WO2023226950A1

WO2023226950A1 - Peptidomimetic stat protein degrader, composition and use thereof

Info

Publication number: WO2023226950A1
Application number: PCT/CN2023/095625
Authority: WO
Inventors: 吴一哲; 周星露; 朱建荣; 刘兴国; 胡苗
Original assignee: 杭州和正医药有限公司
Priority date: 2022-05-25
Filing date: 2023-05-22
Publication date: 2023-11-30
Also published as: CN117126231A

Abstract

The present invention relates to a peptidomimetic STAT protein degrader, a composition and a use thereof. Disclosed are a structure represented by general formula (I), or a stereoisomer thereof, or a stereoisomer mixture thereof or a pharmaceutically acceptable salt thereof, a preparation method therefor, and a use thereof as a STAT protein degrader. The inventor of the present invention has confirmed through experiments that the compound of the present invention can degrade a transcription factor STAT3. The compound of the present invention has obvious proliferation inhibitory activity on MOLM16 and SU-DHL-1 tumor cells. The compound of the present invention has good pharmacokinetic properties. In addition, the compound of the present invention has remarkable anti-tumor efficacy in vivo.

Description

Peptoid STAT protein degradation agents, compositions and applications thereof

Technical field

The invention belongs to the technical field of drug synthesis, and specifically relates to a class of peptoid STAT protein degradation agents, compositions and applications thereof.

Background technique

The JAK-STAT signaling pathway is an important tumor-related signaling pathway. After the cytokine receptor, hormone receptor or growth factor receptor on the cell surface binds to the corresponding ligand, the intracellular JAK kinase is activated, thereby inducing the phosphorylation of the downstream transcription factor STAT and forming a homodimer, thereby entering the cell nucleus. , initiating or inhibiting the transcription of a series of tumor-related genes.

The transcription factor STAT regulates a variety of tumor-related genes, such as: cMyc, Survivin, BCL-XL, VEGF, HIF, NF-kB, etc. Gain-Of-Function mutations of STAT are often associated with tumor cells, leading to over-activation of the pathway. Over-activation of the STAT pathway can lead to: increased proliferation and survival of tumor cells, abnormal proliferation of blood vessels, invasion and migration of tumor cells, and Immune evasion and maintenance of cancer stem cell-like appearance.

In addition, recent studies have found that STAT3 is closely related to the suppressive immune microenvironment of tumor tissues. Excessive activation of STAT in DC cells leads to a decrease in the expression of MHC type II molecules and costimulatory factors, thereby reducing their ability to present antigens and activate T cells. Expression in neutrophils, NK cells, and effector T cells will reduce their ability to recognize, activate and kill tumor cells. At the same time, it can promote the M2 polarization of tumor-associated macrophages, the maturation and expansion of myeloid suppressor cells, induce the differentiation of T cells into regulatory T cells, and induce PD- The expression of L1 increases, thereby forming a suppressive immune microenvironment and promoting tumor immune escape.

In summary, the JAK-STAT signaling pathway can promote tumor proliferation through multiple pathways and is therefore a potential target for anti-tumor drug development.

Although multiple small molecule STAT3 inhibitors have been reported in recent years, due to their poor efficacy, no drugs have been approved for marketing so far. Therefore, there is an urgent need to develop a new generation of highly effective STAT3 inhibitory molecules.

In recent years, significant progress has been made in targeted protein degradation technology (PROTAC), which achieves target protein degradation by inducing ubiquitination of target proteins. Drugs using this technology do not need to continuously occupy the target protein, and the catalytic concentration can achieve target degradation. Therefore, the development of targeted degradation molecules for STAT3 is expected to solve the shortcomings of insufficient efficacy of current small molecule STAT3 inhibitors.

Contents of the invention

The purpose of the present invention is to provide a novel, unreported STAT3-degrading molecule with high-efficiency STAT3-degrading activity and its stereoisomers or stereoisomer mixtures or pharmaceutically acceptable salts thereof.

The object of the present invention is to also provide a compound including the above compound or its stereoisomer or its stereoisomer mixture or its pharmaceutically acceptable salt.

The present invention also provides an application of the above compound or its stereoisomer or its stereoisomer mixture or its pharmaceutically acceptable salt for preparing drugs for treating diseases, disorders or conditions that benefit from degrading STAT3. .

A first aspect of the present invention is to provide a structure as shown in (I):

Or its stereoisomer, or its stereoisomer mixture, or its pharmaceutically acceptable salt;

in

R ₁ and R ₂ are each independently selected from: H, -Me, -Et,

X ₁ is selected from: -CH ₂ -, -CF ₂ -, -CO-;

X ₂ is selected from: S, NRd, O;

X ₃ , X ₄ , X ₅ , X ₆ are independently selected from: CRa, N;

R ₃ is selected from: H, R ₇ , R ₇ -(CH ₂ ) _p -, R ₇ -(CH ₂ ) _p -CO-, R ₇ -(CH ₂ ) _p -O-CO-, R ₇ -( CH ₂ ) _p -NH-CO-, R ₇ -(CH ₂ ) _p -SO ₂ -. Any one or more methylene groups (-CH ₂ -) mentioned above (i.e. -(CH ₂ ) _p -) can be independently replaced by the following groups: -COO-, -CONH-, -OCONH-, -NHCONH -, -O-, -NRa-, -S-, -CO-, -CRa＝CRb-, -C≡C-, -SO-, -SO ₂ -, C ₃ -C ₁₀ cycloalkylene, 3 -10-membered heterocyclylene, phenylene, 5-6-membered heteroarylene, -CRaRb-;

R ₄ is selected from: H, R ₇ , R ₇ -(CH ₂ ) _p -, R ₇ -(CH ₂ ) _r -CO-(CH ₂ ) _s -; the above (i.e. -(CH ₂ ) _p -, - Any one or more methylene groups (-CH ₂ -) in (CH ₂ ) _r -, -(CH ₂ ) _s - can be independently replaced by the following groups: -COO-, -CONH-, -OCONH -, -NHCONH-, -O-, -CF ₂ -, -NRa-, -S-, -CO-, -CRa=CRb-, -C≡C-, -SO-, -SO ₂ -, C ₃ -C _10- membered cycloalkylene, 3-10-membered heterocyclylene, phenylene, 5-6-membered heteroarylene, -CRaRb-;

R ₇ is selected from: H, halogen, -CN, C ₁ -C ₆ alkyl, halogenated C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, halogenated C ₃ -C ₆ cycloalkyl, 3-10 membered heterocyclyl, phenyl, heteroaryl, E3;

Ring A is selected from: C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, and the heteroaryl contains 1 to 4 heteroatoms selected from O, S, and N;

R ₆ is selected from: -(CH ₂ ) _p -P(O)R ₈ R ₉ ;

R ₅ is selected from: H, halogen, CN, -OH, nitro, carboxyl, amino, amide, -P(O)R ₈ R ₉ , acyl, -SO ₂ , sulfonamide, C ₁ -C ₆ alkane Oxygen group, halo C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, hydroxyalkyl group, aminoalkyl group, C ₁ -C ₆ alkyl-sulfonamide group, C ₁ -C ₆ haloalkyl-sulfonamide, C ₃ -C ₈ cycloalkyl, halo C ₃ -C ₈ cycloalkyl, C ₃ -C ₈ cycloalkoxy, alkylamino, haloalkylamino, C ₃ -C ₈ cycloalkylamino, C ₁ -C ₆ alkyl -SO ₂ -, C ₁ -C ₆ haloalkyl -SO ₂ -, C ₃ -C ₈ cycloalkylamino, aminosulfonyl, carbamoyl;

R ₈ and R ₉ are each independently selected from: H, C ₁ -C ₆ alkyl, halogenated C ₁ -C ₆ alkyl;

Or R ₉ in any R ₅ and R ₆ on ring A together with the ring A form a ring, and the ring is optionally substituted by H, halogen, oxo, -CN, -OH, - NHRd, -ORd, -CORd, -COORd, -SO ₂ Rd, -N(Rd)C(=O)-Rj, - N(Rd)C(=O)ORj, -N(Rd)C(=O)NRjRk, -N(Rd)S(=O)NRjRk, -N(Rd)S(O) ₂ NRjRk, nitro, Carboxyl group, amino group, amido group, C ₁ -C ₆ alkyl group, halogenated C ₁ -C ₆ alkyl group, C ₂ -C ₈ alkenyl group, C ₂ -C ₈ alkynyl group, C ₁ -C ₆ alkoxy group, C ₃ -C ₆ cycloalkyl, 3-10 membered heterocyclyl, phenyl, heteroaryl substituted;

Ra and Rb are each independently selected from: H, halogen, C ₁ -C ₆ alkyl, halogenated C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, 3-10 membered heterocyclyl, phenyl, heteroaryl, -CN, -NHRd, -ORd;

Rd, Rj, and Rk are each independently selected from: H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl, 3-10 membered heterocyclyl, phenyl, hetero Aryl;

m is selected from: 0, 1, 2, 3;

n is selected from: 0, 1, 2, 3;

p is selected from: 0, 1, 2, 3, 4, 5, 6, 7, 8;

r is selected from: 0, 1, 2, 3, 4, 5, 6, 7, 8;

s is selected from: 0, 1, 2;

E3 is selected from:

Re is selected from: -Me, -Et, -CF ₃ , -OMe, -OH, -F, -Cl, -CN;

W ₁ , W ₂ , W ₃ and W ₄ are each independently selected from: CH, N.

It should be noted that when the same letters are used to represent substituents in different positions or groups, the same letters have no limiting effect on each other and are independent of each other. They can represent the same group in different positions or groups, or they can represent different groups. For example, R ₈ (or R ₉ ) appears in both R ₆ and R _5. At this time, R ₈ (or R ₉ ) in R ₆ and R ₅ are independent of each other and can be the same or different. For another example, Ra (or Rb) appearing in different groups or positions are independent of each other and can be the same or different. Rd (or R _j , R _k ) appearing in different groups or positions are independent of each other and can be the same or different; similarly, m (or n, p, s, r) appearing in different positions, etc., Independent of each other, they can be the same or different.

In certain embodiments, any R ₅ and R ₄ on Ring A together with the Ring A form a ring, and the ring is optionally replaced by H, halogen, oxo, -CN, -OH, -NHRd, -ORd, -CORd, -COORd, -SO ₂ Rd, -N(Rd)C(=O)-Rj, -N(Rd)C(=O)ORj, -N(Rd)C(= O)NRjRk, -N(Rd)S(=O)NRjRk, -N(Rd)S(O) ₂ NRjRk, nitro group, carboxyl group, amino group, amide group, C ₁ -C ₆ alkyl group, halogenated C ₁ -C ₆ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, 3-10 membered heterocyclyl, phenyl , heteroaryl substitution.

When R ₉ in R ₅ and R ₆ together with the ring A form a combined ring, or R ₅ and R ₄ form a combined ring with the ring A, that is, Transformed into the following structures respectively:

n' and n" are 0,1,2,3.

Furthermore, the preferred compound of the present invention, Re is selected from: H, -Me, -Et, -CF ₃ , -OMe, -OH, -F, -Cl, -CN.

Further, the preferred compound of the present invention, E3 is selected from

Furthermore, the preferred compound of the present invention has the structure represented by general formula II:

in:

X ₁₆ is selected from: CH, N.

Preferably: X ₃ , X ₄ , X ₅ , and X ₆ are each independently selected from: CH, CF, C, CCH ₃ , and N.

As a preference, the preferred compounds of the present invention have the general formula Partially selected from: X ₂ is selected from: S, NRd, O.

Furthermore, the preferred compound of the present invention has the structure represented by general formula III:

in:

Preferably: X ₁ is selected from: -CH ₂ -, -CF ₂ -, -CO-;

Preferably: X ₂ is selected from: S, NH, O, NCH ₃ .

Preferably, X ₁₆ is selected from: CH, N.

As a preference, among the preferred compounds of the present invention, in the general formula Parts are selected from the following structures:

m is selected from: 0, 1, 2, 3;

n’ or n” are each independently selected from: 0, 1, 2, 3;

R ₈ is selected from: methyl, ethyl, propyl, isopropyl;

R ₉ is selected from: methyl, ethyl, propyl, isopropyl.

Furthermore, the preferred compound of the present invention has the structure represented by general formula IV:

Or its stereoisomer, or its stereoisomer mixture, or its pharmaceutically acceptable salt.

Furthermore, preferred compounds of the present invention have the structure of general formula V(a) or V(b) or V(c) or V(d):

Preferably, R ₃ is selected from: CF ₃ CH ₂ -, CF ₃ -, CF ₂ HCH ₂ -, -Me, -Et, -iPr, CH ₃ OCO-, CH ₃ CO-, CH ₃ NHCO-, CH ₃ SO ₂ -, iPrSO ₂ -, R ₇ -(CH ₂ ) _r -, any one or more of the above methylene groups (-CH ₂ -) are independently replaced by the following groups: -COO-, -CONH- , -OCONH-, -NHCONH-, -O-, -NRa-, -S-, -CO-, -CRa＝CRb-, -C≡C-, -SO-, -SO ₂ -, C ₃ -C _10- membered cycloalkylene, 3-10-membered heterocyclylene, phenylene, 5-6-membered heteroarylene, -CRaRb-;

Preferably, R ₁₃ is selected from: R ₇ -(CH ₂ ) _r -, and any one or more of the above methylene groups (-CH ₂ -) are independently replaced by the following groups: -COO-, -CONH- , -OCONH-, -NHCONH-, -O-, -NRa-, -S-, -CO-, -CRa＝CRb-, -C≡C-, -SO-, -SO ₂ -, C ₃ -C _10- membered cycloalkylene, 3-10-membered heterocyclylene, phenylene, 5-6-membered heteroarylene, -CRaRb-;

Preferably, R ₁₄ is selected from: R ₇ -(CH ₂ ) _p -, R ₇ -(CH ₂ ) _p -CO-, R ₇ -(CH ₂ ) _p -O-CO-, R ₇ -(CH ₂ ) _p -NH-CO-, R ₇ -(CH ₂ ) _p -SO ₂ -. Any one or more of the above methylene groups (-CH ₂ -) can be independently replaced by the following groups: -COO-, -CONH-, -OCONH-, -NHCONH-, -O-, -NRa-, - S-, -CO-, -CH=CH-, -C≡C-, -SO-, -SO ₂ -, C ₃ -C ₁₀ cycloalkylene, 3-10 membered heterocyclylene, phenylene , 5-6 membered heteroarylene, -CRaRb-;

R ₈ and R ₉ are each independently selected from ethyl and isopropyl.

Preferably, in the preferred compounds of the present invention, the C atom connected to R4 is a chiral carbon atom with R or S configuration.

Preferably, R ₇ is selected from: E3.

Preferably, r is selected from: 0, 1, 2, 3, 4, 5, 6, 7, 8.

Furthermore, the preferred compound of the present invention has a structure represented by general formula (VI):

in:

X ₁ is selected from: -CF ₂ - or -CO-;

X ₂ is selected from: S, NH or NCH ₃ ;

R ₃ is selected from: CF ₃ CH ₂ -, CF ₃ -, CF ₂ HCH ₂ -, -Me, -Et, -iPr, -Ac, CH ₃ OCO-, CH ₃ CO-, CH ₃ NHCO-, CH ₃ SO ₂ - or iPrSO ₂ -;

R ₅ is selected from: H, halogen, CN, -OH, nitro, carboxyl, amino, amide, -P(O)R ₈ R ₉ , acyl, -SO ₂ , sulfonamide, hydroxyalkyl, aminoalkyl base, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ haloalkoxy group, C ₁ -C ₆ alkyl group, C ₁ -C ₆ haloalkyl group, C ₁ -C ₆ alkyl-sulfonamide group, C ₁ -C ₆ haloalkyl-sulfonamido, C ₃ -C ₈ cycloalkyl, halo C ₃ -C ₈ cycloalkyl, C ₃ -C ₈ cycloalkoxy, alkylamino, haloalkylamino, C ₃ -C ₈ cycloalkylamino, C ₁ -C ₆ alkyl-SO ₂ -, C ₁ -C ₆ haloalkyl -SO ₂ -, C ₃ -C ₈ cycloalkylamino, aminosulfonyl, carbamoyl;

R ₁₃ is selected from: R ₇ -(CH ₂ ) _r -, any of the above methylene groups (-CH ₂ -) can be replaced by the following groups: -COO-, -CONH-, -OCONH-, -NHCONH-, -O-, -NRa-, -S-, -CO-, -CRa＝CRb-, -C≡C-, -SO-, -SO ₂ -, C ₃ -C ₁₀ cycloalkylene, 3-10 1-membered heterocyclylene, phenylene, 5-6 membered heteroarylene, -CRaRb-;

R ₇ is selected from: E3.

Furthermore, R ₅ is preferably: H, fluorine, chlorine, bromine, CN, -OH, nitro, carboxyl, amino, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, Propoxy, isopropoxy, difluoromethyl, difluoromethoxy, trifluoromethyl, trifluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropoxy , cyclobutoxy, cyclopentyloxy, cyclohexyloxy.

The C ₃ -C ₁₀ cycloalkylene group may be selected from: cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, cyclooctylene, cyclononylene, cyclodecylene base,, cyclobutylidene and cyclobutyl, cyclobutylidene and cyclopentyl, cyclobutylidene and cyclohexyl, cyclopentylidene and cyclohexyl, cyclopentylidene and cyclohexyl, cyclohexylidene and Cyclohexyl, cyclopropylidenecyclobutyl, cyclopropylidenecyclopentyl, cyclopropylidenecyclohexyl, cyclobutylidenespirocyclobutyl, cyclobutylidenespirocyclopentyl, cyclobutylene Spirocyclohexyl, cyclopentylidenespirocyclopentyl, cyclopentylenespirocyclohexyl, cyclohexylidenespirocyclohexyl, cyclopropylenespirocyclobutyl, cyclopropylenespirocyclopentyl, cyclopropylene Base spirocyclohexyl; when substituted, optionally by 0-4 C 1-6 selected from H, halogen, OH _, NH ₂ , NO ₂ , COOH, C _1-6 alkyl, oxo, halogen Alkyl group, C _1-6 alkoxy group, halogenated C _1-6 alkoxy group substituted.

3-10 membered heterocyclylene, wherein the heterocyclic ring is selected from: azetidinyl, pyrrolidine, piperidine, piperazine, morpholine, azetidinyl, azetipentyl, piperidine, morpholine , piperazine, pyrrole, pyrazole, imidazole, thiazole, pyridine, pyridazine, pyrimidine, pyrazine, triazole, tetrazole, cyclopropyl azetidinyl, cyclopropyl azetidinyl , cyclopropyl azetidine, cyclopropyl piperidine, cyclobutyl azetidinyl, cyclobutyl azetipentyl, cyclobutyl azetihexyl, cyclobutyl piperidine, cyclopentaazetidinyl, cyclopentaazetidinyl, cyclopentaazetihexyl, cyclopentaazetidine, cyclopenta Hexyl azetidinyl, cyclohexyl azetidinyl, cyclohexyl azetidinyl, cyclohexyl azetidinyl, cyclohexyl azetidinyl, azetidine Butyl azetidinyl, azetidinyl azetidine, azetidinyl piperidine, azetidinyl azetidinyl, azetidinyl azepine Cyclopentyl, azepanyl and azetidine, azepanyl and piperidine, azepanyl and azetidinyl, azepanyl and azetidinyl, nitrogen Heterocyclohexyl azetidine, azetidine, cyclobutylspiroazetidinyl, cyclobutylspiroazetipentyl, cyclobutylspiroazetidine, cyclobutylspiroazetidine Pentylspiroazetidinyl, cyclopentylspiroazetidinyl, cyclopentylspiroazetidinyl, cyclohexylspiroazetidinyl, cyclohexylspiroazetidinyl, cyclohexylspiroazetidinyl Hexylspiroazetihexyl, azetidinylspiroazetidinyl, azetidinylspiroazetipentyl, azetidinylspiroazetihexyl, azetidinyl Spiroazetidinyl, azocyclopentylspiroazetidinyl, azocyclohexylspiroazetidinyl, azocyclohexylspiroazetidine Heterocyclopentyl, cyclohexylspiroazacyclohexyl, cyclobutylspiropiperidine, cyclopentylspiropiperidine, cyclohexylspiropiperidine, azetidinylspiropiperidine, azetidinylspiro Piperidine, azepanylspiropiperidine; when substituted, optionally 0-4 selected from H, halogen, OH, NH ₂ , NO ₂ , COOH, C _1-6 alkyl, oxo, halogen Substituted with substituted C _1-6 alkyl, C _1-6 alkoxy, or halogenated C _1-6 alkoxy.

Preferably, E3 is selected from:

E3 is further preferably:

E3 is preferably

Furthermore: after the -(CH ₂ ) _p or -(CH ₂ ) _r in R ₃ and R ₄ or the replacement, the structure is preferably:

The end marked with # is connected to E3.

Preferably, the compound or its stereoisomer or its stereoisomer mixture or its pharmaceutically acceptable salt is selected from the following compounds:

Terminology

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. Unless otherwise stated, all patent documents, publicly disclosed materials, etc. referred to in the present invention are incorporated by reference in their entirety. If there are multiple definitions for the same term in this invention, the definition in this section shall prevail.

It should be understood that the foregoing general description and the following detailed description are merely exemplary and explanatory, and are not restrictive of any claims. In the present invention, the use of the singular includes the plural unless stated otherwise. It should be noted that in the specification and the appended claims, singular references such as "a", "an" and "the" include plural references unless the context dictates otherwise. It should also be noted that "or" means "and/or" unless stated otherwise. Furthermore, "includes,""includes," and similar terms are not limiting.

"Bond" means that the indicated substituent does not exist, and the two end portions of the substituent are directly connected to form a bond.

"Alkyl" when used as a group or part of a group means a C ₁ -C ₂₀ linear or branched aliphatic hydrocarbon group. Preferably it is a C ₁ -C ₁₀ alkyl group, more preferably a C ₁ -C ₈ alkyl group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-di Methylpropyl, 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-dimethyl Butyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl wait. Alkyl groups may be substituted or unsubstituted.

"Alkenyl" refers to an aliphatic hydrocarbon group containing a carbon-carbon double bond, which can be straight or branched. Preferred is C ₂ -C ₁₀ alkenyl, more preferred is C ₂ -C ₈ alkenyl. Representative examples include, but are not limited to, vinyl, wait. Alkenyl groups may be substituted or unsubstituted.

"Alkynyl" refers to an aliphatic hydrocarbon group containing a carbon-carbon triple bond, which can be straight or branched. It is preferably a C ₂ -C ₁₀ alkynyl group, more preferably a C ₂ -C ₈ alkynyl group, and most preferably a C ₂ -C ₄ alkynyl group. Examples of alkynyl groups include, but are not limited to, ethynyl, wait. Alkynyl groups may be substituted or unsubstituted.

"Cycloalkyl" refers to saturated or partially saturated monocyclic, fused, bridged and spiro carbocyclic rings. Preferred is C ₃ -C ₁₂ cycloalkyl, more preferred is C ₃ -C ₈ cycloalkyl, and most preferred is C ₃ -C ₆ cycloalkyl. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptyltri Alkenyl group, cyclooctyl group, etc., preferably cyclopropyl group and cyclohexenyl group. Cycloalkyl groups may be substituted or unsubstituted.

"Spirocycloalkyl" refers to a polycyclic group with 5 to 18 members, two or more cyclic structures, and the single rings share one carbon atom (called a spiro atom) with each other. The ring may contain 1 or more Multiple double bonds, but none of the rings are aromatic. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of shared spiro atoms between the rings, the spirocycloalkyl group is divided into single spiro, double spiro or polyspiral cycloalkyl, preferably single spiro and double spiro cycloalkyl, preferably 4-membered/5-membered, 4-membered Yuan/6 Yuan, 5 Yuan/5 Yuan or 5 Yuan/6 Yuan. Examples of "spirocycloalkyl" include, but are not limited to: spiro[4.5]decyl, spiro[4.4]nonyl, spiro[3.5]nonyl, spiro[2.4]heptyl.

"Condensed cycloalkyl" refers to an all-carbon polycyclic group with 5 to 18 members and containing two or more cyclic structures sharing a pair of carbon atoms with each other. One or more rings may contain one or more double bonds. However, none of the rings has aromaticity, and it is preferably 6 to 12 members, and more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic condensed ring alkyl groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic alkyl groups. Examples of "fused cycloalkyl" include, but are not limited to: bicyclo[3.1.0]hexyl, bicyclo[3.2.0]hept-1-enyl, bicyclo[3.2.0]heptyl, decalin base or tetradecahydrophenanthyl base.

"Bridged cycloalkyl" refers to an all-carbon polycyclic group with 5 to 18 members, containing two or more cyclic structures, sharing two carbon atoms that are not directly connected to each other. One or more rings may contain one or more Multiple double bonds, but none of the rings are aromatic, preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Examples of "bridged cycloalkyl" include, but are not limited to: (1s,4s)-bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, (1s,5s)-bicycloo[ 3.3.1]nonyl, bicyclo[2.2.2]octyl, (1r,5r)-bicyclo[3.3.2]decyl, bicyclo[1.1.1]pentyl.

"Heterocyclyl", "heterocycle" or "heterocyclic" are used interchangeably in this application and all refer to non-aromatic heterocyclyl, in which one or more ring-forming atoms are heteroatoms, such as N, O, S, P, Se, including single ring, fused ring, bridged ring and spiro ring, the ring may contain one or more double bonds. Preferably it has 3 to 12 ring atoms, more preferably 4 to 7 membered monocyclic ring or 7 to 10 membered bi- or tricyclic ring, which may contain 1, 2 or 3 selected from N, O, S(O) _n ( Where n is selected from 0, 1 or 2), P(O) _m (where m is selected from 0 or 1), Se atoms. Examples of "heterocyclyl" include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydropyranyl, 1,,1-dioxo-thiomorpholinyl, pipera Aldinyl, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl , piperazinyl, 1,2,3,6-tetrahydropyridyl or 3,6-dihydro-2H-pyranyl. Heterocyclyl groups may be substituted or unsubstituted.

"Spiroheterocyclyl" refers to a polycyclic group with 5 to 18 members, two or more cyclic structures, and the single rings share one atom with each other. The ring may contain 1 or more double bonds, but No ring is aromatic in which one or more ring atoms are selected from wherein one or more ring atoms are selected from N, O, S(O) _n (where n is selected from 0, 1 or 2), P(O) _m (where m is selected from 0 or 1), heteroatoms of Se, and the remaining ring atoms are carbon. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of shared spiro atoms between the rings, the spiroheterocyclyl group is divided into a single spiroheterocyclyl group, a double spiroheterocyclyl group or a polyspiroheterocyclyl group, and is preferably a single spiroheterocyclyl group and a double spiroheterocyclyl 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 single spiroheterocyclic group. Examples of "spiroheterocyclyl" include, but are not limited to: 1,7-dioxaspiro[4.5]decyl, 2-oxa-7-azaspiro[4.4]nonyl, 7-oxaspiro[ 3.5]nonyl and 5-oxaspiro[2.4]heptyl.

"Condensed heterocyclyl" refers to an all-carbon polycyclic group containing two or more cyclic structures sharing a pair of atoms with each other. One or more rings may contain one or more double bonds, but none of the rings is aromatic. property, in which one or more ring atoms are selected from N, O, S(O) _n (where n is selected from 0, 1 or 2), P(O) _m (where m is selected from 0 or 1), Se hetero atoms, and the remaining ring atoms are carbon. Preferably it is 6 to 14 yuan, more preferably 7 to 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 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic groups. Non-limiting examples of "fused heterocyclyl" include, but are not limited to: octahydropyrro[3,4-c]pyrrolyl, octahydro-1H-isoindolyl, 3-azabicyclo[3.1. 0]Hexyl, octahydrobenzo[b][1,4]dioxin (dioxine).

"Bridged heterocyclyl" refers to a polycyclic group with 5 to 18 members, containing two or more cyclic structures, sharing two atoms that are not directly connected to each other. One or more rings may contain one or more Double bonds, but neither ring is aromatic, and one or more ring atoms are selected from N, O, S(O) _n (where n is selected from 0, 1 or 2), P(O) _m (where m is selected From 0 or 1), the heteroatom of Se, and the remaining ring atoms are carbon. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Examples of "bridged heterocyclyl" include, but are not limited to: 2-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.2]octyl and 2-azabicyclo[3.3 .2] Decyl.

"Aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be linked together in a fused manner. "Aryl" includes monocyclic or bicyclic aryl groups, such as phenyl, naphthyl, and tetrahydronaphthyl aromatic groups. Preferred aryl groups are C ₆ -C ₁₀ aryl groups, more preferred aryl groups are phenyl and naphthyl, and most preferred are phenyl groups. Aryl groups may be substituted or unsubstituted.

"Heteroaryl" and "heteroaryl ring" are used interchangeably in this application, and both refer to a monocyclic or polycyclic aromatic ring group containing 5 to 14 ring atoms, which may contain 1 to 4 selected from Atoms of N, O, S, and Se. Preferably it contains 5 to 12 ring atoms, more preferably 5 to 6 membered monocyclic heteroaryl or 8 to 10 membered bicyclic heteroaryl. Examples of "heteroaryl" include but are not limited to furan base, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, Pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzodioxolyl, benzothienyl, Benzimidazolyl, indolyl, isoindolyl, 1,3-dioxo-isoindolyl, quinolyl, indazolyl, benzisothiazolyl, benzoxazolyl, benziiso Oxazolyl, Heteroaryl groups may be substituted or unsubstituted.

"Fused ring" refers to a polycyclic group in which two or more cyclic structures share a pair of atoms with each other. One or more rings may contain one or more double bonds, but at least one ring is not aromatic. At the same time, at least one ring is aromatic, in which 0, 1 or more ring atoms are selected from N, O, S(O) _n (where n is selected from 0, 1 or 2), P(O) _m (where m is selected from 0 or 1), heteroatoms of Se, and the remaining ring atoms are carbon. The fused ring preferably includes a bicyclic or tricyclic fused ring, wherein the bicyclic fused ring is preferably a fused ring of an aryl or heteroaryl group and a monocyclic heterocyclyl group or a monocyclic cycloalkyl group. It is preferably 7 to 14 yuan, more preferably 9 to 10 yuan. Examples of "fused rings" include, but are not limited to:

Fused rings may be substituted or unsubstituted.

"Alkoxy" refers to the group (-O-alkyl). Among them, alkyl group is as defined in this article. C ₁ -C ₈ alkoxy groups are preferred. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, isopentoxy, neo Pentyloxy etc. Alkoxy groups may be substituted or unsubstituted.

"Alkylthio" refers to a (-S-alkyl) group. Among them, alkyl group is as defined in this article. C ₁ -C ₈ alkylthio groups are preferred. Examples include, but are not limited to: methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, etc. "Alkylthio" may be substituted or unsubstituted.

"Alkenyloxy" refers to the group (-O-alkenyl). Among them, alkenyl group is as defined in this article. Alkenyloxy groups of C ₂ to _{C 8} are preferred. Alkenyloxy groups may be substituted or unsubstituted.

"Hydroxyalkyl" is the group (-alkyl-OH). Among them, alkyl group is as defined in this article. C ₁ -C ₈ hydroxyalkyl groups are preferred. Examples include, but are not limited to: hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl, hydroxybutyl, etc. Hydroxyalkyl groups may be substituted or unsubstituted.

"Alkylamino" refers to the group (-NH-alkyl). Among them, alkyl group is as defined in this article. C ₁ -C ₈ alkylamino groups are preferred. Examples include, but are not limited to: methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutoxy, tert-butoxy, etc. The alkylamino group can be substituted or unsubstituted, and the substituent can be on the alkyl group or on N, such as dimethylamino and diethylamino.

"Aminoalkyl" refers to the group (-alkyl- _NH2 ). Among them, alkyl group is as defined in this article. Examples include, but are not limited to: aminomethyl, aminoethyl, aminopropyl, aminoisopropyl, aminobutyl, aminopentyl, etc. The aminoalkyl group can be substituted or unsubstituted, and the substituent can be on the alkyl group or on N, such as: dimethylaminoalkyl group.

"Alkylcarbonyl" refers to the group (-C(O)-alkyl). Among them, alkyl group is as defined in this article. Examples include, but are not limited to: methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl, etc. Alkylcarbonyl groups may be substituted or unsubstituted.

"Alkoxycarbonyl" refers to the group (-C(O)-O-alkyl). Among them, alkyl group is as defined in this article. Examples include, but are not limited to: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, etc. Alkoxycarbonyl groups may be substituted or unsubstituted.

"Haloalkyl" refers to an alkyl group substituted by halogen. Among them, halogen and alkyl are defined in this article.

"Haloalkoxy" refers to an alkoxy group substituted by halogen. Among them, halogen and alkoxy are defined in this article.

"Halohydroxyalkyl" refers to a hydroxyalkyl group substituted by halogen. Among them, halogen and hydroxyalkyl are defined in this article.

"Haloalkylamino" refers to an alkylamino group substituted by halogen. Among them, halogen and alkylamino are defined in this article.

"Cycloalkoxy" refers to the group (-O-cycloalkyl). The cycloalkyl group is as defined in this article.

"Heterocyclyloxy" refers to a (-O-heterocyclyl) group. The heterocyclyl group is as defined in this article.

"Halogen" refers to fluorine, chlorine, bromine and iodine.

"Substituted" means that one or more hydrogen atoms in the group, preferably 1 to 5, more preferably 1 to 3 hydrogen atoms, are independently substituted by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the person skilled in the art is able to determine (either experimentally or theoretically) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with a free hydrogen may be unstable when combined with a carbon atom with an unsaturated (eg, olefinic) bond.

"Substituted" or "substituted" mentioned in this specification, unless otherwise specified, means that the group can be substituted by one or more groups selected from the following: hydrogen, halogen, amino, cyano, nitro, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C ₃ -C ₁₂ cycloalkyl, 5-12 membered heterocyclyl, C ₆ -C ₁₀ aryl, 5-12 membered Heteroaryl, -OR ^a' , -C(O)R ^a' , -C(O)OR ^a' , -C(O)N(R ^b' )R ^c' , -NR ^b' R ^c' , -N(R ^b' )C(O)R ^c' , -N(R ^b' )C(O)NR ^c' R ^d' , -N(R ^b' )C(O)OR ^c' , -N (R ^b' )S(O)NR ^b' R ^c' , -N(R ^b' )S(O) ₂ NR ^c' R ^d' , -N(R ^b' )S(O) ₂ R ^c' , -S(O)R ^a' , -S(O)2R ^a' , -S(O) ₂ NR ^b' R ^c' or -P(O)R ^e' R ^f' , the alkyl group, Alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or amino are optionally further substituted by one or more R ^o ';

When 2 R ^o 's are substituted on the same atom, the 2 R ^o 's form a 3-6 membered ring together with the atoms they are connected to, or when the 2 R ^o 's are substituted on adjacent atoms, the 2 R ^{o 's} 'Together with the atoms to which it is connected, it forms a 3-12 membered ring;

R ^a' , R ^b' , R ^c' , R ^d' , R ^e' , R ^f' , and R ^o ' are each independently selected from hydrogen, halogen, amino, cyano, nitro, C _1-8 alkyl , C _2-8 alkenyl, C _2-8 alkynyl, C ₃ -C ₁₂ cycloalkyl, 5-12 membered heterocyclyl, C ₆ -C ₁₀ aryl, 5-12 membered heteroaryl, -OR ^a” , -C(O)R ^a” , -C(O)OR ^a” , -C(O)N(R ^b” )R ^c” , -NR ^b” R ^c” , -N(R ^b” )C(O)R ^c” , -N(R ^b” )C(O)NR ^c” R ^d” , -N(R ^b” )C(O)OR ^c” , -N(R ^b” )S (O)NR ^b” R ^c” , -N(R ^b” )S(O) ₂ NR ^c” R ^d” , -N(R ^b” )S(O) ₂ R ^c” , -S(O) R ^a” , -S(O)2R ^a” , -S(O) ₂ NR ^b” R ^c” or -P(O)R ^e” R ^f” , the alkyl group, alkenyl group, alkynyl group, Cycloalkyl, heterocyclyl, aryl, heteroaryl or amino are optionally further substituted by one or more R ^o” ;

R ^a” , R ^b” , R ^c” , R ^d” , R ^e” , R ^f” , and R ^o” are each independently selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, C _1-8 Alkyl _, C _1-8 alkoxy, halo C 1-8 alkyl, halo C _1-8 alkoxy, C _1-8 alkylamino, C _2-8 alkenyl, C _2-8 alkynyl , C ₃ -C ₁₂ cycloalkyl, 5-12 membered heterocyclyl, C ₆ -C ₁₀ aryl, 5-12 membered heteroaryl, carboxyl, carboxylate group.

"Pharmaceutically acceptable salts" refer to salts of compounds of the present invention with acids or bases suitable for use as pharmaceuticals. Pharmaceutically acceptable salts include inorganic salts and organic salts. One preferred class of salts are the salts of the compounds of the invention with acids. Acids suitable for forming salts include, but are not limited to: hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydriodic acid, sulfuric acid, nitric acid, phosphoric acid, carbonic acid and other inorganic acids, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, amber Organic acids such as acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, camphorsulfonic acid; and Acidic amino acids such as aspartic acid and glutamic acid. One preferred class of salts are salts of compounds of the invention with bases, including but not limited to sodium, potassium, magnesium, and ammonium salts. Bases suitable for forming salts include, but are not limited to: sodium hydroxide, potassium hydroxide, magnesium hydroxide, sodium carbonate, sodium bicarbonate, sodium phosphate, potassium carbonate, magnesium carbonate, potassium bicarbonate, potassium phosphate, magnesium phosphate and other inorganic Alkali, ammonia, triethylamine, diethylamine, piperazine, guanidine, diethanolamine and other organic bases.

The second object of the present invention is to provide a pharmaceutical composition including one or more of the compounds described in any of the above technical solutions. The pharmaceutical composition of the present invention may be composed of one or more of the compounds described in any of the above technical solutions and other compounds, or one or more of the compounds described in any of the above technical solutions. composition.

The present invention provides a pharmaceutical preparation, which contains at least one active component, and the active component is one or more of the compounds described in any of the above technical solutions. The pharmaceutical preparation contains at least one active component and one or more pharmaceutically acceptable carriers or excipients. The active component may be the STAT3 inhibitor compound of the present invention, a stereoisotope of the compound. Any one or more of the configurations, pharmaceutically acceptable salts of the compound or its stereoisomer, and solvates of the compound or its stereoisomer.

The carrier includes conventional diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption accelerators, surfactants, adsorption carriers, lubricants, etc. in the pharmaceutical field, and fragrances can also be added if necessary. agents, sweeteners, etc.

The medicine of the present invention can be made into various forms such as tablets, powders, granules, capsules, oral liquids and injections, granular preparations, sprays, etc. The medicines in each of the above dosage forms can be prepared according to conventional methods in the pharmaceutical field.

On the other hand, the present invention provides a disease that benefits from degrading STAT3 using the compounds described in Formulas I to VI disclosed herein and their optical isomers or pharmaceutically acceptable salts or solvates thereof. , disorder or illness. In a further preferred aspect, the invention provides a method of degrading STAT3 in a subject in need thereof by administering to the subject a composition containing a therapeutically effective amount of at least one compound, wherein the compound The structural formulas are general formula I to general formula VI. In some embodiments, the subject in need thereof has cancer.

In a further preferred embodiment, the compounds of formulas I to VI provided by the present invention are used in combination with immune checkpoint inhibitors, chemotherapy or targeted drugs.

In further embodiments, the immune checkpoint inhibitor includes but is not limited to: PD-1 monoclonal antibody, PD-L1 monoclonal antibody or CTLA-4 monoclonal antibody. The chemotherapeutic drugs include, but are not limited to: mitosis inhibitors (such as vinblastine, vindesine and vinorelbine); tubulin decomposition inhibitors (such as Taxol)); alkylating reagents (such as cisplatin, carbin). platinum, cyclophosphamide, chlorambucil, and bendamustine); antimetabolites (such as 5-fluorouracil, tegafur, methotrexate, cytarabine, and hydroxyurea); insertable antibiotics ( Such as areresin, mitomycin and strobomycin); topoisomerase inhibitors (such as etoposide and camptothecin). The targeted drugs include but are not limited to: BTK inhibitors (such as ibrutinib, acalabrutinib); Bcl-2 inhibitors (such as Venetoclax); anti-CD20 monoclonal antibodies (such as rituximab, ofatumumab, atuzumab); mTOR inhibitors (such as rapamycin, AZD8055), mTORC1 inhibitors (such as everolimus, temsirolimus), AKT inhibitors (such as MK-2206 , GSD690693), PI3K inhibitors (such as Idelalisib, Duvelisib); proteasome inhibitors (such as bortezomib, carfilzomib, ixazomib); EGFR inhibitors (such as erlotinib, gefitinib, Osimertinib), VEGFR inhibitors (sorafenib, cabozantinib, refutinib, lenvatinib, apatinib), CDK inhibitors (such as palbocicib, ribociclib) , Ras inhibitors.

In further embodiments, the subject in need thereof has cancer including, but not limited to:

Hematologic malignancies, including lymphoma, leukemia, multiple myeloma, myelodysplastic syndromes such as diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell Prolymphocytic leukemia, lymphoplasmacytic lymphoma/Waldenström macroglobulinemia ( macroglobulinemia), splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B-cell lymphoma lymph node marginal zone B-cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, Burkitt lymphoma lymphoma), AML, CML, multiple myeloma, or lymphomatoid granulomatosis.

Autoimmune diseases or conditions, including autoimmune conditions of a single organ or single cell type, such as Hashimoto's thyroiditis, autoimmune hemolytic anemia, autoimmune atrophic gastritis with pernicious anemia, autoimmune encephalomyelitis, autoimmune Orchitis, Goodpasture's disease, autoimmune thrombocytopenia, sympathetic ophthalmia, myasthenia gravis, Graves' disease, primary biliary cirrhosis, chronic invasive hepatitis, ulcerative colitis and membranous glomerulopathies, those involving systemic autoimmune disorders (e.g., systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome, Reiter's syndrome, polymyositis dermatomyositis, systemic sclerosis, tuberculosis polyarteritis, multiple sclerosis, and bullous pemphigoid) and other O-cell (humor) or T-cell autoimmune diseases (including Cogan syndrome), inflammatory bowel disease, and ankylosing spondylitis , Idiopathic pulmonary fibrosis, atopic dermatitis, acute graft-versus-host disease, chronic graft-versus-host disease and tissue fibrosis disease Wegener's granulomatosis, autoimmune alopecia, type I diabetes or juvenile-onset diabetes, Psoriasis, or thyroiditis;

Solid tumors include, including gastrointestinal/gastrointestinal cancer, colorectal cancer, liver cancer, skin cancer (including mast cell tumor and squamous cell carcinoma), breast and breast cancer, ovarian cancer, prostate cancer, kidney cancer, lung cancer, muscle cancer, Cancer, bone cancer, bladder cancer, brain cancer, melanoma (including oral and metastatic melanoma), Kaposi's sarcoma, thyroid cancer, retinoblastoma, rhabdomyosarcoma, urinary tract tumors, central nervous system tumors, respiratory system Malignant tumors, nasopharyngeal cancer, pancreatic cancer, head and neck cancer;

The inventor of the present invention has confirmed through experiments that the compound of the present invention can degrade the transcription factor STAT3.

The inventors of the present invention have confirmed through experiments that the compounds of the present invention have obvious proliferation inhibitory activity on MOLM16 and SU-DHL-1 tumor cells.

The inventor of the present invention has confirmed through experiments that the compound of the present invention has good pharmacokinetic properties.

The inventor of the present invention has confirmed through experiments that the compound of the present invention has significant anti-tumor efficacy in vivo.

Detailed ways

Chemical substances represented by some abbreviations in the present invention
DCM: dichloromethane T3P: 1-propylphosphonic anhydride
EA: Ethyl acetate BSTFA: Bis(trimethylsilyl)trifluoroacetamide
THF: Tetrahydrofuran TMS-I: Trimethylsilylated iodine
MeOH: Methanol Pd ₂ (dba) ₃ : Tris(dibenzylideneacetone)dipalladium
AcOH: acetic acid HPOMe ₂ : dimethylphosphine oxide
PE: petroleum ether TSCl: p-toluenesulfonyl chloride
DCC: N,N'-dicyclohexylcarbodiimide NCS: N-chlorosuccinimide
CbzCl: Benzyl chloroformate STAB: Sodium triacetoxyborohydride
HATU: 2-(7-azobenzotriazole)- TBAF: tetrabutylammonium fluoride
N,N,N',N'-tetramethylurea hexafluorophosphate

Synthesis of Intermediate 01

Step 1: (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrole[1,2- a][1,5]Diazepine-8-carboxylic acid methyl ester (01-1)

(5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-6-oxodecahydropyrrolo[1,2-a][1,5]diazepine-8- Methyl carboxylate (220 mg, 0.64 mmol, 1 equiv) and triethylamine (130 mg, 1.29 mmol, 2 equiv) were mixed in DCM (5 mL) and cooled to 0°C. 2,2-difluoroethyl was added dropwise under nitrogen protection. trifluoromethanesulfonate (152 mg, 0.71 mmol, 1.1 equiv). After the dropwise addition was completed, the reaction solution was raised to room temperature and stirred for 18 h. After the reaction was completed, the reaction solution was evaporated to dryness, and the crude product was subjected to column chromatography (PE:EA=7:3, v/v) to obtain 01-1 (150 mg, 0.37 mmol, yield: 50%). LC-MS: (ESI) [M+H] ⁺ =406.2. ¹ H NMR: (400MHz, CDCl ₃ ): δ5.88(d,J＝56.0Hz,1H),5.64(d,J＝7.2Hz,1H),4.50–4.43(m,2H),4.34–4.28( m,1H),3.75(s,3H),3.18–3.01(m,5H),2.87–2.80(m,1H),2.38–2.29(m,1H),2.17–2.07(m,1H),2.03– 1.94(m,1H),1.83–1.78(m,1H),1.73–1.69(m,1H),1.42(s,9H).

Step 2: (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrole[1,2- a][1,5]diazacycline-8-carboxylic acid (intermediate 01)

Dissolve 01-1 (880 mg, 2.17 mmol, 1 equiv) in THF (12 mL), and add an aqueous solution (4 mL) of lithium hydroxide (312 mg, 13.02 mmol, 6 equiv) at room temperature. After the addition is completed, the reaction solution is added at room temperature. Stir for 4 hours, dilute the reaction solution with water (10 mL), concentrate under reduced pressure at low temperature to remove THF, add dilute hydrochloric acid (1N) to the aqueous phase at 0°C to adjust pH=7, and extract with a chloroform/isopropyl alcohol mixed solvent (chloroform:isopropyl alcohol) Alcohol=3:1, 15mL×6), the extract was washed with saturated brine (30mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and dried to obtain Intermediate 01 (800mg, 2.04mmol, yield: 98.7%) . LC-MS: (ESI) [M+H] ⁺ =392.2.

Synthesis of Intermediate 02

The first step: 5-bromobenzothiophene-2-carbonyl chloride (02-1)

Take a single-neck bottle, add 5-bromobenzothiophene-2-carboxylic acid (10g, 39mmol, 1equiv.), add DCM (200mL), slowly add oxalyl chloride (15g, 117mmol, 3equiv.) under ice bath, and then add DMF (1mL). The mixture was ventilated three times and then stirred at room temperature for 2 h. After the reaction, the reaction solution was distilled and concentrated under reduced pressure to obtain 02-1 which was directly used in the next step (11 g, 39 mmol, yield: 100%). LC-MS: (ESI) [M+H] ⁺ =274.9.

Step 2: 5-bromobenzothiophene-2-carboxylic acid benzyl ester (02-2)

Take a single-neck bottle, add 02-1 (11g, 39mmol, 1equiv.), add DCM (200mL), and slowly add benzyl alcohol (51g, 46.8mmol, 1.2equiv.) and triethylamine (118g, 117mmol) under ice bath. The mixture was ventilated three times and then stirred at room temperature for 1 h. The reaction solution was cooled to room temperature, then water was added, and extracted three times with EA (100 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated by distillation under reduced pressure. The residue was purified with a Flash column (DCM: MeOH = 10: 1, v/v) was purified to obtain 02-2 (9g, 26mmol, yield: 67%). LC-MS: (ESI) [M+H] ⁺ =347.0. ¹ H NMR: (400MHz, DMSO): δ8.30(d,J＝2.0Hz,1H),8.24(s,1H),8.08(d,J＝8.0Hz,1H),7.70(dd,J＝8.0 ,2.0Hz,1H),7.51(d,J=6.8Hz,2H),7.47–7.40(m,3H),5.42(s,2H).

Step 3: 5-iodobenzo[b]thiophene-2-carboxylic acid benzyl ester (02-3)

Take a tube and mix 02-2 (4.8g, 13.8mmol, 1equiv), N1,N2-dimethylethane-1,2-diamine (244mg, 2.8mmol, 0.2equiv), cuprous iodide ( 263 mg, 1.38 mmol, 0.1 equiv.) was added to 1,4-dioxane (48 mL). Sealed and heated to 110°C for 16 hours. The reaction solution was cooled to room temperature, filtered, the filtrate was spun dry, and the concentrate was purified by column chromatography (PE:EA=10:1) to obtain 02-3 (4.8g, 12.2mmol, yield: 88.8%). LC-MS: (ESI) [M+Na] ⁺ =395.0. ¹ H NMR: (400MHz, DMSO): δ8.47(d,J＝1.6Hz,1H),8.22-8.19(m,1H),7.92(d,J＝8.4Hz,1H),7.82(dd,J ＝8.4,1.6Hz,1H),7.53-7.48(m,2H),7.46-7.38(m,3H),5.41(s,2H).

Step 4: Benzyl 5-((diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate ((02-4)

Take a 250mL three-necked bottle, evenly disperse zinc powder (3.4g, 48.7mmol, 3equiv) in anhydrous tetrahydrofuran, and add dibromoethane (457mg, 2.4mmol, 0.05equiv) at room temperature. Heat to 50°C under nitrogen protection and hold for 15 minutes. Cool to room temperature, add trimethylsilyl chloride (317 mg, 2.9 mmol, 0.06 equiv) and stir at room temperature for 15 min. Diethyl bromodifluoromethylphosphonate (13.0g, 48.7mmol, 3equiv) was slowly added dropwise to the above reaction solution. After the dripping is completed, heat to 50°C and stir for 1 hour, then cool to room temperature. Cuprous bromide (3.5g, 24.4mmol, 1.5equiv) is quickly added to the above reaction, and stirred at room temperature for 30min. Dissolve 02-3 (6.4 g, 16.2 mmol, 1 equiv) in THF (60 mL) and add dropwise to the above reaction solution at room temperature. After the dripping is completed, heat to 45°C and stir overnight. Cool to room temperature, filter, spin the filtrate to dryness, and perform column chromatography (PE:EA=5:1) to obtain 02-4 (2.3g, 5.0mmol, yield: 31%). LC-MS: (ESI)[M+H] ⁺ =455.1. ¹ H NMR: (400MHz, CDCl ₃ ): δ8.19 (s, 2H), 7.99 (d, J = 8.8Hz, 1H), 7.74 (d, J = 8.8Hz, 1H), 7.53-7.51 (m, 2H),7.48–7.39(m,3H),5.45(s,2H),4.34-4.20(m,2H),1.46-1.30(m,6H).

Step 5: 5-((diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylic acid (Intermediate 02)

Take a 250mL single-neck bottle, dissolve 02-4 (5.8g, 12.8mmol, 1equiv) in methanol (58mL), add palladium on carbon (5.8g) and degas with hydrogen three times. Stir at room temperature overnight. Filter, spin the filtrate to dryness, and perform column chromatography (PE:EA=1:1) to obtain intermediate 02 (1.6g, yield: 35%). LC-MS (ESI) [M+H] ⁺ =365.0. ¹ H NMR: (400MHz, DMSO): δ8.30-8.24(m,3H),7.66(d,J＝8.0Hz,1H),4.21–4.10(m,4H),1.26-1.23(m,6H) .

Synthesis of Intermediate 03

The first step: 4-(3-oxypropyl)piperidine-1-carboxylic acid tert-butyl ester (03-1)

Take a single-neck bottle, add 4-(3-hydroxypropyl)piperidine-1-carboxylic acid tert-butyl ester (2.0g, 8.1mmol, 1equiv.), add DCM (30mL), and slowly add phthalic acid at 0°C Dimethyl ester (10.45g, 24.3mmol, 3equiv.). The mixture was ventilated three times and then stirred at room temperature for 4 h. TLC showed the reaction was complete. Slowly add 30 mL of saturated solutions of sodium thiosulfate and sodium bicarbonate to the reaction solution, extract three times with EA (50 mL The material was purified using a Flash column (PE:EtOAc=4:1, v/v) to obtain 03-1 (1.6g, 6.6mmol, yield: 80%). LC-MS: (ESI) [M+H] ⁺ =242.2. ¹ H NMR: (400MHz, DMSO) δ9.69(s,1H),3.99–3.88(m,2H),2.75–2.57(m,2H),2.50–2.44(m,2H),1.64–1.58(m ,2H),1.50–1.45(m,2H),1.40(s,9H),1.37–1.26(m,1H),1.00–0.91(m,2H).

Step 2: 4-(butyl-3-yn-1-yl)piperidine-1-carboxylic acid tert-butyl ester (03-2)

Take a single-neck bottle, add 03-1 (1.6g, 6.6mmol, 1equiv.), add MeOH (30mL), add (1-diazo-2-oxopropyl)phosphonic acid dimethyl ester (6.3g, 33mmol ,5equiv.). The mixture was ventilated three times and then stirred at room temperature for 3 h. The reaction solution was cooled to room temperature, then water was added, extracted three times with EA (50 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, the organic phase was distilled under reduced pressure and concentrated, and the residue was used with a Flash column (PE:EtOAc=5: 1, v/v) was purified to obtain 03-2 (1.20g, 5.1mmol, yield: 77%). LC-MS: (ESI)[M+H] ⁺ =238.2. ¹ H NMR: (400MHz, DMSO) δ3.93-3.91(m,2H),2.77(t,J＝2.8Hz,1H),2.71-2.65(m,2H),2.22–2.18(m,2H), 1.66-1.62(m,2H),1.56-1.48(m,1H),1.49-1.40(m,11H),1.02-0.91(m,1H).

Step 3: 4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)but-3-yn-1-yl )Piperidine-1-carboxylic acid tert-butyl ester (03-3)

Take a single-neck bottle and add 3-(4-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (985mg, 3.1mmol, 0.6equiv.), tetrakis(triphenyl) Phosphine) palladium (358 mg, 0.31 mmol, 0.1 equiv.), copper iodide (118 mg, 0.62 mmol, 0.2 equiv.), triethylamine (1.56 g, 15.5 mmol, 5 equiv.) and 03-2 (1.2 g, 5.1 mmol, 2 equiv.), then dimethyl sulfoxide (8 mL) was added. The mixture was ventilated three times and then stirred at 80 °C for 4 h. The reaction solution was cooled to room temperature, then water was added, and extracted three times with EA (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated by distillation under reduced pressure. The residue was purified with a Flash column (DCM: MeOH = 5: 1, v/v) was purified to obtain 03-3 (800 mg, 1.67 mmol, yield: 53.8%). LCMS: (ESI)[M-100] ⁺ =480.2.

Step 4: 3-(1-oxo-4-(4-(piperidin-4-yl)butyl-3-yn-1-yl)isoindolin-2-yl)piperidine-2, 6-diketone (intermediate 03)

Take a single-neck bottle, add 03-3 (800 mg, 1.67 mmol, 1 equiv.), add DCM (10 mL), and slowly add trifluoroacetic acid (572 mg, 5.01 mmol, 3 equiv.) under ice bath. The mixture was ventilated three times and then stirred at room temperature for 1 h. The reaction solution was cooled to room temperature, then water was added, extracted three times with EA (50mL×3), the organic phases were combined, and dried over anhydrous sodium sulfate. The organic phase was concentrated by distillation under reduced pressure, and the residue was beaten with a mixture of EA and PE (20 mL) (EA:PE=5:1, v/v) to obtain intermediate 03 trifluoroacetate (550 mg, 1.12 mmol, yield :67.9%). LCMS: (ESI)[M+1] ⁺ =380.2. ¹ H NMR: (400MHz, DMSO) δ11.02(s,1H),8.57(s,1H),8.26(s,1H),7.74(d,J＝8.0Hz,1H),7.66(d,J＝ 8.0Hz,1H),7.57-7.53(m,1H),5.20-5.16(m,1H),4.48(d,J＝17.6Hz,1H),4.34(d,J＝17.6Hz,1H),3.30( d,J＝12.0Hz,2H),2.96–2.84(m,3H),2.64-2.55(m,3H),2.48–2.39(m,1H),2.06–2.01(m,1H),1.89(d, J＝15.6Hz,2H),1.74(s,1H),1.60–1.55(m,2H),1.37–1.26(m,1H).

Example 1: ((2-(((5S,8S,10aR)-8-(((2S)-5-amino-1-(((2S))-3-(4-(dimethylphosphoryl)) Phenyl)-1-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)butan-3-yne- 1-yl)piperidin-1-yl)-1-oxopropan-2-yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2,2- Difluoroethyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl )Difluoromethyl)phosphoric acid (001)

Synthesis step 1: Boc-4-(dimethylphosphoryl)-L-phenylalanine methyl ester (001-1)

Dissolve Boc-4-bromo-L-phenylalanine methyl ester (1g, 2.79mmol) in 1,4-dioxane, add potassium phosphate (900mg, 4.21mmol) and HPOMe ₂ (320mg, 4.10mmol) , Pd ₂ (dba) ₃ (100mg, 0.11mmol), refluxed for 16h under nitrogen protection. After the reaction, the solvent was removed, and the crude product was subjected to silica gel column chromatography to obtain 001-1, which was directly used in the next step. LC-MS: (ESI) [M+H] ⁺ =356.2.

Synthesis step 2: (S)-2-Amino-3-(4-(dimethylphosphoryl)phenyl)propionic acid methyl ester (001-2)

Dissolve 001-1 (500 mg, 1.41 mmol) in 6 mL methanol, add 3 mL hydrochloric acid under ice bath conditions, and react at room temperature for 4 h. Toluene was added to remove water to obtain 001-2, which was directly used in subsequent reactions without purification. LC-MS: (ESI)[M+H] ⁺ =256.1. Synthesis step 3: (S)-2-(R)-5-amino-2-(tert-butoxycarbonyl)amino-5-oxopentanoamide)-3-(4-(dimethylphosphoryl)phenyl )Methyl propionate (001-3)

Dissolve 001-2 (6.0g, 23.67mmol) and (tert-butoxycarbonyl)-L-glutamine (5.8g, 23.67mmol) in N,N-dimethylformamide (120mL), then add N , N-diisopropylethylamine (6.2g, 47.34mmol), stir at room temperature for 3 minutes, then add HATU (9.5g, 24.85mmol) in batches at 10°C, after adding the reaction solution, raise to room temperature and stir for 18h. The reaction solution was poured into water (500 mL) and extracted with EA (150 mL × 3). The extract was washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was column chromatographed to obtain product 001-3. LC-MS: (ESI)[M+H] ⁺ =484.2.

Synthesis step 4: (S)-2-(R)-2,5-diamino-5-oxopentanoyl)-3-(4-(dimethylphosphoryl)phenyl)propionic acid methyl ester ( 001-4)

001-3 (218 mg, 0.45 mmol) was dissolved in DCM (5 mL) and a solution of hydrochloric acid in 1,4-dioxane (1 mL, 4 mmol) was added at room temperature. The reaction solution was stirred at room temperature for 3 h, concentrated and evaporated, and the residue was dried under vacuum to obtain product 001-4. LC-MS: (ESI) [M+H] ⁺ =384.2.

Synthesis step 5: 2-(R)-5-amino-2-(5S,8S,10aR)-5-(tert-butoxycarbonyl)amino)-3-(2,2-difluoroethyl)-6- Oxodecahydropyrrolo[1,2-a][1,5]diazepine-8-carboxamido)-5-oxopentanoyl)-3-(4-(dimethylphosphonium) Methyl acyl)phenyl)propionate (001-5)

Dissolve 001-4 (782mg, 2.04mmol) and intermediate 01 (881mg, 2.25mmol) in N,N-dimethylformamide (20mL), then add N,N-diisopropylethylamine (792mg , 6.13 mmol), stir at room temperature for 3 min, then add HATU (854 mg, 2.25 mmol, 1.1 equiv) in batches at 10°C, after adding the reaction solution, raise to room temperature and stir for 18 h. The reaction solution was poured into water (50 mL), extracted with EA (20 mL :1, v/v) to obtain product 001-5. LC-MS: (ESI) [M+H] ⁺ =757.4.

Synthesis step 6: 2-(R)-5-amino-2-(5S,8S,10aR)-5-(tert-butoxycarbonyl)amino)-3-(2,2-difluoroethyl)-6- Oxodecahydropyrrolo[1,2-a][1,5]diazepine-8-carboxamido)-5-oxopentylamide)-3-(4-(dimethylphosphate) )Phenyl)propionic acid (001-6)

Dissolve 001-5 (318 mg, 0.42 mmol) in THF (4 mL), and add an aqueous solution (1 mL) of lithium hydroxide (60 mg, 2.52 mmol) at room temperature. After the addition is complete, the reaction solution is stirred at room temperature for 4 h, and the reaction proceeds. The solution was diluted with water (3 mL), concentrated under reduced pressure at low temperature to remove THF. Dilute hydrochloric acid (1N) was added to the water phase at 0°C to adjust pH=5, and extracted with a mixed solvent of chloroform and isopropyl alcohol (chloroform: isopropyl alcohol). Alcohol=3:1, 5mL×4), the extract was washed with saturated brine (5mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried to obtain product 001-6. LC-MS: (ESI) [M+H] ⁺ =743.3.

Synthesis step 7: tert-butyl ((5S,8S,10aR)-8-((2R)-5-amino-1-((2S)-3-(4-(4-(2,6-dioxo) Piperidin-3-yl)-1-oxoisoindolin-4-yl)butyl-3-ynyl-1-yl)-1-oxopropan-2-yl)amino)-1,5 -Dioxopent-2-yl)carbamoyl)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diaza Heterocyclooct-5-yl)carbamate (001-7)

001-6 (267mg, 0.36mmol) and intermediate 03 (137mg, 0.36mmol) were dissolved in N,N-dimethylformamide (5mL), and then N,N-diisopropylethylamine (94mg , 0.73mmol) and T3P (115mg, 0.36mmol). After adding the reaction solution, stir at room temperature for 18h. The reaction solution was poured into water (15 mL), extracted with EA (5 mL :1, v/v) to obtain the corresponding product 001-7. LC-MS: (ESI) [M+H] ⁺ =1104.5.

Synthesis step 8: 2R-2-(5S,8S,10aR)-5-amino-3-(2,2-difluoroethyl)-6-oxodecahydropyrrolo[1,2-a][1 ,5]Diazepine-8-carboxamido)-N1-((2S)-3-(4-(4-(2,6-dioxopiperidin-3-yl)-1-oxo Isoindolin-4-yl)butyl-3-ynyl-1-yl)piperidin-1-yl)-1-oxopropan-2-yl)glutaramide (001-8)

001-7 (25 mg, 0.022 mmol) was dissolved in DCM (2 mL) and a solution of hydrochloric acid in 1,4-dioxane (4 mmol) was added at room temperature. The reaction solution was stirred at room temperature for 1 h, concentrated and evaporated, and the residue was dried under vacuum to obtain the corresponding product 001-8. LC-MS: (ESI) [M+H] ⁺ =1004.5.

Synthesis step 9: (2-((5S,8S,10aR)-8-(2R)-5-amino-1-((2S)-3-(4-(dimethylphosphoryl)phenyl)-1 -(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)but-3-ynyl-1-yl) -1-Oxopropan-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(2,2-difluoroethyl)-6-oxo Decahydropyrro[1,2-a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphate (001 -9)

001-8 (351 mg, 0.35 mmol) and intermediate 02 (142 mg, 0.39 mmol) were dissolved in N, N-dimethylformamide (5 mL), and then N, N-diisopropylethylamine (134 mg , 1.04mmol,) and T3P (111mg, 0.35mmol), after adding the reaction solution, stir at room temperature for 18h. The reaction solution was poured into water (15 mL), extracted with EA (5 mL :1, v/v) to obtain the corresponding product 001-9. LC-MS: (ESI) [M+H] ⁺ =1350.5.

Synthesis step 10: ((2-(((5S,8S,10aR)-8-(((2S)-5-amino-1-(((2S)-3-(4-(dimethylphosphoryl)) Phenyl)-1-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)butan-3-yne- 1-yl)piperidin-1-yl)-1-oxopropan-2-yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2,2- Difluoroethyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl )Difluoromethyl)phosphoric acid (001)

001-9 (115 mg, 0.085 mmol) was dissolved in DCM (4 mL) and cooled to 0°C. BSTFA (219 mg, 0.85 mmol) and TMS-I (254 mg, 1.27 mmol) were added dropwise under nitrogen protection. After the dropwise addition was completed, the reaction solution was stirred at 0°C for 2 h. The reaction solution was evaporated to dryness at low temperature, and the residue was dissolved in a mixed solvent acetonitrile/water/trifluoroacetic acid (CH ₃ CN: H ₂ O: TFA = 10:10:3, 7 mL), filtered, and the filtrate was sent to preparative HPLC to obtain the compound. 001. LC-MS: (ESI) [M+H] ⁺ =1294.4.

Example 2: ((2-(((5S,8S,10aR)-8-(((2S)-5-amino-1-((2S))-3-(4-(dimethylphosphoryl)benzene base)-1-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)but-3-ynyl- 1-yl)piperidin-1-yl)-1-oxopropan-2-yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-ethyl-6- Oxodecahydropyrrolo[1,2-a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid ( 002)

Synthesis step 1: (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-3-ethyl-6-oxodecahydropyrrole[1,2-a][1,5]bis Synthesis of azepan-8-carboxylic acid (intermediate 04)

Referring to the synthetic route and method of Intermediate 01, 2,2-difluoroethyl trifluoromethanesulfonate in the first step was replaced with ethyl triflate to synthesize Intermediate 04. LC-MS: (ESI) [M+H] ⁺ =356.2.

Synthesis of step 2:002

Referring to the synthetic route and method of Example 1, the intermediate 01 in the synthesis step 5 was replaced with the intermediate 04, and the target compound 002 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1258.4.

Example 3: ((2-(((5S,8S,10aR)-3-acetyl-8-(((2S)-5-amino-1-(((2S)-3-(4-(di Methylphosphoryl)phenyl)-1-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)butan -3-yn-1-yl)piperidin-1-yl)-1-oxopropan-2-yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-6- Oxodecahydropyrrolo[1,2-a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid ( 003)

Synthesis step 1: (5S,8S,10aR)-3-acetyl-5-((tert-butoxycarbonyl)amino)-6-oxodecahydropyrrolo[1,2-a][1,5] Diazacycline-8-carboxylic acid (Intermediate 05)

Step 1: (5S,8S,10aR)-3-acetyl-5-((tert-butoxycarbonyl)amino)-6-oxodecahydropyrrolo[1,2-a][1,5] Diazacycline-8-carboxylic acid methyl ester (05-1)

(5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-6-oxodecahydropyrrolo[1,2-a][1,5]diazepine-8- Methyl carboxylate (220 mg, 0.64 mmol, 1 equiv), triethylamine (194 mg, 1.92 mmol, 3 equiv), EDCI (368 mg, 1.92 mmol, 3 equiv) and DMAP (156 mg, 1.28 mmol, 2 equiv) were mixed in DCM (5 mL) middle. Acetic acid solution (58 mg, 0.96 mmol, 1.5 equiv) dissolved in DCM was slowly added dropwise at room temperature. After the dropwise addition is completed, stir at 30°C. After the reaction is completed, the reaction liquid is evaporated to dryness, and the crude product is obtained by column chromatography 05-1. LC-MS: (ESI) [M+H] ⁺ =384.2.

Step 2: (5S,8S,10aR)-3-acetyl-5-((tert-butoxycarbonyl)amino)-6-oxodecahydropyrrolo[1,2-a][1,5] Diazacycline-8-carboxylic acid (Intermediate 05)

Refer to the synthetic route and method of the second step of Intermediate 01, replace 01-1 with 05-1, and synthesize Intermediate 05. LC-MS: (ESI) [M+H] ⁺ =370.2.

Synthesis of step 2:003

Referring to the synthetic route and method of Example 1, the intermediate 01 in the synthesis step 5 was replaced with the intermediate 05, and the target compound 003 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1272.4.

Example 4: ((2-(((5S,8S,10aR)-8-(((2S)-5-amino-1-(((2S))-3-(4-(dimethylphosphoryl)) Phenyl)-1-(4-(4-(2-

(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)but-3-yn-1-yl)piperidin-1-yl)-1-oxo Propan-2-yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(methoxycarbonyl)-6-oxodecahydropyrro[1,2- a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (004)

Synthesis step 1: (5S,8S,10aR)-3-(methoxycarbonyl)-5-((tert-butoxycarbonyl)amino)-6-oxodecahydropyrrole[1,2-a][1 ,5] Synthesis of diazacyclooctane-8-carboxylic acid (intermediate 06)

Referring to the synthetic route and method of Intermediate 01, 2,2-difluoroethyl trifluoromethanesulfonate in the first step was replaced with dimethyl dicarbonate to synthesize Intermediate 06. LC-MS: (ESI) [M+H] ⁺ =386.2.

Synthesis of step 2:004

Referring to the synthetic route and method of Example 1, the intermediate 01 in the synthesis step 5 was replaced with the intermediate 06, and the target compound 004 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1288.4.

Example 5: ((2-(((5S,8S,10aR)-8-(((2S)-5-amino-1-(((2S))-3-(4-(dimethylphosphoryl)) Phenyl)-1-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)butan-3-yne- 1-yl)piperazin-1-yl)-1-oxopropan-2-yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2,2- Difluoroethyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl )Difluoromethyl)phosphoric acid (005)

Synthetic step 1: 3-(1-oxo-4-(4-(piperazin-1-yl)butyl-1-yn-1-yl)isoindolin-2-yl)piperidine-2, Synthesis of 6-diketone (intermediate 07)

Referring to the synthetic route and method of Intermediate 03, replace 4-(3-hydroxypropyl)piperidine-1-carboxylic acid tert-butyl ester in the first step with 4-(3-hydroxypropyl)piperazine-1 -tert-butyl carboxylate, synthesized to obtain intermediate 07. LC-MS: (ESI) [M+H] ⁺ =381.2.

Synthesis of step 2:005

Referring to the synthetic route and method of Example 1, intermediate 03 in synthesis step 7 was replaced with intermediate 07, and the target compound 005 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1295.4.

Example 6: ((2-(((5S,8S,10aR)-8-(((2S)-5-amino-1-(((2S))-3-(4-(dimethylphosphoryl)) Phenyl)-1-(4-(3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)propyl-2-yne base-1-yl)oxy)piperidin-1-yl)-1-oxopropan-2-yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3- (2,2-difluoroethyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b] Thiophen-5-yl)difluoromethyl)phosphoric acid (006)

Synthesis step 1: 3-(1-oxo-4-(3-(piperidin-4-oxy)propyl-1-yn-1-yl)isoindolin-2-yl)piperidine-2 ,Synthesis of 6-diketone (intermediate 08)

Referring to the synthetic route and method of Intermediate 03, replace 4-(3-hydroxypropyl)piperidine-1-carboxylic acid tert-butyl ester in the first step with 4-(2-Hydroxyethoxy)piperidine-1-carboxylic acid tert-butyl ester was synthesized to obtain intermediate 08. LC-MS: (ESI) [M+H] ⁺ =382.2.

Synthesis Step 2:006 Synthesis

Referring to the synthetic route and method of Example 1, the intermediate 03 in the synthesis step 7 was replaced with the intermediate 08, and the target compound 006 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1296.4.

Example 7: ((2-(((5S,8S,10aR)-8-(((2S)-5-amino-1-(((2S))-3-(3-chloro-4-(dimethyl Phosphoryl)phenyl)-1-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)butan- 3-yn-1-yl)piperidin-1-yl)-1-oxopropan-2-yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-( 2,2-Difluoroethyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophene -5-yl)difluoromethyl)phosphoric acid (007)

Synthesis step 1: Synthesis of (S)-3-(4-bromo-3-chlorophenyl)-2-((tert-butoxycarbonyl)amino)propionic acid methyl ester (007-2)

The first step: (S)-3-(4-amino-3-chlorophenyl)-2-((tert-butoxycarbonyl)amino)propionic acid methyl ester (007-1)

Dissolve (2S)-3-(4-aminophenyl)-2-[(tert-butoxycarbonyl)amino]propionic acid methyl ester (1.0eq) in DCM, then NCS (1.2eq) dissolved in DCM ) solution was slowly added dropwise into the reaction solution, and the reaction was carried out at room temperature. After the reaction is completed, aqueous solution and DCM are added for extraction, liquid separation, and the organic phase is purified by column chromatography to obtain 007-1. LC-MS: (ESI) [M+H] ⁺ =329.1.

Step 2: (S)-3-(4-Bromo-3-chlorophenyl)-2-((tert-butoxycarbonyl)amino)propionic acid methyl ester (007-2)

Dissolve CuBr ₂ (1.3eq) in ACN and lower the temperature to 0°C. Then dissolve tert-butyl nitrite (1.1eq) in ACN and add it dropwise to the ACN solution of CuBr _2. Keep the temperature at 0°C for ten minutes. . Then add the ACN solution of 007-1 (1.0eq) into the mixed solution, keep the temperature at 0°C for ten minutes, and then turn to room temperature to start the reaction. After the reaction is completed, ACN is concentrated to remove, 0.5NHCl aqueous solution and EA are added for extraction, liquid separation, and the organic phase is purified by column chromatography to obtain 007-2. LC-MS: (ESI) [M+H] ⁺ =392.0.

Synthesis of step 2:007

Referring to the synthetic route and method of Example 1, Boc-4-bromo-L-phenylalanine methyl ester in the synthesis step 1 was replaced with 007-2, and the target compound 007 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1328.4.

Example 8: ((2-(((5S,8S,10aR)-8-(((2S)-5-amino-1-(((2S))-3-(4-(dimethylphosphoryl)) -3-Fluorophenyl)-1-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)butan- 3-yn-1-yl)piperidin-1-yl)-1-oxopropan-2-yl)ammonium (yl)-1,5-dioxopent-2-yl)carbamoyl)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrolo[1,2-a][ 1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (008)

Synthesis step 1: Synthesis of (S)-2-amino-3-(4-(dimethylphosphoryl)-3-fluorophenyl)propionic acid methyl ester (008-1):

Referring to the synthetic route and method of synthetic step 1 in Example 1, replace Boc-4-bromo-L-phenylalanine methyl ester in synthetic step 1 with (S)-2-amino 3-(4-bromo- 3Fluorophenyl)-methyl propionate was synthesized to obtain 008-1. LC-MS: (ESI) [M+H] ⁺ =274.1.

Synthesis step 2:008 synthesis

Referring to the synthetic route and method of synthesis steps 3-10 in Example 1, replace 001-2 in synthesis step 3 with 008-1, and synthesize target compound 008. LC-MS: (ESI) [M+H] ⁺ =1312.4.

Example 9: ((2-(((5S,8S,10aR)-8-(((2S)-5-amino-1-(((2S))-3-(4-(dimethylphosphoryl)) Phenyl)-1-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)butan-3-yne- 1-yl)piperidin-1-yl)-1-oxopropan-2-yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(methylsulfonyl) )-6-Oxodecahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl Phosphoric acid(009)

Synthesis step 1: (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-3-methylsulfonyl-6-oxodecahydropyrrole[1,2-a][1,5 ] Synthesis of diazacycline-8-carboxylic acid (intermediate 09)

Referring to the synthetic route and method of Intermediate 01, 2,2-difluoroethyl trifluoromethanesulfonate in the first step was replaced with methylsulfonyl chloride, and Intermediate 09 was synthesized. LC-MS: (ESI) [M+H] ⁺ =406.2.

Synthesis of step 2:009

Referring to the synthetic route and method of Example 1, replace the intermediate 01 in the synthesis step 5 with the intermediate 09, and synthesize The target compound 009 was obtained. LC-MS: (ESI) [M+H] ⁺ =1308.4.

Example 10: ((2-(((5S,8S,10aR)-8-(((2S)-5-amino-1-(((2S))-3-(4-(dimethylphosphoryl)) Phenyl)-1-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)butan-3-yne- 1-yl)piperidin-1-yl)-1-oxopropan-2-yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2,2- Difluoroethyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl )Difluoromethyl)phosphoric acid (010)

Synthetic step 1: 3-(1-oxo-5-(4-(piperidin-4-yl)butyl-1-yn-1-yl)isoindolin-2-yl)piperidine-2, Synthesis of 6-diketone (intermediate 10)

Referring to the synthetic route and method of Intermediate 03, replace 3-(4-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione in the third step with 3-( 5-Bromo-1-oxisoindol-2-yl)piperidine-2,6-dione was synthesized to obtain intermediate 10. LC-MS: (ESI) [M+H] ⁺ =380.2.

Synthesis of step 2:010

Referring to the synthetic route and method of Example 1, the intermediate 03 in the synthesis step 7 was replaced with the intermediate 10, and the target compound 010 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1294.4.

Example 11: ((2-(((5S,8S,10aR)-8-(((2S)-5-amino-1-(((2S))-3-(4-(dimethylphosphoryl)) Phenyl)-1-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)butan-3 -Alkyn-1-yl)piperidin-1-yl)-1-oxopropan-2-yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2 ,2-difluoroethyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophene- 5-yl)difluoromethyl)phosphoric acid (011)

Synthesis step 1: 2-(2,6-dioxopiperidin-3-yl)-5-(4-(4-(piperidin-4-yl)butan-1-yn-1-yl)isoindole Synthesis of indoline-1,3-dione (intermediate 11)

Referring to the synthetic route and method of Intermediate 03, 3-(4-bromo-1-oxoisoindolin-2-yl)piperidine-2,6- The dione was replaced by 5-bromo-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione, and intermediate 11 was synthesized. LC-MS: (ESI) [M+H] ⁺ =394.2.

Synthesis of step 2:011

Referring to the synthetic route and method of Example 1, the intermediate 03 in the synthesis step 7 was replaced with the intermediate 11, and the target compound 011 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1308.4.

Example 12: ((2-(((5S,8S,10aR)-8-(((2S)-5-amino-1-(((2S))-3-(4-(dimethylphosphoryl)) Phenyl)-1-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethyl (yl)piperidin-1-yl)-1-oxopropan-2-yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2,2-difluoro Ethyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)bis Fluoromethyl)phosphoric acid (012)

Synthesis step 1: 2-(2,6-dioxopiperidin-3-yl)-5-((2-(piperidin-4-yl)ethyl)amino)isoindoline-1,3- Synthesis of diketone (intermediate 12)

Referring to the synthetic route and method of steps 3-4 of intermediate 03, replace 03-2 in step 3 with 2-(N-Boc-4-piperidinyl)ethylamine to synthesize intermediate 12. LC-MS: (ESI) [M+H] ⁺ =385.2.

Synthesis Step 2:012 Synthesis

Referring to the synthetic route and method of Example 1, the intermediate 03 in the synthesis step 7 was replaced with the intermediate 12, and the target compound 012 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1299.4.

Example 13: ((2-(((5S,8S,10aR)-8-(((2S)-5-amino-1-(((2S))-3-(4-(dimethylphosphoryl)) Phenyl)-1-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethyl (yl)piperazin-1-yl)-1-oxopropan-2-yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2,2-difluoro Ethyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)bis Fluoromethyl)phosphoric acid (013)

Synthesis step 1: 2-(2,6-dioxopiperidin-3-yl)-5-((2-(piperazin-1-yl)ethyl)amino)isoindoline-1,3- Synthesis of diketone (intermediate 13)

Referring to the synthetic route and method of steps 3-4 of intermediate 03, replace 03-2 in the third step with 4-(2-aminoethyl)piperazine-1-carboxylic acid tert-butyl ester, and synthesize the intermediate 13. LC-MS: (ESI) [M+H] ⁺ =386.2.

Synthesis of step 2:013

Referring to the synthetic route and method of Example 1, the intermediate 03 in the synthesis step 7 was replaced with (intermediate 13), and the target compound 013 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1300.4.

Example 14: ((2-(((5S,8S,10aR)-8-(((2S)-5-amino-1-(((2S))-3-(4-(dimethylphosphoryl)) Phenyl)-1-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzimidazol-5-yl)but-3-yn-1-yl)piperidin-1-yl)-1-oxopropan-2-yl)amino)-1,5-dioxopent-2- yl)carbamoyl)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl) Carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (014)

Synthesis step 1: 3-(3-methyl-2-oxo-5-(4-(piperidin-4-yl)but-1-yn-1-yl)-2,3-dihydro-1H- Synthesis of benzimidazol-1-yl)piperidine-2,6-dione (intermediate 14)

Refer to the synthetic route and method of steps 3-4 of Intermediate 03. Replace 3-(4-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione in the third step with 3-(5-bromo-3-methyl-2 -Oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione was synthesized to obtain intermediate 14. LC-MS: (ESI) [M+H] ⁺ =395.2.

Synthesis Step 2: Synthesis of 014

Referring to the synthetic route and method of Example 1, intermediate 03 in synthesis step 7 was replaced with intermediate 14, and target compound 014 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1309.4.

Example 15: ((2-(((5S,8S,10aR)-8-(((2S)-5-amino-1-(((2S))-3-(4-(dimethylphosphoryl)) Phenyl)-1-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzimidazol-4-yl)but-3-yn-1-yl)piperidin-1-yl)-1-oxopropan-2-yl)amino)-1,5-dioxopent-2- yl)carbamoyl)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl) Carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (015)

Synthesis step 1: 3-(3-methyl-2-oxo-5-(4-(piperidin-4-yl)but-1-yn-1-yl)-2,3-dihydro-1H- Synthesis of benzimidazol-1-yl)piperidine-2,6-dione (intermediate 15)

Referring to the synthetic route and method of steps 3-4 of intermediate 03, 3-(4-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-di The ketone was replaced with 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione, and the intermediate was synthesized Body 15. LC-MS: (ESI) [M+H] ⁺ =395.2.

Synthesis Step 2: Synthesis of 015

Referring to the synthetic route and method of Example 1, intermediate 03 in synthesis step 7 was replaced with intermediate 15, and the target compound 015 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1309.4.

Example 16: ((2-(((5S,8S,10aR)-8-(((2S)-5-amino-1-(((2S))-3-(4-(dimethylphosphoryl)) Phenyl)-1-(4-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzimidazol-4-yl)propyl-2-ynyl-1-oxy)piperidin-1-yl)-1-oxopropan-2-yl)amino)-1,5-dioxopent -2-yl)carbamoyl)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazacyclooctane-5 -yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (016)

Synthesis step 1: 3-(3-methyl-2-oxo-4-(3-(piperidin-4-oxy)prop-1-yn-1-yl)-2,3-dihydro-1H -Synthesis of benzimidazol-1-yl)piperidine-2,6-dione (intermediate 16)

Referring to the synthetic route and method of steps 3-4 of intermediate 03, 3-(4-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-di The ketone was replaced with 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione and 03- 2 was replaced by 4-(prop-2-yn-1-yloxy)piperidine-1-carboxylic acid tert-butyl ester, and intermediate 16 was synthesized. LC-MS:(ESI) [M+H] ⁺ =397.2.

Synthesis Step 2: Synthesis of 016

Referring to the synthetic route and method of Example 1, intermediate 03 in synthesis step 7 was replaced with intermediate 16, and the target compound 016 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1311.4.

Example 17: ((2-(((5S,8S,10aR)-8-(((2S)-5-amino-1-(((2S))-3-(4-(dimethylphosphoryl)) Phenyl)-1-(4-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzimidazol-5-yl)butyl)piperidin-1-yl)-1-oxopropan-2-yl)amino)-1,5-dioxopent-2-yl)carbamoyl)- 3-(2,2-difluoroethyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[ b]Thien-5-yl)difluoromethyl)phosphoric acid (017)

Synthesis step 1: 3-(3-methyl-2-oxo-5-(4-(piperidin-4-yl)butyl)-2,3-dihydro-1H-benzimidazol-1-yl )Synthesis of piperidine-2,6-dione (intermediate 17)

Referring to the synthetic route and method of steps 3-4 of intermediate 03, 3-(4-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-di The ketone was replaced with 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione and 03- 2 was replaced with 4-butylpyridine (hydrochloride)-1-carboxylic acid tert-butyl ester, and intermediate 17 was synthesized. LC-MS: (ESI) [M+H] ⁺ =399.2.

Synthesis Step 2: Synthesis of 017

Referring to the synthetic route and method of Example 1, intermediate 03 in synthesis step 7 was replaced with intermediate 17, and target compound 017 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1313.5.

Example 18: ((2-(((5S,8S,10aR)-8-(((2S)-5-amino-1-(((2S))-3-(4-(dimethylphosphoryl)) Phenyl)-1-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)butan-3-yne- 1-yl)piperidin-1-yl)-1-oxopropan-2-yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2,2- Difluoroethyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophene-5-carbonyl )Phosphoric acid(018)

Synthesis step 1: Synthesis of 5-((diethoxyphosphoryl)carbonyl)benzo[b]thiophene-2-carboxylic acid (intermediate 18)

The first step: the compound of (2-acetylbenzo[b]thiophene-5-carbonyl)phosphonate diethyl ester and benzyl-L1-oxanide (18-1)

Take a 250mL reaction bottle, combine 02-3, diethyl phosphite and carbon monoxide with tris(dibenzylideneacetone)dipalladium-chloroform adduct, N-ethyl-N, N-diisopropylamine, 4, 5-Bis(diphenylphosphine)-9,9-dimethylxanthene was added to the tetrahydrofuran solution, reacted at -78°C for half an hour, and then raised to room temperature for 16 hours. After the reaction is completed, cool to room temperature, filter, spin the filtrate to dryness, and obtain 18-1 by column chromatography. LC-MS: (ESI)[M+H] ⁺ =448.1.

Step 1: 5-((diethoxyphosphoryl)carbonyl)benzo[b]thiophene-2-carboxylic acid (Intermediate 18)

Referring to the synthetic route and method of the fifth step of Intermediate 02, replace 02-4 with 18-1, and synthesize Intermediate 18. LC-MS: (ESI) [M+H] ⁺ =343.0.

Synthesis Step 2: Synthesis of 018

Referring to the synthetic route and method of Example 1, the intermediate 02 in the synthesis step 9 was replaced with the intermediate 18, and the target compound 018 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1272.4.

Example 19: ((2-(((5S,8S,10aR)-8-(((2S)-5-amino-1-(((2S))-3-(4-(dimethylphosphoryl)) Phenyl)-1-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)butan-3-yne- 1-yl)piperidin-1-yl)-1-oxopropan-2-yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2,2- Difluoroethyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl) Phosphoric acid (019)

Synthesis step 1: Synthesis of 5-(diethoxyphosphate)carbonyl)-1H-indole-2-carboxylic acid (intermediate 19)

For the synthesis of intermediate 19, refer to the synthetic route and method of intermediate 02, replace 5-bromobenzothiophene-2-carboxylic acid in the first step with 5-bromoindole-2-carboxylic acid, and replace 5-bromoindole-2-carboxylic acid in the fourth step. The diethyl bromodifluoromethylphosphonate was replaced with diethyl phosphite and the adduct of carbon monoxide with tris(dibenzylideneacetone)dipalladium-chloroform was synthesized to obtain intermediate 19. LC-MS: (ESI) [M+H] ⁺ =326.1.

Synthesis Step 2: Synthesis of 019

Referring to the synthetic route and method of Example 1, intermediate 02 in synthesis step 9 was replaced with intermediate 19, and target compound 019 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1255.5.

Example 20: ((2-(((5S,8S,10aR)-8-(((2S)-5-amino-1-(((2S))-3-(4-(dimethylphosphoryl)) Phenyl)-1-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)butan-3-yne- 1-yl)piperidin-1-yl)-1-oxopropan-2-yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2,2- Difluoroethyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1-methyl-1H-indole -5-carbonyl)phosphate(020)

Synthesis step 1: Synthesis of 5-(diethoxyphosphate)carbonyl)-1H-indole-2-carboxylic acid (intermediate 20)

The synthesis steps of Intermediate 20 refer to Intermediate 19. The 5-bromoindole-2-carboxylic acid in the first step is replaced by 5-bromo-1-methylindole-2-carboxylic acid to obtain Intermediate 20. LC-MS: (ESI) [M+H] ⁺ =340.1.

Synthesis Step 2: Synthesis of 020

Referring to the synthetic route and method of Example 1, the intermediate 02 in the synthesis step 9 was replaced with the intermediate 20, and the target compound 020 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1269.5.

Example 21: ((2-(((5S,8S,10aR)-8-(((2S)-5-amino-1-(((2S)-3-(2-chloro-4-(dimethyl) Phosphoryl)phenyl)-1-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)butan- 3-yn-1-yl)piperidin-1-yl)-1-oxopropan-2-yl)ammonium (yl)-1,5-dioxopent-2-yl)carbamoyl)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrolo[1,2-a][ 1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (021)

Referring to the synthetic route and method of Example 1, replace Boc-4-bromo-L-phenylalanine methyl ester in synthesis step 1 with (S)-3-(4-bromo-2-chlorophenyl)- 2-((tert-butoxycarbonyl)amino)propionic acid methyl ester was synthesized to obtain target compound 021. LC-MS: (ESI) [M+H] ⁺ =1328.4.

Example 22: (2-(((5S,8S,10aR)-8-(((2S)-5-amino-1-(((2S)-3-(4-(dimethylphosphoryl))benzene base)-1-(4-(4-(6-((2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-3-yl)but-3-yn-1-yl) Piperidin-1-yl)-1-oxopropan-2-yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2,2-difluoroethyl )-6-Oxodecahydropyrro[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophene-5-carbonyl)phosphoric acid (022 )

Synthetic step 1: N-(2,6-dioxopiperidin-3-yl(-5-(4-(piperidin-4-yl(but-1-yn-1-yl))pyridinamide (intermediate) 21) synthesis

Referring to the synthetic route and method of Intermediate 03, replace 3-(4-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione in the third step with 5-bromo -N-(2,6-dioxopiperidin-3-yl)pyridinecarboxamide was synthesized to obtain intermediate 21. LC-MS: (ESI) [M+H] ⁺ =369.2.

Synthesis Step 2: Synthesis of 022

Referring to the synthetic route and method of Example 1, the intermediate 03 in the synthesis step 7 was replaced with the intermediate 21, and the intermediate 02 in the synthesis step 9 was replaced with the intermediate 18, and the target compound 022 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1261.4.

Example 23: ((2-(((5S,8S,10aR)-8-(((2S)-5-amino-1-(((2S))-3-(4-(dimethylphosphoryl)) Phenyl)-1-(4-(4-(6-((2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-3-yl)but-3-yn-1-yl )piperidin-1-yl)-1-oxopropan-2-yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2,2-difluoroethyl) base)-6-oxodecahydropyrrolo[1,2-a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoro Methyl)phosphate(023)

Referring to the synthetic route and method of Example 1, intermediate 03 in synthesis step 7 was replaced with intermediate 21, and the target compound 023 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1283.4.

Example 24: ((2-(((5S,8S,10aR)-8-(((2S)-5-amino-1-(((2S))-3-(4-(dimethylphosphoryl)) Phenyl)-1-(4-((3-(6-((2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-3-yl)prop-2-ynyl-1 -yl)oxy)piperidin-1-yl)-1-oxopropan-2-yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2, 2-Difluoroethyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophene-5 -Difluoromethyl)phosphoric acid (024)

Synthetic step 1: N-(2,6-dioxopiperidin-3-yl(-5-(3-(piperidin-4-yloxy)prop-1-yn-1-yl)pyridinamide( Synthesis of intermediate 22)

Referring to the synthetic route and method of Intermediate 03, replace 4-(3-hydroxypropyl)piperidine-1-carboxylic acid tert-butyl ester in the first step with 4-(2-hydroxyethoxy)piperidine- 1-tert-butylcarboxylate, replace 3-(4-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione in the third step with 5-bromo-N -(2,6-dioxopiperidin-3-yl)pyridinecarboxamide was synthesized to obtain intermediate 22. LC-MS: (ESI) [M+H] ⁺ =371.2.

Synthesis Step 2: Synthesis of 024

Referring to the synthetic route and method of Example 1, intermediate 03 in synthesis step 7 was replaced with intermediate 22, and the target compound 024 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1285.4.

Example 25: ((2-(((5S,8S,10aR)-8-(((2S)-5-amino-1-((2S)-3-(4-(dimethylphosphoryl))benzene base)-1-(4-(4-(6-((2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-3-yl)but-3-yn-1-yl) Piperazin-1-yl)-1-oxopropan-2-yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2,2-difluoroethyl) )-6-Oxodecahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl base) phosphoric acid (025)

Synthetic step 1: N-(2,6-dioxopiperidin-3-yl(-5-(4-(piperazin-1-yl)but-1-yn-1-yl)pyridinamide (intermediate) 23) synthesis

Referring to the synthetic route and method of Intermediate 03, replace 4-(3-hydroxypropyl)piperidine-1-carboxylic acid tert-butyl ester in the first step with 4-(3-hydroxypropyl)piperazine-1 -tert-butyl carboxylate, replacing 3-(4-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione in the third step with 5-bromo-N- (2,6-dioxopiperidin-3-yl)pyridinecarboxamide was synthesized to obtain intermediate 23. LC-MS: (ESI) [M+H] ⁺ =370.2.

Synthesis Step 2: Synthesis of 025

Referring to the synthetic route and method of Example 1, intermediate 03 in synthesis step 7 was replaced with intermediate 23, and the target compound 025 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1284.4.

Example 26: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-(S)-3-(4-(dimethylphosphoryl))benzyl )Amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl -2-Oxo-2,3-dihydro-1H-benzimidazol-5-yl)heptanoyl-6-oxodecahydropyrrolo[1,2-a][1,5]diazacycle Oct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (026)

Synthesis of Intermediate 24

Step one: 3-benzyl 8-methyl(5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-6-oxodecahydropyrrolo[1,2-a][1 ,5]Diazepine-3,8(4H)-dicarboxylate (24-1)

In a round bottom flask, add (5S,8S,10aR)-5-(tert-butoxycarbonyl)amino-6-oxodecahydropyrrolo[1,2-a][1,5]diazozine-8 -Carboxylic acid methyl ester, dissolve it in THF, add water and K ₂ CO ₃ , slowly add CbzCl dissolved in THF dropwise at 0°C, and react at 0°C. After the reaction is completed, water is added to the reaction solution, the pH is adjusted to acidic with acetic acid, and a solid is precipitated, filtered with suction, and dried to obtain 24-1. LC-MS: (ESI)[M+H] ⁺ =476.2.

Step 2: (5S,8S,10aR)-3-((benzyloxy)carbonyl)-5-((tert-butoxycarbonyl)amino)-6-oxodecahydropyrrolo[1,2-a ][1,5]diazoxide-8-carboxylic acid (intermediate 024)

Referring to the second step synthesis route and method of Intermediate 01, replace 01-1 with 24-1, and synthesize Intermediate 24. LC-MS: (ESI)[M+H] ⁺ =462.2

Synthesis of intermediate 25

Step 1: 7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole- 5-yl)hept-6-ynoic acid (25-1)

Refer to the synthetic route and method of step 3 of Intermediate 03. Replacement of 3-(4-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione with 3-(5-bromo-3-methyl-2-oxo-2 ,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione and replacing 03-2 with 6-heptynic acid, 25-1 was synthesized. LC-MS: (ESI) [M+H] ⁺ =384.2.

Step 2: 7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole- 5-yl)heptanoic acid (intermediate 25)

Dissolve 25-1 (600mg, 1.56mmol, 1.0eq.) in THF (10mL), add Raney nickel (previously replaced with THF) (1.0g), replace with hydrogen three times, and the reaction solution is heated at 40°C under normal pressure. After 16 hours of hydrogenation, LCMS detected that the reaction was complete. Filter, and the filtrate is concentrated under reduced pressure to obtain intermediate 25. LC-MS: (ESI) [M+H] ⁺ =388.2.

Synthesis of intermediate 26

Step 1: 4-nitrophenyl 5-((diethoxyphosphate)difluoromethyl)benzo[b]thiophene-2-carboxylate (26-1)

Take the reaction flask, add intermediate 02 (1.0eq), p-nitrophenol and DCC, add DCM, and start the reaction at room temperature. LCMS detected the end of the reaction, and the mixture was directly concentrated under reduced pressure. The crude product was subjected to column chromatography to obtain 26-1LC-MS: (ESI) [M+H] ⁺ =486.1.

Step 2: (Difluoro(2-((4-nitrophenoxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphonic acid (Intermediate 26)

Referring to the synthetic route and method of synthetic step 10 in Example 1, replace 001-9 in synthetic step 10 with 26-1, and synthesize product intermediate 26. LC-MS: (ESI)[M+H] ⁺ =430.0.

Synthesis of 026

Synthesis step 1: (S)-(5-Amino-1-((4-(dimethylphosphoryl)benzyl)amino)-1,5-dioxopentan-2-yl)carbamic acid tert-butyl Ester(026-1)

Referring to the synthetic route and method of synthesis step 3 in Example 1, replace 001-2 in synthesis step 3 with (4-(aminomethyl)phenyl)dimethylphosphine oxide, and synthesize product 026-1. LC-MS:ESI-MS(M+H) ⁺ =312.1.

Synthesis step 2: (5S,8S,10aR)-benzyl 8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino)-1,5-di Oxypentan-2-yl)carbamoyl)-5-((tert-butoxycarbonyl)amino)-6-oxooctahydropyrrolo[1,2-a][1,5]diazozine- 3(4H)-carboxylate (026-2)

Combine 026-1 (1.20g, 2.94mmol, 1.0eq.), intermediate 24 (1.50g, 3.24mmol, 1.1eq.), HATU (1.23g, 3.24mmol, 1.1eq.), DIEA (1.90g, 14.70 mmol, 5.0 eq.), was added to dichloromethane (20 mL). The reaction was stirred at 25 °C for 6 h. LCMS detected the end of the reaction, and the mixture was directly concentrated under reduced pressure. The crude product was subjected to column chromatography (DCM:MeOH=8:1, v/v) to obtain 026-2 as a light yellow solid. LC-MS: ESI-MS (M+H) ⁺ =755.4.

Synthesis step 3: tert-butyl ((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino)-1,5 -Dioxopent-2-yl)carbamoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazolin-5-yl)carboxylate (026-3 )

Dissolve 026-2 (850 mg, 1.13 mmol, 1.0 eq.) in THF (20 mL), add 10% palladium on carbon (0.45 g), replace with hydrogen three times, and hydrogenate the reaction solution at 25°C for 16 hours under normal pressure. LCMS detects the reaction. Finish. Filter, and the filtrate is concentrated under reduced pressure to obtain 026-3. LC-MS: ESI-MS (M+H) ⁺ =621.4.

Synthesis step 4: tert-butyl ((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino)-1,5 -Dioxopent Alk-2-yl)carbamoyl)-3-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-di Hydrogen-1H-benzo[d]imidazol-5-yl)heptanoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazolin-5-yl)carboxylate (026-4)

Combine 026-3 (500mg, 0.81mmol, 1.0eq.), intermediate 25 (380mg, 0.98mmol, 1.2eq.), HATU (373mg, 0.98mmol, 1.2eq.), DIEA (314mg, 2.43mmol, 3.0eq. .), added to DMF (5mL). The reaction was stirred at 25 °C for 16 h. LCMS detected the end of the reaction, the mixture was directly filtered, and the crude product was subjected to preparative HPLC to obtain 026-4. LC-MS: (ESI) [M+H] ⁺ =989.5.

Synthesis step 5: 2S-2-(5S, 8S, 10aR)-5-amino-3-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2 -Oxo-2,3-dihydro-1H-benzimidazol-5-ylheptanoyl)-6-oxodecylhydropyrrolo[1,2-a][1,5]diazozine-8- Carboxamido)-N1-(4-(dimethylphosphoryl)benzyl)glutaramide (026-5)

Referring to the synthetic route and method of synthetic step 8 in Example 1, 001-7 was replaced with 026-4, and 026-5 was synthesized. LC-MS: (ESI)[M+H] ⁺ =890.4

Synthesis step 6: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo -2,3-Dihydro-1H-benzimidazol-5-yl)heptanoyl-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooct-5-yl) Carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (026)

Take the reaction bottle, dissolve 026-5 and intermediate 26 in DCM, then add triethylamine and react at room temperature. After the reaction, extract with DCM and water, dry the organic phase over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Preparative HPLC purification yielded product 026. LC-MS: (ESI)[M+H] ⁺ =1180.4 ¹ H NMR (400MHz, DMSO) δ11.17–10.95(m,1H),9.11–8.56(m,1H),8.48–8.32(m,1H) ),8.29–8.10(m,2H),8.04–7.85(m,2H),7.70–7.50(m,3H),7.31(d,J＝7.8Hz,2H),7.26–7.08(m,3H), 6.99–6.58(m,4H),5.47–5.21(m,1H),4.92–4.69(m,1H),4.44–4.33(m,1H),4.26(s,2H),4.18–4.09(m,2H ),3.91–3.79(m,1H),3.69–3.63(m,1H),3.31–3.22(m,4H),3.01–2.76(m,2H),2.70–2.49(m,4H),2.34–2.22 (m,1H),2.18–2.00(m,3H),1.98–1.81(m,3H),1.80–1.44(m,13H),1.31–1.23(m,3H),1.17–1.13(m,1H) .

Example 27: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2 -Oxo-2,3-dihydro-1H-benzimidazol-5-yl)ethyl)cyclohexane-1-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1 ,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (027)

Synthesis step 1: 4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole Synthesis of -5-yl)ethyl)cyclohexane-1-carboxylic acid (intermediate 27)

Step one: 4-ethynylcyclohexane-1-carboxylic acid (27-1)

Take the reaction bottle, dissolve (4-ethynylcyclohexyl)methanol in acetone, then slowly add Jones reagent (1.2-5.0eq) dropwise, and start the reaction at room temperature after the dropwise addition. After the reaction is completed, isopropyl alcohol is added to quench, and the mixture is extracted with DCM and water. The organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by column chromatography to obtain 27-1. LC-MS: (ESI) [M+H] ⁺ =153.1.

Steps 2 to 3: 4-(2-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole- 5-yl)ethyl)cyclohexane-1-carboxylic acid (Intermediate 27)

Referring to the synthetic route and method of intermediate 25, 6-heptenoic acid was replaced with 27-1, and intermediate 27 was synthesized. LC-MS: (ESI) [M+H] ⁺ =414.2.

Synthesis Step 2: Synthesis of 027

Referring to the synthetic route and method of Example 26, the intermediate 25 in the synthesis step 4 was replaced with the intermediate 27, and the target compound 027 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1206.4.

Example 28: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(2-(4-((1-(2,6-dioxopiperidin-3-yl))-3-methyl- 2-Oxo-2,3-dihydro-1H-benzimidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxodecahydropyrrolo[1,2-a][1, 5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (028)

Synthesis step 1: 2-(4-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo Synthesis of imidazol-5-yl)methyl)cyclohexyl)acetic acid (intermediate 28)

The first step: 2-(4-oxocyclohexylidene)acetate tert-butyl ester (28-1)

In a 25 mL round bottom flask, (4,4-dimethyl-2-oxopentyl)phosphonate diethyl ester (19.86 g, 79.37 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (200 mL). The mixture was cooled to 0°C and sodium hydride (60%) (4.57g, 190.49mmol, 1.5eq.) was added portionwise. The mixture was reacted at 0°C for 1 h. Cyclohexane-1,4-dione (17.80g, 158.74mmol, 2.0eq.) in tetrahydrofuran (200mL) was added, and the reaction was carried out at 25°C for 1 hour. After sampling and testing, the reaction was complete. The reaction solution was poured into 500 mL of saturated ammonium chloride to quench, and extracted with EA (500 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by column chromatography (PE:EA=20:1 to 5:1, v/v) to obtain 28-1. LC-MS: (ESI) [M+H] ⁺ =211.1.

Step 2: 2-(4-oxocyclohexyl)acetate tert-butyl ester (28-2)

28-1 (9.80 g, 46.60 mmol, 1.0 eq.) was dissolved in EA (100 mL). 10% Pd/C (3.00g, 0.3m/m) was added to the mixture. Under hydrogen protection, the mixture was stirred at 25°C for 16 h. The sample was taken for NMR detection and the reaction was completed. The reaction solution was filtered, and the residue was concentrated under reduced pressure to obtain 28-2. LC-MS: (ESI) [M+H] ⁺ =213.1.

Step 3: 2-(4-methylenecyclohexyl)acetate tert-butyl ester (28-3)

In a 500mL three-necked flask, dissolve methyltriphenylphosphine iodide (19.41g, 48.05mmol, 1.5eq.) in THF (200mL), cool the mixture to -78°C, and add n-butyllithium solution (2.5M ) (19.2mL, 48.05mmol, 1.5eq.), the mixture was stirred at -78°C for 1h. 28-2 (6.80g, 32.03mmol, 1.0eq.) tetrahydrofuran solution (75mL) was added dropwise. The reaction solution was heated to 25°C and stirred for 1 h. The sample was taken and tested by TLC, and the reaction was complete. Slowly add 100 mL of saturated ammonium chloride to quench, extract with EA (100 mL × 3), dry the organic phase over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The crude product was separated and purified by column chromatography (PE:EA=20:1 to 10:1, v/v) to obtain 28-3. LC-MS: (ESI) [M+H] ⁺ =211.2.

Step 4: 2-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5 -Methylene)cyclohexyl)tert-butyl acetate (28-4)

In a 100mL round bottom flask, add 3-(5-iodo-3-methyl-2-oxobenzimidazol-1-yl)hexahydropyridine-2,6-dione (1.20g, 3.12mmol, 1.0 eq.), 28-3 (3.28g, 15.58mmol, 5.0eq.), palladium acetate (70mg, 0.31mmol, 0.1eq.), tri-o-tolylphosphine (189mg, 0.62mmol, 0.2eq.), triethyl Amine (950 mg, 9.36 mmol, 3.0 eq.) and DMF (20 mL). The mixture was heated to 100°C under nitrogen protection and stirred for 16 h. The sample was taken and tested by LCMS, and the reaction was complete. Pour the reaction solution into 100 mL of water, extract with EA (100 mL × 3), dry the organic phase over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The crude product was separated and purified by column chromatography (PE:EA=20:1 to 10:1, v/v) to obtain 28-4. LC-MS: (ESI)[M+H] ⁺ =468.2.

Step 5: 2-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5 -Methyl)cyclohexyl)tert-butyl acetate (28-5)

Referring to the synthesis route and method in the second step, replace 28-1 with 28-4 and synthesize 28-5. LC-MS: (ESI) [M+H] ⁺ =470.3.

Step 6: 2-(4-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo Imidazol-5-yl)methyl)cyclohexyl)acetic acid (Intermediate 28)

Referring to the synthetic route and method of the fourth step of Intermediate 03, replace 03-3 with 28-5, and synthesize Intermediate 28. LC-MS: (ESI) [M+H] ⁺ =414.2.

Synthesis Step 2: Synthesis of 028

Refer to the synthetic route and method of Example 26, replace intermediate 25 in synthesis step 4 with intermediate 28, and synthesize The target compound 028 was obtained. LC-MS: (ESI) [M+H] ⁺ =1206.4.

Example 29: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(8-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline- 4-yl)octyl-7-ynyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[ b]Thien-5-yl)difluoromethyl)phosphoric acid (029)

Synthesis step 1: Synthesis of 8-(1-(2,6-dioxopiperidin-3-yl)-2-oxoindolin-7-yl)oct-7-ynic acid (intermediate 29)

Refer to the synthetic route and method of the third step of Intermediate 03. Replace 03-2 with 7-octynic acid and synthesize intermediate 29. LC-MS: (ESI) [M+H] ⁺ =383.2.

Synthesis Step 2: Synthesis of 029

Referring to the synthetic route and method of Example 26, the intermediate 25 in the synthesis step 4 was replaced with the intermediate 29, and the target compound 029 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1175.4.

Example 30: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(8-(6-(2,6-dioxopiperidin-3-yl)-octyl-7-ynyl)- 6-Oxodecahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl) Phosphoric acid (030)

Synthesis step 1: Synthesis of 8-(6-((2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-3-yl)oct-7-ynic acid (intermediate 30)

The first step: 5-bromo-N-(2,6-dioxopiperidin-3-yl)pyridinecarboxamide (30-1)

3-Aminopiperidine-2,6-dione (82mg, 0.64mmol, 1equiv), triethylamine (194mg, 1.92mmol, 3equiv), EDCI (368mg, 1.92mmol, 3equiv) and DMAP (156mg, 1.28mmol , 2 equiv) was mixed in DCM (5 mL). A solution of 5-bromo-2-pyridinecarboxylic acid (193 mg, 0.96 mmol, 1.5 equiv) dissolved in DCM was slowly added dropwise at room temperature. After the dropwise addition is completed, stir at 30°C. After the reaction is completed, the reaction solution is evaporated to dryness, and the crude product is obtained by column chromatography to obtain 30-1. LC-MS: (ESI) [M+H] ⁺ =312.0.

Step 2: 8-(6-((2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-3-yl)oct-7-ynic acid (Intermediate 30)

Refer to the synthesis method of the third step of Intermediate 03. Replace 03-2 with 7-octynic acid; replace 3-(4-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione with 30-1, and synthesize it. Intermediate 30. LC-MS: (ESI) [M+H] ⁺ =372.2.

Synthesis Step 2: Synthesis of 030

Referring to the synthetic route and method of Example 26, the intermediate 25 in the synthesis step 4 was replaced with the intermediate 30, and the target compound 030 was synthesized. LC-MS: (ESI): M+H] ⁺ =1164.4.

Example 31: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)--3-(1-(7-(2-(2,6-dioxopiperidin-3-yl)-1-oxoiso Indolin-4-yl)-7-azaspiro[3.5]nonan-2-yl)piperidin-4-yl)-6-oxodecahydropyrrolo[1,2-a][1, 5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (031)

Synthesis step 1: 1-(7-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-4-yl)-7-azaspiro[3.5]non- Synthesis of 2-yl)piperidin-4-yl 4-methylbenzenesulfonate (intermediate 31)

The first step: 2-(4-hydroxypiperidin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (31-1)

Piperidin-4-ol (1.0 eq) and 2-oxo-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (1.0 eq) were dissolved in DCM (10 V). Then add STAB (1.5eq). Stir at room temperature. LCMS detected the end of the reaction, added NaHCO ₃ solution to quench, extracted with EA and water, and purified by column chromatography to obtain 31-2. LC-MS: (ESI) [M+H] ⁺ =325.2.

Step 2: 1-(7-azaspiro[3.5]nonan-2-yl)piperidin-4-ol (31-2)

Referring to the synthetic route and method of the fourth step of intermediate 03, replace 03-3 with 31-2, and synthesize 31-3. LC-MS: (ESI) [M+H] ⁺ =225.2.

Step 3: 3-(4-(2-(4-hydroxypiperidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-1-oxoisoindoline-2 -yl)piperidine-2,6-dione (31-3)

3-(4-Bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (1.0eq.), 31-2 (1.05eq.), Pd ₂ (dba) ₃ (0.05eq.), Sphos (0.1eq.), Cs ₂ CO ₃ (3.0eq.), toluene and water were added to the reaction flask. The reaction system was replaced with nitrogen three times, and the reaction was stirred at 85°C. Sampling LCMS to detect the end of the reaction, cool the reaction mixture to room temperature, add water, extract three times with ethyl acetate, separate the liquids and combine the organic phases, wash with saturated brine, dry the organic phase over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and synthesize to obtain 31-3. LC-MS: (ESI)[M+H] ⁺ =467.3.

Step 4: 1-(7-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-4-yl)-7-azaspiro[3.5]non- 2-yl)piperidin-4-yl 4-methylbenzenesulfonate (Intermediate 31)

Take the reaction flask, add 31-3 (1.0eq), TSCl (1.1eq), triethylamine (2.2eq), then add DCM to dissolve, and start stirring at room temperature overnight. LCMS detected that the reaction was complete, and the reaction solution was spin-dried and purified by column chromatography to obtain intermediate 31. LC-MS: (ESI): M+H] ⁺ =621.3.

Synthesis Step 2: Synthesis of 031

Referring to the synthetic route and method of Example 26, the intermediate 25 in the synthesis step 4 was replaced with the intermediate 31, and the target compound 031 was synthesized. LC-MS: (ESI): M+H] ⁺ =1259.5.

Example 32: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)--3-(7-(3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoiso Indolin-4-yl)-7-azaspiro[3.5]nonan-2-yl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazacyclooctane -5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (032)

Synthesis step 1: 7-(3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-4-yl)propyl)-7-azaspiro[3.5 Synthesis of nonon-2-yl 4-methylbenzenesulfonate (intermediate 32)

Step 1: 7-(propyl-2-ynyl-1-yl)-7-azaspiro[3.5]nonan-2-ol (32-1)

Add 7-azaspiro[3.5]nonan-2-ol (2.0eq), 3-bromopropyne (1.0eq), and potassium carbonate (2.5eq) to DCM (10 mL) to dissolve, and start stirring at room temperature overnight. LCMS detected that the reaction was complete. Water (10 mL) was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 32-1. LC-MS: (ESI) [M+H] ⁺ =180.1.

Step 2: 3-(4-(3-(2-hydroxy-7-azaspiro[3.5]nonan-7-yl)propyl-1-ynyl-1-yl)-1-oxoiso Indolin-2-yl)piperidine-2,6-dione(32-2)

Refer to the synthetic route and method of the third step of intermediate 03, replace 03-2 with 32-1; replace 3-(4-bromo-1-oxoisoindolin-2-yl)piperidine-2,6 -Dione replaced by 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione, synthesized Got 32-2. LC-MS: (ESI)[M+H] ⁺ =422.2.

Step 3: 3-(4-(3-(2-hydroxy-7-azaspiro[3.5]nonan-7-yl)propyl)-1-oxoisoindolin-2-yl)piper Dipyridine-2,6-dione(32-3)

Referring to the synthetic route and method of the second step of intermediate 25, replace 25-1 with 32-2, and synthesize intermediate 32-3. LC-MS: (ESI)[M+H] ⁺ =426.2.

Step 4: 7-(3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-4-yl)propyl)-7-azaspiro[3.5 ]Non-2-yl 4-methylbenzenesulfonate (Intermediate 32)

Take the reaction flask, add 32-3 (1.0eq), TSCl (1.1eq), triethylamine (2.2eq), then add DCM to dissolve, and start stirring at room temperature overnight. LCMS detected that the reaction was complete, and the reaction solution was spin-dried and purified by column chromatography to obtain intermediate 32. LC-MS: (ESI): M+H] ⁺ =580.2.

Synthesis Step 2: Synthesis of 032

Referring to the synthetic route and method of Example 26, the intermediate 25 in the synthesis step 4 was replaced with the intermediate 32, and the target compound 032 was synthesized. LC-MS: (ESI): M+H] ⁺ =1218.4.

Example 33: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(8-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline- 4-yl)octyl-7-ynyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole Indo-5-yl)difluoromethyl)phosphoric acid (033)

Synthesis step 1: Synthesis of (difluoro(2-((4-nitrophenoxy)carbonyl)-1H-indol-5-yl)methyl)phosphoric acid (intermediate 33)

Refer to the synthetic route and method of intermediate 26. The 5-bromobenzothiophene-2-carboxylic acid in the first step was replaced by 5-bromoindole-2-carboxylic acid, and the intermediate 33 was synthesized. LC-MS: (ESI)[M+H] ⁺ =413.0.

Synthesis Step 2: Synthesis of 033

Referring to the synthetic route and method of Example 26, intermediate 26 in synthesis step 6 was replaced with intermediate 33, and the target compound 033 was synthesized. LC-MS: (ESI): M+H] ⁺ =1158.4.

Example 34: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(8-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylbenzene yl)octyl-7-ynyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b] Thiophen-5-yl)difluoromethyl)phosphoric acid (034)

Synthesis step 1: Synthesis of 8-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenyl)-octan-7-ynic acid (intermediate 34)

The first step: 1-(4-bromo-2-methylphenyl)dihydropyrimidine-2,4(1H,3H(-dione(34-1)

Dissolve 5-bromo-2-fluorotoluene and dihydropyrimidine-2,4(1H,3H)-dione in DMF, then add K ₂ CO ₃ and start the reaction at room temperature. After the reaction is over. Quench with ice water, add EA to extract three times, dry, filter, and concentrate under reduced pressure to obtain 34-1. LC-MS: (ESI) [M+H] ⁺ =283.0.

Step 1: 8-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methoxyphenyl)-octan-7-ynic acid (Intermediate 34)

Refer to the synthetic route and method of the third step of Intermediate 3. Replace 03-2 with 7-octynic acid; replace 3-(4-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione with 34-1, and synthesize the intermediate Body 34. LC-MS: (ESI) [M+H] ⁺ =343.2.

Synthesis Step 2: Synthesis of 034

Referring to the synthetic route and method of Example 26, the intermediate 25 in the synthesis step 4 was replaced with the intermediate 34, and the target compound 034 was synthesized. LC-MS: (ESI): M+H] ⁺ =1135.4.

Example 35: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(8-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)octyl- 7-Alkynyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl )Difluoromethyl)phosphoric acid (035)

Synthesis step 1: Synthesis of 8-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenyl)-octan-7-ynic acid (intermediate 35)

Refer to the synthetic route and method of the third step of Intermediate 03. Replace 03-2 with 7-octynoic acid and replace 3-(4-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione with 1-(4-bromobenzene base)dihydropyrimidine-2,4(1H,3H)-dione, and the intermediate 35 was synthesized. LC-MS: (ESI) [M+H] ⁺ =329.2.

Synthesis Step 2: Synthesis of 035

Referring to the synthetic route and method of Example 26, the intermediate 25 in the synthesis step 4 was replaced by the intermediate 35, and the target compound 035 was synthesized. LC-MS: (ESI): M+H] ⁺ =1121.4.

Example 36: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((S)-3-(4-(dimethylphosphoryl))benzene base)-1-(4-(4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)but-3-yn-1-yl)piperazine-1 -yl)-1-oxopropan-2-yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2,2-difluoroethyl)-6- Oxodecahydropyrrolo[1,2-a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid ( 036)

Synthesis step 1: Synthesis of 8-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenyl)-octan-7-ynic acid (intermediate 36)

Referring to the synthetic route and method of steps 3-4 of Intermediate 03, replace 03-2 in the third step with 4-(but-3-yn-1-yl)piperazine-1-carboxylic acid tert-butyl ester and Replacement of 3-(4-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione with 1-(4-bromophenyl)dihydropyrimidine-2,4(1H ,3H)-diketone, was synthesized to obtain intermediate 36. LC-MS: (ESI) [M+H] ⁺ =327.2.

Synthesis Step 2: Synthesis of 036

Referring to the synthetic route and method of Example 1, intermediate 03 in synthesis step 7 was replaced with intermediate 36, and the target compound 036 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1241.4.

Example 37: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((S)-3-(4-(dimethylphosphoryl))benzene base)-1-(4-(4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)but-3-yn-1-yl)piperidine-1 -yl)-1-oxopropan-2-yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2,2-difluoroethyl)-6- Oxodecahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophene-5-carbonyl)phosphoric acid (037)

Synthesis step 1: Synthesis of 8-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenyl)-octan-7-ynic acid (intermediate 37)

Referring to the synthetic route and method of steps 3-4 of Intermediate 03, 3-(4-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione in the third step Replaced with 1-(4-bromophenyl)dihydropyrimidine-2,4(1H,3H)-dione, the intermediate 37 was synthesized. LC-MS: (ESI) [M+H] ⁺ =326.2.

Synthesis Step 2: Synthesis of 037

Referring to the synthetic route and method of Example 1, the intermediate 03 in the synthesis step 7 was replaced with the intermediate 37; the intermediate 02 in the synthesis step 9 was replaced with the intermediate 18, and the target compound 037 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1218.4.

Example 38: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((S)-3-(4-(dimethylphosphoryl))benzene base)-1-(4-(4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3methylphenyl)but-3-yn-1-yl) Piperidin-1-yl)-1-oxopropan-2-yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2,2-difluoroethyl) )-6-Oxodecahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophene-5-carbonyl)phosphoric acid (038 )

Referring to the synthetic route and method of steps 3-4 of Intermediate 03, 3-(4-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione in the third step Replaced with 34-1, the intermediate 38 was synthesized. LC-MS: (ESI) [M+H] ⁺ =340.2.

Synthesis Step 2: Synthesis of 038

Referring to the synthetic route and method of Example 1, the intermediate 03 in the synthesis step 7 was replaced with the intermediate 38; the intermediate 02 in the synthesis step 9 was replaced with the intermediate 18, and the target compound 038 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1232.4.

Example 39: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(8-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl )octyl-7-ynyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophene -5-yl)difluoromethyl)phosphoric acid (039)

Synthesis step 1: Synthesis of 8-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)-octan-7-ynic acid (intermediate 39)

Referring to the synthetic route and method of intermediate 34, 5-bromo-2-fluorotoluene in the first step was replaced with 4-bromo-1,2-difluorophenyl, and intermediate 39 was synthesized. LC-MS: (ESI) [M+H] ⁺ =347.1.

Synthesis Step 2: Synthesis of 039

Referring to the synthetic route and method of Example 26, the intermediate 25 in the synthesis step 4 was replaced with the intermediate 39, and the target compound 039 was synthesized. LC-MS: (ESI): M+H] ⁺ =1139.3.

Example 40: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(8-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methoxy Phenyl)octyl-7-ynyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b ]Thien-5-yl)difluoromethyl)phosphoric acid (040)

Synthetic step 1: 8-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methoxyphenyl)-octan-7-ynic acid (intermediate 40) synthesis

Referring to the synthetic route and method of intermediate 34, 5-bromo-2-fluorotoluene in the first step was replaced with 2-fluoro-5-bromoanisole, and intermediate 40 was synthesized. LC-MS: (ESI) [M+H] ⁺ =359.2.

Synthesis Step 2: Synthesis of 040

Referring to the synthetic route and method of Example 26, the intermediate 25 in the synthesis step 4 was replaced with the intermediate 40, and the target compound 040 was synthesized. LC-MS: (ESI): M+H] ⁺ =1151.4.

Example 41: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(8-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxy Phenyl)octyl-7-ynyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b ]Thien-5-yl)difluoromethyl)phosphoric acid (041)

Synthetic step 1: 8-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxyphenyl)-octan-7-ynic acid (intermediate 41) synthesis

Refer to the synthetic route and method of intermediate 34. The 5-bromo-2-fluorotoluene in the first step was replaced by 4-bromo-2-fluoroanisole, and intermediate 41 was synthesized. LC-MS: (ESI) [M+H] ⁺ =359.2.

Synthesis Step 2: Synthesis of 041

Referring to the synthetic route and method of Example 26, the intermediate 25 in the synthesis step 4 was replaced with the intermediate 41, and the target compound 041 was synthesized. LC-MS: (ESI): M+H] ⁺ =1151.4.

Example 42: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(8-(4-(2,6-dioxopiperidin-3-yl)carbamoyl)-3-fluorophenyl )octyl-7-ynyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophene -5-yl)difluoromethyl)phosphoric acid (042)

Synthesis step 1: Synthesis of 8-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)-3-fluorophenyl)oct-7-ynic acid (intermediate 42)

Refer to the synthetic route and method of intermediate 30. The 5-bromo-2-pyridinecarboxylic acid in the first step was replaced with 4-bromo-2-fluorobenzoic acid, and intermediate 42 was synthesized. LC-MS: (ESI) [M+H] ⁺ =389.1.

Synthesis Step 2: Synthesis of 042

Referring to the synthetic route and method of Example 26, the intermediate 25 in the synthesis step 4 was replaced with the intermediate 42, and the target compound 042 was synthesized. LC-MS: (ESI): M+H] ⁺ =1181.4.

Example 47: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl))-2-fluorobenzyl)) Amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl- 2-Oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)heptanoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]di Azepan-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (047)

Synthesis step 1: Synthesis of 4-aminomethyl-3-fluorophenyldimethylphosphine oxide (047-3)

The first step: (4-bromo-2-fluorobenzyl)carbamic acid tert-butyl ester (047-1)

Dissolve 4-bromo-3-fluorobenzylamine in DMF, add Et ₃ N dropwise at room temperature, and add Boc ₂ O to the resulting brown solution. After stirring for 10 minutes, the mixture was heated at 40-50°C overnight. The reaction mixture was poured into water and extracted with EA. The aqueous phase was acidified with aqueous HCl solution to pH 4-5, then extracted with DCM, dried and concentrated. The crude product was purified by column chromatography to obtain 047-1. LC-MS: (ESI) [M+H] ⁺ =304.0.

Step 2: (4-(Dimethylphosphoryl)-2-fluorobenzyl)carbamic acid tert-butyl ester (047-2)

Referring to the synthetic route and method of synthetic step 1 in Example 1, Boc-4-bromo-L-phenylalanine methyl ester in synthetic step 1 was replaced with 047-1, and 047-2 was synthesized. LC-MS: (ESI)[M+H] ⁺ =302.1.

Step 3: 4-aminomethyl-3-fluorophenyldimethylphosphine oxide (047-3)

Referring to the synthesis route and method of synthesis step 2 in Example 1, replace 001-1 in synthesis step 2 with 047-2, and synthesize 047-3. LC-MS: (ESI) [M+H] ⁺ =202.1.

Synthesis Step 2: Synthesis of 047

Referring to the synthetic route and method of Example 26, (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthesis step 1 was replaced with 047-3, and the target compound 047 was synthesized. LC-MS: (ESI)[M+H]+=1198.4.

Example 48: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(dimethylphosphoryl))pyridin-3-ylmethyl )Amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl -2-Oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)heptanoyl)-6-oxodecahydropyrrolo[1,2-a][1,5] Diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoro Methyl)phosphate(048)

Synthesis step 1: Synthesis of (5-(aminomethyl)pyridin-2-yl)dimethylphosphine oxide (048-2)

Referring to the synthetic route and method of synthetic steps 1 to 2 in Example 1, replace Boc-4-bromo-L-phenylalanine methyl ester in synthetic step 1 with 5-(N-BOC-aminomethyl)- 2-Bromopyridine was synthesized to obtain 048-2. LC-MS: (ESI) [M+H] ⁺ =185.1.

Synthesis Step 2: Synthesis of 048

Referring to the synthetic route and method of Example 26, (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthesis step 1 was replaced with 048-2, and the target compound 048 was synthesized. LC-MS: (ESI)[M+H]+=1181.4.

Example 49: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((3-(difluoromethoxy))-4-(dimethyl Phosphoryl)benzyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(7-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)heptanoyl)-6-oxodecahydropyrrolo[1,2-a] [1,5]Diazepine-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (049)

Synthesis step 1: Synthesis of 4-(aminomethyl)-2-(difluoromethoxy)phenyl)dimethylphosphine oxide (049-4)

Step one: 4-bromo-3-(difluoromethoxy)benzaldehyde (049-1)

Take the reaction bottle, dissolve 4-bromo-3-hydroxybenzaldehyde and difluoromethyl triflate in DCM, then add KCO ₃ and react at room temperature. After the reaction, extract with DCM three times, dry and concentrate. The crude product was purified by column chromatography to obtain 049- 1. LC-MS: (ESI)[M+H] ⁺ =251.0.

Step 2: N-benzyl-1-(4-bromo-3-difluoromethoxy)phenylmethylamine (049-2)

049-1 (1.0 eq) and benzylamine (1.0 eq) were dissolved in DCM (10 V). Then add STAB (1.5eq). Stir at 50°C. LCMS detected the end of the reaction, added NaHCO ₃ solution to quench, extracted with EA and water, and purified by column chromatography to obtain 049-2. LC-MS: (ESI) [M+H] ⁺ =342.1.

Step 3: 4-Bromo-3-(difluoromethoxy)phenyl)methanamine (049-3)

Take a 250mL single-neck bottle, dissolve 049-2 (1equiv) in methanol, add palladium carbon, and degas with hydrogen three times. Stir at room temperature overnight. Filter, spin the filtrate to dryness, and obtain 049-3 by column chromatography. LC-MS (ESI) [M+H] ⁺ =252.0.

Step 4: 4-(aminomethyl)-2-(difluoromethoxy)phenyl)dimethylphosphine oxide (049-4)

Referring to the synthetic route and method of synthetic step 1 in Example 1, Boc-4-bromo-L-phenylalanine methyl ester in synthetic step 1 was replaced with 049-3, and 049-4 was synthesized. LC-MS: (ESI)[M+H] ⁺ =250.1.

Synthesis Step 2: Synthesis of 049

Referring to the synthetic route and method of Example 26, (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthesis step 1 was replaced with 049-4, and the target compound 049 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1246.4. ¹ H NMR (400MHz, DMSO) δ11.09(s,1H),9.15–8.65(m,1H),8.62–8.51(m,1H),8.37–8.26(m,1H),8.24(s,1H) ,8.09–8.02(m,1H),7.98(d,J＝8.4Hz,1H),7.81–7.72(m,1H),7.62(d,J＝8.4Hz,1H),7.55–7.34(m,1H ),7.32–7.12(m,5H),7.05–6.94(m,2H),6.89–6.68(m,2H),5.41–5.27(m,1H),4.98–4.76(m,1H),4.49–4.40 (m,1H),4.38–4.29(m,2H),4.28–4.16(m,2H),4.01–3.87(m,1H),3.72(s,1H),3.34–3.29(m,4H),2.95 –2.85(m,1H),2.75–2.66(m,1H),2.65–2.57(m,3H),2.55–2.52(m,1H),2.44–2.32(m,1H),2.23–2.07(m, 3H),2.06–1.75(m,6H),1.74–1.69(m,1H),1.68(s,3H),1.64(s,3H),1.62–1.48(m,4H),1.44–1.20(m, 4H).

Example 50: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-amino-3-(dimethylphosphoryl)benzyl)) Amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl- 2-Oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)heptanoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]di Azepan-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (050)

Synthesis step 1 Synthesis of (2-amino-5-aminomethylphenyl)dimethylphosphine oxide (050-4)

The first step: 4-aminomethyl-2-bromoaniline (050-1)

Under an argon atmosphere, add 4-amino-3-bromoxynil to the reaction bottle, add anhydrous THF and stir, then add a solution of _BH3 dissolved in THF at room temperature. The mixture was refluxed for 4.5 h and then cooled to room temperature.

Add HCl aqueous solution (6N) and continue stirring for 1 h. Add NaOH to adjust the pH to 9, extract with DCM (3×10 mL), dry and concentrate. The crude product was purified by column chromatography to obtain 050-1. LC-MS: (ESI)[M+H]+=201.0.

Steps 2 to 4: (2-amino-5-aminomethylphenyl)dimethylphosphine oxide (050-4)

Referring to the experimental route and method for the synthesis of 047-3 in Example 47, 4-bromo-3-fluorobenzylamine was replaced with 050-1, and 050-4 was synthesized. LC-MS: (ESI)[M+H]+=199.1.

Synthesis Step 2: Synthesis of 050

Referring to the synthetic route and method of Example 26, (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthesis step 1 was replaced with 050-4, and the target compound 050 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1195.4. ¹ H NMR (400MHz, DMSO) δ11.08 (s, 1H), 9.09–8.58 (m, 1H), 8.53–8.10 (m, 3H), 8.10–7.97 (m, 2H), 7.62 (d, J＝ 8.5Hz,1H),7.38–7.17(m,3H),7.16–6.89(m,5H),6.88–6.81(m,1H),6.79–6.66(m,1H),6.63–6.49(m,1H) ,5.38–5.28(m,1H),5.04–4.89(m,1H),4.86–4.55(m,1H),4.47–4.34(m,1H),4.34–4.03(m,4H),3.92–3.74( m,2H),3.32–3.30(m,3H),3.01–2.82(m,2H),2.82–2.69(m,1H),2.69–2.65(m,1H),2.64–2.56(m,3H), 2.43–2.31(m,2H),2.12(ddd,J＝14.1,12.7,8.8Hz,3H),2.04–1.97(m,2H),1.94–1.67(m,5H),1.66–1.51(m,9H ),1.39–1.24(m,4H).

Example 51: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-(4-(dimethylphosphoryl))-3-(trifluoromethyl )benzyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(7-(1-(2,6-dioxopiperidin-3-yl)-3 -Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)heptanoyl)-6-oxodecahydropyrrolo[1,2-a][1 ,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (051)

Synthesis step 1: Synthesis of (4-(aminomethyl)-2-(trifluoromethyl)phenyl)dimethylphosphine oxide (051-4)

Referring to the experimental route and method for the synthesis of 050-4 in Example 50, 4-amino-3-bromobenzonitrile was replaced with 3-trifluoromethyl-4-bromobenzonitrile, and 051-4 was synthesized. LC-MS: (ESI)[M+H]+=252.1.

Synthesis Step 2: Synthesis of 051

Referring to the synthetic route and method of Example 26, (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthesis step 1 was replaced with 051-4, and the target compound 051 was synthesized. LC-MS: (ESI)[M+H]+=1248.4.

Example 52: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-(4-(dimethylphosphoryl))-3-(methoxybenzyl) yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl Base-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)heptanoyl)-6-oxodecahydropyrrolo[1,2-a][1,5 ]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (052)

Synthesis step 1: (Synthesis of 4-(aminomethyl)-2-(methoxyphenyl)dimethylphosphine oxide (052-4)

Referring to the experimental route and method for the synthesis of 050-4 in Example 50, 4-amino-3-bromobenzonitrile was replaced with 4-bromo-3-methoxybenzonitrile, and 052-4 was synthesized. LC-MS: (ESI)[M+H]+=214.1.

Synthesis Step 2: Synthesis of 052

Referring to the synthetic route and method of Example 26, (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthesis step 1 was replaced with 052-4, and the target compound 052 was synthesized. LC-MS: (ESI)[M+H]+=1210.4.

Example 53: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-(4-(dimethylphosphoryl))-3-(trifluoromethoxy yl)benzyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(7-(1-(2,6-dioxopiperidin-3-yl)- 3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)heptanoyl)-6-oxodecahydropyrrolo[1,2-a][ 1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (053)

Synthesis step 1: Synthesis of (4-(aminomethyl)-2-(trifluoromethoxy)phenyl)dimethylphosphine oxide (053-4)

Referring to the experimental route and method for the synthesis of 050-4 in Example 50, 4-amino-3-bromobenzonitrile was replaced with 4-bromo-3-trifluoromethoxybenzonitrile, and 053-4 was synthesized. LC-MS: (ESI)[M+H]+=268.1.

Synthesis Step 2: Synthesis of 053

Referring to the synthetic route and method of Example 26, (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthesis step 1 was replaced with 053-4, and the target compound 053 was synthesized. LC-MS: (ESI)[M+H]+=1264.4.

Example 54: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-(4-(dimethylphosphoryl))-3-(difluoromethoxy yl)benzyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(7-(1-(2,6-dioxopiperidin-3-yl)- 3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)heptanoyl)-6-oxodecahydropyrrolo[1,2-a][ 1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (054)

Synthesis of Intermediate 43

Steps 1 to 2: (5-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole) -5-yl)pentyl)carbamic acid tert-butyl ester (43-2)

Referring to the synthetic route and method of intermediate 25, 6-heptenoic acid was replaced with pent-4-yn-1-ylcarbamate tert-butyl ester, and 43-2 was synthesized. LC-MS: (ESI)[M+H]+=445.2.

Step 3: 3-(5-Aminopentyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-ylpiperidine-2,6-dione ( Intermediate 43)

Referring to the synthetic route and method of the fourth step of Intermediate 03, replace 03-3 with 43-2, and synthesize Intermediate 43. LC-MS: (ESI)[M+H]+=345.2.

Synthesis of 054

Synthesis step 1-3: tert-butyl ((5S,8S,10aR)-8-((S)-5-amino-1-(3-(difluoromethoxy)-4-(dimethylphosphoryl) )benzyl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-6-oxodecanylpyrrolo[1,2-a][1,5]diazacycle Oct-5-yl)carbamate (054-3)

Referring to the synthetic route and method of synthetic steps 1-3 in Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 with 049-4, and synthesize the target compound 054-3. . LC-MS: (ESI)[M+H]+=687.3.

Synthesis step 4: tert-butyl ((5S,8S,10aR)-8-((S)-5-amino-1-(3-(difluoromethoxy)-4-(dimethylphosphoryl)benzyl) yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)3-(5-(1-(2,6-dioxopiperidin-3-yl)-3-methyl Base-2-oxoindolin-5-yl)pentyl)carbamoyl)-6-oxodecylhydropyrrolo[1,2-a][1,5]diazepine-5- base) carbamate (054-4)

Take a single-neck bottle, add intermediates 43 (1 equiv.) and 054-3 (1 equiv.), add methylene chloride (60 mL), TEA (3 equiv.), and slowly add triphosgene (0.33 equiv.) under ice bath. The mixture was ventilated three times and then stirred at room temperature for 4 h. Water was added to the reaction solution, and extracted three times with ethyl acetate (60mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated by distillation under reduced pressure. The residue was purified with a Flash column (DCM:MeOH=10:1, v /v) Purify to obtain 054-4. LC-MS: (ESI)[M+H] ⁺ 1056.5.

Synthesis step 5-6: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-(4-(dimethylphosphoryl))-3-(difluoro Methoxy)benzyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(7-(1-(2,6-dioxopiperidin-3-yl) )-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)heptanoyl)-6-oxodecahydropyrrolo[1,2-a ][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (054)

Referring to the synthetic route and method of synthetic step 5-6 in Example 26, replace 026-4 in synthetic step 5 with 054-4, and synthesize the target compound 054. LC-MS: (ESI) [M+H] ⁺ =1247.4.

Example 55: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-(S)-1-(4-(dimethylphosphoryl))benzyl )Amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(5-(1-(2,6-dioxopiperidin-3-yl)-3-methyl -2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)pentyl)carbamoyl)-6-oxodecahydropyrrolo[1,2-a][ 1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (055)

Referring to the synthetic route and method of Example 54, 049-4 in the synthesis step 1 was replaced with (4-(aminomethyl)phenyl)dimethylphosphine oxide, and the target compound 055 was synthesized. LC-MS: (ESI)[M+H]+=1181.4.

Example 56: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-(4-(dimethylphosphoryl))-2-(trifluoromethyl )benzyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(7-(1-(2,6-dioxopiperidin-3-yl)-3 -Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)heptanoyl)-6-oxodecahydropyrrolo[1,2-a][1 ,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (056)

Synthesis step 1: Synthesis of (4-(aminomethyl)-3-(trifluoromethyl)phenyl)dimethylphosphine oxide (056-4)

Referring to the experimental route and method for the synthesis of 050-4 in Example 50, 4-amino-3-bromobenzonitrile was replaced with 2-trifluoromethyl-4-bromobenzonitrile, and 056-4 was synthesized. LC-MS: (ESI)[M+H]+=252.1.

Synthesis Step 2: Synthesis of 056

Referring to the synthetic route and method of Example 26, (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthesis step 1 was replaced with 056-4, and the target compound 056 was synthesized. LC-MS: (ESI)[M+H]+=1248.4. ¹ H NMR (400MHz, DMSO) δ11.09(s,1H),9.10–8.64(m,1H),8.63–8.52(m,1H),8.41–8.30(m,1H),8.25(s,1H) ,8.12–7.92(m,4H),7.63(t,J＝9.6Hz,2H),7.31–7.21(m,2H),7.05–6.93(m,2H),6.89–6.68(m,2H),5.40 –5.26(m,1H),5.00–4.74(m,1H),4.58–4.39(m,3H),4.32–4.14(m,2H),3.96–3.68(m,3H),3.32(s,2H) ,3.30(s,3H),2.96–2.84(m,1H),2.75–2.57(m,4H),2.46–2.31(m,2H),2.15(dt,J＝13.5,6.6Hz,3H),2.05 –1.73(m,7H),1.71–1.65(m,7H),1.57(s,4H),1.35(s,4H).

Example 57: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-(4-(dimethylphosphoryl)benzyl)amino)-1, 5-dioxopent-2-yl)carbamoyl)-3-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo- 2,3-Dihydro-1H-benzo[d]imidazol-5-yl)heptanoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazepine- 5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (057)

Synthesis step 1 Synthesis of: (2-(4-nitrophenoxy)carbonyl)-1H-indole-5-carbonyl)phosphonic acid (intermediate 44)

Referring to the synthetic route and method of Intermediate 26, Intermediate 02 in the first step was replaced with Intermediate 19, and Intermediate 44 was synthesized. LC-MS: (ESI) [M+H] ⁺ =391.0.

Synthesis Step 2: Synthesis of 057

Referring to the synthetic route and method of Example 26, intermediate 26 in synthesis step 6 was replaced with intermediate 44, and target compound 057 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1141.4.

Example 58: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-(-3-(difluoromethoxy)-4-(dimethyl) Phosphoryl)benzyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(7-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)heptanoyl)-6-oxodecahydropyrrolo[1,2-a] [1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (058)

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 with 049-4; replace intermediate 26 in synthetic step 6 with intermediate 44 was synthesized to obtain the target compound 058. LC-MS: (ESI) [M+H] ⁺ =1207.4. ¹ H NMR (400MHz, DMSO) δ12.15–11.78(m,1H),11.07(s,1H),8.98–8.73(m,1H),8.65–8.23(m,2H),7.97(d,J＝ 8.8Hz,1H),7.78(dd,J＝12.0,7.6Hz,1H),7.54–7.13(m,6H),7.06–6.93(m,2H),6.90–6.62(m,2H),5.33(dd ,J＝12.4,5.2Hz,1H),5.05–4.82(m,1H),4.46(t,J＝8.4Hz,1H),4.39–4.29(m,2H),4.27–4.15(m,2H), 3.99–3.88(m,1H),3.80–3.73(m,1H),3.33–3.27(m,4H),3.08–2.84(m,2H),2.75–2.54(m,5H),2.43–2.31(m ,1H),2.25–2.07(m,3H),2.06–1.74(m,6H),1.68(s,3H),1.64(s,3H),1.62–1.47(m,4H),1.41–1.17(m ,7H).

Example 59: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-(-3-(trifluoromethoxy))-4-(dimethyl Phosphoryl)benzyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(7-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-2-oxo-2,3-dihydro-1H-benzo Imidazol-5-yl)heptanoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole- 5-carbonyl)phosphate(059)

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 with 053-4; replace intermediate 26 in synthetic step 6 with intermediate 44 was synthesized to obtain the target compound 059. LC-MS: (ESI) [M+H] ⁺ =1225.4.

Example 60: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-(-3-(difluoromethoxy)-4-(dimethyl) Phosphoryl)benzyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(7-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)pentyl)carbamoyl)-6-oxodecahydropyrrolo[1, 2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (060)

Referring to the synthetic route and method of Example 54, intermediate 26 in synthesis step 6 was replaced with intermediate 44, and target compound 060 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1208.4.

Example 61: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-(-4-(dimethylphosphoryl)benzyl)amino)-1 ,5-dioxopent-2-yl)carbamoyl)-3-(5-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo -2,3-dihydro-1H-benzo[d]imidazol-5-yl)pentyl)carbamoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]di Azepan-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (061)

Referring to the synthetic route and method of Example 54, replace 049-4 in synthetic step 1 with (4-(aminomethyl)phenyl)dimethylphosphine oxide; replace intermediate 26 in synthetic step 6 with intermediate 44, the target compound 061 was synthesized. LC-

MS: (ESI)[M+H] ⁺ =1142.4.

Example 63: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(4-(2-(2-(2,6-dioxopiperidin-3-yl)-3-methyl-2 -Oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)piperidine-1-carbonyl)-6-oxodecahydropyrrolo[1,2-a] [1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (063)

Synthesis of Intermediate 45

Steps 1 to 2: 4-(2-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d ]imidazol-5-yl)ethyl)piperidine-1-carboxylic acid tert-butyl ester (45-2)

Referring to the synthetic route and method of intermediate 25, 6-heptenoic acid was replaced with 1-Boc-4-ethynylpiperidine, and 45-2 was synthesized. LC-MS: (ESI) [M+H] ⁺ =471.3.

Step 3: 4-(2-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5- Ethyl)piperidine-1-carboxylic acid (Intermediate 45)

Referring to the synthetic route and method of the fourth step of Intermediate 03, replace 03-3 with 45-2, and synthesize Intermediate 45. LC-MS: (ESI) [M+H] ⁺ =371.2.

Synthesis of 063

Synthesis step 1: ((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino)-1,5-dioxo Pentyl-2-yl)carbamoyl)-3-(4-(2-(2-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2 ,3-Dihydro-1H-benzo[d]imidazol-5-yl)ethyl)piperidine-1-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5] Diazacyclin-5-yl)carbamate (063-1)

Take a single-neck bottle, add intermediates 45 (1 equiv.) and 026-3 (1 equiv.), add methylene chloride (60 mL), TEA (3 equiv.), and slowly add triphosgene (0.33 equiv.) under ice bath. The mixture was ventilated three times and then stirred at room temperature for 4 h. Water was added to the reaction solution, and extracted three times with ethyl acetate (60mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated by distillation under reduced pressure. The residue was purified with a Flash column (DCM:MeOH=10:1, v /v) Purify to obtain 063-1. LC-MS: (ESI)[M+H] ⁺ 1017.5.

Synthesis step 2-3: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino)) -1,5-dioxopent-2-yl)carbamoyl)-3-(4-(2-(2-(2,6-dioxopiperidin-3-yl))-3-methyl -2-Oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)piperidine-1-carbonyl)-6-oxodecahydropyrrolo[1,2- a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (063)

Referring to the synthetic route and method of synthetic step 5-6 in Example 26, replace 026-4 in synthetic step 5 with 063-1, and synthesize the target compound 063. LC-MS: (ESI) [M+H] ⁺ =1207.4. ¹ H NMR (400MHz, DMSO) δ8.98 (s, 1H), 8.46 (t, J = 6.1Hz, 1H), 8.27 (d, J = 7.8Hz, 1H), 8.19 (s, 1H), 8.02 ( s,1H),7.90(d,J＝8.5Hz,1H),7.68(dd,J＝11.3,7.9Hz,2H),7.61(d,J＝8.7Hz,1H),7.38(dd,J＝8.2 ,2.4Hz,2H),7.25(s,1H),7.04–6.95(m,2H),6.88–6.80(m,1H),6.74(s,1H),5.33(dd,J＝12.7,5.4Hz, 1H),5.07(s,1H),4.42(t,J＝8.4Hz,1H),4.33(d,J＝5.5Hz,2H),4.21(q,J＝7.4Hz,2H),3.65(ddd, J＝53.7,36.7,12.9Hz,6H),3.30(s,5H),3.00–2.84(m,1H),2.80–2.55(m,5H),2.26–1.88(m,6H),1.86–1.65( m,6H),1.61(d,J＝13.3Hz,7H),1.41(d,J＝14.2Hz,1H),1.31–0.99(m,3H).

Example 64: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(2-(4-(2-(1-(2,6-dioxopiperidin-3-yl))-3-methyl Base-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)piperidin-1-yl)acetyl)-6-oxodecahydropyrrolo[ 1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophene-5-carbonyl)phosphoric acid (064)

Synthesis step 1: 2-(4-ethynylpiperidin-1-yl)acetate tert-butyl ester (064-1)

Take the reaction bottle, add 4-ethyne piperidine (1 equiv.) and 2-bromoacetate tert-butyl ester (1.5 equiv.), add DMF (10V), and slowly add DIPEA (2 equiv.) under ice bath. Stir at room temperature for 4h. After the reaction is completed, extract three times with ethyl acetate, combine the organic phases, and dry with anhydrous sodium sulfate. The organic phase is concentrated by distillation under reduced pressure, and the residue is purified by column chromatography to obtain 064-1. LC-MS: (ESI) [M+H] ⁺ =224.2.

Synthesis step 2-3: 2-(4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro- 1H-Benzimidazole-5-yl)ethyl)piperidin-1-yl)acetate tert-butyl ester (064-3)

Referring to the synthetic route and method of intermediate 25, 6-heptinoic acid was replaced with 064-1, and 064-3 was synthesized. LC-MS: (ESI)[M+H] ⁺ =485.3.

Synthesis step 4: 2-(4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- Benzimidazol-5-yl)ethyl)piperidin-1-yl)acetic acid (064-4)

Take the reaction flask, add 064-3, and dissolve it with MeTHF. Then add a MeTHF solution of potassium tert-butoxide, add water, and react at 50°C. After the reaction, spin off the MeTHF, extract with EA and water, dry, filter, and concentrate under reduced pressure to obtain 064-4. LC-MS: (ESI) [M+H] ⁺ =429.2.

Synthesis step 5-7: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino)) -1,5-dioxopent-2-yl)carbamoyl)-3-(2-(4-(2-(1-(2,6-dioxopiperidin-3-yl))-3 -Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)piperidin-1-yl)acetyl)-6-oxodecahydropyrrole And[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophene-5-carbonyl)phosphoric acid (064)

Referring to the synthetic route and method of synthetic steps 4 to 6 in Example 26, replace intermediate 25 in synthetic step 4 with 064-4, replace intermediate 26 in synthetic step 6 with intermediate 44, and synthesize the target compound. 064. LC-MS: (ESI)[M+H] ⁺ =1182.5

Example 65: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl))-2-(trifluoromethyl yl)benzyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(4-(2-(1-(2,6-dioxopiperidine-3- (yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)piperidine-1-carbonyl)-6-oxodecahydro Pyrro[1,2-a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (065)

Synthesis step 1: (S)-2-(5S,8S,10aR)-5-amino-6-oxodecylhydropyrrolo[1,2-a][1,5]diazoheterazine-8-methyl Amide)-N1-(4-(dimethylphosphoryl)-2-trifluoromethyl)benzyl)glutaramide (065-3)

Referring to the synthetic route and method of synthetic steps 1 to 3 in Example 26, (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 was replaced with 056-4, and 065-3 was synthesized. LC-MS: (ESI) [M+H] ⁺ =589.2.

Synthesis Step 2: Synthesis of 065

Referring to the synthetic route and method of Example 63, replacing 026-3 in synthesis step 1 with 065-3, the target compound 065 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1275.4.

Example 66: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl))-3-(difluoromethyl) Oxy)benzyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2-(4-(1-(2,6-dioxopiperidine-3) -yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxodecahydro Pyrrolo[1,2-a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (066)

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 with 049-4; replace Intermediate 25 was replaced with intermediate 28, and the target compound 066 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1272.4.

Example 67: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl))-3-(difluoromethyl) Oxy)benzyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2-(4-(1-(2,6-dioxopiperidine-3) -yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxodecahydro Pyrrolo[1,2-a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (067)

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 with 049-4; replace Intermediate 25 was replaced with intermediate 27, and the target compound 066 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1272.4.

Example 68: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl))-3-(difluoromethyl) Oxy)benzyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-((4-((1-(2,6-dioxopiperidine-3- (yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)carbamoyl)-6-oxodecahydro Pyrrolo[1,2-a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (068)

Synthesis step 1: 3-(5-(4-aminocyclohexyl)methyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl) Piperidine-2,6-dione (Intermediate 46)

Steps 1 to 3: tert-butyl (4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzene And[d]imidazol-5-yl)methyl)cyclohexyl)carbamate (46-3)

Referring to the synthetic route and method of the third to fifth steps of intermediate 28, 28-2 in the third step was replaced with 4-N-Boc-aminocyclohexanone, and 46-3 was synthesized. LC-MS: (ESI) [M+H] ⁺ =471.3.

Step 4: 3-(5-(4-aminocyclohexyl)methyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl) Piperidine-2,6-dione (Intermediate 46)

Take a single-neck bottle, add 46-3 (1 equiv.), add DCM (10 mL), and slowly add trifluoroacetic acid (3 equiv.) under ice bath. The mixture was ventilated three times and then stirred at room temperature for 1 h. The reaction solution was cooled to room temperature, then water was added, and extracted three times with EA (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated by distillation under reduced pressure. The residue was slurried with a mixture of EA and PE (20 mL). That is, intermediate 46 is obtained. LC-MS: (ESI) [M+H] ⁺ =371.2.

Synthesis Step 2: Synthesis of 068

Referring to the synthetic route and method of Example 54, intermediate 43 in synthesis step 4 was replaced with intermediate 46, and target compound 068 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1273.4.

Example 69: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-((4-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2- Oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)carbamoyl)-6-oxodecahydropyrrolo[1,2-a][ 1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (069)

Referring to the synthetic route and method of Example 54, replace 049-4 in synthetic step 1 with (4-(aminomethyl)phenyl)dimethylphosphine oxide; replace intermediate 43 in synthetic step 4 with intermediate 46 was synthesized to obtain the target compound 069. LC-MS: (ESI) [M+H] ⁺ =1207.4.

Example 70: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2 -Oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl)-6-oxodecahydropyrrolo[1,2-a ][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (070)

Referring to the synthetic route and method of Example 26, the intermediate 25 in the synthesis step 4 was replaced with the intermediate 27; the intermediate 26 in the synthesis step 6 was replaced with the intermediate 44, and the target compound 070 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1167.4. ¹ H NMR (400MHz, DMSO) δ12.09–11.80 (m, 1H), 11.08 (s, 1H), 8.97–8.69 (m, 1H), 8.58–7.88 (m, 4H), 7.68 (dd, J＝ 11.2,8.0Hz,2H),7.49–7.33(m,4H),7.31–7.19(m,2H),7.05–6.71(m,4H),5.40–5.27(m,1H),5.03–4.76(m, 1H),4.45(t,J＝8.4Hz,1H),4.39–4.30(m,2H),4.27–4.15(m,2H),4.00–3.88(m,1H),3.76–3.70(m,1H) ,3.36–3.29(m,5H),2.96–2.79(m,2H),2.75–2.57(m,4H),2.24–1.96(m,5H),1.95–1.73(m,7H),1.72–1.53( m,9H),1.53–1.31(m,3H),1.31–0.94(m,3H).

Example 71: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2 -Oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxodecahydropyrrolo[1,2-a][ 1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (071)

Referring to the synthetic route and method of Example 26, the intermediate 25 in the synthesis step 4 was replaced with the intermediate 28; the intermediate 26 in the synthesis step 6 was replaced with the intermediate 44, and the target compound 071 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1167.4. ¹ H NMR (400MHz, DMSO) δ11.08(s,1H),8.90–8.74(m,1H),8.52–8.44(m,1H),8.41–8.23(m,1H),8.12–7.93(m, 1H),7.68(dd,J＝11.2,8.0Hz,2H),7.50–7.43(m,1H),7.41–7.34(m,3H),7.32–7.20(m,2H),7.01–6.92(m, 2H),6.87–6.69(m,2H),5.38–5.27(m,1H),5.00–4.84(m,1H),4.49–4.41(m,1H),4.37–4.29(m,2H),4.27– 4.13(m,2H),4.05–3.90(m,1H),3.88–3.70(m,2H),3.32(s,1H),3.31–3.26(m,3H),3.01–2.80(m,2H), 2.71–2.66(m,1H), 2.64–2.53(m,4H),2.44–2.27(m,1H),2.26–2.08(m,3H),2.06–1.88(m,4H),1.87–1.64(m,6H),1.63(s,3H ),1.59(s,3H),1.52–1.23(m,4H),1.09–0.81(m,2H).

Example 72: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2 -Oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)piperidine-1-carbonyl)-6-oxodecahydropyrrolo[1,2-a] [1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (072)

Referring to the synthetic route and method of Example 63, intermediate 26 in synthesis step 6 was replaced by intermediate 44, and target compound 072 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1168.4.

Example 73: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(1-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2 -Oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)propyl)piperidine-4-carbonyl)-6-oxodecahydropyrrolo[1,2-a] [1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (073)

Synthesis step 1: 1-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole Synthesis of -5-propyl)piperidine-4-carboxylic acid (intermediate 47)

The first step: 1-(propyl-2-yn-1-yl)piperidine-4-carboxylic acid tert-butyl ester (47-1)

Dissolve 3-bromopropyne and 4-piperidinecarboxylic acid tert-butyl ester in DMF, then add K ₂ CO ₃ and start the reaction at room temperature. After the reaction is over. Quench with ice water, add EA to extract three times, dry, filter, and concentrate under reduced pressure to obtain 47-1. LC-MS: (ESI) [M+H] ⁺ =224.2.

Steps 2 to 3: 1-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzene And[d]imidazole-5-propyl)piperidine-4-carboxylic acid tert-butyl ester (47-3)

Referring to the synthetic route and method of intermediate 25, 6-heptenoic acid was replaced with 47-1, and intermediate 47-3 was synthesized. LC-MS: (ESI)[M+H] ⁺ =485.3.

Step 4: 1-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[ d]imidazole-5-propyl)piperidine-4-carboxylic acid (Intermediate 47)

Take the reaction flask, add 47-3, and dissolve it with MeTHF. Then add a MeTHF solution of potassium tert-butoxide, add water, and react at 50°C. After the reaction is completed, spin off the MeTHF, extract with EA and water, dry, filter, and concentrate under reduced pressure to obtain intermediate 47. LC-MS: (ESI) [M+H] ⁺ =429.2.

Synthesis Step 2: Synthesis of 073

Referring to the synthetic route and method of Example 26, the intermediate 25 in the synthesis step 4 was replaced by the intermediate 47; the intermediate 26 in the synthesis step 6 was replaced by the intermediate 44, and the target compound 073 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1182.5.

Example 74: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(4-(4-(1-(2,6-dioxopiperidin-3-yl))-3-methyl-2 -Oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)butyl)piperidine-1-carbonyl)-6-oxodecahydropyrrolo[1,2-a] [1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (074)

Synthesis step 1: 3-(3-methyl-2-oxo-5-(4-(piperidin-4-yl)butyl)-2,3-dihydro-1H-benzo[d]imidazole- Synthesis of 1-yl)piperidine-2,6-dione (intermediate 48)

Refer to the synthetic route and method of intermediate 45. Replace 1-Boc-4-ethynylpiperidine with 03-2 and synthesize intermediate 48. LC-MS: (ESI) [M+H] ⁺ =399.2.

Synthesis Step 1: Synthesis of 074

Referring to the synthetic route and method of Example 63, intermediate 45 in synthesis step 1 was replaced with intermediate 48, intermediate 26 was replaced with intermediate 44, and the target compound 074 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1196.5. ¹ H NMR (400MHz, DMSO) δ11.94(s,1H),11.09(s,1H),8.85(s,1H),8.71–8.19(m,3H),7.98(d,J＝8.8Hz,1H ),7.75–7.60(m,2H),7.45(d,J＝8.8Hz,1H),7.42–7.12(m,6H),7.05 6.95(m,2H),6.84(d,J＝8.0Hz,1H ),6.77(s,1H),5.33(dd,J＝12.8,5.2Hz,1H),5.20–5.06(m,1H),4.42(t,J＝8.0Hz,1H),4.38–4.19(m, 4H),3.80–3.74(m,1H),3.66–3.61(m,2H),3.54–3.49(m,1H),3.34–3.20(m,5H),2.96–2.83(m,1H),2.77– 2.56(m,6H),2.23–1.89(m,6H),1.88–1.50(m,14H),1.41–1.18(m,5H),1.16–0.94(m,2H).

Example 75: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2 -Oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)piperidin-1-yl)-6-oxodecahydropyrrolo[1,2-a] [1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (075)

Referring to the synthetic route and method of synthesis steps 4 to 6 in Example 26, the intermediate 25 in synthesis step 4 is replaced with intermediate 28, and the intermediate 26 in synthesis step 6 is replaced with intermediate 44, and the target compound 075 is synthesized. LC-MS: (ESI) [M+H] ⁺ =1168.4.

Example 76: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl))-2-(trifluoromethyl yl)benzyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(4-(2-(1-(2,6-dioxopiperidine-3- (yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)piperidine-1-carbonyl)-6-oxodecahydro Pyrro[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (076)

Referring to the synthetic route and method of Example 63, replace 026-3 in synthesis step 1 with 065-3; replace intermediate 26 in synthesis step 6 with intermediate 44, and synthesize target compound 076. LC-MS: (ESI) [M+H] ⁺ =1236.4.

Example 77: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl))-3-(difluoromethyl) Oxy)benzyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(4-(4-(1-(2,6-dioxopiperidine-3) -yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)butyl)piperidine-1-carbonyl)-6-oxodeca Hydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (077)

Synthesis step 1: (S)-2-((5S,8S,10aR)-5-amino-6-oxodecylhydropyrrolo[1,2-a][1,5]diazopyrimidine-8-methyl Amide)-N1-(3-(difluoromethoxy)-4-(dimethylphosphoryl)benzyl)glutaramide (077-3)

Referring to the synthetic route and method of synthetic steps 1 to 3 in Example 26, (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 was replaced with 049-4, and 077-3 was synthesized. LC-MS: (ESI) [M+H] ⁺ =587.3.

Synthesis Step 2: Synthesis of 077

Referring to the synthetic route and method of Example 63, replace intermediate 45 in synthesis step 1 with intermediate 48, replace 026-3 with 077-3; replace intermediate 26 in synthesis step 6 with intermediate 44, and synthesize Target compound 077. LC-MS: (ESI) [M+H] ⁺ =1262.5.

Example 78: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl))-3-(difluoromethyl) Oxy)benzyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(4-(2-(1-(2,6-dioxopiperidine-3) -yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)piperidine-1-carbonyl)-6-oxodeca Hydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (078)

Referring to the synthetic route and method of Example 63, replace 026-3 in synthesis step 1 with 077-3; replace intermediate 26 in synthesis step 6 with intermediate 44, and synthesize target compound 078. LC-MS: (ESI) [M+H] ⁺ =1234.4.

Example 79: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl))-3-(difluoromethyl) Oxy)benzyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(4-(2-(1-(2,6-dioxopiperidine-3) -yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl)-6-oxo Decahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (079)

Referring to the synthetic route and method of Example 26, replace 026-3 in synthetic step 1 with 049-4; replace intermediate 25 in synthetic step 4 with intermediate 27; replace intermediate 26 in synthetic step 6 with intermediate 44 was synthesized to obtain the target compound 079. LC-MS: (ESI) [M+H] ⁺ =1233.4.

Example 80: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl))-3-(difluoromethyl) Oxy)benzyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2-(4-(1-(2,6-dioxopiperidine-3) -yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxodecahydro Pyrro[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (080)

Referring to the synthetic route and method of Example 26, replace 026-3 in synthetic step 1 with 049-4; replace intermediate 25 in synthetic step 4 with intermediate 28; replace intermediate 26 in synthetic step 6 with intermediate 44 was synthesized to obtain the target compound 080. LC-MS: (ESI) [M+H] ⁺ =1233.4. ¹ H NMR(400MHz,DMSO)δ12.23–11.77(m,1H), 11.08(s,1H),8.95–8.71(m,1H),8.62–8.24(m,2H),7.97(d,J＝8.8Hz,1H),7.83–7.70(m,1H),7.59–7.09( m,7H),7.04–6.90(m,2H),6.89–6.64(m,2H),5.41–5.25(m,1H),5.07–4.77(m,1H),4.53–4.16(m,5H), 4.06–3.85(m,2H),3.83–3.71(m,2H),3.37–3.24(m,5H),2.95–2.84(m,1H),2.76–2.56(m,4H),2.41–2.32(m ,1H),2.21–1.79(m,9H),1.78–1.62(m,9H),1.54–1.28(m,5H),1.28–0.90(m,2H).

Example 81: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl))-3-(difluoromethyl) Oxy)benzyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-((4-((1-(2,6-dioxopiperidine-3- (yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)carbamoyl)-6-oxodecahydro Pyrro[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (081)

Referring to the synthetic route and method of Example 54, the intermediate 43 in the synthesis step 4 was replaced with the intermediate 46; the intermediate 26 in the synthesis step 6 was replaced with the intermediate 44, and the target compound 081 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1234.4.

Example 82: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-((4-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2- Oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)carbamoyl)-6-oxodecahydropyrrolo[1,2-a][ 1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (082)

Referring to the synthetic route and method of Example 54, replace 049-4 in synthetic step 1 with (4-(aminomethyl)phenyl)dimethylphosphine oxide; replace intermediate 43 in synthetic step 4 with intermediate Compound 46; replace intermediate 26 in synthesis step 6 with intermediate 44, and synthesize target compound 082. LC-MS: (ESI) [M+H] ⁺ =1168.4.

Example 83: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(1-((1-(4-((2,4-dioxotetrahydropyrimidin-1(2H)-yl)- 3-Methylphenyl)piperidin-4-yl)methyl)piperidin-4-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazepine -5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (083)

Synthesis step 1: 1-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenyl)piperidin-4-yl)methyl)piper Synthesis of pyridine-4-carboxylic acid (intermediate 49)

Step 1: 1-(1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)piperidine-4-carboxylic acid (49-1)

Dissolve 1-BOC-4-bromomethylpiperidine and 4-piperidinecarboxylic acid in DMF, then add K ₂ CO ₃ and start the reaction at room temperature. After the reaction is over. Quench with ice water, add EA to extract three times, dry, filter, and concentrate under reduced pressure to obtain 49-1. LC-MS: (ESI) [M+H] ⁺ =327.2.

Step 2: 1-(piperidin-4-yl)methyl)piperidine-4-carboxylic acid (49-2)

Take a single-neck bottle, add 49-1 (l equiv.), add DCM (10 mL), and slowly add trifluoroacetic acid (3 equiv.) under ice bath. The mixture was ventilated three times and then stirred at room temperature for 1 h. The reaction solution was cooled to room temperature, then water was added, extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, the organic phase was concentrated by distillation under reduced pressure, and the residue was treated with a mixture of ethyl acetate and petroleum ether (ethyl acetate). :petroleum ether=5:1, v/v) and beat to get 49-2. LC-MS: (ESI) [M+H] ⁺ =227.2.

Step 3: 1-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenyl)piperidin-4-yl)methyl)piper Copyridine-4-carboxylic acid (Intermediate 49)

Combine 34-1 (1.0eq.), 49-2 (1.05eq.), Pd ₂ (dba) ₃ (0.05eq.), Sphos (0.1eq.), Cs ₂ CO ₃ (3.0eq.), toluene and Water is added to the reaction flask. The reaction system was replaced with nitrogen three times, and the reaction was stirred at 85°C. Take a sample and use LCMS to detect the end of the reaction. The reaction mixture is cooled to room temperature, water is added, and extracted three times with ethyl acetate. The organic phases are separated and combined with saturated Wash with brine, dry the organic phase over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The crude product is subjected to column chromatography to obtain intermediate 49. LC-MS: (ESI) [M+H] ⁺ =429.2.

Synthesis Step 2: Synthesis of 083

Referring to the synthetic route and method of Example 26, intermediate 25 in synthesis step 4 was replaced with intermediate 49, and target compound 083 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1221.5. ¹ H NMR (400MHz, DMSO) δ10.23(s,1H),9.15(s,1H),8.45–8.19(m,2H),8.14–8.03(m,2H),7.99–7.79(m,1H) ,7.73–7.58(m,3H),7.42–7.16(m,3H),7.09–6.99(m,1H),6.96–6.88(m,1H),6.86–6.50(m,3H),5.16–4.79( m,1H),4.58–4.03(m,6H),3.72–3.59(m,5H),3.48–3.41(m,4H),3.04–2.96(m,1H),2.93–2.82(m,2H), 2.75–2.63(m,4H),2.17–2.05(m,6H),2.02–1.87(m,5H),1.84–1.65(m,6H),1.64–1.49(m,7H),1.33–1.10(m ,3H).

Example 84: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(1-((1-(4-((2,4-dioxotetrahydropyrimidin-1(2H)-yl)- 3-methylphenyl)piperidin-4-yl)methyl)azetidine-3-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diaza Heterocyclooct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (084)

Synthesis step 1: 1-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenyl)piperidin-4-yl)methyl)nitrogen Synthesis of heterocyclobutane-3-carboxylic acid (intermediate 50)

Refer to the synthetic route and method of intermediate 49. The 4-piperidinecarboxylic acid in the first step was replaced by azetidine-3-carboxylic acid, and the intermediate 50 was synthesized. LC-MS: (ESI)[M+H] ⁺ =401.2.

Synthesis Step 2: Synthesis of 084

Referring to the synthetic route and method of Example 26, the intermediate 25 in the synthesis step 4 was replaced with the intermediate 50, and the target compound 084 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1193.4.

Example 85: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(7-(1-((2,6-dioxopiperidin-3-yl)-2-oxo-1,2 -Dihydrobenzo[cadmium]indol-6-yl)heptanoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazacyclin-5-yl)ammonium Formyl)-1H-indole-5-carbonyl)phosphate (085)

Synthesis step 1: 7-(1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)heptanoic acid Synthesis of (Intermediate 51)

The first step: 3-bromo-2,6-dioxopiperidine-1-carboxylic acid tert-butyl ester (51-1)

Referring to the experimental route and method for the first step of the synthesis of 047-3 in Example 47, 4-bromo-3-fluorobenzylamine was replaced with 3-bromopiperidine-2,6-dione. LC-MS: (ESI) [M+H] ⁺ =292.0.

Steps 2 to 3: 3-(6-bromo-2-oxobenzo[cd]indole-1(2H)-yl)piperidine-2,6-dione (51-3)

Refer to the synthetic route and method of the first and second steps of intermediate 49. Replace 4-piperidinecarboxylic acid in the first step with 6-bromobenzo[CD]indol-2(1H)-one; replace 1-BOC-4-bromomethylpiperidine with 51-1 to synthesize Got 51-3. LC-MS: (ESI) [M+H] ⁺ =359.0.

Steps 4 to 5: 7-(1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl) Heptanoic acid (intermediate 51)

Refer to the synthetic route and method of intermediate 25. Replace 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione in the first step is 51-3, and the intermediate 51 is synthesized. LC-MS: (ESI)[M+H] ⁺ =409.2. Synthesis Step 2: Synthesis of 085

Referring to the synthetic route and method of Example 26, the intermediate 25 in the synthesis step 4 was replaced with the intermediate 51; the intermediate 26 in the synthesis step 6 was replaced with the intermediate 44, and the target compound 085 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1162.4. ¹ H NMR (400MHz, DMSO) δ12.10–11.82(m,1H),11.13(s,1H),8.92–8.73(m,1H),8.54–8.37(m,2H),8.34–8.29(m, 1H),8.25–8.02(m,2H),7.98(d,J＝8.8Hz,1H),7.89–7.73(m,1H),7.74–7.63(m,2H),7.47–7.41(m,1H) ,7.39–7.33(m,3H),7.31–7.23(m,2H),7.11–7.02(m,1H),6.98–6.89(m,1H),6.83–6.69(m,1H),5.49–5.37( m,1H),5.01–4.85(m,1H),4.48–4.41(m,1H),4.38–4.30(m,2H),4.26–4.14(m,2H),3.94–3.84(m,1H), 3.74(s,2H),3.29(s,2H),3.05–2.90(m,3H),2.80–2.70(m,1H),2.69–2.58(m,2H),2.40–2.31(m,1H), 2.21–2.06(m, 4H),2.02–1.88(m,3H),1.85–1.75(m,2H),1.70–1.64(m,2H),1.62(s,3H),1.59(s,3H),1.56–1.53(m, 1H),1.44–1.34(m,3H),1.32–1.22(m,2H).

Example 86: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-6-oxo-3-(3-(1-(4-(6-oxo-1,6-dihydropyridazine-3- yl)-2-(trifluoromethyl)phenyl)piperidin-4-yl)propionyl)decahydropyrro[1,2-a][1,5]diazacyclooct-5-yl) Carbamoyl)-benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (086)

Synthesis step 1: 3-(1-(4-(6-oxo-1,6-dihydropyridazin-3-yl)-2-(trifluoromethyl)phenyl)piperidin-4-yl) Synthesis of propionic acid (intermediate 52)

Step one: 6-(4-fluoro-3-trifluoromethylphenyl)pyridazin-3(2H)one (52-1)

Dissolve 6-bromo-3-pyridazinol and 4-fluoro-3-trifluoromethylphenylboronic acid in 1,4-dioxane, then add Pd(OAc) ₂ , K ₂ CO ₃ to the reaction in a bottle. The reaction system was replaced with nitrogen three times, and the reaction was stirred at 85°C. Sampling LCMS to detect the end of the reaction, cool the reaction mixture to room temperature, add water, extract three times with ethyl acetate, separate the liquids and combine the organic phases, wash with saturated brine, dry the organic phase over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The crude product is Column chromatography yielded 52-1. LC-MS: (ESI)[M+H] ⁺ =259.0.

Step 2: 3-(1-(4-(6-oxo-1,6-dihydropyridazin-3-yl)-2-(trifluoromethyl)phenyl)piperidin-4-yl) Propionic acid (intermediate 52)

Dissolve 4-piperidinepropionic acid and 52-1 in DMF, then add K ₂ CO ₃ and start the reaction at room temperature. After the reaction is over. Quench with ice water, add EA to extract three times, dry, filter, and concentrate under reduced pressure to obtain intermediate 52. LC-MS: (ESI) [M+H] ⁺ =396.1.

Synthesis Step 2: Synthesis of 086

Referring to the synthetic route and method of Example 26, intermediate 25 in synthesis step 4 was replaced with intermediate 52, and target compound 086 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1188.4.

Example 87: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-6-oxo-3-(2-(1-(4-(6-oxo-1,6-dihydropyridazine-3- yl)-2-(trifluoromethyl)phenyl)piperidin-4-yl)acetyl)decahydropyrro[1,2-a][1,5]diazacyclooct-5-yl) Carbamoyl)-benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (087)

Synthesis step 1: 2-(1-(4-(6-oxo-1,6-dihydropyridazin-3-yl)-2-(trifluoromethyl)phenyl)piperidin-4-yl) Synthesis of acetic acid (intermediate 53)

Referring to the synthetic route and method of Intermediate 52, 4-piperidinepropionic acid in the second step was replaced with 4-picolineacetic acid to synthesize Reference Intermediate 53. LC-MS: (ESI) [M+H] ⁺ =382.2.

Synthesis Step 2: Synthesis of 087

Referring to the synthetic route and method of Example 26, intermediate 25 in synthesis step 4 was replaced by intermediate 53, and target compound 087 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1174.3.

Example 88: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-6-oxo-3-(4-(1-(4-(6-oxo-1,6-dihydropyridazine-3- yl)-2-(trifluoromethyl)phenyl)piperidin-4-yl)butyryl)decahydropyrro[1,2-a][1,5]diazacyclooct-5-yl) Carbamoyl)-benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (088)

Synthesis step 1: 4-(1-(4-(6-oxo-1,6-dihydropyridazin-3-yl)-2-(trifluoromethyl)phenyl)piperidin-4-yl) Synthesis of butyric acid (intermediate 54)

Referring to the synthetic route and method of intermediate 52, 4-piperidinepropionic acid in the second step was replaced with 4-(piperidin-4-yl)butyric acid, and reference intermediate 54 was synthesized. LC-MS: (ESI) [M+H] ⁺ =410.2.

Synthesis Step 2: Synthesis of 088

Referring to the synthetic route and method of Example 26, intermediate 25 in synthesis step 4 was replaced with intermediate 54, and target compound 088 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1202.4.

Example 89: ((2-(((5S,8S,10aR)-8-(((2S)-5-amino-1-(5-(dimethylphosphoryl))-2,3-dihydro- 1H-inden-1-yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(7-(1-(2,6-dioxopiperidine-3- methyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzene And[d]imidazol-5-yl)heptanoyl-6-oxodecahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[ b]Thien-5-yl)difluoromethyl)phosphoric acid (089)

Synthesis step 1: Synthesis of 4-aminomethyl-3-fluorophenyldimethylphosphine oxide (089-3)

Referring to the synthetic route and method of 047-3 synthesis in Example 47, replace 4-bromo-3-fluorobenzylamine in the first step with 5-bromo-2,3-dihydro-1H-indene-1-amine. , synthesized to obtain 089-3. LC-MS: (ESI) [M+H] ⁺ =210.1.

Synthesis Step 2: Synthesis of 089

Referring to the synthetic route and method of Example 26, (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthesis step 1 was replaced with 089-3, and the target compound 089 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1206.4. ¹ H NMR (400MHz, DMSO) δ11.24–10.73(m,1H),9.17–8.67(m,1H),8.42–8.19(m,3H),8.16–8.00(m,2H),7.78–7.58( m,3H),7.40–7.22(m,4H),7.13–6.98(m,2H),6.94–6.78(m,2H),5.45–5.29(m,2H),5.04–4.80(m,1H), 4.54–4.46(m,1H),4.33–4.20(m,2H),4.08–3.92(m,1H),3.81–3.75(m,1H),3.40–3.35(m,3H),3.32–3.27(m ,1H),3.09–2.86(m,3H),2.80–2.71(m,1H),2.71–2.62(m,3H),2.52–2.38(m,2H),2.31–2.15(m,3H),2.10 –1.81(m,7H),1.74(s,1H),1.68(s,3H),1.65(s,3H),1.64–1.53(m,3H),1.43–1.28(m,4H).

Example 90: ((2-(((5S,8S,10aR)-8-(((2S)-5-amino-1-(5-(dimethylphosphoryl))-2,3-dihydro- 1H-inden-1-yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(7-(1-(2,6-dioxopiperidine-3- yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)heptanoyl-6-oxodecahydropyrrolo[1,2-a ][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (090)

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 with 089-3; replace intermediate 26 in synthetic step 6 with intermediate 44 was synthesized to obtain the target compound 090. LC-MS: (ESI) [M+H] ⁺ =1167.4. ¹ H NMR (400MHz, DMSO) δ12.15–11.82(m,1H),11.32–10.70(m,1H),9.01–8.73(m,1H),8.55–8.15(m,3H),8.02(d, J＝8.4Hz,1H),7.73–7.58(m,2H),7.48(d,J＝8.4Hz,1H),7.44–7.30(m,4H),7.10–6.99(m,2H),6.95–6.75 (m,2H),5.46–5.29(m,2H),5.08–4.86(m,1H),4.60–4.47(m,1H),4.35–4.19(m,2H),4.12–3.91(m,2H) ,3.89– 3.75(m,2H),3.39–3.34(m,4H),3.31–3.28(m,1H),3.12–2.99(m,2H),2.98–2.88(m,2H),2.80–2.72(m,1H ),2.71–2.58(m,4H),2.53–2.38(m,2H),2.30–2.16(m,3H),2.11–1.98(m,3H),1.98–1.86(m,3H),1.77–1.59 (m,11H),1.46–1.34(m,4H).

Example 91: ((2-(((5S,8S,10aR)-8-(((2S)-5-amino-1-(5-(dimethylphosphoryl))-2,3-dihydro- 1H-inden-1-yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(4-(4-(1-(2,6-dioxopiperidine) -3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)butyl)piperidine-1-carbonyl)-6-oxo Decahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (091)

Synthesis step 1: (2S)-2-(5S,8S,10aR)-5-amino-6-oxodecylhydropyrrolo[1,2-a][1,5]diazopyrimidine-8-carboxamide base)-N1-(5-dimethylphosphoryl)-2,3-dihydro-1H-inden-1-yl)glutaramide (091-3)

Referring to the synthetic route and method of synthetic steps 1 to 3 in Example 26, (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 was replaced with 089-3, and 091-3 was synthesized. LC-MS: (ESI)[M+H] ⁺ =547.3.

Synthesis Step 2: Synthesis of 091

Referring to the synthetic route and method of Example 77, replace 026-3 in synthesis step 1 with 091-3; the target compound 091 is synthesized. LC-MS: (ESI) [M+H] ⁺ =1222.5.

Example 92: ((2-(((5S,8S,10aR)-8-(((2S)-5-amino-1-(6-(dimethylphosphoryl)pyridin-3-yl)methyl) )Amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl -2-Oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)heptanoyl-6-oxodecahydropyrrolo[1,2-a][1,5]di Azepan-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (092)

Referring to the synthetic route and method of Example 26, (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthesis step 1 was replaced with 048-2, and the target compound 092 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1181.4. ¹ H NMR (400MHz, DMSO) δ9.17–8.69(m,1H),8.64(s,1H),8.61–8.49(m,1H),8.41–8.27(m,1H),8.21(s,1H) ,8.09–7.98(m,1H),7.97–7.75(m,3H),7.62(d,J＝8.4Hz,1H),7.33–7.17(m,1H),7.06–6.92(m,2H),6.90 –6.66(m,2H),5.33(dd,J＝12.4,5.2Hz,1H),4.99–4.72(m,1H),4.48–4.30(m,3H),4.29–4.00(m,3H),3.97 –3.85(m,1H),3.84–3.52(m,3H),3.49–3.27(m,5H),2.99–2.82 (m,1H),2.76–2.66(m,1H),2.65–2.56(m,3H),2.44–2.29(m,1H),2.24–2.07(m,3H),2.05–1.90(m,3H) ,1.86–1.67(m,3H),1.64(s,3H),1.61(s,3H),1.60–1.50(m,3H),1.41–1.32(m,3H).

Example 93: ((2-(((5S,8S,10aR)-8-(((2S)-5-amino-1-(((6-(dimethylphosphoryl))pyridin-3-yl)) Methyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(7-(1-(2,6-dioxopiperidin-3-yl)-3- Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)heptanoyl-6-oxodecahydropyrrolo[1,2-a][1,5 ]Diazepine-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (093)

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 with 048-2; replace intermediate 26 in synthetic step 6 with intermediate 44 was synthesized to obtain the target compound 093. LC-MS: (ESI) [M+H] ⁺ =1142.4.

Example 94: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-(((6-(dimethylphosphoryl))pyridin-3-yl)) Methyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(4-(2-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)piperidine-1-carbonyl)-6-oxodecahydropyrrolo [1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (094)

Synthesis step 1: (S)-2-(5S,8S,10aR)-5-amino-6-oxodecylhydropyrrolo[1,2-a][1,5]diazoxide-8-carboxamide base)-N1-(5-dimethylphosphoryl)pyridine-3-methyl)glutaramide (094-3)

Referring to the synthetic route and method of synthetic steps 1 to 3 in Example 26, (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 was replaced with 048-2, and 094-3 was synthesized. LC-MS: (ESI)[M+H] ⁺ =522.3.

Synthesis Step 2: Synthesis of 094

Referring to the synthetic route and method of Example 63, replacing 026-3 in synthesis step 1 with 094-3, the target compound 094 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1208.4.

Example 95: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(dimethylphosphoryl)pyridin-3-yl)methyl) (base)amino)-1,5- Dioxopent-2-yl)carbamoyl)-3-(4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo -2,3-Dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1 ,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (095)

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 with 048-2; replace intermediate 25 in synthetic step 4 with intermediate 27 was synthesized to obtain the target compound 095. LC-MS: (ESI) [M+H] ⁺ =1207.4.

Example 96: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(dimethylphosphoryl))pyridin-3-yl)methyl) yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2-(4-(1-(2,6-dioxopiperidin-3-yl)- 3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxodecahydropyrrolo[1 ,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (096)

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 with 048-2; replace intermediate 25 in synthetic step 4 with intermediate 28 was synthesized to obtain the target compound 096. LC-MS: (ESI) [M+H] ⁺ =1207.4.

Example 97: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(dimethylphosphoryl))pyridin-3-yl)methyl) yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-((5-(1-(2,6-dioxopiperidin-3-yl)-3- Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)pentyl)carbamoyl)-6-oxodecahydropyrrolo[1,2-a ][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (097)

Referring to the synthetic route and method of Example 54, 049-4 in synthesis step 1 was replaced with 048-2, and the target compound 097 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1182.4.

Example 98: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-(((6-(dimethylphosphoryl))pyridin-3-yl)) Methyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(4-(2-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)piperidine-1-carbonyl)-6-oxodecahydropyrrolo [1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (098)

Referring to the synthetic route and method of Example 63, replace 026-3 in synthetic step 1 with 094-3; replace intermediate 26 in synthetic step 6 with intermediate 44, and synthesize target compound 098. LC-MS: (ESI) [M+H] ⁺ =1169.4.

Example 99: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(dimethylphosphoryl))pyridin-3-yl)methyl) yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(4-(2-(1-(2,6-dioxopiperidin-3-yl)- 3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl)-6-oxodecahydropyrrolo [1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (099)

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 with 048-2; replace intermediate 25 in synthetic step 4 with intermediate Compound 27; replace intermediate 26 in synthesis step 6 with intermediate 44, and synthesize target compound 099. LC-MS: (ESI) [M+H] ⁺ =1168.4.

Example 100: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(dimethylphosphoryl)pyridin-3-yl))methyl (base)amino)-1,5- Dioxopent-2-yl)carbamoyl)-3-(2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo -2,3-Dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxodecahydropyrrolo[1,2-a][1,5 ]Diazepine-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (100)

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 with 048-2; replace intermediate 25 in synthetic step 4 with intermediate Compound 28; replace intermediate 26 in synthesis step 6 with intermediate 44, and synthesize target compound 100. LC-MS: (ESI) [M+H] ⁺ =1168.4.

Example 101: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(dimethylphosphoryl))pyridin-3-yl)methyl) yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-((5-(1-(2,6-dioxopiperidin-3-yl)-3- Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)pentyl)carbamoyl)-6-oxodecahydropyrrolo[1,2-a ][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (101)

Referring to the synthetic route and method of Example 54, replace 049-4 in synthetic step 1 with 048-2; replace intermediate 26 in synthetic step 6 with intermediate 44, and synthesize the target compound 101. LC-MS: (ESI) [M+H] ⁺ =1143.4.

Synthesis of Intermediate 55 or Intermediate 56

(1R,4S)-4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzene And[d]imidazol-5-yl)ethyl)cyclohexane-1-carboxylic acid (intermediate 55)

(1S,4R)-4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzene Imidazol-5-yl)ethyl)cyclohexane-1-carboxylic acid (Intermediate 56)

Intermediate 27 was separated by SFC to obtain two cis-trans isomers, namely intermediate 55 and intermediate 56. Intermediate 55LC-MS: (ESI) [M+H] ⁺ =414.2. Intermediate 56LC-MS: (ESI) [M+H] ⁺ =414.2.

Synthesis of Intermediate 57 or Intermediate 58

2-((1S,4S)-4-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- Benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetic acid (Intermediate 57)

2-((1R,4R)-4-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- Benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetic acid (Intermediate 58)

Intermediate 28 was separated by SFC to obtain two cis-trans isomers, namely intermediate 57 and intermediate 58. Intermediate 57LC-MS: (ESI) [M+H] ⁺ =414.2. Intermediate 58 LC-MS: (ESI) [M+H] ⁺ =414.2.

Example 102: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-((1R,4R)-4-(2-(1-(2,6-dioxopiperidin-3-yl)- 3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl)-6-oxodecahydropyrrolo [1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (102)

Referring to the synthetic route and method of Example 26, the intermediate 25 in the synthesis step 4 was replaced with the intermediate 55; the intermediate 26 in the synthesis step 6 was replaced with the intermediate 44, and the target compound 102 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1167.4.

Example 103: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-((1S,4S)-4-(2-(1-(2,6-dioxopiperidin-3-yl)- 3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl)-6-oxodecahydropyrrolo [1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (103)

Referring to the synthetic route and method of Example 26, the intermediate 25 in the synthesis step 4 was replaced with the intermediate 56; the intermediate 26 in the synthesis step 6 was replaced with the intermediate 44, and the target compound 103 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1167.4.

Example 104: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-((1R,4R)-4-(2-(1-(2,6-dioxopiperidin-3-yl)- 3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl)-6-oxodecahydropyrrolo [1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (104)

Referring to the synthetic route and method of Example 26, the intermediate 25 in the synthesis step 4 was replaced with the intermediate 55, and the target compound 104 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1206.4.

Example 105: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-((1S,4S)-4-(2-(1-(2,6-dioxopiperidin-3-yl)- 3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl)-6-oxodecahydropyrrolo [1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (105)

Referring to the synthetic route and method of Example 26, the intermediate 25 in the synthesis step 4 was replaced with the intermediate 56, and the target compound 105 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1206.4.

Example 106: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(dimethylphosphoryl))pyridin-3-yl)methyl) yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-((1R,4R)-4-(2-(1-(2,6-dioxopiperidine) -3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl)-6- Oxodecahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (106)

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 with 048-2; replace intermediate 25 in synthetic step 4 with intermediate Compound 55; replace intermediate 26 in synthesis step 6 with intermediate 44, and synthesize target compound 106. LC-MS: (ESI) [M+H] ⁺ =1168.4.

Example 107: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(dimethylphosphoryl)pyridin-3-yl))methyl yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-((1S,4S)-4-(2-(1-(2,6-dioxopiperidine) -3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl)-6- Oxodecahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (107)

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 with 048-2; replace intermediate 25 in synthetic step 4 with intermediate Compound 56; replace intermediate 26 in synthesis step 6 with intermediate 44, and synthesize target compound 107. LC-MS: (ESI) [M+H] ⁺ =1168.4.

Example 108: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(dimethylphosphoryl)pyridin-3-yl))methyl yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-((1R,4R)-4-(2-(1-(2,6-dioxopiperidine) -3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl)-6- Oxodecahydropyrrolo[1,2-a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid ( 108)

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 with 048-2; replace intermediate 25 in synthetic step 4 with intermediate 55 was synthesized to obtain the target compound 108. LC-MS: (ESI) [M+H] ⁺ =1207.4.

Example 109: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(dimethylphosphoryl)pyridin-3-yl))methyl yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-((1S,4S)-4-(2-(1-(2,6-dioxopiperidine) -3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl)-6- Oxodecahydropyrrolo[1,2-a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid ( 109)

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 with 048-2; replace intermediate 25 in synthetic step 4 with intermediate 56 was synthesized to obtain the target compound 109. LC-MS: (ESI) [M+H] ⁺ =1207.4.

Example 110: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((3-(difluoromethoxy))-4-(dimethyl Phosphoryl)benzyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-((1R,4R)-4-(2-(1-(2,6-di Oxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl )-6-Oxodecahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphoric acid (110)

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 with 049-4; replace intermediate 25 in synthetic step 4 with intermediate Compound 55; replace intermediate 26 in synthesis step 6 with intermediate 44, and synthesize target compound 110. LC-MS: (ESI) [M+H] ⁺ =1233.4.

Example 111: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((3-(difluoromethoxy))-4-(dimethyl Phosphoryl)benzyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-((1S,4S)-4-(2-(1-(2,6-di Oxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl )-6-Oxodecahydropyrro[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (111)

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 with 049-4; replace intermediate 25 in synthetic step 4 with intermediate Compound 56; replace intermediate 26 in synthesis step 6 with intermediate 44, and synthesize target compound 111. LC-MS: (ESI) [M+H] ⁺ =1233.4.

Example 112: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((3-(difluoromethoxy))-4-(dimethyl Phosphoryl)benzyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-((1R,4R)-4-(2-(1-(2,6-di Oxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl )-6-Oxodecahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl base) phosphate(112)

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 with 049-4; replace intermediate 25 in synthetic step 4 with intermediate 55 was synthesized to obtain the target compound 112. LC-MS: (ESI) [M+H] ⁺ =1272.4.

Example 113: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((3-(difluoromethoxy))-4-(dimethyl Phosphoryl)benzyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-((1S,4S)-4-(2-(1-(2,6-di Oxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl )-6-Oxodecahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl base) phosphoric acid (113)

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 with 049-4; replace intermediate 25 in synthetic step 4 with intermediate 56 was synthesized to obtain the target compound 113. LC-MS: (ESI) [M+H] ⁺ =1272.4.

Example 114: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(2-((1S,4R)-(4-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxodecahydropyrrolo[ 1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (114)

Referring to the synthetic route and method of Example 26, the intermediate 25 in the synthesis step 4 was replaced with the intermediate 57; the intermediate 26 in the synthesis step 6 was replaced with the intermediate 44, and the target compound 114 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1167.4.

Example 115: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(2-((1R,4S)-(4-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxodecahydropyrrolo[ 1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (115)

Referring to the synthetic route and method of Example 26, the intermediate 25 in the synthesis step 4 was replaced with the intermediate 58; the intermediate 26 in the synthesis step 6 was replaced with the intermediate 44, and the target compound 115 was synthesized. LC-MS:(ESI)[M+H] ⁺ =1167.4.

Example 116: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(2-((1S,4R)-(4-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxodecahydropyrrolo[ 1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (116)

Referring to the synthetic route and method of Example 26, the intermediate 25 in the synthesis step 4 was replaced with the intermediate 57, and the target compound 116 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1206.4.

Example 117: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(2-((1R,4S)-(4-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxodecahydropyrrolo[ 1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (117)

Referring to the synthetic route and method of Example 26, intermediate 25 in synthesis step 4 was replaced with intermediate 58, and the target compound 116 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1206.4.

Example 118: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(dimethylphosphoryl))pyridin-3-ylmethyl )Amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2-((1S,4R)-(4-(1-(2,6-dioxopiperidine) -3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxo Decahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (118)

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 with 048-2; replace intermediate 25 in synthetic step 4 with intermediate Compound 57; replace intermediate 26 in synthesis step 6 with intermediate 44, and synthesize target compound 118. LC-MS: (ESI) [M+H] ⁺ =1168.4.

Example 119: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(dimethylphosphoryl))pyridin-3-ylmethyl )Amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2-((1R,4S)-(4-(1-(2,6-dioxopiperidine) -3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxo Decahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (119)

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 with 048-2; replace intermediate 25 in synthetic step 4 with intermediate Compound 58; replace intermediate 26 in synthesis step 6 with intermediate 44, and synthesize target compound 119. LC-MS: (ESI) [M+H] ⁺ =1168.4.

Example 120: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(dimethylphosphoryl))pyridin-3-ylmethyl )Amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2-((1S,4R)-(4-(1-(2,6-dioxopiperidine) -3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxo Decahydropyrrolo[1,2-a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (120)

Referring to the synthetic route and method of Example 26, (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthesis step 1 was replaced with Replace it with 048-2; replace intermediate 25 in synthesis step 4 with intermediate 57, and synthesize the target compound 120. LC-MS: (ESI) [M+H] ⁺ =1207.4.

Example 121: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(dimethylphosphoryl))pyridin-3-ylmethyl )Amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2-((1R,4S)-(4-(1-(2,6-dioxopiperidine) -3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxo Decahydropyrrolo[1,2-a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (121)

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 with 048-2; replace intermediate 25 in synthetic step 4 with intermediate 58 was synthesized to obtain the target compound 121. LC-MS: (ESI) [M+H] ⁺ =1207.4.

Example 122: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl))-3-(difluoromethyl) Oxy)benzyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2-((1S,4R)-(4-(1-(2,6- Dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl) -6-Oxodecahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (122)

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 with 049-4; replace intermediate 25 in synthetic step 4 with intermediate Compound 57; replace intermediate 26 in synthesis step 6 with intermediate 44, and synthesize target compound 122. LC-MS: (ESI) [M+H] ⁺ =1233.4.

Example 123: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl))-3-(difluoromethyl Oxy)benzyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2-((1R,4S)-(4-(1-(2,6- Dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl) -6-Oxodecahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (123)

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 with 049-4; replace intermediate 25 in synthetic step 4 with intermediate Compound 58; replace intermediate 26 in synthesis step 6 with intermediate 44, and synthesize target compound 123. LC-MS: (ESI) [M+H] ⁺ =1233.4.

Example 124: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl))-3-(difluoromethyl) Oxy)benzyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2-((1S,4R)-(4-(1-(2,6- Dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl) -6-Oxodecahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl )Phosphoric acid (124)

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 with 049-4; replace intermediate 25 in synthetic step 4 with intermediate 57; the target compound 124 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1272.4.

Example 125: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl))-3-(difluoromethyl Oxy)benzyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2-((1R,4S)-(4-(1-(2,6- Dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl) -6-Oxodecahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl )Phosphoric acid (125)

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 with 049-4; replace intermediate 25 in synthetic step 4 with intermediate 58 was synthesized to obtain the target compound 125. LC-MS: (ESI) [M+H] ⁺ =1272.4.

Example 126: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(diethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2 -Oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)piperidine-1-carbonyl)-6-oxodecahydropyrrolo[1,2-a] [1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (126)

Synthesis step 1: (4-(aminomethyl)phenyl)diethylphosphine oxide (126-2)

The first step: 4-(diethylphosphoryl)benzyl)carbamic acid tert-butyl ester (126-1)

4-Bromobenzylcarbamic acid tert-butyl ester (2.0g, 7.00mmol, 1.0eq.), diethylphosphine oxide (820mg, 10.50mmol, 1.5eq.), Pd2(dba)3 (641mg, 0.70mmol, 0.1eq.), Xantphos (811mg, 1.40mmol, 0.2eq.), potassium phosphate (4.46g, 21.00mmol, 3.0eq.) and dioxane (30mL) were added to the sealed reaction flask in sequence. The reaction system was replaced with nitrogen three times, and the reaction was stirred at 100°C for 16 hours. LCMS detected the end of the reaction. The reaction mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The crude product was subjected to column chromatography (DCM/MeOH=15/1) to obtain 126-1. LC-MS: (ESI) [M+H] ⁺ =312.2.

Step 2: (4-(aminomethyl)phenyl)diethylphosphine oxide (126-2)

Dissolve 126-1 (900 mg, 3.18 mmol, 1.0 eq.) in dichloromethane (5 mL), and add trifluoroacetic acid (1 mL) dropwise under an ice-water bath. After the addition was completed, the reaction was stirred at 25°C for 1 hour. LCMS detects the end of the reaction. The mixture was directly concentrated under reduced pressure to obtain crude product 126-2. LC-MS: (ESI) [M+H] ⁺ =212.1.

Synthesis step 2: (S)-2-((5S,8S,10aR)-5-amino-6-oxodecylhydropyrrolo[1,2-a][1,5]diazoheterazine-8- Synthesis of carboxamido)-N1-(4-(difluoromethoxy)-4-(diethylphosphoryl)benzyl)glutaramide (126-5)

Referring to the synthetic route and method of synthetic steps 1 to 3 in Example 26, (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 was replaced with 126-2, and 126-5 was synthesized. LC-MS: (ESI) [M+H] ⁺ =549.3.

Synthesis Step 3: Synthesis of 126

Referring to the synthetic route and method of Example 63, 026-3 in synthesis step 1 was replaced with 126-5; intermediate 26 was replaced with intermediate 44, and the target compound 126 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1196.5.

Example 127: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(diethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2 -Oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)piperidine-1-carbonyl)-6-oxodecahydropyrrolo[1,2-a] [1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (127)

Referring to the synthetic route and method of Example 63, replacing 026-3 in synthesis step 1 with 126-5, the target compound 127 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1235.4.

Example 128: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2 -Oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)-1-fluorocyclohexane-1-carbonyl)-6-oxodecahydropyrrolo[1 ,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (128)

Synthesis step 1: 4-(2-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5- Synthesis of ethyl)-1-fluorocyclohexane-1-carboxylic acid (intermediate 59)

Step 1: 4-(((tert-butyldimethylsilyl)oxy)methyl)-1-fluorocyclohexane-1-carboxylic acid (59-1)

Take the reaction flask, add 4-(((tert-butyldimethylsilyl)oxy)methyl)-1-fluorocyclohexane-1-carboxylic acid methyl ester, and dissolve it with MeOH. Then the aqueous solution of LiOH was slowly added dropwise at 0°C. Warm up to room temperature and start the reaction. After the reaction, the solvent was concentrated under reduced pressure, diethyl ether was added to the remaining aqueous solution, and the mixture was extracted twice with water. Combine the aqueous phases, add HCl to adjust the pH to 2, then extract with chloroform three times, dry, and concentrate under reduced pressure to obtain 59-1. LC-MS: (ESI) [M+H] ⁺ =291.2.

Step 2: 4-(((tert-butyldimethylsilyl)oxy)methyl)-1-fluorocyclohexane-1-carboxylic acid tert-butyl ester (59-2)

Take the reaction flask, add 59-1, DCC, t-BuOH and DMAP, and dissolve with DCM. React at room temperature. After the reaction, DCC was filtered off, extracted three times with water and DCM, dried, and concentrated under reduced pressure to obtain 59-2. LC-MS: (ESI) [M+H] ⁺ =347.2.

Step 3: 1-Fluoro-4-(hydroxymethyl)cyclohexane-1-carboxylic acid tert-butyl ester (59-3)

Take the reaction flask, add 59-2, dissolve it in DCM, add TBAF, and start the reaction at room temperature. After the reaction is completed, water is added for extraction, dried, filtered, and concentrated under reduced pressure to obtain 59-3. LC-MS: (ESI) [M+H] ⁺ =233.2.

Step 4: 1-Fluoro-4-formylcyclohexane-1-carboxylic acid tert-butyl ester (59-4)

Take the reaction bottle, add 59-3, dissolve it in DCM, and then slowly add the DMP solution dropwise at 0°C. React at room temperature. After the reaction is completed, wash with Na ₂ CO ₃ and Na ₂ S ₂ O ₃ aqueous solutions. Then it was extracted with water and DCM, dried, and concentrated under reduced pressure to obtain 59-4. LC-MS: (ESI) [M+H] ⁺ =231.1.

Step 5: 4-ethynyl-1-fluorocyclohexane-1-carboxylic acid tert-butyl ester (59-5)

Take the reaction flask, add 59-4 and Ohira Bestmann reagent, and dissolve them with methanol. Then add potassium carbonate at 0°C. Stir for 2h. Continue stirring at room temperature for 1 h. Pour the reaction into water and dilute with pentane. The organic matter was washed with water, dried, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain 59-5. LC-MS: (ESI) [M+H] ⁺ =227.1.

Steps six to seven: 4-(2-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d ] Imidazole-5-ethyl)-1-fluorocyclohexane-1-carboxylic acid tert-butyl ester (59-7)

Referring to the synthetic route and method of intermediate 25, 6-heptinoic acid was replaced with 59-5, and 59-7 was synthesized. LC-MS: (ESI)[M+H] ⁺ =488.3.

Step 8: 4-(2-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-5- Ethyl)-1-fluorocyclohexane-1-carboxylic acid (Intermediate 59)

Take the reaction flask, add 59-7, and dissolve it with MeTHF. Then add a MeTHF solution of potassium tert-butoxide, add water, and react at 50°C. After the reaction, spin off the MeTHF, extract with EA and water, dry, filter, and concentrate under reduced pressure to obtain intermediate 59. LC-MS: (ESI) [M+H] ⁺ =432.2.

Synthesis Step 2: Synthesis of 128

Referring to the synthetic route and method of Example 26, the intermediate 25 in the synthesis step 4 was replaced by the intermediate 59; the intermediate 26 in the synthesis step 6 was replaced by the intermediate 44, and the target compound 128 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1185.4.

Example 129: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2 -Oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)-1-fluorocyclohexane-1-carbonyl)-6-oxodecahydropyrrolo[1 ,2-a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (129)

Referring to the synthetic route and method of Example 26, intermediate 25 in synthesis step 4 was replaced with intermediate 59, and target compound 129 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1224.4.

Example 130: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(diisopropylphosphoryl)benzyl)amino))- 1,5-dioxopent-2-yl)carbamoyl)-3-(4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl- 2-Oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)piperidine-1-carbonyl)-6-oxodecahydropyrrolo[1,2-a ][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (130)

Synthesis step 1: (4-(aminomethyl)phenyl)diisopropylphosphine oxide (130-2)

Referring to the synthetic route and method for the synthesis of 126-2 in Example 126, the diethylphosphine oxide in synthesis step 1 was replaced with diisopropylphosphine oxide to synthesize 130-2. LC-MS: (ESI) [M+H] ⁺ =240.1.

Synthesis step 2: (S)-2-((5S,8S,10aR)-5-amino-6-oxodecahydropyrrolo[1,2-a][1,5]diazoline-8-methyl Synthesis of amide)-N1-(4-(difluoromethoxy)-4-(diisopropylphosphoryl)benzyl)glutaramide (130-5)

Referring to the synthetic route and method of synthetic steps 1 to 3 in Example 26, (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 was replaced with 130-2, and 130-5 was synthesized. LC-MS: (ESI) [M+H] ⁺ =577.3.

Synthesis Step 3: Synthesis of 130

Referring to the synthetic route and method of Example 63, 026-3 in synthesis step 1 was replaced with 130-5; intermediate 26 was replaced with intermediate 44, and the target compound 130 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1224.5.

Example 131: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(diisopropylphosphoryl)benzyl)amino))- 1,5-dioxopent-2-yl)carbamoyl)-3-(4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl- 2-Oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)piperidine-1-carbonyl)-6-oxodecahydropyrrolo[1,2-a ][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (131)

Referring to the synthetic route and method of Example 63, replacing 026-3 in synthesis step 1 with 130-5, the target compound 131 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1263.5.

Example 132: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(dimethylphosphoryl)pyridin-3-yl))methyl yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(4-(2-(1-(2,6-dioxopiperidin-3-yl)- 3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)-1-fluorocyclohexane-1-carbonyl)-6-oxo Decahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (132)

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 with 048-2; replace intermediate 25 in synthetic step 4 with intermediate Compound 59; replace intermediate 26 in synthesis step 6 with intermediate 44, and synthesize target compound 132. LC-MS: (ESI) [M+H] ⁺ =1186.4.

Example 133: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(dimethylphosphoryl)pyridin-3-yl))methyl yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(4-(2-(1-(2,6-dioxopiperidin-3-yl)- 3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)-1-fluorocyclohexane-1-carbonyl)-6-oxo Decahydropyrrolo[1,2-a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (133)

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 with 048-2; replace intermediate 25 in synthetic step 4 with intermediate 59 was synthesized to obtain the target compound 133. LC-MS: (ESI) [M+H] ⁺ =1225.4.

Example 134: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(diethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(4-(4-(1-(2,6-dioxopiperidin-3-yl))-3-methyl-2 -Oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)butyl)piperidine-1-carbonyl)-6-oxodecahydropyrrolo[1,2-a] [1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (134)

Referring to the synthetic route and method of Example 63, intermediate 45 in synthesis step 1 was replaced with intermediate 48, 026-3 was replaced with 126-5; intermediate 26 was replaced with intermediate 44, and the target compound 134 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1224.5.

Example 135: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(diethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(4-(4-(1-(2,6-dioxopiperidin-3-yl))-3-methyl-2 -Oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)butyl)piperidine-1-carbonyl)-6-oxodecahydropyrrolo[1,2-a] [1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (135)

Referring to the synthetic route and method of Example 63, intermediate 45 in synthesis step 1 was replaced with intermediate 48, 026-3 was replaced with 126-5, and the target compound 135 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1263.5.

Example 136: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2 -Oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)bicyclo[2.2.2]octane-1-carbonyl)-6-oxodecahydropyrrolo[ 1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (136)

Synthesis step 1: 4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole Synthesis of -5-yl)ethyl)bicyclo[2.2.2]octane-1-carboxylic acid (intermediate 60)

Step 1: 1-(tert-butyl)4-methylbicyclo[2.2.2]octane-1,4-dicarboxylate (60-1)

Take the reaction flask, add 4-(methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid, DCC, t-BuOH and DMAP, and dissolve in DCM. React at room temperature. After the reaction, DCC was filtered off, extracted three times with water and DCM, dried, and concentrated under reduced pressure to obtain 60-1. LC-MS: (ESI) [M+H] ⁺ =269.2.

Step 2: 4-(tert-butoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid (60-2)

Take the reaction flask, add 60-1, and dissolve it with MeOH. Then the aqueous solution of LiOH was slowly added dropwise at 0°C. rise to room Wen began to react. After the reaction, the solvent was concentrated under reduced pressure, diethyl ether was added to the remaining aqueous solution, and the mixture was extracted twice with water. Combine the water phases, add HCl to adjust the pH to 2, then extract with chloroform three times, dry, and concentrate under reduced pressure to obtain 60-2. LC-MS: (ESI) [M+H] ⁺ =255.2.

Step 3: 4-(hydroxymethyl)bicyclo[2.2.2]octane-1-carboxylic acid tert-butyl ester (60-3)

Take the reaction flask, add 60-2, dissolve it in THF, stir under nitrogen protection, use an ice salt/methanol bath (-10°C) to raise the temperature to about -5°C, and slowly add a 1M solution of borane-tetrahydrofuran complex dropwise. Warm up to room temperature and start the reaction. After the reaction is completed, water is added and acetic acid is quenched. Spin off the THF and pour the remaining solution into ice-cold saturated sodium bicarbonate solution and stir for 20 minutes. Extract with EA and water, dry, filter, and concentrate under reduced pressure to obtain 60-3. LC-MS: (ESI) [M+H] ⁺ =241.2.

Steps 4 to 8: 4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzene And[d]imidazol-5-yl)ethyl)bicyclo[2.2.2]octane-1-carboxylic acid (Intermediate 60)

Referring to the synthetic route and method of steps 4-8 of intermediate 59, replace 59-3 with 60-3, and synthesize intermediate 60. LC-MS: (ESI) [M+H] ⁺ =440.2.

Synthesis Step 2: Synthesis of 136

Referring to the synthetic route and method of Example 26, the intermediate 25 in the synthesis step 4 was replaced with the intermediate 60; the intermediate 26 in the synthesis step 6 was replaced with the intermediate 44, and the target compound 136 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1193.5.

Example 137: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2 -Oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)bicyclo[2.2.2]octane-1-carbonyl)-6-oxodecahydropyrrolo[ 1,2-a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (137)

Referring to the synthetic route and method of Example 26, the intermediate 25 in the synthesis step 4 was replaced with the intermediate 60, and the target compound 137 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1232.4.

Example 138: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(diisopropylphosphoryl)benzyl)amino))- 1,5-dioxopent-2-yl)carbamoyl)-3-(4-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl- 2-Oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)butyl)piperidine-1-carbonyl)-6-oxodecahydropyrrolo[1,2-a ][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (138)

Referring to the synthetic route and method of Example 63, intermediate 45 in synthesis step 1 was replaced with intermediate 48, 026-3 was replaced with 130-5; intermediate 26 was replaced with intermediate 44, and the target compound 138 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1252.5.

Example 139: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(diisopropylphosphoryl)benzyl)amino))- 1,5-dioxopent-2-yl)carbamoyl)-3-(4-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl- 2-Oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)butyl)piperidine-1-carbonyl)-6-oxodecahydropyrrolo[1,2-a ][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (139)

Referring to the synthetic route and method of Example 63, intermediate 45 in synthesis step 1 was replaced with intermediate 48, 026-3 was replaced with 130-5, and the target compound 139 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1291.5.

Example 140: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)pyridin-3-yl))methyl yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(4-(2-(1-(2,6-dioxopiperidin-3-yl)- 3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)bicyclo[2.2.2]octane-1-carbonyl)-6-oxo Decahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (140)

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 with 048-2; replace intermediate 25 in synthetic step 4 with intermediate Compound 60; replacing intermediate 26 with intermediate 44, the target compound 140 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1194.5.

Example 141: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(dimethylphosphoryl)pyridin-3-yl))methyl yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(4-(2-(1-(2,6-dioxopiperidin-3-yl)- 3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)bicyclo[2.2.2]octane-1-carbonyl)-6-oxo Substituted decahydropyrro[1,2-a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (141 )

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 with 048-2; replace intermediate 25 in synthetic step 4 with intermediate 60 was synthesized to obtain the target compound 141. LC-MS: (ESI) [M+H] ⁺ =1233.4.

Example 142: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(diethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2 -Oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxodecahydropyrrolo[1,2-a][ 1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (142)

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 with 126-2; replace intermediate 25 in synthetic step 4 with intermediate Compound 28; replacing intermediate 26 with intermediate 44, the target compound 142 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1195.5.

Example 143: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(diethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2 -Oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxodecahydropyrrolo[1,2-a][ 1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (143)

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 with 126-2; replace intermediate 25 in synthetic step 4 with intermediate 28 was synthesized to obtain the target compound 143. LC-MS: (ESI) [M+H] ⁺ =1234.4.

Example 144: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(diethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2 -Oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl)-6-oxodecahydropyrrolo[1,2-a ][1,5]diazacyclin-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (144)

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 with 126-2; replace intermediate 25 in synthetic step 4 with intermediate Compound 27; replacing intermediate 26 with intermediate 44, the target compound 144 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1195.5.

Example 145: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(diethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2 -Oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl)-6-oxodecahydropyrrolo[1,2-a ][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (145)

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 with 126-2; replace intermediate 25 in synthetic step 4 with intermediate 27 was synthesized to obtain the target compound 145. LC- MS: (ESI)[M+H] ⁺ =1234.4.

Example 146: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(diisopropylphosphoryl)benzyl)amino))- 1,5-dioxopent-2-yl)carbamoyl)-3-(2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl- 2-Oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxodecahydropyrrolo[1,2-a] [1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (146)

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 with 130-2; replace intermediate 25 in synthetic step 4 with intermediate Compound 28 was replaced by intermediate 26 with intermediate 44, and the target compound 146 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1223.5.

Example 147: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(diisopropylphosphoryl)benzyl)amino))- 1,5-dioxopent-2-yl)carbamoyl)-3-(2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl- 2-Oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxodecahydropyrrolo[1,2-a] [1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (147)

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 with 130-2; replace intermediate 25 in synthetic step 4 with intermediate 28 was synthesized to obtain the target compound 147. LC-MS: (ESI) [M+H] ⁺ =1262.5.

Example 148: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(diisopropylphosphoryl)benzyl)amino))- 1,5-dioxopent-2-yl)carbamoyl)-3-(4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl- 2-Oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl)-6-oxodecahydropyrrolo[1,2- a][1,5]diazacyclin-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (148)

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 with 130-2; replace intermediate 25 in synthetic step 4 with intermediate Compound 27; replacing intermediate 26 with intermediate 44, the target compound 148 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1223.5.

Example 149: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(diisopropylphosphoryl)benzyl)amino))- 1,5-dioxopent-2-yl)carbamoyl)-3-(4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl- 2-Oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl)-6-oxodecahydropyrrolo[1,2- a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (149)

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 with 130-2; replace intermediate 25 in synthetic step 4 with intermediate 27 was synthesized to obtain the target compound 149. LC-MS: (ESI) [M+H] ⁺ =1262.5.

Example 150: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(diethylphosphoryl))pyridin-3-yl)methyl) yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2-(4-(1-(2,6-dioxopiperidin-3-yl)- 3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxodecahydropyrrolo[1 ,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (150)

Synthesis step 1: (5-(aminomethyl)pyridin-2-yl)diethylphosphine oxide (150-2)

Referring to the experimental method and route for the synthesis of 126-2 in Example 126, replace 4-bromobenzylcarbamic acid tert-butyl ester in the first step with 5-(N-BOC-aminomethyl)-2-bromopyridine, Synthesize to get 150-2. LC-MS: (ESI)[M+H] ⁺ =213.1

Synthesis Step 2: Synthesis of 150

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 with 150-2; replace intermediate 25 in synthetic step 4 with intermediate Compound 28; replacing intermediate 26 with intermediate 44, the target compound 150 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1196.5.

Example 151: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(diethylphosphoryl)pyridin-3-yl)methyl) yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2-(4-(1-(2,6-dioxopiperidin-3-yl)- 3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxodecahydropyrrolo[1 ,2-a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (151)

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 with 150-2; replace intermediate 25 in synthetic step 4 with intermediate 28 was synthesized to obtain the target compound 151. LC-MS: (ESI) [M+H] ⁺ =1235.4.

Example 152: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(diethylphosphoryl))pyridin-3-yl)methyl) yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(4-(2-(1-(2,6-dioxopiperidin-3-yl)- 3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl)-6-oxodecahydropyrrolo [1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (152)

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 with 150-2; replace intermediate 25 in synthetic step 4 with intermediate Compound 27; replacing intermediate 26 with intermediate 44, the target compound 152 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1196.5.

Example 153: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(diethylphosphoryl)pyridin-3-yl)methyl) (base)amino)-1,5- Dioxopent-2-yl)carbamoyl)-3-(4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo -2,3-Dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1 ,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (153)

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 with 150-2; replace intermediate 25 in synthetic step 4 with intermediate 27 was synthesized to obtain the target compound 153. LC-MS: (ESI) [M+H] ⁺ =1235.4.

Example 154: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(diisopropylphosphoryl)pyridin-3-yl)) Methyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2-(4-(1-(2,6-dioxopiperidin-3-yl)) -3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxodecahydropyrrolo[ 1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (154)

Synthesis step 1: (5-(aminomethyl)pyridin-2-yl)diisopropylphosphine oxide (154-2)

Referring to the experimental method and route for the synthesis of 126-2 in Example 126, 4-bromobenzylcarbamic acid tert-butyl ester in the first step is replaced with 5-(N-BOC-aminomethyl)-2-bromopyridine, Diethylphosphine oxide was replaced by diisopropylphosphine oxide, and 154-2 was synthesized. LC-MS: (ESI)[M+H] ⁺ =241.1

Synthesis Step 2: Synthesis of 154

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 with 154-2; replace intermediate 25 in synthetic step 4 with intermediate Compound 28; replacing intermediate 26 with intermediate 44, the target compound 154 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1224.5.

Example 155: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(diisopropylphosphoryl)pyridin-3-yl)) Methyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2-(4-(1-(2,6-dioxopiperidin-3-yl)) -3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxodecahydropyrrolo[ 1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (155)

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 with 154-2; replace intermediate 25 in synthetic step 4 with intermediate 28 was synthesized to obtain the target compound 155. LC-MS: (ESI) [M+H] ⁺ =1263.5.

Example 156: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(diisopropylphosphoryl)pyridin-3-yl)) Methyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(4-(2-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl)-6-oxodecahydropyrrole And[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (156)

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 with 154-2; replace intermediate 25 in synthetic step 4 with intermediate Compound 27; replacing intermediate 26 with intermediate 44, the target compound 156 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1224.5.

Example 157: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(diisopropylphosphoryl)pyridin-3-yl)) Methyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(4-(2-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl)-6-oxodecahydropyrrole And[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (157)

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 with 154-2; replace intermediate 25 in synthetic step 4 with intermediate 27 was synthesized to obtain the target compound 157. LC-MS: (ESI) [M+H] ⁺ =1263.5.

Example 158: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(diethylphosphoryl)benzyl)amino)amino)-1 ,5-dioxopent-2-yl)carbamoyl)-3-(2-((1S,4R)-(4-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxodecahydropyrrolo[ 1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (158)

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 with 126-2; replace intermediate 25 in synthetic step 4 with intermediate Compound 57; replace intermediate 26 in synthesis step 6 with intermediate 44, and synthesize target compound 158. LC-MS: (ESI) [M+H] ⁺ =1195.5.

Example 159: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(diethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(2-((1R,4S)-(4-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxodecahydropyrrolo[ 1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (159)

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 with 126-2; replace intermediate 25 in synthetic step 4 with intermediate Compound 58; replace intermediate 26 in synthesis step 6 with intermediate 44, and synthesize target compound 159. LC-MS: (ESI) [M+H] ⁺ =1195.5.

Example 160: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(diethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(2-((1S,4R)-(4-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxodecahydropyrrolo[ 1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (160)

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 with 126-2; replace intermediate 25 in synthetic step 4 with intermediate 57 was synthesized to obtain the target compound 160. LC-MS: (ESI) [M+H] ⁺ =1234.4.

Example 161: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(diethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-(2-((1R,4S)-(4-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxodecahydropyrrolo[ 1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (161)

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 with 126-2; replace intermediate 25 in synthetic step 4 with intermediate 58 was synthesized to obtain the target compound 161. LC-MS: (ESI) [M+H] ⁺ =1234.4.

Example 162: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(diethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-((1R,4R)-4-(2-(1-(2,6-dioxopiperidin-3-yl)- 3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl)-6-oxodecahydropyrrolo [1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (162)

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 with 126-2; replace intermediate 25 in synthetic step 4 with intermediate Body 55; replace intermediate 26 in synthesis step 6 Replaced with intermediate 44, the target compound 162 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1195.5.

Example 163: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(diethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-((1S,4S)-4-(2-(1-(2,6-dioxopiperidin-3-yl)- 3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl)-6-oxodecahydropyrrolo [1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (163)

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 with 126-2; replace intermediate 25 in synthetic step 4 with intermediate Compound 56; replace intermediate 26 in synthesis step 6 with intermediate 44, and synthesize target compound 163. LC-MS: (ESI) [M+H] ⁺ =1195.5.

Example 164: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(diethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-((1R,4R)-4-(2-(1-(2,6-dioxopiperidin-3-yl)- 3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl)-6-oxodecahydropyrrolo [1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (164)

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 with 126-2; replace intermediate 25 in synthetic step 4 with intermediate 55 was synthesized to obtain the target compound 164. LC-MS: (ESI) [M+H] ⁺ =1234.4.

Example 165: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(diethylphosphoryl)benzyl)amino))-1 ,5-dioxopent-2-yl)carbamoyl)-3-((1S,4S)-4-(2-(1-(2,6-dioxopiperidin-3-yl)- 3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl)-6-oxodecahydropyrrolo [1,2-a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (165)

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 with 126-2; replace intermediate 25 in synthetic step 4 with intermediate 56 was synthesized to obtain the target compound 165. LC-MS: (ESI) [M+H] ⁺ =1234.4.

Example 166: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(diisopropylphosphoryl)benzyl)amino))- 1,5-dioxopent-2-yl)carbamoyl)-3-(2-((1S,4R)-(4-(1-(2,6-dioxopiperidin-3-yl) )-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxodecahydropyrrolo [1,2-a][1,5]diazacyclin-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (166)

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 with 130-2; replace intermediate 25 in synthetic step 4 with intermediate Compound 57, intermediate 26 was replaced by intermediate 44, and the target compound 166 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1223.5.

Example 167: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(diisopropylphosphoryl)benzyl)amino))- 1,5-dioxopent-2-yl)carbamoyl)-3-(2-((1R,4S)-(4-(1-(2,6-dioxopiperidin-3-yl) )-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxodecahydropyrrolo [1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (167)

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthesis step 1. Replace it with 130-2; replace intermediate 25 in synthesis step 4 with intermediate 58, replace intermediate 26 with intermediate 44, and synthesize the target compound 167. LC-MS: (ESI) [M+H] ⁺ =1223.5.

Example 168: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(diisopropylphosphoryl)benzyl)amino))- 1,5-dioxopent-2-yl)carbamoyl)-3-(2-((1S,4R)-(4-(1-(2,6-dioxopiperidin-3-yl) )-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxodecahydropyrrolo [1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (168)

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 with 130-2; replace intermediate 25 in synthetic step 4 with intermediate 57 was synthesized to obtain the target compound 168. LC-MS: (ESI) [M+H] ⁺ =1262.5.

Example 169: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(diisopropylphosphoryl)benzyl)amino))- 1,5-dioxopent-2-yl)carbamoyl)-3-(2-((1R,4S)-(4-(1-(2,6-dioxopiperidin-3-yl) )-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxodecahydropyrrolo [1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (169)

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 with 130-2; replace intermediate 25 in synthetic step 4 with intermediate 58 was synthesized to obtain the target compound 169. LC-MS: (ESI) [M+H] ⁺ =1262.5.

Example 170: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(diisopropylphosphoryl)benzyl)amino))- 1,5-dioxopent-2-yl)carbamoyl)-3-((1R,4R)-4-(2-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl)-6-oxodecahydropyrrole And[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (170)

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 with 130-2; replace intermediate 25 in synthetic step 4 with intermediate Compound 55; replace intermediate 26 in synthesis step 6 with intermediate 44, and synthesize target compound 170. LC-MS: (ESI) [M+H] ⁺ =1223.5.

Example 171: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(diisopropylphosphoryl)benzyl)amino))- 1,5-dioxopent-2-yl)carbamoyl)-3-((1S,4S)-4-(2-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl)-6-oxodecahydropyrrole And[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (171)

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 with 130-2; replace intermediate 25 in synthetic step 4 with intermediate Compound 56; replace intermediate 26 in synthesis step 6 with intermediate 44, and synthesize target compound 171. LC-MS: (ESI) [M+H] ⁺ =1223.5.

Example 172: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(diisopropylphosphoryl)benzyl)amino))- 1,5-dioxopent-2-yl)carbamoyl)-3-((1R,4R)-4-(2-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl)-6-oxodecahydropyrrole And[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (172)

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 with 130-2; replace intermediate 25 in synthetic step 4 with intermediate 55 was synthesized to obtain the target compound 172. LC-MS: (ESI) [M+H] ⁺ =1262.5.

Example 173: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(diisopropylphosphoryl)benzyl)amino))- 1,5-dioxopent-2-yl)carbamoyl)-3-((1S,4S)-4-(2-(1-(2,6-dioxopiperidin-3-yl) -3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl)-6-oxodecahydropyrrole And[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (173)

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 with 130-2; replace intermediate 25 in synthetic step 4 with intermediate 56 was synthesized to obtain the target compound 173. LC-MS: (ESI) [M+H] ⁺ =1262.5.

Example 174: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(diethylphosphoryl)pyridin-3-yl))methyl yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2-((1S,4R)-(4-(1-(2,6-dioxopiperyl) (ridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxo Decahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (174)

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 with 150-2; replace intermediate 25 in synthetic step 4 with intermediate Compound 57; replacing intermediate 26 with intermediate 44, the target compound 174 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1196.5.

Example 175: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(diethylphosphoryl)pyridin-3-yl)methyl) yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2-((1R,4S)-(4-(1-(2,6-dioxopiperyl) (ridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxo Decahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (175)

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 with 150-2; replace intermediate 25 in synthetic step 4 with intermediate Compound 58; replacing intermediate 26 with intermediate 44, the target compound 175 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1196.5.

Example 176: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(diethylphosphoryl)pyridin-3-yl))methyl yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2-((1S,4R)-(4-(1-(2,6-dioxopiperyl) (ridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxo Substituted decahydropyrrolo[1,2-a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (176 )

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 with 150-2; replace intermediate 25 in synthetic step 4 with intermediate 57 was synthesized to obtain the target compound 176. LC-MS: (ESI) [M+H] ⁺ =1235.4.

Example 177: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(diethylphosphoryl)pyridin-3-yl))methyl yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2-((1R,4S)-(4-(1-(2,6-dioxopiperyl) (ridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxo Substituted decahydropyrro[1,2-a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (177 )

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 with 150-2; replace intermediate 25 in synthetic step 4 with intermediate 58 was synthesized to obtain the target compound 177. LC-MS: (ESI) [M+H] ⁺ =1235.4.

Example 178: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(diethylphosphoryl))pyridin-3-yl)methyl) yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-((1R,4R)-(4-(2-(1-(2,6-dioxopiperyl) (ridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl)-6 -Oxodecahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (178)

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 with 150-2; replace intermediate 25 in synthetic step 4 with intermediate Compound 55; replacing intermediate 26 with intermediate 44, the target compound 178 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1196.5.

Example 179: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(diethylphosphoryl)pyridin-3-yl)methyl) yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-((1S,4S)-(4-(2-(1-(2,6-dioxopiperyl) (ridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl)-6 -Oxodecahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (179)

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 with 150-2; replace intermediate 25 in synthetic step 4 with intermediate Compound 56; replacing intermediate 26 with intermediate 44, the target compound 179 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1196.5.

Example 180: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(diethylphosphoryl))pyridin-3-yl)methyl) yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-((1R,4R)-(4-(2-(1-(2,6-dioxopiperyl) (ridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl)-6 -Oxodecahydropyrrolo[1,2-a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (180)

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 with 150-2; replace intermediate 25 in synthetic step 4 with intermediate 55 was synthesized to obtain the target compound 180. LC-MS: (ESI) [M+H] ⁺ =1235.4.

Example 181: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(diethylphosphoryl)pyridin-3-yl)methyl) yl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-((1S,4S)-(4-(2-(1-(2,6-dioxopiperyl) (ridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl)-6 -Oxodecahydropyrrolo[1,2-a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (181)

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 with 150-2; replace intermediate 25 in synthetic step 4 with intermediate 56 was synthesized to obtain the target compound 181. LC-MS: (ESI) [M+H] ⁺ =1235.4.

Example 182: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(diisopropylphosphoryl)pyridin-3-yl)) Methyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2-((1S,4R)-(4-(1-(2,6-dioxo) Piperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6- Oxodecahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (182)

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthesis step 1. Replace it with 154-2; replace intermediate 25 in synthesis step 4 with intermediate 57; replace intermediate 26 with intermediate 44, and synthesize the target compound 182. LC-MS: (ESI) [M+H] ⁺ =1224.5.

Example 183: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(diisopropylphosphoryl)pyridin-3-yl)) Methyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2-((1R,4S)-(4-(1-(2,6-dioxo) Piperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6- Oxodecahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (183)

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 with 154-2; replace intermediate 25 in synthetic step 4 with intermediate Compound 58; replacing intermediate 26 with intermediate 44, the target compound 183 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1224.5.

Example 184: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(diisopropylphosphoryl)pyridin-3-yl)) Methyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2-((1S,4R)-(4-(1-(2,6-dioxo) Piperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6- Oxodecahydropyrrolo[1,2-a][1,5]diazacyclin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid ( 184)

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 with 154-2; replace intermediate 25 in synthetic step 4 with intermediate 57 was synthesized to obtain the target compound 184. LC-MS: (ESI) [M+H] ⁺ =1263.5.

Example 185: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-(((6-(diisopropylphosphoryl))pyridin-3-yl )methyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-(2-((1R,4S)-(4-(1-(2,6-dioxo Piperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6 -Oxodecahydropyrrolo[1,2-a][1,5]diazacyclin-5-yl) Carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoric acid (185)

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 with 154-2; replace intermediate 25 in synthetic step 4 with intermediate 58 was synthesized to obtain the target compound 185. LC-MS: (ESI) [M+H] ⁺ =1263.5.

Example 186: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((6-(diisopropylphosphoryl)pyridin-3-yl)) Methyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-((1R,4R)-(4-(2-(1-(2,6-dioxo) Piperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl)- 6-Oxodecahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (186)

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthetic step 1 with 154-2; replace intermediate 25 in synthetic step 4 with intermediate Compound 55; replacing intermediate 26 with intermediate 44, the target compound 186 was synthesized. LC-MS: (ESI) [M+H] ⁺ =1224.5.

Example 187: (2-(((5S,8S,10aR)-8-(((S)-5-amino-1-(((6-(diisopropylphosphoryl)pyridin-3-yl)) Methyl)amino)-1,5-dioxopent-2-yl)carbamoyl)-3-((1S,4S)-(4-(2-(1-(2,6-dioxo Piperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexane-1-carbonyl)- 6-Oxodecahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate (187)

Referring to the synthetic route and method of Example 26, replace (4-(aminomethyl)phenyl)dimethylphosphine oxide in synthesis step 1. Replace it with 154-2; replace intermediate 25 in synthesis step 4 with intermediate 56; replace intermediate 26 with intermediate 44, and synthesize the target compound 187. LC-MS: (ESI) [M+H] ⁺ =1224.5.

Example 188. Protein degradation activity test

1. Cell seed plate

Plates are seeded based on specific tumor cells. The tumor cell seeding plate density is 800,000-1 million/well, the PBMC seeding plate is 1.3 million/well, the cell suspension volume is 2mL/well, 12-well plate.

2. Cell drug delivery

Use DMSO to prepare a stock solution of the compound to be tested, with a concentration of 0.1%.

System: 1mL cell culture medium (aspirate 2uL culture medium) + 2uL test compound storage solution.

3. Cell sample processing

Collect suspended cells: Collect the cell suspension into a 2mL centrifuge tube, centrifuge at 1500rpm for 10min, discard the supernatant, add 1mL of PBS and pipet gently, transfer to a 1.5mL sterile centrifuge tube, centrifuge at 1500rpm for 10min, discard the supernatant , try to absorb the liquid as much as possible, and store at -20℃ (storage for one week) or -80℃ (storage for one month) for later use.

Add phosphatase inhibitor and PMSF at a ratio of 100:1 = Ripa lysis solution: (100x phosphatase inhibitor, 100xPMSF), shake well and place on ice. Add 100uL lysis buffer for every 1 million cells, centrifuge at 12500rpm for 15min at 4°C and take the supernatant.

4. Determine the protein concentration using the BCA method according to the instructions of the BCA kit.

5. After SDS-PAGE gel electrophoresis, transfer to membrane, and use Western Blot method to determine STAT3/STAT1 protein concentration.

6. DC ₅₀ calculation: Use ImageJ to quantify the signal intensity of the corresponding band of STAT3/1, and compare it with the DMSO control group to calculate the protein degradation rate at the corresponding concentration. Draw a degradation curve based on the protein content at different concentrations of the compound to be tested, and calculate DC ₅₀ .

Table 1 STAT3 degradation activity of compounds of the present invention

A:DC ₅₀ <50nM;B:50nM<DC ₅₀ <500nM;C:500nM<DC ₅₀

The results in Table 1 show that the compounds of the present invention have potent STAT3 degradation activity.

Table 2 STAT1 degradation activity of compounds of the present invention

A:DC ₅₀ <50nM;B:50nM<DC ₅₀ <500nM;C:500nM<DC ₅₀

The results in Table 2 show that the compounds of the present invention have no significant degradation activity on STAT1.

Compound c:

Example 189. Tumor cell proliferation inhibitory activity test

The anti-tumor activity of the test compound is detected by detecting the inhibitory effect of the test compound on the cell proliferation of MOLM16 or SU-DHL-1. The cell culture medium is RPMI-1640 medium + 10% fetal calf serum. Digest the cells, seed MOLM16 or SU-DHL-1 in a 96-well plate, 80,000/well, and incubate for 1 h at 37°C and 5% _CO2 . Different concentrations of test compound solutions (1000nM, 4-fold dilution, 8 concentration gradients) were added to each well of the 96-well plate, and the control group was 0.1% DMSO solution. After incubation for 96 hours at 37°C, 5% _CO2 , add 20 μL MTS to each well. After incubation for 2 h, 25 μL of 10% SDS was added to each well to terminate the reaction. Measure the absorbance at 490 nm with a microplate reader. _IC50 was calculated using GraphPad Prism 5.0.

Table 3 The inhibitory activity of compounds of the present invention on MOLM16 cell proliferation

A:IC ₅₀ <10nM B:10nM<IC ₅₀ <50nM C:50nM<IC ₅₀

The results in Table 3 show that the compounds of the present invention have obvious proliferation inhibitory activity on MOLM16 cells. Compound a:

Compound b:

Compound e:

Compound f:

Table 4 The inhibitory activity of compounds of the present invention on SU-DHL-1 cell proliferation

A:IC ₅₀ <100nM B:100nM<IC ₅₀ <500nM C:500nM<IC ₅₀

The results in Table 4 show that the compounds of the present invention have obvious proliferation inhibitory activity on SU-DHL-1 cells.

Compound d:

Example 190. Anti-tumor efficacy in vivo

SU-DHL-1 cell line, 10 million cells/mouse were inoculated into the right armpit of NSG mice. After the tumors grew to ^80mm3 , the drugs were administered in groups. Mice in each group were given a corresponding dose of the compound to be tested. The dosage of each compound to be tested was as shown in the table below. The mice were administered once a week by intravenous injection (vehicle: 100% physiological saline). Tumor volume was measured on D1/D4 every week, and the tumor growth curve was drawn based on the measured volume. By comparing the tumor volume with the blank group, the tumor was peeled off and weighed, and the tumor inhibition coefficient was calculated.

Tumor volume: V＝a*b ² /2

a is the long diameter of the tumor, b is the short diameter of the tumor

TGI%=(1- _RTV of administration group/ _RTV of blank group)*100%

Table 5 Anti-tumor efficacy of the compounds of the present invention in vivo

The results in Table 5 show that the compounds of the present invention have significant anti-tumor properties in vivo.

Example 191. In vivo pharmacokinetic test in mice

Precisely weigh the compound to be tested and prepare a solution of corresponding concentration with physiological saline. Male ICR mice were injected into the tail vein with a corresponding concentration of test compound solution at a volume of 10 mL/kg. After intravenous administration, 3 mice were taken at each time point at 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h and 24h, and blood was collected through the orbital vein. The collected blood samples were collected in EP tubes containing EDTA anticoagulation, placed on ice, and centrifuged to separate plasma within 1 hour (centrifugation conditions: 5000 rpm, 10 minutes, 2-8°C). Plasma samples were stored in a -80°C refrigerator before analysis.

After all the compounds to be tested are completely melted, mix well for 10 to 30 seconds, and centrifuge at 4000 rpm and 4°C for 0.5 minutes. Pipette 15.0μL plasma sample (blank sample and internal standard blank sample plus 15.0μL blank plasma) into a 96-well plate, add 150μL 50% methanol acetonitrile solution containing internal standard (50ng/mL) (add 150μL 50% methanol acetonitrile to Doubleblank sample) solution). Vortex the sample for 5 minutes, centrifuge it at 4000 rpm and 4°C for 10 minutes, pipet 100 μL and add it to 100 μL of water, mix evenly, and analyze by LC-MS/MS.

Using blood drug concentration data at different time points, Phoenix WinNonlin8.2.0 was used to calculate pharmacokinetic parameters.

Table 6 Pharmacokinetic properties of compounds of the present invention

Note: DNAUC represents the ratio of the area under the drug curve (AUC) to the corresponding dose mpk.

The results in Table 6 show that the compounds of the present invention have good pharmacokinetic properties.

Claims

A compound characterized by having a structure represented by general formula (I):

Or its stereoisomer, or its stereoisomer mixture, or its pharmaceutically acceptable salt;

in:

R 1 and R 2 are each independently selected from: H, -Me, -Et,

X 1 is selected from: -CH 2 -, -CF 2 -, -CO-;

X 2 is selected from: S, NRd, O;

X 3 , X 4 , X 5 , X 6 are independently selected from: CRa, N;

R 3 is selected from: H, R 7 , R 7 -(CH 2 ) p -, R 7 -(CH 2 ) p -CO-, R 7 -(CH 2 ) p -O-CO-, R 7 -( CH 2 ) p -NH-CO-, R 7 -(CH 2 ) p -SO 2 -; any one or more of the above methylene groups (-CH 2 -) can be independently replaced by the following groups: -COO -, -CONH-, -OCONH-, -NHCONH-, -O-, -NRa-, -S-, -CO-, -CRa＝CRb-, -C≡C-, -SO-, -SO 2 - , C 3 -C 10 cycloalkylene, 3-10 membered heterocyclylene, phenylene, 5-6 membered heteroarylene, -CRaRb-;

R 4 is selected from: H, R 7 , R 7 -(CH 2 ) p -, R 7 -(CH 2 ) r -CO-(CH 2 ) s -; any one or more of the above methylene groups (-CH 2 -) Each independently can be replaced by the following groups: -COO-, -CONH-, -OCONH-, -NHCONH-, -O-, -CF 2 -, -NRa-, -S-, -CO-, -CRa＝CRb-, -C≡C-, -SO-, -SO 2 -, C 3 -C 10 cycloalkylene, 3-10 membered heterocyclylene, phenylene, 5-6 membered heterocyclylene Aryl, -CRaRb-;

R 7 is selected from: H, halogen, -CN, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, halogenated C 3 -C 6 cycloalkyl, 3-10 membered heterocyclyl, phenyl, heteroaryl, E3;

Ring A is selected from: C 6 -C 10 aryl, 5-10 membered heteroaryl, and the heteroaryl contains 1 to 4 heteroatoms selected from O, S, and N;

R 6 is selected from: -(CH 2 ) p -P(O)R 8 R 9 ;

R 5 is selected from: H, halogen, CN, -OH, nitro, carboxyl, amino, amide, -P(O)R 8 R 9 , acyl, -SO 2 , sulfonamide, C 1 -C 6 alkane Oxygen group, halo C 1 -C 6 alkoxy group, C 1 -C 6 alkyl group, C 1 -C 6 haloalkyl group, hydroxyalkyl group, aminoalkyl group, C 1 -C 6 alkyl-sulfonamide group, C 1 -C 6 haloalkyl-sulfonamide, C 3 -C 8 cycloalkyl, halo C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkoxy, alkylamino, haloalkylamino, C 3 -C 8 cycloalkylamino, C 1 -C 6 alkyl -SO 2 -, C 1 -C 6 haloalkyl -SO 2 -, C 3 -C 8 cycloalkylamino, aminosulfonyl, carbamoyl;

R 8 and R 9 are each independently selected from: H, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl;

Or R 9 in any R 5 and R 6 on ring A together with the ring A form a ring, and the ring is optionally substituted by H, halogen, oxo, -CN, -OH, - NHRd, -ORd, -CORd, -COORd, -SO 2 Rd, -N(Rd)C(=O)-Rj, -N(Rd)C(=O)ORj, -N(Rd)C(=O )NRjRk, -N(Rd)S(=O)NRjRk, -N(Rd)S(O) 2 NRjRk, nitro group, carboxyl group, amino group, amide group, C 1 -C 6 alkyl group, halogenated C 1 - C 6 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, 3-10 membered heterocyclyl, phenyl, Heteroaryl substitution;

Or any R 5 and R 4 on ring A together with the ring A form a ring, and the ring is optionally substituted by H, halogen, oxo, -CN, -OH, -NHRd, -ORd , -CORd, -COORd, -SO 2 Rd, -N(Rd)C(=O)-Rj, -N(Rd)C(=O)ORj, -N(Rd)C(=O)NRjRk, - N(Rd)S(=O)NRjRk, -N(Rd)S(O) 2 NRjRk, nitro group, carboxyl group, amino group, amido group, C 1 -C 6 alkyl group, halogenated C 1 -C 6 alkyl group , C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, 3-10 membered heterocyclyl, phenyl, heteroaryl substitution ;

Ra and Rb are each independently selected from: H, halogen, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, 3-10 membered heterocyclyl, phenyl, heteroaryl, -CN, -NHRd, -ORd;

Rd, Rj, and Rk are each independently selected from: H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, 3-10 membered heterocyclyl, phenyl, hetero Aryl;

m is selected from: 0, 1, 2, 3;

n is selected from: 0, 1, 2, 3;

p is selected from: 0, 1, 2, 3, 4, 5, 6, 7, 8;

r is selected from: 0, 1, 2, 3, 4, 5, 6, 7, 8;

s is selected from: 0, 1, 2;

E3 is selected from:

Re is selected from: H, -Me, -Et, -CF 3 , -OMe, -OH, -F, -Cl, -CN;

W 1 , W 2 , W 3 and W 4 are each independently selected from: CH, N.
The compound according to claim 1, characterized in that it has a structure represented by general formula II:

Or its stereoisomer, or its stereoisomer mixture, or its pharmaceutically acceptable salt;

Among them: X 16 is selected from: CH, N.
The compound according to claim 1, characterized in that in the general formula

Partially selected from: X 2 is selected from: S, NRd, O.
The compound according to claim 1, characterized in that it has a structure represented by general formula III:

Or its stereoisomer, or its stereoisomer mixture, or its pharmaceutically acceptable salt;

Among them: X 16 is selected from: CH, N.
The compound according to claim 2 or 3, characterized in that in the general formula;

Parts are selected from the following structures:

m is selected from: 0, 1, 2, 3;

n’ or n” are each independently selected from: 0, 1, 2, 3;

R 8 is selected from: methyl, ethyl, propyl, isopropyl;

R 9 is selected from: methyl, ethyl, propyl, isopropyl.
The compound according to claim 3, characterized in that it has a structure represented by general formula IV

Or its stereoisomer, or its stereoisomer mixture, or its pharmaceutically acceptable salt.
The compound according to claim 6, characterized in that it has a structure represented by the general formula V(a) or V(b) or V(c) or V(d):

Or its stereoisomer, or its stereoisomer mixture, or its pharmaceutically acceptable salt;

in:

R 3 is selected from: CF 3 CH 2 -, CF 3 -, CF 2 HCH 2 -, -Me, -Et, -iPr, CH 3 OCO-, CH 3 CO-, CH 3 NHCO-, CH 3 SO 2 - , iPrSO 2 -, R 7 -(CH 2 ) r -, any one or more of the above methylene groups (-CH 2 -) can be independently replaced by the following groups: -COO-, -CONH-, - OCONH-, -NHCONH-, -O-, -NRa-, -S-, -CO-, -CRa＝CRb-, -C≡C-, -SO-, -SO 2 -, C 3 -C 10 sub Cycloalkyl, 3-10 membered heterocyclylene, phenylene, 5-6 membered heteroarylene, -CRaRb-;

R 13 is selected from: R 7 -(CH 2 ) r -, any one or more of the above methylene groups (-CH 2 -) can be independently replaced by the following groups: -COO-, -CONH-, -OCONH -, -NHCONH-, -O-, -NRa-, -S-, -CO-, -CRa＝CRb-, -C≡C-, -SO-, -SO 2 -, C 3 -C 10 subring Alkyl, 3-10 membered heterocyclylene, phenylene, 5-6 membered heteroarylene, -CRaRb-;

R 14 is selected from: R 7 -(CH 2 ) p -, R 7 -(CH 2 ) p -CO-, R 7 -(CH 2 ) p -O-CO-, R 7 -(CH 2 ) p - NH-CO-, R 7 -(CH 2 ) p -SO 2 -; any one or more of the above methylene groups (-CH 2 -) can be independently replaced by the following groups: -COO-, -CONH- , -OCONH-, -NHCONH-, -O-, -NRa-, -S-, -CO-, -CH＝CH-, -C≡C-, -SO-, -SO 2 -, C 3 -C 10- membered cycloalkylene, 3-10-membered heterocyclylene, phenylene, 5-6-membered heteroarylene, -CRaRb-;

R 7 is selected from: E3;

r is selected from: 0, 1, 2, 3, 4, 5, 6, 7, 8;

R 8 and R 9 are each independently selected from ethyl and isopropyl.
The compound according to claim 1, characterized in that, in the general formula, the C atom connected to R4 is a chiral carbon atom with R or S configuration.
The compound according to claim 7, characterized in that it has a structure represented by general formula (VI);

Or its stereoisomer, or its stereoisomer mixture, or its pharmaceutically acceptable salt;

in:

X 1 is selected from: -CF 2 - or -CO-;

X 2 is selected from: S, NH or NCH 3 ;

R 3 is selected from: CF 3 CH 2 -, CF 3 -, CF 2 HCH 2 -, -Me, -Et, -iPr, -Ac, CH 3 OCO-, CH 3 CO-, CH 3 NHCO-, CH 3 SO 2 - or iPrSO 2 -;

R 5 is selected from: H, halogen, CN, -OH, nitro, carboxyl, amino, amide, -P(O)R 8 R 9 , acyl, -SO 2 , sulfonamide, hydroxyalkyl, aminoalkyl base, C 1 -C 6 alkoxy group, C 1 -C 6 haloalkoxy group, C 1 -C 6 alkyl group, C 1 -C 6 haloalkyl group, C 1 -C 6 alkyl-sulfonamide group, C 1 -C 6 haloalkyl-sulfonamido, C 3 -C 8 cycloalkyl, halo C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkoxy, alkylamino, haloalkylamino, C 3 -C 8 cycloalkylamino, C 1 -C 6 alkyl-SO 2 -, C 1 -C 6 haloalkyl -SO 2 -, C 3 -C 8 cycloalkylamino, aminosulfonyl, carbamoyl;

R 13 is selected from: R 7 -(CH 2 ) r -, any one or more methylene groups (-CH 2 -) in (CH 2 ) r can be independently replaced by the following groups: -COO-, - CONH-, -OCONH-, -NHCONH-, -O-, -NRa-, -S-, -CO-, -CRa=CRb-, -C≡C-, -SO-, -SO 2 -, C 3 -C 10- membered cycloalkylene, 3-10-membered heterocyclylene, phenylene, 5-6-membered heteroarylene, -CRaRb-;

R 7 is selected from: E3.
The compound according to claim 1, characterized in that,

R 5 is selected from: H, fluorine, chlorine, bromine, CN, -OH, nitro, carboxyl, amino, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, Isopropoxy, difluoromethyl, difluoromethoxy, trifluoromethyl, trifluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropoxy, cyclobutoxy base, cyclopentyloxy group, cyclohexyloxy group.
The compound according to any one of claims 1-10, characterized in that E3 is selected from:
The compound according to claim 1, characterized in that, in R 3 or R 4 , the -(CH 2 ) p or -(CH 2 ) r or after the replacement, the structure is as follows:

The end marked with # is connected to E3.
The compound according to claim 1, characterized in that it is selected from the following compounds:

Or its stereoisomer, or its stereoisomer mixture, or its pharmaceutically acceptable salt.
The compound according to any one of claims 1 to 13, characterized in that the pharmaceutically acceptable salt is a salt formed by the corresponding compound and a base, including but not limited to sodium salt, potassium salt, magnesium salt, ammonium salt One or more of the salts.
A pharmaceutical composition, characterized by comprising one or more compounds according to any one of claims 1 to 14.
A pharmaceutical preparation, characterized in that it includes one or more compounds according to any one of claims 1 to 14, including tablets, powders, capsules, injection preparations, granule preparations, and sprays.
A compound according to any one of claims 1 to 14, a pharmaceutical composition according to claim 15 or a pharmaceutical preparation according to claim 16 for use alone or in combination with other drugs to treat patients who benefit from STAT3 degradation. Use in medicines for diseases, disorders or conditions.
The use of claim 17, wherein the disease, disorder or condition is a disease, disorder or condition that benefits from inhibiting the transcription factor STAT3.
The application according to claim 17, characterized in that the combined application of the drug is a combination of immune checkpoint inhibitors, chemotherapy, and targeted therapy.
The application according to claim 17, wherein the disease is selected from the group consisting of hematological malignancies, solid tumors, and autoimmune diseases.
The application according to claim 20, wherein the hematological malignant tumors include leukemia, lymphoma, multiple myeloma, myelodysplastic syndrome, and myelofibrosis; the autoimmune diseases include: rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, insulin-dependent diabetes mellitus (type I), Hashimoto's thyroiditis, Graves' disease, ulcerative colitis, chronic active hepatitis, psoriasis, inflammatory bowel disease disease and ankylosing spondylitis, idiopathic pulmonary fibrosis, atopic dermatitis, acute graft-versus-host disease, chronic graft-versus-host disease and tissue fibrotic diseases; the solid tumors include: digestive system malignant tumors, respiratory Systemic malignant tumors, central nervous system tumors, urinary system malignant tumors, gynecological malignant tumors, sarcoma, melanoma, bone cancer.