PROTAC chimeric compounds, methods for their preparation and uses

Abstract

Compounds of general formula (I) or pharmaceutically acceptable salts or stereoisomers thereof, and their use in the treatment of diseases such as tumors, immune diseases and inflammatory diseases, as well as pharmaceutical formulations and compositions of said compounds, and their uses.

Description

[Technical Field]

[0001] The present invention belongs to the field of medicine, and in particular relates to PROTAC chimeric compounds and their use in the manufacture of medicaments for treating or preventing diseases such as tumors. [Background technology]

[0002] Proteolysis-targeting chimeric molecules (PROTACs) technology originated from a scientist's discovery that ubiquitin (Ub) regulates the protein degradation process. Eukaryotic cells constantly strive to maintain adequate protein levels, producing and degrading thousands of proteins at any given moment. A small protein molecule called ubiquitin is crucial in maintaining this balance. When ubiquitin binds to proteins, these proteins are delivered to the proteasome for degradation.

[0003] Targeted protein degradation is a new direction in pharmaceutical research and development. Targeted protein degraders aim to design small molecules into a new type of drug. While the role of traditional small molecules is to inhibit protein function, the role of targeted protein degraders is to deliver proteins to the proteasome for degradation.

[0004] Dr. Craig Crews and Dr. Raymond Deshaies designed a series of bifunctional chimeric molecules based on polypeptide compounds to induce the degradation of methionyl aminopeptidase 2 (MetAP-2), and formally proposed the concept of PROTACs. They also filed a patent (WO2002020740A3) for this technology. However, these bulky peptide-based compounds, which act as linkers, had low intracellular permeability, and the first generation of PROTACs was considered a failure.

[0005] In 2008, the Crews team designed a second-generation PROTAC based on the E3 ubiquitin-protein ligase MDM2 that was useful for degrading the androgen receptor (AR).

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

[0007] HPK1 (hematopoietic progenitor kinase 1), also known as MAP 4K1 (mitogen-activated protein kinase 1), is a serine / threonine kinase and a member of the MAP4K family, which includes five other members: MAP4K2, MAP4K3, MAP4K4, MAP4K5, and MAP4K6.

[0008] The main processes involved in TCR regulation by HPK1 are as follows: (1) TCR binds extracellular antigen via MHC, thereby activating the TCR pathway and transmitting signals to downstream adaptor protein molecules; (2) the adaptor protein tyrosine kinases Lck and Zap70 activate SLP76, which then phosphorylates HPK1; (3) activated HPK1 then phosphorylates the receptor protein SLP-76; (4) SLP-76 phosphorylation provides multiple protein binding sites for 14-3-3 (TCR pathway inhibitory protein) receptor proteins, thereby forming a complex; (5) the phosphorylated SLP-76 complex is involved in downregulation of the Erk signaling pathway, leading to the ubiquitination degradation of SLP76, resulting in reduced TCR signaling and T cell proliferation. In conclusion, HPK1 can negatively regulate the TCR signaling pathway. Therefore, HPK1 can be used as a novel regulatory mechanism for T cell-mediated immune responses and a novel target for immunological antitumor therapy. HPK1 binds to many adaptor proteins, including the SLP-76 family, CARD11, HIS, HIP-55, GRB2 family, LAT, and CRK family, and activates the JNK / SAPK signaling pathway in hematopoietic stem cells, thereby negatively regulating the TCR pathway. Blockade of the Erk MAPK pathway is an inhibitory mechanism that negatively regulates TCR-induced IL-2 gene transcription.

[0009] HPK1 can interact with many adaptor proteins, including the SLP-76 family, CARD11, HIS, HIP-55, GRB2 family, LAT, and CRK families. Through these interactions, HPK1 activates the JNK / SAPK signaling pathway in hematopoietic stem cells, thereby negatively regulating the TCR signaling pathway. However, MAP4K3, also known as GLK kinase, has a biological function opposite to that of HPK1. GLK can promote the activation of the TCR pathway by binding to downstream adaptor proteins.

[0010] The present invention addresses this significant clinical need by providing PROTAC compounds with novel structures that have HPK1 inhibitory / degradation activity, favorable physicochemical properties, and potential for drug discovery. The compounds of the present invention or pharmaceutically acceptable salts thereof have favorable safety, excellent efficacy, and high bioavailability. Therefore, the compounds of the present invention have good applicability in the treatment of diseases mediated by HPK1. Summary of the Invention

[0011] One object of the present invention is to provide a targeted PROTAC compound or a pharmaceutically acceptable salt or stereoisomer thereof that has good HPK1 inhibitory / degradation activity. The compounds of the present invention also exhibit good performance in terms of HPK1 selectivity, have the effect of inducing IL2 production, and have good HPK1 proteolytic activity. In addition, the compounds of the present invention have good physicochemical properties (e.g., solubility, physical and / or chemical stability), good pharmacokinetic properties (e.g., good bioavailability, good metabolic stability, appropriate half-life and duration of action), good safety (low toxicity (e.g., reduced cardiac toxicity) and / or few side effects), low susceptibility to drug resistance, etc.

[0012] Another object of the present invention is to provide the use of a compound or a pharmaceutically acceptable salt or stereoisomer thereof in the treatment of a disease such as a tumor, an immune disease or an inflammatory disease.

[0013] The compounds of the present invention have the general formula (I): [BL] n -HPK1 ligand (I) [In the formula, The HPK1 ligand is, for example, an HPK1 inhibitor; B is a degradation tag, such as an E3 ligase ligand; L is a linking 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. or a pharmaceutically acceptable salt or stereoisomer thereof.

[0014] The binding site of the group attached to the E3 ligase, the number of bonds, and the choice of binding site on the HPK1 inhibitor all influence the activity of the compound.

[0015] S1.HPK1 Ligand In a first aspect, the HPK1 ligand according to the present invention is a compound of formula (HI) as set forth below. The first aspect includes the following embodiments: Embodiment 1: General formula (HI): [ka] [In the formula, W is CR 1 or N; Ring CyB is selected from 4- to 10-membered cycloalkyl, 4- to 10-membered heterocyclyl, 5- to 8-membered aryl, or 5- to 8-membered heteroaryl; R 1 are independently hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, -NO2, or -OR 1a where -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are each independently selected from halogen, hydroxyl, -C 1-8 optionally substituted by alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R 2 is hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -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 where -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are each independently selected from halogen, hydroxyl, -C 1-8 optionally substituted by alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R 2a , R 2b and R 2c are each independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, where -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl may be selected from the group consisting of at least one substituent R 2d or (R 2a and R 2b ), (R 2b and R 2c ), or (R 2c and R2a ) together with the atom or atoms to which they are attached form a 3- to 9-membered ring containing 0, 1, or 2 heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur as one or more ring members, wherein the ring contains at least one substituent R 2e optionally substituted by; where R 2d and R 2e are each independently hydrogen, halogen, or -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO2, -OR 2f , -SO2R 2f , -COR 2f , -CO2R 2f , -CONR 2f R 2g , -C(=NR 2f )NR 2g R 2h , -NR 2f R 2g , -NR 2f COR 2g , -NR 2f CONR 2g R 2h , -NR 2f CO2R 2g , -NR 2f SONR 2g R 2h , -NR 2f SO2NR 2g R 2h or -NR 2f SO2R 2g where -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are each independently selected from halogen, -C 1-8 Alkyl, -OR 2i , -NR 2i R 2j, optionally substituted by at least one substituent selected from cycloalkyl, heterocyclyl, aryl, or heteroaryl; R 2f , R 2g , R 2h , R 2i and R 2j are each 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 3 is hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 selected from alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN or -NO2; R 4 are 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 4aSO2NR 4b R 4c or -NR 4a SO2R 4b where -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl may be selected from the group consisting of at least one substituent R 4d optionally substituted by; R 4a , R 4b and R 4c are each independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, where -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl may be selected from the group consisting of at least one substituent R 4e optionally substituted by; R 4d and R 4e are each independently hydrogen, halogen, or -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 where -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are each independently selected from halogen, -C 1-8 Alkyl, -OR 4i , -NR 4i R 4j , optionally substituted by at least one substituent selected from cycloalkyl, heterocyclyl, aryl, or heteroaryl; R 4f , R 4g , R 4h , R 4i and R 4j are each 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; s is 0, 1, or 2, provided that valence theory holds; t is 0, 1, 2, 3, or 4, provided that valence theory holds; m is 0, 1, 2, 3, or 4, provided that valence theory holds; CyD is selected from cycloalkyl, heterocyclyl, aryl, or heteroaryl. or a pharmaceutically acceptable salt or stereoisomer thereof.

[0016] Embodiment 2: R 1 But hydrogen, halogen, -C 1-8alkyl, preferably hydrogen, halogen, -C 1-6 The compound according to embodiment 1, wherein R is selected from alkyl, more preferably hydrogen.

[0017] Embodiment 3: The compound of any one of embodiments 1 and 2, wherein CyB is selected from 4- to 10-membered heterocyclyl, 5- to 8-membered aryl, or 5- to 8-membered heteroaryl. Embodiment 4: The compound according to embodiment 3, wherein ring CyB is selected from a 5- to 6-membered nitrogen-containing heterocyclyl, a 5- to 6-membered oxygen-containing heterocyclyl, or a 5- to 6-membered nitrogen-containing heteroaryl.

[0018] Embodiment 5: The compound according to embodiment 4, wherein ring CyB is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, tetrahydropyrrolyl, piperidinyl, or pyridinyl.

[0019] Embodiment 6: The ring CyB is [ka] 6. The compound according to embodiment 5, selected from:

[0020] Embodiment 7: The ring CyB is [ka] 5. The compound according to embodiment 4, selected from:

[0021] Embodiment 8: The R 2 But hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -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 where -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are each independently selected from halogen, hydroxyl, -C 1-8 optionally substituted by alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R 2a , R 2b and R 2c are each independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, where -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl may be selected from the group consisting of at least one halogen, -C 1-8 optionally substituted with alkyl, -CN, hydroxyl, or -NO2; t is 0, 1, 2, 3, or 4; moreover, R 2 But -C 1-8 alkyl, preferably -C 1-3 The compound according to any one of embodiments 1 to 7, wherein t is selected from alkyl, more preferably methyl or ethyl; and t is 0 or 1.

[0022] Embodiment 9: [ka] but, [ka] 9. The compound according to any one of embodiments 3 to 8, selected from:

[0023] Embodiment 10: [ka] but, [ka] 9. The compound according to any one of embodiments 3 to 8, selected from:

[0024] Embodiment 11: The R 3 But hydrogen, halogen, -C 1-8 The compound according to any one of embodiments 1 to 10, wherein s is selected from alkyl, preferably selected from halogen, more preferably fluorine; and s is selected from 0 or 1.

[0025] Embodiment 12: R 4 are independently hydrogen, halogen, -CN, -C 1-8 alkyl, wherein -C 1-8 The alkyl group may have at least one substituent R 4d optionally substituted by; R 4d are each independently hydrogen, halogen, or -C 1-8Alkyl, -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 where -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are each independently selected from halogen, -C 1-8 Alkyl, -OR 4i , -NR 4i R 4j , optionally substituted by at least one substituent selected from cycloalkyl, heterocyclyl, aryl, or heteroaryl; R 4f , R 4g , R 4h , R 4i and R 4j are each independently hydrogen, -C 1-8 Alkyl, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 Alkenyl, -C 2-8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; The compound of any one of embodiments 1 to 11, wherein m is 0, 1, 2, or 3.

[0026] Embodiment 13: The R 4 is -CN, halogen, preferably fluorine, chlorine or bromine, more preferably fluorine or chlorine.

[0027] Embodiment 14: The R 4 But -C 1-8 alkyl, preferably -C 1-3 The compound according to embodiment 12, wherein the alkyl is alkyl, more preferably methyl or ethyl.

[0028] Embodiment 15: The R 4 But, -NR 4f R 4g -C is replaced by 1-8 alkyl, where R 4f and R 4g independently, -C 1-8 The compound according to embodiment 12, wherein the alkyl is preferably methyl.

[0029] Embodiment 16: The R 4 but, [ka] 16. The compound of embodiment 15, wherein

[0030] Embodiment 17: The R 4 But, -OR 4f where R 4f is hydrogen, -C 1-8 alkyl, preferably -C 1-313. The compound according to embodiment 12, wherein the alkyl is selected from alkyl, more preferably selected from methyl or ethyl.

[0031] Embodiment 18: The R 4 but, [ka] 18. The compound of embodiment 17, wherein

[0032] Embodiment 19: The R 4 Methyl, ethyl, fluorine, chlorine, -CN, [ka] and; The compound of any one of embodiments 12 to 17, wherein m is selected from 0, 1, or 2.

[0033] Embodiment 20: R 4 But -C 1-8 alkyl, preferably -C 1-3 13. The compound according to embodiment 12, wherein R is alkyl, more preferably methyl or ethyl, which is substituted with at least one halogen.

[0034] Embodiment 21: 21. The compound according to embodiment 20, wherein halogen is fluorine, chlorine or bromine, preferably fluorine or chlorine.

[0035] Embodiment 22: The R 4 22. The compound according to embodiment 20 or 21, wherein is -CHF2, -CH2F, -CF3, -CH2CHF2, -CH2CH2F or -CH2CF3, preferably -CF3.

[0036] Embodiment 23: The CyD is a 5-membered heteroaryl ring, a phenyl ring, a 6-membered heteroaryl ring, C 8-1223. Compounds according to embodiments 1-22, wherein the heteroaryl ring and heterocyclyl contain, as one or more ring members, zero, one, or two heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur.

[0037] Embodiment 24: The CyD is [ka] is selected from 24. The compound of embodiment 23, wherein X1, X2, and X3 are each independently selected from CH, C, or N.

[0038] Embodiment 25: The CyD is [ka] is selected from 24. The compound of embodiment 23, wherein X1, X2, and X3 are each independently selected from C or N.

[0039] EMBODIMENT 26: 26. The compound of embodiment 25, wherein said CyD is selected from a phenyl ring.

[0040] Embodiment 27: The CyD is [ka] is selected from The compound of embodiment 24, wherein X1, X2, and X3 are each independently selected from CH, C, or N, with the proviso that at least one of X1, X2, and X3 is N.

[0041] EMBODIMENT 28: The CyD is [ka] is selected from The compound of embodiment 25, wherein X1, X2, and X3 are each independently selected from C or N, with the proviso that X1, X2, and X3 are not simultaneously C.

[0042] Embodiment 29: Said CyD is selected from pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl or triazinyl, preferably [ka] 28. The compound according to embodiment 27, selected from:

[0043] Embodiment 30: The CyD is [ka] 29. The compound according to embodiment 28, selected from:

[0044] Embodiment 31: 24. The compound of embodiment 23, wherein CyD is selected from a 5-membered heteroaryl ring containing, as one or more ring members, 0, 1, or 2 heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur.

[0045] Embodiment 32: The CyD is [ka] 32. The compound according to embodiment 31, selected from:

[0046] Embodiment 33: The compound according to any one of embodiments 1 to 32, wherein W is selected from CH or N.

[0047] In a second aspect, the HPK1 ligand according to the present invention is a compound of formula (H-II) as set forth below. The second aspect includes the following embodiments:

[0048] Embodiment 1: General formula (H-II): [ka] [In the formula, R 1 , CyB, R 2 ,t,R 3 ,s,R 4 , m and CyD are each as defined in the first embodiment above. or a pharmaceutically acceptable salt or stereoisomer thereof.

[0049] Embodiment 2: [ka] but, [ka] and preferably [ka] 2. The compound of embodiment 1, wherein

[0050] Embodiment 3: The R 1 and R 3 and n is 0 or 1. The compound of embodiment 1 or 2, wherein each is hydrogen.

[0051] Embodiment 4: The CyD is pyridyl, preferably [ka] The compound of any one of embodiments 1 to 3, wherein

[0052] Embodiment 5: The R 4 The compound of any one of embodiments 1 to 4, wherein is hydrogen.

[0053] In a third aspect, the HPK1 ligand according to the present invention is a compound of formula (H-III) shown below. The third aspect includes the following embodiments: Embodiment 1: General formula (H-III): [ka] [In the formula, W.R. 1 , R 3 ,s,R 4 , m and CyD are each as defined in the first aspect above; R X H and C 1-8 alkyl, wherein C 1-8 Alkyl can be deuterium, tritium, halogen, -OH, -CN, -NR Xa R Xb , -OR Xa , -CO-NHR Xb , -CO-NR Xa R Xb and 3- to 10-membered cycloalkyl; R Xa and R Xb are each independently 1-8 alkyl] A compound represented by the formula:

[0054] Embodiment 2: R X But H and C 1-4 alkyl, wherein C 1-4 Alkyl is deuterium, F, Cl, Br, -OH, -CN, -NR Xa R Xb , -OR Xa , -CO-NHR Xb , -CO-NR Xa R Xb and 3- to 7-membered cycloalkyl; R Xa and R Xbare each independently 1-4 2. The compound according to embodiment 1, wherein the alkyl is selected from:

[0055] Embodiment 3: R X is selected from H and methyl, ethyl, isopropyl, isobutyl, sec-butyl and tert-butyl, where methyl, ethyl, isopropyl, isobutyl, sec-butyl and tert-butyl are selected from deuterium, F, Cl, —OH, —CN, —NR Xa R Xb , -OR Xa , -CO-NHR Xb , -CO-NR Xa R Xb and 3- to 6-membered cycloalkyl; R Xa and R Xb is each independently methyl.

[0056] Embodiment 4: R X is H, methyl, -CD3, ethyl, isopropyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, [ka] 4. The compound according to any one of embodiments 1 to 3, selected from:

[0057] Embodiment 5: General formula (H-III): [ka] [In the formula, W.R. 1 , R 3 ,s,R 4 , m and CyD are each as defined in the first aspect above; R X is C 1-8Alkyl, or -NR Xa C replaced by R 1-8 is alkyl; R Xa and R Xb are each independently 1-8 alkyl, preferably methyl. A compound represented by the formula:

[0058] Embodiment 6: The R X But methyl, [ka] 6. The compound according to embodiment 5, selected from:

[0059] In a fourth aspect, the HPK1 ligand according to the present invention is a compound of formula (H-IV) as set forth below. The fourth aspect includes the following embodiments: Embodiment 1: General formula (H-IV): [ka] [In the formula, R 1 , R 3 ,s,R 4 , m, CyD and R X are each as defined in the third aspect above. A compound represented by the formula:

[0060] In a fifth aspect, the HPK1 ligand according to the present invention is a compound of formula (HV) as set forth below. The fifth aspect includes the following embodiments: Embodiment 1: General formula (HV): [ka] [In the formula, R 4 are independently hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C2-8 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 where -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl may be substituted with at least one substituent R 4d optionally substituted by; R 4a , R 4b and R 4c are each independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, where -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl may be substituted with at least one substituent R 4e optionally substituted by; R4d and R 4e are each independently hydrogen, halogen, or -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 where -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are each independently selected from halogen, -C 1-8 Alkyl, -OR 4i , -NR 4i R 4j , optionally substituted by at least one substituent selected from cycloalkyl, heterocyclyl, aryl, or heteroaryl; R 4f , R 4g , R 4h , R 4i and R 4j are each independently hydrogen, -C 1-8 Alkyl, C 1-8Alkoxy-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 valence theory holds; CyD is selected from cycloalkyl, heterocyclyl, aryl, or heteroaryl. or a pharmaceutically acceptable salt or stereoisomer thereof.

[0061] Embodiment 2: The CyD is a 5-membered heteroaryl ring, a phenyl ring, a 6-membered heteroaryl ring, or C 8-12 The compound of embodiment 1, wherein the heteroaryl ring and heterocyclyl contain zero, one, or two heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur as one or more ring members.

[0062] Embodiment 3: The CyD is [ka] is selected from The compound of embodiment 2, wherein X1, X2, and X3 are each independently selected from CH, C, or N.

[0063] Embodiment 4: The CyD is [ka] is selected from The compound of embodiment 2, wherein X1, X2, and X3 are each independently selected from C or N.

[0064] Embodiment 5: 5. The compound according to embodiment 4, wherein said CyD is selected from phenyl rings.

[0065] Embodiment 6: The CyD is [ka] is selected from The compound of embodiment 3, wherein X1, X2, and X3 are each independently selected from CH, C, or N, with the proviso that at least one of X1, X2, and X3 is N.

[0066] Embodiment 7: The CyD is [ka] is selected from X1, X2 and X3 are each independently selected from C or N, provided that X1, X2 and X3 cannot all simultaneously be C; 5. The compound of embodiment 4.

[0067] Embodiment 8: Said CyD is selected from pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl or triazinyl, preferably [ka] 7. The compound according to embodiment 6, selected from:

[0068] Embodiment 9: The CyD is [ka] Selected from: 8. The compound of embodiment 7.

[0069] Embodiment 10: The compound of embodiment 2, wherein CyD is selected from a 5-membered heteroaryl ring containing, as one or more ring members, 0, 1, or 2 heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur.

[0070] Embodiment 11: The CyD is [ka] 11. The compound according to embodiment 10, selected from:

[0071] Embodiment 12: The R 4 are independently hydrogen, halogen, -CN or -C 1-8 alkyl, wherein -C 1-8 The alkyl group may have at least one substituent R 4d optionally substituted by; R 4d are each independently hydrogen, halogen, or -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 where -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are each independently selected from halogen, -C 1-8 Alkyl, -OR 4i , -NR 4i R 4j , optionally substituted by at least one substituent selected from cycloalkyl, heterocyclyl, aryl, or heteroaryl; R 4f , R 4g , R 4h , R 4i and R 4j are each 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 selected from 0, 1, 2 or 3; 12. A compound according to any one of embodiments 1 to 11.

[0072] Embodiment 13: The R 4 is —CN, halogen, preferably fluorine, chlorine or bromine, more preferably fluorine or chlorine; 13. The compound of embodiment 12.

[0073] Embodiment 14: The R 4 But -C 1-8 alkyl, preferably -C 1-3 alkyl, more preferably methyl or ethyl; 13. The compound of embodiment 12.

[0074] Embodiment 15: The R 4 is selected from methyl, ethyl or fluorine; m is selected from 0 or 1; A compound according to any one of embodiments 12 to 14.

[0075] In a sixth aspect, the HPK1 ligand according to the present invention is a compound of formula (H-VI) as set forth below. The sixth aspect includes the following embodiments: Embodiment 1: General formula (H-VI): [ka] [In the formula, R 5 is hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -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 where -C 1-8 Alkyl, -C 2-8 Alkenyl or -C 2-8 Alkynyl is halogen, hydroxyl, -C 1-8 optionally substituted by alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R 1 , R 2a , R 2b , R 2c , R 4, m and CyD are each as defined in the first embodiment above. or a pharmaceutically acceptable salt or stereoisomer thereof.

[0076] Embodiment 2: The R 5 But -C 1-8 alkyl, preferably -C 1-3 The compound according to embodiment 1, wherein R is alkyl, more preferably methyl or ethyl.

[0077] In a seventh aspect, the HPK1 ligand according to the present invention is a compound of formula (H-VII) as set forth below. The seventh aspect includes the following embodiments: Embodiment 1: General formula (H-VII): [ka] [In the formula, X4 is selected from O or an optionally oxidized S heteroatom; W' is CR 6 or N; R 6 is a halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -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 , -NR2a SONR 2b R 2c , -NR 2a SO2NR 2b R 2c or -NR 2a SO2R 2b where -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are each independently selected from halogen, hydroxyl, -C 1-8 optionally substituted by alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R 2a , R 2b , R 2c , R 4 , m and CyD are each as defined in the first embodiment above. or a pharmaceutically acceptable salt or stereoisomer thereof.

[0078] Embodiment 2: The compound according to embodiment 1, wherein X4 is O or S, preferably S.

[0079] Embodiment 3: W' is CR 6 3. The compound of embodiment 1 or 2, wherein

[0080] Embodiment 4: R 6 is halogen, -CN, -NO2 or -NR 2a R 2b 4. The compound according to any one of embodiments 1 to 3, selected from:

[0081] Embodiment 5: R 6 But, -NR 2a R 2b 5. The compound of embodiment 4, wherein

[0082] Embodiment 6: R2a and R 2b are each independently hydrogen or -C 1-8 alkyl, preferably -C 1-3 The compound according to any one of embodiments 1 to 5, wherein R is alkyl, more preferably methyl or ethyl.

[0083] Embodiment 7: R 6 The compound of embodiment 5, wherein is —NH 2 .

[0084] Embodiment 8: The CyD is C 3-10 The compound of any one of embodiments 1-7, wherein the heteroaryl ring is selected from a cycloalkyl, a phenyl ring, a 5- to 6-membered monocyclic heteroaryl ring, a 9- to 10-membered heteroaryl ring, or a 5- to 10-membered heterocyclyl, wherein the heteroaryl ring and the heterocyclyl contain 1 or 2 heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members.

[0085] Embodiment 9: CyD is a 9- to 10-membered bicyclic heteroaryl ring containing one or two nitrogen heteroatoms, preferably [ka] 9. The compound of embodiment 8, wherein

[0086] In some embodiments, the present invention provides a compound of formula (I) according to any one of the first to seventh aspects, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein the HPK1 ligand compound is one shown in Table 1-1 below: [Table 1-1] [Table 1-2] [Table 1-3]

[0087] The present invention provides the above-mentioned HPK1 ligand compound or a pharmaceutically acceptable salt or isomer thereof, wherein the HPK1 ligand compound is preferably selected from the exemplary compounds of HPK1 ligands disclosed herein shown in Tables 1-2 below: [Table 2]

[0088] S2. Decomposition of Tag B In some embodiments, B is a group that is bound to an E3 ligase, wherein the E3 ligase is selected from the group consisting of 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, R ANBP2, RNF4, RBX1, SMURF1, SMURF2, STUB1, TOPORS, TRIP12, UBE3A, UBE3B, UBE3C, UBE4A, UBE4B, UBOX5, UBR5, WWP 1, WWP2, Parkin, A20 / TNFAIP3, AMFR / gp78, ARA54, β-TrCP1 / BTRC, BRCA1, CBL, CHIP / STUB1, E6, E6AP / UBE3A, F-box protein 15 / FBXO15, FBXW7 / Cdc4, GRAIL / RNF128, HOIP / RNF31, cIAP-1 / HIAP-2, cIAP-2 / HIAP-1, cIAP(pan), ITCH / AIP4, KAP1, MARCH8, MindBomb1 / MIB1, MindBomb2 / MIB2, MuRF1 / TRIM63, ND selected from FIP1, NEDD4, NleL, Parkin, RNF2, RNF4, RNF8, RNF168, RNF43, SART1, Skp2, SMURF2, TRAF-1, TRAF-2, TRAF-3, TRAF-4, TRAF-5, TRAF-6, TRIM5, TRIM21, TRIM32, UBR5 or ZNRF3.

[0089] Furthermore, B is a group that binds to an E3 ligase selected from VHL, Cereblon, MDM2, or cIAP.

[0090] In some embodiments, B is of the formula shown below: [ka] [In the formula, G is independently CR C2 R C3 , N.R. C2 , CO or SO2; Y is selected from a bond or NH; p is selected from 0, 1 or 2; W1, W2, W3, W4 and W5 each independently represent N or CR C4 Selected from; Each X5 is independently selected from O or S; Each V1 is independently absent, NH, O, S, SO, SO2, or SO2NR C2 , CO, CO2, C(O)NR C2 , C(S)NR C2 , N.R. C2 , N.R. C2 CO, NR C2 CONR C3 , -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are each R C4 Preferably, each V1 is independently absent, -O-, -CH2-, -CH=CH- or -NH-; V2 is independently C2 R C3 , N.R. C2 , O or S; Z is independently hydrogen, halogen, hydroxyl, amino, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein -C 1-8 Alkyl, -C 2-8Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are each R C5 optionally substituted by; R C1 , R C2 , R C3 , R C4 and R C5 is hydrogen, carboxy, cyano, nitro, halogen atom, -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 or -NR C6 SO2R C7 where -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl may be selected from the group consisting of at least one substituent R C9 optionally substituted by; R C6 , R C7 , R C8 and R C9 is hydrogen, halogen, hydroxyl, amino, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C2-8 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl].

[0091] Furthermore, G can be CH2, CO, SO2, NH or NC 1-6 alkyl; X5 is selected from O or S; V1 is absent, NH, O, -C 1-8 Alkyl or -C 2-8 alkenyl, preferably absent, -O-, -CH2-, -CH=CH- or -NH-.

[0092] V2 is NH, NC 1-6 Alkyl, NC 6-10 Aryl, N-3 to 10-membered heterocyclyl, N-5 to 10-membered heteroaryl, NC 3-10 cycloalkyl, O or S; Z is C 1-6 Alkyl, C 3-10 selected from alkyl, halogen, or hydrogen; R C1 is hydrogen, C 1-3 selected from alkyl, hydroxyl, or -CH2-3 to 10-membered heterocyclyl; W1, W2, W3, W4 and W5 are independently N or -CR C4 wherein R C4 are each independently hydrogen, halogen, or C 1-3 Alkyl, HaloC 1-3 Alkyl, hydroxy, deuterated C 1-3 Alkyl or [ka] Preferably, W1, W2, W3, W4 and W5 are selected from -CR C4 Selected from R C4 is hydrogen, halogen (fluorine, chlorine), methyl or [ka] is selected from.

[0093] In some embodiments, B is [ka] Selected from; V1 is absent, -O-, -CH2-, -CH=CH- or -NH-.

[0094] In some embodiments, B is [ka] Selected from; V1 is absent or selected from -O-, -CH2-, -CH=CH- or -NH-.

[0095] In some embodiments, B is [ka] Selected from; V1 is absent, -O-, -CH2- or -NH-, preferably absent.

[0096] Furthermore, B is [ka] Selected from; V1 is absent or selected from -O-, -CH2- or -NH-, preferably absent.

[0097] In some embodiments, B is [ka] is selected from, preferably [ka] is.

[0098] In some embodiments, B is [ka] is selected from.

[0099] In some other embodiments, B is of the formula shown below: [ka] [In the formula, CyD, R 4 and m is as defined in the first embodiment in the "S1.HPK1 Ligand" section above].

[0100] In some such embodiments, the CyD is phenyl; R 4 -OR 4f where R 4f is hydrogen, -C 1-8 alkyl, preferably -C 1-3 alkyl, more preferably methyl or ethyl; m is 1.

[0101] In some such embodiments, B is as shown below: [ka]

[0102] S3. Bonding group L L is a linking group between group B and the HPK1 ligand.

[0103] In some embodiments, the L is (LNK) u where: LNK are each independently absent or C 1-8 Alkylene, C 2-8 Alkynylene, [ka] or one or more halogens or C 1-8 selected from cycloalkyl, heterocyclyl, heteroaryl or aryl optionally substituted by alkyl; Here, cycloalkyl is preferably [ka] is selected from Heterocyclyl is preferably [ka] is selected from Aryl is preferably selected from benzene rings; m is selected from an integer from 1 to 8; u is an integer from 1 to 20.

[0104] In some embodiments, the L is (LNK) u where: LNKs are, independently, either absent or C 1-8 Alkylene, C 2-8 Alkynylene, [ka] or one or more halogens or C 1-8 selected from cycloalkyl, heterocycloalkyl, heteroaryl or aryl rings optionally substituted with alkyl; Here, cycloalkyl is [ka] is selected from Heterocycloalkyl is [ka] is selected from The aryl ring is selected from a benzene ring; m is selected from an integer from 1 to 8; u is selected from integers of 1 to 20.

[0105] In some embodiments of the invention, L is [ka] is selected from.

[0106] In some embodiments of the invention, L is [ka] is selected from.

[0107] In some embodiments of the invention, L is [ka] is selected from.

[0108] In some embodiments of the invention, L is [ka] is.

[0109] In some embodiments of the invention, L is [ka] is selected from, preferably [ka] is.

[0110] In some embodiments of the invention, L is [ka] is selected from.

[0111] In some embodiments of the invention, L is [ka] is selected from.

[0112] In some embodiments of the invention, L is [ka] is selected from.

[0113] In some embodiments of the invention, L is [ka] is selected from.

[0114] In some embodiments of the present invention, L is [ka] is selected from.

[0115] In some embodiments of the present invention, the compound of general formula (I) has the formula (II): [ka] [In the formula, The W, R 1 , R 2 ,t,R 3 ,s,CyB,R 4 , m and CyD are each as defined in the first embodiment of the "S1.HPK1 Ligand" section above; wherein L, B, and n are as defined herein. is a compound of

[0116] In particular, B is as defined in section "S2. Degradation Tag B." In particular, L is as defined in section "S3. Linker L."

[0117] In some such embodiments, the CyB is: [ka] is selected from.

[0118] In some embodiments, the CyB is [ka] is selected from.

[0119] In some embodiments, the CyB is [ka] is selected from, preferably [ka] is.

[0120] In some embodiments, [ka] teeth, [ka] is selected from.

[0121] In some embodiments, [ka] teeth, [ka] is selected from.

[0122] In some embodiments, [ka] teeth, [ka] is selected from, preferably [ka] is.

[0123] In some embodiments, W is N.

[0124] In some embodiments, the R 1 and R 3 are hydrogen atoms.

[0125] In some embodiments, the CyD is pyridyl, preferably [ka] is.

[0126] In an exemplary embodiment, the R 4 is hydrogen.

[0127] In some embodiments, L is [ka] is.

[0128] In some embodiments, B is [ka] and preferably [ka] and; V1 is absent, -O-, -CH2- or -NH-, preferably absent.

[0129] Preferably, B is [ka] and more preferably, [ka] is.

[0130] In some embodiments, n is 1.

[0131] In some embodiments, the compound of general formula (I) has formula (III): [ka] [In the formula, The R 4 , m and CyD are each as defined in the second embodiment of the "S1.HPK1 Ligand" section above; wherein L, B, and n are as defined herein. is a compound of

[0132] In particular, B is as defined in section "S2. Degradation Tag B." In particular, L is as defined in section "S3. Linker L."

[0133] In some embodiments, the compound of general formula (I) has formula (IV): [ka] [In the formula, The W, R 1 , R 3 ,s,R 4 and CyD are each as defined in the first aspect of the "S1.HPK1 Ligand" section above; The R X is as defined in the second aspect of the "S1.HPK1 Ligand" section above; wherein L, B, and n are as defined herein. is a compound of

[0134] In particular, B is as defined in section "S2. Degradation Tag B." In particular, L is as defined in section "S3. Linking Group L."

[0135] In some such embodiments, W is N.

[0136] In some embodiments, the R 1 is hydrogen or -C 1-3 It is alkyl, preferably hydrogen.

[0137] In some embodiments, the R 3 is hydrogen or -C 1-3 It is selected from alkyl, preferably hydrogen.

[0138] In some embodiments, s is 0 or 1.

[0139] In some embodiments, R X is C 1-4 alkyl, wherein C 1-4 Alkyl is deuterium, F, Cl, Br, -OH, -CN, -NR Xa R Xb -OR Xa In some such embodiments, C 1-4 Alkyl is selected from methyl, ethyl, isopropyl, isobutyl, sec-butyl and tert-butyl, preferably methyl or ethyl.

[0140] In some embodiments, R Xa and R Xb are each independently 1-4 It is selected from alkyl, preferably methyl.

[0141] In some embodiments, R Xis selected from methyl or ethyl, wherein methyl or ethyl may be optionally substituted with 1, 2, or 3 substituents independently selected from deuterium, F, Cl, —OH, —CN, and —OCH. In some embodiments, R X is selected from methyl or ethyl, wherein methyl or ethyl may be optionally substituted with 1, 2, or 3 substituents independently selected from deuterium, F, and —OCH. In some embodiments, R X is methyl, -CD3, ethyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3 or [ka] is selected from, preferably methyl, -CD3, ethyl, -CH2CH2F, -CH2CHF2, -CH2CF3 or [ka] is selected from.

[0142] In some embodiments, CyD is [ka] wherein X1, X2, and X3 are each independently selected from CH, C, or N, with the proviso that at least one of X1, X2, and X3 is N.

[0143] In some embodiments, CyD is [ka] and X1, X2 and X3 are each independently selected from C or N, provided that X1, X2 and X3 cannot simultaneously be C.

[0144] In some embodiments, CyD is selected from pyridyl, preferably [ka] is selected from.

[0145] In some embodiments, R 4 are independently hydrogen or -C 1-3 It is selected from alkyl, preferably hydrogen.

[0146] In some embodiments, m is 0 or 1.

[0147] In some embodiments, L is [ka] is.

[0148] In some embodiments, B is [ka] and preferably [ka] and; V1 is absent, -O-, -CH2- or -NH-, preferably absent.

[0149] Preferably, B is [ka] and more preferably [ka] is.

[0150] In some embodiments, n is 1.

[0151] The present invention provides compounds described above, or pharmaceutically acceptable salts or stereoisomers thereof, selected from the example compounds disclosed herein, which compounds are shown in Table 2 below.

[0152] [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8] [Table 3-9] [Table 3-10] [Table 3-11] [Table 3-12] [Table 3-13] [Table 3-14] [Table 3-15] [Table 3-16]

[0153] Pharmaceutical Compositions and Uses The present invention also provides a pharmaceutical composition comprising any compound according to the present invention, or a pharmaceutically acceptable salt or stereoisomer thereof, which may optionally contain one or more pharmaceutically acceptable carriers and may be formulated into any pharmaceutically acceptable pharmaceutical formulation.

[0154] The present invention also provides pharmaceutical formulations comprising any compound according to the invention or a pharmaceutically acceptable salt or stereoisomer thereof, and optionally one or more pharmaceutically acceptable carriers.

[0155] The compound of the present invention represented by general formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof has excellent and highly selective inhibitory activity against HPK1, and can treat and / or prevent diseases such as tumors, immune diseases, and inflammatory diseases.

[0156] The present invention provides a method for degrading / inhibiting HPK1 activity, comprising administering to a subject a compound of the present invention, including a compound of general formula (I) or the specific compounds exemplified herein, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0157] The compounds provided by the present invention have good HPK1 inhibitory / degrading activity, and good physicochemical and pharmaceutical properties. The compounds of the present invention have good potential in the treatment of HPK1-mediated diseases.

[0158] WO 2021057872 A1 discloses a PROTAC compound formed by a MAP4K family inhibitor and a Cerebron protein ligand. The present inventors have surprisingly found that the compound of the present invention exhibits improved HPK1 selectivity.

[0159] The present invention also provides a method for treating a patient suffering from a disease that can be regulated by HPK1, comprising administering to the patient an effective amount of a compound according to the present invention (such as a compound according to general formula (I) or a specific compound exemplified herein) or a pharmaceutically acceptable salt or stereoisomer thereof.

[0160] The present invention also provides a method for inhibiting / reducing HPK1 activity in a patient in need of such inhibition, comprising administering to the patient an effective amount of a compound according to the present invention (e.g., a compound according to general formula (I) or a specific compound exemplified herein), or a pharmaceutically acceptable salt or stereoisomer thereof.

[0161] The present invention also provides the use of any one of the compounds according to the present invention, or its pharmaceutically acceptable salt or its stereoisomer, in the manufacture of a medicament for treating or preventing related HPK1-mediated diseases. HPK1 has a negative feedback regulatory effect on T cell-mediated signal transduction pathway.Therefore, the compounds of the present invention can be used as antitumor agents in the treatment of cancer or non-cancerous proliferative diseases. Further, HPK1-mediated diseases include, but are not limited to, lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, breast cancer, ductal 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 organ 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, colon villous adenoma, melanoma, carcinoma and sarcoma, and myelodysplastic syndrome.

[0162] The present invention also provides 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 the present invention, a pharmaceutically acceptable salt thereof, or a composition containing a compound according to the present invention. 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, ductal 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 organ cancer, intraepithelial carcinoma, 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, carcinoma and sarcoma, and myelodysplastic syndrome.

[0163] The present invention also provides a method for treating a cancer patient, comprising administering to the patient an effective amount of a compound of the present invention (e.g., a compound of general formula (I)) or a pharmaceutically acceptable salt or stereoisomer thereof.

[0164] definition The compounds described in this invention are named according to their chemical structure. If the name of a compound is incompatible with the chemical structure when describing the same compound, the chemical structure shall prevail.

[0165] In the present invention, unless otherwise specified, scientific and technical terms used herein have the meanings that are commonly understood by those skilled in the art. In order to better understand the present invention, the definitions of some terms are provided below. If the definitions and interpretations of terms described herein differ from those that are commonly understood by those skilled in the art, the definitions and explanations of terms described herein shall prevail.

[0166] As used herein (including the described embodiments), singular forms such as "a," "an," and "the" are intended to include plural referents unless the context clearly dictates otherwise.

[0167] The term "or" is used to mean, and is used interchangeably with, the term "and / or," unless context clearly dictates otherwise.

[0168] The terms "optional," "optionally," or "optional" mean that the event or circumstance described thereafter may occur, but does not necessarily occur, and that the description includes cases where the event or circumstance occurs and cases where the event or circumstance does not occur.

[0169] The term "substituted" means that any one or more hydrogen atoms on a particular atom may be 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. If the substituent is oxo (i.e., =O), this means that two hydrogen atoms are replaced. Oxo substitution does not occur in aromatic groups. The term "optionally substituted" means substituted or unsubstituted. Unless otherwise specified, the type and number of substituents may be any based on chemically achievable criteria.

[0170] The term "alkyl" refers to a hydrocarbon group selected from linear or 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.

[0171] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0172] The term "haloalkyl" refers to an alkyl group in which one or more hydrogens have been replaced by one or more halogen atoms (such as fluorine, chlorine, bromine, and iodine). Examples of haloalkyl include C 1-8 Haloalkyl, C 1-6 Haloalkyl or C1-4 Haloalkyl includes, but is not limited to, -CF3, -CH2Cl, -CH2CF3, -CHCl2, and the like.

[0173] The term "alkenyl" refers to a hydrocarbon group selected from straight-chain and branched hydrocarbon groups containing at least one C=C double bond and 2 to 18 (e.g., 2 to 8, further e.g., 2 to 6) carbon atoms.

[0174] The term "alkynyl" refers to a hydrocarbon radical selected from straight-chain and branched hydrocarbon groups containing at least one C≡C triple bond and 2 to 18 (e.g., 2 to 8, or even 2 to 6) carbon atoms.

[0175] The term "alkyloxy" or "alkoxy" means 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 include, but are not limited to, methoxy, ethoxy, isopropoxy, propoxy, n-butoxy, tert-butoxy, pentyloxy, hexyloxy, and the like.

[0176] The term "alkoxy-alkyl-" refers to an alkyl group as defined above that is substituted by 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.

[0177] The term "cycloalkyl" refers to a hydrocarbon group selected from saturated cyclic hydrocarbon groups, including monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups. Fused, bridged, or spiro-cycloalkyl groups are also included.

[0178] For example, cycloalkyl can contain 3 to 12 (e.g., 3 to 10, further 3 to 8, further 3 to 6, 3 to 5, 3 to 4) carbon atoms. Further, for example, cycloalkyl can be selected from monocyclic groups containing 3 to 12 (e.g., 3 to 10, further 3 to 8, 3 to 6) carbon atoms. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl. In particular, saturated monocyclic cycloalkyl (e.g., C 3-8 Cycloalkyl) includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0179] The term "spiro-cycloalkyl" refers to a cyclic structure containing carbon atoms and formed from at least two rings that share one atom. For example, a 7-12 membered spiro-cycloalkyl refers to a cyclic structure containing 7-12 carbon atoms and formed from at least two rings that share one atom.

[0180] The term "fused cycloalkyl" refers to a fused ring formed from two or more rings containing carbon atoms and sharing two adjacent atoms. For example, a 4- to 10-membered fused cycloalkyl refers to a fused ring formed from two or more rings containing 4 to 10 ring carbon atoms and sharing two adjacent atoms.

[0181] The term "bridged cycloalkyl" refers to a cyclic structure formed by two rings containing carbon atoms and sharing two non-adjacent atoms. For example, a 7-10 membered bridged cycloalkyl refers to a cyclic structure formed by two rings containing 7-12 carbon atoms and sharing two non-adjacent atoms.

[0182] The term "cycloalkenyl" refers to a non-aromatic cyclic alkyl of 3 to 10 carbon atoms having one or more rings and at least one double bond, preferably one to two double bonds. In one embodiment, cycloalkenyl is cyclopentenyl (1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl) or cyclohexenyl (1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl), preferably cyclohexenyl.

[0183] The term "cycloalkynyl" refers to a non-aromatic cycloalkyl group of from 5 to 10 carbon atoms having single or multiple rings and at least one triple bond.

[0184] The term "aryl", used alone or in combination with other terms, refers to a group selected from the groups set forth below. - 5-6 membered carbocyclic aromatic rings, for example phenyl; bicyclic ring systems, for example 7-12 membered bicyclic ring systems in which at least one ring is carbocyclic and aromatic, for example naphthyl and indanyl; and - Tricyclic ring systems, for example 10-15 membered tricyclic ring systems in which at least one ring is carbocyclic and aromatic, for example fluorenyl.

[0185] The terms "aromatic hydrocarbon ring" and "aryl" can be used interchangeably herein. In some embodiments, the monocyclic or bicyclic aromatic hydrocarbon ring has 5 to 10 ring-forming carbon atoms (i.e., C 5-10 Aryl). Examples of monocyclic or bicyclic aromatic hydrocarbon rings include, but are not limited to, phenyl, naphthalene-1-yl, naphthalene-2-yl, anthracenyl, phenanthrenyl, etc. 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.

[0186] The term "heteroaryl" refers to a group selected from: - a 5-, 6-, or 7-membered aromatic monocyclic ring containing at least one heteroatom, e.g., 1 to 4 heteroatoms, or in some embodiments 1 to 3 heteroatoms, and in some embodiments 1 to 2 heteroatoms, where the heteroatoms are selected from nitrogen (N), sulfur (S), and oxygen (O), and the remaining ring atoms are carbon; - 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, where the heteroatoms are selected from N, O, and S, the remaining ring atoms are carbon, and at least one ring is aromatic, with at least one heteroatom being in the aromatic ring; and - an 11-14 membered tricyclic ring containing at least one heteroatom, e.g., 1-4 heteroatoms, or in some embodiments 1-3 heteroatoms, or in other embodiments 1 or 2 heteroatoms, wherein the heteroatoms are selected from N, O and S, the remaining ring atoms are carbon, at least one ring is aromatic, and at least one heteroatom is in the aromatic ring.

[0187] When the total number of S and O atoms in a heteroaryl exceeds 1, the heteroatoms are not adjacent to each other. In some embodiments, the total number of S and O atoms in a heteroaryl is 2 or less. In some embodiments, the total number of S and O atoms in an aromatic heterocycle is 1 or less. When a heteroaryl contains one or more heteroatoms as ring members, the heteroatoms may be the same or different. Nitrogen atoms contained in one or more rings of a heteroaryl may be oxidized to form an N-oxide. As used herein, the term "C-linked heteroaryl" means that a heteroaryl is attached to a core molecule via a bond from a C atom of the heteroaryl ring.

[0188] The term "heteroaryl" refers, in some embodiments, to a monocyclic or bicyclic aromatic heterocycle having 5, 6, 7, 8, 9, or 10 ring members, wherein 1, 2, 3, or 4 heteroatoms as 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 containing 1 or 2 heteroatoms independently selected from nitrogen (N), sulfur (S), and oxygen (O) as ring members. In some embodiments, the monocyclic or bicyclic aromatic heterocycle is a monocyclic 5- to 6-membered heteroaryl ring having 1 or 2 heteroatoms independently selected from nitrogen (N), sulfur (S), and oxygen (O) as ring members. In some embodiments, the monocyclic or bicyclic aromatic heterocyclic ring is a bicyclic 8- to 10-membered heteroaryl ring having 1 or 2 heteroatoms independently selected from nitrogen, sulfur, and oxygen as ring members.

[0189] The terms "heterocyclyl," "heterocycle," or "heterocyclic" are interchangeable and refer to non-aromatic heterocyclyls 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 spiro rings, i.e., monocyclic heterocyclyls, bridged heterocyclyls, spiro-heterocyclyls, and fused heterocyclyls. As used herein, the term "optionally oxidized sulfur" refers to S, SO, or SO.

[0190] The term "monocyclic heterocyclyl" refers to a monocyclic group in which at least one ring member is a heteroatom selected from nitrogen, oxygen, or optionally oxidized sulfur. The heterocycle may be saturated or partially saturated.

[0191] Representative examples of typical monocyclic 4- to 10-membered heterocyclyls include, but are not limited to, the following groups: [ka] [wherein the wavy line indicates the point of attachment].

[0192] The term "spiro-heterocyclyl" refers to a 5- to 20-membered polycyclic heterocyclyl having rings joined by a common carbon atom (referred to as the spiroatom), containing one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, with the remaining ring members being carbon. One or more rings of a spiro-heterocyclyl may contain one or more double bonds, but no ring has a completely conjugated pi-electron system. Preferably, a spiro-heterocyclyl group has 6 to 14 members, more preferably 7 to 12 members. Spiro-heterocyclyl is classified into monospiro-heterocyclyl, dispiro-heterocyclyl or polyspiro-heterocyclyl groups depending on the number of shared spiro-atoms, and preferably means a monospiro-heterocyclyl or dispiro-heterocyclyl group, more preferably a 4-membered / 4-membered, 3-membered / 5-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered or 5-membered / 6-membered monospiro-heterocyclyl group.

[0193] The term "fused heterocyclyl" refers to a 5- to 20-membered polycyclic heterocyclyl in which each ring in the ring system shares an adjacent pair of atoms (carbon atom-carbon atom or carbon atom-nitrogen atom) with another ring, contains one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur, and the remaining ring members are carbon. One or more rings in the fused heterocyclyl may contain one or more double bonds, but none of the rings has a completely conjugated π-electron system. Preferably, the fused heterocyclyl has 6 to 14 members, preferably 7 to 12 members, and more preferably 7 to 10 members. Depending on the number of ring members, the fused heterocyclyl is classified as a bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclyl group, and preferably refers to a bicyclic or tricyclic fused heterocyclyl group, and more preferably refers to a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclyl group.

[0194] The term "bridged heterocyclyl" or "bridged heterocyclyl" refers to a 5- to 14-membered polycyclic heterocyclyl in which two rings in the ring system share two non-adjacent atoms, and which contains one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, with the remaining ring members being carbon. One or more rings of a bridged heterocyclyl may contain one or more double bonds, but none of the rings has a completely conjugated π-electron system. Preferably, the bridged heterocyclyl has 6 to 14 members, more preferably 7 to 10 members. Depending on the number of ring members, the bridged heterocyclyl is classified as a bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclyl group, and preferably means a bicyclic, tricyclic, or tetracyclic bridged heterocyclyl group, and more preferably means a bicyclic or tricyclic bridged heterocyclyl group.

[0195] The term "alkylene" means a divalent alkyl, as defined above, having 1 to 18 carbon atoms (C 1-18) which may be optionally substituted independently with one or more substituents described below. In another embodiment, alkylene refers to a saturated linear or branched divalent hydrocarbon group having a length of 1 to 8 carbon atoms (C 1-8 ) or 1 to 6 carbon atoms (C 1-6 Examples of alkylene include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), and propylene (-CH2CH2CH2-).

[0196] The term "alkenylene" means a divalent alkenyl, as defined above, having 2 to 8 carbon atoms (C 2-8 "(Cis)" refers to a linear or branched divalent hydrocarbon group having a length of 0.5 to 1.5 mm, optionally substituted independently with one or more substituents described herein, including groups having "cis" and "trans" orientations, or alternatively, "E" and "Z" orientations. Examples include, but are not limited to, vinylidene (-CH=CH-), allylidene (-CHCH=CH-), and the like.

[0197] The term "alkynylene" means a divalent alkynyl, as defined above, having 3 to 8 carbon atoms (C) with at least one site of unsaturation, i.e., a carbon-carbon sp triple bond. 3-8 ) optionally substituted with one or more substituents described herein. Examples include, but are not limited to, propynylene (propargylidene, —CHC≡C—).

[0198] The term "cycloalkylene" means a divalent cycloalkyl as defined above. The term "heterocyclylene" means a divalent heterocyclyl as defined above. The term "arylene" means a divalent aryl as defined above. The term "heteroarylene" means a divalent heteroarylene as defined above.

[0199] The compounds disclosed herein may contain asymmetric centers and therefore can exist as enantiomers. "Enantiomer" refers to two stereoisomers of a compound that are non-superimposable mirror images of one another. When the compounds disclosed herein have two or more asymmetric centers, they can also exist as diastereomers. Enantiomers and diastereomers are broad categories of stereoisomers. All such possible stereoisomers are intended to be included, including substantially pure resolved enantiomers, racemic mixtures thereof, and mixtures of diastereomers. All stereoisomers of the compounds disclosed herein and / or their pharmaceutically acceptable salts are intended to be included. Unless otherwise specified, a reference to one isomer applies to all possible isomers. If the isomeric composition is not specified, all possible isomers are included.

[0200] As used herein, the term "substantially pure" means that the desired stereoisomer contains no more than 35% (e.g., no more than 30%, even no more than 25%, or even no more than 20%) of other stereoisomers by weight. In some embodiments, "substantially pure" means that the desired stereoisomer contains no more than 10% (e.g., no more than 5%, or even no more than 1%) of other stereoisomers by weight.

[0201] When compounds disclosed herein contain olefinic double bonds, unless otherwise specified, such double bond is intended to include both E and Z geometric isomers.

[0202] When the compounds disclosed herein contain a disubstituted cyclohexyl or cyclobutyl, the substituents found on the cyclohexyl or cyclobutyl ring can be in both cis and trans configurations, where cis means that the two substituents are both above the two substitution positions on the carbon atom, and trans means that they are on opposite sides.

[0203] "Pharmaceutically acceptable salt" means a salt that may be used, within the scope of reasonable medical judgment, in contact with the tissues of humans and lower animals, without undue toxicity, irritation, allergic response, etc., 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 function with a suitable organic acid, or by reacting an acidic group with a suitable base.

[0204] Also, if a compound disclosed herein is obtained as an acid addition salt, the free base can be obtained by basifying 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 prepared by dissolving the free base in a suitable organic solvent and / or water and treating the solution with an acid, following conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize, without undue experimentation, a variety of synthetic methods that can be used to prepare non-toxic, pharmaceutically acceptable addition salts.

[0205] As defined herein, "a pharmaceutically acceptable salt thereof" includes at least one salt of a compound of formula (I), a salt of a stereoisomer of a compound of formula (I), such as a salt of an enantiomeric and / or a salt of a diastereomeric form.

[0206] Unless otherwise specified, when a group has one or more bondable sites, any one or more of the sites on the group may be bonded to other groups by chemical bonds. If the type of chemical bond is undefined and an H atom is present at a bondable site, when a chemical bond is formed at that site, the number of H atoms decreases as a function of the number of bonded chemical bonds, resulting in a group with the corresponding valence. The chemical bond connecting the site to another group is represented by a straight solid bond. [ka] or wavy line [ka] For example, the straight solid bond in -OCH3 indicates that this group is bonded to another group through its oxygen atom; [ka] The wavy lines in the figure indicate that the phenyl group is bonded to other groups via the carbon atoms at positions #1 and ##1.

[0207] The terms "administration," "administering," "treating," and "treatment," when applied to an animal, human, experimental subject, cell, tissue, organ, or bodily fluid, refer to contacting an exogenous agent, therapeutic agent, diagnostic agent, or composition with the animal, human, subject, cell, tissue, organ, or bodily fluid. Treatment of a cell includes contacting a reagent with the cell and contacting a reagent with a fluid, where the fluid is contacted with the cell. The terms "administering" and "treating" also refer to in vitro and ex vivo treatments of a cell, for example, with a reagent, diagnostic agent, binding compound, or another cell. As used herein, the term "subject" includes any organism, preferably an animal, more preferably a mammal (rat, mouse, dog, cat, rabbit, etc.), and most preferably a human.

[0208] The term "effective amount" or "therapeutically effective amount" means the amount of an active ingredient (such as a compound) that, 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 for the disease, disorder, or symptom.

[0209] The term "disease" means any disease, illness, condition, symptom or indication, and is interchangeable with the terms "condition" or "disorder."

[0210] Throughout this specification and the embodiments that follow, unless the context requires otherwise, the word "comprise" and variations such as "comprises" and "comprising" are intended to indicate the presence of the feature that follows it, but do not exclude the presence or addition of one or more other features. As used herein, the word "comprising" can be replaced with the words "containing," "including," or in some cases, "having."

[0211] Throughout this specification and the following embodiments, the term "C n-m " indicates a range inclusive of the endpoints, where n and m are integers and indicate the number of carbons. Examples include C 1-8 , C 1-6 And so on.

[0212] Unless expressly defined elsewhere herein, all other technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention pertains.

[0213] Compound identification and characterization

[0214] The Examples provide corresponding data for the preparation and structural identification of representative compounds of formula (I). 1 H NMR spectra were obtained on a Bruker instrument (400 MHz) and chemical shifts are reported in ppm. Tetramethylsilane (0.00 ppm) was used as the internal standard. 1 H NMR notation: s = singlet, d = doublet, t = triplet, m = multiplet, br = broad, dd = doublet of doublets, dt = doublet of triplets. Coupling constants, when given, are reported in Hz.

[0215] Mass spectra were measured using an LC / MS instrument, with the ionization mode being ESI or APCI. Unless otherwise indicated, the test methods are as follows: [Table 4]

[0216] The silica gel plates used for thin layer chromatography were thin layer chromatography (TLC) silica gel plates from Yantai HUANGHAI HSGF254 or Qingdao GF254.

[0217] The silica gel plate used had a size of 0.15 mm to 0.2 mm, and the size for separating and purifying the product by thin-layer chromatography was 0.4 mm to 0.5 mm. For column chromatography, silica gel with a mesh size of 200 to 300 mesh from Yantai Huanghai Silica Gel was generally used as the carrier.

[0218] In the following examples, all temperatures are in degrees Celsius unless otherwise specified. Unless otherwise indicated, the various starting materials and reagents were either commercially available or synthesized according to known methods and were used without further purification. Unless otherwise specified, commercial suppliers include, but are not limited to, Aldrich Chemical Company, ABCR GmbH & Co. KG, Acros Organics, Shanghai Bide Pharmaceutical Technology Co., Ltd, and Shanghai Shaoyuan Reagent Co., Ltd, from which materials and reagents can be purchased.

[0219] DMSO-d6: Deuterated dimethyl sulfoxide

[0220] DIEA: N,N-diisopropylethylamine Rt: retention time

[0221] Unless otherwise specified in the examples, the solutions in the reactions are aqueous solutions.

[0222] The compounds were purified using eluent systems for column chromatography and thin-layer chromatography selected from the following: A: petroleum ether and ethyl acetate; B: dichloromethane and methanol; C: dichloromethane and ethyl acetate; D: dichloromethane and ethanol (the volume ratio of the solvents varies depending on the polarity of the compounds). In addition, a small amount of acidic or basic reagent, such as acetic acid or triethylamine, can be added for adjustment.

[0223] Biological assays The pharmacological properties of the compounds of this invention can be confirmed by a number of biological assays. The following exemplary biological assays have been carried out with the compounds of the invention.

[0224] Experimental Example 1. Assay of HPK1 enzyme activity in vitro IC to measure kinase activity using the ADP-Glo ​​method 50 The human HPK1 inhibitory ability of the compounds was evaluated by the measurement.

[0225] Enzyme buffer conditions: 50 mM Hepes (pH 7.5), 10 mM MgCl2, 1 mM EGTA, 0.01% Brij35, 2 mM DTT.

[0226] Preparation of kinase and substrate mixture: The working concentration of kinase in the HPK1 reaction solution was 7 nM and the working concentration of ATP was 20 uM.

[0227] Test Procedure Compounds were diluted in DMSO in a dilution plate to give a maximum starting concentration of 1 uM with a 10-step concentration gradient of 4-fold dilutions.

[0228] Each of the 10-step compound gradients was then diluted 50-fold in the kinase reaction buffer and shaken for 20 minutes. The kinase was prepared in enzyme reaction buffer, and 2 μl of HPK1 kinase was added per well of the reaction plate at a concentration of 7 nM.

[0229] 1 μL of compound diluted in buffer was added to each well, sealed with plate sealing film, centrifuged at 1000 g for 30 seconds, and left at room temperature for 10 minutes. ATP solution was prepared in enzyme reaction buffer, and 2 μL of this ATP solution was added to the reaction plate (ATP working concentration: 20 μM). The plate was sealed with plate sealing film, centrifuged at 1000 g for 30 seconds, and left at room temperature for 60 minutes. 4 μL of ADP-Glu was transferred to a 384-well reaction plate, centrifuged at 1000 rpm / min for 1 minute, and incubated at 25°C for 40 minutes. 8 μL of detection solution was transferred to a 384-well reaction plate, centrifuged at 1000 rpm / min for 1 minute, and incubated at 25°C for 40 minutes. RLU (relative luminescence units) signals were read using a BMG microplate reader, and the signal intensity was used to assess the kinase activity level.

[0230] Kinase activity data are presented comparing the kinase activity of test compounds with that of a blank group (containing only DMSO) and are expressed as IC 50 The values ​​were obtained by curve fitting using Prism software (GraphPad 7.0).

[0231] The following table shows the HPK1 IC of compounds of the present invention. 50 Indicates the value. [Table 5]

[0232] All of the compounds of the present invention have an HPK1 IC 50 The HPK1 IC value was 60 nM or less, and most of the compounds of the present invention 50The values ​​were 20 nM or less, which indicates that all of the compounds of the present invention have excellent inhibitory activity against HPK1 and have excellent applicability in the treatment of HPK1-mediated diseases.

[0233] Experimental Example 2. IL2 activity assay The EC50 values ​​of IL2 activation in human PBMCs were measured by ELISA to evaluate the T cell activation ability of the compounds.

[0234] (1) Pretreatment of the 96-well plate of the IL2 kit: 5 μg / ml of CD3 antibody was applied at 100 μl per well and allowed to react overnight at 4°C. (2) PBMC cells (10 5 Compounds (10 μM / well) were seeded into a 96-well plate. The compounds were diluted in DMSO in a dilution plate (maximum starting concentration 10 μM, 8-step concentration gradient (3-fold dilution)) and then added to the 96-well plate together with 5 μg / ml of CD28 antibody. The mixture was incubated for 24 hours. (3) The ELISA plate was washed twice with PBS, and 100 μl of ELISA diluent was added to each well. Then, 100 μl of the standard solution and the incubated sample obtained in step 2 were added, and the plate was incubated at room temperature for 2 hours. (4) Each well was washed three times with 400 μL of washing buffer, and finally wiped dry with clean absorbent paper. (5) 200 μL of IL2 conjugate was added to each well, covered with new tape, and incubated at room temperature for 2 hours. Step (4) was then repeated. (6) In the dark, 200 μL of substrate was added to each well, and the plate was incubated at room temperature for 20 minutes. (7) 50 μL of stop solution was added to each well. The color of the wells should change from blue to yellow. The signal at 450 nM was read using a microplate reader, and the signal intensity was used to evaluate the activity level of IL2. The EC50 value was obtained by fitting using Prism software.

[0235] The following table shows that the compounds of the present invention have the effect of inducing IL2 production. [Table 6]

[0236] Experimental Example 3. HPK1 protein degradation assay The in vitro degradation ability of the compounds was evaluated by measuring the degree of HPK1 protein degradation and DC50 / Dmax by the WB method.

[0237] The RAMOS cell line was selected as the degradation cell line. Culture conditions: RPMI 1640 medium supplemented with 10% FBS, 37°C, 5% CO2.

[0238] Testing Procedure: (1) Cell seeding: Add 4 ml of culture medium to a 6 cm dish and seed 2 x 10 6 / Sown in dishes. (2) Drug addition: Compounds (stock concentration: 10 mM) were diluted with DMSO in a dilution plate (maximum starting concentration 10 μM, 7-step concentration gradient (3-fold dilution)). 4 μl of each diluted solution was added to the dish and incubated for 16 hours. (3) Cells were harvested, lysis buffer was added, and the mixture was centrifuged at 12,000 rpm for 20 minutes. The supernatant was collected and quantified using a BCA quantification kit. Then, 5x loading buffer was added and the cells were denatured for 10 minutes. (4) 10 μg of denatured protein was applied to an SDS-PAGE gel. After electrophoresis and membrane transfer, the plate was blocked with 5% BSA for 1 hour, and the primary antibody was added and incubated overnight at 4°C. After washing out the primary antibody, the secondary antibody was added, incubated at room temperature for 1 hour, and then washed out.

[0239] Imaging: Membranes were scanned using a two-color fluorescent imaging system. Western blot results were quantified using Image J software, and DC50 and Dmax were calculated compared to the control.

[0240] The following table shows the degradation activity of the compounds of the present invention against HPK1. [Table 7]

[0241] The compounds of the present invention have excellent ability to degrade HPK1 protein.

[0242] Experimental Example 4. Examination of pharmacokinetic properties Female Balb / c mice (18-22 g body weight) were fasted overnight before the experiment. Test compounds were dissolved in a solvent mixture of DMSO:PEG400:30% captisol:HCl (5:20:70:5 v / v / v / v) and administered orally at a single dose of 10 mg / kg or intravenously at a dose of 2 mg / kg. Blood samples were collected from the retro-orbital venous plexus at 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration. Approximately 0.08 mL of blood was collected at each time point and placed in a 1.5 mL centrifuge tube containing EDTA-2K anticoagulant. Blood samples were centrifuged (3200 g, 10 min, 4°C) within 2 h, and plasma samples were collected. Plasma samples were frozen at -70°C to -80°C in an ultra-low temperature freezer before processing. Plasma samples were removed from the freezer before sample processing. After thawing at room temperature, 20 μL of each plasma sample was added to a 96-well plate, and 120 μL of acetonitrile containing an internal standard was added to precipitate proteins. After vortex mixing, the samples were centrifuged at 4950 g for 15 minutes at 4°C. The supernatant was collected, mixed with an equal volume of 0.1% aqueous formic acid, and subjected to LC-MS / MS analysis.

[0243] SD rats (half male and half female) weighing approximately 220 g were fasted overnight before the experiment. The compounds of the present invention were prepared in a solvent of DMSO:PEG400:30% captisol:HCl = 5:20:70:5 (v / v / v / v). The rats were intravenously administered a single dose of 2 mg / mL of the compounds of the present invention at a volume of 2 mL / kg, and orally administered a single dose of 5 mg / kg, 2 mg / kg, and 1 mg / kg at a volume of 10 mL / kg.

[0244] Blood samples were collected from the retro-orbital venous plexus pre-dose and at 0.083 (intravenous administration only), 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours post-dose. Approximately 0.150 mL of blood was collected at each time point and placed in a 1.5 mL centrifuge tube containing EDTA-2K anticoagulant. Within 1 hour, blood samples were centrifuged (3200 g, 10 min, 4°C) to obtain plasma samples. Plasma samples were frozen at -70°C to -80°C in an ultra-low temperature freezer before processing. Plasma samples were removed from the freezer before sample processing. After thawing at room temperature, 20 μL of each plasma sample was dispensed into a 96-well plate, and 120 μL of acetonitrile containing an internal standard was added to precipitate proteins. After vortex mixing, the samples were centrifuged at 4700 g for 15 minutes at 4°C. The supernatant was collected, mixed with an equal volume of 0.1% aqueous formic acid solution, and subjected to LC-MS / MS analysis.

[0245] The pharmacokinetic results of a single dose in mice are shown in the table below. [Table 8]

[0246] The results show that the compounds of the present invention showed good exposure (AUC) when administered orally and intravenously, and had good oral half-life and oral bioavailability.

[0247] Preparation example The present invention will be described in more detail in conjunction with specific examples, but these examples do not limit the scope of the present invention. The following examples are used to understand the method and core concept of the present invention. Any modifications or substitutions that those skilled in the art can make without departing from the concept of the present invention are intended to fall within the scope of protection of the present invention. In the examples of the present invention, for experimental methods for which specific conditions are not specified, conventional conditions or conditions recommended by manufacturers of raw materials or products are generally used. For reagents for which the source of supply is not specified, conventional reagents that can be purchased through commercial channels are generally used.

[0248] Synthesis of intermediates Preparation of intermediate warhead 3 [ka]

[0249] Step 1: Preparation of Intermediate 2 Compound 1 (10 g, 30.8 mmol) was dissolved in tetrahydrofuran (100 mL). NaH (1.8 g, 46.2 mmol) was added at 0°C, and the mixture was stirred at 0°C under nitrogen protection for 0.5 hours. Then, benzenesulfonyl chloride (8 g, 46.2 mmol) was added to an ice bath, and the mixture was allowed to warm to room temperature and stirred for 3 hours. After the reaction was completed, the reaction solution was poured into ice water and filtered to obtain compound 2. LCMS (ESI) m / z: 464.2 [M+H] + .

[0250] Step 2: Preparation of Intermediate 3 Compound 2 (1.0 g, 2.15 mmol) and compound 1 (0.975 g, 2.585 mmol) were dissolved in dioxane (22 mL). Potassium carbonate (0.595 g, 4.305 mmol) was dissolved in water (7.5 mL) and mixed with the above solution. Pd(dppf)Cl2·CHCl2 (315 mg, 0.43 mmol) was added. The mixture was stirred at 80 °C under nitrogen protection for 1 hour. LCMS showed that no starting material remained. The reaction solution was cooled to room temperature and extracted three times with dichloromethane. The organic layers were combined and washed twice with saturated brine. The organic phase was dried over sodium sulfate and filtered. The filtrate was concentrated. The crude product was purified by column chromatography to give intermediate 3. LCMS (ESI) m / z: 589.2 [M+H] + .

[0251] Step 3: Preparation of Intermediate 4 Compound 3 (7 g, 11.9 mmol) was dissolved in 4 M hydrochloric acid solution in dioxane (70 mL), and the reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, the solvent was directly evaporated to dryness to obtain the crude product. The crude product was washed with ether to obtain intermediate 4. LCMS (ESI) m / z: 488.9 [M+H] + .

[0252] Step 4: Preparation of intermediate warhead 3 Compound 4 (3.5 g, 6.68 mmol) was dissolved in a mixed solvent of acetonitrile (140 mL) and dioxane (36 mL), followed by the sequential addition of acetaldehyde (2.64 mL, 13.36 mmol) and acetic acid (0.38 mL, 6.68 mmol). The reaction solution was stirred at room temperature for 1 hour. Sodium cyanoborohydride (1470 mg, 23.38 mmol) was then added at room temperature. The mixture was stirred at 40 °C for an additional 4 hours, and the above procedure was repeated with continued stirring at 40 °C for an additional 12 hours. After the reaction was complete, the mixture was adjusted to pH 14 with aqueous ammonia. After extraction with dichloromethane, the organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain the crude product. The crude product was purified by column chromatography to obtain intermediate warhead 3, which was dissolved by adding DCM followed by the addition of aqueous ammonia. The organic phase was separated and concentrated. LCMS (ESI) m / z: 515.0 [M+H] + .

[0253] Example 1: Preparation of Compound C001 [ka]

[0254] Step 1: 2,5-Dibromo-3-methylpyridine (5 g, 20.1 mmol), 1-tert-butoxycarbonylpiperazine (5.6 g, 30.1 mmol), and K2CO3 (8.3 g, 60.2 mmol) were dissolved in dimethyl sulfoxide (50 mL), and the mixture was stirred at 120 °C for 36 hours. LCMS showed partial conversion of the reaction, and the product was detected. The reaction solution was cooled to room temperature, quenched by adding water (100 mL), and extracted with ethyl acetate (30 mL * 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by silica gel chromatography to give compound 001a. LCMS: [M+H] + =356.2.

[0255] Step 2: Compound 001a (2.8 g, 7.89 mmol), bis(pinacolato)diboron (3 g, 11.83 mmol), potassium acetate (2.32 g, 23.66 mmol), and Pd(dppf)Cl2 (576 mg, 0.789 mmol) were dissolved in dimethyl sulfoxide (30 mL), and the mixture was stirred at 80 °C under a nitrogen atmosphere for 2 hours. LCMS showed complete conversion of the reaction, and the product was detected. The reaction solution was cooled to room temperature and quenched by adding water (100 mL), followed by extraction with ethyl acetate (30 mL * 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography to give compound 001b. LCMS: [M+H] + =322.4.

[0256] Step 3: Warhead 3 (200 mg, 0.623 mmol), compound 001b (287 mg, 0.623 mmol), potassium carbonate (258 mg, 1.87 mmol), and Brettphos-Pd-G3 (56 mg, 0.0623 mmol) were dissolved in dimethyl sulfoxide (2 mL). The mixture was stirred overnight at 100° C. under a nitrogen atmosphere. LCMS showed complete conversion of the reaction, and the product was detected. The reaction solution was cooled to room temperature, quenched by adding water (50 mL), and extracted with ethyl acetate (30 mL*2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography to give compound 001c. LCMS: [M+H] + =702.5.

[0257] Step 4: Compound 001c (250 mg, 0.357 mmol) was dissolved in a solution of hydrochloric acid in dioxane (5 mL, 4 M) and stirred overnight at room temperature. LCMS showed complete conversion of the reaction, and the product was detected. The reaction solution was distilled under reduced pressure to give crude product 001d. LCMS: [M+H] + =472.2.

[0258] Step 5: Compound 001d (16 mg, 0.028 mmol), 001e (9 mg, 0.036 mmol), HATU (16 mg, 0.042 mmol), and N,N-diisopropylethylamine (15 mg, 0.112 mmol) were dissolved in dimethyl sulfoxide (2 mL) at room temperature, and the reaction solution was stirred at room temperature overnight. LCMS showed complete conversion of the reaction, and the product was detected. The reaction solution was quenched by adding water (50 mL) and extracted with dichloromethane (30 mL * 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a residue. The residue was purified by pre-TLC to give compound C001. LCMS: Rt=2.190 min; LCMS: [M+H] + =688.4.

[0259] Example 2: Preparation of Compound C002 [ka] Compound 002a (35 mg, 0.062 mmol), 002b (19 mg, 0.081 mmol), DIEA (32 mg, 0.248 mmol), and HATU (30.3 mg, 0.08 mmol) were dissolved in dimethyl sulfoxide (2 mL), and the mixture was stirred at room temperature for 16 hours. LCMS showed complete conversion of the reaction, and the product was detected. The reaction solution was cooled to room temperature, quenched by adding water (50 mL), and extracted with dichloromethane (30 mL * 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain the crude product. The crude product was purified by pre-TLC to obtain compound C002. LCMS: Rt=2.099 min; [M+H] + =785.3.

[0260] Example 3: Preparation of Compound C003 [ka] Compound 003a (33 mg, 0.058 mmol), 003b (21 mg, 0.075 mmol), DIEA (30 mg, 0.232 mmol), and HATU (29 mg, 0.075 mmol) were dissolved in dimethyl sulfoxide (2 mL), and the mixture was stirred at room temperature for 16 hours. LCMS showed that the reaction was completely converted, and the product was detected. The reaction solution was cooled to room temperature, quenched by adding water (50 mL), and extracted with dichloromethane (30 mL * 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain the crude product. The crude product was purified by pre-TLC to obtain compound C003. LCMS: [M+H] + =819.3.

[0261] Example 4: Preparation of Compound C004 [ka]

[0262] Step 1: Compound 4a (500 mg, 2.63 mmol) and 4b (795 mg, 3.95 mmol) were dissolved in DMF (10 mL). NaH (210 mg, 5.26 mmol) was added in an ice bath and stirred at room temperature for 12 hours. TLC showed complete conversion of the starting material and the product was detected. 30 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL * 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography to give compound 4c.

[0263] Step 2: Compound 4c (970 mg, 2.61 mmol), B2Pin2 (1.33 g, 5.23 mmol), KOAc (770 mg, 7.84 mmol), and Pd(dppf)Cl2 (212 mg, 0.26 mmol) were dissolved in dioxane (20 mL) at room temperature, purged with nitrogen three times, heated to 80 °C, and stirred at this temperature for 3 h. TLC showed complete conversion of the starting material, and the product was detected. After the reaction was complete, the reaction solution was cooled to room temperature and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography to give compound 4d.

[0264] Step 3: Compound 4d (136 mg, 0.33 mmol), 4e (100 mg, 0.22 μmol), BrettPhos Pd G3 (20 mg, 22 μmol), and K2CO3 (90 mg, 0.65 mmol) were dissolved in DMSO / HO (4 mL / 0.8 mL) at room temperature, purged with nitrogen three times, and heated to 100 °C and stirred at this temperature for 12 h. LCMS showed complete conversion of the reaction, 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 and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by prep-TLC to give compound 4f.

[0265] Step 4: Compound 4f (123 mg, 75.8 μmol) was dissolved in DCM (3 mL). TFA (1 mL) was added with stirring, and stirring was continued at room temperature for 1 hour. LCMS showed complete conversion of the reaction and the product was detected. The reaction solution was distilled under reduced pressure. The crude product was dissolved in MeOH (3 mL), and methanolic ammonia solution (1 mL) was added with stirring, and stirring was continued at room temperature for 1 hour. LCMS showed complete conversion of the reaction and the product was detected. The reaction solution was distilled under reduced pressure to give crude compound 4g.

[0266] Step 5: Compound 4g (83 mg, 0.17 mmol), 4h (69 mg, 0.26 mmol), DIEA (67 mg, 0.51 mmol), and HATU (130 mg, 0.34 mmol) were dissolved in DMSO (2 mL). The mixture was stirred at room temperature for 12 hours. LCMS showed complete conversion of the reaction, and the product was detected. 30 mL of water was added to the reaction solution, and it was extracted with dichloromethane (20 mL * 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by prep-TLC to give the final product C004. LCMS: Rt = 1.918 min, [M+H] + = 737.4.

[0267] 1H NMR (500 MHz, DMSO-d6) δ 12.05 (d, J = 2.8 Hz, 1H), 10.52 (s, 1H), 8.85 (d, J = 2.1 Hz, 2H), 8.38 (d, J = 2.2 Hz, 2H), 8.12 (d, J = 2.7 Hz, 1H), 8.10 (s, 1H), 7.69 - 7.63 (m, 2H), 7.47 (dd, J = 8.2, 2.1 Hz, 1H), 5.43 (dt, J = 7.5, 3.7 Hz, 1H), 3.95 (d, J = 19.7 Hz, 1H), 3.78 (q, J = 9.4, 6.3 Hz, 1H), 3.64 (dt, J = 12.7, 6.4 Hz, 3H), 3.06 - 2.96 (m, 3H), 2.75 (q, J = 7.5, 6.7 Hz, 2H), 2.41 (d, J = 10.0 Hz, 2H), 2.30 (s, 3H), 2.04 (q, J = 14.0, 10.0 Hz, 8H), 1.80 (s, 2H), 1.23 (d, J = 3.6 Hz, 1H), 1.04 (t, J = 7.2 Hz, 3H).

[0268] Example 5: Preparation of Compound C005 [ka]

[0269] Step 1: Compound 5a (1 g, 11.48 mmol) and TEA (1.74 g, 17.22 mmol) were dissolved in DCM (20 mL). BocO (3.26 g, 14.92 mmol) was added in an ice bath and stirred at room temperature for 2 hours. TLC showed complete conversion of the starting material and the product was detected. The reaction solution was distilled under reduced pressure to obtain a residue. The residue was purified by column chromatography to obtain compound 5b.

[0270] Steps 2~6: Steps 2 to 6 were carried out according to the procedures described in Steps 1 to 5 of Example 4, except that compounds 4b and 4a in Step 1 of Example 4 were replaced with compounds 5b and 5c, respectively, and compound 4h in Step 5 of Example 4 was replaced with compound 5i, to give compound C005. LCMS: Rt = 1.773 min, [M+H] + = 689.4, purity = 98.77%.

[0271] 1 H NMR (500 MHz, DMSO-d6) δ 12.16 - 11.95 (m, 1H), 10.44 (d, J = 12.9 Hz, 1H), 8.98 - 8.72 (m, 2H), 8.48 - 8.33 (m, 2H), 8.17 - 8.04 (m, 2H), 7.59 (dd, J = 23.1, 8.2 Hz, 2H), 7.41 (dd, J = 20.2, 8.2 Hz, 2H), 5.65 (d, J = 49.4 Hz, 1H), 4.26 (s, 1H), 3.97 (ddd, J = 31.1, 12.8, 4.7 Hz, 1H), 3.83 (dt, J = 19.8, 6.6 Hz, 2H), 3.73 (dd, J = 9.7, 6.5 Hz, 2H), 3.65 - 3.53 (m, 1H), 3.01 (s, 2H), 2.71 (dt, J = 24.4, 6.6 Hz, 2H), 2.42 (s, 1H), 2.27 (d, J = 35.2 Hz, 3H), 2.05 (s, 5H), 1.05 (t, J = 7.2 Hz, 3H).

[0272] Example 6: Preparation of Compound C006 [ka]

[0273] Step 1: Compound 6a (500 mg, 24.00 mmol), 6b (922 mg, 48.00 mmol), and TEA (486 mg, 48.00 mmol) were dissolved in DMF (20 mL), heated to 100 °C, and stirred at this temperature for 12 hours. TLC showed complete conversion of the starting material, and the product was detected. 30 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL * 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to obtain a residue. The reaction solution was distilled under reduced pressure to obtain a residue. The residue was purified by column chromatography to obtain compound 6c.

[0274] Step 2: Compound 6d (500 mg, 2.63 mmol) and 6e (380 mg, 4.21 mmol) were dissolved in DMF (40 mL). NaH (632 mg, 15.80 mmol) was added in an ice bath and stirred at room temperature for 12 hours. TLC showed complete conversion of the starting material and the product was detected. 100 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL * 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to obtain a residue. The reaction solution was distilled under reduced pressure to obtain a residue. The residue was purified by column chromatography to obtain compound 6f.

[0275] Step 3: Compound 6f (430 mg, 1.65 mmol), B2Pin2 (840 mg, 3.31 mmol), KOAc (485 mg, 4.96 mmol), and Pd(dppf)Cl2 (134 mg, 0.16 mmol) were dissolved in dioxane (15 mL) at room temperature. The mixture was purged with nitrogen three times, heated to 80 °C, and stirred at this temperature for 3 h. TLC showed complete conversion of the starting material, and the product was detected. After the reaction was complete, the reaction solution was cooled to room temperature and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography to give compound 6g.

[0276] Step 4: Compound 6g (300 mg, 0.98 mmol), 6h (300 mg, 0.65 mmol), BrettPhos Pd G3 (59 mg, 65 μmol), and K2CO3 (270 mg, 1.95 mmol) were cooled to DMSO / HO (12 mL / 3 mL) at room temperature, purged with nitrogen three times, and heated to 100 °C and stirred at this temperature for 12 h. LCMS showed complete conversion of the reaction, and the product was detected. To the reaction solution, 30 mL of water and 3 mL of formic acid were added, and the mixture was extracted with dichloromethane (50 mL * 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography to give compound 6i.

[0277] Step 5: Compounds 6i (80 mg, 0.14 mmol) and 6j (65 mg, 0.20 mmol) were dissolved in TFA (5 mL) and stirred at room temperature for 1 hour. LCMS showed complete conversion of the reaction and the product was detected. The reaction solution was distilled under reduced pressure to give the crude product, which was dissolved in DMSO (2 mL). DIEA (53 mg, 0.41 mmol) and HATU (103 mg, 0.27 mmol) were added and stirred at room temperature for 2 hours. LCMS showed complete conversion of the reaction and the product was detected. The product was purified by preparative chromatography to give the final product C006. LCMS: Rt = 1.795 min, [M+H] + = 663.4, purity = 94.00%.

[0278] 1H NMR (500 MHz, DMSO-d6) δ 12.06 (d, J = 2.7 Hz, 1H), 10.77 (s, 1H), 9.72 (s, 1H), 8.86 (s, 1H), 8.81 (d, J = 2.3 Hz, 1H), 8.41 (dd, J = 2.5, 1.0 Hz, 1H), 8.39 (s, 1H), 8.16 (s, 1H), 8.13 (d, J = 2.7 Hz, 1H), 8.11 (d, J = 0.7 Hz, 1H), 7.36 - 7.28 (m, 2H), 6.64 (d, J = 9.0 Hz, 2H), 5.70 (d, J = 7.6 Hz, 1H), 4.99 (s, 2H), 4.44 - 4.22 (m, 2H), 3.16 (d, J = 11.6 Hz, 2H), 2.79 - 2.68 (m, 1H), 2.64 - 2.58 (m, 2H), 2.38 (s, 3H), 2.17 - 2.04 (m, 6H), 1.86 (qd, J = 12.2, 4.6 Hz, 1H), 1.10 (t, J = 7.2 Hz, 3H).

[0279] Example 7: Preparation of Compound C008 [ka] Compound C008 was obtained according to the method described in Steps 2 to 5 of Example 6, except that in Step 2 of Example 6, compound 6d and NaH were replaced with compound 8a and K2CO3, respectively, and the reaction temperature was set to 70 °C. LCMS: Rt = 1.741 min, [M+H] + = 667.4.

[0280] Example 8: Preparation of Compound C009 [ka]

[0281] Step 1: Compound 9a (1.0 g, 5.3 mmol), N-Boc-1,2-ethylenediamine (1.02 g, 6.38 mmol), and K2CO3 (1.47 g, 10.6 mmol) were dissolved in DMSO (20 mL) and reacted at 120 °C for 6 hours. TLC showed complete conversion of the starting material, and the product was detected. 100 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL * 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to obtain a residue. The reaction solution was distilled under reduced pressure to obtain a residue. The residue was purified by column chromatography (PE:EA = 5:1) to obtain compound 9b. [M+H] + =230.0.

[0282] Step 2: Compound 9b (0.5 g, 1.52 mmol), B2Pin2 (578.9 mg, 2.28 mmol), KOAc (447 mg, 4.56 mmol), and Pd(dppf)Cl2 (111 mg, 0.152 mmol) were dissolved in dioxane (5 mL) at room temperature. The mixture was purged with nitrogen three times, heated to 80 °C, and stirred at this temperature for 3 h. TLC showed complete conversion of the starting material, and the product was detected. After the reaction was complete, the reaction solution was cooled to room temperature and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography to give compound 9c. [M+H] + =378.0.

[0283] Step 3: Compound 9c (0.4 g, 1.06 mmol), warhead 3 (300 mg, 0.58 mmol), BrettPhos Pd G3 (60 mg, 66 μmol), and K2CO3 (270 mg, 1.98 mmol) were dissolved in DMSO / HO (4 mL / 1 mL) at room temperature, purged with nitrogen three times, and heated to 100 °C and stirred at this temperature for 12 h. LCMS showed complete conversion of the reaction, and the product was detected. 30 mL of water and 3 mL of formic acid were added to the reaction solution, followed by extraction with dichloromethane (50 mL * 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography to give compound 9d.

[0284] Step 4: Compound 9d was dissolved in 10 ml of HCl / dioxane and stirred at room temperature for 30 minutes to give crude compound 9e. [M+H] + =446.

[0285] Step 5: Compound 9e (130 mg, 0.29 mmol), 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoic acid (68 mg, 0.29 mmol), HATU (165 mg, 0.435 mmol), and DIEA (75 mg, 0.58 mmol) were dissolved in 10 ml of DMSO and reacted at room temperature for 1 hour. LCMS showed complete conversion of the reaction, and the product was detected. The product was purified by preparative chromatography to give the final product C009. [M+H] + =662.4, purity: 95.3%.

[0286] 1H NMR (400 MHz, MeOD) δ 8.75 (s, 1H), 8.59 (d, J = 12.9 Hz, 2H), 8.36 (s, 1H), 8.21 (s, 1H), 8.04 (s, 1H), 7.86 (s, 1H), 7.80 - 7.74 (m, 1H), 7.57 - 7.50 (m, 2H), 4.71 - 4.60 (m, 1H), 3.89 (t, J = 6.7 Hz, 2H), 3.77 (s, 6H), 3.30 - 3.14 (m, 4H), 2.80 (t, J = 6.7 Hz, 2H), 2.41 (d, J = 13.5 Hz, 7H), 1.40 (t, J = 7.3 Hz, 3H).

[0287] Example 9: Preparation of Compound C010 [ka]

[0288] Step 1: Compound 010a (10 g, 53 mmol) was dissolved in anhydrous THF (200 ml). LiHMDS (80.6 mL, 80.65 mmol) was added at 0°C and the mixture was allowed to react for 0.5 hours. 2-Fluoro-3-methyl-5-bromopyridine (10.07 g, 53 mmol) was then added to the reaction system and the mixture was allowed to react at room temperature for 3 hours. LCMS showed complete conversion of the reactant, and the product was detected. 100 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL * 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to obtain a residue. The reaction solution was distilled under reduced pressure to obtain a residue. The residue was purified by column chromatography to obtain compound 010b. [M+H] + =356.1.

[0289] Step 2: Compound 010b (3.0 g, 8.45 mmol), B2Pin2 (3.2 g, 12.67 mmol), KOAc (2.485 g, 25.3 mmol), and Pd(dppf)Cl2 (618 mg, 0.845 mmol) were dissolved in dioxane (30 mL) at room temperature, purged with nitrogen three times, heated to 110 °C, and stirred at this temperature for 3 hours. TLC showed complete conversion of the starting material, and the product was detected. After the reaction was complete, the reaction solution was cooled to room temperature and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography to give compound 010c. [M+H] + =404.0.

[0290] Step 3: Compound 010c (2.14 g, 5.3 mmol), Warhead 3 (2.72 g, 5.3 mmol), Pd(dppf)Cl2 (387 mg, 5.3 mmol), and K2CO3 (1.46 g, 10.6 mmol) were dissolved in DMSO / HO (20 mL / 5 mL) at room temperature, purged with nitrogen three times, and heated to 100 °C and stirred at this temperature for 12 h. LCMS showed complete conversion of the reaction, and the product was detected. 30 mL of water and 3 mL of formic acid were added to the reaction solution, followed by extraction with dichloromethane (50 mL * 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography to give compound 010d. [M+H] + =712.

[0291] Step 4: Compound 010d was dissolved in 20 ml of ethanol, followed by the addition of sodium hydroxide (60 mg, 1.4 mmol) and stirring at 50° C. for 15 minutes. LCMS showed complete conversion of the reaction, and the product was detected. The reaction solution was concentrated in vacuo to give crude compound 010e. [M+H] + =572.

[0292] Step 5: Compound 010e was dissolved in 10 ml of HCl / dioxane and stirred at room temperature for 30 minutes to give crude compound 010f. [M+H] +=472.

[0293] Step 6: Compound 010f (400 mg, 0.85 mmol), methyl 6-bromohexanoate (195 mg, 0.93 mmol), K2CO3 (586.5 mg, 4.25 mmol), and KI (705.5 mg, 4.25 mmol) were dissolved in ACN and reacted at 90 °C for 6 hours. LCMS showed complete conversion of the reactant, and the product was detected. 30 mL of water was added to the reaction solution, and it was extracted with dichloromethane (50 mL * 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to obtain a residue. Compound 010g was obtained by column chromatography.

[0294] Step 7: Compound 010g (200 mg, 0.33 mmol) and LiOH (79 mg, 3.3 mmol) were dissolved in a 10 ml system of 1:1 THF / HO and stirred at room temperature for 20 hours. LCMS showed complete conversion of the reaction, and the product was detected. The product was directly dried by rotary evaporation to give compound 010h. [M+H] + =586.

[0295] Step 8: Compound 010h (100 mg, 0.17 mmol), (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (90 mg, 0.34 mmol), HATU (130 mg, 0.75 mmol), and DIEA (122 mg, 0.044 mmol) were dissolved in DMF (2 ml) and reacted at room temperature for 2 hours. LCMS showed complete conversion of the reaction, and the product was detected. The product was purified by preparative chromatography to give the final product C010. LCMS: Rt=2.180 min; [M+H] + =998.7.

[0296] Example 10: Preparation of Compound C011 [ka]

[0297] Step 1: Compound 010f (400 mg, 0.85 mmol, prepared according to Steps 1 to 5 of Example 9) was dissolved in CAN (10 ml). Tert-butyl 3-(methanesulfonyloxymethyl)azetidine-1-carboxylate (226 mg, 0.85 mmol), DIEA (548 mg, 4.25 mmol), and KI (706 mg, 4.25 mmol) were added, and the reaction was carried out at 100 °C for 16 hours. LCMS showed complete conversion of the reaction product, and the product was detected. 30 mL of water was added to the reaction solution, and the mixture was extracted with dichloromethane (50 mL * 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give a residue. Compound 011g was obtained by column chromatography.

[0298] Step 2: Compound 011g was dissolved in 10 ml of HCl / dioxane and stirred at room temperature for 30 minutes to give crude compound 011h.

[0299] Step 3: Compound 011h (100 mg, 0.185 mmol) was dissolved in DMF (2 ml). 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoic acid (48 mg, 0.185 mmol), HATU (105 mg, 0.27 mmol), and DIEA (95 mg, 0.74 mmol) were added and the reaction was carried out at room temperature for 1 hour. LCMS showed complete conversion of the reaction product, and the product was detected. The product was purified by preparative chromatography to give C011.

[0300] Example 11: Preparation of Compound C017 [ka]

[0301] Step 1: Warhead 3 (167 mg, 0.142 mmol), 4-N-Boc-aminocyclohexanone (113 mg, 0.532 mmol), and acetic acid (21 mg, 0.142 mmol) were dissolved in dichloromethane / dimethyl sulfoxide (4 mL / 4 mL). The mixture was stirred at 35° C. for 16 hours. Sodium triacetylborohydride (376 mg, 1.77 mmol) was then added to the mixture, and the reaction was stirred at 35° C. for 2 hours. LCMS showed complete conversion of the reaction, and the product was detected. The reaction solution was cooled to room temperature and quenched by adding saturated ammonium chloride solution (50 mL) and extracted with dichloromethane (30 mL*2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography to give compound 017a. LCMS: [M+H] + =669.4.

[0302] Step 2: Compound 017a (105 mg, 0.157 mmol) was dissolved in dichloromethane / dimethyl sulfoxide (1 mL / 5 mL), and the reaction solution was stirred at room temperature for 16 hours. LCMS showed that the reaction was completely converted, and the product was detected. The reaction solution was distilled under reduced pressure to give compound 017b. LCMS: [M+H] + =569.4.

[0303] Step 3: Compound 017b (45 mg, 0.079 mmol), 017c (24 mg, 0.103 mmol), HATU (45 mg, 0.118 mmol), and N,N-diisopropylethylamine (41 mg, 0.316 mmol) were dissolved in dimethyl sulfoxide (2 mL), and the mixture was stirred at room temperature overnight. LCMS showed that the reaction was completely converted, and the product was detected. The reaction solution was cooled to room temperature, quenched by adding water (50 mL), and extracted with dichloromethane (30 mL*2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a residue. The residue was purified by pre-TLC to give compound C017. LCMS: [M+H] + =785.6.1 H NMR (500 MHz, DMSO-d6) δ 12.06 (s, 1H), 10.42 (s, 1H), 8.96 (s, 1H), 8.85 (s, 1H), 8.39 (s, 1H), 8.30 (s, 1H), 8.24 (d, J = 6.7 Hz, 1H), 8.17 - 8.06 (m, 2H), 7.80 (d, J = 10.4 Hz, 1H), 7.74 (d, J = 6.8 Hz, 1H), 7.47 (q, J = 8.0 Hz, 2H), 4.47 - 4.39 (m, 1H), 4.07 - 3.90 (m, 2H), 3.87 - 3.79 (m, 2H), 3.27 - 3.10 (m, 5H), 2.82 - 2.56 (m, 6H), 2.38 (s, 3H), 2.33 - 2.06 (m, 6H), 2.03 - 1.73 (m, 7H), 1.66 - 1.48 (m, 4H), 1.18 - 1.04 (m, 3H).

[0304] Example 12: Preparation of Compound C023 [ka]

[0305] Step 1: Compound 23a (1 g, 5.20 mmol) and 23b (645 mg, 10.39 mmol) were dissolved in NMP (20 mL). NaH (416 mg, 10.39 mmol) was added, and the mixture was heated to 110 °C and stirred at this temperature for 12 hours. TLC showed complete conversion of the starting material, and the product was detected. The reaction solution was distilled under reduced pressure to obtain a residue. The residue was purified by column chromatography to obtain compound 23c.

[0306] Step 2: Compound 23c (1.25 g, 5.73 mmol), B2Pin2 (2.91 g, 10.47 mmol), KOAc (1.69 g, 17.20 mmol), and Pd(dppf)Cl2 (465 mg, 0.57 mmol) were dissolved in dioxane (25 mL) at room temperature, purged with nitrogen three times, heated to 80 °C, and stirred at this temperature for 3 h. TLC showed complete conversion of the starting material, and the product was detected. After the reaction was complete, the reaction solution was cooled to room temperature and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography to give compound 8d.

[0307] Step 3: Compound 23d (345 mg, 1.30 mmol), 23e (400 mg, 0.87 mmol), BrettPhos Pd G3 (79 mg, 87 μmol), and K2CO3 (360 mg, 2.60 mmol) were dissolved in DMSO / HO (10 mL / 2 mL) at room temperature, purged with nitrogen three times, and heated to 100 °C and stirred at this temperature for 12 h. LCMS showed complete conversion of the reaction, and the product was detected. 30 mL of water was added to the reaction solution, and the mixture was extracted with dichloromethane (50 mL * 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography to give compound 23f.

[0308] Step 4: Compound 23f (382 mg, 0.68 mmol) was dissolved in ACN (10 mL). IBX (379 mg, 1.36 mmol) was added, and the mixture was heated to 80° C. and stirred at this temperature for 2 hours. LCMS showed that most of the starting material was converted, and the product was detected. After the reaction was complete, the reaction solution was cooled to room temperature and filtered. The filtrate was concentrated in vacuo to obtain a residue. The residue was purified by column chromatography to obtain compound 23g.

[0309] Step 5: Compound 23g (50 mg, 89 μmol) and 23h (36 mg, 0.18 mmol) were dissolved in DMSO / DCM (2 mL / 2 mL) at room temperature. 0.1 mL of acetic acid was added and stirred at room temperature for 1 hour. Sodium borohydride acetate (95 mg, 0.45 mmol) was added and stirred at room temperature for 1 hour. LCMS showed that most of the starting material was 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 and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by prep-TLC to give compound 23i.

[0310] Step 6: Compound 23i (15 mg, 20.1 μmol) was dissolved in TFA (3 mL) and stirred at room temperature for 1 hour. LCMS showed complete conversion of the reaction, and the product was detected. The reaction solution was distilled under reduced pressure to give crude compound 23j.

[0311] Step 7: Compound 23j (10 mg, 20.2 μmol), 23k (8 mg, 30.3 μmol), DIEA (8 mg, 60.5 μmol), and HATU (15 mg, 40.3 mmol) were dissolved in DMSO (2 mL) and stirred at room temperature for 12 hours. LCMS showed complete conversion of the reaction, and the product was detected. 30 mL of water was added to the reaction solution, and it was extracted with dichloromethane (20 mL*3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give a residue. The product was purified by preparative chromatography to give the final product C023. LCMS: Rt = 1.489 min, [M+H] + = 766.4.

[0312] Example 13: Preparation of Compound C025 [ka]

[0313] Step 1: Compound 25a (445 mg, 1.30 mmol), 8b (300 mg, 0.65 mmol), KOAc (320 mg, 3.25 mmol), and Pd(dppf)Cl2 (53 mg, 65.1 μmol) were dissolved in DMSO (10 mL), purged with nitrogen three times, heated to 100 °C, and stirred at this temperature for 3 h. LCMS indicated complete conversion of the starting material. The reaction solution was cooled to room temperature. BrettPhos G3 (59 mg, 65.1 μmol) and K2CO3 (270 mg, 1.95 mmol) were added, purged with nitrogen three times, heated to 100 °C, and stirred at this temperature for 12 h. LCMS indicated complete conversion of the reactants, and the product was detected. 100 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL * 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give a residue. The reaction solution was distilled under reduced pressure to give a residue. The residue was purified by column chromatography to give Compound 25c.

[0314] Step 2: Compound 25c (85 mg, 0.12 mmol) was dissolved in TFA (3 mL) and stirred at room temperature for 1 hour. LCMS showed complete conversion of the reaction, and the product was detected. The reaction solution was distilled under reduced pressure to give crude compound 25d.

[0315] Step 3: Compound 25e (1 g, 6.20 mmol) and 25f (1.59 g, 12.41 mmol) were dissolved in dioxane / 60% KOH aq. (3 mL / 0.2 mL) and stirred at room temperature for 12 hours. TLC showed complete conversion of the reaction, and the product was detected. 30 mL of water was added to the reaction solution, and it was extracted with ethyl acetate (50 mL * 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography to give compound 25g.

[0316] Step 4: Compound 25g (1.09 g, 3.77 mmol) was dissolved in MeOH (5 mL), methanolic hydrochloric acid (10 mL) was added, and the mixture was stirred at room temperature for 12 hours. The reaction solution was distilled under reduced pressure to obtain crude compound 25h.

[0317] Step 5: Compound 25h (425 mg, 3.62 mmol) and 25i (500 mg, 1.81 mmol) were dissolved in MeOH / DIEA (5 mL / 1 mL), heated to 90 °C, and stirred at this temperature for 12 hours. LCMS showed complete conversion of the starting material. The reaction solution was cooled to room temperature. 30 mL of water was added to the reaction solution, adjusted to pH 7 with 1N HCl, and extracted with ethyl acetate (50 mL*3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give a residue. The reaction solution was distilled under reduced pressure to give a residue. The residue was purified by column chromatography to give compound 25j.

[0318] Step 6: Compound 25j (32 mg, 82.0 μmol), 25d (25 mg, 54.6 μmol), DIEA (22 mg, 163.9 μmol), and HATU (42 mg, 109.3 μmol) were dissolved in DMSO (2 mL) and stirred at room temperature for 12 hours. LCMS showed complete conversion of the reaction, and the product was detected. The product was purified by preparative chromatography to give the final product C025. LCMS: Rt = 1.737 min, [M+H] + = 829.6.

[0319] Example 14: Preparation of Compound C026 [ka]

[0320] Step 1: Compound 26a (837 mg, 3.62 mmol) was dissolved in DCM (10 mL). TFA (1 mL) was added and the mixture was stirred at room temperature for 1 hour. The reaction solution was distilled under reduced pressure to give crude Compound 26b.

[0321] Step 2: Compound 26b (474 ​​mg, 3.62 mmol) and 26c (500 mg, 1.81 mmol) were dissolved in MeOH / DIEA (5 mL / 1 mL), heated to 90 °C, and stirred at this temperature for 12 hours. LCMS showed complete conversion of the starting material. The reaction solution was cooled to room temperature. 30 mL of water was added to the reaction solution, adjusted to pH 7 with 1N HCl, and extracted with ethyl acetate (50 mL*3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to obtain a residue. The reaction solution was distilled under reduced pressure to obtain a residue. The residue was purified by column chromatography to obtain compound 26d.

[0322] Step 3: Compound 26d (32 mg, 82.0 μmol), 25d (25 mg, 54.6 μmol), DIEA (22 mg, 163.9 μmol), and HATU (42 mg, 109.3 μmol) were dissolved in DMSO (2 mL) and stirred at room temperature for 12 hours. LCMS showed complete conversion of the reaction, and the product was detected. The product was purified by preparative chromatography to give the final product C026. LCMS: Rt = 1.902 min, [M+H] + = 827.1.

[0323] Example 15: Preparation of Compound C027 [ka]

[0324] Step 1: Compound 027a (900 mg, 2.64 mmol) was dissolved in HCl / dioxane (10 mL, 4 M) at room temperature and stirred for 1 hour. LCMS showed complete conversion of the reaction, and the product was detected. The reaction solution was distilled under reduced pressure to give compound 027b. LCMS: [M+H] + =242.1.

[0325] Step 2: Compound 027b (731 mg, 2.62 mmol) and DIEA (339 mg, 2.62 mmol) were dissolved in dichloromethane / dimethyl sulfoxide (5 mL / 5 mL) and stirred for 10 minutes. Compound 027c (672 mg, 3.15 mmol) and acetic acid (157 mg, 2.62 mmol) were then added to the reaction solution and stirred at 35°C for 16 hours. NaBH(OAc)3 (1.67 g, 7.87 mmol) was then added to the reaction solution and stirred at 35°C for 1 hour. LCMS showed complete conversion and the product was detected. The reaction solution was poured into saturated sodium bicarbonate solution (60 mL) and extracted with dichloromethane (30 mL * 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by flash silica gel column chromatography to give compound 027d. LCMS: [M+H] + =439.2.

[0326] Step 3: Compound 027d (510 mg, 1.16 mmol), potassium acetate (228 mg, 2.33 mmol), bis(pinacolato)diboron (384 mg, 1.51 mmol), and Pd(dppf)Cl2 (85 mg, 0.116 mmol) were dissolved in dimethyl sulfoxide (5 mL). The reaction solution was stirred at 100 °C under a nitrogen atmosphere for 2 hours. LCMS showed complete conversion of the reaction, and the product was detected. The reaction solution was cooled to room temperature, quenched by adding water (60 mL), and extracted with dichloromethane (20 mL * 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by flash silica gel column to give compound 027e. LCMS: [M+H] + =405.2.

[0327] Step 4: Compound 027e (54 mg, 0.159 mmol), Warhead 3 (50 mg, 0.097 mmol), potassium carbonate (44 mg, 0.318 mmol), and BrettPhos-Pd-G3 (49 mg, 0.005 mmol) were dissolved in dimethyl sulfoxide (2 mL). The reaction solution was stirred under a nitrogen atmosphere at 100° C. for 3 hours. LCMS showed complete conversion of the reaction, and the product was detected. The reaction solution was cooled to room temperature, quenched by adding water (50 mL), and extracted with dichloromethane (20 mL*3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by flash silica gel column to give compound 027f. LCMS: [M+H] + =655.4.

[0328] Step 5: Compound 027f (25 mg, 0.0382 mmol) was dissolved in trifluoroacetic acid / dichloromethane (1 mL / 5 mL) at room temperature and stirred for 2 hours. LCMS showed that the reaction was completely converted, and the product was detected. The reaction solution was distilled under reduced pressure to obtain compound 027g. LCMS: [M+H] + =555.2.

[0329] Step 6: Compound 027g (21 mg, 0.038 mmol), 027h (12 mg, 0.045 mmol), DIEA (24 mg, 0.189 mmol) and HATU (19 mg, 0.049 mmol) were dissolved in dimethyl sulfoxide (2 mL). The mixture was stirred at room temperature for 16 hours. LCMS showed that the reaction was completely converted and the product was detected. The reaction solution was cooled to room temperature and quenched by adding water (50 mL) and extracted with dichloromethane (30 mL*2). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain the crude product. The crude product was purified by Pre-TLC to obtain compound C027. LCMS: [M+H] + =805.5.

[0330] Example 16: Preparation of Compound C028 [ka]

[0331] Step 1: Compound 28a (50 mg, 89 μmol) and 28b (38 mg, 0.18 mmol) were dissolved in DMSO / DCM (2 mL / 2 mL) at room temperature. 0.1 mL of acetic acid was added and stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (95 mg, 0.45 mmol) was added and stirred at room temperature for 1 hour. LCMS showed that most of the starting material was converted, and the product was detected. 30 mL of water was added to the reaction solution, and it was extracted with dichloromethane (20 mL*3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by prep-TLC to give compound 28c.

[0332] Step 2: Compound 28c (15 mg, 19.7 μmol) was dissolved in TFA (3 mL) and stirred at room temperature for 1 hour. LCMS showed complete conversion of the reaction, and the product was detected. The reaction solution was distilled under reduced pressure to give crude compound 28d.

[0333] Step 3: Compound 28d (10 mg, 18.9 μmol), 28e (8 mg, 28.3 μmol), DIEA (8 mg, 56.6 μmol), and HATU (15 mg, 37.8 μmol) were dissolved in DMSO (2 mL) and stirred at room temperature for 12 hours. LCMS showed complete conversion of the reaction, and the product was detected. 30 mL of water was added to the reaction solution, and it was extracted with dichloromethane (20 mL*3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give a residue. The product was purified by preparative chromatography to give the final product C028. LCMS: Rt = 1.522 min, [M+H] + = 780.5.

[0334] Example 17: Preparation of Compound C030 [ka]

[0335] Step 1: Compound 30a (2 g, 5.86 mmol), B2Pin2 (2.98 mg, 11.72 mmol), KOAc (1.73 g, 17.58 mmol), and Pd(dppf)Cl2 (475 mg, 0.59 mmol) were dissolved in dioxane (40 mL) at room temperature, purged with nitrogen three times, heated to 90 °C, and stirred at this temperature for 3 h. TLC showed complete conversion of the starting material, and the product was detected. After the reaction was complete, the reaction solution was cooled to room temperature and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography to give compound 30b.

[0336] Step 2: Compound 30b (631 mg, 1.63 mmol), 30c (500 mg, 1.08 mmol), BrettPhos Pd G3 (98 mg, 0.11 mmol), and K2CO3 (450 mg, 3.25 mmol) were dissolved in DMSO / HO (10 mL / 2 mL) at room temperature, purged with nitrogen three times, and heated to 90 °C and stirred at this temperature for 12 h. LCMS showed complete conversion of the reaction, and the product was detected. 30 mL of water was added to the reaction solution, and the mixture was extracted with dichloromethane (50 mL * 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography to give compound 30d.

[0337] Step 3: Compound 28c (354 mg, 0.52 mmol) was dissolved in TFA (3 mL) and stirred at room temperature for 1 hour. LCMS showed complete conversion of the reaction, and the product was detected. The reaction solution was distilled under reduced pressure to give crude compound 30e.

[0338] Step 4: Compound 30e (50 mg, 0.11 mmol) and 30f (53 mg, 0.22 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 borohydride acetate (70 mg, 0.33 mmol) was added and the mixture was stirred at room temperature for 1 hour. LCMS showed that most of the starting material was 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 and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by prep-TLC to give compound 30g.

[0339] Step 5: Compound 30g (57 mg, 83.8 μmol) was dissolved in DCM (3 mL). TFA (1 mL) was added and the mixture was stirred at room temperature for 1 hour. LCMS showed complete conversion of the reaction, and the product was detected. The reaction solution was distilled under reduced pressure to give crude compound 30h.

[0340] Step 6: Compound 30h (49 mg, 82.8 μmol), 30i (33 mg, 124.2 μmol), DIEA (32 mg, 248.4 μmol), and HATU (63 mg, 165.6 μmol) were dissolved in DMSO (2 mL) and stirred at room temperature for 1 hour. LCMS showed complete conversion of the reaction, and the product was detected. 30 mL of water was added to the reaction solution, and it was extracted with dichloromethane (20 mL*3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by prep-TLC to give the final product C030. LCMS: Rt = 1.570 min, [M+H] + = 830.6.

[0341] Example 18: Preparation of Compound C032 [ka]

[0342] Step 1: Compound 032a (100 mg, 0.212 mmol) and 032b (66 mg, 0.275 mmol) were dissolved in dichloromethane / dimethyl sulfoxide (4 mL / 4 mL). The mixture was stirred at 35° C. for 16 hours. Sodium triacetylborohydride (225 mg, 1.06 mmol) was then added to the mixture, and the reaction was stirred at 35° C. for 2 hours. LCMS showed that the reaction was completely converted, and the product was detected. The reaction solution was cooled to room temperature and quenched by adding saturated ammonium chloride solution (50 mL) 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 032c. LCMS: [M+H] + =595.4.

[0343] Step 2: Compound 032c (60 mg, 0.086 mmol) was dissolved in dichloromethane (5 mL). Trifluoroacetic acid (1 mL) was added at room temperature and the reaction was stirred for 2 hours. LCMS showed that the reaction was completely converted and the product was detected. The reaction solution was distilled under reduced pressure to obtain compound 032d. LCMS: [M+H] + =595.4.

[0344] Step 3: Compound 32d (51 mg, 0.086 mmol), 032e (24 mg, 0.087 mmol), and DIEA (55 mg, 0.426 mmol) were added to dimethyl sulfoxide (2 mL) at room temperature, and the reaction solution was stirred at 80° C. for 2 hours. LCMS showed complete conversion of the reaction, and the product was detected. The reaction solution was cooled to room temperature, quenched with water (50 mL), and extracted with methanol / dichloromethane (20 mL / 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 compound C032. LCMS: [M+H] + =851.6. 1H NMR (500 MHz, DMSO-d6) δ 12.04 (s, 1H), 11.09 (s, 1H), 8.96 (d, J = 2.2 Hz, 1H), 8.84 (s, 1H), 8.38 (s, 1H), 8.30 - 8.28 (m, 1H), 8.11 (d, J = 2.5 Hz, 1H), 8.09 (s, 1H), 7.70 - 7.66 (m, 1H), 7.34 (dd, J = 11.7, 7.9 Hz, 2H), 5.09 (dd, J = 12.6, 5.5 Hz, 2H), 4.24 (s, 2H), 3.26 (d, J = 3.7 Hz, 2H), 3.23 - 3.10 (m, 6H), 3.01 - 2.96 (m, 2H), 2.92 - 2.74 (m, 4H), 2.66 - 2.56 (m, 2H), 2.46 (s, 2H), 2.39 - 2.33 (m, 4H), 2.11 - 1.96 (m, 8H), 1.80 - 1.72 (m, 2H), 1.71 - 1.60 (m, 4H), 1.04 (t, J = 7.2 Hz, 3H).

[0345] Example 19: Preparation of Compound C033 [ka]

[0346] Step 1: Compound 33a (1 g, 5.68 mmol) and 33b (1.37 g, 8.52 mmol) were dissolved in THF (20 mL). NaH (570 mg, 14.21 mmol) was added and stirred at room temperature for 12 hours. TLC showed complete conversion of the starting material and the product was detected. 100 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL * 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to obtain a residue. The reaction solution was distilled under reduced pressure to obtain a residue. The residue was purified by column chromatography to obtain compound 33c.

[0347] Step 2: Compound 33c (1.37 g, 4.32 mmol), B2Pin2 (2.19 g, 8.64 mmol), KOAc (1.27 g, 12.96 mmol), and Pd(dppf)Cl2 (350 mg, 0.43 mmol) were dissolved in dioxane (30 mL) at room temperature, purged with nitrogen three times, heated to 80 °C, and stirred at this temperature for 3 h. TLC showed complete conversion of the starting material, and the product was detected. After the reaction was complete, the reaction solution was cooled to room temperature and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography to give compound 33d.

[0348] Step 3: Compound 33d (80 mg, 0.22 mmol), 33e (75 mg, 0.15 mmol), BrettPhos Pd G3 (14 mg, 15 μmol), and K2CO3 (60 mg, 0.44 mmol) were dissolved in DMSO / HO (2 mL / 0.5 mL) at room temperature, purged with nitrogen three times, heated to 90 °C, and stirred at this temperature for 12 h. LCMS showed complete conversion of the reaction, and the product was detected. 30 mL of water was added to the reaction solution, and the mixture was extracted with dichloromethane (50 mL * 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography to give compound 33f.

[0349] Step 4: Compound 33f (69 mg, 0.13 mmol) 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 completely converted and the product was detected. The reaction solution was distilled under reduced pressure to give crude compound 33g.

[0350] Step 5: Compound 33g (56 mg, 0.13 mmol), 33h (53 mg, 0.19 mmol), NMI (37 mg, 0.45 mmol), and TCFH (44 mg, 0.16 mmol) were dissolved in DMSO (2 mL) and stirred at room temperature for 1 hour. LCMS showed complete conversion of the reaction, and the product was detected. 30 mL of water was added to the reaction solution, and it was extracted with dichloromethane (20 mL*3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by prep-TLC to give the final product C033. LCMS: Rt = 1.719 min, [M+H] + = 683.4.

[0351] Example 20: Preparation of Compound C034 [ka]

[0352] Step 1: Compound 034a (1 g, 5.35 mmol), 034b (1.2 g, 5.35 mmol), and cesium carbonate (1.74 g, 5.35 mmol) were dissolved in acetonitrile (10 mL). The reaction solution was stirred at room temperature for 16 hours. TLC showed complete conversion of the reactants, and a new spot was detected. The reaction solution was distilled under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography to obtain compound 034c.

[0353] Step 2: Compound 034c (1.212 g, 3.67 mmol) was dissolved in dimethyl sulfoxide (5 mL). Potassium acetate (1.08 g, 11.01 mmol), bis(pinacolato)diboron (1.21 g, 4.77 mmol), and Pd(dppf)Cl2 (0.27 g, 0.367 mmol) were added at room temperature. The reaction solution was stirred at 100 °C under a nitrogen atmosphere for 2 hours. LCMS showed complete conversion of the reactants, and the product was detected. The crude product was distilled under reduced pressure. The crude product was purified by silica gel chromatography to obtain compound 034d. LCMS: [M-Bu+H]+ =278.1.

[0354] Step 3: Compound 034d (64 mg, 0.176 mmol), Warhead 3 (70 mg, 0.136 mmol), potassium carbonate (56 mg, 0.407 mmol), and BrettPhos-Pd-G3 (12 mg, 0.0136 mmol). The reaction solution was stirred under a nitrogen atmosphere at 90°C. LCMS showed complete conversion of the reaction, and the product was detected. The reaction solution was cooled to room temperature, quenched by adding water (50 mL), and extracted with dichloromethane (20 mL * 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain the crude product. The crude product was purified by silica gel chromatography to obtain compound C034e. LCMS: [M+H] + =546.4.

[0355] Step 4: Compound 034e (42 mg, 0.077 mmol) was dissolved in trifluoroacetic acid / dichloromethane (1 mL / 5 mL) at room temperature and stirred for 2 hours. LCMS showed that the reaction was completely converted, and the product was detected. The reaction solution was distilled under reduced pressure to give compound 034f. LCMS: [M+H] + =446.3.

[0356] Step 5: Compound 034f (34 mg, 0.076 mmol), 034g (25 mg, 0.092 mmol), DIEA (50 mg, 0.381 mmol), and HATU (38 mg, 0.099 mmol) were dissolved in dimethyl sulfoxide (2 mL). The mixture was stirred at room temperature for 16 hours. LCMS showed complete conversion of the reaction, and the product was detected. The reaction solution was cooled to room temperature, quenched by adding water (50 mL), and extracted with dichloromethane (20 mL*2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain the crude product. The crude product was purified by pre-TLC to obtain compound C034. LCMS: Rt=2.200 min; [M+H] + =696.4.

[0357] Example 21: Preparation of Compound C038 [ka] The reaction was carried out according to the method described in Example 19, except that compound 33b was replaced with compound 38b in step 1, to give the final product C038. LCMS: Rt = 1.796 min, [M+H] + = 711.4.

[0358] Example 22: Preparation of Compound C039 [ka] The reaction was carried out according to Example 20, except that in step 1, compound 034b was replaced with N-Boc-3-aminopropyl bromide and acetonitrile was replaced with DMF, to give compound C039. LCMS: [M+H] + =710.4. 1H NMR (500 MHz, DMSO-d6) δ 11.98 (s, 1H), 10.53 (s, 1H), 8.81 (s, 1H), 8.76 (t, J = 5.6 Hz, 1H), 8.36 (s, 1H), 8.12 (s, 1H), 8.08 (d, J = 2.7 Hz, 1H), 8.03 (d, J = 8.2 Hz, 2H), 7.99 (d, J = 2.1 Hz, 1H), 7.87 (dd, J = 8.4, 2.1 Hz, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.09 (d, J = 8.2 Hz, 1H), 4.27 (s, 2H), 4.15 (d, J = 6.0 Hz, 2H), 3.76 (ddd, J = 13.6, 8.2, 5.8 Hz, 1H), 3.63 (dt, J = 11.8, 6.0 Hz, 1H), 3.54 - 3.47 (m, 2H), 3.25 (s, 1H), 3.05 (s, 2H), 2.75 (q, J = 7.2, 6.6 Hz, 2H), 2.30 (s, 3H), 2.21 - 1.96 (m, 8H), 1.12 - 1.03 (m, 3H).

[0359] Compound 039b:LCMS:[M-Bu+H] + =292.2. Compound 039c:LCMS:[M+H] + =560.3. Compound 039d:LCMS:[M+H] + =460.3.

[0360] Example 23: Preparation of Compound C040 [ka] Compound C040 was obtained according to the method described in Example 20, except that in step 1, compound 034b was replaced with 4-(N-tert-butoxycarbonylamino)-1-butanol, THF was replaced with acetonitrile, and the reaction was performed in an ice bath. LCMS: Rt=1.998 min; [M+H] + =724.4.

[0361] Compound 039b:LCMS:[M-Bu+H] + =292.2. Compound 040c:LCMS:[M+H] + =560.3. Compound 040d:LCMS:[M+H] + =460.4.

[0362] Example 24: Preparation of Compound C041 [ka] Compound C041 was obtained according to the method described in Example 19, except that compound 33b was replaced with compound 41b in step 1. LCMS: Rt=1.911 min, [M+H] + =725.4.

[0363] Example 25: Preparation of Compound C042 [ka]

[0364] Step 1: Compound 042a (21 mg, 0.046 mmol), 042b (14 mg, 0.059 mmol), DIEA (30 mg, 0.23 mmol), and HATU (23 mg, 0.059 mmol) were dissolved in dimethyl sulfoxide (2 mL). The mixture was stirred at room temperature for 16 hours. LCMS showed complete conversion of the reaction, and the product was detected. The reaction solution was cooled to room temperature, quenched by adding water (50 mL), and extracted with dichloromethane (20 mL * 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain the crude product. The crude product was purified by pre-TLC to obtain compound C042.

[0365] LCMS: [M+H] + =676.4. 1H NMR (500 MHz, DMSO-d6) δ 12.02 (s, 1H), 10.43 (s, 1H), 8.82 (s, 1H), 8.68 (d, J = 5.6 Hz, 1H), 8.38 (s, 1H), 8.15 (s, 1H), 8.12 (d, J = 2.4 Hz, 1H), 8.04 (d, J = 7.5 Hz, 2H), 7.82 (d, J = 1.8 Hz, 1H), 7.76 - 7.72 (m, 1H), 7.53 - 7.44 (m, 2H), 7.09 (d, J = 8.7 Hz, 1H), 4.14 (t, J = 6.0 Hz, 2H), 3.83 (t, J = 6.7 Hz, 2H), 3.61 - 3.47 (m, 4H), 3.26 (s, 1H), 3.15 - 3.07 (m, 2H), 2.72 (t, J = 6.6 Hz, 2H), 2.31 (s, 3H), 2.07 (dd, J = 12.5, 6.1 Hz, 2H), 1.28 (dd, J = 16.9, 6.6 Hz, 6H), 1.25 - 1.21 (m, 3H).

[0366] Example 26: Preparation of Compound C044 [ka] Compound C044 was obtained according to the method described in Example 19, except that compound 33b was replaced with compound 44b in step 1. LCMS: Rt=1.767 min, [M+H] + =697.4.

[0367] Example 27: Preparation of Compound C091 [ka]

[0368] Step 1: Compound N-Boc-4-methylenepiperidine (2 g, 10.14 mmol) was dissolved in 9-BBN (20 mL) (0.5 min in THF) at room temperature. The mixture was stirred at 60 °C under a nitrogen atmosphere for 3 hours. Then, THF was distilled under reduced pressure. N,N-Dimethylformamide (DMF; SO, 20 mL) and water (SO, 2 mL) were added as solvents. Then, 1-bromo-4-iodobenzene (2.6 g, 9.19 mmol), potassium carbonate (2.8 g, 20.28 mmol), and Pd(dppf)Cl2 (0.74 g, 1.01 mmol) were added, and the mixture was stirred at 60 °C for 2 hours under nitrogen protection. TLC showed complete conversion of the reactants, and a new spot was formed. The reaction solution was poured into water (100 mL) and extracted with ethyl acetate (30 mL * 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel chromatography to give compound 91a.

[0369] Step 2: Compound 91a (1.32 g, 3.73 mmol) was dissolved in dioxane (20 mL) at room temperature. Bis(pinacolato)diboron (1.42 g, 5.59 mmol), potassium acetate (1.10 g, 11.19 mmol), and Pd(dppf)Cl2 (0.27 g, 0.37 mmol) were added, and the mixture was stirred at 100 °C under a nitrogen atmosphere for 2 hours. TLC showed complete conversion of the reaction, and a new spot was detected. The reaction solution was poured into water (50 mL) and then extracted with ethyl acetate (30 mL * 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by silica gel chromatography to give compound 91b.

[0370] Step 3: Compound 91b (1.5 g, 3.73 mmol) was dissolved in toluene (10 mL) and water (5 mL) at room temperature. 5-Bromo-2-iodopyridine (1.32 g, 4.65 mmol), sodium carbonate (1.35 g, 12.69 mmol), and tetrakis(triphenylphosphine)palladium (0.24 g, 0.21 mmol) were added. The mixture was stirred at 90 °C under a nitrogen atmosphere for 16 hours. TLC showed complete conversion of the reaction, and a new spot was detected. The reaction solution was poured into water (50 mL) and extracted with ethyl acetate (30 mL * 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by silica gel chromatography to give compound 91c.

[0371] Step 4: Compound 91c (100 mg, 0.23 mmol) was dissolved in dioxane (5 mL) at room temperature. Potassium acetate (68 mg, 0.69 mmol), bis(pinacolato)diboron (88 mg, 0.35 mmol), and Pd(dppf)Cl2 (0.017 g, 0.023 mmol) were added. The mixture was stirred at 100 °C under a nitrogen atmosphere for 2 hours. LCMS showed complete conversion of the reaction, and the product was detected. The reaction solution was filtered. The filtrate was concentrated in vacuo to give the crude product. The crude product was purified by silica gel chromatography to give compound 91d. LCMS: [M+H] + =397.2.

[0372] Step 5: Compound warhead3 (95 mg, 0.18 mmol) was dissolved in DMSO (2 mL) and water (0.2 mL) at room temperature. Compound 91d (90 mg, 0.23 mmol), potassium carbonate (75 mg, 0.54 mmol), and BrettPhos-G3-Pd (16 mg, 0.018 mmol) were added. The mixture was stirred at 90° C. under a nitrogen atmosphere for 16 hours. LCMS showed complete conversion of the reaction, and the product was detected. The reaction solution was poured into water (50 mL) and then extracted with DCM (30 mL*2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by silica gel chromatography to give compound 91e. LCMS: [M+H] + =647.5.

[0373] Step 6: Compound 91e (118 mg, 0.18 mmol) was dissolved in dichloromethane (10 mL) at room temperature. Trifluoroacetic acid (1 mL) was added and the mixture was stirred at room temperature for 2 hours. LCMS showed complete conversion of the reaction and the product was detected. The reaction was rotary evaporated to dryness to give crude compound 91f. LCMS: [M+H] + =547.3.

[0374] Step 7: Compound 91f (33 mg, 0.060 mmol) was dissolved in DMSO (2 mL) at room temperature. 4-Chloro-3-(2,4-dioxotrihydropyrimidin-1(2H)-yl)benzoic acid (21 mg, 0.078 mmol), HATU (30 mg, 0.079 mmol), and DIPEA (R3, 39 mg, 0.30 mmol) were added. The mixture was stirred under a nitrogen atmosphere at room temperature for 16 hours. LCMS showed complete conversion of the reaction, and the product was detected. The reaction solution was poured into water (50 mL) and then extracted with DCM (30 mL * 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain the crude product. The crude product was purified by pre-TLC to obtain compound C091 (9.69 mg, yield: 18.72%).

[0375] LCMS: [M+H] + =797.4; 1 H NMR (500 MHz, DMSO-d6) δ 12.15 (s, 1H), 10.51 (s, 1H), 9.52 (d, J = 1.7 Hz, 1H), 9.02 (s, 1H), 8.68 (dd, J = 8.4, 2.2 Hz, 1H), 8.42 (s, 1H), 8.18 (d, J = 2.6 Hz, 1H), 8.15 - 8.07 (m, 4H), 7.64 (d, J = 8.2 Hz, 1H), 7.56 (d, J = 1.9 Hz, 1H), 7.39 (dd, J = 8.2, 1.9 Hz, 1H), 7.35 (d, J = 8.2 Hz, 2H), 4.50 - 4.41 (m, 1H), 4.29 - 4.23 (m, 1H), 3.79 - 3.73 (m, 1H), 3.66 - 3.52 (m, 2H), 3.01 (d, J = 10.6 Hz, 3H), 2.75 (q, J = 7.5, 6.8 Hz, 3H), 2.62 (dt, J = 13.7, 6.3 Hz, 3H), 2.39 (q, J = 7.3 Hz, 3H), 2.11 - 1.99 (m, 6H), 1.88 (s, 1H), 1.72 (s, 1H), 1.64 - 1.57 (m, 1H), 1.04 (t, J = 7.2 Hz, 3H).

[0376] Example 28: Preparation of compound C096

change

[0377] Example 29: Preparation of Compound C084 [ka]

[0378] Step 1: Compound C084a (2 g, 10.31 mmol) was dissolved in DMF (10 mL) at room temperature. Cesium carbonate (4.03 g, 12.37 mmol) and 1-methylpiperidin-4-yl 4-methylbenzenesulfonate (1.61 g, 11.34 mmol) were added. The mixture was stirred at room temperature for 16 hours. LCMS showed complete conversion of the reaction, and the product was detected. The reaction solution was filtered. The filtrate was concentrated in vacuo to give crude compound C084b (2.14 g, 99.79% yield).

[0379] Step 2: Compound C084c (530 mg, 1.21 mmol) was dissolved in dioxane (20 mL) at room temperature. Bis(pinacolato)diboron (368.72 mg, 1.45 mmol), potassium acetate (356 mg, 3.63 mmol), and Pd(dppf)Cl2·DCM (99 mg, 0.12 mmol) were added. The mixture was stirred at 90 °C under a nitrogen atmosphere for 6 hours. LCMS showed complete conversion of the reaction, and the product was detected. The reaction solution was cooled to room temperature and filtered through Celite. The filter cake was washed with dioxane (20 mL). The filtrate was collected to give crude compound C084d (480 mg, 1.188 mmol), which was used directly in the next step. LCMS: [M+H] + =404.3.

[0380] Step 3: Compound C084d (52 mg, 0.12 mmol) was dissolved in DMSO (2 mL) and water (0.2 mL) at room temperature. C084e (62 mg, 0.12 mmol), potassium carbonate (50 mg, 0.36 mmol), and BrettPhos-G3-Pd (10 mg, 0.011 mmol) were added. The mixture was stirred at 90 °C under a nitrogen atmosphere for 16 hours. LCMS showed complete conversion of the reaction, and the product was detected. The reaction solution was poured into water (30 mL) and extracted with dichloromethane (20 mL * 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by silica gel chromatography (methanol:dichloromethane = 0-14%) to give compound C084f (37 mg, 0.055 mmol).

[0381] Step 4: Compound C084f (30 mg, 0.054 mmol) was dissolved in dichloromethane (5 mL) at room temperature. TFA (1 mL) was added and the mixture was stirred at room temperature for 2 hours. LCMS showed complete conversion of the reaction and the product was detected. The reaction was poured into water (30 mL) and then extracted with dichloromethane (20 mL*2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give crude compound C084g (24 mg, 0.053 mmol).

[0382] Process 5 Compound C084g (24 mg, 0.053 mmol) was dissolved in DMSO (2 mL) at room temperature. 4-Chloro-3-(2,4-dioxotrihydropyrimidin-1(2H)-yl)benzoic acid (19 mg, 0.071 mmol), HATU (27 mg, 0.071 mmol), and DIPEA (35 mg, 0.27 mmol) were added. The mixture was stirred at room temperature for 16 hours. LCMS showed complete conversion of the reaction, and the product was detected. The reaction solution was poured into water (50 mL) and extracted with DCM (30 mL*2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product. Purification by pre-HPLC gave compound C084 (7.06 mg, yield: 18.07%). LCMS: [M+H] +=792.4.

[0383] Example 30: Preparation of Compound C085 [ka]

[0384] Step 1: Compound C085a (1.8 g, 6.07 mmol), C085b (1.6 g, 9.11 mmol), and K2CO3 (2.1 g, 15.18 mmol) were dissolved in DMSO (40 mL), purged with nitrogen three times, heated to 100 °C, and stirred at this temperature for 4 h. TLC showed complete conversion of the starting material, and the product was detected. 50 mL of water was added to the reaction solution, and the mixture was extracted with EA (50 mL * 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography (PE:EA = 10:1) to give compound C085c (1.09 g, 39.7% yield).

[0385] Step 2: Compound C085c (1.09 g, 2.41 mmol), KOAc (0.71 g, 7.23 mmol), B2pin2 (1.22 g, 4.82 mmol), and Pd(dppf)Cl2 (176 mg, 0.24 mmol) were dissolved in dioxane (20 mL), purged with nitrogen three times, heated to 90 °C, and stirred for 2 h. LCMS showed complete conversion and product was detected. After completion of the reaction, the reaction was filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography (DCM:MeOH = 20:1) to give C085d (180 mg, 15.0% yield).

[0386] Step 3: Compound C085d (119 mg, 0.29 mmol), warhead 3 (100 mg, 0.19 mmol), Pd(PPh3)4 (22 mg, 0.02 mmol), and K2CO3 (79 mg, 0.57 mmol) were dissolved in DMSO and HO (3 mL / 0.5 mL). The mixture was purged with nitrogen three times, heated to 90 °C, and stirred for 12 h. LCMS showed complete conversion and product was detected. After completion of the reaction, the mixture was filtered. 50 mL of water was added to the reaction solution, and the mixture was extracted with DCM (30 mL * 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (DCM:MeOH = 4:1) to give C085e (72 mg, 56.3% yield).

[0387] Step 4: Compound C085e (73 mg, 0.11 mmol) was dissolved in DCM and TFA (3 mL / 0.5 mL) and stirred at room temperature for 1 hour. LCMS showed complete conversion of the reaction, and the product was detected. The reaction solution was distilled under reduced pressure to obtain crude compound C085f.

[0388] Step 5: Compounds C085f, C085g (44.3 mg, 0.17 mmol), and NMI (31.6 mg, 0.39 mmol) were dissolved in DMSO (2 mL). TCFH (337 mg, 0.13 mmol) was added and stirred at room temperature for 2 hours. LCMS showed complete conversion of the reaction, and the product was detected. 50 mL of water was added to the reaction solution, and it was extracted with DCM (30 mL * 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by preparative plate (DCM:NH3 / MeOH = 12:1) to give the final product C085 (31.54 mg, 35.06% yield). LCMS: Rt = 1.817 min, [M+H] + = 818.6.

[0389] Example 31: Preparation of Compound C092 [ka] Following the procedure described in Example 29, except replacing compound C084e with compound C092e in step 3, compound C092 was obtained (7.06 mg, yield: 18.07%). LCMS: [M+H] + =791.4.

[0390] Example 32: Preparation of Compound C098 [ka] Compound C098 was obtained according to the method described in Example 30, except that compound C085a was replaced with compound 98a in step 1. LCMS: Rt=2.120 min; [M+H] + =820.5.

[0391] Example 33: Preparation of Compound C108 [ka]

[0392] Step 1: Compound 108-1 (2 g, 10.31 mmol), compound 108-2 (3.72 g, 20.62 mmol), CsCO (10.08 g, 30.93 mmol), and KI (0.17 g, 1.03 mmol) were dissolved in DMF (40 mL), purged with nitrogen three times, heated to 60 °C, and stirred at this temperature for 12 h. TLC showed complete conversion of the starting material, and the product was detected. After completion of the reaction, the reaction was filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography (PE:EA = 1:3) to give compound 108-3 (3.03 g).

[0393] Step 2: Compound 108-3 (600 mg, 2.16 mmol), compound 108-4 (500 mg, 1.08 mmol), Pd(dppf)Cl (176 mg, 0.22 mmol), and KCO (299 mg, 2.16 mmol) were dissolved in dioxane and HO (10 mL / 3 mL). The mixture was purged with nitrogen three times, heated to 80 °C, and stirred for 3 h. LCMS showed complete conversion and the product was detected. After completion of the reaction, the mixture was filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography (PE:EA = 1:1) to give compound 108-5 (280 mg, 53.2% yield).

[0394] Step 3: Compound 108-5 (100 mg, 0.2 mmol), compound 108-6 (120 mg, 0.3 mmol), BrettPhos Pd G3 (18 mg, 0.02 mmol), and K2CO3 (83 mg, 0.6 mmol) were dissolved in dioxane and HO (3 mL / 0.5 mL), purged with nitrogen three times, heated to 90 °C, and stirred for 12 h. LCMS showed complete conversion and product was detected. After completion of the reaction, the reaction was filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography (pure EA) to give compound 108-7 (87 mg, 67.8% yield).

[0395] Step 4: Compound 108-7 (87 mg, 0.14 mmol) was dissolved in DCM and TFA (3 mL / 0.5 mL) and stirred at room temperature for 1 hour. LCMS showed complete conversion of the reaction, and the product was detected. The reaction solution was distilled under reduced pressure to give crude compound 108-8.

[0396] Step 5: Compound 108-8, compound 108-9 (56.4 mg, 0.21 mmol), and NMI (40 mg, 0.49 mmol) were dissolved in DMSO (2 mL). TCFH (47 mg, 0.17 mmol) was added with stirring and stirred at room temperature for 2 hours. LCMS showed complete conversion of the reaction, and the product was detected. Purification by preparative chromatography gave the final product C108 (37.73 mg, 34.85% yield). LCMS: Rt = 2.000 min, [M+H] + =777.5, purity = 99.51%.

[0397] Example 34: Preparation of Compound C109 [ka] Following the method described in Example 33, except that in step 1, compound 108-1 was replaced with compound 109-2, compound C109 was obtained (19.01 mg, yield: 34.85%, purity: 99.14%). LCMS: Rt=2.145min; [M+H] + =765.3.

[0398] Example 35: Preparation of Compound C110 [ka] Following the procedure described in Example 29, except replacing 1-methylpiperidin-4-yl 4-methylbenzenesulfonate with iodomethane in step 1, compound C110 was obtained (7.06 mg, yield: 18.07%). LCMS: [M+H] + =707.4.

[0399] C110a:LCMS:[M+H] + =208.1. C110c: LCMS: [M+H] + = 404.3. C110f: LCMS: [M+H] + =457.1.

[0400] Example 36: Preparation of Compound C122 [ka]

[0401] Step 1: Ph3PMeBr (12.56 g, 35.16 mmol) was dissolved in THF (40 mL). NaH (1.88 g, 46.88 mmol) was added with stirring in an ice bath, and the mixture was purged with nitrogen three times. The mixture was heated to 90 °C and stirred at this temperature for 3 h. Compound C122-1 (5 g, 23.44 mmol) was dissolved in THF (40 mL), cooled to room temperature, added dropwise with stirring, and stirred at room temperature overnight. TLC showed complete conversion of the starting material and the product was detected. 150 mL of water was added to the reaction solution in an ice bath, and the mixture was extracted with EA (100 mL * 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography (PE:EA = 3:1) to give compound C122-2 (3.83 g, 77.3% yield).

[0402] Step 2: Compound C122-2 (3.81 g, 18.04 mmol) was dissolved in THF (50 mL). 9-BBN (30 mL, 0.5 M in THF) was added with stirring, purged with nitrogen three times, and heated to 90 °C and stirred at this temperature for 2 h. The reaction solution was cooled to room temperature, and the solvent was removed by rotary evaporation. Compound 4 (2.7 g, 13.88 mmol), Pd(dppf)Cl (1.01 g, 1.39 mmol), KCO (5.76 g, 41.64 mmol), DMF, and H O (50 mL / 15 mL) were added, purged with nitrogen three times, and heated to 90 °C and stirred at this temperature for 2 h. LCMS showed complete conversion, and the product was detected. After the reaction was completed, filtration was performed. 150 mL of water was added to the filtrate, and the mixture was extracted with EA (100 mL*3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to obtain a residue. The residue was purified by column chromatography (PE:EA=1:1) to obtain compound C122-5 (4.58 g).

[0403] Step 3: C122-5 (4.58 g, 15.77 mmol) was dissolved in DCM (80 mL). Benzyl bromide (3.78 g, 22.08 mmol) was added dropwise with stirring, and the mixture was stirred at room temperature for 24 hours. LCMS showed complete conversion of the reaction, and the product was detected. The reaction solution was concentrated in vacuo to give crude compound C122-6.

[0404] Step 4: Compound C122-6 was dissolved in MeOH (20 mL). NaBH4 (2.98 g, 78.9 mmol) was added while stirring in an ice bath, and the mixture was slowly warmed to room temperature and stirred for 24 hours. LCMS showed that the reaction was completely converted, and the product was detected. After the reaction was completed, 150 mL of water was added to the reaction solution in an ice bath and extracted with EA (100 mL * 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give crude compound C122-7 (4.58 g).

[0405] Step 5: Compound C122-7 (6 g, 15.52 mmol) was dissolved in MeOH (50 mL). Pd / C (500 mg) was added with stirring, and the mixture was purged with hydrogen three times and stirred at room temperature for 12 hours. LCMS showed complete conversion of the reaction product, and the product was detected. After completion of the reaction, the mixture was filtered. The filtrate was distilled under reduced pressure to obtain crude compound C122-8.

[0406] The subsequent synthetic procedures were carried out in the same manner as described in Example 40 for the synthesis of compound C135. The final product C122 was obtained (10.57 mg, yield: 33.27%, purity: 99.96%).

[0407] Example 37: Preparation of Compound C131 [ka]

[0408] Step 1: Compound C131-1 (5 g, 25.71 mmol) and compound C131-2 (7.76 g, 38.56 mmol) were dissolved in DMF (70 mL). KOtBu (5.77 g, 51.42 mmol) was added with stirring, and the mixture was purged with nitrogen three times. The mixture was heated to 80 °C and stirred at this temperature for 4 h. TLC showed complete conversion of the starting material and the product was detected. After the reaction was completed, the mixture was filtered. The filtrate was added to 150 mL of water and extracted with EA (100 mL * 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography (pure EA) to give compound C131-3 (6.92 g, 96.7% yield).

[0409] The subsequent synthetic procedures were carried out in the same manner as described in the synthesis of compound C122. The final product C131 was obtained (3.32 mg, 30.47% yield, purity = 93.26%). LCMS: Rt = 1.831 min, [M+H] + = 805.5.

[0410] Example 38: Preparation of compound C132 [ka]

[0411] Step 1: Compound C132a (1.4 g, 4.92 mmol) was dissolved in DMF (15 mL) at room temperature. 2-Fluoro-5-nitrotoluene (0.84 g, 5.41 mmol) and cesium carbonate (4.8 g, 14.73 mmol) were added. The mixture was stirred at 120 °C for 5 hours. TLC showed complete conversion of the reaction, and a new spot was detected. The reaction solution was poured into water (100 mL) and extracted with ethyl acetate (30 mL * 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 0-4%) to give compound C132b (689 mg, yield: 33.36%).

[0412] Step 2: Compound C132b (393 mg, 0.94 mmol) was dissolved in methanol (5 mL) and dichloromethane (1 mL) at room temperature. Pd / C (10.00 mg, 0.094 mmol) (5%) was added, and the reaction solution was stirred at room temperature for 16 hours. LCMS showed complete conversion of the reaction, and the product was detected. The reaction solution was filtered and concentrated in vacuo to give crude compound C132c (364 mg, yield: 99.75%). LCMS: [M+H] + =390.3.

[0413] Step 3: Compound tert-butyl nitrite (288 mg, 2.79 mmol, 100% purity) and cuprous bromide (334 mg, 2.33 mmol) were dissolved in acetonitrile (5 mL) at room temperature and heated to 65 °C. Compound C132c (364 mg, 0.93 mmol) dissolved in acetonitrile (10 mL) was then added. The reaction solution was stirred at 65 °C for 2 hours under a nitrogen atmosphere. TLC showed complete conversion of the reactants, and a new spot was detected. The reaction solution was filtered and concentrated in vacuo to obtain the crude product. The crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 0-9%) to obtain compound C132b (73 mg, yield: 17.23%).

[0414] Step 4: Compound C132d (73 mg, 0.16 mmol) was dissolved in dioxane (5 mL) at room temperature. Bis(pinacolato)diboron (82 mg, 0.32 mmol, 100% pure), Pd(dppf)Cl₂·DCM (13 mg, 0.016 mmol), and potassium acetate (48 mg, 0.49 mmol) were added. The reaction solution was stirred at 100°C under a nitrogen atmosphere for 2 hours. LCMS showed complete conversion of the reactants, and the product was detected. The reaction solution was filtered and concentrated in vacuo to obtain the crude product. The crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 0-6%) to obtain compound C132e (56 mg, yield: 69.50%). LCMS: [M+H] + =501.4.

[0415] Step 5: Compound Warhead 3 (56 mg, 0.11 mmol) was dissolved in dioxane (5 mL) and water (1 mL) at room temperature. Compound C132e (55 mg, 0.11 mmol), potassium carbonate (46 mg, 0.33 mmol), and Pd(PPh3)4 (13 mg, 0.011 mmol) were added. The reaction solution was stirred at 80 °C under a nitrogen atmosphere for 16 hours. LCMS showed complete conversion of the reactants, and the product was detected. The reaction solution was filtered and concentrated in vacuo to obtain the crude product. The crude product was purified by silica gel chromatography (methanol:dichloromethane = 0-6%) to obtain compound C132f (86 mg, yield: 97.84%). LCMS: [M+H] + =809.6.

[0416] Step 6: Compound C132f (86 mg, 0.11 mmol) was dissolved in methanol (5 mL) and water (1 mL) at room temperature. NaOH (44 mg, 1.1 mmol) was added, and the reaction solution was stirred at room temperature for 2 hours. LCMS showed complete conversion of the reaction, and the product was detected. The reaction was poured into water (30 mL) and extracted with dichloromethane (30 mL * 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give crude compound C132g (71 mg, yield: 99.86%). LCMS: [M+H] + =669.5.

[0417] Step 7: Compound C132g (71 mg, 0.11 mmol) was dissolved in DCM (5 mL) at room temperature. Trifluoroacetic acid (1 mL) was added and the reaction solution was stirred at room temperature for 2 hours. LCMS showed complete conversion of the reaction and the product was detected. The reaction was concentrated in vacuo to give crude compound C132h (60 mg, yield: 99.38%). LCMS: [M+H] + =569.5.

[0418] Step 8: Compound C132h (60 mg, 0.11 mmol) was dissolved in DMSO (3 mL) at room temperature. 4-Chloro-3-(2,4-dioxotrihydropyrimidin-1(2H)-yl)benzoic acid (39 mg, 0.15 mmol), HATU (55 mg, 0.14 mmol), and DIPEA (71 mg, 0.55 mmol) were added. The reaction solution was stirred at room temperature for 16 hours. LCMS showed complete conversion of the reaction, and the product was detected. The reaction solution was poured into water (50 mL) and then extracted with dichloromethane (20 mL * 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain the crude product. Purification by pre-HPLC gave compound C132 (12.7 mg, yield: 14.60%). LCMS: [M+H] + =819.5.

[0419] 1H NMR (500 MHz, DMSO-d6) δ 11.97 (s, 1H), 10.52 (s, 1H), 8.80 (s, 1H), 8.35 (s, 1H), 8.12 (s, 1H), 8.08 (d, J = 2.3 Hz, 1H), 7.99 (d, J = 8.1 Hz, 2H), 7.65 (d, J = 8.2 Hz, 1H), 7.59 (s, 1H), 7.42 (d, J = 9.3 Hz, 1H), 7.15 (d, J = 8.0 Hz, 1H), 4.22 (m, 1H), 4.03 - 3.96 (m, 1H), 3.81 - 3.75 (m, 2H), 3.64 (m, 2H), 3.12 - 3.05 (m, 3H), 3.03 - 2.97 (m, 2H), 2.79 - 2.69 (m, 5H), 2.44 - 2.38 (m, 2H), 2.37 (s, 3H), 2.17 - 1.93 (m, 10H), 1.70 - 1.57 (m, 3H), 1.55 - 1.41 (m, 3H), 1.04 (t, J = 7.1 Hz, 3H).

[0420] Example 39: Preparation of compound C134 [ka] In step 1, 2-fluoro-5-nitrotoluene [ka] Compound C134 (12.7 mg, yield: 14.60%) was obtained according to the method described in Example 38, except for substituting: LCMS: [M+H] + =824.4.

[0421] C134c:LCMS:[M+H] + =390.3. C134e: LCMS: [M+H] + =501.4. C134f: LCMS: [M+H] + =809.6. C134g: LCMS: [M+H] + =669.5. C134h: LCMS: [M+H] + =569.5.

[0422] Example 40: Preparation of Compound C135 [ka]

[0423] Step 1: Compound C135-1 (2 g, 7.08 mmol), compound C135-2 (1.69 g, 10.62 mmol), and DIEA (1.83 g, 14.16 mmol) were dissolved in ACN (30 mL), heated to 90 °C, and stirred at this temperature for 3 h. TLC showed complete conversion of the starting material, and the product was detected. 50 mL of water was added to the reaction solution, and the mixture was extracted with EA (50 mL * 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to obtain a residue. The residue was purified by column chromatography (PE:EA = 4:1) to obtain compound C135-3 (2.34 g, 78.4% yield).

[0424] Step 2: Compound C135-3 (2.34 g, 5.55 mmol) was dissolved in MeOH (30 mL). Pd / C (230 mg) was added with stirring, and the hydrogen was replaced three times, followed by stirring at room temperature for 1 hour. LCMS showed complete conversion of the reaction product, and the product was detected. After completion of the reaction, filtration was carried out. The filtrate was distilled under reduced pressure to obtain crude compound C135-4.

[0425] Step 3: CuBr (0.95 g, 6.65 mmol) and tBuONO (0.86 g, 8.31 mmol) were dissolved in ACN (15 mL), purged with nitrogen three times, and heated to 65 °C and stirred for 10 minutes. The crude product C135-4 was dissolved in ACN (15 mL) and added dropwise with stirring. The temperature was maintained and the mixture was stirred for 2 hours. LCMS showed complete conversion of the reaction mixture, and the product was detected. After completion of the reaction, the reaction was filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography (PE:EA=9:1) to give compound C135-5 (335 mg, 13.3% yield).

[0426] Step 4: Compound C135-5 (0.34 g, 0.74 mmol), KOAc (0.22 g, 2.22 mmol), B2pin2 (0.38 g, 1.48 mmol), and pd(dppf)Cl2 (55 mg, 0.07 mmol) were dissolved in dioxane (5 mL). The mixture was purged with nitrogen three times, heated to 90 °C, and stirred for 2 h. LCMS showed complete conversion of the reaction mixture, and the product was detected. After completion of the reaction, the reaction was filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography (PE:EA = 4:1) to give compound C135-6 (270 mg, 73.1% yield).

[0427] Step 5: Compound C135-6 (248 mg, 0.49 mmol), Warhead 3 (170 mg, 0.33 mmol), Pd(PPh3)4 (38 mg, 0.07 mmol), and K2CO3 (127 mg, 0.99 mmol) were dissolved in DMSO and HO (3 mL / 0.5 mL). The mixture was purged with nitrogen three times, heated to 90 °C, and stirred for 12 h. LCMS showed complete conversion and the product was detected. After completion of the reaction, the reaction solution was filtered. After completion of the reaction, 50 mL of water was added to the reaction solution, and the mixture was extracted with DCM (30 mL * 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by preparative plate (DCM:MeOH = 4:1) to give compound C135-7 (96 mg, 43.3% yield).

[0428] Step 6: Compound C135-7 (116 mg, 0.17 mmol) was dissolved in DCM and TFA (3 mL / 0.5 mL) and stirred at room temperature for 1 hour. LCMS showed that the reaction was completely converted, and the product was detected. The reaction solution was distilled under reduced pressure to give crude compound C135-8.

[0429] Step 7: Compound C135-8, compound C135-9 (68.5 mg, 0.26 mmol), and NMI (49 mg, 0.6 mmol) were dissolved in DMSO (2 mL). TCFH (57 mg, 0.2 mmol) was added with stirring and stirred at room temperature for 2 hours. LCMS showed complete conversion of the reaction, and the product was detected. The product was purified by preparative chromatography to give the final product (45.22 mg, 32.00% yield, purity = 99.81%). LCMS: Rt = 2.153 min, [M+H] + =821.6.

[0430] Example 41: Preparation of Compound C136 [ka]

[0431] Step 1: Compound C136a (211 mg, 0.75 mmol) was dissolved in DMF (5 mL) at room temperature, and p-fluoronitrobenzene (127 mg, 0.90 mmol) and potassium carbonate (311 mg, 2.25 mmol) were added. The reaction solution was stirred at 100 °C for 3 hours. TLC showed complete conversion, and a new spot was detected. The reaction solution was poured into water (50 mL) and extracted with ethyl acetate (30 mL * 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain the crude product. The crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 0-14%) to obtain compound C136b (193 mg, yield: 64.02%).

[0432] Step 2: Compound C136b (193 mg, 0.48 mmol) was dissolved in methanol (5 mL) at room temperature, and Pd / C (20 mg, 0.19 mmol) (5%) was added. The reaction solution was stirred under a hydrogen atmosphere at room temperature for 16 hours. LCMS showed that the reaction was completely converted, and the product was detected. The reaction solution was filtered. The filtrate was concentrated in vacuo to give compound C136c (178 mg, yield: 99.63%). LCMS: [M+H] + =374.3.

[0433] Step 3: Tert-butyl nitrite (149 mg, 1.44 mmol) and CuBr (172 mg, 1.20 mmol) were dissolved in acetonitrile (5 mL) at room temperature and heated to 65 °C. Compound C136c (178 mg, 0.48 mmol) was then dissolved in acetonitrile (5 mL) and added, and the reaction solution was stirred at 65 °C for 2 h under a nitrogen atmosphere. TLC showed complete conversion of the reactants, and a new spot was detected. The reaction solution was filtered and concentrated in vacuo to obtain the crude product. The crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 0-7%) to obtain compound C136d (43 mg, 20.63%).

[0434] Step 4: Compound C136d (43 mg, 0.098 mmol) was dissolved in 1,4-dioxane (5 mL) at room temperature. Bis(pinacolato)diboron (50 mg, 0.20 mmol), potassium acetate (29 mg, 0.30 mmol), and Pd(dppf)Cl₂·DCM (8 mg, 0.0098 mmol) were added. The reaction solution was stirred at 80 °C under a nitrogen atmosphere for 16 h. TLC showed complete conversion, and a new spot was detected. The reaction solution was filtered and concentrated in vacuo to give the crude product. The crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 0-10%) to give compound C136e (50 mg, yield: 100%).

[0435] Step 5: Compound C136e (50 mg, 0.10 mmol) was dissolved in 1,4-dioxane (5 mL) and water (1 mL) at room temperature. C136f (50 mg, 0.10 mmol), tetrakis(triphenylphosphine)palladium (23.11 mg, 0.020 mmol), and potassium carbonate (55.28 mg, 0.40 mmol) were added. The mixture was stirred at 80 °C under a nitrogen atmosphere. LCMS showed complete conversion of the reaction, and the product was detected. The reaction solution was filtered and concentrated in vacuo to obtain the crude product. The crude product was purified by silica gel chromatography (methanol:dichloromethane = 0 to 7%) to obtain compound C136g (70 mg, yield: 44.33%). LCMS: [M+H] + =765.4.

[0436] Step 6: Compound C136g (70 mg, 0.092 mmol) was dissolved in dichloromethane (2 mL) and DMSO (2 mL) at room temperature. Paraformaldehyde (8.3 mg, 0.28 mmol) and acetic acid (10 mg, 0.17 mmol) were added. The mixture was stirred at 35 °C for 2 hours under a nitrogen atmosphere. Sodium triacetylborohydride (98 mg, 0.46 mmol) was then added to the mixture, and the reaction was stirred at 35 °C for 16 hours. LCMS showed complete conversion and the product was detected. The reaction solution was poured into water (50 mL) and then extracted with dichloromethane (30 mL * 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain the crude product. The crude product was purified by silica gel chromatography (methanol:dichloromethane = 0-6%) to obtain compound C136h (22 mg, yield: 30.82%). LCMS: [M+H] + =779.5.

[0437] Step 7: Compound C136h (22 mg, 0.028 mmol) was dissolved in methanol (5 mL) and water (1 mL) at room temperature. NaOH (11 mg, 0.28 mmol) was added, and the reaction solution was stirred at room temperature for 2 hours. LCMS showed complete conversion of the reaction, and the product was detected. The reaction was poured into water (20 mL) and extracted with dichloromethane (20 mL*2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give crude compound C136i (18 mg, yield: 99.74%). LCMS: [M+H] + =639.5.

[0438] Step 8: Compound C136i (18 mg, 0.028 mmol) was dissolved in DCM (5 mL) at room temperature. TFA (5 mL) was added, and the reaction solution was stirred at room temperature for 1 hour. LCMS showed complete conversion of the reaction, and the product was detected. The reaction was concentrated in vacuo to give crude compound C136j (15 mg, 98.79% yield), which was used in the next step without purification. LCMS: [M+H] + =539.4.

[0439] Step 9: Compound C136j (15 mg, 0.028 mmol) was dissolved in DMSO (2 mL) at room temperature. 4-Chloro-3-(2,4-dioxotrihydropyrimidin-1(2H)-yl)benzoic acid (10 mg, 0.037 mmol), HATU (14 mg, 0.037 mmol), and DIEA (20 mg, 0.15 mmol) were added. The reaction solution was stirred at room temperature for 16 hours. LCMS showed complete conversion of the reaction, and the product was detected. The reaction solution was poured into water (50 mL) and then extracted with dichloromethane (20 mL * 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain the crude product. The crude product was purified by pre-HPLC to obtain compound C136 (4.82 mg, yield: 21.95%). LCMS: Rt = 1.999 min; [M+H] + =789.5.

[0440] Example 42: Preparation of Compound C137 [ka]

[0441] Step 1: Compound 1-tert-butoxycarbonyl-4-fluoro-4-(hydroxymethyl)piperidine (2.1 g, 9.00 mmol) was added to a solution of hydrochloric acid (10 mL) in dioxane (4 M) at room temperature and stirred for 1 hour. The reaction solution was concentrated in vacuo to give crude compound C137a (PO, 1.53 g, yield: 100%), which was used directly in the next step.

[0442] Step 2: Compound C137a was dissolved in DMF (10 mL) at room temperature, and p-fluoronitrobenzene (1.53 g, 10.84 mmol) and potassium carbonate (3.74 g, 27.06 mmol) were added. The mixture was stirred at 80°C under a nitrogen atmosphere for 3 hours. TLC showed complete conversion of the reaction product, and a new point was detected. The reaction solution was poured into water (50 mL) and then extracted with ethyl acetate (30 mL * 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain the crude product. The crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 0 to 47%) to obtain compound C137b (1.3 g, yield: 56.74%).

[0443] Step 3: Compound C137b (1.2 g, 4.72 mmol) was dissolved in acetonitrile (20 mL) at room temperature. IBX (3.95 g, 14.11 mmol) was added, and the reaction solution was stirred at 55 °C for 6 hours. TLC showed complete conversion of the reactants, and a new spot was detected. The reaction solution was filtered to obtain a filtrate. The filtrate was rotary evaporated to obtain crude compound C137c (1.19 g, yield: 99.96%).

[0444] Step 4: Compound C137c (1.19 g, 4.72 mmol) was dissolved in dichloromethane (20 mL) and dimethyl sulfoxide (10 mL) at room temperature. Tert-butyl piperazine-1-carboxylate (1.3 g, 6.98 mmol) was added, and the reaction solution was stirred at room temperature for 1 hour. NaBH(OAc)3 (3 g, 14.15 mmol) was then added, and the mixture was stirred for 16 hours. TLC showed complete conversion, and a new spot was detected. The reaction solution was poured into water (30 mL), followed by extraction with dichloromethane (30 mL * 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 0-23%) to give compound C137d (870 mg, yield: 43.65%).

[0445] Step 5: Compound C137d (870 mg, 2.06 mmol) was dissolved in methanol (10 mL) and dichloromethane (2 mL) at room temperature. Wet palladium on carbon (219.23 mg, 2.06 mmol) (5%) was added, and the reaction solution was stirred under a hydrogen atmosphere at room temperature for 16 hours. LCMS showed complete conversion of the reaction, and the product was detected. The reaction solution was filtered and concentrated in vacuo to obtain the crude product. The crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 0 to 56%) to obtain compound C137e (360 mg, yield: 44.54%). LCMS: [M+H] + =393.3.

[0446] Step 6: Cuprous bromide (330 mg, 2.30 mmol) and tert-butyl nitrite (285 mg, 2.76 mmol) were dissolved in acetonitrile (5 mL) at room temperature and heated to 65°C. Compound C137e (360 mg, 0.92 mmol) was then dissolved in acetonitrile (5 mL) and added, and the reaction solution was stirred at 65°C for 2 hours under a nitrogen atmosphere. LCMS showed complete conversion of the reactants, and the product was detected. The reaction solution was filtered. The filtrate was concentrated in vacuo to obtain the crude product. The crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 0 to 25%) to obtain compound C137f (113 mg, yield: 27.00%). LCMS: [M+H] + =456.2.

[0447] Step 7: Compound C137f (113 mg, 0.25 mmol) was dissolved in dioxane (5 mL) at room temperature. Pd(dppf)Cl2·DCM (20 mg, 0.024 mmol), bis(pinacolato)diboron (127 mg, 0.50 mmol), and potassium acetate (74 mg, 0.75 mmol) were added. The mixture was stirred at 80 °C under a nitrogen atmosphere for 16 hours. LCMS showed complete conversion of the reaction, and the product was detected. The reaction solution was filtered and concentrated in vacuo to obtain the crude product. The crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 0-9%) to obtain compound C137g (99 mg, yield: 79.42%). LCMS: [M+H] + =504.4.

[0448] Step 8: Compound Warhead 3 (80 mg, 0.16 mmol) was dissolved in dioxane (5 mL) and water (1 mL) at room temperature. C137g (99 mg, 0.20 mmol), potassium carbonate (67 mg, 0.48 mmol), and tetrakis(triphenylphosphine)palladium (18 mg, 0.016 mmol) were added. The mixture was stirred under a nitrogen atmosphere at 80 °C for 3 hours. LCMS showed complete conversion of the reaction, and the product was detected. The reaction solution was poured into water (50 mL) and extracted with dichloromethane (30 mL * 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain the crude product. The crude product was purified by silica gel chromatography (methanol:dichloromethane = 0-6%) to obtain compound C137h (63 mg, yield: 49.99%). LCMS: [M+H] + =812.5.

[0449] Step 9: Compound C137h (63 mg, 0.078 mmol) was dissolved in methanol (5 mL) and water (1 mL) at room temperature. Sodium hydroxide (32 mg, 0.80 mmol) was added. The reaction solution was stirred at room temperature for 2 hours. LCMS showed complete conversion of the reaction, and the product was detected. The reaction was poured into water (50 mL) and then extracted with dichloromethane (30 mL*2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give crude compound C137i (52 mg, yield: 99.76%). LCMS: [M+H] + =672.5.

[0450] Step 10: Compound C137i (52 mg, 0.077 mmol) was dissolved in DCM (5 mL) at room temperature. TFA (1 mL) was added, and the reaction solution was stirred at room temperature for 2 hours. LCMS showed that the reaction was completely converted, and the product was detected. The reaction solution was concentrated in vacuo to give crude compound C137j (44 mg, yield: 99.43%), which was used directly in the next step. LCMS: [M+H] + =572.5.

[0451] Step 11: Compound C137j (44 mg, 0.077 mmol) was dissolved in DMSO (2 mL) at room temperature. 4-Chloro-3-(2,4-dioxotrihydropyrimidin-1(2H)-yl)benzoic acid (23 mg, 0.086 mmol), HATU (38 mg, 0.10 mmol), and DIPEA (50 mg, 0.39 mmol) were added. The reaction solution was stirred at room temperature for 16 hours. LCMS showed complete conversion of the reaction, and the product was detected. The reaction solution was poured into water (50 mL) and then extracted with dichloromethane (30 mL * 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain the crude product. The crude product was purified by pre-HPLC to obtain compound C137 (10.26 mg, yield: 16.18%). LCMS: [M+H] + =822.5.

[0452] Example 43: Preparation of compound C140 [ka]

[0453] Step 1: Compound C140e (50 mg, 0.10 mmol, which can be prepared according to Steps 1 to 4 of Example 41) was dissolved in dioxane (5 mL) and water (1 mL) at room temperature. Compound C140f (42 mg, 0.10 mmol), Pd(dppf)Cl·DCM (8 mg, 0.010 mmol), and potassium carbonate (42 mg, 0.30 mmol) were added. The reaction solution was stirred at 90 °C under a nitrogen atmosphere for 16 hours. The reaction solution was filtered and concentrated in vacuo to give the crude product, compound C140g (71 mg, yield: 99.95%).

[0454] Step 2: Compound C140g (71 mg, 0.099 mmol) was dissolved in methanol (5 mL) and water (1 mL) at room temperature. NaOH (40 mg, 0.99 mmol) was added, and the reaction solution was stirred at room temperature for 2 hours. LCMS showed complete conversion of the reaction, and the product was detected. The reaction solution was filtered and concentrated in vacuo to obtain the crude product. The crude product was purified by silica gel chromatography (methanol:dichloromethane = 0 to 4%) to obtain compound C140h (44 mg, yield: 77.11%). LCMS: [M+H] + =574.4.

[0455] Step 3: Compound C140h (44 mg, 0.077 mmol) was dissolved in a solution of hydrochloric acid in dioxane (5 mL, 4 M) at room temperature and stirred for 1 hour. LCMS showed complete conversion of the reaction, and the product was detected. The reaction was concentrated in vacuo to give crude compound C140i (39 mg, yield: 99.70%). LCMS: [M+H] + =474.3.

[0456] Step 4: Compound C140i (39 mg, 0.076 mmol) was dissolved in DMSO (3 mL) at room temperature. 4-Chloro-3-(2,4-dioxotrihydropyrimidin-1(2H)-yl)benzoic acid (20 mg, 0.076 mmol), TCFH (28 mg, 0.099 mmol), and NMI (31 mg, 0.38 mmol) were added. The reaction solution was stirred at room temperature for 16 hours. LCMS showed complete conversion of the reaction, and the product was detected. The reaction solution was poured into water (30 mL) and then extracted with dichloromethane (20 mL * 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain the crude product. The crude product was purified by pre-HPLC to obtain compound C140 (5.71 mg, yield: 10.23%). LCMS: [M+H] + =707.3.

[0457] 1 H NMR (500 MHz, DMSO-d6) δ 9.01 (d, J = 207.9 Hz, 1H), 8.44 - 8.06 (m, 2H), 7.87 - 7.17 (m, 3H), 6.96 (d, J = 7.5 Hz, 1H), 4.22 - 3.79 (m, 4H), 3.52 (s, 1H), 3.00 (d, J = 11.9 Hz, 2H), 2.75 (s, 1H), 1.87 - 1.69 (m, 3H), 1.64 - 1.23 (m,5H)

[0458] Example 44: Preparation of Compound C153 [ka] Compound C153a (30 mg, 0.054 mmol) was dissolved in DMSO (3 mL) at room temperature, and C153b (14 mg, 0.056 mmol), TCFH (16 mg, 0.057 mmol), and NMI (23 mg, 0.28 mmol) were added. The reaction solution was stirred at room temperature for 16 hours. LCMS showed complete conversion of the reaction, and the product was detected. The reaction solution was poured into water (50 mL) and then extracted with dichloromethane (30 mL * 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain the crude product. The crude product was purified by pre-HPLC to obtain compound C153 (5.13 mg, yield: 12.06%). LCMS: [M+H] + =783.6.

[0459] 1 H NMR (500 MHz, DMSO-d6) δ 11.92 (s, 1H), 10.38 (s, 1H), 8.77 (s, 1H), 8.34 (s, 1H), 8.12 - 8.00 (m, 4H), 7.34 (d, J = 7.9 Hz, 1H), 7.31 (s, 1H), 7.25 (d, J = 7.5 Hz, 1H), 7.07 (d, J = 8.8 Hz, 2H), 4.54 - 4.42 (m, 1H), 4.27 - 4.19 (m, 1H), 3.86 - 3.77 (m, 3H), 3.55 - 3.51 (m, 2H), 3.00 (d, J = 11.1 Hz, 2H), 2.82 - 2.65 (m, 5H), 2.39 (q, J = 7.2 Hz, 2H), 2.22 (s, 3H), 2.13 - 1.93 (m, 6H), 1.87 - 1.50 (m, 7H), 1.29 - 1.16 (m, 4H), 1.14 - 1.06 (m, 2H), 1.04 (t, J = 7.1 Hz, 3H).

[0460] Example 45: Preparation of Compound C154 [ka] Compound C154a (30 mg, 0.054 mmol) was dissolved in DMSO (3 mL) at room temperature. C154b (14 mg, 0.056 mmol), TCFH (16 mg, 0.057 mmol), and NMI (23 mg, 0.28 mmol) were added. The reaction solution was stirred at room temperature for 16 hours. LCMS showed complete conversion of the reaction, and the product was detected. The reaction solution was poured into water (50 mL) and then extracted with dichloromethane (30 mL * 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain the crude product. The crude product was purified by pre-HPLC to obtain compound C154 (5.16 mg, yield: 12.06%). LCMS: [M+H] + =787.6.

[0461] 1 H NMR (500 MHz, DMSO-d6) δ 11.92 (s, 1H), 10.53 (s, 1H), 8.77 (s, 1H), 8.34 (s, 1H), 8.14 - 7.99 (m, 4H), 7.50 (d, J = 6.8 Hz, 1H), 7.38 (d, J = 8.6 Hz, 2H), 7.07 (d, J = 8.5 Hz, 2H), 4.52 - 4.38 (m, 1H), 4.27 - 4.16 (m, 1H), 3.82 (d, J = 12.1 Hz, 2H), 3.76 (t, J = 6.5 Hz, 2H), 3.00 (d, J = 11.0 Hz, 2H), 2.78 - 2.35 (m, 4H), 2.39 (q, J = 7.1 Hz, 2H), 2.10 - 1.95 (m, 6H), 1.85 - 1.43 (m, 7H), 1.29 - 1.16 (m, 4H), 1.15 - 1.07 (m, 2H), 1.04 (t, J = 7.2 Hz, 3H).

[0462] Example 46: Preparation of Compound C160 [ka]

[0463] Step 1: Compound C160a (6.2 g, 31.95 mmol) was dissolved in DMF (50 mL) at room temperature. Cesium carbonate (12.49 g, 38.34 mmol) and deuterated iodomethane (5.09 g, 35.15 mmol) were added. The mixture was stirred at room temperature for 16 hours. LCMS showed complete conversion of the reaction, and the product was detected. The reaction solution was filtered, and the filtrate was concentrated in vacuo to give crude compound C160b (6.72 g, yield: 99.64%). LCMS: [M+H] + =211.1.

[0464] Step 2: Compound C160b (1 g, 2.15 mmol) was dissolved in dioxane (10 mL) and water (3 mL) at room temperature. Compound C160c (0.54 g, 2.58 mmol), potassium carbonate (0.89 g, 6.45 mmol), and Pd(dppf)Cl₂·DCM (88 mg, 0.11 mmol) were added. The reaction solution was stirred at 80°C under a nitrogen atmosphere for 4 hours. LCMS showed complete conversion of the reaction, and the product was detected. The reaction solution was filtered and concentrated in vacuo to obtain the crude product. The crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 0 to 30%) to obtain compound C160d (322 mg, yield: 35.47%). LCMS: [M+H] + =422.4.

[0465] Step 3: Compound C160d (60 mg, 0.14 mmol) was dissolved in dioxane (5 mL) and water (1 mL) at room temperature. Compound C160e (59 mg, 0.15 mmol), tetrakis(triphenylphosphine)palladium (8 mg, 0.0071 mmol), and potassium carbonate (60 mg, 0.43 mmol) were added. The reaction solution was stirred at room temperature for 16 hours. LCMS showed complete conversion of the reaction, and the product was detected. The reaction was concentrated in vacuo to give crude compound C160f (99 mg, yield: 99.32%). LCMS: [M+H] + =699.4.

[0466] Step 4: Compound C160f (99 mg, 0.14 mmol) was dissolved in methanol (SO, 5 mL) and water (1 mL) at room temperature. Sodium hydroxide (56.00 mg, 1.40 mmol) was added. The reaction solution was stirred at room temperature for 1 hour. LCMS showed complete conversion of the reaction, and the product was detected. The reaction solution was concentrated in vacuo to obtain the crude product. The crude product was purified by silica gel chromatography (methanol:dichloromethane = 0 to 3%) to obtain compound C160g (70 mg, yield: 88.41%). LCMS: [M+H] + =560.4.

[0467] Step 5: Compound C160g (70 mg, 0.13 mmol) was dissolved in methanol (5 mL) at room temperature. A solution of hydrochloric acid in dioxane (5 mL) was added, and the reaction solution was stirred at room temperature for 2 hours. LCMS showed complete conversion of the reaction, and the product was detected. The reaction was concentrated in vacuo to give crude compound C160h (62 mg, yield: 99.94%). LCMS: [M+H] + =460.5.

[0468] Step 6: Compound C160h (62 mg, 0.12 mmol) was dissolved in DMSO (3 mL) at room temperature. 4-Chloro-3-(2,4-dioxotrihydropyrimidin-1(2H)-yl)benzoic acid (39 mg, 0.15 mmol), TCFH (44 mg, 0.16 mmol), and NMI (50 mg, 0.61 mmol) were added. The reaction solution was stirred at room temperature for 2 hours. LCMS showed complete conversion of the reaction, and the product was detected. The reaction solution was poured into water (30 mL) and then extracted with dichloromethane (30 mL * 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain the crude product. The crude product was purified by pre-HPLC to obtain compound C160 (22.68 mg, yield: 25.07%). LCMS: [M+H] + =710.4. 1H NMR (500 MHz, DMSO-d6) δ 11.98 (s, 1H), 10.54 (s, 1H), 8.97 (s, 1H), 8.80 (s, 1H), 8.34 (d, J = 7.4 Hz, 2H), 8.09 (s, 1H), 8.03 (s, 1H), 7.64 (d, J = 8.2 Hz, 1H), 7.56 (s, 1H), 7.39 (d, J = 8.2 Hz, 1H), 6.97 (d, J = 8.9 Hz, 1H), 4.43 (dd, J = 25.0, 12.6 Hz, 3H), 3.81 - 3.72 (m, 1H), 3.66 - 3.51 (m, 2H), 2.86 (d, J = 12.2 Hz, 2H), 2.81 - 2.67 (m, 3H), 1.70 (dd, J = 49.1, 15.4 Hz, 6H), 1.31 - 0.96 (m, 7H).

[0469] Example 47: Preparation of Compound C162 [ka]

[0470] Step 1: Compounds C162a (1.0 g, 4.5 mmol), C162b (3.7 g, 4.1 mmol), catalyst (150 mg, 0.2 mmol), and potassium carbonate (1.7 g, 12.3 mmol) were sequentially added to a 250 mL one-neck flask, followed by 30 mL of dioxane and 10 mL of water as solvent. A condenser was then attached to the flask. After purging with nitrogen three times using a three-way valve, the flask was heated to 80 °C and reacted for 3 h. The reaction was then confirmed to be complete by LCMS. After filtering the reaction solution, water and dichloromethane were added and extracted three times (10 mL each). The organic phase was cooled, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (EA / PE = 30%). Product C162c (1.05 g, 2.4 mmol) was obtained in 53.3% yield.

[0471] Step 2: Compound C162c (95 mg, 0.22 mmol), C162d (80 mg, 0.20 mmol), catalyst tetrakis(triphenylphosphine)palladium (23 mg, 0.02 mmol), and potassium carbonate (82 mg, 0.60 mmol) were sequentially added to a 100 mL one-neck flask, followed by 10 mL of dioxane and 1 mL of water as solvent. A condenser was then attached to the flask. After three nitrogen purges using a three-way valve, the flask was heated to 90 °C and reacted for 16 h. The reaction was then confirmed to be complete by LCMS. The reaction solution was filtered, concentrated, and used directly in the next step.

[0472] Step 3: The crude product C162e (crude) from step 2 was placed in a 100 mL reaction flask. 5 mL of methanol solvent was added, followed by aqueous sodium hydroxide (100 mg) solution. The reaction was continued at room temperature for approximately 2 hours, after which a small amount of the reaction solution was collected. LCMS confirmed the completion of the reaction. The reaction solution was filtered and extracted three times with dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (MeOH / CHCl=4%) to give product C162f (80 mg).

[0473] Step 4: Compound C162f was added to a 100 mL single-neck flask. HCl / dioxane (2 mol / L, 1 mL) was added, partially precipitating the solid. 2 mL of methanol was added to aid dissolution. After reacting at room temperature for 2 hours, LCMS confirmed the reaction was complete. The solvent was directly evaporated to dryness, and the product was used as the starting material for the next step.

[0474] Step 5: Compounds C162g (50 mg, 0.10 mmol), C162h (35 mg, 0.13 mmol), TCFH (38 mg, 0.14 mmol), and 1-methylimidazole (34 mg, 0.41 mmol) were added sequentially to a 100 mL single-neck flask. The reaction was allowed to proceed overnight at room temperature for 16 hours, and completion of the reaction was confirmed by LCMS. The final product C162 (20.78 mg, 0.02 mmol) was obtained in 30% yield by preparative chromatography. [M+H] + =721.3.

[0475] 1 H NMR (500 MHz, DMSO-d6) δ 11.96 (s, 1H), 10.51 (s, 1H), 8.96 (d, J = 2.2 Hz, 1H), 8.79 (s, 1H), 8.41 - 8.29 (m, 2H), 8.08 (d, J = 2.6 Hz, 1H), 8.05 (s, 1H), 7.64 (d, J = 8.2 Hz, 1H), 7.55 (d, J = 1.7 Hz, 1H), 7.39 (dd, J = 8.2, 1.7 Hz, 1H), 6.96 (d, J = 9.1 Hz, 1H), 4.51 - 4.37 (m, 3H), 4.23 (q, J = 7.3 Hz, 2H), 3.82 - 3.72 (m, 1H), 3.66 - 3.53 (m, 2H), 3.13 - 3.02 (m, 1H), 2.87 (t, J = 11.9 Hz, 2H), 2.75 (q, J = 7.7, 6.7 Hz, 2H), 1.84 - 1.58 (m, 6H), 1.43 (t, J = 7.3 Hz, 3H), 1.29 - 1.02 (m, 7H).

[0476] Example 48: Preparation of Compound C163 [ka]

[0477] Step 1: Compound C163a (1.78 g, 6.29 mmol) was dissolved in DMF (20 mL) at room temperature. 3,4-Difluoronitrobenzene (1 g, 6.29 mmol) and potassium carbonate (2.61 g, 18.87 mmol) were added. The reaction solution was stirred at 85 °C under a nitrogen atmosphere for 3 hours. TLC showed complete conversion of the reactants, and a new spot was detected. The reaction solution was filtered and concentrated in vacuo to obtain the crude product. The crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 0-19%) to obtain compound C163b (1.5 g, yield: 56.61%).

[0478] Step 2: Compound C163b (1.5 g, 3.56 mmol) was dissolved in methanol (30 mL) at room temperature, and Pd / C (0.038 g, 0.36 mmol) (5%) was added. The reaction solution was stirred under a hydrogen atmosphere at room temperature for 4 hours. TLC showed complete conversion of the reactants, and a new spot was detected. The reaction solution was filtered and concentrated in vacuo to give crude compound C163c (1.39 g, yield: 99.76%).

[0479] Step 3: Tert-butyl nitrite (1.10 g, 10.65 mmol) and cuprous bromide (R2, 1.53 g, 10.65 mmol) were dissolved in acetonitrile (10 mL) at room temperature and heated to 65 °C. Compound C163c (1.39 g, 3.55 mmol) dissolved in acetonitrile (10 mL) was then added. The reaction solution was stirred at 65 °C for 2 hours under a nitrogen atmosphere. TLC showed complete conversion of the reactants, and a new spot was detected. The reaction solution was filtered and concentrated in vacuo to obtain the crude product. The crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 0-13%) to obtain compound C163d (296 mg, yield: 18.31%).

[0480] Step 4: Compound C163d (296 mg, 0.65 mmol) was dissolved in dioxane (3 mL) at room temperature. Bis(pinacolato)diboron (0.33 g, 1.3 mmol), Pd(dppf)Cl₂·DCM (53 mg, 0.065 mmol), and potassium acetate (0.19 g, 1.95 mmol) were added. The reaction solution was stirred at 100°C under a nitrogen atmosphere for 16 hours. LCMS showed complete conversion of the reactants, and the product was detected. The reaction solution was filtered and concentrated in vacuo to obtain the crude product. The crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 0-9%) to obtain compound C163e (320 mg, yield: 97.98%). LCMS: [M+H] + =503.3.

[0481] Step 5: Compound C163e (50 mg, 0.10 mmol) was dissolved in dioxane (5 mL) and water (1 mL) at room temperature. Compound C163f (42 mg, 0.10 mmol), Pd(dppf)Cl₂·DCM (8 mg, 0.010 mmol), and potassium carbonate (42 mg, 0.30 mmol) were added. The reaction solution was stirred at 90 °C under a nitrogen atmosphere for 16 hours. The reaction solution was filtered and concentrated in vacuo to give the crude product, compound C163g (71 mg, yield: 99.95%).

[0482] Step 6: Compound C163g (71 mg, 0.099 mmol) was dissolved in methanol (5 mL) and water (1 mL) at room temperature. NaOH (40 mg, 0.99 mmol) was added, and the reaction solution was stirred at room temperature for 2 hours. LCMS showed complete conversion of the reaction, and the product was detected. The reaction solution was filtered and concentrated in vacuo to obtain the crude product. The crude product was purified by silica gel chromatography (methanol:dichloromethane = 0 to 4%) to obtain compound C163h (44 mg, yield: 77.11%). LCMS: [M+H] + =574.4.

[0483] Step 7: Compound C163h (44 mg, 0.077 mmol) was dissolved in a solution of hydrochloric acid in dioxane (5 mL, 4 M) at room temperature and stirred for 1 hour. LCMS showed complete conversion of the reaction, and the product was detected. The reaction was concentrated in vacuo to give crude compound C163i (39 mg, yield: 99.70%). LCMS: [M+H] + =474.3.

[0484] Step 8: Compound C163i (39 mg, 0.076 mmol) was dissolved in DMSO (3 mL) at room temperature. 4-Chloro-3-(2,4-dioxotrihydropyrimidin-1(2H)-yl)benzoic acid (20 mg, 0.076 mmol), TCFH (28 mg, 0.099 mmol), and NMI (31 mg, 0.38 mmol) were added. The reaction solution was stirred at room temperature for 16 hours. LCMS showed complete conversion of the reaction, and the product was detected. The reaction solution was poured into water (30 mL) and then extracted with dichloromethane (20 mL * 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain the crude product. The crude product was purified by pre-HPLC to obtain compound C163 (5.71 mg, yield: 10.23%). LCMS: Rt = 2.019 min; [M+H] + =724.4.

[0485] Example 49: Preparation of Compound C164 [ka] Compound C164a (79 mg, 0.17 mmol) was dissolved in DMSO (3 mL) at room temperature. 3-(2,4-Dioxotrihydropyrimidin-1(2H)-yl)-4-fluorobenzoic acid (56.16 mg, 0.22 mmol), HATU (97 mg, 0.26 mmol), and DIPEA (110 mg, 0.85 mmol) were added. The reaction solution was stirred at room temperature for 16 hours. LCMS showed complete conversion of the reaction, and the product was detected. The reaction solution was poured into water (30 mL) and then extracted with dichloromethane (20 mL * 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain the crude product. The crude product was purified by pre-HPLC to obtain compound C164 (4.33 mg, yield: 3.59%). LCMS: Rt = 2.196 min; [M+H] + =691.4.

[0486] Example 50: Preparation of Compound C165 [ka] Compound C165a (79 mg, 0.17 mmol) was dissolved in DMSO (3 mL) at room temperature. 3-(2,4-Dioxotrihydropyrimidin-1(2H)-yl)-4-methylbenzoic acid (60 mg, 0.22 mmol), HATU (97 mg, 0.26 mmol), and DIPEA (110 mg, 0.85 mmol) were added. The reaction solution was stirred at room temperature for 16 hours. LCMS showed complete conversion of the reaction, and the product was detected. The reaction solution was poured into water (30 mL) and extracted with dichloromethane (20 mL * 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain the crude product. The crude product was purified by pre-HPLC to obtain compound C165 (4.42 mg, yield: 3.61%). LCMS: Rt = 2.200 min; [M+H] + =687.5.

[0487] Example 51: Preparation of Compound C167 [ka]

[0488] Step 1: Compound C167a (6.2 g, 31.95 mmol) was dissolved in DMF (50 mL) at room temperature. Cesium carbonate (12.49 g, 38.34 mmol) and difluoroiodomethane (5.09 g, 35.15 mmol) were added. The mixture was stirred at room temperature for 16 hours. LCMS showed complete conversion of the reaction, and the product was detected. The reaction solution was filtered, and the filtrate was concentrated in vacuo to give crude compound C167b (6.72 g, yield: 99.64%). LCMS: [M+H] + =211.1.

[0489] Step 2: Compound C167b (1 g, 2.15 mmol) was dissolved in dioxane (10 mL) and water (3 mL) at room temperature. Compound C167c (0.54 g, 2.58 mmol), potassium carbonate (0.89 g, 6.45 mmol), and Pd(dppf)Cl₂·DCM (88 mg, 0.11 mmol) were added. The reaction solution was stirred at 80°C under a nitrogen atmosphere for 4 hours. LCMS showed complete conversion of the reaction, and the product was detected. The reaction solution was filtered and concentrated in vacuo to obtain the crude product. The crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 0 to 30%) to obtain compound C167d (322 mg, yield: 35.47%). LCMS: [M+H] + =422.4.

[0490] Step 3: Compound C167d (60 mg, 0.14 mmol) was dissolved in dioxane (5 mL) and water (1 mL) at room temperature. Compound C167e (59 mg, 0.15 mmol), tetrakis(triphenylphosphine)palladium (8 mg, 0.0071 mmol), and potassium carbonate (60 mg, 0.43 mmol) were added. The reaction solution was stirred at room temperature for 16 hours. LCMS showed complete conversion of the reaction, and the product was detected. The reaction was concentrated in vacuo to give crude compound C167f (99 mg, yield: 99.32%). LCMS: [M+H] + =699.4.

[0491] Step 4: Compound C167f (99 mg, 0.14 mmol) was dissolved in methanol (SO, 5 mL) and water (1 mL) at room temperature. Sodium hydroxide (56.00 mg, 1.40 mmol) was added. The reaction solution was stirred at room temperature for 1 hour. LCMS showed complete conversion of the reaction, and the product was detected. The reaction solution was concentrated in vacuo to obtain the crude product. The crude product was purified by silica gel chromatography (methanol:dichloromethane = 0 to 3%) to obtain compound C167g (70 mg, yield: 88.41%). LCMS: [M+H] + =560.4.

[0492] Step 5: Compound C167g (70 mg, 0.13 mmol) was dissolved in methanol (5 mL) at room temperature. A solution of hydrochloric acid in dioxane (5 mL) was added, and the reaction solution was stirred at room temperature for 2 hours. LCMS showed complete conversion of the reaction, and the product was detected. The reaction was concentrated in vacuo to give crude compound C167h (62 mg, yield: 99.94%). LCMS: [M+H] + =460.5.

[0493] Step 6: Compound C167h (62 mg, 0.12 mmol) was dissolved in DMSO (3 mL) at room temperature. 4-Chloro-3-(2,4-dioxotrihydropyrimidin-1(2H)-yl)benzoic acid (39 mg, 0.15 mmol), TCFH (44 mg, 0.16 mmol), and NMI (50 mg, 0.61 mmol) were added. The reaction solution was stirred at room temperature for 2 hours. LCMS showed complete conversion of the reaction, and the product was detected. The reaction solution was poured into water (30 mL) and then extracted with dichloromethane (30 mL * 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain the crude product. The crude product was purified by pre-HPLC to obtain compound C167 (22.68 mg, yield: 25.07%). LCMS: [M+H] + =743.2.

[0494] 1 H NMR (500 MHz, DMSO-d6) δ 9.21 (s, 1H), 9.01 - 8.35 (m, 4H), 8.41 - 7.99 (m, 2H), 7.73 - 6.76 (m, 6H), 4.30 - 3.80 (m, 6H), 3.21 - 2.62 (m, 6H), 1.99 - 1.53 (m, 9H), 1.48 - 1.18 (m, 6H).

[0495] Example 52: Preparation of Compound C169 [ka]

[0496] Step 1: C169a (2.0 g, 10.3 mmol) was dissolved in 20 mL of DMF. Sodium hydride (1.2 g, 30.9 mmol) was added in an ice bath and the reaction was allowed to proceed for 30 minutes. C169b (3.5 g, 20.6 mmol) was added and the reaction was allowed to proceed for 2 hours. LC-MS showed complete conversion of the reaction product, and the product was detected. LC-MS showed complete conversion of the reaction product, and the product was detected. The reaction was then completed. Saturated aqueous ammonium chloride was added to quench the reaction. The reaction solution was extracted three times with ethyl acetate (20 mL*3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. After purification by silica gel chromatography (EA / PE=1:2), the product C169c (2.2 g, 9.3 mmol) was obtained in 90.3% yield.

[0497] Step 2: Compounds C169c (2.1 g, 8.9 mmol), C169d (3.7 g, 8.0 mmol), catalyst (295 mg, 0.4 mmol), and potassium carbonate (3.35 g, 24.2 mmol) were sequentially added to a 250 mL one-neck flask, followed by 60 mL of dioxane and 20 mL of water as solvent. A condenser was then attached to the flask. After purging with nitrogen three times using a three-way valve, the flask was heated to 80 °C and reacted for 3 h. The reaction was then completed by LCMS. The reaction solution was filtered, and water and dichloromethane were added, followed by extraction three times (10 mL each). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (EA / PE = 30%). Product C169e (1.13 g, 2.5 mmol) was obtained in 31.3% yield.

[0498] Step 3: Compounds C169e (97 mg, 0.22 mmol), C169f (80 mg, 0.20 mmol), tetrakis(triphenylphosphine)palladium (23 mg, 0.02 mmol) as a catalyst, and potassium carbonate (82 mg, 0.60 mmol) were sequentially added to a 100 mL single-neck flask, followed by 10 mL of dioxane and 1 mL of water as a solvent. A condenser was then attached to the single-neck flask. After three nitrogen purges using a three-way valve, the flask was heated to 90 °C and reacted for 16 h. The reaction was then confirmed to be complete by LCMS. The reaction solution was filtered, concentrated, and used directly in the next step.

[0499] Step 4: The crude product C169g (crude) from step 3 was added to a 100 mL reaction flask. 5 mL of methanol solvent was added, followed by aqueous sodium hydroxide (100 mg) solution. The reaction was continued at room temperature for approximately 2 hours, after which a small amount of the reaction solution was collected. LCMS confirmed the reaction was complete. The reaction solution was filtered and extracted three times with dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (MeOH / CHCl=4%) to give product C169h (80 mg).

[0500] Step 5: Compound C169h was added to a 100 mL single-neck flask. HCl / dioxane (2 mol / L, 1 mL) was added, partially precipitating the solid. 2 mL of methanol was added to aid dissolution. After 2 hours of reaction at room temperature, LCMS confirmed the reaction was complete. The solvent was directly evaporated to dryness, and the product was used as the starting material for the next step.

[0501] Step 6: Compound C169i (50 mg, 0.10 mmol), C169j (35 mg, 0.13 mmol), TCFH (38 mg, 0.14 mmol), and 1-methylimidazole (34 mg, 0.41 mmol) were added sequentially to a 100 mL single-neck flask. The reaction was allowed to proceed overnight at room temperature for 16 hours, after which LCMS confirmed the reaction was complete. Separation by preparative chromatography afforded the final product C169 (31.2 mg, 0.02 mmol) in 42% yield. [M+H] + =735.3.

[0502] 1H NMR (500 MHz, DMSO-d6) δ 11.96 (s, 1H), 10.53 (s, 1H), 8.95 (d, J = 2.4 Hz, 1H), 8.79 (s, 1H), 8.35 (s, 1H), 8.33 (dd, J = 9.0, 2.5 Hz, 1H), 8.08 (d, J = 2.6 Hz, 1H), 8.07 (s, 1H), 7.64 (d, J = 8.2 Hz, 1H), 7.56 (d, J = 1.9 Hz, 1H), 7.39 (dd, J = 8.2, 1.9 Hz, 1H), 6.97 (d, J = 9.1 Hz, 1H), 4.64 - 4.58 (m, 1H), 4.47 - 4.39 (m, 3H), 3.79 - 3.74 (m, 1H), 3.64 - 3.60 (m, 2H), 2.87 (t, J = 11.7 Hz, 2H), 2.79 - 2.73 (m, 3H), 1.80 - 1.59 (m, 6H), 1.48 (d, J = 6.7 Hz, 6H), 1.26 - 1.02 (m, 7H).

[0503] Example 53: Preparation of Compound C170 [ka] Compound C170 was obtained (10.52 mg, yield: 7.72%) by following steps 2 to 6 of Example 51, except that compound C167b was replaced with compound C170a. LCMS: [M+H] + =733.4. LCMS: [M+H] + =733.4. 1H NMR (500 MHz, DMSO-d6) δ 12.01 (s, 1H), 10.54 (s, 1H), 8.95 (d, J = 2.4 Hz, 1H), 8.79 (s, 1H), 8.36 (s, 1H), 8.32 (dd, J = 9.0, 2.5 Hz, 1H), 8.09 (s, 1H), 8.05 (s, 1H), 7.64 (d, J = 8.2 Hz, 1H), 7.56 (d, J = 2.0 Hz, 1H), 7.39 (dd, J = 8.1, 2.0 Hz, 1H), 6.98 (d, J = 9.1 Hz, 1H), 4.41 (d, J = 13.1 Hz, 3H), 3.86 - 3.73 (m, 2H), 3.62 (dd, J = 17.1, 10.9 Hz, 2H), 2.87 (t, J = 12.4 Hz, 2H), 2.75 (q, J = 7.6, 6.8 Hz, 3H), 1.81 - 1.58 (m, 6H), 1.27 - 1.16 (m, 4H), 1.10 (tt, J = 7.9, 4.8 Hz, 5H), 1.01 (td, J = 7.3, 4.9 Hz, 2H).

[0504] C170c:LCMS:[M+H] + =444.0. C170e:LCMS:[M+H] + =723.3. C170f:LCMS:[M+H] + =583.4. C170g:LCMS:[M+H] + =483.3.

[0505] Example 54: Preparation of compound C172

change

[0506] Project 1: Compound C172a (95 mg, 0.22 mmol), C172b (80 mg, 0.20 mmol), catalyst tetrakis(triphenylphosphine)palladium (23 mg, 0.02 mmol), and potassium carbonate (82 mg, 0.60 mmol) were sequentially added to a 100 mL single-neck flask, followed by 10 mL of dioxane and 1 mL of water as solvent. A condenser was then attached to the single-neck flask. After three nitrogen purges using a three-way valve, the flask was heated to 90 °C and reacted for 16 h. After this, completion of the reaction was confirmed by LCMS. The reaction solution was filtered, concentrated directly, and used in the next step.

[0507] Step 2: The crude product C172c (crude) from step 1 was added to a 100 mL reaction flask. 5 mL of methanol solvent was added, followed by aqueous sodium hydroxide (100 mg) solution. The reaction was continued at room temperature for approximately 2 hours, after which a small amount of the reaction solution was collected. LCMS confirmed the reaction was complete. The reaction solution was filtered and extracted three times with dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (MeOH / CHCl=4%) to give product C172d (60 mg).

[0508] Step 3: Compound C172d was added to a 100 mL single-neck flask. HCl / dioxane (2 mol / L, 1 mL) was added, partially precipitating the solid. 2 mL of methanol was added to aid dissolution. After 2 hours of reaction at room temperature, LCMS confirmed the reaction was complete. The solvent was directly evaporated to dryness, and the product was used as the starting material for the next step.

[0509] Step 4: To a 100 mL single-neck flask were sequentially added C172e (50 mg, 0.10 mmol), C172f (35 mg, 0.13 mmol), TCFH (38 mg, 0.14 mmol), and 1-methylimidazole (34 mg, 0.41 mmol). After 16 hours of reaction time at room temperature overnight, LCMS confirmed the reaction was complete. The final product C172 (33.2 mg, 0.02 mmol) was isolated by preparative chromatography in 45% yield. [M+H] + =738.3.

[0510] 1 H NMR (500 MHz, DMSO-d6) δ 12.03 (s, 1H), 10.53 (s, 1H), 8.85 (s, 1H), 8.34 (s, 1H), 8.11 (d, J = 2.7 Hz, 1H), 8.07 (s, 1H), 8.02 - 7.95 (m, 2H), 7.65 (d, J = 8.2 Hz, 1H), 7.56 (d, J = 2.0 Hz, 1H), 7.39 (dd, J = 8.2, 1.9 Hz, 1H), 7.16 (t, J = 9.0 Hz, 1H), 4.53 - 4.40 (m, 1H), 4.23 (q, J = 7.3 Hz, 2H), 3.79 - 3.74 (m, 1H), 3.67 - 3.52 (m, 2H), 3.46 (d, J = 11.5 Hz, 2H), 2.84 - 2.66 (m, 5H), 1.85 - 1.77 (m, 3H), 1.73 - 1.47 (m, 4H), 1.43 (t, J = 7.3 Hz, 3H), 1.38 - 1.15 (m, 5H), 1.14 - 1.06 (m, 2H).

[0511] Example 55: Preparation of Compound C175 [ka]

[0512] Step 1: Compound C175a (45 mg, 0.090 mmol) was dissolved in dioxane (50 mL) and water (5 mL) at room temperature. C175b (45 mg, 0.11 mmol), potassium carbonate (38 mg, 0.27 mmol), and tetrakis(triphenylphosphine)palladium (R3, 10 mg, 0.0087 mmol, 100% purity) were added. The reaction solution was stirred at 90 °C under a nitrogen atmosphere for 3 hours. The starting material was completely reacted by TLC. The reaction solution was concentrated in vacuo to give the crude product. The crude product was then dissolved in dichloromethane (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give crude compound C175c (62 mg, yield: 96.57%), which was used directly in the next step.

[0513] Step 2: Compound C175c (62 mg, 0.086 mmol) was dissolved in methanol (5 mL) and water (1 mL) at room temperature. Sodium hydroxide (34 mg, 0.86 mmol) was added. The reaction solution was stirred at room temperature for 2 hours. LCMS showed complete conversion of the reaction, and the product was detected. The reaction solution was filtered and concentrated in vacuo to obtain the crude product. The crude product was purified by silica gel chromatography (methanol:dichloromethane = 0 to 4%) to obtain compound C175d (42 mg, yield: 84.21%). LCMS: [M+H] + =577.5.

[0514] Step 3: Compound C175d (42 mg, 0.073 mmol) was dissolved in methanol (3 mL) at room temperature. A solution of hydrochloric acid in dioxane (3 mL, 4 M) was added, and the reaction solution was stirred at room temperature for 2 hours. LCMS confirmed complete conversion of the reaction and detected the product. The reaction solution was concentrated in vacuo to give crude compound C175e (37 mg, yield: 99.03%), which was used directly in the next step. LCMS: [M+H] + =482.3.

[0515] Step 4: Compound C175e (37 mg, 0.078 mmol) was dissolved in DMSO (3 mL) at room temperature. 4-Chloro-3-(2,4-dioxotrihydropyrimidin-1(2H)-yl)benzoic acid (23 mg, 0.086 mmol), TCFH (R2, 33 mg, 0.12 mmol), and NMI (32 mg, 0.39 mmol) were added. The reaction solution was stirred at room temperature for 16 hours. LCMS confirmed complete conversion of the reaction and detected the product. The reaction solution was poured into water (30 mL) and then extracted with dichloromethane (20 mL * 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain the crude product. The crude product was purified by pre-HPLC to obtain compound C175 (14.01 mg, yield: 23.46%). LCMS: Rt = 2.100 min; [M+H] + =727.4.

[0516] Example 56: Preparation of Compound C177 [ka]

[0517] Step 1: Compound C177a (60 mg, 0.13 mmol), C177b (50 mg, 0.12 mmol), catalyst tetrakis(triphenylphosphine)palladium (14 mg, 0.01 mmol), and potassium carbonate (51 mg, 0.36 mmol) were sequentially added to a 100 mL one-neck flask, followed by 10 mL of dioxane and 1 mL of water as solvent. A condenser was then attached to the flask. After three nitrogen purges using a three-way valve, the flask was heated to 90 °C and reacted for 16 h. After this, completion of the reaction was confirmed by LCMS. The reaction solution was filtered, concentrated directly, and used in the next step.

[0518] Step 2: The crude product C177c (crude) from step 1 was placed in a 100 mL reaction flask. 5 mL of methanol solvent was added, followed by aqueous sodium hydroxide (100 mg) solution. The reaction was continued at room temperature for approximately 2 hours, after which a small amount of the reaction solution was collected. LCMS confirmed the completion of the reaction. The reaction solution was filtered and extracted three times with dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (MeOH / CHCl=4%) to give product C177d (60 mg).

[0519] Step 3: Compound C177d was added to a 100 mL single-neck flask. HCl / dioxane (2 mol / L, 1 mL) was added, partially precipitating the solid. 2 mL of methanol was added to aid dissolution. After 2 hours of reaction at room temperature, LCMS confirmed the reaction was complete. The solvent was directly evaporated to dryness, and the product was used as the starting material for the next step.

[0520] Step 4: Compounds C177e (50 mg, 0.10 mmol), C177f (35 mg, 0.13 mmol), TCFH (38 mg, 0.14 mmol), and 1-methylimidazole (34 mg, 0.41 mmol) were added sequentially to a 100 mL single-neck flask. After reacting overnight at room temperature for 16 hours, the reaction was confirmed to be complete by LCMS. The final product C177 (25.03 mg, 0.033 mmol) was isolated by preparative chromatography in 33% yield. [M+H] + =747.3.

[0521] 1H NMR (500 MHz, DMSO-d6) δ 11.98 (s, 1H), 10.53 (s, 1H), 8.95 (s, 1H), 8.81 (s, 1H), 8.41 (s, 1H), 8.36 (d, J = 8.0 Hz, 1H), 8.10 (d, J = 2.7 Hz, 1H), 8.05 (s, 1H), 7.64 (d, J = 8.2 Hz, 1H), 7.56 (d, J = 2.0 Hz, 1H), 7.39 (dd, J = 8.2, 2.0 Hz, 1H), 7.00 (d, J = 6.3 Hz, 1H), 4.51 - 4.34 (m, 3H), 4.06 (d, J = 7.1 Hz, 2H), 3.81 - 3.71 (m, 1H), 3.66 - 3.51 (m, 2H), 2.89 (t, J = 12.0 Hz, 2H), 2.81 - 2.68 (m, 3H), 1.84 - 1.58 (m, 6H), 1.36 - 1.02 (m, 8H), 0.60 - 0.52 (m, 2H), 0.45 - 0.37 (m, 2H).

[0522] Example 57: Preparation of Compound C179 [ka] Compound C179 was prepared according to the procedure described in Example 56, except that compound C177a was replaced with compound C179a in step 1 (25.03 mg, 0.033 mmol, 33% yield). [M+H] + =761.3.

[0523] 1H NMR (500 MHz, DMSO-d6) δ 11.96 (s, 1H), 10.52 (s, 1H), 8.95 (s, 1H), 8.79 (s, 1H), 8.42 - 8.27 (m, 2H), 8.08 (s, 2H), 7.64 (d, J = 7.9 Hz, 1H), 7.56 (s, 1H), 7.39 (d, J = 7.6 Hz, 1H), 6.96 (d, J = 8.5 Hz, 1H), 4.87 - 4.74 (m, 1H), 4.54 - 4.28 (m, 3H), 3.83 - 3.52 (m, 4H), 2.92 - 2.71 (m, 5H), 2.21 - 2.06 (m, 2H), 2.04 - 1.91 (m, 2H), 1.88 - 1.62 (m, 9H), 1.26 - 1.01 (m, 7H).

[0524] Example 58: Preparation of Compound C181 [ka] Compounds C181a and C181 (25.03 mg, 0.033 mmol, 33% yield) were prepared according to the method described in Example 56, except that compound C177a was replaced with compound C181a in step 1. [M+H] + =761.3.

[0525] Example 59: Preparation of Compound C195 [ka] Compound C195 (29 mg, 0.04 mmol, 67% yield) was prepared according to the procedure described in Example 52, except that compound C169b was replaced with compound C195b in step 1. [M+H] + =758.2.

[0526] 1H NMR (500 MHz, DMSO-d6) δ 12.01 (s, 1H), 10.52 (s, 1H), 8.99 (d, J = 2.5 Hz, 1H), 8.81 (s, 1H), 8.48 (s, 1H), 8.33 (dd, J = 9.0, 2.5 Hz, 1H), 8.19 - 8.08 (m, 2H), 7.64 (d, J = 8.2 Hz, 1H), 7.56 (d, J = 2.0 Hz, 1H), 7.39 (dd, J = 8.2, 2.0 Hz, 1H), 6.96 (d, J = 9.1 Hz, 1H), 6.42 (tt, J = 55.1, 3.9 Hz, 1H), 4.74 (td, J = 15.0, 3.7 Hz, 2H), 4.43 (dd, J = 24.0, 9.9 Hz, 3H), 3.82 - 3.71 (m, 1H), 3.68 - 3.50 (m, 2H), 2.87 (t, J = 11.8 Hz, 2H), 2.75 (q, J = 7.5, 6.7 Hz, 3H), 1.85 - 1.54 (m, 6H), 1.29 - 1.03 (m, 7H).

[0527] Example 60: Preparation of Compound C196 [ka] Compound C196 was prepared according to the procedure described in Example 59, except that compound C195b was replaced with compound C196b in step 1. Chromatographic separation afforded the final product C196 in 67% yield. [M+H] + =776.2.

[0528] 1H NMR (500 MHz, DMSO-d6) δ 12.05 (s, 1H), 10.52 (s, 1H), 9.00 (d, J = 2.4 Hz, 1H), 8.81 (s, 1H), 8.55 (s, 1H), 8.33 (dd, J = 9.0, 2.5 Hz, 1H), 8.18 (d, J = 2.5 Hz, 2H), 7.64 (d, J = 8.2 Hz, 1H), 7.56 (d, J = 2.0 Hz, 1H), 7.39 (dd, J = 8.2, 1.9 Hz, 1H), 6.96 (d, J = 9.1 Hz, 1H), 5.26 (q, J = 9.1 Hz, 2H), 4.43 (dd, J = 24.4, 11.2 Hz, 3H), 3.80 - 3.73 (m, 1H), 3.66 - 3.54 (m, 2H), 3.12 - 3.01 (m, 1H), 2.89 (s, 2H), 2.75 (q, J = 7.4, 6.6 Hz, 2H), 1.80 - 1.60 (m, 6H), 1.26 - 1.04 (m, 7H).

[0529] Example 61: Preparation of Compound C197 [ka] Compound C197 was prepared according to the procedure described in Example 59, except that compound C195b was replaced with fluoroethane in step 1. Chromatographic separation afforded the final product C197. [M+H] + =740.2.

[0530] Example 62: Preparation of Compound C198 [ka] Compound C198 was prepared according to the method described in Example 53, except that in step 1, compound C170a was replaced with compound C198a (10.52 mg, yield: 7.72%).

[0531] Example 63: Preparation of Compound C199 [ka]

[0532] Step 1: Compounds C199a (1.5 g, 7.8 mmol), C199b (1.3 g, 14.7 mmol), and TPP (2.4 g, 9.2 mmol) were added to a 100 mL three-neck flask, followed by 30 mL of redistilled tetrahydrofuran. The system was then purged with nitrogen three times and stirred at -20 °C for approximately 30 minutes. 1.8 mL of reagent DEAD (9.2 mmol) was slowly added dropwise. After 2 hours of reaction, the system was transferred to room temperature and allowed to react overnight. Plate spotting indicated the formation of a new product, indicating completion of the reaction. The reaction was quenched by adding saturated aqueous ammonium chloride solution and extracted three times with ethyl acetate (20 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Chromatographic column purification (EA / PE = 30%) afforded a new product, C199c (850 mg).

[0533] Process 2~Process 6: Compound C199 (29 mg, 0.04 mmol) was obtained by following the procedures in steps 2 to 6 of Example 52. [M+H] + =764.3.

[0534] 1H NMR (500 MHz, DMSO-d6) δ 11.99 (s, 1H), 10.51 (s, 1H), 8.93 (s, 1H), 8.80 (s, 1H), 8.40 (s, 1H), 8.35 (d, J = 6.3 Hz, 1H), 8.11 (s, 2H), 7.64 (d, J = 8.2 Hz, 1H), 7.58 - 7.53 (m, 1H), 7.42 - 7.35 (m, 1H), 7.01 (d, J = 6.5 Hz, 1H), 5.17 - 5.11 (m, 1H), 4.56 - 4.33 (m, 3H), 4.07 - 4.00 (m, 2H), 3.97 - 3.92 (m, 1H), 3.90 - 3.84 (m, 1H), 3.80 - 3.71 (m, 1H), 3.67 - 3.52 (m, 2H), 2.90 (t, J = 12.2 Hz, 2H), 2.81 - 2.67 (m, 3H), 2.47 - 2.35 (m, 2H), 2.34 - 2.28 (m, 1H), 1.86 - 1.57 (m, 6H), 1.25 - 1.02 (m, 6H).

[0535] Example 64: Preparation of Compound C200 [ka] Compound C200 was obtained according to the method of Example 63. The final product C200 was isolated by preparative chromatography. [M+H] + = 764.3.

[0536] Example 65: Preparation of Compound C201 [ka] Compound C201 (31 mg, 0.04 mmol) was obtained according to the procedures in Steps 2 to 6 of Example 52, except that compound C169c was replaced with compound C201a in Step 2. [M+H] + =752.3.

[0537] 1H NMR (500 MHz, DMSO-d6) δ 11.96 (s, 1H), 10.51 (s, 1H), 8.96 (d, J = 2.0 Hz, 1H), 8.79 (s, 1H), 8.36 (s, 1H), 8.33 (dd, J = 9.0, 2.3 Hz, 1H), 8.09 (d, J = 2.6 Hz, 1H), 8.05 (s, 1H), 7.64 (d, J = 8.2 Hz, 1H), 7.55 (d, J = 1.7 Hz, 1H), 7.39 (dd, J = 8.2, 1.7 Hz, 1H), 6.96 (d, J = 9.0 Hz, 1H), 4.55 - 4.30 (m, 3H), 4.35 (t, J = 5.3 Hz, 2H), 3.83 - 3.69 (m, 3H), 3.66 - 3.53 (m, 2H), 3.27 (s, 3H), 2.87 (t, J = 12.1 Hz, 2H), 2.82 - 2.69 (m, 3H), 1.82 - 1.58 (m, 6H), 1.29 - 0.99 (m, 7H).

[0538] Example 66: Preparation of Compound C203 [ka] Compound C203 was obtained according to the method described in Example 53, except that compound C170a was replaced with compound C203a in step 1 (10.52 mg, yield: 7.72%). [M+H] + =709.2.

[0539] 1H NMR (500 MHz, DMSO-d6) δ 9.32 - 8.83 (m, 3H), 8.42 - 8.10 (m, 3H), 7.56 (d, J = 7.5 Hz, 1H), 7.41 - 7.08 (m, 2H), 4.08 (d, J = 34.1 Hz, 2H), 3.96 - 3.81 (m, 7H), 3.19 - 2.69 (m, 5H), 1.90 - 1.69 (m, 5H), 1.64 - 1.37 (m, 5H), 1.23 (d, J = 12.5 Hz, 1H).

[0540] Example 67: Preparation of Compound C204 [ka] Compound C204 was obtained by following the procedure described in Example 66. The final product C204 was isolated by preparative chromatography. [M+H] + =688.8.

[0541] Example 68: Preparation of Compound C205 [ka]

[0542] Step 1: Compounds C205a (0.2 g, 1.3 mmol), C205b (0.5 g, 1.1 mmol), catalyst (40 mg, 0.05 mmol), and potassium carbonate (0.5 g, 3.6 mmol) were sequentially added to a 250 mL one-neck flask, followed by 30 mL of dioxane and 10 mL of water as solvent. A condenser was then attached to the flask. After purging with nitrogen three times using a three-way valve, the flask was heated to 80 °C and reacted for 3 h. LCMS confirmed the completion of the reaction. The reaction solution was filtered, and then water and dichloromethane were added and extracted three times (10 mL each). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (EA / PE = 30%). The product, C205c (0.1 g, 0.3 mmol), was obtained in 23% yield.

[0543] Step 2: Compound C205c (100 mg, 0.3 mmol), C205d (70 mg, 0.2 mmol), catalyst tetrakis(triphenylphosphine)palladium (20 mg, 0.02 mmol), and potassium carbonate (100 mg, 0.54 mmol) were sequentially added to a 100 mL one-neck flask, followed by 10 mL of dioxane and 1 mL of water as solvent. A condenser was then attached to the one-neck flask. After purging with nitrogen three times using a three-way valve, the flask was heated to 90 °C and reacted for 26 h. After that, completion of the reaction was confirmed by LCMS. The reaction solution was filtered, directly concentrated, and used in the next step. Completion of the reaction was confirmed by LCMS. Purification by silica gel chromatography (MeOH / CHCl = 4%) gave product C205e (39 mg).

[0544] Step 3: The product of Step 2 was added to a 50 mL single-neck flask, followed by 10% Pd / C (30 mg). The system was purged with hydrogen, and the reaction was initiated at room temperature and continued for 16 hours. LCMS confirmed the completion of the reaction. The reaction mixture was directly filtered through Celite and rotary evaporated to remove methanol, and then used in the next step.

[0545] Step 4: The crude product C205f (crude) from step 3 was placed in a 100 mL reaction flask. 5 mL of methanol solvent was added, followed by aqueous sodium hydroxide (100 mg) solution. The reaction was continued at room temperature for approximately 2 hours, after which a small amount of the reaction solution was collected. LCMS confirmed the reaction was complete. The reaction solution was filtered and extracted three times with dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (MeOH / CHCl=4%) to give product C205g (29 mg).

[0546] Step 5: A 100 mL single-neck flask was charged with 5 g of C20 (29 mg, 0.06 mmol). HCl / dioxane (2 mol / L, 1 mL) was added, partially precipitating the solid. 2 mL of methanol was added to aid dissolution. After 2 h of reaction at ambient temperature, LCMS confirmed the reaction was complete. The solvent was directly evaporated to dryness and used as the starting material in the next step.

[0547] Step 6: Compound C205h (29 mg, 0.07 mmol), C205I (19 mg, 0.07 mmol), TCFH (20 mg, 0.08 mmol), and 1-methylimidazole (20 mg, 0.24 mmol) were added sequentially to a 100 mL single-neck flask. After reacting overnight at room temperature for 16 hours, the reaction was confirmed to be complete by LCMS. The final product C205 (3.6 mg, 0.005 mmol) was isolated by preparative chromatography in 7.1% yield. [M+H] + =655.2.

[0548] Example 69: Preparation of Compound C206 [ka]

[0549] Step 1: Compound C206a (4.5 g, 21.47 mmol) was dissolved in THF (10 mL), methanol (10 mL), and water (5 mL) at room temperature. Lithium hydroxide monohydrate (1.35 g, 32.20 mmol) was added, and the reaction solution was stirred at room temperature for 16 hours. LCMS confirmed complete conversion of the reaction and detected the product. The reaction solution was concentrated in vacuo to give the crude product. The crude product was then dissolved in water (2 mL). 1N HCl solution was added to adjust the pH to about 3, stirred, and filtered. The filter cake was washed with water (30 mL), and then dried to give compound C206b (4.2 g, yield: 100.03%). LCMS: [M+H] + =196.1.

[0550] Step 2: Compound C206b (4.2 g, 21.47 mmol) was dissolved in THF (20 mL) in an ice bath. Compound C206c (2.54 g, 21.47 mmol), triphenylphosphine (5.63 g, 21.47 mmol), and DIAD (4.34 g, 21.47 mmol) were added. The reaction solution was stirred at room temperature under a nitrogen atmosphere for 16 hours. TLC showed that most of the reactants were converted, and a new spot was detected. The reaction solution was poured into water (50 mL) and extracted with ethyl acetate (30 mL * 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain the crude product. The crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 0-4%) to obtain compound C206c (2.14 g, yield: 33.69%).

[0551] Step 3: Compound C206c (2.14 g, 7.23 mmol) was dissolved in DMF (20 mL) at room temperature. NaH (350 mg, 8.75 mmol) (60%) was added in an ice bath and stirred for 10 minutes. Methyl 3-bromopropionate (1.81 g, 10.85 mmol) was then added, and the reaction solution was stirred at room temperature for 16 hours. TLC showed partial conversion of the reaction product, and a new spot was detected. The reaction solution was concentrated in vacuo to give the crude product. The crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 0-9%) to give compound C206d (1.745 g, yield: 63.16%).

[0552] Step 4: Compound C206d (1.7 g, 4.45 mmol) was dissolved in acetic acid (20 mL) at room temperature. Concentrated sulfuric acid (44 mg, 0.45 mmol) was added, and the reaction solution was stirred at 120° C. for 16 hours. LCMS showed complete conversion of the reactants, and the product was detected. The reaction solution was concentrated in vacuo to obtain the crude product. The crude product was purified by silica gel chromatography (methanol:dichloromethane=0-2%) to obtain compound C206e (0.9 g, yield: 75.5%). LCMS: [M+H] + =268.4.

[0553] Step 5: Compound C206f (100 mg, 0.20 mmol) was dissolved in DMSO (3 mL) at room temperature, and C206e (64 mg, 0.24 mmol), TCFH (84.17 mg, 0.30 mmol), and NMI (82.1 mg, 1 mmol) were added. The reaction solution was stirred at room temperature for 16 hours. LCMS showed complete conversion of the reaction, and the product was detected. The reaction solution was poured into water (30 mL) and then extracted with dichloromethane (30 mL * 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain the crude product. The crude product was purified by pre-HPLC to obtain compound C206 (4.4 mg, yield: 2.76%). LCMS: [M+H] + =706.6.

[0554] 1 H NMR (500 MHz, DMSO-d6) δ 11.97 (s, 1H), 10.93 (s, 1H), 8.97 (d, J = 2.5 Hz, 1H), 8.79 (s, 1H), 8.36 - 8.30 (m, 2H), 8.08 (d, J = 2.3 Hz, 1H), 8.02 (s, 1H), 7.56 - 7.52 (m, 1H), 7.37 (d, J = 2.0 Hz, 1H), 7.32 (dd, J = 8.2, 2.1 Hz, 1H), 6.96 (d, J = 9.0 Hz, 1H), 4.48 - 4.39 (m, 3H), 4.31 - 4.24 (m, 1H), 3.93 (s, 3H), 2.87 (t, J = 12.4 Hz, 2H), 2.80 - 2.71 (m, 2H), 2.38 - 2.30 (m, 1H), 2.03 - 1.96 (m, 1H), 1.82 - 1.59 (m, 7H), 1.22 - 1.03 (m, 7H).

[0555] Example 70: Preparation of Compound C209 [ka] Compound C209 (17.8 mg, 0.04 mmol) was obtained in 39% yield according to the methods of Steps 2 to 6 of Example 52, except that compound C169c was replaced with C209a in Step 2. [M+H] + =737.3.

[0556] The compounds provided herein and their uses are described in detail above.

[0557] In this specification, the principle and embodiments of the present invention are described using specific examples. The above description of the embodiments is only used to help understand the method and core idea of ​​the present invention. It should be noted that those skilled in the art can make various improvements and modifications to the present invention without departing from the principle of the present invention, and these improvements and modifications also fall within the scope of protection of the claims of the present invention.

Claims

1. General formula (I): [BL] n -HPK1 ligand (I) [In the formula, HPK1 ligand is an HPK1 inhibitor; B is a degradation tag such as an E3 ligase ligand; L is a linking 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, preferably n is 1. or a pharmaceutically acceptable salt or stereoisomer thereof.

2. The HPK1 ligand has the general formula (HI): 【Chemistry 1】 [In the formula, W is CR 1 or N; Ring CyB is selected from 4- to 10-membered cycloalkyl, 4- to 10-membered heterocyclyl, 5- to 8-membered aryl, or 5- to 8-membered heteroaryl; R 1 are independently hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, -NO 2 -OR 1a where -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are each independently selected from halogen, hydroxyl, -C 1-8 optionally substituted by alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R 2 is hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO 2 , -OR 2a , -SO 2 R 2a , -COR 2a , -CO 2 R 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 CO 2 R 2b , -NR 2a SONR 2b R 2c , -NR 2a SO 2 NR 2b R 2c or -NR 2a SO 2 R 2b where -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are each independently selected from halo, hydroxyl, -C 1-8 optionally substituted by alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R 2a , R 2b and R 2c are each independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, where -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl may be selected from the group consisting of at least one substituent R 2d or (R 2a and R 2b ), (R 2b and R 2c ), or (R 2c and R 2a ) together with the atom or atoms to which they are attached form a 3- to 9-membered ring containing 0, 1, or 2 heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as one or more ring members, wherein the ring contains at least one substituent R 2e optionally substituted by; where R 2d and R 2e are each independently hydrogen, halogen, or -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO 2 , -OR 2f , -SO 2 R 2f , -COR 2f , -CO 2 R 2f , -CONR 2f R 2g , -C(=NR 2f )NR 2g R 2h , -NR 2f R 2g , -NR 2f COR 2g , -NR 2f CONR 2g R 2h , -NR 2f CO 2 R 2g , -NR 2f SONR 2g R 2h , -NR 2f SO 2 NR 2g R 2h or -NR 2f SO 2 R 2g where -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are each independently selected from halo, -C 1-8 Alkyl, -OR 2i , -NR 2i R 2j , optionally substituted by at least one substituent selected from cycloalkyl, heterocyclyl, aryl, or heteroaryl; R 2f , R 2g , R 2h , R 2i and R 2j are each 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 3 is hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -CN, or -NO 2 Selected from; R 4 are independently hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO 2 , -OR 4a , -SO 2 R 4a , -SO 2 NR 4a R 4b , -COR 4a , -CO 2 R 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 CO 2 R 4b , -NR 4a SONR 4b R 4c , -NR 4a SO 2 NR 4b R 4c or -NR 4a SO 2 R 4b where -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl may be selected from the group consisting of at least one substituent R 4d optionally substituted by; R 4a , R 4b and R 4c are each independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, where -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl may be selected from the group consisting of at least one substituent R 4e optionally substituted by; 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, -NO 2 , -OR 4f , -SO 2 R 4f , -SO 2 NR 4f R 4g , -COR 4f , -CO 2 R 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 CO 2 R 4f , -NR 4f SONR 4f R 4g , -NR 4f SO 2 NR 4g R 4h or -NR 4f SO 2 R 4g where -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are each independently selected from halogen, -C 1-8 Alkyl, -OR 4i , -NR 4i R 4j , optionally substituted by at least one substituent selected from cycloalkyl, heterocyclyl, aryl, or heteroaryl; R 4f , R 4g , R 4h , R 4i and R 4j are each 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; s is 0, 1, or 2, provided that valence theory holds; t is 0, 1, 2, 3, or 4, provided that valence theory holds; m is 0, 1, 2, 3, or 4, provided that valence theory holds; CyD is selected from cycloalkyl, heterocyclyl, aryl, or heteroaryl. or a pharmaceutically acceptable salt or stereoisomer thereof.

3. HPK1 ligand, 【Chemistry 2】 [In the formula, R 1 , CyB, R 2 ,t,R 3 ,s,R 4 , m and CyD are each as defined in claim 2; Preferably, 【Transformation 3】 teeth, 【Chemistry 4】 and preferably 【Transformation 5】 and / or R 1 and R 3 are each hydrogen; and / or CyD is pyridyl, preferably 【Transformation 6】 and / or R 4 is hydrogen] 3. The compound of claim 2, wherein the compound is:

4. The HPK1 ligand has the general formula (H-III): 【Transformation 7】 [In the formula, W.R. 1 , R 3 ,s,R 4 , m and CyD are each as defined in claim 2; R X is H and C 1-8 alkyl, wherein C 1-8 Alkyl can be deuterium, tritium, halogen, -OH, -CN, -NR Xa R Xb , -OR Xa , -CO-NHR Xb , -CO-NR Xa R Xb and optionally substituted by one or more substituents independently selected from 3- to 10-membered cycloalkyl; R Xa and R Xb are each independently 1-8 alkyl, Preferably, R 1 is hydrogen or -C 1-3 alkyl, preferably hydrogen; and / or R 3 is hydrogen or -C 1-3 alkyl, preferably hydrogen; and / or s is 0 or 1; and / or R X is C 1-4 alkyl, wherein C 1-4 Alkyl is deuterium, F, Cl, Br, -OH, -CN, -NR Xa R Xb -OR Xa and optionally substituted by one, two, or three substituents independently selected from: 1-4 Alkyl is preferably selected from methyl, ethyl, isopropyl, isobutyl, sec-butyl and tert-butyl, more preferably methyl or ethyl; R Xa and R Xb are preferably each independently C 1-4 alkyl, more preferably methyl; preferably R X is selected from methyl or ethyl, where methyl or ethyl is selected from deuterium, F, Cl, —OH, —CN and —OCH 3 and more preferably selected from methyl or ethyl, wherein methyl or ethyl is selected from deuterium, F and —OCH 3 and optionally substituted by one, two or three substituents independently selected from, more preferably, methyl, -CD 3 , ethyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 or 【Transformation 8】 and even more preferably selected from methyl, -CD 3 , ethyl, -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 or 【Chemistry 9】 and / or CyD is 【Chemistry 10】 where X is selected from 1 , X 2 and X 3 are each independently selected from CH, C, or N, with the proviso that X 1 , X 2 and X 3 at least one of is N; preferably, CyD is pyridyl, preferably 【Chemistry 11】 and / or R 4 are independently hydrogen or -C 1-3 alkyl, preferably hydrogen; and / or m is 0 or 1.

2. The compound of claim 1, wherein

5. The HPK1 ligand has the general formula (H-III): 【Chemistry 12】 [In the formula, W.R. 1 , R 3 ,s,R 4 , m and CyD are each as defined in claim 2; R X is C 1-8 Alkyl, or -NR Xa R Xb C is replaced by 1-8 alkyl; R Xa and R Xb are each independently 1-8 alkyl, preferably methyl.

2. The compound of claim 1, wherein

6. The compound of claim 1, wherein the HPK1 ligand is selected from the compounds listed in Table 1-1 herein.

7. B is a group that is bound to an E3 ligase, wherein the E3 ligase is selected from the group consisting of 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, and HERC1. , 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, Parkin, A20 / TNFAIP3, AMFR / gp78, ARA54, β-TrCP1 / BTRC, BRCA1, CBL, CHIP / STUB1, E6, E6AP / UBE3A, F-box protein 15 / FBXO15, FB XW7 / Cdc4, GRAIL / RNF128, HOIP / RNF31, cIAP-1 / HIAP-2, cIAP-2 / HIAP-1, cIAP(pan), ITCH / AIP4, KAP1, MARCH8, Min selected from dBomb1 / MIB1, MindBomb2 / MIB2, MuRF1 / TRIM63, NDFIP1, NEDD4, NleL, Parkin, RNF2, RNF4, RNF8, RNF168, RNF43, SART1, Skp2, SMURF2, TRAF-1, TRAF-2, TRAF-3, TRAF-4, TRAF-5, TRAF-6, TRIM5, TRIM21, TRIM32, UBR5, or ZNRF3; and B is a group that binds to an E3 ligase selected from VHL, Cereblon, MDM2, or cIAP. A compound according to any one of claims 1 to 6.

8. B is a compound of the general formula: 【Chemistry 13】 [In the formula, G is independently CR C2 R C3 , N.R. C2 , CO or SO 2 Selected from; Y is selected from a bond or NH; p is selected from 0, 1 or 2; W 1 , W 2 , W 3 , W 4 and W 5 are each independently N or CR C4 Selected from; X 5 are each independently selected from O or S; V 1 are each independently absent or NH, O, S, SO, SO 2 , SO 2 NR C2 , CO, CO 2 , C(O)NR C2 , C(S)NR C2 , N.R. C2 , N.R. C2 CO, NR C2 CONR C3 , -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are each R C4 optionally substituted by; preferably by V 1 is absent, -O-, -CH 2 -, -CH=CH- or -NH-; V 2 are each independently C2 R C3 , N.R. C2 , O or S; Z is independently hydrogen, halogen, hydroxyl, amino, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are each R C5 optionally substituted by; R C1 , R C2 , R C3 , R C4 and R C5 is hydrogen, carboxy, cyano, nitro, halogen atom, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR C6 , -SO 2 R C6 , -SO 2 NR C6 R C7 , -COR C6 , -CO 2 R 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 CO 2 R C7 , -NR C6 SO 2 NR C7 R C8 or -NR C6 SO 2 R C7 where -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl may be selected from the group consisting of at least one substituent R C9 optionally substituted by; R C6 , R C7 , R C8 and R C9 is hydrogen, halogen, hydroxyl, amino, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 selected from alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; Preferably, B is 【Chemistry 14】 Selected from; V 1 is absent or -O-, -CH 2 -, -CH=CH-, or -NH-; More preferably, B is 【Chemistry 15】 Selected from; V1 is absent or -O-, -CH 2 - or -NH-, preferably absent. is shown in A compound according to any one of claims 1 to 7.

9. B, 【Chemistry 16】 is selected from, preferably 【Chemistry 17】 That is, A compound according to any one of claims 1 to 8.

10. L is (LNK) u and LNK are each independently absent or C 1-8 Alkylene, C 2-8 Alkynylene, [Chemistry 18] or one or more halogens or C 1-8 selected from cycloalkyl, heterocyclyl, heteroaryl ring or aryl optionally substituted by alkyl; Here, cycloalkyl is preferably 【Chemistry 19】 is selected from Heterocyclyl is preferably 【Chemistry 20】 is selected from Aryl is preferably selected from benzene rings; m is selected from an integer from 1 to 8; u is an integer from 1 to 20; A compound according to any one of claims 1 to 9.

11. L is (LNK) u and LNK are each independently absent or C 1-8 Alkylene, C 2-8 Alkynylene, 【Chemistry 21】 or one or more halogens or C 1-8 selected from cycloalkyl, heterocycloalkyl, heteroaryl or aryl rings optionally substituted with alkyl; Here, cycloalkyl is 【Chemistry 22】 is selected from Heterocycloalkyl is 【Chemistry 23】 is selected from The aryl ring is selected from a benzene ring; m or an integer selected from 1 to 8; u is an integer from 1 to 20; A compound according to any one of claims 1 to 9.

12. L, 【Chemistry 24】 is selected from, preferably 【Chemistry 25】 That is, A compound according to any one of claims 1 to 11.

13. W is N; 【Chemistry 26】 but, 【Chemistry 27】 and preferably 【Chemistry 28】 and; R 1 , R 3 and R 4 are hydrogen; CyD is pyridyl, preferably 【Chemistry 29】 and; L, 【Transformation 30】 and; B, 【Chemistry 31】 and V 1 However, absence, -O-, -CH 2 - or -NH-; Preferably 【Chemistry 32】 and more preferably 【Transformation 33】 and; n is 1, 3. The compound of claim 2.

14. W is N; R 1 is hydrogen or -C 1-3 alkyl, preferably hydrogen; R 3 is hydrogen or -C 1-3 alkyl, preferably hydrogen; s is 0 or 1; R X is selected from methyl or ethyl, where methyl or ethyl is selected from deuterium, F and -OCH 3 and optionally substituted by one, two or three substituents independently selected from: 3 , ethyl, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 or 【Transformation 34】 more preferably, methyl, -CD 3 , ethyl, -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 or 【Chemistry 35】 Selected from; CyD is selected from pyridyl, preferably 【Transformation 36】 Selected from; R 4 is hydrogen or -C 1-3 alkyl, preferably hydrogen; m is 0 or 1; L, 【Chemistry 37】 and; B, 【Transformation 38】 and V 1 However, absence, -O-, -CH 2 - or -NH-; preferably 【Chemistry 39】 and more preferably 【Chemistry 40】 and; n is 1, 3. The compound of claim 2.

15. 10. The compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, selected from the compounds listed in Table 2 herein.

16. 16. A pharmaceutical composition comprising a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable excipient.

17. 16. A pharmaceutical composition comprising a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt or stereoisomer thereof, and one or more therapeutically active ingredients.

18. 19. Use of a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt or stereoisomer thereof, or a composition according to any one of claims 16 to 17, in the manufacture of a medicament for treating and / or preventing HPK1-mediated diseases and associated diseases, wherein the HPK1-mediated diseases and associated diseases are preferably selected from lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, breast cancer, ductal 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, cancer of the female reproductive organs, 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, carcinoma and sarcoma, and myelodysplastic syndrome.

19. 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 15 or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition according to any one of claims 16 to 17, wherein the HPK1-mediated diseases and related diseases are preferably lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, breast cancer, or the like.

1. The method of claim 1, wherein the cancer is selected from breast cancer, ductal 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 organ 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, colon villous adenoma, melanoma, carcinoma and sarcoma, and myelodysplastic syndrome.

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