Compound for selectively degrading SMARCA2 / 4 and application thereof

Abstract

The present disclosure relates to compounds useful as modulators of SMARCA2 / 4. Specifically, the compounds involved in the present disclosure contain on one end a ligand that binds to an E3 ubiquitin ligase and on the other end a ligand that binds to a target protein (SMARCA2 / 4) such that the target protein is positioned in proximity to the ubiquitin ligase to effect degradation (or inhibition) of the target protein.

Description

A compound for selectively degrading SMARCA2 / 4 and its application Technical Field

[0001] The present invention relates to the field of medicine, and in particular to a compound capable of selectively degrading SMARCA2 / 4 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate or polymorph thereof, and its use in preventing or treating diseases or conditions mediated by SMARCA2 / 4. Background Art

[0002] SMARCA2 / 4 are key subunits of the SWI / SNF chromatin remodeling complex, also known as the BAF complex. Chromatin, the carrier of genetic information in eukaryotes, consists of DNA and nucleosomes and is normally highly compacted. When genes at specific loci require transcription, chromatin transitions from a compacted to a loosened state, a process that requires the involvement of chromatin remodeling complexes. Chromatin remodeling complexes utilize energy from ATP hydrolysis to reposition, assemble, migrate, and reorganize nucleosomes, altering chromatin structure and thereby changing the accessibility of transcription factors and cellular proteins to local DNA. When chromatin remodeling factors loosen chromatin, accessibility to chromatin DNA by RNA polymerase II and transcription factors is increased, thereby initiating gene transcription. Conversely, when chromatin becomes compacted, accessibility to chromatin DNA by RNA polymerase II and transcription factors is reduced, thereby repressing transcription of the associated genes. Chromatin remodeling, a crucial component of epigenetic regulation, plays a crucial role in eukaryotic DNA replication, transcription, recombination, and DNA repair, thereby controlling cell proliferation, division, and maturation. SWI / SNF regulates gene expression by altering chromatin disassembly and replacing nucleosome-stabilizing proteins. SMARCA4 (BRG1 protein) and SMARCA2 (BRM protein) are the two mutually exclusive catalytic subunits of the SWI / SNF complex. They share 75% homology at the protein level and possess ATPase activity, providing energy for chromatin remodeling. The ATP-dependent chromatin remodeling activity of SMARCA2 or SMARCA4 is essential, primarily involved in double-strand break and nucleotide excision repair, playing a crucial role in double-strand damage repair. Therefore, SMARCA mutations can lead to uncorrected or inappropriate repair of DNA damage, driving tumorigenesis and progression. Although both SMARCA2 and SMARCA4 are ATP hydrolases, their functions differ, resulting in distinct mutational profiles in malignant tumors, with co-mutations rarely occurring. SMARCA2 loss is relatively rare, occurring in rhabdoid tumors, esophageal cancer, bladder cancer, and gastric cancer. SMARCA4, on the other hand, is a frequently mutated gene in malignant tumors, commonly found in ovarian clear cell carcinoma, renal cancer, hematologic tumors, and medulloblastoma, but is typically not associated with SMARCA2 mutations. In most SMARCA4-deficient tumors, SMARCA2 is upregulated to compensate for the loss of SMARCA4 function. SMARCA4 mutations render cell proliferation more dependent on its alternative ATPase, SMARCA2, making these tumor cells susceptible to SMARCA2 loss. Selective inhibition of SMARCA2 activity has been shown to be an effective therapeutic approach for the growth of SMARCA4-mutant cancer cells, a relationship known as synthetic lethality. In vitro and mouse xenograft studies, knocking down SMARCA2 protein expression using RNAi inhibited the growth of SMARCA4-mutant lung cancer tumors.

[0003] SMARCA proteins are multi-domain proteins. In addition to the conserved ATPase catalytic domain, they also contain bromodomains, which can help the complex bind to specific sites on chromatin by recognizing acetylated residues on the histone "tails." Currently, most SMARCA2 inhibitors under development target the bromodomain, with a few studies acting on the core ATPase catalytic domain. Although studies have found that the synthetic lethality of SMARCA2 and SMARCA4 can be achieved by knocking down SMARCA2 through RNAi or inhibiting ATPase activity, small molecule inhibitors targeting the bromodomain are unable to effectively inhibit tumor cell proliferation. Therefore, the SMARCA2 target contains a bromodomain that is easy to target as a drug but does not play a major role, and an ATPase domain that plays a major role but is more difficult to target as a drug. This structural feature makes the development of drugs that target SMARCA2 more difficult.

[0004] Proteolysis-Targeting Chimeras (PROTACs) are an emerging technology with great prospects, which are expected to turn many potential targets that are "undruggable" into "druggable". Traditional small molecule drugs are often powerless against proteins without enzyme functions, which account for about 80% of human proteins, because these drugs usually need to bind to enzymes or receptors to work. PROTACs consists of three parts: a ligand (amchor) that recruits E3 ubiquitin ligase, a ligand molecule (warhead) that binds to the target protein (protein of interest.POI), and a linker (limker) that connects the two parts. Traditional small molecules need to exert their pharmacological effects by occupying key sites of the target protein (i.e. occupancy-driven), so they need to maintain a certain drug concentration in the body, and the requirements for small molecule binding sites are high. PROTACs achieve pharmacodynamic effects by degrading the target protein, and theoretically do not require very high drug concentrations.

[0005] SMARCA2 and SMARCA4 have two main functional regions, the ATPase region and the bromodomain. The amino acid residue homology of the corresponding functional regions of these two proteins is greater than 90%. Small molecule inhibitors are difficult to achieve selectivity for SMARCA4 and SMARCA2, and usually have strong killing ability against normal cells. There is an urgent need for PROTAC molecules with excellent stability and activity and good selectivity for SMARCA2 or SMARCA4 in clinical practice.

[0006] Summary of the Invention

[0007] The first aspect of the present invention provides a compound having the structure of formula 10:

[0008] PTM-L-ULM (Formula 10),

[0009] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate or polymorph thereof,

[0010] in:

[0011] The L is a bond or chemical linking moiety connecting the ULM and the PTM;

[0012] The PTM is a SMARCA2 / 4 binding moiety, which has the following structure:

[0013] in,

[0014] Cy1 is a saturated or unsaturated cycloalkyl group, a saturated or unsaturated heterocycloalkyl group containing a heteroatom selected from N, O and S, an aryl group, or a heteroaryl group containing a heteroatom selected from N, O and S, which is unsubstituted or substituted with one or more substituents each independently selected from halogen, cyano, haloalkyl, haloalkoxy, alkoxy, alkyl, hydroxy, amino and alkylamino;

[0015] R 10 Selected from and Cy2;

[0016] Cy2 is selected from a saturated or unsaturated 3-10 membered cycloalkyl group, a saturated or unsaturated 3-10 membered heterocycloalkyl group containing 1, 2 or 3 heteroatoms independently selected from N, O and S, a 6-10 membered aryl group, or a 5-10 membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O and S, which is unsubstituted or substituted by one or more substituents independently selected from halogen, cyano, haloalkyl, haloalkoxy, alkoxy, alkyl, hydroxy, amino and alkylamino; preferably, Cy2 is unsubstituted or substituted by one or more substituents independently selected from halogen, cyano, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Alkoxy, C 1-6 Alkyl, hydroxyl, amino and C 1-6 alkylamino substituted with one or more substituents saturated or unsaturated 3-10 membered cycloalkyl, saturated or unsaturated 3-10 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, 6-10 membered aryl, or 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S; more preferably, Cy2 is unsubstituted or substituted by halogen, cyano, C 1-3 Halogenated alkyl, C 1-3Halogenated alkoxy, C 1-3 Alkoxy, C 1-3 Alkyl, hydroxyl, amino and C 1-3 substituted alkylamino group or substituted alkylamino group or substituted alkylamino group or substituted alkylamino group or substituted alkylamino group or substituted alkylamino group or substituted alkylamino group; ... 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 saturated or unsaturated 4-6 membered heterocycloalkyl containing 1, 2 or 3 N atoms or 5-6 membered heteroaryl containing 1, 2 or 3 N atoms substituted by haloalkoxy and amino groups;

[0017] R 15 and R 18 Each independently selected from CR aa and N;

[0018] W5 and W6 are each independently selected from CR aa and N;

[0019] R 14 、R 16 、R 17 and R 19 Each occurrence is independently selected from C(R aa )2, O, CO and NR aa ;

[0020] m13, m14, m15 and m16 are each independently selected from 0, 1, 2, 3, 4 and 5;

[0021] R 13 is selected from a single bond, a C1-C6 alkylene group, a C2-C6 alkenylene group, a C2-C6 alkynylene group, a 3- to 15-membered cycloalkylene group, a 3- to 15-membered heterocycloalkylene group, a 6- to 14-membered arylene group, and a 5- to 14-membered heteroarylene group, wherein the alkylene group, the alkenylene group, the alkynylene group, the cycloalkylene group, the heterocycloalkylene group, the arylene group, and the heteroarylene group are optionally substituted by one, two, or more R aa substituted; preferably, R 13is selected from a single bond, a C1-C6 alkylene, a C2-C6 alkenylene, a C2-C6 alkynylene, a 3- to 15-membered cycloalkylene, a 3- to 15-membered heterocycloalkylene, a 6- to 14-membered arylene, and a 5- to 14-membered heteroarylene, wherein the 3- to 15-membered cycloalkylene and the 3- to 15-membered heterocycloalkylene are each independently a monocyclic, condensed, bridged, or spirocyclic group, the 6- to 14-membered arylene and the 5- to 14-membered heteroarylene are each independently a monocyclic or condensed ring group, and the 3- to 15-membered heterocycloalkylene or the 5- to 14-membered heteroarylene each independently contains 1, 2, 3, 4, or 5 heteroatoms each independently selected from N, O, and S, and the alkylene, alkenylene, alkynylene, cycloalkylene, heterocycloalkylene, arylene, and heteroarylene are optionally substituted by one, two, or more R aa replaced by;

[0022] R aa Each occurrence is independently selected from H, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a hydroxyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, a -N(R g )2、Cyano、-C(O)-N(R g )2、-S(O)-N(R g )2、-S(O)2-N(R g )2、-OR g 、-SR g 、-OC(O)-R g 、-C(O)-R g 、-C(O)-OR g 、-S(O)-R g 、-S(O)2-R g 、-N(R g )-C(O)-R g 、-N(R g )-S(O)-R g 、-N(R g )-C(O)-N(R g )2、-N(R g )-S(O)2-R g and nitro, wherein optionally, the alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from halogen, oxo (=O), hydroxy, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R g )2、Cyano、-C(O)-N(R g )2、-S(O)-N(R g )2、-S(O)2-N(R g )2、-OR g、-SR g 、-OC(O)-R g 、-C(O)-R g 、-C(O)-OR g 、-S(O)-R g 、-S(O)2-R g 、-N(R g )-C(O)-R g 、-N(R g )-S(O)-R g 、-N(R g )-C(O)-N(R g )2、-N(R g )-S(O)2-R g and substituted by one or more substituents in nitro;

[0023] R g Each occurrence is independently selected from H, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, a -C(O)-alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, and a benzyloxycarbonyl group, wherein optionally, each of the alkyl groups, heteroalkyl groups, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group is independently substituted with one or more substituents selected from the group consisting of a halogen, an alkyl group, a heteroalkyl group, an alkoxy group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, a carboxyl group, an alkylamino group, -NH(CO)H, -NH(CO)alkyl, and an acetoxy group;

[0024] R 11 and R 12 are each independently selected from H, alkyl, a deuterium atom, F, Cl, Br, I, hydroxy, haloalkyl, hydroxyalkyl, alkoxy, and -C(=O)-alkyl;

[0025] The ULM is an E3 ubiquitin ligase binding moiety selected from any one of the following structures:

[0026] in:

[0027] W 1 and W 2 The same or different, each independently CR a R b or C(=O), and W 1 and W 2 At least one of them is C(=O);

[0028] G and Z are the same or different and are each independently selected from O, S, and Se;

[0029] R 3a 、R 3b 、R 3c , and R 3d each independently selected from H, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, a nitro group, a cyano group, an amino group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein each of the alkyl groups, the heteroalkyl group, the alkenyl group, the alkynyl group, the alkoxy group, the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group is independently optionally substituted with one or more substituents selected from the group consisting of halogen, an alkyl group, a heteroalkyl group, an alkoxy group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an alkenyl group, an alkynyl group,

[0030] R d 、R e 、R f 、R g 、R D 、R E 、R F , and R G Each occurrence is independently C(R m )2、NR m , C(=O), O or S;

[0031] W 3 and W 4 Each time it appears, it is independently CR m or N;

[0032] R t and R T Each occurrence is N or CR independently 2h ;

[0033] m1 and m2 are each independently an integer of 0, 1, 2, 3, 4, 5, or 6, and m1+m2≤6;

[0034] Each occurrence of m3 is independently an integer of 0, 1, 2, 3, 4, 5, 6, or 7, m4 is an integer of 1, 2, 3, 4, 5, 6, 7, or 8, and m3+m4≤8;

[0035] m5 and m6 are each independently an integer of 0, 1, 2, 3, 4, 5, 6, or 7, and m5 + m6 ≤ 7;

[0036] m7 and m8 are each independently an integer of 0, 1, 2, 3, 4, 5, 6, or 7, and m7+m8≤7;

[0037] R m each occurrence of which is independently selected from H, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, a nitro group, a cyano group, an amino group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein each of said alkyl groups, heteroalkyl groups, an alkenyl group, an alkynyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group is independently optionally substituted with one or more substituents selected from the group consisting of halogen, an alkyl group, a heteroalkyl group, an alkoxy group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an alkenyl group, an alkynyl group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, an aryl group, and a heteroaryl group;

[0038] R 2h selected from H, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, a nitro group, a cyano group, an amino group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, an alkenyl group, and an alkynyl group, wherein said alkyl group, heteroalkyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group are each independently optionally substituted with one or more substituents selected from the group consisting of a halogen, an alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, an aryl group, and a heteroaryl group;

[0039] R 1 is selected from H, halogen, deuterium atom, C1-C6 alkyl, C1-C6 alkoxy, hydroxy, cycloalkyl, C1-C6 haloalkyl, and hydroxyalkyl;

[0040] R 2 、R a , and R b are each independently selected from H, C1-C3 alkyl, C3-C6 cycloalkyl, and C1-C6 alkoxy; and

[0041] n is 0, 1, 2 or 3.

[0042] The second aspect of the present invention provides a compound having the structure of formula I:

[0043] PTM-L-ULM (Formula 1),

[0044] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate or polymorph thereof,

[0045] in:

[0046] The L is a bond or chemical linking moiety connecting the ULM and the PTM;

[0047] The PTM is a SMARCA2 / 4 binding moiety, which has the following structure:

[0048] in,

[0049] Cy1 is a saturated or unsaturated cycloalkyl group, a saturated or unsaturated heterocycloalkyl group containing a heteroatom selected from N, O and S, an aryl group, or a heteroaryl group containing a heteroatom selected from N, O and S, which is unsubstituted or substituted with one or more substituents each independently selected from halogen, cyano, haloalkyl, haloalkoxy, alkyl, hydroxy, amino and alkylamino;

[0050] R 10 Selected from

[0051] R 15 and R 18 Each independently selected from CR aa and N;

[0052] W5 and W6 are each independently selected from CR aa and N;

[0053] R 14 、R 16 、R 17 and R 19 Each occurrence is independently selected from C(R aa )2, O, CO and NR aa ;

[0054] m13, m14, m15 and m16 are each independently selected from 0, 1, 2, 3, 4 and 5;

[0055] R 13 is selected from a single bond, a C1-C6 alkylene group, a C2-C6 alkenylene group, a C2-C6 alkynylene group, a 3- to 15-membered cycloalkylene group, a 3- to 15-membered heterocycloalkylene group, a 6- to 14-membered arylene group, and a 5- to 14-membered heteroarylene group, wherein the alkylene group, the alkenylene group, the alkynylene group, the cycloalkylene group, the heterocycloalkylene group, the arylene group, and the heteroarylene group are optionally substituted by one, two, or more R aa substituted; preferably, R 13is selected from a single bond, a C1-C6 alkylene, a C2-C6 alkenylene, a C2-C6 alkynylene, a 3- to 15-membered cycloalkylene, a 3- to 15-membered heterocycloalkylene, a 6- to 14-membered arylene, and a 5- to 14-membered heteroarylene, wherein the 3- to 15-membered cycloalkylene and the 3- to 15-membered heterocycloalkylene are each independently a monocyclic, condensed, bridged, or spirocyclic group, the 6- to 14-membered arylene and the 5- to 14-membered heteroarylene are each independently a monocyclic or condensed ring group, and the 3- to 15-membered heterocycloalkylene or the 5- to 14-membered heteroarylene each independently contains 1, 2, 3, 4, or 5 heteroatoms each independently selected from N, O, and S, and optionally, the alkylene, alkenylene, alkynylene, cycloalkylene, heterocycloalkylene, arylene, and heteroarylene are substituted by one, two, or more R aa replaced by;

[0056] R aa Each occurrence is independently selected from H, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a hydroxyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, a -N(R g )2、Cyano、-C(O)-N(R g )2、-S(O)-N(R g )2、-S(O)2-N(R g )2、-OR g 、-SR g 、-OC(O)-R g 、-C(O)-R g 、-C(O)-OR g 、-S(O)-R g 、-S(O)2-R g 、-N(R g )-C(O)-R g 、-N(R g )-S(O)-R g 、-N(R g )-C(O)-N(R g )2、-N(R g )-S(O)2-R g and nitro, wherein optionally, the alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from halogen, oxo (=O), hydroxy, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R g )2、Cyano、-C(O)-N(R g )2、-S(O)-N(R g )2、-S(O)2-N(R g )2、-OR g、-SR g 、-OC(O)-R g 、-C(O)-R g 、-C(O)-OR g 、-S(O)-R g 、-S(O)2-R g 、-N(R g )-C(O)-R g 、-N(R g )-S(O)-R g 、-N(R g )-C(O)-N(R g )2、-N(R g )-S(O)2-R g and substituted by one or more substituents in nitro;

[0057] R g Each occurrence is independently selected from H, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, a -C(O)-alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, and a benzyloxycarbonyl group, wherein optionally, each of the alkyl groups, heteroalkyl groups, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group is independently substituted with one or more substituents selected from the group consisting of a halogen, an alkyl group, a heteroalkyl group, an alkoxy group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, a carboxyl group, an alkylamino group, -NH(CO)H, -NH(CO)alkyl, and an acetoxy group;

[0058] R 11 and R 12 are each independently selected from H, alkyl, a deuterium atom, F, Cl, Br, I, hydroxy, haloalkyl, hydroxyalkyl, alkoxy, and -C(=O)-alkyl;

[0059] The ULM is an E3 ubiquitin ligase binding moiety selected from any one of the following structures:

[0060] in:

[0061] W 1 and W 2 The same or different, each independently CR a R b or C(=O), and W 1 and W 2 At least one of them is C(=O);

[0062] G and Z are the same or different and are each independently selected from O, S, and Se;

[0063] R 3a 、R 3b 、R 3c , and R 3d each independently selected from H, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, a nitro group, a cyano group, an amino group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein each of the alkyl groups, the heteroalkyl group, the alkenyl group, the alkynyl group, the alkoxy group, the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group is independently optionally substituted with one or more substituents selected from the group consisting of halogen, an alkyl group, a heteroalkyl group, an alkoxy group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an alkenyl group, an alkynyl group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, an aryl group, and a heteroaryl group;

[0064] R d 、R e 、R f 、R g 、R D 、R E 、R F , and R G Each occurrence is independently C(R m )2、NR m , C(=O), O or S;

[0065] W 3 and W 4 Each time it appears, it is independently CR m or N;

[0066] R t and R T Each occurrence is N or CR independently 2h , and when R D 、R E 、R F , and R G All C(R m )2, R T CR 2h ;

[0067] m1 and m2 are each independently an integer of 0, 1, 2, 3, 4, 5, or 6, and m1+m2≤6;

[0068] Each occurrence of m3 is independently an integer of 0, 1, 2, 3, 4, 5, 6, or 7, m4 is an integer of 1, 2, 3, 4, 5, 6, 7, or 8, and m3+m4≤8;

[0069] m5 and m6 are each independently an integer of 0, 1, 2, 3, 4, 5, 6, or 7, and m5 + m6 ≤ 7;

[0070] m7 and m8 are each independently an integer of 0, 1, 2, 3, 4, 5, 6, or 7, and m7+m8≤7;

[0071] R m each occurrence of which is independently selected from H, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, a nitro group, a cyano group, an amino group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein each of said alkyl groups, heteroalkyl groups, an alkenyl group, an alkynyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group is independently optionally substituted with one or more substituents selected from the group consisting of halogen, an alkyl group, a heteroalkyl group, an alkoxy group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an alkenyl group, an alkynyl group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, an aryl group, and a heteroaryl group;

[0072] R 2h selected from H, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, a nitro group, a cyano group, an amino group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, an alkenyl group, and an alkynyl group, wherein said alkyl group, heteroalkyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group are each independently optionally substituted with one or more substituents selected from the group consisting of a halogen, an alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, an aryl group, and a heteroaryl group;

[0073] R 1 is selected from H, halogen, deuterium atom, C1-C6 alkyl, C1-C6 alkoxy, hydroxy, cycloalkyl, C1-C6 haloalkyl, and hydroxyalkyl;

[0074] R 2 、R a , and R b are each independently selected from H, C1-C3 alkyl, C3-C6 cycloalkyl, and C1-C6 alkoxy; and

[0075] n is 0, 1, 2 or 3.

[0076] In one embodiment, wherein:

[0077] Cy1 is unsubstituted or independently selected from halogen, cyano, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Alkyl, hydroxyl, amino and C 1-6 The alkylamino group is substituted with one or more substituents of a saturated or unsaturated 3-10 membered cycloalkyl group, a saturated or unsaturated 3-10 membered heterocycloalkyl group containing 1, 2 or 3 heteroatoms independently selected from N, O and S, a 6-10 membered aryl group, or a 5-10 membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O and S; preferably, Cy1 is a 6-10 membered aryl group or a 5-10 membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O and S, and the 6-10 membered aryl group and the 5-10 membered heteroaryl group are substituted with one or more substituents each independently selected from hydroxyl, halogen, C 1-6 Alkyl, amino and C 1-6 More preferably, Cy1 is phenyl or a 5-6 membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein the phenyl group and the 5-6 membered heteroaryl group are substituted by one or more hydroxyl, halogen, C 1-6 Alkyl, amino and C 1-6 Preferably, Cy1 is phenyl or a 5-6 membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O and S, and the phenyl and 5-6 membered heteroaryl groups are substituted by 1, 2, 3, 4 or 5 heteroatoms independently selected from hydroxyl, halogen, C 1-6 Alkyl, amino and C 1-6 Preferably, Cy1 is phenyl, and the phenyl group is substituted with 1, 2 or 3 hydroxyl groups; Preferably, Cy1 is and / or

[0078] R 13 is selected from a single bond, a 4-7 membered monocyclic cycloalkylene, a 6-8 membered monocyclic arylene, a 4-7 membered monocyclic heterocycloalkylene or a 5-7 membered monocyclic heteroarylene containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, a 6-12 membered cycloalkylene which is a fused, bridged or spiro ring, a 6-12 membered heterocycloalkylene which is a fused, bridged or spiro ring, and a 6-12 membered arylene which is a fused ring, and a 6-12 membered heteroarylene which is a fused ring and contains 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, wherein the cycloalkylene, heterocycloalkylene, arylene and heteroarylene are optionally substituted by 1, 2, 3, 4 or 5 R aa substituted; preferably, R 13a single bond, a 4-7 membered monocyclic cycloalkylene group, a 6-8 membered monocyclic arylene group, a 4-7 membered monocyclic heterocycloalkylene group or a 5-7 membered monocyclic heteroarylene group containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, a 6-12 membered cycloalkylene group which is a fused, bridged or spiro ring, a 6-12 membered heterocycloalkylene group which is a fused, bridged or spiro ring, a 6-12 membered arylene group which is a fused ring, and a 6-12 membered heteroarylene group which is a fused ring and contains 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, wherein the cycloalkylene group, heterocycloalkylene group, arylene group and heteroarylene group are optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from H, a deuterium atom, F, Cl, Br, I, a hydroxyl group, an amino group, C 1-3 Alkyl, C 1-3 Hydroxyalkyl and C 1-3 Substitution of the alkoxy group by a substituent; and / or

[0079] R aa Each occurrence is independently selected from H, a deuterium atom, a halogen, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a hydroxyl group, a C1-C6 hydroxyalkyl group, a -C(O)-C1-C6 alkyl group, a nitro group, a cyano group, a C3-C 10 Cycloalkyl, C3-C 10 Heterocyclic group, C6-C 10 Aryl, C5-C 10 Heteroaryl, -NHR g , benzyloxycarbonyl, carboxyl, -N(R g )2、-NH(CO)R g , acetoxy and -N(R g )2; preferably, R aa Each occurrence is independently selected from H, a deuterium atom, a halogen, a hydroxyl group, a C1-C3 alkyl group, a C1-C3 hydroxyalkyl group, a C1-C3 alkoxy group, a C1-C3 haloalkyl group, a C1-C3 haloalkoxy group, a cyano group, a nitro group, a benzyloxycarbonyl group, a carboxyl group, a -NH(CO)R g , acetoxy and -N(R g )2; preferably, R aa Each occurrence is independently selected from H, deuterium atoms, halogens, hydroxyl groups, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 haloalkoxy, cyano, nitro, carboxyl, and amino; and / or

[0080] R gEach occurrence is independently selected from H, a deuterium atom, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C1-C6 alkoxy group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a C1-C6 hydroxyalkyl group, a -C(O)-C1-C6 alkyl group, a C6-C 10 Aryl, C5-C 10 Heteroaryl, C3-C 15 Cycloalkyl and C3-C 15 Heterocycloalkyl; preferably, R g Each occurrence is independently selected from H, a deuterium atom, a C1-C3 alkyl group, a C1-C3 heteroalkyl group, a C1-C3 alkoxy group, a C2-C3 alkenyl group, a C2-C3 alkynyl group, a C1-C3 haloalkyl group, a C1-C3 haloalkoxy group, a C1-C3 hydroxyalkyl group, a -C(O)-C 1-3 Alkyl, phenyl, C5-C6 heteroaryl, C3-C6 cycloalkyl and C3-C6 heterocycloalkyl; and / or

[0081] R 11 and R 12 Each is independently selected from H, C1-C6 alkyl, deuterium atom, F, Cl, Br, I, hydroxyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy and -C(O)-C 1-6 Alkyl; preferably, R 11 and R 12 Each independently selected from H, C 1-3 Alkyl, deuterium atom, F, Cl, Br, I, hydroxyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy and -C(O)-C 1-6 Alkyl; More preferably, R 11 and R 12 Each independently selected from H, C 1-3 Alkyl, deuterium atom, F, Cl, Br, I and hydroxyl; further preferably, R 11 and R 12 are each independently H; and / or

[0082] W 1 and W 2 are the same or different, each independently CH2 or C(=O), and W 1 and W 2 At least one of them is C(=O); and / or

[0083] G and Z are both O; and / or

[0084] R D 、R E 、R Fand R G Each occurrence is independently C(R m )2 or O; preferably, R D 、R E 、R F and R G Each occurrence is independently C(R m )2 or O, where R D and R E Each time it appears, R D or R E At least one of them is O; and / or

[0085] R T Each occurrence is N or CR independently 2h Preferably, R T Each occurrence is independently N or CH, and R D and R E Each time it appears, R D or R E At least one of them is O; and / or

[0086] R 3a 、R 3b 、R 3c 、R 3d 、R 2h and R m Each occurrence is independently selected from H, a deuterium atom, a halogen, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a hydroxyl group, a C1-C6 hydroxyalkyl group, a nitro group, a cyano group, an amino group, a C3-C8 cycloalkyl group, a C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl groups are each independently optionally selected from halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C6 alkyl, C1 ... 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 is substituted by one or more substituents in the heteroaryl group; preferably, R 3a 、R 3b 、R3c 、R 3d 、R 2h and R m Each occurrence is independently selected from H, a deuterium atom, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl groups are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 More preferably, R 3a 、R 3b 、R 3c 、R 3d 、R 2h and R m Each occurrence is independently selected from H, deuterium atoms, F, Cl, Br, I, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy and hydroxy; further preferably, R 3a 、R 3b 、R 3c 、R 3d 、R 2h and R m Each occurrence is independently selected from H, deuterium atoms, F, Cl, Br, I, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Haloalkoxy and hydroxy; further preferably, R 3a 、R3b 、R 3c 、R 3d 、R 2h and R m Each occurrence is independently selected from H, F, Cl, Br, I, C 1-3 Alkyl, hydroxyl and C 1-3 Alkoxy; further preferably, R 3a 、R 3b 、R 3c 、R 3d 、R 2h and R m Each occurrence is independently selected from H, F, Cl, Br, I and C 1-3 Alkyl; and / or

[0087] m3 is independently an integer of 0, 1, 2, 3, or 4 at each occurrence, m4 is an integer of 1, 2, 3, 4, or 5, and m3+m4≤5; preferably, m3 is independently an integer of 0, 1, 2, or 3 at each occurrence, m4 is an integer of 1, 2, 3, or 4, and m3+m4=2, m3+m4=3, or m3+m4=4; and / or

[0088] m7 and m8 are each independently an integer of 0, 1, 2, 3 or 4, and m7+m8≤4; preferably, m7 and m8 are each independently an integer of 0, 1, 2 or 3, and m7+m8=2, or m7+m8=3; and / or

[0089] R 1 is selected from H, halogen, deuterium atom, C1-C3 alkyl, and hydroxyl; preferably, R 1 From H, deuterium atoms, F, Cl, Br, I, C1-C3 alkyl and hydroxyl groups; and / or

[0090] R 2 Selected from H, and C1-C3 alkyl; and / or

[0091] n is 0 or 1; preferably n is 1.

[0092] In one embodiment, the ULM is selected from the following structures:

[0093] in:

[0094] W 1 、W 2 、R T 、R 3a 、R 3b 、R 3c , and R 3d As defined above;

[0095] m3 is 1, m4 is 1; or m3 is 1, m4 is 2; or m3 is 2, m4 is 1; or m3 is 2, m4 is 2;

[0096] R D Each occurrence is independently C(R m )2 or O;

[0097] R E 、R F and R G Each occurrence is independently C(R m )2;

[0098] R m As defined above; and

[0099] m7, m11 and m12 are each independently an integer of 0, 1, 2, 3, 4, 5, or 6, and m7+m11+m12≤6; preferably, m7, m11 and m12 are each independently an integer of 0, 1, 2, or 3, and m7+m11+m12≤3; preferably, m7, m11 and m12 are each independently an integer of 0, 1, or 2, and m7+m11+m12=2 or m7+m11+m12=1;

[0100] Preferably:

[0101] R 3a 、R 3b 、R 3c , and R 3d Each occurrence is independently selected from H, a deuterium atom, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl groups are each independently optionally selected from deuterium atoms, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10More preferably, R 3a 、R 3b 、R 3c and R 3d are each independently selected from H, deuterium atoms, F, Cl, Br, I, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Haloalkoxy and hydroxy; further preferably, R 3a 、R 3b 、R 3c and R 3d Each independently selected from H, F, Cl, Br, I, C 1-3 Alkyl, hydroxyl and C 1-3 Alkoxy; further preferably, R 3a 、R 3b 、R 3c and R 3d Each independently selected from H, F, Cl, Br, I and C 1-3 Alkyl; W 1 and W 2 are the same or different, each independently CH2 or C(=O), and W 1 and W 2 At least one of them is C(=O);

[0102] m3 is 1 or 2, m4 is 1 or 2; preferably: m3 is 1, m4 is 1; or m3 is 1, m4 is 2; or m3 is 2, m4 is 1; or m3 is 2, m4 is 2;

[0103] R T Each occurrence is N or CR independently 2h , and when R D 、R E 、R F , and R G All C(R m )2, R T CR 2h ;

[0104] R 2h Selected from H, deuterium atoms, F, Cl, Br, I, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 haloalkoxy and hydroxy; more preferably, R 2h Selected from H, F, Cl, Br, I, C 1-3 Alkyl, hydroxyl and C1-3 Alkoxy; further preferably, R 2h selected from H, F, Cl, Br, I and C 1-3 alkyl;

[0105] R D Each occurrence is independently C(R m )2 or O;

[0106] R E 、R F and R G Each occurrence is independently C(R m )2;

[0107] R m Each occurrence is independently selected from H, deuterium atoms, F, Cl, Br, I, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Haloalkoxy and hydroxy; further preferably, R m Each occurrence is independently selected from H, F, Cl, Br, I, C 1-3 Alkyl, hydroxyl and C 1-3 Alkoxy; further preferably, R m Each occurrence is independently selected from H, F, Cl, Br, I and C 1-3 alkyl; and

[0108] m7, m11 and m12 are each independently an integer of 0, 1, 2, 3, 4, 5, or 6 when they appear, and m7+m11+m12≤6; preferably, m7, m11 and m12 are each independently an integer of 0, 1, 2, or 3 when they appear, and m7+m11+m12≤3; preferably, m7, m11 and m12 are each independently an integer of 0, 1 or 2 when they appear, and m7+m11+m12=2 or m7+m11+m12=1.

[0109] In one embodiment, the ULM is selected from the following structures:

[0110] in:

[0111] W 1 、W 2 、R T 、R 3a 、R 3b 、R 3c , and R 3d As defined above;

[0112] m3 is 1, m4 is 1; or m3 is 1, m4 is 2; or m3 is 2, m4 is 1; or m3 is 2, m4 is 2;

[0113] R D Each occurrence is independently C(R m )2 or O, R E 、R F and R G Each occurrence is independently C(R m )2; and

[0114] R m As defined above;

[0115] Preferably:

[0116] R 3a 、R 3b 、R 3c , and R 3d Each occurrence is independently selected from H, F, Cl, Br, I, C1-C3 alkyl, and C1-C3 alkoxy;

[0117] m3 is 1, m4 is 1; or m3 is 1, m4 is 2; or m3 is 2, m4 is 1; or m3 is 2, m4 is 2;

[0118] W 1 and W 2 are the same or different, each independently CH2 or C(=O), and W 1 and W 2 At least one of them is C(=O);

[0119] R D Each occurrence is independently C(R m )2 or O;

[0120] R E 、R F and R G Each occurrence is independently C(R m )2;

[0121] R m Each occurrence is independently selected from H, deuterium atoms, halogen, C1-C3 alkyl, and C1-C3 alkoxy; preferably, R m Each occurrence is independently selected from H, a deuterium atom, F, Cl, Br, I, C1-C3 alkyl, and C1-C3 alkoxy;

[0122] R T Each occurrence is N or CR independently 2h ;and

[0123] R2h is selected from H, a deuterium atom, F, Cl, Br, I, a C1-C3 alkyl group, a C1-C3 haloalkyl group, a C1-C3 alkoxy group, and a C1-C3 haloalkoxy group.

[0124] In one embodiment, wherein:

[0125] W 1 and W 2 are the same or different, each independently CH2 or C(=O), and W 1 and W 2 At least one of them is C(=O); and / or

[0126] R 3a 、R 3b 、R 3c , and R 3d Each is independently selected from H, a deuterium atom, a halogen, a C1-C6 alkyl group, a heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a hydroxyl group, a C1-C6 hydroxyalkyl group, a nitro group, a cyano group, an amino group, a C3-C8 cycloalkyl group, a C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl groups are each independently optionally selected from halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C6 alkyl, C1 ... 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 The heteroaryl group is substituted by one or more substituents, preferably R 3a 、R 3b 、R 3c , and R 3d Each is independently selected from H, a deuterium atom, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10Heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl groups are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 One or more substituents in the heteroaryl group are substituted; preferably R 3a and R 3b are each independently selected from H, a deuterium atom, a halogen, a C1-C3 alkyl group, and a C1-C3 alkoxy group, preferably R 3c and R 3d are each independently selected from H, a deuterium atom, F, Cl, Br, I, a C1-C3 alkyl group, and a C1-C3 alkoxy group; and / or

[0127] R d 、R e 、R f and R g Each occurrence is independently C(R m )2 or 0; and / or

[0128] R D 、R E 、R F and R G Each occurrence is independently C(R m )2 or 0; and / or

[0129] W 3 and W 4 is CH; and / or

[0130] R 2h selected from H, deuterium atoms, halogen, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxy, C1-C6 hydroxyalkyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl, and C5-C 10 Heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl groups are each independently optionally selected from halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C6 alkyl, C1 ... 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 One or more substituents in the heteroaryl group are substituted; preferably R 2h selected from H, deuterium atoms, F, Cl, Br, I, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl, and C5-C 10 Heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl groups are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 One or more substituents in the heteroaryl group are substituted; preferably R 2h is selected from H, deuterium atoms, halogen, C1-C3 alkyl, and C1-C3 alkoxy; preferably R 2h is selected from H, a deuterium atom, F, Cl, Br, I, a C1-C3 alkyl group, a C1-C3 haloalkyl group, a C1-C3 alkoxy group, and a C1-C3 haloalkoxy group; and / or

[0131] m1 and m2 are each independently an integer of 0, 1, 2, or 3, and m1+m2≤3, preferably m1+m2=1 or m1+m2=2; and / or

[0132] m3 is independently an integer of 0, 1, 2, 3, or 4 at each occurrence, m4 is an integer of 1, 2, 3, 4, or 5, and m3+m4≤5, preferably m3+m4=2, m3+m4=3, or m3+m4=4; and / or

[0133] m5 and m6 are each independently an integer of 0, 1, 2, 3 or 4, and m5+m6≤4, preferably m5+m6=2 or m5+m6=3; and / or

[0134] m7 and m8 are each independently an integer of 0, 1, 2, 3 or 4, and m7+m8≤4, preferably m7+m8=2, or m7+m8=3; and / or;

[0135] R m Each occurrence is independently selected from H, a deuterium atom, a halogen, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a hydroxyl group, a C1-C6 hydroxyalkyl group, a nitro group, a cyano group, an amino group, a C3-C8 cycloalkyl group, a C4-C 10 Heterocyclic, aryl and heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl groups are each independently optionally selected from halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C6 alkyl, C1 ... 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 One or more substituents in the heteroaryl group are substituted; preferably R m Each occurrence is independently selected from H, a deuterium atom, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl groups are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C10 Aryl and C5-C 10 One or more substituents in the heteroaryl group are substituted; preferably R m Each occurrence is independently selected from H, a deuterium atom, a halogen, a C1-C3 alkyl group, and a C1-C3 alkoxy group; and / or

[0136] R 1 is selected from H, halogen, C1-C3 alkyl, and hydroxyl; R 1 Preferably selected from H, F, Cl, Br, I, C1-C3 alkyl and hydroxyl; and / or

[0137] R 2 Selected from H, and C1-C3 alkyl; and / or

[0138] n is 0 or 1.

[0139] In one embodiment, the ULM is selected from the following structures:

[0140] in:

[0141] Preferably, R 3a 、R 3b 、R 3c , and R 3d Each is independently selected from H, a deuterium atom, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl groups are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 is substituted by one or more substituents in a heteroaryl group;

[0142] and

[0143] m7, m11 and m12 are each independently an integer of 0, 1, 2, 3, 4, 5, or 6 when they appear, and m7+m11+m12≤6; preferably, m7, m11 and m12 are each independently an integer of 0, 1, 2, or 3 when they appear, and m7+m11+m12≤3, preferably m7+m11+m12=2 or m7+m11+m12=1.

[0144] In one embodiment, the ULM is selected from the following structures:

[0145] Among them, R 1D 、R 1E Each occurrence is independently C(R m )2; R T N or CR 2h And when R F and R G All C(R m )2, R T CR 2h ;

[0146] Preferably:

[0147] R 3a 、R 3b 、R 3c 、R 3d Each is independently selected from H, a deuterium atom, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl groups are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 is substituted by one or more substituents in heteroaryl; and / or

[0148] m3 is independently an integer of 0, 1, 2, 3, or 4 at each occurrence, m4 is an integer of 1, 2, 3, 4, or 5, and m3+m4≤5, preferably m3+m4=2, m3+m4=3, or m3+m4=4; and / or

[0149] W 1 and W 2 are the same or different, each independently CH2 or C(=O), and W 1 and W 2 At least one of them is C(=O); and / or

[0150] R 1D 、R 1E 、R F , and R G Each occurrence is independently C(R m )2,R m Each occurrence is independently selected from H, a deuterium atom, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl groups are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 is substituted by one or more substituents in heteroaryl; and / or

[0151] R T Each time it appears, it is independently CR 2h , R 2h independently selected from H, deuterium atoms, F, Cl, Br, I, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl, and C5-C 10Heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl groups are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 The heteroaryl group is substituted by one or more substituents.

[0152] In one embodiment, the ULM is selected from the following structures:

[0153] In one embodiment, wherein L is a bond or is -(B L ) q -,

[0154] Among them B L One or more selected from the following structures: -O-, -S-, -S(O)-, -S(O)2-, -CH2-, -C(O)-, -NH-,

[0155] q is 1, 2, 3, 4, 5, 6, 7 or 8; preferably, q is 1, 2, 3, 4, 5 or 6; and

[0156] For the connection point.

[0157] In one embodiment, L is selected from the following structures:

[0158] Covalent bond, -C(O)-, -C(O)-(CH2) j -、-(CH2) j -、-(CH2) p -NH-(CH2) s -、-(CH2) y -NH-(CH2) j -NH-(CH2) s -、-(CH2)p -C(O)-(CH2) s -、-(CH2) p -O-(CH2) s -、-(CH2) y -C(O)-(CH2) j -C(O)-(CH2) s -、-(CH2) y -O-(CH2) j -O-(CH2) s -、-(CH2) y -O-(CH2) j -CO-(CH2) s -、-(CH2) y -C(O)-(CH2) j -O-(CH2) s -、-(CH2) p -NH-(CH2) y -O-(CH2) j -CO-(CH2) s -、-(CH2) y -C(O)-(CH2) j -O-(CH2) s -NH-(CH2) p -、 j, p, s and y are each independently selected from 1, 2, 3 and 4;

[0159] Preferably, L is selected from the following structures: covalent bond, -C(O)-, -C(O)-CH2-, -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -(CH2)7-, -(CH2)8-, -NH-CH2-, -NH-(CH2)2-, -NH-(CH2)3-, -NH-(CH2)4-, -NH-(CH2)5-, -NH-(CH2)6-, -NH-(CH2)7-, -NH-(CH2)8-, -C(O)-NH-,

[0160] In one embodiment, it is characterized in that

[0161] R 13 is a single bond, or R 13 Selected from one, two or more R aa Substituted with the following groups:

[0162] wherein m, n1, m' and n' are each independently 1 or 2;

[0163] R aa Each occurrence is independently selected from H, a deuterium atom, a halogen, a hydroxyl group, a C1-C3 alkyl group, a C1-C3 hydroxyalkyl group, a C1-C3 alkoxy group, a C1-C3 haloalkyl group, a C1-C6 haloalkoxy group, a cyano group, a nitro group, a carboxyl group, and an amino group;

[0164] Preferably, R 13 is a single bond, or, selected from one, two or more R aa Substituted with the following groups:

[0165] wherein m, n1, m' and n' are each independently selected from 1 and 2;

[0166] R aa Each occurrence is independently selected from H, deuterium atoms, F, Cl, Br, I, hydroxyl, amino and C 1-3 alkoxy;

[0167] More preferably, R 13 is a single bond, or, selected from 1, 2, 3, 4 or 5 R aa Substituted with the following groups:

[0168] wherein m, n1, m' and n' are each independently selected from 1 and 2 at each occurrence;

[0169] R aa Each occurrence is independently selected from H, deuterium atoms, F, Cl, Br, I, hydroxyl, amino and C 1-3 Alkoxy.

[0170] In one embodiment, the PTM is selected from the following structures:

[0171] In one embodiment, the compound is selected from:

[0172] The third aspect of the present invention provides a pharmaceutical composition comprising an effective amount of the compound as described above or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0173] The fourth aspect of the present invention provides the use of the compound as described above, or the pharmaceutical composition as described above, in the preparation of a medicament for treating or preventing a disease or condition mediated by SMARCA2 / 4; preferably, the disease or condition is cancer, preferably, the cancer is lung cancer or cervical cancer.

[0174] The fifth aspect of the present invention provides the compound as described above, or the pharmaceutical composition as described above, for treating or preventing a disease or condition mediated by SMARCA2 / 4; preferably, the condition is cancer; preferably, the cancer is lung cancer or cervical cancer.

[0175] In a sixth aspect, the present invention provides a method for treating or preventing a disease or condition mediated by SMARCA2 / 4, comprising administering to a subject in need thereof an effective amount of a compound as described above, or a pharmaceutical composition as described above; preferably, the condition is cancer; preferably, the cancer is lung cancer or cervical cancer. DETAILED DESCRIPTION

[0176] The present disclosure is described in detail below by way of specific embodiments, but this does not imply any adverse limitations on the present disclosure. Various specific embodiments of the present disclosure have been described herein in detail, and it will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present disclosure without departing from the spirit and scope of the present disclosure.

[0177] Terms and Definitions

[0178] The term "alkyl" as used herein refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms, and more preferably an 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, 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, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched-chain isomers thereof. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples of which 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, and the like. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available attachment point. The substituent is preferably independently selected from one or more substituents selected from H atoms, D atoms, halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

[0179] SMARCA2 / 4 refers to either SMARCA2 or SMARCA4 protein.

[0180] The term "heteroalkyl" refers to an alkyl group in which one or more -CH2- are replaced by heteroatoms selected from NH, O and S or one or more -CH- are replaced by N atoms; wherein the alkyl group is as defined above; the heteroalkyl group may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, and the substituents are preferably independently selected from one or more substituents selected from H atoms, D atoms, halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

[0181] The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), where alkyl and cycloalkyl are as defined herein. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy. Alkoxy groups may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from H atoms, D atoms, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

[0182] The term "alkenyl" refers to an alkyl compound containing a carbon-carbon double bond in the molecule, wherein alkyl is as defined above. Alkenyl groups may be substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from hydrogen, alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

[0183] The term "alkynyl" refers to an alkyl compound containing a carbon-carbon triple bond, wherein alkyl is as defined above. Alkyl groups may be substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from hydrogen, alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

[0184] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic, bicyclic or more cyclic hydrocarbon substituent, including, for example, fused rings, bridged rings or spirocyclic groups. The cycloalkyl ring can contain 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 (e.g., 3, 4, 5, 6, 7 and 8) carbon atoms, more preferably 4 to 7 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl etc.

[0185] The cycloalkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available attachment point. The substituent is preferably independently selected from one or more substituents selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

[0186] The term "heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is a heteroatom selected from nitrogen, oxygen or S(O)m (wherein m is an integer from 0 to 2), but excluding the ring portion of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) ring atoms, of which 1 to 4 (e.g., 1, 2, 3 and 4) are heteroatoms; more preferably, it contains 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; more preferably, it contains 3 to 6 ring atoms, of which 1 to 3 are heteroatoms; and most preferably, it contains 5 or 6 ring atoms, of which 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocycloalkyl groups include pyrrolidinyl, tetrahydropyranyl, 1,2.3.6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like.

[0187] Heterocycloalkyl may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment, and the substituent is preferably independently and optionally selected from one or more substituents of hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic is a ring that shares adjacent carbon atoms) group having a conjugated π electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl ring includes an aryl ring as described above fused to a heteroaryl, heterocycloalkyl, or cycloalkyl ring, wherein the ring connected to the parent structure is the aryl ring. The aryl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available attachment point. The substituent is preferably independently selected from one or more substituents selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

[0188] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic is a ring that shares adjacent pairs of carbon atoms) group with a conjugated π electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl ring includes an aryl ring as described above fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is the aryl ring. The aryl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituent is preferably independently selected from one or more substituents selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0189] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 10-membered (e.g., 5, 6, 7, 8, 9, or 10-membered), more preferably 5- or 6-membered, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, and the like. The heteroaryl ring includes a heteroaryl group as described above fused to an aryl, heterocycloalkyl, or cycloalkyl ring, wherein the ring attached to the parent structure is the heteroaryl ring. Heteroaryl groups may be substituted or unsubstituted. When substituted, the substituents may be substituted at any available point of attachment, and the substituents are preferably independently selected from one or more substituents selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0190] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.

[0191] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0192] The term "amino" refers to -NH2.

[0193] The term "cyano" refers to -CN.

[0194] The term "nitro" refers to -NO2.

[0195] The term "ubiquitin ligase" refers to a family of proteins that facilitate the transfer of ubiquitin to specific substrate proteins, targeting them for degradation. For example, cerebellin is an E3 ubiquitin ligase protein that, alone or in combination with an E2 ubiquitin conjugating enzyme, attaches ubiquitin to a lysine on a target protein and subsequently targets the specific protein substrate for degradation via the proteasome. Thus, E3 ubiquitin ligases, alone or in complex with an E2 ubiquitin conjugating enzyme, are responsible for the transfer of ubiquitin to target proteins. Generally speaking, ubiquitin ligases participate in polyubiquitination, where a second ubiquitin is attached to a first ubiquitin, a third ubiquitin to a second ubiquitin, and so on. Polyubiquitination marks proteins for degradation via the proteasome. However, some ubiquitination events are limited to monoubiquitination, in which only a single ubiquitin is added to a substrate molecule by a ubiquitin ligase. Monoubiquitinated proteins are not targeted to the proteasome for degradation but may instead alter their cellular location or function, for example, through binding to other proteins with domains capable of binding ubiquitin. To complicate matters further, different lysines on ubiquitin can be targeted by the E3 for chain preparation. The most common lysine is Lys48 in the ubiquitin chain. This is the lysine used to make polyubiquitin, which is recognized by the proteasome.

[0196] The term "target protein" refers to proteins and peptides with any biological function or activity, including structural, regulatory, hormonal, enzymatic, genetic, immune, contractile, storage, transport, and signal transduction. In some embodiments, target proteins include structural proteins, receptors, enzymes, cell surface proteins, proteins associated with the integral functions of the cell, including proteins involved in catalytic activity, aromatase activity, motor activity, helicase activity, metabolic processes (anabolism and catabolism), antioxidant activity, proteolysis, biosynthesis, proteins with kinase activity, oxidoreductase activity, transferase activity, hydrolase activity, lyase activity, isomerase activity, ligase activity, enzyme regulator activity, signal transducer activity, structural molecule activity, binding activity (protein, lipid carbohydrate), receptor activity, cell motility, membrane fusion, cell communication, regulation of biological processes, development, cell differentiation, stimulus response, behavioral proteins, cell adhesion proteins, proteins involved in cell death, proteins involved in transport (including protein transport activity, nuclear transport, ion transport activity, channel transport activity, carrier activity), permease activity, secretion activity, electron transport activity, pathogenesis, chaperone regulator activity, nucleic acid binding activity, transcription regulator activity, extracellular organization and biogenesis activity, translation regulator activity. Such proteins include proteins from eukaryotic and prokaryotic organisms, including microorganisms, viruses, fungi, and parasites, among many others, including humans, microorganisms, viruses, fungi, and parasites that are targets for drug therapy, other animals including domestic animals, microorganisms that are targets for testing antibiotics and other antimicrobials, plants, and even viruses, among many others.

[0197] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and where it does not. For example, "optionally substituted cyclopropyl" means that the cyclopropyl group may but need not be substituted, and that the description includes instances where the cyclopropyl group is substituted and instances where the cyclopropyl group is not substituted.

[0198] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in a group are replaced independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and a person skilled in the art can determine (by experiment or theory) the possible or impossible substitutions without undue effort.

[0199] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present disclosure that are safe and effective when used in mammals and have the desired biological activity.

[0200] Example

[0201] The following examples are directed to the intermediate compounds and final products identified in the specification and synthesis schemes. The following examples are used to describe the preparation of the compounds of the present invention in detail, but the chemical reactions described are disclosed based on their general applicability to the preparation of the compounds of the present invention. Sometimes, the reactions may not be applicable to each compound within the scope of the present invention as described. Those skilled in the art will readily recognize compounds for which this will occur. In these cases, the reactions can be successfully carried out by conventional modifications known to those skilled in the art. In all preparation methods, all starting materials are known or can be readily prepared using known starting materials.

[0202] The starting materials, chemical reagents, and solvents used in this disclosure are all commercially available and were purchased from companies such as Anage Chemical, Shanghai Bid Pharmaceutical, Beijing Inocare, Jiangsu Aikon, Sinopharm Group, Beijing Bailingwei, and Yunnan Xinlanjing.

[0203] The structures of the compounds synthesized in this application were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS).

[0204] Nuclear magnetic resonance (NMR) measurements were performed using a Bruker AVANCE-400 / 600 NMR spectrometer. Deuterated solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), and tetramethylsilane (TMS) was used as the internal standard.

[0205] Mass spectrometry (MS) was performed by Waters Acquity Plus device implementation.

[0206] High performance liquid chromatography (HPLC) was performed using a Waters 2489 instrument.

[0207] The medium-pressure flash preparative chromatograph was COMBIFLASH NEXTGEN 300+.

[0208] As the thin layer chromatography silica gel plate, Silica gel 60 thin layer chromatography silica gel plate (aluminum plate, containing fluorescence) was used.

[0209] The silica gel (100-200 mesh, 200-300 mesh) used in silica gel thin layer chromatography was purchased from Inokai.

[0210] The reaction progress in the examples was detected by thin layer chromatography (TLC), and the developing solvent used for monitoring the reaction and the eluent used for purifying the compound by column chromatography included: petroleum ether / ethyl acetate system and dichloromethane / methanol system.

[0211] Example 1. Synthesis of Intermediate 1

[0212] 7'-(2,6-dioxapiperidin-3-yl)-3',4'-dihydro-6'H-spiro[piperidin-4,2'-pyrano[2,3-f]isoindole]6',8'(7'H)-dione

[0213] Step 1: Dimethyl 4-hydroxyphthalate (Intermediate 1b)

[0214] To a solution of intermediate 1a (30 g, 164.7 mmol) in methanol (300 mL) was slowly added concentrated sulfuric acid (45 mL). The reaction mixture was stirred at 65°C for 5 hours. The resulting mixture was poured into ice water, filtered, washed with water, and dried in vacuo to afford intermediate 1b (30.0 g, 87%) as a white solid.

[0215] 1 H NMR (600MHz, DMSO-d6) δ10.66(s,1H),7.70(d,J=8.5Hz,1H),6.96(dd,J=8.5,2.5Hz,1H),6.93(d,J=2.5Hz,1H),3.79(s,3H),3.76(s,3H)

[0216] LC-MS(ESI):[MH] + =209.22

[0217] Step 2: Dimethyl 4-hydroxy-5-iodophthalate (Intermediate 1c)

[0218] To a solution of intermediate 1b (20.0 g, 95.2 mmol) in trifluoroacetic acid (60 mL) was slowly added N-iodosuccinimide (23.6 g, 104.7 mmol). The reaction was stirred at room temperature overnight. The resulting mixture was concentrated under vacuum and purified by C18 reverse phase column to give intermediate 1c (16.3 g, 51%) as a white solid.

[0219] 1 H NMR(600MHz,DMSO-d6)δ11.59(s,1H),8.11(s,1H),7.02(s,1H),3.79(s,3H),3.77(s,3H)

[0220] LC-MS(ESI):[MH] + =335.06

[0221] Step 3: Dimethyl 4-acetyl-5-hydroxyphthalate (Intermediate 1d)

[0222] Under nitrogen, intermediate 1c (15.0 g, 44.6 mmol), tributyl(1-ethoxyethylene)tin (32.2 g, 89.3 mmol), and bis(triphenylphosphine)palladium(II) dichloride (3.1 g, 4.5 mmol) were dissolved in tetrahydrofuran (75 mL), heated to 65°C, and stirred for 15 h. After the reaction, 1 M dilute hydrochloric acid solution was added to the system and stirred for 0.5 h, followed by potassium fluoride. The mixture was filtered and the filtrate was concentrated to obtain the crude product. The crude product was purified by column chromatography (PE:EA = 0-40%) to obtain intermediate 1d (9.8 g, 87%) as a yellow oil.

[0223] 1 H NMR (400MHz, CDCl3) δ12.65(s,1H),8.37(s,1H),7.12(s,1H),3.96(s,3H),3.92(s,3H),2.73(s,3H)

[0224] LC-MS(ESI):[M+H] + =253.15

[0225] Step 4: 1'-(tert-butyl) 6,7-dimethyl 4-oxaspiro[chroman-2,4'-piperidine]-1',6,7-tricarboxylate (Intermediate 1e)

[0226] Intermediate 1d (5.0 g, 19.8 mmol), N-(tert-butoxycarbonyl)-4-piperidone (1.4 g, 19.8 mmol), and tetrahydropyrrole (4.0 g, 19.8 mmol) were dissolved in methanol (50 mL), and the mixture was stirred at 70°C overnight. The mixture was dried and purified by column chromatography (PE:EA = 0-35%) to give Intermediate 1e (6.9 g, 80%) as a yellow oil.

[0227] 1 H NMR(600MHz,DMSO-d6)δ8.17(s,1H),7.36(s,1H),3.83(s,3H),3.82(s,3H),3.73(s,2H),3.1 3(d,J=40.7Hz,2H),2.96(s,2H),1.95–1.86(m,2H),1.66(dq,J=13.2,5.0Hz,2H),1.40(s,9H)

[0228] LC-MS(ESI):[MH] + =432.22

[0229] Step 5: 1'-(tert-butyl) 6,7-dimethyl 4-hydroxyspiro[chroman-2,4'-piperidine]-1',6,7-tricarboxylate (Intermediate 1f)

[0230] To a solution of intermediate 1e (5.0 g, 11.5 mmol) in methanol (50 mL) was added sodium borohydride (0.7 g, 17.3 mmol) in an ice bath. The reaction was stirred at 70°C overnight. The resulting mixture was concentrated under vacuum and purified by column chromatography (PE:EA = 0-50%) to afford intermediate 1f (3.3 g, 66%) as a white solid.

[0231] 1 H NMR (600MHz, DMSO-d6) δ7.92(s,1H),7.02(s,1H),5.73(d,J=6.2Hz,1H),4.74(dt,J=9.3,6.1Hz,1H),3.79(s,6H),3.74–3.64(m,2H),3.06(s ,2H),2.18(dd,J=13.6,6.1Hz,1H),1.78(ddt,J=23.0,13.5,6.3Hz,2H),1.72–1.64(m,2H),1.57(ddd,J=13.7,11.3,4.7Hz,1H),1.40(s,9H)

[0232] LC-MS(ESI):[MH] + =464.39

[0233] Step 6: Dimethylspiro[chromene-2,4'-piperidine]-6,7-dicarboxylate (intermediate 1g)

[0234] Intermediate 1f (3.0 g, 6.9 mmol) and triethylsilane (3.2 g, 27.6 mmol) were dissolved in trifluoroacetic acid (30 mL), and the mixture was stirred overnight at 80° C. The resulting mixture was concentrated under vacuum and purified by C18 reverse phase column to give Intermediate 1g (1.8 g, 83%) as a colorless oil.

[0235] 1 H NMR (400MHz, CDCl3) δ7.53(s,1H),7.11(s,1H),6.51(d,J=9.9Hz,1H),5.72(d,J=9.8Hz,1H),4.6 6(s,2H),3.93(s,3H),3.89(s,3H),3.42–3.31(m,4H),2.23(d,J=14.6Hz,2H),2.12–2.02(m,2H)

[0236] LC-MS(ESI):[M+H] + =318.25

[0237] Step 7: Dimethylspiro[chroman-2,4'-piperidine]-6,7-dicarboxylate (Intermediate 1h)

[0238] Intermediate 1g (1.6g, 5.0mmol) was dissolved in methanol (20mL) and palladium on carbon (0.2g) was added. The reaction was stirred at room temperature under hydrogen atmosphere overnight. The mixture was filtered and dried to give Intermediate 1h (1.3g, 81%) as a yellow oil.

[0239] 1 H NMR (400MHz, CDCl3) δ7.61(s,1H),7.14(s,1H),3.93(s,3H),3.89(s,3H),3.35(d,J=6 .2Hz,4H),3.30(s,2H),2.87(t,J=6.8Hz,2H),2.05–2.00(m,2H),1.95(t,J=6.7Hz,2H)

[0240] LC-MS(ESI):[M+H] + =320.28

[0241] Step 8: Spiro[chroman-2,4'-piperidine]-6,7-dicarboxylic acid (Intermediate 1i)

[0242] Intermediate 1h (1.5 g, 4.7 mmol) was dissolved in a suspension of methanol and water, and lithium hydroxide (1.7 g, 70.5 mmol) was added. The reaction was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo. The crude product was used directly in the next step without further purification.

[0243] LC-MS(ESI):[M+H] + =292.21

[0244] Step 9: 7'-(2,6-dioxapiperidin-3-yl)-3',4'-dihydro-6'H-spiro[piperidin-4,2'-pyrano[2,3-f]isoindole]6',8'(7'H)-dione (Intermediate 1)

[0245] Intermediate 1i (1.3 g, 7.7 mmol) was dissolved in acetic acid (15 mL), and 3-aminopiperidine-2,6-dione hydrochloride (1.52 g, 9.2 mmol) and sodium acetate (2.1 g, 15.5 mmol) were added. The reaction was stirred at 110°C for 4 hours. After completion of the reaction, the mixture was purified by reverse phase column chromatography to obtain Intermediate 1 (1.6 g, 81%) as a white solid.

[0246] 1H NMR (400MHz, DMSO-d6) δ11.10(s,1H),7.74(s,1H),7.38(s,1H),5.10(dd,J=12.9,5.4Hz,1H),3.28–3.14(m,4H),2.9 5(t,J=6.8Hz,2H),2.91–2.83(m,1H),2.65–2.53(m,2H),2.07–1.99(m,1H),1.93(q,J=6.2Hz,4H),1.88–1.78(m,2H).

[0247] LC-MS(ESI):[M+H] + =384.32.

[0248] Example 2, Synthesis of Intermediate 2

[0249] 7-(2,6-dioxapiperidin-3-yl)-3,4-dihydro-6H-spiro[pyrano[2,3-f]isoindole-2,3'-pyrrolidine]-6,8(7H)-dione

[0250] Synthesis scheme:

[0251] Step 1: 1'-(tert-butyl) 6,7-dimethyl 4-oxaspiro[chroman-2,3'-pyrrolidine]-1',6,7-tricarboxylate (Intermediate 2a)

[0252] Intermediate 1d was prepared by referring to steps 1 to 3 of Example 1. Intermediate 1d (5.0 g, 19.8 mmol), 1-tert-butoxycarbonyl-3-pyrrolidone (1.4 g, 19.8 mmol), and tetrahydropyrrole (4.0 g, 19.8 mmol) were dissolved in methanol (50 mL), and the mixture was stirred at 70°C overnight. The mixture was dried and purified by column chromatography (PE:EA = 0-35%) to give Intermediate 2a (5.0 g, 60%) as a yellow oil.

[0253] 1 H NMR (400MHz, CDCl3) δ8.44(s,1H),7.18(s,1H),3.95(s,3H),3.91(s,3H),3.89–3.83(m,1H),3.76–3.64(m,1H),3.62–3.50( m,1H),3.40(dd,J=17.4,12.4Hz,1H),3.06–2.86(m,2H),2.36–2.25(m,1H),1.97(ddd,J=13.5,10.4,9.0Hz,1H),1.47(d,9H)

[0254] LC-MS(ESI):[MH] + =418.40

[0255] Step 2: 1'-(tert-Butyl)6,7-dimethyl 4-hydroxyspiro[chroman-2,3'-pyrrolidine]-6,7-dicarboxylate (Intermediate 2b)

[0256] Under ice bath conditions, sodium borohydride (0.7 g, 17.9 mmol) was added to a solution of intermediate 2a (5.0 g, 11.5 mmol) in methanol (50 mL). The reaction was stirred at 70°C overnight. The resulting mixture was concentrated under vacuum and purified by column chromatography (PE:EA = 0-50%) to give intermediate 2b (5.0 g, 99%) as a white solid. The resulting mixture was used directly in the next reaction.

[0257] LC-MS(ESI):[M+Na] + =444.33

[0258] Step 3: Methyl spiro[chromene-2,3'-pyrrolidine]-6,7-dicarboxylate (Intermediate 2c)

[0259] Intermediate 2b (3.0 g, 7.1 mmol) and triethylsilane (3.3 g, 28.5 mmol) were dissolved in trifluoroacetic acid (30 mL), and the mixture was stirred at 80°C overnight. The resulting mixture was concentrated under vacuum and purified by C18 reverse phase column to give Intermediate 2c (1.1 g, 51%) as a colorless oil.

[0260] 1 H NMR (600MHz, CDCl3) δ7.53(s,1H),7.09(s,1H),6.61(d,J=9.8Hz,1H),5.79(d,J=9.9Hz,1H),4.53(br s,2H),3.91(s,3H),3.89(s,3H),3.70–3.55(m,3H),3.27(d,J=12.5Hz,1H),2.54(dd,J=14.2,6.4Hz,1H),2.14(ddd,J=13.8,11.0,6.5Hz,1H)

[0261] LC-MS(ESI):[M+H] + =304.27

[0262] Step 4: Dimethylspiro[chroman-2,3'-pyrrolidine]-6,7-dicarboxylate (Intermediate 2d)

[0263] Intermediate 2c (1.0 g, 3.3 mmol) was dissolved in methanol (20 mL) and palladium on carbon (0.1 g) was added. The reaction was stirred under hydrogen at room temperature overnight. The mixture was filtered and dried to give Intermediate 2d (1.0 g, 99%) as a yellow oil.

[0264] 1 H NMR (600MHz, CDCl3) δ7.61(s,1H),7.09(s,1H),3.90(s,3H),3.88(s,3H),3.52(dtd,J=17.8,11.4,7.8Hz,2H),3.44(dd,J=12.7, 1.6Hz,1H),3.25(d,J=12.6Hz,1H),2.90(dtd,J=17.3,10.7,6.9Hz,2H),2.28–2.23(m,1H),2.14–2.10(m,2H),2.08–2.02(m,1H)

[0265] LC-MS(ESI):[M+H] + =306.22

[0266] Step 5: Spiro[chroman-2,3'-pyrrolidine]-6,7-dicarboxylic acid (Intermediate 2e)

[0267] Intermediate 2d (1.0 g, 3.3 mmol) was dissolved in methanol and water, and lithium hydroxide (1.2 g, 49.1 mmol) was added. The reaction was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo. The crude product was used directly in the next step without further purification.

[0268] LC-MS(ESI):[M+H] + =278.22

[0269] Step 6: 7-(2,6-dioxapiperidin-3-yl)-3,4-dihydro-6H-spiro[pyrano[2,3-f]isoindole-2,3'-pyrrolidine]-6,8(7H)-dione (Intermediate 2)

[0270] Intermediate 2e (801 mg, 4.9 mmol) was dissolved in acetic acid (5 mL), and 3-aminopiperidine-2,6-dione hydrochloride (0.97 g, 6.0 mmol) and sodium acetate (1.3 g, 9.7 mmol) were added. The reaction was stirred at 110°C for 4 hours. After completion of the reaction, the mixture was purified by reverse phase column chromatography to obtain Intermediate 2 (312 mg, 26%) as a white solid.

[0271] 1H NMR (400MHz, DMSO-d6) δ11.11(s,1H),7.78(s,1H),7.18(s,1H),5.10(dd,J=12.9,5. 4Hz,1H),3.50–3.21(m,4H),3.03–2.84(m,4H),2.66–2.53(m,2H),2.24–2.00(m,4H)

[0272] LC-MS(ESI):[M+H] + =370.34

[0273] Example 3, Synthesis of Intermediate 3

[0274] 7'-(2,6-dioxapiperidin-3-yl)-3',4'-dihydro-6'H-spiro[azetidine-3,2'-pyrano[2,3-f]isoindole]-6',8'(7'H)-dione

[0275] 7'-(2,6-dioxapiperidin-3-yl)-3',4'-dihydro-6'H-spiro[azetidine-3,2'-pyrano[2,3-f]isoindole]-6',8'(7'H)-dione was prepared by referring to steps 1 to 9 of Example 1.

[0276] 1 H NMR(600MHz,DMSO-d6)δ11.12(s,1H),9.12(d,J=49.0Hz,2H,NH),7.76(s,1H ),7.30(s,1H),5.10(dd,J=12.9,5.4Hz,1H),4.16(t,J=8.7Hz,4H),2.97(t, J=6.5Hz,2H),2.88(ddd,J=17.0,13.9,5.5Hz,1H),2.59(dt,J=17.1,3.1Hz, 1H), 2.54 (dd, J=13.1, 4.5Hz, 1H), 2.22 (t, J=6.5Hz, 2H), 2.06–2.00 (m, 1H).

[0277] LC-MS(ESI):[M+H] + =356.26

[0278] Example 4. Synthesis of Intermediate 4

[0279] 7'-(2,6-dioxapiperidin-3-yl)-2'H-spiro[piperidin-4,3'-pyrano[2,3-f]isoindole]-6',8'(4'H,7'H)-dione

[0280] Synthesis scheme

[0281] Step 1: Dimethyl 4-methylphthalate (Intermediate 4b)

[0282] Intermediate 4a (10 g, 55.56 mmol) was dissolved in 100 mL of methanol, and then 15 mL of concentrated sulfuric acid was added. The reaction was allowed to react at room temperature overnight. The reaction solution was poured into ice water, extracted with ethyl acetate, and concentrated to obtain Intermediate 4b (10.6 g, 91%) as a colorless oil. The product was used directly in the next step without purification.

[0283] 1 H NMR (400MHz, CDCl3) δ7.66(d,J=7.9Hz,1H),7.46(d,J=1.7Hz,1H),7.32(dd,J=7.9,1.8,1H),3.89(s,3H),3.88(s,3H),2.40(s,3H)

[0284] Step 2: Dimethyl 4-methyl-5-nitrophthalate (Intermediate 4c)

[0285] Intermediate 4b (10 g, 48 mmol) was dissolved in 100 mL of concentrated sulfuric acid, followed by the slow addition of concentrated nitric acid (25 mL, 68%). The reaction was allowed to react overnight at room temperature. After completion of the reaction, the reaction solution was poured into ice water, extracted with ethyl acetate, and concentrated. The crude product was purified by column chromatography to afford Intermediate 4c (5.5 g, 45%) as a white solid.

[0286] 1 H NMR (400MHz, CDCl3) δ8.43(s,1H),7.64(s,1H),3.97(s,3H),3.96(s,3H),2.69(s,3H)

[0287] Step 3: Dimethyl 4-amino-5-methylphthalate (Intermediate 4d)

[0288] Intermediate 4c (5.1 g, 20 mmol) was dissolved in 100 mL of methanol, followed by the addition of 0.51 g of palladium on carbon. The reaction system was purged with nitrogen and hydrogen, and the reaction was allowed to react overnight at room temperature. After completion of the reaction, the mixture was filtered through celite, and the filtrate was collected and concentrated to afford intermediate 4d (4 g, 91%) as a yellow oil. This product was used directly in the next step without purification.

[0289] 1 H NMR(400MHz,DMSO-d6)δ7.46(s,1H),6.68(s,1H),5.91(s,2H),3.75(s,3H),3.71(s,3H)

[0290] LC-MS(ESI):[M+Na] + =246.18

[0291] Step 4: Dimethyl 4-fluoro-5-methylphthalate (Intermediate 4e)

[0292] Intermediate 4d (4 g, 17.92 mmol) was added to 10% fluoroboric acid (32 ml) and the solution was suspended. After stirring for 0.5 h, the mixture was cooled to 0-5°C and diazotization was carried out by slowly adding 4 mL of aqueous NaNO2 (1.36 g, 19.71 mmol). The mixture was stirred in an ice bath for 0.5 h. The tetrafluoroborate was filtered and the filter cake was collected. The solid was dried under vacuum. The toluene solution of the tetrafluoroborate was then placed in an oil bath at 110°C and stirred. After the reaction was completed, the mixture was extracted with ethyl acetate. The organic phase was washed with water and saturated brine and then dried over anhydrous sodium sulfate. The crude product was concentrated and purified by column chromatography to obtain intermediate 4e (2.31 g, 57%) as a light yellow oil.

[0293] 1 H NMR (400MHz, CDCl3) δ7.61(dd,J=7.2,0.9Hz,1H),7.38(d,J=9.4Hz,1H),3.92(s,3H),3.91(s,3H),2.35(d,J=2.0Hz,3H)

[0294] Step 5: Dimethyl 4-(bromomethyl)-5-fluorophthalate (Intermediate 4f)

[0295] Intermediate 4e (2.26 g, 10 mmol) was dissolved in carbon tetrachloride, and N-bromosuccinimide (2.14 g, 12 mmol) and azobisisobutyronitrile (0.16 g, 1 mmol) were added, followed by heating under reflux overnight. After concentration, the mixture was purified by reverse phase column chromatography to obtain Intermediate 4f (2.14 g, 70%) as a white solid.

[0296] 1 H NMR (400MHz, CDCl3) δ7.87(d,J=7.1Hz,1H),7.40(d,J=9.4Hz,1H),4.51(d,J=1.0Hz,2H),3.94(s,3H),3.93(s,3H)

[0297] Step 6: Dimethyl 4-((1-(tert-butyloxycarbonyl)-4-formylpiperidin-4-yl)methyl)-5-fluorophthalate (Intermediate 4g)

[0298] Intermediate 4f (2.14 g, 7 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL) and potassium tert-butoxide (1.18 g, 10.5 mmol) was slowly added at -30 ° C. After 0.5 h of reaction, a solution of 1-tert-butyloxycarbonylpiperidine-4-carboxaldehyde (1.79 g, 8.4 mmol) in tetrahydrofuran (5 mL) was added dropwise at the same temperature. The reaction was brought to room temperature and stirred overnight. The reaction system was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by flash silica gel column chromatography to obtain intermediate 4g (1.68 g, 55%) as a colorless oil.

[0299] 1 H NMR (400MHz, CDCl3) δ9.58(d,J=2.3Hz,1H),7.50(d,J=7.1Hz,1H),7.34(d,J=9.5Hz,1H),3 .96–3.84(m,8H),2.91–2.74(m,4H),1.96(d,J=13.0Hz,2H),1.59–1.46(m,2H),1.44(s,9H)

[0300] LC-MS(ESI):[M-Boc+H] + =338.29

[0301] Step 7: Dimethyl 4-((1-(tert-butyloxycarbonyl)-4-(hydroxymethyl)piperidin-4-yl)methyl)-5-fluorophthalate (Intermediate 4h)

[0302] Intermediate 4g (1.66 g, 3.8 mmol) was dissolved in methanol (15 mL), and sodium borohydride (0.215 g, 5.7 mmol) was added under ice-cooling conditions. The mixture was stirred at room temperature for 3 h. The mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain Intermediate 4h (1.47 g, 88%) as a colorless oil.

[0303] 1 H NMR (400MHz, DMSO-d6) δ7.74(d,J=7.0Hz,1H),7.54(d,J=9.7Hz,1H),4.81(t,J=5.0Hz,1H),3.82(s,3H), 3.82(s,3H),3.48–3.39(m,2H),3.21(d,J=5.0Hz,4H),2.74(s,2H),1.42–1.32(m,11H),1.27–1.14(m,2H)

[0304] LC-MS(ESI):[M-Boc+H] + =340.41

[0305] Step 8: 1'-(tert-Butyloxycarbonyl)spiro[chroman-3,4'-piperidine]-6,7-dicarboxylic acid (Intermediate 4i)

[0306] Intermediate 4h (1.45 g, 3.3 mmol) was dissolved in dry N,N-dimethylformamide (6 mL), and sodium hydride (0.4 g, 16.5 mmol) was added. The mixture was reacted at 110°C for 2 h. After completion, the reaction was quenched with acetic acid and purified using a reverse-phase column to obtain intermediate 4i (0.65 g, 51%) as a white solid.

[0307] 1 H NMR(400MHz,DMSO-d6)δ12.93(s,2H),7.50(s,1H),6.92(s,1H),3.99(s,2H),3. 53–3.42(m,2H),3.33–3.23(m,2H),2.75(s,2H),1.40(s,9H),1.39–1.28(m,4H)

[0308] LC-MS(ESI):[M-Boc+H] + =292.23

[0309] Step 9: 7'-(2,6-dioxapiperidin-3-yl)-2'H-spiro[piperidin-4,3'-pyrano[2,3-f]isoindole]-6',8'(4'H,7'H)-dione (Intermediate 4)

[0310] Intermediate 4i (0.63 g, 1.6 mmol) was dissolved in acetic acid (4 mL), and 3-amino-2,6-piperidinedione hydrochloride (0.33 g, 2.0 mmol) and sodium acetate (0.39 g, 4.8 mmol) were added. The mixture was reacted at 110° C. overnight. After completion of the reaction, the mixture was purified by reverse-phase column chromatography to obtain Intermediate 4 (0.5 g, 82%) as a white solid.

[0311] 1 H NMR (400MHz, DMSO-d6) δ11.12(s,1H),8.51(s,2H),7.69(s,1H),7.29(s,1H),5.10(dd,J=12.7,5.4Hz,1H),4.16( s,2H),3.25–3.05(m,4H),2.92(s,2H),2.90–2.82(m,1H),2.64–2.52(m,2H),2.05–1.99(m,1H),1.67–1.51(m,4H)

[0312] LC-MS(ESI):[M+H] + =384.36

[0313] Example 5. Synthesis of Intermediate 5

[0314] 7'-(2,6-dioxapiperidin-3-yl)-7'-hydro-3'H,6'H-spiro[piperidine-4,2'-[1,4]dioxanyl[2,3-f]isoindole]-6',8'-dione

[0315] Synthesis scheme

[0316] Step 1: Dimethyl 4-fluorophthalate (Intermediate 5b)

[0317] To a solution of Intermediate 5a (5.5 g, 30.0 mmol) in methanol (100 mL) was slowly added concentrated sulfuric acid (15 mL). The reaction was stirred at room temperature overnight. The reaction mixture was poured into ice water and extracted with ethyl acetate. The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. Filtering and concentration under reduced pressure afforded Intermediate 5b (5.7 g, 90%) as a colorless oil. The crude product was used in the next reaction without purification.

[0318] 1 H NMR (400MHz, CDCl3) δ7.82(dd,J=8.6,5.3Hz,1H),7.38(dd,J=8.6,2.6Hz,1H),7.82(ddd,J=8.6,5.3,2.6Hz,1H),3.96(s,3H),3.92(s,3H)

[0319] Step 2: Methyl 4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phthalate (Intermediate 5c)

[0320] Diboronic acid pinacol ester (4.5 g, 17.5 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (0.13 g, 0.47 mmol), and methoxy(cyclooctadiene)iridium dimer (0.16 g, 0.23 mmol) were added to a 10 mL solution of methyl tert-butyl ether. A solution of intermediate 5b (2.5 g, 11.8 mmol) in methyl tert-butyl ether (10 mL) was then added. The atmosphere was purged with nitrogen and the reaction was stirred at 100°C for 4 h. After completion of the reaction, the mixture was filtered through celite and the filtrate was concentrated to obtain a crude product (3.2 g) which was used in the next step without purification.

[0321] Step 3: Dimethyl 4-fluoro-5-hydroxyphthalate (Intermediate 5d)

[0322] To a solution of intermediate 5c (3.38 g, 10 mmol) in acetonitrile (50 mL) was added potassium peroxymonosulfate (6.15 g), and the reaction was stirred at room temperature overnight. The reaction solution was filtered and the filtrate was concentrated. The crude product was purified by silica gel column chromatography to give intermediate 5d (1.6 g, 70%) as a white solid.

[0323] 1 H NMR (400MHz, CDCl3) δ8.39 (s, 1H), 7.50 (d, J = 10.8Hz, 1H), 7.19 (d, J = 8.1Hz, 1H), 3.88 (s, 3H), 3.86 (s, 3H).

[0324] LC-MS(ESI):[M+H] + =229.18

[0325] Step 4: 1'-((Benzyloxy)carbonyl)-3H-spiro[benzo[b][1,4]dioxane-2,4'-piperidine]-6,7-dicarboxylic acid (Intermediate 5e)

[0326] Intermediate 5d (23 mg, 0.1 mmol) was dissolved in 1 ml of ultra-dry N,N-dimethylformamide, followed by the addition of benzyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (25 mg, 0.1 mmol) and sodium hydride (6 mg, 0.25 mmol). The reaction was heated to 110°C and stirred for 2 days. The reaction mixture was then reversed to afford Intermediate 5e (13 mg, 31%) as a white solid.

[0327] 1 H NMR(600MHz,CD3OD)δ7.41–7.35(m,4H),7.33(dd,J=5.9,2.9Hz,1H),7.29(s,1H),7.27(s,1H),5.15(s,2H ),4.07(s,2H),4.01(dt,J=13.6,4.0Hz,2H),3.42–3.32(m,2H),1.82(d,J=13.9Hz,2H),1.76–1.67(m,2H).

[0328] LC-MS(ESI):[M+H] + =428.36

[0329] Step 5: Benzyl 7'-(2,6-dioxapiperidin-3-yl)-6',8'-dioxa-7',8'-dihydro-3'H,6'H-spiro[piperidine-4,2'-[1,4]dioxanyl[2,3-f]isoindole]-1-carboxylate (Intermediate 5f)

[0330] To a solution of Intermediate 5e (13 mg, 0.03 mmol) in acetic acid (1 mL) were added 3-aminopiperidine-2,6-dione hydrochloride (6 mg, 0.036 mmol) and sodium acetate (7 mg, 0.09 mmol). The reaction was heated to 110°C and stirred for 4 hours. After completion of the reaction, the reaction solution was purified by reverse transpiration to afford Intermediate 5f (12 mg, 77%) as a white solid.

[0331] 1 H NMR (600MHz, CD3OD) δ7.42(s,1H),7.40–7.31(m,6H),5.15(s,2H),5.08(dd,J=12.9,5.5Hz,1H),4.14(s,2H),4.01(dt,J=13.8,4.0Hz,2H ),3.43–3.32(m,2H),2.91–2.83(m,1H),2.79–2.69(m,2H),2.14–2.09(m,1H),1.83(d,J=13.9Hz,2H),1.74(td,J=14.4,12.9,4.8Hz,2H).

[0332] LC-MS(ESI):[M+H] + =520.29

[0333] Step 6: 7'-(2,6-dioxapiperidin-3-yl)-7'-hydro-3'H,6'H-spiro[piperidine-4,2'-[1,4]dioxanyl[2,3-f]isoindole]-6',8'-dione (Intermediate 5)

[0334] Palladium carbon (5 mg) was added to a methanol solution of intermediate 5f (11 mg, 0.02 mmol), the atmosphere was replaced with hydrogen, and the reaction solution was stirred under hydrogen for 6 hours. The reaction solution was filtered through celite and the filtrate was concentrated to give white solid intermediate 5 (7 mg, 90%).

[0335] 1 H NMR (400MHz, DMSO-d6) δ11.11(s,1H),7.50(s,1H),7.48(s,1H),5.09(dd,J=12.8,5.3Hz,1H),4.27(s,2H),3.25(d,J=12.7Hz,2H) ,3.18–3.11(m,2H),2.89(ddd,J=16.7,13.7,5.3Hz,1H),2.64–2.53(m,2H),2.03(ddd,J=13.3,5.7,3.4Hz,1H),1.92–1.86(m,4H).

[0336] LC-MS(ESI):[M+H]+ =386.32

[0337] Example 6, Synthesis of Intermediate 6

[0338] 6-(2,6-dioxopiperidin-3-yl)spiro[furo[2,3-f]isoindole-2,4'-piperidine]-5,7(3H,6H)-dione

[0339] Synthesis scheme

[0340] Step 1: tert-Butyl 4-(dibromomethyl)piperidine-1-carboxylate (Intermediate 6b)

[0341] Under nitrogen, intermediate 6a (5 g, 25.1 mmol) and triphenylphosphine (26.3 g, 100.4 mmol) were dissolved in anhydrous acetonitrile (50 mL). Carbon tetrabromide (16.7 g, 50.2 mmol) was added portionwise to the reaction system at 0°C. After 30 minutes of reaction, the reaction system was warmed to room temperature and allowed to react overnight. After completion of the reaction, the reaction system was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain intermediate 6b (5.5 g, 62%) as a white solid.

[0342] 1 H NMR (600MHz, DMSO-d6) δ3.37 (s, 4H), 2.41 (dd, J = 7.2, 4.7Hz, 4H), 1.41 (d, J = 0.9Hz, 9H).

[0343] Step 2: tert-Butyl 4-(bromomethyl)piperidine-1-carboxylate (Intermediate 6c)

[0344] Under nitrogen, intermediate 6b (5.2 g, 18.9 mmol) was dissolved in tetrahydrofuran (34 mL) and methanol (17 mL). Ammonium chloride (4.04 g, 75.6 mmol) was added to the reaction system at 0°C. After reacting at 0°C for 30 min, zinc powder (4.9 g, 75.6 mmol) was added portionwise and allowed to react overnight at room temperature. After completion of the reaction, the reaction system was filtered, and the filter cake was washed with methanol. The resulting filtrate was dried under reduced pressure, and the concentrated crude product was purified by column chromatography to afford intermediate 6c (2.6 g, 50%) as a white oil.

[0345] 1H NMR (600MHz, DMSO-d6) δ6.26(t,J=1.3Hz,1H),3.34(dt,J=16.4,6.3Hz,4H),2.32–2.27(m,2H),2.23(ddd,J=7.2,4.4,1.2Hz,2H),1.41(s,9H).

[0346] Step 3: Dimethyl 4-(1-(tert-Butyloxycarbonyl)piperidin-4-ylidene)methyl)-5-fluorophthalate (Intermediate 6d)

[0347] Under nitrogen, intermediate 6c (2 g, 7.3 mmol), intermediate 5c (2.64 g, 7.8 mmol) prepared via steps 1 and 2 of Example 5, palladium acetate (163 mg, 0.73 mmol), triphenylphosphine (382 mg, 1.46 mmol), and cesium carbonate (7.14 g, 21.9 mmol) were added sequentially to a reaction flask. 1,4-dioxane (20 mL) and water (2 mL) were then added. After nitrogen substitution, the mixture was reacted at 110°C for 4 hours. After completion of the reaction, the reaction system was cooled to room temperature, water was added, and extraction was performed with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The concentrated crude product was purified by column chromatography to yield intermediate 6d (1.4 g, 47%) as a pale yellow oil.

[0348] 1 H NMR (600MHz, DMSO-d6) δ7.65(d,J=7.0Hz,1H),7.60(d,J=9.7Hz,1H),6.32(s,1H),3.83(s,3H),3.82(s,3H ),3.43(t,J=5.8Hz,2H),3.35(s,1H),3.33(s,1H),2.37–2.32(m,2H),2.25(t,J=5.9Hz,2H),1.42(s,9H).

[0349] LC-MS(ESI):[M-Boc+H] + =308.28

[0350] Step 4: Dimethyl 4-(bromo(1-(tert-butyloxycarbonyl)-4-hydroxypiperidin-4-yl)methyl)-5-fluorophthalate (Intermediate 6e)

[0351] Under nitrogen, intermediate 6d (7 g, 17.2 mmol) was dissolved in tetrahydrofuran (140 mL) and water (140 mL). N-bromosuccinimide (6.12 g, 34.4 mmol) was added and allowed to react at room temperature overnight. After completion of the reaction, the excess tetrahydrofuran was removed by concentration under reduced pressure. Water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The crude product was purified by column chromatography to afford intermediate 6e (4.9 g, 56%) as a pale yellow oil.

[0352] LC-MS(ESI):[M-Boc+H] + =404.30 / 406.30

[0353] Step 5: Dimethyl 4-(1-(tert-Butyloxycarbonyl)-4-hydroxypiperidin-4-yl)methyl)-5-fluorophthalate (Intermediate 6f)

[0354] Under nitrogen, intermediate 6e (10.9 g, 21.61 mmol) was dissolved in toluene (80 ml), and tris(trimethylsilyl)silane (8.06 g, 32.42 mmol) and azobisisobutyronitrile (357 mg, 2.16 mmol) were added. The mixture was allowed to react overnight at 90°C. After completion of the reaction, the excess toluene was removed by concentration under reduced pressure. The crude product was purified by column chromatography to afford intermediate 6f (1.5 g, 16%) as a pale yellow oil.

[0355] 1 H NMR(600MHz,DMSO-d6)δ7.77(d,J=6.9Hz,1H),7.52(d,J=9.5Hz,1H),4.62(s,1 H),3.82(d,J=2.1Hz,6H),3.66(s,2H),3.34(s,4H),2.79(s,2H),1.38(s,9H).

[0356] LC-MS(ESI):[M-Boc+H] + =326.37

[0357] Step 6: 1'-(tert-Butyl)5,6-dimethyl 3H-spiro[benzofuran-2,4'-piperidine]-1',5,6 tricarboxylate (Intermediate 6g)

[0358] Under nitrogen, intermediate 6f (1.6 g, 3.76 mmol) was dissolved in N,N-dimethylformamide (2 ml), and sodium hydride (300 mg, 7.52 mmol) was added. The mixture was allowed to react overnight at 110°C. After completion of the reaction, water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The concentrated crude product was purified by reverse transpiration to afford intermediate 6g (660 mg, 43%) as a pale yellow solid.

[0359] 1 H NMR (600MHz, CDCl3) δ7.58(s,1H),7.15(s,1H),3.93(s,3H),3.89(s,3H),3.56(t,J=5.7Hz,2H) ,3.42(t,J=5.8Hz,2H),2.42(t,J=5.9Hz,2H),2.24(t,J=5.9Hz,2H),1.61(s,2H),1.50(s,9H).

[0360] LC-MS(ESI):[M-Boc+H] + =306.23

[0361] Step 7: 1'-(tert-Butyloxycarbonyl)-3H-spiro[benzofuran-2,4'-piperidine]-5,6-dicarboxylic acid (Intermediate 6h)

[0362] Under nitrogen, compound 6g (660 mg, 1.63 mmol) was dissolved in methanol (9 ml) and water (1 ml), and lithium hydroxide (389 mg, 16.28 mmol) was added. The reaction was allowed to proceed overnight at room temperature. The concentrated crude product was purified by reverse transpiration to afford intermediate 6h (600 mg, 97%) as a pale yellow solid.

[0363] 1 H NMR (400MHz, DMSO-d6) δ7.39(s,1H),6.37(s,1H),3.17(s,2H),2.29(d,J=51.9Hz,4H),1.98(dd,J=13.7,6.9Hz,2H),1.64(s,2H),1.41(s,9H).

[0364] LC-MS(ESI):[M-Boc+H] + =278.26

[0365] Step 8: 6-(2,6-dioxopiperidin-3-yl)spiro[furan[2,3-f]isoindole-2,4'-piperidine]-5,7(3H,6H)-dione (Intermediate 6)

[0366] Intermediate 6h (400 mg, 1.06 mmol) was dissolved in acetic acid (5 mL), and 3-aminopiperidine-2,6-dione hydrochloride (169 mg, 1.32 mmol) and sodium acetate (260 mg, 3.18 mmol) were added. The reaction was stirred at 110°C for 4 hours. After completion of the reaction, the mixture was purified by reverse phase column to obtain Intermediate 6 (170 mg, 43%) as a white solid.

[0367] 1 H NMR(400MHz,DMSO-d6)δ7.46(s,1H),7.11(s,1H),5.04(dd,J=12.8,5.4Hz,1H),2.99–2.79(m ,5H),2.62–2.54(m,1H),2.53(s,1H),2.38(q,J=6.3Hz,4H),2.04–1.96(m,1H),1.90(s,2H).

[0368] LC-MS(ESI):[M+H] + =370.34

[0369] Example 7, Synthesis of Intermediate 7

[0370] 2-(2,6-dioxapiperidin-3-yl)-5a,6,7,8,8a,9-hexahydroisoindole[5,6-f]isoindole-1,3(2H,5H)-dione

[0371] Synthesis scheme

[0372] Step 1: 2-Benzyl-3a,4,7,7a-tetrahydro-1H-isoindole-1,3(2H)-dione (Intermediate 7b)

[0373] Intermediate 7a (5 g, 33 mmol) was dissolved in anhydrous acetonitrile (50 ml). Tetrabutylammonium bromide (1.23 g, 3.3 mmol) and anhydrous potassium carbonate (14 g, 99 mmol) were added to the solution. Benzyl chloride (5.5 g, 43 mmol) was slowly added to the system and allowed to react at 30°C overnight. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give Intermediate 7b (7.5 g, 94%) as a white solid.

[0374] 1H NMR (400MHz, CDCl3) δ7.37–7.20(m,5H),5.95–5.83(m,2H),4.63(s,2H),3.20–3.01(m,2H),2.61(m,2H),2.31–2.10(m,2H).

[0375] LC-MS(ESI):[M+H] + =242.22

[0376] Step 2: 2-Benzyl-2,3,3a,4,7,7a-hexahydro-1H-isoindole (Intermediate 7c)

[0377] Lithium aluminum tetrahydride (3.2 g, 82 mmol) was added to 40 mL of anhydrous tetrahydrofuran at 0°C, followed by the addition of intermediate 7b (5 g, 20.7 mmol). After an ice bath for 5 minutes, the reaction system was moved to a 70°C oil bath and allowed to react for 3 hours. After the reaction, water was slowly added dropwise to the reaction solution while still in an ice bath until bubbles ceased. The filtrate was collected by filtration and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. Concentration afforded intermediate 7c (3.2 g, 73%) as a yellow oil.

[0378] 1 H NMR (400MHz, CDCl3) δ7.43–7.24(m,5H),5.87(t,J=2.7Hz,2H),3.67(s,2H),3.05–2.90(m,2H),2.44(m,2H),2.29–2.16(m,4H),1.92(m,2H)

[0379] Step 3: 2-Benzyloctahydro-1H-isoindol-5-ol (Intermediate 7d)

[0380] Intermediate 7c (5 g, 23.44 mmol) was dissolved in 20 mL of tetrahydrofuran at 0°C. 25 mL of 2M borane-tetrahydrofuran complex was added in an ice bath. After 12 h of reaction, 13 mL of anhydrous methanol, 10.5 mL of 3M NaOH solution, and 10.5 mL of hydrogen peroxide were added to the reaction solution, which was then reacted at 60°C for 6 h. After completion of the reaction, the solution was cooled to room temperature and extracted with ethyl acetate. The organic phase was then dried over anhydrous sodium sulfate after saturated brine. The crude product was concentrated and purified by column chromatography to afford Intermediate 7d (1.2 g, 22.2%).

[0381] 1H NMR (400MHz, CDCl3) δ7.43–7.18(m,5H),3.84(m,1H),3.78(s,2H),2.94(dd,J=9.8,6.7Hz,1H),2.82(dd,J=9.5,7.7Hz,1H),2.6 4(dd,J=9.5,8.4Hz,1H),2.60–2.44(m,2H),2.12(m,1H),1.89–1.72(m,3H),1.54(m,1H),1.47–1.35(m,1H),1.35–1.22(m,2H).

[0382] LC-MS(ESI):[M+H] + =232.31

[0383] Step 4: 2-Benzyloctahydro-5H-isoindol-5-one (Intermediate 7e)

[0384] Intermediate 7d (1.2 g, 12.97 mmol) was dissolved in anhydrous dichloromethane. Dess-Martin periodinane (11 g, 25.95 mmol) was added under ice-cooling conditions and allowed to react for 12 h. The reaction was quenched with a 1:1 mixture of saturated sodium bicarbonate and saturated sodium thiosulfate. The filtrate was filtered and extracted with dichloromethane. The organic phases were washed with saturated brine, and the combined organic phases were dried over anhydrous sodium sulfate. Concentration afforded the crude intermediate 7e (1 g). This crude product was used directly in the next reaction.

[0385] Step 5: 2-Benzyl-6-bromo-2,3,3a,4,7,7a-hexahydro-1H-isoindole-5-carbaldehyde (Intermediate 7f)

[0386] Dissolve N,N-dimethylformamide (1.01 mL, 13.08 mmol) in 2 mL of dichloromethane at 0°C. Slowly add phosphorus tribromide (1.13 mL, 11.77 mmol) dropwise and stir at 0°C for 1 hour. Add a dichloro solution of intermediate 7e (1 g, 2.62 mmol) dropwise to the above system, warm to room temperature and react for 10 hours. After the reaction is completed, place the reaction solution at 0°C and add saturated sodium bicarbonate until no bubbles are generated. Extract with dichloromethane. Wash the organic phase with saturated brine and dry it over anhydrous sodium sulfate. Concentrate to obtain a crude product, which is purified by column chromatography to obtain the target compound intermediate 7f (270 mg, 20%).

[0387] 1H NMR (400MHz, CDCl3) δ10.04(s,1H),7.32(d,J=5.8Hz,5H),3.60(s,2H),3.21–3.10(m,2H),2.85– 2.72(m,3H),2.50–2.43(m,1H),2.33(dd,J=9.2,5.0Hz,1H),2.24–2.18(m,1H),1.83–1.74(m,2H)

[0388] LC-MS(ESI):[M+H] + =320.16

[0389] Step 6: 2-Benzyl-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-6,7-dicarboxylic acid methyl ester (Intermediate 7g)

[0390] Intermediate 7f (270 mg, 0.84 mmol), dimethyl itaconate (133.4 mg, 0.84 mmol), palladium acetate (9.5 mg, 0.042 mmol), triphenylphosphine (22.11 mg, 0.084 mmol), and sodium acetate (207.5 mg, 2.53 mmol) were added sequentially to a pressure vessel, dissolved in tetrahydrofuran, replaced with nitrogen, and heated to 120°C for overnight reaction. After cooling the reaction system to room temperature, the tetrahydrofuran was dried, and then separated and purified by preparative liquid chromatography to obtain intermediate 7g (71 mg, 22%).

[0391] 1 H NMR (400MHz, CDCl3) δ7.52–7.39(m,7H),4.38–4.14(m,3H),3.91(d,J=2.8Hz,7H ),3.27(s,3H),2.94(d,J=12.0Hz,1H),2.85–2.72(m,3H),1.55(d,J=6.6Hz,1H)

[0392] LC-MS(ESI):[M+H] + =380.36

[0393] Step 7: 2-Benzyl-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-6,7-dicarboxylic acid (Intermediate 7h)

[0394] Dissolve 7g (71mg, 0.19mmol) of the intermediate in methanol and water, add lithium hydroxide (90mg, 3.74mmol), and react at room temperature for 20h. After the reaction, the water and methanol are dried to obtain a crude product (62mg, 95%). The crude product is used directly in the next step.

[0395] LC-MS(ESI):[M+H] + =352.34

[0396] Step 8: 7-Benzyl-2-(2,6-dioxapiperidin-3-yl)-5a,6,7,8,8a,9-hexahydroisoindole[5,6-f]isoindole-1,3(2H,5H)-dione (Intermediate 7i)

[0397] Intermediate 7h (62 mg, 0.18 mmol) was dissolved in glacial acetic acid, and sodium acetate (43.2 mg, 0.53 mmol) and 3-amino-2,6-piperidinedione hydrochloride (44 mg, 0.26 mmol) were added. The mixture was reacted in an oil bath at 110°C overnight. Methanol and water were then dried and the product was purified by preparative liquid chromatography to obtain intermediate 7i (39 mg, 49%).

[0398] 1 H NMR (400MHz, DMSO-d6) δ11.14(s,1H),7.98–7.72(m,2H),7.64–7.41(m,5H),5.14(dd,J=12.9,5.4Hz,1H),4.53–4.24(m,2H),4.01(dd,J=13.9,7.6H z,1H),3.76(s,3H),3.12(d,J=9.7Hz,1H),3.06–2.91(m,2H),2.92–2.76( m,3H),2.67–2.54(m,2H),2.04(dd,J=12.5,6.2Hz,1H),1.90–1.59(m,2H)

[0399] LC-MS(ESI):[M+H] + =444.41

[0400] Step 9: 2-(2,6-dioxapiperidin-3-yl)-5a,6,7,8,8a,9-hexahydroisoindole[5,6-f]isoindole-1,3(2H,5H)-dione (Intermediate 7)

[0401] Intermediate 7i (39 mg, 0.088 mmol) was dissolved in 2 mL of methanol, 4 mg of palladium carbon was added, hydrogen was replaced, and the mixture was reacted at room temperature overnight. The palladium carbon was removed by filtration and the methanol was dried by spin drying. Intermediate 7 (12 mg, 38%) was obtained by purification by preparative liquid chromatography.

[0402] 1H NMR (400MHz, DMSO-d6) δ11.13(s,1H),9.07–8.95(m,1H),7.95–7.68(m,2H),5.14(dd,J=13.0,5.3Hz,1H),3.96–3.87 (m,2H),3.51(m,2H),3.12(m,1H),3.04–2.82(m,4H),2.72–2.55(m,2H),2.06(m,1H),1.86(m,1H),1.65–1.46(m,1H)

[0403] LC-MS(ESI):[M+H] + =354.41

[0404] Example 8, Synthesis of Intermediate 8

[0405] 7'-(2,6-dioxapiperidin-3-yl)-3',4'-dihydro-6'H-spiro[cyclohexane-1,2'-pyrano[2,3-f]isoindole]-4,6',8'(7'H)-trione

[0406] Synthesis scheme

[0407] Step 1: 1,4-dioxa-9,13-dithiadispiro[4.2.5 8 .2 5 Pentadecane (Intermediate 8b)

[0408] Intermediate 8a (10.0 g, 64.0 mmol) was dissolved in 200 mL of dichloromethane, followed by the addition of 1,3-propanedithiol (7.0 g, 64.0 mmol). 32 mmol of boron trifluoride etherate was added dropwise at -18°C. After the addition was complete, the mixture was stirred at -18°C for 4 h. After completion of the reaction, the solvent was removed under reduced pressure, 500 mL of water was added, and the solid was filtered and purified by C18 column chromatography to yield Intermediate 8b (2 g, 12.7%).

[0409] 1 H NMR(400MHz,DMSO-d6)δ3.85(s,4H),2.84–2.78(m,4H),2.06-1.98(m,4H),1.93–1.80(m,2H),1.70–1.59(m,4H)

[0410] LC-MS(ESI):[M+H] + =247.07

[0411] Step 2: 1,5-dithiaspiro[5.5]undecan-9-one (Intermediate 8c)

[0412] Intermediate 8b (2.0 g, 8.0 mmol) was dissolved in 200 mL of dichloromethane, followed by the addition of 100 mL of trifluoroacetic acid at room temperature. The mixture was stirred at room temperature for 4 h. After completion of the reaction, sodium bicarbonate (aq) solution was added to adjust the pH to 7. The organic phase was extracted, dried, concentrated, and purified by column chromatography to afford Intermediate 8c (1.5 g, 91.0%).

[0413] 1 H NMR(400MHz,DMSO-d6)δ2.93–2.84(m,4H),2.41–2.33(m,4H),2.31-2.25(m,4H),1.94–1.88(m,2H)

[0414] LC-MS(ESI):[M+H] + =203.05

[0415] Step 3: Dimethyl 4-oxadispiro[chroman-2,1'-cyclohexane-4',2"-[1,3]dithiane]-6,7-dicarboxylate (Intermediate 8d)

[0416] Intermediate 8c (2.0 g, 9.9 mmol) was dissolved in 200 mL of tetrahydrofuran, followed by the addition of Intermediate 1d (2.0 g, 9.8 mmol) and tetrahydropyrrole (2.0 g, 28.0 mmol) at room temperature. After addition, the mixture was stirred at 70°C for 4 h. After completion of the reaction, the solvent was removed under reduced pressure, and the residue was purified by column chromatography to yield Intermediate 8d (2.0 g, 46.0%).

[0417] 1 H NMR(400MHz,DMSO-d6)δ8.18(s,1H),7.35(s,1H),3.83(s,3H),3.81(s,3H),2.92(s, 2H),2.90–2.85(m,2H),2.81–2.74(m,2H),2.14–2.10(m,2H),2.02–1.77(m,8H).

[0418] LC-MS(ESI):[M+H] + =437.10

[0419] Step 4: Dimethyl 4-hydroxydispiro[chroman-2,1'-cyclohexane-4',2"-[1,3]dithiane]-6,7-dicarboxylate (Intermediate 8e)

[0420] Intermediate 8d (2.0 g, 4.5 mmol) was dissolved in 50 mL of methanol and 50 mL of tetrahydrofuran, followed by the addition of sodium borohydride (350.0 mg, 9.0 mmol) at room temperature. After the addition, the mixture was stirred at 70°C for 4 h. Upon completion of the reaction, the solvent was removed under reduced pressure, and the residue was purified by column chromatography to afford Intermediate 8e (1.5 g, 75.0%).

[0421] 1 H NMR(600MHz,DMSO-d6)δ7.90(s,1H),7.00(s,1H),5.68(d,J=6.2Hz,1H),4.77-4.71(m,1H ),3.79(s,6H),2.96–2.72(m,4H),2.16–2.01(m,4H),1.93–1.79(m,5H),1.77–1.70(m,3H)

[0422] LC-MS(ESI):[M+H] + =439.12

[0423] Step 5: Dimethyldispiro[chromene-2,1'-cyclohexane-4',2"-[1,3]dithiane]-6,7-dicarboxylate (Intermediate 8f)

[0424] Intermediate 8e (700 mg, 1.5 mmol) was dissolved in 200 mL of dichloromethane, followed by the addition of triethylamine (480.0 mg, 4.5 mmol) and 4-dimethylaminopyridine (100.0 mg, 0.8 mmol) at room temperature. Sulfuryl chloride (720.0 mg, 6.0 mmol) was added dropwise at 0°C. After the addition, the mixture was stirred at 0°C for 4 h, and the reaction was monitored by TLC. Upon completion of the reaction, the solvent was removed under reduced pressure. After the addition, the residue was dissolved in 100 mL of toluene, followed by the addition of 1,8-diazabicycloundec-7-ene (1.6 g, 10.0 mmol) at room temperature. The mixture was stirred at 110°C for 16 h. After completion of the reaction, the solvent was removed under reduced pressure, and the residue was purified by column chromatography to yield Intermediate 8f (400 mg, 59.0%).

[0425] 1 H NMR (400MHz, DMSO-d6) δ7.58(s,1H),7.05(s,1H),6.59(d,J=9.9Hz,1H),5.95(d,J=11.4Hz,1H),3.78(s,3H) ,3.77(s,3H),2.93–2.85(m,2H),2.82–2.73(m,2H),2.18-2.11(m,2H),2.09–1.96(m,2H),1.92–1.77(m,6H)

[0426] LC-MS(ESI):[M+H] + =421.11

[0427] Step 6: Dispiro[chromene-2,1'-cyclohexane-4',2"-[1,3]dithiane]-6,7-dicarboxylic acid (intermediate 8g)

[0428] Intermediate 8f (400.0 mg, 0.9 mmol) was dissolved in 50 mL of methanol, 50 mL of tetrahydrofuran, and 50 mL of water, followed by the addition of lithium hydroxide (120.0 mg, 4.5 mmol) at room temperature. After the addition, the mixture was stirred at room temperature for 16 h. After completion of the reaction, 1.0 M dilute hydrochloric acid was added to the system to adjust the pH to 6. The organic phase was extracted, dried, concentrated, and purified by column chromatography to afford Intermediate 8g (350 mg, 94.0%).

[0429] 1 H NMR (600MHz, DMSO-d6) δ12.90(s,2H),7.52(s,1H),6.99(s,1H),6.57(d,J=9.9Hz,1H),5.90(d,J=9 .9Hz,1H),2.92–2.86(m,2H),2.83–2.73(m,2H),2.11(m,2H),2.09–1.97(m,2H),1.94–1.76(m,6H)

[0430] LC-MS(ESI):[M+H] + =393.08

[0431] Step 7: 7-(2,6-dioxapiperidin-3-yl)-6H-dispiro[pyrano[2,3-f]isoindole-2,1'-cyclohexane-4',2"-[1,3]dithiane]-6,8(7H)-dione (Intermediate 8h)

[0432] Intermediate 8g (300.0 mg, 0.7 mmol) was dissolved in 100 mL of acetic acid, followed by the addition of 3-aminopiperidine-2,6-dione hydrochloride (170.0 mg, 1.3 mmol) and sodium acetate (360.0 mg, 2.1 mmol) at room temperature. After the addition, the mixture was stirred at 110°C for 4 h. After completion of the reaction, the solvent was removed under reduced pressure, and the residue was purified by column chromatography to yield Intermediate 8h (280 mg, 75.0%).

[0433] 1H NMR (400MHz, DMSO-d6) δ11.12(s,1H),7.72(s,1H),7.30(s,1H),6.70(d,J=8.0Hz,1H),6.03(d,J=8.8Hz,1H),5 .13-5.07(m,1H),2.94–2.84(m,3H),2.84–2.76(m,2H),2.64-2.55(m,1H),2.18–1.98(m,6H),1.95–1.78(m,6H)

[0434] LC-MS(ESI):[M+H] + =485.11

[0435] Step 8: 7'-(2,6-oxapiperidin-3-yl)-6'H-spiro[cyclohexane-1,2'-pyrano[2,3-f]isoindole]-4,6',8'(7'H)-trione (Intermediate 8i)

[0436] Intermediate 8h (280.0 mg, 0.5 mmol) was dissolved in 50 mL of acetonitrile, followed by the addition of 50 mL of sodium bicarbonate solution and iodine (1.5 g, 5.0 mmol) at room temperature. After the addition, the mixture was stirred at room temperature for 4 h. Upon completion of the reaction, the solvent was removed under reduced pressure. The organic phase was extracted, dried, concentrated, and purified by column chromatography to afford Intermediate 8i (100 mg, 44.0%).

[0437] 1 H NMR (600MHz, DMSO-d6) δ11.13(s,1H),7.77(s,1H),7.45(s,1H),6.76(d,J=10.0Hz,1H),6.09(d,J=9.9Hz,1H),5 .13-5.09(m,1H),2.92-2.84(m,1H),2.78-2.70(m,2H),2.63-2.57(m,1H),2.26-2.15(m,4H),2.12–2.00(m,4H)

[0438] LC-MS(ESI):[M+H] + =395.12

[0439] Step 9: 7'-(2,6-dioxapiperidin-3-yl)-3',4'-dihydro-6'H-spiro[cyclohexane-1,2'-pyrano[2,3-f]isoindole]-4,6',8'(7'H)-trione (Intermediate 8)

[0440] Intermediate 8i (280.0 mg, 0.7 mmol) was dissolved in 50 mL of tetrahydrofuran, followed by the addition of Pd / C (150.0 mg) at room temperature. After the addition, the mixture was stirred at 50°C under hydrogen for 4 h. Upon completion of the reaction, the reaction mixture was filtered through celite, the solvent was removed under reduced pressure, and purification by preparative liquid chromatography afforded Intermediate 8 (195 mg, 70.0%).

[0441] 1 H NMR(600MHz,DMSO-d6)δ11.11(s,1H),7.68(s,1H),7.35(s,1H),5.12-5.06(m,1H),2.99-2.93(m, 2H),2.92-2.84(m,1H),2.68–2.55(m,3H),2.23-2.15(m,2H),2.13–2.00(m,4H),1.99-1.91(m,4H)

[0442] LC-MS(ESI):[M+H] + =397.13

[0443] Example 9, Synthesis of Intermediate 9

[0444] 7'-(2,6-dioxapiperidin-3-yl)-4',4'-difluoro-3',4'-dihydro-6'H-spiro[piperidin-4,2'-pyrano[2,3-f]isoindole]-6',8'(7'H)-dione

[0445] Synthesis scheme:

[0446] Step 1: 1'-(tert-Butyl)6,7-dimethyl-4,4-difluorospiro[chroman-2,4'-piperidine]-1',6,7-tricarboxylate (Intermediate 9a)

[0447] Diethylaminosulfur trifluoride (4 mL) was added to Intermediate 1e (2 g, 4.6 mmol), and the reaction was stirred at 85°C for 2 hours. The resulting mixture was poured into ice water and extracted three times with ethyl acetate. The organic phase was concentrated in vacuo and the mixture was purified by reverse-phase column chromatography to obtain Intermediate 9a (0.5 g, 24%) as a yellow oily liquid.

[0448] 1H NMR(600MHz,DMSO-d6)δ8.02(s,1H),7.29(s,1H),3.82(s,3H),3.81(s,3H),3.77–3.68(m,2H),3.22–3.0 2(m,2H),2.72(t,J=14.7Hz,2H),1.85(d,J=13.9Hz,2H),1.70(td,J=14.0,11.6,4.7Hz,2H),1.40(s,9H).

[0449] LC-MS(ESI):[M-tBu+H] + =400.31

[0450] Step 2: 1'-(tert-Butyl)-4,4-difluorospiro[chroman-2,4'-piperidine]-6,7-dicarboxylic acid (Intermediate 9b)

[0451] To a solution of intermediate 9a (160 mg, 0.4 mmol) in methanol / tetrahydrofuran (2 ml) was slowly added lithium hydroxide (42 mg, 1.8 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was extracted three times with dichloromethane / methanol (10:1) and the organic phase was concentrated in vacuo to afford intermediate 9b (0.1 g, 67%) as a white solid.

[0452] 1 H NMR(600MHz,DMSO-d6)δ13.27(br s,2H),8.12(s,1H),7.36(s,1H),3.21–3.06(m,2H),2.68(t,J=14.7Hz,2H),2.05–1 .93(m,2H),1.84(d,J=13.8Hz,2H),1.68(td,J=14.0,12.9,4.7Hz,2H),1.40(s,9H).

[0453] LC-MS(ESI):[M-tBu+H] + =372.27

[0454] Step 3: 7'-(2,6-dioxapiperidin-3-yl)-4',4'-difluoro-3',4'-dihydro-6'H-spiro[piperidine-4,2'-pyrano[2,3-f]isoindole]-6',8'(7'H)-dione (Intermediate 9)

[0455] To a solution of intermediate 9b (100 mg, 0.23 mmol) in acetic acid (1 ml) were slowly added 3-aminopiperidine-2,6-dione hydrochloride (77 mg, 0.5 mmol) and sodium acetate (96 mg, 1.2 mmol). The reaction was stirred at 110°C for 2 hours. After completion of the reaction, the mixture was purified by reverse phase column chromatography to obtain intermediate 9 (50 mg, 51%) as a brown solid.

[0456] 1 H NMR (600MHz, DMSO-d6) δ11.15(s,1H),8.10(s,1H),7.68(s,1H),5.16(dd,J=13.0,5.4Hz,1H),3.27–3.15(m,4H),2.92–2.82(m,3H) ),2.61(dt,J=17.2,3.4Hz,1H),2.56–2.51(m,1H),2.11(d,J=14.4Hz,2H),2.05(ddt,J=12.9,5.6,2.5Hz,1H),1.97–1.90(m,2H).

[0457] LC-MS(ESI):[M+H] + =420.36

[0458] Example 10. Synthesis of Intermediate 10

[0459] 7'-(2,6-dioxapiperidin-3-yl)-4',4'-difluoro-3',4'-dihydro-6'H-spiro[azetidine-3,2'-pyrano[2,3-f]isoindole]-6',8'(7'H)-dione

[0460] Synthesis scheme:

[0461] Step 1: 1-(tert-Butyl)6',7'-dimethyl 4',4'-difluorospiro[azetidine-3,2'-chromane]-1,6',7'-tricarboxylate (Intermediate 10b)

[0462] Diethylaminosulfur trifluoride (5 mL) was slowly added to intermediate 10a (1 g, 2.5 mmol). The reaction mixture was stirred at 50°C overnight. The resulting mixture was poured into ice water to quench, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (PE:EA = 0-40%) to give intermediate 10b (500 mg, 47%) as a light yellow solid.

[0463] 1H NMR (400MHz, DMSO-d6) δ8.01 (s, 1H), 7.34 (s, 1H), 4.13 (d, J = 9.7Hz, 2H), 3.91 ( d,J=9.7Hz,2H),3.83(s,3H),3.82(s,3H),3.04(t,J=13.4Hz,2H),1.39(s,9H).

[0464] LC-MS(ESI):[M-Boc+H] + =328.30

[0465] Step 2: 1-(tert-Butyloxycarbonyl)-4',4'-difluorospiro[azetidine-3,2'-chromane]-6',7'-dicarboxylic acid (Intermediate 10c)

[0466] Intermediate 10b (500 mg, 1.2 mmol) was dissolved in methanol (5 mL), and an aqueous solution of lithium hydroxide (140.1 mg, 5.9 mmol) was slowly added at room temperature. The reaction was stirred at room temperature for 2 h. The reaction solution was neutralized with acetic acid to pH 7. The product was concentrated under vacuum and extracted with ethyl acetate to yield a crude white solid, which was used directly in the next step without further purification.

[0467] LC-MS(ESI):[M+H] + =399.28

[0468] Step 3: 7'-(2,6-dioxapiperidin-3-yl)-4',4'-difluoro-3',4'-dihydro-6'H-spiro[azetidine-3,2'-pyrano[2,3-f]isoindole]-6',8'(7'H)-dione (Intermediate 10)

[0469] Under nitrogen, Intermediate 10c (100 mg, 0.3 mmol) was dissolved in acetic acid (1 mL). Sodium acetate (61.6 mg, 0.8 mmol) and 3-aminopiperidine-2,6-dione hydrochloride (64.5 mg, 0.5 mmol) were added, and the mixture was heated to 110°C and stirred for 3 h. After completion of the reaction, the mixture was purified via a C18 reverse-phase column to yield Intermediate 10 (3.6 mg, 4%) as a white solid.

[0470] 1H NMR (600MHz, DMSO-d6) δ11.15(s,1H),8.13(s,1H),7.58(s,1H),5.18(dd,J=13.0,5.4Hz,1H),4.33(d,J=11.7Hz,2H),4. 22(d,J=11.6Hz,2H),3.15(t,J=13.6Hz,2H),2.94–2.87(m,1H),2.65–2.59(m,1H),2.54–2.51(m,1H),2.10–2.05(m,1H).

[0471] LC-MS(ESI):[M+H] + =392.30

[0472] Example 11, Synthesis of Intermediate 11

[0473] 7'-(2,6-dioxapiperidin-3-yl)-3',3'-difluoro-3',4'-dihydro-6'H-spiro[piperidin-4,2'-pyrano[2,3-f]isoindole]-6',8'(7'H)-dione

[0474] Synthesis scheme:

[0475] Step 1: 1'-(tert-Butyl)6,7-dimethyl-3,3-difluoro-4-oxospiro[chromane-2,4'-piperidine]-1',6,7-tricarboxylate (Intermediate 11a)

[0476] Intermediate 1e (5 g, 11.5 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL). The temperature was lowered to -78°C and sodium bis(trimethylsilyl)amide (4.23 g, 23.07 mmol) was added dropwise. The reaction was incubated for 2 h. N-fluorobisbenzenesulfonamide (7.3 g, 23.1 mmol) was then added dropwise at -78°C. The reaction was stirred overnight at -78°C. The resulting mixture was quenched by pouring into saturated ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (PE:EA = 0-40%) to afford intermediate 11a (2.5 g, 46%) as a pale yellow solid.

[0477] 1 H NMR (400MHz, DMSO-d6) δ8.29 (s, 1H), 7.62 (s, 1H), 3.94 (d, J = 11.6Hz, 2H), 3.85 (s, 3H), 3. 86(s,3H),3.08(s,2H),2.07(d,J=13.4Hz,2H),1.74(td,J=13.5,4.7Hz,2H),1.41(s,9H).

[0478] LC-MS(ESI):[M+H] + =470.31

[0479] Step 2: 1'-(tert-Butyl)6,7-dimethyl 3,3-difluoro-4-hydroxyspiro[chromane-2,4'-piperidine]-1',6,7-tricarboxylate (Intermediate 11b)

[0480] Intermediate 11a (2.5 g, 5.3 mmol) was dissolved in ethanol (5 mL) and sodium borohydride (403 mg, 10.7 mmol) was slowly added at 0°C. The reaction was stirred at room temperature for 1 h. The reaction solution was quenched with acetone. After concentration under vacuum, the crude product was purified by column chromatography (PE:EA = 0-40%) to afford Intermediate 11b (2.4 g, 95%) as a white solid.

[0481] 1 H NMR (400MHz, DMSO-d6) δ7.90(s,1H),7.23(s,1H),6.68(d,J=6.1Hz,1H),5.03(dt,J=16.1,7.0Hz,1H),3.97(d,J=14.1Hz, 1H),3.91–3.75(m,7H),3.04(d,J=55.0Hz,2H),1.99(d,J=13.3Hz,1H),1.84–1.74(m,2H),1.70–1.56(m,1H),1.41(s,9H).

[0482] LC-MS(ESI):[M-Boc+H] + =372.34

[0483] Step 3: 1'-(tert-butyl)6,7-dimethyl-3,3-difluoro-4-(toluenesulfonyloxy)spiro[chromane-2,4'-piperidine]-1',6,7-tricarboxylic acid (Intermediate 11c)

[0484] Intermediate 11b (1.5 g, 3.2 mmol) was dissolved in dichloromethane (30 mL). p-Toluenesulfonyl chloride (727 mg, 3.8 mmol) and triethylamine (642 mg, 6.4 mmol) were added under ice-cooling. The mixture was stirred at room temperature for 2 h. After concentration under vacuum, the crude product was purified by column chromatography (PE:EA = 0-40%) to afford Intermediate 11c (1.0 g, 50%) as a white solid.

[0485] 1H NMR (600MHz, DMSO-d6) δ7.98(d,J=8.2Hz,2H),7.56(d,J=8.1Hz,2H),7.41(s,1H),7.35(s,1H),6.25(dd,J=12.9,8.1Hz,1H),3.90(dd,J=2 1.4,8.9Hz,2H),3.81(s,3H),3.79(s,3H),3.06(s,2H),2.48(s,3H),1.99–1.91(m,2H),1.67(dtd,J=39.4,13.3,4.7Hz,2H),1.41(s,9H).

[0486] LC-MS(ESI):[M-Boc+H] + =526.34

[0487] Step 4: 1'-(tert-Butyl)6,7-dimethyl 3,3-difluorospiro[chromane-2,4'-piperidine]-1',6,7-tricarboxylate (Intermediate 11d)

[0488] Intermediate 11c (1.0 g, 1.6 mmol) was dissolved in methanol (20 mL), and palladium on carbon (100 mg) was added. The mixture was stirred under a hydrogen atmosphere at room temperature for 12 h. The mixture was filtered, washed with methanol, and concentrated under vacuum to obtain Intermediate 11d (700 mg, 96%) as a white solid.

[0489] 1 H NMR(600MHz,DMSO-d6)δ7.70(s,1H),7.28(s,1H),3.95–3.88(m,2H),3.86–3.74(m,8H),3 .51(t,J=15.8Hz,2H),1.81(d,J=13.2Hz,2H),1.69(td,J=13.6,4.9Hz,2H),1.42(s,9H).

[0490] LC-MS(ESI):[M-tBu+H] + =400.44

[0491] Step 5: 1'-(tert-Butyloxycarbonyl)-3,3-difluorospiro[chromane-2,4'-piperidine]-6,7-dicarboxylic acid (Intermediate 11e)

[0492] Intermediate 11d (700 mg, 1.5 mmol) was dissolved in methanol and water (10 mL). Lithium hydroxide (184 mg, 7.7 mmol) was added and stirred at room temperature for 2 h. Glacial acetic acid was added to neutralize the mixture to pH 7. Concentrate under vacuum and extract with ethyl acetate to obtain a crude white solid that was used directly in the next step without further purification.

[0493] LC-MS(ESI):[M-Boc+H] + =328.32

[0494] Step 6: 7'-(2,6-dioxapiperidin-3-yl)-3',3'-difluoro-3',4'-dihydro-6'H-spiro[piperidine-4,2'-pyrano[2,3-f]isoindole]-6',8'(7'H)-dione (Intermediate 11)

[0495] Under nitrogen, intermediate 11e (600 mg, 1.4 mmol) was dissolved in acetic acid (10 mL). Sodium acetate (346 mg, 4.2 mmol) and 3-aminopiperidine-2,6-dione hydrochloride (360 mg, 2.8 mmol) were added, and the mixture was heated to 110°C and stirred for 3 h. After completion of the reaction, the mixture was purified via a C18 reverse-phase column to yield intermediate 11 (70 mg, 12%) as a white solid.

[0496] 1 H NMR (400MHz, CD3OD) δ7.78 (s, 1H), 7.55 (s, 1H), 5.13 (dd, J=12.6, 5.4Hz, 1H), 3.60 (t, J= 15.5Hz,2H),3.50–3.34(m,4H),2.93–2.82(m,1H),2.80–2.66(m,2H),2.24–2.09(m,5H).

[0497] LC-MS(ESI):[M+H] + =420.41.

[0498] Example 12, Synthesis of Intermediate 12

[0499] 3-(6'-oxa-3',4',6',8'-tetrahydro-7'H-spiro[piperidin-4,2'-pyrano[2,3-f]isoindol]-7'-yl)piperidin-2,6-dione

[0500] Synthesis scheme:

[0501] Step 1: 1-(5-Bromo-2-hydroxy-4-methylphenyl)ethan-1-one (Intermediate 12b)

[0502] A mixture of intermediate 12a (5.0 g, 26.7 mmol) and acetyl chloride (10.5 g, 134 mmol) was stirred at 60°C for 1 hour, followed by the addition of aluminum chloride (5.4 g, 40.1 mmol) at room temperature. After stirring at 160°C for 2 hours, the mixture was cooled to room temperature, poured into saturated ammonium chloride solution (50 mL), and extracted with EA (50 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to afford crude intermediate 12b as an off-white solid (5.5 g, 90%).

[0503] 1 H NMR (600MHz, DMSO-d6) δ11.81(s,1H),8.01(s,1H),7.00(s,1H),2.62(s,3H),2.34(s,3H).

[0504] Step 2: Methyl 5-acetyl-4-hydroxy-2-methylbenzoate (Intermediate 12c)

[0505] To a solution of Intermediate 12b (5.5 g, 24.01 mmol) in methanol (50 mL) were added triethylamine (9.72 g, 96.04 mmol) and Pd(dppf)Cl2 (1.76 g, 2.40 mmol). The mixture was purged with CO three times and then stirred at 60°C overnight. After the reaction, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting mixture was purified by column chromatography (PE:EA = 6:1) to afford Intermediate 12c (3.26 g, 65%) as a white solid.

[0506] 1 H NMR (600MHz, DMSO-d6) δ12.14(s,1H),8.34(s,1H),6.90(s,1H),3.82(s,3H),2.64(s,3H),2.53(s,3H).

[0507] Step 3: 1'-(tert-butyl)6-methyl-7-methyl-4-oxaspiro[chroman-2,4'-piperidine]-1',6-dicarboxylate (Intermediate 12d)

[0508] To a solution of Intermediate 12c (3.1 g, 14.89 mmol) in ethanol (120 mL) were added N-tert-butyloxycarbonyl-3-azetidinone (2.8 g, 16.38 mmol) and tetrahydropyrrole (1.59 g, 22.33 mmol). The reaction was stirred at 80°C overnight. After completion of the reaction, the resulting mixture was concentrated under vacuum and purified by column chromatography (PE:EA = 0-20%) to afford Intermediate 12d (1.9 g, 35%) as a yellow solid.

[0509] 1 H NMR(600MHz,DMSO-d6)δ8.25(s,1H),7.08(s,1H),3.82(s,3H),3.72(s,2H),3.14(s ,2H),2.89(s,2H),2.55(s,3H),1.91-1.84(m,2H),1.69-1.61(m,2H),1.40(s,9H).

[0510] LC-MS(ESI):[M-Boc+H] + =290.27.

[0511] Step 4: 1'-(tert-Butyl)6-methyl-4-hydroxy-7-methylspiro[chroman-2,4'-piperidine]-1',6-dicarboxylate (Intermediate 12e)

[0512] To a solution of Intermediate 12d (1.6 g, 4.43 mmol) in methanol (40 mL) was added sodium borohydride (504 mg, 13.28 mmol). The reaction was stirred at room temperature for 4 hours. After completion of the reaction, the resulting mixture was concentrated under vacuum and purified by column chromatography (PE:EA = 0-40%) to afford Intermediate 12e (1.5 g, 93.23%) as a yellow solid.

[0513] 1 H NMR (600MHz, DMSO-d6) δ8.01(s,1H),6.73(s,1H),5.52(d,J=4.7Hz,1H),4.68(s,1H),3.78(s,3H),3.68(dd,J=22.7,9.0Hz ,2H),3.13(d,J=77.0Hz,2H),2.46(s,3H),2.13(dd,J=13.5,6.0Hz,1H),1.82-1.62(m,4H),1.59-1.50(m,1H),1.41(s,9H).

[0514] LC-MS(ESI):[M-Boc+H] + =292.30

[0515] Step 5: 1'-(tert-Butyl)6-methyl-7-methylspiro[chromene-2,4'-piperidine]-1',6-dicarboxylate (Intermediate 12f)

[0516] To a solution of intermediate 12e (1.5 g, 4.13 mmol) in toluene (40 mL) was added p-toluenesulfonic acid (712 mg, 4.13 mmol). The reaction was stirred at 110°C overnight. After completion of the reaction, the system was concentrated under vacuum to obtain a mixture, which was dissolved in tetrahydrofuran (40 mL). Triethylamine (2.23 g, 22.02 mmol) and di-tert-butyl dicarbonate (2.4 g, 11.01 mmol) were added, and the mixture was stirred at room temperature overnight. After completion of the reaction, the system was concentrated under vacuum, and the resulting mixture was purified by column chromatography (PE:EA = 0-30%) to afford intermediate 12f (1.1 g, 77%) as a yellow solid.

[0517] 1 H NMR (600MHz, DMSO-d6) δ7.64(s,1H),6.80(s,1H),6.55(d,J=9.9Hz,1H),5.80(d,J=9.8Hz,1H),3.78(s,3H) ,3.70(d,J=13.0Hz,2H),3.30–3.11(m,2H),2.47(s,3H),1.84-1.78(m,2H),1.68-1.60(m,2H),1.41(s,9H).

[0518] LC-MS(ESI):[M-Boc+H] + =274.26

[0519] Step 6: 1'-(tert-butyl)6-methyl7-(bromomethyl)spiro[chromene-2,4'-piperidine]-1',6-dicarboxylate (Intermediate 12g)

[0520] To a solution of intermediate 12f (1 g, 2.90 mmol) in carbon tetrachloride (10 mL) were added N-bromosuccinimide (620 mg, 3.47 mmol) and azobisisobutyronitrile (48 mg, 290 μmol). The reaction was replaced with a nitrogen atmosphere and stirred at 80°C overnight. After completion of the reaction, the system was concentrated under vacuum, and the crude product was used directly in the next step.

[0521] Step 7: 3-(6'-oxa-6',8'-dihydro-7'H-spiro[piperidin-4,2'-pyrano[2,3-f]isoindol]-7'-yl)piperidine-2,6-dione (Intermediate 12h)

[0522] The mixture from the previous step was dissolved in acetonitrile (40 mL), and diisopropylethylamine (1.12 g, 8.70 mmol) and 3-amino-2,6-piperidinedione (446 mg, 3.48 mmol) were added. The mixture was stirred at 80°C overnight. After concentration, acetic acid (10 mL) was added and the reaction continued for 2 hours. After the reaction was complete, the system was concentrated under vacuum, and the resulting mixture was purified by column chromatography (PE:EA = 0-50%) to obtain 12 g (285 mg, 22%) of the black solid intermediate.

[0523] 1 H NMR (600MHz, CD3OD) δ7.52(s,1H),7.13(s,1H),6.69(d,J=9.9Hz,1H),5.83(d,J=9.9Hz,1 H),5.13(dd,J=13.3,5.1Hz,1H),4.45(dd,J=35.2,17.3Hz,2H),3.48-3.40(m,2H),3.38- 3.33(m,2H),2.91(ddd,J=18.2,11.8,5.0Hz,2H),2.82-2.77(m,1H),2.49(ddd,J=17.9,1 2.7,3.8Hz,1H),2.29-2.22(m,2H),2.17(tdd,J=13.4,6.7,4.2Hz,1H),2.03-1.95(m,2H).

[0524] LC-MS(ESI):[M+H] + =368.38.

[0525] Step 8: 3-(6'-oxa-3',4',6',8'-tetrahydro-7'H-spiro[piperidin-4,2'-pyrano[2,3-f]isoindol]-7'-yl)piperidine-2,6-dione (Intermediate 12)

[0526] The intermediate 12 g of the product from the previous step was dissolved in methanol (10 mL), palladium carbon (150 mg) was added thereto, and the reaction system was replaced with a hydrogen atmosphere. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated under vacuum. The mixture was purified by preparative high-performance liquid chromatography to obtain a white solid intermediate 12 (120 mg, two-step yield 35%).

[0527] 1H NMR (600MHz, DMSO-d6) δ10.97(s,1H),7.51(s,1H),7.05(s,1H),5.07(dd,J=13.3,5.1Hz,1H),4.34(d,J=16.9Hz,1H),4.22(d,J=16.9Hz, 1H),3.26-3.20(m,2H),3.16-3.08(m,2H),2.94-2.86(m,3H),2.63-2 .57(m,1H),2.41-2.33(m,1H),2.00-1.87(m,5H),1.85-1.77(m,2H).

[0528] LC-MS(ESI):[M+H] + =370.39.

[0529] Example 13. Synthesis of Intermediate 13

[0530] 3-(6'-oxa-3',4',6',8'-tetrahydro-7'H-spiro[azetidine-3,2'-pyrano[2,3-f]isoindol]-7'-yl)piperidine-2,6-dione

[0531] Synthesis scheme:

[0532] Step 1: 1-(tert-Butyl)6'-methyl7'-methyl-4'-oxaspiro[azetidine-3,2'-chroman]-1,6'-dicarboxylate (Intermediate 13a)

[0533] To a solution of Intermediate 12c (3.1 g, 14.89 mmol) in ethanol (120 mL) were added N-tert-butyloxycarbonyl-3-azetidinone (2.8 g, 16.38 mmol) and tetrahydropyrrole (1.59 g, 22.33 mmol). The reaction was stirred at 80°C overnight. After completion of the reaction, the system was concentrated under vacuum, and the resulting mixture was purified by column chromatography (PE:EA = 0-20%) to afford Intermediate 13a (1.9 g, 35%) as a yellow solid.

[0534] 1 H NMR (600MHz, DMSO-d6) δ8.24(s,1H),7.15(s,1H),4.00(d,J=8.7Hz,2H),3.89(d,J=8.7Hz,2H),3.82(s,3H),3.20(s,2H),2.56(s,3H),1.38(s,9H).

[0535] LC-MS(ESI):[M-Boc+H] +=262.25.

[0536] Step 2: 1-(tert-Butyl)6'-methyl-4'-hydroxy-7'-methylspiro[azetidine-3,2'-chroman]-1,6'-dicarboxylate (Intermediate 13b)

[0537] To a solution of Intermediate 13a (1.6 g, 4.43 mmol) in methanol (40 mL) was added sodium borohydride (504 mg, 13.28 mmol). The reaction was stirred at room temperature for 4 hours. After completion, the system was concentrated under vacuum, and the resulting mixture was purified by column chromatography (PE:EA = 0-40%) to afford Intermediate 13b (1.5 g, 93.23%) as a yellow solid.

[0538] 1 H NMR (600MHz, CD3OD) δ8.02(s,1H),6.81(s,1H),4.82(t,J=5.2Hz,1H),4.28(d,J=9.6Hz,1H),4.04(dd,J=1 9.0,9.1Hz,2H),3.95(d,J=9.7Hz,1H),3.87-3.84(m,3H),2.54(s,3H),2.32(d,J=5.2Hz,2H),1.47(s,9H).

[0539] LC-MS(ESI):[M-Boc+H] + =264.27.

[0540] Step 3: 1-(tert-Butyl)6'-methyl7'-methylspiro[azetidine-3,2'-chromene]-1,6'-dicarboxylate (Intermediate 13c)

[0541] To a solution of intermediate 13b (1.5 g, 4.13 mmol) in toluene (40 mL) was added p-toluenesulfonic acid (712 mg, 4.13 mmol). The reaction was stirred at 110°C overnight. The resulting mixture was concentrated under vacuum, dissolved in tetrahydrofuran (40 mL), and triethylamine (2.23 g, 22.02 mmol) and di-tert-butyl dicarbonate (2.4 g, 11.01 mmol) were added. The mixture was stirred at room temperature overnight. The resulting mixture was concentrated under vacuum and purified by column chromatography (PE:EA = 0-30%) to afford intermediate 13c (1.1 g, 77%) as a yellow solid.

[0542] 1H NMR (600MHz, DMSO-d6) δ7.67(s,1H),6.84(s,1H),6.65(d,J=9.9Hz,1H),6.16(d,J=9.9Hz,1H),4.04(s,4H),3.78(s,3H),2.47(s,3H),1.40(s,9H).

[0543] LC-MS(ESI):[M-Boc+H] + =246.23.

[0544] Step 4: tert-Butyl 7'-(2,6-dioxapiperidin-3-yl)-6'-oxa-7',8'-dihydro-6'H-spiro[azetidine-3,2'-pyrano[2,3-f]isoindole]-1-carboxylate (Intermediate 13d)

[0545] To a solution of Intermediate 13c (1 g, 2.90 mmol) in carbon tetrachloride (10 mL) were added N-bromosuccinimide (620 mg, 3.47 mmol) and azobisisobutyronitrile (48 mg, 290 μmol). The reaction system was replaced with a nitrogen atmosphere and stirred at 80°C overnight. The resulting mixture was concentrated under vacuum, dissolved in acetonitrile (40 mL), and diisopropylethylamine (1.12 g, 8.70 mmol) and 3-amino-2,6-piperidinedione (446 mg, 3.48 mmol) were added. The mixture was stirred at 80°C overnight. The resulting mixture was concentrated under vacuum and purified by column chromatography (PE:EA = 0-50%) to afford Intermediate 13d (285 mg, 22%) as a black solid.

[0546] 1 H NMR (600MHz, CD3OD) δ7.50(s,1H),7.09(s,1H),6.69(d,J=9.9Hz,1H),6.17(d,J=9.8Hz,1H),5.12(dd,J=13.2,5.2Hz,1H),4.50-4.40(m,2H),4.2 4-4.19(m,2H),4.10(d,J=8.9Hz,2H),2.94-2.86(m,1H),2.82-2.77(m,1 H),2.49(ddd,J=26.5,13.2,4.5Hz,1H),2.19-2.15(m,1H),1.48(s,9H).

[0547] LC-MS(ESI):[M+H] + =440.38.

[0548] Step 5: 3-(6'-oxa-6',8'-dihydro-7'H-spiro[azetidine-3,2'-pyrano[2,3-f]isoindol]-7'-yl)piperidine-2,6-dione (Intermediate 13e)

[0549] Intermediate 13d (285 mg, 648.5 μmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (636 mg, 6.49 mmol) was added, and the reaction was stirred at room temperature for 2 hours. After completion of the reaction, the solution was concentrated and used directly in the next step.

[0550] LC-MS(ESI):[M+H] + =340.32.

[0551] Step 6: 3-(6'-oxa-3',4',6',8'-tetrahydro-7'H-spiro[azetidine-3,2'-pyrano[2,3-f]isoindol]-7'-yl)piperidine-2,6-dione (Intermediate 13)

[0552] The mixture from the previous step was dissolved in methanol (10 mL), and palladium on carbon (10%, 150 mg) was added thereto. The reaction system was replaced with a hydrogen atmosphere and stirred at room temperature for 2 hours. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated under vacuum. The product was purified by preparative high-performance liquid chromatography to give a white solid intermediate 13 (120 mg, two-step yield 35%).

[0553] 1 H NMR (400MHz, CD3OD) δ7.57(s,1H),7.10(s,1H),5.11(dd,J=13.3,5.1Hz,1H),4.50-4.35(m,2H),4.24(s,4H),2.97(t,J=5.8Hz,2H),2.91-2. 84(m,1H),2.77(ddd,J=17.6,4.5,2.3Hz,1H),2.46(ddd,J=26.4,13.2,4.7Hz,1H),2.28(t,J=6.1Hz,2H),2.14(dtd,J=12.7,5.2,2.3Hz,1H).

[0554] LC-MS(ESI):[M+H] + =342.32.

[0555] Example 14. Synthesis of Intermediate 14

[0556] 3-(8'-oxa-3',4',6',8'-tetrahydro-7'H-spiro[piperidin-4,2'-pyrano[2,3-f]isoindol]-7'-yl)piperidin-2,6-dione

[0557] Synthesis scheme:

[0558] Step 1: 1-(4-Bromo-2-hydroxy-5-methylphenyl)ethan-1-one (Intermediate 14b)

[0559] Intermediate 14a (15.2 g, 81.27 mmol) was added to acetyl chloride (30 mL) and stirred at 60°C for 1 hour. After the reaction solution cooled to room temperature, aluminum chloride (16.25 g, 121.90 mmol) was slowly added. After completion, the reaction solution was stirred at 160°C for 3 hours. The resulting mixture was poured into ice water, filtered, and washed with saturated aqueous ammonium chloride. The mixture was concentrated under vacuum to obtain a mixture, which was then purified by column chromatography (PE:EA = 0-50%) to obtain Intermediate 14b (18.0 g, 96%) as a yellow-brown solid.

[0560] 1 H NMR (600MHz, CDCl3) δ12.10(s,1H),7.57(s,1H),7.25(s,1H),2.63(s,3H),2.39(s,3H).

[0561] Step 2: Methyl 4-acetyl-5-hydroxy-2-methylbenzoate (Intermediate 14c)

[0562] To a solution of Intermediate 14b (3.0 g, 13.1 mmol) in methanol (60 mL) were added triethylamine (1.99 g, 19.6 mmol) and Pd(dppf)Cl2 (1.42 g, 1.96 mmol). Under a carbon monoxide atmosphere, the reaction was stirred at 60°C overnight. After completion of the reaction, the filtrate was filtered and concentrated under vacuum. The resulting mixture was purified by column chromatography (PE:EA = 0-50%) to afford Intermediate 14c (16.3 g, 51%) as a tan solid.

[0563] 1 H NMR (600MHz, CDCl3) δ11.88(s,1H),7.60(s,1H),7.49(s,1H),3.93(s,3H),2.68(s,3H),2.53(s,3H).

[0564] Step 3: 1'-(tert-butyl)7-methyl-6-methyl-4-oxaspiro[chroman-2,4'-piperidine]-1',7-dicarboxylate (Intermediate 14d)

[0565] Intermediate 14c (10.11 g, 48.56 mmol), N-tert-butyloxycarbonyl-4-piperidone (9.67 g, 48.56 mmol), and tetrahydropyrrole (3.45 g, 48.56 mmol) were dissolved in methanol (50 mL) and refluxed at 80°C for 6 h. After the reaction was complete, the mixture was extracted, filtered, and concentrated to obtain the crude product, which was then purified by column chromatography (PE:EA = 0-50%) to afford Intermediate 14d (15.53 g, 82%) as a pale yellow solid.

[0566] 1 H NMR (600MHz, DMSO-d6) δ7.64(s,1H),7.45(s,1H),3.85(s,3H),3.71(s,2H),3.12(d,J=50.1Hz ,2H),2.88(s,2H),2.43(s,3H),1.90-1.84(m,2H),1.62(td,J=12.7,4.6Hz,2H),1.40(s,9H).

[0567] LC-MS(ESI):[M-Boc+H] + =290.26.

[0568] Step 4: 1'-(tert-Butyl)7-methyl-4-hydroxy-6-methylspiro[chroman-2,4'-piperidine]-1',7-dicarboxylate (Intermediate 14e)

[0569] To a solution of Intermediate 14d (15.53 g, 39.88 mmol) in methanol (70 mL) was added sodium borohydride (6.03 g, 159.51 mmol) in an ice bath. The reaction was stirred at room temperature for 2 hours. After completion of the reaction, the resulting mixture was concentrated under vacuum and purified by column chromatography (PE:EA = 0-50%) to afford Intermediate 14e (15.39 g, 98%) as a yellow foam.

[0570] 1 H NMR (600MHz, CDCl3) δ7.40 (s, 1H), 7.32 (s, 1H), 4.83 (t, J = 7.0Hz, 1H), 3.90-3.84 (m, 5H), 3.31-3.05 (m, 2H), 2.93 (s, 1H), 2.49 (s, 3H), 2.11 ( dd,J=13.6,6.1Hz,1H),1.92-1.85(m,2H),1.78-1.72(m,1H),1.63(td,J=13.3,4.6Hz,1H),1.52(ddd,J=24.7,12.6,7.9Hz,1H),1.46(s,9H).

[0571] LC-MS(ESI):[M-Boc+H] - =292.27.

[0572] Step 5: Methyl 6-methylspiro[chroman-2,4'-piperidine]-7-dicarboxylate (Intermediate 14f)

[0573] Intermediate 14e (15.23 g, 38.91 mmol) and p-toluenesulfonic acid (6.7 g, 38.91 mmol) were dissolved in toluene and refluxed at 110°C overnight. The resulting pale yellow oily mixture was concentrated under vacuum to give Intermediate 14f (8.6 g, 80%). The crude product was used directly in the next step.

[0574] LC-MS(ESI):[M-Boc+H] + =274.29.

[0575] Step 6: 1'-(tert-Butyl)7-methyl6-methylspiro[chromene-2,4'-piperidine]-1',7-dicarboxylate (Intermediate 14g)

[0576] Intermediate 14f (8.6 g, 31.46 mmol), di-tert-butyl dicarbonate (13.73 g, 62.93 mmol) and triethylamine (9.55 g, 94.39 mmol) were dissolved in dichloromethane (30 mL), and the mixture was stirred at room temperature for 4 hours. The resulting mixture was concentrated under vacuum and purified by column chromatography (PE:EA=0-30%) to give Intermediate 14g (1.8 g, 83%) as a colorless solid.

[0577] 1 H NMR (600MHz, CDCl3) δ7.41(s,1H),6.85(s,1H),6.37(d,J=9.8Hz,1H),5.65(d,J=9.6Hz,1H),3.98-3.7 7(m,5H),3.28(s,2H),2.50(s,3H),1.97(d,J=13.4Hz,2H),1.59(td,J=13.4,4.7Hz,2H),1.47(s,9H).

[0578] LC-MS(ESI):[M-Boc+H] + =274.24.

[0579] Step 7: 1'-(tert-Butyl)7-methyl 6-(bromomethyl)spiro[chromene-2,4'-piperidine]-1',7-dicarboxylate (Intermediate 14h)

[0580] Intermediate 14g (5.11 g, 13.68 mmol), N-bromosuccinimide (2.73 g, 15.33 mmol), and azobisisobutyronitrile (0.112 g, 6.84 mmol) were dissolved in carbon tetrachloride (30 mL) and the reaction was refluxed at 80°C overnight under nitrogen. The mixture was extracted and dried to give Intermediate 14h (1.32 g, 21%) as a colorless oil. The crude product was used directly in the next step.

[0581] Step 8: 3-(8'-oxa-6',8'-dihydro-7'H-spiro[piperidin-4,2'-pyrano[2,3-f]isoindol]-7'-yl)piperidine-2,6-dione (Intermediate 14i)

[0582] Intermediate 14g (1.56 g, 3.45 mmol) was dissolved in acetonitrile (20 mL), and 3-aminopiperidine-2,6-dione hydrochloride (0.53 g, 4.14 mmol) and N,N-diisopropylethylamine (1.33 g, 10.35 mmol) were added. The reaction was stirred at 80°C overnight. The mixture was then dried and acetic acid (1 mL) was added and refluxed at 110°C for 2 hours. After completion of the reaction, the mixture was purified by reverse phase column chromatography to obtain intermediate 14i (0.96 g, 75%) as a brown solid.

[0583] 1 H NMR(600MHz,DMSO-d6)δ11.00(s,1H),7.36(s,1H),7.25(s,1H),6.68(d,J=9.8Hz,1H),5.9 9(d,J=9.8Hz,1H),5.08(dd,J=13.3,5.2Hz,1H),4.37(d,J=16.9Hz,1H),4.25(d,J=16.9Hz, 1H),3.26-3.19(m,4H),2.90(ddd,J=17.3,13.7,5.5Hz,1H),2.64-2.57(m,1H),2.39(qd,J= 13.2, 4.5Hz, 1H), 2.10–2.03 (m, 2H), 2.00 (dtd, J=12.8, 5.4, 2.4Hz, 1H), 1.94–1.86 (m, 2H).

[0584] LC-MS(ESI):[M+H] + =368.37.

[0585] Step 9: 3-(8'-oxa-3',4',6',8'-tetrahydro-7'H-spiro[piperidin-4,2'-pyrano[2,3-f]isoindol]-7'-yl)piperidine-2,6-dione (Intermediate 14)

[0586] Intermediate 14i (0.668 g, 1.82 mmol) was dissolved in methanol (15 mL) and palladium on carbon (0.2 g) was added. The reaction was stirred at room temperature under hydrogen atmosphere overnight. The mixture was filtered and dried, and then purified by reverse phase column chromatography to afford Intermediate 14 (0.536 g, 79%) as a white solid.

[0587] 1 H NMR (600MHz, DMSO-d6) δ10.99(s,1H),7.36(s,1H),7.18(s,1H),5.07(dd,J=13.3,5.1Hz,1H),4.34(d,J=16.6Hz,1H),4.21(d,J=16.5Hz,1H),3 .25-3.11(m,4H),2.94-2.87(m,3H),2.63-2.57(m,1H),2.39(qd,J=13. 2,4.5Hz,1H),2.01-1.95(m,1H),1.93-1.87(m,4H),1.82-1.74(m,2H).

[0588] LC-MS(ESI):[M+H] + =370.36.

[0589] Example 15. Synthesis of Intermediate 15

[0590] 3-(8'-oxa-3',4',6',8'-tetrahydro-7'H-spiro[azetidine-3,2'-pyrano[2,3-f]isoindol]-7'-yl)piperidine-2,6-dione

[0591] Synthesis scheme:

[0592] Step 1: 1-(tert-Butyl)7'-methyl-6'-methyl-4'-oxaspiro[azetidine-3,2'-chroman]-1,7'-dicarboxylate (Intermediate 15a)

[0593] To a solution of intermediate 14c (12 g, 57.6 mmol) in ethanol (200 mL) were added 1-Boc-3-azetidinone (9.9 g, 57.6 mmol) and tetrahydropyrrole (4.1 g, 57.6 mmol). The reaction solution was stirred at 80°C for 4 hours. 1-Boc-3-azetidinone (9.9 g, 57.6 mmol) and tetrahydropyrrole (4.1 g, 57.6 mmol) were added to the reaction solution again, and the reaction solution was stirred at 80°C for 16 hours. The resulting mixture was concentrated under vacuum and purified by column chromatography (PE:EA = 0-40%) to give intermediate 15a (8 g, 38%) as a yellow solid.

[0594] 1 H NMR (600MHz, CDCl3) δ7.74(s,1H),7.59(s,1H),4.09(d,J=9.6Hz,2H),3.97(d,J=9.5Hz,2H),3.94(s,3H),3.07(s,2H),2.53(s,3H),1.46(s,9H).

[0595] LC-MS(ESI):[M-Boc+H] + =262.28.

[0596] Step 2: 1-(tert-Butyl)7'-methyl-4'-hydroxy-6'-methylspiro[azetidine-3,2'-chroman]-1,7'-dicarboxylate (Intermediate 15b)

[0597] To a solution of intermediate 15a (5 g, 13.8 mmol) in methanol (100 mL) was slowly added sodium borohydride (786 mg, 20.8 mmol). The reaction solution was stirred at room temperature for 4 hours and extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo to give intermediate 15b (4.2 g, 83%) as a yellow oily liquid.

[0598] 1 H NMR(600MHz, CDCl3)δ7.50(s,1H),7.24(s,1H),4.89(q,J=5.2Hz,1H),4.36(q,J=7.2Hz,1H),4.27–4.23(m,1H),4 .10(d,J=9.3Hz,1H),4.00(dd,J=17.3,9.6Hz,2H),3.90(s,3H),2.54(s,3H),2.35(d,J=5.3Hz,2H),1.47(s,9H).

[0599] LC-MS(ESI):[M-Boc+H] + =264.27.

[0600] Step 3: Methyl 6'-methylspiro[azetidine-3,2'-chromene]-7'-carboxylate (Intermediate 15c)

[0601] To a solution of intermediate 15b (4 g, 13.8 mmol) in toluene (100 mL) was added hydrated p-toluenesulfonic acid (2.3 g, 12.1 mmol). The reaction was stirred at 110°C for 18 h. The reaction was concentrated in vacuo to give a crude yellow solid, which was used directly in the next step without further purification.

[0602] LC-MS(ESI):[M+H] + =246.22.

[0603] Step 4: 1-(tert-Butyl)7'-methyl6'-methylspiro[azetidine-3,2'-chromene]-1,7'-dicarboxylate (Intermediate 15d)

[0604] To a solution of Intermediate 15c (2 g, 8.2 mmol) in dichloromethane (30 mL) were added di-tert-butyl dicarbonate (2.1 g, 9.8 mmol) and triethylamine (3.2 mL). The reaction was stirred at room temperature for 4 hours. The resulting mixture was concentrated under vacuum and purified by column chromatography (PE:EA = 0-40%) to afford Intermediate 15d (2.5 g, 88%) as a colorless liquid.

[0605] 1 H NMR (600MHz, CDCl3) δ7.45(s,1H),6.88(s,1H),6.47(d,J=9.8Hz,1H),6.06(d,J=9.7H z,1H),4.24(d,J=9.5,2H),4.01(d,J=9.5,2H),3.89(s,3H),2.51(s,3H),1.48(s,9H).

[0606] LC-MS(ESI):[M-tBu+H] + =290.20

[0607] Step 5: 1-(tert-Butyl)7'-methyl 6'-(bromomethyl)spiro[azetidine-3,2'-chromene]-1,7'-dicarboxylate (Intermediate 15e)

[0608] To a solution of intermediate 15e (2 g, 5.8 mmol) in carbon tetrachloride (30 mL) were added NBS (1.2 g, 6.4 mmol) and AIBN (99 mg, 0.6 mmol). The reaction was stirred at 80°C for 12 hours. The resulting mixture was concentrated under vacuum and purified by column chromatography (PE:EA = 0-40%) to afford a colorless crude liquid that was used directly in the next step without further purification.

[0609] Step 6: tert-Butyl 7'-(2,6-dioxapiperidin-3-yl)-8'-oxa-7',8'-dihydro-6'H-spiro[azetidine-3,2'-pyrano[2,3-f]isoindole]-1-carboxylate (Intermediate 15f)

[0610] To a solution of Intermediate 15e (2 g, 0.7 mmol) in acetonitrile (15 mL) were added 3-amino-2,6-piperidinedione hydrochloride (173 mg, 1.05 mmol) and N,N-diisopropylethylamine (0.4 mL). The reaction was stirred at 80°C for 12 hours. The resulting mixture was concentrated under vacuum and purified on a C18 reverse phase column to afford Intermediate 15f (120 mg, 38%) as a gray solid.

[0611] 1 H NMR (400MHz, DMSO-d6) δ10.97(s,1H),7.35(s,1H),7.13(s,1H),6.71(d,J=9.9Hz,1H),6.33(d,J=9.8Hz,1H),5.08(dd,J=13.3,5.1Hz ,1H),4.41–4.19(m,2H),4.15–3.96(m,4H),2.97–2.85(m,1H),2.66–2.55(m,1H),2.41–2.30(m,1H),2.03–1.95(m,1H),1.40(s,9H).

[0612] LC-MS(ESI):[M-tBu+H] + =384.35

[0613] Step 7: 3-(8'-oxa-6',8'-dihydro-7'H-spiro[azetidine-3,2'-pyrano[2,3-f]isoindole]-7'-yl)piperidine-2,6-dione (Intermediate 15g)

[0614] Intermediate 15f (120 mg, 0.7 mmol), dichloromethane (3 mL), and trifluoroacetic acid (1 mL) were added. The reaction mixture was stirred at room temperature for 2 hours, and the reaction mixture was concentrated in vacuo. The crude product was used directly in the next step without further purification.

[0615] LC-MS(ESI):[M+H] + =340.34

[0616] Step 8: 3-(8'-oxa-3',4',6',8'-tetrahydro-7'H-spiro[azetidine-3,2'-pyrano[2,3-f]isoindol]-7'-yl)piperidine-2,6-dione (Intermediate 15)

[0617] Palladium on carbon (5 mg) was added to a solution of intermediate 15 g (50 mg, mmol) in methanol (3 mL). The reaction mixture was stirred at room temperature for 12 hours, filtered through celite, and the filtrate was concentrated. Preparative HPLC was performed to obtain intermediate 15 (30 mg, 59%) as a white solid.

[0618] 1 H NMR (400MHz, DMSO-d6) δ10.97(s,1H),7.36(s,1H),7.11(s,1H),5.07(dd,J=13.3,5.1Hz,1H),4.34(d,J=16.8Hz,1H),4.21(d,J=16 .8Hz,1H),4.15–4.04(m,4H),2.91(q,J=5.6,4.4Hz,2H),2.67–2.56(m,2H),2.40–2.31(m,1H),2.20(t,J=6.9Hz,2H),1.98(m,1H).

[0619] LC-MS(ESI):[M+H] + =342.43

[0620] Example 16. Synthesis of Intermediate 16

[0621] 3-(6'-oxa-6',8'-dihydro-3'H,7'H-spiro[piperidin-4,2'-[1,4]dioxin[2,3-f]isoindol]-7'-yl)piperidin-2,6-dione

[0622] Synthesis scheme:

[0623] Step 1: Methyl 4-fluoro-2-methylbenzoate (Intermediate 16b)

[0624] To a solution of intermediate 16a (5.5 g, 35.7 mmol) in methanol (100 mL) was slowly added concentrated sulfuric acid (15 mL). The reaction was stirred at room temperature overnight. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure afforded intermediate 16b (5.0 g, 83%) as a colorless oil. The crude product was used in the next reaction without purification.

[0625] 1 H NMR (600MHz, DMSO-d6) δ7.90(dd,J=8.7,6.2Hz,1H),7.22(dd,J=10.1,2.8Hz,1H),7.15(td,J=8.5,2.7Hz,1H),3.82(s,3H),2.53(s,3H).

[0626] LC-MS(ESI):[M+H] + =169.19.

[0627] Step 2: Methyl 4-fluoro-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (Intermediate 16c)

[0628] Boronic acid pinacol ester (5.7 g, 22.3 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (0.16 g, 0.59 mmol), and methoxy(cyclooctadiene)iridium dimer (0.20 g, 0.30 mmol) were added to a 10 mL solution of methyl tert-butyl ether. A solution of intermediate 16b (2.5 g, 14.9 mmol) in methyl tert-butyl ether (10 mL) was then added. The atmosphere was purged with nitrogen three times, and the reaction was stirred at 85°C for 4 h. After completion of the reaction, the product was filtered through celite, and the filtrate was concentrated to obtain a crude product (4.0 g) that was used in the next step without purification.

[0629] 1 H NMR (600MHz, DMSO-d6) δ8.16(d,J=6.3Hz,1H),7.19(dd,J=10.4,3.2Hz,1H),3.83(s,3H),2.55(s,3H),1.30(s,12H).

[0630] Step 3: Methyl 4-fluoro-5-hydroxyphthalate (Intermediate 16d)

[0631] To a solution of intermediate 16c (4.0 g, 13.6 mmol) in acetonitrile (50 mL) was added potassium peroxymonosulfate (10.9 g), and the reaction was stirred at room temperature overnight. The reaction solution was filtered and the filtrate was concentrated. The crude product was purified by silica gel column chromatography to give intermediate 16d (2.0 g, 80%) as a white solid.

[0632] 1 H NMR (600MHz, DMSO-d6) δ10.04 (s, 1H), 7.47 (d, J = 9.3Hz, 1H), 7.13 (d, J = 12.2Hz, 1H), 3.80 (s, 3H), 2.41 (s, 3H).

[0633] LC-MS(ESI):[M+H] - =183.21.

[0634] Step 4: 1'-(tert-Butyl)6-methyl-7-methyl-3H-spiro[benzo[b][1,4]dioxene-2,4'-piperidine]-1',6-dicarboxylate (Intermediate 16e)

[0635] Intermediate 16d (1.0 g, 5.4 mmol) was dissolved in 10 ml of ultra-dry N,N-dimethylformamide, followed by the addition of tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (1.2 g, 5.3 mmol) and sodium hydride (196 mg, 4.9 mmol). The reaction was heated to 110°C and stirred overnight. The reaction mixture was purified by silica gel column chromatography to afford Intermediate 16e (1.4 g, 68%) as a white solid.

[0636] 1 H NMR(600MHz,DMSO-d6)δ7.37(s,1H),6.85(s,1H),4.04(s,2H),3.77(s,3H),3.73( d,J=13.4Hz,2H),3.24–3.04(m,2H),2.42(s,3H),1.66–1.61(m,4H),1.41(s,9H).

[0637] LC-MS(ESI):[M+H] + =278.29.

[0638] Step 5: 1'-(tert-Butyl)6-methyl7-(bromomethyl)-3H-spiro[benzo[b][1,4]dioxene-2,4'-piperidine]-1',6-dicarboxylate (Intermediate 16f)

[0639] To a solution of intermediate 16e (1.0 g, 2.7 mmol) in carbon tetrachloride (10 mL) were added N-bromosuccinimide (613 mg, 3.4 mmol) and azobisisobutyronitrile (44 mg, 0.3 mmol). The atmosphere was purged with nitrogen three times, and the reaction was stirred at 85°C overnight under nitrogen. After completion of the reaction, the reaction solution was filtered, and the filtrate was concentrated to give a crude product (1.2 g) which was used in the next step without purification.

[0640] Step 6: 3-(6'-oxa-6',8'-dihydro-3'H,7'H-spiro[piperidin-4,2'-[1,4]dioxin[2,3-f]isoindol]-7'-yl)piperidine-2,6-dione (Intermediate 16)

[0641] To a solution of intermediate 16f (1.2 g, 2.7 mmol) in acetonitrile (10 mL) were added 3-aminopiperidine-2,6-dione hydrochloride (655 mg, 4.0 mmol) and N,N-diisopropylethylamine (1.0 g, 8.0 mmol). The reaction was stirred at 80°C overnight. The solution was then concentrated and dissolved in acetic acid (10 mL). The reaction was stirred at 110°C for 2 h. The reaction solution was purified by reverse phase chromatography to afford intermediate 16 (235 mg, 24%) as a white solid.

[0642] 1 H NMR (400MHz, DMSO-d6) δ10.96(s,1H),7.22(s,1H),7.17(s,1H),5.06(dd,J=13. 3,5.1Hz,1H),4.32(d,J=16.8Hz,1H),4.20(d,J=16.8Hz,1H),4.19–4.11(m,2H), 3.30–3.25(m,2H),3.18–3.08(m,2H),2.90(ddd,J=17.3,13.6,5.4Hz,1H),2.59( dt,J=16.6,3.4Hz,1H),2.42–2.30(m,1H),2.00–1.93(m,1H),1.92–1.85(m,4H).

[0643] LC-MS(ESI):[M+H] + =373.35.

[0644] Example 17. Synthesis of Intermediate 17

[0645] 6-(2,6-dioxopiperidin-3-yl)-6-hydrogen-2H,5H-spiro[[2,3-f]isoindole-3,4'-piperidine]-5,7-dione

[0646] Synthesis scheme

[0647] Step 1: Dimethyl 4-hydroxyphthalate (Intermediate 17b)

[0648] Under nitrogen, intermediate 17a (30 g, 165 mmol) was dissolved in methanol (300 mL). Concentrated sulfuric acid (36 mL) was slowly added to the system, and the temperature was raised to 66°C for 8 hours. The reaction system was cooled to room temperature and concentrated under reduced pressure. After adding water (200 mL), the mixture was extracted with ethyl acetate (300 mL x 3). The organic phases were washed with saturated brine (300 mL) and dried over anhydrous sodium sulfate. After concentration, the crude product, intermediate 17b (31 g, 89.5%), was obtained as a pale yellow solid.

[0649] LC-MS(ESI):[M-OMe+H] + =179.12.

[0650] Step 2: Dimethyl 4-bromo-5-hydroxyphthalate (Intermediate 17c)

[0651] Under nitrogen, intermediate 17b (10 g, 47 mmol) was dissolved in trifluoroacetic acid (100 mL). N-bromosuccinimide (4.24 g, 47 mmol) was added to the reaction system and allowed to react overnight at room temperature. The resulting reaction system was concentrated under reduced pressure, water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL x 3). The mixture was washed with saturated brine (100 mL), and the combined organic phases were dried over anhydrous sodium sulfate. The concentrated crude product was purified by reverse-phase column chromatography to yield intermediate 17c (4.6 g, 33%) as a pale yellow solid.

[0652] 1 H NMR (600MHz, CD3OD) δ7.98(s,1H),7.07(s,1H),3.88(s,3H),3.86(s,3H).

[0653] LC-MS(ESI):[M+H] + =289.04.

[0654] Step 3: Dimethyl 4-((1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)methoxy)-5-bromobenzoate (Intermediate 17d)

[0655] Under nitrogen, Intermediate 17c (8 g, 27 mmol, 1.0 eq), (1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)methanol (5.64 g, 27 mmol), and triphenylphosphine (7.2 g, 27 mmol) were dissolved in tetrahydrofuran (80 mL). Diethyl azodicarboxylate (4.08 mL, 27 mmol, 1.0 eq) was added and reacted at room temperature for 4 hours. The resulting reaction system was concentrated under reduced pressure, water (50 mL) was added, and the mixture was extracted with ethyl acetate (3 times with 100 mL). The organic phases were washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. Purification by column chromatography afforded Intermediate 17d as a reddish-brown solid (6 g, 46%).

[0656] 1H NMR (600MHz, CDCl3) δ8.04 (s, 1H), 7.47 (hd, J = 5.4, 1.9Hz, 5H), 7.09 (s, 1H), 5.90 (tt,J=3.2,1.5Hz,1H),4.67–4.55(m,2H),4.38(d,J=12.9Hz,1H),4.28(d,J=12.8 Hz,1H),3.98(d,J=16.7Hz,1H),3.93(s,3H),3.91(s,3H),3.78(dd,J=19.0,12.3 Hz,1H),3.48(d,J=16.5Hz,1H),3.06(s,1H),2.75(s,1H),2.54(d,J=18.6Hz,1H).

[0657] LC-MS(ESI):[M+H] + =474.26 / 476.27.

[0658] Step 4: 1'-Benzyl-2H-spiro[benzofuran-3,4'-piperidine]-5,6-dicarboxylic acid dimethyl ester (Intermediate 17e)

[0659] Under nitrogen, intermediate 17d (8.4 g, 17 mmol), tri-n-butyltin hydroxide (10.2 g, 34 mmol), and azobisisobutyronitrile (574 mg, 3.4 mmol) were dissolved in toluene (84 mL) and heated to 110°C for 4 hours. The reaction system was cooled to room temperature and concentrated under reduced pressure. Water (100 mL) was added, and the mixture was extracted with ethyl acetate (3 times with 100 mL). The organic phases were washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. Purification by column chromatography afforded intermediate 17e (5 g, 71%) as a reddish-brown oil.

[0660] 1 H NMR (400MHz, CDCl3) δ7.67(s,1H),7.55–7.41(m,5H),6.97(s,1H),4.47(s,2H),4.27(s ,2H),3.91(s,3H),3.89(s,3H),3.70(d,J=12.3Hz,2H),2.78–2.63(m,2H),2.52(td,J= 14.3, 4.0Hz, 2H), 1.94 (d, J = 14.5Hz, 2H).

[0661] LC-MS(ESI):[M+H] + =396.40.

[0662] Step 5: 1'-Benzyl-2H-spiro[benzofuran-3,4'-piperidine]-5,6-dicarboxylic acid (Intermediate 17f)

[0663] Intermediate 17e (2.3 g, 5.8 mmol) was dissolved in methanol (20 mL) and water (2 mL), and lithium hydroxide (1.39 g, 58 mmol) was added. The reaction was allowed to react at room temperature for 4 hours. The reaction system was concentrated under reduced pressure, and reverse-phase purification was performed to obtain Intermediate 17f (1.28 g, 60%) as a light reddish-brown solid.

[0664] 1 H NMR(600MHz,DMSO-d6)δ7.51(ddd,J=12.6,6.6,3.4Hz,6H),6.98(s,1H),4.64(s,2H),4.36(s, 2H), 3.39 (s, 2H), 3.13 (t, J = 13.4Hz, 2H), 2.15 (dd, J = 20.6, 8.4Hz, 2H), 1.96 (d, J = 14.1Hz, 2H).

[0665] LC-MS(ESI):[M+H] + =368.34.

[0666] Step 6: 1'-Benzyl-6-(2,6-dioxopiperidin-3-yl)-6-hydro-2H,5H-spiro[[2,3-f]isoindole-3,4'-piperidine]-5,7-dione (Intermediate 17g)

[0667] Under nitrogen, intermediate 17f (3.0 g, 8 mmol), sodium acetate (3.3 g, 24 mmol), and 3-amino-2,6-piperidinedione hydrochloride (1.3 g, 10 mmol, 1.25 eq) were dissolved in acetic acid (30 mL) and reacted at 110°C for 4 hours. The reaction system was cooled to room temperature and concentrated under reduced pressure. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were washed with saturated brine (80 mL), and dried over anhydrous sodium sulfate. Purification by column chromatography afforded intermediate 17g (1.8 g, 48%) as a pale yellow solid.

[0668] 1H NMR (600MHz, CDCl3) δ7.69 (s, 1H), 7.54–7.43 (m, 5H), 7.25 (s, 1H), 4.96 (dd, J = 12.7, 5.4Hz, 1H), 4.56 (s, 2H), 4.2 8(s,2H),2.97–2.75(m,4H),2.70(t,J=13.6Hz,2H),2.63–2.53(m,2H),1.99(d,J=14.6Hz,2H),1.63–1.57(m,2H).

[0669] LC-MS(ESI):[M+H] + =460.34.

[0670] Step 7: 6-(2,6-dioxopiperidin-3-yl)-6-hydro-2H,5H-spiro[[2,3-f]isoindole-3,4'-piperidine]-5,7-dione (Intermediate 17)

[0671] Under nitrogen, intermediate 17g (3.0g, 6.5mmol, 1.0eq) was dissolved in methanol (30mL), and 10% wet palladium on carbon (600mg) was added. After hydrogen substitution three times, the reaction was allowed to proceed overnight at room temperature. The reaction system was filtered, and the filter cake was washed three times with methanol (15mL). The resulting filtrate was dried under reduced pressure, and the concentrated crude product was purified by reverse phase column chromatography to obtain intermediate 17 (630mg, 26%) as a white solid.

[0672] 1 H NMR(600MHz,CD3OD)δ7.78(s,1H),7.26(d,J=0.6Hz,1H),5.14–5.10(m,1H),4.74(s,2H),3.38(dt,J=12.7,3.2Hz,2H),3.05(t d,J=13.1,3.0Hz,2H),2.90–2.85(m,1H),2.78(dd,J=4.4,2.6Hz,1H),2.77–2.69(m,2H),2.14(ddt,J=13.2,11.0,4.1Hz,4H).

[0673] LC-MS(ESI):[M+H] + =370.33.

[0674] Example 18, Synthesis of Intermediate 18

[0675] Synthesis scheme:

[0676] Step 1: Synthesis of 4-bromo-6-iodopyridazin-3-amine and 4,6-dibromopyridazin-3-amine

[0677] Dissolve 4-bromo-6-iodopyridazin-3-amine (5.00 g, 22.62 mmol) in acetonitrile (100 mL) in a single-necked flask. Slowly add N-bromosuccinimide (4.03 g, 22.62 mmol) and stir for 1 h. After completion, quench with aqueous sodium thiosulfate solution and extract three times with ethyl acetate (20 mL). The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product is purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to afford a mixture of compounds 1a and 1b as a yellow solid (2.02 g).

[0678] Step 2: Synthesis of 2-(6-amino-5-bromopyridazin-3-yl)phenol

[0679] A mixture of Intermediates 1a and 1b (555.00 mg, 1.85 mmol), (2-hydroxyphenyl)boronic acid (204.20 mg, 1.48 mmol), tetrakistriphenylphosphine palladium (213.86 mg, 185.06 mmol), and potassium carbonate (639.41 mg, 4.63 mmol) were dissolved in 1,4-dioxane (7 mL) and purified water (1 mL). Under nitrogen, the reaction was stirred at 80°C for 3 hours. After completion of the reaction, excess solvent was removed under reduced pressure, purified water was added, and the mixture was extracted three times with ethyl acetate (20 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to afford Intermediate 18 (147 mg) as a yellow solid.

[0680] 1 H NMR (600MHz, DMSO-d6) δ8.50(s,1H),7.82(dd,J=7.8,1.3Hz,1H),7.29–7.23(m,1H),6.92(t,J=8.2Hz,2H).

[0681] Example 19, Synthesis of Intermediate 19

[0682] Synthesis scheme

[0683] Step 1: Methyl 2-hydroxy-6-methylbenzoate (Intermediate 19a)

[0684] Under nitrogen, 2-hydroxy-6-methylbenzoic acid (10 g, 65.79 mmol) was dissolved in methanol (30 mL), and concentrated sulfuric acid (10 mL) was added. The mixture was reacted at 80°C for 16 h. After completion of the reaction, the excess sulfuric acid was neutralized with 1 mL NaOH solution, washed with water, and extracted with ethyl acetate. The combined organic phases were concentrated to afford intermediate 19a (10 g, 91.6%), which was carried on to the next step without purification.

[0685] 1 H NMR (600MHz, CDCl3) δ11.31(s,1H),7.31-7.28(m,1H),6.87-6.86(m,1H),6.75-6.74(m,1H),3.99(s,3H),2.56(s,3H).

[0686] LC-MS(ESI):[M+H] + =167.13

[0687] Step 2: Methyl 2-hydroxy-3-iodo-6-methylbenzoate (Intermediate 19b)

[0688] Under nitrogen, intermediate 19a (10 g, 60.24 mmol) was dissolved in trifluoroacetic acid (20 mL) and NIS (16.2 g, 72.00 mmol) was added. The mixture was allowed to stand at room temperature for 16 h. After TLC, the reaction was quenched with saturated aqueous NaS₂O₃, washed with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to afford the crude product. The crude product was then purified by reverse-phase purification to afford intermediate 19b (3.8 g, 21.6%).

[0689] 1 H NMR (600MHz, CDCl3) δ12.19(s,1H),7.77(d,J=8.0Hz,1H),6.56(dd,J=8.0,0.8Hz,1H),4.01(s,3H),2.54(s,3H).

[0690] Step 3: Methyl 3-acetyl-2-hydroxy-6-methylbenzoate (Intermediate 19c)

[0691] Under nitrogen, intermediate 19b (3.8 g, 13.02 mmol) and butyl vinyl ether (3.9 g, 39.00 mmol) were dissolved in methanol (20 ml). Pd(dppf)Cl2 (951 mg, 1.30 mmol) and TEA (3.95 g, 39.00 mmol) were added. The atmosphere was purged with nitrogen three times and the reaction was continued at 60°C for 16 h. The reaction was completed by TLC. The reaction solution was dried by spin drying, dissolved in dichloromethane, and washed with 5 M / L HCl and saturated brine. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to afford intermediate 19c (2.0 g, 73.8%).

[0692] 1 H NMR (600MHz, CDCl3) δ12.74(s,1H),7.70(d,J=8.2Hz,1H),6.79(d,J=8.2Hz,1H),3.97(s,3H),2.64(s,3H),2.38(s,3H).

[0693] LC-MS(ESI):[M-OCH3+H] + =177.14

[0694] Step 4: 1'-tert-Butyl 8-methyl 7-methyl-4-oxospiro[chroman-2,4'-piperidine]-1,8-dicarboxylate (Intermediate 19d)

[0695] Under nitrogen, Intermediate 19c (1 g, 4.80 mmol) was dissolved in methanol (30 mL). Pyrrolidine (340 mg, 4.80 mmol) and N-tert-butyloxycarbonyl-4-piperidone (960 mg, 4.80 mmol) were slowly added to the system. The temperature was raised to 70°C and the reaction mixture was allowed to react for 12 hours. After TLC analysis, the reaction system was cooled to room temperature and concentrated under reduced pressure. Water was added, and the mixture was extracted with ethyl acetate, washed with saturated brine, and the combined organic phases were dried over anhydrous sodium sulfate. Purification by column chromatography afforded Intermediate 19d (1.5 g, 80%) as a yellow solid.

[0696] 1 H NMR (600MHz, DMSO-d6) δ7.72(d,J=8.0Hz,1H),6.99(d,J=8.0Hz,1H),3.87(s,3H),3.78(br,2H),2. 99(br,2H),2.84(s,2H),2.28(s,3H),1.96-1.78(m,2H),1.59(td,J=13.3,4.8Hz,2H),1.40(s,9H).

[0697] LC-MS(ESI):[M+H] +=390.35

[0698] Step 5: 1'-tert-Butyl 8-methyl 4-hydroxy-7-oxospiro[chroman-2,4'-piperidine]-1,8-dicarboxylate (Intermediate 19e)

[0699] Under nitrogen, Intermediate 19d (1.5 g, 3.85 mmol) was dissolved in methanol (25 mL). NaBH4 (340 mg, 7.7 mmol) was added to the reaction system and allowed to react at room temperature for 1 h. After TLC analysis, the resulting reaction system was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic phases were then washed with saturated brine and dried over anhydrous sodium sulfate. Concentration afforded the crude product Intermediate 19e (1.5 g, 99%).

[0700] 1 H NMR (600MHz, DMSO-d6) δ7.37(d,J=7.8Hz,1H),6.80(d,J=7.9Hz,1H),5.44(d,J=5.5Hz,1H),4.67(q,J=6.7Hz,1H),3.80(s,3H ),3.76(br,2H),2.97(br,2H),2.17(s,3H),2.06(dd,J=13.5,6.2Hz,1H),1.85-1.66(m,3H),1.60-1.47(m,2H),1.41(s,9H).

[0701] LC-MS(ESI):[M+H] + =392.40

[0702] Step 6: Methyl 7-methyloxospiro[chromene-2,4'-piperidine]-8-carboxylate (Intermediate 19f)

[0703] Under nitrogen, intermediate 19e (1.5 g, 3.83 mmol) was dissolved in toluene (25 mL), and p-toluenesulfonic acid (659.8 mg, 3.83 mmol) was added. The mixture was allowed to react at 110°C for 12 hours. After TLC analysis, the reaction mixture was concentrated under reduced pressure to obtain the crude intermediate 19f (850 mg, 81%), which was then used directly in the next step.

[0704] LC-MS(ESI):[M+H] + =274.25

[0705] Step 7: 1'-tert-Butyl 8-methyl 7-methylspiro[chromene-2,4'-piperidine]-1',8-dicarboxylate (Intermediate 19g)

[0706] Under nitrogen, intermediate 19f (850 mg, 3.11 mmol) was dissolved in dichloromethane (20 mL), and p-Boc2O (1.36 g, 6.22 mmol) and TEA (600 mg, 6.22 mmol) were added. The mixture was allowed to react at room temperature to 25°C for 1 hour. After TLC analysis, the reaction system was cooled to room temperature and concentrated under reduced pressure. Water was added, and the mixture was extracted with ethyl acetate, washed with saturated brine, and the combined organic phases were dried over anhydrous sodium sulfate. Purification by column chromatography afforded intermediate 19g (1 g, 86%) as a white solid.

[0707] 1 H NMR (600MHz, DMSO-d6) δ7.07(d,J=7.6Hz,1H),6.78(d,J=7.6Hz,1H),6.48(d,J=9.8Hz,1H),5.72(d,J=9.8Hz,1H) ,3.83(s,5H),3.07(s,2H),2.18(s,3H),1.81(dq,J=14.3,2.6Hz,2H),1.57(td,J=13.1,4.8Hz,2H),1.41(s,9H).

[0708] LC-MS(ESI):[M+H] + =374.40

[0709] Step 8: 1'-tert-Butyl 8-methyl 7-(bromomethyl)spiro[chromene-2,4'-piperidine]-1',8-dicarboxylate (Intermediate 19h)

[0710] Under nitrogen, Intermediate 19g (1g, 2.68mmol) was dissolved in carbon tetrachloride (20mL), and NBS (620mg, 3.50mmol) and AIBN (43mg, 0.27mmol) were added. The reaction was allowed to proceed at 85°C for 12 hours. After completion of the reaction, the reaction system was concentrated under reduced pressure. The crude product, Intermediate 19h, was directly used in the next step (1.2g, 99%).

[0711] LC-MS(ESI):[M+H] + =452.25

[0712] Step 9: 8'-(2,6-dioxopiperidin-3-yl)-9'-oxo-8',9'-dihydro-7'H-spiro[piperidine-4,2'-pyrano[2,3-e]isoindole]-1-carboxylic acid tert-butyl ester (Intermediate 19i)

[0713] Under nitrogen, intermediate 19h (1.2 g, 2.65 mmol), DIPEA (1 g, 7.95 mmol), and 3-amino-2,6-piperidinedione hydrochloride (654.9 mg, 3.98 mmol) were dissolved in acetonitrile (30 mL) and reacted at 85°C for 16 hours. After TLC analysis, the reaction system was cooled to room temperature and concentrated under reduced pressure. Water was added, and the mixture was extracted with ethyl acetate, washed with saturated brine, and the combined organic phases were dried over anhydrous sodium sulfate. Purification by column chromatography afforded intermediate 19i (400 mg, 32%) as a gray solid.

[0714] 1 H NMR(600MHz,DMSO-d6)δ11.00(s,1H),7.31(d,J=7.5Hz,1H),7.04(d,J=7.5Hz, 1H),6.57(d,J=9.9Hz,1H),5.79(d,J=9.9Hz,1H),4.99(d,J=5.1Hz,1H),4.44-4 .16(m,2H),3.79(s,2H),3.19(d,J=22.8Hz,4H),2.87(ddd,J=18.2,13.6,5.4Hz ,1H),2.73-2.56(m,1H),2.51(p,J=1.9Hz,1H),2.06-1.56(m,3H),1.41(s,9H).

[0715] LC-MS(ESI):[M-Boc+H] + =368.19

[0716] Step 10: 8'-(2,6-dioxopiperidin-3-yl)-9'-oxo-4',7',8',9'-tetrahydro-3'H-spiro[piperidine-4,2'-pyrano[2,3-e]isoindole]-1-carboxylic acid tert-butyl ester (Intermediate 19j)

[0717] Under nitrogen, intermediate 19i (400 mg, 0.85 mmol) was dissolved in THF (10 mL), and 10% wet palladium on carbon (250 mg) was added. The atmosphere was replaced with hydrogen three times, and the reaction was allowed to proceed at 50°C overnight. After TLC, the reaction mixture was filtered, and the filter cake was washed three times with methanol (15 mL). The filtrate was concentrated to dryness under reduced pressure, and the concentrated crude solid intermediate 19j was directly used in the next step (380 mg, 94%).

[0718] LC-MS(ESI):[M-Boc+H] + =370.29

[0719] Step 11: 3-(9'-oxo-3',4',7',9'-tetrahydro-8'H-spiro[piperidin-4,2'-pyrano[2,3-e]isoindol]-8'-yl)piperidine-2,6-dione (Intermediate 19)

[0720] Under nitrogen, intermediate 19j (380 mg, 0.80 mmol) was dissolved in dichloromethane (5 mL), and TFA (2 mL) was added. The reaction was allowed to react at 25°C for 1 h. After TLC, the reaction solution was dried under reduced pressure and analyzed by pre-HPLC to yield intermediate 19 (290 mg, 97%) as a yellow solid.

[0721] 1 H NMR (600MHz, DMSO-d6) δ10.98(s,1H),7.34(d,J=7.7Hz,1H),7.04(d,J=7.6Hz,1H),4.97(dd,J=13.3,5.2,1H),4.43–4.20(m,2H),3. 30-3.08(m,4H),2.97-2.78(m,3H),2.61(dt,J=17.1,3.7Hz,1H),2.47-2.31(m,1H),2.04-1.88(m,5H),1.80(tt,J=12.6,5.0Hz,2H).

[0722] LC-MS(ESI):[M+H] + =370.39

[0723] Example 20, Synthesis of Intermediate 20

[0724] Synthesis scheme

[0725] Step 1: 1-tert-Butyl 8'-methyl 7'-methyl-4'-oxospiro[azetidine-3,2'-chroman]-1,8'-dicarboxylate (Intermediate 20a)

[0726] Under nitrogen, intermediate 19c (2.0 g, 9.61 mmol) was dissolved in ethanol (15 mL), and 1-Boc-3-azetidinone (1.63 g, 9.61 mmol) and tetrahydropyrrole (682 mg, 9.61 mmol) were added. The mixture was reacted at 70°C for 4 h. After TLC analysis, additional 1-Boc-3-azetidinone (0.82 g, 4.81 mmol) and tetrahydropyrrole (340 mg, 4.81 mmol) were added and the reaction continued at 70°C for 16 h. After completion of the reaction, the reaction mixture was evaporated to dryness to obtain the crude product, which was then purified by column chromatography to afford intermediate 20a (1.0 g, 28.8%).

[0727] 1 H NMR (600MHz, CDCl3) δ7.84(d,J=8.0Hz,1H),6.96(d,J=8.0Hz,1H),4.09(d,J=9.5H z,2H),3.99(s,3H),3.96(d,J=9.5Hz,2H),3.06(s,2H),2.39(s,3H),1.46(s,9H).

[0728] LC-MS(ESI):[M-Boc+H] + =262.17

[0729] Step 2: 1-tert-Butyl 8'-methyl 4'-hydroxy-7'-methyl spiro[azetidine-3,2'-chroman]-1,8'-dicarboxylate (Compound 20b)

[0730] Under nitrogen, intermediate 20a (1.0 g, 2.77 mmol) was dissolved in methanol (15 mL) and NaBH4 (157 mg, 4.16 mmol) was added. The mixture was allowed to react at room temperature for 2 h. After TLC, the reaction was quenched by adding saturated NH4Cl, washed with water, extracted with ethyl acetate, washed with saturated brine, and dried to give intermediate 20b (900.0 mg, 89.5%), which was directly carried out in the next step without purification.

[0731] LC-MS(ESI):[M-Boc+H] + =264.17

[0732] Step 3: 7'-methylspiro[azetidine-3,2'-chromene]-8'-carboxylic acid methyl ester (Compound 20c)

[0733] Under nitrogen, intermediate 20b (900.0 mg, 2.48 mmol) was dissolved in toluene (10 mL), and TsOH (471 mg, 2.48 mmol) was added. The mixture was reacted at 110°C for 2 h. After TLC analysis, the reaction mixture was evaporated to dryness to obtain crude intermediate 20c (1.1 g, 181.1%), which was directly used in the next step without purification.

[0734] LC-MS(ESI):[M+H] + =246.11

[0735] Step 4: 1-tert-Butyl 8'-methyl 7'-methyl spiro[azetidine-3,2'-chromene]-1,8'-dicarboxylate (Compound 20d)

[0736] Under nitrogen, intermediate 20c (1.1 g, 1 eq) was dissolved in dichloromethane (15 mL), and (Boc)2O (1.95 g, 2.0 eq) and TEA (1.36 g, 3.0 eq) were added. The mixture was allowed to react at room temperature for 2 h. After TLC, the reaction mixture was evaporated to dryness and filtered through a column to obtain intermediate 20d (300.0 mg, 19.4%).

[0737] 1 H NMR (600MHz, CDCl3) δ6.95(d,J=7.6Hz,1H),6.76(d,J=7.6Hz,1H),6.45(d,J=9.8Hz,1H),5.93(d, J=9.8Hz,1H),4.24(d,J=9.5Hz,2H),3.99(d,J=9.5Hz,2H),3.96(s,3H),2.30(s,3H),1.48(s,9H).

[0738] LC-MS(ESI):[M-Boc+H] + =256.17

[0739] Step 5: 1-tert-Butyl 8'-methyl 7'-(bromomethyl)spiro[azetidine-3,2'-chromene]-1,8'-dicarboxylate (Compound 20e)

[0740] Under nitrogen, intermediate 20d (400.0 mg, 1 eq) was dissolved in CCl4 (10 mL). AIBN (19 mg, 0.1 eq) and NBS (268 mg, 1.3 eq) were added to the reaction mixture, and the mixture was reacted at 85°C for 16 h. After TLC, the reaction mixture was evaporated to dryness to obtain crude intermediate 20e (600 mg), which was directly used for the next step without purification.

[0741] LC-MS(ESI):[M-Boc+H] + =324.07

[0742] Step 6: 8'-(2,6-dioxopiperidin-3-yl)-9'-oxo-8',9'-dihydro-7'H-spiro[azetidine-3,2'-pyrano[2,3-e]isoindole]-1-carboxylic acid tert-butyl ester (Compound 20f)

[0743] Under nitrogen, intermediate 20e (600 mg, 1 eq) was dissolved in ACN (10 mL). 3-Aminopiperidine-2,6-dione hydrochloride (287 mg, 1.5 eq) and DIEA (448 mg, 3.0 eq) were added to the reaction mixture, and the mixture was allowed to react at 80°C for 16 h. After completion of the reaction, the reaction mixture was spin-dried and filtered through a column to obtain intermediate 20f (60 mg, 21.4% yield over two steps).

[0744] 1 H NMR(600MHz,DMSO-d6)δ11.00(s,1H),7.34(d,J=7.6Hz,1H),7.08(d,J=7.6Hz, 1H),6.67(d,J=9.9Hz,1H),6.20(d,J=9.9Hz,1H),4.99(dd,J=13.2,5.2Hz,1H) ,4.37(d,J=17.6Hz,1H),4.25(d,J=17.6Hz,1H),4.04-4.01(m,4H),2.93-2.87 (m,1H),2.62-2.57(m,1H),2.41-2.33(m,1H),2.00-1.96(m,1H),1.41(s,9H).

[0745] LC-MS(ESI):[M-Boc+H] + =340.19

[0746] Step 7: 8'-(2,6-dioxopiperidin-3-yl)-9'-oxo-4',7',8',9'-tetrahydro-3'H-spiro[azetidine-3,2'-pyrano[2,3-e]isoindole]-1-carboxylic acid tert-butyl ester (Compound 20g)

[0747] Under nitrogen, intermediate 20f (60.0 mg, 1 eq) was dissolved in THF (10 mL), and Pd / C (60 mg, 1 eq) was added. The mixture was replaced with hydrogen three times and allowed to react at 50°C for 16 h. After TLC, the reaction mixture was evaporated to dryness to obtain crude intermediate 20g (80 mg), which was directly used in the next step without purification.

[0748] LC-MS(ESI):[M-Boc+H] + =342.17

[0749] Step 8: 3-(9'-oxo-3',4',7',9'-tetrahydro-8'H-spiro[azetidine-3,2'-pyrano[2,3-e]isoindol]-8'-yl)piperidine-2,6-dione (Intermediate 20)

[0750] Under nitrogen protection, intermediate 20g (80mg, 1eq) was dissolved in dichloromethane (5mL), TFA (1mL) was added, and the reaction was allowed to react at room temperature for 2h. After TLC detection, the reaction solution was spin-dried and freeze-dried to obtain the product intermediate 20 (15mg, two-step yield 24.3%).

[0751] 1H NMR (600MHz, DMSO-d6) δ10.98(s,1H),7.35(d,J=7.6Hz,1H),7.08(d,J=7.6Hz,1H),4.97(dd,J=13.2,5.2Hz,1H),4.35(d,J=17.3Hz,1H), 4.23(d,J=17.3Hz,1H),4.14-4.10(m,4H),2.93-2.85(m,3H),2.62-2.58(m,1H),2.42-2.35(m,1H),2.22-2.19(m,2H),1.99-1.95(m,1H).

[0752] LC-MS(ESI):[M+H] + =342.29

[0753] Example 21, Synthesis of Intermediate 21

[0754] 3-(7'-Oxo-3',4',7',9'-tetrahydro-8'H-spiro[piperidin-4,2'-pyrano[2,3-e]isoindol]-8'-yl)piperidine-2,6-dione

[0755] Synthesis scheme:

[0756] Step 1: Methyl 3-hydroxy-2-methylbenzoate (Intermediate 21b)

[0757] To a solution of 3-hydroxy-2-methylbenzoic acid 21a (10 g, 65.73 mmol) in methanol (100 mL) was slowly added thionyl chloride (15.64 g, 131.45 mmol). The reaction mixture was stirred at 80°C for 2 hours. The reaction mixture was dried to give intermediate 21b (10.0 g, 91.56%) as a gray solid.

[0758] 1 H NMR (600MHz, DMSO-d6) δ9.71(s,1H),7.19(dd,J=7.7,1.3Hz,1H),7.09(t,J=7.9Hz,1H),7.02(dd,J=8.0,1.4Hz,1H),3.80(s,3H),2.29(s,3H).

[0759] LC-MS(ESI):[M+H] + =167.23.

[0760] Step 2: Methyl 3-hydroxy-4-iodo-2-methylbenzoate (Compound 21c)

[0761] To a solution of 3-hydroxy-2-methylbenzoic acid 21b (10.0 g, 60.18 mmol) in trifluoroacetic acid (80 mL) and methanol (40 mL) was slowly added N-iodosuccinimide (17.6 g, 78.23 mmol). The reaction was stirred at room temperature for 2 hours. The resulting mixture was concentrated under vacuum and purified by C18 reverse phase column to give 21c (4 g, 22.76%) as a white solid.

[0762] 1 H NMR (600MHz, DMSO-d6) δ9.36 (s, 1H), 7.67 (d, J = 8.2Hz, 1H), 7.03 (d, J = 8.2Hz, 1H), 3.80 (s, 3H), 2.38 (s, 3H).

[0763] LC-MS(ESI):[M+H] + =364.22.

[0764] Step 3: Methyl 4-acetyl-3-hydroxy-2-methylbenzoate (Compound 21d)

[0765] Under nitrogen, intermediate 21c (5.4 g, 18.49 mmol), butyl vinyl ether (5.56 g, 55.47 mmol), and Pd(dppf)Cl2 (1.35 g, 1.85 mmol) were dissolved in methanol (80 mL). Triethylamine (5.61 g, 55.47 mmol) was added, and the mixture was heated to 60°C and stirred for 4 h. After the reaction, the mixture was filtered and the filtrate was concentrated to obtain the crude product. Purification by column chromatography (PE:EA = 20%) afforded 21d (3 g, 77.93%) as a yellow oil.

[0766] 1 H NMR (600MHz, CD3OD) δ7.28(d,J=8.2Hz,1H),7.18(d,J=8.3Hz,1H),3.87(s,3H),2.38(s,3H),1.59(s,3H).

[0767] LC-MS(ESI):[M+H] + =209.15.

[0768] Step 4: 1'-(tert-Butyl)7-methyl-8-methyl-4-oxospiro[chroman-2,4'-piperidine]-1',7-dicarboxylate (Intermediate 21e)

[0769] Intermediate 21d (3.0 g, 14.41 mmol), N-Boc-4-piperidone (3.16 g, 15.85 mmol), and tetrahydropyrrole (1.13 g, 15.85 mmol) were dissolved in methanol (60 mL), and the mixture was stirred at 70°C overnight. The mixture was dried and purified by column chromatography (PE:EA = 30%) to afford 21e (5 g, 89.11%) as a yellow solid.

[0770] 1 H NMR (600MHz, DMSO-d6) δ7.65(d,J=8.2Hz,1H),7.33(d,J=8.2Hz,1H),3.86(s,3H),2.89(s,2H),2.38(s,3 H),1.92(d,J=2.5Hz,1H),1.89(q,J=2.8Hz,1H),1.64(td,J=13.1,4.8Hz,2H),1.43(s,4H),1.40(s,9H).

[0771] LC-MS(ESI):[M-Boc+H] + =290.18.

[0772] Step 5: 1'-(tert-Butyl)7-methyl-4-hydroxy-8-methylspiro[chroman-2,4'-piperidine]-1',7-dicarboxylate (Intermediate 21f)

[0773] To a solution of intermediate 21e (5.0 g, 12.84 mmol) in methanol (80 mL) was added sodium borohydride (0.97 g, 25.68 mmol) in an ice bath. The reaction was stirred at 25°C for 1 hour. The reaction solution was quenched with ammonium chloride solution and extracted with ethyl acetate. The solvent was dried to obtain a yellow oil 21f (5.5 g) which was used directly in the next reaction.

[0774] LC-MS(ESI):[M-Boc+H] + =292.28.

[0775] Step 6: 8-methylspiro[chromene-2,4'-piperidine]-7-carboxylic acid methyl ester (Intermediate 21g)

[0776] Intermediate 21f (5.5 g, 14.05 mmol) and p-toluenesulfonic acid (2.66 g, 15.45 mmol) were dissolved in toluene (80 mL), and the mixture was stirred at 110° C. for 5 hours. The mixture was concentrated under vacuum to give a brown oil 21 g (3.84 g) which was used directly in the next reaction.

[0777] LC-MS(ESI):[M+H] + =274.47.

[0778] Step 7: 1'-(tert-Butyl)7-methyl8-methylspiro[chromene-2,4'-piperidine]-1',7-dicarboxylate (Intermediate 21h)

[0779] Intermediate 21g (3.84g, 14.05mmol) and Boc anhydride (6.13g, 28.10mmol) were dissolved in dichloromethane (100mL) and triethylamine (4.26g, 442.15mmol) was added. The reaction was stirred at room temperature for 2 hours. After the reaction, the mixture was dried and purified by column chromatography (PE:EA = 25%) to obtain 21h (5g, 95.30%) as a yellow oil.

[0780] 1 H NMR (600MHz, CD3OD) δ7.37(d,J=7.9Hz,1H),6.94(d,J=7.9Hz,1H),6.48(d,J=9.8Hz,1H),5.77(d,J=9.7Hz,1H),3.8 7(s,3H),2.45(s,3H),1.97–1.93(m,2H),1.66(td,J=13.9,12.2,4.8Hz,2H),1.58(s,2H),1.53(s,2H),1.49(s,9H).

[0781] LC-MS(ESI):[M-Boc+H] + =274.17.

[0782] Step 8: 1'-(tert-Butyl)7-methyl 8-(bromomethyl)spiro[chromene-2,4'-piperidine]-1',7-dicarboxylate (Intermediate 21i)

[0783] 21h (3.3 g, 8.84 mmol), N-bromosuccinimide (1.89 g, 10.60 mmol), and azobisisobutyronitrile (145.11 mg, 883.65 μmol) were dissolved in carbon tetrachloride (50 mL). The reaction was stirred at 80°C overnight. Concentration under vacuum afforded a brown solid 21i (4 g), which was used directly in the next reaction.

[0784] LC-MS(ESI):[M+H] + =316.08.

[0785] Step 9: 8'-(2,6-dioxopiperidin-3-yl)-7'-oxo-8',9'-dihydro-7'H-spiro[piperidine-4,2'-pyrano[2,3-e]isoindole]-1-carboxylic acid tert-butyl ester (Intermediate 21j)

[0786] Intermediate 21i (4 g, 8.84 mmol) was dissolved in acetonitrile (100 mL), and 3-aminopiperidine-2,6-dione hydrochloride (2.18 g, 13.26 mmol) and N,N-diisopropylethylamine (3.43 g, 26.53 mmol) were added. The reaction was stirred at 80°C overnight. After completion of the reaction, the mixture was purified by normal phase column chromatography (100% EA) to obtain 21j (1 g, 24.19%) as a blue solid.

[0787] LC-MS(ESI):[M-tBu+H] + =412.29.

[0788] Step 10: 8'-(2,6-dioxopiperidin-3-yl)-7'-oxo-4',7',8',9'-tetrahydro-3'H-spiro[piperidine-4,2'-pyrano[2,3-e]isoindole]-1-carboxylic acid tert-butyl ester (Intermediate 21k)

[0789] Intermediate 21j (90 mg, 192.50 umol) was dissolved in tetrahydrofuran (5 mL), palladium on carbon (20 mg) was added, and the atmosphere was replaced with hydrogen three times. The reaction was stirred overnight at 50°C. After completion of the reaction, the mixture was filtered to obtain 21k (90 mg, 99.57%) as a white solid.

[0790] LC-MS(ESI):[M-tBu+H] + =414.39.

[0791] Step 11: 3-(7'-oxo-3',4',7',9'-tetrahydro-8'H-spiro[piperidin-4,2'-pyrano[2,3-e]isoindol]-8'-yl)piperidine-2,6-dione (Intermediate 21)

[0792] Intermediate 21k (90 mg, 191.68 μmol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (1 mL) was added. The reaction was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was dried and purified by preparative liquid chromatography to afford 21 (50 mg, 70.61%) as a white solid.

[0793] 1H NMR (400MHz, CD3OD) δ7.36(d,J=7.8Hz,1H),7.32(d,J=7.8Hz,1H),5.18(dd,J=13.3,5.2Hz,1H),4.55–4.40(m,2H),3.38(dd,J=12.5,3.3Hz,4H ),3.03–2.89(m,3H),2.81(m,J=17.6,4.6,2.4Hz,1H),2.51(m,J=13.3, 4.7Hz,1H),2.24–2.09(m,3H),2.02(t,J=6.8Hz,2H),1.98–1.87(m,2H).

[0794] LC-MS(ESI):[M+H] + =370.39

[0795] Example 22, Synthesis of Intermediate 22

[0796] 3-(6-Oxo-6,8-dihydro-2H,7Hspiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione

[0797] Synthesis scheme:

[0798] Step 1: 5-Bromo-4-iodoisobenzofuran-1(3H)-one (Compound 22b)

[0799] 22a (1 g, 4.69 mmol) was dissolved in trifluoromethanesulfonic acid (10 mL). The solution was protected with nitrogen and cooled to 0°C. N-iodosuccinimide (1.16 g, 5.16 mmol) was added to the reaction solution at 0°C. The reaction solution was warmed to room temperature and reacted overnight. The resulting mixture was poured into ice water and filtered. The filter cake was washed with water and purified by column chromatography (EA:PE = 0%-15%) to afford 22b (800 mg, 50.28%) as a white solid.

[0800] 1 H NMR (600MHz, DMSO-d6) δ7.94–7.91 (m, 1H), 7.78 (dd, J = 8.1, 1.1Hz, 1H), 5.21 (s, 2H).

[0801] LC-MS(ESI):[MH] - =230.86.

[0802] Step 2: 5-Bromo-4-hydroxyisobenzofuran-1(3H)-one (Compound 22c)

[0803] To a solution of intermediate 22b in N,N-dimethylaniline (3.5 mL) was added a solution of sodium hydroxide (413.04 mg, 10.33 mmol) in water (7 mL). Cuprous oxide (59.11 mg, 413.07 μmol) was added to the above solution. The reaction was heated to 80°C and stirred overnight. The reaction solution was neutralized with 1N hydrochloric acid, extracted with ethyl acetate, and the organic phase was washed with saturated brine. The organic phase was concentrated under vacuum and the resulting mixture was purified by column chromatography (EA:PE = 0%-35%) to give 22c (249 mg, 52.64%) as a white solid.

[0804] 1 H NMR (600MHz, DMSO-d6) δ10.91(s,1H),7.73(d,J=8.0Hz,1H),7.24(d,J=8.0Hz,1H),5.35(s,2H).

[0805] LC-MS(ESI):[MH] - =230.86.

[0806] Step 3: 4-((1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)methoxy)-5-bromoisobenzofuran-1(3H)-one (Compound 22d)

[0807] Under nitrogen, intermediate 22c (100 mg, 436.63 μmol) and (1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)methanol (106.51 mg, 523.95 μmol) were dissolved in tetrahydrofuran (1.0 mL). The system was cooled to 0°C, and triphenylphosphine (229.05 mg, 873.25 μmol) was added. Diethyl azodicarboxylate (152.08 mg, 873.25 μmol) was then slowly added. The reaction mixture was warmed to room temperature and stirred overnight. The mixture was purified by preparative column chromatography to afford 22d (105 mg, 58.05%) as a yellow oil.

[0808] 1 H NMR(600MHz,DMSO-d6)δ7.83(d,J=8.0Hz,1H),7.45(d,J=8.0Hz,1H),7.37–7.30(m,4H),7.29–7.19(m,1 H),5.84(s,1H),5.68(s,2H),4.64(s,2H),3.56(s,2H),2.93(s,2H),2.57(t,J=5.7Hz,2H),2.25(s,2H).

[0809] LC-MS(ESI):[M+H] + =414.20.

[0810] Step 4: 1'-Benzyl-2H-spiro[benzo[2,1-b:3,4-c']difuran-3,4'-piperidin]-6(8H)-one (Compound 22e)

[0811] Intermediate 22d (100 mg, 241.37 μmol), azobisisobutyronitrile (79.27 mg, 482.74 μmol), and tri-n-butyltin hydride (210.77 mg, 724.11 μmol) were dissolved in toluene (1.0 mL), and the mixture was stirred overnight at 110° C. The reaction mixture was concentrated in vacuo and purified by C18 reverse phase column chromatography to afford 22e (27 mg, 33.35%) as a yellow oil.

[0812] 1 H NMR (600MHz, CDCl3) δ7.56 (d, J = 7.7Hz, 1H), 7.52–7.46 (m, 6H), 5.26 (s, 2H), 4.54 (s, 2H) ),4.29(s,2H),2.73(t,J=13.1Hz,2H),2.60(td,J=14.6,4.0Hz,2H),2.12–1.91(m,4H).

[0813] LC-MS(ESI):[MH] - =336.30.

[0814] Step 5: 1'-Benzyl-7-(hydroxymethyl)-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxylic acid (Compound 22f)

[0815] To a solution of intermediate 22e (202 mg, 602.26 μmol) in tetrahydrofuran (2.0 mL) was added a solution of sodium hydroxide (120.44 mg, 3.01 mmol) in water (2.0 mL). The reaction was stirred at room temperature overnight. The resulting mixture was concentrated under vacuum and purified by reverse-phase column chromatography to afford 22f (98 mg, 46.04%) as a white solid.

[0816] LC-MS(ESI):[MH] - =354.59.

[0817] Step 6: 1'-benzyl-7-formyl-2H-spiro[benzofuran-3,4'-piperidine]-6-carboxylic acid (Compound 22g)

[0818] Intermediate 1f (20 mg, 56.59 μmol) and IBX (31.69 mg, 113.18 μmol) were dissolved in a 20:1 ratio of tetrahydrofuran and dimethyl sulfoxide (DMSO) (0.5 mL). The mixture was stirred at 80°C for 2 h. The reaction mixture was filtered and concentrated under vacuum. The crude product was used directly in the next step without further purification.

[0819] LC-MS(ESI):[M+H] + =352.30.

[0820] Step 7: 3-(1'-benzyl-6-oxo-6,8-dihydro-2H,7Hspiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (Intermediate 22h)

[0821] Compound 22g (48 mg, 136.60 μmol) and 3-aminopiperidine-2,6-dione hydrochloride (44.96 mg, 273.19 μmol) were dissolved in tetrahydrofuran and dimethyl sulfoxide (DMSO) (20:1) (1.0 mL), and one drop of N,N-diisopropylethylamine was added. The reaction was stirred at 50°C for 1 h. The mixed solution was cooled to room temperature, and sodium triacetoxyborohydride (86.85 mg, 409.79 μmol) and one drop of acetic acid were added. The temperature was raised to 50°C and the reaction was allowed to react for 1 h. The mixture was concentrated under vacuum and purified by reverse-phase HPLC to yield 22h (16 mg, 26.29%) as a white solid.

[0822] 1 H NMR(600MHz,DMSO-d6)δ11.00(s,1H),7.46-7.56(m,5H),7.34(d,J=7.6Hz,1H),7.26(d ,J=7.7Hz,1H),5.09(dd,J=13.3,5.1Hz,1H),4.67(t,J=6.3Hz,2H),4.43–4.34(m,3H),4 .24(d,J=17.1Hz,1H),3.16(d,J=14.4Hz,2H),2.91(ddd,J=18.0,13.7,5.4Hz,1H),2.6 4–2.56(m,1H),2.44(td,J=13.2,4.6Hz,2H),2.12(d,J=15.4Hz,2H),2.03–1.89(m,4H).

[0823] LC-MS(ESI):[M+H] + =446.35.

[0824] Step 8: 3-(6-oxo-6,8-dihydro-2H,7Hspiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione (Intermediate 22)

[0825] Intermediate 22h (150 mg, 336.69 μmol) was dissolved in hexafluoroisopropanol (4.5 mL) and 20% palladium hydroxide on carbon (75 mg) was added. The hydrogen atmosphere was replaced three times, and the mixture was stirred at room temperature under hydrogen for 5 hours. After completion of the reaction, the reaction solution was filtered, concentrated under reduced pressure, and purified by reverse-phase HPLC to obtain a white solid (35 mg, 29.25%).

[0826] 1 H NMR (600MHz, CD3OD) δ7.46–7.40(m,2H),5.16(dd,J=13.4,5.2Hz,1H),4.70(s,2H),4.52–4.40(m,2H),3.54–3.47(m,2H),3.24–3. 14(m,2H),2.96–2.87(m,2H),2.80(m,J=17.7,4.6,2.2Hz,1H),2.52(m,J=13.3,4.6Hz,1H),2.25–2.16(m,3H),2.05–2.01(m,1H).

[0827] LC-MS(ESI):[M+H] + =356.29.

[0828] Example 23. Synthesis of Intermediate 23

[0829] 8'-(2,6-dioxopiperidin-3-yl)-3',4'-dihydro-7'H-spiro[piperidine-4,2'-pyrano[2,3-e]isoindole]-7',9'(8'H)-dione

[0830] Synthesis scheme

[0831] Step 1: Dimethyl 4-acetyl-3-hydroxyphthalate (Intermediate 23b)

[0832] Under nitrogen, dimethyl 4-bromo-3-hydroxyphthalate (10 g, 34.59 mmol) was dissolved in MeOH (100 mL), and 1-(vinyloxy)butane (13.86 g, 138.87 mmol), Pd(dppf)Cl2 (2.53 g, 3.46 mmol), and triethylamine (10.50 g, 103.78 mmol) were added. The reaction was stirred at 70°C for 12 h. After completion of the reaction, HCl-1,4-dioxane (100 mL) was added, and the mixture was stirred at room temperature for 30 minutes. The mixture was then extracted three times with EA. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to afford the crude product, Compound 23b (8 g, 91.6%), as a yellow oil, which was used directly in the next step.

[0833] LC-MS(ESI):[M-32+H] + =211.06

[0834] Step 2: 1'-(tert-Butyl)7,8-dimethyl 4-oxospiro[chroman-2,4'-piperidine]-1',7,8-tricarboxylate (Intermediate 23c)

[0835] Intermediate 23b (8.0 g, 31.72 mmol), N-tert-butyloxycarbonyl-4-piperidone (7.72 g, 31.72 mmol), and tetrahydropyrrole (2.26 g, 31.72 mmol) were dissolved in 80 mL of ethanol and reacted at 85°C for 12 h. After the reaction, the mixture was concentrated and purified by column chromatography (EA:PE = 29%) to afford Intermediate 23c (4.3 g, 31.28%) as a yellow oil.

[0836] 1 H NMR (600MHz, CDCl3) δ7.93(d,J=8.2Hz,1H),7.68(d,J=8.2Hz,1H),4.00(s,3H),3.95(s,3H),3.30 (t,J=9.7Hz,2H),3.17(t,J=9.7Hz,2H),3.14(s,2H),2.47(t,J=9.7Hz,2H),2.06(t,J=9.7Hz,2H).

[0837] LC-MS(ESI):[M+H] + =334.19

[0838] Step 3: 1'-(tert-Butyl)7,8-dimethyl 4-hydroxyspiro[chroman-2,4'-piperidine]-1',7,8-tricarboxylate (Intermediate 23d)

[0839] Intermediate 23c (4.30 g, 9.92 mmol) was dissolved in 40 mL of MeOH. Sodium borohydride (1.13 g, 29.76 mmol) was added under ice-cooling and stirred overnight. After the reaction was completed, the mixture was concentrated, added with water, extracted with ethyl acetate, and dried to afford the crude yellow oil Intermediate 23d (2.8 g, 64.81%). This was used directly in the next step.

[0840] LC-MS (ESI): [M+H] + =336.29

[0841] Step 4: Spiro[chromene-2,4'-piperidine]-7,8-dicarboxylic acid dimethyl ester (Intermediate 23e)

[0842] Intermediate 23d (2.80 g, 6.43 mmol) was dissolved in 3 mL of toluene, and p-toluenesulfonic acid (2.21 g, 12.86 mmol) was added. The mixture was refluxed at 110°C overnight. After concentration, the mixture was added with water, extracted with ethyl acetate, and dried by spin-drying. The mixture was purified by column chromatography to afford Intermediate 23e (1.4 g, 68.6%) as a yellow oil.

[0843] LC-MS(ESI):[M+H] + =318.38

[0844] Step 5: Spiro[chroman-2,4'-piperidine]-7,8-dicarboxylic acid dimethyl ester (Intermediate 23f)

[0845] Intermediate 23e (1.40 g, 4.41 mmol) was dissolved in MeOH, and Pd / C (700 mg) was added. The mixture was replaced with hydrogen and stirred under a hydrogen atmosphere for 4 hours. After completion of the reaction, the mixture was filtered and concentrated to afford Intermediate 23f (1.3 g, 93.8%) as a yellow oil, which was used directly in the next step.

[0846] LC-MS(ESI):[M+H] + =320.58

[0847] Step 6: Spiro[chroman-2,4'-piperidine]-7,8-dicarboxylic acid (Intermediate 23g)

[0848] Compound 23f (1.4 g, 4.38 mmol) was dissolved in a mixture of THF:H2O (4:1), and LiOH (629.87 mg, 26.30 mmol) was added and stirred at room temperature overnight. After completion of the reaction, the mixture was concentrated under reduced pressure to give a crude yellow oil (1.35 g, 96.84%).

[0849] LC-MS (ESI): [M+H] + =306.58

[0850] Step 7: 8'-(2,6-dioxopiperidin-3-yl)-3',4'-dihydro-7'H-spiro[piperidine-4,2'-pyrano[2,3-e]isoindole]-7',9'(8'H)-dione (Intermediate 23)

[0851] Compound 23g (1.50 g, 4.91 mmol), 3-aminopiperidine-2,6-dione hydrochloride (970.30 mg, 5.90 mmol), and sodium acetate (806.02 mg, 9.83 mmol) were dissolved in acetic acid (5 mL). The mixture was stirred at 110°C for 5 h. After completion of the reaction, the mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by prep-HPLC (Phase A = water, Phase B = ACN, 0.1% TFA, B% = 0% to 50% in 30 min) to afford Compound 23 (0.55 g, 31.3%) as a white solid.

[0852] 1 H NMR (600MHz, DMSO-d6) δ11.11(s,1H),7.62(d,J=7.5Hz,1H),7.39(d,J=7.4Hz,1H),5.08(dd,J=12.9,5.5Hz,1H),3.28(t,J=11.8H z,2H),3.09(t,J=11.8Hz,2H),2.96(t,J=12,4Hz,2H),2.91–2.78(m,3H),2.63–2.52(m,2H),2.05–1.94(m,3H),1.91–1.81(m,2H).

[0853] LC-MS (ESI): [M+H] + =384.19

[0854] Example 24, Synthesis of Intermediate 24

[0855] Synthesis of 8'-(2,6-dioxopiperidin-3-yl)-3',4'-dihydro-7'H-spiro[azetidine-3,2'-pyrano[2,3-e]isoindole]-7',9'(8'H)-dione

[0856] Synthesis scheme

[0857] Step 1: Dimethyl 4-acetyl-3-hydroxyphthalate (Intermediate 24b)

[0858] Under nitrogen protection, dimethyl 4-bromo-3-hydroxyphthalate (2.40 g, 8.30 mmol), butyl vinyl ether (4.15 g, 41.5 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (610 mg, 834.47 mmol) and triethylamine (2.53 g, 25.04 mmol) were dissolved in methanol and stirred in an oil bath at 70°C overnight. After the reaction, the reaction solution was spin-dried and the crude product was purified by silica gel column chromatography (EA / PE = 28%) to synthesize intermediate 24b (418 mg, 20.3%) as a yellow oil.

[0859] 1 H NMR (600MHz, DMSO-d6) δ10.70(s,1H),7.48(d,J=7.5Hz,1H),7.12(d,J=7.4Hz,1H),3.88(s,3H),3.87(s,3H),2.42(s,3H).

[0860] LC-MS(ESI):[M-32+H] + =221.16

[0861] Step 2: 1-Benzyl 7',8'-dimethyl 4'-oxospiro[azetidine-3,2'-chroman]-1,7',8'-tricarboxylate (Intermediate 24c)

[0862] Compound 24b (325 mg, 1.58 mmol) was dissolved in methanol, and tetrahydropyrrole (125 mg, 1.76 mmol) was added. The mixture was stirred overnight in an oil bath at 80°C. After the reaction, the mixture was dried by rotary evaporation. The crude product was purified by silica gel column chromatography (EA / PE = 30%) to afford intermediate 24c (310 mg, 44.5%) as a yellow oil with a purity greater than 90%.

[0863] 1 H NMR (600MHz, CDCl3) δ7.99 (dd, J=8.2, 0.9Hz, 1H), 7.71 (dd, J=8.2, 1.0Hz, 1H), 7.42–7.32 (m, 5H), 5.13(s,2H),4.20(d,J=9.7Hz,2H),4.06(d,J=9.7Hz,2H),4.00(s,3H),3.95(s,3H),3.14(s,2H).

[0864] LC-MS(ESI):[M+H] + =438.20

[0865] Step 3: 1-Benzyl 7',8'-dimethyl 4'-hydroxyspiro[azetidine-3,2'-chroman]-1,7',8'-tricarboxylate (Intermediate 24d)

[0866] Compound 24c (310 mg, 705.48 μmol) was dissolved in methanol. Sodium borohydride (80 mg, 2.11 mmol) was added portionwise in an ice-water bath and stirred at room temperature for 3 hours. After the reaction, the mixture was dried by rotary evaporation. The crude product was purified on a silica gel column (DCM / MeOH = 5%) to afford intermediate 24d (180 mg, 57%) as a yellow oil.

[0867] 1 H NMR(600MHz,DMSO-d6)δ7.63(d,J=7.5Hz,1H),7.44(d,J=7.0Hz,1H),7.42–7.30(m,5H),5.11(s,2H), 4.50(s,1H),4.25-4.15(m,1H),4.10(d,J=9.7Hz,4H),3.88(s,3H),3.86(s,3H),2.60(d,J=17.6,2H).

[0868] LC-MS(ESI):[M+H] + =442.29

[0869] Step 4: Spiro[azetidine-3,2'-chromene]-7',8'-dicarboxylic acid dimethyl ester (Intermediate 24e)

[0870] Compound 24d (180 mg, 407.76 μmol) was dissolved in trifluoroacetic acid, followed by the addition of triethylsilane (330 mg, 2.84 mmol). The mixture was stirred in an oil bath at 100°C for 6 hours and then cooled to room temperature. Another portion of triethylsilane (330 mg, 2.84 mmol) was then added. Upon completion of the reaction, the mixture was spin-dried to dryness. The crude product was dissolved in methanol, stirred for 1 hour, and then spin-dried to dryness. The supernatant was discarded, and the product was obtained as the lower layer without purification, yielding intermediate 24e (160 mg, 96.6%) as a yellow oil, which was used directly in the next step.

[0871] LC-MS(ESI):[M+H] + =289.98

[0872] Step 5: Spiro[azetidine-3,2'-chroman]-7',8'-dicarboxylic acid dimethyl ester (Intermediate 24f)

[0873] Under nitrogen, compound 24e (160 mg, 409.28 μmol) was dissolved in methanol, and palladium / carbon (50 mg, 10%) was added. The mixture was replaced with hydrogen and stirred at room temperature overnight. After the reaction, the mixture was filtered and the filtrate was dried to give compound 24f (130 mg, 81.3%) as a yellow oil, which was used directly in the next step without purification.

[0874] LC-MS(ESI):[M+H] + =292.18

[0875] Step 6: Spiro[azetidine-3,2'-chroman]-7',8'-dicarboxylic acid (Intermediate 24g)

[0876] Compound 24f (130 mg, 410.57 μmol) was dissolved in a 1:1:5 mixture of tetrahydrofuran / methanol / water. Lithium hydroxide (150 mg, 6.26 mmol) was added under ice-water conditions and stirred overnight at room temperature. After completion of the reaction, the pH was adjusted to 7 with aqueous hydrochloric acid. The filtrate was then dried to afford intermediate 24g (140 mg, 105%) as a yellow oil, which was used directly in the next step without purification.

[0877] LC-MS(ESI):[M+H] + =264.17

[0878] Step 7: 8'-(2,6-dioxopiperidin-3-yl)-3',4'-dihydro-7'H-spiro[azetidine-3,2'-pyrano[2,3-e]isoindole]-7',9'(8'H)-dione (Intermediate 24)

[0879] Compound 24g (200 mg, 1.22 mmol) and sodium acetate (200 mg, 2.44 mmol) were dissolved in acetic acid and stirred in an oil bath at 120°C overnight. The product was then spin-dried and dissolved in methanol. Reverse phase purification with ACN / H2O (0-20% over 40 min) afforded intermediate 24 (80 mg, 18.4%) as a white solid.

[0880] 1 H NMR (600MHz, DMSO-d6) δ11.13(s,1H),7.63(d,J=7.5Hz,1H),7.44(d,J=7.0Hz,1H),5.09(dd,J=12.9,5.5Hz,1H) ,4.15(s,4H),2.96(t,J=6.5Hz,2H),2.94-2.87(m,1H),2.60-2.54(m,2H),2.31–2.20(m,2H),2.03-1.94(m,1H).

[0881] LC-MS(ESI):[M+H] + =356.30

[0882] Example 25. Synthesis of Intermediate 25

[0883] Synthesis of 7-(2,6-dioxopiperidin-3-yl)-7-hydrogen-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-6,8-dione

[0884] Synthesis scheme

[0885] Step 1: Dimethyl 3-((1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)methoxy)-4-bromophthalate (Intermediate 25b)

[0886] Under nitrogen, dimethyl 4-bromo-3-hydroxyphthalate (1.80 g, 6.23 mmol) was dissolved in tetrahydrofuran (10 mL). (1-Benzyl 1,2,3,6-tetrahydropyridin-4-yl)methanol (1.90 g, 9.34 mmol) and triphenylphosphine (3.27 g, 12.45 mmol) were added, followed by the slow dropwise addition of diisopropyl azodicarboxylate (2.52 g, 12.45 mmol). After addition, the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was removed in vacuo, and the crude product was purified by column chromatography (H₂O:ACN = 0-30%) to afford the title compound as a yellow oil (2.10 g, 71.10%).

[0887] 1 H NMR(600MHz,DMSO-d6)δ7.95(d,J=8.4Hz,1H),7.70(d,J=8.4Hz,1H),7.58-7.45(m,5H),5.87-5.83(m,1H),4 .45(s,2H),3.84(s,3H),3.83(s,3H),3.81(s,2H),3.47–3.30(m,2H),3.25–3.10(m,2H),2.47–2.34(m,2H).

[0888] LC-MS(ESI):[M+H] + =474.09

[0889] Step 2: 1'-Benzyl-2H-spiro[benzofuran-3,4'-piperidine]-6,7-dicarboxylic acid dimethyl ester (Intermediate 25c)

[0890] Under nitrogen, compound 25b (2.10 g, 4.43 mmol) was dissolved in toluene (25 mL), and azobisisobutyronitrile (2.18 g, 13.28 mmol) and tri-n-butyltin hydroxide (2.58 g, 8.85 mmol) were added. The reaction was stirred at 110°C for 4 hours. After completion of the reaction, the solvent was removed in vacuo, and the crude product was purified by column chromatography (H₂O:ACN = 0-30%) to afford the title compound as a yellow oil (1.50 g, 85.68%).

[0891] 1 H NMR (600MHz, DMSO-d6) δ7.55-7.47(m,5H),7.46(d,J=8.4Hz,1H),7.31(d,J=8.4Hz,1H),4.65(s,2H),4.35(s ,2H),3.80(s,3H),3.78(s,3H),3.43–3.30(m,2H),3.15–3.06(m,2H),2.17–2.07(m,2H),2.01–1.94(m,2H).

[0892] LC-MS(ESI):[M+H] + =360.29

[0893] Step 3: 1'-Benzyl-2H-spiro[benzofuran-3,4'-piperidine]-6,7-dicarboxylic acid (Intermediate 25d)

[0894] Intermediate 25c (1.50 g, 3.79 mmol) was dissolved in a 3:1 mixture of methanol and water (15 ml), and lithium hydroxide (454.17 mg, 18.97 mmol) was added. The reaction was stirred at 50°C for 2 hours. After completion of the reaction, the filtrate was concentrated to obtain the crude product as a yellow solid (1.35 g) which was used in the next step without purification.

[0895] LC-MS(ESI):[M+H] + =367.99

[0896] Step 4: 1'-Benzyl-7-(2,6-dioxopiperidin-3-yl)-7-hydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-6,8-dione (Intermediate 25e)

[0897] Intermediate 25d (1.35 g, 3.67 mmol) was dissolved in acetic acid (12 mL), and 3-aminopiperidine-2,6-dione hydrochloride (1.21 g, 7.35 mmol) and sodium acetate (1.21 g, 14.70 mmol) were added. The reaction was stirred at 115°C overnight. After completion of the reaction, the mixture was concentrated in vacuo, and the crude product was purified by column chromatography (H2O:ACN = 0-30%) to afford the compound as a purple oil (1.52 g, 90.02%).

[0898] 1H NMR (600MHz, DMSO-d6) δ11.10(s,1H),7.62(d,J=7.4Hz,1H),7.55-7.47(m,5H),7.43(d,J=7.3Hz,1H),5.11(dd,J=13.0,5.4Hz,1H),4.81( s,2H),3.96(s,2H),3.38(d,J=13.0Hz,2H),3.09–3.01(m,2H),2.91– 2.84(m,1H),2.63-2.58(m,2H),2.08–2.00(m,3H),1.98–1.90(m,2H).

[0899] LC-MS(ESI):[M+H] + =460.49

[0900] Step 5: 7-(2,6-dioxopiperidin-3-yl)-7-hydro-2H,6H-spiro[furo[2,3-e]isoindole-3,4'-piperidine]-6,8-dione (Intermediate 25)

[0901] Intermediate 25e (489 mg, 1.06 mmol) was dissolved in methanol, and palladium on carbon (180 mg) was added. The atmosphere was replaced with hydrogen two to three times. The reaction was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was filtered through celite. The organic phase was dried and concentrated, and the crude product was purified by column chromatography (H₂O:ACN = 15-55%) to afford the title compound as a white solid (170 mg, 43.25%).

[0902] 1 H NMR (600MHz, DMSO-d6) δ11.12(s,1H),7.61(d,J=7.4Hz,1H),7.49(d,J=7.3Hz,1H),5.11(dd,J=13.0,5.4Hz,1H),4.81(s,2 H),3.38(d,J=13.0Hz,2H),3.09–3.00(m,2H),2.92–2.85(m,1H),2.62-2.59(m,2H),2.09–2.01(m,3H),1.98–1.91(m,2H).

[0903] LC-MS(ESI):[M+H] + =370.09

[0904] Example 26, Synthesis of Intermediate 26

[0905] 3-(9'-Oxo-7',9'-dihydro-2'-spiro[piperidin-4,3'-pyrano[2,3-e]isoindol]-8'(4'H)-yl)piperidin-2,6-dione

[0906] Synthesis scheme

[0907] Step 1: 6-Bromo-2-fluoro-3-methylbenzoic acid (Intermediate 26b)

[0908] To a solution of lithium diisopropylamide (1.3M in THF / hexane, 6.9 mL, 13 mmol) in tetrahydrofuran (10.6 mL) was added compound 26a (2.0 g, 10.6 mmol) at -78°C. The mixture was reacted for 2 hours at this temperature and quickly poured into dry ice. After warming to room temperature, the solvent was evaporated to afford compound 26b (2.84 g, 115%) as a white solid, which was used directly in the next step.

[0909] LC-MS(ESI):[MH] - =230.95

[0910] Step 2: Methyl 6-bromo-2-fluoro-3-methylbenzoate (Intermediate 26c)

[0911] To a solution of Intermediate 26b (2.1 g, 8.9 mmol) in N,N-dimethylformamide (12 mL) were added iodomethane (2.5 g, 17.8 mmol) and potassium carbonate (3.7 g, 26.7 mmol). The reaction was allowed to proceed at 80°C for 1 hour. Upon completion, water (50 mL) was added, and the mixture was extracted with ethyl acetate (100 mL x 3), washed with saturated brine (100 mL), and the combined organic phases were dried over anhydrous sodium sulfate. The mixture was then spin-dried and purified by column chromatography (PE:EA = 0-20%) to afford Intermediate 26c (1.9 g, 86%) as a yellow oil.

[0912] 1 H NMR (600MHz, CDCl3) δ7.27 (d, J = 9.2Hz, 1H), 7.14–7.09 (m, 1H), 3.97 (s, 3H), 2.25 (d, J = 1.9Hz, 3H).

[0913] LC-MS(ESI):[M+H] + =247.66.

[0914] Step 3: Methyl 6-bromo-3-(bromomethyl)-2-fluorobenzoate (Intermediate 26d)

[0915] Under nitrogen, to a solution of compound (1.9 g, 7.6 mmol) in carbon tetrachloride (98 mL) were added N-bromosuccinimide (1.6 g, 9.2 mmol) and azobisisobutyronitrile (62.8 mg, 0.38 mmol). The mixture was allowed to react overnight at 85°C. The solvent was evaporated and the product was purified by column chromatography (PE:EA = 0-30%) to afford Intermediate 26d (219.9 mg, 8%) as a yellow oil.

[0916] 1 H NMR (600MHz, CDCl3) δ7.39 (d, J = 8.4Hz, 1H), 7.35–7.31 (m, 1H), 4.45 (s, 2H), 3.98 (s, 3H).

[0917] Step 4: tert-Butyl 4-(4-bromo-2-fluoro-3-(methoxycarbonyl)benzyl)-4-formylpiperidine-1-carboxylic acid methyl ester (Intermediate 26e)

[0918] Under a nitrogen atmosphere, potassium tert-butoxide (75.7 mg, 0.67 mmol) was added to a solution of 1-tert-butyloxycarbonylpiperidine-4-carboxaldehyde (158.4 mg, 0.74 mmol) in tetrahydrofuran (4 mL) at -30°C. The mixture was allowed to react for 1 hour. Compound 26d (219.9 mg, 0.67 mmol) in tetrahydrofuran (3 mL) was then slowly added. The mixture was allowed to react for 2 hours at the same temperature and then allowed to react at room temperature overnight. The solvent was evaporated and the mixture was purified by column chromatography (PE:EA = 0-40%) to afford Intermediate 26e (147.6 mg, 48%) as a colorless oil.

[0919] 1 H NMR (600MHz, CDCl3) δ9.55 (s, 1H), 7.30 (d, J = 8.3Hz, 1H), 7.00–6.95 (m, 1H), 3.96 (s, 3H), 4.00–3. 75(m,2H),2.95–2.70(m,2H),2.77(s,2H),1.94(d,J=13.0Hz,2H),1.58–1.46(m,2H),1.43(s,9H).

[0920] LC-MS(ESI):[M-Boc+H] + =358.19.

[0921] Step 5: tert-Butyl 4-(4-bromo-2-fluoro-3-(methoxycarbonyl)benzyl)-4-(hydroxymethyl)piperidine-1-carboxylate (Intermediate 26f)

[0922] Sodium borohydride (1.9 g, 51.4 mmol) was slowly added portionwise to a solution of compound 26e (4.7 g, 10.3 mmol) in methanol (50 mL) at 0°C. The mixture was then allowed to react at room temperature for 2 hours. The reaction was quenched by the slow addition of water, dried, and purified by column chromatography (PE:EA = 0-50%) to afford intermediate 26f (4.14 g, 88% yield) as a colorless oil.

[0923] 1 H NMR(600MHz,DMSO-d6)δ7.51(d,J=8.3Hz,1H),7.41–7.36(m,1H),4.78(t,J=5.0Hz,1H),3.90( s,3H),3.46–3.39(m,2H),3.20(d,J=4.5Hz,4H),2.66(s,2H),1.99(s,2H),1.42–1.32(m,11H).

[0924] LC-MS(ESI):[M-Boc+H] + =360.29.

[0925] Step 6: 1'-(tert-butyl)8-methyl7-bromospiro[chroman-3,4'-piperidine]-1',8-dicarboxylate (Compound 26g)

[0926] Under a nitrogen atmosphere, Intermediate 26f (125 mg, 0.27 mmol) was slowly added to a solution of sodium hydride (11.9 mg, 0.27 mmol, 60% dispersion in liquid paraffin) in N,N-dimethylformamide (1 mL). The mixture was heated to 110°C and allowed to react for 1 hour. After cooling to room temperature, the reaction was quenched by the slow addition of water (2 mL). After the addition of water (10 mL), the mixture was extracted with ethyl acetate (20 mL x 3) and washed with saturated brine (40 mL). The combined organic phases were purified by column chromatography (PE:EA = 0-40%) to afford Intermediate 26g (73.0 mg, 61%) as a white solid.

[0927] 1 H NMR(600MHz, CDCl3) δ7.03(d,J=8.2Hz,1H),6.92(d,J=8.2Hz,1H),3.92(s,3H),3. 90(s,2H),3.59-3.47(m,2H),3.37–3.28(m,2H),2.61(s,2H),1.50–1.40(m,13H).

[0928] LC-MS(ESI):[M-Boc+H] + =339.99

[0929] Step 7: 1'-(tert-butyl(8-methyl-7-vinylspiro[chroman-3,4'-piperidine]-1',8-dicarboxylate) (Intermediate 26h)

[0930] Under nitrogen, Intermediate 26g (73.0 mg, 0.17 mmol) was dissolved in a tetrahydrofuran / water mixture (10:1, 1.1 mL). Potassium vinyl trifluoroborate (33.5 mg, 0.25 mmol), palladium acetate (7.5 mg, 0.033 mmol), triphenylphosphine (6.1 mmol, 0.023 mmol), and cesium carbonate (108.2 mg, 0.33 mmol) were then added. The mixture was reacted in an 85°C oil bath overnight. The solvent was evaporated and the product was purified by column chromatography (PE:EA = 0-40%) to afford Intermediate 26h (38.9 mg, 45%) as a white solid.

[0931] 1 H NMR (600MHz, CDCl3) δ7.08(d,J=7.9Hz,1H),7.04(d,J=7.8Hz,1H),6.63(dd,J=17.4,11.0Hz,1H),5.69(d,J=17.4Hz,1 H),5.28(d,J=11.0Hz,1H),3.96–3.88(m,5H),3.60–3.50(m,2H),3.38–3.29(m,2H),2.67(s,2H),1.52–1.42(m,13H).

[0932] LC-MS(ESI):[M-Boc+H] + =288.18

[0933] Step 8: 1'-(tert-Butyl)8-methyl7-formylspiro[chroman-3,4'-piperidine]-1',8-dicarboxylate (Intermediate 26i)

[0934] Sodium periodate (64.9 mg, 0.3 mmol) and potassium osmate dihydrate (1.4 mg, 0.003 mmol) were added to a solution of compound 26h (29.4 mg, 0.076 mmol) in acetone / water (5:1, 2.7 mL) and allowed to react overnight at room temperature. The solvent was evaporated and the product was purified by column chromatography (PE:EA = 0-40%) to afford intermediate 26i (8.9 mg, 30%) as a white solid.

[0935] 1H NMR(600MHz, CDCl3)δ9.89(s,1H),7.37(d,J=7.7Hz,1H),7.25(d,J=6.4Hz,1H),4.00–3.94(m, 5H),3.59–3.48(m,2H),3.42–3.33(m,2H),2.75(s,2H),1.54–1.48(m,2H),1.48–1.41(m,11H).

[0936] LC-MS(ESI):[M-Boc+H] + =290.18

[0937] Step 9: Tert-butyl 8'-(2,6-dioxopiperidin-3-yl)-9'-oxo-4',7',8',9'-tetrahydro-2'H-spiro[piperidine-4,3'-pyrano[2,3-e]isoindole]-1-carboxylate (Intermediate 26j)

[0938] Intermediate 26i (500 mg, 1.3 mmol) and 3-amino-2,6-piperidinedione hydrochloride (316 mg, 1.9 mmol) were mixed in a 1 / 2 dichloromethane / methanol mixture (39 mL). After reacting at room temperature for 1 hour, sodium cyanoborohydride (241 mg, 3.8 mmol) was added and the reaction continued overnight at room temperature. The solvent was evaporated, and the mixture was purified by reverse-phase column chromatography to obtain Intermediate 26j (233 mg, 39%) as a white solid.

[0939] 1 H NMR(600MHz,DMSO-d6)δ10.95(s,1H),7.28(d,J=7.6Hz,1H),7.00(d,J=7.6 Hz,1H),5.02(dd,J=13.3,5.1Hz,1H),4.30(d,J=17.2Hz,1H),4.17(d,J=17.1Hz,1H),4.01(s,2H),3.50–3.43(m,2H),3.30–3.25(m, 2H),2.94–2.87(m,1H),2.73(s,2H),2.60–2.55(m,1H),2.38–2.30(m,1H),1.99–1.91(m,1H),1.45–1.35(m,11H),1.35–1.29(m,2H).

[0940] LC-MS(ESI):[M+H] + =470.40

[0941] Step 10: 3-(9'-oxo-7',9'-dihydro-2'-spiro[piperidin-4,3'-pyrano[2,3-e]isoindole]-8'(4'H)-yl)piperidine-2,6-dione (Intermediate 26)

[0942] Trifluoroacetic acid (2 mL) was added to a dichloromethane solution (5 mL) of compound 26j (230 mg, 0.49 mmol) and the reaction was allowed to proceed at room temperature for 1.5 hours. The solvent was evaporated and the mixture was purified by preparative column chromatography to afford intermediate 26 (151.2 mg, 84%) as a white solid.

[0943] 1 H NMR(600MHz,DMSO-d6)δ10.96(s,1H),7.30(d,J=7.6Hz,1H),7.04(d,J=7.4H z,1H),5.01(dd,J=13.2,4.9Hz,1H),4.31(d,J=17.1Hz,1H),4.18(d,J=17.2 Hz,1H),4.11–4.04(m,2H),3.20–3.06(m,4H),2.94–2.86(m,1H),2.77(s,2H ),2.60–2.53m,1H),2.39–2.30(m,1H),1.98–1.91(m,1H),1.69–1.53(m,4H).

[0944] LC-MS(ESI):[M+H] + =370.29

[0945] Example 27, Synthesis of Intermediate 27

[0946] 2-(2,6-dioxopiperidin-3-yl)-2-hydro-1H,7Hspiro[furo[3,2-e]isoindole-8,4'-piperidine]-1,3-dione

[0947] Synthesis scheme

[0948] Step 1: Dimethyl 3-bromo-4-hydroxyphthalate (Intermediate 27a)

[0949] Intermediate 1b (33.6 g, 160 mmol, 1.0 eq) was dissolved in trifluoroacetic acid (100 mL). N-bromosuccinimide (34.2 g, 192 mmol, 1.2 eq) was added to the reaction system and allowed to react overnight at room temperature. The resulting reaction system was concentrated under reduced pressure, water (100 mL) was added, and the mixture was extracted with ethyl acetate (3 times with 100 mL). The mixture was washed with saturated brine (100 mL), and the combined organic phases were dried over anhydrous sodium sulfate. The concentrated crude product was purified by reverse-phase column chromatography to yield Intermediate 27a (9.8 g, 21.3%) as a pale yellow solid.

[0950] 1 H NMR (600MHz, DMSO-d6) δ11.68(s,1H),7.87(d,J=12.0Hz,1H),7.10(d,J=12.0Hz,1H),3.84(s,3H),3.79(s,3H).

[0951] LCMS(ESI):[MH] - =287.09.

[0952] Step 2: Dimethyl 4-((1-benzyl 1,2,3,6-tetrahydropyridin-4-yl)methoxy)-3-bromophthalate (Intermediate 27b)

[0953] Intermediate 27a (9.8 g, 33.9 mmol, 1.0 eq), (1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)methanol (10.3 g, 50.8 mmol, 1.5 eq), and triphenylphosphine (33.3 g, 127 mmol, 2.5 eq) were dissolved in tetrahydrofuran (80 mL). Diethyl azodicarboxylate (22.1 g, 127 mmol, 2.5 eq) was added and reacted at room temperature for 4 hours. The resulting reaction system was concentrated under reduced pressure, water (50 mL) was added, and the mixture was extracted with ethyl acetate (3 times with 100 mL). The organic phases were then washed with saturated brine (100 mL). The combined organic phases were dried over anhydrous sodium sulfate. The crude product was purified by column chromatography to yield Intermediate 27b (8.7 g, 51.3%) as a reddish-brown solid.

[0954] 1H NMR(600MHz,DMSO-d6)δ8.00(d,J=8.8Hz,1H),7.40-7.29(m,5H),7.27-7.24(m,1H),5.84(tt,J=3.4,1.6Hz,1 H),4.68(s,2H),3.86(s,3H),3.81(s,3H),3.54(s,2H),2.93-2.92(m,2H),2.54(t,J=5.7Hz,2H),2.16(s,2H).

[0955] LCMS(ESI):[M+H] + =474.09.

[0956] Step 3: 1'-Benzyl-2H-spiro(benzofuran-3,4'-piperidine)-4,5-dicarboxylic acid dimethyl ester (Intermediate 27c)

[0957] Intermediate 27b (8.7 g, 18.3 mmol, 1.0 eq), tri-n-butyltin hydroxide (10.6 g, 36.6 mmol, 2.0 eq), and azobisisobutyronitrile (0.6 g, 3.7 mmol, 0.2 eq) were dissolved in toluene (84 mL) and reacted at 110°C under nitrogen for 4 hours. The reaction system was cooled to room temperature and concentrated under reduced pressure. Water (100 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The mixture was washed with saturated brine (100 mL), and the combined organic phases were dried over anhydrous sodium sulfate. The crude product was purified by column chromatography to obtain Intermediate 27c (4.7 g, 64.8%) as a reddish-brown oil.

[0958] 1 H NMR (600MHz, DMSO-d6) δ7.84(d,J=8.5Hz,1H),7.38-7.29(m,4H),7.29-7.23(m,1H),7.00(d,J=8.5Hz,1H),4.52(s, 2H),3.86(s,3H),3.78(s,3H),3.48(s,2H),2.75(dd,J=11.6,3.7Hz,2H),2.08~1.93(m,4H),1.58(d,J=12.2Hz,2H).

[0959] LCMS(ESI):[M+H] + =395.71

[0960] Step 4: 1'-Benzyl-2H-spiro[benzofuran-3,4'-piperidine]-4,5-dicarboxylic acid (Intermediate 27d)

[0961] Intermediate 27c (4.7 g, 11.9 mmol, 1.0 eq) was dissolved in methanol (10 mL) and water (10 mL), and potassium hydroxide (33.3 g, 594 mmol, 50 eq) was added. The reaction was allowed to proceed at 90°C for 12 hours. The reaction system was concentrated under reduced pressure, and the crude product was purified by column chromatography to obtain Intermediate 27d (4.3 g, 92.1%) as a white solid.

[0962] 1 H NMR(400MHz,DMSO-d6)δ7.81(d,J=8.5Hz,1H),7.60-7.65(m,2H),7.44-7.39(m,3H),6.94(d ,J=8.5Hz,1H),4.61(s,2H),4.25(s,2H),3.16(s,4H),2.39(s,2H),1.78(d,J=12.2Hz,2H).

[0963] LCMS (ESI) [M+H] + =368.30

[0964] Step 5: 1'-Benzyl-2-(2,6-dioxopiperidin-3-yl)-2-hydro-1H,7H-spiro[furo[3,2-e]isoindole-8,4'-piperidine]-1,3-dione (Intermediate 27e)

[0965] Intermediate 27d (4.3 g, 11.7 mmol, 1.0 eq), sodium acetate (3.8 g, 46.8 mmol, 4.0 eq), and 3-amino-2,6-piperidinedione hydrochloride (2.99 g, 23.4 mmol, 2.0 eq) were dissolved in acetic acid (30 mL) and reacted at 110°C for 12 hours. The reaction system was cooled to room temperature and concentrated under reduced pressure. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The mixture was washed with saturated brine (80 mL), and the combined organic phases were dried over anhydrous sodium sulfate. The crude product was purified by column chromatography to obtain Intermediate 27e (2.5 g, 47.2%) as a white solid.

[0966] 1H NMR (400MHz, CD3OD) δ7.79(d,J=8.2Hz,1H),7.69-7.44(m,5H),7.19(d,J=8.1Hz,1H),5.13(dd,J=12.6,5.4Hz,1H),4.80(s,2H),4.3 8(s,2H),3.55(d,J=13.0Hz,2H),3.35–3.36(m,1H),3.17(t,J=13.4Hz,2H),2.97-2.85(m,2H),2.81-2.65(m,2H),2.17-1.98(m,3H).

[0967] LCMS (ESI) [M+H] + =460.29

[0968] Step 6: 2-(2,6-dioxopiperidin-3-yl)-2-hydro-1H,7H-spiro[furo[3,2-e]isoindole-8,4'-piperidine]-1,3-dione (Intermediate 27)

[0969] Intermediate 27e (50 mg, 1.1 mmol, 1.0 eq) was dissolved in methanol (50 mL), and palladium hydroxide on carbon (14 mg, 0.1 mmol, 0.1 eq) was added. The atmosphere was replaced with hydrogen three times and the mixture was allowed to react at room temperature for 2 hours. The reaction mixture was filtered, and the filter cake was washed three times with methanol (10 mL). The filtrate was dried under reduced pressure, and the concentrated crude product was purified by reverse-phase column chromatography to afford Intermediate 27 (16 mg, 26.2%) as a white solid.

[0970] 1 H NMR (600MHz, CD3OD) δ7.79(dd,J=8.2,1.2Hz,1H),7.19(dd,J=8.1,1.3Hz,1H),5.15(dd,J=12.9,5.4Hz,1H),4.78(s,2H),3.49(dt, J=13.3,2.7Hz,2H),3.14(td,J=13.7,2.8Hz,2H),2.94-2.87(m,3H),2.80-2.70(m,2H),2.18-2.14(m,1H),2.04(d,J=14.3Hz,2H).

[0971] LCMS (ESI) [M+H] + =370.39

[0972] Example 28, Synthesis of Intermediate 28

[0973] Synthesis scheme

[0974] Step 1: 1-Bromo-2-(bromomethyl)-3-fluorobenzene (Intermediate 28b)

[0975] Under nitrogen, to a solution of Intermediate 28a (1 g, 5.3 mmol) in carbon tetrachloride (20 mL) were added N-bromosuccinimide (1.2 g, 6.9 mmol) and azobisisobutyronitrile (173.7 mg, 1.1 mmol), and the mixture was allowed to react overnight at 80°C. The solvent was evaporated, and the product was purified by column chromatography (PE:EA = 0-30%) to afford Intermediate 28b (1.3 g, 90%) as a colorless oil.

[0976] 1 H NMR (600MHz, CDCl3) δ7.39 (d, J = 8.1Hz, 1H), 7.21–7.15 (m, 1H), 7.08–7.03 (m, 1H), 4.65 (d, J = 1.7Hz, 2H).

[0977] Step 2: tert-Butyl 4-(2-bromo-6-fluorobenzyl)-4-formylpiperidine-1-carboxylate (Intermediate 28c)

[0978] Under a nitrogen atmosphere, potassium tert-butoxide (592.5 mg, 5.3 mmol) was added to a solution of 1-tert-butyloxycarbonylpiperidine-4-carboxaldehyde (1.3 g, 4.8 mmol) in tetrahydrofuran (10 mL) at -30°C. The mixture was allowed to react for 1 hour. Compound 28b (1.3 g, 4.8 mmol) in tetrahydrofuran (10 mL) was then slowly added. The reaction continued for 2 hours at the same temperature and then allowed to react at room temperature overnight. The solvent was evaporated and the mixture was purified by column chromatography (PE:EA = 0-20%) to afford Intermediate 28c (710.7 mg, 37%) as a colorless oil.

[0979] 1 H NMR(600MHz, CDCl3)δ9.65(d,J=2.9Hz,1H),7.37(d,J=8.0Hz,1H),7.14–7.08(m,1H),7.04–6.98(m,1H),4.1 5–3.70(m,2H),3.02(d,J=2.4Hz,2H),2.90–2.60(m,2H),2.18–1.94(m,2H),1.76–1.62(m,2H),1.44(s,9H).

[0980] LC-MS(ESI):[M-Boc+H] + =300.06.

[0981] Step 3: tert-Butyl 4-(2-bromo-6-fluorobenzyl)-4-(hydroxymethyl)piperidine-1-carboxylate (Intermediate 28d)

[0982] Sodium borohydride (1.9 g, 51.4 mmol) was slowly added portionwise to a solution of compound 28c (4.7 g, 10.3 mmol) in methanol (50 mL) at 0°C. The mixture was then allowed to react at room temperature for 2 hours. The reaction was quenched by the slow addition of water, dried, and purified by column chromatography (PE:EA = 0-50%) to afford intermediate 28d (4.14 g, 88% yield) as a colorless oil.

[0983] 1 H NMR(600MHz, CDCl3) δ7.39(d,J=8.0Hz,1H),7.12–7.07(m,1H),7.05–6.99(m,1H),3.80–3.65(m,2H),3.62(d,J=6.2Hz,2 H),3.11(t,J=11.0Hz,2H),2.94(d,J=2.6Hz,2H),1.67–1.62(m,2H),1.62–1.59(m,1H),1.55–1.47(m,2H),1.44(s,9H).

[0984] LC-MS(ESI):[M-Boc+H] + =301.98.

[0985] Step 4: tert-Butyl 5-bromospiro[chroman-3,4'-piperidine]-1'-carboxylate (Intermediate 28e)

[0986] Under a nitrogen atmosphere, Intermediate 28d (659.4 mg, 1.64 mmol) was slowly added to a solution of sodium hydride (72.1 mg, 1.8 mmol, 60% dispersion in liquid paraffin) in N,N-dimethylformamide (7 mL). The mixture was heated to 110°C and allowed to react for 1 hour. After cooling to room temperature, the reaction was quenched by the slow addition of water (10 mL). After adding water (10 mL), the mixture was extracted with ethyl acetate (40 mL x 3) and washed with saturated brine (80 mL). The combined organic phases were purified by column chromatography (PE:EA = 0-10%) to afford Intermediate 28e (583.1 mg, 93%) as a white solid.

[0987] 1H NMR(400MHz, CDCl3)δ7.15(dd,J=7.9,1.1Hz,1H),7.02–6.95(m,1H),6.78(dd,J=8.2,1.1H z,1H),3.85(s,2H),3.64–3.51(m,2H),3.45–3.32(m,2H),2.64(s,2H),1.52–1.44(m,13H).

[0988] LC-MS(ESI):[M-tBu+H] + =325.98.

[0989] Step 5: 1'-(tert-Butyl)5-methylspiro[chroman-3,4'-piperidine]-1',5-dicarboxylate (Intermediate 28f)

[0990] Under a carbon monoxide atmosphere, triethylamine (2.5 g, 24.6 mmol) and Pd(dppf)2Cl2·CH2Cl2 (670.7 mg, 0.8 mmol) were added to a 60 mL methanol solution of intermediate 28e (3.1 g, 8.2 mmol). The mixture was then heated to 65°C and allowed to react overnight. After completion of the reaction, the mixture was spin-dried and purified by column chromatography (PE:EA = 0-20%) to afford intermediate 28f (2.7 g, 90%) as a colorless oil.

[0991] 1 H NMR (400MHz, CDCl3) δ7.52(d,J=7.5Hz,1H),7.20–7.11(m,1H),6.99(d,J=8.0Hz,1H),3.90( s,2H),3.88(s,3H),3.60–3.46(m,2H),3.46–3.34(m,2H),3.00(s,2H),1.55–1.40(m,13H).

[0992] LC-MS(ESI):[M-Boc+H] + =262.17.

[0993] Step 6: 1'-(tert-Butoxycarbonyl)spiro[chroman-3,4'-piperidine]-5-carboxylic acid (Intermediate 28g)

[0994] To a 1 / 1 methanol / tetrahydrofuran solution of compound 28f (40 mL, 40 mL) was added a 20 mL aqueous solution of potassium hydroxide (1.5 g, 37 mmol) at 0°C. The mixture was transferred to a 60°C oil bath and allowed to react overnight. The solution was then dried by rotary evaporation, and 1 M hydrochloric acid (50 mL) was added. The mixture was extracted with ethyl acetate (3 times with 40 mL), washed with saturated brine (80 mL), and the combined organic phases were dried by rotary evaporation to afford the intermediate 28 g (2.5 g, 97%) as a white solid, which was used directly in the next step.

[0995] LC-MS(ESI):[MH] - =346.20.

[0996] Step 7: 1'-(tert-Butoxycarbonyl)-6-iodospiro[chroman-3,4'-piperidine]-5-carboxylic acid (Intermediate 28h)

[0997] To a solution of compound 28g (84.9 mg, 0.244 mmol) in N,N-dimethylformamide (1 mL) under air was added elemental iodine (62.0 mg, 0.244 mmol), diethyl iodate (78.7 mg, 0.244 mmol), and palladium acetate (2.7 mg, 0.012 mmol). The mixture was reacted in an 80°C oil bath for half an hour. The mixture was extracted with ethyl acetate (10 mL x 3) and washed with saturated brine (20 mL). The combined organic phases were spin-dried and lyophilized to yield intermediate 28h (72.3 mg, 65%) as a white solid.

[0998] 1 H NMR (400MHz, CDCl3) δ7.54(d,J=8.6Hz,1H),6.63(d,J=8.5Hz,1H),3.89(s, 2H),3.64–3.45(m,2H),3.45–3.26(m,2H),2.71(s,2H),1.52–1.36(m,13H).

[0999] LC-MS(ESI):[MH] - =472.10.

[1000] Step 8: 1'-(tert-Butyl)5-methyl6-iodospiro[chroman-3,4'-piperidine]-1',5-dicarboxylate (Intermediate 28i)

[1001] To a solution of intermediate 28h (200.0 mg, 0.42 mmol) in N,N-dimethylformamide (5 mL) were added iodomethane (120 mg, 0.85 mmol) and potassium carbonate (175.2 mg, 1.27 mmol). The reaction was allowed to proceed at 80°C for 1 hour. Upon completion, water (20 mL) was added, and the mixture was extracted with ethyl acetate (40 mL x 3), washed with saturated brine (40 mL), and the combined organic phases were dried over anhydrous sodium sulfate. The product was then dried and purified by column chromatography (PE:EA = 0-20%) to afford intermediate 28i (203.9 mg, 99%) as a yellow oil.

[1002] 1 H NMR (600MHz, CDCl3) δ7.51 (d, J = 8.7Hz, 1H), 6.62 (d, J = 8.7Hz, 1H), 3.95 (s, 3H), 3. 88(s,2H),3.57–3.47(m,2H),3.40–3.27(m,2H),2.59(s,2H),1.49–1.41(m,13H).

[1003] LC-MS(ESI):[M-Boc+H] + =388.19.

[1004] Step 9: 1'-(tert-Butyl)5-methyl6-vinylspiro[chroman-3,4'-piperidine]-1',5-dicarboxylate (Intermediate 28j)

[1005] Under nitrogen, intermediate 28i (1.36 g, 2.8 mmol) was dissolved in a tetrahydrofuran / water mixture (10:1, 33 mL). Potassium vinyl trifluoroborate (560.7 mg, 4.2 mmol), palladium acetate (125.3 mg, 0.558 mmol), triphenylphosphine (102.5 mg, 0.391 mmol), and cesium carbonate (1.82 g, 5.58 mmol) were then added and reacted in an 85°C oil bath overnight. The solvent was evaporated and the product was purified by column chromatography (PE:EA = 0-40%) to afford intermediate 28j (790 mg, 73%) as a colorless oil, which was used directly in the next step.

[1006] LC-MS(ESI):[M+H] + =388.09.

[1007] Step 10: 1'-(tert-Butyl)5-methyl-6-formylspiro[chroman-3,4'-piperidine]-1',5-dicarboxylate (Intermediate 28k)

[1008] Sodium periodate (6.07 g, 28.4 mmol) and potassium osmate dihydrate (126.8 mg, 0.284 mmol) were added to a solution of Intermediate 28j (2.75 g, 7.1 mmol) in acetone / water (5:1, 210 mL) and allowed to react overnight at room temperature. The solvent was evaporated and the product was purified by column chromatography (PE:EA = 0-40%) to afford Intermediate 28k (930 mg, 33%) as a white solid.

[1009] 1 H NMR(600MHz, CDCl3) δ9.83(s,1H),7.65(d,J=8.5Hz,1H),6.99(d,J=8.5Hz,1H),4.05 –3.95(m,5H),3.58–3.47(m,2H),3.40–3.31(m,2H),2.64(s,2H),1.55–1.29(m,13H).

[1010] LC-MS(ESI):[M-tBu+H] + =334.19.

[1011] Step 11: tert-Butyl 2'-(2,6-dioxopiperidin-3-yl)-1'-oxo-1',2',3',9'-tetrahydro-7'-H-spiro[piperidin-4,8'-pyrano[3,2-e]isoindole]-1-carboxylate (Intermediate 281)

[1012] Intermediate 28k (451 mg, 1.16 mmol) and 3-amino-2,6-piperidinedione hydrochloride (286.2 mg, 1.74 mmol) were mixed in a 1 / 2 dichloromethane / methanol mixture (21 mL) and reacted at room temperature for 1 hour. Sodium cyanoborohydride (218.5 mg, 3.5 mmol) was then added and the reaction continued overnight at room temperature. The solvent was evaporated, and the mixture was purified by reverse-phase column chromatography to yield Intermediate 28l (30.2 mg, 5%) as a white solid.

[1013] 1H NMR (600MHz, DMSO-d6) δ10.99(s,1H),7.29(d,J=8.2Hz,1H),7.02(d,J=8.2Hz,1H),5. 01(dd,J=13.2,5.1Hz,1H),4.30(d,J=16.9Hz,1H),4.19(d,J=16.9Hz,1H),3.98(s,2H) ,3.47–3.38(m,2H),3.31–3.24(m,2H),3.12–3.02(m,2H),2.92–2.85(m,1H),2.63–2.5 6(m,1H),2.42–2.32(m,1H),2.00–1.94(m,1H),1.51–1.30(m,11H),1.38–1.30(m,2H).

[1014] LC-MS(ESI):[M-Boc+H] + =370.29.

[1015] Step 12: 3-(1'-oxo-1',9'-dihydro-7'H-spiro[piperidin-4,8'-pyrano[3,2-e]isoindole]-2'(3'H)-yl)piperidine-2,6-dione (Intermediate 28)

[1016] Trifluoroacetic acid (1 mL) was added to compound 281 (30.2 mg, 0.064 mmol), and the reaction was allowed to proceed overnight at room temperature. The mixture was purified by preparative column chromatography to afford intermediate 28 (21.7 mg, 91%) as a white solid.

[1017] 1 H NMR (600MHz, DMSO-d6) δ11.00(s,1H),7.31(d,J=8.2Hz,1H),7.04(d,J=8.2Hz,1H),5.01(dd,J=13.3,5.1Hz,1H),4.31(d,J=17.0Hz,1H),4.20(d,J=1 7.0Hz,1H),4.05(s,2H),3.21–3.03(m,6H),2.94–2.84(m,1H),2.64–2.56( m,1H),2.38(qd,J=13.0,4.2Hz,1H),2.02–1.91(m,1H),1.70–1.52(m,4H).

[1018] LC-MS(ESI):[M+H] + =370.29.

[1019] Example 29, Synthesis of Intermediate 29

[1020] Synthesis scheme

[1021] Step 1: Methyl 5-bromo-2-(bromomethyl)-4-methoxybenzoate (Intermediate 29a)

[1022] Under nitrogen, methyl 5-bromo-4-methoxy-2-methylbenzoate (5 g, 19.30 mmol), NBS (3.61 g, 20.30 mmol), and AIBN (316.9 mg, 1.90 mmol) were dissolved in carbon tetrachloride (50 mL) and heated to 75°C overnight. After TLC analysis, the reaction system was cooled to room temperature and saturated sodium thiosulfate was added. The mixture was stirred for 30 minutes, extracted with dichloromethane, washed with saturated brine, and the combined organic phases were dried over anhydrous sodium sulfate. After concentration, the crude product was purified by column chromatography to yield Intermediate 29a (6.9 g, 96.7%) as a white solid.

[1023] LC-MS(ESI):[M+H] + =336.90

[1024] Step 2: 3-(6-Bromo-5-methoxy-1-oxoisoindol-2-yl)piperidine-2,6-dione (Intermediate 29b)

[1025] Under nitrogen, intermediate 29a (7 g, 20.70 mmol) and 3-amino-2,6-piperidinedione hydrochloride (5.1 g, 31.10 mmol) were dissolved in acetonitrile (100 mL). N,N-diisopropylethylamine (13.4 g, 103.60 mmol) was added to the reaction system, and the mixture was allowed to react at 80°C overnight. The resulting reaction system was concentrated under reduced pressure, acetic acid (50 mL) was added, and the mixture was allowed to react at 120°C for 2 hours. After TLC analysis, the reaction system was concentrated under reduced pressure and purified by reverse-phase column chromatography to obtain solid intermediate 29b (5.3 g, 72.5%).

[1026] LC-MS(ESI):[M+H] + =353.15

[1027] Step 3: 3-(6-Bromo-5-hydroxy-1-oxoisoindol-2-yl)piperidine-2,6-dione (Intermediate 29c)

[1028] Under nitrogen, intermediate 29b (5 g, 14.20 mmol) was dissolved in dichloromethane (10 mL). A 1 M dichloromethane solution of boron tribromide (140 mL) was slowly added at 0°C. The mixture was allowed to react overnight at room temperature after addition. After TLC analysis, the reaction mixture was concentrated under reduced pressure to remove most of the boron tribromide. Dichloromethane (50 mL) was then added and quenched with a small amount of methanol. The reaction mixture was concentrated under reduced pressure and purified by reverse-phase column chromatography to afford intermediate 29c (3.6 g, 75.0%) as an off-white solid.

[1029] LC-MS(ESI):[M+H] + =338.99

[1030] Step 4: 3-(5-((1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)methoxy)-6-bromo-1-oxoisoindol-2-yl)piperidine-2,6-dione (Intermediate 29d)

[1031] Under nitrogen, Intermediate 29c (180 mg, 0.53 mmol), (1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)methanol (162 mg, 0.80 mmol), and triphenylphosphine (320 mg, 1.22 mmol) were dissolved in tetrahydrofuran (10 mL). Diethyl azodicarboxylate (0.2 mL, 1.2 mmol) was added and the mixture was allowed to react at room temperature for 4 hours. After TLC analysis, the reaction mixture was concentrated under reduced pressure and purified by column chromatography to afford Intermediate 29d (147 mg, 53%) as a pale yellow solid.

[1032] 1 H NMR(600MHz,DMSO-d6)δ11.00(s,1H),7.90(s,1H),7.55-7.46(m,5H),7.42(s,1H),5.9 1(s,1H),5.08(dd,J=13.3,5.1Hz,1H),4.75(s,2H),4.45-4.34(m,3H),4.27(d,J=17.5H z,1H),3.71(s,2H),3.56(s,1H),3.17(s,1H),2.91(ddd,J=17.3,13.6,5.5Hz,1H),2.63 -2.57(m,1H),2.41(ddd,J=21.9,16.2,11.7Hz,3H),2.00(dtd,J=12.7,5.4,2.3Hz,1H).

[1033] LC-MS(ESI):[M+H] + =524.09

[1034] Step 5: 3-(1'-benzyl-5-oxo-5,7-dihydro-2H,6H-spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione (Compound 29e)

[1035] Under nitrogen, Intermediate 28d (120 mg, 0.23 mmol), tri-n-butyltin hydroxide (80 mg, 0.27 mmol), and azobisisobutyronitrile (19 mg, 0.12 mmol) were dissolved in toluene (10 mL) and heated to 110°C for 2 hours. After TLC analysis, the reaction system was cooled to room temperature and concentrated under reduced pressure. Purification by reverse-phase column chromatography afforded Intermediate 29e (51 mg, 50%) as a white solid.

[1036] 1 H NMR(600MHz,DMSO-d6)δ10.97(s,1H),7.56-7.47(m,5H),7.42(s,1H),7.04(s,1H) ),5.03(dd,J=13.2,4.9Hz,1H),4.64(q,J=9.3Hz,2H),4.39-4.33(m,3H),4.23(d, J=17.3Hz,1H),3.33-3.24(m,2H),3.16(d,J=16.2Hz,2H),2.94-2.84(m,1H),2.5 9(d,J=16.7Hz,1H),2.41-2.32(m,1H),2.16(t,J=12.4Hz,2H),2.00-1.92(m,3H).

[1037] LC-MS(ESI):[M+H] + =446.35

[1038] Step 6: 3-(5-oxo-5,7-dihydro-2H,6H-spiro[furo[2,3-f]isoindole-3,4'-piperidin]-6-yl)piperidine-2,6-dione (Intermediate 29)

[1039] Under nitrogen, intermediate 29e (25 mg, 0.06 mmol) was dissolved in methanol (2 mL), and 10% wet palladium on carbon (24 mg) was added. After hydrogen exchange three times, the reaction was allowed to proceed overnight at room temperature. The reaction system was filtered, and the filter cake was washed three times with methanol (5 mL). The filtrate was dried under reduced pressure, and the concentrated crude product was purified by reverse-phase column chromatography to yield intermediate 29 (8.7 mg, 43%) as a white solid.

[1040] 1H NMR (600MHz, DMSO-d6) δ10.97(s,1H),7.47(s,1H),7.04(s,1H),5.06(dd,J=13.3, 5.1Hz,1H),4.65-4.60(m,2H),4.36(d,J=17.2Hz,1H),4.24(d,J=17.2Hz,1H),3.36 -3.34(m,2H),3.04(d,J=8.5Hz,2H),2.95-2.86(m,1H),2.60(d,J=17.1Hz,1H),2.3 8(qd,J=13.2,4.4Hz,1H),2.10-2.03(m,2H),2.00-1.95(m,1H),1.91-1.85(m,2H).

[1041] Example 30, Synthesis of Intermediate 30

[1042] Synthesis of 2-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)spiro[3.5]nonan-7-one

[1043] Synthesis scheme

[1044] Step 1: Synthesis of 8-methylene-1,4-dioxaspiro[4.5]decane (Intermediate 30a)

[1045] Methyltriphenylphosphonium bromide (354.53 g, 992.44 mmol) was dissolved in tetrahydrofuran (500 mL) in a three-necked flask. The mixture was cooled to 0°C under nitrogen and slowly added with a solution of LHMDS in tetrahydrofuran (992.44 mL, 992.44 mmol). The mixture was stirred at 0°C for 1 hour. A solution of 1,4-dioxaspiro[4.5]decan-8-one (50.00 g, 320.14 mmol) in tetrahydrofuran (100 mL) was added to the three-necked flask and stirred at 0°C for 0.5 hour. The mixture was transferred to room temperature and stirred overnight. After completion of the reaction, the mixture was quenched with purified water and extracted three times with ethyl acetate (100 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to afford Intermediate 30a (40.0 g, 11.43%) as a colorless oil.

[1046] Step 2: 1,1-dichloro-8,11-dioxadiazole [3.2.4 7 .2 4 Synthesis of tridecane-2-one (Intermediate 30b)

[1047] Dissolve 30a (20 g, 129.69 mmol) and Zn-Cu reagent (33.44 g, 259.39 mmol) in a single-necked flask containing DME (200 mL). Cool to 0°C, slowly add trichloroacetyl chloride (28.95 mL, 259.39 mmol), and maintain stirring at 0°C for 0.5 h. Transfer to room temperature and continue stirring for 3 h. After completion of the reaction, cool to 0°C, quench with ice water, and extract three times with ethyl acetate (100 mL). The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to yield crude intermediate 30b. This crude product is used directly in the next reaction without further purification.

[1048] Step 3: 8,11-dioxalo[3.2.4 7 .2 4 Synthesis of tridecane-2-one (Intermediate 30c)

[1049] Crude intermediate 30b (68.77 g, 259.39 mmol) and ammonium chloride (41.62 g, 778.17 mmol) were dissolved in methanol (300 mL) in a single-necked flask. The temperature was cooled to 0°C, and zinc powder (67.84 g, 1.04 mol) was slowly added. Stirring was maintained at 0°C for 0.5 h. The mixture was brought to room temperature and stirred for 3 h. After completion of the reaction, the mixture was cooled to 0°C, quenched with ice water, and extracted three times with ethyl acetate (100 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to yield the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to yield intermediate 30c (16 g, 30.37%) as a yellow oil.

[1050] Step 4: 2-methyl-8,11-dioxalo[3.2.4 7 .2 4 Synthesis of Tridecane (Intermediate 30d)

[1051] Methyltriphenylphosphonium bromide (32.77 g, 91.72 mmol) was dissolved in tetrahydrofuran (60 mL) in a three-necked flask. The mixture was cooled to 0°C under nitrogen and slowly added with a solution of LHMDS in tetrahydrofuran (91.72 mL, 91.72 mmol). The mixture was stirred at 0°C for 1 hour. A solution of intermediate 30c (6.00 g, 30.57 mmol) in tetrahydrofuran (12 mL) was added to the three-necked flask and stirred at 0°C for 0.5 hour. The mixture was transferred to room temperature and stirred overnight. After completion of the reaction, the mixture was quenched with purified water and extracted three times with ethyl acetate (100 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to afford intermediate 30d (5.59 g, 94.11%) as a colorless oil.

[1052] 1 H NMR (600MHz, CDCl3) δ4.81–4.79(m,2H),3.94(s,4H),2.41(t,J=2.3Hz,4H),1.69–1.65(m,4H),1.59–1.57(m,4H).

[1053] Step 5: Synthesis of (8,11-dioxaheptylspiro[3.2.47.24]tridecane-2-yl)methanol (Intermediate 30e)

[1054] Intermediate 30d (5.59 g, 28.77 mmol) was dissolved in tetrahydrofuran (50 mL) in a three-necked flask. The mixture was cooled to 0°C under nitrogen, and a solution of dimethyl sulfide in tetrahydrofuran (17.26 mL, 34.53 mmol) was slowly added. The mixture was stirred at 0°C for 1 hour. Sodium hydroxide (3.45 g, 86.32 mmol) was added to the flask, followed by a solution of hydrogen peroxide (8.90 g, 86.32 mmol) and stirred at 0°C for 0.5 hour. The mixture was transferred to room temperature and stirred for 3 hours. After completion of the reaction, the mixture was cooled to 0°C, quenched with ice water, and extracted three times with ethyl acetate (100 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to afford Intermediate 30e (2.35 g, 38.47%) as a colorless oil.

[1055] 1 H NMR (600MHz, CDCl3) δ3.93 (s, 4H), 3.59 (d, J = 6.7Hz, 2H), 2.43 (dt, J = 8.1, 6.9Hz, 1H), 1.91–1.87(m,2H),1.69(dd,J=7.7,4.7Hz,2H),1.63–1.57(m,4H),1.54–1.47(m,4H).

[1056] Step 6: Synthesis of 8,11-dioxaheptylspiro[3.2.47.24]tridecane-2-carbaldehyde (Intermediate 30f)

[1057] Intermediate 30e (2.35 g, 11.07 mmol) was dissolved in dichloromethane (40 mL) in a single-necked flask. The temperature was cooled to 0°C, and Dess-Martin periodinane (9.39 g, 22.14 mmol) was slowly added. The mixture was brought to room temperature and stirred for 1 h. After completion of the reaction, the mixture was quenched with aqueous ammonium chloride solution, the excess solvent was removed under reduced pressure, and the mixture was extracted three times with ethyl acetate (100 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to afford Intermediate 30f (2.20 g, 94.54%) as a colorless oil.

[1058] 1 H NMR (600MHz, CDCl3) δ9.75(d,J=1.8Hz,1H),3.93(s,4H),3.12–3.09(m,1H),2.24–2.20(m,2H),2.16(dd,J=7.3,4.8Hz,2H),2.05–1.99(m,8H).

[1059] Step 7: Synthesis of 2-ethynyl-8,11-dioxadiazole [3.2.47.24] tridecane (intermediate 30g)

[1060] Intermediate 30f (2.20 g, 10.46 mmol) and dimethyl (1-diazo-2-oxopropyl)phosphonate (3.01 g, 15.69 mmol) were dissolved in methanol (20 mL) in a single-necked flask. The temperature was cooled to 0°C, and potassium carbonate (2.89 g, 20.93 mmol) was slowly added. The mixture was stirred at 0°C for 0.5 h. The mixture was brought to room temperature and stirred for 1 h. After the reaction was complete, the excess solvent was removed under reduced pressure, purified water was added, and the mixture was extracted three times with ethyl acetate (20 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain Intermediate 30f (510 mg, 22.74%) as a colorless oil.

[1061] 1 H NMR(600MHz, CDCl3)δ3.92(s,4H),3.13(s,1H),2.97–2.91(m,1H),2.18–2.14(m,2H),1.91–1.87 (m,2H),1.68(dd,J=7.6,4.9Hz,2H),1.63(dd,J=7.6,4.3Hz,2H),1.59–1.56(m,2H),1.53(s,2H).

[1062] Step 8: Synthesis of 2-(5-((8,11-dioxadispiro[3.2.47.24]tridec-2-yl)ethynyl)-6-aminopyridazin-3-yl)phenol (Intermediate 30h)

[1063] Intermediate 30g (217.00 mg, 815.49 μmol), intermediate 18 (185.05 mg, 897.04 μmol), bistriphenylphosphine palladium dichloride (57.24 mg, 81.55 μmol), cuprous iodide (15.53 mg, 81.55 μmol), and triethylamine (226.71 μL, 1.63 mmol) were dissolved in a three-necked flask containing DMF (2 mL). Under nitrogen, the mixture was heated to 80°C and stirred overnight. After completion of the reaction, purified water was added and the mixture was extracted three times with ethyl acetate (20 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain Intermediate 30h (140 mg, 43.85%) as a yellow solid.

[1064] 1 H NMR(600MHz,DMSO-d6)δ13.36(s,1H),8.17(s,1H),7.88(dd,J=8.0,1.4Hz ,1H),7.26–7.22(m,1H),6.92–6.87(m,2H),6.82(s,2H),3.83(s,4H),3.37 (d,J=8.7Hz,1H),2.21(dd,J=11.6,9.3Hz,2H),2.02(dd,J=11.7,8.5Hz,2 H),1.63(dd,J=11.7,4.9Hz,4H),1.52(d,J=6.4Hz,2H),1.48–1.45(m,2H).

[1065] LCMS(ESI):[M+H] + =392.36

[1066] Step 9: Synthesis of 2-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)spiro[3.5]nonan-7-one (Intermediate 30)

[1067] Intermediate 30h (140 mg, 357.63 μmol) was dissolved in dichloromethane (2.5 mL) in a three-necked flask. Trifluoroacetic acid (2.5 mL) was added and stirred for 1 h. After completion of the reaction, excess solvent was removed under reduced pressure, purified water was added, and the mixture was extracted three times with ethyl acetate (20 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain Intermediate 30 (61 mg, 49.09%) as a yellow solid.

[1068] 1H NMR (600MHz, DMSO-d6) δ8.19(s,1H),7.86(d,J=7.5Hz,1H),7.27–7.24(m,1H),6.98(s,2H),6.92(d,J=8.1Hz,1H),6.90(d,J= 6.8Hz,1H),2.62–2.60(m,1H),2.36(d,J=9.4Hz,2H),2.26(d,J=5.9Hz,2H),2.20(dd,J=13.0,7.6Hz,4H),1.91–1.87(m,4H).

[1069] LCMS(ESI):[M+H] + =348.3

[1070] Example 31, Synthesis of Intermediate 31

[1071] Synthesis of 7-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)spiro[3.5]nonan-2-one (Intermediate 31)

[1072] Step 1: Synthesis of ethyl 1,1-dichloro-2-oxospiro[3.5]nonane-7-carboxylate (Intermediate 31a)

[1073] Ethyl 4-methylenecyclohexane-1-carboxylate (10 g, 59.44 mmol) was dissolved in ethylene glycol dimethyl ether (100 mL), and zinc copper reagent (10 g, 154 mmol) was added. Trichloroacetyl chloride (25 mL, 224 mmol) was slowly added dropwise to the reaction system under ice-water cooling, and the reaction was allowed to proceed overnight at room temperature. After completion of the reaction, saturated aqueous sodium bicarbonate was slowly added under ice-water cooling to quench the reaction system. The solid was filtered through celite, and the filtrate was extracted three times with ethyl acetate (100 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a brown oily crude intermediate 31a (16.6 g). The crude product was directly used in the next step without purification.

[1074] Step 2: Synthesis of ethyl 2-oxospiro[3.5]nonane-7-carboxylate (Intermediate 31b)

[1075] Intermediate 31a (16.6 g, 59.46 mmol) and solid ammonium chloride (12.72 g, 237.86 mmol) were dissolved in methanol (160 mL). Zinc powder (38 g, 594 mmol) was slowly added portionwise under an ice-water bath and allowed to react overnight. After completion of the reaction, the solid was filtered through Celite, and the filtrate was concentrated and purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to afford Intermediate 31b (10.45 g, 83.57%) as a colorless oil.

[1076] 1 H NMR (600MHz, DMSO-d6) δ4.06 (q, J=7.1Hz, 2H), 2.74 (s, 4H), 2.36–2.31 (m, 1H),1.83–1.79(m2H),1.76–1.65(m,2H),1.60–1.55(m,2H),1.44–1.38(m,2H),1.18(t,J=7.1Hz,3H).

[1077] Step 3: Synthesis of ethyl 2,2-dimethoxyspiro[3.5]nonane-7-carboxylate (Intermediate 31c)

[1078] Intermediate 31b (10.45 g, 50 mmol), trimethyl orthoformate (67 mL, 612 mmol), and pyridinium p-toluenesulfonate (3.75 g, 15 mmol) were dissolved in methanol (100 mL) and reacted at 75°C overnight. After completion of the reaction, the solvent was evaporated, 5 mL of water was added, and the product was extracted three times with 30 mL of ethyl acetate. The product was dried, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to afford Intermediate 31c (12 g, 94.19%) as a yellow oil.

[1079] 1 H NMR(600MHz,DMSO-d6)δ4.03(q,J=7.1Hz,2H),3.01(s,6H),2.28–2.16(m,1H),1.80(d,J=7 .7Hz,4H),1.70–1.65(m,2H),1.64–1.54(m,2H),1.40–1.29(m,4H),1.16(t,J=7.1Hz,3H).

[1080] Step 4: Synthesis of 2,2-dimethoxyspiro[3.5]nonane-7-methanol (Intermediate 31d)

[1081] Intermediate 31c (12 g, 46 mmol) was dissolved in tetrahydrofuran (120 mL), and lithium aluminum tetrahydride (2.67 g, 70 mmol) was slowly added portionwise under ice-cooling. The reaction was allowed to react at room temperature for four hours. After completion, the reaction was quenched by adding a small amount of water under ice-cooling. The reaction was filtered through celite, and the filtrate was dried and concentrated. Purification by column chromatography (petroleum ether:ethyl acetate = 5:1) afforded Intermediate 31d (7.7 g, 76.75%) as a colorless, transparent liquid.

[1082] 1H NMR(600MHz,DMSO-d6)δ4.33(t,J=5.3Hz,1H),3.17(dd,J=6.4,5.3Hz,2H),3.00(s ,6H),1.79–1.77(m,4H),1.65–1.48(m,4H),1.31–1.20(m,3H),0.95–0.79(m,2H).

[1083] Step 5: Synthesis of 2,2-dimethoxyspiro[3.5]nonane-7-carbaldehyde (Intermediate 31e)

[1084] Intermediate 31d (15.4 g, 71.86 mmol), sodium bicarbonate (30 g, 355 mmol) and Dess-Martin reagent (45.72 g, 107.8 mmol) were dissolved in dichloromethane (150 mL) and reacted at room temperature for two hours. After completion of the reaction, a small amount of water was added to quench the reaction system under ice-water bath, filtered through celite, and the filtrate was dried and concentrated. It was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain colorless transparent liquid intermediate 31e (10.35 g, 67.85%).

[1085] 1 H NMR (600MHz, DMSO-d6) δ9.55 (s, 1H), 3.01 (s, 6H), 2.22 (tt, J = 9.9, 3.9Hz, 1H), 1.82–1. 76(m,4H),1.73–1.66(m,2H),1.59–1.53(m,2H),1.40–1.34(m,2H),1.33–1.25(m,2H).

[1086] Step 6: Synthesis of 7-ethynyl-2,2-dimethoxyspiro[3.5]nonane (Intermediate 31f)

[1087] Intermediate 31e (6.33 g, 29.82 mmol) was dissolved in methanol (60 mL), and potassium carbonate (12.36 g, 89.45 mmol) was added. Dimethyl (1-diazo-2-oxopropyl)phosphonate (7.45 g, 38.76 mmol) was added dropwise under ice bath. The mixture was allowed to react overnight at room temperature. After completion of the reaction, the reaction solution was concentrated and purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to give colorless transparent liquid intermediate 31f (3.02 g, 48.62%).

[1088] 1H NMR (600MHz, DMSO-d6) δ3.00(s,6H),2.83(d,J=2.4Hz,1H),2.32(s,1H),1.79(dd,J=15.7,1.5Hz,4H),1.65–1.57(m,4H),1.37–1.31(m,4H).

[1089] Step 7: Synthesis of 6-chloro-4-(2,2-dimethoxyspiro[3.5]nonan-7-yl)ethynyl)pyridazin-3-amine (Intermediate 31g)

[1090] Intermediate 31f (3 g, 14.4 mmol), 3-amino-4-bromo-6-chloropyridazine (2.5 g, 12 mmol), bistriphenylphosphine palladium dichloride (842 mg, 1.2 mmol), cuprous iodide (228 mg, 1.2 mmol), and triethylamine (6.26 mL, 4.8 mmol) were dissolved in a three-necked flask containing DMF (100 mL). Under nitrogen, the mixture was heated to 110°C and reacted for two hours. After completion of the reaction, the mixture was filtered through celite, and the filtrate was added with 400 mL of purified water and extracted three times with ethyl acetate (30 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain Intermediate 31g (2.37 g, 58.84%) as a yellow solid.

[1091] 1 H NMR(600MHz,DMSO-d6)δ7.48(s,1H),6.71(s,2H),3.02(s,6H),2.67(s,1H),1.85–1.8 1(m,4H),1.79–1.72(m,2H),1.68–1.61(m,2H),1.57–1.47(m,2H),1.41–1.37(m,2H).

[1092] LCMS(ESI):[M+H] + =336.35

[1093] Step 8: Synthesis of 2-(6-amino-5-((2,2-dimethoxyspiro[3.5]nonan-7-yl)ethynyl)pyridazin-3-yl)phenol (Intermediate 31h)

[1094] Intermediate 31g (3.5g, 10.42mmol), 2-hydroxyphenylboronic acid (4.31g, 31.27mmol), methanesulfonic acid (2-dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (94.5mg, 1.04mmol), and potassium carbonate (4.32g, 31.2mmol) were dissolved in 1,4-dioxane (40mL) and water (4mL). Under nitrogen, the mixture was heated to 80°C and stirred overnight. After completion of the reaction, the mixture was filtered through celite, and the filtrate was concentrated. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain Intermediate 31h (2.23g, 58.84%) as a yellow solid.

[1095] 1 H NMR (600MHz, DMSO-d6) δ13.32(s,1H),8.15(s,1H),7.88(dd,J=8.0,1.6Hz,1H),7.26–7.22(m,1H),6.93–6.86(m,2H),6.78 (s,2H),3.02(s,6H),2.71(s,1H),1.88–1.82(m,4H),1.80(s,2H),1.70–1.63(m,2H),1.60–1.51(m,2H),1.45–1.38(m,2H).

[1096] LCMS(ESI):[M+H] + =394.39

[1097] Step 9: Synthesis of 7-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)spiro[3.5]nonan-2-one (Intermediate 31)

[1098] Intermediate 31h (100 mg, 254.14 μmol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (375 μL, 5.08 mmol) was added and reacted for 2 h. After completion of the reaction, the reaction mixture was directly concentrated to obtain yellow solid intermediate 31 (76 mg, 91.83%).

[1099] 1 H NMR (600MHz, Methanol-d4) δ8.34(d,J=8.6Hz,1H),7.67(dd,J=8.1,1.8Hz,1H),7.39(td,J=7.7,7.3,1.6 Hz,1H),7.01(dd,J=7.9,6.5Hz,2H),2.82(dt,J=13.0,1.9Hz,4H),2.12–1.85(m,5H),1.82–1.66(m,4H).

[1100] LCMS(ESI):[M+H] + =348.35

[1101] Example 32, Synthesis of Intermediate 32

[1102] Synthesis of 6-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)spiro[3.3]heptan-2-one

[1103] Synthesis scheme:

[1104] Step 1: Synthesis of compound 6-oxospiro[3.3]heptane-2-carboxylic acid methyl ester (Intermediate 32a)

[1105] 6-Oxospiro[3.3]heptane-2-carboxylic acid (5.00 g, 32.43 mmol) was dissolved in a single-necked bottle containing DMF (50 mL), and iodomethane (4.60 g, 32.43 mmol) and potassium carbonate (4.48 g, 32.43 mmol) were added in sequence and stirred at room temperature for 5 h. After the reaction was completed, water was added to quench the mixture, and the mixture was extracted three times with ethyl acetate (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by column chromatography (0-20% ethyl acetate) to give intermediate 32a (3.83 g) as a colorless oil. Step 2: Synthesis of compound 6,6-dimethoxyspiro[3.3]heptane-2-carboxylic acid methyl ester (intermediate 32b)

[1106] Intermediate 32a (3.00 g, 17.84 mmol) was dissolved in a single-necked flask containing MeOH (30 mL). Trimethyl orthoformate (5.68 g, 53.51 mmol) and 4-methylbenzenesulfonic acid pyridinium (896.48 mg, 3.57 mmol) were added sequentially and stirred at room temperature for 5 h. After completion of the reaction, the mixture was quenched with water and extracted three times with ethyl acetate (50 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by column chromatography (0-30% ethyl acetate) to give intermediate 32b (2.93 g) as a colorless oil.

[1107] Step 3: Synthesis of compound 6,6-dimethoxyspiro[3.3]heptane-2-methanol (Intermediate 32c)

[1108] Methyl 6,6-dimethoxyspiro[3.3]heptane-2-carboxylate (3.00 g, 14.00 mmol) was dissolved in a single-necked flask containing tetrahydrofuran (30 mL). The temperature was cooled to 0°C, and lithium aluminum tetrahydride (1.06 g, 28.00 mmol) was slowly added. The mixture was stirred at 0°C for 0.5 h. The mixture was transferred to room temperature and stirred for 5 h. After the reaction was completed, the mixture was cooled to 0°C, quenched with ice water, and extracted three times with ethyl acetate (40 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (0-50% ethyl acetate) to obtain intermediate 32c (2.35 g) as a colorless oil.

[1109] Step 4: Synthesis of compound 6,6-dimethoxyspiro[3.3]heptane-2-carbaldehyde (Intermediate 32d)

[1110] Methyl 6,6-dimethoxyspiro[3.3]heptane-2-carboxylate (2.17 g, 11.65 mmol) was dissolved in acetonitrile (30 mL) in a single-necked flask. 2-iodobenzoic acid (6.52 g, 23.30 mmol) was slowly added and stirred at 80°C for 2 h under a nitrogen atmosphere. After completion of the reaction, the mixture was cooled to room temperature, filtered, and concentrated to afford the crude product. The crude product was purified by column chromatography (0-20% ethyl acetate) to afford Intermediate 32d (1.63 g) as a colorless oil.

[1111] Step 5: Synthesis of compound 6-ethynyl-2,2-dimethoxyspiro[3.3]heptane (Intermediate 32e)

[1112] 6,6-Dimethoxyspiro[3.3]heptane-2-carbaldehyde (2.15 g, 11.67 mmol) was dissolved in methanol (20 mL) in a single-necked flask. The temperature was cooled to 0°C, and potassium carbonate (3.23 g, 23.34 mmol) was slowly added. The temperature was maintained at 0°C and stirred for 10 minutes. Dimethyl 1-diazo-2-oxopropyl)phosphonate (3.36 g, 17.50 mmol) was added, and stirring was continued for 4 hours. After completion of the reaction, the crude product was filtered and concentrated to obtain the crude product. The crude product was purified by column chromatography (0-20% ethyl acetate) to afford Intermediate 32e (1.03 g) as a colorless oil.

[1113] Step 6: Synthesis of compound spiro[3.3]heptan-2-one, 6-ethynyl (Intermediate 32f)

[1114] Dissolve 6-ethynyl-2,2-dimethoxyspiro[3.3]heptane (1.00 g, 5.55 mmol) in dichloromethane (12 mL) in a glass bottle. Slowly add trifluoroacetic acid (3 mL) and stir at room temperature for 2 h. After the reaction is complete, filter and concentrate to obtain the crude product. The crude product is purified by column chromatography (0-20% ethyl acetate) to afford Intermediate 32f (836.00 mg) as a colorless oil.

[1115] 1 H NMR (400MHz, DMSO) δ3.11(d,J=2.1Hz,2H),3.06(t,J=2.8Hz,2H),3.01(d,J=2 .2Hz,1H),2.99(dd,J=8.2,2.4Hz,1H),2.50–2.46(m,3H),2.30–2.24(m,1H).

[1116] Example 33. Synthesis of Intermediate 33

[1117] Synthesis of 4-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)-4-methoxycyclohexane-1-one (Intermediate 33)

[1118] Synthesis scheme

[1119] Step 1: Synthesis of 8-((trimethylsilyl)ethynyl)-1,4-dioxyacetyl[4.5]decan-8-ol (Intermediate 33a)

[1120] 1,4-Dioxaspiro[4.5]decan-8-one (5.00 g, 32.01 mmol) and trimethylsilyl acetylene (4.72 g, 48.02 mmol) were dissolved in tetrahydrofuran (20 mL) in a three-necked flask. Under nitrogen, the temperature was cooled to 0°C, and LDA (22.41 mL, 44.41 mmol) was slowly added. The mixture was stirred at 0°C for 0.5 h. The mixture was transferred to room temperature and stirred for 1 h. After the reaction was complete, the temperature was cooled to 0°C and quenched with purified water. Excess solvent was removed under reduced pressure, and the mixture was extracted three times with ethyl acetate (20 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to afford Intermediate 33a (5.4 g, 66.3%) as a colorless oil.

[1121] 1 H NMR (600MHz, CDCl3) δ3.94(s,4H),2.04(s,1H),1.97–1.94(m,2H),1.91–1.86(m,2H),1.78(t,J=4.9Hz,4H),0.16(s,9H).

[1122] Step 2: Synthesis of ((8-methoxy-1,4-dioxaspiro[4.5]dec-8-yl)ethynyl)trimethylsilane (Intermediate 33b)

[1123] Intermediate 33a (5.00 g, 20.63 mmol) was dissolved in tetrahydrofuran (20 mL) in a three-necked flask, cooled to 0°C, and sodium hydroxide (907.54 mg, 22.69 mmol) was slowly added. The mixture was stirred at 0°C for 0.5 h. Methyl iodide (5.86 g, 41.26 mmol) was slowly added, stirred at 0°C for 0.5 h, and then transferred to room temperature and stirred for 1 h. After the reaction was complete, the temperature was lowered to 0°C and quenched with purified water. Excess solvent was removed under reduced pressure, and the mixture was extracted three times with ethyl acetate (20 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to afford Intermediate 33b (4.8 g, 90.98%) as a colorless oil.

[1124] Step 3: Synthesis of 8-ethynyl-8-methoxy-1,4-dioxaspiro[4.5]decane (Intermediate 33c)

[1125] Intermediate 33b (4.80 g, 17.88 mmol) and potassium carbonate (4.94 g, 35.76 mmol) were dissolved in methanol (20 mL) in a three-necked flask and stirred for 1 h. After completion of the reaction, excess solvent was removed under reduced pressure, purified water was added, and the mixture was extracted three times with ethyl acetate (20 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain Intermediate 33c (2.7 g, 76.94%) as a colorless oil.

[1126] 1 H NMR (600MHz, Chloroform-d) δ3.94(s,4H),2.73(s,1H),1.94(dd,J=12.3,6.2Hz,2H),1.91–1.83(m,2H),1.80–1.73(m,4H),0.15(s,9H).

[1127] Step 4: Synthesis of 2-(6-amino-5-((8-methoxy-1,4-dioxaspiro[4.5]dec-8-yl)ethynyl)pyridazin-3-yl)phenol (Intermediate 33d)

[1128] Intermediate 33c (2.35 g, 8.83 mmol), Intermediate 18 (1.73 g, 8.83 mmol), bistriphenylphosphine palladium dichloride (619.87 mg, 883.13 μmol), cuprous iodide (168.19 mg, 883.13 μmol), and triethylamine (1.79 g, 17.66 mmol) were dissolved in a three-necked flask containing DMF (20 mL). Under nitrogen, the mixture was heated to 80°C and stirred overnight. After completion of the reaction, purified water was added and the mixture was extracted three times with ethyl acetate (20 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain Intermediate 33b (630 mg, 13.79%) as a yellow solid.

[1129] 1 H NMR(400MHz,Chloroform-d)δ7.92(s,1H),7.61(dd,J=8.0,1.5Hz,1H),7.33(ddd,J=8 .5,7.2,1.5Hz,1H),7.08(dd,J=8.3,1.1Hz,1H),6.98–6.92(m,1H),5.37(s,2H),4.00 (d,J=1.9Hz,4H),3.47(s,3H),2.21–2.08(m,4H),1.89(ddd,J=13.6,7.9,5.8Hz,2H),1.82–1.71(m,2H).

[1130] LCMS(ESI):[M+H] + =382.19

[1131] Step 5: Synthesis of 4-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)-4-methoxycyclohexane-1-one (Intermediate 33)

[1132] Intermediate 33d (630 mg, 1.65 mmol) was dissolved in dichloromethane (2.5 mL) in a three-necked flask. Trifluoroacetic acid (2.5 mL) was added and stirred for 1 h. After completion of the reaction, excess solvent was removed under reduced pressure, purified water was added, and the mixture was extracted three times with ethyl acetate (20 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to afford Intermediate 33 (425 mg, 76.26%) as a yellow solid.

[1133] 1H NMR(400MHz,Chloroform-d)δ7.94(s,1H),7.61(dd,J=8.0,1.6Hz,1H),7.33(ddd,J=8.5,7.2,1.6Hz,1H),7.09(dd,J=8.2,1.2 Hz,1H),6.99–6.91(m,1H),5.39(s,2H),3.57(s,3H),2.72–2.58(m,2H),2.46(ddt,J=15.7,9.9,4.5Hz,4H),2.32–2.21(m,2H).

[1134] LCMS(ESI):[M+H] + =338.29

[1135] Example 34. Synthesis of Intermediate 34

[1136] Synthesis of (1s,4s)-4-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)cyclohexane-1-carbaldehyde (Intermediate 34)

[1137] Synthesis scheme

[1138] Step 1: Synthesis of cis-1,4-cyclohexanedimethanol (Intermediate 34a)

[1139] Cis-1,4-cyclohexanedicarboxylic acid (15.0 g, 87.12 mmol) was dissolved in a reaction flask containing THF (500 mL). LiAlH₄ (9.92 g, 261.35 mmol) was added dropwise under an ice-water bath. The reaction was allowed to react overnight at room temperature. Upon completion, the reaction was quenched by adding a Na₂SO₄·10H₂O solution. The organic phase was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to yield the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:2) to afford Intermediate 34a (9.15 g, 72.83%) as a colorless oil.

[1140] 1 H NMR (400MHz, CDCl3) δ3.55 (d, J=6.9Hz, 4H), 1.74–1.67 (m, 2H), 1.55 (ddt, J=13.0, 6.8, 2.6Hz, 6H), 1.43 (dd, J=11.6, 5.7Hz, 4H).

[1141] Step 2: Synthesis of cis-4-methyl acetate-cyclohexane-1-methanol (Intermediate 34b)

[1142] cis-1,4-Cyclohexanedimethanol (9.10 g, 63.10 mmol) was dissolved in a reaction flask containing THF (150 mL). NaH (2.52 g, 60% dispersion in mineral oil) was added to the flask under an ice-water bath. After reacting at 0°C for half an hour, acetyl chloride was gradually added dropwise. After the addition was complete, the reaction was allowed to proceed at room temperature for 3 hours. After completion of the reaction, purified water was added to quench the reaction, and the organic phase was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to afford Intermediate 34b (6.30 g, 53.61%) as a pale yellow oil.

[1143] 1 H NMR (600MHz, CDCl3) δ3.99(d,J=7.3Hz,2H),3.53(d,J=6.9Hz,2H),2.06(d,J=1.2Hz ,3H),1.87(ddq,J=10.1,7.0,2.9Hz,1H),1.68(pt,J=7.1,4.1Hz,1H),1.54(ddp,J= 13.5, 9.5, 4.8Hz, 4H), 1.42 (tdd, J=12.6, 10.7, 8.8, 5.3Hz, 4H), 1.25 (s, 1H).

[1144] Step 3: Synthesis of cis-4-methyl acetate-cyclohexane-1-carbaldehyde (Intermediate 34c)

[1145] DMSO (6.61 g, 84.56 mmol) was dissolved in a three-necked reaction flask containing DCM (50 mL). Oxalyl chloride (5.51 g, 40.59 mmol) was added dropwise at -78°C. Methyl cis-4-acetate-cyclohexane-1-methanol (6.30 g, 33.83 mmol) dissolved in DCM (30 mL) was then added dropwise at -78°C. After a 1-hour reaction, triethylamine (17.11 g, 169.13 mmol) was added and allowed to react for half an hour under a nitrogen atmosphere. Upon completion, the flask was removed from the cold tank and quenched by the addition of 1 M hydrochloric acid at -10°C. The organic phase was extracted with ethyl acetate and concentrated to yield crude intermediate 34c (6.2 g) as a yellow oil. This compound was stable and used directly in the next step without purification.

[1146] Step 4: Synthesis of cis-4-acetylene-cyclohexane-1-methanol (Intermediate 34d)

[1147] Cis-4-acetic acid methyl ester-cyclohexane-1-carbaldehyde (6.20 g, 33.82 mmol) was dissolved in a reaction flask containing methanol (60 mL). Dimethyl (1-diazo-2-oxopropyl)phosphonate (8.45 g, 43.96 mmol) was added dropwise to the reaction flask at 0°C. Potassium carbonate (14.02 g, 101.45 mmol) was then added to the reaction solution. The mixture was allowed to react overnight at room temperature. After completion of the reaction, the organic phase was extracted with ethyl acetate and concentrated to obtain the crude product, which was then purified by column chromatography (petroleum ether:ethyl acetate = 1:5) to afford Intermediate 34d (3.86 g, 62.59%) as a colorless oil.

[1148] 1 H NMR(600MHz, CDCl3) δ3.49(d,J=6.1Hz,3H),3.45(d,J=6.3Hz,1H),2.81–2.76(m,1H),2 .05(d,J=2.4Hz,3H),1.82(d,J=12.9Hz,4H),1.63(dt,J=12.0,3.7Hz,4H),1.25(s,6H).

[1149] Step 5: Synthesis of cis-4-((3-amino-6-chloropyridazin-4-yl)ethynyl)cyclohexyl)methanol (Intermediate 34e)

[1150] 3-Amino-4-bromo-6-chloropyridazine (5.10 g, 24.47 mmol), cis-4-ethynyl-cyclohexane-1-methanol (4.06 g, 29.36 mmol), Pd(PPh3)2Cl2 (1.72 g, 2.45 mmol), CuI (1.40 g, 7.34 mmol), and DIEA (15.81 g, 122.34 mmol) were dissolved in a reaction flask containing DMSO (100 mL) and reacted at 80°C under a nitrogen atmosphere for 3 hours. After completion of the reaction, the organic phase was washed with saturated brine, extracted with ethyl acetate, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:2) to afford Intermediate 34e (3.14 g, 48.29%) as a colorless oil.

[1151] LCMS(ESI):[M+H] + =266.37

[1152] Step 6: Synthesis of 2-(6-amino-5-((cis-4-(hydroxymethyl)cyclohexyl)ethynyl)pyridazin-3-yl)phenol (Intermediate 34f)

[1153] Intermediate 34e (3.14 g, 11.82 mmol), 2-hydroxyphenylboronic acid (4.89 g, 35.45 mmol), BrettPhO₃Pd G₃ (1.07 g, 1.18 mmol), and K₂CO₃ (4.90 g, 35.45 mmol) were dissolved in a reaction flask containing 1,4-Dioxane / H₂O = 5:1 (84 mL) and reacted overnight at 80°C under a nitrogen atmosphere. After completion of the reaction, the organic phase was washed with saturated brine, extracted with ethyl acetate, and concentrated to afford the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:3) to afford Intermediate 34f (1.40 g, 36.64%) as a colorless oil.

[1154] 1 H NMR(400MHz,DMSO-d6)δ8.17(s,1H),7.80(dd,J=7.9,1.7Hz,1H),7.30–7.24(m ,1H),6.96–6.86(m,2H),4.25(d,J=6.1Hz,1H),3.22(d,J=6.2Hz,2H),2.08(dt, J=13.0,7.4Hz,2H),1.86–1.82(m,1H),1.80–1.72(m,2H),1.49(ddd,J=15.6,1 0.1, 3.9Hz, 2H), 1.37 (tq, J=8.8, 3.4, 2.8Hz, 1H), 0.96 (qd, J=13.1, 3.5Hz, 2H).

[1155] LCMS(ESI):[M+H] + =324.02

[1156] Step 7: Synthesis of cis-4-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)cyclohexane-1-carbaldehyde (Intermediate 34)

[1157] Intermediate 34f (100 mg, 309.22 μmol) and IBX (173.17 g, 618.44 μmol) were dissolved in a reaction flask containing THF (10 mL) and reacted at 50°C for 2 hours. After the reaction, the reaction solution obtained by filtration, Intermediate 34, was directly used in the next reaction.

[1158] LCMS(ESI):[M+H] + =322.30

[1159] Example 35, Compound 1

[1160] Synthesis of 3-(1-(4-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)-4-methoxycyclohexyl)-6'-oxo-3',4',6',8'-tetrahydro-7'-hydrospiro[piperidin-4,2'-pyrano[2,3-f]isoindol]-7'-yl)piperidine-2,6-dione (Compound 1)

[1161] Synthesis scheme:

[1162] Intermediate 12 (20 mg, 54.14 μmol) and intermediate 33 (21.92 mg, 64.97 μmol, 1.2 eq) were dissolved in a reaction flask containing DMSO / THF (1 / 0.2 mL). Ti(O-iPr)4(5d) was added and reacted at 60°C for 1 hour. NaBH3CN (10.21 mg, 162.42 μmol, 3.0 eq) was then added and reacted at 60°C for 1 hour. After completion of the reaction, compound 1 (2.7 mg, 6.6%) was obtained after purification by HPLC.

[1163] 1 H NMR(600MHz, Methanol-d4)δ8.58(s,1H),7.82–7.71(m,1H),7.56(dd,J=23.0,3.8Hz,1H),7.40(q,J=10.3,9.0Hz,1H),7 .14–7.01(m,3H),5.14–5.08(m,1H),4.39(p,J=17.0Hz,2H),3.70–3.41(m,3H),3.40–3.32(m,4H),3.17(d,J=7.5Hz,2H), 3.09(s,1H),2.99(s,1H),2.90(ddd,J=23.8,11.5,5.6Hz,2H),2.78(dd,J=17.6,4.2Hz,2H),2.59(s,1H),2.52–2.41(m, 1H), 2.31 (d, J = 33.0Hz, 1H), 2.21 (s, 2H), 2.14 (dd, J = 11.5, 8.7Hz, 2H), 1.99 (s, 4H), 1.93 (s, 1H), 1.75 (d, J = 12.0Hz, 1H).

[1164] LCMS(ESI):[M+H] + =691.37

[1165] Example 36, Compound 2

[1166] Synthesis of 3-(1-(4-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)-4-methoxycyclohexyl)-8'-oxo-3',4',6',8'-tetrahydro-7'-hydrospiro[azetidine-3,2'-pyrano[2,3-f]isoindol]-7'-yl)piperidine-2,6-dione (Compound 2)

[1167] Synthesis scheme:

[1168] Intermediate 12 (20 mg, 58.59 μmol) and intermediate 33 (23.72 mg, 70.31 μmol, 1.2 eq) were dissolved in a reaction flask containing THF / MeOH (10 / 10 mL). Ti(O-iPr)4(5d) was added and allowed to react at room temperature for 2 hours. NaBH3CN (11.05 mg, 175.76 μmol, 3.0 eq) was then added and allowed to react overnight at room temperature. After completion of the reaction, compound 2 (8 mg, 20.6%) was obtained after purification by HPLC.

[1169] 1 H NMR(600MHz, Methanol-d4)δ8.28(s,1H),7.75–7.67(m,1H),7.42–7.24(m,3H),7.01–6.94(m,2H),5.13(dd,J=13.3,5.1Hz,1H), 4.50-4.30(m,6H),3.45(s,3H),3.01(s,2H),2.94–2.85(m,1H),2.82-2.73(m,1H),2.53-2.40(m,3H),2.28(s,2H),2.20-2.13(m, 1H),2.06–1.83(m,4H),1.66–1.56(m,2H).

[1170] LCMS(ESI):[M+H] + =663.50

[1171] Example 37, Compound 3

[1172] Synthesis of 3-(1-(4-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)-4-methoxycyclohexyl)-6'-oxo-3',4',6',8'-tetrahydro-7'H-spiro[azetidine-3,2'-pyrano[2,3-f]isoindol]-7'-yl)piperidine-2,6-dione (Compound 3)

[1173] Synthesis scheme:

[1174] Intermediate 13 (10 mg, 29.29 μmol) and intermediate 33 (11.86 mg, 35.15 μmol, 1.2 eq) were dissolved in a reaction flask containing THF / MeOH (10 / 10 mL). Ti(O-iPr)4(5d) was added and allowed to react at room temperature for 2 hours. NaBH3CN (5.52 mg, 87.88 μmol, 3.0 eq) was then added and allowed to react overnight at room temperature. After completion of the reaction, compound 3 (5.5 mg, 28.33%) was obtained after purification by HPLC.

[1175] 1 H NMR(600MHz, Methanol-d4)δ8.29(s,1H),7.73–7.67(m,1H),7.58(s,1H),7.33(t,J=7.7Hz,1H ),7.11(s,1H),6.96(dd,J=7.6,5.5Hz,2H),5.11(dd,J=13.3,5.1Hz,1H),4.50–4.29(m,6H),3. 45(s,3H),3.41–3.32(m,1H),2.99(s,2H),2.95–2.85(m,1H),2.77(dd,J=14.5,3.2Hz,1H),2.4 5(t,J=11.1Hz,3H),2.28(s,2H),2.21–2.10(m,1H),2.05–1.84(m,4H),1.61(q,J=12.2Hz,2H).

[1176] LCMS(ESI):[M+H] + =663.47.

[1177] Example 38, Compound 4

[1178] Synthesis of 1-(4-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)-4-methoxycyclohexyl)-7'-(2,6-dioxopiperidin-3-yl)-2'-pyridine-4,3'-pyrano[2,3-f]isoindole]-6'-, 8'-(4'H, 7'H)-dione (Compound 4)

[1179] Synthesis scheme:

[1180] Intermediate 4 (20 mg, 52.16 μmol) and intermediate 33 (21.12 mg, 62.60 μmol, 1.2 eq) were dissolved in a reaction vial containing DCM / MeOH (1 / 1 mL). Ti(O-iPr)4(5d) was added and allowed to react at room temperature for 1 hour. NaBH3CN (9.83 mg, 156.49 μmol, 3.0 eq) was then added and allowed to react overnight at room temperature. After completion of the reaction, compound 4 (7.4 mg, 20.13%) was purified by HPLC.

[1181] 1 H NMR (600MHz, Methanol-d4) δ8.32(s,1H),7.74–7.61(m,2H),7.34(t,J=7.6Hz,1H),7.29–7.23(m,1H),6.98(d,J=4. 6Hz,2H),5.09(dd,J=12.6,5.8Hz,1H),4.32(d,J=12.9Hz,1H),4.02(d,J=12.8Hz,1H),3.56(q,J=11.4,10.5Hz,2H) ,3.50(s,1H),3.46(s,2H),3.37(s,1H),3.08(d,J=14.1Hz,1H),2.91–2.79(m,2H),2.78–2.64(m,3H),2.50(t,J=11 .8Hz,2H),2.30(d,J=12.3Hz,1H),2.14–2.02(m,3H),2.00–1.91(m,3H),1.91–1.76(m,4H),1.71(t,J=13.9Hz,1H).

[1182] LCMS(ESI):[M+H] + =705.47

[1183] Example 39, Compound 5

[1184] Synthesis of 3-(1-(4-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)-4-methoxycyclohexyl)-9'-oxo-7'-,9'-dihydro-2'-H-spiro[piperidin-4,3'-pyrano[2,3-e]isoindole]-8'-(4'H)-yl)piperidine-2,6-dione (Compound 5)

[1185] Synthesis scheme:

[1186] Intermediate 26 (20 mg, 54.14 μmol) and intermediate 33 (21.92 mg, 64.97 μmol, 1.2 eq) were dissolved in a reaction vial containing DCM / MeOH (1 / 1 mL). Ti(O-iPr)4(5d) was added and allowed to react at room temperature for 1 hour. NaBH3CN (10.21 mg, 162.42 μmol, 3.0 eq) was then added and allowed to react overnight at room temperature. After completion of the reaction, compound 5 (5.3 mg, 14.17%) was purified by HPLC.

[1187] 1 H NMR(600MHz, Methanol-d4)δ8.30(t,J=4.9Hz,1H),7.69(dd,J=8.1,1.5Hz,1H),7.40–7.29(m,2H),7.09–7.03(m,1H),7.00–6.92(m,2H),5.08(dd ,J=12.3,6.0Hz,1H),4.39(qd,J=17.1,7.5Hz,2H),4.25(dt,J=29.8,11. 6Hz,1H),4.03–3.94(m,1H),3.61–3.48(m,3H),3.46(s,2H),3.36(t,J=1 0.2Hz,1H),3.03–2.94(m,1H),2.89(ddd,J=18.6,13.5,5.2Hz,1H),2.77(d,J=16.5Hz,1H),2.70(d,J=12.6Hz,1H),2.47(dd,J=22.4,8.7Hz,3H), 2.33–2.26(m,1H),2.19–2.11(m,1H),2.07(d,J=10.6Hz,2H),1.96(t,J= 14.7Hz, 3H), 1.86 (ddd, J=37.1, 20.1, 6.9Hz, 5H), 1.72 (t, J=13.5Hz, 1H).

[1188] LCMS(ESI):[M+H] + =691.47

[1189] Example 40, Compound 6

[1190] Synthesis of 3-(1-(7-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)spiro[3.5]nonan-2-yl)-6'-oxo-3',4',6',8'-tetrahydro-7'H-spiro[piperidine-4,2'-pyrano[2,3-f]isoindol]-7'-yl)piperidine-2,6-dione (Compound 6)

[1191] Synthesis scheme:

[1192] Intermediate 12 (33 mg, 97.46 μmol), intermediate 31 (30 mg, 78.89 μmol), and one drop of tetraisopropyl titanate were dissolved in methanol (2 mL) and stirred at room temperature for 1 hour. Sodium cyanoborohydride (15.3 mg, 243.65 μmol) was added and stirred overnight. After completion of the reaction, the crude product was filtered. The crude product was purified by prep-HPLC (Phase A = water with 0.1% TFA, Phase B = ACN with 0.1% TFA, B% = 20%-60% in 60 min) to afford Compound 6 (9.48 mg, 16.65%) as a yellow solid.

[1193] 1 H NMR(600MHz, Methanol-d4)δ8.22(s,1H),7.70(dd,J=8.1,1.6Hz,1H),7.60(s,1H),7.38–7.31(m,1H),7.09(s,1H),7.02–6.95(m,2H),5 .14(dd,J=13.5,5.2Hz,1H),4.42(q,J=16.7Hz,2H),3.81(p,J=8.4Hz,1H),3.46(d,J=5.7Hz,2H),3.20(q,J=13.3,12.5Hz,2H),3.00(t, J=7.0Hz,2H),2.92(ddd,J=18.4,13.6,5.4Hz,1H),2.87–2.75(m,2H),2.48(qd,J=17.3,15.3,6.6Hz,2H),2.31(d,J=12.1Hz,1H),2.23– 2.12(m,3H),2.06–1.87(m,7H),1.82(d,J=12.9Hz,1H),1.75(d,J=10.7Hz,1H),1.67(t,J=11.4Hz,1H),1.64–1.57(m,2H),1.31(s,2H).

[1194] LCMS(ESI):[M+H] + =701.47

[1195] Example 41, Compound 7

[1196] Synthesis of 3-(1-(7-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)spiro[3.5]nonan-2-yl)-6'-oxo-6',8'-dihydro-3'H,7'H-spiro[piperidine-4,2'-[1,4]dioxa[2,3-f]isoindol]-7'-yl)piperidine-2,6-dione (Compound 7)

[1197] Synthesis scheme:

[1198] Intermediate 16 (56.13 mg, 161 μmol), intermediate 31 (50 mg, 134 μmol), and one drop of tetraisopropyl titanate were dissolved in methanol (4 mL) and stirred at room temperature for 1 hour. Sodium cyanoborohydride (25.3 mg, 268 μmol) was added and stirred overnight. After completion of the reaction, the crude product was filtered. The crude product was purified by prep-HPLC (Phase A = water with 0.1% TFA, Phase B = ACN with 0.1% TFA, B% = 20%-60% in 60 min) to afford compound 7 (7.54 mg, 7.97%) as a yellow solid.

[1199] 1 H NMR(600MHz, Methanol-d4)δ8.25(s,1H),7.69(dd,J=8.1,1.7Hz,1H),7.38–7.33(m,2H),7.18(s,1H),7.02 –6.97(m,2H),5.13(dd,J=13.5,5.2Hz,1H),4.44–4.36(m,2H),4.18–4.12(m,2H),3.82(p,J=8.5Hz,1H),3. 52(d,J=6.3Hz,2H),3.19(d,J=11.3Hz,2H),2.96–2.77(m,4H),2.51–2.42(m,2H),2.18(ddd,J=10.4,5.3,2 .8Hz,2H),2.03–1.92(m,5H),1.81(s,1H),1.75(d,J=10.5Hz,1H),1.68(d,J=9.7Hz,1H),1.63–1.58(m,2H).

[1200] LCMS(ESI):[M+H] + =703.37

[1201] Example 42, Compound 8

[1202] Synthesis of 3-(1-(7-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)spiro[3.5]nonan-2-yl)-6'-oxo-3',4',6',8'-tetrahydro-7'H-spiro[azetidine-3,2'-pyrano[2,3-f]isoindol]-7'-yl)piperidine-2,6-dione (Compound 8)

[1203] Synthesis scheme:

[1204] Intermediate 13 (18 mg, 53 μmol), intermediate 31 (15 mg, 44 μmol), and one drop of tetraisopropyl titanate were dissolved in methanol (2 mL) and stirred at room temperature for 1 hour. Sodium cyanoborohydride (8.28 mg, 106 μmol) was added and stirred overnight. After completion of the reaction, the crude product was filtered. The crude product was purified by prep-HPLC (Phase A = water with 0.1% TFA, Phase B = ACN with 0.1% TFA, B% = 20%-60% in 60 min) to afford Compound 8 (9.54 mg, 32.27%) as a yellow solid.

[1205] 1 H NMR(600MHz, Methanol-d4)δ8.25(s,1H),7.69(dd,J=8.1,1.6Hz,1H),7.60(s,1H),7.36(ddd,J=8.8,7.2,1.6Hz,1H),7 .13(s,1H),7.03–6.95(m,2H),5.14(dd,J=13.4,5.1Hz,1H),4.43(q,J=16.8Hz,3H),4.32(d,J=63.0Hz,3H),3.00(s,2H) ,2.92(ddd,J=17.5,13.6,5.4Hz,1H),2.87–2.75(m,2H),2.48(qd,J=13.3,4.6Hz,1H),2.38(s,1H),2.30(s,3H),2.17( dtd,J=12.8,5.3,2.3Hz,1H),2.01(d,J=12.6Hz,1H),1.91(d,J=15.5Hz,3H),1.82(d,J=12.3Hz,1H),1.62–1.53(m,2H).

[1206] LCMS(ESI):[M+H] + =673.37

[1207] Example 43, Compound 9

[1208] Synthesis of 3-(1-(7-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)spiro[3.5]nonan-2-yl)-8'-oxo-3',4',6',8'-tetrahydro-7'H-spiro[azetidine-3,2'-pyrano[2,3-f]isoindol]-7'-yl)piperidine-2,6-dione (Compound 9)

[1209] Synthesis scheme:

[1210] Intermediate 15 (18 mg, 53 μmol), intermediate 31 (15 mg, 44 μmol), and one drop of tetraisopropyl titanate were dissolved in methanol (2 mL) and stirred at room temperature for 1 hour. Sodium cyanoborohydride (8.28 mg, 106 μmol) was added and stirred overnight. After completion of the reaction, the crude product was filtered. The crude product was purified by prep-HPLC (Phase A = water with 0.1% TFA, Phase B = ACN with 0.1% TFA, B% = 20%-60% in 60 min) to afford Compound 9 (12.37 mg, 41.84%) as a yellow solid.

[1211] 1 H NMR(600MHz, Methanol-d4)δ8.27(s,1H),7.68(dd,J=8.1,1.7Hz,1H),7.40–7.30(m,3H),7.0 2–6.96(m,2H),5.15(dd,J=13.4,5.2Hz,1H),4.49–4.38(m,2H),4.38–4.00(m,5H),3.02(s,2 H),2.96–2.88(m,1H),2.87–2.76(m,2H),2.50(qd,J=13.3,4.6Hz,1H),2.44–2.34(m,1H),2. 34–2.21(m,3H),2.20–2.15(m,1H),2.05–1.79(m,6H),1.78–1.63(m,2H),1.63–1.54(m,2H).

[1212] LCMS(ESI):[M+H] + =673.37

[1213] Example 44, Compound 10

[1214] Synthesis of 3-(1-(7-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)spiro[3.5]nonan-2-yl)-8-oxo-3,4,6,8-tetrahydro-7-spiro[piperidine-4,2'-pyrano[2,3-f]isoindol]-7'-yl)piperidine-2,6-dione (Compound 10) Synthesis Scheme:

[1215] Intermediate 14 (56.13 mg, 162 μmol), intermediate 31 (50 mg, 135 μmol), and one drop of tetraisopropyl titanate were dissolved in methanol (4 mL) and stirred at room temperature for 1 hour. Sodium cyanoborohydride (25.3 mg, 268 μmol) was added and stirred overnight. After completion of the reaction, the crude product was filtered. The crude product was purified by prep-HPLC (Phase A = water with 0.1% TFA, Phase B = ACN with 0.1% TFA, B% = 20%-60% in 60 min) to afford Compound 10 (11.77 mg, 12.41%) as a yellow solid.

[1216] 1 H NMR(600MHz, Methanol-d4)δ8.29(s,1H),7.68(dd,J=8.0,1.7Hz,1H),7.44–7.35(m,2H),7.31(s,1H),7.05–6.96(m,2H),5.14(ddd,J=1 3.4,5.1,1.7Hz,1H),4.48–4.35(m,2H),4.09(s,1H),3.83(p,J=8.4Hz,1H),3.64–3.50(m,1H),3.44(d,J=9.9Hz,2H),3.28–3.07(m,3H) ,3.01(t,J=7.0Hz,2H),2.92(ddd,J=18.5,13.6,5.4Hz,1H),2.89–2.75(m,2H),2.51(td,J=13.2,4.6Hz,1H),2.48–2.39(m,1H),2.31(s ,1H),2.23–2.13(m,2H),2.13–1.97(m,4H),1.97–1.86(m,3H),1.78(dd,J=33.1,12.0Hz,2H),1.68(d,J=11.1Hz,1H),1.64–1.55(m,2H).

[1217] LCMS(ESI):[M+H] + =701.50

[1218] Example 45, Compound 11

[1219] Synthesis of 1-(7-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)spiro[3.5]nonan-2-yl)-7'-(2,6-dioxopiperidin-3-yl)-3',4'-dihydro-6'H-spiro[azetidine-3,2'-pyrano[2,3-f]isoindole]-6',8'(7'H)-dione (Compound 11)

[1220] Synthesis scheme:

[1221] Intermediate 3 (47 mg, 135 μmol), intermediate 31 (40 mg, 112 μmol), and one drop of tetraisopropyl titanate were dissolved in methanol (4 mL) and stirred at room temperature for 1 hour. Sodium cyanoborohydride (16.56 mg, 270 μmol) was added and stirred overnight. After completion of the reaction, the crude product was filtered. The crude product was purified by prep-HPLC (Phase A = water with 0.1% TFA, Phase B = ACN with 0.1% TFA, B% = 20%-60% in 60 min) to afford Compound 11 (14.6 mg, 18.89%) as a yellow solid.

[1222] 1 H NMR(600MHz, Methanol-d4)δ8.30(s,1H),7.71(s,1H),7.67(dd,J=8.1,1.7Hz,1H),7.42–7.36(m,2H),7 .03–6.98(m,2H),5.12(dd,J=12.9,5.4Hz,1H),4.32(s,5H),4.13(s,1H),3.04(d,J=6.7Hz,2H),2.96–2 .82(m,2H),2.79–2.70(m,2H),2.43–2.24(m,4H),2.14(dtd,J=10.7,5.9,3.1Hz,1H),2.00(s,1H),1.91 (d,J=17.0Hz,4H),1.85–1.79(m,1H),1.74(d,J=11.1Hz,1H),1.66(d,J=10.9Hz,1H),1.62–1.56(m,2H).

[1223] LCMS(ESI):[M+H] + =687.17

[1224] Example 46, Compound 12

[1225] 1-(7-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)spiro[3.5]nonan-2-yl)-6-(2,6-dioxo

[1226] Synthesis of 2H,5H-spirofuran[2,3-f]isoindole-3,4'-piperidin-3-yl)-6-hydro-2H,5H-spirofuran[2,3-f]isoindole-3,4'-piperidin-5,7-dione (Compound 12)

[1227] Synthesis scheme:

[1228] Intermediate 25 (45 mg, 130 μmol), intermediate 31 (40 mg, 108 μmol), and one drop of tetraisopropyl titanate were dissolved in methanol (4 mL) and stirred at room temperature for 1 hour. Sodium cyanoborohydride (16.56 mg, 263 μmol) was added and stirred overnight. After completion of the reaction, the crude product was filtered. The crude product was purified by prep-HPLC (Phase A = water with 0.1% TFA, Phase B = ACN with 0.1% TFA, B% = 20%-60% in 60 min) to afford Compound 12 (10.05 mg, 113.24%) as a yellow solid.

[1229] 1 H NMR (600MHz, Methanol-d4) δ8.28(s,1H),7.73(s,1H),7.69(dd,J=8.1,1.7Hz,1H),7.37(td,J=7.6,1.7Hz,1H),7.29(s,1H),7.03–6. 98(m,2H),5.13(dd,J=12.9,5.4Hz,1H),4.76(s,2H),3.72(p,J=8.3Hz,1H),3.66–3.58(m,2H),3.50(s,1H),2.98(t,J=13.1Hz,2H),2. 89(ddd,J=17.4,14.0,5.4Hz,3H),2.81–2.66(m,3H),2.44(s,1H),2.32(s,2H),2.25(t,J=13.8Hz,2H),2.21–2.11(m,3H),2.11–2.00( m,3H),1.96(s,1H),1.94–1.88(m,1H),1.84(d,J=12.9Hz,1H),1.76(d,J=10.7Hz,1H),1.69(d,J=10.9Hz,1H),1.62(t,J=11.4Hz,2H).

[1230] LCMS(ESI):[M+H] + =701.37

[1231] Example 47, Compound 13

[1232] Synthesis of 1-(7-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)spiro[3.5]nonan-2-yl)-7-(2,6-dioxopiperidin-3-yl)-7-hydro-2H,6H-spirofuro[2,3-e]isoindole-3,4'-piperidine]-6,8-dione (Compound 13)

[1233] Synthesis scheme:

[1234] Intermediate 25 (22.57 mg, 65 μmol), intermediate 31 (20 mg, 54 μmol), and one drop of tetraisopropyl titanate were dissolved in methanol (2 mL) and stirred at room temperature for 1 hour. Sodium cyanoborohydride (10.2 mg, 162 μmol) was added and stirred overnight. After completion of the reaction, the crude product was filtered. The crude product was purified by prep-HPLC (Phase A = water with 0.1% TFA, Phase B = ACN with 0.1% TFA, B% = 20%-60% in 60 min) to afford Compound 13 (7.48 mg, 19.71%) as a yellow solid.

[1235] 1 H NMR (600MHz, Methanol-d4) δ8.24(s,1H),7.70(dd,J=8.1,1.6Hz,1H),7.62(d,J=7.3Hz,1H),7.51(d,J=7.3Hz,1H),7.35(td,J=7.6,1.6H z,1H),7.01–6.96(m,2H),5.13(dd,J=12.8,5.4Hz,1H),4.84(s,2H),3.72(p,J=7.9Hz,1H),3.62(t,J=7.7Hz,2H),2.98(t,J=13.1Hz,2H), 2.89(ddd,J=17.4,14.0,5.3Hz,2H),2.80–2.70(m,2H),2.44(s,1H),2.31(s,1H),2.23(d,J=13.2Hz,2H),2.20–2.11(m,3H),2.09–2.00(m ,3H),1.96(s,1H),1.91(d,J=13.4Hz,1H),1.84(d,J=11.8Hz,1H),1.76(d,J=10.7Hz,1H),1.69(d,J=10.7Hz,1H),1.63(d,J=10.7Hz,2H).

[1236] LCMS(ESI):[M+H] + =701.37

[1237] Example 48, Compound 14

[1238] Synthesis of 5-(4-(7-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)spiro[3.5]nonan-2-yl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione (Compound 14)

[1239] Synthesis scheme:

[1240] Intermediate 25 (24 mg, 70 μmol), intermediate 31 (21 mg, 58 μmol), and one drop of tetraisopropyl titanate were dissolved in methanol (2 mL) and stirred at room temperature for 1 hour. Sodium cyanoborohydride (10.2 mg, 162 μmol) was added and stirred overnight. After completion of the reaction, the crude product was filtered. The crude product was purified by prep-HPLC (Phase A = water with 0.1% TFA, Phase B = ACN with 0.1% TFA, B% = 20%-60% in 60 min) to afford Compound 14 (7.42 mg, 18.41%) as a yellow solid.

[1241] 1 H NMR(400MHz, Methanol-d4)δ8.25(s,1H),7.69–7.57(m,3H),7.35(td,J=7.8,1.6Hz,1H),7.01–6.93(m,2 H),5.11(dd,J=12.5,5.4Hz,1H),3.80(p,J=8.4Hz,2H),3.61(s,3H),3.21(d,J=26.4Hz,2H),2.86(ddt,J =19.2,10.6,4.7Hz,2H),2.78–2.65(m,2H),2.42(ddd,J=11.9,7.7,4.2Hz,1H),2.30(ddd,J=12.3,7.7,4 .0Hz,1H),2.23–2.07(m,2H),2.07–1.96(m,3H),1.96–1.84(m,2H),1.84–1.67(m,3H),1.67–1.52(m,3H).

[1242] LCMS(ESI):[M+H] + =692.37

[1243] Example 49, Compound 15

[1244] Synthesis of 3-(5-(4-(7-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)spiro[3.5]nonan-2-yl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 15)

[1245] Synthesis scheme:

[1246] 3-(1-Oxo-5-(piperazin-1-yl)isoindol-2-yl)piperidine-2,6-dione (42 mg, 121 μmol), intermediate 31 (40 mg, 121 μmol), and one drop of tetraisopropyl titanate were dissolved in methanol (4 mL) and stirred at room temperature for 1 hour. Sodium cyanoborohydride (23 mg, 366 μmol) was added and stirred overnight. After completion of the reaction, the crude product was filtered to obtain the product. The crude product was purified by prep-HPLC (Phase A = water with 0.1% TFA, Phase B = ACN with 0.1% TFA, B% = 20%-60% in 60 min) to afford Compound 15 (5.2 mg, 6.47%) as a yellow solid.

[1247] 1 H NMR (600MHz, Methanol-d4) δ8.27(d,J=1.1Hz,1H),7.75–7.67(m,2H),7.37(td,J=8.3,7.8,1.5Hz,1H),7.20(d,J=7.3Hz,2H),7.03–6. 97(m,2H),5.14(dd,J=13.4,5.1Hz,1H),4.51–4.42(m,2H),4.10(s,2H),3.80(p,J=8.4Hz,1H),3.61(d,J=22.0Hz,2H),3.12(s,2H),2.9 2(ddd,J=17.2,13.5,5.3Hz,1H),2.87–2.77(m,2H),2.53–2.42(m,2H),2.35–2.29(m,1H),2.23–2.16(m,1H),2.07–2.00(m,3H),1.96( d,J=0.9Hz,1H),1.91(dt,J=13.2,4.3Hz,1H),1.83(d,J=12.4Hz,1H),1.76(d,J=10.7Hz,1H),1.68(t,J=10.7Hz,1H),1.64–1.59(m,2H)

[1248] LCMS(ESI):[M+H] + =660.47

[1249] Example 50, Compound 16

[1250] Synthesis of 3-(1-(7-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)spiro[3.5]nonan-2-yl)-7'-oxo-3',4',7',9'-tetrahydro-8'H-spiro[piperidine-4,2'-pyrano[2,3-e]isoindol]-8'-yl)piperidine-2,6-dione (Compound 16)

[1251] Synthesis scheme:

[1252] Intermediate 21 (22.6 mg, 65 μmol), intermediate 31 (20 mg, 54 μmol), and one drop of tetraisopropyl titanate were dissolved in methanol (2 mL) and stirred at room temperature for 1 hour. Sodium cyanoborohydride (10.2 mg, 162 μmol) was added and stirred overnight. After completion of the reaction, the crude product was filtered. The crude product was purified by prep-HPLC (Phase A = water with 0.1% TFA, Phase B = ACN with 0.1% TFA, B% = 20%-60% in 60 min) to afford Compound 16 (4.12 mg, 10.86%) as a yellow solid.

[1253] 1H NMR(600MHz, Methanol-d4)δ8.21(s,1H),7.70(dd,J=8.1,1.6Hz,1H),7.38–7.30(m,3H),7.01–6.95(m,2H),5.23–5.18(m,1H),4 .57–4.43(m,3H),3.84(t,J=8.5Hz,1H),3.46(d,J=9.3Hz,2H),3.16(q,J=13.8Hz,2H),3.00(t,J=6.7Hz,2H),2.96(dd,J=11.4,6. 6Hz,1H),2.82(d,J=16.8Hz,2H),2.51(td,J=13.3,4.6Hz,1H),2.45(d,J=17.7Hz,1H),2.31(s,1H),2.20(q,J=9.7,9.0Hz,3H),2 .03(t,J=7.0Hz,4H),1.92(d,J=38.3Hz,4H),1.81(s,1H),1.75(d,J=10.6Hz,1H),1.68(d,J=10.1Hz,1H),1.61(t,J=11.5Hz,2H).

[1254] LCMS(ESI):[M+H] + =701.37

[1255] Example 51, Compound 17

[1256] 3-(1-(7-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)spiro[3.5]nonan-2-yl)-9'-oxo-7',9'-dihydro-2'-hydrospiro[piperidin-4,3'-pyrano[2,3-e]isoindol]-8'(4'H)-yl)piperidine-2,6-dione (Compound 17)

[1257] Synthesis scheme:

[1258] Intermediate 26 (22.57 mg, 65 μmol), intermediate 31 (20 mg, 54 μmol), and one drop of tetraisopropyl titanate were dissolved in methanol (2 mL) and stirred at room temperature for 1 hour. Sodium cyanoborohydride (10.2 mg, 162 μmol) was added and stirred overnight. After completion of the reaction, the crude product was filtered. The crude product was purified by prep-HPLC (Phase A = water with 0.1% TFA, Phase B = ACN with 0.1% TFA, B% = 20%-60% in 60 min) to afford Compound 17 (6.11 mg, 16.60%) as a yellow solid.

[1259] 1H NMR(600MHz, Methanol-d4)δ8.24(d,J=3.5Hz,1H),7.69(dd,J=8.0,1.6Hz,1H),7.41–7.32(m,2H),7.08(dd,J=7.7,4.3Hz,1H),7.02 –6.95(m,2H),5.11(dd,J=13.5,4.8Hz,1H),4.41(q,J=17.1Hz,2H),4.27(q,J=13.2,12.2Hz,1H),4.03(s,1H),3.76(d,J=7.6Hz,1H), 3.46(s,2H),3.06(s,2H),3.00(d,J=5.7Hz,1H),2.91(ddd,J=18.5,13.5,5.4Hz,1H),2.85–2.70(m,3H),2.49(d,J=13.3Hz,1H),2.42 (s,1H),2.29(s,1H),2.19–2.13(m,1H),1.99(dt,J=37.2,14.3Hz,4H),1.90(d,J=14.0Hz,1H),1.85–1.73(m,4H),1.70–1.58(m,3H).

[1260] LCMS(ESI):[M+H] + =701.47

[1261] Example 52, Compound 18

[1262] Synthesis of 1-(7-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)spiro[3.5]nonan-2-yl)-7'-(2,6-dioxopidin-3-yl)-3',4'-dihydro-6'H-spiro[piperidine-4,2'-pyrano[2,3-f]isoindole]-6',8'(7'H)-dione (Compound 18)

[1263] Synthesis scheme:

[1264] Intermediate 1 (35 mg, 91.29 μmol) and intermediate 31 (38.06 mg, 109.55 μmol, 1.2 eq) were dissolved in a reaction flask containing THF / MeOH (2 / 2 mL). Ti(O-iPr)4(5d) was added and allowed to react at room temperature for 2 hours. NaBH3CN (17.21 mg, 273.86 μmol, 3.0 eq) was then added and allowed to react overnight at room temperature. After completion of the reaction, compound 18 (8 mg, 12.26%) was obtained after purification by HPLC.

[1265] 1 H NMR (600MHz, Methanol-d4) δ8.24(s,1H),7.70–7.64(m,2H),7.37(s,1H),7.34(t,J=8.3Hz,1H),6.97(dt,J=7.1,3.0Hz ,2H),5.09(dd,J=12.8,5.4Hz,1H),3.83–3.75(m,1H),3.49–3.40(m,2H),3.18(t,J=13.1Hz,2H),3.02(t,J=6.6Hz,2H), 2.87–2.82(m,1H),2.78–2.75(m,1H),2.73(t,J=5.6Hz,1H),2.41(s,1H),2.28(s,1H),2.17(d,J=14.5Hz,2H),2.14–2.0 8(m,1H),2.06–1.85(m,10H),1.79(d,J=14.6Hz,1H),1.73(d,J=10.1Hz,1H),1.68–1.62(m,1H),1.58(t,J=10.1Hz,2H).

[1266] LCMS(ESI):[M+H] + =715.37

[1267] Example 53, Compound 19

[1268] Synthesis of 1-(7-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)spiro[3.5]nonan-2-yl)-7'-(2,6-dioxopiperidin-3-yl)-2'H-spiro[piperidine-4,3'-pyrano[2,3-f]isoindole]-6',8'(4'H,7'H)-dione (Compound 19)

[1269] Synthesis scheme:

[1270] Intermediate 4 (30 mg, 78.25 μmol) and intermediate 31 (32.62 mg, 93.90 μmol, 1.2 eq) were dissolved in a reaction flask containing THF / MeOH (2 / 2 mL). Ti(O-iPr)4(5d) was added and allowed to react at room temperature for 2 hours. NaBH3CN (14.75 mg, 234.74 μmol, 3.0 eq) was then added and allowed to react overnight at room temperature. After completion of the reaction, compound 19 (6 mg, 16%) was obtained after purification by HPLC.

[1271] 1H NMR (600MHz, Methanol-d4) δ8.20(s,1H),7.66(t,J=10.6Hz,2H),7.33(t,J=7.8Hz,1H),7.27(s,1H),6.96(dt,J= 7.1,3.0Hz,2H),5.09(dd,J=12.8,5.4Hz,1H),4.31(s,1H),4.05(s,1H),3.74(p,J=8.6Hz,1H),3.43(d,J=12.2Hz, 2H),3.08(s,1H),3.03(t,J=12.8Hz,2H),2.91–2.78(m,3H),2.78–2.67(m,2H),2.40(s,1H),2.27(s,1H),2.14–2. 07(m,1H),2.04–1.84(m,6H),1.77(dq,J=25.2,12.7,10.7Hz,5H),1.65(d,J=10.1Hz,1H),1.58(t,J=11.4Hz,2H).

[1272] LCMS(ESI):[M+H] + =715.37

[1273] Example 54, Compound 20

[1274] Synthesis of 1-(7-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)spiro[3.5]nonan-2-yl)-6-(2,6-dioxopiperidin-3-yl)spirofurano[2,3-F]isoindole-2,4'-piperidin]-5,7(3H,6H)-dione (Compound 20)

[1275] Synthesis scheme:

[1276] Intermediate 6 (20 mg, 54.15 μmol) and intermediate 31 (22.57 mg, 64.97 μmol, 1.2 eq) were dissolved in a reaction flask containing MeOH (2 mL). Ti(O-iPr)4(1d) was added and reacted at room temperature for 1 hour. NaBH3CN (10.21 mg, 162.42 μmol, 3.0 eq) was then added and reacted at room temperature overnight. After completion of the reaction, compound 20 (3.27 mg, 8.62%) was obtained after purification by HPLC.

[1277] 1H NMR (600MHz, Methanol-d4) δ8.24(s,1H),7.76(s,1H),7.72–7.67(m,1H),7.35(t,J=7.8Hz,1H),7.24(s,1H),6.99(dt,J=7. 5,3.2Hz,2H),5.11(dd,J=12.9,5.4Hz,1H),3.80(t,J=8.3Hz,1H),3.64(s,1H),3.55(s,2H),3.24(t,J=12.6Hz,2H),3.14(s, 1H),2.88(ddd,J=17.8,14.0,5.4Hz,2H),2.79–2.69(m,2H),2.44(s,1H),2.34(d,J=15.2Hz,3H),2.20–2.08(m,3H),2.08–1. 99(m,3H),1.94(dd,J=20.4,9.7Hz,2H),1.82(s,1H),1.76(d,J=10.8Hz,1H),1.68(d,J=11.0Hz,1H),1.61(t,J=11.3Hz,2H).

[1278] LCMS(ESI):[M+H] + =701.37

[1279] Example 55, Compound 21

[1280] Synthesis of 1-(7-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)spiro[3.5]nonan-2-yl)-8'-(2,6-dioxopiperidin-3-yl)-3',4'-dihydro-7'H-spiro[azetidine-3,2'-pyrano[2,3-e]isoindole]-7',9'(8'H)-dione (Compound 21)

[1281] Synthesis scheme:

[1282] ...

Claims

1. A compound having a structure of formula 10: PTM-L-ULM (Formula 10), or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate or polymorph thereof, in: The L is a bond or chemical linking moiety connecting the ULM and the PTM; The PTM is a SMARCA2 / 4 binding moiety, which has the following structure: in, Cy1 is a saturated or unsaturated cycloalkyl group, a saturated or unsaturated heterocycloalkyl group containing a heteroatom selected from N, O and S, an aryl group, or a heteroaryl group containing a heteroatom selected from N, O and S, which is unsubstituted or substituted with one or more substituents each independently selected from halogen, cyano, haloalkyl, haloalkoxy, alkoxy, alkyl, hydroxy, amino and alkylamino; R 10 Selected from and Cy2; Cy2 is selected from a saturated or unsaturated 3-10 membered cycloalkyl group, a saturated or unsaturated 3-10 membered heterocycloalkyl group containing 1, 2 or 3 heteroatoms independently selected from N, O and S, a 6-10 membered aryl group, or a 5-10 membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O and S, which is unsubstituted or substituted by one or more substituents independently selected from halogen, cyano, haloalkyl, haloalkoxy, alkoxy, alkyl, hydroxyl, amino and alkylamino; preferably, Cy2 is unsubstituted or substituted by one or more substituents independently selected from halogen, cyano, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 1-6 Alkoxy, C 1-6 Alkyl, hydroxyl, amino and C 1-6 alkylamino substituted with one or more substituents saturated or unsaturated 3-10 membered cycloalkyl, saturated or unsaturated 3-10 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, 6-10 membered aryl, or 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S; more preferably, Cy2 is unsubstituted or substituted with halogen, cyano, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, C 1-3 Alkoxy, C 1-3 Alkyl, hydroxyl, amino and C 1-3 Preferably, Cy2 is selected from unsubstituted or substituted by 1, 2, 3, 4 or 5 substituents each independently selected from F, Cl, Br, I, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 substituted halogenated alkoxy, and amino groups substituted with saturated or unsaturated 4-6 membered heterocycloalkyl groups containing 1, 2 or 3 N atoms or 5-6 membered heteroaryl groups containing 1, 2 or 3 N atoms; R 15 and R 18 Each independently selected from CR aa and N; W5 and W6 are each independently selected from CR aa and N; R 14 , R 16 , R 17 and R 19 Each occurrence is independently selected from C(R aa )2, O, CO and NR aa ; m13, m14, m15 and m16 are each independently selected from 0, 1, 2, 3, 4 and 5; R 13 is selected from a single bond, a C1-C6 alkylene group, a C2-C6 alkenylene group, a C2-C6 alkynylene group, a 3- to 15-membered cycloalkylene group, a 3- to 15-membered heterocycloalkylene group, a 6- to 14-membered arylene group, and a 5- to 14-membered heteroarylene group, wherein the alkylene group, the alkenylene group, the alkynylene group, the cycloalkylene group, the heterocyclylene group, the arylene group, and the heteroarylene group are optionally substituted by one, two or more R aa Preferably, R 13 is selected from a single bond, a C1-C6 alkylene group, a C2-C6 alkenylene group, a C2-C6 alkynylene group, a 3- to 15-membered cycloalkylene group, a 3- to 15-membered heterocycloalkylene group, a 6- to 14-membered arylene group, and a 5- to 14-membered heteroarylene group, wherein the 3- to 15-membered cycloalkylene group and the 3- to 15-membered heterocycloalkylene group are each independently a monocyclic, condensed, bridged, or spirocyclic group, and the 6- to 14-membered arylene group is and 5 to 14 membered heteroarylene are each independently a monocyclic or condensed ring group, and the 3 to 15 membered heterocycloalkylene or 5 to 14 membered heteroarylene each independently contains 1, 2, 3, 4, or 5 heteroatoms independently selected from N, O and S, and the alkylene, alkenylene, alkynylene, cycloalkylene, heterocyclylene, arylene, and heteroarylene are optionally substituted by one, two or more R aa replaced by; R aa Each occurrence is independently selected from H, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a hydroxyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, a -N(R g )2, cyano, -C(O)-N(R g )2、-S(O)-N(R g )2、-S(O)2-N(R g )2.-OR g 、-SR g 、-OC(O)-R g 、-C(O)-R g 、-C(O)-OR g 、-S(O)-R g 、-S(O)2-R g 、-N(R g )-C(O)-R g 、-N(R g )-S(O)-R g 、-N(R g )-C(O)-N(R g )2、-N(R g )-S(O)2-R g and nitro, wherein optionally, the alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from halogen, oxo (=O), hydroxy, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R g )2, cyano, -C(O)-N(R g )2、-S(O)-N(R g )2、-S(O)2-N(R g )2.-OR g 、-SR g 、-OC(O)-R g 、-C(O)-R g 、-C(O)-OR g 、-S(O)-R g 、-S(O)2-R g 、-N(R g )-C(O)-R g 、-N(R g )-S(O)-R g 、-N(R g )-C(O)-N(R g )2、-N(R g )-S(O)2-R g and substituted by one or more substituents in nitro; R g Each occurrence is independently selected from H, a deuterium atom, a halogen, an alkyl, a deuterated alkyl, a heteroalkyl, an alkenyl, an alkynyl, an alkoxy, a haloalkyl, a haloalkoxy, a hydroxyl, a hydroxyalkyl, -C(O)-alkyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, and a benzyloxycarbonyl group, wherein optionally, each of the alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, a heterocyclyl, an aryl, and a heteroaryl group is independently substituted with one or more substituents selected from the group consisting of halogen, an alkyl, a heteroalkyl, an alkoxy, a haloalkyl, a hydroxyl, a hydroxyalkyl, a cyano group, an amino group, a nitro group, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, a carboxyl group, an alkylamino group, -NH(CO)H, -NH(CO)alkyl, and an acetoxy group; R 11 and R 12 are each independently selected from H, alkyl, a deuterium atom, F, Cl, Br, I, hydroxy, haloalkyl, hydroxyalkyl, alkoxy and -C(=O)-alkyl; The ULM is an E3 ubiquitin ligase binding moiety selected from any of the following structures: in: W 1 and W 2 The same or different, each independently CR a R b or C(=O), and W 1 and W 2 At least one of them is C(=O); G and Z are the same or different and are each independently selected from O, S, and Se; R 3a , R 3b , R 3c , and R 3d each independently selected from H, a deuterium atom, a halogen, an alkyl, a deuterated alkyl, a heteroalkyl, an alkenyl, an alkynyl, an alkoxyl, a haloalkyl, a haloalkoxy, a hydroxyl, a hydroxyalkyl, a nitro, a cyano, an amino, an alkylamino, an alkylacyl, an alkyloxyacyl, an alkylaminoacyl, a cycloalkyl, a heterocyclyl, an aryl, and a heteroaryl, wherein the alkyl, heteroalkyl, an alkenyl, an alkynyl, an alkoxyl, a cycloalkyl, a heterocyclyl, an aryl, and a heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, an alkyl, a heteroalkyl, an alkoxyl, a haloalkyl, a hydroxyl, a hydroxyalkyl, a cyano, an amino, a nitro, a cycloalkyl, a heterocyclyl, an alkenyl, an alkynyl, an alkylamino, an alkylacyl, an alkyloxyacyl, an alkylaminoacyl, an aryl, and a heteroaryl; R d , R e , R f , R g , R D , R E , R F , and R G Each occurrence is independently C(R m )2. NR m , C(=O), O or S; W 3 and W 4 Each time it appears, it is independently CR m or N; R t and R T Each occurrence is N or CR independently 2h ; m1 and m2 are each independently an integer of 0, 1, 2, 3, 4, 5, or 6, and m1+m2≤6; m3 is independently an integer of 0, 1, 2, 3, 4, 5, 6, or 7 at each occurrence, m4 is an integer of 1, 2, 3, 4, 5, 6, 7, or 8, and m3+m4≤8; m5 and m6 are each independently an integer of 0, 1, 2, 3, 4, 5, 6, or 7 at each occurrence, and m5+m6≤7; m7 and m8 are each independently an integer of 0, 1, 2, 3, 4, 5, 6, or 7 at each occurrence, and m7+m8≤7; R m each occurrence is independently selected from H, a deuterium atom, a halogen, an alkyl, a deuterated alkyl, a heteroalkyl, an alkenyl, an alkynyl, an alkoxyl, a haloalkyl, a haloalkoxyl, a hydroxyl, a hydroxyalkyl, a nitro, a cyano, an amino, an alkylamino, an alkylacyl, an alkyloxyacyl, an alkylaminoacyl, a cycloalkyl, a heterocyclyl, an aryl, and a heteroaryl, wherein each of the alkyl, heteroalkyl, an alkenyl, an alkynyl, an alkoxyl, a cycloalkyl, a heterocyclyl, an aryl, and a heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, an alkyl, a heteroalkyl, an alkoxyl, a haloalkyl, a hydroxyl, a hydroxyalkyl, a cyano, an amino, a nitro, a cycloalkyl, a heterocyclyl, an alkenyl, an alkynyl, an alkylamino, an alkylacyl, an alkyloxyacyl, an alkylaminoacyl, an aryl, and a heteroaryl; R 2h Selected from H, deuterium atoms, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, nitro, cyano, amino, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkenyl and alkynyl, wherein the alkyl, heteroalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, aryl and heteroaryl; R 1 is selected from H, halogen, deuterium atom, C1-C6 alkyl, C1-C6 alkoxy, hydroxy, cycloalkyl, C1-C6 haloalkyl, and hydroxyalkyl; R 2 , R a , and R b are each independently selected from H, C1-C3 alkyl, C3-C6 cycloalkyl, and C1-C6 alkoxy; and n is 0, 1, 2 or 3.

2. A compound having a structure of formula I: PTM-L-ULM (Formula 1), or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate or polymorph thereof, in: The L is a bond or chemical linking moiety connecting the ULM and the PTM; The PTM is a SMARCA2 / 4 binding moiety, which has the following structure: in, Cy1 is a saturated or unsaturated cycloalkyl group, a saturated or unsaturated heterocycloalkyl group containing a heteroatom selected from N, O and S, an aryl group, or a heteroaryl group containing a heteroatom selected from N, O and S, which is unsubstituted or substituted with one or more substituents each independently selected from halogen, cyano, haloalkyl, haloalkoxy, alkyl, hydroxyl, amino and alkylamino; R 10 Selected from R 15 and R 18 Each independently selected from CR aa and N; W5 and W6 are each independently selected from CR aa and N; R 14 , R 16 , R 17 and R 19 Each occurrence is independently selected from C(R aa )2, O, CO and NR aa ; m13, m14, m15 and m16 are each independently selected from 0, 1, 2, 3, 4 and 5; R 13 is selected from a single bond, a C1-C6 alkylene group, a C2-C6 alkenylene group, a C2-C6 alkynylene group, a 3- to 15-membered cycloalkylene group, a 3- to 15-membered heterocycloalkylene group, a 6- to 14-membered arylene group, and a 5- to 14-membered heteroarylene group, wherein the alkylene group, the alkenylene group, the alkynylene group, the cycloalkylene group, the heterocyclylene group, the arylene group, and the heteroarylene group are optionally substituted by one, two or more R aa Preferably, R 13 is selected from a single bond, a C1-C6 alkylene group, a C2-C6 alkenylene group, a C2-C6 alkynylene group, a 3- to 15-membered cycloalkylene group, a 3- to 15-membered heterocycloalkylene group, a 6- to 14-membered arylene group, and a 5- to 14-membered heteroarylene group, wherein the 3- to 15-membered cycloalkylene group and the 3- to 15-membered heterocycloalkylene group are each independently a monocyclic, condensed, bridged, or spirocyclic group, the 6- to 14-membered arylene group and the 5- to 14-membered heteroarylene group are each independently a monocyclic or condensed ring group, and the 3- to 15-membered heterocycloalkylene group or the 5- to 14-membered heteroarylene group each independently contains 1, 2, 3, 4, or 5 heteroatoms each independently selected from N, O, and S, and optionally, the alkylene group, the alkenylene group, the alkynylene group, the cycloalkylene group, the heterocycloalkylene group, the arylene group, and the heteroarylene group are substituted by one, two, or more R aa replaced by; R aa Each occurrence is independently selected from H, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a hydroxyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, a -N(R g )2, cyano, -C(O)-N(R g )2、-S(O)-N(R g )2、-S(O)2-N(R g )2.-OR g 、-SR g 、-OC(O)-R g 、-C(O)-R g 、-C(O)-OR g 、-S(O)-R g 、-S(O)2-R g 、-N(R g )-C(O)-R g 、-N(R g )-S(O)-R g 、-N(R g )-C(O)-N(R g )2、-N(R g )-S(O)2-R g and nitro, wherein optionally, the alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from halogen, oxo (=O), hydroxy, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R g )2, cyano, -C(O)-N(R g )2、-S(O)-N(R g )2、-S(O)2-N(R g )2.-OR g 、-SR g 、-OC(O)-R g 、-C(O)-R g 、-C(O)-OR g 、-S(O)-R g 、-S(O)2-R g 、-N(R g )-C(O)-R g 、-N(R g )-S(O)-R g 、-N(R g )-C(O)-N(R g )2、-N(R g )-S(O)2-R g and substituted by one or more substituents in nitro; R g Each occurrence is independently selected from H, a deuterium atom, a halogen, an alkyl, a deuterated alkyl, a heteroalkyl, an alkenyl, an alkynyl, an alkoxy, a haloalkyl, a haloalkoxy, a hydroxyl, a hydroxyalkyl, -C(O)-alkyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, and a benzyloxycarbonyl group, wherein optionally, each of the alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, a heterocyclyl, an aryl, and a heteroaryl group is independently substituted with one or more substituents selected from the group consisting of halogen, an alkyl, a heteroalkyl, an alkoxy, a haloalkyl, a hydroxyl, a hydroxyalkyl, a cyano group, an amino group, a nitro group, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, a carboxyl group, an alkylamino group, -NH(CO)H, -NH(CO)alkyl, and an acetoxy group; R 11 and R 12 are each independently selected from H, alkyl, a deuterium atom, F, Cl, Br, I, hydroxy, haloalkyl, hydroxyalkyl, alkoxy and -C(=O)-alkyl; The ULM is an E3 ubiquitin ligase binding moiety selected from any of the following structures: in: W 1 and W 2 The same or different, each independently CR a R b or C(=O), and W 1 and W 2 At least one of them is C(=O); G and Z are the same or different and are each independently selected from O, S, and Se; R 3a , R 3b , R 3c , and R 3d each independently selected from H, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, a nitro group, a cyano group, an amino group, an alkylamino group, an alkylacyl group, an alkyloxyacyl group, an alkylaminoacyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, wherein the alkyl group, the heteroalkyl group, the alkenyl group, the alkynyl group, the alkoxy group, the cycloalkyl group, the heterocyclic group, an aryl group, and the heteroaryl group are each independently selected from halogen, an alkyl group, a heteroalkyl group, an alkoxy group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, an alkenyl group, an alkynyl group, R d , R e , R f , R g , R D , R E , R F , and R G Each occurrence is independently C(R m )2. NR m , C(=O), O or S; W 3 and W 4 Each time it appears, it is independently CR m or N; R t and R T Each occurrence is N or CR independently 2h , and when R D , R E , R F , and R G Both are C(R m )2, R T CR 2h ; m1 and m2 are each independently an integer of 0, 1, 2, 3, 4, 5, or 6, and m1+m2≤6; m3 is independently an integer of 0, 1, 2, 3, 4, 5, 6, or 7 at each occurrence, m4 is an integer of 1, 2, 3, 4, 5, 6, 7, or 8, and m3+m4≤8; m5 and m6 are each independently an integer of 0, 1, 2, 3, 4, 5, 6, or 7 at each occurrence, and m5+m6≤7; m7 and m8 are each independently an integer of 0, 1, 2, 3, 4, 5, 6, or 7 at each occurrence, and m7+m8≤7; R m each occurrence is independently selected from H, a deuterium atom, a halogen, an alkyl, a deuterated alkyl, a heteroalkyl, an alkenyl, an alkynyl, an alkoxyl, a haloalkyl, a haloalkoxyl, a hydroxyl, a hydroxyalkyl, a nitro, a cyano, an amino, an alkylamino, an alkylacyl, an alkyloxyacyl, an alkylaminoacyl, a cycloalkyl, a heterocyclyl, an aryl, and a heteroaryl, wherein each of the alkyl, heteroalkyl, an alkenyl, an alkynyl, an alkoxyl, a cycloalkyl, a heterocyclyl, an aryl, and a heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, an alkyl, a heteroalkyl, an alkoxyl, a haloalkyl, a hydroxyl, a hydroxyalkyl, a cyano, an amino, a nitro, a cycloalkyl, a heterocyclyl, an alkenyl, an alkynyl, an alkylamino, an alkylacyl, an alkyloxyacyl, an alkylaminoacyl, an aryl, and a heteroaryl; R 2h Selected from H, deuterium atoms, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, nitro, cyano, amino, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkenyl and alkynyl, wherein the alkyl, heteroalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, aryl and heteroaryl; R 1 is selected from H, halogen, deuterium atom, C1-C6 alkyl, C1-C6 alkoxy, hydroxy, cycloalkyl, C1-C6 haloalkyl, and hydroxyalkyl; R 2 , R a , and R b are each independently selected from H, C1-C3 alkyl, C3-C6 cycloalkyl, and C1-C6 alkoxy; and n is 0, 1, 2 or 3.

3. The compound according to claim 1 or 2, wherein: Cy1 is unsubstituted or substituted independently selected from halogen, cyano, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 1-6 Alkyl, hydroxyl, amino and C 1-6 Preferably, Cy1 is a saturated or unsaturated 3-10 membered cycloalkyl group substituted with one or more substituents of the alkylamino group, a saturated or unsaturated 3-10 membered heterocycloalkyl group containing 1, 2 or 3 heteroatoms independently selected from N, O and S, a 6-10 membered aryl group, or a 5-10 membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O and S; preferably, Cy1 is a 6-10 membered aryl group or a 5-10 membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O and S, and the 6-10 membered aryl group and the 5-10 membered heteroaryl group are substituted with one or more substituents each independently selected from hydroxyl, halogen, C 1-6 Alkyl, amino and C 1-6 More preferably, Cy1 is phenyl or a 5-6 membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein the phenyl group and the 5-6 membered heteroaryl group are substituted by one or more selected from hydroxyl, halogen, C 1-6 Alkyl, amino and C 1-6 Preferably, Cy1 is phenyl or a 5-6 membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein the phenyl group and the 5-6 membered heteroaryl group are substituted by 1, 2, 3, 4 or 5 heteroatoms independently selected from hydroxyl, halogen, C 1-6 Alkyl, amino and C 1-6 Preferably, Cy1 is phenyl, and the phenyl is substituted with 1, 2 or 3 hydroxyl groups; Preferably, Cy1 is and / or R 13 is selected from a single bond, a 4-7 membered monocyclic cycloalkylene group, a 6-8 membered monocyclic arylene group, a 4-7 membered monocyclic heterocycloalkylene group or a 5-7 membered monocyclic heteroarylene group containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, a 6-12 membered cycloalkylene group which is a fused, bridged or spiro ring, a 6-12 membered heterocycloalkylene group which is a fused, bridged or spiro ring, a 6-12 membered arylene group which is a fused ring, and a 6-12 membered heteroarylene group which is a fused ring and contains 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, wherein the cycloalkylene group, heterocycloalkylene group, arylene group and heteroarylene group are optionally substituted by 1, 2, 3, 4 or 5 R aa Preferably, R 13 selected from a single bond, a 4-7 membered monocyclic cycloalkylene group, a 6-8 membered monocyclic arylene group, a 4-7 membered monocyclic heterocycloalkylene group or a 5-7 membered monocyclic heteroarylene group containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, a 6-12 membered cycloalkylene group which is a fused, bridged or spiro ring, a 6-12 membered heterocycloalkylene group which is a fused, bridged or spiro ring, a 6-12 membered arylene group which is a fused ring, and a 6-12 membered heteroarylene group which is a fused ring and contains 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, wherein the cycloalkylene group, the heterocycloalkylene group, the arylene group and the heteroarylene group are optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from H, a deuterium atom, F, Cl, Br, I, a hydroxyl group, an amino group, C 1-3 Alkyl, C 1-3 Hydroxyalkyl and C 1-3 Substitution of the alkoxy group by a substituent; and / or R aa Each occurrence is independently selected from H, a deuterium atom, a halogen, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a hydroxyl group, a C1-C6 hydroxyalkyl group, a -C(O)-C1-C6 alkyl group, a nitro group, a cyano group, a C3-C 10 Cycloalkyl, C3-C 10 Heterocyclic group, C6-C 10 Aryl, C5-C 10 Heteroaryl, -NHR g , benzyloxycarbonyl, carboxyl, -N(R g )2, -NH(CO)R g , acetoxy and -N(R g )2; preferably, R aa Each occurrence is independently selected from H, a deuterium atom, a halogen, a hydroxyl group, a C1-C3 alkyl group, a C1-C3 hydroxyalkyl group, a C1-C3 alkoxy group, a C1-C3 haloalkyl group, a C1-C3 haloalkoxy group, a cyano group, a nitro group, a benzyloxycarbonyl group, a carboxyl group, a -NH(CO)R g , acetoxy and -N(R g )2; preferably, R aa Each occurrence is independently selected from H, deuterium atoms, halogens, hydroxyl groups, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 haloalkoxy, cyano, nitro, carboxyl, and amino; and / or R g Each occurrence is independently selected from H, a deuterium atom, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C1-C6 alkoxy group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a C1-C6 hydroxyalkyl group, a -C(O)-C1-C6 alkyl group, a C6-C 10 Aryl, C5-C 10 Heteroaryl, C3-C 15 Cycloalkyl and C3-C 15 Heterocycloalkyl; preferably, R g Each occurrence is independently selected from H, a deuterium atom, a C1-C3 alkyl group, a C1-C3 heteroalkyl group, a C1-C3 alkoxy group, a C2-C3 alkenyl group, a C2-C3 alkynyl group, a C1-C3 haloalkyl group, a C1-C3 haloalkoxy group, a C1-C3 hydroxyalkyl group, a -C(O)-C 1-3 Alkyl, phenyl, C5-C6 heteroaryl, C3-C6 cycloalkyl and C3-C6 heterocycloalkyl; and / or R 11 and R 12 each independently selected from H, C1-C6 alkyl, a deuterium atom, F, Cl, Br, I, hydroxyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy and -C(O)-C 1-6 Alkyl; preferably, R 11 and R 12 Each independently selected from H, C 1-3 Alkyl, deuterium atom, F, Cl, Br, I, hydroxyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy and -C(O)-C 1-6 Alkyl; More preferably, R 11 and R 12 Each independently selected from H, C 1-3 alkyl, deuterium atom, F, Cl, Br, I and hydroxyl; further preferably, R 11 and R 12 are each independently H; and / or W 1 and W 2 are the same or different, each independently CH2 or C(=O), and W 1 and W 2 At least one of them is C(=O); and / or G and Z are both O; and / or R D , R E , R F and R G Each occurrence is independently C(R m )2 or O; preferably, R D , R E , R F and R G Each occurrence is independently C(R m )2 or O, where R D and R E Each time it appears, R D or R E At least one of them is O; and / or R T Each occurrence is N or CR independently 2h Preferably, R T Each occurrence is independently N or CH, and R D and R E Each time it appears, R D or R E At least one of them is O; and / or R 3a , R 3b , R 3c , R 3d , R 2h and R m Each occurrence is independently selected from H, a deuterium atom, a halogen, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a hydroxyl group, a C1-C6 hydroxyalkyl group, a nitro group, a cyano group, an amino group, a C3-C8 cycloalkyl group, a C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 The heteroaryl groups are each independently optionally selected from halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 is substituted by one or more substituents in a heteroaryl group; preferably, R 3a , R 3b , R 3c , R 3d , R 2h and R m Each occurrence is independently selected from H, a deuterium atom, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 The heteroaryl groups are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 More preferably, R 3a , R 3b , R 3c , R 3d , R 2h and R m Each occurrence is independently selected from H, deuterium atoms, F, Cl, Br, I, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 haloalkoxy and hydroxy; further preferably, R 3a , R 3b , R 3c , R 3d , R 2h and R m Each occurrence is independently selected from H, deuterium atoms, F, Cl, Br, I, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 haloalkoxy and hydroxy; further preferably, R 3a , R 3b , R 3c , R 3d , R 2h and R m Each occurrence is independently selected from H, F, Cl, Br, I, C 1-3 Alkyl, hydroxyl and C 1-3 Alkoxy; further preferably, R 3a , R 3b , R 3c , R 3d , R 2h and R m Each occurrence is independently selected from H, F, Cl, Br, I and C 1-3 Alkyl; and / or m3 is independently an integer of 0, 1, 2, 3, or 4 at each occurrence, m4 is an integer of 1, 2, 3, 4, or 5, and m3+m4≤5; preferably, m3 is independently an integer of 0, 1, 2, or 3 at each occurrence, m4 is an integer of 1, 2, 3, or 4, and m3+m4=2, m3+m4=3, or m3+m4=4; and / or m7 and m8 are each independently an integer of 0, 1, 2, 3 or 4 when they appear, and m7+m8≤4; preferably, m7 and m8 are each independently an integer of 0, 1, 2, or 3 when they appear, and m7+m8=2, or m7+m8=3; and / or R 1 is selected from H, halogen, deuterium atom, C1-C3 alkyl, and hydroxyl; preferably, R 1 From H, deuterium atoms, F, Cl, Br, I, C1-C3 alkyl and hydroxyl groups; and / or R 2 Selected from H, and C1-C3 alkyl; and / or n is 0 or 1; preferably n is 1.

4. The compound of claims 1-3, wherein the ULM is selected from the following structures: in: W 1 , W 2 , R T , R 3a , R 3b , R 3c , and R 3d As defined in any one of claims 1, 2 or 3; m3 is 1, m4 is 1; or m3 is 1, m4 is 2; or m3 is 2, m4 is 1; or m3 is 2, m4 is 2; R D Each occurrence is independently C(R m )2 or O; R E , R F and R G Each occurrence is independently C(R m )2; R m As defined in any one of claims 1, 2 or 3; and m7, m11 and m12 are each independently an integer of 0, 1, 2, 3, 4, 5, or 6 when they appear, and m7+m11+m12≤6; preferably, m7, m11 and m12 are each independently an integer of 0, 1, 2, or 3 when they appear, and m7+m11+m12≤3; preferably, m7, m11 and m12 are each independently an integer of 0, 1 or 2 when they appear, and m7+m11+m12=2 or m7+m11+m12=1; Preferably: R 3a , R 3b , R 3c , and R 3d Each occurrence is independently selected from H, a deuterium atom, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 The heteroaryl groups are each independently optionally selected from a deuterium atom, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 More preferably, R 3a , R 3b , R 3c and R 3d are each independently selected from H, a deuterium atom, F, Cl, Br, I, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 haloalkoxy and hydroxy; further preferably, R 3a , R 3b , R 3c and R 3d Each independently selected from H, F, Cl, Br, I, C 1-3 Alkyl, hydroxyl and C 1-3 Alkoxy; further preferably, R 3a , R 3b , R 3c and R 3d Each independently selected from H, F, Cl, Br, I and C 1-3 Alkyl; W 1 and W 2 are the same or different, each independently CH2 or C(=O), and W 1 and W 2 At least one of them is C(=O); m3 is 1 or 2, m4 is 1 or 2; preferably: m3 is 1, m4 is 1; or m3 is 1, m4 is 2; or m3 is 2, m4 is 1; or m3 is 2, m4 is 2; R T Each occurrence is N or CR independently 2h , and when R D , R E , R F , and R G Both are C(R m )2, R T CR 2h ; R 2h Selected from H, deuterium atoms, F, Cl, Br, I, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 More preferably, R 2h Selected from H, F, Cl, Br, I, C 1-3 Alkyl, hydroxyl and C 1-3 Alkoxy; further preferably, R 2h Selected from H, F, Cl, Br, I and C 1-3 alkyl; R D Each occurrence is independently C(R m )2 or O; R E , R F and R G Each occurrence is independently C(R m )2; R m Each occurrence is independently selected from H, deuterium atoms, F, Cl, Br, I, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 haloalkoxy and hydroxy; further preferably, R m Each occurrence is independently selected from H, F, Cl, Br, I, C 1-3 Alkyl, hydroxyl and C 1-3 Alkoxy; further preferably, R m Each occurrence is independently selected from H, F, Cl, Br, I and C 1-3 Alkyl; and m7, m11 and m12 are each independently an integer of 0, 1, 2, 3, 4, 5, or 6 when they appear, and m7+m11+m12≤6; preferably, m7, m11 and m12 are each independently an integer of 0, 1, 2, or 3 when they appear, and m7+m11+m12≤3; preferably, m7, m11 and m12 are each independently an integer of 0, 1 or 2 when they appear number, and m7+m11+m12=2 or m7+m11+m12=1.

5. The compound of any one of claims 1 to 4, wherein the ULM is selected from the following structures: in: W 1 , W 2 , R T , R 3a , R 3b , R 3c , and R 3d As defined in any one of claims 1, 2 or 3; m3 is 1, m4 is 1; or m3 is 1, m4 is 2; or m3 is 2, m4 is 1; or m3 is 2, m4 is 2; R D Each occurrence is independently C(R m )2 or O, R E , R F and R G Each occurrence is independently C(R m )2; and R m As defined in any one of claims 1, 2 or 3; Preferably: R 3a , R 3b , R 3c , and R 3d Each occurrence is independently selected from H, F, Cl, Br, I, C1-C3 alkyl, and C1-C3 alkoxy; m3 is 1, m4 is 1; or m3 is 1, m4 is 2; or m3 is 2, m4 is 1; or m3 is 2, m4 is 2; W 1 and W 2 are the same or different, each independently CH2 or C(=O), and W 1 and W 2 At least one of them is C(=O); R D Each occurrence is independently C(R m )2 or O; R E , R F and R G Each occurrence is independently C(R m )2; R m Each occurrence is independently selected from H, a deuterium atom, a halogen, a C1-C3 alkyl group, and a C1-C3 alkoxy group; preferably, R m Each occurrence is independently selected from H, a deuterium atom, F, Cl, Br, I, C1-C3 alkyl, and C1-C3 alkoxy; R T Each occurrence is N or CR independently 2h ;and R 2h is selected from the group consisting of H, a deuterium atom, F, Cl, Br, I, a C1-C3 alkyl group, a C1-C3 haloalkyl group, a C1-C3 alkoxy group, and a C1-C3 haloalkoxy group.

6. The compound of claim 2, wherein: W 1 and W 2 are the same or different, each independently CH2 or C(=O), and W 1 and W 2 At least one of them is C(=O); and / or R 3a , R 3b , R 3c , and R 3d Each is independently selected from H, a deuterium atom, a halogen, a C1-C6 alkyl group, a heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a hydroxyl group, a C1-C6 hydroxyalkyl group, a nitro group, a cyano group, an amino group, a C3-C8 cycloalkyl group, a C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 The heteroaryl groups are each independently optionally selected from halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 The heteroaryl group is substituted by one or more substituents, preferably R 3a , R 3b , R 3c , and R 3d each independently selected from H, a deuterium atom, F, Cl, Br, I, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a hydroxyl group, a nitro group, a cyano group, an amino group, a C3-C8 cycloalkyl group, a C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 The heteroaryl groups are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 is substituted by one or more substituents in the heteroaryl group; preferably R 3a and R 3b Each independently selected from H, a deuterium atom, a halogen, a C1-C3 alkyl group, and a C1-C3 alkoxy group, preferably R 3c and R 3d Each is independently selected from H, a deuterium atom, F, Cl, Br, I, a C1-C3 alkyl group, and a C1-C3 alkoxy group; and / or R d , R e , R f and R g Each occurrence is independently C(R m )2 or 0; and / or R D , R E , R F and R G Each occurrence is independently C(R m )2 or 0; and / or W 3 and W 4 is CH; and / or R 2h is selected from the group consisting of H, a deuterium atom, a halogen, a C1-C6 alkyl group, a C1-C6 deuterated alkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a hydroxyl group, a C1-C6 hydroxyalkyl group, a nitro group, a cyano group, an amino group, a C3-C8 cycloalkyl group, a C4-C 10 Heterocyclic group, C6-C 10 Aryl, and C5-C 10 Heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 The heteroaryl groups are each independently optionally selected from halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 is substituted by one or more substituents in the heteroaryl group; preferably R 2h is selected from H, a deuterium atom, F, Cl, Br, I, a C1-C6 alkyl group, a C1-C6 deuterated alkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a hydroxyl group, a nitro group, a cyano group, an amino group, a C3-C8 cycloalkyl group, a C4-C 10 Heterocyclic group, C6-C 10 Aryl, and C5-C 10 Heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 The heteroaryl groups are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 is substituted by one or more substituents in the heteroaryl group; preferably R 2h is selected from H, deuterium atoms, halogens, C1-C3 alkyl groups, and C1-C3 alkoxy groups; preferably R 2h is selected from H, a deuterium atom, F, Cl, Br, I, a C1-C3 alkyl group, a C1-C3 haloalkyl group, a C1-C3 alkoxy group, and a C1-C3 haloalkoxy group; and / or m1 and m2 are each independently an integer of 0, 1, 2, or 3, and m1+m2≤3, preferably m1+m2=1 or m1+m2=2; and / or m3 is independently an integer of 0, 1, 2, 3, or 4 at each occurrence, m4 is an integer of 1, 2, 3, 4, or 5, and m3+m4≤5, preferably m3+m4=2, m3+m4=3, or m3+m4=4; and / or m5 and m6 are each independently an integer of 0, 1, 2, 3 or 4, and m5+m6≤4, preferably m5+m6=2 or m5+m6=3; and / or m7 and m8 are each independently an integer of 0, 1, 2, 3 or 4 when they appear, and m7+m8≤4, preferably m7+m8=2, or m7+m8=3; and / or; R m Each occurrence is independently selected from H, a deuterium atom, a halogen, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a hydroxyl group, a C1-C6 hydroxyalkyl group, a nitro group, a cyano group, an amino group, a C3-C8 cycloalkyl group, a C4-C 10 Heterocyclic, aryl and heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 The heteroaryl groups are each independently optionally selected from halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 is substituted by one or more substituents in the heteroaryl group; preferably R m Each occurrence is independently selected from H, a deuterium atom, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 The heteroaryl groups are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 is substituted by one or more substituents in the heteroaryl group; preferably R m Each occurrence is independently selected from H, a deuterium atom, a halogen, a C1-C3 alkyl group, and a C1-C3 alkoxy group; and / or R 1 is selected from H, halogen, C1-C3 alkyl, and hydroxyl; R 1 Preferably selected from H, F, Cl, Br, I, C1-C3 alkyl and hydroxyl; and / or R 2 Selected from H, and C1-C3 alkyl; and / or n is 0 or 1.

7. The compound of claim 2 or 6, wherein the ULM is selected from the following structures: in: Preferably, R 3a , R 3b , R 3c , and R 3d each independently selected from H, a deuterium atom, F, Cl, Br, I, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a hydroxyl group, a nitro group, a cyano group, an amino group, a C3-C8 cycloalkyl group, a C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 The heteroaryl groups are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 is substituted by one or more substituents in a heteroaryl group; and m7, m11 and m12 are each independently an integer of 0, 1, 2, 3, 4, 5, or 6 when they appear, and m7+m11+m12≤6; preferably, m7, m11 and m12 are each independently an integer of 0, 1, 2, or 3 when they appear, and m7+m11+m12≤3, preferably m7+m11+m12=2 or m7+m11+m12=1.

8. The compound according to claim 2 or 6, wherein the ULM is selected from the following structures: in, R 1D , R 1E Each occurrence is independently C(R m )2; R T N or CR 2h And when R F and R G Both are C(R m )2, R T CR 2h ; Preferably: R 3a , R 3b , R 3c , R 3d each independently selected from H, a deuterium atom, F, Cl, Br, I, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a hydroxyl group, a nitro group, a cyano group, an amino group, a C3-C8 cycloalkyl group, a C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 The heteroaryl groups are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 is substituted by one or more substituents in a heteroaryl group; and / or m3 is independently an integer of 0, 1, 2, 3, or 4 at each occurrence, m4 is an integer of 1, 2, 3, 4, or 5, and m3+m4≤5, preferably m3+m4=2, m3+m4=3, or m3+m4=4; and / or W 1 and W 2 are the same or different, each independently CH2 or C(=O), and W 1 and W 2 At least one of them is C(=O); and / or R 1D , R 1E , R F , and R G Each occurrence is independently C(R m )2,R m Each occurrence is independently selected from H, a deuterium atom, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 The heteroaryl groups are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 is substituted by one or more substituents in a heteroaryl group; and / or R T Each time it appears, it is independently CR 2h , R 2h independently selected from H, deuterium atoms, F, Cl, Br, I, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl, and C5-C 10 Heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 The heteroaryl groups are each independently optionally selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 The heteroaryl group is substituted by one or more substituents.

9. The compound of any one of claims 1 to 8, wherein the ULM is selected from the following structures:

10. The compound of any one of claims 1 to 9, wherein L is a bond or -(B L ) q -, Among them B L One or more selected from the following structures: -O-, -S-, -S(O)-, -S(O)2-, -CH2-, -C(O)-, -NH-, q is 1, 2, 3, 4, 5, 6, 7 or 8; preferably, q is 1, 2, 3, 4, 5 or 6; and For the connection point.

11. The compound of claim 10, wherein L is selected from the following structures: Covalent bond, -C(O)-, -C(O)-(CH2) j -, -(CH2) j -, -(CH2) p -NH-(CH2) s -, -(CH2) y -NH-(CH2) j -NH-(CH2) s -, -(CH2) p -C(O)-(CH2) s -, -(CH2) p -O-(CH2) s -, -(CH2) y -C(O)-(CH2) j -C(O)-(CH2) s -, -(CH2) y -O-(CH2) j -O-(CH2) s -, -(CH2) y -O-(CH2) j -CO-(CH2) s -, -(CH2) y -C(O)-(CH2) j -O-(CH2) s -, -(CH2) p -NH-(CH2) y -O-(CH2) j -CO-(CH2) s -、-(CH2) y -C(O)-(CH2) j -O-(CH2) s -NH-(CH2) p - j, p, s and y are each independently selected from 1, 2, 3 and 4; Preferably, L is selected from the following structures: covalent bond, -C(O)-, -C(O)-CH2-, -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -(CH2)7-, -(CH2)8-, -NH-CH2-, -NH-(CH2)2-, -NH-(CH2)3-, -NH-(CH2)4-, -NH-(CH2)5-, -NH-(CH2)6-, -NH-(CH2)7-, -NH-(CH2)8-, -C(O)-NH-, 12. The compound according to any one of claims 1 to 11, characterized in that R 13 is a single bond, or R 13 Selected from one, two or more R aa Substituted with the following groups: wherein m, n1, m' and n' are each independently 1 or 2; R aa Each occurrence is independently selected from H, a deuterium atom, a halogen, a hydroxyl group, a C1-C3 alkyl group, a C1-C3 hydroxyalkyl group, a C1-C3 alkoxy group, a C1-C3 haloalkyl group, a C1-C6 haloalkoxy group, a cyano group, a nitro group, a carboxyl group, and an amino group; Preferably, R 13 is a single bond, or, selected from aa Substituted with the following groups: wherein m, n1, m' and n' are each independently selected from 1 and 2; R aa Each occurrence is independently selected from H, a deuterium atom, F, Cl, Br, I, a hydroxyl group, an amino group, and C 1-3 Alkoxy; More preferably, R 13 is a single bond, or, is selected from 1, 2, 3, 4 or 5 R aa Substituted with the following groups: wherein m, n1, m' and n' are independently selected from 1 and 2 at each occurrence; R aa Each occurrence is independently selected from H, a deuterium atom, F, Cl, Br, I, a hydroxyl group, an amino group, and C 1-3 Alkoxy.

13. The compound according to any one of claims 1 to 12, characterized in that The PTM is selected from the following structures:

14. The compound according to any one of claims 1 to 13, characterized in that The compound is selected from:

15. A pharmaceutical composition comprising an effective amount of the compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

16. Use of a compound according to any one of claims 1 to 14, or a pharmaceutical composition according to claim 15, in the preparation of a medicament for treating or preventing a disease or condition mediated by SMARCA2 / 4; preferably, the disease or condition is cancer; preferably, the cancer is lung cancer or cervical cancer.

17. A compound according to any one of claims 1 to 14, or a pharmaceutical composition according to claim 15, for use in treating or preventing a disease or condition mediated by SMARCA2 / 4; preferably, the condition is cancer; preferably, the cancer is lung cancer or cervical cancer.

18. A method for treating or preventing a disease or condition mediated by SMARCA2 / 4, comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1 to 14, or a pharmaceutical composition according to claim 15; preferably, the disease is cancer; preferably, the cancer is lung cancer or cervical cancer.