CN116462685A

CN116462685A - Heterocyclic compound, pharmaceutical composition containing same and antitumor application of heterocyclic compound

Info

Publication number: CN116462685A
Application number: CN202310075980.0A
Authority: CN
Inventors: 马欣; 陈永峰; 章涵堃; 刘瑶; 吴瑶; 杜勇; 孔德森; 梁亚楠
Original assignee: Hejing Pharmaceutical Technology Shanghai Co ltd
Current assignee: Hejing Pharmaceutical Technology Shanghai Co ltd
Priority date: 2022-02-08
Filing date: 2023-02-07
Publication date: 2023-07-21
Also published as: WO2023151559A1

Abstract

The invention relates to a compound shown in a general formula (I), a pharmaceutical composition containing the compound and an anti-tumor application thereof. The variables in the general formula are defined in the claims and the specification; HPK1 links-LIN-EL (I).

Description

Heterocyclic compound, pharmaceutical composition containing same and antitumor application of heterocyclic compound

Technical field:

the present invention belongs to the field of pharmaceutical chemistry. In particular to a novel PROTAC molecule targeting HPK1 protein and muteins thereof, a preparation method and application thereof, and a pharmaceutical composition containing the compound.

The background technology is as follows:

HPK1 is a shorthand for hematopoietic progenitor kinase 1 (hematopoietic progenitor kinase 1), also known as MAP4K1, which is one of the members of the MAP4K family, and 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.

HPK1 kinase can bind to a number of adaptor proteins, such as the SLP76 family, gads, HIP-55, GRB2 family, LAT, CRK family, etc., and interact to 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 signals, and can negatively regulate dendritic cell activation and T cell and B cell feedback; whereas inhibition of HPK1 enhances T cell activity, thereby enhancing the anti-tumor immune response.

The ubiquitin-proteasome pathway is a more general way of degradation of endogenous proteins, where the proteins to be degraded are modified by ubiquitination and then broken down by the proteasome into smaller polypeptides, amino acids and re-usable ubiquitin. PROTAC ]proteolysis targeting chimeras), i.e., a protein degradation targeting chimera, is an emerging field of intense research in recent years. The PROTAC molecule can be generally divided into three parts, one end of which is a small molecule fragment (warrhead) which binds to a specific target protein, the other end of which is a ligand (E3 ligase ligand) of E3 ligase having ubiquitination function, and a linker (linker) which connects the two. The PROTAC molecule utilizes a protein ubiquitination degradation pathway of cells, and can selectively degrade target proteins. Specifically, as two ends of the PROTAC molecule are respectively ligand fragments of the target protein and the E3 ligase, the PROTAC molecule can be combined with the target protein and the E3 ligase at the same time, so that ubiquitination of the target protein is promoted, and the target protein is further recognized and degraded by a proteasome.

Over ten years ago, researchers discovered that HPK1 might be a potential cancer immunotherapeutic target, but no related drugs have been marketed until now. Designing a degradant with targeting specific proteins is a new model for drug development, and international patent publication nos. WO2021226262A1, WO2020227325A1 disclose HPK1 protein degradants, however, selectivity, potency, etc. are not very ideal. Therefore, HPK1 degradation agents which provide higher selectivity and better efficacy are of great significance. It is desirable to develop compounds that degrade HPK1 protein using protein degradation techniques in an effort to address unmet clinical needs.

Disclosure of Invention

In one aspect, the present invention provides compounds of formula (I), or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs or isotopic variations thereof, and mixtures thereof,

HPK1Ligands-LIN-EL (I)

wherein HPK1Ligands are Ligands that bind HPK1, such as inhibitors of HPK1, represented by formula (II) and formula (II'):

is a single bond or a double bond;

is the junction of HPK1 links and LIN;

l' is connected to X ¹ In which ring, L is attached to Z ⁴ The ring in which is located, or L' is attached Z ⁴ The ring in which L is attached to X ¹ The ring in which is located, or L', L being simultaneously attached to X ¹ A ring in which the ring is located;

X ¹ 、X ² 、X ³ 、X ⁴ each independently selected from N or CR ^X ；

R ^X Identical or different, and R ^x Each independently is: - (CR' ₂ ) _S -R ^# -(CR ^* ₂ ) _t -R ¹ ；

R' are identical or different and R ^* Identical or different, R', R ^* 、R ¹ Each independently is hydrogen, deuterium, NR ^a R ^b Hydroxy, 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 heterocyclyl, 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 form C _3-8 Cycloalkyl or 4-12 membered heterocyclyl; the C is _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 heterocyclyl, C _6-10 Aryl or 5-14 membered heteroaryl optionally substituted with 1, 2, 3 or 4R ";

R ^# is a chemical bond, O, S, NR ^N 、C(O)、C(O)NR ^N 、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 Alkynylene, C _3-8 Cycloalkylene, 4-12 membered heterocyclylene, C _6-10 Arylene or 5-16 membered heteroarylene; the C is _1-6 Alkylene, C _2-6 Alkenylene, C _2-6 Alkynylene, C _3-8 Cycloalkylene, 4-12 membered heterocyclylene, C _6-10 Arylene or 5-16 membered heteroarylene optionally substituted with 1, 2, 3 or 4R ";

Z ¹ is O, S, N or a C atom, optionally substituted with one or two R ^Z1 Substituted; z is Z ² Is O, S, N or a C atom, optionally substituted with one or two R ^Z2 Substituted; z is Z ³ Is O, S, N or a C atom, optionally substituted with one or two R ^Z3 Substituted;

Z ⁴ is O, S, N or a C atom, optionally substituted with one or two R ^Z4 Substituted; or, Z ¹ Absence of Z ² To and Z ¹ On the attached C atom;

R ^Z1 、R ^Z2 、R ^Z3 、R ^Z4 each independently is absent, hydrogen, deuterium, NR ^a R ^b Hydroxy, halogenPlain, cyano, C (O) NR ^a R ^b 、COR ^d 、-(C(R ⁴ ) ₂ ) _1-6 -R ⁴ ', halogenated C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl, C _1-6 Alkoxy, C _2-6 Alkenyl, C _2-6 Alkynyl, -O-C _3-8 Cycloalkyl, C _3-8 Cycloalkyl, 4-12 membered heterocyclyl, C _6-10 Aryl or 5-14 membered heteroaryl; or, Z ¹ And two R ^Z1 Together form c= O, C _3-8 Cycloalkyl or 4-12 membered heterocyclyl; or, Z ² And two R ^Z2 Together form c= O, C _3-8 Cycloalkyl or 4-12 membered heterocyclyl; or, Z ³ And two R ^Z3 Together form c= O, C _3-8 Cycloalkyl or 4-12 membered heterocyclyl; or, Z ⁴ And two R ^Z4 Together form c= O, C _3-8 Cycloalkyl or 4-12 membered heterocyclyl; the C is _1-6 Alkyl, halogenated C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl, C _1-6 Alkoxy, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 4-12 membered heterocyclyl, C _6-10 Aryl or 5-14 membered heteroaryl optionally substituted with 1, 2, 3 or 4R ";

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 substituted C _1-6 Alkyl, C _1-6 Alkoxy, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 4-12 membered heterocyclyl, C _6-10 Aryl or 5-14 membered heteroaryl; the C is _1-6 Alkyl, halogenated C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl, C _1-6 Alkoxy, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 4-12 membered heterocyclyl, C _6-10 Aryl or 5-14 membered heteroaryl optionally substituted with 1, 2, 3 or 4R "; or two R ⁴ Together with the C atom to which it is attached form C _3-8 Cycloalkyl or 4-12 membered heterocyclyl;

l, L' are each independently a bond or- (CR) ² ₂ ) _p -R ^L -(CR ³ ₂ ) _q -；

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 heterocyclyl, C _6-10 Aryl or 5-14 membered heteroaryl; or two R ² Or two R ³ Together with the attached C form C _3-8 Cycloalkyl or 4-12 membered heterocyclyl; the C is _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 heterocyclyl, C _6-10 Aryl or 5-14 membered heteroaryl optionally substituted with 1, 2, 3 or 4R ^## Substitution;

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- 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 、C _1-6 Alkylene, halogenated C _1-6 Alkylene, C _1-6 Alkyloxy, C _2-6 Alkenylene, C _2-6 Alkynylene, C _3-8 Cycloalkylene, 4-12 membered heterocyclylene, C _6-10 Arylene or 5-16 membered heteroarylene; the C is _1-6 Alkylene, halogenated C _1-6 Alkylene, C _1-6 Alkyloxy, C _2-6 Alkenylene, C _2-6 Alkynylene, C _3-8 Cycloalkylene, 4-12 membered heterocyclylene, C _6-10 Arylene or 5-16 membered heteroarylene optionally substituted with 1, 2, 3 or 4R ^## Substituted;

Y ¹ is an N or C atom, and which is optionally substituted with one or two R ^Y1 Substituted;

Y ² is an N or C atom, and which is optionally substituted with one or two R ^Y2 Substituted; or, Y ² Is absent, Y ¹ And Y is equal to ³ Connecting;

Y ³ is an N or C atom, and which is optionally substituted with one or two R ^Y3 Substituted;

Y ⁴ is an N or C atom, and which is optionally substituted with one or two R ^Y4 Substituted;

Y ⁵ is an N or C atom, and which is optionally substituted with one or two R ^Y5 Substituted;

Y ⁶ is an N or C atom, and which is optionally substituted with one or two R ^Y6 Substituted;

R ^Y1 、R ^Y2 、R ^Y3 、R ^Y4 、R ^Y5 、R ^Y6 each independently is represented by: - (CR) ^e ₂ ) _n1 -R ^#1 -(CR ^f ₂ ) _n2 -R ^#2 ；

R ^e Identical or different, R ^f Identical or different, R ^e 、R ^f 、R ^#2 Each independently is hydrogen, deuterium, NR ^a R ^b Hydroxy, 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 substituted C _1-6 Alkyl, C _1-6 Alkoxy, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 4-12 membered heterocyclyl, 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 form C _3-8 Cycloalkyl or 4-12 membered heterocyclyl; the C is _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 heterocyclyl, C _6-10 Aryl or 5-14 membered heteroaryl optionally substituted with 1, 2, 3 or 4R ^## Substituted;

R ^#1 is a chemical bond, 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 Alkyloxy, C _2-6 Alkenylene, C _2-6 Alkynylene, C _3-8 Cycloalkylene, 4-12 membered heterocyclylene, C _6-10 Arylene or 5-16 membered heteroarylene; or, two R ^Y2 And Y is equal to ² Together form carbonyl, C _3-8 Cycloalkyl, 4-12 membered heterocyclyl, C _6-10 Aryl or 5-14 membered heteroaryl;

or L and Y ¹ 、Y ² 、Y ³ 、Y ⁴ One is connected with Y ⁵ 、Y ⁶ Together with the substituents to which they are attached form C _3-8 Cycloalkyl, 4-12 membered heterocyclyl, C _6-10 Aryl or 5-14 membered heteroaryl; or, Y ² Is absent, L and Y ¹ 、Y ³ 、Y ⁴ 、Y ⁵ 、Y ⁶ One of the remaining ring atoms being joined to adjacent ring atoms together with the substituents to which they are attached to form C _3-8 Cycloalkyl, 4-12 membered heterocyclyl, C _6-10 Aryl or 5-14 membered heteroaryl; the C is _1-6 Alkylene, C _2-6 Alkenylene, C _2-6 Alkynylene, C _3-8 Cycloalkylene, 4-12 membered heterocyclylene, C _6-10 Arylene or 5-16 membered heteroarylene is unsubstituted or optionally substituted with 1, 2, 3 or 4R ^## Substituted;

R ⁰ selected from: c (C) _3-8 Cycloalkylene, 4-12 membered heterocyclylene, C _6-10 Arylene or 5-16 membered heteroarylene; the C is _3-8 Cycloalkylene, 4-12 membered heterocyclylene, C _6-10 Arylene or 5-16 membered heteroarylene optionally substituted with 1, 2, 3, 4 or more R ^## Substituted;

V ¹ 、V ² 、V ³ each independently selected from N or CR ^V ；V ⁴ Is N, O, S or a C atom, optionally substituted with 1 or 2R ^V Substituted;

ring V is C _6-10 Aryl or 5-16 membered heteroaryl, and which is optionally substituted with 1, 2, 3 or 4R ^V Substituted;

R ^V identical 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 ’；

R ^V ’、R ⁵ 、R ⁵ ' each independently selected from hydrogen, deuterium, halogen, NR ^a R ^b Hydroxy, 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 substituted C _1-6 Alkyl, C _1-6 Alkoxy, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 4-12 membered heterocyclyl, C _6-10 Aryl or 5-14 membered heteroaryl; or R is ⁵ 、R ^5’ Or R is ³¹ 、R ³² Together with the C atom to which it is attached form C _3-8 Cycloalkyl or 4-12 membered heterocyclyl; the C is _1-6 Alkyl, halogenated C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl, C _1-6 Alkoxy, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 4-12 membered heterocyclyl, C _6-10 Aryl or 5-14 membered heteroaryl optionally substituted with 1, 2, 3, 4 or more R ^## Substituted;

LIN is represented as-L ¹ -L ² -L ³ -……-L ^r -,

L ¹ 、L ² 、L ³ ……L ^r Each independently selected from chemical bonds, 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 Alkynylene, C _3-16 Cycloalkylene, 4-12 membered heterocyclylene, C _6-10 Arylene or 5-16 membered heteroarylene; the C is _1-10 Alkylene, C _2-10 Alkenylene, C _2-10 Alkynylene, C _3-16 Cycloalkylene, 4-12 membered heterocyclylene, C _6-10 Arylene or 5-16 membered heteroarylene optionally substituted with 1, 2, 3, 4 or more R ^## Substituted;

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 substituted C _1-6 Alkyl, C _1-6 Alkoxy, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 4-12 membered heterocyclyl, C _6-10 Aryl or 5-14 membered heteroaryl; or, R ⁶ 、R ⁶ ' together with the attached C forms c= O, C _3-8 Cycloalkyl or 4-12 membered heterocyclylene; the C is _1-6 Alkyl, halogenated C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl, C _1-6 Alkoxy, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 4-12 membered heterocyclyl, C _6-10 Aryl or 5-14 membered heteroaryl optionally substituted with 1, 2, 3, 4 or more R ^## Substituted;

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

t ₁ 、t ₂ each independently is 0, 1 or 2;

r is a positive integer of 4-20;

EL is represented by general formula (III):

wherein G is ¹ 、G ² 、G ³ 、G ⁴ Each independently is N or CR ^g ；G ¹ 、G ² 、G ³ 、G ⁴ Not both are N;

R ^g the same or different and each independently selected from: hydrogen, deuterium, NR ^a R ^b Hydroxy, halogen, cyano, C (O) NR ^a R ^b 、C _1-6 Alkyl, halogenated C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl, C _1-6 Alkoxy, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 4-12 membered heterocyclyl, C _6-10 Aryl or 5-14 membered heteroaryl; the C is _1-6 Alkyl, halogenated C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl, C _1-6 Alkoxy, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 4-12 membered heterocyclyl, C _6-10 Aryl or 5-14 membered heteroaryl optionally substituted with 1, 2, 3 or 4R ⁰⁰ Substitution;

K ¹ selected from O, S, C or N, optionally substituted with one or two R ^K1 Substituted; k (K) ² Selected from O, S, C or N, optionally substituted with one or two R ^K2 Substituted; k (K) ³ Selected from O, S, C or N, optionally substituted with one or two R ^K3 Substituted; or K ¹ 、K ² Absence of K ⁴ And K is equal to ³ Is connected with K ¹ C atoms in the attached aromatic rings being bound to R ^K Connecting; or, K ¹ 、K ² 、K ³ Are all absent, K ⁴ Is connected to and K ¹ Or K ³ One of the C atoms of the aromatic ring attached, the other C atom of the aromatic ring being attached to R ^K Connecting;

K ⁴ is N or CR ^K4 ；

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 substituted C _1-6 Alkyl, C _1-6 Alkoxy, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 4-12 membered heterocyclyl, C _6-10 Aryl or 5-14 membered heteroaryl;

alternatively, K ¹ And two R ^K1 Together form c= O, C _3-8 Cycloalkyl or 4-12 membered heterocyclyl; alternatively, K ² And two R ^K2 Together form c= O, C _3-8 Cycloalkyl or 4-12 membered heterocyclyl; alternatively, K ³ And two R ^K3 Together form c= O, C _3-8 Cycloalkyl or 4-12 membered heterocyclyl;

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 substituted C _1-6 An alkyl group;

R ^a 、R ^b 、R ^d 、R ^N each independently selected from hydrogen, deuterium, halogen, =nh, NR ^e1 R ^f1 Hydroxy, hydroxyamino, -C _1-6 Alkylene NR ^e1 R ^f1 、CONR ^e1 R ^f1 Acetyl, C _1-6 Alkyl, halogenated C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl, C _1-6 Alkoxy, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 4-12 membered heterocyclyl, C _6-10 Aryl or 5-14 membered heteroaryl; or, R ^a 、R ^b Together with the attached N atom, form a 4-12 membered heterocyclic group; the C is _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 4-12 membered heterocyclyl, C _6-10 Aryl or 5-14 membered heteroaryl optionally substituted with 1, 2, 3 or 4R ⁰⁰ Substitution;

R ⁰⁰ 、R”、R ^## each independently selected from hydrogen, deuterium, =o, halogen, hydroxy, hydroxyamino, =nh, NR ^e1 R ^f1 、CONR ^e1 R ^f1 、COR ⁰¹ 、C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl, - (CR) ^** ₂ ) _1-6 -R ⁰¹ 、-O-(CR ^** ₂ ) _1-6 -R ⁰¹ 、-S-R ⁰¹ 、C _3-8 Cycloalkyl, 4-12 membered heterocyclyl, C _6-10 Aryl or 5-14 membered heteroaryl;

R ^e1 、R ^f1 、R ^** 、R ⁰¹ each independently selected from hydrogen, deuterium, amino, =nh, hydroxy, hydroxyamino, acetyl, amido, C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 4-12 membered heterocyclyl, C _6-10 Aryl or 5-14 membered heteroaryl; or, R ^e1 、R ^f1 Together with the attached N atom, form a 4-12 membered heterocyclic group; or two R ^** Together with the C atom to which it is attached form C _3-6 Cycloalkyl or 4-12 membered heterocyclyl; the C is _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 4-12 membered heterocyclyl, C _6-10 Aryl or 5-14 membered heteroaryl optionally substituted with 1, 2, 3 or 4 groups selected from hydrogen, deuterium, amino, =nh, hydroxy, hydroxyamino, acetyl, amido, C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl, C _2-6 Alkenyl or C _2-6 Alkynyl substituent is substituted;

provided that the conditions are that,

(1) In the formula (II), when Z ¹ In the absence of:

a)Z ² 、Z ³ 、Z ⁴ is C or N, and Z ³ And Z is ² Not simultaneously N, or Z ³ And Z is ⁴ At the same time, the number of the N is not equal,

and whenIs->When X is ¹ 、X ² 、X ³ 、X ⁴ At least two of which are N;

and whenIs->When L and R ⁰ At least one of either or both of L and L' is not phenylene or substituted phenylene; or b) Z ² Or Z is ⁴ C=o;

c) When Z is ² 、Z ³ 、Z ⁴ When one of them is S, L, L' is different from X ¹ The ring at which they are located is connected;

(2) In formula (II '), L' is not

(3) In the formula (II), when Z ¹ 、Z ² 、Z ³ 、Z ⁴ L' and X when both exist ¹ The C atom of the aromatic ring is attached and L is not a bond.

In some embodiments of the present invention, in some embodiments,further expressed as:

represents the point of attachment of the ring atom to L +.>Represents the point of attachment of the ring atom to L;

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, halo C _1-6 Alkyl, hydroxy substituted 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 halo C _1-6 An alkyl group); the C is _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl, C _3-6 Cycloalkyl, 4-7 membered heterocyclyl, phenyl or 5-or 6-membered heteroaryl optionally substituted with 1, 2, 3, 4 or more substituents selected from R ⁴ Is substituted by a substituent of (2);

R ^X selected from hydrogen, deuterium, hydroxy, fluoro, chloro, bromo, 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, halo C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl, OC _3-5 Cycloalkyl, C _3-5 Cycloalkyl or 4-or 5-membered heterocyclyl.

Preferably R ^X Is- (CR' ₂ ) _s -R ¹ 、-NR ^N -R ¹ 、-O-R ¹ or-O- (CR) ^* ₂ ) _t -R ¹ ；

R ^N 、R’、R ^* 、R ¹ Each independently selected from hydrogen, deuterium, NR ^a R ^b 、C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkyl, hydroxy substituted 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's together with the C atom to which they are attached form C _3-6 Cycloalkyl or 4-7 membered heterocyclic ringA base;

R ^a 、R ^b 、R ⁴ each independently selected from hydrogen, deuterium, hydroxy, amino, halogen, amido, acetyl, =nh, C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl, C _3-8 Cycloalkyl, 4-7 membered heterocyclyl, benzene or 5-or 6-membered heteroaryl; or R is ^a 、R ^b Together with the attached N atom, form a 4-7 membered nitrogen heterocycle;

the C is _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl, C _1-6 Alkylene, C _3-6 Cycloalkyl, 4-7 membered heterocyclyl 4-7 membered nitrogen heterocycle optionally substituted with 1, 2 or 3R "; s, t are 0, 1, 2, 3 or 4.

In some embodiments of the present invention, in some embodiments,further selected from:

wherein R is ^a ’、R ^b ' each independently selected from hydrogen, deuterium, methyl, ethyl, propyl, isopropyl (preferably hydrogen).

In some embodimentsRepresents the point of attachment of the ring atom to L +.>Represents the point of attachment of a ring atom to L

In some embodiments, L, L' are each independently selected from the group consisting of a 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 substituted C _1-6 Alkylene, C _2-6 Alkenylene, C _2-6 Alkynylene, 3-6 membered cycloalkyl, 4-7 membered heterocyclyl, benzene or 5-or 6-membered heteroaryl (preferably a bond or NH); l' is further preferably O, S or- (CR) ² ₂ )p-NR ^N -，R ₂ Selected from hydrogen, C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkyl or hydroxy substituted C _1-6 Alkyl (preferably hydrogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, hydroxymethyl, hydroxyethyl or cyclopropyl), or R ₂ 、R ₂ ' together with the C atom to which it is attached form cyclopropyl, cyclobutyl, oxetanyl or azetidinyl; p is 0, 1, 2 or 3.

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 An alkyl group;

l is preferably 1 or 2R ^Q Substituted benzene or 5-or 6-membered heteroarylene, R ^Q Selected from: hydrogen, deuterium, hydroxy, amino, halogen, cyano, amido, acetyl, C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl, C _3-6 Cycloalkyl, -O-C _3-6 Cycloalkyl or

In some embodiments, L, L' are all chemical bonds.

Y ⁷ Is N or=CR ^Y ；Y ⁹ Is N or=CR ^Y ；Y ⁸ Is O or S;

each R is ^Y1 、R ^Y2 、R ^Y3 、R ^Y4 、R ^Y Each independently selected from: hydrogen, deuterium, halogen, C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl, NR ^a R ^b 、CONR ^a R ^b 、C _3-8 Cycloalkyl, -O- (CH) ₂ ) _0-4 -C _3-8 Cycloalkyl, 4-7 membered heterocyclyl, phenyl or 5-14 membered heteroaryl.

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.

Preferably, each R ^Y1 、R ^Y2 、R ^Y3 、R ^Y4 、R ^Y5 、R ^Y6 、R ^Y 、R ⁹ Each independently selected from dimethylamino, diethylamino, and combinations thereof,

Preferably, each R ^Y1 、R ^Y2 、R ^Y3 、R ^Y4 、R ^Y5 、R ^Y6 、R ^Y 、R ⁹ Each independently selected from the group consisting of amide, dicarboxamide, diacetamide, N' -methylethyl amide.

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, and oxapent substituted with 1 or 2 substituentsA group, an azacyclopentyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group,

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;

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.

In some embodiments, R ⁹ Selected from: hydrogen, deuterium, cyano, fluorine, chlorine, bromine, hydroxyl, amino, amido, 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.

Preferred R ⁹ Is C _3-8 Cycloalkyl or 4-7 membered heterocyclyl; preferred R ⁹ Is benzene or 5 or 6 membered heteroaryl.

Preferred R ⁹ is-NR ^N (CH ₂ ) _1-6 NR ^a R ^b The method comprises the steps of carrying out a first treatment on the surface of the Preferred R ⁹ Is halogen, cyano, C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkyl or hydroxy substituted C _1-6 An alkyl group; preferred R ⁹ Is C (O) NR ^a R ^b The method comprises the steps of carrying out a first treatment on the surface of the Preferred R ⁹ For S (O) _1-2 NR ^a R ^b 。

Each R is ^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 substituted C _1-6 Alkyl or C _1-6 An alkoxy group.

Each R is ^a 、R ^b 、R ^N 、R ^d Each independently selected from hydrogen, deuterium, C _1-4 Alkyl, halogenated C _1-4 Alkyl, hydroxy substituted C _1-4 Alkyl or C _1-4 An alkoxy group.

The C is _1-6 The alkyl group is selected from: methyl, ethyl, propyl, isopropyl, n-butyl,N-pentyl, n-hexyl; halogen is fluorine, chlorine or bromine.

Preferably R ^a 、R ^b Together with the N atom to which it is attached, form a 4 to 7 membered nitrogen heterocycle.

The C is _1-6 Alkyl, the C _1-6 Alkoxy, the C _3-8 Cycloalkyl, said 4-12 membered heterocyclyl, said 4-7 membered heterocyclyl, said benzene, said 5-14 membered heteroaryl, said 5-or 6 membered heteroaryl, said 4-7 membered azacyclo optionally substituted with 1 or 2 groups selected from hydrogen, deuterium, halogen, =o, hydroxy, amino, cyano, amido, acetyl, C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl, 4-6 membered heterocyclyl, hydroxy 4-6 membered heterocyclyl.

The 4-to 7-membered nitrogen heterocycle is selected from:

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, halo C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl, NR ^a R ^b 、CONR ^a R ^b ；

R ⁹ Selected from: NR (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 。

In some embodiments, each R ^Y1 、R ^Y2 、R ^Y3 、R ^Y4 、R ^Y Each independently selected from: hydrogen, deuterium, halogen; r is R ⁹ Is C (O) NR ^a R ^b 。

In some embodiments, R ⁰ Is a chemical bond, C _3-8 Cycloalkylene, 4-12 membered heterocyclylene, phenylene, or 5-14 heteroarylene.

Preferred R ⁰ Is 1, 2, 3 or 4R ^Z ' substituted 4-7 membered heterocyclylene (preferably piperidinyl or piperazinylene).

Preferred R ⁰ Is 1 or 2R ^Z ' substituted phenylene or 5-or 6-membered heteroarylene.

Preferred R ⁰ Is 1, 2 or 3R ^Z ' substituted 6-12 membered spirocyclic subunit or 7-12 membered heterospirocyclic subunit.

R ^Z ' selected from hydrogen, deuterium, halogen, hydroxy, cyano, acetyl, C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkyl, -NR ^a R ^b or-CONR ^a R ^b Substituted by substituents (R) ^Z ' preferably hydrogen,Fluoro, methyl, ethyl or trifluoromethyl), R ^a 、R ^b Selected from hydrogen, amino, methyl, ethyl, propyl, isopropyl, n-butyl or isobutyl.

In some embodiments, R ⁰ Expressed as:

is R ⁰ Attachment point to L' -, I->Is R ⁰ A connection point to LIN;

Z ⁵ 、Z ⁶ 、Z ⁷ each independently selected from N or CR ^Z ’；

Z ⁸ 、Z ⁹ 、Z ¹⁰ Each independently is C, N, O or S atom, and Z ⁸ 、Z ⁹ 、Z ¹⁰ Optionally by 1 or 2R ^Z ' substituted; or Z is ⁸ 、Z ⁹ Together with the substituents to which they are attached form a 4-7 membered cycloalkyl or 5-7 membered heterocyclyl group, while LIN and Z ⁸ 、Z ⁹ The formed rings are connected; preferably, Z ⁸ 、Z ⁹ 、Z ¹⁰ Each independently is NR ^N O or CH ₂ ；

R ^Z ' same or different, R ^Z ' each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, acetyl, hydroxy, cyano, -NR ^a R ^b 、-CONR ^a R ^b 、C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl, C _3-6 Cycloalkyl, -O-C _3-6 Cycloalkyl, 4-7 membered heterocyclyl, benzene or 5-14 membered heteroaryl;

or, two R ^Z ' together with the C atom to which it is attached forms c=o.

Preferably, R ^Z ' is selected from: c (C) _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkyl or hydroxy substituted C _1-6 An alkyl group. Preferably R ^Z ' is hydrogen, halogen, cyano, amino or amido.

Preferably, R ^Z ' is selected from: hydrogen, deuterium, C _1-4 Alkyl, C _1-4 Alkoxy, halo C _1-4 Alkyl or hydroxy substituted C _1-4 An alkyl group.

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,

In some embodiments, R ⁰ Is phenylene.

In some embodiments, HPK1 links are further represented as:

Z ¹¹ 、Z ¹² each independently is represented by N or CR ^Z’ ，Q ¹ 、Q ² 、Q ³ Each independently is represented by N or CR ^Q ；

R ^Z’ 、R ^Q Each independently selected from hydrogen, deuterium, halogen, C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl, NR ^a R ^b 、CONR ^a R ^b 、C _3-6 Cycloalkyl, -O- (CH) ₂ ) _0-4 -C _3-6 Cycloalkyl or 4-or 5-membered heterocyclyl;

R ^Z” selected from C _1-6 Alkylene, C _1-6 Alkyleneoxy group, O, S, NR ^N 、CONR ^N 、SO _1-2 NR ^N CO or C _3-6 A cycloalkylene group;

in the general formula (II-f), L and Y ¹ The ring being attached to, or with, Y ⁷ The rings where they are located are connected.

In some embodiments, in formula (II-a), formula (II-b), formula (II-c), formula (II-d), formula (II-e), 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.

In some embodiments, HPK1 links are further represented as:

R ⁰ is optionally substituted with 1, 2, 3 or 4R ^## Substituted phenylene, 4-12 membered heterocyclylene, or 5-16 membered heteroarylene;

l is a bond, NH, O, S, ethenylene, ethynylene, -NHC _1-4 Alkylene or-C _1-4 An alkylene NH;

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 An alkoxy group;

R ^X 、R ^Y2 、R ^Y3 、R ^Y5 each independently selected from: hydrogen, deuterium, F, cl, hydroxy, amino, amido, acetyl, cyano, C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkyl, cyclopropyl, -O-cyclopropyl,

R ⁹ Is hydrogen, deuterium, F, cl, br, hydroxy, cyano, - (CH) ₂ ) _0-4 C(O)NR ^a R ^b 、-(CH ₂ ) _0-4 NR ^a R ^b 、-(CH ₂ ) _0-4 S(O) _1-2 NR ^a R ^b 、C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl, C _3-6 Cycloalkyl, 4-7 membered heterocyclyl, -O- (CH) ₂ ) _0-4 -C _3-6 Cycloalkyl group,

R ^a 、R ^b Each independently is hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, n-butyl,N-pentyl, n-hexyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, -CH ₂ OH、-CH ₂ CH ₂ OH、-CH ₂ CH ₂ CH ₂ OH、-CH ₂ CH ₂ CH ₂ CH ₂ OH、-(CH ₂ ) _1-4 N(CH ₃ ) ₂ 、-(CH ₂ ) _1-4 N(CH ₃ )CH ₂ CH ₃ Or- (CH) ₂ ) _1-4 -4 to 7 membered nitrogen heterocycles, or R ^a 、R ^b Together with the attached N atom, form a 4-7 membered nitrogen heterocycle;

the 4-to 7-membered nitrogen heterocycle is optionally substituted with 1 or 2 substituents selected from hydrogen, deuterium, methyl, ethyl, hydroxy, amino.

In some embodiments, HPK1 links are further represented as:

in some embodiments, HPK1 links are further represented as:

in some embodiments, Y ² Is N, Y ³ 、Y ⁵ Is CH, in some embodiments Y ³ Is N, Y ² 、Y ⁵ Is CH, in some embodiments Y ⁵ Is CH, Y ² 、Y ⁵ N, in some embodiments, Y ² Is CH, Y ³ 、Y ⁵ N, in some embodiments, Y ³ Is CH, Y ³ 、Y ⁵ N, in some embodiments, Y ² 、Y ³ 、Y ⁵ Are CH.

In some embodiments, R ⁰ Is optionally substituted with 1, 2, 3 or 4R ^## Substituted 6-12 membered heterocyclylene;

Y ² 、Y ³ 、Y ⁵ are CH;

l is a bond, NH, O, S, ethenylene, ethynylene;

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 An alkoxy group;

R ^X 、R ^Y2 、R ^Y3 、R ^Y5 Each independently selected from: hydrogen, deuterium, F, cl, hydroxy, amino, C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 An alkyl group;

R ⁹ is- (CH) ₂ ) _0-4 C(O)NR ^a R ^b 、-(CH ₂ ) _0-4 NR ^a R ^b 、-(CH ₂ ) _0-4 S(O) _1-2 NR ^a R ^b 、C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkyl, hydroxy substituted C _1-6 An alkyl group;

R ^a 、R ^b each independently is hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, n-butyl,N-pentyl, n-hexyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, -CH ₂ OH、-CH ₂ CH ₂ OH、-CH ₂ CH ₂ CH ₂ OH、-CH ₂ CH ₂ CH ₂ CH ₂ OH、-(CH ₂ ) _1-4 N(CH ₃ ) ₂ 、-(CH ₂ ) _1-4 N(CH ₃ )CH ₂ CH ₃ 。

In some embodiments, R ⁰ Is optionally substituted with 1, 2, 3 or 4R ^## Substituted 8-12 membered benzoheterocyclylene;

l is a bond;

Y ² 、Y ³ 、Y ⁵ are CH;

R ^a ’、R ^b ' each independently selected from: hydrogen, deuterium;

R ^X 、R ^Y2 、R ^Y3 、R ^Y5 each independently selected from: hydrogen, deuterium;

R ⁹ is- (CH) ₂ ) _0-4 C(O)NR ^a R ^b 、-(CH ₂ ) _0-4 NR ^a R ^b 、-(CH ₂ ) _0-4 S(O) _1-2 NR ^a R ^b ；

R ^a 、R ^b Each independently is hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, n-butyl,N-pentyl, n-hexyl, methoxy, ethoxy, propoxy, isopropoxy, and butoxy.

In the above formula (II-a-2) or formula (II-a-3), each R ^Z ' each independently selected from: hydrogen, deuterium, C _1-4 Alkyl, C _1-4 Alkoxy, halo C _1-4 Alkyl or hydroxy substituted C _1-4 An alkyl group.

In the above formula (II-a-3), Y ² 、Y ³ 、Y ⁵ Are CH; l is a bond; r is R ⁹ Is- (CH) ₂ ) _0-4 C(O)NR ^a R ^b 、-(CH ₂ ) _0-4 NR ^a R ^b Or- (CH) ₂ ) _0-4 S(O) _1-2 NR ^a R ^b The method comprises the steps of carrying out a first treatment on the surface of the Each R is ^Z ' each independently selected from: hydrogen, deuterium, C _1-4 Alkyl, C _1-4 Alkoxy, halo C _1-4 Alkyl or hydroxy substituted C _1-4 An alkyl group.

In some embodiments, HPK1 links are further represented as:

each R is ^X 、R ^Y 、R ^X1 、R ^X2 、R ^Y1 、R ^Y3 Each independently selected from: hydrogen, deuterium, F, cl, hydroxy, amino, amido, acetyl, cyano, C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkyl, cyclopropyl, -O-cyclopropyl,

In some embodiments, HPK1 links are further represented as:

in some embodiments, HPK1 links are further represented as:

in some embodimentsWherein X is ¹ 、X ² One of them is N and the other is CH, Y ¹ 、Y ³ One of (2) is N, in some embodiments X ¹ 、X ² One of them is N and the other is CH, Y ¹ 、Y ³ Are all CH, in some embodiments X ¹ Is N, X ² Is CH, Y ¹ 、Y ³ Are all CH, in some embodiments X ² Is N, X ¹ Is CH, Y ¹ 、Y ³ Are CH.

In some embodiments, R ⁰ Is optionally substituted with 1, 2, 3 or 4R ^## A substituted phenylene group;

X ¹ is N, X ² Is CH, Y ¹ 、Y ³ Are CH;

each R is ^X 、R ^Y 、R ^X1 、R ^X2 、R ^Y1 、R ^Y3 Each independently selected from: hydrogen, deuterium, F, cl, hydroxy, amino, C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkyl, cyclopropyl, -O-cyclopropyl.

X ¹ is N, X ² Is CH, Y ¹ 、Y ³ Are CH;

R ^a ’、R ^b ' each independently selected from: hydrogen, deuterium;

R ^X 、R ^X1 、R ^X2 、R ^Y1 、R ^Y3 each independently selected from: hydrogen, deuterium;

each R is ^Y Each independently selected from hydrogen, deuterium, F, cl, hydroxy, amino, C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 An alkyl group.

In the above 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, preferably each is CH.

In the general formula (II-b-3) or the general formula (II-b-4), Z6 and Z7 are CH; r is R ^a ’、R ^b ' each independently selected from: hydrogen, deuterium; r is R ^Y Selected from hydrogen, deuterium, F, cl, hydroxy, amino, and C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 An alkyl group.

In some embodiments, HPK1 links are further represented as:

R ^a ' is selected from: hydrogen, deuterium, F, cl, C _1-6 Alkyl, halogenated C _1-6 Alkyl or C _1-6 An alkoxy group;

Y ⁷ is N or=CR ^Y ；Y ⁸ Is O or S;

each R is ^X 、R ^Y Each independently selected from: hydrogen, deuterium, F, cl, hydroxy, amino, amido, acetyl, cyano, C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkyl, cyclopropyl, -O-cyclopropyl,

R ^N Selected from hydrogen, deuterium, amino, hydroxyamino, =nh, C _1-6 Alkyl, halogenated C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl or C _1-6 An alkoxy group.

In some embodiments, HPK1 links are further represented as:

in some embodiments, HPK1 links are further represented as:

in some embodiments, Y ⁷ Is N or=CR ^Y ，Y ⁸ Is O or S, in some embodiments Y ⁷ Is=cr ^Y ，Y ⁸ For S, in some embodiments, Y ⁷ Is=cr ^Y ，Y ⁸ Is O, in some embodiments Y ⁷ Is=cr ^Y ，Y ⁸ S.

In some embodiments, Z ¹¹ 、Z ¹² Each independently is represented by N or CR ^Z ' in some embodiments, Z ¹¹ 、Z ¹² One of which is N and the other is CR ^Z ' in some embodiments, Z ¹¹ 、Z ¹² Are all N. Wherein each R ^Z ' each independently selected from hydrogen, deuterium, halogen, C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl is preferably hydrogen.

In some embodiments, R ⁰ Is optionally substituted with 1, 2, 3 or 4R ^## Substituted 4-8 membered heterocyclylene;

l is a bond, NH, O, S, ethenylene, ethynylene;

Y ⁷ is N; y is Y ⁸ Is O or S;

each R is ^X 、R ^Y Each independently selected from: hydrogen, deuterium, F, cl, hydroxy, amino, C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 An alkyl group;

R ^N selected from hydrogen, deuterium, C _1-6 Alkyl group,Halogenated C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl or C _1-6 An alkoxy group.

In some embodiments, R ⁰ Is optionally substituted with 1, 2, 3 or 4R ^## Substituted 4-6 membered nitrogen-containing heterocyclylene;

l is a bond;

R ^a ' is selected from: hydrogen, deuterium;

Y ⁷ is N; y is Y ⁸ Is O or S;

R ^X selected from: hydrogen, deuterium;

each R is ^Y Each independently selected from: hydroxy, amino, C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 An alkyl group;

R ^N selected from hydrogen, deuterium.

In the above formula (II-c-3), R ^N Selected from hydrogen, deuterium; r is R ^a ' is selected from: hydrogen, deuterium; r is R ^Y Selected from: hydroxy, amino, C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 An alkyl group.

In some embodiments, HPK1 links are further represented as:

R ⁰ is a chemical bond; l' is- (CR) ² ₂ ) _p NR ^N -；

R ^N Selected from: hydrogen, deuterium, amino, hydroxyamino, =nh, C _1-6 Alkyl or halo C _1-6 Alkyl (preferably hydrogen or C _1-6 An alkyl group);

R ² selected from hydrogen, deuterium, amino, hydroxyamino, C _1-6 Alkyl, halogenated C _1-6 Alkyl or hydroxy substituted C _1-6 Alkyl (preferably hydrogen or C _1-6 An alkyl group); or two R ² Together with the C atom to which it is attached form cyclopropyl, cyclobutyl, oxetanyl or azetidinyl;

p is 0, 1,2 or 3;

R ^X selected from: hydrogen, deuterium, fluorine, chlorine, bromine, amino, amido, C _1-6 Alkyl, halogenated C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl, - (CR' ₂ ) _m1 NR ^a R ^b 、C _3-6 Cycloalkyl, -O-R ¹ 、-O-(CH ₂ ) _1-2 R ¹ 、

R ^a 、R ^b Each independently selected from: hydrogen, deuterium, fluorine, chlorine, bromine, hydroxyl, amino, acetyl, amido, hydroxyamino, =nh, C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl, C _3-6 Cycloalkyl radicalsPreferably R ^a 、R ^b Together with the N atom to which they are attached form a 4-7 membered nitrogen heterocycle substituted with 1 or 2R';

R ¹ r' are each independently selected from: hydrogen, deuterium, fluorine, chlorine, bromine, hydroxyl, amino, acetyl, amido, hydroxyamino, =nh, C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl, C _3-6 Cycloalkyl radicalsOr two R's together with the C atom to which they are attached form a 3-6 membered cycloalkyl or 4-7 membered nitrogen heterocycle;

R ^Z4 selected from: hydrogen, deuterium, halogen, C _1-6 Alkyl or halo C _1-6 Alkyl (preferably hydrogen);

l is selected from 1 or 2R ^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-pyrimidinylene, 3, 6-pyridazinylene, 3, 5-pyridazinylene or 4, 5-pyridazinylene (preferably 2, 6-pyridylene);

R ^Y Identical or different, R ^Y3 、R ^Y4 、R ^Y 、R ^Q Each independently selected from hydrogen, deuterium, hydroxy, amino, halogen, C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl, cyclopropyl, -O-cyclopropyl,

R "is selected from hydrogen, deuterium, hydroxy, amino, c=o, halogen, C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkyl or hydroxy substituted C _1-6 An alkyl group.

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

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

R’、R ¹ each independently selected from: hydrogen, methyl, ethyl, propyl, isopropyl, hydroxymethyl, hydroxyethyl, trifluoromethyl or trifluoroethyl;

R ^a 、R ^b each independently selected from: hydrogen, methyl, ethyl, propyl, isopropyl, hydroxymethyl, hydroxyethyl, trifluoromethyl or trifluoroethyl;

preferred R ^a 、R ^b Together with the N atom to which it is attached form:

r' is selected from hydrogen, hydroxy, methyl, ethyl, propyl, isopropyl, hydroxymethyl, hydroxyethyl;

p, m1 are 0, 1 or 2.

In some embodiments, HPK1 links are further represented as:

X ² 、X ³ each independently is N or CH;

Y ¹ is N or CH;

R ⁰ is a chemical bond;

l is NH, N (CH) ₃ )、NHCH ₂ 、CH ₂ NH、NHCH ₂ CH ₂ Or CH (CH) ₂ CH ₂ NH；

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 -；

R ^b ’、R ^N Each independently selected from: hydrogen, deuterium, fluorine, chlorine, bromine, hydroxyl, amino, acetyl, amido, C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl, cyclopropyl (preferably hydrogen);

R ² selected from: hydrogen, deuterium, hydroxy, amino, hydroxyamino, C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl, cyclopropyl, cyclobutyl, oxetanyl (preferably hydrogen, methyl or ethyl);

or, two R ² Together with the attached C atom form a cyclopropyl, cyclobutyl, oxetanyl or azetidinyl group;

R ^X selected from hydrogen, deuterium, fluorine, chlorine, bromine, hydroxyl, acetyl, amide, and C _1-6 Alkyl, halogenated C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl, - (CR' ₂ ) _m1 NR ^a R ^b 、C _3-6 Cycloalkyl, -O-R ¹ 、-O-(CH ₂ ) _1-4 R ¹ 、

R ¹ R' are each independently selected from: hydrogen, deuterium, hydroxy, amino, C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl, C _3-6 Cycloalkyl, 4-7 membered heterocyclylOr two R's together with the C atom to which they are attached form C _3-6 Cycloalkyl or 4-7 membered heterocyclyl;

R ^a 、R ^b each independently selected from: hydrogen, deuterium, hydroxy, amino, hydroxyamino, =nh, C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl, C _3-6 Cycloalkyl group,Or R is ^a 、R ^b Together with the N atom to which it is attached, form a 4-7 membered nitrogen heterocycle;

R ^Y selected from hydrogen, deuterium, fluorine, chlorine, bromine, hydroxyl, amino, acetyl, amido, hydroxyamino, C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl, cyclopropyl, -O-cyclopropyl,Or two R ^Y Together with the C atom to which it is attached form a cyclopropyl group;

the C is _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl, C _3-6 Cycloalkyl is optionally substituted with 1 or 2 groups selected from hydrogen, halogen, hydroxy, amino, C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 The substituent of the alkyl group is substituted.

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

X ² CH; y is Y ¹ Each independently is N or CH; l is NH, N (CH) ₃ )、NHCH ₂ Or CH (CH) ₂ NH；

R ^b ' is hydrogen; r is R ^N Selected from: hydrogen or methyl;

R ² selected from: hydrogen, methyl, ethyl, propyl, isopropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, and cycloPropyl, cyclobutyl, hydroxycyclopropyl or fluorocyclopropyl;

R ¹ selected from: hydrogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl,Hydroxymethyl, hydroxyethyl, hydroxypropyl, cyclopropyl, hydroxycyclopropyl, cyclobutyl,/->

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

R ^a 、R ^b Each independently selected from: hydrogen, deuterium, hydroxy, amino, hydroxyamino, methyl, ethyl, propyl, hydroxymethyl, CH ₂ CH ₂ OH、CH ₂ CH ₂ CH ₂ OH, cyclopropyl, cyclobutyl

Preferred R ^a 、R ^b Together with the N atom to which it is attached to form

p is 0, 1 or 2.

In some embodiments, HPK1 links are further represented as:

X ² 、X ³ each independently is N or CH; z is Z ³ Is O, -NR ^Z3 -or-C (R) ^Z3 ) ₂ ；

R ^Z3 Selected from hydrogen, deuterium, fluorine, chlorine, bromine, hydroxyl, amino, and C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkyl or hydroxy substituted C _1-6 Alkyl (preferably hydrogen);

l' is a bond, NH, N (CH) ₃ )、NHCH ₂ 、CH ₂ NH、NHCH ₂ CH ₂ Or CH (CH) ₂ CH ₂ NH (preferably NH);

Y ⁵ substituent, R, attached thereto ^Y6 And together with the ring atoms to which they are attached form a cyclic ring of 1 or 2 Rs ^Y Substituted phenyl or 5 or 6 membered heteroaryl; or R is ^Y1 、R ^Y6 Together with the ring atoms to which they are attached form a ring of 1 or 2R ^Y Substituted phenyl or 5 or 6 membered heteroaryl; or, Y ³ Substituent, R, attached thereto ^Y1 And together with the ring atoms to which they are attached form a cyclic ring of 1 or 2 Rs ^Y Substituted phenyl or 5 or 6 membered heteroaryl; or, Y ⁵ Substituent, R, attached thereto ^Y6 And together with the ring atoms to which they are attached form a cyclic ring of 1 or 2 Rs ^Y Substituted phenyl or 5 or 6 membered heteroaryl;

R ^Y1 、R ^Y3 、R ^Y5 、R ^Y6 、R ^Y 、R ^Z ' each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, hydroxyl, amino, amido, C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl, cyclopropyl, -O-cyclopropyl,

Preferably R ^Y5 、R ^Y6 Together with the ring atoms to which they are attached form a ring of 1 or 2R ^Y Substituted phenyl or pyridyl, R ^Y1 、R ^Y3 、R ^Y 、R ^Z ' each independently selected from hydrogen, deuterium, halogen, C _1-6 Alkyl, C _1-6 Alkoxy or halo C _1-6 An alkyl group.

In the above formula (II-f'), X ² Is N, X ³ CH; in some embodiments, X ³ Is N, X ² CH;

in some embodiments, Y ³ Is N, Y ⁵ Is CR (CR) ^Y5 ，R ^Y1 、R ^Y6 Together with the ring atoms to which they are attachedForm a quilt of 1 or 2R ^Y Substituted phenyl or pyridyl; in some embodiments, Y ³ Is N, Y ⁵ Is CR (CR) ^Y5 ，R ^Y1 、R ^Y6 Together with the ring atoms to which they are attached form a ring of 1 or 2R ^Y Substituted phenyl or pyridyl;

in some embodiments, Y ³ Is CR (CR) ^Y3 ，Y ⁵ Is N, R ^Y1 、R ^Y6 Together with the ring atoms to which they are attached form a ring of 1 or 2R ^Y Substituted phenyl or pyridyl; in some embodiments, Y ³ Is CR (CR) ^Y3 ，Y ⁵ Is N, Y ⁵ 、R ^Y6 Together with the ring atoms to which they are attached form a ring of 1 or 2R ^Y Substituted phenyl or pyridyl;

in some embodiments, Y ³ Is N, Y ⁵ Is N, R ^Y1 、Y ³ Together with the ring atoms to which they are attached form a ring of 1 or 2R ^Y Substituted phenyl or pyridyl; in some embodiments, Y ³ Is N, Y ⁵ Is N, R ^Y1 、R ^Y6 Together with the ring atoms to which they are attached form a ring of 1 or 2R ^Y Substituted phenyl or pyridyl; in some embodiments, Y ³ Is N, Y ⁵ Is N, R ^Y6 、Y ⁵ Together with the ring atoms to which they are attached form a ring of 1 or 2R ^Y Substituted phenyl or pyridyl.

In some embodiments, HPK1 links are further represented as:

V ⁵ 、V ⁶ 、V ⁷ each independently selected from N or CR ^V ；

R ^V Identical or different and are each independently selected from hydrogen, deuterium, halogen, cyano, hydroxy, -C (O) NR ^a R ^b 、NR ^a R ^b 、C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl, C _3-6 Cycloalkyl, -O-C _3-6 Cycloalkyl group,(preferably hydrogen, F, amino, amido, dimethylamino, dicarboxamido, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl or trifluoroethyl);

R ⁰ selected from 5-or 6-membered heteroarylene (preferably)；

R ^V1 、R ^V1 ' each independently selected from hydrogen, deuterium, fluorine, chlorine, hydroxy, C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl, C _3-6 Cycloalkyl, 4-7 membered heterocyclyl, C _3-6 Cycloalkyl or-O-C _3-6 Cycloalkyl (preferably hydrogen, halogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, trifluoromethyl or trifluoroethyl);

R ³¹ 、R ³² selected from hydrogen, deuterium, C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl, C _3-6 Cycloalkyl or a 4-7 membered heterocyclyl (preferably hydrogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, trifluoromethyl, trifluoroethyl, difluoromethyl, difluoroethyl, hydroxymethyl, hydroxyethyl or hydroxypropyl);

R ^a 、R ^b as defined in any one of the above.

In some embodiments, the EL is further represented as:

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, halo C _1-6 Alkyl or hydroxy substituted C _1-6 Alkyl (preferably hydrogen, methyl or ethyl);

K ⁴ is CH or N, K ³ Is NR (NR) ^K3 、CH ₂ Or CO;

R ^K3 selected from hydrogen, deuterium, C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkyl or hydroxy substituted C _1-6 Alkyl (preferably hydrogen, methyl or ethyl);

R ^g selected from hydrogen, deuterium, halogen, cyano, amino, amido, dimethylamino, dicarboxamido, C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkyl or hydroxy substituted C _1-6 An alkyl group; r is R ^g Preferably hydrogen, C _1-6 Alkyl and halogenated C _1-6 Alkyl, further preferred is hydrogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, trifluoromethyl, trifluoroethyl or cyano.

In some embodiments, K ³ Is CH ₂ Or CO.

In some embodiments, the compound of formula (I) above is further represented by:

/>

In some embodiments, the compound of formula (I) is a compound of formulae (II ' -1), (II ' -1-2), (II ' -1-3), (II ' -1-4) and (II ' -1-5) above; wherein, the liquid crystal display device comprises a liquid crystal display device,

l is NH or N (methyl);

R ⁰ is a chemical bond, L' is-CONR ^N -or-COO-;

preferably R ⁰ Is thatL' is a bond;

X ¹ is N or CH;

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, halo C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl or C _3-6 Cycloalkyl; or R is ^V2 、R ^V2’ Or R is ^V1 、R ^V1’ Together with the C atom to which it is attached form c=o or C _3-6 Cycloalkyl;

V ⁴ is NH or O;

R ^V each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, amide, amino, dimethylamino, dicarboxamide, C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl, C _3-6 Cycloalkyl radicals

R ^a Is hydrogen, deuterium, amino, hydroxyamino, C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkyl or hydroxy substituted C _1-6 An alkyl group;

LIN is expressed as: -L ¹ -L ² -L ³ -L ⁴ -L ⁵ -L ⁶ -L ⁷ -,L ⁷ Is connected with the EL;

L ¹ selected from: CH (CH) ₂ 、CH ₂ CH ₂ 、CO、CONH、NHCO、NHCONH、SO、SO ₂ 、SONH、NHSO、SO ₂ NH、NHSO ₂ O, S, NH, N (methyl), OCH ₂ 、CH ₂ O、OCH ₂ CH ₂ Ethenylene, ethynylene, phenylene, pyridylene, pyrimidinylene, triazolylene, tetrazolylene, pyrazolylene, imidazolylene, piperidylene, piperazinylene,

L ² 、L ³ Selected from: CH (CH) ₂ 、CH ₂ CH ₂ CO, CONH, NHCO, O, S, NH, N (methyl), OCH ₂ 、OCH ₂ CH ₂ 、CH ₂ O, phenylene, pyridylene, pyrimidinylene, triazolylene, tetrazolylene, pyrazolylene, imidazolylene, morpholinylene, piperidinyl, piperazinylene or CH ₂ CH ₂ O；

L ⁴ 、L ⁵ Selected from chemical bonds, CH ₂ Or CH (CH) ₂ CH ₂ Or CH (CH) ₂ CH ₂ O；L ⁶ Selected from: chemical bond, O, S, NH, N (methyl), CH ₂ 、CH ₂ CH ₂ 、CH ₂ CH ₂ CH ₂ 、CH ₂ CH ₂ CH ₂ CH ₂ CO, CONH, NHCO or CH ₂ CH ₂ O；L ⁷ Selected from: o, S, NH, N (methyl), CH ₂ An ethenylene group or an ethynylene group;

R ^N selected from hydrogen or methyl; hydrogen of any of the above methylene groups is optionally interrupted by 1 or 2R ^## Substituted, R ^## Selected from deuterium, methyl, ethyl, propyl, cyclopropyl, amino or trifluoromethyl.

In some embodiments, the compound of formula (I) is a compound of 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, the liquid crystal display device comprises a liquid crystal display device,

l is selected from a bond or NH;

Z ¹¹ is N or CH; z is Z ¹² Is N or CH;

R ^Z ,、R ^a ’、R ^N each independently selected from: hydrogen, deuterium, C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkyl or C _3-6 Cycloalkyl (preferably H or methyl);

Y ⁷ is=ch, Y ⁸ Is O or S; or Y ⁷ Is O or S, Y ⁸ Is=ch;

R ^X selected from: hydrogen, deuterium, halogen, C _1-6 Alkyl, C _1-6 Alkoxy or halo C _1-6 Alkyl (preferably hydrogen);

R ^Y4 selected from: hydrogen, deuterium, halogen, cyano, amino, amido, dimethylamino, dicarboxamido, C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkyl, C _3-6 Cycloalkyl, -OC _3-6 Cycloalkyl, -O-methylene cyclopropyl,

L ¹ selected from: chemical bond, CH ₂ 、CH ₂ CH ₂ CO, CONH, NHCO, O, S, NH, N (methyl), OCH ₂ 、CH ₂ O, or

L ² 、L ³ Selected from: chemical bond, CH ₂ 、CH ₂ CH ₂ CO, CONH, NHCO, O, S, NH, N (methyl), OCH ₂ OCH ₂ 、OCH ₂ CH ₂ 、CH ₂ O or CH ₂ CH ₂ O；

L ⁴ 、L ⁵ Selected from CH ₂ Or CH (CH) ₂ CH ₂ ；

L ⁶ Selected from: chemical bond, O, S, NH, N (methyl), CH ₂ 、CH ₂ CH ₂ 、CH ₂ CH ₂ CH ₂ 、CH ₂ CH ₂ CH ₂ CH ₂ CO, CONH or NHCO;

L ⁷ selected from: o, S, NH, N (methyl), CH ₂ An ethenylene group or an ethynylene group;

hydrogen of any of the above methylene groups is optionally interrupted by 1 or 2R ^## Substituted, R ^## Selected from hydrogen, deuterium, halogen, amide, amino, dimethylamino, and C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkyl, C _3-6 Cycloalkyl or 4-7 membered heterocyclyl (preferably methyl, ethyl or propyl).

l is selected from a bond;

Z ¹¹ and Z ¹¹ Are all N;

R ^Z, 、R ^a’ 、R ^N each independently selected from: hydrogen, deuterium;

Y ⁷ is=ch, Y ⁸ Is O or S;

R ^X selected from: hydrogen, deuterium;

R ^Y4 selected from: hydrogen, deuterium, halogen, cyano, amino C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 An alkyl group;

L ² 、L ³ Selected from: chemical bond, CH ₂ 、CH ₂ CH ₂ 、CO、CONH、NHCO、O, S, NH, N (methyl), OCH ₂ OCH ₂ 、OCH ₂ CH ₂ 、CH ₂ O or CH ₂ CH ₂ O；

L ⁴ 、L ⁵ Selected from CH ₂ Or CH (CH) ₂ CH ₂ ；

K ³ is CH ₂ Or CO;

R ^g selected from hydrogen, C _1-6 Alkyl and halogenated C _1-6 An alkyl group;

In some embodiments, the compound of formula (I) is a compound of formula (II-4), (II-4-1), (II-4-2), (II-4-3), (II-4-4), (II-4-5); wherein, the liquid crystal display device comprises a liquid crystal display device,

R ^Y1 、R ^Y2 、R ^Y3 each independently selected from: hydrogen, deuterium, fluorine, chlorine, bromine, hydroxyl, cyano, C _1-6 Alkyl, C _1-6 Alkoxy or halo C _1-6 An alkyl group;

R ⁹ selected from: hydrogen, deuterium, fluorine, chlorine, bromine, hydroxy, cyano or-C (R) ^f ₂ ) _n2 -R ^#2 ；

R ^f Selected from: hydrogen, deuterium, fluorine, hydroxy, amino, C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkyl or hydroxy substituted C _1-6 An alkyl group; or two R ^f Together with the C atom to which it is attached form c= O, C _3-6 Cycloalkyl or 4-7 membered heterocyclyl;

R ^#2 is hydrogen, halogen or C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl, CONR ^a R ^b 、NR ^a R ^b 、C _3-6 Cycloalkyl or 4-7 membered heterocyclyl;

R ^a 、R ^b each independently selected from: hydrogen, deuterium, amino, C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl, -C _1-6 Alkylene-4 to 7 membered nitrogen heterocycles or- (CH) ₂ ) _1-6 -NR ^e1 R ^f1 ；

R ^e1 、R ^f1 Each independently selected from hydrogen, C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkyl, C _3-6 Cycloalkyl or 4-7 membered heterocyclyl (preferably hydrogen, methyl or ethyl);

preferably R ^a 、R ^b Together with the N atom to which they are attached form a 4-to 7-membered nitrogen heterocycle, preferably R ^e1 、R ^f1 Together with the N atom to which it is attached form a 4-to 7-membered nitrogen heterocycle, said C _3-6 Cycloalkyl, 4-7 membered heterocyclyl or 4-to 7-membered nitrogen heterocyclo optionally substituted with 1 or 2 groups selected from deuterium, fluoro, amino, hydroxy, C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl substituted;

X ¹ 、X ² each independently selected from CH or N;

Z ⁵ 、Z ⁶ 、Z ⁷ each independently is CH or N;

R ^a ’、R ^b ' each independently selected from hydrogen, deuterium, C _1-6 Alkyl, C _1-6 Alkoxy or halo C _1-6 Alkyl (preferably hydrogen);

R ^X 、R ^Z ' each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, cyano, amido, acetyl, C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkyl or hydroxy substituted C _1-6 An alkyl group;

L ¹ selected from: CH (CH) ₂ 、CH ₂ CH ₂ CO, CONH, NHCO, O, S, NH, N (methyl), OCH ₂ 、OCH ₂ CH ₂ 、CH ₂ O、CH ₂ CH ₂ O or

L ² Selected from: chemical bond, CH ₂ 、CH ₂ CH ₂ CO, CONH, NHCO, O, S, NH, N (methyl), OCH ₂ 、OCH ₂ CH ₂ 、CH ₂ O、CH ₂ CH ₂ O, piperidinyl or piperazinyl;

L ³ 、L ⁴ selected from: CH (CH) ₂ 、CH ₂ CH ₂ CO, CONH, NHCO, O, S, NH, N (methyl), OCH ₂ 、CH ₂ O、OCH ₂ CH ₂ 、CH ₂ CH ₂ O or piperidinyl;

L ⁵ selected from chemical bonds, CH ₂ 、CH ₂ CH ₂ Or CH (CH) ₂ CH ₂ O；

R ^Y1 、R ^Y2 、R ^Y3 each independently selected from: hydrogen, deuterium, fluorine, chlorine, bromine, C _1-6 Alkyl, C _1-6 Alkoxy or halo C _1-6 An alkyl group;

R ⁹ is-C (R) ^f ₂ ) _n2 -R ^#2 The method comprises the steps of carrying out a first treatment on the surface of the n2 is an integer from 0 to 5;

R ^#2 is CONR ^a R ^b 、NR ^a R ^b ；

R ^a 、R ^b Each independently selected from: hydrogen, deuterium, amino, C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkyl, hydroxy substituted C _1-6 An alkyl group;

X ¹ is N, X ² CH;

Z ⁵ 、Z ⁶ 、Z ⁷ CH-average;

R ^X and each R ^Z ' each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkyl or hydroxy substituted C _1-6 An alkyl group;

L ¹ selected from: CH (CH) ₂ 、CH ₂ CH ₂ 、CO、CONH. NHCO, O, S, NH, N (methyl), OCH ₂ 、OCH ₂ CH ₂ 、CH ₂ O、CH ₂ CH ₂ O or/>

K ³ is CH ₂ Or CO;

R _g selected from hydrogen, C _1-6 Alkyl and halogenated C _1-6 An alkyl group;

In some embodiments, the compound of formula (I) is a compound of formula (II-5), (II-5-1), (II-5-2), (II-5-3), (II-5-4), (II-5-5); wherein, the liquid crystal display device comprises a liquid crystal display device,

Z ⁶ 、Z ⁷ each independently is CH or N;

R ^Y selected from hydrogen, deuterium, halogen, C _1-6 Alkyl, C _1-6 Alkoxy or halo C _1-6 An alkyl group;

R ^Z ’、R ^Y1 、R ^Y2 、R ^Y3 、R ^Y4 each independently selected from: hydrogen, deuterium, fluorine, chlorine, amino, cyano, amido, acetyl, dimethylamino, diethylamino, dicarboxamido, C _1-6 Alkyl, C _1-6 Alkoxy or halo C _1-6 An alkyl group;

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 halo C _1-6 An alkyl group;

L ¹ selected from: chemical bond, CH ₂ 、CH ₂ CH ₂ CO, CONH, NHCO, O, S, NH, N (methyl) or

L ² 、L ³ 、L ⁴ Each independently selected from: chemical bond, CH ₂ 、CH ₂ CH ₂ CO, CONH, NHCO, O, S, NH, N (methyl), OCH ₂ 、OCH ₂ CH ₂ 、CH ₂ CH ₂ O；

L ⁵ 、L ⁶ Selected from chemical bonds, CH ₂ Or CH (CH) ₂ CH ₂ ；

hydrogen of any of the above methylene groups is optionally interrupted by 1 or 2R ^## Substituted; r, R ^## Selected from hydrogen, deuteriumHalogen, amido, amino, dimethylamino, C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkyl, C _3-6 Cycloalkyl or 4-7 membered heterocyclyl (preferably methyl, ethyl or propyl)

R ^N Selected from hydrogen, methyl or ethyl.

Z ⁶ 、Z ⁷ are CH; y is Y ¹ 、Y ² 、Y ³ 、Y ⁴ Are CH;

each R is ^Y Each independently selected from hydrogen, deuterium, halogen, C _1-6 Alkyl, C _1-6 Alkoxy or halo C _1-6 An alkyl group;

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 halo C _1-6 An alkyl group;

R ^a ’、R ^b ’、R ^X each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, C _1-6 Alkyl, C _1-6 Alkoxy or halo C _1-6 An alkyl group;

L ⁵ 、L ⁶ Selected from chemical bonds, CH ₂ Or CH (CH) ₂ CH ₂ ；

K ³ is CH ₂ Or CO;

R ^N selected from hydrogen, methyl or ethyl;

hydrogen of any of the above methylene groups is optionally interrupted by 1 or 2R ^## Substituted; r is R ^## Selected from hydrogen, deuterium, halogen, amide, amino, dimethylamino, and C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkyl, C _3-6 Cycloalkyl or 4-7 membered heterocyclyl (preferably methyl, ethyl or propyl).

In some embodiments, the compound of formula (I) is a compound of formula (II-6), (II-6-1), (II-6-2), (II-6-3), (II-6-4), (II-6-5), (II-6-6); wherein, the liquid crystal display device comprises a liquid crystal display device,

R ^b ’、R ^Y1 、R ^Y2 、R ^Y3 、R ^Y4 、R ^X each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, amido, cyano, C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkyl, C _3-6 Cycloalkyl or 4-7 membered heterocyclyl;

R ^X selected from hydrogen, halogen, C _1-6 Alkyl, -O-R ¹ 、-O-(CH ₂ ) _1-4 R ¹ 、C _3-6 Cycloalkyl or 4-7 membered heterocyclyl;

R ¹ selected from hydrogen, C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkyl group,C _3-6 Cycloalkyl or 4-A 7 membered heterocyclyl;

l' is represented by- (CR) ² ₂ ) _p -NR ^N -；

p is 0, 1, 2 or 3,

R ² selected from: hydrogen, deuterium, amino, C _1-6 Alkyl, C _1-6 Alkoxy or halo C _1-6 Alkyl, or two R ₂ Together with the attached C atom, form c=o, cyclopropyl, oxetanyl or azetidinyl;

R ^N Selected from: hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, amino, =nh or hydroxyamino;

l is selected from a bond, NH or N (methyl);

L ¹ selected from: chemical bond, CH ₂ 、CH ₂ CH ₂ O, S, NH, N (methyl), OCH ₂ 、CH ₂ O、OCH ₂ CH ₂ 、CH ₂ CH ₂ O；

L ² Selected from: chemical bond, CH ₂ 、CH ₂ CH ₂ CO, CONH, NHCO, O, S, NH, N (methyl), OCH ₂ 、CH ₂ O、OCH ₂ CH ₂ 、CH ₂ CH ₂ O, piperidinyl;

L ³ 、L ⁴ selected from: CH (CH) ₂ 、CH ₂ CH ₂ CO, CONH, NHCO, O, S, NH, N (methyl), OCH ₂ 、CH ₂ O or OCH ₂ CH ₂ ；

L ⁵ 、L ⁶ Selected from chemical bonds, CH ₂ 、CH ₂ CH ₂ 、OCH ₂ CH ₂ O, S or NH;

L ⁷ selected from: o, S, NH, N (methyl), CH ₂ Vinylidene or ethynyleneA base;

In some embodiments, the compound of formula (I) is a compound of formula (II-7-1), (II-7-2), (II-7-3), (II-7-4); wherein, the liquid crystal display device comprises a liquid crystal display device,

R ^Y1 、R ^Y2 、R ^Y3 、R ^Y4 、R ^b ' each independently selected from hydrogen, deuterium, fluorine, amino, cyano, amido, acetyl, C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkyl, cyclopropyl, cyclobutyl or oxetanyl;

R ^Y selected from hydrogen, deuterium, fluorine, C _1-6 Alkyl, C _1-6 Alkoxy, trifluoromethyl or difluoromethyl;

R ^X selected from the group consisting of-O- (CH) ₂ ) _s -R ¹ Or- (CR' ₂ ) _s -R ¹ ，R ¹ Selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, and C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkyl, C _3-6 Cycloalkyl or 4-7 membered heterocyclyl; the C is _3-6 Cycloalkyl or 4-7 membered heterocyclyl, preferably cyclopropyl, cyclobutyl, oxetanyl or azetidinyl, said C _3-6 Cycloalkyl or 4-7 membered heterocyclyl optionally substituted with 1 or 2 substituents selected from deuterium, fluoro, methyl, ethyl, hydroxy, hydroxymethyl, amino;

s is 0, 1, 2 or 3; LIN is as defined above.

In some embodiments, the compound of formula (I) is of 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, the liquid crystal display device comprises a liquid crystal display device,

R ^X selected from hydrogen, deuterium, fluorine, chlorine, cyano, NR ^a R ^b 、C _1-6 Alkyl group,Halogenated C _1-6 Alkyl, C _1-6 Alkoxy, C _3-6 Cycloalkyl or 4-7 membered nitrogen heterocycle; preferred R ^X Represented as- (CR' ₂ ) _s -NR ^a R ^b ，

R ^Z4 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 form cyclopropyl, cyclobutyl or cyclopentyl;

Q ¹ 、Q ² 、Q ³ Each independently is N=or CR ^Q ；

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;

Y ⁸ o, S or CH ₂ ；

R ^Y Each independently selected from hydrogen, deuterium, fluorine, amino, C _1-6 Alkyl, halogenated C _1-6 Alkyl or C _1-6 An alkoxy group; or two R ^Y Together with the C atom to which it is attached, form c=o;

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, cyclobutylPreferably, two R's together with the C atom to which they are attached form cyclopropyl or cyclobutyl; preferred R ^a 、R ^b Together with the N atom to which it is attached form a 4-7 membered nitrogen heterocycle,

the C is _3-6 Cycloalkyl or 4-7 membered azacyclic optionally substituted with 1 or 2 substituents selected from F, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl;

l' is selected from: NR (NR) ^N 、O、S、Or- (CR) ² ₂ ) _p -NR ^N -；

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 substituted C _1-6 Alkyl or C _3-6 Cycloalkyl;

L ¹ selected from: chemical bond, CH ₂ 、CH ₂ CH ₂ O, S, NH, N (methyl), OCH ₂ Or CH (CH) ₂ O；

L ² Selected from: chemical bond, CH ₂ 、CH ₂ CH ₂ CO, CONH, NHCO, O, S, NH, N (methyl), OCH ₂ 、CH ₂ O、OCH ₂ CH ₂ Or CH (CH) ₂ CH ₂ O；

In some embodiments, the compound of formula (I) is a compound of formula (II-9), (II-9-1), (II-9-2), (II-9-3), (II-9-4), (II-9-5), (II-9-6); wherein, the liquid crystal display device comprises a liquid crystal display device,

Z ⁴ is CH ₂ ；Z ³ Is NH;

Y ⁵ is N or C, Y ⁶ Is N or C, Y ⁷ 、Y ⁸ 、Y ⁹ 、Y ¹⁰ Each independently is NH or CR ^Y ；

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, halo C _1-6 Alkyl, C _3-6 Cycloalkyl or 4-7 membered heterocyclyl;

l is a bond; l' is NH;

U ⁹ selected from N or CR ^U ”，U ⁸ Selected from N or CR ^U ”，

R ^U "selected from hydrogen, deuterium, halogen, amino, amido, C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl or C _3-6 Cycloalkyl (preferably hydrogen, methyl or ethyl), preferably two R ^U "forms together with the ring atom to which it is attached a 3-8 membered cycloalkyl or 4-7 membered heterocyclyl;

L ¹ selected from C _3-6 Cycloalkyl, 4-12 membered heterocyclyl, CH ₂ 、CH ₂ CH ₂ 、CH ₂ CH ₂ CH ₂ O, S, NH, N (methyl), CO, SO ₂ 、

L ² Selected from C _3-6 Cycloalkyl, 4-7 membered heterocyclyl, CH ₂ 、CH ₂ CH ₂ 、CH ₂ CH ₂ CH ₂ O, S, NH, N (methyl))、OCH ₂ 、CH ₂ O, CONH or NHCO;

L ³ selected from: CH (CH) ₂ 、CH ₂ CH ₂ 、CH ₂ CH ₂ CH ₂ CO, CONH, NHCO, O, S, NH, N (methyl), OCH ₂ OCH ₂ 、OCH ₂ CH ₂ 、CH ₂ O、CH ₂ CH ₂ O；

L ⁴ Selected from chemical bonds, CH ₂ 、CH ₂ CH ₂ CO, CONH, NHCO, O, S, NH, N (methyl), OCH ₂ 、OCH ₂ CH ₂ 、CH ₂ O or CH ₂ CH ₂ O；

L ⁵ Selected from chemical bonds, CH ₂ Or CH (CH) ₂ CH ₂ ；

hydrogen of any of the above methylene groups is optionally interrupted by 1 or 2R ^## Substituted, R ^## Selected from hydrogen, deuterium, halogen, amide, amino, dimethylamino, and C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkyl, C _3-6 Cycloalkyl or 4-7 membered heterocyclyl.

In the above embodiment, Y ⁷ Is N, Y ⁹ Is CR (CR) ^Y In some embodiments, Y ⁷ Is CR (CR) ^Y ，Y ⁹ Is N; in some embodiments, Y ⁷ 、Y ⁹ Are all CR ^Y 。

In some embodiments, LIN is represented as: -L ¹ -L ² -L ³ -L ⁴ -L ⁵ -L ⁶ -L ⁷ -,L ⁷ Is connected with the EL;

L ¹ selected from: chemical bond, O, S, NR ^N 、CH ₂ 、C(CH ₃ ) ₂ 、CH ₂ CH ₂ 、CH ₂ CH ₂ CH ₂ 、CH ₂ CH ₂ CH ₂ CH ₂ 、OCH ₂ CH ₂ 、CH ₂ CH ₂ O、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 Ethenylene, ethynylene, phenylene, pyridylene, pyrimidinylene, pyrazinylene, pyridazinylene, piperazinylene, piperidinylene, triazolylene, tetrazolylene, pyrazolylene, imidazolylene, C _3-6 Cycloalkylene, 4-12 membered heterocyclylene,

L ² Each independently selected from: chemical bond, O, S, NR ^N 、CH ₂ 、CH ₂ CH ₂ 、CH ₂ CH ₂ CH ₂ 、CH ₂ CH ₂ CH ₂ CH ₂ 、C(CH ₃ ) ₂ 、CO、CONR ^N 、NR ^N CO、OCH ₂ CH ₂ 、CH ₂ CH ₂ O, ethenylene, ethynylene, phenylene, pyridylene, pyrimidinylene, piperazinylene, triazolylene, tetrazolylene, pyrazolylene, imidazolylene,C _3-6 Cycloalkylene or 4-12 membered heterocyclylene;

L ³ 、L ⁴ each independently selected from: chemical bond, O, S, NR ^N 、CH ₂ 、CH ₂ CH ₂ 、CH ₂ CH ₂ CH ₂ 、CH ₂ CH ₂ CH ₂ CH ₂ 、CO、CONR ^N 、NR ^N CO、OCH ₂ CH ₂ 、CH ₂ CH ₂ O, ethenylene, ethynylene, phenylene, pyridylene, pyrimidinylene, piperazinylene, triazolylene, tetra-phenyleneAn azolyl group, a pyrazolyl group, and an imidazolyl group;

L ⁵ 、L ⁶ each independently selected from: chemical bond, O, S, NR ^N 、CH ₂ 、CH ₂ CH ₂ 、CH ₂ CH ₂ CH ₂ 、CH ₂ CH ₂ CH ₂ CH ₂ 、CO、CONR ^N 、NR ^N CO、OCH ₂ CH ₂ 、CH ₂ CH ₂ O, ethenylene, ethynylene, phenylene, pyridinyl, pyrimidinylene, piperazinylene, triazolylene, tetrazolylene, pyrazolylene, imidazolylene;

L ⁷ selected from: o, S, NH, N (methyl), CH ₂ Ethenylene, 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 (NR) ^N SO _1-2 NR ^N ；

R ^N Selected from hydrogen or methyl; hydrogen of any of the above methylene groups is optionally interrupted by 1 or 2R ^## Substituted;

the C is _3-6 Cycloalkylene, 4-12 membered heterocyclylene optionally substituted with 1 or 2 groups selected from hydrogen, deuterium, halogen, C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkyl or hydroxy substituted C _1-6 The substituent of the alkyl group is substituted.

L ² Selected from: chemical bond, CH ₂ 、CH ₂ CH ₂ 、CO、CONH、NHCO、O, S, NH, N (methyl), OCH ₂ 、OCH ₂ CH ₂ 、CH ₂ O、CH ₂ CH ₂ O；

L ³ 、L ⁴ Selected from: CH (CH) ₂ 、CH ₂ CH ₂ CO, CONH, NHCO, O, S, NH, N (methyl), OCH ₂ 、CH ₂ O、OCH ₂ CH ₂ 、CH ₂ CH ₂ O；

L ⁷ selected from: o, S, NH, N (methyl), CH ₂ An ethenylene group or an ethynylene group.

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

In some embodiments, the compound of formula (I) is selected from table 1.

Table 1:

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in another aspect the invention provides a pharmaceutical composition comprising a compound according to any one of the above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, and a pharmaceutically acceptable excipient; preferably, it also contains other therapeutic agents.

In a further aspect the invention provides the use of a compound as defined in any one of the preceding claims, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, or a pharmaceutical composition as defined above, for the preparation of a protein inhibitor or degradant.

In some embodiments, the protein is an HPK1 protein.

In a further aspect the present invention provides the use of a compound according to any one of the above or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, in the manufacture of a medicament for the treatment and/or prophylaxis of cancer.

In a further aspect the present invention provides a method of treating and/or preventing cancer in a subject, the method comprising administering to the subject a compound as defined in any one of the above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, or a pharmaceutical composition as defined above.

In a further aspect the present invention provides a compound according to any one of the above or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, as well as mixtures thereof or a pharmaceutical composition as described above, for use in the treatment and/or prophylaxis of cancer.

Use, method or use of a compound or composition as described above, wherein the cancer is selected from bladder cancer, breast cancer, colorectal cancer, gastric cancer, head and neck squamous cell cancer, hodgkin's lymphoma, melk-cell cancer, mesothelioma, melanoma, non-small cell lung cancer, ovarian cancer, uterine cancer, esophageal cancer, liver cancer, pancreatic cancer, prostate cancer, renal cell cancer, thyroid cancer, small cell lung cancer, transitional cell cancer, urothelial cancer, tumors that are resistant to a targeted drug; or a tumor or disease that depends on the HPK1 mutein.

Detailed Description

Definition of the definition

Chemical definition

The definition of specific functional groups and chemical terms is described in more detail below.

When numerical ranges are listed, it is intended to include each and every value and subrange within the range. For example "C _1-6 Alkyl "includes C ₁ 、C ₂ 、C ₃ 、C ₄ 、C ₅ 、C ₆ 、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 、C _3-4 、C _4-6 、C _4-5 And C _5-6 An alkyl group.

“C _1-6 Alkyl "refers to a straight or branched saturated hydrocarbon group having 1 to 6 carbon atoms. In some embodiments, C _1-4 Alkyl groups are preferred. C (C) _1-6 Examples of alkyl groups include: methyl (C) ₁ ) Ethyl (C) ₂ ) N-propyl (C) ₃ ) Isopropyl (C) ₃ ) N-butyl (C) ₄ ) Tert-butyl (C) ₄ ) Sec-butyl (C) ₄ ) Isobutyl (C) ₄ ) N-pentyl (C) ₅ ) 3-pentyl (C) ₅ ) Amyl (C) ₅ ) Neopentyl (C) ₅ ) 3-methyl-2-butyl (C) ₅ ) Tert-amyl (C) ₅ ) And n-hexyl (C) ₆ ). The term "C _1-6 Alkyl "also includes heteroalkyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atomsThe 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, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

“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 groups are preferred. C (C) _2-6 Examples of alkenyl groups include: vinyl (C) ₂ ) 1-propenyl (C) ₃ ) 2-propenyl (C) ₃ ) 1-butenyl (C) ₄ ) 2-butenyl (C) ₄ ) Butadiene group (C) ₄ ) Pentenyl (C) ₅ ) Pentadienyl (C) ₅ ) Hexenyl (C) ₆ ) And so on. 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 with 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.

“C _2-6 Alkynyl "refers to a straight or branched 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 groups are preferred. C (C) _2-6 Examples of alkynyl groups include, but are not limited to: ethynyl (C) ₂ ) 1-propynyl (C) ₃ ) 2-propynyl (C) ₃ ) 1-butynyl (C) ₄ ) 2-butynyl (C) ₄ ) Pentynyl (C) ₅ ) Hexynyl (C) ₆ ) And so on. 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 with 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.

"halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

Thus, "halo C _1-6 Alkyl "means" C "as described above _1-6 Alkyl ", substituted with one or more halo groups. In some embodiments, halo C _1-4 Alkyl groups are particularly preferred, more preferably halogenated C _1-2 An alkyl group. Exemplary such haloalkyl groups include, but are not limited to: -CF ₃ 、-CH ₂ F、-CHF ₂ 、-CHFCH ₂ F、-CH ₂ CHF ₂ 、-CF ₂ CF ₃ 、-CCl ₃ 、-CH ₂ Cl、-CHCl 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.

“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 groups. Cycloalkyl also includes ring systems in which the cycloalkyl ring is fused to one or more aryl or heteroaryl groups, where the point of attachment is on the cycloalkyl ring, and in such cases the number of carbons continues to represent the number of carbons in the cycloalkyl system. Exemplary such cycloalkyl groups include, but are not limited to: cyclopropyl (C) ₃ ) Cyclopropenyl (C) ₃ ) Cyclobutyl (C) ₄ ) Cyclobutenyl (C) ₄ ) Cyclopentyl (C) ₅ ) Cyclopentenyl (C) ₅ ) Cyclohexyl (C) ₆ ) Cyclohexenyl (C) ₆ ) Cyclohexadienyl (C) ₆ ) Cycloheptyl (C) ₇ ) Cycloheptenyl (C) ₇ ) Cycloheptadienyl (C) ₇ ) Cycloheptatrienyl (C) ₇ ) And so on. Cycloalkyl groups may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

"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 a heterocyclic group containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom as the valence permits. In some embodiments, 3-10 membered heterocycles are preferredA group which is a 3 to 10 membered non-aromatic ring system having a ring carbon atom and 1 to 5 ring heteroatoms; in some embodiments, 3-7 membered heterocyclyl is preferred, 3-6 membered heterocyclyl is more preferred, 4-8 membered heterocyclyl is more preferred, and 5-6 membered heterocyclyl is more preferred. Heterocyclyl further includes ring systems 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 ring systems 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 cases the number of ring members continues to represent the number of ring members in the heterocyclyl ring system. Exemplary heterocyclyl groups include, but are not limited to: aziridinyl, oxetanyl, thietanyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, pyrrolyl-2, 5-dione, piperidinyl, tetrahydropyranyl, dihydropyridinyl, thietanyl (thianyl), piperazinyl, morpholinyl, dithiolanyl, dioxanyl. Exemplary AND C ₆ Aryl ring fused 5-membered heterocyclyl groups (also referred to herein as 5, 6-bicyclic heterocyclyl groups) include, but are not limited to: indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary AND C ₆ Aryl ring fused 6 membered heterocyclyl (also referred to herein as 6, 6-bicyclic heterocyclyl) groups include, but are not limited to: tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. 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.

“C _6-10 Aryl "refers to a group of a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system (e.g., having 6 or 10 pi electrons shared in a cyclic arrangement) having 6 to 10 ring carbon atoms and zero heteroatoms. In some embodiments, the aryl group has six ring carbon atoms ("C ₆ Aryl "; for example, phenyl). In some embodiments, aryl groups have ten ring carbon atoms ("C ₁₀ Aryl "; for example, naphthyl groups, such as 1-naphthyl and 2-naphthyl).Aryl 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 represent the number of carbon atoms in the aryl ring system. The aryl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

"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 pi 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 the valency permits. The heteroaryl bicyclic ring system may include one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems in which the above heteroaryl ring is 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.

In some embodiments, 5-10 membered heteroaryl groups are preferred, and in other embodiments, 5-6 membered heteroaryl groups are particularly preferred. Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to: pyrrolyl, furanyl, and thienyl. Exemplary heteroaryl groups include, but are not limited to: imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl (e.g., 1,2, 4-oxadiazolyl), thiadiazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, azetidinyl, oxepinyl, thiepinyl. Exemplary 5, 6-bicyclic heteroaryl groups include, but are not limited to: indolyl, isoindolyl, indazolyl, benzotriazole, benzothienyl, isobenzothienyl, benzofuranyl, benzisotofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzisothiazolyl, benzothiadiazolyl, indenazinyl and purinyl. Exemplary 6, 6-bicyclic heteroaryl groups include, but are not limited to: naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl and quinazolinyl. Heteroaryl groups may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

“C _6-10 Arylene "and" 5-14 membered heteroarylene "each represent" C "as defined above _6-10 Aryl "and" 5-14 membered heteroaryl ", wherein the other hydrogen is removed to form a divalent group, and may be substituted or unsubstituted. Preferably C _6-10 Arylene and 5-10 membered heteroarylene.

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

Exemplary substituents on carbon atoms include, but are not limited to: halogen, -CN, -NO ₂ 、-N ₃ 、-SO ₂ H、-SO ₃ H、-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 、-CO ₂ H、-CHO、-C(OR ^cc ) ₂ 、-CO ₂ R ^aa 、-OC(＝O)R ^aa 、-OCO ₂ R ^aa 、-C(＝O)N(R ^bb ) ₂ 、-OC(＝O)N(R ^bb ) ₂ 、-NR ^bb C(＝O)R ^aa 、-NR ^bb CO ₂ R ^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 SO ₂ R ^aa 、-NR ^bb SO ₂ R ^aa 、-SO ₂ N(R ^bb ) ₂ 、-SO ₂ R ^aa 、-SO ₂ OR ^aa 、-OSO ₂ R ^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) ₂ R ^aa 、-OP(＝O) ₂ R ^aa 、-P(＝O)(R ^aa ) ₂ 、-OP(＝O)(R ^aa ) ₂ 、-OP(＝O)(OR ^cc ) ₂ 、-P(＝O) ₂ N(R ^bb ) ₂ 、-OP(＝O) ₂ N(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 with 0, 1, 2, 3, 4, or 5R ^dd Group substitution;

or two geminal hydrogen-cover groups on carbon atom=o, =s, =nn (R ^bb ) ₂ 、＝NNR ^bb C(＝O)R ^aa 、＝NNR ^bb C(＝O)OR ^aa 、＝NNR ^bb S(＝O) ₂ R ^aa 、＝NR ^bb Or=nor ^cc Substitution;

R ^aa independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R ^aa The groups combine to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groupIndependently by 0, 1, 2, 3, 4 or 5R ^dd Group substitution;

R ^bb independently selected from: hydrogen, -OH, -OR ^aa 、-N(R ^cc ) ₂ 、-CN、-C(＝O)R ^aa 、-C(＝O)N(R ^cc ) ₂ 、-CO ₂ R ^aa 、-SO ₂ R ^aa 、-C(＝NR ^cc )OR ^aa 、-C(＝NR ^cc )N(R ^cc ) ₂ 、-SO ₂ N(R ^cc ) ₂ 、-SO ₂ R ^cc 、-SO ₂ OR ^cc 、-SOR ^aa 、-C(＝S)N(R ^cc ) ₂ 、-C(＝O)SR ^cc 、-C(＝S)SR ^cc 、-P(＝O) ₂ R ^aa 、-P(＝O)(R ^aa ) ₂ 、-P(＝O) ₂ N(R ^cc ) ₂ 、-P(＝O)(NR ^cc ) ₂ Alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R ^bb The groups combine to form a heterocyclyl or heteroaryl ring wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R ^dd Group substitution;

R ^cc independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R ^cc The groups combine to form a heterocyclyl or heteroaryl ring wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R ^dd Group substitution;

R ^dd independently selected from: hydrogen, deuterium, halogen, carboxyl, -CN, -NO ₂ 、-N ₃ 、-SO ₂ H、-SO ₃ H. -OH, -SH, amino, C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkyl, halogenated C _1-6 Alkoxy, hydroxy substituted C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 4-12 membered heterocyclyl, C _6-10 Aryl, 5-14 membered heteroaryl, or two gem R ^dd Substituents may combine to form =o or =s.

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 、-CO ₂ R ^aa 、-SO ₂ R ^aa 、-C(＝NR ^bb )R ^aa 、-C(＝NR ^cc )OR ^aa 、-C(＝NR ^cc )N(R ^cc ) ₂ 、-SO ₂ N(R ^cc ) ₂ 、-SO ₂ R ^cc 、-SO ₂ OR ^cc 、-SOR ^aa 、-C(＝S)N(R ^cc ) ₂ 、-C(＝O)SR ^cc 、-C(＝S)SR ^cc 、-P(＝O) ₂ R ^aa 、-P(＝O)(R ^aa ) ₂ 、-P(＝O) ₂ N(R ^cc ) ₂ 、-P(＝O)(NR ^cc ) ₂ Alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R's attached to a nitrogen atom ^cc The groups combine to form a heterocyclyl or heteroaryl ring wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R ^dd Substituted with radicals, and wherein R ^aa 、R ^bb 、R ^cc And R is ^dd As described above.

Other definitions

The term "cancer" includes, but is not limited to, the following cancers: breast, ovary, cervix, prostate, testis, esophagus, stomach, skin, lung, bone, colon, pancreas, thyroid, biliary tract, buccal cavity and pharynx (mouth), lip, tongue, oral cavity, pharynx, small intestine, colorectal, large intestine, rectum, brain and central nervous system cancers, glioblastoma, neuroblastoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, adenocarcinoma, adenoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma, renal carcinoma, myelodisorders, lymphomas, hodgkin's disease, hairy cell carcinoma and leukemia. More specifically, cancers include, but are not limited to, HER2 positive metastatic breast cancer, HER2 overexpressed metastatic gastric or gastroesophageal junction adenocarcinoma, non-small cell lung cancer with an Epidermal Growth Factor Receptor (EGFR) gene sensitive mutation, 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, castration-resistant prostate cancer.

The term "treating" as used herein relates to reversing, alleviating, inhibiting the progression of, or one or more symptoms of a disorder or condition to which the term applies. The term "treatment" as used herein relates to the action of a verb treatment, the latter as just defined.

The term "pharmaceutically acceptable salts" as used herein means those carboxylate salts, amino acid addition salts of the compounds of the invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response and the like commensurate with a reasonable benefit/risk ratio, and effective for their intended use, including (if possible) zwitterionic forms of the compounds of the invention.

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

The base addition salts of the 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 can be regenerated by contacting the salt form with the acid in a conventional manner, isolating the free acid. The free acid forms differ somewhat in certain physical properties from their respective salt forms, such as solubility in polar solvents, but for the purposes of the present invention, the salts are also equivalent to their respective free acids.

The salt may be a sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide prepared from an inorganic acid, an acid such as hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, and the like. Representative salts include: hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, and the like. Salts may 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, and the like. Representative salts include acetates, propionates, octanoates, isobutyrates, oxalates, and the like. Pharmaceutically acceptable salts may include cations based on alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Salts of amino acids are also contemplated, such as arginine salts, gluconate, galacturonate, and the like.

The "subject" to be administered includes, but is not limited to: a human (i.e., male or female of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle aged adults, or senior adults)) and/or a non-human animal, e.g., a mammal, e.g., a primate (e.g., cynomolgus monkey, rhesus monkey), cow, pig, horse, sheep, goat, rodent, cat, and/or dog. 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.

"disease," "disorder," and "condition" are used interchangeably herein.

As used herein, unless otherwise indicated, the term "treating" includes an effect that occurs when a subject has a particular disease, disorder, or condition, which reduces the severity of the disease, disorder, or condition, or delays or slows the progression of the disease, disorder, or condition ("therapeutic treatment"), as well as an effect that occurs before the subject begins to have the particular disease, disorder, or condition ("prophylactic treatment").

In general, an "effective amount" of a compound refers to an amount sufficient to elicit a biological response of interest. As will be appreciated by those of ordinary skill in the art, the effective amount of the compounds of the present invention may vary depending on the following factors: for example, biological targets, pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age health and symptoms of the subject. The effective amount includes a therapeutically effective amount and a prophylactically effective amount.

As used herein, unless otherwise indicated, a "therapeutically effective amount" of a compound 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 a disease, disorder, or condition. A therapeutically effective amount of a compound refers to that amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of a disease, disorder or condition. The term "therapeutically effective amount" may include an amount that improves overall treatment, reduces or avoids symptoms or causes of a disease or disorder, or enhances the therapeutic effect of other therapeutic agents.

As used herein, unless otherwise indicated, a "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease, disorder, or condition, or to prevent one or more symptoms associated with a disease, disorder, or condition, or to prevent recurrence of a disease, disorder, or condition. A prophylactically effective amount of a compound refers to an amount of a therapeutic agent, alone or in combination with other agents, that provides a prophylactic benefit in preventing a disease, disorder, or condition. The term "prophylactically effective amount" may include an amount that improves overall prophylaxis, or an amount that enhances the prophylactic effect of other prophylactic agents.

"combination" and related terms refer to the simultaneous or sequential administration of a compound of the invention and another therapeutic agent. For example, the compounds of the invention may be administered simultaneously or sequentially with other therapeutic agents in separate unit dosage forms, or simultaneously with other therapeutic agents in a single unit dosage form.

The compounds of the invention may include one or more asymmetric centers and thus may exist in a variety of stereoisomeric forms, for example, enantiomeric and/or diastereomeric forms. For example, the compounds of the invention may be individual enantiomers, diastereomers, or geometric isomers (e.g., cis and trans isomers), or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. The isomers may be separated from the mixtures by methods known to those skilled in the art, including: chiral High Pressure Liquid Chromatography (HPLC), formation and crystallization of chiral salts; alternatively, preferred isomers may be prepared by asymmetric synthesis.

Those skilled in the art will appreciate that the organic compound may form a complex with a solvent in or from which it reacts or from which it precipitates or crystallizes. 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.

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

The term "hydrate" refers to a compound that binds to water. Generally, the ratio of the number of water molecules contained in a hydrate of a compound to the number of molecules of the compound in the hydrate is determined. Thus, the hydrates of the compounds may be represented by, for example, the general formula R x H2O, wherein R is the compound and x is a number greater than 0. A given compound may form more than one hydrate type, including, for example, monohydrate (x is 1), lower hydrate (x is a number greater than 0 and less than 1, e.g., hemihydrate (R0.5h2o)), and polyhydrate (x is a number greater than 1, e.g., dihydrate (R2H 2O) and hexahydrate (R6H 2O)).

The compounds of the present invention may be in amorphous or crystalline form (polymorphs). Furthermore, the compounds of the present invention may exist in one or more crystalline forms. Accordingly, the present invention includes within its scope all amorphous or crystalline forms of the compounds of the present invention. The term "polymorph" refers to a crystalline form (or salt, hydrate or solvate thereof) of a compound of a particular crystal stacking arrangement. All polymorphs have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, optoelectronic properties, stability and solubility. Recrystallization solvent, crystallization rate, storage temperature, and other factors can lead to a crystalline form predominating. Various polymorphs of a compound can be prepared by crystallization under different conditions.

The invention also includes isotopically-labelled compounds (isotopically-variant) which are identical to those recited in formula (I), but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the 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. The compounds of the invention, prodrugs thereof, and pharmaceutically acceptable salts of the compounds or prodrugs thereof, which contain the isotopes described above and/or other isotopes of other atoms, are within the scope of this invention. Certain isotopically-labeled compounds of the present invention, for example those into which radioactive isotopes (e.g., 3H and 14C) are introduced, are useful in drug and/or substrate tissue distribution assays. Tritium, i.e., 3H and carbon-14, i.e., 14C isotopes, are particularly preferred because they are easy to prepare and detect. Further, substitution with heavier isotopes such as deuterium, i.e., 2H, may be preferred in some circumstances because greater metabolic stability may afford therapeutic benefits such as increased in vivo half-life or reduced dosage requirements. Isotopically-labeled compounds of formula (I) of the present invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes and/or examples and preparations below by substituting a readily available isotopically-labeled reagent for a non-isotopically-labeled reagent.

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

Prodrugs are any covalently bonded compounds of the invention which, when administered to a patient, release the parent compound in vivo. Prodrugs are typically prepared by modifying functional groups in such a way that the modification may be performed by conventional procedures or cleavage in vivo to yield the parent compound. Prodrugs include, for example, compounds of the invention wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when administered to a patient, may cleave to form the hydroxy, amino, or sulfhydryl group. Representative examples of prodrugs therefore include, but are not limited to, acetate, formate and benzoate/amide derivatives of hydroxy, mercapto and amino functional groups of compounds of formula (I). In addition, in the case of carboxylic acid (-COOH), esters such as methyl ester, ethyl ester, and the like can be used. The esters themselves may be active and/or may be hydrolysed under in vivo conditions in the human body. Suitable pharmaceutically acceptable in vivo hydrolysable ester groups include those groups which readily decompose in the human body to release the parent acid or salt thereof.

The invention also provides a pharmaceutical formulation 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 are within the scope of the invention.

Pharmaceutical compositions and kits

In another aspect, the invention provides a pharmaceutical composition comprising a compound of the 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 invention. In some embodiments, the pharmaceutical composition comprises a prophylactically effective amount of a compound of the present invention.

Pharmaceutically acceptable excipients for use in the present invention refer to non-toxic carriers, adjuvants or vehicles that do not destroy the pharmacological activity of the co-formulated compounds. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of the invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (e.g., protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin.

The invention also includes kits (e.g., pharmaceutical packages). Kits provided can include a compound of the invention, other therapeutic agent, and first and second containers (e.g., vials, ampoules, bottles, syringes, and/or dispersible packages or other suitable containers) containing a compound of the invention, other therapeutic agent. In some embodiments, the provided kits may also optionally include a third container containing pharmaceutically acceptable excipients for diluting or suspending the compounds of the invention and/or other therapeutic agents. In some embodiments, the compounds of the invention and other therapeutic agents provided in the first and second containers are combined to form one unit dosage form.

Administration of drugs

The pharmaceutical compositions provided herein may be administered by a number of routes including, but not limited to: oral, parenteral, inhalation, topical, rectal, nasal, buccal, vaginal, by implantation or other means of administration. For example, parenteral administration as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intramuscularly, and intracranial injection or infusion techniques.

Typically, an effective amount of a compound provided herein is administered. The amount of the compound actually administered may be determined by a physician, according to the circumstances involved, 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.

When used to prevent a disorder of the present invention, a subject at risk of developing the disorder is administered a compound provided herein, typically based on physician recommendations and administered under the supervision of a physician, at a dosage level as described above. Subjects at risk for developing a particular disorder generally include subjects having a family history of the disorder, or those subjects determined by genetic testing or screening to be particularly susceptible to developing the disorder.

The pharmaceutical compositions provided herein may also be administered chronically ("chronically"). Chronic administration refers to administration of a compound or pharmaceutical composition thereof over a prolonged period of time, e.g., 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or may continue administration indefinitely, e.g., for the remainder 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 prolonged period of time, e.g., within a therapeutic window.

Various methods of administration may be used to further deliver the pharmaceutical compositions of the present invention. For example, in some embodiments, the pharmaceutical composition may be administered as a bolus, e.g., in order to increase the concentration of the compound in the blood to an effective level. Bolus doses depend on the targeted systemic level of active ingredient through the body, e.g., intramuscular or subcutaneous bolus doses cause slow release of the active ingredient, whereas bolus injections delivered directly to veins (e.g., by IV intravenous drip) can be delivered more rapidly, causing the concentration of the active ingredient in the blood to rise rapidly to effective levels. In other embodiments, the pharmaceutical composition may be administered in the form of a continuous infusion, for example, by IV intravenous drip, thereby providing a steady state concentration of the active ingredient in the subject's body. Furthermore, in other embodiments, a bolus dose of the pharmaceutical composition may be administered first, followed by continuous infusion.

Oral compositions may take the form of bulk liquid solutions or suspensions or bulk powders. More typically, however, the compositions are provided in unit dosage form in order to facilitate accurate dosing. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human patients and other mammals, each unit containing a predetermined quantity of active material suitable for producing the desired therapeutic effect in association with a suitable pharmaceutical excipient. Typical unit dosage forms include pre-filled, pre-measured ampoules or syringes of liquid compositions, or in the case of solid compositions, pills, tablets, capsules and the like. In such compositions, the compound is typically a minor component (about 0.1 to about 50 wt.%, or preferably about 1 to about 40 wt.%) with the remainder being various carriers or excipients and processing aids useful for forming the desired administration form.

For oral doses, a typical regimen is one to five oral doses per day, especially two to four oral doses, typically three oral doses. Using these modes of dosing, each dose provides from about 0.01 to about 20mg/kg of a compound of the invention, with preferred doses each providing from about 0.1 to about 10mg/kg, especially from about 1 to about 5mg/kg.

In order to provide similar blood levels to, or lower than, the use of an injected dose, a transdermal dose is typically selected in an amount of about 0.01 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.

From about 1 to about 120 hours, especially 24 to 96 hours, the injection dosage level is in the range of about 0.1 mg/kg/hour to at least 10 mg/kg/hour. To achieve adequate steady state levels, a preloaded bolus of about 0.1mg/kg to about 10mg/kg or more may also be administered. For human patients of 40 to 80kg, the maximum total dose cannot exceed about 2 g/day.

Liquid forms suitable for oral administration may include suitable aqueous or nonaqueous carriers, buffers, suspending and dispersing agents, colorants, flavors, and the like. Solid forms may include, for example, any of the following components, or compounds having similar properties: binders, for example microcrystalline cellulose, gum tragacanth or gelatin; excipients, for example starch or lactose, disintegrants, for example alginic acid, primogel or corn starch; lubricants, for example, magnesium stearate; glidants, for example, colloidal silicon dioxide; sweeteners, for example, sucrose or saccharin; or a flavoring agent, for example, peppermint, methyl salicylate, or orange flavoring.

Injectable compositions are typically based on sterile saline or phosphate buffered saline for injectable use, 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, the remainder being an injectable excipient or the like.

Transdermal compositions are typically formulated as topical ointments or creams containing the active ingredient. When formulated as ointments, the active ingredients are typically combined with a paraffinic or a water-miscible ointment base. Alternatively, the active ingredient may be formulated as a cream 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 stable skin penetration of the active ingredient or formulation. All such known transdermal formulations and compositions are included within the scope provided by the present invention.

The compounds of the invention may also be administered via a transdermal device. Transdermal administration may thus be achieved using a reservoir (reservoir) or porous membrane type, or a variety of solid matrix patches.

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

The compounds of the present invention may also be administered in sustained release form, or from a sustained release delivery system. A description of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.

The invention also relates to pharmaceutically acceptable formulations of the compounds of the 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, optionally including 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, e.g., sulfobutyl ether β -cyclodextrin, also known as Captisol. See, for example, U.S.5,376,645. In some embodiments, the formulation comprises hexapropyl- β -cyclodextrin (e.g., 10-50% in water).

Combination drug

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

In addition to treatment with the compounds of the invention, conventional surgery or radiation therapy or chemotherapy or immunotherapy are involved. Such chemotherapy may be administered simultaneously, sequentially, or separately with the compounds of the invention, and may contain one or more of the following types of antineoplastic agents:

(i) Antiproliferative/antineoplastic agents used in medical oncology and combinations thereof, such as alkylating agents (e.g., cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulfan, temozolomide, nitrosoureas); antimetabolites (e.g., gemcitabine and antifolates, e.g., fluoropyrimidines (e.g., 5-fluorouracil and tegafur), raltitrexed, methotrexate, cytarabine, hydroxyurea); antitumor antibiotics (e.g., anthracyclines such as doxorubicin, bleomycin, doxorubicin, daunorubicin, 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, camptothecins);

(ii) Cytostatic agents, such as antiestrogens (e.g., tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene, ioxifene (iodoxyfene)), antiandrogens (e.g., bicalutamide, flutamide, nilutamide, cyproterone acetate), LHRH antagonists or LHRH agonists (e.g., goserelin, leuprorelin, and buserelin), progestogens (e.g., megestrol acetate), aromatase inhibitors (e.g., anastrozole, letrozole, vorozole), exemestane), 5 alpha-reductase inhibitors (e.g., finasteride);

(iii) Anti-invasive agents (anti-invasions), 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-yloxy quinazoline [ AZD0530 (secatinib) ], 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), and metalloproteinase inhibitors (such as marimastat), inhibitors of urokinase plasminogen activator receptor function or antibodies to heparanase (hepatanase);

(iv) Inhibitors of growth factor function: such inhibitors include, for example, growth factor antibodies and growth factor receptor antibodies (e.g., anti-erbB 2 antibody trastuzumab [ herceptin ], anti-EGFR antibody panitumumab, anti-erbB 1 antibody cetuximab [ Erbitux, C225]; such inhibitors also include tyrosine kinase inhibitors such as 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-morpholinylpropoxy) -quinazolin-4-amine (gefitinib, ZD 1839), N- (3-ethynylphenyl) -6, 7-bis (2-methoxyethoxy) quinazolin-4-amine (erlotinib, OSI 774), 6-acrylamido-N- (3-chloro-4-fluorophenyl) -7- (3-morpholinylpropoxy) -quinazolin-4-amine (CI 1033), 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 (AMN 107), inhibitors of serine/threonine kinases (e.g., ras/Raf signaling inhibitors such as farnesyl transferase inhibitors such as, for example, BAY 43-6, R90062), and F777762 (SCH 773) Cell signaling inhibitors through mkk and/or AKT kinase, 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, AX 39459), cyclin dependent kinase inhibitors, e.g. CDK2 and/or CDK4 inhibitors;

(v) Anti-angiogenic agents, such as agents that inhibit the action of vascular endothelial growth factor, [ such as the anti-human vascular endothelial growth factor antibody bevacizumab (avastin) and for example VEGF receptor tyrosine kinase inhibitors, such as vandetanib (ZD 6474), vatalanib (PTK 787), sunitinib (SU 11248), axitinib (AG-013136), pazopanib (GW 786034), 4- (4-fluoro-2-methylindol-5-yloxy) -6-methoxy-7- (3-pyrrolidin-1-ylpropoxy) quinazoline (AZD 2171), and compounds that act by other mechanisms (such as ranolamine, inhibitors of integrin αvβ3 function and angiostatin (angiostatin)) ];

(vi) Vascular damaging agents such as combretastatin A4;

(vii) Endothelin receptor antagonists such as ziprasidtan (ZD 4054) or atrasentan;

(viii) Antisense therapeutics, such as those directed to the targets listed above, e.g., ISIS2503 (an anti-ras antisense therapeutic);

(ix) Gene therapy methods, including, for example, methods of replacing an abnormal gene (e.g., abnormal p53 or abnormal BRCA1 or BRCA 2); GDEPT (gene-directed enzyme prodrug therapy) methods, such as those using cytosine deaminase, thymidine kinase, or bacterial nitroreductase; methods of increasing patient resistance to chemotherapy or radiation therapy, such as multiple resistance gene therapy; and

(x) Immunotherapeutic methods, including, for example, in vitro and in vivo methods of 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 of reducing T cell inefficiency; methods of using transfected immune cells (e.g., cytokine-transfected dendritic cells); methods of using cytokine-transfected tumor cell lines; methods of using anti-idiotype antibodies; methods of reducing the function of immunosuppressive cells (e.g., regulatory T cells, myeloid-derived (myeoid-derived) suppressor cells, or IDO (indoleamine 2, 3-deoxyenzyme) expressing dendritic cells); and methods of using a cancer vaccine composed of proteins or peptides derived from a tumor associated antigen (e.g., NY-ESO-1, mAGE-3, WT1, or Her 2/neu).

Examples

Preparation of Compounds example

The abbreviations used hereinafter have the following meanings:

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the starting materials in each of the following synthesis steps are provided for non-commercial reagents. The batches corresponding to the raw materials of each step are not necessarily identical to those described in the synthetic method thereof.

Preparation of intermediates

Synthesis of Compound Int-1

Step 1: compound 1-1 (32 g,98.79 mmol) was dissolved in anhydrous THF (50 mL), sodium hydride (5.93 g,148.19mmol,60% wt) was slowly added under nitrogen protection at 0deg.C, and after stirring for 30 min, a solution of di-tert-butyl dicarbonate (28.03 g,29.50 mL) in anhydrous THF (10 mL) was slowly added dropwise and the reaction stirred at room temperature for 3 hours. After the reaction, water (10 mL) was added to quench the reaction, and the mixture was concentrated under reduced pressure to give a crude product. The crude product was slurried with a mixed solution of PE: ea=10:1 (200 mL). Filtration gave compound 1-2 (41 g, yield 97.9%).

Step 2: compound 1-2 (15 g,35.37 mmol) was dissolved in 1, 4-dioxane (300 mL) and 4- (N, N-dicarboxamide) phenylboronic acid (5.12 g,26.53 mmol), pd (dppf) Cl, was added sequentially under nitrogen ₂ ·CH ₂ Cl ₂ (1.44 g,1.77 mmol) and an aqueous solution (30 mL) of potassium carbonate (9.78 g,70.75 mmol) were reacted by heating at 80℃for 3 hours. After the reaction is completed, cooling to room temperature, and concentrating under reduced pressure to obtain a crude product. The crude product was isolated and purified by column chromatography (PE: ea=1:1 to 0:1) to give compound Int-1 (5.43 g, yield 45.9%). LCMS [ M+H] ⁺ 445.0,447.0。

Synthesis of Compound Int-2

Using the compound Int-1 and the bis-pinacolato borate (9.24 g,36.38 mmol) as raw materials, the compound Int-2 (6.4 g, crude product) was obtained by referring to the synthetic method of the compound Int-1 and was directly used in the next reaction. LCMS [ M+H ] ⁺ 411.1。

Synthesis of Compound Int-3

Step 1: using the compound Int-1 and the compound 3.1 as raw materials, a dark brown oily compound 3-1 (5.6 g, yield 61.5%) was obtained with reference to the synthetic method of the compound Int-1. LCMS [ M+H] ⁺ 598.5。

Step 2: compound 3-1 (3.3 g,5.52 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (46.20 g,30 mL) was added and reacted at room temperature for 2 hours. After the reaction is completed, the mixture is concentrated under reduced pressure to obtain yellow solid crudeCompound Int-3 (2.3 g). LCMS [ M+H] ⁺ 398.1。

Synthesis of Compound Int-4

Step 1: compound 4-1 (4.41 g,15.97 mmol) was dissolved in NMP (50 mL), tert-butyl 4-aminobutyrate hydrochloride (5.0 g,25.55 mmol) and DIPEA (6.19 g,47.91 mmol) were added sequentially and reacted by heating at 100deg.C for 3 hours. Cooled to room temperature, water (150 mL) was added, extraction was performed with ethyl acetate (90 mL), and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Filtering, and concentrating under reduced pressure to obtain crude product. The crude product was purified by column chromatography (PE: ea=1:1-0:1) to give compound 4-2 (6.42 g, yield 96.7%) as a pale yellow solid. LCMS [ M+H] ⁺ 415.2。

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

The following intermediates were synthesized starting from the corresponding amines using a preparation similar to Int-4.

Synthesis of Compound Int-8

Compound 8-1 (1.38 g,8.69 mmol) and compound 8-2 (2 g,7.24 mmol) were dissolved in NMP (20 mL), DIPEA (2.81 g,3.78 mL) was added, and the reaction was heated at 120℃for 3 hours. After the reaction is finished, cooling to room temperature, and concentrating under reduced pressure to obtain a crude product. The crude product was purified by reverse phase preparative HPLC (trifluoroacetic acid system) to give compound Int-8 (1 g, 33.3% yield) as a green solid. LCMS [ M+H] ⁺ 416.2. The following intermediates were synthesized starting from compound 4-1 using a procedure similar to Int-8.

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Synthesis of Compound Int-13

Compound 13-1 (12 g,54.03 mmol) was dissolved in glacial acetic acid (80 mL) under nitrogen, 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, a 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. Filtering, and concentrating the filtrate under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (DCM: meoh=100:1 to 10:1) to give the compound Int-13 as a yellow solid (5 g, 40.9% yield). LCMS [ M+H] ⁺ 226.1。

Synthesis of Compound Int-14

Step 1: under nitrogen, int-2 (718.60 mg,1.46 mmol), int-13 (300 mg,1.33 mmol), pd (dppf) Cl ₂ ·CH ₂ Cl ₂ (108.35 mg, 132.68. Mu. Mol) 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 the mixture was heated at 80℃for 2 hours. After the reaction is completed, cooling to room temperature, and concentrating under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (DCM: meoh=100:1 to 10:1) to give compound 14-1 (330 mg, yield 48.6%) as a yellow solid. LCMS [ M+H] ⁺ 512.5。

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

Synthesis of Compound Int-15

Step 1: the compound Int-3 (100 mg, 251.59. Mu. Mol), (6-bromohexyl) carbamic acid tert-butyl ester (70.50 mg, 251.59. Mu. Mol) and DIPEA (97.55 mg, 131.47. Mu.L) were dissolved in DMF (10 mL) under nitrogen and heated at 70℃for 2 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, quenched with a small amount of saturated aqueous ammonium chloride solution, extracted with ethyl acetate (20 mL), and the organic phase was dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate under reduced pressure gave crude product which was isolated and purified by thin layer chromatography (DCM: meoh=8:1) to give compound 15-1 (90 mg, 59.9% yield) as a yellow solid. LCMS [ M+H ] ⁺ 597.6。

Step 2: compound 15-1 (90 mg, 150.81. Mu. Mol) was dissolved in methylene chloride (6 mL) under nitrogen, and trifluoroacetic acid (1.54 g,1 mL) was added dropwise to the solution, followed by reaction at room temperature for 2 hours. After the completion of the reaction, it was concentrated under reduced pressure to give crude compound Int-15 (70 mg, yield 76.0%) as a yellow solid. LCMS [ M+H] ⁺ 497.4。

Synthesis of Compound Int-16

In anhydrous methanol (10 mL) was dissolved, under nitrogen, 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. Mu.L) and reacted at room temperature for 10 hours. After the reaction, the crude product was obtained by concentration under reduced pressure, and was purified by column chromatography (PE: ea=10:1 to 1:1) to obtain the compound Int-16 (2 g, yield 32.6%) as a white solid. LCMS [ M+H] ⁺ 423.9。

Synthesis of Compound Int-17

Under nitrogen, compound 17-1 (49.90 mg, 355.95. Mu. Mol), compound 17-2 (100 mg, 296.63. Mu. Mol), pd (PPh) were reacted with ₂ C _l2 (20.82 mg, 29.66. Mu. Mol), cuI (11.30 mg, 59.33. Mu. Mol) and triethylamine (2.91 g,4.00 mL) were dissolved in DMF (4 mL) and heated at 80℃for 10 hours. After completion of the reaction, the mixture was cooled to room temperature, diluted with water (20 mL), extracted with ethyl acetate (2X 20 mL), and the organic phase was dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate under reduced pressure gave the crude product which was isolated and purified by column chromatography (DCM: meoh=100:1 to 10:1) to give Int-17 as a yellow oil (110 mg, yield 93.6%). LCMS [ M+H ] ⁺ 397.2。

The following intermediates were synthesized using a procedure similar to that of Int-17.

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Synthesis of Compound Int-21

Step 1: 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) under nitrogen, the reaction solution was cooled to 0deg.C, and a solution of DIAD (685.75 mg, 659.38. Mu.L) in anhydrous tetrahydrofuran (1 mL) was slowly added and reacted at room temperature for 10 hours after completion of the dropwise addition. After the reaction, the reaction mixture was concentrated under reduced pressure to give a crude product, which was purified by column chromatography (PE: ea=5:1 to 1:1) to give compound 21-3 (350 mg, yield 65.5%) as a gray solid.

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

Synthesis of Compound Int-22

Using 7-bromo-1, 2,3, 4-tetrahydroisoquinoline as raw material, adopting synthesis method similar to Int-14 to obtain compound Int-22, LCMS [ M+H ]] ⁺ 398.2。

Synthesis of Compound Int-23

The compound Int-23, LCMS [ M+H ] is prepared by taking the compound Int-3 and tert-butyl bromoacetate as raw materials and referring to the synthesis method of the compound Int-15 ] ⁺ 456.3。

Synthesis of Compound Int-24

The compound Int-24 is obtained by taking the compound 4-1 (and (3-aminopropyl) carbamic acid tert-butyl ester as raw materials and referring to the synthesis method of the compound Int-15, LCMS [ M+H ]] ⁺ 331.1。

The following intermediates were synthesized using a procedure similar to that of Int-15.

Intermediate 28: synthesis of Compound Int-28

Step 1: under nitrogen, compound 1-2 (11 g,25.94 mmol) and 4- (t-butoxycarbonyl) phenylboronic acid (2.82 g,12.71 mmol) were added to a mixed solution of 1, 4-dioxane (100 mL) and water (10 mL), followed by Pd (dppf) Cl ₂ ·CH ₂ Cl ₂ (741.47 mg, 907.95. Mu. Mol) and potassium carbonate (5.02 g,36.32 mmol) were reacted at 80℃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 (3X 50 mL), the organic layers combined and dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate to obtain crude product. The crude product was purified by column chromatography (PE: ea=100:1 to 25:1) to give compound 28-1 (3.2 g, yield 53.0%) as a white solid.

LCMS[M+H] ⁺ 474.0。

Step 2: compound 28-1 (3 g,6.32mmol,1 eq) was dissolved in anhydrous 1, 4-dioxane (100 mL) under nitrogen, then Pd (dppf) Cl was added ₂ ·CH ₂ Cl ₂ (516.48 mg, 632.45. Mu. Mol), anhydrous potassium acetate (1.24 g,12.65 mmol) and pinacol borate (3.21 g,12.65 mmol) were reacted by heating at 100℃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 (20 mL), extracted with dichloromethane (3X 30 mL), the organic layers combined and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate gave 28-2 (5.7 g, crude) as a dark brown gum, which was used directly in the next reaction. LCMS [ M+H ] ⁺ 440.1。

Step 3: under nitrogen, compound 28-2 (2.2 g,5mmol,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), followed by Pd (dppf) Cl ₂ ·CH ₂ Cl ₂ (120.60 mg, 147.68. Mu. Mol) and potassium carbonate (816.39 mg,5.91 mmol) were reacted at 80℃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 (20 mL) and then extracted with dichloromethane (3X 30 mL), the organic layers were combined and dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate to obtain crude product. The crude product was purified by column chromatography (DCM: meO)H=100:1 to 40:1) to give compound 28-3 (650 mg, yield 33.9%) as a white solid. LCMS [ M+H] ⁺ 541.3。

Step 4: compound 28-3 (600 mg,1.10 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (5.54 mmol, 410.84. Mu.L) was added thereto and reacted at room temperature for 1 hour. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain Compound Int-28 (640 mg, crude product). Yellow solid was used directly in the next reaction. LCMS [ M+H] ⁺ 385.2。

Synthesis of Compound Int-29

Step 1: under nitrogen, 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) was dissolved in anhydrous tetrahydrofuran (20 mL), and after cooling to 0deg.C, DIAD (5.52 mmol,1.07 mL) was slowly added thereto, and the reaction was completed at room temperature for 1 hour. After the reaction, the reaction mixture was concentrated under reduced pressure to give a crude product. The crude product was isolated and purified by column chromatography (PE: ea=20:1 to 5:1) to give compound 29-2 (600 mg, yield 94.1%) as a yellow oil. LCMS [ M-Boc+H ] ⁺ 247.1。

Step 2: compound 29-2 (600 mg,1.73 mmol) and hydrazine hydrate (3.46 mmol, 198.07. Mu.L, 85% purity) were dissolved in absolute ethanol (10 mL) and heated at 60℃for 1 hour. After the reaction was completed, it was cooled to room temperature, and concentrated under reduced pressure to give crude compound 29-3 (370 mg, yield 98.8%) which was used directly in the next reaction.

Step 3: 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) under nitrogen and heated at 100deg.C for 3 hr. After the reaction was completed, cooled to room temperature, a small amount of saturated aqueous ammonium chloride solution and methylene chloride were added for extraction, and the organic phase was dried over anhydrous sodium sulfate. Filtering, and concentrating the filtrate under reduced pressure to obtain a crude product. The crude product was isolated and purified by column chromatography (PE: ea=10:1 to 1:1) to give compound 29-4 (400 mg, yield 49.5%) as a yellow oil. LCMS [ M+Na] ⁺ 495.4。

Step 4: compound 29-4 (50 mg, 105.81. Mu. Mol) was dissolved in methylene chloride (10 mL), and trifluoroacetic acid (121.0 mg,1.06 mmol) was added thereto and reacted at room temperature for 1 hour. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure to give crude compound Int-29 (60 mg) as a yellow oil. LCMS [ M+H] ⁺ 373.3。

The following intermediates were synthesized using a procedure similar to that of Int-29.

Synthesis of Compound Int-31

Step 1: compound 31-1 (500 mg,2.17 mmol), phthalic anhydride (321.51 mg,2.17 mmol), DIPEA (420.81 mg,3.26 mmol) was dissolved in anhydrous toluene (15 mL) and heated at 110℃for 10 hours. After the reaction was completed, the mixture was cooled to room temperature, a saturated aqueous ammonium chloride solution was added thereto, extraction was performed with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate under reduced pressure gave compound 31-2 (700 mg, yield 89.5%) as a colorless oil. LCMS [ M+Na] ⁺ 383.2。

Step 2-4 Synthesis of reference Compound Int-29 step 2-4 to give Compound Int-31, LCMS [ M+H ]] ⁺ 401.3。

The following intermediates were synthesized using a procedure similar to that of Int-31.

Intermediate 33: synthesis of Compound Int-33

The compound 33-1 is used as a raw material, and the compound Int-33 is obtained by a synthesis method of a reference compound Int-29 or Int-31, LCMS [ M+H ]] ⁺ 429.2。

Synthesis of Compound Int-34

Step 1: compound 34-1 (5.0 g,28.98 mmol) was dissolved in NMP (100 mL), DIPEA (86.92 mmol,15.14 mL) and 1-tert-butyl-piperazine (6.48 g,34.77 mmol) were added sequentially and reacted by heating at 130℃for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, water and ethyl acetate were added thereto, extraction was performed, and the organic phase was dried over anhydrous sodium sulfate. Filtering, and concentrating the filtrate under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (PE: ea=10:1-3:1) to give compound 34-2 (3.3 g, yield 33.4%) as a yellow solid. LCMS [ M+H ] ⁺ 323.2。

Step 2: compound 34-2 (2.3 g,7.13 mmol) was dissolved in anhydrous methanol (50 mL), and wet palladium on carbon (1.5 g,10% Pd) was slowly added under nitrogen and reacted at room temperature for 2 hours. After the reaction was completed, filtration was carried out, and the filtrate was concentrated under reduced pressure to give compound 34-3 (4 g, crude product) as a brown solid. LCMS [ M-H ]] ^- 291.3。

Step 3: compound 34-3 (4 g, crude) was dissolved in absolute ethanol (100 mL), and 3-ethoxy-3-imino-propionic acid ethyl ester hydrochloride (3.21 g,16.42 mmol) was added and reacted by heating at 60℃for 3 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, and the reaction mixture was concentrated under reduced pressure to obtain a crude product. The crude product was isolated and purified by column chromatography (PE: ea=10:1-0:1) to give compound 34-4 (2.2 g,5.66 mmol) as a yellow solid. LCMS [ M+H] ⁺ 389.2。

Step 4: compound 34-4 (2 g,5.15 mmol) and 3-amino-2-cyanothiophene (767.11 mg,6.18 mmol) were dissolved in anhydrous tetrahydrofuran (30 mL), and a solution of lithium bis (trimethylsilyl) amide in tetrahydrofuran (1M, 20.59 mL) was added dropwise at 0℃and the reaction was heated at 45℃for 2 hours. After the reaction is completed, saturated ammonium chloride solution is added(20 mL) was quenched, diluted with water, extracted with ethyl acetate and the organic phase dried over anhydrous sodium sulfate. Filtering, and concentrating under reduced pressure to obtain crude product. The crude product was purified by column chromatography (PE: ea=10:1-1:1) to give compound 34-5 (900 mg, yield 37.5%) as a yellow solid. LCMS [ M+H ] ⁺ 467.1。

Step 5: compound 34-5 (50 mg, 107.17. Mu. Mol) was dissolved in methylene chloride (5 mL), and trifluoroacetic acid (13.51 mmol,1 mL) was added thereto and stirred at room temperature for 2 hours. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure to give Compound Int-34 (50 mg, crude product) as a brown solid. LCMS [ M+H] ⁺ 366.9。

Synthesis of Compound Int-35

Step 1: compound Int-34 (65.56 mg, 136.45. Mu. Mol) was dissolved in DMF (5 mL), and tert-butyl bromoacetate (109.16. Mu. Mol, 16.13. Mu. L) and DIEA (409.34. Mu. Mol, 71.30. Mu. L) were slowly added and reacted at 0℃for 3 hours. After completion of the reaction, water (15 mL) was added thereto for dilution, ethyl acetate (3X 10 mL) was used for extraction, and the organic phase was dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure gave crude compound 35-1 (43 mg, yield 65.6%) as a brown oil. LCMS [ M+H] ⁺ 481.2。

Step 2: compound 35-1 (43 mg, 89.47. Mu. Mol) was dissolved in a 1, 4-dioxane solution (3 mL) of hydrochloric acid and reacted at room temperature for 2 hours. After the reaction, the reaction solution was directly concentrated under reduced pressure to give Compound Int-35 (180 mg, crude product) as a brown solid. LCMS [ M+H] ⁺ 425.2。

Synthesis of Compound Int-36

The compound 36-1 is used as a raw material and is prepared by the same method as Int-13. LCMS [ M+H] ⁺ 242.0。

Synthesis of Compound Int-37

The compound Int-36 is used as a raw material and is prepared by adopting the same method as Int-14. LCMS [ M+H ] ⁺ 428.2。

Synthesis of Compound Int-38

The preparation method is the same as that of Int-8 by taking compound 38-1 and compound 8-2 as raw materials. LCMS [ M+H] ⁺ 420.2。

Synthesis of Compound Int-39

Step 1: 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) under nitrogen, the mixture was cooled to 0deg.C, diisopropyl azodicarboxylate (884.85 mg,4.38 mmol) was then slowly added and the mixture was stirred at 0deg.C for 5 hours. After the reaction, the reaction mixture was directly concentrated under reduced pressure to give a crude product. The crude product was purified by reverse phase column chromatography (formic acid system) to give compound 39-3 (100 mg, yield 14.5%) as a white solid. LCMS [ M+Na] ⁺ 495.4。

Step 2: compound 39-3 (100 mg, 211.63. Mu. Mol), trifluoroacetic acid (3.08 g,27.01mmol,2.00 mL) was dissolved in anhydrous dichloromethane (10 ML) under nitrogen, and the mixture was stirred at 25℃for 10 hours. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure to give Compound Int-39 (80 mg, yield 90.8%) as a yellow oil. LCMS [ M+H] ⁺ 417.2。

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

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

¹ H NMR(400MHz,DMSO-d ₆ )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,2H),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(dd,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),3.80–3.69(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)。

Example 2: synthesis of Compounds EX-2 to EX-16

The compounds EX-2 to EX-16 can be synthesized by a similar method and corresponding starting materials to those of example 1.

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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)

Compound Int-15 (70 mg, 140.95. Mu. Mol), compound 4-1 (38.93 mg, 140.95. Mu. Mol) and DIPEA (704.73. Mu. Mol, 122.75. Mu.L) were dissolved in dimethyl sulfoxide (3 mL) under nitrogen, and the mixture was heated at 100℃for 5 hours. After the completion of the reaction, the reaction mixture was cooled to room temperature and purified by reverse phase preparative HPLC (hydrochloric acid system) to give compound EX-17 hydrochloride (4.68 mg, yield 4.2%) as a yellow solid. LCMS [ M+H] ⁺ 753.4。

¹ H NMR(400MHz,DMSO-d ₆ )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)。

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)

The compounds EX-18 and LCMS [ M+H ] are prepared by taking the compounds Int-3 and Int-16 as raw materials and referring to the synthesis method of EX-17] ⁺ 739.4。

¹ H NMR(400MHz,DMSO-d ₆ )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)。

Example 5:4- (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)]Synthesis of pyrazin-7-yl) -N, N-dimethylbenzamide (EX-19)

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

¹ H NMR(400MHz,DMSO-d ₆ )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,1H),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)。

Example 6: synthesis of Compounds EX-20 to EX-21

The compounds EX-20 to EX-21 can be synthesized by a similar method and corresponding starting materials to those of example 5.

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)

Compounds Int-28 (50 mg, 100.31. Mu. Mol) and Int-27 (38.20 mg, 83.33. Mu. Mol) were added to DMF (1 mL), then EDCI (28.84 mg, 150.47. Mu. Mol) and DMAP (36.76 mg, 300.93. Mu. Mol) were added and reacted at room temperature for 12 hours. After completion of the reaction, 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. Filtering, concentrating the filtrate to obtain crude product. The crude product was purified by reverse phase prep HPLC (formic acid system) to give compound EX-22 (11.2 mg, yield 18.9%) as a yellow solid. LCMS [ M+H ] ⁺ 711.4。

¹ H NMR(400MHz,DMSO-d ₆ )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)。

Example 8: synthesis of Compounds EX-23 to EX-027

The compounds EX-23 to EX-27 can be synthesized by the same method and the corresponding raw materials as in example 7.

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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)

The compound EX-28, LCMS [ M+H ], is prepared by taking the compound Int-6 and the compound Int-34 as raw materials and referring to the synthesis method of EX-1] ⁺ 736.2。

¹ H NMR(400MHz,DMSO-d ₆ )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)。

Example 10: synthesis of 2- (4- (2- (7-amino-5-oxo-4, 5-dihydrothien [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)

The compound EX-29 and LCMS [ M+H ] are prepared by taking the compound Int-35 and the compound Int-24 as raw materials and referring to the synthesis method of EX-1] ⁺ 737.5。 ¹ H NMR(500MHz,DMSO-d ₆ )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)。

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

The compound EX-30 is prepared by taking the compound Int-3 and the compound Int-38 as raw materials and referring to the synthesis method of EX-1. LCMS [ M+H] ⁺ 799.5。 ¹ H NMR(400MHz,DMSO-d ₆ )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)。

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)

The compound EX-31 is prepared by taking the compound Int-3 and the compound Int-39 as raw materials and referring to the synthesis method of EX-1. LCMS [ M+H] ⁺ 796.6。 ¹ H NMR(400MHz,DMSO-d ₆ )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)。

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)

The compound EX-32 is prepared by taking the compound Int-37 and the compound Int-10 as raw materials and referring to a synthesis method of EX-1. LCMS [ M+H] ⁺ 825.6。

¹ H NMR(400MHz,DMSO-d ₆ )δ12.43(brs,1H),11.09(brs,1H),8.96(s,1H),8.53(s,1H),8.39(d,J＝8.1Hz,2H),7.73–7.61(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)。

Pharmacological activity and use

The activity of the compounds of the invention can be demonstrated using the following assay methods.

HPK1 HiBiT protein label detection method

Human acute T lymphocyte leukemia cells Jurkat stably expressing HPK1-HiBiT marker protein were cultured in dishes in a medium of RPMI 1640 (Gibco, product No. 11875093) containing 10% fetal bovine serum (FBS, gibco, product No. 10099141) in a 0.1% penicillin/streptomycin solution (P/S) at 37℃with a relative humidity of 95% and 5% CO ₂ Is cultured in a sterile incubator. Cells in exponential growth phase were inoculated into 96-well plates (Corning, product No. 3903) at a density of 20000 cells/well, and 100 μl of medium was added per well. After 24 hours, compounds of the different concentrations disclosed herein were added to wells of inoculated cells (10 concentration gradients were set for each compound, with a maximum assay concentration of 10 μm, 4-fold gradient dilution) and the final DMSO concentration was 0.1%. After 24 hours, 50. Mu.L of Nano-HiBiT luciferase assay reagent (Progema, product number N3040) and the fluorescent signal was read using Envision. Fitting the data to a dose response curve using GraphPad print 8 resulted in an IC for the test compound ₅₀ Values.

TABLE 2 IC of partial Compounds of the invention for HPK1-HiBiT Signal ₅₀ Value of

Numbering of compounds	IC ₅₀ (nM)	Numbering of compounds	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

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

Wherein HC90-51 (see WO 2020/227325) is a positive control compound having the following structural formula:

the foregoing is a further detailed description of the invention in connection with the preferred embodiments, and it is not intended that the invention be limited to the specific embodiments described. It will be apparent to those skilled in the art that several simple deductions or substitutions may be made without departing from the spirit of the invention, and these should be considered to be within the scope of the invention.

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof,

HPK1 Ligands——LIN——EL (I)

wherein HPK1 Ligands are Ligands that bind HPK1, such as inhibitors of HPK1, represented by formula (II) and formula (II'):

is a single bond or a double bond;

is the junction of HPK1 links and LIN;

X ¹ 、X ² 、X ³ 、X ⁴ each independently selected from N or CR ^X ；

R' are identical or different and R ^* Identical or different, R', R ^* 、R ¹ Each independently is hydrogen, deuterium, NR ^a R ^b Hydroxy, 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 heterocyclyl, 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 form C _3-8 Cycloalkyl or 4-12 membered heterocyclyl; the C is _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 heterocyclyl, C _6-10 Aryl or 5-14 membered heteroaryl optionally substituted with 1, 2, 3 or 4R ";

R ^# is a chemical bond, O, S, NR ^N 、C(O)、C(O)NR ^N 、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 Alkynylene, C _3-8 Cycloalkylene, 4-12 membered heterocyclylene, C _6-10 Arylene or 5-16 membered heteroarylene; the C is _1-6 Alkylene, C _2-6 Alkenylene, C _2-6 Alkynylene, C _3-8 Cycloalkylene, 4-12 membered heterocyclylene, C _6-10 Arylene or 5-16 membered heteroarylene optionally substituted with 1, 2, 3 or 4R ";

Z ¹ is O, S, N or a C atom, optionally substituted with one or two R ^Z1 Substituted;

Z ² is O, S, N or a C atom, optionally substituted with one or two R ^Z2 Substituted;

Z ³ is O, S, N or a C atom, optionally substituted with one or two R ^Z3 Substituted;

Z ⁴ is O, S, N or a C atom, optionally substituted with one or two R ^Z4 Substituted;

or, Z ¹ Absence of Z ² To and Z ¹ On the attached C atom;

R ^Z1 、R ^Z2 、R ^Z3 、R ^Z4 each independently is absent, hydrogen, deuterium, NR ^a R ^b Hydroxy, halogen, cyano, C (O) NR ^a R ^b 、COR ^d 、-(C(R ⁴ ) ₂ ) _1-6 -R ⁴ ', halogenated C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl, C _1-6 Alkoxy, C _2-6 Alkenyl, C _2-6 Alkynyl, -O-C _3-8 Cycloalkyl, C _3-8 Cycloalkyl, 4-12 membered heterocyclyl, C _6-10 Aryl or 5-14 membered heteroaryl; or, Z ¹ And two R ^Z1 Together form c= O, C _3-8 Cycloalkyl or 4-12 membered heterocyclyl; or, Z ² And two R ^Z2 Together form c= O, C _3-8 Cycloalkyl or 4-12 membered heterocyclyl; or, Z ³ And two R ^Z3 Together form c= O, C _3-8 Cycloalkyl or 4-12 membered heterocyclyl; or, Z ⁴ And two R ^Z4 Together form c= O, C _3-8 Cycloalkyl or 4-12 membered heterocyclyl; the C is _1-6 Alkyl, halogenated C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl, C _1-6 Alkoxy, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 4-12 membered heterocyclyl, C _6-10 Aryl or 5-14 membered heteroaryl optionally substituted with 1, 2, 3 or 4R ";

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) _1-2 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 、C _1-6 Alkylene, halogenated C _1-6 Alkylene, C _1-6 Alkyloxy, C _2-6 Alkenylene, C _2-6 Alkynylene, C _3-8 Cycloalkylene, 4-12 membered heterocyclylene, C _6-10 Arylene or 5-16 membered heteroarylene; the C is _1-6 Alkylene, halogenated C _1-6 Alkylene, C _1-6 Alkyloxy, C _2-6 Alkenylene, C _2-6 Alkynylene, C _3-8 Cycloalkylene, 4-12 membered heterocyclylene, C _6-10 Arylene or 5-16 membered heteroarylene optionally substituted with 1, 2, 3 or 4R ^## Substituted;

R ^e Identical or different, R ^f Identical or different, R ^e 、R ^f 、R ^#2 Each independently is hydrogen, deuterium, NR ^a R ^b Hydroxy, 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 substituted C _1-6 Alkyl, C _1-6 Alkoxy, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 4-12 membered heterocyclyl, 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 form C _3-8 Cycloalkyl or 4-12 membered heterocyclyl; by a means ofThe C is _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 heterocyclyl, C _6-10 Aryl or 5-14 membered heteroaryl optionally substituted with 1, 2, 3 or 4R ^## Substituted;

R ^#1 is a chemical bond, 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 Alkyloxy, C _2-6 Alkenylene, C _2-6 Alkynylene, C _3-8 Cycloalkylene, 4-12 membered heterocyclylene, C _6-10 Arylene or 5-16 membered heteroarylene; or, two R ^Y2 And Y is equal to ² Together form carbonyl, C _3-8 Cycloalkyl, 4-12 membered heterocyclyl, C _6-10 Aryl or 5-14 membered heteroaryl; or L and Y ¹ 、Y ² 、Y ³ 、Y ⁴ One is connected with Y ⁵ 、Y ⁶ Together with the substituents to which they are attached form C _3-8 Cycloalkyl, 4-12 membered heterocyclyl, C _6-10 Aryl or 5-14 membered heteroaryl; or, Y ² Is absent, L and Y ¹ 、Y ³ 、Y ⁴ 、Y ⁵ 、Y ⁶ One of the remaining ring atoms being joined to adjacent ring atoms together with the substituents to which they are attached to form C _3-8 Cycloalkyl, 4-12 membered heterocyclyl, C _6-10 Aryl or 5-14 membered heteroaryl; the C is _1-6 Alkylene, C _2-6 Alkenylene, C _2-6 Alkynylene, C _3-8 Cycloalkylene, 4-12 membered heterocyclylene, C _6-10 Arylene or 5-16 membered heteroarylene is unsubstituted or optionally substituted with 1, 2, 3 or 4R ^## Substituted;

R ⁰ selected from: c (C) _3-8 Cycloalkylene, 4-12 membered heterocyclylene, C _6-10 Arylene or 5-16 membered heteroarylene; the C is _3-8 Cycloalkylene, 4-12 membered heterocyclylene, C _6-10 Arylene or 5-)16 membered heteroarylene optionally substituted with 1, 2, 3, 4 or more R ^## Substituted;

LIN is represented as-L ¹ -L ² -L ³ -……-L ^r -,

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 substituted C _1-6 Alkyl, C _1-6 Alkoxy, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 4-12 membered heterocyclyl, C _6-10 Aryl or 5-14 membered heteroaryl; or, R ⁶ 、R ⁶ ' together with the attached C forms c= O, C _3-8 Cycloalkyl or 4-12 membered heterocyclylene; the C is _1-6 Alkyl, halogenated C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl, C _1-6 Alkoxy, C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-8 Cycloalkyl, 4-12 membered heterocyclyl, C _6-10 Aryl or 5-14 membered heteroaryl optionally substituted with 1, 2, 3, 4 or more R ^## Taken outSubstitution;

t ₁ 、t ₂ Each independently is 0, 1 or 2;

r is a positive integer of 4-20;

EL is represented by general formula (III):

K ⁴ is N or CR ^K4 ；

provided that the conditions are that,

(1) In the formula (II), when Z ¹ In the absence of:

and whenIs->When X is ¹ 、X ² 、X ³ 、X ⁴ At least two of which are N;

(2) In formula (II '), L' is not

2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof,

further selected from:

3. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof,further selected from:

Y ⁷ is N or=CR ^Y ；Y ⁹ Is N or=CR ^Y ；Y ⁸ Is O or S;

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, halo C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl, NR ^a R ^b 、CONR ^a R ^b 、C _3-8 Cycloalkyl, -O- (CH) ₂ ) _0-4 -C _3-8 Cycloalkyl, 4-7 membered heterocyclyl, phenyl or 5-14 membered heteroaryl.

4. A compound of the formula (I) as defined in claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate thereofSolvates, hydrates, polymorphs, prodrugs or isotopic variants, and mixtures thereof, R ⁰ Expressed as:

is R ⁰ Attachment point to L' -, I->Is R ⁰ A connection point to LIN;

Z ⁵ 、Z ⁶ 、Z ⁷ each independently selected from N or CR ^Z ’；

or, two R ^Z ' together with the C atom to which it is attached form c=o;

preferably, R ^Z ' is selected from: c (C) _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkyl or hydroxy substituted C _1-6 An alkyl group; preferably R ^Z ' is hydrogen, halogen, cyano, amino or amido;

5. A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, HPK1 Ligands being further represented by:

Z ¹¹ 、Z ¹² each independently is represented by N or CR ^Z ’，Q ¹ 、Q ² 、Q ³ Each independently is represented by N or CR ^Q ；

R ^Z ’、R ^Q Each independently selected from hydrogen, deuterium, halogen, C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkyl, hydroxy substituted C _1-6 Alkyl, NR ^a R ^b 、CONR ^a R ^b 、C _3-6 Cycloalkyl, -O- (CH) ₂ ) _0-4 -C _3-6 Cycloalkyl or 4-or 5-membered heterocyclyl;

R ^Z "selected from C _1-6 Alkylene, C _1-6 Alkyleneoxy group, O, S, NR ^N 、CONR ^N 、SO _1-2 NR ^N CO or C _3-6 A cycloalkylene group;

in the general formula (II-f), L and Y ¹ The ring being attached to, or with, Y ⁷ In which the ring is connectedAnd (5) connecting.

6. A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, EL being further represented by:

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, halo C _1-6 Alkyl or hydroxy substituted C _1-6 Alkyl (preferably hydrogen, methyl or ethyl);

K ⁴ is CH or N, K ³ Is NR (NR) ^K3 、CH ₂ Or CO;

R _g selected from hydrogen, deuterium, halogen, cyano, amino, amido, dimethylamino, dicarboxamido, C _1-6 Alkyl, C _1-6 Alkoxy, halo C _1-6 Alkyl or hydroxy substituted C _1-6 An alkyl group; r is R _g Preferably hydrogen, C _1-6 Alkyl and halogenated C _1-6 Alkyl, further preferred is hydrogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, trifluoromethyl, trifluoroethyl or cyano.

7. A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, further represented by:

/>

8. the compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof,

L ¹ selected from: chemical bond, O, S, NR ^N 、CH ₂ 、C(CH ₃ ) ₂ 、CH ₂ CH ₂ 、CH ₂ CH ₂ CH ₂ 、CH ₂ CH ₂ CH ₂ CH ₂ 、OCH ₂ CH ₂ 、CH ₂ CH ₂ O、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 Ethenylene, ethynylene, phenylene, pyridylene, pyrimidinylene, pyrazinylene, pyridazinylene, piperazinylene, piperidinylene, triazolylene, tetrazolylene, pyrazolylene, imidazolylene, C _3-6 Ring-shaped ringAlkyl, 4-12 membered heterocyclylene,

L ³ 、L ⁴ each independently selected from: chemical bond, O, S, NR ^N 、CH ₂ 、CH ₂ CH ₂ 、CH ₂ CH ₂ CH ₂ 、CH ₂ CH ₂ CH ₂ CH ₂ 、CO、CONR ^N 、NR ^N CO、OCH ₂ CH ₂ 、CH ₂ CH ₂ O, ethenylene, ethynylene, phenylene, pyridinyl, pyrimidinylene, piperazinylene, triazolylene, tetrazolylene, pyrazolylene, imidazolylene;

L ⁷ selected from: o, S, NH, N (methyl), CH ₂ Ethenylene, 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 (NR) ^N SO _1-2 NR ^N ；

9. A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, selected from table 1.

10. A pharmaceutical composition comprising a compound according to any one of claims 1-9, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, and a pharmaceutically acceptable excipient; preferably, it also contains other therapeutic agents.

11. Use of a compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, for the preparation of a medicament for the treatment and/or prophylaxis of cancer.

12. The use of claim 11, wherein the cancer is selected from bladder cancer, breast cancer, colorectal cancer, gastric cancer, head and neck squamous cell carcinoma, hodgkin's lymphoma, melk-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 cancer, tumors that are resistant to the targeted drug; or a tumor or disease that depends on the HPK1 mutein.