CN114907377A

CN114907377A - Condensed tetracyclic compound, preparation method and medical application thereof

Info

Publication number: CN114907377A
Application number: CN202210122528.0A
Authority: CN
Inventors: 李心; 冯斌强; 蔡国栋; 贺峰; 陶维康
Original assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Current assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Priority date: 2021-02-10
Filing date: 2022-02-09
Publication date: 2022-08-16

Abstract

The present disclosure relates to fused tetracyclic compounds, methods for their preparation, and their use in medicine. Specifically, the disclosure relates to a fused tetracyclic compound shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound and application of the compound as a therapeutic agent, in particular to application of the compound in preparing a medicine for inhibiting HPK 1. Wherein each group in the general formula (I) is defined in the specification.

Description

Condensed tetracyclic compound, preparation method and medical application thereof

Technical Field

The disclosure belongs to the field of medicines, and relates to a condensed tetracyclic compound, a preparation method thereof and application thereof in medicines. In particular, the disclosure relates to fused tetracyclic compounds shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the compounds, and application of the fused tetracyclic compounds in preparation of drugs for inhibiting HPK 1.

Background

Anticancer therapy has moved from chemotherapy, targeted therapy, to the years of immunotherapy. Targets for tumor immunotherapy mainly include immune checkpoints, immune agonists, tregs, macrophages, tumor microenvironment metabolites such as IDO, A2AR pathway, and the like. Hematopoietic Progenitor cell Kinase 1(Hematopoietic promoter Kinase1, abbreviated as HPK 1; also known as Mitogen-activated protein Kinase kinase Kinase kinase Kinase1 or Mitogen-activated protein Kinase kinase Kinase1, abbreviated as MAP4K1) is a negative regulator in T cells, and has a negative feedback regulation function after TCR activation, which is related to T cell exhaustion. The signal paths that are more clearly studied are: upon binding of the TCR to the MHC-peptide, LAT is phosphorylated, recruiting the GADS-SLP76 complex, resulting in phosphorylation and pathway activation of downstream PLCs. Meanwhile, ZAP70 phosphorylates the Y381 site of HPK1, which binds to the SH2 region of SLP76, thus phosphorylating the S376 site of the latter. SLP76S376 phosphorylates recruit 14-3-3, leading to ubiquitination, resulting in disassembly of the entire TCR signalosome.

HPK1 is currently considered to be a better immunotherapy target for the following 3-point reasons: (1) the HPK1 expression profile is limited to immune cells, and the safety is good; (2) HPK1 has multiple negative regulation effects at different stages of cancer-immune cycle, and inhibition of HPK1 can regulate the immunosuppressive functions of NK cells, DC cells and T cells and can also regulate B cell activation, wherein T cell activation is the most studied; (3) HPK1 kinase activity is important in suppressing anti-cancer immune responses.

Research shows that the expression of HPK1 is related to T cell exhaustion signature, including CD3E, PD1, CTLA4, TIM-3, LAG-3 and TIGIT, and the high expression of HPK1 is related to short survival time. TCGA PanCancer database analysis showed a positive correlation between HPK1 (but not other MAP4K family members) expression and PD 1.HPK1 was up-regulated in exhausted T cells, and HPK1, TIM3 and LAG3 were more highly expressed in PD1 high T cells than PD1 low T cells. In contrast, HPK1 was down-regulated in CD4+ T cells of Systemic Lupus Erythematosus (SLE) patients, and the SLEDAI score was negatively correlated with HPK1 mRNA levels. HPK1 expression was also down-regulated in peripheral blood cells of psoriatic arthritis (PsA) patients.

The HPK1 knockout mice did not have any abnormalities at rest. Once TCR was activated, mice with either HPK1 knockdown, HPK1 kinase dead knock-in, or SLP76S376A knock-in, gave similar results and activated immune responses. HPK1 deficient mice are more susceptible to Experimental Autoimmune Encephalomyelitis (EAE). HPK1 kinase activity regulates TCR signaling and cytokine secretion in vitro; inhibition of HPK1 may alleviate PGE2 and adenosine-mediated immunosuppression. The HPK1 kinase dead mouse can inhibit the growth of tumors in vivo, and the anti-tumor effect of the HPK 1-/-mouse is almost disappeared after removing CD8+ or CD4+ T cells, which indicates that the T cells mediate most of the immunosuppressive effect of HPK 1.

The data of the mice with HPK1 knockout and kinase dead knock-in indicate that HPK1 mainly acts through kinase activity, but some documents report that the scaffold also has certain functions, so that the drug development idea for inhibiting HPK1 mainly comprises kinase inhibitors and also comprises some PROTAC molecules.

Related patents which have been disclosed so far are WO2016205942A1, WO2019238067A1, WO2021013083A1 and WO2021000925A1, among others.

Disclosure of Invention

The object of the present disclosure is to provide a compound represented by the general formula (I):

wherein:

ring a is selected from aryl, heterocyclyl and heteroaryl;

T ¹ is CR ^T1 Or a nitrogen atom;

G ³ and G ⁴ Are the same or different and are each independently CR ¹ Or a nitrogen atom;

G ⁸ is CR ^G8 Or a nitrogen atom;

G ¹ and G ² Are the same or different and are each independently selected fromCR ² 、NR ³ Nitrogen atom, oxygen atom and sulfur atom;

G ⁵ and G ⁶ Are the same or different and are each independently selected from CR ⁴ R ⁵ 、NR ⁶ Oxygen atom and sulfur atom;

G ⁷ selected from the group consisting of CR ^G7a R ^G7b 、NR ^G7c Oxygen atom and sulfur atom;

G ⁹ selected from the group consisting of CR ^G9a R ^G9b 、NR ^G9c Oxygen atom and sulfur atom;

r is the same or different and is each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy and hydroxyalkyl; or

Two R together form oxo;

R ⁰ 、R ³ 、R ⁶ 、R ^G7c and R ^G9c Are the same or different and are each independently selected from the group consisting of hydrogen atoms, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups;

R’、R ¹ 、R ^T1 、R ^G8 and R ² Are the same or different and are each independently selected from the group consisting of a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, - (CH) ₂ ) _m NR ⁷ R ⁸ 、-OR ⁹ Nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ⁴ 、R ⁵ 、R ^G7a 、R ^G7b 、R ^G9a and R ^G9b Are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a,Alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; or

R ⁴ And R ⁵ 、R ^G7a And R ^G7b Or R ^G9a And R ^G9b Wherein one pair together form oxo;

R ⁷ and R ⁸ Are the same or different and are each independently selected from the group consisting of hydrogen atoms, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups; or

R ⁷ And R ⁸ Together with the nitrogen atom to which it is attached, form a heterocyclyl group, which heterocyclyl group is optionally substituted with one or more of halo, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy and hydroxyalkyl;

R ⁹ selected from the group consisting of hydrogen atoms, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups;

m is 0, 1,2,3 or 4;

q is 0, 1,2,3 or 4; and is

n is 0, 1,2,3, 4,5 or 6.

Another aspect of the present disclosure relates to a compound represented by the general formula (I-1) or (I-2):

wherein, ring A, T ¹ 、G ¹ To G ⁹ 、R’、R ⁰ R, q and n are as defined in formula (I).

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), (I-1) or (I-2) or a pharmaceutically acceptable salt thereof,

wherein

Is composed of

T ³ Is CR ^T3 Or a nitrogen atom, T ⁵ 、T ⁶ And T ⁷ Are the same or different and are each independently CR ¹⁰ Or a nitrogen atom;

T ² and T ⁴ Are the same or different and are each independently selected from CR ¹¹ 、NR ¹² Nitrogen atom, oxygen atom and sulfur atom;

R ¹⁰ 、R ^T3 and R ¹¹ Are the same or different and are each independently selected from the group consisting of a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, - (CH) ₂ ) _m NR ⁷ R ⁸ 、-OR ⁹ Nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ¹² selected from the group consisting of hydrogen atoms, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups;

R ⁷ 、R ⁸ 、R ⁹ and m is as defined in the general formula (I), (I-1) or (I-2).

In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, wherein

Is composed of

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, wherein ring A is selected from the group consisting of 5-6 membered heteroaryl, 5-6 membered heterocyclyl and phenyl.

In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, wherein R is ⁰ Selected from hydrogen atoms, C _1-6 Alkyl and C _1-6 A haloalkyl group; preferably, R ⁰ Is a hydrogen atom.

In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, wherein G ¹ Is a nitrogen atom.

In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, wherein G ² Is NH.

In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, wherein G ⁷ Is CR ^G7a R ^G7b ，R ^G7a And R ^G7b As defined in general formula (I), (I-1) or (I-2); preferably, G ⁷ Is CH ₂ 。

In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, wherein G ⁸ Is a nitrogen atom.

In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, wherein T ² Is CR ¹¹ ，R ¹¹ As defined in general formula (I), (I-1) or (I-2); preferably, R ¹¹ Selected from hydrogen atoms, halogens and C _1-6 An alkyl group; more preferably, T ² Is CH.

In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, wherein T ³ Is CR ^T3 ，R ^T3 As defined in general formula (I), (I-1) or (I-2); preferably, R ^T3 Selected from hydrogen atoms, halogens and C _1-6 An alkyl group; more preferably, T ³ Is CH.

In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, wherein T ⁴ Is an oxygen atom or a sulfur atom; preferably, T ⁴ Is a sulfur atom.

In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, wherein T ⁵ Is CR ¹⁰ ，R ¹⁰ As defined in general formula (I), (I-1) or (I-2); preferably, R ¹⁰ Selected from hydrogen atoms, halogens and C _1-6 An alkyl group; further preferably, T ⁵ Is CR ¹⁰ ，R ¹⁰ Is a hydrogen atom or a halogen; more preferably, T ⁵ Is CH or CF; most preferably, T ⁵ Is CH.

In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, wherein T ⁶ Is CR ¹⁰ ，R ¹⁰ Such as a cartoonAs defined in formula (I), (I-1) or (I-2); preferably, R ¹⁰ Selected from hydrogen atoms, halogens and C _1-6 An alkyl group; more preferably, T ⁶ Is CH.

In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, wherein T ⁷ Is CR ¹⁰ ，R ¹⁰ As defined in general formula (I), (I-1) or (I-2); preferably, R ¹⁰ Selected from hydrogen atoms, halogens and C _1-6 An alkyl group; more preferably, T ⁷ Is CH.

Another aspect of the present disclosure relates to a compound represented by formula (II) or (III):

wherein:

T ¹ 、G ³ 、G ⁴ 、G ⁵ 、G ⁶ 、G ⁹ r, R', q and n are as defined in formula (I).

The disclosure also relates to a compound represented by general formula (II-1), (II-2), (III-1) or (III-2) or a pharmaceutically acceptable salt thereof:

In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1), (I-2), (II-1), (II-2), (III-1), or (III-2), or a pharmaceutically acceptable salt thereof, wherein G is ⁵ Is CR ⁴ R ⁵ Or an oxygen atom; and/or G ⁶ Is CR ⁴ R ⁵ Or an oxygen atom; preferably, G ⁵ And G ⁶ One of them is CR ⁴ R ⁵ And the other is an oxygen atom; r ⁴ And R ⁵ Such as general formula (I), (I-1), (I-2), (II-1), (II-2), (III)III-1) or (III-2); more preferably, G ⁵ And G ⁶ One of them is CH ₂ And the other is an oxygen atom; most preferably, G ⁵ Is an oxygen atom, G ⁶ Is CH ₂ 。

In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1), (I-2), (II-1), (II-2), (III-1), or (III-2), or a pharmaceutically acceptable salt thereof, wherein G is ⁹ Is NR ^G9c ，R ^G9c Is a hydrogen atom or C _1-6 An alkyl group; preferably, G ⁹ Is NCH ₃ Or NH; more preferably, G ⁹ Is NCH ₃ 。

In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1), (I-2), (II-1), (II-2), (III-1), or (III-2), or a pharmaceutically acceptable salt thereof, wherein G is ⁹ Is an oxygen atom.

In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1), (I-2), (II-1), (II-2), (III-1), or (III-2), or a pharmaceutically acceptable salt thereof, wherein G is ³ Is CR ¹ (ii) a And/or G ⁴ Is CR ¹ ；R ¹ As defined in general formula (I), (I-1), (I-2), (II-1), (II-2), (III-1) or (III-2); preferably, R ¹ Selected from hydrogen atoms, halogens and C _1-6 An alkyl group; more preferably, G ³ Is CH; and/or G ⁴ Is CH.

In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1), (I-2), (II-1), (II-2), (III-1) or (III-2), or a pharmaceutically acceptable salt thereof, wherein T is ¹ Is CR ^T1 ；R ^T1 As defined in general formula (I), (I-1), (I-2), (II-1), (II-2), (III-1) or (III-2); preferably, R ^T1 Selected from hydrogen atoms, halogens, C _1-6 Alkyl, amino, cyano, hydroxy, C _1-6 Hydroxyalkyl and-CH ₂ -NH ₂ (ii) a More preferably, T ¹ Is C-NH ₂ 。

In some preferred embodiments of the present disclosure, the followingThe compound shown in the general formula (I), (I-1), (I-2), (II-1), (II-2), (III-1) or (III-2) or a pharmaceutically acceptable salt thereof, wherein R is the same or different and is independently selected from hydrogen atom, halogen, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, cyano, amino, hydroxy and C _1-6 A hydroxyalkyl group; or two R together form oxo; preferably, R is the same or different and each is independently selected from the group consisting of hydrogen, halogen and C _1-6 An alkyl group; more preferably, R is a hydrogen atom.

In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1), (I-2), (II-1), (II-2), (III-1) or (III-2) or a pharmaceutically acceptable salt thereof, wherein R' is the same or different and each is independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, cyano, amino, hydroxy and C _1-6 A hydroxyalkyl group; preferably, R' are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C _1-6 An alkyl group; more preferably, R' is a hydrogen atom or a halogen.

In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1), (I-2), (II-1), (II-2), (III-1), or (III-2), or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, or 2; preferably, m is 0 or 1.

In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1), (I-2), (II-1), (II-2), (III-1), or (III-2), or a pharmaceutically acceptable salt thereof, wherein m is 1 or 2.

In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1), (I-2), (II-1), (II-2), (III-1), or (III-2), or a pharmaceutically acceptable salt thereof, wherein q is 0, 1, or 2; preferably, q is 0 or 1.

In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1), (I-2), (II-1), (II-2), (III-1), or (III-2), or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, or 2; preferably, n is 0 or 1.

In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1), (I-2), (II-1), (II-2), (III-1) or (III-2), or a pharmaceutically acceptable salt thereof, wherein R is ¹ Selected from hydrogen atoms, halogens, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, cyano, amino, - (CH) ₂ ) _m NR ⁷ R ⁸ Hydroxy and C _1-6 Hydroxyalkyl, m is 1 or2, R ⁷ And R ⁸ Are the same or different and are each independently a hydrogen atom or C _1-6 An alkyl group; preferably, R ¹ Selected from hydrogen atoms, halogens, C _1-6 Alkyl, amino, cyano, hydroxy, C _1-6 Hydroxyalkyl and-CH ₂ -NH ₂ (ii) a More preferably, R ¹ Selected from hydrogen atoms, halogens and C _1-6 An alkyl group; most preferably, R ¹ Is a hydrogen atom.

In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1), (I-2), (II-1), (II-2), (III-1) or (III-2), or a pharmaceutically acceptable salt thereof, wherein R is ^T1 Selected from hydrogen atoms, halogens, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, cyano, amino, - (CH) ₂ ) _m NR ⁷ R ⁸ Hydroxy and C _1-6 Hydroxyalkyl, m is 1 or2, R ⁷ And R ⁸ Are the same or different and are each independently a hydrogen atom or C _1-6 An alkyl group; preferably, R ^T1 Selected from hydrogen atoms, halogens, C _1-6 Alkyl, amino, cyano, hydroxy, C _1-6 Hydroxyalkyl and-CH ₂ -NH ₂ (ii) a More preferably, R ^T1 Is an amino group.

In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, wherein R ^G8 Selected from hydrogen atoms, halogens, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, cyano, amino, - (CH) ₂ ) _m NR ⁷ R ⁸ Hydroxy and C _1-6 Hydroxyalkyl, m is 1 or2, R ⁷ And R ⁸ Are the same or different and are each independently a hydrogen atom or C _1-6 An alkyl group; preferably, R ^G8 Selected from hydrogen atoms, halogens, C _1-6 Alkyl, amino, cyano, hydroxy, C _1-6 Hydroxyalkyl and-CH ₂ -NH ₂ (ii) a More preferably, R ^G8 Selected from hydrogen atoms, halogens and C _1-6 An alkyl group.

In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, wherein R ² Selected from hydrogen atoms, halogens, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, cyano, amino, - (CH) ₂ ) _m NR ⁷ R ⁸ Hydroxy and C _1-6 Hydroxyalkyl, m is 1 or2, R ⁷ And R ⁸ Are the same or different and are each independently a hydrogen atom or C _1-6 An alkyl group; preferably, R ² Selected from hydrogen atoms, halogens and C _1-6 An alkyl group.

In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, wherein R ³ Selected from hydrogen atom, C _1-6 Alkyl and C _1-6 A haloalkyl group; preferably, R ³ Is a hydrogen atom.

In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1), (I-2), (II-1), (II-2), (III-1) or (III-2), or a pharmaceutically acceptable salt thereof, wherein R is ⁴ And R ⁵ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, cyano, amino, hydroxy and C _1-6 Hydroxyalkyl, or R ⁴ And R ⁵ Together form an oxo group; preferably, R ⁴ And R ⁵ Are the same or different and are each independently selected from the group consisting of hydrogen atom, halogenAnd C _1-6 An alkyl group; more preferably, R ⁴ And R ⁵ Is a hydrogen atom.

In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, wherein R ^G7a And R ^G7b Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, cyano, amino, hydroxy and C _1-6 Hydroxyalkyl, or R ^G7a And R ^G7b Together form an oxo group; preferably, R ^G7a And R ^G7b Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C _1-6 An alkyl group; more preferably, R ^G7a And R ^G7b Is a hydrogen atom.

In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1), (I-2), (II-1), (II-2), (III-1) or (III-2), or a pharmaceutically acceptable salt thereof, wherein R is ^G9a And R ^G9b Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, cyano, amino, hydroxy and C _1-6 Hydroxyalkyl, or R ^G9a And R ^G9b Together form an oxo group; preferably, R ^G9a And R ^G9b Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C _1-6 An alkyl group.

In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1), (I-2), (II-1), (II-2), (III-1) or (III-2), or a pharmaceutically acceptable salt thereof, wherein R is ⁶ Selected from hydrogen atoms, C _1-6 Alkyl and C _1-6 A haloalkyl group; preferably, R ⁶ Is a hydrogen atom or C _1-6 An alkyl group.

In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, wherein R ^G7c Selected from hydrogen atoms, C _1-6 Alkyl and C _1-6 Alkyl halidesA group; preferably, R ^G7c Is a hydrogen atom or C _1-6 An alkyl group.

In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1), (I-2), (II-1), (II-2), (III-1) or (III-2), or a pharmaceutically acceptable salt thereof, wherein R is ^G9c Selected from hydrogen atoms, C _1-6 Alkyl and C _1-6 A haloalkyl group; preferably, R ^G9c Is a hydrogen atom or C _1-6 Alkyl, more preferably methyl.

In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1), (I-2), (II-1), (II-2), (III-1) or (III-2), or a pharmaceutically acceptable salt thereof, wherein R is ⁷ And R ⁸ Are the same or different and are each independently a hydrogen atom or C _1-6 An alkyl group; preferably, R ⁷ And R ⁸ The same or different, and each independently is a hydrogen atom or a methyl group.

In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1), (I-2), (II-1), (II-2), (III-1) or (III-2), or a pharmaceutically acceptable salt thereof, wherein R is ⁹ Selected from hydrogen atoms, C _1-6 Alkyl and C _1-6 A haloalkyl group.

In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, wherein R ¹⁰ Selected from hydrogen atoms, halogens, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, cyano, amino, - (CH) ₂ ) _m NR ⁷ R ⁸ Hydroxy and C _1-6 Hydroxyalkyl, m is 1 or2, R ⁷ And R ⁸ Are the same or different and are each independently a hydrogen atom or C _1-6 An alkyl group; preferably, R ¹⁰ Selected from hydrogen atoms, halogens, C _1-6 Alkyl, amino, cyano, hydroxy, C _1-6 Hydroxyalkyl and-CH ₂ -NH ₂ (ii) a Further preferably, R ¹⁰ Selected from hydrogen atoms, halogens and C _1-6 An alkyl group; more preferably, R ¹⁰ Is a hydrogen atom or a halogen.

In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, wherein R ^T3 Selected from hydrogen atoms, halogens, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, cyano, amino, - (CH) ₂ ) _m NR ⁷ R ⁸ Hydroxy and C _1-6 Hydroxyalkyl, m is 1 or2, R ⁷ And R ⁸ Are the same or different and are each independently a hydrogen atom or C _1-6 An alkyl group; preferably, R ^T3 Selected from hydrogen atoms, halogens, C _1-6 Alkyl, amino, cyano, hydroxy, C _1-6 Hydroxyalkyl and-CH ₂ -NH ₂ (ii) a More preferably, R ^T3 Selected from hydrogen atoms, halogens and C _1-6 An alkyl group; most preferably, R ^T3 Is a hydrogen atom.

In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, wherein R ¹¹ Selected from hydrogen atoms, halogens, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, cyano, amino, - (CH) ₂ ) _m NR ⁷ R ⁸ Hydroxy and C _1-6 Hydroxyalkyl, m is 1 or2, R ⁷ And R ⁸ Are the same or different and are each independently a hydrogen atom or C _1-6 An alkyl group; preferably, R ¹¹ Selected from hydrogen atoms, halogens and C _1-6 An alkyl group; more preferably, R ¹¹ Is a hydrogen atom.

In some preferred embodiments of the present disclosure, the compound of formula (I), (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, wherein R ¹² Selected from hydrogen atoms, C _1-6 Alkyl and C _1-6 A haloalkyl group; preferably, R ¹² Is a hydrogen atom.

In some preferred embodiments of the present disclosure, the compound of formula (II), (II-1), (II-2), (III-1) or (III-2) or a pharmaceutically acceptable salt thereof, wherein R' is selected from the group consisting of hydrogen, halogen and C _1-6 Alkyl, q is 0 or 1, T ¹ Is CR ^T1 ，R ^T1 Selected from hydrogen atoms, halogens, C _1-6 Alkyl, amino, cyano, hydroxy, C _1-6 Hydroxyalkyl and-CH ₂ -NH ₂ ，G ³ Is CR ¹ ，G ⁴ Is CR ¹ ，R ¹ Each independently selected from hydrogen, halogen and C _1-6 Alkyl radical, G ⁵ And G ⁶ In which one is CH ₂ The other is an oxygen atom, G ⁹ Is NR ^G9c ，R ^G9c Is a hydrogen atom or C _1-6 Alkyl, R is selected from hydrogen atom, halogen and C _1-6 Alkyl, n is 0 or 1.

In some preferred embodiments of the present disclosure, the compound of formula (II), (II-1), (II-2), (III-1) or (III-2) or a pharmaceutically acceptable salt thereof, wherein R' is a hydrogen atom or a halogen, q is 0 or 1, T ¹ Is C-NH ₂ ，G ³ Is CH, G ⁴ Is CH, G ⁵ Is an oxygen atom, G ⁶ Is CH ₂ ，G ⁹ Is NR ^G9c ，R ^G9c Is a hydrogen atom or C _1-6 Alkyl and R are hydrogen atoms.

Table a typical compounds of the present disclosure include, but are not limited to:

another aspect of the present disclosure relates to a compound represented by the general formula (IA) or a salt thereof,

wherein: r ^w Is an alkyl group;

G ¹ to G ⁹ R and n are as defined in formula (I).

Another aspect of the present disclosure relates to a compound represented by the general formula (I-1A) or (I-2A) or a salt thereof,

wherein: r ^w Is an alkyl group;

G ¹ to G ⁹ R and n are as defined in formula (I).

Another aspect of the present disclosure relates to a compound of formula (IIA) or a salt thereof,

wherein: r ^w Is an alkyl group;

G ³ to G ⁶ 、G ⁹ R and n are as defined in formula (II).

Another aspect of the present disclosure relates to a compound represented by the general formula (II-1A) or (II-2A) or a salt thereof,

wherein: r ^w Is an alkyl group;

G ³ to G ⁶ 、G ⁹ R and n are as defined in formula (II).

Another aspect of the present disclosure relates to a compound represented by the general formula (IC) or a salt thereof,

wherein: r ^m Is an amino protecting group; preferably Boc;

ring A, T ¹ 、R’、R ⁰ 、G ¹ To G ⁸ R, q and n are as defined in formula (I). Another aspect of the disclosure relates to a compound of formula (IIC) or (IIIC) or a salt thereof,

wherein: r ^m Is an amino protecting group; preferably Boc;

T ¹ 、R’、G ³ to G ⁶ R, q and n are as defined in formula (II) or (III). Typical intermediate compounds of the present disclosure include, but are not limited to:

another aspect of the present disclosure relates to a method of preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising:

carrying out cyclization reaction on the compound of the general formula (IA) or salt thereof and the compound of the general formula (IB) or salt thereof to obtain the compound of the general formula (I) or pharmaceutically acceptable salt thereof;

wherein:

R ^w is alkyl, preferably ethyl;

T ¹ is C-NH ₂ ；

Ring A, R ⁰ 、R’、q、G ¹ To G ⁹ R and n are as defined in formula (I).

Another aspect of the present disclosure relates to a process for preparing a compound represented by the general formula (I-1) or (I-2), or a pharmaceutically acceptable salt thereof, which comprises:

resolving the compound of the general formula (I) or the pharmaceutically acceptable salt thereof to obtain the compound shown in the general formula (I-1) or (I-2) or the pharmaceutically acceptable salt thereof;

wherein:

ring A, T ¹ 、R ⁰ 、R’、q、G ¹ To G ⁹ R and n are as defined in general formula (I-1) or (I-2).

carrying out cyclization reaction on the compound of the general formula (I-1A) or salt thereof and the compound of the general formula (IB) or salt thereof to obtain the compound of the general formula (I-1) or pharmaceutically acceptable salt thereof; or

Carrying out cyclization reaction on the compound of the general formula (I-2A) or salt thereof and the compound of the general formula (IB) or salt thereof to obtain the compound of the general formula (I-2) or pharmaceutically acceptable salt thereof;

wherein:

R ^w is an alkyl group, preferably an ethyl group;

T ¹ is C-NH ₂ ；

Ring A, R ⁰ 、R’、q、G ¹ To G ⁹ R and n are as defined in general formula (I-1) or (I-2).

Another aspect of the present disclosure relates to a method of preparing a compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

carrying out cyclization reaction on the compound of the general formula (IIA) or salt thereof and the compound of the general formula (IIB) or salt thereof to obtain a compound of the general formula (II) or pharmaceutically acceptable salt thereof;

wherein:

R ^w is an alkyl group, preferably an ethyl group;

T ¹ is C-NH ₂ ；

G ³ 、G ⁴ 、G ⁵ 、G ⁶ 、G ⁹ R, R', q and n are as defined in formula (II).

Another aspect of the present disclosure relates to a method for preparing a compound represented by the general formula (II-1) or (II-2), or a pharmaceutically acceptable salt thereof, comprising:

resolving the compound of the general formula (II) or the pharmaceutically acceptable salt thereof to obtain the compound shown in the general formula (II-1) or (II-2) or the pharmaceutically acceptable salt thereof;

wherein:

T ¹ 、G ³ 、G ⁴ 、G ⁵ 、G ⁶ 、G ⁹ r, R', q and n are as defined in formula (II-1) or (II-2).

a compound of a general formula (II-1A) or a salt thereof and a compound of a general formula (IIB) or a salt thereof are subjected to cyclization reaction to obtain a compound of a general formula (II-1) or a pharmaceutically acceptable salt thereof; or

The compound of the general formula (II-2A) or the salt thereof and the compound of the general formula (IIB) or the salt thereof are subjected to cyclization reaction to obtain the compound of the general formula (II-2) or the pharmaceutically acceptable salt thereof;

wherein:

R ^w is an alkyl group, preferably an ethyl group;

T ¹ is C-NH ₂ ；

G ³ 、G ⁴ 、G ⁵ 、G ⁶ 、G ⁹ R, R', q and n are as defined in formula (II-1) or (II-2).

Another aspect of the present disclosure relates to a method of preparing a compound of formula (III), or a pharmaceutically acceptable salt thereof, comprising:

carrying out cyclization reaction on the compound of the general formula (IIA) or salt thereof and the compound of the general formula (IIIB) or salt thereof to obtain the compound of the general formula (III) or pharmaceutically acceptable salt thereof;

wherein:

R ^w is an alkyl group, preferably an ethyl group;

T ¹ is C-NH ₂ ；

G ³ 、G ⁴ 、G ⁵ 、G ⁶ 、G ⁹ R, R', q and n are as defined in formula (III).

Another aspect of the present disclosure relates to a process for preparing a compound represented by the general formula (III-1) or (III-2), or a pharmaceutically acceptable salt thereof, which comprises:

resolving the compound of the general formula (III) or pharmaceutically acceptable salt thereof to obtain a compound shown in the general formula (III-1) or (III-2) or pharmaceutically acceptable salt thereof;

wherein:

T ¹ 、G ³ 、G ⁴ 、G ⁵ 、G ⁶ 、G ⁹ r, R', q and n are as defined in formula (III-1) or (III-2).

Another aspect of the present disclosure relates to a process for preparing a compound represented by the general formula (III-1) or (III-2) or a pharmaceutically acceptable salt thereof, which comprises:

carrying out cyclization reaction on the compound of the general formula (II-1A) or salt thereof and the compound of the general formula (IIIB) or salt thereof to obtain the compound of the general formula (III-1) or pharmaceutically acceptable salt thereof; or

Carrying out cyclization reaction on the compound of the general formula (II-2A) or salt thereof and the compound of the general formula (IIIB) or salt thereof to obtain the compound of the general formula (III-2) or pharmaceutically acceptable salt thereof;

wherein:

R ^w is an alkyl group, preferably an ethyl group;

T ¹ is C-NH ₂ ；

G ³ 、G ⁴ 、G ⁵ 、G ⁶ 、G ⁹ R, R', q and n are as defined in formula (III-1) or (III-2).

carrying out deprotection reaction on the compound of the general formula (IC) or salt thereof to obtain the compound of the general formula (I) or pharmaceutically acceptable salt thereof;

wherein:

R ^m is a amino groupProtecting a base; preferably Boc;

G ⁹ is NH;

ring A, T ¹ 、R’、R ⁰ 、G ¹ To G ⁸ R, q and n are as defined in formula (I).

Another aspect of the present disclosure relates to a method of preparing a compound represented by general formula (II) or (III), or a pharmaceutically acceptable salt thereof, comprising:

carrying out deprotection reaction on the compound of the general formula (IIC) or salt thereof to obtain a compound of a general formula (II) or pharmaceutically acceptable salt thereof; or

Carrying out deprotection reaction on the compound of the general formula (IIIC) or salt thereof to obtain a compound of a general formula (III) or pharmaceutically acceptable salt thereof;

wherein:

R ^m is an amino protecting group; preferably Boc;

G ⁹ is NH;

T ¹ 、R’、G ³ to G ⁶ R, q and n are as defined in formula (II) or (III).

Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of the general formula (I), (I-1), (I-2), (II-1), (II-2), (III-1), (III-2) and shown in table a of the present disclosure, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

The disclosure further relates to the use of compounds of general formula (I), (I-1), (I-2), (II-1), (II-2), (III-1), (III-2) and shown in table a, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, in the preparation of a medicament for inhibiting HPK 1.

The present disclosure further relates to the use of a compound of formula (I), (I-1), (I-2), (II-1), (II-2), (III-1), (III-2) and shown in table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for the treatment and/or prevention of a disease or condition by inhibition of HPK 1; the use of a disease or condition preferably selected from the group consisting of cancer, autoimmune diseases, inflammatory diseases, infectious diseases, cardiovascular diseases, neurodegenerative diseases, diabetes and reproductive disorders; more preferably, the disease or condition is selected from the group consisting of cancer, allergy, asthma, sepsis, hiv infection, hepatitis b virus infection, ischemia, atherosclerosis, stroke, and alzheimer's disease; the cancer is preferably selected from the group consisting of brain cancer, thyroid cancer, head and neck cancer, throat cancer, oral cancer, salivary gland cancer, esophageal cancer, stomach cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, bile duct cancer, colorectal cancer, small intestine cancer, gastrointestinal stromal tumor, urothelial cancer, urinary tract cancer, bladder cancer, breast cancer, ovarian cancer, uterine cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, leukemia, lymphoma, multiple myeloma, skin cancer, malignant lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, neuroblastoma, and glioblastoma.

The present disclosure further relates to the use of a compound represented by general formula (I), (I-1), (I-2), (II-1), (II-2), (III-1), (III-2) and table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for the treatment and/or prevention of cancer, autoimmune diseases, inflammatory diseases, infectious diseases, cardiovascular diseases, neurodegenerative diseases, diabetes and diseases or conditions of reproductive disorders; preferably, the disease or condition is selected from the group consisting of cancer, allergy, asthma, sepsis, HIV infection, hepatitis B virus infection, ischemia, atherosclerosis, stroke, and Alzheimer's disease; the cancer is preferably selected from the group consisting of brain cancer, thyroid cancer, head and neck cancer, throat cancer, oral cancer, salivary gland cancer, esophageal cancer, stomach cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, bile duct cancer, colorectal cancer, small intestine cancer, gastrointestinal stromal tumor, urothelial cancer, urinary tract cancer, bladder cancer, breast cancer, ovarian cancer, uterine cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, leukemia, lymphoma, multiple myeloma, skin cancer, malignant lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, neuroblastoma, and glioblastoma.

The present disclosure further relates to a method of inhibiting HPK1 comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), (I-1), (I-2), (II-1), (II-2), (III-1), (III-2), and table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The present disclosure further relates to a method of treating and/or preventing a disease or disorder, preferably a disease or disorder treated and/or prevented by inhibiting HPK1, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), (I-1), (I-2), (II-1), (II-2), (III-1), (III-2), and shown in table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same; wherein said disease or condition is preferably selected from the group consisting of cancer, autoimmune diseases, inflammatory diseases, infectious diseases, cardiovascular diseases, neurodegenerative diseases, diabetes and reproductive disorders; more preferably, the disease or condition is selected from the group consisting of cancer, allergy, asthma, sepsis, hiv infection, hepatitis b virus infection, ischemia, atherosclerosis, stroke, and alzheimer's disease; the cancer is preferably selected from the group consisting of brain cancer, thyroid cancer, head and neck cancer, throat cancer, oral cancer, salivary gland cancer, esophageal cancer, stomach cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, bile duct cancer, colorectal cancer, small intestine cancer, gastrointestinal stromal tumor, urothelial cancer, urinary tract cancer, bladder cancer, breast cancer, ovarian cancer, uterine cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, leukemia, lymphoma, multiple myeloma, skin cancer, malignant lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, neuroblastoma, and glioblastoma.

The present disclosure further relates to a method of treating and/or preventing cancer, autoimmune diseases, inflammatory diseases, infectious diseases, cardiovascular diseases, neurodegenerative diseases, diabetes, and diseases or conditions of reproductive disorders comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), (I-1), (I-2), (II-1), (II-2), (III-1), (III-2), and shown in table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same; preferably, the disease or condition is selected from the group consisting of cancer, allergy, asthma, sepsis, HIV infection, hepatitis B virus infection, ischemia, atherosclerosis, stroke, and Alzheimer's disease; the cancer is preferably selected from the group consisting of brain cancer, thyroid cancer, head and neck cancer, throat cancer, oral cancer, salivary gland cancer, esophageal cancer, stomach cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, bile duct cancer, colorectal cancer, small intestine cancer, gastrointestinal stromal tumor, urothelial cancer, urinary tract cancer, bladder cancer, breast cancer, ovarian cancer, uterine cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, leukemia, lymphoma, multiple myeloma, skin cancer, malignant lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, neuroblastoma, and glioblastoma.

The present disclosure further relates to compounds of general formula (I), (I-1), (I-2), (II-1), (II-2), (III-1), (III-2) and shown in Table A or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use as a medicament.

The present disclosure further relates to compounds of general formula (I), (I-1), (I-2), (II-1), (II-2), (III-1), (III-2) and shown in Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use as a medicament for inhibiting HPK 1.

The present disclosure further relates to a compound of formula (I), (I-1), (I-2), (II-1), (II-2), (III-1), (III-2) and table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament for the treatment and/or prevention of a disease or disorder, preferably for use as a medicament for the treatment and/or prevention of a disease or disorder that is treated and/or prevented by inhibition of HPK 1; wherein said disease or condition is preferably selected from the group consisting of cancer, autoimmune diseases, inflammatory diseases, infectious diseases, cardiovascular diseases, neurodegenerative diseases, diabetes and reproductive disorders; preferably, the disease or condition is selected from the group consisting of cancer, allergy, asthma, sepsis, HIV infection, hepatitis B virus infection, ischemia, atherosclerosis, stroke, and Alzheimer's disease; the cancer is preferably selected from the group consisting of brain cancer, thyroid cancer, head and neck cancer, throat cancer, oral cancer, salivary gland cancer, esophageal cancer, stomach cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, bile duct cancer, colorectal cancer, small intestine cancer, gastrointestinal stromal tumor, urothelial cancer, urinary tract cancer, bladder cancer, breast cancer, ovarian cancer, uterine cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, leukemia, lymphoma, multiple myeloma, skin cancer, malignant lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, neuroblastoma, and glioblastoma.

The present disclosure further relates to compounds of general formula (I), (I-1), (I-2), (II-1), (II-2), (III-1), (III-2) and table a, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use as a medicament for the treatment and/or prevention of cancer, autoimmune diseases, inflammatory diseases, infectious diseases, cardiovascular diseases, neurodegenerative diseases, diabetes and reproductive disorders; preferably, the disease or condition is selected from the group consisting of cancer, allergy, asthma, sepsis, HIV infection, hepatitis B virus infection, ischemia, atherosclerosis, stroke, and Alzheimer's disease; the cancer is preferably selected from the group consisting of brain cancer, thyroid cancer, head and neck cancer, throat cancer, oral cancer, salivary gland cancer, esophageal cancer, stomach cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, bile duct cancer, colorectal cancer, small intestine cancer, gastrointestinal stromal tumors, urothelial cancer, urinary tract cancer, bladder cancer, breast cancer, ovarian cancer, uterine cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, leukemia, lymphoma, multiple myeloma, skin cancer, malignant lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, neuroblastoma, and glioblastoma.

Preferably, the brain cancer described in the present disclosure is selected from glioblastoma multiforme or neuroblastoma; soft tissue cancer selected from fibrosarcoma, gastrointestinal sarcoma, rhabdomyoma, leiomyosarcoma, dedifferentiated liposarcoma, liposarcoma polymorpha, malignant fibrous histiocytoma, round cell sarcoma, and synovial sarcoma; the lymphoma is selected from hodgkin's disease and non-hodgkin's lymphoma (e.g., mantle cell lymphoma, diffuse large B-cell lymphoma, follicular center lymphoma, marginal zone B-cell lymphoma, lymphoplasmacytic lymphoma, and peripheral T-cell lymphoma); the liver cancer is preferably hepatocellular carcinoma; lung cancer is selected from non-small cell lung cancer (NSCLC) (e.g., squamous cell carcinoma) and Small Cell Lung Cancer (SCLC); kidney cancer selected from renal cell carcinoma, clear cell and nephroeosinophilic tumor; the leukemia is selected from Chronic Lymphocytic Leukemia (CLL), chronic myelogenous leukemia, Acute Lymphoblastic Leukemia (ALL), T-cell acute lymphoblastic leukemia (T-ALL), Chronic Myelogenous Leukemia (CML) and Acute Myelogenous Leukemia (AML); the skin cancer is selected from malignant melanoma, squamous cell carcinoma, basal cell carcinoma and angiosarcoma; the throat cancer is nasopharyngeal carcinoma.

Colorectal cancer described in the present disclosure is also called colorectal cancer, preferably colon cancer or rectal cancer; preferably, the uterine cancer is endometrial cancer.

The active compounds may be formulated in a form suitable for administration by any suitable route, using one or more pharmaceutically acceptable carriers to formulate compositions of the disclosure by conventional methods. Thus, the active compounds of the present disclosure may be formulated in a variety of dosage forms for oral administration, injection (e.g., intravenous, intramuscular, or subcutaneous), inhalation, or insufflation. The compounds of the present disclosure may also be formulated in dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, lozenges, or syrups.

As a general guide, the active compounds of the present disclosure are preferably in unit dosage form, or in a form in which the patient can self-administer the compound in a single dose. The unit dose of a compound or composition of the present disclosure may be expressed in the form of a tablet, capsule, cachet, bottled liquid, powder, granule, lozenge, suppository, reconstituted powder, or liquid. A suitable unit dose may be 0.1 to 1000 mg.

The pharmaceutical compositions of the present disclosure may contain, in addition to the active compound, one or more excipients selected from the following: fillers (diluents), binders, wetting agents, disintegrants, excipients, and the like. Depending on the method of administration, the compositions may contain from 0.1 to 99% by weight of active compound.

Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be inert excipients, granulating agents, disintegrating agents, binding agents and lubricating agents. These tablets may be uncoated or they may be coated by known techniques which mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.

Oral formulations may also be provided in soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or wherein the active ingredient is mixed with a water soluble carrier or an oil vehicle.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending, dispersing or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.

Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, or in a mineral oil. The oil suspension may contain a thickener. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of antioxidants.

The pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, or a mineral oil or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsions may also contain sweetening, flavoring, preservative and antioxidant agents. Such formulations may also contain a demulcent, a preservative, a colorant and an antioxidant.

The pharmaceutical compositions of the present disclosure may be in the form of a sterile injectable aqueous solution. Among the acceptable vehicles or solvents that may be employed are water, ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oil phase, and the injection or microemulsion may be injected into the bloodstream of a patient by local mass injection. Alternatively, it may be desirable to administer the solution and microemulsion in a manner that maintains a constant circulating concentration of the disclosed compounds. To maintain such a constant concentration, a continuous intravenous delivery device may be used. An example of such a device is an intravenous pump model Deltec CADD-PLUS. TM.5400.

The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous or oleaginous suspensions for intramuscular and subcutaneous administration. The suspensions may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a parenterally-acceptable, non-toxic diluent or solvent. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. Any blend fixed oil may be used for this purpose. In addition, fatty acids can also be prepared into injections.

The compounds of the present disclosure may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and therefore will melt in the rectum to release the drug.

The compounds of the present disclosure can be administered by the addition of water to prepare water-suspended dispersible powders and granules. These pharmaceutical compositions may be prepared by mixing the active ingredient with dispersing or wetting agents, suspending agents, or one or more preservatives.

As is well known to those skilled in the art, the dosage of a drug administered depends on a variety of factors, including, but not limited to: the activity of the particular compound used, the severity of the disease, the age of the patient, the weight of the patient, the health status of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, etc.; in addition, the optimal treatment regimen, such as mode of treatment, daily amount of compound or type of pharmaceutically acceptable salt, can be verified according to conventional treatment protocols.

Description of the terms

Unless stated to the contrary, terms used in the specification and claims have the following meanings.

The term "alkyl group"Refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl (i.e., C) group having 1 to 12 (e.g., 1,2,3, 4,5, 6,7, 8, 9,10, 11, and 12) carbon atoms _1-20 Alkyl), more preferably an alkyl group having 1 to 6 carbon atoms (i.e., C) _1-6 Alkyl groups). Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-dimethylpentyl, 2-dimethylhexyl, 3-dimethylpentyl, 2-ethylhexyl, 3-dimethylhexyl, 2-ethylhexyl, 2-dimethylhexyl, 2-ethylhexyl, 2-dimethylhexyl, 2-dimethylhexyl, 2-dimethylhexyl, 2-ethylhexyl, 2-ethyl, 2-2, 2-2, 2-2, or, 2, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof. More preferred are lower alkyl groups having 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl and the like. The alkyl group may be substituted or unsubstituted, and when substituted, may be substituted at any available point of attachmentPreferably, the substituents are selected from one or more of D atoms, halogens, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups.

The term "alkylene" refers to a saturated straight or branched aliphatic hydrocarbon group, which is a residue derived from the parent alkane by removal of two hydrogen atoms from the same carbon atom or two different carbon atoms, and is a straight or branched group containing 1 to 20 carbon atoms, preferably having 1 to 12 (e.g., 1,2,3, 4,5, 6,7, 8, 9,10, 11, and 12) carbon atoms (i.e., C) _1-12 Alkylene), more preferably alkylene having 1 to 6 carbon atoms (i.e., C) _1-6 Alkylene). Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH) ₂ -), 1-ethylidene (-CH (CH) ₃ ) -), 1, 2-ethylene (-CH) ₂ CH ₂ ) -, 1-propylene (-CH (CH) ₂ CH ₃ ) -), 1, 2-propylene (-CH) ₂ CH(CH ₃ ) -), 1, 3-propylene (-CH) ₂ CH ₂ CH ₂ -) 1, 4-butylene (-CH ₂ CH ₂ CH ₂ CH ₂ -) and the like. The alkylene group may be substituted or unsubstituted and when substituted, may be substituted at any available point of attachment, the substituent preferably being selected from one or more of alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocyclyloxy, cycloalkylthio, heterocyclylthio and oxo.

The term "alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above, preferably having 2 to 12 (e.g., 2,3,4, 5,6, 7, 8, 9,10, 11, and 12) carbon atoms (i.e., C) _2-12 Alkenyl), more preferably alkenyl having 2 to 6 carbon atoms (i.e., C) _2-6 Alkenyl). Non-limiting examples include: ethenyl, propenyl, isopropenyl, butenyl, and the like. An alkenyl group may be substituted or unsubstituted, and when substituted, the substituent groupPreferably one or more selected from the group consisting of alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above. Preferably 2 to 12 (e.g. 2,3,4, 5,6, 7, 8, 9,10, 11 and 12) carbon atoms (i.e. C) _2-12 Alkynyl), more preferably alkynyl having 2 to 6 carbon atoms (i.e., C) _2-6 Alkynyl). Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably selected from one or more of alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably 3 to 14 (e.g., 3,4, 5,6, 7, 8, 9,10, 11, 12, 13, and 14) carbon atoms (i.e., 3 to 14 membered cycloalkyl groups), preferably 3 to 8 (e.g., 3,4, 5,6, 7, and 8) carbon atoms (i.e., 3 to 8 membered cycloalkyl groups), more preferably 3 to 6 carbon atoms (i.e., 3 to 6 membered cycloalkyl groups). Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spirocycloalkyl, fused ring alkyl, and bridged cycloalkyl groups.

The term "spirocycloalkyl" refers to a 5-to 20-membered polycyclic group having a single ring with a single carbon atom in common (referred to as a spiro atom) which may contain one or more double bonds. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). Spirocycloalkyl groups are classified as mono-or polyspirocycloalkyl (e.g., a bispirocycloalkyl group), preferably mono-and bispirocycloalkyl, depending on the number of spiro atoms shared between rings. More preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/3-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 5-membered/7-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered, 6-membered/6-membered, 6-membered/7-membered, 7-membered/5-membered or 7-membered/6-membered spirocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:

the term "fused cyclic alkyl" refers to a 5 to 20 membered all carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more double bonds. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). They may be classified into bicyclic or polycyclic (e.g., tricyclic, tetracyclic) fused cycloalkyl groups according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/3-membered, 5-membered/4-membered, 5-membered/6-membered, 5-membered/7-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered, 6-membered/6-membered, 6-membered/7-membered, 7-membered/5-membered or 7-membered/6-membered bicyclic fused cycloalkyl groups. Non-limiting examples of fused ring alkyl groups include:

the term "bridged cycloalkyl" refers to a 5 to 20 membered all carbon polycyclic group in which any two rings share two carbon atoms not directly attached, which may contain one or more double bonds. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). They may be classified as bicyclic or polycyclic (e.g., tricyclic, tetracyclic) bridged cycloalkyl groups depending on the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

the cycloalkyl ring includes as aboveSaid cycloalkyl (including monocyclic, spiro, fused and bridged rings) is fused to an aryl, heteroaryl or heterocycloalkyl ring wherein the ring(s) attached to the parent structure are cycloalkyl, non-limiting examples of which include

Etc.; preferably, it is

Cycloalkyl groups may be substituted or unsubstituted and, when substituted, may be substituted at any available point of attachment, the substituents preferably being selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.

The term "alkoxy" refers to-O- (alkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy and butoxy. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably selected from the group consisting of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "heterocyclyl" refers to a saturated or partially unsaturated mono-or polycyclic cyclic substituent comprising from 3 to 20 (e.g., 3,4, 5,6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 3-to 20-membered heterocyclyl group) wherein one or more ring atoms is a heteroatom selected from nitrogen, oxygen, and sulfur, which may optionally be oxo (i.e., to form a sulfoxide or sulfone), but does not include a ring moiety of-O-, -O-S-, or-S-, with the remaining ring atoms being carbon. Preferably 3 to 14 (e.g., 3,4, 5,6, 7, 8, 9,10, 11, 12, 13 and 14) ring atoms (i.e., 3 to 14 membered heterocyclyl), of which 1-4 (e.g., 1,2,3 and 4) are heteroatoms; more preferably 3 to 8 ring atoms (e.g., 3,4, 5,6, 7 and 8) (i.e., 3 to 8 membered heterocyclyl) or 6 to 14 ring atoms (e.g., 6,7, 8, 9,10, 11, 12, 13 and 14), wherein 1-3 are heteroatoms (e.g., 1,2 and 3); more preferably 3 to 8 ring atoms, of which 1-3 (e.g. 1,2 and 3) are heteroatoms; most preferably 5 or 6 ring atoms, of which 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3, 6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups.

The term "spiroheterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group having one atom (referred to as the spiro atom) in common between monocyclic rings, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, which may optionally be oxo (i.e., to form a sulfoxide or sulfone), with the remaining ring atoms being carbon. It may contain one or more double bonds. Preferably 6 to 14 (e.g. 6,7, 8, 9,10, 11, 12, 13 and 14) membered (i.e. 6 to 14 membered spiroheterocyclyl), more preferably 7 to 10 (e.g. 7, 8, 9 or 10) membered (i.e. 7 to 10 membered spiroheterocyclyl). Spiro heterocyclic groups are classified into a mono-spiro heterocyclic group or a multi-spiro heterocyclic group (e.g., a double-spiro heterocyclic group), preferably a mono-spiro heterocyclic group and a double-spiro heterocyclic group, according to the number of spiro atoms shared between rings. More preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/3-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 5-membered/7-membered, 6-membered/3-membered, 6-membered/5-membered, 6-membered/6-membered, 6-membered/7-membered, 7-membered/5-membered or 7-membered/6-membered spiroheterocyclic group. Non-limiting examples of spiro heterocyclic groups include:

the term "fused heterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with the other rings in the system, one or more of the rings may contain one or more double bonds, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, which may optionally be oxo (i.e. to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably 6 to 14 (e.g., 6,7, 8, 9,10, 11, 12, 13 and 14) membered (i.e., 6 to 14 membered fused heterocyclyl), more preferably 7 to 10 (e.g., 7, 8, 9 or 10) membered (i.e., 7 to 10 membered fused heterocyclyl). They may be classified into bicyclic or polycyclic (e.g., tricyclic, tetracyclic) fused heterocyclic groups according to the number of constituting rings, preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/3-membered, 5-membered/4-membered, 5-membered/6-membered, 5-membered/7-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered, 6-membered/6-membered, 6-membered/7-membered, 7-membered/5-membered or 7-membered/6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

the term "bridged heterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group in which any two rings share two atoms which are not directly connected and which may contain one or more double bonds, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, which may optionally be oxo (i.e., to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably 6 to 14 (e.g. 6,7, 8, 9,10, 11, 12, 13 and 14) membered (i.e. 6 to 14 bridged heterocyclyl), more preferably 7 to 10 (e.g. 7, 8, 9 or 10) membered (i.e. 7 to 10 bridged heterocyclyl). They may be classified into bicyclic or polycyclic (e.g., tricyclic, tetracyclic) bridged heterocyclic groups depending on the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

the heterocyclyl ring includes a heterocyclyl (including monocyclic, spiroheterocyclic, fused heterocyclic and bridged heterocyclic) fused to an aryl, heteroaryl or cycloalkyl ring as described above, wherein the ring to which the parent structure is attached is a heterocyclyl, non-limiting examples of which include:

and the like.

The heterocyclyl group may be substituted or unsubstituted and when substituted may be substituted at any available point of attachment, the substituents preferably being selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.

The term "aryl" refers to a 6 to 14 membered all carbon monocyclic or fused polycyclic (fused polycyclic is a ring sharing adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, such as phenyl and naphthyl. Such aryl rings include those wherein the aryl ring as described above is fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:

aryl groups may be substituted or unsubstituted and when substituted may be substituted at any available point of attachment, the substituents preferably being selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.

The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms (e.g., 1,2,3, and 4), 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl is preferably 5 to 10 membered (e.g., 5,6, 7, 8, 9 or 10 membered) (i.e., 5 to 10 membered heteroaryl), more preferably 5 or 6 membered, e.g., furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, and the like. The heteroaryl ring includes a heteroaryl fused to an aryl, heterocyclyl or cycloalkyl ring as described above, wherein the ring joined together with the parent structure is a heteroaryl ring, non-limiting examples of which include:

heteroaryl groups may be substituted or unsubstituted, and when substituted, may be substituted at any available point of attachment, preferably with one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.

The above-mentioned cycloalkyl, heterocyclyl, aryl and heteroaryl groups include those derived by removal of one hydrogen atom from the parent ring atom, or those derived by removal of two hydrogen atoms from the parent ring atom or two different ring atoms, i.e., "divalent cycloalkyl", "divalent heterocyclyl", "arylene" and "heteroarylene".

The term "amino protecting group" is intended to protect an amino group with a group that can be easily removed in order to keep the amino group unchanged when the rest of the molecule is subjected to a reaction. Non-limiting examples include (trimethylsilyl) ethoxymethyl, tetrahydropyranyl, t-butyloxycarbonyl, acetyl, benzyl, allyl, and p-methoxybenzyl, and the like. These groups may be optionally substituted with 1 to 3 substituents selected from halogen, alkoxy or nitro.

The term "hydroxyl protecting group" refers to a derivative of a hydroxyl group that is commonly used to block or protect the hydroxyl group while the reaction is carried out on other functional groups of the compound. As an example, the hydroxyl-protecting group may preferably be triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl, methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-Tetrahydropyranyl (THP), formyl, acetyl, benzoyl, p-nitrobenzoyl.

The term "cycloalkyloxy" refers to cycloalkyl-O-wherein cycloalkyl is as defined above.

The term "heterocyclyloxy" refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.

The term "aryloxy" refers to aryl-O-wherein aryl is as defined above.

The term "heteroaryloxy" refers to heteroaryl-O-wherein heteroaryl is as defined above.

The term "alkylthio" refers to an alkyl-S-group wherein alkyl is as defined above.

The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein the alkyl group is as defined above.

The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.

The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.

The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxyl groups, wherein alkyl is as defined above.

The term "halogen" refers to fluorine, chlorine, bromine or iodine.

The term "hydroxy" refers to-OH.

The term "mercapto" refers to-SH.

The term "amino" refers to the group-NH ₂ 。

The term "cyano" refers to — CN.

The term "nitro" means-NO ₂ 。

The term "oxo" or "oxo" means "═ O".

The term "carbonyl" refers to C ═ O.

The term "carboxy" refers to-C (O) OH.

The term "carboxylate" refers to-C (O) O (alkyl), -C (O) O (cycloalkyl), (alkyl) C (O) O-or (cycloalkyl) C (O) O-, wherein alkyl and cycloalkyl are as defined above.

The disclosed compounds may exist in specific stereoisomeric forms. The term "stereoisomers" refers to isomers that are identical in structure but differ in the arrangement of the atoms in space. It includes cis and trans (or Z and E) isomers, (-) -and (+) -isomers, (R) -and (S) -enantiomers, diastereomers, (D) -and (L) -isomers, tautomers, atropisomers, conformers, and mixtures thereof (e.g., racemates, mixtures of diastereomers). Additional asymmetric atoms may be present in substituents in the compounds of the present disclosure. All such stereoisomers, as well as mixtures thereof, are included within the scope of the present disclosure. Optically active (-) -and (+) -isomers, (R) -and (S) -enantiomers, and (D) -and (L) -isomers can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. One isomer of a compound of the present disclosure may be prepared by asymmetric synthesis or chiral auxiliary, or, when a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl) is contained in the molecule, a diastereoisomeric salt is formed with an appropriate optically active acid or base, followed by diastereoisomeric resolution by conventional methods well known in the art to obtain pure isomers. Furthermore, separation of enantiomers and diastereomers is typically accomplished by chromatography.

In the chemical structure of the compounds described in the present disclosure, a bond

Denotes an unspecified configuration, i.e. a bond if a chiral isomer is present in the chemical structure

Can be that

Or

Or at the same time contain

And

two configurations.

The compounds and intermediates of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also referred to as proton transfer tautomers) include interconversion via proton migration, such as keto-enol and imine-enamine, lactam-lactam isomerizations. An example of a keto-enol equilibrium is between A and B as shown below.

Also as when referring to imidazolyl, it is understood to include either of the following two structures or a mixture of both tautomers.

All tautomeric forms are within the scope of the disclosure. The naming of the compounds does not exclude any tautomers.

The compounds of the present disclosure include all suitable isotopic derivatives of the compounds thereof. The term "isotopic derivative" refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes that can be incorporated into compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, and the like, for example, respectively ² H (deuterium, D), ³ H (tritium, T), ¹¹ C、 ¹³ C、 ¹⁴ C、 ¹⁵ N、 ¹⁷ O、 ¹⁸ O、 ³² p、 ³³ p、 ³³ S、 ³⁴ S、 ³⁵ S、 ³⁶ S、 ¹⁸ F、 ³⁶ Cl、 ⁸² Br、 ¹²³ I、 ¹²⁴ I、 ¹²⁵ I、 ¹²⁹ I and ¹³¹ i, etc., preferably deuterium.

Compared with the non-deuterated drugs, the deuterated drugs have the advantages of reducing toxic and side effects, increasing the stability of the drugs, enhancing the curative effect, prolonging the biological half-life of the drugs and the like. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are intended to be encompassed within the scope of the present disclosure. Each available hydrogen atom attached to a carbon atom may be independently replaced by a deuterium atom, where replacement by deuterium may be partial or complete, partial replacement by deuterium meaning replacement of at least one hydrogen by at least one deuterium.

"optionally" or "optionally" means that the subsequently described event or circumstance can, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example "C optionally substituted by halogen or cyano _1-6 Alkyl "means that halogen or cyano may, but need not, be present, and the description includes the case where alkyl is substituted with halogen or cyano and the case where alkyl is not substituted with halogen and cyano.

"substituted" means that one or more, preferably 1 to 6, more preferably 1 to 3, hydrogen atoms in the group are independently substituted with a corresponding number of substituents. Those skilled in the art are able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.

"pharmaceutical composition" means a mixture containing one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof in admixture with other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.

"pharmaceutically acceptable salt" refers to a salt of a compound of the disclosure, which may be selected from inorganic or organic salts. The salt has safety and effectiveness when used in a mammal body, and has due biological activity. Salts may be prepared separately during the final isolation and purification of the compound, or by reacting the appropriate group with an appropriate base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases such as sodium hydroxide and potassium hydroxide, and organic bases such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids as well as organic acids.

The term "therapeutically effective amount" with respect to a drug or pharmacologically active agent refers to a sufficient amount of the drug or agent that is non-toxic but achieves the desired effect. The determination of an effective amount varies from person to person, depending on the age and general condition of the recipient and also on the particular active substance, and an appropriate effective amount in an individual case can be determined by a person skilled in the art according to routine tests.

The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio, and effective for the intended use.

As used herein, the singular forms "a", "an" and "the" include plural references and vice versa unless the context clearly dictates otherwise.

When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it is meant that the parameter may vary by ± 10%, and sometimes more preferably within ± 5%. As will be appreciated by those skilled in the art, when the parameters are not critical, the numbers are generally given for illustrative purposes only and are not limiting.

Synthesis of the compounds of the present disclosure

In order to achieve the purpose of the present disclosure, the present disclosure adopts the following technical solutions:

scheme one

The invention discloses a method for preparing a compound shown as a general formula (I) or a pharmaceutically acceptable salt thereof, which comprises the following steps:

carrying out cyclization reaction on the compound of the general formula (IA) or salt thereof and the compound of the general formula (IB) or salt thereof under alkaline conditions to obtain the compound of the general formula (I) or pharmaceutically acceptable salt thereof;

wherein:

R ^w is an alkyl group, preferably an ethyl group;

T ¹ is C-NH ₂ ；

Scheme two

A process for producing a compound represented by the general formula (I-1) or (I-2) or a pharmaceutically acceptable salt thereof, which comprises:

chiral preparation and resolution are carried out on the compound of the general formula (I) or the pharmaceutically acceptable salt thereof to obtain the compound shown in the general formula (I-1) or (I-2) or the pharmaceutically acceptable salt thereof;

wherein:

Scheme three

a compound of a general formula (I-1A) or a salt thereof and a compound of a general formula (IB) or a salt thereof are subjected to cyclization reaction under alkaline conditions to obtain a compound of a general formula (I-1) or a pharmaceutically acceptable salt thereof; or

Performing cyclization reaction on the compound of the general formula (I-2A) or salt thereof and the compound of the general formula (IB) or salt thereof under alkaline conditions to obtain the compound of the general formula (I-2) or pharmaceutically acceptable salt thereof;

wherein:

R ^w is an alkyl group, preferably an ethyl group;

T ¹ is C-NH ₂ ；

Scheme four

performing cyclization reaction on the compound of the general formula (IIA) or salt thereof and the compound of the general formula (IIB) or salt thereof under alkaline conditions to obtain the compound of the general formula (II) or pharmaceutically acceptable salt thereof;

wherein:

R ^w is an alkyl group, preferably an ethyl group;

T ¹ is C-NH ₂ ；

Scheme five

A process for producing a compound represented by the general formula (II-1) or (II-2) or a pharmaceutically acceptable salt thereof, which comprises:

chiral preparation and resolution are carried out on the compound of the general formula (II) or the pharmaceutically acceptable salt thereof to obtain the compound shown in the general formula (II-1) or (II-2) or the pharmaceutically acceptable salt thereof;

wherein:

Scheme six

performing cyclization reaction on the compound of the general formula (II-1A) or salt thereof and the compound of the general formula (IIB) or salt thereof under alkaline conditions to obtain the compound of the general formula (II-1) or pharmaceutically acceptable salt thereof; or

Performing cyclization reaction on the compound of the general formula (II-2A) or salt thereof and the compound of the general formula (IIB) or salt thereof under alkaline conditions to obtain the compound of the general formula (II-2) or pharmaceutically acceptable salt thereof;

wherein:

R ^w is an alkyl group, preferably an ethyl group;

T ¹ is C-NH ₂ ；

Scheme seven

performing cyclization reaction on the compound of the general formula (IIA) or salt thereof and the compound of the general formula (IIIB) or salt thereof under alkaline condition to obtain the compound of the general formula (III) or pharmaceutically acceptable salt thereof;

wherein:

R ^w is alkyl, preferably ethyl;

T ¹ is C-NH ₂ ；

Scheme eight

A process for producing a compound represented by the general formula (III-1) or (III-2) or a pharmaceutically acceptable salt thereof, which comprises:

chiral preparation and resolution are carried out on the compound of the general formula (III) or the pharmaceutically acceptable salt thereof to obtain the compound shown in the general formula (III-1) or (III-2) or the pharmaceutically acceptable salt thereof;

wherein:

Scheme nine

performing cyclization reaction on the compound of the general formula (II-1A) or salt thereof and the compound of the general formula (IIIB) or salt thereof under alkaline condition to obtain the compound of the general formula (III-1) or pharmaceutically acceptable salt thereof; or

Performing cyclization reaction on the compound of the general formula (II-2A) or salt thereof and the compound of the general formula (IIIB) or salt thereof under alkaline condition to obtain the compound of the general formula (III-2) or pharmaceutically acceptable salt thereof;

wherein:

R ^w is an alkyl group, preferably an ethyl group;

T ¹ is C-NH ₂ ；

Scheme ten

carrying out deprotection reaction on the compound of the general formula (IC) or a salt thereof under an acidic condition to obtain a compound of the general formula (I) or a pharmaceutically acceptable salt thereof;

wherein:

R ^m is an amino protecting group; preferably Boc;

G ⁹ is NH;

Scheme eleven

A process for preparing a compound of the general formula (II) or (III) or a pharmaceutically acceptable salt thereof, which comprises:

carrying out deprotection reaction on the compound of the general formula (IIC) or salt thereof under an acidic condition to obtain a compound of a general formula (II) or pharmaceutically acceptable salt thereof; or

Carrying out deprotection reaction on the compound of the general formula (IIIC) or salt thereof under an acidic condition to obtain a compound of a general formula (III) or pharmaceutically acceptable salt thereof;

wherein:

R ^m is an amino protecting group; preferably Boc;

G ⁹ is NH;

The reagents in the above synthesis schemes that provide basic conditions include organic bases including, but not limited to, triethylamine, pyridine, N-diisopropylethylamine, N-butyllithium, lithium diisopropylamide in tetrahydrofuran, sodium acetate, potassium acetate, sodium tert-butoxide, potassium tert-butoxide, lithium bis (trimethylsilyl) amide in tetrahydrofuran, or 1, 8-diazabicycloundec-7-ene, and inorganic bases including, but not limited to, sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, and potassium hydroxide; preferably lithium diisopropylamide or lithium diisopropylamide in tetrahydrofuran.

Reagents that provide acidic conditions in the above synthetic schemes include organic acids including, but not limited to, trifluoroacetic acid, formic acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, Me, and inorganic acids ₃ SiCl and TMSOTf; the inorganic acids include, but are not limited to, hydrogen chloride, 1, 4-dioxane solution of hydrogen chloride, hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid; trifluoroacetic acid is preferred.

The reaction of the above step is preferably carried out in a solvent including, but not limited to: pyridine, ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, N-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, N-hexane, dimethyl sulfoxide, 1, 4-dioxane, water, N-dimethylformamide, N-dimethylacetamide, 1, 2-dibromoethane and mixtures thereof.

Detailed Description

The present disclosure is further described below with reference to examples, but these examples do not limit the scope of the present disclosure.

Examples

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shift (. delta.) of 10 ^-6 The units in (ppm) are given. NMR was measured using a Bruker AVANCE-400 NMR spectrometer using a solventDeuterated dimethyl sulfoxide (DMSO-d) ₆ ) Deuterated chloroform (CDCl) ₃ ) Deuterated methanol (CD) ₃ OD), internal standard Tetramethylsilane (TMS).

MS measurements were carried out using a FINNIGAN LCQad (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).

High Performance Liquid Chromatography (HPLC) analysis was performed using Agilent HPLC1200 DAD, Agilent HPLC1200VWD and Waters HPLC e2695-2489 HPLC.

Chiral HPLC assay using Agilent 1260DAD HPLC.

High performance liquid preparative chromatographs were prepared using Waters 2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson-281 preparative chromatographs.

Chiral preparation was performed using Shimadzu LC-20AP preparative chromatograph.

CombiFlash flash rapid preparation instrument uses CombiFlash Rf200(TELEDYNE ISCO).

The thin layer chromatography silica gel plate adopts HSGF254 of tobacco yellow sea or GF254 of Qingdao, the specification of the silica gel plate used by Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.

Silica gel column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.

Average inhibition rate of kinase and IC ₅₀ The values were determined with a NovoStar microplate reader (BMG, Germany).

Known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from companies such as ABCR GmbH & Co.KG, Acros Organics, Aldrich Chemical Company, Shao Yuan Chemical technology (Accela ChemBio Inc), Darri Chemicals, and the like.

In the examples, the reaction can be carried out in an argon atmosphere or a nitrogen atmosphere, unless otherwise specified.

An argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to a balloon of argon or nitrogen with a volume of about 1L.

The hydrogen atmosphere refers to a reaction flask connected with a hydrogen balloon with a volume of about 1L.

The pressure hydrogenation reaction used a hydrogenation apparatus of Parr 3916EKX type and a hydrogen generator of Qinglan QL-500 type or a hydrogenation apparatus of HC2-SS type.

The hydrogenation reaction was usually evacuated and charged with hydrogen and repeated 3 times.

The microwave reaction was carried out using a CEM Discover-S908860 type microwave reactor.

In the examples, the solution means an aqueous solution unless otherwise specified.

In the examples, the reaction temperature is, unless otherwise specified, from 20 ℃ to 30 ℃ at room temperature.

The monitoring of the progress of the reaction in the examples employed Thin Layer Chromatography (TLC), a developing solvent used for the reaction, a system of eluents for column chromatography used for purifying compounds and a developing solvent system for thin layer chromatography including: a: dichloromethane/methanol system, B: n-hexane/ethyl acetate system, C: n-hexane/dichloromethane system, D: ethyl acetate/dichloromethane/n-hexane, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of basic or acidic reagents such as triethylamine, acetic acid and the like can be added for adjustment.

Example 1

4-amino-5- (3-methyl-2, 3,4,4a,5, 6-hexahydro-1H, 11H-imidazo [4',5':4,5] benzo [1,2-b ] pyrazino [1,2-d ] [1,4] oxazepan-10-yl) thieno [2,3-b ] pyridin-6 (7H) -one 1

First step of

9, 10-dinitro-1, 2,4,4a,5, 6-hexahydro-3H-benzo [ b ] pyrazino [1,2-d ] [1,4] oxazepan-3-carboxylic acid tert-butyl ester 1c

The compound 1, 2-difluoro-4, 5-dinitrobenzene 1a (1g, 4.3mmol, obtained after finishing Shanghai), 3- (2-hydroxyethyl) piperazine-1-carboxylic acid tert-butyl ester 1B (1.32g, 6.5mmol), potassium hydroxide (730mg, 13mmol) were dissolved in 30mL of dimethyl sulfoxide, reacted at 30 ℃ for 3 hours, then heated to 60 ℃ for 5 hours, 50mL of water was added to the reaction solution, extracted with ethyl acetate (30 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, the filtrate was concentrated under reduced pressure, and column chromatography was purified with an eluent system B to obtain the title compound 1c (1.2g, yield: 70%).

MS m/z(ESI):395.2[M-H]。

Second step of

9, 10-dinitro-2, 3,4,4a,5, 6-hexahydro-1H-benzo [ b ] pyrazino [1,2-d ] [1,4] oxazepan 1d

Compound 1c (1.2g, 3.04mmol) was dissolved in 20mL of dichloromethane, 3mL of trifluoroacetic acid was added, and after stirring for 1 hour, the reaction mixture was concentrated under reduced pressure to give the crude title product 1d (0.89g), which was subjected to the next reaction without purification.

MS m/z(ESI):295.1[M+1]。

The third step

3-methyl-9, 10-dinitro-2, 3,4,4a,5, 6-hexahydro-1H-benzo [ b ] pyrazino [1,2-d ] [1,4] oxazepan 1e

Dissolving compound 1d (890mg, 3.02mmol) in 20mL of methanol, adding 3mL of 37% aqueous formaldehyde solution and three drops of acetic acid, stirring for reaction for 1 hour, adding sodium cyanoborohydride (271.38mg, 4.53mmol), stirring for reaction for 14 hours, concentrating the reaction solution under reduced pressure, and purifying by column chromatography with eluent system a to obtain the title compound 1e (600mg, yield: 60%).

MS m/z(ESI):309.1[M+1]。

The fourth step

1g of ethyl 2- (3-methyl-2, 3,4,4a,5, 6-hexahydro-1H, 9H-imidazo [4',5':4,5] benzo [1,2-b ] pyrazino [1,2-d ] [1,4] oxazepan-10-yl) acetate

Dissolving compound 1e (600mg, 1.94mmol), ethyl 3-ethoxy-3-imidopropionate hydrochloride 1f (1.14g, 5.83mmol, shanghai han hong) in 50mL of absolute ethanol, adding 10% palladium-carbon catalyst (200mg), hydrogen replacing, stirring for 14 hours, heating to 70 ℃ for reaction for 2 hours, filtering the reaction solution, concentrating under reduced pressure, and purifying by column chromatography with eluent system A to obtain the title compound 1g (350mg, yield: 52.2%).

MS m/z(ESI):345.2[M+1]。

The fifth step

Compound 2-aminothiophene-3-carbonitrile was dissolved in 10mL of tetrahydrofuran for 1h (65mg, 523.50. mu. mol), 1g (120mg, 348.42. mu. mol) of compound was added to a 2M tetrahydrofuran solution of lithium diisopropylamide for reaction with stirring for 14 hours, and then concentrated under reduced pressure, followed by purification by high performance liquid chromatography (Waters-2545, column: SharpSil-T C18, 30. mu.150 mm, 5. mu.m; mobile phase 1: water (10mmol/L ammonium hydrogencarbonate); mobile phase 2: acetonitrile, 20-minute gradient ratio: 25% -42%, flow rate: 30mL/min) to give the title compound 1(10mg, yield: 6.79%).

MS m/z(ESI):423.2[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ ):δ12.59(d,1H),12.08(s,1H),10.63(d,1H),7.96(s,1H),7.59(dd,1H),7.33-7.01(m,3H),4.49-4.36(m,1H),4.09-4.02(m,1H),3.18(m,1H),3.11(m,1H),3.00-2.74(m,3H),2.29(s,3H),2.08-1.95(m,2H),1.73(t,2H)。

Examples 1-1, 1-2

(R) -4-amino-5- (3-methyl-2, 3,4,4a,5, 6-hexahydro-1H, 11H-imidazo [4',5':4,5] benzo [1,2-b ] pyrazino [1,2-d ] [1,4] oxazepan-10-yl) thieno [2,3-b ] pyridin-6 (7H) -one 1-1

(S) -4-amino-5- (3-methyl-2, 3,4,4a,5, 6-hexahydro-1H, 11H-imidazo [4',5':4,5] benzo [1,2-b ] pyrazino [1,2-d ] [1,4] oxazepan-10-yl) thieno [2,3-b ] pyridin-6 (7H) -one 1-2

Compound 1(180mg, 426.54. mu. mol) was subjected to chiral preparation (separation conditions: chiral preparation column CHIRALPAK IE20 x 250mm, 5. mu.m; mobile phase 1: n-hexane; mobile phase 2: ethanol (10mmol/L ammonia) flow rate: 20mL/min), and the corresponding fractions were collected and concentrated under reduced pressure to give the title compounds 1-1(70mg, yield: 8.1%), 1-2(65mg, yield: 8.1%).

Single configuration compound 1-1 (shorter retention time):

MS m/z(ESI):423.2[M+1]。

chiral HPLC analysis: retention time 12.19 min, chiral purity: 98% (chromatographic column: CHIRALPAK IE 4.6.6X 150mm,5 μm; mobile phase: n-hexane and ethanol (containing 0.1% diethylamine), ethanol 80% elution, flow rate: 1.0 mL/min).

¹ H NMR(500MHz,DMSO-d ₆ ) Δ 12.59(d,1H),12.11(s,1H),10.63(d,1H),7.96(s,1H),7.59(dd,1H),7.33-7.01(m,3H),4.47-4.43(m,1H),4.07-4.05(m,1H),3.17(m,1H),3.12(m,1H),3.03-2.74(m,3H),2.29(s,3H),2.08-1.95(m,2H),1.73(t, 2H). Single configuration compounds 1-2 (longer retention time):

MS m/z(ESI):423.2[M+1]。

chiral HPLC analysis: retention time 15.64 min, chiral HPLC analysis: chiral purity: 95% (chromatographic column: CHIRALPAK IE 4.6.6X 150mm,5 μm; mobile phase: n-hexane, ethanol (containing 0.1% diethylamine), 80% ethanol elution, flow rate: 1.0 mL/min).

¹ H NMR(500MHz,DMSO-d ₆ ):δ12.60(d,1H),12.08(s,1H),10.63(d,1H),7.95(s,1H),7.58(dd,1H),7.18-7.02(m,3H),4.45-4.40(m,1H),4.07-4.03(m,1H),3.18(m,1H),3.11(m,1H),3.00-2.77(m,3H),2.29(s,3H),2.08-1.95(m,2H),1.73(t,2H)。

Example 2

4-amino-3- (3-methyl-2, 3,4,4a,5, 6-hexahydro-1H, 11H-imidazo [4',5':4,5] benzo [1,2-b ] pyrazino [1,2-d ] [1,4] oxazepan-10-yl) quinolin-2 (1H) -one 2

Using the synthetic route in example 1, the starting compound of the fifth step, 1h, was replaced with the compound 2-aminobenzonitrile to obtain the title compound 2(10mg, yield: 10.33%).

MS m/z(ESI):417.2[M+1]。

¹ H NMR(500MHz,CD ₃ OD):δ8.11(dd,1H),7.60(ddd,1H),7.39-7.34(m,1H),7.33-7.11(m,3H),4.62-4.47(m,1H),4.14(dt,1H),3.23(s,2H),3.00(s,2H),2.80(d,1H),2.52(s,1H),2.44(s,4H),2.15(s,1H),1.76(d,1H)。

Example 3

4-amino-5-fluoro-3- (3-methyl-2, 3,4,4a,5, 6-hexahydro-1H, 11H-imidazo [4',5':4,5] benzo [1,2-b ] pyrazino [1,2-d ] [1,4] oxazepan-10-yl) quinolin-2 (1H) -one 3

(R) -4-amino-5-fluoro-3- (3-methyl-2, 3,4,4a,5, 6-hexahydro-1H, 11H-imidazo [4',5':4,5] benzo [1,2-b ] pyrazino [1,2-d ] [1,4] oxazepan-10-yl) quinolin-2 (1H) -one 3-1

(S) -4-amino-5-fluoro-3- (3-methyl-2, 3,4,4a,5, 6-hexahydro-1H, 11H-imidazo [4',5':4,5] benzo [1,2-b ] pyrazino [1,2-d ] [1,4] oxazepan-10-yl) quinolin-2 (1H) -one 3-2

Using the synthetic route in example 1, the compound of the starting material 1h was replaced with the compound 2-amino-6-fluorobenzonitrile 3a in the fifth step to give the title compound 3(40mg, yield: 7.9%), followed by chiral preparation (separation conditions: apparatus: GILSON 281; column: CHIRALPAK IE 250X 20mm, 5 μm; mobile phase: ethanol (containing 0.1% diethylamine): 100%), and the corresponding fractions were collected and concentrated under reduced pressure to give the title compound 3-1(10mg, yield: 1.98%), 3-2(7mg, yield: 1.38%).

Single configuration compound 3-1 (shorter retention time):

MS m/z(ESI):435.2[M+1]。

chiral HPLC analysis: retention time 29.01 min, purity: 94% (column: CHIRALPAK IE 150)4.6mm, 5 μm; mobile phase: n-hexane and ethanol (containing 0.1% diethylamine), flow rates: 1.0 mL/min). ¹ H NMR(500MHz,CD ₃ OD):δ7.55(td,1H),7.31-7.09(m,3H),7.01(dd,1H),4.59-4.48(m,1H),4.14(dt,1H),3.32-3.23(m,3H),3.00(s,2H),2.80(d,1H),2.51(t,1H),2.44(s,3H),2.15(s,1H),1.76(d,1H)。

Single configuration compound 3-2 (longer retention time):

MS m/z(ESI):435.2[M+1]。

chiral HPLC analysis: retention time 37.89 minutes, purity: 90% (column: CHIRALPAK IE150 x 4.6mm, 5 μm; mobile phase: n-hexane, ethanol (containing 0.1% diethylamine) flow rate: 1.0 mL/min). ¹ H NMR(500MHz,CD ₃ OD):δ7.55(td,1H),7.32-7.10(m,3H),7.01(dd,1H),4.61-4.49(m,1H),4.14(dt,1H),3.27(s,3H),3.01(s,2H),2.81(d,1H),2.53(t,1H),2.45(s,3H),2.15(s,1H),1.76(d,1H)。

Example 4

4-amino-5- (2,3,4,4a,5, 6-hexahydro-1H, 11H-imidazo [4',5':4,5] benzo [1,2-b ] pyrazino [1,2-d ] [1,4] oxazepan-10-yl) thieno [2,3-b ] pyridin-6 (7H) -one 4

(R) -4-amino-5- (2,3,4,4a,5, 6-hexahydro-1H, 11H-imidazo [4',5':4,5] benzo [1,2-b ] pyrazino [1,2-d ] [1,4] oxazepan-10-yl) thieno [2,3-b ] pyridin-6 (7H) -one 4-1

(S) -4-amino-5- (2,3,4,4a,5, 6-hexahydro-1H, 11H-imidazo [4',5':4,5] benzo [1,2-b ] pyrazino [1,2-d ] [1,4] oxazepan-10-yl) thieno [2,3-b ] pyridin-6 (7H) -one 4-2

First step of

10- (2-ethoxy-2-oxyethyl) -1,2,4,4a,5, 6-hexahydro-3H, 9H-imidazo [4',5':4,5] benzo [1,2-b ] pyrazino [1,2-d ] [1,4] oxazepan-3-carboxylic acid tert-butyl ester 4a

Dissolving compound 1c (600mg, 1.94mmol), compound 1f (1.14g, 5.83mmol, shanghai han hong) in absolute ethanol (50mL), adding 10% palladium-carbon catalyst (wet) (200mg), hydrogen gas displacing, stirring for 14 hours, heating to 70 deg.C for 2 hours, filtering the reaction solution, concentrating under reduced pressure, purifying by column chromatography with eluent system A to obtain the title compound 4a (350mg, yield: 52.2%).

MS m/z(ESI):431.2[M+1]。

Second step of

10- (4-amino-6-oxo-6, 7-dihydrothieno [2,3-b ] pyridin-5-yl) -1,2,4,4a,5, 6-hexahydro-3H, 11H-imidazo [4',5':4,5] benzo [1,2-b ] pyrazino [1,2-d ] [1,4] oxazepan-3-carboxylic acid tert-butyl ester 4b

Compound 1h (65mg, 523.50. mu. mol), Compound 4a (120mg, 348.42. mu. mol) were dissolved in tetrahydrofuran (10mL), a 2.0M solution of lithium diisopropylamide in tetrahydrofuran (1.16mL) was added, the reaction was stirred for 14 hours and concentrated under reduced pressure, and column chromatography was performed to purify the title compound 4b (10mg, yield: 6.79%) using eluent system A.

MS m/z(ESI):509.2[M+1]。

The third step

Compound 4b (200mg, 393.2. mu. mol) was dissolved in dichloromethane (20mL), trifluoroacetic acid was added in an amount of 5mL and reacted at room temperature for 0.5 hour, the reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (Waters-2545, column: SharpSil-T C18, 30: 150mM, 5. mu.m; mobile phase: water (10mmol/L ammonium hydrogencarbonate) and acetonitrile, gradient ratio: acetonitrile 38% -45%, flow rate: 30mL/min) to give the title compound 4(80mg, yield: 49.5%), followed by chiral preparation (separation condition: apparatus: GILSON 281; column: CHIRALPAK IE 20: 250mM, 5. mu.m; mobile phase: n-hexane; ethanol (10mM ammonia), flow rate: 20mL/min), the corresponding fractions were collected, concentrated under reduced pressure to give the title compound 4-1(25mg, yield: 31.2%), 4-2(25mg, yield: 31.2%).

Single configuration compound 4-1 (shorter retention time):

MS m/z(ESI):409.2[M+1]。

chiral HPLC analysis: retention time 10.1 min, purity: 95% (column: CHIRALPAK IE20 × 250mm, 5 μm); mobile phase: n-hexane; ethanol (10mM ammonia), flow rate: 20 mL/min).

¹ H NMR(500MHz,DMSO-d ₆ ):δ12.60(d,1H),10.63(d,1H),7.96(s,1H),7.58(dd,1H),7.18-7.02(m,3H),4.45-4.40(m,1H),3.06-3.00(m,4H),2.93-2.84(m,3H),2.02-1.96(m,2H),1.76-1.72(m,1H)。

Single configuration compound 4-2 (longer retention time):

MS m/z(ESI):409.2[M+1]。

chiral HPLC analysis: retention time 15.34 minutes, purity: 95% (column: CHIRALPAK IE20 × 250mm, 5 μm); mobile phase: n-hexane; ethanol (10mM ammonia), flow rate: 20 mL/min).

¹ H NMR(500MHz,DMSO-d ₆ ):δ12.60-12.58(d,1H),10.64-10.60(d,1H),7.96(s,1H),7.59-7.57(dd,1H),7.18-7.01(m,3H),4.48-4.40(m,1H),3.03-3.00(m,4H),2.93-2.84(m,3H),1.98-1.96(m,2H),1.72-1.67(m,1H)。

Biological evaluation

Test example 1 detection of enzyme Activity of HPK1 (ADP-Glo method)

1. Reagent and apparatus

1) ADP-Glo Kinase Assay Kit (including ADP-Glo Reagent and Kinase Detection Reagent)

(Promega,V9101)

2)1M Tris-HCl buffer pH 7.5 (Solibao, T1140)

3)1M MgCl ₂ (Invitrogen,AM9530G)

4)1M DTT(Thermofisher,P2325)

5)20mg/mL Bovine Serum Albumin(BSA)(TAKARA 2320)

6) ATP solution (10mM) (Thermofisiher PV3227)

7) Dephosphorylated MBP (Sigma,13-110) (hereinafter referred to as MBP)

8)HPK1(Signalchem,M23-11G)

9)96-well low volume white plate(Cisbio,66PL96100)

10) PHERA star microplate reader (BMG labtech)

2. Experimental methods

2.1 reagent preparation

Assay buffer 40mM Tris-HCl buffer, 7.5; 20mM MgCl ₂ ；0.1mg/mL BSA；50μM

DTT；

Hpk1 enzyme solution: preparing HPK1 enzyme solution with the final concentration of 1.5 ng/. mu.L by using the assay buffer;

atp and MBP mixed substrates: respectively preparing ATP with the final concentration of 60 mu M and MBP with the final concentration of 0.6 ug/mu L by using the assay buffer, and mixing the prepared ATP and MBP in equal volume;

d. a compound: initial concentration 33.3. mu.M, 3-fold dilution, 9 concentration gradients. Assay for all concentrations of the Compound

The buffer is diluted 33.3 times for standby.

2.2 Experimental procedures

A.96 well plates were loaded with 2. mu.L of the prepared HPK1 enzyme solution per well, no enzyme in column 1, and 2. mu.L of the assay buffer.

b. Add 2. mu.L of compound to each well, no compound to column 1 and last 1, add DMSO as a control, centrifuge, mix well and shake for 2 minutes, incubate for 10 minutes at room temperature.

c. Add 2. mu.L ATP and MBP mixture substrate to each well, centrifuge, mix well and shake for 2 minutes, incubate for 60 minutes at room temperature.

d. Add 6. mu.L ADP-Glo Reagent to each well, centrifuge, mix well and shake for 2 minutes, incubate for 40 minutes at room temperature.

e. Add 12. mu.L of enzyme Detection Reagent (Kinase Detection Reagent) to each well, centrifuge, mix well and shake for 2 minutes, incubate for 40 minutes at room temperature.

f. The microplate reader reads the plate and records the RLU (relative luminescence unit) value.

graph software mapping, calculating Compound IC ₅₀ Values, see table 1.

TABLE 1 inhibition of HPK1 enzymatic Activity IC by Compounds of the present disclosure ₅₀ Value of

Example numbering	HPK1/IC ₅₀ (nM)
		1	0.5
1-1	0.4
		1-2	0.6
2	0.7
		3-1	2.4
3-2	10.5
		4	1.0
4-2	1.1

And (4) conclusion: the disclosed compound has obvious inhibition effect on the activity of HPK1 enzyme.

Test example 2 Jurkat cell SLP76 protein phosphorylation assay (HTRF method)

1. Reagent and apparatus

1) RPMI1640 medium (Gibco,61870044)

2) Total bone Serum (Gibco,10099141C) (hereinafter referred to as FBS)

3)75cm ² Filter cap cell culture bottle (Corning,430641)

4)PBS,pH 7.4(Gibco,10010049)

5)CD3 Antibody,anti-human,pure-functional grade(Miltenyi Biotec,130-093-387)

6)Phospho-SLP-76(Ser376)cellular kit(Cisbio,63ADK076PEG)

7)HTRF 96well low volume plate(Cisbio,66PL96100)

8)96-well plate(Corning,3788)

9) Micropore plate oscillator (Leibeier)

10) PHERA star microplate reader (BMG labtech)

11) Countstar BioMed automatic cell counter (Shanghai Rui Yu biological technology)

12) Clean bench (Thermo,1300ALL)

13)CO ₂ Incubator (Thermo, I160)

2. Cells and culture method

Jurkat E6-1 cells were purchased from American type culture Collection (ATCC, TIB-152) and cultured in RPMI1640 medium (10% FBS). Cell culture density was maintained at 2X 10 ⁵ To 2X 10 ⁶ cells/mL, 2-3 passages a week.

3. Preparation of Compounds

a. Test compounds were dissolved to 5mM in DMSO.

b. Compound starting concentration 5mM, 3-fold dilution, 10 concentration gradients.

c. All concentrations of compounds were diluted 100-fold with culture broth and ready for use.

4. Experimental procedure

Jurkat cell count, cell density adjusted to 5X 10 with fresh medium ⁶ /mL。

b.96 well plates, 20. mu.L of cells were seeded per well and cultured at 37 ℃ for 4 hours.

c. mu.L of compound (5. mu.L of 0.5% DMSO in columns 1 and 12) was added to each well and incubated at 37 ℃ for 1 hour.

d. The CD3 Antibody (CD3 Antibody) was diluted to 20 ng/. mu.L in culture medium, 5. mu.L was added to each well (column 1 plus 5. mu.L of culture medium as a control), and the mixture was incubated at 37 ℃ for half an hour.

e. Cells were lysed by adding 10. mu.L of lysis buffer per well and vortexed at 850rpm for half an hour at room temperature.

f. 16 μ L of cell lysate was transferred to a fresh HTRF 96 well plate, 4 μ L of antibody mix was added to each well and left overnight at room temperature.

g. The plate was read by the microplate reader and signals at 665nm and 620nm were recorded.

Graph software mapping, calculate compound IC ₅₀ Values, see table 2.

TABLE 2 inhibition of SLP76 protein phosphorylation by Compounds of the disclosure IC ₅₀ Value of

Example numbering	SLP76 protein phosphorylation/IC ₅₀ (nM)
		1	65
1-1	31
		1-2	84
2	40
		3-1	92.8
4	83.4
		4-1	27.5
4-2	72

And (4) conclusion: the compound disclosed by the invention has obvious inhibition effect on protein phosphorylation of SLP76 of Jurkat cells.

Claims

1. A compound of the general formula (I) or a pharmaceutically acceptable salt thereof:

wherein:

ring a is selected from aryl, heterocyclyl and heteroaryl;

T ¹ is CR ^T1 Or a nitrogen atom;

G ⁸ is CR ^G8 Or a nitrogen atom;

G ¹ and G ² Are the same or different and are each independently selected from CR ² 、NR ³ Nitrogen atom, oxygen atom and sulfur atom;

Two R together form oxo;

R ⁰ 、R ³ 、R ⁶ 、R ^G7c and R ^G9c Are the same or different and are each independently selected from the group consisting of hydrogen atoms, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups;

R ⁴ 、R ⁵ 、R ^G7a 、R ^G7b 、R ^G9a and R ^G9b The same or different, and each is independently selected from the group consisting of hydrogen atoms, halogens, alkyls, alkenyls, alkynyls, alkoxys, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyls, alkenyls, alkynyls, alkoxys, cycloalkyls, heterocyclyl, aryl, and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogens, alkyls, alkenyls, alkynyls, alkoxys, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; or

R ⁴ And R ⁵ 、R ^G7a And R ^G7b Or R ^G9a And R ^G9b Wherein a pair together form an oxo group;

R ⁷ And R ⁸ Together with the nitrogen atom to which it is attached, form a heterocyclyl optionally substituted with one or more of halo, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy and hydroxyalkyl;

m is 0, 1,2,3 or 4;

q is 0, 1,2,3 or 4; and is

n is 0, 1,2,3, 4,5 or 6.

2. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein

Is composed of

R ¹⁰ 、R ^T3 and R ¹¹ Are the same or different and are each independently selected from the group consisting of a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, - (CH) ₂ ) _m NR ⁷ R ⁸ 、-OR ⁹ Nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, whereinSaid alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ⁷ 、R ⁸ 、R ⁹ and m is as defined in claim 1.

3. The compound according to claim 1 or2, which is a compound represented by the general formula (II) or (III):

wherein:

T ¹ 、G ³ 、G ⁴ 、G ⁵ 、G ⁶ 、G ⁹ r, R', q and n are as defined in claim 1.

4. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein G ⁵ Is CR ⁴ R ⁵ Or an oxygen atom; and/or G ⁶ Is CR ⁴ R ⁵ Or an oxygen atom; preferably, G ⁵ And G ⁶ One of them is CR ⁴ R ⁵ And the other is an oxygen atom; r ⁴ And R ⁵ As defined in claim 1.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein G is ⁹ Is NR ^G9c ，R ^G9c Is a hydrogen atom or C _1-6 An alkyl group; preferably, G ⁹ Is NCH ₃ 。

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein G is ³ Is CR ¹ (ii) a And/or G ⁴ Is CR ¹ ；R ¹ As defined in claim 1.

7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein T ¹ Is CR ^T1 ；R ^T1 As defined in claim 1; preferably, T ¹ Is C-NH ₂ 。

8. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R is the same or different and each is independently selected from the group consisting of hydrogen, halogen and C _1-6 An alkyl group; preferably, R is a hydrogen atom.

9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R' are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, and C _1-6 An alkyl group; preferably, R' is a hydrogen atom or a halogen.

10. A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein q is 0 or 1.

11. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1.

12. A compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, which is a compound of:

13. a compound represented by the general formula (IA):

wherein: r ^w Is an alkyl group;

G ¹ to G ⁹ R and n are as defined in claim 1.

14. A compound selected from the following compounds:

15. a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1, which comprises:

wherein: r ^w Is an alkyl group;

T ¹ is C-NH ₂ ；

Ring A, R ⁰ 、R’、q、G ¹ To G ⁹ R and n are as defined in claim 1.

16. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

17. Use of a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 16, in the manufacture of a medicament for inhibiting HPK 1.

18. Use of a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 16, for the manufacture of a medicament for the treatment and/or prevention of cancer, autoimmune diseases, inflammatory diseases, infectious diseases, cardiovascular diseases, neurodegenerative diseases, diabetes and diseases or conditions of reproductive disorders.

19. The use of claim 18, wherein the disease or condition is selected from the group consisting of cancer, allergy, asthma, sepsis, hiv infection, hepatitis b virus infection, ischemia, atherosclerosis, stroke, and alzheimer's disease; the cancer is preferably selected from brain cancer, thyroid cancer, head and neck cancer, throat cancer, oral cancer, salivary gland cancer, esophageal cancer, stomach cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, bile duct cancer, colorectal cancer, small intestine cancer, gastrointestinal stromal tumor, urothelial cancer, urinary tract cancer, bladder cancer, breast cancer, ovarian cancer, uterine cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, leukemia, lymphoma, multiple myeloma, skin cancer, malignant lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, neuroblastoma, and glioblastoma; the uterine cancer is preferably endometrial cancer.