Heterocyclic compound for inducing degradation of mutant KRAS protein as well as preparation method and application of heterocyclic compound

Abstract

The present invention provides a heterocyclic compound for inducing degradation of mutant KRAS protein, a pharmaceutically acceptable salt, a stereoisomer, a solvate or a prodrug thereof, as shown in formula (I), and the definition of each group in the formula is detailed in the specification. In addition, the invention also discloses a pharmaceutical composition containing the compound, and application of the pharmaceutical composition in preparation of a kit for treating cancers, immune diseases or prognosis evaluation of cancer patients. # imgabs0 #

Description

Technical Field

[0001] The present disclosure relates to the field of medicine, and in particular to a heterocyclic compound for inducing degradation of mutant KRAS protein, a pharmaceutical composition, a preparation method and uses thereof. Background Art

[0002] RAS is a guanine nucleotide binding protein with GTPase activity and has the function of anchoring inside the cell membrane. RAS protein can switch between the inactive state bound by GDP and the active state bound by GTP, affecting multiple downstream signaling pathways such as Raf, PI3K and RalGDS, regulating protein synthesis, gene transcription, cell growth, differentiation, apoptosis and migration, etc.

[0003] RAS mutations lead to persistent activation of downstream signaling pathways, promoting the occurrence and development of tumors. RAS mutations in all tumor types mainly occur in KRAS (85%), and the frequency of mutation of glycine at position 12 to aspartic acid (G12D) on KRAS is the highest (34.2%), and the frequency of tumor occurrence is 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 mutation refers to the mutation of glycine at position 12 of the protein to cysteine, and the frequency of tumor occurrence is pancreatic cancer (57%), colorectal cancer (35%), bile duct cancer (28%), small intestinal cancer (17%), lung cancer (16%), endometrial cancer (15%) and ovarian cancer (14%). In addition to G12C and G12D, KRAS has multiple other mutations, such as G12V, G12A, G12R, G12S, G13D, Y96D, Q61H, Q61K, etc. The frequency of occurrence of different KRAS mutations in different types of cancer cells is also different.

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

[0005] Currently, only the degrader targeting the kras g12d mutant from Astellas has entered Phase 1 clinical trials, and the clinical needs have not been met yet. Therefore, it is of great significance to develop novel-structured KRAS PROTAC molecules with good biological activities. Summary of the Invention

[0006] One aspect of the present invention provides a novel-structured KRAS PROTAC molecule with high biological activity.

[0007] One aspect of the present invention provides a compound of formula (I), a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein the compound is shown as formula (I):

[0008]

[0009] In formula (I), R 1 is selected from H, -CH3, -OCH3, cyclopropyl, cyclopropoxy;

[0010] R 2 is selected from

[0011] wherein R is selected from -CN, -NH2, C 1-3 alkynyl, C 1-3 alkenyl, C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by -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;

[0012] Ring A is selected from saturated or unsaturated 4-10 membered heterocycloalkyl;

[0013] m is optionally 0 or 1;

[0014] q is optionally 0, 1 or 2;

[0015] p is optionally 0, 1, 2, 3 or 4;

[0016] X 1 is selected from -O-, -CH2-, -CHR 7 -, or -C(R 7 )2;

[0017] R at each substitution position 7Each independently selected from -H, -OH, -F, -Cl, -CH3, -CN, -CH2OH, -CH2Cl, -OCH3, -CH2CN, -CH(CH3)2OH, -NHCH3, or two Rs on the same carbon atom of ring A 7 The substituents form a 3-6 membered heterocycle or carbonyl with the carbon atom, or two Rs on adjacent carbon atoms of ring A 7 The substituents form a 3-6 membered cycloalkyl or heterocycloalkyl with the carbon atom to which they are attached;

[0018] M is selected from -O-, -S-, -NR 3 -, C 1-6 alkylene, said R 3 is selected from H, C 1-6 alkyl, said alkylene is substituted by one or more substituents selected from halogen, -OH, -CN, C 1-6 alkyl and C 1-6 haloalkyl;

[0019] L is selected from -L 1 -L 2 -L 3 -L 4 -L 5 -;

[0020] L 1 is a covalent bond, or selected from -O-, -NR 4 (, carbonyl, C 1-6 alkylene ether amino, C 1-6 alkylene, C 3-6 subcycloalkyl, saturated or unsaturated 3-11 membered subheterocyclic group, said R 4 is selected from H, C 1-6 alkyl, said C 1-6 alkylene ether amino, C 1-6 alkylene, C 3-6 subcycloalkyl, saturated or unsaturated 3-11 membered subheterocyclic group is substituted by one or more substituents selected from halogen, -OH, -CN, C 1-6 alkyl and C 1-6 haloalkyl;

[0021] L 2 is a covalent bond, or selected from -O-, -NR 5 (, carbonyl, C 1-6 alkylene ether amino, C 1-6 alkylene, C 3-6 subcycloalkyl, saturated or unsaturated 3-11 membered subheterocyclic group, said R 5 is selected from H, C 1-6 alkyl, said C 1-6 alkylene ether amino, C 1-6 alkylene, C3-6 A subcycloalkyl group, a saturated or unsaturated 3- to 11-membered heterocycloalkylidene group is substituted by one or more substituents selected from halogen, -OH, -CN, C 1-6 alkyl and C 1-6 haloalkyl;

[0022] L 3 is a covalent bond, or is selected from -O-, -NR 6 , carbonyl, C 1-6 alkylene ether amino, C 1-6 alkylene, C 3-6 subcycloalkyl, a saturated or unsaturated 3- to 11-membered heterocycloalkylidene group, wherein the R 6 is selected from H, C 1-6 alkyl, the C 1-6 alkylene ether amino, C 1-6 alkylene, C 3-6 subcycloalkyl, a saturated or unsaturated 3- to 11-membered heterocycloalkylidene group is substituted by one or more substituents selected from halogen, -OH, -CN, C 1-6 alkyl and C 1-6 haloalkyl;

[0023] L 4 is a covalent bond, or is selected from -O-, -NR 8 , carbonyl, C 1-6 alkylene ether amino, C 1-6 alkylene, C 3-6 subcycloalkyl, a saturated or unsaturated 3- to 11-membered heterocycloalkylidene group, wherein the R 8 is selected from H, C 1-6 alkyl, the C 1-6 alkylene ether amino, C 1-6 alkylene, C 3-6 subcycloalkyl, a saturated or unsaturated 3- to 11-membered heterocycloalkylidene group is substituted by one or more substituents selected from halogen, -OH, -CN, C 1-6 alkyl and C 1-6 haloalkyl;

[0024] L 5 is a covalent bond, or is selected from -O-, -NR 9 , carbonyl, C 1-6 alkylene ether amino, C 1-6 alkylene, C 3-6 subcycloalkyl, a saturated or unsaturated 3- to 11-membered heterocycloalkylidene group, wherein the R 9 is selected from H, C 1-6 alkyl, the C 1-6 alkylene ether amino, C 1-6 alkylene, C 3-6A sub-cycloalkyl group, a saturated or unsaturated 3- to 11-membered hetero-subcyclic group is substituted by one or more substituents selected from halogen, -OH, -CN, C 1-6 alkyl and C 1-6 haloalkyl;

[0025] and L 1 、L 2 、L 3 、L 4 、L 5 are not simultaneously single bonds;

[0026] E is selected from small molecule ligands of E3 ubiquitin ligase.

[0027] In some preferred embodiments, its pharmaceutically acceptable salts, stereoisomers, solvates or prodrugs, wherein,

[0028] Preferably, R 1 is selected from H, -CH3, -OCH3;

[0029] Preferably, R 2 is selected from Preferably, ring A is selected from

[0030] Preferably, M is selected from -O-, -S-, -NH-;

[0031] Preferably, L 1 is selected from a single bond, Preferably, L 2 is selected from a single bond,

[0032] Preferably, L 3 is selected from a single bond, carbonyl, -CH2-, -CH2 CH2-, -CH2 CH2OCH2-,

[0033] Preferably, L 4 is selected from a single bond, carbonyl,

[0034] Preferably, L 5 is selected from a single bond, carbonyl, and L 1 、L 2 、L 3 、L 4 、L 5 are not simultaneously single bonds;

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

[0036]

[0037] In some preferred embodiments, its pharmaceutically acceptable salts, stereoisomers, solvates or prodrugs, wherein, preferably, L is selected from

[0038]

[0039]

[0040] In some preferred embodiments, its pharmaceutically acceptable salts, stereoisomers, solvates or prodrugs, and the compound is as shown in formula (I-a), formula (I-b), formula (I-c), formula (I-d), formula (I-e), formula (I-f), formula (I-g), formula (I-h), formula (I-i), formula (I-j), formula (I-k) or formula (I-l),

[0041]

[0042]

[0043] In a preferred embodiment, the compound of formula (I), its pharmaceutically acceptable salts, stereoisomers, solvates or prodrugs, wherein, the compound is selected from the following group:

[0044]

[0045]

[0046]

[0047]

[0048]

[0049]

[0050]

[0051]

[0052]

[0053]

[0054] In a preferred embodiment, the compound of formula (I), its pharmaceutically acceptable salts, stereoisomers, solvates or prodrugs, wherein the pharmaceutically acceptable salts include any one or combination of hydrochloride, hydrobromide, sulfate, phosphate, carbonate, formate, acetate, trifluoroacetate, propionate, mesylate, lactate, benzenesulfonate, p-toluenesulfonate, succinate, maleate, fumarate, tartrate, citrate or malate.

[0055] In another aspect of the present invention, there is provided a pharmaceutical composition, characterized in that the composition comprises the above compound, its pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs and pharmaceutically acceptable excipients.

[0056] In another aspect of the present invention, there is provided the use of the above compound, its pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, and the pharmaceutical composition in a kit for treating cancer, immune diseases or prognostic assessment of cancer patients;

[0057] Preferably, the pharmaceutical composition further comprises another drug for treating cancer or immune diseases;

[0058] Preferably, it is used in the preparation of a drug for treating diseases related to KRAS mutations;

[0059] Preferably, the cancer includes but is not limited to pancreatic cancer, colorectal cancer, lung cancer, cholangiocarcinoma, endometrial cancer and ovarian cancer;

[0060] More preferably, the cancer includes but is not limited to pancreatic cancer, colorectal cancer, lung cancer, cholangiocarcinoma, endometrial cancer and ovarian cancer, etc.

[0061] In another aspect of the present invention, there is provided the use of the above compound, its pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs or the pharmaceutical composition thereof in the preparation of a drug for treating diseases related to KRAS activity or expression level;

[0062] Preferably, it is used in the preparation of a drug for treating diseases related to the inhibition or degradation of KRAS G12D, KRAS G12V, KRAS G12A, KRAS G12S, KRAS G12C, KRAS G13D, KRAS Q61H, KRAS Q61K, KRAS Y96D and other KRAS mutations.

[0063] In another aspect of the present invention, there is provided a method for inhibiting or degrading KRAS in a biological sample for non-disease diagnosis or treatment purposes, which comprises contacting the biological sample with the above compound or its pharmaceutically acceptable salt or the pharmaceutical composition. Detailed Description

[0064] Ⅰ Definition

[0065] According to the content of the present disclosure, and based on the common general knowledge and conventional means in the art, without departing from the basic technical idea of the present disclosure, various other forms of modification, substitution or variation can also be made.

[0066] The term "comprising" or its variations such as "including" or "comprising of" etc. will be understood to include the stated elements or components, without excluding other elements or other components.

[0067] The compounds of the present invention may be asymmetric, for example, having one or more stereoisomers. Unless otherwise specified, all stereoisomers are included, such as enantiomers and diastereomers. Compounds of the present 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 the racemic mixture, or synthesized by using chiral starting materials or chiral reagents. Racemates, diastereomers, and enantiomers are all included within the scope of the present invention.

[0068] The compounds of the present invention also include tautomeric forms. Tautomeric forms result from the exchange of a single bond with an adjacent double bond and the concomitant migration of a proton.

[0069] The term "optionally" or "optionally" means that the subsequent described event or situation may or may not occur, and this description includes the occurrence and non-occurrence of the described event or situation.

[0070] The numerical ranges herein refer to each integer within the given range. For example, "C 1-6 " means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms; "C 3-6 " means that the group may have 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms.

[0071] The term "substituted" or "substituted with" means that any one or more hydrogen atoms on a specific atom or group are replaced by a substituent, provided that the valence state of the specific atom or group is normal and the resulting compound is stable. When the substituent is a keto group (i.e., =O), it means that two hydrogen atoms are replaced. Unless otherwise specified, the type and number of substituents can be arbitrary based on what is chemically achievable.

[0072] In the present disclosure, when any variable (such as R n)When it appears more than once in the composition or structure of a compound, its definition is independent in each case. Thus, for example, if a group is substituted by 1 - 5 Rs, the group may optionally be substituted by up to 5 Rs, and the Rs in each case have independent options. In addition, combinations of substituents and / or their variants are permitted only if such combinations result in stable compounds.

[0073] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched-chain 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 various branched isomers thereof, etc. More preferably, it is a lower alkyl group containing 1 to 6 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, etc. The alkyl group can be substituted or unsubstituted. When substituted, the substituent can be substituted at any available bonding point. The substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate group. The present invention preferably includes methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl, and hydroxy-substituted alkyl.

[0074] The term "alkylene" refers to a divalent saturated aliphatic hydrocarbon group obtained by removing one hydrogen atom from the corresponding "alkyl". 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-), isopropylidene (-CH(CH3)CH2-), which is optionally substituted by one or more (such as 1, 2 or 3) suitable substituents such as halogen.

[0075] The term "alkenyl" refers to an alkyl 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. The alkenyl can be substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.

[0076] The term "cycloalkyl" refers to a saturated monocyclic alkane substituent, the cycloalkyl ring contains at least 3 carbon atoms, preferably contains 3 to 12 carbon atoms, more preferably contains 3 to 6 carbon atoms. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0077] The term "cycloalkylene" refers to a divalent group obtained by removing one hydrogen atom from the corresponding "cycloalkyl".

[0078] The term "heterocyclic group" or "heterocycloalkyl" refers to a saturated monocyclic cyclic hydrocarbon substituent, in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), but does not include the ring portion of -O-O-, -O-S- or -S-S-, and the remaining ring atoms are carbon. Non-limiting examples of heterocyclic groups include pyrrolyl, imidazolyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, etc., preferably pyrrolidinyl, morpholinyl, piperidyl, cycloheptyl, 1,4-diazacycloheptyl and piperazinyl.

[0079] The heterocyclic group can be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, cyano, nitro, chloro, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate group.

[0080] The term "subheterocyclic group" refers to a divalent group obtained by removing one hydrogen atom from the corresponding "heterocyclic group".

[0081] The term "C 1-6 alkoxyamino" means that the amino group is optionally substituted by a C 1-6 alkoxy group, such as and other groups.

[0082] The term "aryl" refers to a 6- to 14-membered fully carbon monocyclic or fused polycyclic (i.e., rings 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 can be fused to a heteroaryl, heterocyclic or cycloalkyl ring, including benzo 5- to 10-membered heteroaryl, benzo 3- to 8-membered cycloalkyl and benzo 3- to 8-membered heteroalkyl, preferably benzo 5- to 6-membered heteroaryl, benzo 3- to 6-membered cycloalkyl and benzo 3- to 6-membered heteroalkyl, where the heterocyclic group is a heterocyclic group containing 1-3 nitrogen atoms, oxygen atoms or sulfur atoms; or also includes a three-membered nitrogen-containing fused ring containing a benzene ring.

[0083] The aryl can be substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydrogen, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate group.

[0084] The term "heteroaryl" refers to a heteroaromatic system containing heteroatoms and carbon atoms, where the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl is preferably 5- or 6-membered, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably triazolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, pyrimidinyl or thiazolyl; more preferably pyrazolyl, pyrrolyl and oxazolyl.

[0085] The heteroaryl can be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydrogen, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate group.

[0086] The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), where alkyl is defined as described above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. The alkoxy can be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydrogen, nitro, chloro, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate group.

[0087] In the present disclosure, refers to the chemical bond connection point.

[0088] Drug or pharmaceutical composition

[0089] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are suitable for contact with human and animal tissues within the scope of reasonable medical judgment without excessive toxicity, irritation, allergic reaction or other problems or complications commensurate with a reasonable benefit / risk ratio.

[0090] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological potency of the free acid and base of a particular compound without biological adverse effects. For example, acid (including organic acid and inorganic acid) addition salts or base addition salts (including organic base and inorganic base).

[0091] The pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compounds containing acid radicals or basic groups by conventional chemical methods. Generally, the preparation method of such salts is: in water or an organic solvent or a mixture of both, these compounds in the free acid or base form are reacted with a stoichiometric amount of an appropriate base or acid to prepare.

[0092] The drugs or pharmaceutical compositions of the present disclosure can be administered orally, topically, parenterally or mucosally (e.g., sublingually, by inhalation or rectally) in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers. It is generally desirable to use the oral route. The active agent can be administered orally in the form of capsules, tablets, etc. (see Remington: The Science and Practice of Pharmacy, 20th Edition).

[0093] For oral administration in the form of tablets or capsules, the active pharmaceutical ingredient can be combined with non-toxic, pharmaceutically acceptable excipients such as binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); 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, behenin, calcium stearate, etc.); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate), colorants and flavorants, gelatin, sweeteners, natural and synthetic gums (such as gum arabic, tragacanth or alginate), buffer salts, carboxymethylcellulose, polyethylene glycol, waxes, etc. For oral administration in liquid form, the pharmaceutical ingredient can be combined with non-toxic, pharmaceutically acceptable inert carriers (e.g., ethanol, glycerol, water), anti-settling agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats), emulsifiers (e.g., lecithin or gum arabic), non-aqueous carriers (e.g., almond oil, esters of fatty acids, ethanol or fractionated vegetable oils), preservatives (e.g., methyl p-hydroxybenzoate or propyl p-hydroxybenzoate or sorbic acid), etc. Stabilizers such as antioxidants (BHA, BHT, propyl gallate, sodium ascorbate, citric acid) can also be added to stabilize the dosage form.

[0094] Tablets containing the active compound as the active ingredient can be coated by methods well known in the art. The compositions of the present disclosure containing a compound of formula I as the active ingredient can also be incorporated into beads, microspheres or microcapsules, for example constructed from polyglycolic acid / lactic acid (PGLA). Preparations for oral administration in liquid form can take the form of, for example, solutions, syrups, emulsions or suspensions or they can be presented as dry products to be reconstituted with water or other suitable excipients before use. Preparations for oral administration can be suitably formulated to provide controlled or delayed release of the active compound.

[0095] The drugs or pharmaceutical compositions of the present disclosure can be delivered parenterally, i.e., by intravenous (i.v.), intracerebroventricular (i.c.v.), subcutaneous (s.c.), intraperitoneal (i.p.), intramuscular (i.m.), subdermal (s.d.) or intradermal (i.d.) administration, by direct injection, for example by bolus injection or continuous infusion. Formulations for injection can be presented in unit dosage forms, for example in ampoules or multi-dose containers with added preservatives. The compositions can take the form of excipients, suspensions, solutions or emulsions in oily or aqueous carriers and can contain formulating agents such as anti-settling agents, stabilizers and / or dispersing agents. Alternatively, the active ingredient can be in powder form and reconstituted with a suitable carrier (e.g., sterile pyrogen-free water) before use.

[0096] The medicaments or pharmaceutical compositions of the present disclosure may also be formulated for rectal administration, for example, in the form of suppositories or retention enemas (e.g., containing conventional suppository bases such as cocoa butter or other glycerides).

[0097] The term "treatment" includes inhibiting, alleviating, preventing or eliminating one or more symptoms or side effects associated with the disease, disorder or condition being treated.

[0098] The use of the terms "reduce", "inhibit", "alleviate" or "decrease" is relative to a control. A person skilled in the art will readily determine the appropriate control for each experiment. For example, the reduced response in a subject or cell treated with a compound is compared with the response in a subject or cell not treated with the compound.

[0099] As used herein, the term "effective amount" or "therapeutically effective amount" refers to a dose sufficient to treat, inhibit or alleviate one or more symptoms of the disease state being treated or otherwise provide the desired pharmacological and / or physiological effect. The exact dose will vary depending on a variety of factors such as subject-dependent variables (e.g., age, immune system health, etc.), the disease or disorder, and the treatment being administered. The effect of the effective amount can be relative to a control. Such controls are known in the art and are discussed herein and can be, for example, the condition of the subject before or without the administration of the medicament or pharmaceutical combination, or in the case of a pharmaceutical combination, the combined effect can be compared with the effect of administering only one of the drugs.

[0100] The term "excipient" is used herein to include any other compound that is not a therapeutic or bioactive compound and that can be included in or on the microparticles. Thus, the excipient should be pharmaceutically or biologically acceptable or relevant, e.g., the excipient is generally non-toxic to the subject. "Excipient" includes a single such compound and is also intended to include a plurality of compounds.

[0101] The term "pharmaceutical composition" means a composition comprising a compound or a pharmaceutically acceptable salt thereof as described in the present disclosure, and at least one pharmaceutically acceptable ingredient selected from the following, depending on the mode of administration and the nature of the dosage form, including but not limited to: carriers, diluents, adjuvants, excipients, preservatives, fillers, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants, dispersants, temperature-sensitive materials, temperature regulators, adhesives, stabilizers, suspending aids, etc.

[0102] Use and treatment method

[0103] The terms "patient", "subject", "individual", etc. are used interchangeably herein and refer to any animal or its cells that are subject to the methods described herein, whether in vitro or in situ. In some non-limiting embodiments, the patient, subject, or individual is a human.

[0104] In accordance with the methods of the present disclosure, a compound or composition can be administered in any amount and by any route of administration effective to treat or reduce the severity of a KRAS-related disease.

[0105] The present disclosure relates to a method of inhibiting or degrading KRAS in a biological sample, comprising the step of contacting the biological sample with a compound of the present disclosure or a composition comprising the compound.

[0106] A method of inhibiting KRAS in a patient, comprising the step of administering to the patient a compound of the present disclosure or a composition comprising the compound.

[0107] The provided compounds are KRAS inhibitors or KRAS degraders and can thus be used to treat one or more conditions associated with KRAS activity. Accordingly, in certain embodiments, the present disclosure provides a method for treating a KRAS-mediated condition, comprising the step of administering to a patient in need thereof a compound of the present disclosure or a pharmaceutically acceptable composition thereof.

[0108] The present disclosure provides a method for treating one or more conditions, diseases, and / or disorders, wherein the condition, disease, or disorder is a proliferative disease, such as cancer, an inflammatory disorder, or a viral infection.

[0109] In certain embodiments, the present disclosure provides a method of treating cancer or another proliferative disorder, comprising administering to a patient having cancer or another proliferative disorder a compound or composition of the present disclosure. In certain embodiments, the method of treating cancer or another proliferative disorder comprises administering a compound and composition of the present disclosure to a mammal. In certain embodiments, the mammal is a human.

[0110] As used herein, the terms "inhibiting cancer" and "inhibiting cancer cell proliferation" refer to inhibiting the growth, division, maturation, or survival of cancer cells, and / or causing the death of cancer cells by cytotoxicity, nutrient depletion, or induction of apoptosis, individually or collectively with other cancer cells.

[0111] 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) breast, prostate, brain, blood, bone marrow, liver, pancreas, epidermis, kidney, colon, ovary, lung, testis, penis, thyroid, parathyroid, pituitary, thymus, retina, uvea, conjunctiva, spleen, head, neck, trachea, gallbladder, rectum, salivary gland, adrenal gland, throat, esophagus, lymph node, sweat gland, sebaceous gland, muscle, heart, and stomach.

[0112] Cancers treatable by the compounds or compositions of the present disclosure 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, etc. In certain embodiments, the cancer is primary effusion lymphoma (PEL).

[0113] The compounds of the present disclosure can be used to treat proliferative diseases selected from the following: benign or malignant tumors, carcinomas; sarcomas, glioblastomas, neuroblastomas, multiple myelomas, or gastrointestinal cancers (especially colorectal cancer or colorectal adenomas) or tumors of the neck and head, epidermal hyperplasia, psoriasis, prostatic hyperplasia, neoplasia, neoplasia of epithelial characteristics, adenomas, adenocarcinomas, keratoacanthomas, epidermoid carcinomas, large cell carcinomas, non-small cell lung cancers, Hodgkins and non-Hodgkins lymphomas, breast cancers, follicular carcinomas, undifferentiated neoplasms, papillary carcinomas, seminomas, melanomas, MYD88-driven disorders, DLBCL, ABC DLBCL, IL-1-driven disorders, and indolent or smoldering multiple myelomas or leukemias of the brain, kidney, liver, adrenal gland, bladder, breast, stomach, gastric tumors, ovary, colon, rectum, prostate, pancreas, lung, vagina, cervix, testis, urogenital tract, esophagus, larynx, skin, bone, or thyroid.

[0114] The cancers described in the present disclosure include (but are not limited to) leukemia (such as acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia), polycythemia vera, lymphoma (such as Hodgkin's disease or non-Hodgkin's disease), Waldenström's macroglobulinemia, multiple myeloma, heavy chain disease, and solid tumors, such as sarcoma and carcinoma (such as fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, 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, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, uterine cancer, testicular cancer, lung cancer, small cell lung cancer, bladder cancer, epithelial cancer, glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, and retinoblastoma).

[0115] In some specific embodiments, the cancer is glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, or retinoblastoma.

[0116] In some specific embodiments, the cancer is acoustic neuroma, astrocytoma (such as grade I - pilocytic astrocytoma, grade II - low-grade astrocytoma, grade III - anaplastic astrocytoma or grade IV - glioblastoma multiforme (GBM)), chordoma, CNS lymphoma, craniopharyngioma, brainstem glioma, ependymoma, mixed glioma, optic nerve glioma, subependymal ependymoma, medulloblastoma, meningioma, metastatic brain tumor, oligodendroglioma, pituitary tumor, primitive neuroectodermal (PNET) tumor or schwannoma. In some embodiments, the cancer is a type that is more common in children than in adults, such as brainstem glioma, craniopharyngioma, ependymoma, juvenile pilocytic astrocytoma (JPA), medulloblastoma, optic nerve glioma, pineal tumor, primitive neuroectodermal tumor (PNET) or rhabdoid tumor. In some embodiments, the patient is an adult patient. In some embodiments, the patient is a child or pediatric patient.

[0117] In another specific embodiment, the cancer includes (but is not limited to): mesothelioma, hepatobiliary (liver and bile duct), bone cancer, pancreatic cancer, skin cancer, head or neck cancer, cutaneous or intraocular melanoma, ovarian cancer, colorectal cancer, rectal cancer, anal area cancer, gastric cancer, gastrointestinal (stomach, colorectal and duodenum), uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, testicular cancer, chronic or acute leukemia, chronic myelogenous leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal cell cancer, renal pelvic cancer, non-Hodgkin's lymphoma, spinal axis tumor, brainstem glioma, pituitary adenoma, adrenocortical carcinoma, gallbladder cancer, multiple myeloma, cholangiocarcinoma, fibrosarcoma, neuroblastoma, retinoblastoma or a combination of one or more of the said cancers.

[0118] In some specific embodiments, the cancer is selected from hepatocellular carcinoma, ovarian cancer, ovarian epithelial cancer or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine serous papillary carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; cholangiohepatoma; soft tissue and bone synovial sarcoma; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing's sarcoma; pleomorphic thyroid cancer; adrenocortical adenoma; pancreatic cancer; pancreatic ductal carcinoma or pancreatic cancer; gastrointestinal / stomach (GIST) cancer; lymphoma; head and neck squamous cell carcinoma (SCCHN); salivary gland cancer; glioma or brain cancer; neurofibromatosis-1 associated malignant peripheral nerve sheath tumor (MPNST); Waldenström's macroglobulinemia; or medulloblastoma.

[0119] 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 lung, liver, intestine, head, or skin, etc., and can be called primary lung cancer, primary liver cancer, primary intestinal cancer, etc.

[0120] The term "inflammatory disease" includes said autoimmune, allergic, and inflammatory disorders, 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 allograft rejection, Behcet's disease, uveitis, psoriasis, dermatitis, atopic dermatitis, dermatomyositis, myasthenia gravis, Graves' disease, Hashimoto's thyroiditis, Sjogren's syndrome, and blistering disorders (such as pemphigus vulgaris), antibody-mediated vasculitis syndromes, including ANCA-associated vasculitis, purpura, and immune complex vasculitis (stages one or two of cancer or infection). The allergic disorders may be particularly selected from contact dermatitis, celiac disease, asthma, hypersensitivity to house dust mites, pollen and related allergens, beryllium poisoning. The respiratory disorders may be particularly selected from asthma, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pulmonary edema, pulmonary embolism, pneumonia, sarcoidosis, silicosis, pulmonary fibrosis, respiratory failure, acute respiratory distress syndrome, primary pulmonary hypertension, and emphysema, etc.

[0121] The term "viral infection" includes but is not limited to retroviral infection, hepatitis virus infection, COVID-19 coronavirus infection, Zika virus infection, dengue virus infection, etc.

[0122] Combined treatment method

[0123] The present disclosure provides combination therapies using the compounds as described in the present disclosure and other therapeutic agents. The term "combination therapy" as used in the present disclosure includes administering these agents in a sequential manner, i.e., where each therapeutic agent is administered at different times, and administering these therapeutic agents, or at least two agents, substantially simultaneously. The order of each reagent, or substantially simultaneous administration, may be affected by any suitable route, including but not limited to, oral route, intravenous route, intramuscular, subcutaneous route, and direct absorption through mucosal tissues. The agents may be administered by the same route or different routes. For example, the first agent may be administered orally, while the second agent is administered intravenously. In addition, the selected combination agent may be administered by intravenous injection, while the other agents in the combination may be administered orally. Or, for example, two or more agents may be administered by intravenous or subcutaneous injection.

[0124] II Examples

[0125] The present disclosure will be further explained below with reference to the embodiments. The description of specific exemplary embodiments of the present disclosure is for the purpose of illustration and exemplification. These descriptions are not intended to limit the present disclosure to the precise forms disclosed, and it is obvious that many changes and variations can be made in accordance with the teachings of the present application specification. The purpose of selecting and describing the exemplary embodiments is to explain the specific principles of the present disclosure and its actual applications, so that those skilled in the art can implement and utilize various different exemplary embodiments of the present disclosure, as well as various different selections and changes.

[0126] Unless otherwise specified, the experimental methods used in the following examples are all conventional methods.

[0127] Unless otherwise specified, the materials, reagents, etc. used in the following examples can all be obtained from commercial sources.

[0128] Instruments and reagents:

[0129] NMR: Agilent 400MR DD2 nuclear magnetic resonance spectrometer, the solvents for measurement are deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD) and deuterated chloroform (CDCl3), and the internal standard is tetramethylsilane (TMS). Liquid chromatography-mass spectrometry LC-MS: Agilent1260Infinity II–InfinityLab LC / MSD mass spectrometer. HPLC: Agilent 1260Infinity II high-pressure liquid chromatography (Sunfire C18 5μm 150x 4.6mm chromatographic column).

[0130] Thin layer chromatography silica gel plate: HSGF254 silica gel plate (Yantai Jiangyou Silica Gel Development Co., Ltd.), specification 0.9mm - 1mm. TLC silica gel plate: GF254 silica gel plate (Yucheng Chemical Industry (Shanghai) Co., Ltd.), specification 0.2mm - 0.25mm. Column chromatography: The carrier is 300 - 400 mesh silica gel (Qingdao Hailang Silica Gel Desiccant Co., Ltd.), Flash column (Agela Technologies Claricep Flash amorphous silica gel purification column).

[0131] Reagents: 2,4,7-trichloro-8-fluoro-5-methylpyrido[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-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane, cesium carbonate, 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride 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, cyclopropane-1,1-diyldimethanol, 6-bromo-1H-indazole, 2-(2,4-bis(benzyloxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, (1R,5S)-tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate, 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride, [n-butylbis(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) mesylate, 4-methylbenzenesulfonyl chloride, 4-dimethylaminopyridine, potassium hydroxide, iodomethane, potassium phosphate, tert-butyl 4-(4-amino-2-fluorophenyl)piperazine-1-carboxylate, 3-bromopiperidine-2,6-dione, 2-oxo-7-azaspiro[3.5]tert-Butyl nonane-7-carboxylate, tert-Butyl 4-(iodomethyl)piperidine-1-carboxylate, (2S,4R)-1-((S)-2-Amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide, 2,2-Dimethyl-4-oxo-3,8,11-trioxa-5-azatridecane-13-carboxylic acid, 2-(2,6-Dioxopiperidin-3-yl)-5-fluoro-1H-isoindole-1,3-dione, 2-(2-((tert-Butoxycarbonyl)amino)ethoxy)acetic acid, 2,2-Dimethyl-4-oxo-3,8,11,14-tetraoxa-5-azaoctadecane-16-carboxylic acid, 1-(tert-Butoxycarbonyl)piperidine-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]dichloropalladium, palladium on carbon (10%), trifluoroacetic acid, acetic acid, sodium cyanoborohydride, potassium carbonate, tert-Butyl 4-formylpiperidine-1-carboxylate, p-Toluenesulfonyl chloride, methyl 3,4-difluorobenzoate, lithium hydroxide monohydrate, dilute hydrochloric acid, 3-Aminopiperidine-2,6-dione, tert-Butyl 4-(2-bromoethyl)piperidine-1-carboxylate, tert-Butyl 4-iodopiperidine-1-carboxylate, tert-Butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate, 3-(5-Bromo-6-fluoro-1-oxoisoindol-2-yl)piperidine-2,6-dione, tert-Butyl 6-oxo-3-azabicyclo[3.2.0]heptane-3-carboxylate, tert-Butyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate, tert-Butyl 4-oxoazetidine-1-carboxylate, tert-Butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate, tert-Butyl 2-oxo-6-azaspiro[3.4]octane-6-carboxylate, 1-(tert-Butoxycarbonyl)azetidine-3-carboxylic acid, tert-Butyl 5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate, tert-Butyl 2-oxo-8-azaspiro[4.5]decane-8-carboxylate, 3-(5-Bromo-1-oxoisoindol-2-yl)piperidine-2,6-dione, tert-Butyl (4-bromo-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate, 5,5,5',5'-Tetramethyl-2,2'-bis(1,3,2-dioxaborolane), potassium acetate, bis(diphenylphosphinophenyl ether)dichloropalladium(II), ((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol, 1,4-Diazabicyclo[2.2.2]octane, 3-Azabicyclo[3.1.Hexane hydrochloride, [(bis(1-adamantyl)butylphosphino)-2-(2'-amino-1,1'-biphenyl)] palladium(II) methanesulfonate, 2,4,7-trichloro-8-fluoro-5-methylpyrido[4,3-d]pyrimidine, tert-butyl 2-bromoacetate, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, tert-butyl 7-oxo-2-azaspiro[3.5]nonane-2-carboxylate, tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate, sodium hydride, 4-(bromomethyl)pyridine, ammonium chloride, (3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methylbenzoic acid, tert-butyl 9-formyl-3-azaspiro[5.5]undecane-3-carboxylate, 1,4-oxacyclopropane, acrylic acid, 3-amino-4-methylbenzoic acid, urea, 2,3,4,5,6-pentafluorophenol, N,N'-dicyclohexylcarbodiimide, titanium(IV) isopropoxide, tert-butyl 4-(2-(piperidin-4-ylmethoxy)ethyl)piperidine-1-carboxylate, (R)-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid, (S)-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid, 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)piperidine-2,6-dione, 3-(1-oxo-5-(1,2,3,6-tetrahydropyridin-4-yl)isoindol-2-yl)piperidine-2,6-dione, tert-butyl 4-formylpiperidine-1-carboxylate, 3-(3-methyl-2-oxo-5-(piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione, tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate, tert-butyl 3-oxoazetidine-1-carboxylate, 1-hydroxybenzotriazole, carbodiimide hydrochloride, and other reagents and starting materials were all purchased from Shanghai Bide, Leyan Reagent Company, Jiangsu Aikon Biopharmaceutical R & D Company, Anajie Chemical Reagent Company, Shanghai Macklin Reagent Company, Saen Chemical Reagent Company, etc., or were synthesized by methods known in the art.

[0132] Unless otherwise specified, all reactions in this disclosure were carried out under continuous magnetic stirring, under dry nitrogen or argon, with the solvent being a dry solvent, and the reaction temperature unit being degrees Celsius.

[0133] The following are the numbers of the intermediates:

[0134]

[0135] Intermediate I-1

[0136] Synthesis of Intermediate I-1: ((1-(((4-(Azido-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl 4-methylbenzenesulfonate:

[0137]

[0138] First Step: Synthesis of 4-(Azido-1-yl)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine (I-1-b)

[0139] Dissolve 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (I-1-a, 2.5 g, 9.90 mmol) and hexamethylenimine (992 mg, 10.00 mmol) in acetonitrile (30 ml), add N,N-diisopropylethylamine (3848 mg, 29.71 mmol), and react at 0 °C for 0.5 h. Quench with water, extract with dichloromethane, collect the organic phase, wash it repeatedly with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the target product 4-(azido-1-yl)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine (I-1-b, 2.8 g, yield 89%). ESI[M+H] + = 314.05

[0140] Second Step: Synthesis of (1-(((4-(Azido-1-yl)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-1-c)

[0141] Dissolve 4-(azido-1-yl)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine (I-1-b, 2.8 g, 8.88 mmol) in N,N-dimethylacetamide (40 ml), then successively add cyclopropane-1,1-diyldimethanol (2722 mg, 26.65 mmol), triethylamine (899 mg, 8.88 mmol), and cesium carbonate (8684 mg, 26.65 mmol), and react under nitrogen protection at room temperature for 16 h. Quench with water, extract with dichloromethane, collect the organic phase, wash it repeatedly with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, and purify by liquid chromatography separation (dichloromethane:methanol = 10:1) to obtain the target product (1-(((4-(azido-1-yl)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-1-c, 2.36 g, yield 68%).

[0142] ESI[M+H] + = 380.14

[0143] Step 3: Synthesis of (1 - ((((4 - (azetidin - 1 - yl) - 8 - fluoro - 7 - (7 - fluoro - 3 - (methoxymethoxy) - 8 - [(triisopropylsilyl)ethynyl]naphthalen - 1 - yl)pyrido[4,3 - d]pyrimidin - 2 - yl)oxy)methyl)cyclopropyl)methanol (I - 1 - d)

[0144] (1 - ((((4 - (azetidin - 1 - yl) - 7 - chloro - 8 - fluoropyrido[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 - dioxaborolan - 2 - yl)naphthalen - 1 - yl)ethynyl)triisopropylsilane (2.9 g, 5.68 mmol), [n - butyldi(1 - adamantyl)phosphine](2 - amino - 1,1'-biphenyl - 2 - yl)palladium(II) methanesulfonate (342 mg, 0.47 mmol), and potassium phosphate (2.0 g, 9.46 mmol) were dissolved in dioxane (20 ml) and water (2 ml). Under nitrogen protection, the reaction was carried out at 100 °C for 16 h. After the reaction solution was cooled to room temperature, it was quenched with water, extracted with ethyl acetate, the organic phase was collected and washed repeatedly with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then purified by liquid chromatography (petroleum ether:ethyl acetate = 1:1) to obtain the target product (1 - ((((4 - (azetidin - 1 - yl) - 8 - fluoro - 7 - (7 - fluoro - 3 - (methoxymethoxy) - 8 - [(triisopropylsilyl)ethynyl]naphthalen - 1 - yl)pyrido[4,3 - d]pyrimidin - 2 - yl)oxy)methyl)cyclopropyl)methanol (I - 1 - d, 2.1 g, yield 61%).

[0145] ESI[M + H] + = 730.37

[0146] Step 4: Synthesis of ((1 - ((((4 - (azetidin - 1 - yl) - 8 - fluoro - 7 - (7 - fluoro - 3 - (methoxymethoxy) - 8 - (triisopropylsilyl)ethynyl)naphthalen - 1 - yl)pyrido[4,3 - d]pyrimidin - 2 - yl)oxy)methyl)cyclopropyl)methyl - 4 - methylbenzenesulfonate (I - 1)

[0147] (1 - (((4-(Aza - 1 - yl)-8 - fluoro - 7-(7 - fluoro - 3-(methoxymethoxy)-8 - [(triisopropylsilyl)ethynyl]naphthalen - 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). Triethylamine (874 mg, 8.64 mmol) and 4 - dimethylaminopyridine (35 mg, 0.29 mmol) were added successively, and p - toluenesulfonyl chloride (1.09 g, 5.76 mmol) was added at 0 °C. The reaction was carried out at room temperature for 16 hours. The reaction was quenched by adding water, extracted with ethyl acetate, and the organic phase was collected and washed repeatedly with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Then it was purified by liquid chromatography separation (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]naphthalen - 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 (400 MHz, DMSO - d6) δ 9.16–9.15 (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).

[0148] Intermediate I - 2

[0149] Intermediate I - 2: Synthesis of 3-(1 - methyl - 6-(piperidin - 4 - yl)-1H - indazol - 3 - yl)piperidine - 2,6 - dione trifluoroacetate

[0150]

[0151] First step: Synthesis of tert - butyl 4-(1H - indazol - 6 - yl)-3,6 - dihydropyridine - 1(2H)-carboxylate (I - 2 - b)

[0152] 6-Bromo-1H-indazole (I-2-a, 6 g, 30.45 mmol) was dissolved in 1,4-dioxane (48 ml) and water (12 ml), then sodium carbonate (10.52 g, 99.27 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (1.24 g, 1.52 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (14.13 g, 45.68 mmol) were added, and the reaction was carried out at 105 °C for 16 h. After filtration of the reaction solution, the solvent was removed by distillation under reduced pressure to obtain a crude product, and 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)-carboxylate (I-2-b, 9.02 g, yield 98.90%). (ESI)[M+H] + = 300.1

[0153] Step 2: Synthesis of tert-butyl 4-(3-iodo-1-methyl-1H-indazol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (I-2-c)

[0154] Tert-butyl 4-(1H-indazol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (I-2-b, 9.02 g, 30.14 mmol) was dissolved in N,N-dimethylformamide (88 ml), then potassium hydroxide (5.07 g, 90.42 mmol) and iodine (11.47 g, 45.21 mmol) were added. After reacting at 25 °C for 2 h, the reaction solution was cooled to 0 °C, then iodomethane (6 g, 42.20 mmol) was added, and the reaction was heated to 25 °C and continued to react for 1 h. After the reaction was completed, the reaction solution was added to 400 ml of water, and extracted with ethyl acetate three times, 200 ml each time. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed by concentration under reduced pressure to obtain a crude product. The crude product was purified by liquid chromatography (petroleum ether:ethyl acetate = 0-15%) to obtain the target product tert-butyl 4-(3-iodo-1-methyl-1H-indazol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (I-2-c, 6.62 g, yield 48.96%). (ESI)[M+H] + = 440.2

[0155] Step 3: Synthesis of tert-butyl 4-(3-(2,4-bis(benzyloxy)phenyl)-1-methyl-1H-indazol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (I-2-d)

[0156] 2-(2,4-Bis(benzyloxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (I-2-c, 4.94 g, 10.77 mmol), cesium carbonate (10.53 g, 32.31 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (882 mg, 1.08 mmol), and tert-butyl 4-(3-iodo-1-methyl-1H-indazol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1-d, 6.62 g, 15.08 mmol) were dissolved in 1,4-dioxane (40 ml) and water (8 ml). After purging with nitrogen three times, the reaction was carried out at 100 °C for 16 h. After completion of the reaction, the reaction solution was added to 500 ml of water, and extracted with ethyl acetate three times, 250 ml each time. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent to obtain a crude product. The crude product was purified by liquid chromatography (petroleum ether:ethyl acetate = 0 - 20%) to obtain the target product tert-butyl 4-(3-(2,4-bis(benzyloxy)phenyl)-1-methyl-1H-indazol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (I-2-d, 7.13 g, yield 100%).

[0157] Step 4: Synthesis of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidine-1-carboxylate (I-2-e)

[0158] tert-Butyl 4-(3-(2,4-bis(benzyloxy)phenyl)-1-methyl-1H-indazol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (I-2-d, 1.79 g, 2.97 mmol) was dissolved in ethanol (24.5 ml) and ethyl acetate (24.5 ml). 1 g of 10% palladium on carbon was added, and after purging with hydrogen three times, the reaction was carried out at 30 °C for 24 h. After filtering the reaction solution through diatomaceous earth, 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 tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidine-1-carboxylate (I-2-e, 0.8 g, yield 62.99%). (ESI)[M+H] + = 427.3

[0159] Step 5: Preparation of 3-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)piperidine-2,6-dione trifluoroacetate (I-2)

[0160] tert-Butyl 4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidine-1-carboxylate (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 distillation under reduced pressure to obtain the target product 3-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)piperidine-2,6-dione trifluoroacetate (I-2, 1.2 g). (ESI)[M+H] + = 327.2. 1 H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 8.74 - 8.71 (d, J = 11.3 Hz, 1H), 8.46 - 8.43 (d, J = 11.2 Hz, 1H), 7.68 - 7.66 (d, J = 8.4 Hz, 1H), 7.39 (s, 1H), 7.03 - 7.01 (d, J = 8.4 Hz, 1H), 4.36 - 4.32 (m, 1H), 3.98 (s, 3H), 3.46 - 3.45 (d, J = 7.0 Hz, 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 = 13.6 Hz, 2H), 1.94 - 1.83 (m, 2H).

[0161] Intermediate I-3

[0162] 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]naphthalen-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl 4-methylbenzenesulfonate (I-3)

[0163]

[0164] First step: Synthesis of 4-(3-azabicyclo[3.1.0]hex-3-yl)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine (I-3-b)

[0165] Dissolve 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (I-3-a, 1 g, 6.97 mmol) in acetonitrile (35 ml), and successively add N,N-diisopropylethylamine (1539 mg, 11.88 mmol) and 3-azabicyclo[3.1.0]hexane hydrochloride (426 mg, 3.56 mmol). React at 0 °C for 0.5 h. Quench with water, extract with ethyl acetate, collect the organic phase and wash it repeatedly with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Then purify by liquid chromatography separation (petroleum ether:ethyl acetate = 2:1) to obtain the target product 4-(3-azabicyclo[3.1.0]hex-3-yl)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine (I-3-b, 865 mg, yield 41.5%). ESI[M+H] + = 299.13

[0166] Step 2: Synthesis of (1-(((4-(3-azabicyclo[3.1.0]hex-3-yl)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-3-c)

[0167] Dissolve 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) in N,N-dimethylacetamide (15 ml), and then successively add cyclopropane-1,1-diyldimethanol (1476 mg, 14.45 mmol), triethylamine (292 mg, 2.88 mmol), and cesium carbonate (2826 mg, 8.65 mmol). React at room temperature for 16 h. Quench with water, extract with ethyl acetate, collect the organic phase and wash it repeatedly with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Then purify by liquid chromatography separation (dichloromethane:methanol = 10:1) to obtain the target product (1-(((4-(3-azabicyclo[3.1.0]hex-3-yl)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-3-c, 1 g, yield 94.8%). ESI[M+H] + = 364.81

[0168] Step 3: Synthesis of (1-(((4-(3-azabicyclo[3.1.0]hex-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl]naphthalen-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-3-d)

[0169] (1-(((4-(3-azabicyclo[3.1.0]hexan-3-yl)-7-chloro-8-fluoropyrido[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-dioxaborolan-2-yl)naphthalen-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). Under nitrogen protection, the reaction was carried out at 100 °C for 16 h. The reaction was quenched by adding water, and the mixture was extracted with ethyl acetate. The organic phase was collected and washed repeatedly with saturated sodium chloride 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 (1-(((4-(3-azabicyclo[3.1.0]hexan-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphthalen-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

[0170] Step 4: Synthesis of (1-(((4-(3-azabicyclo[3.1.0]hexan-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl 4-methylbenzenesulfonate (I-3)

[0171] (1 - (((4-(3 - azabicyclo[3.1.0]hexan - 3 - yl)-8 - fluoro - 7-(7 - fluoro - 3 - (methoxymethoxy)-8 - [(triisopropylsilyl)ethynyl]naphthalen - 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). Triethylamine (170 mg, 1.68 mmol) and 4 - dimethylaminopyridine (7 mg, 0.055 mmol) were added successively, and p - toluenesulfonyl chloride (426 mg, 2.23 mmol) was added at 0 °C. The reaction was carried out at room temperature for 16 h. The reaction was quenched by adding water, extracted with ethyl acetate. The organic phase was collected and washed repeatedly with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by thin - layer chromatography silica gel plate (petroleum ether:ethyl acetate = 1:1) to obtain the target product (1 - (((4-(3 - azabicyclo[3.1.0]hexan - 3 - yl)-8 - fluoro - 7-(7 - fluoro - 3 - (methoxymethoxy)-8 - [(triisopropylsilyl)ethynyl]naphthalen - 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

[0172] Intermediate I - 4

[0173] Intermediate I - 4: Synthesis of (1 - (((4-(3 - azabicyclo[3.1.0]hexan - 3 - yl)-8 - fluoro - 7-(7 - fluoro - 3 - (methoxymethoxy)-8 - [(triisopropylsilyl)ethynyl]naphthalen - 1 - yl)-5 - methylpyrido[4,3 - d]pyrimidin - 2 - yl)oxy)methyl)cyclopropyl)methyl - 4 - methylbenzenesulfonate

[0174]

[0175] First step: Synthesis of 4-(3 - azabicyclo[3.1.0]hexan - 3 - yl)-2,7 - dichloro - 8 - fluoro - 5 - methylpyrido[4,3 - d]pyrimidine

[0176] (I - 4 - b)

[0177] 2,4,7-Trichloro-8-fluoro-5-methylpyrido[4,3-d]pyrimidine (I-4-a, 450 mg, 1.69 mmol) was dissolved in dichloromethane (10 mL). The temperature was lowered 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 successively. The reaction was carried out at 0 °C for 0.5 h. The reaction was quenched with an aqueous solution, extracted with dichloromethane. The organic phase was collected, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product 4-(3-azabicyclo[3.1.0]hex-3-yl)-2,7-dichloro-8-fluoro-5-methylpyrido[4,3-d]pyrimidine (I-4-b, 610 mg, crude). ESI [M+H] + = 360.6

[0178] Step 2: Synthesis of (1-(((4-(3-azabicyclo[3.1.0]hex-3-yl)-7-chloro-8-fluoro-5-methylpyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-4-c)

[0179] 4-(3-Azabicyclo[3.1.0]hex-3-yl)-2,7-dichloro-8-fluoro-5-methylpyrido[4,3-d]pyrimidine (I-4-b, 610 mg, 1.95 mmol) and cyclopropane-1,1-diyldimethanol (600 mg, 5.84 mmol) were dissolved in N,N-dimethylacetamide (1 mL). Triethylamine (197 mg, 1.95 mmol) and cesium carbonate (1.9 g, 5.84 mmol) were added successively. The reaction system was purged with nitrogen three times and reacted at room temperature for 16 h. The reaction was quenched with an aqueous solution, extracted with ethyl acetate. The organic phase was collected, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then purified by liquid chromatography (petroleum ether: ethyl acetate = 0% - 40%) to obtain the target product (1-(((4-(3-azabicyclo[3.1.0]hex-3-yl)-7-chloro-8-fluoro-5-methylpyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-4-c, 340 mg, yield 46%). ESI [M+H] + = 379.6

[0180] Step 3: Synthesis of (1-(((4-(3-azabicyclo[3.1.0]hex-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl]naphthalen-1-yl)-5-methylpyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-4-d)

[0181] (1 - (((4-(3-azabicyclo[3.1.0]hexan-3-yl)-7-chloro-8-fluoro-5-methylpyrido[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-dioxaborolan-2-yl)naphthalen-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). Finally, [(di(1-adamantyl)butylphosphino)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (130 mg, 0.18 mmol) was added. After displacing nitrogen three times, the temperature was raised to 100 °C and the reaction was carried out overnight. The reaction was quenched with water, extracted with ethyl acetate, the organic phase was collected, washed with saturated sodium chloride solution, 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]hexan-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl]naphthalen-1-yl)-5-methylpyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-4-d, 330 mg, yield 62.8%).

[0182] Step 4: Synthesis of (1 - (((4-(3-azabicyclo[3.1.0]hexan-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl]naphthalen-1-yl)-5-methylpyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl-4-methylbenzenesulfonate (I-4)

[0183] (1 - (((4-(3 - azabicyclo[3.1.0]hexan - 3 - yl)-8 - fluoro - 7-(7 - fluoro - 3 - (methoxymethoxy)-8 - [(triisopropylsilyl)ethynyl]naphthalen - 1 - yl)-5 - methylpyrido[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 the reaction was carried out at room temperature for 16 hours. After adding water to the reaction solution, it was extracted with dichloromethane three times. 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]hexan - 3 - yl)-8 - fluoro - 7-(7 - fluoro - 3 - (methoxymethoxy)-8 - [(triisopropylsilyl)ethynyl]naphthalen - 1 - yl)-5 - methylpyrido[4,3 - d]pyrimidin - 2 - yl)oxy)methyl)cyclopropyl)methyl - 4 - methylbenzenesulfonate (I - 4, 95 mg, yield 31.5%).

[0184] Intermediate I - 5

[0185] Intermediate I - 5: Synthesis of (1 - (((4-(3,6 - dihydropyridin - 1(2H)-yl)-8 - fluoro - 7-(7 - fluoro - 3 - (methoxymethoxy)-8 - [(triisopropylsilyl)ethynyl]naphthalen - 1 - yl)-5 - methylpyrido[4,3 - d]pyrimidin - 2 - yl)oxy)methyl)cyclopropyl)methyl - 4 - methylbenzenesulfonate (I - 5)

[0186]

[0187] The first step: Synthesis of 2,7 - dichloro - 4-(3,6 - dihydropyridin - 1(2H)-yl)-8 - fluoro - 5 - methylpyrido[4,3 - d]pyrimidine (I - 5 - b)

[0188] 2,4,7 - Trichloro - 8 - fluoro - 5 - methylpyrido[4,3 - d]pyrimidine (I - 5 - a, 2 g, 7.5 mmol) was dissolved in acetonitrile (50 mL) at 0 °C. First, N,N - diisopropylethylamine (2.9 g, 22.5 mmol) was added, then 1,2,3,6 - tetrahydropyridine hydrochloride (807 mg, 6.75 mmol) was added and the reaction was carried out at 0 °C for 0.5 hour. After concentration under reduced pressure, the crude product was separated and 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 - methylpyrido[4,3 - d]pyrimidine (I - 5 - b, 2.02 g, yield 85.96%). ESI[M + H] += 313.6.

[0189] Step 2: Synthesis of (1 - ((((7-chloro-4-(3,6-dihydropyridin-1(2H)-yl)-8-fluoro-5-methylpyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-5-c)

[0190] Dissolve (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) in acetonitrile (30 mL), then successively add triethylenediamine (179 mg, 1.6 mmol) and cesium carbonate (3.12 g, 9.57 mmol), cyclopropane-1,1-diyldimethanol (652 mg, 6.38 mmol), and react at room temperature for 0.5 h. After concentration under reduced pressure, the target compound (1 - ((((7-chloro-4-(3,6-dihydropyridin-1(2H)-yl)-8-fluoro-5-methylpyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-5-c, 1.02 g, yield 85%)) is obtained by purification through liquid chromatography separation (petroleum ether:ethyl acetate = 0 - 40%).

[0191] Step 3: Synthesis of (1 - ((((4-(3,6-dihydropyridin-1(2H)-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl]naphthalen-1-yl)-5-methylpyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-5-d)

[0192] (1 - (((7-chloro-4-(3,6-dihydropyridin-1(2H)-yl)-8-fluoro-5-methylpyrido[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-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (2.26 g, 4.40 mmol), [n-butylbis(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (267 mg, 0.367 mmol), and potassium phosphate (1.56 g, 7.34 mmol) were dissolved in dioxane (30 mL) and water (3 mL). Under nitrogen protection, the reaction was carried out at 100 °C for 16 h. After the reaction solution was cooled to room temperature, it was quenched with water, extracted with ethyl acetate, the organic phase was collected and washed repeatedly with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then purified by liquid chromatography separation (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]naphthalen-1-yl)-5-methylpyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-5-d, 1.595 g, yield 60.88%).

[0193] Step 4: Synthesis of (1 - (((4-(3,6-dihydropyridin-1(2H)-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl]naphthalen-1-yl)-5-methylpyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl 4-methylbenzenesulfonate (I-5)

[0194] (1 - (((4-(3,6 - dihydropyridin - 1(2H)-yl)-8 - fluoro - 7-(7 - fluoro - 3-(methoxymethoxy)-8 - [(triisopropylsilyl)ethynyl]naphthalen - 1 - yl)-5 - methylpyrido[4,3 - d]pyrimidin - 2 - yl)oxy)methyl)cyclopropyl)methanol (I - 5 - d, 690 mg, 0.95 mmol) was dissolved in dichloromethane (8 mL). Triethylamine (96 mg, 0.95 mmol) and 4 - dimethylaminopyridine (59 mg, 0.48 mmol) were added successively, and p - toluenesulfonyl chloride (543 mg, 2.85 mmol) was added at 0 °C. The reaction was carried out at room temperature for 6 hours. After concentration under reduced pressure, the target product (1 - (((4-(3,6 - dihydropyridin - 1(2H)-yl)-8 - fluoro - 7-(7 - fluoro - 3-(methoxymethoxy)-8 - [(triisopropylsilyl)ethynyl]naphthalen - 1 - yl)-5 - methylpyrido[4,3 - d]pyrimidin - 2 - yl)oxy)methyl)cyclopropyl)methyl 4 - methylbenzenesulfonate (I - 5, 505 mg, yield 60.19%) was obtained by purification through liquid chromatography separation (petroleum ether:ethyl acetate = 0 - 30%).

[0195] Intermediate I - 6

[0196] Intermediate I - 6: Synthesis of methyl ((1 - ((4-(2,5 - dihydro - 1H - pyrrol - 1 - yl)-8 - fluoro - 7-(7 - fluoro - 3-(methoxymethoxy)-8 - ((triisopropylsilyl)ethynyl)naphthalen - 1 - yl)-5 - methylpyrido[4,3 - d]pyrimidin - 2 - yl)oxy)methyl)cyclopropyl) 4 - methylbenzenesulfonate (I - 6)

[0197]

[0198] First step: Synthesis of 2,7 - dichloro - 4-(3,6 - dihydropyridin - 1(2H)-yl)-8 - fluoro - 5 - methylpyrido[4,3 - d]pyrimidine (I - 6 - b)

[0199] 2,4,7 - Trichloro - 8 - fluoro - 5 - methylpyrido[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 was carried out at 0 °C for 0.5 hour. After adding water to the reaction solution, it was extracted with dichloromethane. The organic phase was collected, washed repeatedly 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 - pyrrol - 1 - yl)-8 - fluoro - 5 - methylpyrido[4,3 - d]pyrimidine (I - 6 - b, 1 g, yield 89%).

[0200] Step 2: Synthesis of (1 - ((7-chloro-4-(2,5-dihydro-1H-pyrrol-1-yl)-8-fluoro-5-methylpyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-6-c)

[0201] Dissolve 2,7-dichloro-4-(2,5-dihydro-1H-pyrrol-1-yl)-8-fluoro-5-methylpyrido[4,3-d]pyrimidine (I-6-b, 1 g, 3.35 mmol) in acetonitrile (30 mL), then successively add triethylenediamine (DABCO, 188 mg, 1.675 mmol), cesium carbonate (3.25 g, 10 mmol), and cyclopropane-1,1-diyldimethanol (885 mg, 8.38 mmol), and react at room temperature for 0.5 h. After filtration, concentrate under reduced pressure and purify by liquid chromatography separation (petroleum ether:ethyl acetate = 0 - 50%) to obtain the target compound (1 - ((7-chloro-4-(2,5-dihydro-1H-pyrrol-1-yl)-8-fluoro-5-methylpyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-6-c, 1 g, yield 81.9%).

[0202] Step 3: Synthesis of (1 - ((4-(2,5-dihydro-1H-pyrrol-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5-methylpyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-6-d)

[0203] (1 - ((7-chloro-4-(2,5-dihydro-1H-pyrrol-1-yl)-8-fluoro-5-methylpyrido[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-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (1.83 g, 3.75 mmol), [n-butylbis(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (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). Under nitrogen protection, the reaction was carried out at 100 °C for 16 h. After the reaction solution was cooled to room temperature, it was quenched with water, extracted with ethyl acetate, the organic phase was collected and washed repeatedly with saturated sodium chloride solution, dried over 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-pyrrol-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5-methylpyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-6-d, 1.24 g, yield 63%).

[0204] Step 4: Synthesis of methyl ((1 - ((4-(2,5-dihydro-1H-pyrrol-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5-methylpyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl) 4-methylbenzenesulfonate (I-6)

[0205] (1 - ((4-(2,5-Dihydro-1H-pyrrol-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5-methylpyrido[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). Triethylamine (524 mg, 5.19 mmol) and 4-dimethylaminopyridine (21 mg, 0.17 mmol) were added successively, and p-toluenesulfonyl chloride (660 mg, 3.46 mmol) was added at 0 °C. The reaction was carried out at room temperature for 16 hours. After concentration under reduced pressure, the target product ((1 - ((4-(2,5-Dihydro-1H-pyrrol-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-5-methylpyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl 4-methylbenzenesulfonate (I-6, 700 mg, yield 46.6%) was obtained by purification through liquid chromatography separation (petroleum ether: ethyl acetate = 0 - 35%).

[0206] Intermediate I-7

[0207] Intermediate I-7: Synthesis of (R)-(1 - ((8-Fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(3-hydroxypiperidin-1-yl)-5-methylpyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl 4-methylbenzenesulfonate (I-7)

[0208]

[0209] The first step: Synthesis of (R)-1-(2,7-dichloro-8-fluoro-5-methylpyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol (I-7-a)

[0210] 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. First, N,N-diisopropylethylamine (3.9 mL, 22.5 mmol) was added, then (R)-piperidin-3-ol hydrochloride (929 mg, 6.75 mmol) was added, and the reaction was carried out at 0 °C for 0.5 h. After adding water to the reaction solution, it was extracted with dichloromethane. The organic phase was collected, washed repeatedly with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 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-methylpyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol (I-7-a, 1.94 g, yield 78.23%).

[0211] Step 2: Synthesis of (R)-1-(7-chloro-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol (I-7-b)

[0212] (R)-1-(2,7-Dichloro-8-fluoro-5-methylpyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol (I-7-a, 1.94 g, 5.86 mmol) was dissolved in acetonitrile (60 mL), then triethylenediamine (329 mg, 2.93 mmol), cesium carbonate (5.73 g, 17.58 mmol), and cyclopropane-1,1-diyldimethanol (1.2 g, 11.72 mmol) were added in sequence, and the reaction was carried out at room temperature for 0.5 h. After filtration, it was concentrated under reduced pressure to obtain the target compound (R)-1-(7-chloro-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol (I-7-b, 3.08 g, crude product).

[0213] Step 3: Synthesis of (R)-1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-(hydroxymethyl)cyclopropyl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol (I-7-c)

[0214] (R)-1-(7-Chloro-8-fluoro-2-(((1-(hydroxymethyl)cyclopropyl)methyl)oxy)-5-methylpyrido[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-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (3.58 g, 6.98 mmol), [n-Butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (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). Under nitrogen protection, the reaction was carried out at 100 °C for 16 h. After the reaction solution was cooled to room temperature, it was quenched with water, extracted with ethyl acetate, the organic phase was collected and washed repeatedly with saturated sodium chloride solution, dried over 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)naphthalen-1-yl)-2-(((1-(hydroxymethyl)cyclopropyl)methyl)oxy)-5-methylpyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol (I-7-c, 2.5 g, yield 43%).

[0215] Step 4: Synthesis of Methyl (R)-(1-((8-Fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(3-hydroxypiperidin-1-yl)-5-methylpyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)4-methylbenzenesulfonate (I-7)

[0216] (R)-1-(8-Fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-(hydroxymethyl)cyclopropyl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol (I-7-c, 1.5 g, 2.0 mmol) was dissolved in dichloromethane (15 mL). Triethylamine (607 mg, 6 mmol) and 4-dimethylaminopyridine (24.5 mg, 0.2 mmol) were added successively, and p-toluenesulfonyl chloride (762 mg, 4 mmol) was added at 0 °C. The reaction was carried out at room temperature for 16 hours. After concentration under reduced pressure, the target product (R)-(1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(3-hydroxypiperidin-1-yl)-5-methylpyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl 4-methylbenzenesulfonate (I-7, 480 mg, yield 27%) was obtained by purification through liquid chromatography separation (petroleum ether: ethyl acetate = 0 - 65%).

[0217] Intermediate I-8

[0218] Intermediate I-8: Synthesis of (1-(((4-(azepan-1-yl)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl 4-methylbenzenesulfonate (I-8)

[0219]

[0220] First step: Synthesis of (1-(((4-(azepan-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-8-a)

[0221] (1 - (((4-(azepan-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy))-8-((triisopropylsilyl)ethynyl)naphthalen-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), cesium fluoride (509 mg, 3.35 mmol) was added, and the reaction was carried out at room temperature for 1 hour. After the reaction solution was filtered and concentrated under reduced pressure, the target product (1-((4-(azepan-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-8-a, 500 mg, crude product) was obtained. ESI[M+H] + = 575

[0222] Step 2: Synthesis of (1-((4-(azepan-1-yl)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-8-b)

[0223] (1-((4-(azepan-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[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 replacing the gas with hydrogen three times, 5% palladium on carbon (648 mg) was added. After replacing the gas with hydrogen three times again, the reaction solution was reacted at room temperature for 16 hours. The reaction solution was filtered through diatomaceous earth and concentrated under reduced pressure to obtain the target product (1-((4-(azepan-1-yl)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-8-b, 368 mg, yield 73.14%).

[0224] Step 3: Synthesis of methyl 4-methylbenzenesulfonate of (1-((4-(azepan-1-yl)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl) (I-8)

[0225] Dissolve (1 - ((4-(azepan-1-yl)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-8-b, 368 mg, 0.63 mmol) in dichloromethane (2 mL). Sequentially add triethylamine (191 mg, 1.89 mmol) and 4-dimethylaminopyridine (1.45 mg, 0.063 mmol), and add p-toluenesulfonyl chloride (364 mg, 1.89 mmol) at 0 °C. React at room temperature for 16 hours. After adding water to the reaction solution, extract it with dichloromethane three times. Combine the organic phases, concentrate under reduced pressure, and purify by liquid chromatography (petroleum ether:ethyl acetate = 0 - 25%) to obtain the target product (1 - ((4-(azepan-1-yl)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl 4-methylbenzenesulfonate (I-8, 98 mg, yield 21.2%).

[0226] Intermediate I-9

[0227] Intermediate I-9: Synthesis of (R)-(1 - ((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(3-hydroxypiperidin-1-yl)-5-methylpyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl 4-methylbenzenesulfonate (I-9)

[0228]

[0229] First step: Synthesis of (R)-1-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy]-5-methylpyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol (I-9-a)

[0230] (R)-1-(8-Fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-(hydroxymethyl)cyclopropyl)methoxy)-5-methylpyrido[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), cesium fluoride (1.017 g, 6.7 mmol) was added, and the reaction was carried out at room temperature for 1 hour. The reaction solution was added to 150 mL of water, the product precipitated, and after filtration, drying, and concentration of the reaction solution, the target product (R)-1-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-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, crude product) was obtained.

[0231] Step 2: Synthesis of (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy]-5-methylpyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol (I-9-b)

[0232] (R)-1-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-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). After replacing the gas with hydrogen three times, 5% palladium on carbon (500 mg) was added. After replacing the gas with hydrogen three times again, the reaction solution was reacted at room temperature for 16 hours. The reaction solution was filtered through diatomaceous earth and concentrated under reduced pressure to obtain the target product (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-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, crude product).

[0233] Step 3: Synthesis of (R)-(1-((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(3-hydroxypiperidin-1-yl)-5-methylpyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl) methyl 4-methylbenzenesulfonate (I-9)

[0234] (R)-1-(7-(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-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). Triethylamine (364 mg, 3.6 mmol) and 4-dimethylaminopyridine (15 mg, 0.12 mmol) were added successively, and p-toluenesulfonyl chloride (457 mg, 2.4 mmol) was added at 0 °C. The reaction was carried out at room temperature for 16 h. After adding water to the reaction solution, it was extracted with dichloromethane three times. 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)naphthalen-1-yl)-8-fluoro-4-(3-hydroxypiperidin-1-yl)-5-methylpyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl 4-methylbenzenesulfonate (I-9, 85 mg, yield 9.4%). ESI [M+H] + = 749.3

[0235] Intermediate I-10

[0236] Synthesis of Intermediate I-10: 4-(Azepan-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-(iodomethyl)cyclopropyl)methoxypyrido[4,3-d]pyrimidine (I-10)

[0237]

[0238] First step: Synthesis of 4-(Aza-1-yl)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine (I-10-b)

[0239] 2,4,7-Trichloro-8-fluoropyrido[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). N,N-Diisopropylethylamine (3848 mg, 29.71 mmol) was added and the reaction was carried out at 0 °C for 0.5 h. The reaction was quenched by adding water, extracted with dichloromethane, the organic phase was collected and washed repeatedly with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the target product 4-(Aza-1-yl)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine (I-10-b, 2.8 g, yield 89%). ESI [M+H] + = 314.05

[0240] Step 2: Synthesis of (1-(((4-(azetidin-1-yl)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-10-c)

[0241] Dissolve 4-(azetidin-1-yl)-2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine (I-10-b, 2.8 g, 8.88 mmol) in acetonitrile (40 mL), then successively add 1,4-diazabicyclo[2.2.2]octane (498 mg, 4.44 mmol), cesium carbonate (8684 mg, 26.65 mmol) and cyclopropane-1,1-diyldimethanol (2722 mg, 26.65 mmol), and react at room temperature for 0.5 h. Filter, concentrate under reduced pressure to obtain the target product (1-(((4-(azetidin-1-yl)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-10-c, 2.36 g, yield 68%). ESI [M+H] + = 380.14

[0242] Step 3: Synthesis of (1-(((4-(azetidin-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl]naphthalen-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-10-d)

[0243] (1-(((4-(Azepan-1-yl)-7-chloro-8-fluoropyrido[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-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (2.9 g, 5.68 mmol), [n-butylbis(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (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). Under nitrogen protection, the reaction was carried out at 100 °C for 16 hours. After the reaction solution was cooled to room temperature, it was quenched with water, extracted with ethyl acetate, the organic phase was collected and washed repeatedly with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then purified by liquid chromatography separation (petroleum ether:ethyl acetate = 1:1) to obtain the target product (1-(((4-(azepan-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl]naphthalen-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

[0244] Step 4: Synthesis of 4-(azepan-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-(iodomethyl)cyclopropyl)methoxypyrido[4,3-d]pyrimidine (I-10)

[0245] (1 - (((4-(azetidin-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-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 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 separated by liquid chromatography (petroleum ether:ethyl acetate = 0 - 40%) to obtain the target product 4-(azepan-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-(iodomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidine (I-10, 400 mg, yield 69.59%).

[0246] Intermediate I-11

[0247] Synthesis of Intermediate I-11: 4-(azepan-1-yl)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((1-(iodomethyl)cyclopropyl)methoxy]pyrido[4,3-d]pyrimidine (I-11)

[0248]

[0249] First step: Synthesis of 2-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (I-11-b)

[0250] ((2-Fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (I-11-a, 5 g, 9.8 mmol) was dissolved in N,N-dimethylformamide (40 mL), cesium fluoride (7.5 g, 49 mmol) was added, and the reaction was carried out at room temperature for 4 hours. The reaction solution was added to 200 mL of water. After the product precipitated, it was filtered and dried to obtain the target product 2-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (I-11-b, 3.5 g, crude product).

[0251] Step 2: Synthesis of 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (I-11-c)

[0252] Dissolve 2-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (I-11-b, 3.5 g, 9.8 mmol) in tetrahydrofuran (30 mL), add 5% palladium on carbon (400 mg) and palladium hydroxide (400 mg). After replacing with hydrogen three times, the reaction solution is reacted at room temperature for 16 hours. After filtering and concentrating the reaction solution, it is separated and purified by liquid chromatography (petroleum ether: ethyl acetate = 0 - 10%) to obtain the target product 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (I-11-c, 3.6 g, crude product).

[0253] Step 3: Synthesis of (1-((4-(azepan-1-yl)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-11-d)

[0254] Dissolve (1-(((4-(azepan-1-yl)-7-chloro-8-fluoropyrido[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)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (I-11-c, 957.9 g, 2.63 mmol), [butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (95.41 mg, 0.131 mmol) and potassium phosphate (834.61 mg, 3.93 mmol) in 1,4-dioxane (10 mL) and water (1 mL). After replacing with nitrogen three times, react at 100 °C by microwave for 1.5 hours. After concentrating the reaction solution under reduced pressure, it is separated by liquid chromatography (petroleum ether: ethyl acetate = 0 - 60%) and purified to obtain the target product (1-((4-(azepan-1-yl)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methanol (I-11-d, 270 mg, yield 35.5%).

[0255] Step 4: Synthesis of 4-(azepan-1-yl)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((1-(iodomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidine (I-11))

[0256] Dissolve (1-(((4-(azepan-1-yl)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[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) in dichloromethane (15 mL). Dissolve iodine (1.18 g, 4.66 mmol) in dichloromethane (15 mL) and slowly add it dropwise to the mixture. React at room temperature for 2 hours. After the reaction is completed, concentrate the reaction solution under reduced pressure and separate and purify it by liquid chromatography (petroleum ether: ethyl acetate = 0 - 35%) to obtain the target product 4-(azepan-1-yl)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((1-(iodomethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidine (I-11, 200 mg, yield 62.36%).

[0257] Intermediate I-12

[0258] Intermediate I-12: Preparation of (R)-(1-(((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(3-hydroxy-3-methylpiperidin-1-yl)-5-methoxypyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl 4-methylbenzenesulfonate (I-12)

[0259]

[0260] Step 1: Preparation of 7-chloro-8-fluoro-5-methoxy-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (I-12-b)

[0261] 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, and the reaction was carried out at 50 °C for 16 h. The reaction solution was filtered, and the pH was adjusted to 3 with hydrochloric acid 1,4-dioxane. It was added to water 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

[0262] 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)

[0263] 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). At room temperature, N,N-diisopropylethylamine (25.62 mL, 155.04 mmol) and phosphorus oxychloride (7.22 mL, 77.54 mmol) were added in sequence. After reacting at 80 °C for 1 h, the reaction solution was cooled to 0 °C, then N,N-diisopropylethylamine (12.81 mL, 77.52 mmol) and (R)-3-methylpiperidin-3-ol hydrochloride (4.7 g, 31 mmol) were added, and the reaction was carried out at 0 °C for 1.5 h. The reaction solution was quenched slowly with warm water, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and then purified by liquid chromatography separation (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

[0264] Step 3: Preparation of (R)-1-(7-chloro-8-fluoro-5-methoxy-2-(methylsulfonyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (I-12-d)

[0265] (R)-1-(7-chloro-8-fluoro-5-methoxy-2-(methylsulfanyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (I-12-c, 3 g, 8 mmol), m-chloroperbenzoic acid (4.1 g, 24 mmol) were dissolved in dichloromethane (50 mL), and the reaction was carried out at room temperature for 1 hour. After the reaction solution was quenched with saturated sodium bicarbonate solution, it was 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).

[0266] Step 4: Preparation of (R)-1-(7-chloro-8-fluoro-2-(((1-(hydroxymethyl)cyclopropyl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (I-12-e)

[0267] (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, 7.9 mmol), cesium carbonate (5.86 g, 18 mmol), cyclopropane-1,1-diyldimethanol (1.6 g, 15.8 mmol) and triethylenediamine (DABCO, 443 mg, 3.95 mmol) were dissolved in acetonitrile (50 mL), and the reaction was carried out at room temperature for 1 hour. The reaction solution was filtered and concentrated under reduced pressure, and then purified by liquid chromatography separation (petroleum ether: ethyl acetate = 0 - 80%) to obtain the target product (R)-1-(7-chloro-8-fluoro-2-(((1-(hydroxymethyl)cyclopropyl)methoxy)-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (I-12-e, 2.16 g, yield 64%). ESI[M+H] + = 427.3

[0268] Step 5: Preparation of (R)-1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((1-(hydroxymethyl)cyclopropyl)methoxy]-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (I-12-f)

[0269] (R)-1-(7-chloro-8-fluoro-2-(((1-(hydroxymethyl)cyclopropyl)methyl)oxy)-5-methoxypyrido[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), 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-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (3.89 g, 7.58 mmol) were dissolved in 1,4-dioxane (20 mL) and water (2 mL). Under nitrogen protection, the reaction was carried out at 100 °C for 16 hours. The reaction solution was quenched with water, extracted with ethyl acetate, the organic phase was collected and dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then separated 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)naphthalen-1-yl)-2-(((1-(hydroxymethyl)cyclopropyl)methyl)oxy]-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (I-12-f, 1.80 g, yield 45.7%).

[0270] Step 6: Synthesis of methyl (R)-(1-((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(3-hydroxy-3-methylpiperidin-1-yl)-5-methoxypyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)4-methylbenzenesulfonate (I-12)

[0271] (R)-1-(8-Fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-(hydroxymethyl)cyclopropyl)methoxy]-5-methoxypyrido[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). Triethylamine (702.25 mg, 6.94 mmol) and 4-dimethylaminopyridine (28.22 mg, 0.231 mmol) were added successively, and p-toluenesulfonyl chloride (1.32 g, 6.94 mmol) was added at 0 °C. The reaction was carried out at room temperature for 4 hours. The reaction solution was directly purified by liquid chromatography separation (petroleum ether: ethyl acetate = 0 - 50%) to obtain the target product (R)-(1-((8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-4-(3-hydroxy-3-methylpiperidin-1-yl)-5-methoxypyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl) methyl 4-methylbenzenesulfonate (I-12, 250 mg, yield 11.6%).

[0272] Intermediate I-13

[0273] Intermediate I-13: Preparation of (R)-(1-((7-(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)-5-methoxypyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl) methyl 4-methylbenzenesulfonate (I-13)

[0274]

[0275] First step: Preparation of (R)-1-(7-(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy]-5-methoxypyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (I-13-a)

[0276] (R)-1-(7-chloro-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)-5-methoxypyrido[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)pyrido[4,3-d]pyrimidin-4(3H)-one-2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.05 g, 2.928 mmol) were dissolved in 1,4-dioxane (10 mL) and water (1 mL). 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. Under nitrogen protection, the reaction was carried out at 100 °C for 16 hours. The reaction solution was quenched with water, extracted with ethyl acetate, the organic phase was collected and dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and then separated and purified by liquid chromatography (petroleum ether: ethyl acetate = 0 - 85%) to obtain the target product (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-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, yield 56.96%).

[0277] Step 2: Synthesis of methyl (R)-(1-((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)-5-methoxypyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)4-methylbenzenesulfonate (I-13)

[0278] (R)-1-(7-(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-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-toluenesulfonyl chloride (795 mg, 4.17 mmol) was added at 0 °C, and the reaction was carried out at room temperature for 3 hours. The reaction solution was directly purified by liquid chromatography separation (petroleum ether: ethyl acetate = 0-50%) to obtain the target product (R)-(1-((7-(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)-5-methoxypyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl) 4-methylbenzenesulfonate (I-13, 306 mg, yield 28.26%).

[0279] Example 1: Synthesis of 3-((4-(4-(7-(1-(((4-Aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione trifluoroacetate (1)

[0280]

[0281] First step: Synthesis of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazine-1-carboxylate (1-b)

[0282] tert-Butyl 4-(4-amin-2-fluorophenyl)piperazine-1-carboxylate (1-a, 1 g, 3.38 mmol), 3-bromopiperidine-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 the reaction was carried out at 65 °C for 0.5 hour. After the reaction solution was cooled to room temperature, ethyl acetate was added, and it was washed repeatedly with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then purified by liquid chromatography separation (petroleum ether: ethyl acetate = 1:1) to obtain the target product tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazine-1-carboxylate (1-b, 1.29 g, yield 93.3%). ESI[M+H] + = 406.20

[0283] Step 2: Synthesis of 3-(3-fluoro-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (1-c)

[0284] Dissolve tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazine-1-carboxylate (1-b, 1.29 g, 3.17 mmol) in acetonitrile (10 ml), then add 1,4-dioxane hydrochloride (10 ml), and react at room temperature for 16 h. The reaction solution is directly concentrated under reduced pressure to obtain 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

[0285] Step 3: Synthesis of tert-butyl 2-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1-d)

[0286] Dissolve 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-carboxylate (346 mg, 1.44 mmol) in methanol:acetic acid = 10:1 (5.5 ml), react at room temperature for 1 h, then add sodium cyanoborohydride (228 mg, 3.62 mmol). Under nitrogen protection, continue to react at room temperature for 1 h. Quench with water, extract with ethyl acetate, collect the organic phase and wash it repeatedly with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, and purify by liquid chromatography separation (dichloromethane:methanol = 10:1) after concentration under reduced pressure to obtain the target product tert-butyl 2-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1-d, 313 mg, yield 49%). ESI [M+H] + = 529.31

[0287] 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)

[0288] Dissolve tert-butyl 2-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (1-d, 313 mg, 0.59 mmol) in acetonitrile (3 ml), then add 1,4-dioxane hydrochloride (3 ml), and react at room temperature for 16 h. The reaction solution is directly concentrated under reduced pressure to obtain the target product 3-((4-(4-(7-azaspiro[3.5]nonan-2-yl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (1-e, 614 mg, yield 242%). ESI [M+H] + = 429.25

[0289] Step 5: Synthesis of 3-(4-(4-(7-(1-((4-(azetidin-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl]naphthalen-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (1-f)

[0290] Dissolve ((1-(((4-(azetidin-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl]naphthalen-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]nonan-2-yl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (1-e, 80 mg, 0.186 mmol), potassium iodide (21 mg, 0.126 mmol) and potassium carbonate (86 mg, 0.622 mmol) in acetonitrile (2 ml), react at 60 °C for 6 h, quench with water, extract with ethyl acetate, collect the organic phase and wash repeatedly with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure and purify by thin layer chromatography silica gel plate (dichloromethane:methanol = 10:1) to obtain the target product 3-(4-(4-(7-(1-((4-(azetidin-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl]naphthalen-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (1-f, 40 mg, yield 28.3%). ESI [M+H] + = 1141.62

[0291] Step 6: Synthesis of 3-((4-(4-(7-(1-((((4-(azetidin-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (1-g)

[0292] Dissolve 3-((4-(4-(7-(1-((4-(azetidin-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (1-f, 40 mg, 0.035 mmol) in N,N-dimethylformamide (2 ml), then add cesium fluoride (27 mg, 0.177 mmol), react at room temperature for 1 hour, quench with water, extract with ethyl acetate, collect the organic phase and wash repeatedly with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product 3-((4-(4-(7-(1-((((4-(azetidin-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (1-g, 40 mg, yield 117%). ESI [M+H] + = 985.48

[0293] Step 7: Synthesis of 3-((4-(4-(7-(1-((((4-azetidin-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione trifluoroacetate (1)

[0294] -(4-(4-(7-(1-(((4-(Aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (1-g, 40 mg, 0.04 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 h. The reaction solution was separated and 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-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione trifluoroacetate (1, 1.85 mg, yield 5%). ESI [M+H] + = 941.46 1 H NMR (400 MHz, DMSO-d6) δ 10.83 (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, 1H), 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).

[0295] Example 2: Synthesis of 3-(6-(1-(1-((((4-(Aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-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)piperidine-2,6-dione trifluoroacetate (2)

[0296]

[0297] Step 1: Synthesis of tert-butyl 4-((4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)methyl)piperidine-1-carboxylate (2-a)

[0298] Dissolve 3-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)piperidine-2,6-dione (I-2, 250 mg, 0.57 mmol) in acetonitrile (12.5 ml), then add potassium carbonate (236 mg, 1.71 mmol) and tert-butyl 4-(iodomethyl)piperidine-1-carboxylate (205 mg, 0.63 mmol), and react at 80 °C for 16 hours. After filtering the reaction solution, the solvent is removed by distillation under reduced pressure to obtain the crude product, and the crude product is purified by TLC large plate (dichloromethane:methanol = 10:1) to obtain the target product tert-butyl 4-((4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)methyl)piperidine-1-carboxylate (2-a, 124 mg, yield 41.61%). (ESI)[M+H] + = 524.5

[0299] Step 2: Synthesis of 3-(1-methyl-6-(1-(piperidin-4-ylmethyl)piperidin-4-yl)-1H-indazol-3-yl)piperidine-2,6-dione (2-b)

[0300] Dissolve tert-butyl 4-((4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)methyl)piperidine-1-carboxylate (2-a, 124 mg, 0.24 mmol) in dichloromethane (5 ml), add trifluoroacetic acid (0.5 ml), and react at room temperature for 0.5 hour. The solvent is removed by distillation under reduced pressure to obtain the target product 3-(1-methyl-6-(1-(piperidin-4-ylmethyl)piperidin-4-yl)-1H-indazol-3-yl)piperidine-2,6-dione (2-b, 1.2 g). (ESI)[M+H] + = 424.4.

[0301] Step 3: Synthesis of 3-(6-(1-(1-((((4-(azetidin-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-7-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (2-c)

[0302] (1 - (((4-(Aza - 1 - yl)-8 - fluoro - 7-(7 - fluoro - 3-(methoxymethoxy)-8 - [(triisopropylsilyl)ethynyl]naphthalen - 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), 3-(1 - methyl - 6-(1 - (piperidin - 4 - ylmethyl)piperidin - 4 - yl)-1H - indazol - 3 - yl)piperidine - 2,6 - dione (2 - b, 211 mg, 0.5 mmol) were dissolved in acetonitrile (14 ml), and the reaction was carried out 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 a crude product. The crude product was purified by TLC large plate (methylene chloride: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)naphthalen - 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)piperidine - 2,6 - dione (2 - c, 141 mg, yield 37.60%).

[0303] Step 4: Synthesis of 3-(6-(1-(1 - ((((4-(Aza - 1 - yl)-7-(8 - ethynyl - 7 - fluoro - 3-(methoxymethoxy)naphthalen - 1 - yl)-8 - fluoropyrido[4,3 - d]pyrimidin - 2 - yl)oxy)methyl)cyclopropyl)methyl)piperidin - 4 - yl)methyl (2 - d)

[0304] 3-(6-(1-(1 - ((((4-(Aza - 1 - yl)-8 - fluoro - 7-(7 - fluoro - 3-(methoxymethoxy)-7 - ((triisopropylsilyl)ethynyl)naphthalen - 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)piperidine - 2,6 - dione (2 - c, 100 mmol, 0.09 mmol) was dissolved in N,N - dimethylformamide (5 ml), cesium fluoride (68 mmol, 0.45 mmol) was added, and the reaction was carried out at room temperature for 1 h. After the reaction solution was filtered, the filtrate was distilled under reduced pressure with an oil pump to obtain the target product 3-(6-(1-(1 - ((((4-(Aza - 1 - yl)-7-(8 - ethynyl - 7 - fluoro - 3-(methoxymethoxy)naphthalen - 1 - yl)-8 - fluoropyrido[4,3 - d]pyrimidin - 2 - yl)oxy)methyl)cyclopropyl)methyl)piperidin - 4 - yl)methyl (2 - d, 110 mg). (ESI)[M + H] += 980.6.

[0305] Step 5: Synthesis of 3-(6-(1-(1-((((4-(Azido-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-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)piperidine-2,6-dione trifluoroacetate (2)

[0306] Dissolve 3-(6-(1-(1-((((4-(Azido-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl (2-d, 110 mg, 0.11 mmol) in acetonitrile (10 ml), add 1,4-dioxane hydrochloride solution (3 ml), and react at room temperature for 1 hour. The reaction solution was distilled under reduced pressure to obtain a crude product, and 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-(Azido-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-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)piperidine-2,6-dione trifluoroacetate (2, 53.88 mg, yield 45.69%). (ESI)[M+H] + = 936.6. 1 H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 10.31 (s, 1H), 9.75 (s, 1H), 9.17 - 9.13 (d, J = 15.9 Hz, 2H), 8.01 - 7.97 (m, 1H), 7.69 - 7.67 (d, J = 8.3 Hz, 1H), 7.52 - 7.45 (t, 1H), 7.41 - 7.40 (d, J = 2.3 Hz, 2H), 7.19 - 7.18 (d, J = 2.5 Hz, 1H), 7.04 - 7.02 (d, J = 8.5 Hz, 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).

[0307] Example 3: Synthesis of 3-(6-(1-(7-(1-(((4-(Aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione trifluoroacetate (3)

[0308]

[0309] First step: Synthesis of tert-butyl 2-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (3-a)

[0310] Dissolve 3-(6-(piperidin-4-yl)-1H-indazol-3-yl)piperidine-2,6-dione (I-2, 500 mg, 1.53 mmol) in methanol (15 mL) and tetrahydrofuran (5 mL). Sequentially add tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (439 mg, 1.84 mmol) and acetic acid (92 mg, 1.53 mmol). After stirring at 55 °C for 1 h, add sodium cyanoborohydride (289 mg, 4.59 mmol), and continue stirring at 55 °C for 16 h. Quench with water, extract with ethyl acetate, collect the organic phase, wash it with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Then purify by liquid chromatography (dichloromethane:methanol = 0% - 10%) to obtain the target product tert-butyl 2-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (3-a, 283 mg, yield 33.7%). ESI[M+H] + = 550.5

[0311] Second step: Synthesis of 3-(6-(1-(7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (3-b)

[0312] tert-Butyl 2-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (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, the crude product 3-(6-(1-(7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (3-b, 290 mg) was obtained. ESI[M+H]+ = 450.6

[0313] Step 3: Synthesis of 3-(6-(1-(7-(1-(((4-(azetidin-1-yl))-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (3-c)

[0314] (1-(((4-(azetidin-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl]naphthalen-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]nonan-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (3-b, 76 mg, 0.17 mmol) were dissolved in acetonitrile (5 mL). Potassium iodide (20 mg, 0.113 mmol) and potassium carbonate (78 mg, 0.565 mmol) were added successively, and the mixture was stirred at 60 °C for 6 h. The reaction was quenched by adding water, and the mixture was extracted with ethyl acetate. The organic phase was collected, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by thin-layer chromatography on silica gel plates (dichloromethane:methanol = 10:1) to obtain the target product 3-(6-(1-(7-(1-(((4-(azetidin-1-yl))-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (3-c, 40 mg, yield 30.5%).

[0315] Step 4: Synthesis of 3-(6-(1-(7-(1-(((4-(azetidin-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (3-d)

[0316] Dissolve 3-(6-(1-(7-(1-(((4-(azetidin-1-yl))-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (3-c, 40 mg, 0.034 mmol) in N,N-dimethylformamide (2 mL), add cesium fluoride (26 mg, 0.172 mmol), and react at room temperature for 1 h. Quench with water, extract with ethyl acetate, collect the organic phase, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product 3-(6-(1-(7-(1-(((4-(azetidin-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (3-d, 30 mg). ESI [M+H] + = 1006.6

[0317] Step 5: Synthesis of 3-(6-(1-(7-(1-(((4-(azetidin-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione trifluoroacetate (3)

[0318] 3-(6-(1-(7-(1-(((4-(Aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-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, and the reaction was carried out at room temperature for 2 h. After concentration under reduced pressure, the crude product was separated and 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-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione trifluoroacetate (3, 10 mg, yield 34.5%). ESI [M+H] + = 962.6 1 H NMR (400 MHz, DMSO-d6) δ 10.94 (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).

[0319] Example 4: Synthesis of 3-(6-(1-(2-(2-(((1-(((4-(Aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)amino)ethoxy)ethoxy)acetyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione trifluoroacetate (4)

[0320]

[0321] Step 1: Synthesis of tert-butyl (2-(2-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-oxoethoxy)ethoxyethyl)carbamate (4-a)

[0322] Dissolve 3-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)piperidine-2,6-dione (I-2, 100 mg, 0.3 mmol), 2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azatridecane-13-oic 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) in N,N-dimethylformamide (5 ml), then add N,N-diisopropylethylamine (194 mg, 1.5 mmol), and react at room temperature for 5 hours. After the reaction is completed, add the reaction solution to 50 ml of water, extract with ethyl acetate three times, 20 ml each time, combine the organic phases, dry with anhydrous sodium sulfate, and concentrate under reduced pressure to remove the solvent to obtain the crude product of the target product tert-butyl (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). (ESI)[M+H] + = 572.7.

[0323] Step 2: Synthesis of 3-(6-(1-(2-(2-aminoethoxy)ethoxyacetyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (4-b)

[0324] Dissolve tert-butyl (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) in dichloromethane (5 ml), add trifluoroacetic acid (1 ml), and react at room temperature for 1 hour. Distill off the solvent under reduced pressure to obtain the target product 3-(6-(1-(2-(2-aminoethoxy)ethoxyacetyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (4-b, 200 mg). (ESI)[M+H] + = 472.6.

[0325] Step 3: Synthesis of 3-(6-(1-(2-(2-(1-(((4-(azetidin-1-yl))-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)amino)ethoxy)ethoxy)acetyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (4-c)

[0326] (1-(((4-(azetidin-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl]naphthalen-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), and 3-(6-(1-(2-(2-aminoethoxy)ethoxyacetyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (4-b, 78 mg, 0.17 mmol) were dissolved in acetonitrile (5 ml), and the reaction was carried out at 60 °C for 6 hours. After completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by TLC large plate (methylene chloride:methanol = 100:13) to give the target product 3-(6-(1-(2-(2-(1-(((4-(azetidin-1-yl))-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)amino)ethoxy)ethoxy)acetyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (4-c, 48 mg, yield 36.84%).

[0327] Step 4: Synthesis of 3-(6-(1-(2-(2-(-2-)(((1-(((4-(azetidin-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)amino)ethoxyethoxyacetyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (4-d)

[0328] 3-(6-(1-(2-(2-(1-(((4-(Azido-1-yl))-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)amino)ethoxy)ethoxy)acetyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (4-c, 48 mmol, 0.04 mmol) was dissolved in N,N-dimethylformamide (5 ml), cesium fluoride (61 mmol, 0.4 mmol) was added, and the reaction was carried out at room temperature for 1 h. After the reaction solution was filtered, the filtrate was distilled under reduced pressure with an oil pump to obtain the target product 3-(6-(1-(2-(2-(-2-)(((1-(((4-(Azido-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)amino)ethoxyethoxyacetyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (4-d, 33 mg, yield 80.49%). (ESI)[M+H] + = 1029.5.

[0329] Step 5: Synthesis of 3-(6-(1-(2-(2-(((1-(((4-(Azido-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)amino)ethoxy)ethoxy)acetyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione trifluoroacetate (4)

[0330] 3-(6-(1-(2-(2-(-2-)(((1-(((4-(Aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)amino)ethoxyethoxyacetyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (4-d, 33 mg, 0.03 mmol) was dissolved in acetonitrile (5 ml), and 1,4-dioxane solution of hydrochloric acid (1 ml) was added. The reaction was carried out at room temperature for 0.5 h. The reaction solution was distilled under reduced pressure to obtain a crude product, and 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-(2-(2-(((1-(((4-(Aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)amino)ethoxy)ethoxoxy)acetyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione trifluoroacetate (4, 9.71 mg, yield 29.42%). (ESI)[M+H] + = 984.9. 1 H NMR (400 MHz, DMSO-d6) δ 10.17 (s, 1H), 7.99 - 7.95 (m, 1H), 7.48 - 7.44 (t, 1H), 7.39 - 7.38 (d, J = 2.6 Hz, 1H), 7.24 - 7.23 (d, J = 2.4 Hz, 1H), 5.37 (s, 0.5H), 5.23 (s, 0.5H), 4.21 - 4.04 (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).

[0331] Example 5: Synthesis of 5-(4-(7-((1-((4-(Aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione trifluoroacetate (5)

[0332]

[0333] Step 1: Synthesis of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazine-1-carboxylate (5-b)

[0334] Dissolve 2-(2,6-dioxohesperidin-3-yl)-5-fluoroisoindoline-1,3-dione (5-a, 400 mg, 1.45 mmol), tert-butyl piperazine-1-carboxylate (272 mg, 1.45 mmol) and triethylamine (440 mg, 4.35 mmol) in dimethyl sulfoxide (10 ml), and react at 100 °C for 1 hour under microwave irradiation. After adding water to the reaction solution, extract it three times with ethyl acetate. After concentrating the organic phase under reduced pressure, separate the target product tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazine-1-carboxylate (5-b, 600 mg, yield 93%) by liquid chromatography, ESI[M+H] + = 442.47

[0335] Step 2: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindole-1,3-dione (5-c)

[0336] Dissolve tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazine-1-carboxylate (5-b, 600 mg, 1.35 mmol) in dichloromethane (6 ml), add trifluoroacetic acid (2 ml), and react at room temperature for 1 hour. After concentrating under reduced pressure, obtain the target product 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindole-1,3-dione (5-c, 700 mg, crude), ESI[M+H] + = 342.36

[0337] Step 3: Synthesis of tert-butyl 2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (5-d)

[0338] Dissolve 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindole-1,3-dione (5-c, 230 mg, 0.67 mmol) and tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (193 mg, 0.80 mmol) in methanol (9 ml) and acetic acid (1 ml). After reacting at room temperature for 1 h, add sodium cyanoborohydride (126 mg, 2.00 mmol). React at room temperature for 1 h. Quench with water, extract three times with dichloromethane, collect the organic phase, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Then separate by liquid chromatography to obtain the target product tert-butyl 2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (5-d, 380 mg, crude), ESI[M+H] + = 565.67

[0339] 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)

[0340] Dissolve tert-butyl 2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (5-d, 380 mg, 0.67 mmol) in acetonitrile (10 ml), add dioxane hydrochloride (3 ml), and react at room temperature for 1 h. Concentrate the reaction solution 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)isoindole-1,3-dione (5-e, 450 mg, crude), ESI[M+H] + = 465.55

[0341] Step 5: Synthesis of 5-(4-(7-((1-(((4-(azetidin-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-7-((triisopropylsilyl)ethynyl)naphthalen-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-dioxopiperidin-3-yl)isoindoline-1,3-dione (5-f)

[0342] 5-(4-(7-Azaspiro[3.5]non-2-yl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (5-e, 52 mg, 0.11 mmol), (1-(((4-(azetidin-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl]naphthalen-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 temperature was raised to 60 °C and reacted for 2 hours. The reaction solution was extracted with ethyl acetate, concentrated, and purified by thin layer chromatography silica gel plate to obtain the target product 5-(4-(7-((1-(((4-(azetidin-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-7-((triisopropylsilyl)ethynyl)naphthalen-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-dioxopiperidin-3-yl)isoindoline-1,3-dione (5-f, 30 mg, crude).

[0343] Step 6: Synthesis of 5-(4-(7-(1-(((4-(azetidin-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[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)

[0344] 5-(4-(7-((1-(((4-(azetidin-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-7-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (5-f, 30 mg, 0.025 mmol) and cesium fluoride (19 mg, 0.125 mmol) were dissolved in N,N-dimethylformamide (1 mL), and the reaction was carried out at room temperature for 1 hour. After the reaction mixture was extracted with ethyl acetate and concentrated, the target product 5-(4-(7-(1-(((4-(azetidin-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (5-g, 25 mg, crude) was obtained. ESI [M+H] + = 1022.17

[0345] Step 7: Synthesis of 5-(4-(7-((1-((4-(azetidin-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyridin[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione trifluoroacetate (5)

[0346] 5-(4-(7-(1-(((4-(Aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (5-g, 25 mg, 0.024 mmol) was dissolved in acetonitrile (1 ml), and dioxane hydrochloride (0.2 ml) was added. The reaction was carried out at room temperature for 1 hour. After concentration of the reaction, it 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-hydroxynaphthalen-1-yl)-8-fluoropyridyl[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-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 (400 MHz, CD3OD) δ 9.58 (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).

[0347] Example 6: Synthesis of 3-(6-(1-(7-(1-(1-(((4-(Aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrid[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidine-4-carbonyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione trifluoroacetate (6)

[0348]

[0349] Step 1: Synthesis of tert-butyl 2-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (6-a)

[0350] Dissolve 3-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)piperidine-2,6-dione (I-2, 1 g, 3.06 mmol) in methanol:tetrahydrofuran (4:1, 10 ml), add acetic acid (184 mg, 3.06 mmol) and tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (1466 mg, 6.12 mmol), and react at 55 °C for 1 hour. Then add sodium cyanoborohydride (960 mg, 15.27 mmol), and continue to react at 55 °C for 16 hours. Quench with water, extract with ethyl acetate, collect the organic phase and wash repeatedly with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Then separate by liquid chromatography (dichloromethane:methanol = 10:1) to obtain the target product tert-butyl 2-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (6-a, 850 mg, yield 20%). ESI [M+H] + = 549.72

[0351] Step 2: Synthesis of 3-(6-(1-(7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (6-b)

[0352] Dissolve tert-butyl 2-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (6-a, 350 mg, 0.63 mmol) in acetonitrile (3 ml), then add 1,4-dioxane hydrochloride (3 ml), and react at room temperature for 0.5 hour. Directly concentrate the reaction solution under reduced pressure to obtain the target product 3-(6-(1-(7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (6-b, 600 mg) ESI [M+H] + = 449.60

[0353] Step 3: Synthesis of tert-butyl 4-(2-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-7-azaspiro[3.5]nonane-7-carbonyl)piperidine-1-carboxylate (6-c)

[0354] (3-(6-(1-(7-Azaspiro[3.5]non-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (6-b, 600 mg, 1.33 mmol) was dissolved in N,N-dimethylformamide (6 ml). 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-butoxycarbonyl)piperidine-4-carboxylic acid (367 mg, 1.60 mmol) were added successively, and the reaction was carried out at room temperature for 16 hours. The reaction solution was added with ethyl acetate and washed repeatedly 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-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-7-azaspiro[3.5]non-7-carbonyl)piperidine-1-carboxylate (6-c, 76 mg, yield 9%). ESI[M+H] + = 660.86

[0355] Step 4: Synthesis of 3-(1-methyl-6-(1-(7-(piperidine-4-carbonyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1H-indazol-3-yl)piperidine-2,6-dione (6-d)

[0356] (tert-Butyl 4-(2-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-7-azaspiro[3.5]non-7-carbonyl)piperidine-1-carboxylate (6-c, 76 mg, 0.11 mmol) was dissolved in acetonitrile (1 ml), and hydrochloric acid-1,4-dioxane (1 ml) was added. The reaction was carried out at room temperature for 0.5 hour. The reaction solution was directly concentrated under reduced pressure to obtain the target product 3-(1-methyl-6-(1-(7-(piperidine-4-carbonyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1H-indazol-3-yl)piperidine-2,6-dione (6-d, 100 mg, 163%). ESI[M+H] + = 560.74

[0357] Step 5: Synthesis of 3-(6-(1-(7-(1-(1-(((4-(azetidin-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy))-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidine-4-carbonyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (6-e)

[0358] (1-(((4-(azetidin-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl]naphthalen-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-(piperidine-4-carbonyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-1H-indazol-3-yl)piperidine-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 the reaction was carried out at 60 °C for 8 hours. The reaction was quenched by adding water, and the mixture was extracted with ethyl acetate. The organic phase was collected and washed repeatedly with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by thin-layer chromatography silica gel plate (methylene chloride:methanol = 10:1) to obtain the target product 3-(6-(1-(7-(1-(1-(((4-(azetidin-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy))-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidine-4-carbonyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (6-e, 10 mg, yield 7.1%). ESI [M+H] + = 1273.70

[0359] Step 6: Synthesis of 3-(6-(1-(7-(1-(1-(((4-(azetidin-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidine-4-carbonyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (6-f)

[0360] 3-(6-(1-(7-(1-(1-(((4-(Aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy))-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidine-4-carbonyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (6-e, 10 mg, 0.007 mmol) was dissolved in N,N-dimethylformamide (1 ml), then cesium fluoride (6 mg, 0.039 mmol) was added, and the reaction was carried out at room temperature for 1 hour. The reaction was quenched by adding water, extracted with ethyl acetate, the organic phase was collected and washed repeatedly with saturated sodium chloride solution, 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)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidine-4-carbonyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (6-f, 15 mg). ESI [M+H] + = 1117.36

[0361] Step 7: Synthesis of 3-(6-(1-(7-(1-(1-(((4-(Aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidine-4-carbonyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione trifluoroacetate (6)

[0362] 3-(6-(1-(7-(1-(1-(((4-(Aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidine-4-carbonyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-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 h. The reaction solution was separated and 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-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidine-4-carbonyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione trifluoroacetate (6, 1.28 mg, yield 9.1%). ESI [M+H] + = 1073.30, 1 H NMR (600 MHz, CD3OD) δ 9.13 (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).

[0363] Example 7: Synthesis of 3-(6-(1-(2-(2-((1-(((4-(Aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)amino)ethoxy)acetyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione trifluoroacetate (7)

[0364]

[0365] Step 1: Synthesis of tert-butyl 2-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (7-a)

[0366] Dissolve 3-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)piperidine-2,6-dione (I-2, 100 mg, 0.3 mmol) in N,N-dimethylformamide (5 ml), and successively add 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). React at room temperature for 1 hour. Quench with water, extract with ethyl acetate, collect the organic phase and wash it repeatedly with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the target product tert-butyl 2-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (7-a, 94 mg, yield 59.4%). ESI[M+H] + = 527.62

[0367] Step 2: Synthesis of 3-(6-(1-(2-(2-aminoethoxy)acetyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (7-b)

[0368] tert-Butyl 2-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (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-indazol-3-yl)piperidine-2,6-dione (7-b, 120 mg), ESI [M+H] + = 427.51

[0369] Step 3: Synthesis of 3-(6-(1-(2-(2-((1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy))naphthalen-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)piperidine-2,6-dione (7-c)

[0370] (1-(((4-(aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl]naphthalen-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)piperidine-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). The reaction was carried out at 60 °C for 8 hours, quenched with water, extracted with ethyl acetate. The organic phase was collected and washed repeatedly with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by thin layer chromatography silica gel plate (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))naphthalen-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)piperidine-2,6-dione (7-c, 50 mg, yield 24%).

[0371] ESI [M+H] + = 1140.46

[0372] Step 4: Synthesis of 3-(6-(1-(2-(2-((1-(((4-(azetidin-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)amino)ethoxy)acetyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (7-d)

[0373] Dissolve 3-(6-(1-(2-(2-((1-(((4-(azetidin-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy))naphthalen-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)piperidine-2,6-dione (7-c, 50 mg, 0.043 mmol) in N,N-dimethylformamide (3 ml), then add cesium fluoride (33 mg, 0.22 mmol), react at room temperature for 1 hour, quench with water, extract with ethyl acetate, collect the organic phase and wash repeatedly with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product 3-(6-(1-(2-(2-((1-(((4-(azetidin-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)amino)ethoxy)acetyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (7-d, 25 mg, yield 59.5%). ESI [M+H] + = 983.12

[0374] Step 5: Synthesis of 3-(6-(1-(2-(2-((1-(((4-(azetidin-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)amino)ethoxy)acetyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione trifluoroacetate (7)

[0375] 3-(6-(1-(2-(2-((1-(((4-(Aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)amino)ethoxy)acetyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-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 reaction was carried out at room temperature for 0.5 h. The reaction solution was separated and 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-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidine-4-carbonyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione trifluoroacetate (7, 0.58 mg, yield 2.5%). ESI [M+H] + = 940.07, 1 H NMR (600 MHz, CD3OD) δ 8.92 - 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).

[0376] Example 8: Synthesis of 3-(6-(1-(1-(((4-(Aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[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)piperidine-2,6-dione trifluoroacetate (8)

[0377]

[0378] Step 1: Synthesis of 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 (8-a)

[0379] Dissolve 3-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)piperidine-2,6-dione (I-2, 106 mg, 0.325 mmol), 2,2-dimethyl-4-oxo-3,8,11,14-tetraoxa-5-azapentadecane-16-oic acid (100 mg, 0.325 mmol) and N,N-diisopropylethylamine (127 mg, 0.98 mmol) in N,N-dimethylformamide (3 ml), then add 1-hydroxybenzotriazole (54 mg, 0.4 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (77 mg, 0.4 mmol), and react at room temperature for 5 hours. After adding water to the reaction solution, extract it three times with ethyl acetate. After concentrating the organic phase under reduced pressure, the target product 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 (8-a, 70 mg, yield 53%) is obtained, ESI [M+H] + = 616.4

[0380] Step 2: Synthesis of 3-(6-(1-(2-(2-(2-[(2-aminoethoxy)ethoxy]acetyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (8-b)

[0381] Dissolve 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 (8-a, 70 mg, 0.11 mmol) in dichloromethane (1.5 ml), add trifluoroacetic acid (0.5 ml), and react at room temperature for 1 hour. After concentrating 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)piperidine-2,6-dione (8-b, 90 mg, crude) is obtained, ESI [M+H] + = 516.3

[0382] Step 3: Synthesis of 3-(6-(1-(1-(((4-(Aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-7-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)-5,8,11-trioxo-2-aza-tridecan-13-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (8-c)

[0383] (1-(((4-(Aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl]naphthalen-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-indazol-3-yl)piperidine-2,6-dione (8-b, 115 mg, 0.2 mmol) were 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, water was added to the reaction solution, and it was extracted three times with ethyl acetate. The organic phase was concentrated under reduced pressure and purified by TLC large plate (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)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)-5,8,11-trioxo-2-aza-tridecan-13-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (8-c, 45 mg, yield 21%)

[0384] Step 4: Synthesis of 3-(6-(1-(1-(((4-(Aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)-5,8,11-trioxo-2-aza-tridecan-13-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (8-d)

[0385] 3-(6-(1-(1-(((4-(Aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-7-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)-5,8,11-trioxo-2-aza-tridecan-13-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (8-c, 45 mg, 0.037 mmol) was dissolved in N,N-dimethylformamide (1 ml), cesium fluoride (28 mg, 0.185 mmol) was added, and the reaction was carried out at room temperature for 1 h. After adding water to the reaction solution, it was extracted three times with ethyl acetate. After concentrating the organic phase under reduced pressure, the target product 3-(6-(1-(1-(((4-(Aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)-5,8,11-trioxo-2-aza-tridecan-13-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (8-d, 50 mg, crude product) was obtained. (ESI)[M+H] + = 1073.2

[0386] Step 5: Synthesis of (3-(6-(1-(1-(((4-(Aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)-5,8,11-trioxo-2-aza-tridecan-13-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione trifluoroacetate (8)

[0387] 3-(6-(1-(1-(((4-(Aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)-5,8,11-trioxo-2-aza-tridecan-13-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (8-d, 50 mg, 0.046 mmol) was dissolved in acetonitrile (3 ml), and 1,4-dioxane solution of hydrochloric acid (0.5 ml) was added. The reaction was carried out at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the crude product, and 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-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)-5,8,11-trioxo-2-aza-tridecan-13-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione trifluoroacetate (8, 1.6 mg, yield 3.3%). (ESI) [M + H] + = 1029.4. 1 H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 10.28 (s, 1H), 9.11 (s, 1H), 8.52 (s, 1H), 8.06 - 7.93 (m, 1H), 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).

[0388] Example 9: Synthesis of 3-(6-(1'-(1-((((4-(Aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-carbonyl)-[1,4'-bipiperidine]-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione trifluoroacetate (9)

[0389]

[0390] Step 1: Synthesis of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)-[1,4'-bipiperidine]-1'-carboxylate (9-a)

[0391] Dissolve 3-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)piperidine-2,6-dione (I-2, 150 mg, 0.46 mmol), potassium carbonate (318 mg, 2.3 mmol), and tert-butyl 4-iodopiperidine-1-carboxylate (215 mg, 0.69 mmol) in acetonitrile (7 ml), and react at 80 °C for 16 hours. After the reaction is completed, filter the reaction solution, concentrate the filtrate under reduced pressure to obtain the crude product, and purify the crude product by TLC large plate (dichloromethane:methanol = 10:1) to obtain the target product tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)-[1,4'-bipiperidine]-1'-carboxylate (9-a, 15 mg, yield 6.41%). (ESI)[M+H] + = 510.7.

[0392] Step 2: Synthesis of 3-(6-([1,4'-bipiperidine]-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (9-b)

[0393] Dissolve tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)-[1,4'-bipiperidine]-1'-carboxylate (9-a, 15 mg, 0.03 mmol) in dichloromethane (3 ml), add trifluoroacetic acid (0.5 ml), and react at room temperature for 0.5 hour. Distill off the solvent under reduced pressure to obtain the target product 3-(6-([1,4'-bipiperidine]-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (9-b, 27 mg). (ESI)[M+H] + = 410.7.

[0394] Step 3: Synthesis of tert-butyl 4-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)-[1,4'-bipiperidine]-1'-carbonyl)piperidine-1-carboxylate (9-c)

[0395] Dissolve 3-(6-([1,4'-dipiperidin]-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (9-b, 27 mg, 0.07 mmol), 1-(tert-butoxycarbonyl)piperidine-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) in N,N-dimethylformamide (4 ml), then add N,N-diisopropylethylamine (36 mg, 0.28 mmol), and react at room temperature for 2 hours. After the reaction is completed, add the reaction solution to 50 ml of water, extract with ethyl acetate three times, 20 ml each time, combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to remove the solvent to obtain the target product tert-butyl 4-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)-[1,4'-dipiperidin]-1'-carbonyl)piperidine-1-carboxylate (9-c, 35 mg). (ESI)[M+H] + = 622.0.

[0396] Step 4: Synthesis of 3-(1-methyl-6-(1'-(piperidine-4-carbonyl)-[1,4'-dipiperidin]-4-yl)-1H-indazol-3-yl)piperidine-2,6-dione (9-d)

[0397] Dissolve tert-butyl 4-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)-[1,4'-dipiperidin]-1'-carbonyl)piperidine-1-carboxylate (9-c, 35 mg, 0.06 mmol) in dichloromethane (4 ml), add trifluoroacetic acid (0.5 ml), and react at room temperature for 0.5 hour. Distill off the solvent under reduced pressure to obtain the target product 3-(1-methyl-6-(1'-(piperidine-4-carbonyl)-[1,4'-dipiperidin]-4-yl)-1H-indazol-3-yl)piperidine-2,6-dione (9-d, 53 mg).

[0398] Step 5: Synthesis of 3-(6-(1'-(1-(((4-(azetidin-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl]naphthalen-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidine-4-carbonyl)-[1,4'-bipiperidin]-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (9-e)

[0399] (1 - (((4-(Aza - 1 - yl)-8 - fluoro - 7-(7 - fluoro - 3 - (methoxymethoxy)-8 - [(triisopropylsilyl)ethynyl]naphthalen - 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'-(piperidine - 4 - carbonyl)-[1,4'-bipiperidine]-4 - yl)-1H - indazol - 3 - yl)piperidine - 2,6 - dione (9 - d, 53 mg, 0.1 mmol) were 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 a crude product. The crude product was purified by TLC large plate (methylene chloride: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]naphthalen - 1 - yl)pyrido[4,3 - d]pyrimidin - 2 - yl)oxy)methyl)cyclopropyl)methyl)piperidine - 4 - carbonyl)-[1,4'-bipiperidine]-4 - yl)-1 - methyl - 1H - indazol - 3 - yl)piperidine - 2,6 - dione (9 - e, 13 mg, yield 17.33%).

[0400] Step 6: Synthesis of 3-(6-(1'-(1 - ((((4-(Aza - 1 - yl)-7-(8 - ethynyl - 7 - fluoro - 3 - (methoxymethoxy)naphthalen - 1 - yl)-8 - fluoropyrido[4,3 - d]pyrimidin - 2 - yl)oxy)methyl)cyclopropyl)methyl)piperidine - 4 - carbonyl)-[1,4'-bipiperidine]-4 - yl)-1 - methyl - 1H - indazol - 3 - yl)piperidine - 2,6 - dione (9 - f)

[0401] 3-(6-(1'-(1-(((4-(Aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl]naphthalen-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (9-e, 13 mg, 0.01 mmol) was dissolved in N,N-dimethylformamide (2 ml), cesium fluoride (40 mg, 0.26 mmol) was added, and the reaction was carried out at room temperature for 0.5 h. After the reaction solution was filtered, the filtrate was distilled under reduced pressure with an oil pump to obtain the target product 3-(6-(1'-(1-((((4-(Aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (9-f, 13 mg). (ESI) [M+H] + = 1076.8.

[0402] Step 7: Synthesis of 3-(6-(1'-(1-((((4-(Aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione trifluoroacetate (9)

[0403] Preparation of 3-(6-(1'-(1-((((4-(Aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-carbonyl)-[1,4'-bipiperidin]-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (9-f, 13 mg, 0.01 mmol) was dissolved in acetonitrile (2 ml), and 1,4-dioxane solution of hydrochloric acid (0.5 ml) was added. The reaction was carried out at room temperature for 0.5 h. The reaction solution was distilled under reduced pressure to obtain the crude product, and 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-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-carbonyl)-[1,4'-bipiperidin]-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione trifluoroacetate (9, 5 mg, yield 38.41%). (ESI)[M+H] + = 1032.9. 1 H NMR (600 MHz, DMSO-d6) δ 10.89 (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 = 8.3 Hz, 1H), 7.48 - 7.45 (t, 1H), 7.40 - 7.39 (d, J = 2.7 Hz, 2H), 7.18 - 7.17 (t, 1H), 7.04 - 7.03 (d, J = 8.4 Hz, 1H), 4.57 - 4.54 (d, J = 12.7 Hz, 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).

[0404] Example 10: Synthesis of 3-(6-(1-(1-((((4-(Aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl trifluoroacetate (10)

[0405]

[0406] First step: Synthesis of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (10-b)

[0407] Dissolve 3-(6-bromo-1-oxoisoindol-2-yl)piperidine-2,6-dione (10-a, 500 mg, 1.55 mmol), potassium phosphate (1.22 g, 5.74 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (344 mg, 0.47 mmol), and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (479 mg, 1.55 mmol) in N,N-dimethylformamide (20 ml), displace with nitrogen three times, and react at 90 °C for 18 hours. After the reaction is completed, add the reaction solution to 500 ml of water, extract with ethyl acetate three times, 250 ml each time, combine the organic phases, dry with anhydrous sodium sulfate, concentrate under reduced pressure to remove the solvent to obtain a crude product. The crude product is purified by flash (petroleum ether:ethyl acetate = 0 - 20%) and then concentrated. The sample is further purified by TLC large plate (dichloromethane:methanol = 20:1) to obtain the target product tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (10-b, 170 mg, yield 25.76%). (ESI)[M+H] + = 426.7

[0408] Second step: Synthesis of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidine-1-carboxylate (10-c)

[0409] Dissolve tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (10-b, 170 mg, 0.4 mmol) in tetrahydrofuran (10 ml), add 200 mg of 10% palladium on carbon, replace with hydrogen three times, and react at room temperature for 24 h. After filtering the reaction solution through diatomaceous earth, the filtrate is distilled under reduced pressure to obtain the target product tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidine-1-carboxylate (10-c, 130 mg, yield 76.02%). (ESI)[2M+H] + = 854.9

[0410] Step 3: Synthesis of 3-(1-oxo-6-(piperidin-4-yl)isoindol-2-yl)piperidine-2,6-dione (10-d)

[0411] Dissolve tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidine-1-carboxylate (10-c, 130 mg, 0.3 mmol) in dichloromethane (5 ml), add trifluoroacetic acid (1 ml), and react at room temperature for 0.5 h. The solvent is removed by distillation under reduced pressure to obtain the target product 3-(1-oxo-6-(piperidin-4-yl)isoindol-2-yl)piperidine-2,6-dione (10-d, 178 mg). (ESI)[M+H] + = 328.0.

[0412] Step 4: Synthesis of tert-butyl 4-(((4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)methyl)piperidine-1-carboxylate (10-e)

[0413] Dissolve 3-(1-oxo-6-(piperidin-4-yl)isoindol-2-yl)piperidine-2,6-dione (10-d, 145 mg, 0.44 mmol), tert-butyl 4-(iodomethyl)piperidine-1-carboxylate (101 mg, 0.31 mmol), and potassium carbonate (182 mg, 1.32 mmol) in acetonitrile (8 ml), and react at 80 °C for 6 h. After the reaction is completed, the solvent is removed by concentration under reduced pressure to obtain a crude product, which is purified by TLC large plate (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)piperidine-1-carboxylate (10-e, 48 mg, yield 20.78%). (ESI)[M+H] + = 572.7.

[0414] Step 5: Synthesis of 3-(1-oxo-6-(1-(piperidin-4-ylmethyl)piperidin-4-ylisoindol-2-yl)piperidine-2,6-dione (10-f))

[0415] Dissolve tert-butyl 4-((4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)methyl)piperidine-1-carboxylate (10-e, 48 mg, 0.09 mmol) in dichloromethane (5 ml), add trifluoroacetic acid (1 ml), and react at room temperature for 0.5 h. Remove the solvent by distillation under reduced pressure to obtain the target product 3-(1-oxo-6-(1-(piperidin-4-ylmethyl)piperidin-4-ylisoindol-2-yl)piperidine-2,6-dione (10-f, 74 mg).

[0416] Step 6: Synthesis of 3-(6-(1-(1-((((4-(azetidin-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-7-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-oxoisoindol-2-yl)piperidine-2,6-dione (10-g)

[0417] Dissolve ((1-(((4-(azetidin-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl]naphthalen-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), and 3-(1-oxo-6-(1-(piperidin-4-ylmethyl)piperidin-4-ylisoindol-2-yl)piperidine-2,6-dione (10-f, 74 mg, 0.17 mmol) in acetonitrile (5 ml), and react at 60 °C for 6 h. After the reaction is completed, filter the reaction solution, concentrate the filtrate under reduced pressure to obtain the crude product, and purify the crude product by TLC large plate (dichloromethane:methanol = 100:13) to obtain the target product 3-(6-(1-(1-((((4-(azetidin-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-7-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-oxoisoindol-2-yl)piperidine-2,6-dione (10-g, 27 mg, yield 21.60%). (ESI)[M+H] + = 1137.8.

[0418] Step 7: Synthesis of 3-(6-(1-(1-((((4-(azetidin-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl (10-h)

[0419] Dissolve 3-(6-(1-(1-((((4-(azetidin-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-7-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl piperidin-4-yl)-1-oxoisoindol-2-yl)piperidine-2,6-dione (10-g, 27 mg, 0.02 mmol) in N,N-dimethylformamide (3 ml), add cesium fluoride (30 mmol, 0.2 mmol), and react at room temperature for 0.5 h. After filtering the reaction solution, the filtrate is distilled under reduced pressure with an oil pump to obtain the target product 3-(6-(1-(1-((((4-(azetidin-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl (10-h, 25 mg). (ESI)[M+H] + = 981.7.

[0420] Step 8: Synthesis of 3-(6-(1-(1-((((4-(azetidin-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl trifluoroacetate (10)

[0421] Dissolve 3-(6-(1-(1-((((4-(azetidin-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl (10-h, 25 mg, 0.03 mmol) in acetonitrile (5 ml), add 1,4-dioxane solution of hydrochloric acid (1 ml), and react at room temperature for 0.5 h. The reaction solution is distilled under reduced pressure to obtain a crude product, and the crude product is purified by preparative liquid chromatography (aqueous phase: 0.01% trifluoroacetic acid, organic phase: acetonitrile) to obtain the target product 3-(6-(1-(1-((((4-(azetidin-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl trifluoroacetate (10, 13.88 mg, yield 39.66%). (ESI)[M+H] + = 937.7. 1 H NMR (600 MHz, DMSO-d6) δ 10.99 (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 = 7.4 Hz, 2H), 7.53 - 7.51 (d, 1H), 7.47 - 7.46 (t, 1H), 7.40 - 7.39 (d, J = 2.7 Hz, 1H), 7.20 - 7.18 (d, J = 2.7 Hz, 1H), 5.11 - 5.08 (m, 1H), 4.45 - 4.43 (d, J = 17.0 Hz, 1H), 4.35 - 4.30 (d, J = 16.8 Hz, 3H), 4.03 - 4.01 (t, 4H), 3.94 - 3.93 (d, J = 3.8 Hz, 1H), 3.78 - 3.73 (m, 2H), 3.65 - 3.63 (d, J = 12.1 Hz, 2H), 3.33 - 3.21 (m, 4H), 3.05 - 2.88 (m, 6H), 2.63 - 2.60 (d, J = 16.6 Hz, 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 = 5.5 Hz, 2H).

[0422] Example 11: Synthesis of 3-(6-(1-((1R,3R)-3-(((1-(((4-(azetidin-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)amino)cyclobutane-1-carbonyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione trifluoroacetate (11)

[0423]

[0424] Step 1: Synthesis of tert-butyl ((1R,3R)-3-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidine-1-carbonyl)cyclobutyl)carbamate (11-a)

[0425] Dissolve 3-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)piperidine-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) in N,N-dimethylformamide (3 ml), then add 1-hydroxybenzotriazole (74 mg, 0.55 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (106 mg, 0.55 mmol), and react at room temperature for 2 hours. After adding water to the reaction solution, extract it three times with ethyl acetate. After concentrating the organic phase under reduced pressure, the target product tert-butyl ((1R,3R)-3-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidine-1-carbonyl)cyclobutyl)carbamate (11-a, 210 mg, yield 87.52%) ESI[M+H] + = 524.1

[0426] Step 2: Synthesis of 3-(6-(1-(((1R,3R)-3-aminocyclobutane-1-carbonyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (11-b)

[0427] tert-Butyl ((1R,3R)-3-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidine-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-indazol-3-yl)piperidine-2,6-dione (11-b, 215 mg, crude) ESI[M+H] + = 424.3

[0428] Step 3: Synthesis of 3-(6-(1-((1R,3R)-3-(((1-(((4-(azetidin-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy))naphthalen-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)piperidine-2,6-dione (11-c)

[0429] (1-(((4-(azetidin-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl]naphthalen-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), and 3-(6-(1-(((1R,3R)-3-aminocyclobutane-1-carbonyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (11-b, 100 mg, 0.24 mmol) were 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. The reaction solution was diluted with water and extracted three times with ethyl acetate. The organic phase was concentrated under reduced pressure and then separated and purified by liquid chromatography (dichloromethane / methanol = 10 / 1) to obtain the target product 3-(6-(1-((1R,3R)-3-(((1-(((4-(azetidin-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy))naphthalen-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)piperidine-2,6-dione (11-c, 30 mg, yield 11%) (ESI)[M+H] + = 1136.1

[0430] Step 4: Synthesis of 3-(6-(1-((1R,3R)-3-(((1-(4-(azetidin-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)amino)cyclobutane-1-carbonyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (11-d)

[0431] Dissolve 3-(6-(1-((1R,3R)-3-(((1-(((4-(azetidin-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy))naphthalen-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)piperidine-2,6-dione (11-c, 30 mg, 0.026 mmol) in N,N-dimethylformamide (1 ml), add cesium fluoride (20 mg, 0.13 mmol), and react at room temperature for 1 h. After adding water to the reaction solution, extract it three times with ethyl acetate. After concentrating the organic phase under reduced pressure, the target product (3-(6-(1-((1R,3R)-3-(((1-(4-(azetidin-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)amino)cyclobutane-1-carbonyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (11-d, 25 mg, crude product)) is obtained. (ESI)[M+H] + = 980.2

[0432] Step 5: Synthesis of 3-(6-(1-((1R,3R)-3-(((1-(((4-(azetidin-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)amino)cyclobutane-1-carbonyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione trifluoroacetate (11)

[0433] (3-(6-(1-((1R,3R)-3-(((1-(4-(azetidin-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)amino)cyclobutane-1-carbonyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (11-d, 25 mg, 0.025 mmol) was dissolved in acetonitrile (3 ml), and 1,4-dioxane solution of hydrochloric acid (0.5 ml) was added. The reaction was carried out at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was 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-(azetidin-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)amino)cyclobutane-1-carbonyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione trifluoroacetate (11, 1.21 mg, yield 5%). (ESI) [M+H] + = 936.3 1 H NMR (400 MHz, DMSO-d6) δ 10.87 (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).

[0434] Example 12: Synthesis of 3-(6-(1-(7-(1-(((4-(3-azabicyclo[3.1.0]hexan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione trifluoroacetate (12)

[0435]

[0436] Step 1: Synthesis of tert-butyl 2-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (12-a)

[0437] Dissolve 3-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)piperidine-2,6-dione (I-2, 500 mg, 1.53 mmol), tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (550 mg, 2.3 mmol) in methanol (20 ml) and tetrahydrofuran (5 ml), then add acetic acid (92 mg, 1.53 mmol), react at 55 °C for 1 hour, add sodium cyanoborohydride (288 mg, 4.59 mmol), and continue the reaction at 55 °C for 16 hours. After the reaction is completed, concentrate the solvent under reduced pressure to obtain the crude product. The crude product is purified by TLC large plate (dichloromethane:methanol = 10:1) to obtain the target product tert-butyl 2-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (12-a, 454 mg, yield 53.98%). (ESI)[M+H] + = 550.1.

[0438] Step 2: Synthesis of 3-(6-(1-(7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (12-b)

[0439] Dissolve tert-butyl 2-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (12-a, 454 mg, 0.83 mmol) in dichloromethane (10 ml), add trifluoroacetic acid (2 ml), and react at room temperature for 0.5 hour. Distill off the solvent under reduced pressure to obtain the crude product of the target product 3-(6-(1-(7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (12-b, 576 mg).

[0440] Step 3: Synthesis of 3-(6-(1-(7-(1-((4-(3-azabicyclo[3.1.0]hexan-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl]naphthalen-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (12-c)

[0441] (1-(((4-(3-azabicyclo[3.1.0]hexan-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl]naphthalen-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]nonan-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (12-b, 63 mg, 0.14 mmol) were dissolved in acetonitrile (4 ml), and the reaction was carried out at 60 °C for 6 hours. After the reaction was completed, the solvent was removed by distillation under reduced pressure to obtain the crude product, and the crude product was purified by TLC large plate (methylene chloride: methanol = 100:13) to obtain the target product 3-(6-(1-(7-(1-((4-(3-azabicyclo[3.1.0]hexan-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl]naphthalen-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (12-c, 35 mg, yield 33.98%).

[0442] Step 4: Synthesis of 3-(6-(1-(7-(1-(((4-(3-azabicyclo[3.1.0]hexan-3-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (12-d)

[0443] 3-(6-(1-(7-(1-((4-(3-azabicyclo[3.1.0]hexan-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl]naphthalen-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (12-c, 35 mmol, 0.03 mmol) was dissolved in N,N-dimethylformamide (5 ml), cesium fluoride (46 mg, 0.3 mmol) was added, and the reaction was carried out at room temperature for 0.5 h. After the reaction solution was filtered, the filtrate was distilled under reduced pressure with an oil pump to obtain the crude product of the target compound 3-(6-(1-(7-(1-(((4-(3-azabicyclo[3.1.0]hexan-3-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (12-d, 35 mg). (ESI) [M+H] + = 990.7.

[0444] Step 5: Synthesis of 3-(6-(1-(7-(1-(((4-(3-azabicyclo[3.1.0]hexan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione trifluoroacetate (12)

[0445] 3-(6-(1-(7-(1-(((4-(3-azabicyclo[3.1.0]hexan-3-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (12-d, 35 mg, 0.04 mmol) was dissolved in acetonitrile (5 ml), and 1,4-dioxane solution of hydrochloric acid (1 ml) was added. The reaction was carried out at room temperature for 0.5 h. The reaction solution was concentrated under reduced pressure to obtain a crude product, which 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-(3-azabicyclo[3.1.0]hexan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione trifluoroacetate (12, 19.18 mg, yield 40.80%). (ESI) [M+H] + = 946.20.

[0446] Example 13: Synthesis of 3-(6-(1-((1S,3S)-3-(((1-(((4-(azetidin-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)amino)cyclobutane-1-carbonyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione trifluoroacetate (13)

[0447]

[0448] The first step: Synthesis of tert-butyl ((1S,3S)-3-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidine-1-carbonyl)cyclobutyl)carbamate (13-a)

[0449] 3-(1-Methyl-6-(piperidin-4-yl)-1H-indazole-3-yl)piperidine-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 N,N-dimethylformamide (3 ml), then 1-hydroxybenzotriazole (74 mg, 0.55 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (106 mg, 0.55 mmol) were added, and the reaction was carried out at room temperature for 2 hours. After adding water to the reaction solution, it was extracted with ethyl acetate three times. After concentrating the organic phase under reduced pressure, the target product tert-butyl ((1S,3S)-3-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidine-1-carbonyl)cyclobutyl)carbamate (13-a, 190 mg, yield 79%) ESI[M+H] + = 524.1

[0450] Step 2: Synthesis of 3-(6-(1-(((1S,3S)-3-aminocyclobutane-1-carbonyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (13-b)

[0451] tert-Butyl ((1S,3S)-3-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidine-1-carbonyl)cyclobutyl)carbamate (13-a, 190 mg, 0.4 mmol) was dissolved in dichloromethane (3 ml), trifluoroacetic acid (1 ml) was added, and the reaction was carried out at room temperature for 1 hour. After concentrating under reduced pressure, the target product 3-(6-(1-(((1S,3S)-3-aminocyclobutane-1-carbonyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (13-b, 250 mg, crude) was obtained, ESI[M+H] + = 424.3

[0452] Step 3: Synthesis of 3-(6-(1-(1s,3s)-3-(((1-(((4-(azetidin-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy))naphthalen-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)piperidine-2,6-dione (13-c)

[0453] (1 - (((4-(Aza - 1 - yl)-8 - fluoro - 7-(7 - fluoro - 3-(methoxymethoxy)-8 - [(triisopropylsilyl)ethynyl]naphthalen - 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 - indazol - 3 - yl)piperidine - 2,6 - dione (13 - b, 100 mg, 0.24 mmol) were dissolved in acetonitrile (5 ml) and reacted at 60 °C for 16 hours. After the reaction was completed, the reaction solution was filtered. The reaction solution was diluted with water and extracted with ethyl acetate three times. The organic phase was concentrated under reduced pressure and separated 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-(methoxymethoxy))naphthalen - 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)piperidine - 2,6 - dione (13 - c, 50 mg, yield 18.6%), (ESI)[M + H] + = 1136.1

[0454] Step 4: Synthesis of 3-(6-(1 - ((1s,3s)-3 - ((((1 - (4-(Aza - 1 - yl)-7-(8 - ethynyl - 7 - fluoro - 3-(methoxymethoxy)naphthalen - 1 - yl)-8 - fluoropyrido[4,3 - d]pyrimidin - 2 - yl)oxy)methyl)cyclopropyl)methyl)amino)cyclobutane - 1 - carbonyl)piperidin - 4 - yl)-1 - methyl - 1H - indazol - 3 - yl)piperidine - 2,6 - dione (13 - d)

[0455] 3-(6-(1-(1s,3s)-3-(((1-(((4-(Aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxy-methoxy))naphthalen-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)piperidine-2,6-dione (13-c, 50 mg, 0.044 mmol) was dissolved in N,N-dimethylformamide (1 ml), cesium fluoride (34 mg, 0.22 mmol) was added, and the reaction was carried out at room temperature for 1 h. After adding water to the reaction solution, it was extracted three times with ethyl acetate. 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)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)amino)cyclobutane-1-carbonyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (13-d, 50 mg, crude product). (ESI)[M+H] + = 980.2

[0456] Step 5: Synthesis of 3-(6-(1-(1s,3s)-3-(((1-(((4-(Aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)amino)cyclobutane-1-carbonyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione trifluoroacetate (13)

[0457] (3-(6-(1-((1s,3s)-3-(((1-(4-(azetidin-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)amino)cyclobutane-1-carbonyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (13-d, 50 mg, 0.05 mmol) was dissolved in acetonitrile (3 ml), and 1,4-dioxane solution of hydrochloric acid (0.5 ml) was added. The reaction was carried out at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product, and 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-((1s,3s)-3-(((1-(((4-(azetidin-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)amino)cyclobutane-1-carbonyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione trifluoroacetate (13, 2.44 mg, yield 5%). (ESI) [M+H] + = 936.3 1 H NMR (400 MHz, DMSO-d6) δ 10.88 (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).

[0458] Example 14: Synthesis of 5-(4-(1-((1-(((4-(azetidin-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)azetidin-3-carbonyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione formate (14)

[0459]

[0460] Step 1: Synthesis of tert-butyl 3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazine-1-carbonyl)azetidine-1-carboxylate (14-c)

[0461] Dissolve 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindole-1,3-dione (14-a, 342 mg, 1.0 mmol) in N,N-dimethylformamide (5 mL), add 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)azetidine-3-carboxylic acid (14-b, 201 mg, 1.0 mmol), and react at room temperature for 3 hours. Quench with water, extract with ethyl acetate, collect the organic phase and wash repeatedly with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and then separate by liquid chromatography (dichloromethane:methanol = 0 - 10%) to obtain the target product tert-butyl 3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazine-1-carbonyl)azetidine-1-carboxylate (14-c, 230 mg, yield 43.8%).

[0462] Step 2: Synthesis of 5-(4-(azetidine-3-carbonyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (14-d)

[0463] Dissolve tert-butyl 3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazine-1-carbonyl)azetidine-1-carboxylate (14-c, 230 mg, 0.43 mmol) in dichloromethane (5 mL), add trifluoroacetic acid (1 mL), and react at room temperature for 1 hour. Concentrate the reaction solution directly under reduced pressure to obtain the target product 5-(4-(azetidine-3-carbonyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (14-d, 300 mg, crude product).

[0464] Step 3: Synthesis of 5-(4-(1-(1-(((4-(azetidin-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-7-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)azetidine-3-carbonyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (14-e)

[0465] (1-(((4-(Aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl]naphthalen-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl 4-methylbenzenesulfonate (I-1, 100 mg, 0.11 mmol), 5-(4-(azetidine-3-carbonyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-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), reacted at 60 °C for 6 h, quenched with water, extracted with ethyl acetate, the organic phase was collected and washed repeatedly with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by thin layer chromatography silica gel plate (methylene chloride: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)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)azetidine-3-carbonyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (14-e, 26 mg, yield 20.8%).

[0466] Step 4: Synthesis of 5-(4-(1-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)azetidine-3-carbonyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (14-f)

[0467] 5-(4-(1-(1-(((4-(Aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-7-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)azetidine-3-carbonyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (14-e, 26 mg, 0.022 mmol) was dissolved in N,N-dimethylformamide (2 mL), then cesium fluoride (35 mg, 0.22 mmol) was added, and the reaction was carried out at room temperature for 1 hour. The reaction solution was directly filtered, and after concentration under reduced pressure, the crude product 5-(4-(1-(1-(((4-(Aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)azetidine-3-carbonyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (14-f, 20 mg, yield 95%) was obtained. ESI[M+H] + = 982.4

[0468] Step 5: Synthesis of 5-(4-(1-(1-(((4-(Aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)azetidine-3-carbonyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione formate (14)

[0469] 5-(4-(1-(1-(((4-(Aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)azetidine-3-carbonyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (14-f, 20 mg, 0.02 mmol) was dissolved in acetonitrile (2 mL), hydrochloric acid dioxane (0.5 mL) was added, and the reaction was carried out at room temperature for 0.5 hour. The reaction solution was separated and 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-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)azetidine-3-carbonyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione formate (14, 1.89 mg, yield 10.5%). ESI[M+H]+ = 938.0 1 H NMR (600 MHz, DMSO-d6) δ 11.06 (s, 1H), 10.17 (s, 1H), 9.05 (s, 1H), 8.34 (s, 1H), 7.96 - 7.92 (m, 1H), 7.67 - 7.66 (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).

[0470] Example 15: Synthesis of 1-(5-(9-(4-((1-(((4-(Aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl]-3-azaspiro[5.5]undecane-3-carbonyl)-2-methylphenyl)dihydropyrimidine-2,4(1H, 3H)-dione trifluoroacetate (15)

[0471]

[0472] Step 1: Synthesis of 1-(5-(9-(4-((1-((4-(Aza-1-yl)-8-fluoro-7-(7-fluoro-3-hydroxy-8-(triisopropylsilyl)ethynyl)naphthalen-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)dihydropyrimidine-2,4(1H, 3H)-dione (15-b)

[0473] To a stirred solution of 4-(4-(azetidin-1-yl)-8-fluoro-2-((1-(piperazin-1-ylmethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (15-a, 33 mg, 0.04 mmol) and 3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methylbenzoyl)-3-azaspiro[5.5]undecane-9-carbonyl (35 mg, 0.08 mmol) in DCM (2 mL) / AcOH (0.1 mL), tetra(isopropyl)titanate (57 mg, 0.2 mmol) was added and the mixture was stirred at room temperature for 2 h. The mixture was added with NaBH(OAc)3 (25 mg, 0.12 mmol) at room temperature and stirred for 2 h. After completion of the reaction, the mixture was concentrated and purified by silica gel TLC plate (dichloromethane:methanol = 100:12) to give the target product 1-(5-(9-(4-((1-((4-(azetidin-1-yl)-8-fluoro-7-(7-fluoro-3-hydroxy-8-(triisopropylsilyl)ethynyl)naphthalen-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)dihydropyrimidine-2,4(1H,3H)-dione (15-b, 30 mg, yield 65.22%).

[0474] Step 2: Synthesis of 1-(5-(9-(4-((1-(((4-(azetidin-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl]-3-azaspiro[5.5]undecane-3-carbonyl)-2-methylphenyl)dihydropyrimidine-2,4(1H,3H)-dione trifluoroacetate (15)

[0475] 1-(5-(9-(4-((1-((4-(Aza-1-yl)-8-fluoro-7-(7-fluoro-3-hydroxy-8-(triisopropylsilylethynyl)naphthalen-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)dihydropyrimidine-2,4(1H,3H)-dione (15-b, 30 mg, 0.026 mmol) was dissolved in N,N-dimethylformamide (5 mL), cesium fluoride (39 mg, 0.26 mmol) was added, and the reaction was carried out at room temperature for 0.5 h. After filtration of the reaction solution, it was 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-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl]-3-azaspiro[5.5]undecane-3-carbonyl)-2-methylphenyl)dihydropyrimidine-2,4(1H,3H)-dione trifluoroacetate (15, 17.59 mg, yield 55.35%). (ESI)[M+H] + = 994.7. 1 H NMR (600 MHz, DMSO-d6) δ 10.38 (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 = 7.8 Hz, 1H), 7.30 (s, 1H), 7.25 - 7.23 (d, J = 7.8 Hz, 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).

[0476] Example 17: Synthesis of 3-(6-(1-(1-((1-(4-(3-azabicyclo[3.1.0]hexan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-5-methylpyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-oxoisoindol-2-yl)piperidine-2,6-dione trifluoroacetate (17)

[0477]

[0478] First step: Synthesis of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (17-c)

[0479] Dissolve 3-(6-bromo-1-oxoisoindol-2-yl)piperidine-2,6-dione (17-a, 1 g, 3.09 mmol) in N,N-dimethylformamide (30 mL). Sequentially add tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (17-b, 1913 mg, 6.18 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (340 mg, 0.46 mmol), and potassium phosphate (1970 mg, 9.27 mmol). React at 90 °C for 16 hours under nitrogen protection. Quench with water, extract with ethyl acetate, collect the organic phase and wash it repeatedly with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. Separate by liquid chromatography (dichloromethane:methanol = 0 - 10%) to obtain the target product tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (17-c, 750 mg, yield 57%). ESI[M+H] + = 426.0

[0480] Second step: Synthesis of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidine-1-carboxylate (17-d)

[0481] Dissolve tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (17-c, 750 mg, 1.76 mmol) in methanol (10 mL) and tetrahydrofuran (20 mL), add palladium on carbon (10%) (300 mg, 2.82 mmol), and react at room temperature for 16 hours under a hydrogen atmosphere. Filter the reaction mixture directly and concentrate it under reduced pressure to obtain the target product tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidine-1-carboxylate (17-d, 500 mg, 66.4%). ESI [M+H] + = 372.2

[0482] Step 3: Synthesis of 3-(1-oxo-6-(piperidin-4-yl)isoindol-2-yl)piperidine-2,6-dione (17-e)

[0483] Dissolve tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidine-1-carboxylate (17-d, 500 mg, 1.16 mmol) in dichloromethane (5 mL), then add trifluoroacetic acid (1 mL), and react at room temperature for 1 hour. Concentrate the reaction mixture directly under reduced pressure to obtain the target product 3-(1-oxo-6-(piperidin-4-yl)isoindol-2-yl)piperidine-2,6-dione (17-e, 484 mg, crude product). ESI [M+H] + = 328.2

[0484] Step 4: Synthesis of tert-butyl 4-(((4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)methyl)piperidine-1-carboxylate (17-g)

[0485] Dissolve 3-(1-oxo-6-(piperidin-4-yl)isoindol-2-yl)piperidine-2,6-dione (17-e, 484 mg, 1.47 mmol) in methanol (3 mL), add triethylamine dropwise to adjust the pH to 7 - 8, concentrate under reduced pressure, then dissolve it in methanol:acetic acid / 1:10 (22 mL), add tert-butyl 4-formylpiperidine-1-carboxylate (17-f, 630 mg, 2.95 mmol), react at room temperature for 1 hour, then add sodium cyanoborohydride (278 mg, 4.42 mmol), and continue to react at room temperature for 2 h. Quench with water, extract with ethyl acetate, collect the organic phase and wash it repeatedly with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure to obtain the crude product, and obtain the target product tert-butyl 4-((4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)methyl)piperidine-1-carboxylate (17-g, 520 mg, yield 17.4%) by thin-layer chromatography silica gel plate (dichloromethane:methanol = 10:1) ESI[M+H] + = 525.4

[0486] Step 5: Synthesis of 3-(1-oxo-6-(1-(piperidin-4-ylmethyl)piperidin-4-yl)isoindol-2-yl)piperidine-2,6-dione (17-h)

[0487] Dissolve tert-butyl 4-((4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)methyl)piperidine-1-carboxylate (17-g, 520 mg, 0.99 mmol) in dichloromethane (5 mL), then add trifluoroacetic acid (1 mL), and react at room temperature for 1 hour. Directly concentrate the reaction solution under reduced pressure to obtain the target product 3-(1-oxo-6-(1-(piperidin-4-ylmethyl)piperidin-4-yl)isoindol-2-yl)piperidine-2,6-dione (17-h, 829 mg, crude product) ESI[M+H] + = 425.0

[0488] 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]naphthalen-1-yl)-5-methylpyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-oxoisoindol-2-yl)piperidine-2,6-dione (17-i)

[0489] (1 - (((4-(3 - azabicyclo[3.1.0]hexan - 3 - yl)-8 - fluoro - 7-(7 - fluoro - 3-(methoxymethoxy)-8 - [(triisopropylsilyl)ethynyl]naphthalen - 1 - yl)-5 - methylpyrido[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 - yl)isoindol - 2 - yl)piperidine - 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). The reaction was carried out at 60 °C for 8 hours, quenched with water, extracted with ethyl acetate. The organic phase was collected and washed repeatedly with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by thin - layer chromatography silica gel plate (dichloromethane:methanol = 100:13) to obtain the target product 3-(6-(1-(1 - ((((4-(3 - azabicyclo[3.1.0]hexan - 3 - yl)-8 - fluoro - 7-(7 - fluoro - 3-(methoxymethoxy)-8 - [(triisopropylsilyl)ethynyl]naphthalen - 1 - yl)-5 - methylpyrido[4,3 - d]pyrimidin - 2 - yl)oxy)methyl)cyclopropyl)methyl)piperidin - 4 - yl)methyl)piperidin - 4 - yl)-1 - oxoisoindol - 2 - yl)piperidine - 2,6 - dione (17 - i, 24 mg, yield 26.9%). ESI[M + H] + = 1135.8

[0490] Step 7: Synthesis of 3-(6-(1-(1 - ((1-(4-(3 - azabicyclo[3.1.0]hexan - 3 - yl)-7-(8 - ethynyl - 7 - fluoro - 3-(methoxymethoxy)naphthalen - 1 - yl)-8 - fluoro - 5 - methylpyrido[4,3 - d]pyrimidin - 2 - yl)oxy)methyl)cyclopropyl)methyl)piperidin - 4 - yl)methyl)piperidin - 4 - yl)-1 - oxoisoindol - 2 - yl)piperidine - 2,6 - dione (17 - j)

[0491] 3-(6-(1-(1-((((4-(3-azabicyclo[3.1.0]hexan-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxy-methoxy)-8-[(triisopropylsilyl)ethynyl]naphthalen-1-yl)-5-methylpyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-oxoisoindol-2-yl)piperidine-2,6-dione (17-i, 24 mg, 0.027 mmol) was dissolved in N,N-dimethylformamide (1 mL), and then cesium fluoride (21 mg, 0.13 mmol) was added. The reaction was carried out at room temperature for 1 hour. The reaction solution was directly filtered, and after concentration under reduced pressure, the crude product 3-(6-(1-(1-((1-(4-(3-azabicyclo[3.1.0]hexan-3-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-5-methylpyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methylpiperidin-4-yl)-1-oxoisoindol-2-yl)piperidine-2,6-dione (17-j, 22 mg, yield 84.6%) was obtained. ESI [M+H] + = 979.6

[0492] Step 8: Synthesis of 3-(6-(1-(1-((1-(4-(3-azabicyclo[3.1.0]hexan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-5-methylpyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-oxoisoindol-2-yl)piperidine-2,6-dione trifluoroacetate (17)

[0493] 3-(6-(1-(1-((1-(4-(3-azabicyclo[3.1.0]hexan-3-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-5-methylpyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-oxoisoindol-2-yl)piperidine-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 h. The reaction solution was separated and 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]hexan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-5-methylpyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-oxoisoindol-2-yl)piperidine-2,6-dione trifluoroacetate (17, 8.3 mg, yield 41.5%). ESI [M+H] + = 935.1 1 H NMR (600 MHz, DMSO-d6) δ 11.00 (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, 2H), 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).

[0494] Example 18: Synthesis of 3-(6-(1-(1-(((4-(3,6-dihydropyridin-1(2H)-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-5-methylpyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-oxoisoindol-2-yl)piperidine-2,6-dione formate (18)

[0495]

[0496] Step 1: Synthesis of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (18-c)

[0497] Dissolve 3-(6-bromo-1-oxoisoindol-2-yl)piperidine-2,6-dione (18-a, 1 g, 3.09 mmol) in N,N-dimethylformamide (30 mL), and successively add tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (18-b, 1913 mg, 6.18 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (340 mg, 0.46 mmol), and potassium phosphate (1970 mg, 9.27 mmol). React at 90 °C for 16 hours under nitrogen protection. Quench with water, extract with ethyl acetate, collect the organic phase, wash it repeatedly with saturated sodium chloride solution, dry it over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The target product tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (18-c, 750 mg, yield 57%) is obtained by liquid chromatography separation (methylene chloride:methanol = 0 - 10%). ESI[M+H] + = 426.0

[0498] Step 2: Synthesis of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidine-1-carboxylate (18-d)

[0499] Dissolve tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (18-c, 750 mg, 1.76 mmol) in methanol (10 mL) and tetrahydrofuran (20 mL), add palladium on carbon (10%) (300 mg, 2.82 mmol), and react at room temperature for 16 hours under hydrogen protection. The reaction solution is directly filtered and concentrated under reduced pressure to obtain the target product tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidine-1-carboxylate (18-d, 500 mg, 66.4%). ESI[M+H] + = 372.2

[0500] Step 3: Synthesis of 3-(1-oxo-6-(piperidin-4-yl)isoindol-2-yl)piperidine-2,6-dione (18-e)

[0501] Dissolve tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidine-1-carboxylate (18-d, 500 mg, 1.16 mmol) in dichloromethane (5 mL), then add trifluoroacetic acid (1 mL), and react at room temperature for 1 hour. The reaction solution was directly concentrated under reduced pressure to obtain the target product 3-(1-oxo-6-(piperidin-4-yl)isoindol-2-yl)piperidine-2,6-dione (18-e, 484 mg, crude product) ESI[M+H] + = 328.2

[0502] Step 4: Synthesis of tert-butyl 4-((4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)methyl)piperidine-1-carboxylate (18-g)

[0503] Dissolve 3-(1-oxo-6-(piperidin-4-yl)isoindol-2-yl)piperidine-2,6-dione (18-e, 484 mg, 1.47 mmol) in methanol (3 mL), add triethylamine dropwise to adjust the pH to 7 - 8, concentrate under reduced pressure, then dissolve in methanol: acetic acid / 1:10 (22 mL), add tert-butyl 4-formylpiperidine-1-carboxylate (18-f, 630 mg, 2.95 mmol), react at room temperature for 1 hour, then add sodium cyanoborohydride (278 mg, 4.42 mmol), and continue to react at room temperature for 2 h. Quench with water, extract with ethyl acetate, collect the organic phase and wash it repeatedly with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure to obtain the crude product, and obtain the target product tert-butyl 4-((4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)methyl)piperidine-1-carboxylate (18-g, 520 mg, yield 67.4%) ESI[M+H] + = 525.4

[0504] Step 5: Synthesis of 3-(1-oxo-6-(1-(piperidin-4-ylmethyl)piperidin-4-yl)isoindol-2-yl)piperidine-2,6-dione (18-h)

[0505] Dissolve tert-butyl 4-((4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)methyl)piperidine-1-carboxylate (18-g, 520 mg, 0.99 mmol) in dichloromethane (5 mL), then add trifluoroacetic acid (1 mL), and react 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-yl)isoindol-2-yl)piperidine-2,6-dione (18-h, 829 mg, crude product) ESI[M+H]+ = 425.0

[0506] Step 6: Synthesis of 3-(6-(1-(1-((((4-(3,6-Dihydropyridin-1(2H)-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl]naphthalen-1-yl)-5-methylpyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-oxoisoindol-2-yl)piperidine-2,6-dione (18-i)

[0507] (1-(((4-(3,6-Dihydropyridin-1(2H)-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl]naphthalen-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)piperidine-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 the reaction was carried out at 60 °C for 8 hours. The reaction was quenched by adding water, and the mixture was extracted with ethyl acetate. The organic phase was collected and washed repeatedly with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by thin layer chromatography silica gel plate (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-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl]naphthalen-1-yl)-5-methylpyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-oxoisoindol-2-yl)piperidine-2,6-dione (18-i, 24 mg, yield 26.9%). ESI [M+H] + = 1135.8

[0508] Step 7: Synthesis of 3-(6-(1-(1-((((4-(3,6-Dihydropyridin-1(2H)-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-5-methylpyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methylpiperidin-4-carbonyl)-1-oxoisoindol-2-yl)piperidine-2,6-dione (18-j)

[0509] 3-(6-(1-(1-((((4-(3,6-Dihydropyridin-1(2H)-yl)-8-fluoro-7-(7-fluoro-3-(methoxy-methoxy)-8-[(triisopropylsilyl)ethynyl]naphthalen-1-yl)-5-methylpyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-oxoisoindol-2-yl)piperidine-2,6-dione (18-i, 24 mg, 0.027 mmol) was dissolved in N,N-dimethylformamide (1 mL), then cesium fluoride (21 mg, 0.13 mmol) was added, and the reaction was carried out at room temperature for 1 hour. The reaction solution was directly filtered, and after concentration under reduced pressure, the crude product 3-(6-(1-(1-((((4-(3,6-Dihydropyridin-1(2H)-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-5-methylpyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methylpiperidin-4-yl)-1-oxoisoindol-2-yl)piperidine-2,6-dione (18-j, 25 mg, crude product) was obtained. ESI [M+H] + = 979.6

[0510] Step 8: Synthesis of 3-(6-(1-(1-(((4-(3,6-Dihydropyridin-1(2H)-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-5-methylpyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-oxoisoindol-2-yl)piperidine-2,6-dione formate (18)

[0511] Dissolve 3-(6-(1-(1-((((4-(3,6-dihydropyridin-1(2H)-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-5-methylpyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl)piperidine-4-carbonyl)-1-oxoisoindol-2-yl)piperidine-2,6-dione (18-j, 25 mg, 0.025 mmol) in acetonitrile (2 mL), add dioxane hydrochloride (0.5 mL), and react at room temperature for 0.5 h. The reaction solution was separated and 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-hydroxynaphthalen-1-yl)-8-fluoro-5-methylpyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl)piperidine-4-yl)-1-oxoisoindol-2-yl)piperidine-2,6-dione formate (18, 9.04 mg, yield 39.3%). ESI [M+H] + = 935.1 1 H NMR (600 MHz, DMSO-d6) δ 10.96 (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 - 4.37 (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).

[0512] Example 19: Synthesis of 3-(6-(1-(7-(1-(((4-(azetidin-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-1-oxoisoindol-2-yl)pyridine-2,6-dione trifluoroacetate (19)

[0513]

[0514] Step 1: Synthesis of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (19-c)

[0515] Dissolve 3-(6-bromo-1-oxoisoindol-2-yl)piperidine-2,6-dione (19-a, 1 g, 3.09 mmol) in N,N-dimethylformamide (20 mL). Sequentially add tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (19-b, 957 mg, 3.09 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (679 mg, 0.29 mmol), and potassium phosphate (2430 mg, 11.44 mmol). React under nitrogen protection at 90 °C for 16 hours. Quench with water, extract with ethyl acetate, collect the organic phase and wash it repeatedly with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. Separate by liquid chromatography (dichloromethane:methanol = 100:13) to obtain the target product tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (19-c, 310 mg, yield 23.5%). ESI[M+H] + = 425.49

[0516] Step 2: Synthesis of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidine-1-carboxylate (19-d)

[0517] Dissolve tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (19-c, 310 mg, 0.72 mmol) in tetrahydrofuran (15 mL). Then add palladium on carbon (10%) (500 mg, 4.69 mmol). React under hydrogen protection at room temperature for 16 hours. Filter the reaction solution directly and concentrate under reduced pressure to obtain the crude product. Separate by thin-layer chromatography silica gel plate (dichloromethane:methanol = 100:13) to obtain the target product tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidine-1-carboxylate (19-d, 250 mg, yield 81.4%). ESI[M+H] + = 427.50

[0518] Step 3: Synthesis of 3-(1-oxo-6-(piperidin-4-yl)isoindol-2-yl)piperidine-2,6-dione (19-e)

[0519] Dissolve tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidine-1-carboxylate (19-d, 250 mg, 0.58 mmol) in dichloromethane (2 mL), then add trifluoroacetic acid (1 mL), and react at room temperature for 1 hour. The reaction solution was directly concentrated under reduced pressure to obtain the target product 3-(1-oxo-6-(piperidin-4-yl)isoindol-2-yl)piperidine-2,6-dione (19-e, 370 mg, yield 195%). ESI[M+H] + = 327.28

[0520] Step 4: Synthesis of tert-butyl 2-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)-7-azaspiro[3.5]non-7-ene-7-carboxylate (19-g)

[0521] Dissolve 3-(1-oxo-6-(piperidin-4-yl)isoindol-2-yl)piperidine-2,6-dione (19-e, 300 mg, 0.91 mmol) in methanol:tetrahydrofuran = 4:1 (5 mL), add tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (19-f, 263 mg, 1.09 mmol) and acetic acid (55 mg, 0.91 mmol), react at room temperature for 1 hour, then add sodium cyanoborohydride (173 mg, 2.73 mmol), and continue to react at room temperature for 16 h. Quench with water, extract with ethyl acetate, collect the organic phase and wash it repeatedly with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure to obtain the crude product, and obtain the target product tert-butyl 2-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)-7-azaspiro[3.5]non-7-ene-7-carboxylate (19-g, 125 mg, yield 24.9%) by thin-layer chromatography silica gel plate (dichloromethane:methanol = 0% - 10%). ESI[M+H] + = 550.70

[0522] 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)

[0523] tert-Butyl 2-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)-7-azaspiro[3.5]non-7-ene-7-carboxylate (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-oxoisoindol-2-yl)pyridine-2,6-dione (19-h, 223 mg, crude product). ESI [M+H] + = 450.58

[0524] Step 6: Synthesis of 3-(6-(1-(7-(1-(((4-(azetidin-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl]naphthalen-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1-oxoisoindolin-2-yl)pyridine-2,6-dione (19-i)

[0525] ((1-(((4-(azetidin-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl]naphthalen-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)pyridine-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). The reaction was carried out at 60 °C for 8 hours, quenched with water, extracted with ethyl acetate. The organic phase was collected and washed repeatedly with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by thin layer chromatography silica gel plate (dichloromethane:methanol = 0% - 10%) to obtain the target product 3-(6-(1-(7-(1-(((4-(azetidin-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl]naphthalen-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]non-2-yl)piperidin-4-yl)-1-oxoisoindolin-2-yl)pyridine-2,6-dione (19-i, 32 mg, yield 8.6%). ESI [M+H] + = 1163.54

[0526] Step 7: Synthesis of 3-(6-(1-(7-(1-(((4-(azetidin-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-1-oxoisoindol-2-yl)pyridine-2,6-dione (19-j)

[0527] Dissolve (3-(6-(1-(7-(1-(((4-(azetidin-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl]naphthalen-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-1-oxoisoindolin-2-yl)pyridine-2,6-dione (19-i, 32 mg, 0.027 mmol) in N,N-dimethylformamide (1 mL), then add cesium fluoride (21 mg, 0.13 mmol), react at room temperature for 1 hour, quench with water, extract with ethyl acetate, collect the organic phase and wash repeatedly with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product 3-(6-(1-(7-(1-(((4-(azetidin-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-1-oxoisoindol-2-yl)pyridine-2,6-dione (19-j, 26 mg, crude product). ESI [M+H] + = 1007.20

[0528] Step 8: Synthesis of 3-(6-(1-(7-(1-(((4-(azetidin-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-1-oxoisoindol-2-yl)pyridine-2,6-dione trifluoroacetate (19)

[0529] 3-(6-(1-(7-(1-(((4-(Aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-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 reaction was carried out at room temperature for 0.5 h. The reaction solution was separated and 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-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-1-oxoisoindol-2-yl)pyridine-2,6-dione trifluoroacetate (19, 3.35 mg, yield 13.9%). ESI [M+H] + = 963.14 1 H NMR (600 MHz, DMSO-d6) δ 10.97 (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).

[0530] Example 20: Synthesis of 5-(4-((1-(1-(((4-(Aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-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)

[0531]

[0532] Step 1: Synthesis of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazine-1-carboxylate (20-b)

[0533] 2-(2,6-Dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (20-a, 400 mg, 1.45 mmol), tert-butyl piperazine-1-carboxylate (272 mg, 1.45 mmol), and triethylamine (440 mg, 4.35 mmol) were added to a 20 mL microwave tube. Dimethyl sulfoxide (10 mL) was added, and the reaction was carried out at 100 °C for 1 hour under microwave irradiation. After the reaction was completed, the reaction solution was added to 10 mL of water, and the mixture was extracted with ethyl acetate three times (15 mL 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 tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazine-1-carboxylate (20-b, 600 mg, yield 93%).

[0534] Step 2: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindole-1,3-dione (20-c)

[0535] tert-Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazine-1-carboxylate (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 distillation under reduced pressure to obtain the target product 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindole-1,3-dione (20-c, 700 mg, crude product). (ESI)[M+H] + = 343.6.

[0536] Step 3: Synthesis of tert-butyl 4-(((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidine-1-carboxylate (20-d)

[0537] Dissolve 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindole-1,3-dione (20-c, 270 mg, 0.79 mmol) and tert-butyl 4-formylpiperidine-1-carboxylate (168 mg, 0.79 mmol) in methanol (5 mL), add acetic acid (1 mL), react at room temperature for 1 hour, then add sodium cyanoborohydride (150 mg, 2.37 mmol), and continue to react at room temperature for 1 hour. After the reaction is completed, quench the reaction solution with saturated ammonium chloride, then extract it three times with dichloromethane, 10 mL each time. After collecting the organic phase, remove the solvent by distillation under reduced pressure to obtain the crude product. The crude product is 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-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidine-1-carboxylate (20-d, 230 mg, yield 54%). (ESI)[M+H] + = 540.6.

[0538] Step 4: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-(4-(piperidin-4-ylmethyl)piperazin-1-yl)isoindole-1,3-dione (20-e)

[0539] Dissolve tert-butyl 4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidine-1-carboxylate (20-d, 230 mg, 0.43 mmol) in dichloromethane (5 mL), add trifluoroacetic acid (1 mL), and react at room temperature for 0.5 hour. Remove the solvent by distillation under reduced pressure to obtain the target product 2-(2,6-dioxopiperidin-3-yl)-5-(4-(piperidin-4-ylmethyl)piperazin-1-yl)isoindole-1,3-dione (20-e, 178 mg, crude product).

[0540] Step 5: Synthesis of 5-(4-((1-(1-(((4-(azetidin-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl]naphthalen-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)

[0541] (1 - (((4-(Aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl]naphthalen-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-dioxopiperidin-3-yl)-5-(4-(piperidin-4-ylmethyl)piperazin-1-yl)isoindole-1,3-dione (20-e, 75 mg, 0.17 mmol), potassium carbonate (76 mg, 0.55 mmol), potassium iodide (18 mg, 0.11 mmol) were dissolved in acetonitrile (5 mL) and reacted at 60 °C for 6 h. After the reaction was completed, the solvent was removed by concentration under reduced pressure to obtain a crude product, and the crude product was purified by thin-layer chromatography silica gel plate (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]naphthalen-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.

[0542] Step 6: Synthesis of 5-(4-(((1-(((4-(Aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-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)

[0543] 5-(4-((1-(1-(((4-(Aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl]naphthalen-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), cesium fluoride (30 mmol, 0.2 mmol) was added, and the reaction was carried out at room temperature for 0.5 h. After the reaction solution was filtered, the filtrate was distilled under reduced pressure with an oil pump to obtain the target product 5-(4-(((1-(((4-(Aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-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.

[0544] Step 7: Synthesis of 5-(4-((1-(1-(((4-(Aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-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)

[0545] 5-(4-(((1-(((4-(Aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-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, 0.03 mmol) was dissolved in acetonitrile (5 mL), and 1,4-dioxane solution of hydrochloric acid (1 mL) was added. The reaction was carried out at room temperature for 0.5 h. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was 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-hydroxynaphthalen-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, 8.27 mg, yield 23.36%). (ESI)[M+H] + = 952.1. 1 HNMR(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).

[0546] Example 21: Synthesis of 3-(6-(1-(7-(1-(((4-(3-azabicyclo[3.1.0]hexan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-5-methylpyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione trifluoroacetate (21)

[0547]

[0548] First step: Synthesis of (1-(((4-(3-azabicyclo[3.1.0]hexan-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl]naphthalen-1-yl)-5-methylpyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl 4-methylbenzenesulfonate (21-b)

[0549] Dissolve (1-(((4-(3-azabicyclo[3.1.0]hexan-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl]naphthalen-1-yl)-5-methylpyrido[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) in dichloromethane (10 mL), and react at room temperature for 16 hours. After adding water to the reaction solution, extract it three times with dichloromethane. After concentrating the organic phase under reduced pressure, separate and purify it by liquid chromatography (petroleum ether: ethyl acetate = 0% - 50%) to obtain the target product (1-(((4-(3-azabicyclo[3.1.0]hexan-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl]naphthalen-1-yl)-5-methylpyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl 4-methylbenzenesulfonate (21-b, 190 mg, yield 31.5%)

[0550] Second step: 3-(6-(1-(7-(1-((4-(3-azabicyclo[3.1.0]hexan-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl]naphthalen-1-yl)-5-methylpyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (21-c)

[0551] 1 - ((((4 - (3 - azabicyclo[3.1.0]hex - 3 - yl) - 8 - fluoro - 7 - (7 - fluoro - 3 - (methoxymethoxy) - 8 - [(triisopropylsilyl)ethynyl]naphthalen - 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), 3 - (6 - (1 - (7 - azaspiro[3.5]non - 2 - yl)piperidin - 4 - yl) - 1 - methyl - 1H - indazol - 3 - yl)piperidine - 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. The reaction solution was diluted with water and extracted with ethyl acetate three times. The organic phase was concentrated under reduced pressure and separated and purified by liquid chromatography (methylene chloride: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]naphthalen - 1 - yl) - 5 - methylpyrido[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)piperidine - 2,6 - dione (21 - c, 100 mg, yield 40%).

[0552] 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)naphthalen - 1 - yl) - 8 - fluoro - 5 - methylpyrido[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)piperidine - 2,6 - dione (21 - d)

[0553] ​3-(6-(1-(7-(1-((4-(3-azabicyclo[3.1.0]hexan-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl]naphthalen-1-yl)-5-methylpyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (21-c, 100 mg, 0.086 mmol) was dissolved in N,N-dimethylformamide (3 mL), cesium fluoride (65 mg, 0.43 mmol) was added, and the reaction was carried out at room temperature for 1 h. After the reaction solution was filtered and concentrated under reduced pressure, the target product 3-(6-(1-(7-(1-(((4-(3-azabicyclo[3.1.0]hexan-3-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-5-methylpyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (21-d, 90 mg, crude product) was obtained. (ESI)[M+H] + = 1004.2

[0554] Step 4: Synthesis of 3-(6-(1-(7-(1-(((4-(3-azabicyclo[3.1.0]hexan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-5-methylpyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione trifluoroacetate (21)

[0555] 3-(6-(1-(7-(1-(((4-(3-azabicyclo[3.1.0]hexan-3-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-5-methylpyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (21-d, 90 mg, 0.09 mmol) was dissolved in acetonitrile (3 mL), and 1,4-dioxane solution of hydrochloric acid (0.4 mL) was added. The reaction was carried out at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product, which 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-(3-azabicyclo[3.1.0]hexan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-5-methylpyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione trifluoroacetate (21, 1.7 mg, yield 2%). (ESI) [M+H] + = 960.14 1 H NMR (400 MHz, DMSO-d6) δ 10.87 (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).

[0556] Example 22: Synthesis of 4-(4-(7-((1-((4-(azetidin-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyridin-4-yl)pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)-3-fluorobenzamide trifluoroacetate (22)

[0557]

[0558] Step 1: Synthesis of tert-butyl 4-(2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (22-b)

[0559] Methyl 3,4-difluorobenzoate (22-a, 2.58 g, 15 mmol), tert-butyl piperazine-1-carboxylate (2.79 g, 15 mmol) and potassium carbonate (3.11 mg, 22.5 mmol) were successively added into a single-necked eggplant-shaped flask. Under solvent-free conditions, the reaction was carried out at 100 °C for 16 hours. The reaction was quenched with an aqueous solution, extracted with ethyl acetate, the organic phase was collected, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then purified by liquid chromatography (petroleum ether: ethyl acetate = 0% - 20%) to obtain the target product tert-butyl 4-(2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (22-b, 1.81 g, yield 35.8%). ESI [M+H] + = 338.2

[0560] Step 2: Synthesis of 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-fluorobenzoic acid (22-c)

[0561] tert-Butyl 4-(2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (22-b, 900 mg, 2.67 mmol) was dissolved in tetrahydrofuran (10 mL) and water (1 mL). After adding lithium hydroxide monohydrate (560 mg, 13.35 mmol), the reaction was carried out at 25 °C for 16 hours. 1N dilute hydrochloric acid solution was added to adjust the pH = 4, 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-butoxycarbonyl)piperazin-1-yl)-3-fluorobenzoic acid (22-c, 830 g, yield 96.1%). ESI [M+H] + = 324.1

[0562] Step 3: Synthesis of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)-2-fluorophenyl)piperazine-1-carboxylate (22-d)

[0563] 4-(4-(tert-Butoxycarbonyl)piperazin-1-yl)-3-fluorobenzoic acid (22-c, 830 mg, 2.57 mmol), 3-aminopiperidine-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). Finally, N,N-diisopropylethylamine (996 mg, 7.71 mmol) was added and the reaction was carried out at room temperature for 4 h. Saturated brine (30 mL) was added, and the mixture was extracted with ethyl acetate. The organic phase was collected, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by liquid chromatography (methylene chloride:methanol = 0% - 10%) to obtain the target product tert-butyl 4-(4-(((2,6-dioxopiperidin-3-yl)carbamoyl)-2-fluorophenyl)piperazine-1-carboxylate (22-d, 750 mg, yield 67.3%). ESI[M+H] + = 434.5

[0564] Step 4: Synthesis of N-(2,6-dioxopiperidin-3-yl)-3-fluoro-4-(piperazin-1-yl)benzamide (22-e)

[0565] tert-Butyl 4-(4-(((2,6-dioxopiperidin-3-yl)carbamoyl)-2-fluorophenyl)piperazine-1-carboxylate (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-dioxopiperidin-3-yl)-3-fluoro-4-(piperazin-1-yl)benzamide (22-e, 700 mg, crude product) was obtained. ESI[M+H] + = 335.1

[0566] Step 5: Synthesis of tert-butyl 2-(4-(4-(((2,6-dioxopiperidin-3-yl)carbamoyl)-2-fluorophenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (22-f)

[0567] Dissolve N-(2,6-dioxopiperidin-3-yl)-3-fluoro-4-(piperazin-1-yl)benzamide (22-e, 700 mg, 2.1 mmol) in methanol (15 mL). Sequentially add tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (753 mg, 3.15 mmol) and acetic acid (120 mg, 2.1 mmol). After stirring at 55 °C for 1 h, add sodium cyanoborohydride (397 mg, 6.3 mmol), and continue stirring at 55 °C for 16 h. Quench with water, extract with ethyl acetate, collect the organic phase, wash it with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Then purify by liquid chromatography (dichloromethane:methanol = 0% - 10%) to obtain the target product tert-butyl 2-(4-(4-(((2,6-dioxopiperidin-3-yl)carbamoyl)-2-fluorophenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (22-f, 1.03 g, yield 88.7%). ESI[M+H] + = 557.9

[0568] 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)

[0569] Dissolve tert-butyl 2-(4-(4-(((2,6-dioxopiperidin-3-yl)carbamoyl)-2-fluorophenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (22-f, 1.03 g, 1.73 mmol) in dichloromethane (20 mL). Slowly add trifluoroacetic acid (10 mL), and react at room temperature for 2 h. Concentrate under reduced pressure to obtain the crude product 4-(4-(7-azaspiro[3.5]non-2-yl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)-3-fluorobenzamide (22-g, 700 mg, crude). ESI[M+H]+ = 335.1

[0570] Step 7: Synthesis of 4-(4-(7-((1-(((4-(azetidin-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-7-((triisopropylsilyl)ethynyl)naphthalen-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-dioxopiperidin-3-yl)-3-fluorobenzamide (22-h)

[0571] (1 - (((4-(azetidin-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl]naphthalen-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]nonan-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). Potassium iodide (23 mg, 0.14 mmol) and potassium carbonate (103 mg, 0.7 mmol) were added successively, and 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, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by thin-layer chromatography silica gel plate (dichloromethane:methanol = 0% - 10%) to obtain the target product 4-(4-(7-((1-(((4-(azetidin-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-7-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)-3-fluorobenzamide (22-h, 31 mg, yield 18.7%).

[0572] Step 8: Synthesis of 4-(4-(7-(1-(((4-(azetidin-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)-3-fluorobenzamide (22-i)

[0573] 4-(4-(7-((1-(((4-(azetidin-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-7-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)-3-fluorobenzamide (22-h, 31 mg, 0.03 mmol) was dissolved in N,N-dimethylformamide (2 mL), cesium fluoride (23 mg, 0.15 mmol) was added, and the reaction was carried out at room temperature for 1 h. The reaction was quenched by adding water, extracted with ethyl acetate, 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 the crude product 4-(4-(7-(1-(((4-(azetidin-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)-3-fluorobenzamide (22-i, 20 mg, crude). ESI [M+H] + = 1014.1

[0574] Step 9: Synthesis of 4-(4-(7-((1-((4-(azetidin-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyridyl[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)-3-fluorobenzamide trifluoroacetate (22)

[0575] 4-(4-(7-(1-(((4-(Aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-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 separated and 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-hydroxynaphthalen-1-yl)-8-fluoropyridyl[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)-3-fluorobenzamide trifluoroacetate (22, 1.29 mg, yield 6%). ESI [M+H] + = 970.2 1 H NMR (400 MHz, DMSO-d6) δ 10.83 (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).

[0576] Example 23: Synthesis of 3-(6-(1-(2-(1-(1-(((4-(Aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)ethyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione trifluoroacetate (23)

[0577]

[0578] Step 1: Synthesis of tert-butyl 4-(2-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)ethyl)piperidine-1-carboxylate (23-b)

[0579] Dissolve 3-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)piperidine-2,6-dione (I-2, 100 mg, 0.30 mmol), tert-butyl 4-(2-bromoethyl)piperidine-1-carboxylate (23-a, 60 mg, 0.21 mmol) and potassium carbonate (200 mg, 1.5 mmol) in acetonitrile (5 mL), and heat the reaction mixture to 80 °C for 6 hours. After adding water to the reaction solution, extract it three times with ethyl acetate. Concentrate the organic phase under reduced pressure and separate and purify it by liquid chromatography (dichloromethane:methanol = 0% - 10%) to obtain the target product tert-butyl 4-(2-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)ethyl)piperidine-1-carboxylate (23-b, 40 mg, yield 24.4%) ESI[M+H] + = 538.5

[0580] Step 2: Synthesis of 3-(1-methyl-6-(1-(2-(piperidin-4-yl)ethyl)piperidin-4-yl)-1H-indazol-3-yl)piperidine-2,6-dione (23-c)

[0581] Dissolve tert-butyl 4-(2-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)ethyl)piperidine-1-carboxylate (23-b, 40 mg, 0.074 mmol) in dichloromethane (2 mL), add trifluoroacetic acid (0.5 mL), and react at room temperature for 1 hour. Concentrate under reduced pressure to obtain the target product 3-(1-methyl-6-(1-(2-(piperidin-4-yl)ethyl)piperidin-4-yl)-1H-indazol-3-yl)piperidine-2,6-dione (23-c, 60 mg, crude product) ESI[M+H] + = 438.6

[0582] Step 3: Synthesis of 3-(6-(1-(2-(1-(1-(((4-(azetidin-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy))-8-((triisopropylsilyl)ethynyl)naphthalen-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)piperidine-2,6-dione (23-d)

[0583] (1-(((4-(Aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl]naphthalen-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-indazol-3-yl)piperidine-2,6-dione (23-c, 60 mg, 0.14 mmol) were 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, water was added to the reaction solution, and the mixture was extracted with ethyl acetate three times. The organic phase was concentrated under reduced pressure and then separated and purified by liquid chromatography (methylene chloride: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)naphthalen-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)piperidine-2,6-dione (23-d, 25 mg, yield 15.6%)

[0584] Step 4: Synthesis of 3-(6-(1-(2-(1-(1-(((4-(aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)ethyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (23-e)

[0585] 3-(6-(1-(2-(1-(1-(((4-(Azido-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy))-8-((triisopropylsilyl)ethynyl)naphthalen-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)piperidine-2,6-dione (23-d, 25 mg, 0.022 mmol) was dissolved in N,N-dimethylformamide (1 mL), cesium fluoride (17 mg, 0.11 mmol) was added, and the reaction was carried out at room temperature for 1 h. After filtration and concentration under reduced pressure of the reaction solution, the target product 3-(6-(1-(2-(1-(1-(((4-(Azido-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)ethyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (23-e, 30 mg, crude product) was obtained. (ESI) [M+H] + = 994.6

[0586] Step 5: Synthesis of 3-(6-(1-(2-(1-(1-(((4-(Azido-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)ethyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione trifluoroacetate (23)

[0587] 3-(6-(1-(2-(1-(1-(((4-(Aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)ethyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (23-e, 30 mg, 0.03 mmol) was dissolved in acetonitrile (2 mL), and 1,4-dioxane solution of hydrochloric acid (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 the crude product, and 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-(2-(1-(1-(((4-(Aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)ethyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione trifluoroacetate (23, 2.14 mg, yield 8.5%). (ESI) [M+H] + = 950.5 1 H NMR (400 MHz, DMSO-d6) δ 10.87 (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).

[0588] Example 24: Synthesis of 3-(6-(1'-((1-((4-(Aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-[1,4'-dipiperidin]-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione trifluoroacetate (24)

[0589]

[0590] Step 1: Synthesis of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)-[1,4'-bipiperidine]-1'-carboxylate (24-a)

[0591] Dissolve 3-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)piperidine-2,6-dione (I-2, 300 mg, 0.92 mmol) and tert-butyl 4-iodopiperidine-1-carboxylate (429 mg, 1.38 mmol) in acetonitrile (14 mL), then add potassium carbonate (636 mg, 4.6 mmol), and react at 80 °C for 16 hours. After the reaction is completed, concentrate under reduced pressure to remove the solvent to obtain the crude product. Add 100 mL of water to the crude product, extract with ethyl acetate three times, 50 mL each time, collect the organic phase, concentrate under reduced pressure, and purify by thin-layer chromatography silica gel plate (dichloromethane:methanol = 0 - 10%) to obtain the target product tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)-[1,4'-bipiperidine]-1'-carboxylate (24-a, 69 mg, yield 14.71%). (ESI)[M+H] + = 510.5.

[0592] Step 2: Synthesis of 3-(6-([1,4'-bipiperidine]-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (24-b)

[0593] Dissolve tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)-[1,4'-bipiperidine]-1'-carboxylate (24-a, 69 mg, 0.14 mmol) in dichloromethane (5 mL), add trifluoroacetic acid (1 mL), and react at room temperature for 0.5 hour. Distill off the solvent under reduced pressure to obtain the crude product of the target product 3-(6-([1,4'-bipiperidine]-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (24-b, 80 mg, crude product).

[0594] Step 3: Synthesis of 3-(6-(1'-((1-(((4-(azetidin-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-7-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-[1,4'-bipiperidine]-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (24-c)

[0595] (1 - (((4-(azetidin-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-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), 3-(6-([1,4'-bipiperidin]-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-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 distillation under reduced pressure to obtain the crude product. The crude product was purified by thin layer chromatography silica gel plate (dichloromethane:methanol = 100:14) to obtain the target product 3-(6-(1'-((1-(((4-(azetidin-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-7-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-[1,4'-bipiperidin]-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (24-c, 26 mg, yield 17.81%). (ESI)[M+H] + = 1121.8.

[0596] Step 4: Synthesis of 3-(6-(1'-(1-(((4-(azetidin-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-[1,4'-bipiperidin]-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (24-d)

[0597] 3-(6-(1'-((1-(((4-(Aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-7-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-[1,4'-dipiperidin]-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (24-c, 26 mg, 0.02 mmol) was dissolved in N,N-dimethylformamide (3 mL), cesium fluoride (30 mg, 0.2 mmol) was added, and the reaction was carried out at room temperature for 0.5 h. After the reaction solution was filtered, the filtrate was distilled under reduced pressure with an oil pump to obtain the crude product of the target product 3-(6-(1'-(1-(((4-(Aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-[1,4'-bipiperidin]-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (24-d, 27 mg, crude product). (ESI) [M+CH3OH] + = 998.5.

[0598] Step 5: Synthesis of 3-(6-(1'-((1-((4-(Aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-[1,4'-dipiperidin]-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione trifluoroacetate (24)

[0599] 3-(6-(1'-(1-(((4-(Aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-[1,4'-bipiperidin]-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (24-d, 27 mg, 0.03 mmol) was dissolved in acetonitrile (5 mL), and 1,4-dioxane solution of hydrochloric acid (1 mL) was added. The reaction was carried out at room temperature for 0.5 h. The reaction solution was distilled under reduced pressure to obtain a crude product, and 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-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-[1,4'-dipiperidin]-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione trifluoroacetate (24, 10.79 mg, yield 30.83%). (ESI) [M+H] + = 922.5. 1 H NMR (600 MHz, DMSO-d6) δ 10.22 - 10.06 (d, J = 98.1 Hz, 1H), 9.33 (s, 1H), 9.12 (s, 1H), 7.97 - 7.94 (m, 1H), 7.83 - 7.82 (d, J = 8.4 Hz, 1H), 7.54 (s, 1H), 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 = 5.9 Hz, 4H), 3.97 (s, 3H), 3.93 (s, 1H), 3.90 - 3.88 (m, 1H), 3.85 - 3.84 (d, J = 10.7 Hz, 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).

[0600] Synthesis of 3-(5-(1-(7-(1-(((4-(Azido-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione trifluoroacetate (25)

[0601]

[0602] First step: 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)-carboxylate (25-b)

[0603] Dissolve 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (25-a, 500 mg, 1.48 mmol), potassium phosphate (942 mg, 4.44 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (162 mg, 0.22 mmol), and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (915 mg, 2.96 mmol) in N,N-dimethylformamide (37.5 mL). Replace the gas with nitrogen three times and react at 90 °C for 5 hours. After the reaction is completed, add the reaction solution to 500 mL of water and extract with ethyl acetate three times, 250 mL each time. Combine the organic phases, filter the solvent through diatomaceous earth, and concentrate under reduced pressure to remove the solvent to obtain the crude product. After drying the crude product with an oil pump and mixing the sample, purify it by liquid chromatography (dichloromethane:methanol = 0 - 2%) to obtain the target product 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)-carboxylate (25-b, 460 mg, yield 70.55%). (ESI)[M+H] + = 441.4

[0604] Second step: 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)

[0605] 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-b, 360 mg, 0.82 mmol) was dissolved in dichloromethane (30 mL) and methanol (3 mL). 250 mg of 10% palladium on carbon was added. After replacing the gas with hydrogen three times, 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 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, 355 mg, yield 98%). (ESI)[M+H] + = 443.5.

[0606] Step 3: Synthesis of 3-(3-methyl-2-oxo-5-(piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (25-d)

[0607] 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, 355 mg,, 0.8 mmol) was dissolved in dichloromethane (20 mL). Trifluoroacetic acid (1 mL) was added, and the reaction was carried out at room temperature for 0.5 h. The solvent was removed by distillation under reduced pressure to obtain the target product 3-(3-methyl-2-oxo-5-(piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (25-d, 520 mg, crude product).

[0608] 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]nonane-7-carboxylate (25-e)

[0609] Dissolve 3-(3-methyl-2-oxo-5-(piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (25-d, 250 mg, 0.73 mmol) and tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (263 mg, 1.1 mmol) in methanol (10 mL) and tetrahydrofuran (2.5 mL), add acetic acid (44 mg, 0.73 mmol), after reacting at 55 °C for 1 hour, add sodium cyanoborohydride (138 mg, 2.19 mmol), and continue to react at 55 °C for 16 hours. After the reaction is completed, concentrate under reduced pressure to obtain the crude product, and purify the crude product with a thin-layer chromatography silica gel plate (dichloromethane:methanol = 0 - 10%) to obtain the target product 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]nonane-7-carboxylate (25-e, 150 mg, yield 36.32%). (ESI)[M+H] + = 566.3.

[0610] 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)piperidine-2,6-dione (25-f)

[0611] Dissolve 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]nonane-7-carboxylate (25-e, 206 mg, 0.36 mmol) in dichloromethane (10 mL), add trifluoroacetic acid (1 mL), and react at room temperature for 0.5 hour. Distill off the solvent under reduced pressure 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)piperidine-2,6-dione (25-f, 235 mg, crude product).

[0612] Step 6: Synthesis of 3-(5-(1-(7-(1-(((4-(azetidin-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl]naphthalen-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)piperidine-2,6-dione (25-g)

[0613] (1 - (((4-(Aza - 1 - yl)-8 - fluoro - 7-(7 - fluoro - 3-(methoxymethoxy)-8 - [(triisopropylsilyl)ethynyl]naphthalen - 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)piperidine - 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 a crude product. The crude product was purified by thin - layer chromatography silica gel plate (methylene chloride: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]naphthalen - 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)piperidine - 2,6 - dione (25 - g, 26 mg, yield 20%). (ESI)1 / 2[M + CH3OH] + = 606.0.

[0614] Step 7: Synthesis of 3-(5-(1-(7-(1 - (((4-(aza - 1 - yl)-7-(8 - ethynyl - 7 - fluoro - 3-(methoxymethoxy)naphthalen - 1 - yl)-8 - fluoropyrido[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)piperidine - 2,6 - dione (25 - h)

[0615] 3-(5-(1-(7-(1-(((4-(Aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl]naphthalen-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (25-g, 26 mg, 0.02 mmol) was dissolved in N,N-dimethylformamide (3 mL), cesium fluoride (30 mmol, 0.2 mmol) was added, and the reaction was carried out at room temperature for 0.5 h. After the reaction solution was filtered, the filtrate was distilled under reduced pressure with an oil pump to obtain the target product 3-(5-(1-(7-(1-(((4-(Aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (25-h, 23 mg, crude product). (ESI)1 / 2[M+H] + = 512.1.

[0616] Step 8: Synthesis of 3-(5-(1-(7-(1-(((4-(Aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione trifluoroacetate (25)

[0617] 3-(5-(1-(7-(1-(((4-(Aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (25-h, 23 mg, 0.02 mmol) was dissolved in acetonitrile (5 mL), and 1,4-dioxane solution of hydrochloric acid (1 mL) was added, and the reaction was carried out at room temperature for 0.5 h. The reaction solution was concentrated under reduced pressure to obtain a crude product, and the crude product was 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-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione trifluoroacetate (25, 5.92 mg, yield 24.54%). (ESI)1 / 2[M+H] + = 490.1. 11H NMR (600 MHz, DMSO-d6) δ 11.10 (s, 1H), 10.21 - 10.17 (d, J = 24.1 Hz, 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 = 2.5 Hz, 1H), 7.18 - 7.17 (d, J = 2.5 Hz, 1H), 7.08 - 7.07 (d, J = 8.2 Hz, 1H), 7.05 - 7.00 (m, 1H), 6.92 - 6.89 (d, J = 8.6 Hz, 1H), 5.38 - 5.34 (m, 1H), 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).

[0618] Example 26: Synthesis of 3-(5-(1-(7-(1-(((4-(Aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-6-fluoro-1-oxoisoindol-2-yl)piperidine-2,6-dione trifluoroacetate (26)

[0619]

[0620] First step: Synthesis of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (26-b)

[0621] 3-(5-Bromo-6-fluoro-1-oxoisoindol-2-yl)piperidine-2,6-dione (26-a, 460 mg, 1.35 mmol), potassium phosphate (860 mg, 4.05 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium(II) dichloride (146 mg, 0.2 mmol), and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (835 mg, 2.7 mmol) were dissolved in N,N-dimethylformamide (34 mL). The mixture was purged with nitrogen three times and then reacted at 90 °C for 21 h. After the reaction was completed, the reaction mixture was added to 500 mL of water and extracted with ethyl acetate three times (250 mL each time). The organic phases were combined, filtered through diatomaceous earth, and concentrated under reduced pressure to remove the solvent, obtaining a crude product. The crude product was dried with an oil pump, mixed with a sample, and purified by liquid chromatography (methylene chloride:methanol = 0–2%) to obtain the target product tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (26-b, 300 mg, yield 48%). (ESI)[M+H] + = 444.4.

[0622] Step 2: Synthesis of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperidine-1-carboxylate (26-c)

[0623] tert-Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (26-b, 80 mg, 0.18 mmol) was dissolved in tetrahydrofuran (5 mL) and methanol (1 mL). 100 mg of 10% palladium on carbon was added, and the mixture was purged with hydrogen three times and then reacted at 30 °C for 24 h. After the reaction mixture was filtered through diatomaceous earth, the filtrate was distilled under reduced pressure to obtain the target product tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperidine-1-carboxylate (26-c, 85 mg, crude product). (ESI)[M+H] + = 446.0

[0624] Step 3: Synthesis of 3-(6-fluoro-1-oxo-5-(piperidin-4-yl)isoindol-2-yl)piperidine-2,6-dione (26-d)

[0625] Dissolve tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperidine-1-carboxylate (26-c, 85 mg, 0.19 mmol) in dichloromethane (10 mL), add trifluoroacetic acid (1 mL), and react at room temperature for 0.5 h. Remove the solvent by distillation under reduced pressure to obtain the target product 3-(6-fluoro-1-oxo-5-(piperidin-4-yl)isoindol-2-yl)piperidine-2,6-dione (26-d, 120 mg, crude product).

[0626] Step 4: Synthesis of tert-butyl 2-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (26-e)

[0627] Dissolve 3-(6-fluoro-1-oxo-5-(piperidin-4-yl)isoindol-2-yl)piperidine-2,6-dione (26-d, 120 mg, 0.35 mmol) and tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (168 mg, 0.7 mmol) in methanol (4 mL) and tetrahydrofuran (1 mL), add acetic acid (21 mg, 0.35 mmol), react at 55 °C for 1 h, then add sodium cyanoborohydride (66 mg, 1.05 mmol), and continue to react at 55 °C for 6 h. After the reaction is completed, concentrate under reduced pressure to obtain the crude product, and purify the crude product by thin-layer chromatography silica gel plate (dichloromethane:methanol = 0 - 10%) to obtain the target product tert-butyl 2-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (26-e, 28 mg, yield 14.07%).

[0628] 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)

[0629] Dissolve tert-butyl 2-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (26-e, 28 mg, 0.05 mmol) in dichloromethane (5 mL), add trifluoroacetic acid (0.5 mL), and react at room temperature for 0.5 h. Remove the solvent by distillation under reduced pressure to obtain the target product 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, crude product).

[0630] Step 6: Synthesis of 3-(5-(1-(7-(1-(((4-(Aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-7-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl)pyridine-2,6-dione (26-g)

[0631] (1-(((4-(Aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl]naphthalen-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]nonan-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 a crude product. The crude product was purified by a thin-layer chromatography silica gel plate (methylene chloride: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)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl)pyridine-2,6-dione (26-g, 17 mg, yield 23.98%). (ESI)1 / 2[M+CH3OH] + = 607.2.

[0632] Step 7: Synthesis of 3-(5-(1-(7-(1-(((4-(Aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-6-fluoro-1-oxoisoindol-2-yl)pyridine-2,6-dione (26-h)

[0633] 3-(5-(1-(7-(1-(((4-(Aza-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-7-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl)pyridine-2,6-dione (26-g, 17 mg, 0.014 mmol) was dissolved in N,N-dimethylformamide (3 mL), cesium fluoride (21 mmol, 0.14 mmol) was added, and the reaction was carried out at room temperature for 0.5 h. After the reaction solution was filtered, the filtrate was distilled under reduced pressure with an oil pump to obtain the target product 3-(5-(1-(7-(1-(((4-(Aza-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-6-fluoro-1-oxoisoindol-2-yl)pyridine-2,6-dione (26-h, 16 mg, crude product). (ESI) [M+H] + = 1025.3.

[0634] Step 8: Synthesis of 3-(5-(1-(7-(1-(((4-(Aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-6-fluoro-1-oxoisoindol-2-yl)pyridine-2,6-dione trifluoroacetate (26)

[0635] 3-(5-(1-(7-(1-(((4-(Azido-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-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 solution of hydrochloric acid (1 mL) was added. The reaction was carried out at room temperature for 0.5 h. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was 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-(Azido-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-6-fluoro-1-oxoisoindol-2-yl)pyridine-2,6-dione trifluoroacetate (26, 5.24 mg, yield 27.08%). (ESI)[M+H] + = 981.3. 1 HNMR(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),3.20-3.17(m,1H),3.03-2.87(m,5H),2.62-2.59(d,J=15.5Hz,1H),2.43-2.32(m,2H),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).

[0636] Synthesis of 3-(6-(1-(3-(1-(((4-(Aza-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-3-azabicyclo[3.2.0]heptan-6-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione trifluoroacetate (27)

[0637]

[0638] Step 1: Synthesis of tert-butyl 6-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-3-azabicyclo[3.2.0]heptane-3-carboxylate (27-a)

[0639] Dissolve 3-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)piperidine-2,6-dione (I-2, 150 mg, 0.46 mmol), tert-butyl 6-oxo-3-azabicyclo[3.2.0]heptane-3-carboxylate (146 mg, 0.69 mmol) in methanol (7.5 mL) and tetrahydrofuran (1.8 mL), then add acetic acid (28 mg, 0.46 mmol), react at 55 °C for 1 hour, add sodium cyanoborohydride (87 mg, 1.38 mmol), and continue the reaction at 55 °C for 16 hours. After the reaction is completed, concentrate under reduced pressure to remove the solvent to obtain the crude product. The crude product is purified by thin-layer chromatography silica gel plate (dichloromethane:methanol = 0 - 10%) to obtain the target product tert-butyl 6-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-3-azabicyclo[3.2.0]heptane-3-carboxylate (27-a, 28 mg, yield 11.67%). (ESI)[M+H] + = 522.1.

[0640] Step 2: Synthesis of 3-(6-(1-(3-azabicyclo[3.2.0]heptan-6-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (27-b)

[0641] tert-Butyl 6-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-3-azabicyclo[3.2.0]heptane-3-carboxylate (27-a, 28 mg, 0.05 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, and the reaction was carried out at room temperature for 0.5 h. The solvent was removed by distillation under reduced pressure to obtain the crude product of the target compound 3-(6-(1-(3-azabicyclo[3.2.0]heptan-6-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (27-b, 35 mg, crude).

[0642] Step 3: Synthesis of 3-(6-(1-(3-(1-(((4-(azetidin-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-7-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-3-azabicyclo[3.2.0]heptan-6-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (27-c)

[0643] (1-(((4-(azetidin-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl]naphthalen-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), and 3-(6-(1-(3-azabicyclo[3.2.0]heptan-6-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (27-b, 35 mg, 1.2 mmol) were dissolved in acetonitrile (5 mL), and the reaction was carried out at 60 °C for 6 h. After the reaction was completed, the solvent was removed by distillation under reduced pressure to obtain the crude product, which was purified by thin-layer chromatography silica gel plate (dichloromethane:methanol = 100:13) to obtain the target compound 3-(6-(1-(3-(1-(((4-(azetidin-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-7-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-3-azabicyclo[3.2.0]heptan-6-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (27-c, 18 mg, yield 22.78%). (ESI)[M + CH3OH] + = 1166.7.

[0644] Step 4: Synthesis of 3-(6-(1-(3-(1-(((4-(azetidin-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-3-azabicyclo[3.2.0]heptan-6-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (27-d)

[0645] Dissolve 3-(6-(1-(3-(1-(((4-(azetidin-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-7-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-3-azabicyclo[3.2.0]heptan-6-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (27-c, 18 mg, 0.02 mmol) in N,N-dimethylformamide (2 mL), add cesium fluoride (30 mg, 0.2 mmol), and react at room temperature for 0.5 h. After filtering the reaction solution, the filtrate is distilled under reduced pressure with an oil pump to obtain the crude product of the target compound 3-(6-(1-(3-(1-(((4-(azetidin-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-3-azabicyclo[3.2.0]heptan-6-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (27-d, 17 mg, crude product). (ESI)[M+H] + = 978.6.

[0646] Step 5: Synthesis of 3-(6-(1-(3-(1-(((4-(azetidin-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-3-azabicyclo[3.2.0]heptan-6-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione trifluoroacetate (27)

[0647] 3-(6-(1-(3-(1-(((4-(Azido-1-yl)-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-3-azabicyclo[3.2.0]heptan-6-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (27-d, 17 mg, 0.017 mmol) was dissolved in acetonitrile (5 mL), and 1,4-dioxane solution of hydrochloric acid (1 mL) was added. The reaction was carried out at room temperature for 0.5 h. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was 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-(Azido-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-3-azabicyclo[3.2.0]heptan-6-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione trifluoroacetate (27, 7.14 mg, yield 42.93%). (ESI) [M+H] + = 934.6. 1 H NMR (600 MHz, DMSO-d6) δ 10.88 (s, 1H), 10.19 - 10.14 (t, 1H), 9.89 - 9.85 (d, J = 22.0 Hz, 1H), 9.12 - 9.11 (d, J = 6.7 Hz, 1H), 7.97 (s, 1H), 7.80 - 7.65 (d, J = 87.9 Hz, 1H), 7.52 - 7.29 (m, 4H), 7.17 (s, 1H), 7.03 - 6.98 (d, J = 25.2 Hz, 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 = 10.4 Hz, 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).

[0648] Synthesis of 3-(6-(1-(3-(1-(((4-(azetidin-1-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-3-azaspiro[5.5]undecan-9-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione trifluoroacetate (28)

[0649]

[0650] First step: Synthesis of tert-butyl 9-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-3-azaspiro[5.5]undecane-3-carboxylate (28-a)

[0651] Dissolve 3-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)piperidine-2,6-dione (I-2, 100 mg, 0.31 mmol), tert-butyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate (144 mg, 0.62 mmol) in methanol (5 mL) and tetrahydrofuran (1.25 mL), then add acetic acid (10 mg, 0.16 mmol), react at 55 °C for 1 hour, add sodium cyanoborohydride (129 mg, 2.05 mmol), and continue the reaction at 55 °C for 19 hours. After the reaction is completed, concentrate under reduced pressure to remove the solvent to obtain the crude product. The crude product is purified by a thin-layer chromatography silica gel plate (dichloromethane:methanol = 0 - 10%) to obtain the target product tert-butyl 9-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-3-azaspiro[5.5]undecane-3-carboxylate (28-a, 50 mg, yield 27.93%). Do another batch in equal proportion to obtain 28 mg of the product. (ESI)[M+H] + = 578.2.

[0652] Second step: Synthesis of 3-(6-(1-(3-azaspiro[5.5]undecan-9-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (28-b)

[0653] tert-Butyl 9-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-3-azaspiro[5.5]undecane-3-carboxylate (28-a, 78 mg, 0.14 mmol) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (1 mL) was added, and the reaction was carried out at room temperature for 0.5 h. The solvent was removed by distillation under reduced pressure to obtain the crude product of the target product 3-(6-(1-(3-azaspiro[5.5]undecan-9-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (28-b, 97 mg, crude).

[0654] Step 3: Synthesis of 3-(6-(1-(3-(1-(((4-(azetidin-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-7-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-3-azaspiro[5.5]undecan-9-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (28-c)

[0655] (1-(((4-(Azetidin-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-[(triisopropylsilyl)ethynyl]naphthalen-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), and 3-(6-(1-(3-azaspiro[5.5]undecan-9-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (28-b, 53 mg, 0.11 mmol) were dissolved in acetonitrile (4 mL), and the reaction was carried out at 60 °C for 16 h. After the reaction was completed, the solvent was removed by distillation under reduced pressure to obtain a crude product, which was purified by thin-layer chromatography silica gel plate (dichloromethane:methanol = 100:13) to obtain the target product 3-(6-(1-(3-(1-(((4-(azetidin-1-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-7-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-3-azaspiro[5.5]undecan-9-yl)p...

Claims

1. A compound of formula (I), a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof: In formula (I), R 1 is selected from H, -CH3, -OCH3, cyclopropyl, cyclopropoxy; R 2 selected from wherein R is selected from -CN, -NH2, C 1-3 alkynyl, C 1-3 alkenyl, C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by -CN, -NH2, -N(CH3)2, -OH, 3- to 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- to 10-membered heterocycloalkyl; m is optionally 0 or 1; q is optionally 0, 1 or 2; p is optionally 0, 1, 2, 3 or 4; X 1 selected from -O-, -CH2-, -CHR 7 - or -C(R 7 )2; R at each substitution position 7 Each is independently selected from -H, -OH, -F, -Cl, -CH3, -CN, -CH2OH, -CH2Cl, -OCH3, -CH2CN, -CH(CH3)2OH, -NHCH3, or two Rs on the same carbon atom of ring A 7 The substituents form a 3- to 6-membered heterocycle or carbonyl with the carbon atom, or two Rs on adjacent carbon atoms of ring A 7 The substituents form a 3- to 6-membered cycloalkyl or heterocycloalkyl with the carbon atom to which they are attached; M is selected from -O-, -S-, -NR 3 -, C 1-6 alkylene, and said R 3 is selected from H, C 1-6 alkyl, and said alkylene is substituted by one or more substituents selected from halogen, -OH, -CN, C 1-6 alkyl, and C 1-6 haloalkyl; L is selected from -L 1 -L 2 -L 3 -L 4 -L 5 -; L 1 is a covalent bond, or is selected from -O-, -NR 4 , a carbonyl group, C 1-6 alkyl ether amino group, C 1-6 alkylene group, C 3-6 subcycloalkylene group, a saturated or unsaturated 3- to 11-membered heterocycloalkylene group, wherein the R 4 is selected from H, C 1-6 alkyl group, and the C 1-6 alkyl ether amino group, C 1-6 alkylene group, C 3-6 subcycloalkylene group, a saturated or unsaturated 3- to 11-membered heterocycloalkylene group is substituted by one or more substituents selected from halogen, -OH, -CN, C 1-6 alkyl group and C 1-6 haloalkyl group; L 2 is a covalent bond, or is selected from -O-, -NR 5 , a carbonyl group, C 1-6 alkyl ether amino group, C 1-6 alkylene group, C 3-6 subcycloalkylene group, a saturated or unsaturated 3- to 11-membered heterocycloalkylene group, wherein the R 5 is selected from H, C 1-6 alkyl group, and the C 1-6 alkyl ether amino group, C 1-6 alkylene group, C 3-6 subcycloalkylene group, a saturated or unsaturated 3- to 11-membered heterocycloalkylene group is substituted by one or more substituents selected from halogen, -OH, -CN, C 1-6 alkyl group, and C 1-6 haloalkyl group; L 3 is a covalent bond, or is selected from -O-, -NR 6 , carbonyl, C 1-6 alkylene ether amino group, C 1-6 alkylene, C 3-6 subcycloalkylene, a saturated or unsaturated 3- to 11-membered heterocycloalkylene group, wherein the R 6 is selected from H, C 1-6 alkyl, wherein the C 1-6 alkylene ether amino group, C 1-6 alkylene, C 3-6 subcycloalkylene, a saturated or unsaturated 3- to 11-membered heterocycloalkylene group is substituted by one or more substituents selected from halogen, -OH, -CN, C 1-6 alkyl and C 1-6 haloalkyl; L 4 is a covalent bond, or is selected from -O-, -NR 8 , a carbonyl group, C 1-6 alkyl ether amino group, C 1-6 alkylene group, C 3-6 subcycloalkylene group, a saturated or unsaturated 3- to 11-membered heterocycloalkylene group, wherein the R 8 is selected from H, C 1-6 alkyl group, and the C 1-6 alkyl ether amino group, C 1-6 alkylene group, C 3-6 subcycloalkylene group, a saturated or unsaturated 3- to 11-membered heterocycloalkylene group is substituted by one or more substituents selected from halogen, -OH, -CN, C 1-6 alkyl group and C 1-6 haloalkyl group; L 5 is a covalent bond, or is selected from -O-, -NR 9 , a carbonyl group, C 1-6 alkyl ether amino group, C 1-6 alkylene group, C 3-6 subcycloalkylene group, a saturated or unsaturated 3- to 11-membered heterocycloalkylene group, where the R 9 is selected from H, C 1-6 alkyl group, where the C 1-6 alkyl ether amino group, C 1-6 alkylene group, C 3-6 subcycloalkylene group, a saturated or unsaturated 3- to 11-membered heterocycloalkylene group is substituted by one or more substituents selected from halogen, -OH, -CN, C 1-6 alkyl group and C 1-6 haloalkyl group; and L 1 、L 2 、L 3 、L 4 、L 5 are not all single bonds at the same time; E is selected from small molecule ligands of E3 ubiquitin ligase.

2. The compound, pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof according to claim 1, wherein R 1 selected from H, -CH3, -OCH3; R 2 selected from Ring A is selected from M is selected from -O-, -S-, -NH-; L 1 selected from a single bond, L 2 selected from single bonds, L 3 selected from a single bond, a carbonyl group, -CH2-, -CH2 CH2-, -CH2 CH2OCH2- L 4 selected from a single bond, a carbonyl group, L 5 selected from a single bond, a carbonyl group, and L 1 、L 2 、L 3 、L 4 、L 5 are not simultaneously single bonds; E is selected from small molecule ligands of E3 ubiquitin ligase CRBN, preferably having the following structure:

3. The compound, pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof according to any one of claims 1-2, wherein L is selected from 4. The compound, pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof according to any one of claims 1-3, the compound is represented by formula (I-a), formula (I-b), formula (I-c), formula (I-d), formula (I-e), formula (I-f), formula (I-g), formula (I-h), formula (I-i), formula (I-j), formula (I-k) or formula (I-l), 5. The compound of formula (I), its pharmaceutically acceptable salts, stereoisomers, solvates or prodrugs as claimed in claims 1-4, wherein, The compound is selected from the following group:

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

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

8. Use of the compound, pharmaceutically acceptable salt, stereoisomer, solvate, prodrug thereof according to any one of claims 1-6, the pharmaceutical composition according to claim 7 in the treatment of cancer, immune diseases or a kit for prognostic evaluation of cancer patients; Preferably, the pharmaceutical composition further comprises another drug for treating cancer or immune diseases; Preferably, use in the preparation of a drug for treating diseases related to KRAS mutation; Preferably, the cancer includes pancreatic cancer, colorectal cancer, lung cancer, cholangiocarcinoma, endometrial cancer and ovarian cancer; More preferably, the cancer includes pancreatic cancer, colorectal cancer, lung cancer, cholangiocarcinoma, endometrial cancer and ovarian cancer.

9. Use of the compound, pharmaceutically acceptable salt, stereoisomer, solvate, prodrug thereof according to any one of claims 1-6 or the pharmaceutical composition according to claim 7 in the preparation of a drug for treating diseases related to KRAS activity or expression level; Preferably, use in the preparation of a drug for treating diseases related to inhibition or degradation of KRAS G12D, KRAS G12V, KRAS G12A, KRAS G12S, KRAS G12C, KRAS G13D, KRAS Q61H, KRAS Q61K, KRAS Y96D and other KRAS mutations.

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

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