Cereblon e3 ubiquitin ligase inhibitor

Abstract

The present invention relates to a new human cereblon (CRBN) E3 ubiquitin ligase inhibitor, which can be used for preparing PROTAC molecules. The CRBN E3 ubiquitin ligase inhibitor and the PROTAC molecules can be used for treating cancer and other diseases.

Description

Cerebellin E3 ubiquitin ligase inhibitors Technical Field

[0001] The present disclosure relates to the field of biomedicine, and in particular to cerebellar protein E3 ubiquitin ligase inhibitors and protein degradation targeting chimeras (PROTAC) compounds containing the same, and their use in medicine. Background Art

[0002] Cerebellin (CRBN) is a brain-associated protein with ionolytic protease activity. It interacts with DNA damage binding protein-1 (DDB1), cullin 4 (Cul4A or Cul4B), and regulatory factor cullin 1 (RoC1) to form a functional E3 ubiquitin ligase complex (CRBN-CRL4). Substrate binding leads to proteolysis via the ubiquitin-proteasome pathway. Immunomodulatory drugs (IMiDs) such as thalidomide, lenalidomide, and pomalidomide, when bound to CRBN, recruit new substrates to CRBN-CRL4, leading to increased ubiquitination and proteasome-dependent degradation, which is used to treat cancer and other diseases.

[0003] On this basis, CRBN ligands have been widely used in protein degradation, and a series of protein degradation targeting chimeras (PROTACs) based on CRBN ligands have been developed. Due to the effect of CRBN ligands on the target, they may also degrade domain proteins. Therefore, the design and synthesis of new CRBN ligands are of great significance for the further development of PROTACs molecules.

[0004] Summary of the Invention

[0005] In view of this, the present disclosure provides a series of CRBN ligands with novel structures, which are further used to synthesize corresponding PROTACs molecules.

[0006] The first aspect of the present invention provides a compound as shown in Formula I, or its isomers, isotopic derivatives, polymorphs, prodrugs or pharmaceutically acceptable salts or solvates,

[0007] Among them, A1 is selected from CR a and N;

[0008] A2 and A4 are each independently selected from C(O) and C(R a )2;

[0009] E2 is selected from CR4 and N;

[0010] A3 is NRa ; Preferably, A3 is NH;

[0011] A5 and A6 are connected by a single bond or a double bond. When A5 and A6 are connected by a single bond, A5 and A6 are each independently selected from NR a and C(R a )2; when A5 and A6 are connected by a double bond, A5 and A6 are each independently selected from N and CR a ; Preferably, A6 and A5 are connected by a single bond and are both C(H)2;

[0012] R1 and R2 together with the atoms to which they are attached form a ring Cy1 fused to Cy0, R3, R4 and R5 are each independently selected from H, deuterium atoms, halogens, C 1-6 Alkyl, C 1-6 Deuterated alkyl, carboxyl, C 1-6 Heteroalkyl, alkenyl, alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, hydroxy, C 1-6 Hydroxyalkyl, nitro, cyano, amino, C 1-6 Alkylamino, C 1-6 Alkyl acyl, C 1-6 Alkyloxyacyl, C 1-6 Alkylaminoacyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Heteroalkyl, alkenyl, alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 1-6 Alkyl acyl, C 1-6 Alkyloxyacyl, C 1-6 Alkylaminoacyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more substituents selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, aryl and heteroaryl; preferably, R3, R4 and R5 are each independently selected from H, deuterium atoms, halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Heteroalkyl, alkenyl, alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, hydroxy, C1-6 More preferably, R3, R4 and R5 are each independently selected from H, deuterium atoms, F, Cl, Br, I, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 a haloalkoxy group and a hydroxy group; or

[0013] R2 and R3 together with the atoms to which they are attached form a ring Cy2 fused to Cy0, R1, R4 and R5 are each independently selected from H, a deuterium atom, a halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, carboxyl, C 1-6 Heteroalkyl, alkenyl, alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, hydroxy, C 1-6 Hydroxyalkyl, nitro, cyano, amino, C 1-6 Alkylamino, C 1-6 Alkyl acyl, C 1-6 Alkyloxyacyl, C 1-6 Alkylaminoacyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Heteroalkyl, alkenyl, alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 1-6 Alkyl acyl, C 1-6 Alkyloxyacyl, C 1-6 Alkylaminoacyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more substituents selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, aryl and heteroaryl; preferably, R1, R4 and R5 are each independently selected from H, deuterium atoms, halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Heteroalkyl, alkenyl, alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, hydroxy, C 1-6More preferably, R1, R4 and R5 are each independently selected from H, deuterium atoms, F, Cl, Br, I, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 a haloalkoxy group and a hydroxy group; or

[0014] When R4 is present, R3 and R4 together with the atoms to which they are attached form a ring Cy3 fused to Cy0, and each occurrence of R1, R2 and R5 is independently selected from H, deuterium atoms, halogens, C 1-6 Alkyl, C 1-6 Deuterated alkyl, carboxyl, C 1-6 Heteroalkyl, alkenyl, alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, hydroxy, C 1-6 Hydroxyalkyl, nitro, cyano, amino, C 1-6 Alkylamino, C 1-6 Alkyl acyl, C 1-6 Alkyloxyacyl, C 1-6 Alkylaminoacyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Heteroalkyl, alkenyl, alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 1-6 Alkyl acyl, C 1-6 Alkyloxyacyl, C 1-6 Alkylaminoacyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more substituents selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, aryl and heteroaryl; preferably, R1, R2 and R5 are each independently selected from H, deuterium atoms, halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Heteroalkyl, alkenyl, alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, hydroxy, C 1-6More preferably, R1, R2 and R5 are each independently selected from H, deuterium atoms, F, Cl, Br, I, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 a haloalkoxy group and a hydroxy group; or

[0015] When R4 is present, R4 and R5 together with the atoms to which they are attached form a ring Cy4 fused to Cy0; R1, R2 and R3 are each independently selected from H, a deuterium atom, a halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, carboxyl, C 1-6 Heteroalkyl, alkenyl, alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, hydroxy, C 1-6 Hydroxyalkyl, nitro, cyano, amino, C 1-6 Alkylamino, C 1-6 Alkyl acyl, C 1-6 Alkyloxyacyl, C 1-6 Alkylaminoacyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Heteroalkyl, alkenyl, alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 1-6 Alkyl acyl, C 1-6 Alkyloxyacyl, C 1-6 Alkylaminoacyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more substituents selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, aryl and heteroaryl; preferably, R1, R2 and R3 are each independently selected from H, deuterium atoms, halogen, 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, hydroxy, C 1-6More preferably, R1, R2 and R3 are each independently selected from H, deuterium atoms, F, Cl, Br, I, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy and hydroxy groups;

[0016] The Cy1, Cy2, Cy3 and Cy4 only appear one at a time, selected from the structure in,

[0017] B2 is selected from C(R a )2、NR a , O and S; and when Cy1, Cy2, Cy3 and Cy4 appear as one of the structures When B2 is selected from NR a , O and S;

[0018] B4 and B5 are each independently selected from CR a and N;

[0019] Each occurrence of B1 and B3 is independently selected from C(R a )2 and CO;

[0020] Each time B6 appears, select C(R a )2 and NR a ;

[0021] C3 is selected from C(O) and NR s1 ;

[0022] R s1 Selected from H, deuterium atoms, F, Cl, Br, I, C 1-6 Alkyl, deuterated C 1-6 Alkyl, carboxyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C(O)-C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy, C 1-6 Hydroxyalkyl, nitro, cyano and amino; preferably, R s1 Selected from H, deuterium atoms, F, Cl, Br, I, C 1-6 Alkyl, deuterated C 1-6 Alkyl, carboxyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C(O)-C 1-6Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxyl and C 1-6 More preferably, R s1 Selected from H, deuterium atoms, F, Cl, Br, I, C 1-3 Alkyl, deuterated C 1-3 Alkyl, carboxyl, -C(O)-C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl and halogenated C 1-3 alkoxy;

[0023] n2, n3, n4, n5 and n6 are each independently selected from 0, 1, 2 and 3; and n5 and n6 are not both 0;

[0024] Preferably, when Cy1, Cy2, Cy3 and Cy4 are present as one of the structures When B2 is selected from O and S, n2+n3+n4 is greater than or equal to 2;

[0025] Each time C1 and C2 appear, they are independently C(R a )2;

[0026] R a Each occurrence is independently selected from H, deuterium atoms, F, Cl, Br, I, C 1-6 Alkyl, deuterated C 1-6 Alkyl, carboxyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C(O)-C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy, C 1-6 Hydroxyalkyl, nitro, cyano, amino, C 1-6 Alkylamino, C 1-6 Alkyl acyl, C 1-6 Alkyloxyacyl, C 1-6 Alkylaminoacyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl and 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C(O)-C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 1-6 Alkyl acyl, C 1-6 Alkyloxyacyl, C 1-6 Alkylaminoacyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl and 5-10 membered heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, aryl and heteroaryl; preferably, R a 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, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy, C 1-6 More preferably, R a 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, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy and hydroxyl groups;

[0027] In the Cy1, Cy2, Cy3 or Cy4 structure, represents the attachment site to Cy0;

[0028] The compound is not the following structure:

[0029] The second aspect of the present invention provides a compound as shown in Formula 2, or its isomers, isotopic derivatives, polymorphs, prodrugs, or pharmaceutically acceptable salts or solvates.

[0030] in,

[0031] A1 is selected from CR a and N;

[0032] A2 and A4 are each independently selected from C(O) and C(R a )2;

[0033] A3 is NRa ;

[0034] A5 and A6 are each independently selected from a single bond, NR a and C(R a )2; Preferably, A5 and A6 are each independently C(R a )2;

[0035] Each occurrence of L1 is independently selected from a single bond, alkylene, haloalkylene, -O-, -N(R b )C(O)-, -C(O)-, -OC(O)-, -NR b -, -S-, -SO-, -SO2-, cycloalkylene, heterocyclylene, arylene and heteroarylene, wherein the cycloalkylene, heterocyclylene, arylene and heteroarylene are optionally substituted by 0-6 R b Group substitution; preferably, L1 is a single bond;

[0036] n1 is selected from 1, 2, 3, 4 and 5;

[0037] R1 and R2 together with the atoms to which they are attached form a 3-10 membered heterocycloalkyl, a 3-10 membered cycloalkyl, a 6-10 membered aryl, a 6-10 membered heteroaryl, a 5-15 membered fused cyclic group or a heterofused cyclic group or a 5-15 membered spiro or heterospiro group; the 3-10 membered heterocycloalkyl, the 3-10 membered cycloalkyl, the 6-10 membered aryl, the 6-10 membered heteroaryl, the 5-15 membered fused cyclic group or a heterofused cyclic group or a 5-15 membered spiro or heterospiro group may be optionally substituted by 1, 2 or more radicals. wherein the alkyl radicals are substituted with one or more substituents selected from the group consisting of halogen, carboxyl, alkoxy, alkyl, hydroxy, amino, haloalkyl, 3-10 membered heterocycloalkyl, 3-10 membered cycloalkyl, 6-10 membered aryl, and 6-10 membered heteroaryl, and R3, R4, and R5 are each independently selected from the group consisting of H, a deuterium atom, carboxyl, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, nitro, cyano, amino, and alkyl radicals. , alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, cycloalkyl, heterocyclic, aryl and heteroaryl; preferably, R1 and R2 together with the atoms to which they are attached form a 5-15 membered heterofused cyclic group, or a 5-15 membered spiro or heterospiro cyclic group; the 5-15 membered heterofused cyclic group, or a 5-15 membered spiro or heterospiro cyclic group may be optionally substituted with 1, 2 or more halo, carboxyl, alkoxy, alkyl, hydroxy, amino, haloalkyl, 3-10 membered hetero cycloalkyl, 3-10 membered cycloalkyl, 6-10 membered aryl, 6-10 membered heteroaryl; R3, R4 and R5, at each occurrence, are each independently selected from H, a deuterium atom, carboxyl, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, nitro, cyano, amino, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; or

[0038] R2 and R3 together with the atoms to which they are attached form a 3-10 membered heterocycloalkyl, a 3-10 membered cycloalkyl, a 6-10 membered aryl, a 6-10 membered heteroaryl, a 5-15 membered fused cyclic group or a heterofused cyclic group, a 5-15 membered spiro or a heterospiro group, wherein the 3-10 membered heterocycloalkyl, the 3-10 membered cycloalkyl, the 6-10 membered aryl, the 6-10 membered heteroaryl, the 5-15 membered fused cyclic group or a heterofused cyclic group, the 5-15 membered spiro or a heterospiro group may be optionally substituted by one, two or more of the following: halogen, The present invention is substituted by a substituent selected from the group consisting of carboxyl, alkoxy, alkyl, hydroxy, amino, haloalkyl, 3-10 membered heterocycloalkyl, 3-10 membered cycloalkyl, 6-10 membered aryl and 6-10 membered heteroaryl, and R1, R4 and R5, at each occurrence, are independently selected from H, a deuterium atom, carboxyl, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, nitro, cyano, amino, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; preferably, R2 and R3, together with the atoms to which they are attached, form a 5-15 membered fused ring or heterofused ring, or a 5-15 membered spiro or heterospiro ring. cycloalkyl, wherein the 5-15 membered heterofused cyclic radical, or the 5-15 membered spirocyclic or heterospirocyclic radical is optionally substituted with 1, 2 or more substituents selected from halo, carboxyl, alkoxy, alkyl, hydroxy, amino, haloalkyl, 3-10 membered heterocycloalkyl, 3-10 membered cycloalkyl, 6-10 membered aryl and 6-10 membered heteroaryl; R1, R4 and R5, at each occurrence, are each independently selected from H, a deuterium atom, carboxyl, halo, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, nitro, cyano, amino, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; or

[0039] R3 and R4 together with the atoms to which they are attached form a 3-10 membered heterocycloalkyl, a 3-10 membered cycloalkyl, a 6-10 membered aryl, a 6-10 membered heteroaryl, a 5-15 membered fused cyclic group or a heterofused cyclic group, a 5-15 membered spiro or a heterospiro group, and the 3-10 membered heterocycloalkyl, the 3-10 membered cycloalkyl, the 6-10 membered aryl, the 6-10 membered heteroaryl, the 4-15 membered fused cyclic group or a heterofused cyclic group and the 5-15 membered spiro or a heterospiro group may be optionally replaced by one, two or more wherein the alkyl radicals are substituted with a plurality of substituents selected from the group consisting of halogen, carboxyl, alkoxy, alkyl, hydroxy, amino, haloalkyl, 3-10 membered heterocycloalkyl, 3-10 membered cycloalkyl, 6-10 membered aryl, and 6-10 membered heteroaryl, and each occurrence of R1, R2, and R5 is independently selected from the group consisting of H, a deuterium atom, carboxyl, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, nitro, cyano, amino, alkyl, amino, alkylacyl, alkyloxyacyl, alkylaminoacyl, cycloalkyl, heterocyclic, aryl and heteroaryl; preferably, R3 and R4 together with the atoms to which they are attached form a 5-15 membered heterocondensed cyclic group, or a 5-15 membered spiro or heterospiro cyclic group; the 5-15 membered heterocondensed cyclic group, or a 5-15 membered spiro or heterospiro cyclic group may be optionally substituted by one, two or more groups selected from halo, carboxyl, alkoxy, alkyl, hydroxy, amino, haloalkyl, 3-10 membered heterocycloalkyl, , 3-10 membered cycloalkyl, 6-10 membered aryl and 6-10 membered heteroaryl, R1, R4 and R5, at each occurrence, are each independently selected from H, a deuterium atom, a carboxyl group, 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; or

[0040] R4 and R5 together with the atoms to which they are attached form a 3-10 membered heterocycloalkyl, a 3-10 membered cycloalkyl, a 6-10 membered aryl, a 6-10 membered heteroaryl, a 5-15 membered fused cyclic group or a heterofused cyclic group, a 5-15 membered spiro or a heterospiro group, and the 3-10 membered heterocycloalkyl, the 3-10 membered cycloalkyl, the 6-10 membered aryl, the 6-10 membered heteroaryl, the 5-15 membered fused cyclic group or a heterofused cyclic group, the 5-15 membered spiro or a heterospiro group may be optionally substituted by one, two or more or more substituents selected from the group consisting of halogen, carboxyl, alkoxy, alkyl, hydroxy, amino, haloalkyl, 3-10 membered heterocycloalkyl, 3-10 membered cycloalkyl, 6-10 membered aryl and 6-10 membered heteroaryl, R1, R2 and R3 are each independently selected from H, a deuterium atom, carboxyl, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, nitro, cyano, amino, alkylamino R4 and R5, together with the atoms to which they are attached, form a 5-15 membered hetero-fused cyclic group, or a 5-15 membered spiro or hetero-spiro cyclic group, which may be optionally substituted by one, two or more groups selected from halo, carboxyl, alkoxy, alkyl, hydroxy, amino, haloalkyl, 3-10 membered heterocycloalkyl, , 3-10 membered cycloalkyl, 6-10 membered aryl and 6-10 membered heteroaryl, R1, R2 and R3, at each occurrence, are each independently selected from H, a deuterium atom, a carboxyl group, 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;

[0041] R a and R b Each occurrence is independently selected from H, a deuterium atom, a halogen, an alkyl, a deuterated alkyl, a carboxyl 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 said alkyl, heteroalkyl, alkenyl group, alkynyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, an alkyl, 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, b Each occurrence is independently selected from H, F, Cl, Br, I, C 1-3 Alkyl, C 1-3Alkoxy, hydroxy, amino and -C(O)-C 1-3 alkyl;

[0042] The compound is not the following structure:

[0043] In one embodiment, at least one of A2 and A4 is C(O); preferably, both A and A4 are C(O); and / or

[0044] A3 is NH; and / or

[0045] A5 and A6 are each independently selected from a single bond and C(H)2; preferably, A5 and A6 are C(H)2; and / or

[0046] Each occurrence of L1 is independently selected from a single bond, C 1-6 Alkylene, halogenated C 1-6 Alkylene, -O-, -N(R b )C(O)-, -C(O)-, -OC(O)-, -NR b -、-S-、-SO-、-SO2-、C 3-15 Cycloalkylene, C 3-15 Heterocyclylene, C 6-15 Arylene and C 5-15 Heteroarylene, wherein the cycloalkylene, heterocyclylene, arylene and heteroarylene are optionally substituted by 0-6 R b Group substitution; preferably, L1 is a single bond; and / or

[0047] n1 is selected from 1, 2, 3; and / or

[0048] R1 and R2 together with the atoms to which they are attached form a 3-10 membered saturated or unsaturated heterocyclic alkyl containing 1, 2, or 3 N, O, or S atoms, a 6-10 membered aryl, The 3-10 membered saturated or unsaturated heterocyclic alkyl containing 1, 2 or 3 N, O or S atoms, the 6-10 membered aryl group may be optionally substituted by 1, 2 or more halogen, carboxyl, C 1-6 Alkoxy, C 1-6 Alkyl, hydroxyl, amino, C 1-6 substituted by a haloalkyl, 3-10 membered heterocycloalkyl, 3-10 membered cycloalkyl, 6-10 membered aryl and 6-10 membered heteroaryl substituent, R3, R4 and R5 each appearing, each independently selected from H, deuterium atoms, carboxyl, halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Heteroalkyl, alkenyl, alkynyl, C 1-6 Alkoxy, C 1-6Halogenated alkyl, C 1-6 Haloalkoxy, hydroxy, C 1-6 Hydroxyalkyl, nitro, cyano, amino, C 1-6 Alkylamino, C 1-6 Alkyl acyl, C 1-6 Alkyloxyacyl, C 1-6 Alkylaminoacyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; preferably, R1 and R2 together with the atoms to which they are attached form

[0049] R2 and R3 together with the atoms to which they are attached form a 3-10 membered saturated or unsaturated heterocyclic alkyl group containing 1, 2, or 3 N, O, or S atoms, a 6-10 membered aryl group, The 3-10 membered saturated or unsaturated heterocycloalkyl containing 1, 2, or 3 N, O, or S atoms, the 6-10 membered aryl may be optionally substituted with 1, 2, or more substituents selected from halogen, carboxyl, alkoxy, alkyl, hydroxyl, amino, haloalkyl, 3-10 membered heterocycloalkyl, 3-10 membered cycloalkyl, 6-10 membered aryl, and 6-10 membered heteroaryl. When R5 is present, R1, R4, and R5 are each independently selected from H, a deuterium atom, carboxyl, halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Heteroalkyl, alkenyl, alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, hydroxy, C 1-6 Hydroxyalkyl, nitro, cyano, amino, C 1-6 Alkylamino, C 1-6 Alkyl acyl, C 1-6 Alkyloxyacyl, C 1-6 Alkylaminoacyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; preferably, R2 and R3 together with the atoms to which they are attached form or

[0050] R3 and R4 together with the atoms to which they are attached form a 3-10 membered saturated or unsaturated heterocyclic alkyl containing 1, 2, or 3 N, O, or S atoms, a 6-10 membered aryl ring, The 3-10 membered saturated or unsaturated heterocycloalkyl containing 1, 2, or 3 N, O, or S atoms, the 6-10 membered aryl may be optionally substituted with 1, 2, or more substituents selected from halogen, carboxyl, alkoxy, alkyl, hydroxyl, amino, haloalkyl, 3-10 membered heterocycloalkyl, 3-10 membered cycloalkyl, 6-10 membered aryl, and 6-10 membered heteroaryl. When R5 is present, each occurrence of R1, R2, and R5 is independently selected from H, a deuterium atom, carboxyl, halogen, C 1-6 Alkyl, C1-6 Deuterated alkyl, C 1-6 Heteroalkyl, alkenyl, alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, hydroxy, C 1-6 Hydroxyalkyl, nitro, cyano, amino, C 1-6 Alkylamino, C 1-6 Alkyl acyl, C 1-6 Alkyloxyacyl, C 1-6 Alkylaminoacyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; preferably, R3 and R4 together with the atoms to which they are attached form or

[0051] R4 and R5 together with the atoms to which they are attached form a 3-10 membered saturated or unsaturated heterocyclic alkyl containing 1, 2, or 3 N, O, or S atoms, a 6-10 membered aryl, The 3-10 membered saturated or unsaturated heterocycloalkyl containing 1, 2, or 3 N, O, or S atoms, the 6-10 membered aryl may be optionally substituted with 1, 2, or more substituents selected from halogen, carboxyl, alkoxy, alkyl, hydroxyl, amino, haloalkyl, 3-10 membered heterocycloalkyl, 3-10 membered cycloalkyl, 6-10 membered aryl, and 6-10 membered heteroaryl, and R1, R2, and R3 are each independently selected from H, a deuterium atom, carboxyl, halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Heteroalkyl, alkenyl, alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, hydroxy, C 1-6 Hydroxyalkyl, nitro, cyano, amino, C 1-6 Alkylamino, C 1-6 Alkyl acyl, C 1-6 Alkyloxyacyl, C 1-6 Alkylaminoacyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; preferably, R4 and R5 together with the atoms to which they are attached form

[0052] Each time B2 appears, select C(R a )2、NR a , O and S;

[0053] Each time B4 and B5 appear, they are independently selected from CR a and N;

[0054] Each time C3 appears, choose from C(O), CR c R d and NRa ;

[0055] R c and R d Each occurrence is independently selected from H, deuterium atoms, halogens, C 1-6 Alkyl, C 1-6 Deuterated alkyl, carboxyl, C 1-6 Heteroalkyl, alkenyl, alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, hydroxy, C 1-6 Hydroxyalkyl, nitro, cyano, amino, C 1-6 Alkylamino, C 1-6 Alkyl acyl, C 1-6 Alkyloxyacyl, C 1-6 Alkylaminoacyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, aryl and heteroaryl; or R c and R d and the carbon atom to which it is attached can together form a 3-10 membered heterocycloalkyl, a 3-10 membered cycloalkyl, a 6-10 membered aryl, or a 6-10 membered heteroaryl, wherein the 3-10 membered heterocycloalkyl, the 3-10 membered cycloalkyl, the 6-10 membered aryl, or the 6-10 membered heteroaryl may be optionally substituted with 1, 2 or more substituents selected from the group consisting of halo, carboxyl, alkoxy, alkyl, hydroxy, amino, haloalkyl, 3-10 membered heterocycloalkyl, 3-10 membered cycloalkyl, 6-10 membered aryl, and 6-10 membered heteroaryl;

[0056] n2, n3, n4, n5 and n6 are each independently selected from 0, 1, 2 and 3;

[0057] Each occurrence of B1, B3, B6, C1, C2, D1 and D2 is independently selected from C(R a )2;

[0058] D3 is selected from C(O) and NR a and / or

[0059] R a and R b Each occurrence is independently selected from H, deuterium atoms, F, Cl, Br, I, C 1-6 Alkyl, deuterated C 1-6 Alkyl, carboxyl, C 1-6Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy, C 1-6 Hydroxyalkyl, nitro, cyano, amino, C 1-6 Alkylamino, C 1-6 Alkyl acyl, C 1-6 Alkyloxyacyl, C 1-6 Alkylaminoacyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl and 5-10 membered heteroaryl, wherein said alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, aryl and heteroaryl;

[0060] Indicates the attachment site.

[0061] In one embodiment, the compound is selected from the following structures:

[0062] Among them, R1, R2, R3, R4, R5, B1, B2, B3, B4, B5, B6, C1, C2, C3, R a , n2, n3, n4, n5 and n6, each occurring independently, are as defined above;

[0063] Preferably:

[0064] R1, R2, R3, R4 and R5 are each independently selected from H, F, Cl, Br, I, C 1-3 Alkyl, C 1-3 Alkoxy, hydroxy and amino groups;

[0065] Each time B2 appears, select C(R a )2、NR a , O and S;

[0066] Each occurrence of B1 and B3 is independently selected from C(R a )2 and CO;

[0067] Each time B6 appears, select C(R a )2 and NR a ;

[0068] One of B4 and B5 is N and the other is CR a ;

[0069] Each time C1 and C2 appear, they are independently C(R a )2;

[0070] C3 is selected from C(O) and NR a ;

[0071] R a Each occurrence is independently selected from H, F, Cl, Br, I, C 1-3 Alkyl, C 1-3 Alkoxy, hydroxy, amino and -C(O)-C 1-3 alkyl; and

[0072] n2, n3, n4, n5 and n6 are each independently selected from 0, 1, 2 and 3.

[0073] In some embodiments, the compound is: wherein each group is as defined in any of the preceding embodiments.

[0074] In some embodiments, the compound is: wherein each group is as defined in any of the preceding embodiments.

[0075] In some embodiments, the compound is: wherein each group is as defined in any of the preceding embodiments.

[0076] In some embodiments, the compound is: wherein each group is as defined in any of the preceding embodiments.

[0077] In some embodiments, the compound is: wherein each group is as defined in any of the preceding embodiments.

[0078] In some embodiments, the compound is: wherein each group is as defined in any of the preceding embodiments.

[0079] In some embodiments, the compound is: wherein each group is as defined in any of the preceding embodiments.

[0080] In some embodiments, the compound is: wherein each group is as defined in any of the preceding embodiments.

[0081] In some embodiments, the compound is: wherein each group is as defined in any of the preceding embodiments.

[0082] In some embodiments, the compound is: wherein each group is as defined in any of the preceding embodiments.

[0083] In some embodiments, the compound is: wherein each group is as defined in any of the preceding embodiments.

[0084] In some embodiments, the compound is: wherein each group is as defined in any of the preceding embodiments.

[0085] In some embodiments, the compound is: wherein each group is as defined in any of the preceding embodiments.

[0086] In some embodiments, the compound is: wherein each group is as defined in any of the preceding embodiments.

[0087] In some embodiments, the compound is: wherein each group is as defined in any of the preceding embodiments.

[0088] In some embodiments, the compound is: wherein each group is as defined in any of the preceding embodiments.

[0089] In some embodiments, the compound is: wherein each group is as defined in any of the preceding embodiments.

[0090] In some embodiments, the compound is: Wherein each group is as defined in any of the previous embodiments. In some embodiments, the compound is selected from any of the following structures:

[0091] Preferably, the compound is selected from:

[0092] The third aspect of the present invention provides a compound as shown in Formula II, or its isomers, isotopic derivatives, polymorphs, prodrugs, or pharmaceutically acceptable salts or solvates.

[0093] PTM-L-CLM (Formula II)

[0094] Among them, PTM is the target protein binding part;

[0095] L is a bond or chemical linking moiety that covalently links the PTM and CLM moieties;

[0096] In some embodiments, the compound of formula (II) is preferably a protein degradation targeting chimera, which includes a target protein binding portion, an E3 ligase ligand portion and a linker portion, wherein the PTM is the target protein binding portion, the CLM is the E3 ligase ligand portion, and the L is the linker portion.

[0097] In some embodiments, the target protein is selected from B7.1, B7, TNFR2, NADPH oxidase, BclIBax and other partners in the apoptosis pathway, C5a receptor, HMG-CoA reductase, PDE V phosphodiesterase type, PDE IV phosphodiesterase type 4, PDEI I, PDEI II, PDE III, squalene epoxidase, CXCR1, CXCR2, nitric oxide (NO) synthase, cyclooxygenase 1, cyclooxygenase 2, 5HT receptor, dopamine receptor, G protein (i.e., Gq), histamine receptor, 5-lipoxygenase, trypsin-like serine protease, thymidylate synthase, purine nucleoside phosphorylase, GAPDH trypanosome, glycogen phosphorylase, carbonic anhydrase, chemokine receptor, JAW STAT, RXR and its analogs, HIV1 protease, HIV1 integrase, influenza neuraminidase, hepatitis B reverse transcriptase, sodium channel, multidrug-resistant bacteria, protein P-glycoprotein, tyrosine kinase, CD23, CD124, tyrosinase p561ck, CD4, CD5, IL-2 receptor, IL-1 receptor, TNF-αR, ICAM1, Ca 2+channel, VCAM, VLA-4 integrin, selectin, CD40 / CD40L, inosine monophosphate dehydrogenase, p38 MAP kinase, RaslRaflMEWERK pathway, interleukin-1 converting enzyme, caspase, HCV, NS3 protease, HCV NS3 RNA helicase, glycinamide ribonucleotide formyltransferase, rhinovirus, 3C protease, herpes simplex virus-1 (HSV-1), protease, cytomegalovirus (CMV) protease, poly (ADP-ribose) polymerase, cyclin-dependent kinase 4 / 6, vascular endothelial growth factor, oxytocin receptor, microsomal transfer protein inhibitor, bile acid transport inhibitor, 5α-reductase inhibitor, angiotensin 11, glycine receptor, norepinephrine reuptake receptor, endothelin receptor, neuropeptide Y and receptor, adenosine receptor, adenosine kinase and AMP deaminase, purinergic receptor (P2Y 1, P2Y2, P2Y4, P2Y6, P2X1-7), farnesyltransferase, geranylgeranyltransferase, TrkA receptor of NGF, β-amyloid protein, tyrosine kinase Flk-II KDR, vitronectin receptor, integrin receptor, Her-21 nerve sheath, telomerase inhibition, cytosolic phospholipase A2, ecdysone 20-monooxygenase, GABA-gated chloride channel ion channel, acetylcholinesterase, voltage-sensitive sodium channel protein, calcium release channel and chloride channel, acetyl Coenzyme A carboxylase, adenylate succinate synthetase, protoporphyrinogen oxidase, enolpyruvylshikimate phosphate synthetase, MYC protein, androgen receptor, estrogen receptor, Aurora kinase A, Bcr-Abl protein, epidermal growth factor receptor, anaplastic lymphoma kinase, Bruton's tyrosine kinase, bromodomain protein 4 and interleukin-1 receptor-associated kinase 4 (IRAK4); preferably, the target protein is selected from androgen receptor, estrogen receptor and interleukin-1 receptor-associated kinase 4 (IRAK4).

[0098] In some embodiments, the CLM is a cerebellin E3 ubiquitin ligase binding moiety selected from any of the following structures:

[0099] R 1a 、R 2a 、R 3a 、R 4a and R 5a Each occurrence is independently selected from H, deuterium atoms, halogens, C 1-6 Alkyl, C 1-6 Deuterated alkyl, carboxyl, C 1-6 Heteroalkyl, alkenyl, alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, hydroxy, C 1-6Hydroxyalkyl, nitro, cyano, amino, C 1-6 Alkylamino, C 1-6 Alkyl acyl, C 1-6 Alkyloxyacyl, C 1-6 Alkylaminoacyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Heteroalkyl, alkenyl, alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 1-6 Alkyl acyl, C 1-6 Alkyloxyacyl, C 1-6 Alkylaminoacyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, aryl and heteroaryl; preferably, R 1a 、R 2a 、R 3a 、R 4a and R 5a Each occurrence is independently selected from H, deuterium atoms, halogens, 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, hydroxy, C 1-6 More preferably, R 1a 、R 2a 、R 3a 、R 4a and R 5a 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, amino and hydroxy; further preferably, R 1a 、R 2a 、R 3a 、R 4a and R 5aEach occurrence is independently selected from H, F, Cl, Br, I, C 1-3 Alkyl, C 1-3 Alkoxy, hydroxy and amino groups;

[0100] B 2a Selected from C(R aa )2、NR aa , O and S; and when B 4a and B 5a When B exists 2a Selected from NR aa , O and S;

[0101] B 4a and B 5a Each independently selected from CR aa and N; preferably, B 4a and B 5a One of them is N and the other is CR aa ;

[0102] B 1a and B 3a Each occurrence is independently selected from C(R aa )2 and C(O);

[0103] B 6a Each time it appears, select C(R aa )2 and NR aa ;

[0104] C 1a and C 2a Each occurrence is independently C(R aa )2;

[0105] m2, m3, m4, m5 and m6 are each independently selected from 0, 1, 2 and 3; and m5 and m6 are not 0 at the same time;

[0106] C 31 Selected from N and CR d ;

[0107] R aa and R d Each occurrence is independently selected from H, deuterium atoms, F, Cl, Br, I, C 1-6 Alkyl, deuterated C 1-6 Alkyl, carboxyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -CO-C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy, C1-6 Hydroxyalkyl, nitro, cyano, amino, C 1-6 Alkylamino, C 1-6 Alkyl acyl, C 1-6 Alkyloxyacyl, C 1-6 Alkylaminoacyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl and 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -CO-C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 1-6 Alkyl acyl, C 1-6 Alkyloxyacyl, C 1-6 Alkylaminoacyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl and 5-10 membered heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, aryl and heteroaryl; preferably, R aa and R d Each occurrence is independently selected from H, deuterium atoms, F, Cl, Br, I, C 1-6 Alkyl, deuterated C 1-6 Alkyl, carboxyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -CO-C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy, C 1-6 Hydroxyalkyl, nitro, cyano, amino, C 1-6 Alkylamino, C 1-6 Alkyl acyl, C 1-6 Alkyloxyacyl and C 1-6 Alkylaminoacyl; More preferably, R aa and R d Each occurrence is independently selected from H, F, Cl, Br, I, C 1-6 Alkyl, carboxyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6Alkynyl, -CO-C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy, C 1-6 hydroxyalkyl, nitro, cyano and amino; further preferably, R aa and R d Each occurrence is independently selected from H, F, Cl, Br, I, C 1-3 Alkyl, C 1-3 Alkoxy, hydroxy, amino and -C(O)-C 1-3 alkyl;

[0108] PTM does not

[0109] And when PTM is the IRAK4 binding part, CLM is hour, Not for In one embodiment, the CLM is selected from any of the following structures:

[0110] Preferably, the CLM is selected from:

[0111] In one embodiment,

[0112] Wherein, L is a bond or -(B L ) q -;

[0113] B L Each occurrence is the same or different and is independently selected from CR L1 R L2 、O、S、SO、SO2、NR L3 、SO2NR L3 ,SONR L3 、CONR L3 NR L3 CONR L4 NR L3 SO2NR L4 , CO, CR L1 =CR L2、C≡C、SiR L1 R L2 、P(O)R L1 、P(O)OR L1 NR L3 C(=NCN)NR L4 NR L3 C(=NCN),NR L3 C(=CNO2)NR L4 , cycloalkylene, heterocyclylene, arylene or heteroarylene, wherein the cycloalkylene, heterocyclylene, arylene and heteroarylene are optionally substituted by 0-6 R L1 and / or R L2 group substitution;

[0114] R L1 、R L2 、R L3 and R L4 Each occurrence is independently selected from H, halogen, C 1-8 Alkyl, OC 1-8 Alkyl, SC 1-8 Alkyl, NH-C 1-8 Alkyl, N(C 1-8 Alkyl)2, C 3-11 Cycloalkyl, aryl, heteroaryl, C 3-11 Heterocyclic group, OC 3-8 Cycloalkyl, OC 3-11 Heterocyclyl, O-aryl, O-heteroaryl, SC 3-8 Cycloalkyl, NH-C 3-8 Cycloalkyl, N(C 3-8 Cycloalkyl)2, N(C 3-8 Cycloalkyl)(C 1-8 Alkyl), NH-C 3-8 Heterocyclic group, N(C 3-8 Heterocyclic)2, N(C 3-8 Heterocyclic group) (C 1-8 alkyl), NH-aryl, N(aryl)(C 1-8 alkyl), NH-heteroaryl, N(heteroaryl)(C 1-8 alkyl), OH, NH2, SH, SO2P(O)(OC 1-8 Alkyl)(C 1-8 alkyl), P(O)(OC 1-8 Alkyl)2, C≡CC 1-8 Alkyl, C≡CH, CH=CH-(C 1-8 alkyl), C(C 1-8 alkyl)=CH-(C 1-8 alkyl), C(C 1-8 alkyl)=C(C1-8 alkyl)2、Si(OH)3、Si(C 1-8 Alkyl)3, Si(OH)(C 1-8 Alkyl)2, CO-C 1-8 Alkyl, CO2H, CN, CF3, CHF2, CH2F, NO2, SF5, SO2NH-C 1-8 Alkyl, SO2N(C 1-8 Alkyl)2, SONH-C 1-8 Alkyl, SON(C 1-8 alkyl)2, CONH-C 1-8 Alkyl, CON(C 1-8 Alkyl)2, N(C 1-8 alkyl)CONH(C 1-8 alkyl), N(C 1-8 alkyl)CON(C 1-8 alkyl)2、NHCONH(C 1-8 alkyl), NHCON(C 1-8 alkyl)2、NHCONH2、N(C 1-8 alkyl)SO2NH(C 1-8 alkyl), N(C 1-8 alkyl)SO2N(C 1-8 Alkyl)2, NHSO2NH(C 1-8 alkyl), NH SO2N(C 1-8 Alkyl)2 and NH SO2NH2, the C 1-8 Alkyl, C 3-11 Cycloalkyl, C 3-11 Heterocyclic group, C 6-10 Aryl and C 5-10 each heteroaryl group is independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, hydroxy, haloalkyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, halocycloalkyl, haloheteroalkyl, alkylamino, aryl, heteroaryl, haloaryl, and haloheteroaryl; and

[0115] q is an integer greater than or equal to 1; preferably, q is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.

[0116] In one embodiment,

[0117] Among them, B L One or more selected from the following structures:

[0118] -O-, -S-, -SO-, -SO2-, -CH2-, -CO-, -NH-,

[0119] For the connection point.

[0120] In one embodiment, L is selected from the following structures:

[0121] Covalent bond, -(CH2) j -、-(CH2) p -NH-(CH2) s -、-(CH2) y -NH-(CH2) j -NH-(CH2) s -、-(CH2) p -CO-(CH2) s -、-(CH2) p -O-(CH2) s -、-(CH2) y -CO-(CH2) j -CO-(CH2) s -、-(CH2) y -O-(CH2) j -O-(CH2) s -、-(CH2) y -O-(CH2) j -CO-(CH2) s -、-(CH2) y -CO-(CH2) j -O-(CH2) s -、-(CH2) p -NH-(CH2) y -O-(CH2) j -CO-(CH2) s -、-(CH2) y -CO-(CH2) j -O-(CH2) s -NH-(CH2) p -、

[0122] Wherein, j is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0123] k, s, p, and y are 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

[0124] It is the connection point of CLM or PTM;

[0125] Preferably, L is selected from the following structures: covalent bond, -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-, -CO-NH-CH2-, -CO-NH-(CH2)2-, -CO-NH-(CH2)3-, -CO-NH-(CH2)4-, -CO-NH-(CH2)5-, -CO-NH-(CH2)6-, -CO-NH-(CH2)7-, -CO-NH-(CH2)8-, -CH2-NH-, -(CH2)2-NH-, -(CH2)3-NH-, -(CH2)4-NH-, -(CH2)5-NH-, -(CH2)6-NH-, -(CH2)7-NH-, -(CH2)8-NH-, -NH-CH2-NH-, -NH-(CH2)2-NH-, -NH-(CH2)3-NH-, -NH-(CH2)4-NH-, -NH-(CH2)5-NH-, -NH-(CH2)6-NH-, -NH-(CH2)7-NH-, -NH-(CH2)8-NH-, -(CH2-CH2-O)-CH2-CH2-, -(CH2-CH2-O)2-CH2-CH2-, -(CH2-CH2-O)3-CH2-CH2-, -NH-(CH2-CH2-O)-CH2-CH2-, -NH-(CH2-CH2-O)2-CH2-CH2-, -NH-(CH2-CH2-O)3-CH2-CH2-, -CO-NH-(CH2-CH2-O)-CH2-CH2-, -CO-NH-(CH2-CH2-O)2-CH2-CH2-, -CO-NH-(CH2-CH2-O)3-CH2-CH2-, -(CH2-CH2-O)-CH2-CH2-NH-, -(CH2-CH2-O)2-CH2-CH2-NH-, -(CH2-CH2-O)3-CH2-CH2-NH-, -NH-(CH2-CH2-O)-CH2-CH2-NH-, -NH-(CH2-CH2-O)2-CH2-CH2-NH-, -NH-(CH2-CH2-O)3-CH2-CH2-NH-, -CO-NH-(CH2-CH2-O)-CH2-CH2-NH-, -CO-NH-(CH2-CH2-O)2-CH2-CH2-NH-, -CO-NH-(CH2-CH2-O)3-CH2-CH2-NH--CH2-CH2-(O-CH2-CH2)-、-CH2-CH2-(O-CH2-CH2)2-、-CH2-CH2-(O-CH2-CH2)3-、-NH-CH2-CH2-(O-CH2-CH2)-、-NH-CH2-CH2-(O-CH2-CH2)2-、-NH-CH2-CH2-(O-CH2-CH2)3-、-CO-NH-CH2-CH2-(O-CH2-CH2)-、-CO-NH-CH2-CH2-(O-CH2-CH2)2-、-CO-NH-CH2-CH2-(O-CH2-CH2)2-、-CO-NH-CH2-CH2-(O-CH2-CH2)2-、-CO-NH-CH2-CH2-(O-CH2-CH2)3-、-CH2-CH2-(O-CH2-C H2)-NH-、-CH2-CH2-(O-CH2-CH2)2-NH-、-CH2-CH2-(O-CH2-CH2)3-NH-、-NH-CH2-CH2-(O-CH2-CH2)-NH-、-NH-CH2-CH2-(O-CH2-CH2)2-NH-、-NH-CH2-CH2-(O-CH2-CH2)3-NH-、-NH-CH2-CH2-O-CH2-CH2-CO-、-CO-CH2-CH2-O-CH2-CH2-NH-、-NH-(CH2)4-CO-、-NH-(CH2)5-CO-、-NH-(CH2)6-CO-、-CO-(C H2)4-NH-、-CO-(CH2)5-NH-、-CO-(CH2)6-NH-、-NH-(CH2-CH2-O)-(CH2)3-、-NH-(CH2-CH2-O)-(CH2)4-、-NH-(CH2-CH2-O)-(CH2)5-、-NH-(CH2-CH2-O)-(CH2)6-、-(CH2)3-(O-CH2-CH2)-NH-、-(CH2)4-(O-CH2-CH2)-NH-、-(CH2)5-(O-CH2-CH2)-NH-、-(CH2)6-(O-CH2-CH2)-NH-、-CH2-CH2-O-(CH2)2- CO-、-CH2-CH2-O-(CH2)3-CO-、-CH2-CH2-O-(CH2)4-CO-、-CO-(CH2)2-O-CH2-CH2-、-CO-(CH2)3-O-CH2-CH2-、-CO-(CH2)4-O-CH2-CH2-、-CO-(CH2)2-、-CO-(CH2)3-、-CO-(CH2)4-、-CO-(CH2)5-、-CO-(CH2)6-、-(CH2)2-CO-、-(CH2)3-CO-、-(CH2)4-CO-、-(CH2)5-CO-、-(CH2)6-CO-、-CO-(CH2)2-CO-、-CO-(CH2)3-CO-, -CO-(CH2)4-CO-, -CO-(CH2)5-CO-, -CO-(CH2)6-CO-, -CH2-CO-CH2-, -CH2-CO-(CH2)2-, -CH2-CO-(CH2)3-, -CH2-CO-(CH2)4-, -(CH2)2-CO-CH2-, -(CH2)2-CO-(CH2)2-, -(CH2)2-CO-(CH2)3-, -(CH2)2-CO-(CH2)4-, -(CH2)3-CO-CH2-, -(CH2)3-CO-(CH2)2-, -(CH2)3-CO-(CH2)3-, -(CH2 )3-CO-(CH2)4-, -(CH2)4-CO-CH2-, -(CH2)4-CO-(CH2)2-, -(CH2)4-CO-(CH2)3-, -(CH2)4-CO-(CH2)4-, -CH2-O-CH2-, -CH2-O-(CH2)2-, -CH 2-O-(CH2)3-, -CH2-O-(CH2)4-, -(CH2)2-O-CH2-, -(CH2)2-O-(CH2)2-, -(CH2)2-O-(CH2)3-, -(CH2)2-O-(CH2)4-, -(CH2)3-O-CH2-, -(CH2) 3-O-(CH2)2-, -(CH2)3-O-(CH2)3-, -(CH2)3-O-(CH2)4-, -(CH2)4-O-CH2-, -(CH2)4-O-(CH2)2-, -(CH2)4-O-(CH2)3-, -(CH2)4-O-(CH2)4-,

[0126] In one embodiment, the PTM is a moiety that binds to an androgen receptor;

[0127] Preferably, the PTM is selected from the following structures:

[0128] in,

[0129] F6, F 16 and F 21Each occurrence is independently selected from a single bond, NH, SO, S, O, SO2, alkylene, haloalkylene, heteroalkylene, alkyleneoxy, heteroalkoxy, alkenylene, alkynylene, C(=O), OC(=O), C(=O)O, C(=O)NH and NHC(=O); wherein the alkylene, alkyleneoxy, alkenylene is optionally substituted with 0, 1, 2, 3, 4, 5 or 6 Rc; preferably, F6, F 16 and F 21 Each occurrence is independently selected from a single bond, NH, SO, S, O, SO2, C(=O), OC(=O) and NHC(=O);

[0130] F A1 and F A3 Each independently selected from 6-10 membered aryl and 5-10 membered heteroaryl; said aryl and heteroaryl are optionally substituted by 0, 1, 2, 3, 4, 5 or 6 R da Substituted; preferably, F A1 is phenyl, optionally substituted by 0, 1, 2, 3, 4, 5 or 6 R da Replacement, F A3 is phenyl or a 6-membered heteroaryl group containing 1, 2, or 3 N, O, or S heteroatoms, optionally substituted by 0, 1, 2, 3, 4, 5, or 6 R da replace;

[0131] F A2 is 3-15 membered cycloalkylene, 5-15 membered spirocycloalkylene, 3-15 membered heterocycloalkylene or 5-15 membered spiroheterocycloalkylene, optionally substituted by 0, 1, 2, 3, 4, 5 or 6 R ca Substituted; preferably, F A2 is a 4-6 membered cycloalkylene, a 7-11 membered spirocycloalkylene, a 4-6 membered heterocyclylene or a 7-11 membered heterospirocyclylene, optionally substituted by 0, 1, 2, 3, 4, 5 or 6 R ca Substituted; preferably, F A2 is a 4-, 5- or 6-membered cycloalkylene group, a 10-membered heterospirocyclylene group containing 1, 2 or 3 N atoms; optionally substituted by 0, 1, 2, 3, 4, 5 or 6 R ca replace;

[0132] F A4 is a 6-10 membered aryl fused 7-15 membered heterospirocyclic group, optionally substituted by 0, 1, 2, 3, 4, 5 or 6 R da Substituted; preferably, F A4is a phenyl-fused 7-15 membered heterospirocyclic group containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, optionally substituted by 0, 1, 2, 3, 4, 5 or 6 R da replace;

[0133] R da Each occurrence is independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Heteroalkyl, C 1-6 Alkoxy, C 1-6 Heteroalkoxy, C 3-7 Cycloalkyl, C 3-7 Heterocyclic group, C 6-8 Aryl, C 5-8 heteroaryl, OH, NH2, CN and NO2; preferably, R da Each occurrence is independently selected from H, F, Cl, Br, I, CH3, OCH3, CF3, OH, NH2, CN and NO2;

[0134] R ca Each occurrence is independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Heteroalkyl, C 1-6 Alkoxy, C 1-6 Heteroalkoxy, C 3-7 Cycloalkyl, C 3-7 Heterocyclic group, C 6-8 Aryl, C 5-8 heteroaryl, oxo (=O), thio (=S), OH, NH2, CN and NO2; preferably, R ca Each occurrence is independently selected from H, F, Cl, Br, I, CH3, OCH3, CF3, OH, NH2, CN and NO2;

[0135] Preferably, the PTM is selected from:

[0136] In one embodiment, the structure is selected from:

[0137] In one embodiment, the PTM is a moiety that binds to an estrogen receptor. Preferably, the PTM is selected from the following structures:

[0138] R ea Selected from CR e1a and N;

[0139] R e4is selected from 6-10 membered aryl, 5-10 membered heteroaryl, C1-C6 alkyl and C1-C6 haloalkyl, wherein the 6-10 membered aryl and 5-10 membered heteroaryl may be optionally substituted by 0, 1, 2, 3, 4 or 5 R e1a substituted; preferably, R e4 is selected from phenyl and difluoroethyl, the phenyl group being optionally substituted by 0, 1, 2, 3, 4 or 5 R e1a replace;

[0140] R e1a 、R e2 and R e3 Each occurrence is independently selected from H, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxy, nitro, cyano, and amino. Preferably, R e1a and R e2 Each occurrence is independently selected from hydroxy, H, F, Cl, Br, I, and C1-C3 alkyl;

[0141] Each time e appears, it is selected from 0, 1, 2, 3, and 4;

[0142] Preferably, the PTM is selected from:

[0143] In one embodiment, the compound is selected from

[0144] In some embodiments, the PTM is a portion that binds to the IRAK4 receptor. Preferably, the structure of the PTM is:

[0145] in,

[0146] R 101 is selected from a single bond, a 3-10 membered heterocycloalkylene group, a 3-10 membered cycloalkylene group, a 6-10 membered arylene group and a 5-10 membered heteroarylene group, wherein the 3-10 membered heterocycloalkylene group, the 3-10 membered cycloalkylene group, the 6-10 membered aryl group and the 5-10 membered heteroaryl group are optionally substituted with 1, 2 or more substituents selected from halo, carboxyl, alkoxy, alkyl, hydroxyl, amino and haloalkyl; preferably, R 101 is selected from a single bond, a 5-7 membered heterocycloalkylene, a 5-7 membered cycloalkylene, a 6 membered arylene and a 5-8 membered heteroarylene, wherein the 5-7 membered heterocycloalkylene, the 5-7 membered cycloalkylene, the 6 membered arylene and the 5-8 membered heteroarylene are optionally substituted by 1, 2 or 3 groups selected from F, Cl, Br, I, carboxyl, C 1-3 Alkoxy, C 1-3 Alkyl, hydroxy, amino and halogenated C 1-3 substituted by an alkyl substituent;

[0147] R 102 、R 103 、R 104 、R 105 and R 106 Selected from H, deuterium atoms, halogens, C 1-6 Alkyl, C 1-6 Deuterated alkyl, carboxyl, C 1-6 Heteroalkyl, alkenyl, alkynyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, hydroxy, C 1-6 Hydroxyalkyl, nitro, cyano, amino, C 1-6 Alkylamino, C 1-6 Alkyl acyl, C 1-6 Alkyloxyacyl and C 1-6 Alkylaminoacyl; preferably, R 102 、R 103 、R 104 、R 105 and R 106 Selected from H, F, Cl, Br, I, C 1-3 Alkyl, carboxyl, C 1-3 Heteroalkyl, C 1-3 Alkoxy and C 1-3 More preferably, R 102 C 1-3 Fluorinated alkyl;

[0148] More preferably, the structure of the PTM is:

[0149] In one embodiment, the compound is selected from:

[0150] The fourth aspect of the present invention provides a pharmaceutical composition comprising any one of the compounds described above.

[0151] In some embodiments, the compound or pharmaceutical composition is used to treat or prevent a disease that is treated by degrading a target protein that binds to a target protein ligand; preferably, the target protein is cyclin-dependent kinase 4 / 6, androgen receptor, estrogen receptor, Aurora kinase A, Bcr-Abl protein, epidermal growth factor receptor, anaplastic lymphoma kinase, Bruton's tyrosine kinase, or bromodomain protein 4 or interleukin-1 receptor-associated kinase 4 (IRAK4).

[0152] In some embodiments, the compound or pharmaceutical composition is used to treat or prevent a condition that is treated by binding to cerebellin in vivo.

[0153] In some embodiments, the compound or pharmaceutical composition is used to treat or prevent a condition associated with the accumulation and / or aggregation of a target protein; preferably, the target protein is cyclin-dependent kinase 4 / 6, androgen receptor, estrogen receptor, Aurora kinase A, Bcr-Abl protein, epidermal growth factor receptor, anaplastic lymphoma kinase, Bruton's tyrosine kinase, bromodomain protein 4 or interleukin-1 receptor-associated kinase 4 (IRAK4).

[0154] In some embodiments, the disease is a tumor or cancer; preferably, the tumor or cancer is breast cancer, mammary ductal carcinoma, prostate cancer, mantle cell lymphoma, chronic myeloid leukemia, acute myeloid leukemia, myelomonocytic leukemia, non-small cell lung cancer, lung adenocarcinoma, and / or cervical cancer.

[0155] The fifth aspect of the present invention provides use of any of the aforementioned compounds or pharmaceutical compositions in the preparation of a medicament for treating or preventing a disease that is treated by binding to cerebellum proteins in vivo.

[0156] The fifth aspect of the present invention also provides a method for treating or preventing a disease treated by binding to a cerebellum protein in vivo, comprising administering a therapeutically effective amount of the aforementioned compound or pharmaceutical composition to a subject in need thereof. The sixth aspect of the present invention provides the use of any of the aforementioned compounds or pharmaceutical compositions in the preparation of a medicament for treating or preventing a disease treated by degrading a target protein bound to a target protein ligand, wherein the target protein is cyclin-dependent kinase 4 / 6, androgen receptor, estrogen receptor, Aurora kinase A, Bcr-Abl protein, epidermal growth factor receptor, anaplastic lymphoma kinase, Bruton's tyrosine kinase, bromodomain protein 4, or interleukin-1 receptor-associated kinase 4 (IRAK4).

[0157] The sixth aspect of the present invention also provides a method for treating or preventing a disease by degrading a target protein bound to a target protein ligand, comprising administering a therapeutically effective amount of the aforementioned compound or pharmaceutical composition to a subject in need; preferably, the target protein is cyclin-dependent kinase 4 / 6, androgen receptor, estrogen receptor, Aurora kinase A, Bcr-Abl protein, epidermal growth factor receptor, anaplastic lymphoma kinase, Bruton's tyrosine kinase, bromodomain protein 4 or interleukin-1 receptor-associated kinase 4 (IRAK4).

[0158] The seventh aspect of the present invention provides the use or method of any of the compounds or pharmaceutical compositions described above in the treatment or prevention of diseases associated with the accumulation and / or aggregation of target proteins, wherein the target proteins are preferably cyclin-dependent kinase 4 / 6, androgen receptor, estrogen receptor, Aurora kinase A, Bcr-Abl protein, epidermal growth factor receptor, anaplastic lymphoma kinase, Bruton's tyrosine kinase, bromodomain protein 4, interleukin-1 receptor-associated kinase 4 (IRAK4).

[0159] In a seventh aspect, the present invention further provides a method for treating or preventing a condition associated with the accumulation and / or aggregation of a target protein, comprising administering a therapeutically effective amount of the aforementioned compound or pharmaceutical composition to a subject in need thereof; preferably, the target protein is cyclin-dependent kinase 4 / 6, androgen receptor, estrogen receptor, Aurora kinase A, Bcr-Abl protein, epidermal growth factor receptor, anaplastic lymphoma kinase, Bruton's tyrosine kinase, or bromodomain protein 4 or interleukin-1 receptor-associated kinase 4 (IRAK4). In one embodiment, the condition is a tumor or cancer, preferably breast cancer, mammary ductal carcinoma, prostate cancer, mantle cell lymphoma, chronic myeloid leukemia, acute myeloid leukemia, myelomonocytic leukemia, non-small cell lung cancer, lung adenocarcinoma, and / or cervical cancer.

[0160] In an eighth aspect, the present invention provides a method for inducing degradation of a target protein in a cell, the method comprising administering an effective amount of the aforementioned compound or the aforementioned pharmaceutical composition to an organism in need thereof; preferably, the target protein is cyclin-dependent kinase 4 / 6, androgen receptor, estrogen receptor, Aurora kinase A, Bcr-Abl protein, epidermal growth factor receptor, anaplastic lymphoma kinase, Bruton's tyrosine kinase, bromodomain protein 4 or interleukin-1 receptor-associated kinase 4 (IRAK4). DETAILED DESCRIPTION

[0161] I. Definition

[0162] Unless otherwise indicated, scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. Furthermore, the relevant terms and laboratory procedures used herein are those widely used in the relevant fields and routine procedures. To facilitate a better understanding of the present invention, definitions and explanations of relevant terms are provided below.

[0163] In the description herein, references to “some embodiments,” “some implementation schemes,” or “some implementation plans” describe a subset of all possible embodiments, but it will be understood that “some embodiments” may be the same subset or different subsets of all possible embodiments and may be combined with each other without conflict.

[0164] As used herein and unless otherwise specified, the terms "comprises," "includes," "has," "contains," and their grammatical equivalents should generally be understood as open-ended and non-limiting, e.g., not excluding other unlisted elements or steps.

[0165] As used in this specification and the claims reported herein, the phrase "and / or" is to be interpreted as meaning "either or both" of the elements, ie, the elements may be present in conjunction in some cases or the elements may be present in other cases, separately.

[0166] When a numerical range is listed, it is intended to include every value and sub-range within the stated range. For example, "C 1-6 "Alkyl" includes C1, C2, C3, C4, C5, C6, C 1-6 、C 1-5 、C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-5 、C 2-4 、C 2-3 、C 3-6 、C 3-5 、C 3-4 、C 4-6 、C 4-5 and C 5-6 alkyl.

[0167] The term "alkyl" as contemplated herein refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group containing from 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 from 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, heterocyclic, aryl, and heteroaryl.

[0168] 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, heterocyclyl, aryl, and heteroaryl.

[0169] 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, heterocyclyl, aryl, and heteroaryl.

[0170] The term "alkenyl" refers to an alkyl compound containing a carbon-carbon double bond in the molecule, wherein the definition of alkyl is as described above. Alkenyl is preferably a "C" having 2 to 8 carbon atoms and at least one (e.g., 1 to 2) carbon-carbon double bond. 2-8 More preferably, C 2-6 Alkenyl (ie, alkenyl having 2 to 6 carbon atoms and 1 to 2 carbon-carbon double bonds). More preferably C 2-4 Alkenyl (i.e., an alkenyl group having 2 to 4 carbon atoms and 1 to 2 carbon-carbon double bonds). Specific examples include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, pentenyl, hexenyl, butadienyl, and the like. Alkenyl groups may be substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups independently selected from hydrogen, alkyl, alkoxy, halogen, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0171] The term "alkynyl" refers to an alkyl compound containing a carbon-carbon triple bond in the molecule, wherein the definition of alkyl is as described above. Alkyl is preferably a "C" having 2 to 8 carbon atoms and at least one (e.g., 1 to 2) carbon-carbon triple bond. 2-8 Alkynyl". Preferably C 2-6 Alkynyl (i.e., an alkynyl group having 2 to 6 carbon atoms and 1 to 2 carbon-carbon triple bonds). More preferably, C 2-4Alkynyl (i.e., an alkynyl group having 2 to 4 carbon atoms and 1 to 2 carbon-carbon triple bonds). Specific examples include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl, and the like. Alkynyl groups may be substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups independently selected from hydrogen, alkyl, alkoxy, halogen, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0172] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 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, and more preferably 4 to 7 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like.

[0173] 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, heterocyclyl, aryl, and heteroaryl.

[0174] The term "heterocyclyl" 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 heterocyclyls include pyrrolidinyl, tetrahydropyranyl, 1,2.3.6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like.

[0175] The heterocyclic group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment, and the substituent is preferably independently selected from one or more substituents of hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, 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, heterocyclic 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, heterocyclic, aryl, and heteroaryl.

[0176] 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, heterocyclyl, 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, heterocyclyl, aryl, and heteroaryl. The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0177] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.

[0178] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0179] The term "amino" refers to -NH2.

[0180] The term "cyano" refers to -CN.

[0181] The term "nitro" refers to -NO2.

[0182] 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.

[0183] 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 and plants and even viruses, among many others.

[0184] The term "isomer" means that the compounds of the present invention may have asymmetric centers and racemates, racemic mixtures, and individual diastereomers, all of which are encompassed by the present invention, including stereoisomers and geometric isomers. In the present invention, when a compound or its salt exists in stereoisomeric form (e.g., it contains one or more asymmetric carbon atoms), the individual stereoisomers (enantiomers and diastereomers) and their mixtures are encompassed by the present invention. The present invention also includes individual isomers of the compound or salt, as well as mixtures of isomers in which one or more chiral centers are inverted. The scope of the present invention includes mixtures of stereoisomers, as well as purified enantiomers or enantiomerically / diastereomerically enriched mixtures. The present invention includes mixtures of stereoisomers in all possible different combinations of all enantiomers and diastereomers. The present invention includes all combinations and subsets of stereoisomers for all specific groups defined above. The present invention also includes geometric isomers of the compound or its salt, including cis-trans isomers.

[0185] The term "isotopic derivative" refers to a compound that differs in structure only in the presence of one or more isotopically enriched atoms. For example, a compound having a structure disclosed herein except that "deuterium" or "tritium" is substituted for hydrogen, or "tritium" is substituted for hydrogen. 18 F-fluorine labeling ( 18 F isotope) instead of fluorine, or with 11 C-, 13 C- or 14 C-enriched carbon ( 11 C-, 13 C-, or 14 C-carbon labeling; 11 C-, 13C- or 14 Compounds in which a carbon atom is replaced by a C-isotope) are within the scope of the present disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays, or as in vivo diagnostic imaging tracers for disease, or as tracers for pharmacodynamic, pharmacokinetic, or receptor studies.

[0186] "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.

[0187] "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.

[0188] "Pharmaceutically acceptable salts" or "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.

[0189] In this article, a wavy line on a group, regardless of its appearance, indicates that this is the point of connection to the rest of the molecule. If there is no wavy line on a group, it means that any position in the group may be connected to other positions on the molecule.

[0190] Unless otherwise defined, when a group described in the present invention is substituted by a substituent, it means that all the same groups appearing in the present invention can be substituted by a substituent, that is, the group can be substituted when it exists alone, and it also means that the group can be substituted when it exists in combination with other groups. For example, R is -C 1-6 Alkyl, C 6-10 Aryl, C 3-6Monocyclic cycloalkyl, -C(O)C 1-6 Alkyl, -C 1-4 Alkyl-C 6-10 Aryl or -S(O)2-C 3-6 Monocyclic cycloalkyl, wherein the C 1-6 Alkyl, C 6-10 Aryl, C 3-6 Monocyclic cycloalkyl groups are optionally substituted; this description also includes -C(O)C 1-6 Alkyl, -C 1-4 Alkyl-C 6-10 Aryl and -S(O)2-C 3-6 C in monocyclic cycloalkyl 1-6 Alkyl, C 6-10 Aryl and C 3-6 Monocyclic cycloalkyl groups are optionally substituted.

[0191] Unless otherwise defined, the term "same or different" used in the present invention means that when there are more than one identical substituent group in a general formula, the substituent groups may be the same or different.

[0192] In the present invention, and Indicates the absolute configuration of a stereocenter. Including possible and configuration, as long as the chemical formula allows.

[0193] When the ring appears When the connection position is uncertain, it means that the connection site is located at Any atom in the monocyclic ring, as long as the valence permits.

[0194] II. Examples

[0195] The following examples are offered by way of illustration and not limitation.

[0196] The abbreviations used in this article are as follows:

[0197] MeOH is methanol; H2SO2 is concentrated sulfuric acid; NIS is N-iodosuccinimide; TFA is trifluoroacetic acid; Pd is palladium; Sn is tin; Pyrrolidine is tetrahydropyrrole; OH is hydroxyl; Boc is tert-butyloxycarbonyl; NaBH4 is sodium borohydride; Et3SiH is triethylsilane; H2 is hydrogen; LiOH is lithium hydroxide; NaOAc is sodium acetate; AcOH is acetic acid; PE is petroleum ether; EA is ethyl acetate; CDCl3 is deuterated chloroform; HNO3 is nitric acid; HBF4 is tetrafluoroboric acid; NaNO2 is sodium nitrite; NBS is N-bromosuccinimide; KOtBu is potassium tert-butoxide; NaH is sodium hydride; B2pin2 is boric acid pinacol ester; Oxone is potassium peroxymonosulfonate; Cbz is benzyloxycarbonyl; PPh3 is triphenylphosphine; CBr4 is carbon tetrabromide; Zn is zinc; NH4Cl is ammonium chloride; B is boron; Br is bromine; (TMS)3SiH is tris(trimethylsilyl)silane; AlBN is azobisisobutyronitrile; DMF is N,N-dimethylformamide; K2CO3 is potassium carbonate; TBAB is tetrabutylammonium bromide; Bn is benzyl; LiAlH4 is lithium aluminum hydride; BH3 is borane; THF is tetrahydrofuran; H2O2 is hydrogen peroxide; DMP is Dess-Martin periodinane; PBr3 is phosphorus tribromide; Pd(OAc)2 is palladium acetate; BF3Et2O is boron trifluoride etherate; S is sulfur; MsCl is methanesulfonyl chloride; TEA is triethylamine; DBU is 1,8-diazabicyclo[5.4.0]undec-7-ene; NaHCO3 is sodium bicarbonate; Malonic acid is malonic acid; PPA is polyphosphoric acid; HBr is hydrogen bromide; Tf2O is trifluoromethanesulfonic anhydride; Pd / C is palladium on carbon; DMSO is dimethyl sulfoxide; UPLC is ultra-performance liquid chromatography; MgCl2 is magnesium chloride; NADPH is pyridine triphosphate; NaS2O3 is sodium thiosulfate; Pd(dppf)Cl2 or PdCl2(dppf) is [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride; Boc2O is di-tert-butyl carbonic anhydride; AIBN is azobisisobutyronitrile; DIPEA or DIEA is N,N-diisopropylethylamine; TsOH is p-toluenesulfonic acid; CCl4 is carbon tetrachloride; CAN is ceric ammonium nitrate; IBX is 2-iodoacylbenzoic acid; HATU is 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate.

[0198] 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.

[0199] 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.

[0200] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). 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), with tetramethylsilane (TMS) as the internal standard. Mass spectrometry (MS) measurements were performed using a Waters Acquity Plus equipment. High-performance liquid chromatography was performed using a Waters 2489 instrument. Medium-pressure flash chromatography was performed using a COMBIFLASH NEXTGEN 300+ instrument. Thin-layer chromatography silica gel plates used were Silica gel 60 thin-layer chromatography silica gel plates (aluminum plates, with fluorescence). Silica gel used for silica gel thin-layer chromatography (100-200 mesh, 200-300 mesh) was purchased from Inotech.

[0201] 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.

[0202] Example 1: Synthesis of Compound A1

[0203] 1-(Spiro[chroman-2,4'-piperidin]-7-yl)pyrimidine-2,4(1H,3H)-dione

[0204] Synthesis scheme

[0205] Step 1: tert-Butyl 7-bromo-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (Compound A1-2)

[0206] Compound A1-1 (25 g, 116.3 mmol, 1.0 eq), tert-butyl 4-oxopiperidine-1-carboxylate (23.16 g, 116.3 mmol, 1.0 eq), and tetrahydropyrrole (4.13 g, 58.1 mmol, 0.5 eq) were dissolved in methanol (250 mL). The reaction mixture was heated to 70°C and reacted for 16 hours. After cooling the reaction mixture to room temperature, the mixture was filtered to obtain Compound A1-2 (40 g, 86.83%) as a yellow solid.

[0207] 1 H NMR(400MHz,Chloroform-d)δ7.73(d,J=8.4Hz,1H),7.23(d,J=1.8Hz,1H),7.17(dd,J=8.4,1.8Hz,1H),3.9 0(s,2H),3.21(t,J=12.6Hz,2H),2.73(s,2H),2.02(dd,J=14.4,2.8Hz,2H),1.66–1.58(m,2H),1.48(s,9H).

[0208] LCMS(ESI):[Mt-Bu+H] + =340.20.

[0209] Step 2: tert-Butyl 7-bromo-4-hydroxyspiro[chroman-2,4'-piperidine]-1'-carboxylate (Compound A1-3)

[0210] Compound A1-2 (40 g, 100.9 mmol, 1.0 eq) was dissolved in methanol (400 mL). The reaction system was cooled to 0°C and sodium borohydride (5.73 g, 151.4 mmol, 1.5 eq) was added. The reaction was allowed to react overnight at room temperature. After concentration under reduced pressure, water was added and the mixture was extracted three times with ethyl acetate. The mixture was washed with saturated brine, and the combined organic phases were dried over anhydrous sodium sulfate. The organic phases were concentrated to yield the crude product, Compound A1-3 (40 g, 99.49%), as a white solid.

[0211] LCMS(ESI):[M-Boc+H] + =298.20.

[0212] Step 3: 7-bromospiro[chroman-2,4'-piperidine] (Compound A1-4)

[0213] Compound A1-3 (40.0 g, 100.4 mmol, 1.0 eq) was dissolved in trifluoroacetic acid (200 mL) and triethylsilyl hydrochloride (17.52 g, 150.6 mmol, 1.5 eq) was added. The system was heated to 50°C and reacted overnight. After cooling the reaction system to room temperature, it was concentrated under reduced pressure to obtain crude compound A1-4 (28.0 g), which was used directly in the next step.

[0214] LCMS(ESI):[M+H] + =282.20.

[0215] Step 4: tert-Butyl 7-bromospiro[chroman-2,4'-piperidine]-1'-carboxylate (Compound A1-5)

[0216] Compound A1-4 (28.0 g, 99.2 mmol, 1.0 eq) was dissolved in dichloromethane (300 mL). The reaction system was cooled to 0°C and triethylamine (30.12 g, 297.7 mmol, 3.0 eq) and di-tert-butyl dicarbonate (32.48 g, 148.8 mmol, 1.5 eq) were added. The reaction was allowed to react overnight at room temperature. The reaction system was concentrated under reduced pressure, and the resulting crude product was purified by column chromatography to obtain compound A1-5 (32 g, 84.36%) as a white solid.

[0217] 1 H NMR(400MHz,Chloroform-d)δ7.03(d,J=2.0Hz,1H),7.00–6.91(m,2H),3.90(s,2H),3.21 (s,2H),2.74(t,J=6.8Hz,2H),1.80(q,J=7.7,7.3Hz,4H),1.59–1.50(m,2H),1.49(s,9H).

[0218] Step 5: tert-Butyl 7-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)spiro[chroman-2,4'-piperidine]-1'-carboxylate (Compound A1-6)

[0219] Compound A1-5 (100 mg, 0.26 mmol, 1.0 eq), uracil (29 mg, 0.26 mmol, 1.0 eq), cuprous iodide (5 mg, 0.03 mmol, 0.1 eq), sodium iodide (4 mg, 0.03 mmol, 0.1 eq), potassium phosphate (117 mg, 0.55 mmol, 2.1 eq), and trans-(1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (37 mg, 0.26 mmol, 1.0 eq) were dissolved in dimethyl sulfoxide (1 mL). The mixture was reacted at 110°C overnight. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by column chromatography to obtain Compound A1-6 (20 mg, 18.49%) as a light blue solid.

[0220] 1 H NMR (600MHz, DMSO-d6) δ11.39(d,J=2.2Hz,1H),7.67(d,J=7.9Hz,1H),7.18(d,J=8.7Hz,1H),6.89–6.82(m,2H),5.63(dd,J=7.9,2.3Hz,1H),3.71(d ,J=13.0Hz,2H),3.16(s,2H),2.77(t,J=6.8Hz,2H),1.82(t,J=6.7Hz,2H) ,1.69(d,J=13.6Hz,2H),1.56(td,J=13.3,12.7,4.6Hz,2H),1.41(s,9H).

[0221] LCMS(ESI)[M-tBu+H] + =358.30.

[0222] Step 6: 1-(Spiro[chroman-2,4'-piperidinyl]-7-yl)pyrimidine-2,4(1H,3H)-dione (Compound A1)

[0223] Compound A1-6 (20 mg, 0.05 mmol, 1.0 eq) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (0.1 mL) was added to the mixture. The mixture was allowed to react at room temperature for 12 hours. The reaction system was concentrated, and the crude product was purified by HPLC to afford Compound A1 (2 mg, 13.19%) as a white solid.

[0224] 1H NMR (400MHz, DMSO-d6) δ11.43(d,J=2.2Hz,1H),7.67(d,J=7.9Hz,1H),7.21(d,J=7.9Hz,1H),6.90(d,J=7.8Hz,2H),5 .65(dd,J=7.9,2.2Hz,1H),3.23(d,J=12.7Hz,2H),3.11(d,J=11.4Hz,2H),2.80(t,J=6.7Hz,2H),2.03–1.78(m,7H).

[0225] LCMS (ESI) [M+H] + =314.30

[0226] Example 2: Synthesis of Compound A2

[0227] 1-(Spiro[chroman-2,4'-piperidin]-7-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0228] Synthesis scheme

[0229] Step 1: tert-Butyl 7-(2,4-dioxytetrahydropyrimidin-1(2H)-yl)spiro[chroman-2,4'-piperidine]-1'-carboxylate (Compound A2-1)

[0230] Compound A1-5 (5 g, 13.1 mmol, 1.0 eq), dihydropyrimidine-2,4(1H,3H)-dione (4.48 g, 39.2 mmol, 3.0 eq), (methanesulfonic acid {biscyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphane}(2'-methylamino-1,1'-biphenyl-2-yl)palladium) (601 mg, 0.65 mmol, 0.05 eq), and cesium carbonate (12.78 g, 39.2 mmol, 3.0 eq) were dissolved in dioxane (50 mL). The reaction was carried out at 80° C. overnight. The reaction solution was concentrated under reduced pressure, and the crude product was purified by column chromatography to obtain compound A1-6 (3 g, 55.21%) as a white solid.

[0231] LCMS(ESI)[M-tBu+H] + =360.30.

[0232] Step 2: 1-(Spiro[chroman-2,4'-piperidinyl]-7-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound A2)

[0233] Compound A2-1 (3 g, 7.2 mmol, 1.0 eq) was dissolved in dichloromethane (5 mL), and a hydrochloric acid solution in dioxane (5 mL) was added to the mixture. The mixture was reacted at room temperature for 12 hours. The reaction mixture was filtered to obtain compound A2 (277 mg, 69.4%) as a white solid.

[0234] 1 H NMR (600MHz, DMSO-d6) δ10.35(s,1H),7.10(d,J=8.8Hz,1H),6.87–6.79(m,2H),3.74(t,J=6.6Hz,3H),3.19(d t,J=13.0,3.4Hz,2H),3.07(h,J=9.9Hz,2H),2.75(t,J=6.8Hz,2H),2.68(t,J=6.6Hz,2H),1.93–1.78(m,6H).

[0235] LCMS (ESI) [M+H] + =316.30

[0236] Example 3: Synthesis of Compound A3

[0237] 1-(4'-Oxospiro[chroman-2,1'-cyclohexane]-7-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0238] Synthesis scheme

[0239] Step 1: 7-bromodipyridine [chroman-2,1'-cyclohexane-4',2"-[1,3]dioxolane]-4-one (Compound A3-1)

[0240] Dissolve compound A1-1 (1.0 g, 4.7 mmol, 1.0 eq) in methanol (10 mL), add 1,4-cyclohexanedione monoethylene glycol ketal (726 mg, 4.7 mmol, 1.0 eq) and tetrahydropyrrole (331 mg, 4.7 mmol, 1.0 eq), and stir under reflux under nitrogen for 12 hours. Cool the reaction mixture to room temperature, and filter the precipitated solid to obtain compound A3-1 (1.4 g, 83.4%) as a yellow solid.

[0241] 1H NMR(600MHz,Chloroform-d)δ7.73(d,J=8.4Hz,1H),7.21(d,J=1.8Hz,1H),7.15(dd,J=8.4,1.8Hz,1H),4.03–3.95(m ,4H),2.72(s,2H),2.15–2.09(m,2H),1.98(td,J=13.3,4.1Hz,2H),1.76(td,J=13.6,4.2Hz,2H),1.67–1.61(m,2H).

[0242] LCMS(ESI):[M+H] + =353.19.

[0243] Step 2: 7-bromodipyrrolidone-2,1'-cyclohexane-4',2"-[1,3]dioxolane]-4-ol (Compound A3-2)

[0244] Methanol (10 mL) was added to compound A3-1 (1.0 g, 2.8 mmol, 1.0 eq). Sodium borohydride (160 mg, 4.3 mmol, 1.5 eq) was added at 0°C and allowed to react at room temperature for 2 hours. The reaction system was concentrated under reduced pressure, then water was added and extracted with ethyl acetate. The organic phases were washed with saturated brine, and the combined organic phases were dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure to obtain the crude product, compound A3-2 (1 g).

[0245] LCMS (ESI): [M-OH+H] + =337.19.

[0246] Step 3: 7-bromospiro[chroman-2,1'-cyclohexane]-4'-one (Compound A3-3)

[0247] Compound A3-2 (1.0 g, 2.8 mmol, 1.0 eq) was dissolved in toluene (10 mL), and p-toluenesulfonic acid (533 mg, 3.1 mmol, 1.1 eq) was added. The mixture was reacted at 110°C for 12 hours. After cooling the reaction system to room temperature, the reaction mixture was concentrated under reduced pressure. The resulting crude product was purified by column chromatography to afford compound A3-3 (300 mg, 36.5%) as a yellow oil.

[0248] 1H NMR(400MHz,Chloroform-d)δ7.11–7.03(m,2H),6.91(d,J=7.9Hz,1H),6.43(d,J=9.8Hz,1H),5.6 4(d,J=9.8Hz,1H),2.84(td,J=14.2,6.1Hz,2H),2.51–2.27(m,4H),1.89(td,J=13.8,5.0Hz,2H).

[0249] LCMS(ESI):[M+H] + =294.98.

[0250] Step 4: 7-bromospiro[chroman-2,1'-cyclohexane]-4'-one (Compound A3-4)

[0251] Compound A3-3 (300 mg, 1.0 mmol, 1.0 eq) was dissolved in ethyl acetate (5 mL) and palladium / carbon (60 mg) was added. The reaction was allowed to proceed at room temperature under hydrogen pressure for 12 hours. The reaction system was filtered through celite, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography to obtain compound A3-4 (150 mg, 49.7%) as a white solid.

[0252] 1 H NMR(600MHz,Chloroform-d)δ7.08(d,J=1.8Hz,1H),7.02(dt,J=8.1,1.4Hz,1H),6.97(d,J=8.1Hz,1H),2. 83–2.75(m,4H),2.34–2.28(m,2H),2.26–2.20(m,2H),1.91(t,J=6.8Hz,2H),1.83(td,J=13.7,4.9Hz,2H).

[0253] LCMS (ESI) [M+H] + =296.40.

[0254] Step 5: 1-(4'-oxospiro[chroman-2,1'-cyclohexane]-7-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound A3)

[0255] Compound A3-4 (100 mg, 0.34 mmol, 1.0 eq), dihydrouracil (116 mg, 1.0 mmol, 3.0 eq), (methanesulfonic acid {biscyclohexyl (3-isopropoxy-2', 4', 6'-triisopropyl-[1,1'-biphenyl]-2-yl) phosphane} (2'-methylamino-1,1'-biphenyl-2-yl) palladium (16 mg, 0.02 mmol, 0.05 eq) and cesium carbonate (221 mg, 0.68 mmol, 2.0 eq) were added to ultra-dry 1,4-dioxane (2 mL) and reacted at 100 ° C for 12 hours under nitrogen protection. After cooling the reaction system to room temperature, it was concentrated under reduced pressure and the obtained crude product was purified by column chromatography to obtain white solid compound A3 (70 mg, 62.9%).

[0256] 1 H NMR (600MHz, DMSO-d6) δ10.34(s,1H),7.13–7.09(m,1H),6.85–6.80(m,2H),3.75(t,J=6.6Hz,2H),2.76(t,J= 6.8Hz,2H),2.68(t,J=6.6Hz,2H),2.63–2.53(m,2H),2.22–2.16(m,2H),2.10–2.02(m,2H),1.94–1.86(m,4H).

[0257] LCMS (ESI) [M+H] + =329.28.

[0258] Example 4: Synthesis of Compound A4

[0259] 3-(Spiro[benzopyran-2,4'-piperidin]-7-yl)piperidine-2,6-dione

[0260] Synthesis scheme

[0261] Step 1: 2,6-bisbenzyloxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (Compound A4-2)

[0262] Compound A4-1 (5.2 g, 14.04 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (60 mL). 1,1-Bis(diphenylphosphino)diphenylferric palladium chloride (2.06 g, 2.81 mmol, 0.2 eq), potassium acetate (4.14 g, 42.13 mmol, 3 eq), and pinacol diboron (10.7 g, 42.13 mmol, 3 eq) were added to the reaction system. The reaction was continued at 100°C under nitrogen for 12 hours. The reaction system was concentrated under reduced pressure, and the resulting crude product was purified by normal phase column chromatography to obtain crude product A4-2 (8.2 g, 139.9%) as a pale yellow solid.

[0263] LCMS(ESI):[M+H] + =418.31

[0264] Step 2: tert-Butyl 7-(2,6-bis(benzyloxy)pyridin-3-yl)spiro[benzopyran-2,4'-piperidine]-1'-carboxylate (Compound A4-3)

[0265] Crude compound A4-2 (5 g, 9.59 mmol, 1.5 eq) was dissolved in a mixture of 1,4-dioxane and water (60 mL, 5:1). 1,1-Bis(diphenylphosphino)diphenylferric palladium chloride (0.83 g, 1.28 mmol, 0.2 eq), sodium carbonate (2.03 g, 19.17 mmol, 3 eq), and compound A1-5 (2.44 g, 6.39 mmol, 1 eq) were added to the reaction system. The reaction was incubated at 90°C under nitrogen for 12 hours. The reaction mixture was concentrated under reduced pressure, and the resulting crude product was purified by normal phase column chromatography to obtain A4-3 (2.7 g, 71.3%) as a red oil.

[0266] LCMS(ESI):[M+H] + =593.29

[0267] Step 3: tert-Butyl 7-(2,6-dioxopiperidin-3-yl)spiro[benzopyran-2,4'-piperidine]-1'-carboxylate (Compound A4-4)

[0268] Compound A4-3 (2.7 g, 4.56 mmol, 1.0 eq) was dissolved in methanol (30 mL), and palladium (20%) on carbon (1.35 g, 50%) was added. The atmosphere was purged with hydrogen three times and allowed to react at room temperature for 12 hours. The reaction mixture was filtered, and the filter cake was washed three times with methanol (5 mL). The filtrate was concentrated under reduced pressure. The resulting crude product was purified by normal column chromatography to afford A4-4 (689 mg, 36.5%) as a pale yellow solid.

[0269] LCMS(ESI):[M+H] + =415.22

[0270] Step 4: 3-(Spiro[benzopyran-2,4'-piperidin]-7-yl)piperidine-2,6-dione (Compound A4)

[0271] Compound A4-4 (680 mg, 1.64 mmol, 1.0 eq) was dissolved in dichloromethane (12 mL), and a 1,4-dioxane hydrochloride solution (120 mg, 3.28 mmol, 2 eq) was added thereto. The system was reacted at room temperature for 2 hours, and then preparative liquid separation was performed to obtain a white solid compound A4 (486 mg, 94.2%).

[0272] 1 H NMR (600MHz, DMSO-d6) δ10.83(s,1H),7.06(d,J=7.8Hz,1H),6.72(dd,J=7.8,1.7Hz,1H ),6.69(d,J=1.7Hz,1H),3.77(dd,J=11.2,5.0Hz,1H),3.27–3.17(m,2H),3.15–3.05(m, 2H),2.74(t,J=6.7Hz,2H),2.67–2.58(m,1H),2.47(dt,J=17.2,4.5Hz,1H),2.20–2.10 (m,1H),2.06–1.96(m,1H),1.93–1.87(m,2H),1.83(t,J=6.8Hz,2H),1.81-1.73(m,2H).

[0273] LCMS(ESI):[M+H] + =315.16

[0274] Example 5: Synthesis of Compound A5

[0275] 1-(Spiro[azetidine-3,2'-chroman]-7'-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0276] Synthesis scheme

[0277] Step 1: tert-Butyl 7'-bromo-4'-oxospiro[azetidine-3,2'-chroman]-1-carboxylate (Compound A5-1)

[0278] Compound A1-1 (10.0 g, 46.5 mmol, 1.0 eq) was dissolved in ethanol (100 mL), and tert-butyl 3-oxoazetidine-1-carboxylate (8.8 g, 51.2 mmol, 1.1 eq) and tetrahydropyrrole (3.6 g, 51.2 mmol, 1.1 eq) were added. The mixture was stirred at 50°C under nitrogen for 12 hours. After cooling to room temperature, the reaction system was extracted with ethyl acetate, washed with saturated brine, and the combined organic phases were dried over anhydrous sodium sulfate. The crude product obtained by concentration of the organic phase was purified by column chromatography to obtain Compound A5-1 (5.5 g, 32.1%) as a yellow solid.

[0279] 1 H NMR (600MHz, DMSO-d6) δ7.67(d,J=8.4Hz,1H),7.48(d,J=1.8Hz,1H),7.33(dd,J=8.4 ,1.8Hz,1H),3.99(d,J=9.6Hz,2H),3.90(d,J=9.6Hz,2H),3.19(s,2H),1.38(s,9H).

[0280] LCMS(ESI):[M-Boc+H] + =268.15.

[0281] Step 2: tert-Butyl 7'-bromo-4'-hydroxyspiro[azetidine-3,2'-chroman]-1-carboxylate (Compound A5-2)

[0282] Methanol (50 mL) was added to compound A5-1 (5.5 g, 14.9 mmol, 1.0 eq). Sodium borohydride (969 mg, 25.6 mmol, 1.5 eq) was added at 0°C and allowed to react at room temperature for 12 hours. The reaction system was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic phases were washed with saturated brine, and the combined organic phases were dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure to obtain the crude product, compound A5-2 (5.5 g).

[0283] 1 H NMR (400MHz, DMSO-d6) δ7.31–7.25(m,1H),7.12(dd,J=8.2,2.0Hz,1H),7.07(d,J=2.0Hz,1H),5.56(d,J=5.1Hz,1H),4.75 –4.62(m,1H),4.15(d,J=9.6Hz,1H),4.00(d,J=9.7Hz,1H),3.82(dd,J=19.0,9.5Hz,2H),2.30–2.10(m,2H),1.38(s,9H).

[0284] LCMS(ESI):[M-Boc+H] + =272.17.

[0285] Step 3: 7'-bromospiro[azetidine-3,2'-chroman] (Compound A5-3)

[0286] Compound A5-2 (5.5 g, 14.8 mmol, 1.0 eq) was dissolved in trifluoroacetic acid (20 mL) and triethylsilane (3.5 g, 30.0 mmol, 2.0 eq) was added. The mixture was reacted at 50°C for 1 hour. After cooling the reaction system to room temperature, the reaction solution was concentrated under reduced pressure to obtain the crude product A5-3 (3.8 g).

[0287] LCMS (ESI) [M+H] + =254.17.

[0288] Step 4: tert-Butyl 7'-bromospiro[azetidine-3,2'-chroman]-1-carboxylate (Compound A5-4)

[0289] Compound A5-3 (3.8 g, 14.8 mmol, 1.0 eq) was dissolved in dichloromethane (40 mL). Triethylamine (4.5 g, 44.5 mmol, 3.0 eq) and di-tert-butyl dicarbonate (4.9 g, 22.3 mmol, 1.5 eq) were added at 0°C. The mixture was allowed to react at room temperature for 12 hours. Water was added to the reaction system, and the mixture was extracted with dichloromethane. The mixture was washed with saturated brine, and the combined organic phases were dried over anhydrous sodium sulfate. The crude product obtained by concentration of the organic phase was purified by column chromatography to obtain compound A5-4 (2.3 g, 43.2%) as a white solid.

[0290] 1 H NMR (400MHz, DMSO-d6) δ7.09–7.02(m,3H),3.93(d,J=9.3Hz,2H),3.82(d,J=9.3Hz,2H),2.74(t,J=6.5Hz,2H),2.06(t,J=6.5Hz,2H),1.39(s,9H).

[0291] LCMS(ESI)[M-Boc+H] + =254.17.

[0292] Step 5: tert-Butyl 7'-(2,4-dioxytetrahydropyrimidin-1(2H)-yl)spiro[azetidine-3,2'-chroman]-1-carboxylate (Compound A5-5)

[0293] Compound A5-4 (1.0 g, 2.8 mmol, 1.0 eq), dihydrouracil (966 mg, 8.5 mmol, 3.0 eq), (methanesulfonic acid {biscyclohexyl (3-isopropoxy-2', 4', 6'-triisopropyl-[1,1'-biphenyl]-2-yl) phosphane} (2'-methylamino-1,1'-biphenyl-2-yl) palladium (130 mg, 0.14 mmol, 0.05 eq) and cesium carbonate (2.8 g, 8.5 mmol, 3.0 eq)) were added to ultra-dry 1,4-dioxane (15 mL) and reacted at 100°C under nitrogen for 12 hours. After cooling the reaction system to room temperature, the crude product was concentrated under reduced pressure and purified by column chromatography to obtain compound A5-5 (655 mg, 59.9%) as a white solid.

[0294] 1 H NMR (600MHz, DMSO-d6) δ10.36(s,1H),7.09(d,J=8.2Hz,1H),6.84(dd,J=8.1,2.2Hz,1H),6.82(d,J=2.1Hz,1H),3.93(s, 2H), 3.83 (s, 2H), 3.74 (t, J = 6.7Hz, 2H), 2.77 (t, J = 6.5Hz, 2H), 2.68 (t, J = 6.7Hz, 2H), 2.07 (t, J = 6.5Hz, 2H), 1.40 (s, 9H).

[0295] LCMS(ESI):[M-Boc+H] + =288.38.

[0296] Step 6: 1-(Spiro[azetidine-3,2'-chroman]-7'-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound A5)

[0297] Compound A5-5 (355 mg, 0.92 mmol, 1.0 eq) was dissolved in dichloromethane (5 mL), and a solution of hydrochloric acid in 1,4-dioxane (5 mL) was added. The mixture was allowed to react at room temperature for 2 hours. The reaction mixture was concentrated, and the resulting crude product was purified by reverse-phase column chromatography to afford Compound A5 (180 mg, 68.4%) as a white solid.

[0298] 1H NMR (600MHz, DMSO-d6) δ10.37(s,1H),9.32(s,1H),7.12(d,J=8.2Hz,1H),6.87(dd,J=8.1,2.2Hz,1H),6.84(d,J=2.1 Hz,1H),4.10–4.01(m,4H),3.74(t,J=6.7Hz,2H),2.78(t,J=6.5Hz,2H),2.69(t,J=6.6Hz,2H),2.18(t,J=6.5Hz,2H).

[0299] LCMS (ESI) [M+H] + =288.30.

[0300] Example 6: Synthesis of Compound A6

[0301] 1-(Spiro[chromate-2,4'-piperidinyl]-6-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0302] Synthesis scheme

[0303] Step 1: tert-Butyl 6-bromo-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (Compound A6-2)

[0304] Compound A6-1 (10.0 g, 46.5 mmol, 1.0 eq) was dissolved in methanol (100 mL). N-tert-Butyloxycarbonyl-4-piperidone (10.2 g, 51.2 mmol, 1.1 eq) and tetrahydropyrrole (3.6 g, 51.2 mmol, 1.1 eq) were added and stirred at 80°C under nitrogen for 12 hours. After cooling the reaction system to room temperature, it was extracted with ethyl acetate and washed with saturated brine. The combined organic phases were dried over anhydrous sodium sulfate. The crude product obtained by concentration of the organic phase was purified by column chromatography to obtain Compound A6-2 (17.5 g, 95.0%) as a white solid.

[0305] 1 H NMR (400MHz, DMSO-d6) δ7.78(d,J=2.6Hz,1H),7.74(dd,J=8.8,2.6Hz,1H),7.09(d,J=8.8Hz,1H),3.7 1(d,J=13.4Hz,2H),3.12(s,2H),2.88(s,2H),1.88(d,J=13.6Hz,2H),1.70–1.58(m,2H),1.40(s,9H).

[0306] LCMS(ESI)[M-Boc+H] +=298.18.

[0307] Step 2: tert-Butyl 6-bromo-4-hydroxyspiro[chroman-2,4'-piperidine]-1'-carboxylate (Compound A6-3)

[0308] Methanol (200 mL) was added to compound A6-2 (17.5 g, 44.2 mmol, 1.0 eq). Sodium borohydride (2.5 g, 66.3 mmol, 1.5 eq) was added at 0°C and allowed to react at room temperature for 12 hours. The reaction system was concentrated under reduced pressure, then water was added and extracted with ethyl acetate. The organic phases were washed with saturated brine, and the combined organic phases were dried over anhydrous sodium sulfate. The crude product, compound A6-3 (17.2 g), was obtained by concentration under reduced pressure.

[0309] 1 H NMR (600MHz, DMSO-d6) δ7.53(dd,J=2.6,0.8Hz,1H),7.32–7.27(m,1H),6.76(dd,J=8.7,0.7Hz,1H),5.55(d,J=6.2Hz,1H),4.75–4.64(m, 1H),3.73–3.60(m,2H),3.06(s,2H),2.11(dd,J=13.5,6.1Hz,1H),1.81–1.70(m,2H),1.70–1.63(m,2H),1.64–1.46(m,1H),1.40(s,9H).

[0310] LCMS(ESI):[M-Boc+H] + =300.18.

[0311] Step 3: 6-bromospiro[chromium-2,4'-piperidine] (Compound A6-4)

[0312] Compound A6-3 (1.7 g, 4.2 mmol, 1.0 eq) was dissolved in trifluoroacetic acid (10 mL) and triethylsilane (981 mg, 8.4 mmol, 1.1 eq) was added. The mixture was reacted at 50°C for 1 hour. After cooling the reaction system to room temperature, the reaction solution was concentrated under reduced pressure to obtain the crude product A6-4 (1.2 g).

[0313] LCMS (ESI) [M+H] + =282.28.

[0314] Step 4: tert-Butyl 6-bromospiro[chroman-2,4'-piperidine]-1'-carboxylate (Compound A6-5)

[0315] Compound A6-4 (1.2 g, 4.2 mmol, 1.0 eq) was dissolved in dichloromethane (15 mL). Triethylamine (4.5 g, 44.5 mmol, 3.0 eq) and di-tert-butyl dicarbonate (1.4 g, 6.3 mmol, 1.5 eq) were added at 0°C. The mixture was allowed to react at room temperature for 12 hours. Water was added to the reaction system, and the mixture was extracted with dichloromethane. The mixture was washed with saturated brine, and the combined organic phases were dried over anhydrous sodium sulfate. The crude product obtained by concentration of the organic phase was purified by column chromatography to obtain compound A6-5 (1.2 g, 75.1%) as a white solid.

[0316] 1 H NMR (600MHz, DMSO-d6) δ7.30–7.27(m,1H),7.22(dd,J=8.7,2.5Hz,1H),6.75(d,J=8.7Hz,1H),3.69(d,J=12.9Hz,2H),2.74(t,J=6.8Hz,2H) ,1.78(t,J=6.8Hz,2H),1.66(d,J=13.3Hz,2H),1.52(ddd,J=13.6,11.3,4.7Hz,2H),1.41(s,9H),0.90(t,J=7.9Hz,1H),0.51–0.36(m,1H).

[0317] LCMS(ESI)[M-Boc+H] + =282.18.

[0318] Step 5: tert-Butyl 6-(2,4-dioxytetrahydropyrimidin-1(2H)-yl)spiro[chroman-2,4'-piperidine]-1'-carboxylate (Compound A6-6)

[0319] Compound A6-5 (750 mg, 2.0 mmol, 1.0 eq), dihydrouracil (672 mg, 5.9 mmol, 3 eq), (methanesulfonic acid {biscyclohexyl (3-isopropoxy-2', 4', 6'-triisopropyl-[1,1'-biphenyl]-2-yl) phosphane} (2'-methylamino-1,1'-biphenyl-2-yl) palladium (90 mg, 0.98 mmol, 0.05 eq) and cesium carbonate (1.9 g, 5.9 mmol, 3.0 eq) were added to ultra-dry 1,4-dioxane (10 mL) and reacted at 100°C under nitrogen protection for 12 hours. After cooling the reaction system to room temperature, the crude product was concentrated under reduced pressure and purified by column chromatography to obtain white solid compound A6-6 (282 mg, 34.6%).

[0320] 1H NMR (600MHz, DMSO-d6) δ10.29(s,1H),7.04(d,J=2.5Hz,1H),6.79(d,J=8.5Hz,1H),5.76(s,1H),3.69(t,J=6.7Hz,4H),3.17(s, 2H),2.73(t,J=6.8Hz,2H),2.67(t,J=6.6Hz,2H),1.79(t,J=6.8Hz,2H),1.68(d,J=13.5Hz,2H),1.59–1.48(m,2H),1.41(s,9H).

[0321] LCMS(ESI)[M-Boc+H] + =316.38.

[0322] Step 6: 1-(Spiro[chromate-2,4'-piperidinyl]-6-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound A6)

[0323] Compound A6-6 (1.2 g, 2.9 mmol, 1.0 eq) was dissolved in dichloromethane (10 mL). A solution of hydrochloric acid in 1,4-dioxane (10 mL) was added and allowed to react at room temperature for 2 hours. The reaction mixture was concentrated, and the resulting crude product was purified by reverse-phase column chromatography to afford Compound A6 (1.0 g, 70%) as a white solid.

[0324] 1 H NMR (600MHz, DMSO-d6) δ10.31(s,1H),8.69(s,1H),7.06(d,J=9.0Hz,2H),6.84(d,J=8.4Hz,1H),3.69(t,J=6.7Hz,2H),3.22(d,J=12. 8Hz,2H),3.11(s,2H),2.76(t,J=6.8Hz,2H),2.68(t,J=6.6Hz,2H),1.90(d,J=14.3Hz,2H),1.84(t,J=6.8Hz,2H),1.81–1.74(m,2H).

[0325] LCMS (ESI) [M+H] + =316.30.

[0326] Example 7: Synthesis of Compound A7

[0327] 1-(Spiro[benzopyran-3,4'-piperidin]-7-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0328] Synthesis scheme

[0329] Step 1: 4-(4-bromo-2-fluorobenzyl)piperidine-1,4-dicarboxylic acid 1-tert-butyl 4-ethyl ester (Compound A7-2)

[0330] Dissolve diisopropylamine (2.91 g, 28.74 mmol, 1.1 eq) in ultra-dry tetrahydrofuran (50 mL). Add n-butyllithium (1.84 g, 11.0 mmol, 1.1 eq) to the reaction system and react at -30°C under nitrogen for 30 minutes. Cool to -70°C and add a solution of 1-tert-butyl 4-ethylpiperidine-1,4-dicarboxylate (6.72 g, 26.13 mmol, 1.0 eq) in tetrahydrofuran dropwise. After the addition is complete, react at -70°C for 1 hour. Add a solution of A7-1 (7.0 g, 26.13 mmol, 1.0 eq) in tetrahydrofuran to the reaction system. After the addition is complete, react at -70°C for 2 hours. Add saturated aqueous ammonium chloride to the reaction system and extract with ethyl acetate. Wash with saturated brine. Combine the organic phases and dry over anhydrous sodium sulfate. The crude product obtained by concentrating the organic phase was purified by column chromatography to obtain yellow oily compound A7-2 (8.5 g, 75.9%).

[0331] 1 H NMR(600MHz,DMSO-d6)δ7.50–7.45(m,1H),7.36–7.31(m,1H),7.17–7.11(m,1H),4.10–4.00(m,3H),3.83–3.79(m,2H),2 .81(s,2H),2.71–2.68(m,1H),2.65–2.62(m,1H),1.93–1.87(m,2H),1.38(s,9H),1.19–1.15(m,2H),1.14–1.11(m,2H).

[0332] LCMS(ESI):[M-Boc+H] + =344.29.

[0333] Step 2: tert-Butyl 4-(4-bromo-2-fluorobenzyl)-4-hydroxymethylpiperidine-1-carboxylate (Compound A7-3)

[0334] Compound A7-2 (8.5 g, 19.13 mmol, 1.0 eq) was dissolved in tetrahydrofuran (200 mL). After cooling to 0°C, lithium aluminum hydride (798 mg, 11.04 mmol, 1.1 eq) was added portionwise. The mixture was allowed to return to room temperature and allowed to react for 8 hours. The mixture was quenched by adding water, extracted with ethyl acetate, washed with saturated brine, and the combined organic phases were dried over anhydrous sodium sulfate. The crude product obtained by concentration of the organic phase was purified by column chromatography to obtain compound A7-3 (4.26 g, 55.35%) as a white solid.

[0335] 1 H NMR (600MHz, DMSO-d6) δ7.49–7.44(m,1H),7.37–7.31(m,1H),7.29–7.24(m,1H),4.75–4.71m,1H),3.45–3. 40(m,1H),3.42–3.38(m,1H),3.27–3.17(m,4H),2.67–2.60(m,2H),1.38–1.32(m,11H),1.21–1.13(m,2H).

[0336] LCMS(ESI):[M-Boc+H] + =302.18.

[0337] Step 3: tert-Butyl 7-bromospiro[benzopyran-3,4'-piperidine]-1'-carboxylate (Compound A7-4)

[0338] Compound A7-3 (4.25 g, 10.59 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (20 mL), and sodium hydride (508 mg, 12.71 mmol, 1.2 eq) was added. The reaction was allowed to react at 100°C for 8 hours. The reaction system was cooled to room temperature, quenched with water, and extracted with ethyl acetate. The mixture was washed with saturated brine, and the combined organic phases were dried over anhydrous sodium sulfate. The crude product obtained by concentration of the organic phase was purified by column chromatography to obtain compound A7-4 (2.2 g, 54.3%) as a yellow solid.

[0339] 1 H NMR(400MHz,DMSO-d6)δ7.01–6.95(m,3H),3.91(s,2H),3.50–3.39(m,2H),3.30–3.21(m ,2H),2.64(s,2H),1.40(s,9H),1.38–1.32(m,2H),1.35–1.29(m,1H),1.32–1.14(m,1H).

[0340] LCMS(ESI):[M-Boc+H] +=282.38.

[0341] Step 4: tert-Butyl 7-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)spiro[chromene-3,4'-piperidine]-1'-carboxylate (Compound A7-5)

[0342] Compound A7-4 (1.0 g, 2.62 mmol, 1.0 eq) was dissolved in 1,4-dioxane (10 mL), and dihydrouracil (895 mg, 7.85 mmol, 3.0 eq), cesium carbonate (3.43 g, 10.52 mmol, 3.0 eq), (methanesulfonic acid {biscyclohexyl (3-isopropoxy-2', 4', 6'-triisopropyl-[1,1'-biphenyl]-2-yl) phosphine} ( 2'-Methylamino-1,1'-biphenyl-2-yl)palladium (120 mg, 0.13 mmol, 0.05 eq). The reaction was stirred at 100°C for 16 hours under nitrogen. The reaction solution was concentrated under reduced pressure, and water was added to the system. The mixture was extracted with ethyl acetate and washed with saturated brine. The combined organic phases were dried over anhydrous sodium sulfate. The crude product obtained from the concentrated organic phase was purified by column chromatography to obtain Compound A7-5 (160 mg, 14.7%) as a yellow solid.

[0343] 1 H NMR (600MHz, DMSO-d6) δ10.33(s,1H),7.07–7.03(m,1H),6.82–6.78(m,1H),6.75–6.72(m,1H),3.90(s,2H),3.73(t,J= 6.7Hz,2H),3.51–3.43(m,2H),3.29–3.26(m,2H),2.70–2.65(m,4H),1.40(s,9H),1.40–1.29(m,3H),1.29–1.22(m,1H).

[0344] LCMS(ESI)[M-Boc+H] + =316.38.

[0345] Step 5: 1-(Spiro[benzopyran-3,4'-piperidin]-7-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound A7)

[0346] Compound A7-5 (90 mg, 0.22 mmol, 1.0 eq) was dissolved in 1,4-dioxane hydrochloric acid solution (3 mL). The reaction mixture was allowed to react at room temperature overnight. The reaction mixture was filtered, and the filter cake was washed three times with acetonitrile (10 mL) to obtain Compound A7 (30 mg, 43.9%) as a white solid.

[0347] 1H NMR(600MHz,DMSO-d6)δ10.34(s,1H),7.09–7.05(m,1H),6.86–6.81(m,1H),6.78–6.75(m,1H),3.96(s,2H) ,3.73(t,J=6.6Hz,2H),3.15–3.12(m,2H),3.09(s,2H),2.71(s,2H),2.69–2.64(m,2H),1.67–1.54(m,4H).

[0348] LCMS (ESI) [M+H] + =316.35.

[0349] Example 8: Synthesis of Compound A8

[0350] 1-(Spiro[benzopyran-3,4'-piperidin]-6-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0351] Synthesis scheme

[0352] Step 1: 4-Bromo-2-bromomethyl-1-fluorobenzene (Compound A8-2)

[0353] Compound A8-1 (10.0 g, 52.9 mmol, 1.0 eq) was dissolved in carbon tetrachloride (100 mL). N-bromosuccinimide (11.30 g, 63.5 mmol, 1.2 eq) and azobisisobutyronitrile (868.72 mg, 5.3 mmol, 0.1 eq) were added to the reaction system. Under nitrogen, the reaction mixture was heated to 80°C and allowed to react at this temperature for 12 hours. The resulting reaction system was filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by column chromatography to afford Compound A8-2 (13.89 g, 98.00%) as a colorless oil.

[0354] 1 H NMR (400MHz, DMSO-d6) δ7.79(d,J=6.7,2.6Hz,1H),7.58(d,J=8.7,4.6,2.6Hz,1H),7.23(d,J=9.7,8.8Hz,1H),4.66(d,J=1.0Hz,2H).

[0355] Step 2: tert-Butyl 4-(5-bromo-2-fluorobenzyl)-4-formylpiperidine-1-carboxylate (Compound A8-3)

[0356] Compound 1-tert-Butyloxycarbonylpiperidine-4-carboxaldehyde (12.42 g, 58.23 mmol, 1.3 eq) was dissolved in tetrahydrofuran (120 mL). Potassium tert-butoxide (7.54 g, 67.18 mmol, 1.5 eq) was added at -30°C under nitrogen protection. The mixture was stirred at -30°C for 30 minutes. Compound A8-2 (12 g, 44.79 mmol, 1.0 eq) was then dissolved in tetrahydrofuran (120 mL) and added dropwise to the solution. The solution was stirred at -30°C for 4 hours. The resulting reaction system was concentrated under reduced pressure, and the crude product obtained was purified by column chromatography to obtain compound A8-3 (8.97 g, 50.03%) as a yellow oil.

[0357] 1 H NMR (600MHz, DMSO-d6) δ8.35(d,J=2.7Hz,1H),8.15(d,J=9.0,2.7Hz,1H),7.36–7.22(m,1H),4.65(t,J=5.2Hz ,1H),3.97–3.73(m,3H),3.43(d,J=14.2,I4.8Hz,2H),2.98(d,J=12.4,3.3Hz,1H),2.08(s,4H),1.42(s,9H).

[0358] LCMS(ESI):[M-Boc+H] + =301.17.

[0359] Step 3: tert-Butyl 4-(5-bromo-2-fluorobenzyl)-4-(hydroxymethyl)piperidine-1-carboxylate (Compound A8-4)

[0360] Compound A8-3 (8.95 g, 22.36 mmol, 1.0 eq) was dissolved in methanol (100 mL). Sodium borohydride (1.26 g, 44.72 mmol, 2.0 eq) was slowly added at 0°C and allowed to react at room temperature for 12 hours. The resulting reaction system was concentrated under reduced pressure, water was added, and extraction was performed with ethyl acetate. The mixture was washed with saturated brine, and the combined organic phases were dried over anhydrous sodium sulfate. The organic phases were concentrated to obtain a crude white oil, Compound A8-4 (8.9 g, 98.94%). This crude product was directly carried on to the next step without further purification.

[0361] LCMS(ESI):[M-Boc+H] + =304.28

[0362] Step 4: tert-Butyl 6-bromospiro[chroman-3,4'-piperidine]-1'-carboxylate (Compound A8-5)

[0363] Compound A8-4 (8.9 g, 22.37 mmol, 1 eq) was dissolved in N,N-dimethylformamide (100 mL) and sodium hydride (1.16 g, 29.08 mmol, 1.30 eq) was added. Under nitrogen, the reaction system was heated to 110°C and allowed to react for 2 hours. After cooling to room temperature, saturated aqueous ammonium chloride was added to the reaction system, and extraction was performed with ethyl acetate. The reaction mixture was washed with saturated brine, and the combined organic phases were dried over anhydrous sodium sulfate. The crude product obtained by concentration of the organic phase was purified by column chromatography to obtain compound A8-5 (5.80 g, 67.82%) as a yellow oil.

[0364] 1 H NMR (600MHz, DMSO-d6) δ7.27–7.17(m,2H),6.73(d,J=8.5Hz,1H),3.90(s,2H),3.46(d,J=13.8,6.7,4.0Hz ,2H),3.27(s,2H),2.68(s,2H),1.40(s,9H),1.35(d,J=8.6,4.2Hz,2H),1.30(d,J=13.6,6.8,4.0Hz,2H).

[0365] LCMS(ESI):[M-Boc+H] + =282.28.

[0366] Step 5: tert-Butyl 6-(2,4-dioxotetracillin-1(2D)-yl[chromene-3,4'-piperidine]-1'-carboxylate (A8-6)

[0367] Compound A8-5 (2.0 g, 5.23 mmol, 1.0 eq) was dissolved in 1,4-dioxane (20 mL), and dihydropyrimidine-2,4(1H,3H)-dione (1.79 g, 15.69 mmol, 3.0 eq), (methanesulfonic acid {biscyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine} (2'-methylamino-1,1'-biphenyl-2-yl) palladium (240. The reaction mixture was stirred for 12 hours at 100°C under nitrogen. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain a solid, which was then added to water. The solid was extracted with ethyl acetate and washed with saturated brine. The combined organic phases were dried over anhydrous sodium sulfate. The crude product obtained from the concentrated organic phase was purified by column chromatography to yield Compound A8-6 (463 mg, 21.3%) as a white solid.

[0368] 1H NMR (600MHz, DMSO-d6) δ10.30(s,1H),7.87(d,J=6.6,2.6Hz,1H),7.68(d,J=8.9,4.5,2.6Hz,1H),7.40(s,1H),7.33(d,J=10.4,8.8Hz,1H),7.02(d ,J=8.4Hz,2H),6.77(d,J=8.3Hz,1H),3.90(s,2H),3.70(t,J=6.7Hz,2H), 3.50–3.41(m,2H),2.67(d,J=6.1Hz,4H),1.40(s,9H),1.36–1.32(m,2H).

[0369] LCMS(ESI):[M-Boc+H] + =316.38.

[0370] Step 6: 1-(Spiro[benzopyran-3,4'-piperidin]-6-yl)dihydropyrimidine-2,4(1D,3D)-dione (Compound A8)

[0371] Compound A8-6 (460 mg, 1.11 mmol, 1.0 eq) was dissolved in dichloromethane (2.5 mL) and dioxane hydrochloride solution (2.5 mL) was added. The mixture was allowed to react at room temperature for 12 hours. The reaction mixture was filtered, and the filter cake was slurried with n-hexane and filtered to obtain compound A8 (349.16 mg, 28.64%) as a white solid.

[0372] 1 H NMR (400MHz, DMSO-d6) δ10.31(s,1H),7.04(d,J=7.5Hz,2H),6.79(d,J=8.7,1.2Hz,1H),3.95(s,2H) ,3.70(t,J=6.7Hz,2H),3.10(d,J=11.2,9.7Hz,4H),2.69(d,J=13.6,6.9Hz,4H),1.75–1.49(m,4H).

[0373] LCMS(ESI):[M+H] + =316.48.

[0374] Example 9: Synthesis of Compound A9

[0375] 1-(2H-spiro[benzofuran-3,4'-piperidin]-6-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0376] Synthesis scheme

[0377] Step 1: tert-Butyl 4-(hydroxymethyl)-3,6-dihydropyridine-1(2H)-carboxylate (Compound A9-2)

[0378] Compound A9-1 (10.0 g, 46.9 mmol) was dissolved in toluene (100 mL), and aluminum isopropoxide (12.5 g, 61.0 mmol) was added. The reaction was allowed to react at 120°C for 24 hours. The reaction system was cooled to room temperature, and dilute hydrochloric acid (1.0 mol / L, 200 mL) was added. The mixture was extracted three times with ethyl acetate, and the organic phase was collected. The organic phase was concentrated to obtain a crude product, which was purified by column chromatography to yield compound A9-2 (4.7 g, 47%) as a colorless oil.

[0379] 1 H NMR (600MHz, CDCl3) δ5.67(s,1H),4.07(s,2H),3.98–3.92(m,2H),3.54(dd,J=8.2,4.0Hz,2H),2.15(d,J=6.8Hz,2H),1.49(s,9H).

[0380] LC-MS(ESI):[M-tBu+H] + =158.20

[0381] Step 2: 1-(4-bromo-3-hydroxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione (Compound A9-4)

[0382] Compound A9-3 (3.0 g, 14.55 mmol, 1.0 eq) was dissolved in acetonitrile (35 mL), and N-bromosuccinimide (3.11 g, 17.46 mmol, 1.2 eq) was added to the reaction system. The reaction solution was allowed to react at room temperature for 16 hours. The resulting reaction system was concentrated under reduced pressure, and the resulting crude product was purified by reverse-phase column chromatography to obtain compound A9-2 (3.4 g, 81.97%) as a white solid.

[0383] 1 H NMR (400MHz, DMSO-d6) δ10.44(s,1H),10.40(s,1H),7.47(d,J=8.5Hz,1H),6.95(d ,J=2.4Hz,1H),6.75–6.72(m,1H),3.74(td,J=6.7,2.8Hz,2H),2.72–2.67(m,2H).

[0384] LCMS(ESI):[M+H] + =285.10.

[0385] Step 3: tert-Butyl 4-((2-bromo-5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenoxy)methyl)-3,6-dihydropyridine-1(2H)-carboxylate (A9-5)

[0386] Compound A9-4 (3.4 g, 11.93 mmol, 1.0 eq), compound A9-2 (3.82 g, 17.89 mmol, 1.5 eq), and triphenylphosphine (8.7 g, 23.85 mmol, 2 eq) were dissolved in tetrahydrofuran (50 mL). The temperature was cooled to 0°C, and diethyl azodicarboxylate (5.78 g, 23.85 mmol, 2.0 eq) was added. After the addition was complete, the mixture was allowed to return to room temperature and react for 12 hours. The reaction solution was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The mixture was washed with saturated brine, and the organic phases were combined and dried over anhydrous sodium sulfate. The crude product obtained from the concentrated organic phases was purified by reverse-phase column chromatography to yield compound A9-5 (2.9 g, 50.62%) as a white solid.

[0387] LCMS(ESI):[M+H] + =481.99.

[0388] Step 3: tert-Butyl 6-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2H-spiro[benzofuran-3,4'-piperidine]-1'-carboxylate (Compound A9-6)

[0389] Compound A9-5 (2.9 g, 6.04 mmol, 1.0 eq), tri-n-butyltin hydroxide (7 g, 18.12 mmol, 3.0 eq), and azobisisobutyronitrile (2.2 g, 12.08 mmol, 2 eq) were dissolved in toluene (50 mL) and reacted at 110°C under nitrogen for 16 hours. The reaction system was cooled to room temperature and concentrated under reduced pressure. Water was added and the mixture was extracted with ethyl acetate. The mixture was washed with saturated brine, and the combined organic phases were dried over anhydrous sodium sulfate. The crude product obtained from the concentrated organic phases was purified by column chromatography to yield Compound A9-6 (400 mg, 16.50%) as a yellow solid.

[0390] LCMS(ESI):[M-tBu+H] + =346.30.

[0391] Step 4: 1-(2H-spiro[benzofuran-3,4'-piperidin]-6-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound A9)

[0392] Compound A9-6 (400 mg, 1.0 mmol, 1.0 eq) was dissolved in dichloromethane (5 mL), and dioxane hydrochloride (5 mL) was added dropwise to the reaction mixture. The mixture was allowed to react at room temperature for 1 hour. The organic phase was concentrated to obtain the crude product Compound A9 (203 mg, 67.61%).

[0393] 1 H NMR (600MHz, DMSO-d6) δ10.38(s,1H),7.16(d,J=8.0Hz,1H),6.90–6.86(m,1H),6.82(d,J=1.9Hz,1H),4.52(s,2H),3.74(t,J=6.7Hz,2 H), 3.23 (s, 2H), 3.01 (q, J = 12.0Hz, 2H), 2.69 (t, J = 6.6Hz, 2H), 1.98 (td, J = 13.7, 4.3Hz, 2H), 1.85 (d, J = 14.0Hz, 2H), 1.60–0.68 (m, 1H).

[0394] LCMS(ESI):[M+H] + =302.30.

[0395] Example 10: Synthesis of Compound A10

[0396] 1-(4-Methyl-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,4'-piperidin]-7-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0397] Synthesis scheme

[0398] Step 1: tert-Butyl 4-(((2-bromo-4-nitrophenyl)amino)methyl)-4-hydroxypiperidine-1-carboxylate (Compound A10-2)

[0399] Compound A10-1 (5.0 g, 21.71 mmol, 1.0 eq), 2-bromo-1-iodo-4-nitrobenzene (5.0 g, 15.20 mmol, 0.7 eq), ethylene glycol (2.7 g, 43.42 mmol, 2.0 eq), cuprous iodide (1.03 g, 5.43 mmol, 0.25 eq), and potassium phosphate (9.2 g, 43.42 mmol, 2 eq) were dissolved in isopropanol (50 mL) and reacted at 100°C under nitrogen for 12 hours. The reaction mixture was filtered and concentrated to obtain the crude product, which was then purified by column chromatography to afford A10-2 (3.2 g, 34.2%) as a yellow oil.

[0400] 1H NMR (600MHz, DMSO-d6) δ7.96–7.90(m,2H),7.02(t,J=8.9Hz,1H),6.77(q,J=5.8Hz,1H),4.75(s,1H),3.68(s,2H),3. 25(d,J=6.3Hz,2H),3.04(d,J=41.0Hz,2H),1.50(d,J=13.3Hz,2H),1.43(td,J=13.0,12.5,4.7Hz,2H),1.39(s,9H).

[0401] LCMS(ESI):[M-Boc+H] + =332.19.

[0402] Step 2: tert-Butyl 7-nitro-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,4'-piperidine]-1'-carboxylate (Compound A10-3)

[0403] Compound A10-2 (3.0 g, 7.0 mmol, 1.0 eq), 2-(di-tert-butylphosphino)-1,1'-binaphthyl (833 mg, 2.1 mmol, 0.3 eq), palladium acetate (313 mg, 1.4 mmol, 0.2 eq), and cesium carbonate (2.5 g, 13.9 mmol, 2 eq) were dissolved in toluene and reacted at 100°C under nitrogen for 12 hours. The reaction solution was concentrated to obtain a crude product which was purified by column chromatography to afford A10-3 (1.2 g, 49.3%) as a yellow solid.

[0404] 1 H NMR(400MHz,Chloroform-d)δ7.77(d,J=7.3Hz,2H),6.59–6.54(m,1H),4.04–3.84 (m,2H),3.31–3.19(m,4H),1.79(d,J=13.7Hz,2H),1.66–1.54(m,2H),1.49(s,9H).

[0405] LCMS(ESI):[M-Boc+H] + =250.37.

[0406] Step 3: tert-Butyl 4-methyl-7-nitro-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,4'-piperidine]-1'-carboxylate (Compound A10-4)

[0407] Compound A10-3 (1.0 g, 2.9 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide. Sodium hydride (229 mg, 5.7 mmol, 2.0 eq, 60%) and iodomethane (609 mg, 4.3 mmol, 1.5 eq) were added at 0°C. The mixture was allowed to react at 0°C for 30 minutes. The reaction mixture was poured into ice water, and the precipitated solid was filtered. This yielded crude compound A10-4 (1.0 g).

[0408] LCMS(ESI):[M+H] + =364.35.

[0409] Step 4: tert-Butyl 7-amino-4-methyl-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,4'-piperidine]-1'-carboxylate (Compound A10-5)

[0410] Compound A10-4 (1.0 g, 2.75 mmol, 1.0 eq) was dissolved in methanol (15 mL) and palladium / carbon (100 mg, 10%) was added. The mixture was replaced with hydrogen three times and allowed to react at room temperature for 12 hours. The organic phase was filtered and concentrated to obtain compound A10-5 (1.0 g) as a purple solid. The crude product was directly used in the next step without further purification.

[0411] LCMS(ESI):[M+H] + =334.39.

[0412] Step 5: tert-Butyl 7-(2,4-dioxytetrahydropyrimidin-1(2H)-yl)-4-methyl-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,4'-piperidine]-1'-carboxylate (Compound A10-6)

[0413] Compound A10-5 (1.0 g, 3.0 mmol, 1.0 eq) was dissolved in toluene (10 mL). Acrylic acid (324 mg, 4.5 mmol, 1.5 eq) was added at room temperature and the mixture was allowed to react at 90°C for 3 hours. After cooling to room temperature, acetic acid (5 mL) was added, followed by urea (900 mg, 15.0 mmol, 5.0 eq), and the mixture was allowed to react at 100°C for 12 hours. The reaction mixture was concentrated to obtain the crude product, which was purified by column chromatography to afford A10-6 (300 mg, 23.2%) as a yellow oil.

[0414] 1H NMR (600MHz, DMSO-d6) δ10.25(s,1H),6.74(d,J=8.3Hz,2H),6.70(d,J=8.2Hz,1H),3.73–3.65(m,4H),3.26–3. 10(m,2H),3.04(s,2H),2.85(s,3H),2.66(t,J=6.7Hz,2H),1.68–1.63(m,2H),1.61–1.54(m,2H),1.41(s,9H).

[0415] LCMS(ESI)[M-tBu+H] + =375.39

[0416] Step 6: 1-(4-methyl-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,4'-piperidin]-7-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound A10)

[0417] Compound A10-6 (200 mg, 464 μmol, 1.0 eq) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (1 mL) was added. The reaction was allowed to react at room temperature for 1 hour. The reaction system was concentrated under reduced pressure and purified by preparative liquid chromatography to afford Compound A10 (100 mg, 65.15%) as a white solid.

[0418] 1 H NMR (600MHz, DMSO-d6) δ10.27(s,1H),6.80–6.76(m,2H),6.73(d,J=8.4Hz,1H),3.68(t,J=6.7Hz,2H),3.22 (dt,J=13.2,3.6Hz,2H),3.12–3.05(m,4H),2.88(s,3H),2.66(t,J=6.7Hz,2H),1.86(dd,J=7.8,4.3Hz,4H).

[0419] LCMS (ESI) [M+H] + =331.25

[0420] Example 11: Synthesis of Compound A11

[0421] 1-(3H-spiro[benzofuran-2,4'-piperidin]-6-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0422] Synthesis scheme:

[0423] Step 1: tert-Butyl 4-(4-chloro-2-fluorobenzyl)-4-hydroxypiperidine-1-carboxylate (Compound A11-2)

[0424] A11-1 (2.0 g, 8.95 mmol, 1.0 eq), magnesium (330 mg, 13.42 mmol, 1.5 eq) and iodine (45 mg, 0.18 mmol, 0.02 eq) were dissolved in ether (30 mL), protected by nitrogen, and reacted at 35 ° C for 1 hour to obtain a Grignard reagent. 4-Oxopiperidine-1-carboxylic acid tert-butyl ester (1.8 g, 8.95 mmol, 1.0 eq) was dissolved in ether (10 mL), protected by nitrogen, and cooled to -78 ° C. The obtained Grignard reagent was added to the above reaction solution, reacted at room temperature overnight, quenched with saturated ammonium chloride, washed with water, extracted with ethyl acetate, washed with saturated brine, concentrated under reduced pressure to obtain a crude product, and purified by column chromatography to obtain a yellow oily compound A11-2 (1.8 g, 58.5%).

[0425] 1 H NMR(600MHz,Chloroform-d)δ7.19(t,J=8.1Hz,1H),7.14–7.09(m,2H),3.98–3.7 8(m,2H),3.11(s,2H),2.80(s,2H),1.65-1.61(m,2H),1.51(s,2H),1.47(s,9H).

[0426] LCMS(ESI):[M-tBu-OH+H] + =270.37

[0427] Step 2: tert-Butyl 6-chloro-3H-spiro[benzofuran-2,4'-piperidine]-1'-carboxylate (Compound A11-3)

[0428] Compound A11-2 (1.8 g, 5.24 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (10 mL), and sodium hydride (255 mg, 10.47 mmol, 2.0 eq) was added to the reaction system. The reaction was carried out at 110°C under nitrogen for 2 hours. The reaction was quenched with saturated ammonium chloride, washed with water, extracted with ethyl acetate, and washed with saturated brine. The crude product was concentrated under reduced pressure and purified by column chromatography to afford compound A11-3 (600 mg, 35.4%) as a colorless liquid.

[0429] 1H NMR(600MHz,Chloroform-d)δ7.06(d,J=7.9,1H),6.83(dd,J=7.9,1.8Hz,1H),6.78(d,J=1.8Hz,1H),3.76(s ,2H),3.41(t,J=11.8Hz,2H),2.96(s,2H),1.91(d,J=13.3Hz,2H),1.76–1.68(m,2H),1.50(d,J=1.2Hz,9H).

[0430] LC-MS(ESI)[M-tBu+H] + =268.17

[0431] Step 3: tert-Butyl 6-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3H-spiro[benzofuran-2,4'-piperidine]-1'-carboxylate (Compound A11-4)

[0432] The crude compound A11-3 (600 mg, 1.85 mmol, 1.0 eq) was dissolved in 1,4-dioxane (15 mL), and dihydropyrimidine-2,4(1H,3H)-dione (260 mg, 2.22 mmol, 1.2 eq), (methanesulfonic acid {biscyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine}(2'-methylamino-1,1'-biphenyl-2-yl)palladium (170 mg, 0.18 mmol, 0.1 eq) and cesium carbonate (1.8 g, 5.55 mmol, 3.0 eq) were added. The mixture was protected by nitrogen and reacted at 100 ° C overnight. The reaction system was concentrated under reduced pressure and purified by column chromatography to give a yellow solid compound A11-4 (190 mg, 25.5%).

[0433] 1 H NMR (400MHz, DMSO-d6) δ10.33(s,1H),7.18(d,J=7.8Hz,1H),6.80–6.70(m,2H),3.72(t,J=6.7Hz,2H) ,3.58–3.48(m,2H),3.38(s,2H),3.01(s,2H),2.67(t,J=6.6Hz,2H),1.79-1.67(m,4H),1.42(s,9H).

[0434] LC-MS(ESI)[M-tBu+H] + =346.39

[0435] Step 4: 1-(3H-spiro[benzofuran-2,4'-piperidin]-6-yl)dihydropyrimidine-2,4(1H,3H)-dione (A11)

[0436] Compound A11-4 (1.3 g, 3.25 mmol, 1.0 eq) was dissolved in dichloromethane (5 mL), and dioxane hydrochloride (5 mL) was added. The mixture was reacted at room temperature for 4 hours. The mixture was filtered and the filter cake was washed with dichloromethane to obtain compound A11 (1.12 g, 99.9%) as a white solid.

[0437] 1 H NMR(600MHz,DMSO-d6)δ10.35(s,1H),7.21(d,J=7.9Hz,1H),6.87–6.67(m,2H),3.73(t, J=6.6Hz,2H),3.26–3.13(m,4H),3.10(s,2H),2.68(t,J=6.6Hz,2H),2.04-1.96(m,4H).

[0438] LC-MS (ESI) [M+H] + =302.3

[0439] Example 12: Synthesis of Compound A12

[0440] 1-(3H-spiro[benzofuran-2,4'-piperidin]-5-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0441] Synthesis scheme:

[0442] Step 1: tert-Butyl 3H-spiro[benzofuran-2,4'-piperidine]-1'-carboxylate (Compound A12-1)

[0443] A11-3 (500 mg, 1.54 mmol, 1.0 eq) was dissolved in methanol (10 mL). Palladium / carbon (100 mg) was added to the reaction solution to replace the hydrogen atmosphere. The mixture was reacted at room temperature for 1 hour. The mixture was filtered through celite and concentrated under reduced pressure to obtain a yellow solid compound A12-1 (450 mg, 100.7%).

[0444] 1 H NMR(600MHz,Chloroform-d)δ7.17–7.12(m,2H),6.86(t,J=6.0,1H),6.78(d,J=6.0Hz,1H),3. 75(s,2H),3.47–3.43(m,2H),3.02(s,2H),1.96–1.87(m,2H),1.74–1.70(m,2H),1.50(s,9H).

[0445] LCMS(ESI):[M-Boc+H] +=190.34

[0446] Step 2: tert-Butyl 5-bromo-3H-spiro[benzofuran-2,4'-piperidine]-1'-carboxylate (Compound A12-2)

[0447] Compound A12-1 (450 mg, 1.56 mmol, 1.0 eq) was dissolved in dichloromethane (10 mL). N-bromosuccinimide (340 mg, 1.72 mmol, 1.1 eq) was added to the reaction system and allowed to react at room temperature for 16 hours. The crude product was concentrated under reduced pressure and purified by column chromatography to afford compound A12-2 (420 mg, 73.3%) as a white solid.

[0448] 1 H NMR(600MHz,Chloroform-d)δ7.27–7.26(m,1H),7.24–7.20(m,1H),6.66(d,J=8.4Hz,1H),3.77(s,2 H),3.41(t,J=11.9Hz,2H),3.00(s,2H),1.91(d,J=13.3Hz,2H),1.72(t,J=10.9Hz,2H),1.50(s,9H).

[0449] LC-MS(ESI)[M-tBu+H] + =312.18

[0450] Step 3: tert-Butyl 5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3H-spiro[benzofuran-2,4'-piperidine]-1'-carboxylate (Compound A12-3)

[0451] The crude compound A12-2 (420 mg, 1.14 mmol, 1.0 eq) was dissolved in 1,4-dioxane (15 mL), and dihydropyrimidine-2,4(1H,3H)-dione (260 mg, 2.28 mmol, 2.0 eq), (methanesulfonic acid {biscyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine}(2'-methylamino-1,1'-biphenyl-2-yl)palladium (104 mg, 0.11 mmol, 0.1 eq) and cesium carbonate (1.11 g, 3.42 mmol, 3.0 eq) were added. The mixture was protected by nitrogen and reacted at 100°C overnight. The reaction system was concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography to obtain a yellow solid compound A12-3 (125 mg, 27.3%).

[0452] LC-MS(ESI)[M-tBu+H] + =346.39

[0453] Step 4: 1-(3H-spiro[benzofuran-2,4'-piperidin]-5-yl)dihydropyrimidine-2,4(1H,3H)-dione (A12)

[0454] Compound A12-3 (125 mg, 0.31 mmol, 1.0 eq) was dissolved in dichloromethane (5 mL), and dioxane hydrochloride (2 mL) was added. The mixture was reacted at room temperature for 4 hours. The mixture was filtered and the filter cake was washed with dichloromethane to obtain compound A12 (100 mg, 99.6%) as a white solid.

[0455] 1 H NMR (400MHz, DMSO-d6) δ10.30(s,1H),7.17(d,J=2.2Hz,1H),7.05(dd,J=8.5,2.3Hz,1H),6.79(d,J=8.5 Hz,1H),3.68(t,J=6.6Hz,2H),3.28–3.16(m,4H),3.12(s,2H),2.68(t,J=6.6Hz,2H),2.04-1.90(m,4H).

[0456] LCMS(ESI):[M+H] + =302.3

[0457] Example 13: Synthesis of Compound A13

[0458] 1-(2H-spiro[benzofuran-3,4'-piperidin]-7-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0459] Synthesis scheme

[0460] Step 1: Ethyl 3-(3-bromo-2-methoxyphenyl)amino)propionate (Compound A13-2)

[0461] Combine compound A13-1 (2.0 g, 9.90 mmol, 1.0 eq), ethyl acrylate (1.00 g, 9.99 mmol, 1.0 eq), and trifluoromethanesulfonic acid (150 mg, 999.53 umol, 0.10 eq). Heat the reaction mixture to 100°C and allow to react for 12 hours. This yields crude product A13-2 (3.15 g, 105%).

[0462] LCMS(ESI):[M+H] + =302.18.

[0463] Step 2: 3-(3-bromo-2-methoxyphenyl)amino)propionic acid (Compound A13-3)

[0464] Compound A13-1 (3.15 g, 9.93 mmol, 1.0 eq) was dissolved in a mixture of tetrahydrofuran and water (15 / 3 mL). Lithium hydroxide (2.38 g, 99.28 mmol, 10.0 eq) was added in an ice-water bath. The mixture was allowed to warm to room temperature and allowed to react for 12 hours. Water (50 mL) was added, and the pH of the reaction mixture was adjusted to acidic with dilute hydrochloric acid. The mixture was extracted with ethyl acetate (3 times with 100 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The crude product obtained by concentration of the organic phase was purified on a normal silica gel column to yield Compound A13-3 (1.77 g, 65.04%) as a yellow solid.

[0465] 1 H NMR (600MHz, CDCl3) δ6.89 (m, 2H), 6.61 (m, 1H), 3.82 (s, 3H), 3.51 (t, J = 6.4Hz, 2H), 2.71 (t, J = 6.4Hz, 2H).

[0466] LCMS(ESI):[M+H] + =276.15.

[0467] Step 3: 1-(3-bromo-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione (Compound A13-4)

[0468] Compound A13-3 (1.40 g, 5.11 mmol, 1.0 eq) was dissolved in acetic acid (40 mL), followed by the addition of urea (1.84 g, 30.64 mmol, 6.0 eq) and the reaction mixture was allowed to react at 120°C for 12 hours. The reaction mixture was cooled to room temperature, added with water (100 mL), and extracted with ethyl acetate (100 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. The crude product obtained by concentration of the organic phases was purified by column chromatography to afford compound A13-4 (1.10 g, 72.00%) as a white solid.

[0469] 1 H NMR(600MHz,DMSO)δ10.48(s,1H),7.62(d,J=8.0Hz,1H),7.37(d,J=7.9Hz,1H), 7.14(t,J=8.0Hz,1H),3.75(s,3H),3.67(t,J=6.7Hz,2H),2.72(t,J=6.7Hz,2H).

[0470] LCMS(ESI):[M+H] + =299.10.

[0471] Step 4: 1-(3-bromo-2-hydroxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione (Compound A13-5)

[0472] Compound A13-4 (1.00 g, 3.34 mmol, 1.0 eq) was dissolved in dichloromethane (10 mL). The reaction system was cooled to 0°C, and a boron tribromide solution (13 mL, 13.0 mmol, 4.0 eq) was slowly added dropwise. After the addition was complete, the mixture was allowed to react at room temperature for one hour. The reaction solution was concentrated under reduced pressure, dissolved in dichloromethane, and quenched with methanol in an ice-water bath. The crude product was then concentrated under reduced pressure and purified by column chromatography to afford Compound A12-5 (590 mg, 61.90%) as a yellow solid.

[0473] 1 H NMR (400MHz, DMSO) δ10.40 (s, 1H), 9.75 (s, 1H), 7.48 (dd, J = 8.0, 1.9Hz, 1H), 7.23(dd,J=7.9,1.6Hz,1H),6.80(t,J=7.9Hz,1H),3.61(s,2H),2.72(s,2H).

[0474] LCMS (ESI) [M+H] + =285.10.

[0475] Step 5: 1-(2-((1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)methoxy)-3-bromophenyl)dihydropyrimidine-2,4(1H,3H)-dione (Compound A13-6)

[0476] Compound A13-5 (380 mg, 1.33 mmol, 1.0 eq), triphenylphosphine (525 mg, 2.00 mmol, 1.5 eq), and (1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)methanol (410 mg, 2.02 mmol, 1.5 eq) were dissolved in ultra-dry tetrahydrofuran (10 mL) under nitrogen. Diethyl azodicarboxylate (465 mg, 2.67 mmol, 2.0 eq) was added dropwise in an ice-water bath. The reaction was allowed to react at room temperature for 2 hours. The reaction system was concentrated under reduced pressure, and the resulting crude product was purified by column chromatography to afford crude product A13-6 (580 mg, 92.51%).

[0477] LCMS (ESI) [M+H] + =470.25.

[0478] Step 6: 1-(1'-benzyl-2H-spiro[benzofuran-3,4'-piperidin]-7-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound A13-7)

[0479] Compound A13-6 (380 mg, 807.88 μmol, 1.0 eq) was dissolved in toluene (30 mL), followed by the addition of azobisisobutyronitrile (270 mg, 1.64 mmol, 2.0 eq) and tributyltin hydride (470 mg, 1.61 mmol, 2.0 eq). The resulting reaction mixture was reacted at 110°C for 4 hours. The reaction mixture was concentrated under reduced pressure, and the resulting crude product was purified by reverse transpiration to afford compound A13-7 (210 mg, 66.40%) as a white solid.

[0480] 1 H NMR (400MHz, DMSO) δ10.40(s,1H),7.51(m,5H),7.15(d,J=7.2Hz,1H),7.04(d,J=7.3Hz,1H),6.94(t,J=7.6Hz,1H),4.56(s,2H),4.35(d,J=4 .0Hz,2H),3.65(t,J=6.7Hz,2H),3.37(d,J=12.3Hz,2H),3.21–3.07(m,2H),2.67(t,J=6.7Hz,2H),2.16–2.03(m,2H),1.93(d,J=14.0Hz,2H).

[0481] LCMS (ESI) [M+H] + =392.35.

[0482] Step 7: 1-(2H-spiro[benzofuran-3,4'-piperidin]-7-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound A13)

[0483] Compound A12-7 (150 mg, 383.17 μmol, 1.0 eq) was dissolved in tetrahydrofuran (20 mL). Palladium hydroxide (20%) on carbon (30 mg, 50.66 μmol, 0.13 eq) and palladium (10%) on carbon (30 mg, 19.68 mmol, 0.05 eq) were added. The atmosphere was purged with hydrogen three times and the mixture was allowed to react at 30°C for 12 hours. The reaction mixture was filtered, and the filter cake was washed three times with dichloromethane (15 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by reverse-phase column chromatography to yield Compound A13 (43 mg, 37.24%) as a white solid.

[0484] 1H NMR (600MHz, DMSO) δ10.39(s,1H),8.51(s,1H),7.15(d,J=7.8Hz,1H),7.11(d,J=7.3Hz,1H),6.94(t,J=7.7Hz,1H),4.54(s, 2H),3.66(t,J=6.6Hz,2H),3.29(d,J=14.8Hz,2H),2.98(t,J=12.1Hz,2H),2.68(t,J=6.6Hz,2H),1.99(dt,J=13.5Hz,6.9Hz 2H),1.84(d,J=13.8Hz,2H).

[0485] LCMS (ESI) [M+H] + =302.38

[0486] Example 14: Synthesis of Compound A14

[0487] 1-(Spiro(azetidine-3,2'-chroman)-6'-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0488] Synthesis scheme

[0489] Step 1: tert-Butyl 6'-bromo-4'-oxospiro(azetidine-3,2'-chroman)-1-carboxylate (Compound A14-1)

[0490] Compound A6-1 (10.0 g, 46.50 mmol, 1.0 eq) was dissolved in methanol (100 mL). 3-Oxoazetidine-1-carboxylic acid tert-butyl ester (8.76 g, 51.15 mmol, 1.1 eq) and tetrahydropyrrole (11.39 g, 51.15 mmol, 1.1 eq) were added to the reaction system. The reaction solution was heated to 70°C and allowed to react at this temperature for 16 hours. The mixture was treated with water and extracted twice with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution, dried, and concentrated. The crude product obtained was purified by normal phase column chromatography to obtain Compound A14-1 (8 g, 46.42%) as a yellow solid.

[0491] LCMS(ESI):[M-tBu+H] + =314.15.

[0492] Step 2: tert-Butyl 6'-bromo-4'-hydroxyspiro(azetidine-3,2'-chroman)-1-carboxylate (Compound A14-2)

[0493] Compound A14-1 (8 g, 10.86 mmol, 1.0 eq) was dissolved in methanol (100 mL). The mixture was cooled to 0°C and sodium borohydride (1.64 g, 43.45 mmol, 2.0 eq) was added in batches. After completion of the addition, the mixture was returned to room temperature and allowed to react for 1 hour. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted twice with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution, dried, and concentrated to afford the crude yellow solid compound A14-2 (8 g, 99.46%), which was directly used in the next step.

[0494] LCMS(ESI):[M-Boc+H] + =270.20.

[0495] Step 3: 6'-bromospiro(azetidine-3,2'-chromene) (Compound A14-3)

[0496] Compound A14-2 (8 g, 21.61 mmol, 1.0 eq) was dissolved in toluene (100 mL). p-Toluenesulfonic acid (7.44 g, 43.21 mmol, 2.0 eq) was added to the reaction system. The reaction temperature was raised to 110°C for 16 hours. After cooling the reaction system to room temperature, the crude product, compound A14-3, was concentrated under reduced pressure and carried on to the next step without further treatment.

[0497] LCMS (ESI): [M+H]+=252.15.

[0498] Step 4: tert-Butyl 6'-bromospiro(azetidine-3,2'-chromene)-1-carboxylate (Compound A14-4)

[0499] Compound A14-3 (5.4 g, 21.42 mmol, 1.0 eq) and triethylamine (10.84 g, 107.10 mmol, 5.0 eq) were dissolved in dichloromethane (60 mL). The reaction system was cooled to 0°C and di-tert-butyl dicarbonate (14.02 g, 64.26 mmol, 3.0 eq) was added dropwise. After the addition was complete, the system was returned to room temperature and reacted for 1 hour. The reaction solution was concentrated to obtain a crude product which was purified by column chromatography to afford Compound A14-4 (4.5 g, 59.65%) as a pale yellow solid.

[0500] 1 H NMR (400MHz, DMSO-d6) δ7.39–7.28(m,2H),6.85(d,J=8.6Hz,1H),6.58(d,J=9.8Hz,1H),6.22(d,J=9.8Hz,1H),4.03(s,4H),1.39(s,9H).

[0501] LCMS(ESI):[M-tBu+H] + =296.15.

[0502] Step 5: tert-Butyl 6'-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)spiro(azetidine-3,2'-chromene)-1-carboxylate (Compound A14-5)

[0503] Compound A14-4 (3 g, 8.52 mmol, 1.0 eq) was dissolved in 1,4-dioxane (50 mL), and dihydropyrimidine-2,4(1H,3H)-dione (2.92 g, 25.56 mmol, 3.0 eq), (methanesulfonic acid {biscyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphane}(2'-methylamino-1,1'-biphenyl-2-yl)palladium (391 mg, 0.43 mmol, 0.05 eq) and cesium carbonate (5.55 g, 17.03 mmol, 2.0 eq) were added sequentially. The reaction temperature was raised to 100°C under nitrogen protection and the reaction was reacted for 16 hours. The reaction solution was concentrated and the crude product was purified by column chromatography to obtain white solid compound A14-5 (1.5 g, 45.69%).

[0504] LCMS(ESI):[M-tBu+H] + =330.25.

[0505] Step 6: tert-Butyl 6'-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)spiro(azetidine-3,2'-chroman)-1-carboxylate (Compound A14-6)

[0506] Compound A14-5 (1.5 g, 3.89 mmol, 1.0 eq) was dissolved in methanol (10 mL) and tetrahydrofuran (50 mL). Palladium / carbon (750 mg) was added to the reaction system. The atmosphere was replaced with hydrogen three times and the mixture was allowed to react at room temperature for four days. The reaction system was filtered, and the filter cake was washed three times with methanol (20 mL) and dichloromethane (20 mL). The filtrate was concentrated under reduced pressure. The resulting crude product was purified by column chromatography to afford Compound A14-6 (1 g, 66.32%) as a white solid.

[0507] 1H NMR(600MHz,DMSO-d6)δ10.31(s,1H),7.08–7.03(m,2H),6.86–6.81(m,1H),3.93(s,2H),3.83(s,2H), 3.70(t,J=6.7Hz,2H), 2.78(t,J=6.5Hz,2H), 2.68(t,J=6.7Hz,2H), 2.07(t,J=6.5Hz,2H), 1.40(s,9H).

[0508] LCMS(ESI):[M-tBu+H] + =332.30.

[0509] Step 7: 1-(Spiro(azetidine-3,2'-chroman)-6'-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound A14)

[0510] Compound A14-6 (1 g, 2.58 mmol, 1.0 eq) was dissolved in dichloromethane (15 mL) and trifluoroacetic acid (5 mL) was added dropwise. The reaction was allowed to react at room temperature for 3 hours. The reaction system was concentrated under reduced pressure, and the resulting crude product was slurried with acetonitrile to afford Compound A14 (450 mg, 60.68%) as a white solid.

[0511] 1 H NMR (600MHz, DMSO-d6) δ10.33(s,1H),7.12–7.08(m,1H),7.08(s,1H),6.89–6.84(m,1H),4.09(d,J=11.1Hz,2H),4.05(d ,J=11.3Hz,2H),3.69(t,J=6.7Hz,2H),2.80(t,J=6.5Hz,2H),2.68(t,J=6.7Hz,2H),2.16(t,J=6.5Hz,2H),2.08(s,1H).

[0512] LCMS(ESI):[M+H] + =288.25

[0513] Example 15: Synthesis of Compound A15

[0514] 1-(Spiro[azetidine-3,3'-benzidine]-7'-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0515] Synthesis scheme

[0516] Step 1: 1-tert-butyl-3-ethyl 3-(4-bromo-2-fluorobenzyl)azetidine-1,3-dicarboxylate (Compound A15-1)

[0517] Dissolve diisopropylamine (415 mg, 4.11 mmol, 1.1 eq) in ultra-dry tetrahydrofuran (10 mL). Add n-butyllithium (1.6 mL, 4.11 mmol, 1.1 eq) to the reaction system and react at -30°C under nitrogen for 30 minutes. Cool to -70°C and add a solution of 1-(tert-butyl)-3-ethylazetidine-1,3-dicarboxylate (960 mg, 3.73 mmol, 1.0 eq) in tetrahydrofuran dropwise. After the addition is complete, react at -70°C for 1 hour. Add a solution of A7-1 (1.0 g, 3.73 mmol, 1.0 eq) in tetrahydrofuran to the reaction system. After the addition is complete, react at -70°C for 2 hours. Add saturated aqueous ammonium chloride to the reaction system and extract with ethyl acetate. Wash with saturated brine. Combine the organic phases and dry over anhydrous sodium sulfate. The crude product obtained by concentrating the organic phase was purified by column chromatography to obtain yellow oily compound A15-2 (500 mg, 31.2%).

[0518] 1 H NMR(600MHz,DMSO-d6)δ7.54–7.50(m,1H),7.39–7.34(m,1H),7.27–7.22(m,1H),4.10–4.05 (m,2H),4.02–3.98(m,2H),3.87–3.82(m,2H),3.19(s,2H),1.36(s,9H),1.65–1.12(m,3H).

[0519] LCMS(ESI):[M-Boc+H] + =316.08.

[0520] Step 2: tert-Butyl 3-(4-bromo-2-fluorobenzyl)-3-(hydroxymethyl)azetidine-1-carboxylate (Compound A15-2)

[0521] Compound A15-1 (500 mg, 1.2 mmol, 1.0 eq) was dissolved in tetrahydrofuran (20 mL). After cooling to 0°C, lithium aluminum hydride (59 mg, 1.56 mmol, 1.3 eq) was added portionwise. The mixture was allowed to return to room temperature and reacted for 3 hours. The mixture was quenched by adding water, extracted with ethyl acetate, washed with saturated brine, and the combined organic phases were dried over anhydrous sodium sulfate. The crude product obtained by concentration of the organic phase was purified by column chromatography to obtain compound A15-2 (300 mg, 66.74%) as a white solid.

[0522] 1H NMR (600MHz, DMSO-d6) δ7.55–7.49(m,1H),7.39–7.35(m,1H),7.35–7.27(m,1H),5. 07–5.01(m,1H),3.56(s,4H),3.36(d,J=5.3Hz,2H),2.88–2.82(m,2H),1.32(s,9H).

[0523] LCMS(ESI):[M-Boc+H] + =274.17.

[0524] Step 3: tert-Butyl 7'-bromospiro[azetidine-3,3'-benzidine]-1-carboxylate (Compound A15-3)

[0525] Compound A15-1 (200 mg, 0.49 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (2 mL), and sodium hydride (39 mg, 1.0 mmol, 2.0 eq) was added. The reaction was allowed to react at room temperature for 4 hours. The reaction system was cooled to room temperature, quenched with water, and extracted with ethyl acetate. The mixture was washed with saturated brine, and the combined organic phases were dried over anhydrous sodium sulfate. The crude product obtained by concentration of the organic phase was purified by column chromatography to obtain compound A15-3 (80 mg, 42.9%) as a yellow solid.

[0526] LCMS(ESI):[M-Boc+H] + =254.27.

[0527] Step 4: tert-Butyl 7'-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)spiro[azetidine-3,3'-chromene]-1-carboxylate (Compound A15-4)

[0528] Compound A15-3 (80.0 mg, 0.21 mmol, 1.0 eq) was dissolved in 1,4-dioxane (1 mL), and dihydrouracil (71 mg, 0.63 mmol, 3.0 eq), cesium carbonate (204 mg, 0.63 mmol, 3.0 eq) and (methanesulfonic acid {biscyclohexyl (3-isopropoxy-2', 4', 6'-triisopropyl-[1,1'-biphenyl]-2-yl) phosphane} were added to the reaction system. (2'-Methylamino-1,1'-biphenyl-2-yl)palladium (9 mg, 0.01 mmol, 0.05 eq). The reaction was stirred at 100°C for 16 hours under nitrogen. The reaction solution was concentrated under reduced pressure, and water was added to the system. The mixture was extracted with ethyl acetate and washed with saturated brine. The combined organic phases were dried over anhydrous sodium sulfate. The crude product obtained from the concentrated organic phase was purified by column chromatography to obtain Compound A15-4 (56 mg, 64.4%) as a yellow solid.

[0529] 1 H NMR(400MHz,DMSO-d6)δ7.08(d,J=8.2Hz,1H),6.79–6.83(m,1H),6.75(d,J=2.1Hz,1H),4.1 5(s,2H),3.75–3.66(m,5H),3.62–3.58(m,1H),2.95(s,2H),2.70–2.63(m,2H),1.38(s,9H).

[0530] LCMS(ESI):[M-Boc+H] + =288.38.

[0531] Step 5: 1-(Spiro[azetidine-3,3'-benzidine]-7'-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound A15)

[0532] Compound A15-4 (25 mg, 0.06 mmol, 1.0 eq) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (1 mL) was added. The reaction mixture was allowed to react overnight at room temperature. The crude product obtained by concentration was purified by reverse-phase column chromatography to afford Compound A15 (18 mg, 53.9%) as a white solid.

[0533] 1 H NMR (600MHz, DMSO-d6) δ10.36(s,1H),9.01(s,1H),7.13(d,J=8.2Hz,1H),6.88–6.83(m,1H),6.78( d,J=2.1Hz,1H),4.24(s,2H),3.87–3.78(m,4H),3.74–3.63(m,2H),3.03(s,2H),2.70–2.64(m,2H).

[0534] LCMS(ESI):[M+H] + =288.30.

[0535] Example 16: Synthesis of Compound A16

[0536] 1-(Spiro[azetidine-3,3'-chroman]-6'-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0537] Synthesis scheme

[0538] Step 1: 1-(tert-Butyl)3-ethyl-3-(4-bromo-2-fluorobenzyl)azetidine-1,3-dicarboxylate (Compound A16-1)

[0539] Dissolve diisopropylamine (755 mg, 7.5 mmol, 2.0 eq) in ultra-dry tetrahydrofuran (10 mL), cool to -78°C, add n-butyllithium in n-hexane (3.0 mL, 7.5 mmol, 2.5 M, 2.0 eq), maintain this temperature, and stir for 30 minutes. Then, dissolve 1-(tert-butyl)-3-ethylazetidine-1,3-dicarboxylate (1.3 g, 5.6 mmol, 1.5 eq) in ultra-dry tetrahydrofuran (10 mL) and slowly add dropwise to the reaction system at -78°C. Maintain this temperature and stir for 1.5 hours. Then, dissolve compound A8-1 (1.0 g, 3.7 mmol, 1.0 eq) in ultra-dry tetrahydrofuran (10 mL) and slowly add dropwise to the reaction system at -78°C. Maintain this temperature and stir for 3 hours. Saturated aqueous ammonium chloride was added to the reaction system, extracted with ethyl acetate, washed with saturated brine, and the organic phases were combined and dried over anhydrous sodium sulfate. The crude product obtained by concentrating the organic phase was purified by column chromatography to obtain compound A16-1 (480 mg, 30.9%) as a colorless oil.

[0540] 1 H NMR(400MHz,Chloroform-d)δ7.36(ddd,J=8.7,4.6,2.5Hz,1H),7.28–7.26(m,1H),6.95(t,J=9.1 Hz,1H),4.24–4.16(m,4H),3.90(d,J=8.9Hz,2H),3.25(s,2H),1.46(s,9H),1.26(t,J=7.1Hz,3H).

[0541] LCMS(ESI):[M-Boc+H] + =318.28.

[0542] Step 2: tert-Butyl 3-(4-bromo-2-fluorobenzyl)-3-(hydroxymethyl)azetidine-1-carboxylate (Compound A16-2)

[0543] Compound A16-2 (480 mg, 1.2 mmol, 1.0 eq) was added with tetrahydrofuran (5 mL), and lithium aluminum hydride (57 mg, 1.5 mmol, 1.2 eq) was added at 0°C. The mixture was allowed to react at room temperature for 2 hours. The reaction system was filtered through celite, and the filtrate was concentrated under reduced pressure. Water was added, and the mixture was extracted with ethyl acetate. The organic phases were washed with saturated brine, and the combined organic phases were dried over anhydrous sodium sulfate. The crude product obtained from the concentrated organic phases was purified by column chromatography to yield Compound A16-2 (285 mg, 66.0%) as a colorless oil.

[0544] 1H NMR(600MHz,Chloroform-d)δ7.40(dd,J=6.6,2.5Hz,1H),7.37(ddd,J=8.6,4.5,2.6Hz,1H),6.97(t,J=9.1Hz,1H),3.7 8(d,J=8.7Hz,2H),3.70(d,J=8.7Hz,2H),3.64(d,J=4.9Hz,2H),3.00(s,2H),1.85(dt,J=6.6,3.3Hz,1H),1.46(s,9H).

[0545] LCMS(ESI):[M-Boc+H] + =274.27.

[0546] Step 3: tert-Butyl 6'-bromospiro[azetidine-3,3'-chromene]-1-carboxylate (Compound A16-3)

[0547] Compound A16-2 (280 mg, 0.75 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (5 mL) and sodium hydride (60 mg, 1.5 mmol, 2.0 eq) was added at 0°C. The reaction system was allowed to react at 45°C for 2 hours. After cooling the reaction system to room temperature, ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The mixture was washed with saturated brine, and the combined organic phases were dried over anhydrous sodium sulfate. The crude product obtained by concentration of the organic phase was purified by column chromatography to yield compound A16-3 (150 mg, 56.6%) as a white solid.

[0548] 1 H NMR(400MHz,Chloroform-d)δ7.24–7.18(m,2H),6.71(d,J=8.5Hz,1H),4.16( s,2H),3.82(d,J=8.8Hz,2H),3.71(d,J=8.8Hz,2H),2.96(s,2H),1.46(s,9H).

[0549] LCMS(ESI):[M-tBu+H] + =298.15.

[0550] Step 4: tert-Butyl 6'-(2,4-dioxytetrahydropyrimidin-1(2H)-yl)spiro[azetidine-3,3'-chromene]-1-carboxylate (Compound A16-4)

[0551] Compound A16-3 (150 mg, 0.42 mmol, 1.0 eq), dihydrouracil (145 mg, 1.3 mmol, 3.0 eq), (methanesulfonic acid {biscyclohexyl (3-isopropoxy-2', 4', 6'-triisopropyl-[1,1'-biphenyl]-2-yl) phosphane} (2'-methylamino-1,1'-biphenyl-2-yl) palladium (19 mg, 0.02 mmol, 0.05 eq) and cesium carbonate (276 mg, 0.85 mmol, 2.0 eq) were added to ultra-dry 1,4-dioxane (10 mL) and reacted at 100° C. under nitrogen protection for 12 hours. After cooling the reaction system to room temperature, the crude product was concentrated under reduced pressure and purified by column chromatography to obtain white solid compound A16-4 (100 mg, 61.0%).

[0552] 1 H NMR (400MHz, Chloroform-d) δ7.06–7.00 (m, 2H), 6.87 (d, J = 8.3Hz, 1H), 4.18 (s, 2H), 3. 88–3.79(m,4H),3.74(d,J=8.8Hz,2H),2.99(s,2H),2.84(t,J=6.7Hz,2H),1.47(s,9H).

[0553] LCMS(ESI):[M-Boc+H] + =288.27.

[0554] Step 5: 1-(Spiro[azetidine-3,3'-chroman]-6'-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound A16)

[0555] Compound A16-4 (100 mg, 0.26 mmol, 1.0 eq) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (0.2 mL) was added. The mixture was allowed to react at room temperature for 2 hours. The reaction mixture was concentrated, and the resulting crude product was purified by reverse-phase column chromatography to afford compound A16 (50 mg, 67.4%) as a white solid.

[0556] 1 H NMR (600MHz, DMSO-d6) δ10.33(s,1H),7.11–7.08(m,1H),7.06(dd,J=8.7,2.6Hz,1H),6.81(d,J=8.6Hz, 1H), 4.23 (d, J=2.2Hz, 2H), 3.87–3.81 (m, 4H), 3.70 (t, J=6.7Hz, 2H), 3.04 (s, 2H), 2.69 (t, J=6.7Hz, 2H).

[0557] LCMS(ESI):[M+H] + =288.25.

[0558] Example 17: Synthesis of Compound A17

[0559] 1-(3',3'-difluoro-2H-spiro[benzofuran-3,4'-piperidin]-6-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0560] Synthesis scheme

[0561] Step 1: tert-Butyl 4-((2-bromo-5-nitrophenoxy)methyl)-3,6-dihydropyridine-1(2H)-carboxylate (Compound A17-2)

[0562] Compound A17-1 (5.0 g, 22.94 mmol, 1.0 eq), compound A9-2 (5.38 g, 25.23 mmol, 1.1 eq), and triphenylphosphine (12.03 g, 45.87 mmol, 2.0 eq) were dissolved in tetrahydrofuran (50 mL). The temperature was cooled to 0°C, and diethyl azodicarboxylate (7.99 g, 45.87 mmol, 2.0 eq) was added. After the addition was complete, the mixture was allowed to cool to room temperature and allowed to react overnight. The reaction solution was concentrated under reduced pressure, and water (50 mL) was added. The mixture was extracted with ethyl acetate (3 times with 100 mL), washed with saturated brine (100 mL), and the organic phases were combined and dried over anhydrous sodium sulfate. The crude product obtained from the concentrated organic phases was purified by column chromatography to yield compound A17-2 (8.8 g, 92.84%) as a light yellow oil.

[0563] LCMS(ESI):[M+H-100] + =313.08.

[0564] Step 2: tert-Butyl 6-nitro-2',3'-dihydro-1'H,2H-spiro[benzofuran-3,4'-pyridine]-1'-carboxylate (Compound A17-3)

[0565] Compound A17-2 (8.8 g, 21.29 mmol, 1.0 eq), sodium formate (1.59 g, 23.42 mmol, 1.1 eq), and sodium acetate (4.37 g, 53.23 mmol, 2.5 eq) were dissolved in N,N-dimethylformamide (90 mL). Palladium acetate (478.06 mg, 2.13 mmol, 0.1 eq) and triethylamine (2.37 g, 23.42 mmol, 1.1 eq) were then added. The mixture was reacted at 70°C under nitrogen overnight. After cooling to room temperature, the reaction mixture was filtered and rinsed with ethyl acetate (100 mL). The organic phase was washed with saturated brine (60 mL x 3). The combined organic phases were then dried over anhydrous sodium sulfate. The resulting crude product was concentrated and purified by column chromatography to yield compound A17-3 (4.3 g, 60.76%) as a yellow solid.

[0566] 1 H NMR (400MHz, DMSO-d6) δ7.84–7.75(m,1H),7.65–7.58(m,1H),7.38(d,J=8.1Hz,1H),7.11–6.92(m,1H),4.95–4.74(m,1H),4.57( d,J=9.0Hz,1H),4.37(d,J=9.0Hz,1H),3.80–3.71(m,1H),3.48–3.36(m,1H),2.05–1.94(m,1H),1.86–1.70(m,1H),1.47(s,9H).

[0567] LCMS(ESI):[M+H-56] + =277.25.

[0568] Step 3: tert-Butyl 3'-hydroxy-6-nitro-2H-spiro[benzofuran-3,4'-piperidine]-1'-carboxylate (Compound A17-4)

[0569] Compound A17-3 (2.0 g, 6.02 mmol, 1.0 eq) was dissolved in tetrahydrofuran (200 mL) and cooled to -78°C under nitrogen. Borane solution in tetrahydrofuran (15.04 mL, 15.04 mmol, 2.5 eq) was added dropwise and the mixture was allowed to react at 0°C for 5 hours. Water (2.5 mL) was slowly added dropwise, followed by sodium perborate tetrahydrate (4.63 g, 30.09 mmol, 5.0 eq). The reaction mixture was allowed to warm to room temperature and react overnight. The reaction system was concentrated under reduced pressure, followed by the addition of dichloromethane (300 mL) and washing with saturated brine (150 mL x 2). The organic phases were combined and dried over anhydrous sodium sulfate. The crude product obtained from the concentrated organic phases was purified by column chromatography to yield compound A17-4 (1.59 g, 59.1%) as a yellow solid.

[0570] 1 H NMR (400MHz, DMSO-d6) δ7.76(dd,J=8.2,2.1Hz,1H),7.58–7.54(m,1H),7.51(d,J=2.1Hz,1H),5.34(d,J=4.5Hz,1H),4.81(d, J=9.0Hz,1H),4.51(d,J=9.0Hz,1H),4.06–3.81(m,2H),3.78–3.70(m,1H),2.85–2.57(m,2H),1.87–1.75(m,2H),1.43(s,9H).

[0571] LCMS(ESI):[M+H-100] + =251.27.

[0572] Step 4: tert-Butyl 6-nitro-3'-oxo-2H-spiro[benzofuran-3,4'-piperidine]-1'-carboxylate (Compound A17-5)

[0573] A17-4 (1.59 g, 4.54 mmol, 1.0 eq) was dissolved in dichloromethane (30 mL), and Dess-Martin periodinane (4.81 g, 11.35 mmol, 2.5 eq) was added to the reaction system. The reaction was allowed to react at room temperature for 2.5 hours. Dichloromethane (100 mL) was added to the reaction system and the mixture was diluted with saturated sodium bicarbonate (80 mL twice). The organic phase was washed with saturated brine (60 mL twice) and dried over anhydrous sodium sulfate. The crude product obtained by concentration of the organic phase was purified by column chromatography to obtain compound A17-5 (1.33 g, 84.13%) as a light yellow solid.

[0574] LCMS (ESI) [M+H-100] + =249.27.

[0575] Step 5: tert-Butyl 3',3'-difluoro-6-nitro-2H-spiro[benzofuran-3,4'-piperidine]-1'-carboxylate (Compound A17-6)

[0576] A17-5 (1.33 g, 3.82 mmol, 1.0 eq) was dissolved in dichloromethane (15 mL). Triethylamine trihydrofluoride (3.69 g, 22.91 mmol, 6.0 eq) and DAST fluoroborate (3.93 g, 17.18 mmol, 4.5 eq) were added to the reaction system. Finally, triethylamine (965.87 mg, 9.54 mmol, 2.5 eq) was added and the mixture was allowed to react at room temperature for 2 hours. After completion, the reaction was quenched with saturated sodium bicarbonate solution (50 mL) and extracted with dichloromethane (50 mL x 3). The mixture was washed with saturated brine (50 mL), and the combined organic phases were dried over anhydrous sodium sulfate. The resulting crude product was concentrated and purified by column chromatography to afford compound A17-6 (530 mg, 37.48%) as a light yellow oil.

[0577] 1 H NMR (400MHz, DMSO-d6) δ7.82(dd,J=8.3,2.1Hz,1H),7.67–7.63(m,2H),4.97(d,J=10.1Hz,1H),4.71–4.61(m,1H),4.28– 4.09(m,1H),4.09–3.90(m,1H),3.68–3.44(m,1H),3.04–2.82(m,1H),2.24–2.17(m,1H),2.04–1.96(m,1H),1.44(s,9H).

[0578] LCMS (ESI) [M+H-100] + =271.27.

[0579] Step 6: tert-Butyl 6-amino-3', 3'-difluoro-2H-spiro[benzofuran-3,4'-piperidine]-1'-carboxylate (Compound A17-7)

[0580] A17-6 (530 mg, 1.43 mmol, 1.0 eq) was dissolved in methanol (10 mL), and 10% aqueous palladium on carbon (250 mg) was added to the reaction system. The atmosphere was replaced with hydrogen three times, and the reaction was allowed to proceed overnight at room temperature. After completion of the reaction, the reaction was filtered and the filter cake was washed with methanol. The combined filtrates were concentrated to afford the crude, light yellow solid compound A17-7 (437 mg, 89.72 g), which was used directly in the next step without further purification.

[0581] LCMS (ESI) [M+H] + =341.30.

[0582] Step 7: tert-Butyl 6-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3',3'-difluoro-2H-spiro[benzofuran-3,4'-piperidine]-1'-carboxylate (Compound A17-8)

[0583] A17-7 (500.0 mg, 1.47 mmol, 1.0 eq) was dissolved in toluene (5.0 mL), and acrylic acid (211.72 mg, 2.94 mmol, 2.0 eq) was added to the reaction system. The reaction mixture was heated to 90°C and allowed to react for 48 hours. The reaction system was cooled to room temperature, and acetic acid (3.0 mL) and urea (529.33 mg, 8.81 mmol, 6 eq) were added to the reaction mixture. The reaction mixture was heated to 100°C and allowed to react for 24 hours. The reaction system was concentrated under reduced pressure, and the concentrate was added with saturated sodium bicarbonate (100 mL). The extract was extracted with ethyl acetate (150 mL x 2). The organic phase was washed with saturated sodium bicarbonate (100 mL) and saturated brine (100 mL). The combined organic phases were dried over anhydrous sodium sulfate. The crude product obtained from the concentrated organic phase was purified by column chromatography to obtain compound A17-8 (210 mg, 32.68%) as an off-white solid.

[0584] LCMS (ESI) [M+H-56] + =382.39.

[0585] Step 8: (1-(3',3'-difluoro-2H-spiro[benzofuran-3,4'-piperidin]-6-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound A17)

[0586] Compound A17-8 (100 g, 228.60 μmol, 1.0 eq) was dissolved in dichloromethane (2.0 mL). A solution of hydrochloric acid in 1,4-dioxane (1.0 mL) was added. The reaction was allowed to react at room temperature for 2 hours. The reaction system was concentrated under reduced pressure, and the resulting crude product was purified by reverse-phase column chromatography to afford Compound A17 (50 mg, 62.35%) as an off-white solid.

[0587] 1 H NMR (600MHz, DMSO-d6) δ10.40(s,1H),7.30(d,J=7.8Hz,1H),6.92(dd,J=8.1,1.8Hz,1H),6.88(d,J=1.7Hz,1H),4.92–4.85(m,1H),4.56(dd,J=10.3, 2.7Hz,1H),3.91–3.82(m,1H),3.82–3.68(m,3H),3.37–3.34(m,2H),3.05 –2.95(m,1H),2.69(t,J=6.6Hz,2H),2.40–2.30(m,1H),2.21–2.12(m,1H).

[0588] LCMS (ESI) [M+H] + =338.25

[0589] Example 18: Synthesis of Compound B1

[0590] 1-(2,3,4,4a,5,6-Hexahydro-1H-benzo[b]pyrazino[1,2-d][1,4]oxazepin-9-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0591] Synthesis scheme

[0592] Step 1: (S)-tert-Butyl 4-(2-fluoro-4-nitrophenyl)-3-(2-hydroxyethyl)piperazine-1-carboxylate (Compound B1-2)

[0593] Compound B1-1 (6.0 g, 37.71 mmol, 1.0 eq) was dissolved in dimethyl sulfoxide (20 mL), and 3,4-difluoronitrobenzene (8.69 g, 37.71 mmol, 1.0 eq) was added. The reaction mixture was heated to 100°C and allowed to react at this temperature for 8 hours. After cooling the reaction system to room temperature, it was added to water and extracted with ethyl acetate. The mixture was washed with saturated brine, and the combined organic phases were dried over anhydrous sodium sulfate. The crude product obtained by concentration of the organic phase was purified by column chromatography to obtain Compound B1-2 (12.0 g, 86.1%) as a yellow solid.

[0594] LCMS(ESI):[M-Boc+H] + =270.27.

[0595] Step 2: (S)-9-nitro-1,2,4,4a,5,6-hexahydro-3H-benzo[b]pyrazino[1,2-d][1,4]oxazepine-3-carboxylic acid tert-butyl ester (Compound B1-3)

[0596] Compound B1-2 (12.0 g, 32.49 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (50 mL), and sodium hydride (1.69 g, 42.23 mmol, 1.3 eq) was added. The reaction was allowed to react at 100°C for 8 hours. The reaction system was cooled to room temperature, quenched with water, and extracted with ethyl acetate. The mixture was washed with saturated brine, and the combined organic phases were dried over anhydrous sodium sulfate. The crude product obtained by concentration of the organic phase was purified by column chromatography to obtain compound B1-3 (9.0 g, 79.2%) as a yellow solid.

[0597] LCMS(ESI):[M-Boc+H] + =250.37.

[0598] Step 3: (S)-9-amino-1,2,4,4a,5,6-hexahydro-3H-benzo[b]pyrazino[1,2-d][1,4]oxazepine-3-carboxylic acid tert-butyl ester (Compound B1-4)

[0599] Compound B1-3 (9.0 g, 25.76 mmol, 1.0 eq) was dissolved in methanol (120 mL) and palladium / carbon (1.9 g) was added. The mixture was purged with hydrogen three times and allowed to react at room temperature for 12 hours. The reaction mixture was filtered, and the filter cake was washed three times with methanol. The mixture was concentrated under reduced pressure to obtain crude compound B11-4 (4.7 g).

[0600] LCMS(ESI):[M-Boc+H] + =320.38.

[0601] Step 4: (S)-9-iodo-1,2,4,4a,5,6-hexahydro-3H-benzo[b]pyrazino[1,2-d][1,4]oxazepine-3-carboxylic acid tert-butyl ester (Compound B1-5)

[0602] Compound B1-4 (4.7 g, 14.71 mmol, 1.0 eq) was dissolved in diiodomethane (50 mL), and isoamyl nitrite (3.45 g, 29.43 mmol, 2.0 eq) and potassium iodide (7.33 g, 44.14 mmol, 3.0 eq) were added. The reaction mixture was heated to 80°C under a nitrogen atmosphere and reacted overnight. After cooling the reaction system to room temperature, the organic phase was concentrated and the resulting crude product was purified by column chromatography to afford compound B1-5 (3.5 g, 55.2%) as a yellow oil.

[0603] 1 H NMR (400MHz, DMSO-d6) δ7.25–7.19(m,1H),7.11–7.05(m,1H),6.78–6.70(m,1H),4.35–4.24(m,1H),4.18–4.09(m,1H),3.64–3.56(m ,1H),3.55–3.48(m,1H),3.34–3.24(m,1H),3.19–3.11(m,2H),3.11–3.04(m,2H),2.07–1.94(m,1H),1.89–1.80(m,1H),1.41(s,9H).

[0604] Step 5: 9-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1,2,4,4a,5,6-hexahydro-3H-benzo[b]pyrazino[1,2-d][1,4]oxazepine-3-carboxylic acid tert-butyl ester (Compound B1-6)

[0605] Compound B11-5 (250 mg, 0.58 mmol, 1.0 eq) was dissolved in 1,4-dioxane (3 mL), and dihydrouracil (99 mg, 0.87 mmol, 1.5 eq), cesium carbonate (567 mg, 1.74 mmol, 3.0 eq), (methanesulfonic acid {biscyclohexyl (3-isopropoxy-2', 4', 6'-triisopropyl-[1,1'-biphenyl]-2-yl) phosphine} (2'-methylamino-1,1'-biphenyl-2-yl) palladium (II) (26 mg, 0.029 mmol, 0.05 eq) were added to the reaction system. The mixture was heated at 100 ° C under nitrogen protection. The reaction mixture was allowed to react for 16 hours. After the reaction solution was concentrated under reduced pressure, water was added to the system, extracted with ethyl acetate, washed with saturated brine, and the organic phases were combined and dried over anhydrous sodium sulfate. The crude product obtained by concentrating the organic phase was purified by column chromatography to obtain compound B1-6 (50 mg, 27.2%) as a yellow oil.

[0606] 1 H NMR(400MHz,DMSO-d6)δ10.31(s,1H),6.96–6.90(m,1H),6.88–6.84(m,1H),6.76( d,J=2.5Hz,1H),4.37–4.27(m,1H),4.19–4.09(m,1H),3.72–3.65(m,2H),3.61–3. 57(m,1H),3.54–3.47(m,1H),3.38–3.29(m,1H),3.23(s,1H),3.15(s,1H),3.12–3 .06(m,2H),2.69–2.62(m,2H),1.97–1.95(m,1H),1.91–1.87(m,1H),1.42(s,9H).

[0607] LCMS(ESI):[M+H] + =417.40.

[0608] Step 6: 1-(2,3,4,4a,5,6-hexahydro-1H-benzo[b]pyrazino[1,2-d][1,4]oxazepin-9-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound B1)

[0609] Compound B1-6 (50 mg, 0.116 mmol, 1.0 eq) was dissolved in 1,4-dioxane hydrochloric acid solution (0.5 mL) and dichloromethane (1 mL). The reaction mixture was allowed to react overnight at room temperature. The crude product obtained by concentration was purified by reverse-phase column chromatography to yield Compound B1 (15 mg, 39.1%) as a white solid.

[0610] 1H NMR(600MHz,DMSO-d6)δ10.33(s,1H),9.42(s,1H),7.01–6.97(m,1H),6.95–6.90(m ,1H),6.82–6.79(m,1H),4.47–4.39(m,1H),4.15–4.09(m,1H),3.72–3.68(m,2H),3. 38–3.36(m,1H),3.35–3.27(m,2H),3.27–3.22(m,1H),3.19–3.14(m,1H),3.13–3.08 (m,1H),3.05–2.97(m,1H),2.69–2.64(m,2H),2.12–2.03(m,1H),1.98–1.91(m,1H).

[0611] LCMS(ESI):[M+H] + =317.12.

[0612] Example 19: Synthesis of Compound B2

[0613] (S)-1-(2,3,4,4a,5,6-Hexahydro-1H-benzo[b]pyrazino[1,2-d][1,4]oxazepin-9-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0614] Synthesis scheme

[0615] Step 1: (S)-9-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1,2,4,4a,5,6-hexahydro-3H-benzo[b]pyrazino[1,2-d][1,4]oxazepine-3-carboxylic acid tert-butyl ester (Compound B2-1)

[0616] Dissolve B1-4 (4.0 g, 12.52 mmol, 1.0 eq) in toluene (40 mL), and add acrylic acid (1.35 g, 18.78 mmol, 1.5 eq) to the reaction system. Heat to 90°C and allow to react for 24 hours. Cool the reaction system to room temperature, then add acetic acid (40 mL) and urea (3.76 g, 62.62 mmol, 5 eq). Heat the system to 100°C and allow to react for 24 hours. Add water (200 mL) and sodium bicarbonate to neutralize the reaction system until it becomes weakly alkaline, and extract with ethyl acetate (250 mL x 3). Wash with saturated brine (250 mL), combine the organic phases, and dry over anhydrous sodium sulfate. Concentrate the organic phases to obtain the crude product, which is then purified by column chromatography to yield compound B2-1 (1.5 g, 28.76%) as a light yellow solid.

[0617] 1H NMR (400MHz, DMSO-d6) δ10.31(s,1H),6.94(d,J=8.6Hz,1H),6.87(dd,J=8.5,2.4H z,1H),6.76(d,J=2.4Hz,1H),4.32(t,J=9.6Hz,1H),4.21–4.10(m,1H),3.69(t,J=6 .7Hz,2H),3.66–3.55(m,1H),3.51(d,J=11.1Hz,1H),3.39–3.31(m,1H),3.29–3.0 5(m,4H),2.66(t,J=6.7Hz,2H),2.07–1.95(m,1H),1.95–1.81(m,1H),1.42(s,9H).

[0618] LCMS (ESI) [M+H] + =417.79.

[0619] Step 2: (S)-1-(2,3,4,4a,5,6-hexahydro-1H-benzo[b]pyrazino[1,2-d][1,4]oxazepin-9-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound B2)

[0620] Compound B2-1 (1.5 g, 3.60 mmol, 1.0 eq) was dissolved in dichloromethane (5 mL), and a solution of hydrochloric acid in 1,4-dioxane (15 mL) was added. The reaction was allowed to react at room temperature for 2 hours. The reaction system was concentrated under reduced pressure, and the resulting crude product was slurried with n-hexane to obtain a light yellow solid, Compound B2 (1.4 g, overweight).

[0621] 1 H NMR (600MHz, CD3OD) δ7.07(d,J=8.6Hz,1H),7.02(dd,J=8.5,2.4Hz,1H),6.91(d,J=2.4Hz,1H),4.51–4.44(m,1H),4.24–4.15(m,1H),3.86–3.79( m,2H),3.50–3.37(m,4H),3.31(d,J=12.1Hz,1H),3.25–3.16(m,1H),2.8 1(t,J=6.7Hz,2H),2.21(ddd,J=14.3,9.2,4.4Hz,1H),2.02–1.94(m,1H).

[0622] LCMS (ESI) [M+H] + =317.30

[0623] Example 20: Synthesis of Compound B3

[0624] (R)-1-(2,3,4,4a,5,6-Hexahydro-1H-benzo[b]pyrazino[1,2-d][1,4]oxazepin-9-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0625] Synthesis scheme

[0626] The synthesis method of compound B3 is the same as that of compound B2.

[0627] 1 H NMR (600MHz, DMSO-d6) δ10.33(s,1H),7.00(d,J=8.6Hz,1H),6.93(dd,J=8.5,2.5Hz,1H),6.81(d,J=2.5Hz,1H),4.43(td,J=10.7,2.8Hz,1H),4.12( dt,J=11.3,4.4Hz,1H),3.71(t,J=6.7Hz,2H),3.41–3.22(m,4H),3.22–2. 97(m,3H),2.67(t,J=6.7Hz,2H),2.08(d,J=6.1Hz,1H),2.03–1.90(m,1H).

[0628] LCMS(ESI):[M+H] + =331.39

[0629] Example 21: Synthesis of Compound B4

[0630] (S)-1-(7,7a,8,9,10,11-Hexahydro-6H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0631] Synthesis scheme:

[0632] Step 1: (S)-tert-Butyl 4-(3-fluoro-5-nitropyridin-2-yl)-3-(2-hydroxyethyl)piperazine-1-carboxylate (Compound B4-2)

[0633] Compound B4-1 (4.5 g, 25.5 mmol, 1.0 eq) and compound B1-1 (5.9 g, 25.5 mmol, 1.0 eq) were dissolved in dimethyl sulfoxide (50 mL), reacted at 110 ° C for 16 hours, washed with water, extracted with ethyl acetate, washed with saturated brine, concentrated under reduced pressure to obtain a crude product and purified by column chromatography to obtain a yellow solid compound B4-2 (9.4 g, 95.3%).

[0634] LC-MS(ESI):[M+H] + =371.35

[0635] Step 2: (S)-3-nitro-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepine-9-carboxylic acid tert-butyl ester (Compound B4-3)

[0636] Compound B4-2 (7.0 g, 18.9 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (100 mL). Sodium hydride (1.97 g, 49.2 mmol, 2.6 eq) was added to the reaction system at 0°C and allowed to react at room temperature for 2 hours. The reaction was quenched with ammonium chloride solution, extracted with dichloromethane, and concentrated to obtain the crude product, which was purified by column chromatography to afford compound B4-3 (5.0 g, 75.51%) as a brown solid.

[0637] LC-MS(ESI):[M+H] + =315.30

[0638] 1 H NMR (600MHz, DMSO-d6) δ8.73(d,J=2.4Hz,1H),7.73(d,J=2.4Hz,1H),4.38–4.34(m,1H),4.25–4.21(m,2H),3.99–3.9 7(m,1H),3.81–3.68(m,2H),3.58(s,1H),3.48(dd,J=13.7,6.0Hz,2H),2.17–2.10(m,1H),1.95(s,1H),1.42(s,9H).

[0639] Step 3: (S)-3-amino-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyridino[3,2-b][1,4]oxazepine-9-carboxylic acid tert-butyl ester (Compound B4-4)

[0640] Compound B4-3 (5.0 g, 14.3 mmol, 1.0 eq) was dissolved in methanol (50 mL), palladium / carbon (500 mg) was added, the hydrogen atmosphere was replaced, and the mixture was reacted at room temperature for 16 hours. Filtered through celite, the filtrate was dried to give a brown solid compound B4-4 (4.0 g, 87.49%).

[0641] LC-MS(ESI):[M+H] + =321.30

[0642] Step 4: (S)-3-((3-ethoxy-3-oxypropyl)amino)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyridino[3,2-b][1,4]oxazepine-9-carboxylic acid tert-butyl ester (B4-5)

[0643] Compound B4-4 (1.0 g, 3.1 mmol, 1.0 eq) was dissolved in ethyl acrylate (2 mL) and reacted overnight at 80° C. The crude product was concentrated under reduced pressure and purified by column chromatography to obtain compound B4-5 (140 mg, 10.67%) as a brown oil.

[0644] LC-MS(ESI):[M+H] + =421.35

[0645] Step 5: (S)-3-(2,4-dioxytetrahydropyrimidin-1(2H)-yl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepine-9-carboxylic acid tert-butyl ester (B4-6)

[0646] Compound B4-5 (100 mg, 0.24 mmol, 1.0 eq) was dissolved in tetrahydrofuran (2 mL), and triphosgene (35 mg, 0.12 mmol, 0.5 eq) and N,N-diisopropylethylamine (61 mg, 0.48 mmol, 2.0 eq) were added. The mixture was reacted at 20°C for 2 hours. Ammonia in methanol (2 mL) was added at 0°C, and the temperature was slowly raised to room temperature. The reaction was continued at 100°C overnight. The crude product was concentrated under reduced pressure and purified by column chromatography to afford compound B4-6 (12 mg, 12.09%) as a brown oil.

[0647] LC-MS(ESI):[M+H] + =418.40

[0648] Step 6: (S)-1-(7,7a,8,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (B4)

[0649] Compound B4-6 (12 mg, 0.03 mmol, 1.0 eq) was dissolved in dichloromethane (0.5 mL), trifluoroacetic acid (0.5 mL) was added, and the mixture was reacted at 20°C for 16 hours. The crude product was concentrated under reduced pressure and purified by HPLC to give compound B4 (2 mg, 21.92%) as a white solid.

[0650] LC-MS(ESI):[M+H] + =318.30

[0651] 1 H NMR (600MHz, DMSO-d6) δ10.43(s,1H),7.89(s,1H),7.18(s,1H),4.36–4.32(m,1H),4.23–4.19(m,1H),3.72(t,J=6.7Hz,2H),3.61–3.58(m,2H),3 .27–3.25(m,2H),3.06(d,J=12.1Hz,1H),2.99–2.93(m,2H),2.75(t,J=1 0.9Hz,1H),2.69(t,J=6.6Hz,2H),2.11–2.06(m,1H),2.01–1.92(m,1H).

[0652] Example 22: Synthesis of Compound B5

[0653] (R)-1-(7,7a,8,9,10,11-Hexahydro-6H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxirane-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0654] Synthesis scheme:

[0655] Step 1: (R)-4-(3-fluoro-5-nitropyridin-2-yl)-3-(2-hydroxyethyl)piperazine-1-carboxylic acid tert-butyl ester (Compound B5-2)

[0656] Compound 2-chloro-3-fluoro-5-nitropyridine (2 g, 11.33 mmol, 1 eq) was dissolved in dimethyl sulfoxide, and tert-butyl (R)-3-(2-hydroxyethyl)piperazine-1-carboxylate (2.61 g, 11.33 mmol, 1 eq) and N,N-diisopropylethylamine (4.39 g, 33.99 mmol, 3 eq) were added. The mixture was stirred overnight in an oil bath at 110°C. The reaction solution was diluted with ethyl acetate and extracted three times with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by normal phase column chromatography to obtain compound B5-2 (3.6 g, 85%) as a yellow solid.

[0657] 1 H NMR (600MHz, DMSO-d6) δ8.87(d,J=1.4Hz,1H),8.27(dd,J=13.8,2.3Hz,1H),4.72(s,1H),4.49(s,1H),4.22(d,J=13 .2Hz,1H),3.94(d,J=13.5Hz,2H),3.42(s,2H),3.18(d,J=5.3Hz,1H),3.15–2.85(m,2H),1.78(s,2H),1.43(s,9H).

[0658] LCMS(ESI):[M-tBu+H] + =315.28.

[0659] Step 2: (R)-3-nitro-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxirane-9-carboxylic acid tert-butyl ester (Compound B5-3)

[0660] Compound B5-2 (3.55 g, 9.85 mmol, 1 eq) was dissolved in N,N-dimethylformamide (30 mL), and sodium hydride (996 mg, 24.9 mmol, 2.6 eq) was added in batches at 0°C. The mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate and extracted three times with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product obtained was purified by normal phase column chromatography to obtain yellow solid compound B5-3 (2.25 g, 67.04%).

[0661] 1 H NMR(600MHz, DMSO-d6)δ8.73(d,J=2.2Hz,1H),7.73(d,J=2.3Hz,1H),4.39–4.32(m,1H),4.26–4.18(m,2H),4.03–2.9 8(m,1H),3.80–3.70(m,2H),3.65–3.55(m,1H),3.51–3.40(m,2H),2.17–2.09(m,1H),2.03–1.98(m,1H),1.43(s,9H).

[0662] LCMS(ESI):[M+H] + =351.49.

[0663] Step 3: tert-Butyl (R)-3-amino-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyridino[3,2-b][1,4]oxirane-9-carboxylate (Compound B5-4)

[0664] Compound B5-3 (2.22 g, 6.34 mmol, 1 eq) was dissolved in a mixture of methanol and dichloromethane (v / v = 2:1). Nickel chloride (1.64 g, 12.67 mmol, 2 eq) was added, followed by the addition of sodium borohydride (0.958 g, 25.34 mmol, 4 eq) in portions at 0°C. The mixture was allowed to react in an ice bath for 5 minutes. After completion of the reaction, the mixture was concentrated under reduced pressure. The resulting crude product was purified by normal-phase column chromatography to afford compound B5-4 (1.22 g, 61.10%) as a yellow solid.

[0665] 1 H NMR (600MHz, DMSO-d6) δ7.30(d,J=2.4Hz,1H),6.43(d,J=2.4Hz,1H),4.40–4.32(m,1H),4.12–4.07(m,1H),3.72–3.68(m,1H),3.64 –3.58(m,1H),3.25(dt,J=6.8,3.1Hz,1H),3.20–3.10(m,1H),3.10–2.95(m,3H),2.06–1.98(m,1H),1.82–1.76(m,1H),1.42(s,9H).

[0666] LCMS(ESI):[M+H] + =321.38.

[0667] Step 4: (R)-3-(2,4-dioxytetrahydropyrimidin-1(2H)-yl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxirane-9-carboxylic acid tert-butyl ester (Compound B5-5)

[0668] Under a nitrogen atmosphere, compound B5-4 (1.11 g, 3.46 mmol, 1 eq) was dissolved in toluene (10 mL). Acrylic acid (374.49 mg, 5.20 mmol, 1.5 eq) was added at room temperature. The reaction solution was moved to a 95°C oil bath and reacted for 13 hours. The reaction was stopped and allowed to cool to room temperature. Acetic acid (10 mL) and urea (1.04 g, 17.32 mmol, 1.5 eq) were added, respectively, and the reaction was continued at 100°C under a nitrogen atmosphere for 24 hours. After completion of the reaction, the product was quenched with aqueous sodium bicarbonate solution, diluted with ethyl acetate, and extracted three times with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by normal phase column chromatography to afford compound B5-5 (206 mg, 14.24%) as a yellow solid.

[0669] 1 H NMR (600MHz, DMSO-d6) δ10.38(s,1H),7.84(d,J=2.1Hz,1H),7.15(d,J=2.2Hz,1H),4.34–4.21(m,2H),3.71(t,J=6.7Hz,2H),3. 68–3.58(m,4H),3.47–3.38(m,1H),3.32–3.20(m,2H),2.69(t,J=6.7Hz,2H),2.13–2.04(m,1H),1.94–1.84(m,1H),1.43(s,9H).

[0670] LCMS(ESI):[M+H] + =418.49.

[0671] Step 5: (R)-1-(7,7a,8,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxirane-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound B5)

[0672] To a dichloromethane solution (5 mL) of compound B5-5 (128 mg, 306.61 μmol, 1.0 eq) was added a 1,4-dioxane solution (2 mL) of hydrogen chloride. After reacting at room temperature for 1 hour, the reaction solution was concentrated and lyophilized to give a white solid compound B5 (81.90 mg, 84.17%).

[0673] 1H NMR (600MHz, DMSO-d6) δ10.43 (s, 1H), 7.94 (d, J = 2.3Hz, 1H), 7.26 (d, J = 2. 2Hz,1H),4.42–4.35(m,1H),4.28–4.23(m,1H),3.79–3.72(m,3H),3.72–3 .66(m,1H),3.48–3.42(m,1H),3.32–3.27(m,1H),3.23–3.12(m,2H),2.99 –2.90(m,1H),2.70(t,J=6.7Hz,2H),2.22–2.14(m,1H),2.03–1.96(m,1H).

[0674] LCMS(ESI):[M+H] + =318.48.

[0675] Example 23: Synthesis of Compound B6

[0676] 1-(6-Oxo-1,2,3,4,4a,5,6,7-octahydrobenzo[b]pyrazino[1,2-d][1,4]diazepin-9-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0677] Synthesis scheme:

[0678] Step 1: tert-Butyl 4-(2,4-dinitrophenyl)-3-(2-methoxy-2-oxoethyl)piperazine-1-carboxylate (Compound B6-2)

[0679] B6-1 (5.0 g, 19.3 mmol, 1.0 eq) and 2,4-dinitrofluorobenzene (4.0 g, 21.5 mmol, 1.1 eq) were dissolved in dimethyl sulfoxide (50 mL), reacted at 100 ° C for 16 hours, washed with water, extracted with ethyl acetate, washed with saturated brine, concentrated under reduced pressure to obtain a crude product and purified by column chromatography to obtain a yellow solid compound B6-2 (7.2 g, 78.9%).

[0680] 1 H NMR(400MHz,Chloroform-d)δ8.72(d,J=2.7Hz,1H),8.29(dd,J=9.3,2.8Hz,1H),7.18(d,J=9.3Hz,1H),4. 33-4.01(m,3H),3.56(s,3H),3.52-3.44(m,1H),3.35(s,1H),3.09-3.02(m,2H),2.69(s,2H),1.50(s,9H).

[0681] LC-MS(ESI):[Mt-Bu+H] + =369.29

[0682] Step 2: 2-(4-(tert-Butyloxycarbonyl)-1-(2,4-dinitrophenyl)piperazin-2-yl)acetic acid (Compound B6-3)

[0683] Compound B6-2 (7.2 g, 16.9 mmol, 1.0 eq) was dissolved in 30 mL of tetrahydrofuran:methanol:water (2:2:1). Lithium hydroxide (2.2 g, 50.9 mmol, 3.0 eq) was added to the reaction system and allowed to react at room temperature for 2 hours. The solution was adjusted to pH 4-5 with 2M hydrochloric acid, washed with water, extracted with ethyl acetate, washed with saturated brine, and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography to afford compound B6-3 (2.3 g, 33.0%) as a brown solid.

[0684] LC-MS(ESI):[Mt-Bu+H] + =355.39

[0685] Step 3: 2-(4-(tert-Butyloxycarbonyl)-1-(2,4-diaminophenyl)piperazin-2-yl)acetic acid (Compound B6-4)

[0686] Compound B6-3 (1.2 g, 2.9 mmol, 1.0 eq) was dissolved in methanol (20 mL), palladium / carbon (300 mg) was added, the hydrogen atmosphere was replaced, and the mixture was reacted at room temperature for 2 hours. Filtered through celite, the filtrate was dried to give compound B6-4 (900 mg, 97.8%) as a brown solid.

[0687] LC-MS(ESI):[M+H] + =351.39

[0688] Step 4: tert-Butyl 9-amino-6-oxo-1,2,4a,5,6,7-hexahydrobenzo[b]pyrazino[1,2-d][1,4]diazepine-3(4H)-carboxylate (B6-5)

[0689] Compound B6-4 (900 mg, 2.6 mmol, 1.0 eq) was dissolved in dichloromethane (20 mL), and 1-hydroxybenzotriazole (500 mg, 3.7 mmol, 1.4 eq), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.4 g, 7.3 mmol, 2.8 eq), and N,N-diisopropylethylamine (920 mg, 7.3 mmol, 2.8 eq) were added. The mixture was reacted overnight at room temperature. The crude product was concentrated under reduced pressure and purified by column chromatography to afford compound B6-5 (720 mg, 84.3%) as a brown oil.

[0690] LC-MS(ESI):[M+H] + =333.39

[0691] Step 5: 3-((3-(tert-Butyloxycarbonyl)-6-oxo-1,2,3,4,4a,5,6,7-octahydrobenzo[b]pyrazino[1,2-d][1,4]diazepin-9-yl)amino)propanoic acid (B6-6)

[0692] Dissolve compound B6-5 (720 mg, 2.2 mmol, 1.0 eq) in toluene (20 mL), add acrylic acid (315 mg, 4.4 mmol, 2.0 eq), and react at 110°C for 16 hours or overnight. The resulting reaction solution does not require further treatment; once it cools to room temperature, it can be directly processed into the next step.

[0693] LC-MS(ESI):[M+H] + =404.49

[0694] Step 6: 9-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-6-oxo-1,2,4a,5,6,7-hexahydrobenzo[b]pyrazino[1,2-d][1,4]diazepine-3(4H)-carboxylic acid tert-butyl ester (B6-7)

[0695] To the reaction mixture obtained in the previous step, acetic acid (10 mL) and urea (1.3 g, 21.6 mmol, 10.0 eq) were added and reacted at 110°C for 16 hours or overnight. The mixture was concentrated under reduced pressure to obtain a crude product which was purified by column chromatography to afford compound B6-7 (350 mg, 37.7%) as a yellow solid.

[0696] LC-MS(ESI):[Mt-Bu+H] + =374.49

[0697] 1 H NMR (600MHz, DMSO-d6) δ10.35(s,1H),9.65(d,J=1.7Hz,1H),7.10(d,J=1.4Hz,2H),6.93(t,J=1.4Hz,1H),4.03–3.87(m,2H),3.75-3.7 1(m,2H),3.18-3.15(m,2H),3.09–2.95(m,2H),2.87(s,1H),2.70(t,J=6.7Hz,2H),2.59-2.55(m,1H),2.10–1.97(m,1H),1.43(s,9H).

[0698] Step 7: 1-(6-oxo-1,2,3,4,4a,5,6,7-octahydrobenzo[b]pyrazino[1,2-d][1,4]diazepin-9-yl)dihydropyrimidine-2,4(1H,3H)-dione (B6)

[0699] Compound B6-7 (350 mg, 0.81 mmol, 1.0 eq) was dissolved in dichloromethane (5 mL), and a solution of hydrochloric acid in dioxane (5 mL) was added. The mixture was reacted at room temperature for 1 hour. The crude product was filtered and slurried with methanol to give compound B6 (267 mg, 99.5%) as a yellow solid.

[0700] 1 H NMR (600MHz, DMSO-d6) δ10.37(s,1H),9.77(d,J=1.7Hz,1H),7.20–7.09(m,2H),6.95(d,J=2.4Hz,1H),3.79–3.68(m,2H),3.59–3.54 (m,1H),3.42-3.38(m,2H),3.31–3.23(m,2H),3.03(d,J=40.0Hz,2H),2.71(t,J=6.7Hz,2H),2.67-2.64(m,1H),2.08(d,J=12.0,1H).

[0701] LC-MS(ESI):[M+H] + =333.30

[0702] Example 24: Synthesis of Compound B7

[0703] (S)-1-(7-methyl-1,2,3,4,4a,5,6,7-octahydrobenzo[b]pyrazino[1,2-d][1,4]diazepin-9-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0704] Synthesis scheme

[0705] Step 1: (S)-tert-Butyl 4-(4-bromo-2-nitrophenyl)-3-(2-hydroxyethyl)piperazine-1-carboxylate (Compound B7-2)

[0706] Compound B1-1 (5.0 g, 21.71 mmol, 1.0 eq) was dissolved in dimethyl sulfoxide (30 mL). Compound B7-1 (5.25 g, 23.88 mmol, 1.5 eq) and N,N-diisopropylethylamine (11.3 g, 47.76 mmol, 4.0 eq) were added to the reaction system. The reaction solution was heated to 100°C and allowed to react at this temperature for 12 hours. After cooling to room temperature, the reaction system was concentrated under reduced pressure, water (30 mL) was added, and extraction was performed with ethyl acetate (30 mL x 3). The mixture was washed with saturated brine (30 mL), and the combined organic phases were dried over anhydrous sodium sulfate. The crude product obtained from the concentrated organic phases was purified by column chromatography to obtain compound B7-2 (5.61 g, 60.05%) as a yellow solid.

[0707] 1 H NMR (600MHz, DMSO-d6) δ8.04(d,J=2.3Hz,1H),7.75(dd,J=8.8,2.2Hz,1H),7.37(s,1H),4.44(t,J=4.8H z,1H),3.75–3.35(m,4H),3.33–3.28(m,2H),3.21–3.05(m,1H),2.82–2.72(m,1H),1.54–1.35(m,11H).

[0708] LCMS(ESI):[M-tBu+H] + =374.29.

[0709] Step 2: (S)-tert-Butyl 4-(4-bromo-2-nitrophenyl)-3-(2-((methylsulfonyl)oxy)ethyl)piperazine-1-carboxylate (B7-3)

[0710] Compound B7-2 (6.55 g, 15.22 mmol, 1.0 eq) and N,N-diisopropylethylamine (5.9 g, 45.67 mmol, 3.0 eq) were dissolved in dichloromethane (30 mL). The temperature was cooled to 0°C and methylsulfonyl chloride (5.23 g, 45.67 mmol, 3.0 eq) was added. After the addition was complete, the mixture was allowed to return to room temperature and react for 2 hours. The reaction mixture was concentrated to obtain a crude product which was purified by column chromatography to afford compound B7-3 (4.63 g, 59.83%) as a yellow solid.

[0711] 1H NMR (600MHz, DMSO-d6) δ8.07(d,J=2.3Hz,1H),7.77(dd,J=8.8,2.4Hz,1H),7.43(d,J=7.4Hz,1H),4.23–4.08( m,2H),3.65–3.40(m,4H),3.30–3.10(m,2H),3.07(s,3H),2.80–2.72(m,1H),1.79–1.63(m,2H),1.42(s,9H).

[0712] LCMS(ESI):[M-tBu+H] + =452.19.

[0713] Step 3: (S)-9-bromo-1,2,4a,5,6,7-hexahydrobenzo[b]pyrazino[1,2-d][1,4]diazepine-3(4H)-carboxylic acid tert-butyl ester (B7-4)

[0714] Compound B7-3 (4.50 g, 8.85 mmol, 1.0 eq) and nickel chloride (2.29 g, 17.70 mmol, 2.0 eq) were dissolved in methanol / dichloromethane (40 mL / 20 mL). The mixture was cooled to 0°C and sodium borohydride (1.34 g, 35.41 mmol, 4.0 eq) was added portionwise. The reaction was allowed to proceed at room temperature under nitrogen for 12 hours. The reaction system was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography to obtain compound B7-4 (2.5 g, 73.88%) as a white solid.

[0715] 1 H NMR(600MHz,DMSO-d6)δ6.73–6.68(m,2H),6.65(dd,J=8.4,2.3Hz,1H),5.64(s,1H),3.66(d,J=12.8Hz,1H), 3.55–3.38(m,2H),3.27–2.91(m,5H),2.90–2.80(m,1H),1.92–1.83(m,1H),1.70–1.62(m,1H),1.41(s,9H).

[0716] LCMS(ESI):[M-tBu+H] + =326.38.

[0717] Step 4: (S)-9-bromo-7-methyl-1,2,4a,5,6,7-hexahydrobenzo[b]pyrazino[1,2-d][1,4]diazepine-3(4H)-carboxylic acid tert-butyl ester (Compound B7-5)

[0718] B7-4 (2.0 g, 5.23 mmol, 1.0 eq) and paraformaldehyde (4.71 g, 156.9 mmol, 30.0 eq) were dissolved in methanol (20 mL). Acetic acid (3.14 g, 52.31 mmol, 10.0 eq) was added dropwise to the mixture. The mixture was stirred at room temperature for 3 hours. Sodium cyanoborohydride (986.26 mg, 15.69 mmol, 3.0 eq) was then added to the reaction mixture, followed by reaction at room temperature for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography to obtain compound B7-5 (1.7 g, 81.99%) as a white solid.

[0719] 1 H NMR (600MHz, DMSO-d6) δ6.89(dd,J=8.3,2.3Hz,1H),6.77(d,J=8.4Hz,1H),6.75(d,J=2.3Hz,1H),3.93–3.79(m,1H),3.79–3.61(m,1H),3.57–3 .50(m,1H),3.12–2.83(m,4H),2.80(dt,J=11.7,4.0Hz,1H),2.75(s,3H ),2.69–2.60(m,1H),1.81–1.71(m,1H),1.68–1.57(m,1H),1.42(s,9H).

[0720] LCMS(ESI):[M+H] + =396.39.

[0721] Step 5: (S)-9-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-7-methyl-1,2,4a,5,6,7-hexahydrobenzo[b]pyrazino[1,2-d][1,4]diazepine-3(4H)-carboxylic acid tert-butyl ester (Compound B7-6)

[0722] B7-5 (2.6 g, 6.56 mmol, 1.0 eq) and dihydropyrimidine-2,4(1H,3H)-dione (898.2 mg, 7.87 mmol, 1.2 eq) were dissolved in 1,4-dioxane (25 mL). EPhos Pd G4 (603 mg, 0.656 mmol, 0.1 eq) and cesium carbonate (4.27 g, 13.12 g, 2 eq) were added to the system and reacted in an oil bath at 100°C overnight. The reaction system was concentrated under reduced pressure, and the crude product was purified by column chromatography to obtain compound B7-6 (1.06 g, 37.6%) as a white solid.

[0723] 1H NMR (600MHz, CDCl3) δ7.61 (s, 1H), 6.89 (d, J = 8.3 Hz, 1H), 6.77 (dd, J = 8.3, 1 .4Hz,1H),6.67(s,1H),4.15–3.95(m,1H),3.95–3.71(m,3H),3.66(t,J=11. 5Hz,1H),3.23–2.98(m,4H),2.87(s,3H),2.84(t,J=6.7Hz,2H),2.81–2.75( m,1H),1.98(t,J=13.5Hz,1H),1.68(s,1H),1.66–1.60(m,1H),1.50(s,9H).

[0724] LCMS(ESI):[M+H] + =430.49.

[0725] Step 6: (S)-1-(7-methyl-1,2,3,4,4a,5,6,7-octahydrobenzo[b]pyrazino[1,2-d][1,4]diazepin-9-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound B7)

[0726] Dissolve B7-6 (1.1 g, 2.56 mmol, 1.0 eq) in dichloromethane (10 mL). Add hydrogen chloride in 1,4-dioxane (10 mL) and allow to react at room temperature for 6 hours. Filter the reaction mixture, and vacuum dry the resulting filter cake to yield compound B7 (867 mg, 102.8%) as a white solid.

[0727] 1 H NMR(600MHz,MeOD)δ7.71(d,J=17.1Hz,1H),7.60(dd,J=8.5,2.0Hz,1H),7.47–7.40(m,1H),3.99–3.91(m,2H),3.6 4–3.56(m,2H),3.55–3.45(m,2H),3.41–3.34(m,4H),3.33–3.20(m,4H),2.87(t,J=6.7Hz,2H),2.02–1.82(m,2H).

[0728] LCMS(ESI):[M+H] + =330.48.

[0729] Example 25: Synthesis of Compound B8

[0730] (R)-1-(1,2,3,4,4a,5-Hexahydro-7H-benzo[e]pyrazino[2,1-c][1,4]oxazepin-9-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0731] Synthesis scheme

[0732] Step 1: (R)-tert-Butyl 3-(hydroxymethyl)-4-(2-(hydroxymethyl)-4-nitrophenyl)piperazine-1-carboxylate (Compound B8-2)

[0733] Compound B8-1 (2 g, 5.06 mmol, 1.0 eq.) was dissolved in methanol (40 mL). The reaction system was cooled to 0°C and sodium borohydride (957 mg, 25.29 mmol, 5.0 eq.) was added. The reaction was allowed to react overnight at room temperature. After concentration under reduced pressure, water was added and the mixture was extracted three times with ethyl acetate. The mixture was washed with saturated brine, and the combined organic phases were dried over anhydrous sodium sulfate. The organic phases were concentrated to yield the crude product, Compound B8-2 (1.76 g, 94.71%), as a white solid.

[0734] LCMS(ESI):[M+H] + =368.30.

[0735] Step 2: (R)-9-nitro-1,2,3,4,4,4a,5-hexahydro-7H-benzo[e]pyrazino[2,1-c][1,4]oxazepine (Compound B8-3)

[0736] Compound B8-2 (1.76 g, 4.79 mmol, 1.0 eq) and (+)-10-camphorsulfonic acid (2.23 g, 9.58 mmol, 2.0 eq) were dissolved in toluene (30 mL) and reacted at 100°C under nitrogen for 5 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product B8-3, which was used directly in the next step.

[0737] LCMS(ESI):[M+H] + =250.20.

[0738] Step 3: (R)-9-nitro-1,2,4a,5-tetrahydro-7H-benzo[e]pyrazino[2,1-c][1,4]oxazepine-3(4H)-carboxylic acid tert-butyl ester (Compound B8-4)

[0739] Compound B8-3 (1.2 g, 4.81 mmol, 1.0 eq) was dissolved in dichloromethane (15 mL). The reaction system was cooled to 0°C and triethylamine (1.46 g, 14.44 mmol, 3.0 eq) and di-tert-butyl dicarbonate (1.58 g, 7.22 mmol, 1.5 eq) were added. The reaction was allowed to react overnight at room temperature. The reaction system was concentrated under reduced pressure, and the resulting crude product was purified by column chromatography to obtain compound B8-4 (1.5 g, 89.18%) as a yellow oil.

[0740] 1 H NMR (600MHz, DMSO-d6) δ8.15–8.02(m,2H),7.05(d,J=9.0Hz,1H),4.91(d,J=13.3Hz,1H),4.64(d,J=13.3Hz ,1H),3.82(d,J=9.9Hz,1H),3.74–3.61(m,4H),3.50(dt,J=8.4,4.0Hz,2H),3.43–3.38(m,2H),1.43(s,9H).

[0741] LCMS(ESI):[M+H] + =350.35.

[0742] Step 4: (R)-9-amino-1,2,4a,5-tetrahydro-7H-benzo[e]pyrazino[2,1-c][1,4]oxazepine-3(4H)-carboxylic acid tert-butyl ester (Compound B8-5)

[0743] Compound B8-4 (1.5 g, 4.29 mmol, 1.0 eq) was dissolved in methanol (20 mL), and palladium / carbon (300 mg) was added. After hydrogen substitution three times, the reaction was allowed to proceed at room temperature for 12 hours. The reaction system was filtered, the filter cake was washed with methanol, and the resulting filtrate was concentrated under reduced pressure to obtain the crude product, which was then purified by reverse-phase column chromatography to afford compound B8-5 (620 mg, 45.21%) as a white solid.

[0744] LCMS(ESI):[M+H] + =320.36.

[0745] Step 5: (R)-9-(2,4-dioxytetrahydropyrimidin-1(2H)-yl)-1,2,4-α,5-tetrahydro-7H-benzo[e]pyrazino[2,1-c][1,4]oxirane-3(4H)-carboxylic acid tert-butyl ester (Compound B8-6)

[0746] Compound B8-5 (100 mg, 0.31 mmol, 1.0 eq) and acrylic acid (34 mg, 0.47 mmol, 1.5 eq) were dissolved in toluene (4 mL). The mixture was reacted at 90°C for 16 hours. Urea (94 mg, 1.57 mmol, 5.0 eq) and acetic acid (2 mL) were added to the reaction system and reacted at 110°C for 12 hours. The reaction solution was concentrated under reduced pressure, and the resulting crude product was purified by column chromatography to obtain compound B8-6 (40 mg, 30.68%) as a yellow solid.

[0747] Step 7: (R)-1-(1,2,3,4,4a,5-hexahydro-7H-benzo[e]pyrazino[2,1-c][1,4]oxazepin-9-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound B8)

[0748] Compound B8-6 (40 mg, 0.10 mmol, 1.0 eq) was dissolved in dichloromethane (1 mL). Trifluoroacetic acid (1 mL) was added to the mixture and allowed to react at room temperature for 12 hours. The reaction system was concentrated under reduced pressure to obtain the crude product, which was purified by HPLC to yield compound B8 (5 mg, 16.46%) as a white solid.

[0749] 1 H NMR (600MHz, DMSO-d6) δ10.36 (s, 1H), 7.29 (dd, J = 8.5, 2.6 Hz, 1H), 7.22 (d, J = 2. 5Hz,1H),7.01(d,J=8.5Hz,1H),4.87(d,J=11.6Hz,1H),4.59(d,J=11.6Hz,1H),3 .74(t,J=6.7Hz,2H),3.66(dd,J=13.5,3.1Hz,1H),3.59(dd,J=13.5,3.0Hz,1H) ,3.42–3.38(m,1H),3.31–3.21(m,3H),3.17–3.02(m,3H),2.70(t,J=6.7Hz,2H).

[0750] LCMS(ESI):[M+H] + =317.30

[0751] Example 26: Synthesis of Compound B9

[0752] (S)-1-(1,2,3,4,4a,5-Hexahydro-7H-benzo[e]pyrazino[2,1-c][1,4]oxepin-9-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0753] Synthesis scheme

[0754] Step 1: 4-Bromo-5-hydroxyisobenzofuran-1(3H)-one (Compound B9-2)

[0755] Compound B9-1 (10.0 g, 46.24 mmol, 1.0 eq) was dissolved in dimethyl sulfoxide (100 mL), and methyl 2-fluoro-5-nitrobenzoate (9.21 g, 46.24 mmol, 1.0 eq) was added to the reaction system. The reaction solution was heated to 100°C and reacted at this temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and water (50 mL) was added to the system. The solution was extracted with ethyl acetate (100 mL x 3), washed with saturated brine (100 mL), and the organic phases were combined and dried over anhydrous sodium sulfate. The crude product obtained from the concentrated organic phase was purified by reverse phase column chromatography to obtain compound B9-2 (12.0 g, 71.62%) as a yellow solid.

[0756] LCMS(ESI):[M+H] + =364.37.

[0757] Step 2: (S)-tert-Butyl 3-(hydroxymethyl)-4-(2-(hydroxymethyl)-4-nitrophenyl)piperazine-1-carboxylate (Compound B9-3)

[0758] Compound B9-2 (12.0 g, 33.02 mmol, 1.0 eq) was added to methanol (120 ml). The temperature was lowered to 0°C, and sodium borohydride (6.25 g, 165 mmol) was slowly added. After the addition was complete, the mixture was allowed to return to room temperature and allowed to react for 12 hours. The reaction solution was concentrated under reduced pressure, and water (50 mL) was added. The mixture was extracted with ethyl acetate (100 mL x 3), washed with saturated brine (100 mL), and the organic phases were combined and dried over anhydrous sodium sulfate. The crude product obtained from the concentrated organic phase was purified by reverse phase column chromatography to yield compound B9-3 (8.0 g, 65.49%) as a yellow solid.

[0759] LCMS(ESI):[M+H] + =368.40.

[0760] Step 3: (S)-9-nitro-1,2,3,4,4,4a,5-hexahydro-7H-benzo[e]pyrazino[2,1-c][1,4]oxazepine (Compound B9-4)

[0761] Compound B9-3 (2.0 g, 5.44 mmol, 1.0 eq) and camphorsulfonic acid (2.53 g, 10.89 mmol, 2 eq) were dissolved in toluene (20 mL) and reacted at 100°C under nitrogen for 12 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 (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 crude product obtained from the concentrated organic phases was purified by column chromatography to obtain a crude yellow solid compound B9-4 (3.50 g).

[0762] LCMS(ESI):[M+H] + =250.27.

[0763] Step 4: (S)-9-nitro-1,2,4a,5-tetrahydro-7H-benzo[e]pyrazino[2,1-c][1,4]oxirane-3(4H)-carboxylic acid tert-butyl ester (Compound B9-5)

[0764] Compound B9-4 (3.50 g, 14.05 mmol, 1.0 eq) was dissolved in dichloromethane (35 mL). The reaction system was cooled to 0°C and N,N-diisopropylethylamine (4 mL) and di-tert-butyl dicarbonate (4.59 g, 21.05 mmol, 1.5 eq) were added. After the addition was complete, the system was returned to room temperature and reacted for 12 hours. Saturated aqueous ammonium chloride (50 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (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 resulting crude product was concentrated and purified by column chromatography to yield compound B9-5 (4.5 g, 91.83%) as a yellow oil.

[0765] LCMS (ESI) [M+H] + =350.39.

[0766] Step 5: (S)-9-amino-1,2,4a,5-tetrahydro-7H-benzo[e]pyrazino[2,1-c][1,4]oxirane-3(4H)-carboxylic acid tert-butyl ester (Compound B9-6)

[0767] Compound B9-5 (4.5 g, 12.89 mmol, 1.0 eq) was dissolved in methanol (50 mL) and 10% palladium on carbon (900 mg) was added. The mixture was reacted under a hydrogen atmosphere at room temperature for 12 hours. The reaction system was filtered and the filtrate was concentrated to obtain a crude yellow solid compound B9-6 (5 g).

[0768] LCMS (ESI) [M+H] + =320.41.

[0769] Step 6: (S)-9-(2,4-dioxytetrahydropyrimidin-1(2H)-yl)-1,2,4-α,5-tetrahydro-7H-benzo[e]pyrazino[2,1-c][1,4]oxirane-3(4H)-carboxylic acid tert-butyl ester (Compound B9-7)

[0770] B9-6 (5.0 g, 15.67 mmol, 1.0 eq) was dissolved in toluene (30 mL). Acrylic acid (1.35 g, 18.80 mmol, 1.2 eq) was added to the reaction system. The reaction system was heated to 90°C and allowed to react for 12 hours. Urea (4.7 g, 78.35 mmol, 5.0 eq) and acetic acid (30 mL) were then added. The reaction was continued at 120°C for 12 hours, and the system was returned to room temperature. Saturated aqueous sodium bicarbonate was added to the reaction system to adjust the pH to 8, and the mixture was extracted with ethyl acetate (3 times with 50 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The crude product obtained by concentration of the organic phase was purified by column chromatography to obtain compound B9-7 (3 g, 46.1%) as a white solid.

[0771] LCMS (ESI) [M+H] + =417.48.

[0772] Step 7: (S)-1-(1,2,3,4,4a,5-hexahydro-7H-benzo[e]pyrazino[2,1-c][1,4]oxepin-9-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound B9)

[0773] Compound B9-7 (3 g, 7.21 mmol, 1.0 eq) was dissolved in dichloromethane (30 mL), and trifluoroacetic acid (10 mL) was added to the mixture. The reaction was allowed to react at room temperature for 2 hours. The mixture was concentrated under reduced pressure, and the resulting crude product was purified by reverse-phase column chromatography to afford Compound B9 (2 g, 87.79%) as a white solid.

[0774] 1H NMR (600MHz, DMSO) δ10.37(s,1H),7.31(dd,J=8.5,2.5Hz,1H),7.24(d,J=2.4Hz,1 H),7.02(d,J=8.5Hz,1H),4.90(d,J=11.5Hz,1H),4.59(d,J=11.5Hz,2H),3.74(t, J=6.7Hz,2H),3.67(dd,J=13.5,3.1Hz,1H),3.58(dd,J=13.5,2.6Hz,1H),3.45–3. 27(m,4H),3.24–3.11(m,2H),3.07(dd,J=10.6,2.5Hz,1H),2.70(t,J=6.7Hz,2H).

[0775] LCMS (ESI) [M+H] + =317.36

[0776] Example 27: Synthesis of Compound B10

[0777] 1-(5-oxo-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]-8-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0778] Synthesis scheme

[0779] Step 1: (R)-1-(4-bromo-2-nitrophenyl)-4-(tert-butyloxycarbonyl)piperazine-2-carboxylic acid (Compound B10-1)

[0780] Compound B7-1 (1 g, 4.55 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (10 mL). 1-tert-Butyl piperazine-1,3-dicarboxylate (1.05 g, 4.55 mmol, 1.0 eq) and cesium carbonate (2.81 g, 8.64 mmol, 1.9 eq) were added to the reaction system. The reaction solution was heated to 60°C and allowed to react at this temperature for 12 hours. The reaction system was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The mixture was washed with saturated brine, and the combined organic phases were dried over anhydrous sodium sulfate. The organic phases were concentrated to obtain Compound B10-1 (1.85 g, 94.59%) as a yellow oil. The crude product was directly carried on to the next step without further purification.

[0781] LCMS(ESI):[M-Boc+H] + =332.19.

[0782] Step 2: (R)-8-bromo-5-oxo-1,2,4,4a,5,6-hexahydro-3H-pyrazino[1,2-a]quinoxaline-3-carboxylic acid tert-butyl ester (Compound B10-2)

[0783] Compound B10-1 (1.55 g, 3.60 mmol, 1.0 eq) was dissolved in acetic acid (16 mL), and iron powder (1.01 g, 18.01 mmol, 5.0 eq) was added to the reaction system. The reaction solution was heated to 60°C and allowed to react at this temperature for 1 hour. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. Water was added to the resulting system, and the mixture was extracted with ethyl acetate. The mixture was washed with saturated brine, and the organic phases were combined and dried over anhydrous sodium sulfate. The crude product obtained from the concentrated organic phase was purified by column chromatography to obtain compound B10-2 (732 mg, 53.04%) as a brown solid.

[0784] 1 H NMR(600MHz,Chloroform-d)δ8.28(s,1H),7.14(d,J=8.6,2.2Hz,1H),6.93(d,J=2.2Hz,1H),6. 67(d,J=8.7Hz,1H),4.63(s,1H),4.28(s,1H),3.62–3.45(m,2H),3.12–2.69(m,3H).1.42(s,9H)

[0785] LCMS(ESI):[M-Boc+H] + =284.28.

[0786] Step 3: 8-(2,4-dioxahydropyridin-1(2H)-yl)-5-oxo-1,2,4,4a,5,6-hexahydro-3D-pyrazino[1,2-a]-thioline-3-carboxylic acid tert-butyl ester (Compound B10-3)

[0787] Compound B10-2 (100 mg, 0.36 mmol, 1.0 eq) was dissolved in 1,4-dioxane (2 mL), and dihydropyrimidine-2,4(1H,3H)-dione (90 mg, 0.78 mmol, 3.0 eq), (methanesulfonic acid {biscyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine} (2'-methylamino-1,1'-biphenyl-2-yl) palladium (II) ( The reaction mixture was stirred for 12 hours at 100°C under nitrogen. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain a solid, which was then added to water. The solid was extracted with ethyl acetate and washed with saturated brine. The combined organic phases were dried over anhydrous sodium sulfate. The crude product obtained from the concentrated organic phases was purified by column chromatography to yield Compound B10-3 (70 mg, 64.41%) as a white solid.

[0788] 1 H NMR (400MHz, DMSO-d6) δ10.71(s,1H),10.32(s,1H),6.92–6.83(m,2H),6.81(d,J=2.0Hz,1H),4.34(d,J=13.2Hz,1H),4.03(d,J=7.2Hz ,1H),3.69(t,J=6.7Hz,2H),3.20(td,J=6.8,2.6Hz,2H),2.89(s,2H),2.58(td,J=12.2,3.6Hz,1H),2.44(t,J=6.8Hz,2H),1.43(s,9H).

[0789] LCMS(ESI):[M-Boc+H] + =316.28.

[0790] Step 4: 1-(5-oxo-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]-8-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound B10)

[0791] Compound B10-3 (65 mg, 0.156 mmol, 1.0 eq) was dissolved in dichloromethane (1.5 mL) and trifluoroacetic acid (0.5 mL) was added, allowing the mixture to react at room temperature for 12 hours. The resulting reaction mixture was concentrated under reduced pressure, and the resulting crude product was purified by reverse-phase column chromatography and lyophilized to afford compound B10 (20.0 mg, 40.54%) as a white solid.

[0792] 1H NMR (400MHz, DMSO-d6) δ10.88(s,1H),10.34(s,1H),6.92(d,J=1.5Hz,2H),6.86(d,J=1.5Hz,1H),3.90–3.76( m,2H),3.70(t,J=6.7Hz,3H),3.16–3.09(m,2H),2.96–2.82(m,1H),2.69(t,J=6.7Hz,2H),1.27–1.21(m,2H).

[0793] LCMS(ESI):[M+H] + =316.16.

[0794] Example 28: Synthesis of Compound B11

[0795] 1-(6-methyl-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoxalin-8-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0796] Synthesis scheme

[0797] Step 1: (R)-8-bromo-6-methyl-5-oxo-1,2,4,4a,5,6-hexahydro-3H-pyrazino[1,2-a]quinoxaline-3-carboxylic acid tert-butyl ester (Compound B11-1)

[0798] Compound B10-2 (3 g, 7.85 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (30 mL). Sodium hydride (470.8 mg, 11.77 mmol, 1.5 eq) was added at 0°C under nitrogen. After stirring for 30 minutes and returning to room temperature, iodomethane (1.67 g, 11.77 mmol, 1.5 eq) was added dropwise. After completion of the addition, the mixture was reacted at room temperature for 2 hours. Saturated aqueous ammonium chloride was added to the reaction system, and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic phases were combined and dried over anhydrous sodium sulfate. The crude product obtained by concentration of the organic phase was purified by column chromatography to obtain Compound B11-1 (2.96 g, 95.17%) as a yellow solid.

[0799] 1H NMR (400MHz, DMSO-d6) δ7.24–7.17(m,2H),6.85(d,J=8.6Hz,1H),4.36(d,J=13.1Hz,1H),4.03(d,J=7.2,4.1H z,1H),3.68–3.56(m,2H),3.47(dd,J=10.9,4.0Hz,3H),2.90(s,2H),2.58(d,J=12.1,3.7Hz,1H),1.42(s,9H).

[0800] LCMS(ESI):[M-Boc+H] + =296.18.

[0801] Step 2: (S)-8-bromo-6-methyl-1,2,4,4a,5,6-hexahydro-3H-pyrazino[1,2-a]quinoxaline-3-carboxylic acid tert-butyl ester (Compound B11-2)

[0802] Compound B11-1 (2.96 g, 7.47 mmol, 1.0 eq) was dissolved in tetrahydrofuran (30 mL), and borane dimethyl sulfide (1.70 g, 22.41 mmol, 3.0 eq) was added. The reaction system was heated to 50°C and reacted for 20 hours. After cooling to room temperature, the reaction system was poured into water and stirred for 30 minutes. The mixture was extracted with ethyl acetate, washed with saturated brine, and the combined organic phases were dried over anhydrous sodium sulfate. The crude product obtained by concentration of the organic phase was purified by reverse-phase column chromatography to obtain compound B11-2 (2.68 g, 93.85%) as a white solid.

[0803] 1 H NMR (400MHz, DMSO-d6) δ6.71–6.49(m,3H),3.96(d,J=14.7Hz,2H),3.68(d,J=12.5Hz,1H),3.29(d,J=11. 1,3.2Hz,1H),3.08–2.83(m,3H),2.78(s,3H),2.54(d,J=3.4Hz,1H),2.48(d,J=3.5Hz,1H),1.41(s,9H).

[0804] LCMS(ESI):[M+H] + =383.39.

[0805] Step 3: 8-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-6-methyl-1,2,4,4a,5,6-hexahydro-3H-pyrazino[1,2-a]quinoxaline-3-carboxylic acid tert-butyl ester (Compound B11-3)

[0806] Compound B11-2 (1 g, 2.62 mmol, 1.0 eq) was dissolved in 1,4-dioxane (15 mL), and dihydropyrimidine-2,4(1H,3H)-dione (895 mg, 7.85 mmol, 3.0 eq), (methanesulfonic acid {biscyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine} (2'-methylamino-1,1'-biphenyl-2-yl) palladium(II) (1 The reaction mixture was stirred for 12 hours at 100°C under nitrogen atmosphere. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain a solid, which was then added to water and extracted with ethyl acetate. The solid was washed with saturated brine, and the combined organic phases were dried over anhydrous sodium sulfate. The crude product obtained from the concentrated organic phases was purified by column chromatography to yield Compound B11-3 (300 mg, 27.60%) as a white solid.

[0807] 1 H NMR (400MHz, DMSO-d6) δ10.33(s,1H),7.07(d,J=8.1Hz,1H),6.91–6.68(m,2H),3.73(t,J=6.6Hz,4H),3.14(s, 2H),2.69(d,J=17.7,6.7Hz,4H),1.79(t,J=6.7Hz,2H),1.68(d,J=13.6Hz,2H),1.57–1.47(m,2H),1.40(s,9H).

[0808] LCMS(ESI):[M-Boc+H] + =316.90.

[0809] Step 4: 1-(6-methyl-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoxaline-8-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound B11)

[0810] Compound B11-3 (300 mg, 0.72 mmol, 1.0 eq) was dissolved in dichloromethane (1.5 mL), and dioxane hydrochloride solution (2 mL) was added and reacted at room temperature for 12 hours. The reaction solution was filtered, and the filter cake was slurried with n-hexane and filtered to obtain compound B11 (127 mg, 44.03%) as a white solid.

[0811] 1H NMR(400MHz,DMSO-d6)δ10.33(s,1H),7.07(d,J=8.1Hz,1H),6.68–6.91(m,2H),3.73(t,J=6.6Hz,4H),3 .14(s,2H),2.69(d,J=17.7,6.7Hz,4H),1.79(t,J=6.7Hz,2H),1.68(d,J=13.6Hz,2H),1.57–1.47(m,2H)

[0812] LCMS(ESI):[M+H] + =316.40.

[0813] Example 29: Synthesis of Compound B12

[0814] (S)-1-(3-Acetyl-10-methoxy-2,3,4,4a,5,6-hexahydro-1H-benzo[b]pyrazino[1,2-d][1,4]oxiran-9-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0815] Synthesis scheme

[0816] Step 1: (S)-4-(2-fluoro-5-methoxy-4-nitrophenyl)-3-(2-hydroxyethyl)piperazine-1-carboxylic acid tert-butyl ester (Compound B12-2)

[0817] Compound B12-1 (328 mg, 1.74 mmol, 1.0 eq) was dissolved in dimethyl sulfoxide (2 mL), and compound B1-1 (400 mg, 1.74 mmol, 1.0 eq) was added to the reaction system. The reaction solution was heated to 120°C and allowed to react at this temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and water (50 mL) was added to the system. The mixture was extracted with ethyl acetate (100 mL*3 times), washed with saturated brine (100 mL), and the organic phases were combined and dried over anhydrous sodium sulfate. The crude product obtained from the concentrated organic phase was purified by reverse phase column chromatography to obtain compound B12-2 (289 mg, 41.66%) as a yellow solid.

[0818] LCMS(ESI):[M+H] + =400.42.

[0819] Step 2: (S)-10-methoxy-9-nitro-1,2,4,4a,5,6-hexahydro-3H-benzo[b]pyrazino[1,2-d][1,4]oxirane-3-carboxylic acid tert-butyl ester (Compound B12-3)

[0820] Compound B12-2 (249 mg, 0.623 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (5 mL). The temperature was lowered to 0°C, and sodium hydride (44.88 mg, 1.87 mmol, 3 eq) was added. The reaction mixture was heated to 120°C and allowed to react for 12 hours. The reaction mixture was concentrated under reduced pressure, and water (50 mL) was added. The mixture was extracted with ethyl acetate (100 mL x 3), washed with saturated brine (100 mL), and the organic phases were combined and dried over anhydrous sodium sulfate. The crude product obtained from the concentrated organic phase was purified by reverse phase column chromatography to yield Compound B12-3 (120 mg, 50.73%) as a yellow solid.

[0821] LCMS(ESI):[M+H] + =380.41.

[0822] Step 3: (S)-9-amino-10-methoxy-1,2,4,4a,5,6-hexahydro-3H-benzo[b]pyrazino[1,2-d][1,4]oxirane-3-carboxylic acid tert-butyl ester (Compound B12-4)

[0823] Compound B12-3 (120 mg, 0.316 mmol, 1.0 eq) was dissolved in methanol (5 mL) and 10% palladium on carbon (24 mg) was added. The mixture was reacted under a hydrogen atmosphere at room temperature for 12 hours. The reaction system was filtered and the filtrate was concentrated to obtain a crude gray oil, compound B12-4 (136 mg).

[0824] LCMS(ESI):[M+H] + =350.43.

[0825] Step 4: (S)-1-(3-acetyl-10-methoxy-2,3,4,4a,5,6-hexahydro-1H-benzo[b]pyrazino[1,2-d][1,4]oxirane-9-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound B12)

[0826] B12-4 (110 mg, 0.315 mmol, 1.0 eq) was dissolved in toluene (5 mL). Acrylic acid (27.23 mg, 0.378 mmol, 1.2 eq) was added to the reaction system. The reaction system was heated to 90°C and allowed to react for 12 hours. Urea (78.37 mg, 1.30 mmol, 5.0 eq) and acetic acid (5 mL) were then added. After reacting at 120°C for 12 hours, the system was returned to room temperature. Saturated aqueous sodium bicarbonate was added to the reaction system to adjust the pH to 8, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. The crude product obtained by concentration of the organic phase was purified by column chromatography to obtain compound B12 (20 mg, 16.4%) as a white solid.

[0827] 1 H NMR (400MHz, DMSO) δ10.23(s,1H),6.69(s,1H),6.63(d,J=1.2Hz,1H),4.18-4.05(m,3H),3.74(t,J=5.7Hz,3H) ,3.63(dd,J=15.8,6.6Hz,2H),3.50(t,J=6.7Hz,3H),3.30–3.24(m,2H),2.68–2.58(m,2H),2.07–1.86(m,6H).

[0828] LCMS (ESI) [M+H] + =389.42.

[0829] Example 30: Synthesis of Compound B13

[0830] (S)-1-(10-Fluoro-2,3,4,4a,5,6-hexahydro-1H-benzo[b]pyrazino[1,2-d][1,4]oxiran-9-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0831] Synthesis scheme

[0832] Step 1: (S)-tert-Butyl 3-(2-(2,4-difluoro-5-nitrophenoxy)ethyl)piperazine-1-carboxylate (Compound B13-2)

[0833] Compound B13-1 (5.00 g, 21.71 mmol, 1.0 eq), compound B1-1 (4.94 g, 28.22 mmol, 1.3 eq), and triphenylphosphine (11.39 g, 43.42 mmol, 2.0 eq) were dissolved in tetrahydrofuran (50 mL) under nitrogen. The temperature was lowered to 0°C, and diethyl azodicarboxylate (11.34 g, 65.13 mmol, 3.0 eq) was slowly added to the reaction solution. The system was warmed to room temperature and allowed to react overnight. Saturated aqueous ammonium chloride (200 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (250 mL x 3). The mixture was washed with saturated brine (250 mL), and the combined organic phases were dried over anhydrous sodium sulfate. The crude product obtained by concentration of the organic phase was purified by column chromatography to obtain compound B13-2 (2.70 g, 32.10%) as a light yellow solid.

[0834] LCMS(ESI):[M+H] + =388.49.

[0835] Step 2: (S)-10-Fluoro-9-nitro-1,2,4,4a,5,6-hexahydro-3H-benzo[b]pyrazino[1,2-d][1,4]oxirane-3-carboxylic acid tert-butyl ester (Compound B13-3)

[0836] Compound B13-2 (2.70 g, 6.97 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (30 mL). Potassium carbonate (1.06 g, 7.67 mmol, 1.1 eq) was added to the reaction mixture and allowed to react overnight at room temperature. Saturated aqueous ammonium chloride (200 mL) was added to the reaction system, and extraction was performed with ethyl acetate (250 mL x 3). The mixture was washed with saturated brine (250 mL), and the combined organic phases were dried over anhydrous sodium sulfate. The crude product obtained by concentration of the organic phase was purified by column chromatography to obtain compound B13-3 (1.78 g, 69.52%) as a light yellow solid.

[0837] 1 H NMR(400MHz, DMSO-d6)δ7.51(d,J=7.8Hz,1H),6.91(d,J=14.3Hz,1H),4.30–4.14(m,2H),3.91(dq, J=6.7,3.5Hz,1H),3.64(dd,J=13.4,3.7Hz,2H),3.53–3.29(m,4H),2.11–1.87(m,2H),1.42(s,9H).

[0838] LCMS(ESI):[M+H-Boc] + =268.27.

[0839] Step 3: (S)-9-amino-10-fluoro-1,2,4,4a,5,6-hexahydro-3H-benzo[b]pyrazino[1,2-d][1,4]oxirane-3-carboxylic acid tert-butyl ester (Compound B13-4)

[0840] The synthesis method is the same as the third step of synthesizing compound B1.

[0841] LCMS(ESI):[M+H] + =338.39

[0842] Step 4: (S)-9-(2,4-dioxytetrahydropyrimidin-1(2H)-yl)-10-fluoro-1,2,4,4a,5,6-hexahydro-3H-benzo[b]pyrazino[1,2-d][1,4]oxirane-3-carboxylic acid tert-butyl ester (Compound B13-5)

[0843] The synthesis method is the same as the first step of synthesizing compound B2.

[0844] 1 H NMR (600MHz, DMSO-d6) δ10.40(s,1H),6.86(dd,J=13.3,9.9Hz,2H),4.25(dq,J=10.7,3.6Hz,1H),4.15(ddt,J=16.2,10.8,5.5Hz,1H),3.63(t,J=6.7H z,3H),3.56(d,J=13.0Hz,1H),3.32–3.25(m,2H),3.16(q,J=4.2Hz,2H),2. 68(t,J=6.7Hz,2H),2.05–1.97(m,2H),1.91(d,J=10.6Hz,1H),1.43(s,9H).

[0845] LCMS(ESI)[M+H-tBu] + =379.49.

[0846] Step 5: (S)-1-(10-fluoro-2,3,4,4a,5,6-hexahydro-1H-benzo[b]pyrazino[1,2-d][1,4]oxirane-9-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound B2)

[0847] The synthesis method is the same as the second step of synthesizing compound B2.

[0848] 1H NMR (600MHz, CD3OD) δ6.97–6.92 (m, 2H), 4.38 (ddd, J = 12.0, 8.7, 3.8Hz, 1H), 4. 19(dt,J=11.0,5.3Hz,1H),3.76(t,J=6.7Hz,2H),3.59–3.50(m,2H),3.47–3.3 9(m,2H),3.34(d,J=12.8Hz,2H),3.31(dd,J=11.5,3.9Hz,1H),2.82(t,J=6.7H z,2H),2.19(ddt,J=15.4,8.9,4.5Hz,1H),2.00(dtd,J=15.8,5.9,3.9Hz,1H).

[0849] LCMS (ESI) [M+H] + =335.30

[0850] Example 30-1: Synthesis of Compound B14

[0851] (S)-1-(10-methoxy-2,3,4-4a,5,6-hexahydro-1H-benzo[b]pyrazino[1,2-d][1,4]oxazepan-9-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0852] Synthesis scheme

[0853] Step 1: (S)-1-(3-acetyl-10-methoxy-2,3,4,4a,5,6-hexahydro-1H-benzo[b]pyrazino[1,2-d][1,4]oxirane-9-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound B14-1)

[0854] B12-4 (110 mg, 0.315 mmol, 1.0 eq) was dissolved in toluene (5 mL). Acrylic acid (27.23 mg, 0.378 mmol, 1.2 eq) was added to the reaction system. The reaction system was heated to 90°C and allowed to react for 12 hours. Urea (78.37 mg, 1.30 mmol, 5.0 eq) and acetic acid (5 mL) were then added. After reacting at 90°C for 12 hours, the system was returned to room temperature. Saturated aqueous sodium bicarbonate was added to the reaction system to adjust the pH to 8, and the mixture was extracted with ethyl acetate (3 times with 50 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The crude product obtained by concentration of the organic phase was purified by column chromatography to obtain compound B14-1 (20 mg, 16.4%) as a white solid.

[0855] Step 2: (S)-1-(10-methoxy-2,3,4-4a,5,6-hexahydro-1H-benzo[b]pyrazino[1,2-d][1,4]oxazepan-9-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound B14)

[0856] B14-1 (20 mg, 0.045 mmol, 1.0 eq) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 ml) was added to the reaction system. The reaction system was allowed to react at room temperature for 2 hours. The reaction solution was concentrated to obtain a crude product which was purified by reverse phase column chromatography to obtain compound B14 (8 mg, 51.6%) as a white solid.

[0857] 1 H NMR (400MHz, DMSO-d6) δ10.25(s,1H),6.75(s,1H),6.69(s,1H),4.20(ddd,J=12.1,7.9,4.4Hz,1H),4.07(dt,J=11.0,5. 4Hz,1H),3.75(s,3H),3.37-3.31m,4H),3.26-3.11(m,3H),2.99-3.07(m,2H),2.63(t,J=6.7Hz,2H),2.06-1.91(m,2H).

[0858] LCMS (ESI) [M+H] + =346.39

[0859] Example 30-2: Synthesis of Compound B15

[0860] (S)-1-(10-chloro-2,3,4,4a,5,6-hexahydro-1H-benzo[b]pyrazino[1,2-d][1,4]oxazepin-9-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0861] Synthesis scheme

[0862] Step 1: (S)-tert-Butyl 4-(5-chloro-2-fluoro-4-nitrophenyl)-3-(2-hydroxyethyl)piperazine-1-carboxylate (Compound B15-2)

[0863] Compound B1-1 (500.0 mg, 2.17 mmol, 1.0 eq) and compound B15-1 (420.16 mg, 2.17 mmol, 1.0 eq) were dissolved in dimethyl sulfoxide (5.0 mL), heated to 120°C, and reacted overnight. The reaction solution was purified by reverse-phase column chromatography to obtain compound B15-2 (277 mg, 31.59%) as a light yellow solid.

[0864] 1 H NMR (400MHz, DMSO-d6) δ8.09–7.98(m,1H),7.33–7.21(m,1H),4.13–3.85(m,3H),3.45–2.87(m,7H),1.77–1.52(m,2H),1.42(s,9H).

[0865] LCMS(ESI):[M+H] + =404.35.

[0866] Step 2: (S)-10-chloro-9-nitro-1,2,4,4a,5,6-hexahydro-3H-benzo[b]pyrazino[1,2-d][1,4]oxazepine-3-carboxylic acid tert-butyl ester (Compound B15-3)

[0867] Compound B15-2 (500.0 mg, 1.24 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (5.0 mL). After cooling to 0°C, sodium hydride (148.56 mg, 3.71 mmol, 3.0 eq) was added and allowed to react at room temperature under nitrogen for 2 hours. The reaction system was cooled to 0°C, quenched with saturated ammonium chloride solution, and diluted with ethyl acetate (100 mL). The organic phase was washed with saturated brine (60 mL x 3), combined, and dried over anhydrous sodium sulfate. The crude product obtained by concentration of the organic phase was purified by column chromatography to obtain compound B15-3 (430.0 mg, 90.48%) as a yellow solid.

[0868] LCMS(ESI):[M+H-56] + =328.35.

[0869] Step 3: (S)-9-amino-10-chloro-1,2,4,4a,5,6-hexahydro-3H-benzo[b]pyrazino[1,2-d][1,4]oxazepine-3-carboxylic acid tert-butyl ester (Compound B15-4)

[0870] Compound B15-3 (300.0 mg, 781.60 μmol, 1.0 eq) was dissolved in ethanol (8.0 mL). A solution of ammonium chloride (418.07 mg, 7.82 mmol, 10.0 eq) in water (2.0 mL) and iron powder (218.24 mg, 3.91 mmol, 5.0 eq) were added. The reaction was heated to 80°C under nitrogen and allowed to react overnight. After the reaction, the mixture was quickly filtered. The filtrate was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 2). The mixture was then washed with saturated brine (80 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The organic phases were concentrated to obtain crude compound B15-4 (275 mg, 99.43%) as a yellow solid, which was used directly in the next step.

[0871] LCMS(ESI):[M+H] + =353.39.

[0872] Step 4: (S)-3-((3-(tert-Butyloxycarbonyl)-10-chloro-2,3,4,4a,5,6-hexahydro-1H-benzo[b]pyrazino[1,2-d][1,4]oxazepin-9-yl)amino)propanoic acid (Compound B15-5)

[0873] B15-4 (275 mg, 777.17 μmol, 1.0 eq) was dissolved in toluene (5.0 mL), and acrylic acid (168.02 mg, 2.33 mmol, 3.0 eq) was added to the reaction system. The temperature was raised to 90°C and the reaction was allowed to react for 24 hours. The reaction system was cooled to room temperature, and the organic phase was concentrated to obtain a crude black oil, compound B15-5 (331.0 mg, 100%), which was used directly in the next reaction.

[0874] LCMS (ESI) [M+H] + =426.35.

[0875] Step 5: (S)-10-chloro-9-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1,2,4,4a,5,6-hexahydro-3H-benzo[b]pyrazino[1,2-d][1,4]oxazepine-3-carboxylic acid tert-butyl ester (Compound B15-6)

[0876] B15-5 (331 mg, 777.16 μmol, 1.0 eq) was dissolved in toluene (5.0 mL). Urea (466.73 mg, 7.77 mmol, 10.0 eq) and formic acid (3.0 mL) were added to the reaction system. The reaction was heated to 110°C for 24 hours, and the reaction system was cooled to room temperature. Water (100 mL) and sodium bicarbonate were added to the reaction system to neutralize the system to a weak alkaline state, and the reaction system was extracted with ethyl acetate (100 mL*2 times). The organic phases were washed with saturated brine (100 mL), and the combined organic phases were dried over anhydrous sodium sulfate. The crude product obtained by concentration of the organic phase was purified by column chromatography to obtain compound B15-6 (48 mg, 13.70%) as an off-white solid.

[0877] LCMS (ESI) [M+H] + =451.29.

[0878] Step 6: ((S)-1-(10-chloro-2,3,4,4a,5,6-hexahydro-1H-benzo[b]pyrazino[1,2-d][1,4]oxazepin-9-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound B15)

[0879] Compound B15-6 (48 mg, 106.45 μmol, 1.0 eq) was dissolved in dichloromethane (2.0 mL). A 4M hydrochloric acid solution in 1,4-dioxane (1.0 mL) was added to the mixture. The reaction was allowed to react at room temperature for 3 hours. The reaction system was concentrated under reduced pressure to afford Compound B15 (35 mg, 93.73%) as an off-white solid.

[0880] 1 H NMR (400MHz, DMSO-d6) δ10.41(s,1H),9.27(s,1H),7.16(s,1H),6.97(s,1H),4.46–4.31(m,1H),4.22–4. 07(m,1H),3.76–3.42(m,4H),3.34–3.25(m,2H),3.23–2.96(m,3H),2.78–2.61(m,2H),2.15–1.90(m,2H).

[0881] LCMS (ESI) [M+H] + =351.25

[0882] Experimental Example 1: Binding activity of the E3 ligase inhibitor disclosed in the present invention to E3 ubiquitin ligase CRBN

[0883] The binding activity of the E3 ligase inhibitor disclosed in the present invention and the positive control samples lenalidomide and pomalidomide with the E3 ubiquitin ligase CRBN is determined by the competitive binding of the E3 ligase inhibitor disclosed in the present invention, lenalidomide and pomalidomide with thalidomide labeled with XL665 to the CRBN protein, thereby preventing the occurrence of fluorescence resonance energy transfer (FRET), thereby judging the binding force of the compound to the CRBN protein.

[0884] CRBN binding activity test kit (CEREBLON BINDING KITS (PE, 64BD CRBN PEG)).

[0885] The detection is based on homogeneous time-resolved fluorescence (HTRF) technology. When the donor (Donor) and acceptor (Acceptor) are close to each other, the donor can transfer energy to the acceptor, causing it to be excited and emit light at 665nm.

[0886] This kit uses a europium-labeled GST antibody (GST Eu Cryptate Antibody) as the donor and XL665-labeled thalidomide (Thalidomide-Red reagent) as the receptor. The donor binds to the GST-tagged CRBN protein. The E3 ligase inhibitors disclosed herein, as well as lenalidomide and pomalidomide, compete with thalidomide for binding to the CRBN protein. The binding activity of the compound is determined by the fluorescence emitted by the receptor at 665 nm. Stronger binding compounds produce weaker signals.

[0887] Dilute the donor and acceptor 50-fold using the buffer in the kit (PROTAC binding buffer 1). Dilute the CRBN protein 45-fold. Dilute the 8 mM compound solution disclosed in the present invention 10-fold using the diluent in the kit (1 X diluent), and then perform a 5-fold gradient dilution of the diluent, diluting it 7 times in sequence. Add 5 μl of compound, 5 μl of diluted CRBN protein, and 10 μl of an equal volume mixture of donor and acceptor to the wells of a white 384-well plate (PE, Part number: 6008280). Incubate at room temperature for 3 hours. Calculate the ratio of the acceptor and donor emission signals for each individual well.

[0888] Ratio=665nm signal value / 620nm signal value*10 4

[0889] Calculate the coefficient of variation (CV) = standard deviation (SD) / Ratio mean * 100;

[0890] IC was calculated based on compound concentration, Ratio, and coefficient of variation using GraphPad Prism. 50 value.

[0891] Table 1: shows the IC values ​​of compounds of Examples 1 to 32 of the present disclosure. 50 value

[0892] Conclusion: The E3 ligase inhibitors disclosed in the present invention can bind well to the CRBN protein, and the binding ability of some E3 ligase inhibitors to CRBN is comparable to or even better than that of the positive controls lenalidomide and pomalidomide.

[0893] The present invention uses the above-mentioned compounds to exemplify the synthesis of protein-targeted chimera (PROTAC) compounds targeting androgen receptor, estrogen receptor, and IRAK4 receptor to verify the excellent effects of the compounds provided by the present invention;

[0894] The first part is PROTAC compounds targeting androgen receptor (AR);

[0895] AR-PROTAC compounds were synthesized by the following general formula:

[0896] PROTAC synthetic formula AR-T-1:

[0897] PROTAC synthetic formula

[0898] AR-T-2

[0899] PROTAC synthetic formula AR-T-3

[0900] PROTAC synthetic formula AR-T-4

[0901] Table A: The following compounds of Examples 31 to 43 were synthesized according to the above general formula:

[0902] Experimental Example 2: Degradation activity of the disclosed compounds on AR protein in LNCAP cells

[0903] AR-positive human prostate cancer cells (LNCaP, cell source: ATCC) were cultured in RPMI 1640 (ATCC catalog number 30-2001) containing 10% FBS (Hyclone catalog number SH30406.05) to a concentration of 1.5×10 5 / well was inoculated into a six-well microplate (Thermo catalog number 140675). After the cells were cultured overnight in a carbon dioxide incubator (ESCO), the prepared compound of the present invention and the positive control sample ARV-766 (source: Anaiji) solution of different concentrations were added at a volume of 1 μL / well to make the final concentrations of the compound and the positive control sample reach 100nM and 10nM, respectively. At the same time, the corresponding solvent control was set and cultured for 8 hours. After 8 hours of culture, the culture medium was removed, the cells were washed with PBS, and RIPA lysis buffer containing 1% Protease Inhibitor Cocktail was added. After lysis and centrifugation, the total protein extract was obtained, and the protein concentration in the extract was detected by BCA method. Protein electrophoresis was performed using SDS-PAGE, and then the protein was transferred to a PVDF (Millipore Sigma catalog number PSRP010R5) membrane at a constant voltage of 100V for 60 minutes. The PVDF membrane was placed in a 5% milk powder 1×TBST solution and blocked at room temperature for 1 hour. Prepare the primary antibody solution (Anti-Androgen receptor, Cell Signaling Technology catalog number: 5153S; 1:2000 dilution) and incubate at 4°C overnight. Discard the primary antibody solution and wash the PVDF membrane with 1×TBST for 5 minutes each time, three times. Prepare the secondary antibody solution (Thermo catalog number SA5-35571; 1:7500 dilution) and incubate at room temperature for 1 hour. Discard the secondary antibody solution and wash the PVDF membrane with 1×TBST for 5 minutes each time, three times. Use a dual-color infrared laser imaging system (Licor catalog number Odyssey CLX) for Western membrane imaging. Use Image Studio software to analyze the grayscale of the bands. GAPDH protein bands were also detected for each sample as an internal reference. The AR protein degradation rate of the compound and the positive control sample was calculated based on the grayscale of the protein bands. Among them, "A" means degradation rate ≥ 50%, "B" means 50%> degradation rate ≥ 20%, "C" means 20% degradation rate ≥ 10%, and "D" means degradation rate less than 10%.

[0904] The positive reference used in the present invention is ARV766, and its structure is as follows:

[0905] Table 2: Degradation rate of AR protein in LNCAP cells by the disclosed compounds

[0906] Experimental Example 3: Degradation activity of the disclosed compounds on AR protein in VCAP cells

[0907] AR-positive human prostate cancer cells VCaP (cell source: ATCC) were cultured in DMEM (GiBco catalog number 11995-065) containing 10% FBS (Hyclone catalog number SH30406.05) to a concentration of 3×10 5 / well was inoculated in a six-well microplate (Thermo catalog number 140675). After being cultured overnight in a carbon dioxide incubator (ESCO), the prepared compound of the present invention and the positive control sample ARV-766 (Annaiji) solution of different concentrations were added at a volume of 1 μL / well to make the final concentrations of the compound and the positive control sample reach 5nM and 0.5nM, respectively. At the same time, the corresponding solvent control was set and cultured for 8h. After 8h of culture, the culture medium was removed, and the cells were washed with PBS. RIPA lysis buffer containing 1% Protease Inhibitor Cocktail was added. After lysis and centrifugation, a total protein extract was obtained, and the protein concentration in the extract was detected by BCA method. Protein electrophoresis was performed using SDS-PAGE, and then the protein was transferred to a PVDF (Millipore Sigma catalog number PSRP010R5) membrane at a constant voltage of 100V for 60min. The PVDF membrane was placed in a 5% milk powder 1×TBST solution and blocked at room temperature for 1h. Prepare the primary antibody solution (Anti-Androgen receptor, Cell Signaling Technology catalog number: 5153S; 1:2000 dilution) and incubate at 4°C overnight. Discard the primary antibody solution and wash the PVDF membrane with 1×TBST for 5 minutes each time, three times. Prepare the secondary antibody solution (Thermo catalog number SA5-35571; 1:7500 dilution) and incubate at room temperature for 1 hour. Discard the secondary antibody solution and wash the PVDF membrane with 1×TBST for 5 minutes each time, three times. Use a dual-color infrared laser imaging system (Licor catalog number Odyssey CLX) for Western membrane imaging. Use Image Studio software to analyze the grayscale of the bands. GAPDH protein bands were also detected for each sample as an internal reference. The AR protein degradation rate of the compound and the positive control sample was calculated based on the grayscale of the protein bands. Among them, "A" means degradation rate ≥ 50%, "B" means 50%> degradation rate ≥ 20%, "C" means 20% degradation rate ≥ 10%, and "D" means degradation rate less than 10%.

[0908] The degradation rates of AR protein in VCAP cells by the disclosed compounds are shown in Table 3 below.

[0909] Table 3: Degradation rate of AR protein in VCAP cells by the compounds disclosed in the present invention

[0910] “-” means not tested.

[0911] Test Example 4: Inhibitory activity of the disclosed compounds on LNCAP cell proliferation

[0912] LNCaP FGC cells (ATCC, CLR-1740) were cultured in RPMI 1640 (ATCC, 30-2001) complete medium supplemented with 10% fetal bovine serum (Hyclone, SH30406.05). On the first day of the experiment, LNCaP FGC cells were seeded at a density of 5,000 cells / well in 96-well plates using RPMI 1640 medium supplemented with 10% fetal bovine serum, with 100 μL of cell suspension per well. The cells were cultured overnight in a 37°C, 5% CO2 cell incubator. On the second day, 100 μL of different concentrations of the compound to be tested and the positive control sample ARV-766 (source: Anaiji) prepared in culture medium were added to each well. The final concentration of the compound was 9 concentration points of 5-fold serial dilution starting from 10 μM. The wells to which 100 μL of RPMI 1640 culture medium containing 10% fetal bovine serum was added were set as controls. The cells were cultured in a cell culture incubator at 37°C and 5% CO2 for 96 hours. On the sixth day, the 96-well cell culture plate was removed, and 1 / 10 volume of WST-8 (Beytime, C0040) reagent was added to each well. The absorbance at 450 nm was detected using a microplate reader (TECAN, F50). The 50% proliferation inhibition concentration (IC) was calculated by logistic regression based on the concentration and absorbance values ​​of the compound using GraphpadPrism software. 50 value).

[0913] IC inhibition of LNCAP cell proliferation by the disclosed compounds 50 The values ​​are shown in Table 4 below.

[0914] Table 4: IC values ​​of the compounds disclosed herein for inhibition of LNCAP cell proliferation 50 value

[0915] Test Example 5: Inhibitory activity of the disclosed compounds on VCaP cell proliferation

[0916] VCaP cells (ATCC, CRL-2876) were cultured in DMEM (Gibco, 11995-065) complete medium containing 10% fetal bovine serum (Hyclone, SH30406.05). On the first day of the experiment, VCaP cells were seeded at a density of 15,000 cells / well in a 96-well plate using DMEM medium containing 10% fetal bovine serum, with 100 μL of cell suspension per well, and cultured overnight in a cell culture incubator at 37°C and 5% CO2. On the second day, 100 μL of the compound of the present invention and the positive control ARV-110 (source: Anaiji) prepared in culture medium at different concentrations were added to each well. The final concentration of the compound was 9 concentration points of 5-fold serial dilution starting from 10 μM. The wells to which 100 μL of DMEM medium containing 10% fetal bovine serum was added were set as blank controls and cultured in a cell culture incubator at 37°C and 5% CO2 for 168 hours. On the ninth day, the 96-well cell culture plate was removed and 1 / 10 volume of WST-8 (Beytime, C0040) reagent was added to each well. The absorbance at 450 nm was measured using a microplate reader (TECAN, F50). The 50% proliferation inhibition concentration (IC) was calculated by logistic regression based on the concentration and absorbance of the compound using Graphpad Prism software. 50 value).

[0917] IC inhibition of VCAP cell proliferation by the disclosed compounds 50 The values ​​are shown in Table 5 below.

[0918] Table 5: IC values ​​of the compounds disclosed herein for inhibition of VCAP cell proliferation 50 value

[0919] Conclusion: From the results in Tables 2-5 above, it can be seen that the PROTAC compounds synthesized from the E3 ligase inhibitors provided in this specification and the androgen receptor target protein showed significant AR protein degradation effects in prostate cancer cells LNCAP and VCaP, and also had significant prostate cancer cell proliferation inhibition effects. The target protein degradation effects and cell proliferation inhibition effects of some compounds were significantly better than those of the control compound ARU766.

[0920] The second part is PROTAC compounds targeting estrogen receptor (ER):

[0921] ER PROTAC synthetic formula ER-T-1

[0922] Table B: The following compounds of Examples 44 to 49 were synthesized according to the above general formula:

[0923] Experimental Example 6 Inhibitory Effect of the Disclosed PROTAC Compound on Cell Proliferation in T-47D Cells

[0924] The complete culture medium required for breast ductal carcinoma T-47D cells is 1640 (ATCC, Product number: A10491-01) basal medium containing 10% fetal bovine serum. T-47D cells were seeded in 96-well plates at a density of 3,000 / well, and different concentrations of PROTAC compounds 1-55 provided in the embodiments of the present invention and the positive control sample ARV-471 (source: Inokai) were prepared to treat the cells and incubated at 37°C, 5% CO2 in a cell culture incubator for 6 days. According to the manufacturer's instructions, the CCK-8 kit (Beyotime, Product number: C0040) was used to detect cell viability. The IC of each compound for 6 days was calculated using GraphPadPrism software based on the inhibition rate. 50 The results are shown in Table 6.

[0925] Table 6: IC inhibition of T-47D cell proliferation by PROTAC compounds and positive controls 50 value

[0926] Conclusion: The PROTAC compounds provided by the present invention can effectively inhibit the proliferation of T-47D cells, and the inhibitory effects of some compounds are comparable to or even better than those of the positive control.

[0927] Experimental Example 7 Inhibitory effect of the disclosed PROTAC compound on cell proliferation in MCF-7 cells

[0928] The complete culture medium required for breast cancer MCF-7 cells (source ATCC) is DMEM (gibco, Product number: 11995-065) basal medium containing 10% fetal bovine serum. MCF-7 cells were seeded in 96-well plates at a density of 800 cells / well, and different concentrations of PROTAC compounds 1-55 provided in the embodiments of the present invention and the positive control sample ARV-471 (source: Inokai) were prepared and treated with cells. The cells were incubated at 37 ° C and 5% CO2 in a cell culture incubator for 6 days. Cell viability was detected using a CCK-8 kit (Beyotime, Product number: C0040) according to the manufacturer's instructions. The IC50 value of each PROTAC compound for 6 days was calculated using GraphPad Prism software based on the inhibition rate. The results are shown in Table 7.

[0929] Table 7: IC inhibition of MCF-7 cell proliferation by PROTAC compounds of the present disclosure and positive control samples50 value

[0930] Conclusion: The PROTAC compounds of the present invention can effectively inhibit the proliferation of MCF-7 cells. The inhibitory effects of some PROTAC compounds on MCF-7 cells are comparable to or even better than those of the positive control.

[0931] Experimental Example 8 Degradation of ERα by PROTAC Compounds of the Present Disclosure in MCF-7 Cells

[0932] MCF-7 (ATCC) cells were cultured in DMEM medium (11995-065, Gibco) containing 10% FBS (10099141C, Gibco) at 37°C and 5% CO2 until they entered the logarithmic growth phase. MCF-7 cells were plated at 3×10 5 Cells were seeded at a density of 100 cells / well in a 6-well plate and incubated at 37°C, 5% CO₂ for 24 hours. After cell attachment, 1 μL of compound dimethyl sulfoxide solution (final concentration 0.15–1000 nM) was added and incubated for another 4 hours at 37°C, 5% CO₂. After 4 hours, the culture medium was discarded, and each well was washed once with 1 mL of pre-chilled 1× DPBS. The cells were then lysed with 50 μL of RIPA lysis buffer (P0013B, Beyotime) and 1× protease inhibitor cocktail (P1005, Beyotime). After incubation on ice for 20 minutes, the cells were centrifuged at 14,000 g at 4°C for 30 minutes. The supernatant was carefully removed and analyzed for ERα protein levels by immunoblotting.

[0933] Western blotting: The total protein concentration in the collected cell lysate supernatant was determined using the BCA protein concentration assay kit (enhanced) (P0009, Beyotime). Based on the total protein concentration determined by BCA, the protein concentration was adjusted to 1 μg / μL using RIPA lysis buffer and 5× SDS-PAGE protein loading buffer (MB01015, GenScript). The protein was denatured in a 95°C water bath for 5 minutes. After denaturation, the condensed water on the tube wall was collected by centrifugation and used as the loading sample. Twenty μL of the loading sample (20 μg total protein) was added to the sample well of a 12% precast gel (M00669, GenScript). Electrophoresis was performed at 100 V for 20 minutes, followed by switching to 150 V for 40 minutes. After electrophoresis, the proteins from the SDS-PAGE gel were transferred to a PVDF membrane at a constant voltage of 100 V for 60 minutes. After transfer, the PVDF membrane corresponding to the ERα protein and internal reference protein was cut and incubated in 1× QμickBlock blocking buffer (P0252, Beyotime) for 30 minutes at room temperature on a shaker. After blocking, the ERα primary antibody (1:1000, 8644S, CST) was added and incubated overnight at 4°C on a shaker. The PVDF membrane was washed three times with 1× TBST buffer for 5 minutes each. Rabbit IgG (H+L) secondary antibody (1:7500, SA5-35571, Invitrogen) was added and incubated for 1 hour at room temperature on a shaker. The membrane was then washed again three times with 1× TBST buffer for 5 minutes each. Finally, the membrane was imaged using a dual-color infrared laser imaging system (Odyssey DLx, LI-COR). Protein maps were analyzed using Image Studio Lite software. The grayscale correction value for each sample was calculated using the formula: grayscale correction value = grayscale value of the target protein / grayscale value of the corresponding internal reference. Then the grayscale correction values ​​of the compound group and the control group were compared to calculate the degradation rate of the compound.

[0934] Some of the compounds of the embodiments of the present disclosure have a significant degradation effect on ERα in MCF-7 cells. For example, the degradation rate of ER-P-2 is greater than or equal to 30% at a concentration of 10 nM.

[0935] Experimental Example 9 Degradation of ERα by PROTAC Compounds of the Present Disclosure in T-47D Cells

[0936] T-47D (ATCC) cells were cultured in PRMI-1640 medium (30-2001, ATCC) containing 10% FBS (10099141C, Gibco) at 37°C and 5% CO2 until they entered the logarithmic growth phase. 5Cells were seeded at a density of 100 cells / well in a 6-well plate and incubated at 37°C, 5% CO₂ for 24 hours. After cell attachment, 1 μL of compound dimethyl sulfoxide solution (final concentration 0.15–1000 nM) was added and incubated for another 4 hours at 37°C, 5% CO₂. After 4 hours, the culture medium was discarded, and each well was washed once with 1 mL of pre-chilled 1× DPBS. The cells were then lysed with 50 μL of RIPA lysis buffer (P0013B, Beyotime) and 1× protease inhibitor cocktail (P1005, Beyotime). After incubation on ice for 20 minutes, the cells were centrifuged at 14,000 g at 4°C for 30 minutes. The supernatant was carefully removed and analyzed for ERα protein levels by immunoblotting.

[0937] Some of the compounds in the embodiments of the present disclosure have a significant degradation effect on ERα in T-47D cells. For example, the degradation rates of ER-P-1 and ER-P-3 are greater than or equal to 30% at a concentration of 10 nM.

[0938] The third part is PROTAC compounds targeting IRAK4 receptor:

[0939] PROTAC synthetic formula IR-T-1

[0940] PROTAC synthetic formula IR-T-2

[0941] Table C: The following compounds of Examples 50 to 56 were synthesized according to the above general formula:

[0942] Experimental Example 10: Degradation of IRAK4 in THP-1 cells by compounds

[0943] THP-1(TIB-202 TM , ATCC) cells were cultured in RPMI 1640 medium (30-2001, ATCC) containing 10% FBS (10099141C, Gibco) and 0.05 mM β-mercaptoethanol (M3148, Sigma-Aldrich) at 37°C and 5% CO2 until they entered the logarithmic growth phase. 2 mL of THP-1 cells were seeded per well of a 6-well cell culture plate at a cell density of 4 × 10 5After adding 1 μL of compound dimethyl sulfoxide solution (final concentration 10–10,000 nM) and continuing to incubate at 37°C, 5% CO₂ for 24 hours, cells were collected into 2 mL centrifuge tubes and centrifuged at 125 g at 4°C for 5 minutes. The cell pellet was washed once with 1 mL of pre-chilled 1× DPBS and resuspended and lysed in 50 μL of RIPA lysis buffer (P0013B, Beyotime) and 1× protease inhibitor cocktail (P1005, Beyotime). After incubation on ice for 20 minutes, the cells were centrifuged at 14,000 g at 4°C for 30 minutes. The supernatant was carefully removed and analyzed for IRAK4 protein levels by immunoblotting.

[0944] Western blotting: The total protein concentration in the collected cell lysate supernatant was determined using the BCA protein concentration assay kit (enhanced) (P0009, Beyotime). Based on the total protein concentration detected by BCA, the protein concentration was adjusted to 1 μg / μL using RIPA lysis buffer and 5× SDS-PAGE protein loading buffer (MB01015, GenScript). The protein was denatured in a 95°C water bath for 5 minutes. After denaturation, the condensed water on the centrifuge tube wall was collected by centrifugation and used as the loading sample. 20 μL of the loading sample (20 μg total protein) was added to the sample well of a 12% precast gel (M00669, GenScript). Electrophoresis was performed at 100 V for 20 minutes, then switched to 150 V for 40 minutes. After electrophoresis, the proteins in the SDS-PAGE gel were transferred to a PVDF membrane and transferred at a constant voltage of 100 V for 60 minutes. After transfer, the PVDF membrane corresponding to the IRAK4 protein and internal reference protein was cut and incubated in 1× QuickBlock blocking buffer (P0252, Beyotime) for 30 minutes at room temperature on a shaker. After blocking, the IRAK4 primary antibody (1:1000, 4363S, CST) was added and incubated overnight at 4°C on a shaker. The PVDF membrane was washed three times with 1× TBST buffer for 5 minutes each. Rabbit IgG (H+L) secondary antibody (1:7500, SA5-35571, Invitrogen) was added and incubated for 1 hour at room temperature on a shaker. The membrane was then washed again three times with 1× TBST buffer for 5 minutes each. Finally, the membrane was imaged using a dual-color infrared laser imaging system (Odyssey DLx, LI-COR). Protein maps were analyzed using Image Studio Lite software. The grayscale correction value for each sample was calculated using the formula: grayscale correction value = grayscale value of the target protein / grayscale value of the corresponding internal reference. The grayscale correction values ​​of the compound group and the control group were then compared to calculate the degradation rate of the compound. "A" indicates a degradation rate ≥ 50%, "B" indicates 50% > degradation rate ≥ 20%, "C" indicates 20% degradation rate ≥ 10%, and "D" indicates a degradation rate less than 10%.

[0945] (Structure of reference compound KT-474)

[0946] Table 8: Degradation effect of example compounds on IRAK4 in THP-1 cells

[0947] “-” means not tested.

[0948] Experimental Example 11: Determination of TNFα concentration secreted by PBMC induced by LPS

[0949] After cryopreservation, hPBMC (FPB003F-C, Shanghai Aoneng Biotechnology) cells were resuspended in RPMI 1640 medium (30-2001, ATCC) containing 10% inactivated FBS (10099141C, Gibco) and cultured overnight at 37°C and 5% CO2. The next day, hPBMC cells were plated at 2×10 5 Cells were seeded at a density of 2 × 106 cells / well / 100 μL (2 × 106 cells / mL) in a 96-well cell culture plate, and 100 μL of compound dimethyl sulfoxide solution (final concentration 0.0064–2500 nM) was added. After incubation at 37°C, 5% CO2 for 20 hours, 20 μL of LPS (055:B5) (L5418, Sigma) was added to the drug-treated cell plate at a final concentration of 200 ng / mL. The cell plate was placed in a 37°C, 5% CO2 incubator for 5 hours, and then centrifuged at 1000 rpm for 15 minutes. 100 μL of cell supernatant was collected from each well for cytokine concentration testing, and tested immediately or frozen at -80°C for testing.

[0950] HTRF detection of TNFα

[0951] The TNFα concentration in the supernatant of LPS-induced THP-1 cells was determined using the TNF ALPHAHTRF detection kit (62HTNFAPEG, PerkinElmer).

[0952] TNFα standard solutions of varying concentrations were prepared according to the product instructions, ranging from 0 to 2500 pg / mL. Equal volumes of Eu Cryptate antibody (1×) and d2 antibody (1×) were used to prepare the antibody mixture. 16 μL of standard solution or sample supernatant and 4 μL of the antibody mixture were added to each well of a 384-well white plate. The mixture was centrifuged at 800 rpm for 1 minute and incubated at room temperature for 2 hours. The absorbance at 620 nm and 655 nm was read using a microplate reader (SPARK m1000pro, TECAN). A standard curve was constructed using the signal values ​​of each TNFα standard solution. The TNFα concentration in each sample was determined based on the corresponding concentration of the signal value on the standard curve. The inhibitory rate of the compound on LPS-induced TNFα expression in THP-1 cell supernatants at different drug concentrations was calculated based on the TNFα concentration. The inhibition rate data were plotted in GraphPad Prism 8.0 software, and the IC50 value was calculated.

[0953] Table 9: Degradation effect of example compounds on IRAK4 in PBMC cells

[0954] Experimental Example 12: Determination of IL-6 Concentration Secreted by hPBMC Induced by LPS

[0955] After cryopreservation, hPBMC (FPB003F-C, Shanghai Aoneng Biotechnology) cells were resuspended in RPMI 1640 medium (30-2001, ATCC) containing 10% inactivated FBS (10099141C, Gibco) and cultured overnight at 37°C and 5% CO2. The next day, hPBMC cells were plated at 2×10 5 Cells were seeded at a density of 2 × 106 cells / well / 100 μL (2 × 106 cells / mL) in a 96-well cell culture plate, and 100 μL of compound dimethyl sulfoxide solution (final concentration 0.0064–2500 nM) was added. After incubation at 37°C, 5% CO2 for 20 h, 20 μL of LPS (055:B5) (L5418, Sigma) was added to the drug-treated cell plate at a final concentration of 200 ng / mL. The cell plate was placed in a 37°C, 5% CO2 incubator for 5 h, and then centrifuged at 1000 rpm for 15 min. 100 μL of cell supernatant was taken from each well for cytokine concentration testing, and tested immediately or frozen at -80°C for testing.

[0956] ELISA detection of IL-6

[0957] The IL-6 concentration in the supernatant of hPBMC cells induced by LPS was determined using a Human IL-6 ELISA kit (D6050, RD).

[0958] Prepare IL-6 standard solutions of varying concentrations according to the product instructions, ranging from 0 to 300 pg / mL. Add 100 μL of Assay Diluent RD1W and 100 μL of standard solution or sample supernatant to a pre-coated ELISA plate and incubate at room temperature for 2 hours. Wash the plate four times with 1× wash buffer, then add 200 μL of Human IL-6 Conjugate and incubate at room temperature for 2 hours. Wash the plate four times with 1× wash buffer, then add 200 μL of Substrate Solution and incubate at room temperature for 20 minutes. Finally, add 50 μL of Stop Solution to terminate the reaction. Read the absorbance at 450 nm and 570 nm using a microplate reader (SPARK m1000pro, TECAN). The standard curve was drawn by the signal value of each concentration of IL-6 standard solution, and the IL-6 concentration in each sample was determined according to the corresponding concentration of the signal value of each well on the standard curve. The inhibition rate of the compound on LPS-induced IL-6 in the hPBMC cell supernatant at different drug concentrations was calculated according to the IL-6 concentration. The inhibition rate data were plotted in GraphPad Prism 8.0 software to calculate the IC 50 value.

[0959] Table 10: Inhibitory effect of Example compounds on LPS-induced IL-6 secretion by hPBMC

[0960] “-” means not tested.

[0961] The foregoing descriptions of specific exemplary embodiments of the present invention are for purposes of illustration and description. These descriptions are not intended to limit the invention to the precise forms disclosed, and it is apparent that many modifications and variations are possible in light of the foregoing teachings. The exemplary embodiments have been selected and described for the purpose of explaining the specific principles of the invention and their practical application, thereby enabling those skilled in the art to make and utilize a variety of exemplary embodiments of the invention and various options and variations. The scope of the invention is intended to be defined by the claims and their equivalents.

Claims

1. A compound as shown in formula I, or its isomer, isotopic derivative, polymorph, prodrug or pharmaceutically acceptable salt or solvate, in, A1 is selected from CR a and N; A2 and A4 are each independently selected from C(O) and C(R a )2; E2 is selected from CR4 and N; A3 is NR a ; Preferably, A3 is NH; A5 and A6 are connected by a single bond or a double bond. When A5 and A6 are connected by a single bond, A5 and A6 are each independently selected from NR a and C(R a )2; when A5 and A6 are connected by a double bond, A5 and A6 are each independently selected from N and CR a ; Preferably, A6 and A5 are connected by a single bond and are both C(H)2; R1 and R2 together with the atoms to which they are attached form a ring Cy1 fused to Cy0, and R3, R4 and R5 are each independently selected from H, a deuterium atom, a halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, carboxyl, C 1-6 Heteroalkyl, alkenyl, alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, hydroxy, C 1-6 Hydroxyalkyl, nitro, cyano, amino, C 1-6 Alkylamino, C 1-6 Alkyl acyl, C 1-6 Alkyloxy acyl, C 1-6 Alkylaminoacyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Heteroalkyl, alkenyl, alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 1-6 Alkyl acyl, C 1-6 Alkyloxy acyl, C 1-6 The alkylaminoacyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally substituted by one or more substituents selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, aryl and heteroaryl groups; preferably, R3, R4 and R5 are each independently selected from H, deuterium atoms, halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Heteroalkyl, alkenyl, alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, hydroxy, C 1-6 More preferably, R3, R4 and R5 are each independently selected from H, deuterium atoms, F, Cl, Br, I, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 haloalkoxy and hydroxy; or R2 and R3 together with the atoms to which they are attached form a ring Cy2 fused to Cy0, and R1, R4 and R5 are each independently selected from H, a deuterium atom, a halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, carboxyl, C 1-6 Heteroalkyl, alkenyl, alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, hydroxy, C 1-6 Hydroxyalkyl, nitro, cyano, amino, C 1-6 Alkylamino, C 1-6 Alkyl acyl, C 1-6 Alkyloxy acyl, C 1-6 Alkylaminoacyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Heteroalkyl, alkenyl, alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 1-6 Alkyl acyl, C 1-6 Alkyloxy acyl, C 1-6 The alkylaminoacyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally substituted by one or more substituents selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, aryl and heteroaryl groups; preferably, R1, R4 and R5 are each independently selected from H, deuterium atoms, halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Heteroalkyl, alkenyl, alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, hydroxy, C 1-6 More preferably, R1, R4 and R5 are each independently selected from H, deuterium atoms, F, Cl, Br, I, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 haloalkoxy and hydroxy; or When R4 is present, R3 and R4 together with the atoms to which they are attached form a ring Cy3 fused to Cy0, and each occurrence of R1, R2 and R5 is independently selected from H, a deuterium atom, a halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, carboxyl, C 1-6 Heteroalkyl, alkenyl, alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, hydroxy, C 1-6 Hydroxyalkyl, nitro, cyano, amino, C 1-6 Alkylamino, C 1-6 Alkyl acyl, C 1-6 Alkyloxy acyl, C 1-6 Alkylaminoacyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Heteroalkyl, alkenyl, alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 1-6 Alkyl acyl, C 1-6 Alkyloxy acyl, C 1-6 The alkylaminoacyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally substituted by one or more substituents selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, aryl and heteroaryl groups; preferably, R1, R2 and R5 are each independently selected from H, deuterium atoms, halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Heteroalkyl, alkenyl, alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, hydroxy, C 1-6 More preferably, R1, R2 and R5 are each independently selected from H, deuterium atoms, F, Cl, Br, I, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 haloalkoxy and hydroxy; or When R4 is present, R4 and R5 together with the atoms to which they are attached form a ring Cy4 fused to Cy0, and each occurrence of R1, R2 and R3 is independently selected from H, a deuterium atom, a halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, carboxyl, C 1-6 Heteroalkyl, alkenyl, alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, hydroxy, C 1-6 Hydroxyalkyl, nitro, cyano, amino, C 1-6 Alkylamino, C 1-6 Alkyl acyl, C 1-6 Alkyloxy acyl, C 1-6 Alkylaminoacyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Heteroalkyl, alkenyl, alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 1-6 Alkyl acyl, C 1-6 Alkyloxy acyl, C 1-6 The alkylaminoacyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally substituted by one or more substituents selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, aryl and heteroaryl groups; preferably, R1, R2 and R3 are each independently selected from H, deuterium atoms, halogen, 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, hydroxy, C 1-6 More preferably, R1, R2 and R3 are each independently selected from H, deuterium atoms, F, Cl, Br, I, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and hydroxyl groups; The Cy1, Cy2, Cy3 and Cy4 are present only one at a time, selected from the structure in, B2 is selected from C(R a )2. NR a , O and S; and when Cy1, Cy2, Cy3 and Cy4 appear as a structure When B2 is selected from NR a , O and S; B4 and B5 are each independently selected from CR a and N; Each occurrence of B1 and B3 is independently selected from C(R a )2 and C(O); Each time B6 appears, select C(R a )2 and NR a ; C3 is selected from C(O) and NR s1 ; R s1 Selected from H, deuterium atoms, F, Cl, Br, I, C 1-6 Alkyl, deuterated C 1-6 Alkyl, carboxyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C(O)-C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxyl, C 1-6 hydroxyalkyl, nitro, cyano and amino; preferably, R s1 Selected from H, deuterium atoms, F, Cl, Br, I, C 1-6 Alkyl, deuterated C 1-6 Alkyl, carboxyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C(O)-C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxyl and C 1-6 More preferably, R s1 Selected from H, deuterium atoms, F, Cl, Br, I, C 1-3 Alkyl, deuterated C 1-3 Alkyl, carboxyl, -C(O)-C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl and halogenated C 1-3 Alkoxy; n2, n3, n4, n5 and n6 are each independently selected from 0, 1, 2 and 3; and n5 and n6 are not 0 at the same time; Preferably, when Cy1, Cy2, Cy3 and Cy4 are present in the structure When B2 is selected from O and S, n2+n3+n4 is greater than or equal to 2; Each time C1 and C2 appear, they are independently C(R a )2; R a Each occurrence is independently selected from H, deuterium atoms, F, Cl, Br, I, C 1-6 Alkyl, deuterated C 1-6 Alkyl, carboxyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C(O)-C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxyl, C 1-6 Hydroxyalkyl, nitro, cyano, amino, C 1-6 Alkylamino, C 1-6 Alkyl acyl, C 1-6 Alkyloxy acyl, C 1-6 alkylaminoacyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl and 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C(O)-C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 1-6 Alkyl acyl, C 1-6 Alkyloxy acyl, C 1-6 Alkylaminoacyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl and 5-10 membered heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, aryl and heteroaryl; preferably, R a 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, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxyl, C 1-6 More preferably, R a 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, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy and hydroxyl groups; In the Cy1, Cy2, Cy3 or Cy4 structure, represents the attachment site to Cy0; The compound of formula I is not the following structure:

2. A compound as shown in Formula 2, or its isomer, isotopic derivative, polymorph, prodrug, or pharmaceutically acceptable salt or solvate, in, A1 is selected from CR a and N; A2 and A4 are each independently selected from C(O) and C(R a )2; A3 is NR a ; A5 and A6 are each independently selected from a single bond, NR a and C(R a )2; Preferably, A5 and A6 are each independently C(R a )2; Each occurrence of L1 is independently selected from a single bond, an alkylene group, a haloalkylene group, -O-, -N(R b )C(O)-, -C(O)-, -OC(O)-, -NR b -, -S-, -SO-, -SO2-, cycloalkylene, heterocyclylene, arylene and heteroarylene, wherein the cycloalkylene, heterocyclylene, arylene and heteroarylene are optionally substituted by 0-6 R b Group substitution; preferably, L1 is a single bond; n1 is selected from 1, 2, 3, 4 and 5; R1 and R2 together with the atoms to which they are attached form a 3-10 membered heterocycloalkyl, a 3-10 membered cycloalkyl, a 6-10 membered aryl, a 6-10 membered heteroaryl, a 5-15 membered fused cyclic group or a heterofused cyclic group, or a 5-15 membered spiro or heterospiro cyclic group; the 3-10 membered heterocycloalkyl, the 3-10 membered cycloalkyl, the 6-10 membered aryl, the 6-10 membered heteroaryl, the 5-15 membered fused cyclic group or a heterofused cyclic group, or a 5-15 membered spiro or heterospiro cyclic group may be optionally substituted by 1, 2 or more radicals. or more substituents selected from the group consisting of halogen, carboxyl, alkoxy, alkyl, hydroxy, amino, haloalkyl, 3-10 membered heterocycloalkyl, 3-10 membered cycloalkyl, 6-10 membered aryl and 6-10 membered heteroaryl, and when R5 is present, R3, R4 and R5 are each independently selected from the group consisting of H, deuterium atoms, carboxyl, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, nitro, cyano , amino, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, cycloalkyl, heterocyclic, aryl and heteroaryl; preferably, R1 and R2 together with the atoms to which they are attached form a 5-15 membered heterocondensed cyclic group, or a 5-15 membered spiro or heterospiro cyclic group; the 5-15 membered heterocondensed cyclic group, or a 5-15 membered spiro or heterospiro cyclic group may be optionally substituted by 1, 2 or more halo, carboxyl, alkoxy, alkyl, hydroxyl, amino, haloalkyl, 3-10 membered heterocycloalkyl, 3-10 membered cycloalkyl, 6-10 membered aryl, 6-10 membered heteroaryl; R3, R4 and R5, at each occurrence, are each independently selected from H, a deuterium atom, a carboxyl group, 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; or R2 and R3 together with the atoms to which they are attached form a 3-10 membered heterocycloalkyl, a 3-10 membered cycloalkyl, a 6-10 membered aryl, a 6-10 membered heteroaryl, a 5-15 membered fused cyclic group or a heterofused cyclic group, a 5-15 membered spiro or a heterospiro cyclic group, wherein the 3-10 membered heterocycloalkyl, the 3-10 membered cycloalkyl, the 6-10 membered aryl, the 6-10 membered heteroaryl, the 5-15 membered fused cyclic group or a heterofused cyclic group, the 5-15 membered spiro or a heterospiro cyclic group may be optionally substituted by 1, 2 or more wherein the alkyl radicals are substituted with a substituent selected from the group consisting of halogen, carboxyl, alkoxy, alkyl, hydroxy, amino, haloalkyl, 3-10 membered heterocycloalkyl, 3-10 membered cycloalkyl, 6-10 membered aryl, and 6-10 membered heteroaryl, and each occurrence of R1, R4, and R5 is independently selected from the group consisting of H, a deuterium atom, carboxyl, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, nitro, cyano, amino, alkylamino, , alkyl acyl, alkyloxy acyl, alkyl amino acyl, cycloalkyl, heterocyclic, aryl and heteroaryl; preferably, R2 and R3 together with the atoms to which they are attached form a 5-15 membered fused cyclic group or heterofused cyclic group, or a 5-15 membered spiro or heterospiro cyclic group, and the 5-15 membered heterofused cyclic group, or the 5-15 membered spiro or heterospiro cyclic group may be optionally substituted by 1, 2 or more selected from halo, carboxyl, alkoxy, alkyl, hydroxyl, amino, haloalkyl, 3-10 membered heterocycloalkane, R1, R4 and R5, at each occurrence, are each independently selected from H, a deuterium atom, a carboxyl group, 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; or R3 and R4 together with the atoms to which they are attached form a 3-10 membered heterocycloalkyl, a 3-10 membered cycloalkyl, a 6-10 membered aryl, a 6-10 membered heteroaryl, a 5-15 membered fused cyclic group or a heterofused cyclic group, a 5-15 membered spiro or a heterospiro cyclic group, wherein the 3-10 membered heterocycloalkyl, the 3-10 membered cycloalkyl, the 6-10 membered aryl, the 6-10 membered heteroaryl, the 4-15 membered fused cyclic group or a heterofused cyclic group and the 5-15 membered spiro or a heterospiro cyclic group The heterospirocyclyl may be optionally substituted with 1, 2 or more substituents selected from halo, carboxyl, alkoxy, alkyl, hydroxy, amino, haloalkyl, 3-10 membered heterocycloalkyl, 3-10 membered cycloalkyl, 6-10 membered aryl and 6-10 membered heteroaryl, and each occurrence of R1, R2 and R5 is independently selected from H, a deuterium atom, carboxyl, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy , haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, nitro, cyano, amino, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl; preferably, R3 and R4 together with the atoms to which they are attached form a 5-15 membered heterocondensed cyclic radical, or a 5-15 membered spirocyclic or heterospirocyclic radical; the 5-15 membered heterocondensed cyclic radical, or a 5-15 membered spirocyclic or heterospirocyclic radical may be optionally substituted with 1, 2 or more substituents selected from halo, carboxyl, alkoxy, alkyl, hydroxy, amino, haloalkyl, 3-10 membered heterocycloalkyl, 3-10 membered cycloalkyl, 6-10 membered aryl and 6-10 membered heteroaryl, and R1, R4 and R5 are each independently selected from H, a deuterium atom, carboxyl, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, haloalkyl, halide alkyl, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; or R4 and R5 together with the atoms to which they are attached form a 3-10 membered heterocycloalkyl, a 3-10 membered cycloalkyl, a 6-10 membered aryl, a 6-10 membered heteroaryl, a 5-15 membered fused cyclic group or a heterofused cyclic group, a 5-15 membered spiro or a heterospiro cyclic group, and the 3-10 membered heterocycloalkyl, the 3-10 membered cycloalkyl, the 6-10 membered aryl, the 6-10 membered heteroaryl, the 5-15 membered fused cyclic group or a heterofused cyclic group, the 5-15 membered spiro or a heterospiro cyclic group may be optionally substituted by 1, 2 or more radicals. or more substituents selected from the group consisting of halogen, carboxyl, alkoxy, alkyl, hydroxy, amino, haloalkyl, 3-10 membered heterocycloalkyl, 3-10 membered cycloalkyl, 6-10 membered aryl and 6-10 membered heteroaryl, R1, R2 and R3 are each independently selected from the group consisting of H, deuterium atoms, carboxyl, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, nitro, cyano, amino, alkylamino Preferably, R4 and R5 together with the atoms to which they are attached form a 5-15 membered hetero-fused cyclic group, or a 5-15 membered spiro or hetero-spiro cyclic group, wherein the 5-15 membered hetero-fused cyclic group, or a 5-15 membered spiro or hetero-spiro cyclic group may be optionally substituted by 1, 2 or more alkyl radicals selected from halo, carboxyl, alkoxy, alkyl, hydroxy, amino, haloalkyl, 3-10 membered heterocycloalkyl, , 3-10 membered cycloalkyl, 6-10 membered aryl and 6-10 membered heteroaryl, R1, R2 and R3, at each occurrence, are each independently selected from H, a deuterium atom, a carboxyl group, 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; R a and R b Each occurrence is independently selected from H, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a carboxyl 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 the alkyl group, 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 are each independently optionally substituted with one or more substituents 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 heterocyclyl group, an alkenyl group, an alkynyl group, b Each occurrence is independently selected from H, F, Cl, Br, I, C 1-3 Alkyl, C 1-3 Alkoxy, hydroxy, amino and -C(O)-C 1-3 alkyl; The compound is not the following structure:

3. The compound according to claim 2, or its isomer, isotopic derivative, polymorph, prodrug, or pharmaceutically acceptable salt or solvate, in, At least one of A2 and A4 is C(O); preferably, both A and A4 are C(O); and / or A3 is NH; and / or A5 and A6 are each independently selected from a single bond and C(H)2; preferably, A5 and A6 are C(H)2; and / or Each occurrence of L1 is independently selected from a single bond, C 1-6 Alkylene, halogenated C 1-6 Alkylene, -O-, -N(R b )C(O)-, -C(O)-, -OC(O)-, -NR b -、-S-、-SO-、-SO2-、C 3-15 Cycloalkylene, C 3-15 Heterocyclylene, C 6-15 Arylene and C 5-15 wherein the cycloalkylene, heterocyclylene, arylene and heteroarylene are optionally substituted by 0-6 R b Group substitution; preferably, L1 is a single bond; and / or n1 is selected from 1, 2, 3; and / or R1 and R2 together with the atoms to which they are attached form a 3-10 membered saturated or unsaturated heterocyclic alkyl group containing 1, 2, or 3 N, O, or S atoms, 6-10 membered aromatic group, The 3-10 membered saturated or unsaturated heterocyclic alkyl containing 1, 2 or 3 N, O or S atoms, and the 6-10 membered aryl group may be optionally substituted by 1, 2 or more halogen, carboxyl, C 1-6 Alkoxy, C 1-6 Alkyl, hydroxyl, amino, C 1-6 wherein R5 is present, and each occurrence of R3, R4 and R5 is independently selected from H, a deuterium atom, a carboxyl group, a halogen, a C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Heteroalkyl, alkenyl, alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, hydroxy, C 1-6 Hydroxyalkyl, nitro, cyano, amino, C 1-6 Alkylamino, C 1-6 Alkyl acyl, C 1-6 Alkyloxy acyl, C 1-6 Alkylaminoacyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; preferably, R1 and R2 together with the atoms to which they are attached form R2 and R3 together with the atoms to which they are attached form a 3-10 membered saturated or unsaturated heterocyclic alkyl group containing 1, 2, or 3 N, O, or S atoms, a 6-10 membered aryl group, The 3-10 membered saturated or unsaturated heterocycloalkyl containing 1, 2, or 3 N, O, S atoms, the 6-10 membered aryl may be optionally substituted by 1, 2 or more substituents selected from halogen, carboxyl, alkoxy, alkyl, hydroxyl, amino, haloalkyl, 3-10 membered heterocycloalkyl, 3-10 membered cycloalkyl, 6-10 membered aryl and 6-10 membered heteroaryl, and when R5 is present, R1, R4 and R5 are each independently selected from H, deuterium atoms, carboxyl, halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Heteroalkyl, alkenyl, alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, hydroxy, C 1-6 Hydroxyalkyl, nitro, cyano, amino, C 1-6 Alkylamino, C 1-6 Alkyl acyl, C 1-6 Alkyloxy acyl, C 1-6 Alkylaminoacyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; preferably, R2 and R3 together with the atoms to which they are attached form or R3 and R4 together with the atoms to which they are attached form a 3-10 membered saturated or unsaturated heterocyclic alkyl containing 1, 2, or 3 N, O, S atoms, a 6-10 membered aryl ring, The 3-10 membered saturated or unsaturated heterocycloalkyl containing 1, 2, or 3 N, O, S atoms, the 6-10 membered aryl may be optionally substituted by 1, 2 or more substituents selected from halogen, carboxyl, alkoxy, alkyl, hydroxyl, amino, haloalkyl, 3-10 membered heterocycloalkyl, 3-10 membered cycloalkyl, 6-10 membered aryl and 6-10 membered heteroaryl, and when R5 is present, R1, R2 and R5 are each independently selected from H, deuterium atoms, carboxyl, halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Heteroalkyl, alkenyl, alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, hydroxy, C 1-6 Hydroxyalkyl, nitro, cyano, amino, C 1-6 Alkylamino, C 1-6 Alkyl acyl, C 1-6 Alkyloxy acyl, C 1-6 Alkylaminoacyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; preferably, R3 and R4 together with the atoms to which they are attached form or R4 and R5 together with the atoms to which they are attached form a 3-10 membered saturated or unsaturated heterocyclic alkyl group containing 1, 2, or 3 N, O, or S atoms, a 6-10 membered aryl group, The 3-10 membered saturated or unsaturated heterocycloalkyl containing 1, 2, or 3 N, O, S atoms, the 6-10 membered aryl may be optionally substituted by 1, 2 or more substituents selected from halogen, carboxyl, alkoxy, alkyl, hydroxyl, amino, haloalkyl, 3-10 membered heterocycloalkyl, 3-10 membered cycloalkyl, 6-10 membered aryl and 6-10 membered heteroaryl, R1, R2 and R3 are each independently selected from H, deuterium atoms, carboxyl, halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Heteroalkyl, alkenyl, Alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, hydroxy, C 1-6 Hydroxyalkyl, nitro, cyano, amino, C 1-6 Alkylamino, C 1-6 Alkyl acyl, C 1-6 Alkyloxy acyl, C 1-6 Alkylaminoacyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; preferably, R4 and R5 together with the atoms to which they are attached form Each time B2 appears, select C(R a )2. NR a , O and S; Each time B4 and B5 appear, they are independently selected from CR a and N; Each time C3 appears, choose from C(O), CR c R d and NR a ; R c and R d Each occurrence is independently selected from H, deuterium atoms, halogens, C 1-6 Alkyl, C 1-6 Deuterated alkyl, carboxyl, C 1-6 Heteroalkyl, alkenyl, alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, hydroxy, C 1-6 Hydroxyalkyl, nitro, cyano, amino, C 1-6 Alkylamino, C 1-6 Alkyl acyl, C 1-6 Alkyloxy acyl, C 1-6 Alkylaminoacyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl, wherein the alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic radical, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic radical, alkenyl, alkynyl, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, aryl and heteroaryl; or R c and R d and the carbon atom to which it is attached can together form a 3-10 membered heterocycloalkyl, a 3-10 membered cycloalkyl, a 6-10 membered aryl, a 6-10 membered heteroaryl, wherein the 3-10 membered heterocycloalkyl, the 3-10 membered cycloalkyl, the 6-10 membered aryl, the 6-10 membered heteroaryl may be optionally substituted with 1, 2 or more substituents selected from halo, carboxyl, alkoxy, alkyl, hydroxyl, amino, haloalkyl, 3-10 membered heterocycloalkyl, 3-10 membered cycloalkyl, 6-10 membered aryl and 6-10 membered heteroaryl; n2, n3, n4, n5 and n6 are each independently selected from 0, 1, 2 and 3; Each occurrence of B1, B3, B6, C1, C2, D1 and D2 is independently selected from C(R a )2; D3 is selected from C(O) and NR a ; and / or R a and R b Each occurrence is independently selected from H, deuterium atoms, F, Cl, Br, I, C 1-6 Alkyl, deuterated C 1-6 Alkyl, carboxyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxyl, C 1-6 Hydroxyalkyl, nitro, cyano, amino, C 1-6 Alkylamino, C 1-6 Alkyl acyl, C 1-6 Alkyloxy acyl, C 1-6 Alkylaminoacyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl and 5-10 membered heteroaryl, wherein the alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, aryl and heteroaryl; Indicates the connection site.

4. The compound according to any one of claims 1 to 3, wherein the compound is selected from the following structures: in, R1, R2, R3, R4, R5, B1, B2, B3, B4, B5, B6, C1, C2, C3, R a , n2, n3, n4, n5 and n6 are as defined in any one of claims 1 to 3; Preferably: R1, R2, R3, R4 and R5 are each independently selected from H, F, Cl, Br, I, C 1-3 Alkyl, C 1-3 Alkoxy, hydroxyl and amino groups; Each time B2 appears, select C(R a )2. NR a , O and S; Each occurrence of B1 and B3 is independently selected from C(R a )2 and CO; Each time B6 appears, select C(R a )2 and NR a ; One of B4 and B5 is N and the other is CR a ; Each time C1 and C2 appear, they are independently C(R a )2; C3 is selected from C(O) and NR a ; R a Each occurrence is independently selected from H, F, Cl, Br, I, C 1-3 Alkyl, C 1-3 Alkoxy, hydroxy, amino and -C(O)-C 1-3 Alkyl; and n2, n3, n4, n5 and n6 are each independently selected from 0, 1, 2 and 3.

5. The compound according to any one of claims 1 to 4, wherein the compound is selected from any one of the following structures: Preferably, the compound is selected from:

6. A compound as shown in formula II, or its isomer, isotopic derivative, polymorph, prodrug, or pharmaceutically acceptable salt or solvate, PTM-L-CLM (Formula II) in, L is a bond or chemical linking moiety that covalently links the PTM and CLM moieties; and PTM is a target protein binding portion; preferably, the target protein is selected from B7.1, B7, TNFR2, NADPH oxidase, BclIBax and other partners in the apoptosis pathway, C5a receptor, HMG-CoA reductase, PDE V phosphodiesterase type, PDEIV phosphodiesterase type 4, PDEI I, PDEI II, PDE III, squalene epoxidase, CXCR1, CXCR2, nitric oxide (NO) synthase, cyclooxygenase 1, cyclooxygenase 2, 5HT receptor, dopamine receptor, G protein (i.e. Gq), histamine receptor, 5-lipoxygenase, trypsin-like serine protease, thymidylate synthase, purine nucleoside phosphorylase, GAPDH trypanosome, glycogen phosphorylase, carbonic anhydrase, chemokine receptor, JAW STAT, RXR and its analogs, HIV1 protease, HIV1 integrase, influenza neuraminidase, hepatitis B reverse transcriptase, sodium channel, multidrug-resistant bacteria, protein P-glycoprotein, tyrosine kinase, CD23, CD124, tyrosinase p561ck, CD4, CD5, IL-2 receptor, IL-1 receptor, TNF-αR, ICAM1, Ca 2+ channel, VCAM, VLA-4 integrin, selectin, CD40 / CD40L, inosine monophosphate dehydrogenase, p38 MAP kinase, RaslRaflMEWERK pathway, interleukin-1 converting enzyme, caspase, HCV, NS3 protease, HCVNS3RNA helicase, glycinamide ribonucleotide formyltransferase, rhinovirus, 3C protease, herpes simplex virus-I (HSV-I), protease, cytomegalovirus (CMV) protease, poly (ADP-ribose) polymerase, cyclin-dependent Kinase 4 / 6, vascular endothelial growth factor, oxytocin receptor, microsomal transfer protein inhibitor, bile acid transport inhibitor, 5α reductase inhibitor, angiotensin 11, glycine receptors, norepinephrine reuptake receptors, endothelin receptors, neuropeptide Y and receptors, adenosine receptors, adenosine kinase and AMP deaminase, purinergic receptors (P2Y1, P2Y2, P2Y4, P2Y6, P2X1-7), farnesyltransferase, geranylgeranyltransferase, TrkA receptor of NGF, beta-amyloid protein, tyrosine kinase Flk-II KDR, vitronectin receptor, integrin receptor, Her-21 nerve sheath, telomerase inhibition, cytosolic phospholipase A2, ecdysone 20-monooxygenase, GABA-gated chloride channel ion channel, acetylcholinesterase, voltage-sensitive sodium channel protein, calcium release channel and chloride channel, acetyl CoA carboxylase, adenylate succinate synthetase, protoporphyrinogen oxidase, enolpyruvylshikimate phosphate synthetase, MYC protein, androgen receptor, estrogen receptor, Aurora kinase A, Bcr-Abl protein, epidermal growth factor receptor, anaplastic lymphoma kinase, Bruton's tyrosine kinase, bromodomain protein 4 and interleukin-1 receptor associated kinase 4 (IRAK4); preferably, the target protein is selected from androgen receptor, estrogen receptor and interleukin-1 receptor associated kinase 4 (IRAK4); and CLM is a cerebellar protein E3 ubiquitin ligase binding moiety selected from any of the following structures: Among them, R 1a , R 2a , R 3a , R 4a and R 5a Each occurrence is independently selected from H, deuterium atoms, halogens, C 1-6 Alkyl, C 1-6 Deuterated alkyl, carboxyl, C 1-6 Heteroalkyl, alkenyl, alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, hydroxy, C 1-6 Hydroxyalkyl, nitro, cyano, amino, C 1-6 Alkylamino, C 1-6 Alkyl acyl, C 1-6 Alkyloxy acyl, C 1-6 Alkylaminoacyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Heteroalkyl, alkenyl, alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 1-6 Alkyl acyl, C 1-6 Alkyloxy acyl, C 1-6 Alkylaminoacyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more substituents selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, aryl and heteroaryl; preferably, R 1a , R 2a , R 3a , R 4a and R 5a Each occurrence is independently selected from H, deuterium atoms, halogens, 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, hydroxy, C 1-6 More preferably, R 1a , R 2a , R 3a , R 4a and R 5a 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, amino and hydroxy; further preferably, R 1a , R 2a , R 3a , R 4a and R 5a Each occurrence is independently selected from H, F, Cl, Br, I, C 1-3 Alkyl, C 1-3 Alkoxy, hydroxyl and amino groups; B 2a Selected from C(R aa )2. NR aa , O and S; and when B 4a and B 5a When present, B 2a Selected from NR aa , O and S; B 4a and B 5a Each independently selected from CR aa and N; preferably, B 4a and B 5a One of them is N and the other is CR aa ; B 1a and B 3a Each occurrence is independently selected from C(R aa )2 and C(O); B 6a Each time it appears, select C(R aa )2 and NR aa ; C 1a and C 2a Each time it appears, it is independently C(R aa )2; m2, m3, m4, m5 and m6 are each independently selected from 0, 1, 2 and 3; and m5 and m6 are not 0 at the same time; C 31 Selected from N and CR d ; R aa and R d Each occurrence is independently selected from H, deuterium atoms, F, Cl, Br, I, C 1-6 Alkyl, deuterated C 1-6 Alkyl, carboxyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -CO-C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxyl, C 1-6 Hydroxyalkyl, nitro, cyano, amino, C 1-6 Alkylamino, C 1-6 Alkyl acyl, C 1-6 Alkyloxy acyl, C 1-6 alkylaminoacyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl and 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -CO-C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 1-6 Alkyl acyl, C 1-6 Alkyloxy acyl, C 1-6 Alkylaminoacyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl and 5-10 membered heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, alkenyl, alkynyl, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, aryl and heteroaryl; preferably, R aa and R d Each occurrence is independently selected from H, deuterium atoms, F, Cl, Br, I, C 1-6 Alkyl, deuterated C 1-6 Alkyl, carboxyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -CO-C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxyl, C 1-6 Hydroxyalkyl, nitro, cyano, amino, C 1-6 Alkylamino, C 1-6 Alkyl acyl, C 1-6 Alkyloxy acyl and C 1-6 More preferably, R aa and R d Each occurrence is independently selected from H, F, Cl, Br, I, C 1-6 Alkyl, carboxyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -CO-C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxyl, C 1-6 hydroxyalkyl, nitro, cyano and amino; further preferably, R aa and R d Each occurrence is independently selected from H, F, Cl, Br, I, C 1-3 Alkyl, C 1-3 Alkoxy, hydroxy, amino and -C(O)-C 1-3 alkyl; PTM does not And when PTM is the IRAK4 binding part, CLM is hour, Not for 7. The compound according to claim 6, characterized in that The CLM is selected from any of the following structures: Preferably, the CLM is selected from:

8. The compound according to claim 6 or 7, in, L is a bond or -(B L ) q -; B L Each occurrence is the same or different and is independently selected from CR L1 R L2 、O、S、SO、SO2、NR L3 、SO2NR L3 ,SONR L3 ,CONR L3 NR L3 CONR L4 NR L3 SO2NR L4 ,CO,CR L1 =CR L2 、C≡C、SiR L1 R L2 、P(O)R L1 、P(O)OR L1 NR L3 C(=NCN)NR L4 NR L3 C(=NCN),NR L3 C(=CNO2)NR L4 , cycloalkylene, heterocyclylene, arylene or heteroarylene, wherein the cycloalkylene, heterocyclylene, arylene and heteroarylene are optionally substituted by 0-6 R L1 and / or R L2 Group substitution; R L1 , R L2 , R L3 and R L4 Each occurrence is independently selected from H, halogen, C 1-8 Alkyl, OC 1-8 Alkyl, SC 1-8 Alkyl, NH-C 1-8 Alkyl, N(C 1-8 Alkyl)2, C 3-11 Cycloalkyl, aryl, heteroaryl, C 3-11 Heterocyclic group, OC 3-8 Cycloalkyl, OC 3-11 Heterocyclyl, O-aryl, O-heteroaryl, SC 3-8 Cycloalkyl, NH-C 3-8 Cycloalkyl, N(C 3-8 Cycloalkyl)2, N(C 3-8 Cycloalkyl)(C 1-8 Alkyl), NH-C 3-8 Heterocyclic group, N(C 3-8 Heterocyclic)2, N(C 3-8 Heterocyclic group (C 1-8 alkyl), NH-aryl, N(aryl)(C 1-8 alkyl), NH-heteroaryl, N(heteroaryl)(C 1-8 alkyl), OH, NH2, SH, SO2P(O)(OC 1-8 Alkyl)(C 1-8 alkyl), P(O)(OC 1-8 Alkyl)2, C≡CC 1-8 Alkyl, C≡CH, CH=CH-(C 1-8 alkyl), C(C 1-8 alkyl)=CH-(C 1-8 alkyl), C(C 1-8 alkyl)=C(C 1-8 alkyl)2, Si(OH)3, Si(C 1-8 Alkyl)3, Si(OH)(C 1-8 Alkyl)2, CO-C 1-8 Alkyl, CO2H, CN, CF3, CHF2, CH2F, NO2, SF5, SO2NH-C 1-8 Alkyl, SO2N(C 1-8 Alkyl)2, SONH-C 1-8 Alkyl, SON(C 1-8 Alkyl)2, CONH-C 1-8 Alkyl, CON(C 1-8 Alkyl)2, N(C 1-8 alkyl)CONH(C 1-8 Alkyl), N(C 1-8 alkyl)CON(C 1-8 Alkyl)2, NHCONH(C 1-8 alkyl), NHCON(C 1-8 alkyl)2, NHCONH2, N(C 1-8 Alkyl)SO2NH(C 1-8 Alkyl), N(C 1-8 Alkyl)SO2N(C 1-8 Alkyl)2, NHSO2NH(C 1-8 alkyl), NH SO2N(C 1-8 Alkyl)2 and NH SO2NH2, the C 1-8 Alkyl, C 3-11 Cycloalkyl, C 3-11 Heterocyclic group, C 6-10 Aryl and C 5-10 The heteroaryl groups are each independently optionally selected from halogen, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, hydroxy, haloalkyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, halocycloalkyl, haloheteroalkyl, alkylamino substituted by one or more substituents selected from the group consisting of alkyl, aryl, heteroaryl, halogenated aryl and halogenated heteroaryl; and q is an integer greater than or equal to 1; preferably, q is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.

9. The compound according to claim 8, wherein B L One or more selected from the following structures: -O-、-S-、-SO-、-SO2-、-CH2-、-CO-、-NH-、 For the connection point.

10. The compound of any one of claims 6 to 9, wherein L is selected from the following structures: Covalent bond, -(CH2) j -, -(CH2) p -NH-(CH2) s -, -(CH2) y -NH-(CH2) j -NH-(CH2) s -, -(CH2) p -CO-(CH2) s -, -(CH2) p -O-(CH2) s -, -(CH2) y -CO-(CH2) j -CO-(CH2) s -, -(CH2) y -O-(CH2) j -O-(CH2) s -, -(CH2) y -O-(CH2) j -CO-(CH2) s -, -(CH2) y -CO-(CH2) j -O-(CH2) s -, -(CH2) p -NH-(CH2) y -O-(CH2) j -CO-(CH2) s -, -(CH2) y -CO-(CH2) j -O-(CH2) s -NH-(CH2) p -, in, j is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; k, s, p and y are 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; is the binding site of CLM or PTM; Preferably, L is selected from the following structures: covalent bond, -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-, -CO-NH-CH2-, -CO-NH-(CH2)2-, -CO-NH-(CH2)3-, -CO-NH-(CH2)4-, -CO-NH-(CH2)5-, -CO-NH-(CH2)6-, -CO-NH-(CH2)7-, -CO-NH-(CH2)8-, -CH2-NH-, -(CH2)2-NH-, -(CH2)3-NH-, -(CH2)4-NH-, -(CH2)5-NH-, -(CH2)6-NH-, -(CH2)7-NH-, -(CH2)8-NH-, -NH-CH2-NH-, -NH-(CH2)2-NH-, -NH-(CH2)3-NH-, -NH-(CH2)4-NH-, -NH-(CH2)5-NH-, -NH-(CH2)6-NH-, -NH-(CH2)7-NH-, -NH-(CH2)8-NH-, -(CH2-CH2-O)-CH2-CH2-, -(CH2-CH2-O)2-CH2-CH2-, -(CH2-CH2-O)3-CH2-CH2-, -NH-(CH2-CH2-O)-CH2-CH2-, -NH-(CH2-CH2-O)2-CH2-CH2-, -NH-(CH2-CH2-O)3-CH2-CH2-, -CO-NH-(CH2-CH2-O)-CH2-CH2-, -CO-NH-(CH2-CH2-O)2-CH2-CH2-, -CO-NH-(CH2-CH2-O)3-CH2-CH2-, -(CH2-CH2-O)-CH2-CH2-NH-, -(CH2-CH2-O)2-CH2-CH2-NH-, -(CH2-CH2-O)3-CH2-CH2-NH-, -NH-(CH2-CH2-O)-CH2-CH2-NH-, -NH-(CH2-CH2-O)2-CH2-CH2-NH-, -NH-(CH2-CH2-O)3-CH2-CH2-NH-, -CO-NH-(CH2-CH2-O)-CH2-CH2-NH-, -CO-NH-(CH2-CH2-O)2-CH2-CH2-NH-, -CO-NH-(CH2-CH2-O)3-CH2-CH2-NH--CH2-CH2-(O-CH2-CH2)-、-CH2-CH2-(O-CH2-CH2)2-、-CH2-CH2-(O-CH2-CH2)3-、-NH-CH2-CH2-(O-CH2-CH2)-、-NH-CH2-CH2-(O-CH2-CH2)2-、-NH-CH2-CH2-(O-CH2-CH2)3-、-CO-NH-CH2-CH2-(O-CH2-CH2)-、-CO-NH-CH2-CH2-(O-CH2-CH2)2-、-CO-NH-CH2-CH2-(O-CH2-CH2)2-、-CO-NH-CH2-CH2-(O-CH2-CH2)2-、-CO-NH-CH2-CH2-(O-CH2-CH2)3-、-CH2-CH2-(O-CH2-C H2)-NH-、-CH2-CH2-(O-CH2-CH2)2-NH-、-CH2-CH2-(O-CH2-CH2)3-NH-、-NH-CH2-CH2-(O-CH2-CH2)-NH-、-NH-CH2-CH2-(O-CH2-CH2)2-NH-、-NH-CH2-CH2-(O-CH2-CH2)3-NH-、-NH-CH2-CH2-O-CH2-CH2-CO-、-CO-CH2-CH2-O-CH2-CH2-NH-、-NH-(CH2)4-CO-、-NH-(CH2)5-CO-、-NH-(CH2)6-CO-、-CO-(C H2)4-NH-、-CO-(CH2)5-NH-、-CO-(CH2)6-NH-、-NH-(CH2-CH2-O)-(CH2)3-、-NH-(CH2-CH2-O)-(CH2)4-、-NH-(CH2-CH2-O)-(CH2)5-、-NH-(CH2-CH2-O)-(CH2)6-、-(CH2)3-(O-CH2-CH2)-NH-、-(CH2)4-(O-CH2-CH2)-NH-、-(CH2)5-(O-CH2-CH2)-NH-、-(CH2)6-(O-CH2-CH2)-NH-、-CH2-CH2-O-(CH2)2- CO-、-CH2-CH2-O-(CH2)3-CO-、-CH2-CH2-O-(CH2)4-CO-、-CO-(CH2)2-O-CH2-CH2-、-CO-(CH2)3-O-CH2-CH2-、-CO-(CH2)4-O-CH2-CH2-、-CO-(CH2)2-、-CO-(CH2)3-、-CO-(CH2)4-、-CO-(CH2)5-、-CO-(CH2)6-、-(CH2)2-CO-、-(CH2)3-CO-、-(CH2)4-CO-、-(CH2)5-CO-、-(CH2)6-CO-、-CO-(CH2)2-CO-、-CO-(CH2)3-CO-, -CO-(CH2)4-CO-, -CO-(CH2)5-CO-, -CO-(CH2)6-CO-, -CH2-CO-CH2-, -CH2-CO-(CH2)2-, -CH2-CO-(CH2)3-, -CH2-CO-(CH2)4-, -(CH2)2-CO-CH2-, -(CH2)2-CO-(CH2)2-、-(CH2)2-CO-(CH2)3-、-(CH2)2-CO-(CH2)4-、-(CH2)3-CO-CH2-、-(CH2)3-CO-(CH2)2-、-(CH2)3-CO-(CH2)3-、-(CH2)3-CO-(CH2)4-、-(CH2)4-CO-CH2-、-(CH2)4-CO-(CH2)2-、-(CH2)4-CO-(CH2)3-、-(CH2)4-CO-(CH2)4-、-CH2-O-CH2-、-CH2-O-(CH2)2-、-CH 2-O-(CH2)3-、-CH2-O-(CH2)4-、-(CH2)2-O-CH2-、-(CH2)2-O-(CH2)2-、-(CH2)2-O-(CH2)3-、-(CH2)2-O-(CH2)4-、-(CH2)3-O-CH2-、-(CH2)3-O-(CH2)2-、-(CH2)3-O-(CH2)3-、-(CH2)3-O-(CH2)4-、-(CH2)4-O-CH2-、-(CH2)4-O-(CH2)3-、 11. The compound according to any one of claims 6 to 10, wherein the PTM is a portion that binds to an androgen receptor; preferably, the PTM is selected from the following structures: in, F6, F 16 and F 21 Each occurrence is independently selected from a single bond, NH, SO, S, O, SO2, alkylene, haloalkylene, heteroalkylene, alkyleneoxy, heteroalkoxy, alkenylene, alkynylene, C(=O), OC(=O), C(=O)O, C(=O)NH and NHC(=O) in combination of one or more; wherein the alkylene, alkyleneoxy and alkenylene are optionally substituted with 0, 1, 2, 3, 4, 5 or 6 Rc; preferably, F6, F 16 and F 21 Each occurrence is independently selected from a single bond, NH, SO, S, O, SO2, C(=O), OC(=O) and NHC(=O); F A1 and F A3 Each independently selected from 6-10 membered aryl and 5-10 membered heteroaryl; the aryl and heteroaryl are optionally substituted by 0, 1, 2, 3, 4, 5 or 6 R da preferably, F A1 is phenyl, optionally substituted by 0, 1, 2, 3, 4, 5 or 6 R da Replacement, F A3 is phenyl or a 6-membered heteroaryl group containing 1, 2, or 3 N, O, or S heteroatoms, optionally substituted by 0, 1, 2, 3, 4, 5, or 6 R da replace; F A2 is 3-15 membered cycloalkylene, 5-15 membered spirocycloalkylene, 3-15 membered heterocycloalkylene or 5-15 membered spiroheterocycloalkylene, optionally substituted by 0, 1, 2, 3, 4, 5 or 6 R ca preferably, F A2 is a 4-6 membered cycloalkylene group, a 7-11 membered spirocycloalkylene group, a 4-6 membered heterocyclylene group or a 7-11 membered heterospirocyclylene group, optionally substituted by 0, 1, 2, 3, 4, 5 or 6 R ca preferably, F A2 is a 4-, 5- or 6-membered cycloalkylene group, a 10-membered heterospirocyclylene group containing 1, 2 or 3 N atoms; optionally substituted by 0, 1, 2, 3, 4, 5 or 6 R ca replace; F A4 is a 6-10 membered aryl-fused 7-15 membered heterospirocyclic group, optionally substituted by 0, 1, 2, 3, 4, 5 or 6 R da preferably, F A4 is a phenyl-fused 7-15 membered heterospirocyclic group containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, optionally substituted by 0, 1, 2, 3, 4, 5 or 6 R da replace; R da Each occurrence is independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 1-6 Alkoxy, C 1-6 Heteroalkoxy, C 3-7 Cycloalkyl, C 3-7 Heterocyclic group, C 6-8 Aryl, C 5-8 heteroaryl, OH, NH2, CN and NO2; preferably, R da Each occurrence is independently selected from H, F, Cl, Br, I, CH3, OCH3, CF3, OH, NH2, CN and NO2; R ca Each occurrence is independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, C 1-6 Alkoxy, C 1-6 Heteroalkoxy, C 3-7 Cycloalkyl, C 3-7 Heterocyclic group, C 6-8 Aryl, C 5-8 heteroaryl, oxo (=O), thio (=S), OH, NH2, CN and NO2; preferably, R ca Each occurrence is independently selected from H, F, Cl, Br, I, CH3, OCH3, CF3, OH, NH2, CN and NO2; Preferably, the PTM is selected from:

12. The compound according to claim 11, whose structure is selected from:

13. The compound according to any one of claims 6 to 10, wherein the PTM is a moiety that binds to an estrogen receptor, preferably, the PTM is selected from the following structures: R ea Selected from CR e1a and N; R e4 is selected from 6-10 membered aryl, 5-10 membered heteroaryl, C1-C6 alkyl and C1-C6 haloalkyl, wherein the 6-10 membered aryl and 5-10 membered heteroaryl may be optionally substituted by 0, 1, 2, 3, 4 or 5 R e1a Substituted; preferably, R e4 is selected from phenyl and difluoroethyl, the phenyl group may be optionally substituted by 0, 1, 2, 3, 4 or 5 R e1a replace; R e1a , R e2 and R e3 Each occurrence is independently selected from H, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino. Preferably, R e1a and R e2 Each occurrence is independently selected from hydroxy, H, F, Cl, Br, I and C1-C3 alkyl; Each time e appears, it is selected from 0, 1, 2, 3, and 4; Preferably, the PTM is selected from:

14. The compound of claim 13, selected from 15. The compound according to any one of claims 6 to 10, wherein the PTM is a portion that binds to the IRAK4 receptor, and preferably, the structure of the PTM is: in, R 101 is selected from a single bond, a 3-10 membered heterocycloalkylene group, a 3-10 membered cycloalkylene group, a 6-10 membered arylene group and a 5-10 membered heteroarylene group, wherein the 3-10 membered heterocycloalkylene group, the 3-10 membered cycloalkylene group, the 6-10 membered aryl group and the 5-10 membered heteroaryl group are optionally substituted with 1, 2 or more substituents selected from halo, carboxyl, alkoxy, alkyl, hydroxyl, amino and haloalkyl; preferably, R 101 is selected from a single bond, a 5-7 membered heterocycloalkylene, a 5-7 membered cycloalkylene, a 6 membered arylene and a 5-8 membered heteroarylene, wherein the 5-7 membered heterocycloalkylene, the 5-7 membered cycloalkylene, the 6 membered arylene and the 5-8 membered heteroarylene are optionally substituted by 1, 2 or 3 selected from F, Cl, Br, I, carboxyl, C 1-3 Alkoxy, C 1-3 Alkyl, hydroxy, amino and halo 1-3 substituted by an alkyl substituent; R 102 , R 103 , R 104 , R 105 and R 106 Selected from H, deuterium atoms, halogens, C 1-6 Alkyl, C 1-6 Deuterated alkyl, carboxyl, C 1-6 Heteroalkyl, alkenyl, alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, hydroxy, C 1-6 Hydroxyalkyl, nitro, cyano, amino, C 1-6 Alkylamino, C 1-6 Alkyl acyl, C 1-6 Alkyloxy acyl and C 1-6 Alkylaminoacyl; preferably, R 102 , R 103 , R 104 , R 105 and R 106 Selected from H, F, Cl, Br, I, C 1-3 Alkyl, carboxyl, C 1-3 Heteroalkyl, C 1-3 Alkoxy and C 1-3 More preferably, R 102 C 1-3 Fluorinated alkyl; More preferably, the structure of the PTM is:

16. The compound of claim 15, wherein the compound is selected from:

17. A pharmaceutical composition comprising the compound according to any one of claims 1 to 16.

18. The compound of any one of claims 6 to 16 or the pharmaceutical composition of claim 17, which is used to treat or prevent a disease that is treated by degrading a target protein that binds to a target protein ligand; preferably, the target protein is cyclin-dependent kinase 4 / 6, androgen receptor, estrogen receptor, Aurora kinase A, Bcr-Abl protein, epidermal growth factor receptor, anaplastic lymphoma kinase, Bruton's tyrosine kinase, or bromodomain protein 4 or interleukin-1 receptor-associated kinase 4 (IRAK4).

19. A compound according to any one of claims 6 to 16 or a pharmaceutical composition according to claim 17 for use in treating or preventing a disease that is treated by binding to cerebellin in vivo.

20. A compound according to any one of claims 6 to 16 or a pharmaceutical composition according to claim 17, for treating or preventing a condition associated with the accumulation and / or aggregation of a target protein; preferably, the target protein is cyclin-dependent kinase 4 / 6, androgen receptor, estrogen receptor, Aurora kinase A, Bcr-Abl protein, epidermal growth factor receptor, anaplastic lymphoma kinase, Bruton's tyrosine kinase, bromodomain protein 4 or interleukin-1 receptor-associated kinase 4 (IRAK4).

21. The compound or pharmaceutical composition of any one of claims 18-20, wherein the disease is a tumor or cancer; preferably, the tumor or cancer is breast cancer, mammary ductal carcinoma, prostate cancer, mantle cell lymphoma, chronic myeloid leukemia, acute myeloid leukemia, myelomonocytic leukemia, non-small cell lung cancer, lung adenocarcinoma, and / or cervical cancer.

22. Use of a compound according to any one of claims 1 to 5 or a pharmaceutical composition according to claim 17 in the preparation of a medicament for treating or preventing a disease that is treated by binding to cerebellar protein in vivo.

23. Use of the compound according to any one of claims 6 to 16 or the pharmaceutical composition according to claim 17 in the preparation of a medicament for treating or preventing a disease treated by degrading a target protein that binds to a target protein ligand; preferably, the target protein is cyclin-dependent kinase 4 / 6, androgen receptor, estrogen receptor, Aurora kinase A, Bcr-Abl protein, epidermal growth factor receptor, anaplastic lymphoma kinase, Bruton's tyrosine kinase, bromodomain protein 4 or interleukin-1 receptor-associated kinase 4 (IRAK4).

24. Use of the compound of any one of claims 6 to 16 or the pharmaceutical composition of claim 17 in the preparation of a medicament for treating or preventing a disease associated with the accumulation and / or aggregation of a target protein; preferably, the target protein is cyclin-dependent kinase 4 / 6, androgen receptor, estrogen receptor, Aurora kinase A, Bcr-Abl protein, epidermal growth factor receptor, anaplastic lymphoma kinase, Bruton's tyrosine kinase, bromodomain protein 4 or interleukin-1 receptor-associated kinase 4 (IRAK4).

25. The use according to any one of claims 23 to 25, wherein the disease is a tumor or cancer; preferably, the tumor or cancer is breast cancer, mammary ductal carcinoma, prostate cancer, mantle cell lymphoma, chronic myeloid leukemia, acute myeloid leukemia, myelomonocytic leukemia, non-small cell lung cancer, lung adenocarcinoma, and / or cervical cancer.

26. A method for treating or preventing a disease treated by degrading a target protein bound to a target protein ligand, comprising administering a therapeutically effective amount of a compound according to any one of claims 6 to 16 or a pharmaceutical composition according to claim 17 to a subject in need thereof; preferably, the target protein is cyclin-dependent kinase 4 / 6, androgen receptor, estrogen receptor, Aurora kinase A, Bcr-Abl protein, epidermal growth factor receptor, anaplastic lymphoma kinase, Bruton's tyrosine kinase, bromodomain protein 4 or interleukin-1 receptor-associated kinase 4 (IRAK4).

27. A method for treating or preventing a condition that is treated by binding to cerebellin in vivo, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 6 to 16 or a pharmaceutical composition according to claim 17.

28. A method for treating or preventing a condition associated with the accumulation and / or aggregation of a target protein, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 6 to 16 or a pharmaceutical composition according to claim 17; preferably, the target protein is cyclin-dependent kinase 4 / 6, androgen receptor, estrogen receptor, Aurora kinase A, Bcr-Abl protein, epidermal growth factor receptor, anaplastic lymphoma kinase, Bruton's tyrosine kinase, or bromodomain protein 4 or interleukin-1 receptor-associated kinase 4 (IRAK4).

29. The method of any one of claims 26-28, wherein the disease is a tumor or cancer; preferably, the tumor or cancer is breast cancer, mammary ductal carcinoma, prostate cancer, mantle cell lymphoma, chronic myeloid leukemia, acute myeloid leukemia, myelomonocytic leukemia, non-small cell lung cancer, lung adenocarcinoma, and / or cervical cancer.

30. A method for inducing degradation of a target protein in a cell, the method comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 6 to 16 or a pharmaceutical composition according to claim 17; preferably, the target protein is cyclin-dependent kinase 4 / 6, androgen receptor, estrogen receptor, Aurora kinase A, Bcr-Abl protein, epidermal growth factor receptor, anaplastic lymphoma kinase, Bruton's tyrosine kinase, bromodomain protein 4 or interleukin-1 receptor-associated kinase 4 (IRAK4).

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