Heterocyclic compound for inducing degradation of mutant KRAS protein, and preparation method therefor and use thereof

Abstract

The present invention provides a heterocyclic compound for inducing degradation of a mutant KRAS protein or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof. As shown in formula (I), the definition of each group in the formula is detailed in the description. In addition, also disclosed are a pharmaceutical composition comprising the compound and a use in preparation of a kit for the treatment of cancer and immune diseases or the prognostic evaluation of patients with cancer.

Description

Heterocyclic compounds that induce degradation of mutant KRAS protein, their preparation methods and applications Technical Field

[0001] This disclosure relates to the pharmaceutical field, and in particular to a heterocyclic compound, pharmaceutical composition, preparation method and use thereof for inducing degradation of mutant KRAS protein. Background Technology

[0002] RAS is a guanine nucleotide-binding protein with GTPase activity and an intracellular anchoring function. RAS proteins can switch between an inactive state bound to GDP and an active state bound to GTP, influencing multiple downstream signaling pathways such as Raf, PI3K, and RalGDS, and regulating protein synthesis, gene transcription, cell growth, differentiation, apoptosis, and migration.

[0003] RAS mutations lead to persistent activation of downstream signaling pathways, promoting tumor development and progression. Among all tumor types, RAS mutations primarily occur in the KRAS (85%), with the highest frequency (34.2%) occurring at position 12 of the KRAS, where glycine is replaced by aspartic acid (G12D). The tumor frequencies of this mutation are, in descending order: pancreatic cancer (25.0%), colorectal cancer (13.3%), rectal cancer (10.1%), non-small cell lung cancer (4.1%), and small cell lung cancer (1.7%). KRAS G12C mutations refer to the mutation at position 12 of the protein, where glycine is replaced by cysteine. The tumor frequencies of this mutation are, in descending order: pancreatic cancer (57%), colorectal cancer (35%), cholangiocarcinoma (28%), small bowel cancer (17%), lung cancer (16%), endometrial cancer (15%), and ovarian cancer (14%). Besides G12C and G12D, KRAS has several other mutations, such as G12V, G12A, G12R, G12S, G13D, Y96D, Q61H, and Q61K. The frequency of different KRAS mutations varies in different types of cancer cells.

[0004] Proteolysis-targeting chimeras (PROTACs) are bifunctional molecules with a structure consisting of three parts: (1) a part that binds to the target protein substrate; (2) a part that binds to E3 ubiquitin ligase; and (3) a chain connecting the first two parts. PROTACs can recognize both the target protein and the E3 ubiquitin ligase, bringing the target protein closer to the E3 ubiquitin ligase. By inducing the recruitment of the E3 ubiquitin ligase to the surface of the target protein, they initiate ubiquitination and induce the degradation of the target protein. PROTAC molecules have advantages such as broad pharmacological activity, high target selectivity, applicability to the degradation of difficult-to-degrade target proteins, strong degradation efficacy, and the ability to maintain catalytic degradation even at low concentrations.

[0005] Currently, only Astellas's degradative agent targeting the kras g12d mutant has entered Phase 1 clinical trials, which does not yet meet clinical needs. Therefore, it is of great significance to develop KRAS PROTAC molecules with novel structures and good biological activity. Summary of the Invention

[0006] In one aspect, the present invention provides a novel KRAS PROTAC molecule with high biological activity.

[0007] In one aspect, the present invention provides a compound of formula (I), a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a solvate thereof, or a prodrug thereof, said compound being of formula (I):

[0008] In equation (I), R 1 Selected from H, -CH3, -OCH3, cyclopropane, and cyclopropoxy groups;

[0009] R 2 Selected from

[0010] Where R is selected from -CN, -NH2, C 1-3 alkynyl group, C 1-3 alkenyl, C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with -CN, -NH2, -N(CH3)2, -OH, 3-8 membered cycloalkyl or heterocycloalkyl, preferably, R is selected from ethynyl, vinyl, -CH2CH3, -CH2CH2CN, -CH2CH2NH2, -CH2CH2N(CH3)2, -CH2CH2OH;

[0011] Ring A is selected from Ring A is selected from saturated or unsaturated 4-10 membered heterocyclic alkyl groups;

[0012] m can be 0 or 1 at will;

[0013] q can be any value of 0, 1, or 2;

[0014] p can be 0, 1, 2, 3 or 4;

[0015] X 1 Selected from -O-, -CH2-, -CHR 7 -or-C(R) 7 )2;

[0016] R for each replacement position 7Each is independently selected from -H, -OH, -F, -Cl, -CH3, -CN, -CH2OH, -CH2Cl, -OCH3, -CH2CN, -CH(CH3)2OH, -NHCH3, or two R atoms on the same carbon atom of ring A. 7 The substituent forms a 3-6 membered heterocycle or carbonyl group with the carbon atom, or two R groups on the adjacent carbon atom of ring A. 7 The substituents form 3-6 membered cycloalkyl or heterocycloalkyl groups with the carbon atoms they are attached to;

[0017] M is selected from -O-, -S-, -NR 3 -、C 1-6 Alkylene, the R 3 Selected from H, C 1-6 Alkyl group, wherein the alkylene group is selected from one or more halogens, -OH, -CN, C 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups;

[0018] L is selected from -L 1 -L 2 -L 3 -L 4 -L 5 -;

[0019] L 1 It is a covalent bond, or selected from -O-, -NR 4 carbonyl group, C 1-6 Alkyl ether amino, C 1-6 Alkylene, C 3-6 Cycloalkylene, saturated or unsaturated 3-11 membered heterocyclic alkylene groups, wherein R 4 Selected from H, C 1-6 Alkyl, the C 1-6 Alkyl ether amino, C 1-6 Alkylene, C 3-6 The cycloalkyl group, saturated or unsaturated, consists of a 3-11 membered heterocyclic group selected from halogen, -OH, -CN, C. 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups;

[0020] L 2 It is a covalent bond, or selected from -O-, -NR 5 carbonyl group, C 1-6 Alkyl ether amino, C 1-6 Alkylene, C 3-6 Cycloalkylene, saturated or unsaturated 3-11 membered heterocyclic alkylene groups, wherein R 5 Selected from H, C 1-6 Alkyl, the C 1-6 Alkyl ether amino, C 1-6 Alkylene, C3-6 The cycloalkyl group, saturated or unsaturated, consists of a 3-11 membered heterocyclic group selected from halogen, -OH, -CN, C. 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups;

[0021] L 3 It is a covalent bond, or selected from -O-, -NR 6 carbonyl group, C 1-6 Alkyl ether amino, C 1-6 Alkylene, C 3-6 Cycloalkylene, saturated or unsaturated 3-11 membered heterocyclic alkylene groups, wherein R 6 Selected from H, C 1-6 Alkyl, the C 1-6 Alkyl ether amino, C 1-6 Alkylene, C 3-6 The cycloalkyl group, saturated or unsaturated, consists of a 3-11 membered heterocyclic group selected from halogen, -OH, -CN, C. 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups;

[0022] L 4 It is a covalent bond, or selected from -O-, -NR 8 carbonyl group, C 1-6 Alkyl ether amino, C 1-6 Alkylene, C 3-6 Cycloalkylene, saturated or unsaturated 3-11 membered heterocyclic alkylene groups, wherein R 8 Selected from H, C 1-6 Alkyl, the C 1-6 Alkyl ether amino, C 1-6 Alkylene, C 3-6 The cycloalkyl group, saturated or unsaturated, consists of a 3-11 membered heterocyclic group selected from halogen, -OH, -CN, C. 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups;

[0023] L 5 It is a covalent bond, or selected from -O-, -NR 9 carbonyl group, C 1-6 Alkyl ether amino, C 1-6 Alkylene, C 3-6 Cycloalkylene, saturated or unsaturated 3-11 membered heterocyclic alkylene groups, wherein R 9 Selected from H, C 1-6 Alkyl, the C 1-6 Alkyl ether amino, C 1-6 Alkylene, C 3-6The cycloalkyl group, saturated or unsaturated, consists of a 3-11 membered heterocyclic group selected from halogen, -OH, -CN, C. 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups;

[0024] And L 1 L 2 L 3 L 4 L 5 Not both are single keys;

[0025] E is selected from the small molecule ligand of E3 ubiquitin ligase.

[0026] In some preferred embodiments, the pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, wherein,

[0027] Preferred, R 1 Selected from H, -CH3, -OCH3;

[0028] Preferred, R 2 Selected from Preferably, ring A is selected from

[0029] Preferably, M is selected from -O-, -S-, and -NH-;

[0030] Preferred, L 1 Selected from single bonds, Preferred, L 2 Selected from single bonds,

[0031] Preferred, L 3 Selected from single bonds, carbonyl groups, -CH2-, -CH2CH2-, -CH2CH2OCH2-、

[0032] Preferred, L 4 Selected from single bonds, carbonyl groups,

[0033] Preferred, L 5 Selected from single bonds, carbonyl groups,

[0034] And L 1 L 2 L 3 L 4 L 5 Not both are single keys;

[0035] Preferably, E is selected from small molecule ligands of E3 ubiquitin ligase CRBN, and its structure is preferably shown in the following formula.

[0036] In some preferred embodiments, the pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, wherein,

[0037] Preferably, L is selected from

[0038] In some preferred embodiments, the compounds are pharmaceutically acceptable salts, stereoisomers, solvates, or prodrugs, such as those shown in formulas (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), or (Il).

[0039] In a preferred embodiment, the compound of formula (I), its pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, wherein the compound is selected from the group consisting of:

[0040] In a preferred embodiment, the compound of formula (I), its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug, wherein the pharmaceutically acceptable salt comprises any one or combination of hydrochloride, hydrobromide, sulfate, phosphate, carbonate, formate, acetate, trifluoroacetate, propionate, methanesulfonate, lactate, benzenesulfonate, p-toluenesulfonate, succinate, maleate, fumarate, tartrate, citrate or malate.

[0041] In another aspect, the present invention provides a pharmaceutical composition, characterized in that the composition comprises the above-described compound, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a solvate thereof, a prodrug thereof, and a pharmaceutically acceptable excipient.

[0042] In another aspect of the present invention, there is provided the use of the above-mentioned compound, its pharmaceutically acceptable salt, stereoisomer, solvate, its prodrug, and the pharmaceutical composition in a kit for treating cancer, immune diseases, or for prognostic assessment of cancer patients.

[0043] Preferably, the pharmaceutical composition further comprises another drug for treating cancer or immune diseases;

[0044] Preferred use is in the preparation of a medicament for treating diseases associated with KRAS mutations;

[0045] Preferably, the cancers include, but are not limited to, pancreatic cancer, colorectal cancer, lung cancer, bile duct cancer, endometrial cancer, and ovarian cancer;

[0046] More preferably, the cancers include, but are not limited to, pancreatic cancer, colorectal cancer, lung cancer, bile duct cancer, endometrial cancer, and ovarian cancer.

[0047] In another aspect, the present invention provides the use of the above-mentioned compound, its pharmaceutically acceptable salt, stereoisomer, solvate, its prodrug or a pharmaceutical composition thereof in the preparation of a medicament for treating diseases related to KRAS activity or expression levels;

[0048] Preferably, it is used in the preparation of medicaments for treating and inhibiting or degrading KRAS G12D, KRAS G12V, KRAS G12A, KRAS G12S, KRAS G12C, KRAS G13D, KRAS Q61H, KRAS Q61K, KRAS Y96D and other KRAS mutation-related diseases.

[0049] In another aspect, the present invention provides a method for inhibiting or degrading KRAS in a biological sample for non-disease diagnostic or therapeutic purposes, comprising contacting the biological sample with the aforementioned compound or a pharmaceutically acceptable salt thereof or the aforementioned pharmaceutical composition. Detailed Implementation

[0050] Ⅰ Definition

[0051] Based on the content of this disclosure, and in accordance with common technical knowledge and practices in the art, various other modifications, substitutions, or alterations can be made without departing from the basic technical ideas described in this disclosure.

[0052] The term “comprising” or its variations such as “including” or “including” will be understood to include the stated elements or components without excluding other elements or other components.

[0053] The compounds of this invention may be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers are included, such as enantiomers and diastereomers. The compounds of this invention containing asymmetric carbon atoms can be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from racemic mixtures or synthesized using chiral starting materials or chiral reagents. Racemic, diastereomers, and enantiomers are all included within the scope of this invention.

[0054] The compounds of this invention also include tautomer forms. Tautomer forms arise from the exchange of a single bond with an adjacent double bond, accompanied by the migration of a proton.

[0055] The term “optional” or “optionally” means that the event or situation described below may or may not occur, including both the occurrence and non-occurrence of the event or situation.

[0056] The range of numbers in this article refers to the integers within a given range. For example, "C 1-6 "" means that the group can have 1, 2, 3, 4, 5, or 6 carbon atoms; "C 3-6 "" means that the group can have 3, 4, 5 or 6 carbon atoms.

[0057] The terms "substituted" or "substituted" refer to the substitution of one or more hydrogen atoms on a particular atom or group by a substituent, provided that the valence state of the particular atom or group is normal and the resulting compound is stable. When the substituent is a ketone group (i.e., =O), it means that two hydrogen atoms are substituted. Unless otherwise specified, the type and number of substituents can be arbitrary on a chemically feasible basis.

[0058] In this disclosure, when any variable (e.g., R) n When a substituent appears more than once in the composition or structure of a compound, its definition is independent in each case. Therefore, for example, if a group is substituted by 1-5 Rs, the group can optionally be substituted by up to 5 Rs, and the Rs in each case have independent options. Furthermore, combinations of substituents and / or their variants are only permitted if such combinations produce a stable compound.

[0059] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, and most preferably an alkyl group containing 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-Dimethylpentyl, 2,2-Dimethylpentyl, 3,3-Dimethylpentyl, 2-Ethylpentyl, 3-Ethylpentyl, n-Octyl, 2,3-Dimethylhexyl, 2,4-Dimethylhexyl, 2,5-Dimethylhexyl, 2,2-Dimethylhexyl, 3,3-Dimethylhexyl, 4,4-Dimethylhexyl, 2-Ethylhexyl, 3-Ethylhexyl, 4-Ethylhexyl, 2-Methyl-2-Ethylpentyl, 2-Methyl-3-Ethylpentyl, n-Nonyl, 2-Methyl-2-Ethylhexyl, 2-Methyl-3-Ethylhexyl, 2,2-Diethylpentyl, n-Decyl, 2,2-Diethylhexyl, 2,2-Diethylhexyl, and their various branched isomers, etc. More preferably, lower alkyl groups containing 1 to 6 carbon atoms are used. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. Alkyl groups can be substituted or unsubstituted. When substituted, the substituent can be substituted at any usable connection point. The substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester groups. The present invention preferably uses methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuteralkyl, alkoxy-substituted alkyl, and hydroxy-substituted alkyl.

[0060] The term "alkylene" refers to a divalent saturated aliphatic hydrocarbon group obtained by removing a hydrogen atom from the corresponding "alkyl" group. For example, as used herein, the term "C 1-6 "Alkylene" refers to an alkylene having 1 to 6 carbon atoms, such as methylene (-CH2-), ethylene (-CH2CH2-), isopropylene (-CH(CH3)CH2-), which is optionally substituted by one or more (such as 1, 2 or 3) suitable substituents such as halogens.

[0061] The term "alkenyl" refers to an alkyl group as defined above, consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, etc. Alkenyl groups can be substituted or unsubstituted; when substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio.

[0062] The term "cycloalkyl" refers to a saturated monocyclic alkane substituent, wherein the cycloalkyl ring contains at least 3 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0063] The term "cycloalkylene" refers to a divalent group obtained by removing one hydrogen atom from the corresponding "cycloalkyl".

[0064] The term "heterocyclic group" or "heterocyclic alkyl group" refers to a saturated monocyclic cyclic hydrocarbon substituent in which one or more ring atoms are selected from nitrogen, oxygen, or S(O). m (where m is an integer from 0 to 2) heteroatoms, but excluding the ring portion of -OO-, -OS-, or -SS-, with the remaining ring atoms being carbon. Non-limiting examples of heterocyclic groups include pyrrole, imidazolyl, tetrahydrofuranyl, tetrahydrothiophene, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrole, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, etc., preferably pyrroleyl, morpholinyl, piperidinyl, cycloheptyl, 1,4-diazacycloheptyl, and piperazinyl.

[0065] The heterocyclic group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, cyano, nitro, chloro, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester group.

[0066] The term "subheterocyclic group" refers to a divalent group obtained by removing a hydrogen atom from the corresponding "heterocyclic group".

[0067] Term "C" 1-6 Alkyl ether amino "amino" amino is randomly C 1-6 Alkyl ether substitution, for example Groups such as α and β.

[0068] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6- to 12-membered, such as phenyl and naphthyl. More preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclic, or cycloalkyl ring, including benzo5- to 10-membered heteroaryl, benzo3- to 8-membered cycloalkyl, and benzo3- to 8-membered heteroalkyl, preferably benzo5- to 6-membered heteroaryl, benzo3- to 6-membered cycloalkyl, and benzo3- to 6-membered heteroalkyl, wherein the heterocyclic group is a heterocyclic group containing 1-3 nitrogen, oxygen, and sulfur atoms; or may further include a ternary nitrogen-containing fused ring containing a benzene ring.

[0069] The aryl group can be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydrogen, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group.

[0070] The term "heteroaryl" refers to a heteroaryl system containing a heteroatom and a carbon atom, wherein the heteroatom is selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5- or 6-membered, such as imidazolyl, furanyl, thiophene, thiazolyl, pyrazolyl, pyrroleyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably triazolyl, thiophene, imidazolyl, pyrazolyl, oxazolyl, pyrimidinyl, or thiazolyl; more preferably pyrazolyl, pyrroleyl, and oxazolyl.

[0071] The heteroaryl group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydrogen, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group.

[0072] The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where alkyl is defined as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy. Alkoxy groups can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydrogen, nitro, chloro, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylic acid ester group.

[0073] In this disclosure, It refers to the junction of chemical bonds.

[0074] Drugs or drug compositions

[0075] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms that are suitable for use in human and animal tissues to the extent of reasonable medical judgment without excessive toxicity, irritation, allergic reactions, or other problems or complications in proportion to a reasonable benefit / risk ratio.

[0076] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological potency of a particular compound as a free acid or base without any adverse biological effects. Examples include acid (including organic and inorganic acids) addition salts or base addition salts (including organic and inorganic bases).

[0077] The pharmaceutically acceptable salts disclosed herein can be synthesized from parent compounds containing an acid radical or a base using conventional chemical methods. Generally, such salts are prepared by reacting these compounds, in their free acid or base form, with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture thereof.

[0078] The pharmaceutical products or pharmaceutical compositions disclosed herein can be administered orally, topically, parenterally, or via mucosal routes (e.g., sublingually, by inhalation, or rectally) in dosage units comprising a conventional, non-toxic, pharmaceutically acceptable carrier. Oral administration is generally preferred. The active agent can be administered orally in capsule, tablet, or other similar forms (see Remington: The Science and Practice of Pharmacy, 20th Edition).

[0079] For oral administration in tablet or capsule form, the active pharmaceutical ingredient may be combined with non-toxic, pharmaceutically acceptable excipients such as binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone, or hydroxypropyl methylcellulose); fillers (e.g., lactose, sucrose, glucose, mannitol, sorbitol, and other reducing and non-reducing sugars, microcrystalline cellulose, calcium sulfate, or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc or silica, stearic acid, sodium stearyl fumarate, glyceryl docosanoate, calcium stearate, etc.); disintegrants (e.g., potato starch or sodium hydroxyacetic acid starch); or wetting agents (e.g., sodium lauryl sulfate), colorants and flavorings, gelatin, sweeteners, natural and synthetic gums (e.g., gum arabic, tragacanth, or alginate), buffer salts, carboxymethyl cellulose, polyethylene glycol, waxes, etc. For oral administration in liquid form, the pharmaceutical component may be combined with a non-toxic, pharmaceutically acceptable inert carrier (e.g., ethanol, glycerol, water), an anti-settling agent (e.g., sorbitol syrup, cellulose derivatives, or hydrogenated edible fats), an emulsifier (e.g., lecithin or gum arabic), a non-aqueous carrier (e.g., almond oil, esters, ethanol, or fractionated vegetable oils), and a preservative (e.g., methylparaben, propylparaben, or sorbic acid). Stabilizers such as antioxidants (BHA, BHT, propyl iodide, sodium ascorbate, citric acid) may also be added to stabilize the dosage form.

[0080] Tablets containing the active compound can be coated using methods well known in the art. The compositions of this disclosure containing a compound of formula I as the active compound can also incorporate beads, microspheres, or microcapsules, for example, constructed from polyglycolic acid / lactic acid (PGLA). Liquid formulations for oral administration can take the form of, for example, solutions, syrups, emulsions, or suspensions, or they can be presented as dry products reconstituted with water or other suitable excipients prior to use. Formulations for oral administration can be suitably formulated to allow for controlled or delayed release of the active compound.

[0081] The pharmaceutical products or pharmaceutical compositions disclosed herein can be delivered parenterally, i.e., administered intravenously (IV), intraventricularly (ICV), subcutaneously (SC), intraperitoneally (IP), intramuscularly (IM), subcutaneously (SD), or intradermally (ID), by direct injection, such as rapid concentration or continuous infusion. Formulations for injection may be presented in unit dosage forms, such as in ampoules or multi-dose containers with added preservatives. The compositions may be in the form of excipients, suspensions, solutions, or emulsions in oil or aqueous carriers, and may contain formulation agents such as anti-settling agents, stabilizers, and / or dispersants. Alternatively, the active ingredient may be reconstituted in powder form with a suitable carrier (e.g., sterile, pyrogen-free water) prior to use.

[0082] The pharmaceutical or pharmaceutical composition disclosed herein can also be formulated for rectal administration, for example as a suppository or retention enema (e.g., containing a conventional suppository base such as cocoa butter or other glycerides).

[0083] The term "treatment" includes suppressing, alleviating, preventing, or eliminating one or more symptoms or side effects associated with the disease, condition, or disorder being treated.

[0084] The terms “reduction,” “inhibition,” “mitigation,” or “reduction” are used relative to a control. Those skilled in the art will readily determine the appropriate control for each experiment. For example, a reduced response in a subject or cell treated with the compound is compared to a response in a subject or cell not treated with the compound.

[0085] As used herein, the term "effective dose" or "therapeutic effective dose" refers to a dose sufficient to treat, suppress, or alleviate one or more symptoms of the treated disease state or otherwise provide the desired pharmacological and / or physiological effect. The precise dose will vary depending on a variety of factors, such as subject-dependent variables (e.g., age, immune system health, etc.), the disease or illness, and the treatment administered. The effect of an effective dose can be relative to a control. These controls are known in the art and discussed herein, and can be, for example, the condition of the subject before or without administration of the drug or combination of drugs, or, in the case of a combination of drugs, the combined effect can be compared to the effect of administration of only one drug.

[0086] The term "excipient" is used herein to include any other compound that is not therapeutic or biologically active and may be contained in or on microparticles. Therefore, excipients should be pharmaceutically or biologically acceptable or relevant, for example, excipients that are generally non-toxic to the subject. "Excipient" includes a single such compound and is also intended to include multiple compounds.

[0087] The term "pharmaceutical composition" means a composition comprising the compounds described in this disclosure or their pharmaceutically acceptable salts, and at least one pharmaceutically acceptable ingredient selected from the following, depending on the manner of administration and the nature of the dosage form: carriers, diluents, adjuvants, excipients, preservatives, fillers, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants, dispersants, thermosensitive materials, temperature regulators, adhesives, stabilizers, suspending agents, etc.

[0088] Uses and treatments

[0089] The terms “patient,” “subject,” “individual,” etc., are used interchangeably herein and refer to any animal or its cells, whether in vitro or in situ, that conform to the methods described herein. In some non-limiting embodiments, the patient, subject, or individual is a person.

[0090] According to the methods of this disclosure, compounds or compositions may be administered in any amount and via any route of administration that is effective in treating KRAS-related diseases or reducing their severity.

[0091] This disclosure relates to a method for inhibiting or degrading KRAS in a biological sample, comprising the step of contacting the biological sample with a compound of this disclosure or a composition containing the compound.

[0092] The present disclosure discloses a method for inhibiting KRAS in a patient, comprising the step of administering the disclosed compound or a composition comprising the compound to the patient.

[0093] The provided compounds are KRAS inhibitors or KRAS degraders, and therefore can be used to treat one or more conditions associated with KRAS activity. Accordingly, in some embodiments, this disclosure provides a method for treating KRAS-mediated conditions comprising the step of administering a compound of this disclosure or a pharmaceutically acceptable composition thereof to a patient in need.

[0094] This disclosure provides a method for treating one or more conditions, diseases, and / or symptoms, wherein the condition, disease, or symptom is a proliferative disease, such as cancer, inflammatory conditions, or viral infections.

[0095] In some embodiments, this disclosure provides a method of treating cancer or another proliferative condition, comprising administering a compound or composition of the disclosed invention to a patient suffering from cancer or another proliferative condition. In some embodiments, the method of treating cancer or another proliferative condition comprises administering a compound or composition of the disclosed invention to a mammal. In some embodiments, the mammal is a human.

[0096] As used herein, the terms “cancer inhibition” and “cancer cell proliferation inhibition” refer to inhibiting the growth, division, maturation, or survival of cancer cells, and / or causing cancer cell death through cytotoxicity, nutrient depletion, or induction of apoptosis, individually or collectively with other cancer cells.

[0097] Examples of tissues containing cancer cells whose proliferation is inhibited by the compounds and compositions described herein and to which the methods described herein are applicable include (but are not limited to) the breast, prostate, brain, blood, bone marrow, liver, pancreas, epidermis, kidney, colon, ovary, lung, testis, penis, thyroid gland, parathyroid gland, pituitary gland, thymus, retina, uvea, conjunctiva, spleen, head, neck, trachea, gallbladder, rectum, salivary glands, adrenal glands, pharynx, esophagus, lymph nodes, sweat glands, sebaceous glands, muscles, heart, and stomach.

[0098] Cancers treated with the compounds or compositions disclosed herein include, but are not limited to, melanoma, liposarcoma, lung cancer, breast cancer, prostate cancer, leukemia, kidney cancer, esophageal cancer, brain cancer, lymphoma, or colorectal cancer. In some embodiments, the cancer is primary exudative lymphoma (PEL).

[0099] The compounds disclosed herein may be used to treat proliferative diseases selected from the following: benign or malignant tumors or carcinomas of the brain, kidneys, liver, adrenal glands, bladder, breast, stomach, gastric tumors, ovaries, colon, rectum, prostate, pancreas, lungs, vagina, cervix, testes, genitourinary tract, esophagus, larynx, skin, bone, or thyroid gland; sarcomas, glioblastomas, neuroblastomas, multiple myeloma, or gastrointestinal cancers (especially colorectal cancer or colorectal adenomas) or tumors of the neck and head; epidermal hyperplasia; psoriasis; benign prostatic hyperplasia; tumor formation; epithelial-characteristic tumor formation; adenoma; adenocarcinoma; keratoacanthoma; epidermoid carcinoma; large cell carcinoma; non-small cell lung cancer; Hodgkin's and non-Hodgkin's lymphomas; breast cancer; follicular carcinoma; undifferentiated tumors; papillary carcinoma; seminoma; melanoma; MYD88-driven diseases; DLBCL; ABC. DLBCL, IL-1 driven diseases, mild or indolent multiple myeloma or leukemia.

[0100] The cancers described in this disclosure include (but are not limited to) leukemias (e.g., acute leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia), polycythemia vera, lymphomas (e.g., Hodgkin's disease or non-Hodgkin's disease), Waldenström's macroglobulinemia, multiple myeloma, heavy chain disease, and solid tumors such as sarcomas and carcinomas (e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, chordoma, angiosarcoma, endothelial sarcoma, lymphangiosarcoma, lymphoendothelial sarcoma, synovoma, mesothelioma, Ewing's tumor). Tumors, leiomyosarcomas, rhabdomyosarcomas, colorectal cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystic adenocarcinoma, medullary carcinoma, bronchial carcinoma, renal cell carcinoma, liver tumor, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, uterine cancer, testicular cancer, lung cancer, small cell lung cancer, bladder cancer, epithelial carcinoma, glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pineal tumor, angioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, and retinoblastoma.

[0101] In some specific embodiments, the cancer is glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pineal tumor, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, or retinoblastoma.

[0102] In some specific embodiments, the cancer is an acoustic neuroma, an astrocytoma (e.g., grade I - pilocytic astrocytoma, grade II - low-grade astrocytoma, grade III - pleomorphic astrocytoma, or grade IV - glioblastoma (GBM)), a chordoma, a CNS lymphoma, a craniopharyngioma, a brainstem glioma, an ependymoma, a mixed glioma, an optic glioma, a subependymal ependymoma, a medulloblastoma, a meningioma, a metastatic brain tumor, an oligodendroglioma, a pituitary tumor, a primary neuroectodermal tumor (PNET), or a schwannoma. In some embodiments, the cancer is a type more common in children than in adults, such as a brainstem glioma, a craniopharyngioma, an ependymoma, a juvenile pilocytic astrocytoma (JPA), a medulloblastoma, an optic glioma, a pineal tumor, a primary neuroectodermal tumor (PNET), or a rhabdoid tumor. In some embodiments, the patient is an adult patient. In some embodiments, the patient is a child or a pediatric patient.

[0103] In another specific embodiment, cancers include (but are not limited to): mesothelioma, hepatobiliary (liver and bile ducts), bone cancer, pancreatic cancer, skin cancer, head or neck cancer, melanoma of the skin or eye, ovarian cancer, colorectal cancer, rectal cancer, anal cancer, gastrointestinal cancer (stomach, colon, rectum, and duodenum), uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small bowel cancer, endocrine system cancers, thyroid cancer, parathyroid cancer, etc. Adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, testicular cancer, chronic or acute leukemia, chronic myeloid leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvis cancer, non-Hodgkin's lymphoma, spinal axis tumor, brainstem glioma, pituitary adenoma, adrenocortical carcinoma, gallbladder cancer, multiple myeloma, bile duct cancer, fibrosarcoma, neuroblastoma, retinoblastoma, or one or more of the aforementioned cancers.

[0104] In some specific embodiments, the cancer is selected from hepatocellular carcinoma, ovarian cancer, ovarian epithelial carcinoma, or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine serous papillary carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; bile duct hepatocellular carcinoma; soft tissue and bone synovial sarcoma; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing's sarcoma; pleomorphic thyroid carcinoma; adrenocortical adenoma; pancreatic cancer; pancreatic duct carcinoma or pancreatic cancer; gastrointestinal / stomach (GIST) cancer; lymphoma; head and neck squamous cell carcinoma (SCCHN); salivary gland cancer; glioma or brain cancer; neurofibroma-1-associated malignant peripheral nerve sheath tumor (MPNST); Waldenström's macroglobulinemia; or medulloblastoma.

[0105] The term "primary tumor" is relative to secondary tumors. A primary tumor refers to a tumor that first appears in a certain location, such as the lungs, liver, intestines, head, or skin. It can be called primary lung cancer, primary liver cancer, primary intestinal cancer, etc.

[0106] The term "inflammatory disease" includes the aforementioned autoimmune, allergic, and inflammatory conditions, such as those selected from arthritis, ankylosing spondylitis, inflammatory bowel disease, ulcerative colitis, gastritis, pancreatitis, Crohn's disease, celiac disease, multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, rheumatic fever, gout, organ or transplant rejection, acute or chronic graft-versus-host disease, chronic allogeneic graft rejection, Bechtel's disease, uveitis, psoriasis, dermatitis, atopic dermatitis, dermatomyositis, myasthenia gravis, Graves' disease, Hashimoto's thyroiditis, Sjögren's syndrome, and blistering conditions (e.g., pemphigus vulgaris), antibody-mediated vasculitis syndromes, including ANCA-associated vasculitis, purpura, and immune complex vasculitis (stage I or II cancer or infection). The aforementioned allergic conditions may be particularly selected from contact dermatitis, celiac disease, asthma, hypersensitivity to house dust mites, pollen and related allergens, and beryllium poisoning. The respiratory conditions mentioned may be selected in particular from asthma, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pulmonary edema, pulmonary embolism, pneumonia, pulmonary sarcoma, silicosis, pulmonary fibrosis, respiratory failure, acute respiratory distress syndrome, primary pulmonary hypertension, and emphysema.

[0107] The term "viral infection" includes, but is not limited to, retroviral infection, hepatitis virus infection, COVID-19 infection, Zika virus infection, dengue virus infection, etc.

[0108] combination therapy

[0109] This disclosure provides combination therapies using compounds as described herein in combination with other therapeutic agents. As used herein, the term "combination therapy" includes the sequential administration of these agents, i.e., each therapeutic agent is administered at different times, and the administration of these agents, or at least two agents, substantially simultaneously. The order, or substantially simultaneous administration, of each agent may be influenced by any suitable route, including, but not limited to, oral, intravenous, intramuscular, subcutaneous routes, and direct absorption through mucosal tissues. Agents may be administered via the same or different routes. For example, a first agent may be administered orally, while a second agent may be administered intravenously. Furthermore, selected combinations may be administered intravenously, while other agents in the combination may be administered orally. Alternatively, for example, two or more agents may be administered intravenously or subcutaneously.

[0110] Example II

[0111] The present disclosure is further illustrated below with reference to embodiments. The description of specific exemplary embodiments of the present disclosure is for illustrative and explanatory purposes. These descriptions are not intended to limit the present disclosure to the precise forms disclosed, and it will be apparent that many changes and variations can be made in accordance with the teachings of this specification. The exemplary embodiments were chosen and described in order to explain the specific principles of the present disclosure and their practical application, thereby enabling those skilled in the art to implement and utilize various different exemplary embodiments of the present disclosure, as well as various different choices and variations.

[0112] Unless otherwise specified, the experimental methods used in the following examples are conventional methods.

[0113] Unless otherwise specified, all materials and reagents used in the following examples are commercially available.

[0114] Instruments and reagents:

[0115] NMR: Agilent 400MR DD2 NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3) as solvents, and tetramethylsilane (TMS) as the internal standard. LC-MS: Agilent 1260 Infinity II–InfinityLab LC / MSD mass spectrometer. HPLC: Agilent 1260 Infinity II high-performance liquid chromatograph (Sunfire C18 5μm 150 x 4.6mm column).

[0116] Thin-layer chromatography silica gel plates: HSGF254 silica gel plates (Yantai Jiangyou Silica Gel Development Co., Ltd.), 0.9mm-1mm. TLC silica gel plates: GF254 silica gel plates (Yucheng Chemical (Shanghai) Co., Ltd.), 0.2mm-0.25mm. Column chromatography: 300-400 mesh silica gel carrier (Qingdao Hailang Silica Gel Desiccant Co., Ltd.), Flash column (Agilent Claricep Flash amorphous silica gel purification column).

[0117] Reagents: 2,4,7-trichloro-8-fluoro-5-methylpyridinone[4,3-d]pyrimidine, N,N-diisopropylethylamine, ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolin-7a(5H)-yl)methanol, (2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxyborane-2-yl)naphth-1-yl)ethynyl)triisopropylsilane, cesium carbonate, 1,1'-bis(diphenylphosphine)ferrocene palladium dichloromethane complex, dioxane hydrochloride, cesium fluoride, hexamethyleneimine, 3-azabicyclo[3.2.0]heptane hydrochloride, sodium hydroxide, 2,5-dihydro-1H-pyrrole, 6-azaspiro[2.5]octane, cyclo Propane-1,1-dimethyldiethanol, 6-bromo-1H-indazole, 2-(2,4-bis(benzyloxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane, (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester, 1,1'-bisdiphenylphosphine ferrocene palladium dichloride, methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II), 4-methylbenzenesulfonyl chloride, 4-dimethylaminopyridine, potassium hydroxide, iodomethane, potassium phosphate, 4-(4-amino-2-fluorophenyl)piperazine-1-carboxylic acid tert-butyl ester, 3-bromopiperidine-2,6-dione, 2-oxo-7-azaspiro[3.2.1].5] Nonane-7-carboxylic acid tert-butyl ester, 4-(iodomethyl)piperidin-1-carboxylic acid tert-butyl ester, (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazolyl-5-yl)benzyl)pyrrolidine-2-carboxamide, 2,2-dimethyl-4-oxo-3,8,11-trioxo-5-azatridecane-13-acid, 2-(2,6-dioxadipinidin-3-yl)-5-fluoroisoindoline-1,3-dione, 2-(2-((tert-butoxycarbonyl)amino)ethoxy)acetic acid, 2,2-dimethyl-4-oxo-3,8,11,14-tetraoxo-5-azahexadecane-16-acid, 1-(tert-butoxycarbonyl)piperidin-4- Carboxylic acid, (1R,3R)-3-((tert-butoxycarbonyl)amino)cyclobutane-1-carboxylic acid, 1-hydroxybenzotriazole, carbodiimide hydrochloride, (1S,3S)-3-((tert-butoxycarbonyl)amino)cyclobutane-1-carboxylic acid, potassium iodide, 3-(6-bromo-1-oxoisoindol-2-yl)piperidine-2,6-dione, triethylamine, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, palladium on carbon (10%), trifluoroacetic acid, acetic acid, sodium cyanoborohydride, potassium carbonate, tert-butyl 4-formylpiperidine-1-carboxylic acid, p-toluenesulfonyl chloride, methyl 3,4-difluorobenzoate, lithium hydroxide monohydrate, dilute hydrochloric acid, 3-aminopiperidine-2,6-dione, 4-(2-bromoethyl)piperidine-1-carboxylic acid tert-butyl ester, tert-butyl 4-iodopiperidin-1-carboxylate, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate, 3-(5-bromo-6-fluoro-1-oxoisoindol-2-yl)piperidin-2,6-dione, 6-oxo-3-azabicyclo[3.2.0]heptane-3-carboxylate tert-butyl ester, 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate tert-butyl ester, 4-oxoazacyclopropane-1-carboxylate tert-butyl ester, 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate tert-butyl ester, 2-oxo-6-azaspiro[3.4]octane-6-carboxylate tert-butyl ester, 1-(tert-butoxycarbonyl)azabicyclo Butane-3-carboxylic acid, 5-oxohexahydrocyclopentane[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester, 2-oxo-8-azaspiro[4.5]dec-8-carboxylic acid tert-butyl ester, 3-(5-bromo-1-oxoisoindol-2-yl)piperidin-2,6-dione, (4-bromo-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate tert-butyl ester, 5,5,5',5'-tetramethyl-2,2'-bis(1,3,2-dioxaborane), potassium acetate, bis(diphenylphosphine ether)palladium(II) dichloride, ((2R,7aS)-2-fluorotetrahydro-1H-pyrroloazin-7a(5H)-yl)methanol, 1,4-diazidadicyclo[2.2.2]octane, 3-azabicyclo[3.1.[0] Hexane hydrochloride, [(di(1-adamantyl)butylphosphino)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate, 2,4,7-trichloro-8-fluoro-5-methylpyridino[4,3-d]pyrimidine, tert-butyl 2-bromoacetate, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 7-oxo-2-azaspiro[3.5]non-2-carboxylic acid tert-butyl ester, 4-(2-hydroxyethyl)piperidine-1-carboxylic acid tert-butyl ester, sodium hydrogen, 4-(bromomethyl)pyridine, ammonium chloride, (3-(2 ,4-Dioxytetrahydropyrimidin-1(2H)-yl)-4-methylbenzoic acid, 9-formyl-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester, 1,4-oxacyclopropane, acrylic acid, 3-amino-4-methylbenzoic acid, urea, 2,3,4,5,6-pentafluorophenol, N,N'-dicyclohexylcarbodiimide, tetraisopropyl titanate, 4-(2-(piperidin-4-ylmethoxy)ethyl)piperidin-1-carboxylic acid tert-butyl ester, (R)-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid, (S)-1-(tert-butoxycarbonyl) (R)-3-methylpiperidin-3-ol hydrochloride, 1,2,3,6-tetrahydropyridine hydrochloride, triethylenediamine, (R)-3-methylpiperidin-3-ol hydrochloride, 4-dimethylaminopyridine urea, sodium triacetoxyborohydride, 3-(3-fluoro-4-(piperazin-1-yl)phenyl)amino)piperidin-2,6-dione, 3-(1-oxo-5-(1,2,3,6-tetrahydropyridin-4-yl)isoindol-2-yl)piperidin-2,6-dione, 4-formylpiperidin-1-carboxylic acid tert-butyl ester, 3-(3-methyl-2-oxo-5-(piperidin) (-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6-dione, 6-oxo-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester, 3-oxoazacyclobutane-1-carboxylic acid tert-butyl ester, 1-hydroxybenzotriazole, carbodiimide hydrochloride, and other reagents and starting materials were purchased from Shanghai Bide, Leyan Reagent Company, Jiangsu Aikon Biomedical R&D Company, Anaiji Chemical Reagent Company, Shanghai Maclean Reagent Company, Saen Chemical Reagent Company, etc., or synthesized using methods known in the art.

[0118] Unless otherwise specified, all reactions in this disclosure are carried out under continuous magnetic stirring, in dry nitrogen or argon atmosphere, in dry solvent, and at temperatures in degrees Celsius.

[0119] The following are the intermediate numbers:

[0120] Intermediate I-1

[0121] Synthesis of intermediate I-1: ((1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl-4-methylbenzenesulfonate:

[0122] Step 1: Synthesis of 4-(aza-1-yl)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine (I-1-b)

[0123] 2,4,7-Trichloro-8-fluoropyridano[4,3-d]pyrimidine (I-1-a, 2.5 g, 9.90 mmol) and hexamethyleneimine (992 mg, 10.00 mmol) were dissolved in acetonitrile (30 mL), and N,N-diisopropylethylamine (3848 mg, 29.71 mmol) was added. The reaction was carried out at 0 °C for 0.5 h. The reaction was quenched with water, extracted with dichloromethane, and the organic phase was collected and repeatedly washed with saturated sodium chloride solution. After drying with anhydrous sodium sulfate, the mixture was filtered, concentrated under reduced pressure, and the target product 4-(aza-1-yl)-2,7-dichloro-8-fluoropyridano[4,3-d]pyrimidine (I-1-b, 2.8 g, 89% yield) was obtained. ESI[M+H] + =314.05

[0124] Step 2: Synthesis of (1-(((4-(aza-1-yl)-7-chloro-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-1-c)

[0125] 4-(aza-1-yl)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine (I-1-b, 2.8 g, 8.88 mmol) was dissolved in N,N-dimethylacetamide (40 ml), and then cyclopropane-1,1-dimethyldiethanol (2722 mg, 26.65 mmol), triethylamine (899 mg, 8.88 mmol), and cesium carbonate (8684 mg, 26.65 mmol) were added sequentially. The mixture was reacted at room temperature under nitrogen protection for 16 hours. The product was quenched with water, extracted with dichloromethane, and the organic phase was collected and repeatedly washed with saturated sodium chloride solution. After drying with anhydrous sodium sulfate, the product was filtered, concentrated under reduced pressure, and purified by liquid chromatography (dichloromethane:methanol = 10:1) to obtain the target product (1-(((4-(aza-1-yl)-7-chloro-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-1-c, 2.36 g, yield 68%).

[0126] ESI[M+H] + =380.14

[0127] Step 3: Synthesis of (1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-1-d)

[0128] (1-(((4-(aza-1-yl)-7-chloro-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-1-c, 1.8 g, 4.73 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxyborane-2-yl)naphth-1-yl)ethynyl)triisopropylsilane (2.9 g, 5.68 mmol), methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (342 mg, 0.47 mmol), and potassium phosphate (2.0 g, 9.46 mmol) were dissolved in dioxane (20 ml) and water (2 ml), and the mixture was reacted at 100 °C for 16 hours under nitrogen protection. The reaction solution was cooled to room temperature and quenched with water. It was extracted with ethyl acetate, and the organic phase was collected and repeatedly washed with saturated sodium chloride solution. It was dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by liquid chromatography (petroleum ether: ethyl acetate = 1:1) to obtain the target product (1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-1-d, 2.1 g, yield 61%).

[0129] ESI[M+H] + =730.37

[0130] Step 4: Synthesis of ((1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl-4-methylbenzenesulfonate (I-1)

[0131] (1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-1-d, 2.1 g, 2.88 mmol) was dissolved in dichloromethane (5 ml), followed by the addition of triethylamine (874 mg, 8.64 mmol) and 4-dimethylaminopyridine (35 mg, 0.29 mmol), and p-toluenesulfonyl chloride (1.09 g, 5.76 mmol) at 0 °C. The reaction was carried out at room temperature for 16 hours. Quenching with water, extraction with ethyl acetate, collection of the organic phase and repeated washing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtration, concentration under reduced pressure, and purification by liquid chromatography (petroleum ether: ethyl acetate = 1:1) yielded the target product ((1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl-4-methylbenzenesulfonate (I-1, 1.3 g, 52%). ESI [M+H + =885.16 1 H NMR (400MHz, DMSO-d6) δ9.16–9.15(m,1H),8.13–8.09(m,1H),7.75–7.72(m,2H),7.59–7. 55(m,1H),7.47–7.45(m,1H),7.35–7.31(m,2H),7.12–7.10(m,1H),5.37(s,2H),4.70–4. 59(m,2H),4.37–4.09(m,3H),4.07–4.00(m,4H),3.43(s,3H),2.60–2.50(m,1H),2.36–2. 27(m,3H),1.99–1.58(m,10H),1.33–1.15(m,2H),0.96–0.65(m,16H),0.56–0.47(m,3H).

[0132] Intermediate I-2

[0133] Synthesis of intermediate I-2: 3-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)piperidin-2,6-dione trifluoroacetate

[0134] Step 1: Synthesis of tert-butyl 4-(1H-indazol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid (I-2-b)

[0135] 6-Bromo-1H-indazole (I-2-a, 6 g, 30.45 mmol) was dissolved in 1,4-dioxane (48 ml) and water (12 ml), and then sodium carbonate (10.52 g, 99.27 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane dichloride complex (1.24 g, 1.52 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (14.13 g, 45.68 mmol) were added. The mixture was reacted at 105 °C for 16 hours. The reaction solution was filtered and the solvent was removed by vacuum distillation to obtain a crude product. The crude product was purified by liquid chromatography (petroleum ether:ethyl acetate = 0–30%) to obtain the target product, tert-butyl 4-(1H-indazol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid (I-2-b, 9.02 g, yield 98.90%). (ESI)[M+H] + =300.1

[0136] Step 2: Synthesis of tert-butyl 4-(3-iodo-1-methyl-1H-indazol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid (I-2-c)

[0137] 4-(1H-indazol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (I-2-b, 9.02 g, 30.14 mmol) was dissolved in N,N-dimethylformamide (88 ml), followed by the addition of potassium hydroxide (5.07 g, 90.42 mmol) and iodine (11.47 g, 45.21 mmol). The reaction was carried out at 25 °C for 2 h, then the reaction solution was cooled to 0 °C, and iodomethane (6 g, 42.20 mmol) was added. The reaction was then heated to 25 °C. The reaction was continued at ℃ for 1 hour. After the reaction was completed, the reaction solution was added to 400 ml of water and extracted three times with 200 ml of ethyl acetate each time. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent, yielding a crude product. The crude product was purified by liquid chromatography (petroleum ether: ethyl acetate = 0-15%) to obtain the target product 4-(3-iodo-1-methyl-1H-indazole-6-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (I-2-c, 6.62 g, yield 48.96%). (ESI)[M+H] + =440.2

[0138] Step 3: Synthesis of tert-butyl 4-(3-(2,4-bis(benzyloxy)phenyl)-1-methyl-1H-indazol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid (I-2-d)

[0139] 2-(2,4-bis(benzyloxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (I-2-c, 4.94 g, 10.77 mmol), cesium carbonate (10.53 g, 32.31 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (882 mg, 1.08 mmol), and 4-(3-iodo-1-methyl-1H-indazol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (I-d, 6.62 g, 15.08 mmol) were dissolved in 1,4-dioxane (40 ml) and water (8 ml), purged three times with nitrogen, and reacted at 100 °C for 16 hours. After the reaction was completed, the reaction solution was added to 500 ml of water and extracted three times with 250 ml of ethyl acetate each time. The organic phases were combined, dried with anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent to obtain the crude product. The crude product was purified by liquid chromatography (petroleum ether: ethyl acetate = 0-20%) to obtain the target product 4-(3-(2,4-bis(benzyloxy)phenyl)-1-methyl-1H-indazol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (I-2-d, 7.13 g, yield 100%).

[0140] Step 4: Synthesis of tert-butyl 4-(3-(2,6-dioxadiazin-3-yl)-1-methyl-1H-indazol-6-yl)piperidine-1-carboxylic acid (I-2-e)

[0141] 4-(3-(2,4-bis(benzyloxy)phenyl)-1-methyl-1H-indazole-6-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (I-2-d, 1.79 g, 2.97 mmol) was dissolved in ethanol (24.5 ml) and ethyl acetate (24.5 ml), and 1 g of 10% palladium on carbon was added. After three hydrogen purgings, the mixture was reacted at 30 °C for 24 h. The reaction solution was filtered through diatomaceous earth, and the filtrate was distilled under reduced pressure to obtain a crude product. The crude product was purified by liquid chromatography (petroleum ether: ethyl acetate = 0–50%) to obtain the target product 4-(3-(2,6-dioxadiazin-3-yl)-1-methyl-1H-indazole-6-yl)piperidine-1-carboxylic acid tert-butyl ester (I-2-e, 0.8 g, yield 62.99%). (ESI)[M+H] + =427.3

[0142] Step 5: Preparation of 3-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)piperidin-2,6-dione trifluoroacetate (I-2)

[0143] 4-(3-(2,6-dioxadiazin-3-yl)-1-methyl-1H-indazole-6-yl)piperidine-1-carboxylic acid tert-butyl ester (I-2-e, 780 mg, 1.83 mmol) was dissolved in dichloromethane (20 mL), and trifluoroacetic acid (2 mL) was added. The reaction was carried out at room temperature for 2 hours. The solvent was removed by vacuum distillation to obtain the target product 3-(1-methyl-6-(piperidine-4-yl)-1H-indazole-3-yl)piperidine-2,6-dione trifluoroacetate (I-2, 1.2 g). (ESI)[M+H] + =327.2. 1 H NMR (400MHz, DMSO-d6) δ10.91(s,1H),8.74-8.71(d,J=11.3Hz,1H),8.46-8.43(d,J=11. 2Hz,1H),7.68-7.66(d,J=8.4Hz,1H),7.39(s,1H),7.03-7.01(d,J=8.4Hz,1H),4.36-4. 32(m,1H),3.98(s,3H),3.46-3.45(d,J=7.0Hz,2H),3.11-2.94(m,3H),2.73-2.56(m,2H ),2.38-2.31(m,1H),2.19-2.12(m,1H),2.02-1.98(d,J=13.6Hz,2H),1.94-1.83(m,2H).

[0144] Intermediate I-3

[0145] Intermediate I-3: Synthesis of (1-(((4-(3-azabicyclo[3.1.0]hex-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl-4-methylbenzenesulfonate (I-3)

[0146] Step 1: Synthesis of 4-(3-azabicyclo[3.1.0]hex-3-yl)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine (I-3-b)

[0147] 2,4,7-Trichloro-8-fluoropyridano[4,3-d]pyrimidine (I-3-a, 1 g, 6.97 mmol) was dissolved in acetonitrile (35 mL), and N,N-diisopropylethylamine (1539 mg, 11.88 mmol) and 3-azabicyclo[3.1.0]hexane hydrochloride (426 mg, 3.56 mmol) were added sequentially. The reaction was carried out at 0 °C for 0.5 h. The mixture was quenched with water, extracted with ethyl acetate, and the organic phase was collected and repeatedly washed with saturated sodium chloride solution. After drying with anhydrous sodium sulfate, the mixture was filtered, concentrated under reduced pressure, and purified by liquid chromatography (petroleum ether:ethyl acetate = 2:1) to obtain the target product 4-(3-azabicyclo[3.1.0]hex-3-yl)-2,7-dichloro-8-fluoropyridano[4,3-d]pyrimidine (I-3-b, 865 mg, yield 41.5%). ESI[M+H] + =299.13

[0148] Step 2: Synthesis of (1-(((4-(3-azabicyclo[3.1.0]hex-3-yl)-7-chloro-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-3-c)

[0149] 4-(3-azabicyclo[3.1.0]hex-3-yl)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine (I-3-b, 865 mg, 2.89 mmol) was dissolved in N,N-dimethylacetamide (15 ml), and then cyclopropane-1,1-dimethyldiethanol (1476 mg, 14.45 mmol), triethylamine (292 mg, 2.88 mmol), and cesium carbonate (2826 mg, 8.65 mmol) were added sequentially. The mixture was reacted at room temperature for 16 hours. The solution was quenched with water, extracted with ethyl acetate, and the organic phase was collected and repeatedly washed with saturated sodium chloride solution. After drying with anhydrous sodium sulfate, the solution was filtered, concentrated under reduced pressure, and purified by liquid chromatography (dichloromethane:methanol = 10:1) to obtain the target product (1-(((4-(3-azabicyclo[3.1.0]hex-3-yl)-7-chloro-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-3-c, 1 g, yield 94.8%). ESI[M+H) + =364.81

[0150] Step 3: Synthesis of (1-(((4-(3-azabicyclo[3.1.0]hex-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-3-d)

[0151] (1-(((4-(3-azabicyclo[3.1.0]hex-3-yl)-7-chloro-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-3-c, 1 g, 2.74 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxyborane-2-yl)naphth-1-yl)ethynyl) Triisopropylsilane (1685 mg, 3.28 mmol), [(di(1-adamantyl)butylphosphino)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (200 mg, 0.27 mmol) and potassium phosphate (1164 mg, 5.48 mmol) were dissolved in dioxane (10 ml) and water (1 ml) and reacted at 100 °C for 16 h under nitrogen protection. The solution was quenched with water, extracted with ethyl acetate, and the organic phase was collected and repeatedly washed with saturated sodium chloride solution. After drying with anhydrous sodium sulfate, the solution was filtered, concentrated under reduced pressure, and purified by liquid chromatography (petroleum ether: ethyl acetate = 1:1) to obtain the target product (1-(((4-(3-azabicyclo[3.1.0]hex-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-3-d, 400 mg, yield 20.4%) ESI[M+H]+ = 714.93

[0152] Step 4: Synthesis of (1-(((4-(3-azabicyclo[3.1.0]hex-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl-4-methylbenzenesulfonate (I-3)

[0153] (1-(((4-(3-azabicyclo[3.1.0]hex-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-3-d, 400 mg, 0.55 mmol) was dissolved in dichloromethane (5 ml), followed by the addition of triethylamine (170 mg, 1.68 mmol) and 4-dimethylaminopyridine (7 mg, 0.055 mmol), and p-toluenesulfonyl chloride (426 mg, 2.23 mmol) at 0 °C. The reaction was carried out at room temperature for 16 hours. The solution was quenched with water, extracted with ethyl acetate, and the organic phase was collected and repeatedly washed with saturated sodium chloride solution. After drying with anhydrous sodium sulfate, the solution was filtered, concentrated under reduced pressure, and purified by thin-layer chromatography on silica gel plates (petroleum ether: ethyl acetate = 1:1) to obtain the target product (1-(((4-(3-azabicyclo[3.1.0]hex-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl-4-methylbenzenesulfonate (I-3, 160 mg, 33.4%). ESI[M+H) + =869.11

[0154] Intermediate I-4

[0155] Synthesis of Intermediate I-4: (1-(((4-(3-azabicyclo[3.1.0]hex-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)-5-methylpyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl-4-methylbenzenesulfonate)

[0156] Step 1: Synthesis of (4-(3-azabicyclo[3.1.0]hex-3-yl)-2,7-dichloro-8-fluoro-5-methylpyridine[4,3-d]pyrimidine (I-4-b)

[0157] 2,4,7-Trichloro-8-fluoro-5-methylpyridano[4,3-d]pyrimidine (I-4-a, 450 mg, 1.69 mmol) was dissolved in dichloromethane (10 mL), cooled to 0 °C, and N,N-diisopropylethylamine (438 mg, 3.38 mmol) and 3-azabicyclo[3.1.0]hexane hydrochloride (202 mg, 1.69 mmol) were added sequentially, and the reaction was carried out at 0 °C for 0.5 h. The reaction was quenched with aqueous solution, extracted with dichloromethane, and the organic phase was collected and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude 4-(3-azabicyclo[3.1.0]hex-3-yl)-2,7-dichloro-8-fluoro-5-methylpyridano[4,3-d]pyrimidine (I-4-b, 610 mg, crude). ESI[M+H] + =360.6

[0158] Step 2: Synthesis of (1-(((4-(3-azabicyclo[3.1.0]hex-3-yl)-7-chloro-8-fluoro-5-methylpyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-4-c)

[0159] 4-(3-azabicyclo[3.1.0]hex-3-yl)-2,7-dichloro-8-fluoro-5-methylpyridin[4,3-d]pyrimidine (I-4-b, 610 mg, 1.95 mmol) and cyclopropane-1,1-dimethyldiethanol (600 mg, 5.84 mmol) were dissolved in N,N-dimethylacetamide (1 mL), and then triethylamine (197 mg, 1.95 mmol) and cesium carbonate (1.9 g, 5.84 mmol) were added sequentially. The mixture was purged with nitrogen three times and reacted at room temperature for 16 hours. Quenching with aqueous solution, extraction with ethyl acetate, collection of the organic phase and washing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtration, concentration under reduced pressure, and purification by liquid chromatography (petroleum ether: ethyl acetate = 0%–40%) yielded the target product (1-(((4-(3-azabicyclo[3.1.0]hexyl-3-yl)-7-chloro-8-fluoro-5-methylpyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-4-c, 340 mg, yield 46%). ESI[M+H] + =379.6

[0160] Step 3: Synthesis of (1-(((4-(3-azabicyclo[3.1.0]hex-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)-5-methylpyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-4-d)

[0161] (1-(((4-(3-azabicyclo[3.1.0]hex-3-yl)-7-chloro-8-fluoro-5-methylpyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-4-c, 340 mg, 0.9 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxyborane-2-yl)naphth-1-yl)ethynyl)triisopropylsilane (692 mg, 1.35 mmol) and potassium phosphate (765 mg, 3.6 mmol) were dissolved in dioxane (10 mL) and water (1 mL), and finally [(di(1-adamantyl)butylphosphino)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (130 mg, 0.18 mmol). After purging with nitrogen three times, the mixture was heated to 100°C and reacted overnight. The reaction was quenched with water, extracted with ethyl acetate, and the organic phase was collected and washed with saturated sodium chloride solution. It was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by liquid chromatography (petroleum ether: ethyl acetate = 0%–50%) to obtain the target product (1-(((4-(3-azabicyclo[3.1.0]hex-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)-5-methylpyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-4-d, 330 mg, yield 62.8%).

[0162] Step 4: Synthesis of (1-(((4-(3-azabicyclo[3.1.0]hex-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)-5-methylpyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl-4-methylbenzenesulfonate (I-4)

[0163] (1-(((4-(3-azabicyclo[3.1.0]hex-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)-5-methylpyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-4-d, 250 mg, 0.35 mmol), triethylamine (105 mg, 1.03 mmol) and p-toluenesulfonyl chloride (263 mg, 1.38 mmol) were dissolved in dichloromethane (5 mL) and reacted at room temperature for 16 hours. The reaction solution was extracted three times with dichloromethane after adding water. The organic phase was concentrated under reduced pressure and then separated and purified by liquid chromatography (petroleum ether: ethyl acetate = 0%~50%) to obtain the target product (1-(((4-(3-azabicyclo[3.1.0]hex-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)-5-methylpyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl-4-methylbenzenesulfonate (I-4, 95 mg, yield 31.5%).

[0164] Intermediate I-5

[0165] Intermediate I-5: Synthesis of (1-(((4-(3,6-dihydropyridin-1(2H)-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)-5-methylpyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl-4-methylbenzenesulfonate)

[0166] Step 1: Synthesis of 2,7-dichloro-4-(3,6-dihydropyridin-1(2H)-yl)-8-fluoro-5-methylpyrido[4,3-d]pyrimidine (I-5-b)

[0167] 2,4,7-Trichloro-8-fluoro-5-methylpyridano[4,3-d]pyrimidine (I-5-a, 2 g, 7.5 mmol) was dissolved in acetonitrile (50 mL) at 0 °C. N,N-diisopropylethylamine (2.9 g, 22.5 mmol) was added first, followed by 1,2,3,6-tetrahydropyridine hydrochloride (807 mg, 6.75 mmol), and the mixture was reacted at 0 °C for 0.5 hours. After concentration under reduced pressure, the crude product was purified by liquid chromatography (petroleum ether: ethyl acetate = 0–30%) to obtain the target product 2,7-dichloro-4-(3,6-dihydropyridin-1(2H)-yl)-8-fluoro-5-methylpyridano[4,3-d]pyrimidine (I-5-b, 2.02 g, yield 85.96%). ESI [M+H] + =313.6.

[0168] Step 2: Synthesis of (1-(((7-chloro-4-(3,6-dihydropyridin-1(2H)-yl)-8-fluoro-5-methylpyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-5-c)

[0169] (2,7-Dichloro-4-(3,6-dihydropyridin-1(2H)-yl)-8-fluoro-5-methylpyrido[4,3-d]pyrimidine (I-5-b, 1 g, 3.19 mmol) was dissolved in acetonitrile (30 mL), followed by the sequential addition of triethylenediamine (179 mg, 1.6 mmol), cesium carbonate (3.12 g, 9.57 mmol), and cyclopropane-1,1-dimethyldiethanol (652 mg, 1.6 mmol). 6.38 mmol), and reacted at room temperature for 0.5 hours. After concentration under reduced pressure, the target compound (1-(((7-chloro-4-(3,6-dihydropyridin-1(2H)-yl)-8-fluoro-5-methylpyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-5-c, 1.02 g, yield 85%) was obtained by purification by liquid chromatography (petroleum ether: ethyl acetate = 0-40%).

[0170] Step 3: Synthesis of (1-(((4-(3,6-dihydropyridin-1(2H)-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)-5-methylpyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-5-d)

[0171] (1-(((7-chloro-4-(3,6-dihydropyridin-1(2H)-yl)-8-fluoro-5-methylpyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-5-c, 1.39 g, 3.67 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxyborane-2-yl)naphthalene-1- Triisopropylsilane (2.26 g, 4.40 mmol), methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (267 mg, 0.367 mmol) and potassium phosphate (1.56 g, 7.34 mmol) were dissolved in dioxane (30 mL) and water (3 mL), and the reaction was carried out at 100 °C for 16 hours under nitrogen protection. After the reaction solution was cooled to room temperature, it was quenched with water, extracted with ethyl acetate, the organic phase was collected and repeatedly washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by liquid chromatography (petroleum ether: ethyl acetate = 0-40%) to obtain the target product (1-(((4-(3,6-dihydropyridin-1(2H)-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)-5-methylpyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-5-d, 1.595 g, yield 60.88%).

[0172] Step 4: Synthesis of (1-(((4-(3,6-dihydropyridin-1(2H)-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)-5-methylpyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl-4-methylbenzenesulfonate (I-5)

[0173] (1-(((4-(3,6-dihydropyridin-1(2H)-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)-5-methylpyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-5-d, 690 mg, 0.95 mmol) was dissolved in dichloromethane (8 mL), followed by the addition of triethylamine (96 mg, 0.95 mmol) and 4-dimethylaminopyridine (59 mg, 0.48 mmol), and p-toluenesulfonyl chloride (543 mg, 2.85 mmol) at 0 °C. The reaction was carried out at room temperature for 6 hours. After concentration under reduced pressure, the product was purified by liquid chromatography (petroleum ether: ethyl acetate = 0-30%) to obtain the target product (1-(((4-(3,6-dihydropyridin-1(2H)-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)-5-methylpyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl-4-methylbenzenesulfonate (I-5, 505 mg, yield 60.19%).

[0174] Intermediate I-6

[0175] Intermediate I-6: Synthesis of methyl 4-methylbenzenesulfonate (I-6) of 1-((4-(2,5-dihydro-1H-pyrrolo-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-5-methylpyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)4-methylbenzenesulfonate

[0176] Step 1: Synthesis of 2,7-dichloro-4-(3,6-dihydropyridin-1(2H)-yl)-8-fluoro-5-methylpyrido[4,3-d]pyrimidine (I-6-b)

[0177] 2,4,7-Trichloro-8-fluoro-5-methylpyridano[4,3-d]pyrimidine (I-6-a, 1 g, 3.75 mmol) was dissolved in acetonitrile (20 mL) at 0 °C. N,N-diisopropylethylamine (1.3 mL, 7.5 mmol) was added first, followed by 2,5-dihydro-1H-pyrrole hydrochloride (400 mg, 3.75 mmol). The reaction mixture was reacted at 0 °C for 0.5 h. The reaction solution was extracted with dichloromethane after adding water. The organic phase was collected and repeatedly washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the target product 2,7-dichloro-4-(2,5-dihydro-1H-pyrrole-1-yl)-8-fluoro-5-methylpyridano[4,3-d]pyrimidine (I-6-b, 1 g, 89% yield).

[0178] Step 2: Synthesis of (1-((7-chloro-4-(2,5-dihydro-1H-pyrrolo-1-yl)-8-fluoro-5-methylpyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-6-c)

[0179] 2,7-Dichloro-4-(2,5-dihydro-1H-pyrrolo-1-yl)-8-fluoro-5-methylpyrido[4,3-d]pyrimidine (I-6-b, 1 g, 3.35 mmol) was dissolved in acetonitrile (30 mL), and then triethylenediamine (DABCO, 188 mg, 1.675 mmol), cesium carbonate (3.25 g, 10 mmol), and cyclopropane-1,1-dimethyldiethanol (885 mg, 8.38 mmol) were added sequentially. The mixture was reacted at room temperature for 0.5 hours. After filtration and concentration under reduced pressure, the target compound (1-((7-chloro-4-(2,5-dihydro-1H-pyrrolo-1-yl)-8-fluoro-5-methylpyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-6-c, 1 g, yield 81.9%) was obtained by liquid chromatography (HPLC) after separation (petroleum ether: ethyl acetate = 0-50%).

[0180] Step 3: Synthesis of (1-((4-(2,5-dihydro-1H-pyrrolo-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8((triisopropylsilyl)ethynyl)naphth-1-yl)-5-methylpyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-6-d)

[0181] (1-((7-chloro-4-(2,5-dihydro-1H-pyrrolo-1-yl)-8-fluoro-5-methylpyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-6-c, 1 g, 2.75 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxyborane-2-yl)naphth-1-yl)acetylene) Triisopropylsilane (1.83 g, 3.75 mmol), methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (204 mg, 0.28 mmol), and potassium phosphate (1.75 g, 8.25 mmol) were dissolved in 1,4-dioxane (20 mL) and water (2 mL), and the reaction was carried out at 100 °C for 16 hours under nitrogen protection. The reaction solution was cooled to room temperature and quenched with water. It was extracted with ethyl acetate, and the organic phase was collected and repeatedly washed with saturated sodium chloride solution. It was dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by liquid chromatography (petroleum ether: ethyl acetate = 0-35%) to obtain the target product (1-((4-(2,5-dihydro-1H-pyrrolo-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8((triisopropylsilyl)ethynyl)naphth-1-yl)-5-methylpyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-6-d, 1.24 g, yield 63%).

[0182] Step 4: Synthesis of methyl ((1-((4-(2,5-dihydro-1H-pyrrolo-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-5-methylpyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)4-methylbenzenesulfonate (I-6)

[0183] (1-((4-(2,5-dihydro-1H-pyrrolo-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8((triisopropylsilyl)ethynyl)naphth-1-yl)-5-methylpyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-6-d, 1.24 g, 1.73 mmol) was dissolved in dichloromethane (15 mL), followed by the addition of triethylamine (524 mg, 5.19 mmol) and 4-dimethylaminopyridine (21 mg, 0.17 mmol), and p-toluenesulfonyl chloride (660 mg, 3.46 mmol) at 0 °C. The reaction was carried out at room temperature for 16 hours. After concentration under reduced pressure, the product was purified by liquid chromatography (petroleum ether: ethyl acetate = 0-35%) to obtain the target product ((1-((4-(2,5-dihydro-1H-pyrrolo-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-5-methylpyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)4-methylbenzenesulfonate methyl ester (I-6, 700 mg, yield 46.6%).

[0184] Intermediate I-7

[0185] Intermediate I-7: Synthesis of (R)-(1-((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-4-(3-hydroxypiperidin-1-yl)-5-methylpyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)4-methylbenzenesulfonate (I-7)

[0186] Step 1: Synthesis of (R)-1-(2,7-dichloro-8-fluoro-5-methylpyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol (I-7-a)

[0187] 2,4,7-Trichloro-8-fluoro-5-methylpyrido[4,3-d]pyrimidine (I-6-a, 2 g, 7.5 mmol) was dissolved in acetonitrile (50 mL) at 0 °C. N,N-diisopropylethylamine (3.9 mL, 22.5 mmol) was added first, followed by (R)-piperidine-3-ol hydrochloride (929 mg, 6.75 mmol), and the reaction was carried out at 0 °C for 0.5 h. The reaction solution was then extracted with dichloromethane after adding water. The organic phase was collected and repeatedly washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by liquid chromatography (dichloromethane:methanol = 0-10%) to obtain the target product (R)-1-(2,7-dichloro-8-fluoro-5-methylpyridino[4,3-d]pyrimidin-4-yl)piperidin-3-ol (I-7-a, 1.94 g, yield 78.23%).

[0188] Step 2: Synthesis of (R)-1-(7-chloro-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)-5-methylpyridano[4,3-d]pyrimidin-4-yl)piperidin-3-ol (I-7-b)

[0189] (R)-1-(2,7-dichloro-8-fluoro-5-methylpyridano[4,3-d]pyrimidin-4-yl)piperidin-3-ol (I-7-a, 1.94 g, 5.86 mmol) was dissolved in acetonitrile (60 mL), followed by the sequential addition of triethylenediamine (329 mg, 2.93 mmol), cesium carbonate (5.73 g, 17.58 mmol), and cyclopropane-1,1-diyldiethanol (1.2 g, 11.72 mmol). The reaction was carried out at room temperature for 0.5 hours. After filtration and concentration under reduced pressure, the target compound (R)-1-(7-chloro-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)-5-methylpyridano[4,3-d]pyrimidin-4-yl)piperidin-3-ol (I-7-b, 3.08 g, crude product) was obtained.

[0190] Step 3: Synthesis of (R)-1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-2-((1-(hydroxymethyl)cyclopropyl)methoxy)-5-methylpyridino[4,3-d]pyrimidin-4-yl)piperidin-3-ol (I-7-c)

[0191] (R)-1-(7-chloro-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)-5-methylpyridino[4,3-d]pyrimidin-4-yl)piperidin-3-ol (I-7-b, 3.08 g, 7.76 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxyborane-2-yl)naphth-1-yl)ethynyl Triisopropylsilane (3.58 g, 6.98 mmol), methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (568 mg, 0.78 mmol), and potassium phosphate (3.29 g, 15.52 mmol) were dissolved in 1,4-dioxane (50 mL) and water (5 mL), and the mixture was reacted at 100 °C for 16 hours under nitrogen protection. After the reaction solution was cooled to room temperature, it was quenched with water, extracted with ethyl acetate, the organic phase was collected and repeatedly washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by liquid chromatography (petroleum ether: ethyl acetate = 0-35%) to obtain the target product (R)-1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-2-((1-(hydroxymethyl)cyclopropyl)methoxy)-5-methylpyridino[4,3-d]pyrimidin-4-yl)piperidin-3-ol (I-7-c, 2.5 g, yield 43%).

[0192] Step 4: Synthesis of (R)-(1-((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-4-(3-hydroxypiperidin-1-yl)-5-methylpyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)4-methylbenzenesulfonate (I-7)

[0193] (R)-1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-2-((1-(hydroxymethyl)cyclopropyl)methoxy)-5-methylpyridino[4,3-d]pyrimidin-4-yl)piperidin-3-ol (I-7-c, 1.5 g, 2.0 mmol) was dissolved in dichloromethane (15 mL), followed by the addition of triethylamine (607 mg, 6 mmol) and 4-dimethylaminopyridine (24.5 mg, 0.2 mmol), and p-toluenesulfonyl chloride (762 mg, 4 mmol) at 0 °C. The reaction was carried out at room temperature for 16 hours. After concentration under reduced pressure, the product was purified by liquid chromatography (petroleum ether: ethyl acetate = 0-65%) to obtain the target product (R)-(1-((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-4-(3-hydroxypiperidin-1-yl)-5-methylpyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)4-methylbenzenesulfonate (I-7, 480 mg, yield 27%).

[0194] Intermediate I-8

[0195] Intermediate I-8: Synthesis of methyl 1-((4-(azacycloheptan-1-yl)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)4-methylbenzenesulfonate (I-8)

[0196] Step 1: Synthesis of (1-((4-(azacycloheptane-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-8-a)

[0197] (1-(((4-(azacycloheptan-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy))-8-((triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-1-d, 490 mg, 0.67 mmol) was dissolved in N,N-dimethylformamide (5 mL), and cesium fluoride (509 mg, 3.35 mmol) was added. The mixture was reacted at room temperature for 1 hour. The reaction solution was filtered and concentrated under reduced pressure to obtain the target product (1-((4-(azacycloheptane-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-8-a, 500 mg, crude product). ESI[M+H) +=575

[0198] Step 2: Synthesis of (1-((4-(azacycloheptane-1-yl)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-8-b)

[0199] (1-((4-(azacycloheptan-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-8-a, 500 mg, 0.87 mmol)) was dissolved in tetrahydrofuran (5 mL). After purging with hydrogen three times, 5% palladium on carbon (648 mg) was added, and after purging with hydrogen three more times, the reaction solution was reacted at room temperature for 16 hours. The reaction solution was filtered with diatomaceous earth and then concentrated under reduced pressure to obtain the target product (1-((4-(azacycloheptane-1-yl)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-8-b, 368 mg, yield 73.14%).

[0200] Step 3: Synthesis of methyl (1-((4-(azacycloheptan-1-yl)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)4-methylbenzenesulfonate (I-8)

[0201] (1-((4-(azacycloheptane-1-yl)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-8-b, 368 mg, 0.63 mmol) was dissolved in dichloromethane (2 mL), followed by the addition of triethylamine (191 mg, 1.89 mmol) and 4-dimethylaminopyridine (1.45 mg, 0.063 mmol), and p-toluenesulfonyl chloride (364 mg, 1.89 mmol) at 0 °C. The reaction was carried out at room temperature for 16 hours. The reaction solution was extracted three times with dichloromethane after adding water. The combined organic phases were concentrated under reduced pressure and then purified by liquid chromatography (petroleum ether: ethyl acetate = 0-25%) to obtain the target product (methyl 1-((4-(azacycloheptane-1-yl)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)4-methylbenzenesulfonate (I-8, 98 mg, yield 21.2%).

[0202] Intermediate I-9

[0203] Intermediate I-9: Synthesis of (R)-(1-((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-4-(3-hydroxypiperidin-1-yl)-5-methylpyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)4-methylbenzenesulfonate (I-9)

[0204] Step 1: Synthesis of (R)-1-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy]-5-methylpyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol (I-9-a)

[0205] (R)-1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-2-((1-(hydroxymethyl)cyclopropyl)methoxy”)-5-methylpyridino[4,3-d]pyrimidin-4-yl)piperidin-3-ol (I-7-c, 1 g, 1.34 mmol) was dissolved in N,N-dimethylformamide (10 mL), and cesium fluoride (1.017 g, 6. 7 mmol), reacted at room temperature for 1 hour. The reaction solution was added to 150 mL of water, the product precipitated, and the reaction solution was filtered, dried and concentrated to obtain the target product (R)-1-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy]-5-methylpyridino[4,3-d]pyrimidin-4-yl)piperidin-3-ol (I-9-a, 790 mg, crude product).

[0206] Step 2: Synthesis of (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy]-5-methylpyridano[4,3-d]pyrimidin-4-yl)piperidin-3-ol (I-9-b)

[0207] (R)-1-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy]-5-methylpyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol (I-9-a, 790 mg, 1.34 mmol) was dissolved in tetrahydrofuran (10 mL), purged three times with hydrogen, and then 5% palladium on carbon (500 mg) was added. After being replaced with hydrogen three times, the reaction solution was reacted at room temperature for 16 hours. The reaction solution was filtered with diatomaceous earth and concentrated under reduced pressure to obtain the target product (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy]-5-methylpyridino[4,3-d]pyrimidin-4-yl)piperidin-3-ol (I-9-b, 715 mg, crude product).

[0208] Step 3: Synthesis of (R)-(1-((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-4-(3-hydroxypiperidin-1-yl)-5-methylpyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)4-methylbenzenesulfonate (I-9)

[0209] (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy]-5-methylpyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol (I-9-b, 715 mg, 1.2 mmol) was dissolved in dichloromethane (10 mL), followed by the addition of triethylamine (364 mg, 3.6 mmol) and 4-dimethylaminopyridine (15 mg, 0.12 mmol), and then p-toluenesulfonyl chloride (457 mg, 2 mmol) at 0 °C. The reaction mixture was reacted at room temperature for 16 hours (0.4 mmol). After adding water, the reaction solution was extracted three times with dichloromethane. The combined organic phases were concentrated under reduced pressure and purified by liquid chromatography (petroleum ether: ethyl acetate = 0–65%) to obtain the target product (R)-(1-((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-4-(3-hydroxypiperidin-1-yl)-5-methylpyridano[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)4-methylbenzenesulfonate (I-9, 85 mg, yield 9.4%). ESI [M+H] + =749.3

[0210] Intermediate I-10

[0211] Intermediate I-10: Synthesis of 4-(azacycloheptane-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-2-((1-(iodomethyl)cyclopropyl)methoxypyrido[4,3-d]pyrimidine)

[0212] Step 1: Synthesis of 4-(aza-1-yl)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine (I-10-b)

[0213] 2,4,7-Trichloro-8-fluoropyridano[4,3-d]pyrimidine (I-10-a, 2.5 g, 9.90 mmol) and hexamethyleneimine (992 mg, 10.00 mmol) were dissolved in acetonitrile (30 mL), and N,N-diisopropylethylamine (3848 mg, 29.71 mmol) was added. The reaction was carried out at 0 °C for 0.5 h. The reaction was quenched with water, extracted with dichloromethane, and the organic phase was collected and repeatedly washed with saturated sodium chloride solution. After drying with anhydrous sodium sulfate, the mixture was filtered, concentrated under reduced pressure, and the target product 4-(aza-1-yl)-2,7-dichloro-8-fluoropyridano[4,3-d]pyrimidine (I-10-b, 2.8 g, 89% yield) was obtained. ESI[M+H] + =314.05

[0214] Step 2: Synthesis of (1-(((4-(aza-1-yl)-7-chloro-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-10-c)

[0215] 4-(aza-1-yl)-2,7-dichloro-8-fluoropyridano[4,3-d]pyrimidine (I-10-b, 2.8 g, 8.88 mmol) was dissolved in acetonitrile (40 mL), followed by the sequential addition of triethylenediamine (498 mg, 4.44 mmol), cesium carbonate (8684 mg, 26.65 mmol), and cyclopropane-1,1-diyldiethanol (2722 mg, 26.65 mmol). The reaction was carried out at room temperature for 0.5 hours. After filtration and concentration under reduced pressure, the target product (1-(((4-(aza-1-yl)-7-chloro-8-fluoropyridano[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-10-c, 2.36 g, yield 68%) was obtained. ESI[M+H] + =380.14

[0216] Step 3: Synthesis of (1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-10-d)

[0217] (1-(((4-(aza-1-yl)-7-chloro-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-10-c, 1.8 g, 4.73 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxyborane-2-yl)naphth-1-yl)ethynyl)triisopropylsilane (2.9 g, 5.68 mmol), methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (342 mg, 0.47 mmol), and potassium phosphate (2.0 g, 9.46 mmol) were dissolved in 1,4-dioxane (20 mL) and water (2 mL), and the mixture was reacted at 100 °C for 16 hours under nitrogen protection. The reaction solution was cooled to room temperature and quenched with water. Extraction was performed with ethyl acetate, and the organic phase was collected and repeatedly washed with saturated sodium chloride solution. After drying with anhydrous sodium sulfate, the solution was filtered, concentrated under reduced pressure, and purified by liquid chromatography (petroleum ether:ethyl acetate = 1:1) to obtain the target product (1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-10-d, 2.1 g, yield 61%). ESI[M+H) + =730.37

[0218] Step 4: Synthesis of 4-(azacycloheptane-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-2-((1-(iodomethyl)cyclopropyl)methoxypyrido[4,3-d]pyrimidine)

[0219] (1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-10-d, 500 mg, 0.684 mmol), triphenylphosphine (7.18 g, 27.38 mmol) and imidazole (2.31 g, 34 mmol) were dissolved in dichloromethane (30 mL). Iodine (1.72 g, 6.84 mmol) was dissolved in dichloromethane (30 mL) and then slowly added dropwise to the mixture. The reaction was carried out at room temperature for 4 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and then separated and purified by liquid chromatography (petroleum ether: ethyl acetate = 0-40%) to obtain the target product 4-(azacycloheptane-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-2-((1-(iodomethyl)cyclopropyl)methoxypyrido[4,3-d]pyrimidine (I-10, 400 mg, yield 69.59%).

[0220] Intermediate I-11

[0221] Intermediate I-11: Synthesis of 4-(azacycloheptane-1-yl)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-((1-(iodomethyl)cyclopropyl)methoxy]pyrido[4,3-d]pyrimidine (I-11)

[0222] Step 1: Synthesis of 2-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (I-11-b)

[0223] ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)naphth-1-yl)ethynyl)triisopropylsilane (I-11-a, 5 g, 9.8 mmol)) was dissolved in N,N-dimethylformamide (40 mL), and cesium fluoride (7.5 g, 49 mmol) was added. The reaction was carried out at room temperature for 4 hours. The reaction solution was added to 200 mL of water, and the product precipitated. After filtration and drying, the target product 2-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaboran (I-11-b, 3.5 g, crude product) was obtained.

[0224] Step 2: Synthesis of 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (I-11-c)

[0225] 2-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (I-11-b, 3.5 g, 9.8 mmol) was dissolved in tetrahydrofuran (30 mL), and 5% palladium on carbon (400 mg) and palladium hydroxide (400 mg) were added. After purging with hydrogen three times, the reaction solution was reacted at room temperature for 16 hours. The reaction solution was filtered, concentrated, and purified by liquid chromatography (petroleum ether: ethyl acetate = 0–10%) to obtain the target product 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (I-11-c, 3.6 g, crude product).

[0226] Step 3: Synthesis of (1-((4-(azacycloheptane-1-yl)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-11-d)

[0227] (1-(((4-(aza-1-yl)-7-chloro-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-10-c, 500 mg, 1.315 mmol), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (I-11-c, 957 mg) 0.9 g (2.63 mmol), methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (95.41 mg, 0.131 mmol), and potassium phosphate (834.61 mg, 3.93 mmol) were dissolved in 1,4-dioxane (10 mL) and water (1 mL). After purging with nitrogen three times, the mixture was microwaved at 100 °C for 1.5 hours. The reaction solution was concentrated under reduced pressure and purified by liquid chromatography (petroleum ether: ethyl acetate = 0-60%) to obtain the target product (1-((4-(azacycloheptan-1-yl)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-11-d, 270 mg, yield 35.5%).

[0228] Step 4: Synthesis of 4-(azacycloheptane-1-yl)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-((1-(iodomethyl)cyclopropyl)methoxy]pyrido[4,3-d]pyrimidine (I-11)

[0229] (1-((4-(azacycloheptane-1-yl)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-11-d, 270 mg, 0.466 mmol), triphenylphosphine (4.89 g, 18.6 mmol) and imidazole (1.58 g, 23.3 mmol) were dissolved in dichloromethane (15 mL). Iodine (1.18 g, 4.66 mmol) was dissolved in dichloromethane (15 mL) and then slowly added dropwise to the mixture. The reaction was carried out at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and then separated and purified by liquid chromatography (petroleum ether: ethyl acetate = 0-35%) to obtain the target product 4-(azacycloheptane-1-yl)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-((1-(iodomethyl)cyclopropyl)methoxy]pyrido[4,3-d]pyrimidine (I-11, 200 mg, yield 62.36%).

[0230] Intermediate I-12

[0231] Intermediate I-12: Preparation of (R)-(1-((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-4-(3-hydroxy-3-methylpiperidin-1-yl)-5-methoxypyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)4-methylbenzenesulfonate (I-12)

[0232] Step 1: Preparation of 7-chloro-8-fluoro-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (I-12-b)

[0233] 5,7-Dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (I-12-a, 7 g, 2.5 mmol) was dissolved in N,N-dimethylacetamide (37.5 mL) and methanol (6.5 mL), then sodium methoxide (10 g, 18.5 mmol) was added. The reaction was carried out at 50 °C for 16 hours. The reaction solution was filtered, and the pH was adjusted to 3 with 1,4-dioxane hydrochloride. Water was added and stirred, and a solid precipitated. After filtration and drying, the target product 7-chloro-8-fluoro-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (I-12-b, 7.9 g, crude product) was obtained. ESI[M+H] + =275.4

[0234] Step 2: Preparation of (R)-1-(7-chloro-8-fluoro-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (I-12-c)

[0235] 7-Chloro-8-fluoro-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (I-12-b, 7.1 g, 25.84 mmol) was dissolved in acetonitrile (300 mL), and N,N-diisopropylethylamine (25.62 mL, 155.04 mmol) and phosphorus oxychloride (7.22 mL, 77.54 mmol) were added sequentially at room temperature. After reacting at 80 °C for 1 hour, the reaction solution was cooled to 0 °C, and then N,N-diisopropylethylamine (12.81 mL, 77.52 mmol) and (R)-3-methylpiperidin-3-ol hydrochloride (4.7 g, 31 mmol) were added. The reaction was carried out at 0 °C for 1.5 hours. The reaction solution was slowly quenched with warm water, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the solution was purified by liquid chromatography (petroleum ether:ethyl acetate = 0–50%) to obtain the target product (R)-1-(7-chloro-8-fluoro-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (I-12-c, 7.58 g, yield 78.67%). ESI [M+H] + =373.1

[0236] Step 3: Preparation of (R)-1-(7-chloro-8-fluoro-5-methoxy-2-(methanesulfonyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (I-12-d)

[0237] (R)-1-(7-chloro-8-fluoro-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (I-12-c, 3 g, 8 mmol) and m-chloroperoxybenzoic acid (4.1 g, 24 mmol) were dissolved in dichloromethane (50 mL) and reacted at room temperature for 1 hour. The reaction solution was quenched with saturated sodium bicarbonate solution and extracted with dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the target product (R)-1-(7-chloro-8-fluoro-5-methoxy-2-(methylsulfonyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (I-12-d, 3.2 g, crude product).

[0238] Step 4: Preparation of (R)-1-(7-chloro-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)-5-methoxypyridino[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (I-12-e)

[0239] The following substances were added: (R)-1-(7-chloro-8-fluoro-5-methoxy-2-(methanesulfonyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (I-12-d, 3.2 g, 7.9 mmol), cesium carbonate (5.86 g, 18 mmol), cyclopropane-1,1-dimethyldiethanol (1.6 g, 15.8 mmol), and triethylenediamine (DABCO, 443 mg, 3.95 mmol). The solution was dissolved in acetonitrile (50 mL) and reacted at room temperature for 1 hour. The reaction solution was filtered, concentrated under reduced pressure, and purified by liquid chromatography (petroleum ether: ethyl acetate = 0–80%) to obtain the target product (R)-1-(7-chloro-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)-5-methoxypyridano[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (I-12-e, 2.16 g, yield 64%). ESI [M+H] + =427.3

[0240] Step 5: Preparation of (R)-1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-2-((1-(hydroxymethyl)cyclopropyl)methoxy]-5-methoxypyridino[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (I-12-f)

[0241] The following were added: (R)-1-(7-chloro-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)-5-methoxypyridino[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (I-12-e, 2.16 g, 5.05 mmol), potassium phosphate (2.14 g, 10.1 mmol), and methanesulfonic acid (2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'-amino- 1,1'-Biphenyl-2-yl)palladium(II) (368 mg, 0.5 mmol) and ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)naphth-1-yl)ethynyl)triisopropylsilane (3.89 g, 7.58 mmol) were dissolved in 1,4-dioxane (20 mL) and water (2 mL) and reacted at 100 °C for 16 hours under nitrogen protection. The reaction solution was quenched with water, extracted with ethyl acetate, and the organic phase was collected, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by liquid chromatography (petroleum ether: ethyl acetate = 0-65%) to obtain the target product (R)-1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-2-((1-(hydroxymethyl)cyclopropyl)methoxy]-5-methoxypyridino[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (I-12-f, 1.80 g, yield 45.7%).

[0242] Step 6: Synthesis of (R)-(1-((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-4-(3-hydroxy-3-methylpiperidin-1-yl)-5-methoxypyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)4-methylbenzenesulfonate (I-12)

[0243] (R)-1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-2-((1-(hydroxymethyl)cyclopropyl)methoxy]-5-methoxypyridino[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (I-12-f, 1.80 g, 2.31 mmol) was dissolved in dichloromethane (18 mL), followed by the sequential addition of triethylamine (702.25 mg, 6.94 mmol) and 4-dimethylaminopyridine (28.22 mg, 0.231 mmol), and then added at 0 °C. p-Toluenesulfonyl chloride (1.32 g, 6.94 mmol) was reacted at room temperature for 4 hours. The reaction solution was directly purified by liquid chromatography (petroleum ether: ethyl acetate = 0–50%) to obtain the target product (R)-(1-((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-4-(3-hydroxy-3-methylpiperidin-1-yl)-5-methoxypyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)4-methylbenzenesulfonate (I-12, 250 mg, yield 11.6%).

[0244] Intermediate I-13

[0245] Intermediate I-13: Preparation of (R)-(1-((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)-5-methoxypyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)4-methylbenzenesulfonate (I-13)

[0246] Step 1: Preparation of (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy]-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (I-13-a)

[0247] The following ingredients were added: (R)-1-(7-chloro-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)-5-methoxypyridino[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (I-12-e, 1.04 g, 2.44 mmol), potassium phosphate (1.03 g, 4.88 mmol), and 5,7-dichloro-8-fluoro-2-(methylthio)pyridino[4,3-d]pyrimidin-4(3H)-one-2-(8-ethyl-7-fluoro-3-(methoxymethyl) (Oxy)naphthyl-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (1.05 g, 2.928 mmol) was dissolved in 1,4-dioxane (10 mL) and water (1 mL), and methanesulfonic acid (2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (177.22 mg, 0.244 mmol) was added. The reaction was carried out at 100 °C for 16 hours under nitrogen protection. The reaction solution was quenched with water, extracted with ethyl acetate, and the organic phase was collected, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then purified by liquid chromatography (petroleum ether: ethyl acetate = 0-85%) to obtain the target product (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy]-5-methoxypyridino[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (I-13-a, 870 mg, yield 56.96%).

[0248] Step 2: Synthesis of (R)-(1-((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)-5-methoxypyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)4-methylbenzenesulfonate (I-13)

[0249] (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy]-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (I-13-a, 870 mg, 1.39 mmol), triethylamine (421.9 mg, 4.17 mmol), and 4-dimethylaminopyridine (16.89 mg, 0.139 mmol) were dissolved in dichloromethane (8.7 mL), and p-methylpyridine was added at 0 °C. Benzenesulfonyl chloride (795 mg, 4.17 mmol) was reacted at room temperature for 3 hours. The reaction solution was directly purified by liquid chromatography (petroleum ether: ethyl acetate = 0–50%) to obtain the target product (R)-(1-((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)-5-methoxypyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)4-methylbenzenesulfonate methyl ester (I-13, 306 mg, yield 28.26%).

[0250] Example 1: Synthesis of 3-((4-(4-(7-(1-(((4-aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3,5]non-2-yl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione trifluoroacetate (1)

[0251] Step 1: Synthesis of tert-butyl 4-(4-((2,6-dioxadiazin-3-yl)amino)-2-fluorophenyl)piperazine-1-carboxylic acid (1-b)

[0252] 4-(4-amino-2-fluorophenyl)piperazine-1-carboxylic acid tert-butyl ester (1-a, 1 g, 3.38 mmol), 3-bromopiperidin-2,6-dione (1625 mg, 8.46 mmol), and sodium bicarbonate (996 mg, 11.85 mmol) were dissolved in N,N-dimethylformamide (10 ml) and reacted at 65 °C for 0.5 h. After cooling the reaction solution to room temperature, ethyl acetate was added, and the mixture was repeatedly washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by liquid chromatography (petroleum ether:ethyl acetate = 1:1) to obtain the target product 4-(4-((2,6-dioxadiazin-3-yl)amino)-2-fluorophenyl)piperazine-1-carboxylic acid tert-butyl ester (1-b, 1.29 g, yield 93.3%). ESI [M+H] + =406.20

[0253] Step 2: Synthesis of 3-(3-fluoro-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (1-c)

[0254] 4-(4-((2,6-dioxadiazin-3-yl)amino)-2-fluorophenyl)piperazine-1-carboxylic acid tert-butyl ester (1-b, 1.29 g, 3.17 mmol) was dissolved in acetonitrile (10 mL), and then 1,4-dioxane hydrochloride (10 mL) was added. The reaction was carried out at room temperature for 16 h. The reaction solution was then directly concentrated under reduced pressure to give the target product 3-(3-fluoro-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (1-c, 1.46 g, yield 151%). ESI[M+H] + =306.15

[0255] Step 3: Synthesis of tert-butyl 2-(4-((2,6-dioxadiazin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)-7-azaspiro[3.5]non-7-carboxylic acid (1-d)

[0256] 3-(3-fluoro-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (1-c, 370 mg, 1.21 mmol) and tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylic acid (346 mg, 1.44 mmol) were dissolved in methanol:acetic acid = 10:1 (5.5 ml) and reacted at room temperature for 1 h. Then sodium cyanoborohydride (228 mg, 3.62 mmol) was added, and the reaction was continued at room temperature for 1 h under nitrogen protection. The solution was quenched with water, extracted with ethyl acetate, and the organic phase was collected and repeatedly washed with saturated sodium chloride solution. After drying with anhydrous sodium sulfate, the solution was filtered, concentrated under reduced pressure, and purified by liquid chromatography (dichloromethane:methanol = 10:1) to obtain the target product 2-(4-((2,6-dioxadiazin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)-7-azaspiro[3.5]non-7-carboxylic acid tert-butyl ester (1-d, 313 mg, yield 49%). ESI[M+H] + =529.31

[0257] Step 4: Synthesis of 3-((4-(4-(7-azaspiro[3.5]non-2-yl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (1-e)

[0258] 2-(4-((2,6-dioxadiazin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)-7-azaspiro[3.5]non-7-carboxylic acid tert-butyl ester (1-d, 313 mg, 0.59 mmol) was dissolved in acetonitrile (3 ml), and then 1,4-dioxane hydrochloride (3 ml) was added. The reaction was carried out at room temperature for 16 h. The reaction solution was then concentrated under reduced pressure to obtain the target product 3-((4-(4-(7-azaspiro[3.5]non-2-yl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (1-e, 614 mg, yield 242%). ESI[M+H] + =429.25

[0259] Step 5: Synthesis of 3-(4-(4-(7-(1-((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3,5]non-2-yl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (1-f)

[0260] (1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl-4-methylbenzenesulfonate (I-1, 110 mg, 0.124 mmol), 3-((4-(4-(7-azaspiro[3.5]non-2-yl)piperazin-1-yl)-3-fluorophenyl)amino)piperidin-2,6-dione (I-e, 80 mg, 0.186 mmol), potassium iodide (21 mg, 0.126 mmol) and potassium carbonate (86 mg, 0.622 mmol) were dissolved in acetonitrile (2 ml) and heated in 6 The reaction was carried out at 0℃ for 6 hours, quenched with water, extracted with ethyl acetate, and the organic phase was collected and repeatedly washed with saturated sodium chloride solution. After drying with anhydrous sodium sulfate, the mixture was filtered, concentrated under reduced pressure, and purified by thin-layer chromatography on silica gel plates (dichloromethane:methanol = 10:1) to obtain the target product 3-(4-(4-(7-(1-((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3,5]non-2-yl)piperazin-1-yl)-3-fluorophenyl)amino)piperidin-2,6-dione (1-f, 40 mg, yield 28.3%). ESI[M+H] + =1141.62

[0261] Step 6: Synthesis of 3-(4-(4-(7-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3,5]non-2-yl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (1-g)

[0262] 3-(4-(4-(7-(1-((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3,5]non-2-yl)piperazin-1-yl)-3-fluorophenyl)amino)piperidin-2,6-dione (1-f, 40 mg, 0.035 mmol) was dissolved in N,N-dimethylformamide (2 ml), and then cesium fluoride (27 mg, 0.177 mmol) was added. The reaction was carried out at room temperature for 1 hour, quenched with water, extracted with ethyl acetate, and the organic phase was collected and repeatedly washed with saturated sodium chloride solution. After drying with anhydrous sodium sulfate, the mixture was filtered and concentrated under reduced pressure to give crude 3-(4-(4-(7-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3,5]non-2-yl)piperazin-1-yl)-3-fluorophenyl)amino)piperidin-2,6-dione (1 g, 40 mg, yield 117%). ESI[M+H + =985.48

[0263] Step 7: Synthesis of 3-((4-(4-(7-(1-(((4-aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione trifluoroacetate (1)

[0264] Dissolve -(4-(4-(7-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (1 g, 40 mg, 0.04 mmol) in acetonitrile (1 ml), add dioxane hydrochloride (0.2 ml), and react at room temperature for 0.5 hours. The reaction solution was purified by preparative liquid chromatography to obtain the target product 3-((4-(4-(7-(1-(((4-aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3,5]non-2-yl)piperazin-1-yl)-3-fluorophenyl)amino)piperidin-2,6-dione trifluoroacetate (1, 1.85 mg, yield 5%). ESI [M+H] + =941.46 1 H NMR(400MHz,DMSO-d6)δ10.83(s,1H),10.24(s,1H),9.96(s,1H),8.76(s,1H),8.01–7.94(m,1H), 7.50–7.46(m,1H),7.40(s,1H),7.17(s,1H),6.89–6.84(m,1H),6.55-6.53(m,1H),6.45-6.44(m,1 H),4.35–4.29(m,3H),4.01(s,3H),3.95(s,1H),3.76(s,4H),3.30–3.21(m,6H),2.96–2.91(m,6H ),2.76-2.70(m,4H),2.33(s,2H),2.09(s,2H),1.95–1.79(m,8H),1.62(s,4H),0.87-0.77(m,4H).

[0265] Example 2: Synthesis of 3-(6-(1-(1-((((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl(piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione trifluoroacetate (2)

[0266] Step 1: Synthesis of tert-butyl 4-((4-(3-(2,6-dioxoperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)methyl)piperidin-1-carboxylic acid (2-a)

[0267] 3-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)piperidin-2,6-dione (I-2, 250 mg, 0.57 mmol) was dissolved in acetonitrile (12.5 mL), followed by the addition of potassium carbonate (236 mg, 1.71 mmol) and tert-butyl 4-(iodomethyl)piperidin-1-carboxylate (205 mg, 0.63 mmol). The reaction mixture was reacted at 80 °C for 16 hours. The reaction solution was filtered, and the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by TLC (dichloromethane:methanol = 10:1) to obtain the target product tert-butyl 4-((4-(3-(2,6-dioxadipinidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)methyl)piperidin-1-carboxylate (2-a, 124 mg, yield 41.61%). (ESI)[M+H] + =524.5

[0268] Step 2: Synthesis of 3-(1-methyl-6-(1-(piperidin-4-ylmethyl)piperidin-4-yl)-1H-indazol-3-yl)piperidin-2,6-dione (2-b)

[0269] 4-((4-(3-(2,6-dioxadiazin-3-yl)-1-methyl-1H-indazole-6-yl)piperidin-1-yl)methyl)piperidin-1-carboxylic acid tert-butyl ester (2-a, 124 mg, 0.24 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (0.5 mL) was added. The reaction was carried out at room temperature for 0.5 hours. The solvent was removed by vacuum distillation to obtain the target product 3-(1-methyl-6-(1-(piperidin-4-ylmethyl)piperidin-4-yl)-1H-indazole-3-yl)piperidin-2,6-dione (2-b, 1.2 g). (ESI)[M+H] + =424.4.

[0270] Step 3: Synthesis of 3-(6-(1-(1-((((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-7-((triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methylpiperidin-4-methyl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (2-c)

[0271] (1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl-4-methylbenzenesulfonate (I-1, 292 mg, 0.33 mmol), potassium carbonate (249 mg, 1.8 mmol), potassium iodide (60 mg, 0.36 mmol), and 3-(1-methyl-6-(1-(piperidin-4-ylmethyl)piperidin-4-yl)-1H-indazol-3-yl)piperidin-2,6-dione (2-b, 211 mg, 0.5 mmol) were dissolved in acetonitrile (14 ml) and reacted at 60 °C for 6 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by TLC (dichloromethane:methanol = 100:13) to obtain the target product 3-(6-(1-(1-((((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-7-((triisopropylsilyl)ethynyl)naphth-1-yl)pyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methylpiperidin-4-methyl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (2-c, 141 mg, yield 37.60%).

[0272] Step 4: Synthesis of 3-(6-(1-(1-((((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl (2-d)

[0273] 3-(6-(1-(1-((((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-7-((triisopropylsilyl)ethynyl)naphth-1-yl)pyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methylpiperidin-4-methyl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (2-c, 100 mmol, 0.09 mmol) was dissolved in N,N-dimethylformamide (5 ml), and cesium fluoride (68 mmol, 0.45 mmol) was added. The reaction was carried out at room temperature for 1 h. After filtration of the reaction solution, the filtrate was distilled under reduced pressure using an oil pump to obtain the target product 3-(6-(1-(1-((((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl (2-d, 110 mg). (ESI)[M+H] +=980.6.

[0274] Step 5: Synthesis of 3-(6-(1-(1-((((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl(piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione trifluoroacetate (2)

[0275] 3-(6-(1-(1-((((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl (2-d, 110 mg, 0.11 mmol) was dissolved in acetonitrile (10 ml), and 1,4-dioxane hydrochloride solution (3 ml) was added. The reaction was carried out at room temperature for 1 hour. The reaction solution was distilled under reduced pressure to obtain the crude product. The crude product was separated by preparative liquid chromatography (aqueous phase: The target product, 3-(6-(1-(1-((((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl(piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione trifluoroacetate (2,53.88 mg, yield 45.69%), was obtained by purification with 0.01% trifluoroacetic acid (organic phase: acetonitrile). (ESI)[M+H] + =936.6. 1 H NMR (400MHz, DMSO-d6) δ10.94(s,1H),10.31(s,1H),9.75(s,1H),9.17-9.13(d,J=15.9Hz,2H),8.01-7.97(m,1H), 7.69-7.67(d,J=8.3Hz,1H),7.52-7.45(t,1H),7.41-7.40(d,J=2.3Hz,2H),7.19-7.18(d,J=2.5Hz,1H),7.04-7.0 2(d,J=8.5Hz,1H),4.41-4.27(m,3H),4.03-3.95(m,8H),3.81-3.71(m,3H),3.69-3.56(m,3H),3.25-3.19(t,1H), 3.11-2.92(m,6H),2.73-2.55(m,2H),2.41-2.32(m,1H),2.18-1.91(m,12H),1.67-1.49(m,6H),0.91-0.73(m,4H).

[0276] Example 3: Synthesis of 3-(6-(1-(7-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione trifluoroacetate (3)

[0277] Step 1: Synthesis of tert-butyl 2-(4-(3-(2,6-dioxadiazin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-7-azaspiro[3.5]non-7-carboxylic acid (3-a)

[0278] 3-(6-(piperidin-4-yl)-1H-indazole-3-yl)piperidin-2,6-dione (I-2, 500 mg, 1.53 mmol) was dissolved in methanol (15 mL) and tetrahydrofuran (5 mL), followed by the addition of 2-oxo-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (439 mg, 1.84 mmol) and acetic acid (92 mg, 1.53 mmol). The mixture was stirred at 55 °C for 1 h, followed by the addition of sodium cyanoborohydride (289 mg, 4.59 mmol), and the mixture was stirred at 55 °C for another 16 h. The solution was quenched with water, extracted with ethyl acetate, and the organic phase was collected and washed with saturated sodium chloride solution. After drying with anhydrous sodium sulfate, the solution was filtered, concentrated under reduced pressure, and purified by liquid chromatography (dichloromethane:methanol = 0%–10%) to obtain the target product 2-(4-(3-(2,6-dioxadiazin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-7-azaspiro[3.5]non-7-carboxylic acid tert-butyl ester (3-a, 283 mg, yield 33.7%). ESI[M+H] + =550.5

[0279] Step 2: Synthesis of 3-(6-(1-(7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (3-b)

[0280] 2-(4-(3-(2,6-dioxadiazin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-7-azaspiro[3.5]non-7-carboxylic acid tert-butyl ester (3-a, 283 mg, 0.51 mmol) was dissolved in acetonitrile (5 mL), and dioxane hydrochloride (1 mL) was slowly added. The reaction was carried out at room temperature for 1 h. After concentration under reduced pressure, crude product 3-(6-(1-(7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (3-b, 290 mg) was obtained. ESI[M+H]+=450.6

[0281] Step 3: Synthesis of 3-(6-(1-(7-(1-(((4-(aza-1-yl))-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (3-c)

[0282] (1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl-4-methylbenzenesulfonate (I-1, 100 mg, 0.113 mmol) and 3-(6-(1-(7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (3-b, 76 mg, 0.17 mmol) were dissolved in acetonitrile (5 mL), and potassium iodide (20 mg, 0.113 mmol) and potassium carbonate (78 mg, 0.565 mmol) were added sequentially. The mixture was stirred at 60 °C for 6 h. Quenching with water, extraction with ethyl acetate, collection of the organic phase and washing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtration, concentration under reduced pressure, and purification by thin-layer chromatography on silica gel plates (dichloromethane:methanol = 10:1) yielded the target product 3-(6-(1-(7-(1-(((4-(aza-1-yl))-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)pyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione (3-c, 40 mg, yield 30.5%).

[0283] Step 4: Synthesis of 3-(6-(1-(7-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (3-d)

[0284] 3-(6-(1-(7-(1-(((4-(aza-1-yl))-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)pyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (3-c, 40 mg, 0.034 mmol) was dissolved in N,N-dimethylformamide (2 mL), and cesium fluoride (26 mg, 0.172 mmol) was added. The mixture was reacted at room temperature for 1 h. Quenching with water, extraction with ethyl acetate, collection of the organic phase and washing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtration, and concentration under reduced pressure yielded the crude product 3-(6-(1-(7-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione (3-d, 30 mg). ESI[M+H] + =1006.6

[0285] Step 5: Synthesis of 3-(6-(1-(7-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione trifluoroacetate (3)

[0286] 3-(6-(1-(7-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione (3-d, 30 mg, 0.03 mmol) was dissolved in acetonitrile (1 mL), and dioxane hydrochloride (0.5 mL) was slowly added. The reaction was carried out at room temperature for 2 h. After concentration under reduced pressure, the crude product was purified by preparative liquid chromatography (aqueous phase: 0.01% trifluoroacetic acid, organic phase: acetonitrile) to obtain the target 3-(6-(1-(7-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione trifluoroacetate (3, 10 mg, yield 34.5%). ESI[M+H] + =962.6 1 H NMR(400MHz,DMSO-d6)δ10.94(s,1H),10.27(s,1H),10.04(s,1H),9.14(s,1H),8.86(s,1H),7.99-7.97 (m,1H),7.68-7.66(d,1H),7.53-7.37(m,3H),7.18(s,1H),7.03-7.00(d,1H),4.33-4.27(m,3H),4.00- 3.96(d,3H),3.98(s,2H),3.96(s,1H),3.69(s,2H),3.22(s,4H),3.22-2.89(d,6H),2.72-2.65(m,3H), 2.35(s,3H),2.22-2.01(m,6H),1.96(s,6H),1.83-1.62(d,4H),1.62(s,4H),0.88(s,2H),0.78(s,2H).

[0287] Example 4: Synthesis of 3-(6-(1-(2-(2-(((1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)amino)ethoxy)ethoxyoxy)acetyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione trifluoroacetate (4)

[0288] Step 1: Synthesis of tert-butyl(2-(2-(4-(3-(2,6-dioxoperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-oxoethoxy)ethoxyethyl)carbamate (4-a)

[0289] 3-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)piperidin-2,6-dione (I-2, 100 mg, 0.3 mmol), 2,2-dimethyl-4-oxo-3,8,11-trioxo-5-azatridecane-13-acid (95 mg, 0.36 mmol), 1-hydroxybenzotriazole (49 mg, 0.36 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (69 mg, 0.36 mmol) were dissolved in N,N-dimethylformamide (5 ml), and then N,N-diisopropylethylamine (194 mg, 1.5 mmol) was added. The mixture was reacted at room temperature for 5 hours. After the reaction was complete, the reaction solution was added to 50 ml of water, and extracted three times with 20 ml of ethyl acetate each time. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent, yielding the crude target product, tert-butyl(2-(2-(4-(3-(2,6-dioxoperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-oxoethoxy)ethoxyethyl)carbamate (4-a, 112 mg). (ESI)[M+H] + =572.7.

[0290] Step 2: Synthesis of 3-(6-(1-(2-(2-aminoethoxy)ethoxyacetyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (4-b)

[0291] Tert-butyl(2-(2-(2-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-oxoethoxy)ethoxyethyl)carbamate (4-a, 112 mg, 0.2 mmol) was dissolved in dichloromethane (5 ml), and trifluoroacetic acid (1 ml) was added. The reaction was carried out at room temperature for 1 hour. The solvent was removed by vacuum distillation to obtain the target product 3-(6-(1-(2-(2-aminoethoxy)ethoxyacetyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (4-b, 200 mg). (ESI)[M+H] + =472.6.

[0292] Step 3: Synthesis of 3-(6-(1-(2-(2-(1-(((4-(aza-1-yl))-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)amino)ethoxy)ethoxyoxy)acetyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (4-c)

[0293] (1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl-4-methylbenzenesulfonate (I-1, 100 mg, 0.11 mmol), potassium carbonate (76 mg, 0.55 mmol), potassium iodide (18 mg, 0.11 mmol), 3-(6-(1-(2-(2-aminoethoxy)ethoxyacetyl)piperidin-4-yl)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione (4-b, 78 mg, 0.17 mmol) were dissolved in acetonitrile (5 ml) and reacted at 60 °C for 6 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by TLC (dichloromethane:methanol = 100:13) to obtain the target product 3-(6-(1-(2-(2-(1-(((4-(aza-1-yl))-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)amino)ethoxy)ethoxy)acetyl)piperidin-4-yl)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione (4-c, 48 mg, yield 36.84%).

[0294] Step 4: Synthesis of 3-(6-(1-(2-(2-(-2-)(((1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)amino)ethoxyethoxyacetyl)piperidin-4-yl)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione (4-d)

[0295] 3-(6-(1-(2-(2-(1-(((4-(aza-1-yl))-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)amino)ethoxy)ethoxy)acetyl)piperidin-4-yl)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione (4-c, 48 mmol, 0.04 mmol) was dissolved in N,N-dimethylformamide (5 ml), and cesium fluoride (61 mmol, 0.4 mmol) was added. The reaction was carried out at room temperature for 1 h. After filtration of the reaction solution, the filtrate was distilled under reduced pressure using an oil pump to obtain the target product 3-(6-(1-(2-(2-(-2-)(((1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)amino)ethoxyethoxyacetyl)piperidin-4-yl)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione (4-d, 33 mg, yield 80.49%). (ESI)[M+H + =1029.5.

[0296] Step 5: Synthesis of 3-(6-(1-(2-(2-(((1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)amino)ethoxy)ethoxyoxy)acetyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione trifluoroacetate (4)

[0297] 3-(6-(1-(2-(2-)(((1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)amino)ethoxyethoxyacetyl)piperidin-4-yl)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione (4-d, 33 mg, 0.03 mmol) was dissolved in acetonitrile (5 ml), and 1,4-dioxane hydrochloride solution (1 ml) was added. The reaction was carried out at room temperature for 0.5 hours. The reaction solution was then subjected to a reduction test. The crude product was obtained by pressure distillation, and purified by preparative liquid chromatography (aqueous phase: 0.01% trifluoroacetic acid, organic phase: acetonitrile) to obtain the target product 3-(6-(1-(2-(2-(((1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)amino)ethoxy)ethoxyoxy)acetyl)piperidin-4-yl)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione trifluoroacetate (4,9.71 mg, yield 29.42%). (ESI)[M+H + =984.9. 1 H NMR(400MHz,DMSO-d6)δ10.17(s,1H),7.99-7.95(m,1H),7.48-7.44(t,1H),7.39-7.38 (d,J=2.6Hz,1H),7.24-7.23(d,J=2.4Hz,1H),5.37(s,0.5H),5.23(s,0.5H),4.21-4.0 4(m,3H),3.92-3.79(m,2H),3.65-3.60(m,1H),3.52-3.47(m,2H),3.15-2.98(m,4H),2 .89-2.83(m,1H),2.70(s,3H),2.19-2.00(m,5H),1.89-1.74(m,3H),1.65-1.59(m,2H).

[0298] Example 5: Synthesis of 5-(4-(7-((1-((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoropyridyl[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione trifluoroacetate (5)

[0299] Step 1: Synthesis of tert-butyl 4-(2-(2,6-dioxadiazin-3-yl)-1,3-dioxoisoindoline-5-yl)piperazine-1-carboxylic acid (5-b)

[0300] 2-(2,6-dioxohesperidin-3-yl)-5-fluoroisoindoline-1,3-dione (5-a, 400 mg, 1.45 mmol), piperazine-1-carboxylic acid tert-butyl ester (272 mg, 1.45 mmol), and triethylamine (440 mg, 4.35 mmol) were dissolved in dimethyl sulfoxide (10 mL) and reacted in a microwave at 100 °C for 1 hour. The reaction mixture was extracted three times with ethyl acetate after adding water. The organic phase was concentrated under reduced pressure and separated by liquid chromatography to obtain the target product 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperazine-1-carboxylic acid tert-butyl ester (5-b, 600 mg, yield 93%), ESI [M+H]. + =442.47

[0301] Step 2: Synthesis of 2-(2,6-dioxadipinidin-3-yl)-5-(piperazin-1-yl)isoindole-1,3-dione (5-c)

[0302] 4-(2-(2,6-dioxadipinidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperazine-1-carboxylic acid tert-butyl ester (5-b, 600 mg, 1.35 mmol) was dissolved in dichloromethane (6 ml) and trifluoroacetic acid (2 ml) was added. The reaction was carried out at room temperature for 1 hour. After concentration under reduced pressure, the target product 2-(2,6-dioxadipinidin-3-yl)-5-(piperazine-1-yl)isoindoline-1,3-dione (5-c, 700 mg, crude) was obtained, ESI [M+H]. + =342.36

[0303] Step 3: Synthesis of tert-butyl 2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperazin-1-yl)-7-azaspiro[3.5]non-7-carboxylic acid (5-d)

[0304] 2-(2,6-dioxadiazin-3-yl)-5-(piperazin-1-yl)isoindol-1,3-dione (5-c, 230 mg, 0.67 mmol) and tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylic acid (193 mg, 0.80 mmol) were dissolved in methanol (9 ml) and acetic acid (1 ml). After reacting at room temperature for 1 h, sodium cyanoborohydride (126 mg, 2.00 mmol) was added. The reaction was then allowed to proceed for another 1 h at room temperature. The solution was quenched with water, extracted three times with dichloromethane, and the organic phase was collected and washed with saturated sodium chloride solution. After drying with anhydrous sodium sulfate, the solution was filtered, concentrated under reduced pressure, and then separated by liquid chromatography to obtain the target product 2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperazin-1-yl)-7-azaspiro[3.5]non-7-carboxylic acid tert-butyl ester (5-d, 380 mg, crude), ESI[M+H]. + =565.67

[0305] Step 4: Synthesis of 5-(4-(7-azaspiro[3.5]non-2-yl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (5-e)

[0306] 2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperazin-1-yl)-7-azaspiro[3.5]non-7-carboxylic acid tert-butyl ester (5-d, 380 mg, 0.67 mmol) was dissolved in acetonitrile (10 ml), and dioxane hydrochloride (3 ml) was added. The reaction mixture was reacted at room temperature for 1 hour. The reaction solution was concentrated to dryness to obtain the target product 5-(4-(7-azaspiro[3.5]non-2-yl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (5-e, 450 mg, crude), ESI[M+H] + =465.55

[0307] Step 5: Synthesis of 5-(4-(7-((1-(((4-(azacyclopent-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-7-((triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3,5]non-2-yl)piperazin-1-yl)-2-(2,6-dioxypiperidin-3-yl)isoindoline-1,3-dione (5-f)

[0308] 5-(4-(7-azaspiro[3.5]non-2-yl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindol-1,3-dione (5-e, 52 mg, 0.11 mmol), (1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl-4-methylbenzenesulfonate (I-1, 100 mg, 0.11 mmol), potassium carbonate (75 mg, 0.55 mmol) and potassium iodide (19 mg, 0.11 mmol) were dissolved in dimethyl sulfoxide (2 ml), and the mixture was heated to 60 °C and reacted for 2 hours. The reaction solution was extracted and concentrated with ethyl acetate and purified by thin-layer chromatography on silica gel plates to obtain the target product 5-(4-(7-((1-(((4-(azacyclopent-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-7-((triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3,5]non-2-yl)piperazin-1-yl)-2-(2,6-dioxypiperidin-3-yl)isoindoline-1,3-dione (5-f, 30 mg, crude).

[0309] Step 6: Synthesis of 5-(4-(7-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3,5]non-2-yl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (5-g)

[0310] 5-(4-(7-((1-(((4-(azacyclopent-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-7-((triisopropylsilyl)ethynyl)naphth-1-yl)pyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3,5]non-2-yl)piperazin-1-yl)-2-(2,6-dioxypiperidin-3-yl)isoindoline-1,3-dione (5-f, 30 mg, 0.025 mmol) and cesium fluoride (19 mg, 0.125 mmol) were dissolved in NN dimethylformamide (1 ml) and reacted at room temperature for 1 hour. The reaction solution was extracted and concentrated with ethyl acetate to obtain the target product 5-(4-(7-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3,5]non-2-yl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindol-1,3-dione (5-g, 25mg, crude), ESI[M+H) + =1022.17

[0311] Step 7: Synthesis of 5-(4-(7-((1-((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoropyridyl[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione trifluoroacetate (5)

[0312] 5-(4-(7-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3,5]non-2-yl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindol-1,3-dione (5-g, 25mg, 0.024mmol) was dissolved in acetonitrile (1ml), and dioxane hydrochloride (0.2ml) was added. The mixture was reacted at room temperature for 1 hour. After concentration, the product was separated by preparative liquid chromatography (aqueous phase: 0.01% trifluoroacetic acid, organic phase: acetonitrile) to obtain the target product 5-(4-(7-((1-((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoropyridinyl[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione trifluoroacetate (5, 1.74 mg, yield 7.2%) ESI[M+H) + =978.11, 1 H NMR (400MHz, CD3OD) δ9.58(s,1H),9.14(s,1H),8.46(s,1H),7.95–7.85(m,1H),7.79–7. 77(m,1H),7.63–7.57(m,1H),7.49–7.47(m,1H),7.41–7.30(m,2H),7.24–7.23(m,1H),5. 13–5.08(m,2H),4.55–4.43(m,2H),4.29–4.02(m,4H),3.59(m,9H),3.21–2.65(m,8H),2 .61–2.45(m,2H),2.41–1.84(m,10H),1.73(s,2H),1.39–1.13(m,4H),1.03–0.88(m,4H).

[0313] Example 6: Synthesis of 3-(6-(1-(7-(1-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-carbonyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione trifluoroacetate (6)

[0314] Step 1: Synthesis of tert-butyl 2-(4-(3-(2,6-dioxadiazin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-7-azaspiro[3.5]non-7-carboxylic acid (6-a)

[0315] 3-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)piperidin-2,6-dione (I-2, 1 g, 3.06 mmol) was dissolved in methanol:tetrahydrofuran (4:1, 10 ml), acetic acid (184 mg, 3.06 mmol) and tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylic acid (1466 mg, 6.12 mmol) were added, and the mixture was reacted at 55 °C for 1 hour. Then sodium cyanoborohydride (960 mg, 15.27 mmol) was added, and the reaction was continued at 55 °C for 16 hours. The solution was quenched with water, extracted with ethyl acetate, and the organic phase was collected and repeatedly washed with saturated sodium chloride solution. After drying with anhydrous sodium sulfate, the solution was filtered, concentrated under reduced pressure, and then separated by liquid chromatography (dichloromethane:methanol = 10:1) to obtain the target product 2-(4-(3-(2,6-dioxadiazin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-7-azaspiro[3.5]non-7-carboxylic acid tert-butyl ester (6-a, 850 mg, yield 20%). ESI[M+H] + =549.72

[0316] Step 2: Synthesis of 3-(6-(1-(7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (6-b)

[0317] 2-(4-(3-(2,6-dioxadiazin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-7-azaspiro[3.5]non-7-carboxylic acid tert-butyl ester (6-a, 350 mg, 0.63 mmol) was dissolved in acetonitrile (3 ml), and then 1,4-dioxane hydrochloride (3 ml) was added. The reaction was carried out at room temperature for 0.5 hours. The reaction solution was directly concentrated under reduced pressure to obtain the target product 3-(6-(1-(7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (6-b, 600 mg) ESI[M+H] + =449.60

[0318] Step 3: Synthesis of tert-butyl 4-(2-(4-(3-(2,6-dioxypiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-7-azaspiro[3.5]non-7-carbonyl)piperidin-1-carboxylic acid (6-c)

[0319] (3-(6-(1-(7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (6-b, 600 mg, 1.33 mmol) was dissolved in N,N-dimethylformamide (6 ml), followed by the addition of 1-hydroxybenzotriazole (360 mg, 2.66 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (512 mg, 2.66 mmol), triethylamine (405 mg, 3.99 mmol), and 1-(tert-butyloxycarbonyl)piperidin- 4-Carboxylic acid (367 mg, 1.60 mmol) was reacted at room temperature for 16 hours. The reaction solution was added to ethyl acetate and repeatedly washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by liquid chromatography (dichloromethane:methanol = 10:1) to obtain the target product tert-butyl 4-(2-(4-(3-(2,6-dioxypiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-7-azaspiro[3.5]non-7-carbonyl)piperidine-1-carboxylic acid (6-c, 76 mg, yield 9%). ESI[M+H] + =660.86

[0320] Step 4: Synthesis of 3-(1-methyl-6-(1-(7-(piperidin-4-carbonyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1H-indazol-3-yl)piperidin-2,6-dione (6-d)

[0321] (4-(2-(4-(3-(2,6-dioxypiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-7-azaspiro[3.5]non-7-carbonyl)piperidin-1-carboxylic acid tert-butyl ester (6-c, 76 mg, 0.11 mmol) was dissolved in acetonitrile (1 ml), and 1,4-dioxane hydrochloride (1 ml) was added. The reaction was carried out at room temperature for 0.5 hours. The reaction solution was directly concentrated under reduced pressure to obtain the target product 3-(1-methyl-6-(1-(7-(piperidin-4-carbonyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1H-indazol-3-yl)piperidin-2,6-dione (6-d, 100 mg, 163%). ESI[M+H] + =560.74

[0322] Step 5: Synthesis of 3-(6-(1-(7-(1-(1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy))-8-((triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-carbonyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione (6-e)

[0323] (1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl-4-methylbenzenesulfonate (I-1, 105 mg, 0.11 mmol), 3-(1-methyl-6-(1-(7-(piperidin-4-carbonyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1H-indazol-3-yl)piperidin-2,6-dione (6-d, 100 mg, 0.17 mmol), potassium iodide (20 mg, 0.12 mmol) and potassium carbonate (82 mg, 0.59 mmol) were dissolved in acetonitrile (3 ml) and heated at 60 °C. The reaction was carried out for 8 hours, quenched with water, extracted with ethyl acetate, and the organic phase was collected and repeatedly washed with saturated sodium chloride solution. After drying with anhydrous sodium sulfate, the mixture was filtered, concentrated under reduced pressure, and purified by thin-layer chromatography on silica gel plates (dichloromethane:methanol = 10:1) to obtain the target product 3-(6-(1-(7-(1-(1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy))-8-((triisopropylsilyl)ethynyl)naphth-1-yl)pyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-carbonyl)-7-azaspiro[3,5]non-2-yl)piperidin-4-yl)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione (6-e, 10 mg, yield 7.1%). ESI[M+H] + =1273.70

[0324] Step 6: Synthesis of 3-(6-(1-(7-(1-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-carbonyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione (6-f)

[0325] 3-(6-(1-(7-(1-(1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy))-8-((triisopropylsilyl)ethynyl)naphth-1-yl)pyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-carbonyl)-7-azaspiro[3,5]non-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (6-e, 10 mg, 0.007 mmol) was dissolved in N,N-dimethylformamide (1 ml), and then cesium fluoride (6 mg, 0.039 mmol) was added. The reaction was carried out at room temperature for 1 hour, quenched with water, extracted with ethyl acetate, and the organic phase was collected and repeatedly washed with saturated sodium chloride solution. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product 3-(6-(1-(7-(1-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-carbonyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione (6-f, 15 mg). ESI[M+H] + =1117.36

[0326] Step 7: Synthesis of 3-(6-(1-(7-(1-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-carbonyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione trifluoroacetate (6)

[0327] 3-(6-(1-(7-(1-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-carbonyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione (6-f, 15 mg, 0.013 mmol) was dissolved in acetonitrile (1 ml), and dioxane hydrochloride (0.2 ml) was added. The reaction was carried out at room temperature for 0.5 hours. The reaction solution was purified by preparative liquid chromatography (aqueous phase: 0.01% trifluoroacetic acid, organic phase: acetonitrile) to obtain the target product 3-(6-(1-(7-(1-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-carbonyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione trifluoroacetate (6, 1.28 mg, yield 9.1%). ESI[M+H] + =1073.30, 1 H NMR(600MHz,CD3OD)δ9.13(s,1H),7.89-7.87(m,1H),7.71-7.69(m,1H),7.39-7.37(m,1H),7.35-7.32(m,1H), 7.25-7.23(m,1H),7.11-7.09(m,1H),4.56-4.54(m,1H),4.42-4.35(m,2H),4.112-4.11(m,3H),4.02(s,2H),3. 90-3.88(m,3H),3.74(s,1H),3.64-3.50(m,6H),3.41(s,1H),3.18(s,1H),3.07-2.95(m,6H),2.80-2.71(m,2H) ,2.58-2.30(m,6H),2.20-2.02(m,12H),1.72(s,6H),1.64-1.60(m,2H),1.28(s,2H),0.99(s,2H),0.88(s,2H).

[0328] Example 7: Synthesis of 3-(6-(1-(2-(2-((1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)amino)ethoxy)acetyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione trifluoroacetate (7)

[0329] Step 1: Synthesis of tert-butyl 2-(4-(3-(2,6-dioxadiazin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-7-azaspiro[3.5]non-7-carboxylic acid (7-a)

[0330] 3-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)piperidin-2,6-dione (I-2, 100 mg, 0.3 mmol) was dissolved in N,N-dimethylformamide (5 ml), and 1-hydroxybenzotriazole (50 mg, 0.36 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (70 mg, 0.36 mmol), N,N-diisopropylethylamine (198 mg, 1.52 mmol) and 2-(2-((tert-butoxycarbonyl)amino)ethoxy)acetic acid (10-a, 81 mg, 0.36 mmol) were added sequentially. The mixture was reacted at room temperature for 1 hour. The solution was quenched with water, extracted with ethyl acetate, and the organic phase was collected and repeatedly washed with saturated sodium chloride solution. After drying with anhydrous sodium sulfate, the solution was filtered and concentrated under reduced pressure to obtain the target product, 2-(4-(3-(2,6-dioxadiazin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-7-azaspiro[3.5]non-7-carboxylic acid tert-butyl ester (7-a, 94 mg, yield 59.4%). (ESI[M+H]) + =527.62

[0331] Step 2: Synthesis of 3-(6-(1-(2-(2-aminoethoxy)acetyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (7-b)

[0332] 2-(4-(3-(2,6-dioxadiazin-3-yl)-1-methyl-1H-indazole-6-yl)piperidin-1-yl)-7-azaspiro[3.5]non-7-carboxylic acid tert-butyl ester (7-a, 94 mg, 0.17 mmol) was dissolved in dichloromethane (1 ml), and then trifluoroacetic acid (1 ml) was added. The reaction was carried out at room temperature for 1 hour. The reaction solution was directly concentrated under reduced pressure to obtain the target product 3-(6-(1-(2-(2-aminoethoxy)acetyl)piperidin-4-yl)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione (7-b, 120 mg), ESI[M+H] + =427.51

[0333] Step 3: Synthesis of 3-(6-(1-(2-(2-((1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy))naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)amino)ethoxy)acetyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (7-c)

[0334] (1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl-4-methylbenzenesulfonate (I-1, 166 mg, 0.18 mmol), 3-(6-(1-(2-(2-aminoethoxy)acetyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (7-b, 120 mg, 0.28 mmol), potassium iodide (31 mg, 0.18 mmol), and potassium carbonate (129 mg, 0.9 mmol) were dissolved in acetonitrile ( 5 ml), reacted at 60℃ for 8 hours, quenched with water, extracted with ethyl acetate, collected the organic phase and washed repeatedly with saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by thin-layer chromatography on silica gel plates (dichloromethane:methanol = 10:1) to obtain the target product 3-(6-(1-(2-(2-((1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy))naphth-1-yl)pyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)amino)ethoxy)acetyl)piperidin-4-yl)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione (7-c, 50 mg, yield 24%).

[0335] ESI[M+H] + =1140.46

[0336] Step 4: Synthesis of 3-(6-(1-(2-(2-((1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)amino)ethoxy)acetyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (7-d)

[0337] 3-(6-(1-(2-(2-((1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy))naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)amino)ethoxy)acetyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (7-c, 50 mg, 0.043 mmol) was dissolved in N,N-dimethylformamide (3 ml), then cesium fluoride (33 mg, 0.22 mmol) was added, and the reaction was carried out at room temperature for 1 hour. The solution was quenched in water, extracted with ethyl acetate, and the organic phase was collected and repeatedly washed with saturated sodium chloride solution. After drying with anhydrous sodium sulfate, the solution was filtered and concentrated under reduced pressure to give crude 3-(6-(1-(2-(2-((1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)amino)ethoxy)acetyl)piperidin-4-yl)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione (7-d, 25 mg, yield 59.5%). ESI[M+H + =983.12

[0338] Step 5: Synthesis of 3-(6-(1-(2-(2-((1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)amino)ethoxy)acetyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione trifluoroacetate (7)

[0339] 3-(6-(1-(2-(2-((1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)amino)ethoxy)acetyl)piperidin-4-yl)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione (7-d, 25 mg, 0.025 mmol) was dissolved in acetonitrile (2 ml), and dioxane hydrochloride (0.4 ml) was added. The mixture was reacted at room temperature for 0.5 hours. The reaction solution was purified by preparative liquid chromatography (aqueous phase: 0.01% trifluoroacetic acid, organic phase: acetonitrile) to obtain the target product 3-(6-(1-(7-(1-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-carbonyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione trifluoroacetate (7, 0.58 mg, yield 2.5%). ESI[M+H] + =940.07, 1 H NMR(600MHz,CD3OD)δ8.92-8.91(m,1H),7.87-7.84(m,1H),7.62–7.56(m,1H),7.36–7.29(m,3H),7. 17-7.16(m,1H),7.04-7.03(m,1H),4.67–4.51(m,4H),4.42–4.29(m,4H),4.11–4.024(m,4H),3.95-3 .94(m,3H),3.84–3.81(m,4H),3.63-3.62(m,1H),2.99-2.94(m,1H),2.79-2.65(m,4H),2.43–2.39(m ,2H),2.29-2.24(m,2H),1.97-1.92(m,4H),1.78–1.55(m,8H),0.67–0.59(m,2H),0.52-0.47(m,2H).

[0340] Example 8: Synthesis of 3-(6-(1-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoropyridinium[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)-5,8-11-trioxo-2-azatridecane-13-acyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione trifluoroacetate (8)

[0341] Step 1: Synthesis of tert-butyl(2-(2-(-2-(4-(3-(2,6-dioxoperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-oxoethoxy)ethoxyethyl)carbamate (8-a)

[0342] 3-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)piperidin-2,6-dione (I-2, 106 mg, 0.325 mmol), 2,2-dimethyl-4-oxo-3,8,11,14-tetraoxo-5-azahexadecane-16-acid (100 mg, 0.325 mmol) and N,N-diisopropylethylamine (127 mg, 0.98 mmol) were dissolved in N,N-dimethylformamide (3 ml), and then 1-hydroxybenzotriazole (54 mg, 0.4 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (77 mg, 0.4 mmol) were added. The mixture was reacted at room temperature for 5 hours. The reaction solution was extracted three times with ethyl acetate after adding water. The organic phase was concentrated under reduced pressure to give the target product, tert-butyl(2-(2-(-2-(4-(3-(2,6-dioxoperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-oxoethoxy)ethoxyethyl)carbamate (8-a, 70 mg, yield 53%), ESI[M+H). + =616.4

[0343] Step 2: Synthesis of 3-(6-(1-(2-(2-(2-[(2-aminoethoxy)ethoxy]acetyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (8-b)

[0344] Tert-butyl(2-(2-(2-(-2-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-oxoethoxy)ethoxyethyl)carbamate (8-a, 70 mg, 0.11 mmol) was dissolved in dichloromethane (1.5 ml) and trifluoroacetic acid (0.5 ml) was added. The reaction was carried out at room temperature for 1 hour. After concentration under reduced pressure, the target product 3-(6-(1-(2-(2-(2-[(2-aminoethoxy)ethoxy]acetyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (8-b, 90 mg, crude) was obtained, ESI[M+H]. + =516.3

[0345] Step 3: Synthesis of 3-(6-(1-(1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-7-((triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)-5,8-11-trioxo-2-azatridecane-13-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (8-c)

[0346] Dissolve (1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl-4-methylbenzenesulfonate (I-1, 170 mg, 0.192 mmol), potassium carbonate (121 mg, 0.875 mmol), potassium iodide (30 mg, 0.175 mmol), 3-(6-(1-(2-(2-(2-[(2-aminoethoxy)ethoxy]acetyl)piperidin-4-yl)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione (8-b, 115 mg, 0.2 mmol) in water) The reaction mixture was reacted in acetonitrile (5 ml) at 60 °C for 16 hours. After the reaction was complete, the reaction solution was filtered, and water was added. The solution was then extracted three times with ethyl acetate. The organic phase was concentrated under reduced pressure and purified by TLC (dichloromethane / methanol = 10 / 1) to obtain the target product 3-(6-(1-(1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-7-((triisopropylsilyl)ethynyl)naphth-1-yl)pyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)-5,8-11-trioxo-2-azatridecane-13-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (8-c, 45 mg, yield 21%).

[0347] Step 4: Synthesis of 3-(6-(1-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)-5,8-11-trioxo-2-azatridecane-13-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (8-d)

[0348] 3-(6-(1-(1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-7-((triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)-5,8-11-trioxo-2-azatridecane-13-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (8-c, 45 mg, 0.037 mmol) was dissolved in N,N-dimethylformamide (1 ml), and cesium fluoride (28 mg, 0.185 mmol) was added. The mixture was reacted at room temperature for 1 h. The reaction solution was extracted three times with ethyl acetate after adding water. The organic phase was concentrated under reduced pressure to obtain the target product 3-(6-(1-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)-5,8-11-trioxo-2-azatridecane-13-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (8-d, 50 mg, crude product). (ESI)[M+H] + =1073.2

[0349] Step 5: Synthesis of (3-(6-(1-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoropyridinium[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)-5,8-11-trioxo-2-azatridecane-13-acyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione trifluoroacetate (8)

[0350] 3-(6-(1-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)-5,8-11-trioxo-2-azatridecane-13-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (8-d, 50 mg, 0.046 mmol) was dissolved in acetonitrile (3 ml), and 1,4-dioxane hydrochloride solution (0.5 ml) was added. The mixture was reacted at room temperature for 1 hour. The reaction solution was distilled under reduced pressure to obtain a crude product, which was then purified by preparative liquid chromatography (aqueous phase: 0.01% trifluoroacetic acid, organic phase: acetonitrile) to obtain the target product 3-(6-(1-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoropyridinium[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)-5,8-11-trioxo-2-azatridecane-13-acyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione trifluoroacetate (8, 1.6 mg, yield 3.3%). (ESI)[M+H] + =1029.4. 1 H NMR(400MHz,DMSO-d6)δ10.87(s,1H),10.28(s,1H),9.11(s,1H),8.52(s,1H),8.06-7.93(m,1 H),7.62-7.60(m,1H),7.51-7.40(m,2H),7.17(s,1H),7.03-6.97(m,1H),4.50-4.46(m,2H),4. 36-3.83(m,9H),3.72-3.48(m,7H),3.45-3.35(m,7H),3.32-3.21(m,4H),3.19-3.01(m,3H),2 .98-2.73(m,2H),2.72-2.57(m,2H),2.42-2.09(m,3H),2.07-1.36(m,10H),0.53-0.39(m,4H).

[0351] Example 9: Synthesis of 3-(6-(1'-(1-((((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-carbonyl)-[1,4'-bispiperidin]-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione trifluoroacetate (9)

[0352] Step 1: Synthesis of tert-butyl 4-(3-(2,6-dioxadiazin-3-yl)-1-methyl-1H-indazol-6-yl)-[1,4'-dipiperidine]-1'-carboxylic acid (9-a)

[0353] 3-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)piperidin-2,6-dione (I-2, 150 mg, 0.46 mmol), potassium carbonate (318 mg, 2.3 mmol), and tert-butyl 4-iodopiperidin-1-carboxylate (215 mg, 0.69 mmol) were dissolved in acetonitrile (7 mL) and reacted at 80 °C for 16 hours. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by TLC (dichloromethane:methanol = 10:1) to obtain the target product tert-butyl 4-(3-(2,6-dioxadipinidin-3-yl)-1-methyl-1H-indazol-6-yl)-[1,4'-dipiperidin]-1'-carboxylic acid (9-a, 15 mg, yield 6.41%). (ESI)[M+H] + =510.7.

[0354] Step 2: Synthesis of 3-(6-([1,4'-dipiperidin]-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (9-b)

[0355] 4-(3-(2,6-dioxadiazin-3-yl)-1-methyl-1H-indazole-6-yl)-[1,4'-dipiperidine]-1'-carboxylic acid tert-butyl ester (9-a, 15 mg, 0.03 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (0.5 mL) was added. The reaction was carried out at room temperature for 0.5 hours. The solvent was removed by vacuum distillation to obtain the target product 3-(6-([1,4'-dipiperidine]-4-yl)-1-methyl-1H-indazole-3-yl)piperidine-2,6-dione (9-b, 27 mg). (ESI)[M+H] + =410.7.

[0356] Step 3: Synthesis of tert-butyl piperidine-1-carboxylate (4-(4-(3-(2,6-dioxadipinidin-3-yl)-1-methyl-1H-indazol-6-yl)-[1,4'-dipiperidine]-1'-carbonyl)piperidine-1-carboxylate (9-c)

[0357] 3-(6-([1,4'-dipiperidin]-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (9-b, 27 mg, 0.07 mmol), 1-(tert-butoxycarbonyl)piperidin-4-carboxylic acid (19 mg, 0.08 mmol), 1-hydroxybenzotriazole (11 mg, 0.08 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (15 mg, 0.08 mmol) were dissolved in N,N-dimethylformamide (4 ml), and then N,N-diisopropylethylamine (36 mg, 0.28 mmol) was added. The mixture was reacted at room temperature for 2 hours. After the reaction was complete, the reaction solution was added to 50 ml of water, and extracted three times with 20 ml of ethyl acetate each time. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent, yielding the target product, tert-butyl 4-(4-(3-(2,6-dioxadiazin-3-yl)-1-methyl-1H-indazol-6-yl)-[1,4'-dipiperidine]-1'-carbonyl)piperidine-1-carboxylic acid (9-c, 35 mg). (ESI)[M+H] + =622.0.

[0358] Step 4: Synthesis of 3-(1-methyl-6-(1'-(piperidin-4-carbonyl)-[1,4'-dipiperidin]-4-yl)-1H-indazol-3-yl)piperidin-2,6-dione (9-d)

[0359] 4-(4-(3-(2,6-dioxadiazin-3-yl)-1-methyl-1H-indazole-6-yl)-[1,4'-dipiperidine]-1'-carbonyl)piperidine-1-carboxylic acid tert-butyl ester (9-c, 35 mg, 0.06 mmol) was dissolved in dichloromethane (4 ml), and trifluoroacetic acid (0.5 ml) was added. The reaction was carried out at room temperature for 0.5 hours. The solvent was removed by vacuum distillation to obtain the target product 3-(1-methyl-6-(1'-(piperidine-4-carbonyl)-[1,4'-dipiperidine]-4-yl)-1H-indazole-3-yl)piperidine-2,6-dione (9-d, 53 mg).

[0360] Step 5: Synthesis of 3-(6-(1'-(1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-carbonyl)-[1,4'-bispiperidin]-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (9-e)

[0361] (1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl-4-methylbenzenesulfonate (I-1, 62 mg, 0.07 mmol), potassium carbonate (12 mg, 0.35 mmol), potassium iodide (12 mg, 0.07 mmol), 3-(1-methyl-6-(1'-(piperidin-4-carbonyl)-[1,4'-dipiperidin]-4-yl)-1H-indazole-3-yl)piperidin-2,6-dione (9-d, 53 mg, 0.1 mmol) was dissolved in acetonitrile (3 ml) and reacted at 60 °C for 6 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by TLC (dichloromethane:methanol = 100:13) to obtain the target product 3-(6-(1'-(1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-carbonyl)-[1,4'-bispiperidin]-4-yl)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione (9-e, 13 mg, yield 17.33%).

[0362] Step 6: Synthesis of 3-(6-(1'-(1-((((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-carbonyl)-[1,4'-bispiperidin]-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (9-f)

[0363] 3-(6-(1'-(1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-carbonyl)-[1,4'-bispiperidin]-4-yl)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione (9-e, 13 mg, 0.01 mmol) was dissolved in N,N-dimethylformamide (2 ml), and cesium fluoride (40 mg, 0.26 mmol) was added. The mixture was reacted at room temperature for 0.5 h. After filtration of the reaction solution, the filtrate was distilled under reduced pressure using an oil pump to obtain the target product 3-(6-(1'-(1-((((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-carbonyl)-[1,4'-bispiperidin]-4-yl)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione (9-f, 13 mg). (ESI)[M+H + =1076.8.

[0364] Step 7: Synthesis of 3-(6-(1'-(1-((((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-carbonyl)-[1,4'-bispiperidin]-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione trifluoroacetate (9)

[0365] Preparation of 3-(6-(1'-(1-((((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-carbonyl)-[1,4'-bispiperidin]-4-yl)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione (9-f, 13 mg, 0.01 mmol): Dissolved in acetonitrile (2 ml), added to 1,4-dioxane hydrochloride solution (0.5 ml), and reacted at room temperature for 0.5 hours. The reaction solution was distilled under reduced pressure to obtain a crude product, which was then purified by preparative liquid chromatography (aqueous phase: 0.01% trifluoroacetic acid, organic phase: acetonitrile) to obtain the target product 3-(6-(1'-(1-((((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-carbonyl)-[1,4'-bispiperidin]-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione trifluoroacetate (9.5 mg, yield 38.41%). (ESI)[M+H + =1032.9. 1 H NMR(600MHz,DMSO-d6)δ10.89(s,1H),10.19(s,1H),9.56(s,1H),9.13(s,1H ),8.80(s,1H),8.00-7.97(t,1H),7.69-7.66(d,J=8.3Hz,1H),7.48-7.45(t, 1H),7.40-7.39(d,J=2.7Hz,2H),7.18-7.17(t,1H),7.04-7.03(d,J=8.4Hz, 1H),4.57-4.54(d,J=12.7Hz,1H),4.36-4.29(m,3H),4.17-4.14(m,1H),4.03 -4.01(t,4H),3.98(s,3H),3.93(s,1H),3.78-3.73(t,2H),3.22-3.13(m,4H ),3.08-2.95(m,6H),2.71-2.66(m,1H),2.63-2.54(m,2H),2.39-2.33(m,1H) ,2.19-2.15(m,1H),2.12-2.10(m,4H),2.05-2.03(m,2H),2.01-1.87(m,9H) ,1.69-1.56(m,6H),1.53-1.45(m,1H),0.88-0.84(m,2H),0.79-0.78(t,2H).

[0366] Example 10: Synthesis of 3-(6-(1-(1-((((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyltrifluoroacetate (10)

[0367] Step 1: Synthesis of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid (10-b)

[0368] 3-(6-bromo-1-oxoisoindol-2-yl)piperidin-2,6-dione (10-a, 500 mg, 1.55 mmol), potassium phosphate (1.22 g, 5.74 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (344 mg, 0.47 mmol), and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (479 mg, 1.55 mmol) were dissolved in N,N-dimethylformamide (20 ml), purged three times with nitrogen, and reacted at 90 °C for 18 hours. After the reaction was complete, the reaction solution was added to 500 ml of water, and extracted three times with 250 ml of ethyl acetate each time. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent, yielding a crude product. The crude product was purified by flash chromatography (petroleum ether: ethyl acetate = 0–20%) and concentrated. The sample was then purified by TLC (dichloromethane: methanol = 20:1) to obtain the target product 4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (10-b, 170 mg, yield 25.76%). (ESI)[M+H] + =426.7

[0369] Step 2: Synthesis of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)piperidine-1-carboxylate (10-c)

[0370] 4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (10-b, 170 mg, 0.4 mmol) was dissolved in tetrahydrofuran (10 mL), and 200 mg of 10% palladium on carbon was added. After three hydrogen purgings, the reaction mixture was reacted at room temperature for 24 h. The reaction solution was filtered through diatomaceous earth, and the filtrate was distilled under reduced pressure to obtain the target product, 4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)piperidin-1-carboxylic acid tert-butyl ester (10-c, 130 mg, yield 76.02%). (ESI)[2M+H] + =854.9

[0371] Step 3: Synthesis of 3-(1-oxo-6-(piperidin-4-yl)isoindol-2-yl)piperidin-2,6-dione (10-d)

[0372] 4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)piperidin-1-carboxylic acid tert-butyl ester (10-c, 130 mg, 0.3 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (1 mL) was added. The reaction was carried out at room temperature for 0.5 hours. The solvent was removed by vacuum distillation to obtain the target product 3-(1-oxo-6-(piperidin-4-yl)isoindoline-2-yl)piperidin-2,6-dione (10-d, 178 mg). (ESI)[M+H] + =328.0.

[0373] Step 4: Synthesis of tert-butyl 4-((4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)piperidin-1-yl)methyl)piperidin-1-carboxylic acid (10-e)

[0374] 3-(1-oxo-6-(piperidin-4-yl)isoindolin-2-yl)piperidin-2,6-dione (10-d, 145 mg, 0.44 mmol), tert-butyl 4-(iodomethyl)piperidin-1-carboxylate (101 mg, 0.31 mmol), and potassium carbonate (182 mg, 1.32 mmol) were dissolved in acetonitrile (8 mL) and reacted at 80 °C for 6 hours. After the reaction was completed, the solvent was removed by concentration under reduced pressure to obtain a crude product. The crude product was purified by TLC (dichloromethane:methanol = 100:13) to obtain the target product tert-butyl 4-((4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)methyl)piperidin-1-carboxylate (10-e, 48 mg, yield 20.78%). (ESI)[M+H] + =572.7.

[0375] Step 5: Synthesis of 3-(1-oxo-6-(1-(piperidin-4-ylmethyl)piperidin-4-ylisoindol-2-yl)piperidin-2,6-dione (10-f)

[0376] 4-((4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)piperidin-1-yl)methyl)piperidin-1-carboxylic acid tert-butyl ester (10-e, 48 mg, 0.09 mmol) was dissolved in dichloromethane (5 ml), and trifluoroacetic acid (1 ml) was added. The reaction was carried out at room temperature for 0.5 hours. The solvent was removed by vacuum distillation to obtain the target product 3-(1-oxo-6-(1-(piperidin-4-ylmethyl)piperidin-4-ylisoindoline-2-yl)piperidin-2,6-dione (10-f, 74 mg).

[0377] Step 6: Synthesis of 3-(6-(1-(1-((((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-7-((triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methylpiperidin-4-yl)-1-oxoisoindol-2-yl)piperidin-2,6-dione (10-g)

[0378] (1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl-4-methylbenzenesulfonate (I-1, 97 mg, 0.11 mmol), potassium carbonate (76 mg, 0.55 mmol), potassium iodide (18 mg, 0.11 mmol), 3-(1-oxo-6-(1-(piperidin-4-ylmethyl)piperidin-4-ylisoindol-2-yl)piperidin-2,6-dione (10-f, 74 mg, 0.17 mmol) dissolved in acetonitrile ( 5 ml), reacted at 60℃ for 6 hours. After the reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by TLC (dichloromethane:methanol = 100:13) to obtain the target product 3-(6-(1-(1-((((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-7-((triisopropylsilyl)ethynyl)naphth-1-yl)pyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methylpiperidin-4-yl)-1-oxoisoindol-2-yl)piperidin-2,6-dione (10-g, 27 mg, yield 21.60%). (ESI)[M+H + =1137.8.

[0379] Step 7: Synthesis of 3-(6-(1-(1-((((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl (10-h)

[0380] 3-(6-(1-(1-(((((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-7-((triisopropylsilyl)ethynyl)naphth-1-yl)pyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methylpiperidin-4-yl)-1-oxoisoindol-2-yl)piperidin-2,6-dione (10-g, 27mg, 0.02mmol) was dissolved in N,N-dimethylformamide (3ml), and cesium fluoride (30mmol, 0.2mmol) was added. The reaction was carried out at room temperature for 0.5h. After filtration of the reaction solution, the filtrate was distilled under reduced pressure using an oil pump to obtain the target product 3-(6-(1-(1-((((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl (10-h, 25 mg). (ESI)[M+H] + =981.7.

[0381] Step 8: Synthesis of 3-(6-(1-(1-((((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyltrifluoroacetate (10)

[0382] 3-(6-(1-(1-(((((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl (10-h, 25 mg, 0.03 mmol) was dissolved in acetonitrile (5 ml), and 1,4-dioxane hydrochloride solution (1 ml) was added. The reaction was carried out at room temperature for 0.5 hours. The reaction solution was distilled under reduced pressure to obtain crude... The crude product was purified by preparative liquid chromatography (aqueous phase: 0.01% trifluoroacetic acid, organic phase: acetonitrile) to obtain the target product 3-(6-(1-(1-((((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyltrifluoroacetate (10, 13.88 mg, yield 39.66%). (ESI)[M+H] + =937.7. 1 H NMR(600MHz,DMSO-d6)δ10.99(s,1H),10.21(s,1H),9.43(s,1H),9.13(s,1H),9.00(s,1H),7.99(m,1H),7.60-7.59(d,J=7.4Hz,2H),7.53-7.51 (d,1H),7.47-7.46(t,1H),7.40-7.39(d,J=2.7Hz,1H),7.20-7.18(d,J =2.7Hz,1H),5.11-5.08(m,1H),4.45-4.43(d,J=17.0Hz,1H),4.35-4.30 (d,J=16.8Hz,3H),4.03-4.01(t,4H),3.94-3.93(d,J=3.8Hz,1H),3.78 -3.73(m,2H),3.65-3.63(d,J=12.1Hz,2H),3.33-3.21(m,4H),3.05-2.8 8(m,6H),2.63-2.60(d,J=16.6Hz,1H),2.45-2.37(m,1H),2.14-1.94(m, 12H),1.67-1.50(m,6H),0.90-0.86(m,2H),0.79-0.78(d,J=5.5Hz,2H).

[0383] Example 11: Synthesis of 3-(6-(1-(1R,3R)-3-(((1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)amino)cyclobutane-1-carbonyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione trifluoroacetate (11)

[0384] Step 1: Synthesis of tert-butyl ((1R,3R)-3-(4-(3-(2,6-dioxoperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-carbonyl)cyclobutyl)carbamate (11-a)

[0385] 3-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)piperidin-2,6-dione (I-2, 150 mg, 0.46 mmol), (1R,3R)-3-((tert-butoxycarbonyl)amino)cyclobutane-1-carboxylic acid (100 mg, 0.46 mmol) and N,N-diisopropylethylamine (178 mg, 1.38 mmol) were dissolved in NN dimethylformamide (3 ml), and then 1-hydroxybenzotriazole (74 mg, 0.55 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (106 mg, 0.55 mmol) were added. The mixture was reacted at room temperature for 2 hours. The reaction solution was extracted three times with ethyl acetate after adding water. The organic phase was concentrated under reduced pressure to obtain the target product, tert-butyl((1R,3R)-3-(4-(3-(2,6-dioxoperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-carbonyl)cyclobutyl)carbamate (11-a, 210 mg, yield 87.52%) ESI[M+H]. + =524.1

[0386] Step 2: Synthesis of 3-(6-(1-(((1R,3R)-3-aminocyclobutane-1-carbonyl)piperidin-4-yl)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione (11-b)

[0387] Tert-butyl ((1R,3R)-3-(4-(3-(2,6-dioxadiazin-3-yl)-1-methyl-1H-indazole-6-yl)piperidin-1-carbonyl)cyclobutyl)carbamate (11-a, 210 mg, 0.4 mmol) was dissolved in dichloromethane (3 ml) and dioxane hydrochloride (1 ml) was added. The reaction was carried out at room temperature for 1 hour. After concentration under reduced pressure, the target product 3-(6-(1-(((1R,3R)-3-aminocyclobutane-1-carbonyl)piperidin-4-yl)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione (11-b, 215 mg, crude) ESI[M+H] was obtained. + =424.3

[0388] Step 3: Synthesis of 3-(6-(1-(1R,3R)-3-(((1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxy-methoxy))naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)amino)cyclobutane-1-carbonyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (11-c)

[0389] (1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl-4-methylbenzenesulfonate (I-1, 212 mg, 0.24 mmol), potassium carbonate (166 mg, 1.2 mmol), potassium iodide (40 mg, 0.24 mmol), 3-(6-(1-(((1R,3R)-3-aminocyclobutane-1-carbonyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (11-b, 100 mg, 0.24 mmol) was dissolved in acetonitrile. (5 ml), reacted at 60℃ for 16 hours. After the reaction, the reaction solution was filtered, and water was added. The solution was then extracted three times with ethyl acetate. The organic phase was concentrated under reduced pressure and purified by liquid chromatography (dichloromethane / methanol = 10 / 1) to obtain the target product 3-(6-(1-(1R,3R)-3-(((1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxy-methoxy))naphth-1-yl)pyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)amino)cyclobutane-1-carbonyl)piperidin-4-yl)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione (11-c, 30 mg, yield 11%) (ESI)[M+H) + =1136.1

[0390] Step 4: Synthesis of 3-(6-(1-((1R,3R)-3-(((1-(4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)amino)cyclobutane-1-carbonyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (11-d)

[0391] 3-(6-(1-(1R,3R)-3-(((1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxy-methoxy))naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)amino)cyclobutane-1-carbonyl)piperidin-4-yl)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione (11-c, 30 mg, 0.026 mmol) was dissolved in N,N-dimethylformamide (1 ml), and cesium fluoride (20 mg, 0.13 mmol) was added. The mixture was reacted at room temperature for 1 h. The reaction solution was extracted three times with ethyl acetate after adding water. The organic phase was concentrated under reduced pressure to obtain the target product (3-(6-(1-((1R,3R)-3-(((1-(4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)amino)cyclobutane-1-carbonyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (11-d, 25 mg, crude product). (ESI)[M+H] + =980.2

[0392] Step 5: Synthesis of 3-(6-(1-(1R,3R)-3-(((1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridin [4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)amino)cyclobutane-1-carbonyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione trifluoroacetate (11)

[0393] Dissolve (3-(6-(1-((1R,3R)-3-(((1-(4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)amino)cyclobutane-1-carbonyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (11-d, 25 mg, 0.025 mmol) in acetonitrile (3 ml), add 1,4-dioxane hydrochloride solution (0.5 ml), and react at room temperature for 1 hour. The reaction solution was distilled under reduced pressure to obtain a crude product, which was then purified by preparative liquid chromatography (aqueous phase: 0.01% trifluoroacetic acid, organic phase: acetonitrile) to obtain the target product 3-(6-(1-(1R,3R)-3-(((1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)amino)cyclobutane-1-carbonyl)piperidin-4-yl)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione trifluoroacetate (11, 1.21 mg, yield 5%). (ESI)[M+H + =936.3 1 H NMR (400MHz, DMSO-d6) δ10.87(s,1H),10.17(s,1H),9.12(s,1H),8.77(s,2H),8.01–7.94(m,1H),7. 62–7.60(m,1H),7.48–7.38(m,2H),7.18–7.17(m,1H),7.04–7.01(m,1H),4.58–4.55(m,1H),4.36–4. 28(m,2H),4.01–3.95(m,5H),3.75–3.64(m,2H),3.58–3.39(m,4H),3.22–2.85(m,6H),2.75–2.54(m ,4H),2.46–2.26(m,4H),2.18–2.14(m,2H),1.96–1.82(m,5H),1.73–1.41(m,6H),0.80–0.78(m,4H).

[0394] Example 12: Synthesis of 3-(6-(1-(7-(1-(((4-(3-azabicyclo[3.1.0]hex-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione trifluoroacetate (12)

[0395] Step 1: Synthesis of tert-butyl 2-(4-(3-(2,6-dioxadiazin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-7-azaspiro[3.5]non-7-carboxylic acid (12-a)

[0396] 3-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)piperidin-2,6-dione (I-2, 500 mg, 1.53 mmol) and tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylic acid (550 mg, 2.3 mmol) were dissolved in methanol (20 ml) and tetrahydrofuran (5 ml), then acetic acid (92 mg, 1.53 mmol) was added, and the mixture was reacted at 55 °C for 1 hour. Sodium cyanoborohydride (288 mg) was then added. mg, 4.59 mmol), the reaction was continued at 55 °C for 16 hours. After the reaction was completed, the solvent was removed by vacuum concentration to obtain the crude product. The crude product was purified by TLC (dichloromethane:methanol = 10:1) to obtain the target product 2-(4-(3-(2,6-dioxadiazin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-7-azaspiro[3.5]non-7-carboxylic acid tert-butyl ester (12-a, 454 mg, yield 53.98%). (ESI)[M+H) + =550.1.

[0397] Step 2: Synthesis of 3-(6-(1-(7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (12-b)

[0398] 2-(4-(3-(2,6-dioxadiazin-3-yl)-1-methyl-1H-indazole-6-yl)piperidin-1-yl)-7-azaspiro[3.5]non-7-carboxylic acid tert-butyl ester (12-a, 454 mg, 0.83 mmol) was dissolved in dichloromethane (10 ml), and trifluoroacetic acid (2 ml) was added. The reaction was carried out at room temperature for 0.5 hours. The solvent was removed by vacuum distillation to obtain the crude target product 3-(6-(1-(7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione (12-b, 576 mg).

[0399] Step 3: Synthesis of 3-(6-(1-(7-(1-((4-(3-azabicyclo[3.1.0]hex-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (12-c)

[0400] (1-(((4-(3-azabicyclo[3.1.0]hex-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl-4-methylbenzenesulfonate (I-3, 80 mg, 0.09 mmol), potassium carbonate (62 mg, 0.45 mmol), potassium iodide (15 mg, 0.09 mmol), 3-(6-(1-(7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione (12-b, 63 mg, 0.14 mmol) were dissolved in acetonitrile (4 ml) and reacted at 60 °C for 6 hours. After the reaction was completed, the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by TLC (dichloromethane:methanol = 100:13) to obtain the target product 3-(6-(1-(7-(1-((4-(3-azabicyclo[3.1.0]hex-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione (12-c, 35 mg, yield 33.98%).

[0401] Step 4: Synthesis of 3-(6-(1-(7-(1-(((4-(3-azabicyclo[3.1.0]hex-3-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (12-d)

[0402] 3-(6-(1-(7-(1-((4-(3-azabicyclo[3.1.0]hex-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (12-c, 35 mmol, 0.03 mmol) was dissolved in N,N-dimethylformamide (5 ml), and cesium fluoride (46 mg, 0.3 mmol) was added. The reaction was carried out at room temperature for 0.5 h. After filtration of the reaction solution, the filtrate was distilled under reduced pressure using an oil pump to obtain the crude target product 3-(6-(1-(7-(1-(((4-(3-azabicyclo[3.1.0]hex-3-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (12-d, 35 mg). (ESI)[M+H] + =990.7.

[0403] Step 5: Synthesis of 3-(6-(1-(7-(1-(((4-(3-azabicyclo[3.1.0]hex-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione trifluoroacetate (12)

[0404] 3-(6-(1-(7-(1-(((4-(3-azabicyclo[3.1.0]hex-3-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione (12-d, 35 mg, 0.04 mmol) was dissolved in acetonitrile (5 ml), and 1,4-dioxane hydrochloride solution (1 ml) was added. The reaction was carried out at room temperature for 0.5 hours. The reaction solution was distilled under reduced pressure to obtain a crude product, which was then purified by preparative liquid chromatography (aqueous phase: 0.01% trifluoroacetic acid, organic phase: acetonitrile) to obtain the target product 3-(6-(1-(7-(1-(((4-(3-azabicyclo[3.1.0]hex-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione trifluoroacetate (12, 19.18 mg, yield 40.80%). (ESI)[M+H + =946.20.

[0405] Example 13: Synthesis of 3-(6-(1-(1s,3s)-3-(((1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)amino)cyclobutane-1-carbonyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione trifluoroacetate (13)

[0406] Step 1: Synthesis of tert-butyl ((1S,3S)-3-(4-(3-(2,6-dioxoperidin-3-yl)-1-methyl-1H-indazole-6-yl)piperidin-1-carbonyl)cyclobutyl)carbamate (13-a)

[0407] 3-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)piperidin-2,6-dione (I-2, 150 mg, 0.46 mmol), (1R,3R)-3-((tert-butoxycarbonyl)amino)cyclobutane-1-carboxylic acid (100 mg, 0.46 mmol) and N,N-diisopropylethylamine (178 mg, 1.38 mmol) were dissolved in NN dimethylformamide (3 ml), and then 1-hydroxybenzotriazole (74 mg, 0.55 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (106 mg, 0.55 mmol) were added. The mixture was reacted at room temperature for 2 hours. The reaction solution was extracted three times with ethyl acetate after adding water. The organic phase was concentrated under reduced pressure to obtain the target product, tert-butyl((1S,3S)-3-(4-(3-(2,6-dioxoperidin-3-yl)-1-methyl-1H-indazole-6-yl)piperidin-1-carbonyl)cyclobutyl)carbamate (13-a, 190 mg, yield 79%) ESI[M+H]. + =524.1

[0408] Step 2: Synthesis of 3-(6-(1-(((1S,3S)-3-aminocyclobutane-1-carbonyl)piperidin-4-yl)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione (13-b)

[0409] Tert-butyl ((1S,3S)-3-(4-(3-(2,6-dioxadiazin-3-yl)-1-methyl-1H-indazole-6-yl)piperidin-1-carbonyl)cyclobutyl)carbamate (13-a, 190 mg, 0.4 mmol) was dissolved in dichloromethane (3 ml) and trifluoroacetic acid (1 ml) was added. The reaction was carried out at room temperature for 1 hour. After concentration under reduced pressure, the target product 3-(6-(1-(((1S,3S)-3-aminocyclobutane-1-carbonyl)piperidin-4-yl)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione (13-b, 250 mg, crude) was obtained, ESI[M+H] + =424.3

[0410] Step 3: Synthesis of 3-(6-(1-(1s,3s)-3-(((1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxy-methoxy))naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)amino)cyclobutane-1-carbonyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (13-c)

[0411] (1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl-4-methylbenzenesulfonate (I-1, 212 mg, 0.24 mmol), potassium carbonate (166 mg, 1.2 mmol), potassium iodide (40 mg, 0.24 mmol), 3-(6-(1-(((1s,3s)-3-aminocyclobutane-1-carbonyl)piperidin-4-yl)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione (13-b, 100 mg, 0.24 mmol) dissolved in acetonitrile ( 5 ml), reacted at 60℃ for 16 hours. After the reaction, the reaction solution was filtered, water was added, and the solution was extracted three times with ethyl acetate. The organic phase was concentrated under reduced pressure and purified by liquid chromatography (dichloromethane / methanol = 10 / 1) to obtain the target product 3-(6-(1-(1s, 3s)-3-(((1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxy-methoxy))naphth-1-yl)pyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)amino)cyclobutane-1-carbonyl)piperidin-4-yl)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione (13-c, 50 mg, yield 18.6%), (ESI)[M+H). + =1136.1

[0412] Step 4: Synthesis of 3-(6-(1-((1s,3s)-3-(((1-(4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)amino)cyclobutane-1-carbonyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (13-d)

[0413] 3-(6-(1-(1s,3s)-3-(((1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxy-methoxy))naphth-1-yl)pyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)amino)cyclobutane-1-carbonyl)piperidin-4-yl)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione (13-c, 50 mg, 0.044 mmol) was dissolved in N,N-dimethylformamide (1 ml), and cesium fluoride (34 mg, 0.22 mmol) was added. The mixture was reacted at room temperature for 1 h. The reaction solution was extracted three times with ethyl acetate after adding water. The organic phase was concentrated under reduced pressure to obtain the target product (3-(6-(1-((1s,3s)-3-(((1-(4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)amino)cyclobutane-1-carbonyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (13-d, 50 mg, crude). (ESI)[M+H] + =980.2

[0414] Step 5: Synthesis of 3-(6-(1-(1s,3s)-3-(((1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)amino)cyclobutane-1-carbonyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione trifluoroacetate (13)

[0415] Dissolve (3-(6-(1-((1s,3s)-3-(((1-(4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)amino)cyclobutane-1-carbonyl)piperidin-4-yl)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione (13-d, 50 mg, 0.05 mmol) in acetonitrile (3 ml), add 1,4-dioxane hydrochloride solution (0.5 ml), and react at room temperature for 1 hour. The reaction solution was distilled under reduced pressure to obtain a crude product, which was then purified by preparative liquid chromatography (aqueous phase: 0.01% trifluoroacetic acid, organic phase: acetonitrile) to obtain the target product 3-(6-(1-(1s,3s)-3-(((1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)amino)cyclobutane-1-carbonyl)piperidin-4-yl)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione trifluoroacetate (13, 2.44 mg, yield 5%). (ESI)[M+H] + =936.3 1 H NMR(400MHz,DMSO-d6)δ10.88(s,1H),10.29(s,1H),9.17–9.11(m,1H),9.03(s,1H),8 .04–8.00(m,1H),7.63–7.61(m,1H),7.54–7.39(m,3H),7.17(s,1H),7.05–7.02(m,1H) ,4.62–4.17(m,8H),4.12–3.92(m,6H),3.21–2.88(m,6H),2.72–2.57(m,4H),2.49–2. 29(m,4H),2.20–2.13(m,1H),2.06–1.82(m,6H),1.70–1.46(m,6H),0.58–0.37(m,4H).

[0416] Example 14: Synthesis of 5-(4-(1-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)azacyclobutane-3-carbonyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione carbamate (14)

[0417] Step 1: Synthesis of tert-butyl 3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperazine-1-carbonyl)azacyclobutane-1-carboxylic acid (14-c)

[0418] 2-(2,6-dioxadiazin-3-yl)-5-(piperazin-1-yl)isoindole-1,3-dione (14-a, 342 mg, 1.0 mmol) was dissolved in N,N-dimethylformamide (5 mL), and 1-hydroxybenzotriazole (163 mg, 1.2 mmol), carbodiimide hydrochloride (230 mg, 1.2 mmol), N,N-diisopropylethylamine (645 mg, 5.0 mmol) and 1-(tert-butoxycarbonyl)azacyclobutane-3-carboxylic acid (14-b, 201 mg, 1.0 mmol) were added, and the mixture was reacted at room temperature for 3 hours. The solution was quenched with water, extracted with ethyl acetate, and the organic phase was collected and repeatedly washed with saturated sodium chloride solution. After drying with anhydrous sodium sulfate, the solution was filtered, concentrated under reduced pressure, and then separated by liquid chromatography (dichloromethane:methanol = 0-10%) to obtain the target product 3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperazine-1-carbonyl)azacyclobutane-1-carboxylic acid tert-butyl ester (14-c, 230 mg, yield 43.8%).

[0419] Step 2: Synthesis of 5-(4-(azacyclobutane-3-carbonyl)piperazin-1-yl)-2-(2,6-dioxadiazin-3-yl)isoindole-1,3-dione (14-d)

[0420] 3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperazin-1-carbonyl)azacyclobutane-1-carboxylic acid tert-butyl ester (14-c, 230 mg, 0.43 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (1 mL) was added. The reaction was carried out at room temperature for 1 hour. The reaction solution was directly concentrated under reduced pressure to obtain the target product 5-(4-(azacyclobutane-3-carbonyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (14-d, 300 mg, crude product).

[0421] Step 3: Synthesis of 5-(4-(1-(1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-7-((triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)azacyclobutane-3-carbonyl)piperazin-1-yl)-2-(2,6-dioxypiperidin-3-yl)isoindoline-1,3-dione (14-e)

[0422] (1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl-4-methylbenzenesulfonate (I-1, 100 mg, 0.11 mmol), 5-(4-(azacyclobutane-3-carbonyl)piperazin-1-yl)-2-(2,6-dioxadiazin-3-yl)isoindol-1,3-dione (14-d, 14 mg, 0.17 mmol), potassium iodide (20 mg, 0.12 mmol), and potassium carbonate (78 mg, 0.59 mmol) were dissolved in acetonitrile (3 mL) and reacted at 60 °C. After 6 hours, the mixture was quenched with water, extracted with ethyl acetate, and the organic phase was collected and repeatedly washed with saturated sodium chloride solution. It was then dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by thin-layer chromatography on silica gel plates (dichloromethane:methanol = 10:1) to obtain the target product 5-(4-(1-(1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-7-((triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)azacyclobutane-3-carbonyl)piperazin-1-yl)-2-(2,6-dioxypiperidin-3-yl)isoindoline-1,3-dione (14-e, 26 mg, yield 20.8%).

[0423] Step 4: Synthesis of 5-(4-(1-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)azacyclobutane-3-carbonyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (14-f)

[0424] 5-(4-(1-(1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-7-((triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)azacyclobutane-3-carbonyl)piperazin-1-yl)-2-(2,6-dioxypiperidin-3-yl)isoindoline-1,3-dione (14-e, 26 mg, 0.022 mmol) was dissolved in N,N-dimethylformamide (2 mL), and then fluorinated... Cesium (35 mg, 0.22 mmol) was reacted at room temperature for 1 hour. The reaction solution was directly filtered and concentrated under reduced pressure to give crude 5-(4-(1-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)azacyclobutane-3-carbonyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (14-f, 20 mg, 95% yield). ESI[M+H] + =982.4

[0425] Step 5: Synthesis of 5-(4-(1-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)azacyclobutane-3-carbonyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione carbamate (14)

[0426] 5-(4-(1-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)azacyclobutane-3-carbonyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindol-1,3-dione (14-f, 20 mg, 0.02 mmol) was dissolved in acetonitrile (2 mL), and dioxane hydrochloride (0.5 mL) was added. The mixture was reacted at room temperature for 0.5 hours. The reaction solution was purified by preparative liquid chromatography (aqueous phase: 0.1% formic acid, organic phase: acetonitrile) to obtain the target product 5-(4-(1-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)azacyclobutane-3-carbonyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione carbamate (14, 1.89 mg, yield 10.5%). ESI[M+H]+ =938.0 1 H NMR(600MHz,DMSO-d6)δ11.06(s,1H),10.17(s,1H),9.05(s,1H),8.34(s,1H),7.96-7.92(m,1H),7.67-7.6 6(m,1H),7.46-7.42(m,1H),7.36(s,1H),7.30(s,1H),7.22-7.15(m,2H),6.64(s,1H),5.33-5.30(m,2H),5 .06-5.03(m,1H),4.21-4.15(m,2H),3.98-3.97(m,3H),3.56-3.49(m,4H),3.14(s,2H),2.86(s,3H),2.28- 2.24(m,1H),2.00-1.88(m,6H),1.66-1.39(m,8H),1.27-1.26(m,2H),0.86-0.81(m,2H),0.49-0.42(m,4H).

[0427] Example 15: Synthesis of 1-(5-(9-(4-((1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl]-3-azaspiro[5.5]undecane-3-carbonyl)-2-methylphenyl)dihydropyrimidin-2,4(1H,3H)-diketone trifluoroacetate (15)

[0428] Step 1: Synthesis of 1-(5-(9-(4-((1-((4-(a-1-yl)-8-fluoro-7-(7-fluoro-3-hydroxy-8-(triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl-3-azaspiro[5.5]undecane-3-carbonyl)-2-methylphenyl)dihydropyrimidin-2,4(1H,3H)-dione (15-b)

[0429] To a stirred solution of 4-(4-(aza-1-yl)-8-fluoro-2-((1-(piperazin-1-ylmethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphth-2-ol (15-a, 33 mg, 0.04 mmol) and 3-(3-(2,4-dioxytetrahydropyrimidin-1(2H)-yl)-4-methylbenzoyl)-3-azaspiro[5.5]undec-9-carbonyl (35 mg, 0.08 mmol) in DCM (2 mL) / AcOH (0.1 mL), tetraisopropyl titanate (57 mg, 0.2 mmol) was added, and the mixture was stirred at room temperature for 2 hours. NaBH(OAc)3 (25 mg, 0.12 mmol) was then added to the mixture at room temperature, and the mixture was stirred for 2 hours. After the reaction was completed, the mixture was concentrated and purified by thin-layer chromatography on silica gel plates (dichloromethane:methanol = 100:12) to obtain the target product 1-(5-(9-(4-((1-((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-hydroxy-8-(triisopropylsilyl)ethynyl)naphth-1-yl)pyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl-3-azaspiro[5.5]undecane-3-carbonyl)-2-methylphenyl)dihydropyrimidin-2,4(1H,3H)-dione (15-b, 30 mg, yield 65.22%).

[0430] Step 2: Synthesis of 1-(5-(9-(4-((1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl]-3-azaspiro[5.5]undecane-3-carbonyl)-2-methylphenyl)dihydropyrimidin-2,4(1H,3H)-diketone trifluoroacetate (15)

[0431] 1-(5-(9-(4-((1-((4-((aza-1-yl)-8-fluoro-7-(7-fluoro-3-hydroxy-8-(triisopropylsilyl)ethynyl)naphth-1-yl)pyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl-3-azaspiro[5.5]undecane-3-carbonyl)-2-methylphenyl)dihydropyrimidin-2,4(1H,3H)-dione (15-b, 30 mg, 0.026 mmol) was dissolved in N,N-dimethylformamide (5 mL), and cesium fluoride (39 mg, 0.26 mmol) was added. The reaction was carried out at room temperature for 0.5 h. The reaction solution was filtered and purified by preparative liquid chromatography (aqueous phase: 0.01% trifluoroacetic acid, organic phase: acetonitrile) to obtain the target product 1-(5-(9-(4-((1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl]-3-azaspiro[5.5]undecane-3-carbonyl)-2-methylphenyl)dihydropyrimidin-2,4(1H,3H)-diketone trifluoroacetate (15, 17.59 mg, yield 55.35%). (ESI)[M+H + =994.7. 1 H NMR(600MHz,DMSO-d6)δ10.38(s,1H),10.20(s,1H),9.10(s,1H),7.99-7.96(m,1H),7.46-7.45(t,1H),7.39(s,1H),7 .35-7.34(d,J=7.8Hz,1H),7.30(s,1H),7.25-7.23(d,J=7.8Hz,1H),7.17(s,1H),4.34-4.25(m,2H),3.98-3.96(m,5H) ,3.83-3.77(m,1H),3.66-3.50(m,9H),3.35-3.19(m,6H),3.09-2.83(m,1H),2.71-2.70(m,1H),2.69-2.67(m,1H),2. 21(s,3H),1.96-1.91(t,4H),1.71-1.57(m,8H),1.52(s,4H),1.37-1.33(m,2H),1.13-1.02(m,4H),0.75-0.58(m,4H).

[0432] Example 17: Synthesis of 3-(6-(1-(1-((1-(4-(3-azabicyclo[3.1.0]hex-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-5-methylpyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-oxoisoindol-2-yl)piperidin-2,6-dione trifluoroacetate (17)

[0433] Step 1: Synthesis of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid (17-c)

[0434] 3-(6-bromo-1-oxoisoindol-2-yl)piperidin-2,6-dione (17-a, 1 g, 3.09 mmol) was dissolved in N,N-dimethylformamide (30 mL), and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (17-b, 1913 mg, 6.18 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (340 mg, 0.46 mmol) and potassium phosphate (1970 mg, 9.27 mmol) were added sequentially. The reaction was carried out at 90 °C for 16 hours under nitrogen protection. The solution was quenched with water, extracted with ethyl acetate, and the organic phase was collected and repeatedly washed with saturated sodium chloride solution. After drying with anhydrous sodium sulfate, the solution was filtered, concentrated under reduced pressure to obtain a crude product, which was then separated by liquid chromatography (dichloromethane:methanol = 0–10%) to obtain the target product 4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (17-c, 750 mg, yield 57%). ESI [M+H] + =426.0

[0435] Step 2: Synthesis of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)piperidin-1-carboxylate (17-d)

[0436] 4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (17-c, 750 mg, 1.76 mmol) was dissolved in methanol (10 mL) and tetrahydrofuran (20 mL), and palladium on carbon (10%) (300 mg, 2.82 mmol) was added. The reaction was carried out at room temperature for 16 hours under hydrogen protection. The reaction solution was directly filtered and concentrated under reduced pressure to obtain the target product 4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)piperidin-1-carboxylic acid tert-butyl ester (17-d, 500 mg, 66.4%). ESI [M+H] + =372.2

[0437] Step 3: Synthesis of 3-(1-oxo-6-(piperidin-4-yl)isoindol-2-yl)piperidin-2,6-dione (17-e)

[0438] 4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidine-1-carboxylic acid tert-butyl ester (17-d, 500 mg, 1.16 mmol) was dissolved in dichloromethane (5 mL), and then trifluoroacetic acid (1 mL) was added. The reaction was carried out at room temperature for 1 hour. The reaction solution was directly concentrated under reduced pressure to obtain the target product 3-(1-oxo-6-(piperidine-4-yl)isoindolin-2-yl)piperidine-2,6-dione (17-e, 484 mg, crude product) ESI[M+H] + =328.2

[0439] Step 4: Synthesis of tert-butyl 4-((4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)piperidin-1-yl)methyl)piperidin-1-carboxylate (17-g)

[0440] 3-(1-oxo-6-(piperidin-4-yl)isoindol-2-yl)piperidin-2,6-dione (17-e, 484 mg, 1.47 mmol) was dissolved in methanol (3 mL), and the pH was adjusted to 7-8 by adding triethylamine dropwise. The solution was concentrated under reduced pressure and then dissolved in methanol:acetic acid / 1:10 (22 mL). 4-Formylpiperidin-1-carboxylic acid tert-butyl ester (17-f, 630 mg, 2.95 mmol) was added, and the reaction was carried out at room temperature for 1 hour. Then, sodium cyanoborohydride (278 mg, 4.42 mmol) was added, and the reaction was continued at room temperature for 2 hours. The solution was quenched with water, extracted with ethyl acetate, and the organic phase was collected and repeatedly washed with saturated sodium chloride solution. After drying with anhydrous sodium sulfate, the solution was filtered, concentrated under reduced pressure to obtain the crude product, and then subjected to thin-layer chromatography on silica gel plates (dichloromethane:methanol = 10:1) to obtain the target product 4-((4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)piperidin-1-yl)methyl)piperidin-1-carboxylic acid tert-butyl ester (17-g, 520mg, yield 17.4%) ESI[M+H). + =525.4

[0441] Step 5: Synthesis of 3-(1-oxo-6-(1-(piperidin-4-ylmethyl)piperidin-4-ylisoindol-2-yl)piperidin-2,6-dione (17-h)

[0442] 4-((4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)piperidin-1-yl)methyl)piperidin-1-carboxylic acid tert-butyl ester (17-g, 520 mg, 0.99 mmol) was dissolved in dichloromethane (5 mL), and then trifluoroacetic acid (1 mL) was added. The reaction was carried out at room temperature for 1 hour. The reaction solution was directly concentrated under reduced pressure to obtain the target product 3-(1-oxo-6-(1-(piperidin-4-ylmethyl)piperidin-4-ylisoindoline-2-yl)piperidin-2,6-dione (17-h, 829 mg, crude product) ESI[M+H] + =425.0

[0443] Step 6: Synthesis of 3-(6-(1-(1-((((4-(3-azabicyclo[3.1.0]hex-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxy-methoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)-5-methylpyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-oxoisoindol-2-yl)piperidin-2,6-dione (17-i)

[0444] (1-(((4-(3-azabicyclo[3.1.0]hex-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)-5-methylpyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl-4-methylbenzenesulfonate (I-4, 70 mg, 0.079 mmol), 3-(1-oxo-6-(1-(piperidin-4-ylmethyl)piperidin-4-ylisoindol-2-yl)piperidin-2,6-dione (17-h, 50 mg, 0.12 mmol), potassium iodide (13 mg, 0.079 mmol) and potassium carbonate (55 mg, 0.39 mmol) were dissolved in acetonitrile (3 mL) and reacted at 60 °C. After 8 hours, the solution was quenched with water, extracted with ethyl acetate, and the organic phase was collected and repeatedly washed with saturated sodium chloride solution. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by thin-layer chromatography on silica gel plates (dichloromethane:methanol = 100:13) to obtain the target product 3-(6-(1-(1-((((4-(3-azabicyclo[3.1.0]hexyl-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxy-methoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)-5-methylpyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-oxoisoindol-2-yl)piperidin-2,6-dione (17-i, 24 mg, yield 26.9%). ESI[M+H] + =1135.8

[0445] Step 7: Synthesis of 3-(6-(1-(1-((1-(4-(3-azabicyclo[3.1.0]hex-3-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-5-methylpyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methylpiperidin-4-yl)-1-oxoisoindol-2-yl)piperidin-2,6-dione (17-j)

[0446] 3-(6-(1-(1-(((((4-(3-azabicyclo[3.1.0]hex-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxy-methoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)-5-methylpyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)1-oxoisoindol-2-yl)piperidin-2,6-dione (17-i, 24 mg, 0.027 mmol) was dissolved in N,N-dimethylformamide (1 mL), and then cesium fluoride was added. (21 mg, 0.13 mmol), reacted at room temperature for 1 hour, the reaction solution was directly filtered, concentrated under reduced pressure to give crude product 3-(6-(1-(1-((1-(4-(3-azabicyclo[3.1.0]hex-3-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-5-methylpyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methylpiperidin-4-yl)-1-oxoisoindol-2-yl)piperidin-2,6-dione (17-j, 22 mg, yield 84.6%). ESI[M+H + =979.6

[0447] Step 8: Synthesis of 3-(6-(1-(1-((1-(4-(3-azabicyclo[3.1.0]hex-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-5-methylpyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-oxoisoindol-2-yl)piperidin-2,6-dione trifluoroacetate (17)

[0448] 3-(6-(1-(1-((1-(4-(3-azabicyclo[3.1.0]hex-3-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-5-methylpyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methylpiperidin-4-yl)-1-oxoisoindol-2-yl)piperidin-2,6-dione (17-j, 22 mg, 0.022 mmol) was dissolved in acetonitrile (2 mL), and dioxane hydrochloride (0.5 mL) was added. The reaction was carried out at room temperature for 0.5 hours. The reaction solution was purified by preparative liquid chromatography (aqueous phase: 0.01% trifluoroacetic acid, organic phase: acetonitrile) to obtain the target product 3-(6-(1-(1-((1-(4-(3-azabicyclo[3.1.0]hexyl-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-5-methylpyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-oxoisoindol-2-yl)piperidin-2,6-dione trifluoroacetate (17, 8.3 mg, yield 41.5%). ESI[M+H] + =935.1 1 H NMR(600MHz,DMSO-d6)δ11.00(s,1H),10.20(s,1H),9.33(s,1H),8.91(s,1H),8.00-7.96(m,1H),7.60-7. 59(m,2H),7.53-7.52(m,1H),7.48-7.45(m,1H),7.39(s,1H),7.21(s,1H),5.11-5.08(m,1H),4.45-4.42(m ,1H),4.33-4.30(m,3H),3.77(s,3H),3.66-3.64(m,3H),3.12-2.87(m,10H),2.60(s,3H),2.44-2.37(m,2 H),2.04-2.00(m,8H),1.65(s,2H),1.54-1.52(m,3H),1.23(s,2H),0.89(s,2H),0.78(s,2H),0.60(s,2H).

[0449] Example 18: Synthesis of 3-(6-(1-(1-(((4-(3,6-dihydropyridin-1(2H)-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-5-methylpyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-oxoisoindol-2-yl)piperidin-2,6-dione carbamate (18)

[0450] Step 1: Synthesis of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid (18-c)

[0451] 3-(6-bromo-1-oxoisoindol-2-yl)piperidin-2,6-dione (18-a, 1 g, 3.09 mmol) was dissolved in N,N-dimethylformamide (30 mL), and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (18-b, 1913 mg, 6.18 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (340 mg, 0.46 mmol) and potassium phosphate (1970 mg, 9.27 mmol) were added sequentially. The reaction was carried out at 90 °C for 16 hours under nitrogen protection. The solution was quenched with water, extracted with ethyl acetate, and the organic phase was collected and repeatedly washed with saturated sodium chloride solution. After drying with anhydrous sodium sulfate, the solution was filtered, concentrated under reduced pressure to obtain a crude product, which was then separated by liquid chromatography (dichloromethane:methanol = 0–10%) to obtain the target product 4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (18-c, 750 mg, yield 57%). ESI [M+H] + =426.0

[0452] Step 2: Synthesis of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)piperidine-1-carboxylate (18-d)

[0453] 4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (18-c, 750 mg, 1.76 mmol) was dissolved in methanol (10 mL) and tetrahydrofuran (20 mL), and palladium on carbon (10%) (300 mg, 2.82 mmol) was added. The reaction was carried out at room temperature for 16 hours under hydrogen protection. The reaction solution was directly filtered and concentrated under reduced pressure to obtain the target product 4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)piperidin-1-carboxylic acid tert-butyl ester (18-d, 500 mg, 66.4%). ESI [M+H] + =372.2

[0454] Step 3: Synthesis of 3-(1-oxo-6-(piperidin-4-yl)isoindol-2-yl)piperidin-2,6-dione (18-e)

[0455] 4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidine-1-carboxylic acid tert-butyl ester (18-d, 500 mg, 1.16 mmol) was dissolved in dichloromethane (5 mL), and then trifluoroacetic acid (1 mL) was added. The reaction was carried out at room temperature for 1 hour. The reaction solution was directly concentrated under reduced pressure to obtain the target product 3-(1-oxo-6-(piperidine-4-yl)isoindolin-2-yl)piperidine-2,6-dione (18-e, 484 mg, crude product) ESI[M+H] + =328.2

[0456] Step 4: Synthesis of tert-butyl 4-((4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)piperidin-1-yl)methyl)piperidin-1-carboxylic acid (18-g)

[0457] 3-(1-oxo-6-(piperidin-4-yl)isoindol-2-yl)piperidin-2,6-dione (18-e, 484 mg, 1.47 mmol) was dissolved in methanol (3 mL), and the pH was adjusted to 7-8 by adding triethylamine dropwise. The solution was concentrated under reduced pressure and then dissolved in methanol:acetic acid / 1:10 (22 mL). 4-Formylpiperidin-1-carboxylic acid tert-butyl ester (18-f, 630 mg, 2.95 mmol) was added, and the reaction was carried out at room temperature for 1 hour. Then, sodium cyanoborohydride (278 mg, 4.42 mmol) was added, and the reaction was continued at room temperature for 2 hours. The solution was quenched with water, extracted with ethyl acetate, and the organic phase was collected and repeatedly washed with saturated sodium chloride solution. After drying with anhydrous sodium sulfate, the solution was filtered, concentrated under reduced pressure to obtain the crude product, and then subjected to thin-layer chromatography on silica gel plates (dichloromethane:methanol = 10:1) to obtain the target product 4-((4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)piperidin-1-yl)methyl)piperidin-1-carboxylic acid tert-butyl ester (18-g, 520mg, yield 67.4%) ESI[M+H). + =525.4

[0458] Step 5: Synthesis of 3-(1-oxo-6-(1-(piperidin-4-ylmethyl)piperidin-4-ylisoindol-2-yl)piperidin-2,6-dione (18-h)

[0459] 4-((4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)piperidin-1-yl)methyl)piperidin-1-carboxylic acid tert-butyl ester (18-g, 520 mg, 0.99 mmol) was dissolved in dichloromethane (5 mL), and then trifluoroacetic acid (1 mL) was added. The reaction was carried out at room temperature for 1 hour. The reaction solution was directly concentrated under reduced pressure to obtain the target product 3-(1-oxo-6-(1-(piperidin-4-ylmethyl)piperidin-4-ylisoindoline-2-yl)piperidin-2,6-dione (18-h, 829 mg, crude product) ESI[M+H]+ =425.0

[0460] Step 6: Synthesis of 3-(6-(1-(1-((((4-(3,6-dihydropyridin-1(2H)-yl)-8-fluoro-7-(7-fluoro-3-(methoxy-methoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)-5-methylpyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-oxoisoindol-2-yl)piperidin-2,6-dione (18-i)

[0461] (1-(((4-(3,6-dihydropyridin-1(2H)-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)-5-methylpyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl-4-methylbenzenesulfonate (I-5, 70 mg, 0.079 mmol), 3-(1-oxo-6-(1-(piperidin-4-ylmethyl)piperidin-4-ylisoindol-2-yl)piperidin-2,6-dione (18-h, 50 mg, 0.12 mmol), potassium iodide (13 mg, 0.079 mmol), and potassium carbonate (55 mg, 0.39 mmol) were dissolved in acetonitrile (3 mL) and reacted at 60 °C. After 8 hours, the mixture was quenched with water, extracted with ethyl acetate, and the organic phase was collected and repeatedly washed with saturated sodium chloride solution. It was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by thin-layer chromatography on silica gel plates (dichloromethane:methanol = 100:13) to obtain the target product 3-(6-(1-(1-((((4-(3,6-dihydropyridin-1(2H)-yl)-8-fluoro-7-(7-fluoro-3-(methoxy-methoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)-5-methylpyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-oxoisoindol-2-yl)piperidin-2,6-dione (18-i, 24 mg, yield 26.9%). ESI[M+H + =1135.8

[0462] Step 7: Synthesis of 3-(6-(1-(1-(((((4-(3,6-dihydropyridin-1(2H)-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-5-methylpyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methylpiperidin-4-acyl)-1-oxoisoindol-2-yl)piperidin-2,6-dione (18-j)

[0463] 3-(6-(1-(1-(((((4-(3,6-dihydropyridin-1(2H)-yl)-8-fluoro-7-(7-fluoro-3-(methoxy-methoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)-5-methylpyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-oxoisoindol-2-yl)piperidin-2,6-dione (18-i, 24 mg, 0.027 mmol) was dissolved in N,N-dimethylformamide (1 mL), and then added Cesium fluoride (21 mg, 0.13 mmol) was reacted at room temperature for 1 hour. The reaction solution was directly filtered and concentrated under reduced pressure to give crude 3-(6-(1-(1-(((((4-(3,6-dihydropyridin-1(2H)-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-5-methylpyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methylpiperidin-4-acyl)-1-oxoisoindol-2-yl)piperidin-2,6-dione (18-j, 25 mg, crude). ESI[M+H] + =979.6

[0464] Step 8: Synthesis of 3-(6-(1-(1-((((4-(3,6-dihydropyridin-1(2H)-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-5-methylpyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-oxoisoindol-2-yl)piperidin-2,6-dione carbamate (18)

[0465] 3-(6-(1-(1-(((((4-(3,6-dihydropyridin-1(2H)-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-5-methylpyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methylpiperidin-4-acyl)-1-oxoisoindol-2-yl)piperidin-2,6-dione (18-j, 25 mg, 0.025 mmol) was dissolved in acetonitrile (2 mL), and dioxane hydrochloride (0.5 mL) was added. The mixture was reacted at room temperature for 0.5 hours. The reaction solution was purified by preparative liquid chromatography (aqueous phase: 0.1% formic acid, organic phase: acetonitrile) to obtain the target product 3-(6-(1-(1-(((4-(3,6-dihydropyridin-1(2H)-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-5-methylpyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)1-oxoisoindol-2-yl)piperidin-2,6-dione carbamate (18, 9.04 mg, yield 39.3%). ESI[M+H] + =935.1 1 H NMR(600MHz,DMSO-d6)δ10.96(s,1H),8.14(s,1H),7.97-7.93(m,1H),7.53(s,1H),7.50(s,2H),7 .45-7.42(m,1H),7.37(s,1H),7.21(s,1H),5.89(s,1H),5.81(s,1H),5.10-5.07(m,1H),4.40-4.3 7(m,1H),4.27(s,3H),3.88-3.67(m,5H),2.95-2.87(m,6H),2.64(s,3H),2.39-2.28(m,4H),2.12 (s,2H),2.20-1.89(m,6H),1.75-1.73(m,7H),1.48(s,1H),1.03(s,2H),0.64(s,2H),0.41(s,2H).

[0466] Example 19: Synthesis of 3-(6-(1-(7-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1-oxoisoindol-2-yl)pyridine-2,6-dione trifluoroacetate (19)

[0467] Step 1: Synthesis of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid (19-c)

[0468] 3-(6-bromo-1-oxoisoindol-2-yl)piperidin-2,6-dione (19-a, 1 g, 3.09 mmol) was dissolved in N,N-dimethylformamide (20 mL), and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (19-b, 957 mg, 3.09 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (679 mg, 0.29 mmol) and potassium phosphate (2430 mg, 11.44 mmol) were added sequentially. The reaction was carried out at 90 °C for 16 hours under nitrogen protection. The solution was quenched with water, extracted with ethyl acetate, and the organic phase was collected and repeatedly washed with saturated sodium chloride solution. After drying with anhydrous sodium sulfate, the solution was filtered, concentrated under reduced pressure to obtain a crude product, and separated by liquid chromatography (dichloromethane:methanol = 100:13) to obtain the target product 4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (19-c, 310 mg, yield 23.5%). ESI [M+H] + =425.49

[0469] Step 2: Synthesis of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)piperidin-1-carboxylate (19-d)

[0470] 4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (19-c, 310 mg, 0.72 mmol) was dissolved in tetrahydrofuran (15 mL), and then palladium on carbon (10%) (500 mg, 4.69 mmol) was added. The reaction was carried out under hydrogen protection at room temperature for 16 hours. The reaction solution was directly filtered, concentrated under reduced pressure to obtain a crude product, and then subjected to thin-layer chromatography on silica gel plates (dichloromethane:methanol = 100:13) to obtain the target product 4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)piperidin-1-carboxylic acid tert-butyl ester (19-d, 250 mg, yield 81.4%). ESI [M+H] + =427.50

[0471] Step 3: Synthesis of 3-(1-oxo-6-(piperidin-4-yl)isoindol-2-yl)piperidin-2,6-dione (19-e)

[0472] 4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidine-1-carboxylic acid tert-butyl ester (19-d, 250 mg, 0.58 mmol) was dissolved in dichloromethane (2 mL), and then trifluoroacetic acid (1 mL) was added. The reaction was carried out at room temperature for 1 hour. The reaction solution was directly concentrated under reduced pressure to give the target product 3-(1-oxo-6-(piperidine-4-yl)isoindolin-2-yl)piperidine-2,6-dione (19-e, 370 mg, yield 195%). ESI[M+H] + =327.28

[0473] Step 4: Synthesis of tert-butyl 2-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)piperidin-1-yl)-7-azaspiro[3.5]nonene-7-carboxylic acid (19-g)

[0474] 3-(1-oxo-6-(piperidin-4-yl)isoindol-2-yl)piperidin-2,6-dione (19-e, 300 mg, 0.91 mmol) was dissolved in methanol:tetrahydrofuran = 4:1 (5 mL), and 2-oxo-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (19-f, 263 mg, 1.09 mmol) and acetic acid (55 mg, 0.91 mmol) were added. The mixture was reacted at room temperature for 1 hour, and then sodium cyanoborohydride (173 mg, 2.73 mmol) was added. The reaction was continued at room temperature for 16 hours. The solution was quenched with water, extracted with ethyl acetate, and the organic phase was collected and repeatedly washed with saturated sodium chloride solution. It was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Thin-layer chromatography on silica gel plates (dichloromethane:methanol = 0%–10%) yielded the target product 2-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)piperidin-1-yl)-7-azaspiro[3.5]nonen-7-carboxylic acid tert-butyl ester (19 g, 125 mg, yield 24.9%) ESI[M+H). + =550.70

[0475] Step 5: Synthesis of 3-(6-(1-(7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1-oxoisoindol-2-yl)pyridine-2,6-dione (19-h)

[0476] 2-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)piperidin-1-yl)-7-azaspiro[3.5]nonen-7-carboxylic acid tert-butyl ester (19-g, 125 mg, 0.22 mmol) was dissolved in dichloromethane (2 mL), and then trifluoroacetic acid (0.4 mL) was added. The reaction was carried out at room temperature for 1 hour. The reaction solution was directly concentrated under reduced pressure to obtain the target product 3-(6-(1-(7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1-oxoisoindoline-2-yl)pyridine-2,6-dione (19-h, 223 mg, crude product). ESI[M+H] + =450.58

[0477] Step 6: Synthesis of 3-(6-(1-(7-(1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3,5]non-2-yl)piperidin-4-yl)-1-oxoisoindoline-2-yl)pyridine-2,6-dione (19-i)

[0478] (1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl-4-methylbenzenesulfonate (I-1, 292 mg, 0.32 mmol), 3-(6-(1-(7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1-oxoisoindol-2-yl)pyridin-2,6-dione (19-h, 223 mg, 0.49 mmol), potassium iodide (55 mg, 0.33 mmol), and potassium carbonate (228 mg, 1.65 mmol) were dissolved in acetonitrile (5 mL) and reacted at 60 °C. After 8 hours, the solution was quenched with water, extracted with ethyl acetate, and the organic phase was collected and repeatedly washed with saturated sodium chloride solution. It was then dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by thin-layer chromatography on silica gel plates (dichloromethane:methanol = 0%–10%) to obtain the target product 3-(6-(1-(7-(1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)pyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1-oxoisoindoline-2-yl)pyridin-2,6-dione (19-i, 32 mg, yield 8.6%). ESI[M+H) + =1163.54

[0479] Step 7: Synthesis of 3-(6-(1-(7-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1-oxoisoindol-2-yl)pyridine-2,6-dione (19-j)

[0480] (3-(6-(1-(7-(1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)pyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1-oxoisoindoline-2-yl)pyridin-2,6-dione (19-i, 32 mg, 0.027 mmol) was dissolved in N,N-dimethylformamide (1 mL), and then cesium fluoride (21 mg, 0.13 mmol) was added. l), reacted at room temperature for 1 hour, quenched with water, extracted with ethyl acetate, the organic phase was collected and repeatedly washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude 3-(6-(1-(7-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1-oxoisoindol-2-yl)pyridin-2,6-dione (19-j, 26 mg, crude). ESI[M+H + =1007.20

[0481] Step 8: Synthesis of 3-(6-(1-(7-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1-oxoisoindol-2-yl)pyridine-2,6-dione trifluoroacetate (19)

[0482] 3-(6-(1-(7-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1-oxoisoindol-2-yl)pyridine-2,6-dione (19-j, 26 mg, 0.025 mmol) was dissolved in acetonitrile (2 mL), and dioxane hydrochloride (0.5 mL) was added. The mixture was reacted at room temperature for 0.5 hours. The reaction solution was purified by preparative liquid chromatography (aqueous phase: 0.01% trifluoroacetic acid, organic phase: acetonitrile) to obtain the target product 3-(6-(1-(7-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1-oxoisoindol-2-yl)pyridin-2,6-dione trifluoroacetate (19, 3.35 mg, yield 13.9%). ESI[M+H] + =963.14 1 H NMR(600MHz,DMSO-d6)δ10.97(s,1H),10.21(s,1H),9.85(s,1H),9.11(s,1H),8.76(s,1H),7.99-7.93(m,1H) ,7.57(s,1H),7.51-7.50(m,1H),7.46-7.43(m,1H),7.38(s,1H),7.16(s,1H),5.08-5.06(m,1H),4.44-4.41( m,1H),4.31-4.28(m,2H),4.00(s,3H),3.90(s,1H),3.70-3.55(m,4H),3.20-3.17(m,4H),3.05-2.80(m,6H), 2.61-2.58(m,1H),2.44-2.29(m,3H),2.18-1.72(m,14H),1.602-1.59(m,4H),1.21(s,2H),0.86-0.76(m,4H).

[0483] Example 20: Synthesis of 5-(4-((1-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl]piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione trifluoroacetate (20)

[0484] Step 1: Synthesis of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperazine-1-carboxylic acid (20-b)

[0485] 2-(2,6-dioxadipinidin-3-yl)-5-fluoroisoindoline-1,3-dione (20-a, 400 mg, 1.45 mmol), piperazine-1-carboxylic acid tert-butyl ester (272 mg, 1.45 mmol), and triethylamine (440 mg, 4.35 mmol) were added to a 20 mL microwave-safe tube, followed by 10 mL of dimethyl sulfoxide. The mixture was microwaved at 100 °C for 1 hour. After the reaction, the reaction solution was added to 10 mL of water and extracted three times with 15 mL of ethyl acetate each time. The organic phases were combined, concentrated under reduced pressure to remove the solvent, and the crude product was obtained. The crude product was purified by liquid chromatography (dichloromethane:methanol = 0–10%) to obtain the target product 4-(2-(2,6-dioxadipinidin-3-yl)-1,3-dioxadipinidindoline-5-yl)piperazine-1-carboxylic acid tert-butyl ester (20-b, 600 mg, yield 93%).

[0486] Step 2: Synthesis of 2-(2,6-dioxadiazin-3-yl)-5-(piperazin-1-yl)isoindole-1,3-dione (20-c)

[0487] 4-(2-(2,6-dioxadipinidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperazine-1-carboxylic acid tert-butyl ester (20-b, 600 mg, 1.35 mmol) was dissolved in dichloromethane (6 mL), and trifluoroacetic acid (2 mL) was added. The reaction was carried out at room temperature for 1 hour. The solvent was removed by vacuum distillation to obtain the target product 2-(2,6-dioxadipinidin-3-yl)-5-(piperazine-1-yl)isoindoline-1,3-dione (20-c, 700 mg, crude product). (ESI)[M+H] + =343.6.

[0488] Step 3: Synthesis of tert-butyl 4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperazin-1-yl)methyl)piperidin-1-carboxylic acid (20-d)

[0489] 2-(2,6-dioxadiazin-3-yl)-5-(piperazin-1-yl)isoindole-1,3-dione (20-c, 270 mg 0.79 mmol) and 4-formylpiperidin-1-carboxylic acid tert-butyl ester (168 mg 0.79 mmol) were dissolved in methanol (5 mL), acetic acid (1 mL) was added, and the mixture was reacted at room temperature for 1 hour. Then, sodium cyanoborohydride (150 mg 2.37 mmol) was added, and the mixture was reacted at room temperature for another hour. After the reaction was completed, the reaction solution was quenched with saturated ammonium chloride, and then extracted three times with 10 mL of dichloromethane each time. The organic phase was collected and the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by liquid chromatography (dichloromethane:methanol = 0-10%) to obtain the target product tert-butyl 4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperazin-1-yl)methyl)piperidin-1-carboxylic acid (20-d, 230 mg, yield 54%). (ESI)[M+H] + =540.6.

[0490] Step 4: Synthesis of 2-(2,6-dioxadiazin-3-yl)-5-(4-(piperidin-4-ylmethyl)piperazin-1-yl)isoindole-1,3-dione (20-e)

[0491] 4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperazin-1-yl)methyl)piperidin-1-carboxylic acid tert-butyl ester (20-d, 230 mg, 0.43 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (1 mL) was added. The reaction was carried out at room temperature for 0.5 hours. The solvent was removed by vacuum distillation to obtain the target product 2-(2,6-dioxopiperidin-3-yl)-5-(4-(piperidin-4-ylmethyl)piperazin-1-yl)isoindoline-1,3-dione (20-e, 178 mg, crude product).

[0492] Step 5: Synthesis of 5-(4-((1-(1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl]piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (20-f)

[0493] (1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl-4-methylbenzenesulfonate (I-1, 100 mg, 0.11 mmol), 2-(2,6-dioxadipinidin-3-yl)-5-(4-(piperidin-4-ylmethyl)piperazin-1-yl)isoindol-1,3-dione (20-e, 75 mg, 0.17 mmol), potassium carbonate (76 mg, 0.55 mmol), and potassium iodide (18 mg, 0.11 mmol) were dissolved in acetonitrile (5 mL) and reacted at 60 °C for 6 hours. After the reaction was completed, the solvent was removed by concentration under reduced pressure to obtain a crude product. The crude product was purified by thin-layer chromatography on silica gel plates (dichloromethane:methanol = 100:14) to obtain the target product 5-(4-((1-(1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl]piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (20-f, 23 mg, yield 18.11%). (ESI)[M+H + =1152.0.

[0494] Step 6: Synthesis of 5-(4-(((1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl]piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (20-g)

[0495] 5-(4-((1-(1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl]piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (20-f, 23 mg, 0.02 mmol) was dissolved in N,N-dimethylformamide (3 mL), and cesium fluoride (30 mmol, 0.2 mmol) was added. The reaction was carried out at room temperature for 0.5 h. After filtration of the reaction solution, the filtrate was distilled under reduced pressure using an oil pump to obtain the target product 5-(4-(((1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl]piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (20-g, 25 mg, crude product). (ESI)[M+H] + =996.0.

[0496] Step 7: Synthesis of 5-(4-((1-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl]piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione trifluoroacetate (20)

[0497] 5-(4-(((1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl]piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (20-g, 25mg 0.03mmol) was dissolved in acetonitrile (5mL), and 1,4-dioxane hydrochloride solution (1mL) was added. The reaction was carried out at room temperature for 0.5 hours. The reaction solution was distilled under reduced pressure to obtain a crude product, which was then purified by preparative liquid chromatography (aqueous phase: 0.01% trifluoroacetic acid, organic phase: acetonitrile) to obtain the target product 5-(4-((1-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl]piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione trifluoroacetate (20, 8.27 mg, yield 23.36%). (ESI)[M+H + =952.1. 1 H NMR (600MHz, DMSO-d6) δ11.09(s,1H),10.21(s,1H),9.93(s,1H),9.13(s,1H),8.97(s,1H),8.00-7.97(m,1H),7.77-7.76(d,J=8.3Hz,1H) ,7.53-7.44(m,2H),7.40-7.39(d,J=2.6Hz,1H),7.36-7.35(d,J=8.3Hz,1H),7.18-7.17(d,J=2.7Hz,1H),5.11-5.08(m,1H),4.34-4.30(t, 2H),4.22(s,1H),4.03-4.01(t,4H),3.93(s,1H),3.78-3.72(m,2H), 3.47-3.42(m,4H),3.33-3.29(m,2H),3.24-3.21(m,2H),3.11-3.05(m ,3H),2.98-2.86(m,3H),2.62-2.53(m,2H),2.05-1.90(m,8H),1.67- 1.58(m,4H),1.55-1.42(m,2H),0.90-0.88(m,2H),0.79-0.78(m,2H).

[0498] Example 21: Synthesis of 3-(6-(1-(7-(1-(((4-(3-azabicyclo[3.1.0]hex-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-5-methylpyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione trifluoroacetate (21)

[0499] Step 1: Synthesis of (1-(((4-(3-azabicyclo[3.1.0]hex-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)-5-methylpyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl-4-methylbenzenesulfonate (21-b)

[0500] (1-(((4-(3-azabicyclo[3.1.0]hex-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)-5-methylpyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (21-a, 500 mg, 0.69 mmol), triethylamine (210 mg, 2.07 mmol) and p-toluenesulfonyl chloride (526 mg, 2.76 mmol) were dissolved in dichloromethane (10 mL) and reacted at room temperature for 16 hours. The reaction solution was extracted three times with dichloromethane after the addition of water. The organic phase was concentrated under reduced pressure and then purified by liquid chromatography (petroleum ether: ethyl acetate = 0%–50%) to obtain the target product (1-(((4-(3-azabicyclo[3.1.0]hex-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)-5-methylpyridano[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl-4-methylbenzenesulfonate (21-b, 190 mg, yield 31.5%).

[0501] Step 2: 3-(6-(1-(7-(1-((4-(3-azabicyclo[3.1.0]hex-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)-5-methylpyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (21-c)

[0502] 1-(((4-(3-azabicyclo[3.1.0]hex-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)-5-methylpyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl-4-methylbenzenesulfonate (21-b, 190 mg, 0.215 mmol), potassium carbonate (150 mg, 1.075 mmol), potassium iodide (36 mg, 0.215 mmol), and 3-(6-(1-(7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione (97 mg, 0.215 mmol) were dissolved in acetonitrile (5 mL) and reacted at 60 °C for 6 hours. After the reaction was completed, the reaction solution was filtered, and water was added to the reaction solution. The solution was then extracted three times with ethyl acetate. The organic phase was concentrated under reduced pressure and purified by liquid chromatography (dichloromethane:methanol = 0%~10%) to obtain the target product 3-(6-(1-(7-(1-((4-(3-azabicyclo[3.1.0]hex-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)-5-methylpyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione (21-c, 100 mg, yield 40%).

[0503] Step 3: Synthesis of 3-(6-(1-(7-(1-(((4-(3-azabicyclo[3.1.0]hex-3-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-5-methylpyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (21-d)

[0504] 3-(6-(1-(7-(1-((4-(3-azabicyclo[3.1.0]hex-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)-5-methylpyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (21-c, 100 mg, 0.086 mmol) was dissolved in N,N-dimethylformamide (3 mL), and cesium fluoride (65 mg, 0.43 mmol) was added. The reaction was carried out at room temperature for 1 h. The reaction solution was filtered and concentrated under reduced pressure to obtain the target product 3-(6-(1-(7-(1-(((4-(3-azabicyclo[3.1.0]hex-3-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-5-methylpyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (21-d, 90 mg, crude product). (ESI)[M+H] + =1004.2

[0505] Step 4: Synthesis of 3-(6-(1-(7-(1-(((4-(3-azabicyclo[3.1.0]hex-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-5-methylpyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione trifluoroacetate (21)

[0506] 3-(6-(1-(7-(1-(((4-(3-azabicyclo[3.1.0]hex-3-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-5-methylpyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (21-d, 90 mg, 0.09 mmol) was dissolved in acetonitrile (3 mL), and 1,4-dioxane hydrochloride solution (0.4 mL) was added. The reaction was carried out at room temperature for 1 hour. The reaction solution was distilled under reduced pressure to obtain a crude product, which was then purified by preparative liquid chromatography (aqueous phase: 0.01% trifluoroacetic acid, organic phase: acetonitrile) to obtain the target product 3-(6-(1-(7-(1-(((4-(3-azabicyclo[3.1.0]hex-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-5-methylpyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione trifluoroacetate (21, 1.7 mg, yield 2%). (ESI)[M+H] + =960.14 1 H NMR(400MHz,DMSO-d6)δ10.87(s,1H),10.13(s,1H),8.01-7.93(m,1H),7.60(s,2H),7.47-7.42( m,1H),7.38(s,1H),7.22(s,1H),7.04-7.02(m,1H),6.52(s,1H),4.37-4.13(m,4H),3.96(s,2H) ,3.82-3.80(m,2H),3.68-3.39(m,5H),3.25-3.13(m,2H),3.04-2.78(m,4H),2.70-2.55(m,4H), 2.41-2.11(m,6H),2.04-1.34(m,14H),1.29-1.23(m,3H),0.62-0.59(m,2H),0.43-0.36(m,2H).

[0507] Example 22: Synthesis of 4-(4-(7-((1-((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoropyridyl[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3,5]non-2-yl)piperazin-1-yl)-N-(2,6-dioxoperidin-3-yl)-3-fluorobenzamide trifluoroacetate (22)

[0508] Step 1: Synthesis of tert-butyl 4-(2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylic acid (22-b)

[0509] Methyl 3,4-difluorobenzoate (22-a, 2.58 g, 15 mmol), piperazine-1-carboxylic acid tert-butyl ester (2.79 g, 15 mmol), and potassium carbonate (3.11 mg, 22.5 mmol) were sequentially added to a single-necked flask and reacted at 100 °C for 16 hours without solvent. The reaction was quenched with aqueous solution, extracted with ethyl acetate, and the organic phase was collected and washed with saturated sodium chloride solution. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by liquid chromatography (petroleum ether:ethyl acetate = 0%–20%) to obtain the target product 4-(2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester (22-b, 1.81 g, yield 35.8%). ESI [M+H] + =338.2

[0510] Step 2: Synthesis of 4-(4-(tert-Butoxycarbonyl)piperazin-1-yl)-3-fluorobenzoic acid (22-c)

[0511] 4-(2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester (22-b, 900 mg, 2.67 mmol) was dissolved in tetrahydrofuran (10 mL) and water (1 mL). Lithium hydroxide monohydrate (560 mg, 13.35 mmol) was added, and the mixture was reacted at 25 °C for 16 hours. The pH was adjusted to 4 with 1 N dilute hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The organic phase was collected, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the target product, 4-(4-(tert-butyloxycarbonyl)piperazine-1-yl)-3-fluorobenzoic acid (22-c, 830 g, yield 96.1%). ESI [M+H] + =324.1

[0512] Step 3: Synthesis of 4-(4-((2,6-dioxadiazin-3-yl)carbamoyl)-2-fluorophenyl)piperazine-1-carboxylic acid tert-butyl ester (22-d)

[0513] 4-(4-(tert-Butoxycarbonyl)piperazin-1-yl)-3-fluorobenzoic acid (22-c, 830 mg, 2.57 mmol), 3-aminopiperidin-2,6-dione (423 mg, 2.57 mmol), 1-hydroxybenzotriazole (419 mg, 3.08 mmol) and carbodiimide hydrochloride (590 mg, 3.08 mmol) were added to N,N-dimethylformamide (15 mL), and finally N,N-diisopropylethylamine (996 mg, 7.71 mmol) was added. The reaction was carried out at room temperature for 4 hours. Add saturated brine (30 mL), extract with ethyl acetate, collect the organic phase and wash with saturated sodium chloride solution, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by liquid chromatography (dichloromethane:methanol = 0%–10%) to obtain the target product 4-(4-((2,6-dioxadiidine-3-yl)carbamoyl)-2-fluorophenyl)piperazine-1-carboxylic acid tert-butyl ester (22-d, 750 mg, yield 67.3%). ESI [M+H] + =434.5

[0514] Step 4: Synthesis of N-(2,6-dioxadiazin-3-yl)-3-fluoro-4-(piperazin-1-yl)benzamide (22-e)

[0515] 4-(4-((2,6-dioxadiazin-3-yl)carbamoyl)-2-fluorophenyl)piperazine-1-carboxylic acid tert-butyl ester (22-d, 750 mg, 1.73 mmol) was dissolved in dichloromethane (20 mL), and trifluoroacetic acid (9 mL) was slowly added. The reaction was carried out at room temperature for 4 h. After concentration under reduced pressure, the crude product N-(2,6-dioxadiazin-3-yl)-3-fluoro-4-(piperazine-1-yl)benzamide (22-e, 700 mg, crude product) was obtained. ESI[M+H] + =335.1

[0516] Step 5: Synthesis of tert-butyl 2-(4-(4-(((2,6-dioxadiazin-3-yl)carbamoyl)-2-fluorophenyl)piperazin-1-yl)-7-azaspiro[3.5]non-7-carboxylic acid (22-f)

[0517] N-(2,6-dioxadiazin-3-yl)-3-fluoro-4-(piperazin-1-yl)benzamide (22-e, 700 mg, 2.1 mmol) was dissolved in methanol (15 mL), and 2-oxo-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (753 mg, 3.15 mmol) and acetic acid (120 mg, 2.1 mmol) were added sequentially. The mixture was stirred at 55 °C for 1 h, and then sodium cyanoborohydride (397 mg, 6.3 mmol) was added. The mixture was stirred at 55 °C for another 16 h. Quenching with water, extraction with ethyl acetate, collection of the organic phase and washing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtration, concentration under reduced pressure, and purification by liquid chromatography (dichloromethane:methanol = 0%–10%) yielded the target product 2-(4-(4-(((2,6-dioxadiazin-3-yl)carbamoyl)-2-fluorophenyl)piperazin-1-yl)-7-azaspiro[3.5]non-7-carboxylic acid tert-butyl ester (22-f, 1.03 g, yield 88.7%). ESI[M+H] + =557.9

[0518] Step 6: Synthesis of 4-(4-(7-azaspiro[3.5]non-2-yl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)-3-fluorobenzamide (22-g)

[0519] 2-(4-(4-((((2,6-dioxadiazin-3-yl)carbamoyl)-2-fluorophenyl)piperazin-1-yl)-7-azaspiro[3.5]non-7-carboxylic acid tert-butyl ester (22-f, 1.03 g, 1.73 mmol) was dissolved in dichloromethane (20 mL), and trifluoroacetic acid (10 mL) was slowly added. The reaction was carried out at room temperature for 2 h. After concentration under reduced pressure, crude product 4-(4-(7-azaspiro[3.5]non-2-yl)piperazin-1-yl)-N-(2,6-dioxadiazin-3-yl)-3-fluorobenzamide (22-g, 700 mg, crude product) was obtained. ESI[M+H]+=335.1

[0520] Step 7: Synthesis of 4-(4-(7-((1-(((4-(azacyclopent-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-7-((triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3,5]non-2-yl)piperazin-1-yl)-N-(2,6-dioxypiperidin-3-yl)-3-fluorobenzamide (22-h)

[0521] (1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl-4-methylbenzenesulfonate (I-1, 126 mg, 0.14 mmol) and 4-(4-(7-azaspiro[3.5]non-2-yl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)-3-fluorobenzamide (22-g, 98 mg, 0.21 mmol) were dissolved in acetonitrile (5 mL), and potassium iodide (23 mg, 0.14 mmol) and potassium carbonate (103 mg, 0.7 mmol) were added sequentially. The mixture was stirred at 60 °C for 16 h. Saturated brine was added, and the mixture was extracted with ethyl acetate. The organic phase was collected and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by thin-layer chromatography on silica gel plates (dichloromethane:methanol = 0%–10%) to obtain the target product 4-(4-(7-((1-(((4-(azacyclopent-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-7-((triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3,5]non-2-yl)piperazin-1-yl)-N-(2,6-dioxypiperidin-3-yl)-3-fluorobenzamide (22-h, 31 mg, yield 18.7%).

[0522] Step 8: Synthesis of 4-(4-(7-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3,5]non-2-yl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)-3-fluorobenzamide (22-i)

[0523] 4-(4-(7-((1-(((4-(azacyclopent-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-7-((triisopropylsilyl)ethynyl)naphth-1-yl)pyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3,5]non-2-yl)piperazin-1-yl)-N-(2,6-dioxypiperidin-3-yl)-3-fluorobenzamide (22-h, 31 mg, 0.03 mmol) was dissolved in N,N-dimethylformamide (2 mL), and cesium fluoride (23 mg, 0.15 mmol) was added. The mixture was reacted at room temperature for 1 h. Quenching with water, extraction with ethyl acetate, collection of the organic phase and washing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtration, and concentration under reduced pressure yielded the crude product 4-(4-(7-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3,5]non-2-yl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)-3-fluorobenzamide (22-i, 20 mg, crude product). ESI[M+H] + =1014.1

[0524] Step 9: Synthesis of 4-(4-(7-((1-((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoropyridyl[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3,5]non-2-yl)piperazin-1-yl)-N-(2,6-dioxoperidin-3-yl)-3-fluorobenzamide trifluoroacetate (22)

[0525] 4-(4-(7-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)-3-fluorobenzamide (22-i, 20 mg, 0.02 mmol) was dissolved in acetonitrile (1 mL), and dioxane hydrochloride (0.5 mL) was slowly added. The reaction was carried out at room temperature for 2 h. After concentration under reduced pressure, the crude product was purified by preparative liquid chromatography (aqueous phase: 0.01% trifluoroacetic acid, organic phase: acetonitrile) to obtain the target product 4-(4-(7-((1-((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridinyl[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)piperazin-1-yl)-N-(2,6-dioxadiazin-3-yl)-3-fluorobenzamide trifluoroacetate (22, 1.29 mg, yield 6%). ESI[M+H] + =970.2 1 H NMR(400MHz,DMSO-d6)δ10.83(s,1H),10.19(s,1H),9.05(s,1H),8.64-8.62(m,1H),8.33(s,2H),7.99-7.93(m,1H ),7.67-63(m,2H),7.48-7.44(m,1H),7.38(s,1H),7.18-7.15(m,1H),7.05-7.00(m,1H),4.73(s,1H),4.28-4.26(m ,2H),3.98-3.96(m,2H),3.08(s,4H),2.77-2.72(m,2H),2.66-2.65(m,2H),2.53-2.48(m,2H),2.27-2.25(m,4H), 2.21-2.00(m,2H),1.99-1.93(m,6H),1.86-1.62(m,4H),1.58-1.47(m,4H),1.22(s,1H),0.83(s,2H),0.60(s,2H).

[0526] Example 23: Synthesis of 3-(6-(1-(2-(1-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)ethyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione trifluoroacetate (23)

[0527] Step 1: Synthesis of tert-butyl 4-(2-(4-(3-(2,6-dioxypiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)ethyl)piperidin-1-carboxylic acid (23-b)

[0528] 3-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)piperidin-2,6-dione (I-2, 100 mg, 0.30 mmol), tert-butyl 4-(2-bromoethyl)piperidin-1-carboxylate (23-a, 60 mg, 0.21 mmol) and potassium carbonate (200 mg, 1.5 mmol) were dissolved in acetonitrile (5 mL) and the mixture was heated to 80 °C and reacted for 6 hours. The reaction solution was extracted three times with ethyl acetate after adding water. The organic phase was concentrated under reduced pressure and then purified by liquid chromatography (dichloromethane:methanol = 0%–10%) to obtain the target product 4-(2-(4-(3-(2,6-dioxypiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)ethyl)piperidin-1-carboxylic acid tert-butyl ester (23-b, 40 mg, yield 24.4%) ESI[M+H]. + =538.5

[0529] Step 2: Synthesis of 3-(1-methyl-6-(1-(2-(piperidin-4-yl)ethyl)piperidin-4-yl)-1H-indazol-3-yl)piperidin-2,6-dione (23-c)

[0530] 4-(2-(4-(3-(2,6-dioxypiperidin-3-yl)-1-methyl-1H-indazole-6-yl)piperidin-1-yl)ethyl)piperidin-1-carboxylic acid tert-butyl ester (23-b, 40 mg, 0.074 mmol) was dissolved in dichloromethane (2 mL) and added to trifluoroacetic acid (0.5 mL). The reaction was carried out at room temperature for 1 hour. After concentration under reduced pressure, the target product 3-(1-methyl-6-(1-(2-(piperidin-4-yl)ethyl)piperidin-4-yl)-1H-indazole-3-yl)piperidin-2,6-dione (23-c, 60 mg, crude product) ESI[M+H] was obtained. + =438.6

[0531] Step 3: Synthesis of 3-(6-(1-(2-(1-(1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy))-8-((triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)ethyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (23-d)

[0532] (1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl-4-methylbenzenesulfonate (I-1, 150 mg, 0.168 mmol), potassium carbonate (97 mg, 0.7 mmol), potassium iodide (24 mg, 0.14 mmol), 3-(1-methyl-6-(1-(2-(piperidin-4-yl)ethyl)piperidin-4-yl)-1H-indazole-3-yl)piperidin-2,6-dione (23-c, 60 mg, 0.14 mmol) was dissolved in acetonitrile (5 mL), and the reaction was carried out at 60 °C for 16 hours. After the reaction was completed, the reaction solution was filtered, and water was added to the reaction solution. The solution was then extracted three times with ethyl acetate. The organic phase was concentrated under reduced pressure and purified by liquid chromatography (dichloromethane:methanol = 0%–10%) to obtain the target product 3-(6-(1-(2-(1-(1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy))-8-((triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)ethyl)piperidin-4-yl)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione (23-d, 25 mg, yield 15.6%).

[0533] Step 4: Synthesis of 3-(6-(1-(2-(1-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)ethyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (23-e)

[0534] 3-(6-(1-(2-(1-(1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy))-8-((triisopropylsilyl)ethynyl)naphth-1-yl)pyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)ethyl)piperidin-4-yl)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione (23-d, 25 mg, 0.022 mmol) was dissolved in N,N-dimethylformamide (1 mL), and cesium fluoride (17 mg, 0.11 mmol) was added. The mixture was reacted at room temperature for 1 h. The reaction solution was filtered and concentrated under reduced pressure to obtain the target product 3-(6-(1-(2-(1-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)ethyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (23-e, 30 mg, crude product). (ESI)[M+H] + =994.6

[0535] Step 5: Synthesis of 3-(6-(1-(2-(1-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)ethyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione trifluoroacetate (23)

[0536] 3-(6-(1-(2-(1-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)ethyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (23-e, 30 mg, 0.03 mmol) was dissolved in acetonitrile (2 mL), and 1,4-dioxane hydrochloride solution (0.4 mL) was added. The mixture was reacted at room temperature for 1 hour. The reaction solution was distilled under reduced pressure to obtain a crude product, which was then purified by preparative liquid chromatography (aqueous phase: 0.01% trifluoroacetic acid, organic phase: acetonitrile) to obtain the target product 3-(6-(1-(2-(1-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)ethyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione trifluoroacetate (23, 2.14 mg, yield 8.5%). (ESI)[M+H + =950.5 1 H NMR(400MHz,DMSO-d6)δ10.87(s,1H),10.18(s,1H),9.32(s,1H),9.12(s,1H),8.72(s,1H),7.99-7.93(m,1H),7 .67-7.64(m,1H),7.48-7.44(m,1H),7.38(s,1H),7.18-7.16(m,1H),7.02-7.00(m,1H),4.35-4.29(m,2H),4.01( s,3H),3.97(s,2H),3.92(s,1H),3.75-3.66(m,2H),3.58-3.57(m,2H),3.29-3.17(m,4H),3.14-2.85(m,8H),2. 71-2.53(m,3H),2.38-2.31(m,1H),2.17-2.04(m,3H),1.96-1.87(m,6H),1.61-1.45(m,10H),0.87-0.76(m,4H).

[0537] Example 24: Synthesis of 3-(6-(1'-((1-((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-[1,4'-piperidin]-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione trifluoroacetate (24)

[0538] Step 1: Synthesis of tert-butyl 4-(3-(2,6-dioxadiazin-3-yl)-1-methyl-1H-indazol-6-yl)-[1,4'-dipiperidine]-1'-carboxylic acid (24-a)

[0539] 3-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)piperidin-2,6-dione (I-2, 300 mg, 0.92 mmol) and tert-butyl 4-iodopiperidin-1-carboxylate (429 mg, 1.38 mmol) were dissolved in acetonitrile (14 mL), and then potassium carbonate (636 mg, 4.6 mmol) was added. The reaction was carried out at 80 °C for 16 hours. After the reaction was completed, the solvent was removed by concentration under reduced pressure. The crude product was obtained, and extracted three times with 50 mL of ethyl acetate (100 mL each time) after adding 100 mL of water. The organic phase was collected, concentrated under reduced pressure, and purified by thin-layer chromatography on silica gel plates (dichloromethane:methanol = 0–10%) to obtain the target product 4-(3-(2,6-dioxadiazin-3-yl)-1-methyl-1H-indazol-6-yl)-[1,4'-dipiperidine]-1'-carboxylic acid tert-butyl ester (24-a, 69 mg, yield 14.71%). (ESI)[M+H + =510.5.

[0540] Step 2: Synthesis of 3-(6-([1,4'-dipiperidin]-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (24-b)

[0541] 4-(3-(2,6-dioxypiperidin-3-yl)-1-methyl-1H-indazole-6-yl)-[1,4'-dipiperidin]-1'-carboxylic acid tert-butyl ester (24-a, 69 mg, 0.14 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (1 mL) was added. The reaction was carried out at room temperature for 0.5 hours. The solvent was removed by vacuum distillation to obtain the crude target product 3-(6-([1,4'-dipiperidin]-4-yl)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione (24-b, 80 mg, crude).

[0542] Step 3: Synthesis of 3-(6-(1'-((1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-7-((triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-[1,4'-dipiperidin]-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (24-c)

[0543] (1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl-4-methylbenzenesulfonate (I-1, 115 mg, 0.13 mmol), potassium carbonate (90 mg, 0.65 mmol), potassium iodide (22 mg, 0.13 mmol), and 3-(6-([1,4'-dipiperidin]-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (24-b, 80 mg, 0.2 mmol) were dissolved in acetonitrile (5 mL) and reacted at 60 °C for 6 hours. After the reaction was completed, the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by thin-layer chromatography on silica gel plates (dichloromethane:methanol = 100:14) to obtain the target product 3-(6-(1'-((1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-7-((triisopropylsilyl)ethynyl)naphth-1-yl)pyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-[1,4'-dipiperidin]-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (24-c, 26 mg, yield 17.81%). (ESI)[M+H] + =1121.8.

[0544] Step 4: Synthesis of 3-(6-(1'-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-[1,4'-piperidin]-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (24-d)

[0545] 3-(6-(1'-((1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-7-((triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-[1,4'-dipiperidin]-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (24-c, 26 mg, 0.02 mmol) was dissolved in N,N-dimethylformamide (3 mL), and cesium fluoride (30 mg, 0.2 mmol) was added. The mixture was reacted at room temperature for 0.5 h. After filtration of the reaction solution, the filtrate was distilled under reduced pressure using an oil pump to obtain the crude target product, 3-(6-(1'-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-[1,4'-piperidin]-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (24-d, 27 mg, crude product). (ESI)[M+CH3OH] + =998.5.

[0546] Step 5: Synthesis of 3-(6-(1'-((1-((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-[1,4'-piperidin]-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione trifluoroacetate (24)

[0547] 3-(6-(1'-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-[1,4'-piperidine]-4-yl)-1-methyl-1H-indazole-3-yl)piperidine-2,6-dione (24-d, 27 mg, 0.03 mmol) was dissolved in acetonitrile (5 mL), and 1,4-dioxane hydrochloride solution (1 mL) was added. The reaction was carried out at room temperature for 0.5 hours. The reaction solution was distilled under reduced pressure to obtain a crude product, which was then purified by preparative liquid chromatography (aqueous phase: 0.01% trifluoroacetic acid, organic phase: acetonitrile) to obtain the target product 3-(6-(1'-((1-((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-[1,4'-piperidin]-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione trifluoroacetate (24 mg, 10.79 mg, yield 30.83%). (ESI)[M+H + =922.5. 1 H NMR (600MHz, DMSO-d6) δ10.22-10.06(d,J=98.1Hz,1H),9.33(s,1H),9.12(s,1H),7.97-7.94(m,1H),7.83-7.82(d,J=8.4Hz,1H),7.54(s,1 H),7.46-7.37(m,2H),7.31(s,1H),7.18(s,1H),7.00-6.95(m,2H),4. 38-4.29(m,2H),4.03-4.01(d,J=5.9Hz,4H),3.97(s,3H),3.93(s,1H) ,3.90-3.88(m,1H),3.85-3.84(d,J=10.7Hz,1H),3.57-3.53(m,3H), 3.32-3.29(m,1H),3.25-3.20(m,1H),3.18-3.15(m,2H),3.08-3.04(m ,2H),2.98-2.94(t,1H),2.37-2.25(m,5H),2.19-2.13(m,2H),2.09-1 .93(m,10H),1.67-1.58(m,4H),0.92-0.89(m,2H),0.84-0.74(m,2H).

[0548] Example 25: Synthesis of 3-(5-(1-(7-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6-dione trifluoroacetate (25)

[0549] Step 1: Synthesis of tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid (25-b)

[0550] 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6-dione (25-a, 500 mg, 1.48 mmol), potassium phosphate (942 mg, 4.44 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (162 mg, 0.22 mmol), and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (915 mg, 2.96 mmol) were dissolved in N,N-dimethylformamide (37.5 mL), purged with nitrogen three times, and reacted at 90 °C for 5 hours. After the reaction was complete, the reaction solution was added to 500 mL of water, and extracted three times with 250 mL of ethyl acetate each time. The organic phases were combined, and the solvent was filtered through diatomaceous earth. The solvent was then concentrated under reduced pressure to obtain the crude product. The crude product was dried by an oil pump, mixed, and purified by liquid chromatography (dichloromethane:methanol = 0–2%) to obtain the target product 4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (25-b, 460 mg, yield 70.55%). (ESI)[M+H + =441.4

[0551] Step 2: Synthesis of tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidine-1-carboxylate (25-c)

[0552] 4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (25-b, 360 mg, 0.82 mmol) was dissolved in dichloromethane (30 mL) and methanol (3 mL), and 250 mg of 10% palladium on carbon was added. After three purgings with hydrogen, the reaction was carried out at room temperature for 6 h. The reaction solution was filtered through diatomaceous earth, and the filtrate was distilled under reduced pressure to obtain the target product, 4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidin-1-carboxylic acid tert-butyl ester (25-c, 355 mg, 98% yield). (ESI)[M+H] + =443.5.

[0553] Step 3: Synthesis of 3-(3-methyl-2-oxo-5-(piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6-dione (25-d)

[0554] 4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidine-1-carboxylic acid tert-butyl ester (25-d, 355 mg, 0.8 mmol) was dissolved in dichloromethane (20 mL), and trifluoroacetic acid (1 mL) was added. The reaction was carried out at room temperature for 0.5 hours. The solvent was removed by vacuum distillation to obtain the target product 3-(3-methyl-2-oxo-5-(piperidine-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (25-d, 520 mg, crude product).

[0555] Step 4: Synthesis of tert-butyl 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-carboxylic acid (25-e)

[0556] 3-(3-methyl-2-oxo-5-(piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6-dione (25-d, 250 mg, 0.73 mmol) and tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylic acid (263 mg, 1.1 mmol) were dissolved in methanol (10 mL) and tetrahydrofuran (2.5 mL), acetic acid (44 mg, 0.73 mmol) was added, and the mixture was reacted at 55 °C for 1 hour. Then, sodium cyanoborohydride (138 mg, 2.19 mmol) was added, and the reaction was continued at 55 °C for 16 hours. After the reaction was completed, the product was concentrated under reduced pressure to obtain a crude product. The crude product was purified by thin-layer chromatography using silica gel plates (dichloromethane:methanol = 0-10%) to obtain the target product 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-carboxylic acid tert-butyl ester (25-e, 150 mg, yield 36.32%). (ESI)[M+H + =566.3.

[0557] Step 5: Synthesis of 3-(5-(1-(7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6-dione (25-f)

[0558] 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-carboxylic acid tert-butyl ester (25-e, 206 mg, 0.36 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (1 mL) was added. The reaction was carried out at room temperature for 0.5 hours. The solvent was removed by vacuum distillation to obtain the target product 3-(5-(1-(7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6-dione (25-f, 235 mg, crude product).

[0559] Step 6: Synthesis of 3-(5-(1-(7-(1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3,5]non-2-yl)piperidin-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6-dione (25-g)

[0560] (1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl-4-methylbenzenesulfonate (I-1, 100 mg, 0.11 mmol), potassium carbonate (76 mg, 0.55 mmol), potassium iodide (18 mg, 0.11 mmol), 3-(5-(1-(7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6-dione (25-f, 79 mg, 0.17 mmol) were dissolved in acetonitrile (5 mL) and reacted at 60 °C for 6 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by thin-layer chromatography on silica gel plates (dichloromethane:methanol = 100:13) to obtain the target product 3-(5-(1-(7-(1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)pyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3,5]non-2-yl)piperidin-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6-dione (25-g, 26 mg, yield 20%). (ESI)1 / 2[M+CH3OH) + =606.0.

[0561] Step 7: Synthesis of 3-(5-(1-(7-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6-dione (25-h)

[0562] 3-(5-(1-(7-(1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)pyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6-dione (25-g, 26mg, 0.02mmol) was dissolved in N,N-dimethylformamide (3mL), and cesium fluoride (30mmol, 0.2mmol) was added. The reaction was carried out at room temperature for 0.5h. After filtration of the reaction solution, the filtrate was distilled under reduced pressure using an oil pump to obtain the target product 3-(5-(1-(7-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6-dione (25-h, 23 mg, crude product). (ESI)1 / 2[M+H + =512.1.

[0563] Step 8: Synthesis of 3-(5-(1-(7-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6-dione trifluoroacetate (25)

[0564] 3-(5-(1-(7-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6-dione (25-h, 23 mg, 0.02 mmol) was dissolved in acetonitrile (5 mL), and 1,4-dioxane hydrochloride solution (1 mL) was added. The reaction was carried out at room temperature for 0.5 hours. The reaction solution was distilled under reduced pressure to obtain a crude product, which was then purified by preparative liquid chromatography (aqueous phase: 0.01% trifluoroacetic acid, organic phase: acetonitrile) to obtain the target product 3-(5-(1-(7-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6-dione trifluoroacetate (25, 5.92 mg, yield 24.54%). (ESI)1 / 2[M+H + =490.1. 1H NMR (600MHz, DMSO-d6) δ11.10 (s, 1H), 10.21-10.17 (d, J = 24.1Hz, 1H), 9.96 -9.89(t,1H),9.13(s,1H),8.81(s,1H),7.99-7.97(m,1H),7.49-7.45(m,1H ),7.40-7.39(d,J=2.5Hz,1H),7.18-7.17(d,J=2.5Hz,1H),7.08-7.07(d,J =8.2Hz,1H),7.05-7.00(m,1H),6.92-6.89(d,J=8.6Hz,1H),5.38-5.34(m,1 H),4.35-4.28(m,2H),4.04-4.01(t,4H),3.93(s,1H),3.73-3.67(m,2H),3 .46-3.44(m,3H),3.34-3.32(m,3H),3.26-3.18(m,2H),2.93-2.85(m,4H),2 .75-2.67(m,1H),2.64-2.61(m,1H),2.41-2.33(m,1H),2.14-2.09(t,2H),2 .08-1.78(m,16H),1.66-1.58(m,4H),0.89-0.88(m,2H),0.80-0.75(m,2H).

[0565] Example 26: Synthesis of 3-(5-(1-(7-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-6-fluoro-1-oxoisoindol-2-yl)piperidin-2,6-dione trifluoroacetate (26)

[0566] Step 1: Synthesis of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindoline-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid (26-b)

[0567] 3-(5-bromo-6-fluoro-1-oxoisoindol-2-yl)piperidin-2,6-dione (26-a, 460 mg, 1.35 mmol), potassium phosphate (860 mg, 4.05 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (146 mg, 0.2 mmol), and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (835 mg, 2.7 mmol) were dissolved in N,N-dimethylformamide (34 mL), purged three times with nitrogen, and reacted at 90 °C for 21 hours. After the reaction was complete, the reaction solution was added to 500 mL of water, and extracted three times with 250 mL of ethyl acetate each time. The organic phases were combined, and the solvent was filtered through diatomaceous earth. The solvent was then removed by vacuum concentration to obtain the crude product. The crude product was dried by an oil pump, mixed, and purified by liquid chromatography (dichloromethane:methanol = 0–2%) to obtain the target product 4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindoline-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (26-b, 300 mg, yield 48%). (ESI)[M+H] + =444.4.

[0568] Step 2: Synthesis of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindoline-5-yl)piperidin-1-carboxylic acid (26-c)

[0569] 4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindoline-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (26-b, 80 mg, 0.18 mmol) was dissolved in tetrahydrofuran (5 mL) and methanol (1 mL), and 100 mg of 10% palladium on carbon was added. After three hydrogen purgings, the mixture was reacted at 30 °C for 24 h. The reaction solution was filtered through diatomaceous earth, and the filtrate was distilled under reduced pressure to obtain the target product, 4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindoline-5-yl)piperidin-1-carboxylic acid tert-butyl ester (26-c, 85 mg, crude product). (ESI)[M+H] + =446.0

[0570] Step 3: Synthesis of 3-(6-fluoro-1-oxo-5-(piperidin-4-yl)isoindol-2-yl)piperidin-2,6-dione (26-d)

[0571] 4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperidin-1-carboxylic acid tert-butyl ester (26-c, 85 mg, 0.19 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (1 mL) was added. The reaction was carried out at room temperature for 0.5 hours. The solvent was removed by vacuum distillation to obtain the target product 3-(6-fluoro-1-oxo-5-(piperidin-4-yl)isoindolin-2-yl)piperidin-2,6-dione (26-d, 120 mg, crude product).

[0572] Step 4: Synthesis of tert-butyl 2-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindoline-5-yl)piperidin-1-yl)-7-azaspiro[3.5]non-7-carboxylic acid (26-e)

[0573] 3-(6-fluoro-1-oxo-5-(piperidin-4-yl)isoindol-2-yl)piperidin-2,6-dione (26-d, 120 mg, 0.35 mmol) and tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylic acid (168 mg, 0.7 mmol) were dissolved in methanol (4 mL) and tetrahydrofuran (1 mL), acetic acid (21 mg, 0.35 mmol) was added, and the mixture was reacted at 55 °C for 1 hour. Then, sodium cyanoborohydride (66 mg, 1.05 mmol) was added, and the mixture was reacted at 55 °C for another 6 hours. After the reaction was completed, the crude product was concentrated under reduced pressure. The crude product was purified by thin-layer chromatography on silica gel plates (dichloromethane: methanol = 0-10%) to obtain the target product 2-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindoline-5-yl)piperidin-1-yl)-7-azaspiro[3.5]non-7-carboxylic acid tert-butyl ester (26-e, 28 mg, yield 14.07%).

[0574] Step 5: Synthesis of 3-(5-(1-(7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-6-fluoro-1-oxoisoindol-2-yl)pyridine-2,6-dione (26-f)

[0575] 2-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperidin-1-yl)-7-azaspiro[3.5]non-7-carboxylic acid tert-butyl ester (26-e, 28 mg, 0.05 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (0.5 mL) was added. The reaction was carried out at room temperature for 0.5 hours. The solvent was removed by vacuum distillation to obtain the target product 3-(5-(1-(7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl)pyridine-2,6-dione (26-f, 37 mg, crude product).

[0576] Step 6: Synthesis of 3-(5-(1-(7-(1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-7-((triisopropylsilyl)ethynyl)naphth-1-yl)pyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3,5]non-2-yl)piperidin-4-yl)-6-fluoro-1-oxoisoindoline-2-yl)pyridine-2,6-dione (26-g)

[0577] (1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl-4-methylbenzenesulfonate (I-1, 53 mg, 0.06 mmol), potassium carbonate (41 mg, 0.3 mmol), potassium iodide (10 mg, 0.06 mmol), 3-(5-(1-(7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-6-fluoro-1-oxoisoindol-2-yl)pyridine-2,6-dione (26-f, 37 mg, 0.08 mmol) were dissolved in acetonitrile (3 mL) and reacted at 60 °C for 16 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by thin-layer chromatography on silica gel plates (dichloromethane:methanol = 100:13) to obtain the target product 3-(5-(1-(7-(1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-7-((triisopropylsilyl)ethynyl)naphth-1-yl)pyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3,5]non-2-yl)piperidin-4-yl)-6-fluoro-1-oxoisoindoline-2-yl)pyridin-2,6-dione (26-g, 17mg, yield 23.98%). (ESI)1 / 2[M+CH3OH) + =607.2.

[0578] Step 7: Synthesis of 3-(5-(1-(7-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-6-fluoro-1-oxoisoindol-2-yl)pyridine-2,6-dione (26-h)

[0579] 3-(5-(1-(7-(1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-7-((triisopropylsilyl)ethynyl)naphth-1-yl)pyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-6-fluoro-1-oxoisoindoline-2-yl)pyridine-2,6-dione (26-g, 17mg, 0.014mmol) was dissolved in N,N-dimethylformamide (3mL), and cesium fluoride (21mmol, 0.14mmol) was added. The reaction was carried out at room temperature for 0.5h. After filtration of the reaction solution, the filtrate was distilled under reduced pressure using an oil pump to obtain the target product 3-(5-(1-(7-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-6-fluoro-1-oxoisoindol-2-yl)pyridin-2,6-dione (26-h, 16 mg, crude product). (ESI)[M+H] + =1025.3.

[0580] Step 8: Synthesis of 3-(5-(1-(7-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-6-fluoro-1-oxoisoindol-2-yl)piperidin-2,6-dione trifluoroacetate (26)

[0581] 3-(5-(1-(7-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-6-fluoro-1-oxoisoindol-2-yl)pyridine-2,6-dione (26-h, 16 mg, 0.016 mmol) was dissolved in acetonitrile (5 mL), and 1,4-dioxane hydrochloride solution (1 mL) was added. The reaction was carried out at room temperature for 0.5 hours. The reaction solution was distilled under reduced pressure to obtain a crude product, which was then purified by preparative liquid chromatography (aqueous phase: 0.01% trifluoroacetic acid, organic phase: acetonitrile) to obtain the target product 3-(5-(1-(7-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-6-fluoro-1-oxoisoindol-2-yl)piperidin-2,6-dione trifluoroacetate (26, 5.24 mg, yield 27.08%). (ESI)[M+H + =981.3. 1 H NMR(600MHz,DMSO-d6)δ11.00(s,1H),10.20(s,1H),9.84(s,1H),9.13(s ,1H),8.76(s,1H),7.99-7.97(m,1H),7.56-7.53(t,2H),7.47-7.45(t,1H ),7.39(s,1H),7.17(s,1H),5.14-5.11(m,1H),4.48-4.44(d,J=17.1Hz, 1H),4.36-4.28(m,3H),4.02-4.01(t,4H),3.92(s,1H),3.68-3.63(m,3H) ,3.52(s,1H),3.49-3.48(m,2H),3.26-3.23(d,J=18.4Hz,2H),3.20-3.1 7(m,1H),3.03-2.87(m,5H),2.62-2.59(d,J=15.5Hz,1H),2.43-2.32(m,2 H),2.13-2.12(d,J=8.3Hz,2H),2.06-1.99(m,4H),1.95-1.93(m,7H),1. 80-1.77(m,2H),1.64-1.60(m,4H),0.88-0.87(m,2H),0.78-0.75(m,2H).

[0582] Example 27: Synthesis of 3-(6-(1-(3-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-3-azabicyclo[3.2.0]heptane-6-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione trifluoroacetate (27)

[0583] Step 1: Synthesis of tert-butyl 6-(4-(3-(2,6-dioxadiazin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-3-azabicyclo[3.2.0]heptane-3-carboxylic acid (27-a)

[0584] 3-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)piperidin-2,6-dione (I-2, 150 mg, 0.46 mmol) and 6-oxo-3-azabicyclo[3.2.0]heptane-3-carboxylic acid tert-butyl ester (146 mg, 0.69 mmol) were dissolved in methanol (7.5 mL) and tetrahydrofuran (1.8 mL), then acetic acid (28 mg, 0.46 mmol) was added, and the mixture was reacted at 55 °C for 1 hour. Sodium cyanoborohydride (87 mg) was then added. The reaction was continued at 55°C for 16 hours. After the reaction was completed, the solvent was removed by concentration under reduced pressure to obtain the crude product. The crude product was purified by thin-layer chromatography on silica gel plates (dichloromethane:methanol = 0-10%) to obtain the target product 6-(4-(3-(2,6-dioxadiazin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-3-azabicyclo[3.2.0]heptane-3-carboxylic acid tert-butyl ester (27-a, 28 mg, yield 11.67%). (ESI)[M+H + =522.1.

[0585] Step 2: Synthesis of 3-(6-(1-(3-azabicyclo[3.2.0]heptane-6-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (27-b)

[0586] 6-(4-(3-(2,6-dioxadiazin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-3-azabicyclo[3.2.0]heptane-3-carboxylic acid tert-butyl ester (27-a, 28 mg, 0.05 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (1 mL) was added. The reaction was carried out at room temperature for 0.5 hours. The solvent was removed by vacuum distillation to obtain the crude target product 3-(6-(1-(3-azabicyclo[3.2.0]heptane-6-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (27-b, 35 mg, crude product).

[0587] Step 3: Synthesis of 3-(6-(1-(3-(1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-7-((triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-3-azabicyclo[3.2.0]heptane-6-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (27-c)

[0588] (1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl-4-methylbenzenesulfonate (I-1, 62 mg, 0.07 mmol), potassium carbonate (48 mg, 0.35 mmol), potassium iodide (12 mg, 0.08 mmol), 3-(6-(1-(3-azabicyclo[3.2.0]heptane-6-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (27-b, 35 mg, 1.2 mmol) were dissolved in acetonitrile (5 mL) and reacted at 60 °C for 6 hours. After the reaction was completed, the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by thin-layer chromatography on silica gel plates (dichloromethane:methanol = 100:13) to obtain the target product 3-(6-(1-(3-(1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-7-((triisopropylsilyl)ethynyl)naphth-1-yl)pyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-3-azabicyclo[3.2.0]heptane-6-yl)piperidin-4-yl)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione (27-c, 18 mg, yield 22.78%). (ESI)[M+CH3OH] + =1166.7.

[0589] Step 4: Synthesis of 3-(6-(1-(3-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-3-azabicyclo[3.2.0]heptane-6-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (27-d)

[0590] 3-(6-(1-(3-(1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-7-((triisopropylsilyl)ethynyl)naphth-1-yl)pyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-3-azabicyclo[3.2.0]heptane-6-yl)piperidin-4-yl)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione (27-c, 18 mg, 0.02 mmol) was dissolved in N,N-dimethylformamide (2 mL), and cesium fluoride (30 mg, 0.2 mmol) was added. The reaction was carried out at room temperature for 0.5 h. After filtration of the reaction solution, the filtrate was distilled under reduced pressure using an oil pump to obtain the crude target product 3-(6-(1-(3-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-3-azabicyclo[3.2.0]heptane-6-yl)piperidin-4-yl)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione (27-d, 17 mg, crude product). (ESI)[M+H + =978.6.

[0591] Step 5: Synthesis of 3-(6-(1-(3-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-3-azabicyclo[3.2.0]heptane-6-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione trifluoroacetate (27)

[0592] 3-(6-(1-(3-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-3-azabicyclo[3.2.0]heptane-6-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (27-d, 17 mg, 0.017 mmol) was dissolved in acetonitrile (5 mL), and 1,4-dioxane hydrochloride solution (1 mL) was added. The reaction was carried out at room temperature for 0.5 hours. The reaction solution was distilled under reduced pressure to obtain a crude product, which was then purified by preparative liquid chromatography (aqueous phase: 0.01% trifluoroacetic acid, organic phase: acetonitrile) to obtain the target product 3-(6-(1-(3-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-3-azabicyclo[3.2.0]heptane-6-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione trifluoroacetate (27, 7.14 mg, yield 42.93%). (ESI)[M+H + =934.6. 1 H NMR (600MHz, DMSO-d6) δ10.88(s,1H),10.19-10.14(t,1H),9.89-9.85(d,J=22.0Hz,1H),9.12-9.11(d,J=6.7Hz,1H),7.97(s,1H) ,7.80-7.65(d,J=87.9Hz,1H),7.52-7.29(m,4H),7.17(s,1H),7.03-6.98(d,J=25.2Hz,1H),4.34-4.32(m,1H),4.29-4.09(m,2H), 4.01(s,4H),3.97-3.91(m,4H),3.89-3.77(m,2H),3.56(s,1H),3.21-3.15(m,2H),3.07-2.91(m,4H),2.68-2.67(d,J=10.4Hz,1H ),2.61(s,1H),2.56-2.51(m,1H),2.39-2.24(m,3H),2.17-2.09(m,2H),2.03-1.95(m,10H),1.61-1.58(m,5H),0.98-0.78(m,4H).

[0593] Example 28: Synthesis of 3-(6-(1-(3-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-3-azaspiro[5.5]undecane-9-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione trifluoroacetate (28)

[0594] Step 1: Synthesis of tert-butyl 9-(4-(3-(2,6-dioxadiazin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-3-azaspiro[5.5]undecane-3-carboxylic acid (28-a)

[0595] 3-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)piperidin-2,6-dione (I-2, 100 mg, 0.31 mmol) and 9-oxo-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (144 mg, 0.62 mmol) were dissolved in methanol (5 mL) and tetrahydrofuran (1.25 mL), then acetic acid (10 mg, 0.16 mmol) was added, and the mixture was reacted at 55 °C for 1 hour. Sodium cyanoborohydride (129 g) was then added. The reaction was continued at 55°C for 19 hours. After the reaction was completed, the solvent was removed by concentration under reduced pressure to obtain the crude product. The crude product was purified by thin-layer chromatography on silica gel plates (dichloromethane:methanol = 0-10%) to obtain the target product 9-(4-(3-(2,6-dioxadiazin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (28-a, 50 mg, yield 27.93%). Another batch was prepared in the same proportion to obtain 28 mg of product. (ESI)[M+H] + =578.2.

[0596] Step 2: Synthesis of 3-(6-(1-(3-azaspiro[5.5]undecane-9-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (28-b)

[0597] 9-(4-(3-(2,6-dioxadiazin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (28-a, 78 mg, 0.14 mmol) was dissolved in dichloromethane (6 mL), and trifluoroacetic acid (1 mL) was added. The reaction was carried out at room temperature for 0.5 hours. The solvent was removed by vacuum distillation to obtain the crude target product 3-(6-(1-(3-azaspiro[5.5]undecane-9-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (28-b, 97 mg, crude product).

[0598] Step 3: Synthesis of 3-(6-(1-(3-(1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-7-((triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-3-azaspiro[5.5]undecane-9-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (28-c)

[0599] (1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl-4-methylbenzenesulfonate (I-1, 65 mg, 0.07 mmol), potassium carbonate (48 mg, 0.35 mmol), potassium iodide (12 mg, 0.07 mmol), 3-(6-(1-(3-azaspiro[5.5]undecane-9-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (28-b, 53 mg, 0.11 mmol) were dissolved in acetonitrile (4 mL) and reacted at 60 °C for 16 hours. After the reaction was completed, the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by thin-layer chromatography on silica gel plates (dichloromethane:methanol = 100:13) to obtain the target product 3-(6-(1-(3-(1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-7-((triisopropylsilyl)ethynyl)naphth-1-yl)pyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-3-azaspiro[5.5]undecane-9-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (28-c, 33 mg, yield 39.76%). (ESI)[M+H] + =1189.9.

[0600] Step 4: Synthesis of 3-(6-(1-(3-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-3-azaspiro[5.5]undecane-9-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (28-d)

[0601] 3-(6-(1-(3-(1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-7-((triisopropylsilyl)ethynyl)naphth-1-yl)pyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-3-azaspiro[5.5]undecane-9-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (28-c, 33 mg, 0.03 mmol) was dissolved in N,N-dimethylformamide (3 mL), and cesium fluoride (46 mg, 0.3 mmol) was added. The mixture was reacted at room temperature for 0.5 h. After filtration of the reaction solution, the filtrate was distilled under reduced pressure using an oil pump to obtain the crude target product 3-(6-(1-(3-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-3-azaspiro[5.5]undecane-9-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (28-d, 37 mg, crude product). (ESI)[M+H] + =1034.0.

[0602] Step 5: Synthesis of 3-(6-(1-(3-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-3-azaspiro[5.5]undecane-9-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione trifluoroacetate (28)

[0603] 3-(6-(1-(3-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-3-azaspiro[5.5]undecane-9-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (28-d, 37 mg, 0.04 mmol) was dissolved in acetonitrile (5 mL), and 1,4-dioxane hydrochloride solution (1 mL) was added. The reaction was carried out at room temperature for 0.5 hours. The reaction solution was distilled under reduced pressure to obtain a crude product, which was then purified by preparative liquid chromatography (aqueous phase: 0.01% trifluoroacetic acid, organic phase: acetonitrile) to obtain the target product 3-(6-(1-(3-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-3-azaspiro[5.5]undecane-9-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione trifluoroacetate (28 mg, 13.46 mg, yield 29.55%). (ESI)[M+H + =990.0. 1H NMR(600MHz,DMSO-d6)δ10.89(s,1H),10.21(s,1H),9.31(s,1H),9.14(s,1H),8. 68(s,1H),8.00-7.98(m,1H),7.68-7.67(d,J=8.4Hz,1H),7.51-7.46(m,1H),7.4 1-7.40(d,J=3.4Hz,2H),7.18-7.17(d,J=2.6Hz,1H),7.04-7.03(d,J=8.5Hz,1H) ,4.39-4.29(m,3H),4.04-4.01(m,4H),3.99(s,3H),3.94-3.92(d,J=9.9Hz,1H),3 .61-3.53(m,4H),3.23-3.12(m,5H),3.10-2.99(m,3H),2.72-2.70(m,1H),2.63- 2.58(m,1H),2.37-2.33(m,1H),2.26-2.24(d,J=13.6Hz,1H),2.19-2.14(m,2H), 2.11-2.09(d,J=14.0Hz,2H),2.05-1.96(m,7H),1.88-1.87(m,2H),1.73-1.71(m ,1H),1.67-1.58(m,6H),1.50-1.36(m,4H),0.88...

Claims

1. A compound of formula (I), its pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug: In equation (I), R 1 Selected from H, -CH3, -OCH3, cyclopropane, and cyclopropoxy groups; R 2 Selected from Where R is selected from -CN, -NH2, C 1-3 alkynyl group, C 1-3 alkenyl, C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with -CN, -NH2, -N(CH3)2, -OH, 3-8 membered cycloalkyl or heterocycloalkyl, preferably, R is selected from ethynyl, vinyl, -CH2CH3, -CH2CH2CN, -CH2CH2NH2, -CH2CH2N(CH3)2, -CH2CH2OH; Ring A is selected from Ring A is selected from saturated or unsaturated 4-10 membered heterocyclic alkyl groups; m can be 0 or 1 at will; q can be any value of 0, 1, or 2; p can be 0, 1, 2, 3 or 4; X 1 Selected from -O-, -CH2-, -CHR 7 -or-C(R) 7 )2; R for each replacement position 7 Each is independently selected from -H, -OH, -F, -Cl, -CH3, -CN, -CH2OH, -CH2Cl, -OCH3, -CH2CN, -CH(CH3)2OH, -NHCH3, or two R atoms on the same carbon atom of ring A. 7 The substituent forms a 3-6 membered heterocycle or carbonyl group with the carbon atom, or two R groups on the adjacent carbon atom of ring A. 7 The substituents form 3-6 membered cycloalkyl or heterocycloalkyl groups with the carbon atoms they are attached to; M is selected from -O-, -S-, -NR 3 -、C 1-6 Alkylene, the R 3 Selected from H, C 1-6 Alkyl group, wherein the alkylene group is selected from one or more halogens, -OH, -CN, C 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups; L is selected from -L 1 -L 2 -L 3 -L 4 -L 5 -; L 1 It is a covalent bond, or selected from -O-, -NR 4 carbonyl group, C 1-6 Alkyl ether amino, C 1-6 Alkylene, C 3-6 Cycloalkylene, saturated or unsaturated 3-11 membered heterocyclic alkylene groups, wherein R 4 Selected from H, C 1-6 Alkyl, the C 1-6 Alkyl ether amino, C 1-6 Alkylene, C 3-6 Cycloalkyl groups, saturated or unsaturated 3-11 membered heterocyclic groups, are surrounded by one or more groups selected from halogens, -OH, -CN, C. 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups; L 2 It is a covalent bond, or selected from -O-, -NR 5 carbonyl group, C 1-6 Alkyl ether amino, C 1-6 Alkylene, C 3-6 Cycloalkylene, saturated or unsaturated 3-11 membered heterocyclic alkylene groups, wherein R 5 Selected from H, C 1-6 Alkyl, the C 1-6 Alkyl ether amino, C 1-6 Alkylene, C 3-6 Cycloalkyl groups, saturated or unsaturated 3-11 membered heterocyclic groups, are surrounded by one or more groups selected from halogens, -OH, -CN, C. 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups; L 3 It is a covalent bond, or selected from -O-, -NR 6 carbonyl group, C 1-6 Alkyl ether amino, C 1-6 Alkylene, C 3-6 Cycloalkylene, saturated or unsaturated 3-11 membered heterocyclic alkylene groups, wherein R 6 Selected from H, C 1-6 Alkyl, the C 1-6 Alkyl ether amino, C 1-6 Alkylene, C 3-6 Cycloalkyl groups, saturated or unsaturated 3-11 membered heterocyclic groups, are surrounded by one or more groups selected from halogens, -OH, -CN, C. 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups; L 4 It is a covalent bond, or selected from -O-, -NR 8 carbonyl group, C 1-6 Alkyl ether amino, C 1-6 Alkylene, C 3-6 Cycloalkylene, saturated or unsaturated 3-11 membered heterocyclic alkylene groups, wherein R 8 Selected from H, C 1-6 Alkyl, the C 1-6 Alkyl ether amino, C 1-6 Alkylene, C 3-6 Cycloalkyl groups, saturated or unsaturated 3-11 membered heterocyclic groups, are surrounded by one or more groups selected from halogens, -OH, -CN, C. 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups; L 5 It is a covalent bond, or selected from -O-, -NR 9 carbonyl group, C 1-6 Alkyl ether amino, C 1-6 Alkylene, C 3-6 Cycloalkylene, saturated or unsaturated 3-11 membered heterocyclic alkylene groups, wherein R 9 Selected from H, C 1-6 Alkyl, the C 1-6 Alkyl ether amino, C 1-6 Alkylene, C 3-6 Cycloalkyl groups, saturated or unsaturated 3-11 membered heterocyclic groups, are surrounded by one or more groups selected from halogens, -OH, -CN, C. 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups; And L 1 L 2 L 3 L 4 L 5 Not both are single keys; E is selected from the small molecule ligand of E3 ubiquitin ligase.

2. The compound according to claim 1, its pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug, wherein, R 1 Selected from H, -CH3, -OCH3; R 2 Selected from Ring A is selected from M is selected from -O-, -S-, and -NH-; L 1 Selected from single bonds, L 2 Selected from single bonds, L 3 Selected from single bonds, carbonyl groups, -CH2-, -CH2CH2-, -CH2CH2OCH2-、 L 4 Selected from single bonds, carbonyl groups, L 5 Selected from single bonds, carbonyl groups, And L 1 L 2 L 3 L 4 L 5 Not both are single keys; E is selected from small molecule ligands of the E3 ubiquitin ligase CRBN, preferably with the structure shown in the following formula.

3. The compound according to any one of claims 1-2, its pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug, wherein, L is selected from 4. The compound according to any one of claims 1-3, its pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug, wherein the compound is as shown in formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), or (Il).

5. The compound of formula (I) according to claims 1-4, its pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug, wherein, The compound is selected from the group consisting of:

6. The compound according to any one of claims 1-5, its pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug, wherein, The pharmaceutically acceptable salts include any one or a combination of hydrochloride, hydrobromide, sulfate, phosphate, carbonate, formate, acetate, trifluoroacetate, propionate, methanesulfonate, lactate, benzenesulfonate, p-toluenesulfonate, succinate, maleate, fumarate, tartrate, citrate, or malate.

7. A pharmaceutical composition, characterized in that, The composition comprises the compound according to any one of claims 1-6, its pharmaceutically acceptable salt, stereoisomer, solvate, its prodrug, and its pharmaceutically acceptable excipient.

8. Use of the compound of any one of claims 1-6, its pharmaceutically acceptable salt, stereoisomer, solvate, its prodrug, or the pharmaceutical composition of claim 7 in a kit for treating cancer, immune diseases, or for prognostic assessment of cancer patients; Preferably, the pharmaceutical composition further comprises another drug for treating cancer or immune diseases; Preferred use is in the preparation of a medicament for treating diseases associated with KRAS mutations; Preferably, the cancers include pancreatic cancer, colorectal cancer, lung cancer, bile duct cancer, endometrial cancer, and ovarian cancer; More preferably, the cancers include pancreatic cancer, colorectal cancer, lung cancer, bile duct cancer, endometrial cancer, and ovarian cancer.

9. The use of the compound of any one of claims 1-6, its pharmaceutically acceptable salt, stereoisomer, solvate, its prodrug, or the pharmaceutical composition of claim 7 in the preparation of a medicament for treating diseases related to KRAS activity or expression levels; Preferably, it is used in the preparation of medicaments for treating and inhibiting or degrading KRAS G12D, KRAS G12V, KRAS G12A, KRAS G12S, KRAS G12C, KRAS G13D, KRAS Q61H, KRAS Q61K, KRAS Y96D and other KRAS mutation-related diseases.

10. A method for inhibiting or degrading KRAS in a biological sample for non-disease diagnostic or therapeutic purposes, comprising contacting the biological sample with a compound of any one of claims 1-6 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of claim 7.

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