WO2021143822A1 - Bicyclic imide derivative, preparation method thereof, and application thereof in medicine - Google Patents

Abstract

The present invention relates to a bicyclic imide derivative, a preparation method thereof, and an application thereof in medicine. Specifically, the present invention relates to a novel ligand compound of bicyclic imide represented by general formula (IM) binding to a cereblon E3 ubiquitin ligase protein. The present invention also relates to a proteolysis targeting chimera (PROTAC) containing the same, the preparation method and the application thereof in medicine. The definition of each group in general formula (IM) is the same as in the description.

Description

Bicyclic imide derivatives, preparation method thereof and application in medicine

This application claims the priority of the Chinese patent application CN202010046668.5 with the filing date of January 16, 2020 and the Chinese patent application CN202011501193.0 with the filing date of December 18, 2020. This application quotes the full text of the aforementioned Chinese patent application.

Technical field

The present disclosure belongs to the field of medicine, and relates to a novel cereblon E3 ubiquitin ligase protein-binding ligand compound and protein degradation targeting chimera (PROTACs) compound containing the same, and its preparation Method, and its application in medicine. Specifically, the present disclosure relates to a novel cyclic imide cerebellar protein E3 ubiquitin ligase protein-binding ligand compound represented by general formula (IM) and protein degradation targeting chimeras (PROTACs) containing the same Compound, its preparation method, and its application in medicine. The medical application of the present disclosure demonstrates (but is not limited to) its use as an estrogen receptor degrading agent to treat estrogen receptor-mediated or dependent diseases or conditions.

Background technique

The concept of PROTACs (PROteolysis TArgeting Chimeras) technology was proposed in 2001 (Proc. Natl. Acad. Sci. USA, 2001, 98, 8584). Early PROTACs recruited E3 ligase through peptides, which had poor molecular permeability and limited activity; in 2008, small molecule PROTACs based on MDM2E3 ligase appeared, but the activity of these molecules was not good; until 2010 to 2012, The current commonly used ligands for E3 ligase based on cerebellar protein (CRBN, cereblon) and VHL (von Hippel-Lindau) have appeared, making the binding level of small molecule ligands and E3 ligase reach the micromolar level, which is the next PROTACs The development of the company laid the foundation.

The PROTACs molecule is a bifunctional molecule. One end contains a ligand that binds to E3 ubiquitin ligase, and the other end contains a ligand that binds to the target protein. The two parts are connected by a connecting unit. The linking unit is pulled closer, so that the E3 ligase and the target protein are very close, which in turn causes the polyubiquitination of the target protein and the degradation of the proteasome. PROTACs adopt a completely different mechanism of action and mechanism from small molecule inhibitors. First, the ligand of E3 ubiquitin ligase recruits E3 ubiquitin ligase to the vicinity of the target protein, and then the target protein is labeled with ubiquitination by narrowing the distance with the target protein. The labeled target protein will be degraded by the proteasome system in the body to inhibit the corresponding protein pathway (Cell Biochem Funct. 2019, 37, 21-30). Compared with traditional small molecule drugs, due to changes in the binding mechanism, PROTACs only need to instantaneously bind to the target protein to complete the process of ubiquitin transfer to achieve irreversible degradation of the target protein. Therefore, PROTACs have the following advantages: 1) stronger degradation and longer-lasting efficacy; 2) higher selectivity for the target protein; 3) can overcome the traditional small molecule inhibitors caused by the mutation of the target protein Drug resistance (Cell Chem. Biol. 2018, 25, 67-77).

The discovery process of CRBN type E3 ligase ligand is related to the study of thalidomide's mechanism of action. In 2010, while studying the toxicity of thalidomide, scientists discovered that cereblon is a binding protein of thalidomide (Science 2010, 327, 1345). Cerebellar protein is part of the E3 ubiquitin ligase protein complex, which acts as a substrate receptor to select ubiquitinated proteins. The study shows that thalidomide-cerebellar protein binding in vivo may be the cause of thalidomide teratogenicity. Subsequent studies found that the compound and related structures can be used as anti-inflammatory agents, anti-angiogenic agents and anti-cancer agents. Lenalidomide and pomalidomide obtained by further modification of the structure of thalidomide have greatly improved their safety and significantly reduced their teratogenic effects. Lenalidomide has been approved by the FDA in 2006 for marketing. Two groundbreaking papers published in Science in 2014 pointed out that lenalidomide works by degrading two special B cell transcription factors, Ikaros family zinc finger structural proteins 1 and 3 (IKZF1 and IKZF3), which further reveals The structure of thalidomide may be combined with the E3 ubiquitin ligase protein complex of the cerebellar protein to further play a role in degrading the target protein (Science, 2014, 343, 301; Science, 2014, 343, 305).

On this basis, CRBN ligands are widely used in protein degradation, and a series of PROTACs molecules based on CRBN ligands have been developed. Due to the influence of CRBN ligand itself on the target point, it may additionally degrade zinc finger domain protein. Therefore, the design and synthesis of new and highly selective CRBN ligands is also particularly important in the synthesis of PROTACs molecules.

The present disclosure has developed a new type of cyclic imide derivatives, which can be used as effective CRBN ligands, and can further synthesize corresponding PROTACs molecules. These molecules demonstrate their application as estrogen receptor degrading agents to treat estrogen receptor-mediated or dependent diseases.

Published CRBN ligand patent applications include WO2015160845, WO2016197032, WO2016105518, WO2017197046, WO2017197051 and WO2018144649.

Summary of the invention

The purpose of the present disclosure is to provide a compound with the structure of CLM-L-PTM, or tautomers, mesosomes, racemates, enantiomers, diastereomers, or isotopes thereof Derivative, or a mixture form or a pharmaceutically acceptable salt thereof, wherein CLM is a cerebellar protein E3 ubiquitin ligase protein binding ligand compound represented by general formula (IM);

in:

G ¹ and G ^{2 are the} same or different, each is independently CH ₂ or C (=O), and ^{at least one of G 1} and G ² is C (=O);

One or two groups of R ¹ and R ² , R ² and R ³ , R ³ and R ⁴ together with the carbon atoms to which they are connected form a four- to fourteen-membered heterocyclic group, wherein the heterocyclic group contains 1 to 2 heteroatoms selected from N atom, O atom and S atom, optionally selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, One or more substituents of nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;

Or R ¹ , R ² , R ³ and R ^{4 are the} same or different, and are each independently selected from covalent bond, hydrogen atom, deuterium atom, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkyne Group, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein the alkyl, heteroalkyl, Alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano , Amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl substituted by one or more substituents, provided that R ¹ and R ² , R ² and R ³ , R ³ and R ⁴ There is at least one group of heterocyclic groups forming a four- to fourteen-membered ring together with the carbon atom to which it is connected;

L is a linking unit, one end of which can be arbitrarily connected to the heterocyclic group formed by ^{R 1} , R ² , R ³ , R ⁴ and R ¹ and R ² , R ² and R ³ , R ³ and R ^{4 on the formula (IM)} The substitution site is connected by a covalent bond, and the other end is connected with PTM;

PTM is a small molecule compound ligand that binds to a target protein or polypeptide, which is connected to L by a covalent bond;

n is 0, 1, or 2.

In some embodiments of the present disclosure, there is provided a compound having the structure of CLM-L-PTM, or its tautomer, meso, racemate, enantiomer, or diastereomer CLM is a cerebellar protein E3 ubiquitin ligase protein binding ligand compound represented by the general formula (IM);

in:

G ¹ and G ^{2 are the} same or different, each is independently CH ₂ or C (=O), and ^{at least one of G 1} and G ² is C (=O);

One or two groups of R ¹ and R ² , R ² and R ³ , R ³ and R ⁴ together with the carbon atoms to which they are connected form a four- to fourteen-membered heterocyclic group, wherein the heterocyclic group contains 1 to 2 heteroatoms selected from N atom, O atom and S atom, optionally selected from halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, ring Substituted by one or more substituents in the alkyl group, heterocyclic group, aryl group and heteroaryl group;

Or R ¹ , R ² , R ³ and R ^{4 are the} same or different, and are each independently selected from covalent bond, hydrogen atom, deuterium atom, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkyne Group, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein the alkyl, heteroalkyl, Alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro Is substituted by one or more substituents in the group, cycloalkyl, heterocyclyl, aryl and heteroaryl, provided that at least one ^{of R 1} and R ² , R ² and R ³ , R ³ and R ⁴ Form a four to fourteen membered ring heterocyclic group together with the carbon atom to which it is connected;

L is a linking unit, one end of which can be arbitrarily connected to the heterocyclic group formed by ^{R 1} , R ² , R ³ , R ⁴ and R ¹ and R ² , R ² and R ³ , R ³ and R ^{4 on the formula (IM)} The substitution site is connected by a covalent bond, and the other end is connected with PTM;

PTM is a small molecule compound ligand that binds to a target protein or polypeptide, which is connected to L by a covalent bond;

n is 0, 1, or 2.

In some embodiments of the present disclosure, there is provided a compound having the structure of CLM-L-PTM, or tautomers, mesoisomers, racemates, enantiomers, and diastereomers thereof , Isotopic derivatives, or mixtures thereof or pharmaceutically acceptable salts thereof, wherein the compound of general formula (IM) is selected from general formula (IM-1), general formula (IM-2), general formula (IM-3), The cerebellar protein E3 ubiquitin ligase protein binding ligand compound represented by the general formula (IM-1aa), the general formula (IM-2aa) and the general formula (IM-3aa):

in:

Ring A, Ring B and Ring C are the same or different, and are each independently a four- to fourteen-membered heterocyclic group, wherein the heterocyclic group contains 1 to 2 atoms selected from the group consisting of N atoms, O atoms and S atoms Heteroatom

Ring E, ring D and ring M are the same or different, and are each independently a four- to fourteen-membered N-containing heterocyclic group, wherein the N-containing heterocyclic group contains 1 N atom and optionally Contain 1 heteroatom selected from N atom, O atom and S atom;

R ^{5a is} selected from covalent bond, hydrogen atom, alkyl, heteroalkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ⁵ are the same or different, and are each independently selected from covalent bonds, hydrogen atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, hydroxyl groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, Heterocyclic group, aryl group and heteroaryl group;

R ^f are the same or different, and are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, Aryl and heteroaryl;

In general formula (IM-1), general formula (IM-2), general formula (IM-3) and general formula (IM-2aa), p is 0, 1, 2, 3 or 4;

In general formula (IM-1aa) and general formula (IM-3aa), p is 1, 2, 3 or 4;

f is 0, 1, 2, 3 or 4;

Any one of R ¹ , R ² , R ³ , R ^{4 and any R 5} is connected to the connecting unit L through a covalent bond;

G ¹ , G ² , R ¹ to R ⁴ and n are as defined in the compound of general formula (IM).

In some embodiments of the present disclosure, there is provided a compound having the structure of CLM-L-PTM, or tautomers, mesoisomers, racemates, enantiomers, and diastereomers thereof , Isotopic derivatives, or mixtures thereof or pharmaceutically acceptable salts thereof, wherein the compound of general formula (IM) is selected from the group consisting of general formula (IM-1aa), general formula (IM-2aa) and general formula (IM-3aa) The shown cerebellar protein E3 ubiquitin ligase protein binding ligand compound:

in:

Ring B is a four- to fourteen-membered heterocyclic group, wherein the heterocyclic group contains 1 to 2 heteroatoms selected from N atoms, O atoms and S atoms;

Ring E, ring D and ring M are the same or different, and are each independently a four- to fourteen-membered N-containing heterocyclic group, wherein the N-containing heterocyclic group contains 1 N atom and optionally Contain 1 heteroatom selected from N atom, O atom and S atom;

R ^{5a is} selected from covalent bond, hydrogen atom, alkyl, heteroalkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ⁵ are the same or different, and are each independently selected from covalent bonds, hydrogen atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, hydroxyl groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, Heterocyclic group, aryl group and heteroaryl group;

R ^f are the same or different, and are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, Aryl and heteroaryl;

In the general formula (IM-2aa), p is 0, 1, 2, 3 or 4;

In general formula (IM-1aa) and general formula (IM-3aa), p is 1, 2, 3 or 4;

f is 0, 1, 2, 3 or 4;

Any one of R ¹ , R ³ , R ⁴ , R ^{5a and any R 5} is connected to the connecting unit L through a covalent bond;

G ¹ , G ² , R ¹ to R ⁴ and n are as defined in the compound of general formula (IM).

In some embodiments of the present disclosure, there is provided a compound having the structure of CLM-L-PTM, or its tautomer, meso, racemate, enantiomer, or diastereomer Conformers, isotopic derivatives, or mixtures thereof or pharmaceutically acceptable salts thereof, wherein the compound of general formula (IM) is selected from general formula (IM-4), general formula (IM-5), general formula (IM-6) ), general formula (IM-7), general formula (IM-8), general formula (IM-9), general formula (IM-10), general formula (IM-11), general formula (IM-12), General formula (IM-13), general formula (IM-15) and general formula (IM-13aa) represented by the cerebellar protein E3 ubiquitin ligase protein binding ligand compound:

Preferred

in:

Ring E is a four- to fourteen-membered N-containing heterocyclic group, wherein the N-containing heterocyclic group contains, in addition to one N atom, optionally one selected from the group consisting of N atom, O atom and S atom Heteroatom

R ⁵ are the same or different, and are each independently selected from covalent bonds, hydrogen atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, hydroxyl groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, Heterocyclic group, aryl group and heteroaryl group;

R ^{5a is} selected from covalent bond, hydrogen atom, alkyl, heteroalkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ^f are the same or different, and are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, Aryl and heteroaryl;

Any one of R ¹ , R ² , R ³ , R ⁴ and R ^5a is connected to the connecting unit L through a covalent bond;

r is 1 or 2;

s is 0 or 1;

t is 0, 1 or 2;

g is 1, 2 or 3;

p is 0, 1, 2 or 3;

f is 0, 1, 2, 3 or 4;

G ¹ , G ² , R ¹ to R ⁴ and n are as defined in the compound of general formula (IM).

In some embodiments of the present disclosure, there is provided a compound having the structure of CLM-L-PTM, or its tautomer, meso, racemate, enantiomer, or diastereomer Conformers, isotopic derivatives, or mixtures thereof or pharmaceutically acceptable salts thereof, wherein the compound of general formula (IM-13) is preferably the cerebellar protein E3 ubiquitin ligase protein binding complex represented by general formula (IM-14) Body compound:

Wherein G ¹ , G ² , R ¹ , R ⁵ , R ^5a , g and n are as defined in the compound of general formula (IM-13).

In some embodiments of the present disclosure, there is provided a compound having the structure of CLM-L-PTM, or its tautomer, meso, racemate, enantiomer, or diastereomer Conformers, isotopic derivatives, or mixtures thereof or pharmaceutically acceptable salts thereof, wherein the compound of general formula (IM) is selected from any of the following compounds:

in:

R ^{5a is} selected from covalent bond, hydrogen atom, alkyl, heteroalkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl;

Any one of R ¹ , R ² , R ³ , R ⁴ and R ^5a is connected to the connecting unit L through a covalent bond;

R ¹ to R ⁴ are as defined in the compound of general formula (IM).

In some embodiments of the present disclosure, there is provided a compound having the structure of CLM-L-PTM, or its tautomer, meso, racemate, enantiomer, or diastereomer A conformer, an isotopic derivative, or a mixture thereof or a pharmaceutically acceptable salt thereof, wherein ^{any one of R 2} and R ^5a is connected to the linking unit L through a covalent bond; R ² and R ^{5a are} as defined above.

In some embodiments of the present disclosure, there is provided a compound having the structure of CLM-L-PTM, or its tautomer, meso, racemate, enantiomer, or diastereomer A conformer, an isotopic derivative, or a mixture thereof or a pharmaceutically acceptable salt thereof, wherein R ^5a is a covalent bond, which is connected to the linking unit L.

In some embodiments of the present disclosure, there is provided a compound having the structure of CLM-L-PTM, or its tautomer, meso, racemate, enantiomer, or diastereomer Conformers, isotopic derivatives, or mixtures thereof or pharmaceutically acceptable salts thereof, wherein -L- is selected from -L ¹ -, ^{-L 2} -, -R ^1L -, -R ^2L -, -Q ¹ -, -Q ² -、

-L ¹ -and -L ² -are the same or different, and are each independently selected from a covalent bond, -O-, -S-, -NR ⁶ -, -CR ⁷ R ⁸ -, -C(O)-, -S(O)-, -S(O) ₂ -, -C(S)-, -C(O)O-, -C(O)NR ⁶ -and -NR ⁶ C(O)-;

R ^1L and R ^{2L are the} same or different, and are each independently selected from a covalent bond, an alkylene group, a heteroalkylene group, an alkenylene group and an alkynylene group, wherein the alkylene group, heteroalkylene group, and alkylene group Alkenyl and alkynylene groups are optionally selected from halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, oxo, cycloalkyl, heterocyclyl, aryl and heteroaryl Substituted by one or more substituents in the group;

Q ¹ and Q ^{2 are the} same or different, and are each independently selected from cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently Is optionally selected from one of halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, oxo, cycloalkyl, heterocyclyl, aryl and heteroaryl or Replaced by multiple substituents;

R ^{6 is} selected from a hydrogen atom, an alkyl group, a heteroalkyl group, a halogenated alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;

R ⁷ and R ^{8 are the} same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, oxo, cycloalkyl, heterocycle Group, aryl and heteroaryl.

In some embodiments of the present disclosure, there is provided a compound having the structure of CLM-L-PTM, or its tautomer, meso, racemate, enantiomer, or diastereomer Conformers, isotopic derivatives, or mixtures thereof or pharmaceutically acceptable salts thereof, wherein -L- is selected from -R ^1L -,

-Q ¹ -, ^{-Q 2} -, -R ^1L -, -R ^2L -, ^{-L 1} -and -L ² -are as defined above.

In some embodiments of the present disclosure, there is provided a compound having the structure of CLM-L-PTM, or its tautomer, meso, racemate, enantiomer, or diastereomer Conformers, isotopic derivatives, or mixtures thereof or pharmaceutically acceptable salts thereof, wherein -L- is selected from: -(CH ₂ ) _v -,

v is an integer from 1 to 10;

j is an integer from 0 to 10; and

k is an integer from 0 to 10;

Preferably, L is -(CH ₂ ) _v -or

v is an integer from 1 to 10.

In some embodiments of the present disclosure, there is provided a compound having the structure of CLM-L-PTM, or its tautomer, meso, racemate, enantiomer, or diastereomer A conformer, an isotope derivative, or a mixture thereof or a pharmaceutically acceptable salt thereof, wherein L is selected from:

j is an integer from 0 to 10; and

k is an integer from 0 to 10.

In some embodiments of the present disclosure, there is provided a compound having the structure of CLM-L-PTM, or its tautomer, meso, racemate, enantiomer, or diastereomer Conformers, isotopic derivatives, or mixtures thereof or pharmaceutically acceptable salts thereof, which are general formula (I-1) or general formula (I-2) or tautomers, mesosomes, exo Racemates, enantiomers, diastereomers, isotopic derivatives, or mixtures thereof or pharmaceutically acceptable salts thereof,

in:

L is a connecting unit, preferably R ^2L or Q ¹ -R ^2L ;

R ^{2L is} selected from covalent bond, C _1-12 alkylene, 1 to 12 membered heteroalkylene, C _2-12 alkenylene and C _2-12 alkynylene, wherein the C _1-12 alkylene Alkyl, 1 to 12 membered heteroalkylene, C _2-12 alkenylene and C _2-12 alkynylene are optionally selected from halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, hydroxy, C _1-6 hydroxyalkyl, cyano, amino, oxo, 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclic group, 6 to 10 membered aryl and 5 to 10 One or more substituents in the membered heteroaryl group; preferably, R ^2L is a covalent bond or a C _1-12 alkylene group, wherein the C _1-12 alkylene group is optionally selected from halogen , C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, hydroxy, C _1-6 hydroxyalkyl, cyano, amino, oxo, 3 to 8 membered cycloalkyl, 3 To 8-membered heterocyclic group, 6- to 10-membered aryl group and 5- to 10-membered heteroaryl group substituted by one or more substituents;

Q ^{1 is} selected from 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclic group, 6 to 10 membered aryl and 5 to 10 membered heteroaryl, wherein the 3 to 8 membered cycloalkyl, 3 to 8 The membered heterocyclic group, the 6 to 10 membered aryl group and the 5 to 10 membered heteroaryl group are each independently optionally selected from halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl , Hydroxy, C _1-6 hydroxyalkyl, cyano, amino, oxo, 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclic group, 6 to 10 membered aryl group and 5 to 10 membered heteroaryl group Is substituted by one or more substituents; preferably, Q ^{1 is} selected from 3 to 8 membered heterocyclic groups, wherein the 3 to 8 membered heterocyclic groups are optionally selected from halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, hydroxy, C _1-6 hydroxyalkyl, cyano, amino, and oxo are substituted by one or more substituents;

PTM is a small molecule compound ligand that binds to a target protein or polypeptide;

In the general formula (I-2), p is 0, 1, 2, 3 or 4;

In the general formula (I-1), p is 1, 2, 3 or 4;

Ring B, ring D, ring E, R ¹ , R ³ -R ⁵ , R ^f , G ¹ , G ² , f and n are as defined in the general formula (IM-1aa) and the general formula (IM-2aa).

In some embodiments of the present disclosure, there is provided a compound having the structure of CLM-L-PTM, or its tautomer, meso, racemate, enantiomer, or diastereomer Conformers, isotopic derivatives, or mixtures thereof or pharmaceutically acceptable salts thereof, which are of general formula (I-3) or general formula (I-4), or their tautomers, meso, Racemates, enantiomers, diastereomers, isotopic derivatives, or mixtures thereof or pharmaceutically acceptable salts thereof,

in:

t is 0, 1 or 2;

g is 1, 2 or 3;

p is 0, 1, 2 or 3;

PTM, L, ring E, R ¹ , R ³ -R ⁵ , R ^f , G ¹ , G ² , f and n are as defined in general formula (IM-9) or general formula (IM-13aa).

In some embodiments of the present disclosure, the compound having the structure of CLM-L-PTM as described above, or its tautomer, meso, racemate, enantiomer, or diastereomer Isomers, isotopic derivatives, or mixtures thereof or pharmaceutically acceptable salts thereof, wherein PTM is a small molecule compound ligand that binds to a target protein or polypeptide, which is selected from compounds that bind to estrogen receptors, Compounds targeting the androgen receptor, binding to kinase inhibitors, binding to phosphatase inhibitors, MDM2 inhibitors, compounds binding to targeting proteins containing human BET Bromo domains, Hsp90 inhibitors, HDAC inhibitors , Human lysine methyltransferase inhibitors, compounds that bind to RAF receptors, compounds that bind to FKBP, angiogenesis inhibitors, compounds that inhibit immunity, compounds that bind to aromatic hydrocarbon receptors , Binding to a compound targeting the thyroid hormone receptor, a compound targeting HIV protease, a compound targeting HIV integrase, a compound targeting HCV protease, or a compound targeting acyl protein thioesterase 1 And/or the compound of 2; preferably, PTM is a small molecule compound ligand that binds to a target protein or polypeptide, which is selected from compounds that bind to estrogen receptors, compounds that bind to target androgen receptors, kinase inhibitors Agent, a compound that binds to a protein that targets a human BET Bromo domain.

In some embodiments of the present disclosure, the compound having the structure of CLM-L-PTM as described above, or its tautomer, meso, racemate, enantiomer, diastereomer Isomers, isotopic derivatives, or mixtures thereof or pharmaceutically acceptable salts thereof, wherein PTM is a compound that binds to the estrogen receptor, preferably selected from:

in:

E is O atom or NH;

Z is a covalent bond, or selected from O atom, NR ^m and CH ₂ ;

M ¹ , M ² , M ³ , M ⁴ and M ^{5 are the} same or different, and each independently is an N atom or CR ⁿ ;

R ^{1p are the} same or different, and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkoxy group, a halogenated alkyl group, a halogenated alkoxy group, a hydroxyl group, a hydroxyalkyl group Group, cyano group, amino group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group;

R ^2p , R ^3p and R ^{4p are the} same or different, and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkoxy group, a halogenated alkyl group, and a halogenated alkoxy group. Group, hydroxy, hydroxyalkyl, cyano, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl;

Or R ^3p and R ^4p together with the attached carbon atom form a cycloalkyl or heteroalkyl group;

R ^{5p is} selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, a halogenated alkyl group, a hydroxyl group, a hydroxyalkyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group ；

R ^6p are the same or different, and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkoxy group, a halogenated alkyl group, a halogenated alkoxy group, a hydroxyl group, and a hydroxyl group. Alkyl, cyano, amino, cycloalkyl, heterocyclic, aryl and heteroaryl;

R ^7p are the same or different, and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkoxy group, a halogenated alkyl group, a halogenated alkoxy group, a hydroxyl group, and a hydroxyl group. Alkyl, cyano, amino, cycloalkyl, heterocyclic, aryl and heteroaryl;

R ^{m is} selected from a hydrogen atom, an alkyl group, a heteroalkyl group, a haloalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;

R ^{n is} selected from hydrogen atom, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, cycloalkyl, heterocyclic, aryl and heteroaryl base;

h is 0, 1, 2, 3, 4 or 5;

q is 0, 1, 2, 3, 4 or 5; and

y is 0, 1, 2, 3, 4, or 5.

In some embodiments of the present disclosure, the compound having the structure of CLM-L-PTM as described above, or its tautomer, meso, racemate, enantiomer, diastereomer Isomers, isotopic derivatives, or mixtures thereof or pharmaceutically acceptable salts thereof, wherein PTM is a compound that binds to the estrogen receptor, preferably selected from:

Wherein: Z, M ¹ -M ⁵ , R ^1p -R ^4p , R ^6p , R ^7p , h, q and y are as defined above.

In some embodiments of the present disclosure, the compound having the structure of CLM-L-PTM as described above, or its tautomer, meso, racemate, enantiomer, diastereomer Isomers, isotopic derivatives, or mixtures thereof or pharmaceutically acceptable salts thereof, wherein PTM is selected from:

Another aspect of the present disclosure provides a compound represented by general formula (IM), or a tautomer, meso, racemate, enantiomer, diastereomer, or isotope thereof Derivatives, or mixtures thereof or pharmaceutically acceptable salts thereof,

in:

G ¹ and G ^{2 are the} same or different, each is independently CH ₂ or C (=O), and ^{at least one of G 1} and G ² is C (=O);

One or two groups of R ¹ and R ² , R ² and R ³ , R ³ and R ⁴ together with the carbon atoms to which they are connected form a four- to fourteen-membered heterocyclic group, wherein the heterocyclic group contains 1 to 2 heteroatoms selected from N atom, O atom and S atom, optionally selected from halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, R ^w , substituted by one or more substituents in cycloalkyl, heterocyclic, aryl and heteroaryl;

Or R ¹ , R ² , R ³ and R ^{4 are the} same or different, and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, and an alkoxy group. Group, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein the alkyl, heteroalkyl, alkoxy, Cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, R ^w , Cycloalkyl, heterocyclyl, aryl and heteroaryl groups are substituted by one or more substituents, provided that at least one ^{of R 1} and R ² , R ² and R ³ , R ³ and R ^{4 is} The connected carbon atoms together form a four- to fourteen-membered heterocyclic group;

R ^w is an amino protecting group, preferably tert-butoxycarbonyl;

n is 0, 1, or 2.

Another aspect of the present disclosure provides a compound represented by general formula (IM), or a tautomer, meso, racemate, enantiomer, diastereomer, or isotope thereof Derivatives, or mixtures thereof or pharmaceutically acceptable salts thereof,

in:

G ¹ and G ^{2 are the} same or different, each is independently CH ₂ or C (=O), and ^{at least one of G 1} and G ² is C (=O);

One or two groups of R ¹ and R ² , R ² and R ³ , R ³ and R ⁴ together with the carbon atoms to which they are connected form a four- to fourteen-membered heterocyclic group, wherein the heterocyclic group contains 1 to 2 heteroatoms selected from N atom, O atom and S atom, optionally selected from halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, ring Substituted by one or more substituents in the alkyl group, heterocyclic group, aryl group and heteroaryl group;

Or R ¹ , R ² , R ³ and R ^{4 are the} same or different, and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, and an alkoxy group. Group, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein the alkyl, heteroalkyl, alkoxy, Cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkane Is substituted by one or more substituents in the group, heterocyclic group, aryl group and heteroaryl group, provided ^{that at least one of R 1} and R ² , R ² and R ³ , R ³ and R ⁴ has a carbon attached to it The atoms together form a four- to fourteen-membered heterocyclic group;

n is 0, 1, or 2.

Another aspect of the present disclosure provides a compound represented by general formula (IM), or a tautomer, meso, racemate, enantiomer, diastereomer, or isotope thereof Derivatives, or mixtures thereof or pharmaceutically acceptable salts thereof, which are selected from general formula (IM-1), general formula (IM-2), general formula (IM-3), general formula (IM-1aa), The cerebellar protein E3 ubiquitin ligase protein binding ligand compound represented by general formula (IM-2aa) and general formula (IM-3aa):

in:

Ring M is a four- to fourteen-membered N-containing heterocyclic group, wherein the N-containing heterocyclic group contains, in addition to one N atom, optionally one selected from the group consisting of N atom, O atom and S atom Heteroatom

R ¹ , R ² , R ³ and R ^{4 are the} same or different, and are each independently selected from hydrogen atom, halogen, C _1-6 alkyl, C _1-6 deuterated alkyl, 1 to 6 membered 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 hydroxyalkyl, cyano, Amino, 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclic group, 6 to 10 membered aryl and 5 to 10 membered heteroaryl; wherein the C _1-6 alkyl group, 1 to 6 membered heteroalkyl Group, C _1-6 alkoxy group, 3 to 8 membered cycloalkyl group, 3 to 8 membered heterocyclic group, 6 to 10 membered aryl group and 5 to 10 membered heteroaryl group are each independently optionally selected from halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, hydroxy, C _1-6 hydroxyalkyl, cyano, amino, nitro, R ^w , 3 to 8 membered cycloalkyl , 3 to 8 membered heterocyclic group, 6 to 10 membered aryl group and 5 to 10 membered heteroaryl group substituted by one or more substituents;

R ⁵ are each the same or different, and are each independently selected from hydrogen atom, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, hydroxy, C _1-6 hydroxyalkyl, Cyano, amino, nitro, R ^w , 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclic group, 6 to 10 membered aryl and 5 to 10 membered heteroaryl;

R ^{5a is} selected from hydrogen atom, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, hydroxy, C _1-6 hydroxyalkyl, cyano, amino, nitro, R ^w , 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclic group, 6 to 10 membered aryl group and 5 to 10 membered heteroaryl group substituted by one or more substituents;

R ^w is an amino protecting group, preferably tert-butoxycarbonyl;

Ring A, ring B, ring C, G ¹ , G ² , n and p are as defined in the general formulas (IM-1), (IM-2) and (IM-3) above; ring D, ring E, R ^f , p and f are as defined in the above general formulas (IM-1aa), (IM-2aa) and (IM-3aa).

Another aspect of the present disclosure provides a compound represented by general formula (IM), or a tautomer, meso, racemate, enantiomer, diastereomer, or isotope thereof Derivatives, or mixtures thereof or pharmaceutically acceptable salts thereof, which are the cerebellar protein E3 ubiquitin ligase represented by the general formula (IM-1aa), the general formula (IM-2aa) and the general formula (IM-3aa) Protein binding ligand compounds:

in:

R ¹ , R ² , R ³ and R ^{4 are the} same or different, and are each independently selected from hydrogen atom, halogen, C _1-6 alkyl, C _1-6 deuterated alkyl, 1 to 6 membered 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 hydroxyalkyl, cyano, Amino group, 3 to 8 membered cycloalkyl group, 3 to 8 membered heterocyclic group, 6 to 10 membered aryl group and 5 to 10 membered heteroaryl group; wherein said C _1-6 alkyl group, 1 to 6 membered heteroalkyl group Group, C _1-6 alkoxy group, 3 to 8 membered cycloalkyl group, 3 to 8 membered heterocyclic group, 6 to 10 membered aryl group and 5 to 10 membered heteroaryl group are each independently optionally selected from halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, hydroxy, C _1-6 hydroxyalkyl, cyano, amino, nitro, R ^w , 3 to 8 membered cycloalkyl , 3 to 8 membered heterocyclic group, 6 to 10 membered aryl group and 5 to 10 membered heteroaryl group substituted by one or more substituents;

R ⁵ are each the same or different, and are each independently selected from hydrogen atom, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, hydroxy, C _1-6 hydroxyalkyl, Cyano, amino, nitro, R ^w , 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclic group, 6 to 10 membered aryl and 5 to 10 membered heteroaryl;

R ^{5a is} selected from hydrogen atom, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, hydroxy, C _1-6 hydroxyalkyl, cyano, amino, nitro, R ^w , 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclic group, 6 to 10 membered aryl group and 5 to 10 membered heteroaryl group substituted by one or more substituents;

R ^w is an amino protecting group, preferably tert-butoxycarbonyl;

G ¹ and G ^{2 are the} same or different, each is independently CH ₂ or C (=O), and ^{at least one of G 1} and G ² is C (=O);

Ring B is a four- to fourteen-membered heterocyclic group, wherein the heterocyclic group contains 1 to 2 heteroatoms selected from N atoms, O atoms and S atoms;

Ring E, ring D and ring M are the same or different, and are each independently a four- to fourteen-membered N-containing heterocyclic group, wherein the N-containing heterocyclic group contains 1 N atom and optionally Contain 1 heteroatom selected from N atom, O atom and S atom;

R ^f are the same or different, and are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, Aryl and heteroaryl;

f is 0, 1, 2, 3 or 4;

In the general formula (IM-2aa), p is 0, 1, 2, 3 or 4;

In general formula (IM-1aa) and general formula (IM-3aa), p is 1, 2, 3 or 4; and

n is 0, 1, or 2.

Another aspect of the present disclosure provides a compound represented by general formula (IM), or a tautomer, meso, racemate, enantiomer, diastereomer, or isotope thereof Derivatives, or mixtures thereof or pharmaceutically acceptable salts thereof, which are selected from:

in:

R ¹ , R ² , R ³ and R ^{4 are the} same or different, and are each independently selected from covalent bond, hydrogen atom, halogen, C _1-6 alkyl, C _1-6 deuterated alkyl, 1 to 6 member 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 hydroxyalkyl , Cyano, amino, 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclic group, 6 to 10 membered aryl and 5 to 10 membered heteroaryl; wherein the C _1-6 alkyl, 1 to 6-membered heteroalkyl, C _1-6 alkoxy, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl are each independently optionally Selected from halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, hydroxy, C _1-6 hydroxyalkyl, cyano, amino, nitro, R ^w , 3 to 8 It is substituted by one or more substituents in the membered cycloalkyl group, the 3- to 8-membered heterocyclic group, the 6- to 10-membered aryl group and the 5- to 10-membered heteroaryl group;

R ^{5a is} selected from a hydrogen atom, an alkyl group, a heteroalkyl group, a haloalkyl group, a hydroxy group, a hydroxyalkyl group, an amino group, R ^w , a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;

R ^w is an amino protecting group, preferably tert-butoxycarbonyl.

Typical compounds represented by the compounds of general formula (IM) in the present disclosure include but are not limited to:

Typical compounds of the compounds with the structure of CLM-L-PTM described in the present disclosure include but are not limited to:

In some embodiments of the present disclosure, the compound having the structure of CLM-L-PTM as described above, or its tautomer, meso, racemate, enantiomer, diastereomer Isomers, isotopic derivatives, or mixtures thereof or pharmaceutically acceptable salts thereof, wherein PTM is a small molecule compound ligand that binds to a target protein or polypeptide, wherein the target protein is selected from structural proteins, receptors, Enzymes, cell surface proteins; proteins related to cell integration functions, including proteins involved in catalytic activity, aromatase activity, exercise activity, helicase activity, metabolic process, antioxidant activity, proteolysis, and biosynthesis; with kinase activity , Oxidoreductase activity, transferase activity, hydrolase activity, lyase activity, isomerase activity, ligase activity, enzyme regulation activity, signal transduction activity, structural molecule activity, binding activity, receptor activity, cell motility , Membrane fusion, cell communication, biological process regulation, development, cell differentiation, and stimulate response proteins; behavioral proteins; cell adhesion proteins; proteins involved in cell necrosis; proteins involved in transport, including protein transport activity, nuclear transport activity, Ion transport activity, channel transport activity, carrier activity, permease activity, secretion activity, electron transport activity, pathogenesis, chaperone protein regulator activity, nucleic acid binding activity, transcription regulator activity, activity of extracellular tissue and biological origin, and Translation regulator activity.

In some embodiments of the present disclosure, the compound having the structure of CLM-L-PTM as described above, or its tautomer, meso, racemate, enantiomer, diastereomer Isomers, isotopic derivatives, or mixtures thereof or pharmaceutically acceptable salts thereof, wherein PTM is a small molecule compound ligand that binds to a target protein, wherein the target protein is selected from B7.1 and 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 cyclase inhibitor, CXCR1, CXCR2, nitric oxide (NO) synthetase, cyclooxygenase 1, cyclooxygenase 2, 5HT receptor, dopamine receptor, G protein namely Gq, histamine Receptor, 5-lipoxygenase, tryptase serine protease, thymidylate synthase, purine nucleoside phosphorylase, GAPDH trypanosoma, glycogen phosphorylase, carbonic anhydrase, chemokine receptor, JAW STAT, RXR and analogs, HIV1 protease, HIV1 integrase, influenza neuraminidase, hepatitis B reverse transcriptase, sodium channels, multidrug resistance (MDR), protein P-glycoprotein, tyrosine kinase, CD23, CD124, tyrosinase p561ck, CD4, CD5, 1L-2 receptor, 1L-1 receptor, TNF-αR, ICAM1, Cat+ channel, VCAM, VLA-4 integrin, selectin, CD40/CD40L, inosine Monophosphate dehydrogenase, p38MAP kinase, RaslRaflMEWERK pathway, interleukin-1 convertase, caspase, HCV, NS3 protease, HCV NS3RNA helicase, glycinamide ribonucleotide formyltransferase, rhinovirus, 3C protease, herpes simplex virus-I (HSV-I), protease, cytomegalovirus (CMV) protease, poly(ADP-ribose) polymerase, cyclin-dependent kinase, 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 receptors, adenosine kinase and AMP deaminase, purinergic receptors (P2Y 1, P2Y2, P2Y4, P2Y6, P2X1-7), farnesyl transferase, geranylgeranyl transferase, NGF TrkA receptor, β-amyloid protein, tyrosine kinase Flk-II KDR, vitronectin receptor, integrin receptor, Her-21 nerve sheath, telomerase inhibition, cytosolic phospholipase A2 and EGF receptor Tyrosine kinase, ecdysone 20-monooxygenase, GABA-gated chloride channel ion channel, acetylcholinesterase, voltage-sensitive sodium channel protein, calcium release channel and chloride ion channel, acetyl-Coenzyme A carboxylase , Adenosuccinate synthase, protoporphyrinogen oxidase and enolpyruvylshikimate phosphate synthase.

Another aspect of the present disclosure relates to a method for preparing compounds of general formula (I-1) or general formula (I-2), or tautomers, mesosomes, racemates, enantiomers thereof , Diastereomers, isotopic derivatives, or mixtures thereof or pharmaceutically acceptable salts thereof, which include:

The compound of general formula (I-1A) and the compound of general formula (IM-1aa) undergo reductive amination reaction to obtain the compound of general formula (I-1);

The compound of general formula (I-2A) and the compound of general formula (IM-2aa) undergo reductive amination reaction to obtain the compound of general formula (I-2);

in:

R ^5a is a hydrogen atom;

L is R ^2L'- CH ₂ or Q ¹ -CH ₂ ;

R ^2L 'is selected from covalent bond, C _1-12 alkylene, 1 to 12 membered heteroalkylene, C _2-12 alkenylene and C _2-12 alkynylene, wherein the C _1-12 Alkylene, 1 to 12 membered heteroalkylene, C _2-12 alkenylene and C _2-12 alkynylene are optionally selected from halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, hydroxy, C _1-6 hydroxyalkyl, cyano, amino, oxo, 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclic group, 6 to 10 membered aryl and 5 to One or more substituents in the 10-membered heteroaryl group; preferably, R ^2L 'is a covalent bond or a C _1-12 alkylene group, wherein the C _1-12 alkylene group is optionally selected From halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, hydroxy, C _1-6 hydroxyalkyl, cyano, amino, oxo, 3 to 8 membered cycloalkyl , 3 to 8 membered heterocyclic group, 6 to 10 membered aryl group and 5 to 10 membered heteroaryl group substituted by one or more substituents;

In general formula (IM-2aa) and general formula (I-2), p is 0, 1, 2, 3 or 4;

In general formula (IM-1aa) and general formula (I-1), p is 1, 2, 3 or 4;

PTM, Q ¹ , ring B, ring D, ring E, G ¹ , G ² , R ¹ , R ³ -R ⁵ , R ^f , f and n are as general formula (I-1) and general formula (I-2 ).

Another aspect of the present disclosure relates to a method for preparing compounds of general formula (I-3) or general formula (I-4), or tautomers, mesosomes, racemates, enantiomers thereof , Diastereomers, isotopic derivatives, or mixtures thereof or pharmaceutically acceptable salts thereof, which include:

The compound of general formula (I-1A) and the compound of general formula (IM-9) undergo reductive amination reaction to obtain the compound of general formula (I-3);

The compound of general formula (I-2A) and the compound of general formula (IM-13aa) undergo reductive amination reaction to obtain the compound of general formula (I-4);

in:

R ^5a is a hydrogen atom;

L is R ^2L'- CH ₂ or Q ¹ -CH ₂ ;

R ^2L 'is selected from covalent bond, C _1-12 alkylene, 1 to 12 membered heteroalkylene, C _2-12 alkenylene and C _2-12 alkynylene, wherein the C _1-12 Alkylene, 1 to 12 membered heteroalkylene, C _2-12 alkenylene and C _2-12 alkynylene are optionally selected from halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, hydroxy, C _1-6 hydroxyalkyl, cyano, amino, oxo, 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclic group, 6 to 10 membered aryl and 5 to One or more substituents in the 10-membered heteroaryl group; preferably, R ^2L 'is a covalent bond or a C _1-12 alkylene group, wherein the C _1-12 alkylene group is optionally selected From halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, hydroxy, C _1-6 hydroxyalkyl, cyano, amino, oxo, 3 to 8 membered cycloalkyl , 3 to 8 membered heterocyclic group, 6 to 10 membered aryl group and 5 to 10 membered heteroaryl group substituted by one or more substituents;

PTM, Q ¹ , ring E, G ¹ , G ² , R ¹ , R ³ -R ⁵ , R ^f , g, f, p, n and t are as general formula (I-3) and general formula (I-4 ).

Another aspect of the present disclosure relates to a method for preparing a compound of general formula (I-3), or its tautomer, meso, racemate, enantiomer, diastereomer, The method of isotopic derivative, or its mixture form or its pharmaceutically acceptable salt, which includes:

The compound of general formula (I-1A) and the compound of general formula (IM-9') undergo a reductive amination reaction, and then under basic conditions, an intramolecular ring-closure reaction occurs to obtain a compound of general formula (I-3);

Wherein: X is a leaving group, preferably but not limited to chlorine, bromine and iodine;

R ^5a is a hydrogen atom;

L is R ^2L'- CH ₂ or Q ¹ -CH ₂ ;

R ^2L 'is selected from covalent bond, C _1-12 alkylene, 1 to 12 membered heteroalkylene, C _2-12 alkenylene and C _2-12 alkynylene, wherein the C _1-12 Alkylene, 1 to 12 membered heteroalkylene, C _2-12 alkenylene and C _2-12 alkynylene are optionally selected from halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, hydroxy, C _1-6 hydroxyalkyl, cyano, amino, oxo, 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclic group, 6 to 10 membered aryl and 5 to One or more substituents in the 10-membered heteroaryl group; preferably, R ^2L 'is a covalent bond or a C _1-12 alkylene group, wherein the C _1-12 alkylene group is optionally selected From halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, hydroxy, C _1-6 hydroxyalkyl, cyano, amino, oxo, 3 to 8 membered cycloalkyl , 3 to 8 membered heterocyclic group, 6 to 10 membered aryl group and 5 to 10 membered heteroaryl group substituted by one or more substituents;

R ^5b , R ^5c , R ^5d and R ^5e are each the same or different, and are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, and a nitro group , Cycloalkyl, heterocyclyl, aryl and heteroaryl;

t is 0, 1 or 2; preferably, t is 0 or 1;

PTM, Q ¹ , G ¹ , G ² , R ³ -R ⁵ , p and n are as defined in the general formula (I-3).

Another aspect of the present disclosure relates to a pharmaceutical composition containing a compound represented by any of the above-mentioned general formulas of the present disclosure or its tautomer, mesosome, racemate, or enantiomer Conformers, diastereomers, isotopic derivatives, or mixtures thereof, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

The present disclosure further relates to compounds represented by any of the above general formulas or tautomers, mesoisomers, racemates, enantiomers, diastereomers, isotopic derivatives, or mixtures thereof The use of the form, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same in the preparation of a medicament for the treatment or prevention of a disease that is treated by degrading a target protein bound to a targeting ligand.

The present disclosure further relates to compounds represented by any of the above general formulas or tautomers, mesoisomers, racemates, enantiomers, diastereomers, isotopic derivatives, or mixtures thereof The use of the form, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same in the preparation of a medicament for the treatment or prevention of diseases treated by binding to cerebellar protein protein in the body.

The present disclosure further relates to compounds represented by any of the above general formulas or tautomers, mesoisomers, racemates, enantiomers, diastereomers, isotopic derivatives, or mixtures thereof Use of the form, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same in the preparation of a medicament for the treatment or prevention of estrogen receptor-mediated or dependent diseases or disorders.

The present disclosure also relates to a method for treating or preventing a condition treated by degrading a target protein bound to a targeting ligand, which comprises administering to a patient a therapeutically effective amount of a compound represented by any of the above general formulas or a mutual variation thereof Conformers, mesosomes, racemates, enantiomers, diastereomers, isotopic derivatives, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them .

The present disclosure also relates to a method for treating or preventing diseases treated by binding to cerebellar protein protein in the body, which comprises administering to a patient a therapeutically effective amount of a compound represented by any of the above general formulas or a tautomer, internal Racemates, racemates, enantiomers, diastereomers, isotopic derivatives, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them.

The present disclosure also relates to a method for treating or preventing estrogen receptor-mediated or dependent diseases or disorders, which comprises administering to a patient a therapeutically effective amount of a compound represented by any of the above general formulas or its tautomers Isomers, mesosomes, racemates, enantiomers, diastereomers, isotopic derivatives, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them.

The present disclosure further relates to a compound represented by any of the above general formulas or its tautomers, mesosomes, racemates, enantiomers, diastereomers, isotopic derivatives, or In the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, it is used as a medicine.

The present disclosure further relates to compounds represented by any of the above general formulas or tautomers, mesoisomers, racemates, enantiomers, diastereomers, isotopic derivatives, or mixtures thereof The form, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used for the treatment or prevention of a condition that is treated by degrading a target protein bound to a targeting ligand.

The present disclosure further relates to compounds represented by any of the above general formulas or tautomers, mesoisomers, racemates, enantiomers, diastereomers, isotopic derivatives, or mixtures thereof Form, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, which is used for the treatment or prevention of conditions that are treated by binding to cerebellar protein in the body.

The present disclosure further relates to compounds represented by any of the above general formulas or tautomers, mesoisomers, racemates, enantiomers, diastereomers, isotopic derivatives, or mixtures thereof Form, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, which is used to treat or prevent estrogen receptor-mediated or dependent diseases or disorders.

In the present disclosure, the diseases treated by degrading the target protein bound to the targeting ligand and the diseases treated by binding to the cerebellar protein protein in the body are preferably selected from abnormal cell proliferation, tumors, immune diseases, diabetes, and cardiovascular diseases. Diseases, infectious diseases and inflammatory diseases; more preferably tumors and infectious diseases. Wherein the tumor is cancer; preferably selected from breast cancer, endometrial cancer, uterine cancer, testicular cancer, cervical cancer, prostate cancer, ovarian cancer, fallopian tube tumor, ovarian tumor, leukemia, skin cancer, squamous cell carcinoma, Basal cell carcinoma, adenocarcinoma, renal cell carcinoma, bladder cancer, bowel cancer, colon cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, neck cancer, pancreatic cancer, stomach cancer, lymphoma, non-Hodgkin's lymph Tumor, melanoma, myeloproliferative disease, sarcoma, angiosarcoma, peripheral neuroepithelioma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, adult Neurocytoma, gangliocytoma, ganglion glioma, medulloblastoma, pineal cell tumor, meningioma, meningiosarcoma, neurofibroma, schwannoma, thyroid cancer, esophageal cancer, Hodge King’s tumor, Wilms’ tumor and teratoma; more preferably selected from breast cancer, endometrial cancer, uterine cancer, testicular cancer, cervical cancer, prostate cancer, ovarian cancer, fallopian tube tumor and ovarian tumor. The infectious disease is selected from viral pneumonia, avian influenza, meningitis, gonorrhea or infection with HIV, HBV, HCV, HSV, HPV, RSV, CMV, Ebola virus, flavivirus, scar virus, rotavirus Virus, influenza, coronavirus, EBV, drug-resistant virus, RNA virus, DNA virus, adenovirus, poxvirus, picornavirus, togavirus, orthomyxovirus, retrovirus, hepatotropic DNA virus, Gram Negative bacteria, Gram-positive bacteria, atypical bacteria, Staphylococcus, Streptococcus, Escherichia coli, Salmonella, Helicobacter pylori, Chlamydiaceae, Mycoplasma, fungi, protozoa, intestinal worms, worms, prions or parasites.

The active compound can be formulated into a form suitable for administration by any appropriate route, and the active compound is preferably in a unit dose form, or in a form in which the patient can self-administer in a single dose. The unit dose of the compound or composition of the present disclosure can be expressed in the form of a tablet, capsule, cachet, bottled syrup, powder, granule, lozenge, suppository, rejuvenated powder or liquid preparation.

The dosage of the compound or composition used in the treatment methods of the present disclosure will generally vary with the severity of the disease, the weight of the patient, and the relative efficacy of the compound. However, as a general guide, a suitable unit dose may be 0.1-1000 mg.

In addition to the active compound, the pharmaceutical composition of the present disclosure may contain one or more excipients selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients Wait. Depending on the method of administration, the composition may contain 0.1 to 99% by weight of the active compound.

The pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as tablets, dragees, lozenges, water or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Elixirs. Oral compositions can be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions can contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, coloring agents and preservatives, To provide pleasing and delicious medicinal preparations. The tablet contains the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for the preparation of tablets for mixing. These excipients can be inert excipients, granulating agents, disintegrating agents, binders and lubricants. These tablets may be uncoated or may be coated by known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release effect over a longer period of time.

Oral preparations can also be provided in soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent or the active ingredient is mixed with a water-soluble carrier or oil vehicle.

Aqueous suspensions contain the active substance and excipients suitable for the preparation of aqueous suspensions for mixing. Such excipients are suspending agents, dispersing agents or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.

Oil suspensions can be formulated by suspending the active ingredients in vegetable oil or mineral oil. The oil suspension may contain thickeners. The above-mentioned sweeteners and flavoring agents can be added to provide a palatable preparation. These compositions can be preserved by adding antioxidants.

The pharmaceutical composition of the present disclosure may also be in the form of an oil-in-water emulsion. The oil phase can be vegetable oil, mineral oil or a mixture thereof. Suitable emulsifiers can be naturally occurring phospholipids, and the emulsions can also contain sweeteners, flavoring agents, preservatives and antioxidants. Such preparations may also contain a demulcent, a preservative, a coloring agent and an antioxidant.

The pharmaceutical composition of the present disclosure may be in the form of a sterile injectable aqueous solution. Acceptable solvents or solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. The sterile injection preparation can be a sterile oil-in-water injection microemulsion in which the active ingredient is dissolved in the oil phase, and the injection or microemulsion can be injected into the patient's bloodstream by local mass injection. Alternatively, it is best to administer the solution and microemulsion in a manner that maintains a constant circulating concentration of the compound of the present disclosure. To maintain this constant concentration, a continuous intravenous delivery device can be used. An example of such a device is the Deltec CADD-PLUS.TM. 5400 intravenous pump.

The pharmaceutical composition of the present disclosure may be in the form of a sterile injection water or oil suspension for intramuscular and subcutaneous administration. The suspension can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. The sterile injection preparation may also be a sterile injection solution or suspension prepared in a parenterally acceptable non-toxic diluent or solvent. In addition, sterile fixed oil can be conveniently used as a solvent or suspending medium. For this purpose, any blended fixed oil can be used. In addition, fatty acids can also be used to prepare injections.

The compounds of the present disclosure can be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid in the rectum and thus will melt in the rectum to release the drug.

As is well known to those skilled in the art, the dosage of the drug depends on many factors, including but not limited to the following factors: the activity of the specific compound used, the age of the patient, the weight of the patient, the health of the patient, and the behavior of the patient. , The patient’s diet, time of administration, mode of administration, rate of excretion, combination of drugs, etc.; in addition, the best treatment mode such as the mode of treatment, the daily dosage of the compound or the type of pharmaceutically acceptable salt can be based on the traditional The treatment plan to verify.

Detailed description of the invention

Unless stated to the contrary, the terms used in the specification and claims have the following meanings.

The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably containing 1 to 12 (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms, more preferably alkyl groups containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-Dimethylpropyl, 2,2-Dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -Methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethyl Pentyl, 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-ethyl Hexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethyl Hexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers. More preferred are lower alkyl groups containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, and sec-butyl. Group, 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-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Group, 2,3-dimethylbutyl, etc. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituent is preferably independently selected from the group consisting of H atom, D atom, halogen, and alkane. Is substituted by one or more substituents in the group, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

The term "heteroalkyl" means an alkyl of one or more -CH ₂ - is selected from NH, O and substituted with S or one or more selected -CH- substituted N atom; wherein said Alkyl groups are as defined above; heteroalkyl groups can be substituted or unsubstituted. When substituted, the substituents can be substituted at any available point of attachment, and the substituents are preferably independently optionally selected from the H atom One or more of, D atom, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, heteroaryl Substituents are substituted.

The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where the definition of alkyl or cycloalkyl is described herein. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. The alkoxy group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from H atom, D atom, halogen, alkyl group, alkoxy group , Haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl substituted by one or more substituents.

The term "alkylene" refers to a saturated linear or branched aliphatic hydrocarbon group, which has two residues derived from the removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent alkane, which is A straight or branched chain group containing 1 to 20 carbon atoms, preferably containing 1 to 12 (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbons Atom, more preferably an alkylene group containing 1 to 6 carbon atoms. Non-limiting examples of alkylene include, but are not limited to, methylene (-CH ₂ -), 1,1-ethylene (-CH(CH ₃ )-), 1,2-ethylene (-CH _{2 -)} CH ₂ )-, 1,1-propylene (-CH(CH ₂ CH ₃ )-), 1,2-propylene (-CH ₂ CH(CH ₃ )-), 1,3-propylene (-CH ₂ CH ₂ CH ₂ -), 1,4-butylene (-CH ₂ CH ₂ CH ₂ CH ₂ -), etc. The alkylene group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituent is preferably independently optionally selected from alkyl, alkenyl, alkynyl , Alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy Substituted by one or more substituents in the group, cycloalkylthio group, heterocycloalkylthio group and oxo group.

The term "heteroalkylene" means that one or more -CH ₂ -in an alkylene group is substituted by a heteroatom selected from N, O and S; wherein the alkylene group is as defined above; heteroalkylene It can be substituted or unsubstituted. When substituted, the substituents can be substituted at any available attachment point. The substituents are preferably independently selected from H atom, D atom, halogen, alkyl, Alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl are substituted by one or more substituents.

The term "alkenyl" refers to an alkyl compound containing a carbon-carbon double bond in the molecule, wherein the definition of the alkyl group is as described above. Alkenyl groups may be substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, which are independently selected from hydrogen atoms, alkyl groups, alkoxy groups, halogens, halogenated alkyl groups, hydroxyl groups, One or more substituents among hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl groups are substituted.

The term "alkenylene" refers to a residue having two residues derived from the same carbon atom or two different carbon atoms of the parent alkenyl group by removing two hydrogen atoms, wherein the definition of the alkenyl group is as described above.

The term "alkynyl" refers to an alkyl compound containing a carbon-carbon triple bond in the molecule, wherein the definition of the alkyl group is as described above. The alkynyl group may be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from hydrogen atoms, alkyl groups, alkoxy groups, halogens, halogenated alkyl groups, hydroxyl groups, One or more substituents among hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl groups are substituted.

The term "alkynylene" refers to a residue having two residues derived from the same carbon atom or two different carbon atoms of the parent alkynyl group by removing two hydrogen atoms, wherein the alkynyl group is defined as described above.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent. 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, more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Groups, cyclooctyl, etc.; polycyclic cycloalkyls include spiro, fused, and bridged cycloalkyls.

The term "spirocycloalkyl" refers to a polycyclic group that shares one carbon atom (called a spiro atom) between 5- to 20-membered monocyclic rings, which may contain one or more double bonds. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan). According to the number of shared spiro atoms between the ring and the ring, the spirocycloalkyl group is classified into a single spirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a single spirocycloalkyl group and a bispirocycloalkyl group. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered monospirocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:

The term "fused cycloalkyl" refers to a 5- to 20-membered all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or Multiple double bonds. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl groups, preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered , 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 5-membered and 6-membered/6-membered bicyclic alkyl groups. Non-limiting examples of fused cycloalkyl groups include:

The term "bridged cycloalkyl" refers to a 5- to 20-membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, which may contain one or more double bonds. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyls, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

The cycloalkyl ring includes the cycloalkyl as described above (including monocyclic, spiro, fused and bridged rings) fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein it is connected to the parent structure The ring together is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, etc.; preferably indanyl, tetrahydronaphthyl.

Cycloalkyl groups can be substituted or unsubstituted. When substituted, the substituents can be substituted at any available point of attachment. The substituents are preferably independently optionally selected from hydrogen atoms, halogens, alkyl groups, Alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl are substituted by one or more substituents.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) _m (where m is an integer of 0 to 2) heteroatoms, but does not include the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. It preferably contains 3 to 12 (for example, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) ring atoms, of which 1 to 4 (for example, 1, 2, 3, and 4) are hetero Atom; more preferably contains 3 to 8 ring atoms, of which 1-3 are heteroatoms; more preferably contains 3 to 6 ring atoms, of which 1-3 are heteroatoms; most preferably contains 5 or 6 ring atoms, wherein 1-3 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, tetrahydropyranyl, 1,2.3.6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, Homopiperazinyl and so on. Polycyclic heterocyclic groups include spiro, condensed, and bridged heterocyclic groups.

The term "spiroheterocyclic group" refers to a polycyclic heterocyclic group that shares one atom (called a spiro atom) between 5- to 20-membered monocyclic rings, in which one or more ring atoms are selected from nitrogen, oxygen or S(O ) _{Heteroatoms of m} (where m is an integer of 0 to 2), and the remaining ring atoms are carbon. It can contain one or more double bonds. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiro atoms shared between the ring and the ring, the spiro heterocyclic group is classified into a single spiro heterocyclic group, a dispiro heterocyclic group or a polyspiro heterocyclic group, preferably a single spiro heterocyclic group and a dispiro heterocyclic group. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered monospiro heterocyclic group. Non-limiting examples of spiroheterocyclic groups include:

The term "fused heterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system. One or more rings may contain one or more Double bonds, one or more of the ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) _m (wherein m is an integer of 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered , 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 5-membered and 6-membered/6-membered bicyclic fused heterocyclic groups Non-limiting examples of fused heterocyclic groups include:

The term "bridged heterocyclic group" refers to a 5- to 14-membered polycyclic heterocyclic group with any two rings sharing two atoms that are not directly connected, which may contain one or more double bonds, one or more of the ring atoms It is a heteroatom selected from nitrogen, oxygen or S(O) _m (where m is an integer of 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

The heterocyclyl ring includes the heterocyclic group as described above (including monocyclic, spiro heterocyclic, fused heterocyclic and bridged heterocyclic ring) fused on an aryl, heteroaryl or cycloalkyl ring, wherein it is combined with the parent The rings linked together in the structure are heterocyclic groups, non-limiting examples of which include:

The heterocyclic group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituents are preferably independently optionally selected from hydrogen atoms, halogens, alkyl groups, Alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl are substituted by one or more substituents.

The term "aryl" refers to a 6 to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic ring is a ring that shares adjacent pairs of carbon atoms) with a conjugated π-electron system, preferably 6 to 10 membered , Such as phenyl and naphthyl. The aryl ring includes the aryl ring as described above fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, and non-limiting examples thereof include :

Aryl groups can be substituted or unsubstituted. When substituted, the substituents can be substituted at any available attachment point. The substituents are preferably independently optionally selected from hydrogen atoms, halogens, alkyl groups, and alkyl groups. One or more substituents of oxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl are substituted.

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, where the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl groups are preferably 5 to 10 members (for example, 5, 6, 7, 8, 9 or 10 members), more preferably 5 or 6 members, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkane Pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl and the like. The heteroaryl ring includes the above-mentioned heteroaryl group fused on an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected with the parent structure is a heteroaryl ring, and non-limiting examples thereof include :

Heteroaryl groups can be substituted or unsubstituted. When substituted, the substituents can be substituted at any available point of attachment. The substituents are preferably independently optionally selected from hydrogen atoms, halogens, alkyl groups, Alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl are substituted by one or more substituents.

The above-mentioned cycloalkyl, heterocyclyl, aryl and heteroaryl groups have one residue derived by removing one hydrogen atom from the parent ring atom, or two residues derived from the same or two different ring atoms of the parent. Residues derived from three hydrogen atoms, namely "divalent cycloalkyl", "divalent heterocyclic group", "arylene", and "heteroarylene".

The term "amino protecting group" is to keep the amino group unchanged when other parts of the molecule react, and to protect the amino group with a group that is easy to remove. Non-limiting examples include tetrahydropyranyl, tert-butoxycarbonyl, acetyl, benzyl, allyl, p-methoxybenzyl, and the like. These groups may be optionally substituted with 1-3 substituents selected from halogen, alkoxy or nitro. The amino protecting group is preferably tetrahydropyranyl.

The term "cycloalkyloxy" refers to cycloalkyl-O-, where cycloalkyl is as defined above.

The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, where the alkyl group is as defined above.

The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, where the alkyl group is as defined above.

The term "hydroxy" refers to the -OH group.

The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, where the alkyl group is as defined above.

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

The term "amino" refers to -NH ₂ .

The term "cyano" refers to -CN.

The term "nitro" refers to -NO ₂ .

The term "carbonyl" refers to C=O.

The term "oxo" refers to =O.

The term "carboxy" refers to -C(O)OH.

The term "carboxylate group" refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O- or (cycloalkyl)C(O ) O-, wherein alkyl and cycloalkyl are as defined above.

The term "ubiquitin ligase" refers to a family of proteins that promote the transfer of ubiquitin to a specific substrate protein and target the substrate protein for degradation. For example, cerebellar protein is an E3 ubiquitin ligase protein that alone or in combination with E2 ubiquitin ligase causes ubiquitin to attach to lysine on a target protein and then target a specific protein substrate for degradation by the proteasome. Therefore, E3 ubiquitin ligase alone or in combination with E2 ubiquitin conjugating enzyme is the reason for the transfer of ubiquitin to the target protein. Generally, ubiquitin ligase participates in polyubiquitination so that the second ubiquitin is linked to the first ubiquitin, the third ubiquitin is linked to the second ubiquitin, and so on. Polyubiquitinated labeled proteins are used for degradation by the proteasome. However, there are some ubiquitination events that are limited to monoubiquitination, where only a single ubiquitin is added to the substrate molecule by ubiquitin ligase. Monoubiquitinated proteins are not targeted to the proteasome for degradation, but may instead change in their cellular location or function, for example via binding to other proteins that have domains capable of binding ubiquitin. To make matters more complicated, different lysines on ubiquitin can be targeted by E3 to make chains. The most common lysine is Lys48 on the ubiquitin chain. This is the lysine used to make polyubiquitin, which is recognized by the proteasome.

The term "target protein" refers to proteins and peptides that have any biological function or activity (including structure, regulation, hormones, enzymatic, genetic, immune, contraction, storage, transportation, and signal transduction). In some embodiments, the target protein includes structural proteins, receptors, enzymes, cell surface proteins, and proteins related to the integrated functions of cells, including proteins involved in each of the following: catalytic activity, aromatase activity, locomotor activity, helix Enzyme activity, metabolic process (anabolism and catabolism), antioxidant activity, proteolysis, biosynthesis, protein 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, biological process regulation, development , Cell differentiation, stimulus, behavioral proteins, cell adhesion proteins, white matter involved in cell death, proteins involved in transport (including protein transport activity, nuclear transport, ion transport activity, channel transport activity, carrier activity), communication Permease activity, secretion activity, electron transport activity, pathogen, associated protein regulator activity, nucleic acid binding activity, transcription regulator activity, extracellular structure and biological origin activity, translation regulator activity. The protein includes proteins from eukaryotes and prokaryotes, including microorganisms, viruses, fungi, and parasites, as well as many others, including humans, microorganisms, viruses, fungi, and others that are targets of drug therapy. Parasites, other animals include domestic animals, microorganisms and other antimicrobials and plants and even viruses used to determine antibiotic targets and many others.

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, with the structure of the present disclosure, except for replacing hydrogen with "deuterium" or "tritium", or replacing ^{fluorine with 18} F-fluorine label ( ¹⁸ F isotope), or enriching ^{with 11} C-, ¹³ C- or ^{14 C-} Compounds in which carbon atoms ( ¹¹ C-, ¹³ C-, or ¹⁴ C-carbon labels; ¹¹ C-, ¹³ C- or ¹⁴ C- isotopes) replace carbon atoms are within the scope of the present disclosure. Such compounds can be used, for example, as analytical tools or probes in biological assays, or as tracers for in vivo diagnostic imaging of diseases, or as tracers for pharmacodynamics, pharmacokinetics, or receptor studies.

The present disclosure also includes compounds of general formula in various deuterated forms. Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can refer to relevant literature to synthesize deuterated compounds of the general formula. Commercially available deuterated starting materials can be used when preparing the deuterated form of the general formula compound, or they can be synthesized using conventional techniques using deuterated reagents. Deuterated reagents include but are not limited to deuterated borane and tri-deuterated borane. Tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated ethyl iodide and deuterated methyl iodide, etc.

"Optional" or "optionally" means that the event or environment described later can but need not occur, and the description includes the occasion where the event or environment occurs or does not occur. For example, "heterocyclic group optionally substituted by an alkyl group" means that an alkyl group may but does not have to be present, and the description includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group. .

"Substituted" refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of each other, substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine possible or impossible substitutions (by experiment or theory) without too much effort. For example, an amino group or a hydroxyl group having free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.

"Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers And excipients. The purpose of the pharmaceutical composition is to promote the administration to the organism, which is beneficial to the absorption of the active ingredient and thus the biological activity.

"Pharmaceutically acceptable salt" refers to the salt of the compound of the present disclosure, which is safe and effective when used in mammals, and has due biological activity.

For drugs or pharmacologically active agents, the term "therapeutically effective amount" refers to a sufficient amount of a drug or agent that is non-toxic but can achieve the desired effect. The determination of the effective amount varies from person to person, and depends on the age and general conditions of the recipient, as well as the specific active substance. The appropriate effective amount in each case can be determined by those skilled in the art according to routine experiments.

resolve resolution

Option One

Another aspect of the present disclosure relates to a method for preparing a compound of general formula (I-1) or general formula (I-2), or a pharmaceutically acceptable salt thereof, which comprises:

Compounds of general formula (I-1A) and compounds of general formula (IM-1aa) undergo reductive amination under acidic conditions (preferably acetic acid) in the presence of a reducing agent to obtain compounds of general formula (I-1); or The strong acid salt of the compound of general formula (I-1A) and the compound of general formula (IM-1aa) (preferably hydrochloride and trifluoroacetate), under alkaline conditions (preferably sodium acetate), in a reducing agent In the presence, a reductive amination reaction occurs to obtain a compound of general formula (I-1);

Compounds of general formula (I-2A) and compounds of general formula (IM-2aa) undergo a reductive amination reaction under acidic conditions (preferably acetic acid) in the presence of a reducing agent to obtain compounds of general formula (I-2); or The compound of formula (I-2A) and the compound of general formula (IM-2aa) are strong acid salts (preferably hydrochloride and trifluoroacetate), under alkaline conditions (preferably sodium acetate), in the presence of a reducing agent , A reductive amination reaction occurs to obtain a compound of general formula (I-2);

in:

R ^5a is a hydrogen atom;

L is R ^2L'- CH ₂ or Q ¹ -CH ₂ ;

R ^2L 'is selected from covalent bond, C _1-12 alkylene, 1 to 12 membered heteroalkylene, C _2-12 alkenylene and C _2-12 alkynylene, wherein the C _1-12 Alkylene, 1 to 12 membered heteroalkylene, C _2-12 alkenylene and C _2-12 alkynylene are optionally selected from halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, hydroxy, C _1-6 hydroxyalkyl, cyano, amino, oxo, 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclic group, 6 to 10 membered aryl and 5 to One or more substituents in the 10-membered heteroaryl group; preferably, R ^2L 'is a covalent bond or a C _1-12 alkylene group, wherein the C _1-12 alkylene group is optionally selected From halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, hydroxy, C _1-6 hydroxyalkyl, cyano, amino, oxo, 3 to 8 membered cycloalkyl , 3 to 8 membered heterocyclic group, 6 to 10 membered aryl group and 5 to 10 membered heteroaryl group substituted by one or more substituents;

In general formula (IM-2aa) and general formula (I-2), p is 0, 1, 2, 3 or 4;

In general formula (IM-1aa) and general formula (I-1), p is 1, 2, 3 or 4;

PTM, Q ¹ , ring B, ring D, ring E, G ¹ , G ² , R ¹ , R ³ -R ⁵ , R ^f , f, and n are as general formula (I-1) and general formula (I- 2) as defined in.

Option II

Another aspect of the present disclosure relates to a method for preparing a compound of general formula (I-3) or general formula (I-4), or a pharmaceutically acceptable salt thereof, which comprises:

Compounds of general formula (I-1A) and compounds of general formula (IM-9) undergo a reductive amination reaction under acidic conditions (preferably acetic acid) in the presence of a reducing agent to obtain compounds of general formula (I-3); or The strong acid salt of the compound of formula (I-1A) and the compound of general formula (IM-9) (preferably hydrochloride and trifluoroacetate), under alkaline conditions (preferably sodium acetate), in the presence of a reducing agent Next, a reductive amination reaction occurs to obtain a compound of general formula (I-4);

Compounds of general formula (I-2A) and compounds of general formula (IM-13aa) undergo a reductive amination reaction under acidic conditions (preferably acetic acid) in the presence of a reducing agent to obtain compounds of general formula (I-4); or The strong acid salt of the compound of formula (I-2A) and the compound of general formula (IM-13aa) (preferably hydrochloride and trifluoroacetate), under alkaline conditions (preferably sodium acetate), in the presence of a reducing agent Next, a reductive amination reaction occurs to obtain a compound of general formula (I-4);

in:

R ^5a is a hydrogen atom;

L is R ^2L'- CH ₂ or Q ¹ -CH ₂ ;

R ^2L 'is selected from covalent bond, C _1-12 alkylene, 1 to 12 membered heteroalkylene, C _2-12 alkenylene and C _2-12 alkynylene, wherein the C _1-12 Alkylene, 1 to 12 membered heteroalkylene, C _2-12 alkenylene and C _2-12 alkynylene are optionally selected from halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, hydroxy, C _1-6 hydroxyalkyl, cyano, amino, oxo, 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclic group, 6 to 10 membered aryl and 5 to One or more substituents in the 10-membered heteroaryl group; preferably, R ^2L 'is a covalent bond or a C _1-12 alkylene group, wherein the C _1-12 alkylene group is optionally selected From halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, hydroxy, C _1-6 hydroxyalkyl, cyano, amino, oxo, 3 to 8 membered cycloalkyl , 3 to 8 membered heterocyclic group, 6 to 10 membered aryl group and 5 to 10 membered heteroaryl group substituted by one or more substituents;

PTM, Q ¹ , ring E, G ¹ , G ² , R ¹ , R ³ -R ⁵ , R ^f , g, f, p, n and t are as general formula (I-3) and general formula (I-4 ).

third solution

Another aspect of the present disclosure relates to a method for preparing a compound of general formula (I-3), or a pharmaceutically acceptable salt thereof, which comprises:

Compounds of general formula (I-1A) and compounds of general formula (IM-9') undergo reductive amination under acidic conditions (preferably acetic acid) in the presence of a reducing agent, and then under alkaline conditions (preferably carbonic acid) Potassium), an intramolecular ring-closure reaction to obtain a compound of general formula (I-3)

in:

X is a leaving group, preferably but not limited to chlorine, bromine and iodine;

R ^5a is a hydrogen atom;

L is R ^2L' -CH ₂ or Q ¹ -CH ₂ ;

R ^2L 'is selected from covalent bond, C _1-12 alkylene, 1 to 12 membered heteroalkylene, C _2-12 alkenylene and C _2-12 alkynylene, wherein the C _1-12 Alkylene, 1 to 12 membered heteroalkylene, C _2-12 alkenylene and C _2-12 alkynylene are optionally selected from halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, hydroxy, C _1-6 hydroxyalkyl, cyano, amino, oxo, 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclic group, 6 to 10 membered aryl and 5 to One or more substituents in the 10-membered heteroaryl group; preferably, R ^2L 'is a covalent bond or a C _1-12 alkylene group, wherein the C _1-12 alkylene group is optionally selected From halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, hydroxy, C _1-6 hydroxyalkyl, cyano, amino, oxo, 3 to 8 membered cycloalkyl , 3 to 8 membered heterocyclic group, 6 to 10 membered aryl group and 5 to 10 membered heteroaryl group substituted by one or more substituents;

R ^5b , R ^5c , R ^5d and R ^5e are each the same or different, and are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, and a nitro group , Cycloalkyl, heterocyclyl, aryl and heteroaryl;

t is 0, 1 or 2; preferably, t is 0 or 1;

PTM, Q ¹ , G ¹ , G ² , R ³ -R ⁵ , p and n are as defined in the general formula (I-3).

In the above synthesis scheme, providing acidic conditions can be organic or inorganic acids, including but not limited to acetic acid, trifluoroacetic acid, phosphoric acid, benzenesulfonic acid, preferably acetic acid; it can also be strong acid salts including but not limited to hydrochloride, Sulfate, nitrate, benzenesulfonate, trifluoromethanesulfonate, trifluoroacetate, etc., preferably hydrochloride or trifluoroacetate;

In the above synthesis scheme, the reagents that provide alkaline conditions include organic bases and inorganic bases. The organic bases include but are not limited to triethylamine, N,N-diisopropylethylamine, n-butyllithium, and Lithium isopropylamide, potassium acetate, sodium acetate, sodium ethoxide, sodium tert-butoxide or potassium tert-butoxide, the inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, Sodium hydroxide, lithium hydroxide monohydrate, lithium hydroxide and potassium hydroxide; preferably sodium acetate or potassium carbonate.

In the above synthesis scheme, the reducing agent includes, but is not limited to, sodium triacetoxyborohydride, sodium borohydride, lithium borohydride, sodium cyanoborohydride, sodium acetylborohydride, etc., preferably sodium triacetoxyborohydride .

The above synthesis scheme is preferably carried out in a solvent. The solvents used include but are not limited to: ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, N-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide and mixtures thereof.

Detailed ways

The following embodiments are used to further describe the present disclosure, but these embodiments do not limit the scope of the present disclosure.

Example

The structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). The NMR shift (δ) is given in units of ^{10 -6 (ppm).} NMR was measured with Bruker AVANCE-400 nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD), and the internal standard was four Methylsilane (TMS).

For MS measurement, Agilent 1200/1290 DAD-6110/6120 Quadrupole MS liquid-mass spectrometer (manufacturer: Agilent, MS model: 6110/6120 Quadrupole MS), waters ACQuity UPLC-QD/SQD (manufacturer: waters, MS Model: waters ACQuity Qda Detector/waters SQ Detector), THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).

High performance liquid chromatography (HPLC) analysis uses Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 high pressure liquid chromatograph.

Chiral HPLC analysis and determination use Agilent 1260 DAD high performance liquid chromatograph.

The HPLC preparation uses Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs.

For chiral preparation, Shimadzu LC-20AP preparative chromatograph was used.

CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).

The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm～0.2mm, and the size of the thin layer chromatography separation and purification product is 0.4mm. ~0.5mm.

Silica gel thin-layer chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

The average value of ₅₀ measured kinase inhibition rate and IC NovoStar using a microplate reader (BMG, Germany).

The known starting materials of the present disclosure can be synthesized by or according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Shanghai Bi Get Pharmaceuticals, Darui Chemicals, Adamas Reagents, Aladdin Reagents, Tichiai (Shanghai) Chemical Industry Development Co., Ltd. and other companies

There is no special description in the examples, and the reaction can all be carried out under an argon atmosphere or a nitrogen atmosphere.

The argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1L.

The hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1L.

The pressure hydrogenation reaction uses Parr 3916EKX hydrogenator and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenator.

The hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.

The microwave reaction uses the CEM Discover-S 908860 microwave reactor.

There is no special description in the examples, and the solution refers to an aqueous solution.

There are no special instructions in the examples, and the reaction temperature is room temperature, which is 20°C to 30°C.

The monitoring of the reaction progress in the examples adopts thin layer chromatography (TLC), the developing solvent used in the reaction, the eluent system of column chromatography used in the purification of the compound, and the developing reagent system of thin layer chromatography include: A: Dichloromethane/methanol system; B: n-hexane/ethyl acetate system. The volume ratio of the solvent is adjusted according to the polarity of the compound, and it can also be adjusted by adding a small amount of basic or acidic reagents such as triethylamine and acetic acid.

Example 1

3-(6-oxo-2,3,6,8-tetrahydropyrrolo[3,4-g]indole-7(1H)-yl)piperidine-2,6-dione 1

first step

3-(4-Amino-5-(2,2-dimethoxy-1-(methylthio)ethyl)-1-oxoisoindolin-2-yl)piperidine-2,6- Dione 1b

Dissolve 3-(4-amino-1-oxo-isoindolin-2-yl)piperidine-2,6-dione 1a (1.0g, 3.85mmol, Shaoyuan Chemical Technology) in 25mL N,N -In a mixed solvent of dimethylformamide and 1,2-dichloromethane (V/V=2/3). At 0°C, add 1,1-dimethoxy-2-methylthioethane (526mg, 3.85mmol, Tishai (Shanghai) Chemical Industry Development Co., Ltd.), stir for 10 minutes, add N-chlorine in batches Substituted succinimide (516mg, 3.85mmol), stirred at 0°C for 1 hour. Then, triethylamine (391 mg, 3.85 mmol) was added dropwise, after dropping, the reaction was stirred for 15 minutes, the reaction was raised to room temperature, and the oil bath was heated to 75° C. for 8 hours. The reaction was cooled to room temperature, water (20 mL) was added, and the mixture was extracted with dichloromethane (25 mL×5). The organic phases were combined and dried over anhydrous sodium sulfate. It was filtered and concentrated under reduced pressure to remove the solvent to obtain the crude title compound 1b (1.51 g), which was directly used in the next reaction.

MS m/z(ESI): 394.0[M+1].

Second step

3-(3-(Methylthio)-6-oxo-6,8-dihydropyrrolo[3,4-g]indole-7(1H)-yl)piperidine-2,6-dione 1c

Compound 1b (1.51 g, 1.92 mmol) was suspended in methyl tert-butyl ether (6 mL), and 2M hydrochloric acid (10.5 mL, 21.09 mmol) was added dropwise under ice bath. After dripping, the mixture was stirred and reacted for 16 hours. Saturated sodium bicarbonate was added dropwise to adjust the pH of the reaction solution to about 8, a large amount of solid was precipitated, filtered, and dried to obtain the title compound 1c (400 mg), yield: 63%.

MS m/z(ESI): 330.0[M+1].

third step

3-(6-oxo-6,8-dihydropyrrolo[3,4-g]indole-7(1H)-yl)piperidine-2,6-dione 1d

Compound 1c (200mg, 0.607mmol) was dissolved in acetone (20mL), Raney nickel (1.0g, 17.03mmol) was added, heated to 60°C for 3 hours, filtered, concentrated under reduced pressure, and the residue was chromatographed on silica gel column The method was purified with eluent system A to obtain the title compound 1d (30 mg, 52% purity), yield: 9%.

MS m/z(ESI): 284.1[M+1].

the fourth step

3-(6-oxo-2,3,6,8-tetrahydropyrrolo[3,4-g]indole-7(1H)-yl)piperidine-2,6-dione 1

Compound 1d (30 mg, 0.053 mmol, 52% purity) was dissolved in glacial acetic acid (3 mL), sodium cyanoborohydride (13 mg, 0.217 mmol) was added, and the reaction was stirred for 5 hours. The solvent was removed by concentration under reduced pressure, and the crude product was prepared by HPLC (Waters 2767-SQ Detecor2, elution system: amine acetate, water, acetonitrile) to obtain the title compound 1 (10 mg), yield: 66%.

MS m/z(ESI): 286.1[M+1].

¹ H NMR (400MHz, DMSO-d ₆ ) 8.06 (s, 1H), 7.17 (d, 1H), 6.94 (d, 1H), 5.06-5.00 (m, 1H), 4.58 (s, 1H), 4.19 ( d,1H),4.10(d,1H),3.53(t,2H),3.02(t,2H),2.98-2.82(m,1H),2.63-2.52(m,1H),2.42-2.25(m, 1H), 2.03-1.90 (m, 1H).

Example 2

2-(2,6-dioxopiperidin-3-yl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,4-g]isoquinoline-1,3(2H) -Dione 2,2,2-trifluoroacetate 2

first step

6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride 2b

Dissolve 2-(3,4-dimethoxyphenyl)ethyl-1-amine 2a (18.1g, 100mmol, Shanghai Biotech) in absolute ethanol (30mL), add paraformaldehyde (3.6g, 120mmol) ). After the addition, the reaction was stirred for 2 hours, and then concentrated hydrochloric acid was added to adjust the pH of the reaction solution to about 2. The reaction was heated and refluxed for 4 hours. The reaction solution was cooled to room temperature, and a solid precipitated out. The filter cake was washed with cold ethanol (50 mL×2) and dried under vacuum to obtain the title compound 2b (16.76 g). Yield: 73%.

MS m/z(ESI): 194.2[M+1].

Second step

1,2,3,4-Tetrahydroisoquinoline-6,7-diphenol hydrobromide 2c

Compound 2b (5.0 g, 21.77 mmol) was added to a hydrobromic acid solution in acetic acid (50 mL, 33 wt.%, Adamas reagent), and the reaction solution was heated to 110° C. and stirred for 16 hours. After cooling to room temperature, the mixture was filtered and dried in vacuum to obtain the crude title compound 2c (4.2 g), which was directly used in the next reaction.

MS m/z(ESI): 166.2[M+1].

third step

6,7-Dihydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester 2d

Compound 2c (2.0g, 8.13mmol) was dissolved in water, added tetrahydrofuran (10mL), triethylamine (2.05g, 20.33mmol), and then di-tert-butyl dicarbonate (1.93g, 8.943mmol) in tetrahydrofuran ( 10 mL) was added dropwise to the reaction solution, and the reaction was stirred overnight. After concentration under reduced pressure, the residue was dissolved in ethyl acetate (20 mL), washed with water (100 mL×2), saturated sodium chloride solution (20 mL), and dried over anhydrous sodium sulfate. Filtration, concentration under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 2d (1.21 g), yield: 56%.

¹ H NMR (400MHz, DMSO-d6): δ8.75(s,1H), 8.72(s,1H), 6.49(s,1H), 6.47(s,1H), 4.28(brs,2H), 3.46( t, 2H), 2.56 (t, 2H), 1.41 (s, 9H).

the fourth step

6,7-bis(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester 2e

Compound 2d (1.17g, 4.41mmol) was dissolved in dichloromethane (10mL), triethylamine (1.12g, 11.03mmol) was added, and trifluoromethanesulfonic anhydride (2.55g, 9.04mmol), and then react at room temperature for 2 hours. Dilute with dichloromethane (30 mL), wash with saturated sodium bicarbonate solution (10 mL×2) and saturated sodium chloride solution (10 mL×2) successively, and dry the organic phase with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain the crude title compound 2e (2.37 g), which was directly used in the next reaction.

MS m/z(ESI): 473.9[M-55].

the fifth step

2-(tert-butyl)6,7-dimethyl 3,4-dihydroisoquinoline-2,6,7(1H)-tricarboxylate 2f

Compound 2e (500mg, 0.94mmol) was dissolved in methanol (5mL), and palladium acetate (31.8mg, 0.14mmol), 1,1'-bis(diphenylphosphine)ferrocene (157mg, 0.28mmol) and three Ethylamine (419.72mg, 4.15mmol), the mixed solution was heated to 80°C under carbon monoxide atmosphere and reacted overnight. The reaction solution was filtered, and the filtrate was dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 2f (120 mg), yield: 36%.

¹ H NMR (400MHz, CDCl ₃ ): δ7.50 (s, 1H), 7.49 (s, 1H), 4.61 (s, 2H), 3.90 (s, 6H), 3.67-3.64 (m, 2H), 2.89 -2.87 (m, 2H), 1.49 (s, 9H).

Sixth step

2-(tert-Butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-6,7-dicarboxylic acid 2g

Compound 2f (500 mg, 1.43 mmol) was added to a mixed solution of lithium hydroxide monohydrate (361.00 mg, 8.59 mmol) in 8 mL of tetrahydrofuran and water (V/V=5/3), and the reaction was heated to 30°C. Reaction 4 Hour. The reaction solution was concentrated under reduced pressure to remove most of the tetrahydrofuran. The residue was diluted with water (10mL) and washed with ether (5mL×3). The aqueous solution was adjusted to pH 2-3 with 4M potassium hydrogen sulfate solution and then dichloromethane (10mL×3) was used. After extraction, the organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 2 g (363 mg) of the crude title compound, which was directly used in the next reaction.

Seventh step

1,3-dioxo-1,5,7,8-tetrahydrofuro[3,4-g]isoquinoline-6(3H)-carboxylic acid tert-butyl ester 2h

Compound 2g (227mg, 0.71mmol) was dissolved in anhydrous tetrahydrofuran (8mL), then acetic anhydride (1.2mL) was added, and the reaction was refluxed overnight. Concentrate under reduced pressure to obtain the crude title compound 2h (225 mg), and the crude product was directly used in the next reaction.

Eighth step

2-(2,6-dioxopiperidin-3-yl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,4-g]isoquinoline-1,3(2H) -Diketone trifluoroacetate 2

Dissolve compound 2h (100mg, 0.33mmol) in acetic acid (7mL), add potassium acetate (32mg, 0.33mmol) and 3-aminopiperidine-2,6-dione hydrochloride (53mg, 0.33mmol, Shanghai Bide Medicine), heated to 100°C under a nitrogen atmosphere and reacted overnight. Concentrated under reduced pressure, and the residue was prepared by HPLC (Waters 2767-SQ Detecor 2, elution system: trifluoroacetic acid, water, acetonitrile) to obtain the title compound 2 (9 mg), yield: 9%.

MS m/z(ESI): 313.9[M+1].

¹ H NMR (400MHz, DMSO-d6): δ11.11 (s, 1H), 9.30 (brs, 1H), 7.84 (s, 1H), 7.82 (s, 1H), 5.13 (dd, 1H), 4.46 ( s, 2H), 3.43 (t, 2H), 3.17 (t, 2H), 2.90-2.84 (m, 1H), 2.62-2.51 (m, 2H), 2.06-2.03 (m, 1H).

Example 3

3-(7-oxo-3,4,7,9-tetrahydro-[1,4]oxazino[2,3-e]isoindole-8(2H)-yl)piperidine-2, 6-diketone 3

first step

3-hydroxy-2-methyl-4-nitrobenzoic acid 3b

Dissolve potassium nitrate (3.322g, 32.86mmol) in 15mL of water, then add concentrated sulfuric acid (3.223g, 32.86mmol, 2.0mL), add 3-hydroxy-2-methylbenzoic acid 3a (5.0g, 32.86mmol) with stirring , Shanghai Beat Medicine), the reaction was heated to 70°C and stirred for 2 hours. Dilute with water, extract with ethyl acetate (50mL×3), combine the organic phases, wash with saturated sodium chloride solution (50mL), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting residue is chromatographed on a silica gel column. Chromatography was purified with the developing solvent system A to obtain the title compound 3b (4.0 g), yield: 62%.

MS m/z(ESI): 196[M-1].

Second step

3-acetoxy-2-methyl-4-nitrobenzoic acid 3c

Compound 3b (2.0g, 10.14mmol) was dissolved in a mixed solvent of 24mL of dichloromethane and pyridine (V/V=5/1), and acetyl chloride (1.194g, 15.22mmol, 1.1mL) was added under ice bath and kept Reaction in ice bath for 30 minutes. Slowly add 1M hydrochloric acid solution to adjust the pH of the reaction solution to about 5, extract with dichloromethane (50mL×3), combine the organic phases, wash with saturated sodium chloride solution (50mL), dry with anhydrous sodium sulfate, filter, and reduce the filtrate After pressure concentration, the obtained residue was purified by silica gel column chromatography with developing solvent system B to obtain the title compound 3c (2.3 g), yield: 95%.

MS m/z(ESI): 238[M-1].

third step

Methyl 3-acetoxy-2-methyl-4-nitrobenzoate 3d

Compound 3c (600mg, 2.51mmol) was dissolved in a mixed solvent of 15mL of dichloromethane and methanol (V/V=2/1), and trimethylsilylated diazomethane (2M, 1.9mL) was slowly added dropwise and stirred React for 1 hour. After concentration, the obtained residue was purified by silica gel column chromatography with developing solvent system B to obtain the title compound 3d (540 mg), yield: 85%.

MS m/z(ESI): 254[M+1].

the fourth step

Methyl 3-acetoxy-2-(bromomethyl)-4-nitrobenzoate 3e

Compound 3d (300mg, 1.18mmol) was dissolved in carbon tetrachloride (10mL), azobisisobutyronitrile (58mg, 0.355mmol) and N-bromosuccinimide (337mg, 1.90mmol) were added, in Under a nitrogen atmosphere, the reaction was heated to 80°C with reflux stirring for 15 hours. Concentrate under reduced pressure to remove the solvent, dilute with water (10 mL), extract with ethyl acetate (30 mL×3), combine the organic phases, wash with saturated sodium chloride solution (30 mL), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure The obtained residue was purified by silica gel column chromatography with developing solvent system B to obtain the title compound 3e (380 mg), yield: 96%.

MS m/z(ESI): 332[M+1].

the fifth step

3-(4-Hydroxy-5-nitro-1-oxoisoindol-2-yl)piperidine-2,6-dione 3f

Compound 3e (380mg, 1.14mmol) was dissolved in acetonitrile (10mL), then triethylamine (231mg, 2.29mmol) and compound 3-aminopiperidine-2,6-dione hydrochloride (226mg, 1.37mmol) were added ), the reaction was stirred at room temperature for 30 minutes, and then heated to 80°C and stirred overnight. It was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with developing solvent system A to obtain the title compound 3f (270 mg), yield: 77%.

MS m/z(ESI): 306[M+1].

Sixth step

3-(5-Amino-4-hydroxy-1-oxoisoindol-2-yl)piperidine-2,6-dione 3g

Compound 3f (270 mg, 0.88 mmol) was dissolved in methanol (100 mL), then palladium on carbon (282 mg, 0.265 mmol, 10% wt.) was added, and hydrogen was replaced 3 times, and the reaction was stirred for 2 hours. The palladium carbon was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain 3 g (220 mg) of the crude title compound, which was directly used in the next reaction.

MS m/z(ESI): 276[M+1].

Seventh step

3-(5-((2-chloroethyl)amino)-4-hydroxy-1-oxoisoindol-2-yl)piperidine-2,6-dione 3h

Compound 3g (140mg, 0.51mmol), 2-chloroacetaldehyde (149mg, 0.76mmol, 40% aqueous solution, Aladdin's reagent) were dissolved in 10mL of methanol, acetic acid (91mg, 1.53mmol) was added, and the reaction was stirred at room temperature for 1 hour . Then pyridine borane (142 mg, 1.53 mmol) was added, and the reaction was stirred at room temperature for 1 hour. Water (30mL) was added to the reaction system under ice bath, extracted with ethyl acetate (30mL×3), the organic phases were combined, washed with saturated sodium chloride solution (30mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure The obtained residue was purified by silica gel column chromatography with developing solvent system A to obtain the title compound 3h (98 mg), yield: 57%.

MS m/z(ESI): 338[M+1].

Eighth step

3-(7-oxo-3,4,7,9-tetrahydro-[1,4]oxazino[2,3-e]isoindole-8(2H)-yl)piperidine-2, 6-diketone 3

Compound 3h (40 mg, 0.12 mmol) was dissolved in N,N-dimethylformamide (2 mL), then potassium carbonate (49 mg, 0.36 mmol) was added, and the reaction was stirred for 2 hours. The crude product was prepared by high performance liquid phase (Waters 2767-SQ Detecor 2, elution system: amine acetate, water, acetonitrile) to obtain the title compound 3 (15 mg), yield: 42%.

MS m/z(ESI): 302[M+1].

¹ H NMR (400MHz, DMSO-d ₆ ) 11.42-10.65 (brs, 1H), 7.06 (d, 1H), 6.66 (d, 1H), 6.53 (s, 1H), 5.01 (dd, 1H), 4.32 4.13 (m, 3H), 4.07 (d, 1H), 3.30-3.25 (m, 2H), 2.96-2.80 (m, 1H), 2.70-2.56 (m, 1H), 2.40-2.28 (m, 1H), 1.98-1.83 (m, 1H).

Example 4

3-(8-oxo-3,4,6,8-tetrahydro-[1,4]oxazino[2,3-f]isoindole-7(2H)-yl)piperidine-2, 6-diketone 4

first step

5-hydroxy-2-methyl-4-nitrobenzoic acid 4b

The compound 5-hydroxy-2-methylbenzoic acid 4a (5.0g, 32.86mmol, Shanghai Bi De Pharmaceutical) was dissolved in 30mL of acetic acid, and nitric acid (2.96g, 32.86mmol, 70% Wt) was slowly added dropwise at room temperature, and stirred The reaction was carried out for 30 minutes, and then the reaction was heated to 50° C., and the reaction was stirred for 1 hour. The reaction was diluted with water, extracted with ethyl acetate (50mL×3), washed with saturated sodium chloride solution (50mL), dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the silica gel column chromatography was used to develop solvent system A The resulting residue was purified to obtain the title compound 4b (4.0 g) with a yield of 61%.

MS m/z(ESI): 196[M-1].

Second step

Methyl 5-hydroxy-2-methyl-4-nitrobenzoate 4c

Compound 4b (4.0g, 20.3mmol) was dissolved in 60mL of a mixed solvent of dichloromethane and methanol (V/V=2/1), and 2N trimethylsilylated diazomethane in n-hexane solution was slowly added ( 10.2mL), react for 1 hour. The solvent was removed by concentration under reduced pressure, and the resulting residue was purified by silica gel column chromatography with the developing solvent system B to obtain the title compound 4c (3.1 g) with a yield of 72%.

MS m/z(ESI): 212[M+1].

third step

Methyl 5-acetoxy-2-methyl-4-nitrobenzoate 4d

Dissolve compound 4c (2.0g, 9.47mmol) in 40mL of dichloromethane, add triethylamine (2.87g, 28.41mmol) and acetyl chloride (1.19g, 15.22mmol, 1.1mL) under an ice bath. The reaction was stirred for 30 minutes. Adjust the pH of the reaction solution to 5 with 1N HCl solution, extract with dichloromethane (50mL×3), wash with saturated sodium chloride solution (50mL), dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and use a silica gel column The residue obtained was purified by chromatography with the developing solvent system B to obtain the title compound 4d (2.2 g) with a yield of 92%.

MS m/z(ESI): 254[M+1].

the fourth step

Methyl 5-acetoxy-2-(bromomethyl)-4-nitrobenzoate 4e

Compound 4d (1.0g, 3.95mmol) was dissolved in carbon tetrachloride (40mL), azobisisobutyronitrile (AIBN) (162mg, 0.99mmol) and N-bromosuccinimide (1.13g, 6.32mmol), the nitrogen was pumped three times, the reaction was heated to 80°C, and the reaction was stirred at reflux for 18 hours. Concentrate under reduced pressure to remove the solvent, dilute with water (10mL), extract with ethyl acetate (30mL×3), wash with saturated sodium chloride solution (30mL), dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and use silica gel column chromatography The resulting residue was purified by chromatography with the developing solvent system B to obtain the title compound 4e (1.0 g) with a yield of 76%.

MS m/z(ESI): 332[M+1].

the fifth step

3-(6-Hydroxy-5-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione 4f

Compound 4e (500mg, 1.50mmol) was dissolved in acetonitrile (15mL), followed by the addition of triethylamine (457mg, 4.52mmol) and 3-aminopiperidine-2,6-dione hydrochloride (272.6mg, 1.66mmol) , Shanghai Beat Medicine), the reaction was stirred at room temperature for 30 minutes, and then the reaction was heated to 80°C and stirred overnight. It was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with the developing solvent system A to obtain the title compound 4f (290 mg) with a yield of 55%.

MS m/z(ESI): 306[M+1].

Sixth step

3-(5-Amino-4-hydroxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione 4g

Compound 4f (260 mg, 0.85 mmol) was dissolved in methanol (40 mL), then palladium on carbon (91 mg, 10% Wt) was added, and hydrogen was replaced three times and reacted for 2 hours. The palladium carbon was removed by filtration and concentrated under reduced pressure to obtain 4 g (230 mg) of the crude title compound. The crude product was directly used in the next reaction.

MS m/z(ESI): 276[M+1].

Seventh step

3-(5-((2-chloroethyl)amino)-6-hydroxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione 4h

Dissolve compound 4g (100mg, 0.36mmol), 2-chloroacetaldehyde (142mg, 0.72mmol, 40% Wt in water) in methanol (10mL), add acetic acid (65mg, 1.1mmol), stir at room temperature for 1 hour, then Add pyridine borane (101 mg, 1.09 mmol) and react for 1 hour. Under ice bath, add water (30mL) to the reaction system, extract with ethyl acetate (30mL×3), wash with saturated sodium chloride solution (30mL), dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and use silica gel column The residue obtained was purified by chromatography with the developing solvent system A to obtain the title compound 4h (56 mg) with a yield of 46%.

MS m/z(ESI): 338[M+1].

Eighth step

3-(8-oxo-3,4,6,8-tetrahydro-[1,4]oxazino[2,3-f]isoindole-7(2H)-yl)piperidine-2, 6-diketone 4

Compound 4h (56 mg, 0.16 mmol) was dissolved in N,N-dimethylformamide (3 mL), then potassium carbonate (69 mg, 0.50 mmol) was added, and the reaction was carried out for 2 hours. The crude product was prepared by high performance liquid phase (Waters 2767-SQ Detecor2, elution system: 1/1000 volume of trifluoroacetic acid in water and acetonitrile, gradient of acetonitrile: 10%-25%, flow rate: 30mL/min) to obtain the title compound 4 (20mg), yield: 40%.

MS m/z(ESI): 302[M+1].

¹ HNMR (500MHz, DMSO-d ₆ ) 10.92 (s, 1H), 6.90 (s, 1H), 6.66 (s, 1H), 6.58 (s, 1H), 5.00 (dd, 1H), 4.30-3.91 (m , 4H), 3.37-3.35 (m, 2H), 2.96-2.82 (m, 1H), 2.59-2.51 (m, 1H), 2.37-2.25 (m, 1H), 2.02-1.87 (m, 1H).

Example 5

3-(7-oxo-1,2,3,4,7,9-hexahydro-8H-pyrrolo[3,4-h]quinolin-8-yl)piperidine-2,6-dione 5

first step

8-methylquinoline-7-carboxylic acid 5b

In a 250mL flask, add 3-amino-2-methyl-benzoic acid 5a (15g, 99mmol, Shanghai Bi De Pharmaceutical), glycerin (27.4g, 297.7mmol, 21.4mL), nitrobenzene (7.9g, 64.5 mmol), phenylboronic acid (4.6g, 74.4mmol), and slowly added concentrated sulfuric acid (36.8g, 375mmol, 20mL), the addition process pay attention to the reaction exotherm. The system was heated to 160°C, and the reaction was stirred for 10 hours. Cool the reaction to room temperature, pour the reaction solution into ice water, add 10N sodium hydroxide solution to neutralize excess sulfuric acid (about 75 mL), and adjust the system to a pH of about 6. The reaction solution was spread over celite and filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with the developing solvent system A to obtain the title compound 5b (8.5 g), yield: 46%.

MS m/z(ESI): 188.1[M+1].

Second step

8-methylquinoline-7-carboxylic acid tert-butyl ester 5c

Dissolve compound 5b (4.4g, 23.5mmol) in dioxane (50mL), add di-tert-butyl dicarbonate (7.7g, 35.2mmol), 4-dimethylaminopyridine (579mg, 4.7mmol), triethyl Amine (7.1g, 70.5mmol), the reaction was heated to 90°C and stirred for 24 hours. Add saturated ammonium chloride solution (40mL), extract with ethyl acetate (50mL×3), wash with saturated sodium chloride solution (30mL), dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and chromatograph on silica gel column chromatography The obtained residue was purified with the developing solvent system B to obtain the title compound 5c (1.34 g), yield: 23%.

MS m/z(ESI): 244.1[M+1].

third step

Tert-Butyl 8-(bromomethyl)quinoline-7-carboxylate 5d

In a 100mL flask, add compound 5c (650mg, 2.67mmol), 1-bromopyrrolidine-2,5-dione (571mg, 3.2mmol), benzoyl peroxide (172mg, 0.53mmol, 75% purity), Carbon tetrachloride (15 mL), the reaction was stirred at 80°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with the developing solvent system B to obtain the title compound 1d (790 mg), yield: 92%.

MS m/z(ESI): 322.0[M+1].

the fourth step

3-(7-oxo-7,9-dihydro-8H-pyrrolo[3,4-h]quinolin-8-yl)piperidine-2,6-dione 5e

Add compound 5d (0.72g, 2.2mmol), 3-aminopiperidine-2,6-dione hydrochloride (734mg, 4.46mmol) to N,N-dimethylformamide (15mL), add three Ethylamine (677mg, 6.7mmol), the reaction was heated to 100°C and stirred for 3.5 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with the developing solvent system A to obtain the title compound 5e (600 mg), yield: 91%.

MS m/z(ESI): 296.1[M+1].

the fifth step

3-(7-oxo-1,2,3,4,7,9-hexahydro-8H-pyrrolo[3,4-h]quinolin-8-yl)piperidine-2,6-dione 5

Compound 5e (700mg, 2.37mmol), nickel chloride hexahydrate (351mg, 1.18mmol) were added to methanol (20mL), under ice bath, slowly added sodium borohydride (717mg, 19.0mmol), after the addition, react at room temperature 1.5 hours. Under ice bath, add ammonium chloride solution to quench the reaction. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with the developing solvent system A to obtain the title compound 5 (420 mg), yield: 43%.

Take 10mg product and prepare by high performance liquid phase (Waters 2545, elution system: 1/1000 trifluoroacetic acid aqueous solution and acetonitrile, gradient of acetonitrile 50%-70%, flow rate: 30mL/min) to obtain title compound 5 (2.1mg ).

MS m/z(ESI): 300.1[M+1].

¹ H NMR(400MHz,DMSO-d ₆ )δ10.99(s,1H), 7.01(d,1H), 6.82(d,1H), 6.54(s,1H), 5.08(dd,1H), 4.14( d, 1H), 4.04 (d, 1H), 3.30-3.21 (m, 2H), 2.96-2.84 (m, 1H), 2.83-2.69 (m, 2H), 2.67-2.58 (m, 1H), 2.35 2.21 (m, 1H), 1.98-1.91 (m, 1H), 1.89-1.75 (m, 2H).

Example 6 and Example 6'

3-(6-oxo-1,2,3,4,6,8-hexahydro-7H-pyrrolo[3,4-g]quinolin-7-yl)piperidine-2,6-dione 6

3-(3-oxo-1,3,6,7,8,9-hexahydro-2H-pyrrolo[3,4-f]quinolin-7-yl)piperidine-2,6-dione 6'

first step

7-methylquinoline-6-carboxylic acid 6b and 5-methylquinoline-6-carboxylic acid 6b'

In a 250mL flask, add 4-amino-2-methylbenzoic acid 6a (10.0g, 66.1mmol, Shanghai Bi De Pharmaceutical), nitrobenzene (5.3g, 43.0mmol), glycerol (18.28g, 198.5mmol) and Boric acid (3.06 g, 49.6 mmol). Concentrated sulfuric acid (24.3 g, 250 mmol, 13.3 mL) was slowly added thereto, and then the temperature was slowly raised to 160° C., and the reaction was carried out for 8 hours. The reaction was cooled to room temperature, the reaction solution was poured into ice water, 10N sodium hydroxide solution was added to neutralize the excess sulfuric acid (about 60 mL), and the pH of the system was adjusted to about 6. The reaction solution was spread over Celite and filtered, concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography with a developing solvent system A to obtain a mixture of title compounds 6b and 6b' (7.4g). The total yield: 60%.

MS m/z(ESI): 188.1[M+1].

Second step

7-methylquinoline-6-carboxylic acid methyl ester 6c and 5-methylquinoline-6-carboxylic acid methyl ester 6c'

The mixture of compound 6b and 6b' (6.5g, 34.7mmol) was dissolved in N,N-dimethylformamide (50mL), potassium carbonate (9.58g, 69.5mmol) was added, and iodine was added dropwise under an ice bath. Methane (5.42g, 38.2mmol), and the reaction was stirred for 1 hour. Ammonium chloride solution (40mL) was added, extracted with ethyl acetate (40mL×3), washed with saturated sodium chloride solution (30mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography The residue obtained from the purification by the developing reagent system B is pure to obtain a mixture (6.8 g) of the title compound 6c and 6c', with a total yield: 97%.

MS m/z(ESI): 202.1[M+1].

third step

7-(bromomethyl)quinoline-6-carboxylic acid methyl ester 6d and 5-(bromomethyl)quinoline-6-carboxylic acid methyl ester 6d'

The mixture of compound 6c and 6c' (210mg, 1.04mmol) was dissolved in carbon tetrachloride (2mL), azobisisobutyronitrile (AIBN) (17.1mg, 0.10mmol), 1-bromopyrrolidine-2, 5-dione (204mg, 1.15mmol) was reacted at 80°C for 4 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with a developing solvent system B to obtain a mixture of title compounds 6d and 6d' (280 mg), with a total yield: 96%.

MS m/z(ESI): 280.0[M+1].

the fourth step

3-(6-oxo-6,8-dihydro-7H-pyrrolo[3,4-g]quinolin-7-yl)piperidine-2,6-dione 6e and 3-(3-oxo Substitution-1,3-dihydro-2H-pyrrolo[3,4-f]quinolin-2-yl)piperidine-2,6-dione 6e'

Dissolve the mixture of compounds 6d and 6d' (140mg, 0.50mmol) and 3-aminopiperidine-2,6-dione hydrochloride (165mg, 1.0mmol) in N,N-dimethylformamide (3mL) , Triethylamine (323mg, 2.50mmol) was added, and the reaction was stirred at 100°C for 4 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with the developing solvent system A to obtain a mixture of title compounds 6e, 6e' (135 mg), with a total yield: 97%.

MS m/z(ESI): 296.0[M+1].

the fifth step

3-(6-oxo-1,2,3,4,6,8-hexahydro-7H-pyrrolo[3,4-g]quinolin-7-yl)piperidine-2,6-dione 6 and 3-(3-oxo-1,3,6,7,8,9-hexahydro-2H-pyrrolo[3,4-f]quinolin-2-yl)piperidine-2,6- Dione 6'

The mixture of compound 6e and 6e' (100mg, 0.34mmol) was dissolved in methanol (6mL), and under ice bath, nickel chloride hexahydrate (100mg, 0.34mmol) and sodium borohydride (102mg, 2.71mmol) were added to react Stir under ice bath for 2 hours. The reaction solution was concentrated under reduced pressure, and the crude product was prepared by HPLC (Waters 2545, elution system: 1/1000 trifluoroacetic acid aqueous solution and acetonitrile, gradient of acetonitrile 35%-50%, flow rate: 30mL/min) to obtain the title Compound 6 (2.7 mg), yield: 2.6% and 6'(2.7 mg), yield: 2.6%.

Title compound 6:

MS m/z(ESI): 300.1[M+1].

¹ H NMR (500MHz, DMSO-d ₆ ) δ 10.91 (s, 1H), 7.17 (s, 1H), 6.50 (s, 1H), 6.45 (s, 1H), 4.99 (dd, 1H), 4.20 ( d, 1H), 4.07 (d, 1H), 3.24 (t, 2H), 2.94-2.83 (m, 1H), 2.73 (t, 2H), 2.58 (d, 1H), 2.40-2.22 (m, 1H) , 2.03-1.86 (m, 1H), 1.84-1.71 (m, 2H).

Title compound 6':

MS m/z(ESI): 300.1[M+1].

¹ H NMR (500MHz, DMSO-d ₆ ) δ 10.92 (s, 1H), 7.21 (d, 1H), 6.52 (d, 1H), 6.44 (s, 1H), 5.02 (dd, 1H), 4.21 ( d, 1H), 4.05 (d, 1H), 3.23 (t, 2H), 2.97-2.82 (m, 1H), 2.65-2.54 (m, 3H), 2.44-2.30 (m, 1H), 1.97-1.90 ( m, 1H), 1.88-1.73 (m, 2H).

Example 7

2-(2,6-dioxopiperidin-3-yl)-1-oxo-2-3,7,8-tetrahydro-1H-pyrrolo[3,4-g]isoquinoline-6 (5H)-tert-Butyl carboxylate 7

first step

6-Hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester 7b

Dissolve 1,2,3,4-tetrahydroisoquinoline-6-phenol 7a (3.55g, 23.8mmol, Shanghai Bi De Pharmaceutical) in tetrahydrofuran (50mL), add triethylamine (6.02g) under ice bath , 59.5mmol) and di-tert-butyl dicarbonate (6.24g, 28.6mmol), the reaction was slowly returned to room temperature and stirred for 2 hours. The reaction was quenched by adding saturated ammonium chloride solution (30 mL), extracted with ethyl acetate (40 mL×3), washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and layered on a silica gel column The residue obtained was purified by chromatography with the developing solvent system B to obtain the title compound 7b (3.14 g), yield: 53%.

MS m/z(ESI): 194.0[M-55].

Second step

7-formyl-6-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester 7c

Compound 7b (3.14 g, 12.6 mmol), paraformaldehyde (3.78 g, 125.9 mmol), and magnesium chloride (3.60 g, 37.8 mmol) were added to tetrahydrofuran (70 mL) and reacted at 65°C for 7 hours. Add water (50mL), extract with ethyl acetate (50mL×3), wash with saturated sodium chloride solution (30mL), dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product title compound 7c, which is used directly in the next step reaction.

MS m/z(ESI): 222.1[M-55].

third step

7-formyl-6-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester 7d

Compound 7c (3.05g, 11.0mmol) was dissolved in dichloromethane (60mL), pyridine (4.35g, 55.0mmol) was added under ice bath, trifluoromethanesulfonic anhydride (4.65g, 16.5mmol) was added slowly, and the addition was complete. , React at room temperature for 2 hours. Add saturated sodium bicarbonate solution (30mL), extract with ethyl acetate (40mL×3), wash with saturated sodium chloride solution (30mL), dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and chromatograph on silica gel column chromatography The obtained residue was purified with the developing solvent system B to obtain the title compound 7d (3.3 g), the yield: 73%.

MS m/z(ESI): 354.0[M-55].

the fourth step

2-(tert-butyl)6-methyl7-formyl-3,4-dihydroisoquinoline-2,6(1H)-dicarboxylate 7e

Compound 7d (1.0g, 2.44mmol), palladium acetate (55mg, 0.24mmol), 4,5-bis-diphenylphosphine-9,9-dimethylxanthene (Xantphos) (170mg, 0.29mmol), Triethylamine (1.24 g, 12.21 mmol) was added to N,N-dimethylformamide (12 mL), and the reaction solution was stirred for 10 minutes. Methanol (12 mL) was added, carbon monoxide gas was replaced three times, and then reacted at 50°C for 4 hours. Ethyl acetate (30 mL) was added, filtered through a short silica gel column, washed with ethyl acetate (250 mL), the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with the developing solvent system B to obtain the title compound 7e (207 mg ), yield: 27%.

MS m/z(ESI): 320.1[M+1].

the fifth step

2-tert-Butoxycarbonyl-7-formyl-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid 7f

Compound 7e (207 mg, 0.65 mmol) was dissolved in tetrahydrofuran (10 mL), water (2.5 mL) and lithium hydroxide monohydrate (82 mg, 1.95 mmol) were added, and the reaction was carried out for 3 hours. The pH of the reaction solution was adjusted to 6 with 1N dilute hydrochloric acid, extracted with ethyl acetate (40 mL×3), washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude title compound 7f (196mg), the crude product was directly used in the next reaction.

MS m/z(ESI): 306.0[M+1].

Sixth step

2-(tert-Butoxycarbonyl)-7-(((2,6-dioxopiperidin-3-yl)amino)methyl)-1,2,3,4-tetrahydroisoquinoline-6- Carboxylic

Acid 7g

Dissolve compound 7f (110mg, 0.36mmol), 3-aminopiperidine-2,6-dione hydrochloride (62mg, 0.38mmol) in methanol (6mL), add sodium acetate (89mg, 1.08mmol), and stir for 1 After hours, sodium cyanoborohydride (65 mg, 1.08 mmol) was added, and the reaction was stirred overnight. The reaction was quenched by adding saturated ammonium chloride solution (0.2 mL). The reaction solution was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography with the developing solvent system A to obtain 7 g (120 mg) of the title compound. Yield: 80%.

MS m/z(ESI): 418.0[M+1].

Seventh step

2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3,7,8-tetrahydro-1H-pyrrolo[3,4-g]isoquinoline-6 (5H)-tert-Butyl carboxylate 7

Compound 7g (120mg, 0.287mmol), N, N, N', N'-tetramethyl-O-(7-azabenzotriazol-1-yl) urea hexafluorophosphate (HATU) (164mg, 0.43mmol) was dissolved in N,N-dimethylformamide (4mL), triethylamine (186mg, 1.4391mmol) was added and reacted for 2 hours. Add water (20mL), extract with ethyl acetate (30mL×3), wash with saturated sodium chloride solution (30mL×2), dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and use silica gel column chromatography to develop the solvent system A. Purify the resulting residue to obtain the title compound 7 (98mg), yield: 86%.

15mg of crude product was prepared by high performance liquid phase (Waters 2545, elution system: 1/1000 trifluoroacetic acid aqueous solution and acetonitrile, gradient of acetonitrile 40%-60%, flow rate: 30mL/min) to obtain title compound 7 (6mg ).

MS m/z(ESI): 400.0[M+1].

¹ H NMR (500MHz, DMSO-d ₆ ) δ 10.98 (s, 1H), 7.55 (s, 1H), 7.43 (s, 1H), 5.10 (dd, 1H), 4.61 (s, 2H), 4.41 ( d, 1H), 4.28 (d, 1H), 3.56 (t, 2H), 2.97-2.84 (m, 3H), 2.65-2.56 (m, 1H), 2.44-2.33 (m, 1H), 2.02-1.96 ( m, 1H), 1.44 (s, 9H).

Example 8

4-(7-(2,6-dioxopiperidin-3-yl)-8-oxo-7,8-dihydro-6H-[1,3]dioxalano[4,5 -e]isoindol-4-yl)piperazine-1-carboxylic acid tert-butyl ester 8

first step

3-Fluoro-4,5-dihydroxybenzaldehyde 8b

3-Fluoro-4-hydroxy-5-methoxybenzaldehyde 8a (5g, 29.39mmol, Shanghai Bi De Pharmaceutical) was dissolved in dichloromethane (70 mL). Under ice bath, 1N dichloromethane solution (73.5 mL) of boron tribromide was added. After the addition, the reaction was carried out at room temperature for 2 hours. The reaction was quenched by adding methanol (40 mL), the reaction solution was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography with developing solvent system B to obtain the title compound 8b (4.0 g), yield: 87%.

MS m/z(ESI): 156.9[M+1].

Second step

2-Bromo-5-fluoro-3,4-dihydroxybenzaldehyde 8c

Compound 8b (4.5 g, 28.8 mmol) was dissolved in acetic acid (50 mL). Under an ice bath, acetic acid solution (50 mL) of liquid bromine (4.84 g, 30.2 mmol) was added dropwise, and the mixture was slowly returned to room temperature and stirred for 3 hours. After adding n-hexane (50 mL), the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with developing solvent system B to obtain the title compound 8c (3.2 g), yield: 47%.

MS m/z(ESI): 234.9[M+1].

third step

4-bromo-7-fluorobenzo[d][1,3]dioxolane-5-carbaldehyde 8d

Dissolve compound 8c (3.2g, 13.62mmol) in N,N-dimethylformamide (70mL), add dibromomethane (3.3g, 19.1mmol) and cesium carbonate (13.31g, 40.85mmol), and react at 70°C for 3.5 Hour. The reaction was cooled, concentrated under reduced pressure to remove most of the N,N-dimethylformamide, ethyl acetate (50mL) and dichloromethane (50mL) were added, celite and filtered, and the filter residue was washed with ethyl acetate (50mL) and dichloromethane. Wash with methyl chloride (50 mL). The organic phases were combined and washed sequentially with water (50 mL) and saturated sodium chloride solution (50 mL). Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The obtained residue was purified by silica gel column chromatography with developing solvent system B to obtain the title compound 8d (2.3g), yield: 68%.

MS m/z(ESI): 246.8[M+1].

the fourth step

4-bromo-5-(1,3-dioxolane-2-yl)-7-fluorobenzo[d][1,3]dioxolane 8e

Compound 8d (1.1g, 4.45mmol) and ethylene glycol (829mg, 13.4mmol) were added to toluene (40mL), p-toluenesulfonic acid monohydrate (84.7mg, 0.45mmol) was added, and the solution React at 80°C for 1 hour and reflux at 110°C for 2 hours. The reaction was cooled to room temperature, and triethylamine (1 mL) was added to quench the reaction. The reaction solution was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography with developing solvent system B to obtain the title compound 8e (1.23g) in yield. : 95%.

MS m/z(ESI): 290.8[M+1].

the fifth step

5-(1,3-dioxolane-2-yl)-7-fluorobenzo[d][1,3]dioxolane-4-carboxylic acid ethyl ester 8f

Compound 8e (1.74g, 5.98mmol) was dissolved in dry tetrahydrofuran (50mL), cooled to -78°C in a dry ice acetone bath, and n-butyllithium (2.5M, 2.6mL) was slowly added dropwise. The reaction was stirred at -78°C for 1 hour, ethyl cyanoformate (829 mg, 8.37 mmol) was added, and the reaction was stirred at -78°C for 1 hour. Add saturated sodium bicarbonate solution (30mL), extract with ethyl acetate (30mL×3), wash the organic phase with saturated sodium chloride solution (30mL), dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and use a silica gel column The resulting residue was purified by chromatography with the developing solvent system B to obtain the title compound 8f (1.38 g), yield: 81%.

MS m/z(ESI): 284.9[M+1].

Sixth step

7-Fluoro-5-formylbenzo[d][1,3]dioxolane-4-carboxylic acid ethyl ester 8g

Compound 8f (1.0 g, 3.52 mmol) was dissolved in tetrahydrofuran (25 mL), 2N sulfuric acid solution (18 mL) was added, and the reaction was stirred for 1 hour. Saturated sodium bicarbonate solution (60mL) was added, extracted with ethyl acetate (30mL×3), washed with saturated sodium chloride solution (30mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and chromatographed on silica gel column. The obtained residue was purified by the developer system B by the method to obtain 8 g (810 mg) of the title compound, with a yield of 96%.

MS m/z(ESI): 240.9[M+1].

Seventh step

7-Fluoro-5-formylbenzo[d][1,3]dioxolane-4-carboxylic acid 8h

Compound 8g (840 mg, 3.50 mmol) was dissolved in tetrahydrofuran (16 mL), water (4 mL) and lithium hydroxide monohydrate (441 mg, 10.50 mmol) were added, and the reaction was stirred for 1 hour. Add water (30mL), adjust the pH of the reaction solution to 6 with 1N hydrochloric acid, extract with ethyl acetate (30mL×3), wash with saturated sodium chloride solution (30mL), dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain The crude product title compound 8h (740mg), the crude product was directly used in the next reaction.

MS m/z(ESI): 213.0[M+1].

Eighth step

7-(4-(tert-Butoxycarbonyl)piperazin-1-yl)-5-formylbenzo[d][1,3]dioxolane-4-carboxylic acid 8i

Compound 8h (740mg, 3.49mmol) and tert-butyl piperazine-1-carboxylate (1.95g, 10.47mmol) were dissolved in N-methylpyrrolidone (25mL), and diisopropylethylamine (2.25g , 17.4mmol), react at 95°C for 24 hours. Concentrate under reduced pressure to remove most of N-methylpyrrolidone, add water (30mL), extract with ethyl acetate (50mL×3), wash with saturated sodium chloride solution (30mL), dry with anhydrous sodium sulfate, filter, and reduce the filtrate After concentration, the residue was purified by silica gel column chromatography with a developing solvent system B to obtain the title compound 8i (0.5 g), yield: 38%.

MS m/z(ESI): 322.9[M-55].

Step 9

4-(7-((benzyloxy)carbonyl)-6-formylbenzo[d][1,3]dioxolane-4-yl)piperazine-1-carboxylic acid tert-butyl ester 8j

Compound 8i (340 mg, 0.90 mmol) was dissolved in N,N-dimethylformamide (8 mL), benzyl bromide (768 mg, 4.50 mmol) and potassium carbonate (248 mg, 1.80 mmol) were added, and the reaction was carried out for 2 hours. Add water (30mL), extract with ethyl acetate (50mL×3), wash with saturated sodium chloride solution (30mL×2), dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and use silica gel column chromatography to develop The residue obtained was purified by reagent system B to obtain the title compound 8j (330 mg), yield: 78%.

MS m/z(ESI): 491.0[M+23].

Tenth step

4-(7-((benzyloxy)carbonyl)-6-(((2,6-dioxopiperidin-3-yl)amino)methyl)benzo[d][1,3]diox Heteropentyl-4-yl)piperazine-1-carboxylic acid tert-butyl ester 8k

Dissolve compound 8j (300mg, 0.64mmol) and 3-aminopiperidine-2,6-dione hydrochloride (137mg, 0.83mmol) in methanol (3mL), add sodium acetate (158mg, 1.92mmol), and stir at room temperature React for 2 hours. Sodium cyanoborohydride (58mg, 0.96mmol) was added and stirred at room temperature overnight. The reaction was quenched by adding saturated ammonium chloride solution (0.2 mL), the reaction solution was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography with developing solvent system A to obtain the title compound 8k (160 mg), yield: 43% .

MS m/z(ESI): 581.2[M+1].

Eleventh step

7-(4-(tert-butoxycarbonyl)piperazin-1-yl)-5-(((2,6-dioxopiperidin-3-yl)amino)methyl)benzo[d][ 1,3] Dioxolane-4-carboxylic acid 8l

Compound 8k (45 mg, 77.5 μmol) was dissolved in methanol (2 mL), palladium hydroxide/carbon (20 mg, 77.5 μmol, 20% Wt, containing 50% water) was added, hydrogen replacement was performed three times, and the reaction was stirred for 4 hours. Dichloromethane (30 mL) was added, filtered, and washed with dichloromethane (40 mL). The filtrate was concentrated under reduced pressure to obtain the crude title compound 8l (37 mg). The crude product was directly used in the next reaction.

MS m/z(ESI). 491.2[M+1].

Twelfth step

4-(7-(2,6-dioxopiperidin-3-yl)-8-oxo-7,8-dihydro-6H-[1,3]dioxalano[4,5 -e]isoindol-4-yl)piperazine-1-carboxylic acid tert-butyl ester 8

Compound 8l (120mg, 0.244mmol) and N, N, N', N'-tetramethyl-O-(7-azabenzotriazol-1-yl) urea hexafluorophosphate (HATU) (140mg, 0.367mmol) was dissolved in N,N-dimethylformamide (3mL), diisopropylethylamine (149mg, 1.22mmol) was added and reacted for 2 hours. Add ethyl acetate (50mL), wash with saturated sodium chloride solution (30mL×2), dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the resulting residue by silica gel column chromatography with developing solvent system B The title compound 8 (82 mg) was obtained with a yield of 71%.

Take 20mg of crude product and prepare high performance liquid phase (Waters 2545, elution system of 1/1000 trifluoroacetic acid aqueous solution and acetonitrile, gradient of acetonitrile 32%-44%, flow rate: 30mL/min) to obtain title compound 8 (7mg) .

MS m/z(ESI): 473.0[M+1].

¹ H NMR(500MHz,DMSO-d ₆ )δ10.95(s,1H),6.66(s,1H),6.17-6.05(m,2H),5.01(dd,1H),4.31(d,1H), 4.19(d,1H),3.57-3.51(m,4H),3.25-3.07(m,4H),2.94-2.83(m,1H),2.66-2.55(m,1H),2.38-2.27(m,1H) ), 2.02-1.87 (m, 1H), 1.42 (s, 9H).

Example 9

3-(4-(7-(3,5-Difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4 ,9-Tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)heptyl)-7-oxo-3,4,7,9-tetrahydro-[1 ,4]oxazino[2,3-e]isoindole-8(2H)-yl)piperidine-2,6-dione 9

first step

(1R,3R)-1-(4-((7,7-dimethoxyheptyl)oxy)-2,6-difluorophenyl)-2-(2-fluoro-2-methylpropane Yl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole 9c

Compound 9a (80 mg, 0.205 mmol, prepared by the method disclosed in Example 10 on page 77 of the specification of patent application WO2019223715) and 9b (74 mg, 0.309 mmol, using the well-known method "Biosci. Biotech. Biochem. 1992, 56(9), 1417-1419" prepared) was dissolved in N,N-dimethylformamide (5mL), cesium carbonate (134mg, 0.412mmol) was added, and the reaction was heated to 50°C and stirred for 1 hour. Dilute with water (10mL), extract with ethyl acetate (25mL×3), wash with saturated sodium chloride solution (30mL), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain the title compound 9c, which is used directly without purification In the next step.

MS m/z(ESI): 547.1 [M+1].

Second step

7-(3,5-Difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro- 1H-pyrido[3,4-b]indol-1-yl)phenoxy)heptanal 9d

Compound 9c (112 mg, 0.205 mmol) was dissolved in tetrahydrofuran (15 mL), and then 2N sulfuric acid (2.0 mL, 4.0 mmol) was added and reacted for 2 hours. Add saturated sodium bicarbonate solution (5mL), extract with ethyl acetate (25mL×3), dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify the resulting residue by silica gel column chromatography with eluent system A , The title compound 9d (75mg) was obtained, yield: 73%.

MS m/z(ESI): 501.1[M+1].

third step

3-(5-((2-chloroethyl)(7-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3- Methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)heptyl)amino)-4-hydroxy-1-oxo Isoindolin-2-yl)piperidine-2,6-dione 9e

Compound 9d (30mg, 0.06mmol) and compound 3h (20mg, 0.06mmol) were dissolved in a mixed solvent of 2mL of dichloromethane and methanol (V/V=1/1), and then acetic acid (18mg, 0.3mmol) and Sodium triacetoxyborohydride (25.4 mg, 0.2 mmol), the reaction was stirred overnight. The reaction solution was concentrated under reduced pressure to obtain the crude product 9e, which was directly used in the next reaction.

MS m/z(ESI): 822.2[M+1].

the fourth step

3-(4-(7-(3,5-Difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4 ,9-Tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)heptyl)-7-oxo-3,4,7,9-tetrahydro-[1 ,4]oxazino[2,3-e]isoindole-8(2H)-yl)piperidine-2,6-dione 9

Compound 9e (49 mg, 0.06 mmol) was dissolved in N,N-dimethylformamide (2 mL), then potassium carbonate (17 mg, 0.2 mmol) was added, and the reaction was carried out for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was prepared by HPLC (Waters 2767-SQ Detecor2, elution system: 10mmol/L ammonium bicarbonate aqueous solution and acetonitrile, gradient of acetonitrile: 25%-50%, flow rate: 30mL/min ) Purification to obtain the title compound 9 (6mg), yield: 13%.

MS m/z(ESI): 786.3[M+1].

¹ H NMR (500MHz, DMSO-d ₆ ): δ 10.93 (s, 1H), 10.52 (s, 1H), 7.39 (d, 1H), 7.22-7.10 (m, 2H), 7.05-6.86 (m, 2H), 6.81 (d, 1H), 6.72-6.55 (m, 2H), 5.12 (s, 1H), 5.02 (dd, 1H), 4.30-4.18 (m, 3H), 4.08 (d, 1H), 4.01 -3.92(m,2H),3.44-3.39(m,2H),3.38-3.28(m,2H),2.96-2.81(m,2H),2.68-2.52(m,1H),2.44-2.25(m, 2H), 2.06-1.85 (m, 2H), 1.73-1.62 (m, 2H), 1.63-1.45 (m, 3H), 1.44-0.96 (m, 16H).

Example 10

3-(4-(4-(5-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalene-1-yl)phenoxy) (Pentyl)piperazin-1-yl)-8-oxo-6H-[1,3]dioxo[4,5-e]isoindole-7(8H)-yl)piperidine- 2,6-Diketone 10

first step

3-(8-oxo-4-(piperazin-1-yl)-6H-[1,3]dioxo[4,5-e]isoindole-7(8H)-yl) Piperidine-2,6-dione hydrochloride 10a

Compound 8 (55mg, 0.116mmol) was dissolved in a mixed solution of 2mL of dichloromethane and 1,4-dioxane (V/V=1/1), and 4N hydrogen chloride of 1,4- With dioxane solution (1.2 mL), the reaction was slowly returned to room temperature and stirred for 4 hours. The reaction solution was concentrated under reduced pressure and drained under vacuum to obtain the title compound 10a. The crude product was directly used in the next reaction.

MS m/z(ESI): 373.0[M+1].

Second step

3-(4-(4-(5-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalene-1-yl)phenoxy) Pentyl) piperazine-1-

Yl)-8-oxo-6H-[1,3]dioxo[4,5-e]isoindole-7(8H)-yl)piperidine-2,6-dione 10

Compound 10a (25mg, 0.061mmol) and compound 10b (29.4mg, 0.073mmol, prepared by the method disclosed in Example 2 on page 225 of the specification of patent application WO2019199816) were dissolved in 3mL of a mixed solvent of dichloromethane and methanol Medium (V/V=1/1), add acetic acid (18mg, 0.306mmol) and sodium acetate (15mg, 0.183mmol), stir the reaction at room temperature for 3 hours, then add sodium triacetoxyborohydride (26mg, 0.122mmol) , Reaction for 16 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was prepared by high performance liquid phase (Waters-2545, mobile phase: 1/1000 trifluoroacetic acid aqueous solution and acetonitrile, gradient of acetonitrile: 33%-47%, flow rate: 30mL/min) Purification gave the title compound 10 (21 mg, yield: 40%).

MS m/z(ESI): 757.0[M+1].

¹ H NMR (500MHz, DMSO-d ₆ ) δ 10.96 (s, 1H), 9.13 (s, 1H), 7.24-7.05 (m, 3H), 6.86-6.82 (m, 2H), 6.73 (s, 1H) ),6.66-6.60(m,2H),6.56-6.51(m,2H),6.49(dd,1H),6.28(d,2H),6.18-6.08(m,2H),5.03(dd,1H), 4.32(d,1H),4.25-4.13(m,2H),3.95-3.76(m,4H),3.73-3.60(m,2H),3.38-3.27(m,2H),3.24-3.02(m,6H) ), 2.99-2.82 (m, 3H), 2.68-2.56 (m, 1H), 2.45-2.33 (m, 1H), 2.13-1.93 (m, 3H), 1.78-1.62 (m, 3H), 1.52-1.39 (m, 2H).

Example 11

3-(4-(4-((1-(3,5-Difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2 ,3,4,9-Tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-8 -Oxo-6H-[1,3]dioxolano[4,5-e]isoindole-7(8H)-yl)piperidine-2,6-dione 11

first step

(1R,3R)-1-(4-(4-(Dimethoxymethyl)piperidin-1-yl)-2,6-difluorophenyl)-2-(2-fluoro-2-methyl Propyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole 11b

Compound 11a (200mg, 0.44mmol, prepared by the method disclosed in Example 145 on page 143 of the specification in patent application WO2016097072), 4-(dimethoxymethyl)piperidine (92mg, 0.58mmol), 2 -Dicyclohexylphosphine-2,4,6-triisopropylbiphenyl (X-Phos) (42mg, 0.088mmol), sodium tert-butoxide (106mg, 1.10mmol) were added to 10mL of toluene, and then palladium acetate was added (15mg, 0.067mmol), the reaction was heated to 90°C and stirred for 12 hours. The reaction was cooled to room temperature, water (25mL) was added, extracted with ethyl acetate (30mL×3), the organic phases were combined, washed with saturated sodium chloride solution (30mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography with eluent system B to obtain the title compound 11b (165 mg), yield: 70%.

MS m/z(ESI): 530.2[M+1].

Second step

1-(3,5-Difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro- 1H-pyrido[3,4-b]indol-1-yl)phenyl)piperidine-4-carbaldehyde 11c

Compound 11b (165mg, 0.31mmol) was added to tetrahydrofuran (10mL), 2N dilute sulfuric acid (1.6mL) was added dropwise, reacted for 2 hours, neutralized with saturated sodium bicarbonate in an ice bath, and the pH of the reaction solution was adjusted to 7～8 , Extracted with ethyl acetate (30mL×3), combined the organic phases, washed with saturated sodium chloride solution (30mL×2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and washed by silica gel column chromatography. The residue obtained was purified by the removal system A to obtain the title compound 11c (50 mg), the yield: 33%.

MS m/z(ESI): 484.2[M+1].

third step

3-(4-(4-((1-(3,5-Difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2 ,3,4,9-Tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-8 -Oxo-6H-[1,3]dioxolano[4,5-e]isoindole-7(8H)-yl)piperidine-2,6-dione 11

Compound 11d (11mg, 0.019mmol) was added to a mixture of 2mL methanol and dichloromethane (V/V=1/1), anhydrous sodium acetate (7mg, 0.086mmol) was added, stirred for 30 minutes, and compound 10a was added (9mg, 0.019mmol), the reaction was stirred for 30 minutes, then sodium cyanoborohydride (3mg, 0.047mmol) was added, and the reaction was stirred for 4 hours. The reaction solution was concentrated under reduced pressure, and the crude product was prepared by HPLC (Waters 2767-SQ Detecor2, elution system: 10mmol/L ammonium bicarbonate aqueous solution and acetonitrile, gradient of acetonitrile: 55%-75%, flow rate: 30mL/min) Purification gave the title compound 11 (5.2 mg), yield: 33%.

MS m/z(ESI): 840.3[M+1].

¹ H NMR (500MHz, DMSO-d ₆ ) δ 10.95 (s, 1H), 10.49 (s, 1H), 7.38 (d, 1H), 7.18 (d, 1H), 7.01-6.90 (m, 2H), 6.63(s,1H),6.53(d,2H),6.10(d,2H),5.08(s,1H),5.01(dd,1H),4.30(d,1H),4.18(d,1H),3.75 (d,2H),3.56-3.42(m,1H),3.23(s,3H),3.01-2.77(m,3H),2.72(t,2H),2.63-2.52(m,2H),2.41-2.26 (m,2H),2.20(d,2H),1.97-1.86(m,2H),1.82-1.61(m,3H),1.57-1.41(m,1H),1.37-1.20(m,6H),1.19 -1.08 (m, 5H), 1.04 (d, 3H).

Example 12

3-(4-(4-((1-(4-((1S,2R)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalene-1-yl)phenyl) Piperidin-4-yl)methyl)piperazin-1-yl)-8-oxo-6H-[1,3]dioxo[4,5-e]isoindole-7(8H )-Yl)piperidine-2,6-dione 12

Compound 10a (24mg, 0.047mmol) was added to 2mL of a mixture of methanol and dichloromethane (V/V=1/1), anhydrous sodium acetate (17mg, 0.21mmol) was added, stirred for 30 minutes, and compound 12a was added (17mg, 0.042mmol, prepared by the method disclosed in Example 341 on page 477 of the specification of patent application WO2018102725), continue to stir for 30 minutes, then add sodium triacetoxyborohydride (18mg, 0.085mmol), reaction 16 Hour. The reaction solution was concentrated under reduced pressure, and the crude product was prepared by HPLC (Waters 2767-SQ Detecor2, elution system: 10mmol/L ammonium bicarbonate aqueous solution and acetonitrile, gradient of acetonitrile: 65%-85%, flow rate: 30mL/min) Purification gave the title compound 12 (10 mg), yield: 32%.

MS m/z(ESI): 768.3[M+1].

¹ H NMR (500MHz, DMSO-d ₆ ) δ 10.95 (s, 1H), 9.10 (s, 1H), 7.26-7.05 (m, 3H), 6.84 (d, 2H), 6.72-6.58 (m, 3H) ), 6.54(d, 2H), 6.49-6.40(d, 1H), 6.20(d, 2H), 6.09(d, 2H), 5.01(dd, 1H), 4.30(d, 2H), 4.25-4.06( m, 2H), 3.61-3.44 (m, 2H), 3.32-3.13 (m, 5H), 3.03-2.78 (m, 3H), 2.67-2.52 (m, 3H), 2.40-2.27 (m, 1H), 2.26-2.04 (m, 3H), 2.03-1.83 (m, 2H), 1.80-1.45 (m, 4H), 1.35-1.20 (m, 2H), 1.18-1.04 (m, 2H).

Example 13

3-(4-(4-((1-(5-((2-(4-fluorophenyl)-6-hydroxybenzo(b)thiophen-3-yl)oxy)pyridin-2-yl) Piperidin-4-yl)methyl)piperazin-1-yl)-8-oxo-6H-[1,3]dioxalano[4,5-e]isoindole-7(8H )-Yl)piperidine-2,6-dione 13

first step

3-(4-(4-((1-(5-((6-(benzyloxy)-2-(4-fluorophenyl)benzo(b)thiophen-3-yl)oxy)pyridine- 2-yl)piperidin-4-yl)methyl)piperazin-1-yl)-8-oxo-6H-[1,3]dioxo[4,5-e]isoindole -7(8H)-yl)piperidine-2,6-dione 13b

Compound 10a (25mg, 0.061mmol) and compound 13a (40mg, 0.073mmol, prepared by the method disclosed in Example 232 on page 390 of the specification of patent application WO2018140809) were dissolved in 2 mL of a mixed solution of dichloromethane and methanol (V/V=1/1), add sodium acetate (15mg, 0.183mmol) and acetic acid (18mg, 0.306mmol), stir at room temperature for 1 hour, add sodium triacetoxyborohydride (26mg, 0.122mmol), stir at room temperature Reaction for 16 hours. After the reaction is complete, add saturated ammonium chloride solution (5 mL), extract with ethyl acetate (25 mL×3), combine the organic phases, wash with saturated sodium chloride solution (20 mL), dry the organic phase with anhydrous sodium sulfate, and filter The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 13b (36 mg), yield: 65%.

MS m/z(ESI): 895.0[M+1].

Second step

3-(4-(4-((1-(5-((2-(4-fluorophenyl)-6-hydroxybenzo(b)thiophen-3-yl)oxy)pyridin-2-yl) Piperidin-4-yl)methyl)piperazin-1-yl)-8-oxo-6H-[1,3]dioxalano[4,5-e]isoindole-7(8H )-Yl)piperidine-2,6-dione 13

Compound 13b (36mg, 0.040mmol) was dissolved in 2mL of a mixed solution of dichloromethane and methanol (V/V=1/1), palladium on carbon (20mg, 20% palladium content, 50% water content) and acetic acid were added (24.2mg, 0.402mmol), replaced with hydrogen three times, and stirred at room temperature for 16 hours. After the reaction, the solid was filtered off, and the filter residue was rinsed with dichloromethane and methanol (V/V=5:1) (20 mL). The residue obtained after the filtrate was concentrated was purified by high performance liquid phase preparation (Waters-2545, an aqueous solution of one thousandth of trifluoroacetic acid and acetonitrile, gradient of acetonitrile: 33%-47%, flow rate: 30mL/min) to obtain the title compound 13 ( 20 mg, yield: 61%).

MS m/z(ESI): 805.0[M+1].

¹ H NMR (500MHz, DMSO-d ₆ ) δ 10.96 (s, 1H), 9.49 (s, 1H), 7.90 (d, 1H), 7.78-7.65 (m, 2H), 7.35-7.26 (m, 3H) ), 7.25-7.19 (m, 1H), 7.17 (dd, 1H), 8.86 (dd, 1H), 8.82 (d, 1H), 6.73 (s, 1H), 6.14 (d, 2H), 5.03 (dd, 1H),4.33(d,1H),4.21(d,1H),4.18-4.10(m,2H),3.91-3.77(m,2H),3.69-3.56(m,2H),3.14-3.01(m, 2H), 2.97-2.82 (m, 2H), 2.80-2.71 (m, 2H), 2.67-2.56 (m, 1H), 2.41-2.29 (m, 1H), 2.04-1.93 (m, 2H), 1.86 1.69 (m, 2H), 1.38-1.10 (m, 5H).

Example 14

4-(7-(2,6-dioxopiperidin-3-yl)-6,8-dioxo-7,8-dihydro-6H-[1,3]dioxolano[ 4,5-e)isoindol-4-yl)piperazine-1-carboxylic acid tert-butyl ester 14

first step

4-bromo-7-fluorobenzo[d][1,3]dioxolane-5-carboxylic acid 14a

Compound 8d (700 mg, 2.83 mmol) was dissolved in acetonitrile (30 mL) and water (6 mL), sodium chlorite (385 mg, 4.26 mmol) and sulfamic acid (550 mg, 5.66 mmol) were added, and the reaction was carried out at room temperature for 2 hours. The reaction solution was diluted with water (20mL), extracted with ethyl acetate (30mL×2), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 14a crude product ( 690mg), directly used in the next reaction.

MS m/z(ESI): 261.0[M-1].

Second step

4-bromo-7-fluorobenzo[d][1,3]dioxolane-5-carboxylic acid methyl ester 14b

The crude product 14a (668mg, 2.54mmol) was dissolved in methanol (10mL), thionyl chloride (300mg, 2.54mmol) was added dropwise, and the reaction was carried out at 80°C for 16 hours. The reaction solution was concentrated under reduced pressure, and purified by thin-layer chromatography with the developing solvent system A to obtain the title compound 14b (570 mg). Yield: 81%.

¹ H NMR (500MHz, DMSO-d ₆ ): δ 7.48 (d, 1H), 6.34 (s, 2H), 3.83 (s, 3H).

third step

7-Fluorobenzo[d][1,3]dioxolane-4,5-dicarboxylate dimethyl 14c

Compound 14b (570mg, 2.06mmol), palladium acetate (47mg, 0.21mmol), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (143mg, 0.25mmol) and triethylamine ( 625 mg, 6.18 mmol) was dissolved in N,N-dimethylformamide (5 mL), and reacted at 80°C for 16 hours under a nitrogen atmosphere. The reaction solution was filtered with Celite, the filtrate was concentrated under reduced pressure, and the residue was purified by thin-layer chromatography with the developing solvent system A to obtain the title compound 14c (257 mg), yield: 49%.

¹ H NMR (500MHz, DMSO-d ₆ ): δ 7.41 (d, 1H), 6.33 (s, 2H), 3.81 (s, 3H), 3.80 (s, 3H).

the fourth step

7-Fluorobenzo[d][1,3]dioxolane-4,5-dicarboxylic acid 14d

Compound 14c (257 mg, 1 mmol) was dissolved in tetrahydrofuran (6 mL), water (2 mL) and lithium hydroxide (169 mg, 4.03 mmol) were added, and the reaction was stirred for 16 hours. The reaction solution was concentrated under reduced pressure, water (10 mL) was added, and the pH of the reaction solution was adjusted to weakly acidic (~4) with 1M dilute hydrochloric acid. Concentrate under reduced pressure to obtain the crude title compound 14d (228 mg), which was directly used in the next reaction.

MS m/z(ESI): 227.1[M-1].

the fifth step

7-(2,6-dioxopiperidin-3-yl)-4-fluoro-6H-[1,3]dioxo[4,5-e]isoindole-6,8( 7H)-Diketone 14e

3-Aminopiperidine-2,6-dione hydrochloride (329mg, 2mmol) was dissolved in acetic acid (5mL), anhydrous sodium acetate (246mg, 3mmol) was added, the reaction was stirred at room temperature for 30 minutes, and compound 14d (228mg , 1mmol), react at 110°C for 16 hours. The reaction solution was concentrated under reduced pressure and purified by thin-layer chromatography with developing solvent system B to obtain the title compound 14e (220 mg), yield: 69%.

MS m/z(ESI): 321.0[M+1].

Sixth step

4-(7-(2,6-dioxopiperidin-3-yl)-6,8-dioxo-7,8-dihydro-6H-[1,3]dioxolano[ 4,5-e)isoindol-4-yl)piperazine-1-carboxylic acid tert-butyl ester 14

Compound 14e (242mg, 0.76mmol) was dissolved in N,N-dimethylformamide (5mL), piperazine-1-carboxylic acid tert-butyl ester (423mg, 2.27mmol) and N,N-diisopropyl were added Ethylamine (489mg, 3.78mmol) was reacted at 80°C for 21 hours. The reaction solution was concentrated under reduced pressure, and purified by silica gel column chromatography with the developing solvent system B to obtain the title compound 14 crude product (150 mg).

Take 20 mg of crude product and prepare it with HPLC (Waters 2545, the elution system is one-thousandth of trifluoroacetic acid aqueous solution and acetonitrile, gradient of acetonitrile: 32%-44%, flow rate: 30 mL/min) to obtain the title compound 14 ( 4mg).

MS m/z(ESI): 431.1[M-55].

1H NMR (500MHz, DMSO-d ₆ ): δ11.11 (s, 1H), 7.04 (s, 1H), 6.30 (s, 2H), 5.08-5.04 (m, 1H), 3.46-3.42 (m, 3H) ),3.34-3.29(m,3H),2.88-2.85(m,1H),2.65-2.54(m,2H),2.38-2.37(m,1H),2.03-1.97(m,2H),1.43(s ,7H),1.24(s,2H).

Biological evaluation

The following further describes and explains the present disclosure in conjunction with test examples, but these examples are not meant to limit the scope of the present disclosure.

Test Example 1 The binding activity of the compound of the present disclosure and E3 ubiquitin ligase cerebellar protein (CRBN)

The binding activity of the compound of the present disclosure and E3 ubiquitin ligase CRBN is reflected by the activity of the compound of the present disclosure to inhibit the binding of NanoLuc-CRBN expressed in HEK293 cells (ATCC, CRL-1573) and the CRBN tracer in ^{NanoBRET TM cells.} HEK293 cells were transfected with NanoLuc-CRBN plasmid in NanoBRET ^™ TE In-Cell CRBN kit (Promega, Cat#CS1810C135). Each well of a 6-well plate was inoculated with 1×10 ⁶ HEK293 cells and cultured with DMEM/High Glucose (GE Healthcare, Cat#SH30243.01) complete medium containing 10% fetal bovine serum. Using Lipofectamine ^TM 3000 transfection reagent (Invitrogen, Cat#L3000015), cells in each well were transfected with 0.5 μg NanoLuc-CRBN plasmid, and incubated overnight in a 37° C. incubator.

The transfected HEK293 cells were trypsinized and washed with phenol red-free Opti-MEM medium (Gibco, Cat#11058021). Then, the cell density was adjusted to 2.2×10 ⁵ cells/mL with phenol red-free Opti-MEM medium, and 45 μL, namely 10,000 cells, were added to each well of a white flat-bottomed 384-well plate (Corning, Cat#3574). The Bravo automatic liquid dispensing system was used to formulate the test compound in DMSO to 10 concentration points with the initial concentration of 2mM and 3-fold dilutions. The compound was further diluted 10-fold with phenol red-free Opti-MEM medium, and 5 μL of the diluted compound was added to each well of a 384-well plate to mix with the cells, and then incubated in a 37° C. incubator for 1 hour. Dilute 400μM intracellular-CRBN tracer to 50μM with DMSO, and then further dilute it to 10μM with NanoBRET tracer dilution buffer in the kit, and add 2.5μL of the diluted tracer to each well in a 384-well plate Add the corresponding volume of DMSO diluted with buffer solution to the control wells without tracer, repeatedly suck and mix with a discharge gun, then place it in a 37°C incubator and incubate for 2 hours. Dilute the substrate and inhibitor in the kit by 166.7 and 500 times respectively with phenol red-free Opti-MEM to prepare the substrate solution. Add 25μL of the substrate solution to each well of the 384-well plate, and mix with a dispense gun repeatedly. Use the Luminescence dual emission module of PHERAstar FS to read the fluorescence values of 450nm (Donor emission) and 610nm (Acceptor emission), according to the formula [(Acceptor emission signal _sample /Donor emission) of the signal _sample) - (acceptor emission _control signal has _{no tracer} / donor emission signal _{without tracer} calculated _{according to the} BRET ratio value)] × 1000. The BRET ratio value of the negative control well without tracer was set to 100% inhibition, and the BRET ratio value of the compound-free well was set to 0% inhibition. Calculating inhibition ratio of each compound concentration with the tracer CRBN binding protein, plotted using GraphPad Prism software compound dose-response curve and _IC50 values _are calculated IC.

The binding activities of the compounds of the present disclosure and E3 ubiquitin ligase CRBN are shown in Table 1 below.

_{Table 1 The IC 50} value of the compounds of the present disclosure inhibiting the binding of E3 ubiquitin ligase CRBN in HEK293 cells

Compound	IC 50 (nM)
1	900
3	154
4	525
5	1356
6	504
6'	150
7	5191
8	1896
9	116
14	286

Conclusion: The compound of the present disclosure can bind E3 ubiquitin ligase cerebellar protein (CRBN) well.

Test Example 2 The degrading activity of the compound of the present disclosure on ERα in MCF7 cells

ERa-positive breast cancer cell line MCF7 cells were cultured with DMEM/F12 medium (HyClone, SH30023.01) containing 10% fetal bovine serum (Corning, 35-010-CV). On the first day of the experiment, after the cells were digested, the cells were washed with phenol red-free DMEM/F12 medium (ThermoFisher, 11039-021) containing 5% activated charcoal-treated fetal bovine serum (BIOSUN, BS-0004-500) The cells were suspended and counted, and the cell density was adjusted to 1.79×10 ⁵ cells/mL. In a 48-well plate (Corning, 3548), 280 μL of cell suspension was added to each well, and the cells were placed in a 37° C., 5% CO ₂ incubator and cultured overnight. On the second day of the experiment, the compound was serially diluted with DMSO, and further diluted with phenol red-free DMEM/F12 medium containing 5% activated charcoal-treated fetal bovine serum. Add 20 μL of the diluted compound to each well of the 48-well plate cells, and the final concentrations are 300, 30, 3, 0.3, 0.03, 0.003, and 0.0003 nM, respectively. Place the 48-well plate in the incubator for 16 to 18 hours. Use the capture antibody in the human ERα/NR3A1 total protein detection kit (R&D, DYC5715-5) to coat a 96-well plate, prepare the capture antibody with PBS to 1 μg/mL, and place it in a 96-well plate (Corning, 3590). Add 100μL to the well and place it in an incubator at 26°C overnight. On the third day of the experiment, wash the antibody-coated 96-well plate with PBS, add 200 μL of PBS containing 1% BSA to each well, and incubate in a 37° C. incubator for 1.5 hours for blocking. Discard the cell culture supernatant, wash the cells with PBS, and add 60 μL of cell lysate to each well. The cell lysate was PBS containing 6M urea, 1mM EDTA, 0.5% TritonX-100, 1mM PMSF and protease inhibitor (Roche, 04693159001). The cells were lysed on ice for 15 minutes, and then 300 μL of PBS containing 1 mM EDTA and 0.5% TritonX-100 per well was added to dilute the urea to 1M. The blocking solution in the blocked 96-well plate was discarded, 100 μL of diluted cell lysate was added to each well, placed in a 37° C. incubator and incubated for 2 hours, and the plate was washed five times with PBS containing 0.1% Tween. Dilute the biotinylated detection antibody to 0.4 μg/mL with PBS containing 1% BSA, then add 100 μL of detection antibody to each well, and incubate in a 37° C. incubator for 1 hour. Then the well plate was washed five times, 100 μL of avidin-HRP diluted 200 times with PBS containing 1% BSA was added to each well, and incubated at 37°C for 30 minutes. Wash the well plate five times, add 100μL of TMB substrate to each well, incubate at room temperature until blue color appears, and add 100μL of stop solution to each well. Use PHERAstar multi-function microplate reader to read OD450 and OD540 signal values. Graphpad Prism software was used to calculate the DC ₅₀ value of the compound's degradation activity.

The degrading activity of the compounds of the present disclosure on ERa in MCF-7 cells is shown in Table 2 below.

_{Table 2 Degradation DC 50} values of compounds of the present disclosure on ERa in MCF-7 cells

Compound	DC 50 (nM)
9	0.83
10	0.58
11	0.27
12	0.41
13	0.49

Conclusion: The compound of the present disclosure can degrade estrogen receptor (ERα) well.

Test Example 3 The inhibitory activity of the compound of the present disclosure on MCF7 cell proliferation

MCF7 cells (ATCC, HTB-22) were cultured with MEM (GE Healthcare, SH30024.01) complete medium containing 10% fetal bovine serum. On the first day of the experiment, use MEM medium containing 2% fetal bovine serum to seed MCF7 cells in a 96-well plate at a density of 3,000 cells/well, with 135 μL of cell suspension per well, and place 37°C, 5% CO ₂ cell culture Incubate overnight. On the second day, add 15 μL of test compounds of different concentrations prepared with culture medium to each well. The final concentration of the compound is 9 concentration points starting from 100 nM in a 4-fold gradient dilution. A blank control containing 0.5% DMSO is set and placed 37. Incubate for 144 hours in a 5% CO _{2 cell incubator.} On the eighth day, take out the 96-well cell culture plate and add 75μL to each well

Luminescent Cell Viability Assay (Promega, G7573), placed at room temperature for 10 minutes, use a multi-label microplate microplate reader (PerkinElmer, VICTOR 3) to read the luminescence signal value, and use Graphpad Prism software to calculate according to the compound concentration and luminescence signal value _{The IC 50} value of the compound's inhibitory activity.

Compounds of the present disclosure MCF7 cell proliferation inhibition IC ₅₀ values in Table 3 below.

_{Table 3 The inhibitory IC 50} value of the compounds of the present disclosure on the proliferation of MCF7 cells

Compound	IC 50 (nM)
9	2.83
10	0.71
11	1.25
12	0.38
13	1.84

Conclusion: The compound of the present disclosure can well inhibit the proliferation of MCF7 cells.

Test Example 4 The inhibitory activity of the compounds of the present disclosure on the proliferation of MCF7 cells expressing ERα mutants

MCF7 cells expressing ERaY537S mutant were constructed by lentiviral infection. MCF7/ERαY537S cells were cultured in MEM (GE Healthcare, SH30024.01) complete medium containing 10% fetal bovine serum. On the first day of the experiment, use MEM medium containing 2% fetal bovine serum to seed cells in a 96-well plate at a density of 3,000 cells/well, with 135 μL of cell suspension per well, and place in a 37°C, 5% CO ₂ cell incubator Cultivate overnight. On the second day, add 15 μL of test compounds of different concentrations prepared with culture medium to each well. The final concentration of the compound is 9 concentration points starting from 100 nM in a 4-fold gradient dilution. A blank control containing 0.5% DMSO is set and placed 37. Incubate for 144 hours in a 5% CO _{2 cell incubator.} On the eighth day, take out the 96-well cell culture plate and add 75μL to each well

Luminescent Cell Viability Assay (Promega, G7573), placed at room temperature for 10 minutes, use a multi-label microplate microplate reader (PerkinElmer, VICTOR 3) to read the luminescence signal value, and use Graphpad Prism software to calculate according to the compound concentration and luminescence signal value _{The IC 50} value of the compound's inhibitory activity.

_{The inhibitory IC 50} values of the compounds of the present disclosure on the proliferation of MCF7 cells expressing ERa mutants are shown in Table 4 below.

_{Table 4 The inhibitory IC 50} values of the compounds of the present disclosure on the proliferation of MCF7 cells expressing ERα mutants

Compound	IC 50 (nM)
9	5.85

10	3.03
11	5.37
12	1.27
13	9.61

Conclusion: The compound of the present disclosure can well inhibit the proliferation of MCF7/ERαY537S cells.

Claims (31)

1. A compound with the structure of CLM-L-PTM, or its tautomers, mesosomes, racemates, enantiomers, diastereomers, isotopic derivatives, or mixtures thereof Form or a pharmaceutically acceptable salt thereof, wherein CLM is a cerebellar protein E3 ubiquitin ligase protein binding ligand compound represented by general formula (IM);

   

   in:

   G ¹ and G ^{2 are the} same or different, each is independently CH ₂ or C (=O), and ^{at least one of G 1} and G ² is C (=O);

   One or two groups of R ¹ and R ² , R ² and R ³ , R ³ and R ⁴ together with the carbon atoms to which they are connected form a four- to fourteen-membered heterocyclic group, wherein the heterocyclic group contains 1 to 2 heteroatoms selected from N atom, O atom and S atom, optionally selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, One or more substituents of nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;

   Or R ¹ , R ² , R ³ and R ^{4 are the} same or different, and are each independently selected from covalent bond, hydrogen atom, deuterium atom, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkyne Group, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein the alkyl, heteroalkyl, Alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano , Amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl substituted by one or more substituents, provided that R ¹ and R ² , R ² and R ³ , R ³ and R ⁴ There is at least one group of heterocyclic groups forming a four- to fourteen-membered ring together with the carbon atom to which it is connected;

   L is a linking unit, one end of which can be arbitrarily connected to the heterocyclic group formed by ^{R 1} , R ² , R ³ , R ⁴ and R ¹ and R ² , R ² and R ³ , R ³ and R ^{4 on the formula (IM)} The substitution site is connected by a covalent bond, and the other end is connected with PTM;

   PTM is a small molecule compound ligand that binds to a target protein or polypeptide, which is connected to L by a covalent bond;

   n is 0, 1, or 2.
2. The compound with the structure of CLM-L-PTM according to claim 1, or its tautomer, meso, racemate, enantiomer, diastereomer, isotopic derivative thereof Compound, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound of general formula (IM) is selected from the cerebellum represented by general formula (IM-1), general formula (IM-2) and general formula (IM-3) Protein E3 ubiquitin ligase protein binding ligand compound:

   

   in:

   Ring A, Ring B and Ring C are the same or different, and are each independently a four- to fourteen-membered heterocyclic group, wherein the heterocyclic group contains 1 to 2 atoms selected from the group consisting of N atoms, O atoms and S atoms Heteroatom

   R ⁵ are the same or different, and are each independently selected from covalent bonds, hydrogen atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, hydroxyl groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, Heterocyclic group, aryl group and heteroaryl group;

   p is 0, 1, 2, 3 or 4;

   Any one of R ¹ , R ² , R ³ , R ^{4 and any R 5} is connected to the connecting unit L through a covalent bond;

   G ¹ , G ² , R ¹ to R ⁴ and n are as defined in claim 1.
3. The compound having the structure of CLM-L-PTM according to claim 1 or 2, or its tautomer, meso, racemate, enantiomer, diastereomer, Isotope derivatives, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein the compound of general formula (IM) is selected from general formula (IM-1aa), general formula (IM-2aa) and general formula (IM-3aa) The cerebellar protein E3 ubiquitin ligase protein binding ligand compound:

   

   in:

   Ring B is a four- to fourteen-membered heterocyclic group, wherein the heterocyclic group contains 1 to 2 heteroatoms selected from N atoms, O atoms and S atoms;

   Ring E, ring D and ring M are the same or different, and are each independently a four- to fourteen-membered N-containing heterocyclic group, wherein the N-containing heterocyclic group contains 1 N atom and optionally Contain 1 heteroatom selected from N atom, O atom and S atom;

   R ^{5a is} selected from covalent bond, hydrogen atom, alkyl, heteroalkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl;

   R ⁵ are the same or different, and are each independently selected from covalent bonds, hydrogen atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, hydroxyl groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, Heterocyclic group, aryl group and heteroaryl group;

   R ^f are the same or different, and are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, Aryl and heteroaryl;

   The general formula (IM-2aa) p is 0, 1, 2, 3 or 4;

   In general formula (IM-1aa) and general formula (IM-3aa), p is 1, 2, 3 or 4;

   f is 0, 1, 2, 3 or 4;

   Any one of R ¹ , R ³ , R ⁴ , R ^{5a and any R 5} is connected to the connecting unit L through a covalent bond;

   G ¹ , G ² , R ¹ to R ⁴ and n are as defined in claim 1.
4. The compound having the structure of CLM-L-PTM according to any one of claims 1 to 3, or a tautomer, meso, racemate, enantiomer, or diastereomer thereof Isomers, isotopic derivatives, or mixtures thereof or pharmaceutically acceptable salts thereof, wherein the compound of general formula (IM) is selected from general formula (IM-4), general formula (IM-5), general formula (IM- 6) General formula (IM-7), general formula (IM-8), general formula (IM-9), general formula (IM-10), general formula (IM-11), general formula (IM-12) , General formula (IM-13), general formula (IM-15) and general formula (IM-13aa) represented by the cerebellar protein E3 ubiquitin ligase protein binding ligand compound:

   

   

   in:

   Ring E is a four- to fourteen-membered N-containing heterocyclic group, wherein the N-containing heterocyclic group contains 1 N atom and optionally 1 selected from the group consisting of N atom, O atom and S atom. Heteroatom

   R ⁵ are the same or different, and are each independently selected from covalent bonds, hydrogen atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, hydroxyl groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, Heterocyclic group, aryl group and heteroaryl group;

   R ^{5a is} selected from covalent bond, hydrogen atom, alkyl, heteroalkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl;

   R ^f are the same or different, and are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, Aryl and heteroaryl;

   Any one of R ¹ , R ² , R ³ , R ⁴ and R ^5a is connected to the connecting unit L through a covalent bond;

   r is 1 or 2;

   s is 0 or 1;

   t is 0, 1 or 2;

   g is 1, 2 or 3;

   p is 0, 1, 2 or 3;

   f is 0, 1, 2, 3 or 4;

   G ¹ , G ² , R ¹ to R ⁴ and n are as defined in claim 1.
5. The compound having the structure of CLM-L-PTM according to any one of claims 1 to 4, or a tautomer, meso, racemate, enantiomer, or diastereomer thereof Isomers, isotopic derivatives, or mixtures thereof or pharmaceutically acceptable salts thereof, wherein the general formula (IM) is selected from the following compounds:

   

   

   in:

   R ^{5a is} selected from covalent bond, hydrogen atom, alkyl, heteroalkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl;

   Any one of R ¹ , R ² , R ³ , R ⁴ and R ^5a is connected to the connecting unit L through a covalent bond;

   R ¹ to R ^{4 are} as defined in claim 1.
6. The compound having the structure of CLM-L-PTM according to any one of claims 3 to 5, or its tautomer, meso, racemate, enantiomer, or diastereomer Isomers, isotopic derivatives, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein ^{any one of R 2} and R ^5a is connected to the linking unit L through a covalent bond; R ² and R ^{5a are} as claimed in claim 3 As defined in.
7. The compound having the structure of CLM-L-PTM according to any one of claims 3 to 6, or its tautomer, meso, racemate, enantiomer, diastereomer Isomers, isotopic derivatives, or mixtures thereof or pharmaceutically acceptable salts thereof, wherein R ^5a is a covalent bond, which is connected to the linking unit L.
8. The compound having the structure of CLM-L-PTM according to any one of claims 1 to 7, or its tautomer, meso, racemate, enantiomer, diastereomer Isomers, isotopic derivatives, or mixtures thereof or pharmaceutically acceptable salts thereof, wherein -L- is selected from -L ¹ -, ^{-L 2} -, -R ^1L -, -R ^2L -, -Q ^1- ,

   

   -L ¹ -and -L ² -are the same or different, and are each independently selected from a covalent bond, -O-, -S-, -NR ⁶ -, -CR ⁷ R ⁸ -, -C(O)-, -S(O)-, -S(O) ₂ -, -C(S)-, -C(O)O-, -C(O)NR ⁶ -and -NR ⁶ C(O)-;

   R ^1L and R ^{2L are the} same or different, and are each independently selected from a covalent bond, an alkylene group, a heteroalkylene group, an alkenylene group and an alkynylene group, wherein the alkylene group, heteroalkylene group, and alkylene group Alkenyl and alkynylene groups are optionally selected from halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, oxo, cycloalkyl, heterocyclyl, aryl and heteroaryl Substituted by one or more substituents in the group;

   Q ¹ and Q ^{2 are the} same or different, and are each independently selected from cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently Is optionally selected from one of halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, oxo, cycloalkyl, heterocyclyl, aryl and heteroaryl or Replaced by multiple substituents;

   R ^{6 is} selected from a hydrogen atom, an alkyl group, a heteroalkyl group, a halogenated alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;

   R ⁷ and R ^{8 are the} same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, oxo, cycloalkyl, heterocycle Group, aryl and heteroaryl.
9. The compound having the structure of CLM-L-PTM according to any one of claims 1 to 8, or a tautomer, meso, racemate, enantiomer, or diastereomer thereof Isomers, isotopic derivatives, or mixtures thereof or pharmaceutically acceptable salts thereof, wherein -L- is selected from -R ^1L -,

   

   

   

   -Q ¹ -, ^{-Q 2} -, -R ^1L -, -R ^2L -, ^{-L 1} -and -L ² -are as defined in claim 8.
10. The compound having the structure of CLM-L-PTM according to any one of claims 1 to 9, or its tautomer, meso, racemate, enantiomer, or diastereomer Isomers, isotopic derivatives, or mixtures thereof or pharmaceutically acceptable salts thereof, wherein -L- is selected from: -(CH ₂ ) _v -,

    

    

    

    v is an integer from 1 to 10;

    j is an integer from 0 to 10; and

    k is an integer from 0 to 10.
11. The compound having the structure of CLM-L-PTM according to any one of claims 1 to 3, or a tautomer, meso, racemate, enantiomer, or diastereomer thereof Isomers, isotopic derivatives, or mixtures thereof, or pharmaceutically acceptable salts thereof, which are of general formula (I-1) or general formula (I-2), or tautomers or meso forms thereof , Racemates, enantiomers, diastereomers, isotopic derivatives, or mixtures thereof or pharmaceutically acceptable salts thereof,

    

    in:

    L is a connecting unit, preferably R ^2L or Q ¹ -R ^2L ;

    R ^{2L is} selected from covalent bond, C _1-12 alkylene, 1 to 12 membered heteroalkylene, C _2-12 alkenylene and C _2-12 alkynylene, wherein the C _1-12 alkylene Alkyl, 1 to 12 membered heteroalkylene, C _2-12 alkenylene and C _2-12 alkynylene are optionally selected from halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, hydroxy, C _1-6 hydroxyalkyl, cyano, amino, oxo, 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclic group, 6 to 10 membered aryl and 5 to 10 One or more substituents in the membered heteroaryl group; preferably, R ^2L is a covalent bond or a C _1-12 alkylene group, wherein the C _1-12 alkylene group is optionally selected from halogen , C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, hydroxy, C _1-6 hydroxyalkyl, cyano, amino, oxo, 3 to 8 membered cycloalkyl, 3 To 8-membered heterocyclic group, 6- to 10-membered aryl group and 5- to 10-membered heteroaryl group substituted by one or more substituents;

    Q ^{1 is} selected from 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclic group, 6 to 10 membered aryl and 5 to 10 membered heteroaryl, wherein the 3 to 8 membered cycloalkyl, 3 to 8 The membered heterocyclic group, the 6 to 10 membered aryl group and the 5 to 10 membered heteroaryl group are each independently optionally selected from halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl , Hydroxy, C _1-6 hydroxyalkyl, cyano, amino, oxo, 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclic group, 6 to 10 membered aryl group and 5 to 10 membered heteroaryl group Is substituted by one or more substituents; preferably, Q ^{1 is} selected from 3 to 8 membered heterocyclic groups, wherein the 3 to 8 membered heterocyclic groups are optionally selected from halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, hydroxy, C _1-6 hydroxyalkyl, cyano, amino, and oxo are substituted by one or more substituents;

    PTM is a small molecule compound ligand that binds to a target protein or polypeptide;

    In the general formula (I-2), p is 0, 1, 2, 3 or 4;

    In the general formula (I-1), p is 1, 2, 3 or 4;

    Ring B, ring D, ring E, R ¹ , R ³ -R ⁵ , R ^f , G ¹ , G ² , f, and n are as defined in claim 3.
12. The compound having the structure of CLM-L-PTM according to any one of claims 1 to 3 and 11, or its tautomer, meso, racemate, enantiomer, non- Enantiomers, isotopic derivatives, or mixtures thereof, or pharmaceutically acceptable salts thereof, which are of general formula (I-3) or general formula (I-4), or their tautomers, internal elimination Rotates, racemates, enantiomers, diastereomers, isotopic derivatives, or mixtures thereof or pharmaceutically acceptable salts thereof,

    

    in:

    t is 0, 1 or 2;

    g is 1, 2 or 3;

    p is 0, 1, 2 or 3;

    PTM, L, ring E, R ¹ , R ³ -R ⁵ , R ^f , G ¹ , G ² , f, and n are as defined in claim 11.
13. The compound having the structure of CLM-L-PTM according to any one of claims 1 to 12, or a tautomer, meso, racemate, enantiomer, or diastereomer thereof Isomers, isotopic derivatives, or mixtures thereof or pharmaceutically acceptable salts thereof, wherein PTM is a small molecule compound ligand that binds to a target protein or polypeptide, which is selected from compounds that bind to estrogen receptors, Compounds targeting the androgen receptor, binding to kinase inhibitors, binding to phosphatase inhibitors, MDM2 inhibitors, compounds binding to targeting proteins containing human BET Bromo domains, Hsp90 inhibitors, HDAC inhibitors , Human lysine methyltransferase inhibitors, compounds that bind to RAF receptors, compounds that bind to FKBP, angiogenesis inhibitors, compounds that inhibit immunity, compounds that bind to aromatic hydrocarbon receptors , Binding to a compound targeting the thyroid hormone receptor, a compound targeting HIV protease, a compound targeting HIV integrase, a compound targeting HCV protease, or a compound targeting acyl protein thioesterase 1 And/or the compound of 2; preferably, the PTM is selected from the group consisting of compounds that bind to the estrogen receptor, compounds that bind to the androgen receptor, kinase inhibitors, and those that bind to the human BET bromo domain Protein compounds.
14. The compound having the structure of CLM-L-PTM according to any one of claims 1 to 13, or a tautomer, meso, racemate, enantiomer, or diastereomer thereof Isomers, isotopic derivatives, or mixtures thereof or pharmaceutically acceptable salts thereof, wherein PTM is a compound that binds to the estrogen receptor, preferably selected from:

    

    Preferably selected from

    

    

    in:

    E is O atom or NH;

    Z is a covalent bond, or selected from O atom, NR ^m and CH ₂ ;

    M ¹ , M ² , M ³ , M ⁴ and M ^{5 are the} same or different, and each independently is an N atom or CR ⁿ ;

    R ^{1p are the} same or different, and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkoxy group, a halogenated alkyl group, a halogenated alkoxy group, a hydroxyl group, a hydroxyalkyl group Group, cyano group, amino group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group;

    R ^2p , R ^3p and R ^{4p are the} same or different, and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkoxy group, a halogenated alkyl group, and a halogenated alkoxy group. Group, hydroxy, hydroxyalkyl, cyano, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl;

    Or R ^3p and R ^4p together with the attached carbon atom form a cycloalkyl or heteroalkyl group;

    R ^{5p is} selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, a halogenated alkyl group, a hydroxyl group, a hydroxyalkyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group ；

    R ^6p are the same or different, and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkoxy group, a halogenated alkyl group, a halogenated alkoxy group, a hydroxyl group, and a hydroxyl group. Alkyl, cyano, amino, cycloalkyl, heterocyclic, aryl and heteroaryl;

    R ^7p are the same or different, and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkoxy group, a halogenated alkyl group, a halogenated alkoxy group, a hydroxyl group, and a hydroxyl group. Alkyl, cyano, amino, cycloalkyl, heterocyclic, aryl and heteroaryl;

    R ^{m is} selected from a hydrogen atom, an alkyl group, a heteroalkyl group, a haloalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;

    R ^{n is} selected from hydrogen atom, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, cycloalkyl, heterocyclic, aryl and heteroaryl base;

    h is 0, 1, 2, 3, 4 or 5;

    q is 0, 1, 2, 3, 4 or 5;

    y is 0, 1, 2, 3, 4, or 5.
15. The compound having the structure of CLM-L-PTM according to claim 14, or its tautomer, meso, racemate, enantiomer, diastereomer, or isotopic derivative thereof In the form of a substance, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein PTM is selected from:

    
16. A compound represented by general formula (IM), or its tautomer, meso, racemate, enantiomer, diastereomer, isotopic derivative, or a mixture thereof Form or its pharmaceutically acceptable salt,

    

    in:

    G ¹ and G ^{2 are the} same or different, each is independently CH ₂ or C (=O), and ^{at least one of G 1} and G ² is C (=O);

    One or two groups of R ¹ and R ² , R ² and R ³ , R ³ and R ⁴ together with the carbon atoms to which they are connected form a four- to fourteen-membered heterocyclic group, wherein the heterocyclic group contains 1 to 2 heteroatoms selected from N atom, O atom and S atom, optionally selected from halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, R ^w , substituted by one or more substituents in cycloalkyl, heterocyclic, aryl and heteroaryl;

    Or R ¹ , R ² , R ³ and R ^{4 are the} same or different, and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, and an alkoxy group Group, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein the alkyl, heteroalkyl, alkoxy, Cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, R ^w , Cycloalkyl, heterocyclyl, aryl, and heteroaryl substituted by one or more substituents, provided that at least one ^{of R 1} and R ² , R ² and R ³ , R ³ and R ^{4 and} The connected carbon atoms together form a four- to fourteen-membered heterocyclic group;

    R ^w is an amino protecting group, preferably tert-butoxycarbonyl;

    n is 0, 1, or 2.
17. The compound represented by the general formula (IM) according to claim 16, or its tautomer, meso, racemate, enantiomer, diastereomer, isotopic derivative thereof Substance, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein,

    One or two groups of R ¹ and R ² , R ² and R ³ , R ³ and R ⁴ together with the carbon atoms to which they are connected form a four- to fourteen-membered heterocyclic group, wherein the heterocyclic group contains 1 to 2 heteroatoms selected from N atom, O atom and S atom, optionally selected from halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, ring Substituted by one or more substituents in the alkyl group, heterocyclic group, aryl group and heteroaryl group;

    Or R ¹ , R ² , R ³ and R ^{4 are the} same or different, and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, and an alkoxy group Group, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein the alkyl, heteroalkyl, alkoxy, Cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkane Is substituted by one or more substituents in the group, heterocyclic group, aryl group and heteroaryl group, provided ^{that at least one of R 1} and R ² , R ² and R ³ , R ³ and R ⁴ has a carbon attached to it The atoms together form a four to fourteen membered heterocyclic group.
18. The compound represented by the general formula (IM) according to claim 16, or its tautomer, meso, racemate, enantiomer, diastereomer, isotopic derivative thereof Cerebellar protein E3 ubiquitin ligase protein represented by general formula (IM-1), general formula (IM-2) and general formula (IM-3) Binding ligand compound:

    

    in:

    R ¹ , R ² , R ³ and R ^{4 are the} same or different, and are each independently selected from hydrogen atom, halogen, C _1-6 alkyl, C _1-6 deuterated alkyl, 1 to 6 membered 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 hydroxyalkyl, cyano, Amino group, 3 to 8 membered cycloalkyl group, 3 to 8 membered heterocyclic group, 6 to 10 membered aryl group and 5 to 10 membered heteroaryl group; wherein said C _1-6 alkyl group, 1 to 6 membered heteroalkyl group Group, C _1-6 alkoxy group, 3 to 8 membered cycloalkyl group, 3 to 8 membered heterocyclic group, 6 to 10 membered aryl group and 5 to 10 membered heteroaryl group are each independently optionally selected from halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, hydroxy, C _1-6 hydroxyalkyl, cyano, amino, nitro, R ^w , 3 to 8 membered cycloalkyl , 3 to 8 membered heterocyclic group, 6 to 10 membered aryl group and 5 to 10 membered heteroaryl group substituted by one or more substituents;

    R ⁵ are each the same or different, and are each independently selected from hydrogen atom, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, hydroxy, C _1-6 hydroxyalkyl, Cyano, amino, nitro, R ^w , 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclic group, 6 to 10 membered aryl and 5 to 10 membered heteroaryl;

    R ^w is an amino protecting group, preferably tert-butoxycarbonyl;

    G ¹ and G ^{2 are the} same or different, each is independently CH ₂ or C (=O), and ^{at least one of G 1} and G ² is C (=O);

    Ring A, Ring B and Ring C are the same or different, and are each independently a four- to fourteen-membered heterocyclic group, wherein the heterocyclic group contains 1 to 2 atoms selected from the group consisting of N atoms, O atoms and S atoms Heteroatom

    p is 0, 1, 2, 3 or 4; and

    n is 0, 1, or 2.
19. The compound represented by the general formula (IM) according to claim 16 or 18, or its tautomer, meso, racemate, enantiomer, diastereomer, Isotope derivatives, or mixtures thereof, or pharmaceutically acceptable salts thereof, which are ubiquitin-linked cerebellar protein E3 represented by general formula (IM-1aa), general formula (IM-2aa) and general formula (IM-3aa) Enzyme protein binding ligand compound:

    

    in:

    R ¹ , R ² , R ³ and R ^{4 are the} same or different, and are each independently selected from hydrogen atom, halogen, C _1-6 alkyl, C _1-6 deuterated alkyl, 1 to 6 membered 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 hydroxyalkyl, cyano, Amino group, 3 to 8 membered cycloalkyl group, 3 to 8 membered heterocyclic group, 6 to 10 membered aryl group and 5 to 10 membered heteroaryl group; wherein said C _1-6 alkyl group, 1 to 6 membered heteroalkyl group Group, C _1-6 alkoxy group, 3 to 8 membered cycloalkyl group, 3 to 8 membered heterocyclic group, 6 to 10 membered aryl group and 5 to 10 membered heteroaryl group are each independently optionally selected from halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, hydroxy, C _1-6 hydroxyalkyl, cyano, amino, nitro, R ^w , 3 to 8 membered cycloalkyl , 3 to 8 membered heterocyclic group, 6 to 10 membered aryl group and 5 to 10 membered heteroaryl group substituted by one or more substituents;

    R ⁵ are each the same or different, and are each independently selected from hydrogen atom, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, hydroxy, C _1-6 hydroxyalkyl, Cyano, amino, nitro, R ^w , 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclic group, 6 to 10 membered aryl and 5 to 10 membered heteroaryl;

    R ^{5a is} selected from hydrogen atom, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, hydroxy, C _1-6 hydroxyalkyl, cyano, amino, nitro, R ^w , 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclic group, 6 to 10 membered aryl group and 5 to 10 membered heteroaryl group substituted by one or more substituents;

    R ^w is an amino protecting group, preferably tert-butoxycarbonyl;

    G ¹ and G ^{2 are the} same or different, each is independently CH ₂ or C (=O), and ^{at least one of G 1} and G ² is C (=O);

    Ring B is a four- to fourteen-membered heterocyclic group, wherein the heterocyclic group contains 1 to 2 heteroatoms selected from N atoms, O atoms and S atoms;

    Ring E, ring D and ring M are the same or different, and are each independently a four- to fourteen-membered N-containing heterocyclic group, wherein the N-containing heterocyclic group contains 1 N atom and optionally Contain 1 heteroatom selected from N atom, O atom and S atom;

    R ^f are the same or different, and are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, Aryl and heteroaryl;

    f is 0, 1, 2, 3 or 4;

    In the general formula (IM-2aa), p is 0, 1, 2, 3 or 4;

    In general formula (IM-1aa) and general formula (IM-3aa), p is 1, 2, 3 or 4; and

    n is 0, 1, or 2.
20. The compound represented by the general formula (IM) according to any one of claims 16 to 19, or its tautomer, meso, racemate, enantiomer, diastereomer Isomers, isotopic derivatives, or mixtures thereof or pharmaceutically acceptable salts thereof, which are selected from the following compounds:

    
21. The compound having the structure of CLM-L-PTM according to any one of claims 1 to 15, or a tautomer, meso, racemate, enantiomer, or diastereomer thereof Isomers, isotopic derivatives, or mixtures thereof or pharmaceutically acceptable salts thereof, which are selected from the following compounds:

    

    
22. The compound having the structure of CLM-L-PTM according to any one of claims 1 to 15, or a tautomer, meso, racemate, enantiomer, or diastereomer thereof Isomers, isotopic derivatives, or mixtures thereof or pharmaceutically acceptable salts thereof, wherein PTM is a small molecule compound ligand that binds to a target protein or polypeptide, wherein the target protein is selected from structural proteins, receptors, Enzymes, cell surface proteins; proteins related to cell integration functions, including proteins involved in catalytic activity, aromatase activity, exercise activity, helicase activity, metabolic process, antioxidant activity, proteolysis, and biosynthesis; with kinase activity , Oxidoreductase activity, transferase activity, hydrolase activity, lyase activity, isomerase activity, ligase activity, enzyme regulation activity, signal transduction activity, structural molecule activity, binding activity, receptor activity, cell motility , Membrane fusion, cell communication, biological process regulation, development, cell differentiation, and stimulate response proteins; behavioral proteins; cell adhesion proteins; proteins involved in cell necrosis; proteins involved in transport, including protein transport activity, nuclear transport activity, Ion transport activity, channel transport activity, carrier activity, permease activity, secretion activity, electron transport activity, pathogenesis, chaperone protein regulator activity, nucleic acid binding activity, transcription regulator activity, activity of extracellular tissue and biological origin, and Translation regulator activity.
23. The compound having the structure of CLM-L-PTM according to any one of claims 1 to 15 and 22, or its tautomer, meso, racemate, enantiomer, non- Enantiomers, isotopic derivatives, or mixtures thereof or pharmaceutically acceptable salts thereof, wherein PTM is a small molecule compound ligand that binds to a target protein, wherein the target protein is selected from B7.1 and 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 cyclase inhibitor, CXCR1, CXCR2, nitric oxide synthase, cyclooxygenase 1, cyclooxygenase 2, 5HT receptor, dopamine receptor, G protein that is Gq, histamine receptor Body, 5-lipoxygenase, tryptase serine protease, thymidylate synthase, purine nucleoside phosphorylase, GAPDH trypanosoma, glycogen phosphorylase, carbonic anhydrase, chemokine receptor, JAW STAT , RXR and analogs, HIV1 protease, HIV1 integrase, influenza neuraminidase, hepatitis B reverse transcriptase, sodium channel, multi-drug resistant protein P-glycoprotein, tyrosine kinase, CD23, CD124, tyrosine Enzymes p561ck, CD4, CD5, 1L-2 receptor, 1L-1 receptor, TNF-αR, ICAM1, Cat+ channel, VCAM, VLA-4 integrin, selectin, CD40/CD40L, inosine monophosphate dehydrogenase , P38MAP kinase, RaslRaflMEWERK pathway, interleukin-1 converting enzyme, caspase, HCV, NS3 protease, HCV NS3 RNA helicase, glycinamide ribonucleotide formyltransferase, rhinovirus, 3C protease, simple Herpesvirus-I (HSV-I), protease, cytomegalovirus (CMV) protease, poly(ADP-ribose) polymerase, cyclin-dependent kinase, 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 receptors (P2Y 1, P2Y2, P2Y4, P2Y6, P2X1-7), farnesyl transferase, geranylgeranyl transferase, TrkA receptor of NGF, β-amyloid, tyrosine kinase Flk-II KDR, vitronectin receptor, integrin receptor, Her-21 nerve sheath, telomerase inhibition, cytosolic phospholipase A2 and EGF receptor tyrosine kinase , Ecdysone 20-monooxygenase, GABA-gated chloride channel ion channel, acetylcholinesterase, voltage-sensitive sodium channel protein, calcium release channel and chloride ion channel, acetyl-CoA carboxylase, adenylate succinate Acid synthase, protoporphyrinogen oxidase and enolpyruvylshikimate phosphate synthase.
24. A method for preparing compounds of general formula (I-1) or general formula (I-2), or tautomers, mesosomes, racemates, enantiomers, and diastereomers thereof , Isotope derivatives, or mixtures thereof or pharmaceutically acceptable salts thereof, which include:

    

    The compound of general formula (I-1A) and the compound of general formula (IM-1aa) undergo reductive amination reaction to obtain the compound of general formula (I-1);

    The compound of general formula (I-2A) and the compound of general formula (IM-2aa) undergo reductive amination reaction to obtain the compound of general formula (I-2);

    in:

    R ^5a is a hydrogen atom;

    L is R ^2L' -CH ₂ or Q ¹ -CH ₂ ;

    R ^{2L' is} selected from covalent bond, C _1-12 alkylene, 1 to 12 membered heteroalkylene, C _2-12 alkenylene and C _2-12 alkynylene, wherein the C _1-12 Alkylene, 1 to 12 membered heteroalkylene, C _2-12 alkenylene and C _2-12 alkynylene are optionally selected from halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, hydroxy, C _1-6 hydroxyalkyl, cyano, amino, oxo, 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclic group, 6 to 10 membered aryl and 5 to One or more substituents in the 10-membered heteroaryl group; preferably, R ^2L' is a covalent bond or a C _1-12 alkylene group, wherein the C _1-12 alkylene group is optionally selected From halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, hydroxy, C _1-6 hydroxyalkyl, cyano, amino, oxo, 3 to 8 membered cycloalkyl , 3 to 8 membered heterocyclic group, 6 to 10 membered aryl group and 5 to 10 membered heteroaryl group substituted by one or more substituents;

    In general formula (IM-2aa) and general formula (I-2), p is 0, 1, 2, 3 or 4;

    In general formula (IM-1aa) and general formula (I-1), p is 1, 2, 3 or 4;

    PTM, Q ¹ , ring B, ring D, ring E, G ¹ , G ² , R ¹ , R ³ -R ⁵ , R ^f , f, and n are as defined in claim 11.
25. A pharmaceutical composition containing the compound according to any one of claims 1 to 23 or its tautomer, meso, racemate, enantiomer, Diastereoisomers, isotopic derivatives, or mixtures thereof or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
26. The compound according to any one of claims 1 to 23 or its tautomer, meso, racemate, enantiomer, diastereomer, isotopic derivative, or Use of the mixture form, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 25 in the preparation of a medicament for the treatment or prevention of diseases treated by degrading the target protein bound to the targeting ligand.
27. The compound according to any one of claims 1 to 23 or its tautomer, meso, racemate, enantiomer, diastereomer, isotopic derivative, or Use of the mixture form, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 25 in the preparation of a medicament for the treatment or prevention of diseases treated by binding to cerebellar protein in the body.
28. The use according to claim 26 or 27, wherein the disorder is selected from the group consisting of abnormal cell proliferation, tumors, immune diseases, diabetes, cardiovascular diseases, infectious diseases and inflammatory diseases; preferably tumors and infectious diseases.
29. The use according to claim 28, wherein the tumor is cancer; preferably selected from breast cancer, endometrial cancer, uterine cancer, testicular cancer, cervical cancer, prostate cancer, ovarian cancer, fallopian tube tumor, ovarian tumor, leukemia , Skin cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, renal cell carcinoma, bladder cancer, bowel cancer, colon cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, neck cancer, pancreatic cancer, stomach cancer, Lymphoma, non-Hodgkin's lymphoma, melanoma, myeloproliferative disease, sarcoma, angiosarcoma, peripheral neuroepithelioma, glioma, astrocytoma, oligodendroglioma, ependymal Tumor, glioblastoma, neuroblastoma, gangliocytoma, ganglioglioma, medulloblastoma, pineal cell tumor, meningioma, meningiosarcoma, neurofibroma, schwannoma , Thyroid cancer, esophageal cancer, Hodgkin’s tumor, Wilms’ tumor and teratocarcinoma; more preferably selected from breast cancer, endometrial cancer, uterine cancer, testicular cancer, cervical cancer, prostate cancer, ovarian cancer, fallopian tube Tumors and ovarian tumors.
30. The use according to claim 28, wherein the infectious disease is selected from viral pneumonia, avian influenza, meningitis, gonorrhea or infected with HIV, HBV, HCV, HSV, HPV, RSV, CMV, Ebola virus , Flavivirus, scar virus, rotavirus, influenza, coronavirus, EBV, resistant virus, RNA virus, DNA virus, adenovirus, poxvirus, picornavirus, togavirus, orthomyxovirus, retrovirus , Hepatotropic DNA virus, Gram-negative bacteria, Gram-positive bacteria, atypical bacteria, Staphylococcus, Streptococcus, Escherichia coli, Salmonella, Helicobacter pylori, Chlamydia, Mycoplasma, fungi, protozoa, intestinal worm , Worms, prions or parasites.
31. The compound according to any one of claims 1 to 23 or its tautomer, meso, racemate, enantiomer, diastereomer, isotopic derivative, or Use of the mixture form, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 25 in the preparation of a medicament for the treatment or prevention of estrogen receptor-mediated or dependent diseases or disorders.