WO2022194269A1

WO2022194269A1 - Novel egfr degradation agent

Info

Publication number: WO2022194269A1
Application number: PCT/CN2022/081618
Authority: WO
Inventors: 潘建峰; 孙大庆
Original assignee: 上海齐鲁制药研究中心有限公司
Priority date: 2021-03-19
Filing date: 2022-03-18
Publication date: 2022-09-22
Also published as: TW202237597A; CN116888108A

Abstract

A novel bifunctional compound (I) capable of degrading an EGFR, a pharmaceutical composition containing the compound, a preparation method, and a method for treating a cell proliferative disease, such as a cancer, by using the compound.

Description

Novel EGFR degraders

Technical field:

The invention belongs to the field of medicinal chemistry, and particularly relates to a novel bifunctional compound capable of degrading EGFR, a pharmaceutical composition containing the compound, a preparation method thereof, and a method for treating EGFR-mediated cancer using the compound of the present invention.

Background technique:

In recent years, the PROTAC technology (Proteolysis Targeting Chimeria) based on the ubiquitin-proteasome system (UPS) has been rapidly developed. PROTAC technology originated from the Nobel Prize in Chemistry in 2004 – the discovery by Israeli scientists Aaron Ciechanover, Avram Hershko and American scientist Irwin Rose that cells degrade harmful proteins, that is, ubiquitin-regulated protein degradation.

PROTAC is a bifunctional small molecule triplet compound, which can be divided into three parts: target protein ligand, Linker (linker), and E3 ligase ligand (degron). After the PROTAC molecule enters the cell, the protein of interest (POI) ligand in its structure can specifically bind to the corresponding target protein, while the other end can recruit E3 ligase to form a POI-Linker-E3 ligase ternary A complex in which the E3 ligase mediates the ubiquitination of POIs by the ubiquitin-conjugating enzyme E2. The ubiquitin-tagged POI is recognized and degraded by the proteasome.

Theoretically, PROTAC is an event-driven pharmacological mode of action. This process does not require the target protein ligand to occupy the binding site for a long time. The ubiquitination of the target protein can be instantaneously completed only by the short-term formation of the ternary complex. Therefore, compared with traditional small molecule inhibitors and macromolecular antibodies, PROTAC has obvious advantages, and it is expected to target those proteins that are difficult to make medicines, and may have the advantages of small dosage, low toxicity, and no drug resistance. It relies on the advantages of affinity, high selectivity, and overcoming drug resistance caused by target protein mutation/overexpression.

EGFR, the epidermal growth factor receptor (epidermal growth factor receptor), is widely distributed on the surface of mammalian epithelial cells, fibroblasts, glial cells and other cells. The EGFR signaling pathway plays an important role in physiological processes such as cell growth, proliferation and differentiation. EGFR mutation is also the most common type of mutation in NSCLC patients, especially in Asian populations, which can account for 40% to 50%. Therefore, EGFR has always been one of the most popular targets in pharmaceutical industry research.

At present, there are first, second and third generation EGFR inhibitors on the market. The first generation is reversible targeted drugs, such as gefitinib, erlotinib, and icotinib. The second generation is irreversible targeted drugs, such as afatinib and dacomitinib. Although the first and second-generation targeted drugs are effective, most patients will develop drug resistance within 1-2 years of use. Among patients with EGFR inhibitor resistance, 50% of the resistance is related to the T790M mutation. The third-generation EGFR-targeted drug osimertinib can bind to the T790M mutation site of EGFR-sensitive mutation to inhibit tumor resistance caused by T790M mutation. Its advent has brought good survival benefits to more lung cancer patients . However, resistance to third-generation EGFR inhibitors is inevitable due to the C797S mutation.

For the current resistance to osimertinib, there is no mature treatment method. Based on the imminent clinical needs and the unique advantages of PROTAC technology, the present invention aims to develop a bifunctional small molecule that can specifically degrade EGFR protein. triplet compound.

Invention content:

The present invention provides a novel bifunctional compound that can be used to degrade EGFR, a pharmaceutical composition containing the compound, its preparation method and its use in the treatment of EGFR-mediated cancer.

The compound according to the present invention is a triplet compound comprising a targeting ligand, a linker and a degron, as shown in formula (X),

Among them, the targeting ligand can specifically bind to the target protein, such as EGFR and/or mutated EGFR, and is connected to the linker through a covalent bond in the triplet compound; the linker is the linking group between the targeting ligand and the degron , one end is covalently bound to the targeting ligand, and the other end is covalently bound to the degron; the degron can bind ubiquitin ligases, such as E3 ubiquitin ligase, to covalently bind to the linker.

Specifically, the present invention provides a bifunctional compound represented by formula (I) and stereoisomers, tautomers or pharmaceutically acceptable salts, prodrugs, hydrates, solvates, isotopes thereof labelled derivatives,

Formula (TL) is a targeting ligand, which is covalently bound to the linker through the R ¹ group, wherein,

R ¹ is selected from

or ^A optionally substituted with one or more R groups;

A is selected from 3-7-membered heterocycloalkyl, 3-7-membered heterocycloalkyl-O-, 3-7-membered heterocycloalkyl-NR ^a- , -(3-7-membered heterocycloalkyl)-( 3-7-membered heterocycloalkyl)-, 6-14-membered spiro heterocyclyl, 6-14-membered bridged heterocyclyl, 6-14-membered heterocyclyl;

R ² is selected from C _6-10 aryl, 5-12 membered heteroaryl, 5-6 membered heterocycloalkenyl, wherein said C _6-10 aryl, 5-12 membered heteroaryl, 5-6 membered The heterocycloalkenyl groups are each independently optionally substituted with one or more R ¹⁰ groups;

R ³ is selected from H, halogen, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 haloalkoxy;

M is selected from N or CR ¹¹ ;

R ⁴ is selected from H, halogen, -CN, C _1-4 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkyl;

R ⁵ is selected from _-C (=O) ^NRbRc ,-S(=O) ^2Rb ,-P(=O ⁾ ^RbRc , ^-P ⁽ =O ⁾ ^RbNRcRd ,- P(=O) ^RbORc ,-P(=O) ^ORbORc ,-P(=S ⁾ ^RbRc ,-P ⁽ =S ⁾ ^RbNRcRd , ^-P ⁽ =S )R ^b OR ^c , -P(=S)OR ^b OR ^c , -S(=O) ₂ NR ^b R ^c , -NR ^c S(=O) ₂ R ^b , or -NR ^b C(O)R ^c ;

R ⁶ , R ⁷ , R ⁸ are each independently selected from H, C _1-4 alkyl, halogen, C _3-6 cycloalkyl;

Alternatively, R ⁶ , R ⁷ and the atoms to which they are attached are cyclized to C _4-6 cycloalkyl, 4-7 membered heterocycloalkyl, 5-7 membered heteroaryl;

Or R ⁷ , R ⁸ and the atoms to which they are attached are cyclized together to form C _4-6 cycloalkyl, 4-7 membered heterocycloalkyl, 5-7 membered heteroaryl;

Each R ⁹ is independently selected from H, halogen, -OH, -NH ₂ , C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, -C _0-4 alkyl-NR ^a R ^b ;

Each R ¹⁰ is independently selected from H, halogen, C _1-4 alkyl, C _1-4 haloalkyl, C _3-6 cycloalkylsulfonyl;

R ¹¹ is selected from H, halogen, C _1-4 alkyl;

R ^a is selected from H, C _1-4 alkyl;

R ^b , R ^c , and R ^d are each independently selected from H, C _1-4 alkyl, C _3-6 cycloalkyl;

The linker is the group covalently bound to the R1 group and the ^degron in the targeting ligand;

A degron is a group capable of binding to ubiquitin ligases.

In some embodiments of the present invention, the compound represented by the above formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt, prodrug, hydrate, solvate, isotopic label derivatization things, of which,

R ¹ is selected from

or ^A optionally substituted with one or more R groups;

A is selected from 3-7-membered heterocycloalkyl, 3-7-membered heterocycloalkyl-O-, 3-7-membered heterocycloalkyl-NR ^a- , -(3-7-membered heterocycloalkyl)-( 3-7 membered heterocycloalkyl)-, 6-14 membered spiro heterocyclyl, 6-14 membered bridged heterocyclyl, 6-14 membered heterocyclyl;

M is selected from N or CR ¹¹ ;

R ⁶ , R ⁷ , R ⁸ are each independently selected from H, C _1-4 alkyl;

Alternatively, R ⁶ , R ⁷ and the atoms to which they are attached are cyclized together to form C _4-6 cycloalkyl, 5-7 membered heteroaryl;

Or R ⁷ , R ⁸ and the atoms to which they are attached are cyclized together to form C _4-6 cycloalkyl, 5-7 membered heteroaryl;

R ¹¹ is selected from H, halogen, C _1-4 alkyl;

R ^a is selected from H, C _1-4 alkyl;

A degron is a group capable of binding to ubiquitin ligases.

R ¹ is selected from

or ^A optionally substituted with one or more R groups;

A is selected from 3-7-membered heterocycloalkyl, 3-7-membered heterocycloalkyl-O-, 3-7-membered heterocycloalkyl-NR ^a- , -(3-7-membered heterocycloalkyl)-( 3-7 membered heterocycloalkyl)-, 6-14

Member spiro heterocyclyl, 6-14 membered heterocyclyl;

R ² is selected from 5-6 membered heteroaryl groups, wherein the 5-6 membered heteroaryl groups are optionally substituted with one or more R ¹⁰ groups;

R ³ is selected from C _1-4 alkoxy;

M is selected from CR ¹¹ ;

R ⁴ is selected from H, halogen, C _1-4 alkyl;

R ⁵ is selected from -P(=O)R ^b R ^c , -NR ^c S(=O) ₂ R ^b ;

R ⁶ , R ⁷ and R ⁸ are each independently selected from H, C _1-4 alkyl;

Alternatively, R ⁶ , R ⁷ and the atoms to which they are attached are cyclized together to form a 5-7 membered heteroaryl;

each R ⁹ is independently selected from H, halogen, -OH, -NH ₂ , C _1-4 alkyl;

Each R ¹⁰ is independently selected from H, C _1-4 alkyl;

R ¹¹ is selected from H, halogen;

R ^a is selected from H, C _1-4 alkyl;

R ^b and R ^c are each independently selected from H, C _1-4 alkyl;

A degron is a group capable of binding to ubiquitin ligases.

In some aspects of the invention, A is selected from the group consisting of 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkyl-O-, 5-6 membered heterocycloalkyl-NR ^a- , -(5-6 membered heterocycloalkyl)-(5-6 membered heterocycloalkyl)-, 7-11 membered spiroheterocyclyl, 8-10 membered heterocyclyl.

In some aspects of the invention, A is selected from the group consisting of 5-6 membered azacycloalkyl, 5-6 membered azacycloalkyl-O-, 5-6 membered azacycloalkyl-NR ^a- , -( 5-6 membered heterocycloalkyl)-(5-6 membered heterocycloalkyl)-, 7-11 membered spiroheterocyclyl, 8-10 membered azanocyclyl.

In some embodiments of the invention, A is selected from 5-6 membered azacycloalkyl.

In some embodiments of the invention, A is selected from 11-membered azaspirocyclyl.

In some aspects of the invention, A is selected from 8-membered azacyclocyclyl.

In some aspects of the invention, M is selected from CH.

In some aspects of the invention, M is selected from CF.

In some aspects of the present invention, A above is selected from

^Ra is as defined above.

In some aspects of the present invention, A above is selected from

In some aspects of the present invention, A above is selected from

In some aspects of the invention, the above formula R ¹ is selected from

^Ra is as defined above.

In some aspects of the present invention, the above R ¹ is selected from

In some aspects of the present invention, the above R ¹ is selected from

In some aspects of the present invention, A above is selected from

In some aspects of the present invention, the above R ¹ is selected from

In some embodiments of the present invention, the above R ¹⁰ is selected from H, methyl, ethyl or difluoromethyl.

In some aspects of the invention, the above R ² is selected from

In some aspects of the invention, the above R ² is selected from

In some embodiments of the present invention, the above ^R3 is selected from methoxy.

In some aspects of the present invention, the above ^R3 is selected from H, methyl, F.

^In some embodiments of the present invention, the above R4 is selected from F, Cl, Br or methyl.

^In some aspects of the invention, the above R4 is selected from Br.

^In some aspects of the invention, R4 above is selected from H.

^In some embodiments of the present invention, the above R4 is selected from trifluoromethyl.

In some aspects of the invention, the above R ⁵ is selected from

In some aspects of the present invention, the above R ⁶ , R ⁷ , R ⁸ are selected from H.

In some embodiments of the present invention, the above R ⁶ , R ⁷ , and R ⁸ are each independently selected from CH ₃ , cyclopropyl, and fluorine.

In some aspects of the present invention, the above R ⁶ and R ⁷ are selected from CH ₃ .

In some embodiments of the present invention, the above R ⁶ is selected from H, and R ⁷ is selected from CH ₃ , cyclopropyl, and fluorine.

^In some embodiments of the present invention, R6, ^R7 above, and the atoms to which they are attached are cyclized together to form a pyrazine ring.

^In some aspects of the invention, R6, ^R7 above, and the atoms to which they are attached are cyclized together to form a pyridine ring.

In some aspects of the invention, the targeting ligand formula (TL) is selected from:

The targeting ligand is

Covalently binds to the linker.

In some aspects of the invention, the above linker has the formula LA:

or its stereoisomers,

Wherein, p ₁ is selected from an integer of 0-6; p ₂ is selected from an integer of 0-6; p ₃ is selected from an integer of 0-6;

U is a bond, or is selected from C=O, O, NH or NR ¹² ;

each Q is independently selected from a bond, _CH2 , O, S, NH or ^NR12 ;

W is a bond, or selected from C=O, O, NH, NR ¹² , C≡C;

wherein said R ¹² is selected from C _1-4 alkyl;

The linker is covalently bound to R ¹ in the targeting ligand (formula TL) through the U group, and the W group is covalently bound to the degron.

In some aspects of the present invention, above-mentioned TL-LA is selected from:

Wherein, p ₁ , p ₂ and p ₃ are as defined above, TL represents targeting ligand, which does not belong to linker LA, but only represents the connection relationship between linker LA and targeting ligand; and formula TL has the above-mentioned definition.

In some aspects of the invention, the above linker has the formula LB:

or its stereoisomers,

Wherein, p ₁ is selected from an integer of 0-6; p ₂ is selected from an integer of 0-6; p ₃ is selected from an integer of 0-6, p ₄ is selected from an integer of 0-6; p ₅ is selected from an integer of 0-6 integer;

U is a bond, or is selected from C=O, O, NH or NR ¹³ ;

each Q is independently selected from a bond, _CH2 , O, S, NH or ^NR13 ;

W is a bond, or selected from C=O, O, NH, NR ¹³ , C≡C;

wherein said R ¹³ is selected from C _1-4 alkyl;

Each Z ₁ is independently selected from absent, phenyl, C _3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, wherein the phenyl, C _{3- 6} -membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl are each independently optionally substituted with one or more R ¹⁴ groups; each R ¹⁴ is independently selected from halogen, C _{1 -4} alkyl, hydroxyl;

or each Z ₁ is independently selected from a 7-11 membered azaspirocycle, wherein the 7-11 membered azaspirocycle is optionally substituted with one or more R ¹⁴ groups; each R ¹⁴ is independently selected from halogen, C _1-4 alkyl, hydroxyl;

The linker is covalently bound to R ¹ in the targeting ligand through the U group, and the W group is covalently bound to the degron.

In some aspects of the invention, the above-mentioned linker LB is selected from:

Here, p ₁ , p ₂ , p ₃ , p ₄ , U, W, and Z ₁ are as defined above.

In some aspects of the present invention, above-mentioned TL-LB is selected from:

Wherein, p ₁ , p ₃ , p ₄ , and Z ₁ are as defined above, and TL represents a targeting ligand, which does not belong to the linker LB, but only represents the connection relationship between the linker LB and the targeting ligand; and the formula TL has the above-mentioned formula Definition.

Here, p ₁ , p ₃ , p ₄ , and Z ₁ are defined as described above.

Among them, p ₁ , p ₂ , and Z ₁ are defined as above.

In some aspects of the present invention, the above-mentioned TL-LB is selected from

In some aspects of the invention, the degron is of formula D1,

or its stereoisomers,

wherein each R ¹⁵ is independently selected from C _1-4 alkyl;

R ¹⁶ is selected from H, deuterium;

each R ¹⁷ is independently selected from halogen, C _1-4 alkyl, C _1-4 alkoxy, hydroxy;

Z ₂ is selected from CH ₂ or C=O;

Y is a bond, O or NH; it is connected to the linker by a covalent bond;

m is selected from an integer from 0 to 3;

n is selected from an integer of 0-4.

In some embodiments of the present invention, Z ₂ in the degron D1 is selected from C=O.

In some embodiments of the present invention, Y in the degron D1 is selected from bond or NH.

In some embodiments of the present invention, Y in the degron D1 is selected from O.

In some aspects of the invention, the degron D1 is selected from:

In some aspects of the invention, the degron D1 is selected from:

In some aspects of the invention, the degron D1 is selected from:

In some aspects of the invention, the degron D1 is selected from:

In some aspects of the invention, the degron is of formula D2,

or its stereoisomers,

wherein, each R ¹⁵ is arbitrarily independently selected from C _1-4 alkyl;

R ^16, selected from H, deuterium;

each R ^17, optionally independently selected from halogen, C _1-4 alkyl, C _1-4 alkoxy;

Y' is a bond, O or NH, which is connected to the linker by a covalent bond;

m is selected from an integer from 0 to 3;

n is selected from an integer of 0-4.

In some aspects of the invention, the degron D2 is selected from:

In some aspects of the invention, the degron is of formula D3,

or its stereoisomers,

Wherein, R ¹⁸ is selected from H, C _1-4 alkyl;

each R ¹⁹ is arbitrarily independently selected from C _1-4 alkyl;

R ²⁰ is selected from H, C _1-4 alkyl;

q is an integer selected from 0-4;

wherein the degron is

Covalently binds to the linker.

In some embodiments of the invention, R ¹⁸ in said degron D3 is selected from methyl.

In some embodiments of the invention, R ²⁰ in said degron D3 is selected from methyl.

In some aspects of the invention, the degron D3 is selected from:

In some aspects of the invention, the degron has the formula D3 ^' ,

or its stereoisomers,

Wherein, R ^18a is selected from H, C _1-4 alkyl;

Each R ^19a is arbitrarily independently selected from C _1-4 alkyl, C _1-4 alkoxy;

R ^20a and R ^20b are independently selected from H, C _1-4 alkyl;

Or R ^20a is connected with R ^20b , and cyclized to form C _3-6 cycloalkyl;

Or R ^19a and R ^20a or R ^19a and R ^20b are connected, and cyclized to form a 3-6 membered heterocycloalkyl;

r is an integer selected from 0-4;

wherein the degron is

Covalently binds to the linker.

In some embodiments of the invention, R ^18a in said degron D3' is selected from methyl.

In some embodiments of the invention, R ^20a , R ^20b in the degron D3' and the atoms to which they are attached are cyclized together to form a cyclopropyl group.

In some embodiments of the present invention, R ^19a in the degron D3' is cyclized with R ^20a and the atom to which it is attached, or R ^19a is cyclized with R ^20b and the atom to which it is attached to form tetrahydropyridine pyran ring.

In some aspects of the invention, the degron has formula D3', selected from:

In some aspects of the invention, the degron is of formula D4,

or its stereoisomers,

Y is a bond, or NH, which is covalently attached to the linker.

In some aspects of the invention, the degron D4 is selected from:

In some aspects of the invention, the degron is of formula D5,

wherein M is selected from NH, O or S;

V is a bond, NH or O, which is covalently attached to the linker;

Each R is ^{independently} selected from halogen;

S is selected from 0, 1, 2 or 3.

In some aspects of the present invention, the degron D5 is

In some aspects of the present invention, the degron D5 is

In some aspects of the present invention, the degron D5 is

In some aspects of the present invention, the degron D5 is

In some aspects of the present invention, the degron D5 is

In some aspects of the invention, the degron is selected from

In some aspects of the invention, the degron is selected from

In some embodiments of the present invention, the compound represented by the above formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt, prodrug, hydrate, solvate, isotopic label derivatization is selected from the following structures:

wherein A, M, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ²⁰ , Y, R ¹⁵ , n, linker, degron are as defined above.

In some embodiments of the present invention, the compound represented by the above formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt, prodrug, hydrate, solvate, isotopic label derivatization object, selected from the following structures:

wherein M, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ²⁰ , Y, R ¹⁵ , n, linker and degron are as defined above.

In some embodiments of the present invention, the compound represented by the above formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt, prodrug, hydrate, solvate, isotopic label derivatization compound selected from formula (Ic-A) or (Ic-B):

wherein R ₆ , R ₇ , R ¹⁵ , Y, n, linker and degron are as defined above.

In some embodiments of the present invention, the compound represented by the above formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt, prodrug, hydrate, solvate, isotopic label derivatization substance, selected from formula (Ic):

wherein the linker and degron are as defined above.

In some embodiments of the present invention, the compound represented by the above formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt, prodrug, hydrate, solvate, isotopic label derivatization thing, selected from formula (Id):

wherein the linker and degron are as defined above.

Wherein, the linker, R ²⁰ , Y, R ¹⁵ , and n are as defined above.

The bifunctional compounds provided by the present invention or their stereoisomers, tautomers or pharmaceutically acceptable salts, prodrugs, hydrates, solvates and isotopically labeled derivatives are selected from:

The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of the above-mentioned bifunctional compound or its stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, hydrate, solvate, Isotopically labeled derivatives and pharmaceutically acceptable carriers.

The pharmaceutical compositions according to the present invention can be formulated for various conventional or specific routes of administration, such as oral administration, parenteral administration, rectal administration, and the like. Dosage forms for oral administration, such as tablets, capsules (including sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, sprays dry dispersions), syrups and emulsions; parenteral administration, for example, by subcutaneous, intravenous, intramuscular, or intrasternal injection, or infusion techniques (for example, as sterile injectable aqueous or non-aqueous solutions or suspensions ); nasal administration, for example to the nasal mucosa, by inhalation spray; topical administration, for example in the form of creams or ointments; rectal administration, for example in the form of suppositories. The compounds according to the present invention may be administered alone, but will generally be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

"Pharmaceutically acceptable carrier" refers to a medium generally acceptable in the art for delivering biologically active agents to animals, particularly mammals, including, for example, adjuvants, excipients or excipients depending on the mode of administration and the nature of the dosage form Excipients such as diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, perfuming agents, antibacterial agents, antifungal agents, lubricants agent and dispersant.

A pharmaceutically acceptable carrier can be selected and formulated in combination with a number of factors within the purview of one of ordinary skill in the art. It includes, but is not limited to: the type and nature of the active agent formulated, the subjects to whom the composition containing the agent is to be administered, the intended route of administration of the composition and the target therapeutic indication, and the like. Pharmaceutically acceptable carriers include both aqueous and non-aqueous media and various solid and semisolid dosage forms. In addition to the active agent, such carriers may include many different ingredients and additives, and it is well known to those of ordinary skill in the art to include additional ingredients in formulations for a variety of reasons (eg, stabilizing the active agent, binders, etc.).

Dosage regimens for compounds of the present invention may, of course, vary depending on known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration, the species, age, sex, health, medical condition and weight of the recipient. , nature and extent of symptoms, types of coexisting treatments, frequency of treatments, route of administration, renal and hepatic function of the patient, and desired effects. The therapeutically effective dose of the compound, pharmaceutical composition or combination thereof depends on the species, body weight, age and individual condition of the subject, the condition or disease being treated or its severity. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each active ingredient required to prevent, treat or inhibit the progression of a disorder or disease.

The present invention also provides the above-mentioned bifunctional compounds or their stereoisomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates, isotopically labeled derivatives or the preparation of the above-mentioned pharmaceutical compositions Application in the treatment of cancer drugs.

Epidermal growth factor receptor EGFR (epidermal growth factor receptor) is widely distributed on the surface of mammalian epithelial cells, fibroblasts, glial cells and other cells. The EGFR signaling pathway plays an important role in physiological processes such as cell growth, proliferation and differentiation. EGFR mutation is also the most common type of mutation in NSCLC patients, especially in Asian populations, which can account for 40% to 50%.

Accordingly, the present invention also provides a method of treating cancer, comprising administering to a patient a therapeutically effective amount of the compound described above, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, hydrate, solvent thereof compounds, isotopically labeled derivatives or the above-mentioned pharmaceutical compositions. The above cancers include lymphoma, non-Hodgkin lymphoma, ovarian cancer, cervical cancer, prostate cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, leukemia, stomach cancer, uterus Endometrial cancer, lung cancer, hepatocellular carcinoma, gastrointestinal stromal tumor (GIST), acute myeloid leukemia (AML), cholangiocarcinoma, kidney cancer, thyroid cancer, anaplastic large cell lymphoma, mesothelioma, multiple Myeloma, melanoma.

The present invention also provides the above-mentioned compounds or their stereoisomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates, isotopically labeled derivatives or the above-mentioned pharmaceutical compositions in the preparation of treatment Applications in EGFR-related cancer drugs. The above cancers include lymphoma, non-Hodgkin lymphoma, ovarian cancer, cervical cancer, prostate cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, leukemia, stomach cancer, uterus Endometrial cancer, lung cancer, hepatocellular carcinoma, gastrointestinal stromal tumor (GIST), acute myeloid leukemia (AML), cholangiocarcinoma, kidney cancer, thyroid cancer, anaplastic large cell lymphoma, mesothelioma, multiple Myeloma, melanoma.

In some embodiments of the invention, the above cancer is lung cancer.

The above-mentioned bifunctional compounds provided by the present invention or their stereoisomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates, isotopically labeled derivatives or the above-mentioned pharmaceutical compositions are used For the treatment of cancers including lymphoma, non-Hodgkin lymphoma, ovarian cancer, cervical cancer, prostate cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, leukemia , gastric cancer, endometrial cancer, lung cancer, hepatocellular carcinoma, gastric cancer, gastrointestinal stromal tumor (GIST), acute myeloid leukemia (AML), cholangiocarcinoma, kidney cancer, thyroid cancer, anaplastic large cell lymphoma, Mesothelioma, Multiple Myeloma, Melanoma.

In some embodiments of the invention, the above cancer is lung cancer.

The compounds described herein can be prepared by methods known to those in the art and, by way of general example only, can be prepared using the following schemes:

General scheme one:

General plan two:

As shown in the general scheme 1, the linker and the targeting ligand can be linked by chemical reaction first, and then the degron is added to prepare the triplet compound of the present invention; or as shown in the general scheme 2, the linker is first combined with The degrons are connected by chemical reaction, and then the targeting ligand is added to prepare the triplet compound of the present invention;

It should be noted that when the two parts in the triplet compound are connected, the two parts may be prepared separately and then connected, or they may be connected first, and then the synthesis of each part is completed. For example, in the general scheme 1, the targeting ligand is connected with the linker part. It can be that the prepared targeting ligand is connected to the linker, or a part of the targeting ligand is first connected to the linker, and after the connection is completed, the The preparation of the targeting ligand itself is completed.

The connection of the two parts in the triplet compound is prepared by conventional chemical reactions, such as steps 1 and 2 in general schemes 1 and 2, which can be achieved by nucleophilic substitution, condensation or coupling reactions.

Specifically, the triplet compound in the present invention can be prepared in the following manner:

After the targeting ligand is connected to the linker, it is then connected to the degron to obtain:

or

After the linker is connected to the degron, it is then connected to the targeting ligand to obtain:

Wherein, targeting ligand, linker, degron are as defined above.

Representative synthetic route one:

In step 1, the carboxylic acid in the linker and the amino group in the degron undergo condensation reaction under the action of a condensation reagent to form an amide bond. Commonly used condensation reagents include but are not limited to 4-(4,6-dimethoxytriazine)- 4-Methylmorpholine hydrochloride (DMTMM), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC) and 1-(3-dimethylaminopropyl)-3 -Ethylcarbodiimide (EDCI), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU), etc.

In step 2, the amino group in the targeting ligand attacks the LG group of the degron, and the LG leaves and undergoes a nucleophilic substitution reaction to prepare a triplet compound; wherein, LG represents a common leaving group, such as trifluoromethanesulfonic acid group, Methanesulfonic acid group, p-toluenesulfonic acid group, and halogen atoms such as fluorine, bromine, iodine, and chlorine.

The above two-step reactions are often carried out under the catalysis of bases, and commonly used base catalysts include triethylamine, pyridine, N,N-diisopropylethylamine, sodium acetate, sodium carbonate, potassium carbonate and the like.

Representative synthetic route two:

Step 1, the amino group in the targeting ligand attacks the LG group in the linker, and the LG leaves to undergo a nucleophilic substitution reaction; LG represents a common leaving group, such as trifluoromethanesulfonate, methanesulfonate, p-toluene Sulfonate and halogen atoms such as fluorine, bromine, iodine, chlorine; PG in the linker represents a commonly used amino protecting group, including but not limited to tert-butoxycarbonyl, benzyloxycarbonyl, p-toluenesulfonyl, watmethoxycarbonyl, p- Methoxybenzyl, benzyl, trityl, etc.

In step 2, the amino protecting group is generally removed under the action of acid, and commonly used acids include but are not limited to hydrochloric acid, formic acid, trifluoroacetic acid, hydrobromic acid and the like.

In step 3, the amino group in the targeting ligand-linker attacks the LG group in the degron, and the LG leaves to undergo a nucleophilic substitution reaction to prepare a triplet compound. LG represents a common leaving group such as triflate, methanesulfonate, p-toluenesulfonate, and halogen atoms such as fluorine, bromine, iodine, chlorine, and the like.

Steps 1 and 3 are usually carried out under the catalysis of bases, and commonly used base catalysts include triethylamine, pyridine, N,N-diisopropylethylamine, sodium acetate, sodium carbonate, potassium carbonate and the like.

Representative synthetic route three:

In step 1, under the action of a catalyst, the linker and the degron undergo a coupling reaction, and the commonly used catalyst is bis(triphenylphosphine) palladium(II), tetrakis(triphenylphosphine) palladium or [1, 1'-bis (diphenylphosphino) ferrocene] palladium dichloride and cuprous iodide, etc.

Subsequently, the hydroxyl group in step 2 is converted into an easily leaving group LG, and undergoes a nucleophilic substitution reaction with the amino group in the targeting ligand to generate a triplet compound.

For the targeting ligand used in the present invention, reference may be made to the targeting ligand in the preparation method of related compounds in CN112538072A, and the relevant content is incorporated into this application by reference.

The individual group variables in the above equations are as defined above.

Technical effect:

The compound of the present invention has a good inhibitory effect on the cell proliferation of the Ba/F3 Del19/T790M/C797S EGFR triple mutant cell line and the Ba/F3 L858R/T790M/C797S EGFR triple mutant cell line.

The compounds of the present invention can significantly induce the degradation of EGFR protein.

Description and Definitions:

Unless otherwise specified, the following terms and phrases used herein have the following meanings. A particular term or phrase should not be considered indeterminate or unclear without specific definitions, but should be understood in its ordinary meaning.

The term "pharmaceutically acceptable" means, within the scope of sound medical judgment, suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic reactions or other problems or complications, with a reasonable benefit/risk ratio those compounds, materials, compositions and/or dosage forms.

The term "pharmaceutically acceptable salts" refers to derivatives of compounds of the present invention prepared with relatively non-toxic acids or bases. These salts can be prepared during the synthesis, isolation, purification of the compound, or the free form of the purified compound alone can be reacted with a suitable acid or base. When the compounds contain relatively acidic functional groups, they react with alkali metal, alkaline earth metal hydroxides or organic amines to obtain base addition salts, including alkali metal and alkaline earth metal based cations and non-toxic ammonium, quaternary ammonium and amine cations, Also contemplated are salts of amino acids and the like. When the compound contains a relatively basic functional group, it reacts with an organic acid or an inorganic acid to obtain an acid addition salt.

The compounds provided by the present invention also include the form of prodrugs, which represent compounds that are rapidly transformed in vivo to obtain the parent compound of the above formula, which can be converted into the compounds of the present invention by chemical or biochemical methods in an in vivo or in vitro environment, such as by means of blood of hydrolysis.

The compounds of the present invention can exist in unsolvated as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent in pharmaceutical effect to the unsolvated forms and are also encompassed within the scope of the present invention.

The compounds of the present invention exist as "tautomers", the term "tautomer" refers to a type of functional group isomer which has a different point of attachment by displacement of one or more double bonds, eg, a ketone and its enol form is a keto-enol tautomer.

The compounds of the present invention exist as geometric isomers as well as stereoisomers, such as cis-trans isomers, enantiomers, diastereomers, racemic mixtures and other mixtures, all of which belong to the present invention within the range.

The term "enantiomers" refers to stereoisomers that are mirror images of each other.

The term "diastereomer" refers to a stereoisomer in which a molecule has two or more chiral centers and the molecules are in a non-mirror-image relationship.

The term "cis-trans isomer" refers to a configuration in which a double bond or a single bond of a ring-forming carbon atom cannot rotate freely and exists in a molecule.

Use solid wedge keys unless otherwise specified

and wedge-dotted keys

Indicate the absolute configuration of a stereocenter, using a straight solid key

and straight dashed keys

Represents the relative configuration of the stereocenter.

Stereoisomers of the compounds of the present invention can be prepared by chiral synthesis or chiral reagents or other conventional techniques. For example, an enantiomer of a certain compound of the present invention can be prepared by asymmetric catalysis technology or chiral auxiliary derivatization technology. Alternatively, compounds with a single stereoconfiguration can be obtained from a mixture by chiral resolution techniques. Alternatively, it can be prepared directly from chiral starting materials. Separation of optically pure compounds in the present invention is usually accomplished by preparative chromatography, and a chiral chromatographic column is used to achieve the purpose of separating chiral compounds.

In general, when an optically pure compound participates in the reaction as a starting material, the steric configuration of the chiral atoms in its structure will also be transferred. There are no special circumstances, and its configuration is considered to remain unchanged during the reaction, that is, the product has the same When the starting materials have the same configuration, when an optically pure mixture is involved in the reaction, the resulting compound is also an optically pure corresponding mixture. For example, (R)-3-methylmorpholine participates in the reaction as a starting material, and the obtained compound is also in R configuration; trans-2,6-dimethylmorpholine participates in the reaction as a starting material, and the obtained compound is Racemates of 2S,6S and 2R,6R configurations.

The term "optically pure" or "enantiomerically enriched" means that the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95% or greater, or 96% or greater, or 97% or greater, or 98% or greater, or 99% or greater, or 99.5% or greater, or 99.6% or greater, or 99.7% or greater, or 99.8 or greater %, or greater than or equal to 99.9%.

The absolute stereo configuration of a compound can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction method can also confirm the absolute configuration of the compound by the chiral structure of the raw material and the reaction mechanism of asymmetric synthesis.

The present invention also includes isotopically labeled derivatives. Including isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as ² H, ³ H, ¹³ C, ¹¹ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, respectively , ³⁵ S, ¹⁸ F and ³⁶ Cl. Compounds of the present invention containing the above isotopes and/or other isotopes of other atoms are within the scope of the present invention.

The term "prophylactically or therapeutically effective amount" refers to a compound of the invention or a stereoisomer, tautomer or pharmaceutically acceptable salt, prodrug, hydrate, solvate, isotopically labeled derivative thereof suitable for use in A sufficient amount of the compound to treat the disorder with a reasonable effect/risk ratio for any medical treatment and/or prevention. However, it should be recognized that the compounds represented by formula I of the present invention or their stereoisomers, tautomers or pharmaceutically acceptable salts, prodrugs, hydrates, solvates, isotopically labeled derivatives and compositions The total daily dosage must be determined by the attending physician within the scope of sound medical judgment. For any particular patient, the particular therapeutically effective dosage level will depend upon a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the particular compound employed; the particular composition employed; age, weight, general health, sex, and diet of the patient; time of administration, route of administration, and excretion rate of the particular compound employed; duration of treatment; drugs used in combination or concomitantly with the particular compound employed; and Similar factors well known in the medical field. For example, it is the practice in the art to start with a dose of the compound below that required to obtain the desired therapeutic effect and gradually increase the dose until the desired effect is obtained. Generally speaking, the dosage of the compound represented by formula I of the present invention or a pharmaceutically acceptable salt thereof for mammals, especially humans, can range from 0.001 to 1000 mg/kg body weight/day, for example, from 0.01 to 100 mg/kg body weight/day. day, for example between 0.01-10 mg/kg body weight/day.

The term "optionally substituted" means that the term "optionally substituted" may or may not be substituted. Unless otherwise specified, the type and number of substituents may be arbitrary on the basis of chemical realization, for example, the term "optionally substituted""Optionally substituted with one or more R ₀ " means that it may be substituted with one or more R ₀ or _not .

When any variable (eg, R ₁₂ ) occurs more than once in the composition or structure of a compound, its definition in each case is independent. For example, if a group is substituted with 0-2 R ₁₂ , the group may optionally be substituted with up to two R ₁₂ , with independent options for R ₁₂ in each case.

When the number of a linking group is 0, such as -O(CH ₂ ) _n CH ₃ , n=0 indicates that the linking group is a single bond, ie -OCH ₃ .

When a substituent's bond can be cross-linked to two atoms on a ring, the substituent can bond to any atom on the ring. For example, structural unit

It means that the substituent R ₁₂ can be substituted at any position on the benzene ring.

When the listed substituents do not indicate through which atom they are attached to the general chemical structure, such substituents may be bonded through any of their atoms. For example, pyrazole as a substituent means that any carbon atom on the pyrazole ring is attached to the substituted group; when the structure appears

or

, indicating that the atom is a bonding atom, for example

and

Both indicate that the N atom on the morpholine ring is a bonding atom.

Unless otherwise specified, "ring" refers to saturated, partially saturated or unsaturated monocycles as well as polycycles, "polycycles" including spiro, paracyclic or bridged rings. Representative "rings" include substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl, or heteroaryl.

The term "hetero" refers to substituted or unsubstituted heteroatoms and oxidized forms of heteroatoms, the heteroatoms generally selected from N, O, S, the oxidized forms generally including NO, SO, S(O) ₂ , the nitrogen atom may be is substituted, that is, NR (R is H or other substituents as defined in the text); the number of atoms on the ring is usually defined as the number of ring members, for example, "3-6 membered heterocycloalkyl" refers to 3-6 A ring of atoms arranged around each other, each ring optionally contains 1 to 3 heteroatoms, namely N, O, S, NO, SO, S(O) ₂ or NR, and each ring is optionally surrounded by R group is substituted, and R is any substituent as defined in the present invention.

Unless otherwise specified, "cycloalkyl" refers to a saturated monocyclic hydrocarbon group. Cycloalkyl is preferably 3-8 membered monocycloalkyl, more preferably 3-6 membered monocycloalkyl, examples of these monocycloalkyl include but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl , cycloheptyl, cyclooctyl.

Unless otherwise specified, "heterocycloalkyl" refers to a monoheterocycloalkyl group containing a number of heteroatoms or heteroatomic groups in the ring, generally selected from N, O, S, NO, SO, S (O) ₂ and NR. Heterocycloalkyl is preferably 3-8 membered monoheterocycloalkyl, more preferably 3-6 membered monoheterocycloalkyl, examples of these monoheterocycloalkyl include, but are not limited to, oxiranyl, tetrahydropyrrolyl , piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, 1,3-dioxolane, 1,4-dioxane, etc.

Unless otherwise specified, "spirocyclyl" refers to a polycyclic system in which a single carbon atom (called a spiro atom) is shared between the single rings, and each single ring may contain a certain number of double bonds, and the spirocyclyl is preferably 5- 13 membered spirocyclyl, 6-12 membered spirocyclyl, or 7-11 membered spirocyclyl. Examples of spirocyclyl groups include, but are not limited to, spiro[2.2]pentyl, spiro[2.3]hexyl, spiro[2.4]heptyl, spiro[2.5]octyl, spiro[2.6]nonyl, spiro[3.3]heptyl , spiro[3.4]octyl, spiro[3.5]nonyl, spiro[3.6]decyl, spiro[4.4]nonyl, spiro[4.5]decyl, spiro[4.6]undecyl, spiro[5.5]tenyl Monoalkyl, spiro[5.6]dodecyl, spiro[6.6]tridecyl, spiro[6.7]tetradecyl.

"Spiroheterocyclyl" refers to a spirocyclyl in which one or more carbon atoms in the spirocyclic skeleton structure are substituted with a heteroatom or heteroatom group selected from N, O, S, NO, SO , S(O) ₂ , etc. The spiroheterocyclic group is preferably a 5-13 membered spiroheterocyclic group, a 6-12 membered spiroheterocyclic group, a 7-11 membered spiroheterocyclic group and a 7-11 membered azaspirocyclic group. Examples of spiroheterocyclyl groups include, but are not limited to, 2-oxa-7-azaspiro[5.3]nonan-7-yl, 2-oxa-7-azaspiro[4.4]nonan-7-yl , 2-oxa-6-azaspiro[3.3]heptane-6-yl, 2-oxa-8-azaspiro[4.5]decane-8-yl, 1,4,9-triaza Spiro[5.5]undecan-9-yl, 3-oxa-9-azaspiro[5.5]undecan-9-yl, 2,6-diazaspiro[3.3]heptane-2-yl , 2,7-diazaspiro[5.3]nonan-7-yl, 2,7-diazaspiro[5.3]nonyl, 3,9-diazaspiro[5.5]undecan-3- base, 1-oxa-4,9-diazaspiro[5.5]undecan-9-yl, 1-oxa-4,8-diazaspiro[5.4]decane-8-yl, 3 -Azaspiro[5.5]undecan-3-yl, 7-azaspiro[3.5]decane-7-yl, 1-oxa-4,9-diazaspiro[5.5]undecan- 4-yl, 6-oxa-2,9-diazaspiro[4.5]decane-9-yl, 9-oxa-2,6-diazaspiro[4.5]decane-6-yl, 3-Azaspiro[5.5]undecan-3-yl, 4-oxa-1,9-diazaspiro[5.5]undecan-9-yl.

Unless otherwise specified, "bridged cyclyl" refers to a polycyclic ring system that shares two non-directly linked carbon atoms, which system may contain a certain number of double bonds. The bridged ring group is preferably a 4-13-membered bridged ring group, a 5-12-membered bridged ring group, a 6-12-membered bridged ring group, a 6-11-membered bridged ring group, and a 7-11-membered bridged ring group. Examples of bridged ring groups include, but are not limited to

Wait.

"Bridged heterocyclyl" refers to a bridged ring radical in which one or more carbon atoms constituting the bridged ring skeleton are substituted with a heteroatom or heteroatom group selected from N, O, S, NO, SO, S(O) ₂ etc. The bridged heterocyclic group is preferably a 4-13-membered bridged heterocyclic group, a 5-12-membered bridged heterocyclic group, a 6-12-membered bridged heterocyclic group, a 6-11-membered bridged heterocyclic group, and a 7-11-membered bridged heterocyclic group. Examples of bridged heterocyclyl groups include, but are not limited to

Wait.

Unless otherwise specified, "paracyclic" refers to a polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein each ring may contain a certain number of double bonds. Said bacyl is preferably a 5-14 membered bacyl group, more preferably a 7-12 membered bacyl group, more preferably an 8-10 membered bacyl group, and examples of the bacyl group include but are not limited to

Wait.

"Para-heterocycle" refers to a para-cyclic group in which one or more carbon atoms constituting the para-ring skeleton are substituted with a heteroatom or heteroatom group selected from N, O, S, NO, SO, S (O) ₂ and so on. Preferred are 5-14-membered no-heterocyclyl, more preferably 7-12-membered no-heterocyclyl, more preferably 8-10-membered no-heterocyclyl, more preferably 8-10-membered aza-heterocyclyl, examples of no-heterocyclyl including but not limited to

Wait.

Cycloalkyl, heterocycloalkyl, aryl, and heteroaryl can all be condensed with a benzene ring to form a corresponding polycyclic structure. e.g. structure

In, "R ₇ and R ₈ can be cyclized to C _4-6 cycloalkyl" means that the structure can be

Examples of "R ₇ and R ₈ can be cyclized into 4-6 membered heterocycloalkyl" include but are not limited to

Examples of "R ₇ and R ₈ can be cyclized into a 5-7 membered heteroaryl group" include but are not limited to

Unless otherwise specified, the term "aryl" refers to a polyunsaturated, aromatic hydrocarbon group, which may be a single ring or multiple rings fused together. Examples of aryl groups include, but are not limited to, phenyl. naphthyl.

Unless otherwise specified, the term "heteroaryl" means a stable monocyclic or polycyclic aryl containing at least one heteroatom or heteroatom group (N, O, S, NO, SO, S(O) ₂ or NR) family group. Preferably 5-12 membered heteroaryl, more preferably 5, 6, 7 membered monocyclic or 6, 7, 8, 9 or 10 membered bicyclic heteroaryl; preferably containing carbon atoms and 1, 2, 3 or 4 independently Ring heteroatom selected from N, O and S. Examples of heteroaryl groups include, but are not limited to, pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, benzoxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, Pyrimidyl, benzothiazolyl, purinyl, benzimidazolyl, indolyl, isoquinolinyl, quinoxalinyl, quinolinyl.

Unless otherwise specified, the term "alkyl" refers to a straight or branched chain saturated hydrocarbon group. Preferably a C _1-6 alkyl group, more preferably a C _1-3 alkyl group, examples of alkyl groups include but are not limited to methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, pentyl , isopentyl, neopentyl, n-hexyl, etc.

Unless otherwise specified, the term "halogen" refers to a fluorine, chlorine, bromine or iodine atom.

Unless otherwise specified, the term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by halogen atoms. C _1-6 haloalkyl groups are preferred, examples of haloalkyl groups include but are not limited to monofluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, tribromomethyl, 2,2,2-trifluoroethyl base, 2,2,2 trichloroethyl, etc.

Unless otherwise specified, the term "alkoxy" refers to an alkyl group attached through an oxygen bridge, ie, a group obtained by substituting an alkyl group for a hydrogen atom in a hydroxyl group. A C _1-6 alkoxy group is preferable, and a C _1-3 alkoxy group is more preferable. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, neopentyloxy base, n-hexyloxy, etc.

Unless otherwise specified, the term "cycloalkyloxy" refers to a cycloalkyl group attached through an oxygen bridge, ie, a group resulting from the substitution of a cycloalkyl group for a hydrogen atom in a hydroxy group. The cycloalkyloxy group is preferably a 3-7 membered, 4-7 membered, or 5-7 membered cycloalkoxy group. Examples of cycloalkyloxy include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.

Unless otherwise specified, the term "haloalkoxy" refers to an alkoxy group in which one or more hydrogen atoms are replaced by halogen atoms. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, trichloromethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, and the like.

Unless otherwise specified, the term "cycloalkenyl" refers to a stable monocyclic or polycyclic hydrocarbon group containing one or more unsaturated carbon-carbon double bonds in the ring. Examples of such cycloalkenyl groups include, but are not limited to, cyclopropene, cyclobutene, cyclopentenyl, cyclohexenyl, 1,3-cyclohexadienyl, 1,4-cyclohexadienyl, and the like.

Unless otherwise specified, the term "heterocycloalkenyl" refers to a cycloalkenyl group containing 1-3 heteroatoms or groups of heteroatoms in the ring.

Specifically, all combinations of substituents and/or variants thereof herein are permissible only if such combinations result in stable compounds.

In the examples of the present invention, the nomenclature of the title compound was converted from the compound structure by means of Chemdraw. If there is any inconsistency between the compound name and the compound structure, it can be determined by synthesizing relevant information and reaction routes; if it cannot be confirmed by other methods, the given compound structural formula shall prevail.

The preparation methods of some compounds in the present invention refer to the preparation methods of the aforementioned similar compounds. Those skilled in the art should know that when using or referring to the preparation methods cited therein, the charging ratio of the reactants, the reaction solvent, and the reaction temperature can be appropriately adjusted according to the different reactants.

The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments enumerated below, embodiments formed in combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalent to alternatives, preferred embodiments include, but are not limited to, the embodiments of the present invention.

Abbreviations used in the embodiments of the present invention and their corresponding chemical names are as follows:

缩写abbreviation	化学名称Chemical Name
HATUHATU	2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯2-(7-Azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate
DMAPDMAP	4-二甲氨基吡啶4-Dimethylaminopyridine
DIEADIEA	N,N-二异丙基乙胺N,N-Diisopropylethylamine
DMSODMSO	二甲基亚砜dimethyl sulfoxide
DMFDMF	N,N-二甲基甲酰胺N,N-Dimethylformamide
NMPNMP	N-甲基吡咯烷酮N-Methylpyrrolidone

Detailed ways:

The present invention will be described in detail by the following examples, but it does not mean any unfavorable limitation of the present invention.

The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts ([delta]) are given in parts per million (ppm). NMR was measured with a Bruker Avance III 400M nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated methanol (CD ₃ OD) and deuterated chloroform (CDCl ₃ ), and the internal standard was four Methylsilane (TMS).

The determination of LC-MS was performed with a Shimadzu LCMS-2020 mass spectrometer (the ion source was electrospray ionization). The determination of HPLC used Shimadzu LCMS-20 high performance liquid chromatography.

Preparative high performance liquid chromatography used Waters 2767-2489 (Xbridge, C18, 10 μm, OBD 250 cm×19 cm) or Waters 2767-2489 (Sunfire Prep, C18, 10 μm, OBD 250 cm×19 cm).

The thin layer chromatography silica gel plate uses GF254 silica gel plate of Yantai Jiangyou Silica Gel Development Co., Ltd. or GF254 silica gel plate of Rushan Shangbang New Materials Co., Ltd. The 200-300 mesh silica gel used in Cheng Chemical Industry Co., Ltd. is used as the carrier.

The starting materials in the examples of the present invention are known and commercially available, or can be synthesized using or according to methods known in the art.

Unless otherwise specified, all the reactions of the present invention are carried out under continuous magnetic stirring, in a dry nitrogen or argon atmosphere, the solvent is a dry solvent, and the reaction temperature is in degrees Celsius.

Embodiment 1:

(2S,4R)-1-((S)-2-(6-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl) )amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)hexamido)- 3,3-Dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

Reaction process:

Reaction steps:

Step 1: Dissolve quinoxalin-6-amine (5.0 g, 34.5 mmol) in acetic acid (150 mL) at room temperature, slowly add a solution of iodine chloride (6.1 g, 37.6 mmol) in acetic acid (55 mL) dropwise, under argon Stir at 20°C for 2 hours under atmosphere until the reaction is complete. The reaction solution was directly concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=20/1～3/1) to obtain 5-iodoquinoxalin-6-amine (6.0 g) , the yield is 64%).

MS(ESI)M/Z: 272.1[M+H] ⁺ .

Step 2: 5-Iodoquinoxalin-6-amine (6.0 g, 22.1 mmol), dimethylphosphine oxide (2.6 g, 33.2 mmol) and potassium phosphate (7.0 g, 33.2 mmol) were dissolved in N' at room temperature To N-dimethylformamide (100 mL) and water (20 mL), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (1.2 g, 2.2 mmol) and palladium acetate (494 mg) were added , 2.2 mmol). The reaction solution was heated to 120°C under an argon atmosphere and stirred for 24 hours until the reaction was complete. Cool to room temperature and concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1～1/1) to obtain (6-aminoquinoxalin-5-yl)dimethylphosphine oxide (4.0 g , the yield is 82%).

MS(ESI)M/Z: 221.9[M+H] ⁺ .

Step 3: Dissolve (6-aminoquinoxalin-5-yl)dimethylphosphine oxide (1.0 g, 4.5 mmol) in ethanol (20 mL) at room temperature, add 5-bromo-2,4-dichloropyridine (2.0 g, 9.0 mmol) and N,N-diisopropylethylamine (3.5 g, 27.1 mmol). The reaction solution was heated to 120°C under argon protection and stirred for 72 hours until the reaction was complete. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1～1/1) to obtain (6-((5-bromo-2-chloropyrimidin-4-yl)amino) Quinoxalin-5-yl)dimethylphosphine oxide (0.5 g, 27% yield).

MS(ESI)M/Z: 411.9[M+H] ⁺ .

Step 4: 1-Bromo-2-fluoro-4-methoxy-5-nitrobenzene (5.0 g, 20.1 mmol) and tert-butyl piperazine-1-carboxylate (4.1 g, 22.0 mmol) were dissolved in To N'N-dimethylformamide (60 mL), potassium carbonate (8.3 g, 60.0 mmol) was added, and the temperature was raised to 60° C. and stirred overnight. The reaction solution was diluted with water (300 mL) and extracted with ethyl acetate (200 mL×3 times). The organic phases were combined, washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=8/1) to obtain 4-(2-bromo-5-methoxy-4-nitrophenyl)piperazine-1 - tert-butyl carboxylate (6.9 g, 83% yield).

MS(ESI)M/Z:416.0[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ): δ 8.22 (s, 1H), 6.58 (s, 1H), 3.96 (s, 3H), 3.64 (t, J=4.8 Hz, 4H), 3.12 (t, J) =4.8Hz,4H),1.49(s,9H).

Step 5: 4-(2-Bromo-5-methoxy-4-nitrophenyl)piperazine-1-carboxylate tert-butyl ester (3.0 g, 7.2 mmol) and 1-methyl-4 -1H-Pyrazole borate pinacol ester (2.25g, 10.8mmol) was dissolved in dioxane (60mL) and water (6mL), sodium carbonate (2.3g, 21.6mmol) and ferrocene dichloride were added Palladium (587.5 mg, 0.72 mmol). The reaction solution was heated to 105°C under an argon atmosphere and stirred overnight. The reaction solution was cooled to room temperature, diluted with water (300 mL), and extracted with ethyl acetate (200 mL×3 times). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=2/1) to obtain 4-(5-methoxy-2-(1-methyl-1H-pyrazole-4-) (2.4 g, 80% yield).

MS(ESI)M/Z: 418.3[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ): δ 7.93(s, 1H), 7.86(s, 1H), 7.71(s, 1H), 6.60(s, 1H), 3.98(s, 3H), 3.96(s ,3H),3.50(br,4H),2.95(br,4H),1.47(s,9H).

Step 6: To tert-butyl 4-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperazine-1-carboxylate ( To a solution of 1.9 g, 4.6 mmol) in methanol (2 mL) was added a solution of hydrochloric acid in dioxane (12 mL, 4 M). After stirring at room temperature for 18 hours, the mixture was concentrated under reduced pressure to obtain 1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperazine hydrochloride ( 1.4g, crude).

MS(ESI)M/Z: 318.1[M+H] ⁺ .

Step 7: Add 1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperazine hydrochloride (1.0 g, crude , about 2.8 mmol) and methyl 6-bromohexanoate (0.6 mL, 3.8 mmol) in N'N-dimethylformamide (41 mL) was added cesium carbonate (3.5 g, 10.8 mmol). The reaction solution was stirred at room temperature for 18 hours. The reaction solution was diluted with water (200 mL) and extracted with ethyl acetate (150 mL×3 times). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=19/1) to give 6-(4-(5-methoxy-2-(1-methyl-1H-pyrazole-) Methyl 4-yl)-4-nitrophenyl)piperazin-1-yl)hexanoate (927 mg, 64% yield).

MS(ESI)M/Z: 446.1[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ): δ 7.92(s, 1H), 7.86(s, 1H), 7.69(s, 1H), 6.61(s, 1H), 3.97(s, 3H), 3.95(s ,3H),3.67(s,3H),3.03(brs,4H),2.52(brs,4H),2.38(t,J=7.6Hz,2H),2.32(t,J=7.6Hz,2H),1.67 -1.60(m,4H),1.54-1.49(m,2H).

Step 8: Addition of 6-(4-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperazin-1-yl) at room temperature To a solution of methyl hexanoate (927 mg, 2.1 mmol) in methanol (20 mL) was added 10% palladium-carbon catalyst Pd/C (223 mg). After three hydrogen replacements, the reaction was stirred overnight under a 15 psi hydrogen atmosphere. The reaction solution was filtered, the filter cake was washed with methanol (20 mL), and the filtrate was concentrated under reduced pressure to obtain 6-(4-(4-amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl) )phenyl)piperazin-1-yl)hexanoate methyl ester (592 mg, 68% yield).

MS(ESI) M/Z: 416.2[M+H ⁺ ].

Step 9: Addition of 6-(4-(4-amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)hexyl at room temperature acid methyl ester (204 mg, 0.49 mmol) and (6-((5-bromo-2-chloropyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (203 mg, 0.49 mmol) To a solution of isopropanol (8 mL) was added trifluoroacetic acid (0.36 mL, 4.9 mmol). The reaction solution was heated to 100°C and stirred for 36 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=40/1) to obtain 6-(4-(4-((5-bromo- 4-((5-(Dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazole Methyl-4-yl)phenyl)piperazin-1-yl)hexanoate (277 mg, 71% yield).

MS(ESI)M/Z:791.2[M+H] ⁺ .

Step 10: Addition of 6-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino at room temperature )-methyl 5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)hexanoate (200 mg, 0.25 mmol) in tetrahydrofuran (2 mL) Lithium hydroxide (32 mg, 0.75 mmol) was added to the mixed solution with water (1 mL). The reaction solution was stirred at room temperature for 2 hours, and the pH value of the reaction solution was adjusted to 5 with dilute hydrochloric acid, and the obtained mixture was directly purified by reverse-phase column chromatography to obtain 6-(4-(4-((5-bromo-4- ((5-(Dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazole-4 -yl)phenyl)piperazin-1-yl)hexanoic acid (111 mg, 57% yield).

MS(ESI) M/Z: 777.5[M+H] ⁺ .

Step 11: 6-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino )-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)hexanoic acid (60 mg, 0.077 mmol), HATU (44 mg, 0.10 mmol) ) and triethylamine (23 mg, 0.11 mmol) were dissolved in N'N-dimethylformamide (4 mL), stirred at room temperature for 0.1 hour, and then added (2S,4R)-1-((S)-2-amino -3,3-Dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidinyl-2-carboxamide hydrochloride (34 mg, 0.077 mmol). The reaction solution was stirred at room temperature for 3 hours, water (8 mL) was added, a yellow solid was precipitated, filtered, and the filter cake was purified by high performance liquid chromatography to obtain the target compound (2S,4R)-1-((S)-2- (6-(4-(4-((5-Bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy yl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)hexamido)-3,3-dimethylbutyryl)-4-hydroxy-N -(4-(4-Methylthiazol-5-yl)benzyl)pyrrolidinyl-2-carboxamide (35 mg, 38% yield).

MS(ESI)M/Z: 1189.5[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d6): δ12.60(s, 1H), 8.97(s, 1H), 8.84-8.80(m, 3H), 8.57(t, J=6.0Hz, 1H), 8.42( s, 1H), 8.27(s, 1H), 7.99(s, 1H), 7.87(d, J=9.2Hz, 1H), 7.79(s, 1H), 7.57(br, 2H), 7.42(d, J ＝8.4Hz, 2H), 7.38(d, J＝8.0Hz, 2H), 6.84(s, 1H), 5.14(d, J＝3.6Hz, 1H), 4.56(d, J＝9.2Hz, 1H), 4.45-4.40(m, 2H), 4.35(brs, 1H), 4.21(d, J=16.0Hz, 5.6Hz, 1H), 3.81(s, 3H), 3.75(s, 3H), 3.71-3.63(m ,2H),2.87(br,4H),2.51-2.49(m,4H),2.44(s,3H),2.35-2.27(m,3H),2.18-2.13(m,1H),2.10(s,3H) ), 2.03(s, 3H), 2.10-2.02(m, 1H), 1.99-1.90(m, 1H), 1.60-1.40(m, 4H), 1.35-1.25(m, 2H), 0.94(s, 9H) ).

Embodiment 2:

(2S,4R)-1-((S)-2-(5-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl) )amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)pentanamido)- 3,3-Dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

Reaction process:

Reaction steps:

Step 1: 1-(5-Methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperazine (2.0 g, 6.3 mmol) and DMAP (766 mg, 6.3 mmol) was added to dichloromethane (20 mL) and stirred for 5 minutes, then trifluoroacetic anhydride (2.64 g, 12.6 mmol) was added, and the reaction was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=20/1～5/1) to obtain 2,2,2-trifluoro-1-(4). -(5-Methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperazin-1-yl)ethane-1-one (2.0 g, yield 77%).

MS(ESI)M/Z:414.1[M+H] ⁺ .

Step 2: 2,2,2-Trifluoro-1-(4-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrobenzene yl)piperazin-1-yl)ethan-1-one (2.0 g, 4.8 mmol) and 10% palladium on carbon (500 mg) were added to ethanol (30 mL), and the reaction was stirred at 55 °C under a hydrogen balloon atmosphere. 2 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain 1-(4-(4-amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl) Piperazin-1-yl)-2,2,2-trifluoroethane-1-one was used directly in the next reaction (1.7 g, 92% yield).

MS(ESI)M/Z: 384.1[M+H] ⁺ .

Step 3: 1-(4-(4-Amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)- 2,2,2-Trifluoroethane-1-one (1.0 g, 2.6 mmol), (6-((5-bromo-2-chloropyrimidin-4-yl)amino)quinoxalin-5-yl) Dimethylphosphine oxide (859 mg, 2.1 mmol) and trifluoroacetic acid (2.96 g, 26.0 mmol) were successively added to isopropanol (30 mL), and the temperature was raised to 95° C. under argon to stir the reaction for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/1) to obtain 1-(4-(4-((5-bromo- 4-((5-(Dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazole -4-yl)phenyl)piperazin-1-yl)-2,2,2-trifluoroethyl-1-one (1.5 g, 76% yield).

MS(ESI)M/Z:759.1[M+H] ⁺ .

Step 4: 1-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino )-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)-2,2,2-trifluoroethyl-1-one (2.5 g, 3.3 mmol) and potassium hydroxide (1.85 g, 33.0 mmol) were added to methanol (100 mL) and water (10 mL), and the temperature was raised to 60° C. and stirred for 5 hours. The reaction solution was cooled to room temperature, diluted with dichloromethane (100 mL), and separated. The organic phase was first washed with saturated brine (100 mL), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to obtain ((6-((5-bromo-2-((2-methoxy-5-( 1-Methyl-1H-pyrazol-4-yl)-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethyloxide Phosphine (1.5 g, 69% yield).

MS(ESI)M/Z:663.0[M+H] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD): δ 8.84-8.65 (m, 3H), 8.25-8.11 (m, 1H), 7.93 (d, J=14.4 Hz, 1H), 7.78 (d, J=6.0 Hz,1H),7.41(s,2H),6.81-6.56(m,1H),3.86(s,3H),3.63(s,3H),2.95-2.87(m,4H),2.85-2.77(m, 4H), 2.13(d, J=4.8Hz, 3H), 2.08(s, 3H).

Step 5: 5-Chloropentanoic acid (62 mg, 0.45 mmol) was dissolved in N,N-dimethylformamide (3 mL) at room temperature, followed by HATU (172 mg, 0.45 mmol) and DIEA (135 mg, 1.05 mmol) After stirring for 30 minutes, (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methyl) was added dropwise Thiazol-5-yl)benzyl)pyrrolidinyl-2-carboxamide (150 mg, 0.35 mmol) in N,N-dimethylformamide (2 mL) and stirring was continued at room temperature for 3 hours. LCMS monitoring showed the disappearance of starting material, and water (10 mL) was added to the reaction to quench the reaction. The mixture was extracted with ethyl acetate (20 mL×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (20 mL×3 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1) to obtain (2S,4R)-1-((S)-2-(5-chloropentamido)-3 ,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (125 mg, 65% yield).

MS(ESI) M/Z: 549.5[M+H] ⁺ .

Step 6: (2S,4R)-1-((S)-2-(5-chloropentamido)-3,3-dimethylbutyryl)-4-hydroxy-N-(4- (4-Methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (125 mg, 0.23 mmol) was dissolved in N,N-dimethylformamide (5 mL), followed by sodium iodide (51 mg) , 0.34 mmol), DIEA (88 mg, 0.76 mmol) and ((6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)) -4-(Piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (151 mg, 0.23 mmol), the reaction was heated to 90 ℃ and stirred for 4 hours. LCMS monitoring showed that the raw materials disappeared, the reaction solution was cooled to room temperature, and water (10 mL) was added to quench the reaction. The mixed solution was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined, and the organic phase was first used Washed with saturated brine (20 mL×3 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained residue was purified by reverse-phase column chromatography (eluent: acetonitrile/10% ammonium bicarbonate = 11 /9) to obtain the final product (2S,4R)-1-((S)-2-(5-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoline) Oxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl )pentamido)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (15.4mg , the yield is 6%).

MS(ESI)M/Z: 1175.3[M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ): δ 12.59 (s, 1H), 8.98 (dd, J=9.6, 4.4 Hz, 1H), 8.78-8.63 (m, 3H), 8.29 (s, 1H), 8.19 (s,1H),7.75-7.51(m,3H),7.43-7.30(m,6H),6.72(s,1H),6.21(brs,1H),4.75(t,J=8.0Hz,1H), 4.57-4.53(m, 3H), 4.35(dd, J=14.8, 5.2Hz, 1H), 4.10(d, J=11.2Hz, 1H), 3.89(s, 3H), 3.70(s, 3H), 3.60 (d, J=8.0Hz, 2H), 3.02(brs, 4H), 2.67(s, 3H), 2.54-2.51(m, 6H), 2.37-2.15(m, 4H), 2.14(s, 3H), 2.10(s, 3H), 1.62-1.55(m, 2H), 1.34-1.21(m, 2H), 0.94(s, 9H).

Embodiment 3:

(2R,4S)-1-((S)-2-(6-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)) Amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)hexamido)-3 ,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidinyl-2-carboxamide

Reaction process:

Reaction steps:

With (2R,4S)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl base) pyrrolidinyl-2-carboxamide and 6-bromohexanoic acid as raw materials, and the final product (2R,4S)-1-((S)-2-(6-(4- (4-((5-Bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1 -Methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)hexamido)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4 -Methylthiazol-5-yl)benzyl)pyrrolidinyl-2-carboxamide (22 mg).

MS(ESI)M/Z: 1189.5[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ): δ 12.56 (s, 1H), 9.01-8.97 (m, 1H), 8.72 (d, J=2.0Hz, 1H), 8.70 (d, J=2.0Hz, 1H ),8.66(s,1H),8.28(s,1H),8.19(s,1H),7.68(s,1H),7.64-7.57(m,2H),7.42-7.37(m,3H),7.32- 7.29(m, 3H), 6.73(s, 1H), 6.04-6.01(d, J=7.2Hz, 1H), 4.75-4.72(m, 1H), 4.64-4.62(m, 1H), 4.58-4.53( m,1H),4.36-4.29(m,2H),4.16-4.12(m,1H),3.89(s,3H),3.73(s,3H),3.66-3.62(m,1H),2.92-2.90( m, 4H), 2.52(s, 3H), 2.52-2.47(m, 4H), 2.33-2.28(m, 2H), 2.24-2.11(m, 1H), 2.14(s, 3H), 2.11(s, 3H), 2.07-1.94(m, 2H), 1.47-1.42(m, 4H), 1.32-1.21(m, 4H), 1.08(s, 9H).

Embodiment 4:

(2S,4R)-1-((S)-2-(7-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl) )amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)heptanamido)- 3,3-Dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

Reaction process:

Reaction steps:

With (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl base)pyrrolidinyl-2-carboxamide and 7-bromoheptanoic acid as raw materials, the final product (2S,4R)-1-((S)-2-(7-(4- (4-((5-Bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-( 1-Methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)heptamido)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-( 4-Methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (37.9 mg).

MS(ESI)M/Z: 1203.2[M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ): δ 12.59 (s, 1H), 8.99 (dd, J=9.6, 4.4 Hz, 1H), 8.75-8.64 (m, 3H), 8.29 (s, 1H), 8.22 (s,1H),7.65-7.61(m,3H),7.38-7.33(m,6H),6.73(s,1H),6.12-5.98(m,1H),4.74(t,J=8.0Hz,1H ), 4.63-4.47(m, 3H), 4.33(dd, J=14.8, 5.2Hz, 1H), 4.12(d, J=11.2Hz, 1H), 3.89(s, 3H), 3.73(s, 3H) ,3.60(dd,J＝11.2,3.6Hz,1H),2.94(br s,4H),2.65-2.25(m,9H),2.21-2.20(m,2H),2.14(s,3H),2.11( s,3H),1.76-1.40(m,6H),1.32(brs,4H),0.93(s,9H).

Embodiment 5:

(2S,4R)-1-((S)-2-(4-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl) )amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)butanamido)- 3,3-Dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

Reaction process:

Reaction steps:

With (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl base)pyrrolidinyl-2-carboxamide and 4-chlorobutyric acid as raw materials, the final product (2S,4R)-1-((S)-2-(4-(4- (4-((5-Bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-( 1-Methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)butanamido)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-( 4-Methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (22.4 mg).

MS(ESI) M/Z: 1161.2[M+H ⁺ ].

¹ H NMR (400 MHz, CDCl ₃ ): δ 12.59 (s, 1H), 8.98 (dd, J=9.6, 4.0 Hz, 1H), 8.71 (dd, J=10.0, 2.0 Hz, 2H), 8.66 (s ,1H),8.29(s,1H),8.20(s,1H),7.75-7.59(m,2H),7.55-7.44(m,2H),7.38-7.29(m,5H),6.95-6.71(m ,2H),4.79(t,J＝8.0Hz,1H),4.63-4.45(m,3H),4.37(dd,J＝14.8,5.2Hz,1H),4.17(d,J＝11.6Hz,1H) ,3.90(s,3H),3.75(d,J=4.8Hz,1H),3.68(s,3H),3.59(dd,J=11.2,3.2Hz,1H),3.26-2.75(m,10H), 2.67-2.47(m, 5H), 2.36(d, J=13.2Hz, 1H), 2.26-2.17(m, 1H), 2.14(s, 3H), 2.11(s, 3H), 1.99(brs, 2H) ,0.97(s,9H).

Embodiment 6:

4-((2-(2-(2-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino) pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)ethoxy)ethoxy) Ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Reaction process:

Reaction steps:

Step 1: ((6-((5-Bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperazine- 1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (50 mg, 0.076 mmol) and (2-(2-(2-(2-bromo) Ethoxy)ethoxy)ethoxy)ethyl)carbamate (50 mg, 0.14 mmol) was dissolved in N,N-dimethylformamide (5 mL) and DIEA (39 mg, 0.30 mmol) was added and catalytic amount of sodium iodide, the reaction system was heated to 85 ° C and stirred for 5 hours. LCMS monitoring showed that the raw materials disappeared, the reaction solution was cooled to room temperature, and water (10 mL) was added to quench the reaction. The mixed solution was quenched with ethyl acetate (20 mL × 3 times) extraction, the organic phases were combined, the organic phase was washed with saturated brine (20 mL×3 times), then dried with anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to obtain (2-(2-(2-(2). -(4-(4-((5-Bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy - tert-butyl 2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)ethoxy)ethoxy)ethoxy)ethyl)carbamate (70 mg ,Crude).

MS(ESI)M/Z: 938.3[M+H] ⁺ .

Step 2: To (2-(2-(2-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl) )amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)ethoxy)ethyl To a solution of tert-butyl oxy)ethoxy)ethyl)carbamate (90 mg, ca. 0.096 mmol) in dichloromethane (2 mL) was added a solution of hydrochloric acid in dioxane (12 mL, 4M). After stirring at room temperature for 2 hours, the mixture was concentrated under reduced pressure to obtain (6-((2-((4-(4-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethoxy)ethyl) yl)piperazin-1-yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-5-bromopyrimidin-4-yl)amino) Quinoxalin-5-yl)dimethylphosphine oxide hydrochloride (60 mg, crude).

MS(ESI)M/Z:838.3[M+H] ⁺ .

Step 3: (6-((2-((4-(4-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)piperazine at room temperature -1-yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-5-bromopyrimidin-4-yl)amino)quinoxaline- 5-yl) dimethylphosphine oxide hydrochloride (60 mg, about 0.072 mmol) and 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindole-1,3-dione (20 mg, 0.72 mmol) was dissolved in DMSO (5 mL), DIEA (47 mg, 0.36 mmol) and a catalytic amount of sodium iodide were added, and the reaction system was heated to 110 °C and stirred for 12 hours. LCMS monitoring showed the disappearance of starting material, the reaction was cooled to room temperature, and water (10 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (20 mL×3 times), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by high performance preparative liquid chromatography to give the final product 4-((2-(2-(2-(2-(4-(4-((5-bromo-4-((5-(dimethyl Phosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazine -1-yl)ethoxy)ethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-di Ketone (1 mg).

MS(ESI) M/Z: 1093.7[M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ): δ 12.57 (s, 1H), 8.98-8.95 (m, 1H), 8.75 (d, J=1.2 Hz, 1H), 8.70 (d, J=1.6 Hz, 1H ), 8.29(s, 1H), 8.20(s, 1H), 7.66(brs, 2H), 7.52-7.46(m, 2H), 7.35-7.26(m, 2H), 7.10(d, J=6.8Hz, 1H), 6.91(d, J=8.4Hz, 1H), 6.71(s, 1H), 6.53(t, J=5.2Hz, 1H), 4.94-4.89(m, 1H), 3.89(s, 3H), 3.73-3.62(m, 13H), 3.48-3.43(m, 2H), 3.0-2.7(m, 12H), 2.26-2.18(m, 2H), 2.14(s, 3H), 2.11(s, 3H), 2.07-1.95(m,2H).

Embodiment 7:

(2S,4R)-1-((S)-2-(6-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)phenyl)amino)pyrimidine- 2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)hexamido)-3,3-di Methylbutyryl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

Reaction process:

Reaction steps:

Step 1: 1-(4-(4-Amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)- 2,2,2-Trifluoroethane-1-one (400 mg, 1.04 mmol), (2-((5-bromo-2-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide ( 331 mg, 0.92 mmol) and trifluoroacetic acid (296 mg, 2.6 mmol) were successively added to isopropanol (20 mL), and the temperature was raised to 95° C. under argon to stir the reaction for 16 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/1) to give 1-(4-(4-((5-bromo-4-((2-(dimethylphosphorus) Acyl)phenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazolyl-4-yl)phenyl)piperazin-1-yl) -2,2,2-Trifluorothiophen-1-one (510 mg, 78% yield).

MS(ESI)M/Z:707.4[M+H] ⁺ .

Step 2: 1-(4-(4-((5-bromo-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-5-methyl at room temperature Oxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)-2,2,2-trifluorothiophen-1-one (510 mg, 0.72 mmol ) and potassium hydroxide (403 mg, 7.2 mmol) were added to methanol (15 mL) and water (6 mL), the temperature was raised to 60° C. and the reaction was stirred for 4 hours. The reaction solution was cooled to room temperature, diluted with dichloromethane (100 mL), and separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to obtain (2-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazole-4- (370 mg, 84% yield).

MS(ESI)M/Z:611.2[M+H] ⁺ .

With (2-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperazin-1-yl)phenyl )amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide and (2S,4R)-1-((S)-2-(6-chlorohexamido)-3,3-dimethyl ylbutyryl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide as raw material, the final product (2S,4R) was prepared with reference to Example 2 )-1-((S)-2-(6-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl) Amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)hexamido)-3,3-dimethylbutyryl )-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (45.5 mg).

MS(ESI)M/Z: 1137.4[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ): δ 10.67(s, 1H), 8.68(s, 1H), 8.49-8.45(m, 1H), 8.22(d, J=3.6Hz, 2H), 7.79(s ,1H),7.52(s,1H),7.39-7.29(m,7H),7.03-6.95(m,2H),6.71(s,1H),6.10(brs,1H),4.75(t,J=8.0 Hz,1H),4.61-4.51(m,3H),4.36-4.31(m,1H),4.10(d,J=11.2Hz,1H),3.88(s,3H),3.85(s,3H),3.60 -3.57(m,1H),2.98(br s,4H),2.60-2.52(m,9H),2.26-2.13(m,4H),1.86(s,3H),1.83(s,3H),1.75- 1.50(m, 4H), 1.37-1.32(m, 2H), 0.93(s, 9H).

Embodiment 8:

4-((2-(2-(3-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidine-2 -yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl-3-oxopropoxy)ethoxy) Ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Reaction process:

Reaction steps:

(6-((5-Bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperazin-1-yl) Phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (50 mg, 0.076 mmol) was dissolved in DMF (5 mL), followed by the addition of 3-(2-(2- ((2-(2,6-Dioxypiperidin-3-yl)-1,3-dioxoisoindol-4-yl)amino)ethoxy)propionic acid (43 mg, 0.10 mmol), HATU ( 57mg, 0.15mmol) and DIEA (20mg, 0.15mmol), the reaction system was heated to 25 ° C and stirred for 3 hours. LCMS monitoring showed that the raw materials disappeared, and water (20 mL) was added to the reaction solution to quench. The mixed solution was quenched with ethyl acetate (20 mL). × 3 times) extraction. Combine the organic phases, first wash with saturated brine (20 mL × 3 times), then dry with anhydrous sodium sulfate, filter, and finally concentrate under reduced pressure. The obtained residue is purified by high performance preparative liquid chromatography to obtain the final Product 4-((2-(2-(3-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidine- 2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl-3-oxopropoxy)ethoxy )ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (26.8 mg, 33% yield).

MS(ESI)M/Z: 1077.9[M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD): δ 8.86-8.85 (m, 2H), 8.75-8.61 (m, 1H), 8.28 (s, 1H), 7.96 (s, 1H), 7.65 (brs, 2H) ),7.58-7.54(m,1H),7.48-7.44(m,1H),7.01-6.95(m,2H),6.82(s,1H),5.02-4.98(m,1H),3.88(s,3H ), 3.79-3.76(m, 4H), 3.72-3.69(m, 2H), 3.68-3.57(m, 8H), 3.44-3.42(m, 2H), 2.91-2.84(m, 4H), 2.80-2.75 (m,1H), 2.70-2.61(m,4H), 2.17-2.13(m,6H), 2.04-1.98(m,1H), 1.32-1.28(m,1H).

Embodiment 9:

4-((15-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)- 5-Methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)-15-oxo-3,6,9,12-tetraoxopentane yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Reaction process:

Reaction steps:

1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9, 12-Tetraoxopentadecyl-15-oleic acid (120 mg, 0.23 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylureahexa Fluorophosphate (105 mg, 0.28 mmol) and N,N-diisopropylethylamine (59 mg, 0.46 mmol) were dissolved in DMF (5 mL), and after stirring for one hour, ((6-((5-bromo-2- ((2-Methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoline Oxalin-5-yl) dimethyl phosphine oxide (152mg, 0.23mmol), continued to stir for 3 hours. The LCMS monitoring reaction was basically completed, the reaction solution was filtered, and the filtrate was purified by high performance preparative liquid chromatography to obtain the final product 4-((15 -(4-(4-((5-Bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy -2-(1-Methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)-15-oxo-3,6,9,12-tetraoxopendecyl)amino)- 2-(2,6-Dioxopiperidin-3-yl)isoindoline-1,3-dione (42 mg, 16% yield).

MS(ESI)M/Z: 1166.4[M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ): δ 12.58 (s, 1H), 8.98-8.94 (m, 1H), 8.88-8.83 (m, 1H), 8.74 (d, J=1.6Hz, 1H), 8.70 (d, J＝2.0Hz, 1H), 8.29(s, 1H), 8.23(s, 1H), 7.67(s, 1H), 7.66-7.56(m, 2H), 7.51-7.45(m, 1H), 7.38(s, 1H), 7.10(d, J=6.8Hz, 1H), 6.91(d, J=8.4Hz, 1H), 6.65(s, 1H), 6.50-6.48(m, 1H), 4.96-4.85 (m,1H),3.89(s,3H),3.83-3.80(t,J=4.8Hz,2H),3.73-3.64(m,18H),3.55-3.53(m,2H),3.53-3.48(m ,2H),2.89(brs,4H),2.67-2.64(m,2H),2.58(t,J=6.8Hz,2H),2.24-2.20(m,1H),2.14(s,3H),2.11( s,3H),2.02-1.98(m,1H),1.31-1.26(m,1H).

Embodiment 10:

4-((2-(2-(2-(3-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino) pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)-3-oxopropoxy) Ethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Reaction process:

Reaction steps:

(6-((5-Bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperazin-1-yl) Phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (50 mg, 0.076 mmol) was dissolved in DMF (5 mL), followed by the addition of 3-(2-(2- (2-((2-(2,6-Dioxypiperidin-3-yl)-1,3-dioxoisoindol-4-yl)amino)ethoxy)ethoxy)propionic acid (35 mg , 0.073mmol), HATU (57mg, 0.15mmol) and DIEA (20mg, 0.15mmol), the reaction system was heated to 25 ° C and stirred for 3 hours. LCMS monitoring showed that the raw materials disappeared, and water (20 mL) was added to the reaction solution to quench. Mixing The liquid was extracted with ethyl acetate (20 mL×3 times). The organic phases were combined, washed with saturated brine (20 mL×3 times), then dried with anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained residue was subjected to high-efficiency Purification by preparative liquid chromatography gave the final product 4-((2-(2-(2-(3-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxa) olin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl) -3-Oxopropoxy)ethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (23.6 mg, 29% yield).

MS(ESI)M/Z: 1121.9[M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD): δ 8.86-8.84(m, 2H), 8.77-8.57(m, 1H), 8.28(s, 1H), 7.96(s, 1H), 7.64(s, 2H) ),7.55-7.52(m,1H),7.47-7.43(m,1H),6.99-6.95(m,2H),6.82(s,1H),5.03-4.98(m,1H),3.88(s,3H ), 3.78-3.69(m, 7H), 3.68-3.58(m, 11H), 3.40(t, J=5.2Hz, 2H), 2.95-2.87(m, 4H), 2.83-2.78(m, 1H), 2.73-2.59(m, 4H), 2.16(s, 3H), 2.13(s, 3H), 2.08-1.99(m, 1H), 1.33-1.28(m, 1H).

Embodiment 11:

4-((9-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)- 5-Methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)-9-oxynonyl)amino)-2-(2,6- Dioxopiperidin-3-yl)isoindoline-1,3-dione

Reaction process:

Reaction steps:

(6-((5-Bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperazin-1-yl) Phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (50 mg, 0.076 mmol) was dissolved in DMF (5 mL), followed by the addition of 9-((2-(2 ,6-Dioxypiperidin-3-yl)-1,3-dioxoisoindol-4-yl)amino)nonanoic acid (32 mg, 0.075 mmol), HATU (57 mg, 0.15 mmol) and DIEA (20 mg, 0.15 mmol), the reaction system was heated to 25 °C and stirred for 3 hours. LCMS monitoring showed the disappearance of starting material, and the reaction was quenched by adding water (20 mL). The mixture was extracted with ethyl acetate (20 mL×3 times). The organic phases were combined, washed with saturated brine (20 mL×3 times), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained residue was purified by high performance preparative liquid chromatography to give the final product 4-((9-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxaline-6- (yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)-9-oxo Nonyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (21.5 mg, 27% yield).

MS(ESI)M/Z: 1074.0[M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD): δ 8.88-8.85(m, 2H), 8.74-8.59(m, 1H), 8.25(s, 1H), 7.98(s, 1H), 7.75-7.57(m) ,3H),7.53-7.49(m,1H),7.02-6.99(m,2H),6.85(s,1H),5.05-5.00(m,1H),3.89(s,3H),3.80-3.62(m ,7H),2.97-2.86(m,4H),2.84-2.60(m,3H),2.43(t,J=7.6Hz,2H),2.17(s,3H),2.14(s,3H),2.10- 1.99(m,2H),1.67-1.58(m,4H),1.47-1.28(m,9H).

Example 12:

4-((2-(3-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl) Amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)propoxy)ethyl)amino)-2-(2 ,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Reaction process:

Reaction steps:

Step 1: 2-(2,6-dioxopiperidin-3-yl)-4-((2-(3-hydroxypropoxy)ethyl)amino)isoindoline-1, The 3-diketone (100 mg, 0.27 mmol) was dissolved in dichloromethane (5 mL) and triethylamine (40 mg, 0.40 mmol) was added. The temperature was lowered to 0°C, methanesulfonyl chloride (46 mg, 0.40 mmol) was slowly added dropwise, and the mixture was stirred at 0°C for 1 hour. TLC monitoring showed that the reaction was complete and was quenched by the addition of saturated aqueous sodium bicarbonate (20 mL). The mixture was extracted with dichloromethane (20 mL×3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxisoindoline-4- yl)amino)ethoxy)propyl mesylate.

MS(ESI) M/Z: 454.3[M+H] ⁺ .

Step 2: (6-((5-Bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperazine-1 -yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (48 mg, 0.073 mmol) and 3-(2-((2-(2,6- Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)propyl mesylate (50 mg, 0.11 mmol) was dissolved in N,N- To dimethylformamide (5 mL), DIEA (28.7 mg, 0.22 mmol) and a catalytic amount of sodium iodide were added, and the reaction was heated to 80°C and stirred overnight. LCMS monitoring showed the disappearance of starting material, the reaction was cooled to room temperature, and water (10 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (20 mL×3 times), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by high performance preparative liquid chromatography to give the final product 4-((2-(3-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxaline) -6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)propane oxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (26.7 mg, 35% yield).

MS(ESI)M/Z: 1020.3[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ): δ 13.34 (brs, 1H), 10.97 (brs, 1H), 10.39 (brs, 1H), 8.90 (s, 1H), 8.78 (d, J=1.2Hz, 1H ), 8.71-8.68(m, 1H), 8.08(s, 1H), 7.92(d, J=9.2Hz, 1H), 7.83(s, 1H), 7.64(s, 1H), 7.58-7.54(m, 1H), 7.39(s, 1H), 7.16(d, J=6.8Hz, 1H), 6.95(d, J=8.4Hz, 1H), 6.75(s, 1H), 6.54(t, J=4.8Hz, 1H), 5.01-4.96(m, 1H), 3.90(s, 3H), 3.74-3.69(m, 9H), 3.62-3.58(m, 2H), 3.51-3.49(m, 2H), 3.40-3.38( m,1H),3.28-3.21(m,3H),3.13-3.08(m,2H),3.00-2.92(m,2H),2.81-2.76(m,1H),2.35-2.18(m,3H), 2.14(s, 3H), 2.11(s, 3H).

Example 13:

5-(4-((1-(4-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidine-2 -yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazine-1-carbonyl)phenyl)piperidin-4-yl)methyl yl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Reaction process:

Reaction steps:

4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazine-1- yl)methyl)piperidin-1-yl)benzoic acid (73 mg, 0.13 mmol) was dissolved in DMF (5 mL), followed by (6-((5-bromo-2-((2-methoxy-5 -(1-Methyl-1H-pyrazol-4-yl)-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethyl phosphine oxide (87 mg, 0.13 mmol), HATU (99 mg, 0.26 mmol) and DIEA (67 mg, 0.52 mmol), and the reaction system was stirred at room temperature for 1 hour. LCMS monitoring showed the disappearance of starting material, and the reaction was quenched by adding water (20 mL). The mixture was extracted with ethyl acetate (20 mL×3 times). The organic phases were combined, washed with saturated brine (20 mL×3 times), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained residue was purified by high performance preparative liquid chromatography to obtain the final product 5-(4-((1-(4-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)) quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazine-1- Carbonyl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-di Ketone (7.2 mg, 4.6% yield).

MS(ESI)M/Z: 1204.4[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d6): δ12.66(s,1H), 11.07(s,1H), 8.84-8.80(m,3H), 8.40(s,1H), 8.28(s,1H), 8.12(s,1H),7.75(s,1H),7.69-7.64(m,2H),7.36-7.32(m,3H),7.27-7.23(m,1H),6.89(s,1H),6.54( d, J＝8.8Hz, 2H), 5.09-5.05(m, 1H), 3.82(s, 3H), 3.78(s, 3H), 3.70-3.68(m, 4H), 3.51-3.44(m, 6H) ,3.39-3.36(m,2H),2.90-2.83(m,6H),2.67-2.51(m,6H),2.44-2.40(m,2H),2.33-2.27(m,1H),2.19-2.13( m,1H),2.03(s,3H),2.00(s,3H),1.69-1.64(m,3H).

Example 14:

5-(3-(4-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidine-2- yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)-2-oxoethyl)piperidine-1 -yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Reaction process:

Reaction steps:

Step 1: Combine 2-(piperidin-4-yl)ethyl acetate hydrochloride (500 mg, 2.4 mmol), 1-Boc-3-iodoazetidine (1.05 g, 3.6 mmol) and sodium iodide (36 mg, 0.24 mmol) was dissolved in acetonitrile (100 mL), potassium carbonate (1.0 g, 7.2 mmol) was added, and the reaction system was heated to 80° C. and stirred for 16 hours. LCMS monitoring showed that the reaction was complete, the reaction solution was cooled to room temperature and poured into ice water (200 mL). The mixture was extracted with ethyl acetate (200 mL×3 times), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=5:1) to obtain 3-(4-(2-ethoxy-2-oxoethyl)piperidin-1-yl) Azetidine-1-carboxylate tert-butyl ester (304 mg, 39% yield).

MS(ESI)M/Z: 327.2[M+H] ⁺ .

Step 2: Dissolve tert-butyl 3-(4-(2-ethoxy-2-oxoethyl)piperidin-1-yl)azetidine-1-carboxylate (240 mg, 0.74 mmol) In a solution of hydrogen chloride in dioxane (3M, 5 mL), it was stirred at room temperature for 3 hours. LCMS monitoring showed that the reaction was completed, and the reaction solution was concentrated under reduced pressure to obtain 190 mg of ethyl 2-(1-(azetidin-3-yl)piperidin-4-yl)ethyl acetate hydrochloride.

MS(ESI)M/Z: 227.2[M+H] ⁺ .

Step 3: Combine 2-(1-(azetidin-3-yl)piperidin-4-yl)ethyl acetate hydrochloride (250 mg, 0.95 mmol) and 2-(2,6-dioxo Piperidin-3-yl)-5-fluoro-isoindoline-1,3-dione (263 mg, 0.95 mmol) was dissolved in acetonitrile (100 mL), N,N-diisopropylethylamine (245 mg) was added , 1.90 mmol), the reaction system was heated to 85 °C and stirred for 16 hours. LCMS monitoring showed that the reaction was complete, the reaction solution was cooled to room temperature and poured into ice water (200 mL). The mixture was extracted with ethyl acetate (200 mL×3 times), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:1) to obtain 2-(1-(1-(2-(2,6-dioxopiperidin-3-yl)) -1,3-dioxoisoindolin-5-yl)azetidine-3-yl)piperidin-4-yl)acetate (143 mg, 31% yield).

MS(ESI) M/Z: 483.2[M+H] ⁺ .

Step 4: Convert 2-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azacyclic Ethyl butan-3-yl)piperidin-4-yl)acetate (140 mg, 0.29 mmol) was dissolved in water (5 mL), cooled to 0°C, and concentrated sulfuric acid (1 mL) was slowly added dropwise. The reaction system was heated to 100°C and stirred for 16 hours. LCMS monitoring showed that the reaction was complete. Saturated aqueous sodium bicarbonate solution was added to adjust the pH to neutrality, concentrated under reduced pressure, and the obtained residue was purified by high performance preparative liquid chromatography to obtain 2-(1-(1-(2-(2,6-dioxopiperidine- 3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperidin-4-yl)acetic acid (103 mg, 78% yield).

MS(ESI) M/Z: 455.2[M+H] ⁺ .

Step 5: Convert 2-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azacyclic Butan-3-yl)piperidin-4-yl)acetic acid (27.7 mg, 0.06 mmol) was dissolved in DMF (3 mL), followed by (6-((5-bromo-2-((2-methoxy -5-(1-Methyl-1H-pyrazol-4-yl)-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl) Dimethylphosphine oxide (33 mg, 0.05 mmol), HATU (57 mg, 0.15 mmol) and DIEA (20 mg, 0.15 mmol) were stirred at room temperature for 2 hours. LCMS monitoring showed the disappearance of starting material, and the reaction was quenched by adding water (20 mL). The mixture was extracted with ethyl acetate (20 mL×3 times). The organic phases were combined, washed with saturated brine (20 mL×3 times), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained residue was purified by high performance preparative liquid chromatography to give the final product 5-(3-(4-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoline. Oxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl )-2-oxoethyl)piperidin-1-yl)azetidine-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1 ,3-dione (3.6 mg, 6.6% yield).

MS(ESI)M/Z: 1099.4[M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ): δ 12.56 (s, 1H), 8.99-8.96 (m, 1H), 8.74-8.70 (m, 2H), 8.30-8.24 (m, 2H), 8.03 (s, 1H), 7.65-7.62(m, 3H), 7.36(s, 1H), 6.78(s, 1H), 6.64(s, 1H), 6.52(d, J=9.4Hz, 1H), 5.36-5.30(m ,1H),4.95-4.90(m,1H),4.11(t,J=7.6Hz,2H),3.90(brs,4H),3.73(brs,4H),3.53(s,2H),2.90-2.84( m, 6H), 2.80-2.72(m, 2H), 2.29(d, J=6.4Hz, 1H), 2.24-2.20(m, 1H), 2.14(s, 3H), 2.11(s, 3H), 2.02 -1.98(m,4H),1.90-1.84(m,2H),1.28-1.25(m,3H).

Example 15:

4-(4-(4-((5-Bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy yl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl) -1,3-Dioxisoindolin-4-yl)butanamide

Reaction process:

Reaction steps:

4-Chloro-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)butanamide (100 mg, 0.26 mmol) , (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperazin-1-yl)phenyl )amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (176 mg, 0.26 mmol) and sodium iodide (5 mg, 0.03 mmol) in N,N-dimethylmethane To the amide (5 mL), DIEA (68 mg, 0.52 mmol) was added, and the reaction system was heated to 90° C. and stirred for 16 hours. LCMS monitoring showed that the reaction was complete, the reaction solution was cooled to room temperature, filtered and concentrated under reduced pressure. The resulting residue was purified by high performance preparative liquid chromatography to give the final product 4-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino) pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)-N-(2-(2 ,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)butanamide (10.5 mg, 4% yield).

MS(ESI)M/Z: 1004.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d6): δ12.69(s, 1H), 11.16(s, 1H), 9.85(s, 1H), 9.69-9.58(m, 1H), 8.85(d, J=2.0 Hz,1H),8.81-8.78(m,2H),8.45-8.43(m,2H),8.29(s,1H),8.05(s,1H),7.89-7.82(m,2H),7.68-7.66( m, 2H), 6.77(s, 1H), 5.18-5.13(m, 1H), 3.84(s, 3H), 3.78(s, 3H), 3.60-3.56(m, 2H), 3.27-3.22(m, 6H), 3.00-2.95(m, 3H), 2.67-2.55(m, 5H), 2.09-2.06(m, 2H), 2.04(s, 3H), 2.00(s, 3H).

Example 16:

7-(4-(4-((5-Bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy yl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl) -1,3-Dioxoisoindolin-4-yl)heptamide

Reaction process:

Reaction steps:

With (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperazin-1-yl)phenyl )amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide and 7-bromo-N-(2-(2,6-dioxopiperidin-3-yl)- 1,3-Dioxoisoindolin-4-yl)heptamide was used as raw material, and the final product 7-(4-(4-((5-bromo-4-(((5-( was then prepared with reference to Example 15) Dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl ) piperazin-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)heptamide (34.1 mg).

MS(ESI)M/Z: 1046.4[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d6): δ12.78(s,1H), 11.16(s,1H), 9.71(s,1H), 9.29(brs,1H), 8.86(s,1H), 8.82- 8.77(m, 2H), 8.59(brs, 1H), 8.48(d, J=8.0Hz, 1H), 8.31(s, 1H), 8.03(s, 1H), 7.84-7.81(m, 2H), 7.65 -7.62(m, 2H), 6.77(s, 1H), 5.16-5.12(m, 1H), 3.84(s, 3H), 3.78(s, 3H), 3.25-3.22(m, 8H), 2.97-2.91 (m,4H),2.67-2.55(m,4H),2.04(s,3H),2.01(s,3H),1.69(brs,4H),1.40(brs,4H).

Example 17:

3-(4-(5-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino )-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)pent-1-yn-1-yl)-1-oxo isoindolin-2-yl)piperidine-2,6-dione

Reaction process:

Reaction steps:

With (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperazin-1-yl)phenyl )amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide and 5-(2-(2,6-dioxopiperidin-3-yl)-1-oxo Isoindolin-4-yl)pent-4-yn-1-yl methanesulfonate was used as the raw material (for its preparation, see WO2017176958A1), and the final product 3-(4-(5-(4) was prepared with reference to Example 15. -(4-((5-Bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2- (1-Methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)pent-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine Pyridin-2,6-dione (15.1 mg).

MS(ESI)M/Z: 971.3[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ): δ 13.17(s,1H), 10.61(s,1H), 8.80(s,1H), 8.76(s,1H), 8.69-8.65(m,1H), 8.06 (s,1H),7.97(s,1H),7.89-7.85(m,2H),7.59(d,J=7.6Hz,1H),7.52-7.41(m,2H),7.30(s,1H), 6.75(s, 1H), 5.34-5.29(m, 1H), 4.67-4.49(m, 2H), 3.93(s, 3H), 3.78(s, 3H), 3.74-3.67(m, 1H), 3.63- 3.56(m,1H), 3.41-3.36(m,2H), 3.26-3.24(m,3H), 3.18-3.13(m,1H), 2.98-2.91(m,2H), 2.87-2.85(m,2H ), 2.67-2.65(m, 2H), 2.58-2.10(m, 8H), 1.27-1.24(m, 2H).

Example 18:

3-(4-(5-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino )-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)pentyl)-1-oxoisoindoline-2- yl)piperidine-2,6-dione

Reaction process:

Reaction steps:

With (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperazin-1-yl)phenyl )amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide and 5-(2-(2,6-dioxopiperidin-3-yl)-1-oxo Isoindolin-4-yl)pentyl methanesulfonate was used as the raw material (for its preparation, see WO2017176958A1), and the final product 3-(4-(5-(4-(4-(((5) was prepared with reference to Example 15) -Bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H -Pyrazol-4-yl)phenyl)piperazin-1-yl)pentyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (17 mg).

MS(ESI) M/Z: 975.4[M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ): δ 13.17 (s, 1H), 9.62 (s, 1H), 8.73 (d, J=2.0 Hz, 1H), 8.69 (d, J=1.6 Hz, 1H), 8.62-8.57(m,1H),7.99(s,1H),7.95(s,1H),7.75-7.70(m,1H),7.64-7.61(m,1H),7.45-7.40(m,2H), 7.34-7.29(m, 2H), 6.67(s, 1H), 5.23-5.18(m, 1H), 4.47-4.28(m, 2H), 3.79(s, 3H), 3.72(s, 3H), 3.57- 3.54(m, 2H), 3.32-3.26(m, 1H), 3.20-3.13(m, 3H), 2.95-2.88(m, 4H), 2.84-2.78(m, 1H), 2.66-2.61(m, 2H ), 2.49-2.36(m, 1H), 2.18-2.15(m, 2H), 2.07(s, 3H), 2.04(s, 3H), 1.24-1.19(m, 2H), 0.80-0.74(m, 4H ).

Example 19:

Reaction process:

Reaction steps:

Step 1: 2-(2,6-dioxopiperidin-3-yl)-4-((5-hydroxypentyl)amino)isoindoline-1,3-dione (65mg, 0.18 mmol, prepared, see Journal of Medicinal Chemistry, 2020, 192, 112186) was dissolved in dichloromethane (10 mL) and triethylamine (27 mg, 0.27 mmol) was added. The temperature was lowered to 0°C, methanesulfonyl chloride (31 mg, 0.27 mmol) was slowly added dropwise, and the mixture was stirred at 0°C for 1 hour. TLC monitoring showed that the reaction was complete and was quenched by the addition of saturated aqueous sodium bicarbonate (20 mL). The mixture was extracted with dichloromethane (20 mL×3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxisoindolin-4-yl)amino ) pentyl mesylate (65 mg, 82% yield).

MS(ESI)M/Z:438.0[M+H] ⁺ .

Step 2: (6-((5-Bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperazine-1 -yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (98 mg, 0.15 mmol) and 5-((2-(2,6-dioxo) Piperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentylmethanesulfonate (65 mg, 0.15 mmol) was dissolved in acetonitrile (5 mL) and DIEA (48 mg, 0.15 mmol) was added. 0.37 mmol) and a catalytic amount of sodium iodide, the reaction was heated to 80°C and stirred for 12 hours. LCMS monitoring showed the disappearance of the raw materials, the reaction solution was cooled to room temperature, purified by high performance liquid chromatography to obtain the final product 3-(4-(5-(4-(4-((5-bromo-4-(((5-( Dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl ) piperazin-1-yl)pentyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (20.5 mg, 35% yield).

MS(ESI)M/Z: 1004.5[M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ): δ 12.58 (s, 1H), 8.99 (dd, J=4.4, 9.6 Hz, 1H), 8.73 (d, J=2.0 Hz, 1H), 8.70 (d, J = 2.0Hz, 1H), 8.43(brs, 1H), 8.29(s, 1H), 8.21(s, 1H), 7.65-7.61(m, 3H), 7.53-7.47(m, 1H), 7.34(s, 1H), 7.10(d, J＝7.2Hz, 1H), 6.89(d, J＝8.8Hz, 1H), 6.74(s, 1H), 6.24(t, J＝5.6Hz, 1H), 4.94-4.89( m,1H),3.89(s,3H),3.72(s,3H),3.32-3.26(m,2H),2.96(brs,4H),2.91-2.59(m,8H),2.45(brs,2H) ,2.14(s,3H),2.11(s,3H),1.75-1.67(m,4H),1.51-1.43(m,2H).

Example 20:

4-((3-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)- 5-Methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)propyl)amino)-2-(2,6-dioxopiperidine) pyridin-3-yl)isoindoline-1,3-dione

Reaction process:

Reaction steps:

With (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperazin-1-yl)phenyl )amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide and 2-(2,6-dioxopiperidin-3-yl)-4-((3-hydroxyl) Using propyl)amino)isoindoline-1,3-dione as raw material, the final product 4-((3-(4-(4-((5-bromo-4-(((5) -(Dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl) Phenyl)piperazin-1-yl)propyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (6.7 mg).

MS(ESI)M/Z: 976.4[M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ): δ 12.58 (s, 1H), 9.00-8.96 (m, 1H), 8.74 (d, J=1.6 Hz, 1H), 8.70 (d, J=1.6 Hz, 1H ), 8.29(s, 1H), 8.21(s, 1H), 7.66(brs, 2H), 7.52(t, J=6.4Hz, 1H), 7.34(s, 1H), 7.14-7.11(m, 1H) ,7.00-6.96(m,1H),6.75(s,1H),6.47(brs,1H),4.94-4.89(m,1H),3.91(s,3H),3.69(s,3H),3.42(brs ,2H),3.39-2.58(m,12H),2.14(s,3H),2.11(s,3H),2.00-1.78(m,2H),1.31-1.25(m,2H).

Example 21:

3-(4-(3-(3-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidine-2- (yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)propoxy)propyl)-3-methyl -2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

Reaction process:

Reaction steps:

With (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperazin-1-yl)phenyl )amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide and 3-(4-(3-(3-hydroxypropoxy)propyl)-3-methyl- 2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (see WO2020113233A1 for preparation) was used as raw material, and the final product was prepared with reference to Example 19 3-(4-(3-(3-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidine-2- (yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)propoxy)propyl)-3-methyl -2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (12.3 mg).

MS(ESI)M/Z: 1020.2[M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ): δ 12.59 (s, 1H), 8.99-8.95 (m, 1H), 8.75 (d, J=1.2 Hz, 1H), 8.71 (d, J=1.6 Hz, 1H) ), 8.30(s, 1H), 8.22(s, 1H), 7.90(brs, 1H), 7.69(d, J=8.8Hz, 1H), 7.37(brs, 2H), 7.02-6.89(m, 2H) ,6.74(s,1H),6.67(d,J=8.0Hz,1H),5.26-5.21(m,1H),3.90(s,3H),3.70(s,3H),3.66-3.64(m,3H) ), 3.53-3.47(m, 2H), 3.42-3.37(m, 2H), 3.13-2.71(m, 12H), 2.66-2.59(m, 2H), 2.15(s, 3H), 2.11(s, 3H ),1.98-1.86(m,6H).

Example 22:

(2S,4R)-1-((S)-2-(7-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl) )amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)heptanamido)- 3,3-Dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-methyl Amide

Reaction process:

Reaction steps:

Step 1: Dissolve 7-bromoheptanoic acid (210 mg, 1.0 mmol) in DMF (3 mL), add HATU (1.1 g, 3.0 mmol) and DIEA (387 mg, 3.0 mmol), stir at room temperature for 30 minutes, then dropwise Add (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methyl) Thiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (444 mg, 1.0 mmol) in DMF (2 mL), and the reaction was stirred at room temperature for 1 hour. LCMS monitoring showed the disappearance of starting material, and the reaction was quenched by adding water (20 mL). The mixture was extracted with ethyl acetate (20 mL×3 times). The organic phases were combined, washed with saturated brine (20 mL×3 times), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to obtain (2S,4R)-1-((S)-2-(7- Bromoheptanoylamino)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl) Pyrrolidine-2-carboxamide (200 mg, 32% yield).

MS(ESI)M/Z: 635.3[M+H] ⁺ .

Step 2: (6-((5-Bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperazine-1 -yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (105 mg, 0.16 mmol) and (2S,4R)-1-((S)-2 -(7-Bromoheptanoylamino)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl) )ethyl)pyrrolidine-2-carboxamide (100 mg, 0.16 mmol) was dissolved in DMF (5 mL), DIEA (62 mg, 0.48 mmol) and a catalytic amount of sodium iodide were added, and the reaction system was heated to 80 °C and stirred overnight. LCMS monitoring showed that the raw materials disappeared, the reaction solution was cooled to room temperature, and purified by high performance preparative liquid chromatography to obtain the final product (2S,4R)-1-((S)-2-(7-(4-(4-((5 -Bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H -Pyrazol-4-yl)phenyl)piperazin-1-yl)heptanoylamino)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4- (4-Methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (22.5 mg, 12% yield).

MS(ESI)M/Z: 1217.5[M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ): δ 12.59 (s, 1H), 8.99-8.95 (m, 1H), 8.74 (d, J=1.6 Hz, 1H), 8.71 (d, J=2.0 Hz, 1H) ), 8.66(s, 1H), 8.30(s, 1H), 8.21(s, 1H), 7.75(s, 1H), 7.72-7.68(m, 1H), 7.51(d, J=7.2Hz, 1H) ,7.39-7.36(m,6H),6.71(s,1H),6.28(d,J=8.0Hz,1H),5.12-5.05(m,1H),4.77(t,J=8.2Hz,1H), 4.62(d, J=9.2Hz, 1H), 4.49(s, 1H), 4.11(d, J=11.6Hz, 1H), 3.91(s, 3H), 3.67(s, 3H), 3.58-5.54(m ,1H),3.35-3.15(m,5H),2.91-2.85(m,2H),2.52(s,3H),2.50-2.39(m,1H),2.35-2.27(m,2H),2.24-2.18 (m, 2H), 2.14(s, 3H), 2.11(s, 3H), 1.81-1.72(m, 4H), 1.63-1.55(m, 2H), 1.48(d, J=7.2Hz, 3H), 1.39-1.30(m, 4H), 1.05(s, 9H).

Example 23:

(2S,4R)-1-((S)-2-(6-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)) Amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)hexamido)-3 ,3-Dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

Reaction process:

Reaction steps:

With (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methyl) Thiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide, 6-bromohexanoic acid and (6-((5-bromo-2-((2-methoxy-5-(1- Methyl-1H-pyrazol-4-yl)-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide is The raw materials were prepared by referring to the steps of Example 22 to obtain the final product (2S,4R)-1-((S)-2-(6-(4-(4-((5-bromo-4-((5-(di Methylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidine Azin-1-yl)hexamido)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)benzene yl)ethyl)pyrrolidine-2-carboxamide (54.3 mg).

MS(ESI)M/Z: 1203.4[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ): δ 12.59 (s, 1H), 9.00-8.96 (m, 1H), 8.74 (d, J=2.0Hz, 1H), 8.70 (d, J=1.6Hz, 1H ),8.66(s,1H),8.29(s,1H),8.22(s,1H),7.68(brs,2H),7.49-7.32(m,7H),6.72(s,1H),6.36-6.18( m,1H),5.12-5.04(m,1H),4.78-4.74(m,1H),4.59(d,J=8.8Hz,1H),4.49(s,1H),4.12(d,J=11.2Hz ,1H),3.90(s,3H),3.70(s,3H),3.59-3.54(m,2H),3.24-2.90(m,5H),2.90-2.59(m,4H),2.53(s,3H) ), 2.30-2.23(m, 2H), 2.14(s, 3H), 2.11(s, 3H), 1.85-1.66(m, 6H), 1.48(d, J=6.8Hz, 3H), 1.40-1.35( m,2H),1.05(s,9H).

Example 24:

4-((9-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5 -Methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)nonyl)amino)-2-(2,6-dioxopiperidine -3-yl)isoindoline-1,3-dione

Reaction process:

Reaction steps:

Step 1: 9-Aminononan-1-ol (95 mg, 0.60 mmol) and 2-(2,6-dioxopiperidin-3-yl)-4-fluoro-isoindoline-1,3- The diketone (110 mg, 0.40 mmol) was dissolved in NMP (3 mL), N,N-diisopropylethylamine (0.1 mL) was added, and the reaction system was heated to 140° C. and stirred for 20 minutes. TLC monitoring showed that the reaction was complete, the reaction solution was cooled to room temperature and poured into water (10 mL). The mixture was extracted with ethyl acetate (10 mL×4 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=0:1) to obtain 2-(2,6-dioxopiperidin-3-yl)-4-((9-hydroxynonane) yl)amino)isoindoline-1,3-dione (80 mg, 48% yield).

MS(ESI)M/Z: 416.2[M+H] ⁺ .

Step 2: 2-(2,6-dioxopiperidin-3-yl)-4-((9-hydroxynonyl)amino)isoindoline-1,3-dione (80 mg, 0.19 mmol) was dissolved in dichloromethane (5 mL) and triethylamine (0.04 mL) was added. The temperature was lowered to 0°C, methanesulfonyl chloride (31 mg, 0.27 mmol) was slowly added dropwise, and the mixture was stirred at 0°C for 1 hour. TLC monitoring showed that the reaction was complete, and the reaction solution was poured into water (10 mL). The mixture was extracted with ethyl acetate (10 mL×2 times), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=5:1) to obtain 9-((2-(2,6-dioxopiperidin-3-yl)-1,3- Dioxisoindolin-4-yl)amino)nonylmethanesulfonate (55 mg, 58% yield).

MS(ESI)M/Z: 494.2[M+H] ⁺ .

Step 3: (6-((5-Bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperazine-1 -yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (52 mg, 0.08 mmol) and 9-((2-(2,6-dioxo) Piperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)nonylmethanesulfonate (55 mg, 0.11 mmol) was dissolved in acetonitrile (5 mL), DIEA (0.04 mL) was added ) and a catalytic amount of sodium iodide, the reaction was heated to 80°C and stirred for 16 hours. LCMS monitoring showed disappearance of starting material, the reaction was cooled to room temperature and poured into water (5 mL). The mixture was extracted with dichloromethane (10 mL×2 times), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained residue was purified by preparative thin layer chromatography on silica gel plate (dichloromethane:methanol=20:1) to obtain the final product 4-((9-(4-(4-((5-bromo-4-((5 -(Dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)benzene yl)piperazin-1-yl)nonyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (31 mg, 37% yield ).

MS(ESI)M/Z: 1060.3[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ): δ 12.58 (s, 1H), 8.99-8.95 (m, 1H), 8.75 (d, J=1.2Hz, 1H), 8.70 (d, J=1.2Hz, 1H ),8.29(s,1H),8.21(s,1H),7.76-7.68(m,2H),7.52-7.48(m,1H),7.44(s,1H),7.37(s,1H),7.09( d,J＝7.2Hz,1H),6.89(d,J＝8.4Hz,1H),6.73(s,1H),6.25(t,J＝6.0Hz,1H),4.93-4.89(m,1H), 3.91(s,3H),3.68(s,3H),3.29-3.28(m,2H),3.14(brs,4H),2.95-2.66(m,8H),2.15(s,3H),2.11(s, 3H), 1.96-1.80(m, 10H), 1.70-1.64(m, 4H), 1.47-1.39(m, 2H).

Example 25:

4-((7-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5 -Methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)heptyl)amino)-2-(2,6-dioxopiperidine -3-yl)isoindoline-1,3-dione

Reaction process:

Reaction steps:

2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindolin-1,3-dione, 7-aminoheptan-1-ol and (6-((5-bromo -2-((2-Methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl) Amino)quinoxalin-5-yl)dimethylphosphine oxide is used as raw material, and the final product 4-((7-(4-(4-((5-bromo-4-((( 5-(Dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl) Phenyl)piperazin-1-yl)heptyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (23 mg).

MS(ESI)M/Z: 1032.3[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d6): δ 12.74(s, 1H), 11.11(s, 1H), 9.50(brs, 1H), 8.87(d, J=2.0Hz, 1H), 8.82(d, J=2.0Hz, 1H), 8.53(s, 1H), 8.31(s, 1H), 8.04(s, 1H), 7.82(s, 1H), 7.68(s, 1H), 7.63-7.59(m, 1H) ),7.50(brs,1H),7.12(d,J=8.8Hz,1H),7.05(d,J=7.2Hz,1H),6.78(s,1H),6.55(brs,1H),5.09-5.04 (m,1H),3.85(s,3H),3.79(s,3H),3.57-3.54(m,2H),3.37-3.16(m,8H),3.00-2.96(m,3H),2.64-2.56 (m,1H),2.05(s,3H),2.02(s,3H),1.70-1.62(m,4H),1.39(brs,6H),1.24(brs,2H).

Example 26:

4-((8-(4-(4-((5-Bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5 -Methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)octyl)amino)-2-(2,6-dioxopiperidine -3-yl)isoindoline-1,3-dione

Reaction process:

Reaction steps:

2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindolin-1,3-dione, 8-aminooctan-1-ol and (6-((5-bromo -2-((2-Methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl) Amino)quinoxalin-5-yl)dimethylphosphine oxide is used as raw material, and the final product 4-((8-(4-(4-((5-bromo-4-((( 5-(Dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl) Phenyl)piperazin-1-yl)octyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (23 mg).

MS(ESI)M/Z: 1046.3[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ): δ 13.26 (s, 1H), 9.28 (s, 1H), 8.83-8.77 (m, 2H), 8.73 8.64 (m, 1H), 8.05-8.02 (m, 2H) ),7.69-7.67(m,1H),7.54-7.50(m,1H),7.45-7.42(m,2H),7.10(d,J=6.8Hz,1H),6.91(d,J=8.8Hz, 1H), 6.74(s, 1H), 4.97-4.92(m, 1H), 3.84(s, 3H), 3.82(s, 3H), 3.67-3.60(m, 2H), 3.32-3.24(m, 6H) ,3.07-2.98(m,4H),2.81-2.70(m,4H),2.15(s,3H),2.11(s,3H),1.74-1.69(m,4H),1.47-1.26(m,8H) .

Example 27:

4-((6-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5 -Methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)hexyl)amino)-2-(2,6-dioxopiperidine- 3-yl)isoindoline-1,3-dione

Reaction process:

Reaction steps:

2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindolin-1,3-dione, 6-aminohexan-1-ol and (6-((5-bromo -2-((2-Methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl) Amino)quinoxalin-5-yl)dimethylphosphine oxide was used as raw material, and the final product 4-((6-(4-(4-((5-bromo-4-(( was then prepared by referring to the procedure of Example 24, however. 5-(Dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl) Phenyl)piperazin-1-yl)hexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (22 mg).

MS(ESI)M/Z: 1018.4[M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ): δ 12.59 (s, 1H), 8.99-8.95 (m, 1H), 8.75 (d, J=1.6 Hz, 1H), 8.71 (d, J=1.6 Hz, 1H) ), 8.29(s, 1H), 8.22(s, 1H), 7.69(brs, 1H), 7.54-7.48(m, 1H), 7.35(s, 1H), 7.11(d, J=7.2Hz, 1H) ,6.91(d,J＝9.2Hz,1H),6.72(s,1H),6.25-6.23(m,1H),4.94-4.89(m,1H),3.90(s,3H),3.66(s,3H) ),3.34-3.31(m,2H),3.11-2.60(m,12H),2.15(s,3H),2.11(s,3H),1.72-1.68(m,4H),1.52-1.36(m,6H ).

Example 28:

4-((9-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5 -Methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)nonyl)oxo)-2-(2,6-dioxopiperidine pyridin-3-yl)isoindoline-1,3-dione

Reaction process:

Reaction steps:

Step 1: Combine 9-bromo-1-nonanol (222 mg, 1.0 mmol) and 2-(2,6-dioxopiperidin-3-yl)-4-hydroxy-isoindoline-1,3- The diketone (274 mg, 1.0 mmol) was dissolved in DMF (10 mL), sodium bicarbonate (168 mg, 2.0 mmol) was added, and the reaction system was warmed to 70° C. and stirred for 12 hours. TLC monitoring showed that the reaction was complete, the reaction solution was cooled to room temperature and poured into water (100 mL). The mixture was extracted with ethyl acetate (50 mL×2 times), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to obtain 2-(2,6-dioxopiperidin-3-yl)- 4-((9-Hydroxynonyl)oxo)isoindoline-1,3-dione (390 mg, 93% yield).

MS(ESI) M/Z: 417.3[M+H] ⁺ .

Subsequent steps use 2-(2,6-dioxopiperidin-3-yl)-4-((9-hydroxynonyl)oxo)isoindoline-1,3-dione as raw material, refer to the implementation The preparation of Example 24 gave the final product 4-((9-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidine- 2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)nonyl)oxo)-2-( 2,6-Dioxopiperidin-3-yl)isoindoline-1,3-dione (21.3 mg).

MS(ESI)M/Z: 1061.2[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ): δ 12.90(s,1H), 12.76(s,1H), 11.24(s,1H), 9.45(s,1H), 8.87-8.82(m,1H), 8.79 (d, J=2.0Hz, 1H), 8.73(s, 1H), 8.19(s, 1H), 7.89(s, 2H), 7.75-7.68(m, 2H), 7.45(d, J=7.2Hz, 1H), 7.31(s, 1H), 7.22(s, 1H), 6.70(s, 1H), 5.02-4.95(m, 1H), 4.20(t, J＝6.0Hz, 2H), 3.89(s, 3H) ),3.71(s,3H),3.58-3.56(m,2H),3.27-3.18(m,2H),3.10-3.01(m,2H),3.00-2.97(m,2H),2.88-2.86(m ,2H),2.83-2.76(m,2H),2.14(s,3H),2.11(s,3H),1.91-1.87(m,2H),1.57-1.52(m,2H),1.48-1.46(m ,2H),1.46-1.34(m,10H).

Example 29:

3-(4-(10-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino) -5-Methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)dec-1-yn-1-yl)-1-oxoiso indolin-2-yl)piperidine-2,6-dione

Reaction process:

Reaction steps:

Step 1: 3-(4-Bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (50 mg, 0.16 mmol), bis(triphenylphosphine)dichloride Palladium(II) (43 mg, 0.06 mmol) and cuprous iodide (17 mg, 0.09 mmol) were dissolved in DMF (5 mL), replaced with nitrogen three times, then DIEA (216 mg, 1.7 mmol) and dec-9-yne were added -1-ol (213 mg, 1.4 mmol), the reaction system was warmed to 65°C and stirred for 16 hours. TLC monitoring showed that the reaction was complete, the reaction solution was cooled to room temperature and poured into water (100 mL). The mixture was extracted with ethyl acetate (50 mL×2 times), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=0:1) to obtain 3-(4-(10-hydroxydec-1-yn-1-yl)-1-oxoisoindium Doolin-2-yl)piperidine-2,6-dione (34 mg, 56% yield).

MS(ESI) M/Z: 397.2[M+H] ⁺ .

Subsequent steps use 3-(4-(10-hydroxydec-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione as raw material, refer to the implementation The preparation method of Example 24 gave the final product 3-(4-(10-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino) pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)dec-1-yn-1- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (3.9 mg).

MS(ESI)M/Z: 1041.2[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ): δ 12.58(s, 1H), 9.00-8.96(m, 1H), 8.74-8.70(m, 2H), 8.30-8.28(m, 1H), 8.19(s, 1H), 7.81-7.32(m, 8H), 6.72(s, 1H), 5.29-5.24(m, 1H), 4.51-4.31(m, 2H), 3.91(s, 3H), 3.71(s, 3H) ,2.97-2.82(m,6H),2.71-2.45(m,6H),2.35-2.21(m,4H),2.14(s,3H),2.10(s,3H),1.53-1.46(m,4H) ,1.37-1.25(m,8H).

Example 30:

5-((2-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5 -Methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)ethyl)amino)-2-(2,6-dioxopiperidine -3-yl)isoindoline-1,3-dione

Reaction process:

Reaction steps:

Step 1: 2-Aminoethan-1-ol (166 mg, 2.7 mmol) and 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-isoindoline-1,3- The diketone (500 mg, 1.8 mmol) was dissolved in NMP (10 mL), N,N-diisopropylethylamine (351 mg, 2.7 mmol) was added, and the reaction system was heated to 140° C. and stirred for 20 minutes. TLC monitoring showed that the reaction was complete, the reaction solution was cooled to room temperature and poured into water (50 mL). The mixture was extracted with ethyl acetate (40 mL×4 times), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=0:1) to obtain 2-(2,6-dioxopiperidin-3-yl)-5-((2-hydroxyethyl acetate). yl)amino)isoindoline-1,3-dione (200 mg, 35% yield).

MS(ESI)M/Z: 318.1[M+H] ⁺ .

Subsequent steps use 2-(2,6-dioxopiperidin-3-yl)-5-((2-hydroxyethyl)amino)isoindoline-1,3-dione as raw material, refer to Examples The preparation method of 24 gives the final product 5-((2-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidine-2 -yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)ethyl)amino)-2-(2, 6-Dioxopiperidin-3-yl)isoindoline-1,3-dione (5 mg).

MS(ESI)M/Z: 962.2[M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ): δ 13.19 (s, 1H), 9.58 (brs, 1H), 8.79 (d, J=1.6 Hz, 1H), 8.75 (d, J=1.6 Hz, 1H), 8.73-8.69(m,1H),8.09(s,1H),8.05(s,1H),7.68-7.61(m,3H),7.35(s,1H),6.99-6.95(m,2H),6.70( s,1H),4.98-4.93(m,1H),3.84(s,3H),3.77(s,3H),3.58-3.50(m 4H),3.38-3.32(m,4H),3.30-3.10(m ,4H),2.95-2.76(m,4H),2.14(s,3H),2.10(s,3H).

Example 31:

5-((5-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5 -Methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)pentyl)amino)-2-(2,6-dioxopiperidine -3-yl)isoindoline-1,3-dione

Reaction process:

Reaction steps:

2-(2,6-dioxopiperidin-3-yl)-5-fluoro-isoindolin-1,3-dione, 5-aminopentan-1-ol and (6-((5- Bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl ) amino) quinoxalin-5-yl) dimethyl phosphine oxide as raw material, the final product 5-((5-(4-(4-((5-bromo-4-( (5-(Dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl )phenyl)piperazin-1-yl)pentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (3.2 mg).

MS(ESI)M/Z: 1004.2[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ): δ 12.58 (s, 1H), 9.00-8.96 (m, 1H), 8.74 (d, J=2.0Hz, 1H), 8.70 (d, J=2.0Hz, 1H ), 8.29(s, 1H), 8.21(s, 1H), 7.67-7.52(m, 4H), 7.35(s, 1H), 6.97(d, J=2.4Hz, 1H), 6.79-6.76(m, 1H),6.74(s,1H),4.95-4.90(m,1H),3.90(s,3H),3.70(s,3H),3.28-3.23(m,2H),3.05(brs,4H),2.92 -2.70(m,6H),2.59(brs,2H),2.14(s,3H),2.11(s,3H),1.54-1.47(m,4H),1.34-1.22(m,4H).

Example 32:

4-((5-(4-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino )-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)piperidin-1-yl)pentyl)amino)-2- (2,6-Dioxopiperidin-3-yl)isoindoline-1,3-dione

Reaction process:

Reaction steps:

Step 1: (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperazin-1-yl) )phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (500 mg, 0.76 mmol) and tert-butyl 4-iodopiperidine-1-carboxylate (705 mg, 2.3 mmol) was dissolved in acetonitrile (10 mL), potassium carbonate (312 mg, 2.3 mmol) was added, and the reaction system was heated to 100° C. and stirred for 36 hours. TLC monitoring showed that the reaction was complete, the reaction solution was cooled to room temperature, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:1) to give 4-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)) quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazine-1- yl)piperidine-1-carboxylate tert-butyl ester (460 mg, 72% yield).

MS(ESI)M/Z:846.3[M+H] ⁺ .

Step 2: Addition of 4-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino) at room temperature -5-Methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)piperidine-1-carboxylate tert-butyl ester (460 mg, 0.54 mmol) A solution of hydrochloric acid in dioxane (10 mL, 4M) was added to a solution of dichloromethane (5 mL). After stirring at room temperature for 30 minutes, the mixture was concentrated under reduced pressure to obtain (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-( 4-(Piperidin-4-yl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphonium oxide hydrochloride (500 mg, crude ).

MS(ESI)M/Z:746.2[M+H] ⁺ .

Step 3: (6-((5-Bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(piperidine) pyridin-4-yl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide hydrochloride (68 mg, about 0.08 mmol) and 5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentylmethanesulfonate (60 mg, 0.14 mmol) in acetonitrile (5 mL), DIEA (35 mg, 0.27 mmol) and a catalytic amount of sodium iodide were added, and the reaction was heated to 85 °C and stirred for 12 hours. LCMS monitoring showed the disappearance of the raw materials, the reaction solution was cooled to room temperature, and purified by high performance preparative liquid chromatography to obtain the final product 4-((5-(4-(4-(4-((5-bromo-4-(((5- (Dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl )piperazin-1-yl)piperidin-1-yl)pentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione ( 8.2 mg, 37% yield).

MS(ESI)M/Z: 1087.5[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ): δ 12.57 (s, 1H), 8.99-8.96 (m, 1H), 8.73 (d, J=1.6Hz, 1H), 8.70 (d, J=1.6Hz, 1H ), 8.28(s, 1H), 8.19(s, 1H), 7.64(brs, 3H), 7.53-7.47(m, 1H), 7.32(s, 1H), 7.09(d, J=7.2Hz, 1H) ,6.89(d,J=8.4Hz,1H),6.74(s,1H),6.25(t,J=5.4Hz,1H),4.93-4.88(m,1H),3.89(s,3H),3.71( s,3H),3.31-3.26(m 2H),3.11-3.03(m,2H),2.95(brs,4H),2.91-2.74(m,4H),2.72-2.69(m,4H),2.51-2.15 (m,5H),2.14(s,3H),2.11(s,3H),1.95-1.88(m,2H),1.53-1.43(m,4H),1.34-1.25(m,4H).

Example 33:

4-((3-(4-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino )-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)piperidin-1-yl)propyl)amino)-2- (2,6-Dioxopiperidin-3-yl)isoindoline-1,3-dione

Reaction process:

Reaction steps:

with 3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propyl methanesulfonate and (6 -((5-Bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(piperidin-4-yl)piperazine The final product 4-( (3-(4-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5 -Methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)piperidin-1-yl)propyl)amino)-2-(2, 6-Dioxopiperidin-3-yl)isoindoline-1,3-dione (6 mg).

MS(ESI)M/Z: 1059.4[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ): δ 12.54 (s, 1H), 8.97-8.93 (m, 1H), 8.73 (d, J=2.0Hz, 1H), 8.70 (d, J=2.0Hz, 1H) ), 8.28(s, 1H), 8.16(s, 1H), 7.68-7.46(m, 5H), 7.31(s, 1H), 7.08(d, J=6.8Hz, 1H), 6.92(d, J= 8.8Hz,1H),6.86-6.83(m,1H),6.76(s,1H),4.90-4.86(m,1H),3.89(s,3H),3.70(s,3H),3.38-3.33(m ,2H),3.04-3.01(m,6H),2.87-2.63(m,9H),2.47-2.44(m,2H),2.29-2.23(m,2H),2.14(s,3H),2.11(s ,3H),1.77-1.64(m,4H),1.33-1.23(m,2H).

Example 34:

3-(4-(5-(4-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl )amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)piperidin-1-yl)pent-1-yn- 1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

Reaction process:

Reaction steps:

With 5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)pent-4-yn-1-ylmethanesulfonate and ( 6-((5-Bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(piperidin-4-yl)piperidine The final product 3- (4-(5-(4-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino )-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)piperidin-1-yl)pent-1-yn-1- yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (10.8 mg).

MS(ESI)M/Z: 1054.2[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ): δ 13.04(s,1H), 9.67(s,1H), 8.80(s,1H), 8.79-8.72(m,2H), 8.14(s,1H), 7.86 -7.84(m, 2H), 7.75(s, 1H), 7.66-7.64(m, 1H), 7.58(d, J=7.2Hz, 1H), 7.47(t, J=7.6Hz, 1H), 7.39( s,1H),6.69(s,1H), 5.36-5.33(m,2H),4.58-4.41(m,2H),3.86(s,3H),3.76(s,3H),3.26(brs,4H) ,2.95-2.76(m,5H),2.67-2.60(m,2H),2.54-2.34(m,6H),2.24-2.20(m,4H),2.14(s,3H),2.10(s,3H) ,1.31-1.25(m,6H).

Example 35:

5-(3-(4-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino) -5-Methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)piperidin-1-yl)azetidin-1-yl )-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Reaction process:

Reaction steps:

Step 1: (6-((5-Bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(piperidine- 4-yl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide hydrochloride (110 mg, 0.13 mmol) and 3-iodo Azetidine-1-carboxylate tert-butyl ester (209 mg, 0.74 mmol) was dissolved in acetonitrile (10 mL), potassium carbonate (102 mg, 0.74 mmol) was added, and the reaction system was heated to 100 °C and stirred for 5 days. TLC monitoring showed that the reaction was complete, the reaction solution was cooled to room temperature, filtered and concentrated under reduced pressure. The resulting residue was purified by preparative thin layer chromatography on silica gel plate to give 3-(4-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl) )amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)piperidine-1- base) tert-butyl azetidine-1-carboxylate (90 mg, 77% yield).

MS(ESI)M/Z:901.3[M+H] ⁺ .

Step 2: 3-(4-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino )-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)piperidin-1-yl)azetidine-1- tert-Butyl carboxylate (90 mg, 0.10 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (10 mL) was added, and the mixture was stirred at room temperature for 30 minutes. LCMS monitoring showed that the reaction was completed, and the reaction solution was concentrated under reduced pressure to obtain (6-((2-((4-(4-(1-(azetidin-3-yl)piperidin-4-yl)piperazine- 1-yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-5-bromopyrimidin-4-yl)amino)quinoxaline-5 -yl) dimethylphosphorus oxide trifluoroacetate (50 mg, 55% yield).

MS(ESI)M/Z:801.3[M+H] ⁺ .

Step 3: (6-((2-((4-(4-(1-(azetidin-3-yl)piperidin-4-yl)piperazin-1-yl)-2 -Methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-5-bromopyrimidin-4-yl)amino)quinoxalin-5-yl)dimethyl Phosphorus oxide trifluoroacetate (25mg, 0.03mmol) and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (25mg, 0.09 mmol) was dissolved in DMSO (5 mL), DIEA (12 mg, 0.09 mmol) and a catalytic amount of sodium iodide were added and the reaction was heated to 60°C and stirred overnight. LCMS monitoring showed the disappearance of the raw materials, the reaction solution was cooled to room temperature, and purified by high performance preparative liquid chromatography to obtain the final product 5-(3-(4-(4-(4-((5-bromo-4-(((5-( Dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl) Piperazin-1-yl)piperidin-1-yl)azetidine-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3 -diketone (11.4 mg, 35% yield).

MS(ESI)M/Z: 1057.3[M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ): δ 13.23 (s, 1H), 8.80 (d, J=1.2 Hz, 1H), 8.75 (d, J=1.6 Hz, 1H), 8.86-8.72 (m, 1H) ),8.58(brs,1H),8.07(s,1H),7.93(s,1H),7.69-7.60(m,2H),7.52-7.50(m,1H),7.43(s,1H),6.82( d, J＝1.2Hz, 1H), 6.71(s, 1H), 6.60-6.57(m, 1H), 4.97-4.92(m, 1H), 4.19-4.08(m, 4H), 3.84(s, 3H) ,3.79(s,3H),3.69-3.65(m,1H),3.57-3.51(m,2H),3.35-3.27(m,6H),2.93-2.68(m,5H),2.49(m,4H) ,2.30-2.27(m,4H),2.14(s,3H),2.11(s,3H).

Example 36:

5-(4-((4-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino )-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)piperidin-1-yl)methyl)piperidine-1- yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Reaction process:

Reaction steps:

Step 1: 2-(2,6-dioxopiperidin-3-yl)-5-(4-(hydroxymethyl)piperidin-1-yl)isoindoline-1,3- The diketone (100 mg, 0.27 mmol, see WO2018140809A1 for preparation) was dissolved in dichloromethane (5 mL) and triethylamine (81.5 mg, 0.81 mmol) was added. The temperature was lowered to 0°C, methanesulfonyl chloride (34 mg, 0.30 mmol) was slowly added dropwise, and the mixture was stirred at 0°C for 1 hour. TLC monitoring showed that the reaction was complete. The reaction solution was diluted with dichloromethane (20 mL), washed with saturated aqueous sodium bicarbonate solution (10 mL×2 times), the organic phase was dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=5:1) to obtain (1-(2-(2,6-dioxopiperidin-3-yl)-1,3- Dioxisoindolin-5-yl)piperidin-4-yl)methylmethanesulfonate (52 mg, 42% yield).

MS(ESI) M/Z: 450.1[M+H] ⁺ .

Step 2: (6-((5-Bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(piperidine) Perid-4-yl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide hydrochloride (86 mg, about 0.10 mmol) and (1-(2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methylmethanesulfonate (52 mg, 0.12 mmol) was dissolved in acetonitrile (5 mL), DIEA (45 mg, 0.35 mmol) and a catalytic amount of sodium iodide were added and the reaction was heated to 85°C and stirred for 12 hours. LCMS monitoring showed that the raw materials disappeared, the reaction solution was cooled to room temperature, and purified by high performance liquid chromatography to obtain the final product 5-(4-((4-(4-(4-((5-bromo-4-(((5- (Dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl )piperazin-1-yl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1, 3-diketone (2.2 mg, 2% yield).

MS(ESI)M/Z: 1099.1[M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD): δ 8.88-8.77(m, 3H), 8.29(s, 1H), 7.95(s, 1H), 7.78(s, 1H), 7.66(d, J=8.4 Hz,1H),7.55(brs,2H),7.00(d,J＝2.0Hz,1H),6.89-6.80(m,2H),5.08-5.06(m,1H),3.94(s,3H),3.89 -3.81(m, 2H), 3.70(s, 3H), 3.68-3.53(m, 4H), 3.52-3.46(m, 4H), 3.26-3.24(m, 2H), 3.17-3.13(m, 4H) ,2.89-2.48(m,1H),2.76-2.69(m,2H),2.61-2.49(m,2H),2.50-2.22(m,3H),2.17(s,3H),2.14(s,3H) ,2.12-2.04(m,5H),1.99-1.97(m,2H),1.88-1.78(m,1H).

Example 37:

5-(4-((9-(4-((5-Bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5 -Methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)piperidine -1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Reaction process:

Reaction steps:

Step 1: Addition of 9-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)-3,9-diazaspiro[ 5.5] To a solution of tert-butyl undecane-3-carboxylate (346 mg, 0.71 mmol, see CN112538072A for preparation) in dichloromethane (2 mL) was added a solution of hydrochloric acid in dioxane (12 mL, 4 M). After stirring at room temperature for 2 hours, it was concentrated under reduced pressure to obtain 3-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)-3,9-di Azaspiro[5.5]undecane hydrochloride (458 mg, crude).

MS(ESI)M/Z: 386.2[M+H] ⁺ .

Step 2: 3-(5-Methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)-3,9-diazaspiro[ 5.5] Undecane hydrochloride (458mg, crude product) and DMAP (342mg, 2.8mmol) were added to dichloromethane (10mL), stirred for 5 minutes, then added trifluoroacetic anhydride (588mg, 2.8mmol), stirred at room temperature React for 2 hours. The reaction solution was concentrated under reduced pressure to obtain 2,2,2-trifluoro-1-(9-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitro Phenyl)-3,9-diazaspiro[5.5]undecan-3-yl)ethan-1-one (382 mg, crude).

MS(ESI) M/Z: 482.3[M+H] ⁺ .

Step 3: 2,2,2-Trifluoro-1-(9-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrobenzene yl)-3,9-diazaspiro[5.5]undecan-3-yl)ethan-1-one (382 mg, crude) and 10% palladium on carbon (50 mg) were added to methanol (15 mL), hydrogen After three replacements, the reaction was stirred at room temperature for 2 hours. Filtration, the filtrate was concentrated under reduced pressure to obtain 1-(9-(4-amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-3,9-diazepine Heterospiro[5.5]undecan-3-yl)-2,2,2-trifluoroethane-1-one (371 mg, crude).

MS(ESI) M/Z: 452.2[M+H] ⁺ .

Step 4: 1-(9-(4-Amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-3,9-diazepine Spiro[5.5]undecan-3-yl)-2,2,2-trifluoroethane-1-one (371 mg, crude), (6-((5-bromo-2-chloropyrimidin-4-yl ) Amino)quinoxalin-5-yl)dimethylphosphine oxide (310mg, 0.75mmol) and trifluoroacetic acid (857mg, 7.5mmol) were added to isopropanol (10mL) successively, and the temperature was raised to 100 under argon protection. The reaction was stirred for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the obtained residue was purified by preparative TLC plate to obtain 1-(9-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxaline) -6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-3,9-diazepine Spiro[5.5]undecan-3-yl)-2,2,2-trifluoroethyl-1-one (277 mg, 47% over four steps).

MS(ESI)M/Z:827.0[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ): δ 12.59 (s, 1H), 9.02-8.98 (m, 1H), 8.73 (d, J=1.6Hz, 1H), 8.70 (d, J=1.6Hz, 1H) ), 8.29(s, 1H), 8.19(s, 1H), 7.68-7.61(m, 3H), 7.34(s, 1H), 6.72(s, 1H), 3.91(s, 3H), 3.72(s, 3H), 3.68-3.64(m, 2H), 3.57(brs, 2H), 2.90-2.83(m, 4H), 2.14(s, 3H), 2.11(s, 3H), 1.64(brs, 8H).

Step 5: 1-(9-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino )-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-3,9-diazaspiro[5.5]undecan-3-yl)-2 , 2,2-Trifluoroethyl-1-one (237 mg, 0.29 mmol) and potassium hydroxide (160 mg, 2.9 mmol) were added to methanol (10 mL) and water (4 mL), the temperature was raised to 60 °C and the reaction was stirred for 4 hours . The reaction solution was cooled to room temperature, diluted with dichloromethane (20 mL), and separated. The organic phase was first washed with saturated brine (20 mL), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to obtain (6-((5-bromo-2-((2-methoxy-5-(1 -Methyl-1H-pyrazol-4-yl)-4-(3,9-diazaspiro[5.5]undecan-3-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoline Oxalin-5-yl)dimethylphosphine oxide (174 mg, 83% yield).

MS(ESI)M/Z:731.2[M+H] ⁺ .

Step 6: (6-((5-Bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(3,9- Diazaspiro[5.5]undecan-3-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (54 mg, 0.074 mmol) and (1 -(2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methylmethanesulfonate (50mg , 0.11 mmol) was dissolved in acetonitrile (5 mL), DIEA (29 mg, 0.22 mmol) and a catalytic amount of sodium iodide were added, and the reaction was heated to 85 °C and stirred overnight. LCMS monitoring showed that the raw materials disappeared, the reaction solution was cooled to room temperature, and purified by high performance preparative liquid chromatography to obtain the final product 5-(4-((9-(4-((5-bromo-4-((5-(dimethyl Phosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-3 ,9-diazaspiro[5.5]undecan-3-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline -1,3-Dione (18.2 mg, 23% yield).

MS(ESI)M/Z: 1084.4[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ): δ 13.35(s, 1H), 12.55(brs, 1H), 8.80(d, J=1.2Hz, 1H), 8.76-8.72(m, 2H), 8.05(d , J=2.0Hz, 1H), 8.03(s, 1H), 7.80(s, 1H), 7.69-7.64(m, 2H), 7.58(d, J=9.2Hz, 1H), 7.46(s, 1H) ,6.92(d,J＝0.8Hz,1H),6.74(s,1H),6.67(d,J＝8.0Hz,1H),4.96-4.91(m,1H),3.85(s,6H),3.63- 3.38(m,6H),3.10-3.05(m,2H),2.96-2.75(m,8H),2.39(brs,2H),2.29(brs,2H),2.14(s,3H),2.11(s, 3H),1.98(brs,6H),1.79-1.69(m,5H).

Example 38:

5-(4-((5-(4-((5-Bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5 -Methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)hexahydropyrrole[3,4-c]pyrrol-2(1H)-yl)methyl)piperidine- 1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Reaction process:

Reaction steps:

Step 1: Combine 1-bromo-2-fluoro-4-methoxy-5-nitrobenzene (250 mg, 1.0 mmol) and tert-hexahydropyrrole[3,4-c]pyrrole-2(1H)-carboxylic acid Butyl ester (233 mg, 1.1 mmol) was dissolved in N'N-dimethylformamide (10 mL), potassium carbonate (414 mg, 3.0 mmol) was added, and the temperature was raised to 60°C and stirred overnight. The reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (50 mL×3 times). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by slurrying with ethyl acetate to give tertiary 5-(2-bromo-5-methoxy-4-nitrophenyl)hexahydropyrrole[3,4-c]pyrrole-2(1H)-carboxylic acid Butyl ester (280 mg, 63% yield).

MS(ESI)M/Z: 442.1[M+H] ⁺ .

Step 2: 5-(2-Bromo-5-methoxy-4-nitrophenyl)hexahydropyrrole[3,4-c]pyrrole-2(1H)-carboxylate tert-butyl ester (280mg , 0.63 mmol) and 1-methyl-4-1H-pyrazole boronate pinacol ester (197 mg, 0.95 mmol) were dissolved in dioxane (10 mL) and water (2 mL), potassium phosphate (267 mg, 1.26 mL) was added mmol) and ferrocene palladium dichloride (46 mg, 0.06 mmol). The reaction solution was heated to 110°C under an argon atmosphere and stirred for 12 hours. The reaction solution was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (50 mL×3 times). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified by slurrying with ethyl acetate to give 5-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)hexahydropyrrole[3, 4-c]pyrrole-2(1H)-carboxylate tert-butyl ester (170 mg, 60% yield).

MS(ESI)M/Z: 444.2[M+H] ⁺ .

Step 3: Addition of 5-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)hexahydropyrrole[3,4-c] at room temperature To a solution of tert-butyl pyrrole-2(1H)-carboxylate (170 mg, 0.38 mmol) in dichloromethane (2 mL) was added a solution of hydrochloric acid in dioxane (8 mL, 4 M). After stirring at room temperature for 2 hours, it was concentrated under reduced pressure to obtain 2-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)octahydropyrrole[3, 4-c] Pyrrole hydrochloride (164 mg, crude).

MS(ESI)M/Z: 344.2[M+H] ⁺ .

Step 4: 2-(5-Methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)octahydropyrrole[3,4-c] Pyrrole hydrochloride (20 mg, about 0.046 mmol) and (1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine Perid-4-yl)methylmethanesulfonate (36 mg, 0.08 mmol) was dissolved in acetonitrile (10 mL), DIEA (16 mg, 0.12 mmol) and a catalytic amount of sodium iodide were added, and the reaction system was heated to 85° C. Stir overnight. LCMS monitoring showed that the starting material disappeared, the reaction solution was cooled to room temperature, diluted with water (50 mL) and extracted with ethyl acetate (50 mL×3 times). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified with preparative TLC plates to give 2-(2,6-dioxopiperidin-3-yl)-5-(4-((5-(5-methoxy-2-(1-methyl) yl-1H-pyrazol-4-yl)-4-nitrophenyl)hexahydropyrrole[3,4-c]pyrrol-2(1H)-yl)methyl)piperidin-1-yl)isoindium Doline-1,3-dione (21 mg, 65% yield).

MS(ESI)M/Z: 697.3[M+H] ⁺ .

Step 5: 2-(2,6-dioxopiperidin-3-yl)-5-(4-((5-(5-methoxy-2-(1-methyl-1H- Pyrazol-4-yl)-4-nitrophenyl)hexahydropyrrole[3,4-c]pyrrol-2(1H)-yl)methyl)piperidin-1-yl)isoindoline-1 , 3-dione (21 mg, 0.03 mmol) and 10% palladium on carbon (10 mg) were added to tetrahydrofuran (6 mL), and the reaction was stirred at room temperature for 2 hours after hydrogen replacement for three times. Filtration, the filtrate was concentrated under reduced pressure to obtain 5-(4-((5-(4-amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)hexahydropyrrole [3,4-c]pyrrol-2(1H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1 ,3-dione (18 mg, 90% yield).

MS(ESI)M/Z: 667.3[M+H] ⁺ .

Step 6: 5-(4-((5-(4-Amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)hexahydropyrrole[ 3,4-c]pyrrol-2(1H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1, 3-Dione (18 mg, 0.027 mmol), (6-((5-bromo-2-chloropyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (12 mg, 0.029 mmol) and trifluoroacetic acid (34 mg, 0.3 mmol) were successively added to isopropanol (4 mL), and the temperature was raised to 95° C. under argon protection, and the reaction was stirred for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the obtained residue was purified by high performance preparative liquid chromatography to obtain the final product 5-(4-((5-(4-((5-bromo-4-((5-(di Methylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)hexa Hydropyrrole[3,4-c]pyrrol-2(1H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline -1,3-Dione (6.6 mg, 23% yield).

MS(ESI)M/Z: 1042.3[M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ): δ 13.37 (s, 1H), 13.04 (s, 1H), 8.9 (dd, J=8.8, 1.2 Hz, 2H), 8.13 (s, 1H), 8.05 (s ,1H),7.71-7.66(m,3H),7.39(s,1H),7.34(s,1H),6.95(s,1H),6.70(d,J＝8.4Hz,2H),4.96-4.91( m,1H),4.02(brs,2H),3.85(s,3H),3.82(s,3H),3.67-3.61(m,2H),3.60-3.50(m,2H),3.49-3.38(m, 2H), 3.19(brs, 4H), 3.11(d, J=9.6Hz, 4H), 2.70-2.56(m, 4H), 2.14(s, 3H), 2.11(s, 3H), 2.06-1.96(m ,4H),1.70-1.50(m,1H).

Example 39:

4-((5-(4-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino )-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)piperazin-1-yl)pentyl)amino)-2- (2,6-Dioxopiperidin-3-yl)isoindoline-1,3-dione

Reaction process:

Reaction steps:

Step 1: 4-(Piperidin-4-yl)piperazine-1-carboxylate tert-butyl ester (2.0 g, 7.4 mmol), 1-bromo-2-fluoro-4-methoxy-5- Nitrobenzene (1.9 g, 7.4 mmol) was dissolved in DMF (50 mL) and potassium carbonate (2.1 g, 15.0 mmol) was added. The reaction was heated to 60°C and stirred overnight. LCMS monitoring showed disappearance of starting material. The reaction solution was cooled to room temperature, poured into water (250 mL), and extracted with ethyl acetate (200 mL×2). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to obtain 4-(1-(2 -Bromo-5-methoxy-4-nitrophenyl)piperidin-4-yl)piperazine-1-carboxylate tert-butyl ester (1.9 g, 51% yield).

MS(ESI)M/Z: 499.2[M+H] ⁺ .

Step 2: 4-(1-(2-Bromo-5-methoxy-4-nitrophenyl)piperidin-4-yl)piperazine-1-carboxylate tert-butyl ester (1.9 g, 3.8mmol) and 1-methyl-4-1H-pyrazole boronate pinacol ester (0.95g, 4.6mmol) were dissolved in dioxane (50mL) and water (10mL), potassium phosphate (1.6g, 7.6 mmol) and ferrocene palladium dichloride (0.28 g, 0.38 mmol), the reaction solution was heated to 110 °C under nitrogen atmosphere and stirred overnight. The end of the reaction was monitored by LCMS, the reaction solution was cooled to room temperature, diluted with water (300 mL) and extracted with ethyl acetate (200 mL×3 times). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 2/1) to obtain 4-(1-(5-methoxy-2-(1-methyl-1H-pyrazole) -4-yl)-4-nitrophenyl)piperidin-4-yl)piperazine-1-carboxylate tert-butyl ester (1.3 g, 68% yield).

MS(ESI)M/Z:501.3[M+H] ⁺ .

Subsequent steps were followed by 4-(1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)piperazine- 1-Carboxylic acid tert-butyl ester is a raw material, with reference to the preparation method of Example 37 to obtain the final product 4-((5-(4-(1-(4-((5-bromo-4-((5-(dimethyl Phosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidine -4-yl)piperazin-1-yl)pentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (8.0 mg) .

MS(ESI)M/Z: 1087.2[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ): δ 13.32(s,1H), 10.74(brs,1H), 9.41(s,1H), 8.84(s,1H), 8.76(s,1H), 8.70-8.64 (m, 1H), 8.04(s, 1H), 7.79(s, 1H), 7.66(s, 1H), 7.58-7.48(m, 4H), 7.15(d, J=7.2Hz, 1H), 6.92( d, J＝8.4Hz, 1H), 6.68(s, 1H), 4.99-4.93(m, 1H), 3.91(s, 3H), 3.86(s, 3H), 3.83-3.79(m, 2H), 3.37 -3.06(m, 9H), 2.96-2.86(m, 2H), 2.82-2.64(m, 8H), 2.15(s, 3H), 2.11(s, 3H), 1.91-1.88(m, 4H), 1.78 -1.56(m,6H).

Example 40:

4-((5-(4-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino )-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)piperidin-1-yl)pentyl)oxo)-2 -(2,6-Dioxopiperidin-3-yl)isoindoline-1,3-dione

Reaction process:

Reaction steps:

Step 1: 2-(2,6-dioxopiperidin-3-yl)-4-((5-hydroxypentyl)oxo)isoindoline-1,3-dione (16mg , 0.044 mmol, see CN112552293A for preparation) was dissolved in dichloromethane (10 mL), and DIEA (17 mg, 0.13 mmol) was added. The temperature was lowered to 0°C, methanesulfonyl chloride (6 mg, 0.05 mmol) was slowly added dropwise, and the mixture was stirred at 0°C for 19 hours. TLC monitoring showed that the reaction was complete. The reaction solution was diluted with dichloromethane (10 mL), washed with saturated aqueous sodium bicarbonate solution (10 mL×2 times), the organic phase was dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified with a preparative TLC plate (dichloromethane:methanol=30:1) to give 5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline) Indolin-4-yl)oxo)pentyl mesylate (10 mg, 52% yield).

MS(ESI) M/Z: 439.1[M+H] ⁺ .

Step 2: (6-((5-Bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(piperidine) Peridin-4-yl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide hydrochloride (17 mg, about 0.02 mmol) and 5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxo)pentylmethanesulfonate (10 mg, 0.023 mmol) was dissolved in acetonitrile (5 mL), potassium carbonate (10 mg, 0.072 mmol) and a catalytic amount of sodium iodide were added and the reaction was heated to 90°C and stirred for 16 hours. LCMS monitoring showed the disappearance of the raw materials, the reaction solution was cooled to room temperature, and purified by high performance preparative liquid chromatography to obtain the final product 4-((5-(4-(4-(4-((5-bromo-4-(((5- (Dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl )piperazin-1-yl)piperidin-1-yl)pentyl)oxo)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (5.1 mg, 21% yield).

MS(ESI)M/Z: 1088.1[M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.85-8.76 (m, 4H), 8.22 (s, 1H), 7.86-7.83 (m, 1H), 7.76-7.72 (m, 1H), 7.67-7.62 ( m, 2H), 7.51(d, J=8.0Hz, 1H), 7.29-7.25(m, 1H), 6.75(s, 1H), 5.03-4.99(m, 1H), 4.25-4.22(m, 2H) ,3.90(s,3H),3.80-3.64(m,6H),3.55-3.47(m,2H),3.44-3.39(m,2H),3.33-3.22(s,8H),3.17-2.99(m, 4H), 2.86-2.70(m, 4H), 2.14(s, 3H), 2.11(s, 3H), 2.02-1.94(m, 4H), 1.77-1.70(m, 2H).

Example 41:

3-(4-(6-(4-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl )amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)piperidin-1-yl)hex-1-yn- 1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

Reaction process:

Reaction steps:

With 3-(4-(6-hydroxyhexyl-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (see WO202191575A1 for preparation) and ( 6-((5-Bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(piperidin-4-yl)piperidine Using oxazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide hydrochloride as raw material, 30.4mg of final product was prepared by referring to the procedure of Example 40 3-(4-(6-(4-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl )amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)piperidin-1-yl)hex-1-yn- 1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione.

MS(ESI)M/Z: 1068.1[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ): δ 13.29(s, 1H), 10.57(brs, 1H), 10.24(s, 1H), 8.83(s, 1H), 8.76(s, 1H), 8.62(d , J＝7.2Hz, 1H), 8.04(s, 1H), 7.89(brs, 1H), 7.82(d, J＝7.6Hz, 1H), 7.58(d, J＝7.6Hz, 2H), 7.48-7.44 (m,3H),6.66(s,1H),5.28-5.23(m,1H),4.58-4.42(m,2H),3.80(brs,6H),3.65-3.45(m,3H),3.30-3.25 (m,8H),3.10-3.02(m,4H),2.91-2.84(m,4H),2.60-2.54(m,6H),2.14(s,3H),2.10(s,3H),2.10-2.03 (m,2H),1.71-1.65(m,2H).

Example 42:

3-(4-(6-(4-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl )amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)piperazin-1-yl)hexyl)-1-oxo substituted isoindolin-2-yl)piperidine-2,6-dione

Reaction process:

Reaction steps:

3-(4-(6-hydroxyhexyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (see WO202191575A1 for preparation) and (6-((5-bromo- 2-((2-Methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl ) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethylphosphine oxide as raw material, and referring to the procedure of Example 40, 3.3 mg of the final product 3-(4-(6-(4- (1-(4-((5-Bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2 -(1-Methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)piperazin-1-yl)hexyl)-1-oxoisoindolin-2-yl)piperidine pyridine-2,6-dione.

MS(ESI)M/Z: 1072.2[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ): δ 13.26(s, 1H), 10.80(brs, 1H), 9.13(brs, 1H), 8.84(s, 1H), 8.76(d, J=0.8Hz, 1H ), 8.69-8.65(m, 1H), 8.05(s, 1H), 7.81(s, 1H), 7.77(d, J=7.2Hz, 1H), 7.69(s, 1H), 7.52(d, J= 9.2Hz, 2H), 7.46(d, J=7.6Hz, 1H), 7.39(d, J=7.2Hz, 1H), 6.68(s, 1H), 5.29-5.24(m, 1H), 4.48-4.31( m, 2H), 3.92(s, 3H), 3.86(s, 3H), 3.34-3.21(m, 4H), 3.03-2.89(m, 6H), 2.7-2.69(m, 7H), 2.28-2.22( m, 2H), 2.17(s, 3H), 2.13(s, 3H), 2.09-2.04(m, 2H), 1.78-1.62(m, 6H), 1.44-1.28(m, 6H).

Example 43:

4-((8-(2-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5 -Methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-2,6-dihydropyrrolo[3,4-c]lopyrazol-5(4H)-yl )octyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Reaction process:

Reaction steps:

Step 1: 1-Bromo-2-fluoro-4-methoxy-5-nitrobenzene (1.5 g, 6.0 mmol), 2,6-dihydropyrrolo[3,4-c]pyrazole at room temperature tert-Butyl-5(4H)-carboxylate (1.3 g, 6.0 mmol) was dissolved in DMF (50 mL) and potassium carbonate (1.7 g, 12.0 mmol) was added. The reaction system was heated to 85°C and stirred for 18 hours. LCMS monitoring showed disappearance of starting material. The reaction solution was cooled to room temperature, poured into water (100 mL), and extracted with ethyl acetate (100 mL×2). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to obtain 2-(2-bromo- 5-Methoxy-4-nitrophenyl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate tert-butyl ester (1.6 g, 61% yield ).

MS(ESI) M/Z: 439.1[M+H] ⁺ .

Step 2: 2-(2-Bromo-5-methoxy-4-nitrophenyl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)- tert-Butyl carboxylate (1.6 g, 3.6 mmol) and 1-methyl-4-1H-pyrazole boronic acid pinacol ester (0.76 g, 3.7 mmol) were dissolved in 1,4-dioxane (100 mL) and In water (20 mL), cesium carbonate (3.6 g, 10.9 mmol) and ferrocene palladium dichloride (0.27 g, 0.36 mmol) were added, and the reaction solution was heated to 110° C. under nitrogen atmosphere and stirred for 18 hours. The reaction was monitored by LCMS, the reaction solution was cooled to room temperature, most of 1,4-dioxane was removed by rotary evaporation, diluted with water (100 mL), and extracted with ethyl acetate (100 mL×3 times). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=2/1) to obtain 2-(5-methoxy-2-(1-methyl-1H-pyrazole-4-) (1.4 g, 84% yield).

MS(ESI)M/Z:441.2[M+H] ⁺ .

Step 3: Addition of 2-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)-2,6-dihydropyrrolo[ To a solution of tert-butyl 3,4-c]pyrazole-5(4H)-carboxylate (1.4 g, 3.1 mmol) in dichloromethane (100 mL) was added trifluoroacetic acid (25 mL) dropwise. After stirring at room temperature for 2 hours, it was concentrated under reduced pressure to obtain 2-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)-2,4,5 ,6-Tetrahydropyrrolo[3,4-c]pyrazole trifluoroacetate (1.1 g, crude).

MS(ESI)M/Z: 341.2[M+H] ⁺ .

Step 4: 2-(5-Methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)-2,4,5,6-tetra Hydropyrrolo[3,4-c]pyrazole trifluoroacetate (1.1 g, crude) and DMAP (789 mg, 6.5 mmol) were added to dichloromethane (50 mL) and stirred for 5 min, followed by trifluoroethyl Acid anhydride (1.4 g, 6.5 mmol) was stirred at room temperature for 2 hours. It was quenched by adding water (100 mL) and extracted with dichloromethane (100 mL×3 times). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=2/1) to obtain 2,2,2-trifluoro-1-(2-(5-methoxy-2-( 1-Methyl-1H-pyrazol-4-yl)-4-nitrophenyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)ethane -1-one (1.1 g, 2-step yield 79%).

MS(ESI) M/Z: 437.3[M+H] ⁺ .

Step 5: 2,2,2-Trifluoro-1-(2-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrobenzene yl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)ethan-1-one (1.1 g, 2.5 mmol) and 10% wet palladium on carbon (110 mg) It was added to a mixed solution of dichloromethane (25 mL) and methanol (25 mL), replaced by a hydrogen balloon three times, and stirred at room temperature for 2 hours. LCMS detected that the reaction was complete, filtered, and the filtrate was concentrated under reduced pressure to obtain 1-(2-(4-amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-2 ,6-Dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-2,2,2-trifluoroethane-1-one (960 mg, 94% yield).

MS(ESI)M/Z: 407.2[M+H] ⁺ .

Step 6: 1-(2-(4-Amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-2,6-dihydropyrrole at room temperature [3,4-c]pyrazol-5(4H)-yl)-2,2,2-trifluoroethane-1-one (960 mg, 2.4 mmol), (6-((5-bromo-2 -Chloropyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (975 mg, 2.4 mmol) and trifluoroacetic acid (2.7 g, 23.6 mmol) were added sequentially to n-butanol (25 mL) , the temperature was raised to 110 °C under argon protection and the reaction was stirred for 16 hours. LCMS detected that the reaction was complete, the reaction solution was cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (100 mL×3 times). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=2/1) to give 1-(2-(4-((5-bromo-4-((5-(dimethyl) Phosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-2 ,6-Dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-2,2,2-trifluoroethane-1-one (540 mg, 29% yield).

MS(ESI)M/Z:782.1[M+H] ⁺ .

Step 7: 1-(2-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino )-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H )-yl)-2,2,2-trifluoroethane-1-one (540 mg, 0.69 mmol) and potassium hydroxide (77 mg, 1.4 mmol) were added to methanol (10 mL) and water (5 mL), and the temperature was raised to The reaction was stirred at 60°C for 2 hours. The reaction solution was cooled to room temperature, most methanol was removed by rotary evaporation, and extracted with ethyl acetate (50 mL×3 times). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to obtain (6-((5-bromo-2-((4-(5,6-dihydropyrrolo[3,4-c]pyridine) oxazol-2(4H)-yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxaline- 5-yl)dimethylphosphine oxide (480 mg, crude).

MS(ESI)M/Z: 686.2[M+H] ⁺ .

Step 8: (6-((5-Bromo-2-((4-(5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)-2- Methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (140 mg, about 0.20 mmol) and 8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octylmethanesulfonate (98 mg, 0.20 mmol, see patent WO201889736A1 for preparation) was dissolved in acetonitrile (25 mL), DIEA (77 mg, 0.60 mmol) and a catalytic amount of sodium iodide were added, the reaction system was heated to 80° C. and stirred for 16 hours. LCMS monitoring showed that the raw materials disappeared, the reaction solution was cooled to room temperature, and purified by high performance preparative liquid chromatography to obtain the final product 4-((8-(2-(4-((5-bromo-4-((5-(dimethyl Phosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-2 ,6-Dihydropyrro[3,4-c]lopyrazol-5(4H)-yl)octyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindole olin-1,3-dione (34 mg, 16% yield).

MS(ESI)M/Z: 1069.5[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ): δ 13.02 (s, 1H), 9.44 (s, 1H), 8.78-8.73 (m, 3H), 8.59 (s, 1H), 8.21 (s, 1H), 8.17 (s, 1H), 7.62(d, J=9.2Hz, 1H), 7.53-7.49(m, 1H), 7.19(s, 1H), 7.10(d, J=7.2Hz, 1H), 7.01(s, 1H), 6.91-6.86(m, 2H), 6.68(s, 1H), 6.25(brs, 1H), 5.00-4.89(m, 3H), 4.20-4.06(m, 2H), 3.92(s, 3H) ,3.72(s,3H),3.37-3.27(m,4H),3.11-2.99(m,8H),2.90-2.73(m,4H),2.16(s,3H),2.12(s,3H),1.89 -1.85(m,2H),1.70-1.65(m,2H).

Example 44:

4-((5-(4-(4-(4-((5-Chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-5-methyl Oxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)piperidin-1-yl)pentyl)amino)-2-(2,6- Dioxopiperidin-3-yl)isoindoline-1,3-dione

Reaction process:

Reaction steps:

Step 1: 1-(4-(4-Amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)- 2,2,2-Trifluoroethane-1-one (0.5 g, 1.3 mmol), (2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide ( 375 mg, 1.2 mmol) and trifluoroacetic acid (1.35 g, 11.8 mmol) were successively added to isopropanol (20 mL), and the temperature was raised to 100 °C under argon protection, and the reaction was stirred for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the obtained residue was purified by beating with ethyl acetate to obtain 1-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl) )amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)-2,2, 2-Trifluoroethyl-1-one (480 mg, 60% yield).

MS(ESI)M/Z: 663.5[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ): δ 11.03(s,1H), 8.56-8.52(m,1H), 8.22(s,1H), 8.10(s,1H), 7.84(s,1H), 7.51 (s,1H),7.00-6.99(m,2H),6.64(s,1H),3.90(s,3H),3.86(s,3H),3.79(brs,2H),3.71-3.67(m,2H) ),2.99-2.94(m,4H),1.86(s,3H),1.83(s,3H).

Step 2: 1-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-5-methyl at room temperature Oxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)-2,2,2-trifluoroethyl-1-one (430 mg, 0.65 mmol ) and potassium hydroxide (363 mg, 6.5 mmol) were added to methanol (10 mL) and water (4 mL), the temperature was raised to 60° C. and the reaction was stirred for 4 hours. The reaction solution was cooled to room temperature, diluted with dichloromethane (20 mL), and separated. The organic phase was first washed with saturated brine (20 mL), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to obtain (2-((5-chloro-2-((2-methoxy-5-(1 -Methyl-1H-pyrazol-4-yl)-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (304 mg, yield 69%).

MS(ESI) M/Z: 567.3[M+H] ⁺ .

The next step is (2-((5-chloro-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperazin-1-yl) Phenyl) amino) pyrimidin-4-yl) amino) phenyl) dimethyl phosphine oxide as raw material, referring to the preparation method of Example 32 to obtain the final product 4-((5-(4-(4-(4-( (5-Chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazole- 4-yl)phenyl)piperazin-1-yl)piperidin-1-yl)pentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1 , 3-diketone (20.2 mg).

MS(ESI)M/Z: 989.4[MH] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ): δ 12.01 (s, 1H), 10.59 (brs, 1H), 10.15 (s, 1H), 8.35-8.31 (m, 1H), 7.87 (d, J=5.6Hz) ,2H),7.58-7.50(m,2H),7.42(s,1H),7.17-7.12(m,2H),6.99-6.92(m,2H),6.68(s,1H),6.25(brs,1H) ), 4.94-4.89(m, 1H), 3.89(s, 3H), 3.81(s, 3H), 3.57(d, J=10.4Hz, 2H), 3.39-3.36(m, 2H), 3.28(brs, 5H), 2.97-2.86(m, 4H), 2.80-2.74(m, 4H), 2.58-2.53(m, 4H), 2.36-2.27(m, 6H), 1.86(s, 3H), 1.83(s, 3H), 1.78-1.73(m, 2H), 1.63-1.59(m, 2H).

Example 45:

4-((5-(4-(4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-methylpyrimidin-2-yl)amino)-5-methoxy -2-(1-Methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)pentyl)amino)-2-(2,6-dioxopiperidin-3-yl ) isoindoline-1,3-dione

Reaction process:

Reaction steps:

Step 1: 1-(4-(4-Amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)- 2,2,2-Trifluoroethane-1-one (714 mg, 1.9 mmol), (2-((2-chloro-5-methylpyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (500 mg, 1.7 mmol) and trifluoroacetic acid (1.94 g, 17.0 mmol) were successively added to isopropanol (50 mL), and the temperature was raised to 95° C. under argon to stir the reaction for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the resulting residue was purified by preparative TLC plate to give 1-(4-(4-((4-((2-(dimethylphosphoryl)phenyl)amino)- 5-Methylpyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)-2,2 , 2-Trifluoroethyl-1-one (690 mg, 63% yield).

MS(ESI)M/Z: 643.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ 11.83(s,1H), 9.51(s,1H), 8.46(s,1H), 8.18(s,1H), 7.86(s,2H), 7.63 -7.57(m,2H),7.20-7.03(m,2H),6.92(s,1H),3.86(s,3H),3.82(s,3H),3.79(brs,4H),3.01-2.94(m ,4H),2.13(s,3H),1.83(s,3H),1.80(s,3H).

Step 2: 1-(4-(4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-methylpyrimidin-2-yl)amino)-5- Methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)-2,2,2-trifluoroethyl-1-one (500 mg, 0.78 mmol) and potassium hydroxide (437 mg, 7.8 mmol) were added to methanol (50 mL) and water (20 mL), the temperature was raised to 60° C. and the reaction was stirred for 4 hours. The reaction solution was cooled to room temperature, diluted with dichloromethane (50 mL), and separated. The organic phase was first washed with saturated brine (20 mL), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to obtain (2-((2-((2-methoxy-5-(1-methyl- 1H-pyrazol-4-yl)-4-(piperazin-1-yl)phenyl)amino)-5-methylpyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (315 mg, received rate 74%).

MS(ESI) M/Z: 547.3[M+H] ⁺ .

Step 3: (2-((2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperazin-1-yl)benzene yl)amino)-5-methylpyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (50 mg, 0.092 mmol) and 5-((2-(2,6-dioxopiperidine-3 -yl)-1,3-dioxoisoindolin-4-yl)amino)pentylmethanesulfonate (60 mg, 0.14 mmol) was dissolved in acetonitrile (5 mL), DIEA (35 mg, 0.27 mmol) and DIEA (35 mg, 0.27 mmol) were added. A catalytic amount of sodium iodide, the reaction was heated to 110°C and stirred overnight. LCMS monitoring showed that the raw materials disappeared, the reaction solution was cooled to room temperature, and purified by high performance preparative liquid chromatography to obtain the final product 4-((5-(4-(4-((4-((2-(dimethylphosphoryl)benzene) (yl)amino)-5-methylpyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl )pentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (10 mg, 12% yield).

MS(ESI)M/Z:888.4[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ 11.09 (s, 1H), 10.84 (s, 1H), 8.60-8.56 (m, 1H), 7.90 (d, J=12.0Hz, 2H), 7.83 (d, J＝4.8Hz, 2H), 7.65(s, 1H), 7.61-7.57(m, 1H), 7.52-7.45(m, 1H), 7.11(d, J＝8.4Hz, 1H), 7.03( d, J＝7.2Hz, 1H), 6.95-6.94(m, 2H), 6.79(s, 1H), 6.56-6.52(m, 1H), 5.07-5.02(m, 1H), 3.82(s, 3H) ,3.81(s,3H),2.92-2.83(m,6H),2.67-2.56(m,4H),2.42-2.33(m,2H),2.06(s,3H),2.02-1.98(m,2H) ,1.79(s,3H),1.76(s,3H),1.64-1.58(m,2H),1.55-1.51(m,2H),1.42-1.37(m,2H),1.28-1.24(m,2H) .

Example 46:

4-((5-(4-(4-(4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-methylpyrimidin-2-yl)amino)-5- Methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)piperidin-1-yl)pentyl)amino)-2-(2,6 -Dioxopiperidin-3-yl)isoindoline-1,3-dione

Reaction process:

Reaction steps:

with (2-((2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperazin-1-yl)phenyl)amino)- 5-methylpyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide was used as raw material, and the final product 4-(((5-(4-(4-(4-((( 4-((2-(Dimethylphosphoryl)phenyl)amino)-5-methylpyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazole- 4-yl)phenyl)piperazin-1-yl)piperidin-1-yl)pentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1 , 3-dione (9.3 mg).

MS(ESI) M/Z: 971.4[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ11.11(brs,1H), 10.83(s,1H), 8.60-8.57(m,1H), 7.92(s,1H), 7.89(s,1H) ,7.84(d,J＝2.4Hz,2H),7.65(s,1H),7.61-7.58(m,1H),7.53-7.46(m,1H),7.11(d,J＝8.4Hz,1H), 7.03(d, J＝6.8Hz, 1H), 6.97-6.95(m, 2H), 6.82(s, 1H), 6.56-6.53(m, 1H), 5.08-5.04(m, 1H), 3.83(s, 3H), 3.81(s, 3H), 2.94-2.85(m, 8H), 2.62-2.55(m, 6H), 2.27-2.24(m, 2H), 2.20-2.15(m, 1H), 2.07(s, 3H), 2.04-1.98(m, 2H), 1.90-1.83(m, 2H), 1.80(s, 3H), 1.77(s, 3H), 1.64-1.58(m, 2H), 1.49-1.33(m, 6H), 1.24(d, J=1.2Hz, 2H).

Example 47:

4-((5-(4-(4-(4-((5-Chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-( 1-Methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)piperidin-1-yl)pentyl)amino)-2-(2,6-dioxopiperidine- 3-yl)isoindoline-1,3-dione

Reaction process:

Reaction steps:

Step 1: 2-Bromo-1-fluoro-4-nitrobenzene (5.0 g, 22.8 mmol), tert-butyl piperazine-1-carboxylate (4.3 g, 23.0 mmol) were dissolved in DMF (50 mL) at room temperature To this, potassium carbonate (9.5 g, 68.8 mmol) was added. The reaction was heated to 60°C and stirred overnight. LCMS monitoring showed disappearance of starting material. The reaction solution was cooled to room temperature, poured into water (300 mL), and extracted with ethyl acetate (300 mL×2). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10/1) to obtain 4-(2-bromo- 4-Nitrophenyl)piperazine-1-carboxylate tert-butyl ester (6.1 g, 69% yield).

MS(ESI) M/Z: 386.1[M+H] ⁺ .

Step 2: Combine tert-butyl 4-(2-bromo-4-nitrophenyl)piperazine-1-carboxylate (6.0 g, 15.6 mmol) and 1-methyl-4-1H-pyrazoleboronic acid at room temperature Pinacol ester (3.23g, 15.6mmol) was dissolved in DMF (50mL), sodium carbonate (4.9g, 46.6mmol) and ferrocene palladium dichloride (0.6g, 0.8mmol) were added, and the reaction solution was heated under argon. The mixture was heated to 110°C under atmosphere and stirred for 12 hours. The reaction was monitored by LCMS, the reaction solution was cooled to room temperature, diluted with water (500 mL), and extracted with ethyl acetate (250 mL×3 times). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=40/1) to give 4-(2-(1-methyl-1H-pyrazol-4-yl)-4-nitro (5.3 g, 88% yield).

MS(ESI) M/Z: 388.2[M+H] ⁺ .

Step 3: To tert-butyl 4-(2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperazine-1-carboxylate (5.3 g, 13.7 mmol at room temperature) ) solution in dichloromethane (30 mL) was added 5M hydrochloric acid/dioxane (30 mL, 150 mmol) and stirred at room temperature for 2 hours. LCMS monitored the disappearance of the starting material, and concentrated directly to obtain 1-(2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperazine hydrochloride (2.8 g, crude product).

MS(ESI)M/Z: 288.2[M+H] ⁺ .

Step 4: Combine 1-(2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperazine hydrochloride (2.1 g, crude) and DMAP (1.8 g) at room temperature , 14.6 mmol) was added to DMF (50 mL), stirred for 5 minutes, then added trifluoroacetic anhydride (3.1 g, 14.6 mmol), and stirred at room temperature overnight. The reaction solution was poured into ice water (300 mL), and extracted with ethyl acetate (200 mL×3 times). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to obtain 2,2,2-trifluoro-1-(4-(2-(1-methyl-1H-pyrazol-4-yl)) -4-Nitrophenyl)piperazin-1-yl)ethan-1-one (2.2 g, crude).

MS(ESI) M/Z: 384.3[M+H] ⁺ .

Step 5: 2,2,2-Trifluoro-1-(4-(2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperazine-1 -yl)ethan-1-one (2.2 g, crude product) and 10% wet palladium on carbon (200 mg) were added to methanol (30 mL), replaced by hydrogen balloon three times, and stirred at room temperature overnight. LCMS detected that the reaction was complete, filtered, and the filtrate was concentrated under reduced pressure to obtain 1-(4-(4-amino-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)- 2,2,2-Trifluoroethane-1-one (1.55 g, crude).

MS(ESI) M/Z: 354.2[M+H] ⁺ .

Step 6: 1-(4-(4-Amino-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)-2,2,2- Trifluoroethane-1-one (0.35 g, crude), (2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (0.32 g, 1.0 mmol) and Trifluoroacetic acid (0.35 g, 3.0 mmol) was successively added to isopropanol (10 mL), the temperature was raised to 110° C. under argon protection, and the reaction was stirred for 16 hours. LCMS detected that the reaction was complete, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=30/1) to give 1-(4-(4-((5-chloro-4-((2-(dimethylphosphorus) Acyl)phenyl)amino)pyrimidin-2-yl)amino)-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)-2,2,2- Trifluoroethane-1-one (420 mg, 29% yield over four steps).

MS(ESI)M/Z: 633.1[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ 11.19(s,1H), 9.28(s,1H), 8.58(s,1H), 8.18(s,2H), 7.84(s,1H), 7.66 (d, J=2.4Hz, 1H), 7.59-7.57(m, 1H), 7.46(d, J=8.6Hz, 1H), 7.25(s, 1H), 7.09-7.05(m, 2H), 3.88( s,3H),3.74-3.70(m,4H),2.87-2.83(m,4H),1.80(s,3H),1.77(s,3H).

Step 7: 1-(4-(4-((5-Chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-( 1-Methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)-2,2,2-trifluoroethane-1-one (1.3 g, 2.1 mmol) and potassium hydroxide (1.2 g, 21.0 mmol) was added to methanol (15 mL) and water (6 mL), the temperature was raised to 60°C and the reaction was stirred for 4 hours. The reaction solution was cooled to room temperature, diluted with dichloromethane (30 mL), and washed with saturated brine (20 mL×3 times). The organic phase was dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to obtain (2-((5-chloro-2-((3-(1-methyl-1H-pyrazol-4-yl)-4-( Piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (1.0 g, 91% yield).

MS(ESI) M/Z: 537.2[M+H] ⁺ .

Subsequent steps were followed by (2-((5-chloro-2-((3-(1-methyl-1H-pyrazol-4-yl)-4-(piperazin-1-yl)phenyl)amino)pyrimidine -4-yl)amino)phenyl)dimethylphosphine oxide as the raw material, referring to the preparation method of Example 32 to obtain the final product 4-((5-(4-(4-(4-((5-chloro-4 -((2-(Dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazine-1- yl)piperidin-1-yl)pentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (16.9 mg).

MS(ESI)M/Z: 961.4[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ): δ 12.15(s,1H), 11.58(brs,1H), 10.10(s,1H), 8.48-8.45(m,1H), 7.93(s,1H), 7.84 (s,1H),7.57-7.50(m,3H),7.39(d,J=2.0Hz,1H),7.35-7.29(m,2H),7.20-7.14(m,2H),7.03(d,J =8.8Hz,1H),6.93(d,J=8.4Hz,1H),6.24(brs,1H),4.94-4.89(m,1H),3.93(s,3H),3.62-3.45(m,2H) ,3.38(brs,4H),3.24(brs,5H),2.98-2.87(m,4H),2.81-2.73(m,4H),2.71-2.62(m,2H),2.58-2.44(m,4H) ,2.35-2.24(m,2H),1.89(s,3H),1.85(s,3H),1.78-1.59(m,4H).

Example 48:

5-(3-(4-(2-(4-(4-((5-chloro-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl )amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)ethyl)piperidin-1-yl)azacycle Butan-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Reaction process:

Reaction steps:

Step 1: 4-(4-Amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazine-1-carboxylate tert-butyl ester ( 1.7 g, 4.5 mmol), (6-((2,5-dichloropyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (1.5 g, 4.1 mmol) and trifluoroacetic acid (4.68 g, 41.0 mmol) were successively added to n-butanol (30 mL), and the temperature was raised to 98° C. under argon and stirred overnight. The reaction solution was cooled to room temperature, concentrated under reduced pressure, tetrahydrofuran (30 mL) was added, then triethylamine (1.24 g, 12.3 mmol) was added to the solution, stirred for 10 minutes, and di-tert-butyl dicarbonate (900 mg, 4.1 mmol) was added. , and stirred at room temperature for 2 hours. Water (30 mL) was added to the reaction solution for quenching, and ethyl acetate (40 mL×2) was used for extraction. The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=30/1) to obtain 4-(4-((5-chloro-4-((5-(dimethylphosphoryl)quinoxa) Lin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazine-1-carboxylic acid tert-Butyl ester (2.0 g, 75% yield).

MS(ESI)M/Z:719.4[M+H] ⁺ .

Step 2: 4-(4-((5-Chloro-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methyl Oxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazine-1-carboxylate tert-butyl ester (2.0 g, 2.8 mmol) was dissolved in ethyl acetate (25 mL), 5M hydrochloric acid/dioxane (18.5 mL, 92.5 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. TLC monitoring the disappearance of raw materials, direct concentration to obtain (6-((5-chloro-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperazine) -1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide hydrochloride (2.0 g, crude).

MS(ESI)M/Z:619.0[M+H] ⁺ .

Step 3: (6-((5-Chloro-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperazin-1-yl) )phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide hydrochloride (500 mg, about 0.70 mmol) was dissolved in 1,2 dichloroethane (20 mL) and Triethylamine (232 mg, 2.3 mmol) was added to N,N-dimethylformamide (4 mL), stirred for 5 minutes, and then 4-(2-oxoethyl)piperidine-1-carboxylate tert-butyl ester was added (347 mg, 1.5 mmol), stirred for 15 minutes, added acetic acid (0.75 mL), and finally added sodium triacetoxyborohydride (486 mg, 2.3 mmol), and stirred at room temperature for 2 hours. TLC monitored the disappearance of the raw materials, the reaction solution was quenched by adding saturated sodium bicarbonate (20 mL), and extracted with ethyl acetate (30 mL×2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/1) to obtain 4-(2-(4-(4-((5-chloro-4-((5-(dimethylene) (ylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidine Azin-1-yl)ethyl)piperidine-1-carboxylate tert-butyl ester (380 mg, 65% yield).

MS(ESI)M/Z:830.3[M+H] ⁺ .

Step 4: Convert 4-(2-(4-(4-((5-chloro-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl) Amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)ethyl)piperidine-1-carboxylate tert-butyl ester ( 380 mg, 0.46 mmol) was dissolved in ethyl acetate (6 mL), 5M hydrochloric acid/dioxane solution (3.5 mL) was added, and the mixture was stirred at room temperature for 30 minutes. TLC monitored the disappearance of the raw materials, and concentrated directly under reduced pressure to obtain (6-((5-chloro-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-( 4-(2-(Piperidin-4-yl)ethyl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide salt acid salt (350 mg, crude).

MS(ESI) M/Z: 730.4[M+H] ⁺ .

Subsequent steps were followed by (6-((5-chloro-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(2-(piperidine) Perid-4-yl)ethyl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethyl phosphine oxide hydrochloride as raw material, refer to the implementation The preparation method of Example 35 gave the final product 5-(3-(4-(2-(4-(4-((5-chloro-4-((5-(dimethylphosphoryl)quinoxalin-6-yl) )amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)ethyl)piperidine -1-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (25.1 mg).

MS(ESI)M/Z: 1041.0[M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ): δ 12.78 (s, 1H), 9.14 (dd, J=9.6, 4.0 Hz, 1H), 8.73 (dd, J=14.8, 1.8 Hz, 2H), 8.23-8.19 (m,3H),7.83(s,1H),7.73-7.60(m,2H),7.55-7.33(m,2H),6.79(d,J＝2.0Hz,1H),6.73(s,1H), 6.53(dd,J=8.4,2.0Hz,1H),4.95-4.90(m,1H),4.11(t,J=7.2Hz,2H),3.91(s,3H),3.91-3.83(m,2H) ,3.71(s,3H),3.35(brs,2H),3.30-2.67(m,15H),2.15(s,3H),2.11(s,3H),1.95-1.91(m,2H),1.85-1.29 (m,7H).

Example 49:

5-(3-(4-((4-(4-((5-chloro-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino )-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)azetidine- 1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Reaction process:

Reaction steps:

Step 1: (6-((5-Chloro-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperazin-1-yl) )phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide hydrochloride (500 mg, about 0.70 mmol) was dissolved in 1,2 dichloroethane (20 mL) and Triethylamine (232 mg, 2.3 mmol) was added to N,N-dimethylformamide (4 mL), stirred for 5 minutes, and then tert-butyl 4-formylpiperidine-1-carboxylate (325 mg, 1.5 mmol) was added ), stirred for 15 minutes, added acetic acid (0.75 mL), and finally added sodium triacetoxyborohydride (486 mg, 2.3 mmol), and stirred at room temperature for 2 hours. TLC monitored the disappearance of the raw materials, the reaction solution was quenched by adding saturated sodium bicarbonate (20 mL), and extracted with ethyl acetate (30 mL×2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/1) to obtain 4-((4-(4-((5-chloro-4-((5-(dimethylphosphorus) Acyl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazine- 1-yl)methyl)piperidine-1-carboxylate tert-butyl ester (420 mg, 74% yield).

MS(ESI)M/Z:816.4[M+H] ⁺ .

Step 2: 4-((4-(4-((5-chloro-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino) -5-Methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)methyl)piperidine-1-carboxylate tert-butyl ester (420 mg, 0.52 mmol) was dissolved in ethyl acetate (7 mL), 5M hydrochloric acid/dioxane solution (3.9 mL) was added, and the mixture was stirred at room temperature for 30 minutes. TLC monitored the disappearance of the raw materials, and concentrated directly under reduced pressure to obtain (6-((5-chloro-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-( 4-(Piperidin-4-ylmethyl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide hydrochloride (400mg ,Crude).

MS(ESI)M/Z:716.5[M+H] ⁺ .

The next step was (6-((5-chloro-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(piperidine-4 -ylmethyl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethyl phosphine oxide hydrochloride as raw material, with reference to the preparation of Example 35 The method gives the final product 5-(3-(4-((4-(4-((5-chloro-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidine-2 -yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)nitrogen Hetidine-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (5.8 mg).

MS(ESI)M/Z: 1027.3[M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ): δ 12.78 (s, 1H), 9.15 (dd, J=9.2, 3.6 Hz, 1H), 8.73 (d, J=14.0 Hz, 2H), 8.26-8.07 (m ,3H),7.80-7.65(m,3H),7.38(brs,2H),6.79(s,1H),6.74(s,1H),6.53(d,J＝7.6Hz,1H),4.95-4.91( m, 1H), 4.11(t, J＝6.8Hz, 2H), 3.92(s, 3H), 3.72(s, 3H), 3.70-3.49(m, 4H), 3.36(brs, 1H), 3.22-2.66 (m, 14H), 2.15(s, 3H), 2.11(s, 3H), 2.00-1.25(m, 7H).

Example 50:

4-((5-(4-(4-((5-Chloro-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5 -Methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)pentyl)amino)-2-(2,6-dioxopiperidine- 3-yl)isoindoline-1,3-dione

Reaction process:

Reaction steps:

Step 1: 1-Bromo-2-fluoro-4-methyl-5-nitrobenzene (2.0 g, 8.6 mmol) and tert-butyl piperazine-1-carboxylate (1.9 g, 10.2 mmol) were dissolved in N To 'N-dimethylformamide (12 mL), potassium carbonate (2.4 g, 17.1 mmol) was added, and the temperature was raised to 60°C and stirred overnight. The reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (50 mL×3 times). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=8/1) to obtain 4-(2-bromo-5-methyl-4-nitrophenyl)piperazine-1- tert-Butyl carboxylate (3.2 g, 93% yield).

MS(ESI)M/Z:400.1[M+H] ⁺ .

Step 2: 4-(2-Bromo-5-methyl-4-nitrophenyl)piperazine-1-carboxylate tert-butyl ester (3.2 g, 8.0 mmol) and 1-methyl-4- 1H-Pyrazole borate pinacol ester (2.16g, 10.4mmol) was dissolved in dioxane (70mL) and water (14mL), sodium carbonate (1.7g, 16.0mmol) and ferrocene palladium dichloride were added (586 mg, 0.7 mmol). The reaction solution was heated to 80°C under nitrogen atmosphere and stirred overnight. The reaction solution was cooled to room temperature, diluted with water (200 mL), and extracted with ethyl acetate (100 mL×3 times). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/1) to give 4-(5-methyl-2-(1-methyl-1H-pyrazol-4-yl) -4-Nitrophenyl)piperazine-1-carboxylic acid tert-butyl ester (2.1 g, 66% yield).

MS(ESI)M/Z:402.3[M+H] ⁺ .

Step 3: Add iron powder (1.5 g, 27.0 mmol), silicon dioxide (100-200 mesh, 3.1 g) and ammonium chloride (0.9 g, 17.0 mmol) to ethanol (20 mL) and water (20 mL), heat up to 65°C, add 4-(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperazine-1-carboxylate tert-butyl ester (1.7 g, 4.2 mmol) in tetrahydrofuran (15 mL), and the reaction was stirred at 65°C for 1.5 hours. The disappearance of the starting materials was monitored by TLC, and the reaction solution was poured into saturated brine (100 mL) and ethyl acetate (200 mL). Filtration, separation, the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 4-(4-amino-5-methyl-2-(1-methyl-1H- Pyrazol-4-yl)phenyl)piperazine-1-carboxylate tert-butyl ester (1.7 g, 92% yield).

MS(ESI)M/Z: 372.2[M+H] ⁺ .

Step 4: 4-(4-Amino-5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazine-1-carboxylate tert-butyl ester (1.0 g, 2.7 mmol), (6-((2,5-dichloropyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (830 mg, 2.3 mmol) and trifluoroacetic acid (2.5 g, 22.4 mmol) were successively added to n-butanol (20 mL), and the temperature was raised to 98 °C under nitrogen protection and stirred overnight. The reaction solution was cooled to room temperature, concentrated under reduced pressure, tetrahydrofuran (16 mL) was added, then triethylamine (0.68 g, 6.7 mmol) was added to the solution, stirred for 10 minutes, and di-tert-butyl dicarbonate (488 mg, 2.2 mmol) was added. , and stirred at room temperature for 2 hours. Water (30 mL) was added to the reaction solution for quenching, and ethyl acetate (40 mL×2) was used for extraction. The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=30/1) to obtain 4-(4-((5-chloro-4-((5-(dimethylphosphoryl)quinoxa) Lin-6-yl)amino)pyrimidin-2-yl)amino)-5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazine-1-carboxylic acid tert. Butyl ester (1.0 g, 66% yield).

MS(ESI)M/Z:703.2[M+H] ⁺ .

Step 5: 4-(4-((5-Chloro-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methyl tert-butyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazine-1-carboxylate (1.0 g, 1.4 mmol) was dissolved in ethyl acetate (20 mL) and added 5M hydrochloric acid/dioxane (11 mL, 55.0 mmol), stirred at room temperature for 30 minutes. TLC monitored the disappearance of the raw materials, and concentrated directly to obtain (6-((5-chloro-2-((2-methyl-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperazine- 1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide hydrochloride (1.0 g, crude).

MS(ESI)M/Z: 603.6[M+H] ⁺ .

Step 6: Convert (6-((5-Chloro-2-((2-methyl-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperazin-1-yl) Phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide hydrochloride (110 mg, about 0.14 mmol) was dissolved in N,N dimethylformamide (20 mL) , followed by adding N,N-diisopropylethylamine (407mg, 3.1mmol), 5-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoindole olin-4-yl)amino)pentylmethanesulfonate (411 mg, 0.94 mmol) and sodium iodide (30 mg), the reaction solution was stirred at 60°C overnight. TLC monitored the disappearance of the raw materials, the reaction solution was quenched by adding saturated sodium bicarbonate solution (50 mL), and extracted with dichloromethane (25 mL×2). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by high performance preparative liquid chromatography to obtain the final product 4-((5-(4-(4-((5-chloro-4-((5-(dimethylphosphoryl)quinoxalin-6-yl) )amino)pyrimidin-2-yl)amino)-5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)pentyl)amino)- 2-(2,6-Dioxopiperidin-3-yl)isoindoline-1,3-dione (15.8 mg, 12% yield).

MS(ESI)M/Z: 944.9[M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ): δ 12.81 (s, 1H), 9.08 (dd, J=9.6, 4.0 Hz, 1H), 8.74-8.63 (m, 2H), 8.14 (s, 1H), 7.90 (brs,1H),7.77-7.65(m,2H),7.59(d,J=9.6Hz,1H),7.54-7.50(m,1H),7.11(d,J=7.2Hz,1H),6.97( s, 1H), 6.91(d, J=8.4Hz, 1H), 6.66(s, 1H), 6.25(t, J=5.6Hz, 1H), 4.94-4.90(m, 1H), 3.82(s, 3H) ),3.32-3.30(m,2H),3.06(brs,4H),2.95-2.52(m,8H),2.28(s,3H),2.12-2.09(m,8H),1.76-1.63(m,6H ).

Example 51:

4-((5-(4-(4-((5-Chloro-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5 -Methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)pentyl)amino)-2-(2,6-dioxopiperidine -3-yl)isoindoline-1,3-dione

Reaction process:

Reaction steps:

With (6-((5-chloro-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperazin-1-yl)phenyl ) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethyl phosphine oxide hydrochloride as raw material, the final product 4-((5-(4-( 4-((5-Chloro-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1- Methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)pentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-Dione (13.6 mg).

MS(ESI)M/Z: 960.8[M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ): δ 12.77 (s, 1H), 9.14 (dd, J=9.6, 4.0 Hz, 1H), 8.73 (dd, J=14.6, 1.8 Hz, 2H), 8.22-8.19 (m,2H),7.76(brs,1H),7.68-7.56(m,2H),7.54-7.47(m,1H),7.36(s,1H),7.11(d,J=6.8Hz,1H), 6.90(d, J=8.4Hz, 1H), 6.73(s, 1H), 6.25(t, J=5.6Hz, 1H), 4.95-4.91(m, 1H), 3.90(s, 3H), 3.73(s ,3H),3.31-3.25(m,2H),3.03(brs,4H),2.94-2.37(m,8H),2.15-2.10(m,8H),1.77-1.66(m,6H).

Example 52:

5-(3-(4-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino) -5-Methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)piperazin-1-yl)azetidin-1-yl )-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione

Reaction process:

Reaction steps:

With (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(piperazin-1-yl) )piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide as raw material, the final product 5- (3-(4-(1-(4-((5-Bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5 -Methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)piperazin-1-yl)azetidin-1-yl)- 2-(2,6-Dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione (17.8 mg).

MS(ESI)M/Z: 1075.3[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ 12.71(s, 1H), 11.09(s, 1H), 9.41(brs, 1H), 8.86(d, J=2.0Hz, 1H), 8.81(d , J = 1.6Hz, 2H), 8.45(s, 1H), 8.29(s, 1H), 7.94(s, 1H), 7.84(s, 1H), 7.66-7.60(m, 2H), 6.96(d, J=7.6Hz, 1H), 6.81(s, 1H), 5.10-5.05(m, 1H), 4.31-4.26(m, 2H), 4.07-4.01(m, 2H), 3.81(s, 3H), 3.76 (s,3H),3.35-3.28(m,2H),3.23-3.07(m,8H),2.90-2.82(m,1H),2.72-2.59(m,4H),2.35-2.28(m,3H) ,2.19-2.11(m,2H),2.04(s,3H),2.00(s,3H),1.87-1.77(m,2H).

Example 53:

5-(3-(4-(4-(4-((5-chloro-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino) -5-Methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)piperidin-1-yl)azetidin-1-yl )-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Reaction process:

Reaction steps:

Step 1: (6-((5-Chloro-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperazin-1-yl) )phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide hydrochloride (1.0 g, about 1.5 mmol) was dissolved in 1,2 dichloroethane (50 mL) and N,N-dimethylformamide (10 mL), add triethylamine (500 mg, 5.0 mmol), stir for 5 minutes, and then add 4-oxopiperidine-1-carboxylate tert-butyl ester (1.3 g , 6.5 mmol), stirred for 15 minutes, finally added acetic acid (1.5 mL) and sodium triacetoxyborohydride (1.6 g, 7.5 mmol), and stirred at room temperature overnight. TLC monitored the disappearance of the raw materials, the reaction solution was quenched by adding saturated sodium bicarbonate solution (20 mL), and extracted with ethyl acetate (30 mL×2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/1) to give 4-(4-(4-((5-chloro-4-((5-(dimethylphosphorus) Acyl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazine- 1-yl)piperidine-1-carboxylate tert-butyl ester (840 mg, 69% yield).

MS(ESI) M/Z: 702.7[M-Boc+H] ⁺ .

Step 2: 4-(4-(4-((5-chloro-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)- 5-Methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)piperidine-1-carboxylic acid tert-butyl ester (840 mg, 1.0 mmol) was dissolved in In ethyl acetate (16 mL), 5M hydrochloric acid/dioxane solution (8 mL) was added, and the mixture was stirred at room temperature for 30 minutes. TLC monitored the disappearance of the raw materials, and concentrated directly under reduced pressure to obtain (6-((5-chloro-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-( 4-(Piperidin-4-yl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide hydrochloride (800 mg, crude ).

MS(ESI)M/Z:702.3[M+H] ⁺ .

The next step was (6-((5-chloro-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(piperidine-4 -yl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethyl phosphine oxide hydrochloride as raw material, obtained by referring to the preparation method of Example 35 Final product 5-(3-(4-(4-(4-((5-chloro-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl) Amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)piperidin-1-yl)azetidine-1 -yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (29.4 mg).

MS(ESI)M/Z: 1013.5[M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ): δ 12.78 (s, 1H), 9.14 (dd, J=9.6, 4.0 Hz, 1H), 8.73 (dd, J=15.6, 2.0 Hz, 2H), 8.23 (s ,1H),8.19(s,1H),8.12(brs,1H),7.82(brs,1H),7.75-7.63(m,3H),7.59-7.49(m,1H),7.39(brs,1H), 6.80(d,J=2.0Hz,1H),6.74(s,1H),6.55(dd,J=8.4,2.0Hz,1H),4.96-4.92(m,1H),4.25-4.23(m,1H) ,4.22-4.08(m,2H),3.91(s,3H),3.91-3.87(m,2H),3.70(brs,4H),3.39(brs,2H),3.28-2.67(m,12H),2.15 (s,3H),2.11(s,3H),2.08-1.96(m,2H),1.77-1.65(m,4H).

Example 54:

3-((4-(1-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidine-2- yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)-2-oxoethyl)piperidine-4 -yl)phenyl)amino)piperidine-2,6-dione

Reaction process:

Reaction steps:

Step 1: Combine 1-bromo-4-nitrobenzene (4.8 g, 23.8 mmol), N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (7.3 g, 23.8 mmol) ), Pd(dppf)Cl ₂ (1.7g, 2.4mmol) and potassium phosphate (9.85g, 71.3mmol) were successively added to dioxane/water (40mL/10mL), nitrogen was replaced three times, the temperature was raised to 100°C and stirred overnight . The disappearance of raw materials was monitored by LCMS, the reaction solution was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (30 mL×3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=5/1) to obtain 4-(4-nitrophenyl)-3,6-dihydropyridine-1(2H)- tert-Butyl carboxylate (4.5 g, 62% yield).

MS(ESI)M/Z:305.1[M+H] ⁺ .

Step 2: 4-(4-Nitrophenyl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl ester (2.0 g, 6.6 mmol) and 10% wet palladium on carbon (350 mg) were combined at room temperature ) was added to methanol/DMF (10 mL/10 mL), replaced with hydrogen three times, and stirred at room temperature overnight. LCMS detected that the reaction was complete, and the reaction solution was filtered and concentrated under reduced pressure to obtain tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (1.68 g, yield 92%).

MS(ESI)M/Z: 277.2[M+H] ⁺ .

Step 3: 4-(4-Aminophenyl)piperidine-1-carboxylate tert-butyl ester (252 mg, 0.9 mmol), 3-bromopiperidine-2,6-dione (175 mg, 0.9 mmol) at room temperature and sodium bicarbonate (230 mg, 2.7 mmol) were successively added to DMF (10 mL), and the temperature was raised to 50° C. and stirred overnight. LCMS monitored the disappearance of the raw materials, added water (50 mL) to dilute, and extracted with ethyl acetate (30 mL×3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 3/1) to obtain 4-(4-((2,6-dioxopiperidin-3-yl)amino)benzene yl)piperidine-1-carboxylate tert-butyl ester (112 mg, 32% yield).

MS(ESI) M/Z: 388.2[M+H] ⁺ .

Step 4: Combine tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidine-1-carboxylate (60 mg, 0.16 mmol) and 5M HCl/ Dioxane (10 mL) was added to DCM (5 mL) and stirred at room temperature for 30 minutes. The reaction was monitored by LCMS for completion. The reaction solution was concentrated under reduced pressure to obtain 3-((4-(piperidin-4-yl)phenyl)amino)piperidine-2,6-dione hydrochloride (47 mg, crude product).

MS(ESI)M/Z: 288.2[M+H] ⁺ .

Step 5: 3-((4-(piperidin-4-yl)phenyl)amino)piperidine-2,6-dione hydrochloride (27 mg, crude), sodium bicarbonate (44 mg, 0.5 mmol) and tert-butyl bromoacetate (21 mg, 0.1 mmol) were added to acetonitrile (6 mL) as required, and the temperature was raised to 50°C and stirred overnight. LCMS monitored the disappearance of the raw materials, added water (30 mL) to dilute, and extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative TLC plate to give tert-butyl 2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)acetate (30 mg, 2-step yield 84%).

MS(ESI)M/Z:402.3[M+H] ⁺ .

Step 6: tert-butyl 2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)acetate (30 mg, 0.075 mmol) and 5M HCl/dioxane (5 mL) were added to DCM (5 mL) and stirred at room temperature for 1 hour. The reaction was monitored by LCMS for completion. The reaction solution was concentrated under reduced pressure to obtain 2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)acetic acid hydrochloride (25 mg, Crude).

MS(ESI) M/Z: 346.2[M+H] ⁺ .

Step 7: 2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)acetic acid hydrochloride (25mg, Crude product), (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperazin-1-yl) Phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (60 mg, 0.09 mmol), HATU (55 mg, 0.14 mmol) and DIEA (28 mg, 0.22 mmol) were added sequentially into DMF (5 mL) and stirred at room temperature for 10 minutes. LCMS monitored the disappearance of the raw materials, added water (30 mL) to dilute, and extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by high performance preparative liquid chromatography to obtain the final product 3-((4-(1-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoline. Oxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl )-2-oxoethyl)piperidin-4-yl)phenyl)amino)piperidine-2,6-dione (7.8 mg, 11% over two steps).

MS(ESI)M/Z: 990.3[M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ): δ 12.57 (s, 1H), 8.99-8.96 (m, 1H), 8.73 (d, J=1.6 Hz, 1H), 8.71 (d, J=1.6 Hz, 1H) ), 8.29(s, 1H), 8.24(s, 1H), 8.11(brs, 1H), 7.68(s, 1H), 7.64-7.61(m, 2H), 7.36(s, 1H), 7.05(d, J=7.6Hz, 2H), 6.66-6.62(m, 3H), 4.09-4.05(m, 1H), 3.89(s, 3H), 3.75(s, 3H), 3.71-3.68(m, 2H), 3.34 (brs,2H),3.10-3.06(m,2H),2.91-2.88(m,6H),2.79-2.70(m,2H),2.56-2.52(m,2H),2.46-2.41(m,2H) ,2.34-2.28(m,2H),2.24-2.20(m,1H),2.15(s,3H),2.11(s,3H),2.03-2.00(m,2H).

Example 55:

5-(4-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino) -5-Methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-2-(2, 6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione

Reaction process:

Reaction steps:

Step 1: Dissolve 2-(piperidin-4-yl)ethan-1-ol (219.5 mg, 1.7 mmol) in NMP (5 mL), add 2-(2,6-dioxopiperidine-3 -yl)-5,6-difluoroisoindoline-1,3-dione (500 mg, 1.7 mmol, see US202016143A1 for preparation), and the temperature was raised to 140° C. for 5 minutes under microwave. LCMS monitored the end of the reaction, poured the reaction solution into water, a solid was precipitated, filtered, and rinsed with petroleum ether to obtain 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(4- (2-Hydroxyethyl)piperidin-1-yl)isoindoline-1,3-dione (560 mg, 82% yield).

MS(ESI) M/Z: 385.1[MH ₂ O] ⁺ .

Step 2: 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(4-(2-hydroxyethyl)piperidin-1-yl)isoindole at room temperature Lin-1,3-dione (100 mg, 0.25 mmol) was dissolved in dichloromethane (3 mL), triethylamine (38 mg, 0.37 mmol) was added, the temperature was lowered to 0 °C, and methanesulfonyl chloride (42.6 mg, 0.37 mmol) was slowly added dropwise. 0.37 mmol) and stirred at 0 °C for 30 minutes. The end of the reaction was monitored by LCMS, the reaction solution was diluted with dichloromethane (15 mL), and washed with saturated aqueous sodium bicarbonate solution (20 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=2/1) to give 2-(1-(2-(2,6-dioxopiperidin-3-yl)- 6-Fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)ethylmethanesulfonate (100 mg, 84% yield).

MS(ESI)M/Z: 482.1[M+H] ⁺ .

Step 3: 2-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl) at room temperature Piperidin-4-yl)ethylmethanesulfonate (37 mg, 0.077 mmol), (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyridine) oxazol-4-yl)-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (51 mg, 0.077 mmol) dissolved in In acetonitrile (3 mL), DIEA (30 mg, 0.23 mmol) and a catalytic amount of sodium iodide were added, and the reaction was stirred at 85° C. for 15 hours. The disappearance of the starting material was monitored by LCMS, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The obtained residue was purified by high performance preparative liquid chromatography to obtain the final product 5-(4-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxaline-6) -yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)ethyl) Piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione (18.7 mg, 23% yield).

MS(ESI)M/Z: 1048.4[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ 12.73(s, 1H), 11.11(s, 1H), 9.53(brs, 1H), 8.86(d, J=1.6Hz, 1H), 8.82(d , J=2.0Hz, 1H), 8.80(brs, 1H), 8.52(s, 1H), 8.30(s, 1H), 8.03(s, 1H), 7.83(s, 1H), 7.73(d, J= 11.6Hz, 1H), 7.66(s, 1H), 7.48(d, J=7.2Hz, 1H), 6.78(s, 1H), 5.13-5.08(m, 1H), 3.84(s, 3H), 3.78( s,3H),3.69-3.55(m,4H),3.32-3.21(m,4H),3.03-2.85(m,4H),2.62-2.51(m,2H),2.04(s,3H),2.01( s,3H),1.88-1.79(m,2H),1.75-1.67(m,2H),1.62-1.55(m,1H),1.44-1.35(m,2H),1.29-1.21(m,4H).

Example 56:

5-(4-((4-(4-((5-Bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5 -Methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-(2,6- Dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione

Reaction process:

Reaction steps:

Using 2-(2,6-dioxopiperidin-3-yl)-5,6-difluoroisoindoline-1,3-dione and piperidin-4-ylmethanol as raw materials, refer to Example The procedure of 55 prepared the final product 5-(4-((4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidine- 2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl) -2-(2,6-Dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione (30.7 mg).

MS(ESI)M/Z: 1034.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ 12.78(s,1H), 11.11(s,1H), 9.77(brs,1H), 8.87(s,1H), 8.83(s,1H), 8.63 (s, 1H), 8.33(s, 1H), 8.05(s, 1H), 7.83(s, 1H), 7.70-7.60(m, 2H), 7.50(brs, 1H), 7.09(d, J=6.8 Hz,1H),6.80(s,1H),5.11-5.06(m,1H),3.84-3.60(m,11H),3.28(brs,8H),3.03-2.86(m,3H),2.63-2.52( m, 2H), 2.33(brs, 1H), 2.18(brs, 1H), 2.06(s, 3H), 2.02(s, 3H), 1.90(brs, 2H), 1.71(brs, 1H).

Example 57:

5-(3-(4-((4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino )-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)azetidine- 1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Reaction process:

Reaction steps:

With (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperazin-1-yl)phenyl ) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethyl phosphine oxide and 4-formyl piperidine-1-carboxylic acid tert-butyl ester as raw materials, prepared with reference to the operation steps of Example 49 The final product 5-(3-(4-((4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidine-2- yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)aza Cyclobutan-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (16.1 mg).

MS(ESI)M/Z: 1070.9[M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ): δ 12.58 (s, 1H), 8.99 (dd, J=9.6, 4.0 Hz, 1H), 8.72 (dd, J=12.0, 1.6 Hz, 2H), 8.29 (s ,1H),8.21(brs,2H),7.80-7.52(m,4H),7.36(s,1H),6.81-6.71(m,2H),6.52(dd,J=8.4,2.0Hz,1H), 4.94-4.92(m, 1H), 4.11(t, J=7.6Hz, 2H), 3.90(brs, 5H), 3.72(s, 3H), 3.37-3.33(m, 1H), 3.22-2.66(m, 14H), 2.15-2.11(m, 8H), 1.96-1.89(m, 5H), 1.45-1.27(m, 2H).

Example 58:

5-(4-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino) -5-Methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-2-(2, 6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Reaction process:

Reaction steps:

With 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindolin-1,3-dione and 2-(piperidin-4-yl)ethan-1-ol As raw material, the final product 5-(4-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxaline- 6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)ethyl )piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (12.8 mg).

MS(ESI)M/Z: 1030.3[M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ): δ 12.59 (s, 1H), 8.99 (dd, J=9.6, 4.0 Hz, 1H), 8.73 (dd, J=13.6, 1.6 Hz, 2H), 8.30 (s ,1H),8.23(s,1H),8.14(brs,1H),7.77-7.55(m,4H),7.36(s,1H),7.28(d,J＝2.4Hz,1H),7.05(dd, J=8.4, 2.4Hz, 1H), 6.72(s, 1H), 4.96-4.93(m, 1H), 3.98-3.87(m, 5H), 3.71(s, 3H), 3.05-2.38(m, 14H) ,2.15(s,3H),2.11(s,3H),1.86-1.82(m,2H),1.68-1.57(m,5H),1.40-1.23(m,2H).

Example 59:

5-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5- Methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-2- (2,6-Dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione

Reaction process:

Reaction steps:

Step 1: (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperazin-1-yl) )phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (1.7 g, about 2.6 mmol) was dissolved in methanol (20 mL) and dichloromethane (5 mL), 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl ester (740 mg, 3.1 mmol) was added, and after stirring at room temperature for 1 hour, sodium cyanoborohydride (650 mg) was slowly added under an ice bath. , 10.3 mmol), and stirred at room temperature for 16 hours. TLC monitored the disappearance of the raw materials, the reaction solution was quenched by adding saturated sodium bicarbonate (20 mL), and extracted with ethyl acetate (40 mL×2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=40/1～20/1) to obtain 2-(4-(4-((5-bromo-4-((5-(di Methylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl) Piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (810 mg, 36% yield).

MS(ESI)M/Z:886.5[M+H] ⁺ .

Step 2: Convert 2-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)- 5-Methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylic acid tert. Butyl ester (810 mg, 0.92 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (6 mL) was added under ice bath, and the mixture was stirred at room temperature for 3 hours. TLC monitored the disappearance of the raw materials, and concentrated directly under reduced pressure to obtain (6-((2-((4-(4-(7-azaspiro[3.5]nonan-2-yl)piperazin-1-yl)-2- Methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-5-bromopyrimidin-4-yl)amino)quinoxalin-5-yl)dimethyloxide Phosphine trifluoroacetic acid (800 mg, crude).

MS(ESI) M/Z: 786.7[M+H] ⁺ .

Step 3: (6-((2-((4-(4-(7-azaspiro[3.5]nonan-2-yl)piperazin-1-yl)-2-methoxy- 5-(1-Methyl-1H-pyrazol-4-yl)phenyl)amino)-5-bromopyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide trifluoroacetic acid (200 mg, crude), 2-(2,6-dioxopiperidin-3-yl)-5,6-difluoroisoindoline-1,3-dione (200 mg, 0.68 mmol) was dissolved in N, To N-dimethylformamide (6 mL), potassium carbonate (152 mg, 1.1 mmol) and a catalytic amount of sodium iodide were added, and the reaction was stirred at 75° C. for 16 hours. The disappearance of the starting material was monitored by LCMS, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The obtained residue was purified by high performance preparative liquid chromatography to obtain the final product 5-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)) Amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)-7-azaspiro [3.5] Nonan-7-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione (28.6 mg, yield 12 %).

MS(ESI)M/Z: 1060.3[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ12.68(s,1H), 11.12(s,1H), 8.85-8.81(m,3H), 8.44(s,1H), 8.28(s,1H) ,8.00(s,1H),7.80(s,1H),7.73-7.44(m,4H),6.87(m,1H),5.13-5.08(m,1H),3.81(s,3H),3.76(s ,3H),3.23-3.15(m,4H),2.89-2.85(m,8H),2.66-2.50(m,3H),2.05-2.01(m,8H),1.74-1.64(m,6H),1.25 -1.15(m,2H).

Example 60:

5-(3-(1'-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5 -Methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-[4,4'-dipiperidin]-1-yl)azetidin-1-yl) -2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Reaction process:

Reaction steps:

Step 1: [4,4'-Dipiperidine]-1-carboxylate tert-butyl ester (1.6 g, 6.0 mmol), 1-bromo-2-fluoro-4-methoxy-5-nitro Benzene (1.4 g, 5.6 mmol) was dissolved in DMF (20 mL), potassium carbonate (0.8 g, 6.0 mmol) was added, and the mixture was stirred at room temperature for 16 hours. LCMS monitoring showed disappearance of starting material. The reaction solution was cooled to room temperature, poured into ice water (100 mL), and extracted with ethyl acetate (120 mL×2). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure, and purified by petroleum ether crystallization to obtain 1'-(2-bromo-5-methoxy-4-nitrophenyl)-[ 4,4'-Bipiperidine]-1-carboxylic acid tert-butyl ester (1.6 g, 57% yield).

MS(ESI)M/Z: 498.2[M+H] ⁺ .

Step 2: 1'-(2-Bromo-5-methoxy-4-nitrophenyl)-[4,4'-bipiperidine]-1-carboxylic acid tert-butyl ester (1.6 g, 3.2mmol) and 1-methyl-4-1H-pyrazole boronate pinacol ester (0.8g, 3.8mmol) were dissolved in dioxane (10mL) and water (1mL), potassium phosphate (1.3g, 6.4 mmol) and ferrocene palladium dichloride (0.12 g, 0.16 mmol), the reaction solution was heated to 80°C under nitrogen atmosphere and stirred for 16 hours. The reaction was monitored by LCMS, the reaction solution was cooled to room temperature, diluted with water (200 mL) and extracted with ethyl acetate (100 mL×3 times). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to obtain 1'-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitro Phenyl)-[4,4'-bipiperidine]-1-carboxylic acid tert-butyl ester (1.3 g, crude).

MS(ESI)M/Z:500.4[M+H] ⁺ .

Step 3: 1'-(5-Methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)-[4,4'-bipiperidine Pyridinyl]-1-carboxylate tert-butyl ester (1.1 g, crude) and 10% palladium on carbon (110 mg) were added to methanol (15 mL) and stirred at room temperature for 4 hours under a hydrogen balloon atmosphere. TLC monitoring showed the disappearance of the starting material, the filtrate was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/ethyl acetate=1/1) to obtain 1'-(4-amino-5- Methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-[4,4'-bipiperidine]-1-carboxylate tert-butyl ester (0.75g, received in two steps rate 59%).

MS(ESI) M/Z: 470.4[M+H] ⁺ .

The next step was 1'-(4-amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-[4,4'-bipiperidine]-1 - tert-butyl carboxylate as raw material, with reference to the preparation methods of Example 35 and Example 48 to obtain the final product 5-(3-(1'-(4-((5-bromo-4-((5-(dimethyl Phosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-[ 4,4'-Dipiperidin-1-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3- Diketone (33.6 mg).

MS(ESI)M/Z: 1056.5[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ): δ 12.68(s, 1H), 11.09(s, 1H), 8.84-8.81(m, 3H), 8.45(s, 1H), 8.26(s, 1H), 8.01 (s,1H),7.71(s,1H),7.67-7.65(m,1H),7.56(s,2H),6.81(d,J=8.0Hz,2H),6.69-6.67(m,1H), 5.10-5.06(m, 1H), 4.14-4.10(m, 2H), 3.84-3.79(m, 2H), 3.79(s, 3H), 3.75(s, 3H), 3.37-3.31(m, 2H), 3.15-3.12(m, 2H), 2.91-2.85(m, 3H), 2.66-2.52(m, 6H), 2.03(s, 3H), 1.99(s, 3H), 1.93-1.70(m, 6H), 1.35-1.10(m,4H).

Example 61:

5-(3-(4-(4-(4-((5-bromo-4-((2-(dimethylphosphono)-3,4-dimethylphenyl)amino)pyrimidin-2-yl )amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)piperidin-1-yl)azetidine- 1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Reaction process:

Reaction steps:

Step 1: Dissolve (6-amino-2,3-dimethylphenyl)dimethylphosphine oxide (1.1 g, 5.6 mmol) in acetone (50 mL) at room temperature, add 5-bromo-2,4- Dichloropyridine (1.3 g, 5.6 mmol) and N,N-diisopropylethylamine (1.4 g, 11.2 mmol). The reaction solution was heated to 60°C and stirred for 3 hours under nitrogen protection until the reaction was complete. The reaction solution was cooled to room temperature, concentrated under reduced pressure, added with water (50 mL), and extracted with ethyl acetate (50 mL×3 times). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to obtain (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-2,3-dimethyl phenyl) dimethylphosphine oxide (1.7 g, 78% yield).

MS(ESI) M/Z: 388.0[M+H] ⁺ .

Step 2: Dissolve (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-2,3-dimethylphenyl)dimethylphosphine oxide (1.7 g, 4.4 mmol) at room temperature In n-butanol (50 mL), 1-(4-(4-amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazine-1- base)-2,2,2-trifluoroethane-1-one (1.7 g, 4.4 mmol) and trifluoroacetic acid (5.0 g, 43.7 mmol), replaced with nitrogen twice, warmed to 110 °C and stirred overnight, monitored by LCMS The reaction is complete. The reaction solution was cooled to room temperature, concentrated under reduced pressure, added with water (50 mL), and extracted with ethyl acetate (50 mL×3 times). The organic phases were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to obtain 1-(4-(4-((5-bromo-4-((2-(dimethylphosphono) -3,4-Dimethylphenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazine -1-yl)-2,2,2-trifluoroethane-1-one (3.2 g, 99% yield).

MS(ESI)M/Z:735.2[M+H] ⁺ .

Step 3: 1-(4-(4-((5-bromo-4-((2-(dimethylphosphono)-3,4-dimethylphenyl)amino)pyrimidin-2-yl )amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)-2,2,2-trifluoroethane-1 - Ketone (3.2 g, 4.4 mmol) was dissolved in methanol (50 mL) and water (10 mL), potassium hydroxide (487 mg, 8.7 mmol) was added, and the temperature was raised to 60° C. under nitrogen protection and stirred for 1 hour, and the reaction was completed by LCMS monitoring. The reaction solution was cooled to room temperature, concentrated under reduced pressure, added with water (50 mL), and extracted with ethyl acetate/methanol=10:1 (50 mL×3 times). The organic phases were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1) to obtain ( 6-((5-Bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperazin-1-yl)phenyl)amino ) pyrimidin-4-yl)amino)-2,3-dimethylphenyl)dimethylphosphorus oxide (2.2 g, 79% yield).

MS(ESI)M/Z: 639.2[M+H] ⁺ .

Step 4: Convert (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperazin-1-yl) )phenyl)amino)pyrimidin-4-yl)amino)-2,3-dimethylphenyl)dimethylphosphorus oxide (2.2 g, 3.4 mmol) and tert-4-iodopiperidine-1-carboxylic acid Butyl ester (2.1 g, 6.9 mmol) was dissolved in acetonitrile (10 mL), potassium carbonate (1.4 g, 10.3 mmol) was added, and after nitrogen replacement 3 times, the reaction system was heated to 100° C. and stirred for 4 days. LCMS monitoring showed that the reaction was complete, the reaction solution was cooled to room temperature, filtered and concentrated under reduced pressure. Water (50 mL) was added and extracted with dichloromethane (50 mL x 3 times). The organic phases were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1～5/ 1) 4-(4-(4-((5-bromo-4-((2-(dimethylphosphono)-3,4-dimethylphenyl)amino)pyrimidin-2-yl)amino) -5-Methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)piperidine-1-carboxylic acid tert-butyl ester (1.5 g, yield 53%).

MS(ESI)M/Z:822.3[M+H] ⁺ .

Step 5: 4-(4-(4-((5-bromo-4-((2-(dimethylphosphono)-3,4-dimethylphenyl)amino)pyrimidin-2-yl)amino )-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)piperidine-1-carboxylate tert-butyl ester (1.5 g, 1.8 mmol) was dissolved in dichloromethane (50 mL), trifluoroacetic acid (10 mL) was added, and the mixture was stirred at room temperature for 3 hours. LCMS monitoring showed that the reaction was complete, water (50 mL) was added and extracted with dichloromethane (50 mL x 3 times). The organic phases were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to obtain (6-((5-bromo-2-((2-methoxy-5-(1-methyl) -1H-pyrazol-4-yl)-4-(4-(piperidin-4-yl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-di Methylphenyl)dimethylphosphorus oxide trifluoroacetate (1.2 g, crude).

MS(ESI)M/Z:722.3[M+H] ⁺ .

Step 6: Convert (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(piperidine- 4-yl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dimethylphenyl)dimethylphosphorus oxide trifluoroacetate salt (0.5 g , crude product) and tert-butyl 3-iodoazetidine-1-carboxylate (588 mg, 2.1 mmol) were dissolved in acetonitrile (50 mL), potassium carbonate (477 mg, 3.5 mmol) was added, and after nitrogen replacement 3 times, The reaction system was heated to 100°C and stirred for 4 days. LCMS monitoring showed that the reaction was complete, the reaction solution was cooled to room temperature, filtered and concentrated under reduced pressure. Water (50 mL) was added and extracted with dichloromethane (50 mL x 3 times). The organic phases were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1～5/ 1) 3-(4-(4-(4-((5-bromo-4-((2-(dimethylphosphono)-3,4-dimethylphenyl)amino)pyrimidine-2- yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)piperidin-1-yl)azetidine - 1-Carboxylic acid tert-butyl ester (280 mg, 2-step yield 42%).

MS(ESI) M/Z: 877.3[M+H] ⁺ .

Step 7: 3-(4-(4-(4-((5-bromo-4-((2-(dimethylphosphono)-3,4-dimethylphenyl)amino)pyrimidine-2 -yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)piperidin-1-yl)azetidine Alkane-1-carboxylate tert-butyl ester (280 mg, 0.32 mmol) was dissolved in dichloromethane (50 mL), trifluoroacetic acid (10 mL) was added, and the mixture was stirred at room temperature for 3 hours. LCMS monitoring showed that the reaction was complete, water (30 mL) was added and extracted with dichloromethane (30 mL x 3 times). The organic phases were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to obtain (6-((2-((4-(4-(1-(azetidine-3- yl)piperidin-4-yl)piperazin-1-yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-5-bromopyrimidine -4-yl)amino)-2,3-dimethylphenyl)dimethylphosphorus oxide as trifluoroacetate salt (220 mg, crude).

MS(ESI) M/Z: 777.3[M+H] ⁺ .

Step 8: (6-((2-((4-(4-(1-(azetidin-3-yl)piperidin-4-yl)piperazin-1-yl)-2 -Methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-5-bromopyrimidin-4-yl)amino)-2,3-dimethylphenyl) Trifluoroacetate salt of dimethylphosphorus oxide (120 mg, crude) and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (43 mg, 0.15 mmol) was dissolved in DMSO (5 mL) and acetonitrile (5 mL), DIEA (40 mg, 0.31 mmol) was added and the reaction was heated to 80°C and stirred for 16 hours. LCMS monitoring showed the disappearance of the raw materials, the reaction solution was cooled to room temperature, and purified by high performance preparative liquid chromatography to obtain the final product 5-(3-(4-(4-(4-((5-bromo-4-(((2-( Dimethylphosphono)-3,4-dimethylphenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl) Phenyl)piperazin-1-yl)piperidin-1-yl)azetidine-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-Dione (23.1 mg, 15% yield).

MS(ESI)M/Z: 1033.2[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ /CD ₃ OD): δ 8.08 (s, 1H), 7.98-7.95 (m, 1H), 7.71-7.64 (m, 4H), 7.50 (s, 1H), 6.86 ( s, 1H), 6.77-6.71(m, 2H), 6.65-6.62(m, 1H), 4.98-4.95(m, 1H), 4.26(t, J=7.6Hz, 2H), 3.93(s, 3H) ,3.89(s,3H),3.88-3.81(m,1H),3.75-3.50(m,4H),3.28(brs,6H),2.88-2.75(m,3H),2.71-2.59(m,2H) ,2.40-2.29(m,6H),2.20-2.11(m,8H),2.02(s,3H),1.99(s,3H).

Example 62:

5-(3-(4-(4-(5-bromo-4-(5-(dimethylphosphono)quinoxalin-6-ylamino)pyrimidin-2-yl)amino)-5-methoxy base-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-1,4'-bispiperidin-1'-yl)azetidin-1-yl)-2- (2,6-Dioxopiperidin-3-yl)isoindoline-1,3-dione

Reaction process:

Reaction steps:

Step 1: 4-(5-Methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)-3,6-dihydropyridine-1(2H )-carboxylate tert-butyl ester (770 mg, 1.9 mmol, the preparation can refer to patent WO2021/104441A1) was dissolved in methanol (20 mL), and 10% Pd/C (80 mg) was added. The reaction was stirred at room temperature under 10 kg hydrogen pressure for 16 hours. Filtration, and the filtrate was concentrated under reduced pressure to obtain tert-butyl 4-(4-amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidine-1-carboxylate (600 mg, yield 84%), which was directly used in the next step.

MS(ESI)M/Z: 387.2[M+H] ⁺ .

Step 2: 4-(4-Amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidine-1-carboxylate tert-butyl ester ( 370 mg, 0.96 mmol), (6-((5-bromo-2-chloropyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (357 mg, 0.87 mmol) and trifluoroacetic acid ( 992 mg, 8.7 mmol) were successively added to n-butanol (10 mL), and the temperature was raised to 98 °C under nitrogen protection and stirred overnight. The reaction solution was cooled to room temperature, concentrated under reduced pressure, tetrahydrofuran (10 mL) was added, then triethylamine (90 mg, 0.89 mmol) was added to the solution, stirred for 10 minutes, and di-tert-butyl dicarbonate (285 mg, 1.3 mmol) was added, Stir at room temperature for 2 hours. Water (50 mL) was added to the reaction solution for quenching, and ethyl acetate (50 mL×2) was used for extraction. The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=50/1) to obtain 4-(4-((5-bromo-4-((5-(dimethylphosphono)quinoxa) Lin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidine-1-carboxylic acid tert-Butyl ester (370 mg, 56% yield).

MS(ESI) M/Z: 761.7[M+H] ⁺ .

Step 3: 4-(4-((5-Bromo-4-((5-(dimethylphosphono)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methyl Oxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidine-1-carboxylate tert-butyl ester (370 mg, 0.49 mmol) was dissolved in ethyl acetate (8 mL) and added 5M hydrogen chloride/ethyl acetate solution (5 mL) was stirred at room temperature for 30 minutes. TLC monitored the disappearance of the raw material, filtered, and the filter cake was adjusted to pH 9 with saturated potassium carbonate solution, and extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain (6-((5-bromo-2-((2-methoxy-5-(1-methyl) -1H-pyrazol-4-yl)-4-(piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (300 mg, yield 93%).

MS(ESI)M/Z: 661.9[M+H] ⁺ .

Subsequent steps were followed by (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperidin-4-yl) Phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide was used as raw material, and the final product 5-(3-(4 was obtained with reference to the preparation methods of Example 35 and Example 53) -(4-(5-Bromo-4-(5-(dimethylphosphono)quinoxalin-6-ylamino)pyrimidin-2-yl)amino)-5-methoxy-2-(1- Methyl-1H-pyrazol-4-yl)phenyl)-1,4'-bispiperidin-1'-yl)azetidin-1-yl)-2-(2,6-dioxo piperidin-3-yl)isoindoline-1,3-dione (4 mg).

MS(ESI)M/Z: 1056.6[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ): δ 12.77(s,1H), 8.90-8.80(m,1H), 8.78(s,1H), 8.73(s,1H), 8.22(s,1H), 8.10 (s,1H),8.00(brs,1H),7.67-7.64(m,2H),7.34-7.26(m,2H),7.10(s,1H),6.83-6.80(m,1H),6.56-6.54 (m,1H),4.95-4.93(m,1H),4.20-4.05(m,2H),3.95-3.80(m,8H),3.60-3.40(m,4H),2.85-2.65(m,6H) ,2.20-2.00(m,9H),2.00-1.60(m,6H),1.30-1.20(m,4H).

Example 63:

5-(4-(3-(4-(4-((5-bromo-4-((5-(dimethylphosphono)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino )-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)azetidin-1-yl)piperidine-1- yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Reaction process:

Reaction steps:

Step 1: (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperazin-1-yl) ) phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphorus oxide hydrochloride (0.5 g, 0.72 mmol) and 3-iodoazetidine-1 - tert-butyl carboxylate (1.1 g, 3.9 mmol) was dissolved in acetonitrile (20 mL), potassium carbonate (521 mg, 3.8 mmol) was added, and after nitrogen replacement 3 times, the reaction system was heated to 98 °C and stirred for 3 days. TLC monitoring showed that the reaction was completed, the reaction solution was cooled to room temperature, quenched by adding saturated sodium bicarbonate solution (100 mL), and extracted with dichloromethane (50 mL×2 times). The organic phases were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=8/1) to obtain 3 -(4-(4-((5-Bromo-4-((5-(dimethylphosphono)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy - 2-(1-Methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)azetidine-1-carboxylate tert-butyl ester (230 mg, 39% yield).

MS(ESI)M/Z:818.6[M+H] ⁺ .

Step 2: 3-(4-(4-((5-bromo-4-((5-(dimethylphosphono)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)- 5-Methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)azetidine-1-carboxylate tert-butyl ester (230 mg, 0.28 mmol) was dissolved in ethyl acetate (5 mL), 5M hydrogen chloride/1,4-dioxane solution (5 mL) was added, and the mixture was stirred at room temperature for 30 minutes. TLC monitored the disappearance of the raw materials, and concentrated directly under reduced pressure to obtain (6-((2-((4-(4-(azetidin-3-yl)piperazin-1-yl)-2-methoxy-5 Hydrochloride salt of -(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-5-bromopyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (200 mg, crude).

MS(ESI)M/Z:718.2[M+H] ⁺ .

Step 3: (6-((2-((4-(4-(azetidin-3-yl)piperazin-1-yl)-2-methoxy-5-(1-methyl) -1H-pyrazol-4-yl)phenyl)amino)-5-bromopyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide hydrochloride (200 mg, crude) was dissolved in Triethylamine (118 mg, 1.2 mmol) was added to 1,2 dichloroethane (10 mL) and N,N-dimethylformamide (2 mL), stirred for 5 minutes, and then 4-oxopiperidine-1 was added - tert-butyl carboxylate (155 mg, 0.78 mmol), stirred for 15 minutes, finally added acetic acid (0.4 mL) and sodium triacetoxyborohydride (248 mg, 1.2 mmol) and stirred at room temperature for 2 hours. TLC monitored the disappearance of the raw materials, the reaction solution was quenched by adding saturated sodium bicarbonate solution (20 mL), and extracted with ethyl acetate (30 mL×2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol = 20/1) to give 4-(3-(4-(4-((5-bromo-4-(((5-(di Methylphosphono)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl) Piperazin-1-yl)azetidine-1-yl)piperidine-1-carboxylate tert-butyl ester (190 mg, 75% over two steps).

MS(ESI)M/Z:901.5[M+H] ⁺ .

Step 4: 4-(3-(4-(4-((5-bromo-4-((5-(dimethylphosphono)quinoxalin-6-yl)amino)pyrimidin-2-yl) Amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)azetidin-1-yl)piperidine-1 - tert-butyl carboxylate (190 mg, 0.21 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (10 mL) was added, and the mixture was stirred at room temperature for 30 minutes. TLC monitored the disappearance of the raw materials, and concentrated directly under reduced pressure to obtain (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-( 4-(1-(Piperidin-4-yl)azetidine)-3-yl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxaline-5- yl) dimethylphosphine oxide trifluoroacetate (200 mg, crude).

MS(ESI)M/Z:801.5[M+H] ⁺ .

Step 5: (6-((5-Bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(1 -(Piperidin-4-yl)azetidine)-3-yl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethyl Phosphine oxide trifluoroacetate (200 mg, crude) and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (207 mg, 0.75 mmol) was dissolved in DMSO (10 mL), DIEA (163 mg, 1.3 mmol) and a catalytic amount of sodium iodide were added and the reaction was heated to 60 °C and stirred overnight. LCMS monitoring showed that the raw materials disappeared, the reaction solution was cooled to room temperature, quenched by adding saturated sodium bicarbonate solution (20 mL), and extracted with ethyl acetate (15 mL×2). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by high performance preparative liquid chromatography to give the final product 5-(4-(3-(4-(4-((5-bromo-4-((5-(dimethylphosphono)quinoxaline- 6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)aza Cyclobutan-1-yl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (8.5mg, received in two steps rate 3.8%).

MS(ESI)M/Z: 1057.5[M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ): δ 12.59 (s, 1H), 8.97 (dd, J=9.6, 4.2 Hz, 1H), 8.73 (dd, J=12.0 1.8 Hz, 2H), 8.37 (s, 1H), 8.29(s, 1H), 8.22(s, 1H), 7.70(d, J=8.4Hz, 1H), 7.65-7.40(m, 3H), 7.38(s, 1H), 7.06(dd, J =8.6,1.8Hz,1H),6.70(s,1H),4.95(dd,J=12.0,5.2Hz,1H),4.03-3.93(m,2H),3.91(s,3H),3.75(s, 3H), 3.55(brs, 2H), 3.13-2.65(m, 12H), 2.49(brs, 4H), 2.15(s, 3H), 2.11(s, 3H), 2.07-1.95(m, 6H).

Example 64:

5-(4-(3-(4-(4-(5-bromo-4-(5-(dimethylphosphono)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)- 5-Methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)azetidin-1-yl)piperidin-1-yl) -2-(2,6-Dioxypiperidin-3-yl)-6-fluoroisoindoline-1,3-dione

Reaction process:

Reaction steps:

with (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(1-(piperidine- 4-yl)azetidine)-3-yl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide trifluoro Acetate and 2-(2,6-dioxopiperidin-3-yl)-5,6-difluoroisoindoline-1,3-dione were used as raw materials, and were prepared by referring to the operation steps of Example 63 The final product 5-(4-(3-(4-(4-(5-bromo-4-(5-(dimethylphosphono)quinoxalin-6-yl)amino)pyrimidin-2-yl) is obtained Amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)azetidin-1-yl)piperidine-1 -yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione (25.6 mg).

MS(ESI)M/Z: 1075.5[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ 12.68(s, 1H), 11.12(s, 1H), 8.85-8.80(m, 3H), 8.45(s, 1H), 8.27(s, 1H) ,7.98(s,1H),7.81(s,1H),7.73-7.70(m,1H),7.56(s,1H),7.46-7.44(m,1H),6.86(s,1H),5.13-5.08 (m,1H),3.81(s,3H),3.76(s,3H),3.55-3.40(m,2H),3.00-2.80(m,14H),2.60-2.20(m,4H),2.10-1.95 (m,10H),1.80-1.70(m,2H).

Example 65:

5-(3-(4-(2-(4-(4-(5-bromo-4-(5-(dimethylphosphono)quinoxalin-6-yl)amino)pyrimidin-2-yl) Amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)ethyl)piperidin-1-yl)azetidine Alk-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Reaction process:

Reaction steps:

Step 1: (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperazin-1-yl) )phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide hydrochloride (830 mg, 1.2 mmol) was dissolved in 1,2 dichloroethane (35 mL) and N , N-dimethylformamide (7 mL), was added triethylamine (380 mg, 3.8 mmol), stirred for 5 minutes, and then added 4-(2-oxoethyl) piperidine-1-carboxylate tert-butyl ester ( 570 mg, 2.5 mmol), stirred for 15 minutes, added acetic acid (1.2 g), and finally added sodium triacetoxyborohydride (790 mg, 3.8 mmol), and stirred at room temperature for 16 hours. TLC monitored the disappearance of the raw materials, the reaction solution was quenched by adding saturated sodium bicarbonate solution (20 mL), and extracted with ethyl acetate (50 mL×2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=50/1～20/1) to obtain 4-(2-(4-(4-((5-bromo-4-((5 -(Dimethylphosphono)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl) Phenyl)piperazin-1-yl)ethyl)piperidine-1-carboxylate tert-butyl ester (600 mg, 58% yield).

MS(ESI) M/Z: 873.9[M+H] ⁺ .

Step 2: 4-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphono)quinoxalin-6-yl)amino)pyrimidin-2-yl) Amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)ethyl)piperidine-1-carboxylate tert-butyl ester ( 600 mg, 0.69 mmol) was dissolved in ethyl acetate (3 mL), 3.7 M hydrogen chloride/dioxane solution (3 mL) was added under ice bath, and the mixture was stirred at room temperature for 16 hours. TLC monitored the disappearance of the starting material, filtered, and the filter cake was washed once with ethyl acetate (3 mL) and dried to give (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H- Pyrazol-4-yl)-4-(4-(2-(piperidin-4-yl)ethyl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxaline -5-yl)dimethylphosphine oxide hydrochloride (560 mg, crude).

MS(ESI) M/Z: 773.9[M+H] ⁺ .

Subsequent steps were followed by (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(2-(piperidine) Perid-4-yl)ethyl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethyl phosphine oxide hydrochloride as raw material, refer to the implementation The preparation method of Example 35 gave the final product 5-(3-(4-(2-(4-(4-(5-bromo-4-(5-(dimethylphosphono)quinoxalin-6-yl)) Amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)ethyl)piperidine- 1-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (36 mg).

MS(ESI)M/Z: 1085.5[M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ): δ 12.60 (s, 1H), 8.98 (dd, J=9.2, 4.0 Hz, 1H), 8.75 (s, 1H), 8.71 (s, 1H), 8.30 (s ,1H),8.23-8.15(m,2H),8.10(s,1H),7.80-7.70(m,2H),7.63-7.60(m,1H),7.38(s,1H),6.78(s,1H) ),6.72(s,1H),6.51(d,J=8.4Hz,1H),4.95-4.92(m,1H),4.15-4.05(m,2H),3.91-3.80(m,5H),3.68( s,3H),3.60-2.90(m,9H),2.90-2.65(m,8H),2.15(s,3H),2.11(s,3H),1.95-1.90(m,2H),1.79-1.70( m,2H),1.60-1.20(m,5H).

Example 66:

5-(3-(4-(2-(4-(4-(5-bromo-4-(5-(dimethylphosphono)quinoxalin-6-yl)amino)pyrimidin-2-yl) Amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)ethyl)piperidin-1-yl)azetidine Alkyl-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione

Reaction process:

Reaction steps:

(6-((2-((4-(4-(2-(1-(azetidin-3-yl)piperidin-4-yl)ethyl)piperazin-1-yl )-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-5-bromopyrimidin-4-yl)amino)quinoxalin-5-yl) Dimethylphosphine oxide trifluoroacetate (134 mg, about 0.14 mmol) and 2-(2,6-dioxopiperidin-3-yl)-5,6-difluoroisoindoline-1,3- The diketone (143 mg, 0.48 mmol) was dissolved in DMSO (6 mL), DIEA (105 mg, 0.81 mmol) and a catalytic amount of sodium iodide were added and the reaction was heated to 60°C and stirred for 16 hours. TLC monitoring showed that the raw material disappeared, the reaction solution was cooled to room temperature, quenched by adding water (20 mL), and extracted with dichloromethane (60 mL×2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by high performance preparative liquid chromatography to give the final product 5-(3-(4-(2-(4-(4-(5-bromo-4-(5-(dimethylphosphono)quinoxaline)) -6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)ethyl yl)piperidin-1-yl)azetidine-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-di Ketone (49.7 mg, 32% yield).

MS(ESI)M/Z: 1103.5[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ 12.68(s, 1H), 11.11(s, 1H), 8.84-8.81(m, 3H), 8.45(s, 1H), 8.27(s, 1H) , 7.99(s, 1H), 7.81(s, 1H), 7.63-7.56(m, 3H), 6.92(d, J=7.2Hz, 1H), 6.84(s, 1H), 5.10-5.05(m, 1H) ),4.23(brs,2H),3.96(brs,2H),3.81(s,3H),3.76(s,3H),3.20(brs,1H),2.87-2.71(m,8H),2.60-2.30( m, 8H), 2.03(s, 3H), 2.00(s, 3H), 1.83-1.78(m, 4H), 1.40-1.15(m, 5H).

Example 67:

5-(3-(4-((4-(4-(5-bromo-4-(5-(dimethylphosphono)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino) -5-Methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)azetidine- 1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione

Reaction process:

Reaction steps:

(6-((2-((4-(4-((1-(azetidin-3-yl)piperidin-4-yl)methyl)piperazin-1-yl)- 2-Methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-5-bromopyrimidin-4-yl)amino)quinoxalin-5-yl)dimethyl Phosphine oxide trifluoroacetate (200 mg, about 0.22 mmol) and 2-(2,6-dioxopiperidin-3-yl)-5,6-difluoroisoindoline-1,3-dione (217 mg, 0.74 mmol) was dissolved in DMSO (5 mL), DIEA (142 mg, 1.1 mmol) and a catalytic amount of sodium iodide were added and the reaction was heated to 60°C and stirred for 16 hours. TLC monitoring showed that the raw material disappeared, the reaction solution was cooled to room temperature, quenched by adding water (20 mL), and extracted with dichloromethane (60 mL×2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by high performance preparative liquid chromatography to give the final product, 5-(3-(4-((4-(4-(5-bromo-4-(5-(dimethylphosphono)quinoxaline-6). -yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)methyl) piperidin-1-yl)azetidine-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione ( 43.5 mg, 18% yield).

MS(ESI)M/Z: 1089.3[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ12.68(s,1H), 11.11(s,1H), 8.90-8.80(m,3H), 8.43(s,1H), 8.28(s,1H) ,8.00(s,1H),7.80(s,1H),7.63-7.57(m,3H),6.94-6.86(m,2H),5.08-5.05(m,1H),4.23(brs,2H),4.14 -4.10(m, 2H), 3.97(brs, 2H), 3.81(s, 3H), 3.76(s, 3H), 3.30-3.20(m, 2H), 2.90-2.75(m, 7H), 2.58-2.50 (m,4H),2.22(brs,2H),2.03(s,3H),2.00(s,3H),1.83-1.55(m,5H),1.20-1.10(m,2H).

Example 68:

5-(3-(4-(4-(4-(5-bromo-4-(5-(dimethylphosphono)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)- 2-(1-Ethyl-1H-pyrazol-4-yl)-5-methoxyphenyl)piperazin-1-yl)piperidin-1-yl)azetidin-1-yl) -2-(2,6-Dioxypiperidin-3-yl)isoindoline-1,3-dione

Reaction process:

Reaction steps:

Step 1: 4-(2-Bromo-5-methoxy-4-nitrophenyl)piperazine-1-carboxylate tert-butyl ester (1.3 g, 3.1 mmol) and 1-ethyl-1H at room temperature -Pyrazol-4-ylboronic acid (0.57g, 4.1mmol) was dissolved in dioxane (20mL) and water (4mL), sodium carbonate (0.66g, 6.2mmol) and ferrocene palladium dichloride ( 0.23 g, 0.31 mmol), the reaction solution was heated to 80 °C under nitrogen atmosphere and stirred for 16 hours. The end of the reaction was monitored by LCMS, the reaction solution was cooled to room temperature, diluted with water (100 mL) and extracted with ethyl acetate (50 mL×3 times). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=5/1～1/1) to obtain 4- (2-(1-Ethyl-1H-pyrazol-4-yl)-5-methoxy-4-nitrophenyl)piperazine-1-carboxylate tert-butyl ester (0.7 g, 52% yield ).

MS(ESI)M/Z:432.1[M+H] ⁺ .

Step 2: Reduced iron powder (1.1 g, 19.6 mmol), silica gel (2.2 g, 100-200 mesh) and ammonium chloride (0.65 g, 36 mmol) were added to ethanol (8 mL) and water (8 mL) at room temperature, The temperature was raised to 65°C and stirred for 0.5 hour. Then add 4-(2-(1-ethyl-1H-pyrazol-4-yl)-5-methoxy-4-nitrophenyl)piperazine-1-carboxylate tert-butyl ester (1.3 g, 3.0 mmol) in tetrahydrofuran (10 mL), and the reaction system was stirred at 65°C for 1.5 hours. TLC monitored the end of the reaction, filtered through celite, added water (10 mL) to the filtrate to dilute, and extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1～1/1) to obtain 4-(4-amino-2-(1-ethyl-1H-pyrazole- 4-yl)-5-methoxyphenyl)piperazine-1-carboxylate tert-butyl ester (1.2 g, 99% yield).

MS(ESI)M/Z:402.4[M+H] ⁺ .

Step 3: 4-(4-Amino-2-(1-ethyl-1H-pyrazol-4-yl)-5-methoxyphenyl)piperazine-1-carboxylate tert-butyl ester ( 1.1 g, 2.7 mmol), (6-((5-bromo-2-chloropyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (1.2 g, 2.9 mmol) and trifluoro Acetic acid (3.1 g, 27.2 mmol) was successively added to n-butanol (10 mL), and the temperature was raised to 98° C. and stirred overnight under nitrogen protection. The reaction solution was cooled to room temperature, concentrated under reduced pressure, tetrahydrofuran (10 mL) was added, then triethylamine (270 mg, 2.7 mmol) was added to the solution, stirred for 10 minutes, and di-tert-butyl dicarbonate (0.89 g, 4.0 mmol) was added. , and stirred at room temperature for 2 hours. Water (50 mL) was added to the reaction solution for quenching, and ethyl acetate (50 mL×2) was used for extraction. The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=50/1) to obtain 4-(4-((5-bromo-4-((5-(dimethylphosphono)quinoxa) Lin-6-yl)amino)pyrimidin-2-yl)amino)-2-(1-ethyl-1H-pyrazol-4-yl)-5-methoxyphenyl)piperazine-1-carboxylic acid tert-Butyl ester (0.9 g, 43% yield).

MS(ESI) M/Z: 777.4[M+H] ⁺ .

Step 4: Convert 4-(4-((5-bromo-4-((5-(dimethylphosphono)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2-( 1-Ethyl-1H-pyrazol-4-yl)-5-methoxyphenyl)piperazine-1-carboxylate tert-butyl ester (900 mg, 1.2 mmol) was dissolved in dichloromethane (10 mL) and added 5M hydrogen chloride/ethyl acetate solution (2 mL) was stirred at room temperature for 30 minutes. TLC monitored the disappearance of the raw material, filtered, and the filter cake was adjusted to pH 9 with saturated potassium carbonate solution, and extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain (6-((5-bromo-2-((5-(1-ethyl-1H-pyrazole- 4-yl)-2-methoxy-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (550 mg, yield 70%).

MS(ESI) M/Z: 677.4[M+H] ⁺ .

Step 5: Convert (6-((5-bromo-2-((5-(1-ethyl-1H-pyrazol-4-yl)-2-methoxy-4-(piperazin-1-yl )phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (900 mg, 1.3 mmol) was dissolved in DCM (7.5 mL) and MeOH (7.5 mL), added 4 -Oxopiperidine-1-carboxylate tert-butyl ester (1.1 g, 5.3 mmol), stirred for 1 hour, then added sodium cyanoborohydride (500 mg, 8.0 mmol), and stirred at room temperature for 16 hours. TLC monitoring showed the disappearance of the starting material, water (20 mL) and ethyl acetate (50 mL) were added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (30 mL). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=50/1～25/1) to obtain 4-(4-(4-((5-bromo-4-((5-(di Methylphosphono)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-ethyl-1H-pyrazol-4-yl)phenyl) Piperazin-1-yl)piperidine-1-carboxylate tert-butyl ester (570 mg, 50% yield).

MS(ESI)M/Z:860.4[M+H] ⁺ .

Step 6: Convert 4-(4-(4-((5-bromo-4-((5-(dimethylphosphono)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)- 5-Methoxy-2-(1-ethyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)piperidine-1-carboxylate tert-butyl ester (570 mg, 0.66 mmol) was dissolved in In DCM (10 mL), trifluoroacetic acid (4 mL) was added under ice bath, stirred at room temperature for 0.5 hours, TLC monitoring showed the disappearance of the starting material, the pH was adjusted to 9 with saturated potassium carbonate solution, and extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain (6-((5-bromo-2-((5-(1-ethyl-1H-pyrazole- 4-yl)-2-methoxy-4-(4-(piperidin-4-yl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxaline-5- base) dimethylphosphine oxide (350 mg, 70% yield).

MS(ESI)M/Z:760.0[M+H] ⁺ .

Step 7: Convert (6-((5-bromo-2-((5-(1-ethyl-1H-pyrazol-4-yl)-2-methoxy-4-(4-(piperidine- 4-yl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (350 mg, 0.46 mmol) and 3-iodoazepine Butane-1-carboxylate tert-butyl ester (651 mg, 2.3 mmol) was dissolved in acetonitrile (30 mL), potassium carbonate (318 mg, 2.3 mmol) was added, and the reaction system was heated to 98° C. and stirred for 2 days. TLC monitoring showed that the reaction was complete, the reaction solution was cooled to room temperature, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=50/1～25/1) to obtain 3-(4-(4-(4-((5-bromo-4-((5 -(Dimethylphosphono)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2-(1-ethyl-1H-pyrazol-4-yl)-5-methoxybenzene (250 mg, 59% yield).

MS(ESI)M/Z: 915.5[M+H] ⁺ .

Step 8: 3-(4-(4-(4-((5-bromo-4-((5-(dimethylphosphono)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino )-2-(1-ethyl-1H-pyrazol-4-yl)-5-methoxyphenyl)piperazin-1-yl)piperidin-1-yl)azetidine-1- tert-Butyl carboxylate (250 mg, 0.27 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (3 mL) was added, and the mixture was stirred at room temperature for 30 minutes. TLC monitoring showed that the reaction was completed, and the reaction solution was concentrated under reduced pressure to obtain (6-((2-((4-(4-(1-(azetidin-3-yl)piperidin-4-yl)piperazine- 1-yl)-5-(1-ethyl-1H-pyrazol-4-yl)-2-methoxyphenyl)amino)-5-bromopyrimidin-4-yl)amino)quinoxaline-5 -yl) dimethylphosphorus oxide trifluoroacetate (200 mg, 79% yield).

MS(ESI)M/Z:814.9[M+H] ⁺ .

Step 9: (6-((2-((4-(4-(1-(azetidin-3-yl)piperidin-4-yl)piperazin-1-yl)-5 -(1-Ethyl-1H-pyrazol-4-yl)-2-methoxyphenyl)amino)-5-bromopyrimidin-4-yl)amino)quinoxalin-5-yl)dimethyl Phosphorus oxide trifluoroacetate (200mg, 0.22mmol) and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (204mg, 0.73 mmol) was dissolved in DMSO (10 mL), DIEA (160 mg, 1.2 mmol) and a catalytic amount of sodium iodide were added, and the reaction was heated to 60°C and stirred for 16 hours. TLC monitoring showed that the raw material disappeared, the reaction solution was cooled to room temperature, water (20 mL) was added, and the mixture was extracted with dichloromethane (60 mL×2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by high performance preparative liquid chromatography to give the final product 5-(3-(4-(4-(4-(5-bromo-4-(5-(dimethylphosphono)quinoxaline-6-) yl)amino)pyrimidin-2-yl)amino)-2-(1-ethyl-1H-pyrazol-4-yl)-5-methoxyphenyl)piperazin-1-yl)piperidine-1 -yl)azetidine-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (58.7 mg, 25% yield) .

MS(ESI)M/Z: 1071.8[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ 12.68(s, 1H), 11.10(s, 1H), 8.84-8.80(m, 3H), 8.46(s, 1H), 8.28(s, 1H) ,8.10(s,1H),7.83(s,1H),7.67-7.45(m,3H),6.85-6.75(m,2H),6.70-6.60(m,1H),5.09-5.04(m,1H) ,4.11-4.05(m,4H),3.85-3.75(m,5H),2.90-2.80(m,8H),2.70-2.50(m,8H),2.03(s,3H),1.99(s,3H) ,1.91-1.80(m,4H),1.45(brs,2H),1.31-1.20(m,3H).

Example 69:

5-(3-(4-(4-(4-(5-bromo-4-(5-(5-(dimethylphosphono)quinoxalin-6-yl)amino)pyrimidin-2-yl) -2-(1-(Difluoromethyl)-1H-pyrazol-4-yl)-5-methoxyphenyl)piperazin-1-yl)piperidin-1-yl)-2-(2 ,6-Dioxypiperidin-3-yl)isoindoline-1,3-dione

Reaction process:

Reaction steps:

Using 1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1H-pyrazole as raw material, refer to the implementation The preparation of Example 68 gave the final product 5-(3-(4-(4-(4-(5-bromo-4-(5-(5-(dimethylphosphono)quinoxalin-6-yl)) Amino)pyrimidin-2-yl)-2-(1-(difluoromethyl)-1H-pyrazol-4-yl)-5-methoxyphenyl)piperazin-1-yl)piperidine-1 -yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (33.6 mg).

MS(ESI)M/Z: 1093.6[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ12.68(s,1H), 11.10(s,1H), 8.84-8.79(m,3H), 8.55(brs,2H), 8.31(s,1H) ,8.20(brs,1H),7.74-7.55(m,4H),6.95-6.91(m,1H),6.81(s,1H),6.68-6.65(m,1H),5.09-5.04(m,1H) ,4.15-4.10(m,2H),3.85-3.80(m,5H),2.95-2.80(m,8H),2.70-2.50(m,8H),2.03(s,3H),1.99(s,3H) ,1.90-1.80(m,4H),1.45(brs,2H).

Example 70:

5-(3-(4-(4-(4-(4-(5-(dimethylphosphono)quinoxalin-6-yl)amino)-5-(trifluoromethyl)pyrimidine-2- yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)piperidin-1-yl)azetidine -1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Reaction process:

Reaction steps:

Using (6-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphorus oxide (see WO2021/190417A1 for preparation) as raw material, Referring to the preparation method of Example 68, the final product 5-(3-(4-(4-(4-(4-(5-(dimethylphosphono)quinoxalin-6-yl)amino)-5- (Trifluoromethyl)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)piperidine -1-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (14.1 mg).

MS(ESI)M/Z: 1047.5[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ 12.64(s,1H), 11.09(s,1H), 9.00(brs,1H), 8.84-8.81(m,2H), 8.51(brs,1H) ,8.44(s,1H),7.99(s,1H),7.80(s,1H),7.65(d,J=8.0,1H),7.50(s,1H),7.43(brs,1H),6.83(s ,1H),6.80(s,1H),6.66(dd,J=8.4,1.6Hz,1H),5.10-5.00(m,1H),4.11(t,J=7.6,2H),3.90-3.70(m ,8H),2 85(brs,8H),2.70-2.50(m,8H),2.01(s,3H),1.99(s,3H),1.90-1.80(m,4H),1.55-1.40(m, 2H).

Example 71:

3-((4-(1-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphono)quinoxalin-6-yl)amino)pyrimidine-2- yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)-2-oxoethyl)piperidine-4 -yl)-3-fluorophenyl)amino)piperidine-2,6-dione

Reaction process:

Reaction steps:

Using 4-bromo-3-fluoroaniline as raw material, with reference to the preparation method of Example 54, the final product 3-((4-(1-(2-(4-(4-((5-bromo-4-(( 5-(Dimethylphosphono)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl) Phenyl)piperazin-1-yl)-2-oxoethyl)piperidin-4-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (29.2 mg).

MS(ESI)M/Z: 1008.3[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ12.80(s,1H), 10.81(s,1H), 9.60(brs,1H), 8.87-8.78(m,3H), 8.63(s,1H) ,8.32(s,1H),8.10(d,J=6.8Hz,1H),7.78(s,1H),7.67(s,1H),7.53(brs,1H),7.02-6.96(m,1H), 6.82(s,1H),6.52-6.46(m,2H),4.48(brs,2H),3.82(s,3H),3.78(s,3H),3.73(brs,2H),3.63-3.55(m, 4H), 3.19-3.10(m, 2H), 3.05-2.83(m, 6H), 2.79-2.70(m, 1H), 2.62-2.54(m, 1H), 2.13-2.06(m, 2H), 2.05( s,3H),2.01(s,3H),1.96-1.74(m,4H).

Example 72:

3-((4-(1-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphono)quinoxalin-6-yl)amino)pyrimidine-2- yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)-2-oxoethyl)piperidine-4 -yl)-2-fluorophenyl)amino)piperidine-2,6-dione

Reaction process:

Reaction steps:

Using 4-bromo-2-fluoroaniline as raw material, with reference to the preparation method of Example 54, the final product 3-((4-(1-(2-(4-(4-((5-bromo-4-(( 5-(Dimethylphosphono)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl) Phenyl)piperazin-1-yl)-2-oxoethyl)piperidin-4-yl)-2-fluorophenyl)amino)piperidine-2,6-dione (26.4 mg).

MS(ESI)M/Z: 1008.4[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ12.71(s,1H), 10.82(s,1H), 9.54(brs,1H), 8.86-8.81(m,3H), 8.46(s,1H) ,8.30(s,1H),8.09(d,J=6.0Hz,1H),7.78(s,1H),7.67(s,1H),7.53(brs,1H),6.97-6.93(m,1H), 6.88-6.78(m, 3H), 4.39-4.35(m, 2H), 3.82(s, 3H), 3.78(s, 3H), 3.75-3.68(m, 2H), 3.63-3.55(m, 4H), 3.09(brs, 2H), 2.94-2.87(m, 4H), 2.85-2.64(m, 3H), 2.61-2.55(m, 1H), 2.13-1.97(m, 12H).

Example 73:

3-(4-(1-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphono)quinoxalin-6-yl)amino)pyrimidin-2-yl )amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)-2-oxoethyl)piperidine-4- yl)phenoxy)piperidine-2,6-dione

Reaction process:

Reaction steps:

Using 4-(4-((2,6-dioxopiperidin-3-yl)oxo)phenyl)piperidine-1-carboxylate tert-butyl ester (refer to WO2021/83949A1 for preparation) as raw material, refer to Examples The preparation method of 54 gave the final product 3-(4-(1-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphono)quinoxalin-6-yl)) Amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)-2-oxoethyl yl)piperidin-4-yl)phenoxy)piperidine-2,6-dione (30.8 mg).

MS(ESI)M/Z: 991.9[M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 12.67 (s, 1H), 10.88 (s, 1H), 8.81 (d, J=1.6 Hz, 2H), 8.76 (d, J=1.6 Hz, 1H) ), 8.41(s, 1H), 8.27(s, 1H), 8.11(s, 1H), 7.77(s, 1H), 7.61(s, 1H), 7.54(brs, 1H), 6.91-6.81(m, 5H), 5.02-4.99(m, 1H), 3.79(s, 6H), 3.74(brs, 2H), 3.66(brs, 2H), 3.25(s, 2H), 3.04(brs, 4H), 2.85(brs ,4H),2.68-2.64(m,1H),2.60-2.56(m,6H),2.19-2.13(m,1H),2.11-2.05(m,1H),2.03(s,3H),1.99(s , 3H).

Example 74:

3-(4-(1-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphono)quinoxalin-6-yl)amino)pyrimidin-2-yl )amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)-2-oxoethyl)piperidine-4- yl)benzene)thio)piperidine-2,6-dione

Reaction process:

Reaction steps:

Step 1: 4-Bromothiophenol (2.0 g, 10.6 mmol), 3-bromopiperidine-2,6-dione (2.0 g, 10.6 mmol) and anhydrous potassium carbonate (4.4 g, 31.8 mmol) were combined at room temperature ) was successively added to acetonitrile (20 mL), and the temperature was raised to 50°C and stirred overnight. TLC monitoring the disappearance of raw materials, adding water (50 mL) to dilute, and extracting with ethyl acetate (50 mL×3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 3-((4-bromophenyl)thio)piperidine-2,6-dione (3.17 g, crude product), used directly in the next step.

MS(ESI)M/Z:300.0[M+H] ⁺ .

Step 2: Combine 3-((4-bromophenyl)thio)piperidine-2,6-dione (3.17 g, crude), N-Boc-1,2,5,6-tetrahydropyridine-4 -Pinacol borate (3.3g, 10.6mmol), Pd(dppf)Cl ₂ (775mg, 1.06mmol) and anhydrous potassium carbonate (4.4g, 31.8mmol) were successively added to DMF (30mL), nitrogen was replaced three times, The temperature was raised to 100°C and stirred overnight. The completion of the reaction was monitored by TLC, the reaction solution was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=60/1) to give 4-(4-((2,6-dioxopiperidin-3-yl)thio)benzene yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl ester (1.72 g, 40% yield over two steps).

MS(ESI)M/Z:403.2[M+H] ⁺ .

Step 3: 4-(4-((2,6-dioxopiperidin-3-yl)thio)phenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert. Butyl ester (1.12 g, 2.8 mmol) and 10% wet palladium on carbon (300 mg) were added to methanol (10 mL), hydrogen was replaced three times, and the temperature was raised to 50°C and stirred overnight. LCMS detected that the reaction was complete, the reaction solution was filtered, concentrated under reduced pressure, and the obtained residue was purified by high performance preparative liquid chromatography to obtain 4-(4-((2,6-dioxopiperidin-3-yl)thio)phenyl ) piperidine-1-carboxylate tert-butyl ester (100 mg, 9% yield).

MS(ESI)M/Z:405.2[M+H] ⁺ .

Subsequent steps take 4-(4-((2,6-dioxopiperidin-3-yl)thio)phenyl)piperidine-1-carboxylic acid tert-butyl ester as raw material, refer to the preparation method of Example 54 The final product 3-(4-(1-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphono)quinoxalin-6-yl)amino)pyrimidine- 2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)-2-oxoethyl)piperidine -4-yl)phenyl)thio)piperidine-2,6-dione (4.2 mg).

MS(ESI)M/Z: 1007.3[M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ): δ 12.62 (s, 1H), 8.96 (dd, J=9.6, 4.0 Hz, 1H), 8.75 (d, J=1.8 Hz, 1H), 8.71 (d, J ＝1.8Hz, 1H), 8.29(s, 1H), 8.23(s, 1H), 7.76(s, 1H), 7.68-7.59(m, 2H), 7.57(s, 1H), 7.53-7.35(m, 3H), 6.64(s, 1H), 5.36-5.34(m, 1H), 3.91(s, 3H), 3.73(s, 3H), 3.56-3.50(m, 2H), 3.41-3.44(m, 2H) ,2.93-2.78(m,6H),2.65-2.58(m,1H), 2.50-2.40(brs,1H),2.38-2.29(m,1H),2.24-2.16(m,2H),2.15(s, 3H), 2.11(s, 3H), 2.03-1.99(m, 4H), 1.66-1.61(m, 4H).

Example 75:

3-(4-(1-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphono)quinoxalin-6-yl)amino)pyrimidin-2-yl )amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)-2-oxoethyl)piperidine-4- yl)-2,3-dihydrobenzofuran-7-yl)amino)piperidine-2,6-dione

Reaction process:

Reaction steps:

Using 4-bromo-2,3-dihydrobenzofuran-7-amine (see CN106220644A for preparation) as raw material, the final product 3-(4-(1-(2-(4- (4-((5-Bromo-4-((5-(dimethylphosphono)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1 -Methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)-2-oxoethyl)piperidin-4-yl)-2,3-dihydrobenzofuran-7 -yl)amino)piperidine-2,6-dione (22 mg).

MS(ESI)M/Z: 1030.3[MH] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ): δ 12.58 (s, 1H), 8.99-8.96 (m, 1H), 8.72 (d, J=11.2 Hz, 2H), 8.30 (s, 1H), 8.24 (s ,1H),8.11(brs,1H),7.67-7.62(m,3H),7.38(s,1H),6.66(s,1H),6.61(d,J=8.0Hz,1H),6.46(d, J=8.4Hz, 1H), 4.62-4.57(m, 2H), 4.13-4.09(m, 1H), 3.90(s, 3H), 3.75(s, 3H), 3.67(brs, 2H), 3.39(brs ,2H),3.20-3.11(m,4H),2.90(brs,5H),2.82-2.69(m,2H),2.52-2.43(m,5H),2.15(s,3H),2.11(s,3H ),2.00-1.89(m,5H).

Example 76:

4-(1-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphono)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino) -5-Methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)-2-oxoethyl)piperidin-4-yl)- N-(2,6-Dioxopiperidin-3-yl)-2-fluorobenzamide

Reaction process:

Reaction steps:

Step 1: Combine 4-bromo-2-fluorobenzoic acid (2.0 g, 9.1 mmol), N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (2.8 g, 9.1 mmol) ), Pd(PPh ₃ ) ₄ (1.1 g, 0.9 mmol) and potassium carbonate (3.8 g, 27.4 mmol) were successively added to dioxane/water (20 mL/5 mL), replaced with nitrogen three times, and the temperature was raised to 100° C. to stir the reaction 2 hours. The reaction was monitored by TLC, the reaction solution was cooled to room temperature, diluted with water (30 mL), washed with ethyl acetate (30 mL×3), and then adjusted to slightly acidic pH with dilute hydrochloric acid. A solid was precipitated, filtered, and the filter cake was collected and dried to obtain 4-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-fluorobenzoic acid (2.1 g, yield 72%).

MS(ESI)M/Z: 322.1[M+H] ⁺ .

Step 2: Combine 4-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-fluorobenzoic acid (1.0 g, 3.1 mmol) with 10% at room temperature Wet palladium on carbon (100 mg) was added to methanol (20 mL), hydrogen was replaced three times, and the reaction was stirred at room temperature for 2 hours. TLC detected that the reaction was complete, the reaction solution was filtered with celite, and the filtrate was concentrated under reduced pressure to obtain 4-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-fluorobenzoic acid (0.7 g, yield 70%) ).

MS(ESI)M/Z: 324.2[M+H] ⁺ .

Step 3: Dissolve 4-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-fluorobenzoic acid (650 mg, 2.0 mmol) in dichloromethane (10 mL) at room temperature and cool under _N2 protection At 0°C, oxalyl chloride (0.35 mL, 4.0 mmol) and DMF (0.2 mL) were added dropwise, and after stirring for 10 minutes, the temperature was raised to room temperature, and the reaction was continued at room temperature for 1 hour. The completion of the reaction was monitored by TLC, and the reaction solution was concentrated under reduced pressure to obtain tert-butyl 4-(4-(chlorocarbonyl)-3-fluorophenyl)piperidine-1-carboxylate (670 mg, crude product).

MS(ESI)M/Z: 342.2[M+H] ⁺ .

Step 4: 3-Aminopiperidine-2,6-dione (1.0 g, 8.0 mmol) and DIEA (3.5 mL, 20.1 mmol) were dissolved in dichloromethane (20 mL) at room temperature and cooled to 0 under _N2 protection At °C, a solution of tert-butyl 4-(4-(chlorocarbonyl)-3-fluorophenyl)piperidine-1-carboxylate (670 mg, crude product) in tetrahydrofuran was added dropwise, and the reaction system was stirred at 0 °C for 2 hours. The completion of the reaction was monitored by TLC, water (40 mL) was added, and the mixture was extracted with dichloromethane (30 mL×3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=50/1) to give 4-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)- 3-Fluorophenyl)piperidine-1-carboxylate tert-butyl ester (502 mg, 58% over two steps).

MS(ESI) M/Z: 434.2[M+H] ⁺ .

Using 4-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidine-1-carboxylate tert-butyl ester as raw material, the following steps refer to Examples The preparation method of 54 gives the final product 4-(1-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphono)quinoxalin-6-yl)amino)pyrimidine -2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)-2-oxoethyl)piperidine pyridin-4-yl)-N-(2,6-dioxopiperidin-3-yl)-2-fluorobenzamide (22.9 mg).

MS(ESI)M/Z: 1036.3[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ): δ 12.58 (s, 1H), 9.02-8.95 (m, 1H), 8.78-8.68 (m, 2H), 8.32-8.22 (m, 3H), 8.04-8.00 ( m,1H),7.66(brs,3H),7.54-7.50(m,1H),7.40(s,1H),7.15(d,J=8.0Hz,1H),7.02(d,J=8.0Hz,1H) ),6.66(s,1H),4.83-4.74(m,1H),3.90(s,3H),3.75(s,3H),3.66-3.62(m,2H),3.44-3.34(m,2H), 3.17-3.09(m, 2H), 2.92-2.90(m, 4H), 2.85-2.69(m, 3H), 2.67-2.45(m, 3H), 2.15(s, 3H), 2.11(s, 3H), 2.08-1.94(m,7H).

Example 77:

5-(3-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphono)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino )-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl ) azetidine-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Reaction process:

Reaction steps:

Step 1: (6-((2-((4-(4-(7-azaspiro[3.5]nonan-2-yl)piperazin-1-yl)-2-methoxy-5- (1-Methyl-1H-pyrazol-4-yl)phenyl)amino)-5-bromopyrimidin-4-yl)amino)quinoxalin-5-yl)trifluoroethyl of dimethylphosphorus oxide acid (1.5 g, 1.7 mmol) and tert-butyl 3-iodoazetidine-1-carboxylate (2.6 g, 9.0 mmol) were dissolved in DMF (25 mL), potassium carbonate (1.3 g, 9.0 mmol) was added ), after 3 times of nitrogen replacement, the reaction system was heated to 75°C and stirred for 16 hours. TLC monitoring showed that the reaction was complete, the reaction solution was cooled to room temperature, filtered and concentrated under reduced pressure. Water (50 mL) was added and extracted with ethyl acetate (50 mL x 3 times). The organic phases were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=100/1～50/ 1) to obtain 3-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphono)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino )-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl ) tert-butyl azetidine-1-carboxylate (450 mg, 28% yield).

MS(ESI)M/Z: 941.2[M+H] ⁺ .

Step 2: Convert 3-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphono)quinoxalin-6-yl)amino)pyrimidin-2-yl) Amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7- base) tert-butyl azetidine-1-carboxylate (450 mg, 0.48 mmol) was dissolved in ethyl acetate (5 mL), and a solution of hydrogen chloride in ethyl acetate (4 M, 5 mL) was added under ice bath, and stirred at room temperature 3 hours. LCMS monitoring showed that the reaction was complete, and concentrated under reduced pressure to obtain (6-((2-((4-(4-(7-(azetidin-3-yl)-7-azaspiro[3.5]nonane- 2-yl)piperazin-1-yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-5-bromopyrimidin-4-yl) Amino)quinoxalin-5-yl)dimethylphosphorus oxide hydrochloride (450 mg, crude).

MS(ESI)M/Z:841.3[M+H] ⁺ .

Step 3: (6-((2-((4-(4-(7-(azetidin-3-yl)-7-azaspiro[3.5]nonan-2-yl) Piperazin-1-yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-5-bromopyrimidin-4-yl)amino)quinoxa Lin-5-yl) dimethylphosphorus oxide hydrochloride (210 mg, crude) and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1, The 3-diketone (210 mg, 0.76 mmol) was dissolved in DMF (6 mL), potassium carbonate (160 mg, 1.16 mmol) and a catalytic amount of sodium iodide were added, and the reaction was heated to 75 °C and stirred for 16 hours. TLC monitoring showed that the raw materials disappeared, the reaction solution was cooled to room temperature, water (30 mL) was added, and extracted with ethyl acetate (60 mL×2 times). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained residue was purified by high performance preparative liquid chromatography to obtain the final product 5-(3-(2-(4-(4- ((5-Bromo-4-((5-(dimethylphosphono)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl) yl)-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)azetidin-1-yl)-2- (2,6-Dioxypiperidin-3-yl)isoindoline-1,3-dione (20.3 mg, 8.3% over two steps).

MS(ESI)M/Z: 1096.9[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ): δ 12.60 (s, 1H), 9.02-8.92 (m, 1H), 8.76 (d, J=1.6Hz, 1H), 8.72 (d, J=1.6Hz, 1H) ),8.30(s,1H),8.23(s,1H),8.08(s,1H),7.81-7.63(m,3H),7.39(s,1H),6.78(s,1H),6.72(s, 1H), 6.53(dd, J=8.4, 2.0Hz, 1H), 4.95-4.90(m, 1H), 4.10(t, J=7.2Hz, 2H), 3.92(s, 3H), 3.87-3.80(m ,2H),3.67(s,3H),3.58-3.45(m,5H),3.40-3.25(m,2H),3.20-3.12(m,2H),2.88-2.66(m,7H),2.30-2.20 (m, 2H), 2.15(s, 3H), 2.11(s, 3H), 2.00-1.80(m, 8H).

Example 78:

5-(3-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphono)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino )-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl ) azetidine-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione

Reaction process:

Reaction steps:

(6-((2-((4-(4-(7-(azetidin-3-yl)-7-azaspiro[3.5]nonan-2-yl)piperazine- 1-yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-5-bromopyrimidin-4-yl)amino)quinoxaline-5 -yl) dimethylphosphorus oxide hydrochloride (210 mg, about 0.24 mmol) and 2-(2,6-dioxopiperidin-3-yl)-5,6-difluoroisoindoline-1 ,3-dione (210 mg, 0.71 mmol) was dissolved in DMF (6 mL), potassium carbonate (160 mg, 1.2 mmol) and a catalytic amount of sodium iodide were added, and the reaction was heated to 75° C. and stirred for 16 hours. TLC monitoring showed that the raw material disappeared, the reaction solution was cooled to room temperature, quenched by adding water (20 mL), and extracted with dichloromethane (60 mL×2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by high performance preparative liquid chromatography to give the final product 5-(3-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphono)quinoxaline- 6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)-7 -Azaspiro[3.5]nonan-7-yl)azetidine-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline- 1,3-Dione (2.1 mg, 0.8% yield).

MS(ESI)M/Z: 1116.0[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ): δ 12.60(s, 1H), 9.00-8.97(m, 1H), 8.76(s, 1H), 8.72(s, 1H), 8.30(s, 1H), 8.25 (s,1H),8.06(brs,1H),7.81-7.73(m,2H),7.40-7.30(m,2H),6.84-6.82(m,1H),6.71(s,1H),4.92-4.89 (m,1H),4.25(brs,2H),4.10-4.00(m,2H),3.92(s,3H),3.67(s,3H),3.55-3.45(m,5H),3.40-3.25(m ,2H),3.25-3.10(m,2H),2.89-2.66(m,7H),2.35-1.80(m,16H).

Example 79:

5-(4-(3-(4-(4-(5-bromo-4-(5-(dimethylphosphono)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5 -Methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)propyl)piperidin-1-yl)-2-(2,6- Dioxopiperidin-3-yl)isoindoline-1,3-dione

Reaction process:

Reaction steps:

Step 1: Combine 3-(piperidin-4-yl)propyl-1-ol (250 mg, 1.75 mmol) and 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-iso Indoline-1,3-dione (482 mg, 1.75 mmol) was dissolved in NMP (30 mL) and N,N-diisopropylethylamine (15 mL), and the reaction system was warmed to 110° C. and stirred for 6 hours. TLC monitoring showed that the reaction was complete, the reaction solution was cooled to room temperature and poured into water (100 mL). Extracted with ethyl acetate (100 mL×3 times), combined the organic phases, washed twice with saturated brine (100 mL), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=3:1) to obtain 2-(2,6-oxopiperidin-3-yl)-5-(4-(3-hydroxyl) Propyl)piperidin-1-yl)isoindoline-1,3-dione (310 mg, 44% yield).

MS(ESI)M/Z: 400.2[M+H] ⁺ .

Step 2: 2-(2,6-oxopiperidin-3-yl)-5-(4-(3-hydroxypropyl)piperidin-1-yl)isoindoline-1,3 at room temperature - The diketone (300 mg, 0.75 mmol) was dissolved in dichloromethane (10 mL) and triethylamine (114 mg, 1.1 mmol) was added. The temperature was lowered to 0°C, methanesulfonyl chloride (129 mg, 1.1 mmol) was slowly added dropwise, and the mixture was stirred at room temperature overnight. TLC monitoring showed that the reaction was complete and was quenched by the addition of saturated aqueous sodium bicarbonate (20 mL). The mixture was extracted with dichloromethane (20 mL×3 times). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=5:1) to obtain 3-(1-(2-(2,6-oxopiperidin-3-yl)-1,3) -Dioxoisoindolin-5-yl)piperidin-4-yl)propyl mesylate (270 mg, 75% yield).

MS(ESI) M/Z: 478.2[M+H] ⁺ .

Step 3: (6-((5-Bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperazine-1 -yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide hydrochloride (200 mg, 0.29 mmol) and 3-(1-(2-(2, 6-oxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)propyl mesylate (164 mg, 0.34 mmol) in N , N-dimethylformamide (5 mL), DIEA (184 mg, 1.4 mmol) and a catalytic amount of sodium iodide were added, and the reaction system was heated to 80° C. and stirred overnight. LCMS monitoring showed the disappearance of starting material, the reaction was cooled to room temperature, and water (20 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (20 mL×3 times), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by high performance preparative liquid chromatography to give the final product 5-(4-(3-(4-(4-(5-bromo-4-(5-(dimethylphosphono)quinoxalin-6-yl)) )amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)propyl)piperidine -1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (21.3 mg, 7% yield).

MS(ESI) M/Z: 1044.7[M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ): δ 12.59 (s, 1H), 8.98 (d, J=4.4 Hz, 1H), 8.74 (d, J=1.6 Hz, 1H), 8.71 (d, J=1.6 Hz,1H),8.53(brs,1H),8.30(s,1H),8.22(s,1H),7.76-7.54(m,4H),7.38(s,1H),7.05-7.03(m,1H) ,6.74(s,1H),4.95-4.85(m,1H),3.97-3.90(m,2H),3.90(s,3H),3.70(s,3H),3.08(brs,4H),3.00-2.54 (m,10H),2.15(s,3H),2.11(s,3H),1.85-1.51(m,6H),1.33-1.25(m,5H).

Example 80:

5-(4-(3-(4-(4-(5-bromo-4-(5-(dimethylphosphono)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5 -Methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)propyl)piperidin-1-yl)-2-(2,6- Dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione

Reaction process:

Reaction steps:

Using 2-(2,6-dioxopiperidin-3-yl)-5,6-difluoro-isoindoline-1,3-dione as raw material, refer to the preparation method of Example 79 to obtain the final product 5-(4-(3-(4-(4-(5-bromo-4-(5-(dimethylphosphono)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5 -Methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)propyl)piperidin-1-yl)-2-(2,6- Dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione (26.4 mg).

MS(ESI)M/Z: 1063.2[M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ): δ 12.50 (s, 1H), 8.92 (d, J=5.6 Hz, 1H), 8.67-8.64 (m, 3H), 8.22 (s, 1H), 8.13 (s ,1H),7.60-7.55(m,3H),7.39-7.30(m,3H),6.67(s,1H),4.87-4.85(m,1H),3.82(s,3H),3.64(s,3H) ), 3.59-3.56(m, 2H), 2.96(brs, 4H), 2.86-2.37(m, 10H), 2.07(s, 3H), 2.04(s, 3H), 1.78-1.28(m, 11H).

Example 81:

4-(4-(3-(4-(4-(5-Bromo-4-(5-(dimethylphosphono)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5 -Methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)propyl)piperidin-1-yl)-2-(2,6- Dioxopiperidin-3-yl)isoindoline-1,3-dione

Reaction process:

Reaction steps:

2-(2,6-dioxopiperidin-3-yl)-4-(4-(3-hydroxypropyl)piperidin-1-yl)isoindoline-1,3-dione ( For the preparation, refer to WO2020/113233A1) as the raw material, and refer to the preparation method of Example 79 to obtain the final product 4-(4-(3-(4-(4-(5-bromo-4-(5-(dimethylphosphono)) quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazine-1- (2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (27.2 mg).

MS(ESI)M/Z: 1045.2[M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ): δ 12.58 (s, 1H), 8.98 (dd, J=9.6 Hz, 4.4 Hz, 1H), 8.74 (d, J=2.0 Hz, 1H), 8.71 (d, J=1.6Hz, 1H), 8.37(brs, 1H), 8.29(s, 1H), 8.22(s, 1H), 7.65(brs, 3H), 7.65-7.55(m, 1H), 7.36(d, J =6.8Hz,2H),7.18(d,J=8.4Hz,1H),6.75(s,1H),4.98-4.90(m,1H),3.90(s,3H),3.74-3.72(m,5H) ,3.02(brs,4H),2.91-2.65(m,6H),2.47(brs,4H),2.13(s,3H),2.13(s,3H),1.88-1.57(m,6H),1.48-1.35 (m,5H).

Example 82:

5-(4-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphono)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino) -5-Methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)- 2-(2,6-Dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione

Reaction process:

Reaction steps:

Step 1: Combine 2-(piperidin-4-yl)acetic acid (500 mg, 3.5 mmol) and 2-(2,6-dioxopiperidin-3-yl)-5,6-difluoroisoindoline -1,3-Dione (368 mg, 1.25 mmol) was dissolved in NMP (30 mL) and N,N-diisopropylethylamine (15 mL), and the reaction system was warmed to 110° C. and stirred for 6 hours. TLC monitoring showed that the reaction was over, the reaction solution was cooled to room temperature, poured into water (100 mL), adjusted to pH 4-5 with dilute hydrochloric acid, extracted with ethyl acetate (100 mL × 3 times), combined with the organic phases, saturated brine ( 100 mL) washed twice, then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to obtain 2-(1-(2-(2,6-oxopiperidin-3-yl)-6-fluoro-1,3 -Dioxoisoindolin-5-yl)piperidin-1-yl)acetic acid (310 mg, crude), used directly in the next reaction.

MS(ESI)M/Z: 418.1[M+H] ⁺ .

Step 2: Add 2-(1-(2-(2,6-oxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidine at room temperature Perid-1-yl)acetic acid (119 mg, crude), (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)- 4-(Piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide hydrochloride (200 mg, 0.29 mmol), HATU (163 mg, 0.43 mmol) and DIEA (147 mg, 1.1 mmol) were sequentially added to dichloromethane (5 mL) and stirred at room temperature overnight. LCMS monitored the disappearance of the raw material, added water (20 mL) to dilute, and extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by high performance preparative liquid chromatography to obtain the final product 5-(4-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphono)quinoxaline-6) -yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)-2- Oxoethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione (40mg, two steps yield 13%).

MS(ESI)M/Z: 1062.5[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ): δ 12.77 (brs, 1H), 8.95-8.90 (m, 1H), 8.76 (d, J=1.6Hz, 1H), 8.72 (d, J=1.6Hz, 1H) ), 8.43(s, 1H), 8.26(s, 1H), 8.15(s, 1H), 7.67-7.61(m, 3H), 7.45(d, J=6.8Hz, 1H), 7.39(d, J= 7.2Hz, 1H), 6.66(s, 1H), 4.95-4.85(m, 1H), 3.90(s, 3H), 3.75(brs, 5H), 3.66-3.63(m, 2H), 3.56(brs, 2H) ), 2.89-2.65(m, 9H), 2.35-2.30(m, 2H), 2.15-2.11(m, 8H), 1.95-1.92(m, 2H), 1.47-1.44(m, 2H).

Example 83:

5-(4-(4-((4-(4-((5-bromo-4-((5-(dimethylphosphono)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino )-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)methyl)phenyl)piperazin-1-yl)-2 -(2,6-Dioxopiperidin-3-yl)isoindoline-1,3-dione

Reaction process:

Reaction steps:

Step 1: (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperazin-1-yl) )phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide hydrochloride (500 mg, 0.72 mmol) and triethylamine (454 mg, 4.5 mmol) in dichloro In ethane (10 mL) and DMF (2 mL), after stirring for 15 minutes, add 4-(4-formylphenyl)piperazine-1-carboxylate tert-butyl ester (311 mg, 1.1 mmol), stirring for 15 minutes, then adding Sodium triacetoxyborohydride (216 mg, 2.1 mmol) was stirred at room temperature overnight. TLC monitoring showed the disappearance of the starting material, water (20 mL) and ethyl acetate (50 mL) were added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (30 mL). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=50/1) to obtain 4-(4-((4-(4-(5-bromo-4-(5-(dimethylphosphine)) Acyl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazine- 1-yl)methyl)phenyl)piperazine-1-carboxylate tert-butyl ester (110 mg, 16% yield).

MS(ESI)M/Z: 936.8[M+H] ⁺ .

Step 2: 4-(4-((4-(4-(5-bromo-4-(5-(dimethylphosphono)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino) -5-Methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)methyl)phenyl)piperazine-1-carboxylate tert-butyl ester (110 mg, 0.12 mmol) was dissolved in DCM (3 mL), 6N hydrogen chloride/dioxane solution (10 mL) was added under ice bath, stirred at room temperature for 1 hour, TLC monitoring showed that the starting material disappeared, and concentrated under reduced pressure to obtain (6-(( 5-Bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(4-(piperazin-1-yl)benzyl) ) piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide hydrochloride (110 mg, crude).

MS(ESI)M/Z:836.8[M+H] ⁺ .

Step 3: (6-((5-Bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(4 -(Piperazin-1-yl)benzyl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide hydrochloride (110mg , crude product) and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (99 mg, 0.36 mmol) were dissolved in N,N-dimethyl To the base formamide (5 mL), potassium carbonate (83 mg, 0.60 mmol) and a catalytic amount of sodium iodide were added, and the reaction was heated to 80°C and stirred overnight. LCMS monitoring showed the disappearance of starting material, the reaction was cooled to room temperature, and water (20 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (20 mL×3 times), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by high performance preparative liquid chromatography to give the final product 5-(4-(4-((4-(4-((5-bromo-4-((5-(dimethylphosphono)quinoxaline- 6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)methyl ) phenyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (17.9 mg, 14% yield for two steps) ).

MS(ESI)M/Z: 1092.9[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ): δ12.59(s,1H), 8.99-8.96(m,1H), 8.75-8.71(m,2H), 8.29(s,1H), 8.22(s,1H) ,7.84(brs,1H),7.71-7.69(m,2H),7.45(brs,2H),7.37(s,1H),7.26-7.24(m,2H),7.07-7.05(m,1H),6.92 -6.90(m,2H),6.72(s,1H),4.99-4.96(m,1H),3.96-3.85(m,5H),3.70-3.55(m,9H),3.40(brs,6H),3.10 -2.63(m, 8H), 2.15(s, 3H), 2.11(s, 3H).

Example 84:

5-(3-(4-(4-(4-((5-Bromo-4-((5-(dimethylphosphono)-2,3-dihydrobenzo[b][1,4]di Oxin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl )piperidin-1-yl)azetidine-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Reaction process:

Reaction steps:

Step 1: (6-Amino-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxide (487 mg, 2.1 mmol) was dissolved in n-butyl at room temperature To the alcohol (10 mL) was added 5-bromo-2,4-dichloropyridine (977 mg, 4.3 mmol) and N,N-diisopropylethylamine (555 mg, 4.3 mmol). The reaction solution was heated to 100°C under nitrogen protection and stirred for 1 hour until the reaction was complete. The reaction solution was cooled to room temperature and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1) to obtain (6-((5-bromo-2-chloropyrimidine- 4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxide (874 mg, 98% yield).

MS(ESI)M/Z:418.0[M+H] ⁺ .

Step 2: (6-((5-Bromo-2-chloropyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl at room temperature ) dimethylphosphine oxide (824 mg, 2.0 mmol) was dissolved in n-butanol (20 mL), 1-(4-(4-amino-5-methoxy-2-(1-methyl-1H-pyrazole) was added -4-yl)phenyl)piperazin-1-yl)-2,2,2-trifluoroethane-1-one (755 mg, 2.0 mmol) and trifluoroacetic acid (2.3 g, 20.0 mmol), purged with nitrogen 2 times, the temperature was raised to 110° C. and stirred for 16 hours, and the reaction was completed by LCMS monitoring. The reaction solution was cooled to room temperature and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1) to obtain 1-(4-(4-((5-bromo- 4-((5-(Dimethylphosphono)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)pyrimidin-2-yl)amino)-5- Methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)-2,2,2-trifluoroethane-1-one (1.05 g, yield 69%).

MS(ESI)M/Z:765.1[M+H] ⁺ .

Step 3: 1-(4-(4-((5-bromo-4-((5-(dimethylphosphono)-2,3-dihydrobenzo[b][1,4]di Oxin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl )-2,2,2-trifluoroethane-1-one (950mg, 1.24mmol) was dissolved in methanol (5mL) and water (1mL), potassium hydroxide (700mg, 12.4mmol) was added, and the temperature was raised under nitrogen protection Stir at 60°C for 1 hour, and the reaction was completed by LCMS monitoring. The reaction solution was cooled to room temperature, concentrated under reduced pressure, added with water (30 mL), and extracted with dichloromethane (30 mL×3 times). The organic phases were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=8/1) to obtain ( 6-((5-Bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperazin-1-yl)phenyl)amino ) pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphorus oxide (808 mg, 97% yield).

MS(ESI)M/Z: 669.2[M+H] ⁺ .

The next step is (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperazin-1-yl) Phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphorus oxide as raw material, refer to examples The preparation of 53 and 61 gave the final product 5-(3-(4-(4-(4-((5-bromo-4-((5-(dimethylphosphono)-2,3-dihydrobenzoyl) [b][1,4]Dioxin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl) Phenyl)piperazin-1-yl)piperidin-1-yl)azetidine-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-Dione (2.0 mg).

MS(ESI)M/Z: 1063.3[M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ): δ 12.60 (s, 1H), 7.98-7.95 (m, 1H), 7.85-7.77 (m, 2H), 7.71-7.66 (m, 1H), 7.61 (s, 1H), 7.52(s, 1H), 6.83(s, 1H), 6.71(s, 1H), 6.61-6.56(m, 1H), 6.39-6.34(m, 1H), 4.96-4.92(m, 1H) ,4.30-4.18(m,7H),4.10-4.07(m,2H),3.92(s,3H),3.83(s,3H),3.78-3.75(m,1H),3.57-3.41(m,4H) ,3.33-3.28(m,6H),2.90-2.74(m,4H),2.64-2.52(m,4H),2.35-2.20(m,2H),1.90(s,3H),1.86(s,3H) .

Example 85:

5-(3-(4-(4-(4-((5-bromo-4-((4-cyclopropyl-2-(dimethylphosphono)phenyl)amino)pyrimidin-2-yl)amino )-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)piperidin-1-yl)azetidine-1- yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Reaction process:

Reaction steps:

Step 1: (2-Amino-5-cyclopropylphenyl)dimethylphosphine oxide (1.0 g, 4.8 mmol) was dissolved in n-butanol (25 mL) at room temperature, 5-bromo-2,4- Dichloropyridine (2.2 g, 9.6 mmol) and N,N-diisopropylethylamine (1.85 g, 14.3 mmol). The reaction solution was heated to 100°C under nitrogen protection and stirred for 16 hours until the reaction was complete. The reaction solution was cooled to room temperature and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/1) to obtain (2-((5-bromo-2-chloropyrimidine- 4-yl)amino)-5-cyclopropylphenyl)dimethylphosphine oxide (510 mg, 27% yield).

MS(ESI)M/Z:400.0[M+H] ⁺ .

Step 2: (2-((5-Bromo-2-chloropyrimidin-4-yl)amino)-5-cyclopropylphenyl)dimethylphosphine oxide (510 mg, 2.0 mmol) was dissolved in n-butyl at room temperature alcohol (50 mL), add 1-(4-(4-amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)- 2,2,2-Trifluoroethane-1-one (489 mg, 1.3 mmol) and trifluoroacetic acid (1.45 g, 12.7 mmol) were replaced with nitrogen twice, heated to 100° C. and stirred for 16 hours. LCMS monitored the completion of the reaction. The reaction solution was cooled to room temperature, poured into petroleum ether (50 mL), a solid was precipitated, filtered, and the obtained filter cake was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1) to obtain 1-( 4-(4-((5-Bromo-4-((4-cyclopropyl-2-(dimethylphosphono)phenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2 -(1-Methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)-2,2,2-trifluoroethane-1-one (450 mg, 46% yield).

MS(ESI) M/Z: 746.9[M+H] ⁺ .

Step 3: 1-(4-(4-((5-bromo-4-((4-cyclopropyl-2-(dimethylphosphono)phenyl)amino)pyrimidin-2-yl)amino )-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)-2,2,2-trifluoroethane-1-one (450 mg, 0.60 mmol) was dissolved in methanol (5 mL) and water (1 mL), potassium hydroxide (338 mg, 6.0 mmol) was added, the temperature was raised to 60° C. under nitrogen and stirred for 2 hours, and the reaction was completed by LCMS monitoring. The reaction solution was cooled to room temperature, concentrated under reduced pressure, added with water (30 mL), and extracted with dichloromethane (30 mL×3 times). The organic phases were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to obtain (2-((5-bromo-2-((2-methoxy-5-(1-methyl) -1H-pyrazol-4-yl)-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-cyclopropylphenyl)dimethylphosphorus oxide ( 260 mg, 66% yield).

MS(ESI)M/Z:651.2[M+H] ⁺ .

Subsequent steps were followed by (2-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperazin-1-yl) Phenyl)amino)pyrimidin-4-yl)amino)-5-cyclopropylphenyl)dimethylphosphorus oxide was used as raw material, and the final product 5-(3-(4-() was obtained with reference to the preparation method of Example 61. 4-(4-((5-Bromo-4-((4-cyclopropyl-2-(dimethylphosphono)phenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2 -(1-Methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)piperidin-1-yl)azetidin-1-yl)-2-(2,6 -Dioxopiperidin-3-yl)isoindoline-1,3-dione (10.0 mg).

MS(ESI)M/Z: 1045.1[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ): δ 12.60(s, 1H), 8.37(s, 1H), 8.28(s, 1H), 8.20(s, 1H), 7.66(d, J=8.0Hz, 1H ), 7.52-7.49(m, 2H), 7.43(d, J=6.8Hz, 1H), 7.36(d, J=7.6Hz, 2H), 7.02-6.98(m, 1H), 6.79-6.75(m, 2H), 6.55-6.53(m1H), 4.95-4.90(m, 1H), 4.12(t, J=7.2Hz, 2H), 4.03-3.95(m, 1H), 3.91(s, 3H), 3.88(s ,3H),3.65-3.35(m,4H),3.20-3.00(m,6H),2.93-2.74(m,3H),2.50-2.46(m,2H),2.28-2.00(m,8H),1.85 (s,3H),1.82(s,3H),1.25-1.20(m,1H),0.98-0.93(m,2H),0.58-0.53(m,2H).

Example 86:

3-((4-(1-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphono)quinoxalin-6-yl)amino)pyrimidine-2- yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)-2-oxoethyl)piperidine-4 -yl)-3-chlorophenyl)amino)piperidine-2,6-dione

Reaction process:

Reaction steps:

Using 4-bromo-3-chloroaniline as raw material, with reference to the preparation method of Example 54, the final product 3-((4-(1-(2-(4-(4-((5-bromo-4-(( 5-(Dimethylphosphono)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl) Phenyl)piperazin-1-yl)-2-oxoethyl)piperidin-4-yl)-3-chlorophenyl)amino)piperidine-2,6-dione (14.4 mg).

MS(ESI)M/Z: 1024.0[M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ): δ 12.56 (s, 1H), 8.97 (dd, J=9.2, 4.0 Hz, 1H), 8.73 (s, 1H), 8.71 (s, 1H), 8.29-8.19 (m,3H),7.67(s,1H),7.63-7.60(m,2H),7.39(s,1H),7.06(d,J=8.0Hz,1H),6.67(d,J=5.6Hz, 2H), 6.56(dd, J=8.0, 1.2Hz, 1H), 4.68(brs, 1H), 4.08-4.04(m, 1H), 3.89(s, 3H), 3.75(s, 3H), 3.64(s ,2H),3.49(brs,2H),3.21(brs,2H),2.98-2.85(m,6H),2.80-2.71(m,1H),2.58-2.49(m,3H),2.14(s,3H) ), 2.11(s, 3H), 2.01-1.81(m, 6H).

Example 87:

5-(3-(2-(4-(4-((5-bromo-4-((2-(dimethylphosphono)-3,4-dimethylphenyl)amino)pyrimidine-2- yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane- 7-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Reaction process:

Reaction steps:

Step 1: (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperazin-1-yl) )phenyl)amino)pyrimidin-4-yl)amino)-2,3-dimethylphenyl)dimethylphosphine oxide (200 mg, 0.31 mmol) was dissolved in DMSO (5 mL) and 2-oxo- 7-Azaspiro[3.5]nonane-7-carboxylate tert-butyl ester (116mg, 0.48mmol), 15 drops of acetic acid were added dropwise, after stirring at room temperature for 1 hour, sodium triacetoxyborohydride was slowly added under ice bath (204 mg, 0.96 mmol), and then the temperature was raised to 70°C and stirred for 12 hours. TLC monitored the disappearance of the raw materials, the reaction solution was quenched by adding saturated sodium bicarbonate (20 mL), and extracted with ethyl acetate (40 mL×2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/1) to obtain 2-(4-(4-((5-bromo-4-((2-(dimethylphosphono) )-3,4-dimethylphenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidine Azin-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl ester (60 mg, 36% yield).

MS(ESI)M/Z:862.4[M+H] ⁺ .

Step 2: Convert 2-(4-(4-((5-bromo-4-((2-(dimethylphosphono)-3,4-dimethylphenyl)amino)pyrimidin-2-yl) Amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7- Tert-butyl carboxylate (60 mg, 0.07 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (2 mL) was added under ice bath, and the mixture was stirred at room temperature for 1 hour. TLC monitored the disappearance of the raw materials, and concentrated directly under reduced pressure to obtain (6-((2-((4-(4-(7-azaspiro[3.5]nonan-2-yl)piperazin-1-yl)-2- Methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-5-bromopyrimidin-4-yl)amino)-2,3-dimethylphenyl)di Methylphosphine oxide trifluoroacetate (48 mg, crude).

MS(ESI)M/Z:762.3[M+H] ⁺ .

Step 3: (6-((2-((4-(4-(7-azaspiro[3.5]nonan-2-yl)piperazin-1-yl)-2-methoxy-5- (1-Methyl-1H-pyrazol-4-yl)phenyl)amino)-5-bromopyrimidin-4-yl)amino)-2,3-dimethylphenyl)dimethylphosphine oxide trifluoro Acetate (48 mg, 0.06 mmol) and tert-butyl 3-iodoazetidine-1-carboxylate (43 mg, 0.16 mmol) were dissolved in acetonitrile (10 mL), potassium carbonate (32 mg, 0.23 mmol) was added, After nitrogen replacement three times, the reaction system was heated to 100°C and stirred for 5 days. TLC monitoring showed that the reaction was complete, the reaction solution was cooled to room temperature, filtered and concentrated under reduced pressure. Water (20 mL) was added and extracted with ethyl acetate (20 mL x 3 times). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1) to obtain 3-(2-(4). -(4-((5-Bromo-4-((2-(dimethylphosphono)-3,4-dimethylphenyl)amino)pyrimidin-2-yl)amino)-5-methoxy -2-(1-Methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)azetidine- 1-Carboxylic acid tert-butyl ester (41 mg, 81% yield).

MS(ESI)M/Z: 917.4[M+H] ⁺ .

Step 4: 3-(2-(4-(4-((5-bromo-4-((2-(dimethylphosphono)-3,4-dimethylphenyl)amino)pyrimidine-2 -yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane -7-yl) tert-butyl azetidine-1-carboxylate (35 mg, 0.04 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (2 mL) was added under ice bath, and stirred at room temperature for 1 hour . LCMS monitoring showed that the reaction was complete, and concentrated under reduced pressure to obtain (6-((2-((4-(4-(7-(azetidin-3-yl)-7-azaspiro[3.5]nonane- 2-yl)piperazin-1-yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-5-bromopyrimidin-4-yl) Amino)-2,3-dimethylphenyl)dimethylphosphine oxide as trifluoroacetate salt (27 mg, crude).

MS(ESI)M/Z:817.3[M+H] ⁺ .

Step 5: (6-((2-((4-(4-(7-(azetidin-3-yl)-7-azaspiro[3.5]nonan-2-yl) Piperazin-1-yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-5-bromopyrimidin-4-yl)amino)-2 ,3-Dimethylphenyl) dimethylphosphine oxide trifluoroacetate (27 mg, crude) and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindone Doline-1,3-dione (22 mg, 0.08 mmol) was dissolved in DMSO (3 mL), DIEA (42 mg, 0.33 mmol) and a catalytic amount of sodium iodide were added and the reaction was heated to 60°C and stirred overnight. TLC monitoring showed that the raw materials disappeared, the reaction solution was cooled to room temperature, and purified by high performance liquid chromatography to obtain the final product 5-(3-(2-(4-(4-((5-bromo-4-(((2-( Dimethylphosphono)-3,4-dimethylphenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl ) phenyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)azetidin-1-yl)-2-(2,6-dioxopiperidine- 3-yl)isoindoline-1,3-dione (3.2 mg, 7.8% over two steps).

MS(ESI) M/Z: 1073.4[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ 12.08(s,1H), 11.10(s,1H), 10.26(s,1H), 8.27(brs,1H), 8.17(s,1H), 8.04 (s,1H),7.90-7.83(m,2H),7.75(d,J=8.0Hz,1H),7.68(s,1H),6.92(s,1H),6.78-6.75(m,2H), 6.66(s, 1H), 5.11-5.06(m, 1H), 4.36-4.25(m, 5H), 3.90-3.80(m, 8H), 3.25-3.20(m, 4H), 3.15-3.00(m, 3H ),2.99-2.85(m,6H),2.60-2.50(m,2H),2.25(s,3H),2.09(s,3H),2.05-2.00(m,4H),1.91(s,3H), 1.87(s,3H),1.83-1.75(m,4H).

Example 88:

5-(3-(2-(4-(4-((5-bromo-4-((4-cyclopropyl-2-(dimethylphosphono)phenyl)amino)pyrimidin-2-yl) Amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7- yl)azetidine-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Reaction process:

Reaction steps:

With (2-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperazin-1-yl)phenyl ) amino) pyrimidin-4-yl) amino)-5-cyclopropylphenyl) dimethyl phosphine oxide as raw material, with reference to the preparation method of Example 87 to obtain the final product 5-(3-(2-(4-( 4-((5-Bromo-4-((4-cyclopropyl-2-(dimethylphosphono)phenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-( 1-Methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)azetidin-1-yl) -2-(2,6-Dioxypiperidin-3-yl)isoindoline-1,3-dione (7.2 mg).

MS(ESI)M/Z: 1085.3[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ): δ 10.58(s,1H), 8.40-8.36(m,1H), 8.27(s,1H), 8.20(s,1H), 8.01(s,1H), 7.93 (s,1H),7.64(d,J=8.4Hz,1H),7.32-7.30(m,2H),7.02-6.98(m,1H),6.78(brs,2H),6.70(s,1H), 6.54-6.51(m, 1H), 4.95-4.90(m, 1H), 4.10-4.08(m, 2H), 3.91(s, 3H), 3.87(s, 3H), 3.60-3.41(m, 5H), 3.31(brs,2H),3.17-3.14(m,2H),2.91-2.80(m,2H),2.76-269(m,4H),2.37-2.11(m,8H),2.12-1.89(m,2H) ),1.85(s,3H),1.81(s,3H),1.68(brs,4H),0.98-0.96(m,2H),0.60-0.58(m,2H).

Example 89:

5-(3-(2-(4-(4-((5-Bromo-4-(((5-(dimethylphosphono)-2,3-dihydrobenzo[b][1,4]) Dioxin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazine-1- yl)-7-azaspiro[3.5]nonan-7-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-Dione

Reaction process:

Reaction steps:

With (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperazin-1-yl)phenyl ) amino)pyrimidin-4-yl)amino)-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxide as raw material, and the final product was obtained with reference to the preparation method of Example 87 5-(3-(2-(4-(4-((5-Bromo-4-(((5-(dimethylphosphono)-2,3-dihydrobenzo[b][1,4]) Dioxin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazine-1- yl)-7-azaspiro[3.5]nonan-7-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-Dione (2.2 mg).

MS(ESI)M/Z: 1103.3[M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.99-7.95 (m, 1H), 7.89-7.80 (m, 2H), 7.70-7.65 (m, 1H), 7.62-7.55 (m, 1H), 7.52- 7.48(m,1H),6.87-6.79(m,1H),6.73-6.68(m,1H),6.63-6.57(m,1H),6.42-6.34(m,1H),4.98-4.91(m,1H) ),4.42-4.20(m,9H),3.91(s,3H),3.83(s,3H),3.64-3.42(m,5H),3.30-3.18(m,5H),3.05-2.73(m,7H ),2.58-2.47(m,4H),2.25-1.99(m,4H),1.90(s,3H),1.86(s,3H).

Example 90:

5-(4-(2-(4-(4-((5-bromo-4-((2-(dimethylphosphono)-4-methylphenyl)amino)pyrimidin-2-yl)amino) -5-Methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-2-(2, 6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione

Reaction process:

Reaction steps:

Step 1: (2-Amino-5-methylphenyl)dimethylphosphine oxide (8.1 g, crude, about 37.6 mmol) was dissolved in N-methylpyrrolidone (80 mL) at room temperature, 5-bromo- 2,4-Dichloropyridine (15.1 g, 66.3 mmol) and N,N-diisopropylethylamine (11.4 g, 88.4 mmol). The reaction solution was heated to 80°C under nitrogen protection and stirred for 4 hours until the reaction was complete. The reaction solution was cooled to room temperature, water (500 mL) was added, and the mixture was extracted with ethyl acetate (150 mL×3 times). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=90/1) to obtain (2 -((5-Bromo-2-chloropyrimidin-4-yl)amino)-5-methylphenyl)dimethylphosphine oxide (10.0 g, 71% yield).

MS(ESI) M/Z: 373.9[M+H] ⁺ .

Step 2: (2-((5-Bromo-2-chloropyrimidin-4-yl)amino)-5-methylphenyl)dimethylphosphine oxide (508 mg, 1.4 mmol) was dissolved in n-butanol at room temperature (15 mL), add 1-(4-(4-amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)-2 , 2,2-trifluoroethane-1-one (400 mg, 1.0 mmol) and trifluoroacetic acid (1.2 g, 10.4 mmol) were replaced with nitrogen twice, and the temperature was raised to 100 °C and stirred overnight. The reaction was completed by LCMS monitoring. The reaction solution was cooled to room temperature, water (200 mL) was added, and the mixture was extracted with ethyl acetate (100 mL×3 times). The organic phases were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/1) to obtain 1 -(4-(4-((5-Bromo-4-((2-(dimethylphosphono)-4-methylphenyl)amino)pyrimidin-2-yl)amino)-5-methoxy- 2-(1-Methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)-2,2,2-trifluoroethane-1-one (519 mg, 69% yield) .

MS(ESI)M/Z:721.1[M+H] ⁺ .

Step 3: 1-(4-(4-((5-bromo-4-((2-(dimethylphosphono)-4-methylphenyl)amino)pyrimidin-2-yl)amino) at room temperature -5-Methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)-2,2,2-trifluoroethane-1-one ( 519 mg, 0.72 mmol) was dissolved in methanol (10 mL) and water (2 mL), sodium hydroxide (287 mg, 7.2 mmol) was added, the temperature was raised to 60° C. and stirred for 1 hour under nitrogen protection, and the reaction was completed by LCMS monitoring. The reaction solution was cooled to room temperature, water (50 mL) was added, and the mixture was extracted with dichloromethane (50 mL×3 times). The organic phases were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to obtain (2-((5-bromo-2-((2-methoxy-5-(1-methyl) -1H-pyrazol-4-yl)-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-methylphenyl)dimethylphosphorus oxide (442mg , the yield is 98%).

MS(ESI)M/Z: 625.2[M+H] ⁺ .

Step 4: (2-((5-Bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperazine-1 -yl)phenyl)amino)pyrimidin-4-yl)amino)-5-methylphenyl)dimethylphosphorus oxide (50 mg, 0.08 mmol) and 2-(1-(2-(2,6- Oxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)ethylmethanesulfonate (48 mg, 0.10 mmol) dissolved in In acetonitrile (5 mL), DIEA (103 mg, 0.80 mmol) and a catalytic amount of sodium iodide were added, and the reaction was heated to 100 °C and stirred overnight. LCMS monitoring showed the disappearance of starting material, the reaction was cooled to room temperature, and water (20 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (20 mL×3 times), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained residue was purified by preparative thin layer chromatography (eluent: dichloromethane/methanol=10/1) to give the final product 5-(4-(2-(4-(4-((5-bromo-4- ((2-(Dimethylphosphono)-4-methylphenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazole-4- yl)phenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1 ,3-dione (16.6 mg, 20% yield).

MS(ESI)M/Z: 1010.3[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ): δ 10.53 (s, 1H), 8.34 (dd, J=8.6, 4.6 Hz, 1H), 8.25 (s, 1H), 8.19 (s, 1H), 8.02 (s ,1H),7.77(s,1H),7.65(s,1H),7.45(d,J=11.2Hz,1H),7.38(s,J=7.2Hz,1H),7.28(s,1H),7.05 -7.01(m,1H),6.85-6.79(m,1H),6.73(s,1H),4.95-4.91(m,1H),3.88(s,3H),3.87(s,3H),3.66-3.63 (m,2H),3.02-2.68(m,10H),2.65-2.44(m,5H),2.25(s,3H),2.19-2.11(m,1H),1.85-1.81(m,2H),1.84 (s,3H),1.81(s,3H),1.58-1.35(m,5H).

Example 91:

5-(4-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphono)quinolin-6-yl)amino)pyrimidin-2-yl)amino)- 5-Methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-2-(2,6 -Dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione

Reaction process:

Reaction steps:

Using (6-aminoquinolin-5-yl) dimethyl phosphine oxide as raw material, referring to the preparation method of Example 90, the final product 5-(4-(2-(4-(4-((5-bromo- 4-((5-(Dimethylphosphono)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazole-4 -yl)phenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline- 1,3-Dione (45.8 mg).

MS(ESI)M/Z: 1047.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ 12.38(brs,1H), 11.12(s,1H), 8.78(s,1H), 8.55-8.50(m,1H), 8.44-8.42(m, 1H), 8.28(brs, 1H), 8.22(s, 1H), 7.95(s, 1H), 7.83(s, 1H), 7.73-7.70(m, 1H), 7.56-7.44(m, 4H), 6.81 (s,1H),5.13-5.08(m,1H),3.80(s,3H),3.77(s,3H),3.63-3.60(m,2H),3.35-3.20(m,2H),2.89-2.85 (m,8H),2.65-2.40(m,5H),2.05-2.02(m,7H),1.84-1.81(m,2H),1.60-1.45(m,3H),1.40-1.30(m,2H) .

Example 92:

5-(4-(2-(4-(4-((5-bromo-4-((2-(dimethylphosphono)-3,4-dimethylphenyl)amino)pyrimidin-2-yl )amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-2- (2,6-Dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione

Reaction process:

Reaction steps:

Using (6-amino-2,3-dimethylphenyl) dimethyl phosphine oxide as raw material, referring to the preparation method of Example 90, the final product 5-(4-(2-(4-(4-(( 5-Bromo-4-((2-(dimethylphosphono)-3,4-dimethylphenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl) yl)-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)- 6-Fluoroisoindoline-1,3-dione (32.8 mg).

MS(ESI)M/Z: 1024.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ 12.19(s,1H), 11.12(s,1H), 9.57(brs,1H), 8.45(brs,1H), 8.19(s,1H), 8.05 (s,1H),7.88-7.85(m,2H),7.75-7.72(m,1H),7.66(s,1H),7.48(d,J=7.2Hz,1H),6.76(s,1H), 6.64(brs,1H),5.14-5.10(m,1H),3.88(s,3H),3.84(s,3H),3.65-3.23(m,4H),3.01-2.83(m,8H),2.66- 2.40(m,5H),2.25(s,3H),2.10-1.95(m,4H),1.91(s,3H),1.88(s,3H),1.83(brs,2H),1.71(brs,2H) ,1.60(brs,1H),1.44-1.34(m,2H).

Example 93:

5-(4-(2-(4-(4-((5-bromo-4-((4-cyclopropyl-2-(dimethylphosphono)phenyl)amino)pyrimidin-2-yl)amino )-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-2-(2 ,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione

Reaction process:

Reaction steps:

Using (2-amino-5-cyclopropylphenyl) dimethyl phosphine oxide as raw material, referring to the preparation method of Example 90, the final product 5-(4-(2-(4-(4-(((5- Bromo-4-((4-cyclopropyl-2-(dimethylphosphono)phenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H- Pyrazol-4-yl)phenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroiso Indoline-1,3-dione (37.5 mg).

MS(ESI)M/Z: 1036.3[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ 11.11(s,1H), 11.04(s,1H), 9.54(brs,1H), 8.46(brs,1H), 8.20(s,1H), 8.14 (brs,1H),8.02(s,1H),7.95(s,1H),7.76-7.67(m,2H),7.47(d,J=7.2Hz,1H),7.24-7.20(m,1H), 6.76(s,1H),6.45(brs,1H),5.13-5.08(m,1H),3.86(s,3H),3.83(s,3H),3.66-3.56(m,4H),3.31-3.21( m,6H),3.03-2.86(m,5H),2.69-2.53(m,3H),2.08-2.00(m,1H),1.84-1.72(m,2H),1.77(s,3H),1.74( s,3H),1.73-1.67(m,2H),1.59(brs,1H),1.42-1.34(m,2H),0.94-0.88(m,2H),0.56-0.51(m,2H).

Example 94:

5-(4-(2-(4-(4-((5-Bromo-4-((5-(dimethylphosphono)-2,3-dihydrobenzo[b][1,4]di Oxin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl )ethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione

Reaction process:

Reaction steps:

Using (6-amino-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethylphosphine oxide as raw material, referring to the preparation method of Example 90, the final product 5- (4-(2-(4-(4-((5-Bromo-4-(((5-(dimethylphosphono)-2,3-dihydrobenzo[b][1,4]dioxin) -6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)ethyl yl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione (7.8 mg).

MS(ESI)M/Z: 1054.3[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ 11.63(s, 1H), 11.10(s, 1H), 8.12-8.08(m, 2H), 8.02(s, 1H), 7.94-7.87(m, 1H), 7.80(s, 1H), 7.72-7.68(m, 1H), 7.58(s, 1H), 7.45(d, J=7.6Hz, 1H), 6.81(s, 1H), 6.44-6.34(m ,1H),5.12-5.08(m,1H),4.31-4.20(m,4H),3.84(s,3H),3.79(s,3H),3.60-3.30(m,4H),2.93-2.88(m ,8H),2.50-2.40(m,5H),2.08-1.80(m,1H),1.90-1.80(m,8H),1.60-1.40(m,3H),1.35-1.20(m,2H).

Example 95:

5-(4-(2-(4-(4-((5-bromo-4-((2-(dimethylphosphono)-4-fluorophenyl)amino)pyrimidin-2-yl)amino)- 5-Methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-2-(2,6 -Dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione

Reaction process:

Reaction steps:

Using (2-amino-5-fluorophenyl) dimethyl phosphine oxide as raw material, referring to the preparation method of Example 90, the final product 5-(4-(2-(4-(4-((5-bromo- 4-((2-(Dimethylphosphono)-4-fluorophenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazole-4 -yl)phenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline- 1,3-Dione (32.4 mg).

MS(ESI)M/Z: 1014.2[M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ): δ 10.39 (s, 1H), 8.39-8.33 (m, 1H), 8.19 (d, J=7.2 Hz, 2H), 8.04 (s, 1H), 7.74 (s ,1H),7.62(s,1H),7.46(d,J=11.2Hz,1H),7.38(d,J=7.2Hz,1H),7.31(s,1H),6.97-6.90(m,1H) ,6.73(s,1H),6.59(brs,1H),4.95-4.91(m,1H),3.91(s,3H),3.89(s,3H),3.66-3.63(m,2H),2.98-2.63 (m,10H),2.56-2.42(m,5H),2.16-2.11(m,1H),1.86-1.82(m,8H),1.58-1.40(m,5H).

Example 96:

3-(5-(4-(2-(4-(4-(5-bromo-4-(5-(dimethylphosphono)quinoxalin-6-yl)amino)pyrimidin-2-yl) Amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-6-fluoro -1-oxoisoindolin-2-yl)piperidine-2,6-dione

Reaction process:

Reaction steps:

Step 1: Methyl 4,5-difluoro-2-methylbenzoate (500 mg, 2.7 mmol) was dissolved in 1,2-dichloroethane (10 mL) at room temperature, and azobisisobutyronitrile ( 22 mg, 0.13 mmol). The reaction solution was heated to 80°C under nitrogen protection and stirred for 20 hours until the reaction was complete. The reaction solution was cooled to room temperature and quenched by the addition of saturated aqueous sodium thiosulfate solution (10 mL). The mixture was extracted with dichloromethane (20 mL×3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=20/1) to obtain methyl 2-(bromomethyl)-4,5-difluorobenzoate (741 mg, crude).

MS(ESI)M/Z: 265.0[M+H] ⁺ .

Step 2: Methyl 2-(bromomethyl)-4,5-difluorobenzoate (741 mg, crude) was dissolved in acetonitrile (10 mL) at room temperature, 3-aminopiperidine-2,6-dione was added The hydrochloride salt (506 mg, 3.1 mmol) and DIEA (542 mg, 4.2 mmol). The reaction solution was heated to 80°C under nitrogen protection and stirred for 20 hours until the reaction was complete. The reaction solution was cooled to room temperature, water (50 mL) and ethyl acetate (50 mL) were added, the layers were separated, the organic phase was washed with saturated brine (50 mL) once, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to obtain 3- (5,6-Difluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (750 mg, 99% over two steps).

MS(ESI)M/Z: 281.1[M+H] ⁺ .

Step 3: 3-(5,6-Difluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (2.0 g, 7.1 mmol) was dissolved in DMSO (20 mL) at room temperature ), 2-(piperidin-4-yl)ethanol (2.8 g, 21.4 mmol) and triethylamine (2.2 g, 21.4 mmol) were added, and the temperature was raised to 80° C. and stirred for 20 hours under nitrogen protection. The disappearance of the starting material was monitored by TLC, the reaction solution was cooled to room temperature, diluted with water (50 mL), and extracted four times with ethyl acetate (50 mL). The organic phases were combined, washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=50/1). yielded 3-(6-fluoro-5-(4-(2-hydroxyethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (0.9 g, 33% yield).

MS(ESI) M/Z: 389.6[M+H] ⁺ .

Step 4: 3-(6-Fluoro-5-(4-(2-hydroxyethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidin-2,6 -Diketone (500 mg, 1.3 mmol) and triethylamine (261 mg, 2.6 mmol) were dissolved in dichloromethane (20 mL), methanesulfonyl chloride (220 mg, 1.9 mmol) was added dropwise under ice bath, and the mixture was stirred at room temperature for 2 hours. The disappearance of the starting material was monitored by TLC, quenched by adding water (50 mL), and extracted three times with dichloromethane (50 mL). The organic phases were combined, washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=50/1). to give 2-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperidin-4-yl)ethane Methanesulfonate (89 mg, 15% yield).

MS(ESI)M/Z: 468.2[M+H] ⁺ .

Step 5: (6-((5-Bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperazine-1 -yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide hydrochloride (126 mg, 0.18 mmol) and 2-(1-(2-(2, 6-Dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperidin-4-yl)ethylmethanesulfonate (89 mg, 0.19 mmol) dissolved in In acetonitrile (10 mL), DIEA (74 mg, 0.57 mmol) and a catalytic amount of sodium iodide were added and the reaction was heated to 80°C and stirred overnight. LCMS monitoring showed the disappearance of starting material, the reaction was cooled to room temperature, and water (50 mL) was added to quench the reaction. The mixture was extracted with dichloromethane (50 mL×3 times), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained residue was purified by high performance preparative liquid chromatography to give the final product 3-(5-(4-(2-(4-(4-(5-bromo-4-(5-(dimethylphosphono)quinoxaline)) -6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)ethyl yl)piperidin-1-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (23.2 mg, 12% yield).

MS(ESI)M/Z: 1034.3[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ): δ 13.73(s,1H), 12.72(s,1H), 8.86(s,1H), 8.79(s,1H), 8.65-8.64(m,1H), 8.05 -8.02(m,2H),7.75(s,1H),7.65-7.62(m,1H),7.52-7.50(m,2H),6.75(s,1H),5.18-5.14(m,1H),4.48 -4.35(m, 2H), 3.85(s, 6H), 3.66-3.60(m, 6H), 3.35-2.80(m, 9H), 2.40-2.20(m, 3H), 2.16(s, 3H), 2.14 (s,3H),2.10-1.50(m,7H).

Example 97:

3-((4-(1-(2-(4-(4-((5-bromo-4-((2-(dimethylphosphono)-3,4-dimethylphenyl)amino)) pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)-2-oxoethyl) piperidin-4-yl)-3-fluorophenyl)amino)piperidine-2,6-dione

Reaction process:

Reaction steps:

2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-1-yl)acetic acid hydrochloride (50 mg , about 0.13 mmol), (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperazine-1 -yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dimethylphenyl)dimethylphosphine oxide (78 mg, 0.12 mmol), HATU (91 mg, 0.24 mmol) and DIEA (78 mg) , 0.60 mmol) was successively added to DMF (3 mL), the temperature was raised to 35 °C and stirred for 30 minutes. LCMS monitored the disappearance of the raw material, added water (30 mL) to dilute, and extracted with ethyl acetate (30 mL×3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by high performance preparative liquid chromatography to obtain the final product 3-((4-(1-(2-(4-(4-((5-bromo-4-((2-(dimethylphosphono)) -3,4-Dimethylphenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazine -1-yl)-2-oxoethyl)piperidin-4-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (21.6 mg, 18% yield).

MS(ESI)M/Z: 982.2[MH] ⁺ .

¹ H NMR (400MHz, CDCl ₃ /CD ₃ OD): δ 8.18(s, 1H), 8.14(s, 1H), 8.10-8.06(m, 1H), 7.70(s, 1H), 7.63(s, 1H), 6.92(t, J=8.0Hz, 1H), 6.80(d, J=7.2Hz, 1H), 6.68(s, 1H), 6.44-6.39(m, 2H), 4.13-4.09(m, 1H) ),3.88(s,6H),3.84-3.66(m,4H),3.57(brs,2H),3.45-3.39(m,3H),2.93-2.80(m,7H),2.48-2.38(m,1H ), 2.31(s, 3H), 2.13(s, 3H), 2.00(s, 3H), 1.97(s, 3H), 1.94-1.76(m, 6H).

Example 98:

3-((4-(1-(2-(4-(4-((5-bromo-4-((2-(dimethylphosphono)-4-methylphenyl)amino)pyrimidine-2 -yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)-2-oxoethyl)piperidine- 4-yl)-3-fluorophenyl)amino)piperidine-2,6-dione

Reaction process:

Reaction steps:

2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-1-yl)acetic acid hydrochloride (35mg , 0.09mmol), (2-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperazine-1- yl)phenyl)amino)pyrimidin-4-yl)amino)-5-methylphenyl)dimethylphosphine oxide (63 mg, 0.10 mmol), HATU (54 mg, 0.14 mmol) and DIEA (37 mg, 0.29 mmol) It was sequentially added to DMF (2 mL) and stirred at room temperature for 2 hours. LCMS monitored the disappearance of the raw materials, added water (20 mL) to dilute, a solid was precipitated, filtered, and the filter cake was purified by preparative thin layer chromatography (eluent: dichloromethane/methanol=10/1) to obtain the final product 3-((4 -(1-(2-(4-(4-((5-Bromo-4-((2-(dimethylphosphono)-4-methylphenyl)amino)pyrimidin-2-yl)amino) -5-Methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)-2-oxoethyl)piperidin-4-yl)- 3-Fluorophenyl)amino)piperidine-2,6-dione (18.7 mg, 21% yield).

MS(ESI)M/Z: 970.0[M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ): δ 10.55 (s, 1H), 8.34 (dd, J=8.4, 4.4 Hz, 1H), 8.29 (s, 1H), 8.20 (s, 1H), 7.90 (s ,1H),7.77(s,1H),7.64(s,1H),7.31(s,1H),7.07-7.02(m,2H),6.84-6.81(m,1H),6.65(s,1H), 6.41(dd,J=8.2,2.2Hz,1H),6.33(dd,J=12.4,2.4Hz,1H),4.71-4.70(m,1H),4.06-4.01(m,1H),3.89(s, 3H), 3.88(s, 3H), 3.74-3.70(m, 4H), 3.27-3.22(brs, 2H), 3.03-2.99(m, 2H), 2.91-2.86(m, 5H), 2.80-2.71( m, 2H), 2.56-2.51(m, 1H), 2.26(s, 3H), 2.30-2.10(m, 1H), 1.85(s, 3H), 1.81(s, 3H), 1.95-1.75(m, 5H).

Example 99:

3-((4-(1-(2-(4-(4-((5-bromo-4-((2-(dimethylphosphono)-4-fluorophenyl)amino)pyrimidine-2- yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)-2-oxoethyl)piperidine-4 -yl)-3-fluorophenyl)amino)piperidine-2,6-dione

Reaction process:

Reaction steps:

2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-1-yl)acetic acid hydrochloride (56 mg , 0.14mmol), (2-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperazine-1- yl)phenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)dimethylphosphine oxide (75 mg, 0.12 mmol), HATU (68 mg, 0.18 mmol) and DIEA (31 mg, 0.24 mmol) sequentially It was added to DMF (3 mL) and stirred at room temperature for 1 hour. LCMS monitored the disappearance of the raw material, added water (20 mL) to dilute, and extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by high performance preparative liquid chromatography to obtain the final product 3-((4-(1-(2-(4-(4-((5-bromo-4-((2-(dimethylphosphono)) -4-Fluorophenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl )-2-oxoethyl)piperidin-4-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (22.3 mg, 19% yield).

MS(ESI)M/Z: 974.1[M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.78 (d, J=3.2 Hz, 2H), 8.30 (brs, 1H), 8.21 (d, J=3.2 Hz, 1H), 8.18 (s, 1H) ), 8.12(s, 1H), 7.81(s, 1H), 7.64(s, 1H), 7.43-7.35(m, 1H), 6.96(t, J=8.6Hz, 1H), 6.79(s, 1H) ,6.68(brs,1H),6.44(s,1H),6.40(s,1H),5.99(d,J=7.6Hz,1H),4.33-4.26(m,1H),3.86(s,3H), 3.79(s,3H),3.74-3.71(m,2H),3.63(brs,2H),3.19(s,2H),2.95-2.87(m,4H),2.81-2.50(m,5H),2.14- 2.05(m,3H),1.93-1.82(m,1H),1.79(s,3H),1.76(s,3H),1.65(brs,4H).

Embodiment 100:

5-(3-(4-((4-(4-((5-bromo-4-((5-(dimethylphosphono)quinolin-6-yl)amino)pyrimidin-2-yl)amino) -5-Methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)azetidine-1 -yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Reaction process:

Reaction steps:

With (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperazin-1-yl)phenyl ) amino) pyrimidin-4-yl) amino) quinolin-5-yl) dimethyl phosphine oxide and 4-formyl piperidine-1-carboxylic acid tert-butyl ester as raw materials, with reference to the operation steps of Examples 49 and 35 The final product 5-(3-(4-((4-(4-((5-bromo-4-((5-(dimethylphosphono)quinolin-6-yl)amino)pyrimidine-2- yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)aza Cyclobutan-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (14.9 mg).

MS(ESI)M/Z: 1069.9[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ 12.37(s, 1H), 11.08(s, 1H), 8.78(d, J=3.6Hz, 1H), 8.58-8.52(m, 1H), 8.44 (d, J=9.6Hz, 1H), 8.27(s, 1H), 8.22(s, 1H), 7.96(s, 1H), 7.83(s, 1H), 7.66(d, J=8.0Hz, 1H) ,7.60-7.49(m,3H),6.81(brs,2H),6.67-6.65(m,1H),5.10-5.04(m,1H),4.66(brs,8H),4.12(brs,2H),3.85 -3.75(m,8H),2.87(brs,7H),2.20(brs,3H),2.10-1.96(m,8H),1.90-1.70(m,4H).

Example 101:

5-(3-(4-((4-(4-((5-bromo-4-((4-cyclopropyl-2-(dimethylphosphono)phenyl)amino)pyrimidin-2-yl) Amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)azetidine -1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Reaction process:

Reaction steps:

With (2-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperazin-1-yl)phenyl ) amino) pyrimidin-4-yl) amino)-5-cyclopropylphenyl) dimethyl phosphine oxide and 4-formyl piperidine-1-carboxylic acid tert-butyl ester as raw materials, with reference to Examples 49 and 35 The final product 5-(3-(4-((4-(4-((5-bromo-4-((4-cyclopropyl-2-(dimethylphosphono)phenyl)amino)) pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)methyl)piperidine-1- yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (17.2 mg).

MS(ESI)M/Z: 1059.1[M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ): δ 10.51 (s, 1H), 8.32-8.29 (m, 1H), 8.20 (s, 1H), 8.13 (s, 1H), 7.88 (brs, 1H), 7.58 (d, J＝8.0Hz, 1H), 7.26(s, 1H), 6.95-6.90(m, 1H), 6.72-6.64(m, 3H), 6.47(d, J＝8.8Hz, 1H), 4.8- 4.84(m, 1H), 4.08-4.01(m, 2H), 3.83(s, 3H), 3.80(s, 3H), 3.67-3.26(m, 5H), 3.10-3.03(m, 2H), 2.92- 2.64(m, 10H), 2.09-2.03(m, 2H), 2.01-1.92(m, 5H), 1.78(s, 3H), 1.75(s, 3H), 1.50-1.25(m, 3H), 0.90- 0.88(m,2H),0.53-0.49(m,2H).

Example 102:

5-(3-(4-((4-(4-((5-bromo-4-((2-(dimethylphosphono)-4-fluorophenyl)amino)pyrimidin-2-yl)amino) -5-Methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)azetidine-1 -yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Reaction process:

Reaction steps:

Step 1: Ethyl piperidine-4-carboxylate (8.9 g, 56.6 mmol) and N-tert-butoxycarbonyl-3-azetidinone (9.7 g, 56.6 mmol) were dissolved in tetrahydrofuran (180 mL) at room temperature , sodium triacetoxyborohydride (36.0 g, 169.8 mmol) was slowly added under an ice bath. The reaction system was stirred at room temperature for 16 hours, and LC-MS indicated that the reaction was complete. Saturated aqueous sodium bicarbonate solution (300 mL) was slowly added to the reaction solution to quench, and the mixture was extracted with ethyl acetate (100 mL×3 times). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=30/1) to obtain 1-(1-(tert-butoxycarbonyl)azetidin-3-yl) Ethyl piperidine-4-carboxylate (16.0 g, 90% yield).

MS(ESI)M/Z: 313.2[M+H] ⁺ .

Step 2: Under nitrogen protection, tetrahydrofuran (170 mL) was cooled to 0 °C, lithium aluminum hydride (2.9 g, 76.8 mmol) was slowly added, and after stirring for 10 minutes, 1-(1-(tert-butoxycarbonyl) nitrogen was slowly added dropwise Hetetan-3-yl)piperidine-4-carboxylic acid ethyl ester (16.0 g, 51.3 mmol) in tetrahydrofuran (30 mL), the reaction system was stirred at 0°C for 1 hour. TLC showed the reaction was complete, the reaction was quenched with sodium sulfate decahydrate at 0°C and filtered. The filtrate was concentrated under reduced pressure to obtain tert-butyl 3-(4-(hydroxymethyl)piperidin-1-yl)azetidine-1-carboxylate (10.5 g, yield 76%).

MS(ESI)M/Z: 271.2[M+H] ⁺ .

Step 3: Combine tert-butyl 3-(4-(hydroxymethyl)piperidin-1-yl)azetidine-1-carboxylate (10.5 g, 38.9 mmol) and imidazole (5.5 g, 81.2 mmol) at room temperature ) was dissolved in dichloromethane (200 mL), tert-butyldiphenylchlorosilane (15.2 g, 55.4 mmol) was slowly added in an ice bath, and the reaction system was stirred at room temperature for 16 hours. LC-MS showed that the reaction was completed, and water (300 mL) was added to the reaction solution, followed by extraction with ethyl acetate (100 mL×3 times). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3/1) to obtain 3-(4-((tert-butyldiphenylsiloxy)methyl)piperidine-1 -yl)azetidine-1-carboxylate tert-butyl ester (17.2 g, 87% yield).

MS(ESI) M/Z: 509.3[M+H] ⁺ .

Step 4: tert-butyl 3-(4-((tert-butyldiphenylsiloxy)methyl)piperidin-1-yl)azetidine-1-carboxylate (17.2 g, 33.8 mmol) was dissolved in dichloromethane (200 mL), and trifluoroacetic acid (25.9 mL, 338 mmol) was slowly added under an ice bath. The reaction system was stirred at room temperature for 5 hours, and LC-MS indicated that the reaction was complete. The reaction solution was concentrated under reduced pressure, neutralized by adding saturated aqueous sodium bicarbonate solution (400 mL), and extracted with dichloromethane (150 mL×3 times). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/tetrahydrofuran=10/1) to obtain 1-(azetidin-3-yl)-4-((tert-butyldiphenylsiloxane) yl)methyl)piperidine (13.2 g, 96% yield).

MS(ESI) M/Z: 409.3[M+H] ⁺ .

Step 5: Combine 1-(azetidin-3-yl)-4-((tert-butyldiphenylsiloxy)methyl)piperidine (2.0 g, 4.9 mmol) and 2-(2 ,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (1.35 g, 4.9 mmol) was dissolved in dimethyl sulfoxide (20 mL), N, N-Diisopropylethylamine (6.3 g, 49.0 mmol). The reaction system was heated to 140°C and stirred for 30 minutes. LC-MS showed the disappearance of the starting material, the reaction solution was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (50 mL×3 times). The organic phases were combined, washed with saturated brine (50 mL×3 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1/1) to obtain 5-(3-(4-((tert-butyldiphenylsiloxy)methyl)piperidine) Perid-1-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (1.5 g, yield 46%).

MS(ESI)M/Z: 665.3[M+H] ⁺ .

Step 6: Convert 5-(3-(4-((tert-butyldiphenylsiloxy)methyl)piperidin-1-yl)azetidin-1-yl)-2-(2,6 -Dioxopiperidin-3-yl)isoindoline-1,3-dione (1.3g, 1.95mmol) was dissolved in tetrahydrofuran (15mL), and a solution of tetrabutylammonium fluoride in tetrahydrofuran was added under ice bath (1M, 3.9 mL, 3.9 mmol). The reaction system was stirred at room temperature for 2 hours. LC-MS showed the disappearance of the starting material, water (20 mL) was added to the reaction solution to dilute, and the mixture was extracted with ethyl acetate (20 mL×3 times). The organic phases were combined, washed with saturated brine (20 mL×3 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=30/1) to obtain 2-(2,6-dioxopiperidin-3-yl)-5-(3-(4 -(Hydroxymethyl)piperidin-1-yl)azetidin-1-yl)isoindoline-1,3-dione (630 mg, 76% yield).

MS(ESI)M/Z: 427.1[M+H] ⁺ .

Step 7: Under nitrogen protection, oxalyl chloride (66 mg, 0.52 mmol) was dissolved in dry dichloromethane (3 mL), cooled to -78°C, dimethyl sulfoxide (81 mg, 1.04 mmol) was added dropwise, and after stirring for 10 minutes , and then dropwise added 2-(2,6-dioxopiperidin-3-yl)-5-(3-(4-(hydroxymethyl)piperidin-1-yl)azetidin-1-yl ) isoindoline-1,3-dione (200 mg, 0.47 mmol) in dry dichloromethane (2 mL). The reaction system was continued to stir at -78°C for 1 hour, then triethylamine (238 mg, 2.35 mmol) was added dropwise and stirred for 10 minutes. LC-MS showed that the starting material disappeared, the reaction solution was naturally warmed to room temperature, diluted with water (10 mL), and extracted with dichloromethane (10 mL×3 times). The organic phases were combined, washed with saturated brine (10 mL×3 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=40/1) to obtain 1-(1-(2-(2,6-dioxopiperidin-3-yl)-1) ,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperidine-4-carbaldehyde (80 mg, 40% yield).

MS(ESI)M/Z: 425.0[M+H] ⁺ .

Step 8: Convert 1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3 -yl)piperidine-4-carbaldehyde (40 mg, 0.094 mmol) and (2-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazole-4- yl)-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)dimethylphosphine oxide (59 mg, 0.094 mmol) was dissolved in tetrahydrofuran/N, To N-dimethylformamide (2.7 mL/0.3 mL), sodium triacetoxyborohydride (60 mg, 0.28 mmol) was added under an ice bath. The reaction system was stirred at room temperature for 2 hours. LC-MS showed the disappearance of the starting material, the reaction solution was quenched by adding water (10 mL), and extracted with dichloromethane (10 mL×3 times). The organic phases were combined, washed with saturated brine (10 mL×3 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by high performance preparative liquid chromatography to give the final product 5-(3-(4-((4-(4-((5-bromo-4-((2-(dimethylphosphono)-4-fluoro) Phenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)methyl) Piperidin-1-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (36.5 mg, received rate 37%).

MS(ESI)M/Z: 1037.1[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ): δ 10.37(s,1H), 8.37-8.30(m,1H), 8.23-8.17(m,2H), 8.10(s,1H), 7.73(s,1H) ,7.63(d,J＝8.0Hz,1H),7.60(s,1H),7.34(s,1H),6.98-6.90(m,1H),6.78(d,J＝2.0Hz,1H),6.71( s,1H),6.58(brs,1H),6.53(dd,J=8.4,2.0Hz,1H),4.95-4.90(m,1H),4.10(t,J=7.4Hz,2H),3.91-3.88 (m,8H),3.39-3.31(m,1H),2.94-2.70(m,9H),2.57(brs,4H),2.32-2.30(m,2H),2.15-2.10(m,1H),1.94 -1.82(m,10H),1.64-1.60(brs,1H),1.34-1.24(m,2H).

Example 103:

5-(3-(4-((4-(4-((5-bromo-4-((2-(dimethylphosphono)-3,4-dimethylphenyl)amino)pyrimidine-2- yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)aza Cyclobutan-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Reaction process:

Reaction steps:

1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl) Piperidine-4-carbaldehyde (47 mg, 0.11 mmol) and (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)- 4-(Piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dimethylphenyl)dimethylphosphine oxide (60 mg, 0.094 mmol) in tetrahydrofuran/N , N-dimethylformamide (2.5 mL/0.5 mL) was added with sodium triacetoxyborohydride (60 mg, 0.28 mmol) under an ice bath. The reaction system was stirred at room temperature for 2 hours. LC-MS showed the disappearance of the starting material, the reaction solution was quenched by adding water (10 mL), and extracted with dichloromethane (10 mL×3 times). The organic phases were combined, washed with saturated brine (10 mL×3 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by high performance preparative liquid chromatography to give the final product 5-(3-(4-((4-(4-((5-bromo-4-((2-(dimethylphosphono)-3,4) -Dimethylphenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl ) methyl)piperidin-1-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione ( 37.1 mg, 31% yield).

MS(ESI)M/Z: 1047.1[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ): δ 11.77(s,1H), 8.23(s,1H), 8.17-8.13(m,2H), 8.04(brs,1H), 7.74(s,1H), 7.70 (s,1H),7.63(d,J=8.4Hz,1H),7.24(s,1H),6.83(d,J=8.0Hz,1H),6.78(d,J=2.4Hz,1H),6.71 (s,1H),6.52(dd,J=8.4,2.0Hz,1H),4.95-4.90(m,1H),4.10(t,J=7.6Hz,2H),3.91-3.86(m,8H), 3.37-3.31(m,1H),2.92-2.68(m,9H),2.55(brs,4H),2.30-2.28(m,5H),2.13(s,4H),2.00(s,3H),1.97( s,3H),1.93-1.83(m,4H),1.60(brs,1H),1.33-1.23(m,2H).

Example 104:

5-(3-(4-((4-(4-((5-bromo-4-((2-(dimethylphosphono)-4-methylphenyl)amino)pyrimidin-2-yl)amino )-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)azetidine- 1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Reaction process:

Reaction steps:

1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl) Piperidine-4-carbaldehyde (40 mg, 0.094 mmol) and (2-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)- 4-(Piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-methylphenyl)dimethylphosphine oxide (59 mg, 0.094 mmol) in tetrahydrofuran/N,N- To dimethylformamide (2.7 mL/0.3 mL), sodium triacetoxyborohydride (60 mg, 0.28 mmol) was added under an ice bath. The reaction system was stirred at room temperature for 2 hours. LC-MS showed the disappearance of the starting material, the reaction solution was quenched by adding water (10 mL), and extracted with dichloromethane (10 mL×3 times). The organic phases were combined, washed with saturated brine (10 mL×3 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by high performance preparative liquid chromatography to give the final product 5-(3-(4-((4-(4-((5-bromo-4-((2-(dimethylphosphono)-3,4) -Dimethylphenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl ) methyl)piperidin-1-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione ( 34.5 mg, 36% yield).

MS(ESI)M/Z: 1033.1[M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ): δ 10.51 (s, 1H), 8.34 (dd, J=8.6, 4.6 Hz, 1H), 8.24 (s, 1H), 8.19 (s, 1H), 8.06 (s ,1H),7.74(s,1H),7.67(s,1H),7.63(d,J=8.0Hz,1H),7.30(s,1H),7.03(d,J=14.4Hz,1H),6.82 -6.77(m, 2H), 6.72(s, 1H), 6.52(dd, J=8.2, 2.2Hz, 1H), 4.95-4.90(m, 1H), 4.10(t, J=7.4Hz, 2H), 3.91-3.86(m, 8H), 3.37-3.31(m, 1H), 2.93-2.70(m, 9H), 2.56(brs, 4H), 2.29(d, J=6.4Hz, 2H), 2.25(s, 3H), 2.15-2.10(m, 1H), 1.94-1.81(m, 10H), 1.60(brs, 1H), 1.33-1.24(m, 2H).

Example 105:

5-((R)-3-(2-(4-(4-((5-bromo-4-((2-(dimethylphosphono)-3,4-dimethylphenyl)amino)pyrimidine -2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)ethyl)pyrrolin-1-yl )-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione

Reaction process:

Reaction steps:

Step 1: Dissolve (S)-tert-butyl 3-(2-hydroxyethyl)pyrroline-1-carboxylate (200 mg, 0.93 mmol) in dichloromethane (2 mL) at room temperature, add hydrogen chloride under ice bath /1,4-dioxane solution (4M, 1 mL, 4 mmol). The reaction system was stirred at room temperature for 1 hour, and LC-MS indicated that the reaction was complete. The reaction solution was concentrated under reduced pressure, saturated aqueous sodium bicarbonate solution (5 mL) was added, and the mixture was extracted with dichloromethane (5 mL×3 times). The organic phases were combined, washed with saturated brine (5 mL×3 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain (S)-2-(pyrrolin-3-yl)ethan-1-ol (110 mg, crude product), which was directly used in the next reaction.

MS(ESI) M/Z: 116.2[M+H ⁺ ].

Step 2: Combine (S)-2-(pyrrolin-3-yl)ethan-1-ol (110 mg, crude) and 2-(2,6-dioxopiperidin-3-yl)-5 at room temperature ,6-difluoroisoindoline-1,3-dione (281 mg, 0.96 mmol) was dissolved in dimethyl sulfoxide (2 mL), and N,N-diisopropylethylamine (1.3 g, 10.0 mmol). The reaction system was heated to 140°C and stirred for 30 minutes. LC-MS showed the disappearance of the starting material, the reaction solution was cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (10 mL×3 times). The organic phases were combined, washed with saturated brine (10 mL×3 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/1) to obtain 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-( (S)-3-(2-hydroxyethyl)pyrrolin-1-yl)isoindoline-1,3-dione (307 mg, 85% yield).

MS(ESI)M/Z: 390.1[M+H] ⁺ .

Step 3: 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-((S)-3-(2-hydroxyethyl)pyrrolin-1-yl at room temperature ) isoindoline-1,3-dione (100 mg, 0.26 mmol) was dissolved in dichloromethane (4 mL), triethylamine (78 mg, 0.77 mmol) and methanesulfonyl chloride (44 mg, 0.39 mmol) were added under ice bath mmol). The reaction system was stirred under an ice bath for 1 hour. LC-MS showed the disappearance of the starting material, which was diluted with saturated aqueous sodium bicarbonate solution (8 mL) and water (5 mL), and extracted with dichloromethane (20 mL×3 times). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1/2) to obtain 2-((3S)-1-(2-(2,6-dioxopiperidine-3) -yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)pyrrolin-3-yl)ethylmethanesulfonate (78 mg, 65% yield).

MS(ESI)M/Z: 468.1[M+H] ⁺ .

Step 4: (6-((5-Bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperazine-1 -yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dimethylphenyl)dimethylphosphine oxide (107 mg, 0.17 mmol) and 2-((3S)-1-(2 -(2,6-Dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)pyrrolin-3-yl)ethylmethanesulfonate (78 mg, 0.17 mmol) was dissolved in acetonitrile (5 mL), DIEA (216 mg, 1.7 mmol) and a catalytic amount of sodium iodide were added, and the reaction was heated to 85°C and stirred overnight. LCMS monitoring showed the disappearance of the starting material, the reaction solution was cooled to room temperature, and the reaction was quenched by the addition of saturated aqueous sodium bicarbonate solution (10 mL). The mixture was extracted with dichloromethane/anhydrous methanol=10/1 (33 mL×3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained residue was purified by preparative thin layer chromatography (eluent: dichloromethane/methanol=10/1) to obtain the final product 5-((R)-3-(2-(4-(4-(((5- Bromo-4-((2-(dimethylphosphono)-3,4-dimethylphenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl- 1H-Pyrazol-4-yl)phenyl)piperazin-1-yl)ethyl)pyrrolin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6- Fluoroisoindoline-1,3-dione (52.2 mg, 31% yield).

MS(ESI)M/Z: 1010.1[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ): δ 11.79(s, 1H), 8.25(s, 1H), 8.17-8.14(m, 2H), 7.99(s, 1H), 7.77(s, 1H), 7.68 (s, 1H), 7.38(d, J=12.4Hz, 1H), 7.22(s, 1H), 7.01(d, J=7.6Hz, 1H), 6.87-6.83(m, 1H), 6.71(s, 1H), 4.94-4.89(m, 1H), 3.88(s, 3H), 3.87(s, 3H), 3.76-3.72(m, 1H), 3.65-3.58(m, 2H), 3.28-3.22(m, 1H), 2.99-2.65(m, 8H), 2.61-2.45(m, 5H), 2.37-2.29(m, 4H), 2.23-2.11(m, 5H), 2.00(s, 3H), 1.97(s, 3H),1.72-1.56(m,3H).

Example 106:

5-((S)-3-(2-(4-(4-((5-bromo-4-((2-(dimethylphosphono)-3,4-dimethylphenyl)amino)pyrimidine -2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)ethyl)pyrrolin-1-yl )-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione

Reaction process:

Reaction steps:

Using (R)-3-(2-hydroxyethyl)pyrroline-1-carboxylate tert-butyl ester as raw material, the final product 5-((S)-3-(2- (4-(4-((5-Bromo-4-((2-(dimethylphosphono)-3,4-dimethylphenyl)amino)pyrimidin-2-yl)amino)-5-methoxy yl)-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)ethyl)pyrrolin-1-yl)-2-(2,6-dioxo Piperidin-3-yl)-6-fluoroisoindoline-1,3-dione (23.6 mg).

MS(ESI)M/Z: 1010.1[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ 11.92(s, 1H), 11.08(s, 1H), 8.11(s, 1H), 7.99(s, 2H), 7.90-7.88(m, 1H) ,7.79(s,1H),7.61-7.57(m,2H),7.06(d,J=7.6Hz,1H),6.79(s,1H),6.69(brs,1H),5.08-5.04(m,1H ),3.84(s,3H),3.79(s,3H),3.76-3.71(m,1H),3.66-3.56(m,2H),3.27-3.21(m,1H),2.92-2.84(m,5H ), 2.68-2.56(m, 5H), 2.50-2.43(m, 3H), 2.34-2.21(m, 4H), 2.17-1.99(m, 5H), 1.88(s, 3H), 1.85(s, 3H) ),1.66-1.61(m,3H).

Example 107:

5-(3-((R)-3-((4-(4-((5-bromo-4-((2-(dimethylphosphono)-3,4-dimethylphenyl)amino) pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)methyl)pyrroline-1- yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Reaction process:

Reaction steps:

Step 1: Dissolve (S)-tert-butyl 3-(hydroxymethyl)pyrroline-1-carboxylate (500 mg, 2.5 mmol) in dichloromethane (8 mL) at room temperature, add DIEA (641 mg) under ice bath , 5.0 mmol) and methylsulfonyl chloride (427 mg, 3.7 mmol). The reaction system was stirred at room temperature for 1 hour. LC-MS showed the disappearance of the starting material, which was diluted with water (20 mL) and extracted with dichloromethane (20 mL x 3 times). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=5/1) to obtain (S)-3-((methylsulfonyloxy)methyl)pyrroline-1-carboxylic acid tert-Butyl ester (540 mg, 78% yield).

MS(ESI)M/Z: 280.1[M+H] ⁺ .

Step 2: (6-((5-Bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperazine-1 -yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dimethylphenyl)dimethylphosphine oxide (200 mg, 0.31 mmol) and (S)-3-((methylsulfonyl) Oxy)methyl)pyrroline-1-carboxylate tert-butyl ester (131 mg, 0.47 mmol) was dissolved in DMSO (8 mL), DIEA (121 mg, 0.94 mmol) and a catalytic amount of sodium iodide were added, and the reaction system was heated Stir to 100°C overnight. LCMS monitoring showed the disappearance of starting material, the reaction was cooled to room temperature, and water (40 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (40 mL×3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=30/1) to obtain (R)-3-((4-(4-((5-bromo-4-(((2- (Dimethylphosphono)-3,4-dimethylphenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl )phenyl)piperazin-1-yl)methyl)pyrroline-1-carboxylate tert-butyl ester (140 mg, 55% yield).

MS(ESI)M/Z:822.3[M+H] ⁺ .

Step 3: (R)-3-((4-(4-((5-bromo-4-((2-(dimethylphosphono)-3,4-dimethylphenyl)amino) at room temperature pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)methyl)pyrroline-1- tert-Butyl carboxylate (140 mg, 0.17 mmol) was dissolved in dichloromethane (6 mL), and a solution of hydrogen chloride/1,4-dioxane (4 M, 3 mL, 12 mmol) was added under ice bath. The reaction system was stirred at room temperature for 1 hour, and LC-MS indicated that the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain (S)-(6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-( 4-(pyrrolin-3-ylmethyl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dimethylphenyl)dimethylphosphine oxide hydrochloride The salt (140 mg, crude) was used directly in the next reaction.

MS(ESI) M/Z: 722.3[M+H ⁺ ].

Subsequent steps were followed by (S)-(6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-( Pyrrolin-3-ylmethyl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dimethylphenyl)dimethyl phosphine oxide hydrochloride as raw material , referring to the preparation method of Example 35 to obtain the final product 5-(3-((R)-3-((4-(4-((5-bromo-4-((2-(dimethylphosphono)-3 ,4-Dimethylphenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazine-1 -yl)methyl)pyrrolin-1-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-di Ketone (6.6 mg).

MS(ESI)M/Z: 1033.4[M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ /CD ₃ OD): δ 8.08-7.88 (m, 4H), 7.64 (d, J=1.8 Hz, 1H), 7.53-7.58 (m, 3H), 6.74-6.66 ( m,3H),6.54-6.45(m,1H),4.90-4.80(m,1H),4.09-4.07(m,2H),3.88-3.92(m,4H),3.82(s,3H),3.80( s,3H),3.25-2.88(m,5H),2.75-2.63(m,6H),2.60-2.40(m,4H),2.26(s,3H),2.13-2.10(m,2H),2.04( s,3H),1.93(s,3H),1.89(s,3H),1.60-1.46(m,3H).

Example 108:

5-(3-((S)-3-((4-(4-((5-bromo-4-((2-(dimethylphosphono)-3,4-dimethylphenyl)amino) pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)methyl)pyrroline-1- yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Reaction process:

Reaction steps:

Using (R)-3-(hydroxymethyl)pyrroline-1-carboxylic acid tert-butyl ester as raw material, referring to the preparation method of Example 107, the final product 5-(3-((S)-3-((4 -(4-((5-Bromo-4-((2-(dimethylphosphono)-3,4-dimethylphenyl)amino)pyrimidin-2-yl)amino)-5-methoxy- 2-(1-Methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)methyl)pyrrolin-1-yl)azetidin-1-yl)-2-( 2,6-Dioxopiperidin-3-yl)isoindoline-1,3-dione (12.9 mg).

MS(ESI)M/Z: 1033.1[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ): δ 11.74(s, 1H), 8.19-8.07(m, 4H), 7.76(s, 1H), 7.57(d, J=8.0Hz, 1H), 7.45(s) ,1H),6.82(s,1H),6.71(s,1H),6.63(s,1H),6.46(d,J=8.0Hz,1H),4.87-4.83(m,1H),4.04(t, J=6.8Hz, 2H), 3.94-3.88(m, 2H), 3.80(s, 6H), 3.50(brs, 2H), 3.22-3.06(m, 3H), 2.85-2.53(m, 12H), 2.23 (s,3H),2.18-2.13(m,2H),2.10(s,3H),1.93(s,3H),1.90(s,3H),1.60-1.46(m,3H).

Example 109:

5-(4-(2-(4-(4-((5-bromo-4-((2-(dimethylphosphono)-3,4-dimethylphenyl)amino)pyrimidin-2-yl )amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)ethyl)-4-methylpiperidine-1- yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione

Reaction process:

Reaction steps:

With 2-(2,6-dioxopiperidin-3-yl)-5,6-difluoroisoindoline-1,3-dione and 2-(4-methylpiperidin-4-yl ) ethane-1-ol (for preparation, refer to Collection of Czechoslovak Chemical Communications, 1953, vol.18, p.818, 821) as raw material, and the final product 5-(4-(2- (4-(4-((5-Bromo-4-((2-(dimethylphosphono)-3,4-dimethylphenyl)amino)pyrimidin-2-yl)amino)-5-methoxy base-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)ethyl)-4-methylpiperidin-1-yl)-2-(2, 6-Dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione (7 mg).

MS(ESI)M/Z: 1038.1[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ): δ 11.78 (s, 1H), 8.24 (s, 1H), 8.17-8.14 (m, 2H), 8.00 (brs, 1H), 7.80 (s, 1H), 7.61 (s,1H),7.46(d,J=11.2Hz,1H),7.40(d,J=7.2Hz,1H),7.24(s,1H),6.89-6.82(m,1H),6.70(s, 1H), 4.95-4.91(m, 1H), 3.88(s, 3H), 3.87(s, 3H), 3.37-3.30(m, 2H), 3.22-3.15(m, 2H), 3.00(brs, 4H) ,2.93-2.68(m,6H),2.63-2.53(m,3H),2.30(s,3H),2.18-2.11(m,4H),2.00(s,3H),1.97(s,3H),1.60 -1.45(m,6H),1.05(s,3H).

Example 110:

5-(4-(2-(4-(4-((5-bromo-4-((2-(dimethylphosphono)-3,4-dimethylphenyl)amino)pyrimidin-2-yl )amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)ethyl)-4-fluoropiperidin-1-yl )-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione

Reaction process:

Reaction steps:

Step 1: Under nitrogen protection, tetrahydrofuran (10 mL) was cooled to 0 °C, lithium aluminum hydride (176 mg, 4.6 mmol) was slowly added, and after stirring for 10 minutes, 4-(2-ethoxy-2-oxo) was slowly added dropwise Ethyl)-4-fluoropiperidine-1-carboxylate benzyl ester (1.0 g, 3.1 mmol) in tetrahydrofuran (2 mL), the reaction system was stirred at 0 °C for 0.5 h. LCMS showed that the reaction was completed, ethyl acetate (20 mL) was added to the reaction solution under ice bath to dilute, and then water (0.5 mL), 10% aqueous sodium hydroxide solution (0.4 mL) and water (0.5 mL) were added successively. The mixture was filtered, and the filtrate was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give benzyl 4-fluoro-4-(2-hydroxyethyl)piperidine-1-carboxylate (800 mg, crude).

MS(ESI)M/Z: 282.0[M+H] ⁺ .

Step 2: Benzyl 4-fluoro-4-(2-hydroxyethyl)piperidine-1-carboxylate (800 mg, crude) was dissolved in methanol (10 mL) at room temperature, and 10% wet palladium on carbon (240 mg) was added . The reaction system was stirred overnight under a hydrogen balloon atmosphere. LCMS showed that the reaction was complete, and the reaction solution was concentrated under reduced pressure to obtain 2-(4-fluoropiperidin-4-yl)ethane-1-ol (520 mg, crude product).

MS(ESI)M/Z: 148.1[M+H] ⁺ .

Subsequent steps were performed with 2-(2,6-dioxopiperidin-3-yl)-5,6-difluoroisoindoline-1,3-dione and 2-(4-fluoropiperidine-4- Base) ethane-1-ol was used as raw material, and the final product 5-(4-(2-(4-(4-((5-bromo-4-(((2-(di Methylphosphono)-3,4-dimethylphenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)benzene yl)piperazin-1-yl)ethyl)-4-fluoropiperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline- 1,3-Dione (41.1 mg).

MS(ESI)M/Z: 1042.2[M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.92 (s, 1H), 11.10 (s, 1H), 8.11 (s, 1H), 7.99 (s, 2H), 7.89 (dd, J=7.8, 3.4Hz, 1H), 7.79(s, 1H), 7.74(d, J=11.6Hz, 1H), 7.58(s, 1H), 7.51(d, J=7.6Hz, 1H), 6.77(s, 1H) ,6.71(brs,1H),5.13-5.08(m,1H),3.84(s,3H),3.80(s,3H),3.51-3.47(m,2H),3.33-3.29(m,1H),3.19 -3.12(m, 2H), 2.93-2.80(m, 5H), 2.68-2.53(m, 7H), 2.22(s, 3H), 2.07-2.00(m, 4H), 1.96-1.81(m, 12H) .

Example 111:

3-(4-(4-(2-(4-(4-((5-bromo-4-((2-(dimethylphosphono)-3,4-dimethylphenyl)amino)pyrimidine -2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)-2-oxoethyl)- 4-Hydroxypiperidin-1-yl)-3-fluorophenyl)piperidine-2,6-dione

Reaction process:

Reaction steps:

2-(1-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetic acid hydrochloride ( 50mg, 0.14mmol, prepared with reference to patent WO2021/127561A1), (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)- 4-(Piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dimethylphenyl)dimethylphosphine oxide (88 mg, 0.14 mmol), HATU (80 mg, 0.21 mmol) and DIEA (35 mg, 0.27 mmol) were sequentially added to DMF (3 mL) and stirred at room temperature for 1 hour. LCMS monitored the disappearance of the raw material, added water (10 mL) to dilute, and extracted with ethyl acetate (10 mL×3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by high performance preparative liquid chromatography to give the final product 3-(4-(4-(2-(4-(4-((5-bromo-4-((2-(dimethylphosphono)- 3,4-Dimethylphenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazine- 1-yl)-2-oxoethyl)-4-hydroxypiperidin-1-yl)-3-fluorophenyl)piperidine-2,6-dione (68.8 mg, 50% yield).

MS(ESI)M/Z: 985.1[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ 11.91(s, 1H), 10.81(s, 1H), 8.11(d, J=7.6Hz, 2H), 7.99(s, 1H), 7.89(d , J=5.2Hz, 1H), 7.75(s, 1H), 7.63(s, 1H), 7.02-6.93(m, 3H), 6.78(s, 1H), 6.70(brs, 1H), 4.94(s, 1H), 3.86(s, 3H), 3.79(brs, 4H), 3.70(brs, 4H), 3.10-2.98(m, 4H), 2.83(brs, 4H), 2.69-2.57(m, 4H), 2.23 -2.15(m, 4H), 2.08(s, 3H), 2.03-1.97(m, 1H), 1.89(s, 3H), 1.85(s, 3H), 1.83-1.68(m, 4H).

Example 112:

5-(4-(2-(4-(4-((5-bromo-4-((2-(dimethylphosphono)-3,4-dimethylphenyl)amino)pyrimidine-2- yl)amino)-2,5-dichlorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)- 6-Fluoroisoindoline-1,3-dione

Reaction process:

Reaction steps:

Step 1: 1,4-Dichloro-2-fluoro-5-nitrobenzene (11.5 g, 55.0 mmol) and tert-butyl piperazine-1-carboxylate (12.2 g, 65.6 mmol) were dissolved in acetonitrile (300 mL) ), potassium carbonate (15.1 g, 109 mmol) was added, and the temperature was raised to 70°C and stirred overnight. The reaction solution was cooled to room temperature, concentrated under reduced pressure to remove most of the solvent, diluted with ethyl acetate (300 mL), washed with saturated brine (200 mL×3), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=20/1) to obtain 4-(2,5-dichloro-4-nitrophenyl)piperazine-1-carboxylic acid tert-Butyl ester (18.6 g, 90% yield).

MS(ESI) M/Z: 376.0[M+H] ⁺ .

Step 2: To a solution of tert-butyl 4-(2,5-dichloro-4-nitrophenyl)piperazine-1-carboxylate (15.6 g, 41.6 mmol) in dichloromethane (50 mL) was added at room temperature Hydrogen chloride solution in dioxane (50 mL, 4M). After stirring at room temperature for 3 hours, the mixture was concentrated under reduced pressure to obtain 1-(2,5-dichloro-4-nitrophenyl)piperazine hydrochloride (10.1 g, crude product).

MS(ESI)M/Z: 276.1[M+H] ⁺ .

Step 3: 1-(2,5-Dichloro-4-nitrophenyl)piperazine hydrochloride (10.1 g, crude) and DMAP (8.9 g, 73.2 mmol) were added to dichloromethane (150 mL) at room temperature ), stirred for 5 minutes, then added trifluoroacetic anhydride (11.5 g, 54.9 mmol), and stirred at room temperature for 1 hour. The reaction solution was poured into ice water (150 mL), and extracted with dichloromethane (100 mL×3 times). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 20/1) to obtain 1-(4-(2,5-dichloro-4-nitrophenyl)piperazine-1 -yl)-2,2,2-trifluoroethane-1-one (9.1 g, 59% over two steps).

MS(ESI) M/Z: 372.0[M+H] ⁺ .

Step 4: 1-(4-(2,5-Dichloro-4-nitrophenyl)piperazin-1-yl)-2,2,2-trifluoroethane-1-one (9.1 g, 24.5 mmol) was dissolved in methanol (100 mL) and water (20 mL), followed by adding ammonium chloride and iron powder of the same weight as the raw materials, heated to 70° C. and stirred for 2 hours. LCMS detected that the reaction was complete, the reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=5/1) to obtain 1-(4-(4-amino-2,5-dichlorophenyl)piperazine-1- yl)-2,2,2-trifluoroethane-1-one (4.2 g, 50% yield).

MS(ESI)M/Z: 342.1[M+H] ⁺ .

Step 5: 1-(4-(4-Amino-2,5-dichlorophenyl)piperazin-1-yl)-2,2,2-trifluoroethane-1-one (176 mg, 0.52 mmol), (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-2,3-dimethylphenyl)dimethylphosphine oxide (200 mg, 0.52 mmol) and trifluoroacetic acid (582 mg, 5.1 mmol) were successively added to n-butanol (10 mL), and the temperature was raised to 110° C. under nitrogen protection and stirred overnight. LCMS detected that the reaction was complete, the reaction solution was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (50 mL×3 times). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=25/1) to give 1-(4-(4-((5-bromo-4-((2-(dimethylphosphine) Acyl)-3,4-dimethylphenyl)amino)pyrimidin-2-yl)amino)-2,5-dichlorophenyl)piperazin-1-yl)-2,2,2-trifluoroethyl Alkan-1-one (84 mg, 24% yield).

MS(ESI)M/Z: 693.1[M+H] ⁺ .

Step 6: 1-(4-(4-((5-bromo-4-((2-(dimethylphosphono)-3,4-dimethylphenyl)amino)pyrimidine-2- yl)amino)-2,5-dichlorophenyl)piperazin-1-yl)-2,2,2-trifluoroethane-1-one (84 mg, 0.12 mmol) and potassium hydroxide (34 mg, 0.60 mmol) was added to methanol (8 mL) and water (2 mL), the temperature was raised to 60° C. and the reaction was stirred for 1 hour. The reaction was monitored by LCMS, the reaction solution was cooled to room temperature, diluted with ice water (20 mL), and extracted with ethyl acetate (20 mL×3 times). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The obtained residue was purified by preparative thin layer chromatography (eluent: dichloromethane/methanol=15/1) to give (6-((5-bromo-2-((2,5-dichloro-4-(piperidine) Azin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dimethylbenzene)dimethylphosphine oxide (23 mg, 32% yield).

MS(ESI) M/Z: 597.1[M+H] ⁺ .

Step 7: (6-((5-Bromo-2-((2,5-dichloro-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)- 2,3-Dimethylbenzene)dimethylphosphine oxide (23 mg, 0.039 mmol) and 2-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1 ,3-dioxoisoindolin-5-yl)piperidin-4-yl)ethylmethanesulfonate (19 mg, 0.040 mmol) was dissolved in acetonitrile (3 mL), DIEA (15 mg, 0.12 mmol) was added and a catalytic amount of sodium iodide, the reaction was heated to 85°C and stirred for 15 hours. LCMS monitoring showed that the raw materials disappeared, the reaction solution was cooled to room temperature, and purified by high performance preparative liquid chromatography to obtain the final product 5-(4-(2-(4-(4-((5-bromo-4-(((2-( Dimethylphosphono)-3,4-dimethylphenyl)amino)pyrimidin-2-yl)amino)-2,5-dichlorophenyl)piperazin-1-yl)ethyl)piperidine- 1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione (6.5 mg, 17% yield).

MS(ESI)M/Z:982.1[M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ): δ 12.61 (s, 1H), 8.01 (d, J=5.6 Hz, 2H), 7.88-7.85 (m, 2H), 7.47 (d, J=10.8 Hz, 1H) ), 7.38(d, J=7.2Hz, 1H), 7.14-7.11(m, 2H), 4.96-4.91(m, 1H), 3.76-3.64(m, 4H), 3.44-3.31(m, 4H), 3.19-3.15(m, 2H), 3.09-3.04(m, 2H), 2.88-2.81(m, 4H), 2.78-2.69(m, 2H), 2.30(s, 3H), 2.24(s, 3H), 2.16-2.12(m, 1H), 2.00(s, 3H), 1.97(s, 3H), 1.86-1.81(m, 3H), 167-1.59(m, 1H), 1.54-1.45(m, 2H).

Example 113:

5-(4-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphono)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino )-2,5-Dichlorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoro isoindoline-1,3-dione

Reaction process:

Reaction steps:

Using (6-((5-bromo-2-chloropyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide as raw material, the final product 5- (4-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphono)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)- 2,5-Dichlorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindone Doline-1,3-dione (20 mg).

MS(ESI)M/Z:1006.0[M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ): δ 12.66 (s, 1H), 8.93 (dd, J=9.6, 4.0 Hz, 1H), 8.78 (d, J=2.0 Hz, 1H), 8.73 (d, J =1.6Hz,1H),8.37(s,1H),8.31(s,1H),8.21(d,J=9.2Hz,1H),8.08(brs,1H),7.45(d,J=11.2Hz,1H) ), 7.39(d, J＝7.2Hz, 1H), 7.30(s, 1H), 7.09(s, 1H), 4.95-4.91(m, 1H), 3.65(d, J＝12.4Hz, 2H), 3.10 (brs,4H),2.93-2.69(m,8H),2.60-2.56(m,2H),2.16(s,3H),2.12(s,3H),1.84(brs,4H),1.62-1.45(m , 5H).

Example 114:

1-(6-(1-(2-(4-(4-((5-bromo-4-((2-(dimethylphosphono)-3,4-dimethylphenyl)amino)pyrimidine -2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)-2-oxoethyl)- 3,3-Difluoropiperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Reaction process:

Reaction steps:

2-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-3,3-difluoro Piperidin-1-yl)acetic acid trifluoroacetate (see patent WO2021/127561A1 for preparation) and (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H) -Pyrazol-4-yl)-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dimethylphenyl)dimethylphosphine oxide as raw material , prepare the final product 1-(6-(1-(2-(4-(4-((5-bromo-4-((2-(dimethylphosphono)-3 ,4-Dimethylphenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazine-1 -yl)-2-oxoethyl)-3,3-difluoropiperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H, 3H)-dione (46 mg).

MS(ESI)M/Z: 1042.3[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ): δ 11.94(s, 1H), 8.21(s, 1H), 8.15-8.12(m, 2H), 7.77(s, 1H), 7.70(s, 1H), 7.68 (s,1H), 7.63(d,J＝8.8Hz,1H),7.29(s,1H),7.11(d,J＝8.4Hz,1H),6.83(d,J＝7.6Hz,1H),6.66 (s,1H),4.09(t,J＝6.8Hz,2H),4.00(s,3H),3.90(s,3H),3.85(s,3H),3.76-3.67(m,3H),3.47- 3.34(m, 2H), 3.27-3.22(m, 1H), 3.13-3.03(m, 2H), 2.95-2.87(m, 7H), 2.73-2.63(m, 1H), 2.55-2.50(m, 1H ), 2.30(s, 3H), 2.15(s, 3H), 2.00(s, 3H), 1.97(s, 3H), 1.72(brs, 2H).

Example 115:

1-(6-(1-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphono)quinoxalin-6-yl)amino)pyrimidine-2- yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)-2-oxoethyl)piperidine-4 -yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Reaction process:

Reaction steps:

with 2-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl) Acetic acid trifluoroacetate (see patent WO2021/127561A1 for preparation) and (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl) )-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide as raw material, prepared with reference to the operation steps of Example 111 Final product 1-(6-(1-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphono)quinoxalin-6-yl)amino)pyrimidine- 2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)-2-oxoethyl)piperidine -4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (14.8 mg).

MS(ESI)M/Z: 1029.9[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ): δ 12.59(s, 1H), 9.03-8.93(m, 1H), 8.72(d, J=12.6Hz, 2H), 8.30(s, 1H), 8.25(s ,1H),7.74-7.57(m,5H),7.40(d,J=0.9Hz,1H),7.15(s,1H),7.05(d,J=7.6Hz,1H),6.67(s,1H) ,4.10-4.07(m,2H),3.98(s,3H),3.89(s,3H),3.75-3.71(m,6H),3.35-3.25(m,2H),3.09-3.05(m,2H) ,2.91-2.84(m,4H),2.72-2.62(m,1H),2.40-2.27(m,2H),2.15(s,3H),2.11(s,3H),1.93-1.84(m,7H) .

Example 116:

3-(5-(4-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphono)quinoxalin-6-yl)amino)pyrimidin-2-yl )amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione

Reaction process:

Reaction steps:

With 3-(5-(4-(2-hydroxyethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (see patent for preparation US2020/339572A1) and (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperazine-1- base)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide as raw material, and the final product 3-(5-(4- (2-(4-(4-((5-Bromo-4-((5-(dimethylphosphono)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy yl)-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-1-oxoisoindoline-2 -yl)piperidine-2,6-dione (7.1 mg).

MS(ESI)M/Z: 1016.1[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ12.68(s,1H), 10.96(s,1H), 8.85-8.81(m,3H), 8.43(s,1H), 8.28(s,1H) ,8.00(s,1H),7.81(s,1H),7.52-7.45(m,3H),7.10-7.00(m,2H),6.83(s,1H),5.07-5.04(m,1H),4.34 -4.22(m, 2H), 3.90-3.87(m, 2H), 3.82(s, 3H), 3.76(s, 3H), 2.90-2.75(m, 8H), 2.70-2.40(m, 6H), 2.03 -1.90(m,8H),1.80-1.70(m,2H),1.55-1.40(m,5H).

Example 117:

3-((4-(4-(2-(4-(4-((5-bromo-4-((2-(dimethylphosphono)-3,4-dimethylphenyl)amino)) pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)-2-oxoethyl) -4-Hydroxypiperidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione

Reaction process:

Reaction steps:

2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetate at room temperature acid salt (80 mg, 0.19 mmol, prepared with reference to patent WO2021/127561A1), (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazole-4- yl)-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dimethylphenyl)dimethylphosphine oxide (183 mg, 0.22 mmol), HATU (123 mg, 0.32 mmol) and DIEA (105 mg, 0.81 mmol) were sequentially added to DMF (5 mL) and stirred at room temperature for 3 hours. LCMS monitored the disappearance of the raw materials, the reaction solution was poured into water (20 mL), and extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed twice with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by high performance preparative liquid chromatography to obtain the final product 3-((4-(4-(2-(4-(4-((5-bromo-4-((2-(dimethylphosphono)) -3,4-Dimethylphenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazine -1-yl)-2-oxoethyl)-4-hydroxypiperidin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (95 mg, 49% yield) .

MS(ESI)M/Z: 1000.3[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ 11.98(s, 1H), 10.86(s, 1H), 8.18(d, J=2.0Hz, 2H), 8.09(s, 1H), 7.95(d , J=4.0Hz, 1H), 7.83(s, 1H), 7.69(brs, 1H), 6.92-6.90(m, 1H), 6.85(s, 1H), 6.80-6.70(m, 1H), 6.58- 6.54(m,1H),6.49-6.46(m,1H),5.87-5.83(m,1H),4.95(s,1H),4.40-4.28(m,1H),3.93(s,3H),3.86( s,3H),3.77-3.70(m,4H),2.90-2.75(m,9H),2.63-2.56(m,3H),2.29(s,3H),2.14-2.05(m,5H),1.95( s,3H),1.92(s,3H),1.85-1.65(m,4H).

Example 118:

1-(4-(4-(2-(4-(4-((5-bromo-4-((2-(dimethylphosphono)-3,4-dimethylphenyl)amino)pyrimidine -2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)-2-oxoethyl)- 4-Hydroxypiperidin-1-yl)-3-fluorophenyl)dihydropyrimidine-2,4(1H,3H)-dione

Reaction process:

Reaction steps:

2-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetic acid ( 150mg, 0.41mmol, the preparation refers to patent WO2021/127561A1), (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)- 4-(Piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dimethylphenyl)dimethylphosphine oxide (277 mg, 0.43 mmol), HATU (187 mg, 0.49 mmol) and DIEA (159 mg, 1.23 mmol) were sequentially added to DMF (5 mL) and stirred at room temperature for 3 hours. LCMS monitored the disappearance of the raw materials, the reaction solution was poured into water (20 mL), and extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed twice with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by high performance preparative liquid chromatography to give the final product 1-(4-(4-(2-(4-(4-((5-bromo-4-((2-(dimethylphosphono)- 3,4-Dimethylphenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazine- 1-yl)-2-oxoethyl)-4-hydroxypiperidin-1-yl)-3-fluorophenyl)dihydropyrimidine-2,4(1H,3H)-dione (55.8 mg, received rate 14%).

MS(ESI)M/Z: 986.5[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ 11.92(s, 1H), 10.38(s, 1H), 8.12(d, J=2.0Hz, 2H), 8.03(s, 1H), 7.88(d , J=4.0Hz, 1H), 7.77(s, 1H), 7.62(s, 1H), 7.18-7.14(m, 1H), 7.07-7.05(m, 2H), 6.78(s, 1H), 6.76( brs,1H),4.96(s,1H),3.86(s,3H),3.79(s,3H),3.75-3.65(m,6H),3.10-2.95(m,4H),2.83-2.80(m, 4H), 2.68(t, J＝6.8Hz, 2H), 2.58(brs, 2H), 2.23(s, 3H), 2.08(s, 3H), 1.89(s, 3H), 1.85(s, 3H), 1.80-1.69(m,4H).

Example 119:

5-(4-(2-(4-(4-((5-bromo-4-((2-(dimethylphosphono)phenyl)amino)pyrimidin-2-yl)amino)-2,5 -Dichlorophenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline- 1,3-Dione

Reaction process:

Reaction steps:

Using (2-((5-bromo-2-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide as raw material, the final product 5-(4-(2 was prepared with reference to the operation steps of Example 112 -(4-(4-((5-Bromo-4-((2-(dimethylphosphono)phenyl)amino)pyrimidin-2-yl)amino)-2,5-dichlorophenyl)piperidine oxazin-1-yl)ethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione ( trifluoroacetate, 26.2 mg).

MS(ESI)M/Z: 953.9[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ): δ 13.00 (s, 1H), 11.64 (s, 1H), 11.32 (brs, 1H), 8.14-8.10 (m, 1H), 8.06 (s, 1H), 8.01 (s, 1H), 7.63(s, 1H), 7.47(d, J=10.8Hz, 1H), 7.38(d, J=7.6Hz, 1H), 7.30-7.21(m, 3H), 7.16(s, 1H),4.96-4.91(m,1H),3.78(d,J=11.6Hz,2H),3.65(d,J=12.8Hz,2H),3.47(d,J=11.6Hz,2H),3.45( t, J=11.8Hz, 2H), 3.22-3.17(m, 2H), 3.13-3.07(m, 2H), 2.94-2.72(m, 5H), 2.18-2.11(m, 1H), 1.89-1.83( m,10H),1.65-1.61(m,1H),1.55-1.43(m,2H).

Example 120:

5-(4-(2-(4-(2,5-Dichloro-4-((5-chloro-4-((2-(dimethylphosphono)-3,4-dimethylphenyl) )amino)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)- 6-Fluoroisoindoline-1,3-dione

Reaction process:

Reaction steps:

Using (6-((2,5-dichloropyrimidin-4-yl)amino)-2,3-dimethylphenyl)dimethylphosphine oxide as raw material, the final product was prepared with reference to the operation steps of Example 116 5-(4-(2-(4-(2,5-Dichloro-4-((5-chloro-4-((2-(dimethylphosphono)-3,4-dimethylphenyl) )amino)pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)ethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)- 6-Fluoroisoindoline-1,3-dione (35 mg).

MS(ESI)M/Z: 938.3[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ): δ 12.03(s, 1H), 8.45(s, 1H), 8.17-8.14(m, 2H), 8.07(s, 1H), 7.46(d, J=10.8Hz ,1H),7.38(d,J＝8.0Hz,2H),7.25(s,1H),7.07(s,1H),4.95-4.91(m,1H),3.65(d,J＝12.0Hz,2H) ,3.10(brs,4H),2.89-2.80(m,8H),2.64-2.61(m,2H),2.32(s,3H),2.28(s,3H),2.16-2.12(m,2H),2.01 (s,3H),1.97(s,3H),1.86(d,J=11.6Hz,2H),1.63-1.55(m,3H),1.50-1.42(m,2H).

Example 121:

3-(4-(1-(2-(4-(4-((5-bromo-4-((2-(dimethylphosphono)-3,4-dimethylphenyl)amino)pyrimidine -2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)-2-oxoethyl)piperidine pyridin-4-yl)-3-fluorophenyl)piperidine-2,6-dione

Reaction process:

Reaction steps:

Step 1: Combine 6-benzyl-2-(benzyloxy)-3-bromopyridine (826 mg, 2.3 mmol) and 4-(2-fluoro-4-(4,4,5,5-tetramethyl) at room temperature Base-1,3,2-dioxocyclopentaboran-2-yl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (900 mg, 2.2 mmol, preparation reference Patent WO2014/6554A1) was dissolved in dioxane (20 mL) and water (4 mL), potassium phosphate (946 mg, 4.4 mmol) and ferrocene palladium dichloride (162 mg, 0.21 mmol) were added, and the reaction system was placed in a nitrogen atmosphere. was heated to 100°C and stirred for 3 hours. The end of the reaction was monitored by LCMS, the reaction solution was cooled to room temperature, diluted with water (30 mL) and extracted with ethyl acetate (20 mL×3 times). The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=50/1～5/1) to obtain 4-(4-(2,6-bis(benzyloxy)pyridine-3-) (527 mg, 42% yield).

MS(ESI) M/Z: 567.3[M+H] ⁺ .

Step 2: 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-2-fluorophenyl)-3,6-dihydropyridine-1(2H)-carboxylate at room temperature tert-Butyl acid (400 mg, 0.71 mmol) was dissolved in methanol/ethyl acetate (5 mL/5 mL) and 10% wet palladium on carbon (40 mg) was added. The reaction system was stirred under a hydrogen balloon atmosphere for 15 hours. LCMS showed that the reaction was completed, the reaction solution was filtered with celite, and the filtrate was concentrated under reduced pressure to obtain 4-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)piperidine-1- tert-Butyl carboxylate (258 mg, 94% yield).

MS(ESI)M/Z: 391.2[M+H] ⁺ .

Step 3: Combine tert-butyl 4-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)piperidine-1-carboxylate (110 mg, 0.28 mmol) and 5M HCl /dioxane (3 mL) was added to DCM (5 mL) and stirred at room temperature for 2 hours. The reaction was monitored by LCMS for completion. The reaction solution was concentrated under reduced pressure to obtain 3-(3-fluoro-4-(piperidin-4-yl)phenyl)piperidine-2,6-dione hydrochloride (87 mg, crude product).

MS(ESI)M/Z: 291.1[M+H] ⁺ .

Step 4: Combine 3-(3-fluoro-4-(piperidin-4-yl)phenyl)piperidine-2,6-dione hydrochloride (87 mg, crude), DIEA (194 mg, 1.5 mmol) at room temperature ) and tert-butyl 2-bromoacetate (59 mg, 0.3 mmol) were successively added to DMSO (2 mL), and the temperature was raised to 50° C. and stirred for 3 hours. LCMS monitored the disappearance of the raw material, added water (20 mL) to dilute, and extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative TLC plate (eluent: ethyl acetate) to give 2-(4-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)piperidine tert-Butyl pyridin-1-yl)acetate (78 mg, 69% over two steps).

MS(ESI)M/Z:405.2[M+H] ⁺ .

Step 5: tert-butyl 2-(4-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)piperidin-1-yl)acetate (47 mg, 0.12 mmol ) and trifluoroacetic acid (1 mL) were added to DCM (2 mL) and stirred at room temperature for 1 hour. The reaction was monitored by LCMS for completion. The reaction solution was concentrated under reduced pressure to obtain 2-(4-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)piperidin-1-yl)acetic acid trifluoroacetate ( 47 mg, crude).

MS(ESI) M/Z: 349.2[M+H] ⁺ .

Step 6: 2-(4-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)piperidin-1-yl)acetic acid trifluoroacetate ( 47mg, crude), (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperazine-1- yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dimethylphenyl)dimethylphosphine oxide (72 mg, 0.11 mmol), HATU (86 mg, 0.23 mmol) and DIEA (72 mg, 0.56 mmol) was sequentially added to DMF (2 mL) and stirred at room temperature for 1 hour. LCMS monitored the disappearance of the raw material, added water (10 mL) to dilute, and extracted with ethyl acetate (10 mL×3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by high performance preparative liquid chromatography to give the final product 3-(4-(1-(2-(4-(4-((5-bromo-4-((2-(dimethylphosphono)- 3,4-Dimethylphenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazine- 1-yl)-2-oxoethyl)piperidin-4-yl)-3-fluorophenyl)piperidine-2,6-dione (13.5 mg, 13% over two steps).

MS(ESI)M/Z: 969.2[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ): δ 12.90 (s, 1H), 10.43 (brs, 1H), 8.26 (s, 1H), 7.92 (s, 2H), 7.82-7.61 (m, 2H), 7.51 (d, J＝12.4Hz, 1H), 7.11-6.79(m, 2H), 6.63(brs, 2H), 4.31-4.19(m, 2H), 3.96(s, 3H), 3.83(s, 3H), 3.78-3.69(m, 4H), 3.60-3.46(m, 4H), 3.23-3.13(m, 2H), 3.02-2.84(m, 3H), 2.69-2.77(m, 2H), 2.40-2.24(m ,6H),2.11(s,3H),2.04-1.80(m,10H).

Example 122:

5-((R)-3-(2-(4-(4-((5-bromo-4-((5-(dimethylphosphono)quinoxalin-6-yl)amino)pyrimidine-2- yl)amino)-2,5-dichlorophenyl)piperazin-1-yl)ethyl)pyrrolin-1-yl)-2-(2,6-dioxopiperidin-3-yl)- 6-Fluoroisoindoline-1,3-dione

Reaction process:

Reaction steps:

2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-((S)-3-(2-hydroxyethyl)pyrrolin-1-yl)isoindoline -1,3-Dione and (6-((5-bromo-2-((2,5-dichloro-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino ) quinoxalin-5-yl) dimethyl phosphine oxide as raw material, the final product 5-((R)-3-(2-(4-(4-(((5- Bromo-4-((5-(dimethylphosphono)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2,5-dichlorophenyl)piperazin-1-yl)ethyl yl)pyrrolin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione (10.2 mg).

MS(ESI)M/Z: 992.1[M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ /D ₂ O): δ 8.93(dd, J=9.4Hz, 3.8HZ, 1H), 8.78(s, 1H), 8.73(s, 1H), 8.37(s, 1H ), 8.31(s, 1H), 8.21(d, J=9.2Hz, 1H), 7.39(d, J=12.4Hz, 1H), 7.08(s, 1H), 7.02(d, J=7.6Hz, 1H) ),4.94-4.89(m,1H),3.78-3.60(m,3H),3.29-3.23(m,1H),3.14-3.01(m,4H),2.93-2.67(m,7H),2.63(brs ,2H),2.40-2.25(m,1H),2.50-2.12(m,8H),1.75-1.62(m,3H).

Example 123:

5-(3-(4-(2-(4-(4-((5-bromo-4-((2-(dimethylphosphono)-3,4-dimethylphenyl)amino)pyrimidine -2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)ethyl)piperidin-1-yl ) azetidine-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Reaction process:

Reaction steps:

With (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(piperazin-1-yl)phenyl ) amino) pyrimidin-4-yl) amino)-2,3-dimethylphenyl) dimethyl phosphine oxide as the raw material, and the final product 5-(3-(4-(2) was obtained with reference to the preparation method of Example 65. -(4-(4-((5-Bromo-4-((2-(dimethylphosphono)-3,4-dimethylphenyl)amino)pyrimidin-2-yl)amino)-5- Methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)ethyl)piperidin-1-yl)azetidin-1-yl )-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (78 mg).

MS(ESI)M/Z: 1061.5[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ 11.93(s, 1H), 11.10(s, 1H), 8.12(s, 1H), 8.04-8.00(m, 2H), 7.90-7.85(m, 1H), 7.81(s, 1H), 7.64(d, J=8.4Hz, 1H), 7.50(s, 1H), 6.79-6.76(m, 2H), 6.66-6.63(m, 2H), 5.09-5.04 (m,1H),4.18-4.12(m,2H),3.84-3.80(m,8H),3.40-3.20(m,5H),2.90-2.84(m,8H),2.70-2.50(m,3H) ,2.20(s,3H),2.10(s,3H),2.10-2.00(m,1H),1.90-1.80(m,8H),1.73-1.60(m,2H),1.50-1.10(m,5H) .

Example 124:

5-(3-(4-(2-(4-(4-((5-bromo-4-((2-(dimethylphosphono)-3,4-dimethylphenyl)amino)pyrimidine -2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)ethyl)piperidin-1-yl ) azetidine-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione

Reaction process:

Reaction steps:

with (6-((2-((4-(4-(2-(1-(azetidin-3-yl)piperidin-4-yl)ethyl)piperazin-1-yl)- 2-Methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-5-bromopyrimidin-4-yl)amino)-2,3-dimethylphenyl ) dimethyl phosphine oxide as raw material, with reference to the preparation method of Example 66 to obtain the final product 5-(3-(4-(2-(4-(4-((5-bromo-4-((2-(2 Methylphosphono)-3,4-dimethylphenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl) Phenyl)piperazin-1-yl)ethyl)piperidin-1-yl)azetidine-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6- Fluoroisoindoline-1,3-dione (47 mg).

MS(ESI)M/Z: 1079.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ 11.93(s, 1H), 11.12(s, 1H), 8.12(d, J=2.4Hz, 1H), 8.05-8.02(m, 2H), 7.79 -7.88(m,1H),7.83(s,1H),7.64-7.61(m,2H),6.94-6.92(m,1H),6.77-6.60(m,2H),5.10-5.05(m,1H) ,4.24(brs,2H),3.97(brs,2H),3.84(s,3H),3.80(s,3H),3.55-3.45(m,1H),3.40-3.10(m,2H),3.00-2.80 (m,6H),2.60-2.30(m,7H),2.20(s,3H),2.10(s,3H),2.10-2.04(m,1H),1.89-1.85(m,8H),1.75-1.60 (m,2H),1.40-1.10(m,5H).

Example 125:

5-(3-(4-((4-(4-((5-Bromo-4-((5-(dimethylphosphono)-2,3-dihydrobenzo[b][1,4] Dioxin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazine-1- yl)methyl)piperidin-1-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Reaction process:

Reaction steps:

1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl) Piperidine-4-carbaldehyde (30 mg, 0.07 mmol) and (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)- 4-(Piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)dimethyl Phosphine oxide (40 mg, 0.06 mmol) was dissolved in tetrahydrofuran/N,N-dimethylformamide (2.5 mL/0.5 mL), and sodium triacetoxyborohydride (32 mg, 0.18 mmol) was added under ice bath. The reaction system was stirred at room temperature for 2 hours. LC-MS showed the disappearance of the starting material, the reaction solution was quenched by adding water (10 mL), and extracted with dichloromethane (10 mL×3 times). The organic phases were combined, washed with saturated brine (10 mL×3 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by high performance preparative liquid chromatography to give the final product 5-(3-(4-((4-(4-((5-bromo-4-((5-(dimethylphosphono)-2,3) -Dihydrobenzo[b][1,4]dioxin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazole -4-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)azetidin-1-yl)-2-(2,6-dioxopiperidine-3- yl)isoindoline-1,3-dione (trifluoroacetate, 28.7 mg, 40% yield).

MS(ESI) M/Z: 1077.4[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ 11.93(brs,1H), 11.10(s,1H), 10.52(brs,1H), 9.68(brs,1H), 8.60(brs,1H), 8.18 (s,1H),8.09(s,1H),7.87(brs,2H),7.75(d,J=8.0Hz,1H),7.66(s,1H),6.91(s,1H),6.80-6.72( m, 2H), 5.11-5.06(m, 1H), 4.50-4.15(m, 12H), 3.87(s, 3H), 3.83(s, 3H), 3.66-3.50(m, 4H), 3.33-3.21( m,3H),3.07-3.01(m,2H),2.94-2.81(m,3H),2.68-2.54(m,2H),2.18-1.93(m,4H),1.82(s,3H),1.78( s,3H),1.54-1.37(m,2H).

Example 126:

5-(4-(2-(4-(4-((5-bromo-4-((2-(dimethylphosphono)-4-fluorophenyl)amino)pyrimidin-2-yl)amino)- 5-Methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)ethyl)-4-methylpiperidin-1-yl)-2 -(2,6-Dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione

Reaction process:

Reaction steps:

With 2-(2,6-dioxopiperidin-3-yl)-5,6-difluoroisoindoline-1,3-dione and 2-(4-methylpiperidin-4-yl ) ethane-1-ol (for preparation, refer to Collection of Czechoslovak Chemical Communications, 1953, vol.18, p.818, 821) as raw material, and the final product 5-(4-(2- (4-(4-((5-Bromo-4-((2-(dimethylphosphono)-4-fluorophenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2- (1-Methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)ethyl)-4-methylpiperidin-1-yl)-2-(2,6-dioxo piperidin-3-yl)-6-fluoroisoindoline-1,3-dione (trifluoroacetate salt, 30.8 mg).

MS(ESI)M/Z: 1028.3[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ 11.11(s,1H), 10.94(s,1H), 9.55(brs,1H), 8.50(s,1H), 8.27(brs,1H), 8.22 (s,1H),8.03(s,1H),7.90(s,1H),7.73(d,J=11.6Hz,1H),7.65(s,1H),7.50-7.39(m,2H),6.76( s,1H),6.65(brs,1H),5.13-5.09(m,1H),3.86(s,3H),3.83(s,3H),3.61(d,J＝10.4Hz,2H),3.40-3.10 (m,6H),2.98-2.84(m,3H),2.62-2.50(m,6H),2.09-1.98(m,1H),1.84-1.68(m,8H),1.64-1.51(m,4H) ,1.04(s,3H).

Example 127:

5-(4-(2-(4-(4-((5-bromo-4-((2-(dimethylphosphono)-4-fluorophenyl)amino)pyrimidin-2-yl)amino)- 5-Methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)ethyl)-4-fluoropiperidin-1-yl)-2- (2,6-Dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione

Reaction process:

Reaction steps:

With 2-(2,6-dioxopiperidin-3-yl)-5,6-difluoroisoindoline-1,3-dione and 2-(4-fluoropiperidin-4-yl) Ethane-1-ol was used as the raw material, and the final product 5-(4-(2-(4-(4-((5-bromo-4-((2-(dimethylphosphine was then prepared by referring to the operation procedure of Example 55, however,) Acyl)-4-fluorophenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazine-1 -yl)ethyl)-4-fluoropiperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione (28.9 mg).

MS(ESI)M/Z: 1032.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ 11.11(s,1H), 10.80(s,1H), 8.34(brs,1H), 8.30(s,1H), 8.23(s,1H), 8.01 (s, 1H), 7.86(s, 1H), 7.75(d, J=11.2Hz, 1H), 7.62(s, 1H), 7.52(d, J=7.2Hz, 1H), 7.44-7.37(m, 1H), 6.78(s, 1H), 6.69(brs, 1H), 5.13-5.09(m, 1H), 3.85(s, 3H), 3.82(s, 3H), 3.53-3.49(m, 3H), 3.19 -3.10(m,3H),3.01-2.79(m,6H),2.72-2.50(m,4H),2.09-1.84(m,7H),1.80-1.76(m,7H).

2. Biological activity test

Test Example 1: Evaluation of the anti-proliferation effect of the compounds of the present invention on the Ba/F3 cell line stably expressing triple mutant epidermal growth factor receptor

In this experiment, the intracellular ATP content was measured by fluorescence method to detect the inhibitory effect of the compound on the cell line stably expressing triple mutant epidermal growth factor receptor (EGFR triple mutants), and it was concluded that the compound had no effect on triple mutant epidermal growth factor receptor (EGFR triple mutant). mutants) cell lines inhibited the proliferation of the half inhibitory concentration IC50.

1. Experimental materials

RPMI-1640 medium, fetal bovine serum (FBS), 100X Pen/Strep, GlutaMAX-I Supplement were purchased from GIBCO Company. Cell Titer-Glo luminescence assay reagent for cell viability was purchased from Promega.

2. Experimental method

1) Count the stably transfected Ba/F3 (DEL19/T790M/C797S and L858R/T790M/C797S) cells with a cell counter, and inoculate the cells in a 96-well culture plate at a density of 3000 cells per well, 100 μL per well . Incubate overnight in an incubator (37°C, 5% _CO2 ).

2) Day 0: Use D300e (TECAN) to add 500nL of the compound to be tested in a gradient dilution (initial concentration of 30 μM, 10 concentrations, 1:3 ratio dilution) to the cells in the culture plate, and the final concentration of DMSO is 0.5%. Plates were incubated in a cell incubator (37°C, 5% _CO2 ) for 72 hours. The blank control was added with 500 nL of DMSO per well.

3) Day 3: Add 100 μL of Cell Titer-Glo reagent to each well, shake at 500 rpm for 2 minutes, centrifuge at 1000 rpm for 1 minute, and incubate at room temperature for 10 minutes to stabilize the luminescence signal.

4) Envision microplate reader (PerkinElmer) detects the luminescent signal.

5) Use GraphPad Prism 6 software for data analysis to calculate the IC50 of the compound.

It has been determined that the compounds of the present invention have a good inhibitory effect on the cell proliferation of the Ba/F3 Del19/T790M/C797S EGFR triple mutant cell line and the Ba/F3 L858R/T790M/C797S EGFR triple mutant cell line, and their IC ₅₀ values are generally low. The IC ₅₀ values of some compounds of the present invention are lower than 0.5 μM, and the IC ₅₀ values of more excellent compounds of the present invention are lower than 0.1 μM, even lower than 0.015 μM. Table 1 shows the inhibitory results of some compounds of the present invention on the Ba/F3 cell line with triple mutant epidermal growth factor receptor.

Table 1

Each value represents the following range: A:<100nM; 100nM≤B<500nM; 500nM≤C<1000nM; 1000nM≤C<2500nM; ≤AB<50nM; 50nM≤AC<100nM;

N.D. stands for not determined.

Test Example 2: EGFR PROTAC ELISA experiment

1. Experimental materials

HCC827 cell culture medium (RPMI-1640 medium, 10% fetal bovine serum (FBS), 100X Pen/Strep, GlutaMAX-I Supplement) were purchased from GIBCO Company. 10×RIPA was purchased from CST Company, and protease inhibitor was purchased from Roche Company. EGFR antibody and goat anti-rabbit secondary antibody were from Abcam Company, and EGFR protein was purchased from SignalChem Company. Bovine serum albumin (BSA), TMB solution and Tween-20 were from Sigma. 20×PBS and ELISA stop solution were purchased from Shenggong Bio. ELISA-coated plates were purchased from Thermo.

2. Experimental method

6) Count HCC827 cells with a cell counter (more than 85% viable cells can be used for subsequent experiments), and inoculate cells in a 96-well culture plate at a density of 40,000 cells per well, with 100 μL per well. Incubate overnight in an incubator (37°C, 5% CO2).

7) Day 1: Use D300e (TECAN) to add serially diluted test compounds (initial concentration of 1 μM, 9 concentrations, 1:3 ratio dilution, 3 duplicate wells) to the cells in the culture plate, and the final concentration of DMSO is 0.5% , the blank control was added with 500nL of DMSO per well. The culture plate was incubated in a cell incubator for 8 hours (37°C, 5% CO ₂ ), PBS was added to wash the cells once, and 100 μL of RIPA lysis solution containing protease inhibitors was added to each well, and stored at -80°C.

8) Day 2: Take 10 μL of cell lysate from each well, make up to 100 μL with PBS, and transfer it to an ELISA-coated plate. EGFR protein is used as a standard. After dilution, the highest concentration is 10 ng/mL, 7 concentrations, 1:2 Proportional dilutions were added to ELISA-coated plates. Incubate the coated plate at 4°C overnight.

9) Day 3: Add 300 μL of washing buffer (PBS containing 0.05% tween-20) to each well and wash 4 times. 200 μL of blocking buffer (1% BSA) was then added and incubated for 1 hour at room temperature. After 4 washes with 300 μL of wash buffer, 100 μL of primary antibody (diluted 1:2000 in blocking buffer) was added and incubated for 2 hours at room temperature. After continuing to wash 4 times with 300 μL of wash buffer, 100 μL of secondary antibody (diluted 1:1000 in blocking buffer) was added and incubated for 1 hour at room temperature. After washing 4 times with 300 μL of washing buffer, add 100 μL of TMB solution to each well, incubate at room temperature for 5-10 minutes in the dark, add 50 μL of stop solution to each well, shake and mix well, and use a microplate reader to read the absorbance at 450 nm.

10) Calculation: Use the known protein concentration of EGFR as a standard curve, linearly fit, calculate the EGFR protein content of the corresponding sample well, and use the blank control as a reference to calculate the EGFR degradation rate after drug addition.

EGFR%=(EGFR protein level of cells in treatment group/EGFR protein level of cells in control group)×100%

Curve fitting using Prism software, 4-parameter method

Y=Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))

The _DC50 of the drug to degrade the EGFR protein was calculated.

It can be seen from the experimental results in Table 2 that the compounds of the present invention can significantly induce the degradation of EGFR protein. Preferably, the DC ₅₀ of some compounds of the present invention is less than 50 nM, more preferably, the DC ₅₀ of some compounds is less than 10 nM.

Table 2

实施例Example	DC ₅₀(nM) _DC50 (nM)
11	B’B’
44	A’A’
1919	A’A’
22twenty two	A’A’
24twenty four	B’B’
3232	A’A’
2828	A’A’
3535	A’A’
3636	A’A’
4949	A’A’
5454	A’A’
5555	B’B’
5757	A’A’
6666	A’A’
7575	A’A’
9292	B’B’
9494	B’B’
9898	A’A’
9999	A’A’
100100	A’A’
114114	A’A’
115115	A’A’

Each value represents the following ranges: A': <10 nM; B': 10-50 nM;

The present invention has been described in detail herein, and specific embodiments thereof have also been disclosed. For those skilled in the art, various changes and modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope of the invention. will be obvious.

Claims

A bifunctional compound having the formula:

or a stereoisomer, tautomer or pharmaceutically acceptable salt, prodrug, hydrate, solvate, isotopically labeled derivative thereof,

in,

R 1 is selected from
or A optionally substituted with one or more R groups;

A is selected from 3-7-membered heterocycloalkyl, 3-7-membered heterocycloalkyl-O-, 3-7-membered heterocycloalkyl-NR a- , -(3-7-membered heterocycloalkyl)-( 3-7-membered heterocycloalkyl)-, 6-14-membered spiro heterocyclyl, 6-14-membered bridged heterocyclyl, 6-14-membered heterocyclyl;

R 2 is selected from C 6-10 aryl, 5-12-membered heteroaryl, 5-6-membered heterocycloalkenyl, wherein the C 6-10 aryl, 5-12-membered heteroaryl, 5-6 membered The heterocycloalkenyl groups are each independently optionally substituted with one or more R 10 groups;

R 3 is selected from H, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy;

M is selected from N or CR 11 ;

R 4 is selected from H, halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl;

R 5 is selected from -C (=O) NRbRc ,-S(=O) 2Rb ,-P(=O ) RbRc , -P ( =O ) RbNRcRd ,- P(=O) RbORc ,-P(=O) ORbORc ,-P(=S ) RbRc ,-P ( =S ) RbNRcRd , -P ( =S )R b OR c , -P(=S)OR b OR c , -S(=O) 2 NR b R c , -NR c S(=O) 2 R b , or -NR b C(O)R c ;

R 6 , R 7 , R 8 are each independently selected from H, C 1-4 alkyl, halogen, C 3-6 cycloalkyl;

Alternatively, R 6 , R 7 and the atoms to which they are attached are cyclized to C 4-6 cycloalkyl, 4-7 membered heterocycloalkyl, 5-7 membered heteroaryl;

Or R 7 , R 8 and the atoms to which they are attached are cyclized together to form C 4-6 cycloalkyl, 4-7 membered heterocycloalkyl, 5-7 membered heteroaryl;

R 9 is optionally selected from H, halogen, -OH, -NH 2 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, -C 0-4 alkyl-NR a R b ;

R 10 is selected from H, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkylsulfonyl;

R 11 is selected from H, halogen, C 1-4 alkyl;

R a is selected from H, C 1-4 alkyl;

R b , R c , and R d are each independently selected from H, C 1-4 alkyl, C 3-6 cycloalkyl;

The linker is the group covalently bound to the R1 group and the degron in the targeting ligand;

A degron is a group capable of binding to ubiquitin ligases.
The bifunctional compound according to claim 1, wherein, in the compound of formula (I),

R 1 is selected from
or A optionally substituted with one or more R groups;

A is selected from 3-7-membered heterocycloalkyl, 3-7-membered heterocycloalkyl-O-, 3-7-membered heterocycloalkyl-NR a- , -(3-7-membered heterocycloalkyl)-( 3-7-membered heterocycloalkyl)-, 6-14-membered spiro heterocyclyl, 6-14-membered bridged heterocyclyl, 6-14-membered heterocyclyl;

R 2 is selected from C 6-10 aryl, 5-12-membered heteroaryl, 5-6-membered heterocycloalkenyl, wherein the C 6-10 aryl, 5-12-membered heteroaryl, 5-6 membered The heterocycloalkenyl groups are each independently optionally substituted with one or more R 10 groups;

R 3 is selected from H, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy;

M is selected from N or CR 11 ;

R 4 is selected from H, halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl;

R 5 is selected from -C (=O) NRbRc ,-S(=O) 2Rb ,-P(=O ) RbRc , -P ( =O ) RbNRcRd ,- P(=O) RbORc ,-P(=O) ORbORc ,-P(=S ) RbRc ,-P ( =S ) RbNRcRd , -P ( =S )R b OR c , -P(=S)OR b OR c , -S(=O) 2 NR b R c , -NR c S(=O) 2 R b , or -NR b C(O)R c ;

R 6 , R 7 , R 8 are each independently selected from H, C 1-4 alkyl;

Alternatively, R 6 is cyclized together with R 7 and the atom to which it is attached to a C 4-6 cycloalkyl, 5-7 membered heteroaryl;

Or R 7 is cyclized with R 8 and the atom to which it is attached to form C 4-6 cycloalkyl, 5-7 membered heteroaryl;

R 9 is optionally selected from H, halogen, -OH, -NH 2 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, -C 0-4 alkyl-NR a R b ;

R 10 is selected from H, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkylsulfonyl;

R 11 is selected from H, halogen, C 1-4 alkyl;

R a is selected from H, C 1-4 alkyl;

R b , R c , and R d are each independently selected from H, C 1-4 alkyl, C 3-6 cycloalkyl;

The linker is the group covalently bound to the R1 group and the degron in the targeting ligand;

A degron is a group capable of binding to ubiquitin ligases.
The bifunctional compound according to claim 1, wherein, in the compound of formula (I),

R 1 is selected from
or A optionally substituted with one or more R groups;

A is selected from 3-7-membered heterocycloalkyl, 3-7-membered heterocycloalkyl-O-, 3-7-membered heterocycloalkyl-NR a- , -(3-7-membered heterocycloalkyl)-( 3-7 membered heterocycloalkyl)-, 6-14 membered spiroheterocyclyl, 6-14 membered heterocyclyl;

R 2 is selected from 5-6 membered heteroaryl groups, wherein the 5-6 membered heteroaryl groups are optionally substituted with one or more R 10 groups;

R 3 is selected from C 1-4 alkoxy;

M is selected from CR 11 ;

R 4 is selected from H, halogen, C 1-4 alkyl;

R 5 is selected from -P(=O)R b R c , -NR c S(=O) 2 R b ;

R 6 , R 7 and R 8 are each independently selected from H, C 1-4 alkyl;

Alternatively, R 6 , R 7 and the atoms to which they are attached are cyclized together to form a 5-7 membered heteroaryl;

R 9 is optionally selected from H, halogen, -OH, -NH 2 , C 1-4 alkyl;

R 10 is selected from H, C 1-4 alkyl;

R 11 is selected from H, halogen;

R a is selected from H, C 1-4 alkyl;

R b and R c are each independently selected from H, C 1-4 alkyl;

The linker is the group covalently bound to the R1 group and the degron in the targeting ligand;

A degron is a group capable of binding to ubiquitin ligases.
The bifunctional compound according to any one of claims 1-3, M is selected from CH.
The bifunctional compound according to any one of claims 1-4, wherein R 1 is selected from
The bifunctional compound according to any one of claims 1-4, wherein A is selected from

Ra is as defined in any one of claims 1-4.
The bifunctional compound of claim 6, wherein A is selected from
The bifunctional compound according to any one of claims 1-7, wherein R 2 is selected from
The bifunctional compound according to any one of claims 1-7, wherein ring R 2 is selected from
The bifunctional compound of any one of claims 1-9, wherein R3 is selected from methoxy.
The bifunctional compound of any one of claims 1-9, wherein R3 is selected from H, methyl.
The bifunctional compound of any one of claims 1-11, wherein R4 is selected from F, Cl, Br, methyl or trifluoromethyl.
The bifunctional compound of claim 12 , wherein R4 is selected from Br.
The bifunctional compound according to any one of claims 1-13, wherein R 5 is selected from
The bifunctional compound of claim 14, wherein R 5 is selected from
The bifunctional compound according to any one of claims 1-15, wherein R 6 , R 7 , R 8 are selected from H.
The bifunctional compound according to any one of claims 1-15, wherein R 6 , R 7 , R 8 are each independently selected from CH 3 , cyclopropyl, fluoro.
The bifunctional compound according to any one of claims 1-15, wherein R 6 , R 7 and the atoms to which they are attached are cyclized together to form a pyrazine ring, a pyridine ring.
The bifunctional compound of any one of claims 1-18, wherein the linker has the formula LA:

or its stereoisomers,

Wherein, p 1 is selected from an integer of 0-6; p 2 is selected from an integer of 0-6; p 3 is selected from an integer of 0-6;

U is a bond, or is selected from C=O, O, NH or NR 12 ;

each Q is independently selected from a bond, CH2 , O, S, NH or NR12 ;

W is a bond, or is selected from C=O, O, NH, NR 12 , C≡C;

wherein said R 12 is selected from C 1-4 alkyl;

The linker is covalently bound to R 1 in the targeting ligand TL through the U group, and the W group is covalently bound to the degron.
The bifunctional compound of claim 19, wherein the TL-LA is selected from:

Wherein, p 1 is selected from an integer of 0-6; p 2 is selected from an integer of 0-6; p 3 is selected from an integer of 0-6.
The bifunctional compound of claim 20, wherein the TL-LA is selected from:
The bifunctional compound of claim 20, wherein the TL-LA is selected from:
The bifunctional compound of any one of claims 1-18, wherein the linker has the formula LB:

or its stereoisomers,

Wherein, p 1 is selected from an integer of 0-6; p 2 is selected from an integer of 0-6; p 3 is selected from an integer of 0-6, p 4 is selected from an integer of 0-6; p 5 is selected from an integer of 0-6 integer;

U is a bond, or is selected from C=O, O, NH or NR 13 ;

each Q is independently selected from a bond, CH2 , O, S, NH or NR13 ;

W is a bond, or selected from C=O, O, NH, NR 13 , C≡C;

wherein said R 13 is selected from C 1-4 alkyl;

Each Z 1 is independently selected from absent, phenyl, C 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, wherein said phenyl, C 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl are each independently optionally substituted by one or more R 14 groups, R 14 is selected from halogen, C 1-4 alkyl , hydroxyl;

or each Z 1 is independently selected from a 7-11 membered azaspirocycle, wherein the 7-11 membered azaspirocycle is optionally substituted with one or more R 14 groups; R 14 is selected from halogen , C 1-4 alkyl, hydroxyl;

The linker is covalently bound to R 1 in the targeting ligand through the U group, and the W group is covalently bound to the degron.
The bifunctional compound of claim 23, wherein the linker LB is selected from:

wherein p 1 , p 2 , p 3 , p 4 , U, W, Z 1 are as defined in claim 23 .
The bifunctional compound of claim 24, wherein TL-LB is selected from:

wherein p 1 , p 2 , p 3 , p 4 , and Z 1 are as defined in claim 24 .
The bifunctional compound of claim 25, wherein the TL-LB is selected from:
The bifunctional compound of claim 24, wherein the TL-LB is selected from:
The bifunctional compound of claim 24, wherein the TL-LB is selected from:
The bifunctional compound of any one of claims 1-28, wherein the degron has formula D1:

or its stereoisomers,

wherein, each R 15 is arbitrarily independently selected from C 1-4 alkyl;

R 16 is selected from H, deuterium;

Each R 17 is arbitrarily and independently selected from halogen, C 1-4 alkyl, C 1-4 alkoxy, hydroxy;

Z 2 is selected from CH 2 or C=O;

Y is a bond, O, or NH, which is covalently attached to the linker;

m is selected from an integer from 0 to 3;

n is selected from an integer of 0-4.
The bifunctional compound of claim 29, wherein Z 2 in the degron D1 is selected from C=O.
The bifunctional compound according to claim 29, wherein Y in the degron D1 is selected from bond or NH.
The bifunctional compound of claim 29, wherein the degron D1 is selected from the group consisting of:
The bifunctional compound of any one of claims 1-28, wherein the degron has formula D2:

or its stereoisomers,

wherein each R 15 ' is arbitrarily and independently selected from C 1-4 alkyl;

R 16 ' is selected from H, deuterium;

each R 17 ' is arbitrarily and independently selected from halogen, C 1-4 alkyl, C 1-4 alkoxy;

Y' is a bond, O or NH, which is connected to the linker by a covalent bond;

m is selected from an integer from 0 to 3;

n is selected from an integer of 0-4.
The bifunctional compound of claim 33, wherein said degron D2 is selected from:
The bifunctional compound of any one of claims 1-28, wherein the degron has formula D3:

or its stereoisomers,

Wherein, R 18 is selected from H, C 1-4 alkyl;

each R 19 is arbitrarily independently selected from C 1-4 alkyl;

R 20 is selected from H, C 1-4 alkyl;

q is selected from an integer of 0-4.
The bifunctional compound of claim 35, wherein R18 in said degron D3 is methyl.
The bifunctional compound of claim 35, wherein R20 in said degron D3 is methyl.
The bifunctional compound of claim 35, wherein the degron D3 is selected from:
The bifunctional compound of any one of claims 1-28, wherein the degron has formula D4:

or its stereoisomers,

Y is a bond, or NH, which is covalently attached to the linker.
The bifunctional compound of claim 39, wherein said degron D4 is selected from:
The bifunctional compound of any one of claims 1-28, wherein the degron has the formula D5,

wherein, M is selected from NH, O or S;

V is a bond, NH or O, which is covalently attached to the linker;

R 21 is selected from halogen;

S is selected from 0, 1, 2 or 3.
The bifunctional compound of claim 41, wherein said degron D5 is selected from:
The bifunctional compound of any one of claims 1-28, wherein the degron is selected from:
The bifunctional compound according to any one of claims 1-43, wherein the targeting ligand (TL) is selected from:

The targeting ligand is
Covalently binds to the linker.
The bifunctional compound according to any one of claims 1-43, wherein the targeting ligand (TL) is selected from:
The bifunctional compound according to any one of claims 1-45, which is selected from:

Wherein, A, M, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , Y, R 20 , R 15 , n, linker, degron are as in any of claims 1-45 item defined.
The bifunctional compound of claim 46 selected from the group consisting of:

R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , Y, R 20 , R 15 , n, M, linkers and degrons are as defined in claim 46 .
The bifunctional compound of claim 47 selected from the group consisting of:

wherein R 6 , R 7 , R 15 , Y, n, linkers and degrons are as defined in claim 47 .
The bifunctional compound of claim 48 selected from the group consisting of:

wherein the linker, Y, R 20 , R 15 , and n are as defined in claim 48 .
Bifunctional compounds or stereoisomers, tautomers or pharmaceutically acceptable salts, prodrugs, hydrates, solvates, isotopically labeled derivatives thereof selected from:
A pharmaceutical composition comprising the bifunctional compound of any one of claims 1-50, and a pharmaceutically acceptable carrier.
Use of the bifunctional compound of any one of claims 1-50 or the pharmaceutical composition of claim 51 in the preparation of a drug for treating EGFR-mediated cancer.
The use according to claim 52, wherein the cancer is selected from the group consisting of lymphoma, non-Hodgkin's lymphoma, ovarian cancer, cervical cancer, prostate cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, Plasmoblastoma, Melanoma, Leukemia, Gastric Cancer, Endometrial Cancer, Lung Cancer, Hepatocellular Carcinoma, Gastrointestinal Stromal Tumor (GIST), Acute Myeloid Leukemia (AML), Cholangiocarcinoma, Kidney Cancer, Thyroid Cancer, Anaplastic large cell lymphoma, mesothelioma, multiple myeloma, melanoma.
Bifunctional compound as described in any one of claim 1-50, its preparation method comprises the following steps:

After the targeting ligand is connected to the linker, it is then connected to the degron to obtain:

Alternatively, the linker is linked to the degron and then linked to the targeting ligand to obtain:

Wherein, the targeting ligand, linker, and degron are as described in any one of claims 1-50.