Heterocyclic compound, pharmaceutical composition containing the same and anti-tumor application thereof

Abstract

The present invention relates to a compound represented by general formula (I), a pharmaceutical composition containing the compound, and an anti-tumor application thereof. In the general formula, each variable is defined as in the claims and the specification; HPK1 Ligands——LIN——EL (I).

Description

Technical Field

[0001] The present invention belongs to the field of medicinal chemistry and specifically relates to a novel PROTAC molecule targeting HPK1 protein and its mutant protein, a preparation method and application thereof, and a pharmaceutical composition containing such compound. Background Art

[0002] HPK1 is the abbreviation of hematopoietic progenitor kinase 1, also known as MAP4K1. It is a member of the MAP4K family. It is a serine / threonine protein kinase that is mainly expressed in hematopoietic stem cells, T cells, B cells, NK cells, dendritic cells and other hematopoietic immune-related cells.

[0003] HPK1 kinase can bind to many adaptor proteins, such as SLP76 family, Gads, HIP-55, GRB2 family, LAT, CRK family, etc., and activate the SAPK / JNK signaling pathway of hematopoietic stem cells, thereby negatively regulating the TCR pathway. HPK1 kinase is a key negative feedback regulator of TCR signaling, which can negatively regulate dendritic cell activation and T cell and B cell feedback; inhibiting HPK1 can enhance T cell activity, thereby improving anti-tumor immune response.

[0004] The ubiquitin-proteasome pathway is a common way of endogenous protein degradation. The protein to be degraded is first ubiquitinated and then broken down by the proteasome into smaller peptides, amino acids, and reusable ubiquitin. PROTAC( pro Teolysis ta rgeting c PROTAC molecules can generally be divided into three parts, one end is a small molecule fragment (warhead) that binds to a specific target protein, the other end is a ligand (E3 ligase ligand) of an E3 ligase with ubiquitination function, and a linker that connects the two. PROTAC molecules utilize the protein ubiquitination degradation pathway of the cell and can selectively degrade the target protein. Specifically, since the two ends of the PROTAC molecule are the ligand fragments of the target protein and the E3 ligase, respectively, the PROTAC molecule can bind to the target protein and the E3 ligase at the same time, promoting the ubiquitination of the target protein, which is then recognized and degraded by the proteasome.

[0005] More than a decade ago, researchers discovered that HPK1 may be a potential target for cancer immunotherapy, but no related drugs have been marketed so far. Designing degraders that target specific proteins is a new model for drug development. International patents with publication numbers WO2021226262A1 and WO2020227325A1 disclose HPK1 protein degraders, but their selectivity and efficacy are not very ideal. Therefore, it is of great significance to provide HPK1 degraders with higher selectivity and better efficacy. We hope to use protein degradation technology to develop compounds that can degrade HPK1 protein in order to address unmet clinical needs. Summary of the invention

[0006] In one aspect, the present invention provides a compound represented by general formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and a mixture thereof.

[0007] HPK1Ligands-LIN-EL (I)

[0008] Among them, HPK1 Ligands are ligands that bind to HPK1, such as HPK1 inhibitors, and are represented by general formula (II) and general formula (II'):

[0009]

[0010] is a single bond or a double bond;

[0011] It is the connection point between HPK1Ligands and LIN;

[0012] L' is connected to X 1 The ring where L is connected to Z 4 The ring where L' connects Z 4 The ring where L is connected to X 1 The ring where L' and L are connected to X 1 The ring where it is located;

[0013] X 1 , X 2 , X 3 , X 4 Each independently selected from N or CR X ;

[0014] R X Same or different, and R x Each is independent of: -(CR'2) S -R # -(CR * 2)t -R 1 ;

[0015] R' is the same or different, R * Same or different, R', R * , R 1 Each independently represents hydrogen, deuterium, NR a R b , hydroxyl, halogen, cyano, COR d 、C(O)NR a R b NR N C(O)R d NR N C(O)NR a R b 、C(O)OR d 、OC(O)R d 、S(O) 1-2 R d 、S(O) 1-2 NR a R b NR N S(O) 1-2 R d 、S(O) 1-2 OR d 、OS(O) 1-2 R d 、P(=O)R a R b , C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 4-12 membered heterocyclic group, C 6-10 Aryl or 5-14 membered heteroaryl; or, two R' or two R * Together with the C atom to which it is attached, it forms C 3-8 Cycloalkyl or 4-12 membered heterocyclic group; 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 4-12 membered heterocyclic group, C 6-10 Aryl or 5-14 membered heteroaryl is optionally substituted with 1, 2, 3 or 4 R";

[0016] R # For chemical bonds, O, S, NR N 、C(O)、C(O)NRN NR N C(O), C(O)O, OC(O), S(O) 1-2 、S(O) 1-2 NR N NR N S(O) 1-2 、S(O) 1-2 O、OS(O) 1-2 , C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, C 3-8 Cycloalkylene, 4-12 membered heterocyclylene, C 6-10 Arylene or 5-16 membered heteroarylene; said C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, C 3-8 Cycloalkylene, 4-12 membered heterocyclylene, C 6-10 Arylene or 5-16 membered heteroarylene is optionally substituted by 1, 2, 3 or 4 R";

[0017] Z 1 is an O, S, N or C atom, which is optionally replaced by one or two R Z1 Replaced by; Z 2 is an O, S, N or C atom, which is optionally replaced by one or two R Z2 Replaced by; Z 3 is an O, S, N or C atom, which is optionally replaced by one or two R Z3 replaced by;

[0018] Z 4 is an O, S, N or C atom, which is optionally replaced by one or two R Z4 or, Z 1 Does not exist, Z 2 Connect to Z 1 On the connected C atoms;

[0019] R Z1 , R Z2 , R Z3 , R Z4 Each independently is absent, hydrogen, deuterium, NR a R b , hydroxyl, halogen, cyano, C(O)NR a R b , COR d 、-(C(R 4 )2) 1-6 -R 4 ', halogenated C 1-6 Alkyl, hydroxy C 1-6Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 3-8 Cycloalkyl, C 3-8 Cycloalkyl, 4-12 membered heterocyclic group, C 6-10 Aryl or 5-14 membered heteroaryl; or, Z 1 With two R Z1 Together they form C=O, C 3-8 Cycloalkyl or 4-12 membered heterocyclic group; or, Z 2 With two R Z2 Together they form C=O, C 3-8 Cycloalkyl or 4-12 membered heterocyclic group; or, Z 3 With two R Z3 Together they form C=O, C 3-8 Cycloalkyl or 4-12 membered heterocyclic group; or, Z 4 With two R Z4 Together they form C=O, C 3-8 Cycloalkyl or 4-12 membered heterocyclic group; 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 4-12 membered heterocyclic group, C 6-10 Aryl or 5-14 membered heteroaryl is optionally substituted with 1, 2, 3 or 4 R";

[0020] R 4 , R 4 'Each independently selected from hydrogen, deuterium, NR a R b , hydroxyl, halogen, C(O)NR a R b , COR d , C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 4-12 membered heterocyclic group, C 6-10 Aryl or 5-14 membered heteroaryl; said C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6Alkynyl, C 3-8 Cycloalkyl, 4-12 membered heterocyclic group, C 6-10 Aryl or 5-14 membered heteroaryl is optionally substituted with 1, 2, 3 or 4 R"; or two R 4 Together with the C atom to which it is attached, it forms C 3-8 Cycloalkyl or 4-12 membered heterocyclic group;

[0021] L and L' are each independently a chemical bond or -(CR 2 2) p -R L -(CR 3 2) q -;

[0022] R 2 , R 3 Each independently selected from hydrogen, deuterium, NR N , C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 4-12 membered heterocyclic group, C 6-10 Aryl or 5-14 membered heteroaryl; or two R 2 or two R 3 Together with the connected C, it forms C 3-8 Cycloalkyl or 4-12 membered heterocyclic group; 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 4-12 membered heterocyclic group, C 6-10 Aryl or 5-14 membered heteroaryl is optionally substituted by 1, 2, 3 or 4 R ## replace;

[0023] R L Selected from O, S, NR N ,C(O),C(O)O,OC(O),C(O)NR N NR N C(O),NR N C(O)NR N 、S(O) 1-2 、S(O) 1- 2O、OS(O) 1-2 、S(O) 1-2 NR N NR N S(O) 1-2 NRN S(O) 1-2 NR N , C 1-6 Alkylene, halogenated C 1-6 Alkylene, C 1-6 Alkyleneoxy, C 2-6 Alkenylene, C 2-6 Alkynylidene, C 3-8 Cycloalkylene, 4-12 membered heterocyclylene, C 6-10 Arylene or 5-16 membered heteroarylene; said C 1-6 Alkylene, halogenated C 1-6 Alkylene, C 1-6 Alkyleneoxy, C 2-6 Alkenylene, C 2-6 Alkynylidene, C 3-8 Cycloalkylene, 4-12 membered heterocyclylene, C 6-10 Arylene or 5-16 membered heteroarylene is optionally substituted by 1, 2, 3 or 4 R ## replaced by;

[0024] Y 1 is a N or C atom, and is optionally replaced by one or two R Y1 replaced by;

[0025] Y 2 is a N or C atom, and is optionally replaced by one or two R Y2 or, Y 2 Does not exist, Y 1 With Y 3 connect;

[0026] Y 3 is a N or C atom, and is optionally replaced by one or two R Y3 replaced by;

[0027] Y 4 is a N or C atom, and is optionally replaced by one or two R Y4 replaced by;

[0028] Y 5 is a N or C atom, and is optionally replaced by one or two R Y5 replaced by;

[0029] Y 6 is a N or C atom, and is optionally replaced by one or two R Y6 replaced by;

[0030] R Y1 , R Y2 , R Y3 , R Y4 , R Y5 , R Y6Each is independently expressed as: -(CR e 2) n1 -R #1 -(CR f 2) n2 -R #2 ;

[0031] R e Same or different, R f Same or different, R e , R f , R #2 Each independently represents hydrogen, deuterium, NR a R b , hydroxyl, halogen, cyano, C(O)R d 、C(O)OR d 、OC(O)R d 、C(O)NR a R b NR N C(O)R d 、S(O) 1-2 R d 、S(O) 1-2 NR a R b NR N S(O) 1-2 R d 、S(O) 1-2 OR d 、OS(O) 1-2 R d 、P(=O)R a R b , C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 4-12 membered heterocyclic group, C 6-10 Aryl or 5-14 membered heteroaryl; or, two R e or two R f Together with the C atom to which it is attached, it forms C 3-8 Cycloalkyl or 4-12 membered heterocyclic group; 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 4-12 membered heterocyclic group, C 6-10Aryl or 5-14 membered heteroaryl is optionally substituted by 1, 2, 3 or 4 R ## replaced by;

[0032] R #1 For chemical bonds, O, S, NR N 、C(O)、C(O)NR N NR N C(O),NR N C(O)NR N 、C(O)O、OC(O、S(O) 1-2 、S(O) 1-2 NR N NR N S(O) 1-2 NR N S(O) 1-2 NR N 、S(O) 1-2 O、OS(O) 1-2 , C 1-6 Alkylene, C 1-6 Alkyleneoxy, C 2-6 Alkenylene, C 2-6 Alkynylidene, C 3-8 Cycloalkylene, 4-12 membered heterocyclylene, C 6-10 Arylene or 5-16 membered heteroarylene; or, two R Y2 With Y 2 Together they form a carbonyl group, C 3-8 Cycloalkyl, 4-12 membered heterocyclic group, C 6-10 Aryl or 5-14 membered heteroaryl;

[0033] or, L and Y 1 , Y 2 , Y 3 , Y 4 One connection, Y 5 , Y 6 Together with the substituent to which it is attached, it forms C 3-8 Cycloalkyl, 4-12 membered heterocyclic group, C 6-10 Aryl or 5-14 membered heteroaryl; or, Y 2 Does not exist, L and Y 1 , Y 3 , Y 4 , Y 5 , Y 6 The adjacent two ring atoms of the remaining ring atoms together with the substituents to which they are connected form a C 3-8 Cycloalkyl, 4-12 membered heterocyclic group, C 6-10 Aryl or 5-14 membered heteroaryl; said C 1-6 Alkylene, C 2-6 Alkenylene, C2-6 Alkynylidene, C 3-8 Cycloalkylene, 4-12 membered heterocyclylene, C 6-10 The arylene or 5-16 membered heteroarylene is unsubstituted or optionally substituted with 1, 2, 3 or 4 R ## replaced by;

[0034] R 0 Selected from: C 3-8 Cycloalkylene, 4-12 membered heterocyclylene, C 6-10 Arylene or 5-16 membered heteroarylene; said C 3-8 Cycloalkylene, 4-12 membered heterocyclylene, C 6-10 Arylene or 5-16 membered heteroarylene is optionally substituted by 1, 2, 3, 4 or more R ## replaced by;

[0035] V 1 、V 2 、V 3 Each independently selected from N or CR V ; V 4 is N, O, S or a C atom, which is optionally replaced by 1 or 2 R V replaced by;

[0036] Ring V is C 6-10 aryl or 5-16 membered heteroaryl, and it is optionally substituted by 1, 2, 3 or 4 R V replaced by;

[0037] R V Same or different, R V , R V1 , R V1 '、R V2 , R V2 '、R V3 , R 31 , R 32 Each independently selected from -O-(CR 5 R 5 ') m1 -R V '、-(CR 5 R 5 ') m1 -R V ' or -NR N -(CR 5 R 5 ') m1 -R V ';

[0038] R V '、R 5 , R 5 'Each independently selected from hydrogen, deuterium, halogen, NRa R b , hydroxyl, cyano, C(O)NR a R b 、-NR N COR d 、-NR N CONR a R b 、-COR d 、-COOR d 、-OCOR d 、S(O) 1-2 R d 、S(O) 1-2 NR a R b NR N S(O) 1-2 R d NR N S(O) 1-2 NR a R b 、S(O) 1-2 OR d 、OS(O) 1-2 R d 、P(=O)R a R b , C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 4-12 membered heterocyclic group, C 6-10 Aryl or 5-14 membered heteroaryl; or R 5 , R 5’ or R 31 , R 32 Together with the C atom to which it is attached, it forms C 3-8 Cycloalkyl or 4-12 membered heterocyclic group; 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 4-12 membered heterocyclic group, C 6-10 Aryl or 5-14 membered heteroaryl is optionally substituted by 1, 2, 3, 4 or more R ## replaced by;

[0039] LIN is represented by -L 1 -L2 -L 3 -……-L r -,

[0040] L 1 , L 2 , L 3 ...L r Each independently selected from a chemical bond, O, S, NR N 、-(CR 6 R 6 ') m2 -、C(O)、C(O)NR N NR N C(O),NR N C(O)NR N ,C(O)O,OC(O),OC(O)O,S(O) 1-2 、S(O) 1-2 O、OS(O) 1-2 、S(O) 1-2 NR N NR N S(O) 1-2 NR N S(O) 1-2 NR N 、-OC 1-10 Alkylene, C 2-10 Alkenylene, C 2-10 Alkynylidene, C 3-16 Cycloalkylene, 4-12 membered heterocyclylene, C 6-10 Arylene or 5-16 membered heteroarylene; said C 1-10 Alkylene, C 2-10 Alkenylene, C 2-10 Alkynylidene, C 3-16 Cycloalkylene, 4-12 membered heterocyclylene, C 6-10 Arylene or 5-16 membered heteroarylene is optionally substituted by 1, 2, 3, 4 or more R ## replaced by;

[0041] R 6 , R 6 'Each independently selected from hydrogen, deuterium, NR a R b , halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 4-12 membered heterocyclic group, C 6-10 aryl or 5-14 membered heteroaryl; or, R6 , R 6 'Together with the connected C, form C=O, C 3-8 Cycloalkyl or 4-12 membered heterocyclylene; said C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 4-12 membered heterocyclic group, C 6-10 Aryl or 5-14 membered heteroaryl is optionally substituted by 1, 2, 3, 4 or more R ## replaced by;

[0042] s, t, p, q, n1, n2, m1, m2, and u are each independently 0, 1, 2, 3, 4, 5, 6, 7, or 8;

[0043] t1 and t2 are independently 0, 1 or 2;

[0044] r is a positive integer from 4 to 20;

[0045] EL is represented by the general formula (III):

[0046]

[0047] Among them, G 1 , G 2 , G 3 , G 4 Each is N or CR independently g ; G 1 , G 2 , G 3 , G 4 Not all are N;

[0048] R g The same or different and each independently selected from: hydrogen, deuterium, NR a R b , hydroxyl, halogen, cyano, C(O)NR a R b , C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 4-12 membered heterocyclic group, C 6-10 Aryl or 5-14 membered heteroaryl; said C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 4-12 membered heterocyclic group, C 6-10 Aryl or 5-14 membered heteroaryl is optionally substituted by 1, 2, 3 or 4 R 00 replace;

[0049] K 1 is selected from O, S, C or N, which is optionally replaced by one or two R K1 Replaced by; K 2 is selected from O, S, C or N, which is optionally replaced by one or two R K2 Replaced by; K 3 is selected from O, S, C or N, which is optionally replaced by one or two R K3 replaced by; or K 1 , K 2 Does not exist, K 4 With K 3 Connect with K 1 The C atoms on the aromatic rings connected to R K Connect; or, K 1 , K 2 , K 3 None exist, K 4 Connect to K 1 or K 3 One of the C atoms of the aromatic ring connected to R K connect;

[0050] K 4 N or CR K4 ;

[0051] R K1 , R K2 , R K3 Each independently is absent, hydrogen, deuterium, NR a R b , C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 4-12 membered heterocyclic group, C 6-10 Aryl or 5-14 membered heteroaryl;

[0052] Or, K 1 With two R K1 Together they form C=O, C 3-8Cycloalkyl or 4-12 membered heterocyclic group; or, K 2 With two R K2 Together they form C=O, C 3-8 Cycloalkyl or 4-12 membered heterocyclic group; or, K 3 With two R K3 Together they form C=O, C 3-8 Cycloalkyl or 4-12 membered heterocyclic group;

[0053] R K , R K4 , R 7 , R 7 '、R 8 , R 8 'Each independently selected from hydrogen, deuterium, halogen, cyano, NR a R b , C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy or hydroxy C 1-6 alkyl;

[0054] R a , R b , R d , R N Each independently selected from hydrogen, deuterium, halogen, =NH, NR e1 R f1 , hydroxyl, hydroxylamino, -C 1-6 Alkylene NR e1 R f1 ,CONR e1 R f1 , acetyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 4-12 membered heterocyclic group, C 6-10 aryl or 5-14 membered heteroaryl; or, R a , R b Together with the connected N atom, it forms a 4-12 membered heterocyclic group; the C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 4-12 membered heterocyclic group, C 6-10 Aryl or 5-14 membered heteroaryl is optionally substituted by 1, 2, 3 or 4 R00 replace;

[0055] R 00 , R”, R ## Each independently selected from hydrogen, deuterium, =O, halogen, hydroxyl, hydroxylamino, =NH, NR e1 R f1 ,CONR e1 R f1 , COR 01 , C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, -(CR ** 2) 1-6 -R 01 、-O-(CR ** 2) 1-6 -R 01 、-SR 01 , C 3-8 Cycloalkyl, 4-12 membered heterocyclic group, C 6-10 Aryl or 5-14 membered heteroaryl;

[0056] R e1 , R f1 , R ** , R 01 Each independently selected from hydrogen, deuterium, amino, =NH, hydroxyl, hydroxyamino, acetyl, amide, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 4-12 membered heterocyclic group, C 6-10 aryl or 5-14 membered heteroaryl; or, R e1 , R f1 Together with the connected N atom, they form a 4-12 membered heterocyclic group; or two R ** Together with the C atom to which it is attached, it forms C 3-6 Cycloalkyl or 4-12 membered heterocyclic group; 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 4-12 membered heterocyclic group, C 6-10Aryl or 5-14 membered heteroaryl is optionally substituted by 1, 2, 3 or 4 groups selected from hydrogen, deuterium, amino, =NH, hydroxyl, hydroxyamino, acetyl, amide, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 substituted by a substituent of the alkynyl group;

[0057] The condition is,

[0058] (1) In formula (II), when Z 1 When not present:

[0059] a) Z 2 , Z 3 , Z 4 is C or N, and Z 3 With Z 2 Not N or Z at the same time 3 With Z 4 Not N at the same time,

[0060] And when for When X 1 , X 2 , X 3 , X 4 At least two of them are N;

[0061] And when for When L and R 0 or at least one of L and L' is not phenylene or substituted phenylene; or b) Z 2 or Z 4 C=O;

[0062] c) When Z 2 , Z 3 , Z 4 When one of them is S, L and L' are not the same as X 1 The ring connection where it is located;

[0063] (2) In formula (II'), L' is not

[0064] (3) In formula (II), when Z 1 , Z 2 , Z 3 , Z 4 When both exist, L' and X 1 The C atoms of the aromatic rings are connected, and L is not a chemical bond.

[0065] In some embodiments, Further expressed as:

[0066]

[0067] Indicates the point of attachment of the ring atom to L' represents the point of attachment of the ring atom to L;

[0068] R a '、R b 'Selected from hydrogen, deuterium, cyano, fluorine, chlorine, bromine, hydroxyl, NR a R b 、-COR d 、-CONR a R b 、-NR N COR d , C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-7 membered heterocyclyl, phenyl or 5 or 6 membered heteroaryl (preferably hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy or halogenated C 1-6 Alkyl); the C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-7 membered heterocyclyl, phenyl or 5 or 6 membered heteroaryl are optionally substituted by 1, 2, 3, 4 or more selected from R 4 substituted by a substituent;

[0069] R X Selected from hydrogen, deuterium, hydroxyl, fluorine, chlorine, bromine, cyano, NR a R b 、-COR d 、-CONR a R b , C 1-6 Alkyl, -C 1-6 Alkylene NR a R b , C 1-6 Alkoxy, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, OC 3-5 Cycloalkyl, C 3-5 Cycloalkyl or 4 or 5 membered heterocyclic group.

[0070] Preferred R X =-(CR'2)s -R 1 、-NR N -R 1 、-OR 1 or -O-(CR * 2) t -R 1 ;

[0071] R N , R', R * , R 1 Each independently selected from hydrogen, deuterium, NR a R b , C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, benzene, 5- or 6-membered heteroaryl, -C 1-6 Alkylene NR a R b , -C 1-6 Alkylene-benzene or 5 or 6 membered heteroaryl; or, two R' together with the attached C atom form C 3-6 Cycloalkyl or 4-7 membered heterocyclic group;

[0072] R a , R b , R 4 Each independently selected from hydrogen, deuterium, hydroxyl, amino, halogen, amide, acetyl, =NH, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 3-8 Cycloalkyl, 4-7 membered heterocyclyl, benzene or 5- or 6-membered heteroaryl; or R a , R b Together with the attached N atom, it forms a 4-7 membered nitrogen heterocyclic ring;

[0073] The C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 1-6 Alkylene, C 3-6 Cycloalkyl, 4-7 membered heterocyclyl, 4-7 membered nitrogen heterocycle are optionally substituted by 1, 2 or 3 R"; s, t are 0, 1, 2, 3 or 4.

[0074] In some embodiments, Further selected from:

[0075]

[0076] Among them, R a '、R b ' are each independently selected from hydrogen, deuterium, methyl, ethyl, propyl, isopropyl (preferably hydrogen).

[0077] In some embodiments Indicates the point of attachment of the ring atom to L' Indicates the point of attachment of the ring atom to L

[0078] In some embodiments, L and L' are each independently selected from a chemical bond, NH, O, S, -C 1-6 Alkylene NH-, -NHC 1-6 Alkylene-, -C 1-6 Alkylene O-, -OC 1-6 Alkylene-, C 1-6 Alkylene, hydroxy C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkyne, 3-6 membered cycloalkyl, 4-7 membered heterocyclic, benzene or 5- or 6-membered heteroaryl (preferably a chemical bond or NH); L' is further preferably O, S or -(CR 2 2) p-NR N -, R2 is selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or hydroxy C 1-6 Alkyl (preferably hydrogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, hydroxymethyl, hydroxyethyl or cyclopropyl), or R2, R2' together with the C atom to which they are attached form cyclopropyl, cyclobutyl, oxetanyl or azetidinyl; P is 0, 1, 2 or 3.

[0079] Preferably, L' is C(O)NR N NR N C(O),NR N C(O)NR N 、S(O) 1-2 、S(O) 1-2 NR N NR N S(O) 1-2 NR N S(O) 1-2 NR N , R N is hydrogen, deuterium or C 1-6 alkyl;

[0080] L is preferably composed of 1 or 2 R Q Substituted benzene or 5- or 6-membered heteroarylene, R Q Selected from: hydrogen, deuterium, hydroxyl, amino, halogen, cyano, amide, acetyl, C1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl or

[0081] In some embodiments, L and L' are both chemical bonds.

[0082] In some embodiments, Further selected from:

[0083]

[0084] Y 7 N or =CR Y ; Y 9 N or =CR Y ; Y 8 O or S;

[0085] Each R Y1 , R Y2 , R Y3 , R Y4 , R Y Each independently selected from: hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, NR a R b ,CONR a R b , C 3-8 Cycloalkyl, -O-(CH2) 0-4 -C 3-8 Cycloalkyl, 4-7 membered heterocyclyl, phenyl or 5-14 membered heteroaryl.

[0086] In some embodiments, each R Y1 , R Y2 , R Y3 , R Y4 , R Y5 , R Y6 , R Y , R 9 Each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, =NH, methyl, ethyl, propyl, isopropyl, n-butyl, n-pentyl, n-hexyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethyl, difluoromethyl, trifluoroethyl, hydroxymethyl or hydroxyethyl.

[0087] Preferably, each RY1 , R Y2 , R Y3 , R Y4 , R Y5 , R Y6 , R Y , R 9 Each independently selected from dimethylamino, diethylamino,

[0088] Preferably, each R Y1 , R Y2 , R Y3 , R Y4 , R Y5 , R Y6 , R Y , R 9 Each is independently selected from amide, diformamide, diacetylamino, and N,N'-methylethylamide.

[0089] Preferably, each R Y1 , R Y2 , R Y3 , R Y4 , R Y5 , R Y6 , R Y , R 9 Each independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, oxolyl, azopentyl, piperidinyl, piperazinyl, morpholinyl,

[0090] Preferably, each R Y1 , R Y2 , R Y3 , R Y4 , R Y5 , R Y6 , R Y , R 9 Each independently selected from phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thienyl, thiazolyl, furanyl, tetrazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, indolyl, isoindolyl substituted with 1 or 2 substituents;

[0091] The substituents are selected from hydrogen, deuterium, amino, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethyl, difluoromethyl, trifluoroethyl, hydroxymethyl, hydroxyethyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, hydroxyazetidinyl, cyclopentyl, azetidinyl, hydroxyazetidinyl or phenyl.

[0092] In some embodiments, R 9 Selected from: hydrogen, deuterium, cyano, fluorine, chlorine, bromine, hydroxyl, amino, amide, C 1-6 Alkyl, C 1-6 Alkoxy, NR a R b 、C(O)NR a R b 、-C(O)R d 、S(O) 1-2 NR a R b 、-S(O) 1-2 R d , C 3-8 Cycloalkyl, 4-12 membered heterocyclyl, benzene or 5-14 membered heteroaryl.

[0093] Preferred R 9 C 3-8 Cycloalkyl or 4-7 membered heterocyclic group; preferably R 9 is benzene or a 5- or 6-membered heteroaryl group.

[0094] Preferred R 9 For-NR N (CH2) 1-6 NR a R b ; Preferred R 9 For halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or hydroxy C 1-6 Alkyl; preferably R 9 C(O)NR a R b ; Preferred R 9 S(O) 1-2 NR a R b .

[0095] Each R a , R b , R N , R d Each independently selected from hydrogen, deuterium, amino, hydroxyamino, =NH, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl or C 1-6 Alkoxy.

[0096] Each R a , R b , R N , R d Each independently selected from hydrogen, deuterium, C 1-4Alkyl, halogenated C 1-4 Alkyl, hydroxy C 1-4 Alkyl or C 1-4 Alkoxy.

[0097] The C 1-6 Alkyl is selected from: methyl, ethyl, propyl, isopropyl, n-butyl, n-pentyl, n-hexyl; halogen is fluorine, chlorine or bromine.

[0098] Preferred R a , R b Together with the nitrogen atom to which it is attached, it forms a 4- to 7-membered nitrogen heterocyclic ring.

[0099] The C 1-6 Alkyl, the C 1-6 Alkoxy, the C 3-8 The cycloalkyl, the 4-12 membered heterocyclyl, the 4-7 membered heterocyclyl, the benzene, the 5-14 membered heteroaryl, the 5 or 6 membered heteroaryl, the 4 to 7 membered nitrogen heterocycle are optionally substituted by 1 or 2 selected from hydrogen, deuterium, halogen, =O, hydroxyl, amino, cyano, amide, acetyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, hydroxy C 1-6 The alkyl group is substituted by a substituent of an alkyl group, a 4-6 membered heterocyclic group, or a hydroxy 4-6 membered heterocyclic group.

[0100] The 4 to 7-membered nitrogen heterocyclic ring is selected from:

[0101] In some embodiments, each R Y1 , R Y2 , R Y3 , R Y4 , R Y Each independently selected from: hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, NR a R b ,CONR a R b ;

[0102] R 9 Selected from: NR a R b 、C(O)NR a R b 、-C(O)R d 、S(O) 1-2 NR a R b 、-S(O)1-2 R d .

[0103] In some embodiments, each R Y1 , R Y2 , R Y3 , R Y4 , R Y Each independently selected from: hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, NR a R b ,CONR a R b ;

[0104] R 9 Selected from: NR a R b 、C(O)NR a R b 、-C(O)R d 、S(O) 1-2 NR a R b 、-S(O) 1-2 R d .

[0105] In some embodiments, each R Y1 , R Y2 , R Y3 , R Y4 , R Y Each independently selected from: hydrogen, deuterium, halogen; R 9 C(O)NR a R b .

[0106] In some embodiments, R 0 For chemical bonds, C 3-8 Cycloalkylene, 4-12 membered heterocyclylene, phenylene or 5-14 membered heteroarylene.

[0107] Preferred R 0 For 1, 2, 3 or 4 R Z 'substituted 4-7 membered heterocyclylene (preferably piperidylene or piperazinylene).

[0108] Preferred R 0 For 1 or 2 R Z 'substituted phenylene or 5 or 6 membered heteroarylene.

[0109] Preferred R 0 For 1, 2 or 3 RZ 'substituted 6-12 membered spirocyclic group or 7-12 membered heterospirocyclic group.

[0110] R Z 'Selected from hydrogen, deuterium, halogen, hydroxyl, cyano, acetyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, -NR a R b or-CONR a R b Substituents (R Z 'preferably hydrogen, fluorine, methyl, ethyl or trifluoromethyl), R a , R b is selected from hydrogen, amino, methyl, ethyl, propyl, isopropyl, n-butyl or isobutyl.

[0111] In some embodiments, R 0 It is expressed as:

[0112]

[0113] For R 0 The connection point with L', For R 0 Connection point to LIN;

[0114] Z 5 , Z 6 , Z 7 Each independently selected from N or CR Z ';

[0115] Z 8 , Z 9 , Z 10 are each independently a C, N, O or S atom, and Z 8 , Z 9 , Z 10 Optional 1 or 2 R Z ' replaced; or Z 8 , Z 9 Together with the substituents connected thereto, they form a 4-7 membered cycloalkyl or a 5-7 membered heterocyclic group, and LIN and Z 8 , Z 9 The ring formed is connected; preferably, Z 8 , Z 9 , Z 10 Each is independent of NR N , O or CH2;

[0116] R Z 'Same or different, R Z'Each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, acetyl, hydroxyl, cyano, -NR a R b 、-CONR a R b , C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, 4-7 membered heterocyclyl, benzene or 5-14 membered heteroaryl;

[0117] or, two R Z 'Together with the C atom to which it is connected, it forms C=O.

[0118] Preferably, R Z 'Selected from: C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or hydroxy C 1-6 Alkyl. Preferably R Z ' is hydrogen, halogen, cyano, amino or amide.

[0119] Preferably, R Z 'Selected from: hydrogen, deuterium, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl or hydroxy C 1-4 alkyl.

[0120] Preferably, R Z ' is selected from: hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, n-butyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethyl, difluoromethyl, trifluoroethyl, hydroxymethyl, hydroxyethyl, cyclopropyl, cyclobutyl,

[0121] In some embodiments, R 0 It is phenylene.

[0122] In some embodiments, HPK1 Ligands are further represented by:

[0123]

[0124]

[0125] Z 11 , Z 12 Each is independently represented by N or CR Z’ , Q 1 , Q 2 , Q3 Each is independently represented by N or CR Q ;

[0126] R Z’ , R Q Each independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, NR a R b ,CONR a R b , C 3-6 Cycloalkyl, -O-(CH2) 0-4 -C 3-6 Cycloalkyl or 4- or 5-membered heterocyclic group;

[0127] R Z” Selected from C 1-6 Alkylene, C 1-6 Alkyleneoxy, O, S, NR N ,CONR N 、SO 1-2 NR N , CO or C 3-6 Cycloalkylene;

[0128] In the general formula (II-f), L and Y 1 The ring is connected to or connected to Y 7 The ring where it is located is connected.

[0129] In some embodiments, in Formula (II-a), Formula (II-b), Formula (II-c), Formula (II-d), Formula (II-e), and Formula (II-f), each X 1 , X 2 , Y 1 , Y 2 , Y 3 , X 2 , Z 5 , Z 6 , Z 7 , Z 8 , Z 9 , Z 10 , R 9 , R N , R a, , R b, , R z, , R z,, , R X , R Y Each independently as described above.

[0130] In some embodiments, HPK1 Ligands are further represented by:

[0131]

[0132] R 0 is optionally 1, 2, 3 or 4 R ## substituted phenylene, 4-12 membered heterocyclylene or 5-16 membered heteroarylene;

[0133] L is a chemical bond, NH, O, S, vinylene, ethynylene, -NHC 1-4 Alkylene or -C 1-4 Alkylene NH;

[0134] R a’ , R b’ Each independently selected from: hydrogen, deuterium, F, Cl, C 1-6 Alkyl, halogenated C 1-6 Alkyl or C 1-6 Alkoxy;

[0135] R X , R Y2 , R Y3 , R Y5 Each independently selected from: hydrogen, deuterium, F, Cl, hydroxyl, amino, amide, acetyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, cyclopropyl, -O-cyclopropyl,

[0136] R 9 Hydrogen, deuterium, F, Cl, Br, hydroxyl, cyano, -(CH2) 0-4 C(O)NR a R b 、-(CH2) 0-4 NR a R b 、-(CH2) 0-4 S(O) 1-2 NR a R b , C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-7 membered heterocyclic group, -O-(CH2) 0-4 -C 3-6 Cycloalkyl,

[0137] R a , Rb Each is independently hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, n-butyl, n-pentyl, n-hexyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH2CH2CH2OH, -(CH2) 1-4 N(CH3)2, -(CH2) 1-4 N(CH3)CH2CH3 or -(CH2) 1-4 -4 to 7-membered nitrogen heterocyclic ring, or R a , R b Together with the attached N atom, it forms a 4-7 membered nitrogen heterocyclic ring;

[0138] The 4- to 7-membered nitrogen heterocycle is optionally substituted by 1 or 2 substituents selected from hydrogen, deuterium, methyl, ethyl, hydroxyl, and amino.

[0139] In some embodiments, HPK1 Ligands are further represented by:

[0140]

[0141] In some embodiments, HPK1 Ligands are further represented by:

[0142]

[0143] In some embodiments, Y 2 N, Y 3 , Y 5 is CH, in some embodiments, Y 3 N, Y 2 , Y 5 is CH, in some embodiments, Y 5 CH, Y 2 , Y 5 is N, in some embodiments, Y 2 CH, Y 3 , Y 5 is N, in some embodiments, Y 3 CH, Y 3 , Y 5 is N, in some embodiments, Y 2 , Y 3 , Y 5 All are CH.

[0144] In some embodiments, R 0 is optionally 1, 2, 3 or 4 R ## substituted 6-12 membered heterocyclylene;

[0145] Y 2 , Y 3 , Y 5 All are CH;

[0146] L is a chemical bond, NH, O, S, vinylene, or ethynylene;

[0147] R a '、R b 'Each independently selected from: hydrogen, deuterium, F, Cl, C 1-6 Alkyl, halogenated C 1-6 Alkyl or C 1-6 Alkoxy;

[0148] R X , R Y2 , R Y3 , R Y5 Each independently selected from: hydrogen, deuterium, F, Cl, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 alkyl;

[0149] R 9 -(CH2) 0-4 C(O)NR a R b 、-(CH2) 0-4 NR a R b 、-(CH2) 0-4 S(O) 1-2 NR a R b , C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, hydroxy C 1-6 alkyl;

[0150] R a , R b Each is independently hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, n-butyl, n-pentyl, n-hexyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH2CH2CH2OH, -(CH2) 1-4 N(CH3)2, -(CH2) 1-4 N(CH3)CH2CH3.

[0151] In some embodiments, R 0 is optionally 1, 2, 3 or 4 R ## substituted 8-12 membered benzoheterocyclylene;

[0152] L is a chemical bond;

[0153] Y 2 , Y 3 , Y 5 All are CH;

[0154] R a '、R b 'Each independently selected from: hydrogen, deuterium;

[0155] R X , R Y2 , R Y3 , R Y5 Each independently selected from: hydrogen, deuterium;

[0156] R 9 -(CH2) 0-4 C(O)NR a R b 、-(CH2) 0-4 NR a R b 、-(CH2) 0-4 S(O) 1-2 NR a R b ;

[0157] R a , R b Each is independently hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, n-butyl, n-pentyl, n-hexyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy.

[0158] In the above general formula (II-a-2) or formula (II-a-3), each R Z ' are each independently selected from: hydrogen, deuterium, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl or hydroxy C 1-4 alkyl.

[0159] In the above general formula (II-a-3), Y 2 , Y 3 , Y 5 All are CH; L is a chemical bond; R 9 -(CH2) 0-4 C(O)NR a R b 、-(CH2) 0-4 NR a R b or -(CH2) 0-4 S(O)1-2 NR a R b ; Each R Z ' are each independently selected from: hydrogen, deuterium, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl or hydroxy C 1-4 alkyl.

[0160] In some embodiments, HPK1 Ligands are further represented by:

[0161]

[0162] R 0 is optionally 1, 2, 3 or 4 R ## substituted phenylene, 4-12 membered heterocyclylene or 5-16 membered heteroarylene;

[0163] R a '、R b 'Each independently selected from: hydrogen, deuterium, F, Cl, C 1-6 Alkyl, halogenated C 1-6 Alkyl or C 1-6 Alkoxy;

[0164] Each R X , R Y , R X1 , R X2 , R Y1 , R Y3 Each independently selected from: hydrogen, deuterium, F, Cl, hydroxyl, amino, amide, acetyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, cyclopropyl, -O-cyclopropyl,

[0165] In some embodiments, HPK1 Ligands are further represented by:

[0166]

[0167] In some embodiments, HPK1 Ligands are further represented by:

[0168]

[0169] In some embodiments, X 1 , X 2 One of them is N, the other is CH, Y 1 , Y 3 One of which is N, in some embodiments, X1 , X 2 One of them is N, the other is CH, Y 1 , Y 3 are CH, in some embodiments, X 1 N, X 2 CH, Y 1 , Y 3 are CH, in some embodiments, X 2 N, X 1 CH, Y 1 , Y 3 All are CH.

[0170] In some embodiments, R 0 is optionally 1, 2, 3 or 4 R ## Substituted phenylene;

[0171] X 1 N, X 2 CH, Y 1 , Y 3 All are CH;

[0172] R a '、R b 'Each independently selected from: hydrogen, deuterium, F, Cl, C 1-6 Alkyl, halogenated C 1-6 Alkyl or C 1-6 Alkoxy;

[0173] Each R X , R Y , R X1 , R X2 , R Y1 , R Y3 Each independently selected from: hydrogen, deuterium, F, Cl, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, cyclopropyl, -O-cyclopropyl.

[0174] In some embodiments, R 0 is optionally 1, 2, 3 or 4 R ## Substituted phenylene;

[0175] X 1 N, X 2 CH, Y 1 , Y 3 All are CH;

[0176] R a '、R b 'Each independently selected from: hydrogen, deuterium;

[0177] R X , R X1 , R X2 , R Y1 , R Y3 Each independently selected from: hydrogen, deuterium;

[0178] Each R Y Each independently selected from hydrogen, deuterium, F, Cl, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 alkyl.

[0179] In the above general formula (II-b-2) or formula (II-b-3) or formula (II-b-4), Z6 and Z7 are each independently selected from CH or N, and are preferably both CH.

[0180] In the above general formula (II-b-3) or formula (II-b-4), Z6 and Z7 are both CH; R a '、R b ' are independently selected from: hydrogen, deuterium; R Y Selected from hydrogen, deuterium, F, Cl, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 alkyl.

[0181] In some embodiments, HPK1 Ligands are further represented by:

[0182]

[0183] R 0 is optionally 1, 2, 3 or 4 R ## substituted phenylene, 4-12 membered heterocyclylene or 5-16 membered heteroarylene;

[0184] L is a chemical bond, NH, O, S, vinylene, ethynylene, -NHC 1-4 Alkylene or -C 1-4 Alkylene NH;

[0185] R a 'Selected from: hydrogen, deuterium, F, Cl, C 1-6 Alkyl, halogenated C 1-6 Alkyl or C 1-6 Alkoxy;

[0186] Y 7 N or =CR Y ; Y 8 O or S;

[0187] Each R X , RY Each independently selected from: hydrogen, deuterium, F, Cl, hydroxyl, amino, amide, acetyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, cyclopropyl, -O-cyclopropyl,

[0188] R N Selected from hydrogen, deuterium, amino, hydroxyamino, =NH, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl or C 1-6 Alkoxy.

[0189] In some embodiments, HPK1 Ligands are further represented by:

[0190]

[0191] In some embodiments, HPK1 Ligands are further represented by:

[0192]

[0193] In some embodiments, Y 7 N or =CR Y , Y 8 is O or S. In some embodiments, Y 7 =CR Y , Y 8 is S, in some embodiments, Y 7 =CR Y , Y 8 is O, in some embodiments, Y 7 =CR Y , Y 8 For S.

[0194] In some embodiments, Z 11 , Z 12 Each is independently represented by N or CR Z ', in some embodiments, Z 11 , Z 12 One of them is N and the other is CR Z ', in some embodiments, Z 11 , Z 12 All are N. Among them, each R Z ' are each independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, hydroxy C1-6 Alkyl, preferably hydrogen.

[0195] In some embodiments, R 0 is optionally 1, 2, 3 or 4 R ## substituted 4-8 membered heterocyclylene;

[0196] L is a chemical bond, NH, O, S, vinylene, or ethynylene;

[0197] R a 'Selected from: hydrogen, deuterium, F, Cl, C 1-6 Alkyl, halogenated C 1-6 Alkyl or C 1-6 Alkoxy;

[0198] Y 7 N; Y 8 O or S;

[0199] Each R X , R Y Each independently selected from: hydrogen, deuterium, F, Cl, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 alkyl;

[0200] R N Selected from hydrogen, deuterium, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl or C 1-6 Alkoxy.

[0201] In some embodiments, R 0 is optionally 1, 2, 3 or 4 R ## a substituted 4-6 membered nitrogen-containing heterocyclylene group;

[0202] L is a chemical bond;

[0203] R a 'Selected from: hydrogen, deuterium;

[0204] Y 7 N; Y 8 O or S;

[0205] R X Selected from: hydrogen, deuterium;

[0206] Each R Y Each independently selected from: hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 alkyl;

[0207] RN Selected from hydrogen and deuterium.

[0208] In the above general formula (II-c-3), R N is selected from hydrogen, deuterium; R a ' is selected from: hydrogen, deuterium; R Y Selected from: hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 alkyl.

[0209] In some embodiments, HPK1 Ligands are further represented by:

[0210]

[0211] R 0 is a chemical bond; L' is -(CR 2 2) p NR N -;

[0212] R N Selected from: hydrogen, deuterium, amino, hydroxyamino, =NH, C 1-6 Alkyl or halogenated C 1-6 Alkyl (preferably hydrogen or C 1-6 alkyl);

[0213] R 2 Selected from hydrogen, deuterium, amino, hydroxyamino, C 1-6 Alkyl, halogenated C 1-6 Alkyl or hydroxy C 1-6 Alkyl (preferably hydrogen or C 1-6 alkyl); or two R 2 Together with the C atom to which it is attached, it forms a cyclopropyl, cyclobutyl, oxetanyl or azetidinyl group;

[0214] p is 0, 1, 2 or 3;

[0215] R X Selected from: hydrogen, deuterium, fluorine, chlorine, bromine, amino, amide, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, -(CR'2) m1 NR a R b , C 3-6 Cycloalkyl, -OR 1 、-O-(CH2) 1-2 R 1 ,

[0216] R a , R bEach independently selected from: hydrogen, deuterium, fluorine, chlorine, bromine, hydroxyl, amino, acetyl, amide, hydroxylamino, =NH, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 3-6 Cycloalkyl Preferred R a , R b Together with the N atom to which it is attached, it forms a 4-7 membered nitrogen heterocyclic ring substituted with 1 or 2 R";

[0217] R 1 , R' are each independently selected from: hydrogen, deuterium, fluorine, chlorine, bromine, hydroxyl, amino, acetyl, amide, hydroxylamino, =NH, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 3-6 Cycloalkyl or two R' together with the C atom to which they are attached form a 3-6 membered cycloalkyl or a 4-7 membered nitrogen heterocycle;

[0218] R Z4 Selected from: hydrogen, deuterium, halogen, C 1-6 Alkyl or halogenated C 1-6 Alkyl (preferably hydrogen);

[0219] L is selected from 1 or 2 R Q substituted 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 2,6-pyridylene, 2,5-pyridylene, 2,4-pyridylene, 2,3-pyridylene, 3,4-pyridylene, 3,5-pyridylene, 2,6-pyrimidylene, 3,6-pyrimidylene, 3,6-pyridazinylene, 3,5-pyridazinylene or 4,5-pyridazinylene (preferably 2,6-pyridylene);

[0220] R Y Same or different, R Y3 , R Y4 , R Y , R Q Each independently selected from hydrogen, deuterium, hydroxyl, amino, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, cyclopropyl, -O-cyclopropyl,

[0221] R" is selected from hydrogen, deuterium, hydroxyl, amino, C=O, halogen, C 1-6 Alkyl, C 1-6Alkoxy, halogenated C 1-6 Alkyl or hydroxy C 1-6 alkyl.

[0222] In the general formula (II-e-1), (II-e-2) or (II-e-3) of the above embodiment,

[0223] R 2 is selected from hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, hydroxymethyl, hydroxyethyl, trifluoromethyl or trifluoroethyl;

[0224] R'、R 1 Each independently selected from: hydrogen, methyl, ethyl, propyl, isopropyl, hydroxymethyl, hydroxyethyl, trifluoromethyl or trifluoroethyl;

[0225] R a , R b Each independently selected from: hydrogen, methyl, ethyl, propyl, isopropyl, hydroxymethyl, hydroxyethyl, trifluoromethyl or trifluoroethyl;

[0226] Preferred R a , R b Together with the N atom to which it is attached, it forms:

[0227] R" is selected from hydrogen, hydroxy, methyl, ethyl, propyl, isopropyl, hydroxymethyl, hydroxyethyl;

[0228] p, m1 are 0, 1 or 2.

[0229] In some embodiments, HPK1 Ligands are further represented by:

[0230]

[0231] X 2 , X 3 Each independently is N or CH;

[0232] Y 1 N or CH;

[0233] R 0 is a chemical bond;

[0234] L is NH, N(CH3), NHCH2, CH2NH, NHCH2CH2 or CH2CH2NH;

[0235] L' is selected from: chemical bond, O, S, -CO, -CONR N 、-NR N CO, -NR N CONR N -or-(CR 2 2)P NR N -;

[0236] R b '、R N Each independently selected from: hydrogen, deuterium, fluorine, chlorine, bromine, hydroxyl, amino, acetyl, amide, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, cyclopropyl (preferably hydrogen);

[0237] R 2 Selected from: hydrogen, deuterium, hydroxyl, amino, hydroxyamino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, cyclopropyl, cyclobutyl, oxetanyl (preferably hydrogen, methyl or ethyl);

[0238] or, two R 2 Together with the attached C atom, it forms a cyclopropyl, cyclobutyl, oxetanyl or azetidinyl group;

[0239] R X is selected from hydrogen, deuterium, fluorine, chlorine, bromine, hydroxyl, acetyl, amide, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, -(CR'2) m1 NR a R b , C 3-6 Cycloalkyl, -OR 1 、-O-(CH2) 1-4 R 1 ,

[0240] R 1 , R' are each independently selected from: hydrogen, deuterium, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-7 membered heterocyclic group or two R' together with the C atom to which they are attached form C 3-6 Cycloalkyl or 4-7 membered heterocyclic group;

[0241] R a , R b Each independently selected from: hydrogen, deuterium, hydroxyl, amino, hydroxyamino, =NH, C 1-6 Alkyl, C1-6 Alkoxy, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 3-6 Cycloalkyl, or R a , R b Together with the N atom to which it is attached, it forms a 4-7 membered nitrogen heterocyclic ring;

[0242] R Y is selected from hydrogen, deuterium, fluorine, chlorine, bromine, hydroxyl, amino, acetyl, amide, hydroxylamino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, cyclopropyl, -O-cyclopropyl, or two R Y Together with the C atom to which it is attached, it forms a cyclopropyl group;

[0243] The C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 3-6 The cycloalkyl group is optionally substituted by 1 or 2 groups selected from hydrogen, halogen, hydroxy, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 The alkyl group is substituted with an alkyl substituent.

[0244] In the general formula (II-d-1), (II-d-2) or (II-d-3) in the above embodiment,

[0245] X 2 CH; Y 1 Each is independently N or CH; L is NH, N(CH3), NHCH2 or CH2NH;

[0246] R b ' is hydrogen; R N Selected from: hydrogen or methyl;

[0247] R 2 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, cyclopropyl, cyclobutyl, hydroxycyclopropyl or fluorocyclopropyl;

[0248] R 1 Selected from: hydrogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, Hydroxymethyl, hydroxyethyl, hydroxypropyl, cyclopropyl, hydroxycyclopropyl, cyclobutyl,

[0249] R' is selected from: methyl, ethyl, propyl, trifluoromethyl, trifluoroethyl, hydroxymethyl, cyclopropyl or cyclobutyl;

[0250] R a , R b Each independently selected from: hydrogen, deuterium, hydroxyl, amino, hydroxyamino, methyl, ethyl, propyl, hydroxymethyl, CH2CH2OH, CH2CH2CH2OH, cyclopropyl, cyclobutyl

[0251] Preferred R a , R b Together with the N atom to which it is attached,

[0252] p is 0, 1 or 2.

[0253] In some embodiments, HPK1 Ligands are further represented by:

[0254]

[0255] X 2 , X 3 Each independently represents N or CH; Z 3 O, -NR Z3 -or-C(R Z3 )2;

[0256] R Z3 Selected from hydrogen, deuterium, fluorine, chlorine, bromine, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or hydroxy C 1-6 Alkyl (preferably hydrogen);

[0257] L' is a chemical bond, NH, N(CH3), NHCH2, CH2NH, NHCH2CH2 or CH2CH2NH (preferably NH);

[0258] Y 5 The substituent group connected to it, R Y6 Together with the ring atoms to which it is attached, it forms a ring surrounded by 1 or 2 R Y substituted phenyl or 5- or 6-membered heteroaryl; or R Y1 , R Y6 Together with the ring atoms to which it is attached, it forms a Y substituted phenyl or 5- or 6-membered heteroaryl; or, Y 3 The substituent group connected to it, R Y1 Together with the ring atoms to which it is attached, it forms a ring surrounded by 1 or 2 R Y substituted phenyl or 5- or 6-membered heteroaryl; or, Y 5The substituent group connected to it, R Y6 Together with the ring atoms to which it is attached, it forms a ring surrounded by 1 or 2 R Y substituted phenyl or 5- or 6-membered heteroaryl;

[0259] R Y1 , R Y3 , R Y5 , R Y6 , R Y , R Z ' are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, hydroxyl, amino, amide, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, cyclopropyl, -O-cyclopropyl,

[0260] Preferred R Y5 , R Y6 Together with the ring atoms to which it is attached, it forms a Y Substituted phenyl or pyridyl, R Y1 , R Y3 , R Y , R Z ' are each independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy or halogenated C 1-6 alkyl.

[0261] In the above general formula (II-f'), X 2 N, X 3 is CH; in some embodiments, X 3 N, X 2 for CH;

[0262] In some embodiments, Y 3 N, Y 5 CR Y5 , R Y1 , R Y6 Together with the ring atoms to which it is attached, it forms a Y substituted phenyl or pyridyl; in some embodiments, Y 3 N, Y 5 CR Y5 , R Y1 , R Y6 Together with the ring atoms to which it is attached, it forms a Y substituted phenyl or pyridyl;

[0263] In some embodiments, Y 3 CR Y3 , Y5 N, R Y1 , R Y6 Together with the ring atoms to which it is attached, it forms a Y substituted phenyl or pyridyl; in some embodiments, Y 3 CR Y3 , Y 5 N, Y 5 , R Y6 Together with the ring atoms to which it is attached, it forms a Y substituted phenyl or pyridyl;

[0264] In some embodiments, Y 3 N, Y 5 N, R Y1 , Y 3 Together with the ring atoms to which it is attached, it forms a Y substituted phenyl or pyridyl; in some embodiments, Y 3 N, Y 5 N, R Y1 , R Y6 Together with the ring atoms to which it is attached, it forms a Y substituted phenyl or pyridyl; in some embodiments, Y 3 N, Y 5 N, R Y6 , Y 5 Together with the ring atoms to which it is attached, it forms a Y Substituted phenyl or pyridyl.

[0265] In some embodiments, HPK1 Ligands are further represented by:

[0266]

[0267] V 5 、V 6 、V 7 Each independently selected from N or CR V ;

[0268] R V are the same or different and are each independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, -C(O)NR a R b NR a R b , C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 3-6 Cycloalkyl, -OC3-6 Cycloalkyl, (preferably hydrogen, F, amino, amido, dimethylamino, diformamido, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl or trifluoroethyl);

[0269] R 0 Selected from 5 or 6 membered heteroarylene (preferably );

[0270] R V1 , R V1 'Each independently selected from hydrogen, deuterium, fluorine, chlorine, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-7 membered heterocyclic group, C 3-6 Cycloalkyl or -OC 3-6 Cycloalkyl (preferably hydrogen, halogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, trifluoromethyl or trifluoroethyl);

[0271] R 31 , R 32 Selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 3-6 Cycloalkyl or 4-7 membered heterocyclyl (preferably hydrogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, trifluoromethyl, trifluoroethyl, difluoromethyl, difluoroethyl, hydroxymethyl, hydroxyethyl or hydroxypropyl);

[0272] R a , R b As defined in any of the above items.

[0273] In some embodiments, EL is further represented by:

[0274]

[0275] R N , R 7 , R 7’ , R 8 , R 8’ , R K Each independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or hydroxy C 1-6 Alkyl (preferably hydrogen, methyl or ethyl);

[0276] K 4 CH or N, K 3 NR K3 , CH2 or CO;

[0277] R K3 Selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or hydroxy C 1-6 Alkyl (preferably hydrogen, methyl or ethyl);

[0278] R g is selected from hydrogen, deuterium, halogen, cyano, amino, amide, dimethylamino, dimethylamide, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or hydroxy C 1-6 Alkyl; R g Preferably hydrogen, C 1-6 Alkyl and halogenated C 1-6 The alkyl group is further preferably hydrogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, trifluoromethyl, trifluoroethyl or cyano.

[0279] In some embodiments, K 3 is CH2 or CO.

[0280] In some embodiments, the compound represented by the above general formula (I) is further represented as:

[0281]

[0282]

[0283]

[0284]

[0285]

[0286] In some embodiments, the compound represented by the general formula (I) is the above-mentioned general formula (II'-1), (II'-1-1), (II'-1-2), (II'-1-3), (II'-1-4) and (II'-1-5); wherein,

[0287] L is NH or N(methyl);

[0288] R 0 is a chemical bond, L' is -CONR N -or-COO-;

[0289] Preferred R 0 for L' is a chemical bond;

[0290] X 1 N or CH;

[0291] R V1 , R V1’ , R V2 , R V2’ , R 31 , R 32 Each independently selected from: hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl or C 3-6 Cycloalkyl; or R V2 , R V2’ or R V1 , R V1’ Together with the C atom it is connected to, it forms C=O or C 3-6 Cycloalkyl;

[0292] V 4 NH or O;

[0293] R V Each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, amide, amino, dimethylamino, dimethylamide, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 3-6 Cycloalkyl

[0294] R a is hydrogen, deuterium, amino, hydroxylamino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or hydroxy C 1-6 alkyl;

[0295] LIN is represented by: -L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -L 7 -,L 7 Connect with EL;

[0296] L 1Selected from: CH2, CH2CH2, CO, CONH, NHCO, NHCONH, SO, SO2, SONH, NHSO, SO2NH, NHSO2, O, S, NH, N(methyl), OCH2, CH2O, OCH2CH2, vinylene, ethynylene, phenylene, pyridylene, pyrimidylene, triazolylene, tetrazolylene, pyrazolylene, imidazolylene, piperidylene, piperazinylene,

[0297] L 2 , L 3 Selected from: CH2, CH2CH2, CO, CONH, NHCO, O, S, NH, N(methyl), OCH2, OCH2CH2, CH2O, phenylene, pyridinylene, pyrimidinylene, triazolylene, tetrazolylene, pyrazolylene, imidazolylene, morpholinylene, piperidinylene, piperazinylene or CH2CH2O;

[0298] L 4 , L 5 is selected from a chemical bond, CH2 or CH2CH2 or CH2CH2O; L 6 Selected from: chemical bond, O, S, NH, N(methyl), CH2, CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CO, CONH, NHCO or CH2CH2O; L 7 Selected from: O, S, NH, N(methyl), CH2, vinylene or ethynylene;

[0299] R N Selected from hydrogen or methyl; the hydrogen of any of the above methylene groups is optionally replaced by 1 or 2 R ## Replaced by R ## Selected from deuterium, methyl, ethyl, propyl, cyclopropyl, amino or trifluoromethyl.

[0300] In some embodiments, the compound represented by the general formula (I) is the general formula (II-3), (II-3-1), (II-3-2), (II-3-3), (II-3-4), (II-3-5), (II-3-6), (II-3-7); wherein,

[0301] L is selected from a chemical bond or NH;

[0302] Z 11 N or CH; Z 12 N or CH;

[0303] R Z ,、R a '、R N Each independently selected from: hydrogen, deuterium, C 1-6 Alkyl, C1-6 Alkoxy, halogenated C 1-6 Alkyl or C 3-6 Cycloalkyl (preferably H or methyl);

[0304] Y 7 =CH, Y 8 O or S; or Y 7 O or S, Y 8 =CH;

[0305] R X Selected from: hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy or halogenated C 1-6 Alkyl (preferably hydrogen);

[0306] R Y4 Selected from: hydrogen, deuterium, halogen, cyano, amino, amide, dimethylamino, dimethylamide, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, -O-methylenecyclopropyl,

[0307] LIN is represented by: -L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -L 7 -,L 7 Connect with EL;

[0308] L 1 Selected from: chemical bond, CH2, CH2CH2, CO, CONH, NHCO, O, S, NH, N(methyl), OCH2, CH2O, or

[0309] L 2 , L 3 Selected from: a chemical bond, CH2, CH2CH2, CO, CONH, NHCO, O, S, NH, N(methyl), OCH2 OCH2, OCH2CH2, CH2O or CH2CH2O;

[0310] L 4 , L 5 Selected from CH2 or CH2CH2;

[0311] L 6Selected from: chemical bond, O, S, NH, N(methyl), CH2, CH2CH2, CH2CH2 CH2, CH2CH2CH2CH2, CO, CONH or NHCO;

[0312] L 7 Selected from: O, S, NH, N(methyl), CH2, vinylene or ethynylene;

[0313] The hydrogen atoms of any of the above methylene groups are optionally replaced by 1 or 2 R ## Replaced by R ## is selected from hydrogen, deuterium, halogen, amide, amino, dimethylamino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl or 4-7 membered heterocyclic group (preferably methyl, ethyl or propyl).

[0314] In some embodiments, the compound represented by the general formula (I) is the general formula (II-3), (II-3-1), (II-3-2), (II-3-3), (II-3-4), (II-3-5), (II-3-6), (II-3-7); wherein,

[0315] L is selected from a chemical bond;

[0316] Z 11 and Z 11 All are N;

[0317] R Z, , R a’ , R N Each independently selected from: hydrogen, deuterium;

[0318] Y 7 =CH, Y 8 O or S;

[0319] R X Selected from: hydrogen, deuterium;

[0320] R Y4 Selected from: hydrogen, deuterium, halogen, cyano, amino C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 alkyl;

[0321] LIN is represented by: -L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -L 7 -,L 7Connect with EL;

[0322] L 1 Selected from: chemical bond, CH2, CH2CH2, CO, CONH, NHCO, O, S, NH, N(methyl), OCH2, CH2O, or

[0323] L 2 , L 3 Selected from: a chemical bond, CH2, CH2CH2, CO, CONH, NHCO, O, S, NH, N(methyl), OCH2 OCH2, OCH2CH2, CH2O or CH2CH2O;

[0324] L 4 , L 5 Selected from CH2 or CH2CH2;

[0325] L 6 Selected from: chemical bond, O, S, NH, N(methyl), CH2, CH2CH2, CH2CH2 CH2, CH2CH2CH2CH2, CO, CONH or NHCO;

[0326] L 7 Selected from: O, S, NH, N(methyl), CH2, vinylene or ethynylene;

[0327] K 3 is CH2 or CO;

[0328] R g Selected from hydrogen, C 1-6 Alkyl and halogenated C 1-6 alkyl;

[0329] The hydrogen atoms of any of the above methylene groups are optionally replaced by 1 or 2 R ## Replaced by R ## is selected from hydrogen, deuterium, halogen, amide, amino, dimethylamino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl or 4-7 membered heterocyclic group (preferably methyl, ethyl or propyl).

[0330] In some embodiments, the compound represented by the general formula (I) is the general formula (II-4), (II-4-1), (II-4-2), (II-4-3), (II-4-4), (II-4-5); wherein,

[0331] R Y1 , R Y2 , R Y3Each independently selected from: hydrogen, deuterium, fluorine, chlorine, bromine, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy or halogenated C 1-6 alkyl;

[0332] R 9 Selected from: hydrogen, deuterium, fluorine, chlorine, bromine, hydroxyl, cyano or -C(R f 2) n2 -R #2 ;

[0333] R f Selected from: hydrogen, deuterium, fluorine, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or hydroxy C 1-6 Alkyl; or two R f Together with the C atoms connected to it, they form C=O, C 3-6 Cycloalkyl or 4-7 membered heterocyclic group;

[0334] R #2 For hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, CONR a R b NR a R b , C 3-6 Cycloalkyl or 4-7 membered heterocyclic group;

[0335] R a , R b Each independently selected from: hydrogen, deuterium, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl, -C 1-6 Alkylene-4 to 7-membered nitrogen heterocycle or -(CH2) 1-6 -NR e1 R f1 ;

[0336] R e1 , R f1 Each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl or 4-7 membered heterocyclic group (preferably hydrogen, methyl or ethyl);

[0337] Preferred R a , Rb Together with the nitrogen atom to which it is connected, it forms a 4- to 7-membered nitrogen heterocyclic ring, preferably R e1 , R f1 Together with the nitrogen atom to which it is connected, a 4- to 7-membered nitrogen heterocyclic ring is formed. 3-6 Cycloalkyl, 4-7 membered heterocyclyl or 4-7 membered nitrogen heterocyclic ring is optionally substituted by 1 or 2 selected from deuterium, fluorine, amino, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, hydroxy C 1-6 Alkyl substituted;

[0338] X 1 , X 2 Each is independently selected from CH or N;

[0339] Z 5 , Z 6 , Z 7 Each independently is CH or N;

[0340] R a '、R b 'Each independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy or halogenated C 1-6 Alkyl (preferably hydrogen);

[0341] R X , R Z ' are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, cyano, amide, acetyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or hydroxy C 1-6 alkyl;

[0342] LIN is represented by: -L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -L 7 -,L 7 Connect with EL;

[0343] L 1 Selected from: CH2, CH2CH2, CO, CONH, NHCO, O, S, NH, N(methyl), OCH2, OCH2CH2, CH2O, CH2CH2O or

[0344] L 2Selected from: a chemical bond, CH2, CH2CH2, CO, CONH, NHCO, O, S, NH, N(methyl), OCH2, OCH2CH2, CH2O, CH2CH2O, piperidinyl or piperazinyl;

[0345] L 3 , L 4 Selected from: CH2, CH2CH2, CO, CONH, NHCO, O, S, NH, N(methyl), OCH2, CH2O, OCH2CH2, CH2CH2O or piperidinyl;

[0346] L 5 Selected from a chemical bond, CH2, CH2CH2 or CH2CH2O;

[0347] L 6 Selected from: a chemical bond, O, S, NH, N(methyl), CH2, CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CO, CONH or NHCO;

[0348] L 7 Selected from: O, S, NH, N(methyl), CH2, vinylene or ethynylene;

[0349] The hydrogen atoms of any of the above methylene groups are optionally replaced by 1 or 2 R ## Replaced by R ## is selected from hydrogen, deuterium, halogen, amide, amino, dimethylamino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl or 4-7 membered heterocyclic group (preferably methyl, ethyl or propyl).

[0350] In some embodiments, the compound represented by the general formula (I) is the general formula (II-4), (II-4-1), (II-4-2), (II-4-3), (II-4-4), (II-4-5); wherein,

[0351] R Y1 , R Y2 , R Y3 Each independently selected from: hydrogen, deuterium, fluorine, chlorine, bromine, C 1-6 Alkyl, C 1-6 Alkoxy or halogenated C 1-6 alkyl;

[0352] R 9 -C(R f 2) n2 -R #2 ; n2 is an integer from 0 to 5;

[0353] R f Selected from: hydrogen, deuterium, fluorine, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or hydroxy C 1-6 Alkyl; or two R f Together with the C atoms connected to it, they form C=O, C 3-6 Cycloalkyl or 4-7 membered heterocyclic group;

[0354] R #2 CONR a R b NR a R b ;

[0355] R a , R b Each independently selected from: hydrogen, deuterium, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, hydroxy C 1-6 alkyl;

[0356] X 1 N, X 2 for CH;

[0357] Z 5 , Z 6 , Z 7 All CH;

[0358] R a '、R b 'Each independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy or halogenated C 1-6 Alkyl (preferably hydrogen);

[0359] R X and each R Z 'Each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or hydroxy C 1-6 alkyl;

[0360] LIN is represented by: -L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -L 7 -,L 7 Connect with EL;

[0361] L 1 Selected from: CH2, CH2CH2, CO, CONH, NHCO, O, S, NH, N(methyl), OCH2, OCH2CH2, CH2O, CH2CH2O or

[0362] L 2 Selected from: a chemical bond, CH2, CH2CH2, CO, CONH, NHCO, O, S, NH, N(methyl), OCH2, OCH2CH2, CH2O, CH2CH2O, piperidinyl or piperazinyl;

[0363] L 3 , L 4 Selected from: CH2, CH2CH2, CO, CONH, NHCO, O, S, NH, N(methyl), OCH2, CH2O, OCH2CH2, CH2CH2O or piperidinyl;

[0364] L 5 Selected from a chemical bond, CH2, CH2CH2 or CH2CH2O;

[0365] L 6 Selected from: a chemical bond, O, S, NH, N(methyl), CH2, CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CO, CONH or NHCO;

[0366] L 7 Selected from: O, S, NH, N(methyl), CH2, vinylene or ethynylene;

[0367] K 3 is CH2 or CO;

[0368] R g Selected from hydrogen, C 1-6 Alkyl and halogenated C 1-6 alkyl;

[0369] The hydrogen atoms of any of the above methylene groups are optionally replaced by 1 or 2 R ## Replaced by R ## is selected from hydrogen, deuterium, halogen, amide, amino, dimethylamino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl or 4-7 membered heterocyclic group (preferably methyl, ethyl or propyl).

[0370] In some embodiments, the compound represented by the general formula (I) is the general formula (II-5), (II-5-1), (II-5-2), (II-5-3), (II-5-4), (II-5-5); wherein,

[0371] Z 6 , Z 7 Each independently is CH or N;

[0372] R Y Selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy or halogenated C 1-6 alkyl;

[0373] R Z '、R Y1 , R Y2 , R Y3 , R Y4 Each independently selected from: hydrogen, deuterium, fluorine, chlorine, amino, cyano, amide, acetyl, dimethylamino, diethylamino, diformamide, C 1-6 Alkyl, C 1-6 Alkoxy or halogenated C 1-6 alkyl;

[0374] R a '、R b '、R X Each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy or halogenated C 1-6 alkyl;

[0375] LIN is represented by: -L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -L 7 -,L 7 Connect with EL;

[0376] L 1 Selected from: chemical bond, CH2, CH2CH2, CO, CONH, NHCO, O, S, NH, N(methyl) or

[0377] L 2 , L 3 , L 4 Each is independently selected from: a chemical bond, CH2, CH2CH2, CO, CONH, NHCO, O, S, NH, N(methyl), OCH2, OCH2CH2, CH2CH2O;

[0378] L 5 , L 6 Selected from a chemical bond, CH2 or CH2CH2;

[0379] L 7 Selected from: O, S, NH, N(methyl), CH2, vinylene or ethynylene;

[0380] The hydrogen atoms of any of the above methylene groups are optionally replaced by 1 or 2 R ## Replaced by; R ## is selected from hydrogen, deuterium, halogen, amide, amino, dimethylamino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl or 4-7 membered heterocyclic group (preferably methyl, ethyl or propyl)

[0381] R N is selected from hydrogen, methyl or ethyl.

[0382] In some embodiments, the compound represented by the general formula (I) is the general formula (II-5), (II-5-1), (II-5-2), (II-5-3), (II-5-4), (II-5-5); wherein,

[0383] Z 6 , Z 7 All are CH; Y 1 , Y 2 , Y 3 , Y 4 All are CH;

[0384] Each R Y are each independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy or halogenated C 1-6 alkyl;

[0385] R Z '、R Y1 , R Y2 , R Y3 , R Y4 Each independently selected from: hydrogen, deuterium, fluorine, chlorine, amino, C 1-6 Alkyl, C 1-6 Alkoxy or halogenated C 1-6 alkyl;

[0386] R a '、R b '、R X Each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, C 1-6Alkyl, C 1-6 Alkoxy or halogenated C 1-6 alkyl;

[0387] LIN is represented by: -L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -L 7 -,L 7 Connect with EL;

[0388] L 1 Selected from: chemical bond, CH2, CH2CH2, CO, CONH, NHCO, O, S, NH, N(methyl) or

[0389] L 2 , L 3 , L 4 Each independently selected from: a chemical bond, CH2, CH2CH2, CO, CONH, NHCO, O, S, NH, N(methyl), OCH2, OCH2CH2, CH2CH2O;

[0390] L 5 , L 6 Selected from a chemical bond, CH2 or CH2CH2;

[0391] L 7 Selected from: O, S, NH, N(methyl), CH2, vinylene or ethynylene;

[0392] K 3 is CH2 or CO;

[0393] R g Selected from hydrogen, C 1-6 Alkyl and halogenated C 1-6 alkyl;

[0394] R N is selected from hydrogen, methyl or ethyl;

[0395] The hydrogen atoms of any of the above methylene groups are optionally replaced by 1 or 2 R ## Replaced by; R ## is selected from hydrogen, deuterium, halogen, amide, amino, dimethylamino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl or 4-7 membered heterocyclic group (preferably methyl, ethyl or propyl).

[0396] In some embodiments, the compound represented by the general formula (I) is the general formula (II-6), (II-6-1), (II-6-2), (II-6-3), (II-6-4), (II-6-5), (II-6-6); wherein,

[0397] R b '、R Y1 , R Y2 , R Y3 , R Y4 , R X Each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, amide, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl or 4-7 membered heterocyclic group;

[0398] R X Selected from hydrogen, halogen, C 1-6 Alkyl, -OR 1 、-O-(CH2) 1-4 R 1 , C 3-6 Cycloalkyl or 4-7 membered heterocyclic group;

[0399] R 1 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 alkyl, C 3-6 Cycloalkyl or 4-7 membered heterocyclic group;

[0400] R Y Selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy or halogenated C 1-6 alkyl;

[0401] L' is expressed as -(CR 2 2) p -NR N -;

[0402] p is 0, 1, 2, or 3,

[0403] R 2 Selected from: hydrogen, deuterium, amino, C 1-6 Alkyl, C 1-6 Alkoxy or halogenated C 1-6 Alkyl, or two R2 together with the attached C atom form C=O, cyclopropyl, oxetanyl or azetidinyl;

[0404] RN is selected from: hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, amino, =NH or hydroxyamino;

[0405] L is selected from a chemical bond, NH or N(methyl);

[0406] LIN is represented by: -L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -L 7 -,L 7 Connect with EL;

[0407] L 1 Selected from: chemical bond, CH2, CH2CH2, O, S, NH, N(methyl), OCH2, CH2O, OCH2CH2, CH2CH2O;

[0408] L 2 Selected from: chemical bond, CH2, CH2CH2, CO, CONH, NHCO, O, S, NH, N(methyl), OCH2, CH2O, OCH2CH2, CH2CH2O, piperidinyl;

[0409] L 3 , L 4 Selected from: CH2, CH2CH2, CO, CONH, NHCO, O, S, NH, N(methyl), OCH2, CH2O or OCH2CH2;

[0410] L 5 , L 6 is selected from a chemical bond, CH2, CH2CH2, OCH2CH2, O, S or NH;

[0411] L 7 Selected from: O, S, NH, N(methyl), CH2, vinylene or ethynylene;

[0412] The hydrogen atoms of any of the above methylene groups are optionally replaced by 1 or 2 R ## Replaced by R ## is selected from hydrogen, deuterium, halogen, amide, amino, dimethylamino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl or 4-7 membered heterocyclic group (preferably methyl, ethyl or propyl).

[0413] In some embodiments, the compound represented by the general formula (I) is the general formula (II-7-1), (II-7-2), (II-7-3), (II-7-4); wherein,

[0414] R Y1 , R Y2 , R Y3 , R Y4 , R b 'Each independently selected from hydrogen, deuterium, fluorine, amino, cyano, amide, acetyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, cyclopropyl, cyclobutyl or oxetanyl;

[0415] R Y Selected from hydrogen, deuterium, fluorine, C 1-6 Alkyl, C 1-6 Alkoxy, trifluoromethyl or difluoromethyl;

[0416] R X Selected from -O-(CH2) s -R 1 or -(CR'2) s -R 1 , R 1 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl or 4-7 membered heterocyclic group; 3-6 The cycloalkyl or 4-7 membered heterocyclic group is preferably cyclopropyl, cyclobutyl, oxetanyl or azetidinyl, wherein the C 3-6 Cycloalkyl or 4-7 membered heterocyclyl is optionally substituted by 1 or 2 substituents selected from deuterium, fluorine, methyl, ethyl, hydroxyl, hydroxymethyl, amino;

[0417] s is 0, 1, 2, or 3; LIN is as defined in the previous item.

[0418] In some embodiments, the compound represented by the general formula (I) is the general formula (II-8), (II-8-1), (II-8-2), (II-8-3), (II-8-4), (II-8-5), (II-8-6), (II-8-7) or (II-8-8); wherein,

[0419] R X Selected from hydrogen, deuterium, fluorine, chlorine, cyano, NR a R b , C 1-6 Alkyl, halogenated C 1-6 Alkyl, C1-6 Alkoxy, C 3-6 Cycloalkyl or 4-7 membered nitrogen heterocycle; preferably R X Expressed as -(CR'2) s -NR a R b ,

[0420] R Z4 is selected from hydrogen, deuterium, fluorine, amino, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, propoxy, isopropoxy, or two R Z4 Together with the C atom to which it is attached, it forms a cyclopropyl, cyclobutyl or cyclopentyl group;

[0421] Q 1 , Q 2 , Q 3 Each is independently N= or CR Q ;

[0422] R Y1 , R Y2 , R Y3 , R Y4 , R Q Each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, cyano, CONR a R b NR a R b , C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 4-7 membered nitrogen heterocycle;

[0423] Y 8 O, S or CH2;

[0424] R Y Each independently selected from hydrogen, deuterium, fluorine, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl or C 1-6 Alkoxy; or two R Y Together with the C atom to which it is attached, it forms C=O;

[0425] R'、R a , R b Each independently selected from hydrogen, deuterium, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, cyclopropyl, cyclobutyl Preferably, two R's together with the C atom to which they are attached form a cyclopropyl or cyclobutyl group; preferably R a , R bTogether with the nitrogen atom to which it is connected, it forms a 4-7-membered nitrogen heterocyclic ring.

[0426] The C 3-6 Cycloalkyl or 4-7 membered nitrogen heterocycle is optionally substituted by 1 or 2 substituents selected from F, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl;

[0427] L'Selected from: NR N , O, S, or -(CR 2 2) p -NR N -;

[0428] R 2 , R N Each independently selected from hydrogen, deuterium, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, hydroxy C 1-6 Alkyl or C 3-6 Cycloalkyl;

[0429] LIN is represented by: -L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -L 7 -,L 7 Connect with EL;

[0430] L 1 Selected from: a chemical bond, CH2, CH2CH2, O, S, NH, N(methyl), OCH2 or CH2O;

[0431] L 2 Selected from: a chemical bond, CH2, CH2CH2, CO, CONH, NHCO, O, S, NH, N(methyl), OCH2, CH2O, OCH2CH2 or CH2CH2O;

[0432] L 3 , L 4 Selected from: CH2, CH2CH2, CO, CONH, NHCO, O, S, NH, N(methyl), OCH2, CH2O or OCH2CH2;

[0433] L 5 , L 6 is selected from a chemical bond, CH2, CH2CH2, OCH2CH2, O, S or NH;

[0434] L 7Selected from: O, S, NH, N(methyl), CH2, vinylene or ethynylene;

[0435] The hydrogen atoms of any of the above methylene groups are optionally replaced by 1 or 2 R ## Replaced by R ## is selected from hydrogen, deuterium, halogen, amide, amino, dimethylamino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl or 4-7 membered heterocyclic group (preferably methyl, ethyl or propyl).

[0436] In some embodiments, the compound represented by the general formula (I) is the general formula (II-9), (II-9-1), (II-9-2), (II-9-3), (II-9-4), (II-9-5), (II-9-6); wherein,

[0437] Z 4 is CH2; Z 3 for NH;

[0438] Y 5 N or C, Y 6 N or C, Y 7 , Y 8 , Y 9 , Y 10 Each is independently NH or CR Y ;

[0439] R Y1 , R Y3 , R Y4 , R Y Each independently selected from hydrogen, deuterium, halogen, amide, amino, dimethylamino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl or 4-7 membered heterocyclic group;

[0440] L is a chemical bond; L' is NH;

[0441] U 9 Select from N or CR U ”,U 8 Select from N or CR U ”,

[0442] R U " is selected from hydrogen, deuterium, halogen, amino, amide, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, hydroxy C 1-6Alkyl or C 3-6 Cycloalkyl (preferably hydrogen, methyl or ethyl), preferably two R U " together with the ring atoms to which it is attached, form a 3-8 membered cycloalkyl or a 4-7 membered heterocyclyl;

[0443] LIN is represented by: -L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -L 7 -,L 7 Connect with EL;

[0444] L 1 Selected from C 3-6 Cycloalkyl, 4-12 membered heterocyclic group, CH2, CH2CH2, CH2CH2CH2, O, S, NH, N(methyl), CO, SO, SO2,

[0445] L 2 Selected from C 3-6 Cycloalkyl, 4-7 membered heterocyclyl, CH2, CH2CH2, CH2CH2CH2, O, S, NH, N(methyl), OCH2, CH2O, CONH or NHCO;

[0446] L 3 Selected from: CH2, CH2CH2, CH2CH2CH2, CO, CONH, NHCO, O, S, NH, N(methyl), OCH2 OCH2, OCH2CH2, CH2O, CH2CH2O;

[0447] L 4 is selected from a chemical bond, CH2, CH2CH2, CO, CONH, NHCO, O, S, NH, N(methyl), OCH2, OCH2CH2, CH2O or CH2CH2O;

[0448] L 5 Selected from a chemical bond, CH2 or CH2CH2;

[0449] L 6 Selected from: a chemical bond, O, S, NH, N(methyl), CH2, CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CO, CONH or NHCO;

[0450] L 7 Selected from: O, S, NH, N(methyl), CH2, vinylene or ethynylene;

[0451] The hydrogen atoms of any of the above methylene groups are optionally replaced by 1 or 2 R## Replaced by R ## is selected from hydrogen, deuterium, halogen, amide, amino, dimethylamino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl or 4-7 membered heterocyclic group.

[0452] In the above embodiment, Y 7 N, Y 9 CR Y In some embodiments, Y 7 CR Y , Y 9 is N; in some embodiments, Y 7 , Y 9 All CR Y .

[0453] In some embodiments, LIN is represented by: 1 -L 2 -L 3 -L 4 -L 5 -L 6 -L 7 -,L 7 Connect with EL;

[0454] L 1 Selected from: chemical bond, O, S, NR N , CH2, C(CH3)2, CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, OCH2CH2, CH2CH2O, CO, CONR N NR N CO、NR N CONR N 、SO 1-2 、SO 1-2 NR N NR N SO 1-2 NR N SO 1-2 NR N , vinylene, ethynylene, phenylene, pyridylene, pyrimidylene, pyrazinylene, pyridazinylene, piperazinylene, piperidinylene, triazolylene, tetrazolylene, pyrazolylene, imidazolylene, C 3-6 Cycloalkylene, 4-12 membered heterocyclylene,

[0455] L 2 Each independently selected from: chemical bond, O, S, NR N, CH2, CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, C(CH3)2, CO, CONR N NR N CO, OCH2CH2, CH2CH2O, vinylene, ethynylene, phenylene, pyridylene, pyrimidylene, piperazinylene, triazolylene, tetrazolylene, pyrazolylene, imidazolylene, C 3-6 Cycloalkylene or 4-12 membered heterocyclylene;

[0456] L 3 , L 4 Each independently selected from: chemical bond, O, S, NR N , CH2, CH2CH2, CH2CH2 CH2, CH2CH2CH2CH2, CO, CONR N NR N CO, OCH2CH2, CH2CH2O, vinylene, ethynylene, phenylene, pyridylene, pyrimidylene, piperazinylene, triazolylene, tetrazolylene, pyrazolylene, imidazolylene;

[0457] L 5 , L 6 Each independently selected from: chemical bond, O, S, NR N , CH2, CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CO, CONR N NR N CO, OCH2CH2, CH2CH2O, vinylene, ethynylene, phenylene, pyridylene, pyrimidylene, piperazinylene, triazolylene, tetrazolylene, pyrazolylene, imidazolylene;

[0458] L 7 Selected from: O, S, NH, N(methyl), CH2, vinylene, ethynylene, CONR N NR N CO、NR N CONR N 、SO 1-2 、SO 1-2 NR N NR N SO 1-2 or NR N SO 1-2 NR N ;

[0459] R N Selected from hydrogen or methyl; the hydrogen of any of the above methylene groups is optionally replaced by 1 or 2 R ## replaced by;

[0460] The C 3-6 Cycloalkylene, 4-12 membered heterocyclylene, optionally substituted by 1 or 2 selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or hydroxy C 1-6 The alkyl group is substituted with an alkyl substituent.

[0461] In some embodiments, LIN is represented by: 1 -L 2 -L 3 -L 4 -L 5 -L 6 -L 7 -,L 7 Connect with EL;

[0462] L 1 Selected from: CH2, CH2CH2, CO, CONH, NHCO, O, S, NH, N(methyl), OCH2, OCH2CH2, CH2O, CH2CH2O or

[0463] L 2 Selected from: chemical bond, CH2, CH2CH2, CO, CONH, NHCO, O, S, NH, N(methyl), OCH2, OCH2CH2, CH2O, CH2CH2O;

[0464] L 3 , L 4 Selected from: CH2, CH2CH2, CO, CONH, NHCO, O, S, NH, N(methyl), OCH2, CH2O, OCH2CH2, CH2CH2O;

[0465] L 5 Selected from a chemical bond, CH2, CH2CH2 or CH2CH2O;

[0466] L 6 Selected from: a chemical bond, O, S, NH, N(methyl), CH2, CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CO, CONH or NHCO;

[0467] L 7 Selected from: O, S, NH, N(methyl), CH2, vinylene or ethynylene.

[0468] In some embodiments, each of the above groups is independently a corresponding group in the compounds EX-1 to EX-32 prepared in the examples.

[0469] In some embodiments, the compound represented by general formula (I) is selected from Table 1.

[0470] Table 1:

[0471]

[0472]

[0473]

[0474]

[0475]

[0476]

[0477]

[0478]

[0479]

[0480]

[0481]

[0482]

[0483]

[0484]

[0485]

[0486]

[0487] On the other hand, the present invention provides a pharmaceutical composition comprising a compound as described above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and a mixture thereof, and a pharmaceutically acceptable excipient; preferably, it also contains other therapeutic agents.

[0488] Another aspect of the present invention provides a compound as described above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotope variant thereof, and a mixture thereof, or use of the pharmaceutical composition as described above in the preparation of protein inhibitors or degraders.

[0489] In some embodiments, the protein is HPK1 protein.

[0490] Another aspect of the present invention is to provide a compound as described above or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotope variant thereof, and a mixture thereof for use in the preparation of a medicament for treating and / or preventing cancer.

[0491] Another aspect of the present invention also provides a method for treating and / or preventing cancer in a subject, the method comprising administering to the subject a compound as described above or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and a mixture thereof or the above-mentioned pharmaceutical composition.

[0492] On the other hand, the present invention also provides a compound as described above or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotope variant thereof and a mixture thereof or the above-mentioned pharmaceutical composition, which is used for treating and / or preventing cancer.

[0493] The use, method or use of the above-mentioned compound or composition, wherein the cancer is selected from bladder cancer, breast cancer, colorectal cancer, gastric cancer, head and neck squamous cell carcinoma, Hodgkin's lymphoma, Merkel cell carcinoma, mesothelioma, melanoma, non-small cell lung cancer, ovarian cancer, uterine cancer, esophageal cancer, liver cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, thyroid cancer, small cell lung cancer, transitional cell carcinoma, urothelial carcinoma, tumors resistant to targeted drugs; or tumors or diseases dependent on HPK1 mutant protein. DETAILED DESCRIPTION

[0494] definition

[0495] Chemical Definition

[0496] Definitions of specific functional groups and chemical terms are described in more detail below.

[0497] When a numerical range is listed, it is intended to include every value and sub-range within the stated range. For example, "C 1-6 "Alkyl" includes C1, C2, C3, C4, C5, C6, C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C3-4 , C 4-6 , C 4-5 and C 5-6 alkyl.

[0498] “C 1-6 "Alkyl" refers to a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms. In some embodiments, C 1-4 Alkyl groups are preferred. 1-6 Examples of alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), and n-hexyl (C6). The term “C 1-6 "Alkyl" also includes heteroalkyl groups in which one or more (e.g., 1, 2, 3 or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkyl group may be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents or 1 substituent.

[0499] “C 2-6 "Alkenyl" refers to a straight or branched hydrocarbon group having 2 to 6 carbon atoms and at least one carbon-carbon double bond. In some embodiments, C 2-4 Alkenyl is preferred. 2-6 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. The term “C 2-6 "Alkenyl" also includes heteroalkenyl groups in which one or more (e.g., 1, 2, 3 or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkenyl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0500] “C 2-6 "Alkynyl" refers to a straight or branched chain hydrocarbon group having 2 to 6 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. In some embodiments, C 2-4 Alkynyl is preferred. 2-6 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), hexynyl (C6), and the like. The term “C 2-6"Alkynyl" also includes heteroalkynyl groups, in which one or more (e.g., 1, 2, 3 or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). Alkynyl groups may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0501] "Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0502] Therefore, "halogenated C 1-6 "Alkyl" refers to the above-mentioned "C 1-6 "alkyl", which is substituted by one or more halogen groups. In some embodiments, the halogenated C 1-4 Alkyl is particularly preferred, and halogenated C 1-2 Alkyl. Exemplary haloalkyl groups include, but are not limited to: -CF3, -CH2F, -CHF2, -CHFCH2F, -CH2CHF2, -CF2CF3, -CCl3, -CH2Cl, -CHCl2, 2,2,2-trifluoro-1,1-dimethyl-ethyl, and the like. The haloalkyl group may be substituted at any available point of attachment, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0503] “C 3-8 "Cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 8 ring carbon atoms and zero heteroatoms. In some embodiments, C 3-7 Cycloalkyl and C 3-6 Cycloalkyl is particularly preferred, more preferably C 5-6 Cycloalkyl. Cycloalkyl also includes a ring system in which the above-mentioned cycloalkyl ring is fused with one or more aryl or heteroaryl groups, wherein the connection point is on the cycloalkyl ring, and in such a case, the number of carbons continues to represent the number of carbons in the cycloalkyl system. Exemplary cycloalkyls include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), etc. The cycloalkyl group may be optionally substituted by one or more substituents, for example, substituted by 1 to 5 substituents, 1 to 3 substituents or 1 substituent.

[0504] "4-12 membered heterocyclyl" refers to a group of a 4-12 membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon. In heterocyclyls containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom as long as the valence permits. In some embodiments, a 3-10 membered heterocyclyl is preferred, which is a 3-10 membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms; in some embodiments, a 3-7 membered heterocyclyl is preferred, a 3-6 membered heterocyclyl is further preferred, a 4-8 membered heterocyclyl is further preferred, and a 5-6 membered heterocyclyl is more preferred. Heterocyclyl also includes a ring system in which the above heterocyclyl ring is fused to one or more cycloalkyl groups, wherein the point of attachment is on the cycloalkyl ring, or a ring system in which the above heterocyclyl ring is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring; and in such a case, the number of ring members continues to represent the number of ring members in the heterocyclyl ring system. Exemplary heterocyclic groups include, but are not limited to, aziridine, oxirane, thiorenyl, azetidinyl, oxetane, thietanyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, pyrrolyl-2,5-dione, piperidinyl, tetrahydropyranyl, dihydropyridinyl, thianyl, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 5-membered heterocyclic groups fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclic groups) include, but are not limited to, dihydroindole, isoindole, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinone, and the like. Exemplary 6-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as 6,6-bicyclic heterocyclyl groups) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc. The heterocyclyl group may be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0505] “C 6-10 "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic arrangement) having 6-10 ring carbon atoms and zero heteroatoms. In some embodiments, aryl has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, aryl has ten ring carbon atoms ("C 10Aryl also includes ring systems in which the above aryl ring is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the aryl ring, in which case the number of carbon atoms continues to refer to the number of carbon atoms in the aryl ring system. Aryl groups can be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0506] "5-14 membered heteroaryl" refers to a group of a 5-14 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic arrangement) having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom as long as valence permits. Heteroaryl bicyclic ring systems may include one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems in which the above-mentioned heteroaryl rings are fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the heteroaryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the heteroaryl ring system.

[0507] In some embodiments, 5-10 membered heteroaryls are preferred, and in other embodiments, 5-6 membered heteroaryls are particularly preferred. Exemplary 5 membered heteroaryls containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thienyl. Exemplary heteroaryls include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl), thiadiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, azacycloheptatrienyl, oxacycloheptatrienyl, thiacycloheptatrienyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indazinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolyl, isoquinolyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. The heteroaryl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0508] “C 6-10 "Arylene" and "5-14 membered heteroarylene" respectively refer to the above-mentioned "C 6-10 "Aryl" and "5-14 membered heteroaryl" are divalent groups formed by removing another hydrogen, and may be substituted or unsubstituted. Preferably C6-10 Arylene and 5- to 10-membered heteroarylene.

[0509] Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups and the like as defined herein are optionally substituted groups.

[0510] Exemplary substituents on carbon atoms include, but are not limited to, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa 、-ON(R bb )2、-N(R bb )2、-N(R bb )3 + X - 、-N(OR cc )R bb , -SH, -SR aa 、-SSR cc 、-C(=O)R aa 、-CO2H、-CHO、-C(OR cc 2. -CO2R aa 、-OC(=O)R aa 、-OCO2R aa 、-C(=O)N(R bb )2, -OC(=O)N(R bb )2.-NR bb C(=O)R aa 、-NR bb CO2R aa 、-NR bb C(=O)N(R bb )2, -C(=NR bb )R aa 、-C(=NR bb )OR aa 、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2, -OC(=NR bb )N(R bb )2.-NR bb C(=NR bb )N(R bb )2, -C(=O)NR bb S02R aa 、-NR bb S02R aa 、-SO2N(R bb 2. -SO2Raa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3.-OSi(R aa )3. -C(=S)N(R bb )2, -C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)R aa 、-P(=O)2R aa 、-OP(=O)2R aa ,-P(=O)(R aa )2.-OP(=O)(R aa )2.-OP(=O)(OR cc )2、-P(=O)2N(R bb )2、-OP(=O)2N(R bb )2, -P(=O)(NR bb )2, -OP(=O)(NR bb )2.-NR bb P(=O)(OR cc )2.-NR bb P(=O)(NR bb )2. -P(R cc )2. -P(R cc )3.-OP(R cc )2.-OP(R cc )3. -B(R aa )2、-B(OR cc )2. -BR aa (OR cc ), alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R dd Group substitution;

[0511] Or the two geminal hydrogen atoms on the carbon atom are replaced by groups =O, =S, =NN (R bb )2, =NNR bb C(=O)R aa , =NNR bbC(=O)OR aa , =NNR bb S(=O)2R aa , =NR bb or = NOR cc replace;

[0512] R aa Each of R is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R aa The groups are combined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is independently substituted by 0, 1, 2, 3, 4 or 5 R dd Group substitution;

[0513] R bb Each of is independently selected from: hydrogen, -OH, -OR aa 、-N(R cc )2, -CN, -C(=O)R aa 、-C(=O)N(R cc 2. -CO2R aa 、-SO2R aa 、-C(=NR cc )OR aa 、-C(=NR cc )N(R cc )2、-SO2N(R cc 2. -SO2R cc 、-SO2OR cc 、-SOR aa 、-C(=S)N(R cc )2, -C(=O)SR cc 、-C(=S)SR cc 、-P(=O)2R aa 、-P(=O)(R aa )2、-P(=O)2N(R cc )2, -P(=O)(NR cc )2, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R bb The groups are combined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is independently substituted by 0, 1, 2, 3, 4 or 5 R dd Group substitution;

[0514] R cc Each of R is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R ccThe groups are combined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is independently substituted by 0, 1, 2, 3, 4 or 5 R dd Group substitution;

[0515] R dd Each of is independently selected from: hydrogen, deuterium, halogen, carboxyl, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -SH, amino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 4-12 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, or two geminal R dd The substituents may combine to form =0 or =S.

[0516] Exemplary substituents on nitrogen atoms include, but are not limited to, hydrogen, -OH, -OR aa 、-N(R cc )2, -CN, -C(=O)R aa 、-C(=O)N(R cc 2. -CO2R aa 、-SO2R aa 、-C(=NR bb )R aa 、-C(=NR cc )OR aa 、-C(=NR cc )N(R cc )2、-SO2N(R cc 2. -SO2R cc 、-SO2OR cc 、-SOR aa 、-C(=S)N(R cc )2, -C(=O)SR cc 、-C(=S)SR cc 、-P(=O)2R aa 、-P(=O)(R aa )2、-P(=O)2N(R cc )2, -P(=O)(NR cc )2, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R attached to the nitrogen atom ccThe groups are combined to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl group is independently substituted by 0, 1, 2, 3, 4 or 5 R dd substituted with a group, and wherein R aa , R bb , R cc and R dd As mentioned above.

[0517] Other definitions

[0518] The term "cancer" includes, but is not limited to, the following cancers: cancers of the breast, ovary, cervix, prostate, testicle, esophagus, stomach, skin, lung, bone, colon, pancreas, thyroid, bile duct, buccal cavity and pharynx (mouth), lip, tongue, oral cavity, pharynx, small intestine, colorectal, large intestine, rectum, brain and central nervous system, glioblastoma, neuroblastoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, adenocarcinoma, adenoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder cancer, liver cancer, kidney cancer, bone marrow disorders, lymphatic disorders, Hodgkin's disease, hairy cell cancer, and leukemia. More specifically, cancer includes but is not limited to HER2-positive metastatic breast cancer, HER2-overexpressing metastatic gastric adenocarcinoma or gastroesophageal junction adenocarcinoma, non-small cell lung cancer with sensitive mutations in the epidermal growth factor receptor (EGFR) gene, locally advanced or metastatic squamous histological type non-small cell lung cancer with disease progression during or after platinum-containing chemotherapy, metastatic advanced breast cancer, and castration-resistant prostate cancer.

[0519] The term "treating" as used herein relates to reversing, alleviating, inhibiting the progression of the disorder or condition to which the term applies, or one or more symptoms of such disorder or condition. The noun "treating" as used herein relates to the action of the verb treat, the latter being as just defined.

[0520] The term "pharmaceutically acceptable salt" as used herein refers to those carboxylates, amino acid addition salts of the compounds of the present invention which are suitable for use in contact with patient tissues within the scope of sound medical judgment, do not produce undue toxicity, irritation, allergic response, etc., are commensurate with a reasonable benefit / risk ratio, and are effective for their intended use, including (where possible) zwitterionic forms of the compounds of the present invention.

[0521] Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali metals and alkaline earth metal hydroxides or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, etc. Examples of suitable amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine and procaine.

[0522] Base addition salts of acidic compounds may be prepared by contacting the free acid form with a sufficient amount of the desired base to form the salt in a conventional manner. The free acid may be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner. The free acid forms differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but for purposes of the present invention, the salts are equivalent to their respective free acids.

[0523] Salts can be sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides prepared from inorganic acids, such as hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, etc. Representative salts include: hydrobromates, hydrochlorides, sulfates, bisulfates, nitrates, acetates, oxalates, etc. Salts can also be prepared from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Representative salts include acetates, propionates, octanoates, isobutyrates, oxalates, etc. Pharmaceutically acceptable salts may include alkali and alkaline earth metal based cations, such as sodium, lithium, potassium, calcium, magnesium, etc., and non-toxic ammonium, quaternary ammonium and amine cations, including but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, etc. Also contemplated are salts of amino acids, such as arginate, gluconate, galacturonate, etc.

[0524] "Subjects" for administration include, but are not limited to, humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)) and / or non-human animals, e.g., mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0525] "Disease," "disorder," and "condition" are used interchangeably herein.

[0526] As used herein, and unless otherwise indicated, the terms "treatment," "treating," "treating," "treating," and "treatment" include actions that occur while a subject has a particular disease, disorder, or condition, that reduce the severity of, or delay or slow the development of, the disease, disorder, or condition ("therapeutic treatment"), and also include actions that occur before a subject develops a particular disease, disorder, or condition ("prophylactic treatment").

[0527] Generally, the "effective amount" of a compound refers to an amount sufficient to cause a target biological response. As will be appreciated by those of ordinary skill in the art, the effective amount of the compounds of the invention may vary depending on factors such as the biological target, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and symptoms of the subject. An effective amount includes a therapeutically effective amount and a prophylactically effective amount.

[0528] Unless otherwise specified, a "therapeutically effective amount" of a compound as used herein is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition. A therapeutically effective amount of a compound refers to an amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeutically effective amount" can include an amount that improves overall treatment, reduces or avoids symptoms or causes of a disease or condition, or enhances the therapeutic effect of other therapeutic agents.

[0529] Unless otherwise specified, a "prophylactically effective amount" of a compound as used herein is an amount sufficient to prevent a disease, disorder, or condition, or an amount sufficient to prevent one or more symptoms associated with a disease, disorder, or condition, or an amount to prevent the recurrence of a disease, disorder, or condition. A prophylactically effective amount of a compound refers to an amount of a therapeutic agent that provides a prophylactic benefit in the process of preventing a disease, disorder, or condition when used alone or in combination with other agents. The term "prophylactically effective amount" may include an amount that improves overall prevention, or an amount that enhances the prophylactic effect of other prophylactic agents.

[0530] "Combination" and related terms refer to the simultaneous or sequential administration of the compounds of the invention and other therapeutic agents. For example, the compounds of the invention can be administered simultaneously or sequentially with the other therapeutic agents in separate unit dosage forms, or can be administered simultaneously with the other therapeutic agents in a single unit dosage form.

[0531] The compounds of the present invention may include one or more asymmetric centers and may therefore exist in a variety of stereoisomeric forms, for example, enantiomers and / or diastereoisomeric forms. For example, the compounds of the present invention may be individual enantiomers, diastereomers or geometric isomers (e.g., cis and trans isomers), or may be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers may be separated from the mixture by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis.

[0532] Those skilled in the art will appreciate that organic compounds can form complexes with solvents in which they react or from which they precipitate or crystallize. These complexes are referred to as "solvates". When the solvent is water, the complex is referred to as a "hydrate". The present invention encompasses all solvates of the compounds of the present invention.

[0533] The term "solvate" refers to a form of a compound or a salt thereof that is combined with a solvent, usually formed by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, ether, etc. The compounds described herein can be prepared, for example, in crystalline form and can be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric solvates and non-stoichiometric solvates. In some cases, the solvate will be able to separate, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. "Solvate" includes solvates in solution and separable solvates. Representative solvates include hydrates, ethanolates and methanolates.

[0534] The term "hydrate" refers to a compound that is combined with water. Generally, the ratio of the number of water molecules contained in the hydrate of a compound to the number of molecules of the compound in the hydrate is determined. Therefore, the hydrate of a compound can be represented by, for example, the general formula R xH2O, wherein R is the compound, and x is a number greater than 0. A given compound can form more than one type of hydrate, including, for example, a monohydrate (x is 1), a lower hydrate (x is a number greater than 0 and less than 1, for example, a hemihydrate (R0.5H2O)) and a polyhydrate (x is a number greater than 1, for example, a dihydrate (R 2H2O) and a hexahydrate (R 6H2O)).

[0535] The compounds of the present invention can be in amorphous or crystalline form (polymorph). In addition, the compounds of the present invention can exist in one or more crystalline forms. Therefore, the present invention includes all amorphous or crystalline forms of the compounds of the present invention within its scope. The term "polymorph" refers to the crystalline form (or its salt, hydrate or solvate) of a compound with a specific crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardnesses, crystal shapes, photoelectric properties, stability and solubility. Recrystallization solvents, crystallization rates, storage temperatures and other factors can lead to a dominant crystalline form. The various polymorphs of a compound can be prepared by crystallization under different conditions.

[0536] The present invention also includes isotope-labeled compounds (isotope variants), which are equivalent to those described in formula (I), but one or more atoms are replaced by atoms whose atomic mass or mass number is different from the atomic mass or mass number common in nature. Examples of isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 2H, 3H, 13C, 11C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F and 36Cl, respectively. Compounds of the present invention containing other isotopes of the above-mentioned isotopes and / or other atoms, their prodrugs and pharmaceutically acceptable salts of the compounds or the prodrugs all belong to the scope of the present invention. Certain isotope-labeled compounds of the present invention, such as those that introduce radioactive isotopes (such as 3H and 14C), can be used for drug and / or substrate tissue distribution determinations. Tritium, i.e. 3H and carbon-14, i.e. 14C isotopes are particularly preferred because they are easy to prepare and detect. Furthermore, substitution with heavier isotopes, such as deuterium, i.e., 2H, may be preferred in some cases due to greater metabolic stability, which may provide therapeutic benefits, such as increased half-life in vivo or reduced dosage requirements. Isotopically labeled compounds of formula (I) of the present invention and their prodrugs can generally be prepared by replacing non-isotopically labeled reagents with readily available isotopically labeled reagents when carrying out the processes disclosed in the following schemes and / or the Examples and Preparation Examples.

[0537] Furthermore, prodrugs are also included in the context of the present invention. The term "prodrug" as used herein refers to a compound that is converted in vivo, for example by hydrolysis in the blood, into its active form having a medical effect.

[0538] Prodrugs are any covalently bonded compounds of the present invention that release the parent compound in vivo when such prodrugs are administered to a patient. Prodrugs are usually prepared by modifying functional groups, and the modification is carried out in a manner that allows the modification to be cleaved to produce the parent compound by conventional manipulation or in vivo. Prodrugs include, for example, compounds of the present invention in which hydroxyl, amino or sulfhydryl groups are bonded to any group, which can be cleaved to form hydroxyl, amino or sulfhydryl groups when administered to a patient. Therefore, representative examples of prodrugs include, but are not limited to, acetate / amide, formate / amide and benzoate / amide derivatives of hydroxyl, sulfhydryl and amino functional groups of compounds of formula (I). In addition, in the case of carboxylic acid (-COOH), esters such as methyl esters, ethyl esters, etc. can be used. Esters themselves can be active and / or can be hydrolyzed under human body conditions. Suitable pharmaceutically acceptable in vivo hydrolyzable ester groups include those groups that are easily decomposed in the human body to release the parent acid or its salt.

[0539] The present invention also provides a pharmaceutical preparation comprising a therapeutically effective amount of a compound of formula (I) or a therapeutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient thereof. All of these forms belong to the present invention.

[0540] Pharmaceutical compositions and kits

[0541] On the other hand, the present invention provides a pharmaceutical composition comprising a compound of the present invention (also referred to as an "active ingredient") and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises an effective amount of a compound of the present invention. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of the present invention. In some embodiments, the pharmaceutical composition comprises a preventive effective amount of a compound of the present invention.

[0542] The pharmaceutically acceptable excipient used in the present invention refers to a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compound formulated together. Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the composition of the present invention include (but are not limited to) ion exchangers, aluminum oxide, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and lanolin.

[0543] The present invention also includes a kit (e.g., a pharmaceutical package). The kit provided may include a compound of the invention, other therapeutic agents, and a first and second container (e.g., a vial, an ampoule, a bottle, a syringe, and / or a dispersible package or other suitable container) containing the compound of the invention and other therapeutic agents. In some embodiments, the kit provided may also optionally include a third container containing a pharmaceutical excipient for diluting or suspending the compound of the invention and / or other therapeutic agents. In some embodiments, the compound of the invention and other therapeutic agents provided in the first container and the second container are combined to form a unit dosage form.

[0544] Drug administration

[0545] Pharmaceutical composition provided by the invention can be administered by many ways, including but not limited to: oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal administration, oral administration, vaginal administration, administration by implant or other modes of administration. For example, parenteral administration used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intraarticular administration, intraarterial administration, intrasynovial cavity administration, intrasternal administration, intrathecal administration, intralesional administration and intracranial injection or infusion technology.

[0546] Generally, an effective amount of the compounds provided herein is administered. The amount of the compound actually administered can be determined by a physician according to the relevant circumstances, including the condition being treated, the route of administration selected, the compound actually administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, and the like.

[0547] When used to prevent the conditions described herein, the compounds provided herein are administered to a subject at risk of developing the condition, typically based on the advice of a physician and under the supervision of a physician, at dosage levels as described above. Subjects at risk of developing a specific condition typically include those with a family history of the condition, or those identified by genetic testing or screening as being particularly susceptible to developing the condition.

[0548] The pharmaceutical compositions provided herein can also be administered over a long period of time ("chronic administration"). Chronic administration refers to administration of a compound or a pharmaceutical composition thereof over a long period of time, e.g., 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or administration may continue indefinitely, e.g., for the rest of the subject's life. In some embodiments, chronic administration is intended to provide a constant level of the compound in the blood over a long period of time, e.g., within a therapeutic window.

[0549] Various methods of administration can be used to further deliver the pharmaceutical composition of the present invention. For example, in some embodiments, the pharmaceutical composition can be administered by push injection, for example, in order to increase the concentration of the compound in the blood to an effective level. The push dose depends on the target systemic level of the active component through the body, for example, the intramuscular or subcutaneous push dose slowly releases the active component, and the push delivered directly to the vein (for example, by IV intravenous drip) can be delivered more quickly, so that the concentration of the active component in the blood is quickly increased to an effective level. In other embodiments, the pharmaceutical composition can be given in a continuous infusion form, for example, by IV intravenous drip, so as to provide a steady-state concentration of the active component in the subject's body. In addition, in other embodiments, the pharmaceutical composition of the push dose can be first given, and then continuous infusion.

[0550] Oral compositions can be in the form of bulk liquid solutions or suspensions or bulk powders. However, more generally, in order to facilitate accurate dosing, the composition is provided in unit dosage form. The term "unit dosage form" refers to a physical discrete unit suitable as a unit dose for human patients and other mammals, each unit containing a predetermined amount of active substances suitable for producing the desired therapeutic effect and a suitable pharmaceutical excipient. Typical unit dosage forms include pre-filled, pre-measured ampoules or syringes of liquid compositions, or pills, tablets, capsules, etc. in the case of solid compositions. In such compositions, the compound is usually a relatively small component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), and the remainder is various carriers or excipients and processing aids useful for forming the desired administration form.

[0551] For oral dosage, a representative regimen is one to five oral doses per day, especially two to four oral doses, typically three oral doses. Using these dosage modes, each dose provides about 0.01 to about 20 mg / kg of the compound of the invention, and preferred doses each provide about 0.1 to about 10 mg / kg, especially about 1 to about 5 mg / kg.

[0552] In order to provide blood levels similar to those using an injectable dose, or lower blood levels than using an injectable dose, a transdermal dose is generally selected in an amount of about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight, preferably about 0.1 to about 10% by weight, and more preferably about 0.5 to about 15% by weight.

[0553] From about 1 to about 120 hours, especially 24 to 96 hours, the injected dosage level is in the range of about 0.1 mg / kg / hour to at least 10 mg / kg / hour. In order to obtain sufficient steady state levels, a preload bolus of about 0.1 mg / kg to about 10 mg / kg or more may also be given. For a 40 to 80 kg human patient, the maximum total dose cannot exceed about 2 g / day.

[0554] Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous carrier and buffers, suspending and dispersing agents, colorants, flavoring agents, etc. Solid forms may include, for example, any of the following components, or compounds of a similar nature: binders, such as microcrystalline cellulose, tragacanth, or gelatin; excipients, such as starch or lactose, disintegrants, such as alginic acid, Primogel, or corn starch; lubricants, such as magnesium stearate; glidants, such as colloidal silicon dioxide; sweeteners, such as sucrose or saccharin; or flavoring agents, such as peppermint, methyl salicylate, or orange flavoring.

[0555] Injectable compositions are typically based on injectable sterile saline or phosphate buffered saline, or other injectable excipients known in the art. As previously mentioned, in such compositions, the active compound is typically a minor component, often about 0.05 to 10% by weight, and the remainder is an injectable excipient, etc.

[0556] Typically, transdermal compositions are formulated as topical ointments or creams containing active ingredients. When formulated as an ointment, the active ingredient is typically combined with a paraffin or water-miscible ointment base. Alternatively, the active ingredient can be formulated as an ointment together with, for example, an oil-in-water cream base. Such transdermal formulations are well known in the art and typically include other components for enhancing the stable skin penetration of the active ingredient or formulation. All such known transdermal formulations and components are included within the scope provided by the invention.

[0557] The compounds of the invention may also be administered by transdermal means. Thus, transdermal administration may be achieved using patches of the reservoir or porous membrane type, or a variety of solid matrices.

[0558] The above components of compositions for oral administration, injection or topical administration are merely representative.

[0559] The compounds of the invention may also be administered in sustained release form or from a sustained release delivery system. Descriptions of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.

[0560] The present invention also relates to pharmaceutically acceptable formulations of the compounds of the present invention. In one embodiment, the formulation comprises water. In another embodiment, the formulation comprises a cyclodextrin derivative. The most common cyclodextrins are α-, β- and γ-cyclodextrins consisting of 6, 7 and 8 α-1,4-linked glucose units, respectively, which optionally include one or more substituents on the linked sugar moiety, including but not limited to: methylated, hydroxyalkylated, acylated and sulfoalkyl ether substitutions. In some embodiments, the cyclodextrin is a sulfoalkyl ether β-cyclodextrin, for example, sulfobutyl ether β-cyclodextrin, also known as Captisol. See, for example, US5,376,645. In some embodiments, the formulation includes hexapropyl-β-cyclodextrin (e.g., in water, 10-50%).

[0561] Combination medication

[0562] The treatment defined herein may be applied as sole therapy or may include conventional surgery or radiotherapy or chemotherapy in addition to the compounds of the invention. Thus, the compounds of the invention may also be used in combination with existing therapeutic agents for the treatment of cancer.

[0563] In addition to the treatment with the compounds of the present invention, conventional surgery or radiotherapy or chemotherapy or immunotherapy is also involved. This chemotherapy and the compounds of the present invention can be administered simultaneously, continuously, or separately, and may contain one or more of the following types of anti-tumor agents:

[0564] (i) antiproliferative / antineoplastic drugs and combinations thereof used in medical oncology, such as alkylating agents (e.g., cisplatin, oxaliplatin, carboplatin, cyclophosphamide, mechlorethamine, melphalan, chlorambucil, busulfan, temozolomide, nitrosoureas); antimetabolites (e.g., gemcitabine and antifolates, such as fluoropyrimidines (e.g., 5-fluorouracil and tegafur), raltitrexed, methotrexate, cytarabine, hydroxyurea); antineoplastic antibiotics (e.g., anthracyclines, such as aldosterone); mycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin C, actinomycin, mithramycin); antimitotic agents (e.g., vinca alkaloids, such as vincristine, vinblastine, vindesine, vinorelbine; and taxanes, such as paclitaxel, taxotere, polo kinase inhibitors); topoisomerase inhibitors (e.g., epipodophyllotoxins (e.g., etoposide, teniposide), amsacrine, topotecan, camptothecin);

[0565] (ii) cytostatic agents, such as antiestrogens (e.g. tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene, iodoxyfene), antiandrogens (e.g. bicalutamide, flutamide, nilutamide, cyproterone acetate), LHRH antagonists or LHRH agonists (e.g. goserelin, leuprolide, and buserelin), progestins (e.g. megestrol acetate), aromatase inhibitors (e.g. anastrozole, letrozole, vorazole, exemestane), 5α-reductase inhibitors (e.g. finasteride);

[0566] (iii) anti-invasion agents, such as inhibitors of the c-Src kinase family, such as 4-(6-chloro-2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxyquinazoline [AZD0530 (sarcatinib)], N-(2-chloro-6-methylphenyl)-2-{6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-ylamino}thiazole-5-carboxamide (dasatinib, BMS-354825) and bosutinib (SKI-606), as well as metalloproteinase inhibitors (such as marimastat), inhibitors of urokinase plasminogen activator receptor function or antibodies to heparanase];

[0567] (iv) Inhibitors of growth factor function: For example, such inhibitors include growth factor antibodies and growth factor receptor antibodies (e.g., anti-erbB2 antibody trastuzumab [Herceptin], anti-EGFR antibody panitumumab, anti-erbB1 antibody cetuximab [Erbitux, C225]); such inhibitors also include: tyrosine kinase inhibitors, for example, inhibitors of the epidermal growth factor family (e.g., EGFR family tyrosine kinase inhibitors, such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)-quinazolin-4-amine (gefitinib, ZD1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774), 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine ( amine (CI1033), erbB2 tyrosine kinase inhibitors (e.g., lapatinib); inhibitors of the hepatocyte growth factor family; inhibitors of the insulin growth factor family; inhibitors of the platelet-derived growth factor family, such as imatinib and / or nilotinib (AMN107); inhibitors of serine / threonine kinases (e.g., Ras / Raf signaling inhibitors, such as farnesyl transferase inhibitors, such as sorafenib (BAY43-9006), tipifarnib (R115777), lonafarnib (SCH66336)), inhibitors of cell signaling through mEK and / or AKT kinases, c-kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1R kinase inhibitors, IGF receptor (insulin-like growth factor) kinase inhibitors; aurora kinase (aurora kinase) inhibitors (e.g. AZD1152, PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528, AX39459), cyclin-dependent kinase inhibitors, such as CDK2 and / or CDK4 inhibitors;

[0568] (v) anti-angiogenic agents, for example agents that inhibit the action of vascular endothelial growth factor [for example the anti-human vascular endothelial growth factor antibody bevacizumab (Avastin) and for example VEGF receptor tyrosine kinase inhibitors, for example vandetanib (ZD6474), vatalanib (PTK787), sunitinib (SU11248), axitinib (AG-013736), pazopanib (GW786034), 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (AZD2171), and compounds acting by other mechanisms (for example ranolamide, inhibitors of integrin αvβ3 function and angiostatin)];

[0569] (vi) Vascular damaging agents, such as Compretin A4;

[0570] (vii) endothelin receptor antagonists, such as zilpotentan (ZD4054) or atrasentan;

[0571] (viii) antisense therapeutics, such as those directed to the targets listed above, such as ISIS2503 (an anti-ras antisense therapeutic);

[0572] (ix) gene therapy approaches, including, for example, approaches that replace abnormal genes (e.g., abnormal p53 or abnormal BRCA1 or BRCA2); GDEPT (gene-directed enzyme prodrug therapy) approaches, such as those using cytosine deaminase, thymidine kinase, or bacterial nitroreductase; approaches that increase a patient's tolerance to chemotherapy or radiation therapy, such as multidrug resistance gene therapy; and

[0573] (x) Immunotherapeutic methods, including, for example, in vitro and in vivo methods for increasing the immunogenicity of a patient's tumor cells, such as transfection with cytokines (e.g., interleukin 2, interleukin 4, or granulocyte macrophage colony stimulating factor); methods for reducing T cell anergy; methods using transfected immune cells (e.g., cytokine-transfected dendritic cells); methods using cytokine-transfected tumor cell lines; methods using anti-idiotypic antibodies; methods for reducing the function of immunosuppressive cells (e.g., regulatory T cells, myeloid-derived suppressor cells, or dendritic cells expressing IDO (indoleamine 2,3-deoxygenase)); and methods using cancer vaccines composed of proteins or peptides derived from tumor-associated antigens (e.g., NY-ESO-1, mAGE-3, WT1, or Her2 / neu).

[0574] Example

[0575] Compound Preparation Examples

[0576] The abbreviations used in the following text have the following meanings:

[0577]

[0578]

[0579] For the raw materials in the following synthesis steps, the synthesis steps are provided for non-commercial reagents. The batches corresponding to the raw materials in each step are not necessarily the same as the batches described in the synthesis method.

[0580] Preparation of intermediates

[0581] Synthesis of compound Int-1

[0582]

[0583] Step 1: Dissolve compound 1-1 (32 g, 98.79 mmol) in anhydrous THF (50 mL), slowly add sodium hydride (5.93 g, 148.19 mmol, 60% wt) at 0 ° C under nitrogen protection, stir for 30 minutes, slowly add di-tert-butyl dicarbonate (28.03 g, 29.50 mL) in anhydrous THF (10 mL), stir at room temperature for 3 hours. After the reaction is completed, add water (10 mL) to quench, and concentrate under reduced pressure to obtain a crude product. The crude product is slurried with a mixed solution of PE:EA=10:1 (200 mL). Filter to obtain compound 1-2 (41 g, yield 97.9%).

[0584] Step 2: Dissolve compound 1-2 (15 g, 35.37 mmol) in 1,4-dioxane (300 mL), add 4-(N,N-dimethylamino)phenylboronic acid (5.12 g, 26.53 mmol), Pd(dppf)Cl2·CH2Cl2 (1.44 g, 1.77 mmol) and potassium carbonate (9.78 g, 70.75 mmol) aqueous solution (30 mL) in sequence under nitrogen protection, and heat at 80°C for 3 hours. After the reaction is completed, cool to room temperature and concentrate under reduced pressure to obtain a crude product. The crude product is separated and purified by column chromatography (PE: EA = 1: 1 to 0: 1) to obtain compound Int-1 (5.43 g, yield 45.9%). LCMS [M+H] + 445.0,447.0.

[0585] Synthesis of compound Int-2

[0586]

[0587] Compound Int-1 and bis-pinacol borate (9.24 g, 36.38 mmol) were used as raw materials, and the synthetic method of compound Int-1 was referred to to obtain compound Int-2 (6.4 g, crude product), which was directly used in the next step. LCMS [M+H] + 411.1.

[0588] Synthesis of compound Int-3

[0589]

[0590] Step 1: Using compound Int-1 and compound 3.1 as raw materials, refer to the synthesis method of compound Int-1 to obtain dark brown oily compound 3-1 (5.6 g, yield 61.5%). LCMS [M+H] + 598.5.

[0591] Step 2: Dissolve compound 3-1 (3.3 g, 5.52 mmol) in dichloromethane (10 mL), add trifluoroacetic acid (46.20 g, 30 mL), and react at room temperature for 2 hours. After the reaction is completed, concentrate under reduced pressure to obtain a yellow solid crude compound Int-3 (2.3 g). LCMS [M+H] + 398.1.

[0592] Synthesis of compound Int-4

[0593]

[0594] Step 1: Dissolve compound 4-1 (4.41 g, 15.97 mmol) in NMP (50 mL), add tert-butyl 4-aminobutyrate hydrochloride (5.0 g, 25.55 mmol) and DIPEA (6.19 g, 47.91 mmol) in sequence, and heat at 100 ° C for 3 hours. Cool to room temperature, add water (150 mL), extract with ethyl acetate (90 mL), wash the organic layer with saturated brine, and dry over anhydrous sodium sulfate. Filter and concentrate under reduced pressure to obtain a crude product. The crude product is separated and purified by column chromatography (PE: EA = 1: 1-0: 1) to obtain a light yellow solid compound 4-2 (6.42 g, yield 96.7%). LCMS [M + H] + 415.2.

[0595] Step 2: Dissolve compound 4-2 (6.42 g, 15.45 mmol) in dichloromethane (50 mL), add trifluoroacetic acid (9.89 g, 86.71 mmol, 6.42 mL), and stir at room temperature for 3 hours. After concentration under reduced pressure and freeze-drying, a yellow solid compound Int-4 (3.4 g, yield 61.2%) was obtained. LCMS [M+H] + 360.1.

[0596] The synthesis of the following intermediates was carried out using the corresponding amines as starting materials, using a preparation method similar to that of Int-4.

[0597]

[0598] Synthesis of compound Int-8

[0599]

[0600] Compound 8-1 (1.38 g, 8.69 mmol) and compound 8-2 (2 g, 7.24 mmol) were dissolved in NMP (20 mL), and DIPEA (2.81 g, 3.78 mL) was added, and the mixture was heated at 120°C for 3 hours. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure to obtain a crude product. The crude product was purified by reverse phase preparative HPLC (trifluoroacetic acid system) to obtain compound Int-8 (1 g, yield 33.3%), a green solid. LCMS [M+H] + The synthesis of the following intermediates was prepared using compound 4-1 as the starting material in a similar manner to Int-8.

[0601]

[0602]

[0603] Synthesis of compound Int-13

[0604]

[0605] Under nitrogen protection, compound 13-1 (12 g, 54.03 mmol) was dissolved in glacial acetic acid (80 mL), and then sodium borohydride (7.15 g, 189.12 mmol) was slowly added thereto and stirred at room temperature for 3 hours. After the reaction was completed, saturated ammonium chloride solution was added to quench, and after extraction with water and ethyl acetate, the organic phase was dried over anhydrous sodium sulfate. Filtered, the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (DCM: MeOH = 100: 1 ~ 10: 1) to obtain a yellow solid compound Int-13 (5 g, yield 40.9%). LCMS [M + H] + 226.1.

[0606] Synthesis of compound Int-14

[0607]

[0608] Step 1: Under nitrogen protection, compound Int-2 (718.60 mg, 1.46 mmol), Int-13 (300 mg, 1.33 mmol), Pd(dppf)Cl2·CH2Cl2 (108.35 mg, 132.68 μmol) and potassium carbonate (366.74 mg, 2.65 mmol) were dissolved in a mixed solution of 1,4-dioxane (20 mL) and water (0.8 mL), and heated at 80 ° C for 2 hours. After the reaction was completed, it was cooled to room temperature and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (DCM: MeOH = 100: 1 ~ 10: 1) to obtain compound 14-1 (330 mg, yield 48.6%), a yellow solid. LCMS [M + H]+ 512.5.

[0609] Step 2: Under nitrogen protection, compound 14-1 (330 mg, 645.02 μmol) was dissolved in a solution of hydrochloric acid in dioxane (4M, 10 mL) and reacted at room temperature for 3 hours. After the reaction, the reaction mixture was concentrated under reduced pressure to obtain compound Int-14 (200 mg, yield 69.2%) as a yellow solid. LCMS [M+H] + 412.3.

[0610] Synthesis of compound Int-15

[0611]

[0612] Step 1: Under nitrogen protection, compound Int-3 (100 mg, 251.59 μmol), (6-bromohexyl) carbamic acid tert-butyl ester (70.50 mg, 251.59 μmol) and DIPEA (97.55 mg, 131.47 μL) were dissolved in DMF (10 mL) and heated at 70 ° C for 2 hours. After the reaction was completed, it was cooled to room temperature, quenched by adding a small amount of saturated ammonium chloride aqueous solution, extracted with ethyl acetate (20 mL), and the organic phase was dried over anhydrous sodium sulfate. Filter, concentrate the filtrate under reduced pressure to obtain a crude product, and separate and purify by thin layer chromatography (DCM: MeOH = 8: 1) to obtain compound 15-1 (90 mg, yield 59.9%), a yellow solid. LCMS [M + H] + 597.6.

[0613] Step 2: Under nitrogen protection, compound 15-1 (90 mg, 150.81 μmol) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (1.54 g, 1 mL) was added dropwise, and the mixture was reacted at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain a crude compound Int-15 (70 mg, yield 76.0%) as a yellow solid. LCMS [M+H] + 497.4.

[0614] Synthesis of compound Int-16

[0615]

[0616] Under nitrogen protection, lenalidomide 16-1 (3.76 g, 14.52 mmol), 6-bromohexanal 16-2 (2.6 g, 14.52 mmol), sodium cyanoborohydride (1.00 g, 15.97 mmol) and glacial acetic acid (546.00 mg, 520.0 μL) were dissolved in anhydrous methanol (10 mL) and reacted at room temperature for 10 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography (PE: EA = 10: 1 to 1: 1) to obtain compound Int-16 (2 g, yield 32.6%) as a white solid. LCMS [M+H] + 423.9.

[0617] Synthesis of compound Int-17

[0618]

[0619] Under nitrogen protection, compound 17-1 (49.90 mg, 355.95 μmol), compound 17-2 (100 mg, 296.63 μmol), Pd(PPh)2C l2 (20.82mg, 29.66μmol), CuI (11.30mg, 59.33μmol) and triethylamine (2.91g, 4.00mL) were dissolved in DMF (4mL) and heated at 80℃ for 10 hours. After the reaction was completed, it was cooled to room temperature, diluted with water (20mL), extracted with ethyl acetate (2×20mL), and the organic phase was dried over anhydrous sodium sulfate. Filtered, the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography (DCM: MeOH = 100: 1~10: 1) to obtain a yellow oily compound Int-17 (110mg, yield 93.6%). LCMS [M+H] + 397.2.

[0620] The synthesis of the following intermediates was prepared by a method similar to Int-17.

[0621]

[0622]

[0623] Synthesis of compound Int-21

[0624]

[0625] Step 1: Under nitrogen protection, compound 21-1 (293.44 mg, 1.36 mmol), compound 21-2 (310 mg, 1.13 mmol), triphenylphosphine (889.50 mg, 3.39 mmol) were dissolved in anhydrous THF (15 mL), the reaction solution was cooled to 0 ° C, DIAD (685.75 mg, 659.38 μL) in anhydrous tetrahydrofuran (1 mL) was slowly added, and the reaction was carried out at room temperature for 10 hours after the addition. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography (PE: EA = 5: 1 to 1: 1) to obtain compound 21-3 (350 mg, yield 65.5%), a gray solid.

[0626] Step 2: Under nitrogen protection, compound 21-3 (300 mg, 634.88 μmol) was dissolved in a solution of hydrochloric acid in 1,4-dioxane (4M, 5 mL) and reacted at room temperature for 2 hours. After the reaction, the reaction mixture was concentrated under reduced pressure to obtain compound Int-21 (260 mg, yield 98.3%) as a gray oil. LCMS [M+H] + 417.2.

[0627] Synthesis of compound Int-22

[0628]

[0629] Using 7-bromo-1,2,3,4-tetrahydroisoquinoline as the raw material, the compound Int-22 was prepared by a synthetic method similar to Int-14. LCMS [M+H] + 398.2.

[0630] Synthesis of compound Int-23

[0631]

[0632] Compound Int-23 was prepared using compound Int-3 and tert-butyl bromoacetate as raw materials and referring to the synthetic method of compound Int-15. LCMS [M+H] + 456.3.

[0633] Synthesis of compound Int-24

[0634]

[0635] Compound 4-1 (and (3-aminopropyl) carbamic acid tert-butyl ester) was used as raw materials, and the synthetic method of compound Int-15 was referred to obtain compound Int-24. LCMS [M+H] + 331.1.

[0636] The synthesis of the following intermediates was prepared by a method similar to that of Int-15.

[0637]

[0638] Intermediate 28: Synthesis of Compound Int-28

[0639]

[0640] Step 1: Under nitrogen protection, compound 1-2 (11 g, 25.94 mmol) and 4-(tert-butyloxycarbonyl)phenylboronic acid (2.82 g, 12.71 mmol) were added to a mixed solution of 1,4-dioxane (100 mL) and water (10 mL), and then Pd(dppf)Cl2·CH2Cl2 (741.47 mg, 907.95 μmol) and potassium carbonate (5.02 g, 36.32 mmol) were added, and the mixture was heated at 80°C for 3 hours. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with water (70 mL), extracted with dichloromethane (3×50 mL), and the organic layers were combined and dried over anhydrous sodium sulfate. Filtered, the filtrate was concentrated to obtain a crude product. The crude product was separated and purified by column chromatography (PE:EA=100:1-25:1) to obtain compound 28-1 (3.2 g, yield 53.0%) as a white solid.

[0641] LCMS [M+H] + 474.0.

[0642] Step 2: Under nitrogen protection, compound 28-1 (3g, 6.32mmol, 1eq) was dissolved in anhydrous 1,4-dioxane (100mL), and then Pd(dppf)Cl2·CH2Cl2 (516.48mg, 632.45μmol), anhydrous potassium acetate (1.24g, 12.65mmol) and bis-naphthalene alcohol borate (3.21g, 12.65mmol) were added, and the reaction was heated at 100°C for 3 hours. After the reaction was completed, it was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with water (20mL), extracted with dichloromethane (3×30mL), and the organic layers were combined and dried over anhydrous sodium sulfate. Filtered, the filtrate was concentrated to obtain a dark brown gummy compound 28-2 (5.7g, crude product), which was directly used in the next step. LCMS [M+H] + 440.1.

[0643] Step 3: Under nitrogen protection, compound 28-2 (2.2 g, 5 mmol, 1.4 eq) and compound 28.2 (801.39 mg, 3.54 mmol) were added to a mixed solution of 1,4-dioxane (20 mL) and water (2 mL), and then Pd(dppf)Cl2·CH2Cl2 (120.60 mg, 147.68 μmol) and potassium carbonate (816.39 mg, 5.91 mmol) were added, and the mixture was heated at 80°C for 3 hours. After the reaction was completed, it was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with water (20 mL), then extracted with dichloromethane (3×30 mL), the organic layers were combined, and dried over anhydrous sodium sulfate. Filtered, the filtrate was concentrated to obtain a crude product. The crude product was separated and purified by column chromatography (DCM: MeOH = 100: 1 to 40: 1) to obtain compound 28-3 (650 mg, yield 33.9%) as a white solid. LCMS [M+H] + 541.3.

[0644] Step 4: Dissolve compound 28-3 (600 mg, 1.10 mmol) in dichloromethane (10 mL), then add trifluoroacetic acid (5.54 mmol, 410.84 μL) and react at room temperature for 1 hour. After the reaction is completed, the reaction solution is concentrated under reduced pressure to obtain compound Int-28 (640 mg, crude product). The yellow solid is directly used in the next step. LCMS [M+H] + 385.2.

[0645] Synthesis of compound Int-29

[0646]

[0647] Step 1: Under nitrogen protection, compound 29-1 (400 mg, 1.84 mmol), isoindoline-1,3-dione (270.83 mg, 1.84 mmol), triphenylphosphine (1.45 g, 5.52 mmol) were dissolved in anhydrous tetrahydrofuran (20 mL), cooled to 0 ° C, DIAD (5.52 mmol, 1.07 mL) was slowly added thereto, and the mixture was allowed to react at room temperature for 1 hour. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (PE: EA = 20: 1 to 5: 1) to obtain a yellow oily compound 29-2 (600 mg, yield 94.1%). LCMS [M-Boc + H] + 247.1.

[0648] Step 2: Compound 29-2 (600 mg, 1.73 mmol) and hydrazine hydrate (3.46 mmol, 198.07 μL, 85% purity) were dissolved in anhydrous ethanol (10 mL) and heated at 60°C for 1 hour. After the reaction, the mixture was cooled to room temperature and directly concentrated under reduced pressure to obtain a crude compound 29-3 (370 mg, yield 98.8%), which was directly used in the next step.

[0649] Step 3: Under nitrogen protection, compound 29-3 (370 mg, 1.71 mmol), compound 4-1 (472.46 mg, 1.71 mmol) and DIPEA (442.12 mg, 3.42 mmol) were dissolved in dimethyl sulfoxide (10 mL) and heated at 100 ° C for 3 hours. After the reaction was completed, it was cooled to room temperature, a small amount of saturated aqueous ammonium chloride solution and dichloromethane were added for extraction, and the organic phase was dried over anhydrous sodium sulfate. Filter, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (PE: EA = 10: 1 to 1: 1) to obtain a yellow oily compound 29-4 (400 mg, yield 49.5%). LCMS [M + Na] + 495.4.

[0650] Step 4: Dissolve compound 29-4 (50 mg, 105.81 μmol) in dichloromethane (10 mL), add trifluoroacetic acid (121.0 mg, 1.06 mmol), and react at room temperature for 1 hour. After the reaction is completed, the reaction solution is concentrated under reduced pressure to obtain a crude compound Int-29 (60 mg) as a yellow oil. LCMS [M+H] + 373.3.

[0651] The synthesis of the following intermediates was prepared by a method similar to that of Int-29.

[0652]

[0653] Synthesis of compound Int-31

[0654]

[0655] Step 1: Dissolve compound 31-1 (500 mg, 2.17 mmol), phthalic anhydride (321.51 mg, 2.17 mmol), and DIPEA (420.81 mg, 3.26 mmol) in anhydrous toluene (15 mL), and heat at 110°C for 10 hours. After the reaction is completed, cool to room temperature, add saturated aqueous ammonium chloride solution, extract with ethyl acetate, and dry the organic phase with anhydrous sodium sulfate. Filter, and concentrate the filtrate under reduced pressure to obtain a colorless oil compound 31-2 (700 mg, yield 89.5%). LCMS [M+Na] + 383.2.

[0656] Steps 2 to 4 refer to the synthetic steps 2 to 4 of compound Int-29 to obtain compound Int-31, LCMS [M+H] + 401.3.

[0657] The synthesis of the following intermediates was prepared by a method similar to Int-31.

[0658]

[0659]

[0660] Intermediate 33: Synthesis of compound Int-33

[0661]

[0662] Compound 33-1 was used as the raw material, and the compound Int-33 was obtained by referring to the synthesis method of compound Int-29 or Int-31. LCMS [M+H] + 429.2.

[0663] Synthesis of compound Int-34

[0664]

[0665] Step 1: Dissolve compound 34-1 (5.0 g, 28.98 mmol) in NMP (100 mL), add DIPEA (86.92 mmol, 15.14 mL) and 1-tert-butyl-piperazine (6.48 g, 34.77 mmol) in turn, and heat at 130°C for 12 hours. After the reaction is completed, cool to room temperature, add water and ethyl acetate for extraction, and dry the organic phase with anhydrous sodium sulfate. Filter, and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product is separated and purified by column chromatography (PE: EA = 10: 1-3: 1) to obtain compound 34-2 (3.3 g, yield 33.4%), a yellow solid. LCMS [M + H] + 323.2.

[0666] Step 2: Dissolve compound 34-2 (2.3 g, 7.13 mmol) in anhydrous methanol (50 mL), slowly add wet palladium carbon (1.5 g, 10% Pd) under nitrogen protection, and react at room temperature for 2 hours. After the reaction is completed, filter and concentrate the filtrate under reduced pressure to obtain compound 34-3 (4 g, crude product) as a brown solid. LCMS [MH] - 291.3.

[0667] Step 3: Dissolve compound 34-3 (4 g, crude product) in anhydrous ethanol (100 mL), add 3-ethoxy-3-imino-propionic acid ethyl ester hydrochloride (3.21 g, 16.42 mmol), and heat at 60°C for 3 hours. After the reaction is completed, cool to room temperature, and concentrate the reaction solution under reduced pressure to obtain a crude product. The crude product is separated and purified by column chromatography (PE: EA = 10: 1-0: 1) to obtain compound 34-4 (2.2 g, 5.66 mmol), a yellow solid. LCMS [M + H] + 389.2.

[0668] Step 4: Dissolve compound 34-4 (2g, 5.15mmol) and 3-amino-2-cyanothiophene (767.11mg, 6.18mmol) in anhydrous tetrahydrofuran (30mL), add a tetrahydrofuran solution of lithium bis(trimethylsilyl)amide (1M, 20.59mL) dropwise at 0°C, and heat at 45°C for 2 hours. After the reaction is completed, add saturated ammonium chloride solution (20mL) to quench, dilute with water, extract with ethyl acetate, and dry the organic phase with anhydrous sodium sulfate. Filter and concentrate under reduced pressure to obtain a crude product. The crude product is separated and purified by column chromatography (PE: EA = 10: 1-1: 1) to obtain compound 34-5 (900mg, yield 37.5%), a yellow solid. LCMS [M + H] + 467.1.

[0669] Step 5: Dissolve compound 34-5 (50 mg, 107.17 μmol) in dichloromethane (5 mL), add trifluoroacetic acid (13.51 mmol, 1 mL), and stir at room temperature for 2 hours. After the reaction is completed, the reaction solution is concentrated under reduced pressure to obtain compound Int-34 (50 mg, crude product) as a brown solid. LCMS [M+H] + 366.9.

[0670] Synthesis of compound Int-35

[0671]

[0672] Step 1: Dissolve compound Int-34 (65.56 mg, 136.45 μmol) in DMF (5 mL), slowly add tert-butyl bromoacetate (109.16 μmol, 16.13 μL) and DIEA (409.34 μmol, 71.30 μL), and react at 0°C for 3 hours. After the reaction is completed, dilute with water (15 mL), extract with ethyl acetate (3×10 mL), and dry the organic phase with anhydrous sodium sulfate. Filter and concentrate under reduced pressure to obtain crude compound 35-1 (43 mg, yield 65.6%), brown oil. LCMS [M+H] + 481.2.

[0673] Step 2: Dissolve compound 35-1 (43 mg, 89.47 μmol) in a hydrochloric acid solution of 1,4-dioxane (3 mL) and react at room temperature for 2 hours. After the reaction is completed, the reaction solution is directly concentrated under reduced pressure to obtain compound Int-35 (180 mg, crude product) as a brown solid. LCMS [M+H] + 425.2.

[0674] Synthesis of compound Int-36

[0675]

[0676] Compound 36-1 was used as the starting material and prepared in the same manner as Int-13. LCMS [M+H] + 242.0.

[0677] Synthesis of compound Int-37

[0678]

[0679] Compound Int-36 was used as the starting material and prepared in the same manner as Int-14. LCMS [M+H] + 428.2.

[0680] Synthesis of compound Int-38

[0681]

[0682] Compound 38-1 and compound 8-2 were used as raw materials and prepared in the same manner as Int-8. LCMS [M+H] + 420.2.

[0683] Synthesis of compound Int-39

[0684]

[0685] Step 1: Under nitrogen protection, compound 39-1 (378.63 mg, 1.75 mmol), compound 39-2 (400.00 mg, 1.46 mmol), triphenylphosphine (1.15 g, 4.38 mmol) were dissolved in tetrahydrofuran (10 mL) solution, the mixture was cooled to 0 ° C, and then diisopropyl azodicarboxylate (884.85 mg, 4.38 mmol) was slowly added, and the mixture was stirred at 0 ° C for 5 hours. After the reaction was completed, the reaction mixture was directly concentrated under reduced pressure to obtain a crude product. The crude product was purified by reverse phase column chromatography (formic acid system) to obtain compound 39-3 (100 mg, yield 14.5%), a white solid. LCMS [M + Na] + 495.4.

[0686] Step 2: Under nitrogen protection, compound 39-3 (100 mg, 211.63 μmol) and trifluoroacetic acid (3.08 g, 27.01 mmol, 2.00 mL) were dissolved in anhydrous dichloromethane (10 ML) solution, and the mixture was stirred at 25 ° C for 10 hours. After the reaction, the reaction mixture was directly concentrated under reduced pressure to obtain compound Int-39 (80 mg, yield 90.8%), a yellow oil. LCMS [M+H] + 417.2.

[0687] Example 1: Synthesis of 4-(2-(2-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butyryl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-5H-pyrrolo[2,3-b]pyrazine-7-yl)-N,N-dimethylbenzamide (EX-1)

[0688]

[0689] Compound Int-3 (50 mg, 139.15 μmol) was dissolved in DMF (2 mL), and EDCI (53.35 mg, 278.29 μmol), DMAP (25.5 mg, 208.73 μmol) and compound Int-4 (66.37 mg, 166.98 μmol) were added to the reaction solution in sequence, and the mixture was reacted at room temperature for 2 hours. After the reaction was completed, the reaction mixture was purified by reverse phase preparative HPLC to obtain compound EX-1 (30 mg, yield 29.0%) as a yellow solid. LCMS [M+H] + 739.2.

[0690] 1H NMR (400MHz, DMSO-d6) δ12.42(d,J=3.0Hz,1H),11.09(s,1H),8.91(s,1H),8.53(d,J=3.0Hz,1H),8.38(d,J=8.1Hz,2 H),8.04(d,J=8.2Hz,1H),8.01(s,1H),7.61–7.54(m,1H),7.51(d,J=8.1Hz,2H),7.36(dd,J=13.1,8.0Hz,1H),7.18(d d,J=11.1,8.6Hz,1H),6.99(d,J=7.0Hz,1H),6.69(brs,1H),5.05(dd,J=12.9,5.4Hz,1H),4.71(d,J=12.3Hz,2H),3.8 0–3.69(m,2H),3.36(s,2H),3.01(s,6H),2.99–2.81(m,3H),2.61–2.45(m,4H),2.06–1.98(m,1H),1.91–1.80(m,2H).

[0691] Example 2: Synthesis of Compounds EX-2 to EX-16

[0692] The synthesis of compounds EX-2 to EX-16 can be carried out using a method similar to that of Example 1 and corresponding raw materials.

[0693]

[0694]

[0695]

[0696]

[0697]

[0698] Example 3: Synthesis of 4-(2-(2-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)-N,N-dimethylbenzamide (EX-17)

[0699]

[0700] Under nitrogen protection, compound Int-15 (70 mg, 140.95 μmol), compound 4-1 (38.93 mg, 140.95 μmol) and DIPEA (704.73 μmol, 122.75 μL) were dissolved in dimethyl sulfoxide (3 mL) and heated at 100 ° C for 5 hours. After the reaction was completed, it was cooled to room temperature and the reaction mixture was purified by reverse phase preparative HPLC (hydrochloric acid system) to obtain compound EX-17 hydrochloride (4.68 mg, yield 4.2%) as a yellow solid. LCMS [M+H] + 753.4.

[0701] 1 H NMR (400MHz, DMSO-d6) δ12.48(d,J=3.0Hz,1H),11.10(s,1H),10.33(brs,1H),8.95(s,1H),8.55(d,J=3.0Hz,1H),8.37(d,J=8.2Hz,2H),8.13(d, J=8.6Hz,1H),8.11(s,1H),7.60(dd,J=8.6,7.1Hz,1H),7.51(d,J=8.1Hz,2H),7.39(d,J=8.1Hz,1H),7.12(d,J=8.7Hz,1H),7.04(d,J=7.0Hz,1H) ,6.56(t,J=5.8Hz,1H),5.05(dd,J=12.9,5.4Hz,1H),4.63(d,J=15.7Hz, 1H),4.36(dd,J=15.8,8.0Hz,1H),3.83–3.73(m,1H),3.53–3.43(m,2H), 3.28–3.15(m,5H),3.01(s,6H),2.94–2.82(m,1H),2.64–2.45(m,2H),2. 08–1.98(m,1H),1.88–1.75(m,2H),1.67–1.58(m,2H),1.49–1.31(m,4H).

[0702] Example 4: Synthesis of 4-(2-(2-(6-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)hexyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)-N,N-dimethylbenzamide (EX-18)

[0703]

[0704] Compounds Int-3 and Int-16 were used as raw materials and compound EX-18 was prepared according to the synthetic method of EX-17. LCMS [M+H]+ 739.4.

[0705] 1 H NMR (400MHz, DMSO-d6) δ12.51(d,J=3.0Hz,1H),11.14(brs,1H),11.02(s,1H),8.94(s,1H),8.54(d,J=3.0Hz,1H),8.38(d,J=8.3Hz,2H ),8.11(dd,J=8.1,1.8Hz,1H),8.08(s,1H),7.51(d,J=8.3Hz,2H),7.41–7.32(m,2H),7.07(d,J=7.5Hz,1H),6.93(d,J=8.1Hz,1H),5.12 (dd,J=13.3,5.1Hz,1H),4.60(d,J=15.6Hz,1H),4.40–4.19(m,3H),3.79–3.69(m,1H),3.46–3.28(m,2H),3.27–3.10(m,5H),3.00(s,6H ),2.98–2.87(m,1H),2.66–2.58(m,1H),2.37–2.25(m,1H),2.09–1.99(m,1H),1.92–1.79(m,2H),1.72–1.61(m,2H),1.51–1.34(m,4H).

[0706] Example 5: Synthesis of 4-(2-(2-(2-((3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propyl)amino)-2-oxoethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)-N,N-dimethylbenzamide (EX-19)

[0707] Under nitrogen protection, compound Int-23 (50 mg, 101.63 μmol), Int-24 (43.51 mg, 97.91 μmol), EDCI (96.46 mg, 503.18 μmol) and DMAP (30.74 mg, 251.59 μmol) were dissolved in DMF (2.5 mL) and reacted at room temperature for 6 hours. After the reaction, the reaction mixture was purified by reverse phase preparative HPLC to obtain compound EX-19 (10 mg, yield 11.6%) as a yellow solid. LCMS [M+H] + 768.7.

[0708] 1H NMR (400MHz, DMSO-d6) δ12.50(d,J=3.1Hz,1H),11.10(s,1H),10.73(brs,1H),8.94(s,1H),8.84(t,J=5.7Hz,1H),8.54(d,J=3.0Hz,1H) ,8.37(d,J=8.4Hz,2H),8.15–8.08(m,2H),7.61(dd,J=8.6,7.1Hz,1H),7.51(d,J=8.4Hz,2H),7.40(d,J=8.1Hz,1H),7.15(d,J=8.6Hz,1 H),7.05(d,J=7.0Hz,1H),6.68(brs,1H),5.06(dd,J=12.8,5.4Hz,1H),4.69–4.57(m,1H),4.57–4.44(m,1H),4.14(s,2H),3.76–3.72(m ,1H),3.55–3.51(m,1H),3.44–3.13(m,6H),3.00(s,6H),2.96–2.82(m,1H),2.64–2.46(m,2H),2.09–1.99(m,1H),1.78(p,J=6.6Hz,2H).

[0709] Example 6: Synthesis of Compounds EX-20 to EX-21

[0710] The synthesis of compounds EX-20 to EX-21 can be carried out using a method similar to that of Example 5 and corresponding raw materials.

[0711]

[0712]

[0713] Example 7: Synthesis of N-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propyl)-N-methyl-4-(2-(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)benzamide (EX-22)

[0714]

[0715] Compounds Int-28 (50 mg, 100.31 μmol) and Int-27 (38.20 mg, 83.33 μmol) were added to DMF (1 mL), followed by EDCI (28.84 mg, 150.47 μmol) and DMAP (36.76 mg, 300.93 μmol), and the mixture was reacted at room temperature for 12 hours. After the reaction was completed, the reaction mixture was diluted with water (5 mL), extracted with ethyl acetate (3×5 mL), and the organic layers were combined and dried over anhydrous sodium sulfate. The mixture was filtered and the filtrate was concentrated to obtain a crude product. The crude product was purified by reverse phase preparative HPLC (formic acid system) to obtain compound EX-22 (11.2 mg, yield 18.9%) as a yellow solid. LCMS [M+H] + 711.4.

[0716] 1 H NMR(400MHz,DMSO-d6)δ12.18(brs,1H),10.82(brs,1H),8.85(s,1H),8.37(s,1H),8.30(d,J=7.9Hz,2H), 7.99–7.91(m,2H),7.57(t,J=7.8Hz,1H),7.45(d,J=7.9Hz,2H),7.23(d,J=7.9Hz,1H),7.08(d,J=8.6Hz,1H ),6.97(d,J=7.1Hz,1H),6.52(brs,1H),4.95(dd,J=12.3,5.5Hz,1H),3.69(s,2H),3.53(t,J=7.2Hz,2H),3 .37–3.31(m,2H),3.04–2.97(m,5H),2.88–2.75(m,3H),2.60–2.48(m,2H),2.47(s,3H),2.00–1.90(m,3H).

[0717] Example 8: Synthesis of compounds EX-23 to EX-027

[0718] The synthesis of compounds EX-23 to EX-27 can be carried out using the same method and corresponding raw materials as in Example 7.

[0719]

[0720]

[0721]

[0722] Example 9: Synthesis of 4-((6-(4-(2-(7-amino-5-oxo-4,5-dihydrothieno[3,2-b]pyridin-6-yl)-1H-benzo[d]imidazol-6-)yl)piperazin-1-yl)-6-oxohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (EX-28)

[0723]

[0724] Compound Int-6 and compound Int-34 were used as raw materials, and compound EX-28 was prepared according to the synthetic method of EX-1. LCMS [M+H] + 736.2.

[0725] 1 H NMR (400MHz, DMSO-d6) δ11.85(s,1H),11.10(s,1H),7.97(d,J=5.3Hz,1H),7.62–7.54(m,2H),7.32 (brs,1H),7.14–7.07(m,2H),7.02(d,J=7.0Hz,1H),7.01(d,J=5.3Hz,1H),6.55(brs,1H),5.05(dd, J=12.9,5.4Hz,1H),3.68(brs,4H),3.31(t,J=7.5Hz,2H),3.20(d,J=18.2Hz,4H),2.96–2.81(m,1H) ,2.62–2.44(m,2H),2.39(t,J=7.3Hz,2H),2.07–1.98(m,1H),1.66–1.52(m,4H),1.44–1.33(m,2H).

[0726] Example 10: Synthesis of 2-(4-(2-(7-amino-5-oxo-4,5-dihydrothiophene[3,2-b]pyridin-6-yl)-1H-benzo[d]imidazol-6-yl)piperazin-1-yl)-N-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propyl)acetamide (EX-29)

[0727]

[0728] Compound Int-35 and compound Int-24 were used as raw materials and compound EX-29 was prepared according to the synthetic method of EX-1. LCMS [M+H] + 737.5. 1H NMR(500MHz,DMSO-d6)δ12.73(s,0.5H),12.72(s,0.5H),11.79(s,0.5H),11.09(s,0.5H),10.76–10.43(m,0.5H),7.97–7.91(m,2H),7. 83(brs,0.5H),7.58(dd,J=8.2,7.4Hz,1H),7.51(d,J=8.7Hz,0.5H),7.44(d,J=8.8Hz,0.5H),7.20(d,J=2.0Hz,0.5H),7.11–7.07(m,1. 5H),7.04–7.00(m,2H),6.92–6.87(m,1H),6.74(t,J=5.9Hz,1H),5.04(dd,J=12.7,5.5Hz,1H),3.32(q,J=6.4Hz,2H),3.21(q,J=6.4Hz, 2H),3.18–3.13(m,4H),2.99(s,2H),2.92–2.83(m,1H),2.64–2.58(m,4H),2.57–2.47(m,2H),2.06–1.98(m,1H),1.72(p,J=6.5Hz,2H).

[0729] Example 11: Synthesis of 4-(2-(2-(2-(2-(2-((2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethoxy)acetyl)-1,2,3,4-tetrahydroisoindolin-6-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)-N,N-dimethylbenzamide (EX-30)

[0730]

[0731] Compound EX-30 was prepared using compound Int-3 and compound Int-38 as raw materials and referring to the synthetic method of EX-1. LCMS [M+H] + 799.5. 1H NMR(400MHz,DMSO-d6)δ12.40(brs,1H),11.04(brs,1H),8.90(s,1H),8.52(s,1H),8.37(d,J=8.1Hz,2H), 8.06–8.01(m,1H),8.00(s,1H),7.55–7.48(m,3H),7.41–7.29(m,1H),7.19(t,J=7.0Hz,1H),7.02(s,1H), 6.91–6.86(m,1H),5.01(dd,J=13.0,5.4Hz,1H),4.68(s,2H),4.29(d,J=4.4Hz,2H),3.76–3.57(m,8H),3. 40–3.35(m,2H),3.00(s,6H),2.98–2.79(m,3H),2.59–2.52(m,1H),2.46–2.38(m,1H),2.02–1.91(m,1H).

[0732] Example 12: Synthesis of 4-(2-(2-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)octanoyl)-1,2,3,4-tetrahydroisoindolin-6-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)-N,N-dimethylbenzamide (EX-31)

[0733]

[0734] Compound EX-31 was prepared using compound Int-3 and compound Int-39 as raw materials and referring to the synthetic method of EX-1. LCMS [M+H] + 796.6. 1H NMR (400MHz, DMSO-d6) δ12.42(brs,1H),11.11(brs,1H),8.90(d,J=2.1Hz,1H),8.52(d,J=4.5Hz,1H),8.37(dd,J=8.3,3 .1Hz,2H),8.07–8.00(m,2H),7.79(dd,J=13.7,8.3Hz,1H),7.51(d,J=8.1Hz,2H),7.43–7.27(m,3H),5.11(dd,J=13.0,5. 2Hz,1H),4.73(s,1H),4.67(s,1H),4.20–4.10(m,2H),3.73(t,J=5.9Hz,2H),3.00(s,6H),2.99–2.96(m,1H),2.94–2.82( m,2H),2.63–2.52(m,2H),2.48–2.38(m,2H),2.08–2.00(m,1H),1.80–1.66(m,2H),1.62–1.50(m,2H),1.48–1.28(m,6H).

[0735] Example 13: Synthesis of 4-(2-(2-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octanoyl)-8-methoxy-1,2,3,4-tetrahydroisoindolin-6-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)-N,N-dimethylbenzamide (EX-32)

[0736]

[0737] Compound EX-32 was prepared using compound Int-37 and compound Int-10 as raw materials and referring to the synthetic method of EX-1. LCMS [M+H] + 825.6.

[0738] 1H NMR (400MHz, DMSO-d6) δ12.43(brs,1H),11.09(brs,1H),8.96(s,1H),8.53(s,1H),8.39(d,J=8.1Hz,2H),7.73–7.6 1(m,2H),7.60–7.53(m,1H),7.51(d,J=8.0Hz,2H),7.11–7.03(m,1H),7.00(t,J=6.5Hz,1H),6.56–6.45(m,1H),5.04 (dd,J=13.0,5.4Hz,1H),4.55(d,J=7.2Hz,2H),4.03–3.93(m,3H),3.75–3.66(m,2H),3.32–3.21(m,2H),3.00(s,6H ),2.98–2.79(m,3H),2.62–2.54(m,2H),2.46–2.37(m,2H),2.08–1.97(m,1H),1.64–1.48(m,4H),1.42–1.26(m,6H).

[0739] Pharmacological activity and application

[0740] The activity of the compounds of the invention can be demonstrated using the following assays.

[0741] HPK1 HiBiT protein tag detection method

[0742] Human acute T lymphoblastic leukemia Jurkat cells stably expressing HPK1-HiBiT marker protein were cultured in a culture dish, and the culture medium was RPMI 1640 (Gibco, product number 11875093) containing 10% fetal bovine serum (FBS, Gibco, product number 10099141), 0.1% penicillin / streptomycin solution (P / S), and cultured in a sterile incubator at a temperature of 37°C, a relative humidity of 95%, and 5% CO2. Cells in the exponential growth phase were taken and inoculated into a 96-well plate (Corning, product number 3903) at a density of 20,000 cells / well, and 100 μL of culture medium was added to each well. After 24 hours, the compounds disclosed in this article at different concentrations were added to the wells where the cells had been inoculated (10 concentration gradients were set for each compound, the highest detection concentration was 10 μM, and the gradient was diluted 4 times), and the final concentration of DMSO was 0.1%. After 24 hours, 50 μL Nano- HiBiT luciferase assay reagent (Progema, product number N3040) was used to read the fluorescence signal using Envision. The data were fitted to a dose-response curve using GraphPad prisim 8 to obtain the IC of the test compound. 50 value.

[0743] Table 2 IC values ​​of some compounds of the present invention for HPK1-HiBiT signal 50 value

[0744] Compound No. <![CDATA[IC 50 (nM)]]> Compound No. <![CDATA[IC 50 (nM)]]> EX-4 B EX-8 A EX-10 B EX-28 A EX-29 A EX-30 B EX-31 B HC90-51 D

[0745] A:<100nM; B:100-500nM; C:500-5000nM; D:>5000nM

[0746] Among them, HC90-51 (see WO 2020 / 227325) is a positive control compound, and its structural formula is as follows:

[0747]

[0748] The above contents are further detailed descriptions of the present invention in combination with specific preferred embodiments, and it cannot be determined that the specific implementation of the present invention is limited to these descriptions. For ordinary technicians in the technical field to which the present invention belongs, several simple deductions or substitutions can be made without departing from the concept of the present invention, which should be regarded as falling within the protection scope of the present invention.

Claims

1. A compound, or a pharmaceutically acceptable salt, prodrug, or mixture thereof, characterized in that: The compound is selected from the following compounds: Among them, prodrugs include acetamide, formamide and benzamide derivatives of the amino functional group of the compound.

2. The compound according to claim 1, or a pharmaceutically acceptable salt, prodrug thereof, and a mixture thereof, characterized in that: The compound is selected from the following compounds:

3. A pharmaceutical composition comprising the compound according to any one of claims 1 to 2, or a pharmaceutically acceptable salt, prodrug, or mixture thereof, and a pharmaceutically acceptable excipient.

4. The pharmaceutical composition according to claim 3, characterized in that The pharmaceutical composition may also contain other therapeutic agents.

5. Use of the compound according to any one of claims 1 to 2 or a pharmaceutically acceptable salt, prodrug thereof, and a mixture thereof in the preparation of a medicament for treating and / or preventing cancer.

6. The use of claim 5, wherein the cancer is selected from bladder cancer, breast cancer, colorectal cancer, gastric cancer, head and neck squamous cell carcinoma, Hodgkin's lymphoma, Merkel-cell carcinoma, mesothelioma, melanoma, non-small cell lung cancer, ovarian cancer, uterine cancer, esophageal cancer, liver cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, thyroid cancer, small cell lung cancer, transitional cell carcinoma, urothelial carcinoma, tumors resistant to targeted drugs; or tumors or diseases dependent on HPK1 mutant protein.

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