmol) and acetic acid (31.33 mg, 244.36 pmol) were dissolved in DMF (2 mL), tert-Butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (87.72 mg, 366.55 pmol) was added, stirred at room temperature for 30 min, then sodium triacetoxyborohydride (103.58 mg, 488.73 pmol) was added, and the reaction was stirred at 25 °C for 16 h. The reaction was filtered, and the filtrate was purified by reverse phase column (eluent: acetonitrile / water (0.05% formic acid) = 7 / 3, volume ratio) to give the title compound (40 mg, yield 59.5%).

[0603] MS m / z (ESI): 551.3 [M+H] + .

[0604] Step 5: Preparation of 1-(6-(1-(7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1-methyl-1H-indazol- 3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0605] tert-Butyl 2-(4-(3-(2,4-dioxotetrahydropyrimidin-1 (2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (40 mg, 72.64 pmol) was dissolved in 4 M hydrogen chloride solution in 1,4-dioxane (1 mL) and dichloromethane (1 mL), stirred at 25 °C for 2 hours. The reaction solution was concentrated to obtain the title compound (35 mg, yield: 98.9%).

[0606] MS m / z (ESI): 451.3 [M+H] + .

[0607] Intermediate Preparation Example 33: Preparation of 1-(1-methyl-6-(3,9-diazaspiro[5.5]undecan-3-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0608] First Step: Preparation of tert-butyl 9-(3-(2,4-dioxotetrahydropyrimidin-1 (2H)-yl)-1-methyl-1H-indazol-6-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate

[0609] tert-Butyl 1-(6-bromo-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (150 mg, 440.98 pmol), tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (236.15 mg, 881.96 pmol), dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridinyl)palladium (35.94 mg, 44.10 pmol) and cesium carbonate (362.83 mg, 1.10 mmol) were added into dioxane (3 mL) in turn, replaced with nitrogen for three times, stirred at 100 °C for 3 hours. The reaction solution was cooled to room temperature, the reaction solution was diluted with ethyl acetate (25 mL), washed with saturated brine (15 mL) for two times, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, the residue was separated and purified by silica gel column chromatography (eluent: dichloromethane / methanol = 15 / 1, volume ratio) to obtain the title compound (70 mg, yield: 30.4%).

[0610] MS m / z (ESI): 497.3 [M+H] + .

[0611] Second Step: Preparation of 1-(1-methyl-6-(3,9-diazaspiro[5.5]undecan-3-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0612] Tert-butyl 9-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)- 3,9-diazaspiro[5.5]undecane-3-carboxylate (70 mg, 133.91 pmol) was dissolved in 4 M hydrogen chloride in 1,4-dioxane (1 mL) and dichloromethane (1 mL) and stirred at 25 °C for 2 h. The reaction was concentrated to give the title compound (60 mg, yield: 98.3%).

[0613] MS m / z (ESI): 397.3 [M+H] + .

[0614] Intermediate Preparation Example 34: Preparation of 3-(1-methyl-6-(2,7- diazaspiro[3.5]non-2-yl)-1H-indazol-3-yl)piperidine-2,6-dione

[0615] The title compound was obtained using the synthetic route in Intermediate Preparation Example 5, replacing tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate in the first step with tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (200 mg, yield: 97.1%).

[0616] MS m / z (ESI): 368.2 [M+H] + .

[0617] Intermediate Preparation Example 35: Preparation of 3-(1-methyl-6-(2,8- diazaspiro[4.5]dec-2-yl)-1H-indazol-3-yl)piperidine-2,6-dione

[0618] The title compound was obtained using the synthetic route in Intermediate Preparation Example 5, replacing tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate in the first step with tert-butyl 2,8-diazaspiro[4.5]decane-8-carboxylate (130 mg, yield: 97.2%).

[0619] MS m / z (ESI): 382.2 [M+H] + .

[0620] Intermediate Preparation Example 36: Preparation of 3-(3-((3- azaspiro[5.5]undecan-9-yl)oxy)phenyl)piperidine-2,6-dione

[0621] The title compound was obtained using the synthetic route in Intermediate Preparation Example 30, replacing 4-iodophenol in the second step with 3-iodophenol (120 mg, yield: 97.23%).

[0622] MS m / z (ESI): 357.3 [M+H] + .

[0623] Preparation of Intermediate 37: 3-(5-(1-(7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0624] The synthetic route in Intermediate Preparation 32 was adopted and the first step reaction material 1-(6-bromo-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione was replaced by 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione to obtain the title compound (60 mg, yield: 96.6%).

[0625] MS m / z (ESI): 466.3 [M+H] + .

[0626] Preparation of Intermediate 38: 3-(3-methyl-2-oxo-5-(3,9-diazaspiro[5.5]undecan-3-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0627] The synthetic route in Intermediate Preparation 33 was adopted and the first step reaction material 1-(6-bromo-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione was replaced by 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione to obtain the title compound (240 mg, yield: 74.6%).

[0628] MS m / z (ESI): 412.2 [M+H] + .

[0629] Preparation of Intermediate 39: 3-(1-oxo-5-(4-(piperazin-1-ylmethyl)piperidin-1-yl)isoindolin-2-yl)piperidine-2,6-dione

[0630] Step 1: Preparation of 3-(5-(4-(dimethoxymethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0631] To a solution of 3-(5-bromo-l-oxoisoindolin-2-yl)piperidine-2,6-dione (500 mg, 1.47 mmol), 4-(dimethoxymethyl)piperidine (477.66 mg, 2.94 mmol), dichloro[l,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium (119.82 mg, 146.99 μmol) and cesium carbonate (1.45 g, 4.41 mmol) in dioxane (2 mL) was added under nitrogen for three times. The reaction mixture was stirred at 110 °C for 3 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (25 mL), washed with saturated brine (15 mL) twice, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (eluent: dichloromethane / methanol = 15 / 1, volume ratio) to give the title compound (180 mg, yield: 28.98%).

[0632] MS m / z (ESI): 402.2 [M+H]+. + .

[0633] Second Step: Preparation of l-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)piperidine-4-carbaldehyde

[0634] The starting material 3-(5-(4-(dimethoxymethyl)piperidin-l-yl)-l-oxoisoindolin-2-yl)piperidine-2,6-dione (180 mg, 425.95 μmol) was dissolved in tetrahydrofuran (2 mL), and trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give the title compound (90 mg, yield: 56.48%).

[0635] MS m / z (ESI): 356.2 [M+H]+.

[0636] Third Step: Preparation of tert-butyl 4-((l-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazine-l-carboxylate

[0637] Piperidin-4-yl 4-((1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)piperidin-4-yl)methyl)piperazine-1-carboxylate (70 mg, 126.51 μmol) was dissolved in dichloromethane (2 mL), 4M hydrogen chloride solution in 1,4-dioxane (0.5 mL) was added, and stirred at room temperature for 2 hours. The reaction solution was concentrated to give the title compound (60 mg, yield: 97.5%).

[0638] MS m / z (ESI): 526.3 [M+H]+.

[0639] Fourth step: Preparation of 3-(1-oxo-5-(4-(piperazin-1-ylmethyl)piperidin-1-yl)isoindolin-2-yl)piperidine-2,6-dione

[0640] Piperidin-4-yl 4-((1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)piperidin-4-yl)methyl)piperazine-1-carboxylate (70 mg, 126.51 μmol) was dissolved in dichloromethane (2 mL), 4M hydrogen chloride solution in 1,4-dioxane (0.5 mL) was added, and stirred at room temperature for 2 hours. The reaction solution was concentrated to give the title compound (60 mg, yield: 97.5%).

[0641] MS m / z (ESI): 426.2 [M+H]+.

[0642] Intermediate Preparation Example 40: Preparation of 3-(2-oxo-5-(3,9- diazaspiro[5.5]undecan-3-yl)indolin-1-yl)piperidine-2,6-dione

[0643] First step: Preparation of tert-butyl 9-(3-(2-(allyloxy)-2-oxoethyl)-4- nitrophenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate

[0644] Allyl 2-(5-fluoro-2-nitrophenyl)acetate (450 mg, 1.79 mmol), tert-butyl 3,9- diazaspiro[5.5]undecane-3-carboxylate (551.04 mg, 2.14 mmol) and N,N- diisopropylethylamine (699.94 mg, 5.36 mmol) were dissolved in dimethyl sulfoxide (5 mL) and stirred at 110 °C for 3 hours. The reaction was cooled to room temperature, diluted with ethyl acetate (25 mL), washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (eluent: dichloromethane / methanol = 15 / 1, volume ratio) to give the title compound (800 mg, yield: 89.8%).

[0645] MS m / z (ESI): 474.3 [M+H] + .

[0646] Second step: Preparation of tert-butyl 9-(3-(2-(allyloxy)-2-oxoethyl)-4- aminophenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate

[0647] Tert-butyl 9-(3-(2-(allyloxy)-2-oxoethyl)-4-nitrophenyl)-3,9-diazaspiro[5.5]undecane-3- carboxylate (700 mg, 1.40 mmol) and tetrahydroxydiboron (379.15 mg, 4.21 mmol) were dissolved in DMF (10 mL), then 4,4-bipyridine (22.19 mg, 140.43 μmol) was slowly added and stirred at 25 °C for 2 hours. The reaction was diluted with ethyl acetate (20 mL), washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (eluent: dichloromethane / methanol = 15 / 1, volume ratio) to give the title compound (600 mg, yield: 77.1%).

[0648] MS m / z (ESI): 444.3 [M+H] + .

[0649] Third step: Preparation of tert-butyl 9-(3-(2-(allyloxy)-2-oxoethyl)-4-((2,6-dioxopiperidin-3- yl)amino)phenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate

[0650] tert-Butyl 9-(3-(2-(allyloxy)-2-oxoethyl)-4-aminophenyl)-3,9-diazaspiro[5.5]undecane-3- carboxylate (600 mg, 1.08 mmol) and sodium bicarbonate (272.69 mg, 3.25 mmol) were mixed in DMF (6 mL), 3-bromopiperidine-2,6-dione (262.45 mg, 1.3 mmol) was added, and the reaction was reacted at 80 °C for 2 hours. The reaction was filtered, and the filtrate was purified by a reverse phase column (eluent: acetonitrile / water (0.05% formic acid) = 3 / 2, volume ratio) to obtain the title compound (600 mg, yield: 94.9%).

[0651] MS m / z (ESI): 555.3 [M+H] + .

[0652] Fourth step: Preparation of 2-(5-(9-(tert-butoxycarbonyl)-3,9-diazaspiro[5.5]undecan-3-yl)-2- ((2,6-dioxopiperidin-3-yl)amino)phenyl)acetic acid

[0653] tert-Butyl 9-(3-(2-(allyloxy)-2-oxoethyl)-4-((2,6-dioxopiperidin-3-yl)amino)phenyl)-3,9- diazaspiro[5.5]undecane-3-carboxylate (600 mg, 1.03 mmol) was dissolved in anhydrous DMF (10 mL), 1,3-dimethylbarbituric acid (480.93 mg, 3.08 mmol) and tetrakis triphenylphosphine palladium (237.50 mg, 205.53 μmol) were added, and the reaction was replaced with nitrogen three times and reacted at 20 °C for 4 hours. The reaction was filtered, and the filtrate was purified by a reverse phase column (eluent: acetonitrile / water (0.05% formic acid) = 3 / 2, volume ratio) to obtain the title compound (350 mg, yield 62.8%).

[0654] MS m / z (ESI): 515.3 [M+H] + .

[0655] Fifth step: Preparation of tert-Butyl 9-(1-(2,6-dioxopiperidin-3-yl)-2-oxoindol-5-yl)-3,9- diazaspiro[5.5]undecane-3-carboxylate

[0656] (3mL), benzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (85.90 mg, 221.53 μmol) and N,N-diisopropylethylamine (72.30 mg, 553.81 μmol) were added. The reaction was stirred at 25 °C for 12 h. The reaction was filtered, and the filtrate was purified by reverse phase column (eluent: acetonitrile / water (0.05% formic acid) = 4 / 3, volume ratio) to give the title compound (80 mg, yield: 87.3%).

[0657] MS m / z (ESI): 497.3 [M+H] + .

[0658] Step 6: Preparation of 3-(2-oxo-5-(3,9-diazaspiro[5.5]undecan-3-yl)indolin-1-yl)piperidine- 2,6-dione

[0659] tert-butyl 9-(1-(2,6-dioxopiperidin-3-yl)-2-oxoindolin-5-yl)-3,9-diazaspiro[5.5]undecane- 3-carboxylate (80 mg, 153.04 μmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added, and the reaction was stirred at 25 °C for 4 h. The reaction was concentrated to give the title compound (80 mg, yield: 97.3%).

[0660] MS m / z (ESI): 397.3 [M+H] + .

[0661] Intermediate Preparation Example 41: Preparation of 1-(2-chloro-5-(3,9- diazaspiro[5.5]undecan-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0662] Step 1: Preparation of tert-butyl 9-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)- 3,9-diazaspiro[5.5]undecane-3-carboxylate

[0663] To a solution of 4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoic acid (100 mg, 353.62 pmol) and N,N-diisopropylethylamine (144.32 mg, 1.06 mmol) and tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (100.00 mg, 373.48 pmol) in DMF (3 mL) was added benzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (212.17 mg, 530.42 pmol) and the reaction was stirred at 25 °C for 3 h. The reaction was diluted with ethyl acetate (20 mL), washed twice with saturated brine (20 mL), 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 (150 mg, yield: 79.8%).

[0664] MS m / z (ESI): 505.2 [M+H] + .

[0665] Second Step: Preparation of 1-(2-chloro-5-(3,9-diazaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0666] To a solution of tert-butyl 9-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)- yl)benzoyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (150 mg, 282.18 pmol) in dichloromethane (1 mL) was added 4 M hydrogen chloride solution in 1,4-dioxane (1 mL) and the reaction was stirred at 25 °C for 4 h. The reaction was concentrated to give the title compound (125 mg, yield: 95.3%).

[0667] MS m / z (ESI): 405.2 [M+H] + .

[0668] Intermediate Preparation Example 42: Preparation of (S)-(1-(((2-(3-cyano-2-(((dimethylamino)methylene)amino)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-3'-yl)-6-((4- (trifluoromethyl)pyrimidin-5-yl)oxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl methanesulfonate

[0669] Using the synthetic route in Intermediate Preparation Example 1, the first step reaction material 5-hydroxypyrimidine was replaced with 4-(trifluoromethyl)pyrimidin-5-ol to give the title compound (190 mg, yield: 76.2%).

[0670] MS m / z (ESI): 679.2 [M+H] + .

[0671] Preparation of intermediate: 3-(1-methyl-6-(4-oxopiperidin-1-yl)-1H-indazol-3-yl)piperidine- 2,6-dione

[0672] First step: Preparation of 1-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin- 4-one

[0673] Dissolve 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-1-methyl-1H-indazole (500 mg, 949.3 μmol), piperidin-4-one (286 mg, 1.90 mmol), tris(dibenzylideneacetone)dipalladium (89 mg, 94.9 μmol), 5-di-tert-butylphosphine-1',3',5'-tri-phenyl-1'H-[1,4']bipyrazol (98 mg, 189.9 μmol) and cesium carbonate (1.25 g, 3.8 mmol) in 1,4-dioxane (10 mL), replace with nitrogen for three times, stir the reaction at 100 °C for 12 hours. Concentrate the reaction, purify the residue by silica gel column chromatography (eluent: dichloromethane / ethyl acetate = 10 / 1, by volume), to obtain the title compound (190 mg, yield: 38.2%).

[0674] MS m / z (ESI): 519.2 [M+H] + .

[0675] Second step: Preparation of 3-(1-methyl-6-(4-oxopiperidin-1-yl)-1H-indazol-3-yl)piperidine-2,6-dione

[0676] Dissolve 1-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-4-one (190 mg, 362.7 μmol) in a mixture solvent of tetrahydrofuran (3.5 mL) and ethanol (3.5 mL), add 10% palladium on carbon (25 mg), stir the reaction under hydrogen atmosphere at 25 °C for 12 hours. Filter the reaction through celite, rinse the filter cake with ethanol for 2-3 times, concentrate the filtrate, to obtain the title compound (101 mg, yield: 77.7%).

[0677] MS m / z (ESI): 341.1 [M+H] + .

[0678] Intermediate Preparation Example 44: Preparation of 1-(5-(4-(7-azaspiro[3.5]nonan-2- yl)piperazine-1-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0679] First Step: Preparation of tert-butyl 4-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)- yl)benzoyl)piperazine-1-carboxylate

[0680] tert-Butyl 4-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperazine-1- carboxylate (510 mg, 700.4 µmol) was dissolved in 4 M hydrogen chloride in 1,4-dioxane (2.5 mL) and stirred at 25 °C for 2 hours. The reaction was concentrated to give the title compound (258 mg, yield: 98.9 %).

[0681] MS m / z (ESI): 437.2 [M+H] + .

[0682] Second Step: Preparation of 1-(2-chloro-5-(piperazine-1-carbonyl)phenyl)dihydropyrimidine- 2,4(1H,3H)-dione

[0683] tert-Butyl 4-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperazine-1- carboxylate (510 mg, 700.4 µmol) was dissolved in 4 M hydrogen chloride in 1,4-dioxane (2.5 mL) and stirred at 25 °C for 2 hours. The reaction was concentrated to give the title compound (258 mg, yield: 98.9 %).

[0684] MS m / z (ESI): 337.1 [M+H] + .

[0685] Third Step: Preparation of tert-butyl 2-(4-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)- yl)benzoyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate

[0686] To a solution of 1-(2-chloro-5-(piperazin-1-ylcarbonyl)phenyl)dihydropyrimidine- 2,4(1H,3H)-dione (497 mg, 692.4 μmol), tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7- carboxylate (436 mg, 1.73 mmol) and N,N-diisopropylethylamine (136 mg, 1.04 mmol) in DMF (3.5 mL) was stirred at room temperature for 30 min, sodium cyanoborohydride (92 mg, 1.38 mmol) was added, and the reaction was stirred at 25 °C for 5 h. The reaction was diluted with ethyl acetate (50 mL), washed with saturated brine (80 mL) twice, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (eluent: dichloromethane / methanol = 15 / 1, volume ratio) to give the title compound (167 mg, yield: 42.6%).

[0687] MS m / z (ESI): 560.3 [M+H] + .

[0688] Fourth Step: Preparation of 1-(5-(4-(7-azaspiro[3.5]nonan-2-yl)piperazin-1- ylcarbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0689] To a solution of tert-butyl 2-(4-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)- yl)benzoyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (167 mg, 295.2 μmol) in 4 M hydrogen chloride in 1,4-dioxane (1 mL) was stirred at 25 °C for 2 h. The reaction was concentrated to give the title compound (128 mg, yield: 94.3%).

[0690] MS m / z (ESI): 460.2 [M+H] + .

[0691] Intermediate Preparation Example 45: Preparation of 3-(1-methyl-6-(2,7- diazaspiro[3.5]nonan-7-yl)-1H-indazol-3-yl)piperidine-2,6-dione

[0692] Using the synthetic route in Intermediate Preparation Example 5, the first step reaction material tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate was replaced by tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate to give the title compound (81 mg, yield: 81.2%).

[0693] MS m / z (ESI): 368.3 [M+H] + .

[0694] Intermediate Preparation Example 46: Preparation of 3-(1-methyl-6-(2,8- diazaspiro[4.5]dec-8-yl)-1H-indazol-3-yl)piperidine-2,6-dione

[0695] The first step reaction material 3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester in the synthetic route in Intermediate Preparation Example 5 was replaced by 2,8-diazaspiro[4.5]decane-2-carboxylic acid tert-butyl ester to obtain the title compound (243 mg, yield: 98.2%).

[0696] MS m / z (ESI): 382.3 [M+H] + .

[0697] Intermediate Preparation Example 47: Preparation of 3-((3-fluoro-4-(3,9- diazaspiro[5.5]undec-3-yl)phenyl)amino)piperidine-2,6-dione

[0698] First Step: Preparation of 9-(2-fluoro-4-nitrophenyl)-3,9-diazaspiro[5.5]undecane- 3-carboxylic acid tert-butyl ester

[0699] 1,2-difluoro-4-nitrobenzene (300 mg, 1.85 mmol) and 3,9-diazaspiro[5.5]undecane-3- carboxylic acid tert-butyl ester (528 mg, 2.03 mmol) were dissolved in tetrahydrofuran (3 mL), N,N-diisopropylethylamine (290 mg, 2.22 mmol) was added, and the reaction was stirred at 25 °C for 12 hours. The reaction was diluted with ethyl acetate (50 mL), washed with saturated brine (70 mL) twice, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was separated and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1, by volume) to obtain the title compound (626 mg, yield: 81.8%).

[0700] MS m / z (ESI): 394.2 [M+H] + .

[0701] Second Step: Preparation of 9-(4-amino-2-fluorophenyl)-3,9-diazaspiro[5.5]undecane- 3-carboxylic acid tert-butyl ester

[0702] tert-Butyl 9-(2-fluoro-4-nitrophenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (626 mg, 1.51 mmol) was dissolved in methanol (10 mL), 10% palladium on carbon (184 mg) was added, and the reaction was stirred under an atmosphere of hydrogen at 25 °C for 12 h. The reaction was filtered through celite, the filter cake was rinsed with methanol 2-3 times, and the filtrate was concentrated to give the title compound (578 mg, yield: 99.9%).

[0703] MS m / z (ESI): 364.3 [M+H] + .

[0704] Third Step: Preparation of tert-Butyl 9-(4-((2,6-dioxopiperidin-3-yl)amino)-2- fluorophenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate

[0705] tert-Butyl 9-(4-amino-2-fluorophenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (578 mg, 1.51 mmol), 3-bromopiperidine-2,6-dione (444 mg, 2.27 mmol), and sodium bicarbonate (385 mg, 4.53 mmol) were dissolved in DMF (7 mL), and the reaction was stirred at 80 °C for 16 h. The reaction was diluted with ethyl acetate (60 mL), washed with saturated brine (50 mL) twice, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (eluent: dichloromethane / methanol = 15 / 1, volume ratio) to give the title compound (750 mg, yield: 99.4%).

[0706] MS m / z (ESI): 475.3 [M+H] + .

[0707] Fourth Step: Preparation of 3-((3-fluoro-4-(3,9-diazaspiro[5.5]undecan-3-yl)phenyl)amino)piperidine-2,6-dione

[0708] tert-Butyl 9-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (750 mg, 1.50 mmol) was dissolved in a 4 M solution of hydrogen chloride in 1,4-dioxane (5 mL), and the reaction was stirred at 25 °C for 12 h. The reaction was concentrated to give the title compound (350 mg, yield: 62.3%).

[0709] MS m / z (ESI): 375.3 [M+H] + .

[0710] Intermediate Preparation 48: Preparation of 3-(4-(3,9-diazaspiro[5.5]undecan-3- yl)phenoxy)piperidine-2,6-dione

[0711] First Step: Preparation of tert-butyl 9-(4-(benzyloxy)phenyl)-3,9-diazaspiro[5.5]undecane- 3-carboxylate

[0712] Dissolve 1-benzyloxy-4-bromo-benzene (300 mg, 1.13 mmol), tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (326 mg, 1.24 mmol), tris(dibenzylideneacetone)dipalladium (105 mg, 112.9 μmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'- biphenyl (111 mg, 225.7 μmol) and sodium tert-butoxide (332 mg, 3.39 mmol) in toluene (6 mL), replace with nitrogen for three times, stir the reaction at 90 °C for 12 hours. Concentrate the reaction, purify the residue by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1, by volume) to give the title compound (483 mg, yield: 97.0%).

[0713] MS m / z (ESI): 437.3 [M+H] + .

[0714] Second Step: Preparation of tert-butyl 9-(4-hydroxyphenyl)-3,9-diazaspiro[5.5]undecane-3- carboxylate

[0715] Dissolve tert-butyl 9-(4-(benzyloxy)phenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (483 mg, 1.10 mmol) in a mixture solvent of tetrahydrofuran (2 mL) and ethanol (10 mL), add 10% palladium carbon (117 mg), stir the reaction in hydrogen atmosphere at 25 °C for 12 hours. Filter the reaction through celite, rinse the filter cake with ethanol for 2-3 times, concentrate the filtrate to give the title compound (360 mg, yield: 90.1%).

[0716] MS m / z (ESI): 347.3 [M+H] + .

[0717] Third Step: Preparation of tert-butyl 9-(4-((2,6-dioxopiperidin-3-yl)oxy)phenyl)-3,9- diazaspiro[5.5]undecane-3-carboxylate

[0718] tert-Butyl 9-(4-hydroxyphenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (360 mg, 987.1 μmol) was dissolved in DMF (9 mL), sodium hydride (59 mg, 1.48 mmol) was added, and the reaction was stirred at room temperature for 30 minutes. 3-Bromopiperidine-2,6-dione (290 mg, 1.48 mmol) was added, and the reaction was stirred at 25°C for 3 hours. Saturated aqueous ammonium chloride solution (10 mL) was added to the system to quench the reaction, and the reaction was extracted with ethyl acetate (20 mL) three times. The organic phase was washed with saturated brine (100 mL) twice, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was separated and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1, by volume) to obtain the title compound (94 mg, yield: 20.6%).

[0719] MS m / z (ESI): 458.2 [M+H] + .

[0720] Fourth step: Preparation of 3-(4-(3,9-diazaspiro[5.5]undecan-3-yl)phenoxy)piperidine-2,6-dione

[0721] tert-Butyl 9-(4-hydroxyphenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (360 mg, 987.1 μmol) was dissolved in DMF (9 mL), sodium hydride (59 mg, 1.48 mmol) was added, and the reaction was stirred at room temperature for 30 minutes. 3-Bromopiperidine-2,6-dione (290 mg, 1.48 mmol) was added, and the reaction was stirred at 25°C for 3 hours. Saturated aqueous ammonium chloride solution (10 mL) was added to the system to quench the reaction, and the reaction was extracted with ethyl acetate (20 mL) three times. The organic phase was washed with saturated brine (100 mL) twice, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was separated and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1, by volume) to obtain the title compound (94 mg, yield: 20.6%).

[0722] MS m / z (ESI): 458.2 [M+H] + .

[0723] Intermediate Preparation Example 49: Preparation of 3-(3-(3,9-diazaspiro[5.5]undecan-3-yl)phenoxy)piperidine-2,6-dione

[0724] The synthetic route in Intermediate Preparation Example 48 was used, and 1-benzyloxy-4-bromobenzene in the first step was replaced with 1-benzyloxy-3-bromobenzene to obtain the title compound (44 mg, yield: 99.4%).

[0725] MS m / z (ESI): 458.2 [M+H] + .

[0726] Intermediate Preparation Example 50: Preparation of (S)-(1-(((2-(3-cyano-2-(((dimethylamino)methylene)amino)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-3'-yl)-6-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)methanesulfonate

[0727] The synthetic route in Intermediate Preparation Example 1 was adopted, and the raw material for the second step reaction, 5-hydroxypyrimidine, was replaced by tetrahydropyran-4-ol, to obtain the title compound (55 mg, yield: 63%).

[0728] MS m / z (ESI): 697.3 [M+H] + .

[0729] Intermediate Preparation Example 51: Preparation of (S)-N'-(3-cyano-3'-(4-((1- formylcyclopropyl)methoxy)-6-(1,4-oxazepan-4-yl)pyrimidin-2-yl)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-2-yl)-N,N-dimethylformamidine

[0730] First Step: Preparation of (S)-3-(4-((1-(hydroxymethyl)cyclopropyl)methoxy)-6-(1,4-oxazepan-4-yl)pyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazole-7,1'-cyclohexan]-2'-one

[0731] (7S)-3-[4-chloro-6-[[1-(hydroxymethyl)cyclopropyl]methoxy]pyrimidin-2-yl]spiro[5,6-dihydro-4H-1,2-benzoxazole-7,2'-cyclohexan]-1'-one (150 mg, 341 μmol), 1,4-oxazepane (53 mg, 511.5 μmol) and cesium carbonate (168 mg, 511.5 μmol) were dissolved in acetonitrile (5 mL), and the reaction was stirred at 80 °C for 2 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / ethyl acetate = 3 / 1, by volume) to obtain the title compound (164 mg, yield: 99.8%).

[0732] MS m / z (ESI): 483.3 [M+H] + .

[0733] Step 2: Preparation of (S)-2-amino-3'-(4-((1-(hydroxymethyl)cyclopropyl)methoxy)-6-(1,4- oxazepan-4-yl)pyrimidin-2-yl)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'- benzo[d]isoxazole]-3-carbonitrile

[0734] (S)-3-(4-((1-(hydroxymethyl)cyclopropyl)methoxy)-6-(1,4-oxazepan-4-yl)pyrimidin-2-yl)-5,6- dihydro-4H-spiro[benzo[d]isoxazole-7,1'-cyclohexan]-2'-one (164 mg, 340.4 pmol), ammonium acetate (106 mg, 1.36 mmol) and sulfur (44 mg, 1.36 mmol) were dissolved in ethanol (10 mL), stirred at 60 °C for 15 min, a solution of malononitrile (114 mg, 1.70 mmol) in ethanol (2 mL) was added, and the reaction was stirred at 80 °C for 16 h. The reaction was concentrated, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane / methanol = 15 / 1, volume ratio) to give the title compound (166 mg, yield: 86.5%).

[0735] MS m / z (ESI): 563.2 [M+H] + .

[0736] Step 3: Preparation of (S)-N'-(3-cyano-3'-(4-((1-(hydroxymethyl)cyclopropyl)methoxy)-6-(1,4- oxazepan-4-yl)pyrimidin-2-yl)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'- benzo[d]isoxazole]-2-yl)-N,N-dimethylformamidine

[0737] (S)-2-amino-3'-(4-((1-(hydroxymethyl)cyclopropyl)methoxy)-6-(1,4-oxazepan-4-yl)pyrimidin-2- yl)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-3-carbonitrile (166 mg, 294.3 pmol) was dissolved in tetrahydrofuran (4 mL), N,N-dimethylformamide dimethyl acetal (70 mg, 588.6 pmol) was added, and the reaction was stirred at 25 °C for 2 h. The reaction was concentrated, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane / ethyl acetate = 2 / 1, volume ratio) to give the title compound (98 mg, yield: 53.8%).

[0738] MS m / z (ESI): 618.3 [M+H] + .

[0739] Fourth Step: Preparation of (S)-N'-(3-cyano-3'-(4-((1-formylcyclopropyl)methoxy)-6-(1,4-oxazepan-4-yl)pyrimidin-2-yl)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-2-yl)-N,N-dimethylformamidine

[0740] (S)-N'-(3-cyano-3'-(4-((1-(hydroxymethyl)cyclopropyl)methoxy)-6-(1,4-oxazepan-4-yl)pyrimidin-2-yl)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-2-yl)-N,N-dimethylformamidine (98 mg, 158.4 μmol) was dissolved in dichloromethane (5 mL), and Dess-Martin oxidant (106 mg, 237.6 μmol) was added, and the reaction was stirred at 25 °C for 3 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / ethyl acetate = 3 / 1, volume ratio) to obtain the title compound (48 mg, yield: 49.7%).

[0741] MS m / z (ESI): 616.3 [M+H] + .

[0742] Intermediate Preparation Example 52: Preparation of (S)-N'-(3-cyano-3'-(4-((1-formylcyclopentyl)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-dimethylformamidine

[0743] First Step: Preparation of (S)-3-(4-chloro-6-((1-(hydroxymethyl)cyclopentyl)methoxy)pyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazole-7,1'-cyclohexan]-2'-one

[0744] (S)-3-(4,6-dichloropyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazole-7,1'- cyclohexan]-2'-one (0.5 g, 1.4 mmol) was dissolved in DMF (5 mL), 1,1- cyclopentanediol (278 mg, 2.14 mmol) and cesium carbonate (1.16 g, 3.56 mmol) were added, and stirred at room temperature for 2 hours. The reaction solution was diluted with water (20 mL), extracted with ethyl acetate (20 mL) three times, 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, by volume) to obtain the title compound (0.42 g, yield: 78.7%).

[0745] MS m / z (ESI): 446.2 [M+H] + .

[0746] Second step: Preparation of (S)-3-(4-((1-(hydroxymethyl)cyclopentyl)methoxy)-6- (pyrimidin-5-yloxy)pyrimidin-2-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazole-7,1'- cyclohexan]-2'-one

[0747] (S)-3-(4-chloro-6-((1-(hydroxymethyl)cyclopentyl)methoxy)pyrimidin-2-yl)-5,6- dihydro-4H-spiro[benzo[d]isoxazole-7,1'-cyclohexan]-2'-one (0.42 g, 0.94 mmol), 5- hydroxypyrimidine (126 mg, 1.32 mmol), triethylenediamine (16.2 mg, 0.14 mmol), and potassium carbonate (168.4 mg, 1.22 mmol) were suspended in acetonitrile (10 mL), and stirred at 60°C for 16 hours. The reaction solution was cooled to room temperature, poured into water (50 mL), and a solid was precipitated, filtered, the filter cake was collected and dried to obtain the title compound (0.46 g, yield: 95.8%).

[0748] MS m / z (ESI): 506.2 [M+H] + .

[0749] Third step: Preparation of (S)-2-amino-3'-(4-((1-(hydroxymethyl)cyclopentyl)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

[0750] (S)-3-(4-((1-(hydroxymethyl)cyclopentyl)methoxy)-6-(pyrimidin-5-yloxy)pyrimidin-2-yl)- 5,6-dihydro-4H-spiro[benzo[d]isoxazole-7,1'-cyclohexan]-2'-one (0.46 g, 0.91 mmol), ammonium acetate (0.21 g, 2.73 mmol) and sulfur (87 mg, 2.73 mmol) were dissolved in ethanol (10 mL), stirred at 60 °C for 15 minutes, then a solution of malononitrile (0.24 g, 3.64 mmol) in ethanol (5 mL) was added dropwise, and stirred at 80 °C for 16 hours. The reaction solution was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / ethyl acetate = 3 / 2, by volume) to obtain the title compound (0.35 g, yield: 66.1%).

[0751] MS m / z (ESI): 586.2 [M+H] + .

[0752] Fourth step: Preparation of (S)-N'-(3-cyano-3'-(4-((1-(hydroxymethyl)cyclopentyl)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-dimethylformamidine

[0753] (S)-2-amino-3'-(4-((1-(hydroxymethyl)cyclopentyl)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 (0.35 g, 0.6 mmol) was dissolved in tetrahydrofuran (5 mL), N,N-dimethylformamide dimethyl acetal (178 mg, 1.5 mmol) was added, and stirred at room temperature for 2 hours. The reaction solution was concentrated to obtain the title compound (0.38 g, yield: 99.5%).

[0754] MS m / z (ESI): 641.2 [M+H] + .

[0755] Fifth step: Preparation of (S)-N'-(3-cyano-3'-(4-((1-formylcyclopentyl)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-dimethylformamidine

[0756] (S)-N'-(3-cyano-3'-(4-((1-(hydroxymethyl)cyclopentyl)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-dimethylformamidine (0.38 g, 0.59 mmol) was dissolved in dichloromethane (5 mL), and Dess-Martin oxidizing agent (0.5 g, 1.18 mmol) was added, and the reaction was stirred at 25°C for 3 hours. The reaction solution was concentrated, and the residue was separated and purified by silica gel column chromatography (eluent: dichloromethane / ethyl acetate = 3 / 1, by volume) to obtain the title compound (162 mg, yield: 42.7%).

[0757] MS m / z (ESI): 639.3 [M+H] + .

[0758] Preparation Example 53: Preparation of (S)-N'-(3-cyano-3'-(4-((4-cyclopropylpyrimidin-5-yl)oxy)-6-((1-formylcyclopropyl)methoxy)pyrimidin-2-yl)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-2-yl)-N,N-dimethylformamidine

[0759] Using the synthetic route in Preparation Example 52, the first step reaction material 1,1-cyclopentanediol was replaced with 1,1-cyclopropanediol, and the second step reaction material 5-hydroxypyrimidine was replaced with 4-cyclopropylpyrimidin-5-ol, to obtain the title compound (77 mg, yield: 55.3%).

[0760] MS m / z (ESI): 651.2 [M+H] + .

[0761] Preparation Example 54: Preparation of (S)-N'-(3-cyano-3'-(4-((1-formylcyclopropyl)methoxy)-6-((4-isopropylpyrimidin-5-yl)oxy)pyrimidin-2-yl)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-2-yl)-N,N-dimethylformamidine

[0762] Using the synthetic route in Preparation Example 52, the first step reaction material 1,1-cyclopentanediol was replaced with 1,1-cyclopropanediol, and the second step reaction material 5-hydroxypyrimidine was replaced with 4-cyclopropylpyrimidin-5-ol, to obtain the title compound (77 mg, yield: 55.3%).

[0763] MS m / z (ESI): 653.2 [M+H] + .

[0764] Intermediate Preparation Example 55: Preparation of (S)-N'-(3-cyano-3'-(4-((4- ethylpyrimidin-5-yl)oxy)-6-((1-formylcyclopropyl)methoxy)pyrimidin-2-yl)-5',6,6',7- tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-2-yl)-N,N- dimethylformamidine

[0765] Using the synthetic route in Intermediate Preparation Example 52, the first step reaction material 1,1-cyclopentanediol was replaced with (3,3-difluorocyclobutane-1,1- diyl)dimethanol, and the second step reaction material 5-hydroxypyrimidine was replaced with 4-ethylpyrimidin-5-ol, to obtain the title compound (66 mg, yield: 49.3%).

[0766] MS m / z (ESI): 639.2 [M+H] + .

[0767] Intermediate Preparation Example 56: Preparation of (S)-N'-(3-cyano-3'-(4-((3,3- difluoro-1-formylcyclobutyl)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- dimethylformamidine

[0768] Using the synthetic route in Intermediate Preparation Example 52, the first step reaction material 1,1-cyclopentanediol was replaced with (3,3-difluorocyclobutane-1,1- diyl)dimethanol, and the second step reaction material 5-hydroxypyrimidine was replaced with 4-ethylpyrimidin-5-ol, to obtain the title compound (66 mg, yield: 49.3%).

[0769] MS m / z (ESI): 661.2 [M+H] + .

[0770] Intermediate Preparation Example 57: Preparation of (S)-N'-(3-cyano-3'-(4-((1- formylcyclobutyl)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-dimethylformamidine

[0771] Using the synthetic route in Intermediate Preparation 52, replace the first step reaction material 1,1-cyclopentanediol with 1,1-cyclobutanediol to afford the title compound (66 mg, yield: 49.3%).

[0772] MS m / z (ESI): 625.2 [M+H] + .

[0773] Intermediate Preparation 58: Preparation of N'-((4S)-3-cyano-3'-(4-((2,2-difluoro-1- formylcyclopropyl)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-dimethylformamidine

[0774] Using the synthetic route in Intermediate Preparation 52, replace the first step reaction material 1,1-cyclopentanediol with (2,2-difluorocyclopropane-1,1-diyl)dimethanol to afford the title compound (42 mg, yield: 41.2%).

[0775] MS m / z (ESI): 647.2 [M+H] + .

[0776] Synthetic Example

[0777] Example 1: Preparation of (4S)-2-amino-3'-(4-((1-((9-(3-(2,6-dioxopiperidin-3-yl)-1- methyl-1H-indazol-6-yl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)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 (Compound 5)

[0778] First Step: Preparation of N'-((4S)-3-cyano-3'-(4-((1-((9-(3-(2,6-dioxopiperidin-3-yl)-1- methyl-1H-indazol-6-yl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)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-dimethylformamidine

[0779] (4S)-2-amino-3'-(4-((1-((9-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)- 3,9-diazaspiro[5.5]undec-3-yl)methyl)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

[0780] MS m / z (ESI): 990.2 [M+H] + .

[0781] Step 2: Preparation of (4S)-2-amino-3'-(4-((1-((9-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H- indazol-6-yl)-3,9-diazaspiro[5.5]undec-3-yl)methyl)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

[0782] N'-((4S)-3-cyano-3'-(4-((1-((9-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)- 3,9-diazaspiro[5.5]undec-3-yl)methyl)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- dimethylformamidine (50 mg, 49.99 µmol) was dissolved in tetrahydrofuran (2 mL), 2M diluted hydrochloric acid (1 mL) was added, and the reaction was carried out at 60°C for 2 hours. The reaction was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (Condition 2) to obtain the title compound (7 mg, yield: 14.6%)

[0783] MS m / z (ESI): 935.4 [M+H] + .

[0784] 1 H-NMR (400 MHz, DMSO-d6) δ 9.15 (s, 1H), 8.91 (s, 2H), 7.46 (d, J = 12.0 Hz, 1H), 6.94 (s, 2H), 6.90 (d, J = 12.0 Hz, 1H), 6.82 (s, 1H), 6.77 (s, 1H), 4.39 (s, 2H), 4.26-4.22 (m, 1H), 3.87 (s, 3H), 3.19 (s, 4H), 2.69-2.54 (m, 4H), 2.40 (s, 4H), 2.34-2.13 (m, 6H), 1.98-1.73 (m, 8H), 1.53 (s, 4H), 1.45 (s, 4H), 0.69 (s, 2H), 0.44 (s, 2H).

[0785] Example 2: Preparation of (4S)-2-amino-3'-(4-((1-((2-(4-(3-(2,6-dioxopiperidin-3-yl)-1- methyl-1H-indazol-6-yl)piperidin-1-yl)-7-azaspiro[3.5]non-7-yl)methyl)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 (Compound 6)

[0786] Using the synthetic route in Example 1, replacing the first step reaction material 3-(1- methyl-6-(3,9-diazaspiro[5.5]undecan-3-yl)-1H-indazol-3-yl)piperidine-2,6-dione with 3-(6-(1- (7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione, the title compound was obtained (30 mg, yield: 18.4%).

[0787] MS m / z (ESI): 989.2 [M+H] + .

[0788] 1H-NMR (400 MHz, CD3OD) δ 9.12 (s, 1H), 8.84 (s, 2H), 7.68 (d, J = 8.0 Hz, 1H), 7.39 (s, 1H), 7.11 (d, J = 8.0 Hz, 1H), 6.67 (s, 1H), 4.62 (s, 1H), 4.38-4.34 (m, 1H), 4.13 (d, J = 12.0 Hz, 1H), 4.02 (s, 3H), 3.42-3.34 (m, 3H), 3.24-3.07 (m, 4H), 2.99-2.95 (m, 2H), 2.79-2.73 (m, 2H), 2.68-2.58 (m, 4H), 2.48-2.41 (m, 2H), 2.34-2.25 (m, 3H), 2.09-1.85 (m, 19H), 1.76-1.70 (m, 1H), 0.97-0.86 (m, 3H), 0.78-0.72 (m, 1H).

[0789] Example 3: Preparation of (4S)-2-amino-3'-(4-((1-((4-(2-(4-(3-(2,6-dioxopiperidin-3-yl)-1- methyl-1H-indazol-6-yl)piperidin-1-yl)acetyl)piperazin-1-yl)methyl)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 (Compound 8)

[0790] Using the synthetic route in Example 1, the first step reaction material 3-(1- methyl-6-(3,9-diazaspiro[5.5]undecan-3-yl)-1H-indazol-3-yl)piperidine-2,6-dione was replaced with 3-(1-methyl-6-(1-(2-oxo-2-(piperazin-1-yl)ethyl)piperidin-4-yl)-1H-indazol-3- yl)piperidine-2,6-dione to obtain the title compound (1.37 mg, yield: 1.9%).

[0791] MS m / z (ESI): 992.5 [M+H] + .

[0792] 1H-NMR (400 MHz, DMSO-d6) δ 9.18 (s, 1H), 8.91 (s, 2H), 7.68 (d, J = 8.0, 1H), 7.42 (s, 1H), 7.06 (d, J = 8.0, 1H), 6.95 (s, 2H), 6.79 (s, 1H), 4.48-4.32 (m, 6H), 3.99 (s, 3H), 3.62-3.56 (s, 6H), 3.16-2.98 (s, 6H), 2.66-2.61 (m, 4H), 2.38-2.31 (m, 2H), 2.20-1.71 (m, 16H), 0.94-0.74 (m, 4H).

[0793] Example 4: Preparation of (4S)-2-amino-3'-(4-((1-((4-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)-[1,4'-bipiperidin]-1'-yl)methyl)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 (Compound 3)

[0794] Using the synthetic route in Example 1, the first step reaction material 3-(1-methyl-6-(3,9- diazaspiro[5.5]undecan-3-yl)-1H-indazol-3-yl)piperidine-2,6-dione was replaced with 3-(5-([1,4'- bipiperidin]-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione to give the title compound (14 mg, yield: 24.7%).

[0795] MS m / z (ESI): 950.4 [M+H] + .

[0796] 1 H-NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 9.16 (s, 1H), 8.92 (s, 2H), 7.63 (d, J = 8.0 Hz, 1H), 7.47 (s, 1H), 7.37 (d, J = 8.0 Hz, 1H), 6.94 (s, 2H), 6.77 (s, 1H), 5.10 (dd, J = 13.2, 5.2 Hz, 1H), 4.57-4.20 (m, 5H), 3.04-2.83 (m, 5H), 2.76-2.55 (m, 5H), 2.43-2.1.53 (m, 23H), 1.35 (d, J = 12.4 Hz, 2H), 0.69 (s, 2H), 0.42 (d, J = 6.0 Hz, 2H).

[0797] Example 5: Preparation of (4S)-2-amino-3'-(4-((1-((2-(4-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)piperidin-1-yl)-7-azaspiro[3.5]non-7-yl)methyl)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 (Compound 4)

[0798] The title compound (9 mg, yield: 13.6%) was obtained by replacing the first step reaction material 3-(1-methyl-6-(3,9-diazaspiro[5.5]undecan-3-yl)-1H-indazol-3-yl)piperidine-2,6-dione with 3-(5-(1-(7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione in the synthetic route in Example 1.

[0799] MS m / z (ESI): 990.4 [M+H] + .

[0800] 1 H-NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 9.15 (s, 1H), 8.91 (s, 2H), 7.63 (d, J = 6.8 Hz, 1H), 7.49 (s, 1H), 7.43-7.22 (m, 1H), 6.94 (s, 2H), 6.76 (s, 1H), 5.09 (dd, J = 11.2, 5.2 Hz, 1H), 4.49-4.18 (m, 4H), 2.92 (dd, J = 12.0, 4.4 Hz, 3H), 2.69-2.53 (m, 6H), 2.46-2.13 (m, 6H), 2.04-1.59 (m, 18H), 1.55-1.35 (m, 7H), 0.68 (s, 2H), 0.42 (s, 2H).

[0801] Example 6: Preparation of (4S)-2-amino-3'-(4-((1-((4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)piperidin-1-yl)acetyl)piperazin-1-yl)methyl)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 (Compound 7)

[0802] The synthetic route in Example 1 was adopted, and the raw material for the first step, 3-(1-methyl-6-(3,9-diazaspiro[5.5]undecan-3-yl)-1H-indazol-3-yl)piperidine-2,6-dione, was replaced by 3-(1-oxo-5-(1-(2-oxo-2-(piperazin-1-yl)ethyl)piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione to obtain the title compound (3 mg, yield: 9.0%).

[0803] MS m / z (ESI): 993.4 [M+H] + .

[0804] 1 H-NMR (400MHz, DMSO-d6) δ 10.99 (s, 1H), 9.15 (s, 1H), 8.91 (s, 2H), 7.64 (d, J = 7.8 Hz, 1H), 7.48 (s, 1H), 7.37 (d, J = 1.6 Hz, 1H), 6.94 (s, 2H), 6.78 (s, 1H), 5.10 (dd, J = 13.2, 5.2 Hz, 1H), 4.48-4.36 (m, 3H), 4.28 (d, J = 7.2 Hz, 1H), 3.55 (s, 3H), 3.15 (s, 2H), 2.91 (dd, J = 11.2, 9.6 Hz, 4H), 2.76-2.55 (m, 4H), 2.47-2.05 (m, 10H), 2.02-1.56 (m, 13H), 1.30-1.17 (m, 1H), 0.71 (s, 2H), 0.46 (s, 2H).

[0805] Example 7: Preparation of (4S)-2-amino-3'-(4-((1-((9-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)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 (Compound 9)

[0806] The synthetic route in Example 1 was adopted, and the raw material for the first step, 3-(1-methyl-6-(3,9-diazaspiro[5.5]undecan-3-yl)-1H-indazol-3-yl)piperidine-2,6-dione, was replaced by 3-(1-oxo-5-(3,9-diazaspiro[5.5]undecan-3-yl)isoindolin-2-yl)piperidine-2,6-dione to obtain the title compound (20 mg, yield: 23.5%).

[0807] MS m / z (ESI): 936.4 [M+H] + .

[0808] 1 H-NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 9.15 (s, 1H), 8.91 (s, 2H), 7.49 (d, J = 9.2 Hz, 1H), 7.08 - 6.91 (m, 4H), 6.76 (s, 1H), 5.04 (dd, J = 13.2, 5.2 Hz, 1H), 4.36 (d, J = 12.8 Hz, 2H), 4.31 - 4.12 (m, 2H), 3.27 (d, J = 6.4 Hz, 4H), 2.90 (dd, J = 13.6, 5.6 Hz, 1H), 2.65 - 2.54 (m, 3H), 2.38 (t, J = 5.6 Hz, 4H), 2.34 - 2.18 (m, 6H), 2.03 - 1.84 (m, 4H), 1.86 - 1.73 (m, 4H), 1.46 (dd, J = 17.6, 5.6 Hz, 8H), 0.69 (s, 2H), 0.44 (s, 2H).

[0809] Example 8: Preparation of (4S)-2-amino-3'-(4-((1-((4-(3-(2,6-dioxopiperidin-3-yl)-1- methyl-1H-indazol-6-yl)-[1,4'-bipiperidin]-1'-yl)methyl)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 (Compound 2)

[0810] Using the synthetic route in Example 1, the first step reaction material 3-(1- methyl-6-(3,9-diazaspiro[5.5]undecan-3-yl)-1H-indazol-3-yl)piperidine-2,6-dione was replaced by 3-(6-([1,4'-bipiperidin]-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione to give the title compound (2 mg, yield: 37.2%).

[0811] MS m / z (ESI): 984.4 [M+H] + .

[0812] 1H-NMR (400 MHz, CD3OD) δ 9.08 (s, 1H), 8.84 (s, 2H), 7.63 (d, J = 8.4 Hz, 1H), 7.34 (s, 1H), 7.08 (d, J = 8.4 Hz, 1H), 6.59 (s, 1H), 4.62-4.33 (m, 5H), 4.00 (s, 3H), 3.21-3.08 (m, 3H), 2.81-2.16 (m, 12H), 2.10-1.54 (m, 14H), 1.33-1.28 (m, 4H), 0.90 (t, J = 6.8 Hz, 1H), 0.73 (s, 2H), 0.51 (s, 2H).

[0813] Example 9: Preparation of (4S)-2-amino-3'-(4-((1-((4-((4-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)piperidin-1-yl)methyl)piperidin-1-yl)methyl)cyclopropyl)methoxy)- 6-methoxy-pyrimidin-2-yl)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'- benzo[d]isoxazole]-3-carbonitrile (Compound 1)

[0814] Using the synthetic route in Example 1, the first step reaction material 3-(1-methyl-6-(3,9- diazaspiro[5.5]undecan-3-yl)-1H-indazol-3-yl)piperidine-2,6-dione was replaced with 3-(1- oxo-5-(1-(piperidin-4-ylmethyl)piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione, the first step reaction material (S)-(1-((2-(3-cyano-2-((dimethylamino)methylene)amino)-5',6,6',7- tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-3'-yl)-6-(pyrimidin-5- yloxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)methanesulfonate was replaced with (S)-(1-(((2-(3-cyano-2-(((dimethylamino)methylene)amino)-5',6,6',7-tetrahydro-4'H,5H- spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-3'-yl)-6-methoxypyrimidin-4-yl)oxy)methyl) cyclopropyl)methyl)methanesulfonate to give the title compound (3.7 mg, yield: 3.9%).

[0815] MS m / z (ESI): 900.4 [M+H] + .

[0816] 1H-NMR (400 MHz, CD3OD) δ 8.51 (s, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.53-7.47 (m, 1H), 7.44 (d, J = 8.0 Hz, 1H), 6.24 (s, 1H), 5.16 (dd, J = 13.2, 5.2 Hz, 1H), 4.84-4.80 (m, 1H), 4.63 (s, 1H), 4.48 (t, J = 17.2 Hz, 2H), 4.09 (dd, J = 11.2, 2.4 Hz, 1H), 4.06 (d, J = 1.2 Hz, 3H), 3.67-3.50 (m, 2H), 3.25 (d, J = 3.2 Hz, 1H), 3.18-3.15 (m, 1H), 3.05-2.97 (m, 1H), 2.97-2.79 (m, 5H), 2.78-2.75 (m, 1H), 2.60 (t, J = 5.2 Hz, 2H), 2.49 (dd, J = 13.2, 4.8 Hz, 1H), 2.46-2.37 (m, 2H), 2.35-2.24 (m, 2H), 2.21-1.95 (m, 11H), 1.95-1.89 (m, 5H), 1.67-1.51 (m, 2H), 1.36 (d, J = 6.8 Hz, 1H), 0.97-0.90 (m, 2H), 0.87-0.72 (m, 2H).

[0817] Example 10: Preparation of (4S)-2-amino-3'-(4-((1-((9-(3-(2,6-dioxopiperidin-3-yl)-1- methyl-1H-indazol-6-yl)-3-azaspiro[5.5]undecan-3-yl)methyl)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 (Compound 26)

[0818] Using the synthetic route in Example 1, replacing the first step reaction material 3-(1- methyl-6-(3,9-diazaspiro[5.5]undecan-3-yl)-1H-indazol-3-yl)piperidine-2,6-dione with 3-(1- methyl-6-(3-azaspiro[5.5]undecan-9-yl)-1H-indazol-3-yl)piperidine-2,6-dione, the title compound was obtained (10 mg, yield: 18.6%).

[0819] MS m / z (ESI): 934.4 [M+H] + .

[0820] 1H-NMR (400 MHz, DMSO-d6) δ 10.88 (s, 1H), 9.15 (s, 1H), 8.91 (s, 2H), 7.58 (d, J = 8.0 Hz, 1H), 7.43 (s, 1H), 7.02 (d, J = 8.0 Hz, 1H), 6.93 (s, 4H), 6.77 (s, 1H), 4.43-4.30 (m, 4H), 3.98 (s, 3H), 2.89-2.52 (m, 6H), 2.45-2.32 (m, 2H), 2.00-1.62 (m, 18H), 1.32-1.18 (m, 6H), 0.69 (s, 2H), 0.44 (s, 2H).

[0821] Example 11: Preparation of (4S)-2-amino-3'-(4-((1-((9-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)cyclopropyl)methoxy)-6-methylpyrimidin-2-yl)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-3-carbonitrile (Compound 42)

[0822] First Step: Preparation of N'-((4S)-3-cyano-3'-(4-((1-((9-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)cyclopropyl)methoxy)-6-methylpyrimidin-2-yl)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-2-yl)-N,N-dimethylformamidine

[0823] (S)-N'-(3-cyano-3'-(4-((1-formylcyclopropyl)methoxy)-6-methylpyrimidin-2-yl)- 5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-2-yl)- N,N-dimethylformamidine (95 mg. 177 pmol) and 3-(5-fluoro-1-methyl-6-(3,9- diazaspiro[5.5]undecan-3-yl)-1H-indazol-3-yl)piperidine-2,6-dione (80 mg, 177 pmol) were dissolved in dimethyl sulfoxide (3 mL), tetraethyl orthotitanate (50 mg, 177 pmol) was added, and the reaction was allowed to proceed at 25 °C for 30 minutes. Sodium triacetoxyborohydride (75 mg, 354 pmol) was added, and the reaction was allowed to proceed at 25 °C for 1 hour. The reaction was filtered to remove solids, and the filtrate was purified by reverse phase column chromatography (eluent: water (0.05% TFA) / acetonitrile = 3 / 7, volume ratio) to obtain the title compound (80 mg, yield: 48.1%).

[0824] MS m / z (ESI): 928.3 [M+H] + .

[0825] Second step: Preparation of (4S)-2-amino-3'-(4-((1-((9-(3-(2,6-dioxopiperidin-3-yl)-5- fluoro-1-methyl-1H-indazol-6-yl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)cyclopropyl)- methoxy)-6-methylpyrimidin-2-yl)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'- benzo[d]isoxazole]-3-carbonitrile

[0826] N'-((4S)-3-cyano-3'-(4-((1-((9-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-1-methyl-1H- indazol-6-yl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)cyclopropyl)methoxy)-6- methylpyrimidin-2-yl)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]- isoxazole]-2-yl)-N,N-dimethylformamidine (70 mg, 74 pmol) was dissolved in tetrahydrofuran (3 mL), 2M dilute hydrochloric acid (1 mL) was added, and the reaction was allowed to proceed at 65 °C for 3 hours. The reaction was concentrated, and the residue was purified by high performance liquid chromatography (Condition 2) to obtain the title compound (10 mg, yield: 14.5%).

[0827] MS m / z (ESI): 873.4 [M+H] + .

[0828] 1H-NMR (400 MHz, DMSO-d6) δ 10.86 (s, 1H), 8.25 (s, 1H), 7.44 (d, J = 12.0 Hz, 1H), 7.13 (d, J = 8.0 Hz, 1H), 6.96 (s, 2H), 6.88 (s, 1H), 4.35 (s, 2H), 4.28-4.24 (m, 1H), 3.93 (s, 3H), 3.11-3.06 (m, 2H), 3.02-2.97 (m, 4H), 2.65-2.58 (m, 2H), 2.56-2.52 (m, 2H), 2.45 (s, 3H), 2.42-2.36 (m, 4H), 2.33-2.30 (m, 2H), 2.16-2.10 (m, 1H), 2.04-1.92 (m, 4H), 1.88-1.80 (m, 4H), 1.59-1.53 (m, 4H), 1.49-1.43 (m, 4H), 0.68-0.64 (m, 2H), 0.44-0.40 (m, 2H).

[0829] Example 12: Preparation of (4S)-2-amino-3'-(4-((1-((9-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)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 (Compound 30)

[0830] First Step: Preparation of N'-((4S)-3-cyano-3'-(4-((1-((9-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)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-dimethylformamidine

[0831] (S)-N'-(3-cyano-3'-(4-((1-formylcyclopropyl)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-dimethylformamidine (50 mg. 81.9 umol) and 3-(5-fluoro-1-methyl-6-(3,9-diazaspiro[5.5]undecan-3-yl)-1H-indazol-3-yl)piperidine-2,6-dione (33.9 mg, 81.9 umol) were dissolved in dimethyl sulfoxide (2 mL), tetraethyl orthotitanate (37.3 mg, 163.8 umol) was added, and the reaction was allowed to react at 25°C for 30 minutes. Sodium triacetoxyborohydride (34.7 mg, 163.8 umol) was added, and the reaction was allowed to react at 25°C for 5 hours. The reaction solution was filtered to remove solids, and the filtrate was purified by reverse phase column chromatography (eluent: water (0.05% TFA) / acetonitrile = 6 / 4, volume ratio) to obtain the title compound (45 mg, yield: 54.5%).

[0832] MS m / z (ESI): 1008.4 [M+H] + .

[0833] Second step: Preparation of (4S)-2-amino-3'-(4-((1-((9-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)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

[0834] N'-((4S)-3-cyano-3'-(4-((1-((9-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)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-dimethylformamidine (45 mg, 44.6 umol) was dissolved in tetrahydrofuran (3 mL), 2M dilute hydrochloric acid (1 mL) was added, and the reaction was allowed to react at 65°C for 3 hours. The reaction solution was concentrated, and the residue was purified by high performance liquid chromatography (Condition 1) to obtain the title compound (15 mg, yield: 35.3%).

[0835] MS m / z (ESI): 953.4 [M+H] + .

[0836] 1 H-NMR (400 MHz, DMSO-d6) δ 10.86 (s, 1H), 9.15 (s, 1H), 8.91 (s, 2H), 7.42 (d, J = 12.0 Hz, 1H), 7.13 (d, J = 8.0 Hz, 1H), 6.95 (s, 2H), 6.78 (s, 1H), 4.40 (dd, J = 12.0, 8.0 Hz, 2H), 4.28-4.24 (m, 1H), 3.93 (s, 3H), 3.00 (s, 4H), 2.68-2.53 (m, 4H), 2.40-1.48 (m, 26H), 0.69 (s, 2H), 0.44 (s, 2H).

[0837] Example 13: Preparation of (4S)-2-amino-3'-(4-((1-((9-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-3,9-diazaspiro[5.5]undec-3-yl)methyl)cyclopropyl)methoxy)-6-((4-methylpyrimidin-5-yl)oxy)pyrimidin-2-yl)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-3-carbonitrile (Compound 43)

[0838] The title compound (6 mg, yield: 6.3%) was obtained by replacing the first step reaction material 3-(1-methyl-6-(3,9-diazaspiro[5.5]undec-3-yl)-1H-indazol-3-yl)piperidine-2,6-dione with 3-(5-fluoro-1-methyl-6-(3,9-diazaspiro[5.5]undec-3-yl)-1H-indazol-3-yl)piperidine-2,6-dione and replacing the reaction material (S)-(1-((2-(3-cyano-2-((dimethylamino)methylene)amino)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-3'-yl)-6-(pyrimidin-5-yloxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl methanesulfonate with (S)-(1-(((2-(3-cyano-2-(((dimethylamino)methylene)amino)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-3'-yl)-6-((4-methylpyrimidin-5-yl)oxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl methanesulfonate in the synthetic route in Example 1.

[0839] MS m / z (ESI): 967.4 [M+H] + .

[0840] 1 H-NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H), 9.01 (s, 1H), 8.73 (s, 1H), 7.42 (d, J = 12.0 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 6.93 (s, 2H), 6.76 (s, 1H), 4.38 (dd, J = 12.0, 8.0 Hz, 2H), 4.28-4.24 (m, 1H), 3.93 (s, 3H), 3.00 (s, 4H), 2.66-2.54 (m, 4H), 2.41-1.47 (m, 29H), 0.69 (s, 2H), 0.44 (s, 2H).

[0841] Example 14: Preparation of (4S)-2-amino-3'-(4-((4,6-dimethylpyrimidin-5-yl)oxy)-6-((1-((9-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)cyclopropyl)methoxy)pyrimidin-2-yl)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-3-carbonitrile (Compound 50)

[0842] Using the synthetic route in Example 1, replacing the first step reaction material 3-(1-methyl-6-(3,9-diazaspiro[5.5]undecan-3-yl)-1H-indazol-3-yl)piperidine-2,6-dione with 3-(5-fluoro-1-methyl-6-(3,9-diazaspiro[5.5]undecan-3-yl)-1H-indazol-3-yl)piperidine-2,6-dione, and replacing the reaction material (S)-(1-((2-(3-cyano-2-((dimethylamino)methylene)amino)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-3'-yl)-6-(pyrimidin-5-yloxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl methanesulfonate with (S)-(1-(((2-(3-cyano-2-(((dimethylamino)methylene)amino)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-3'-yl)-6-((4,6-dimethylpyrimidin-5-yl)oxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl methanesulfonate, the title compound (5 mg, yield: 9.8%) was obtained.

[0843] MS m / z (ESI): 981.4 [M+H] +.

[0844] 1 H-NMR (400 MHz, DMSO-d6) δ 10.86 (s, 1H), 8.85 (s, 1H), 7.42 (d, J = 12.0 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 6.93 (s, 2H), 6.77 (s, 1H), 4.39 (dd, J = 12.0, 8.0 Hz, 2H), 4.28-4.24 (m, 1H), 3.93 (s, 3H), 3.00 (s, 4H), 2.60-2.52 (m, 3H), 2.48-2.21 (m, 15H), 2.18-1.47 (m, 18H), 0.69 (s, 2H), 0.44 (s, 2H).

[0845] Example 15: Preparation of (4S)-2-amino-3'-(4-((1-((6-(4-(3-(2,6-dioxopiperidin-3-yl)-1- methyl-1H-indazol-6-yl)piperidin-1-yl)-2-azaspiro[3.3]heptan-2-yl)methyl)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 (Compound 18)

[0846] Using the synthetic route in Example 12, replacing the first step reaction material 3-(5-fluoro-1- methyl-6-(3,9-diazaspiro[5.5]undecan-3-yl)-1H-indazol-3-yl)piperidine-2,6-dione with 3-(6-(1-(2- azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione, the title compound was obtained (13 mg, yield: 7.1%).

[0847] MS m / z (ESI): 961.5 [M+H] + .

[0848] 1H-NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 9.90 (s, 1H), 9.19 (s, 1H), 8.92 (s, 2H), 7.69 (d, J = 8.0 Hz, 1H), 7.40 (s, 1H), 7.04 (d, J = 8.0 Hz, 1H), 6.95 (s, 1H), 6.83 (s, 1H), 4.40-4.29 (m, 4H), 4.28-4.15 (m, 4H), 3.98 (s, 3H), 3.66-3.58 (m, 2H), 3.32-3.30 (m, 1H), 3.05-2.83 (m, 4H), 2.78-2.56 (m, 6H), 2.41-2.31 (m, 2H), 2.22-1.72 (m, 16H), 0.86-0.74 (m, 4H).

[0849] Example 16: Preparation of (4S)-2-amino-3'-(4-((1-((9-(3-(2,6-dioxopiperidin-3-yl)phenyl)-3,9- diazaspiro[5.5]undec-3-yl)methyl)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 (Compound 28)

[0850] The title compound was obtained using the synthetic route in Example 12 by replacing the first step reaction material 3-(5-fluoro-l-methyl-6-(3,9-diazaspiro[5.5]undec-3-yl)-lH-indazol-3- yl)piperidine-2,6-dione with 3-(3-(3,9-diazaspiro[5.5]undec-3-yl)phenyl)piperidine-2,6-dione (12 mg, yield: 11.4%).

[0851] MS m / z (ESI): 881.2 [M+H] + .

[0852] 1H-NMR (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 9.15 (s, 1H), 8.90 (s, 2H), 7.13 (t, J = 8.0 Hz, 1H), 6.92 (s, 2H), 6.83-6.79 (m, 1H), 6.77-6.74 (m, 2H), 6.57 (d, J = 8.0 Hz, 1H), 4.42-4.35 (m, 2H), 3.76-3.72 (m, 1H), 3.13-3.04 (m, 4H), 2.65-2.55 (m, 2H), 2.42-2.34 (m, 4H), 2.34-2.30 (m, 2H), 2.29-2.08 (m, 3H), 2.05-1.60 (m, 11H), 1.52-1.46 (m, 4H), 1.44-1.38 (m, 4H), 0.72-0.64 (m, 2H), 0.46-0.40 (m, 2H).

[0853] Example 17: Preparation of (4S)-2-amino-3'-(4-((1-((9-(3-(2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-3,9-diazaspiro[5.5]undec-3-yl)methyl)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 (Compound 35)

[0854] The title compound (12 mg, yield: 11.4%) was obtained by replacing the first step reaction material 3-(5-fluoro-1-methyl-6-(3,9-diazaspiro[5.5]undec-3-yl)-1H-indazol-3-yl)piperidine-2,6-dione with 3-(2-oxo-6-(3,9-diazaspiro[5.5]undec-3-yl)benzo[d]oxazol-3(2H)-yl)piperidine-2,6-dione in the synthetic route in Example 12.

[0855] MS m / z (ESI): 938.3 [M+H] + .

[0856] 1H-NMR (400 MHz, DMSO-d6) δ 11.18 (s, 1H), 9.15 (s, 1H), 8.91 (s, 2H), 7.08-7.03 (m, 2H), 6.94 (s, 2H), 6.78-6.74 (m, 2H), 5.31-5.26 (m, 1H), 4.41-4.35 (m 2H), 3.09-3.01 (m, 4H), 2.89-2.82 (m, 1H), 2.72-2.59 (m, 3H), 2.47-2.41 (m, 4H), 2.37 (s, 2H), 2.33-2.06 (m, 4H), 1.99-1.73 (m, 8H), 1.54-1.48 (m, 4H), 1.47-1.41 (m, 4H), 0.72-0.66 (m, 2H), 0.48-0.42 (m, 2H).

[0857] Example 18: Preparation of (4S)-2-amino-3'-(4-((1-((7-(4-(3-(2,6-dioxopiperidin-3-yl)-1- methyl-1H-indazol-6-yl)piperidin-1-yl)-2-azaspiro[3.5]nonan-2-yl)methyl)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 (Compound 16)

[0858] Using the synthetic route in Example 12, replace the first step reaction material 3-(5-fluoro-1- methyl-6-(3,9-diazaspiro[5.5]undecan-3-yl)-1H-indazol-3-yl)piperidine-2,6-dione with 3-(6-(1-(2- azaspiro[3.5]nonan-7-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione to afford the title compound (2.1 mg, yield: 1.4%).

[0859] MS m / z (ESI): 989.5 [M+H] + .

[0860] 1H-NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 9.15 (s, 1H), 8.79 (d, J = 8.0 Hz, 2H), 7.68-7.63 (m, 1H), 7.45 (s, 1H), 7.06 (d, J = 8.0 Hz, 1H), 6.95 (s, 2H), 6.84 (s, 1H), 4.44-4.31 (m, 4H), 4.01-3.98 (m, 1H), 3.96 (s, 3H), 3.90-3.85 (m, 2H), 3.62-3.60 (m, 1H), 3.48-3.46 (m, 2H), 3.20-3.16 (m, 2H), 3.08-2.98 (m, 4H), 2.75-2.71 (m, 1H), 2.63-2.57 (m, 2H), 2.44-2.38 (m, 3H), 2.18-2.08 (m, 6H), 1.87-1.71 (m, 15H), 0.88 (s, 4H).

[0861] Example 19: Preparation of (4S)-2-amino-3'-(4-((1-((9-(4-(3-(2,6-dioxopiperidin-3-yl)-1- methyl-1H-indazol-6-yl)piperidin-1-yl)-3-azaspiro[5.5]undecan-3-yl)methyl)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 (Compound 17)

[0862] Using the synthetic route in Example 12, replacing the first step reaction material 3-(5-fluoro-1- methyl-6-(3,9-diazaspiro[5.5]undecan-3-yl)-1H-indazol-3-yl)piperidine-2,6-dione with 3-(6-(1-(3- azaspiro[5.5]undecan-9-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione, the title compound was obtained (2.0 mg, yield: 1.2%).

[0863] MS m / z (ESI): 1017.6 [M+H] + .

[0864] 1H-NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 9.19 (s, 1H), 8.92 (s, 2H), 7.68 (d, J = 8.0 Hz, 1H), 7.40 (s, 1H), 7.04 (d, J = 8.0 Hz, 1H), 6.96 (s, 2H), 6.75 (s, 1H), 4.45-4.32 (m, 4H), 3.99 (s, 3H), 3.60-3.50 (m, 5H), 3.20-3.02 (m, 8H), 2.76-2.72 (m, 1H), 2.64-2.58 (m, 2H), 2.46-2.44 (m, 1H), 2.38-2.35 (m, 1H), 2.20-2.07 (m, 7H), 1.86-1.62 (m, 14H), 1.52-1.43 (m, 4H), 0.94-0.90 (m, 2H), 0.84-0.80 (m, 2H).

[0865] Example 20: Preparation of (4S)-2-amino-3'-(4-((1-((4-((1-(3-(2,6-dioxopiperidin-3-yl)-1- methyl-1H-indazol-6-yl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)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 (Compound 10)

[0866] Using the synthetic route in Example 12, the first step reaction material 3-(5-fluoro-1- methyl-6-(3,9-diazaspiro[5.5]undecan-3-yl)-1H-indazol-3-yl)piperidine-2,6-dione was replaced with 3-(1-methyl-6-(4-(piperazin-1-ylmethyl)piperidin-1-yl)-1H-indazol-3-yl)piperidine-2,6- dione to give the title compound (36 mg, yield: 28.6%).

[0867] MS m / z (ESI): 964.5 [M+H] + .

[0868] 1H-NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 9.18 (s, 1H), 8.92 (s, 2H), 7.51 (d, J = 8.0 Hz, 1H), 6.94 (d, J = 8.0 Hz, 2H), 6.89 (s, 1H), 6.78 (s, 1H), 4.43-4.34 (m, 2H), 4.28-4.24 (m, 1H), 3.90 (s, 3H), 3.84-3.78 (m, 2H), 2.97-2.89 (m, 2H), 2.82-2.74 (m, 4H), 2.65-2.54 (m, 4H), 2.46-2.39 (m, 2H), 2.33-2.23 (m, 2H), 2.22-2.12 (m, 3H), 2.02-1.67 (m, 14H), 1.38-1.22 (m, 5H), 0.84-0.76 (m, 2H), 0.69-0.58 (m, 2H).

[0869] Example 21: Preparation of (4S)-2-amino-3'-(4-((1-((9-(3-(2,6-dioxopiperidin-3-yl)-1- ethyl-5-fluoro-1H-indazol-6-yl)-3,9-diazaspiro[5.5]undec-3-yl)methyl)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 (Compound 46)

[0870] The title compound (35 mg, yield: 26.8%) was obtained by replacing the first step reaction material 3-(5-fluoro-1-methyl-6-(3,9-diazaspiro[5.5]undec-3-yl)-1H-indazol-3-yl)piperidine- 2,6-dione with 3-(1-ethyl-5-fluoro-6-(3,9-diazaspiro[5.5]undec-3-yl)-1H-indazol-3-yl)piperidine- 2,6-dione in the synthetic route in Example 12.

[0871] MS m / z (ESI): 967.4 [M+H] + .

[0872] 1H-NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 9.16 (s, 1H), 8.91 (s, 2H), 7.42 (d, J = 12.0 Hz, 1H), 7.15 (d, J = 8.0 Hz, 1H), 6.95 (s, 2H), 6.77 (s, 1H), 4.43-4.25 (m, 5H), 3.00 (s, 4H), 2.65-2.55 (m, 3H), 2.46-2.41 (m, 4H), 2.37-2.32 (m, 3H), 2.27-2.09 (m, 3H), 2.02-1.74 (m, 9H), 1.60-1.55 (m, 4H), 1.52-1.46 (m, 4H), 1.33 (t, J = 8.0 Hz, 3H), 0.72-0.68 (m, 2H), 0.48-0.44 (m, 2H).

[0873] Example 22: Preparation of (4S)-2-amino-3'-(4-((1-((9-(4-(2,6-dioxopiperidin-3-yl)-3,5- difluorophenyl)-3,9-diazaspiro[5.5]undec-3-yl)methyl)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 (Compound 31)

[0874] The synthetic route in Example 1 was adopted, and the first step reaction material 3-(1- methyl-6-(3,9-diazaspiro[5.5]undec-3-yl)-1H-indazol-3-yl)piperidine-2,6-dione was replaced by 3-(2,6-difluoro-4-(3,9-diazaspiro[5.5]undec-3-yl)phenyl)piperidine-2,6-dione to obtain the title compound (8 mg, yield: 33.9%).

[0875] MS m / z (ESI): 917.4 [M+H] + .

[0876] 1H-NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 9.22 (s, 1H), 8.98 (s, 2H), 7.49 (d, J = 12.4 Hz, 1H), 7.19 (d, J = 7.2 Hz, 1H), 6.99 (s, 2H), 6.83 (s, 1H), 4.50-4.31 (m, 4H), 4.00 (s, 3H), 3.08-2.97 (m, 3H), 2.83-2.60 (m, 4H), 2.57-1.80 (m, 14H), 1.75-1.57 (m, 9H), 0.77 (s, 2H), 0.53 (s, 2H).

[0877] Example 23: Preparation of (4S)-2-amino-3'-(4-((1-((9-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-5-yl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)cyclopropyl)methoxy)pyrimidin-2-yl)- 5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-3-carbonitrile (Compound 32)

[0878] The title compound was obtained by replacing the reaction material of the first step, (S)-(1-((2-(3-cyano-2-((dimethylamino)methylene)amino)-5',6,6',7-tetrahydro-4'H,5H- spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-3'-yl)-6-(pyrimidin-5-yloxy)pyrimidin-4-yl)oxy)methyl) cyclopropyl)methyl methanesulfonate, with (S)-(1-(((2-(3-cyano-2-(((dimethylamino)methylene)amino)-5',6,6',7- tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-3'-yl)pyrimidin-4-yl)oxy)methyl) cyclopropyl)methyl methanesulfonate, and replacing the reaction material 3-(1-methyl-6-(3,9- diazaspiro[5.5]undecan-3-yl)-1H-indazol-3-yl)piperidine-2,6-dione with 3-(3-methyl-2-oxo-5-(3,9- diazaspiro[5.5]undecan-3-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione in the synthetic route of Example 1.

[0879] MS m / z (ESI): 857.4 [M+H] + .

[0880] 1H-NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 8.64 (s, 1H), 7.04-6.87 (m, 4H), 6.81 (s, 1H), 6.62 (d, J = 8.4 Hz, 1H), 5.35-5.25 (m, 1H), 4.37 (s, 2H), 3.20-3.02 (m, 8H), 2.71-2.65 (m, 5H), 2.42-2.31 (m, 5H), 2.04-1.85 (m, 10H), 1.52-1.42 (m, 9H), 0.69 (s, 2H), 0.43 (s, 2H).

[0881] Example 24: Preparation of (4S)-2-amino-3'-(4-((1-((9-(3-(2,6-dioxopiperidin-3-yl)-1- methyl-1H-indazol-6-yl)-3,9-diazaspiro[5.5]undec-3-yl)methyl)cyclopropyl)methoxy)-6- ((4-methylpyridin-3-yl)oxy)pyrimidin-2-yl)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene- 4,7'-benzo[d]isoxazole]-3-carbonitrile (Compound 36)

[0882] Using the synthetic route in Example 1, replacing the first step reaction material (S)-(1- ((2-(3-cyano-2-((dimethylamino)methyleneamino)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophen-4,7'-benzo[d]isoxazole]-3'-yl)-6-(pyrimidin-5-yloxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl methanesulfonate with (S)-(1-(((2-(3-cyano-2-(((dimethylamino)methyleneamino)-5',6,6',7- tetrahydro-4'H,5H-spiro[benzo[b]thiophen-4,7'-benzo[d]isoxazole]-3'-yl)-6-((4- methylpyridin-3-yl)oxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl methanesulfonate, the title compound was obtained (3 mg, yield: 20.3%).

[0883] MS m / z (ESI): 948.4 [M+H] + .

[0884] 1H-NMR (400 MHz, DMSO-d6) δ 10.86 (s, 1H), 8.40 (d, J = 6.0 Hz, 2H), 7.48-7.43 (m, 2H), 7.11-6.71 (m, 4H), 6.62 (s, 1H), 4.39-4.33 (m, 2H), 4.26-4.22 (m, 1H), 4.15-4.11 (m, 3H), 3.87 (s, 3H), 3.18-3.16 (m, 3H), 2.71-2.54 (m, 3H), 2.47-1.67 (m, 18H), 1.71-1.42 (m, 8H), 1.23 (s, 2H), 0.68 (s, 2H), 0.43 (s, 2H).

[0885] Example 25: Preparation of (4S)-2-amino-3'-(4-((1-((9-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)cyclopropyl)methoxy)-6-((4-methylpyridin-3-yl)oxy)pyrimidin-2-yl)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-3-carbonitrile (Compound 39)

[0886] Using the synthetic route in Example 1, the first step reaction material (S)-(1-((2-(3-cyano-2-((dimethylamino)methylene)amino)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-3'-yl)-6-(pyrimidin-5-yloxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl methanesulfonate was replaced by (S)-(1-(((2-(3-cyano-2-(((dimethylamino)methylene)amino)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-3'-yl)-6-((4-methylpyridin-3-yl)oxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl methanesulfonate, and the reaction material 3-(1-methyl-6-(3,9-diazaspiro[5.5]undecan-3-yl)-1H-indazol-3-yl)piperidine-2,6-dione was replaced by 3-(5-fluoro-1-methyl-6-(3,9-diazaspiro[5.5]undecan-3-yl)-1H-indazol-3-yl)piperidine-2,6-dione to obtain the title compound (1.5 mg, yield: 7.6%).

[0887] MS m / z (ESI): 966.4 [M+H] + .

[0888] 1 H-NMR (400 MHz, DMSO-d6) δ 10.88 (s, 1H), 8.42 (d, J = 6.4 Hz, 2H), 7.76-7.28 (m, 2H), 7.14 (d, J = 7.2 Hz, 1H), 6.95 (s, 2H), 6.63 (s, 1H), 4.42-4.26 (m, 3H), 3.95 (s, 3H), 3.01 (s, 4H), 2.69-2.60 (m, 4H), 2.41-2.33 (m, 8H), 2.21-1.76 (m, 13H), 1.58-1.48 (m, 8H), 0.70 (s, 2H), 0.45 (s, 2H).

[0889] Example 26: Preparation of (4S)-2-amino-3'-(4-((1-((9-(4-(2,6-dioxopiperidin-3-yl)phenoxy)-3- azaspiro[5.5]undec-3-yl)methyl)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 (Compound 38)

[0890] The synthetic route in Example 1 was adopted, and the first step reaction material 3-(1- methyl-6-(3,9-diazaspiro[5.5]undec-3-yl)-1H-indazol-3-yl)piperidine-2,6-dione was replaced by 3-(4-((3-azaspiro[5.5]undecan-9-yl)oxy)phenyl)piperidine-2,6-dione to obtain the title compound (22 mg, yield: 39%).

[0891] MS m / z (ESI): 896.4 [M+H] + .

[0892] 1 H-NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 9.15 (s, 1H), 8.90 (s, 2H), 7.09 (d, J = 8.4 Hz, 2H), 7.00-6.81 (m, 4H), 6.76 (s, 1H), 4.41-4.29 (m, 3H), 3.78-3.74 (m, 1H), 2.73-2.55 (m, 2H), 2.41-1.71 (m, 20H), 1.62-1.09 (m, 12H), 0.68 (s, 2H), 0.43 (s, 2H).

[0893] Example 27: Preparation of (4S)-3'-(4-((8-oxabicyclo[3.2.1]octan-3-yl)oxy)-6-((1-((9-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)cyclopropyl)methoxy)pyrimidin-2-yl)-2-amino-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-3-carbonitrile (Compound 47)

[0894] The title compound (4 mg, yield: 27%) was obtained by replacing the first step reaction material (S)-(1-((2-(3-cyano-2-((dimethylamino)methylene)amino)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-3'-yl)-6-(pyrimidin-5-yloxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)methyl sulfonate with (1-(((6-((8-oxabicyclo[3.2.1]octan-3-yl)oxy)-2-((S)-3-cyano-2-(dimethylamino)methylene)amino)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-3'-yl)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)methyl sulfonate, and the reaction material 3-(1-methyl-6-(3,9-diazaspiro[5.5]undecan-3-yl)-1H-indazol-3-yl)piperidine-2,6-dione with 3-(5-fluoro-1-methyl-6-(3,9-diazaspiro[5.5]undecan-3-yl)-1H-indazol-3-yl)piperidine-2,6-dione in the synthetic route in Example 1.

[0895] MS m / z (ESI): 985.4 [M+H] + .

[0896] 1H-NMR (400 MHz, DMSO-d6) δ 10.86 (s, 1H), 7.42 (d, J = 12.4 Hz, 1H), 7.12 (d, J = 7.2 Hz, 1H), 6.97 (s, 2H), 6.29 (s, 1H), 5.54-5.41 (m, 1H), 4.43 (s, 2H), 4.43-4.28 (m, 3H), 3.93 (s, 3H), 3.12-2.99 (m, 5H), 2.71-2.58 (m, 4H), 2.43-2.23 (m, 7H), 2.21-1.74 (m, 15H), 1.69-1.43 (m, 9H), 1.25-1.22 (m, 2H), 0.65 (s, 2H), 0.41 (s, 2H).

[0897] Example 28: Preparation of (S)-2-amino-3'-(4-((l-((2-(4-(3-(2,4-dioxotetrahydro- pyrimidin-l(2H)-yl)-l-methyl-lH-indazol-6-yl)piperidin-l-yl)-7-azaspiro[3.5]non-7- yl)methyl)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 (Compound 20)

[0898] Using the synthetic route in Example 12, replace the first step reaction material 3-(5- fluoro-l-methyl-6-(3,9-diazaspiro[5.5]undecan-3-yl)-lH-indazol-3-yl)piperidine-2,6- dione with l-(6-(l-(7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-l-methyl-lH-indazol-3-yl) dihydropyrimidine-2,4(lH,3H)-dione to obtain the title compound (5 mg, yield: 17.6%).

[0899] MS m / z (ESI): 990.5 [M+H] + .

[0900] 1H-NMR (400 MHz, DMSO-d6) δ 10.55 (s, 1H), 9.15 (s, 1H), 8.91 (s, 2H), 7.53 (d, J = 8.4 Hz, 1H), 7.46 (s, 1H), 7.03 (d, J = 8.8 Hz, 1H), 6.95 (s, 2H), 6.76 (s, 1H), 4.37 (s, 2H), 3.96 (s, 3H), 3.90 (t, J = 6.8 Hz, 2H), 2.91 (d, J = 6.4 Hz, 2H), 2.75 (t, J = 6.8 Hz, 2H), 2.70-2.57 (m, 3H), 2.38-2.15 (m, 4H), 2.03-1.59 (m, 22H), 1.55-1.38 (m, 5H), 0.71-0.65 (m, 2H), 0.42 (s, 2H).

[0901] Example 29: Preparation of (S)-2-amino-3'-(4-((l-((9-(3-(2,4-dioxotetrahydro- pyrimidin-l(2H)-yl)-l-methyl-lH-indazol-6-yl)-3,9-diazaspiro[5.5]undec-3-yl)methyl)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 (Compound 12)

[0902] Using the synthetic route in Example 12, replacing the first step reaction material 3-(5- fluoro-l-methyl-6-(3,9-diazaspiro[5.5]undec-3-yl)-lH-indazol-3-yl)piperidine-2,6-dione with l-(l-methyl-6-(3,9-diazaspiro[5.5]undec-3-yl)-lH-indazol-3-yl)dihydropyrimidine- 2,4(lH,3H)-dione, the title compound was obtained (7 mg, yield: 14.8%).

[0903] MS m / z (ESI): 936.4 [M+H] + .

[0904] 1H-NMR (400 MHz, DMSO-d6) δ 10.51 (s, 1H), 9.15 (s, 1H), 8.91 (s, 2H), 7.42 (d, J = 9.2 Hz, 1H), 6.94 (s, 2H), 6.90 (d, J = 9.2 Hz, 1H), 6.79 (d, J = 13.2 Hz, 2H), 4.39 (s, 2H), 3.88 (d, J = 6.4 Hz, 5H), 3.21 (s, 6H), 2.79-2.64 (m, 2H), 2.41 (s, 5H), 2.34 (s, 2H), 1.97 (d, J = 10.4 Hz, 4H), 1.86-1.75 (m, 4H), 1.68 (s, 1H), 1.53 (s, 4H), 1.46 (s, 4H), 0.73-0.66 (m, 2H), 0.49 -0.42 (m, 2H).

[0905] Example 30: Preparation of (4S)-2-amino-3'-(4-((1-((2-(3-(2,6-dioxopiperidin-3-yl)-1- methyl-1H-indazol-6-yl)-2,7-diazaspiro[3.5]non-7-yl)methyl)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 (Compound 27)

[0906] The title compound was obtained using the synthetic protocol in Example 12 by replacing the first step reaction material 3-(5-fluoro-1-methyl-6-(3,9-diazaspiro[5.5]undecan-3-yl)-1H- indazol-3-yl)piperidine-2,6-dione with 3-(1-methyl-6-(2,7-diazaspiro[3.5]nonan-2-yl)-1H- indazol-3-yl)piperidine-2,6-dione (0.97 mg, yield: 5.4%).

[0907] MS m / z (ESI): 907.4 [M+H] + .

[0908] 1H-NMR (400 MHz, DMSO-d6) δ 10.84 (s, 1H), 9.15 (d, J = 2.4 Hz, 1H), 8.91 (s, 2H), 7.46 (d, J = 8.8 Hz, 1H), 6.94 (s, 2H), 6.78 (s, 1H), 6.39 - 6.28 (m, 2H), 4.38 (d, J = 11.2 Hz, 2H), 4.23 (dd, J = 9.2, 5.2 Hz, 1H), 3.83 (s, 2H), 3.64 - 3.52 (m, 4H), 2.65 - 2.55 (m, 4H), 2.36 - 2.09 (m, 5H), 2.07 - 1.88 (m, 2H), 1.87 - 1.64 (m, 11H), 1.24 (s, 4H), 0.89 - 0.81 (m, 1H), 0.71 (s, 2H), 0.45 (s, 2H).

[0909] Example 31: Preparation of (4S)-2-amino-3'-(4-((1-((2-(3-(2,6-dioxopiperidin-3-yl)-1- methyl-1H-indazol-6-yl)-2,8-diazaspiro[4.5]dec-8-yl)methyl)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 (Compound 25)

[0910] The title compound was obtained (8 mg, yield: 15.4%) using the synthetic route in Example 12 by replacing the first step reaction material 3-(5-fluoro-1-methyl-6-(3,9- diazaspiro[5.5]undec-3-yl)-1H-indazol-3-yl)piperidine-2,6-dione with 3-(1-methyl-6-(2,8- diazaspiro[4.5]dec-2-yl)-1H-indazol-3-yl)piperidine-2,6-dione.

[0911] MS m / z (ESI): 921.4 [M+H] + .

[0912] 1H-NMR (400 MHz, DMSO-d6) δ 10.84 (s, 1H), 9.15 (s, 1H), 8.91 (s, 2H), 7.44 (d, J = 8.8 Hz, 1H), 6.94 (s, 2H), 6.77 (s, 1H), 6.56-6.56 (m, 1H), 6.36-6.29 (m, 1H), 4.41 (s, 2H), 4.22 (dd, J = 8.8, 5.2 Hz, 1H), 3.83 (s, 3H), 3.14 (s, 2H), 2.81-2.54 (m, 5H), 2.42-2.30 (m, 5H), 2.30-2.10 (m, 3H), 2.07-1.87 (m, 2H), 1.86-1.62 (m, 11H), 1.54 (s, 4H), 0.70 (s, 2H), 0.45 (s, 2H).

[0913] Example 32: Preparation of (4S)-2-amino-3'-(4-((1-((9-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)cyclopropyl)methoxy)-6-methoxypyrimidin-2-yl)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-3-carbonitrile (Compound 37)

[0914] The title compound (8 mg, yield: 9.4%) was obtained by replacing the first step reaction material (S)-(1-((2-(3-cyano-2-((dimethylamino)methyleneamino)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-3'-yl)-6-(pyrimidin-5-yloxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl methanesulfonate with (S)-(1-(((2-(3-cyano-2-(((dimethylamino)methyleneamino)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-3'-yl)-6-methoxypyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl methanesulfonate and replacing the reaction material 3-(1-methyl-6-(3,9-diazaspiro[5.5]undecan-3-yl)-1H-indazol-3-yl)piperidine-2,6-dione with 3-(5-fluoro-1-methyl-6-(3,9-diazaspiro[5.5]undecan-3-yl)-1H-indazol-3-yl)piperidine-2,6-dione in the synthetic route in Example 1.

[0915] MS m / z (ESI): 889.4 [M+H] + .

[0916] 1 H-NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H), 7.42 (d, J = 12.4 Hz, 1H), 7.12 (d, J = 7.2 Hz, 1H), 6.95 (s, 2H), 6.33 (s, 1H), 4.51 - 4.17 (m, 3H), 3.95 (d, J = 14.4 Hz, 6H), 3.15 - 2.94 (m, 5H), 2.80 - 2.54 (m, 5H), 2.45 - 2.19 (m, 4H), 2.18 - 1.91 (m, 6H), 1.85 (d, J = 5.6 Hz, 3H), 1.52 (d, J = 9.2 Hz, 8H), 1.30 - 1.21 (m, 3H), 0.67 (s, 2H), 0.42 (s, 2H).

[0917] Example 33: Preparation of (4S)-2-amino-3'-(4-((1-((9-(3-(2,6-dioxopiperidin-3-yl)phenoxy)-3- azaspiro[5.5]undec-3-yl)methyl)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 (Compound 33)

[0918] Using the synthetic route in Example 12, replace the first step reaction material 3-(5-fluoro-1- methyl-6-(3,9-diazaspiro[5.5]undec-3-yl)-1H-indazol-3-yl)piperidine-2,6-dione with 3-(3-((3- azaspiro[5.5]undecan-9-yl)oxy)phenyl)piperidine-2,6-dione to obtain the title compound (7 mg, yield: 14.9%).

[0919] MS m / z (ESI): 896.4 [M+H] + .

[0920] 1H-NMR (400 MHz, DMSO-d6) δ 10.82 (s, 1H), 9.15 (s, 1H), 8.90 (s, 2H), 7.20 (t, J = 8.0 Hz, 1H), 6.93 (s, 2H), 6.86-6.72 (m, 4H), 4.48-4.25 (m, 3H), 3.80 (dd, J = 11.2, 4.8 Hz, 1H), 2.71-2.57 (m, 2H), 2.43-2.11 (m, 9H), 2.07-1.86 (m, 4H), 1.78 (d, J = 11.6 Hz, 5H), 1.67-1.31 (m, 12H), 1.22 (d, J = 8.4 Hz, 2H), 0.68 (s, 2H), 0.43 (s, 2H).

[0921] Example 34: Preparation of (4S)-2-amino-3'-(4-((1-((2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-5-yl)piperidin-1-yl)-7-azaspiro[3.5]non-7-yl)methyl)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 (Compound 21)

[0922] The title compound (6 mg, yield: 7.9%) was obtained by replacing the first step reaction material 3-(5-fluoro-1-methyl-6-(3,9-diazaspiro[5.5]undecan-3-yl)-1H-indazol-3-yl)piperidine-2,6-dione with 3-(5-(1-(7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-1-yl)piperidine-2,6-dione in the synthetic route in Example 12.

[0923] MS m / z (ESI): 1005.5 [M+H] + .

[0924] 1H-NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 9.16 (s, 1H), 8.91 (s, 2H), 7.10 (s, 1H), 7.02-6.85 (m, 4H), 6.76 (s, 1H), 5.33 (dd, J = 12.4, 5.6 Hz, 1H), 4.37 (s, 2H), 3.09-2.83 (m, 3H), 2.77-2.58 (m, 3H), 2.44-2.15 (m, 3H), 2.07-1.87 (m, 6H), 1.89-1.60 (m, 12H), 1.49 (d, J = 13.2 Hz, 6H), 1.23 (d, J = 7.6 Hz, 5H), 1.04-0.95 (m, 3H), 0.90-0.77 (m, 2H), 0.69 (s, 2H), 0.44 (s, 2H).

[0925] Example 35: Preparation of (4S)-2-amino-3'-(4-((1-((9-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-5-yl)-3,9-diazaspiro[5.5]undec-3-yl)methyl)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 (Compound 13)

[0926] The title compound (30 mg, yield: 21.2%) was obtained by replacing the first step reaction material 3-(5-fluoro-1-methyl-6-(3,9-diazaspiro[5.5]undec-3-yl)-1H-indazol-3-yl)piperidine-2,6-dione with 3-(3-methyl-2-oxo-5-(3,9-diazaspiro[5.5]undec-3-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione in the synthetic route in Example 12.

[0927] MS m / z (ESI): 951.4 [M+H] + .

[0928] 1H-NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 9.15 (s, 1H), 8.91 (s, 2H), 6.99-6.87 (m, 3H), 6.86-6.73 (m, 2H), 6.62 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 5.28 (dd, J = 12.8, 5.6 Hz, 1H), 4.44-4.33 (m, 2H), 3.29 (s, 3H), 3.04 (d, J = 6.4 Hz, 4H), 2.96-2.79 (m, 1H), 2.74-2.53 (m, 4H), 2.44-2.28 (m, 6H), 2.30-2.15 (m, 1H), 2.05-1.60 (m, 8H), 1.60-1.46 (m, 10H), 0.69 (s, 2H), 0.44 (s, 2H).

[0929] Example 36: Preparation of (4S)-2-amino-3'-(4-((1-((4-((1-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)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 (Compound 11)

[0930] Using the synthetic route in Example 12, the first step reaction material 3-(5-fluoro-1- methyl-6-(3,9-diazaspiro[5.5]undecan-3-yl)-1H-indazol-3-yl)piperidine-2,6-dione was replaced with 3-(1-oxo-5-(4-(piperazin-1-ylmethyl)piperidin-1-yl)isoindolin-2-yl)piperidine-2,6-dione to give the title compound (5 mg, yield: 17.6%).

[0931] MS m / z (ESI): 965.4 [M+H] + .

[0932] 1H-NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 9.15 (s, 1H), 8.91 (s, 2H), 7.56-7.44 (m, 1H), 7.13-6.89 (m, 4H), 6.76 (s, 1H), 5.04 (dd, J = 13.2, 5.2 Hz, 1H), 4.44-4.26 (m, 3H), 4.18 (d, J = 16.8 Hz, 1H), 3.85 (d, J = 12.4 Hz, 2H), 3.00-2.71 (m, 4H), 2.70-2.52 (m, 5H), 2..42-2.16 (m, 9H), 2.09 (d, J = 6.4 Hz, 2H), 2.03-1.88 (m, 4H), 1.78-1.65 (m, 9H), 1.25-1.05 (m, 2H), 0.68 (s, 2H), 0.43 (s, 2H).

[0933] Example 37: Preparation of (4S)-2-amino-3'-(4-((1-((9-(1-(2,6-dioxopiperidin-3-yl)-2- oxoindol-5-yl)-3,9-diazaspiro[5.5]undec-3-yl)methyl)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 (Compound 44)

[0934] The title compound was obtained using the synthetic route in Example 12 by replacing the first step reaction material 3-(5-fluoro-1-methyl-6-(3,9-diazaspiro[5.5]undec-3-yl)-1H- indazol-3-yl)piperidine-2,6-dione with 3-(2-oxo-5-(3,9-diazaspiro[5.5]undec-3-yl)indolin-1- yl)piperidine-2,6-dione (1.7 mg, yield: 12.0%).

[0935] MS m / z (ESI): 936.4 [M+H] + .

[0936] 1H-NMR (400 MHz, CD3OD) δ 9.10 (s, 1H). 8.88-8.81 (m, 2H), 7.06 (d, J = 2.4 Hz, 1H), 6.87 (dd, J = 8.8, 2.4 Hz, 1H), 6.78 (d, J = 8.8 Hz, 1H), 6.61 (d, J = 1.2 Hz, 1H), 5.17 (d, J = 12.0 Hz, 1H), 4.54-4.34 (m, 3H), 3.61-3.42 (m, 1H), 3.18-2.99 (m, 4H), 2.90-2.85 (m, 1H), 2.82-2.66 (m, 2H), 2.61-2.28 (m, 8H), 2.16-1.80 (m, 6H), 1.79-1.67 (m, 1H), 1.67-1.49 (m, 8H), 1.29 (d, J = 7.2 Hz, 4H), 1.00-0.82 (m, 1H), 0.73 (s, 2H), 0.52 (s, 2H).

[0937] Example 38: Preparation of (S)-2-amino-3'-(4-((l-((9-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)benzoyl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)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 (Compound 15)

[0938] Using the synthetic route in Example 12, the first step reaction material 3-(5-fluoro-l-methyl-6-(3,9-diazaspiro[5.5]undecan-3-yl)-lH-indazol-3-yl)piperidine-2,6-dione was replaced by l-(2-chloro-5-(3,9-diazaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(lH,3H)-dione to get the title compound (1.75 mg, yield: 4.6%).

[0939] MS m / z (ESI): 944.3 [M+H] + .

[0940] 1H-NMR (400 MHz, CD3OD) δ 9.11 (s, 1H), 8.83 (s, 2H), 8.52 (s, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.54 (d, J = 2.0 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 6.67 (d, J = 6.0 Hz, 1H), 5.10 (s, 1H), 4.68-4.55 (m, 1H), 4.18-3.90 (m, 1H), 3.79 (t, J = 6.8 Hz, 2H), 3.70 (s, 2H), 3.44 (d, J = 7.6 Hz, 2H), 3.16 (d, J = 5.6 Hz, 3H), 2.91-2.87 (m, 3H), 2.55 (s, 2H), 2.42 (d, J = 17.2 Hz, 1H), 2.31-2.16 (m, 1H), 2.11-1.97 (m, 2H), 1.96-1.87 (m, 4H), 1.82 (s, 7H), 1.73-1.58 (m, 2H), 1.49 (s, 2H), 0.94 (d, J = 11.2 Hz, 3H), 0.78-0.66 (m, 1H).

[0941] Example 39: Preparation of (4S)-2-amino-3'-(4-((1-((9-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-3,9-diazaspiro[5.5]undec-3-yl)methyl)cyclopropyl)methoxy)-6-((4-(trifluoromethyl)pyrimidin-5-yl)oxy)pyrimidin-2-yl)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-3-carbonitrile (Compound 51)

[0942] Using the synthetic sequence in Example 1, replacing the reaction material of the first step (S)-(1-((2-(3-cyano-2-((dimethylamino)methylene)amino)-5',6,6',7- tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-3'-yl)-6- (pyrimidin-5-yloxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)methanesulfonate with (S)-(1-(((2-(3-cyano-2-(((dimethylamino)methylene)amino)-5',6,6',7- tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-3'-yl)-6-((4- (trifluoromethyl)pyrimidin-5-yl)oxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)methanesulfonate, and replacing the reaction material 3-(1-methyl-6-(3,9- diazaspiro[5.5]undecan-3-yl)-1H-indazol-3-yl)piperidine-2,6-dione with 3-(5-fluoro-1- methyl-6-(3,9-diazaspiro[5.5]undecan-3-yl)-1H-indazol-3-yl)piperidine-2,6-dione, the title compound was obtained (70 mg, yield: 36.9%).

[0943] MS m / z (ESI): 1021.4 [M+H] + .

[0944] 1 H-NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 9.38 (s, 2H), 7.43 (d, J = 12.4 Hz, 1H), 7.12 (d, J = 7.2 Hz, 1H), 6.93 (d, J = 10.0 Hz, 3H), 4.40 (t, J = 10.8 Hz, 2H), 4.27 (t, J = 6.8 Hz, 1H), 3.93 (s, 5H), 3.66-3.46 (m, 2H), 3.00 (s, 4H), 2.60 (s, 3H), 2.37 (d, J = 12.0 Hz 7H), 2.24-2.07 (m, 2H), 2.04-1.70 (m, 5H), 1.52 (d, J = 8.0 Hz, 7H), 1.39-1.19 (m, 2H), 0.70 (s, 2H), 0.45 (s, 2H).

[0945] Example 40: Preparation of (S)-2-amino-3'-(4-((1-((2-(4-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperazin-1-yl)-7-azaspiro[3.5]non-7-yl)methyl)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 (Compound 23)

[0946] Using the synthetic route in Example 12, the first step reaction material 3-(5-fluoro-1-methyl-6-(3,9-diazaspiro[5.5]undecan-3-yl)-1H-indazol-3-yl)piperidine-2,6-dione was replaced by 1-(5-(4-(7-azaspiro[3.5]nonan-2-yl)piperazine-1-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione to give the title compound (2.56 mg, yield: 13.5%).

[0947] MS m / z (ESI): 999.4 [M+H] + .

[0948] 1 H-NMR (400 MHz, DMSO-d6) δ 10.52 (s, 1H), 9.15 (s, 1H), 8.90 (s, 2H), 7.64 (d, J = 8.4 Hz, 1H), 7.55 (d, J = 2.0 Hz, 1H), 7.38 (dd, J = 8.0, 2.0 Hz, 1H), 6.94 (s, 2H), 6.75 (s, 1H), 4.36 (s, 2H), 3.77-3.72 (m, 1H), 3.64-3.56 (m, 3H), 2.76-2.70 (m, 3H), 2.63 (d, J = 7.6 Hz, 2H), 2.24 (s, 5H), 2.21-2.16 (m, 3H), 1.96 (t, J = 7.2 Hz, 3H), 1.89-1.73 (m, 10H), 1.72-1.58 (m, 2H), 1.47-1.42 (m, 7H), 0.67 (s, 2H), 0.41 (s, 2H).

[0949] Example 41: Preparation of (4S)-2-amino-3'-(4-((1-((7-(3-(2,6-dioxopiperidin-3-yl)-1- methyl-1H-indazol-6-yl)-2,7-diazaspiro[3.5]nonan-2-yl)methyl)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 (Compound 24)

[0950] The title compound was obtained (2.05 mg, yield: 4.9%) using the synthetic route in Example 12, replacing the first step reaction material 3-(5-fluoro-1-methyl-6-(3,9- diazaspiro[5.5]undecan-3-yl)-1H-indazol-3-yl)piperidine-2,6-dione with 3-(1-methyl-6-(2,7- diazaspiro[3.5]nonan-7-yl)-1H-indazol-3-yl)piperidine-2,6-dione.

[0951] MS m / z (ESI): 907.4 [M+H] + .

[0952] 1 H-NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H), 9.15 (s, 1H), 8.91 (s, 2H), 7.47 (d, J = 8.8 Hz, 1H), 6.93 (s, 2H), 6.89 (d, J = 10.0 Hz, 1H), 6.80 (d, J = 15.2 Hz, 2H), 4.35-4.29 (m, 2H), 4.24 (dd, J = 8.8, 5.2 Hz, 1H), 3.87-3.56 (m, 4H), 3.16-3.01 (m, 7H), 2.63-2.58 (m, 2H), 2.30 (s, 1H), 2.26-2.12 (m, 3H), 2.01-1.87 (m, 4H), 1.87-1.84 (m, 2H), 1.79-1.71 (m, 8H), 1.68-1.62 (m, 1H), 1.23 (s, 1H), 0.67 (s, 2H), 0.44 (s, 2H).

[0953] Example 42: Preparation of (4S)-2-amino-3'-(4-((1-((8-(3-(2,6-dioxopiperidin-3-yl)-1- methyl-1H-indazol-6-yl)-2,8-diazaspiro[4.5]dec-2-yl)methyl)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 (Compound 29)

[0954] The title compound was obtained (1.96 mg, yield: 13.9%) using the synthetic route in Example 12, replacing the first step reaction material 3-(5-fluoro-1-methyl-6-(3,9- diazaspiro[5.5]undecan-3-yl)-1H-indazol-3-yl)piperidine-2,6-dione with 3-(1-methyl-6-(2,8- diazaspiro[4.5]dec-8-yl)-1H-indazol-3-yl)piperidine-2,6-dione.

[0955] MS m / z (ESI): 921.4 [M+H] + .

[0956] 1 H-NMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 9.14 (s, 1H), 8.90 (s, 2H), 7.46 (d, J = 8.8 Hz, 1H), 6.91 (s, 2H), 6.88 (dd, J = 9.2, 1.6 Hz, 1H), 6.80 (s, 1H), 6.76 (s, 1H), 4.40 (dd, J = 23.6, 10.8 Hz, 2H), 4.24 (dd, J = 9.2, 5.2 Hz, 1H), 3.86 (s, 3H), 3.22 - 3.10 (m, 4H), 2.59 - 2.52 (m, 5H), 2.43 - 2.36 (m, 4H), 2.31 - 2.21 (m, 2H), 2.21 - 2.13 (m, 1H), 2.02 - 1.83 (m, 4H), 1.82 - 1.74 (m, 4H), 1.59 (dd, J = 17.6, 10.4 Hz, 6H), 1.23 (s, 2H), 0.67 (s, 2H), 0.45 (s, 2H).

[0957] Example 43: Preparation of (4S)-2-amino-3'-(4-((1-((9-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)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 (Compound 14)

[0958] The title compound was obtained (1.9 mg, in yield: 9.0%) using the synthetic route in Example 12 by replacing the first step reaction material 3-(5-fluoro-1-methyl-6-(3,9-diazaspiro[5.5]undecan-3-yl)-1H-indazol-3-yl)piperidine-2,6-dione with 3-((3-fluoro-4-(3,9-diazaspiro[5.5]undecan-3-yl)phenyl)amino)piperidine-2,6-dione.

[0959] MS m / z (ESI): 914.4 [M+H] + .

[0960] 1 H-NMR (400 MHz, CD3OD) δ 9.09 (s, 1H), 8.84 (s, 2H), 7.35 (dd, J = 14.4, 2.4 Hz, 1H), 7.13-7.02 (m, 2H), 6.60 (s, 1H), 4.72 (dd, J = 8.4, 3.6 Hz, 2H), 4.34 (d, J = 11.6 Hz, 1H), 3.01-2.98 (m, 3H), 2.81-2.68 (m, 5H), 2.63-2.47 (m, 5H), 2.34-2.29 (m, 2H), 2.15-2.05 (m, 3H), 2.02-1.81 (m, 8H), 1.76-1.73 (m, 1H), 1.67 (d, J = 3.2 Hz, 6H), 1.31 (dd, J = 10.4, 7.6 Hz, 2H), 0.95-0.84 (m, 1H), 0.81 (s, 2H), 0.64 (s, 2H).

[0961] Example 44: Preparation of (4S)-2-amino-3'-(4-((1-((9-(4-((2,6-dioxopiperidin-3-yl)oxy)phenyl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)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 (Compound 45)

[0962] Using the synthetic route in Example 12, replace the first step reactant 3-(5-fluoro-l-methyl-6-(3,9-diazaspiro[5.5]undecan-3-yl)-lH-indazol-3-yl)piperidine-2,6-dione with 3-(4-(3,9-diazaspiro[5.5]undecan-3-yl)phenoxy)piperidine-2,6-dione, afford the title compound (2.43 mg, yield: 26.1%).

[0963] MS m / z (ESI): 897.4 [M+H] + .

[0964] 1 H-NMR (400MHz, CD3OD) δ 9.09 (s, 1H), 8.83 (s, 2H), 6.97 (s, 4H), 6.59 (s, 1H), 4.61 (s, 4H), 3.07-2.99 (m, 4H), 2.83-2.64 (m, 4H), 2.63-2.52 (m, 6H), 2.36-2.24 (m, 2H), 2.23-2.08 (m, 2H), 2.07-1.97 (m, 3H), 1.94 (dd, J = 9.6, 3.2 Hz, 2H), 1.63 (d, J = 4.4 Hz, 4H), 1.59 (s, 4H), 1.37-1.23 (m, 2H), 0.75 (s, 2H), 0.56 (d, J = 3.2 Hz, 2H).

[0965] Example 45: Preparation of (4S)-2-amino-3'-(4-((l-((9-(3-((2,6-dioxopiperidin-3-yl)oxy)phenyl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)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 (Compound 41)

[0966] Using the synthetic route in Example 12, replace the first step reactant 3-(5-fluoro-l-methyl-6-(3,9-diazaspiro[5.5]undecan-3-yl)-lH-indazol-3-yl)piperidine-2,6-dione with 3-(3-(3,9-diazaspiro[5.5]undecan-3-yl)phenoxy)piperidine-2,6-dione, afford the title compound (3.2 mg, yield: 29.5%).

[0967] MS m / z (ESI): 897.4 [M+H] + .

[0968] 1 H-NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 9.18 (s, 1H), 8.91 (s, 2H), 7.13-7.06 (m, 1H), 6.94 (s, 1H), 6.77 (s, 1H), 6.58 (d, J = 8.0 Hz, 2H), 6.44 (d, J = 7.2 Hz, 1H), 5.17 (dd, J = 10.4, 5.2 Hz, 1H), 4.39 (dd, J = 26.0, 11.6 Hz, 2H), 3.18-3.07 (m, 8H), 3.04 (s, 1H), 2.90 (d, J = 6.0 Hz, 1H), 2.76-2.68 (m, 1H), 2.63-2.56 (m, 1H), 2.22-2.05 (m, 4H), 1.98-1.58 (m, 16H), 1.49 (s, 2H), 1.23 (d, J = 6.8 Hz, 1H), 0.92 (s, 2H), 0.82 (s, 2H).

[0969] Example 46: Preparation of (4S)-2-amino-3'-(4-((l-((9-(4-(2,6-dioxopiperidin-3-yl)benzoyl)-3,9- diazaspiro[5.5]undec-3-yl)methyl)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 (Compound 34)

[0970] First Step: Preparation of (S)-9-((l-(((2-(3-cyano-2-(((dimethylamino)methylene)amino)- 5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-3'-yl)-6- (pyrimidin-5-yloxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)-3,9-diazaspiro[5.5]undecane- 3-carboxylic acid tert-butyl ester

[0971] (S)-N'-(3-cyano-3'-(4-((1-formylcyclopropyl)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-dimethylformamidine (40 mg, 64.9 μmol) and tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (22 mg, 84.3 μmol) were dissolved in dichloromethane (1 mL), after stirring at 25 °C for 1 hour, sodium triacetoxyborohydride (42 mg, 194.5 μmol) was added, and stirring was performed at 25 °C for 6 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 15 / 1, volume ratio) to obtain the title compound (53 mg, yield: 96.7%).

[0972] MS m / z (ESI): 849.4 [M+H] + .

[0973] Second step: Preparation of (S)-N'-(3'-(4-((1-((3,9-diazaspiro[5.5]undecan-3-yl)methyl)cyclopropyl)methoxy)-6-(pyrimidin-5-yloxy)pyrimidin-2-yl)-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-2-yl)-N,N-dimethylformamidine

[0974] (S)-9-((1-(((2-(3-cyano-2-(((dimethylamino)methylene)amino)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-3'-yl)-6-(pyrimidin-5-yloxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)-3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (71 mg, 62.7 μmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (0.5 mL) was added, and stirring was performed at 25 °C for 3 hours. The reaction solution was concentrated to obtain the title compound (52 mg, yield: 95.1%).

[0975] MS m / z (ESI): 749.4 [M+H] + .

[0976] Step 3: Preparation of N'-((4S)-3-cyano-3'-(4-((1-((9-(4-(2,6-dioxopiperidin-3-yl)benzoyl)- 3,9-diazaspiro[5.5]undecan-3-yl)methyl)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- dimethylformamidine

[0977] N'-(3'-(4-((1-((3,9-diazaspiro[5.5]undecan-3-yl)methyl)cyclopropyl)methoxy)-6-(pyrimidin-5- yloxy)pyrimidin-2-yl)-3-cyano-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'- benzo[d]isoxazole]-2-yl)-N,N-dimethylformamidine (52 mg, 60.3 μmol), 4-(2,6-dioxo-3- piperidyl)benzoic acid (15 mg, 63.7 μmol) and N,N-diisopropylethylamine (42 mg, 318.4 μmol) were dissolved in DMF (1 mL), 2-(7-azobenzo-triazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (37 mg, 95.5 μmol) was added and the reaction was stirred at 25 °C for 12 hours. The reaction was diluted with ethyl acetate (20 mL), washed with saturated brine (10 mL) twice, 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 (14 mg, yield: 22.6%).

[0978] MS m / z (ESI): 964.3 [M+H] + .

[0979] Step 4: Preparation of (4S)-2-amino-3'-(4-((1-((9-(4-(2,6-dioxopiperidin-3-yl)benzoyl)-3,9- diazaspiro[5.5]undecan-3-yl)methyl)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

[0980] N'-((4S)-3-cyano-3'-(4-((1-((9-(4-(2,6-dioxopiperidin-3-yl)benzoyl)-3,9- diazaspiro[5.5]undecan-3-yl)methyl)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-dimethylformamidine (14 mg, 14.4 μmol) was dissolved in tetrahydrofuran (3 mL), 2M hydrochloric acid solution (1.5 mL) was added, and the reaction was stirred at 70°C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (Condition 2) to obtain the title compound (2.7 mg, yield: 20.3%).

[0981] MS m / z (ESI): 909.4 [M+H] + .

[0982] 1 H-NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 9.15 (s, 1H), 8.90 (s, 2H), 7.30 (dd, J = 12.0, 8.0 Hz, 4H), 6.93 (s, 2H), 6.76 (s, 1H), 4.42-4.32 (m, 2H), 3.91 (dd, J = 11.6, 4.8 Hz, 1H), 3.59-3.54 (m, 1H), 3.08-2.92 (m, 1H), 2.69-2.66 (m, 2H), 2.40-2.34 (m, 2H), 2.30-2.16 (m, 5H), 2.08-1.88 (m, 6H), 1.87-1.73 (m, 6H), 1.71-1.59 (m, 2H), 1.54-1.25 (m, 9H), 0.70 (s, 2H), 0.43 (s, 2H).

[0983] Example 47: Preparation of (4S)-2-amino-3'-(4-((1-((9-(3-(2,6-dioxopiperidin-3-yl)-5- fluoro-1-methyl-1H-indazol-6-yl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)cyclopropyl)- methoxy)-6-(1,4-oxazepan-4-yl)pyrimidin-2-yl)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-3-carbonitrile (Compound 40)

[0984] Using the synthetic sequence in Example 12, the first step reaction material (S)-N'-(3-cyano-3'-(4-((1-formylcyclopropyl)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-dimethylformamidine was replaced with (S)-N'-(3-cyano-3'-(4-((1-formylcyclopropyl)methoxy)-6-(1,4-oxazepan-4-yl)pyrimidin-2-yl)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-2-yl)-N,N-dimethylformamidine to give the title compound (9.2 mg, yield: 25.3%).

[0985] MS m / z (ESI): 958.4 [M+H] + .

[0986] 1 H-NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H), 8.19 (s, 1H), 7.42 (d, J = 12.4 Hz, 1H), 7.12 (d, J = 7.2 Hz, 1H), 6.94 (s, 2H), 6.03 (d, J = 4.4 Hz, 1H), 4.28-4.19 (m, 3H), 3.93 (s, 3H), 3.73 (s, 3H), 3.65-3.59 (m, 3H), 3.00 (s, 6H), 2.69-2.63 (m, 2H), 2.60 (dd, J = 11.2, 5.2 Hz, 2H), 2.55 (dd, J = 7.2, 4.0 Hz, 1H), 2.43 (s, 3H), 2.37-2.30 (m, 4H), 2.16-2.10 (m, 1H), 2.06-1.78 (m, 10H), 1.54 (d, J = 32.8 Hz, 8H), 0.64 (s, 2H), 0.40 (s, 2H).

[0987] Example 48: Preparation of (4S)-2-amino-3'-(4-((1-((9-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-3,9-diazaspiro[5.5]undec-3-yl)methyl)cyclopropyl)methoxy)-6-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidin-2-yl)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-3-carbonitrile (Compound 48)

[0988] Using the synthetic sequence in Example 1, the reaction starting material in the first step, (S)-(1-((2-(3-cyano-2-((dimethylamino)methylene)amino)-5',6,6',7- tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-3'-yl)-6- (pyrimidin-5-yloxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)methyl sulfamate, was replaced with (S)-(1-(((2-(3-cyano-2-(((dimethylamino)methylene)amino)- 5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-3'-yl)-6- ((tetrahydro-2H-pyran-4-yl)oxy)pyrimidin-4-yl)oxy)methyl)cyclopropyl)methyl)methyl sulfamate, the reaction starting material 3-(1-methyl-6-(3,9-diazaspiro[5.5]undecan-3-yl)- 1H-indazol-3-yl)piperidine-2,6-dione was replaced with 3-(5-fluoro-1-methyl-6-(3,9- diazaspiro[5.5]undecan-3-yl)-1H-indazol-3-yl)piperidine-2,6-dione, to give the title compound (2.01 mg, yield: 12.8%).

[0989] MS m / z (ESI): 959.5 [M+H] + .

[0990] 1 H-NMR (400 MHz, DMSO-d6) δ 10.86 (s, 1H), 7.42 (d, J = 12.4 Hz, 1H), 7.12 (d, J = 7.2 Hz, 1H), 6.95 (d, J = 6.0 Hz, 2H), 6.34 (s, 1H), 5.31-5.21 (m, 1H), 4.34-4.23 (m, 3H), 3.93 (s, 3H), 3.90-3.85 (m, 2H), 3.53-3.47 (m, 2H), 3.32 (s, 4H), 2.99 (s, 4H), 2.63-2.56 (m, 4H), 2.38 (s, 3H), 2.29 (s, 2H), 2.08-1.94 (m, 7H), 1.86-1.83 (m, 2H), 1.68-1.64 (m, 2H), 1.58-1.54 (m, 4H), 1.48-1.43 (m, 4H), 1.23 (s, 2H), 0.65 (s, 2H), 0.41 (s, 2H).

[0991] Example 49: Preparation of (4S)-2-amino-3'-(4-((4-cyclopropylpyrimidin-5-yl)oxy)-6-((1-((9-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-3,9-diazaspiro[5.5]undec-3-yl)methyl)cyclopropyl)methoxy)pyrimidin-2-yl)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-3-carbonitrile (Compound 57)

[0992] The title compound (11.6 mg, yield: 18.3%) was obtained by replacing the first step reaction material (S)-N'-(3-cyano-3'-(4-((1-formylcyclopropyl)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-dimethylformamidine with (S)-N'-(3-cyano-3'-(4-((4-cyclopropylpyrimidin-5-yl)oxy)-6-((1-formylcyclopropyl)methoxy)pyrimidin-2-yl)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-2-yl)-N,N-dimethylformamidine in the synthetic route in Example 12.

[0993] MS m / z (ESI): 993.4 [M+H] + .

[0994] 1 H-NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 8.94 (s, 1H), 8.65 (s, 1H), 7.43 (d, J = 12.4 Hz, 1H), 7.12 (d, J = 7.2 Hz, 1H), 6.94 (s, 2H), 6.79 (s, 1H), 4.37 (dd, J = 24.0, 10.8 Hz, 2H), 4.26 (dd, J = 9.6, 5.2 Hz, 1H), 3.93 (s, 3H), 3.00 (s, 4H), 2.64-2.54 (m, 4H), 2.43-2.35 (m, 4H), 2.35-2.30 (m, 2H), 2.10 (dd, J = 12.8, 9.6 Hz, 3H), 1.99-1.90 (m, 3H), 1.88-1.74 (m, 5H), 1.70 (dd, J = 7.2, 3.6 Hz, 1H), 1.58 (s, 5H), 1.48 (s, 4H), 1.10-1.01 (m, 4H), 0.70 (s, 2H), 0.46 (s, 2H).

[0995] Example 50: Preparation of (4S)-2-amino-3'-(4-((1-((9-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-3,9-diazaspiro[5.5]undec-3-yl)methyl)cyclopentyl)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 (Compound 53)

[0996] The synthetic route in Example 12 was adopted, and the first step reaction material (S)-N'-(3-cyano-3'-(4-((1-formylcyclopropyl)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-dimethylformamidine was replaced by (S)-N'-(3-cyano-3'-(4-((1-formylcyclopentyl)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-dimethylformamidine to obtain the title compound (33.38 mg, yield: 23.8%).

[0997] MS m / z (ESI): 981.4 [M+H] + .

[0998] 1 H-NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 9.16 (s, 1H), 8.92 (s, 2H), 7.41 (d, J = 12.0 Hz, 1H), 7.10 (d, J = 8.0 Hz, 1H), 6.95 (s, 2H), 6.77 (s, 1H), 4.35-4.24 (m, 3H), 3.92 (s, 3H), 3.02-2.96 (m, 4H), 2.59-2.54 (m, 4H), 2.48-2.42 (m, 4H), 2.39 (s, 2H), 2.28-2.08 (m, 4H), 2.00-1.76 (m, 10H), 1.70-1.50 (m, 8H), 1.48-1.38 (m, 6H).

[0999] Example 51: Preparation of (4S)-2-amino-3'-(4-((1-((9-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-3,9-diazaspiro[5.5]undec-3-yl)methyl)-3,3-difluorocyclobutyl)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 (Compound 54)

[1000] The title compound was obtained (30.2 mg, yield: 25.1%) by replacing the first step reaction material (S)-N'-(3-cyano-3'-(4-((1-formylcyclopropyl)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-dimethylformamidine with (S)-N'-(3-cyano-3'-(4-((3,3-difluoro-1-formylcyclobutyl)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-dimethylformamidine in the synthetic route in Example 12.

[1001] MS m / z (ESI): 1003.3 [M+H] + .

[1002] 1 H-NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 9.16 (s, 1H), 8.92 (s, 2H), 7.41 (d, J = 12.0 Hz, 1H), 7.11 (d, J = 4.0 Hz, 1H), 6.95 (s, 2H), 6.78 (s, 1H), 4.58-4.51 (m, 2H), 4.28-4.24 (m, 1H), 3.93 (s, 3H), 3.02-2.96 (m, 4H), 2.72-2.54 (m, 8H), 2.42-2.38 (m, 4H), 2.38-2.10 (m, 4H), 2.00-1.76 (m, 10H), 1.60-1.40 (m, 8H).

[1003] Example 52: Preparation of (4S)-2-amino-3'-(4-((1-((9-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-3,9-diazaspiro[5.5]undec-3-yl)methyl)cyclopropyl)methoxy)-6-((4-isopropylpyrimidin-5-yl)oxy)pyrimidin-2-yl)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-3-carbonitrile (Compound 56)

[1004] The synthetic route in Example 12 was adopted, and the first step reaction material (S)-N'-(3-cyano-3'-(4-((1-formylcyclopropyl)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-dimethylformamidine was replaced with (S)-N'-(3-cyano-3'-(4-((1-formylcyclopropyl)methoxy)-6-((4-isopropylpyrimidin-5-yl)oxy)pyrimidin-2-yl)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-2-yl)-N,N-dimethylformamidine to obtain the title compound (3 mg, yield: 15.3%).

[1005] MS m / z (ESI): 995.4 [M+H] + .

[1006] 1 H-NMR (400 MHz, DMSO-d6) δ 10.86 (s, 1H), 9.09 (s, 1H), 8.72 (s, 1H), 7.43 (d, J = 12.4 Hz, 1H), 7.12 (d, J = 7.2 Hz, 1H), 6.93 (s, 2H), 6.80 (s, 1H), 4.43-4.24 (m, 3H), 3.93 (s, 3H), 3.17-3.14 (m, 1H), 3.00 (s, 3H), 2.73-2.52 (m, 4H), 2.47-2.28 (m, 7H), 2.25-1.35 (m, 18H), 1.23-1.14 (m, 8H), 0.69 (s, 2H), 0.44 (s, 2H).

[1007] Example 53: Preparation of (4S)-2-amino-3'-(4-((1-((9-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-3,9-diazaspiro[5.5]undec-3-yl)methyl)-2,2-difluorocyclopropyl)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 (Compound 55)

[1008] The title compound was obtained (1.51 mg, yield: 2.7%) by replacing the first step reaction material (S)-N'-(3-cyano-3'-(4-((1-formylcyclopropyl)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-dimethylformamidine in the synthetic route in Example 12 with N'-((4S)-3-cyano-3'-(4-((2,2-difluoro-1-formylcyclopropyl)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-dimethylformamidine.

[1009] MS m / z (ESI): 989.4 [M+H] + .

[1010] 1 H-NMR (400 MHz, CD3OD) δ 8.99 (s, 1H), 8.74 (s, 2H), 7.24 (d, J = 12.4 Hz, 1H), 6.93 (d, J = 6.8 Hz, 1H), 6.53 (s, 1H), 5.24 (d, J = 4.8 Hz, 1H), 4.69 (d, J = 12.0 Hz, 1H), 4.56 (dd, J = 22.8, 12.0 Hz, 2H), 4.17 (dd, J = 9.2, 5.2 Hz, 1H), 3.86 (s, 3H), 2.97 (t, J = 5.6 Hz, 4H), 2.75-2.54 (m, 2H), 2.47 (s, 2H), 2.37 (d, J = 7.6 Hz, 4H), 2.18 (dd, J = 13.6, 6.0 Hz, 1H), 2.03-1.71 (m, 5H), 1.56 (d, J = 6.8 Hz, 4H), 1.46 (s, 4H), 1.29 (d, J = 11.6 Hz, 1H), 1.19 (s, 6H), 0.79 (d, J = 7.2 Hz, 2H).

[1011] Example 54: Preparation of (4S)-2-amino-3'-(4-((1-((9-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-3,9-diazaspiro[5.5]undec-3-yl)methyl)cyclobutyl)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 (Compound 52)

[1012] The synthetic route in Example 12 was adopted, and the first step reaction material (S)-N'-(3-cyano-3'-(4-((1-formylcyclopropyl)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-dimethylformamidine was replaced by (S)-N'-(3-cyano-3'-(4-((1-formylcyclobutyl)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-dimethylformamidine to obtain the title compound (1.32 mg, yield: 6.6%).

[1013] MS m / z (ESI): 967.5 [M+H] + .

[1014] 1 H-NMR (400 MHz, CD3OD) δ 9.09 (s, 1H), 8.84 (s, 2H), 7.34 (d, J = 12.4 Hz, 1H), 7.02 (d, J = 6.8 Hz, 1H), 6.61 (s, 1H), 4.71 (d, J = 2.4 Hz, 1H), 4.62 (s, 1H), 4.27 (dd, J = 9.2, 5.2 Hz, 1H), 3.96 (s, 3H), 3.10-3.03 (m, 4H), 2.83-2.62 (m, 5H), 2.62-2.49 (m, 6H), 2.48-2.26 (m, 4H), 2.11-1.89 (m, 12H), 1.66 (s, 4H), 1.57 (s, 4H), 1.35-1.29 (m, 2H).

[1015] Example 55: Preparation of (4S)-2-amino-3'-(4-((1-((9-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-3,9-diazaspiro[5.5]undec-3-yl)methyl)cyclopropyl)methoxy)-6-((4-ethylpyrimidin-5-yl)oxy)pyrimidin-2-yl)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-3-carbonitrile (Compound 58)

[1016] The synthetic route in Example 12 was adopted, and the first step reaction raw material (S)-N'-(3-cyano-3'-(4-((1-formylcyclopropyl)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-dimethylformamidine was replaced with (S)-N'-(3-cyano-3'-(4-((4-ethylpyrimidin-5-yl)oxy)-6-((1-formylcyclopropyl)methoxy)pyrimidin-2-yl)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-2-yl)-N,N-dimethylformamidine to obtain the title compound (1.70 mg, yield: 3.1%).

[1017] MS m / z (ESI): 981.5 [M+H] + .

[1018] 1 H-NMR (400 MHz, CD3OD) δ 9.02 (s, 1H), 8.64 (s, 1H), 8.54 (s, 1H), 7.36 (d, J = 12.4 Hz, 1H), 7.03 (d, J = 6.8 Hz, 1H), 6.67 (s, 1H), 4.61 (s, 2H), 4.31-4.22 (m, 2H), 3.98 (s, 3H), 3.15-3.04 (m, 5H), 2.83-2.75 (m, 4H), 2.74-2.71 (m, 1H), 2.55 (s, 2H), 2.49-2.14 (m, 6H), 2.09-1.96 (m, 3H), 1.92 (d, J = 10.8 Hz, 4H), 1.76 (d, J = 17.6 Hz, 10H), 1.26 (t, J = 7.6 Hz, 3H), 0.90 (s, 2H), 0.74 (s, 2H).

[1019] Biological Example:

[1020] Test Example 1: Test of compound on KRAS-G12D protein degradation in cells

[1021] • Test system and parameters:

[1022] Cells: human colon cancer cells GP2D

[1023] Protein quantification: Pierce TM BCA Protein Assay Kit (Thermofisher)

[1024] Protein electrophoresis: electrophoresis tank (Thermo) 180V constant voltage electrophoresis

[1025] Protein transfer: transfer tank (BIO-RAD) 300mA constant current transfer

[1026] • Test steps

[1027] (1) Compound treatment of cells

[1028] Cells were plated in a six-well plate at a cell amount of 1.5x10 6 cells per well. Adherent culture overnight, add compound (concentration is 0, 0.8, 4nM) treatment for 24h.

[1029] (2) Sample processing

[1030] 1) Discard the culture medium, add 2ml PBS to wash the cells. Discard the wash solution, add appropriate amount of lysis buffer (CST, 9803), lyse on ice for 30min, then centrifuge at 12000rpm at 4°C for 10min, and take the supernatant.

[1031] 2) According to the BCA kit instructions, take 40μL standard concentration protein (2mg / ml) and gradient dilute the lysis buffer 1:1 to 1, 0.5, 0.25, 0.125, 0.0625mg / ml, take 10μL sample supernatant dilution and standard concentration protein dilution and add them to the 96-well plate sample wells, add 200μL A and B reagent mixture (50:1) per well. Shake at 37°C for 30min, then detect OD value at 562nm. Fit the standard curve, calculate the sample concentration according to the curve and adjust the sample to the same concentration.

[1032] 3) Add 5X SDS loading buffer (Bi Yun Tian, P0015L) to the sample, denature the protein at 100°C for 10min.

[1033] (3) Protein separation and transfer and development

[1034] 1) Protein samples were separated by 180V constant voltage electrophoresis using NuPAGE 4-12% gradient protein precast gel (Thermofisher). The gel was transferred to membrane at 4℃ 300mA constant current for 90 minutes using a transblot cell, and blocked in 5% skim milk powder for 1 hour.

[1035] 2) After dilution according to the antibody instruction, the membrane was incubated with Ras(G12D specific mutation) antibody (CST, 14429) and a-Tubulin antibody (CST, 2125S) at 4℃ overnight, and washed with TBST for 3 times, 10 minutes each time. After dilution according to the antibody instruction, the membrane was incubated with goat anti-rabbit HRP secondary antibody (CST, 7074) at room temperature for 1 hour, and washed with TBST for 3 times, 10 minutes each time.

[1036] 3) The membrane was soaked in ECL luminescence solution (Millipore\WBKLS0500), and the fluorescence signal was collected using a Bio-rad gel imager.

[1037] • Data processing

[1038] The results were quantified, and the degradation rate of KRAS G12D protein was calculated by comparing with the control group without adding the compound. The calculation formula is as follows:

[1039] Degradation rate (%) = (1-(experimental group KRAS-G12D gray / experimental group a-Tubulin gray) / (control group KRAS-G12D gray / control group a-Tubulin gray)) x 100%.

[1040] • Test results

[1041] The degradation effect of the compound on KRAS G12D protein in GP2D cells was determined according to the above method, and the results are shown in Table 1-1.

[1042] Table 1-1. Degradation rate of KRAS G12D protein by compound

[1043] • Test conclusion

[1044] The test results show that the compound of the present application has a high degradation rate on KRAS-G12D, for example, compound 30 can reach a degradation rate of 63.1% at a dose of 0.8nM.

[1045] Test Example 2: Test of cell proliferation inhibition activity of compound

[1046] • Test system and steps

[1047] AsPC-1 (human metastatic pancreatic adenocarcinoma cells), GP2D (human colon cancer cells), LOVO (human colon cancer cells), SK-CO-1 (human colorectal adenocarcinoma cells) and MKN1 (human gastric cancer cells) were cultured in monolayer in vitro under the following conditions: AsPC-1 and MKN1 cells were cultured in RPMI1640 + 10% fetal bovine serum (FBS) medium, GP2D and LOVO cells were cultured in DMEM + 10% FBS medium, and SK-CO-1 cells were cultured in MEM + 10% FBS + 1% non-essential amino acids + 1 mM sodium pyruvate medium in a 37°C carbon dioxide incubator. Cells were plated in 96-well flat-bottomed cell culture plates at 2000 cells per well, and the next day, pre-diluted compounds were added, with DMSO added to the negative control group and medium added to the blank control group, with a final DMSO concentration of 1%.

[1048] After incubation of the compounds with AsPC-1 cells, GP2D cells, SK-CO-1 cells, LOVO cells and MKN1 cells at 37°C in a carbon dioxide incubator for 5 days, the relative chemiluminescence unit value (RLU) was read using Cell Counting-LiteTM 2.0 reagent (Nanjing Nvigan Biotech Co., Ltd.) in a chemiluminescence detection mode on a microplate reader.

[1049] • Data processing

[1050] The percentage inhibition of different concentrations of compounds was calculated according to the following formula:

[1051] The percentage inhibition was calculated according to the following formula: (1- (chemiluminescence signal value of the test compound - chemiluminescence signal value of the blank control) / (chemiluminescence signal value of the negative control - chemiluminescence signal value of the blank control)) * 100%, and the half maximal inhibitory concentration (IC 50 ) of the compound was calculated by fitting the curve to a four-parameter model.

[1052] • Test results

[1053] The proliferation inhibition activity of the compounds on KRAS mutant cells was determined according to the above method, and the results are shown in Tables 2-1, 2-2, 2-3, 2-4 and 2-5.

[1054] Table 2-1. Proliferation inhibition activity of compounds on KRAS G12D mutant cells (AsPC-1)

[1055] Table 2-2. Proliferation inhibition activity of compounds on KRAS G12D mutant cells (GP2D)

[1056] Table 2-3. Proliferation inhibitory activity of compounds against KRAS G12V Proliferation inhibitory activity against mutant cells (SK-CO-1)

[1057] Table 2-4. Proliferation inhibitory activity of compounds against KRAS G13D Proliferation inhibitory activity against mutant cells (LOVO)

[1058] Table 2-5. Proliferation inhibitory activity of compounds against wild type KRAS cells (MKN1)

[1059] • Test conclusion

[1060] The compounds of the present application exhibit strong proliferation inhibitory activity against KRAS mutant cells.

[1061] The foregoing examples are not intended to limit the scope of the present application in any way. Numerous modifications to the examples described herein will be apparent to those skilled in the art in light of the foregoing description. Such modifications are intended to fall within the scope of the appended claims. Each of the references cited in the present application, including all patents, patent applications, journal articles, books and any other publications, are incorporated herein by reference in their entirety.

Claims

1. A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, said compound having the structure of formula (I): wherein Ring A is C 3-6 Cycloalkyl or 3-6 membered heterocyclyl, optionally substituted with one or more substituents selected from halo, C 1-6 alkyl and C 1-6 haloalkyl; Ring B is a 3-12 membered nitrogen-containing heterocyclyl; Cycloalkyl is optionally substituted with one or more substituents selected from the group consisting of halo, C 6-10 Aryl, 5-12 membered heteroaryl, or 3-12 membered heterocyclyl, said aryl, heteroaryl, or heterocyclyl optionally substituted with one or more substituents selected from the group consisting of halo, C 1-6 Alkyl, C 1-6 Haloalkyl, oxo, -O-C 1-6 Alkyl, -O-C 1-6 Haloalkyl, and -O-C 3-6 Cycloalkyl is optionally substituted with one or more substituents selected from the group consisting of halo, C X 1 and X 2 are each independently selected from O and N; X 3 , X 4 and X 5 are each independently selected from CR 3 and N; X 6 is selected from CH and N; L is a covalent bond, or is selected from the group consisting of O, S and NR 4 ; L 1 selected from O, S and NR 5 ; L 2 selected from C 1-6 alkylene and haloC 1-6 alkylene; L 3 selected from C 1-6 alkylene and haloC 1-6 alkylene; L 4 is a covalent bond, or is selected from O, NR 6 , C 1-6 alkylene, -O-C 1-6 alkylene-, -C 1-6 alkylene-O-, -C 1-6 alkylene-O-C 1-6 alkylene-, -C(=O)-, -C(=O)-C 1-6 alkylene- and a 3-12 membered heterocyclyl group, which heterocyclyl group is optionally substituted by one or more substituents selected from halogen, hydroxy, cyano, C 1-6 alkyl, C 1-6 haloalkyl; L 5 is a covalent bond, or is selected from O, NR 7 , C 1-6 alkylene, -O-C 1-6 alkylene-, -C 1-6 alkylene-O-, -C 1-6 alkylene-O-C 1-6 alkylene-, -C(=O)-, -C(=O)-C 1-6 alkylene- and a 3-12 membered heterocyclyl group, which heterocyclyl group is optionally substituted by one or more substituents selected from halogen, hydroxy, cyano, C 1-6 alkyl, C 1-6 haloalkyl; L 6 is a covalent bond, or is selected from O, NR 8 and -C(=O)-NR 9 -; preferably, L 6 is a covalent bond, or is selected from NR 8 and -C(=O)-NR 9 -; Each R 1 Independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl groups 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- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, -C 1-6 alkylene-C 3-6 cycloalkyl, -C 1-6 alkylene-3- to 12-membered heterocyclyl and -C 1-6 alkylene-5- to 10-membered heteroaryl, said alkyl, alkylene, cycloalkyl, aryl, heterocyclyl and heteroaryl are optionally substituted with one or more substituents selected from halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, -O-C 1-6 alkyl, -C 1-6 alkylene-OH, -NR 10a R 10b , -C 1-6 alkylene-O-C 1-6 alkyl and -O-C 1- 6haloalkyl; R is selected from hydrogen, halogen, cyano, C 2 alkyl, C 1-6 haloalkyl, -O-C 3-6 alkyl, -C 6-10 alkylene-OH, -NR 1-6 R 3-6 , -C 1-6 alkylene-3-12 membered heterocyclyl and -C 1-6 alkylene-5-10 membered heteroaryl, said alkyl, alkylene, cycloalkyl, aryl, heterocyclyl and heteroaryl are optionally substituted with one or more substituents selected from halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 1-6 haloalkyl, -O-C 1-6 alkyl, -C 1-6 alkylene-OH, -NR 10a R 10b , -C 1-6 alkylene-O-C 1-6 alkyl and -O-C 1-6 haloalkyl; each R is independently selected from hydrogen, C 3 haloalkyl, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 1-6 alkoxy and -O-C 1-6 haloalkyl; R 4 selected from hydrogen and C 1-6 alkyl, C 1-6 haloalkyl and C 3-6 cycloalkyl; R 5 selected from hydrogen and C 1-6 alkyl; R 6 selected from hydrogen and C 1-6 alkyl; R 7 selected from hydrogen and C 1-6 alkyl; R 8 selected from hydrogen and C 1-6 alkyl; R 9 selected from hydrogen and C 1-6 alkyl; R 10a and R 10b each independently is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, -C 1-6 alkylene-OH and -C 1-6 alkylene-O-C 1-6 alkyl, or R 10a and R 10b together with the N to which they are attached form a 3-6 membered nitrogen containing heterocyclyl; m is selected from 0, 1, 2, 3, and 4.

2. The compound of claim 1 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 (II-A), (II-B), (II-C), or (II-D): wherein ring A, ring B, ring E, R 2 , L, L 1 , L 2 , L 3 , L 4 , L 5 , L 6 and X 6 are as defined in claim 1.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein L 1 is -0-.

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein: L 2 is C 1-3 alkylene, L 3 is C 1-3 alkylene, ring A is C 3-6 cycloalkyl, which is optionally substituted by one or more substituents selected from halogen; Preferably, L 2 C 1-3 Alkylene, L 3 C 1-3 Alkylene, with ring A being C 3-6 cycloalkyl; Preferably, L 2 is -CH2-, L 3 is -CH2-, ring A is C 3-6 cycloalkyl, which cycloalkyl is optionally substituted by one or more substituents selected from halogen; Preferably, L 2 is -CH2-, L 3 is -CH2-, ring A is C 3-6 cycloalkyl; More preferably, L is -CH2-, 2 is -CH2-, L is -CH2-, 3 is -CH2-, ring A is selected from cyclopropyl, cyclobutyl, cyclopentyl, More preferably, L 2 is -CH2-, L 3 is -CH2-, and ring A is cyclopropyl.

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein: Ring B is selected from a 3-8 membered nitrogen-containing monoheterocyclyl, a 5-12 membered nitrogen-containing bridged heterocyclyl, a 6-12 membered nitrogen-containing fused heterocyclyl, and a 7-12 membered nitrogen-containing spiroheterocyclyl; Preferably, ring B is Preferably, preferably, ring B is More preferably, ring B is More preferably, ring B is 6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein L 4 is a covalent bond, or is selected from O, C 1-3 alkylene, -C(=O)-C 1-3 alkylene- and 4-8 membered nitrogen-containing heterocyclyl; Preferably, L 4 is a covalent bond, or is selected from C 1-3 alkylene, -C(=O)-C 1-3 alkylene- and 4-8 membered nitrogen-containing heterocyclyl; Preferably, L 4 is a covalent bond, or is selected from O, -CH2-, -C(=O)-CH2-, Preferably, L 4 is a covalent bond, or is selected from -CH2-, -C(=0)-CH2-, 7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein: L 5 is a covalent bond, or is selected from -C(=0)- and 4-8 membered nitrogen-containing heterocyclyl; Preferably, L 5 is a covalent bond, or is selected from -C(=0)-, Preferably, L is a covalent bond, or is selected from -C(=0)- and -C(=S)-. 5 is a covalent bond, or is selected from -C(=0)- and -C(=S)-.

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein: fragment - L 4 - L 5 - is selected from: a covalent bond, -O-, -C(=O)-, Preferably, the fragment -L 4 -L 5 - is selected from: a covalent bond, -C(=0)-, 9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein: Cycloalkyl is optionally substituted with one or more substituents selected from the group consisting of halo, C 6-10 Aryl, 6-10 membered heteroaryl, or 6-10 membered heterocyclyl, said phenyl, heteroaryl and heterocyclyl groups are optionally substituted with one or more substituents selected from the group consisting of halo, C 1-6 Alkyl, C 1-6 Haloalkyl, oxo, -O-C 1-6 Alkyl, -O-C 1-6 Haloalkyl and -O-C 3-6 Cycloalkyl is optionally substituted with one or more substituents selected from the group consisting of halo, C Preferably, ring E is phenyl, 6-9 membered heteroaryl or phenyl and 5-6 membered heterocyclyl, said phenyl, heteroaryl and heterocyclyl being optionally substituted with one or more substituents selected from the group consisting of halogen, C 1-3 alkyl, C 1-3 haloalkyl, oxo and -O-C 1-3 alkyl; Preferably, ring E is phenyl, 6-9 membered heteroaryl or phenyl and 5-6 membered heterocyclyl, said phenyl, heteroaryl and heterocyclyl being optionally substituted with one or more substituents selected from halogen, C 1-3 alkyl, oxo and -O-C 1-3 alkyl, oxo and -O-C More preferably, ring E is selected from More preferably, ring E is selected from Even more preferably, ring E is selected from Even more preferably, ring E is selected from 10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein: L 6 is a covalent bond, or is selected from O, NR 8 and -C(=O)-NR 9 -; preferably, L 6 is a covalent bond, or is selected from NR 8 and -C(=O)-NR 9 -; R 8 selected from hydrogen and C 1-3 alkyl; R 9 selected from hydrogen and C 1-3 alkyl; Preferably, L 6 is a covalent bond, O or NR 8 ; preferably, L 6 is a covalent bond or NR 8 ; R 8 selected from hydrogen and C 1-3 alkyl; More preferably, L 6 is a covalent bond, O or NH; More preferably, L 6 is a covalent bond or NH.

11. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein: fragment selected from the group consisting of: Preferably, the fragment selected from the group consisting of: Preferably, the fragment selected from the group consisting of: Preferably, the fragment selected from the group consisting of:

12. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein: L is a covalent bond, or is selected from the group consisting of O and NR 4 ; R 4 selected from hydrogen and C 1-3 alkyl; Preferably, L is a covalent bond, O, or NH; More preferably, L is a covalent bond or O.

13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein: R 2 selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 4-8 membered heterocyclyl, 5-7 membered heteroaryl, -C 1-6 alkylene-C 3-6 cycloalkyl, -C 1-6 alkylene-4-8 membered heterocyclyl, and -C 1-6 alkylene-5-7 membered heteroaryl, said alkyl, alkylene, cycloalkyl, aryl, heterocyclyl, and heteroaryl being optionally substituted with one or more substituents selected from halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, -O-C 1-6 alkyl, -C 1-6 alkylene-OH, -NR 10a R 10b , -C 1-6 alkylene-O-C 1-6 alkyl, and -O-C 1-6 haloalkyl; R 10a and R 10b are each independently selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, -C 1-6 alkylene-OH, and -C 1-6 alkylene-O-C 1-6 alkyl; Preferably, R 2 Selected from hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, C 6-10 Aryl, 4-8 membered heterocyclic, 5-7 membered heteroaryl, -C 1-6 Alkylene-C 3-6 cycloalkyl, -C 1-6 alkylene-4-8-membered heterocyclic groups and -C 1-6 Alkylene-5-7-membered heteroaryl, wherein the alkyl, alkylene, cycloalkyl, aryl, heterocyclic, and heteroaryl groups are optionally selected from one or more halogens, hydroxyl groups, amino groups, cyano groups, C6 groups, and C7 groups. 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Alkyl, -C 1- 6-alkylene-OH, -NR 10a R 10b -C 1-6 Alkylene-OC 1-6 Alkyl and -OC 1-6 Substitution of alkyl halogroups, R 10a and R 10b Each is independently selected from hydrogen and C. 1-6 Alkyl, C 3-6 cycloalkyl, -C 1-6 alkylene -OH and -C 1-6 Alkylene-OC 1-6 alkyl; Preferably, R 2 selected from hydrogen, Preferably, preferably, R 2 selected from hydrogen, Preferably, the fragment -L-R is selected from the group consisting of 2 selected from the group consisting of hydrogen, 14. The compound of any one of claims 1-13, 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), (III-B), (III-C), or (III-D): wherein ring A, ring B, ring E, R 2 , L, L 1 , L 2 , L 3 , L 4 , L 5 , L 6 and X 6 are as defined in any one of claims 1-14.

15. The compound of claims 1-14, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein the compound is selected from:

16. A pharmaceutical composition comprising a prophylactically and / or therapeutically effective amount of a compound of any one of claims 1-15, 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.

17. Use of a compound of any one of claims 1-15, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, or a composition of claim 16, for the manufacture of a medicament, particularly for the manufacture of a medicament for the prevention and / or treatment of a disease, particularly a KRAS-mediated related disease. Preferably, the disease is a tumor or cancer.

18. A method for preparing a compound of formula (II-A), comprising one or more steps of steps (1) to (7) as shown in Route 1: Route 1 wherein: ring A, ring B, ring E, R 2 , L, L 1 , L 2 , L 3 , L 4 , L 5 , L 6 and X 6 as defined in any one of claims 1-15; LG 1 , LG 2 and LG 3 each independently represents a leaving group, for example, halogen, triflate, tosylate or mesylate; or, when L 3 is C 1-3 alkylene, LG 3 and L 3 are linked together to form a carbonyl group; and 3 when L the Route 1 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; or, subjecting compound II-A3 to a dehalogenation reaction to obtain compound II-A5; (3) subjecting compound II-A5 to a ring-closing reaction with compound II-A5a to obtain compound II-A6; (4) subjecting compound II-A6 to an upper protection reaction to obtain compound II-A7; (5) reacting compound II-A7 with a reagent containing a -LG 3 group to give compound II-A8; or, oxidizing compound II-A7 to give compound II-A8; (6) reacting compound II-A8 with compound II-A9 to obtain compound II-A10 and (7) subjecting compound II-A10 to a deprotection reaction to obtain compound II-A; or, the method comprises one or more steps of steps (1) to (9) as shown in Route 2: Route 2 wherein: ring A, ring B, ring E, R 2 , L, L 1 , L 2 , L 3 , L 4 , L 5 , L 6 and X 6 as defined in any one of claims 1-15; LG 1 , LG 2 and LG 3 each independently represents a leaving group, for example, halogen, triflate, tosylate or mesylate; or, when L 3 is C 1-3 alkylene, LG 3 and L 3 the carbon to which LG 3 is attached forms a carbonyl group together with the carbon to which L PG 1 denotes a protecting group, such as an alkoxycarbonyl amino protecting group, for example carbobenzyloxy (Cbz), tert-butoxycarbonyl (Boc), pivaloyloxycarbonyl (Piv), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), meth(o / eth)oxycarbonyl; an acyl amino protecting group, for example phthaloyl (Pht), p-toluenesulfonyl (Tos), trifluoroacetyl (Tfa), o-(p)-nitrobenzenesulfonyl (Ns), pivaloyl, benzoyl, tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, allyloxycarbonyl, trichloroethoxycarbonyl, trimethylsilylethoxycarbonyl, carbobenzyloxy, p-methylbenzenesulfonyl, p-nitrobenzenesulfonyl, trifluoroacetyl, methoxycarbonyl, or ethoxycarbonyl; an alkyl amino protecting group, for example trityl (Trt), 2,4-dimethoxybenzyl (Dmb), 4-methoxybenzyl (PMB), benzyl (Bn), preferably carbobenzyloxy (Cbz), tert-butoxycarbonyl (Boc) or benzyl; 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-closing reaction with compound II-A5a to obtain compound II-A6; (4) subjecting compound II-A6 to an upper protection reaction to obtain compound II-A7; (5) subjecting compound II-A7 to an oxidation reaction to obtain compound II-A8; (6) reacting compound II-A8 with compound II-A9a to obtain compound II-A10a; (7) subjecting compound II-A10a to a deprotection reaction to obtain compound II-A11a; (8) reacting compound II-A11a with compound II-A12a to obtain compound II-A10 and (9) subjecting compound II-A10 to a deprotection reaction to obtain compound II-A.

19. A compound as illustrated below or a salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound thereof, wherein ring A, ring B, ring E, R 2 , L, L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , X 6 , PG 1 , LG 1 , LG 2 , and LG 3 as defined in claim 18.

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