WO2023143482A1

WO2023143482A1 - 2-aminopyrimidine compound or salt, preparation method therefor and use thereof

Info

Publication number: WO2023143482A1
Application number: PCT/CN2023/073500
Authority: WO
Inventors: 王永辉; 余发志; 程耀邦; 陈伟
Original assignee: 上海辉启生物医药科技有限公司
Priority date: 2022-01-29
Filing date: 2023-01-28
Publication date: 2023-08-03

Abstract

The present invention relates to a 2-aminopyrimidine compound as shown in formula (I), a pharmaceutically acceptable salt, a tautomer, a stereoisomer, a solvate or a prodrug thereof, a preparation method therefor, and a pharmaceutical composition comprising same. The present invention also relates to a method for treating or preventing cyclin-dependent kinase 12 (CDK12)-related diseases or disorders, and a use of the compound in the preparation of a drug for treating or preventing CDK12-related diseases or disorders.

Description

2-aminopyrimidine compound or its salt and its preparation method and use

technical field

The present invention relates to 2-aminopyrimidine compounds and their pharmaceutically acceptable salts, tautomers, stereoisomers, solvates or prodrugs, their preparation methods, and their pharmaceutical compositions. The present invention also relates to methods for treating or preventing cyclin-dependent kinase 12 (CDK12)-related diseases or disorders, and the use of the compound in the preparation of medicaments for treating or preventing CDK12-related diseases or disorders.

Background technique

Cyclin-dependent kinases (CDKs) are a family of protein kinases that catalyze the phosphorylation of serine/threonine, and 21 different CDKs have been discovered so far. According to the specific functional differences, it can be divided into two categories: one is the CDKs related to the regulation of cell cycle, including CDK1, 2, 4, 6 and 7; the other is the CDKs related to the regulation of RNA transcription, including CDK7, 8, 9, 11 , 12 and 13.

The gene encoding cyclin-dependent kinase 12 (CDK12) is located on autosome 17, encoding 1490 amino acids, and the protein molecular weight is 164kDa. The main structure includes proline-rich anchor structures (proline-rich motifs, PRM), Arginine/serine rich motifs (RS) and a catalytic kinase domain. CDK12 is currently known to have three main functions: (1) CDK12 phosphorylates RNA polymerase PoL II to promote transcription elongation; (2) CDK12 interacts with RNA processing factors to regulate splicing; (3) CDK12 mediates transcriptional RNA Polyadenylation of introns by polymerase II phosphorylation and mRNA 3'-end processing. Studies have shown that knocking out the CDK12 gene can lead to the expression silencing of its downstream genes, including DNA damage repair genes important to cells (such as BRCA1, ATR, FANCI, and FANCD2), forming a state similar to "DNA damage repair gene deficiency" , causing cells to become more sensitive to extrinsic conditions that cause DNA damage. At the same time, CDK12 regulates splicing of exons by localizing in nuclear speckles and pre-mRNA splice bodies. Overall, CDK12 is mainly involved in DNA damage response or stress response by regulating genome transcription and expression.

CDK12 is considered to be involved in the transcription elongation response of genes with long gene length, and affects the expression of genes such as BRCA1, ATR, FANCD2 (Blazek D. et al., Genes Dev., 2011, 25, 2158-2172). All these genes are a group of genes involved in DNA damage response (DDR), mainly involved in maintaining the stability of genomic DNA through DNA repair mechanism. Inhibition of CDK12 reduces the expression of DDR-related genes, thereby inhibiting DNA repair responses. As a result, the damaged DNA of cancer cells cannot be repaired, and the growth and survival of cancer cells are inhibited. In particular, it has been shown that inhibition of PARP and CDK12, both involved in DNA repair, completely suppresses the DNA repair response and induces cell death in cancer cells through synthetic lethality (Bajrami I. et al., Cancer Res., 2014, 74, 287-297).

Therefore, inhibition of CDK12 is very useful for treating or preventing tumors and/or cancers. CDK12 has specific contextual roles in tumor and cancer development, providing effective therapeutic approaches.

In recent years, several CDK12 inhibitors have been developed. THZ531 is a covalent inhibitor selective for CDK12/13 (European Journal of Medicinal Chemistry 221(2021) 113481). WO2019193509A1, EP3782986A1, Bioorg.Med.Chem.Lett.25(17), 3420-3435(2015)) etc. reported other types of CDK12 inhibitors respectively. However, the small molecule inhibitors of CDK12 reported so far have many hidden dangers of druggability: for example, the metabolic stability of mouse liver microsomes is poor, the exposure in vivo is low, and the metabolic half-life is short. On the other hand, the current small-molecule inhibitors of CDK12 basically show a considerable inhibitory effect on CDK13, and there are potential safety issues. Moreover, studies have shown that the existing small molecule inhibitors of CDK12 induce the generation of drug-resistant cell lines soon after administration (Jiang B. et al., Nat. Chem. Bio. 2021, 17, 675-683.).

Compounds that exploit cellular mechanisms involved in protein homeostasis, such as ubiquitination and proteasomal degradation, to target degradation of certain proteins have been found to be useful as therapeutic agents. Proteolysis-targeting chimeras (PROTACs) are a type of drug that uses the ubiquitin-proteasome pathway to target target proteins, which can cause intracellular degradation of target proteins (Eur J Med Chem.2018, 146 :251-259). PROTACs consist of three functional structures: (1) a part that can bind to a target protein; (2) a part that can bind to E3 ubiquitin ligase; and (3) a connecting chain between the first two parts. PROTACs can simultaneously bind the target protein and E3 ubiquitin ligase, so that the target protein that could not bind to E3 can bind to E3 and be ubiquitinated, and then be recognized and degraded by the proteasome (Angew.Chem.Int.Ed.Engl. , 2016, 55(6), 1996-1973).

Therefore, it is necessary to provide a bifunctional compound that binds both the target protein CDK12 and E3 ubiquitin ligase, so as to target and ubiquitinate CDK12, induce proteasome degradation of CDK12, and be used for treating related diseases or conditions. More advantageously, the bifunctional compound has good CDK12 specificity, improved physical and chemical properties and/or improved pharmacokinetic properties. Moreover, through the development of CDK12 degradation agents, problems such as drug resistance mutations of existing CDK12 small molecule inhibitors have been overcome.

Contents of the invention

Brief description of the invention

The present inventors unexpectedly found that the compound of the present invention can bind to both the target protein CDK12 and E3 ubiquitin ligase, thereby targeting and ubiquitinating CDK12, inducing proteasomal degradation of CDK12, and having good CDK12 degradation activity And good activity of inhibiting the proliferation of cancer cells. The inventors also unexpectedly found that the compounds of the present invention have good CDK12 specificity, improved physical and chemical stability and/or improved pharmacokinetic properties such as improved metabolic stability, and can be well formulated into medicines. Moreover, the compound of the present invention is not easy to cause drug resistance mutations, and overcomes the defects of known small molecule inhibitors of CDK12.

Accordingly, in a first aspect there is provided a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, stereoisomer, solvate or prodrug.

In a second aspect, there is provided a pharmaceutical composition comprising a compound of the invention together with a pharmaceutically acceptable carrier, diluent or excipient.

In a third aspect, there is provided a compound of the invention for use in the treatment or prevention of a CDK12-associated disease or disorder.

In a fourth aspect, there is provided a method of treating or preventing a CDK12-associated disease or condition in an individual, the method comprising administering to the individual an effective amount of a compound of the invention.

In the fifth aspect, the use of the compound of the present invention in the preparation of a medicament for treating or preventing CDK12-related diseases or disorders is provided.

In a sixth aspect, there is provided a compound of the invention in combination with another active agent.

In a seventh aspect, there is provided a process for the preparation of a compound of the invention.

These and other aspects of the invention are described in more detail below.

Detailed description of the invention

In one embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, stereoisomer, solvate or prodrug thereof,

in

X is N, C or CR ^x1 ;

Y is each independently O, N, CR ^y1 , CR ^y1 R ^y2 or NR ^y3 ;

Z is each independently O, N, CR ^z1 , CR ^z1 R ^z2 or NR ^z3 ;

m and n are each independently 0, 1 or 2, and m+n≤2;

When m is 2, the two Zs can be the same or different; when n is 2, the two Ys can be the same or different;

R ^x1 is selected from H, hydroxyl, halogen, CN or C _1-6 alkyl;

R ^y1 , R ^y2 , R ^z1 , R ^z2 and R ₄ are each independently selected from H, halogen, CN, NR ₆ R ₇ , oxo, C _1-6 alkyl, -OC _1-6 alkyl, C _3-8 cycloalkyl, -OC _3-8 cycloalkyl, -C _1-3 alkylene-C _3-8 cycloalkyl, or -OC _1-3 alkylene-C _3-8 cycloalkyl , each of the C _1-6 alkyl, C _1-3 alkylene and C _3-8 cycloalkyl is optionally substituted by a group selected from halogen, C _1-6 alkyl or C _1-6 haloalkyl ;

^Ry3 and ^Rz3 are each independently selected from H, C _1-6 alkyl, C _3-8 cycloalkyl, -CO-C _1-6 alkyl, nitrogen protecting group;

Indicates that the ring may be saturated, partially unsaturated, or aromatic;

R ₂ is selected from hydrogen, halogen, CN, C _1-3 alkyl, C _2-3 alkenyl, C _2-3 alkynyl, C _1-3 alkoxy, C _1-3 haloalkyl and cyclopropyl;

R ₁ and R ₃ are each independently selected from H; Halogen; CN; -OR ₅ ; -NR ₆ R ₇ ; C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{3- 8} cycloalkyl groups, 3-10 membered heterocyclic hydrocarbon groups, each of which is optionally substituted by one or more R ₈ ; C _6-10 aryl or 5-10 membered heteroaryl groups, each of which is optionally substituted by one or more R ₉ substitution; -CO-R _10a ; -COOR _10b ; -CO-NHR _10c ; -SO-R _10d ; -SO ₂ -R _10e ; or -P(=O)R ₁₁ R ₁₂ ;

R _is selected from H; C _1-6 alkyl optionally substituted by halogen, hydroxyl, CN and/or C _3-8 cycloalkyl; optionally substituted by halogen, CN and/or C _3-8 cycloalkyl C _3-8 cycloalkyl; optionally one or more R ₈ substituted 3-10 membered heterocyclic hydrocarbon group, one or more R ₉ substituted C _6-10 aryl, optionally one Or multiple R ₉ substituted 5-10 membered heteroaryls;

R ₆ and R ₇ are each independently selected from H; C _1-6 alkyl, C _3-8 cycloalkyl or 3-10 membered heterocyclic hydrocarbon group, each of which is optionally replaced by one or more selected from halogen, CN, Substituents of OH, C _1-6 alkyl and/or C _3-8 cycloalkyl; C _6-10 aryl or 5-7 membered heteroaryl, each of which is optionally selected from one or more halogen , CN, C _1-6 alkyl, C _1-6 haloalkyl, -C _1-3 alkylene-C _3-8 cycloalkyl, C _3-8 cycloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, -OC _1-3 alkylene-C _3-8 cycloalkyl, -SO-C _1-6 alkyl, -SO ₂ -C _1-6 alkyl, -SO-C _3-8 cycloalkyl, -SO ₂ -C _3-8 cycloalkyl, or -P(=O)R ₁₁ R ₁₂ substituent substitution; -CO-R _10a ; -CO-NHR _10c ; -SO- R _10d ; and -SO ₂ -R _10e ; or R ₆ and R ₇ can form a 4-7 membered heterocyclic hydrocarbon group together with the N they are connected to;

R ₈ is selected from halogen, CN, OH, C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl, C _3-8 cycloalkoxy;

R ₉ is selected from halogen, CN, OH, -NH ₂ , -NH(C _1-6 alkyl), -N(C _1-6 alkyl) ₂ , C _1-6 alkyl, C _1-6 haloalkyl , C _1-6 alkoxy, -C _1-3 alkylene-C _1-6 alkoxy, C _3-8 cycloalkyl, C _3-8 cycloalkoxy, -C _1-3 alkylene -C _3-8 cycloalkyl, -C _3-8 cycloalkylene-C _1-6 alkyl, -C(O)-NHC _1-6 alkyl, -C(O)-NHC _3-8 Cycloalkyl, -SO-C _1-6 alkyl, -SO-C _3-8 cycloalkyl, -SO ₂ -C _1-6 alkyl, -SO ₂ -C _3-8 cycloalkyl, -P (=O)R ₁₁ R ₁₂ or C _6-10 aryl;

R _10a , R _10b , R _10c , R _10d , R _10e are each independently selected from C _1-6 alkyl, C _3-8 cycloalkyl, 3-10 membered heterocyclic hydrocarbon group, C _6-10 aryl and 5 -10 membered heteroaryl;

R ₁₁ and R ₁₂ are each independently selected from C _1-6 alkyl or C _3-8 cycloalkyl;

L is an absent or saturated or partially unsaturated divalent C _1-24 hydrocarbon chain, wherein one or more hydrocarbon chain units of the hydrocarbon chain are optionally independently selected from the group consisting of -O-, -CO-, - NR ^L3 -, -SO-, -SO ₂ - and/or units of 3-12 membered cyclic groups are replaced, and L is optionally replaced by one or more independently selected from deuterium, halogen, CN, OH, NH ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, 4-8 membered heterocyclic hydrocarbon groups containing oxygen atoms or nitrogen atoms, and C _3-8 cycloalkyl substituents, Wherein R ^L3 is H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl or nitrogen protecting group; And wherein, when the two cyclic groups in the linking base L are adjacent , which optionally together form a fused ring, a spiro ring or a bridged ring; and

E is the E3 ubiquitin ligase binding moiety.

In some embodiments, X is N, C or CH.

In some embodiments, each Y is independently O, N, CH or _CH2 , preferably N, CH or _CH2 .

In some embodiments, each Z is independently O, N, CH or _CH2 , preferably N, CH or _CH2 .

In some embodiments, m is 1 and n is 0. In other embodiments, m is 1 and n is 1. In other embodiments, m is 0 and n is 1. In other embodiments, m is 0 and n is 2. In other embodiments, m is 2 and n is 0.

In some embodiments, compounds of Formula (I) of the present invention have the structure of Formula (Ia):

Wherein, each variable is as defined herein.

Those skilled in the art can understand that, Each may be saturated, partially unsaturated, or aromatic. The selection of X, Y, Z and substituents on the ring should conform to the rules of valence and be chemically feasible, which can be routinely determined by those skilled in the art. When vacant valences are shown on a ring member, it indicates that an unmarked hydrogen atom is attached to the ring member.

In some embodiments, Moieties are subunit moieties derived from the following: cyclobutane, azetidine, oxetane, cyclopentane, azacyclopentane, oxolane, diazolane, cyclo Pentene, cyclopentadiene, pyrrole, pyrazole, imidazole, triazole, furan or oxazole. Preferably, said moiety is a subunit moiety derived from: azacyclopentane, pyrrole, pyrazole, triazole.

In some embodiments, Sections can be selected from:

In some embodiments, R ₄ is selected from H, halogen, CN, oxo, C _1-6 alkyl, or C _3-8 cycloalkyl. Preferably, R ₄ is selected from H, halogen, CN, oxo or C _1-3 alkyl. More preferably, _R4 is hydrogen.

In some embodiments, R _is selected from H, halogen, CN, C _1-3 alkyl, C _2-3 alkenyl, C _2-3 alkynyl, and C _1-3 haloalkyl. Preferably, R ₂ is H, halogen, CN or C _1-3 haloalkyl. More preferably, _R2 is H, halogen, CN or _CF3 , most preferably halogen. In some preferred embodiments, R ₂ is halogen or C _1-3 haloalkyl, preferably Cl or CF ₃ .

In other embodiments, R ₁ and R ₃ are each independently selected from H; halogen; CN; OH; NR ₆ R ₇ ; C _1-6 _alkyl , optionally substituted by one or more R ₈ ; _-10 aryl or 5-10 membered heteroaryl, each of which is optionally substituted by one or more R ₉ .

In some embodiments, R ₆ is H.

In other embodiments, R _is selected from H; C _3-8 cycloalkyl or 3-10 membered heterocyclyl, each of which is optionally replaced by one or more selected from halogen, CN, OH, C _1-3 Substituents of alkyl and/or C _3-6 cycloalkyl; and C _6-10 aryl such as phenyl or 5-7 membered heteroaryl, each of which is optionally selected from one or more C _{1- 6} alkyl, -SO-(C _1-6 alkyl), -SO ₂ -(C _1-6 alkyl) or -P(=O)(C _1-6 alkyl)(C _1-6 alkyl ) substituent substitution. Preferably, R ₇ is selected from H; and C _6-10 aryl such as phenyl or 5-7 membered heteroaryl, each of which is optionally replaced by one or more each independently selected from C _1-6 alkyl, - Substituents of SO-(C _1-6 alkyl), -SO ₂ -(C _1-6 alkyl) or -P(=O)(C _1-6 alkyl)(C _1-6 alkyl) .

In some embodiments, each R ₈ is independently selected from halogen, CN, OH, C _1-6 alkyl, and C _1-6 alkoxy. Preferably, each R ₈ is independently selected from halogen, CN, OH, C _1-3 alkyl and C _1-3 alkoxy. More preferably, _{each R8} is independently selected from halogen and OH.

In some embodiments, each R ₉ is independently selected from halogen, CN, OH, -NH ₂ , -NH(C _1-6 alkyl), -N(C _1-6 alkyl) ₂ , C _1-6 Alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, -C _1-3 alkylene-C _3-8 cycloalkyl, C _3-8 cycloalkyl, C _3-8 cycloalkoxy group, -C _3-8 cycloalkylene-C _1-3 alkyl, SO-(C _1-6 alkyl), -SO ₂ -(C _1-6 alkyl) or -P(=O)( C _1-6 alkyl) (C _1-6 alkyl). Preferably, each R ₉ is independently selected from halogen, CN, OH, -NH ₂ , C _1-6 alkyl, C _1-6 haloalkyl, -C _1-3 alkylene-C _3-6 cycloalkyl , SO-(C _1-6 alkyl), -SO ₂ -(C _1-6 alkyl) or -P(=O)(C _1-6 alkyl)(C _1-6 alkyl).

In some embodiments, _one of R _and R is H, and the other is selected from H; C _1-6 haloalkyl; C _1-6 hydroxyalkyl; NR ₆ R ₇ , wherein R ₆ is H, and R ₇ is optionally selected from one or more groups selected from C _1-6 alkyl, -SO-(C _1-6 alkyl), -SO ₂ -(C _1-6 alkyl) or -P(=O) (C _1-6 alkyl) (C _1-6 alkyl) substituent substituted phenyl or 5-7 membered nitrogen-containing heteroaryl; phenyl; halogenated phenyl; 5-10 membered nitrogen-containing heteroaryl A group such as pyrazolyl, pyridyl, indolyl, indazolyl or azaindolyl, optionally replaced by one or more selected from halogen, CN, C _1-6 alkyl, C _1-6 haloalkyl, -C _1-3 alkylene-C _3-6 cycloalkyl, SO-(C _1-6 alkyl), -SO ₂ -(C _1-6 alkyl) or -P(=O)(C _{1 -6} alkyl) (C _1-6 alkyl) substituent substitution.

In some embodiments, _one of R _and R is H, and the other is selected from H, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, phenyl, halophenyl,

In some embodiments, the formula (I) has the structure of formula (Ib):

Wherein, each variable is as defined herein.

In some embodiments, _the linker L is absent or is a saturated or partially unsaturated divalent C _1-24 hydrocarbon chain, preferably a C _1-18 hydrocarbon chain, more preferably a C _1-12 hydrocarbon chain, wherein the hydrocarbon chain One or more hydrocarbon chain units of are optionally independently replaced by -O-, -CO-, -NH-, -SO-, -SO ₂ - and/or 3-10 membered cyclic groups, and wherein L is any One or more are independently selected from deuterium, halogen, CN, OH, NH ₂ , C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 hydroxyalkyl, 4- Substituents of 6-membered heterocyclic hydrocarbon group and C _3-6 cycloalkyl group; and wherein, when the two cyclic groups in the linker L are adjacent, they optionally form a condensed ring, a spiro ring or a bridged ring together form.

Preferably, the cyclic groups that are part of L are each independently selected from divalent groups derived from: C _3-8 cycloalkane; 3-8 membered nitrogen-containing heterocyclic hydrocarbon; C _6-10 aromatic ring; 5 -7-membered nitrogen-containing heteroaromatic ring; wherein when two cyclic groups are adjacent, they optionally form a condensed ring, a spiro ring or a bridged ring together; and the cyclic group is optionally surrounded by one or more Substituents independently selected from deuterium, halogen, OH, NH ₂ are substituted.

Preferably, the cyclic groups that are part of L are each independently selected from divalent groups derived from: C _3-8 cycloalkane; 3-8 membered nitrogen-containing heterocyclic hydrocarbon; C _6-10 aromatic ring; 5 - a 7-membered nitrogen-containing heteroaryl ring; wherein when two cyclic groups are adjacent, they optionally together form a condensed ring, a spiro ring or a bridged ring.

More preferably, the cyclic groups that are part of L are each independently selected from divalent groups selected from the group consisting of: cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclohexane, azepine Cyclopropane, azetidine, pyrrole, dihydropyrrole, pyrrolidine, pyrazole, pyrazoline, pyrazolidine, imidazole, imidazoline, imidazolidine, triazole, triazolidine, tetrazole, tetrazolidine , pyridine, dihydropyridine, tetrahydropyridine, piperidine, pyridazine, dihydropyridazine, tetrahydropyridazine, hexahydropyridazine, pyrimidine, dihydropyrimidine, tetrahydropyrimidine, hexahydropyrimidine, pyrazine, two Hydropyrazine, tetrahydropyrazine, piperazine and benzene ring; wherein when two cyclic groups are adjacent, they optionally form a condensed ring, a spiro ring or a bridged ring together.

In some embodiments, L is a saturated or partially unsaturated divalent C _1-18 hydrocarbon chain, preferably a C _1-12 hydrocarbon chain, wherein one or more hydrocarbon chain units of said hydrocarbon chain are optionally independently represented by - O-, -CO-, -NH-, -SO-, -SO ₂ -, 3-8 membered nitrogen-containing heterocycloalkanes and/or 5-7 membered nitrogen-containing heteroaromatic rings, and wherein, when the linker L When two cyclic groups in are adjacent to each other, they optionally form a condensed ring, a spiro ring or a bridged ring together.

In other embodiments, L is a saturated or partially unsaturated divalent C _1-12 hydrocarbon chain, wherein one or more hydrocarbon chain units of the hydrocarbon chain are optionally independently represented by -O-, -CO-, -NH- and/or 4-7 membered nitrogen-containing heterocycloalkanes (such as piperidine ring, piperazine ring, tetrahydropyrrole, azetidine, etc.) are replaced, and wherein, when the two rings in the linker L When the like groups are adjacent, they optionally together form a fused ring, a spiro ring or a bridged ring.

It will be appreciated that the units used to replace the hydrocarbon chain units may or may not be adjacent when there is more than one.

It is also understood that a cyclic group that is part of L may be attached to the rest of the linker L via any available ring member on the ring, as chemically feasible. When two cyclic groups in the linker L are adjacent, they together form a condensed ring, a spiro ring or a bridged ring, such as 7 containing one or more heteroatoms independently selected from N, O and/or S -10-membered bridge ring, spiro ring or condensed ring form, for example with form.

It is also understood that optional substituents on linker L may be on any chain unit, including on hydrocarbon chain units and/or on replacement units for hydrocarbon chain units.

In some embodiments, L is selected from:

In some preferred embodiments, L is selected from:

In some embodiments, L is selected from:

(i) -(CH ₂ ) _i -(4-7 membered nitrogen-containing heterocycloalkane)-(CH ₂ ) _ii -, wherein i and ii are integers from 0 to 11, and i+ii≤11; preferably, -(4-7 membered nitrogen-containing heterocycloalkane)-(CH ₂ ) _0-11 -;

(ii) -(CH ₂ ) _a -(4-7 membered nitrogen-containing heterocycloalkane)-CO-(CH ₂ ) _b -, wherein a and b are integers from 0 to 10, and a+b≤10; preferably Ground, -(4-7 membered nitrogen-containing heterocycloalkane)-CO-(CH ₂ ) _0-10 -;

(iii) -O-(CH ₂ ) _x -CO-NH-(CH ₂ ) _y -, wherein x and y are integers from 0 to 9, and x+y≤9;

(iv)-O-(CH ₂ ) _r -CO-(4-7-membered nitrogen-containing heterocycloalkane)-(CH ₂ ) _s -(4-7-membered nitrogen-containing heterocycloalkane)-(CH ₂ ) _t - CO-, where r, s and t are integers from 0 to 7, and r+s+t≤7;

(v)-(CH ₂ ) _a -(4-7 membered nitrogen-containing heterocycloalkane)-(CH ₂ ) _b -(4-7 membered nitrogen-containing heterocycloalkane)-(CH ₂ ) _c -, where a, b and c are integers from 0 to 10, and a+b+c≤10; preferably, -(4-7-membered nitrogen-containing heterocycloalkane)-(CH ₂ ) _b -(4-7-membered nitrogen-containing heterocycle Alkanes)-( _CH2 ) _c- , wherein b and c are integers from 0 to 10, and b+c≤10;

(vi)-(CH ₂ ) _x -(4-7 membered nitrogen-containing heterocycloalkane)-(CH ₂ ) _y -(4-7 membered nitrogen-containing heterocycloalkane)-(CH ₂ ) _z -CO-, where x, y and z are integers from 0 to 9, and x+y+z≤9; preferably, -(4-7-membered nitrogen-containing heterocycloalkane)-(CH ₂ ) _y -(4-7-membered Heterocycloalkane)-( _CH2 ) _z -CO-, y and z are integers from 0 to 9, and y+z≤9; and

(vii) -(CH ₂ ) _x -(4-7 membered nitrogen-containing heterocycloalkane)-(CH ₂ ) _y -(4-7 membered nitrogen-containing heterocycloalkane)-CO-(CH ₂ ) _z -, where x, y and z are integers from 0 to 9, and x+y+z≤9; preferably, -(4-7-membered nitrogen-containing heterocycloalkane)-(CH ₂ ) _y -(4-7-membered Heterocycloalkane)-CO-(CH ₂ ) _z -, y and z are integers from 0 to 9, and y+z≤9;

Preferably, the 4-7 membered nitrogen-containing heterocycloalkane is piperazine ring, piperidine ring, tetrahydropyrrole or azetidine.

In some embodiments, L is selected from:

Wherein, the 4-7 membered nitrogen-containing heterocycloalkane is optionally substituted by OH;

It is understood that, unless otherwise indicated, the above-mentioned L moiety can be attached to the remaining two moieties of the molecule in any direction, for example, from left to right, or from right to left.

In some embodiments, E is an E3 ubiquitin ligase binding moiety. It can specifically bind E3 ubiquitin ligase in vivo. In some embodiments, E is a moiety of formula (Ea):

in,

V is N or CR _v , wherein R _v is hydrogen or C _1-6 alkyl optionally substituted by one or more halogen, hydroxyl and/or CN; preferably, V is N, CH, -C(C _{1 -6} alkyl)-; More preferably, V is N or CH;

W is a single bond, -NH-, -NH-CO-, -NH- _Rw- , or _Rw , wherein _Rw is C _1-6 optionally substituted by one or more halogen, hydroxyl and/or CN Alkylene; preferably, W is a single bond, -NH-, -NH-CO-, -NH-C _1-6 alkylene-, or -C _1-6 alkylene-; more preferably, W is a single bond, -NH-, -NH-CO-, -NH-C _1-3 alkylene-, or -C _1-3 alkylene-;

R _is selected from H, halogen, CN or C _1-6 alkyl; preferably, R _is selected from H, halogen, CN or C _1-3 alkyl; and

B is a 3-10 membered cyclic group, preferably a _C3-8 cycloalkyl group, a 3-10 membered heterocyclic hydrocarbon group (such as a 3-8 membered monocyclic heterocyclic hydrocarbon group or a 7-10 membered bicyclic heterocyclic hydrocarbon group) , C _6-10 aryl (for example phenyl) or 5-10 membered heteroaryl (for example 5-8 membered monocyclic heteroaryl or 7-10 membered bicyclic heteroaryl), any of the cyclic groups Optionally replaced by one or more R _s2 ;

wherein R _s2 are each independently selected from halogen, CN, OH, oxo, NH ₂ , -NH(C _1-6 alkyl), -N(C _1-6 alkyl) ₂ , C _1-6 alkyl , C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, C _3-6 cycloalkyloxy base, -C(O)-C _1-6 alkyl, -C(O)-C _3-6 cycloalkyl, -SO-C _1-6 alkyl, -SO-C _3-6 cycloalkyl, -SO ₂ -C _1-6 alkyl, -SO ₂ -C _3-6 cycloalkyl, C _6-10 aryl and halogenated C _6-10 aryl; preferably, each R _s2 is independently selected from halogen , CN, OH, oxo, NH ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl and C _1-6 alkoxy; more preferably, each of R _s2 is independently is selected from halogen, CN, OH, NH ₂ and C _1-6 alkyl.

In some embodiments, V is N, CH, -C(C _1-6 alkyl)-, preferably N or CH.

In some embodiments, W is a single bond, -NH-, -NH-CO-, -NH-C _1-6 alkylene-, or -C _1-6 alkylene-. Preferably, W is a single bond, -NH-, -NH-CO-, -NH-C _1-3 alkylene-, or -C _1-3 alkylene-.

In some embodiments, B is C _3-8 cycloalkyl, 3-10 membered heterocycloalkyl (such as 3-8 membered monocyclic heterocycloalkyl or 7-10 membered bicyclic heterocycloalkyl), C _6-10 Aryl (eg phenyl) or 5-10 membered heteroaryl (eg 5-8 membered monocyclic heteroaryl or 7-10 membered bicyclic heteroaryl), each optionally substituted by one or more R _s2 .

In some embodiments, each R _s2 is independently selected from halogen, CN, OH, oxo, NH ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, and C _{1 -6} alkoxy. Preferably, each R _s2 is independently selected from halogen, CN, OH, NH ₂ and C _1-6 alkyl.

In some embodiments, the moiety of formula (Ea) has the structure of formula (Ea1):

wherein q is 0, 1, 2, 3 or 4, and other variables are as defined herein. In some embodiments, V is N or CH; W is a single bond, -NH-, -NH-C _1-6 alkylene-, or -C _1-6 alkylene-; Ra is H; and q is 0. It will be appreciated that the moiety of formula (Ea1) is attached to the rest of the molecule through any available position on the right-hand phenyl ring.

In some preferred embodiments, the structure of formula (Ea1) is:

In some embodiments, E has the structure of formula (Ea2):

in,

R _a is H, halogen, CN or C _1-6 alkyl; preferably H or C _1-3 alkyl;

U is -CO-, -CR _u1 R _u1 - or -CO-CR _u1 R _u1 -, wherein CR _u1 and R _u1 are each independently H or C _1-6 alkyl; preferably, U is -CO- or _-CH2- ;

R _s2 are each independently selected from halogen, CN, OH, NH ₂ _, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl and C _1-6 alkoxy; preferably, R _s2 are each independently selected from halogen, CN, OH, C _1-3 alkyl or C _1-3 haloalkyl; and

r is 0, 1, 2, 3 or 4.

It will be appreciated that the moiety of formula (Ea2) is attached to the rest of the molecule through any available position on the right-hand benzo ring.

Preferably, R _a is H or C _1-3 alkyl. Also preferably, U is -CO- or -CH ₂ -. Also preferably, R _s2 is halogen, CN, OH, C _1-6 alkyl or C _1-6 haloalkyl, preferably halogen, CN, OH, C _1-3 alkyl or C _1-3 haloalkyl, more Halogen is preferred.

In some preferred embodiments, the structure of formula (Ea2) is:

In some embodiments, the moiety of formula (Ea) has the structure of formula (Ea3):

in,

P is N, C or CH;

Q is N, NH, -CO-, -CR _q1 R _q1 - or -CO- _CR _q1 R _q1 -, wherein CR _q1 and R _q1 are each independently H or C _1-6 alkyl such as C _1-3 alkane group; preferably, Q is N, NH, -CO- or -CH ₂ -; and

R _s2 is H or C _1-6 alkyl such as C _1-3 alkyl;

represents a single or double bond; and

V, W and _Ra are as defined herein.

It will be appreciated that the moiety of formula (Ea3) is attached to the rest of the molecule through any available position on the right-hand benzo ring.

In some preferred embodiments, the structure of formula (Ea3) is:

In other embodiments, E is a moiety of formula (Eb):

in:

R _S3 and R _S4 are each independently selected from H; C _1-6 alkyl, C _3-8 cycloalkyl or 3-10 membered heterocyclic hydrocarbon group, each of which is optionally substituted by halogen or hydroxyl; C _6-10 aromatic or 5-10 membered heteroaryl, each of which is optionally substituted by one or more R ₉ ; or R _S3 , R _S4 and the carbon atom to which they are attached together form C optionally substituted by one or more R ₈ _3-8 cycloalkyl;

R _S5 is O, -NH-, C _3-8 cycloalkylene optionally substituted by one or more R ₈ , C _6-10 arylene optionally substituted by one or more R ₉ , optionally A 5-10 membered heteroarylene group substituted by one or more R ₉ ;

R _S6 and R _S7 are each independently selected from H and C _1-6 alkyl optionally substituted by one or more R ₈ ;

R _S8 _is H; _Halogen ; CN; OH _; NO ₂ _; -NR _S9 _R _S10 ; -OR _S11 ; -CONR _S9 _R _S10 _; _S10 ; C _1-6 alkyl, C _3-8 cycloalkyl or 3-10 membered heterocyclic hydrocarbon group, each of which is optionally substituted by one or more R ₈ ; C _6-10 aryl or 5-10 membered heterocyclic Aryl, each of which is optionally substituted by one or more R ₉ ;

Each of R _S9 and R _S10 is independently hydrogen or C _1-6 alkyl optionally substituted by one or more R ₈ .

In particular, Part E is selected from:

In a preferred embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, stereoisomer, solvate or prodrug thereof, wherein

X is N, C or CH;

Y is each independently N, CH or _CH2 ;

Z is each independently N, CH or _CH2 ;

m and n are each independently 0, 1 or 2, and m+n≤2;

_R is selected from H, halogen, CN and OH, more preferably H;

Indicates that the ring may be saturated, partially unsaturated, or aromatic;

R ₂ is H, halogen, CN or C _1-3 haloalkyl;

R ₁ and R ₃ are each independently selected from H; -NHR ₇ ; C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl; phenyl optionally substituted by halogen; or 5- 10-membered heteroaryl, which is optionally substituted by one or more R ₉ ;

R ₇ is C _6-10 aryl (such as phenyl) or 5-7 membered heteroaryl, optionally replaced by C _1-6 alkyl, -SO-(C _1-6 alkyl), -SO ₂ -( C _1-6 alkyl) or -P (=O) (C _1-6 alkyl) (C _1-6 alkyl) substitution;

R ₉ are each independently selected from halogen, CN, C _1-6 alkyl, C _1-6 haloalkyl, -C _1-3 alkylene-C _3-6 cycloalkyl, -SO-(C _1-6 alkyl), -SO ₂ -(C _1-6 alkyl) and -P(=O)(C _1-6 alkyl)(C _1-6 alkyl);

L is an absent or saturated or partially unsaturated divalent C _1-18 hydrocarbon chain, preferably a C _1-12 hydrocarbon chain, wherein one or more hydrocarbon chain units of the hydrocarbon chain are optionally independently replaced by -O- , -CO-, -NH-, -SO-, -SO ₂ - and/or 3-10 membered cyclic groups (for example derived from C _3-8 cycloalkane, 3-8 membered heterocyclic hydrocarbon, C _{6- 10} aryl or a divalent group of a 5-7 membered heteroaryl ring), and wherein L is optionally replaced by one or more independently selected from deuterium, halogen, CN, OH, NH ₂ , C _1-3 alkyl , C _1-3 haloalkyl, C _1-3 hydroxyalkyl, a 4-6 membered heterocyclic hydrocarbon group containing an oxygen atom, and a C _3-6 cycloalkyl substituent; and wherein, when the linking group L When two cyclic groups are adjacent, they optionally together form a fused ring, a spiro ring or a bridged ring; and

E is an E3 ubiquitin ligase binding moiety, preferably a moiety of formula (Ea), more preferably a moiety of formula (Ea1), (Ea2) or (Ea3).

In some embodiments, there is provided a compound of formula (I), or a pharmaceutically acceptable salt, tautomer, stereoisomer, solvate or prodrug thereof, wherein:

X is N, C or CH;

Y is each independently N, CH or _CH2 ;

Z is each independently N, CH or _CH2 ;

m and n are each independently 0, 1 or 2, and m+n≤2;

_R is selected from H, halogen, CN and OH, more preferably H;

Indicates that the ring may be saturated, partially unsaturated, or aromatic;

R ₂ is H, halogen, CN or C _1-3 haloalkyl;

One of R ₁ and R ₃ is H, and the other is H; -NHR ₇ ; 5-10 yuan nitrogen-containing heteroaryl, such as 7-10 yuan nitrogen-containing heteroaryl, such as indolyl;

R ₇ is phenyl, optionally replaced by -SO-(C _1-6 alkyl), -SO ₂ -(C _1-6 alkyl) or -P(=O)(C _1-6 alkyl) (C _1-6 alkyl) substitution;

L is a saturated or partially unsaturated divalent C _1-18 hydrocarbon chain, preferably a C _1-12 hydrocarbon chain, wherein one or more hydrocarbon chain units of the hydrocarbon chain are optionally independently represented by -O-, -CO- , -NH-, -SO-, -SO ₂ -, 3-8 membered nitrogen-containing heterocycloalkane and/or 5-7 membered nitrogen-containing heteroaromatic rings, and wherein, when the two rings in the linker L When the groups are adjacent, they optionally together form a fused ring, a spiro ring or a bridged ring; and

E is part of the following formula:

wherein R _a is H or C _1-3 alkyl, and U is -CO- or -CH ₂ -.

X is N, C or CH;

Y is each independently N, CH or _CH2 ;

Z is each independently N, CH or _CH2 ;

m and n are each independently 0, 1 or 2, and m+n≤2;

_R is selected from H, halogen, CN and OH, more preferably H;

Indicates that the ring may be saturated, partially unsaturated, or aromatic;

R ₂ is H, halogen, CN or C _1-3 haloalkyl;

E is part of the following formula:

wherein R _a is H or C _1-3 alkyl, and U is -CO- or -CH ₂ - _; R _s2 are each independently selected from halogen, CN, or C _1-3 alkyl, preferably halogen; and r is 0 or 1;

Preferably, each R _s2 is independently selected from halogen, and r is 0 or 1; more preferably, each R _s2 is independently selected from F, and r is 0 or 1.

In other embodiments, there is provided a compound of formula (I), or a pharmaceutically acceptable salt, tautomer, stereoisomer, solvate or prodrug thereof, wherein said compound has formula (Ib):

and among them

R ₂ is H, halogen, CN or C _1-3 haloalkyl, preferably H, halogen, CN, CF ₃ ; more preferably halogen;

L is a saturated or partially unsaturated divalent C _1-12 hydrocarbon chain, wherein one or more hydrocarbon chain units of the hydrocarbon chain are optionally independently replaced by -O-, -CO-, -NH- and/or 4 -7-membered nitrogen-containing heterocycloalkane (such as piperidine ring, piperazine ring, tetrahydropyrrole, azetidine) replacement, and wherein, when the two cyclic groups in the linker L are adjacent, they Optionally together form a condensed ring, a spiro ring or a bridged ring (for example with in the form of ); and

E is part of the following formula:

wherein R _a is H or C _1-3 alkyl, and U is -CO- or -CH ₂ -.

and among them

One of R ₁ and R ₃ is H, and the other is H; -NHR ₇ ; 5-10 yuan nitrogen-containing heteroaryl, for example 7-10 yuan nitrogen-containing heteroaryl, such as indolyl or 1H-pyrrole [ 2,3-[2,3-b]pyridine (1H-pyrrolo[2,3-b]pyridine);

E is part of the following formula:

The above and other aspects of the present invention can be combined arbitrarily to form technical solutions not directly described.

In a preferred embodiment, the compound of the invention is selected from the compounds of the Examples, such as:

definition

In this application, unless otherwise specified, the terms used in this application have the meanings defined below. Terms not explicitly defined in the present application have ordinary meanings generally understood by those skilled in the art.

As used in this application, the terms "a", "an", "the" and similar terms should be understood to include both the singular and the plural unless the context specifically dictates otherwise or is clearly contradicted by context.

A dash ("-") not between two letters or symbols indicates the point of attachment of a substituent. For example, -NR ₆ R ₇ means that the group is attached to the rest of the molecule through a nitrogen atom. However, "-" can be omitted when the point of attachment of the substituent is obvious to those skilled in the art (eg, for halogen, hydroxyl, _NR6R7 _, etc.).

When the bond of the group has a wavy line When , it means that the group is attached to the rest of the molecule through this bond.

When a dashed ring is used in a ring structure, it means that the ring structure may be saturated, partially unsaturated, or aromatic.

When a valence bond passes through a ring, such as in In , it means that the ring is connected to other moieties through any available position on the ring.

symbol Indicates a single or double bond. This can be determined by a person skilled in the art on the basis of conventional knowledge in the field of chemistry.

The term "halogen" or "halo" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I). Preferred halogens are fluorine and chlorine.

The term "alkyl" alone or as part of another group denotes a fully saturated straight or branched chain hydrocarbon group consisting of carbon and hydrogen atoms. The alkyl group preferably has 1-12 carbon atoms (i.e. C _1-12 alkyl), more preferably 1-8 carbon atoms (i.e. C _1-8 alkyl), 1-6 carbon atoms (i.e. C _1-6 Alkyl), 1-4 carbon atoms (ie C _1-4 alkyl) or 1-3 carbon atoms (ie C _1-3 alkyl). Representative examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (Pr) (including n-propyl and isopropyl), butyl (Bu) (including n-butyl, isopropyl butyl, sec-butyl and tert-butyl), pentyl (including n-pentyl, isopentyl, neopentyl, etc.), hexyl, heptyl, octyl, nonyl, decyl, dodecyl, etc.

The term "alkylene", alone or as part of another group, denotes a fully saturated straight or branched chain divalent hydrocarbon group composed of carbon and hydrogen atoms. The alkylene group preferably has 1-12 carbon atoms (i.e. C _1-12 alkylene), more preferably 1-8 carbon atoms (i.e. C _1-8 alkylene), 1-6 carbon atoms (i.e. C _1-6 alkylene), 1-4 carbon atoms (ie C _1-4 alkylene) or 1-3 carbon atoms (ie C _1-3 alkylene). Representative examples of alkylene include, but are not limited to, methylene, ethylene, propylene, butylene, and the like.

The term "alkenyl" alone or as part of another group denotes a straight or branched chain hydrocarbon group consisting of carbon atoms and hydrogen atoms containing at least one double bond. Alkenyl preferably has 2-12 carbon atoms (ie C _2-12 alkenyl ₎ , more preferably 2-8 carbon atoms (ie C _2-8 alkenyl), 2-6 carbon atoms (ie C _2-6 alkenyl), 2-4 carbon atoms (i.e. C _2-4 alkenyl) or 2-3 carbon atoms (i.e. C _2-3 alkenyl). Representative examples of alkenyl include, but are not limited to, vinyl, propenyl, allyl, butenyl, isobutenyl, pentenyl, isopentenyl, hexenyl, heptenyl, and the like.

The term "alkenylene" alone or as part of another group denotes a straight or branched divalent hydrocarbon group consisting of carbon atoms and hydrogen atoms containing at least one double bond. Alkenylene preferably has 2-12 carbon atoms (ie C _2-12 alkenylene), more preferably 2-8 carbon atoms (ie C _2-8 alkenylene), 2-6 carbon atoms (ie C _2-6 alkenylene), 2-4 carbon atoms (ie C _2-4 alkenylene) or 2-3 carbon atoms (ie C _2-3 alkenylene). Representative examples of alkenylene include, but are not limited to, ethenylene, propenylene, allylylene, butenylene, and the like.

The term "alkynyl" alone or as part of another group denotes a straight or branched chain hydrocarbon group consisting of carbon atoms and hydrogen atoms containing at least one triple bond. The alkynyl preferably contains 2-12 carbon atoms (ie C _2-12 alkynyl), more preferably 2-8 carbon atoms _{(ie C 2-8} _alkynyl ), 2-6 carbon atoms (ie C _2-6 alkynyl), 2-4 carbon atoms (ie C _2-4 alkynyl) or 2-3 carbon atoms (ie C _2-3 alkynyl). Representative examples of alkynyl include, but are not limited to, ethynyl, propynyl, propargyl, butynyl, isobutynyl, pentynyl, isopentynyl, hexynyl, heptynyl, and the like.

The term "alkynylene" alone or as part of another group denotes a straight or branched divalent hydrocarbon group consisting of carbon atoms and hydrogen atoms containing at least one triple bond. Alkynylene preferably has 2-12 carbon atoms (i.e. C _2-12 alkynylene), more preferably 2-8 carbon atoms (i.e. C _2-8 alkynylene), 2-6 carbon atoms (i.e. C _2-6 alkynylene), 2-4 carbon atoms (ie C _2-4 alkynylene), or 2-3 carbon atoms (ie C _2-3 alkynylene). Representative examples of alkynylene include, but are not limited to, ethynylene, propynylene, butynylene, and the like.

The term "haloalkyl" refers to a group as defined herein wherein one or more hydrogen atoms, such as 1, 2, 3, 4, 5, 6 or 7 hydrogen atoms, such as 1, 2 or 3 hydrogen atoms, are replaced by a halogen alkyl. It is understood that when there is more than one halogen substituent, the halogens may be the same or different and may be located on the same or different carbon atoms. Haloalkyl is preferably C _1-12 haloalkyl, More preferably, it is C _1-8 haloalkyl, C _1-6 haloalkyl, C _1-4 haloalkyl or C _1-3 haloalkyl. Representative examples of haloalkyl include, but are not limited to, fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, fluorochloromethyl, trifluoromethyl, trichloromethyl, dichlorofluoromethyl, 2 , 2-difluoroethyl, trifluoroethyl, trichloroethyl, difluorochloroethyl, difluoropropyl and trifluoropropyl, etc.

Similarly, the terms "haloalkenyl" and "haloalkynyl" refer to one or more hydrogen atoms, such as 1, 2, 3, 4, 5, 6 or 7 hydrogen atoms, such as 1, 2 or 7 hydrogen atoms, respectively. Alkenyl and alkynyl groups as defined herein with 3 hydrogen atoms replaced by halogen. It is understood that when there is more than one halogen substituent, the halogens may be the same or different and may be located on the same or different carbon atoms.

The term "hydroxyalkyl" refers to a group as defined herein wherein one or more hydrogen atoms, such as 1, 2, 3, 4, 5, 6 or 7 hydrogen atoms, such as 1, 2 or 3 hydrogen atoms, are replaced by a hydroxyl group of alkyl. The hydroxyalkyl group is preferably a C _1-12 hydroxyalkyl group, more preferably a C _1-8 hydroxyalkyl group, a C _1-6 hydroxyalkyl group, a C _1-4 hydroxyalkyl group or a _C _1-3 hydroxyalkyl group. Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxypropyl, and the like.

The terms "alkoxy" or "alkyloxy" are used interchangeably to denote an alkyl group as defined above attached through an oxygen bridge. Alkoxy preferably has 1-12 carbon atoms (ie C _1-12 alkoxy), more preferably 1-8 carbon atoms (ie C _1-8 alkoxy), 1-6 carbon atoms (ie C _1-6 alkoxy), 1-4 carbon atoms (ie C _1-4 alkoxy) or 1-3 carbon atoms (ie C _1-3 alkoxy). Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy, isopropoxy), butoxy (including n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, etc.), pentyloxy (including n-pentyloxy, isopentyloxy, neopentyloxy, etc.), hexyloxy, heptyloxy, octyloxy, nonyloxy, Decyloxy, etc.

The terms "haloalkoxy" or "haloalkyloxy" are used interchangeably to denote a haloalkyl group as defined above attached through an oxygen bridge. The haloalkoxy is preferably C _1-12 haloalkoxy, more preferably C _1-8 haloalkoxy, C _1-6 haloalkoxy, C _1-4 haloalkoxy or C _1-3 haloalkoxy.

The term "cycloalkyl" refers to a saturated or partially unsaturated non-aromatic monocyclic or bicyclic hydrocarbon group. When a "cycloalkyl" is fully saturated, it may be referred to as a "cycloalkyl". Cycloalkyl or cycloalkyl preferably has 3-12 ring carbon atoms (ie C _3-12 cycloalkyl or C _3-12 cycloalkyl), more preferably 3-8 ring carbon atoms (ie C _3-8 cycloalkyl or C _3-8 cycloalkyl), most preferably 4-7 ring carbon atoms (ie C _4-7 cycloalkyl or C _4-7 cycloalkyl) or 3-6 ring carbon atoms (ie C _3-6 cycloalkyl or C _3-6 cycloalkyl). Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, bicyclo[1.1.1]pentyl, base, bicyclo[2.2.1]heptyl, spiro[3.4]octyl, bicyclo[3.1.1]hexyl, bicyclo[3.1.1]heptyl or bicyclo[3.2.1]octyl, etc.

The terms "cycloalkylene" and "cycloalkylene" refer to cycloalkylene and cycloalkylene, respectively, as defined herein, except that they are divalent. Cycloalkylene or cycloalkylene preferably has 3-12 ring carbon atoms (ie C _3-12 cycloalkylene or C _3-12 cycloalkylene), more preferably 3-8 ring carbon atoms (ie C _{3 -8} cycloalkylene or C _3-8 cycloalkylene), most preferably 4-7 ring carbon atoms (i.e. C _4-7 cycloalkylene or C _4-7 cycloalkylene) or 3-6 ring carbon atom (ie C _3-6 cycloalkylene or C _3-6 cycloalkylene).

The terms "cycloalkoxy" or "cycloalkyloxy" are used interchangeably to denote a cycloalkyl group as defined above attached through an oxygen bridge. Cycloalkoxy preferably has 3-12 ring carbon atoms (i.e. C _3-12 cycloalkoxy), more preferably 3-8 ring carbon atoms (i.e. C _3-8 cycloalkoxy), most preferably 3- 6 ring carbon atoms (ie C _3-6 cycloalkoxy). Representative examples of cycloalkoxy include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclopentenyloxy, cyclohexyloxy, cyclohexenyloxy, and the like.

The term "cycloalkylalkyl" or "cycloalkylalkyl-" denotes an alkyl group substituted by a cycloalkyl group, wherein cycloalkyl and alkyl are respectively as defined herein, with the point of attachment at the alkyl group. The term may also be denoted "cycloalkyl-alkylene-", ie a cycloalkyl group attached through an alkylene group. For example, cycloalkylalkyl means substituted by C _3-12 cycloalkyl, preferably C _3-8 cycloalkyl, more preferably C _3-6 cycloalkyl C _1-12 alkyl, preferably C _1-8 alkyl, more preferably C _1-6 alkyl, C _1-4 alkyl or C _1-3 alkyl. Preferably, "cycloalkylalkyl" is C _3-6 cycloalkyl-C _1-6 alkyl-, ie, C _3-6 cycloalkyl-C _1-6 alkylene-.

The term "alkoxyalkyl" or "alkoxyalkyl-" denotes an alkyl group substituted by an alkoxy group, wherein alkoxy and alkyl are respectively as defined herein, and the point of attachment is at the alkyl group. The term may also be denoted "alkoxy-alkylene-", ie, an alkoxy group attached through an alkylene group. For example, alkoxyalkyl represents C _1-12 alkoxy, preferably C _1-8 _alkoxy , more preferably C _1-6 alkoxy, C _1-4 alkoxy or C _1-3 alkoxy C _1-12 alkyl group substituted, preferably C _1-8 alkyl group, more preferably C _1-6 alkyl group, C _1-4 alkyl group or C _1-3 alkyl group. Preferably, "alkoxyalkyl" is C _1-6 alkoxy-C _1-6 alkyl- or C _1-6 alkoxy-C _1-6 alkylene-.

The term "alkylcycloalkyl" or "alkylcycloalkyl-" denotes a cycloalkyl group substituted by an alkyl group, wherein alkyl and cycloalkyl are respectively as defined herein, with the point of attachment being the cycloalkyl group. The term may also be denoted "alkyl-cycloalkylene-", ie, an alkyl group attached through a cycloalkylene. For example, alkylcycloalkyl means C 3 alkyl substituted _by C _1-12 alkyl, preferably C _1-8 alkyl, more preferably C _1-6 alkyl, C _1-4 alkyl or C _1-3 _-12 cycloalkyl, preferably C _3-8 cycloalkyl, more preferably C _3-6 cycloalkyl. Preferably, "alkylcycloalkyl" is C _1-6 alkyl-C _3-6 cycloalkyl- or C _1-6 alkyl-C _3-6 cycloalkylene-.

The term "aryl" refers to a monovalent carbocyclic ring having one or more rings, for example 1, 2 or 3 rings, of which at least one ring is aromatic and the other rings, if present, may be aromatic or non-aromatic of. Aryl preferably has 6-14 (i.e. C _6-14 aryl), more preferably 6-10 (i.e. C _6-10 aryl), most preferably ₆ ring carbon atoms (i.e. C aryl or phenyl ). Representative examples of aryl include, but are not limited to, phenyl (ie, C _aryl ), naphthyl, tetrahydronaphthyl, indenyl, dihydroindenyl, tetrahydronaphthyl, or anthracenyl, and the like.

The term "arylene" refers to an aryl group as defined herein except that it is divalent. The arylene group preferably has 6-14 ring carbon atoms (i.e. C _6-14 arylene), more preferably 6-10 ring carbon atoms (i.e. C _6-10 arylene), most preferably 6 ring carbon atoms (i.e. C ₆ arylene or phenylene).

The terms "heterocycle", "heterocyclyl", "heterocyclic group" and "heterocyclic" are used interchangeably and refer to having one or more, such as 1-6, more preferably 1, 2, 3 or A fully saturated, partially unsaturated or aromatic monocyclic, bicyclic or tricyclic ring group having 4 heteroatoms independently selected from N, O or S and the remaining ring members being carbon. The carbon members of the heterocycle can be replaced by -CO-, and the arbitrary N and S heteroatoms can be optionally oxidized (for example in NO, SO, SO ₂ ) and the arbitrary N heteroatoms can be optionally quaternized (for example in [NR] ⁺ Cl ^- , [NR] ⁺ OH ^- ). The term encompasses fully saturated "heterocycloalkyl", fully saturated or partially unsaturated "heterocycloalkyl", aromatic "heteroaryl" and the like. Preferably, the heterocycle has 3-20 ring members, more preferably 3-12 ring members, for example 3 to 10, 5 to 10, 3 to 8, 5 to 7, 7 to 10, 4 to 6, or 5 to 6 ring members.

The term "nitrogen-containing" means that the associated heterocyclic group (including heterocycloalkyl, heterocycloalkyl, heteroaryl, etc.) contains only nitrogen atoms as ring heteroatoms and other ring members are carbon, such as in nitrogen-containing heterocyclic hydrocarbons , nitrogen-containing heterocycloalkanes, nitrogen-containing heteroaryl groups, nitrogen-containing heteroaromatic rings, etc.

The terms "heterocyclic hydrocarbon" and "heterocycloalkyl" are used interchangeably and refer to having one or more, such as 1-6, more preferably 1, 2, 3 or 4, independently selected from N, O or S A saturated or partially unsaturated non-aromatic monocyclic, bicyclic or tricyclic cyclic group with heteroatoms and the remaining ring members being carbon. When a "heterocycloalkyl" is fully saturated, it may be referred to as a "heterocycloalkyl". The carbon members of the heterocyclic hydrocarbon can be replaced by -CO-, and the arbitrary N and S heteroatoms can be optionally oxidized (for example in NO, SO, SO ₂ ) and the arbitrary N heteroatoms can be optionally quaternized Ammonification (eg in [NR] ⁺ Cl ⁻ , [NR] ⁺ OH ⁻ ). The heterocycloalkyl group may have 3-20 ring members, such as 3-12 ring members, such as 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 ring members or combinations thereof Ring members in any numerical range, such as 3-10, 3-8, 4-7 ring members, such as 3-8 membered monocyclic heterocycloalkyl or 7-10 membered Bicyclic heterocycloalkyl. Representative examples thereof include, but are not limited to: aziridinyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, dihydropyrrolyl, pyrrolidinyl , pyrrolidonyl, dihydrofuranyl, tetrahydrofuryl, dihydrothienyl, tetrahydrothienyl, tetrahydrothienyl 1-oxide, tetrahydrothienyl 1,1-dioxide, dihydropyrazolyl, pyr Oxazolidinyl, imidazolinyl, imidazolidinyl, imidazolone, dihydroimidazolone, tetrahydroimidazolidinyl, dihydrooxazolyl, oxazolidinyl, dihydroisoxazolyl, isoxazolidine Dihydrothiazolyl, thiazolidinyl, dihydroisothiazolyl, isothiazolidinyl, dihydropyridyl, tetrahydropyridyl, piperidinyl, piperidonyl, dihydropyridazinyl, tetrahydropyridyl Azinyl, hexahydropyridazinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, hexahydropyrimidinyl, dihydropyrazinyl, tetrahydropyrazinyl, piperazinyl, pyranyl, dihydropyranyl, Tetrahydropyranyl, thiopyranyl, dihydrothiopyranyl, tetrahydrothiopyranyl, oxazinyl, isoxazinyl, dihydrooxazinyl, oxazinyl, morpholinyl, thiomorpholinyl , Thiomorpholine 1-oxide, Thiomorpholine 1,1-dioxide, Dihydroindolyl, Dihydrobenzofuryl, Dihydroisobenzofuryl, Dihydrobenzothienyl, Dihydro Benzothiazolyl, chromenyl, dihydrobenzopyranyl, tetrahydroquinolyl, tetrahydroisoquinolyl, etc. The heterocycloalkyl group can be attached to the rest of the molecule through a carbon atom or a heteroatom, wherever chemically feasible.

The term "heterocycloalkyloxy" refers to a heterocycloalkyl attached through an oxygen bridge, wherein the heterocycloalkyl is as defined herein.

The term "heteroaryl" refers to a monocyclic ring having one or more, preferably 1-6, more preferably 1, 2, 3 or 4 heteroatoms independently selected from N, O or S and the remaining ring members being carbon , a bicyclic or tricyclic cyclic group wherein at least one ring is aromatic and the other rings, if present, may be aromatic or non-aromatic. Any N and S heteroatoms of the heteroaryl group may be optionally oxidized (eg in NO, SO, SO ₂ ) and said arbitrary N heteroatoms may be optionally quaternized (eg in [NR] ⁺ Cl ⁻ , [NR] ⁺ OH ^- medium). Heteroaryl is preferably 5-14 membered, more preferably 5-10 membered heteroaryl, for example 5-7 membered heteroaryl (e.g. monocyclic, e.g. nitrogen-containing) or 7-10 membered heteroaryl (e.g. bicyclic, such as nitrogenous). Representative examples of heteroaryl include, but are not limited to: pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isothiazolyl, thiazolyl, isothiazolyl, triazolyl, pyridyl, Pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, thiopyranyl, oxazinyl, oxadiazinyl, indolyl, isoindolyl, azaindolyl (e.g. 7-azaindole base, 6-azaindolyl, 5-azaindolyl, 4-azaindolyl), benzofuryl, isobenzofuryl, benzothienyl, benzothiazolyl, indazole Base, benzimidazolyl, benzoxazolyl, quinolinyl, isoquinolyl, benzopyranyl, cinnolinyl, quinazolinyl, quinoxalinyl, benzoxazinyl, benzo Triazolyl, purinyl, indolizine, pyrrolopyridyl, pyrrolopyrimidinyl, pyrrolopyrazinyl, imidazopyridyl, imidazopyrimidinyl, pyrazolopyridyl, pyrazolopyridazinyl , pyrazolopyrimidinyl, pyrazolopyrazinyl, pyridopyrazinyl, pyridopyrimidinyl, pyrimidopyrimidinyl, pyrazinopyrazinyl, phthalazine, naphthyridinyl, etc. A heteroaryl group can be attached to the rest of the compound through a carbon atom or a heteroatom, wherever chemically feasible.

The term "heteroarylene" refers to a heteroaryl group as defined herein except that it is divalent.

The term "cyclic group" refers herein to a functional group derived by removal of one or two hydrogen atoms from a ring system such as a cyclohydrocarbon, cycloalkane, heterocyclohydrocarbon, heterocycloalkane, aromatic ring or heteroaryl ring , which may be monovalent or divalent as appropriate, preferably having 3-20 ring members, more preferably 3-14 ring members, for example 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 ring members or any combination of ring members, such as 3-12, 6-14, 3-10, 3-8, 5-10 or 5-8 ring members. The cyclic group that is part of the linker L is divalent. In particular, the term "cyclic group" as used herein includes C _3-8 cycloalkane, 3-10 membered heterocyclic hydrocarbon (such as 3-8 membered heterocyclic hydrocarbon or 4-7 membered heterocyclic hydrocarbon), C _{6- 14} aromatic rings or 5-10 membered heteroaromatic rings (such as 5-7 membered heteroaromatic rings or 7-10 membered heteroaromatic rings), wherein the meanings of cycloalkane, heterocyclic hydrocarbon, aromatic ring and heteroaromatic ring are similar respectively Cycloalkyl, heterocycloalkyl, aryl and heteroaryl as defined herein, except for valence.

The term "subunit" means a divalent group derived by removing two hydrogen atoms from a molecule.

The term "oxo" denotes oxygen attached by a double bond, ie =O.

The term "CN" means cyano.

The term "OH" means hydroxyl.

The term " _NH2 " denotes an amino group.

The term "-CO-" denotes a carbonyl group.

The term "-SO-" denotes a sulfinyl group.

The term " _-SO2- " denotes a sulfonyl group.

The term "hydrocarbon chain" denotes a saturated or unsaturated linear or branched hydrocarbon chain composed of carbon and hydrogen atoms, which may optionally contain one or more double or triple bonds.

The term "hydrocarbon chain unit" means _-CH2- , -CH= or -C≡.

The term "E3 ubiquitin ligase binding moiety" refers to a group or moiety that specifically binds to an E3 ubiquitin ligase.

The term "nitrogen protecting group" refers to a group that protects nitrogen from undesired chemical reactions when chemically reacted and is easily removed after the reaction. Examples include, but are not limited to, carbamates, amides, alkyls, aryls, imines, and the like. In particular, nitrogen protecting groups include, but are not limited to, benzyloxycarbonyl (Cbz), p-methoxybenzyl (Pmb), tert-butoxycarbonyl (Boc), 9-fluorenylmethoxycarbonyl (Fmoc), acetyl, benzene Formyl, benzyl, p-methoxyphenyl, 3,4-dimethoxybenzyl, etc.

The expression "optional,""optional," or "optionally" means that the subsequently described event may or may not occur, and that the expression includes instances where said event occurs and instances where it does not. For example, "optionally substituted by one or more R ₈ " includes the case of being unsubstituted and the case of being substituted by one or more R ₈ , and wherein each of the R ₈ may be the same or different. "Optional substituent" indicates that the substituent may or may not exist. Those skilled in the art will understand that for any group containing one or more substituents, the group does not include any sterically impractical, chemically incorrect, synthetically infeasible and/or or intrinsically unstable substitution patterns.

When any variable appears more than once in a formula, it is defined independently at each occurrence. For example, regarding the expression "optionally substituted by one or more R ₈ ", when substituted by multiple R ₈ , each of the R ₈ may be the same or different.

Combinations of substituents and/or variables are permissible only if such compositions result in stable compounds.

When a dotted ring is used in a ring structure, this means that the ring structure may be saturated, partially saturated or unsaturated.

In some embodiments, divalent groups are described generically without specifying bonding arrangements. It is understood that this description is intended to include both bonding arrangements unless otherwise indicated. For example, in the group R'-R"-R"', if the group R" is described as _-CH2C (O)-, it is understood that the group can be bonded as R'- _CH2C (O )-R" and R'-C(O)CH2 _- R"', unless otherwise indicated.

The term "comprising" or "comprising" means including stated elements, integers or steps, but not excluding any other elements, integers or steps. Herein, when the term "comprising" or "comprising" is used, unless otherwise specified, it also covers the situation of combining the mentioned elements, integers or steps.

The term "compound of the present invention" or "compound of the present application" refers to a compound or a salt thereof, particularly a pharmaceutically acceptable salt and a stereoisomer thereof, according to formula (I) or a subform thereof such as formula (Ia) or (Ib) (including diastereomers, enantiomers and racemates), geometric isomers, conformational isomers (including rotamers and atropisomers), tautomers, Metabolites, Prodrugs, and Isotopes Labeled compounds, including deuterium substitutions, include polymorphs, solvates and/or hydrates. In some embodiments, "compounds of the present invention" specifically refer to the compounds of the examples or their salts, especially pharmaceutically acceptable salts and stereoisomers, geometric isomers, conformational isomers, tautomers, Metabolites, prodrugs, and isotopically labeled compounds, including polymorphs, solvates, and/or hydrates. In some embodiments, solvates, metabolites, isotopes or prodrugs or any combination thereof are excluded.

In this context, references to formula (I) also include subforms thereof, eg formula (Ia) or (Ib).

The phrases "pharmaceutically acceptable" or "pharmaceutically acceptable" are used interchangeably to refer to a substance or composition that does not produce adverse, allergic or other undesired reactions when administered to an animal, such as a human.

The compounds of the invention may be in the form of salts, eg pharmaceutically acceptable salts. "Pharmaceutically acceptable salt" includes acid addition salts and base addition salts. "Pharmaceutically acceptable acid addition salts" refers to those salts that retain the biological effectiveness and properties of the free bases and are not biologically or otherwise undesirable. Acid addition salts may be formed with inorganic or organic acids such as hydrochloride, hydrobromide, sulfate, hydrogensulfate, nitrate, carbonate, phosphate, etc., and organic acid salts such as Formate, Acetate, Trifluoroacetate, Propionate, Glycolate, Gluconate, Lactate, Pyruvate, Oxalate, Malate, Malonate, Pentadiol adipate, succinate, fumarate, maleate, tartrate, citrate, aspartate, xinafoate, ascorbate, glutamate, o-amino Benzoate, benzoate, cinnamate, mandelate, pamoate, phenylacetate, methanesulfonate, ethanesulfonate, edisylate, benzenesulfonate, p-toluenesulfonate, xylenesulfonate, mesitylate, isethionate, naphthalenesulfonate, naphthalene disulfonate, camphorsulfonate, salicylate, Oleate, nicotinate, saccharinate, palmitate, stearate, furoate, hippurate, orotate, pamoate, etc. Salts also include those derived from inorganic bases, such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like; and those derived from nontoxic organic bases: primary amines, secondary amines and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylamine aminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, Glucosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resin, etc. Salts can be synthesized from the parent compound by conventional methods.

Pharmaceutically acceptable salts are preferred. However, other salts may also be useful, for example in isolation or purification steps, which may be used during preparation and are thus encompassed within the scope of this disclosure.

The compounds of the invention may contain one or more asymmetric carbon atoms. Accordingly, compounds may exist as diastereomers, enantiomers or mixtures thereof. The synthesis of compounds may employ racemates, diastereomers or isomers as starting materials or as intermediates. A mixture of particular diastereomeric compounds may be separated or enriched in one or more particular diastereoisomers by chromatographic or crystallization methods. Similarly, enantiomeric mixtures may be separated or enantiomerically enriched using the same technique or other techniques known in the art. The asymmetric carbon or nitrogen atoms may each be in the R or S configuration, both configurations being within the scope of this invention. In the structures shown herein, when the stereochemistry of any particular chiral atom is not indicated, then all stereoisomers are included as compounds of the invention. The stereochemical definitions and conventions used herein follow the usual conventions in the art.

The term "diastereomer" refers to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties such as melting points, boiling points, spectral properties and biological activities. Diastereomeric mixtures can be separated by high resolution analytical procedures such as electrophoresis and chromatography such as HPLC.

The term "enantiomer" refers to two stereoisomers of a compound that are non-superimposable mirror images of each other.

The term "tautomer" refers to structural isomers of different energies that are interconvertible through a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol isomerization and imine-enamine isomerization. Bonded tautomers include interconversions by recombination of some of the bonding electrons.

The term "metabolite" refers to the product produced by the metabolism of a specific compound or its salt in the body. Such products may result from, for example, oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, etc. of the administered compound. Metabolite structures are determined in a conventional manner, eg by MS, LC/MS or NMR analysis. In general, metabolite analysis is performed in the same manner as conventional drug metabolism studies well known to those skilled in the art. Metabolites are useful in diagnostic assays for therapeutic doses of the compounds of the invention, provided they are not found in vivo.

The term "prodrug" refers to a chemically modified active or inactive compound that is converted to a compound of the present invention by in vivo physiological effects (eg, hydrolysis, metabolism, etc.) after administration to an individual. Techniques for making and using prodrugs are well known to those skilled in the art.

The term "polymorph" refers to crystalline forms that have the same chemical structure/composition but differ in the spatial arrangement of the molecules and/or ions forming the crystals. The compounds of the invention may be provided as amorphous solids or crystalline solids. The scope of the present invention is intended to encompass all such physical forms.

Some of the compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. The term "solvate" refers to an association or complex of one or more solvent molecules with a compound of the invention. Examples of solvents that form solvates include water, isopropanol, EtOH, MeOH, DMSO, EA, AcOH, and ethanolamine. The term "hydrate" refers to a complex in which the solvent molecule is water. Methods of solvation are well known in the art.

The term "individual" or "patient" refers to an animal, preferably a mammal. Examples of subjects include, but are not limited to, primates (eg, humans and non-human primates such as monkeys), horses, cows, sheep, cats, dogs, rabbits, rabbits, and rodents (eg, mice and rats). In some embodiments, the individual is a human, including a child, adolescent, or adult.

The term "treating" refers to (i) treating or preventing a particular disease, condition or disorder, (ii) attenuating, ameliorating or eliminating one or more symptoms of a particular disease, condition or disorder and optionally (iii) preventing or delaying the The onset of one or more symptoms of the specified disease, condition or disorder. In some embodiments, "treating" refers to improving at least one physical parameter, which may not be perceived by the patient. In other embodiments, "treating" refers to modulating a disease or condition either physically (eg, stabilizing a perceived symptom) or physiologically (eg, stabilizing a parameter of the body), or both.

The term "prevention" refers to the administration of one or more pharmaceutical substances, especially the compounds of the present invention and/or pharmaceutically acceptable salts thereof, to an individual having a predisposing predisposition to the disease or condition in order to prevent the individual from suffering from the disease.

The terms "inhibit" and "alleviate" and the like refer to the alleviation or inhibition of a particular condition, symptom or disorder or disease, or to a significant reduction in the baseline activity of a biological activity or process.

The term "effective amount" refers to an amount effective, at dosages required and for periods of time required, to achieve the desired therapeutic or prophylactic effect. It can be determined by the participating physician or veterinary practitioner and will vary with the compound, the disease state being treated, the severity of the disease being treated, the age and relative health of the individual, the route and form of administration, the attending physician or veterinary practitioner Depending on factors such as the judgment of the examiner. Typically, a "prophylactically effective amount" will be less than a "therapeutically effective amount".

The term "degradation" of CDK12 refers to the use of ubiquitin-proteasome pathway, which leads to the degradation of CDK12 protein under the action of ubiquitin ligase White matter is ubiquitinated and degraded.

The term "formulation" or "pharmaceutical composition" refers to a composition comprising at least one active ingredient and at least one inactive ingredient, such as a pharmaceutically acceptable excipient, suitable for administration to animals, preferably mammals, including humans. The preparation of the present invention may be any preparation suitable in the art, such as tablet, capsule, liquid preparation and the like.

The term "pharmaceutically acceptable excipient" refers to an ingredient of a pharmaceutical formulation other than the active ingredient, which is non-toxic to the individual. Examples of pharmaceutically acceptable carriers include, but are not limited to, binders, disintegrants, lubricants, solvents, dispersion media, buffers, excipients, antioxidants, preservatives, or flavoring agents.

"Treating", "contacting" and "reacting" when referring to a chemical reaction mean adding or mixing two or more reagents under appropriate conditions to produce the indicated and/or desired product. It is to be understood that the reaction leading to the shown and/or desired product may not necessarily result directly from the combination of the two reagents originally added, i.e. there may be one or more intermediates formed in the mixture which eventually lead to formation of the indicated and/or desired products.

The expression A "and/or" B includes A alone, B alone and A+B.

Generally, the term "about" when used in conjunction with a numerical value indicates a range of ±20%, preferably ±10%, more preferably ±5% of the numerical value.

effect

The compound of the present invention has cell cyclin-dependent kinase 12 (CDK12) degrading activity and has good selectivity to CDK12. The compounds of the present invention show good activity of inhibiting the proliferation of cancer cells. Moreover, the compounds of the present invention have improved physical and chemical properties and good pharmacokinetic properties (such as good metabolic stability), good druggability, few side effects, and high resistance to drug resistance. The compounds of the invention are useful in a variety of applications where inhibition or degradation of CDK12 is desired.

Specifically, it has been found through research that the compound of the present invention can effectively degrade CDK12 and/or effectively inhibit the activity of tumor cell lines, and can achieve one or more of the following technical effects:

High CDK12 degradation rate: CDK12 protein degradation experiment (Western Blot) results show that at 200nM concentration, the compounds of the present invention can degrade CDK12 protein to varying degrees;

High tumor cell line proliferation inhibitory activity, for example: high HCC70 cell line proliferation inhibitory activity, the IC50 of HCC70 cell proliferation inhibition is 50-3000nM, preferably 50-2500nM, more preferably 50-2000nM, and preferably 50-1500nM, Most preferably the scope of 50～1000nM, as verified by activity example A; On JurKat cell, also show the advantage of obvious proliferation inhibitory activity; To HT-29 cell (human colon cancer cell) and A-673 cell (human striated muscle sarcoma cells) also exhibit significant proliferation inhibitory activity; and/or

Good pharmacokinetic properties, such as longer t _1/2 , so that, for example, the dosing interval can be increased, and the half-life can be longer, so that patients have better compliance, as verified by active example C ;and / or

• Excellent physicochemical properties, such as solubility, physical and/or chemical stability.

CDK12-associated diseases or conditions are, for example, abnormal cell proliferative diseases, myotonic dystrophy type 1 (DM1), infections (such as viruses such as herpes, HIV infection, fungal infections, etc.), inflammatory conditions (such as rheumatoid arthritis , osteoarthritis, etc.), autoimmune diseases (such as psoriasis, lupus, type 1 diabetes, diabetic nephropathy, multiple sclerosis, glomerulonephritis, etc.), cardiovascular diseases (such as myocardial infarction, stroke, atherosclerosis sclerosis, postoperative vascular stenosis, etc.), neurodegenerative diseases (such as Alzheimer's disease, Parkinson's disease, etc.) and hematopoietic toxic diseases caused by radiation (such as bone marrow suppression, neutropenia, leukopenia, anemia, etc.).

In a possible implementation manner, the abnormal cell proliferation disease is tumor and/or cancer; optionally, the cancer is selected from CDK12-related diseases or disorders are tumor and/or cancer, such as breast cancer, ovarian cancer , prostate cancer, central nervous system tumors (eg, spinal tumors, brainstem gliomas, glioblastoma multiforme, astrocytoma), esophageal cancer, bowel cancer, gastric cancer, liver cancer, pancreatic cancer (eg, pancreatic Ductal carcinoma, pancreatic endocrine tumors), colorectal cancer (e.g. colon, rectal), lung (e.g. non-small cell lung, small cell lung, bronchoalveolar cell carcinoma), kidney cancer, skin cancer (e.g. benign and malignant basal sarcoma), glioblastoma, schwannoma, ependymoma, medulloblastoma, neuroblastoma, squamous cell carcinoma, pituitary adenoma, sarcomas (e.g. Ewing sarcoma, angiosarcoma, liposarcoma, myoma), osteochondroma, osteoma, osteosarcoma, seminoma, testicular tumor, uterine cancer (e.g. cervical cancer, endometrial cancer), head and neck tumor (e.g. maxillary bone tumor, pharyngeal cancer, laryngeal, tongue, intraoral), multiple myeloma, benign and malignant lymphomas (e.g. reticulocyte sarcoma, lymphosarcoma, Hodgkin lymphoma, mantle cell lymphoma), polycythemia vera, leukemia (e.g. Acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia), thyroid tumors, ureteral tumors, bladder tumors, gallbladder cancer, bile duct cancer, choriocarcinoma, pediatric tumors (eg, Ewing family sarcoma , Wilms sarcoma, rhabdomyosarcoma, embryonal testicular tumor, retinoblastoma, Wilms tumor), etc., or a combination of one or more of the above cancers.

In a possible implementation manner, the cancer is selected from breast cancer, ovarian cancer, prostate cancer, gastric cancer, esophageal cancer, endometrial cancer, uterine cancer, bladder cancer, colorectal cancer, pancreatic ductal carcinoma, neuroblastoma tumor and Ewing's sarcoma.

In one possible realization, the disease is selected from myotonic dystrophy type I (DM1).

In some embodiments, compounds of the invention are useful for treating or preventing CDK12-associated diseases or disorders, such as tumors or cancers.

In a preferred embodiment, the compounds of the present invention are useful for the treatment or prevention of lung cancer, non-small cell lung cancer, bronchoalveolar cell lung cancer, breast cancer, ovarian cancer, prostate cancer, gastric cancer, esophageal cancer, endometrial cancer, uterine cancer, Bladder cancer, colorectal cancer, pancreatic ductal carcinoma, neuroblastoma, Ewing's sarcoma and other tumors or cancers.

Pharmaceutical composition and administration

The compounds of the present invention may be administered in the form of pharmaceutical compositions by any suitable route, such as but not limited to oral administration (in the form of tablets, coated tablets, lozenges, hard and soft gelatin capsules, solutions, emulsions or suspensions). form), inhalation (for example, in the form of a spray), rectally (for example, in the form of a suppository), or parenterally (for example, in the form of an injection, such as intravenous, intramuscular, subcutaneous, intraperitoneal, intracranial, etc.). Oral, intranasal and parenteral administration are particularly preferred.

Techniques for preparing compounds of the invention into pharmaceutical compositions are well known in the art. For example, the compounds of the present invention can be processed into the form of pharmaceutical compositions, such as tablets, coated tablets, capsules, liquid preparations (such as injections) using one or more pharmaceutically acceptable carriers, diluents or excipients. liquid, infusion, syrup, emulsion, suspension, etc.), powder, powder injection, dispersion, spray, suppository, liposome, etc. Pharmaceutically acceptable carriers, diluents or excipients are well known in the art, such as fillers, disintegrants, solvents, solubilizers, stabilizers, wetting agents, emulsifiers, preservatives, sweeteners, colorants, corrective agents, Flavoring agents, salts for changing osmotic pressure, buffers, masking agents or antioxidants, etc.

The dosage may vary widely and, of course, must be adjusted to the individual needs in each particular case. The appropriate dose can be determined by the attending physician as appropriate based on the type and severity of the disease to be treated, the individual's health status and previous medical history, shared drugs, the specific compound administered and the route of administration, etc. A daily dosage for oral administration to a 70 kg human adult is typically from about 0.01 mg to about 1000 mg of a compound of the invention or a corresponding amount of a pharmaceutically acceptable salt. The compound of the present invention may be used in an amount outside this dosage range as required. The daily dose can be administered as a single dose or in divided doses.

drug combination

The compounds of the present invention may be used alone or in combination with one or more other active agents or therapies, which may have the same or different pharmacological efficacy as the compounds of the present invention. The compounds of the invention may be administered simultaneously with, prior to, or subsequent to the other active agent or therapy.

When the compounds of the present invention are administered in combination with other active agents, the dosage of the active agents administered in combination will of course vary depending on such factors as the co-medicaments, the condition being treated, the general health of the individual, the judgment of the physician or veterinarian, and the like. The compounds of the present invention may be administered simultaneously, separately or sequentially with other co-active agents by the same or different routes of administration. They can be contained in the same pharmaceutical composition (fixed composition), or they can be combined in separate form, eg in the form of a kit. They may be formulated and/or supplied by the same or different manufacturers. Furthermore, the compounds of the invention and other active agents may be obtained (i) (i) prior to sending the combination product to a physician (for example, in the case of a kit comprising the compounds of the invention and other active agents); (ii) immediately prior to administration. The physician himself (or under the direction of the physician); or (iii) by the patient himself, for example during the sequential administration of the compound of the invention and the other active agent together in the combination therapy.

In some embodiments, the application provides pharmaceutical compositions comprising a compound of the invention and one or more other active agents. Optionally, the pharmaceutical composition may comprise one or more pharmaceutically acceptable carriers, diluents or excipients.

In some embodiments, the application provides pharmaceutical combination products, such as kits, comprising two or more separate pharmaceutical compositions, at least one of which contains a compound of the invention. In some embodiments, the kit includes means for containing the compositions separately, such as containers, divided bottles, or divided foil pouches.

The kits of the present application can be used for administering different dosage forms, such as oral and parenteral dosage forms, for administering individual compositions at different dosage intervals, or for stepping up individual compositions relative to one another. To aid compliance, the kits of the present application will generally contain instructions for administration.

General Synthetic Method

The compounds of the present invention can be prepared by a variety of methods, including methods known in the art, methods in the schemes below, methods given in the examples, or methods analogous thereto. Suitable reaction conditions for the individual reaction steps are known to or can be readily determined by the person skilled in the art. Starting materials are generally commercially available or can be readily prepared using methods known in the art or described herein. Each variable in the general formula has the meaning defined herein, unless otherwise stated.

For purposes of illustration only, the following schemes provide exemplary routes to the synthesis of compounds of the invention. Those skilled in the art understand that other synthetic routes are also available and that the compounds prepared by the methods described below can be further modified from the context of the present application using conventional compounds well known to those skilled in the art.

In the preparation of compounds of the present invention, protection of groups (eg amino protecting groups, hydroxy protecting groups) may be required as can be readily determined by one skilled in the art. For a general description of protecting groups and their uses, see TW Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

Synthetic scheme 1

Synthetic Scheme 1 of the present invention provides a method for the synthesis of compounds of formula (I), wherein R', R", R"' and R"" are terminal functional groups, and other variables are as defined herein for compounds of formula (I), which Include the following steps:

Step a: reacting the compound of formula (I-1) with compound R"-LR"' to obtain the compound of formula (I-2). Such reactions include, but are not limited to, nucleophilic substitution reactions, condensation reactions, reductive amination reactions, etc., depending on the nature of the terminal functional groups of groups X and L. The nucleophilic substitution reaction can be carried out in the presence of a base, which includes but not limited to sodium carbonate, K ₂ CO ₃ , cesium carbonate, N,N-diisopropylethylamine (DIPEA), triethylamine (Et ₃ One or more of N), HOBt, pyridine, and KI; preferably, the base is used in conjunction with DIPEA and KI. The condensation reaction can be performed in the presence of condensing agents well known in the art for coupling carboxylic acids to amines, including but not limited to 1-propylphosphoric anhydride ( _T3P ), EDC, DCC , HATU, EDCI, etc. The reductive amination reaction can be carried out in the presence of a reducing agent, which is a condensing agent well known in the art for reductive amination, including but not limited to sodium borohydride (NaBH ₄ ), sodium cyanoborohydride (NaBH ₃ CN), sodium triacetoxyborohydride (NaBH(AcO) ₃ ), etc. In particular, these reactions are preferably carried out in a suitable organic solvent, which may be selected from dichloromethane (DCM), tetrahydrofuran (THF), ethers (such as diethyl ether, ethylene glycol monomethyl ether, etc.), N-methyl Nylpyrrolidone (NMP), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), 1,4-dioxane (dioxane), dimethyl sulfoxide ( DMSO) and any combination thereof. These reactions are preferably carried out at a suitable temperature, such as 0-200°C, 10-100°C, 20-50°C or room temperature (about 20-25°C).

Step b: reacting the compound of formula (I-2) with compound ER"" to obtain the compound of formula (I). Such reactions include, but are not limited to, nucleophilic substitution reactions, condensation reactions, reductive amination reactions, Suzuki coupling reactions, Chan-Lam reactions, Sonogashira coupling reactions, depending on the group E and the terminal functional group of (I-2) nature. Nucleophilic substitution reaction, condensation reaction, and reductive amination reaction are the same as step a. Pd(PPh ₃ ) ₄ , PdCl ₂ (Amphos) ₂ , Cu(OAc) ₂ , Pd(PPh ₃ ) ₂ Cl ₂ , Pd(dppp)Cl can be used for Suzuki coupling reaction, Chan-Lam reaction, and Sonogashira coupling reaction ₂ and so on as a catalyst. In particular, these reactions are preferably carried out in a suitable organic solvent, which may be selected from dichloromethane (DCM), tetrahydrofuran (THF), ethers (such as diethyl ether, ethylene glycol monomethyl ether, etc.), N-methyl Nylpyrrolidone (NMP), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), 1,4-dioxane (dioxane), dimethyl sulfoxide ( DMSO), toluene and any combination thereof. These reactions are preferably carried out at a suitable temperature, such as 0-200°C, 10-100°C, 20-50°C or room temperature (about 20-25°C).

Synthetic scheme 2

Synthetic Scheme 2 of the present invention provides another method for the synthesis of compounds of formula (I), wherein R', R", R"' and R"" are terminal functional groups, and other variables are as described herein for compounds of formula (I) definition, which includes the following steps:

Step a: react the compound of formula (In-1) with the compound R"-LR"' to obtain the compound of formula (In-2). Such reactions include, but are not limited to, nucleophilic substitution reactions, condensation reactions, reductive amination reactions, Suzuki coupling reactions, Chan-Lam reactions, Sonogashira coupling reactions, depending on the nature of the terminal functionality of groups E and L. The nucleophilic substitution reaction, condensation reaction, and reductive amination reaction are the same as those described above. Pd(PPh ₃ ) ₄ , PdCl ₂ (Amphos) ₂ , Cu(OAc) ₂ , Pd(PPh ₃ ) ₂ Cl ₂ , Pd(dppp)Cl can be used for Suzuki coupling reaction, Chan-Lam reaction, and Sonogashira coupling reaction ₂ and so on as a catalyst. In particular, these reactions are preferably carried out in a suitable organic solvent, which may be selected from dichloromethane (DCM), tetrahydrofuran (THF), ethers (such as diethyl ether, ethylene glycol monomethyl ether, etc.), N-methyl Nylpyrrolidone (NMP), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), 1,4-dioxane (dioxane), dimethyl sulfoxide ( DMSO), toluene and any combination thereof. These reactions are preferably carried out at a suitable temperature, such as 0-200°C, 10-100°C, 20-50°C or room temperature (about 20-25°C).

Step b: reacting the compound of formula (In-2) with the compound of formula (I-1) to obtain the compound of formula (I). Such reactions include, but are not limited to, nucleophilic substitution reactions, condensation reactions, reductive amination reactions, etc., depending on the nature of the terminal functional groups of groups X and L. The nucleophilic substitution reaction can be carried out in the presence of a base, which includes but not limited to sodium carbonate, K ₂ CO ₃ , cesium carbonate, N,N-diisopropylethylamine (DIPEA), triethylamine (Et ₃ One or more of N), HOBt, pyridine, and KI; preferably, the base is used in conjunction with DIPEA and KI. The condensation reaction can be performed in the presence of condensing agents well known in the art for coupling carboxylic acids to amines, including but not limited to 1-propylphosphoric anhydride ( _T3P ), EDC, DCC , HATU, EDCI, etc. The reductive amination reaction can be carried out in the presence of a reducing agent, which is a condensing agent well known in the art for reductive amination, including but not limited to sodium borohydride (NaBH ₄ ), sodium cyanoborohydride (NaBH ₃ CN), sodium triacetoxyborohydride (NaBH(AcO) ₃ ), etc. In particular, these reactions are preferably carried out in a suitable organic solvent, which may be selected from dichloromethane (DCM), tetrahydrofuran (THF), ethers (such as diethyl ether, ethylene glycol monomethyl ether, etc.), N-methyl Nylpyrrolidone (NMP), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), 1,4-dioxane (dioxane), dimethyl sulfoxide ( DMSO) and any combination thereof. These reactions are preferably carried out at a suitable temperature, such as 0-200°C, 10-100°C, 20-50°C or room temperature (about 20-25°C).

The above synthetic schemes are just examples of the preparation methods of some compounds of the present invention. The compounds of the present invention or their stereoisomers, tautomers, stable isotopic derivatives, pharmaceutically acceptable salts or solvates can be obtained by various methods, including the methods given above, in the Examples The given method or a similar method is prepared by those skilled in the art on the basis of the above synthesis scheme and in combination with conventional techniques in the field.

Description of drawings

Figure 1 shows the dose-response curves of the inhibitory activity of compound BSJ-04-023 and the compound of Example 20 on the proliferation of Jurkat cells.

Figure 2 shows the Western Blot diagram of the degradation activity of compound BSJ-04-023 on CDK12 protein (Example B).

Figure 3 shows the Western Blot diagram of the degrading activity of the compound of Example 27 on CDK12 protein (Example B).

Figure 4 shows the Western Blot graph of the degrading activity of the compounds of Examples 19 and 20 on CDK12 protein (Example B).

Figure 5 shows the time dependence of the degradation of CDK12 by Example 111.

Figure 6 shows the time dependence of the degradation of CDK12 by Example 112.

Detailed ways

The following examples are provided to further illustrate the invention. It should be understood that it is only for better understanding of the present invention and does not limit the scope of the present invention in any way.

The reagents used in the examples are either commercially available or readily prepared by methods known in the art or as described herein.

In this application, when the chemical name and the structural formula are inconsistent, the structural formula shall prevail, unless the chemical name rather than the structural formula can be inferred from the context to be correct. For simplicity, not all hydrogen atoms are explicitly denoted in some of the compound formulas given in this application. When a vacant valence exists in a compound, it indicates the presence of an unmarked hydrogen atom.

Abbreviations used in this application have meanings commonly understood in the art, unless otherwise clearly defined in the specification. The meanings of the abbreviations used in the specification are listed below:
HATU 2-(7-Azobenzotriazole)-N,N,N,N,-tetramethyluronium hexafluorophosphate
HOBt 1-Hydroxybenzotriazole DIPEA N,N-Diisopropylethylamine
DCM Dichloromethane DCE 1,2-Dichloroethane
DCC Dicyclohexylcarbodiimide EA Ethyl acetate
EDC 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide
EDCI 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
PE petroleum ether NIS N-iodosuccinimide
DMF N,N-Dimethylformamide ACN Acetonitrile
DHP 3,4-Dihydro-2H-pyran NMP N-methylpyrrolidone
LC-MS liquid chromatography mass spectrometry coupled with ESI electrospray ionization
m/z mass-to-charge ratio HPLC high-performance liquid chromatography
TFA Trifluoroacetic acid FA Formic acid
AcOH Acetate Na ₂ SO ₄ Sodium Sulfate KI Potassium Iodide K ₂ CO ₃ Potassium Carbonate
NH ₄ HCO ₃ Ammonium Bicarbonate/Ammonia NaHCO ₃ Sodium Bicarbonate
EtOH Ethanol MeOH Methanol NaBH(OAc) ₃ Acetate Sodium Borohydride
LiOH Lithium Hydroxide MsCl Methanesulfonyl Chloride hr/hrs hours

In the preparation method of the target compound provided by the present invention, column chromatography adopts silica gel (100-200 order and 200-300 order) produced by Shanghai Titan Technology Co., Ltd.; thin-layer chromatography adopts GF254 (0.25 mm); nuclear magnetic resonance chromatography (NMR ) was determined using a Bruker Avance III 400MHz nuclear magnetic resonance instrument.

The liquid mass spectrometry (LC/MS) method used in the embodiment of the present application has:

Method A: SHIMADZU LC-20AD-PDA; Column: sunfire C18 4.6*50mm; Mobile phase A: 0.1% FA in H ₂ O (V/V), Mobile phase B: 0.1% FA in ACN (V/V); Flow rate 2mL/min; injection volume (2μL); 2.6min; 254nm; column temperature 40°C.

Method B: Agilent 1260 DAD-6120-ELSD; Column: Xbridge C18 5μm 4.6*50mm; Mobile phase A: 0.1% NH ₃ .H ₂ O in H ₂ O (V/V), Mobile phase B: 0.1% NH ₃ .H ₂ O in ACN (V/V); flow rate 2mL/min; injection volume (2μL); 2.6min; 254nm, column temperature 40°C.

Method C: Waters ACQUITY UPLC Hclass-QDa LCMS; Column: ACQUITY UPLC BEH C18 2.1*50mm 1.7μm; Mobile phase A: 0.1% FA in H ₂ O (V/V), Mobile phase B: 0.1% FA in ACN ( V/V); flow rate 2mL/min; injection volume (2μL); 2.0min; 254nm; column temperature 40°C.

Method D: ACQUITY UPLC BEH 1.7um 2.1*50mm 2.0min 0.6mL/min; Column temperature: 40℃; Gradient: 10%B increase to 30%B for 0.10min,increase to 95%B within 1.20min,95%B hold for 0.80min.

Method E: SunFire C18 50*4.6mm 5um 2.6min 2.0mL/min; Column temperature: 40℃; Gradient: 10%B increase to 30%B for 0.40min, increase to 95%B within 1.60min, 95%B for 0.90min, back to 10% B within 0.01min.

In addition, all operations involving easily oxidized or hydrolyzed raw materials were carried out under nitrogen protection. Unless otherwise specified, the raw materials used in the present invention are all commercially available raw materials, which can be used directly without further purification, and the temperatures used in the present invention are all degrees Celsius (° C.). The ratio of liquids is by volume, eg in PE:EA.

Synthetic example

Example 1: N-(7-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)- 7-oxoheptyl)-2-((2- (2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)oxy)ethyl Amide

Step 1: Synthesis of 3-(2,5-dichloropyrimidin-4-yl)-1H-indole

Methylmagnesium bromide (6.50 g, 10.8 mmol) was added dropwise to a nitrogen-protected solution of indole (6.39 g, 54.5 mmol) in THF (50.0 mL) at 0° C. within 10 minutes. The solution was then stirred at 0-2°C for 0.5 hr. Then add 2,4,5-trichloropyrim Pyridine (5.00 g, 27.3 mmol) gave a yellow solution. The ice bath was removed, followed by stirring at room temperature for 1 hr, resulting in a red solution. The reaction solution was heated to 60°C, and then stirred at 60°C for 1.5 hrs. The reaction solution was then cooled to room temperature. And AcOH (5.00 mL) was added dropwise, water (50.0 mL) and THF (10.0 mL) were added, and then the mixture was stirred at 60° C. for 20 minutes, resulting in a biphasic solution, which was separated. n-Hexane (60.0 mL) was added to the organic phase, resulting in crystallization of the solid. The solid was collected by filtration, washed with n-hexane (50.0 mL), and dried in vacuo to obtain the target compound (4.70 g, yield 65.3%, yellow solid). LC-MS (ESI) m/z: 264.1 [M+H] ⁺ .

Step 2: Synthesis of (R)-tert-butyl 3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidine-1-carboxylate

3-(2,5-dichloropyrimidin-4-yl)-1H-indole (4.00g, 15.2mmol), (R)-3-aminopyrrolidine-1-carboxylic acid tert-butyl ester (5.64g, 30.3 mmol) and DIPEA (9.79 g, 75.7 mmol) were sequentially added to NMP (30.0 mL). The reaction solution was stirred overnight at 120° C. under nitrogen protection. The reaction solution was cooled to room temperature, diluted with EA, washed with water and saturated brine successively, the organic phase was dried over anhydrous Na ₂ SO ₄ , and the solvent was distilled off under reduced pressure to obtain the target compound (5.80 g, yield 92.5%, yellow solid ). LC-MS (ESI) m/z: 358.2 [M+H-56] ⁺ .

Step 3: Synthesis of (R)-5-chloro-4-(1H-indol-3-yl)-N-(pyrrolidin-3-yl)pyrimidin-2-amine

At room temperature, (R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester (4.00g, 9.66 mmol) was dissolved in DCM (20.0 mL) and TFA (6.00 mL) was added. The resulting reaction solution was stirred at room temperature for 3 hrs, and the solvent was distilled off under reduced pressure to obtain the target compound (2.90 g, yield 95.7%, brown solid). LC-MS (ESI) m/z: 314.2 [M+H] ⁺ .

Step 4: (R)-(7-(3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)-7-oxo Synthesis of tert-butyl carbamate

(R)-5-Chloro-4-(1H-indol-3-yl)-N-(pyrrolidin-3-yl)pyrimidin-2-amine (512mg, 1.63mmol), 7-((tert-butyl (oxycarbonyl)amino)heptanoic acid (200mg, 0.815mmol), HATU (372mg, 0.978mmol), DIPEA (632mg, 4.89mmol) were dissolved in DMF (5.00mL). The resulting reaction solution was stirred overnight at room temperature, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (PE:EA=1:4) to obtain the target compound (291 mg, yield 66.0%, colorless liquid). LC-MS (ESI) m/z: 441.3 [M+H-100] ⁺ .

Step 5: (R)-7-Amino-1-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)heptan Synthesis of alkan-1-ones

At room temperature, (R)-(7-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)-7- tert-butyl (oxoheptyl)carbamate (291 mg, 0.538 mmol) was dissolved in DCM (5.00 mL) and TFA (2.00 mL) was added. The resulting reaction solution was stirred at room temperature for 3 hrs, and the solvent was distilled off under reduced pressure to obtain the target compound (221 mg, yield 93.2%, brown solid). LC-MS (ESI) m/z: 441.3 [M+H] ⁺ .

Step 6: N-(7-((R)-3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)-7 -Oxoheptyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)oxy)acetamide Synthesis

(R)-7-amino-1-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)heptane- 1-keto (150mg, 0.340mmol), 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy ) Acetic acid (170 mg, 0.510 mmol), HATU (207 mg, 0.544 mmol), DIPEA (264 mg, 2.04 mmol) were dissolved in DMF (5.00 mL). The resulting reaction solution was stirred overnight at room temperature under nitrogen protection, and the reaction solution was purified by Prep-HPLC (column: SunFire Prep C8 OBD 10um 19*250mm; mobile phase: A-0.1% FA aqueous solution, B-ACN; gradient: B% = 10% ~ 45%; flow rate 20mL/min), to obtain the title compound (82.2mg, yield 32.0 %, yellow solid). LC-MS (ESI) m/z: 755.4 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.90(s, 1H), 11.12(s, 1H), 8.71–8.55(m, 1H), 8.50(t, J=3.2Hz, 1H), 8.31( s,1H),7.96–7.88(m,1H),7.85–7.75(m,1H),7.72–7.56(m,1H),7.49(dd,J＝7.0,3.6Hz,2H),7.39(dd, J=8.4,5.2Hz,1H),7.26–7.12(m,2H),5.12(dd,J=12.9,5.1Hz,1H),4.76(d,J=5.8Hz,2H),4.54–4.37(m ,1H),3.85–3.72(m,1H),3.68–3.57(m,1H),3.56–3.47(m,1H),3.46–3.37(m,1H),3.20–3.06(m,2H),2.96 –2.80(m,1H),2.68–2.52(m,2H),2.33–2.09(m,3H),2.09–1.86(m,2H),1.53–1.38(m,4H),1.27(d,J= 9.8Hz, 4H).

Example 2: N-(7-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)heptan Base)-2-((2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)oxy)acetamide

Step 1: Synthesis of tert-butyl (7-bromoheptyl)carbamate

Under ice bath conditions, 7-bromoheptanonitrile (1.00g, 5.26mmol), nickel chloride hexahydrate (1.25g, 5.26mmol), (Boc) ₂ O (2.30g, 5.26mmol) were dissolved in DCM (15.0 mL), sodium borohydride (199 mg, 5.26 mmol) was added to the reaction solution, stirring was continued for 5 minutes under ice-bath conditions, and EtOH (5.00 mL) was slowly added dropwise to the above mixed solution. The resulting reaction solution was stirred at room temperature for 16 hrs under nitrogen protection. After the reaction was completed, water (20.0 mL) was added to the reaction liquid for dilution, and extracted with DCM (30.0 mL×2). The organic phases were combined, washed with saturated brine, dried over anhydrous Na ₂ SO ₄ , and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (PE:EA=10:1) to obtain the title compound (950 mg, yield 61.4%, colorless oil). LC-MS (ESI) m/z: 238.1 [M-56] ⁺ .

Step 2: (R)-(7-(3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)heptyl)amino Synthesis of tert-butyl formate

(7-Bromoheptyl)carbamate tert-butyl ester (180mg, 0.610mmol), (R)-5-chloro-4-(1H-indol-3-yl)-N-(pyrrolidin-3- yl) pyrimidin-2-amine (192 mg, 0.610 mmol), KI (10.1 mg, 0.0610 mmol) and K ₂ CO ₃ (169 mg, 1.22 mmol) were dissolved in DMF (3.00 mL). The resulting reaction solution was stirred at 50° C. for 16 hrs under the protection of nitrogen. After the reaction was completed, water (20.0 mL) was added to the reaction liquid for dilution, and extracted with EA (20.0 mL×2). The organic phases were combined, washed with saturated brine, dried over anhydrous Na ₂ SO ₄ , and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (PE:EA=2:1) to obtain the target compound (67.0 mg, yield 20.8%, yellow solid). LC-MS (ESI) m/z: 527.4 [M+H] ⁺ .

Step 3: Synthesis of (R)-N-(1-(7-aminoheptyl)pyrrolidin-3-yl)-5-chloro-4-(1H-indol-3-yl)pyrimidin-2-amine

(R)-(7-(3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)heptyl)carbamic acid tert Butyl ester (67.0 mg, 0.130 mmol) was dissolved in dioxane hydrochloride (4N, 1.00 mL). The resulting reaction solution was stirred at room temperature for 2hrs, The solvent was distilled off under reduced pressure to obtain the target compound (52.0 mg, yield 98.0%, yellow solid). LC-MS (ESI) m/z: 427.2 [M+H] ⁺ .

Step 4: N-(7-((R)-3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)heptyl Synthesis of )-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamide

(R)-N-(1-(7-aminoheptyl)pyrrolidin-3-yl)-5-chloro-4-(1H-indol-3-yl)pyrimidin-2-amine (52.0mg, 0.130mmol), 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)oxy)acetic acid (41.4mg, 0.130mmol), DIPEA (32.2mg, 0.250mmol) were dissolved in DMF (2.00mL), and after stirring for 5 minutes, HATU (56.9mg, 0.160mmol) was added to the above mixture. The resulting reaction solution was stirred at room temperature for 3hrs. After the reaction, the reaction solution was purified by Prep-HPLC (column: Waters Xbridge C18 10um OBD 19*250mm; mobile phase: A-0.1% NH ₄ HCO ₃ aqueous solution, B-ACN; gradient : B%=15%～47%; flow rate: 20mL/min), the title compound (7.00mg, yield 7.20%, white solid) was obtained. LC-MS (ESI) m/z: 741.3 [M+H] ⁺ . ¹ H NMR (400MHz, MeOH-d ₄ )δ8.52–8.43(m,1H),8.33(s,1H),8.11–8.05(m,1H),7.66(t,J＝8.0Hz,1H), 7.40(d, J＝8.0Hz, 1H), 7.35(d, J＝8.0Hz, 1H), 7.26(d, J＝8.0Hz, 1H), 7.16–7.02(m, 2H), 5.06–4.94(m ,1H),4.61(s,2H),4.56–4.46(m,2H),3.17–3.09(m,1H),3.06–2.97(m,1H),2.88–2.75(m,2H),2.67–2.50 (m,4H),2.42–2.29(m,1H),2.12–1.76(m,4H),1.53–1.42(m,4H),1.28–1.24(m,4H),1.19–1.15(m,2H) .

Example 3: N-(6-(((1S,3S)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)cyclopentyl)amino )hexyl)-2-((2- (2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)oxy)acetamide

Step 1: Synthesis of tert-butyl ((1S,3S)-3–((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)cyclopentyl)carbamate

3-(2,5-dichloropyrimidin-4-yl)-1H-indole (600mg, 2.27mmol), ((1S,3S)-3-aminocyclopentyl)carbamate tert-butyl ester (501mg , 2.50mmol) and DIPEA (1.47g, 11.4mmol) were sequentially added to NMP (15.0mL). The obtained reaction solution was stirred overnight at 120° C. under the protection of nitrogen. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (PE:EA=3:2) to obtain the target compound (876 mg, yield 90.1%, colorless liquid). LC-MS (ESI) m/z: 428.4 [M+H] ⁺ .

Step 2: Synthesis of (1S,3S)-N ¹ -(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)cyclopentane-1,3-diamine

At room temperature, ((1S,3S)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)cyclopentyl)carbamate tert-butyl ester ( 876 mg, 2.05 mmol) was dissolved in DCM (5.00 mL) and TFA (2.00 mL) was added. The resulting reaction solution was stirred at room temperature for 3 hrs, and the solvent was distilled off under reduced pressure to obtain the target compound (649 mg, yield 96.7%, brown solid). LC-MS (ESI) m/z: 328.2 [M+H] ⁺ .

Step 3: (6-(((1S,3S)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)cyclopentyl)amino)hexyl) Synthesis of tert-butyl carbamate

(1S,3S)-N ¹ -(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)cyclopentane-1,3-diamine (600mg, 2.27mmol), Tert-butyl (6-bromohexyl)carbamate (513 mg, 1.83 mmol) and K ₂ CO ₃ (506 mg, 3.66 mmol) were sequentially added to DMF (5.00 mL). The resulting reaction solution was stirred overnight at room temperature under nitrogen protection. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (PE:EA, EA%=0-100%) to obtain the target compound (181 mg, yield 28.1%, colorless liquid). LC-MS (ESI) m/z: 527.4 [M+H] ⁺ .

Step 4: (1S,3S) ^-N1- (6-aminohexyl) ^-N3- (5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)cyclopentane-1 , Synthesis of 3-diamine

At room temperature, (6-(((1S,3S)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)cyclopentyl)amino)hexyl ) tert-butyl carbamate (181 mg, 0.343 mmol) was dissolved in DCM (5.00 mL) and TFA (1.00 mL) was added. The resulting reaction solution was stirred overnight at room temperature, and the solvent was distilled off under reduced pressure to obtain the target compound (136 mg, yield 92.8%, brown liquid). LC-MS (ESI) m/z: 427.4 [M+H] ⁺ .

Step 5: N-(6-(((1S,3S)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)cyclopentyl)amino) Synthesis of Hexyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamide

(1S,3S)-N ¹ -(6-aminohexyl)-N ³ -(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)cyclopentane-1,3 -Diamine (136mg, 0.319mmol), 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)oxy ) Acetic acid (138 mg, 0.414 mmol), HATU (194 mg, 0.510 mmol) and DIPEA (206 mg, 1.59 mmol) were dissolved in DMF (5.00 mL). The resulting reaction solution was stirred overnight at room temperature under nitrogen protection. After the reaction, the reaction solution was purified by Prep-HPLC (column: SunFire Prep C8 OBD 10um 19*250mm; mobile phase: A-0.1% TFA aqueous solution, B-ACN; gradient: B%=13%～40%; flow rate: 20 mL/min), the title compound (98.2 mg, yield 41.6%, yellow solid) was obtained. LC-MS (ESI) m/z: 741.5 [M+H] ⁺ . ¹ H NMR (400MHz,DMSO-d ₆ )δ11.89(s,1H),11.13(s,1H),8.67–8.54(m,1H),8.48(d,J=3.0Hz,1H),8.47– 8.36(m, 2H), 8.29(s, 1H), 7.97(t, J=5.6Hz, 1H), 7.87–7.73(m, 1H), 7.51(d, J=7.3Hz, 2H), 7.40(d ,J=8.5Hz,1H),7.30–7.13(m,2H),5.12(dd,J=12.7,5.4Hz,1H),4.78(s,2H),4.52–4.34(m,1H),3.70– 3.63(m,1H),3.16(dd,J＝12.8,6.5Hz,2H),3.02–2.72(m,3H),2.67–2.53(m,2H),2.28–2.14(m,2H),2.11– 1.99(m,3H), 1.75–1.61(m,2H), 1.61–1.52(m,2H), 1.50–1.40(m,2H), 1.36–1.24(m,4H).

Example 4: N-(7-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)azetidin-1-yl)heptyl )-2-((2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)oxy)acetamide

Step 1: Synthesis of tert-butyl 3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)azetidine-1-carboxylate

3-(2,5-dichloropyrimidin-4-yl)-1H-indole (600mg, 2.27mmol), 3-aminoazetidine-1-carboxylic acid tert-butyl ester (783mg, 4.54mmol) and DIPEA (1.47 g, 11.4 mmol) were sequentially added to NMP (15.0 mL). The obtained reaction solution was stirred overnight at 120° C. under the protection of nitrogen. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (PE/EA=1/1) to obtain the target compound (549 mg, yield 60.4%, colorless liquid). LC-MS (ESI) m/z: 400.3 [M+H] ⁺ .

Step 2: Synthesis of N-(azetidin-3-yl)-5-chloro-4-(1H-indol-3-yl)pyrimidin-2-amine

At room temperature, tert-butyl 3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)azetidine-1-carboxylate (549mg, 1.37mmol ) was dissolved in DCM (5.00 mL) and TFA (2.00 mL) was added. The resulting reaction solution was stirred at room temperature for 3 hrs, and the solvent was distilled off under reduced pressure to obtain the target compound (403 mg, yield 97.9%, brown liquid). LC-MS (ESI) m/z: 300.2 [M+H] ⁺ .

Step 3: (7-(3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)azetidin-1-yl)heptyl)carbamate Synthesis of tert-butyl ester

N-(azetidin-3-yl)-5-chloro-4-(1H-indol-3-yl)pyrimidin-2-amine (306mg, 1.02mmol), (6-bromohexyl)amino Tert-butyl formate (200 mg, 0.680 mmol), KI (11.0 mg, 0.068 mmol) and K ₂ CO ₃ (470 mg, 3.40 mmol) were sequentially added to DMF (5.00 mL). The resulting reaction solution was stirred overnight at room temperature under nitrogen protection. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (DCM/MeOH=19/1) to obtain the target compound (171 mg, yield 49.0%, colorless liquid). LC-MS (ESI) m/z: 513.4 [M+H] ⁺ .

Step 4: Synthesis of N-(1-(7-aminoheptyl)azetidin-3-yl)-5-chloro-4-(1H-indol-3-yl)pyrimidin-2-amine

At room temperature, (7-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)azetidin-1-yl)heptyl)amino tert-Butyl formate (171 mg, 0.333 mmol) was dissolved in DCM (5.00 mL) and TFA (2.00 mL) was added. The resulting reaction solution was stirred at room temperature for 3 hrs, and the solvent was distilled off under reduced pressure to obtain the target compound (131 mg, yield 95.2%, brown liquid). LC-MS (ESI) m/z: 413.3 [M+H] ⁺ .

Step 5: N-(7-(3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)azetidin-1-yl)heptyl) Synthesis of 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamide

N-(1-(7-aminoheptyl)azetidin-3-yl)-5-chloro-4-(1H-indol-3-yl)pyrimidin-2-amine (131mg, 0.317mmol ), 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetic acid (105mg, 0.317mmol) , HATU (181 mg, 0.476 mmol) and DIPEA (164 mg, 1.27 mmol) were dissolved in DMF (5.00 mL). The resulting reaction solution was stirred overnight at room temperature under nitrogen protection, and the reaction solution was purified by Prep-HPLC (column: SunFire Prep C8 OBD 10um 19*250mm; mobile phase: A-0.1% TFA aqueous solution, B-ACN; gradient: B%=10 %～40%; flow rate: 20 mL/min), the title compound (17.6 mg, yield 7.60%, yellow solid) was obtained. LC-MS (ESI) m/z: 727.5 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.94(s, 1H), 11.13(s, 1H), 8.67(d, J=7.2Hz, 1H), 8.58–8.43(m, 1H), 8.35( s,1H),8.14–7.88(m,2H),7.88–7.75(m,1H),7.51(d,J＝6.4Hz,2H),7.39(d,J＝8.2Hz,1H),7.37–7.13 (m,2H),5.19–5.05(m,1H),4.77(s,3H),4.55–4.43(m,1H),4.36–4.12(m,1H),4.11–3.92(m,1H),3.27 –3.10(m,4H),3.03–2.79(m,2H),2.64–2.54(m,2H),2.09–1.96(m,1H),1.72–1.54(m,1H),1.50–1.40(m, 3H), 1.32–1.22 (m, 6H).

Example 5: N-(7-(4-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)heptyl )-2-((2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)oxy)acetamide

Step 1: Synthesis of 5-chloro-4-(1H-indol-3-yl)-N-(1H-pyrazol-4-yl)pyrimidin-2-amine

3-(2,5-dichloropyrimidin-4-yl)-1H-indole (600mg, 2.27mmol), 1H-pyrazol-4-amine (378mg, 4.54mmol) and DIPEA (1.47g, 11.4mmol ) were sequentially added to NMP (15.0 mL). The obtained reaction solution was stirred overnight at 120° C. under the protection of nitrogen. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (PE/EA=2/3) to obtain the target compound (451 mg, yield 63.9%, white solid). LC-MS (ESI) m/z: 311.2 [M+H] ⁺ .

Step 2: (7-(4-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)heptyl)carbamate Synthesis of tert-butyl ester

5-Chloro-4-(1H-indol-3-yl)-N-(1H-pyrazol-4-yl)pyrimidin-2-amine (222mg, 0.714mmol), (6-bromohexyl)carbamate Tert-butyl ester (200 mg, 0.680 mmol), KI (11.0 mg, 0.0680 mmol) and K ₂ CO ₃ (282 mg, 2.04 mmol) were sequentially added to DMF (5.00 mL). The resulting reaction solution was stirred overnight at room temperature under nitrogen protection. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (DCM/MeOH=19/1) to obtain the target compound (265 mg, yield 74.4%, white solid). LC-MS (ESI) m/z: 524.4 [M+H] ⁺ .

Step 3: Synthesis of N-(1-(7-aminoheptyl)-1H-pyrazol-4-yl)-5-chloro-4-(1H-indol-3-yl)pyrimidin-2-amine

At room temperature, (7-(4-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)heptyl)amino tert-Butyl formate (265 mg, 0.506 mmol) was dissolved in DCM (5.00 mL) and TFA (2.00 mL) was added. The resulting reaction solution was stirred at room temperature for 3 hrs, and the solvent was distilled off under reduced pressure to obtain the target compound (193 mg, yield 90.0%, brown liquid). LC-MS (ESI) m/z: 424.4 [M+H] ⁺ .

Step 4: N-(7-(4-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)heptyl) Synthesis of 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamide

N-(1-(7-aminoheptyl)-1H-pyrazol-4-yl)-5-chloro-4-(1H-indol-3-yl)pyrimidin-2-amine (150mg, 0.354mmol ), 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)oxy)acetic acid (118mg, 0.354mmol) , HATU (175 mg, 0.460 mmol) and DIPEA (229 mg, 1.77 mmol) were dissolved in DMF (5.00 mL). The resulting reaction solution was stirred overnight at room temperature under nitrogen protection, and the reaction solution was purified by Prep-HPLC (column: SunFire Prep C8 OBD 10um 19*250mm; mobile phase: A-0.1% TFA aqueous solution, B-ACN; gradient: B%=10 %～35%; flow rate: 20 mL/min), the title compound (60.8 mg, yield 23.3%, yellow solid) was obtained. LC-MS (ESI) m/z: 738.5 [M+H] ⁺ . ¹ H NMR (400MHz,DMSO-d ₆ )δ11.13(s,1H),9.60–9.29(m,1H),8.58–8.45(m,1H),8.39(s,1H),7.92(t,J =5.5Hz,1H),7.79(s,2H),7.76(d,J=8.0Hz,1H),7.60(d,J=8.2Hz,1H),7.46(d,J=7.3Hz,1H), 7.37(d, J=8.6Hz, 1H), 7.28(t, J=7.6Hz, 1H), 7.23–7.10(m, 1H), 5.11(dd, J=12.9, 5.1Hz, 1H), 4.75(s ,2H),4.31(t,J＝6.9Hz,2H),3.21–3.03(m,2H),2.97–2.79(m,1H),2.62–2.54(m,1H),2.08–1.89(m,1H ), 1.85–1.69(m,2H), 1.50–1.34(m,2H), 1.36–1.08(m,7H).

Example 6: N-(5-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)oxy )acetamido)pentyl) -3-((5-(trifluoromethyl)pyrimidin-2-yl)amino)cyclopentane-1-carboxamide

Example 7: 3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-N-(5-(2-((2-(2,6- Dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)oxy)acetamido)pentyl)cyclopentane-1-carboxamide

Example 8: N-(7-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)heptyl )-2-((2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)oxy)acetamide

Prepared similarly to Example 5, LC-MS (ESI) m/z: 738.5[M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.11(s, 1H), 8.87(d, J=7.3Hz, 1H), 8.78–8.62(m, 2H), 8.41(s, 1H), 7.90( t,J=5.6Hz,1H),7.80–7.73(m,1H),7.71–7.58(m,1H),7.46(d,J=7.3Hz,1H),7.42–7.20(m,3H),6.07 (s,1H),5.10(dd,J=12.8,5.2Hz,1H),4.76(d,J=7.3Hz,2H),4.35(t,J=6.7Hz,2H),3.12(dd,J= 12.8,6.5Hz,2H),2.95–2.80(m,1H),2.64–2.54(m,1H),2.06–1.92(m,1H),1.89–1.74(m,2H),1.46–1.37(m, 2H), 1.33–1.21 (m, 7H).

Example 9: N-(7-(5-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-oxopiperidin-1-yl) Heptyl)-2-((2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)oxy)acetamide

Step 1: Synthesis of tert-butyl (7-(5-nitro-2-oxopyridin-1(2H)-yl)heptyl)carbamate

(7-bromoheptyl) tert-butyl carbamate (630mg, 2.14mmol), 5-nitropyridin-2 (1H)-one (300mg, 2.14mmol), KI (71.0mg, 0.430mmol) and K ₂ CO ₃ (591 mg, 4.28 mmol) was sequentially added to DMF (10.0 mL). The resulting reaction solution was stirred at 40° C. for two hrs under nitrogen protection. The reaction solution was diluted with EA (50.0mL), washed with water (50.0mL) and saturated brine (50.0mL×2) successively, the organic phase was dried with anhydrous Na ₂ SO ₄ , filtered, and the filtrate was evaporated under reduced pressure to remove the solvent, and the residue was passed through Purified by silica gel chromatography (PE/EA=3/1) to obtain the target compound (336 mg, yield 60.4%, yellow liquid). LC-MS (ESI) m/z: 254.3 [M+H-100] ⁺ .

Step 2: Synthesis of tert-butyl (7-(5-amino-2-oxopiperidin-1-yl)heptyl)carbamate

Dissolve tert-butyl (7-(5-amino-2-oxopiperidin-1-yl)heptyl)carbamate (336 mg, 0.950 mmol) in methanol (6.00 mL) at room temperature, and add wet Palladium on carbon (150 mg). The resulting reaction solution was stirred overnight at room temperature under a hydrogen atmosphere, filtered with diatomaceous earth, and the solvent was distilled off under reduced pressure to obtain the target compound (256 mg, yield 82.3%, black liquid). LC-MS (ESI) m/z: 328.2 [M+H] ⁺ .

Step 3: (7-(5-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-oxopiperidin-1-yl)heptyl) Synthesis of tert-butyl carbamate

3-(2,5-dichloropyrimidin-4-yl)-1H-indole (310mg, 1.17mmol), (7-(5-amino-2-oxopiperidin-1-yl)heptyl)amino tert-Butyl formate (192 mg, 0.580 mmol) and DIPEA (378 mg, 2.93 mmol) were sequentially added to NMP (12.0 mL). The obtained reaction solution was stirred overnight at 130° C. under the protection of nitrogen. The reaction solution was diluted with EA (50.0mL), washed with water (50.0mL) and saturated brine (50.0mL×2) successively, the organic phase was dried with anhydrous Na ₂ SO ₄ , filtered, and the filtrate was evaporated under reduced pressure to remove the solvent, and the residue was passed through Purified by silica gel chromatography to obtain the target compound (40.0 mg, yield 9.20%, yellow solid). LC-MS (ESI) m/z: 555.2 [M+H] ⁺ .

Step 4: Synthesis of 1-(7-aminoheptyl)-5-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)piperidin-2-one

At room temperature, (7-(5-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-oxopiperidin-1-yl)heptyl) tert-Butyl carbamate (40.0 mg, 0.0700 mmol) was dissolved in DCM (4.00 mL) and TFA (1.00 mL) was added. The resulting reaction solution was stirred for two hrs under ice-bath conditions, and the solvent was distilled off under reduced pressure to obtain the target compound (40.0 mg, yield 100%, yellow liquid). LC-MS (ESI) m/z: 455.1 [M+H] ⁺ .

Step 5: N-(7-(5-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-oxopiperidin-1-yl)heptan Synthesis of yl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamide

1-(7-aminoheptyl)-5-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)piperidin-2-one (32.0mg, 0.0900 mmol), 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)oxy)acetic acid (29.0mg, 0.0900 mmol), HATU (43.0 mg, 0.0110 mmol) and DIPEA (34.0 mg, 0.270 mmol) were dissolved in DMF (5.00 mL). The obtained reaction solution was stirred at room temperature for two hrs under the protection of nitrogen, the reaction solution was diluted with EA (50.0 mL), washed with water (50.0 mL) and saturated brine (50.0 mL×2) successively, and the organic phase was dried with anhydrous Na ₂ SO ₄ , filtered, the filtrate was distilled off under reduced pressure to remove the solvent, and the residue was purified by prep-HPLC (column: SunFire Prep C8 OBD 10um 19*250mm; Mobile phase: A-0.1% FA aqueous solution, B-ACN; Gradient: B%=25% ~45%; flow rate: 20 mL/min), the title compound (1.30 mg, yield 2.00%, off-white solid) was obtained. LC-MS (ESI) m/z: 769.3 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.87(s, 1H), 11.12(s, 1H), 8.78–8.50(m, 1H), 8.48(d, J=2.8Hz, 1H), 8.30( s,1H),7.91(t,J=5.5Hz,1H),7.83–7.74(m,1H),7.49(dd,J=7.6,2.3Hz,2H),7.40(dd,J=12.8,7.9Hz ,2H),7.22(t,J=7.4Hz,1H),7.13(t,J=7.4Hz,1H),5.11(dd,J=12.8,5.4Hz,1H),4.76(s,2H),4.35 –4.12(m,1H),3.11(dd,J＝12.8,6.7Hz,3H),2.98–2.82(m,2H),2.70–2.55(m,2H),2.45–2.40(m,1H),2.39 –2.32 (m, 1H), 2.07 – 1.96 (m, 3H), 1.92 – 1.85 (m, 1H), 1.54 – 1.33 (m, 5H), 1.31 – 1.23 (m, 6H).

Example 10: N-(7-(5-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-oxopyridine-1(2H)- Base)heptyl)-2- ((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)oxy)acetamide

(7-bromoheptyl) tert-butyl carbamate (2.00g, 6.80mmol), 5-nitropyridin-2 (1H)-one (952mg, 6.80mmol), KI (233mg, 1.40mmol) and K ₂ CO ₃ (1.80 g, 13.6 mmol) was sequentially added to DMF (40.0 mL). The resulting reaction solution was stirred at 40° C. for two hrs under nitrogen protection. The reaction solution was diluted with EA (100mL), washed with water (100mL) and saturated brine ( _100mL ×2) successively, the organic phase was dried over anhydrous _Na2SO4 , filtered, the filtrate was distilled off under reduced pressure, and the residue was chromatographed on silica gel. Purification (PE/EA=3/1) gave the target compound (800 mg, yield 33.0%, yellow liquid). LC-MS (ESI) m/z: 254.3 [M+H-100] ⁺ .

Step 2: Synthesis of tert-butyl (7-(5-amino-2-oxopyridin-1(2H)-yl)heptyl)carbamate

(7-(5-Nitro-2-oxopyridin-1(2H)-yl)heptyl)carbamate (tert-butyl) (430 mg, 1.22 mmol) was dissolved in EtOH (10.0 mL) and water ( 2.00mL), iron powder (683mg, 12.2mmol) and ammonium chloride (653mg, 12.2mmol) were added. The resulting reaction solution was stirred overnight at 80°C. After the reaction, adjust the pH to 9-10 with saturated NaHCO ₃ aqueous solution, extract with EA (100mL×2), combine the organic phases and wash with saturated brine (100mL×2). It was dried over anhydrous Na ₂ SO ₄ , filtered, and the solvent was distilled off from the filtrate under reduced pressure to obtain the target compound (300 mg, yield 76.0%, gray liquid). LC-MS (ESI) m/z: 324 [M+H] ⁺ .

Step 3: (7-(5-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-oxopyridin-1(2H)-yl)heptan base) synthesis of tert-butyl carbamate

3-(2,5-Dichloropyrimidin-4-yl)-1H-indole (244mg, 0.930mmol), (7-(5-amino-2-oxopyridin-1(2H)-yl)heptan base) tert-butyl carbamate (300 mg, 0.930 mmol) and DIPEA (720 mg, 5.58 mmol) were sequentially added to NMP (5.00 mL). The obtained reaction solution was stirred overnight at 130° C. under the protection of nitrogen. The reaction solution was diluted with EA (50.0mL), washed with water (50.0mL) and saturated brine (50.0mL×2) successively, the organic phase was dried with anhydrous Na ₂ SO ₄ , filtered, and the filtrate was evaporated under reduced pressure to remove the solvent, and the residue was passed through Purification by silica gel chromatography (PE/EA=3/1, DCM/MeOH=10/1, 1% NH ₃ ·H ₂ O) gave the target compound (130 mg, yield 25.0%, yellow solid). LC-MS (ESI) m/z: 551.2 [M+H] ⁺ .

Step 4: 1-(7-Aminoheptyl)-5-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyridin-2(1H)-one synthesis

(7-(5-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-oxopyridin-1(2H)-yl)heptan base) tert-butyl carbamate (130 mg, 0.230 mmol) was dissolved in DCM (10.0 mL) and TFA (2.00 mL) was added. The resulting reaction solution was stirred at room temperature for 1 hr, and the solvent was distilled off under reduced pressure to obtain the target compound (100 mg, yield 94.0%, yellow liquid). LC-MS (ESI) m/z: 450.9 [M+H] ⁺ .

Step 5: N-(-(5-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-oxopyridin-1(2H)-yl) Synthesis of Heptyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamide

1-(7-aminoheptyl)-5-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyridin-2(1H)-one (100mg, 0.220mmol), 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)oxy)acetic acid (73.0mg, 0.220 mmol), HATU (110 mg, 0.290 mmol) and DIPEA (170 mg, 1.32 mmol) were dissolved in DMF (10.0 mL). The resulting reaction solution was stirred at room temperature for two hrs under nitrogen protection, the reaction solution was diluted with EA (50.0 mL), washed with water (50.0 mL) and saturated brine (50.0 mL×2) in sequence, and the organic phase was dried with anhydrous Na ₂ SO ₄ , Filtration, the filtrate was distilled off the solvent under reduced pressure, and the residue was purified by prep-HPLC (column: SunFire Prep C8 OBD 10um 19*250mm; Mobile phase: A-0.1% FA aqueous solution, B-ACN; Gradient: B%=15%～ 45%; flow rate: 20 mL/min), the title compound (12.7 mg, yield 7.50%, yellow solid) was obtained. LC-MS (ESI) m/z: 764.7 [M+H] ⁺ . ¹ H NMR (400MHz,DMSO-d ₆ )δ11.93(s,1H),11.12(s,1H),9.16(s,1H),8.47(s,1H),8.39(s,2H),8.03( d,J=2.2Hz,1H),7.92(s,1H),7.80(t,J=7.9Hz,1H),7.68–7.44(m,4H),7.38(d,J=8.5Hz,1H), 7.21(t, J=7.3Hz, 1H), 7.06(s, 1H), 6.43(d, J=9.6Hz, 1H), 5.12(dd, J=12.9, 5.3Hz, 1H), 4.76(s, 2H ),3.83(t,J＝7.0Hz,2H),3.19–3.02(m,2H),2.98–2.82(m,1H),2.67–2.53(m,2H),2.14–1.94(m,1H), 1.58(s,2H),1.38(s,2H),1.24(s,6H).

Example 11: N-(7-(5-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)heptyl )-2-((2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)oxy)acetamide

Prepared similarly to Example 5, LC-MS (ESI) m/z: 738.5[M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ9.03(d, J=7.9Hz, 1H), 8.86–8.62(m, 2H), 8.46(d, J=57.3Hz, 1H), 7.90(t, J＝5.4Hz, 1H), 7.84–7.73(m, 1H), 7.68–7.49(m, 2H), 7.46(d, J＝7.2Hz, 1H), 7.41–7.09(m, 3H), 6.72(s ,1H),5.10(dd,J＝12.9,5.4Hz,1H),4.75(s,2H),4.41–4.27(m,2H),3.22–3.05(m,3H),2.97–2.79(m,1H ), 2.62–2.54(m,2H), 2.09–1.94(m,1H), 1.86–1.72(m,2H), 1.44–1.36(m,2H), 1.35–1.08(m,8H).

Example 12: 4-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)- 2-oxoethoxy) -2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Step 1: 4-(2-((R)-3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)-2 Synthesis of -oxoethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

(R)-5-Chloro-4-(1H-indol-3-yl)-N-(pyrrolidin-3-yl)pyrimidin-2-amine (106mg, 0.320mmol), 2-((2- (2,6-dioxopiperidin-3-yl)-1,3-dioxoisoquinolin-4-yl)oxy)acetic acid (100mg, 0.320mmol), HATU (182mg, 0.480mmol) and DIPEA (206 mg, 1.60 mmol) was dissolved in DMF (5.00 mL). The resulting reaction solution was stirred at room temperature for two hrs under nitrogen protection, the reaction solution was diluted with EA (50.0 mL), washed with water (50.0 mL) and saturated brine (50.0 mL×2) in sequence, and the organic phase was dried with anhydrous Na ₂ SO ₄ , Filtration, the filtrate was distilled off the solvent under reduced pressure, and the residue was purified by prep-HPLC (column: Waters Xbridge C18 10um OBD 19*250mm; mobile phase: A-0.1% NH ₄ HCO ₃ aqueous solution, B-ACN; Gradient: B%= 10%-35%; flow rate: 20 mL/min), the title compound (13.1 mg, yield 6.50%, yellow solid) was obtained. LC-MS (ESI) m/z: 627.7 [M+H] ⁺ . ¹ H NMR (400MHz,DMSO-d ₆ )δ11.88(s,1H),11.11(s,1H),8.62(s,1H),8.49(d,J=2.7Hz,1H),8.32(d, J=3.2Hz,1H),7.84–7.73(m,1H),7.61(dd,J=21.8,6.2Hz,1H),7.56–7.33(m,3H),7.31–7.10(m,2H),5.19 –5.01(m, 3H), 4.54(d, J＝37.9Hz, 1H), 3.95–3.52(m, 4H), 2.90(t, J＝14.9Hz, 1H), 2.69–2.54(m, 2H), 2.37–1.98(m ,3H).

Example 13: N-(7-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)heptan Base)-2-((2-(1-methyl -2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)oxy)ethyl Amide, trifluoroacetate

Step 1: 2-((2-(1-Methyl-2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetic acid Synthesis of tert-butyl ester

tert-butyl 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetate (388 mg, 1.00 mmol), iodomethane (425 mg, 3.00 mmol) and K ₂ CO ₃ (276 mg, 2.00 mmol) were dissolved in DMF (10.0 mL). The resulting reaction was stirred overnight at room temperature. After the reaction, add water (20.0 mL) to dilute, extract with EA (30.0 mL×2), combine the organic phases, dry with anhydrous Na ₂ SO ₄ , filter, and concentrate the filtrate under reduced pressure to obtain the crude product. Purification by silica gel chromatography (PE/EA=5/1) gave the target compound (301 mg, yield 74.8%, white solid). LC-MS (ESI) m/z: 347.1 [M-56] ⁺ .

Step 2: 2-((2-(1-Methyl-2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetic acid Synthesis

2-((2-(1-Methyl-2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)oxy)acetic acid tert-butyl The base ester (301 mg, 0.780 mmol) was dissolved in DCM (2.50 mL). TFA (2.50 mL) was slowly added dropwise to the above mixture, and the resulting reaction solution was stirred at room temperature for 2 hrs under nitrogen protection. After the reaction, the reaction solution was concentrated under reduced pressure to obtain the target compound (256 mg, yield 98.0%, white solid). LC-MS (ESI) m/z: 347.1 [M+H] ⁺ .

Step 3: N-(7-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)heptyl )-2-((2-(1-methyl-2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)oxy)acetamide synthesis

(R)-N-(1-(7-aminoheptyl)pyrrolidin-3-yl)-5-chloro-4-(1H-indol-3-yl)pyrimidin-2-amine (100mg, 0.230 mmol), 2-((2-(1-methyl-2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)oxy)acetic acid (96.9mg, 0.280mmol) and HATU (131mg, 0.345mmol) were dissolved in DMF (3.00mL). After stirring for 5 minutes, DIPEA (1.00mL) was slowly added dropwise to the solution, and the resulting reaction solution was stirred at room temperature under nitrogen protection. 2hrs. After the reaction, the reaction solution was purified by Prep-HPLC (column: SunFire Prep C8 OBD 10um 19*250mm; mobile phase: A-0.1% TFA aqueous solution, B-ACN; gradient: B%=20%～50%; flow rate: 20 mL/min), the title compound (25.5 mg, yield 14.7%, yellow solid) was obtained. LC-MS (ESI) m/z: 755.2 [M+H] ⁺ . ¹ H NMR (400MHz,DMSO-d ₆ )δ11.83(s,1H),8.61(s,1H),8.45(d,J=2.8Hz,1H),8.26(s,1H),8.17(s, 1H),7.94–7.88(m,1H),7.84–7.78(m,1H),7.51–7.46(m,2H),7.41–7.35(m,2H),7.24–7.11(m,2H),5.22– 5.13(m,1H),4.76(s,2H),4.40(s,1H),3.16–3.08(m,3H),3.02(s,3H),2.96-2.93(m,2H),2.78(s, 1H), 2.73(s,1H),2.68-2.66(m,2H),2.26–2.15(m,1H),2.09–1.99(m,1H),1.87–1.74(m,1H),1.48–1.35(m,5H ),1.28-1.26(m,8H).

Example 14: 4-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)ethyl Oxy)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3-dione, FA salt

Step 1: (R)-2-(3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)ethane-1- Alcohol synthesis

At room temperature, (R)-5-chloro-4-(1H-indol-3-yl)-N-(pyrrolidin-3-yl)pyrimidin-2-amine (700mg, 2.23mmol), 2-bromomethane -1-ol (335 mg, 2.68 mmol), KI (37.0 mg, 0.223 mmol) and K ₂ CO ₃ (925 mg, 6.69 mmol) were sequentially added to ACN (15.0 mL). The resulting reaction solution was stirred overnight at 85° C. under nitrogen protection. After the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (DCM/MeOH=19/1) to obtain the target compound (621 mg, yield 77.8%, yellow solid). LC-MS (ESI) m/z: 358.3 [M+H] ⁺ .

Step 2: Ethyl (R)-2-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)methylsulfonate Synthesis of esters

At 0°C, (R)-2-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)ethane- 1-Alcohol (200 mg, 0.559 mmol) and Et ₃ N (170 mg, 1.68 mmol) were dissolved in DCM (6.00 mL). Methanesulfonyl chloride (77.0 mg, 0.671 mmol) was slowly added dropwise, and the resulting reaction solution was stirred at room temperature for 3 hrs under nitrogen protection. The reaction solution was diluted with water (10.0 mL), extracted with DCM (10.0 mL×2), the organic phases were combined, dried with anhydrous Na ₂ SO ₄ , filtered, and the filtrate was distilled off under reduced pressure to obtain the target compound (231 mg, yield 94.7 %, yellow solid). LC-MS (ESI) m/z: 436.3 [M+H] ⁺ .

Step 3: 4-(2-((R)-3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)ethoxy Synthesis of 2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

At room temperature, (R)-2-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)methanesulfonic acid Ethyl ester (231mg, 0.530mmol), 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindoline-1,3-dione (145mg, 0.530mmol), KI ( 9.00 mg, 0.053 mmol) and NaHCO ₃ (134 mg, 1.59 mmol) were sequentially added to DMF (5.00 mL). The resulting reaction solution was stirred overnight at room temperature under nitrogen protection. The reaction solution is directly purified by prep-HPLC (column: SunFire Prep C8 OBD 10um 19*250mm; Mobile phase: A-0.1% FA aqueous solution, B-ACN; Gradient: B%=15%～50%; Flow rate: 20mL/min ), to obtain the title compound (17.0 mg, yield 5.20%, white solid). LC-MS (ESI) m/z: 614.1 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.85(s, 1H), 11.08(s, 1H), 8.61(s, 1H), 8.45(d, J=2.7Hz, 1H), 8.41–8.29( m, 1H), 8.25(s, 1H), 7.85–7.75(m, 1H), 7.53(d, J＝8.6Hz, 1H), 7.48(d, J＝8.4Hz, 1H), 7.45-7.42(m 1H),7.41-7.34(m 1H),7.25–7.15(m,1H),7.15–7.05(m,1H),5.06(dd,J＝12.6,5.4Hz,1H),4.53–4.36(m,1H ),4.33(t,J＝5.5Hz,2H),3.08–2.98(m,1H),2.91–2.86(m,2H),2.86–2.78(m,2H),2.72–2.62(m,2H), 2.61–2.56(m,1H), 2.56–2.53(m,1H), 2.27–2.13(m,1H), 2.05–1.88(m,1H), 1.86–1.74(m,1H).

Example 15: 4-(3-((R)-3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)propane Oxy)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3-dione, FA salt

Step 1: (R)-3-(3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)propan-1-ol Synthesis

K ₂ CO ₃ (659mg, 4.77mmol) and KI (26.5mg, 0.160mmol) were added to (R)-5-chloro-4-(1H-indol-3-yl)-N-(pyrrole Alk-3-yl)pyrimidin-2-amine (500mg, 1.59mmol) and 3-bromopropan-1-ol (266mg, 1.91mmol) in DMF (8.00mL) were stirred at 60°C for 16hrs. After the reaction mixture was cooled to room temperature, it was diluted with water (100 mL), extracted with EA (50.0 mL×2), the organic phases were combined, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure, and the residue was subjected to silica gel chromatography (DCM/MeOH =10/1) separation and purification to obtain the target compound (409 mg, yield 81.7%, yellow solid). LC-MS (ESI) m/z: 372.2 [M+H] ⁺ .

Step 2: Propyl (R)-3-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)methylsulfonate Synthesis of esters

At 0°C, MsCl (92.8mg, 0.810mmol) was slowly added dropwise to (R)-3-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl) Amino)pyrrolidin-1-yl)propan-1-ol (100 mg, 0.270 mmol) and Et ₃ N (82.0 mg, 0.810 mmol) in DCM (8.00 mL), the reaction mixture was stirred at 0° C. for 3 hrs. The reaction mixture was quenched by adding NaHCO ₃ aqueous solution (30.0 mL), extracted with DCM (15.0 mL×2), combined organic phases, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure, and the residue was subjected to silica gel chromatography (DCM/ MeOH=40/1) separation and purification to obtain the target compound (118 mg, yield 97.5%, yellow solid). LC-MS (ESI) m/z: 450.1 [M+H] ⁺ .

Step 3: 4-(3-((R)-3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)propoxy Synthesis of 2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione formate

NaHCO ₃ (70.5 mg, 0.510 mmol) and KI (3.30 mg, 20.0 mmol) were added to (R)-3-(3-((5-chloro-4-(1H-indol-3-yl )pyrimidin-2-yl)amino)pyrrolidin-1-yl)propyl methanesulfonate (76.0mg, 0.170mmol) and 2-(2,6-dioxopiperidin-3-yl)-4- In a solution of hydroxyisoindoline-1,3-dione (46.6 mg, 0.170 mmol) in DMF (5.00 mL), the reaction mixture was stirred at 100° C. for 16 hrs. After the reaction mixture was cooled to room temperature, it was concentrated under reduced pressure, and the residue was subjected to Prep-HPLC (column: SunFire Prep C8 OBD 10um 19*250mm; mobile phase: A-water (0.1% FA)/B-CH ₃ CN; B% =35%-45%; flow rate: 20mL/min) separation and purification to obtain the title compound (7.38mg, yield 9.70%, yellow solid). LC-MS (ESI) m/z: 628.1 [M+H] ⁺ . ¹ H NMR (400MHz,DMSO-d ₆ )δ11.83(s,1H),11.09(s,1H),8.61(s,1H),8.45(d,J=3.0Hz,1H),8.26(s, 1H),8.22(s,1H),7.83–7.77(m,1H),7.56–7.45(m,2H),7.45–7.36(m,2H),7.26–7.08(m,2H),5.11–5.03( m,1H),4.42(s,1H),4.28(t,J＝6.2Hz,2H),3.01–2.78(m,3H),2.74–2.54(m,4H),2.36–2.14(m,2H) ,2.09–1.85(m,4H),1.87–1.73(m,1H),1.38–1.16(m,2H).

Example 16: 4-(2-(4-((1-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl) Amino)pyrrolidin-1-yl)acetyl)piperidin -4-yl)methyl)piperazin-1-yl)-2-oxoethoxy)-2-(2,6-dioxopiper Pyridine-3-yl)isoindoline-1,3-dione, FA salt

Step 1: Synthesis of (R)-methyl 2-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)acetate

At 0°C, (R)-5-chloro-4-(1H-indol-3-yl)-N-(pyrrolidin-3-yl)pyrimidin-2-amine (1.00g, 3.19mmol) was dissolved in To DCM (15.0 mL) was added _Et3N (1.61 g, 15.9 mmol). The resulting reaction solution was stirred at room temperature for 3 hrs, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM/MeOH=20/1) to obtain the target compound (1.21 g, yield 98.4%, yellow liquid). LC-MS (ESI) m/z: 386.3 [M+H] ⁺ .

Step 2: Synthesis of (R)-2-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)acetic acid

(R)-2-(3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)acetic acid methyl ester (1.21g, 3.14 mmol) was dissolved in MeOH/water (4/1, 6.00 mL), and LiOH (150 mg, 6.27 mmol) was added. The resulting reaction solution was stirred at room temperature overnight, the reaction solution was concentrated under reduced pressure, adjusted to pH=2-3 with dilute hydrochloric acid, and the solvent was distilled off under reduced pressure to obtain the target compound (1.13 g, yield 96.6%, white solid). LC-MS (ESI) m/z: 372.3 [M+H] ⁺ .

Step 3: (R)-4-(1-(2-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl )Synthesis of acetyl)piperidin-4-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester

At room temperature, (R)-2-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)acetic acid (600mg, 1.61mmol), 4-(piperidin-4-ylmethyl)piperazine-1-carboxylic acid tert-butyl ester (457mg, 1.61mmol), HATU (789mg, 2.10mmol) and DIPEA (626mg, 4.84mmol) were dissolved in in DMF (10.0 mL). The resulting reaction solution was stirred overnight at room temperature under nitrogen protection, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM/MeOH=20/1) to obtain the target compound (689 mg, yield 66.9%, white solid). LC-MS (ESI) m/z: 637.5 [M+H] ⁺ .

Step 4: (R)-2-(3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)-1-(4 Synthesis of -(piperazin-1-ylmethyl)piperidin-1-yl)ethan-1-one

At room temperature, (R)-4-(1-(2-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1- Base) acetyl) piperidin-4-yl) methyl) piperazine-1-carboxylic acid tert-butyl ester (689mg, 1.08mmol) was added to MeOH (5.00mL), then HCl·MeOH solution (4N, 5.00mL ). The resulting reaction solution was stirred overnight at room temperature, and the solvent was distilled off under reduced pressure to obtain the target compound (573 mg, yield 98.7%, yellow-green solid). LC-MS (ESI) m/z: 537.5 [M+H] ⁺ .

Step 5: 4-(2-(4-((1-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino )pyrrolidin-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-oxoethoxy)-2-(2,6-dioxopiperidine Synthesis of -3-yl)isoindoline-1,3-dione

At room temperature, (R)-2-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)-1-( 4-(piperazin-1-ylmethyl)piperidin-1-yl)ethane-1-one (100mg, 0.186mmol), 2-((2-(2,6-dioxopiperidine-3 -yl)isoindoline-1,3-dione-4-yl)oxy)acetic acid (93.0mg, 0.279mmol), HATU (106mg, 0.279mmol) and DIPEA (120mg, 0.931mmol) were dissolved in DMF ( 5.00mL). The resulting reaction solution was stirred overnight at room temperature under nitrogen protection, filtered, and the filtrate was Purify directly by prep-HPLC (column: Waters Xbridge C18 10um OBD 19*250mm; Mobile phase: A-0.1% FA aqueous solution, B-ACN; Gradient: B%=15%～35%; Flow velocity 20mL/min), obtain The title compound (16.9 mg, yield 10.7%, white solid). LC-MS (ESI) m/z: 851.6 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.84(s, 1H), 11.11(s, 1H), 9.05–8.48(m, 1H), 8.46(d, J=2.9Hz, 1H), 8.26( s,1H),8.20(s,1H),7.80-7.74(m,1H),7.49(d,J＝7.9Hz,1H),7.45(d,J＝7.2Hz,1H),7.42–7.34(m ,1H),7.32(d,J=8.5Hz,1H),7.25–7.10(m,2H),5.22–5.05(m,3H),4.50–4.36(m,1H),4.30(d,J=12.5 Hz,1H),4.09–3.92(m,2H),3.28–3.07(m,4H),3.06–2.83(m,4H),2.79–2.68(m,1H),2.65–2.53(m,4H), 2.48–2.41(m,1H),2.41–2.34(m,1H),2.34–2.24(m,2H),2.24–2.14(m,2H),2.15–2.10(m,1H),2.10–1.93(m ,2H), 1.91–1.79(m,1H), 1.78–1.60(m,3H), 1.12–0.96(m,1H), 0.94–0.69(m,1H).

Example 17: 4-(2-(4-((1-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrole Alkane-1-carbonyl)piperidin-4- yl)methyl)piperazin-1-yl)-2-oxoethoxy)-2-(2,6-dioxopiperidin-3-yl) Isoindoline-1,3-dione, FA salt

Step 1: Synthesis of tert-butyl 4-(1-((4-nitrophenoxy)carbonyl)piperidin-4-yl)methyl)piperazine-1-carboxylate

At room temperature, tert-butyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate (250mg, 0.880mmol), 4-nitrophenylcarbonyl chloride (177mg, 0.880mmol) and DIPEA (56.9 mg, 0.440 mmol) was dissolved in DCM (8.00 mL), and the resulting reaction solution was stirred at room temperature for 2 hrs under nitrogen protection. After the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (PE/EA=1/1) to obtain the title compound (200 mg, yield 80.0%, white solid). LC-MS (ESI) m/z: 449.3 [M+H] ⁺ .

Step 2: (R)-4-((1-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)piper Synthesis of pyridin-4-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester

4-(1-((4-nitrophenoxy)carbonyl)piperidin-4-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester (150mg, 0.330mmol), (R)-5 -Chloro-4-(1H-indol-3-yl)-N-(pyrrolidin-3-yl)pyrimidin-2-amine (104mg, 0.330mmol) and DIPEA (216mg, 1.67mmol) were dissolved in ACN (8.00 mL). The resulting reaction solution was stirred at 80° C. for 16 hrs under nitrogen protection. After the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (DCM/MeOH=20/1) to obtain the title compound (221 mg, yield 79.7%, yellow solid). LC-MS (ESI) m/z: 623.2 [M+H] ⁺ .

Step 3: (R)-(3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)(4-(piperazine- Synthesis of 1-ylmethyl)piperidin-1-yl)methanone

(R)-4-((1-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)piperidine- 4-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester (221 mg, 0.350 mmol) was dissolved in MeOH (3.00 mL), and HCl·MeOH (4N, 3.00 mL) solution was added dropwise to the mixture. Gained reaction solution was stirred at room temperature under nitrogen protection for 10hrs, and after the reaction was completed, the reaction The solvent was distilled off from the liquid under reduced pressure to obtain the target compound (170 mg, yield 76.9%, yellow solid). LC-MS (ESI) m/z: 523.2 [M+H] ⁺ .

Step 4: 4-(2-(4-((1-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidine -1-carbonyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-oxoethoxy)-2-(2,6-dioxopiperidin-3-yl)iso Synthesis of Indoline-1,3-dione

(R)-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)(4-(piperazine-1- methyl)piperidin-1-yl)methanone (100mg, 0.190mmol) and 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindoline-1,3- Diketone (63.1mg, 0.190mmol) was dissolved in DMF (5.00mL), then HATU (72.6mg, 0.190mmol) and DIPEA (74.1mg, 0.570mmol) were added to the above mixture, and the resulting reaction solution was Stirring for 16hrs, after the reaction, the reaction solution was directly purified by Prep-HPLC (column: SunFire Prep C8 OBD 10um 19*250mm; mobile phase: A-0.1% FA aqueous solution, B-ACN; gradient: B%=5%～ 40%; flow rate: 20 mL/min), the title compound (22.1 mg, yield 22.1%, yellow solid) was obtained. LC-MS (ESI) m/z: 837.3 [M+H] ⁺ . ¹ H NMR (400MHz,DMSO-d ₆ )δ11.85(s,1H),11.10(s,1H),8.74–8.51(m,1H),8.74–8.51(m,1H),8.49(t,J ＝12.0Hz,1H),8.29(s,1H),8.21(s,1H),7.87–7.68(m,1H),7.60–7.39(m,3H),7.32(d,J＝8.6Hz,1H) ,7.26–7.08(m,2H),5.16(s,2H),5.14–5.04(m,1H),4.38(s,1H),3.73–3.60(m,3H),3.54–3.46(m,2H) ,3.45–3.39(m,4H),3.04–2.78(m,2H),2.72–2.59(m,3H),2.59–2.54(m,1H),2.38(s,2H),2.34–2.26(m, 2H), 2.20–2.06(m,3H), 2.06–1.98(m,1H), 1.98–1.87(m,1H), 1.75–1.59(m,3H), 1.07–0.90(m,2H).

Example 18: 4-(4-((1-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrole Alkyl-1-yl)acetyl)piperidin -4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1 ,3-diketone

Step 1: 4-(4-((1-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidine -1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1, Synthesis of 3-diketones

At room temperature, (R)-2-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)-1-( 4-(piperazin-1-ylmethyl)piperidin-1-yl)ethane-1-one (100mg, 0.186mmol), 2-(2,6-dioxopiperidin-3-yl)- 4-Fluoroisoindoline-1,3-dione (57.0 mg, 0.204 mmol) and DIPEA (96.0 mg, 0.745 mmol) were dissolved in DMSO (5.00 mL). The resulting reaction solution was stirred at 130°C for 6hrs under nitrogen protection, cooled to room temperature, filtered, and the filtrate was directly purified by prep-HPLC (column: Waters Xbridge C18 10um OBD 19*250mm; mobile phase: A-0.1%NH ₄ HCO ₃ Aqueous solution, B-ACN; Gradient: B%=5%～35%; Flow rate: 20mL/min) to obtain the title compound (49.5mg, yield 33.5%, yellow solid). LC-MS (ESI) m/z: 793.6 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.82(s, 1H), 11.08(s, 1H), 8.79–8.50(m, 1H), 8.46(d, J=2.7Hz, 1H), 8.26( s,1H),7.70(dd,J=8.2,7.4Hz,1H),7.49(d,J=7.6Hz,1H),7.41–7.34(m,2H),7.33–7.25(m,1H),7.25 –7.10(m,2H),5.09(dd, J=12.9,5.3Hz,1H),4.62–4.34(m,1H),4.31(d,J=12.7Hz,1H),4.03(t,1H),3.51–3.37(m,1H),3.37–3.33 (m,1H),3.30–3.14(m,5H),3.16–3.03(m,1H),3.04–2.80(m,3H),2.76–2.65(m,1H),2.66–2.52(m,5H) ,2.48–2.30(m,2H),2.28–2.12(m,2H),2.12–1.93(m,2H),1.92–1.65(m,4H),1.16–0.97(m,1H),0.98–0.68( m, 1H).

Example 19: 5-(4-((1-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrole Alkyl-1-yl)acetyl)piperidin -4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1 ,3-diketone

Step 1: 5-(4-((1-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidine -1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1, Synthesis of 3-diketones

At room temperature, (R)-2-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)-1-( 4-(piperazin-1-ylmethyl)piperidin-1-yl)ethane-1-one (100mg, 0.186mmol), 2-(2,6-dioxopiperidin-3-yl)- 5-Fluoro-isoindoline-1,3-dione (67.0 mg, 0.242 mmol) and DIPEA (96.0 mg, 0.744 mmol) were dissolved in DMSO (5.00 mL). The resulting reaction solution was stirred at 130°C for 6hrs under nitrogen protection, cooled to room temperature, filtered, and the filtrate was directly purified by prep-HPLC (column: Waters Xbridge C18 10um OBD 19*250mm; mobile phase: A-0.1%NH ₄ HCO ₃ Aqueous solution, B-ACN; Gradient: B%=5%～35%; flow rate 20mL/min) to obtain the title compound (48.1mg, yield 32.6%, yellow solid). LC-MS (ESI) m/z: 793.6 [M+H] ⁺ . ¹ H NMR (400MHz,DMSO-d ₆ )δ11.83(s,1H),11.09(s,1H),8.94–8.53(m,1H),8.47(s,1H),8.26(s,1H), 7.67(d,J=8.5Hz,1H),7.50(d,J=7.8Hz,1H),7.43–7.26(m,2H),7.26–7.04(m,3H),5.22–4.95(m,1H) ,4.58–4.22(m,2H),4.03(dd,J＝14.2,7.1Hz,1H),3.60–3.37(m,3H),3.32–3.16(m,2H),3.15–2.65(m,5H) ,2.65–2.52(m,4H),2.48–2.33(m,3H),2.31–2.09(m,3H),2.11–1.99(m,2H),1.97–1.45(m,5H),1.13–0.67( m,2H).

Example 20: 5-(4-((4-(((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidine- 1-yl)methyl)piperidin- 1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3 - diketone, FA salt

Step 1: (R)-4-((3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)methyl)piper Synthesis of tert-butyl pyridine-1-carboxylate

(R)-5-Chloro-4-(1H-indol-3-yl)-N-(pyrrolidin-3-yl)pyrimidin-2-amine (318mg, 1.01mmol) and 4-formylpiperidine - tert-butyl 1-carboxylate (259mg, 1.22mmol) was dissolved in DCE (10.0mL), then AcOH (3.00mL) was added, at room temperature After stirring at low temperature for 30 minutes, NaBH(OAc) ₃ (537 mg, 2.53 mmol) was added to the above reaction solution, and the resulting reaction solution was stirred at room temperature for 2 hrs under nitrogen protection. The reaction solution was diluted with water (20.0 mL), extracted with DCM (20.0 mL×2). The organic phases were combined, washed with saturated brine, dried over anhydrous Na ₂ SO ₄ , and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (DCM/MeOH=5/1) to obtain the title compound (450 mg, yield 88.1%, yellow oil). LC-MS (ESI) m/z: 511.2 [M+H] ⁺ .

Step 2: (R)-5-Chloro-4-(1H-indol-3-yl)-N-(1-(piperidin-4-ylmethyl)pyrrolidin-3-yl)pyrimidine-2- Amine Synthesis

(R)-4-((3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)methyl)piperidine- 1-tert-butyl carboxylate (450 mg, 0.880 mmol) was dissolved in MeOH (2.00 mL), and 4N HCl·MeOH (1.00 mL) solution was slowly added dropwise, and the resulting reaction solution was stirred at room temperature for 12 hrs under nitrogen protection. After the reaction, the solvent was distilled off from the reaction solution under reduced pressure to obtain the target compound (360 mg, yield 98.6%, yellow oil). LC-MS (ESI) m/z: 411.2 [M+H] ⁺ .

Step 3: (R)-4-((4-((3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl) Synthesis of tert-butyl methyl)piperidine-1-yl)methyl)piperidine-1-carboxylate

(R)-5-chloro-4-(1H-indol-3-yl)-N-(1-(piperidin-4-ylmethyl)pyrrolidin-3-yl)pyrimidin-2-amine ( 360mg, 0.870mmol), tert-butyl 4-formylpiperidine-1-carboxylate (2.24g, 10.5mmol) were dissolved in DCE (30.0mL), and AcOH (5.00mL) was added, and the resulting reaction solution was heated at room temperature Stir for 30 minutes. NaBH(OAc) ₃ (557 mg, 2.63 mmol) was added to the above reaction solution, and the resulting reaction solution was stirred at room temperature for 2 hrs under nitrogen protection. After the reaction was completed, water (20.0 mL) was added to the above reaction liquid for dilution, and extracted with DCM (20.0 mL×2). The organic phases were combined, washed with saturated brine, dried over anhydrous Na ₂ SO ₄ , and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (DCM/MeOH=8/1) to obtain the title compound (210 mg, yield 40.2%, yellow oil). LC-MS (ESI) m/z: 608.3 [M+H] ⁺ .

Step 4: (R)-5-Chloro-4-(1H-indol-3-yl)-N-(1-((1-(piperidin-4-ylmethyl)piperidin-4-yl) Synthesis of Methyl)pyrrolidin-3-yl)pyrimidin-2-amine

(R)-4-((4-((3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)methyl )piperidin-1-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester (210mg, 0.350mmol) was dissolved in MeOH (2.00mL), and 4N HCl MeOH (1.00mL) solution was slowly added dropwise, The resulting reaction solution was stirred at room temperature for 12 hrs under nitrogen protection. After the reaction, the solvent was distilled off from the reaction solution under reduced pressure to obtain the target compound (112 mg, yield 62.9%, yellow oil). LC-MS (ESI) m/z: 508.2 [M+H] ⁺ .

Step 5: 5-(4-((4-(((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1 -yl)methyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3- Synthesis of diketones

(R)-5-chloro-4-(1H-indol-3-yl)-N-(1-((1-(piperidin-4-ylmethyl)piperidin-4-yl)methyl )pyrrolidin-3-yl)pyrimidin-2-amine (112mg, 0.220mmol), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3- Diketone (73.0 mg, 0.260 mmol) and DIPEA (1.00 mL) were dissolved in DMSO (2.50 mL), and the resulting reaction solution was stirred at 120° C. for 1 hr under nitrogen protection. After the reaction, the reaction solution was directly purified by Prep-HPLC (column: SunFire Prep C8 OBD 10um 19*250mm; mobile phase: A-0.1% FA aqueous solution, B-ACN; gradient: B%=15%～55%; flow rate : 20 mL/min), the title compound (20.5 mg, yield 12.2%, yellow solid) was obtained. LC-MS (ESI) m/z: 764.3 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.84(s, 1H), 11.07(s, 1H), 8.67–8.52(m, 1H), 8.46(d, J=3.0Hz, 1H), 8.26( s,1H),8.17(s,1H),7.64(d,J=8.6Hz,1H),7.49(d,J=8.1Hz,1H),7.41-7.32(m,1H),7.29(s,1H ),7.25–7.18(m,2H),7.17–7.11(m,1H),5.10–5.02(m,1H),4.46–4.35(m,1H),4.02 (d,J=12.9Hz,2H),3.00–2.80(m,9H),2.34–2.26(m,3H),2.14(d,J=6.8Hz,2H),2.04–1.97(m,1H), 1.92–1.66(m,10H), 1.48–1.33(m,1H), 1.21–1.03(m,4H).

Example 21: 5-(4-((4-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1 -yl)piperidin-1-yl)methyl )piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Step 1: (R)-4-(3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)piperidine-1- Synthesis of tert-butyl formate

(R)-5-chloro-4-(1H-indol-3-yl)-N-(pyrrolidin-3-yl)pyrimidin-2-amine (314mg, 1.00mmol) and 4-oxopiperidine -1-tert-butyl carboxylate (1.99 g, 10.0 mmol) was dissolved in DCE (25.0 mL), and AcOH (3.00 mL) was added, and the resulting reaction solution was stirred at room temperature for 30 minutes. NaBH(OAc) ₃ (637 mg, 3.00 mmol) was added to the above reaction solution, and the resulting reaction solution was stirred at room temperature for 2 hrs under nitrogen protection. After the reaction was completed, water (20.0 mL) was added to the reaction liquid for dilution, and extracted with DCM (20.0 mL×2). The organic phases were combined, washed with saturated brine, dried over anhydrous Na ₂ SO ₄ , and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (DCM/MeOH=5/1) to obtain the title compound (460 mg, yield 92.5%, yellow oil). LC-MS (ESI) m/z: 497.3 [M+H] ⁺ .

Step 2: (R)-5-Chloro-4-(1H-indol-3-yl)-N-(1-(piperidin-4-yl)pyrrolidin-3-yl)pyrimidin-2-amine synthesis

(R)-4-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)piperidine-1-carboxylic acid tert Butyl ester (460 mg, 0.920 mmol) was dissolved in MeOH (2.00 mL), and HCl·MeOH solution (4N, 1.00 mL) was slowly added dropwise. The resulting reaction solution was stirred at room temperature for 12 hrs under nitrogen protection. After the reaction, the solvent was distilled off from the reaction solution under reduced pressure to obtain the target compound (271 mg, yield 74.2%, yellow oil). LC-MS (ESI) m/z: 397.2 [M+H] ⁺ .

Step 3: (R)-4-((4-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)piper Synthesis of pyridine-1-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester

(R)-5-Chloro-4-(1H-indol-3-yl)-N-(1-(piperidin-4-yl)pyrrolidin-3-yl)pyrimidin-2-amine (271mg, 0.680mmol) and tert-butyl 4-formylpiperidine-1-carboxylate (1.45g, 6.80mmol) were dissolved in DCE (5.00mL), then AcOH (1.00mL) was added, and the resulting reaction solution was stirred at room temperature for 30 minute. NaBH(OAc) ₃ (424 mg, 2.04 mmol) was added to the above reaction solution, and the resulting reaction solution was stirred at room temperature for 2 hrs under nitrogen protection. After the reaction was completed, water (20.0 mL) was added to the reaction liquid for dilution, and extracted with DCM (20.0 mL×2). The organic phases were combined, washed with saturated brine, dried over anhydrous Na ₂ SO ₄ , and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (DCM/MeOH=8/1) to obtain the title compound (124 mg, yield 30.7%, yellow oil). LC-MS (ESI) m/z: 594.2 [M+H] ⁺ .

Step 4: (R)-5-Chloro-4-(1H-indol-3-yl)-N-(1-(1-(piperidin-4-ylmethyl)piperidin-4-yl)pyrrole Synthesis of alk-3-yl)pyrimidin-2-amine (HQ-0012-149)

(R)-4-((4-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)piperidine- 1-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester (124mg, 0.208mmol) was dissolved in MeOH (2.00mL), and then HCl·MeOH was slowly added dropwise to dissolve solution (4N, 1.00 mL), and the resulting reaction solution was stirred at room temperature for 12 hrs under nitrogen protection. After the reaction, the solvent was distilled off from the reaction solution under reduced pressure to obtain the target compound (101 mg, yield 98.3%, yellow oil). LC-MS (ESI) m/z: 494.2 [M+H] ⁺ .

Step 5: 5-(4-((4-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1- Synthesis of yl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

(R)-5-chloro-4-(1H-indol-3-yl)-N-(1-(1-(piperidin-4-ylmethyl)piperidin-4-yl)pyrrolidin- 3-yl)pyrimidin-2-amine (101mg, 0.200mmol), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (62.1 mg, 0.220mmol) and DIPEA (1.00mL) were dissolved in DMSO (2.50mL), and the resulting reaction solution was stirred at 120°C for 1hr under nitrogen protection. The reaction solution was directly purified by Prep-HPLC (column: Waters Xbridge C18 10um OBD 19*250mm; mobile phase: A-0.1% NH ₄ HCO ₃ aqueous solution, B-ACN; gradient: B%=30%～70%; flow rate: 20 mL/min), the title compound (6.31 mg, yield 4.00%, yellow solid) was obtained. LC-MS (ESI) m/z: 750.2 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.83(s, 1H), 11.07(s, 1H), 7.18–7.13(m, 1H), 8.46(d, J=2.9Hz, 1H), 8.26( s,1H),7.64(d,J=8.5Hz,1H),7.49(d,J=8.2Hz,1H),7.42–7.33(m,1H),7.33–7.27(m,1H),7.22(dt ,J=11.2,3.2Hz,2H),7.18–7.13(m,1H),5.10–5.02(m,1H),4.45–4.35(m,1H),4.03(d,J=14.2Hz,2H), 3.00–2.90(m,3H),2.90–2.86(m,1H),2.85–2.75(m,3H),2.23–2.16(m,1H),2.15–2.08(m,2H),2.06–1.96(m ,2H), 1.95–1.86(m,2H), 1.86–1.70(m,7H), 1.49–1.30(m,2H), 1.29–1.21(m,2H), 1.20–1.05(m,3H).

Example 22: 4-(2-(4-((1-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl) Amino)pyrrolidin-1-yl)-2-oxoethyl) piperidin-4-yl)methyl)piperazin-1-yl)-2-oxoethoxy)-2-(2,6 -dioxopiperidin-3-yl)isoindoline-1,3-dione

Step 1: Synthesis of tert-butyl 4-((1-(2-methoxy-2-oxoethyl)piperidin-4-yl)methyl)piperazine-1-carboxylate

At 0°C, tert-butyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate (800 mg, 2.82 mmol) was dissolved in DCM (15.0 mL), and Et ₃ N (1.43 g , 14.1mmol). The resulting reaction solution was stirred overnight at room temperature, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (DCM/MeOH=20/1) to obtain the target compound (689 mg, yield 68.9%, yellow liquid). LC-MS (ESI) m/z: 356.4 [M+H] ⁺ .

Step 2: Synthesis of 2-(4-((4-(tert-butyloxycarbonyl)piperazin-1-yl)methyl)piperidin-1-yl)acetic acid

tert-butyl 4-((1-(2-methoxy-2-oxoethyl)piperidin-4-yl)methyl)piperazine-1-carboxylate (689 mg, 1.94 mmol) was dissolved in MeOH /water (4/1, 10.0 mL), and LiOH (93.0 mg, 3.88 mmol) was added. The resulting reaction solution was stirred overnight at room temperature. After the reaction solution was concentrated under reduced pressure, dilute hydrochloric acid was added to adjust the pH to 2-3. Then it was extracted with EA, and the organic phase was distilled off under reduced pressure to obtain the target compound (550 mg, yield 83.1%, yellow solid). LC-MS (ESI) m/z: 342.4 [M+H] ⁺ .

Step 3: (R)-4-((1-(2-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-)amino)pyrrolidin-1-yl Synthesis of )-2-oxoethyl)piperidin-4-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester

At room temperature, 2-(4-((4-(tert-butyloxycarbonyl)piperazin-1-yl)methyl)piperidin-1-yl)acetic acid (500mg, 1.46mmol), (R)- 5-Chloro-4-(1H-indol-3-yl)-N-(pyrrolidin-3-yl)pyrimidin-2-amine (689mg, 2.2mmol), HATU (724mg, 1.90mmol) and DIPEA (757mg , 5.86mmol) was dissolved in DMF (10.0mL). The resulting reaction solution was stirred overnight at room temperature under nitrogen protection, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM/MeOH=20/1) to obtain the target compound (530 mg, yield 56.8%, yellow solid). LC-MS (ESI) m/z: 637.3 [M+H] ⁺ .

Step 4: (R)-1-(3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)-2-(4 Synthesis of -(piperazin-1-ylmethyl)piperidin-1-yl)ethan-1-one

At room temperature, (R)-4-((1-(2-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-)amino)pyrrolidin-1-yl )-2-oxoethyl)piperidin-4-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester (500mg, 0.785mmol) was dissolved in MeOH (5.00mL), and HCl MeOH solution was added (4N, 4.00 mL). The resulting reaction solution was stirred overnight at room temperature, and the solvent was distilled off under reduced pressure to obtain the target compound (418 mg, yield 99.2%, yellow solid). LC-MS (ESI) m/z: 537.4 [M+H] ⁺ .

Step 5: 4-(2-(4-((1-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyridin-2-yl)amino )pyrrolidin-1-yl)-2-oxoethyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-oxoethoxy)-2-(2,6- Synthesis of dioxopiperidin-3-yl)isoindoline-1,3-dione

At room temperature, (R)-1-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)-2-( 4-(piperazin-1-ylmethyl)piperidin-1-yl)ethane-1-one (100mg, 0.186mmol), 2-((2-(2,6-dioxopiperidine-3 -yl)isoindoline-1,3-dione-4-yl)oxy)acetic acid (93.0mg, 0.279mmol), HATU (106mg, 0.279mmol) and DIPEA (120mg, 0.931mmol) were dissolved in DMF ( 5.00mL). The resulting reaction solution was stirred overnight at room temperature under nitrogen protection, filtered, and the filtrate was directly purified by prep-HPLC (column: Waters Xbridge C18 10um OBD 19*250mm; mobile phase: A-0.1% NH ₄ HCO ₃ aqueous solution, B-ACN; Gradient: B%=5%～30%; flow rate: 20mL/min), the title compound (26.7mg, yield 16.8%, white solid) was obtained. LC-MS (ESI) m/z: 851.5 [M+H] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ1H NMR(400MHz,DMSO)δ11.84(s,1H),11.10(s,1H),8.83–8.50(m,1H),8.47(dd,J=9.1 ,3.0Hz,1H),8.30(d,J=2.7Hz,1H),7.83–7.68(m,1H),7.56–7.47(m,2H),7.45(d,J=7.2Hz,1H),7.35 -7.28(m,1H),7.25-7.19(m,1H),7.18–7.12(m,1H),5.19-5.05(m,3H),4.53–4.33(m,1H),4.00–3.55(m, 3H),3.47–3.40(m,2H),3.40–3.35(m,2H),3.15–3.04(m,1H),2.94–2.83(m,2H),2.78–2.65(m,1H),2.65– 2.52(m,2H),2.43–2.35(m,1H),2.36–2.27(m,2H),2.25–2.10(m,3H),2.09–1.99(m,3H),2.00–1.83(m,3H ), 1.72–1.57(m,1H), 1.56–1.19(m,3H), 1.17–0.80(m,2H).

Example 23: 4-(4-((1-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrole Alkyl-1-yl)-2-oxoethyl )piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)iso Indoline-1,3-dione

Step 1: 4-(4-((1-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidine -1-yl)-2-oxoethyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindo Synthesis of Indoline-1,3-dione

At room temperature, (R)-1-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)-2-( 4-(piperazin-1-ylmethyl)piperidin-1-yl)ethane-1-one (100mg, 0.186mmol), 2-(2,6-dioxopiperidin-3-yl)- 4-Fluoroisoindoline-1,3-dione (77.0 mg, 0.279 mmol) and DIPEA (96.0 mg, 0.745 mmol) were dissolved in DMSO (5.00 mL). The resulting reaction solution was stirred at 130°C for 6hrs under nitrogen protection, cooled to room temperature, filtered, and the filtrate was directly purified by prep-HPLC (column: SunFire Prep C8 OBD 10um 19*250mm; mobile phase: A-0.1% TFA aqueous solution, B -ACN; Gradient: B%=5%-40%; Flow rate: 20mL/min) to obtain the title compound (113mg, yield 76.5%, yellow solid). LC-MS (ESI) m/z: 793.3 [M+H] ⁺ . ¹ HNMR (400MHz, DMSO-d ₆ )δ11.93(s,1H),11.10(s,1H),8.83–8.52(m,1H),8.51-8.47(m,1H),8.33(d,J＝ 1.8Hz, 1H), 7.84–7.73(m, 1H), 7.64(dd, J=25.7, 5.5Hz, 1H), 7.55–7.45(m, 2H), 7.44-7.35(m, 1H), 7.26–7.13 (m,2H),5.14-5.08(m,1H),4.65–4.45(m,1H),3.91–3.82(m,2H),3.81–3.60(m,5H),3.59–3.53(m,2H) ,3.52–3.39(m,2H),3.36–3.20(m,4H),3.20–3.10(m,2H),3.08–2.82(m,3H),2.71–2.52(m,2H),2.48–2.27( m,1H), 2.28–1.80(m,6H), 1.82–1.47(m,2H).

Example 24: 5-(4-((1-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrole Alkyl-1-yl)-2-oxyethyl) piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindol Indoline-1,3-dione

Step 1: 5-(4-((1-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidine -1-yl)-2-oxoethyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole Synthesis of Phenyl-1,3-Diones

At room temperature, (R)-1-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)-2-( 4-(piperazin-1-ylmethyl)piperidin-1-yl)ethane-1-one (120mg, 0.223mmol), 2-(2,6-dioxopiperidin-3-yl)- 5-Fluoro-isoindoline-1,3-dione (93.0 mg, 0.335 mmol) and DIPEA (116 mg, 0.894 mmol) were dissolved in DMSO (5.00 mL). The resulting reaction solution was stirred at 130°C for 6hrs under nitrogen protection, cooled to room temperature, filtered, and the filtrate was directly purified by prep-HPLCc (column: SunFire Prep C8 OBD 10um 19*250mm; mobile phase: A-0.1% TFA aqueous solution, B -Acetonitrile; Gradient: B%=5%～40%; Flow rate: 20mL/min) to obtain the title compound (133mg, yield 74.9%, yellow solid). LC-MS (ESI) m/z: 793.5 [M+H] ⁺ . ¹ HNMR (400MHz, DMSO-d ₆ )δ11.94(s,1H),11.10(s,1H),8.69–8.51(m,1H),8.51 8.45(m,1H),8.33(d,J=2.1 Hz,1H),7.80-7.71(m,1H),7.64(dd,J=25.7,5.9Hz,1H),7.51(d,J=7.6Hz,2H),7.42–7.33(m,1H),7.27 –7.10(m,2H),5.10(dd,J＝12.8,5.2Hz,1H),4.68–4.42(m,1H),4.36–3.95(m,4H),3.84–3.69(m,1H),3.69 –3.59(m,2H),3.59–3.42(m,4H),3.42–3.35(m,1H),3.23–3.06(m,4H),3.05–2.79(m,3H),2.65–2.51(m, 2H), 2.42–2.23(m,1H), 2.23–1.85(m,6H), 1.89–1.66(m,1H), 1.67–1.41(m,2H).

Example 25: N-(6-(((1S,3R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)cyclopentyl)amino )hexyl)-2-((2- (2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)oxy)acetamide

Step 1: Synthesis of tert-butyl ((1S,3R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)cyclopentyl)carbamate

At room temperature, 3-(2,5-dichloropyrimidin-4-yl)-1H-indole (500mg, 1.89mmol), ((1R,3S)-3-aminocyclopentyl)carbamate tert-butyl Ester (417mg, 2.08mmol) and DIPEA (1.20g, 9.47mmol) were dissolved in NMP (10.0mL), and the resulting reaction solution was stirred at 120°C for 16hrs under nitrogen protection. After the reaction was completed, water (50.0 mL) was added to the reaction liquid for dilution, and extracted with EA (50.0 mL×3). The organic phases were combined, washed with saturated brine, dried over anhydrous Na ₂ SO ₄ , and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (PE/EA=4/1) to obtain the target compound (585 mg, yield 63.8%, yellow solid). LC-MS (ESI) m/z: 428.2 [M+H] ⁺ .

Step 2: Synthesis of (1R,3S)-N ¹ -(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)cyclopentane-1,3-diamine

((1S,3R)-3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)cyclopentyl)carbamate tert-butyl ester (585mg, 1.37 mmol) and TFA (1.00 mL) were dissolved in DCM (4.00 mL). The resulting reaction solution was stirred at room temperature for 3 hrs under nitrogen protection. After the reaction, the solvent was distilled off from the reaction liquid under reduced pressure to obtain the target compound (500 mg, yield 85.5%, white solid). LC-MS (ESI) m/z: 328.1 [M+H] ⁺ .

Step 3: (6-(((1S,3R)-3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)cyclopentyl)amino)hexyl) Synthesis of tert-butyl carbamate

(1R,3S)-N ¹ -(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)cyclopentane-1,3-diamine (300mg, 0.920mmol) and (6-Bromohexyl)carbamate tert-butyl (258mg, 0.920mmol) was dissolved in DMF (6.00mL), KI (15.2mg, 0.0900mmol) and K ₂ CO ₃ (380mg, 2.75mmol) were added to the above In the mixed solution, the resulting reaction solution was stirred at room temperature for 16 hrs under nitrogen protection. After the reaction was completed, water (50.0 mL) was added to the reaction liquid for dilution, and extracted with EA (40.0 mL×3). The organic phases were combined, washed with saturated brine, dried over anhydrous Na ₂ SO ₄ , and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (DCM/MeOH=10/1) to obtain the title compound (190 mg, yield 63.3%, yellow oil). LC-MS (ESI) m/z: 527.2 [M+H] ⁺ .

Step 4: (1S,3R)-N ¹ -(6-aminohexyl)-N ³ -(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)cyclopentane-1 , Synthesis of 3-diamine

(6-(((1S,3R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)cyclopentyl)amino)hexyl)carbamate tert-Butyl ester (190 mg, 0.360 mmol) was dissolved in MeOH (4.00 mL). Then 4N HCl·MeOH (2.00 mL) solution was slowly added dropwise, and the resulting reaction solution was stirred at room temperature for 10 hrs. After the reaction, the solvent was distilled off from the reaction solution under reduced pressure to obtain the target compound (150 mg, yield 78.9%, yellow solid). LC-MS (ESI) m/z: 427.3 [M+H] ⁺ .

Step 5: N-(6-(((1S,3R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)cyclopentyl)amino) Synthesis of Hexyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamide

At room temperature, (1S,3R)-N ¹ -(6-aminohexyl)-N ³ -(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)cyclopentane- 1,3-Diamine (150mg, 0.350mmol) and 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl )oxy)acetic acid (116mg, 0.350mmol) was dissolved in DMF (4.00mL), then HATU (133mg, 0.350mmol) and DIPEA (136mg, 1.05mmol) were added, and the resulting reaction solution was stirred at room temperature for 16hrs. After the reaction, the reaction solution was directly purified by Prep-HPLC (column: SunFire Prep C8 OBD 10um 19*250mm; mobile phase: A-0.1% FA aqueous solution, B-ACN; gradient: B%=10%～35%; Flow rate: 20 mL/min), the title compound (25.1 mg, yield 16.8%, yellow solid) was obtained. LC-MS (ESI) m/z: 741.3 [M+H] ⁺ . ¹ H NMR (400MHz,DMSO-d ₆ )δ11.85(s,1H),8.59(s,1H),8.45(d,J=2.9Hz,1H),8.33(s,1H),8.25(s, 1H),7.99–7.89(m,1H),7.87–7.73(m,1H),7.51–7.46(m,2H),7.39(d,J＝8.5Hz,2H),7.23–7.11(m,2H) ,5.19–5.06(m,1H),4.77(s,2H),4.27(s,1H),3.18–3.11(m,3H),2.95–2.80(m,2H),2.71–2.55(m,4H) ,2.33(s,1H),2.09–1.98(m,1H),1.92(s,2H),1.79–1.59(m,2H),1.52–1.39(m,5H),1.34–1.25(m,4H) .

Example 26: 5-(4-((4-(3-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrole Alkyl-1-yl)propyl)piperidin -1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1 ,3-Diketone,FA salt

Step 1: Synthesis of tert-butyl 4-(3-oxopropyl)piperidine-1-carboxylate

tert-butyl 4-(3-hydroxypropyl)piperidine-1-carboxylate (1.00 g, 4.10 mmol) and Dess-Martin oxidant (1.92 g, 4.50 mmol) were dissolved in DCM (15.0 mL) at 0 °C )middle. The resulting reaction solution was stirred at room temperature for 2 hrs under nitrogen protection. After the reaction was completed, saturated aqueous sodium thiosulfate (10.0 mL) and saturated aqueous NaHCO ₃ (5.00 mL) were added to the reaction solution, and the resulting mixture was extracted with DCM (10.0 mL×2). The organic phases were combined, washed with saturated brine, dried over anhydrous Na ₂ SO ₄ , and filtered. The solvent was evaporated from the filtrate under reduced pressure to obtain the target compound (892 mg, yield 89.9%, white oil). ¹ H NMR (400MHz, CHCl ₃ -d) δ9.78(t, J=1.7Hz, 1H), 4.09(s, 3H), 2.66(t, J=12.1Hz, 2H), 2.47(td, J= 7.6, 1.6Hz, 2H), 1.45(s, 12H), 1.17–1.03(m, 3H).

Step 2: (R)-4-(3-(3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)propyl ) Synthesis of piperidine-1-carboxylic acid tert-butyl ester

(R)-5-Chloro-4-(1H-indol-3-yl)-N-(pyrrolidin-3-yl)pyrimidin-2-amine (460mg, 1.47mmol) and 4-(3-oxo ((xopropyl)piperidine-1-carboxylic acid tert-butyl ester (707 mg, 2.93 mmol) was dissolved in DCE (15.0 mL). Further AcOH (5.00 mL) was added, and the resulting reaction solution was stirred at room temperature for 30 minutes. NaBH(OAc) ₃ (935 mg, 4.41 mmol) was added to the above reaction solution, and the resulting reaction solution was stirred at room temperature for 2 hrs under nitrogen protection. After the reaction was completed, water (20.0 mL) was added to the reaction solution for dilution, and extracted with DCM (20.0 mLx2). The organic phases were combined, washed with saturated brine, dried over anhydrous Na ₂ SO ₄ , and filtered. filtrate minus Concentrate under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (DCM/MeOH=25/2) to obtain the title compound (539 mg, yield 68.2%, yellow oil). LC-MS (ESI) m/z: 539.3 [M+H] ⁺ .

Step 3: (R)-5-Chloro-4-(1H-indol-3-yl)-N-(1-(3(piperidin-4-yl)propyl)pyrrolidin-3-yl)pyrimidine Synthesis of -2-amine

(R)-4-(3-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)propyl)piper tert-butyl pyridine-1-carboxylate (539 mg, 1.00 mmol) was dissolved in MeOH (4.00 mL), and HCl·MeOH solution (4N, 1.00 mL) was slowly added dropwise, and the reaction solution was stirred at room temperature for 12 hrs under nitrogen protection. After the reaction, the solvent was distilled off from the reaction solution under reduced pressure to obtain the target compound (402 mg, yield 91.8%, yellow oil). LC-MS (ESI) m/z: 439.3 [M+H] ⁺ .

Step 4: (R)-4-((4-(3-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1- Synthesis of tert-butyl (yl)propyl)piperidin-1-yl)methyl)piperidine-1-carboxylate

(R)-5-chloro-4-(1H-indol-3-yl)-N-(1-(3-(piperidin-4-yl)propyl)pyrrolidin-3-yl)pyrimidine- 2-Amine (402 mg, 0.915 mmol) and tert-butyl 4-formylpiperidine-1-carboxylate (586 g, 2.75 mmol) were dissolved in DCE (15.0 mL). Further AcOH (3.00 mL) was added, and the resulting reaction solution was stirred at room temperature for 30 minutes. NaBH(OAc) ₃ (582 mg, 2.75 mmol) was added to the above reaction solution, and the resulting reaction solution was stirred at room temperature for 2 hrs under nitrogen protection. After the reaction was completed, water (20.0 mL) was added to the reaction liquid for dilution, and extracted with DCM (20.0 mL×2). The organic phases were combined, washed with saturated brine, dried over anhydrous Na ₂ SO ₄ , and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (DCM/MeOH=10/1) to obtain the title compound (215 mg, yield 36.9%, yellow oil). LC-MS (ESI) m/z: 636.3 [M+H] ⁺ .

Step 5: (R)-5-Chloro-4-(1H-indol-3-yl)-N-(1-(3-(1-(piperidin-4-ylmethyl)piperidine-4- Synthesis of yl)propyl)pyrrolidin-3-yl)pyrimidin-2-amine

(R)-4-((4-(3-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl) Propyl)piperidin-1-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester (215 mg, 0.340 mmol) was dissolved in MeOH (2.00 mL), and the resulting reaction solution was stirred at room temperature for 12 hrs. After the reaction, the solvent was distilled off from the reaction solution under reduced pressure to obtain the target compound (153 mg, yield 83.9%, yellow oil). LC-MS (ESI) m/z: 536.3 [M+H] ⁺ .

Step 6: 5-(4-((4-(3-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidine -1-yl)propyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1, Synthesis of 3-diketones

(R)-5-chloro-4-(1H-indol-3-yl)-N-(1-(3-(1-(piperidin-4-ylmethyl)piperidin-4-yl) Propyl)pyrrolidin-3-yl)pyrimidin-2-amine (153mg, 0.285mmol), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1, 3-Diketone (102 mg, 0.371 mmol) and DIPEA (1.00 mL) were dissolved in DMSO (2.50 mL), and the resulting reaction solution was stirred at 120° C. for 1 hr under nitrogen protection. After the reaction, the reaction solution was directly purified by Prep-HPLC (column: SunFire Prep C8 OBD 10um 19*250mm; mobile phase: A-0.1% FA aqueous solution, B-ACN; gradient: B%=15%～55%; flow rate : 20 mL/min), the title compound (23.1 mg, yield 10.2%, yellow solid) was obtained. LC-MS (ESI) m/z: 792.3 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.84(s, 1H), 11.07(s, 1H), 8.73–8.52(m, 1H), 8.46(d, J=2.9Hz, 1H), 8.26( s,1H),8.20(s,1H),7.64(d,J=8.6Hz,1H),7.49(d,J=7.7Hz,1H),7.43–7.33(m,1H),7.29(s,1H ),7.24–7.18(m,2H),7.15(t,J＝7.1Hz,1H),5.10–5.02(m,1H),4.50–4.32(m,1H),4.02(d,J＝13.3Hz, 2H),3.00–2.86(m,6H),2.83–2.76(m,3H),2.69–2.66(m,1H),2.62–2.59(m,1H),2.58–2.55(m,1H),2.10( d,J=6.6Hz,2H),1.89–1.71(m,7H),1.60(d,J=11.0Hz,2H),1.50–1.39(m,2H),1.27–1.19(m,3H),1.18 –1.01(m,6H).

Example 27: 5-(4-((4-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrole Alkyl-1-yl)ethyl)piperidin -1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1 ,3-Diketone,FA salt

Step 1: (R)-4-(2-(3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)ethyl ) Synthesis of piperidine-1-carboxylic acid tert-butyl ester

At room temperature, (R)-5-chloro-4-(1H-indol-3-yl-N-(pyrrolidin-3-yl)pyrimidin-2-amine (350mg, 1.12mmol) and 4-(2 -Oxoethyl)piperidine-1-carboxylic acid tert-butyl ester (1.27g, 5.58mmol) was dissolved in DCE (6.00mL), and then AcOH (1.50mL) was added, and the resulting mixture was stirred at room temperature for 0.5hr, Then add NaBH(OAc) ₃ (946mg, 4.46mmol), and the resulting reaction solution was stirred at room temperature for 16hrs. After the reaction was completed, dilute with water (100mL), extract with EA (50.0mL×2), combine the organic phases, and concentrate under reduced pressure The crude product was obtained. The crude product was purified by silica gel chromatography (DCM/MeOH=10/1) to obtain the target compound (744 mg, yield 89.9%, white solid). LC-MS (ESI) m/z: 525.3 [M+ H] ⁺ .

Step 2: (R)-5-Chloro-4-(1H-indol-3-yl)-N-(1-(2-(piperidin-4-yl)ethyl)pyrrolidin-3-yl) Synthesis of pyrimidin-2-amine

(R)-4-(2-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)ethyl)piper tert-Butyl pyridine-1-carboxylate (744 mg, 1.42 mmol) was dissolved in anhydrous MeOH (4.00 mL), and 4N HCl·MeOH solution (2.00 mL) was added. The resulting reaction solution was stirred at room temperature for 16 hrs. After the reaction, the solvent was distilled off from the reaction solution under reduced pressure to obtain the target compound (610 mg, yield 81.9%, yellow solid). LC-MS (ESI) m/z: 425.2 [M+H] ⁺ .

Step 3: (R)-4-((4-(2-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1- Synthesis of tert-butyl)ethyl)piperidin-1-yl)methyl)piperidine-1-carboxylate

At room temperature, (R)-5-chloro-4-(1H-indol-3-yl)-N-(1-(2-(piperidin-4-yl)ethyl)pyrrolidin-3-yl ) pyrimidine-2-amine (500mg, 1.18mmol) and tert-butyl 4-formylpiperidine-1-carboxylate (1.25g, 5.88mmol) were dissolved in DCE (6.00mL), and Et ₃ N (1.50 mL), the resulting mixture was stirred at room temperature for 0.5 hr, then NaBH(OAc) ₃ (1.25 g, 5.88 mmol) was added, and the resulting reaction solution was stirred at room temperature for 16 hrs. After the reaction was completed, it was diluted with water (100 mL), extracted with EA (30.0 mL×3), and the organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (DCM/MeOH=10/1) to obtain the title compound (500 mg, yield 84.9%, white solid). LC-MS (ESI) m/z: 622.3 [M+H] ⁺ .

Step 4: (R)-5-Chloro-4-(1H-indol-3-yl)-N-(1-(2-(1-(1-(piperidin-4-ylmethyl)piperidine Synthesis of -4-yl)ethyl)pyrrolidin-3-yl)pyrimidin-2-amine

At room temperature, (R)-4-((4-(2-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1 -yl)ethyl)piperidin-1-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester (500mg, 0.800mmol) was dissolved in anhydrous MeOH (4.00mL), then slowly added dropwise 4N HCl. MeOH solution (1.50 mL), the resulting reaction solution was stirred at room temperature for 16 hrs. After the reaction, the reaction solution The solvent was distilled off under reduced pressure to obtain the target compound (450 mg, yield 93.2%, yellow oil). LC-MS (ESI) m/z: 522.3 [M+H] ⁺ .

Step 5: 5-(4-((4-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidine -1-yl)ethyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1, 3-diketone

At room temperature, (R)-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)(4-(piperazine -1-ylmethyl)piperidin-1-yl)methanone (200mg, 0.380mmol) and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1 , 3-Diketone (158 mg, 0.570 mmol) was dissolved in DMSO (4.00 mL). After 5 minutes, DIPEA (248 mg, 1.92 mmol) was added to the above mixture, and the resulting reaction solution was stirred at 130° C. for 3 hrs. After the reaction, dilute with water (50.0mL), extract with EA (30.0mL×2), combine the organic phases, wash with saturated brine, and concentrate the organic phase under reduced pressure to obtain a crude product, which is purified by Prep-HPLC (column: SunFire Prep C8 OBD 10um 19*250mm; mobile phase: A-0.1% FA aqueous solution, B-ACN; gradient: B% = 10% ~ 25%; flow rate: 20mL/min), to obtain the title compound (50.5mg, yield 25.3%, yellow solid). LC-MS (ESI) m/z: 778.3 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.84(s, 1H), 11.07(s, 1H), 8.74–8.50(m, 1H), 8.46(d, J=3.0Hz, 1H), 8.27( s,1H),8.18(s,1H),7.64(d,J=8.6Hz,1H),7.49(d,J=8.0Hz,1H),7.41-7.35(m,1H),7.29(d,J ＝1.9Hz,1H),7.26–7.18(m,2H),7.18–7.12(m,1H),5.09–5.02(m,1H),4.47–4.32(m,1H),4.05–3.97(m,2H ),3.02–2.86(m,4H),2.86–2.75(m,3H),2.75–2.63(m,2H),2.63–2.58(m,1H),2.58–2.53(m,3H),2.21(s ,1H),2.12(d,J=7.0Hz,2H),2.01(d,J=5.6Hz,1H),1.90–1.69(m,6H),1.62(d,J=12.7Hz,2H),1.43 –1.34 (m, 2H), 1.32 – 1.21 (m, 1H), 1.21 – 1.05 (m, 4H).

Example 28: 4-(2-(4-((1-(3-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl) Amino)pyrrolidin-1-yl)propionyl) piperidin-4-yl)methyl)piperazin-1-yl)-2-oxoethoxy)-2-(2,6-dioxopiper Pyridine-3-yl)isoindoline-1,3-dione

Step 1: (R)-3-(3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)propanoic acid methyl ester synthesis

(R)-5-Chloro-4-(1H-indol-3-yl)-N-(pyrrolidin-3-yl)pyrimidin-2-amine (400 mg, 1.66 mmol) was dissolved in DCM ( 10.0 mL), Et ₃ N (645 mg, 6.37 mmol) was added, and the resulting reaction solution was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (DCM/MeOH=20/1) to obtain the target compound (473 mg, yield 92.8%, yellow liquid). LC-MS (ESI) m/z: 400.3 [M+H] ⁺ .

Step 2: Synthesis of (R)-2-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)propanoic acid

(R)-2-(3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)propionic acid methyl ester (473mg, 1.18mmol) was added into MeOH/water (4/1, 10.0mL), then LiOH (42.0mg, 1.77mmol) was added, and the resulting reaction solution was Stir overnight at room temperature. The solvent was distilled off from the reaction solution under reduced pressure to obtain the target compound (431 mg, yield 94.4%, yellow solid). LC-MS (ESI) m/z: 386.2 [M+H] ⁺ .

Step 3: (R)-4-(1-(2-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl )propionyl)piperidin-4-yl)methyl)piperazine-1-formic acid tert-butyl ester

At room temperature, (R)-2-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)propionic acid (613mg , 1.59mmol), 4-(piperidin-4-ylmethyl)piperazine-1-carboxylic acid tert-butyl ester (300mg, 1.06mmol), HATU (523mg, 1.38mmol) and DIPEA (684mg, 5.29mmol) in DMF (10.0 mL). The resulting reaction solution was stirred overnight at room temperature under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (DCM/MeOH=20/1) to obtain the target compound (311 mg, yield 45.1%, yellow liquid). LC-MS (ESI) m/z: 651.5 [M+H] ⁺ .

Step 4: (R)-2-(3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)-1-(4 Synthesis of -(piperazin-1-ylmethyl)piperidin-1-yl)propan-1-one

At room temperature, (R)-4-(1-(2-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1- Base)propionyl)piperidin-4-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester (221mg, 0.324mmol) was added into MeOH (3.00mL), then slowly added dropwise HCl·MeOH solution (4N, 2.00 mL), and the resulting reaction solution was stirred overnight at room temperature. The solvent was distilled off from the reaction solution under reduced pressure to obtain the target compound (143 mg, yield 80.1%, yellow solid). LC-MS (ESI) m/z: 551.4 [M+H] ⁺ .

Step 5: 4-(2-(4-((1-(3-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino )pyrrolidin-1-yl)propionyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-oxoethoxy)-2-(2,6-dioxopiperidine Synthesis of -3-yl)isoindoline-1,3-dione

At room temperature, (R)-2-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)-1-( 4-(piperazin-1-ylmethyl)piperidin-1-yl)propan-1-one (100mg, 0.181mmol), 2-((2-(2,6-dioxopiperidine-3- yl)isoindoline-1,3-dione-4-yl)oxy)acetic acid (77.0mg, 0.236mmol), HATU (88mg, 0.236mmol) and DIPEA (65mg, 0.544mmol) were dissolved in DMF (5.00 mL), the resulting reaction solution was stirred overnight at room temperature under nitrogen protection. The reaction solution was directly purified by prep-HPLC (column: Waters Xbridge C18 10um OBD 19*250mm; mobile phase: A-0.1% NH ₄ HCO ₃ aqueous solution, B-ACN; gradient: B%=5%～35%; mobile phase Phase: 20 mL/min), the title compound (50.6 mg, yield 32.2%, white solid) was obtained. LC-MS (ESI) m/z: 865.5 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.83(s, 1H), 11.10(s, 1H), 8.96–8.50(m, 1H), 8.46(d, J=2.8Hz, 1H), 8.26( s,1H),7.85–7.65(m,1H),7.47(dd,J＝17.0,7.6Hz,2H),7.41–7.26(m,2H),7.25–7.08(m,2H),5.16(s, 2H), 5.10(dd, J＝12.7, 5.3Hz, 1H), 4.47–4.20(m, 2H), 3.84(d, J＝12.6Hz, 1H), 3.42(s, 4H), 3.01–2.79(m ,3H),2.74–2.52(m,7H),2.49–2.41(m,3H),2.40–2.32(m,2H),2.32–2.23(m,2H),2.24–2.14(m,1H),2.15 –2.08(m,2H), 2.08–1.98(m,1H), 1.85–1.60(m,4H), 1.07–0.70(m,2H).

Example 29: 5-(4-((1-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrole Alkyl-1-yl)acetyl)piperidin -4-yl)methyl)piperazin-1-yl)-2-(1-methyl-2,6-dioxopiperidin-3-yl)iso Indoline-1,3-dione

Step 1: 5-(4-((1-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidine -1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(1-methyl-2,6-dioxopiperidin-3-yl)isoindol Synthesis of Indoline-1,3-dione

At room temperature, (R)-2-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)-1-( 4-(piperazin-1-ylmethyl)piperidin-1-yl)ethane-1-one (150mg, 0.279mmol), 5-fluoro-2-(1-methyl-2,6-dioxo Substituted piperidin-3-yl) isoindoline-1,3-dione (122mg, 0.419mmol) and DIPEA (119mg, 0.922mmol) were dissolved in DMSO (5.00mL), and the resulting reaction solution was heated under nitrogen protection for 130 °C and stirred overnight. The reaction solution was cooled to room temperature, filtered, and the filtrate was directly purified by prep-HPLC (column: Waters Xbridge C18 10um OBD 19*250mm; mobile phase: A-0.1% NH ₄ HCO ₃ aqueous solution, B-ACN; gradient: B%= 5%-40%; flow rate: 20 mL/min), the title compound (45.6 mg, yield 20.2%, yellow solid) was obtained. LC-MS (ESI) m/z: 807.6 [M+H] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ1H NMR(400MHz,DMSO)δ11.83(s,1H),8.84–8.48(m,1H),8.46(s,1H),8.26(s,1H), 7.68(d,J=8.5Hz,1H),7.50(d,J=8.1Hz,1H),7.42–7.27(m,2H),7.27–7.18(m,2H),7.19-7.13(m,1H) ,5.14(dd,J＝13.0,5.3Hz,1H),4.58–4.21(m,2H),4.12–3.92(m,1H),3.52–3.38(m,3H),3.28–3.07(m,2H) ,3.01(s,3H),3.00–2.83(m,3H),2.82–2.69(m,2H),2.68–2.52(m,4H),2.48–2.38(m,3H),2.33–2.10(m, 3H), 2.10–1.95(m,2H), 1.92–1.63(m,4H), 1.54–0.42(m,3H).

Example 30: 5-((R)-3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)-2-( 2,6-dioxopiperidin -3-yl)isoindoline-1,3-dione

Step 1: 5-((R)-3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)-2-(2 ,Synthesis of 6-dioxopiperidin-3-yl)isoindoline-1,3-dione

(R)-5-Chloro-4-(1H-indol-3-yl)-N-(pyrrolidin-3-yl)pyrimidin-2-amine (81.8mg, 0.260mmol), 2-(2, 6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (80.0mg, 0.290mmol) and DIPEA (0.500mL) were dissolved in DMSO (2.50mL) to obtain The reaction solution was stirred at 120° C. for 1 hr under the protection of nitrogen. After the reaction, the reaction solution was purified by Prep-HPLC (column: SunFire Prep C8 OBD 10um 19*250mm; mobile phase: A-0.1% FA aqueous solution, B-ACN; gradient: B%=25%～65%; flow rate: 20 mL/min), the title compound (20.5 mg, yield 13.8%, yellow solid) was obtained. LC-MS (ESI) m/z: 570.2 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.86(s, 1H), 11.06(s, 1H), 8.68–8.56(m, 1H), 8.48(d, J=3.0Hz, 1H), 8.32( s,1H),7.71-7.21(m,1H),7.49(d,J=7.8Hz,1H),7.24–7.13(m,2H),6.94(d,J=1.7Hz,1H),6.87–6.82 (m,1H),5.09–5.01(m,1H),4.67(s,1H),3.88-3.80(m,1H),3.71–3.63(m,1H),3.59–3.53(m,1H),3.52 –3.46(m,1H),2.94–2.82(m,1H),2.60(s,1H),2.57–2.53(m,2H),2.38(s,1H),2.24–2.16(m,1H),2.05 –1.96(m,1H).

Example 31: 5-(1-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1- Base) acetyl) piperidin- 4-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Step 1: 5-(1-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl Synthesis of )acetyl)piperidin-4-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

At room temperature, (R)-2-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)acetic acid (110mg, 0.300mmol) and 2-(2,6-dioxopiperidin-3-yl)-5-(piperidin-4-yl)isoindoline-1,3-dione (1.25g, 5.88mmol) Dissolved in DMF (4.00mL), then added DIPEA (191mg, 1.48mmol), stirred for 5 minutes, then added HATU (124mg, 0.330mmol), and the resulting reaction solution was stirred at room temperature for 2hrs. After the reaction, dilute with water (100mL), extract with EA (50.0mL×2), combine the organic phases, and concentrate the organic phases under reduced pressure to obtain a crude product, which is purified by Prep-HPLC (column: Waters Xbridge C18 10um OBD 19*250mm; Mobile phase: A-0.1% NH ₄ HCO ₃ aqueous solution, B-ACN; Gradient: B%=10%～55%; Flow rate: 20mL/min) to obtain the title compound (10.0mg, yield 9.10%, white solid) . LC-MS (ESI) m/z: 695.2 [M+H] ⁺ . ¹ H NMR (400MHz,DMSO-d ₆ )δ11.82(s,1H),11.11(s,1H),8.65–8.52(m,1H),8.45(s,1H),8.26(s,1H), 7.92–7.63(m,3H),7.55–7.32(m,2H),7.26–7.03(m,2H),5.21–5.06(m,1H),4.63–4.31(m,2H),4.31–4.13(m ,1H),3.53–3.38(m,1H),3.21–2.95(m,3H),2.96–2.83(m,2H),2.82–2.69(m,1H),2.71–2.56(m,5H),2.42 –2.26(m,1H),2.28–2.12(m,1H),2.12–1.98(m,1H),1.91–1.78(m,3H),1.76–1.58(m,1H),1.58–1.37(m, 1H).

Example 32: 5-(4-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1- Base)ethyl)piperidin-1- yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione, FA salt

Step 1: 5-(4-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl Synthesis of )ethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

At room temperature, (R)-2-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)acetic acid (150mg, 0.350mmol) and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (146mg, 0.530mmol) were dissolved in DMSO (4.00mL) , and then DIPEA (228 mg, 1.76 mmol) was added to the above mixture, and the resulting reaction solution was stirred at 130° C. for 3 hrs. After the reaction, filter, and the filtrate is directly purified by prep-HPLC (column: SunFire Prep C18 OBD 10um 19*250mm; mobile phase: A-0.1% FA aqueous solution, B-ACN; gradient: B%=10%～37%; Flow rate: 20 mL/min), the title compound (13.6 mg, yield 9.04%, yellow solid) was obtained. LC-MS (ESI) m/z: 681.2 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.84(s, 1H), 11.07(s, 1H), 8.72-8.52(m, 1H), 8.46(d, J=3.1Hz, 1H), 8.27( s,1H),8.19(s,1H),7.64(d,J=8.5Hz,1H),7.49(d,J=7.9Hz,1H),7.38(s,1H),7.29(s,1H), 7.25–7.10(m,3H),5.15–4.96(m,1H),4.41(s,1H),4.02(d,J=12.1 Hz,2H),3.03–2.81(m,5H),2.77–2.63(m,1H),2.64–2.53(m,4H),2.39–2.08(m,2H),2.06–1.93(m,1H), 1.90–1.70(m,3H), 1.63(s,1H), 1.50–1.30(m,2H), 1.28–1.02(m,2H).

Example 33: 5-(4-(((R)-3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl) Methyl)piperidin-1-yl) -2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Step 1: (R)-5-Chloro-4-(1H-indol-3-yl)-N-(1-(piperidin-4-ylmethyl)pyrrolidin-3-yl)pyrimidine-2- Amine Synthesis

(R)-4-((3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)methyl)piperidine- 1-tert-butyl carboxylate (200 mg, 0.390 mmol) was dissolved in MeOH (2.00 mL), and 4N HCl·MeOH (2.00 mL) solution was slowly added dropwise, and the resulting reaction solution was stirred at room temperature for 12 hrs under nitrogen protection. After the reaction, the solvent was distilled off from the reaction solution under reduced pressure to obtain the target compound (146 mg, yield 89.7%, brown oil). LC-MS (ESI) m/z: 411.2 [M+H] ⁺ .

Step 2: 5-(4-(((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)methanol Synthesis of yl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

(R)-5-chloro-4-(1H-indol-3-yl)-N-(1-(piperidin-4-ylmethyl)pyrrolidin-3-yl)pyrimidin-2-amine ( 146mg, 0.360mmol), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (128mg, 0.460mmol) and DIPEA (1.50mL) It was dissolved in DMSO (2.00 mL), and the resulting reaction solution was stirred at 120° C. for 1 hr under nitrogen protection. After the reaction, the reaction solution was purified by Prep-HPLC (column: Waters Xbridge C18 10um OBD 19*250mm; mobile phase: A-0.1% _NH4HCO3 aqueous solution, B-ACN; _gradient : B%=30%～60% ; flow rate: 20 mL/min), the title compound (39.6 mg, yield 16.5%, yellow solid) was obtained. LC-MS (ESI) m/z: 667.2 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.95(s, 1H), 11.07(s, 1H), 8.75–8.52(m, 1H), 8.46(d, J=3.0Hz, 1H), 8.26( s,1H),7.64(d,J=8.6Hz,1H),7.50(d,J=8.0Hz,1H),7.42-7.33(m,1H),7.29(d,J=2.0Hz,1H), 7.25–7.18(m,2H),7.18–7.13(m,1H),5.06(dd,J=12.9,5.4Hz,1H),4.41(s,1H),4.02(d,J=11.6Hz,2H) ,3.00–2.82(m,5H),2.70–2.65(m,1H),2.62–2.58(m,2H),2.46–2.41(m,1H),2.35–2.25(m,3H),2.05–1.95( m,1H), 1.88–1.79(m,3H), 1.78–1.69(m,1H), 1.19–1.11(m,2H).

Example 34: 5-(4-((R)-3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)piper Pyridin-1-yl)-2- (2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Step 1: (R)-5-Chloro-4-(1H-indol-3-yl)-N-(1-(piperidin-4-yl)pyrrolidin-3-yl)pyrimidin-2-amine synthesis

(R)-4-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)piperidine-1-carboxylic acid tert Butyl ester (150mg, 0.300mmol) was dissolved in MeOH (2.00mL), and HCl·MeOH solution (4N, 2.00mL) was slowly added dropwise, the resulting The obtained reaction solution was stirred at room temperature for 12 hrs under the protection of nitrogen. After the reaction, the solvent was distilled off from the reaction solution under reduced pressure to obtain the target compound (271 mg, yield 74.2%, yellow oil). LC-MS (ESI) m/z: 397.2 [M+H] ⁺ .

Step 2: 5-(4-((R)-3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)piperidine Synthesis of -1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

(R)-5-Chloro-4-(1H-indol-3-yl)-N-(1-(piperidin-4-yl)pyrrolidin-3-yl)pyrimidin-2-amine (92.0mg , 0.230mmol), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (83.2mg, 0.300mmol) and DIPEA (1.00mL) It was dissolved in DMSO (2.00 mL), and the resulting reaction solution was stirred at 120° C. for 1 hr under nitrogen protection. After the reaction, the reaction solution was purified by Prep-HPLC (column: Waters Xbridge C18 10um OBD 19*250mm; mobile phase: A-0.1% _NH4HCO3 aqueous solution, B-ACN; _gradient : B%=30%～55% ; flow rate: 20 mL/min), the title compound (20.1 mg, yield 13.4%, yellow solid) was obtained. LC-MS (ESI) m/z: 653.2 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.83(s, 1H), 11.07(s, 1H), 8.76–8.51(m, 1H), 8.46(d, J=3.0Hz, 1H), 8.26( s,1H),7.65(d,J=8.6Hz,1H),7.49(d,J=8.0Hz,1H),7.41-7.34(m,1H),7.32(d,J=1.9Hz,1H), 7.27–7.16(m,2H),7.16–7.10(m,1H),5.10–5.01(m,1H),4.40(s,1H),3.95(d,J＝11.3Hz,2H),3.13–3.01( m,3H),2.95–2.81(m,2H),2.78–2.69(m,1H),2.65–2.58(m,2H),2.56-2.54(m,1H),2.38–2.30(m,1H), 2.25–2.15(m,1H), 2.06–1.96(m,1H), 1.96–1.85(m,2H), 1.85–1.76(m,1H), 1.54–1.41(m,2H).

Example 35: 5-(4-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1- Base)ethyl)piperazin-1- yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione, FA salt

Step 1: (R)-4-(2-(3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)ethyl ) Synthesis of piperazine-1-carboxylic acid tert-butyl ester

Mix tert-butyl 4-(2-bromoethyl)piperazine-1-carboxylate (400mg, 1.37mmol) and (R)-5-chloro-4-(1H-indol-3-yl)-N- (Pyrrolidin-3-yl)pyrimidin-2-amine (429mg, 1.37mmol) was dissolved in DMF (9.00mL), and K ₂ CO ₃ (568mg, 4.11mmol) was added, and the resulting reaction solution was stirred at room temperature for 2.5hrs . After the reaction, add EA (10.0mL) to dilute, wash with saturated NaHCO ₃ aqueous solution (5.00mL), water (5.00mL) successively, the organic phase is dried with anhydrous Na ₂ SO ₄ , filtered, concentrated under pressure, and the residue is passed through Purification by silica gel chromatography (DCM/MeOH=20/1) gave the target product (410 mg, yield 56.8%, yellow oil). LC-MS (ESI) m/z: 526.3 [M+H] ⁺ .

Step 2: (R)-5-Chloro-4-(1H-indol-3-yl)-N-(1-(2-(piperazin-1-yl)ethyl)pyrrolidin-3-yl) Synthesis of pyrimidin-2-amine

(R)-4-(2-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)ethyl)piper Tert-butyloxine-1-carboxylate (400 mg, 0.781 mmol) was dissolved in DCM (10.0 mL), and 4N HCl·MeOH (20.0 mL) solution was slowly added dropwise, and the resulting reaction solution was stirred at room temperature for 4 hrs. After the reaction, the solvent was distilled off from the reaction solution under reduced pressure to obtain the target compound (360 mg, crude product, yellow oil). LC-MS (ESI) m/z: 426.2 [M+H] ⁺ .

Step 3: 5-(4-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl Synthesis of )ethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

(R)-5-chloro-4-(1H-indol-3-yl)-N-(1-(2-(piperazin-1-yl)ethyl)pyrrolidin-3-yl)pyrimidine- 2-Amine (360mg, 0.850mmol), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (282mg, 1.02mmol) and DIPEA (660mg, 5.10mmol) was sequentially added to NMP (12.0mL). The resulting reaction solution was stirred at 120° C. for 5 hrs under nitrogen protection. The reaction solution was cooled to room temperature, diluted with EA (10.0 mL), washed successively with saturated saline solution (10.0 mL), water (10.0 mL), and the organic phase was dried over anhydrous Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and the residue The material was purified by silica gel chromatography (DCM/MeOH=20/1) to obtain a crude product, and the crude product was purified by prep-HPLC (column: Waters sunfire C18 10um OBD 19*250mm; mobile phase: A-0.1% FA aqueous solution, B- ACN; Gradient: B%=20%-50%; Flow rate: 20mL/min) to obtain the title product (271mg, yield 41.2%, yellow solid). LC-MS (ESI) m/z: 682.2 [M+H] ⁺ . 1HNMR (400MHz, DMSO-d ₆ )δ11.84(s,1H), 11.08(s,1H), 8.79–8.50(m,1H), 8.46(d,J=2.9Hz,1H), 8.27(s, 1H), 8.22(s, 1H), 7.66(d, J＝8.5Hz, 1H), 7.49(d, J＝7.8Hz, 1H), 7.43–7.35(m, 1H), 7.35–7.29(m, 1H ),7.26–7.12(m,3H),5.15–4.98(m,1H),4.55–4.30(m,1H),3.86–3.54(m,5H),3.06–2.94(m,1H),2.94–2.82 (m,2H),2.81–2.70(m,1H),2.71–2.59(m,5H),2.61–2.55(m,4H),2.29–2.14(m,1H),2.08–1.95(m,1H) ,1.89–1.74(m,1H).

Example 36: 5-(4-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1- yl)acetyl)piperazin- 1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione, FA salt

Step 1: (R)-2-(3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)acetic acid methyl ester synthesis

(R)-5-Chloro-4-(1H-indol-3-yl)-N-(pyrrolidin-3-yl)pyrimidin-2-amine (1.00 g, 3.17 mmol) was dissolved in DCM at room temperature (5.00mL), Et ₃ N (1.61g, 15.9mmol) was added at 0°C, the resulting mixture was stirred at 0°C for 5 minutes, and 2-bromoacetate methyl ester (585mg, 3.82mmol) was slowly added dropwise to obtain The reaction solution was stirred at 0° C. for 3 hrs. After the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (DCM/MeOH=20/1) to obtain the target compound (1.10 g, yield 89.4%, yellow solid). LC-MS (ESI) m/z: 386.1 [M+H] ⁺ .

(R)-2-(3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)acetic acid methyl ester (1.00g , 2.59 mmol) was dissolved in a mixture of anhydrous MeOH and water (MeOH/H ₂ O=4/1, 10.0 mL), and then LiOH (124 mg, 5.18 mmol) was added, and the resulting reaction solution was stirred at room temperature for 4 hrs. After the reaction was completed, hydrochloric acid (2N, 1.00 mL) was added to the reaction solution, and after stirring for 10 minutes, the solvent was distilled off from the reaction solution under reduced pressure to obtain the target compound (950 mg, yield 86.4%, yellow solid). LC-MS (ESI) m/z: 372.1 [M+H] ⁺ .

Step 3: (R)-4-(2-(3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)acetyl ) Synthesis of piperazine-1-carboxylic acid tert-butyl ester

At room temperature, (R)-2-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)acetic acid (450mg, 1.21mmol), piperazine-1-carboxylic acid tert-butyl ester (248mg, 1.33mmol) was dissolved in DMF (5.00mL), then added DIPEA (782mg, 6.05mmol), the resulting reaction solution was stirred at room temperature for 5 minutes, and then HATU (460 mg, 1.21 mmol) was added, and the resulting reaction solution was stirred at room temperature for 3 hrs. After the reaction, add water (100 mL) to dilute, extract with EA (30.0 mL×3), combine the organic phases, and concentrate under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (DCM/MeOH=20/1) to obtain the target compound (342 mg, yield 38.4%, yellow solid). LC-MS (ESI) m/z: 540.2 [M+H] ⁺ .

Step 4: (R)-2-(3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)-1-(piper Synthesis of oxin-1-yl)ethan-1-one

At room temperature, (R)-4-(2-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)acetyl Base) tert-butyl piperazine-1-carboxylate (342mg, 0.630mmol) was dissolved in anhydrous MeOH (3.00mL), then slowly added dropwise 4N HCl MeOH solution (1.00mL), the resulting reaction solution was stirred at room temperature 4hrs. After the reaction, the solvent was distilled off from the reaction solution under reduced pressure to obtain the target compound (300 mg, yield 92.4%, yellow solid). LC-MS (ESI) m/z: 440.2 [M+H] ⁺ .

Step 5: 5-(4-(2-((R)-3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl Synthesis of )acetyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

At room temperature, (R)-2-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)-1-( Piperazin-1-yl)ethane-1-one (100mg, 0.230mmol) and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3- Diketone (94.0 mg, 0.340 mmol) was dissolved in DMSO (4.00 mL), DIPEA (147 mg, 1.14 mmol) was added to the above mixture, and the resulting reaction solution was stirred at 130° C. for 3 hrs. After the reaction, filter, and the filtrate is directly purified by prep-HPLC (column: SunFire Prep C8 OBD 10um 19*250mm; mobile phase: A-0.1% FA aqueous solution, B-ACN; gradient: B%=10%～35%; Flow rate: 20 mL/min), the title compound (23.0 mg, yield 23.0%, yellow solid) was obtained. LC-MS (ESI) m/z: 696.2 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.82(s, 1H), 11.08(s, 1H), 8.69–8.48(m, 1H), 8.44(d, J=3.0Hz, 1H), 8.22( s,1H),8.16(s,1H),7.66(s,1H),7.47(d,J＝7.9Hz,1H),7.42–7.37(m,1H),7.33(s,1H),7.25–7.09 (m,3H),5.12–5.04(m,1H),4.41(s,1H),3.80–3.44(m,8H),2.99–2.82(m,2H),2.76(d,J＝6.3Hz,1H ), 2.69–2.54 (m, 6H), 2.27 (d, J=47.1Hz, 1H), 2.10–1.95 (m, 1H), 1.84 (d, J=5.6Hz, 1H).

Example 37: 5-(4-((1-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)piper Pyridin-1-yl)acetyl)piperidin -4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1 ,3-Diketone,FA salt

Step 1: Synthesis of (R)-methyl 2-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)piperidin-1-yl)acetate

(R)-5-Chloro-4-(1H-indol-3-yl)-N-(piperidin-3-yl)pyrimidin-2-amine (500 mg, 1.53 mmol) was dissolved in DCM (7.00 mL) , Et ₃ N (772mg, 7.63mL) was added at 0°C, the resulting mixture was stirred at 0°C for 10 minutes, and 2-bromoacetate methyl ester (280mg, 1.83mmol) was slowly added dropwise, and the resulting reaction solution was at 0°C Stir for 2 hrs. After the reaction, depressurize Concentration gave a crude product, which was purified by silica gel chromatography (PE/EA=2/1) to obtain the target compound (606 mg, yield 90.3%, yellow solid). LC-MS (ESI) m/z: 400.1 [M+H] ⁺ .

Step 2: Synthesis of (R)-2-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)piperidin-1-yl)acetic acid

(R)-2-(3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)piperidin-1-yl)acetic acid methyl ester (606mg, 1.52 mmol) was dissolved in a mixture of anhydrous MeOH and water (MeOH/H ₂ O=4/1, 10.0 mL), and LiOH (73.0 mg, 3.03 mmol) was added, and the resulting reaction solution was stirred at room temperature for 4 hrs. After the reaction was completed, hydrochloric acid (2N, 1.00 mL) was added to the reaction solution, stirred for 10 minutes, and the solvent was distilled off from the reaction solution under reduced pressure to obtain the target compound (505 mg, yield 83.3%, white solid). LC-MS (ESI) m/z: 386.2 [M+H] ⁺ .

Step 3: (R)-4-((1-(2-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)piperidine-1- Synthesis of tert-butyl)acetyl)piperidin-4-yl)methyl)piperazine-1-carboxylate

At room temperature, (R)-2-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)piperidin-1-yl)acetic acid (505mg, 1.31mmol) and tert-butyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate (445mg, 1.57mmol) were dissolved in DMF (8.00mL), and DIPEA (847mg, 6.55mmol) was added and HATU (548mg, 1.44mmol), the resulting reaction solution was stirred at room temperature for 4hrs. After the reaction was completed, it was diluted with water (100 mL), extracted with EA (30.0 mL×3), and the organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (DCM/MeOH=20/1) to obtain the title compound (360 mg, yield 71.3%, colorless oil). LC-MS (ESI) m/z: 651.3 [M+H] ⁺ .

Step 4: (R)-2-(3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)piperidin-1-yl)-1-(4 Synthesis of -(piperazin-1-ylmethyl)piperidin-1-yl)ethan-1-one

At room temperature, (R)-4-((1-(2-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)piperidine-1 -yl)acetyl)piperidin-4-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester (360mg, 0.550mmol) was dissolved in anhydrous MeOH (4.00mL), then slowly added dropwise 4N HCl. MeOH solution (2.00 mL), the resulting reaction solution was stirred at room temperature for 16 hrs. After the reaction, the solvent was distilled off from the reaction liquid under reduced pressure to obtain the target compound (306 mg, yield 85.0%, yellow solid). LC-MS (ESI) m/z: 551.3 [M+H] ⁺ .

Step 5: 5-(4-((1-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)piperidine -1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1, Synthesis of 3-diketones

At room temperature, (R)-2-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)piperidin-1-yl)-1-( 4-(piperazin-1-ylmethyl)piperidin-1-yl)ethan-1-one (170mg, 0.310mmol) and 2-(2,6-dioxopiperidin-3-yl)- 5-fluoroisoindoline-1,3-dione (127mg, 0.460mmol) was dissolved in DMSO (4.00mL), and then DIPEA (199mg, 1.54mmol) was added to the above mixture, and the resulting reaction solution was Stir at °C for 3hrs. After the reaction, the reaction solution was cooled to room temperature, filtered, and the filtrate was directly purified by prep-HPLC (column: SunFire Prep C8 OBD 10um 19*250mm; mobile phase: A-0.1% FA aqueous solution, B-ACN; gradient: B%= 10%-30%; flow rate: 20 mL/min), the title compound (14.6 mg, yield 8.60%, yellow solid) was obtained. LC-MS (ESI) m/z: 807.2 [M+H] ⁺ . ¹ H NMR (400MHz,DMSO-d ₆ )δ11.83(s,1H),11.08(s,1H),8.73–8.55(m,1H),8.55–8.40(m,1H),8.26–8.14(m ,1H),8.17(s,1H),7.68(d,J=8.5Hz,1H),7.49(d,J=8.0Hz,1H),7.33(s,1H),7.28–7.02(m,4H) ,5.13–5.01(m,1H),4.35–4.21(m,1H),4.17–3.92(m,2H),3.50–3.35(m,5H),3.27–3.21(m,1H),3.10–2.99( m,1H),2.98–2.91(m,1H),2.91–2.82(m,2H),2.72–2.58(m,2H),2.58–2.56(m,1H), 2.56–2.53(m,1H),2.40–2.29(m,2H),2.23–1.93(m,6H),1.92–1.60(m,5H),1.61–1.46(m,1H),1.47–1.18(m ,1H), 1.17–0.94(m,1H),0.92–0.69(m,1H).

Example 38: 5-(4-((1-(2-((R)-3-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidine-2 -yl)amino)pyrrolidin- 1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl) Isoindoline-1,3-dione

Step 1: (R)-3-((5-Chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl Synthesis of esters

2,5-dichloro-N-(2-(isopropylsulfonyl)phenyl)pyrimidin-4-amine (1.60g, 4.62mmol), (R)-3-aminopyrrolidine-1-carboxylic acid tert Butyl ester (1.03g, 5.55mmol) and DIPEA (1.78g, 13.8mmol) were sequentially added to NMP (23.0mL), and the resulting reaction solution was stirred at 130°C for 3hrs under nitrogen protection. The reaction solution was diluted with water (50.0 mL), extracted with EA (50.0 mL), the organic phase was washed with saturated brine (50.0 mL×2), dried over anhydrous Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and the residue was passed through a silica gel layer Purification by analysis (PE/EA=4/1) gave the target compound (2.10 g, yield 92.8%, white solid). LC-MS (ESI) m/z: 496.2 [M+H] ⁺ .

Step 2: Synthesis of (R)-5-chloro-N ⁴ -(2-(isopropylsulfonyl)phenyl)-N ² -(pyrrolidin-3-yl)pyrimidine-2,4-diamine

At room temperature, (R)-3-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl The base ester (1.00 g, 2.00 mmol) was dissolved in MeOH (10.0 mL), and HCl·MeOH (4N, 10.0 mL) solution was slowly added dropwise, and the resulting reaction solution was stirred overnight at room temperature. The solvent was distilled off from the reaction solution under reduced pressure to obtain the target compound (791 mg, yield 100%, white solid). LC-MS (ESI) m/z: 396.1 [M+H] ⁺ .

Step 3: (R)-2-(3-((5-Chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)pyrrolidin-1-yl ) Synthesis of methyl acetate

(R)-5-Chloro-N ⁴ -(2-(isopropylsulfonyl)phenyl)-N ² -(pyrrolidin-3-yl)pyrimidine-2,4-diamine (791mg, 2.00mmol ) and Et ₃ N (1.00 g, 10.0 mmol) were sequentially added to DCM (20.0 mL). Under ice-bath conditions, methyl 2-bromoacetate (367 mg, 2.40 mmol) was added to the above mixture, and the resulting reaction solution was stirred at 0° C. for 3 hrs under nitrogen protection. The reaction solution was diluted with DCM (50.0 mL), washed with water (50.0 mL), the organic phase was dried over anhydrous Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and the residue was purified by silica gel chromatography (DCM/MeOH=40/1) , to obtain the target compound (814 mg, yield 87.0%, white solid). LC-MS (ESI) m/z: 468.1 [M+H] ⁺ .

Step 4: (R)-2-(3-((5-Chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)pyrrolidin-1-yl ) Synthesis of acetic acid

(R)-2-(3-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)pyrrolidin-1-yl)acetic acid Methyl ester (400 mg, 0.850 mmol) and LiOH (41.0 mg, 1.71 mmol) were sequentially added to MeOH (10.0 mL) and water (5.00 mL), and the resulting reaction solution was stirred overnight at room temperature. Add 4N HCl MeOH solution to the reaction solution to adjust pH=6～7, reduce The solvent was distilled off under reduced pressure to obtain the title compound (400 mg, crude product, colorless oil). LC-MS (ESI) m/z: 454.1 [M+H] ⁺ .

Step 5: (R)-4-((1-(2-(3-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino Synthesis of )pyrrolidin-1-yl)acetyl)piperidin-4-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester

At room temperature, (R)-2-(3-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)pyrrolidin-1- base) acetic acid (400mg, 0.850mmol), tert-butyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate (241mg, 0.850mmol), DIPEA (330mg, 2.55mmol) and HATU (420mg , 1.11 mmol) were successively dissolved in DMF (10.0 mL), and the resulting reaction solution was stirred at room temperature for 3 hrs. The reaction solution was diluted with EA (100 mL), washed with water (100 mL), the organic phase was washed with saturated brine, dried over anhydrous Na ₂ SO ₄ , filtered, concentrated, concentrated under reduced pressure, and the residue was purified by silica gel chromatography (DCM/MeOH =30/1), the target compound (570 mg, yield 94.0%, brown oil) was obtained. LC-MS (ESI) m/z: 719.3 [M+H] ⁺ .

Step 6: (R)-2-(3-((5-Chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)pyrrolidin-1-yl Synthesis of )-1-(4-(piperazin-1-ylmethyl)piperidin-1-yl)ethan-1-one

At room temperature, (R)-4-((1-(2-(3-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl) Amino)pyrrolidin-1-yl)acetyl)piperidin-4-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester (570mg, 0.800mmol) was dissolved in MeOH (5.00mL), then slowly drop HCl·MeOH (4N, 5.00 mL) solution was added, and the resulting reaction solution was stirred overnight at room temperature. The solvent was distilled off from the reaction solution under reduced pressure to obtain the target compound (490 mg, yield 100%, white solid). LC-MS (ESI) m/z: 619.3 [M+H] ⁺ .

Step 7: 5-(4-((1-(2-((R)-3-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidine-2- Base)amino)pyrrolidin-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)iso Synthesis of Indoline-1,3-dione

(R)-2-(3-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)pyrrolidin-1-yl)- 1-(4-(piperazin-1-ylmethyl)piperidin-1-yl)ethan-1-one (490mg, 0.800mmol), 2-(2,6-dioxopiperidin-3- base)-5-fluoroisoindoline-1,3-dione (220mg, 0.800mmol) and DIPEA (516mg, 4.00mmol) were sequentially added to NMP (10.0mL), and the resulting reaction solution was kept at 120°C under nitrogen protection Stir overnight. The reaction solution was diluted with EA (50.0 mL), washed with water (50.0 mL), the organic phase was washed with saturated brine (50.0 mL×2), dried over anhydrous Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and the residue was passed through prep-HPLC Purification (column: SunFire Prep C8 OBD 10um 19*250mm; mobile phase: A-0.1% FA aqueous solution, B-ACN; gradient: B% = 5% ~ 45%; flow rate: 20mL/min), the title compound (142mg , yield 20.0%, white solid). LC-MS (ESI) m/z: 875.3 [M+H] ⁺ . ¹ H NMR (400MHz,DMSO-d ₆ )δ11.11(s,1H),9.58–9.35(m,1H),9.00–8.55(m,1H),8.13(s,1H),7.90–7.62(m ,3H),7.54–7.17(m,4H),5.20–5.02(m,1H),4.42–4.08(m,2H),4.08–3.90(m,1H),3.38–3.06(m,6H),3.05 –2.81(m,3H),2.81–2.64(m,2H),2.64–2.51(m,3H),2.50–2.31(m,6H),2.24–1.94(m,4H),1.87–1.64(m, 4H), 1.17 (d, J=6.8Hz, 6H), 1.10–0.97 (m, 1H), 0.98–0.71 (m, 1H).

Example 39: 5-(4-((1-(2-((R)-3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidine-2 -yl)amino)pyrrolidin- 1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl) Isoindoline-1,3-dione, FA salt

Step 1: (R)-3-((5-Chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl Synthesis of esters

(2-((2,5-Dichloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (1.50g, 4.77mmol), DIPEA (3.10g, 23.9mmol) and 3-aminopyrrolidine - tert-butyl 1-carboxylate (1.35 g, 7.20 mmol) was added to NMP (20.0 mL), and the resulting reaction solution was stirred at 120° C. overnight. The reaction solution was diluted with water (10.0 mL), extracted with EA (10.0 mL×2), the organic phases were combined, dried over anhydrous Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and the residue was purified by silica gel chromatography (DCM/MeOH= 20/1), the target compound (2.37g, yield 97.5%, brown liquid) was obtained. LC-MS (ESI) m/z: 466.2 [M+H] ⁺ .

Step 2: Synthesis of (R)-(2-((5-chloro-2-(pyrrolidin-3-ylamino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

To (R)-3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester ( 1.18 g, 2.55 mmol) of MeOH (10.0 mL) solution was slowly added dropwise with 4N HCl·MeOH (5.00 mL) solution, and the resulting reaction solution was stirred at room temperature for 6 hrs. The solvent was distilled off from the reaction solution under reduced pressure to obtain the target compound (933 mg, crude product, yellow liquid) which was directly used in the next reaction. LC-MS (ESI) m/z: 366.1 [M+H] ⁺ .

Step 3: (R)-2-(3-((5-Chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)pyrrolidin-1-yl ) Synthesis of methyl acetate

(R)-(2-((5-chloro-2-(pyrrolidin-3-ylamino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (682mg, 1.72mmol ) in DCM (20.0 mL) was added Et ₃ N (1.74 g, 17.2 mmol), and after stirring for 5 minutes, methyl 2-bromoacetate (631 mg, 4.13 mmol) was added, and the resulting reaction solution was stirred at 0° C. for 3 hrs. The reaction solution was diluted with water (10.0 mL), extracted with DCM (10.0 mL×2), the organic phases were combined, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure, and the residue was purified by silica gel chromatography (DCM/MeOH= 40/1), the target compound (582 mg, yield 77.2%, yellow oily liquid) was obtained. LC-MS (ESI) m/z: 438.1 [M+H] ⁺ .

Step 4: (R)-2-(3-((5-Chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)pyrrolidin-1-yl ) Synthesis of acetic acid

(R)-2-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)pyrrolidin-1-yl)acetic acid Methyl ester (582mg, 1.33mmol) was added to MeOH (10.0mL), water (5.00mL) was added, LiOH (76.3mg) was added, and the resulting reaction solution was stirred at room temperature for 6hrs. The reaction solution was adjusted to pH=5 with 4N HCl·MeOH solution, and the solvent was distilled off under reduced pressure to obtain the target compound (564 mg, crude product, yellow liquid). LC-MS (ESI) m/z: 424.1 [M+H] ⁺ .

Step 5: (R)-4-((1-(2-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino Synthesis of )pyrrolidin-1-yl)acetyl)piperidin-4-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester

(R)-2-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)pyrrolidin-1-yl)acetic acid (464mg, 1.10mmol) and tert-butyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate (435mg, 1.54mmol) were dissolved in DMF (15.0mL), and DIPEA (851mg, 6.60 mmol), then add HATU (544mg, 1.43mmol), the resulting reaction The solution was stirred at room temperature for 6 hrs. The reaction solution was diluted with water (10.0 mL), extracted with EA (10.0 mL×2), and the organic phases were combined, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (DCM/MeOH=10/1) to obtain the target compound (621 mg, yield 81.9%, brown-yellow solid). LC-MS (ESI) m/z: 689.3 [M+H] ⁺ .

Step 6: (R)-2-(3-((5-Chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)pyrrolidin-1-yl Synthesis of )-1-(4-(piperazin-1-ylmethyl)piperidin-1-yl)ethan-1-one

(R)-4-((1-(2-(3-((5-chloro-4-((2-(dimethylphosphoryl) phenyl) amino) pyrimidin-2-yl) amino) pyrrole Alk-1-yl)acetyl)piperidin-4-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester (300 mg, 0.440 mmol) was dissolved in DCM (10.0 mL) and TFA (2.00 mL) was added Afterwards, the resulting reaction solution was stirred at room temperature for 1-2 hrs. The reaction solution was directly distilled off the solvent under reduced pressure to obtain the target compound (258 mg, crude product, yellow liquid), which was directly used in the next reaction. LC-MS (ESI) m/z: 589.3 [M+H] ⁺ .

Step 7: 5-(4-((1-(2-((R)-3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidine-2- Base)amino)pyrrolidin-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)iso Synthesis of Indoline-1,3-dione

(R)-2-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)pyrrolidin-1-yl)- 1-(4-(piperazin-1-ylmethyl)piperidin-1-yl)ethane-1-one (258mg, 0.440mmol), DIPEA (342mg, 2.64mmol) and 2-(2,6- Dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (122 mg, 0.440 mmol) was added to NMP (12.0 mL), and the resulting reaction solution was stirred at 120° C. for 6 hrs. The reaction solution was diluted with water (10.0 mL), extracted with EA (10.0 mL×2), and the organic phases were combined, dried over anhydrous _Na2SO4 , filtered, and concentrated under reduced _pressure to obtain a yellow liquid, which was directly purified by prep-HPLC (column : SunFire Prep C8 OBD 10um 19*250mm; Mobile phase: A-0.1% FA aqueous solution, B-ACN; Gradient: B%=5%～25%; Flow rate: 20mL/min), to obtain the title compound (20.1mg, yield Yield 10.4%, yellow solid). LC-MS (ESI) m/z: 845.3 [M+H] ⁺ . ¹ H NMR (400MHz,DMSO-d ₆ )δ11.23–10.97(m,2H),9.08–8.53(m,1H),8.17(s,1H),8.11–7.91(m,1H),7.68(d ,J＝8.3Hz,1H),7.61–7.45(m,2H),7.39–7.03(m,4H),5.18–4.96(m,1H),4.41–4.13(m,3H),4.12–3.89(m ,3H),3.56–3.22(m,7H),3.20–3.13(m,1H),3.04–2.67(m,5H),2.65–2.52(m,4H),2.22–1.97(m,5H),1.80 (d, J=33.2Hz, 6H), 1.73–1.61 (m, 2H), 1.16–0.99 (m, 1H), 0.96–0.74 (m, 1H).

Example 40: 5-(4-((4-((R)-3-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl) Amino)pyrrolidin-1- yl)methyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole Phenyl-1,3-dione

Step 1: Synthesis of (R)-5-chloro-N ⁴ -(2-(isopropylsulfonyl)phenyl)-N ² -(pyrrolidin-3-yl)pyrimidine-2,4-diamine

At room temperature, (R)-3-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl The base ester (1.10 g, 2.00 mmol) was dissolved in MeOH (10.0 mL), and HCl·MeOH (4N, 10.0 mL) solution was slowly added dropwise, and the resulting reaction solution was stirred overnight at room temperature. The solvent was distilled off from the reaction solution under reduced pressure to obtain the target compound (1.10 g, crude product, white solid). LC-MS (ESI) m/z: 396.1 [M+H] ⁺ .

Step 2: (R)-4-((3-((5-Chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)pyrrolidin-1- Synthesis of tert-butyl)methyl)piperidine-1-carboxylate

(R)-5-chloro-N ⁴ -(2-(isopropylsulfonyl)phenyl)-N ² -(pyrrolidin-3-yl)pyrimidine-2,4-diamine (1.10g, 2.78 mmol), tert-butyl 4-formylpiperidine-1-carboxylate (1.77g, 8.33mmol) and Et ₃ N (365mg, 2.61mmol) were added to DCE (33.0mL), stirred for 1hr, and then NaBH ( OAc) ₃ (1.77g, 8.33mmol), the resulting reaction solution was stirred at room temperature for 3hrs, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM/MeOH=40/1) to obtain the target compound (1.25 g, yield 76.0%, white solid). LC-MS (ESI) m/z: 593.3 [M+H] ⁺ .

Step 3: (R)-5-Chloro-N ⁴ -(2-(isopropylsulfonyl)phenyl)-N ² -(1-(piperidin-4-ylmethyl)pyrrolidin-3-yl ) Synthesis of pyrimidine-2,4-diamine

At room temperature, (R)-4-((3-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)pyrrolidin-1 -yl)methyl)piperidine-1-carboxylic acid tert-butyl ester (1.25g, 2.10mmol) was dissolved in MeOH (10.0mL), and HCl·MeOH (4N, 10.0mL) solution was slowly added dropwise, and the resulting mixture was Stir overnight. The solvent was distilled off from the reaction solution under reduced pressure to obtain the target compound (1.00 g, yield 100%, white solid). LC-MS (ESI) m/z: 493.2 [M+H] ⁺ .

Step 4: (R)-4-((4-((3-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)pyrrole Synthesis of tert-butyl (alk-1-yl)methyl)piperidin-1-yl)methyl)piperidine-1-carboxylate

(R)-5-chloro-N ⁴ -(2-(isopropylsulfonyl)phenyl)-N ² -(1-(piperidin-4-ylmethyl)pyrrolidin-3-yl)pyrimidine -2,4-Diamine (1.00g, 2.10mmol), tert-butyl 4-formylpiperidine-1-carboxylate (1.30g, 6.30mmol) and Et ₃ N (276mg, 2.70mmol) were added to DCE (30.0 mL), after stirring for 1 hr, NaBH(OAc) ₃ (1.30 g, 6.30 mmol) was added, and the resulting reaction solution was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (DCM/MeOH=20/1) to obtain the target compound (1.56 g, crude product, white solid). LC-MS (ESI) m/z: 690.3 [M+H] ⁺ .

Step 5: (R)-5-Chloro- ^N4- (2-(isopropylsulfonyl)phenyl) ^-N2- (1-((1-(piperidin-4-ylmethyl)piperidine Synthesis of -4-yl)methyl)pyrrolidin-3-yl)pyrimidine-2,4-diamine

At room temperature, (R)-4-((4-((3-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino) Pyrrolidin-1-yl)methyl)piperidin-1-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester (360 mg, 0.520 mmol) was dissolved in DCM (2.00 mL) and TFA (1.00 mL), the resulting reaction solution was stirred at room temperature for 2hrs. The solvent was distilled off from the reaction solution under reduced pressure to obtain the target compound (301 mg, crude product, yellow oil). LC-MS (ESI) m/z: 590.3 [M+H] ⁺ .

Step 6: 5-(4-((4-((R)-3-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino )pyrrolidin-1-yl)methyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline Synthesis of -1,3-diketones

(R)-5-chloro-N ⁴ -(2-(isopropylsulfonyl)phenyl)-N ² -(1-((1-(piperidin-4-ylmethyl)piperidine-4 -yl)methyl)pyrrolidin-3-yl)pyrimidine-2,4-diamine (301mg, 0.510mmol), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroiso Indoline-1,3-dione (141mg, 0.510mmol) and DIPEA (395mg, 3.06mmol) were sequentially added to NMP (9.00mL), and the resulting reaction solution was stirred at 120°C for 4hrs under nitrogen protection. The reaction solution was diluted with EA (50.0 mL), and the organic phase was washed with saturated brine (50.0 mL×2), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure, and the residue was purified by prep-HPLC (column: Waters Xbridge C18 10um OBD 19*250mm; Mobile phase: A-0.1% NH ₄ HCO ₃ aqueous solution, B-ACN; Gradient: B%=50%～70%; Flow rate: 20mL/min), to obtain the title compound (66.4mg, yield 15.0%, yellow solid). LC-MS (ESI) m/z: 846.3 [M+H] ⁺ . ¹ H NMR (400MHz,DMSO-d ₆ )δ11.08(s,1H),9.59–9.27(m,1H),9.03–8.51(m,1H),8.12(s,1H),7.83(d,J ＝7.8Hz,1H),7.78–7.68(m,1H),7.65(d,J＝8.5Hz,1H),7.42–7.26(m,3H),7.26–7.18(m,1H),5.21–4.91( m,1H),4.38–4.09(m,1H),4.02(d,J＝12.6Hz,2H),3.26–3.11(m,2H),3.04–2.86(m,3H),2.86–2.68(m, 3H), 2.66– 2.54(m,2H),2.50–2.38(m,1H),2.40–2.28(m,1H),2.27–2.17(m,2H),2.10(d,J＝5.5Hz,3H),2.06–1.93( m,1H), 1.94–1.56(m,8H), 1.50–1.27(m,1H), 1.23–1.14(m,6H), 1.16–0.97(m,4H).

Example 41: 5-(4-((4-(((R)-3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl )amino)pyrrolidin-1- yl)methyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindol Indoline-1,3-dione, FA salt

Step 1: (R)-4-((3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)pyrrolidin-1- Synthesis of tert-butyl)methyl)piperidine-1-carboxylate

To (R)-(2-((5-chloro-2-(pyrrolidin-3-ylamino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (487mg, 1.34mmol) in DCE (10.0mL) was added Et ₃ N (176mg, 1.74mmol), then added tert-butyl 4-formylpiperidine-1-carboxylate (2.86g, 13.4mmol), stirred for 5 minutes, then added NaBH (OAc ) ₃ (1.14g, 5.36mmol), the resulting reaction solution was stirred overnight at room temperature. After the reaction was completed, it was diluted with DCM (50.0 mL), and the organic phase was washed with saturated NaHCO ₃ aqueous solution (50.0 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM/MeOH=10/1) to obtain the target compound (420 mg, yield 55.7%, pale yellow oily liquid). LC-MS (ESI) m/z: 563.3 [M+H] ⁺ .

Step 2: (R)-(2-((5-Chloro-2-((1-(piperidin-4-ylmethyl)pyrrolidin-3-yl)amino)pyrimidin-4-yl)amino)benzene base) Synthesis of Dimethylphosphine Oxide

To (R)-4-((3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)pyrrolidin-1-yl) Methyl)piperidine-1-carboxylic acid tert-butyl ester (420 mg, 0.748 mmol) was added with HCl·MeOH solution (4N, 10.0 mL) and MeOH solution (4.00 mL), and the resulting reaction solution was stirred overnight at room temperature. After the reaction, the solvent was distilled off under reduced pressure to obtain the target compound (346 mg, crude product, yellow liquid). LC-MS (ESI) m/z: 463.2 [M+H] ⁺ .

Step 3: (R)-4-((4-((3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)pyrrole Synthesis of tert-butyl (alk-1-yl)methyl)piperidin-1-yl)methyl)piperidine-1-carboxylate

To (R)-(2-((5-chloro-2-((1-(piperidin-4-ylmethyl)pyrrolidin-3-yl)amino)pyrimidin-4-yl)amino)phenyl) Add Et ₃ N (100mg, 0.980mmol) to a DCE solution (10.0mL) of dimethylphosphine oxide (346mg, 0.750mmol), then add tert-butyl 4-formylpiperidine-1-carboxylate (0.800g, 3.75 mmol), after stirring for 5 minutes, NaBH(OAc) ₃ (636 mg, 3.00 mmol) was added, and the resulting reaction solution was stirred overnight at room temperature. After the reaction was completed, DCM (50.0 mL) was added to dilute, the organic phase was washed with saturated NaHCO ₃ aqueous solution (50.0 mL), dried over anhydrous Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and the residue was purified by silica gel chromatography (DCM/MeOH =10/1), the target compound (208 mg, yield 41.4%, white solid) was obtained. LC-MS (ESI) m/z: 660.4 [M+H] ⁺ .

Step 4: (R)-(2-((5-Chloro-2-((1-((1-(piperidin-4-ylmethyl)piperidin-4-yl)methyl)pyrrolidine-3 Synthesis of -yl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

(R)-4-((4-((3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)pyrrolidine- 1-yl)methyl)piperidin-1-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester (208 mg, 0.316 mmol) was dissolved in HCl·MeOH solution (4N, 15.0 mL) and MeOH solution (8.00 mL), the resulting reaction solution was stirred overnight at room temperature. After the reaction, the solvent was distilled off under reduced pressure to obtain the target compound (177 mg, crude product, yellow liquid). LC-MS (ESI) m/z: 560.3 [M+H] ⁺ .

Step 5: 5-(4-((4-(((R)-3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl) Amino)pyrrolidin-1-yl)methyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole Synthesis of Phenyl-1,3-Diones

(R)-(2-((5-chloro-2-((1-((1-(piperidin-4-ylmethyl)piperidin-4-yl)methyl)pyrrolidin-3-yl )amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (177mg, 0.317mmol), DIPEA (246mg, 1.90mmol) and 2-(2,6-dioxopiperidin-3-yl )-5-fluoroisoindoline-1,3-dione (132 mg, 0.476 mmol) was added to NMP (15.0 mL), and the resulting reaction solution was stirred at 120° C. for 6 hrs. After the reaction solution was cooled to room temperature, it was diluted with EA (50.0 mL), and the organic phase was washed with water (50.0 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure, and the residue was purified by prep-HPLC (column: SunFire Prep C8 OBD10um 19*250mm; mobile phase: A-0.1% FA aqueous solution, B-ACN; gradient: B% = 5% ~ 35%; flow rate: 20mL/min), to obtain the title compound (162mg, yield 62.4%, yellow solid). LC-MS (ESI) m/z: 816.3 [M+H] ⁺ . ¹ H NMR (400MHz,DMSO-d ₆ )δ11.22–11.14(m,1H),11.09(s,1H),9.85(s,1H),9.41–8.95(m,1H),8.61(s,1H) ),8.10(s,1H),7.69(d,J＝8.5Hz,1H),7.66–7.51(m,2H),7.36(s,1H),7.31–7.24(m,1H),7.23–7.14( m,1H),5.14–5.02(m,1H),4.57–4.39(m,1H),4.10(d,J＝13.3Hz,2H),4.03–3.62(m,4H),3.29–3.09(m, 3H),3.10–2.79(m,8H),2.72–2.54(m,2H),2.36–2.08(m,2H),2.10–1.88(m,4H),1.88–1.64(m,8H),1.61– 1.37(m,2H),1.37–1.14(m,2H).

Example 42: 2-(((3R)-1-(2-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo Isoindoline-5-yl)piperidin-4- yl)methyl)piperidin-4-yl)ethyl)pyrrolidin-3-yl)amino)pyrimidine-5-carbonitrile,diformate

Step 1: Synthesis of (R)-2-(pyrrolidine-3-amino)pyrimidine-5-carbonitrile

To a MeOH solution (5.00 mL) of (R)-3-((5-cyanopyrimidin-2-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester (600 mg, 2.10 mmol) was added 4N HCl MeOH (15.0 mL) solution, and the resulting reaction solution was stirred overnight at room temperature. The reaction solution was directly distilled off the solvent under reduced pressure to obtain a crude product, which was directly used in the next reaction. LC-MS (ESI) m/z: 190.1 [M+H] ⁺ .

Step 2: (R)-tert-butyl 4-(2-(3-((5-cyanopyrimidin-2-yl)amino)pyrrolidin-1-yl)ethyl)piperidine-1-carboxylate synthesis

(R)-2-(pyrrolidine-3-amino)pyrimidine-5-carbonitrile (397mg, 2.10mmol), 4-(2-oxoethyl)piperidine-1-carboxylic acid tert-butyl ester (477mg , 2.10mmol) and Et ₃ N (276mg, 2.73mmol) were added to DCE (15.0mL), and after stirring for half an hr, NaBH(OAc) ₃ (1.78g, 8.40mmol) was added, and the resulting reaction solution was stirred overnight at room temperature. The reaction solution was diluted with DCM (20.0 mL), and the organic phase was washed successively with saturated NaHCO ₃ aqueous solution (10.0 mL) and water (10.0 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM/MeOH=40/1) to obtain the target compound (810 mg, yield 96.0%, pale yellow solid). LC-MS (ESI) m/z: 401.2 [M+H] ⁺ .

Step 3: Synthesis of (R)-2-((1-(2-(piperidin-4-yl)ethyl)pyrrolidin-3-yl)amino)pyrimidine-5-carbonitrile.

(R)-tert-butyl 4-(2-(3-((5-cyanopyrimidin-2-yl)amino)pyrrolidin-1-yl)ethyl)piperidine-1-carboxylate (810mg, 2.03 mmol) was added to DCM (10.0 mL) and TFA (5.00 mL), and the resulting reaction solution was stirred at room temperature overnight. The reaction solution was directly distilled off the solvent under reduced pressure to obtain a crude product, which was directly used in the next reaction. LC-MS (ESI) m/z: 301.2 [M+H] ⁺ .

Step 4: 4-((3-(2-((R)-3-((5-cyanopyrimidin-2-yl)amino)pyrrolidin-1-yl)ethyl)piperidin-1-yl) Synthesis of tert-butyl methyl)piperidine-1-carboxylate

To the 1,2 -Add Et ₃ N (1.02g, 10.0mmol) to dichloroethane solution (10.0mL), then add tert-butyl 4-formylpiperidine-1-carboxylate (3.56g, 16.7mmol), stir for 5 minutes Afterwards, NaBH(OAc) ₃ (1.42 g, 6.68 mmol) was added, and the resulting reaction solution was stirred overnight at room temperature. The reaction solution was diluted with DCM (5.00 mL), and the organic phase was washed successively with saturated NaHCO ₃ aqueous solution (5.00 mL) and water (5.00 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM/MeOH/NH ₃ ·H ₂ O=10/1/0.1) to obtain the target compound (680 mg, yield 81.0%, pale yellow liquid). LC-MS (ESI) m/z: 498.4 [M+H] ⁺ .

Step 5: 2-(((3R)-1-(2-(1-(piperidin-4-ylmethyl)piperidin-3-yl)ethyl)pyrrolidin-3-yl)amino)pyrimidine- Synthesis of 5-carbonitrile

4-((3-(2-((R)-3-((5-cyanopyrimidin-2-yl)amino)pyrrolidin-1-yl)ethyl)piperidin-1-yl)methyl ) tert-butyl piperidine-1-carboxylate (580 mg, 1.17 mmol) was dissolved in DCM (10.0 mL), and TFA (2.00 mL) was added, and the resulting reaction solution was stirred at room temperature for 2 hrs. The reaction solution was directly concentrated under reduced pressure to obtain a crude product, which was directly used in the next reaction. LC-MS (ESI) m/z: 398.2 [M+H] ⁺ .

Step 6: 2-(((3R)-1-(2-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoiso Synthesis of Indoline-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)ethyl)pyrrolidin-3-yl)amino)pyrimidine-5-carbonitrile

2-(((3R)-1-(2-(1-(piperidin-4-ylmethyl)piperidin-3-yl)ethyl)pyrrolidin-3-yl)amino)pyrimidine-5- Nitrile (100mg, 1.20mmol), DIPEA (931mg, 7.20mmol) and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (324mg , 1.20mmol) was added into NMP (15.0mL), and the resulting reaction solution was stirred overnight at 120°C. The reaction solution was diluted with water (10.0 mL), extracted with EA (10.0 mL×2), and the organic phases were combined, and the organic phase was dried with anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to obtain a yellow liquid (crude product, 865 mg). pre-HPLC purification (column: SunFire Prep C8 OBD 10um 19*250mm; mobile phase: A-0.1% FA aqueous solution, B-ACN; gradient: B% = 5% ~ 30%; flow rate: 20mL/min), get the title Compound (46.9 mg, yield 5.97%). LC-MS (ESI) m/z: 654.4 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.10(s, 1H), 8.78–8.63(m, 2H), 8.57(d, J=6.8Hz, 1H), 8.27(s, 2H), 7.65( d,J=8.5Hz,1H),7.30(s,1H),7.26–7.18(m,1H),5.20–4.88(m,1H),4.48–4.26(m,2H),4.03(d,J= 12.7Hz, 2H), 3.14–3.03(m, 1H), 3.02–2.82(m, 6H), 2.81–2.60(m, 5H), 2.59–2.53(m, 1H), 2.32(d, J＝6.6Hz ,2H),2.29–2.15(m,1H),2.15–1.98(m,3H),1.94–1.73(m,4H),1.66(d,J＝11.6Hz,2H),1.51–1.30(m,3H ), 1.30–1.07(m,4H).

Example 43 : 2-(((3R)-1-((1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol Indoline-5-yl)piperidin-4-yl) methyl(piperidin-4-yl)methyl)pyrrolidin-3-yl)amino)pyrimidine-5-carbonitrile, FA salt

Step 1: 2-(((3R)-1-((1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole Lin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)pyrrolidin-3-yl)amino)pyrimidine-5-carbonitrile

At room temperature, 1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidine-4- (R)-methyl)piperidine-4-carbaldehyde (68.0mg, 0.150mmol) and (R)-2-(pyrrolidin-3-ylamino)pyrimidine-5-carbonitrile (28.4mg, 0.150mmol) were dissolved in DCE (4.00 mL), AcOH (0.100 mL) was added, the resulting mixture was stirred at room temperature for 0.5 hr, then NaBH(OAc) ₃ (61.8 mg, 0.290 mmol) was added, and the resulting reaction solution was stirred at room temperature for 2 hrs. The reaction solution was filtered, and the filtrate was directly purified by Prep-HPLC (column: SunFire Prep C8 OBD 10um, 19*250mm; mobile phase: A-0.1% FA aqueous solution, B-ACN; gradient: B%=5%～25%; Flow rate: 20 mL/min), the title compound (31.3 mg, yield 33.9%, yellow solid) was obtained. LC-MS (ESI) m/z: 640.2 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ11.07(s, 1H), 8.71(d, J=2.9Hz, 1H), 8.64(d, J=2.9Hz, 1H), 8.44(d, J= 7.0Hz, 1H), 8.21(s, 1H), 7.64(d, J＝8.5Hz, 1H), 7.35–7.13(m, 2H), 5.18–4.93(m, 1H), 4.38–4.27(m, 1H ),4.02(d,J＝13.3Hz,2H),3.00–2.90(m,3H),2.90–2.73(m,4H),2.62–2.58(m,4H),2.40–2.31(m,1H), 2.29–2.20(m,2H),2.14–2.08(m,3H),2.04–1.96(m,1H),1.89–1.73(m,6H),1.73–1.63(m,2H),1.43–1.31(m ,1H),1.25–1.00(m,4H).

Example 44: 2-(2,6-dioxopiperidin-3-yl)-5-(4-((4-(((R)-3-((5-(trifluoromethyl)pyrimidine -2-yl)amino)pyrrolidin-1- yl)methyl)piperidin-1-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione, FA salt

Step 1: Synthesis of (R)-tert-butyl 3-((5-(trifluoromethyl)pyrimidin-2-yl)amino)pyrrolidine-1-carboxylate

2-Chloro-5-(trifluoromethyl)pyrimidine (870 mg, 4.77 mmol) and (R)-3-aminopyrrolidine-1-carboxylic acid tert-butyl ester (888 mg, 4.77 mmol) were dissolved in DMF (10.0 mL ), DIPEA (2.50 mL) was added, and the resulting reaction solution was stirred at 40° C. for 16 hrs under nitrogen protection. After the reaction, the solvent was distilled off the reaction solution under reduced pressure to obtain the target compound (1.52 g, yield 95.8%, yellow oil). LC-MS (ESI) m/z: 333.2 [M+H] ⁺ .

Step 2: Synthesis of (R)-N-(pyrrolidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine

(R)-tert-butyl 3-((5-(trifluoromethyl)pyrimidin-2-yl)amino)pyrrolidine-1-carboxylate (1.52 g, 4.57 mmol) was dissolved in DCM (2.00 mL) , TFA (1.00 mL) was slowly added dropwise to the solution, and the resulting reaction solution was stirred at room temperature for 3 hrs under nitrogen protection. After the reaction, the solvent was distilled off from the reaction solution under reduced pressure to obtain the target compound (1.03 g, yield 97.2%, yellow oil), which was directly used in the next step. LC-MS (ESI) m/z: 233.3 [M+H] ⁺ .

Step 3: (R)-4-((3-((5-(trifluoromethyl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)methyl)piperidine-1-carboxylic acid tert-butyl Synthesis of esters

(R)-N-(pyrrolidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (1.03g, 4.44mmol) and 4-formylpiperidine-1-carboxylic acid tert-butyl The ester (4.73g, 22.2mmol) was dissolved in DCE (10.0mL), AcOH (5.00mL) was added to the above reaction solution, the resulting mixture was stirred at room temperature for 30 minutes, NaBH(OAc) ₃ (2.81g, 13.3mmol) Added to the above mixed solution, the resulting reaction solution was stirred at room temperature for 2 hrs under the protection of nitrogen. After the reaction, add water (20.0 mL) to the reaction solution to dilute, extract with DCM (20.0 mL×2), combine the organic phases, wash the organic phases with saturated brine, dry over anhydrous Na ₂ SO ₄ , and filter. The filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (DCM/MeOH=9/1) to obtain the target compound (1.86 g, yield 97.7%, yellow oil). LC-MS (ESI) m/z: 430.2 [M+H] ⁺ .

Step 4: Synthesis of (R)-N-(1-(piperidin-4-ylmethyl)pyrrolidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine

(R)-4-((3-((5-(trifluoromethyl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester ( 1.86 g, 4.33 mmol) was dissolved in DCM (10.0 mL), TFA (5.00 mL) was slowly added dropwise to the solution, and the resulting reaction solution was stirred at room temperature for 2 hrs under nitrogen protection. After the reaction, the solvent was distilled off from the reaction solution under reduced pressure to obtain the target compound (1.31 g, yield 93.0%, yellow oil). LC-MS (ESI) m/z: 330.2 [M+H] ⁺ .

Step 5: (R)-4-((4-((3-((5-(trifluoromethyl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)methyl)piperidine-1- Synthesis of tert-butyl)methyl)piperidine-1-carboxylate

(R)-N-(1-(piperidin-4-ylmethyl)pyrrolidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (1.31g, 3.98mmol) and 4 -Formylpiperidine-1-carboxylic acid tert-butyl ester (2.56g, 12.0mmol) was dissolved in MeOH (15.0mL), Et ₃ N (3.00mL) was added to the above reaction solution, stirred at room temperature for 30 minutes, and NaBH(OAc) ₃ (2.54 g, 12.0 mmol) was added to the above mixture, and the resulting reaction solution was stirred at room temperature for 2 hrs under nitrogen protection. After the reaction, add water (30.0 mL) to the reaction solution to dilute, extract with DCM (30.0 mL×2), combine the organic phases, wash the organic phases with saturated brine, dry over anhydrous Na ₂ SO ₄ , and filter. The filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (DCM/MeOH=10/1) to obtain the title compound (1.75 g, yield 82.5%, yellow oil). LC-MS (ESI) m/z: 527.3 [M+H] ⁺ .

Step 6: (R)-N-(1-((1-(piperidin-4-ylmethyl)piperidin-4-yl)methyl)pyrrolidin-3-yl)-5-(trifluoromethane base) synthesis of pyrimidin-2-amine

(R)-4-((4-((3-((5-(trifluoromethyl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)methyl)piperidin-1-yl) Methyl)piperidine-1-carboxylic acid tert-butyl ester (300mg, 0.350mmol) was dissolved in MeOH (2.00mL), and 4N HCl MeOH (1.00mL) solution was slowly added dropwise to the solution, and the resulting reaction solution was protected under nitrogen Stir at room temperature for 12hrs. After the reaction, the solvent was distilled off from the reaction solution under reduced pressure to obtain the target compound (186 mg, yield 76.6%, yellow oil). LC-MS (ESI) m/z: 427.2 [M+H] ⁺ .

Step 7: 2-(2,6-dioxopiperidin-3-yl)-5-(4-((4-(((R)-3-((5-(trifluoromethyl)pyrimidine- Synthesis of 2-yl)amino)pyrrolidin-1-yl)methyl)piperidin-1-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione

(R)-N-(1-((1-(piperidin-4-ylmethyl)piperidin-4-yl)methyl)pyrrolidin-3-yl)-5-(trifluoromethyl) Pyrimidin-2-amine (186mg, 0.440mmol), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (157mg, 0.570mmol) and DIPEA (0.500 mL) were dissolved in DMSO (3.00 mL), and the resulting reaction solution was stirred at 120° C. for 2 hrs under nitrogen protection. After the reaction, filter, and the filtrate is directly purified by prep-HPLC (column: SunFire Prep C18 10um OBD 19*250mm; mobile phase: A-0.1% FA aqueous solution, B-ACN; gradient: B%=13%～33%; Flow rate: 20mL/min), get titled compound (15.8 mg, yield 13.8%, yellow solid). LC-MS (ESI) m/z: 683.2 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.06(s, 1H), 8.62(d, J=17.3Hz, 2H), 8.18(d, J=9.6Hz, 2H), 7.64(d, J= 8.5Hz,1H),7.30(d,J=1.9Hz,1H),7.26–7.17(m,1H),5.09–5.02(m,1H),4.33(d,J=8.4Hz,1H),4.02( d,J＝12.8Hz,2H),3.01–2.90(m,3H),2.86–2.77(m,4H),2.57–2.54(m,2H),2.40–2.31(m,2H),2.28–2.21( m,2H),2.12(d,J=6.7Hz,3H),2.04–1.97(m,1H),1.92–1.80(m,3H),1.77(d,J=11.9Hz,3H),1.73–1.64 (m,3H), 1.39(s,1H), 1.17–1.04(m,4H). ¹⁹ F NMR 377MHz, DMSO-d ₆ ) δ 59.28(s).

Example 45: 5-(4-((1-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrole Alkyl-1-yl)ethyl)-1H- 1,2,3-triazol-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidine-3 -yl) isoindoline-1,3-dione, trifluoroacetate

(R)-5-chloro-4-(1H-indol-3-yl)-N-(pyrrolidin-3-yl)pyrimidin-2-amine (1.00g, 3.19mmol), 2-bromomethane-1 -Alcohol (398mg, 3.19mmol), KI (106mg, 0.640mmol) and K ₂ CO ₃ (1.30g, 9.57mmol) were sequentially added to ACN (30.0mL), and the resulting reaction solution was stirred overnight at 80°C under nitrogen protection. The solvent was evaporated from the reaction solution under reduced pressure, and the residue was purified by silica gel chromatography (DCM/MeOH=10/1, 1% NH ₃ ·H ₂ O) to obtain the target compound (790 mg, yield 69.1%, yellow solid). LC-MS (ESI) m/z: 358.1 [M+H] ⁺ .

(R)-2-(3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)ethane-1- Alcohol (890mg, 2.49mmol) and Et ₃ N (756mg, 7.47mmol) were dissolved in DCM (30.0mL), under ice-cooling conditions, methanesulfonyl chloride (427mg, 3.73mmol) was added, and the resulting reaction solution was Stir at room temperature for 2hrs. The solvent was distilled off from the reaction solution under reduced pressure to obtain the target compound (1.09 g, crude product, yellow oily liquid), which was directly used in the next step. LC-MS (ESI) m/z: 436.1 [M+H] ⁺ .

Step 3: (R)-N-(1-(2-azidoethyl)pyrrolidin-3-yl)-5-chloro-4-(1H-indol-3-yl)pyrimidin-2-amine synthesis

(R)-2-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)methylsulfonate ethyl ester ( 1.09 g, 2.49 mmol) and sodium azide (809 mg, 12.5 mmol) were sequentially added to DMF (20.0 mL), and the resulting reaction solution was stirred overnight at 80° C. under nitrogen protection. The reaction solution was diluted with EA (50.0 mL), the organic phase was washed with saturated brine (50.0 mL×2), dried over anhydrous Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and the residue was purified by silica gel chromatography (DCM/MeOH=40 /1) to obtain the target compound (143 mg, yield 15.0%, yellow solid). LC-MS (ESI) m/z: 383.1 [M+H] ⁺ .

Step 4: 5-(4-((1-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidine -1-yl)ethyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidine-3- base) synthesis of isoindoline-1,3-dione

(R)-N-(1-(2-azidoethyl)pyrrolidin-3-yl)-5-chloro-4-(1H-indol-3-yl)pyrimidin-2-amine ( 90.0mg, 0.235mmol), 2-(2,6-dioxopiperidin-3-yl)-5-(4-(propyl-2-yn-1-yl)piperazin-1-yl)iso Indoline-1,3-dione (98.0mg, 0.258mmol) and cuprous iodide (9.00mg, 0.0470mmol) were dissolved in DMF (1.00mL) and After the resulting mixture was stirred at room temperature for 5 minutes in THF (5.00 mL), a mixture of DIPEA (152 mg, 1.18 mmol) and THF (1.00 mL) was added to the above solution, and the resulting reaction solution was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, 4N HCl MeOH solution was added dropwise, the pH was adjusted to 1-2, solids were precipitated, filtered, the filter cake was dissolved in DMF, and the resulting solution was passed through prep-HPLC (column: SunFire Prep C8 OBD 10um 19*250mm; Mobile phase: A-0.1% TFA aqueous solution, B-ACN; gradient: B%=10%-35%; flow rate: 20mL/min) to obtain the title compound (18.9mg, yield 10.0%, yellow solid). LC-MS (ESI) m/z: 763.3 [M+H] ⁺ . ¹ H NMR (400MHz,DMSO-d ₆ )δ11.97(s,1H),11.11(s,1H),10.81–10.28(m,1H),8.73–8.46(m,2H),8.36(d,J ＝10.5Hz,2H),7.83–7.57(m,2H),7.57–7.41(m,2H),7.32(d,J＝8.4Hz,1H),7.28–7.04(m,2H),5.19–5.03( m,1H),4.99–4.81(m,2H),4.74–4.58(m,1H),4.54(s,1H),4.11–3.81(m,7H),3.50–3.10(m,8H),2.98– 2.81(m,1H), 2.62–2.54(m,2H), 2.46–2.29(m,1H), 2.24–2.09(m,1H), 2.09–1.96(m,1H). ¹⁹ F NMR (377 MHz, DMSO-d ₆ ) δ-68.78–-78.13 (m).

Example 46: 5-(1-(1-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidine -1-yl)ethyl)piperidin- 4-yl)-1H-1,2,3-triazol-4-yl)-2-(2,6-dioxopiperidin-3-yl) Isoindoline-1,3-dione

Example 47: 5-(1-((1-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrole Alkyl-1-yl)ethyl)piperidin -4-yl)methyl)-1H-1,2,3-triazol-4-yl)-2-(2,6-dioxopiperidine- 3-yl)isoindoline-1,3-dione

Example 48: 5-(4-((4-(((R)-3-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazole- 4-yl)pyrimidin-2-yl)amino)pyrrolidin -1-yl)methyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxo Piperidin-3-yl)isoindoline-1,3-dione

Step 1: Synthesis of cyclopropyl(1-methyl-1H-pyrazol-5-yl)methanol

At -78°C, a solution of n-butyllithium (2.5N, 60.0mL, 150mmol) was slowly added dropwise to 1-methyl-1H-pyrazole (8.20g, 100mmol) in anhydrous THF (200mL). After stirring for 1 hr at high temperature, cyclopropanaldehyde (8.20g, 100mmol) was added dropwise solution in THF (80.0 mL), then stirred at room temperature for 16 hrs. The reaction mixture was quenched with NH ₄ Cl aqueous solution (300 mL), extracted with EA (100 mL×2), combined organic phases, washed with saturated brine (200 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE/EA=8/1～0/1) to obtain the target compound (13.0 g, yield 85.4%, yellow oily liquid). LC-MS (ESI) m/z: 153.2 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) 7.29(d, J=1.8Hz, 1H), 6.23(d, J=1.7Hz, 1H), 5.34(d, J=5.7Hz, 1H), 4.10(dd , J=7.5, 5.8Hz, 1H), 3.82(s, 3H), 1.31–1.15(m, 1H), 0.61–0.39(m, 3H), 0.32–0.22(m, 1H).

Step 2: Synthesis of 5-(cyclopropyl)-1-methyl-1H-pyrazole

At room temperature, TFA (78.0mL, 1.02mol) and triethoxysilane (156mL, 1.02mol) were added dropwise to cyclopropyl(1-methyl-1H-pyrazol-5-yl)methanol (13.0g , 85.4mmol) in DCE (78.0mL), then stirred at 40°C for 36hrs. After the reaction mixture was cooled to room temperature, the pH was adjusted to 8 with saturated NaHCO ₃ aqueous solution, extracted with DCM (100 mL×2), the organic phases were combined, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure, and the residue was passed through a silica gel layer. (PE/EA=8/1～2/1) separation and purification to obtain the target compound (7.50g, yield 64.5%, yellow oily liquid). LC-MS (ESI) m/z: 137.2 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ7.09(d, J=1.6Hz, 1H), 5.93(d, J=1.4Hz, 1H), 3.53(s, 3H), 2.35(d, J= 6.9Hz, 2H), 0.87–0.75(m, 1H), 0.40–0.28(m, 2H), 0.04–0.05(m, 2H).

Step 3: Synthesis of 4-bromo-5-(cyclopropyl)-1-methyl-1H-pyrazole

Under ice bath, NBS (863 mg, 4.80 mmol) was added to 5-(cyclopropyl)-1-methyl-1H-pyrazole (600 mg, 4.40 mmol) in DCM (10.0 mL), then stirred at room temperature for 2 hrs. The reaction mixture was concentrated under reduced pressure, and the residue was separated and purified by silica gel chromatography (PE/EA=20/1) to obtain the target compound (600 mg, yield 63.0%, colorless oily liquid). LC-MS (ESI) m/z: 217.0 [M+H+2] ⁺ .

Step 4: 5-(cyclopropylmethyl)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -Synthesis of 1H-pyrazole

At -78°C, a solution of n-butyllithium (1.6N, 4.20mL, 5.60mmol) was slowly added dropwise to 4-bromo-5-(cyclopropyl)-1-methyl-1H-pyrazole (600mg, 2.80 mmol) in anhydrous THF (15.0 mL), stirred at this temperature for 0.5 hr, then added dropwise 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dihe Oxaborane (1.00 g, 5.60 mmol) in THF (2.00 mL) was then stirred at room temperature for 0.5 hr. The reaction mixture was quenched by adding NH ₄ Cl aqueous solution (50.0 mL), extracted with EA (100 mL), combined the organic phases, washed with saturated brine (100 mL), dried over anhydrous Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and the residue The compound was separated and purified by silica gel chromatography (PE/EA=20/1～10/1) to obtain the target compound (570 mg, yield 77.0%, white solid). LC-MS (ESI) m/z: 263.1 [M+H] ⁺ .

Step 5: Synthesis of 2,5-dichloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidine

Under nitrogen protection, add PdCl ₂ (Amphos) ₂ (77.0mg, 0.110mmol) to 5-(cyclopropylmethyl)-1-methyl-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-pyrazole (570mg, 2.17mmol), 2,4,5-trichloropyrimidine (479mg, 2.61mmol) and Na ₂ CO ₃ ( 2N, 2.40 mL, 4.78 mmol) in DME (10.0 mL), then stirred at 85 °C for 3 hrs. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was separated and purified by silica gel chromatography (PE/EA=20/1-5/1) to obtain the target compound (340 mg, yield 55.0%, yellow liquid). LC-MS (ESI) m/z: 283.0 [M+H] ⁺ .

Step 6: (R)-3-((5-Chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino) Synthesis of tert-butyl pyrrolidine-1-carboxylate

Add DIPEA (800mg, 6.20mmol) to 2,5-dichloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidine (350mg , 1.24mmol) and (R)-3-aminopyrrolidine-1-carboxylic acid tert-butyl ester (460mg, 2.48mmol) NMP (8.00 mL), then stirred at 130 °C for 4 hrs. After the reaction mixture was cooled to room temperature, it was diluted with water (100 mL), extracted with EA (100 mL), the organic phase was washed with saturated brine (50 mL), dried over anhydrous Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and the residue was subjected to silica gel chromatography (PE/EA=1/1) separation and purification to obtain the target compound (450 mg, yield 84.0%, yellow solid). LC-MS (ESI) m/z: 333.0 [M+H-100] ⁺ .

Step 7: (R)-5-Chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-N-(pyrrolidin-3-yl)pyrimidine Synthesis of -2-amine

At room temperature, HCl·MeOH (4N, 4.00 mL) solution was added dropwise to (R)-3-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyridine Azol-4-yl)pyrimidin-2-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester (140 mg, 0.323 mmol) in MeOH (9.00 mL), then stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to obtain the title compound (107 mg, crude product, white solid). LC-MS (ESI) m/z: 333.1 [M+H] ⁺ .

Step 8: 5-(4-((4-(((R)-3-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazole-4 -yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)methyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiper Synthesis of pyridin-3-yl)isoindoline-1,3-dione

Et ₃ N (34.1 mg, 0.338 mmol) was added to (R)-5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-N -(pyrrolidin-3-yl)pyrimidin-2-amine (75.0mg, 0.225mmol) and 1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3 -Isoindoline-5-yl)piperidin-4-yl)methyl)piperidine-4-carbaldehyde (105mg, 0.225mmol) in DCE (15.0mL), after stirring at room temperature for 0.5hr, NaBH(OAc ) ₃ (143mg, 0.675mmol), then stirred overnight at room temperature. The reaction mixture was quenched with water (50.0 mL), extracted with DCM/MeOH (10/1, 50.0 mL), the organic phase was dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure, and the residue was subjected to Prep-HPLC (column: Waters Xbridge C18 10um OBD 19*250mm; mobile phase: A-water (0.1%NH ₃ H ₂ O)/B-CH ₃ CN; B%=40%-65%; flow rate: 20mL/min) separation and purification, obtained The title compound (10.7 mg, yield 6.06%, yellow solid). LC-MS (ESI) m/z: 783.4 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ10.95(s, 1H), 8.17(s, 1H), 7.85(s, 1H), 7.52(d, J=8.5Hz, 1H), 7.34–7.24( m,1H),7.21–7.14(m,1H),7.14–7.06(m,1H),5.05–4.87(m,1H),4.36–4.14(m,1H),3.90(d,J＝12.6Hz, 2H),3.73(s,3H),3.06–2.88(m,2H),2.88–2.69(m,6H),2.60–2.40(m,2H),2.34–1.96(m,6H),1.95–1.81( m,3H),1.71–1.52(m,6H),1.44–1.23(m,2H),1.09–0.94(m,5H),0.92–0.75(m,1H),0.35–0.20(m,2H), 0.07–-0.06(m,2H).

Example 49: 5-(4-((4-(((R)-3-((5-chloro-4-(4-(cyclopropylmethyl)-1H-pyrazol-3-yl)pyrimidine -2-yl)amino)pyrrolidin- 1-yl)methyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidine-3- base) isoindoline-1,3-dione

Example 50: (E)-N-(4-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1 -Carbonyl)phenyl)-4- (4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperazine- 1-yl)butyl-2-enamide

Example 51: (E)-N-(4-((R)-3-((5-chloro-4-(4-methyl-1H-pyrazol-3-yl)pyrimidin-2-yl)amino )pyrrolidine-1-carbonyl)phenyl )-4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5- Base) piperazin-1-yl) butyl-2-enamide

Example 52: (E)-N-(4-((R)-3-((5-chloro-4-(4,5-dimethyl-1H-pyrazol-3-yl)pyrimidine-2- Base)amino)pyrrolidine-1-carbonyl )phenyl)-4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole Lin-5-yl)piperazin-1-yl)butyl-2-enamide

Example 53: 5-(4-((4-(((R)-3-((5-chloro-4-(6-methylpyridin-3-yl)pyrimidin-2-yl)amino)pyrrolidine -1-yl)methyl)piperidin -1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1, 3-diketone

Example 54: 5-(4-((4-(((R)-3-((5-chloro-4-(trifluoromethyl)pyrimidin-2-yl)amino)pyrrolidin-1-yl) Methyl)piperidin-1-yl) methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Example 55: 5-(4-((4-(((R)-3-((5-chloro-4-(2-hydroxypropan-2-yl)pyrimidin-2-yl)amino)pyrrolidine- 1-yl)methyl)piperidin -1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3 - dione

Example 56: 5-(4-((4-(2-((R)-3-((5-chloro-4-(4-methyl-1H-pyrazol-3-yl)pyrimidine-2- Base)amino)pyrrolidin-1-yl)ethyl) piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)iso Indoline-1,3-dione

Example 57: 5-(4-((4-(2-((R)-3-((5-chloro-4-(trifluoromethyl)pyrimidin-2-yl)amino)pyrrolidin-1- Base) ethyl) piperidin-1- yl) methyl) piperidin-1-yl) -2-(2,6-dioxopiperidin-3-yl) isoindoline-1,3-di ketone

Example 58: 5-(4-((4-(2-((R)-3-((5-chloro-4-(2-hydroxypropan-2-yl)pyrimidin-2-yl)amino)pyrrole Alkyl-1-yl)ethyl)piperidin -1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1 ,3-diketone

Example 59: 5-(4-((4-(((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidine- 1-yl)methyl)piperidin- 1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline -1,3-dione

Example 60: 3-(5-(4-((4-(((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino) Pyrrolidin-1-yl)methyl)piperidin -1-yl)methyl)piperidin-1-yl)-6-fluoro-1-oxoisoindoline-2-yl)piperidine-2, 6-diketone

Example 61: 3-(6-(4-((4-(((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino) Pyrrolidin-1-yl)methyl)piperidin -1-yl)methyl)piperidin-1-yl)-5-fluoro-1-oxoisoindoline-2-yl)piperidine-2, 6-diketone

Example 62: 3-((4-(4-((4-(((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino )pyrrolidin-1-yl)methyl)piperidin-1 -yl)methyl)piperidin-1-yl)benzyl)amino)piperidine-2,6-dione

Example 63: 3-((4-(4-((4-(((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino )pyrrolidin-1-yl)methyl)piperidin-1 -yl)methyl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione

Example 64: (R)-1-(4-(4-((4-((3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino) Pyrrolidin-1-yl)methyl)piperidin-1 -yl)methyl)piperidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

Example 65: (R)-1-(6-(4-((4-((3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino) Pyrrolidin-1-yl)methyl)piperidin-1 -yl)methyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4( 1H,3H)-Diketone

Example 66: (R)-1-(4-(1-((1-(2-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl) Amino)pyrrolidin-1-yl)ethyl)piperidin- 4-yl)methyl)piperidin-4-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

Example 67: (R)-1-(4-(1'-(2-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrole Alkyl-1-yl)ethyl)-[1,4'- bipiperidinyl]-4-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

Example 68: (R)-1-(4-(1-(1-(2-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino )pyrrolidin-1-yl)ethyl)piperidin- 4-yl)azetidin-3-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

Example 69: (R)-1-(4-(1'-(2-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrole Alk-1-yl)ethyl)-[1,3'- diazetidine]-3-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

Example 70: 4-(4-((R)-3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)piper Pyridin-1-yl)-2- (2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione, FA salt

(R)-4-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)piperidine-1-carboxylic acid tert Butyl ester (900 mg, 1.81 mmol) was dissolved in MeOH (2.00 mL), and 4N HCl·MeOH (2.00 mL) solution was slowly added dropwise to the solution, and the resulting reaction solution was stirred at room temperature for 12 hrs under nitrogen protection. After the reaction, the solvent was distilled off from the reaction solution under reduced pressure to obtain the target compound (402 mg, yield 55.9%, yellow oil). LC-MS (ESI) m/z: 397.2 [M+H] ⁺ .

Step 2: 4-(4-((R)-3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)piperidine Synthesis of -1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

(R)-5-Chloro-4-(1H-indol-3-yl)-N-(1-(piperidin-4-yl)pyrrolidin-3-yl)pyrimidin-2-amine (65.0mg , 0.164mmol), 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (54.4mg, 0.197mmol) and DIPEA (0.500mL) It was dissolved in DMSO (2.00 mL), and the resulting reaction solution was stirred at 120° C. for 1 hr under nitrogen protection. After the reaction, filter, and the filtrate is directly purified by prep-HPLC (column: SunFire Prep C8 OBD 10um 19*250mm; mobile phase: A-0.1% FA aqueous solution, B-ACN; gradient: B%=10%～55%; Flow rate: 20 mL/min), the title compound (43.8 mg, yield 40.8%, yellow solid) was obtained. LC-MS (ESI) m/z: 653.0 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.83(s, 1H), 11.08(s, 1H), 8.76–8.52(m, 1H), 8.46(d, J=2.9Hz, 1H), 8.27( s,1H),8.15(s,1H),7.71–7.64(m,1H),7.49(d,J＝7.9Hz,1H),7.45–7.37(m,1H),7.36–7.30(m,2H) ,7.24–7.13(m,2H),5.13–5.05(m,1H),4.43(s,1H),3.72–3.64(m,2H),2.99–2.89(m,3H),2.85–2.79(m, 1H),2.74–2.65(m,1H),2.64–2.59(m,2H),2.39–2.29(m,2H),2.27–2.18(m,1H),2.06–1.91(m,4H),1.89– 1.80(m,1H),1.68–1.58(m,2H).

Example 71: 4-(4-(((R)-3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl) Methyl)piperidin-1-yl) -2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione, FA salt

(R)-4-((3-((5-chloro-4-)1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)methyl)piperidine- 1-tert-butyl carboxylate (156 mg, 0.305 mmol) was dissolved in MeOH (2.00 mL), and 4N HCl·MeOH (5.00 mL) solution was slowly added dropwise to the solution, and the resulting reaction solution was stirred at room temperature for 12 hrs under nitrogen protection. After the reaction, the solvent was distilled off from the reaction solution under reduced pressure to obtain the target compound (46.0 mg, yield 36.7%, brown oil). LC-MS (ESI) m/z: 411.2 [M+H] ⁺ .

Step 2: 4-(4-(((R)-3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)methanol Synthesis of yl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

(R)-5-chloro-4-(1H-indol-3-yl)-N-(1-(piperidin-4-ylmethyl)pyrrolidin-3-yl)pyrimidin-2-amine ( 46.0mg, 0.110mmol), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (37.0mg, 0.130mmol) and DIPEA (0.300 mL) was dissolved in DMSO (2.00 mL), and the resulting reaction solution was stirred at 120° C. for 1 hr under nitrogen protection. After the reaction, filter, and the filtrate is directly purified by prep-HPLC (column: SunFire Prep C8 OBD 10um 19*250mm; mobile phase: A-0.1% FA aqueous solution, B-ACN; gradient: B%=10%～55%; Flow rate: 20 mL/min), the title compound (6.52 mg, yield 8.88%, yellow solid) was obtained. LC-MS (ESI) m/z: 667.1 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.84(s, 1H), 11.08(s, 1H), 8.82–8.52(m, 1H), 8.46(d, J=3.0Hz, 1H), 8.27( s,1H),8.16(s,1H),7.72–7.62(m,1H),7.49(d,J＝7.9Hz,1H),7.43–7.35(m,1H),7.35–7.26(m,2H) ,7.26–7.11(m,2H),5.13–5.02(m,1H),4.43(s,1H),3.68(d,J＝10.8Hz,2H),3.02–2.94(m,1H),2.90–2.80 (m,3H),2.70–2.64(m,1H),2.62–2.55(m,3H),2.40–2.31(m,2H),2.22(s,1H),2.08(d,J＝5.0Hz,1H ), 2.06–1.98(m,1H), 1.92–1.76(m,3H), 1.65(s,1H), 1.40–1.22(m,2H).

Example 72: 4-(3-((R)-3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)piper Pyridin-1-yl)-2- (2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione, FA salt

Step 1: 3-((R)-3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)piperidine-1- tert-butyl formate

(R)-5-Chloro-4-(1H-indol-3-yl)-N-(pyrrolidin-3-yl)pyrimidin-2-amine (100 mg, 0.320 mmol) was dissolved in DCE (5.00 mL) In , Et ₃ N (48.0mg, 0.480mmol) was added dropwise, and the resulting mixture was stirred at room temperature for 10 minutes, and then tert-butyl 3-oxopiperidine-1-carboxylate (319mg, 1.60mmol) was added to obtain The mixture was stirred at room temperature for 16 hrs, then NaBH(OAc) ₃ (271 mg, 1.28 mmol) was added, and the resulting reaction solution was stirred at room temperature for 1 hr. After the reaction was completed, ice water (20.0 mL) was added to the reaction liquid to dilute, and extracted with DCM (20.0 mL×2). The organic phases were combined, washed with saturated brine, dried over anhydrous Na ₂ SO ₄ , and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (DCM/MeOH=15/1) to obtain the title compound (600 mg, yield 54.2%, yellow solid). LC-MS (ESI) m/z: 497.2 [M+H] ⁺ .

Step 2: 5-Chloro-4-(1H-indol-3-yl)-N-((3R)-1-(piperidin-3-yl)pyrrolidin-3-yl)pyrimidin-2-amine

3-((R)-3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)piperidine-1-carboxylic acid tert Butyl ester (400 mg, 0.800 mmol) was dissolved in DCM (5.00 mL), and TFA (1.00 mL) was added dropwise, and the resulting reaction solution was stirred at room temperature for 1 hr. The reaction solution was directly distilled off the solvent under reduced pressure to obtain the TFA salt of the target product (317 mg, yield 100%, yellow oil). LC-MS (ESI) m/z: 397.1 [M+H] ⁺ .

Step 3: 4-(3-((R)-3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)piperidine -1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

5-Chloro-4-(1H-indol-3-yl)-N-((3R)-1-(piperidin-3-yl)pyrrolidin-3-yl)pyrimidin-2-amine (159 mg, 0.400mmol), 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (166mg, 0.600mmol) and DIPEA (4.00mmol) were dissolved in In NMP (10.0 mL), the resulting reaction solution was stirred at 120° C. for 16 hrs under the protection of argon. The reaction solution was cooled to room temperature, diluted with DCM (50.0 mL), and the organic phase was washed with water (40.0 mL×2) and saturated brine (40.0 mL) successively, dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated under reduced pressure to obtain The product was purified by silica gel chromatography (DCM/MeOH=10/1) to obtain a crude product, and the crude product was purified by Prep-HPLC (column: SunFire Prep C8 OBD 10um 19*250mm; mobile phase: A-0.1% FA aqueous solution, B -ACN; Gradient: B%=15%～40%; Flow rate: 20mL/min) to obtain the title compound (45.9mg, yield 17.2%, yellow solid). LC-MS (ESI) m/z: 651.2 [M+H] ⁺ . ¹ H NMR (400MHz,DMSO-d ₆ )δ11.84(s,1H),11.06(s,1H),8.75–8.52(m,1H),8.48–8.43(m,1H),8.34–8.17(m ,2H),7.68–7.64(m,1H),7.49–7.47(m,1H),7.37–7.30(m,3H),7.22–7.13(m,2H),5.07–5.05(m,1H),4.49 –4.30(m,1H),3.91–3.89(m,1H),3.60–3.58(m,1H),3.15–2.95(m,3H),2.85–2.74(m,3H),2.73–2.55(m, 4H), 2.24–2.11(m,1H), 2.07–1.91(m,2H), 1.85–1.62(m,2H), 1.72–1.62(m,1H), 1.33–1.24(m,1H).

Example 73: 5-(3-((R)-3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)piper Pyridin-1-yl)-2- (2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Step 1: 3-((R)-3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)piperidine-1- Synthesis of tert-butyl formate

(R)-5-Chloro-4-(1H-indol-3-yl)-N-(pyrrolidin-3-yl)pyrimidin-2-amine (100 mg, 0.320 mmol) was dissolved in DCE (5.00 mL) In , Et ₃ N (48.0mg, 0.480mmol) was added dropwise, and the resulting mixture was stirred at room temperature for 10 minutes, and then tert-butyl 3-oxopiperidine-1-carboxylate (319mg, 1.60mmol) was added to obtain The reaction solution was stirred at room temperature for 16 hrs, and then NaBH(OAc) ₃ (271 mg, 1.28 mmol) was added, and the resulting reaction solution was stirred at room temperature for 1 hr. After the reaction was completed, ice water (20.0 mL) was added to the reaction liquid to dilute, and extracted with DCM (20.0 mL×2). The organic phases were combined, washed with saturated brine, dried over anhydrous Na ₂ SO ₄ , and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (DCM/MeOH=15/1) to obtain the title compound (600 mg, yield 54.2%, yellow solid). LC-MS (ESI) m/z: 497.2 [M+H] ⁺ .

Step 3: 5-(3-((R)-3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)piperidine -1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

5-Chloro-4-(1H-indol-3-yl)-N-((3R)-1-(piperidin-3-yl)pyrrolidin-3-yl)pyrimidin-2-amine (159 mg, 0.400mmol), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (166mg, 0.600mmol) and DIPEA (4.00mmol) were dissolved in In NMP (10.0 mL), the resulting reaction solution was stirred at 120° C. for 16 hrs under the protection of argon. The reaction solution was cooled to room temperature, diluted with DCM (50.0 mL), and the organic phase was washed with water (40.0 mL×2) and saturated brine (40.0 mL) successively, dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM/MeOH=10/1) to obtain a crude product, which was then purified by Prep-HPLC (column: SunFire Prep C8 OBD 10um 19*250mm; mobile phase: A-0.1%FA in water, B -ACN; Gradient: B%=20%～47%; Flow rate: 20mL/min) to obtain the title compound (21.4mg, yield 8.10%, yellow solid). LC-MS (ESI) m/z: 653.1 [M+H] ⁺ . ¹ H NMR (400MHz,DMSO-d ₆ )δ11.83(s,1H),11.07(s,1H),8.61(m,1H),8.46(d,J=2.7Hz,1H),8.27(s, 1H),7.64–7.61(m,1H),7.50–7.48(m,1H),7.38(s,1H),7.30(s,1H),7.26–7.13(m,3H),5.08–5.03(m, 1H),4.42(s,1H),4.12–4.06(m,1H),3.96–3.93(m,1H),3.09–2.83(m,5H),2.79–2.70(m,1H),2.67–2.56( m,3H), 2.33–2.19(m,2H), 2.06–1.93(m,2H), 1.86–1.72(m,2H), 1.52–1.45(m,2H).

Example 74: 5-(3-(((R)-3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl) Methyl)piperidin-1-yl) -2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Step 1: 3-(((R)-3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)methyl)piper Synthesis of tert-butyl pyridine-1-carboxylate

Add TEA (387mg, 3.82mmol) to (R)-5-chloro-4-(1H-indol-3-yl-N-(pyrrolidin-3-yl)pyrimidin-2-amine (200mg , 0.640mmol) and tert-butyl 3-formylpiperidine-1-carboxylate (162mg, 0.760mmol) in DCE (6.00mL), after stirring at room temperature for 0.5hr, NaHB(OAc) ₃ (676mg, 3.19mmol) was added , then stirred at room temperature for 2hrs.The reaction mixture was concentrated under reduced pressure, and the residue was separated and purified by silica gel chromatography (DCM/MeOH=20/1) to obtain the target compound (274mg, yield 84.1%, colorless oil).LC-MS ( ESI) m/z: 511.3 [M+H] ⁺ .

Step 2: 5-Chloro-4-(1H-indol-3-yl)-N-((3R)-1-(piperidin-3-ylmethyl)pyrrolidin-3-yl)pyrimidine-2- Amine Synthesis

Slowly add HCl·MeOH (4N, 2.00mL) solution dropwise to 3-(((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino )pyrrolidin-1-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester (274 mg, 0.536 mmol) in MeOH (4.00 mL), then stirred at room temperature for 16 hrs. The reaction mixture was concentrated under reduced pressure to obtain the target compound (190 mg, yield 86.4%, yellow solid). LC-MS (ESI) m/z: 411.1 [M+H] ⁺ .

Step 3: 5-(3-(((R)-3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)methanol Synthesis of yl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Add DIPEA (252 mg, 1.95 mmol) to 5-chloro-4-(1H-indol-3-yl)-N-((3R)-1-(piperidin-3-ylmethyl)pyrrole at room temperature Alk-3-yl)pyrimidin-2-amine (160mg, 0.389mmol) and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (129 mg, 0.467 mmol) in DMSO (5.00 mL), then stirred at 130 °C for 3 hrs. After the reaction mixture was cooled to room temperature, it was concentrated under reduced pressure, and the residue was subjected to prep-HPLC (column: Waters Xbridge C18 10um OBD19*250mm; mobile phase: A-0.1% NH ₄ HCO ₃ aqueous solution, B-ACN; Gradient: B% =30%～55%; flow rate: 20 mL/min) separation and purification to obtain the title compound (22.2 mg, yield 13.9%, yellow solid). LC-MS (ESI) m/z: 667.2 [M+H] ⁺ . ¹ H NMR (400MHz,DMSO-d ₆ )δ11.82(s,1H),11.06(s,1H),8.75–8.53(m,1H),8.45(s,1H),8.27(d,J=1.7 Hz,1H),7.67–7.53(m,1H),7.47(s,1H),7.42(s,1H),7.29(s,1H),7.20–7.09(m,3H),5.10–4.99(m, 1H),4.43(s,1H),4.01–3.71(m,2H),3.18–3.05(m,1H),3.01–2.75(m,4H),2.75–2.63(m,1H),2.63–2.54( m,3H),2.46–2.11(m,3H),2.11–1.92(m,1H),1.92–1.73(m,3H),1.73–1.61(m,1H),1.63–1.36(m,1H), 1.36–0.91 (m,1H).

Example 75: 5-(4-((4-(2-((R)-3-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidine-2 -yl)amino)pyrrolidin- 1-yl)ethyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl) Isoindoline-1,3-dione, FA salt

Step 1: (R)-3-((5-Chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester Synthesis

Add DIPEA (1.87mg, 14.4mmol) to 2,5-dichloro-N-(2-(isopropylsulfonyl)phenyl)pyrimidin-4-amine (1.00g, 2.89mmol) and (R)- tert-butyl 3-aminopyrrolidine-1-carboxylate (808mg, 4.34mmol) in NMP (15.0mL), then stirred at 120°C overnight. After the reaction mixture was cooled to room temperature, it was diluted with water (100 mL), extracted with EA (100 mL×2), the organic phases were combined, dried with anhydrous _Na2SO4 , filtered, concentrated under reduced _pressure , and the residue was subjected to silica gel chromatography (PE/ EA=1/1) separation and purification to obtain the target compound (1.50 g, crude product, yellow solid). LC-MS (ESI) m/z: 496.2 [M+H] ⁺ .

HCl·MeOH (4N, 5.00 mL) solution was slowly added dropwise to (R)-3-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl )amino)pyrrolidine-1-carboxylic acid tert-butyl ester (1.50 g, 3.10 mmol) in MeOH (10.0 mL), then stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to obtain the title compound (1.38 g, crude product, yellow solid). LC-MS (ESI) m/z: 396.1 [M+H] ⁺ .

Step 3: (R)-4-(2-(3-((5-Chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)pyrrolidine- Synthesis of tert-butyl 1-yl)ethyl)piperidine-1-carboxylate

TEA (172 mg, 1.70 mmol) was added to (R)-5-chloro-N ⁴ -(2-(isopropylsulfonyl)phenyl)-N ² -(pyrrolidin-3-yl)pyrimidine-2, 4-Diamine (500mg, 1.27mmol) and 4-(2-oxoethyl)piperidine-1-carboxylic acid tert-butyl ester (2.62g, 11.5mmol) in DCE (10.0mL), stirred at room temperature for 0.5hr, and then NaHB(OAc) ₃ (1.07 g, 5.08 mmol) was added, followed by stirring at room temperature overnight under nitrogen protection. The reaction mixture was diluted with DCM (50.0 mL), washed with saturated aqueous NaHCO ₃ (50.0 mL) and water (50.0 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to obtain the target compound (800 mg, crude product, yellow oily liquid). LC-MS (ESI) m/z: 607.3 [M+H] ⁺ .

Step 4: (R)-5-Chloro-N ⁴ -(2-(isopropylsulfonyl)phenyl)-N ² -(1-(2-(piperidin-4-yl)ethyl)pyrrolidine Synthesis of -3-yl)pyrimidine-2,4-diamine

TFA (3.00 mL) was added to (R)-4-(2-(3-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl) Amino)pyrrolidin-1-yl)ethyl)piperidine-1-carboxylic acid tert-butyl ester (250 mg, 0.420 mmol) in DCM (8.00 mL), then stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, the residue was added saturated NaHCO ₃ aqueous solution (50.0 mL), extracted with DCM solution (50.0 mL), the organic phase was dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to obtain the title compound (230 mg, Crude product, yellow oily liquid). LC-MS (ESI) m/z: 507.23 [M+H] ⁺ .

Step 5: 5-(4-((4-(2-((R)-3-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidine-2- Base) amino) pyrrolidin-1-yl) ethyl) piperidin-1-yl) methyl) piperidin-1-yl) -2-(2,6-dioxopiperidin-3-yl) iso Synthesis of indoline-1,3-dione formate

A catalytic amount of acetic acid (2 drops) was added to (R)-5-chloro-N ⁴ -(2-(isopropylsulfonyl)phenyl)-N ² -(1-(2-(piperidine-4- Base) ethyl) pyrrolidin-3-yl) pyrimidine-2,4-diamine (100mg, 0.200mmol) and 1-(2-(2,6-dioxopiperidin-3-yl)-1, 3-dioxoisoindoline-5-yl)piperidine-4-carbaldehyde (332mg, 0.900mmol) in DCE (10.0mL), stirred for 0.5hr, then added NaHB(OAc) ₃ (128mg, 0.800mmol ), and stirred overnight at room temperature. The reaction mixture was diluted with DCM (50.0 mL), washed successively with aqueous NaHCO ₃ (50.0 mL) and brine (50.0 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure, and the residue was subjected to prep-HPLC (column: The title compound (14.5mg, Yield 8.42%, yellow solid). LC-MS (ESI) m/z: 860.3 [M+H] ⁺ . ¹ H NMR (400MHz,DMSO-d ₆ )δ11.15–10.99(m,1H),9.54–9.29(m,1H),8.93–8.49(m,1H),8.27(s,1H),8.13(s ,1H),7.87–7.79(m,1H),7.79–7.71(m,1H),7.68–7.61(m,1H),7.53–7.33(m,2H),7.32–7.28(m,1H),7.25 –7.17(m,1H),5.10–5.03(m,1H),4.30–4.10(m,1H),4.08–3.98(m,2H),3.00–2.91(m,3H),2.90–2.83(m,2H ),2.83–2.72(m,4H),2.43–2.372(m,3H),2.14–2.06(m,3H),2.02(dd,J＝8.2,5.2Hz,2H),1.86–1.73(m,6H ), 1.66–1.53(m,3H), 1.40–1.30(m,2H), 1.29–1.22(m,1H), 1.18(d,6H), 1.15–1.05(m,4H).

Example 76: 5-(4-((4-(2-((R)-3-((5-chloro-4-((2-(ethylsulfonyl)phenyl)amino)pyrimidine-2- Base) amino) pyrrolidin-1- yl) ethyl) piperidin-1-yl) methyl) piperidin-1-yl) -2-(2,6-dioxopiperidin-3-yl) iso Indoline-1,3-dione, FA salt

Step 1: Synthesis of (R)-3-((5-chloro-4-((2-(ethylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester

Add DIPEA (484 mg, 3.75 mmol) to 2,5-dichloro-N-(2-(ethylsulfonyl)phenyl)pyrimidin-4-amine (250 mg, 0.750 mmol) and (R)-3-aminopyrrole tert-butyl alkane-1-carboxylate (182mg, 0.975mmol) in NMP (12.0mL), then stirred at 120°C overnight. After the reaction mixture was cooled to room temperature, it was diluted with water (30.0 mL), extracted with EA (30.0 mL×2) The combined organic phases were taken, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel chromatography (PE/EA=1/1) to obtain the target compound (500 mg, yellow oily liquid), which was directly for the next reaction. LC-MS (ESI) m/z: 482.2 [M+H] ⁺ .

Step 2: Synthesis of (R)-5-chloro-N ⁴ -(2-(ethylsulfonyl)phenyl)-N ² -(pyrrolidin-3-yl)pyrimidine-2,4-diamine

TFA (4.00 mL) was slowly added dropwise to (R)-3-((5-chloro-4-((2-(ethylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)pyrrolidin-1 - in tert-butyl formate (450 mg, 0.930 mmol) in DCM (10.0 mL), then stirred at room temperature for 3 hrs. The reaction mixture was concentrated under reduced pressure, adjusted to pH 9-10 with NaHCO ₃ (1M) solution, extracted with DCM (50.0 mL×2), combined organic phases, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to obtain the target The compound (388mg, yellow oily liquid) was directly used in the next reaction. LC-MS (ESI) m/z: 382.1 [M+H] ⁺ .

Step 3: 5-(4-((4-(2-((R)-3-((5-chloro-4-((2-(ethylsulfonyl)phenyl)amino)pyrimidin-2-yl) Amino)pyrrolidin-1-yl)ethyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole Synthesis of Phenyl-1,3-Diketone Formate

2-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidine-4- Base)methyl)piperidin-4-yl)acetaldehyde (40.0mg, 80.0mmol) was added to (R)-5-chloro-N ⁴ -(2-(ethylsulfonyl)phenyl)-N ² -( Pyrrolidin-3-yl)pyrimidine-2,4-diamine (27.0mg, 70.0mmol) in DCM (2.50mL)/MeOH (2.50mL), after stirring at room temperature for 5hrs, NaHB(OAc) ₃ (45.0mg , 0.210mmol), then stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, diluted with DCM (30.0 mL), washed successively with saturated aqueous NaHCO ₃ (30.0 mL) and brine (30.0 mL), dried over anhydrous Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and the residue was subjected to prep -HPLC (column: SunFire Prep C8 OBD 10um 19*250mm; Mobile phase: A-0.1% FA aqueous solution, B-ACN; Gradient: B%=5%～35%; Flow rate: 20mL/min) separation and purification, obtain title Compound (7.18 mg, yield 6.89%, yellow solid, formate salt). LC-MS (ESI) m/z: 846.3 [M+H] ⁺ . ¹ H NMR (400MHz,DMSO-d ₆ )δ11.08(s,1H),9.36(s,1H),8.95–8.55(m,1H),8.27(s,1H),8.12(s,1H), 7.89–7.83(m,1H),7.78–7.71(m,1H),7.67–7.62(m,1H),7.38–7.31(m,2H),7.30(d,J＝1.7Hz,1H),7.26– 7.19(m,1H),5.09–5.01(m,1H),4.30–4.11(m,2H),4.07–3.96(m,3H),3.01–2.86(m,3H),2.86–2.73(m,4H ),2.10(t,J＝7.1Hz,3H),2.05–1.97(m,1H),1.88–1.67(m,8H),1.65–1.50(m,3H),1.40–1.21(m,4H), 1.18–1.13(m,2H),1.13–1.00(m,7H).

Example 77: 5-(4-((4-(2-((R)-3-((5-chloro-4-((2-(methylsulfonyl)phenyl)amino)pyrimidine-2- Base) amino) pyrrolidin-1- yl) ethyl) piperidin-1-yl) methyl) piperidin-1-yl) -2-(2,6-dioxopiperidin-3-yl) iso Indoline-1,3-dione, TFA salt

Step 1: 5-(4-((4-(2-((R)-3-((5-chloro-4-((2-(thysulfonyl)phenyl)amino)pyrimidin-2-yl) Amino)pyrrolidin-1-yl)ethyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole Synthesis of Phenyl-1,3-dione Trifluoroacetate

A catalytic amount of acetic acid (3 drops) was added to (R)-5-chloro-N ⁴ -(2-(methylsulfonyl)phenyl)-N ² -(1-(2-(piperidin-4-yl) Ethyl)pyrrolidin-3-yl)pyrimidine-2,4-diamine (120mg, 0.250mmol) and 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-di Oxyisooctanol-5-yl)piperidine-4-carbaldehyde (186mg, 0.500mmol) in DCE (10.0mL), stirred for 1hr, then added NaHB(OAc) ₃ (212mg, 1.00 mmol), then stirred overnight at room temperature. The reaction mixture was diluted with DCM (50.0 mL), washed successively with aqueous NaHCO ₃ (50.0 mL) and brine (50.0 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure, and the residue was subjected to prep-HPLC (column: The title compound (4.40mg, Yield 2.11%, yellow solid). LC-MS (ESI) m/z: 832.3 [M+H] ⁺ . ¹ H NMR (400MHz,DMSO-d ₆ )δ11.09(s,1H),9.98(s,1H),9.32(d,J=7.0Hz,1H),9.03(s,1H),8.52(s, 1H), 8.19(s, 1H), 7.93(dd, J=8.0, 1.4Hz, 1H), 7.76(t, J=7.5Hz, 1H), 7.68(d, J=8.5Hz, 1H), 7.38( dd,J=14.8,7.0Hz,2H),7.31–7.21(m,1H),5.07(dd,J=12.8,5.4Hz,1H),4.41(s,1H),4.09(d,J=12.7Hz ,2H),3.65-3.62(m,6H),3.27(s,3H),3.21-3.18(m,3H),3.06–2.94(m,4H),2.93–2.83(m,2H),2.72–2.53 (m,2H),2.11(s,2H),2.07–1.95(m,2H),1.85-1.81(m,4H),1.56(s,2H),1.46-1.42(m,2H),1.28-1.27 (m,3H). ¹⁹ F NMR (377 MHz, DMSO-d ₆ ) δ-73.86(s).

Example 78: 5-(4-((4-(2-((R)-3-((5-chloro-4-((2-(dimethylphosphono)phenyl)amino)pyrimidine-2 -yl)amino)pyrrolidin- 1-yl)ethyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl) Isoindoline-1,3-dione, TFA salt

Step 1: (R)-tert-butyl 3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)pyrrolidine-1-carboxylate Synthesis

DIPEA (1.04 mg, 8.00 mmol) was added to (2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (500 mg, 1.60 mmol) and (R)-3 -Aminopyrrolidine-1-carboxylic acid tert-butyl ester (596 mg, 3.20 mmol) in NMP (7.00 mL), then stirred at 120° C. overnight. The reaction mixture was cooled to room temperature and quenched with water (50.0 mL), extracted with EA (50.0 mL×2), combined organic phases, dried over anhydrous Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and the residue was subjected to silica gel chromatography (DCM /MeOH=40/1) separation and purification to obtain the target compound (900 mg, crude product, yellow liquid). LC-MS (ESI) m/z: 466.20 [M+H] ⁺ .

Add HCl·MeOH (4N, 5.00 mL) solution dropwise to (R)-3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl) Amino)pyrrolidine-1-carboxylic acid tert-butyl ester (900mg, 1.93mmol) in MeOH (10.0mL), then stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to obtain the title compound (706 mg, crude product, yellow liquid). LC-MS (ESI) m/z: 366.10 [M+H] ⁺ .

Step 3: (R)-4-(2-(3-((5-Chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)pyrrolidine- Synthesis of tert-butyl 1-yl)ethyl)piperidine-1-carboxylate

Add Et ₃ N (498 mg, 4.92 mmol) to (R)-(2-((5-chloro-2-(pyrrolidin-3-ylamino)pyrimidin-4-yl)amino)phenyl)dimethyl Phosphine oxide (300mg, 0.820mmol) and tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate (1.50g, 6.56mmol) in DCE (10.0mL), stirred at room temperature for 0.5hr, added NaHB ( OAc) ₃ (695mg, 3.28mmol), then stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, diluted by adding DCM (30.0 mL), washed with saturated aqueous NaHCO ₃ (30.0 mL) and water (30.0 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to obtain the title compound (217 mg , yield 45.8%, yellow solid). LC-MS (ESI) m/z: 577.30 [M+H] ⁺ .

Step 4: (R)-(2-((5-Chloro-2-((1-(2-(piperidin-4-yl)ethyl)pyrrolidin-3-yl)amino)pyrimidin-4-yl ) amino) phenyl) dimethyl phosphine oxide synthesis

Add HCl·MeOH (4N, 5.00mL) solution dropwise to (R)-4-(2-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino) Pyrimidin-2-yl)amino)pyrrolidin-1-yl)ethyl)piperidine-1-carboxylic acid tert-butyl ester (400 mg, 0.700 mmol) in MeOH (8.00 mL), then stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, adjusted to pH 9-10 with 1M NaHCO ₃ aqueous solution, extracted with DCM (50.0 mL×2), combined organic phases, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to obtain the title compound (333 mg , crude product, pale yellow solid). LC-MS (ESI) m/z: 477.20 [M+H] ⁺ .

Step 5: 5-(4-((4-(2-((R)-3-)((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidine-2 -yl)amino)pyrrolidin-1-yl)ethyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl) Synthesis of Isoindoline-1,3-dione Trifluoroacetate

Add 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carbaldehyde (231mg, 0.625mmol) To (R)-(2-((5-chloro-2-((1-(2-(piperidin-4-yl)ethyl)pyrrolidin-3-yl)amino)pyrimidin-4-yl)amino ) phenyl) dimethylphosphine oxide (120mg, 0.250mmol) in DCM (3.00mL)/MeOH (3.00mL), stirred at room temperature for 1hr, added NaHB(OAc) ₃ (159mg, 0.750mmol), then stirred at room temperature Over night, the reaction mixture was concentrated under reduced pressure, DCM (30.0 mL) was added, washed with saturated NaHCO ₃ aqueous solution (30.0 mL) and brine (30.0 mL), the organic phase was dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to obtain a residue The material was separated and purified by prep-HPLC (column: SunFire Prep C8 OBD 10um 19*250mm; mobile phase: A-0.1% TFA aqueous solution, B-ACN; gradient: B%=15%～45%; flow rate: 20mL/min) , to obtain the title compound (10.4 mg, yield 5.03%, yellow solid). LC-MS (ESI) m/z: 830.3 [M+H] ⁺ . ¹ H NMR (400MHz,DMSO-d ₆ )δ11.19–11.12(m,1H),11.09(s,1H),10.19–9.91(m,1H),9.22–8.96(m,1H),8.78–8.45 (m,1H),8.10(s,1H),7.72–7.65(m,1H),7.63–7.52(m,2H),7.35(s,1H),7.30–7.24(m,1H),7.21–7.13 (m,1H),5.13–5.01(m,1H),4.55–4.37(m,1H),4.15–4.00(m,2H),4.00–3.66(m,2H),3.27–3.13(m,5H) ,3.10–2.93(m,5H),2.92–2.71(m,3H),2.21–1.96(m,4H),1.92–1.74(m,11H),1.69–1.51(m,4H),1.49–1.36( m,2H), 1.32–1.20(m,2H). ¹⁹ F NMR (377 MHz, DMSO-d ₆ ) δ-73.93(s).

Example 79: 3-((4-(4-((4-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl )amino)pyrrolidin-1-yl)ethyl)piperidin- 1-yl)methyl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione

Step 1: Synthesis of 4-(((tert-butyldimethylsilyl)oxy)methyl)piperidine

At 0°C, TBSCl (21.6 g, 143 mmol) was added to 4-hydroxymethylpiperidine (15.0 g, 130 mmol) in DCM (50.0 mL), followed by DMAP (1.59 mg, 13.0 mmol) and Et3N (15.8 g , 156mmol), then stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was separated and purified by silica gel chromatography (MeOH/DCM=1/19) to obtain the target compound (19.3 g, yield 64.6%, white solid). LC-MS (ESI) m/z: 230.2 [M+H]+.

Step 2: Synthesis of (1-(4-nitrophenyl)piperidin-4-yl)methanol

1-Fluoro-4-nitrobenzene (2.31 g, 16.3 mmol) and DIPEA (4.22 g, 32.7 mmol) were added to 4-(((tert-butyldimethylsilyl)oxy)methyl ) piperidine (500 mg, 0.692 mmol) in DMSO (20.0 mL), then stirred at 130° C. for 3 hrs. After the reaction mixture was cooled to room temperature, it was concentrated under reduced pressure, and the residue was separated and purified by silica gel chromatography (EA/PE=1/1) to obtain the target compound (2.10 g, yield 81.7%, yellow solid). LC-MS (ESI) m/z: 237.1 [M+H] ⁺ .

Step 3: Synthesis of 1-(4-nitrophenyl)piperidine-4-carbaldehyde

Dess-Martin (7.00 g, 16.5 mmol) was added to (1-(4-nitrophenyl)piperidin-4-yl)methanol (1.30 g, 5.50 mmol) in DCM (30.0 mL) at room temperature, It was then stirred at 50 °C for 3 hrs. The reaction mixture was concentrated under reduced pressure, and the residue was separated and purified by silica gel chromatography (EA/PE=1/1) to obtain the target compound (713 mg, yield 55.3%, yellow solid). LC-MS (ESI) m/z: 235.1 [M+H] ⁺ .

Step 4: (R)-5-Chloro-4-(1H-indol-3-yl)-N-(1-(2-(1-((1-(4-nitrophenyl)piperidine- Synthesis of 4-yl)methyl)piperidin-4-yl)ethyl)pyrrolidin-3-yl)pyrimidin-2-amine

NaBH(OAc) ₃ (814mg, 3.84mmol) was added to 1-(4-nitrophenyl)piperidine-4-carbaldehyde (300mg, 1.28mmol) and (R)-5-chloro-4- (1H-indol-3-yl)-N-(1-(2-(piperidin-4-yl)ethyl)pyrrolidin-3-yl)pyrimidin-2-amine (708mg, 1.66mmol) in DMSO (10.0 mL), then stirred at room temperature for 5 hrs. The reaction mixture was concentrated under reduced pressure, and the residue was separated and purified by silica gel chromatography (MeOH/DCM=1/19) to obtain the target compound (363 mg, yield 56.4%, yellow solid). LC-MS (ESI) m/z: 643.4 [M+H] ⁺ .

Step 5: (R)-N-(1-(2-(1-((1-(4-aminophenyl)piperidin-4-yl)methyl)piperidin-4-yl)ethyl)pyrrole Synthesis of alk-3-yl)-5-chloro-4-(1H-indol-3-yl)pyrimidin-2-amine

At room temperature, zinc powder (184mg, 2.82mmol) was added to (R)-5-chloro-4-(1H-indol-3-yl)-N-(1-(2-(1-((1- (4-nitrophenyl)piperidin-4-yl)methyl)piperidin-4-yl)ethyl)pyrrolidin-3-yl)pyrimidin-2-amine (363 mg, 0.564 mmol) and NH ₄ Cl (151 mg, 2.82 mmol) in EtOH/water (10.0 mL, 4/1), then stirred at 80 °C for 3 hrs. After the reaction mixture was cooled to room temperature, it was filtered and concentrated under reduced pressure. The residue was separated and purified by silica gel chromatography (MeOH/DCM=1/19) to obtain the target compound (317 mg, yield 91.6%, white solid). LC-MS (ESI) m/z: 613.4 [M+H] ⁺ .

Step 6: 3-((4-(4-((4-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl) Synthesis of amino)pyrrolidin-1-yl)ethyl)piperidin-1-yl)methyl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione

At 0°C, (R)-N-(1-(2-(1-((1-(4-aminophenyl)piperidin-4-yl)methyl)piperidin-4-yl)ethyl )pyrrolidin-3-yl)-5-chloro-4-(1H-indol-3-yl)pyrimidin-2-amine (100mg, 0.163mmol) was added to 3-bromopiperidine-2,6-dione (63mg, 0.326mmol) and NaHCO ₃ (41.0mg, 0.489mmol) in DMF (5.00mL), then stirred at 60°C overnight. After the reaction mixture was cooled to room temperature, it was filtered, and the filtrate was subjected to Prep-HPLC (column: Waters Xbridge C18 10um OBD 19*250mm; mobile phase: A-water (0.1% TFA)/B-CH ₃ CN; B%=5%- 40%; flow rate: 20mL/min) separation and purification to obtain the title compound (17.23mg, yield 14.6%, yellow solid). LC-MS (ESI) m/z: 724.5 [M+H] ⁺ . ¹ H NMR (400MHz,DMSO-d ₆ )δ11.96(s,1H),10.83(s,1H),10.50–10.10(m,1H),9.83–9.41(m, 1H),8.75–8.39(m,2H),8.35(s,1H),7.82–7.47(m,2H),7.46–7.30(m,2H),7.29–7.14(m,2H),6.78(d, J＝8.0Hz,2H),4.79–4.52(m,1H),4.49–4.31(m,1H),4.17–3.96(m,1H),3.94–3.69(m,4H),3.36–3.12(m, 6H),3.16–2.98(m,3H),2.97–2.82(m,2H),2.82–2.66(m,1H),2.69–2.55(m,1H),2.39–2.17(m,2H),2.17– 1.98(m,4H), 1.99–1.78(m,3H), 1.78–1.54(m,5H), 1.56–1.38(m,2H).

Example 80: (R)-1-(4-(4-((4-(2-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl) Amino)pyrrolidin-1-yl)ethyl)piperidin -1-yl)methyl)piperidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

Step 1: Synthesis of ethyl 3-((4-(4-((tert-butyldimethylsilyloxy)methyl)piperidin-1-yl)phenyl)amino)propanoate (1.12g, 12.5mmol) was added to DBU (1.90g, 12.5mmol), and after stirring for 2hrs, the mixture was added to 4-(4-((tert-butyldimethylsilyloxy)methyl)piperidine -1-yl)aniline (2.00g, 6.24mmol), after stirring for 5 minutes, ethyl acrylate (6.25g, 62.4mmol) was added, and then stirred overnight at 80°C. After the reaction mixture was cooled to room temperature, it was quenched with water (50.0 mL), extracted with EA (100 mL×2), the organic phases were combined, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure, and the residue was subjected to silica gel chromatography (PE /EA=10/1～1/1) separation and purification to obtain the target compound (389 mg, yield 14.8%, brown solid). LC-MS (ESI) m/z: 421.3 [M+H] ⁺ .

Step 2: Synthesis of ethyl 3-(N-(4-(4-((tert-butyldimethylsilyloxy)methyl)piperidin-1-yl)phenyl)cyanamido)propionate

CNBr (816 mg, 7.69 mmol) was added to 3-((4-(4-((tert-butyldimethylsilyloxy)methyl)piperidin-1-yl)phenyl)amino)propane at room temperature ethyl acetate (1.08 g, 2.56 mmol) and NaOAc (1.05 g, 12.8 mmol) in EtOH (40.0 mL), then stirred at 95 °C overnight. After the reaction mixture was cooled to room temperature, it was quenched with water (50.0 mL), extracted with EA (100 mL), the organic phases were combined, dried over anhydrous Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and the residue was subjected to silica gel chromatography (PE/EA =10/1～4/1) separation and purification to obtain the target compound (837 mg, yield 73.3%, brown oil). LC-MS (ESI) m/z: 446.3 [M+H] ⁺ .

Step 3: Synthesis of ethyl 3-(1-(4-(4-((tert-butyldimethylsilyloxy)methyl)piperidin-1-yl)phenyl)ureido)propanoate

Ethyl (3-(N-(4-(4-((tert-butyldimethylsilyloxy)methyl)piperidin-1-yl)phenyl)cyanamido)propionate (837mg, 1.88 mmol) was added to indium chloride (42.0mg, 0.188mmol) and acetaldehyde oxime (333mg, 5.64mmol) in toluene (15.0mL), then stirred at 120°C for 1hr. After the reaction mixture was cooled to room temperature, water (50.0 mL) was quenched, extracted with EA (100mL×2), the organic phases were combined, dried over anhydrous Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and the residue was subjected to silica gel chromatography (PE/EA=10/1～1/1 ) separation and purification to obtain the target compound (476 mg, yield 54.6%, brown oil). LC-MS (ESI) m/z: 464.3 [M+H] ⁺ .

Step 4: 1-(4-(4-((tert-Butyldimethylsilyloxy)methyl)piperidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-di Ketone synthesis

Triton-B (40% in MeOH, 646 mg, 1.55 mmol) was added dropwise to 3-(1-(4-(4-((tert-butyldimethylsilyloxy)methyl)piperidine- 1-yl)phenyl)ureido)propanoic acid ethyl ester (476 mg, 1.03 mmol) in CH ₃ CN (15.0 mL), It was then stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, quenched with water (50.0 mL), extracted with EA (100 mL×2), combined organic phases, dried over anhydrous Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and the residue was subjected to silica gel chromatography (PE/ EA=10/1～1/1) separation and purification to obtain the target compound (450 mg, crude product, yellow oil), which was directly used in the next reaction. LC-MS (ESI) m/z: 418.3 [M+H] ⁺ .

Step 5: Synthesis of 1-(4-(4-(hydroxymethyl)piperidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

At room temperature, TBAF (275 mg, 1.05 mmol) was added to 1-(4-(4-((tert-butyldimethylsilyloxy)methyl)piperidin-1-yl)phenyl)dihydropyrimidine- 2,4(1H,3H)-diketone (400 mg, 0.958 mmol) in THF (6.00 mL), then stirred at room temperature for 1 hr. The reaction mixture was quenched with water (50.0 mL), extracted with DCM (100 mL×2), the organic phases were combined, dried over anhydrous Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and the residue was subjected to silica gel chromatography (DCM/MeOH=30/ 1) Separation and purification to obtain the target compound (400 mg, crude product, yellow oil). LC-MS (ESI) m/z: 304.2 [M+H] ⁺ .

Step 6: Synthesis of (1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl 4-methylbenzenesulfonate

Add p-toluenesulfonyl chloride (358 mg, 1.88 mmol) to 1-(4-(4-(hydroxymethyl)piperidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H )-diketone (190 mg, 0.626 mmol), Et ₃ N (158 mg, 1.56 mmol) and DMAP (305 mg, 2.50 mmol) in DCM (23.0 mL), then stirred at 50° C. for 4 hrs. After the reaction mixture was cooled to room temperature, it was quenched with water (50.0 mL), extracted with EA (100 mL), dried over anhydrous Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and the residue was subjected to Prep-TLC (DCM/MeOH=12/1 ) to obtain the target compound (64.0 mg, crude product, yellow oil). LC-MS (ESI) m/z: 458.2 [M+H] ⁺ .

Step 7: (R)-1-(4-(4-(2-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidine- Synthesis of 1-yl)ethyl)piperidin-1-yl)methyl)piperidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

Add DIPEA (54.2 mg, 0.420 mmol) to (1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methanol at room temperature 4-methylbenzenesulfonate (64.0mg, 0.140mmol) and (R)-5-chloro-4-(1H-indol-3-yl)-N-(1-(2-(piperidine- 4-yl)ethyl)pyrrolidin-3-yl)pyrimidin-2-amine (59.0mg, 0.140mmol) in DMSO (6.00mL), then stirred at 80°C for 3hrs. After the reaction mixture was cooled to room temperature, it was filtered, and the filtrate was subjected to Prep-HPLC (column: SunFire Prep C8 OBD 10um 19*250mm; mobile phase: A-water (0.1% FA)/B-ACN; B%=5%-25% ; flow rate: 20mL/min) separation and purification to obtain the title compound (1.68mg, yield 3.58%, white solid). LC-MS (ESI) m/z: 710.4 [M+H] ⁺ . ¹ H NMR (400MHz,DMSO-d ₆ )δ11.87(s,1H),10.21(s,1H),8.78–8.42(m,2H),8.37–8.21(m,3H),7.59–7.33(m ,2H),7.28–7.04(m,4H),6.49(d,J＝8Hz,2H),3.75–3.62(m,4H),3.32–3.14(m,6H),3.00–2.79(m,4H) ,2.76–2.61(m,3H),2.45–2.35(m,2H),2.30–2.18(m,2H),2.16–2.06(m,1H),2.05–1.90(m,2H),1.86–1.77( m,1H), 1.71–1.54(m,5H), 1.47–1.29(m,3H), 1.24–1.10(m,2H).

Example 81: 3-((4-(4-((3-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl )amino)pyrrolidin-1-yl)ethyl)azetidin- 1-yl)methyl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione

Example 82: 3-((4-(3-((4-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl )amino)pyrrolidin-1-yl)ethyl)piperidin- 1-yl)methyl)azetidin-1-yl)phenyl)amino)piperidine-2,6-dione

Example 83: 3-((4-(4-(3-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl) Amino)pyrrolidin-1-yl)ethyl)azetidin-1-yl) piperidin-1-yl)phenyl)amino)piperidine-2,6-dione

Example 84: 3-((4-(3-(4-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl) Amino)pyrrolidin-1-yl)ethyl)piperidin- 1-yl)azetidin-1-yl)phenyl)amino)piperidine-2,6-dione

Example 85: 3-((4-(3-(2-((R)-3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrole Alk-1-yl)ethyl)-[1,3'- diazetidine]-1'-yl)phenyl)amino)piperidine-2,6-dione

Example 86: 5-(4-((1-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrole Alkyl-1-yl)-1,1-difluoroethyl )piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl ) Isoindoline-1,3-dione

Example 87: 5-(4-((1-(1-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrole Alkyl-1-yl)-2-methylpropan- 2-yl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidine-3 -yl)isoindoline-1,3-dione

Example 88: 5-(4-((1-(3-(((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino) Pyrrolidin-1-yl)methyl)oxetan- 3-yl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidine -3-yl)isoindoline-1,3-dione

Example 89: 5-(4-((4-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrole Alkyl-1-yl)ethyl)-4- hydroxypiperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)iso Indoline-1,3-dione

Step 1: (R)-4-(2-(3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)ethyl ) Synthesis of piperidin-4-ol

TFA (3.00 mL) was added to (R)-4-(2-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1 -yl)ethyl)-tert-butyl 4-hydroxypiperidine-1-carboxylate (55.0 mg, 0.101 mmol) in DCM (8.00 mL), then stirred at room temperature for 3 hrs. The reaction mixture was concentrated under reduced pressure to obtain the title compound (53.0 mg, crude product, yellow oily solid). LC-MS (ESI) m/z: 441.2 [M+H] ⁺ .

Step 2: 5-(4-((4-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidine -1-yl))ethyl)-4-hydroxypiperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoind Synthesis of Indoline-1,3-dione

1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidine-4-carbaldehyde (40.0mg, 0.110mmol ) to (R)-4-(2-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)ethyl ) piperidin-4-ol (40.0mg, 0.0900mmol) in DMSO (3.00mL), after stirring for 0.5hr, NaHB(OAc) ₃ (76.3mg, 0.360mmol) was added, It was then stirred overnight at 30°C. The reaction mixture was quenched with water (50.0 mL), extracted with EA (70.0 mL×2), the organic phases were combined, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure, and the residue was subjected to Prep-HPLC (column: SunFire Prep C8 OBD 10um 19*250mm; mobile phase: A-water (0.1%TFA)/B-CH ₃ CN; B%=15%-35%; flow rate: 20mL/min) separation and purification to obtain the title compound (4.28mg, yield Yield 5.99%, yellow solid). LC-MS (ESI) m/z: 794.5 [M+H] ⁺ . ¹ H NMR (400MHz, MeOD-d ₄ )δ8.61–8.53(m,1H),8.46(s,1H),8.35–8.25(m,1H),7.68(d,J＝8.3Hz,1H), 7.53–7.44(m,1H),7.40–7.32(m,1H),7.28–7.15(m,3H),4.14–4.03(m,3H),3.52–3.46(m,7H),3.14–2.98(m ,3H), 2.87–2.64(m,3H), 2.23–2.07(m,2H), 1.98–1.88(m,8H), 1.47–1.39(m,4H), 1.36–1.20(m,5H).

Example 90: 5-(4-((4-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrole Alkyl-1-yl)ethyl)-4-fluoropiperidin -1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindol Indoline-1,3-dione

Example 91: 3-(4-(4-((4-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl) Amino)pyrrolidin-1-yl)ethyl)piperidin-1-yl)methyl) piperidin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzene [d]imidazol-1-yl)piperidine-2,6-dione

Example 92: 3-(4-(3-((1-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl) Amino)pyrrolidin-1-yl)ethyl)piperidin- 4-yl)oxy)propane-1-yn-1-yl)-3-methyl-2-oxo-2,3-dihydro- 1H-Benzo[d]imidazol-1-yl)piperidine-2,6-dione

Example 93: (R)-1-(4-(4-((4-((3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino) Pyrrolidin-1-yl)ethyl)piperidin- 1-yl)methyl)piperidin-1-yl)benzyl)dihydropyrimidine-2,4(1H,3H)-dione

Example 94: 5-(4-((4-(((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidine- 1-yl)methyl)-4-hydroxypiperidin -1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline -1,3-Diketone, FA salt

Step 1: (R)-4-((3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)methyl)- Synthesis of tert-butyl 4-hydroxypiperidine-1-carboxylate

tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (136 mg, 0.639 mmol) was added to (R)-5-chloro-4-(1H-indol-3-yl) -Nitro-pyrrolidin-3-yl)pyrimidin-2-amine (200mg, 0.639mmol) in isopropanol (1.50mL) was added dropwise with DIPEA (0.70mL), then stirred overnight at 90°C under nitrogen protection. After the reaction mixture was cooled to room temperature, it was diluted with water (200 mL), extracted with DCM (200 mL×3), the organic phases were combined, concentrated under reduced pressure, and the residue was separated and purified by silica gel chromatography (DCM/MeOH=10/1) to obtain the title compound (220mg, yield 65.5%, white solid). LC-MS (ESI) m/z: 528.0 [M+H] ⁺ .

Step 2: (R)-4-((3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)methyl)piper Synthesis of Pyridin-4-ol

Add TFA (2.00 mL) to (R)-4-((3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl )methyl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (220mg, 0.418mmol) in DCM (6.00mL), then stirred at room temperature for 2hrs under nitrogen protection. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the target compound (177 mg, yield 99.4%, white solid). LC-MS (ESI) m/z: 427.2 [M+H] ⁺ .

Step 3: 5-(4-((4-(((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1 -yl)methyl)-4-hydroxypiperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline- Synthesis of 1,3-diketoformate

(R)-4-((3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)methyl)piperidine- 4-alcohol (240mg, 0.562mmol), 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidine-4- Add formaldehyde (416mg, 1.12mmol) and triethylamine (74mg, 0.731mmol) to DCE (6.00mL)/MeOH (6.00mL), stir at room temperature for 1hr, then add NaHB(OAc) ₃ (357mg, 1.69mmol), It was then stirred at room temperature for 3 hrs. The reaction solution was concentrated under reduced pressure, and the residue was sequentially subjected to silica gel chromatography (DCM/MeOH=8/1, 1% ammonia water), Prep-HPLC (column: SunFire Prep C8 OBD 10um 19*250mm; mobile phase: A-water (0.1 %FA)/B-CH ₃ CN; B%=5%～35%; flow rate: 20mL/min) was separated and purified to obtain the title compound (108mg, yield 24.5%, yellow solid). LC-MS (ESI) m/z: 780.3 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.85(s, 1H), 11.07(s, 1H), 8.72–8.53(m, 1H), 8.46(d, J=3.0Hz, 1H), 8.26( s,1H),8.21(s,1H),7.65(d,J＝8.6Hz,1H),7.49(d,J＝7.9Hz,1H),7.44–7.35(m,1H),7.33–7.27(m ,1H),7.26–7.12(m,3H),5.13–5.00(m,1H),4.50–4.27(m,1H),4.02(d,J=12.6Hz,2H),3.12–3.00(s,1H ),2.99–2.79(m,4H),2.77–2.62(m,2H),2.63–2.53(m,3H),2.49–2.44(m,3H),2.44–2.33(m,3H),2.29–2.22 (m,2H),2.22–2.13(m,1H),2.06–1.96(m,1H),1.89–1.73(m,4H),1.64–1.54(m,2H),1.54–1.43(m,2H) ,1.21–1.04(m,2H).

Example 95: 5-(4-((4-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrole Alkyl-1-yl)ethyl)piperidin- 1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindo Indoline-1,3-dione

Step 1: 3-(5-(4-((4-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino ) pyrrolidin-1-yl) ethyl) piperidin-1-yl) methyl) piperidin-1-yl)-6-fluoro-1-oxoisoindoline-2-yl) piperidine-2 , Synthesis of 6-diketone FA salt

1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-3-oxoisoindoline-5-yl)piperidine-4-carbaldehyde (61.7mg, 0.145 mmol) to (R)-5-chloro-4-(1H-indol-3-yl)-N-(1-(2-(piperidin-4-yl) ethyl)pyrrolidin-3-yl ) pyrimidin-2-amine (65.0mg, 0.174mmol) in DMSO (5.00mL), after stirring for 40 minutes, NaHB(OAc) ₃ (123mg, 0.580mmol) was added, then stirred overnight at 30°C. The reaction mixture was quenched with water (50.0 mL), extracted with EA (30.0 mL×2), the organic phases were combined, dried with anhydrous Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and the residue was subjected to prep-HPLC (column: SunFire Prep C8 OBD 10um 19*250mm; mobile phase: A-0.1% FA aqueous solution, B-ACN; gradient: B% = 25% ~ 45%; flow rate: 20mL/min) separation and purification to obtain the title compound (21.5mg, yield 19.0%, white solid, FA salt). LC-MS (ESI) m/z: 796.2 [M+H] ⁺ . ¹ H NMR (400MHz,DMSO-d ₆ )δ11.84(s,1H),11.11(s,1H),8.47(s,1H),8.27(s,1H),8.20(s,1H),7.70( d,J＝11.0Hz,1H),7.56–7.27(m,3H),7.21-7.18(m,2H),5.11-5.09(m,1H),4.41(brs,1H),3.61-3.56(m, 2H),2.88-2.86(m,6H),2.68(s,2H),2.21-2.16(m,4H),2.05-2.01(m,2H),1.86-1.84(m,7H),1.69-1.58( m,3H), 1.38-1.34(m,2H), 1.28-1.24(m,6H).

Example 96: 5-(3-((4-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrole Alkyl-1-yl)ethyl)piperidin- 1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1 ,3-Diketone,TFA salt

Step 1: 3-((4-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1- Synthesis of tert-butyl)ethyl)piperidin-1-yl)methyl)piperidine-1-carboxylate

At room temperature, TEA (215 mg, 2.12 mmol) was added to (R)-5-chloro-4-(1H-indol-3-yl)-N-(1-(2-(piperidin-4-yl) Ethyl)pyrrolidin-3-yl)pyrimidin-2-amine (180mg, 0.424mmol) and tert-butyl 3-formylpiperidine-1-carboxylate (109mg, 0.509mmol) in DCE (6.00mL), room temperature Stir for 0.5 hr, then add NaHB(OAc) ₃ (360 mg, 1.70 mmol), then stir at room temperature for 2 hrs. The reaction mixture was concentrated under reduced pressure, and the residue was separated and purified by silica gel chromatography (DCM/MeOH=10/1) to obtain the target compound (228 mg, yield 86.7%, colorless oil). LC-MS (ESI) m/z: 622.4 [M+H] ⁺ .

Step 2: 5-Chloro-4-(1H-indol-3-yl)-N-((3R)-1-(2-(1-(piperidin-3-ylmethyl)piperidine-4- Synthesis of base)ethyl)pyrrolidin-3-yl)pyrimidin-2-amine

Add HCl·MeOH (4N, 2.00mL) solution dropwise to 3-((4-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidine- 2-yl)amino)pyrrolidin-1-yl)ethyl)piperidin-1-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester (228 mg, 0.334 mmol) in MeOH (3.00 mL), then Stir at room temperature for 16 hrs. The reaction mixture was concentrated under reduced pressure to obtain the target compound (205 mg, yield 89.9%, yellow solid). LC-MS (ESI) m/z: 522.3 [M+H] ⁺ .

Step 3: 5-(3-((4-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidine -1-yl)ethyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1, Synthesis of 3-diketone trifluoroacetate

Add DIPEA (65.0 mg, 0.503 mmol) to 5-chloro-4-(1H-indol-3-yl)-N-((3R)-1-(2-(1-(piperidine- 3-ylmethyl)piperidin-4-yl)ethyl)pyrrolidin-3-yl)pyrimidin-2-amine (87.5mg, 0.168mmol) and 2-(2,6-dioxopiperidine-3 -yl)-5-fluoroisoindoline-1,3-dione (69.4mg, 0.251mmol) in DMSO (4.00mL), then stirred at 130°C for 2hrs. The reaction mixture was cooled to room temperature and filtered, and the filtrate was subjected to prep-HPLC (column: SunFire Prep C8 OBD 10um 19*250mm; mobile phase: A-0.1% TFA aqueous solution, B-ACN; gradient: B%=10%～29%; Flow rate: 20 mL/min) separation and purification to obtain the title compound (20.8 mg, yield 18.2%, yellow solid). LC-MS (ESI) m/z: 778.4 [M+H] ⁺ . ¹ H NMR (400MHz,DMSO-d ₆ )δ11.92(s,1H),11.08(s,1H),9.95(s,1H),9.07(s,1H),8.68–8.53(m,1H), 8.54–8.45(m,1H),8.43–8.26(m,1H),7.73–7.67(m,1H),7.55–7.47(m,1H),7.42–7.33(m,1H),7.32–7.12(m ,3H),5.13–5.01(m,1H),4.69–4.54(m,1H),4.10–4.00(m,2H),3.97–3.90(m,2H),3.45–3.37(m,1H),3.28 –3.18(m,4H),3.13–3.04(m,2H),3.02–2.91(m,2H),2.90–2.82(m,2H),2.81–2.72(m,1H),2.71–2.59(m, 1H),2.35–2.27(m,1H),2.19–2.08(m,2H),2.06–1.97(m,1H),1.95–1.83(m,3H),1.82–1.67(m,2H),1.64– 1.51 (m, 4H), 1.50–1.37 (m, 2H), 1.36–1.19 (m, 2H).

Example 97: 5-(4-(2-(3-(((R)-3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrole Alkyl-1-yl)methyl)piperidin- 1-yl)ethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1 ,3-Diketone,TFA salt

Step 1: 4-(2-(3-(((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1- Synthesis of tert-butyl)methyl)piperidine-1-yl)ethyl)piperidine-1-carboxylate

Add TEA (163 mg, 1.61 mmol) to 5-chloro-4-(1H-indol-3-yl)-N-((3R)-1-(piperidin-3-ylmethyl)pyrrole at room temperature Alkyl-3-yl)pyrimidin-2-amine (220mg, 0.535mmol) and tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate (146mg, 0.642mmol) in DCE (6.00mL) , after stirring at room temperature for 0.5 hrs, NaHB(OAc) ₃ (454 mg, 2.14 mmol) was added, followed by stirring at room temperature for 2.5 hrs. The reaction mixture was concentrated under reduced pressure, and the residue was separated and purified by silica gel chromatography (DCM/MeOH=40/1) to obtain the target compound (654 mg, yield 65.7%, yellow solid). LC-MS (ESI) m/z: 622.4 [M+H] ⁺ .

Step 2: 5-Chloro-4-(1H-indol-3-yl)-N-((3R)-1-((1-(2-(piperidin-4-yl)ethyl)piperidine- Synthesis of 3-yl)methyl)pyrrolidin-3-yl)pyrimidin-2-amine

HCl·MeOH (4N, 3.00mL) solution was slowly added dropwise to 4-(2-(3-(((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidine -2-yl)amino)pyrrolidin-1-yl)methyl)piperidin-1-yl)ethyl)piperidine-1-carboxylic acid tert-butyl ester (654 mg, 1.05 mmol) in MeOH (3.00 mL), It was then stirred at room temperature for 16 hrs. The reaction mixture was concentrated under reduced pressure to obtain the target compound (600 mg, yield 92.2%, yellow solid). LC-MS (ESI) m/z: 522.3 [M+H] ⁺ .

Step 3: 5-(4-(2-(3-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidine- 1-yl)methyl)piperidin-1-yl)ethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3 -Synthesis of diketone trifluoroacetate

Add DIPEA (223 mg, 1.72 mmol) to 5-chloro-4-(1H-indol-3-yl)-N-((3R)-1-((1-(2-(piperidine- 4-yl) ethyl) piperidin-3-yl) methyl) pyrrolidin-3-yl) pyrimidin-2-amine (300mg, 0.515mmol) and 2-(2,6-dioxopiperidine-3 -yl)-5-fluoroisoindoline-1,3-dione (238mg, 0.862mmol) in DMSO (4.00mL), then stirred at 130°C for 2hrs. After the reaction mixture was cooled to room temperature, it was subjected to prep-HPLC (column: SunFire Prep C8 OBD 10um 19*250mm; mobile phase: A-0.1% TFA aqueous solution, B-ACN; gradient: B%=10%～31%; flow rate : 20 mL/min) to obtain the title compound (112 mg, yield 25.1%, yellow solid). LC-MS (ESI) m/z: 778.3 [M+H] ⁺ . ¹ H NMR (400MHz,DMSO-d ₆ )δ11.92(s,1H),11.08(s,1H),9.97(s,1H),9.37(s,1H),8.71–8.53(m,1H), 8.50(s,1H),8.35(s,1H),7.70–7.64(m,1H),7.55–7.48(m,1H),7.40–7.28(m,1H),7.28–7.12(m,3H), 5.11–5.02(m,1H),4.71–4.56(m,1H),4.09–4.00(m,5H),3.86–3.77(m,1H),3.76–3.67(m,1H),3.61–3.53(m ,1H),3.51–3.43(m,1H),3.23–3.10(m,4H),2.97–2.81(m,3H),2.73–2.58(m,1H),2.39–2.28(m,1H),2.28 –2.09(m,2H),2.06–1.95(m,1H),1.94–1.83(m,2H),1.81–1.70(m,3H),1.66–1.56(m,4H),1.29–1.13(m, 4H).

Example 98: 5-(4-(2-(4-(((R)-3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrole Alkyl-1-yl)methyl)piperidin- 1-yl)ethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1 ,3-diketone

Add HCl·MeOH (4N, 5.00 mL) solution dropwise to (R)-4-((3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino) Pyrrolidin-1-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester (400mg, 0.780mmol) in MeOH (1.00mL), then stirred at room temperature under nitrogen protection for 16hrs. Concentration under reduced pressure gave the target compound (221 mg, yield 68.9%, yellow oil), which was directly used in the next reaction. LC-MS (ESI) m/z: 411.2 [M+H] ⁺ .

Step 2: (R)-4-(2-(4-((3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1- Synthesis of tert-butyl)methyl)piperidine-1-yl)ethyl)piperidine-1-carboxylate

(R)-5-chloro-4-(1H-indol-3-yl)-N-(1-(piperidin-4-ylmethyl)pyrrolidin-3-yl)pyrimidin-2-amine ( 180mg, 0.440mmol) was added to a solution of tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate (200mg, 0.880mmol) in DMSO (8.00mL), After stirring at room temperature for 1 hr, NaHB(OAc) ₃ (279 mg, 1.31 mmol) was added, and then stirred at room temperature for 2 hrs under nitrogen protection. The reaction mixture was quenched with water (20.0 mL), extracted with EA (20.0 mL×2), the organic phases were combined, dried with anhydrous Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and the residue was subjected to silica gel chromatography (DCM/MeOH= 10/1) separation and purification to obtain the target compound (217 mg, yield 79.3%, yellow oil). LC-MS (ESI) m/z: 622.4 [M+H] ⁺ .

Step 3: (R)-5-Chloro-4-(1H-indol-3-yl)-N-(1-((1-(2-(piperidin-4-yl)ethyl)piperidine- Synthesis of 4-yl)methyl)pyrrolidin-3-yl)pyrimidin-2-amine

Add HCl·MeOH (4N, 9.00mL) solution dropwise to (R)-4-(2-(4-((3-((5-chloro-4-(1H-indol-3-yl)pyrimidine- 2-yl)amino)pyrrolidin-1-yl)methyl)piperidin-1-yl)ethyl)piperidine-1-carboxylic acid tert-butyl ester (200 mg, 0.320 mmol) in MeOH (1.00 mL), Then it was stirred at room temperature for 16 hrs under the protection of nitrogen. Concentration under reduced pressure gave the target compound (130 mg, yield 77.8%, yellow solid), which was directly used in the next reaction. LC-MS (ESI) m/z: 522.4 [M+H] ⁺ .

Step 4: 5-(4-(2-(4-(((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidine -1-yl)methyl)piperidin-1-yl)ethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1, Synthesis of 3-diketones

(R)-5-chloro-4-(1H-indol-3-yl)-N-(1-((1-(2-(piperidin-4-yl)ethyl)piperidine-4- Base) methyl) pyrrolidin-3-yl) pyrimidin-2-amine (130mg, 0.250mmol) was added to 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline- 1,3-Diketone (72.0 mg, 0.260 mmol) and DIPEA (1.00 mL) in DMSO (3.00 mL), then stirred at 130° C. for 2 hrs under nitrogen protection. After the reaction mixture was cooled to room temperature, it was filtered, and the filtrate was subjected to prep-HPLC (column: SunFire Prep C8 OBD 10um 19*250mm; mobile phase: A-0.1% TFA aqueous solution, B-ACN; gradient: B%=10%～29 %; flow rate: 20mL/min) separation and purification to obtain the title compound (5.03mg, yield 2.59%, yellow solid). LC-MS (ESI) m/z: 778.2 [M+H] ⁺ . ¹ H NMR (400MHz,DMSO-d ₆ )δ12.12(s,1H),11.08(s,1H),8.69–8.55(m,1H),8.51–8.46(m,1H),8.39–8.28(m ,1H),7.82–7.71(m,1H),7.70–7.60(m,1H),7.54–7.48(m,1H),7.32(s,1H),7.29–7.17(m,3H),5.14–4.98 (m,1H),4.87–4.57(m,1H),4.10–4.00(m,2H),3.20–3.10(m,4H),3.07–2.98(m,3H),2.90–2.82(m,2H) ,2.70(s,1H),2.21–2.09(m,4H),2.08–1.96(m,4H),1.78–1.62(m,9H),1.24–1.18(m,5H).

Example 99: 5-(4-((4-(2-((R)-3-((5-chloro-4-(1H-pyrazol-4-yl)pyrimidin-2-yl)amino)pyrrole Alkyl-1-yl)ethyl)piperidin- 1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1 ,3-Diketone, FA salt

Step 1: Synthesis of tert-butyl 4-(2,5-dichloropyrimidin-4-yl)-1H-pyrazole-1-carboxylate

Under nitrogen protection, Pd(dppf)Cl ₂ ·DCM (884mg, 1.09mmol) was added to 2,4,5-trichloropyrimidine (2.00g, 10.9mmol) and K ₃ PO ₄ (4.63g, 21.8mmol) In THF/H ₂ O (30.0mL/10.0mL), a solution of 1-Boc-pyrazole-4-boronic acid pinacol ester (3.20g, 10.9mmol) in THF (10.0mL) was added dropwise while stirring, and then in Stir at 30°C for 3hrs. After the reaction mixture was cooled to room temperature, it was quenched with water (50.0 mL), extracted with EA (100 mL), and the organic phase was dried with Na ₂ SO ₄ , over After filtration and concentration under reduced pressure, the residue was separated and purified by silica gel chromatography (PE/EA=16/1-8/1) to obtain the target compound (1.70 g, yield 49.4%, white solid). LC-MS (ESI) m/z: 213.1 [MH-100] ^- .

Step 2: Synthesis of (R)-tert-butyl 3-((5-chloro-4-(1H-pyrazol-4-yl)pyrimidin-2-yl)amino)pyrrolidine-1-carboxylate

At room temperature, DIEPA (2.20 g, 17.3 mmol) was added to tert-butyl 4-(2,5-dichloropyrimidin-4-yl)-1H-pyrazole-1-carboxylate (1.82 g, 5.76 mmol) and ( R)-tert-butyl 3-aminopyrrolidine-1-carboxylate (2.57 g, 13.8 mmol) in DMSO (35.0 mL), then stirred at 130° C. for 3 hrs. After the reaction mixture was cooled to room temperature, it was quenched with water (100 mL), extracted with EA (100 mL), the organic phase was dried over anhydrous Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and the residue was subjected to silica gel chromatography (DCM/MeOH=100 /1～60/1) separation and purification to obtain the target compound (1.30g, yield 62.3%, white solid). LC-MS (ESI) m/z: 365.2 [M+H] ⁺ .

Step 3: Synthesis of (R)-5-chloro-4-(1H-pyrazol-4-yl)-N-(pyrrolidin-3-yl)pyrimidin-2-amine

Add HCl·MeOH (4N, 10.0 mL) solution dropwise to (R)-3-((5-chloro-4-(1H-pyrazol-4-yl)pyrimidin-2-yl)amino)pyrrole at room temperature tert-butyl alkane-1-carboxylate (1.30 g, 3.56 mmol) in MeOH (30.0 mL), then stirred at 30 °C for 3 hrs. The reaction mixture was concentrated under reduced pressure, quenched with water (10.0 mL), adjusted to pH=14 with aqueous NaOH (1N), extracted with DCM/MeOH (10/1, 100 mL×5), combined organic phases, anhydrous Na ₂ SO ₄ Dry, filter, and concentrate under reduced pressure. The residue is separated and purified by Prep-TLC (DCM/MeOH=10/1) to obtain the target compound (400 mg, yield 42.4%, light yellow solid). LC-MS (ESI) m/z: 265.1 [M+H] ⁺ .

Step 4: 5-(4-((4-(2-((R)-3-((5-chloro-4-(1H-pyrazol-4-yl)pyrimidin-2-yl)amino)pyrrolidine -1-yl)ethyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1, Synthesis of 3-diketone FA salt

At room temperature, (R)-5-chloro-4-(1H-pyrazol-4-yl)-N-(pyrrolidin-3-yl)pyrimidin-2-amine (24.0 mg, 91.0 mmol) was added to 2 -(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl) Methyl)piperidin-4-yl)acetaldehyde (43.6mg, 91.0mmol) in DMSO (2.00mL), stirred for 1hr, added NaHB(OAc) ₃ (58.0mg, 0.273mmol), then stirred at 35°C overnight. The reaction mixture was quenched with water (20.0 mL), extracted with EA (30.0 mL), the organic phase was dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure, and the residue was subjected to Prep-HPLC (column: SunFire Prep C8 OBD 10um 19 *250mm; mobile phase: A-water (0.1%FA)/B-CH ₃ CN; B%=10%-30%; flow rate: 20mL/min) separation and purification to obtain the title compound (1.06mg, yield 1.59%) , yellow solid). LC-MS (ESI) m/z: 729.5 [M+H] ⁺ . (SunFire C18 50*4.6mm 5um 2.6min 2.0mL/min; Temperature: 40℃; Gradient: 10%B increase to 30%B for 0.40min, increase to 95%B within 1.60min, 95%B hold for 0.90min , back to 10% B within 0.01min) RT = 0.977min. ¹ H NMR (400MHz,DMSO-d ₆ )δ11.08(s,1H),8.48–8.20(m,5H),7.65(d,J＝8.0Hz,1H),7.46–7.26(m,2H), 7.25–7.16(m,1H),5.12–5.02(m,1H),4.37–4.26(m,1H),4.11–3.98(m,2H),3.02–2.91(m,3H),2.92–2.84(m ,2H),2.84–2.77(m,2H),2.71–2.56(m,4H),2.46–2.31(m,4H),2.24–2.08(m,2H),2.05–2.00(m,1H),1.89 –1.73 (m, 4H), 1.69 – 1.55 (m, 2H), 1.43 – 1.32 (m, 2H), 1.32 – 1.22 (m, 2H), 1.19 – 1.06 (m, 4H).

Example 100: 5-(4-((4-2-((R)-3-((5-chloro-4-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine- 2-yl)amino)pyrrolidin-1- yl)ethyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl ) isoindoline-1,3-dione, trifluoroacetate

Step 1: Synthesis of 3-bromo-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine

At 0°C, NaH (974mg, 24.4mmol, 60.0%) was added to 3-bromo-1H-pyrrolo[2,3-b]pyridine (3.00g, 15.23mmol) in THF (30.0mL), stirred for half After hr, p-toluenesulfonyl chloride (3.48 g, 18.3 mmol) was added, and then stirred overnight at room temperature under nitrogen protection. It was concentrated under reduced pressure, and the residue was separated and purified by silica gel chromatography (EA/PE=5/95) to obtain the target compound (5.10 g, yield 95.3%, white solid). LC-MS (ESI) m/z: 351.0 [M+H] ⁺ .

Step 2: 3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1-p-toluenesulfonyl-1H-pyrrolo[2,3 -b] Synthesis of pyridine

Under nitrogen protection, Pd(dppf)Cl ₂ ·DCM (692mg, 0.854mmol) was added to 3-bromo-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (3.00g, 8.54mmol ), pinacol diboronate (3.25 g, 12.8 mmol) and KOAc (1.68 g, 17.1 mmol) in ethylene glycol dimethyl ether (50.0 mL), then stirred at 90° C. overnight. After the reaction mixture was cooled to room temperature, it was filtered and concentrated under reduced pressure. The residue was separated and purified by silica gel chromatography (EA/PE=1/19) to obtain the target compound (3.30 g, yield 97.1%, white solid). LC-MS (ESI) m/z: 399.1 [M+H] ⁺ .

Step 3: Synthesis of 3-(2,5-dichloropyrimidin-4-yl)-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine

Under nitrogen protection, add Pd(dppf)Cl ₂ ·DCM (551mg, 0.753mmol) to 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2- base)-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (3.00g, 7.53mmol), 2,4,5-trichloropyrimidine (1.38g, 7.53mmol) and K ₃ PO ₄ (3.20g, 15.1mmol) in THF/water (40.0mL, 4/1), then stirred overnight at 30°C. The reaction mixture was filtered and concentrated under reduced pressure, and the residue was separated and purified by silica gel chromatography (EA/PE=1/4) to obtain the target compound (613 mg, yield 19.4%, white solid). LC-MS (ESI) m/z: 420.9 [M+H] ⁺ .

Step 4: Synthesis of 3-(2,5-dichloropyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine

At room temperature, tetrabutylammonium fluoride (640 mg, 2.45 mmol) was added to 3-(2,5-dichloropyrimidin-4-yl)-1-p-toluenesulfonyl-1H-pyrrolo[2,3- b] Pyridine (513 mg, 1.22 mmol) in THF (10.0 mL), then stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was separated and purified by silica gel chromatography (EA/PE=3/2) to obtain the target compound (323 mg, yield 99.6%, white solid). LC-MS (ESI) m/z: 263.0 [M+H] ⁺ .

Step 5: (R)-3-((5-Chloro-4-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)amino)pyrrolidine-1-carboxylic acid tert Synthesis of Butyl Ester

Add (R)-1-Boc-3-aminopyrrolidine (454mg, 2.44mmol) and N,N-diisopropylethylamine (472mg, 3.66mmol) to 3-(2,5-di Chloropyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine (323mg, 1.22mmol) in DMSO (10.0mL), then stirred at 130°C for 3hrs. After the reaction mixture was cooled to room temperature, it was concentrated under reduced pressure, and the residue was separated and purified by silica gel chromatography (MeOH/DCM=3/97) to obtain the target compound (425 mg, yield 84.1%, white solid). LC-MS (ESI) m/z: 415.2 [M+H] ⁺ .

Step 6: Synthesis of (R)-5-chloro-N-(pyrrolidin-3-yl)-4-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-amine

At 0°C, add HCl·MeOH (3.00mL, 4N) solution dropwise to (R)-3-((5-chloro-4-(1H-pyrrolo[2,3-b]pyridin-3-yl) Pyrimidin-2-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester (425 mg, 1.02 mmol) in MeOH (10.0 mL), then stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to obtain the target compound (267 mg, yield 82.2%, white solid). LC-MS (ESI) m/z: 315.1 [M+H] ⁺ .

Step 7: (R)-4-(2-(3-((5-Chloro-4-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)amino)pyrrole Synthesis of tert-butyl alk-1-yl)ethyl)piperidine-1-carboxylate

At 0°C, NaHB(OAc) ₃ (519mg, 2.45mmol) was added to (R)-5-chloro-N-(pyrrolidin-3-yl)-4-(1H-pyrrolo[2,3-b ]pyridin-3-yl)pyrimidin-2-amine (257 mg, 0.816 mmol) and tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate (371 mg, 1.63 mmol) in DMSO (5.00 mL) medium, then stirred at 30 °C for 3 hrs. The reaction mixture was concentrated under reduced pressure, and the residue was separated and purified by silica gel chromatography (MeOH/DCM=1/19) to obtain the target compound (183 mg, yield 42.6%, yellow solid). LC-MS (ESI) m/z: 526.2 [M+H] ⁺ .

Step 8: (R)-5-Chloro-N-(1-(2-(piperidin-4-yl)ethyl)pyrrolidin-3-yl)-4-(1H-pyrrolo[2,3- b] Synthesis of pyridin-3-yl)pyrimidin-2-amine

At 0°C, add HCl·MeOH (2.00mL, 4N) solution dropwise to (R)-4-(2-(3-((5-chloro-4-(1H-pyrrolo[2,3-b] pyridin-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)ethyl)piperidine-1-carboxylic acid tert-butyl ester (183 mg, 0.348 mmol) in MeOH (3.00 mL), then at room temperature Stir overnight. The reaction mixture was concentrated under reduced pressure to obtain the target compound (113 mg, yield 76.3%, white solid). LC-MS (ESI) m/z: 426.2 [M+H] ⁺ .

Step 9: 5-(4-((4-2-((R)-3-((5-chloro-4-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-2 -yl)amino)pyrrolidin-1-yl)ethyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl) Synthesis of isoindoline-1,3-dione trifluoroacetate At room temperature, NaHB(OAc) ₃ (45.0 mg, 0.211 mmol) was added to (R)-5-chloro-N-(1-( 2-(piperidin-4-yl)ethyl)pyrrolidin-3-yl)-4-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-amine (30.0mg, 0.070mmol) and 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoquinolin-5-yl)piperidine-4-carbaldehyde (52.0mg, 0.141mmol ) in DMSO (3.00 mL), then stirred overnight at 50°C. After the reaction mixture was cooled to room temperature, it was filtered, and the filtrate was subjected to Prep-HPLC (column: Waters Xbridge C18 10um OBD 19*250mm; mobile phase: A-water (0.1% TFA)/B-ACN; B%=5%-35% ; flow rate: 20mL/min) separation and purification to obtain the title compound (17.91mg, yield 32.2%, yellow solid). LC-MS (ESI) m/z: 779.6 [M+H] ⁺ . (ACQUITY UPLC BEH 1.7um 2.1*50mm 2.0min 0.6mL/min; Temperature: 40℃; Gradient: 10%B increase to 30%B for 0.10min, increase to 95%B within 1.20min, 95%B hold for 0.80 min) RT = 1.02 min. ¹ HNMR (400MHz, DMSO-d ₆ )δ12.49(s,1H),11.09(s,1H),10.02(s,1H),8.99(s,1H),8.68–8.53(m,1H),8.40 (s,1H),8.37(dd,J=4.6,1.5Hz,1H),7.90–7.60(m,2H),7.36(d,J=1.6Hz,1H),7.32–7.18(m,2H), 5.08(dd,J=12.9,5.4Hz,1H),4.74–4.42(m,1H),4.10(d,J=12.9Hz,2H),4.05–3.91(m,1H),3.84–3.72(m, 1H),3.30–3.16(m,4H),3.13–2.93(m,5H),2.93–2.77(m,3H),2.65–2.54(m,2H),2.41–2.24(m,1H),2.25– 2.06(m,2H),2.07–1.97(m,1H),1.92–1.77(m,4H),1.78–1.65(m,1H),1.65–1.51(m,3H),1.51–1.35(m,2H ), 1.34–1.17(m,2H). ¹⁹ FNMR (377 MHz, DMSO-d ₆ ) δ-73.89.

Example 101: 5-(4-(2-(4-((R)-3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidine -1-yl)piperidin-1-yl) ethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-di Ketones, FA salts

Step 1: 5-(4-(2-(4-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidine- 1-yl)piperidin-1-yl)ethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione Synthesis of FA salt

(R)-5-chloro-4-(1H-indol-3-yl)-N-(1-(piperidin-4-yl)pyrrolidin-3-yl)pyrimidin-2-amine (40.0mg ,0.100mmol) and 2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidine-4- Base) acetaldehyde (42.0mg, 0.110mmol) was dissolved in DMSO (2.50mL), stirred at room temperature for 0.5hr, then NaHB(OAc) ₃ (117mg, 1.42mmol) was added, then stirred at room temperature for 5hrs under nitrogen protection. The reaction solution was directly subjected to Prep-HPLC (column: SunFire Prep C8 OBD 10um 19*250mm; mobile phase: A-water (0.1% FA)/B-CH ₃ CN; B%=5%-37%; flow rate: 20mL/ min) separation and purification to obtain the title compound (15.78 mg, yield 20.65%, yellow solid, FA salt). LC-MS (ESI) m/z: 764.3 [M+H] ⁺ . (SunFire C18 50*4.6mm 5um 2.6min 2.0mL/min; Temperature:40℃; Gradient:10%B increase to 30%B for 0.40min,increase to 95%B within 1.60min,95%B for 0.90min, back to 10% B within 0.01min) RT = 1.118min. ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.85(s, 1H), 11.07(s, 1H), 8.88–8.52(m, 1H), 8.46(d, J=2.8Hz, 1H), 8.26( s,1H),8.21(s,1H),7.64(d,J=8.6Hz,1H),7.49(d,J=8.0Hz,1H),7.38(s,1H),7.29(s,1H), 7.24–7.12(m,3H),5.11–4.99(m,1H),4.39(s,1H),4.02(d,J＝12.6Hz,2H),2.99–2.81(m,6H),2.77–2.69( m,1H),2.66–2.57(m,2H),2.57–2.53(m,2H),2.39–2.30(m,2H),2.27–2.12(m,1H),2.10–1.93(m,4H), 1.85–1.70(m,5H), 1.61–1.51(m,1H), 1.48–1.32(m,4H), 1.28–1.11(m,2H).

Example 102: 3-(5-(4-((4-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl) Amino)pyrrolidin-1-yl)ethyl)piperidin -1-yl)methyl)piperidin-1-yl)-1-oxoisoindoline-2-yl)piperidine-2,6- Diketone, FA salt

Step 1: Synthesis of 3-(5-(4-(hydroxymethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

Add DIPEA (740mg, 5.73mmol) to 3-(5-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (500mg, 1.91mmol) and piperidine-4 -dimethanol (880mg, 7.64mmol) in DMSO (10.0mL), then stirred at 120°C overnight. After the reaction mixture was cooled to room temperature, it was diluted with water (50.0 mL), extracted with EA (100 mL×2), the organic phases were combined, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (DCM /MeOH=30/1) separation and purification to obtain the target compound (80.0 mg, yield 11.7%, yellow liquid). LC-MS (ESI) m/z: 358.2 [M+H] ⁺ .

Step 2: Synthesis of 1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidine-4-carbaldehyde

Add Dess-Martin oxidant (119 mg, 0.280 mmol) to 3-(5-(4-(hydroxymethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine -2,6-dione (50.0 mg, 0.140 mmol) in DCM (20.0 mL), then stirred at 35°C for 1 hr. reaction The mixture was filtered and concentrated under reduced pressure, and the residue was separated and purified by silica gel chromatography (DCM/MeOH=30/1) to obtain the target compound (40.0 mg, crude product, yellow liquid). LC-MS (ESI) m/z: 356.2 [M+H] ⁺ .

Step 3: 3-(5-(4-((4-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino )pyrrolidin-1)-yl)ethyl)piperidin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindoline-2-yl)piperidin-2,6- Synthesis of diketone FA salt

(R)-5-chloro-4-(1H-indol-3-yl)-N-(1-(2-(piperidin-4-yl)ethyl)pyrrolidin-3-yl)pyrimidine- 2-Amine (47.0mg, 0.110mmol) was added to 1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)piperidine-4- Formaldehyde (40.0 mg, 0.110 mmol) in DMSO (3.00 mL) was stirred for 0.5 hr, then NaHB(OAc) ₃ (93.0 mg, 0.440 mmol) was added, followed by stirring at 30°C for 1 hr. The reaction mixture was quenched with water (100 mL), extracted with EA (100 mL×2), combined organic phases, dried over anhydrous Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and the residue was subjected to Prep-HPLC (column: SunFire Prep C8 OBD 10um 19*250mm; mobile phase: A-water (0.1% FA)/B-CH ₃ CN; B%=5%-25%; flow rate: 20mL/min) separation and purification to obtain the title compound (4.44mg, yield 5.28 %, white solid). LC-MS (ESI) m/z: 764.4 [M+H] ⁺ . (SunFire C18 50*4.6mm 5um 2.6min 2.0mL/min; Temperature:40℃; Gradient:10%B increase to 30%B for 0.40min,increase to 95%B within 1.60min,95%B for 0.90min, back to 10% B within 0.01min) RT = 0.872min. ¹ H NMR (400MHz, MeOD-d ₄ ) δ8.61–8.49(m,2H),8.48–8.41(m,1H),8.29–8.17(m,1H),7.70–7.54(m,1H),7.52 –7.42(m,1H),7.28–7.16(m,2H),7.12–7.00(m,2H),5.12–5.03(m,1H),4.71–4.55(m,4H),4.45–4.28(m, 2H),4.01–3.86(m,2H),3.20–3.03(m,2H),3.00–2.82(m,5H),2.80–2.63(m,3H),2.62–2.35(m,4H),2.18– 2.02(m,2H), 2.01–1.77(m,5H), 1.66–1.51(m,3H), 1.50–1.24(m,5H).

Example 103: 5-(4-((4-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrole Alkyl-1-yl)ethyl)piperidin- 1-yl)methyl)-4-hydroxypiperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindo Indoline-1,3-dione, FA salt

Step 1: (R)-4-((4-(2-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1- Synthesis of (yl)ethyl)piperidin-1-yl)methyl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester

Add DIPEA (246 mg, 1.91 mmol) to (R)-5-chloro-4-(1H-indol-3-yl)-N-(1-(2-(piperidin-4-yl) Ethyl)pyrrolidin-3-yl)pyrimidin-2-amine (270mg, 0.635mmol) and tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (271mg, 1.27mmol) solution in anhydrous EtOH (6.00 mL), then stirred at 70 °C for 3 hrs. After the reaction mixture was cooled to room temperature, it was diluted with water (50.0 mL), extracted with EA (100 mL×2), the organic phases were combined, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure, and the residue was subjected to silica gel chromatography (DCM/ MeOH=10/1) separation and purification to obtain the target compound (400 mg, yield 88.9%, yellow solid). LC-MS (ESI) m/z: 638.3 [M+H] ⁺ .

Step 2: (R)-4-((4-(2-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1- Synthesis of (yl)ethyl)piperidin-1-yl)methyl)piperidin-4-ol

Add TFA (357 mg, 3.13 mmol) to (R)-4-((4-(2-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl) Amino)pyrrolidin-1-yl)ethyl)piperidin-1-yl)methyl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (400 mg, 0.627 mmol) in DCM (6.00 mL), then Stir at room temperature for 3hrs. The reaction mixture was concentrated under reduced pressure to obtain the target compound (603 mg, yield 66.3%, yellow oil), which was directly used in the next reaction. LC-MS (ESI) m/z: 538.4 [M+H] ⁺ .

Step 3: 5-(4-((4-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidine -1-yl)ethyl)piperidin-1-yl)methyl)-4-hydroxypiperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole Synthesis of phenoline-1,3-dione FA salt

Add DIPEA (115 mg, 0.892 mmol) to (R)-4-((4-(2-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidine-2 -yl)amino)pyrrolidin-1-yl)ethyl)piperidin-1-yl)methyl)piperidin-4-ol (160mg, 0.297mmol) and 2-(2,6-dioxopiperidine -3-yl)-5-fluoroisoindoline-1,3-dione (164 mg, 0.595 mmol) in DMSO (3.00 mL), then stirred at 130°C for 1 hr. After the reaction mixture was cooled to room temperature, it was filtered, and the filtrate was subjected to Prep-HPLC (column: SunFire Prep C8 OBD 10um 19*250mm; mobile phase: A-water (0.1% FA)/B-CH ₃ CN; B%=10% -35%; flow rate: 20mL/min) separation and purification to obtain the title compound (45.3mg, yield 19.1%, yellow solid). LC-MS (ESI) m/z: 794.5 [M+H] ⁺ . (SunFire C18 50*4.6mm 5um 2.6min 2.0mL/min; Temperature: 40℃; Gradient: 10%B increase to 30%B for 0.40min, increase to 95%B within 1.60min, 95%B hold for 0.90min , back to 10% B within 0.01min) RT = 0.864min. ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.88(s, 1H), 11.07(s, 1H), 8.74–8.52(m, 1H), 8.48(d, J=2.8Hz, 1H), 8.32( s,1H),8.14(s,1H),7.65(d,J＝8.5Hz,1H),7.59–7.45(m,2H),7.38–7.29(m,1H),7.27–7.11(m,3H) ,5.29–4.82(m,1H),4.67–4.37(m,1H),3.93–3.66(m,2H),3.21–2.76(m,8H),2.70–2.53(m,4H),2.41–2.16( m,4H), 2.17–1.83(m,3H), 1.69–1.38(m,8H), 1.39–1.15(m,4H).

Example 104: 5-(4-((4-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrole Alkyl-1-yl)ethyl)piperidin- 1-yl)methyl)-4-hydroxypiperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindo Indoline-1,3-dione, trifluoroacetate

Step 1: (R)-4-((4-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)piper Synthesis of tert-butyl pyridine-1-yl)methyl)-4-hydroxypiperidine-1-carboxylate

At room temperature, DIPEA (195 mg, 1.51 mmol) was added to (R)-5-chloro-4-(1H-indol-3-yl)-N-(1-(piperidin-4-yl)pyrrolidine- 3-yl)pyrimidin-2-amine (200mg, 0.504mmol) and tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (215mg, 1.01mmol) in anhydrous EtOH (6.00 mL), then stirred at 70 °C for 3 hrs. After the reaction mixture was cooled to room temperature, it was diluted with water (40.0 mL), extracted with EA (30.0 mL×2), the organic phases were combined, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure, and the residue was subjected to silica gel chromatography (DCM /MeOH=10/1) separation and purification to obtain the target compound (289 mg, yield 81.6%, yellow solid). LC-MS (ESI) m/z: 610.3 [M+H] ⁺ .

Step 2: (R)-4-((4-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)piper Synthesis of Pyridin-1-yl)methyl)piperidin-4-ol

Add TFA (252 mg, 2.21 mmol) to (R)-4-((4-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrole Alk-1-yl)piperidin-1-yl)methyl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (270 mg, 0.442 mmol) in DCM (6.00 mL), then stirred at room temperature for 2 hrs. The reaction mixture was concentrated under reduced pressure to obtain the target compound (450 mg, yield 50.1%, yellow oil), which was directly used in the next reaction. LC-MS (ESI) m/z: 510.2 [M+H] ⁺ .

Step 3: 5-(4-((4-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1- Base) piperidin-1-yl)methyl)-4-hydroxypiperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3- Synthesis of diketone trifluoroacetate

Add DIPEA (228 mg, 1.76 mmol) to (R)-4-((4-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl) Amino)pyrrolidin-1-yl)piperidin-1-yl)methyl)piperidin-4-ol (300mg, 0.588mmol) and 2-(2,6-dioxopiperidin-3-yl)- 5-fluoroisoindoline-1,3-dione (325 mg, 1.18 mmol) in DMSO (4.00 mL), then stirred at 130° C. for 1 hr. After the reaction mixture was cooled to room temperature, it was filtered, and the filtrate was subjected to Prep-HPLC (column: SunFire Prep C8 OBD 10um 19*250mm; mobile phase: A-water (0.1% TFA)/B-CH ₃ CN; B%=20%- 77%; flow rate: 20mL/min) separation and purification to obtain the title compound (69.2mg, yield 15.3%, yellow solid). LC-MS (ESI) m/z: 766.5 [M+H] ⁺ . (SunFire C18 50*4.6mm 5um 2.6min 2.0mL/min; Temperature: 40℃; Gradient: 10%B increase to 30%B for 0.40min, increase to 95%B within 1.60min, 95%B hold for 0.90min , back to 10% B within 0.01min) RT = 0.824min. ¹ H NMR (400MHz,DMSO-d ₆ )δ11.92(s,1H),11.08(s,1H),8.77–8.24(m,3H),7.77–7.65(m,1H),7.62–7.48(m ,1H),7.37(s,1H),7.32–7.15(m,3H),5.58–5.38(m,1H),5.14–4.95(m,1H),4.69–4.57(m,1H),4.07–3.92 (m,1H),3.91–3.80(m,2H),3.79–3.63(m,2H),3.63–3.49(m,1H),3.48–3.30(m,4H),3.27–3.12(m,3H) ,3.11–2.97(m,2H),2.96–2.79(m,1H),2.30–2.12(m,4H),2.11–1.93(m,4H),1.78–1.58(m,4H),1.30–1.20( m, 1H).

Example 105: 5-(4-(2-((R)-3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1- Base) ethyl)-[1,4'- bipiperidin-1'-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-di Ketones, FA salts

Step 1: (R)-4-(2-(3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)ethyl Synthesis of )-[1,4'-bipiperidine]-1'-tert-butyl carboxylate

4-Oxopiperidine-1-carboxylic acid tert-butyl ester (140mg, 0.700mmol) was added to (R)-5-chloro-4-(1H-indol-3-yl)-N-(1-(2 -(piperidin-4-yl)ethyl)pyrrolidin-3-yl)pyrimidin-2-amine (200mg, 0.470mmol) in DMSO (5.00mL), stirred at room temperature under nitrogen for 0.5hr, then added NaBH (OAc) ₃ (498mg, 2.35mmol), then stirred at room temperature for 5hrs under nitrogen protection. The reaction mixture was quenched with water (30.0 mL), extracted with EA (30.0 mL×2), the organic phases were combined, dried over anhydrous Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and the residue was subjected to silica gel chromatography (PE/EA=10 /1) Separation and purification to obtain the target compound (335 mg, yield 85.5%, yellow solid). LC-MS (ESI) m/z: 608.3 [M+H] ⁺ .

Step 2: (R)-N-(1-(2-([1,4'-bipiperidin]-4-yl)ethyl)pyrrolidin-3-yl)-5-chloro-4-(1H Synthesis of -indol-3-yl)pyrimidin-2-amine

HCl·MeOH (4N, 8.00mL) solution was slowly added dropwise to (R)-4-(2-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl )amino)pyrrolidin-1-yl)ethyl)-[1,4'-bipiperidine]-1'-carboxylic acid tert-butyl ester (300mg, 0.490mmol) in MeOH (2.00mL), then under nitrogen protection Stir at room temperature for 16 hrs. The reaction solution was concentrated under reduced pressure to obtain the target compound (210 mg, yield 84.5%, yellow solid). LC-MS (ESI) m/z: 508.2 [M+H] ⁺ .

Step 3: 5-(4-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl )ethyl)-[1,4'-bipiperidinyl]-1'-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione Synthesis of FA salt

(R)-N-(1-(2-([1,4'-bipiperidin]-4-yl)ethyl)pyrrolidin-3-yl)-5-chloro-4-(1H-indole -3-yl)pyrimidin-2-amine (100mg, 0.190mmol), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione ( 65.6 mg, 0.230 mmol) and DIPEA (5.00 mL) were dissolved in DMSO (10.0 mL), then stirred at 120 °C for 2 hrs. After the reaction mixture was cooled to room temperature, it was filtered, and the filtrate was subjected to Prep-HPLC (column: SunFire Prep C8 OBD 10um 19*250mm; mobile phase: A-water (0.1% FA)/B-CH ₃ CN; B%=15% -45%; flow rate: 20 mL/min) separation and purification to obtain the title compound (15.1 mg, yield 10.4%, yellow solid, FA salt). LC-MS (ESI) m/z: 764.3 [M+H] ⁺ . (SunFire C18 50*4.6mm 5um 2.6min 2.0mL/min; Temperature:40℃; Gradient:10%B increase to 30%B for 0.40min,increase to 95%B within 1.60min,95%B for 0.90min, back to 10% B within 0.01min) RT = 1.033min. ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.86(s, 1H), 11.08(s, 1H), 8.78–8.50(m, 1H), 8.47(d, J=2.8Hz, 1H), 8.28( s,1H),8.16(s,1H),7.67(d,J=8.6Hz,1H),7.50(d,J=8.0Hz,1H),7.43(d,J=6.2Hz,1H),7.33( s,1H),7.29–7.11(m,3H),5.11–5.00(m,1H),4.45(s,1H),4.11(d,J＝13.2Hz,2H),3.04–2.82(m,8H) ,2.69–2.59(m,3H),2.58–2.53(m,2H),2.41–2.18(m,4H),2.08–1.96(m,1H),1.93–1.82(m,3H),1.74–1.62( m,2H), 1.59–1.46(m,2H), 1.47–1.31(m,3H), 1.26–1.11(m,2H).

Example 106: 3-(5-(4-((4-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl) Amino) pyrrolidin-1-yl) ethyl) piperazin -1-yl) methyl) piperidin-1-yl)-6-fluoro-1-oxoisoindoline-2-yl) piperidine- 2,6-Diketone, trifluoroacetate

Step 1: Step 1: 3-(5-(4-((4-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidine-2- Base) amino) pyrrolidin-1-yl) ethyl) piperazin-1-yl) methyl) piperidin-1-yl)-6-fluoro-1-oxoisoindoline-2-yl) pipe Synthesis of pyridine-2,6-dione trifluoroacetate

1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-3-oxoisoindoline-5-yl)piperidine-4-carbaldehyde (45.0mg, 0.120 mmol) to (R)-5-chloro-4-(1H-indol-3-yl)-N-(1-(2-piperazin-1-yl)ethyl)pyrrolidin-3-yl) Pyrimidin-2-amine (26.0 mg, 0.060 mmol) in DMSO (6.00 mL) was stirred at room temperature for 0.5 hr, then NaBH(OAc) ₃ (51.0 mg, 0.240 mmol) was added, followed by stirring at 35°C for 2 hrs. The reaction mixture was quenched with water ₍ 30mL), extracted with EA (60mL×2), the organic phases were combined, dried over anhydrous _Na2SO4 , filtered, concentrated under reduced pressure, and the residue was subjected to Prep-HPLC (column: SunFire Prep C8 OBD 10um 19*250mm; mobile phase: A-water (0.1%TFA)/B-CH ₃ CN; B%=10%-34%; flow rate: 20mL/min) separation and purification to obtain the title compound (6.61mg, yield 14.0 %, yellow solid). LC-MS (ESI) m/z: 783.5 [M+H] ⁺ . (SunFire C18 50*4.6mm 5um 2.6min 2.0mL/min; Temperature:40℃; Gradient:10%B increase to 30% B for 0.40min, increase to 95% B within 1.60min, 95% B for 0.90min, back to 10% B within 0.01min) RT=1.934min. ¹ H NMR (400MHz, MeOD-d ₄ ) δ8.68–8.52(m,2H),8.33–8.17(m,1H),7.55–7.46(m,1H),7.41(d,J=11.4Hz,1H ),7.32–7.23(m,2H),7.22–7.16(m,1H),5.24–5.03(m,1H),4.47–4.32(m,2H),4.27–4.11(m,1H),3.98–3.79 (m,2H),3.63–3.53(m,3H),3.51–3.39(m,3H),3.17–3.02(m,2H),2.96–2.69(m,10H),2.67–2.39(m,5H) ,2.38–2.23(m,1H),2.21–2.00(m,2H),1.98–1.78(m,3H),1.57–1.39(m,2H).

Example 107: (R)-1-(3-(4-((4-(2-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl) Amino)pyrrolidin-1-yl)ethyl)piperazin -1-yl)methyl)piperidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione, FA salt

Step 1: (R)-1-(3-(4-((4-(2-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino )pyrrolidin-1-yl)ethyl)piperazin-1-yl)methyl)piperidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione FA salt synthesis

Add 1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (216 mg, 0.720 mmol) to (R)-5-chloro- 4-(1H-indol-3-yl)-N-(1-(2-(piperazin-1-yl)ethyl)pyrrolidin-3-yl)pyrimidin-2-amine (150mg, 0.350mmol) After stirring for 40 minutes in DMSO (5.00 mL), NaHB(OAc) ₃ (228 mg, 1.10 mmol) was added, followed by stirring overnight at 35°C. The reaction mixture was diluted with water (50.0 mL), extracted with EA (50.0 mL×2), the organic phases were combined, dried over anhydrous Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and the residue was subjected to Prep-HPLC (column: SunFire Prep C18 OBD 10um 19*250mm; mobile phase: A-water (0.1%FA)/B-CH ₃ CN; B%=10%-30%; flow rate: 20mL/min) separation and purification to obtain the title compound (20.9mg, yield 8.41%, yellow solid, FA salt). LC-MS (ESI) m/z: 710.3 [M+H] ⁺ . (SunFire C18 50*4.6mm 5um 2.6min 2.0mL/min; Temperature: 40℃; Gradient: 10%B increase to 30%B for 0.40min, increase to 95%B within 1.60min, 95%B hold for 0.90min , back to 10% B within 0.01min) RT = 1.027min. 1H NMR (400MHz,DMSO-d ₆ )δ11.89(s,1H),10.80(s,1H),8.77–8.55(m,1H),8.48(s,1H),8.27(d,J=15.6Hz ,2H),7.59–7.35(m,2H),7.28–7.05(m,3H),7.03–6.85(m,1H),6.88–6.51(m,2H),4.57–4.37(m,1H),3.91 –3.79(m,2H),3.83–3.69(m,4H),3.19–2.88(m,2H),2.88–2.69(m,4H),2.68–2.56(m,4H),2.52–2.26(m, 7H), 2.22–2.01(m, 4H), 1.94–1.83(m, 1H), 1.74(d, J＝11.0Hz, 2H), 1.67–1.53(m, 1H), 1.29–1.05(m, 2H) .

Example 108: 3-(4-(4-((4-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl) Amino)pyrrolidin-1-yl)ethyl)piperazin- 1-yl)methyl)piperidin-1-yl)phenyl)piperidine-2,6-dione, trifluoroacetate

Step 1: (R)-4-(2-(3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)ethyl ) Synthesis of piperazine-1-formic acid tert-butyl ester

Add tert-butyl 4-(2-bromoethyl)piperazine-1-carboxylate (880mg, 3.00mmol) to (R)-5-chloro-4-(1H-indol-3-yl)-N- (Pyrrolidin-3-yl)pyrimidin-2-amine (940 mg, 2.99 mmol) and K ₂ CO ₃ (1.24 g, 8.97 mmol) in DMF (10.0 mL), then stirred at 90° C. overnight. After the reaction mixture was cooled to room temperature, it was diluted with water (50.0 mL), extracted with EA (70.0 mL×2), the organic phases were combined, dried over anhydrous Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and the residue was subjected to silica gel chromatography (DCM /MeOH=20/1) separation and purification to obtain the target compound (544 mg, yield 34.6%, yellow solid). LC-MS (ESI) m/z: 526.4 [M+H] ⁺ .

HCl·MeOH (4N, 6.00mL) solution was slowly added dropwise to (R)-4-(2-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl )amino)pyrrolidin-1-yl)ethyl)piperazine-1-carboxylic acid tert-butyl ester (50.0 mg, 0.0900 mmol) in MeOH (3.00 mL), then stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to obtain the title compound (50.0 mg, crude product, yellow solid). LC-MS (ESI) m/z: 426.3 [M+H] ⁺ .

Step 3: 3-(4-(4-((4-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino )pyrrolidin-1-yl)ethyl)piperazin-1-yl)methyl)piperidin-1-yl)phenyl)piperidine-2,6-dione trifluoroacetate

Add 1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carbaldehyde (72.0 mg, 0.240 mmol) to (R)-5-chloro-4-( 1H-indol-3-yl)-N-(1-(2-(piperazin-1-yl)ethyl)pyrrolidin-3-yl)pyrimidin-2-amine (50.0mg, 0.120mmol) in DMSO (5.00 mL), after stirring for 0.5 hr, NaHB(OAc) ₃ (76.0 mg, 0.360 mmol) was added, followed by stirring overnight at 35°C. After the reaction mixture was cooled to room temperature, it was quenched with water (20.0 mL), extracted with EA (30.0 mL×2), the organic phases were combined, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure, and the residue was subjected to Prep-HPLC ( Column: SunFire Prep C8 OBD 10um 19*250mm; mobile phase: A-water (0.1%TFA)/B-CH ₃ CN; B%=10%-35%; flow rate: 20mL/min) separation and purification to obtain the target compound (4.28mg, yield 5.99%, yellow solid). LC-MS (ESI) m/z: 710.2 [M+H] ⁺ . (SunFire C18 50*4.6mm 5um 2.6min 2.0mL/min; Temperature: 40℃; Gradient: 10%B increase to 30%B for 0.40min, increase to 95%B within 1.60min, 95%B hold for 0.90min , back to 10% B within 0.01min) RT = 1.127min. ¹ H NMR (400MHz, MeOD-d ₄ ) δ8.66–8.56(m,1H),8.54(s,1H),8.29(s,1H),7.53–7.47(m,1H),7.37–7.29(m ,4H),7.28–7.22(m,2H),3.95–3.83(m,2H),3.72(d,J＝12.4Hz,3H),3.51–3.39(m,4H),3.27–3.13(m,4H ),3.01–2.90(m,3H),2.87–2.76(m,3H),2.73–2.57(m,5H),2.31–2.13(m,6H),1.99(d,J＝13.2Hz,2H), 1.74–1.55 (m,3H). ¹⁹ F NMR (400 MHz, MeOD-d ₄ ) δ-73.07.

Example 109: 3-(5-(4-((4-(2-((R)-3-((4-(1H-indol-3-yl)-5-(trifluoromethyl)pyrimidine -2-yl)amino)pyrrolidin-1-yl)ethyl)piperidin- 1-yl)methyl)piperidin-1-yl)-6-fluoro-1-oxoisoindoline-2- base) piperidine-2,6-dione

Step 1: Synthesis of 3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole

At -5°C, a solution of methylmagnesium bromide (10.1mL, 3.2M, 21.0mmol) was slowly added dropwise to anhydrous DCE (60.0mL) of indole (2.46g, 42.7mmol), and stirred at this temperature After 0.5 hr, 2,4-dichloro-5-(trifluoromethyl)pyrimidine (3.50 g, 16.1 mmol) was added slowly, followed by stirring at room temperature for 2 hrs. The reaction mixture was quenched with ice water (50.0 mL), and a pale yellow solid was precipitated, which was filtered and dried to obtain the target compound (3.90 g, yield 83.3%, yellow solid). LC-MS (ESI) m/z: 298.1 [M+H] ⁺ .

Step 2: (R)-3-((4-(1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester synthesis

(R)-tert-butyl 3-aminopyrrolidine-1-carboxylate (2.68g, 14.4mmol) and DIEPA (5.08g, 39.3mmol) were added to 3-(2-chloro-5-(trifluoro Methyl)pyrimidin-4-yl)-1H-indole (3.90g, 13.1mmol) in DMSO (50.0mL), then stirred at 130°C overnight. After the reaction mixture was cooled to room temperature, it was concentrated under reduced pressure, and the residue was separated and purified by silica gel chromatography (EA/PE=3/2) to obtain the target compound (4.30 g, yield 73.4%, yellow solid). LC-MS (ESI) m/z: 448.4 [M+H] ⁺ .

Step 3: Synthesis of (R)-4-(1H-indol-3-yl)-N-(pyrrolidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine

At room temperature, HCl·MeOH (4N, 6.00 mL) solution was added dropwise to (R)-3-((4-(1H-indol-3-yl)-5-(trifluoromethyl)pyrimidine-2- (yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester (3.80 g, 8.49 mmol) in MeOH (30.0 mL), then stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to obtain the target compound (2.70 g, yield 91.5%, orange solid). LC-MS (ESI) m/z: 348.2 [M+H] ⁺ .

Step 4: (R)-4-(2-(3-((4-(1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)pyrrolidin-1 Synthesis of -yl)ethyl)piperidine-1-carboxylic acid tert-butyl ester

At room temperature, tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate (851 mg, 3.74 mmol) and NaHB(OAc) ₃ (1.83 g, 8.64 mmol) were sequentially added to (R)-4 -(1H-indol-3-yl)-N-(pyrrolidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (1.00g, 2.88mmol) in DMSO (20.0mL) , and then stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was separated and purified by silica gel chromatography (MeOH/DCM=1/19) to obtain the target compound (1.50 g, yield 93.2%, orange solid). LC-MS (ESI) m/z: 559.4 [M+H] ⁺ .

Step 5: (R)-4-(1H-indol-3-yl)-N-(1-(2-(piperidin-4-yl)ethyl)pyrrolidin-3-yl)-5-( Synthesis of Trifluoromethyl)pyrimidin-2-amine

At room temperature, a solution of HClMeOH (4N, 6.00 mL) was added dropwise to (R)-4-(2-(3-((4-(1H-indol-3-yl)-5-(trifluoromethyl) Pyrimidin-2-yl)amino)pyrrolidin-1-yl)ethyl)piperidine-1-carboxylic acid tert-butyl ester (1.50 g, 2.69 mmol) in MeOH (30.0 mL), then stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to obtain the target compound (1.10 g, yield 89.4%, orange solid). LC-MS (ESI) m/z: 459.4 [M+H] ⁺ .

Step 6: 3-(5-(4-((4-(2-((R)-3-((4-(1H-indol-3-yl)-5-(trifluoromethyl)pyrimidine- 2-yl) amino) pyrrolidin-1-yl) ethyl) piperidin-1-yl) methyl) piperidin-1-yl)-6-fluoro-1-oxoisoindoline-2-yl ) Synthesis of piperidine-2,6-dione

At room temperature, 1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindoline-5-yl)piperidine-4-carbaldehyde (70.0 mg, 0.188mmol) and NaHB(OAc) ₃ (119mg, 0.563mmol) were sequentially added to (R)-4-(1H-indol-3-yl)-N-(1-(2-(piperidine-4 -yl)ethyl)pyrrolidin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (86.0 mg, 0.188 mmol) in DMSO (5.00 mL), then stirred at room temperature overnight. The reaction mixture was filtered, and the filtrate was subjected to Prep-HPLC (column: Waters Xbridge C18 10um OBD 19*250mm; mobile phase: A-water (0.1% FA)/B-CH ₃ CN; B%=5%-35%; flow rate: 20 mL/min) to obtain the title compound (37.5 mg, yield 24.5%, white solid). LC-MS (ESI) m/z: 831.5 [M+H] ⁺ . (ACQUITY UPLC BEH 1.7um 2.1*50mm 2.0min 0.6mL/min; Temperature: 40℃; Gradient: 10%B increase to 30%B for 0.10min, increase to 95%B within 1.20min, 95%B hold for 0.80 min) RT = 1.12 min. ¹ H NMR (400MHz,DMSO-d ₆ )δ11.96–11.64(m,1H),10.97(s,1H),8.56(d,J＝18.4Hz,1H),8.27(s,1H),8.05– 7.92(m,1H),7.83(s,1H),7.49(t,J=9.6Hz,1H),7.39(d,J=11.6Hz,1H),7.20(t,J=7.0Hz,2H), 7.14(t, J=7.6Hz, 1H), 5.06(dd, J=13.2, 4.8Hz, 1H), 4.52–4.40(m, 1H), 4.35(d, J=16.8Hz, 1H), 4.23(d ,J＝17.0Hz,1H),3.49–3.41(m,3H),2.97–2.84(m,2H),2.84–2.76(m,2H),2.77–2.54(m,5H),2.46–2.39(m ,2H),2.39–2.28(m,1H),2.26–2.07(m,3H),2.03–1.91(m,1H),1.91–1.73(m,5H),1.73–1.55(m,3H),1.43 –1.32 (m, 2H), 1.32 – 1.19 (m, 3H), 1.19 – 1.04 (m, 2H). ¹⁹ F NMR (377MHz, DMSO-d ₆ ) δ -56.06(s), -56.51(s), -122.00(s).

Example 110: 5-(4-(2-(4-((R)-3-((5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidine -1-yl)piperidin-1-yl) -2-oxoethyl)-4-hydroxypiperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)iso Indoline-1,3-dione, FA salt

Step 1: (R)-4-(2-(4-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl Synthesis of )piperidin-1-yl)-2-oxoethyl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester

2-(1-(tert-butoxycarbonyl)-4-hydroxypiperidin-4-yl)acetic acid (250mg, 0.950mmol) and (R)-5-chloro-4-(1H-indol-3-yl )-N-(1-(piperidin-4-yl)pyrrolidin-3-yl)pyrimidin-2-amine (380mg, 0.950mmol) was dissolved in DMF (10.0mL) and HATU (562mg, 1.42mmol) was added and DIPEA (2.50 mL), then stirred at room temperature for 4 hrs. The reaction mixture was diluted with water (20.0 mL), extracted with EA (20.0 mL×2), the organic phases were combined, dried over anhydrous Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and the residue was subjected to silica gel chromatography (DCM/MeOH=10/ 1) Separation and purification to obtain the target compound (320 mg, yield 52.8%, yellow solid). LC-MS (ESI) m/z: 638.3 [M+H] ⁺ .

Step 2: (R)-1-(4-(3-(5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)piperidine- Synthesis of 1-yl)-2-(4-hydroxypiperidin-4-yl)ethan-1-one

HCl·MeOH (4N, 4.00mL) solution was slowly added dropwise to (R)-4-(2-(4-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidine- 2-yl)amino)pyrrolidin-1-yl)piperidin-1-yl)-2-oxoethyl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (250 mg, 0.390 mmol) in MeOH ( 1.00mL), then stirred at room temperature for 16hrs. The reaction mixture was concentrated under reduced pressure to obtain the target compound (184 mg, yield 87.8%, yellow solid). LC-MS (ESI) m/z: 538.2 [M+H] ⁺ .

Step 3: 5-(4-(2-(4-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidine- 1-yl)piperidin-1-yl)-2-oxoethyl)-4-hydroxypiperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindo Synthesis of Indoline-1,3-dione FA Salt

Add DIPEA (2.00 mL) to (R)-1-(4-(3-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidin-1- Base) piperidin-1-yl)-2-(4-hydroxypiperidin-4-yl)ethan-1-one (300mg, 0.540mmol) and 2-(2,6-dioxopiperidin-3- Dione)-5-fluoroisoindoline-1,3-dione (166mg, 0.600mmol) in DMSO (5.00mL), then stirred at 130°C for 2hrs. After the reaction mixture was cooled to room temperature, it was subjected to Prep-HPLC (column: SunFire Prep C8 OBD 10um 19*250mm; mobile phase: A-water (0.1% FA)/B-CH CN; B%=5%-43%; flow rate : 20mL/min) separation and purification to obtain the title compound (15.3mg, yield 3.56%, yellow solid). LC-MS (ESI) m/z: 794.3 [M+H] ⁺ . (SunFire C18 50*4.6mm 5um 2.6min 2.0mL/min; Temperature:40℃; Gradient:10%B increase to 30%B for 0.40min,increase to 95% B within 1.60 min, 95% B for 0.90 min, back to 10% B within 0.01 min) RT = 1.075 min. ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.84(s, 1H), 11.07(s, 1H), 8.77–8.51(m, 1H), 8.46(d, J=2.9Hz, 1H), 8.26( s,1H),8.21(s,1H),7.64(d,J=8.6Hz,1H),7.49(d,J=8.0Hz,1H),7.37(s,1H),7.32(s,1H), 7.25–7.12(m,3H),5.14(s,1H),5.10–5.02(m,1H),4.40(s,1H),4.23(d,J＝13.1Hz,1H),3.91(d,J＝ 12.5Hz, 1H), 3.79(d, J＝13.4Hz, 2H), 3.12–3.03(m, 2H), 2.94–2.82(m, 2H), 2.80–2.65(m, 3H), 2.65–2.58(m ,2H),2.58–2.53(m,3H),2.36–2.25(m,2H),2.24–2.12(m,1H),2.05–1.95(m,1H),1.88–1.74(m,4H),1.63 (s,5H).

Example 111: 3-(5-(4-((4-(2-((R)-3-((4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-5 -(trifluoromethyl)pyrimidin-2-yl)amino) pyrrolidin-1-yl)ethyl)piperidin-1-yl)methyl)piperidin-1-yl)-6-fluoro-1-oxygen (isoindolin-2-yl)piperidine-2,6-dione, FA salt

Step 1: (R)-4-(2-(3-((4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidine-2- Synthesis of tert-butyl)amino)pyrrolidin-1-yl)ethyl)piperidine-1-carboxylate

4-(2-Oxoethyl)piperidine-1-carboxylic acid tert-butyl ester (1.00g, 2.86mmol) and (R)-N-(pyrrolidin-3-yl)-4-(1H-pyrrolidine [2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (1.30g, 5.74mmol) was dissolved in DMSO (10.0mL), stirred at room temperature for 0.5hr, then added NaBH(OAc) ₃ (1.20 g, 5.72 mmol), then stirred at room temperature for 5 hrs. The reaction mixture was quenched with water (50.0 mL), extracted with EA (100 mL×2), the organic phases were combined, dried over anhydrous Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and the residue was subjected to silica gel chromatography (DCM/MeOH=20/ 1) Separation and purification to obtain the target compound (801 mg, yield 50.0%, yellow liquid). LC-MS (ESI) m/z: 560.4 [M+H] ⁺ .

Step 2: (R)-N-(1-(2-(piperidin-4-yl)ethyl)pyrrolidin-3-yl)-4-(1H-pyrrolo[2,3-b]pyridine- Synthesis of 3-yl)-5-(trifluoromethyl)pyrimidin-2-amine

HCl·MeOH (4N, 5.00mL) solution was slowly added dropwise to (R)-4-(2-(3-((4-(1H-pyrrolo[2,3-b]pyridin-3-yl)- tert-butyl 5-(trifluoromethyl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)ethyl)piperidine-1-carboxylate (701 mg, 1.25 mmol) in MeOH (20.0 mL), then Stir overnight at room temperature. The reaction mixture was concentrated under reduced pressure, adjusted to pH 9-10 with 1M NaOH aqueous solution, extracted with DCM (100 mL×2), combined organic phases, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to obtain the title compound (720 mg, crude product, white liquid). LC-MS (ESI) m/z: 460.1 [M+H] ⁺ .

Step 3: 3-(5-(4-((4-(2-((R)-3-((4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-5- (Trifluoromethyl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)ethyl)piperidin-1-yl)methyl)piperidin-1-yl)-6-fluoro-1-oxo Synthesis of Isoindoline-2-yl)piperidine-2,6-dione FA Salt

1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindol-5-yl)piperidine-4-carbaldehyde (65.0mg, 0.174mmol ) to (R)-N-(1-(2-(piperidin-4-yl) ethyl) pyrrolidin-3-yl)-4-(1H-pyrrolo[2,3-b]pyridine- 3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (65.0mg, 0.174mmol) in DMSO (6.00mL), after stirring for 0.5hr, NaBH(OAc) ₃ (148mg, 0.696mmol) was added, It was then stirred overnight at room temperature. The reaction mixture was quenched with water (100 mL), extracted with EA (100 mL×2), the organic phases were combined, dried over anhydrous Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and the residue was subjected to Prep-HPLC (column: SunFire Prep C8 OBD 10um 19*250mm; mobile phase: A-water (0.1%FA)/B-CH ₃ CN; B%=10%-30%; flow rate: 20mL/min) separation and purification to obtain the title compound (32.3mg, yield rate 22.5%, white solid). LC-MS (ESI) m/z: 817.1 [M+H] ⁺ . (Sunfire C18 4.6*50mm 5um 2.6min 2.0mL/min; Temperature: 40℃; Gradient: 10%B increase to 30%B for 0.40min, increase to 95%B within 1.60min, 95%B for 0.90min, back to 10% B within 0.01min) RT = 0.831min. ¹ H NMR (400MHz,DMSO-d ₆ )δ12.59–12.29(m,1H),11.08–10.89(m,1H),8.95–8.80(m,1H),8.62–8.56(m,1H),8.41 –8.30(m,1H),8.28–8.19(m,1H),8.17–8.04(m,1H),7.99–7.88(m,1H),7.45–7.34(m,1H),7.29–7.15(m, 2H),5.12–5.01(m,1H),4.56–4.41(m,1H),4.41–4.31(m,1H),4.29–4.19(m,1H),3.02–2.81(m,5H),2.81– 2.65(m,4H),2.64–2.53(m,4H),2.44–2.31(m,1H),2.27–2.15(m,3H),2.04–1.73(m,7H),1.71–1.58(m,3H ), 1.47–1.08(m,8H).

Example 112: 3-(4-(4-((4-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl) Amino)pyrrolidin-1-yl)ethyl)piperazin- 1-yl)methyl)piperidin-1-yl)phenyl)piperidine-2,6-dione, FA salt

Step 1: 3-(5-(4-(2-((R)-3-((4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl Base) pyrimidin-2-yl) amino) pyrrolidin-1-yl) ethyl)-[1,4'-bipiperidinyl]-1'-yl)-6-fluoro-1-oxoisoindoline Synthesis of -2-yl)piperidine-2,6-dione FA salt

A catalytic amount of acetic acid (3 drops) was added to (R)-N-(1-(2-(piperidin-4-yl)ethyl)pyrrolidin-3-yl)-4-(1H-pyrrolo[2 ,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (90.0mg, 0.194mmol) and 3-(6-fluoro-1-oxo-5-(4- Oxopiperidin-1-yl)) isoindoline-2-yl) piperidine-2,6-dione (70.0mg, 0.194mmol) in DMSO (6.00mL), after stirring for 0.5hr, NaBH was added (OAc) ₃ (164mg, 0.776mmol), then stirred at 35°C for 2hrs. The reaction mixture was quenched with water (20.0 mL), extracted with EA (50.0 mL×2), the organic phases were combined, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure, and the residue was subjected to Prep-HPLC (column: SunFire Prep C8 OBD 10um 19*250mm; mobile phase: A-water (0.1%FA)/B-CH ₃ CN; B%=10%-25%; flow rate: 20mL/min) separation and purification to obtain the title compound (10.2mg, yield 6.58%, white solid). LC-MS (ESI) m/z: 803.1 [M+H] ⁺ . (Sunfire C18 4.6*50mm 5um 2.6min 2.0mL/min; Temperature: 40℃; Gradient: 10%B increase to 30%B for 0.40min, increase to 95%B within 1.60min, 95%B for 0.90min, back to 10% B within 0.01min) RT = 0.841min. ¹ H NMR (400MHz,DMSO-d ₆ )δ12.56–12.24(m,1H),11.16–10.83(m,1H),8.98–8.72(m,1H),8.64–8.55(m,1H),8.38 –8.32(m,1H),8.29–8.24(m,1H),8.18–8.04(m,1H),8.01–7.88(m,1H),7.48–7.36(m,1H),7.30–7.19(m, 2H),5.16–4.98(m,1H),4.55–4.42(m,1H),4.40–4.19(m,2H),3.06–2.85(m,6H),2.83–2.69(m,4H),2.43– 2.16(m,6H), 2.03–1.80(m,5H), 1.76–1.53(m,5H), 1.48–1.29(m,4H), 1.26–1.10(m,3H). ¹⁹ F NMR (377 MHz, DMSO-d ₆ ) δ-56.62 (d, J=253.8 Hz), -121.84 (s).

Example 113: 3-(5-(4-((R)-3-((4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl) Pyrimidin-2-yl)amino)pyrrolidin -1-yl)-[1,4'-bipiperidin-1'-yl)-6-fluoro-1-oxoisoindoline-2-yl) piperidine-2,6-dione

Step 1: 3-(5-(4-((R)-3-((4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidine -2-yl)amino)pyrrolidin-1-yl)-[1,4'-bipiperidin-1'-yl)-6-fluoro-1-oxoisoindoline-2-yl)piper Synthesis of pyridine-2,6-dione

At room temperature, NaHB(OAc) ₃ (209 mg, 0.99 mmol) was added to (R)-N-(1-(piperidin-4-yl)pyrrolidin-3-yl)-4-(1H-pyrrole[2 ,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (50.0mg, 0.330mmol) and 3-(6-fluoro-1-oxo-5-(4-oxo Piperidin-1-yl)isoindolin-2-yl)piperidine-2,6-dione (255mg, 0.660mmol) in DMSO (5.00mL), then stirred at 35°C for 16hrs. After the reaction mixture was filtered, it was filtered by Prep-HPLC (column: SunFire Prep C18 OBD 10um 19*250mm; mobile phase: A-water (0.1% FA)/B-CH ₃ CN; B%=10%-25%; flow rate: 20mL /min) separation and purification to obtain the title compound (5.21 mg, yield 5.80%, white solid). LC-MS (ESI) m/z: 773.4 [MH] ^- . (SunFire C18 50*4.6mm 5um 2.6min 2.0mL/min; Temperature: 40℃; Gradient: 10%B increase to 50%B for 0.40min, increase to 95%B within 1.60min, 95%B hold for 0.90min , back to 10% B within 0.01min) RT = 0.691min. ¹ H NMR (400MHz, DMSO-d ₆ ) δ12.36(s, 1H), 10.96(s, 1H), 8.61–8.55(m, 1H), 8.33(d, J=4.0Hz, 1H), 8.24( s,1H),8.15–8.00(m,1H),7.92(d,J=9.6Hz,1H),7.40(d,J=11.6Hz,1H),7.23(d,J=7.6Hz,2H), 5.13–5.00(m,1H),4.44(brs,1H),4.36–4.18(m,2H),3.51(s,3H),2.95–2.84(m,4H),2.80–2.62(m,4H), 2.45–2.27(m,3H),2.24–2.12(m,3H),1.90–1.75(m,2H),1.82(m,5H),1.65–1.52(m,2H),1.42–1.29(m,2H ). ¹⁹ F NMR (377MHz, DMSO) δ -55.64(s), -121.95(s).

Example 114: 3-(5-(4-((4-((R)-3-((4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(tri Fluoromethyl)pyrimidin-2-yl)amino)pyrrolidin -1-yl)piperidin-1-yl)methyl)piperidin-1-yl)-6-fluoro-1-oxoisoindoline -2-yl)piperidine-2,6-dione, trifluoroacetate

Step 1: 3-(5-(4-((4-((R)-3-((4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoro Methyl) pyrimidin-2-yl) amino) pyrrolidin-1-yl) piperidin-1-yl) methyl) piperidin-1-yl)-6-fluoro-1-oxoisoindoline-2 Synthesis of -yl)piperidine-2,6-dione trifluoroacetate

(R)-N-(1-(piperidin-4-yl)pyrrolidin-3-yl)-4-(1H-pyrrole[2,3-b]pyridin-3-yl)-5-(tri Fluoromethyl)pyrimidin-2-amine (80.0mg, 0.180mmol) was added to 1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindole Lin-5-yl)piperidine-4-carbaldehyde (69.0mg, 0.180mmol) in DMSO (4.00mL), after stirring at room temperature for 1hr, NaHB(OAc) ₃ (118mg, 0.560mmol) was added, and then at 35°C Stir for 16hrs. The reaction mixture was filtered, and the filtrate was subjected to Prep-HPLC (column: SunFire Prep The title compound ( _25.0mg , Yield 17.2%, white solid). LC-MS (ESI) m/z: 789.4 [M+H] ⁺ . (SunFire C18 50*4.6mm 5um 2.6min 2.0mL/min; Temperature: 40℃; Gradient: 10%B increase to 50%B for 0.40min, increase to 95%B within 1.60min, 95%B hold for 0.90min , back to 10% B within 0.01min) RT = 0.637min. ¹ H NMR (400MHz, MeOD-d ₄ )δ8.86(s, 1H), 8.64(s, 1H), 8.32(d, J=3.4Hz, 1H), 8.01(s, 1H), 7.42(d, J＝11.4Hz, 1H), 7.30–7.25(m, 1H), 7.20(d, J＝7.4Hz, 1H), 5.12–5.08(m, 1H), 4.46–4.34(m, 2H), 3.78(s ,4H),3.63–3.42(m,5H),3.23–2.96(m,4H),2.94–2.76(m,4H),2.61(s,1H),2.54–2.38(m,3H),2.36–2.27 (m,1H),2.26–1.96(m,5H),1.92(d,J＝12.4Hz,2H),1.59–1.47(m,2H). ¹⁹ F NMR(377MHz,MeOD)δ-77.08(s) ,-123.51(s).

Example 115: 3-(3-(4-((4-(2-((R)-3-((4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-5 -(trifluoromethyl)pyrimidin-2-yl)amino) pyrrolidin-1-yl)ethyl)piperazin-1-yl)methyl)piperidin-1-yl)phenyl)piperidine-2, 6-diketone

Step 1: (R)-4-(2-(3-((4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidine-2- Synthesis of tert-butyl)amino)pyrrolidin-1-yl)ethyl)piperazine-1-carboxylate

4-(2-Bromoethyl)piperazine-1-carboxylic acid tert-butyl ester (500 mg, 1.80 mmol) was added to (R)-N-(pyrrolidin-3-yl)-4-(1H-pyrrolo[ 2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine (1.00 g, 2.80 mmol) and K ₂ CO ₃ (1.20 g, 8.60 mmol) in DMF (30.0 mL ), and then stirred overnight at 60 °C. After the reaction mixture was cooled to room temperature, it was diluted with water (50.0 mL), extracted with EA (50.0 mL×2), the organic phases were combined, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure, and the residue was subjected to silica gel chromatography (DCM/ MeOH=20/1) separation and purification to obtain the target compound (630 mg, yield 40.1%, yellow solid). LC-MS (ESI) m/z: 561.4 [M+H] ⁺ .

Step 2: (R)-N-(1-(2-(piperazin-1-yl)ethyl)pyrrolidin-3-yl)-4-(1H-pyrrolo[2,3-b]pyridine- Synthesis of 3-yl)-5-(trifluoromethyl)pyrimidin-2-amine

HCl MeOH (4N, 6.00mL) solution was slowly added dropwise to (R)-4-(2-(3-((4-(1H-pyrrolo[2,3-b]pyridin-3-yl)- tert-butyl 5-(trifluoromethyl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)ethyl)piperazine-1-carboxylate (300 mg, 0.540 mmol) in MeOH (15.0 mL), then Stir overnight at room temperature. The reaction mixture was concentrated under reduced pressure to obtain the title compound (240 mg, crude product, yellow solid). LC-MS (ESI) m/z: 461.3 [M+H] ⁺ .

Step 3: 3-(3-(4-((4-(2-((R)-3-((4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-5- (Trifluoromethyl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)ethyl)piperazin-1-yl)methyl)piperidin-1-yl)phenyl)piperidine-2,6 - Synthesis of diketones

Add 1-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carbaldehyde (215mg, 0.720mmol) to (R)-N-(1-(2- (Piperazin-1-yl)ethyl)pyrrolidin-3-yl)-4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidine- 2-Amine (165 mg, 0.360 mmol) in DMSO (5.00 mL) was stirred for 40 minutes, then NaHB(OAc) ₃ (228 mg, 1.10 mmol) was added, followed by stirring overnight at 35°C. The reaction mixture was quenched with water (50.0 mL), extracted with EA (50.0 mL×2), and the organic phase, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure, and the residue was subjected to Prep-HPLC (column: SunFire Prep C8 OBD 10um 19*250mm; mobile phase: A-water (0.1% NH ₄ HCO ₃ )/B -CH ₃ CN; B%=30%-45%; flow rate: 20mL/min) was separated and purified to obtain the title compound (4.94mg, yield 1.84%, white solid). LC-MS (ESI) m/z: 745.1 [M+H] ⁺ . (SunFire C18 50*4.6mm 5um 2.6min 2.0mL/min; Temperature:40℃; Gradient:10%B increase to 30%B for 0.40min,increase to 95%B within 1.60min,95%B for 0.90min, back to 10% B within 0.01min) RT = 0.787min. ¹ H NMR (400MHz,DMSO-d ₆ )δ12.86–12.08(m,1H),10.78(s,1H),8.62–8.55(m,2H),8.33(d,J＝4.0Hz,1H), 8.13–7.87(m,2H),7.27–7.08(m,3H),6.95–6.71(m,2H),6.57(d,J＝7.5Hz,1H),4.51–4.36(m,1H),3.80– 3.70(m,1H),3.69–3.60(m,3H),2.93–2.77(m,2H),2.72–2.56(m,5H),2.45–2.31(m,9H),2.23–2.15(m,3H ), 2.14–2.07(m,2H), 2.04–1.99(m,1H), 1.85–1.69(m,3H), 1.67–1.55(m,2H), 1.27–1.09(m,3H). ¹⁹ F NMR (377 MHz, DMSO-d ₆ ) δ-56.57.

Example 116: 3-(5-(4-(2-(4-((R)-3-((4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-5- (Trifluoromethyl)pyrimidin-2-yl)amino) pyrrolidin-1-yl)piperidin-1-yl)ethyl)piperidin-1-yl)-6-fluoro-1-oxoisoindole Lin-2-yl)piperidine-2,6-dione

Step 1: (R)-4-(3-((4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino ) Synthesis of pyrrolidin-1-yl)piperidine-1-carboxylic acid tert-butyl ester

At room temperature, (R)-N-(pyrrolidin-3-yl)-4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidine- 2-Amine (1.50g, 4.31mmol) was added to tert-butyl 4-oxopiperidine-1-carboxylate (1.72g, 8.61mmol) and glacial acetic acid (1.00mL) in DCE (30.0mL), stirred at room temperature for 1hr Finally, NaHB(OAc) ₃ (2.74 g, 12.9 mmol) was added, followed by stirring at room temperature for 16 hrs. The reaction mixture was quenched with water (200 mL), extracted with DCM (200 mL×2), combined organic phases, dried over anhydrous Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and the residue was subjected to silica gel chromatography (PE/EA=100/1 ) separation and purification to obtain the target compound (2.00g, yellow oil). LC-MS (ESI) m/z: 532.3 [M+H] ⁺ .

Step 2: (R)-N-(1-(piperidin-4-yl)pyrrolidin-3-yl)-4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-5 Synthesis of -(trifluoromethyl)pyrimidin-2-amine

Add HCl·MeOH (4N, 10.0 mL) solution dropwise to (R)-4-(3-((4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(tri Fluoromethyl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)piperidine-1-carboxylic acid tert-butyl ester (1.00 g, 2.18 mmol) in MeOH (2.00 mL), then stirred at room temperature for 4 hrs. The reaction mixture was adjusted to pH 9-10 with NaOH (1M) solution, then extracted with DCM (150mL×2), the organic phases were combined, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to obtain the target compound (1.00g, yellow solid), directly used in the next reaction. LC-MS (ESI) m/z: 432.2 [M+H] ⁺ .

Step 3: 3-(5-(4-(2-(4-((R)-3-((4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-5-( Trifluoromethyl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)piperidin-1-yl)ethyl)piperidin-1-yl)-6-fluoro-1-oxoisoindoline Synthesis of -2-yl)piperidine-2,6-dione

(R)-N-(1-(piperidin-4-yl)pyrrolidin-3-yl)-4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-5-( Trifluoromethyl)pyrimidin-2-amine (142mg, 0.330mmol) was added to 2-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoquinol Lin-5-yl)piperidin-4-yl)acetaldehyde (255mg, 0.660mmol) in DMSO (5.00mL), after stirring at room temperature for 1hr, NaHB(OAc) ₃ (209mg, 0.990mmol) was added, then at 35 Stir at °C for 16 hrs. The reaction mixture was filtered, and the filtrate was subjected to Prep-HPLC (column: SunFire Prep C18 OBD 10um 19*250mm; mobile phase: A-water (0.1% FA)/B-CH ₃ CN; B%=5%-50%; flow rate: 20 mL/min) to obtain the title compound (14.2 mg, yield 5.4%, white solid). LC-MS (ESI) m/z: 803.4 [M+H] ⁺ . (SunFire C18 50*4.6mm 5um 2.6min 2.0mL/min; Temperature: 40℃; Gradient: 10%B increase to 50%B for 0.40min, increase to 95%B within 1.60min, 95%B for 0.90min, back to 10% B within 0.01min) RT = 0.730min. ¹ H NMR (400MHz, MeOD-d ₄ ) δ8.84–8.72 (m, 1H), 8.53 (d, J=18.4Hz, 2H), 8.30 (d, J=4.0Hz, 1H), 7.98 (s, 1H),7.50–7.37(m,1H),7.30–7.23(m,1H),7.19(d,J＝7.4Hz,1H),5.14–5.08(m,1H),4.52–4.34(m,2H) ,3.65–3.48(m,2H),3.45–3.35(m,2H),3.29–3.10(m,2H),3.01–2.94(m,2H),2.94–2.68(m,8H),2.67–2.21( m,4H),2.20–2.03(m,3H),2.00–1.91(m,1H),1.85(d,J＝11.2Hz,2H),1.78-1.72(m,1H),1.71–1.61(m, 2H), 1.60–1.10(m, 4H). ¹⁹ F NMR (377MHz, MeOD-d ₄ ) δ -59.53(s), -123.39(s).

Example 117: 3-(4-(4-((4-(2-((R)-3-((4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-5 -(trifluoromethyl)pyrimidin-2-yl)amino) pyrrolidin-1-yl)ethyl)piperazin-1-yl)methyl)piperidin-1-yl)phenyl)piperidine-2, 6-diketone

Step 1: 3-(4-(4-((4-(2-((R)-3-((4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-5- (Trifluoromethyl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)ethyl)piperazin-1-yl)methyl)piperidin-1-yl)phenyl)piperidine-2,6 - Synthesis of diketones

Add 1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carbaldehyde (508mg, 1.69mmol) to (R)-N-(1-(2- (Piperazin-1-yl)ethyl)pyrrolidin-3-yl)-4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)pyrimidine- 2-Amine (260 mg, 0.570 mmol) in DMSO (8.00 mL) was stirred for 0.5 hr, then NaHB(OAc) ₃ (359 mg, 1.69 mmol) was added, followed by stirring overnight at 35°C. The reaction mixture was quenched with water (40.0 mL), extracted with EA (100 mL×2), the organic phases were combined, dried over anhydrous Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and the residue was subjected to Prep-HPLC (column: Waters Xbridge C18 10um OBD 19*250mm; mobile phase: A-water (0.1%FA)/B-CH ₃ CN; B%=10%-15%; flow rate: 20mL/min) separation and purification to obtain the title compound (4.48mg, yield 1.06%, yellow solid). LC-MS (ESI) m/z: 745.5 [M+H] ⁺ . (SunFire C18 50*4.6mm 5um 2.6min 2.0mL/min; Temperature:40℃; Gradient:10%B increase to 30%B for 0.40min,increase to 95%B within 1.60min,95%B for 0.90min, back to 10% B within 0.01min) RT = 0.727min. ¹ H NMR (400MHz,DMSO-d ₆ )δ12.49–12.32(m,1H),10.77(s,1H),8.63–8.55(m,1H),8.35-8.33(m,3H),7.97–7.89 (m,1H),7.33–7.15(m,1H),7.03(d,J=8.2Hz,2H),6.87(d,J=7.7Hz,2H),4.54–4.41(m,1H),3.75– 3.68(m,2H),2.71–2.58(m,10H),2.39–2.31(m,10H),2.12(d,J＝3.2Hz,5H),2.05–1.96(m,1H),1.89–1.80( m,1H), 1.79–1.70(m,2H), 1.66–1.54(m,1H), 1.24–1.08(m,2H). ¹⁹ F NMR (377 MHz, DMSO-d ₆ ) δ-56.61.

Example 118: 3-(5-(4-((4-(2-((R)-3-((5-chloro-4-(1H-pyrrolo[2,3-b]pyridine-3- Base) pyrimidin-2-yl) amino) pyrrolidin -1-yl) ethyl) piperidin-1-yl) methyl) piperidin-1-yl)-6-fluoro-1-oxoisoindoline -2-yl)piperidine-2,6-dione

Step 1: (R)-4-(2-(3-((5-chloro-4-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)amino)pyrrole Synthesis of tert-butyl alk-1-yl)ethyl)piperidine-1-carboxylate

At room temperature, (R)-5-chloro-N-(pyrrolidin-3-yl)-4-(1H-pyrrolo[2,3-b]pyridin-3-ylpyrimidin-2-amine (200mg, 0.640mmol) was added to 4-(2-oxoethyl)piperidine-1-carboxylic acid tert-butyl ester (144mg, 0.640mmol) in DMSO (5.00mL), after stirring at room temperature for 1hr, NaHB(OAc) ₃ ( 404mg, 1.92mmol), and then stirred at 35°C for 16hrs. The reaction mixture was quenched with water (100mL), extracted with DCM (100mL×2), the organic phases were combined, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure, The residue was separated and purified by silica gel chromatography (DCM/MeOH=20/1) to obtain the target compound (100 mg, yield 29.7%, yellow oil). LC-MS (ESI) m/z: 526.5 [M+H] ⁺ .

Step 2: (R)-5-chloro-N-(1-(2-(piperidin-4-yl)ethyl)pyrrolidin-3-yl)-4-(1H-pyrrolo[2,3- b] Synthesis of pyridin-3-yl)pyrimidin-2-amine

Add HCl·MeOH (4N, 5.00mL) solution dropwise to (R)-4-(2-(3-((5-chloro-4-(1H-pyrrolo[2,3-b]pyridine-3- yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)ethyl)piperidine-1-carboxylic acid tert-butyl ester (100 mg, 0.110 mmol) in MeOH (1.00 mL), then stirred at room temperature for 4 hrs. The reaction mixture was adjusted to pH 9-10 with NaOH (1M) solution, then extracted with DCM (50.0 mL×2), the organic phases were combined, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to obtain the title compound (60.0 mg , yellow solid), directly used in the next reaction. LC-MS (ESI) m/z: 426.3 [M+H] ⁺ .

Step 3: 3-(5-(4-((4-(2-((R)-3-((5-chloro-4-(1H-pyrrolo[2,3-b]pyridin-3-yl ) pyrimidin-2-yl) amino) pyrrolidin-1-yl) ethyl) piperidin-1-yl) methyl) piperidin-1-yl)-6-fluoro-1-oxoisoindoline- Synthesis of 2-yl)piperidine-2,6-dione

(R)-5-chloro-N-(1-(2-(piperidin-4-yl)ethyl)pyrrolidin-3-yl)-4-(1H-pyrrolo[2,3-b] Pyridin-3-yl)pyrimidin-2-amine (45.0mg, 0.110mmol) was added to 1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoiso Indoline-5-yl)piperidine-4-carbaldehyde (39.6mg, 0.110mmol) in DMSO (3.00mL), after stirring at room temperature for 1hr, NaHB(OAc) ₃ (44.8mg, 0.220mmol) was added, and then Stir at 35°C for 16hrs. The reaction mixture was filtered, and the filtrate was subjected to Prep-HPLC (column: SunFire Prep C18 OBD 10um 19*250mm; mobile phase: A-water (0.1% FA)/B-CH ₃ CN; B%=10%-23%; flow rate: 20 mL/min) to obtain the title compound (16.9 mg, yield 20.4%, white solid). LC-MS (ESI) m/z: 783.5 [M+H] ⁺ . (SunFire C18 50*4.6mm 5um 2.6min 2.0mL/min; Temperature: 40℃; Gradient: 10%B increase to 50%B for 0.40min, increase to 95%B within 1.60min, 95%B for 0.90min, back to 10% B within 0.01min) RT = 0.667min. ¹ H NMR (400MHz,DMSO-d ₆ )δ12.39(s,1H),10.96(s,1H),8.55(s,1H),8.41-8.31(m,1H),8.29(s,1H), 8.23(s,1H),7.55-7.42(m,1H),7.39(d,J＝11.6Hz,1H),7.24-7.18(m,2H),5.11-5.01(m,1H),4.37-4.21( m,3H),3.48–3.43(m,3H),2.90–2.60(m,9H),2.42–2.33(m,3H),2.20-2.10(m,3H),2.00-1.94(m,1H), 1.86-1.77(m,5H),1.67-1.58(m,3H), 1.40-1.84 (s, 2H), 1.31-1.21 (m, 3H), 1.17-1.10 (m, 2H). ¹⁹ F NMR (377 MHz, DMSO) δ-122.00 (s).

Example 119: 5-(4-((4-(2-((R)-3-((4-(1H-indol-3-yl)-5-(trifluoromethyl)pyrimidine-2- Base)amino)pyrrolidin-1-yl)ethyl) piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)iso Indoline-1,3-dione

Step 1: 5-(4-((4-(2-((R)-3-((4-(1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl )amino)pyrrolidin-1-yl)ethyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindo Synthesis of Indoline-1,3-dione

1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidine-4-carbaldehyde (120mg, 0.300mmol) Add to (R)-4-(1H-indol-3-yl)-N-(1-(2-(piperidin-4-yl)ethyl)pyrrolidin-3-yl)-5-(tri Fluoromethyl)pyrimidin-2-amine (150 mg, 0.300 mmol) in DMSO (5.00 mL) was stirred for 0.5 hr, then NaHB(OAc) ₃ (190 mg, 0.900 mmol) was added, then stirred at 35°C overnight. The reaction mixture was quenched with water (30.0 mL), extracted with EA (40.0 mL×2), the organic phases were combined, dried over anhydrous Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and the residue was subjected to Prep-HPLC (column: Waters Xbridge C18 10um OBD 19*250mm; mobile phase: A-water (0.1%FA)/B-CH ₃ CN; B%=10%-30%; flow rate: 20mL/min) separation and purification to obtain the title compound (56.2mg, yield yield 23.1%, white solid). LC-MS (ESI) m/z: 812.4 [M+H] ⁺ . (ACQUITY UPLC BEH 1.7um 2.1*50mm 2.0min 0.6mL/min; Temperature: 40℃; Gradient: 10%B increase to 30%B for 0.10min, increase to 95%B within 1.20min, 95%B hold for 0.80 min) RT = 0.837 min. ¹ H NMR (400MHz,DMSO-d ₆ )δ11.83–11.73(m,1H),11.08(s,1H),8.63–8.53(m,1H),8.29–8.15(m,1H),8.02–7.95 (m,1H),7.88–7.81(m,1H),7.65(d,J＝8.5Hz,1H),7.53–7.47(m,1H),7.35–7.27(m,1H),7.25–7.11(m ,3H),5.12–5.00(m,1H),4.54–4.39(m,1H),4.09–3.96(m,2H),3.00–2.78(m,9H),2.25–2.10(m,3H),2.06 –1.94(m,2H),1.90–1.73(m,6H),1.69–1.57(m,2H),1.43–1.34(m,2H),1.26(d,J＝14.7Hz,4H),1.19–1.07 (m,4H). ¹⁹ F NMR (377 MHz, DMSO-d ₆ ) δ-56.29 (d, J=171.9 Hz).

Example 120: 5-(4-((4-(2-((R)-3-((4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(tri Fluoromethyl)pyrimidin-2-yl)amino)pyrrolidin -1-yl)ethyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxo Piperidin-3-yl)isoindoline-1,3-dione

Step 1: 5-(4-((4-(2-((R)-3-((4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoro Methyl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)ethyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiper Synthesis of pyridin-3-yl)isoindoline-1,3-dione

(R)-N-(1-(2-(piperidin-4-yl)ethyl)pyrrolidin-3-yl)-4-(1H-pyrrolo[2,3-b]pyridine-3- Base)-5-(trifluoromethyl)pyrimidin-2-amine (80.0mg, 0.170mmol) was added to 1-(2-(2,6-dioxopiperidin-3-yl)-1,3- Dioxoisoindolin-5-yl)piper Pyridine-4-carbaldehyde (64.3 mg, 0.170 mmol) in DMSO (4.00 mL) was stirred at room temperature for 1 hr, then NaHB(OAc) ₃ (111 mg, 0.510 mmol) was added, followed by stirring at 35°C for 16 hrs. The reaction mixture was filtered, and the filtrate was subjected to Prep-HPLC (column: SunFire Prep C18 OBD 10um 19*250mm; mobile phase: A-water (0.1% FA)/B-CH ₃ CN; B%=5%-30%; flow rate: 20 mL/min) to obtain the title compound (71.0 mg, yield 17.2%, yellow solid). LC-MS (ESI) m/z: 813.4 [M+H] ⁺ . (SunFire C18 50*4.6mm 5um 2.6min 2.0mL/min; Temperature: 40℃; Gradient: 10%B increase to 50%B for 0.40min, increase to 95%B within 1.60min, 95%B hold for 0.90min , back to 10% B within 0.01min) RT = 0.637min. 1H NMR (400MHz, MeOD-d ₄ )δ8.90-8.70(m,1H),8.58(s,1H),8.51(s,1H),8.31(d,J＝3.4Hz,1H),7.99(s ,1H),7.67(d,J=8.6Hz,1H),7.34(d,J=2.2Hz,1H),7.29-7.19(m,2H),5.09–5.03(m,1H),4.75–4.55( m,1H),4.06(d,J＝14Hz,2H),3.06-3.35(m,1H),3.26–3.09(m,2H),3.06–2.93(m,4H),2.93–2.80(m,3H ),2.79–2.60(m,5H),2.59–2.40(m,3H),2.13–1.99(m,3H),1.92–1.82(m,4H),1.57(s,3H),1.47–1.31(m ,4H). ¹⁹ F NMR (377 MHz, MeOD-d ₄ ) δ-59.57 (s).

Example 121: 3-(4-(4-((4-(2-((R)-3-((5-chloro-4-(1H-pyrrolo[2,3-b]pyridine-3- Base) pyrimidin-2-yl) amino) pyrrolidin -1-yl) ethyl) piperidin-1-yl) methyl) piperidin-1-yl) phenyl) piperidine-2,6-dione, FA salt

Step 1: Synthesis of (R)-5-chloro-N-(pyrrolidin-3-yl)-4-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-amine

At room temperature, HCl·MeOH (4N, 9.00mL) solution was slowly added dropwise to (R)-3-((5-chloro-4-(1-(benzenesulfonyl)-1H-pyrrolo[2,3- b] pyridin-3-yl)pyrimidin-2-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester (600 mg, 1.08 mmol) in MeOH (28.0 mL), then stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to obtain the target compound (340 mg, crude product, yellow solid) LC-MS (ESI) m/z: 315.1 [M+H] ⁺ .

Step 2: (R)-4-(2-(3-((5-chloro-4-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)amino)pyrrole Synthesis of tert-butyl alk-1-yl)ethyl)piperidine-1-carboxylate

(R)-5-Chloro-N-(pyrrolidin-3-yl)-4-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-amine (130mg, 0.420mmol ) was added to 4-(2-oxoethyl)piperidine-1-carboxylic acid tert-butyl ester (141mg, 0.620mmol) in DMSO (9.00mL), after stirring for 0.5hr, NaHB(OAc) ₃ (350mg, 1.65mmol), then stirred at room temperature for 3hrs. The reaction mixture was quenched with water (50.0 mL), extracted with EA (50.0 mL×2), the organic phases were combined, dried over anhydrous Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and the residue was subjected to silica gel chromatography (DCM/MeOH=20 /1) Separation and purification to obtain the target compound (170 mg, yield 76.9%, yellow solid). LC-MS (ESI) m/z: 526.1 [M+H] ⁺ .

Step 3: (R)-5-Chloro-N-(1-(2-(piperidin-4-yl)ethyl)pyrrolidin-3-yl)-4-(1H-pyrrolo[2,3- b] Synthesis of pyridin-3-yl)pyrimidin-2-amine

HCl·MeOH (4N, 4.00mL) solution was slowly added dropwise to (R)-4-(2-(3-((5-chloro-4-(1H-pyrrolo[2,3-b]pyridine-3 -yl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)ethyl)piperidine-1-carboxylic acid tert-butyl ester (170mg, 0.320mmol) in MeOH (15.0 mL), then stirred at room temperature for 2hrs. The reaction mixture was concentrated under reduced pressure, adjusted to pH=8-9 with NaOH aqueous solution (2N), extracted with DCM/MeOH (10/1, 100 mL), combined organic phases, dried over anhydrous Na ₂ SO ₄ , and concentrated under reduced pressure to obtain the title compound (90.0 mg, crude product, yellow solid). LC-MS (ESI) m/z: 426.3 [M+H] ⁺ .

Step 4: 3-(4-(4-((4-(2-((R)-3-((5-chloro-4-(1H-pyrrolo[2,3-b]pyridin-3-yl )pyrimidin-2-yl)amino)pyrrolidin-1-yl)ethyl)piperidin-1-yl)methyl)piperidin-1-yl)phenyl)piperidin-2,6-dione FA salt Synthesis

(R)-5-chloro-N-(1-(2-(piperidin-4-yl)ethyl)pyrrolidin-3-yl)-4-(1H-pyrrolo[2,3-b] Pyridin-3-yl)pyrimidin-2-amine (90.0mg, 0.210mmol) was added to 1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carbaldehyde ( 190 mg, 0.530 mmol) in DMSO (8.00 mL), after stirring for 0.5 hr, NaHB(OAc) ₃ (135 mg, 0.630 mmol) was added, followed by stirring overnight at 35°C. The reaction mixture was quenched with water (100 mL), extracted with EA (100 mL×2), combined organic phases, dried over anhydrous Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and the residue was subjected to Prep-HPLC (column: SunFire Prep C18 OBD 10um 19*250mm; mobile phase: A-water (0.1% FA)/B-CH ₃ CN; B%=10%-30%; flow rate: 20mL/min) separation and purification to obtain the title compound (1.80mg, yield 8.51 %, light yellow solid, FA salt). LC-MS (ESI) m/z: 710.5 [M+H] ⁺ . (SunFire C18 50*4.6mm 5um 2.6min 2.0mL/min; Temperature:40℃; Gradient:10%B increase to 30%B for 0.40min,increase to 95%B within 1.60min,95%B for 0.90min, back to 10% B within 0.01min) RT = 0.707min. ¹ H NMR (400MHz,DMSO-d ₆ )δ12.42(s,1H),10.76(s,1H),9.32-8.17(m,1H),8.56(s,1H),8.40–8.27(m,2H ),8.22–8.13(m,1H),7.54(s,1H),7.23(d,J=12.4Hz,1H),7.02(d,J=8.8Hz,1H),6.87(d,J=8.8Hz ,2H),4.47–4.37(m,1H),3.75–3.68(m,2H),3.63(d,J＝12.0Hz,2H),3.05–2.96(m,1H),2.88–2.76(m,3H ),2.68–2.53(m,7H),2.49–2.38(m,1H),2.30–2.14(m,3H),2.14–2.06(m,1H),2.04–1.97(m,1H),1.96–1.80 (m,3H),1.75(d,J=12.0Hz,2H),1.63(d,J=10.8Hz,3H),1.46–1.36(m,2H),1.34–1.25(m,1H),1.25– 1.11(m,4H).

Example 122: 5-(4-((1-(3-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrole Alkyl-1-yl)propyl)-1H- 1,2,3-triazol-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidine-3 -yl)isoindoline-1,3-dione

Add 3-bromopropan-1-ol (232mg, 1.67mmol) to (R)-5-chloro-4-(1H-indol-3-yl)-N-(pyrrolidin-3-yl)pyrimidine- 2-Amine (500mg, 1.59mmol), K ₂ CO ₃ (440mg, 3.19mmol) and KI (396mg, 2.39mmol) in DMF (10.0mL), then stirred at 80°C for 16hrs under nitrogen protection. After the reaction mixture was cooled to room temperature, it was diluted with water (20.0 mL), extracted with EA (20.0 mL×2), the organic phases were combined, dried with anhydrous Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and the residue was subjected to silica gel chromatography. (DCM/MeOH=10/1) separation and purification to obtain the target compound (315 mg, yield 53.4%, yellow oil). LC-MS (ESI) m/z: 372.1 [M+H] ⁺ .

Step 2: Synthesis of (R)-N-(1-(3-bromopropyl)pyrrolidin-3-yl)-5-chloro-4-(1H-indol-3-yl)pyrimidin-2-amine

PPh ₃ (425 mg, 1.40 mmol) was added to (R)-3-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino at 0°C )pyrrolidin-1-yl)propan-1-ol (260mg, 0.700mmol) and CBr ₄ (464mg, 1.40mmol) in DCM (5.00mL), then stirred at room temperature under nitrogen for 16hrs. The reaction mixture was concentrated under reduced pressure, and the residue was separated and purified by silica gel chromatography (DCM/MeOH=10/1) to obtain the target compound (310 mg, yield 98.6%, yellow oil). LC-MS (ESI) m/z: 434.8 [M+H] ⁺ .

Step 3: (R)-N-(1-(3-azidopropyl)pyrrolidin-3-yl)-5-chloro-4-(4-methyl-1H-pyrrol-3-yl)pyrimidine- Synthesis of 2-Amines

(R)-N-(1-(3-bromopropyl)pyrrolidin-3-yl)-5-chloro-4-(1H-indol-3-yl)pyrimidin-2-amine (310mg, 0.710 mmol) and sodium azide (231 mg, 3.55 mmol) were dissolved in DMF (10.0 mL), then stirred at 80° C. for 16 hrs under nitrogen protection. After the reaction mixture was cooled to room temperature, it was diluted with water (20.0 mL), extracted with EA (20.0 mL×2), the organic phases were combined, dried with anhydrous Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and the residue was subjected to silica gel chromatography. (DCM/MeOH=10/1) separation and purification to obtain the target compound (92.0 mg, yield 32.6%, yellow oil). LC-MS (ESI) m/z: 397.1 [M+H] ⁺ .

Step 4: 5-(4-((1-(3-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidine -1-yl)propyl)-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidine-3- base) synthesis of isoindoline-1,3-dione

Add CuI (9.40mg, 50.0mmol) to (R)-N-(1-(3-azidopropyl)pyrrolidin-3-yl)-5-chloro-4-(4-methyl-1H- Pyrrol-3-yl)pyrimidin-2-amine (92.0mg, 0.250mmol) and 2-(2,6-dioxopiperidin-3-yl)-5-(4-(prop-2-yn-1 -yl)piperazin-1-yl)isoindoline-1,3-dione (98.5mg, 0.250mmol) in THF (3.00mL), then stirred at room temperature for 5 minutes, then added DIPEA (0.180mL), Then it was stirred at room temperature for 5 hrs under nitrogen protection. The reaction mixture was filtered, and the filtrate was subjected to Prep-HPLC (column: SunFire Prep C8 OBD 10um 19*250mm; mobile phase: A-water (0.1% TFA)/B-CH ₃ CN; B%=10%-35%; flow rate: 20 mL/min) to obtain the title compound (13.0 mg, yield 6.78%, yellow solid). LC-MS (ESI) m/z: 777.1 [M+H] ⁺ . LC-MS (Sunfire C18 4.6*50mm 5um 2.6min 2.0mL/min; Temperature: 40℃; Gradient: 10%B increase to 30%B for 0.40min, increase to 95%B within 1.60min, 95%B for 0.90 min, back to 10% B within 0.01min) RT = 1.016min. ¹ H NMR (400MHz,DMSO-d ₆ )δ11.90(s,1H),11.08(s,1H),8.66–8.51(m,1H),8.49(s,1H),8.34(s,1H), 8.27(s,1H),7.79–7.66(m,1H),7.56–7.47(m,2H),7.44(s,1H),7.31(s,1H),7.24–7.13(m,2H),5.16– 5.03(m,1H),4.61(s,2H),4.51(s,3H),4.05–3.98(m,1H),3.83–3.74(m,2H),3.68(s,3H),2.89(m, J = 20.2, 11.9, 7.4 Hz, 4H), 2.67 (s, 2H), 2.33 (s, 2H), 2.26 (s, 4H), 2.08 (s, 3H), 2.05–1.97 (m, 2H).

Example 123: 5-(4-((4-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrole Alkyl-1-yl)ethyl)piperidin- 1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindo Indoline-1,3-dione

Step 1: 5-(4-((4-(2-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)pyrrolidine -1-yl)ethyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindole Synthesis of Phenyl-1,3-Diones

(R)-5-chloro-4-(1H-indol-3-yl)-N-(1-(2-(1-(piperidin-4-ylmethyl)piperidin-4-yl) Ethyl)pyrrolidin-3-yl)pyrimidin-2-amine (131mg, 0.250mmol) was added to 2-(2,6-dioxopiperidin-3-yl)-5,6-difluoroisoindole Phenyl-1,3-dione (73.5mg, 0.250mmol) and DIPEA (129mg, 1.00mmol) in DMSO (3.00mL), then stirred at 130°C for 4hrs. The reaction mixture was cooled to room temperature and filtered, and the filtrate was subjected to Prep-HPLC (column: SunFire Prep C8 OBD 10um 19*250mm; mobile phase: A-water (0.1%TFA)/B-CH ₃ CN; B%=10%-35 %; flow rate: 20mL/min) separation and purification to obtain the title compound (51.2mg, yield 25.7%, yellow solid). LC-MS (ESI) m/z: 796.2 [M+H] ⁺ . LC-MS (Sunfire C18 4.6*50mm 5um 2.6min 2.0mL/min; Temperature: 40℃; Gradient: 10%B increase to 30%B for 0.40min, increase to 95%B within 1.60min, 95%B for 0.90 min, back to 10% B within 0.01min) RT = 1.103min. ¹ H NMR (400MHz,DMSO-d ₆ )δ11.84(s,1H),11.11(s,1H),8.47(s,1H),8.27(s,1H),8.20(s,1H),7.70( d,J＝11.0Hz,1H),7.56–7.27(m,3H),7.21-7.18(m,2H),5.11-5.09(m,1H),4.41(brs,1H),3.61-3.56(m, 2H),2.88-2.86(m,6H),2.68(s,2H),2.21-2.16(m,4H),2.05-2.01(m,2H),1.86-1.84(m,7H),1.69-1.58( m,3H), 1.38-1.34(m,2H), 1.28-1.24(m,6H).

Comparative Example 1: N-(7-((R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)piperidin-1-yl)heptan Base)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)oxy)acetamide, Prepared according to the method of WO2020219650A1 Example I-1 (BSJ-04-023).

Examples of in vitro biological experiments

Unless otherwise specified, the experimental materials, reagents, operations and methods used in the following examples of in vitro biological experiments can be obtained from commercially available sources or easily known or prepared based on the prior art.

Embodiment A: Cell Proliferation Inhibition Experiment

HCC70 cells (human breast cancer cells, Zhejiang Meisen Cell Technology Co., Ltd. (CTCC-007-0281)) cultured in RPMI-1640 medium (Gibco, #11875093) (containing 10% FBS and 10% P/S) Seed in 96-well plates at a density of 3 × ¹⁰³ cells per well. Plates were incubated overnight in a 37°C, 5% CO ₂ incubator (overnight attachment step). The next day, various concentrations of test compounds diluted in 100% DMSO were added to each well (final DMSO concentration was 0.2%). After continuing to culture for 72 hrs in a 37°C, 5% CO ₂ incubator, 10 μL of CCK8 (Beyotime, #C0042) was added to each well. Incubate for another 2.5-4hrs at 37°C and 5% CO ₂ incubator, then detect the absorbance value at 450nm with a Tecan microplate reader, and use GraphPad7.0 software to statistically analyze the data and calculate the IC ₅₀ value.

The Jurkat cell (human peripheral blood leukemia T cell, Kebai Bio (DAMZ, ACC-282) proliferation inhibition experiment was carried out similarly to the above operation, except that the density of 5×10 ³ cells per well was used and overnight paste was not performed. Wall steps.

The specific description of this experiment is as follows:

Experimental principle

Cell Counting Kit-8, referred to as CCK-8 kit, is a rapid and high-sensitivity detection kit based on WST-8 that is widely used in cell proliferation and cytotoxicity. WST-8 [chemical name: 2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfonic acid benzene)-2H- Tetrazolium monosodium salt] In the presence of electron coupling reagents (that is, cells are alive, respiration, and energy metabolism), it can be reduced by some dehydrogenases in mitochondria to produce highly water-soluble orange-yellow formazan products formazan. The more and faster the cell proliferation, the darker the color; the greater the cytotoxicity, the lighter the color. For the same cell, there is a linear relationship between the depth of the color and the number of cells.

Experimental Materials

(1) Test compound: the compound of the present invention, and the comparative compound BSJ-04-023 from WO2020/219650A1:

(2) Cells used in the experiment

HCC70: human breast cancer cells, Zhejiang Meisen Cell Technology Co., Ltd. (CTCC-007-0281)

Jurkat: human peripheral blood leukemia T cells, Kebai Bio (DAMZ, ACC-282)

Reagents and consumables

Experimental procedure

1. Compound Preparation

(1) Mother solution preparation: Dissolve the test compound in DMSO (Solarbio D8371) into a 10mM mother solution in a 1.5mL EP tube, store in a 4°C refrigerator for later use. (Mother solution is recommended to be stored at -20°C, it can be stored for about half a year)

(2) Compound dilution: the compound mother solution was diluted with DMSO gradient to a certain concentration, and then used.

(3) Compound dilution: the compound was first diluted to an intermediate concentration with medium, and then added to a 96-well plate in a certain volume to obtain a set final concentration, ensuring that the final concentration of DMSO was <0.2%.

2. Experimental plate layout: 96-well plate

3. Cell Drug Administration Treatment

For HCC70 cells :

(1) HCC70 cell culture: RPMI 1640 (Gibco 11875093) + 10% FBS (Gibco 10099141C) + 10% Penicilin/Streptomycin (10% P/S) (Absin abs9244).

(2) Cell plating: HCC70 cells were plated on a 96-well plate at 3×10 ³ cells/well, and adhered to the wall overnight.

(3) Cell administration: the next day, the compound diluted in gradient was first diluted to an intermediate concentration with medium, and then added to a 96-well plate in a certain volume to obtain the set final concentration, ensuring that the final concentration of DMSO was <0.2% . Gently tap the wall of the plate to make it evenly mixed, and incubate for 72 hours in a 37°C incubator (containing 5% CO ₂ ).

For Jurkat cells :

(1) Jurkat cell culture: RPMI 1640 (Gibco 11875093) + 10% FBS (Gibco 10099141C) + 10% Penicilin/Streptomycin (10% P/S) (Absin abs9244)

(2) Cell plating: Jurkat cells were spread in 96-well plates at 5×10 ³ cells/well

(3) Cell administration: the gradiently diluted compound was first diluted to an intermediate concentration with medium, and then added to a 96-well plate in a certain volume to obtain a set final concentration, ensuring that the final concentration of DMSO was <0.2%. Gently tap the wall of the plate to make it evenly mixed, and incubate for 72 hours in a 37°C incubator (containing 5% CO ₂ ).

4. Detection and data processing

(1) Detection of cell viability:

(a) Add 10 μL of CCK-8 to each well of 96 wells, and incubate for 2.5-4 hours in a 37° C. incubator (containing 5% CO ₂ ).

(b) Detect the absorbance at 450nm on a TECAN SPARK multifunctional microplate reader.

(c) The cell viability was directly calculated according to the absorbance value.

Cell survival rate (%)=[(experimental well-blank well)/(control well-blank well)]x 100

(2) Data processing: GraphPad software was used to count the data, and the IC ₅₀ value was obtained.

See Table 1 for the anti-proliferation activity of the compounds of the present invention on HCC70 cells. The IC50 of the compounds of the examples shown in Table 1 on the proliferation inhibition of HCC70 cells is in the range of 50-3000nM, preferably 50-2500nM, more preferably 50-2000nM, further preferably 50-1500nM, most preferably 50-1000nM. Most of the compounds of the examples showed significantly better ability than the comparative compound BSJ-04-023 in anti-proliferation activity of HCC70 cells. "++++" in Table 1 indicates that the IC50 of the inhibition of HCC70 cell proliferation by the test compound is less than 200nM, and "+++" indicates that the test compound has an inhibitory effect on the HCC70 cell proliferation. The IC50 for the inhibition of cell proliferation is 200-500nM, "++" means that the IC50 for the inhibition of HCC70 cell proliferation by the test compound is 500-1000nM, and "+" means that the IC50 for the inhibition of HCC70 cell proliferation by the test compound is 1000-3000nM .

Table 1: Inhibitory activity of compounds of the present invention on HCC70 cell proliferation

The compounds of the present invention, especially the compounds of the Examples also showed inhibitory activity in the Jurat cell proliferation inhibition test. Fig. 1 shows the dose-response curve (mean ± SD) of the inhibitory activity of comparative compound BSJ-04-023 and Example 20 on Jurkat cell proliferation. It can be seen that after treating Jurkat cells with the compound BSJ-04-023 or the compound of Example 20 for 72hrs, the IC50 of the inhibition of the Jurkat cell proliferation by the comparison compound is 252.5nM, and the compound of Example 20 is 252.5nM for the inhibition of the Jurkat cell proliferation. IC50 is 23.0nM. This shows that the compounds of the present invention, especially the compounds of the examples, compared to the comparative compound (BSJ-04-023), not only exhibit the advantage of anti-proliferative activity on HCC70 cells (Table 1), but also have an antiproliferative effect on JurKat cells. Also exhibited a clear advantage of anti-proliferative activity. Especially in Example 20, the anti-proliferation activity of JurKat cells is 10-20 times that of the comparative compound, which fully demonstrates that the compound of the present invention has better anti-proliferation activity.

Various other cell lines (including human colon cancer HT-29 cell line and human rhabdomyosarcoma A-673 cell line) were also used to similarly carry out tumor cell proliferation inhibition experiments. The results show that the compound of the present invention effectively inhibits tumor cell proliferation. For example, the compound of Example 20 can effectively inhibit the proliferation of other different tumor cells. The IC50 for inhibiting the proliferation of HT-29 cells is 90.7nM, and the IC50 for inhibiting the proliferation of A-673 cells is 20.1nM.

Embodiment B: CDK12 protein degradation experiment (Western Blot)

The degrading activity of the compound of the present invention on the CDK12 protein and the time-dependent relationship of the compound degrading the CDK12 protein were detected in two different cells of Jurkat and HT-29 by Western Blot method.

1. Western Blot sample preparation

(1) Jurkat cells: the Jurkat cells cultured in RPMI1640 (containing 10% FBS and 10% P/S) medium were seeded in a 12-well plate at a density of 2×10 ⁶ cells per well, and each well was added with Test compounds diluted in 100% DMSO with different concentrations (the final concentration of DMSO is 0.2%) were incubated at 37° C. and 5% CO ₂ incubator for 6 hrs. Then gently blow and mix, transfer the cells to a 1.5mL centrifuge tube, centrifuge at 500×g for 5min, remove the supernatant, and wash once with pre-cooled PBS. After removing the supernatant, add 100 μL of RIPA cell lysate (Beyotime, #P0013B), protease inhibitor cocktail (Absin, #abs9161), phosphatase inhibitor cocktail (Beyotime, #P1051), 4 mM MgCl ₂ and super Nuclease (Beyotime, #D7121-5KU), placed on ice for lysis for 25 minutes. After centrifugation at 4°C and 14000 rpm for 10 min, the protein in the supernatant was titrated with Pierce BCA protein detection kit (Thermo Fisher Scientific, #23227).

(2) HT-29 cells: seed HT-29 cells cultured in McCoy's 5A (containing 10% FBS and 10% P/S) medium in a 12-well plate at a density of 5×10 ⁵ cells per well , add different concentrations of test compounds diluted with 100% DMSO to each well (the final concentration of DMSO is 0.2%), incubate at 37°C and 5% CO ₂ incubator for 6hrs, remove the medium, and replace with pre-cooled PBS Wash once. After discarding PBS, add 100 μL RIPA cell lysate (Beyotime, #P0013B), protease inhibitor cocktail (Absin, #abs9161), phosphatase inhibitor cocktail (Beyotime, #P1051), 4mM MgCl ₂ and super Nuclease (Beyotime, #D7121-5KU), placed on ice for lysis for 25 minutes. After centrifugation at 4°C and 14000 rpm for 10 min, the protein in the supernatant was titrated with Pierce BCA protein detection kit (Thermo Fisher Scientific, #23227).

(3) Time-dependent relationship of CDK12 protein degradation: HT-29 cells cultured in McCoy's 5A (containing 10% FBS and 10% P/S) medium were seeded at a density of 5×10 ⁵ cells per well on 12 In the well plate, each well was added with 100% DMSO diluted test compound with a concentration of 2.5 μM (the final concentration of the compound was 5 nM), and incubated at 37 ° C and 5% CO ₂ incubator for 2 hrs, 4 hrs, 6 hrs, 24 hrs and After 48 hrs, remove the medium, wash once with pre-cooled PBS, and then lyse the cells according to the method (2) for protein quantification.

2. Western Blot

Add 25-30 μg of protein to the sample prepared in step 1 and separate it on a large-pore 4-15% SDS-PAGE gradient gel, and use Bio-RAD Turbo ^TM transferred protein to PVDF membrane, blocked with Bio Rad blocking solution at room temperature for 5 minutes, washed the membrane 3 times with TBST, and added rabbit-derived anti-CDK12 antibody diluted in Bio Rad blocking solution (Cell Signaling Technology, #11973S) at 4°C overnight, wash the membrane 3 times with TBST, add goat anti-rabbit HRP-labeled IgG antibody diluted with 5% skimmed milk powder-TBST, incubate at room temperature for 1 hr, wash the membrane 3 times with TBST, add ECL for color development Reagent (Bio Rad, #170-5061), color development with e-Blot chromogenic instrument, semi-quantitative.

The results show that the compound of the present invention has high activity of degrading CDK12 protein, for example, degrading more than 10%, preferably more than 20%, more preferably more than 50%, most preferably more than 90% at a concentration of 200nM. Table 2 shows the CDK12 protein degradation activity in Jurkat cells of the test compound at a concentration of 200nM in this experiment, wherein, "++++" means that more than 90% of the CDK12 protein is degraded; "+++" means that 90-50 % CDK12 protein is degraded; "++" indicates that 50-20% of CDK12 protein is degraded; "+" indicates that less than 20% of CDK12 protein is degraded. Table 2a shows the CDK12 protein degradation activity in HT-29 cells of the test compound at a concentration of 200nM in this experiment, wherein, "++++" means that more than 90% of the CDK12 protein is degraded; "+++" means 90 ~50% of CDK12 protein is degraded; "++" indicates that 50-20% of CDK12 protein is degraded; "+" indicates that less than 20% of CDK12 protein is degraded.

Table 2: CDK12 protein degradation activity of compounds of the present invention (Jurkat cells)

Table 2a: CDK12 protein degradation activity of compounds of the present invention (HT-29 cells)

See Figures 2-4 for the results of Western Blot experiments on the degradation of CDK12 protein by comparative compound BSJ-04-023, Example 27, Example 19 and Example 20, respectively. Figure 2 shows that the comparative compound BSJ-04-023 can degrade CDK12 and CDK13 which is highly homologous to CDK12. Figure 4 shows that Example 19 and Example 20 can degrade CDK12 and CDK13, and the activity of degrading CDK12 is better than that of the comparative compound BSJ-04-023. Figure 3 shows that Example 27 can effectively degrade CDK12, and the activity of degrading CDK12 is significantly better than that of the comparative compound BSJ-04-023. Example 27 cannot degrade CDK13, indicating that Example 27 has higher CDK12 selectivity than the comparative compound BSJ-04-023 in degrading CDK13, which is highly homologous to CDK12.

Figures 5-6 show the time-dependence of the degradation of CDK12 in Example 111 and Example 112, respectively. At a test concentration of 5 nM, the ability of Example 111 and Example 112 to degrade CDK12 was significantly positively correlated with the incubation time of the compound, that is, the longer the incubation time, the stronger the degradation activity on CDK12. Proteasome inhibitor MG132 or NEDD8 activating enzyme (NAE) inhibitor MLN4924 can effectively prevent the degradation of Example 111 and Example 112, indicating that Example 111 and Example 112 degrade CDK12 protein through the ubiquitin-proteasome system.

Example C: Liver Microsome Metabolic Stability Experiment

Human or CD-1 mouse liver microsome mixes were purchased from Corning (#452117) and Xenotech (#M1000), respectively. Liver microsomes were diluted with PBS buffer to an appropriate concentration. Add 10 μL of test compound (final concentration 1 μM), 80 μL liver microsomes (final concentration 0.5 mg/mL) and 10 μL 100 mM potassium phosphate buffer into a 96-well plate, pre-incubate in a 37°C water bath for 10 minutes, and then Add 10 μL of NADPH (Vendor: BONTAC, #BT04) to the regeneration system, continue to incubate at 37°C, and start timing. When the reaction was carried out for 5, 10, 20, 30, and 60 minutes, 300 μL of reaction termination solution (acetonitrile containing 200 ng/mL tolbutamide and 200 ng/mL labetalol) was added to the reaction system to terminate the reaction, and Mix well and centrifuge. Transfer 100 μL of the reaction solution to a new 96-well plate containing 300 μL of ultrapure water. After mixing thoroughly, LC-MS/MS analyzes the amount of the remaining compound in the reaction solution, and fits the natural logarithm of the remaining compound (%) and Time linear regression, calculate the slope (Slope). Calculate T _1/2 and CLint(mic) (μL/min/mg) using the first-order kinetic equation, where Ke is the slope (Slope).

The results show that the compounds of the present invention, especially the compounds of the examples, have better metabolic stability in liver microsomes than the comparative compound (BSJ-04-023). In particular, the examples 20, 21, 27, 39, 40, 41, 77, 78, 95 and 109, etc., in which the L group comprises the ring structure have significantly improved metabolic stability of liver microsomes in mice/humans , the half-life is 10-40 times better than that of the comparative compound in which the L group is a chain structure (Table 3).

The compound of the present invention has good drug metabolism stability, and the t _1/2 is far greater than that of the comparative compound BSJ-04-023, so that the drug can exert pharmacological activity in the body for a prolonged period of time, thus allowing to increase the dosing interval and reduce the Dosage, so that patients have better compliance and reduce potential side effects.

Table 3: Metabolic Stability of Compounds of the Invention

All references mentioned in this application are hereby incorporated by reference in their entirety, as if each were individually set forth. It should be understood that after reading the disclosure of the present invention, those skilled in the art may make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims

A compound of formula (I) or a pharmaceutically acceptable salt, tautomer, stereoisomer, solvate or prodrug thereof,

in

X is N, C or CR x1 ;

Y is each independently O, N, CR y1 , CR y1 R y2 or NR y3 ;

Z is each independently O, N, CR z1 , CR z1 R z2 or NR z3 ;

m and n are each independently 0, 1 or 2, and m+n≤2;

When m is 2, the two Zs can be the same or different; when n is 2, the two Ys can be the same or different;

R x1 is selected from H, hydroxyl, halogen, CN or C 1-6 alkyl;

R y1 , R y2 , R z1 , R z2 and R 4 are each independently selected from H, halogen, CN, NR 6 R 7 , oxo, C 1-6 alkyl, -OC 1-6 alkyl, C 3-8 cycloalkyl, -OC 3-8 cycloalkyl, -C 1-3 alkylene-C 3-8 cycloalkyl, or -OC 1-3 alkylene-C 3-8 cycloalkyl , each of the C 1-6 alkyl, C 1-3 alkylene and C 3-8 cycloalkyl is optionally substituted by a group selected from halogen, C 1-6 alkyl or C 1-6 haloalkyl ;

Ry3 and Rz3 are each independently selected from H, C 1-6 alkyl, C 3-8 cycloalkyl, -CO-C 1-6 alkyl, nitrogen protecting group;

Indicates that the ring may be saturated, partially unsaturated, or aromatic;

R 2 is selected from hydrogen, halogen, CN, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 alkoxy, C 1-3 haloalkyl and cyclopropyl;

R 1 and R 3 are each independently selected from H; Halogen; CN; -OR 5 ; -NR 6 R 7 ; C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 8 cycloalkyl groups, 3-10 membered heterocyclic hydrocarbon groups, each of which is optionally substituted by one or more R 8 ; C 6-10 aryl or 5-10 membered heteroaryl groups, each of which is optionally substituted by one or more R 9 substitution; -CO-R 10a ; -COOR 10b ; -CO-NHR 10c ; -SO-R 10d ; -SO 2 -R 10e ; or -P(=O)R 11 R 12 ;

R is selected from H; C 1-6 alkyl optionally substituted by halogen, hydroxyl, CN and/or C 3-8 cycloalkyl; optionally substituted by halogen, CN and/or C 3-8 cycloalkyl C 3-8 cycloalkyl; optionally one or more R 8 substituted 3-10 membered heterocyclic hydrocarbon group, one or more R 9 substituted C 6-10 aryl, optionally one Or multiple R 9 substituted 5-10 membered heteroaryls;

R 6 and R 7 are each independently selected from H; C 1-6 alkyl, C 3-8 cycloalkyl or 3-10 membered heterocyclic hydrocarbon group, each of which is optionally replaced by one or more selected from halogen, CN, Substituents of OH, C 1-6 alkyl and/or C 3-8 cycloalkyl; C 6-10 aryl or 5-7 membered heteroaryl, each of which is optionally selected from one or more halogen , CN, C 1-6 alkyl, C 1-6 haloalkyl, -C 1-3 alkylene-C 3-8 cycloalkyl, C 3-8 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -OC 1-3 alkylene-C 3-8 cycloalkyl, -SO-C 1-6 alkyl, -SO 2 -C 1-6 alkyl, -SO-C 3-8 cycloalkyl, -SO 2 -C 3-8 cycloalkyl, or -P(=O)R 11 R 12 substituent substitution; -CO-R 10a ; -CO-NHR 10c ; -SO- R 10d ; and -SO 2 -R 10e ; or R 6 , R 7 can form a 4-7 membered heterocyclic ring together with the N they are attached to hydrocarbon group;

R 8 is selected from halogen, CN, OH, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy;

R 9 is selected from halogen, CN, OH, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 1-6 haloalkyl , C 1-6 alkoxy, -C 1-3 alkylene-C 1-6 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, -C 1-3 alkylene -C 3-8 cycloalkyl, -C 3-8 cycloalkylene-C 1-6 alkyl, -C(O)-NHC 1-6 alkyl, -C(O)-NHC 3-8 Cycloalkyl, -SO-C 1-6 alkyl, -SO-C 3-8 cycloalkyl, -SO 2 -C 1-6 alkyl, -SO 2 -C 3-8 cycloalkyl, -P (=O)R 11 R 12 or C 6-10 aryl;

R 10a , R 10b , R 10c , R 10d , R 10e are each independently selected from C 1-6 alkyl, C 3-8 cycloalkyl, 3-10 membered heterocyclic hydrocarbon group, C 6-10 aryl and 5 -10 membered heteroaryl;

R 11 and R 12 are each independently selected from C 1-6 alkyl or C 3-8 cycloalkyl;

L is an absent or saturated or partially unsaturated divalent C 1-24 hydrocarbon chain, wherein one or more hydrocarbon chain units of the hydrocarbon chain are optionally independently selected from the group consisting of -O-, -CO-, - NR L3 -, -SO-, -SO 2 - and/or units of 3-12 membered cyclic groups are replaced, and L is optionally replaced by one or more independently selected from deuterium, halogen, CN, OH, NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, 4-8 membered heterocyclic hydrocarbon groups containing oxygen atoms or nitrogen atoms, and C 3-8 cycloalkyl substituents, Wherein R L3 is H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl or nitrogen protecting group; And wherein, when the two cyclic groups in the linking base L are adjacent , which optionally together form a fused ring, a spiro ring or a bridged ring; and

E is the E3 ubiquitin ligase binding moiety.
The compound according to claim 1, wherein X is N, C or CH; Y is each independently O, N, CH or CH 2 , preferably N, CH or CH 2 , and Z is each independently O, N, CH or CH2 , preferably N, CH or CH2 .
A compound according to any one of the preceding claims, wherein m is 1 and n is 0; or m is 1 and n is 1; or m is 0 and n is 1; or m is 0 and n is 2; or m is 2 and n is 0.
The compound according to any one of the preceding claims, wherein said formula (I) has the structure of formula (Ia):

Wherein, each variable is as defined in claim 1.
A compound according to any one of the preceding claims, wherein Moieties are subunit moieties derived from: azacyclopentane, pyrrole, pyrazole, triazole.
The compound according to any one of the preceding claims, wherein R is selected from H, halogen, CN, oxo, C 1-6 alkyl or C 3-8 cycloalkyl; preferably, R is selected from H , halogen, CN, oxo or C 1-3 alkyl; more preferably, R 4 is hydrogen.
The compound according to any one of the preceding claims, wherein R 1 and R 3 are each independently selected from H; Halogen; CN; OH; NR 6 R 7 ; R 8 is substituted; C 6-10 aryl or 5-10 membered heteroaryl, each of which is optionally substituted by one or more R 9 ;

R6 is H;

R 7 is selected from H; C 3-8 cycloalkyl or 3-10 membered heterocyclic hydrocarbon group, each of which is optionally replaced by one or more selected from halogen, CN, OH, C 1-3 alkyl and/or C 3 Substituents of -6 cycloalkyl; and C 6-10 aryl such as phenyl or 5-7 membered heteroaryl, each of which is optionally selected from one or more C 1-6 alkyl, -SO- Substituents of (C 1-6 alkyl), -SO 2 -(C 1-6 alkyl) or -P(=O)(C 1-6 alkyl)(C 1-6 alkyl);

Preferably, R 7 is selected from H; and C 6-10 aryl such as phenyl or 5-7 membered heteroaryl, each of which is optionally replaced by one or more each independently selected from C 1-6 alkyl, - Substituents of SO-(C 1-6 alkyl), -SO 2 -(C 1-6 alkyl) or -P(=O)(C 1-6 alkyl)(C 1-6 alkyl) ;

R 8 are each independently selected from halogen, CN, OH, C 1-6 alkyl and C 1-6 alkoxy; preferably, R 8 are each independently selected from halogen, CN, OH, C 1-3 alkyl and C 1-3 alkoxy; more preferably, each R is independently selected from halogen and OH; and

Each R 9 is independently selected from halogen, CN, OH, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 1- 6 haloalkyl, C 1-6 alkoxy, -C 1-3 alkylene-C 3-8 cycloalkyl, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, -C 3- 8 Cycloalkylene-C 1-3 alkyl, SO-(C 1-6 alkyl), -SO 2 -(C 1-6 alkyl) or -P(=O)(C 1-6 alkyl )(C 1-6 alkyl); preferably, each R 9 is independently selected from halogen, CN, OH, -NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, -C 1-3 ethylene Alkyl-C 3-6 cycloalkyl, SO-(C 1-6 alkyl), -SO 2 -(C 1-6 alkyl) or -P(=O)(C 1-6 alkyl)( C 1-6 alkyl).
A compound according to any one of the preceding claims, wherein one of R and R is H, and the other is selected from H; C 1-6 haloalkyl; C 1-6 hydroxyalkyl; NR 6 R 7 , wherein R 6 is H, and R 7 is optionally selected from one or more groups selected from C 1-6 alkyl, -SO-(C 1-6 alkyl), -SO 2 -(C 1-6 alkyl) or - P(=O)(C 1-6 alkyl)(C 1-6 alkyl) substituent substituted phenyl or 5-7 membered nitrogen-containing heteroaryl; phenyl; halophenyl; 5-10 Elementary nitrogen-containing heteroaryl such as pyrazolyl, pyridyl, indolyl, indazolyl or azaindolyl, optionally replaced by one or more selected from halogen, CN, C 1-6 alkyl, C 1 -6 haloalkyl, -C 1-3 alkylene-C 3-6 cycloalkyl, SO-(C 1-6 alkyl), -SO 2 -(C 1-6 alkyl) or -P(= O) Substituent substituent of (C 1-6 alkyl)(C 1-6 alkyl).
A compound according to any one of the preceding claims, wherein one of R and R is H, and the other is selected from H, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, phenyl, halophenyl ,
The compound according to any one of the preceding claims, wherein said formula (I) has the structure of formula (Ib):

Wherein, each variable is as defined in claim 1.
A compound according to any one of the preceding claims, wherein the linker L is absent or is a saturated or partially unsaturated divalent C 1-24 hydrocarbon chain, preferably a C 1-18 hydrocarbon chain, more preferably a C 1-12 hydrocarbon chain, Wherein one or more hydrocarbon chain units of the hydrocarbon chain are optionally independently replaced by -O-, -CO-, -NH-, -SO-, -SO 2 - and/or 3-10 membered cyclic groups , and wherein L is optionally selected from one or more independently selected from deuterium, halogen, CN, OH, NH 2 , C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, containing one A 4-6 membered heterocyclic hydrocarbon group of an oxygen atom and a substituent of a C 3-6 cycloalkyl group are substituted; and wherein, when two cyclic groups in the linker L are adjacent, they optionally form a condensed ring together, in the form of spiro or bridged rings;

Preferably, the cyclic groups that are part of L are each independently selected from divalent groups derived from: C 3-8 cycloalkane; 3-8 membered nitrogen-containing heterocyclic hydrocarbon; C 6-10 aromatic ring; 5 -7-membered nitrogen-containing heteroaromatic ring; wherein when two cyclic groups are adjacent, they optionally form a condensed ring, a spiro ring or a bridged ring together; and the cyclic group is optionally surrounded by one or more Substituents independently selected from deuterium, halogen, OH, NH 2 are substituted.
A compound according to any one of the preceding claims, wherein the linker L is selected from:

(i) -(CH 2 ) i -(4-7 membered nitrogen-containing heterocycloalkane)-(CH 2 ) ii -, wherein i and ii are integers from 0 to 11, and i+ii≤11; preferably, -(4-7 membered nitrogen-containing heterocycloalkane)-(CH 2 ) 0-11 -;

(ii) -(CH 2 ) a -(4-7 membered nitrogen-containing heterocycloalkane)-CO-(CH 2 ) b -, wherein a and b are integers from 0 to 10, and a+b≤10; preferably Ground, -(4-7 membered nitrogen-containing heterocycloalkane)-CO-(CH 2 ) 0-10 -;

(iii) -O-(CH 2 ) x -CO-NH-(CH 2 ) y -, wherein x and y are integers from 0 to 9, and x+y≤9;

(iv)-O-(CH 2 ) r -CO-(4-7-membered nitrogen-containing heterocycloalkane)-(CH 2 ) s -(4-7-membered nitrogen-containing heterocycloalkane)-(CH 2 ) t - CO-, where r, s and t are integers from 0 to 7, and r+s+t≤7;

(v)-(CH 2 ) a -(4-7 membered nitrogen-containing heterocycloalkane)-(CH 2 ) b -(4-7 membered nitrogen-containing heterocycloalkane)-(CH 2 ) c -, where a, b and c are integers from 0 to 10, and a+b+c≤10; preferably, -(4-7-membered nitrogen-containing heterocycloalkane)-(CH 2 ) b -(4-7-membered nitrogen-containing heterocycle alkane)-( CH2 ) c- , wherein b and c are integers from 0 to 10, and b+c≤10; and

(vi)-(CH 2 ) x -(4-7 membered nitrogen-containing heterocycloalkane)-(CH 2 ) y -(4-7 membered nitrogen-containing heterocycloalkane)-(CH 2 ) z -CO-, where x, y and z are integers from 0 to 9, and x+y+z≤9; preferably, -(4-7-membered nitrogen-containing heterocycloalkane)-(CH 2 ) y -(4-7-membered Heterocycloalkane)-( CH2 ) z -CO-, y and z are integers from 0 to 9, and y+z≤9; and

(vii) -(CH 2 ) x -(4-7 membered nitrogen-containing heterocycloalkane)-(CH 2 ) y -(4-7 membered nitrogen-containing heterocycloalkane)-CO-(CH 2 ) z -, where x, y and z are integers from 0 to 9, and x+y+z≤9; preferably, -(4-7-membered nitrogen-containing heterocycloalkane)-(CH 2 ) y -(4-7-membered Heterocycloalkane)-CO-(CH 2 ) z -, y and z are integers from 0 to 9, and y+z≤9;

Wherein, the 4-7 membered nitrogen-containing heterocycloalkanes are each independently optionally substituted by OH or halogen.
A compound according to any one of the preceding claims, wherein the linker L is selected from:
A compound according to any one of the preceding claims, wherein E is a moiety of formula (Ea):

in,

V is N or CR v , wherein R v is hydrogen or C 1-6 alkyl optionally substituted by one or more halogen, hydroxyl and/or CN; preferably, V is N, CH, -C(C 1 -6 alkyl)-; More preferably, V is N or CH;

W is a single bond, -NH-, -NH-CO-, -NH- Rw- , or Rw , wherein Rw is C 1-6 optionally substituted by one or more halogen, hydroxyl and/or CN Alkylene; preferably, W is a single bond, -NH-, -NH-CO-, -NH-C 1-6 alkylene-, or -C 1-6 alkylene-; more preferably, W is a single bond, -NH-, -NH-CO-, -NH-C 1-3 alkylene-, or -C 1-3 alkylene-;

R is selected from H, halogen, CN or C 1-6 alkyl; preferably, R is selected from H, halogen, CN or C 1-3 alkyl; and

B is a 3-10 membered cyclic group, preferably a C3-8 cycloalkyl group, a 3-10 membered heterocyclic hydrocarbon group (such as a 3-8 membered monocyclic heterocyclic hydrocarbon group or a 7-10 membered bicyclic heterocyclic hydrocarbon group) , C 6-10 aryl (for example phenyl) or 5-10 membered heteroaryl (for example 5-8 membered monocyclic heteroaryl or 7-10 membered bicyclic heteroaryl), any of the cyclic groups Optionally replaced by one or more R s2 ;

wherein R s2 are each independently selected from halogen, CN, OH, oxo, NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , C 1-6 alkyl , C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 halocycloalkyl, C 3-6 cycloalkyloxy base, -C(O)-C 1-6 alkyl, -C(O)-C 3-6 cycloalkyl, -SO-C 1-6 alkyl, -SO-C 3-6 cycloalkyl, -SO 2 -C 1-6 alkyl, -SO 2 -C 3-6 cycloalkyl, C 6-10 aryl and halogenated C 6-10 aryl; preferably, each R s2 is independently selected from halogen , CN, OH, oxo, NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl and C 1-6 alkoxy; more preferably, each of R s2 is independently is selected from halogen, CN, OH, NH 2 and C 1-6 alkyl.
A compound according to claim 13, wherein the moiety of formula (Ea) has the structure of formula (Ea1):

wherein q is 0, 1, 2, 3 or 4, and other variables are as defined in claim 13;

Preferably, wherein: V is N or CH; W is a single bond, -NH-, -NH-C 1-6 alkylene-, or -C 1-6 alkylene-; R a is H; and q is 0.
A compound according to claim 13, wherein the moiety of formula (Ea) has the structure of formula (Ea2):

in,

R a is H, halogen, CN or C 1-6 alkyl; preferably H or C 1-3 alkyl;

U is -CO-, -CR u1 R u1 - or -CO-CR u1 R u1 -, wherein CR u1 and R u1 are each independently H or C 1-6 alkyl; preferably, U is -CO- or -CH2- ;

R s2 are each independently selected from halogen, CN, OH, NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl and C 1-6 alkoxy; preferably, R s2 are each independently selected from halogen, CN, OH, C 1-3 alkyl or C 1-3 haloalkyl; and

r is 0, 1, 2, 3 or 4.
A compound according to claim 13, wherein the moiety of formula (Ea) has the structure of formula (Ea3):

in,

P is N, C or CH;

Q is N, NH, -CO-, -CR q1 R q1 - or -CO- CR q1 R q1 -, wherein CR q1 and R q1 are each independently H or C 1-6 alkyl such as C 1-3 alkane group; preferably, Q is N, NH, -CO- or -CH 2 -; and

R s2 is H or C 1-6 alkyl such as C 1-3 alkyl;

represents a single or double bond; and

V, W and Ra are as defined in claim 13.
A compound according to claim 13, wherein the moiety of formula (Ea) is selected from:
The compound of formula (I) or its pharmaceutically acceptable salt, tautomer, stereoisomer, solvate or prodrug according to claim 1, wherein

X is N, C or CH;

Y is each independently N, CH or CH2 ;

Z is each independently N, CH or CH2 ;

m and n are each independently 0, 1 or 2, and m+n≤2;

When m is 2, the two Zs can be the same or different; when n is 2, the two Ys can be the same or different;

R is selected from H, halogen, CN and OH, more preferably H;

Indicates that the ring may be saturated, partially unsaturated, or aromatic;

R 2 is H, halogen, CN or C 1-3 haloalkyl;

One of R 1 and R 3 is H, and the other is H; -NHR 7 ; 5-10 yuan nitrogen-containing heteroaryl, for example 7-10 yuan nitrogen-containing heteroaryl, such as indolyl or 1H-pyrrole [ 2,3-[2,3-b]pyridine (1H-pyrrolo[2,3-b]pyridine);

R 7 is phenyl, optionally replaced by -SO-(C 1-6 alkyl), -SO 2 -(C 1-6 alkyl) or -P(=O)(C 1-6 alkyl) (C 1-6 alkyl) substitution;

L is a saturated or partially unsaturated divalent C 1-18 hydrocarbon chain, preferably a C 1-12 hydrocarbon chain, wherein one or more hydrocarbon chain units of the hydrocarbon chain are optionally independently represented by -O-, -CO- , -NH-, -SO-, -SO 2 -, 3-8 membered nitrogen-containing heterocycloalkanes and/or 5-7 membered nitrogen-containing heterocycloalkanes Aromatic ring substitution, and wherein, when two cyclic groups in the linker L are adjacent, they optionally form together a fused ring, a spiro ring or a bridged ring; and

E is part of the following formula:

wherein R a is H or C 1-3 alkyl, and U is -CO- or -CH 2 -; R s2 are each independently selected from halogen, CN, or C 1-3 alkyl, preferably halogen; and

r is 0 or 1.
A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, tautomer, stereoisomer, solvate or prodrug thereof, wherein said compound has formula (Ib):

in

R 2 is H, halogen, CN or C 1-3 haloalkyl, preferably H, halogen, CN or CF 3 , more preferably halogen;

One of R 1 and R 3 is H, and the other is H; -NHR 7 ; 5-10 yuan nitrogen-containing heteroaryl, for example 7-10 yuan nitrogen-containing heteroaryl, such as indolyl or 1H-pyrrole [ 2,3-[[]pyridyl;

R 7 is phenyl, optionally replaced by -SO-(C 1-6 alkyl), -SO 2 -(C 1-6 alkyl) or -P(=O)(C 1-6 alkyl) (C 1-6 alkyl) substitution;

L is a saturated or partially unsaturated divalent C 1-12 hydrocarbon chain, wherein one or more hydrocarbon chain units of the hydrocarbon chain are optionally independently replaced by -O-, -CO-, -NH- and/or 4 -7-membered nitrogen-containing heterocycloalkane (such as piperidine ring, piperazine ring, tetrahydropyrrole, azetidine) replacement, and wherein, when the two cyclic groups in the linker L are adjacent, they optionally taken together to form a fused, spiro or bridged ring; and

E is part of the following formula:

wherein R a is H or C 1-3 alkyl, and U is -CO- or -CH 2 -; R s2 are each independently selected from halogen, CN, or C 1-3 alkyl, preferably halogen; and

r is 0 or 1.
The compound according to claim 1, wherein said compound is selected from:
A pharmaceutical composition comprising a compound according to any one of claims 1-21 or a pharmaceutically acceptable salt, tautomer, stereoisomer, solvate or prodrug thereof, and one or more pharmaceutically acceptable carrier, diluent or excipient.
The compound of any one of claims 1-21 or a pharmaceutically acceptable salt, tautomer, stereoisomer, solvate or prodrug thereof for use in the treatment or prevention of CDK12-related diseases or disorders.
A method for treating or preventing a CDK12-associated disease or disorder in an individual, the method comprising administering to the individual an effective amount of the compound of any one of claims 1-21 or a pharmaceutically acceptable salt, tautomer, stereo isomers, solvates or prodrugs.
Use of the compound of any one of claims 1-21 or its pharmaceutically acceptable salt, tautomer, stereoisomer, solvate or prodrug in the preparation of a medicament, wherein the medicament is used for the treatment or Prevention of a CDK12-associated disease or condition.
A compound, method or use according to any one of claims 23 to 25, wherein the disease is selected from abnormal cell proliferation Reproductive disease, myotonic dystrophy type I, infection (e.g. viral eg herpes, HIV infection, fungal infection), inflammatory condition (e.g. rheumatoid arthritis, osteoarthritis), autoimmune disease (e.g. psoriasis , lupus, type 1 diabetes, diabetic nephropathy, multiple sclerosis, glomerulonephritis), cardiovascular diseases (such as myocardial infarction, stroke, atherosclerosis, postoperative vascular stenosis), neurodegenerative diseases (such as Alzheimer's Alzheimer's disease, Parkinson's disease) and radiation-induced hematopoietic toxicity (eg, myelosuppression, neutropenia, leukopenia, anemia).
The compound, method or use according to any one of claims 23 to 25, wherein the CDK12-associated disease or condition is tumor and/or cancer, such as breast cancer, ovarian cancer, prostate cancer, central nervous system tumor (such as spinal tumor, brainstem tumor) Glioma, glioblastoma multiforme, astrocytoma), esophagus, bowel, stomach, liver, pancreas (e.g., pancreatic ductal carcinoma, pancreatic endocrine tumors), colorectal (e.g., colon , rectal cancer), lung cancer (eg, non-small cell lung cancer, small cell lung cancer, bronchoalveolar cell carcinoma), renal cancer, skin cancer (eg, benign and malignant melanoma, basal sarcoma), glioblastoma, schwannoma, Ependymoma, medulloblastoma, neuroblastoma, squamous cell carcinoma, pituitary adenoma, sarcoma (eg, Ewing's sarcoma, angiosarcoma, liposarcoma, myoma), osteochondroma, osteoma, osteosarcoma , seminoma, testicular tumor, uterine cancer (eg, cervical cancer, endometrial cancer), head and neck tumor (eg, maxillary bone tumor, pharyngeal cancer, laryngeal cancer, tongue cancer, intraoral cancer), multiple myeloma, benign and malignant lymphomas (eg, reticulocyte sarcoma, lymphosarcoma, Hodgkin's lymphoma, mantle cell lymphoma), polycythemia vera, leukemias (eg, acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia), thyroid tumors, ureteral tumors, bladder tumors, gallbladder carcinoma, cholangiocarcinoma, choriocarcinoma, pediatric tumors (eg, Ewing familial sarcoma, Wilms sarcoma, rhabdomyosarcoma, embryonal testicular tumor, retinoblastoma Tumor, Wilms tumor).
A pharmaceutical combination product comprising a compound according to any one of claims 1-21 and other active agents.