PROTAC chimeric compound as well as preparation method and application thereof

Abstract

Disclosed are a chimeric compound represented by formula (I) or a pharmaceutically acceptable salt and a stereoisomer thereof, and an application thereof in the treatment of diseases such as tumors, immunity or inflammations. The invention also discloses a pharmaceutical preparation, a pharmaceutical composition and application of the chimeric compound.

Description

A PROTAC chimeric compound and its preparation method and use Technical Field

[0001] The present invention belongs to the field of medicine, and specifically relates to a PROTAC chimeric compound and its use in preparing a medicament for treating or preventing diseases such as tumors. Background Art

[0002] Protein degradation targeting chimeras (PROTAC) technology stems from the discovery of ubiquitin (Ub)-regulated protein degradation. Eukaryotic cells constantly strive to maintain appropriate protein levels, producing and degrading thousands of proteins at any given moment. A key factor in maintaining protein homeostasis is a small protein molecule called ubiquitin. When ubiquitin is linked to proteins, it transports them to the proteasome for degradation.

[0003] Targeted protein degradation is an emerging area of ​​drug development. These drugs attempt to engineer small molecules into novel therapeutics. While traditional small molecules block protein function, targeted protein degraders degrade these proteins by delivering them to the proteasome.

[0004] Drs. Craig Crews and Raymond Deshaies designed a series of bifunctional chimeric molecules based on peptide compounds to induce the degradation of methionyl aminopeptidase 2 (MetAP-2). They formally proposed the PROTAC concept and applied for related patent WO2002020740A3. However, because these large and bulky peptide-based linker compounds had difficulty entering cells, the first generation of PROTACs failed.

[0005] In 2008, Crews' team designed the second-generation PROTACs based on the E3 ubiquitin protein ligase MDM2 to degrade the androgen receptor (AR).

[0006] In 2015, Crews' team designed a new generation of PROTACs based on the novel E3 ubiquitin ligase VHL and CRBN ligand.

[0007] Hematopoietic progenitor kinase 1 (HPK1), also known as MAP4K1 (mitogen-activated protein kinase kinase 1), is a serine / threonine kinase and a member of the MAP4K family. There are five other members in the family, including MAP4K2, MAP4K3, MAP4K4, MAP4K5, and MAP4K6.

[0008] The main processes involved in the regulation of TCR by HPK1 are as follows: (1) TCR binds to extracellular antigens through MHC, thereby activating the TCR pathway and transmitting signals to downstream adaptor protein molecules; (2) SLP76 activated by the adaptor protein tyrosine kinases Lck and Zap70 then phosphorylates HPK1; (3) Activated HPK1 then phosphorylates the receptor protein SLP-76; (4) The phosphorylation reaction of SLP-76 provides multiple protein binding sites for the 14-3-3 (TCR pathway inhibitory protein) receptor protein, forming a complex; (5) The SLP-76 phosphorylated complex participates in the downregulation of the Erk signaling pathway and is connected to the ubiquitination and degradation process of SLP76, thereby leading to a decrease in the TCR signaling pathway and T cell proliferation. In summary, HPK1 can negatively regulate the TCR signaling pathway. Therefore, HPK1 can serve as a new regulatory mechanism for T cell-mediated immune responses and become a new target for immune anti-tumor therapy. HPK1 can bind to and interact with numerous adaptor proteins, including the SLP-76 family, CARD11, HIS, HIP-55, GRB2 family, LAT, and CRK family, activating the JNK / SAPK signaling pathway in hematopoietic stem cells, thereby negatively regulating the TCR pathway. Blockade of the Erk MAPK pathway is a mechanism for negatively regulating TCR-induced IL-2 gene transcription.

[0009] HPK1 can interact with numerous adaptor proteins, including those in the SLP-76 family, CARD11, HIS, HIP-55, the GRB2 family, LAT, and the CRK family, activating the JNK / SAPK signaling pathway in hematopoietic stem cells and negatively regulating the TCR pathway. MAP4K3, also known as GLK kinase, has biological effects that are directly opposite to those of HPK1. GLK can promote TCR pathway activation by binding to downstream adaptor proteins.

[0010] To better meet the enormous clinical needs, the present invention aims to provide a novel PROTAC compound with HPK1 inhibitory / degrading activity, which has excellent physicochemical properties and druggability. The compound of the present invention or its pharmaceutically acceptable salt has good safety, good efficacy, and high bioavailability. Therefore, the compound of the present invention has great application potential in the treatment of HPK1-mediated diseases. The compound of the present invention also shows good performance in HPK1 selectivity.

[0011] Summary of the Invention

[0012] One object of the invention is to provide a series of chimeric compounds, wherein the compounds of the present invention have good HPK1 inhibition / degradation activity and are protein degradation-targeted chimeric compounds that can induce HPK1 degradation, as well as the use of the chimeric compounds and their pharmaceutically acceptable salts and stereoisomers in the treatment of tumors, immune or inflammatory diseases.

[0013] The present invention discloses a chimeric compound described by general formula (I):

[0014] [BL] n -HPK1 ligand (I), or a pharmaceutically acceptable salt or stereoisomer thereof,

[0015] The HPK1 ligand is, for example, an HPK1 inhibitor, B is a degradation tag, such as an E3 ligase ligand, L is a linker group between B and the HPK1 ligand, and n is the number of degradation tags attached to the HPK1 ligand, selected from 1, 2, or 3. The choice of the attachment site, number of attachments, and attachment site on the HPK1 inhibitor for the E3 ligase-binding group can affect the activity of the chimeric compound.

[0016] HPK1 ligands

[0017] In a first embodiment, the present invention discloses an HPK1 ligand comprising a moiety of formula (HA) or formula (HB). The first embodiment includes the following embodiments

[0018] Scheme 1: HPK1 ligands include a moiety of formula (HA) or formula (HB)

[0019] or a pharmaceutically acceptable salt, stereoisomer thereof,

[0020] wherein the linking group L of the chimeric compound is independently connected to R 4 or Cy3;

[0021] X0 is C or N, preferably C;

[0022] R 1 It is hydrogen, halogen, -C 1-8 Alkyl, -C2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO2, -OR 1a 、-SO2R 1a 、-COR 1a 、-CO2R 1a 、-CONR 1a R 1b 、-C(=NR 1a )NR 1b R 1c 、-NR 1a R 1b 、-NR 1a COR 1b 、-NR 1a CONR 1b R 1c 、-NR 1a CO2R 1b 、-NR 1a SONR 1b R 1c 、-NR 1a SO2NR 1b R 1c , or -NR 1a SO2R 1b , the-C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with halogen, hydroxy, -C 1-8 Alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl substitution;

[0023] The condition is: when X0 is N, R 1 does not exist;

[0024] R 1a 、R 1b , and R 1c are independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups are each optionally substituted with at least one substituent R 1d Replace; or

[0025] (R 1a and R 1b )、(R 1b and R1c ), or (R 1c and R 1a ) together with the atom or atoms to which they are attached form a 3- to 9-membered ring comprising 0, 1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members, said ring optionally substituted with at least one substituent R 1e replace;

[0026] where R 1d and R 1e are independently hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO2, -OR 1f 、-SO2R 1f 、-COR 1f 、-CO2R 1f 、-CONR 1f R 1g 、-C(=NR 1f )NR 1g R 1h 、-NR 1f R 1g 、-NR 1f COR 1g 、-NR 1f CONR 1g R 1h 、-NR 1f CO2R 1g 、-NR 1f SONR 1g R 1h 、-NR 1f SO2NR 1g R 1h , or -NR 1f SO2R 1g , the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2- 8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with at least one selected from halogen, -C 1-8 Alkyl, -OR 1i 、-NR 1i R 1j , cycloalkyl, heterocyclyl, aryl, or heteroaryl substituents;

[0027] R 1f 、R 1g 、R 1h 、R 1i and R 1jare independently hydrogen, -C 1-8 Alkyl, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

[0028] R 2 It is hydrogen, halogen, -C 1-8 Alkyl, preferably hydrogen;

[0029] R 3 It is hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, -NO2, -OR 2a 、-SO2R 2a 、-COR 2a 、-CO2R 2a 、-CONR 2a R 2b 、-C(=NR 2a )NR 2b R 2c 、-NR 2a R 2b 、-NR 2a COR 2b 、-NR 2a CONR 2b R 2c 、-NR 2a CO2R 2b 、-NR 2a SONR 2b R 2c 、-NR 2a SO2NR 2b R 2c , or -NR 2a SO2R 2b , the-C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with halogen, hydroxy, -C 1-8 Alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl substitution;

[0030] R 2a 、R 2b , and R 2c are independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

[0031] L 1 is a single bond, carbonyl (-C(=O)-), C 3-8 Alkylene, halogenated C 3-8 Alkylene, alkenylene, halogenated alkenylene, C 3-8 Alkynylidene, halo C 3-8 Alkynylidene,* 1 -O-Alkylene-** 1 、* 1 -alkylene-O-** 1 、* 1 -NH-alkylene-** 1 、* 1 -alkylene-NH-** 1 、* 1 -NHC(O)-** 1 、* 1 -C(O)NH-** 1 、* 1 -Alkylene-NHC(O)-** 1 、* 1 -alkylene-C(O)NH-** 1 、* 1 -NHC(O)-alkylene-** 1 、* 1 -C(O)NH-alkylene-** 1 ;

[0032] in* 1 refers to the position of attachment to the pyrazole ring, and ** 1 refers to the position of attachment to the backbone (e.g., pyrrolopyridazine);

[0033] R 4 , at each occurrence thereof, is independently hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO2, -OR 4a 、-SO2R 4a 、-SO2NR 4a R 4b 、-COR 4a 、-CO2R 4a 、-CONR 4a R 4b 、-C(=NR 4a )NR 4b R 4c 、-NR 4a R4b 、-NR 4a COR 4b 、-NR 4a CONR 4b R 4c 、-NR 4a CO2R 4b 、-NR 4a SONR 4b R 4c 、-NR 4a SO2NR 4b R 4c , or -NR 4a SO2R 4b , the-C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups are each optionally substituted with at least one substituent R 4d replace;

[0034] R 4a 、R 4b , and R 4c are independently hydrogen, hydroxyl, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups are each optionally substituted with at least one substituent R 4e Replace; or

[0035] (R 4a and R 4b )、(R 4b and R 4c ), or (R 4c and R 4a ) together with the atom or atoms to which they are attached form a 3 to 12 membered ring comprising 0, 1, 2 or 3 further heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members, said ring optionally substituted with at least one substituent R 4e Replace; or

[0036] R 4d and R 4e are independently hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO2, -OR4f 、-SO2R 4f 、-SO2NR 4f R 4g 、-COR 4f 、-CO2R 4f 、-CONR 4f R 4g 、-C(=NR 4f )NR 4g R 4h 、-NR 4f R 4g 、-NR 4f COR 4g 、-NR 4f CONR 4g R 4h 、-NR 4f CO2R 4f 、-NR 4f SONR 4f R 4g 、-NR 4f SO2NR 4g R 4h , or -NR 4f SO2R 4g , the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2- 8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with at least one selected from halogen, -C 1-8 Alkyl, -OR 4i 、-NR 4i R 4j , cycloalkyl, heterocyclyl, aryl, or heteroaryl substituents;

[0037] R 4f 、R 4g 、R 4h 、R 4i , and R 4j are independently hydrogen, -C 1-8 Alkyl, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

[0038] L 2 is a single bond, carbonyl (-C(=O)-), alkylene, cycloalkylene, * 2 -O-** 2 、* 2 -O-Alkylene-** 2 、* 2-alkylene-O-** 2 、* 2 -NH-alkylene-** 2 、* 2 -alkylene-NH-** 2 、* 2 -NHC(O)-** 2 、* 2 -C(O)NH-** 2 , alkenylene, or alkynylene;

[0039] in* 2 is the location of Cy2 attachment, and ** 2 refers to the position of attachment to the backbone (e.g., pyrrolopyridazine);

[0040] Cy2 is a cycloalkylene, heterocyclylene, arylene, or heteroarylene group, each of which is optionally replaced by R 6 replace;

[0041] R 6 Is halogen, hydroxyl, amino, cyano, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO2, -OR 6a 、-SO2R 6a 、-SO2NR 6a R 6b 、-COR 6a 、-CO2R 6a 、-CONR 6a R 6b 、-C(=NR 6a )NR 6b R 6c 、-NR 6a R 6b 、-NR 6a COR 6b 、-NR 6a CONR 6b R 6c 、-NR 6a CO2R 6b 、-NR 6a SONR 6b R 6c 、-NR 6a SO2NR 6b R 6c , or -NR 6a SO2R 6b , the-C 1-8 Alkyl, -C 2-8 Alkenyl, -C2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups are each optionally substituted with at least one substituent R 6d replace;

[0042] R 6a 、R 6b , and R 6c are independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups are each optionally substituted with at least one substituent R 6e replace;

[0043] R 6d and R 6e are independently hydrogen, hydroxy, amino, cyano, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO2, -OR 6f 、-SO2R 6f 、-SO2NR 6f R 6g 、-COR 6f 、-CO2R 6f 、-CONR 6f R 6g 、-C(=NR 6f )NR 6g R 6h 、-NR 6f R 6g 、-NR 6f COR 6g 、-NR 6f CONR 6g R 6h 、-NR 6f CO2R 6f 、-NR 6f SONR 6f R 6g 、-NR 6f SO2NR 6g R 6h , or -NR 6f SO2R 6g , the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with at least one selected from halogen, hydroxy, amino, cyano, -C 1-8 Alkyl, -C 1-8 Alkyl-OH, -OR 6i 、-NR 6i R 6j , cycloalkyl, heterocyclyl, aryl, or heteroaryl substituents;

[0044] R 6f 、R 6g 、R 6h 、R 6i , and R 6j are independently hydrogen, -C 1-8 Alkyl, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

[0045] m is 0, 1, 2, 3 or 4, provided that the valence theory is satisfied (i.e., the resulting valence is chemically possible);

[0046] L 3 Is a single bond, -O- or C 1-8 alkylene;

[0047] Cy3 is a cycloalkyl, heterocyclyl, aryl or heteroaryl group, each of which is replaced by R 7 substituted and optionally by R 8 replace;

[0048] R 7 and R 8 are independently hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO2, -OR 7a 、-SO2R 7a 、-SO2NR 7a R 7b 、-COR 7a 、-CO2R 7a 、-CONR 7a R 7b 、-C(=NR 7a )NR 7b R 7c 、-NR 7a R 7b 、-NR 7a COR 7b 、-NR7a CONR 7b R 7c 、-NR 7a CO2R 7b 、-NR 7a SONR 7b R 7c 、-NR 7a SO2NR 7b R 7c , or -NR 7a SO2R 7b , the-C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups are each optionally substituted with at least one substituent R 7d replace;

[0049] R 7a 、R 7b , and R 7c are independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups are each optionally substituted with at least one substituent R 7e Replace; or

[0050] When m≥1 and p≥1, (R 6 and R 8 ) together with the atom or atoms to which they are attached form a 3 to 12 membered ring comprising 0, 1, 2 or 3 further heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members, said ring optionally substituted with at least one substituent R 7e replace;

[0051] R 7d and R 7e are independently hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO2, -OR 7f 、-SO2R 7f 、-SO2NR 7f R 7g 、-COR 7f 、-CO2R 7f 、-CONR7f R 7g 、-C(=NR 7f )NR 7g R 7h 、-NR 7f R 7g 、-NR 7f COR 7g 、-NR 7f CONR 7g R 7h 、-NR 7f CO2R 7f 、-NR 7f SONR 7f R 7g 、-NR 7f SO2NR 7g R 7h , or -NR 7f SO2R 7g , the-C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2- 8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with at least one selected from halogen, -C 1-8 Alkyl, -OR 7i 、-NR 7i R 7j , cycloalkyl, heterocyclyl, aryl, or heteroaryl substituents;

[0052] R 7f 、R 7g 、R 7h 、R 7i , and R 7j are independently hydrogen, -C 1-8 Alkyl, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

[0053] p is 0, 1, 2, or 3;

[0054] Preferably, X0 is C and / or L 1 and L 2 Each is a single bond.

[0055] Scheme 2: A compound according to Scheme 1, wherein R 4 It is hydrogen, fluorine, amino, or cyano, preferably H.

[0056] Scheme 3: A compound according to Scheme 1, wherein R 4 Yes-C 1-8 Alkyl, -C2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with at least one substituent R 4d replace.

[0057] Scheme 4: A compound according to Scheme 3, wherein R 4 Yes-C 1-6 Alkyl or heterocyclic group, the -C 1-6 The alkyl or heterocyclic group is optionally substituted by at least one substituent R 4d replace.

[0058] Scheme 5: A compound according to Scheme 3 or Scheme 4, wherein R 4d It is hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO2, -OR 4f 、-SO2R 4f 、-SO2NR 4f R 4g 、-COR 4f 、-CO2R 4f 、-CONR 4f R 4g 、-C(=NR 4f )NR 4g R 4h 、-NR 4f R 4g 、-NR 4f COR 4g 、-NR 4f CONR 4g R 4h 、-NR 4f CO2R 4f 、-NR 4f SONR 4f R 4g 、-NR 4f SO2NR 4g R 4h , or -NR 4f SO2R 4g , the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with at least one selected from halogen, -C 1-8Alkyl, -OR 4i , or -NR 4i R 4j substituted by a substituent, wherein R 4f 、R 4g 、R 4h 、R 4i and R 4j are each independently hydrogen or -C 1-8 alkyl.

[0059] Scheme 6: A compound according to Scheme 5, wherein R 4d It is hydrogen, F, Cl, -C 1-4 Alkyl, OH, C 3-6 Cycloalkyl, a monocyclic 4-, 5- or 6-membered saturated heterocyclic group containing one oxygen heteroatom as a ring member, or -NR 4f R 4g , the-C 1-4 Alkyl, cycloalkyl or heterocyclyl are each optionally substituted by at least one selected from halogen, -C 1-4 Alkyl, -OR 4i , or -NR 4i R 4j substituted by a substituent, wherein R 4f 、R 4g 、R 4h 、R 4i and R 4j are each independently hydrogen or -C 1-4 alkyl.

[0060] Scheme 7: Compounds according to Scheme 6, wherein R 4d is hydrogen; F; OH; methyl, ethyl, isopropyl, each of which is optionally substituted with one OH; cyclopropyl; oxetanyl; or -NR 4f R 4g .

[0061] Scheme 8: A compound according to any one of Schemes 3 to 7, wherein R 4 Yes-C 1-6 Alkyl (e.g. methyl, ethyl, isopropyl, isopentyl, preferably methyl or ethyl), which is optionally substituted by 1, 2 or 3 F (preferably 1 or 2 F), or 1 -NR 4f R 4g Substituted, where R 4f and R 4g are each independently hydrogen, methyl or ethyl, preferably methyl; preferably, R 4 is unsubstituted -C 1-6 alkyl.

[0062] Scheme 9: A compound according to Scheme 8, wherein R 4It is methyl, ethyl, isopropyl, CHF2, CHF3, Preferred are methyl and ethyl.

[0063] Scheme 10: A compound according to any one of Schemes 3 to 7, wherein R 4 It is a monocyclic 4-, 5-, 6- or 7-membered (preferably 4-, 5- or 6-membered, more preferably 4- or 5-membered) heterocyclic group containing one oxygen heteroatom as a ring member, preferably a monocyclic 4-, 5-, 6- or 7-membered (preferably 4-, 5- or 6-membered, more preferably 4- or 5-membered) saturated heterocyclic group, preferably the heterocyclic group is unsubstituted.

[0064] Scheme 11: A compound according to Scheme 10, wherein R 4 yes (For example Preferred ),or More preferred (For example ).

[0065] Scheme 12: A compound according to any one of Schemes 3 to 7, wherein R 4 is a monocyclic 4-, 5-, 6- or 7-membered (preferably 5- or 6-membered, more preferably 6-membered) heterocyclic group containing one nitrogen heteroatom and optionally one additional heteroatom selected from nitrogen, oxygen or optionally oxidized sulfur as ring members, preferably a monocyclic 4-, 5-, 6- or 7-membered (preferably 5- or 6-membered, more preferably 6-membered) saturated heterocyclic group containing one nitrogen heteroatom and optionally one additional heteroatom selected from nitrogen or oxygen as ring members (preferably pyrrolidinyl, piperidinyl, piperazinyl or oxazepanyl, more preferably piperidinyl), preferably the heterocyclic group is substituted by at least one substituent R 4d More preferably, the heterocyclic group is substituted on the nitrogen ring atom by at least one substituent R 4d replace.

[0066] Scheme 13: A compound according to Scheme 12, wherein R 4 Selected from:

[0067] (For example ), Preferred

[0068] Scheme 14: A compound according to Scheme 12 or Scheme 13, wherein R 4d Selected from hydrogen, -C 1-4 Alkyl, C 3-6 Cycloalkyl, a monocyclic 4-, 5- or 6-membered saturated heterocyclic group containing one oxygen heteroatom as a ring member, said -C 1-4 The alkyl group is optionally substituted with at least one hydroxy group,

[0069] Preferably, R 4d is hydrogen, methyl or ethyl, each of which is optionally substituted with one OH; cyclopropyl; or oxetanyl;

[0070] More preferably, R 4d is hydrogen, methyl, ethyl or oxetanyl.

[0071] Scheme 15: A compound according to Scheme 12, wherein R 4 yes:

[0072] (For example ), (For example ), Preferred

[0073] Scheme 16: A compound according to any one of Schemes 3 to 7, wherein R 4 is a bicyclic 7 to 12 membered heterocyclyl group comprising one nitrogen heteroatom and 0, 1 or 2 further heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members, said heterocyclyl group being optionally substituted on the nitrogen ring atom by at least one substituent R 4e replace.

[0074] Scheme 17: A compound according to Scheme 16, wherein R 4e It is hydrogen, -C 1-8 Alkyl (preferably -C 1-6 alkyl, more preferably methyl or ethyl).

[0075] Scheme 18: A compound according to Scheme 16 or Scheme 17, wherein the heterocyclyl is a bicyclic bridged 7 to 12 membered heterocyclyl.

[0076] Scheme 19: A compound according to Scheme 18, wherein the heterocyclyl is azabicyclo[3.2.1]octane containing 0 or 1 additional nitrogen or oxygen atoms as ring members.

[0077] Scheme 20: A compound according to Scheme 16 or Scheme 17, wherein R 4 yes More preferred

[0078] Scheme 21: A compound according to Scheme 16 or Scheme 17, wherein the heterocyclyl is a bicyclic spiro 7 to 12 membered heterocyclyl.

[0079] Scheme 22: A compound according to Scheme 21, wherein the heterocyclyl is azaspiro[3.3]heptane, azaspiro[3.5]nonane, azaspiro[3.4]octane, azaspiro[5.5]undecane, or azaspiro[4.5]decane, each of which contains 0 or 1 additional nitrogen or oxygen atoms as ring members.

[0080] Scheme 23: A compound according to Scheme 16 or Scheme 17, wherein R 4 yes

[0081] Scheme 24: A compound according to any one of Schemes 3 to 7, wherein R 4 is optionally substituted with halogen, oxo, -C 1-8 Alkyl, -OR 4f , or -NR 4f R 4g Substituted cycloalkyl, wherein R 4f and R 4g are each independently hydrogen or -C 1-8 alkyl.

[0082] Scheme 25: A compound according to Scheme 16 or Scheme 17, wherein R 4 is optionally replaced by -C 1-4 Alkyl (preferably methyl), OH, or -NR 4f R 4g Substituted cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, wherein R 4f and R 4g are each independently hydrogen or -C 1-6 Alkyl (preferably -C 1-4 alkyl, more preferably methyl or ethyl).

[0083] Scheme 26: A compound according to Scheme 16 or Scheme 17, wherein R 4 yes

[0084] Scheme 27: A compound according to Scheme 1, wherein:

[0085] R 1 It is H;

[0086] R 3 It is H;

[0087] X is C;

[0088] L 1 It is a single bond;

[0089] R 4 It is H, -C 1-6 Alkyl, or heterocyclic group, the -C 1-6The alkyl or heterocyclic group is optionally substituted by at least one substituent R 4d replace; and

[0090] R 4d It is hydrogen, halogen, -C 1-8 Alkyl, cycloalkyl, heterocyclic, -OR 4f , or -NR 4f R 4g , the-C 1-8 Alkyl, cycloalkyl or heterocyclyl are each optionally substituted by at least one selected from halogen, -C 1-8 Alkyl, -OR 4i substituted by a substituent, wherein R 4f 、R 4g and R 4i are each independently hydrogen or -C 1-8 alkyl.

[0091] Scheme 28: A compound according to Scheme 27, wherein R 4d It is hydrogen, F, Cl, -C 1-4 Alkyl, OH, C 3-6 Cycloalkyl, a monocyclic 4-, 5- or 6-membered saturated heterocyclic group containing one oxygen heteroatom as a ring member, or -NR 4f R 4g , the-C 1-4 The alkyl group is optionally substituted with at least one OH group, wherein R 4f and R 4g Each independently is -C 1-4 alkyl.

[0092] Scheme 29: A compound according to Scheme 27 or Scheme 28, wherein R 4d is hydrogen, F; OH; methyl or ethyl, each of which is optionally substituted by one OH; cyclopropyl; or oxetanyl, preferably methyl, ethyl or oxetanyl.

[0093] Scheme 30: A compound according to any one of Schemes 27 to 29, wherein R 4 Yes-C 1-6 Alkyl (preferably methyl, ethyl, isopropyl, isopentyl, more preferably methyl or ethyl), which is optionally substituted by 1 or 2 F, or 1 -NR 4f R 4g Substituted, where R 4f and R 4g are each independently hydrogen, methyl or ethyl, preferably methyl; preferably, R 4 is unsubstituted -C 1-6 alkyl.

[0094] Scheme 31: A compound according to Scheme 30, wherein R 4It is methyl, ethyl, CHF2, A methyl group or an ethyl group is preferred, and a methyl group is more preferred.

[0095] Scheme 32: A compound according to Scheme 27 or Scheme 28, wherein R 4 It is a monocyclic 4-, 5-, 6- or 7-membered (preferably 4-, 5- or 6-membered, more preferably 4- or 5-membered) heterocyclic group containing one oxygen heteroatom as a ring member, preferably a monocyclic 4-, 5-, 6- or 7-membered (preferably 4-, 5- or 6-membered, more preferably 4- or 5-membered) saturated heterocyclic group, preferably the heterocyclic group is unsubstituted.

[0096] Scheme 33: A compound according to Scheme 32, wherein R 4 yes (For example ),or More preferred (Preferred ), more preferably (Preferred ).

[0097] Scheme 34: A compound according to Scheme 27 or Scheme 28, wherein R 4 is a monocyclic 4-, 5-, 6- or 7-membered (preferably 5- or 6-membered, more preferably 6-membered) saturated heterocyclic group (preferably pyrrolidinyl, piperidinyl or piperazinyl, more preferably piperidinyl) containing one nitrogen heteroatom as a ring member, preferably the heterocyclic group is substituted by at least one substituent R 4d More preferably, the heterocyclic group is substituted on the nitrogen ring atom by at least one substituent R 4d replace.

[0098] Scheme 35: A compound according to Scheme 34, wherein R 4 Selected from:

[0099] (For example ), Preferred More preferred

[0100] Scheme 36: A compound according to Scheme 34 or Scheme 35, wherein R 4d Selected from hydrogen, -C 1-4 Alkyl, C 3-6 Cycloalkyl, a monocyclic 4-, 5- or 6-membered saturated heterocyclic group containing one oxygen heteroatom as a ring member, said -C 1-4 The alkyl group is optionally substituted with at least one hydroxy group,

[0101] Preferably, R 4d is hydrogen, methyl or ethyl, each optionally substituted with one OH; cyclopropyl; or oxetanyl;

[0102] More preferably, R 4d is hydrogen, methyl, ethyl or oxetanyl, even more preferably methyl or ethyl.

[0103] Scheme 37: A compound according to Scheme 34, wherein R 4 yes:

[0104] (For example ), (For example ),

[0105] Preferred More preferred

[0106] Scheme 38: A compound according to any one of Schemes 27 to 29, wherein R 4 is a bicyclic bridged 7 to 12-membered heterocyclic group or a bicyclic spiro 7 to 12-membered heterocyclic group containing one nitrogen heteroatom, wherein the heterocyclic group is optionally substituted on the nitrogen ring atom by at least one substituent R 4e replace; and

[0107] where R 4e It is hydrogen, -C 1-8 Alkyl (preferably -C 1-6 alkyl, more preferably methyl or ethyl).

[0108] Scheme 39: A compound according to Scheme 38, wherein the bridged heterocyclic group is azabicyclo[3.2.1]octane, which is optionally substituted on the nitrogen ring atom by hydrogen or one -C 1-6 Alkyl substituted, preferably More preferred

[0109] Scheme 40: A compound according to Scheme 38, wherein the spiroheterocyclyl is azaspiro[3.3]heptane, azaspiro[3.5]nonane, azaspiro[3.4]octane, azaspiro[5.5]undecane, or azaspiro[4.5]decane, each of which is optionally substituted on the nitrogen ring atom by hydrogen or one -C 1-6 Alkyl substituted, preferably

[0110] Scheme 41: A compound according to any one of Schemes 1 to 40, wherein:

[0111] R 1 It is H;

[0112] R 3 It is H;

[0113] X is C;

[0114] L 1 It is a single bond;

[0115] R 4 Selected from: H; unsubstituted -C 1-6 alkyl; unsubstituted 4-, 5- or 6-membered (preferably 4- or 5-membered) saturated monocyclic heterocyclic group containing one oxygen heteroatom as a ring member; 5- or 6-membered (preferably 6-membered) saturated monocyclic heterocyclic group containing one nitrogen heteroatom as a ring member (preferably pyrrolidinyl, piperidinyl or piperazinyl, more preferably piperidinyl), said heterocyclic group being substituted on the nitrogen ring atom by at least one substituent R 4d and a bicyclic bridged 7 to 12 membered heterocyclic group containing one nitrogen heteroatom, the heterocyclic group being optionally substituted on the nitrogen ring atom by at least one substituent R 4e replace;

[0116] R 4d is hydrogen, unsubstituted -C 1-8 alkyl or unsubstituted 4-, 5- or 6-membered saturated monocyclic heterocyclyl containing one oxygen heteroatom as a ring member; and

[0117] R 4e is hydrogen, -C 1-8 alkyl.

[0118] Scheme 42: A compound according to Scheme 41, wherein R 4d It is hydrogen-C 1-4 Alkyl, preferably hydrogen, methyl, ethyl or oxetanyl; and / or

[0119] R 4e It is hydrogen-C 1-6 Alkyl, preferably hydrogen, methyl or ethyl.

[0120] Scheme 43: A compound according to Scheme 41 or Scheme 42, wherein:

[0121] R 4 Selected from: methyl, ethyl; (For example ), preferably (For example ); Preferred as well as

[0122] Azabicyclo[3.2.1]octane, optionally substituted on the nitrogen ring atom by a -C 1-6 Alkyl substituted, preferably More preferred

[0123] Scheme 44: A compound according to Scheme 1, wherein:

[0124] R 1 It is H;

[0125] R 3 It is H;

[0126] X is C;

[0127] L 1 It is a single bond;

[0128] n is 0;

[0129] R 4 It is H, -C 1-6 Alkyl, or heterocyclic group, the heterocyclic group is optionally substituted by at least one R 4d replace; and

[0130] R 4d is hydrogen, -C 1-8 an alkyl group or a heterocyclic group.

[0131] Scheme 45: A compound according to Scheme 44, wherein R 4 is hydrogen, methyl or ethyl, preferably methyl or ethyl.

[0132] Scheme 46: A compound according to Scheme 44, wherein R 4 It is a monocyclic 4-, 5- or 6-membered heterocyclic group containing one oxygen heteroatom as a ring member, preferably a monocyclic 4- or 5-membered heterocyclic group.

[0133] Scheme 47: A compound according to Scheme 46, wherein R 4 yes Preferred (Preferred More preferred ).

[0134] Scheme 48: A compound according to Scheme 44, wherein R 4 is a monocyclic 5- to 7-membered heterocyclic group containing one nitrogen heteroatom as a ring member, preferably a monocyclic 6-membered heterocyclic group (preferably piperidinyl), which is optionally substituted on the nitrogen ring atom by at least one substituent R 4d replace;

[0135] Preferably, R 4 for

[0136] Scheme 49: A compound according to Scheme 48, wherein R 4d is hydrogen, -C 1-4 Alkyl, or a monocyclic 4-, 5- or 6-membered saturated heterocyclic group containing one oxygen heteroatom as a ring member;

[0137] Preferably, R 4d It is hydrogen, methyl, ethyl, or oxetanyl, preferably hydrogen, methyl, or ethyl.

[0138] Scheme 50: A compound according to Scheme 48 or Scheme 49, wherein R 4 yes:

[0139] Preferred

[0140] Scheme 51: A compound according to Scheme 44, wherein R 4 is a bicyclic 7- to 12-membered heterocyclic group containing one nitrogen heteroatom, said heterocyclic group being optionally substituted on the nitrogen ring atom by at least one substituent R 4e replace; and

[0141] where R 4e It is hydrogen, -C 1-8 Alkyl (preferably -C 1-6 alkyl, more preferably methyl or ethyl).

[0142] Scheme 52: A compound according to Scheme 51, wherein R 4 is an azabicyclo[3.2.1]octane optionally substituted on the nitrogen ring atom by hydrogen or one -C 1-6 Alkyl substituted, preferably

[0143] Scheme 53: A compound according to any one of Schemes 41 to 44, wherein:

[0144] R 4 Selected from: methyl, ethyl; Preferred Preferred More preferred

[0145] Scheme 54: A compound according to any one of Schemes 1 to 53, wherein R 4 As defined in any one of Schemes 1 to 53),

[0146] L 2 It is a single bond;

[0147] Cy2 is phenylene, pyridylene or pyridone, preferably phenylene or pyridylene;

[0148] m is 1 or 2;

[0149] When m is 1, R 6 relative to the attachment point L 23 or 5, and L 3 relative to the attachment point L 2 3 or 4 (preferably 4);

[0150] When m is 2, an R 6 relative to the attachment point L 2 On the 3rd position, another R 6 relative to the attachment point L 2 5, and L 3 relative to the attachment point L 2 4th position;

[0151] R 6 Is halogen, hydroxyl, amino, cyano, -C 1-8 Alkyl, -CN, nitro, or -OR 6a , the-C 1-8 The alkyl group is optionally substituted with at least one substituent R 6d replace;

[0152] R 6a Yes-C 1-8 Alkyl, the -C 1-8 The alkyl group is optionally substituted with at least one substituent R 6e replace;

[0153] R 6d and R 6e are independently hydroxy, amino, cyano, halogen, -C 1-8 Alkyl, or -NR 6f R 6g , the-C 1-8 The alkyl group is optionally substituted with at least one selected from halogen, hydroxy, amino, cyano, -C 1-8 Alkyl-OH, -C 1-8 Alkyl, -OR 6i , or -NR 6i R 6j Substituents substituted;

[0154] R 6f 、R 6g 、R 6i , and R 6j are each independently hydrogen, or -C 1-8 alkyl.

[0155] Scheme 55: A compound according to Scheme 54, wherein:

[0156] The Cy2 is a phenylene group,

[0157] The Cy2 is a pyridylene group,

[0158] The Cy2 is a pyridinone group,

[0159] Among them, #1 refers to L 2 Attachment location, and ##1 refers to the L 3 Attachment location.

[0160] Scheme 56: A compound according to Scheme 54 or Scheme 56, wherein R 6 A group selected from Groups (1) to (3):

[0161] (1) halogen, preferably fluorine, chlorine, or bromine, more preferably fluorine or chlorine; hydroxyl, amino, or cyano;

[0162] (2) optionally substituted with at least one substituent R 6d Substituted -C 1-6 Alkyl (preferably -C 1-4 alkyl, such as methyl, ethyl or isopropyl, more preferably methyl or ethyl), wherein each R 6d are independently hydroxy, amino, cyano, halogen (preferably fluorine, chlorine, bromine, more preferably fluorine, chlorine), -OR 6f or -NR 6f R 6g , where R 6f and R 6g Each independently is -C 1-6 Alkyl (preferably -C 1-4 alkyl, such as methyl, ethyl or isopropyl, more preferably methyl or ethyl); preferably, each R 6d are independently F or -N(CH3)2;

[0163] (3)-OR 6a , where R 6a is optionally substituted by at least one substituent R 6e Substituted -C 1-6 Alkyl (preferably -C 1-4 alkyl, such as methyl, ethyl or isopropyl, more preferably methyl or ethyl), R 6e is halogen (preferably fluorine, chlorine, bromine, more preferably fluorine, chlorine), hydroxyl or amino; preferably, R 6e It is fluorine;

[0164] Preferably, when R 6 When the group is selected from the groups (1) to (3), Cy2 is the phenylene group.

[0165] Scheme 57: A compound according to any one of Schemes 54 to 56, wherein R 6 It is methyl, ethyl, isopropyl, CF3, F, Cl, Preferred are methyl, ethyl, CF3, F, More preferably, methyl or

[0166] Scheme 58: A compound according to any one of Schemes 1 to 57, wherein L 3 Is a single bond, -O- or C 1-3 The alkylene group (e.g., -CH2-, -CH2CH2-, or -CH(CH3)-) is preferably a single bond, -O-, or -CH2-, and more preferably a single bond.

[0167] Scheme 59: A compound according to any one of Schemes 1 to 58, wherein Cy3 is C 3-12 Cycloalkyl, C 3-12 Heterocyclic group, C 4-5 Aryl, benzene ring, C 7- 12 Aryl, C 4-5 Heteroaryl, C6 heteroaryl or C 7-12 heteroaryl, each of which is replaced by R 7 substituted and optionally by R 8 replace.

[0168] Scheme 60: A compound according to Scheme 59, wherein Cy3 is a monocyclic 3-, 4-, 5-, 6-, or 7-membered cycloalkyl group, preferably

[0169] Scheme 61: A compound according to Scheme 59, wherein Cy3 is a monocyclic 3-, 4-, 5-, 6-, or 7-membered heterocyclyl, or a bicyclic 5- to 12-membered heterocyclyl, each of which contains one or two heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members.

[0170] Scheme 62: A compound according to Scheme 61, wherein Cy3 is a monocyclic 3-, 4-, 5-, 6-, or 7-membered heterocyclyl comprising one or two nitrogen atoms or one oxygen atom as one or more ring members.

[0171] Scheme 63: A compound according to Scheme 61 or Scheme 62, wherein Cy3 is a monocyclic 3-, 4-, 5-, 6-, or 7-membered heterocyclic group containing 0, 1 or 2 nitrogen atoms and 0 or 1 oxygen atoms as one or more ring members, preferably ).

[0172] Scheme 64: A compound according to Scheme 61, wherein Cy3 is a monocyclic 3, 4, 5, 6, or 7-membered heterocyclyl containing 0, 1 or 2 nitrogen atoms and 0 or 1 oxygen atoms as one or more ring members, or a monocyclic 3, 4, 5, 6, or 7-membered heterocyclyl containing 1 or 2 heteroatoms independently selected from optionally oxidized sulfur as ring members, preferably More preferred

[0173] Scheme 65: The compound according to Scheme 61, wherein Cy3 is a bicyclic 5- to 12-membered heterocyclyl containing 0, 1 or 2 nitrogen atoms and 0 or 1 oxygen atoms as one or more ring members, preferably

[0174] Scheme 66: A compound according to Scheme 59, wherein Cy3 is a monocyclic 4-, 5- or 7-membered heteroaryl or a bicyclic 7- to 12-membered heteroaryl, each of which contains one or two heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur.

[0175] Scheme 67: A compound according to any one of Schemes 59 to 66, wherein Cy3 is replaced by R 7 substituted and optionally by R 8 is substituted, and p is 0 or 1.

[0176] Scheme 68: A compound according to any one of Schemes 59 to 67, wherein R 7 is hydrogen, -C 1-8 Alkyl, heterocyclic, -NR 7a R 7b OR 7a , the -C 1-8 The alkyl or heterocyclic group is optionally replaced by an R 7d replace,

[0177] where R 7d Yes-C 1-8 Alkyl (preferably -C 1-6 alkyl, more preferably methyl, ethyl, isopropyl or n-propyl), cycloalkyl (preferably C 3-6 cycloalkyl, more preferably cyclopropyl) or -OR 7f , the -C 1-8 Alkyl, or cycloalkyl is optionally substituted by at least one selected from halogen, -OR 7i , or -NR 7i R 7j Substituents substituted;

[0178] R 7a or R 7b is hydrogen or -C 1-8 Alkyl (preferably -C 1-6 alkyl, more preferably methyl, ethyl, isopropyl or n-propyl);

[0179] where R 7f 、R 7i and R 7j are independently hydrogen, -C 1-8 Alkyl (preferably -C1-6 alkyl, more preferably methyl, ethyl, isopropyl or n-propyl).

[0180] Scheme 69: A compound according to any one of Schemes 59 to 67, wherein R 7 is hydrogen, -C 1-8 Alkyl, heterocyclic, -NR 7a R 7b OR 7a , the -C 1-8 The alkyl or heterocyclic group is optionally replaced by an R 7d replace,

[0181] where R 7d Yes-C 1-8 Alkyl (preferably -C 1-6 alkyl, more preferably methyl, ethyl, isopropyl or n-propyl), cycloalkyl (preferably C 3-6 cycloalkyl, more preferably cyclopropyl), -OR 7f 、-NR 7f R 7g , or a monocyclic 4-, 5- or 6-membered saturated heterocyclic group containing one oxygen heteroatom as a ring atom, wherein the -C 1-8 Alkyl, or cycloalkyl is optionally substituted by at least one selected from halogen, -OR 7i , or -NR 7i R 7j Substituents substituted;

[0182] R 7a or R 7b is hydrogen or -C 1-8 Alkyl (preferably -C 1-6 alkyl, more preferably methyl, ethyl, isopropyl or n-propyl);

[0183] where R 7f 、R 7g 、R 7i and R 7j are independently hydrogen, -C 1-8 Alkyl (preferably -C 1-6 alkyl, more preferably methyl, ethyl, isopropyl or n-propyl).

[0184] Scheme 70: A compound according to any one of Schemes 59 to 69, wherein R 7 Yes-OR 7a , where R 7a is hydrogen or -C 1-8 Alkyl (preferably -C 1-6 alkyl, more preferably methyl, ethyl, isopropyl or n-propyl).

[0185] Scheme 71: A compound according to any one of Schemes 59 to 69, wherein R7 Yes-NR 7a R 7b , where R 7a and R 7b independently selected from hydrogen or -C 1-8 Alkyl (preferably -C 1-6 alkyl, more preferably methyl, ethyl, isopropyl or n-propyl).

[0186] Scheme 72: A compound according to any one of Schemes 59 to 69, wherein R 7 is optionally replaced by an R 7d Substituted -C 1-8 Alkyl, where R 7d Yes-C 1- 8 alkyl (preferably -C 1-6 alkyl, more preferably methyl, ethyl, isopropyl or n-propyl), cycloalkyl (preferably C 3-6 cycloalkyl, more preferably cyclopropyl) or -OR 7f , where R 7f is hydrogen, -C 1-8 Alkyl (preferably -C 1-6 alkyl, more preferably methyl, ethyl, isopropyl or n-propyl).

[0187] Scheme 73: A compound according to any one of Schemes 59 to 69, wherein R 7 is optionally replaced by an R 7d Substituted -C 1-8 Alkyl, where R 7d Yes-C 1- 8 alkyl (preferably -C 1-6 alkyl, more preferably methyl, ethyl, isopropyl or n-propyl), cycloalkyl (preferably C 3-6 cycloalkyl, more preferably cyclopropyl), -OR 7f 、-NR 7f R 7g , or a monocyclic 4-, 5- or 6-membered saturated heterocyclic group containing one oxygen heteroatom as a ring atom, wherein R 7f and R 7g are independently hydrogen, -C 1-8 Alkyl (preferably -C 1-6 alkyl, more preferably methyl, ethyl, isopropyl or n-propyl).

[0188] Scheme 74: A compound according to Scheme 72 or Scheme 73, wherein R 7 It is methyl, cyclopropylmethyl, or hydroxyethyl, preferably methyl.

[0189] Scheme 75: A compound according to Scheme 72 or Scheme 73, wherein R 7 It is methyl, ethyl, cyclopropylmethyl, hydroxyethyl, Preferred are methyl and ethyl.

[0190] Scheme 76: A compound according to any one of Schemes 59 to 69, wherein R 7 is a heterocyclic group, the heterocyclic group is optionally substituted by one R 7d replace,

[0191] where R 7d Yes-C 1-8 Alkyl (preferably -C 1-6 alkyl, more preferably methyl, ethyl, isopropyl or n-propyl), the -C 1-8 The alkyl group is optionally substituted with at least one selected from halogen, -OR 7i , or -NR 7i R 7j substituted by a substituent, wherein R 7i and R 7j are independently hydrogen, -C 1-8 Alkyl (preferably -C 1-6 alkyl, more preferably methyl).

[0192] Scheme 77: A compound according to Scheme 76, wherein the heterocyclyl is a monocyclic 5- or 6-membered heterocyclyl comprising one or two heteroatoms selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members.

[0193] Scheme 78: A compound according to Scheme 77, wherein the heterocyclyl is a monocyclic 6-membered heterocyclyl containing one nitrogen or oxygen as a ring member.

[0194] Scheme 79: A compound according to Scheme 77, wherein said heterocyclyl is piperidinyl or tetrahydropyranyl.

[0195] Scheme 80: A compound according to Scheme 68 or Scheme 69, wherein R 7 yes

[0196] Methyl is preferred.

[0197] Scheme 81: A compound according to Scheme 68 or Scheme 69, wherein R 7 Is ethyl or Ethyl is preferred.

[0198] Scheme 82: A compound according to any one of Scheme 67 to Scheme 81, wherein p is 0.

[0199] Scheme 83: A compound according to any one of Schemes 67 to 81, wherein p is 1, and

[0200] R 8 Yes-C 1-8 Alkyl, oxo, -CN, -OR7a 、-NR 7a R 7b or -CONR 7a R 7b , the -C 1-8 The alkyl group is optionally replaced by an R 7d Substituted, where R 7d Yes-C 1-8 Alkyl (preferably -C 1-6 alkyl, more preferably methyl, ethyl, isopropyl or n-propyl), cycloalkyl (preferably C 3-6 cycloalkyl, more preferably cyclopropyl) or -OR 7f , the -C 1-8 Alkyl, or cycloalkyl is optionally substituted by at least one selected from halogen, -OR 7i , or -NR 7i R 7j Substituents substituted;

[0201] where R 7a and R 7b are each independently hydrogen or -C 1-8 Alkyl (preferably -C 1-6 alkyl, more preferably methyl, ethyl, isopropyl or n-propyl), the -C 1-8 The alkyl group is optionally substituted with at least one substituent R 7e replace,

[0202] R 7e is phenyl, heteroaryl, heterocyclic, wherein the heterocyclic, phenyl, or heteroaryl groups are each optionally substituted by at least one selected from halogen, -C 1-8 Alkyl, -OR 7i , or -NR 7i R 7j Substituents substituted,

[0203] R 7f 、R 7i and R 7j are each independently hydrogen or -C 1-8 Alkyl (preferably -C 1-6 alkyl, more preferably methyl, ethyl, isopropyl or n-propyl).

[0204] Scheme 84: A compound according to Scheme 83, wherein p is 1, and R 8 Yes-C 1-8 Alkyl (preferably -C 1-6 alkyl, more preferably methyl, ethyl, isopropyl or n-propyl).

[0205] Scheme 85: A compound according to Scheme 83, wherein p is 1, and R 8 Yes-C 1-8 Alkyl (preferably -C1-6 alkyl, more preferably methyl, ethyl, isopropyl or n-propyl), and the alkyl is substituted by at least one selected from halogen, -OR 7i , or -NR 7i R 7j substituted by a substituent, wherein R 7i and R 7j are independently hydrogen, -C 1-8 Alkyl (preferably -C 1-6 alkyl, more preferably methyl).

[0206] Scheme 86: A compound according to Scheme 83, wherein p is 1, and

[0207] R 8 Yes-OR 7a , where R 7a is hydrogen or -C 1-8 Alkyl (preferably -C 1-6 alkyl, more preferably methyl, ethyl, isopropyl or n-propyl).

[0208] Scheme 87: A compound according to Scheme 83, wherein p is 1, and

[0209] R 8 Yes-NR 7a R 7b , where R 7a and R 7b independently selected from hydrogen or -C 1-8 Alkyl (preferably -C 1-6 alkyl, more preferably methyl, ethyl, isopropyl or n-propyl).

[0210] Scheme 88: A compound according to Scheme 83, wherein p is 1, and

[0211] R 8 Yes-CONR 7a R 7b ,

[0212] where R 7a is hydrogen, and R 7b is optionally substituted by at least one substituent R 7e Substituted -C 1-8 Alkyl (preferably -C 1-6 alkyl, more preferably methyl, ethyl, isopropyl or n-propyl),

[0213] R 7eis phenyl, heteroaryl (preferably a 5- or 6-membered heteroaryl containing one or two nitrogen atoms as one or more ring members, more preferably pyridyl or pyrimidinyl), heterocyclyl (preferably a monocyclic 4-, 5-, 6-, or 7-membered heterocyclyl or a bicyclic 7- to 12-membered heterocyclyl, each of which contains one or two heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur, more preferably piperidinyl or piperazinyl), each of which is optionally substituted by at least one selected from halogen, -C 1- 8-alkyl, -OR 7i , or -NR 7i R 7j Substituents substituted,

[0214] R 7i and R 7j are each independently hydrogen or -C 1-8 Alkyl (preferably -C 1-6 alkyl, more preferably methyl, ethyl, isopropyl or n-propyl).

[0215] Scheme 89: A compound according to Scheme 83, wherein R 8 yes

[0216] Scheme 90: A compound according to any one of Schemes 54 to 89, wherein, when m≥1 and p≥1, R 6 and R 8 The ring is a 4-, 5-, 6-, 7-, or 8-membered ring containing 1 nitrogen atom and 0 additional heteroatoms (e.g., azetidinyl, pyrrolidinyl, tetrahydropyrrole, pyridine, pyridone, piperidinyl, and azepanyl), which is optionally substituted by at least one substituent R 7e replace.

[0217] Scheme 91: A compound according to any one of Schemes 54 to 89, wherein, when m≥1 and p≥1, R 6 and R 8 The ring formed is a 4-, 5-, 6-, 7- or 8-membered ring (e.g., morpholinyl, piperazinyl, ), said ring is optionally substituted with at least one substituent R 7e replace.

[0218] Scheme 92: A compound according to any one of Schemes 90 to 91, wherein R 7e It is amino, -C 1-8 Alkyl (preferably -C 1-6 alkyl, more preferably methyl or ethyl), -OR 7f 、-NR 7f R 7g , the-C 1-8The alkyl group is optionally substituted with at least one selected from halogen, -NR 7i R 7j , or a cycloalkyl substituent, wherein R 7f 、R 7g 、R 7i and R 7j are independently hydrogen, -C 1-8 Alkyl (preferably -C 1-6 alkyl, more preferably methyl), or C 1-8 Alkoxy-C 1-8 Alkyl-(preferably methoxy-C 1-6 alkyl-, more preferably methoxy-ethyl-).

[0219] Scheme 93: A compound according to Scheme 92, wherein R 7e It is methoxy, methoxy-ethoxy-, -NH2, -N(CH3)2, -NH(CH3), hydroxy, amino, methyl, ethyl, N(CH3)2-(CH2)2-, or cyclopropyl-CH2-.

[0220] Scheme 94: A compound according to Scheme 91, wherein m is 1 or 2, and p is 1.

[0221] Scheme 95: A compound according to Scheme 94, wherein Partly

[0222] where R 6 Is H, or -C 1-4 an alkyl group (e.g., a methyl group or an ethyl group, preferably a methyl group); and

[0223] R 7 It is hydrogen, -C 1-4 Alkyl (eg methyl or ethyl, preferably methyl).

[0224] Scheme 96: A compound according to Scheme 95, wherein Partly (include Preferred ), (include Preferred ).

[0225] Scheme 97: A compound according to any one of Schemes 1 to 59, wherein:

[0226] L 3 It is a single bond;

[0227] Cy3 is a monocyclic 3, 4, 5, 6 or 7-membered cycloalkyl, a monocyclic 3, 4, 5, 6 or 7-membered heterocyclyl containing 0, 1 or 2 nitrogen atoms and 0 or 1 oxygen atoms as one or more ring members, or a monocyclic 3, 4, 5, 6 or 7-membered heterocyclyl containing 1 or 2 heteroatoms independently selected from optionally oxidized sulfur as ring members, wherein each of the cycloalkyl and heterocyclyl groups is replaced by R 7 substituted (preferably on an available ring N atom) and optionally by R 8 replace;

[0228] p is 0 or 1;

[0229] R 7 It is hydrogen, -C 1-6 Alkyl or -NR 7a R 7b , the-C 1-6 The alkyl group is optionally replaced by an R 7d replace,

[0230] R 7d Yes-OR 7f 、-NR 7f R 7g , or a monocyclic 4-, 5- or 6-membered saturated heterocyclyl containing one oxygen heteroatom as a ring atom; and

[0231] When p is 1, then m ≥ 1, and 1 R 6 and R 8 to form a 4-, 5-, 6-, 7- or 8-membered ring comprising 1 nitrogen atom and 1 additional nitrogen or oxygen heteroatom as ring members (e.g., morpholinyl, piperazinyl, ), said ring is optionally substituted with at least one substituent R 7e replace;

[0232] R 7e It is amino, -C 1-6 Alkyl (preferably -C 1-4 alkyl, more preferably methyl or ethyl), -OR 7f 、-NR 7f R 7g , the-C 1-6 The alkyl group is optionally substituted with at least one selected from halogen, -NR 7i R 7j , or a cycloalkyl substituent, and

[0233] R 7a 、R 7b 、R 7f 、R 7g 、R 7i and R 7j are independently hydrogen, -C 1-6 Alkyl (preferably -C1-4 alkyl, more preferably methyl), or C 1-6 Alkoxy-C 1-6 Alkyl-(preferably methoxy-C 1-4 alkyl-, more preferably methoxy-ethyl-), preferably hydrogen or -C 1-4 Alkyl (more preferably methyl).

[0234] Scheme 98: The compound according to Scheme 97, wherein Cy3 is selected from the group consisting of: A monocyclic 3-, 4-, 5-, 6-, or 7-membered heterocyclyl group containing one or two heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members, preferably Preferred More preferred

[0235] Scheme 99: A compound according to Scheme 97 or Scheme 98, wherein R 7 Selected from:

[0236] H;

[0237] -NR 7a R 7b , where R 7a and R 7b independently selected from hydrogen or -C 1-4 Alkyl (preferably methyl, ethyl);

[0238] Optionally replaced by an R 7d Substituted -C 1-4 Alkyl, where R 7d Yes-OR 7f 、-NR 7f R 7g , or a monocyclic 4-, 5- or 6-membered saturated heterocyclic group containing one oxygen heteroatom as a ring atom (preferably ), where R 7f and R 7g are independently hydrogen, -C 1-4 Alkyl (preferably methyl, ethyl);

[0239] Preferably, R 7 It is H, methyl, ethyl, hydroxyethyl, More preferably R 7 is hydrogen, methyl, ethyl or

[0240] Scheme 100: A compound according to Scheme 97, wherein Partly

[0241] where R 6 Is H, or -C1-4 an alkyl group (e.g., a methyl group or an ethyl group, preferably a methyl group); and

[0242] R 7 It is hydrogen, -C 1-4 Alkyl (e.g., methyl or ethyl, preferably methyl);

[0243] Preferably, Partly (include Preferred ), (include Preferred ).

[0244] The present invention provides the HPK1 ligand compound described above, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the HPK1 ligand compound is selected from the exemplary HPK1 ligand compounds disclosed herein, as shown in Table 1 below:

[0245] The linker L portion of the chimeric compound is independently linked to the R portion of the HPK1 ligand compound. 4 Or Cy3 position (such as the example HPK1 ligand compound in Table 1 above), can be R 4 Alternatively, R 4 Or a substituent on Cy3 (such as methyl, ethyl, propyl, hydroxyethyl, etc.) to form a connection. For example:

[0246] wait.

[0247] In some embodiments, the HPK1 ligand comprises the structure:

[0248] In some embodiments, the HPK1 ligand comprises a moiety of formula (H-1) or (H-2)

[0249] or a pharmaceutically acceptable salt, stereoisomer thereof,

[0250] X0 is CH or N, preferably CH;

[0251] X is CH or N;

[0252] m is 0, 1, or 2;

[0253] R 6 Is halogen, hydroxyl, amino, cyano, -C 1-8 Alkyl, -CN, nitro, or -OR 6a , the-C 1-8 The alkyl group is optionally substituted with at least one substituent R 6d replace;

[0254] R 6a Yes-C 1-8 Alkyl, the -C 1-8 The alkyl group is optionally substituted with at least one substituent R 6e replace;

[0255] R 6d and R 6e are independently hydroxy, amino, cyano, halogen, -C 1-8 Alkyl, or -NR 6f R 6g , the-C 1-8 The alkyl group is optionally substituted with at least one selected from halogen, hydroxy, amino, cyano, -C 1-8 Alkyl-OH, -C 1-8 Alkyl, -OR 6i , or -NR 6i R 6j Substituents substituted;

[0256] R 6f 、R 6g 、R 6i , and R 6j are each independently hydrogen, or -C 1-8 alkyl.

[0257] In some embodiments, the HPK1 ligand is selected from:

[0258] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0259] B is a degradation label.

[0260] In some embodiments, B is a group that binds to an E3 ligase, wherein the E3 ligase is selected from von Hippel-Lindau (VHL), Cereblon, XIAP, E3A, MDM2, anaphase-promoting complex (APC), UBR5 (EDD1), SOCS / BC-box / eloBC / CUL5 / RING, LNXp80, CBX4, CBLL1, HACE1, HECTD1, HECTD2, HECTD3, HECW1, HECW2, HE RC1, HERC2, HERC3, HERC4, HUWE1, ITCH, NEDD4, NEDD4L, PPIL2, PRPF19, PIAS1, PIAS2, PIAS3, PIAS4, RANBP2, RNF4 , RBX1, SMURF1, SMURF2, STUB1, TOPORS, TRIP12, UBE3A, UBE3B, UBE3C, UBE4A, UBE4B, UBOX5, UBR5, WWP1, WWP2, Park in, A20 / TNFAIP3, AMFR / gp78, ARA54, β-TrCP1 / BTRC, BRCA1, CBL, CHIP / STUB1, E6, E6AP / UBE3A, F-box protein 15 / FBXO1 5. FBXW7 / Cdc4, GRAIL / RNF128, HOIP / RNF31, cIAP-1 / HIAP-2, cIAP-2 / HIAP-1, cIAP(pan), ITCH / AIP4, KAP1, MARCH 8. MindBomb1 / MIB1, MindBomb2 / MIB2, MuRF1 / TRIM63, NDFIP1, NEDD4, NleL, Parkin, RNF2, RNF4, RNF8, RNF168, RN F43, SART1, Skp2, SMURF2, TRAF-1, TRAF-2, TRAF-3, TRAF-4, TRAF-5, TRAF-6, TRIM5, TRIM21, TRIM32, UBR5, or ZNRF3.

[0261] Furthermore, the B is a group that binds to an E3 ligase selected from VHL, Cereblon, MDM2 or cIAP.

[0262] In some embodiments, the general formula of B is as follows:

[0263] in,

[0264] Each G is independently selected from CR C2 R C3 NRC2 , CO, SO2;

[0265] Y is selected from absent, NH;

[0266] s is selected from 0, 1 or 2;

[0267] Each of W1, W2, W3, W4, and W5 is independently selected from N or CR C4 ;

[0268] Each X1 is independently selected from O or S;

[0269] Each V1 is independently selected from the group consisting of absent, NH, O, S, SO, SO2, SO2NR C2 、CO、CO2、C(O)NR C2 、C(S)NR C2 NR C2 NR C2 CO、NR C2 CONR C3 、-C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are each optionally replaced by R C4 Substitution, preferably selected from absence, -O-, -CH2-, -CH=CH-, -NH-;

[0270] Each V2 is independently selected from CR C2 R C3 NR C2 , O or S;

[0271] Each Z is independently selected from hydrogen, halogen, hydroxy, amino, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are each optionally replaced by R C5 replace;

[0272] R C1 、R C2 、R C3 、R C4 、R C5 Selected from hydrogen, carboxyl, cyano, nitro, halogen atoms, -C 1-8Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR C6 、-SO2R C6 、-SO2NR C6 R C7 、-COR C6 、-CO2R C6 、-CONR C6 R C7 、-POR C6 R C7 、-NR C6 R C7 、-NR C6 COR C7 、-NR C6 CONR C7 R C8 、-NR C6 CO2R C7 、-NR C6 SO2NR C7 R C8 、-NR C6 SO2R C7 , the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are each optionally substituted with at least one substituent R C9 replace;

[0273] R C6 、R C7 、R C8 、R C9 Selected from hydrogen, halogen, hydroxy, amino, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl.

[0274] Further,

[0275] G is selected from CH2, CO, SO2, NH or NC 1-6 alkyl;

[0276] X1 is selected from O or S;

[0277] V1 is selected from the group consisting of absent, NH, O, -C 1-8 Alkyl, -C 2-8 Alkenyl is preferably selected from absent, -O-, -CH2-, -CH=CH-, and -NH-.

[0278] V2 is selected from NH, NC 1-6Alkyl, NC 6-10 Aryl, N-3-10 membered heterocyclic group, N-5-10 membered heteroaryl, NC 3-10 Cycloalkyl, O or S;

[0279] Z is selected from C 1-6 Alkyl, C 3-10 cycloalkyl, halogen or hydrogen;

[0280] R C1 Selected from hydrogen, C 1-3 Alkyl, hydroxy or -CH2-3-10 membered heterocyclic group;

[0281] W1, W2, W3, W4, W5 are independently selected from N or -CR C4 , each of the R C4 Independently selected from hydrogen, halogen, C 1-3 Alkyl, halogenated C 1-3 Alkyl, hydroxyl, deuterated C 1-3 alkyl, Preferably, W1, W2, W3, W4, and W5 are selected from -CR C4 , and R C4 Selected from hydrogen, halogen (fluorine, chlorine), methyl,

[0282] Furthermore, the B is selected from:

[0283] V1 is selected from the group consisting of absent, -O-, -CH2-, -CH=CH-, and -NH-.

[0284] Furthermore, the B is selected from:

[0285] V1 is selected from absent, -O-, -CH2-, -NH-, preferably absent.

[0286] In some embodiments, the general formula of B is as follows:

[0287] in,

[0288] V3 is independently selected from the group consisting of absent, NH, O, S, SO, SO2, SO2NR h6 SR h6 、-R h6 CO-、-COR h6 -、CO、CO2、C(O)NR h6 、C(O)NR h6 R h6 、C(S)NR h6 NRh6 NR h6 CO, R h6 NR h6 CO、NR h6 CONR h7 、-C 1-8 Alkylene, -C 2-8 Alkenylene, -C 2-8 Alkyne, cycloalkyl, heterocyclic, aryl, heteroaryl, the -C 1-8 Alkylene, -C 2-8 Alkenylene, -C 2-8 Alkyne, cycloalkyl, heterocyclyl, aryl, heteroaryl are each optionally substituted by one or more R h8 replace;

[0289] R H1 Independently selected from amino, NR h6 R h7 , aryl, heteroaryl, wherein the aryl and heteroaryl are each optionally replaced by one or more R h8 replace;

[0290] R h Selected from hydrogen, halogen, C 1-8 alkyl,

[0291] R h1 and R h3 Independently selected from hydrogen, NR h6 R h7 、-C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C 3-9 Cycloalkyl, C 3-9 Heterocyclic group, the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C 3-9 Cycloalkyl, C 3-9 The heterocyclic groups are each optionally substituted by one or more R h9 replace;

[0292] R h2 independently selected from hydrogen, deuterium, halogen, nitro, cyano, amino, hydroxyl, carboxyl, nitro, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR C6 、-SO2R h6 、-SO2NR h6 R h7 、-CORh6 、-CO2R h6 、-CONR h6 R h7 、-POR h6 R h7 、-NR h6 R h7 、-NR h6 COR h7 、-NR h6 CONR h7 R h8 、-NR h6 CO2R h7 、-NR h6 SO2NR h7 R h8 、-NR h6 SO2R h7 , the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are each optionally substituted with at least one substituent R h10 replace;

[0293] q is 1 or 2;

[0294] R h4 、R h5 、R h6 、R h7 independently selected from hydrogen, deuterium, halogen, nitro, cyano, amino, hydroxyl, carboxyl, nitro, -C 1-8 Alkyl, -C(O)R h12 , the -C 1-8 The alkyl group is optionally replaced by one or more R h11 replace;

[0295] R h8 、R h9 、R h10 、R h11 independently selected from hydrogen, deuterium, CN, halogen, carbonyl, nitro, cyano, amino, hydroxyl, carboxyl, nitro, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl.

[0296] R h12 Selected from C 3-9 Cycloalkyl, the C 3-9 The cycloalkyl group is optionally substituted by CN, halogen, nitro, cyano, amino, hydroxy, carboxyl, nitro, -C 1-3 Alkyl substitution.

[0297] In some embodiments, the general formula of B is as follows:

[0298] in,

[0299] V3 is independently selected from absent, NH, O, S, SO, SO2, SO2NR h6 、CO、CO2、C(O)NR h6 、C(S)NR h6 NR h6 NR h6 CO、NR h6 CONR h7 、-C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2- 8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are each optionally substituted by one or more R h8 substituted, preferably selected from absent, -O-, -NH-, -CH2-, -CH=CH-, optionally with one or more R h8 substituted aryl, optionally substituted with one or more R h8 substituted heteroaryl;

[0300] V4 is independently selected from absent, amino, NR h6 R h7 , aryl, heteroaryl, wherein the aryl and heteroaryl are each optionally replaced by one or more R h8 replace,

[0301] R h1 and R h3 Independently selected from hydrogen, NR h6 R h7 、-C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C 3-9 Cycloalkyl, C 3-9 Heterocyclic group, the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C 3-9 Cycloalkyl, C 3-9 The heterocyclic groups are each optionally substituted by one or more R h9 replace;

[0302] R h2 independently selected from hydrogen, deuterium, halogen, nitro, cyano, amino, hydroxyl, carboxyl, nitro, -C1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR C6 、-SO2R h6 、-SO2NR h6 R h7 、-COR h6 、-CO2R h6 、-CONR h6 R h7 、-POR h6 R h7 、-NR h6 R h7 、-NR h6 COR h7 、-NR h6 CONR h7 R h8 、-NR h6 CO2R h7 、-NR h6 SO2NR h7 R h8 、-NR h6 SO2R h7 , the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are each optionally substituted with at least one substituent R h10 replace;

[0303] q is 1 or 2;

[0304] R h4 、R h5 、R h6 、R h7 independently selected from hydrogen, deuterium, halogen, nitro, cyano, amino, hydroxyl, carboxyl, nitro, -C 1-8 Alkyl, -C(O)R h12 , the -C 1-8 The alkyl group is optionally replaced by one or more R h11 replace;

[0305] R h8 、R h9 、R h10 、R h11 independently selected from hydrogen, deuterium, CN, halogen, carbonyl, nitro, cyano, amino, hydroxyl, carboxyl, nitro, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl.

[0306] R h12 Selected from C 3-9 Cycloalkyl, the C 3-9 The cycloalkyl group is optionally substituted by CN, halogen, nitro, cyano, amino, hydroxy, carboxyl, nitro, -C 1-3 Alkyl substitution.

[0307] Further,

[0308] R h1 One selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl;

[0309] R h2 One selected from hydrogen, deuterium, halogen, nitro, cyano, amino, hydroxyl, methyl, ethyl, deuterated methyl or halomethyl;

[0310] R h3 One selected from hydrogen, methyl, ethyl, propyl or isopropyl;

[0311] R h4 One selected from hydrogen, deuterium, halogen, nitro, cyano, amino, hydroxyl, methyl, ethyl, deuterated methyl or halomethyl;

[0312] R h5 One selected from hydrogen, deuterium, halogen, nitro, cyano, amino, hydroxyl, methyl, ethyl, deuterated methyl or halomethyl;

[0313] V3 is selected from absent, -O-, -NH-, -CH2-, -CH=CH-;

[0314] V4 is selected from

[0315] As mentioned above -C 1-8 Alkyl refers to a straight or branched chain alkyl group having 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, etc.; the halogen refers to fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

[0316] Furthermore, the B is selected from:

[0317] L is the linker between B and the HPK1 ligand.

[0318] The L is

[0319] in,

[0320] Each of Y1, Y2, LNK and Y3 is independently selected from the group consisting of absent, halogen, hydroxy, amino, O, S, SO, SO2, SO2NR L1 、CO、CO2、C(O)NR L1 、C(S)NR L1 NR L1 NR L1 CO、NR L1 CONR L2 、-C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are each optionally substituted by one or more R L3 replace;

[0321] R L1 、R L2 , and R L3 are independently hydrogen, halogen, hydroxy, amino, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

[0322] u is an integer between 1 and 20.

[0323] In some embodiments, each of Y1, Y2, LNK and Y3 is independently selected from absent, halogen, hydroxy, amino, O, S, SO, SO2, SO2NR L1 、CO、CO2、C(O)NR L1 、C(S)NR L1 NR L1 NR L1 CO、NR L1 CONR L2 、-C 1-8 Alkyl, C 3-8 Monocyclic alkyl, C 3-8 Monoheterocyclic group, C 6-10 Aryl, C 6-10 Heteroaryl, C 4-14 Fused cycloalkyl, C 4-14 Fused heterocyclic group, C 4-14 Bridged cycloalkyl, C 4-14 Bridged heterocyclic group, C 4-14 Spirocycloalkyl, C 4-14 Spiroheterocyclic group; the -C 1-8 Alkyl, C 3-8 Monocyclic alkyl, C3-8 Monoheterocyclic group, C 6-10 Aryl, C 6-10 Heteroaryl, C 4-14 Fused cycloalkyl, C 4-14 Fused heterocyclic group, C 4-14 Bridged cycloalkyl, C 4-14 Bridged heterocyclic group, C 4-14 Spirocycloalkyl, C 4-14 The spiro heterocyclic groups are each optionally substituted by one or more R L3 replace;

[0324] R L1 、R L2 , and R L3 are independently hydrogen, halogen, hydroxy, amino, -C 1-8 Alkyl, C 3-8 Monocyclic alkyl, C 3-8 Monoheterocyclic group, C 4-14 Fused heterocyclic group, C 3-8 Monoheterocyclic group, C 4-14 Spiroalkyl, C 4-14 spiroheterocyclyl;

[0325] u is an integer between 1 and 20.

[0326] In some embodiments, LNK is selected from or does not exist;

[0327] Each Y1, Y2, and Y3 are independently selected from the group consisting of:

[0328] m is selected from an integer between 0 and 8;

[0329] X L Selected from O, S, -NR L1 -, -C(=O)-, -C(=O)NH-, -NHC(=O)-;

[0330] R L1 Selected from hydrogen, -C 1-8 alkyl;

[0331] u is an integer between 1 and 20.

[0332] In some embodiments of the present invention, L is selected from:

[0333] does not exist,

[0334] In a more preferred embodiment, L is selected from

[0335] The present invention provides the chimeric compound described above, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the chimeric compound is selected from the exemplary chimeric compounds disclosed herein, as shown in Table 2 below:

[0336] Table 2:

[0337] The present invention also claims a pharmaceutical composition comprising any compound of the present invention or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the pharmaceutical composition may optionally contain one or more pharmaceutical carriers and be prepared into any pharmaceutically acceptable pharmaceutical preparation.

[0338] In a specific embodiment of the present invention, the aforementioned pharmaceutical composition may further comprise one or more second therapeutic agents. The second therapeutic agents are antimetabolites, growth factor inhibitors, mitotic inhibitors, anti-tumor hormones, alkylating agents, metals, topoisomerase inhibitors, hormonal drugs, immunomodulators, tumor suppressor genes, cancer vaccines, immune checkpoints, or antibodies or small molecule drugs related to tumor immunotherapy.

[0339] The present invention also claims a pharmaceutical preparation comprising any compound of the present invention or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the pharmaceutical preparation may optionally contain one or more pharmaceutically acceptable carriers.

[0340] The chimeric compound of formula (I) or a pharmaceutically acceptable salt thereof provided by the present invention, and its stereoisomers have excellent HPK1 highly selective inhibitory activity and can treat and / or prevent tumor, immune, inflammation and other related diseases.

[0341] The present invention provides a method for degrading / inhibiting HPK1 activity, comprising administering to a subject a compound disclosed herein or a pharmaceutically acceptable salt, stereoisomer thereof, including a compound of formula (I) or a specific compound exemplified herein.

[0342] The chimeric compounds provided by the present invention have excellent HPK1 inhibitory / degradation activity, good physicochemical properties and drug-forming properties, and exhibit good selectivity, particularly good selectivity for HPK1. The compounds of the present invention or their pharmaceutically acceptable salts have good safety, good efficacy, and high bioavailability. Therefore, the compounds of the present invention have great application potential in the treatment of diseases mediated by HPK1.

[0343] WO2021057872A1 discloses PROTAC compounds formed by MAP4Ks family inhibitors and Cereblon protein ligands. Surprisingly, it was found that the chimeric compounds of the present invention showed improved HPK1 selectivity.

[0344] The present invention also claims a method of treating a patient suffering from a disease modulatable by HPK1, comprising administering to the subject an effective amount of a compound disclosed herein (such as a chimeric compound conforming to formula (I) or a specific compound exemplified herein) or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

[0345] The present invention also claims a method for inhibiting / degrading HPK1 activity in a patient in need of HPK1 activity inhibition, comprising administering to the patient an effective amount of a compound disclosed herein (such as a chimeric compound conforming to formula (I) or a specific compound exemplified herein) or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

[0346] The present invention further claims the use of any compound described herein, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a combination thereof, in the preparation of a medicament for treating or preventing diseases mediated by HPK1. HPK1 has a negative feedback regulatory role in T cell-mediated signaling pathways, and therefore HPK1 inhibitors can be used as immunotherapy to treat cancer or non-cancerous proliferative diseases. Furthermore, the diseases include, but are not limited to, lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, breast cancer, mammary duct cancer, head and neck cancer, endometrial cancer, uterine cancer, rectal cancer, liver cancer, kidney cancer, renal pelvis cancer, esophageal cancer, esophageal adenocarcinoma, glioma, prostate cancer, thyroid cancer, female reproductive system cancer, carcinoma in situ, lymphoma, neurofibromatosis, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, gastrointestinal stromal tumor, oral cancer, pharyngeal cancer, multiple myeloma, leukemia, non-Hodgkin's lymphoma, colorectal villous adenoma, melanoma, cell tumor and sarcoma, myelodysplastic syndrome.

[0347] The present invention also claims a method for preventing and / or treating HPK1-mediated diseases and related diseases, comprising administering to a subject a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a combination thereof. Furthermore, the HPK1-mediated diseases and related diseases are selected from lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, breast cancer, mammary duct carcinoma, head and neck cancer, endometrial cancer, uterine corpus cancer, rectal cancer, liver cancer, kidney cancer, renal pelvis cancer, esophageal cancer, esophageal adenocarcinoma, glioma, prostate cancer, thyroid cancer, female reproductive system cancer, carcinoma in situ, lymphoma, neurofibromatosis, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, gastrointestinal stromal tumor, oral cancer, pharyngeal cancer, multiple myeloma, leukemia, non-Hodgkin's lymphoma, colorectal villous adenoma, melanoma, sarcoma, and myelodysplastic syndrome.

[0348] The present invention also claims a method for treating a patient suffering from cancer, comprising administering to the patient an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a combination thereof.

[0349] The present invention also claims a method for treating a patient with a cancer disease, comprising administering to the patient an effective amount of an HPK1 inhibitor / degrader (e.g., a compound represented by structural formula (I)) or a pharmaceutically acceptable salt, or a stereoisomer thereof, and an effective amount of a second anti-cancer treatment (e.g., a chemotherapeutic agent, a targeted therapy, radiation, or surgery).

[0350] The present invention also claims a method for treating a patient with a cancer disease, comprising administering to a subject an effective amount of an HPK1 inhibitor / degrader (e.g., a compound represented by structural formula (I)) or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and an effective amount of an immunomodulator such as a checkpoint inhibitor (e.g., an anti-PD-1 antibody, an anti-CTLA4 antibody, or an anti-PD-L1 antibody) or a tryptophan oxidation inhibitor (e.g., an IDO1, IDO2, or TDO2 inhibitor).

[0351] The present invention further claims a chimeric compound (e.g., a compound represented by structural formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof) in combination with a PD-1 inhibitor, such as nivolumab, pembrolizumab, pidilizumab, BMS 936559, MPDL3280A, MSB0010718C or MEDI4736, for use in preparing a medicament for treating or preventing HPK1-mediated diseases, wherein the diseases include lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, breast cancer, mammary duct carcinoma, head and neck cancer, endometrial cancer, uterine cancer, rectal cancer, liver cancer, kidney cancer, renal pelvis cancer, esophageal cancer, esophageal adenocarcinoma, glioma, prostate cancer, thyroid cancer, female reproductive system cancer, carcinoma in situ, lymphoma, neurofibromatosis, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, gastrointestinal stromal tumor, oral cancer, pharyngeal cancer, multiple myeloma, leukemia, non-Hodgkin's lymphoma, colorectal villous adenoma, melanoma, cell tumor and sarcoma, and myelodysplastic syndrome.

[0352] Detailed Description of the Invention

[0353] The compounds described in the present invention are named according to their chemical structural formulas. If the name of the compound and the chemical structural formula do not match when representing the same compound, the chemical structural formula shall prevail.

[0354] Unless otherwise specified, scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. However, for a better understanding of the present invention, definitions of some terms are provided below. When the definitions and interpretations of terms provided herein differ from the meanings commonly understood by those skilled in the art, the definitions and interpretations of the terms provided herein shall prevail.

[0355] As used herein (including the appended aspects), singular forms such as "a," "an," and "the" include their corresponding plural referents unless the context clearly dictates otherwise.

[0356] Unless the context clearly dictates otherwise, the term "or" is used to mean and is interchangeable with the term "and / or."

[0357] The term "optional" or "optionally" or "optional" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0358] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups. The term "optionally substituted" means that it may be substituted or unsubstituted, and unless otherwise specified, the type and number of substituents can be any on the basis of chemical achievable.

[0359] The term "alkyl" refers to a hydrocarbon group selected from straight-chain and branched saturated hydrocarbon groups containing 1 to 18 (such as 1 to 12, further such as 1 to 10, further such as 1 to 8, or 1 to 6, or 1 to 4, or 1 to 3, or 1 to 2) carbon atoms.

[0360] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0361] The term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by one or more halogen atoms such as fluorine, chlorine, bromine and iodine. Examples of haloalkyl groups include halo-C 1-8 Alkyl, halogenated C 1-6 Alkyl or halogenated C 1-4 Alkyl groups include, but are not limited to, -CF3, -CH2Cl, -CH2CF3, -CHCl2, CF3, etc.

[0362] The term "alkenyl" refers to a hydrocarbon group selected from straight and branched hydrocarbon groups containing at least one C=C double bond and 2 to 18 (such as 2 to 8, further such as 2 to 6) carbon atoms.

[0363] The term "alkynyl" refers to a hydrocarbon group selected from straight and branched hydrocarbon groups containing at least one C≡C triple bond and 2 to 18 (such as 2 to 8, further such as 2 to 6) carbon atoms.

[0364] The term "alkyloxy" or "alkoxy" refers to an alkyl group, as defined above, attached to the parent molecular moiety through an oxygen atom. 1-6 Alkyloxy or C 1-4 Examples of alkyloxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, propoxy, n-butoxy, tert-butoxy, pentyloxy, hexyloxy, and the like.

[0365] The term "alkoxy-alkyl-" refers to an alkyl group as defined above that is further substituted with an alkoxy group as defined above. 1-8 Alkoxy-C 1-8 Examples of alkyl-) include, but are not limited to, methoxymethyl, ethoxymethyl, isopropoxymethyl, or propoxymethyl, and the like.

[0366] The term "cycloalkyl" refers to a hydrocarbon group selected from saturated cyclic hydrocarbon groups, including monocyclic and polycyclic (eg, bicyclic and tricyclic) groups, including fused cycloalkyl groups, bridged cycloalkyl groups, or spirocycloalkyl groups.

[0367] For example, cycloalkyl can comprise 3 to 12 (such as 3 to 10, further such as 3 to 8, further such as 3 to 6, 3 to 5 or 3 to 4) carbon atoms. Even further for example, cycloalkyl can be selected from the monocyclic group comprising 3 to 12 (such as 3 to 10, further such as 3 to 8, 3 to 6) carbon atoms. The example of monocyclic cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl. Specifically, saturated monocyclic cycloalkyl (for example, C 3-8 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0368] The term "spirocycloalkyl" refers to a cyclic structure containing carbon atoms and formed by at least two rings sharing one atom. For example, a 7- to 12-membered spirocycloalkyl refers to a cyclic structure containing 7 to 12 carbon atoms and formed by at least two rings sharing one atom.

[0369] The term "fused cycloalkyl" refers to a fused ring containing carbon atoms and formed by two or more rings sharing two adjacent atoms. For example, a 4- to 10-membered fused cycloalkyl refers to a fused ring containing 4 to 10 ring carbon atoms and formed by two or more rings sharing two adjacent atoms.

[0370] The term "bridged cycloalkyl" refers to a cyclic structure containing carbon atoms and formed by two rings sharing two non-adjacent atoms. For example, a 7- to 10-membered bridged cycloalkyl refers to a cyclic structure containing 7 to 12 carbon atoms and formed by two rings sharing two non-adjacent atoms.

[0371] The term "cycloalkenyl" refers to a non-aromatic cyclic alkyl group of 3 to 10 carbon atoms, which has a monocyclic or polycyclic ring and has at least one double bond and preferably 1 to 2 double bonds. In one embodiment, the cycloalkenyl group is a cyclopentenyl group (1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl) or a cyclohexenyl group (1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl), preferably a cyclohexenyl group.

[0372] The term "cycloalkynyl" refers to a non-aromatic cycloalkyl group of 5 to 10 carbon atoms, which has a single ring or multiple rings and has at least one triple bond.

[0373] The term "aryl" used alone or in combination with other terms refers to a group selected from:

[0374] - 5- and 6-membered carbocyclic aromatic rings, such as phenyl;

[0375] - bicyclic ring systems, such as 7- to 12-membered bicyclic ring systems, in which at least one ring is carbocyclic and aromatic, for example naphthyl and indanyl; and

[0376] - a tricyclic ring system, such as a 10- to 15-membered tricyclic ring system, wherein at least one ring is carbocyclic and aromatic, for example fluorenyl.

[0377] The terms "aromatic hydrocarbon ring" and "aryl" are used interchangeably throughout the disclosure herein. In some embodiments, the monocyclic or bicyclic aromatic hydrocarbon ring has 5 to 10 ring carbon atoms (i.e., C 5-10 Examples of monocyclic or bicyclic aromatic hydrocarbon rings include, but are not limited to, phenyl, naphthalene-1-yl, naphthalene-2-yl, anthracenyl, phenanthrenyl, and the like. In some embodiments, the aromatic hydrocarbon ring is a naphthalene ring (naphthalene-1-yl or naphthalene-2-yl) or a phenyl ring. In some embodiments, the aromatic hydrocarbon ring is a phenyl ring.

[0378] The term "heteroaryl" refers to a group selected from:

[0379] - a 5-, 6-, or 7-membered aromatic monocyclic ring containing at least one heteroatom, for example 1 to 4 heteroatoms, or in some embodiments 1 to 3 heteroatoms, in some embodiments 1 to 2 heteroatoms, selected from nitrogen (N), sulfur (S), and oxygen (O), the remaining ring atoms being carbon;

[0380] - a 7- to 12-membered bicyclic ring containing at least one heteroatom, e.g., 1 to 4 heteroatoms, or in some embodiments 1 to 3 heteroatoms, or in other embodiments 1 or 2 heteroatoms, selected from N, O, and S, the remaining ring atoms being carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring; and

[0381] - an 11- to 14-membered tricyclic ring containing at least one heteroatom, for example 1 to 4 heteroatoms, or in some embodiments 1 to 3 heteroatoms, or in other embodiments 1 or 2 heteroatoms, selected from N, O and S, the remaining ring atoms being carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring.

[0382] When the total number of S and O atoms in the heteroaryl group exceeds 1, those heteroatoms are not adjacent to each other. In some embodiments, the total number of S and O atoms in the heteroaryl group is not greater than 2. In some embodiments, the total number of S and O atoms in the aromatic heterocycle is not greater than 1. When the heteroaryl group contains more than one heteroatom ring member, the heteroatoms may be the same or different. The nitrogen atom in one or more rings of the heteroaryl group may be oxidized to form an N-oxide. As used herein, the term "C-connected heteroaryl" means that the heteroaryl group is connected to the core molecule via a bond from a C-atom of the heteroaryl ring.

[0383] The term "heteroaryl" refers to a monocyclic or bicyclic aromatic heterocycle having 5, 6, 7, 8, 9 or 10 ring members, wherein 1, 2, 3 or 4 heteroatom ring members are independently selected from nitrogen (N), sulfur (S) and oxygen (O), and the remaining ring members are carbon. In some embodiments, the monocyclic or bicyclic aromatic heterocycle is a monocyclic or bicyclic ring comprising 1 or 2 heteroatom ring members independently selected from nitrogen (N), sulfur (S) and oxygen (O). In some embodiments, the monocyclic or bicyclic aromatic heterocycle is a 5 to 6 membered heteroaryl ring, which is a monocyclic ring and has 1 or 2 heteroatom ring members independently selected from nitrogen (N), sulfur (S) and oxygen (O). In some embodiments, the ring of the monocyclic or bicyclic aromatic heterocycle is an 8 to 10 membered heteroaryl ring, which is bicyclic and has 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur and oxygen.

[0384] "Heterocyclyl," "heterocycle," or "heterocyclic" are interchangeable and refer to non-aromatic heterocyclic groups containing one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, with the remaining ring members being carbon, including monocyclic, fused, bridged, and spirocyclic rings, i.e., monocyclic heterocyclic, bridged, spiroheterocyclic, and fused heterocyclic groups. The term "optionally oxidized sulfur" as used herein refers to S, SO, or SO2.

[0385] The term "monocyclic heterocyclyl" refers to a monocyclic group wherein at least one ring member is a heteroatom selected from nitrogen, oxygen or optionally oxidized sulfur. The heterocycle may be saturated or partially saturated.

[0386] The term "spiro heterocyclic radical " refers to a 5 to 20 yuan polycyclic heterocyclic radical with a ring connected by a shared carbon atom (called spiral atom), comprising one or more heteroatoms selected from nitrogen, oxygen or the optionally oxidized sulphur as ring members, and the remaining ring members are carbon. One or more rings of spiro heterocyclic radical can contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, spiro heterocyclic radical is 6 to 14 yuan, and more preferably 7 to 12 yuan. According to the number of shared spiral atoms, spiro heterocyclic radical is divided into single spiral heterocyclic radical, two spiral heterocyclic radicals or multiple spiral heterocyclic radicals, and preferably refers to single spiral heterocyclic radical or two spiral heterocyclic radicals, and more preferably 4 yuan / 4 yuan, 3 yuan / 5 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spiral heterocyclic radicals.

[0387] The term "fused heterocyclic group" refers to a 5 to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms (carbon and carbon atoms or carbon and nitrogen atoms) with another ring, comprising one or more heteroatoms selected from nitrogen, oxygen or optionally oxidized sulfur as ring members, and the remaining ring members are carbon. One or more rings of the fused heterocyclic group may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, the fused heterocyclic group is 6 to 14 members, preferably 7 to 12 members and more preferably 7 to 10 members. Depending on the number of member rings, the fused heterocyclic group is divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic fused heterocyclic group, and more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group.

[0388] The term "bridged heterocyclic group" or "bridged heterocyclic group" refers to a 5- to 14-membered polycyclic heterocyclic group in which every two rings in the system share two non-connected atoms, containing one or more heteroatoms selected from nitrogen, oxygen or optionally oxidized sulfur as ring members, and the remaining ring members are carbon. One or more rings of the bridged heterocyclic group may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, the bridged heterocyclic group is 6- to 14-membered, and more preferably 7- to 10-membered. Depending on the number of member rings, the bridged heterocyclic group is divided into a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group, and preferably refers to a bicyclic, tricyclic or tetracyclic bridged heterocyclic group, and more preferably a bicyclic or tricyclic bridged heterocyclic group.

[0389] The term "alkylene" refers to a divalent alkyl group as defined above, having a length of 1 to 18 carbon atoms (C 1-18 ) is a saturated straight or branched divalent hydrocarbon group, wherein the alkylene group may be optionally substituted independently with one or more substituents as described below. In another embodiment, the alkylene group has one to eight carbon atoms (C 1-8 ) or one to six carbon atoms (C 1-6Examples of alkylene groups include, but are not limited to, methylene (—CH 2 —), ethylene (—CH 2 CH 2 —), propylene (—CH 2 CH 2 CH 2 —), and the like.

[0390] The term "alkenylene" refers to a divalent alkenyl group as defined above, having a length of two to eight carbon atoms (C 2-8 ) has at least one unsaturated site, namely, carbon-carbon sp 2 A double-bonded, linear or branched divalent hydrocarbon group, wherein the alkenylene group may be optionally substituted independently with one or more substituents described herein and includes groups having "cis" and "trans" orientations or "E" and "Z" orientations. Examples include, but are not limited to, vinylene (-CH=CH-), allylene (-CH2CH=CH-), and the like.

[0391] The term "alkynylene" refers to a divalent alkynyl group as defined above, having a length of three to eight carbon atoms (C 3-8 ) is a straight or branched divalent hydrocarbon group having at least one unsaturated site, i.e., a carbon-carbon sp triple bond, wherein the alkynylene group may be optionally substituted independently with one or more substituents described herein. Examples include, but are not limited to, propynylene (propargylene, -CH2C≡C-), and the like.

[0392] The term "cycloalkylene" refers to a divalent cycloalkyl group as defined above. The term "heterocyclylene" refers to a divalent heterocyclyl group as defined above. The term "arylene" refers to a divalent aryl group as defined above. The term "heteroarylene" refers to a divalent heteroarylene group as defined above.

[0393] Compounds disclosed herein may contain asymmetric centers and therefore may exist as enantiomers. "Enantiomers" refer to two stereoisomers of a compound that are non-superimposable mirror images of each other. In the case where compounds disclosed herein have two or more asymmetric centers, they may additionally exist as diastereomers. Enantiomers and diastereomers belong to a wider range of stereoisomer categories. It is intended to include all these possible stereoisomers as substantially pure resolved enantiomers, their racemic mixtures, and mixtures of diastereomers. It is intended to include all stereoisomers of compounds disclosed herein and / or their pharmaceutically acceptable salts. Unless otherwise specifically mentioned, reference to an isomer is applicable to any possible isomer. Whenever an isomer composition is not specified, all possible isomers are included.

[0394] As used herein, the term "substantially pure" means that the target stereoisomer contains no more than 35% (such as no more than 30%, further such as no more than 25%, even further such as no more than 20%) of any other stereoisomer(s) by weight. In some embodiments, the term "substantially pure" means that the target stereoisomer contains no more than 10% (e.g., no more than 5%, such as no more than 1%) of any other stereoisomer(s) by weight.

[0395] When compounds disclosed herein contain olefinic double bonds, unless specified otherwise, such double bonds are intended to include both E and Z geometric isomers.

[0396] When the compounds disclosed herein contain disubstituted cyclohexyl or cyclobutyl groups, the substituents found on the cyclohexyl or cyclobutyl ring can be in cis and trans forms. Cis formation means that both substituents are found on the upper side of the 2 substituent positions on the carbon, while trans means that they are on opposite sides.

[0397] "Pharmaceutically acceptable salts" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compounds disclosed herein, or separately by reacting a free base functional group with a suitable organic acid or by reacting an acidic group with a suitable base.

[0398] In addition, if the compounds disclosed herein are obtained as acid addition salts, the free base can be obtained by alkalizing a solution of the acid salt. Conversely, if the product is a free base, an addition salt, such as a pharmaceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and / or water and treating the solution with an acid according to conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable addition salts without undue experimentation.

[0399] As defined herein, "pharmaceutically acceptable salts thereof" include salts of at least one compound of formula (I) and salts of stereoisomers of compounds of formula (I), such as enantiomeric salts and / or diastereomeric salts.

[0400] Unless otherwise specified, when a group has one or more connectable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When the chemical bond connection mode is non-positional and there are H atoms at the connectable sites, when the chemical bond is connected, the number of H atoms at the site will decrease accordingly with the number of connected chemical bonds, and become a group with a corresponding valence. The chemical bond connecting the site to other groups can be a straight solid bond. or wavy lines For example, the straight solid bond in -OCH3 indicates that it is connected to other groups through the oxygen atom in the group; The wavy line in the phenyl group indicates that it is connected to other groups through the carbon atoms #1 and ##1 in the phenyl group;

[0401] The terms "administration," "administering," "treating," and "treatment" when applied to animals, humans, experimental subjects, cells, tissues, organs, or biological fluids, refer to the contact of an exogenous agent, therapeutic agent, diagnostic agent, or composition with the animal, human, subject, cell, tissue, organ, or biological fluid. Treatment of cells encompasses contact of an agent with a cell, and contact of an agent with a fluid, wherein the fluid is in contact with the cell. The terms "administering" and "treating" also refer to in vitro and ex vivo treatment of, for example, a cell, by an agent, diagnostic agent, binding compound, or by another cell. The term "subject" herein includes any organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, and rabbit), and most preferably a human.

[0402] The term "effective amount" or "therapeutically effective amount" refers to an amount of an active ingredient, such as a compound, which, when administered to a subject for treating a disease or at least one clinical symptom of a disease or disorder, is sufficient to affect such treatment of the disease, disorder or symptom.

[0403] The term "disease" refers to any illness, ailment, disease, symptom, or indication and is interchangeable with the terms "condition" or "disorder."

[0404] Throughout the specification and subsequent aspects, unless the context requires otherwise, the term "comprises" and variations such as "comprises" and "comprising" are intended to indicate the presence of the following features, but do not preclude the presence or addition of one or more other features. When used herein, the term "comprises" may be replaced by the terms "contains," "includes," or sometimes "has."

[0405] Throughout the specification and subsequent aspects, the term "C n-m" indicates a range including the endpoints, where n and m are integers and indicate the number of carbons. Examples include C 1-8 、C 1-6 wait.

[0406] Unless explicitly defined elsewhere in this document, all other technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0407] Compound identification and characterization

[0408] The examples provide the preparation of representative compounds represented by formula (I) and related structural identification data. 1 H NMR spectra were obtained using a Bruker instrument (400 MHz), and chemical shifts are expressed in ppm using tetramethylsilane as an internal standard (0.00 ppm). 1 H NMR notation: s = singlet, d = doublet, t = triplet, m = multiplet, br = broadened, dd = doublet of a doublet, dt = doublet of a triplet. Coupling constants, when given, are given in Hz.

[0409] Mass spectra were obtained using LC / MS, and the ionization method could be ESI or APCI.

[0410] Thin layer chromatography silica gel plates were used, such as Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates, for thin layer chromatography (TLC).

[0411] The silica gel plates used are 0.15mm to 0.2mm in size, and the thin layer chromatography separation and purification products are 0.4mm to 0.5mm in size. Column chromatography generally uses Yantai Huanghai 200-300 mesh silica gel as the carrier.

[0412] In the following examples, unless otherwise indicated, all temperatures are in degrees Celsius. Unless otherwise indicated, various starting materials and reagents are commercially available or synthesized according to known methods. Commercially available raw materials and reagents are used directly without further purification. Unless otherwise indicated, commercial manufacturers include but are not limited to Aldrich Chemical Company, ABCR GmbH & Co. KG, Acros Organics, Shanghai Bid Pharmaceutical Technology Co., Ltd. and Shanghai Shaoyuan Reagent Co., Ltd.

[0413] CD3OD: deuterated methanol.

[0414] CDCl3: deuterated chloroform.

[0415] DMSO-d6: deuterated dimethyl sulfoxide.

[0416] T3P: tripropylphosphoric anhydride.

[0417] DPPA: diphenylphosphoryl azide.

[0418] DIEA: N,N-diisopropylethylamine.

[0419] Unless otherwise specified in the examples, the solution in the reaction refers to an aqueous solution.

[0420] The compound is purified using an eluent system for column chromatography and thin-layer chromatography, wherein the system is selected from: A: petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: dichloromethane and ethyl acetate system; D: dichloromethane and ethanol system, wherein the volume ratio of the solvent varies according to the polarity of the compound, and a small amount of acidic or alkaline reagents, such as acetic acid or triethylamine, may also be added to adjust the conditions.

[0421] 1. Biological Assay

[0422] The pharmacological properties of the compounds of the present invention can be demonstrated by a number of biological assays.The following exemplary biological assays have been performed with the compounds of the present invention.

[0423] 1. HPK1 in vitro enzyme activity detection method

[0424] The ADP-Glo ​​method was used to detect kinase activity and determine the IC50 value to evaluate the inhibitory ability of the compound on human HPK1.

[0425] Enzyme buffer conditions: 50 mM Hepes (pH 7.5), 10 mM MgCl2, 1 mM EGTA, 0.01% Brij35, 2 mM DTT.

[0426] Kinase and substrate mixture configuration: The working concentration of kinase in the HPK1 reaction solution is 7 nM, and the working concentration of ATP is 20 uM.

[0427] Test steps:

[0428] The compounds were diluted with DMSO in a dilution plate with a maximum starting concentration of 1 uM and 10 concentration gradient points (4-fold dilution).

[0429] The compound was diluted 50-fold into kinase reaction buffer at each of the 10 concentration gradient points above and shaken on a shaker for 20 minutes. The kinase was prepared in enzyme reaction buffer and 2 μl of HPK1 kinase was added to each well of the reaction plate to a concentration of 7 nM HPK1 kinase in the reaction solution.

[0430] Add 1 μl of compound diluted in buffer to each well, seal the plate with film, centrifuge at 1000g for 30 seconds, and incubate at room temperature for 10 minutes. Prepare ATP solution in enzyme reaction buffer and add 2 μl of ATP solution to the reaction plate (working concentration of ATP is 20 μM). Seal the plate with film and centrifuge at 1000g for 30 seconds. Incubate at room temperature for 60 minutes. Transfer 4 μL of ADP-Glo ​​to a 384-well reaction plate, centrifuge at 1000 rpm / min for 1 minute, and incubate at 25°C for 40 minutes. Transfer 8 μL of detection solution to a 384-well reaction plate, centrifuge at 1000 rpm / min for 1 minute, and incubate at 25°C for 40 minutes. Read the RLU (Relative luminescence unit) signal using a BMG microplate reader. The signal intensity is used to indicate the activity of the kinase.

[0431] The kinase activity data were expressed as the ratio of the kinase activity of the test compound to the kinase activity of the blank group (containing only DMSO), and the IC50 value was obtained by curve fitting using Prism software (GraphPad 7.0).

[0432] 2. MAP4K3 (GLK) in vitro enzyme activity detection method

[0433] ADP-Glo ​​assay was used to detect kinase activity and determine IC 50 The inhibitory ability of the test compound on human GLK was evaluated by the kinase inhibitory value.

[0434] Enzyme buffer conditions: 50 mM Hepes (pH 7.5), 10 mM MgCl2, 1 mM EGTA, 0.01% Brij35, 2 mM DTT.

[0435] Kinase and substrate mixture configuration: GLK reaction solution working concentration is 2nM, substrate MBP working concentration is 0.1mg / ml, ATP working concentration is 10uM.

[0436] Assay Procedure: Compounds were diluted in DMSO in a dilution plate, starting at a maximum concentration of 10 μM, with a 10-point 4-fold dilution gradient. Each of the 10-point compound gradients was further diluted 50-fold into kinase reaction buffer and shaken for 20 minutes. Kinase was prepared in enzyme reaction buffer and 2 μl of GLK kinase was added to each well of the reaction plate (the GLK reaction solution was at a 2 nM concentration). 1 μl of the compound diluted in buffer was added to each well, the plate was sealed with film, and centrifuged at 1000 g for 30 seconds. The reaction was allowed to stand at room temperature for 10 minutes. MBP and ATP solutions were prepared in enzyme reaction buffer and 2 μl of MBP / ATP solution (working concentration of substrate MBP: 0.1 mg / ml, ATP: 10 μM) was added to the reaction plate. The plate was sealed with film, and centrifuged at 1000 g for 30 seconds. The reaction was allowed to stand at room temperature for 60 minutes. Transfer 4 μL of ADP-Glo ​​to a 384-well plate, centrifuge at 1000 rpm / min for 1 minute, and incubate at 25°C for 40 minutes. Transfer 8 μL of detection solution to a 384-well plate, centrifuge at 1000 rpm / min for 1 minute, and incubate at 25°C for 40 minutes. Read the RLU (Relative Luminescence Unit) signal using a BMG microplate reader. Signal intensity is used to indicate kinase activity.

[0437] The kinase activity data were expressed as the ratio of the kinase activity of the test compound to the kinase activity of the blank group (containing only DMSO), and the IC50 value was obtained by curve fitting using Prism software (GraphPad 7.0).

[0438] The table below shows the HPK1 IC50 values ​​and MAP4K3 IC50 values ​​of the compounds, as well as the HPK1 / GLK selectivity.

[0439] HPK1IC of the compounds tested in the present invention 50 The range of nM is no greater than 100 nM, with compounds of the present invention exhibiting no greater than 50 nM, compounds of the present invention exhibiting no greater than 20 nM, some compounds exhibiting no greater than 10 nM, and some compounds exhibiting no greater than 5 nM, indicating that the compounds of the present invention have good inhibitory activity against HPK1 and have great potential for treating diseases mediated by HPK1. Furthermore, the compounds of the present invention exhibit good selectivity for HPK1, with some compounds exhibiting inhibitory activity against HPK1 several times greater than their inhibitory activity against MAP4K3, demonstrating that the compounds of the present invention have good safety and have great potential for treating diseases mediated by HPK1.

[0440] 3. HPK1 protein degradation detection

[0441] The degradation of HPK1 protein and DC50 / Dmax were tested by WB method to evaluate the in vitro degradation ability of the compounds.

[0442] RAMOS cell line was selected as the degradation cell line, and the culture conditions were RMPI 1640 medium with 10% FBS, 37°C, and 5% CO2.

[0443] Experimental steps:

[0444] (1) Cell plating: In a 6 cm culture dish, 4 ml of culture medium was used to plate 2 × 10 cells. 6 Pieces / dish.

[0445] (2) Drug addition: Dilute the compound (stock concentration 10 mM) with DMSO in a dilution plate. The maximum starting concentration of the compound is 10 uM, and there are 7 concentration gradient points (3-fold dilution). Take 4 μl of each and add it to the above culture dish and incubate for 16 h.

[0446] (3) Collect cells and add lysis buffer. Centrifuge at 12,000 rpm for 20 min and collect the supernatant. After quantification using the BCA quantification kit, add 5× loading buffer for denaturation for 10 min.

[0447] (4) Add 10 μg of denatured protein to SDS-PAGE gel, perform electrophoresis, transfer to membrane, block with 5% BSA for 1 h, incubate with primary antibody at 4°C overnight, wash the primary antibody, incubate with secondary antibody at room temperature for 1 h, and wash the secondary antibody.

[0448] (5) Imaging: Scan the membrane using a dual-color fluorescence imaging system. Quantify the Western blot results using Image J software, and calculate DC50 and Dmax by comparing with the control group.

[0449] The following table shows the DC50 and Dmax of HPK1 degradation of the compounds of the present invention

[0450] Remark:

[0451] 2. Preparation Example

[0452] The present invention is further described in detail below with reference to specific examples, but these examples do not limit the scope of the present invention. The following examples are used to understand the methods and core ideas of the present invention. For those skilled in the art, any possible changes or substitutions without departing from the concept of the present invention are within the scope of protection of the present invention. The experimental methods for which specific conditions are not specified in the examples of the present invention are generally conventional conditions, or conditions recommended by the raw material or commodity manufacturer; reagents for which the source is not specified are generally conventional reagents available through commercial channels.

[0453] Synthesis of intermediates

[0454] Preparation of intermediate warhead 1

[0455] Step 1: Preparation of compound 2

[0456] Dissolve 20 g of 4-bromo-2,6-dimethylaniline, 36.3 g of nitrogen mustard hydrochloride, and 1.9 g of p-toluenesulfonic acid hydrate in 200 mL of xylene. Replace the atmosphere with nitrogen three times and stir at 150°C overnight. LCMS analysis indicated that the reaction was no longer progressing. The reaction solution was concentrated in vacuo, and the crude product was purified by column chromatography to obtain Compound 2.

[0457] Step 2: Preparation of compound 3

[0458] 9 g of compound 2, 23.2 mL of TEA, and 408 mg of DMAP were dissolved in 90 mL of THF. 14.6 g of BocO was added with stirring, and the mixture was stirred at room temperature overnight. LCMS indicated that the reaction was no longer progressing. The mixture was extracted with water and EA. The combined organic phases were washed, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography to yield compound 3.

[0459] Step 3: Preparation of compound 4

[0460] 11 g of compound 3, 9.1 g of B2pin2, 4.4 g of KOAc, and 2.2 g of Pd(dppf)Cl2 were dissolved in 110 mL of dioxane, the atmosphere was purged with nitrogen three times, and the mixture was stirred at 70°C for 2.5 hours. LCMS analysis indicated that the reaction was no longer progressing. The mixture was extracted with water and EA. The combined organic phases were washed, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography to yield compound 4.

[0461] Step 4: Preparation of compound 6

[0462] 683 mg of compound 4, 500 mg of compound 5, 605 mg of K2CO3, and 143 mg of Pd(dtbpf)Cl2 were dissolved in 15 mL of dioxane, the atmosphere was purged with nitrogen three times, and the mixture was stirred at 100°C for 1 hour. LCMS analysis indicated that the reaction was no longer progressing. The mixture was extracted with water and EA. The combined organic phases were washed, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography to yield compound 6.

[0463] Step 5: Preparation of compound 7

[0464] 420 mg of compound 6 was dissolved in 17 mL of MeOH, and 3.4 mL of 2 M NaOH solution was added, followed by stirring at room temperature for 16 hours. LCMS analysis indicated that the reaction was no longer proceeding. The reaction solution was concentrated in vacuo, extracted with water and EA, and the combined organic phases were washed, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was slurried with diethyl ether to obtain compound 7.

[0465] Step 6: Preparation of compound warhead 1

[0466] 400 mg of compound 7 was dissolved in 2 mL of MeOH, 5 mL of HCl / dioxane (4 M) was added, and the mixture was stirred at room temperature for 1 hour. LCMS showed that the reaction was no longer proceeding. The reaction solution was concentrated in vacuo, dissolved in a small amount of MeOH, and 20 mL of EA was added. The precipitated solid was collected by filtration and slurried with diethyl ether to obtain compound warhead 1. LCMS (ESI) m / z: [M+H + ]=471.2. 1 H NMR (400MHz, DMSO-d6) δ13.97(s,1H),11.03(s,1H),9.46(s,2H),8.95(d,J=16.0Hz,2H),8.58(s,1H),8.23(d,J=6.0Hz,1H),7.82 (d,J=7.1Hz,2H),4.52(d,J=6.9Hz,1H),3.33(d,J=4.8Hz,4H),3.25–3.14(m,8H),2.78(d,J=4.8Hz,3H),2.45(s,5H),2.35(s,3H).

[0467] Example 001: Preparation of Compound C001

[0468] Step 1: Dissolve tetrabromoethylene glycol (2 g, 7.8 mmol), 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindoline-1,3-dione (1.1 g, 4.0 mmol), KHCO₃ (779 mg, 7.8 mmol), and KI (155 mg, 0.93 mmol) in DMF (18 mL) and stir at 70°C for 16 hours. LCMS analysis indicated no further reaction. The reaction mixture was filtered, the filtrate concentrated in vacuo, and the crude product purified by column chromatography to yield Compound 001a.

[0469] Step 2: Dissolve compound 001a (1.4 g, 3.11 mmol) and IBX (3.4 g, 12.1 mmol) in 30 mL of MeCN and stir at 80°C for 2 hours. LCMS analysis indicated no further reaction. Filter the reaction solution, concentrate the filtrate in vacuo, and purify the crude product by column chromatography to afford 001b.

[0470] Step 3: Warhead 1 (86 mg, 0.183 mmol) and compound 001b (232 mg, 0.518 mmol) were dissolved in MeCN (5.3 mL) and dioxane (1.5 mL). 17 uL of acetic acid was added and the mixture was stirred at room temperature for 1 hour. Sodium cyanoborohydride (78 mg, 0.368 mmol) was added and the mixture was stirred at room temperature for 1 hour. LCMS showed that the reaction was no longer proceeding. The reaction solution was concentrated in vacuo and the crude product was purified by HPLC to obtain C001. LCMS (ESI) m / z: [M+H + ]=903.2. 1 H NMR (400MHz, DMSO) δ12.72(s,1H),11.11(s,1H),9.81(s,1H),8.47(s,1H),8.38(s,1H),8.28(s,1H),8.12(s,1H),7.8 8(s,1H),7.80(d,J=7.5Hz,2H),7.51(d,J=8.6Hz,1H),7.44(d,J=7.2Hz,1H),5.08(dd,J=12.7,5.3Hz,1H),4.52(t,J= 11.5Hz,1H),4.34(d,J=3.9Hz,2H),3.82(d,J=4.0Hz,4H),3.62(ddd,J=13.0,7.2,3.0Hz,14H),3.24(s,6H),3.09(d,J=12 .8Hz,2H),2.85(s,3H),2.59(d,J=20.0Hz,2H),2.41(s,6H),2.31(dd,J=27.3,11.0Hz,4H),2.08(dd,J=46.3,41.1Hz,2H).

[0471] Example 002: Preparation of Compound C002

[0472] Step 1: Dissolve tetrabromoethylene glycol (2 g, 7.8 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindoline-1,3-dione (1.1 g, 4.01 mmol), KHCO (779 mg, 7.8 mmol), and KI (155 mg, 0.93 mmol) in DMF (18 mL) and stir at 70°C for 16 hours. LCMS analysis indicated that the reaction was no longer progressing. The reaction solution was filtered, the filtrate was concentrated in vacuo, and the crude product was purified by column chromatography to afford 002a.

[0473] Step 2: Dissolve compound 002a (1.4 g, 3.11 mmol) and IBX (3.4 g, 12.1 mmol) in MeCN (30 mL) and stir at 80°C for 2 hours. LCMS analysis indicated no further reaction. The reaction mixture was filtered, the filtrate was concentrated in vacuo, and the crude product was purified by column chromatography to afford 002b.

[0474] Step 3: Warhead 1 (90 mg, 0.191 mmol) and compound 002b (135 mg, 0.301 mmol) were dissolved in MeCN (5.3 mL) and dioxane (1.5 mL). 10 μL of acetic acid was added and the mixture was stirred at room temperature for 1 hour. Sodium cyanoborohydride (78 mg, 0.368 mmol) was added and the mixture was stirred at room temperature for 1 hour. LCMS analysis indicated that the reaction was no longer proceeding. The reaction solution was concentrated in vacuo and the crude product was purified by HPLC to obtain C002. LCMS (ESI) m / z: [M+H] + =903.2.

[0475] 1H NMR (400MHz, DMSO-d6) δ12.78(s,1H),11.11(s,1H),9.93(s,2H),8.49(s,1H),8.39(s,1H),8.31(s,1H),8.14(d,J=10.5Hz ,1H),7.88(s,1H),7.81(d,J=8.3Hz,2H),7.43(d,J=2.1Hz,1H),7.35–7.29(m,1H),5.10(dd,J=12.7,5.4Hz,1H),4.52(dd,J =13.5,9.4Hz,1H),4.33–4.28(m,2H),3.80(dd,J=12.9,8.8Hz,4H),3.62(d,J=3.2Hz,8H),3.59(s,6H),3.24(s,6H),3.09( d,J=11.7Hz,2H),2.86(d,J=11.4Hz,4H),2.70–2.54(m,2H),2.41(s,6H),2.26(dd,J=30.3,16.2Hz,4H),2.08–1.99(m,1H).

[0476] Example 003: Preparation of Compound C003

[0477] Step 1: Dissolve tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (450 mg, 1.88 mmol) in DCM (6 mL). Add TFA (3 mL) dropwise under ice-cooling and stir at room temperature for 1 hour. If the reaction is no longer proceeding, remove the solvent by rotary evaporation. Dissolve the mixture in DMSO (5 mL), add 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (200 mg, 0.725 mmol) and DIEA (2 mL), and stir at 80°C for 7 hours. If the reaction is no longer proceeding, extract with water and DCM. The organic phases are combined, washed, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product is purified by column chromatography to afford 003a.

[0478] Step 2: Warhead 1 (60 mg, 0.138 mmol) and compound 003a (80 mg, 0.202 mmol) were dissolved in DCE (3 mL) / DMSO (0.6 mL), 0.5 mL of acetic acid was added, and the mixture was stirred at room temperature for 2 hours. Sodium acetate borohydride (150 mg, 0.707 mmol) was added, and the mixture was stirred at room temperature overnight. LCMS showed that the reaction was no longer progressing, and the mixture was quenched with saturated sodium bicarbonate solution and extracted with DCM. The organic phases were combined, washed, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography to obtain C003. LCMS (ESI) m / z: [M+H +]=850.7.

[0479] 1 H NMR (500MHz, DMSO-d6) δ12.48(s,1H),11.09(s,1H),8.40(d,J=7.2Hz,2H),8.15(d,J =2.5Hz,1H),8.08(s,1H),7.84(d,J=7.5Hz,1H),7.67(d,J=8.4Hz,1H),7.36(s,1H), 7.27(d,J=8.8Hz,1H),5.07(dd,J=12.8,5.5Hz,1H),3.51(s,2H),3.43(s,2H),3.10( s,2H),2.65–2.53(m,1H),2.42(s,6H),2.26(s,5H),2.05–1.96(m,1H),1.67(s,4H).

[0480] Example 004: Preparation of Compound C004

[0481] Step 1: Warhead 1 (100 mg, 0.213 mmol) and 1-Boc-4-piperidinecarboxaldehyde (300 mg, 1.41 mmol) were dissolved in DMSO (5 mL) / DCE (5 mL). 0.2 mL of acetic acid was added and the mixture was stirred at room temperature for 1 hour. Sodium acetate borohydride (200 mg, 0.943 mmol) was added and stirred at room temperature overnight. LCMS indicated that the reaction was no longer progressing. The mixture was quenched with saturated sodium bicarbonate solution and extracted with DCM. The combined organic phases were washed, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography to afford 004a.

[0482] Step 2: Compound 004a (51.5 mg, 0.077 mmol) was dissolved in DCM (4 mL), TFA (1 mL) was added dropwise under ice bath, and stirred at room temperature for 1 hour. LCMS showed that the reaction was no longer proceeding. The solvent was removed by rotary evaporation, and the product was dissolved in DMSO / DCM (2 mL / 2 mL). 1-Boc-3-azetidinone (60 mg, 0.351 mmol) and 0.1 mL of acetic acid were added to the crude product, and the mixture was stirred at 60°C for 1 hour. 60 mg of sodium acetate borohydride was added, and the mixture was stirred at room temperature overnight. LCMS showed that the reaction was no longer proceeding. The product was quenched with saturated sodium bicarbonate solution, extracted with DCM, and the organic phases were combined, washed, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography to obtain 004b.

[0483] Step 3: Compound 004b (40.4 mg, 0.056 mmol) was dissolved in DCM (4 mL), 0.8 mL of TFA was added dropwise under ice bath, and the mixture was stirred at room temperature for 1 hour. LCMS showed that the reaction no longer proceeded, the solvent was removed by rotary evaporation, the mixture was dissolved in DMSO (4 mL), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (30 mg, 0.108 mmol) and 0.8 mL of DIEA were added, and the mixture was stirred at 80°C for 5 hours. LCMS showed that the reaction no longer proceeded, the mixture was extracted with water and DCM, the organic phases were combined and washed, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography to obtain C004. LCMS (ESI) m / z: [M+H + ]=879.7.

[0484] 1 H NMR (500MHz, DMSO-d6) δ12.43(d,J=2.6Hz,1H),11.09(s,1H),8.38(d,J=5.7Hz,2H),8.12(d,J=2.5Hz,1H),8.02(s,1H),7.8 3(s,2H),7.66(d,J=8.2Hz,1H),6.80(d,J=2.1Hz,1H),6.66(dd,J=8.5,2.1Hz,1H),5.06(dd,J=12.7,5.5Hz,1H),4.24(s,1H) ,4.11(t,J=7.6Hz,2H),3.88–3.79(m,2H),3.08(s,4H),3.02(s,2H),2.87–2.81(m,2H),2.65–2.53(m,1H),2.41(s,6H),2.35 (d,J=10.0Hz,2H),2.22(s,1H),2.09(s,4H),2.05–1.98(m,1H),1.86(s,1H),1.76(d,J=12.3Hz,2H),1.14(d,J=12.3Hz,2H).

[0485] Example 005: Preparation of Compound C005

[0486] Step 1:

[0487] Warhead 1 (100 mg, 0.213 mmol) and tert-butyl 3-formylazetidine-1-carboxylate (200 uL) were dissolved in DMSO / DCE (5 mL / 5 mL), 0.2 mL of acetic acid was added, and the mixture was stirred at room temperature for 1 hour. Sodium acetate borohydride (120 mg, 0.566 mmol) was added, and the mixture was stirred at room temperature overnight. LCMS analysis showed that the reaction was no longer proceeding, and the mixture was quenched with saturated sodium bicarbonate solution and extracted with DCM. The organic phases were combined, washed, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography to obtain 005a.

[0488] Step 2:

[0489] N-tert-Butyloxycarbonyl-4-piperidone (500 mg, 2.51 mmol) was dissolved in DCM (6 mL), TFA (3 mL) was added dropwise under ice-cooling, and the mixture was stirred at room temperature for 1 hour. LCMS showed that the reaction was no longer proceeding. The solvent was removed by rotary evaporation, and the mixture was dissolved in DMSO (5 mL). 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (200 mg, 0.725 mmol) and DIEA (2 mL) were added, and the mixture was stirred at 80°C for 12 hours. LCMS showed that the reaction was no longer proceeding. The mixture was extracted with water and DCM. The organic phases were combined, washed, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography to obtain 005b.

[0490] Step 3:

[0491] Compound 005b (42 mg, 0.118 mmol) was dissolved in DCM (4 mL), TFA (1 mL) was added dropwise under ice bath, and the mixture was stirred at room temperature for 1 hour. LCMS detected that the reaction no longer proceeded, the solvent was removed by rotary evaporation, and then dissolved in DMSO / DCE (4 mL / 4 mL), compound 005a (50.1 mg, 0.078 mmol) was added, 0.2 mL of acetic acid was added, and the mixture was stirred at 80 ° C for 2 hours. Sodium acetate borohydride (60 mg, 0.283 mmol) was added and stirred at room temperature overnight. LCMS detected that the reaction no longer proceeded, and the mixture was quenched with saturated sodium bicarbonate solution, extracted with DCM, and the organic phases were combined and washed, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography to obtain C005. LCMS (ESI) m / z: [M+H + ]=879.7.

[0492] Example 006: Preparation of Compound C006

[0493] Step 1:

[0494] Oxalyl chloride (1.1 g, 8.73 mmol) was dissolved in anhydrous DCM (16 mL), the atmosphere was replaced with N2 three times, the temperature was lowered to -78°C, and DMSO (1.25 mL) was added. Compound 006a (1 g, 4.35 mmol) was dissolved in anhydrous DCM (4 mL) and added dropwise to the reaction mixture at -78°C. The temperature was maintained and stirred for 0.5 hours. TEA (3.6 mL, 25.9 mmol) was added, and the mixture was slowly warmed to room temperature and stirred for 1.5 hours. TLC indicated that the reaction was no longer progressing. The mixture was quenched with saturated sodium bicarbonate solution and extracted with DCM. The organic phases were combined, washed, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography to yield 006b.

[0495] Step 2:

[0496] Warhead 1 (100 mg, 0.213 mmol) and compound 006b (270 mg, 1.18 mmol) were dissolved in DMSO / DCE (5 mL / 5 mL). 0.2 mL of acetic acid was added, and the mixture was stirred at room temperature for 1 hour. Sodium acetate borohydride (120 mg, 4.72 mmol) was added, and the mixture was stirred at room temperature overnight. LCMS analysis indicated that the reaction was no longer progressing. The mixture was quenched with saturated sodium bicarbonate solution and extracted with DCM. The combined organic phases were washed, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography to yield 006c.

[0497] Step 3:

[0498] Compound 006c (24.8 mg, 0.036 mmol) was dissolved in DCM (4 mL), TFA (0.8 mL) was added dropwise under ice bath, and stirred at room temperature for 1 hour. LCMS detected that the reaction no longer proceeded, the solvent was removed by rotary evaporation, and then dissolved in DMSO (4 mL). 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (30 mg, 0.109 mmol), 0.8 mL DIEA, were added to the crude product and stirred at 80 ° C for 5 hours. LCMS detected that the reaction no longer proceeded, and the product was extracted with water and DCM. The organic phases were combined and washed, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography to obtain C006. LCMS (ESI) m / z: [M+H + ]=839.7.

[0499] Example 007: Preparation of Compound C007

[0500] Step 1:

[0501] Warhead 1 (100 mg, 0.213 mmol) and tert-butyl 3-formylazetidine-1-carboxylate (200 uL) were dissolved in DMSO / DCE (4 mL / 4 mL), 0.2 mL of acetic acid was added, and the mixture was stirred at room temperature for 1 hour. Sodium acetate borohydride (120 mg, 0.563 mmol) was added, and the mixture was stirred at room temperature overnight. LCMS analysis showed that the reaction was no longer proceeding, and the mixture was quenched with saturated sodium bicarbonate solution and extracted with DCM. The organic phases were combined, washed, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography to obtain 007a.

[0502] Step 2:

[0503] Compound 007a (58.2 mg, 0.091 mmol) was dissolved in DCM (4 mL), TFA (0.8 mL) was added dropwise under an ice bath, and the mixture was stirred at room temperature for 1 hour. LCMS detected that the reaction no longer proceeded, the solvent was removed by rotary evaporation, and the mixture was dissolved in DCE / DMSO (2 mL / 2 mL), followed by the addition of 1-Boc-3-azetidinone (70 mg, 0.409 mmol) and 0.1 mL of acetic acid. The mixture was stirred at 65 ° C for 2 hours, and 60 mg of sodium acetate borohydride was added. The mixture was stirred at room temperature overnight. LCMS detected that the reaction no longer proceeded, and the mixture was quenched with saturated sodium bicarbonate solution and extracted with DCM. The organic phases were combined, washed, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography to obtain 007b.

[0504] Step 3:

[0505] Compound 007b (37.6 mg, 0.054 mmol) was dissolved in DCM (4 mL), 0.5 mL of TFA was added dropwise under ice bath, and the mixture was stirred at room temperature for 1 hour. LCMS showed that the reaction no longer proceeded, the solvent was removed by rotary evaporation, and then the mixture was dissolved in DMSO (4 mL), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (50 mg, 0.181 mmol) and DIEA (0.8 mL) were added, and the mixture was stirred at 85°C for 3 hours. LCMS showed that the reaction no longer proceeded, the mixture was extracted with water and DCM, the organic phases were combined and washed, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography to obtain C007. LCMS (ESI) m / z: [M+H + ]=851.7. 1H NMR (500MHz, DMSO-d6) δ12.42(d,J=2.6Hz,1H),11.09(s,1H),8.38(d,J=6.8Hz,2H),8.11(d,J=2.4Hz,1H),8.01(s ,1H),7.82(s,2H),7.65(d,J=8.2Hz,1H),6.79(d,J=2.1Hz,1H),6.65(dd,J=8.4,2.1Hz,1H),5.06(dd,J=12.8,5.4 Hz,1H),4.19(s,1H),4.03(dd,J=8.8,7.0Hz,2H),3.82(dd,J=8.9,4.3Hz,2H),3.60(t,J=5.5Hz,1H),3.39(t,J=7. 0Hz,2H),3.06(s,4H),2.99–2.82(m,3H),2.63–2.55(m,2H),2.40(s,6H),2.27(s,3H),2.06(q,J=4.4,4.0Hz,3H).

[0506] Example 008: Preparation of Compound C008

[0507] Step 1:

[0508] Warhead 1 (150 mg, 0.319 mmol) and tert-butyl 3-formylazetidine-1-carboxylate (300 uL) were dissolved in DMSO / DCE (7 mL / 7 mL), 0.3 mL of acetic acid was added, and the mixture was stirred at room temperature for 1 hour. Sodium acetate borohydride (180 mg, 0.849 mmol) was added, and the mixture was stirred at room temperature overnight. LCMS analysis showed that the reaction was no longer proceeding, and the mixture was quenched with saturated sodium bicarbonate solution and extracted with DCM. The organic phases were combined, washed, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography to obtain 008a.

[0509] Step 2:

[0510] Compound 008a (82 mg, 0.128 mmol) was dissolved in 4 mL of DCM, TFA (1 mL) was added dropwise under an ice bath, and the mixture was stirred at room temperature for 1 hour. LCMS detection showed that the reaction no longer proceeded, the solvent was removed by rotary evaporation, and the mixture was dissolved in DCE / DMSO (2 mL / 2 mL). 1-Boc-3-azetidinone (95 mg, 0.56 mmol) was added to the crude product, 0.2 mL of acetic acid was added, and the mixture was stirred at 65 ° C for 2 hours. Sodium acetate borohydride (90 mg, 0.424 mmol) was added and the mixture was stirred at room temperature overnight. LCMS detection showed that the reaction no longer proceeded, and the mixture was quenched with saturated sodium bicarbonate solution, extracted with DCM, and the organic phases were combined and washed, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography to give 008b.

[0511] Step 3:

[0512] The compound (60.3 mg, 0.087 mmol) was dissolved in DCM (3 mL), TFA (0.6 mL) was added dropwise under an ice bath, and the mixture was stirred at room temperature for 1 hour. LCMS detection showed that the reaction no longer proceeded, the solvent was removed by rotary evaporation, and the mixture was dissolved in DCE / DMSO (2 mL / 2 mL), 1-Boc-3-azetidinone (40 mg, 0.234 mmol) was added, 0.2 mL of acetic acid was added, and the mixture was stirred at 65 ° C for 2 hours. Sodium acetate borohydride (60 mg, 0.283 mmol) was added and the mixture was stirred at room temperature overnight. LCMS detection showed that the reaction no longer proceeded, and the mixture was quenched with saturated sodium bicarbonate solution, extracted with DCM, and the organic phases were combined, washed, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography to obtain 008c.

[0513] Step 4:

[0514] Compound 008c (43.1 mg, 0.0575 mmol) was dissolved in DCM (4 mL), TFA (0.8 mL) was added dropwise under ice bath, and the mixture was stirred at room temperature for 1 hour. LCMS showed that the reaction no longer proceeded, the solvent was removed by rotary evaporation, and then the mixture was dissolved in DMSO (4 mL), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (50 mg, 0.181 mmol) and DIEA (0.8 mL) were added, and the mixture was stirred at 85°C for 3 hours. LCMS showed that the reaction no longer proceeded, the mixture was extracted with water and DCM, the organic phases were combined and washed, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography to obtain C008. LCMS (ESI) m / z: [M+H + ]=906.8. 1H NMR (500MHz, DMSO-d6) δ12.42(d,J=2.7Hz,1H),11.09(s,1H),8.38(d,J=6.9Hz,2H),8.11(d,J=2.4Hz,1H),8.01(s,1H ),7.82(s,2H),7.64(d,J=8.3Hz,1H),6.79(d,J=2.1Hz,1H),6.65(dd,J=8.4,2.1Hz,1H),5.06(dd,J=12.7,5.4Hz,1H) ,4.19(s,1H),4.08–3.99(m,2H),3.78(dd,J=9.0,4.3Hz,2H),3.65–3.57(m,1H),3.30–3.22(m,3H),3.06(d,J=5.8Hz, 4H),2.98(d,J=4.2Hz,2H),2.95–2.86(m,1H),2.66–2.51(m,3H),2.39(s,6H),2.27(s,3H),2.05(q,J=4.7,4.1Hz,3H).

[0515] Example 009: Preparation of Compound C009

[0516] Step 1:

[0517] Warhead 1 (100 mg, 0.213 mmol), tert-butyl 3-formylazetidine-1-carboxylate (43 mg, 0.232 mmol), and TEA (22 uL) were dissolved in MeOH / 3 mL DCM (1.5 mL / 3 mL). After stirring for 5 minutes, 24 uL of acetic acid was added, and the mixture was stirred at 50°C for 2 hours. Sodium acetate borohydride (225 mg, 1.06 mmol) was added, and the mixture was stirred at 50°C for 0.5 hours. LCMS analysis showed that the reaction was no longer progressing, and the mixture was quenched with saturated sodium bicarbonate solution and extracted with DCM. The organic phases were combined, washed, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography to obtain 009a.

[0518] Step 2:

[0519] Compound 009a (66 mg, 0.103 mmol) was dissolved in DCM (4 mL), TFA (0.8 mL) was added dropwise under ice bath, and stirred at room temperature for 1 hour. LCMS detected that the reaction no longer proceeded, the solvent was removed by rotary evaporation, and then dissolved in DMSO (4 mL), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (36 mg, 0.13 mmol) and DIEA (0.8 mL) were added, and stirred at 85 ° C for 5 hours. LCMS detected that the reaction no longer proceeded, and the mixture was extracted with water and DCM. The organic phases were combined and washed, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography to obtain C009. LCMS (ESI) m / z: [M+H + ]=796.6. 1 H NMR(500MHz,DMSO-d6)δ12.43(s,1H),11.09(s,1H),8.39(d,J=6.8Hz,2H),8.14–8.09(m,1H),8.01(s,1H) ,7.83(s,2H),7.65(d,J=8.2Hz,1H),6.80(s,1H),6.70–6.63(m,1H),5.09–5.03(m,1H),4.17(t,J=7.8Hz,3 H),4.01–3.94(m,1H),3.79–3.70(m,2H),3.16–3.02(m,5H),2.94–2.85(m,3H),2.71(dd,J=13.4,7.3Hz,2 H),2.64–2.59(m,1H),2.55(d,J=6.3Hz,4H),2.41(s,6H),2.24(s,3H),2.05(td,J=18.6,18.1,6.7Hz,7H).

[0520] Example 010: Preparation of Compound C010

[0521] Step 1:

[0522] Warhead 1 (100 mg, 0.213 mmol), 1-tert-butyloxycarbonylpiperidine-4-carboxaldehyde (37 mg, 0.174 mmol), and 22 μL of TEA were dissolved in MeOH / DCM (1.5 mL / 3 mL). After stirring for 5 minutes, 24 μL of acetic acid was added, and the mixture was stirred at 50°C for 2 hours. Sodium acetate borohydride (225 mg, 1.06 mmol) was added, and the mixture was stirred at 50°C for 0.5 hours. LCMS analysis indicated that the reaction was no longer progressing, so the mixture was quenched with saturated sodium bicarbonate solution and extracted with DCM. The combined organic phases were washed, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography to obtain 010a.

[0523] Step 2:

[0524] Compound 010a (35 mg, 0.052 mmol) was dissolved in DCM (4 mL), TFA (0.8 mL) was added dropwise under ice bath, and stirred at room temperature for 1 hour. LCMS detected that the reaction no longer proceeded, the solvent was removed by rotary evaporation, and then dissolved in DMSO (4 mL). 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (36 mg, 0.13 mmol) and DIEA (0.8 mL) were added to the crude product and stirred at 85 ° C for 5 hours. LCMS detected that the reaction no longer proceeded, and the product was extracted with water and DCM. The organic phases were combined and washed, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography to obtain C010. LCMS (ESI) m / z: [M+H + ]=824.7. 1 H NMR (500MHz, DMSO-d6) δ12.45(s,1H),11.10(s,1H),8.39(d,J=4.2Hz,2H),8.12(s,1H),8.01(s,1H),7.83(s,1H),7. 66(d,J=8.5Hz,1H),7.33(s,1H),7.25(dd,J=8.7,2.3Hz,1H),6.90(s,1H),5.07(dd,J=12.8,5.4Hz,1H),4.21–4.12(m ,2H),4.11–4.03(m,2H),3.97(t,J=6.6Hz,2H),3.15–3.05(m,4H),3.02–2.95(m,2H),2.87(dd,J=16.7,5.5Hz,3H),2 .73(t,J=7.6Hz,2H),2.65–2.52(m,3H),2.41(s,6H),2.25(s,1H),2.22(s,3H),2.09–1.99(m,7H),1.91–1.80(m,4H).

[0525] Example 011: Preparation of Compound C011

[0526] Step 1:

[0527] Warhead 1 (100 mg, 0.213 mmol), 1-Boc-3-azetidinone (40 mg, 0.234 mmol), and TEA (22 uL) were dissolved in MeOH / DCM (1.5 mL / 3 mL). After stirring for 5 minutes, 24 uL of acetic acid was added and the mixture was stirred at 50°C for 2 hours. Sodium acetate borohydride (225 mg, 1.06 mmol) was added and stirred at 50°C for 0.5 hours. LCMS analysis indicated that the reaction was no longer progressing. The mixture was quenched with saturated sodium bicarbonate solution and extracted with DCM. The organic phases were combined, washed, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography to obtain 011a.

[0528] Step 2:

[0529] The compound (55 mg, 0.088 mmol) was dissolved in DCM (4 mL), TFA (0.8 mL) was added dropwise under ice bath, and stirred at room temperature for 1 hour. LCMS detected that the reaction no longer proceeded, the solvent was removed by rotary evaporation, and then dissolved in DMSO (4 mL), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (32 mg, 0.116 mmol) and DIEA (0.8 mL) were added, and stirred at 85 ° C for 5 hours. LCMS detected that the reaction no longer proceeded, and the mixture was extracted with water and DCM. The organic phases were combined and washed, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography to obtain C011. LCMS (ESI) m / z: [M+H + ]=782.6. 1 H NMR (500MHz, DMSO-d6) δ12.46(s,1H),11.10(s,1H),8.39(d,J=5.5Hz,2H),8.12(d,J=2.1Hz,1H),8.02(s ,1H),7.85(d,J=4.1Hz,2H),7.67(d,J=8.3Hz,1H),6.83(s,1H),6.69(d,J=8.2Hz,1H),5.07(dd,J=12.8,5 .4Hz,1H),4.17(q,J=8.6,7.5Hz,3H),3.92(dd,J=7.1,3.8Hz,2H),3.65–3.39(m,3H),3.12(d,J=14.3Hz, 4H),2.96–2.83(m,3H),2.65–2.52(m,4H),2.42(s,6H),2.26(s,3H),2.05(ddt,J=24.4,15.1,8.2Hz,7H).

[0530] Example 012: Preparation of Compound C012

[0531] Step 1:

[0532] The preparation method of compound 012a is shown in 010a of Example 012.

[0533] Step 2:

[0534] 4,5-Difluorophthalic anhydride (500 mg, 2.72 mmol), 3-amino-2,6-piperidinedione hydrochloride (470 mg, 2.86 mmol), and KOAc (293 mg, 2.99 mmol) were dissolved in acetic acid (10 mL) and stirred at 90°C overnight. LCMS analysis indicated that the reaction was no longer proceeding. The solvent was removed by rotary evaporation, and the mixture was extracted with water and DCM. The combined organic phases were washed, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography to afford 012b.

[0535] Step 3:

[0536] Compound 012a (37.4 mg, 0.056 mmol) was dissolved in DCM (4 mL), TFA (0.8 mL) was added dropwise under ice bath, and the mixture was stirred at room temperature for 1 hour. LCMS showed that the reaction was no longer proceeding. The solvent was removed by rotary evaporation, and the mixture was then dissolved in DMSO (4 mL). Compound 012b (23 mg, 0.078 mmol) and DIEA (0.8 mL) were added, and the mixture was stirred at 85°C for 3 hours. LCMS showed that the reaction was no longer proceeding. The mixture was extracted with water and DCM. The organic phases were combined, washed, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography to obtain C012. LCMS (ESI) m / z: [M+H + ]=842.7. 1 H NMR (500MHz, DMSO-d6) δ12.45(s,1H),11.12(s,1H),8.39(d,J=2.0Hz,2H),8.13(d,J=2.4 Hz,1H),8.04(s,1H),7.84(s,2H),7.72(d,J=11.4Hz,1H),7.46(d,J=7.4Hz,1H),5.11(dd, J=12.9,5.4Hz,1H),4.43–4.15(m,2H),3.85–3.48(m,4H),3.10(s,6H),2.99–2.76(m,4H) ,2.66–2.51(m,5H),2.42(s,6H),2.40–2.24(m,4H),2.23–1.98(m,6H),1.97–1.72(m,4H).

[0537] Example 013: Preparation of Compound C013

[0538] Step 1:

[0539] 3-Amino-4-methoxybenzoic acid (2.5 g, 15 mmol) was dissolved in acrylic acid (4 mL) and stirred at 100°C for 3 hours. LCMS analysis indicated that the reaction was no longer proceeding. The mixture was cooled to room temperature, and acetic acid (16.5 mL) and urea (5.5 g, 91.7 mmol) were added. The mixture was stirred at 120°C for 8 hours. LCMS analysis indicated that the reaction was no longer proceeding. The mixture was cooled to room temperature and poured into 3N HCl under an ice bath. The mixture was maintained at 0°C overnight, and the solid was collected by filtration and slurried with MTBE to yield 013a.

[0540] Step 2:

[0541] Warhead 1 (64 mg, 0.136 mmol), compound 013a (36 mg, 0.136 mmol), HATU (51 mg, 0.134 mmol), and DIEA (53 mmol, 0.408 mmol) were dissolved in DMF (2 mL) and stirred at 35°C for 16 hours. LCMS analysis indicated that the reaction was no longer progressing. The mixture was extracted with water and DCM, and the combined organic phases were washed, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography to obtain C013. LCMS (ESI) m / z: [M+H + ]=814.7. 1 H NMR (500MHz, DMSO-d6) δ12.43(s,1H),10.36(s,1H),8.38(d,J=5.4Hz,2H),8.12(d,J=2.4Hz,1H) ,8.02(s,1H),7.83(s,2H),7.38(dd,J=8.5,2.0Hz,1H),7.34(d,J=2.0Hz,1H),7.17(d,J=8.6Hz,1 H),4.54–4.31(m,2H),4.29–4.09(m,2H),3.85(s,3H),3.61(t,J=6.5Hz,2H),3.16–2.86(m,8H), 2.69(t,J=6.3Hz,2H),2.55(d,J=7.8Hz,2H),2.40(s,6H),2.38–1.99(m,12H),1.96–1.55(m,5H).

[0542] Example 014: Preparation of Compound C014

[0543] Step 1:

[0544] Dissolve 0.26 mL of bromoethanol, 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindoline-1,3-dione (0.5 g, 1.82 mmol), NaHCO₃ (0.3 g, 3.57 mmol), and NaI (0.27 g, 1.8 mmol) in 3 mL of DMF and stir at 90°C for 24 hours. LCMS analysis indicated that the reaction was no longer progressing. The reaction solution was filtered, and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography to afford 014a.

[0545] Step 2:

[0546] Compound 014a (120 mg, 0.377 mmol) and IBX (215 mg, 0.768 mmol) were dissolved in 7 mL of MeCN and stirred at 80°C for 2 hours. LCMS analysis indicated that the reaction was no longer progressing. The reaction solution was filtered and the filtrate was concentrated in vacuo to yield the crude product, compound 014b, which was carried on to the next step without further purification.

[0547] Step 3:

[0548] Warhead 1 (50 mg, 0.106 mmol) and compound 014b (119 mg, 0.377 mmol) were dissolved in 1.5 mL of EtOH and 1.5 mL of DCM. 0.1 mL of acetic acid was added, and the mixture was stirred at room temperature for 1 hour. 60 mg of sodium acetate borohydride was added, and the mixture was stirred at room temperature overnight. LCMS analysis indicated that the reaction was no longer progressing. The reaction solution was concentrated in vacuo, and the crude product was purified by column chromatography to obtain C014. LCMS (ESI) m / z: [M+H + ]=771.6. 1 H NMR (500MHz, DMSO-d6) δ12.42(d,J=2.6Hz,1H),11.12(s,1H),8.38(d,J=7.5Hz,2H),8. 12(d,J=2.6Hz,1H),8.01(s,1H),7.87–7.80(m,3H),7.59(d,J=8.6Hz,1H),7.48(d,J=7. 2Hz,1H),5.10(dd,J=12.8,5.4Hz,1H),4.40(t,J=5.6Hz,2H),3.06(t,J=4.6Hz,4H),2.8 7–2.83(m,2H),2.72–2.67(m,4H),2.40(s,6H),2.26(s,3H),2.05(q,J=4.7,4.2Hz,4H).

[0549] Example 015: Preparation of Compound C015

[0550] Step 1:

[0551] Warhead 1 (100 mg, 0.213 mmol) and tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (120 mg, 0.569 mmol) were dissolved in DMSO / DCE (2 mL / 2 mL). 0.2 mL of acetic acid was added, and the mixture was stirred at 60°C for 1 hour. Sodium acetate borohydride (1.2 g, 0.94 mmol) was added, and the mixture was stirred at room temperature overnight. LCMS analysis indicated that the reaction was no longer proceeding, and the mixture was quenched with saturated sodium bicarbonate solution and extracted with DCM. The organic phases were combined, washed, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography to afford 015a.

[0552] Step 2:

[0553] Compound 015a (51.3 mg, 0.077 mmol) was dissolved in DCM (4 mL), 0.8 mL of TFA was added dropwise under ice bath, and the mixture was stirred at room temperature for 1 hour. LCMS detected that the reaction no longer proceeded, the solvent was removed by rotary evaporation, and then dissolved in DMSO (4 mL), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (50 mg, 0.181 mmol), DIEA (0.8 mL), and stirred at 85 ° C for 5 hours. LCMS detected that the reaction no longer proceeded, and the mixture was extracted with water and DCM. The organic phases were combined and washed, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography to obtain C015. LCMS (ESI) m / z: [M+H + ]=822.7.

[0554] Example 016: Preparation of Compound C016

[0555] Step 1:

[0556] Tert-butyl 4-aminobenzoate (1.25 g, 6.48 mmol), acrylic acid (500 mg, 6.94 mmol), and 0.2 mL of acetic acid were dissolved in toluene (12 mL) and stirred at 100°C overnight. LCMS analysis indicated that the reaction was no longer progressing. The mixture was cooled to room temperature and poured into 50 mL of a 20:1 PE:EA mixture. A large amount of solid precipitated, which was collected by filtration to yield 016a.

[0557] Step 2:

[0558] Compound 016a (800 mg, 3.02 mmol), urea (1.09 g, 18.2 mmol) and acetic acid were dissolved in 2.5 mL of acetic acid and stirred overnight at 100°C. LCMS analysis indicated that the reaction was no longer progressing. The reaction mixture was cooled to room temperature and poured into 20 mL of ice water. A large amount of solid precipitated, which was collected by filtration and washed with acetonitrile to obtain 016b.

[0559] Step 3:

[0560] Compound 016b (65.0 mg, 0.224 mmol) was dissolved in 5 mL of DCM, TFA (5 mL) was added, and the mixture was stirred at room temperature for 1 hour. LCMS detected that the reaction no longer proceeded, the solvent was removed by rotary evaporation, and then dissolved in DMF (2 mL), and warhead 1 (64 mg, 0.136 mmol), HATU (44 mg, 0.116 mmol), and DIEA (0.6 mL) were added, and the mixture was stirred at room temperature overnight. LCMS detected that the reaction no longer proceeded, and the mixture was quenched with saturated sodium bicarbonate solution, extracted with DCM, and the organic phases were combined and washed, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography to obtain C016. LCMS (ESI) m / z: [M+H + ]=784.7. 1 H NMR (500MHz, DMSO-d6) δ12.42(d,J=2.6Hz,1H),10.47(s,1H),8.38(d,J=8.1Hz,2H),8.12(d,J=2.5Hz ,1H),8.01(s,1H),7.83(s,2H),7.40(s,4H),4.48(s,1H),4.18(td,J=9.8,5.0Hz,1H),3.84(t,J=6.6 Hz,2H),3.64(s,1H),3.08(s,4H),2.90(d,J=7.7Hz,2H),2.78(s,1H),2.72(t,J=6.7Hz,2H),2.49(s, 3H),2.40(s,6H),2.24(s,5H),2.15-1.99(m,6H),1.92-1.64(m,4H),1.23(s,1H),1.17-1.05(m,2H).

[0561] Example 017: Preparation of Compound C017

[0562] Step 1:

[0563] 2-(2,6-Dioxo-piperidin-3-yl)-4-hydroxy-isoindole-1,3-dione (549 mg, 1.99 mmol) and DMAP (244 mg, 2 mmol) were dissolved in dioxane (10 mL). Boc2O (476 mg, 2.18 mmol) was slowly added dropwise and stirred at room temperature overnight. LCMS analysis indicated that the reaction was no longer proceeding. The mixture was extracted with water and EA. The combined organic phases were washed, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography to afford 017a.

[0564] Step 2:

[0565] 1,3-Dibromopropane (423 mg, 2.115 mmol), K2CO3 (344 mg, 2.49 mmol), and potassium iodide (2 mg, 0.012 mmol) were dissolved in DMF (2 mL). Compound 017a (310 mg, 0.83 mmol) was dissolved in DMF (3 mL) and added dropwise to the reaction mixture with stirring. The mixture was stirred at room temperature for 2 hours. LCMS analysis indicated that the reaction was no longer proceeding. The mixture was extracted with water and EA. The organic phases were combined, washed, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography to yield 017b.

[0566] Step 3:

[0567] Compound 017b (40 mg) was dissolved in DCM (3 mL), TFA (1 mL) was added, and the mixture was stirred at room temperature for 1 hour. LCMS showed that the reaction was no longer proceeding. The solvent was removed by rotary evaporation, and then the mixture was dissolved in DMSO (3 mL). Warhead 1 (30 mg, 0.064 mmol) and DIEA (45 uL) were added and stirred at 80°C for 2 hours. LCMS showed that the reaction was no longer proceeding. The reaction solution was diluted with saturated brine, and a large amount of solid precipitated. The solid was filtered and collected. The obtained solid was redissolved and purified by column chromatography to obtain C017. LCMS (ESI) m / z: [M+H + ]=785.6. 1 H NMR(500MHz,DMSO-d6)δ12.45(s,1H),11.16(br,1H),8.39(s,2H),8.14(d,J=2.4Hz,1H),8 .07(s,1H),7.83(s,2H),7.66(q,J=11.4,9.6Hz,1H),7.34(d,J=7.1Hz,1H),7.27(d,J=8.5H z,1H),5.18(dd,J=13.0,5.5Hz,1H),4.34(s,1H),3.83-3.68(m,2H),3.28-3.03(m,6H),3.0 4-2.91(m,2H),2.85-2.70(m,6H),2.69-2.52(m,8H),2.42-2.33(s,9H),1.83-1.57(m,3H).

[0568] Example 018: Preparation of Compound C018

[0569] Step 1:

[0570] TsCl (1 g, 5.26 mmol), diethylene glycol (3.5 mL), DMAP (65 mg), and 0.8 mL of TEA were dissolved in 20 mL of DCM and stirred at room temperature for 2 hours. LCMS indicated that the reaction was no longer progressing. The reaction solution was filtered, the filtrate was concentrated in vacuo, and the crude product was purified by column chromatography to afford 018a.

[0571] Step 2:

[0572] Compound 018a (950 mg, 3.65 mmol), 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindoline-1,3-dione (500 mg, 1.82 mmol), NaHCO (305 mg, 3.63 mmol), and NaI (275 mg, 1.83 mmol) were dissolved in DMF (10 mL) and stirred at 90°C for 1 h. LCMS analysis indicated that the reaction was no longer progressing. The reaction solution was filtered, and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography to afford 018b.

[0573] Step 3:

[0574] Compound 018b (250 mg, 0.69 mmol) and IBX (400 mg, 1.43 mmol) were dissolved in MeCN (5 mL) and stirred at 80°C for 2 hours. LCMS showed that the reaction was no longer progressing. The reaction solution was filtered, the filtrate was concentrated in vacuo, and the crude product was purified by column chromatography to obtain 018c.

[0575] Step 3:

[0576] Warhead 1 (50 mg, 0.106 mmol) and compound 018c (148 mg, 0.569 mmol) were dissolved in EtOH (1.5 mL) and DCM (1.5 mL). 0.1 mL of acetic acid was added and the mixture was stirred at room temperature for 1 hour. Sodium acetate borohydride (60 mg, 0.283 mmol) was added and the mixture was stirred at room temperature overnight. LCMS showed that the reaction was no longer progressing. The mixture was quenched with saturated sodium bicarbonate solution and extracted with water and DCM. The organic phases were combined, washed, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography to obtain compound C018. LCMS (ESI) m / z: [M+H + ]=815.6.

[0577] Example 019: Preparation of Compound C019

[0578] Step 1

[0579] 19a (11 g, 73 mmol) was dissolved in dichloromethane (100 mL), cooled to 0°C, and triethylamine (1.95 g, 19 mmol) and 4-dimethylaminopyridine (46 mg, 0.3 mmol) were added at this temperature. 4-Toluenesulfonyl chloride (3.5 g, 18.4 mmol) dissolved in dichloromethane (150 mL) was then slowly added dropwise at 0°C. The mixture was warmed to room temperature and stirred overnight. TLC (petroleum ether:ethyl acetate = 1:1) showed the formation of new spots and the complete disappearance of the starting material. After the reaction, water (100 mL) was slowly poured into the mixture while stirring. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to obtain a residue. Compound 19b was purified by column chromatography.

[0580] Step 2

[0581] Compound 19c (200 mg, 0.113 mmol), 19b (664 mg, 2.18 mmol), sodium iodide (108 mg, 0.73 mmol) and sodium bicarbonate (124 mg, 1.48 mmol) were dissolved in N,N-dimethylformamide (2 mL) at room temperature and stirred at 70 ° C for 16 hours. LCMS showed that the reactants were completely converted and the product was detected. 30 mL of water was added to the reaction solution, and the product was extracted with dichloromethane (20 mL*2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to obtain a residue. The residue was purified by flash column chromatography to obtain the final product 19d. LCMS (ESI) m / z: 407.7 [M+H] + .

[0582] Step 3:

[0583] Compound 19d (294 mg, 0.724 mmol) and IBX (405 mg, 1.44 mmol) were dissolved in N,N-dimethylformamide (2 mL) at room temperature and stirred at 75°C for 2 hours. LCMS showed complete conversion and product was detected. The reaction solution was filtered, and the filtrate was distilled under reduced pressure to obtain crude product 19e. LCMS (ESI) m / z: 405.3 [M+H] + .

[0584] Step 4:

[0585] Compound 19f (80 mg, 0.158 mmol), 19e (77 mg, 0.19 mmol) and triethylamine (16 mg, 0.158 mmol) were dissolved in methanol / dichloromethane (2 mL / 4 mL) at room temperature and stirred at 50°C for 2 hours. Sodium triacetylborohydride (167 mg, 0.788 mmol) was then added to the reaction solution, which was stirred at 50°C for 30 minutes and then stirred at room temperature overnight. LCMS showed that nearly half of the reactants were converted and the product was detected. After the reaction solution was cooled to room temperature, saturated sodium bicarbonate solution (30 mL) was added for quenching and the mixture was extracted with dichloromethane (30 mL*2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain a residue. The residue was purified by Pre-TLC to obtain the final product. The reaction solution was filtered, and the filtrate was distilled under reduced pressure to obtain the final product C019. LCMS (ESI) m / z: 859.6 [M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ12.43(s,1H),10.36(s,1H),8.38(d,J=5.1Hz,2H),8.12(d,J=2.4Hz,1H),8.0 2(s,1H),7.83(s,2H),7.38(dd,J=8.5,1.9Hz,1H),7.34(d,J=2.0Hz,1H),7.17(d,J=8.6Hz,1H),4.46( dd,J=5.3,3.5Hz,2H),4.23(dd,J=11.4,6.5Hz,2H),3.85(s,2H),3.61(t,J=6.5Hz,2H),3.32–3.29(m ,1H),3.26–2.88(m,8H),2.75–2.66(m,2H),2.48–2.18(m,13H),2.19–2.00(m,5H),1.97–1.55(m,6H).

[0586] Example 020: Preparation of Compound C020

[0587] Step 1:

[0588] 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (1 g, 3.62 mmol), 1-amino-3,6,9-trioxa-11-undecanol (0.65 mL), and DIEA (0.75 mL) were dissolved in dioxane (15 mL) and stirred at 105°C overnight. LCMS analysis indicated that the reaction was no longer progressing. The reaction solution was concentrated in vacuo, and the crude product was purified by column chromatography to afford 020a.

[0589] Step 2:

[0590] 300 mg of compound 020a (300 mg, 0.668 mmol), TsCl (190 mg, 1 mmol), TEA (0.14 mL, 1 mmol), and 65 mg of DMAP (65 mg, 0.53 mmol) were dissolved in DCM (5 mL) and stirred at room temperature for 1 hour. LCMS analysis indicated that the reaction was no longer progressing. The reaction solution was concentrated in vacuo, and the crude product was purified by column chromatography to afford 020b.

[0591] Step 3:

[0592] Warhead 1 (70 mg, 0.149 mmol), compound 020b (55 mg, 0.091 mmol), and DIEA (6 uL) were dissolved in DMSO (2 mL) and stirred at 80°C for 8 hours. LCMS analysis indicated that the reaction was no longer progressing. The mixture was extracted with water and DCM. The organic phases were combined, washed, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography to obtain C020. LCMS (ESI) m / z: [M+H + ]=902.7.

[0593] 1 H NMR (500MHz, DMSO-d6) δ12.42(s,1H),11.13(s,1H),8.38(d,J=6.0Hz,2H),8.11(d,J=2.6Hz,1H),8.01(s,1H),7.82(s, 2H),7.58(dd,J=8.5,7.1Hz,1H),7.15(d,J=8.6Hz,1H),7.03(d,J=7.0Hz,1H),6.62(t,J=5.8Hz,1H),5.06(dd,J=12.7, 5.5Hz,1H),4.18(s,1H),3.64(t,J=5.5Hz,2H),3.61–3.51(m,8H),3.48(d,J=6.3Hz,1H),3.31(s,1H),3.05(s,4H),2.8 7(dd,J=21.7,9.2Hz,3H),2.65–2.63(m,1H),2.54(s,2H),2.39(s,6H),2.23(d,J=12.9Hz,2H),2.03(d,J=21.7Hz,9H).

[0594] Example 021: Preparation of Compound C021

[0595] Step 1:

[0596] Warhead 1 (100 mg, 0.213 mmol) and N-Boc-hexahydro-5-oxocyclopenta[C]pyrrole (120 mg, 0.543 mmol) were dissolved in DMSO / DCE (2 mL / 2 mL). 0.2 mL of acetic acid was added, and the mixture was stirred at 60°C for 1 hour. Sodium acetate borohydride (226 mg, 1.065 mmol) was added, and the mixture was stirred at room temperature overnight. LCMS analysis indicated that the reaction was no longer proceeding, and the mixture was quenched with saturated sodium bicarbonate solution and extracted with DCM. The organic phases were combined, washed, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography to afford 021a.

[0597] Step 2:

[0598] Compound 021a (35.4 mg, 0.052 mmol) was dissolved in DCM (4 mL), TFA (0.8 mL) was added dropwise under ice bath, and stirred at room temperature for 1 hour. LCMS detected that the reaction no longer proceeded, the solvent was removed by rotary evaporation, and then dissolved in DMSO (4 mL), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (30 mg, 0.109 mmol) and DIEA (0.8 mL) were added, and stirred at 85 ° C for 5 hours. LCMS detected that the reaction no longer proceeded, and the mixture was extracted with water and DCM. The organic phases were combined and washed, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography to obtain C021. LCMS (ESI) m / z: [M+H + ]=836.7. 1 H NMR (500MHz, DMSO-d6) δ12.42(d,J=2.6Hz,1H),11.09(s,1H),8.37(d,J=6.4Hz,2H),8.11(d,J=2.5Hz,1H),8.01(s, 1H),7.81(s,2H),7.66(d,J=8.3Hz,1H),6.97(d,J=2.1Hz,1H),6.87(dd,J=8.5,2.2Hz,1H),5.07(dd,J=13.0,5.3Hz, 1H),3.59(dd,J=10.4,7.2Hz,2H),3.38(d,J=10.8Hz,2H),3.06(s,4H),2.95–2.88(m,2H),2.8 1(s,2H),2.58–2.53(m,1H),2.38(s,6H),2.24(s,4H),2.18(s,1H),2.04(q,J=4.5,4.1Hz,3H).

[0599] Example 022: Preparation of Compound C022

[0600] Step 1:

[0601] Warhead 1 (60 mg, 0.128 mmol) and 1-Boc-3-pyrrolidinecarboxaldehyde (128 mg, 0.643 mmol) were dissolved in DMSO / DCE (2 mL / 1 mL), 0.1 mL of acetic acid was added, and the mixture was stirred at room temperature for 1 hour. Sodium acetate borohydride (271 mg, 1.28 mmol) was added, and the mixture was stirred at room temperature for 2 hours. LCMS analysis showed that the reaction was no longer proceeding, and the mixture was quenched with saturated sodium bicarbonate solution and extracted with DCM. The organic phases were combined, washed, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography to obtain 022a.

[0602] Step 2:

[0603] Compound 022a (65.0 mg, 0.099 mmol) was dissolved in DCM (5 mL), TFA (1 mL) was added, and the mixture was stirred at room temperature for 1 hour. LCMS detected that the reaction no longer proceeded, the solvent was removed by rotary evaporation, and then dissolved in DMSO (2 mL), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (83 mg, 0.3 mmol), DIEA (0.15 mL), and stirred at 80 ° C for 5 hours. LCMS detected that the reaction no longer proceeded, and the reaction solution was diluted with saturated brine. A large amount of solid precipitated, filtered, and the solid was collected. The obtained solid was redissolved and purified by column chromatography to obtain C022. LCMS (ESI) m / z: [M+H + ]=810.7. 1 H NMR (500MHz, DMSO-d6) δ12.42(s,1H),11.09(s,1H),8.38(d,J=8.8Hz,2H),8.12(d,J=2.5Hz,1H),8.02(s,1H),7.84(s ,2H),7.66(d,J=8.4Hz,1H),6.93(d,J=2.2Hz,1H),6.84(dd,J=8.6,2.2Hz,1H),5.06(dd,J=12.9,5.4Hz,1H),4.19(br, 1H),3.61(dd,J=10.0,7.1Hz,1H),3.52(d,J=6.1Hz,1H),3.42(q,J=8.9,8.3Hz,1H),3.19(dd,J=10.3,6.9Hz,1H),3.12 (br,4H),2.98-2.83(m,3H),2.72-2.52(m,6H),2.47-2.34(m,8H),2.27(br,3H),2.21-1.93(m,9H),1.86-1.76(m,1H).

[0604] Example 023: Preparation of Compound C023

[0605] Step 1:

[0606] Warhead 1 (100 mg, 0.212 mmol) and 4-N-Boc-aminocyclohexanone (127 mg, 0.596 mmol) were dissolved in DMSO / DCE (2 mL / 1 mL), 0.1 mL of acetic acid was added, and the mixture was stirred at room temperature for 1 hour. Sodium acetate borohydride (250 mg, 1.18 mmol) was added, and the mixture was stirred at room temperature for 3 hours. LCMS analysis showed that the reaction was no longer proceeding, and the mixture was quenched with saturated sodium bicarbonate solution and extracted with DCM. The organic phases were combined, washed, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography to obtain 023a.

[0607] Step 2:

[0608] Compound 023a (65.0 mg, 0.097 mmol) was dissolved in TFA / DCM (5 mL / 5 mL) and reacted at room temperature for 1 hour. LCMS showed that the reaction was no longer proceeding. The solvent was removed by concentration under reduced pressure and the product was dried in vacuo to obtain 023b.

[0609] Step 3:

[0610] Compound 023b (45 mg, 0.079 mmol), 2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione (68 mg, 0.246 mmol), and DIPEA (103 mg, 0.798 mmol) were dissolved in DMF (2 mL) and stirred at 90 ° C for 6 hours. LCMS detection showed that the reaction no longer proceeded. The reaction solution was diluted with saturated brine, and a large amount of solid precipitated. The solid was filtered and collected. The obtained solid was redissolved and purified by column chromatography to obtain C023. LCMS (ESI) m / z: [M+H + ]=824.7; 1H NMR (500MHz, DMSO-d6) δ12.43(d,J=2.6Hz,1H),11.13(s,1H),8.39(d,J=6.5Hz,2H),8.12(d,J=2.5Hz, 1H),8.02(s,1H),7.83(s,2H),7.61(ddd,J=10.6,7.3,3.4Hz,1H),7.18(dd,J=8.7,4.4Hz,1H),7.05(t, J=7.1Hz,1H),6.48(d,J=8.2Hz,1H),5.13–5.01(m,1H),4.19(br,1H),3.88(br,1H),3.10(br,4H),2.98 –2.82(m,3H),2.68–2.53(m,4H),2.41(s,6H),2.36–2.21(s,5H),2.17–1.99(m,7H),1.94–1.42(m,9H).

[0611] Example 024: Preparation of Compound C024

[0612] Step 1:

[0613] N-Boc-3-aminopropyl bromide (34 mg, 0.143 mmol), warhead 1 (60 mg, 0.128 mmol), and DIPEA (50 mg, 0.387 mmol) were added to DMSO (1 mL) and reacted at 80°C for 3 h. LCMS confirmed complete conversion of the starting material. The reaction solution was cooled to room temperature and diluted with 5 mL of water. A large amount of solid precipitated, which was collected by filtration. The solid was redissolved and purified by silica gel column chromatography to yield 024a.

[0614] Step 3:

[0615] Compound 024a (40 mg, 0.064 mmol) was dissolved in trifluoroacetic acid / DCM (5 mL / 5 mL) and added, and the mixture was reacted at room temperature for 1 hour. LCMS showed that the conversion of the starting material was complete. The reaction solution was concentrated under reduced pressure, and the residue was dried under vacuum to obtain 024b.

[0616] Step 4:

[0617] Compound 024b (30 mg, 0.057 mmol), DIPEA (74 mg, 0.574 mmol), and 2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione (50 mg, 0.181 mmol) were dissolved in 2 mL of DMF and stirred at 90 ° C for 5 hours. LCMS detection showed that the reaction no longer proceeded. The reaction solution was diluted with saturated brine, and a large amount of solid precipitated. The solid was filtered and collected. The obtained solid was redissolved and purified by column chromatography to obtain C024. LCMS (ESI) m / z: [M+H + ]=784.6; 1 H NMR (500MHz, DMSO-d6) δ12.43(d,J=2.6Hz,1H),11.14(s,1H),8.39(d,J=6.4Hz,2H),8.12(d,J=2.5Hz,1H ),8.01(s,1H),7.82(s,2H),7.61(dd,J=8.6,7.1Hz,1H),7.17(d,J=8.6Hz,1H),7.04(d,J=7.0Hz,1H),6.9 3(t,J=5.8Hz,1H),5.06(dd,J=12.8,5.4Hz,1H),4.19(d,J=11.7Hz,1H),3.52–3.37(m,3H),3.20–3.05(m ,5H),2.98–2.85(m,4H),2.66–2.52(m,5H),2.42(s,6H),2.25(s,3H),2.15(m,7H),1.81(q,J=6.5Hz,2H).

[0618] Example 025: Preparation of Compound C025

[0619] Step 1:

[0620] 4-(N-tert-Butyloxycarbonylamino)-1-butanol (568 mg, 3 mmol) and triethylamine (909 mg, 9 mmol) were dissolved in dichloromethane (15 mL). TsCl (600 mg, 3.16 mmol) was added portionwise and allowed to react at room temperature overnight. LCMS confirmed complete conversion of the starting material. The reaction solution was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to afford 025a.

[0621] Step 2:

[0622] Compound 025a (44 mg, 0.128 mmol), warhead 1 (60 mg, 0.127 mmol), and DIPEA (50 mg, 0.388 mmol) were added to DMSO (2 mL) and reacted at 60°C overnight. LCMS confirmed complete conversion of the starting material. The reaction solution was cooled to room temperature, diluted with 5 mL of water, and extracted with DCM. The organic phases were combined. The organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 025b.

[0623] Step 3:

[0624] Compound 025b (60 mg, 0.0936 mmol) was dissolved in trifluoroacetic acid / DCM (5 mL / 5 mL) and reacted at room temperature for 1 hour. LCMS confirmed complete conversion of the starting material. The reaction solution was concentrated under reduced pressure, and the resulting residue was dried under vacuum to afford 025c.

[0625] Step 4:

[0626] Compound 025c (40 mg, 0.0739 mmol), DIPEA (48 mg, 0.372 mmol), and 2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione (62 mg, 0.225 mmol) were dissolved in DMF (3 mL) and stirred at 80°C for 5 hours. LCMS showed that the reaction was no longer proceeding. The reaction solution was diluted with saturated brine, and a large amount of solid precipitated. The solid was filtered and collected. The obtained solid was redissolved and purified by column chromatography to obtain C025. LCMS (ESI) m / z: [M+H + ]=798.6; 1 H NMR (500MHz, DMSO-d6) δ12.43(d,J=2.6Hz,1H),11.12(s,1H),8.39(s,1H),8.38(s,1H),8.12(d,J=2.4Hz, 1H),8.02(s,1H),7.83(s,2H),7.60(dd,J=8.6,7.1Hz,1H),7.16(d,J=8.6Hz,1H),7.04(d,J=7.0Hz,1H),6. 62(t,J=6.0Hz,1H),5.08–5.03(m,1H),4.21(tt,J=9.9,5.6Hz,1H),3.12–3.04(m,4H),3.00–2.84(m,4H),2 .65–2.34(m,5H),2.47–2.34(m,9H),2.30(s,3H),2.24–2.15(m,2H),2.13–1.98(m,6H),1.68–1.54(m,4H).

[0627] Example 026: Preparation of Compound C026

[0628] Step 1:

[0629] Compound 26a (9.3 g, 60 mmol), 26b (13 g, 180 mmol), and concentrated sulfuric acid (0.5 mL) were dissolved in acetic acid (40 mL), heated to 100°C, and stirred at this temperature for 5.5 hours. LCMS showed complete conversion and the product was detected. The reaction was used directly in the next step without further workup. LCMS (ESI) m / z: 228.1 [M+H] + .

[0630] Step 2:

[0631] Acetic acid (60 mL) and urea (18.0 g, 60 mmol) were added to the untreated reaction solution 26c from the previous step, the temperature was raised to 120°C and stirred at this temperature for 16 h. LCMS showed that some starting material was still present and the product was detected. After the reaction was completed, the reaction solution was cooled to room temperature and slowly poured into an ice-mixed solution of water (60 mL) and concentrated hydrochloric acid (30 mL) while stirring, and then placed in a 5°C refrigerator for overnight. The next day, the solution was taken out and filtered, and the filter cake was washed with water (100 mL) and dried. The filter cake was ground into a powder, added to 0.05 M dilute hydrochloric acid, filtered again, and the filter cake was washed with methyl tert-butyl ether (100 mL). Compound 26d was obtained by distillation under reduced pressure. LCMS (ESI) m / z: 253.2 [M+H] + .

[0632] Step 3:

[0633] Compound warhead1 (30 mg, 0.0529 mmol), 26d (16 mg, 0.0635 mmol), triethylamine (16 mg, 0.158 mmol) and HATU (30 mg, 0.0789 mmol) were dissolved in N,N-dimethylformamide (2 mL) at room temperature and stirred at room temperature for 16 h. LCMS showed that the reactants were completely converted and the product was detected. 30 mL of water was added to the reaction solution, extracted with dichloromethane (20 mL*2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to obtain a residue. The residue was purified by Pre-TLC (methanol: dichloromethane = 12:100, NH3) to obtain the final product C026. LCMS (ESI) m / z: 802.7 [M+H] + ; 1H NMR(500MHz,DMSO-d6)δ12.46(s,1H),10.56(s,1H),8.39(s,2H),8.14(d,J=2.3Hz,1H),8 .06(s,1H),7.84(s,2H),7.52(d,J=6.7Hz,1H),7.39(d,J=8.3Hz,2H),4.54–4.30(m,3H), 3.77(t,J=6.7Hz,2H),3.64(dd,J=20.3,6.1Hz,2H),3.31–3.19(m,2H),3.17–2.93(m,6H) ,2.90–2.66(m,5H),2.61–2.53(m,3H),2.41(s,6H),2.32–2.13(m,6H),1.98–1.53(m,6H).

[0634] Example 027: Preparation of Compound C027

[0635] Step 1:

[0636] Compound 27a (500 mg, 2.73 mmol) and lithium hydroxide monohydrate (256 mg, 6.1 mmol) were dissolved in tetrahydrofuran / water (8 mL / 2 mL) at room temperature and stirred for 16 hours. LCMS showed that most of the starting material had been converted and product was detected. The reaction solution was distilled under reduced pressure and 2M aqueous hydrochloric acid (3 mL) was added to adjust the pH to 4. The mixture was then cooled in an ice-water bath to precipitate a solid, which was filtered. The filter cake was washed with water (30 mL) and dried to obtain compound 27b. LCMS (ESI) m / z: 253.2 [M+H] + .

[0637] Step 2:

[0638] Compound 27b (314 mg, 1.86 mmol) and 27c (540 mg, 7.5 mmol) were dissolved in toluene (1 mL), heated to 100°C, and stirred at this temperature for 3.5 hours. LCMS showed complete conversion and product was detected. The reaction solution was distilled under reduced pressure to obtain crude compound 27d. LCMS (ESI) m / z: 242.5 [M+H] + .

[0639] Step 3:

[0640] Compound 27d (447 mg, 1.85 mmol) and urea (668 mg, 11.13 mmol) were dissolved in acetic acid (5 mL) at room temperature, heated to 120°C, and stirred at this temperature for 8 h. LCMS showed complete conversion of the starting material and the detection of product. After the reaction, the reaction mixture was cooled to room temperature and slowly poured into a mixture of water (30 mL) and concentrated hydrochloric acid (10 mL) on ice while stirring. The mixture was then placed in a refrigerator at 5°C overnight. The next day, the mixture was removed and filtered. The filter cake was washed with water (50 mL) and dried to yield compound 27e.

[0641] LCMS (ESI) m / z: 267.1 [M+H] + .

[0642] Step 4:

[0643] Compound 27f (30 mg, 0.0529 mmol), 27e (17 mg, 0.0635 mmol), triethylamine (16 mg, 0.158 mmol) and HATU (30 mg, 0.0789 mmol) were dissolved in N,N-dimethylformamide (2 mL) at room temperature and stirred at room temperature for 16 h. LCMS showed that the reactants were completely converted and the product was detected. 30 mL of water was added to the reaction solution, and the product was extracted with dichloromethane (20 mL*2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to obtain a residue. The residue was purified by Pre-TLC to obtain the final product C027. LCMS (ESI) m / z: 816.6 [M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ12.45(s,1H),10.42(s,1H),8.39(s,2H),8.13(d,J=2.3H z,1H),8.05(s,1H),7.83(s,2H),7.36(d,J=6.5Hz,1H),7.26(d,J=10.1Hz,1H),4. 54–4.47(m,1H),4.42–4.27(m,2H),3.87–3.71(m,2H),3.57–3.36(m,4H),3.32–2. 96(m,10H),2.86–2.67(m,4H),2.40(s,6H),2.32–2.10(m,9H),1.97–1.63(m,6H).

[0644] Example 028: Preparation of Compound C028

[0645] Step 1:

[0646] 3-Amino-4-chlorobenzoic acid (1.72 g, 10 mmol) and acrylic acid (792 mg, 11 mmol) were added to a flask and reacted at 100°C overnight. LCMS confirmed complete conversion of the starting material. The reaction solution was poured into 50 mL of a 20:1 PE:EA mixture, resulting in the precipitation of a large amount of solid. The solid was collected by filtration and dried under vacuum to yield 028a.

[0647] Step 2:

[0648] Compound 028a (1.69 g, 6.95 mmol) and urea (2.5 g, 41.7 mmol) were added to acetic acid (5 mL) and reacted at 120°C overnight. LCMS confirmed complete conversion of the starting material. The reaction solution was cooled to room temperature and diluted with 20 mL of ice water. A large amount of solid precipitated, which was filtered and the filter cake was washed with 3 mL of acetonitrile to collect the solid. The solid was then dried under vacuum to yield 028b.

[0649] Step 3:

[0650] Compound 028b (40 mg, 0.149 mmol) and compound 028c (110 mg, 0.194 mmol) were dissolved in DMF (3 mL), and HATU (85 mg, 0.224 mmol) and DIPEA (193 mg, 1.5 mmol) were added. The mixture was allowed to react at room temperature overnight. LCMS analysis showed that the starting material was completely converted. The reaction solution was diluted with saturated brine to precipitate a solid, which was collected by filtration. The resulting solid was redissolved and purified by silica gel column chromatography to obtain C028. LCMS (ESI) m / z: [M+H + ]=818.6. 1 H NMR(500MHz,DMSO-d6)δ12.43(s,1H),10.54(s,1H),8.38(d,J=7.8Hz,2H),8.12(s,1H),8.01(s, 1H),7.83(s,2H),7.65(d,J=8.2Hz,1H),7.57(s,1H),7.40(d,J=8.3Hz,1H),4.47(s,1H),4.25–4 .12(m,1H),3.82(d,J=7.4Hz,2H),3.64(s,1H),3.09(s,5H),2.91(d,J=7.3Hz,2H),2.72(t,J=6. 7Hz,3H),2.39(s,7H),2.23(s,5H),2.19–1.92(m,7H),1.78(d,J=76.0Hz,4H),1.21–0.98(m,3H).

[0651] Example 029: Preparation of Compound C029

[0652] Step 1:

[0653] 3-Aminobenzoic acid (2.16 g, 15.8 mmol) and acrylic acid (1.25 g, 17.4 mmol) were dissolved in xylene (20 mL) and reacted at 100°C overnight. LCMS confirmed complete conversion of the starting material. The reaction solution was poured into 50 mL of a 20:1 PE:EA mixture, resulting in the precipitation of a large amount of solid. The solid was collected by filtration and dried under vacuum to yield 029a.

[0654] Step 2:

[0655] Compound 029a (2.72 g, 13 mmol) and urea (1.09 g, 18.2 mmol) were added to acetic acid (8 mL) and reacted at 120°C overnight. LCMS confirmed complete conversion of the starting material. The reaction solution was cooled to room temperature and diluted with 20 mL of ice water. A large amount of solid precipitated, which was filtered and the filter cake was washed with 3 mL of acetonitrile to collect the solid. The solid was then dried under vacuum to yield 029b.

[0656] Step 3:

[0657] Compound 029b (46 mg, 0.196 mmol) and compound 029c (92 mg, 0.162 mmol) were dissolved in DMF (2 mL), and HATU (112 mg, 0.295 mmol) and DIPEA (210 mg, 1.63 mmol) were added. The mixture was allowed to react at room temperature overnight. LCMS analysis showed that the starting material was completely converted. The reaction solution was diluted with saturated brine to precipitate a solid, which was collected by filtration. The resulting solid was redissolved and purified by silica gel column chromatography to obtain C029. LCMS (ESI) m / z: [M+H + ]=784.7. 1H NMR (500MHz, DMSO-d6) δ12.42(d,J=2.6Hz,1H),10.44(s,1H),8.38(d,J=8.1Hz,2H),8.11(d,J=2.4Hz,1H), 8.01(s,1H),7.83(s,2H),7.46(t,J=7.8Hz,1H),7.43–7.38(m,1H),7.36(t,J=1.9Hz,1H),7.25–7.21(m,1H) ,4.48(s,1H),4.24–4.13(m,1H),3.83(d,J=7.4Hz,2H),3.65(s,1H),3.08(s,5H),2.92(d,J=7.3Hz,2H),2. 73(t,J=6.7Hz,3H),2.40(s,7H),2.25(s,5H),2.20–1.94(m,7H),1.79(d,J=76.0Hz,4H),1.20–0.99(m,3H).

[0658] Example 030: Preparation of Compound C030

[0659] Step 1:

[0660] Compound 030a (44 mg, 0.188 mmol) and warhead 1 (70 mg, 0.148 mmol) were dissolved in DMF (1 mL), and HATU (86 mg, 0.226 mmol) and DIPEA (58 mg, 0.45 mmol) were added. The reaction mixture was allowed to react at room temperature overnight. LCMS confirmed complete conversion of the starting material. The reaction solution was diluted with water, extracted with DCM, and the organic phases were combined. The organic phase was washed with water and saturated brine in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain CO30. LCMS (ESI) m / z: [M+H + ]=687.5; 1 H NMR(500MHz,DMSO-d6)δ12.43(d,J=2.7Hz,1H),10.46(s,1H),8.39(d,J=13.6Hz, 2H),8.12(d,J=2.4Hz,1H),8.02(s,1H),7.85(s,2H),7.50(d,J=8.5Hz,2H),7.43( d,J=8.4Hz,2H),4.19(s,1H),3.85(s,2H),3.78(s,2H),3.51(s,2H),3.12(s,4H) ,2.92(s,2H),2.73(t,J=6.6Hz,2H),2.43(s,6H),2.26(s,3H),2.16–1.98(m,6H).

[0661] Example 031: Preparation of Compound C031

[0662] Step 1:

[0663] 031a (75 mg, 0.274 mmol), 031b (137 mg, 0.926 mmol), and sodium bicarbonate (84 mg, 1 mmol) were dissolved in DMF (2 mL), and the mixture was stirred at 70°C for 2 hours. LCMS showed complete conversion of the reactants and the product was detected. After the reaction solution was cooled to room temperature, water (30 mL) was added for quenching, and the mixture was extracted with dichloromethane and ethyl acetate (20 mL*2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain a residue. Purification by column chromatography gave compound 031c.

[0664] Step 2:

[0665] Compound 031c (40 mg, 0.117 mmol) and warhead 1 (55 mg, 0.117 mmol) were dissolved in DCE / DMSO (2 mL / 2 mL), acetic acid (0.05 mL) was added, and the mixture was allowed to react at room temperature for 16 hours. Sodium acetate borohydride (212 mg, 1 mmol) was then added, and the reaction solution was diluted with saturated brine. Solids precipitated and were filtered to collect the crude product. The crude product was purified by silica gel column chromatography to obtain C031. LCMS (ESI) m / z: 797.6 [M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ12.42(d,J=2.6Hz,1H),11.11(s,1H),8.38(d,J=5.5Hz,2H),8.12(d,J=2 .3Hz,1H),8.02(s,1H),7.82(s,2H),7.77(d,J=8.1Hz,1H),7.23–7.14(m,2H),5.10(dd,J=12.9,5 .4Hz,1H),4.25(dt,J=17.7,8.9Hz,2H),3.07(s,4H),3.02–2.84(m,3H),2.73(dt,J=17.4,3.3Hz ,1H),2.55(d,J=18.2Hz,2H),2.45(d,J=7.8Hz,2H),2.39(s,9H),2.35(m,7H),2.15–1.93(m,6H).

[0666] Example 032: Preparation of Compound C032

[0667] Step 1:

[0668] Compound 32a (42 mg, 0.089 mmol), 32b (31 mg, 0.116 mmol), diisopropylethylamine (35 mg, 0.271 mmol) and HATU (51 mg, 0.134 mmol) were dissolved in N,N-dimethylformamide (3 mL) at room temperature and stirred at room temperature for 2 h. LCMS showed that the reactants were completely converted and the product was detected. 30 mL of water was added to the reaction solution, and the product was extracted with dichloromethane (20 mL*2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to obtain a residue. The residue was purified by Pre-TLC to obtain the final product C032. LCMS (ESI) m / z: 717.6 [M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ12.43(d,J=2.6Hz,1H),10.36(s,1H),8.38(d,J=12.4Hz,2H),8.11(d,J= 2.4Hz,1H),8.01(s,1H),7.85(s,2H),7.48(dd,J=8.6,2.1Hz,1H),7.43(d,J=2.1Hz,1H),7.20(d ,J=8.5Hz,1H),4.16(dt,J=9.9,4.9Hz,1H),3.86(s,3H),3.62(t,J=6.6Hz,6H),3.10(s,4H),2.9 0(d,J=6.3Hz,2H),2.70(t,J=5.9Hz,2H),2.43(s,6H),2.23(s,3H),2.06(dd,J=18.1,8.9Hz,6H).

[0669] Example 033: Preparation of Compound C033

[0670] Step 1:

[0671] Compound 33a (64 mg, 0.119 mmol) and 33b (28 mg, 0.142 mmol) were dissolved in dimethyl sulfoxide / dichloromethane (2 mL / 2 mL), and the mixture was stirred at 60 ° C for 1 hour. Then sodium triacetyl borohydride (126 mg, 0.593 mmol) was added to the mixture and stirred at 60 ° C for another 30 min. LCMS showed that the reactants were completely converted and the product was detected. After the reaction solution was cooled to room temperature, saturated sodium bicarbonate solution (30 mL) was added for quenching and extracted with dichloromethane (20 mL*2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain a residue. The residue was purified by silica gel chromatography to obtain compound 33c. LCMS (ESI) m / z: 723.7 [M+H] + .

[0672] Step 2:

[0673] Compound 33c (69 mg, 0.0956 mmol) was dissolved in trifluoroacetic acid / dichloromethane (0.5 mL / 5 mL) and stirred at room temperature for 3 h. LCMS showed complete conversion and product was detected. 30 mL of toluene was added to the reaction solution, which was then concentrated under vacuum to afford crude compound 33d. LCMS (ESI) m / z: 623.6 [M+H] + .

[0674] Step 3:

[0675] Compound 33d (59 mg, 0.0956 mmol), diisopropylethylamine (37 mg, 0.28 mmol) and compound 33e (33 mg, 0.12 mmol) were dissolved in DMF (2 mL), and the mixture was stirred at room temperature for 16 hours. LCMS showed that the reactants were completely converted and the product was detected. After the reaction solution was cooled to room temperature, saturated sodium bicarbonate solution (30 mL) was added for quenching and extracted with dichloromethane (20 mL*2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain a residue. The residue was purified by Pre-TLC to obtain the final product C033. LCMS (ESI) m / z: 869.8 [M+H] + ; 1 H NMR(500MHz,DMSO-d6)δ12.45(s,1H),10.36(s,1H),8.42–8.33(m,2H),8.13(d,J=1.9Hz,1H ),8.03(s,1H),7.83(s,2H),7.42–7.36(m,1H),7.35–7.30(m,1H),7.17(d,J=8.6Hz,1H),4.4 3–4.02(m,4H),3.88–3.79(m,3H),3.60(t,J=6.5Hz,2H),3.38(s,4H),3.24–2.92(m,9H),2. 86–2.60(m,6H),2.59–2.52(m,3H),2.46–2.30(m,9H),2.26–2.03(m,5H),1.97–1.52(m,5H).

[0676] Example 035: Preparation of Compound C035

[0677] Step 1:

[0678] 4-Hydroxycyclohexanone glycol acetal (32 mg, 0.2 mmol) and PPh3 (53 mg, 0.2 mmol) were dissolved in dry THF (5 mL), cooled to 0°C, and DEAD (32 mg, 0.2 mmol) was slowly added dropwise. After the addition was complete, the mixture was maintained at 0°C and stirred for 20 min. 35a (40 mg, 0.1 mmol) was added, and the mixture was slowly warmed to room temperature and stirred for 12 h. LCMS analysis indicated that the reaction was no longer proceeding. The reaction solution was then distilled under reduced pressure, and the resulting residue was purified by column chromatography to yield compound 35b. LCMS (ESI) m / z: 567.4 [M+Na] + .

[0679] Step 2:

[0680] Compound 35b (49 mg, 0.09 mmol) was dissolved in THF (3 mL), and 3M HCl (1 mL) was added. The mixture was allowed to react at room temperature for 2 days. LCMS analysis indicated that the reaction was no longer progressing. The solvent was removed by concentration under reduced pressure, and the mixture was dried under vacuum to obtain compound 35c. LCMS (ESI) m / z: 371.2 [M+H] + .

[0681] Step 3:

[0682] 35d (48 mg, 0.10 mmol) and 35c (31 mg, 0.08 mmol) were dissolved in DMSO (1 mL) and DCE (1 mL), and acetic acid was added.

[0683] (0.05 mL), stirred at room temperature for 1 hour, sodium acetate borohydride (85 mg, 0.40 mmol) was added, and stirred at room temperature for 2 hours. LCMS detection showed that the reaction was no longer proceeding, and the product was quenched with saturated sodium bicarbonate solution and extracted with DCM. The organic phases were combined, washed, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by large-scale plate preparation to obtain compound C035. LCMS (ESI) m / z: 825.6 [M+H] + .

[0684] Example 036: Preparation of Compound C036

[0685] Step 1:

[0686] 36a (50 mg, 0.11 mmol) and 36b (40 mg, 0.21 mmol) were dissolved in DMSO / DCM (2 mL / 2 mL) at room temperature. 0.1 mL of acetic acid was added and the mixture was stirred at room temperature for 1 hour. Sodium acetate borohydride (113 mg, 0.53 mmol) was added and the mixture was stirred at room temperature overnight. LCMS showed that most of the starting material had been converted and the product was detected. 30 mL of water was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to obtain a residue. Compound 36c was purified by column chromatography.

[0687] Step 2:

[0688] 36c (48.5 mg, 75.8 umol) was dissolved in DCM (3 mL), and TFA (1 mL) was added with stirring. The mixture was stirred at room temperature for 1 hour. LCMS showed complete conversion of the reactant and the product was detected. The reaction solution was evaporated under reduced pressure to give crude compound 36d.

[0689] Step 3:

[0690] 36d (40.1 mg, 74.3 μmol) and 36e (41 mg, 148.6 μmol) were dissolved in DMSO (2 mL) at room temperature, DIEA (19 mg, 148.6 μmol) was added, the temperature was raised to 100°C, and stirred at this temperature for 12 h. LCMS showed complete conversion of the starting materials and the product was detected. After the reaction was completed, the reaction solution was cooled to room temperature, 30 mL of water was added to the reaction solution, and the solution was extracted with dichloromethane (20 mL*2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to obtain a residue. The residue was purified by Pre-TLC to obtain the final product C036. LCMS (ESI) m / z: [M+H] + =796.5.

[0691] Example 037: Preparation of Compound C037

[0692] Step 1

[0693] 37a (100 mg, 0.213 mmol), 37b (59 mg, 0.319 mmol) and acetic acid (13 mg, 0.213 mmol) were dissolved in dichloromethane / methanol (4 mL / 2 mL), and the mixture was stirred at 50 ° C for 2 hours. Then, sodium triacetyl borohydride (225 mg, 1.06 mmol) was added to the mixture and the reaction was stirred at 50 ° C for 0.5 hours. LCMS showed that the reactants were completely converted and the product was detected. After the reaction solution was cooled to room temperature, saturated ammonium chloride solution (50 mL) was added for quenching and extracted with dichloromethane (30 mL*2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain a residue. The residue was purified by silica gel chromatography to obtain compound 37c. LCMS (ESI) m / z: [M+H] + =640.5.

[0694] Step 2:

[0695] 37c (70 mg, 0.091 mmol) was dissolved in dichloromethane / methanol (1 mL / 5 mL) and stirred at room temperature for 16 hours. LCMS showed complete conversion and product was detected. The reaction solution was distilled under reduced pressure to give compound 37d. LCMS (ESI) m / z: [M+H] + =540.4.

[0696] Step 3:

[0697] 37d (50 mg, 0.0928 mmol), 37e (28 mg, 0.139 mmol) and acetic acid (6 mg, 0.0928 mmol) were dissolved in dichloromethane / dimethyl sulfoxide (4 mL / 4 mL), and the mixture was stirred at 50 ° C for 2 hours. Sodium triacetyl borohydride (98 mg, 0.464 mmol) was then added to the mixture and the reaction was stirred at 50 ° C for 0.5 hours. LCMS showed that the reactants were completely converted and the product was detected. After the reaction solution was cooled to room temperature, saturated ammonium chloride solution (50 mL) was added for quenching and extracted with dichloromethane (30 mL*2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain a residue. The residue was purified by silica gel chromatography to obtain compound 37f. LCMS (ESI) m / z: [M+H] + =723.6.

[0698] Step 4:

[0699] 37f (31 mg, 0.0429 mmol) was dissolved in dichloromethane / methanol (1 mL / 5 mL) and stirred at room temperature for 16 hours. LCMS showed complete conversion and product was detected. The reaction solution was distilled under reduced pressure to give compound 37g. LCMS (ESI) m / z: [M+H]+ =623.5.

[0700] Step 5:

[0701] 37g (26.7mg, 0.040mmol), 37h (14mg, 0.052mmol), HATU (22.8mg, 0.06mmol) and N,N-diisopropylethylamine (21mg, 0.16mmol) were dissolved in dimethyl sulfoxide (2mL), and the mixture was stirred at room temperature overnight. LCMS showed that the reactants were completely converted and the product was detected. After the reaction solution was cooled to room temperature, water (50mL) was added for quenching and extracted with dichloromethane (30mL*2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain a residue. Purification by Pre-TLC gave compound C037. LCMS (ESI) m / z: [M+H] + =869.6.

[0702] Example 038: Preparation of Compound C038

[0703] Step 1

[0704] 38a (100 mg, 0.21 mmol) and 38b (136 mg, 0.64 mmol) were dissolved in DMSO / DCE (5 mL / 5 mL) at room temperature. 0.2 mL of acetic acid was added and the mixture was stirred at room temperature for 1 hour. Sodium acetate borohydride (225 mg, 1.06 mmol) was added and the mixture was stirred at room temperature overnight. LCMS showed that most of the starting material had been converted and the product was detected. 30 mL of water was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to obtain a residue. Compound 38c was purified by column chromatography.

[0705] Step 2:

[0706] Compound 38c (54.5 mg, 81.6 umol) was dissolved in DCM (3 mL), and TFA (1 mL) was added with stirring. The mixture was stirred at room temperature for 1 hour. LCMS showed complete conversion of the reactant and the product was detected. The reaction solution was evaporated under reduced pressure to give crude compound 38d.

[0707] Step 3:

[0708] 38e (1.5 g, 9.67 mmol) and acrylic acid (767 mg, 10.64 mmol) were dissolved in xylene (5 mL) at room temperature, heated to 100°C, and stirred at this temperature for 12 h. LCMS showed complete conversion of the starting material and the product was detected. After the reaction, the reaction mixture was cooled to room temperature and poured into a solution of (petroleum ether:ethyl acetate = 20:1). The mixture was stirred at room temperature for 2 h, and the solid was collected by filtration and dried to yield 38f.

[0709] Step 4:

[0710] 38f (1 g, 3.34 mmol) and urea (501 mg, 8.35 mmol) were dissolved in acetic acid (5 mL) at room temperature, heated to 120°C, and stirred at this temperature for 8 h. LCMS showed complete conversion of the starting material and the product was detected. After the reaction, the reaction mixture was cooled to room temperature and slowly poured into a mixture of water (30 mL) and concentrated hydrochloric acid (10 mL) on ice while stirring. The mixture was then placed in a refrigerator at 5°C for 7 days. The filter cake was removed and filtered, washed with water (50 mL), and dried to yield compound 38g.

[0711] Step 5:

[0712] 38d (46.3 mg, 81.7 μmol), 38g (41 mg, 163.1 μmol), DIEA (31.6 mg, 244.6 μmol) and HATU (93 mg, 244.6 μmol) were dissolved in DMSO (2 mL) at room temperature and stirred at room temperature for 12 h. LCMS showed complete conversion of the reactants and the product was detected. 30 mL of water was added to the reaction solution, and the product was extracted with dichloromethane (20 mL*2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to obtain a residue. The residue was purified by Pre-TLC to obtain the final product C038. LCMS (ESI) m / z: [M+H] + =802.5.

[0713] Example 039: Preparation of Compound C039

[0714] Step 1:

[0715] 39a (180 mg, 0.38 mmol) and 3-(Boc-amino)-1-cyclobutanone (141 mg, 0.76 mmol) were dissolved in DMSO (2 mL) and DCE (2 mL). Acetic acid (0.1 mL) was added and the mixture was stirred at room temperature for 1 hour. Sodium acetate borohydride (403 mg, 1.90 mmol) was added and the mixture was stirred at room temperature for 2 hours. LCMS analysis indicated that the reaction was no longer progressing. The mixture was quenched with saturated sodium bicarbonate solution and extracted with DCM. The organic phases were combined, washed, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography to obtain compound 39b. LCMS (ESI) m / z: 640.4 [M+H] + .

[0716] Step 2

[0717] Compound 39b (94 mg, 0.15 mmol) was dissolved in DCM (5 mL) and TFA (5 mL) was added. The mixture was allowed to react at room temperature for 1 hour. LCMS analysis indicated that the reaction was no longer progressing. The solvent was removed by concentration under reduced pressure and the mixture was dried under vacuum to obtain compound 39c. LCMS (ESI) m / z: 540.3 [M+H] + .

[0718] Step 3:

[0719] Compound 39c (21 mg, 0.09 mmol) was added to DCM (3 mL), and one drop of DMF was added dropwise. The reaction system was cooled to 0°C, and oxalyl chloride (35 mg, 0.27 mmol) was slowly added dropwise. Stirring was continued at 0°C for 30 min. The solvent was removed by distillation under reduced pressure, and the resulting residue was dissolved in dry DCM and set aside.

[0720] Compound 39d (26 mg, 0.05 mmol) and DIPEA (33 mg, 0.25 mmol) were dissolved in DMF (2 mL). The DCM solution obtained in the previous step was added dropwise at 0°C and stirred at room temperature for 5 min. LCMS analysis indicated that the reaction was no longer progressing, and the product was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to yield compound C039. LCMS (ESI) m / z: 756.6 [M+H] + ; 1H NMR(500MHz,DMSO-d6)δ12.43(s,1H),10.46(s,1H),8.69(s,1H),8.39(d,J=5.2Hz,2H),8.13 (d,J=2.6Hz,1H),8.05(s,1H),7.92–7.86(m,2H),7.84(s,2H),7.43(d,J=8.5Hz,2H),4.39(s ,2H),3.85(t,J=6.6Hz,2H),3.31–3.26(m,2H),3.20–3.05(m,5H),2.73(t,J=6.6Hz,2H),2.4 9–2.38(s,10H),2.37–2.34(m,1H),2.32–2.25(m,2H),2.23–2.05(m,6H),1.28–1.20(m,4H).

[0721] Example 040: Preparation of Compound C040

[0722] Step 1:

[0723] Compound 40a (58 mg, 0.1 mmol), DIPEA (52 mg, 0.4 mmol), and 40b (39 mg, 0.2 mmol) were dissolved in DMF (1 mL) and reacted at 60°C for 16 h. LCMS analysis confirmed complete conversion of the starting material. The reaction solution was diluted with water, extracted with DCM, and the organic phases were combined. The organic phases were washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain compound C040. LCMS (ESI) m / z: 582.4 [M+H] + ; 1 H NMR(500MHz,DMSO-d6)δ12.41(d,J=2.6Hz,1H),10.65(s,1H),8.38(d,J=7.9Hz,2H), 8.11(d,J=2.5Hz,1H),8.01(s,1H),7.83(s,2H),4.24(m,1H),3.46(dd,J=10.6,4.3Hz ,1H),3.12–3.02(m,4H),2.93(br,2H),2.82(dd,J=10.6,4.6Hz,2H),2.78–2.72(m,2H ),2.60–2.53(m,2H),2.42(s,6H),2.26(s,3H),2.14–2.02(m,6H),2.00–1.89(m,2H).

[0724] Example 041: Preparation of Compound C041

[0725] Step 1:

[0726] 41a (26.7 mg, 0.0429 mmol), 41b (13 mg, 0.0558 mmol), HATU (25 mg, 0.0644 mmol), and N,N-diisopropylethylamine (22 mg, 0.172 mmol) were dissolved in dimethyl sulfoxide (3 mL), and the mixture was stirred at room temperature for 16 hours. LCMS showed complete conversion and product was detected. The reaction mixture was cooled to room temperature and quenched with water (50 mL), followed by extraction with dichloromethane (30 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain a residue. Purification by Pre-TLC afforded compound C041. LCMS (ESI) m / z: [M+H]+ = 640.6.

[0727] Example 042: Preparation of Compound C042

[0728] Step 1: Dissolve 42a (30 mg, 63.75 μmol) and 42b (40 mg, 95.62 μmol) in DMSO (2 mL) at room temperature, add DIEA (16.5 mg, 127.49 μmol), and heat to 80°C with stirring for 3 h. LCMS showed that most of the starting material had been converted and the product was detected. 30 mL of water was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL*3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to obtain a residue. Purification by column chromatography gave the final compound C042. LCMS (ESI) m / z: [M+H] + =727.4. 1 H NMR (500MHz, DMSO-d6) δ12.42(s,1H),11.08(s,1H),8.39(d,J=17.4Hz,2H),8.11(d,J=2 .4Hz,1H),8.02(s,1H),7.87(s,2H),7.72(d,J=8.4Hz,1H),7.42(d,J=2.2Hz,1H),7.34(d d,J=8.7,2.4Hz,1H),5.09(dd,J=12.9,5.4Hz,1H),4.23(s,2H),3.62(d,J=5.2Hz,4H),3 .24(t,J=4.7Hz,4H),2.99(s,2H),2.44(s,6H),2.38–2.28(m,3H),2.08(d,J=8.7Hz,5H).

[0729] Example 043: Preparation of Compound C043

[0730] Step 1

[0731] Compounds 43a (30 mg, 63.75 μmol) and 43b (40 mg, 95.62 μmol) were dissolved in DMSO (2 mL) at room temperature, and DIEA (16.5 mg, 127.49 μmol) was added. The mixture was heated to 80°C and stirred for 3 h. LCMS indicated that most of the starting material had been converted and the product was detected. 30 mL of water was added to the reaction mixture, and the mixture was extracted with dichloromethane (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to obtain a residue. Compound C043 was purified by column chromatography. LCMS (ESI) m / z: [M+H] + =727.5. 1 H NMR (500MHz, DMSO-d6) δ12.41(s,1H),11.09(s,1H),8.39(d,J=17.6Hz,2H),8.11(d,J=2 .1Hz,1H),8.01(s,1H),7.87(s,2H),7.75(t,J=7.8Hz,1H),7.42(dd,J=21.1,7.9Hz,2H), 5.13(dd,J=13.0,5.5Hz,1H),4.19(s,1H),3.62(d,J=32.3Hz,1H),3.44(d,J=5.3Hz,4H) ,2.90(d,J=17.8Hz,3H),2.65–2.52(m,2H),2.47(s,6H),2.26(s,4H),2.09–1.98(m,6H).

[0732] Example 044: Preparation of Compound C044

[0733] Step 1:

[0734] Compounds 44a (100 mg, 0.21 mmol) and 44b (136 mg, 0.64 mmol) were dissolved in DMSO (5 mL) at room temperature. DIEA (82 mg, 0.64 mmol) was added, and the mixture was heated to 80°C and stirred at this temperature for 3 h. LCMS showed that most of the starting material had been converted, and product was detected. 30 mL of water was added to the reaction mixture, and the mixture was extracted with dichloromethane (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to yield a residue. Purification by column chromatography afforded compound 44c.

[0735] Step 2:

[0736] 44c (32.2 mg, 57.8 μmol) was dissolved in MeOH and water (3 mL / 1 mL), and lithium hydroxide (4.2 mg, 173.5 μmol) was added. The mixture was stirred at room temperature for 12 hours. LCMS showed complete conversion and product was detected. The reaction solution was distilled under reduced pressure to yield crude compound 44d.

[0737] Step 3:

[0738] 44d (30 mg, 55.3 μmol), VHL (23.8 mg, 55.3 μmol), and DIEA (14.3 mg, 110.6 μmol) were dissolved in DMSO (2 mL) at room temperature, one drop of T3P solution was added, and the mixture was stirred at room temperature for 3 h. LCMS showed complete conversion of the reactants and the product was detected. 30 mL of water was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL*2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to obtain a residue. The residue was purified by Pre-TLC to obtain the final product, C044. LCMS (ESI) m / z: [M+H] + =955.7.

[0739] Example 045: Preparation of Compound C045

[0740] Step 1:

[0741] 45a (500 mg, 0.34 mmol) was dissolved in DCM (10 mL) at room temperature. Dess-Martin periodinane (1.45 g, 0.34 mmol) was added under ice and stirred at room temperature for 12 h. TLC indicated that most of the starting material had been converted and product was detected. 30 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to yield a residue. Compound 45b was purified by column chromatography.

[0742] Step 2:

[0743] 45b (30.6 mg, 0.21 mmol) and 45c (50 mg, 0.11 mmol) were dissolved in DMSO / DCM (2 mL / 2 mL) at room temperature. 0.1 mL of acetic acid was added and the mixture was stirred at room temperature for 1 hour. Sodium acetate borohydride (112 mg, 0.53 mmol) was added and the mixture was stirred at room temperature overnight. LCMS showed that most of the starting material had been converted and the product was detected. 30 mL of water was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL*3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to obtain a residue. Compound 45d was purified by column chromatography.

[0744] Step 3:

[0745] 45d (38.5 mg, 64.3 μmol) was dissolved in MeOH and water (3 mL / 1 mL), and lithium hydroxide (4.6 mg, 193.9 μmol) was added. The mixture was stirred at room temperature for 12 hours. LCMS showed complete conversion and product was detected. The reaction solution was distilled under reduced pressure to afford crude compound 45e.

[0746] Step 4:

[0747] 45e (35 mg, 59.9 μmol), VHL (25.8 mg, 59.9 μmol), and DIEA (15.5 mg, 119.7 μmol) were dissolved in DMSO (2 mL) at room temperature, and five drops of T3P solution were added. The mixture was stirred at room temperature for 3 h. LCMS showed complete conversion of the reactants and the product was detected. 30 mL of water was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL*2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to obtain a residue. The residue was purified by Pre-TLC to obtain the final product, C045. LCMS (ESI) m / z: [M+H] + =997.7.

[0748] 1 H NMR (500MHz, DMSO-d6) δ12.40(d,J=2.6Hz,1H),8.98(s,1H),8.56(t,J=6.1Hz,1H),8.37(d,J=9.4Hz,2H),8.10(d,J=2.1Hz,1H),8.00(d,J=0. 7Hz,1H),7.87(d,J=9.4Hz,1H),7.82(s,2H),7.45–7.32(m,4H),5.13(d,J=3.6Hz,1H),4.56(d,J=9.3Hz,1H),4.49–4.40(m,2H),4.36(s,1H), 4.28–4.12(m,2H),3.78–3.59(m,2H),3.08(s,4H),2.91(d,J=8.4Hz,2H),2.42(d,J=21.6Hz,9H),2.39–2.32(m,1H),2.29(dd,J=14.5,7.4Hz, 1H),2.24(s,3H),2.09–2.01(m,4H),1.91(ddd,J=12.8,8.6,4.6Hz,1H ),1.60–1.42(m,3H),1.35(s,1H),1.23(d,J=3.1Hz,4H),0.95(s,10H).

[0749] Example 046: Preparation of Compound C046

[0750] Step 1:

[0751] 46a (60 mg, 0.13 mmol) and 1-Boc-azetidine-3-carboxaldehyde (119 mg, 0.64 mmol) were dissolved in DMSO (2 mL) and DCE (1 mL). Acetic acid (0.1 mL) was added and the mixture was stirred at room temperature for 1 hour. Sodium acetate borohydride (271 mg, 1.28 mmol) was added and the mixture was stirred at room temperature for 2 hours. LCMS showed that the reaction was no longer progressing. The mixture was quenched with saturated sodium bicarbonate solution and extracted with DCM. The organic phases were combined, washed, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography to obtain compound 46b. LCMS (ESI) m / z: 640.4 [M+H] + .

[0752] Step 2:

[0753] Compound 46b (65.0 mg, 0.1 mmol) was dissolved in DCM (5 mL) and TFA (5 mL) was added. The mixture was allowed to react at room temperature for 1 hour. LCMS analysis indicated that the reaction was no longer progressing. The solvent was removed by concentration under reduced pressure and the mixture was dried under vacuum to obtain compound 46c. LCMS (ESI) m / z: 540.3 [M+H] + .

[0754] Step 3:

[0755] Compound 46c (52 mg, 0.1 mmol), HATU (57 mg, 0.15 mmol), DIPEA (66 mg, 0.5 mmol), and 46d (31 mg, 0.13 mmol) were dissolved in DMSO (2 mL) and stirred at room temperature for 1 hour. LCMS analysis indicated that the reaction was no longer progressing. The reaction solution was diluted with saturated brine, and a large amount of solid precipitated. The solid was filtered and collected. The resulting solid was redissolved and purified by column chromatography to obtain compound C046. LCMS (ESI) m / z: 755.5 [M+H] + . 1H NMR(500MHz,DMSO-d6)δ12.40(s,1H),10.43(s,1H),8.38(s,1H),8.36(s,1H),8.10(d,J=2.4Hz,1H),8.00 (s,1H),7.82(s,2H),7.61(d,J=1.3Hz,1H),7.51–7.45(m,3H),4.42(t,J=8.3Hz,1H),4.17(dq,J=13.7,8.8 ,6.8Hz,2H),4.04–3.94(m,1H),3.84(t,J=6.7Hz,2H),3.78–3.69(m,1H),3.07(s,4H),3.00–2.79(m,4H),2 .73(t,J=6.7Hz,2H),2.65(d,J=7.2Hz,2H),2.53–2.51(m,2H)2.40(s,6H),2.24(s,3H),2.17–1.90(m,7H).

[0756] Example 047: Preparation of Compound C047

[0757] Step 1:

[0758] Compound 47a (21 mg, 0.09 mmol) was added to DCM (3 mL), and one drop of DMF was added dropwise. The reaction system was cooled to 0°C, and oxalyl chloride (35 mg, 0.27 mmol) was slowly added dropwise. Stirring was continued at 0°C for 30 min. The solvent was removed by distillation under reduced pressure, and the resulting residue was dissolved in dry DCM to obtain a DCM solution of compound 47b for later use.

[0759] Step 2:

[0760] Compound 47c (26 mg, 0.05 mmol) and DIPEA (33 mg, 0.25 mmol) were dissolved in DCM (2 mL). The DCM solution of 47b was added dropwise at 0°C and stirred at room temperature for 5 min. LCMS analysis indicated no further reaction, and the product was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to afford compound C047. LCMS (ESI) m / z: 756.6 [M+H] + .

[0761] Example 048: Preparation of Compound C048

[0762] Step 1:

[0763] Dissolve 48a (1 g, 5.83 mmol) in acrylic acid (840 mg, 11.66 mmol) and heat to 100°C, stirring at this temperature for 12 h. LCMS indicated complete conversion of the starting material and the presence of product. After the reaction was complete, the reaction mixture was cooled to room temperature and carried on to the next step without further treatment.

[0764] Step 2:

[0765] Compound 48b and urea (1.45 g, 17.48 mmol) were dissolved in acetic acid (5 mL) at room temperature, heated to 120°C, and stirred at this temperature for 12 h. LCMS indicated complete conversion of the starting material and the presence of product. After the reaction, the reaction mixture was cooled to room temperature and slowly poured into a mixture of water (30 mL) and concentrated hydrochloric acid (10 mL) on ice while stirring. The mixture was then refrigerated at 5°C overnight. Filter the mixture, wash the filter cake with water (50 mL), and dry to obtain compound 48c.

[0766] Step 3:

[0767] 48c (42.1 mg, 159.4 μmol), 48d (50 mg, 106.2 μmol), DIEA (27.5 mg, 212.5 μmol) and HATU (80.8 mg, 212.5 μmol) were dissolved in DMSO (2 mL) at room temperature and stirred at room temperature for 3 h. LCMS showed complete conversion of the reactants and the product was detected. 30 mL of water was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL*2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to obtain a residue. The residue was purified by Pre-TLC to obtain the final product C048. LCMS (ESI) m / z: [M+H] + =721.4.

[0768] Example 049: Preparation of Compound C049

[0769] Step 1:

[0770] 49a (18 mg, 0.03 mmol), 49b (11 mg, 0.039 mmol) and N,N-diisopropylethylamine (16 mg, 0.121 mmol) were dissolved in dimethyl sulfoxide (1 mL), and the mixture was stirred at 80°C for 4 hours. LCMS showed that the reactants were completely converted and the product was detected. After the reaction solution was cooled to room temperature, water (50 mL) was added for quenching and extracted with dichloromethane (30 mL*2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain a residue. Purification by Pre-HPLC gave compound C049. LCMS (ESI) m / z: [M+H] + =640.6.

[0771] Example 050: Preparation of Compound C050

[0772] Step 1:

[0773] Compound 50a (24 mg, 0.09 mmol) was added to DCM (3 mL), and one drop of DMF was added dropwise. The reaction system was cooled to 0°C, and oxalyl chloride (35 mg, 0.27 mmol) was slowly added dropwise. Stirring was continued at 0°C for 30 min. The solvent was removed by distillation under reduced pressure, and the resulting residue was dissolved in dry DCM to obtain a DCM solution of compound 50b for later use.

[0774] Step 2:

[0775] Compound 50c (26 mg, 0.05 mmol) and DIPEA (33 mg, 0.25 mmol) were dissolved in DCM (2 mL). The DCM solution of 50b was added dropwise at 0°C and stirred at room temperature for 5 min. LCMS analysis indicated no further reaction, and the product was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to yield compound C050. LCMS (ESI) m / z: 790.6 [M+H] + ; 1 H NMR(500MHz,DMSO-d6)δ12.47(s,1H),10.55(s,1H),8.75(s,1H),8.39(s,2H),8.14( d,J=2.5Hz,1H),8.09(s,1H),7.99(d,J=2.1Hz,1H),7.91–7.80(m,3H),7.74–7.66(m, 1H),4.49(s,1H),4.21(s,1H),3.77(dt,J=13.6,7.1Hz,1H),3.69–3.36(m,5H),3.21 –3.03(m,5H),2.90–2.68(m,6H),2.47–2.33(m,9H),2.32–2.12(m,5H),1.97(br,3H).

[0776] Example 051: Preparation of Compound C051

[0777] Step 1:

[0778] 51a (500 mg, 2.99 mmol) was dissolved in acrylic acid (431 mg, 5.98 mmol) and stirred at 100°C for 12 h. LCMS indicated complete conversion of the starting material and the presence of product. After the reaction was complete, the reaction mixture was cooled to room temperature and carried on to the next step without further treatment.

[0779] Step 2:

[0780] 51b and urea (1.06 g, 17.95 mmol) were dissolved in acetic acid (5 mL) at room temperature, heated to 120°C, and stirred at this temperature for 12 h. LCMS showed complete conversion of the starting material and the presence of product. After the reaction, the reaction mixture was cooled to room temperature and slowly poured into a mixture of water (30 mL) and concentrated hydrochloric acid (10 mL) on ice while stirring. The mixture was then refrigerated at 5°C overnight. Filter, wash the filter cake with water (50 mL), and dry to obtain compound 51c.

[0781] Step 3:

[0782] 51c (20.2 mg, 76.5 μmol), 51d (30 mg, 63.75 μmol), DIEA (16.5 mg, 127.5 μmol) and HATU (36.4 mg, 95.62 μmol) were dissolved in DMSO (2 mL) at room temperature and stirred at room temperature for 3 h. LCMS showed complete conversion of the reactants and the product was detected. 30 mL of water was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL*2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to obtain a residue. The residue was purified by Pre-TLC to obtain the final product C051. LCMS (ESI) m / z: [M+H] + =717.4. 1 H NMR(500MHz,DMSO-d6)δ12.41(d,J=2.6Hz,1H),10.42(s,1H),8.38(d,J=13.7 Hz,2H),8.11(d,J=2.3Hz,1H),8.01(s,1H),7.85(s,2H),7.02(d,J=1.9Hz,2H ),6.89(t,J=1.8Hz,1H),3.84(d,J=6.6Hz,2H),3.10(d,J=46.2Hz,5H),2.96( s, 2H), 2.72 (t, J = 6.6Hz, 2H), 2.43 (s, 5H), 2.30 (s, 3H), 2.06 (d, J = 8.3Hz, 4H).

[0783] The chimeric compound and its application provided by the present invention are introduced in detail above.

[0784] Specific examples are used herein to illustrate the principles and implementation methods of the present invention. The above examples are merely intended to facilitate understanding of the methods and central concepts of the present invention. It should be noted that those skilled in the art may make various improvements and modifications to the present invention without departing from the principles of the present invention, and such improvements and modifications are also protected by the claims of the present invention.

Claims

1. Chimeric compound represented by formula (I): [BL] n -HPK1 ligand (I), or a pharmaceutically acceptable salt or stereoisomer thereof, The HPK1 ligand is, for example, an HPK1 inhibitor, B is a degradation tag, such as an E3 ligase ligand, L is a linker between B and the HPK1 ligand, and n is the number of degradation tags attached to the HPK1 ligand, selected from 1, 2 or 3, preferably n is 1.

2. The chimeric compound of claim 1, wherein the HPK1 ligand comprises a moiety of formula (HA) or formula (HB) or a pharmaceutically acceptable salt, stereoisomer thereof, in, The linker L portion of the chimeric compound is independently connected to R 4 or Cy3; X0 is C or N, preferably C; R 1 It is hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO2, -OR 1a 、-SO2R 1a 、-COR 1a 、-CO2R 1a 、-CONR 1a R 1b 、-C(=NR 1a )NR 1b R 1c 、-NR 1a R 1b 、-NR 1a COR 1b 、-NR 1a CONR 1b R 1c 、-NR 1a CO2R 1b 、-NR 1a SONR 1b R 1c 、-NR 1a SO2NR 1b R 1c , or -NR 1a SO2R 1b , the-C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with halogen, hydroxy, -C 1-8 Alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl substitution; The condition is: when X0 is N, R 1 does not exist; R 1a 、R 1b , and R 1c are independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups are each optionally substituted with at least one substituent R 1d Replace; or (R 1a and R 1b )、(R 1b and R 1c ), or (R 1c and R 1a ) together with the atom or atoms to which they are attached form a 3- to 9-membered ring comprising 0, 1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members, said ring optionally substituted with at least one substituent R 1e replace; where R 1d and R 1e are independently hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO2, -OR 1f 、-SO2R 1f 、-COR 1f 、-CO2R 1f 、-CONR 1f R 1g 、-C(=NR 1f )NR 1g R 1h 、-NR 1f R 1g 、-NR 1f COR 1g 、-NR 1f CONR 1g R 1h 、-NR 1f CO2R 1g 、-NR 1f SONR 1g R 1h 、-NR 1f SO2NR 1g R 1h , or -NR 1f SO2R 1g , the-C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2- 8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with at least one selected from halogen, -C 1-8 Alkyl, -OR 1i 、-NR 1i R 1j , cycloalkyl, heterocyclyl, aryl, or heteroaryl substituents; R 1f 、R 1g 、R 1h 、R 1i and R 1j are independently hydrogen, -C 1-8 Alkyl, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R 2 It is hydrogen, halogen, -C 1-8 Alkyl, preferably hydrogen; R 3 It is hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, -NO2, -OR 2a 、-SO2R 2a 、-COR 2a 、-CO2R 2a 、-CONR 2a R 2b 、-C(=NR 2a )NR 2b R 2c 、-NR 2a R 2b 、-NR 2a COR 2b 、-NR 2a CONR 2b R 2c 、-NR 2a CO2R 2b 、-NR 2a SONR 2b R 2c 、-NR 2a SO2NR 2b R 2c , or -NR 2a SO2R 2b , the-C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with halogen, hydroxy, -C 1-8 Alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl substitution; R 2a 、R 2b , and R 2c are independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; L 1 is a single bond, carbonyl (-C(=O)-), C 3-8 Alkylene, halogenated C 3-8 Alkylene, alkenylene, halogenated alkenylene, C 3-8 Alkynylidene, halo C 3-8 Alkynylidene,* 1 -O-Alkylene-** 1 、* 1 -alkylene-O-** 1 、* 1 -NH-alkylene-** 1 、* 1 -alkylene-NH-** 1 、* 1 -NHC(O)-** 1 、* 1 -C(O)NH-** 1 、* 1 -Alkylene-NHC(O)-** 1 、* 1 -alkylene-C(O)NH-** 1 、* 1 -NHC(O)-alkylene-** 1 、* 1 -C(O)NH-alkylene-** 1 ; in* 1 refers to the position of attachment to the pyrazole ring, and ** 1 refers to the position of attachment to the backbone (e.g., pyrrolopyridazine); R 4 , at each occurrence thereof, is independently hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO2, -OR 4a 、-SO2R 4a 、-SO2NR 4a R 4b 、-COR 4a 、-CO2R 4a 、-CONR 4a R 4b 、-C(=NR 4a )NR 4b R 4c 、-NR 4a R 4b 、-NR 4a COR 4b 、-NR 4a CONR 4b R 4c 、-NR 4a CO2R 4b 、-NR 4a SONR 4b R 4c 、-NR 4a SO2NR 4b R 4c , or -NR 4a SO2R 4b , the-C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups are each optionally substituted with at least one substituent R 4d replace; R 4a 、R 4b , and R 4c are independently hydrogen, hydroxyl, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups are each optionally substituted with at least one substituent R 4e Replace; or (R 4a and R 4b )、(R 4b and R 4c ), or (R 4c and R 4a ) together with the atom or atoms to which they are attached form a 3 to 12 membered ring comprising 0, 1, 2 or 3 further heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members, said ring optionally substituted with at least one substituent R 4e Replace; or R 4d and R 4e are independently hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO2, -OR 4f 、-SO2R 4f 、-SO2NR 4f R 4g 、-COR 4f 、-CO2R 4f 、-CONR 4f R 4g 、-C(=NR 4f )NR 4g R 4h 、-NR 4f R 4g 、-NR 4f COR 4g 、-NR 4f CONR 4g R 4h 、-NR 4f CO2R 4f 、-NR 4f SONR 4f R 4g 、-NR 4f SO2NR 4g R 4h , or -NR 4f SO2R 4g , the-C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2- 8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with at least one selected from halogen, -C 1-8 Alkyl, -OR 4i 、-NR 4i R 4j , cycloalkyl, heterocyclyl, aryl, or heteroaryl substituents; R 4f 、R 4g 、R 4h 、R 4i , and R 4j are independently hydrogen, -C 1-8 Alkyl, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; L 2 is a single bond, carbonyl (-C(=O)-), alkylene, cycloalkylene, * 2 -O-** 2 、* 2 -O-Alkylene-** 2 、* 2 -alkylene-O-** 2 、* 2 -NH-alkylene-** 2 、* 2 -alkylene-NH-** 2 、* 2 -NHC(O)-** 2 、* 2 -C(O)NH-** 2 , alkenylene, or alkynylene; in* 2 refers to the location of Cy2 attachment, and ** 2 refers to the position of attachment to the backbone (e.g., pyrrolopyridazine); Cy2 is a cycloalkylene, heterocyclylene, arylene, or heteroarylene group, each of which is optionally replaced by R 6 replace; R 6 Is halogen, hydroxyl, amino, cyano, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO2, -OR 6a 、-SO2R 6a 、-SO2NR 6a R 6b 、-COR 6a 、-CO2R 6a 、-CONR 6a R 6b 、-C(=NR 6a )NR 6b R 6c 、-NR 6a R 6b 、-NR 6a COR 6b 、-NR 6a CONR 6b R 6c 、-NR 6a CO2R 6b 、-NR 6a SONR 6b R 6c 、-NR 6a SO2NR 6b R 6c , or -NR 6a SO2R 6b , the-C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups are each optionally substituted with at least one substituent R 6d replace; R 6a 、R 6b , and R 6c are independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups are each optionally substituted with at least one substituent R 6e replace; R 6d and R 6e are independently hydrogen, hydroxy, amino, cyano, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO2, -OR 6f 、-SO2R 6f 、-SO2NR 6f R 6g 、-COR 6f 、-CO2R 6f 、-CONR 6f R 6g 、-C(=NR 6f )NR 6g R 6h 、-NR 6f R 6g 、-NR 6f COR 6g 、-NR 6f CONR 6g R 6h 、-NR 6f CO2R 6f 、-NR 6f SONR 6f R 6g 、-NR 6f SO2NR 6g R 6h , or -NR 6f SO2R 6g , the-C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with at least one selected from halogen, hydroxy, amino, cyano, -C 1-8 Alkyl, -C 1-8 Alkyl-OH, -OR 6i 、-NR 6i R 6j , cycloalkyl, heterocyclyl, aryl, or heteroaryl substituents; R 6f 、R 6g 、R 6h 、R 6i , and R 6j are independently hydrogen, -C 1-8 Alkyl, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; m is 0, 1, 2, 3 or 4, provided that the valence theory is satisfied (i.e., the resulting valence is chemically possible); L 3 Is a single bond, -O- or C 1-8 alkylene; Cy3 is a cycloalkyl, heterocyclyl, aryl or heteroaryl group, each of which is replaced by R 7 substituted and optionally by R 8 replace; R 7 and R 8 are independently hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO2, -OR 7a 、-SO2R 7a 、-SO2NR 7a R 7b 、-COR 7a 、-CO2R 7a 、-CONR 7a R 7b 、-C(=NR 7a )NR 7b R 7c 、-NR 7a R 7b 、-NR 7a COR 7b 、-NR 7a CONR 7b R 7c 、-NR 7a CO2R 7b 、-NR 7a SONR 7b R 7c 、-NR 7a SO2NR 7b R 7c , or -NR 7a SO2R 7b , the-C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups are each optionally substituted with at least one substituent R 7d replace; R 7a 、R 7b , and R 7c are independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups are each optionally substituted with at least one substituent R 7e Replacement; or when m≥1 and p≥1, (R 6 and R 8 ) together with the atom or atoms to which they are attached form a 3 to 12 membered ring comprising 0, 1, 2 or 3 further heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members, said ring optionally substituted with at least one substituent R 7e replace; R 7d and R 7e are independently hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO2, -OR 7f 、-SO2R 7f 、-SO2NR 7f R 7g 、-COR 7f 、-CO2R 7f 、-CONR 7f R 7g 、-C(=NR 7f )NR 7g R 7h 、-NR 7f R 7g 、-NR 7f COR 7g 、-NR 7f CONR 7g R 7h 、-NR 7f CO2R 7f 、-NR 7f SONR 7f R 7g 、-NR 7f SO2NR 7g R 7h , or -NR 7f SO2R 7g , the-C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2- 8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with at least one selected from halogen, -C 1-8 Alkyl, -OR 7i 、-NR 7i R 7j , cycloalkyl, heterocyclyl, aryl, or heteroaryl substituents; R 7f 、R 7g 、R 7h 、R 7i , and R 7j are independently hydrogen, -C 1-8 Alkyl, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; p is 0, 1, 2, or 3; Preferably, X0 is C and / or L 1 and L 2 Each is a single bond.

3. The chimeric compound according to claim 1, wherein B is a group that binds to an E3 ligase, wherein the E3 ligase is selected from von Hippel-Lindau (VHL), Cereblon, XIAP, E3A, MDM2, anaphase-promoting complex (APC), UBR5 (EDD1), SOCS / BC-box / eloBC / CUL5 / RING, LNXp80, CBX4, CBLL1, HACE1, HECTD1, HECTD2, HECTD3, HECW1 ,HECW2,HERC1,HERC2,HERC3,HERC4,HUWE1,ITCH,NEDD4,NEDD4L,PPIL2,PRPF19,PIAS1,PIAS2,PIAS3,PIAS4,RANB P2, RNF4, RBX1, SMURF1, SMURF2, STUB1, TOPORS, TRIP12, UBE3A, UBE3B, UBE3C, UBE4A, UBE4B, UBOX5, UBR5, WWP1, WWP 2. Parkin, A20 / TNFAIP3, AMFR / gp78, ARA54, β-TrCP1 / BTRC, BRCA1, CBL, CHIP / STUB1, E6, E6AP / UBE3A, F-box protein 15 / F BXO15, FBXW7 / Cdc4, GRAIL / RNF128, HOIP / RNF31, cIAP-1 / HIAP-2, cIAP-2 / HIAP-1, cIAP(pan), ITCH / AIP4, KAP1, MA RCH8, MindBomb1 / MIB1, MindBomb2 / MIB2, MuRF1 / TRIM63, NDFIP1, NEDD4, NleL, Parkin, RNF2, RNF4, RNF8, RNF168, R NF43, SART1, Skp2, SMURF2, TRAF-1, TRAF-2, TRAF-3, TRAF-4, TRAF-5, TRAF-6, TRIM5, TRIM21, TRIM32, UBR5, or ZNRF3; Furthermore, the B is a group that binds to an E3 ligase selected from VHL, Cereblon, MDM2 or cIAP.

4. The chimeric compound according to claim 3, wherein the general formula of B is as follows: in, Each G is independently selected from CR C2 R C3 NR C2 , CO, SO2; Y is selected from absent, NH; s is selected from 0, 1 or 2; Each of W1, W2, W3, W4, and W5 is independently selected from N or CR C4 ; Each X1 is independently selected from O or S; Each V1 is independently selected from the group consisting of absent, NH, O, S, SO, SO2, SO2NR C2 、CO、CO2、C(O)NR C2 、C(S)NR C2 NR C2 NR C2 CO、NR C2 CONR C3 、-C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are each optionally substituted by one or more R C4 Substitution, preferably selected from absence, -O-, -CH2-, -CH=CH-, -NH-; Each V2 is independently selected from CR C2 R C3 NR C2 , O or S; Each Z is independently selected from hydrogen, halogen, hydroxy, amino, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are each optionally substituted by one or more R C5 replace; R C1 、R C2 、R C3 、R C4 、R C5 Selected from hydrogen, carboxyl, cyano, nitro, halogen atoms, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR C6 、-SO2R C6 、-SO2NR C6 R C7 、-COR C6 、-CO2R C6 、-CONR C6 R C7 、-POR C6 R C7 、-NR C6 R C7 、-NR C6 COR C7 、-NR C6 CONR C7 R C8 、-NR C6 CO2R C7 、-NR C6 SO2NR C7 R C8 、-NR C6 SO2R C7 , the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are each optionally substituted with at least one substituent R C9 replace; R C6 、R C7 、R C8 、R C9 Selected from hydrogen, halogen, hydroxy, amino, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; Furthermore, the B is selected from: V1 is selected from absent, -O-, -CH2-, -CH=CH-, -NH-; Furthermore, the B is selected from: V1 is selected from absent, -O-, -CH2-, -NH-, preferably absent.

5. The chimeric compound according to claim 3, wherein the general formula of B is as follows: in, V3 is independently selected from the group consisting of absent, NH, O, S, SO, SO2, SO2NR h6 SR h6 、-R h6 CO-、-COR h6 -、CO、CO2、C(O)NR h6 、C(O)NR h6 R h6 、C(S)NR h6 NR h6 NR h6 CO, R h6 NR h6 CO、NR h6 CONR h7 、-C 1-8 Alkylene, -C 2-8 Alkenylene, -C 2-8 Alkyne, cycloalkyl, heterocyclic, aryl, heteroaryl, the -C 1-8 Alkylene, -C 2-8 Alkenylene, -C 2-8 Alkyne, cycloalkyl, heterocyclyl, aryl, heteroaryl are each optionally substituted by one or more R h8 replace; R H1 Independently selected from amino, NR h6 R h7 , aryl, heteroaryl, wherein the aryl and heteroaryl are each optionally replaced by one or more R h8 replace; R h Selected from hydrogen, halogen, C 1-8 alkyl, R h1 and R h3 independently selected from hydrogen, NR h6 R h7 、-C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C 3-9 Cycloalkyl, C 3-9 Heterocyclic group, the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C 3-9 Cycloalkyl, C 3-9 The heterocyclic groups are each optionally substituted by one or more R h9 replace; R h2 independently selected from hydrogen, deuterium, halogen, nitro, cyano, amino, hydroxyl, carboxyl, nitro, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR C6 、-SO2R h6 、-SO2NR h6 R h7 、-COR h6 、-CO2R h6 、-CONR h6 R h7 、-POR h6 R h7 、-NR h6 R h7 、-NR h6 COR h7 、-NR h6 CONR h7 R h8 、-NR h6 CO2R h7 、-NR h6 SO2NR h7 R h8 、-NR h6 SO2R h7 , the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are each optionally substituted with at least one substituent R h10 replace; q is 1 or 2; R h4 、R h5 、R h6 、R h7 independently selected from hydrogen, deuterium, halogen, nitro, cyano, amino, hydroxyl, carboxyl, nitro, -C 1-8 Alkyl, -C(O)R h12 , the -C 1-8 The alkyl group is optionally replaced by one or more R h11 replace; R h8 、R h9 、R h10 、R h11 independently selected from hydrogen, deuterium, CN, halogen, carbonyl, nitro, cyano, amino, hydroxyl, carboxyl, nitro, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; R h12 Selected from C 3-9 Cycloalkyl, the C 3-9 The cycloalkyl group is optionally substituted by CN, halogen, nitro, cyano, amino, hydroxy, carboxyl, nitro, -C 1-3 Alkyl substitution.

6. The chimeric compound according to claim 3, wherein the general formula of B is as follows: in, V3 is independently selected from absent, NH, O, S, SO, SO2, SO2NR h6 、CO、CO2、C(O)NR h6 、C(S)NR h6 NR h6 NR h6 CO、NR h6 CONR h7 、-C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2- 8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are each optionally substituted by one or more R h8 substituted, preferably selected from absent, -O-, -NH-, -CH2-, -CH=CH-, optionally with one or more R h8 substituted aryl, optionally substituted with one or more R h8 substituted heteroaryl; V4 is independently selected from absent, amino, NR h6 R h7 , aryl, heteroaryl, wherein the aryl and heteroaryl are each optionally replaced by one or more R h8 replace, R h1 and R h3 independently selected from hydrogen, NR h6 R h7 、-C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C 3-9 Cycloalkyl, C 3-9 Heterocyclic group, the -C 1-8 alkyl Base, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C 3-9 Cycloalkyl, C 3-9 The heterocyclic groups are each optionally substituted by one or more R h9 replace; R h2 independently selected from hydrogen, deuterium, halogen, nitro, cyano, amino, hydroxyl, carboxyl, nitro, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR C6 、-SO2R h6 、-SO2NR h6 R h7 、-COR h6 、-CO2R h6 、-CONR h6 R h7 、-POR h6 R h7 、-NR h6 R h7 、-NR h6 COR h7 、-NR h6 CONR h7 R h8 、-NR h6 CO2R h7 、-NR h6 SO2NR h7 R h8 、-NR h6 SO2R h7 , the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are each optionally substituted with at least one substituent R h10 replace; q is 1 or 2; R h4 、R h5 、R h6 、R h7 independently selected from hydrogen, deuterium, halogen, nitro, cyano, amino, hydroxyl, carboxyl, nitro, -C 1-8 Alkyl, -C(O)R h12 , the -C 1-8 The alkyl group is optionally replaced by one or more R h11 replace; R h8 、R h9 、R h10 、R h11 independently selected from hydrogen, deuterium, CN, halogen, carbonyl, nitro, cyano, amino, hydroxyl, carboxyl, nitro, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; R h12 Selected from C 3-9 Cycloalkyl, the C 3-9 The cycloalkyl group is optionally substituted by CN, halogen, nitro, cyano, amino, hydroxy, carboxyl, nitro, -C 1-3 Alkyl substitution; Further, R h1 One selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl; R h2 One selected from hydrogen, deuterium, halogen, nitro, cyano, amino, hydroxyl, methyl, ethyl, deuterated methyl or halomethyl; R h3 One selected from hydrogen, methyl, ethyl, propyl or isopropyl; R h4 One selected from hydrogen, deuterium, halogen, nitro, cyano, amino, hydroxyl, methyl, ethyl, deuterated methyl or halomethyl; R h5 One selected from hydrogen, deuterium, halogen, nitro, cyano, amino, hydroxyl, methyl, ethyl, deuterated methyl or halomethyl; V3 is selected from absent, -O-, -NH-, -CH2-, -CH=CH-; V4 is selected from As mentioned above -C 1-8 Alkyl refers to a straight or branched chain alkyl group having 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, etc.; the halogen refers to fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine; Furthermore, the B is selected from:

7. The chimeric compound according to claim 1, wherein L is in, Each of Y1, Y2, LNK and Y3 is independently selected from the group consisting of absent, halogen, hydroxy, amino, O, S, SO, SO2, SO2NR L1 、CO、CO2、C(O)NR L1 、C(S)NR L1 NR L1 NR L1 CO、NR L1 CONR L2 、-C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are each optionally substituted by one or more R L3 replace; R L1 、R L2 , and R L3 are independently hydrogen, halogen, hydroxy, amino, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; u is an integer between 1 and 20; Preferably, each of Y1, Y2, LNK and Y3 is independently selected from the group consisting of absence, halogen, hydroxy, amino, O, S, SO, SO2, SO2NR L1 、CO、CO2、C(O)NR L1 、C(S)NR L1 NR L1 NR L1 CO、NR L1 CONR L2 、-C 1-8 Alkyl, C 3-8 Monocyclic alkyl, C 3-8 Monoheterocyclic group, C 6-10 Aryl, C 6-10 Heteroaryl, C 4-14 Fused cycloalkyl, C 4-14 Fused heterocyclic group, C 4-14 Bridged cycloalkyl, C 4-14 Bridged heterocyclic group, C 4-14 Spirocycloalkyl, C 4-14 Spiroheterocyclic group; the -C 1-8 Alkyl, C 3-8 Monocyclic alkyl, C 3-8 Monoheterocyclic group, C 6-10 Aryl, C 6-10 Heteroaryl, C 4-14 Fused cycloalkyl, C 4-14 Fused heterocyclic group, C 4-14 Bridged cycloalkyl, C 4-14 Bridged heterocyclic group, C 4-14 Spirocycloalkyl, C 4-14 The spiro heterocyclic groups are each optionally substituted by one or more R L3 replace; R L1 、R L2 , and R L3 are independently hydrogen, halogen, hydroxy, amino, -C 1-8 Alkyl, C 3-8 Monocyclic alkyl, C 3-8 Monoheterocyclic group, C 4-14 Fused heterocyclic group, C 3-8 Monoheterocyclic group, C 4-14 Spiroalkyl, C 4-14 spiroheterocyclyl; u is an integer between 1 and 20.

8. The chimeric compound according to claim 7, wherein the LNK is selected from or does not exist; and / or Each Y1, Y2, and Y3 are independently selected from the group consisting of: and / or m is selected from an integer between 0 and 8; and / or X L Selected from O, S, -NR L1 -, -C(=O)-, -C(=O)NH-, -NHC(=O)-; and / or R L1 Selected from hydrogen, -C 1-8 Alkyl; and / or u is an integer between 1 and 20.

9. The chimeric compound according to claim 7, wherein L is selected from: does not exist, Preferably, L is selected from 10. The chimeric compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the chimeric compound is selected from the chimeric compounds listed in Table 2 in the specification.

11. A pharmaceutical composition comprising the chimeric compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier.

12. A pharmaceutical composition comprising the chimeric compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt or stereoisomer thereof, and one or more therapeutically active ingredients.

13. Use of the chimeric compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt or stereoisomer thereof, or the composition according to any one of claims 11 to 12, in the preparation of a medicament for treating and / or preventing HPK1-mediated diseases and related diseases; further, wherein the HPK1-mediated diseases and related diseases are selected from lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, breast cancer, mammary duct carcinoma, head and neck cancer, endometrial cancer, uterine cancer, rectal cancer, liver cancer, kidney cancer, renal pelvis cancer, esophageal cancer, esophageal adenocarcinoma, glioma, prostate cancer, thyroid cancer, female reproductive system cancer, carcinoma in situ, lymphoma, neurofibromatosis, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, gastrointestinal stromal tumor, oral cancer, pharyngeal cancer, multiple myeloma, leukemia, non-Hodgkin's lymphoma, colorectal villous adenoma, melanoma, cell tumor and sarcoma and myelodysplastic syndrome.

14. A method for preventing and / or treating HPK1-mediated diseases and related diseases, comprising administering to a subject a therapeutically effective amount of a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a composition according to any one of claims 11 to 12; further, wherein the HPK1-mediated diseases and related diseases are selected from lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, breast cancer, mammary duct carcinoma, head and neck cancer, endometrial cancer, uterine corpus cancer, rectal cancer, liver cancer, kidney cancer, renal pelvis cancer, esophageal cancer, esophageal adenocarcinoma, glioma, prostate cancer, thyroid cancer, female reproductive system cancer, carcinoma in situ, lymphoma, neurofibromatosis, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, gastrointestinal stromal tumor, oral cancer, pharyngeal cancer, multiple myeloma, leukemia, non-Hodgkin's lymphoma, colorectal villous adenoma, melanoma, cell tumor and sarcoma and myelodysplastic syndrome.