CN115734966A

CN115734966A - Heterocyclic compounds and their use

Info

Publication number: CN115734966A
Application number: CN202180041106.4A
Authority: CN
Inventors: 米国瑞; 张颜; 徐艳霞; 王松雨; 耿佳; 张安琪; 赵方亮; 杨梦宇
Original assignee: CSPC Zhongqi Pharmaceutical Technology Shijiazhuang Co Ltd
Current assignee: CSPC Zhongqi Pharmaceutical Technology Shijiazhuang Co Ltd
Priority date: 2020-06-12
Filing date: 2021-04-28
Publication date: 2023-03-03
Also published as: WO2021249057A1

Abstract

SHP2 inhibitors represented by formula (I-1) or pharmaceutically acceptable salts, stereoisomers, pharmaceutical compositions thereof, and their use in the treatment and/or prevention of diseases, disorders and conditions mediated by SHP2 activity.

Description

[ invention name prepared by ISA according to rules 37.2 ] heterocyclic compound and application thereof

Cross Reference to Related Applications

This application claims the benefit and priority of the chinese patent application No. 202010534482.4 filed on 12.06.12.2020 by the national intellectual property office of the people's republic of china, the entire contents of which are hereby incorporated by reference in their entirety.

Technical Field

The present application relates to the field of pharmaceutical technology, and in particular, to a novel class of compounds having SHP2 inhibitor activity and their use in the treatment and prevention of diseases, disorders and conditions mediated by SHP2 activity, such as hyperproliferative diseases.

Background

SHP2 (Src homology domain), encoded by the protein tyrosine phosphatase non-receptor type 11 (PTP nonreceptor 11, PTPN11), catalyzes protein tyrosine dephosphorylation reaction. Generally, the N terminal of SHP2 comprises 2 SH2 domains including an N-src homology 2 domain (SH 2) and C-SH2, the C terminal comprises 1 PTP domain with catalytic activity, in an inactivated state, SHP2 is in a self-inhibition state, and the combination of N-SH2 and C-PTP inhibits phosphatase activity. In the presence of extracellular stimuli, they bind to the relevant receptors, activating downstream multiple signaling pathways, such as multiple signaling pathways including Ras/MAPK, PI3K/AKT, and the like, regulating cell proliferation, differentiation, apoptosis, and survival.

The literature discloses (Eur J Med genet.2015.58: 509. Studies by Revolution medicins also indicate that SHP2 plays an important role in the oncogenic growth and survival signals of up to 45% of non-small cell lung cancers, as well as some other common cancers.

In addition, studies have shown (Sci adv.2020.6 (5): eaay 4458), that programmed death 1 (PD-1) is also involved in mediating and activating SHP2. In cancer, PD-1 inhibits T cell stimulation and mediates immune escape, upon which PD-1 is phosphorylated at its immunoreceptor tyrosine-based inhibitory motif (ITIM) and immunoreceptor tyrosine-based switching motif (ITSM), and then binds to SHP2, initiating T cell inactivation. Thus, SHP2 inhibitors can stimulate adaptive and innate immune activity in the tumor microenvironment, with the potential to restore anti-tumor immune responses that have been silenced by cancer cells. Thus, there is a great need for compounds useful as SHP2 inhibitors to treat and prevent diseases, disorders, and conditions mediated by SHP2 activity.

Summary of The Invention

In one aspect, the present application provides a compound represented by formula (I-1) or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof,

X is selected from a bond or-S-;

X ₁ and X ₂ Each independently selected from N and CR ₈ (ii) a Wherein each R ₈ Independently selected from-H, halogen, -NH ₂ 、-NHR _8b 、-NR _8b R _8c 、-NHCOR _8a 、-CN、-OH、-NO ₂ 、-COOH、-CONH ₂ 、-CONHR _8b 、-CONR _8b R _8c 、-COOR _8b Substituted or unsubstituted C _1～6 Alkyl, substituted or unsubstituted C _1～6 Alkoxy, substituted or unsubstituted C _3～6 Cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted mono spirocycloalkyl, substituted or unsubstituted hetero mono spirocycloalkyl, substituted or unsubstituted C _6～14 Aryl and substituted or unsubstituted 5-to 14-membered heteroaryl, wherein said substituted C _1～6 Alkyl, substituted C _1～6 Alkoxy, substituted C _3～6 Cycloalkyl, substituted 3-6 membered heterocycloalkyl, substituted mono spirocycloalkyl, substituted hetero mono spirocycloalkyl, substituted C _6～14 Aryl and substituted 5-to 14-membered heteroaryl are each independently selected from-OH, halogen, unsubstituted C _1-6 Alkyl, -NH ₂ 、-NO ₂ unsubstituted-COC _1-6 Alkyl, -CN and = O;

R _8a selected from:

R _8b and R _8c Each independently selected from unsubstituted C _1～6 An alkyl group;

R ₁ and R ₃ Each independently selected from-H, halogen, -NH ₂ 、-CN、-OH、-NO ₂ -COOH, substituted or unsubstituted C _1～6 Alkyl and substituted or unsubstituted C _1～6 Alkoxy, wherein said substituted C _1～6 Alkyl and substituted C _1～6 Alkoxy is independently selected from-OH, halogen, unsubstituted C _1-6 Alkyl, -NH ₂ 、-NO ₂ Unsubstituted or substitutedOf (C-COC) _1-6 Alkyl, -CN, and = O;

R ₂ selected from-H, halogen, -NH ₂ 、-CN、-OH、-NO ₂ Carboxy, -NHR _2a 、-NR _2a R _2b 、-CONH ₂ 、-CONHR _2a 、-CONR _2a R _2b 、-COR _2a 、-COOR _2a 、-NHCOR _2a 、-N(R _2a )-COR _2b Substituted or unsubstituted C _1～6 Alkyl, substituted or unsubstituted C _1～6 Alkoxy, substituted or unsubstituted C _3～6 Cycloalkyl, substituted or unsubstituted 3-to 6-membered heterocycloalkyl, substituted or unsubstituted mono-spirocycloalkyl, substituted or unsubstituted hetero-mono-spirocycloalkyl, substituted or unsubstituted C _4～8 Bridged cycloalkyl and substituted or unsubstituted 4-8 membered heterobridged cycloalkyl, wherein said substituted C _1～6 Alkyl, substituted C _1～6 Alkoxy, substituted C _3～6 Cycloalkyl, substituted 3-to 6-membered heterocycloalkyl, substituted mono-spirocycloalkyl, substituted hetero-mono-spirocycloalkyl, substituted C _4～8 The bridged cycloalkyl group and the substituted 4-8 membered heterobridged cycloalkyl group are each independently selected from-OH, halogen, unsubstituted C _1-6 Alkyl, -NH ₂ 、-NO ₂ unsubstituted-COC _1-6 Alkyl, -CN and = O;

or R ₂ To adjacent R ₃ By ring closure to form substituted or unsubstituted C ₆ Or C ₁₀ Aryl, substituted or unsubstituted 5-to 8-membered heteroaryl or substituted or unsubstituted non-aromatic 5-to 8-membered heterocyclyl, wherein C is substituted ₆ Or C ₁₀ Aryl, substituted 5-to 8-membered heteroaryl or substituted non-aromatic 5-to 8-membered heterocyclyl is each independently selected from-OH, halogen, unsubstituted C _1-6 Alkyl, -NH ₂ 、-NO ₂ unsubstituted-COC _1-6 Alkyl, -CN, and = O;

R _2a and R _2b Each independently selected from unsubstituted C _1～6 An alkyl group;

R ₇ selected from-H, halogen, -CN, -COOR _7a 、-COR _7b Substituted or unsubstituted C _2-6 Alkenyl, substituted or unsubstituted C _2-6 Alkynyl, -CONH ₂ 、-C(O)-COOR _7a Substituted or unsubstituted C _3～6 Cycloalkyl, substituted or unsubstituted C _2～6 Heterocycloalkyl, substituted or unsubstituted mono spirocycloalkyl and substituted or unsubstituted hetero mono spirocycloalkyl; r is _7a is-H, substituted or unsubstituted C _1-6 Alkyl or substituted or unsubstituted C _3-6 A cycloalkyl group; r _7b Selected from-H, substituted or unsubstituted C _1～6 Alkyl, substituted or unsubstituted C _3～6 Cycloalkyl, substituted or unsubstituted 3-to 6-membered heterocycloalkyl, substituted or unsubstituted C _6～14 Aryl and substituted or unsubstituted 5-to 10-membered heteroaryl; wherein, said substituted C _2-6 Alkenyl, substituted C _2-6 Alkynyl, substituted C _3～6 Cycloalkyl, substituted C _2～6 Heterocycloalkyl, substituted mono-spirocycloalkyl, substituted hetero-mono-spirocycloalkyl, substituted C _1-6 Alkyl, substituted 3-to 6-membered heterocycloalkyl, substituted C _6～14 Aryl and substituted 5-to 10-membered heteroaryl are each independently selected from-OH, halogen, -NH ₂ 、-NO ₂ Unsubstituted C _1～6 Alkyl, unsubstituted C _1～6 Alkoxy, unsubstituted C _3～6 Cycloalkyl, unsubstituted-NH-C _1～6 Alkyl, unsubstituted-N (C) _1～6 Alkyl) (C _1～6 Alkyl), unsubstituted-NH-C _3～6 Cycloalkyl, unsubstituted-N (C) _3～6 Cycloalkyl) (C) _3～6 Cycloalkyl), unsubstituted 3-to 6-membered heterocycloalkyl,Unsubstituted C _6～14 Aryl or unsubstituted 5-to 10-membered heteroaryl;

indicates the presence or absence of a bond;

i)

when no bond is present, X ₃ Nor is present, R ₄ And R ₅ Each independently selected from hydrogen, hydroxy, halogen, = O, substituted or unsubstituted C _1～6 Alkyl and substituted or unsubstituted C _1～6 Alkoxy radical, wherein R ₄ And R ₅ Each independently selected from "= O" means that another hydrogen atom at the same substitution position is simultaneously substituted by the oxygen atom, wherein the substituted C _1～6 Alkyl and substituted C _1～6 Alkoxy is independently selected from-OH, halogen, unsubstituted C _1-6 Alkyl, -NH ₂ 、-NO ₂ unsubstituted-COC _1-6 Alkyl, -CN and = O;

ii)

when a bond is present, X ₃ Is CH ₂ ，R ₄ And R ₅ Are all hydrogen;

represents a single bond or a double bond;

i) When in use

When represents a single bond, ring A and- (R) ₆ ) _m Is absent, Y ₁ And Y ₂ Each independently is CR ₉ R ₁₀ O or NR ₁₀ ；

Each R ₉ And R ₁₀ Independently selected from-H, halogen, -OH, substituted or unsubstituted C _1～6 Alkyl and substituted or unsubstituted C _1～6 Alkoxy, wherein said substituted C _1～6 Alkyl and substituted C _1～6 Alkoxy is independently selected from OH, halogen, unsubstituted C _1-6 Alkyl, -NH ₂ 、-NO ₂ unsubstituted-COC _1-6 Alkyl, -CN, and = O;

ii) when

When represents a double bond, Y ₁ And Y ₂ Are both C, ring A is present, ring A is selected from naphthyl, phenyl or 5-to 6-membered heteroaryl;

R ₆ selected from halogen, -NH ₂ 、-NHR _6a 、-NR _6a R _6b 、-CN、-CONH ₂ 、-CONHR _6a 、-CONR _6a R _6b 、-COR _6a -COOH, -OH, substituted or unsubstituted-SO _n C _1-6 Alkyl, substituted or unsubstituted C _1-6 Alkyl and substituted or unsubstituted C _1～6 Alkoxy radical, wherein R _6a And R _6b Each independently of the other being unsubstituted C _1～6 An alkyl group; n is selected from 0, 1 or 2, wherein said substituted-SO _n C _1-6 Alkyl, substituted C _1-6 Alkyl and substituted C _1～6 Alkoxy is independently of each otherIs selected from-OH, halogen, unsubstituted C _1-6 Alkyl, -NH ₂ 、-NO ₂ unsubstituted-COC _1-6 Alkyl, -CN and = O;

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

wherein the number of ring atoms of the mono-and hetero-spirocycloalkyl groups is independently selected from the group consisting of 3-membered/5-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered and 5-membered/6-membered rings, wherein the count for each ring includes a spiro atom; and

The substituent "= O" means that two hydrogen atoms at the same substitution position are substituted with an oxygen atom.

In some embodiments of the present application, the compounds of formula (I) do not include the following compounds:

in another aspect, the present application provides a pharmaceutical composition comprising a therapeutically effective amount of a compound represented by formula (I-1) or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

In yet another aspect, the present application provides a method for treating and/or preventing diseases, disorders, and conditions mediated by SHP2 activity, the method comprising administering a compound represented by formula (I-1) or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to a subject in need thereof.

In yet another aspect, the present application provides the use of a compound of formula (I-1) or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the treatment and/or prevention of diseases, disorders, and conditions mediated by SHP2 activity.

In yet another aspect, the present application provides a compound represented by formula (I-1) or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the treatment and/or prevention of diseases, disorders, and conditions mediated by SHP2 activity.

In yet another aspect, the present application provides the use of a compound of formula (I-1) or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the treatment and/or prevention of diseases, disorders, and conditions mediated by SHP2 activity.

Detailed Description

In the following description, certain specific details are included to provide a thorough understanding of various disclosed embodiments. One skilled in the relevant art will recognize, however, that the embodiments may be practiced without one or more of the specific details, or with other methods, components, materials, and so forth.

Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to be open-ended, inclusive meaning that "includes but is not limited to".

Reference throughout this specification to "one embodiment," "some embodiments," or "an embodiment" or "in another embodiment" or "in certain embodiments" means that a particular reference element, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrase "in one embodiment" or "in an embodiment" or "in another embodiment" or "in certain embodiments" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular elements, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

It should be understood that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a reaction comprising "a catalyst" includes one catalyst, or two or more catalysts. It will also be understood that the term "or" is generally employed in its sense including "and/or" unless the context clearly dictates otherwise.

The present application aims to provide a novel class of heterocyclic compounds useful as SHP2 inhibitors, or prodrugs, tautomers, stereoisomers, solvates, isotopic derivatives, or pharmaceutically acceptable salts thereof, as well as the use of such compounds, or prodrugs, tautomers, stereoisomers, solvates, isotopic derivatives, or pharmaceutically acceptable salts thereof, in the treatment and prevention of diseases, disorders, and conditions mediated by SHP2 activity.

In one aspect, the present application provides a compound represented by formula (I-1), or a prodrug, tautomer, optical isomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof,

x is selected from a bond or-S-;

X ₁ and X ₂ Each independently selected from N and CR ₈ (ii) a Wherein each R ₈ Independently selected from-H, halogen, -NH ₂ 、-NHR _8b 、-NR _8b R _8c 、-NHCOR _8a 、-CN、-OH、-NO ₂ 、-COOH、-CONH ₂ 、-CONHR _8b 、-CONR _8b R _8c 、-COOR _8b Substituted or unsubstituted C _1～6 Alkyl, substituted or unsubstituted C _1～6 Alkoxy, substituted or unsubstituted C _3～6 Cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted mono spirocycloalkyl, substituted or unsubstituted hetero mono spirocycloalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroarylSubstituted or unsubstituted C _6～14 Aryl and substituted or unsubstituted 5-to 14-membered heteroaryl, wherein said substituted C _1～6 Alkyl, substituted C _1～6 Alkoxy, substituted C _3～6 Cycloalkyl, substituted 3-6 membered heterocycloalkyl, substituted mono spirocycloalkyl, substituted hetero mono spirocycloalkyl, substituted C _6～14 Aryl and substituted 5-to 14-membered heteroaryl are each independently selected from-OH, halogen, unsubstituted C _1-6 Alkyl, -NH ₂ 、-NO ₂ unsubstituted-COC _1-6 Alkyl, -CN, and = O;

R _8a selected from:

R ₁ and R ₃ Each independently selected from-H, halogen, -NH ₂ 、-CN、-OH、-NO ₂ -COOH, substituted or unsubstituted C _1～6 Alkyl and substituted or unsubstituted C _1～6 Alkoxy, wherein said substituted C _1～6 Alkyl and substituted C _1～6 Alkoxy is independently selected from-OH, halogen, unsubstituted C _1-6 Alkyl, -NH ₂ 、-NO ₂ unsubstituted-COC _1-6 Alkyl, -CN, and = O;

R ₂ selected from-H, halogen, -NH ₂ 、-CN、-OH、-NO ₂ Carboxy, -NHR _2a 、-NR _2a R _2b 、-CONH ₂ 、-CONHR _2a 、-CONR _2a R _2b 、-COR _2a 、-COOR _2a 、-NHCOR _2a 、-N(R _2a )-COR _2b Substituted or unsubstituted C _1～6 Alkyl, substituted or unsubstituted C _1～6 Alkoxy, substituted or unsubstituted C _3～6 Cycloalkyl, substituted or unsubstituted 3-to 6-membered heterocycloalkyl, substituted or unsubstituted mono-spirocycloalkyl, substituted or unsubstituted hetero mono-spirocycloalkyl, substituted or unsubstituted C _4～8 Bridged cycloalkyl and substituted or unsubstituted 4-8 membered heterobridged cycloalkyl, wherein said substituted C _1～6 Alkyl, substituted C _1～6 Alkoxy, substituted C _3～6 Cycloalkyl, substituted 3-to 6-membered heterocycloalkyl, substituted mono-spirocycloalkyl, substituted hetero mono-spirocycloalkyl, substituted C _4～8 The bridged cycloalkyl group and the substituted 4-8 membered heterobridged cycloalkyl group are each independently selected from-OH, halogen, unsubstituted C _1-6 Alkyl, -NH ₂ 、-NO ₂ unsubstituted-COC _1-6 Alkyl, -CN and = O;

or R ₂ To adjacent R ₃ By cyclization to form substituted or unsubstituted C ₆ Or C ₁₀ Aryl, substituted or unsubstituted 5-to 8-membered heteroaryl or substituted or unsubstituted non-aromatic 5-to 8-membered heterocyclyl, wherein C is substituted ₆ Or C ₁₀ Aryl, substituted 5-to 8-membered heteroaryl or substituted non-aromatic 5-to 8-membered heterocyclyl are each independently selected from-OH, halogen, unsubstituted C _1-6 Alkyl, -NH ₂ 、-NO ₂ unsubstituted-COC _1-6 Alkyl, -CN, and = O;

R ₇ selected from-H, halogen, -CN, -COOR _7a 、-COR _7b Substituted or unsubstituted C _2-6 Alkenyl, substituted or unsubstituted C _2-6 Alkynyl, -CONH ₂ 、-C(O)-COOR _7a Substituted or unsubstituted C _3～6 Cycloalkyl, substituted or unsubstituted C _2～6 Heterocycloalkyl, substituted or unsubstituted mono-spirocycloalkyl and substituted or unsubstituted hetero-mono-spirocycloalkyl; r is _7a is-H, substituted or unsubstituted C _1-6 Alkyl or substituted or unsubstituted C _3-6 A cycloalkyl group; r is _7b Selected from-H, substituted or unsubstituted C _1～6 Alkyl, substituted or unsubstituted C _3～6 Cycloalkyl, substituted or unsubstituted 3-to 6-membered heterocycloalkyl, substituted or unsubstituted C _6～14 Aryl and substituted or unsubstituted 5-to 10-membered heteroaryl; wherein, said substituted C _2-6 Alkenyl, substituted C _2-6 Alkynyl, substituted C _3～6 Cycloalkyl, substituted C _2～6 Heterocycloalkyl, substituted mono-spirocycloalkyl, substituted hetero-mono-spirocycloalkyl, substituted C _1-6 Alkyl, substituted 3-to 6-membered heterocycloalkyl, substituted C _6～14 Aryl and substituted 5-to 10-membered heteroaryl are each independently selected from-OH, halogen, -NH ₂ 、-NO ₂ Unsubstituted C _1～6 Alkyl, unsubstituted C _1～6 Alkoxy, unsubstituted C _3～6 Cycloalkyl, unsubstituted-NH-C _1～6 Alkyl, unsubstituted-N (C) _1～6 Alkyl) (C _1～6 Alkyl), unsubstituted-NH-C _3～6 Cycloalkyl, unsubstituted-N (C) _3～6 Cycloalkyl) (C) _3～6 Cycloalkyl), unsubstituted 3-to 6-membered heterocycloalkyl, unsubstituted C _6～14 Aryl or unsubstituted 5-to 10-membered heteroaryl;

Indicates the presence or absence of a bond;

i)

when it indicates that a bond is absent, X ₃ Nor is present, R ₄ And R ₅ Each independently selected from hydrogen, hydroxy, halogen, = O, substituted or unsubstituted C _1～6 Alkyl and substituted or unsubstituted C _1～6 Alkoxy radical, wherein R ₄ And R ₅ Each independently selected from "= O" means that another hydrogen atom at the same substitution position is simultaneously substituted by the oxygen atom, wherein the substituted C is _1～6 Alkyl and substituted C _1～6 Alkoxy is independently selected from-OH, halogen, unsubstituted C _1-6 Alkyl, -NH ₂ 、-NO ₂ unsubstituted-COC _1-6 Alkyl, -CN and = O;

ii)

when a bond is present, X ₃ Is CH ₂ ，R ₄ And R ₅ Are all hydrogen;

represents a single or double bond;

i) When the temperature is higher than the set temperature

Each R ₉ And R ₁₀ Independently selected from-H, halogen,-OH, substituted or unsubstituted C _1～6 Alkyl and substituted or unsubstituted C _1～6 Alkoxy, wherein said substituted C _1～6 Alkyl and substituted C _1～6 Alkoxy is independently selected from OH, halogen, unsubstituted C _1-6 Alkyl, -NH ₂ 、-NO ₂ unsubstituted-COC _1-6 Alkyl, -CN and = O;

ii) when

When representing a double bond, Y ₁ And Y ₂ Both C, ring A is present and is selected from naphthyl, phenyl or 5-to 6-membered heteroaryl;

R ₆ selected from halogen, -NH ₂ 、-NHR _6a 、-NR _6a R _6b 、-CN、-CONH ₂ 、-CONHR _6a 、-CONR _6a R _6b 、-COR _6a -COOH, -OH, substituted or unsubstituted-SO _n C _1-6 Alkyl, substituted or unsubstituted C _1-6 Alkyl and substituted or unsubstituted C _1～6 Alkoxy radical, wherein R _6a And R _6b Each independently of the other being unsubstituted C _1～6 An alkyl group; n is selected from 0, 1 or 2, wherein said substituted-SO _n C _1-6 Alkyl, substituted C _1-6 Alkyl and substituted C _1～6 Alkoxy is independently selected from-OH, halogen, unsubstituted C _1-6 Alkyl, -NH ₂ 、-NO ₂ unsubstituted-COC _1-6 Alkyl, -CN and = O;

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

wherein the number of ring atoms of the mono-and hetero-spirocycloalkyl groups are independently selected from the group consisting of 3-membered/5-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, and 5-membered/6-membered rings, wherein the count for each ring includes a spiro atom; and

in some embodiments of the present application, there is provided compounds of formula (I) and pharmaceutically acceptable salts thereof,

X is selected from a bond or S;

X ₁ and X ₂ Each independently selected from N or CR ₈ (ii) a Wherein R is ₈ Selected from-H, halogen, -NH ₂ 、-NHR _8b 、-NR _8b R _8c 、-NHCOR _8a 、-CN、-OH、-NO ₂ 、-COOH、-CONH ₂ 、-CONHR _8b 、-CONR _8b R _8c 、-COOR _8b Substituted or unsubstituted C _1～6 Alkyl, substituted or unsubstituted C _1～6 Alkoxy, substituted or unsubstituted C _3～6 Cycloalkyl, substituted or unsubstituted heteromonospirocycloalkyl; the term "substituted" means that the substituents are independently selected from one or more of-OH, halogen, C _1-6 Alkyl, -NH ₂ 、-NO ₂ 、-COCH ₃ And, -CN and = O, the case where the substituent is "= O" means that two hydrogen atoms at the same substitution position are substituted with an oxygen atom;

wherein R is _8a Selected from:

R _8b and R _8c Each independently selected from C _1～6 An alkyl group;

R ₁ and R ₃ Each independently selected from-H, halogen, -NH ₂ 、-CN、-OH、-NO ₂ -COOH, substituted or unsubstituted C _1～6 Alkyl, substituted or unsubstituted C _1～6 An alkoxy group; the term "substituted" means that the substituents are independently selected from one or more of-OH, halogen, C _1-6 Alkyl, -NH ₂ 、-NO ₂ 、-COCH ₃ And, -CN and = O, the case where the substituent is "= O" means that two hydrogen atoms at the same substitution position are substituted with an oxygen atom;

R ₂ selected from-H, halogen, -NH ₂ 、-CN、-OH、-NO ₂ Carboxy, -NHR _2a 、-NR _2a R _2b 、-CONH ₂ 、-CONHR _2a 、-CONR _2a R _2b 、-COR _2a 、-COOR _2a 、-NHCOR _2a 、-N(R _2a )-COR _2b Substituted or unsubstituted C _1～6 Alkyl, substituted or unsubstituted C _1～6 Alkoxy, substituted or unsubstituted C _3～6 Cycloalkyl, substituted or unsubstituted 3-to 6-membered heterocycloalkyl, substituted or unsubstituted mono-spirocycloalkyl, substituted or unsubstituted hetero-mono-spirocycloalkyl, substituted or unsubstituted C _4～8 Bridged cycloalkyl and substituted or unsubstituted 4-8 membered heterobridged cycloalkyl; wherein said mono-spirocycloalkyl and heteroThe number of ring atoms of the spirocycloalkyl group is selected from the group consisting of 3-membered/5-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered and 5-membered/6-membered rings, wherein each ring count includes a spiro atom; the term "substituted" means that the substituents are independently selected from one or more of-OH, halogen, C _1-6 Alkyl, -NH ₂ 、-NO ₂ 、-COCH ₃ And, -CN and = O, the case where the substituent is "= O" means that two hydrogen atoms at the same substitution position are substituted with an oxygen atom;

or R ₂ To adjacent R ₃ Cyclizing to form a substituted or unsubstituted 5-to 8-membered heteroaryl or a substituted or unsubstituted non-aromatic 5-to 8-membered heterocyclic group; the term "substituted" means that the substituents are independently selected from one or more of-OH, halogen, C _1-6 Alkyl, -NH ₂ 、-NO ₂ 、-COCH ₃ And, -CN and = O, the case where the substituent is "= O" means that two hydrogen atoms at the same substitution position are substituted with an oxygen atom;

R _2a and R _2b Each independently selected from C _1～6 An alkyl group;

R ₇ selected from-H, halogen, -CN, -COOR _7a 、-COR _7b 、C _2-6 Alkenyl, -CONH ₂ Substituted or unsubstituted C _3～6 Cycloalkyl, substituted or unsubstituted C _3～6 Heterocycloalkyl and a substituted or unsubstituted heteromonospirocycloalkyl group containing 1 or 2 heteroatoms, wherein the number of ring atoms of the heteromonospirocycloalkyl group is selected from 3-membered/5-membered, 4-membered/4-membered, 4-membered/5-membered, the number of each ring counted including the spiro atom; r _7a is-H or substituted or unsubstituted C _1-6 An alkyl group; r _7b Selected from-H, substituted or unsubstituted C _1～6 Alkyl, substituted or unsubstituted C _3～6 Cycloalkyl, substituted or unsubstituted 3-to 6-membered heterocycloalkyl, substituted or unsubstituted C _6～14 Aryl or substituted or unsubstituted 5-to 10-membered heteroaromatic ring; the term "substituted" means that the substituents are independently selected from one or more of-OH, halogen, -NH ₂ 、-NO ₂ 、C _1～6 Alkyl radical, C _1～6 Alkoxy radical, C _3～6 Cycloalkyl, -NH-C _1～6 Alkyl, -N (C) _1～6 Alkyl) -C _1～6 Alkyl, -NH-C _3～6 Cycloalkyl, -N (C) _3～6 Cycloalkyl) -C _3～6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C _6～14 Aryl or 5-to 10-membered heteroaromatic ring group;

indicates the presence or absence of a bond;

i)

when it indicates that a bond is absent, X ₃ Nor is present, R ₄ And R ₅ Each independently selected from hydrogen, hydroxy, halogen, = O, substituted or unsubstituted C _1～6 Alkyl and substituted or unsubstituted C _1～6 An alkoxy group; r ₄ And R ₅ Each independently selected from "= O" means that another hydrogen atom at the same substitution position is simultaneously substituted by the oxygen atom; the term "substituted" means that the substituents are independently selected from one or more of-OH, halogen, C _1-6 Alkyl, -NH ₂ 、-NO ₂ 、-COCH ₃ And, -CN and = O, the case where the substituent is "= O" means that two hydrogen atoms at the same substitution position are substituted with an oxygen atom;

ii)

When a bond is present, X ₃ Is CH ₂ ，R ₄ And R ₅ Are all hydrogen;

represents a single bond or a double bond;

1) When in use

When represents a single bond, ring A and- (R) ₆ ) _m Absence, Y ₁ And Y ₂ Each independently is CR ₉ R ₁₀ O or NR ₁₀ ；

Each R ₉ And R ₁₀ Independently selected from-H, halogen, -OH, substituted or unsubstituted C _1～6 Alkyl, substituted or unsubstituted C _1～6 An alkoxy group; the term "substituted" means that the substituents are independently selected from one or more of-OH, halogen, C _1-6 Alkyl, -NH ₂ 、-NO ₂ 、-COCH ₃ And, -CN and = O, the case where the substituent is "= O" means that two hydrogen atoms at the same substitution position are substituted by oxygen atoms;

ii) when

When representing a double bond, Y ₁ And Y ₂ Are both C, ring A is present, ring A is selected from phenyl or 5-to 6-membered heteroaryl;

R ₆ selected from halogen, -NH ₂ 、-NHR _6a 、-NR _6a R _6b 、-CN、-CONH ₂ 、-CONHR _6a 、-CONR _6a R _6b 、-COR _6a 、-COOH、-OH、-SO _n C _1-6 Alkyl, substituted or unsubstituted C _1-6 Alkyl, substituted or unsubstituted C _1～6 An alkoxy group; wherein R is _6a And R _6b Each independently is C _1～6 An alkyl group; n is selected from 0, 1 or 2; the term "substituted" means that the substituents are independently selected from one or more of-OH, halogen, C _1-6 Alkyl, -NH ₂ 、-NO ₂ 、-COCH ₃ And, -CN and = O, the case where the substituent is "= O" means that two hydrogen atoms at the same substitution position are substituted with an oxygen atom;

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

unless otherwise indicated, the heteroatoms in the above heterocycloalkyl, heteroaryl, heterocyclyl, heteromonospiro, heterobridged ring groups are independently selected from O, N or S, and the number of heteroatoms is 1, 2 or 3.

x is selected from a bond or S;

X ₁ and X ₂ Each independently selected from N or CR ₈ (ii) a Wherein R is ₈ Selected from-H, halogen, -NH ₂ 、-NHR _8b 、-NR _8b R _8c 、-NHCOR _8a 、-CN、-OH、-NO ₂ 、-COOH、-CONH ₂ 、-CONHR _8b 、-CONR _8b R _8c 、-COOR _8b Substituted or unsubstituted C _1～6 Alkyl, substituted or unsubstituted C _1～6 Alkoxy, substituted or unsubstituted C _3～6 Cycloalkyl, substituted or unsubstituted heteromonospirocycloalkyl;

wherein R is _8a Selected from:

R _8b and R _8c Each independently selected from C _1～6 An alkyl group;

R ₁ and R ₃ Each independently selected from-H, halogen, -NH ₂ 、-CN、-OH、-NO ₂ -COOH, substituted or unsubstituted C _1～6 Alkyl, substituted or unsubstituted C _1～6 An alkoxy group;

R ₂ selected from-H, halogen, -NH ₂ 、-CN、-OH、-NO ₂ Carboxy, -NHR _2a 、-NR _2a R _2b 、-CONH ₂ 、-CONHR _2a 、-CONR _2a R _2b 、-COR _2a 、-COOR _2a 、-NHCOR _2a 、-N(R _2a )-COR _2b Substituted or unsubstituted C _1～6 Alkyl, substituted or unsubstituted C _1～6 Alkoxy, substituted or unsubstituted C _3～6 Cycloalkyl, substituted or unsubstituted 3-to 6-membered heterocycloalkyl, substituted or unsubstituted mono-spirocycloalkyl, substituted or unsubstituted hetero-mono-spirocycloalkyl, substituted or unsubstituted C _4～8 Bridged cycloalkyl and substituted or unsubstituted 4-8 membered heterobridged cycloalkyl; wherein the number of ring atoms of said monospiroalkyl and heteromonospirocycloalkyl groups is selected from the group consisting of 3-membered/5-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered and 5-membered/6-membered rings, wherein the number of rings in each ring includes a spiro atom;

Or R ₂ To adjacent R ₃ Cyclizing to form a substituted or unsubstituted 5-to 8-membered heteroaryl or a substituted or unsubstituted non-aromatic 5-to 8-membered heterocyclic group;

R _2a and R _2b Each independently selected from C _1～6 An alkyl group;

R ₇ selected from halogen, -CN, -COOR _7a 、C _2-6 Alkenyl, -CONH ₂ Substituted or unsubstituted C _3～6 Cycloalkyl, substituted or unsubstituted C _3～6 HeterocycloalkanesA group and a substituted or unsubstituted heteromonospirocycloalkyl group containing 1 or 2 heteroatoms, wherein the heteromonospirocycloalkyl group has a ring atom number selected from 3-membered/5-membered, 4-membered/4-membered, 4-membered/5-membered, and the number of rings in each ring includes a spiro atom; r is _7a Is H or C _1-6 An alkyl group;

indicates the presence or absence of a bond;

i)

when it indicates that a bond is absent, X ₃ Nor is present, R ₄ And R ₅ Each independently selected from hydrogen, hydroxy, halogen, = O, substituted or unsubstituted C _1～6 Alkyl and substituted or unsubstituted C _1～6 An alkoxy group; r ₄ And R ₅ Each independently selected from "= O" means that another hydrogen atom at the same substitution position is simultaneously substituted by the oxygen atom;

ii)

when a bond is present, X ₃ Is CH ₂ ，R ₄ And R ₅ Are all hydrogen;

represents a single bond or a double bond;

1) When in use

When represents a single bond, ring A and- (R) ₆ ) _m Is absent from，Y ₁ And Y ₂ Each independently is CR ₉ R ₁₀ O or NR ₁₀ ；

Each R ₉ And R ₁₀ Independently selected from-H, halogen, -OH, substituted or unsubstituted C _1～6 Alkyl, substituted or unsubstituted C _1～6 An alkoxy group;

ii) when

When represents a double bond, Y ₁ And Y ₂ Are both C, ring A is present, ring A is selected from phenyl or 5-to 6-membered heteroaryl;

R ₆ selected from halogen, -NH ₂ 、-NHR _6a 、-NR _6a R _6b 、-CN、-CONH ₂ 、-CONHR _6a 、-CONR _6a R _6b 、-COR _6a 、-COOH、-OH、-SO _n C _1-6 Alkyl, substituted or unsubstituted C _1-6 Alkyl, substituted or unsubstituted C _1～6 An alkoxy group; wherein R is _6a And R _6b Each independently is C _1～6 An alkyl group; n is selected from 0, 1 or 2;

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

the term "substituted" means that the substituents are independently selected from one or more of-OH, halogen, C _1-6 Alkyl, -NH ₂ 、-NO ₂ 、-COCH ₃ And, -CN and = O, the case where the substituent is "= O" means that two hydrogen atoms at the same substitution position are substituted with an oxygen atom;

In some embodiments of the present application, a compound provided herein, or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, has a structure according to formula (I-a):

wherein R is ₁ ，R ₂ ，R ₃ ，R ₄ ，R ₅ ，R ₆ ，R ₇ ，X ₁ ，X ₂ ，X ₃ ，Y ₁ ，Y ₂ Ring a and m are defined as the compounds of formula (I-1) herein.

In some embodiments of the present application, a compound provided herein, or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, has a structure according to formula (I-b):

In some embodiments of the present application, there is provided a compound of formula (I-1), formula (I-a), and formula (I-b) or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein the heteroatoms in the heterocycloalkyl, heteroaryl, heterocyclyl, heteromonospirocycloalkyl, and heterobridged cycloalkyl groups are independently selected from O, N, or S, and the number of heteroatoms is 1, 2, or 3.

In some embodiments of the present application, the present application provides compounds of formula (I-1), formula (I-a), and formula (I-b) or prodrugs, tautomers, stereoisomers, solvates, isotopic derivatives, or pharmaceutically acceptable salts thereof, wherein R is ₁ And R ₃ Each independently selected from-H, halogen, -NH ₂ 、-CN、-OH、-NO ₂ -COOH, substituted or unsubstituted C _1～6 Alkyl and substituted or unsubstituted C _1～6 Alkoxy, wherein said substituted C _1～6 Alkyl and substituted C _1～6 Alkoxy is independently selected from-OH, halogen, -NH ₂ 、-NO ₂ 、-COC _1-6 Alkyl and one or more substituents of the-CN group; or,

R ₁ and R ₃ Each independently selected from-H, halogen, -NH ₂ -CN, -OH, substituted or unsubstituted C _1～6 Alkyl and substituted or unsubstituted C _1～6 Alkoxy, wherein said substituted C _1～6 Alkyl and substituted C _1～6 Alkoxy is independently selected from halogen, -NO ₂ 、-COC _1-6 Alkyl (e.g., -COCH) ₃ ) And one or more substituents in the-CN group; or,

R ₁ and R ₃ Each independently selected from-H, halogen, -NH ₂ 、-CN、-OH、-NO ₂ COOH, halogen substituted or unsubstituted C _1～6 Alkyl and halogen substituted or unsubstituted C _1～6 An alkoxy group; or alternatively

R ₁ And R ₃ Each independently selected from-H, halogen and halogen substituted C _1～6 An alkyl group; or

R ₁ And R ₃ Each independently selected from-H, -F, -Cl and fluoro-substituted methyl (e.g., CF) ₃ ) (ii) a Or

R ₁ And R ₃ One of which is selected from-H and the other is selected from-F, -Cl and fluoro-methyl (e.g., CF) ₃ ) (ii) a Or

R ₁ And R ₃ One of which is selected from-H and the other is selected from-Cl.

In some embodiments of the present application, provided herein are compounds and pharmaceutically acceptable salts thereof, wherein R is ₁ And R ₃ Each independently selected from-H, -F, -Cl, -Br and-NH ₂ OH, halogenated or unsubstituted C _1～6 Alkyl, halo or unsubstituted C _1～6 An alkoxy group.

In some embodiments of the present application, provided herein are compounds and pharmaceutically acceptable salts thereof, wherein R is ₁ And R ₃ Each independently selected from-H, -F, -Cl, -NH ₂ OH, fluoro or unsubstituted C _1～6 Alkyl, fluoro or unsubstituted C _1～6 An alkoxy group.

In some embodiments of the present application, provided herein are compounds and pharmaceutically acceptable salts thereof, wherein R is ₁ And R ₃ Each independently selected from-H, -F, -Cl, -NH ₂ Fluoro or unsubstituted methyl.

In some embodiments of the present application, the present application provides compounds of formula (I-1), formula (I-a), and formula (I-b) or prodrugs, tautomers, stereoisomers, solvates, isotopic derivatives, or pharmaceutically acceptable salts thereof, wherein R is ₂ Selected from-H, halogen, -NH ₂ 、-OH、-NHR _2a 、-NR _2a R _2b 、-CONH ₂ 、-CONHR _2a 、-CONR _2a R _2b 、-COR _2a 、-COOR _2a 、-NHCOR _2a 、-N(R _2a )-COR _2b Substituted or unsubstituted C _1～6 Alkyl, substituted or unsubstituted C _1～6 Alkoxy, substituted or unsubstituted C _3～6 Cycloalkyl, substituted or unsubstitutedSubstituted 3-to 6-membered heterocycloalkyl, substituted or unsubstituted mono-spirocycloalkyl and substituted or unsubstituted hetero-mono-spirocycloalkyl, wherein R _2a And R _2b Each independently selected from unsubstituted C _1～6 Alkyl, the number of ring atoms of said mono-and hetero-spirocycloalkyl groups being independently selected from 3-membered/5-membered, 4-membered/4-membered or 4-membered/5-membered rings, wherein each ring count includes a spiro atom, and said substituted C _1～6 Alkyl, substituted C _1～6 Alkoxy, substituted C _3～6 Cycloalkyl, substituted 3-to 6-membered heterocycloalkyl, substituted mono-spirocycloalkyl and substituted hetero mono-spirocycloalkyl each independently selected from the group consisting of-OH, halogen, C _1-6 Alkyl, -NH ₂ 、-COC _1-6 Alkyl (e.g., -COCH) ₃ ) And one or more substituents in the-CN group; or R ₂ To adjacent R ₃ By ring closure to form substituted or unsubstituted C ₆ Aryl, substituted or unsubstituted 5-to 6-membered heteroaryl or substituted or unsubstituted non-aromatic 5-to 6-membered heterocyclyl, wherein C is substituted ₆ Aryl, substituted 5-to 6-membered heteroaryl or substituted non-aromatic 5-to 6-membered heterocyclyl are each independently selected from halogen, -NO ₂ 、-COC _1-6 Alkyl (e.g., -COCH) ₃ ) And one or more substituents in the-CN group; or alternatively

R ₂ Selected from-H, halogen, -NH ₂ 、-OH、-NHR _2a 、-NR _2a R _2b 、-CONH ₂ 、-NHCOR _2a 、-N(R _2a )-COR _2b Substituted or unsubstituted C _1～6 Alkyl, substituted or unsubstituted C _1～6 Alkoxy, substituted or unsubstituted C _3～6 Cycloalkyl, substituted or unsubstituted 3-to 6-membered heterocycloalkyl, substituted or unsubstituted mono-spirocycloalkyl and substituted or unsubstituted hetero-mono-spirocycloalkyl, wherein R _2a And R _2b Each independently selected from unsubstituted C _1～3 Alkyl, said mono-spirocycloalkyl and heteroThe number of ring atoms of the spirocycloalkyl group is 4-membered/4-membered ring, wherein each ring includes a spiro atom in its number, and the substituted C _1～6 Alkyl, substituted C _1～6 Alkoxy, substituted C _3～6 Cycloalkyl, substituted 3-to 6-membered heterocycloalkyl, substituted mono-spirocycloalkyl and substituted hetero-mono-spirocycloalkyl each independently selected from-OH, halogen, C _1-3 Alkyl and-NH ₂ Substituted by one or more substituents in the radical, or R ₂ To adjacent R ₃ Ring-closure to form a substituted or unsubstituted 5-to 6-membered heteroaryl or a substituted or unsubstituted non-aromatic 5-to 6-membered heterocyclyl, wherein said substituted 5-to 6-membered heteroaryl or substituted non-aromatic 5-to 6-membered heterocyclyl are each independently selected from halo (e.g., -F and-Cl), -COC _1-6 Alkyl (e.g., -COCH) ₃ ) And one or more substituents in the-CN group; or,

R ₂ selected from-H, halogen (e.g., -F, -Cl, and-Br), -NH ₂ 、-OH、-NHR _2a 、-NR _2a R _2b Substituted or unsubstituted C _1～6 Alkyl (e.g., methyl), substituted or unsubstituted C _1～6 Alkoxy (e.g., methoxy), substituted or unsubstituted C _3～6 Cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted 3-to 6-membered heterocycloalkyl (e.g., azetidinyl), and substituted or unsubstituted heteromonospirocycloalkyl, wherein R _2a And R _2b Each independently selected from unsubstituted C _1～3 Alkyl (e.g., methyl), said heteromonospirocycloalkyl having 4-membered/4-membered rings in the number of ring atoms (e.g., a 4-membered/4-membered spirocyclic ring containing 1O atom and 1N atom), wherein each ring count includes the spiro atom, and said substituted C _1～6 Alkyl, substituted C _1～6 Alkoxy, substituted C _3～6 Cycloalkyl, substituted 3-to 6-membered heterocycloalkyl and substituted heteromonospirocycloalkyl are each independently selected from-OH, halogen, C _1-3 Alkyl and-NH ₂ One or more of the radicalsSubstituent group substitution; or R ₂ To adjacent R ₃ Ring closure to form a substituted or unsubstituted 5-to 6-membered heteroaryl or a substituted or unsubstituted non-aromatic 5-to 6-membered heterocyclyl, wherein said substituted 5-to 6-membered heteroaryl or substituted non-aromatic 5-to 6-membered heterocyclyl are each independently selected from halo (e.g., F and Cl), -COC _1-6 Alkyl (e.g., -COCH) ₃ ) And one or more substituents in the-CN group; or,

R ₂ selected from-H, -F, -Cl, -NH ₂ OH, substituted or unsubstituted C _1～6 Alkyl (e.g., methyl), substituted or unsubstituted C _3～6 Cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted 3-to 6-membered heterocycloalkyl (e.g., azetidinyl), and substituted or unsubstituted heteromonospirocycloalkyl having a 4-membered/4-membered ring (e.g., a 4-membered/4-membered spirocyclic ring containing 1O atom and 1N atom), wherein each ring includes a spiro atom in its number of ring atoms, and said substituted C _1～6 Alkyl, substituted C _3～6 Cycloalkyl, substituted 3-to 6-membered heterocycloalkyl and substituted heteromonospirocycloalkyl are each independently selected from-OH, halogen, C _1-3 Alkyl and-NH ₂ One or more substituents in the group; or R ₂ Selected from-H, -F, -Cl or-NH ₂ (ii) a Or R ₂ Is selected from-H or-NH ₂ (ii) a Or,

R ₂ to adjacent R ₃ Ring closure to form a substituted or unsubstituted non-aromatic 5-to 6-membered heterocyclic group, wherein said substituted non-aromatic 5-to 6-membered heterocyclic group is independently selected from halogen (e.g., F and Cl), -COC _1-6 Alkyl (e.g., -COCH) ₃ ) And one or more substituents in the-CN group; or,

R ₂ to adjacent R ₃ Ring closure to form a substituted or unsubstituted non-aromatic 5-membered heterocyclic group, the number of heteroatoms is N and the number of heteroatoms is 1, wherein the substituted non-aromatic 5-membered heterocyclic group is independently substitutedIs selected from-F and-COCH ₃ And one or more substituents in the-CN group; or,

R ₂ to adjacent R ₃ By ring closure to form

In some embodiments of the present application, provided herein are compounds and pharmaceutically acceptable salts thereof, wherein R is ₂ Selected from-H, -F, -Cl, -Br, -NH ₂ 、-OH、-NHR _2a 、-NR _2a R _2b 、-CONH ₂ 、-CONHR _2a 、-CONR _2a R _2b 、-COR _2a 、-COOR _2a 、-NHCOR _2a 、-N(R _2a )-COR _2b Substituted or unsubstituted C _1～6 Alkyl, substituted or unsubstituted C _1～6 Alkoxy, substituted or unsubstituted C _3～6 Cycloalkyl, substituted or unsubstituted 3-to 6-membered heterocycloalkyl; wherein R is _2a And R _2b Each independently selected from C _1～6 An alkyl group; or R ₂ To adjacent R ₃ Cyclizing to form a substituted or unsubstituted 5-6 membered heteroaryl or a substituted or unsubstituted non-aromatic 5-6 membered heterocyclic group; wherein R is ₂ Or R ₂ And R ₃ The hetero atom in the ring-closing structure is N, O or S, and the number of the hetero atoms is selected from 1 and 2; r is ₂ Structure or R ₂ And R ₃ By "substituted" in the ring-closing structure is meant that the substituents are independently selected from one or more of OH, -F, -Cl, -CH ₃ 、-COCH ₃ And a group of-CN.

In some embodiments of the present application, provided herein are compounds and pharmaceutically acceptable salts thereof, wherein R is ₂ Selected from-H, -F, -Cl, -Br and-NH ₂ 、-OH、-NHCH ₃ 、-N(CH ₃ ) ₂ and-CONH ₂ (ii) a Or R ₂ To the adjacent R ₃ Cyclized to form a substituted or unsubstituted 5-membered heteroaryl or a substituted or unsubstituted non-aromatic 5-membered heterocyclyl, R ₂ And R ₃ The heteroatom in the ring-closing structure is N, the number of the heteroatom is 1, wherein the substituent is selected from one or more of-F and-COCH ₃ And a group of-CN.

In some embodiments of the present application, provided herein are compounds and pharmaceutically acceptable salts thereof, wherein R is ₂ To adjacent R ₃ Ring closure to form a substituted or unsubstituted 5-membered heteroaryl or a substituted or unsubstituted non-aromatic 5-membered heterocyclyl, wherein the heteroatom is N and the number of heteroatoms is 1, wherein "substituted" means that the substituents are independently selected from one or more of-F, -COCH ₃ And a group of-CN.

In some embodiments of the present application, provided herein are compounds and pharmaceutically acceptable salts thereof, wherein R is ₂ To the adjacent R ₃ Ring closure to form the following groups:

in some embodiments of the present application, provided herein are compounds and pharmaceutically acceptable salts thereof, wherein R is ₂ To adjacent R ₃ Ring closure to form the following groups:

in some embodiments of the present application, provided herein are compounds of formula (I-1), formula (I-a), and formula (I-b) or prodrugs, tautomers, stereoisomers, solvates, isotopic derivatives, or pharmaceutically acceptable salts thereof, wherein R is ₇ Selected from halogen, -CN, -COOR _7a 、-COR _7b 、-C(O)-COOR _7a Unsubstituted C _2-4 Alkenyl, unsubstituted C _2-4 Alkynyl, -CONH ₂ 、-C(O)-COOR _7a Substituted or unsubstituted C _3～6 Cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted monospirocycloalkyl and substituted or unsubstituted heteromonospirocycloalkyl containing 1 or 2 heteroatoms wherein the number of ring atoms of said monospirocycloalkyl and heteromonospirocycloalkyl is independently selected from 3-to 5-membered, 4-to 4-membered or 4-to 5-membered rings, wherein the count for each ring includes a spiro atom, wherein R is _7a is-H, unsubstituted C _1-6 Alkyl or unsubstituted C _3-6 A cycloalkyl group; r is _7b Selected from-H, substituted or unsubstituted C _1～6 Alkyl, substituted or unsubstituted C _3～6 Cycloalkyl, substituted or unsubstituted 3-to 6-membered heterocycloalkyl, substituted or unsubstituted C _6～14 Aryl and substituted or unsubstituted 5-to 10-membered heteroaryl; wherein said substituted C _3～6 Cycloalkyl, substituted 3-to 6-membered heterocycloalkyl, substituted mono-spirocycloalkyl, substituted hetero-mono-spirocycloalkyl, substituted C _1-6 Alkyl, substituted C _6～14 Aryl and substituted 5-to 10-membered heteroaryl are each independently selected from-OH, halogen, -NH ₂ 、C _1～6 Alkyl radical, C _1～6 Alkoxy, -NH-C _1～6 Alkyl, -N (C) _1～6 Alkyl) (C _1～6 Alkyl) and unsubstituted 3-to 6-membered heterocycloalkyl; or,

R ₇ selected from-F, -Cl, -Br, -CN, -COOR _7a 、-COR _7b 、-C(O)-COOR _7a Unsubstituted C ₂ Alkenyl, unsubstituted C ₂ Alkynyl, -CONH ₂ 、-C(O)-COOR _7a Substituted or unsubstituted 3-to 6-membered heterocycloalkyl and substituted or unsubstituted heteromonospirocycloalkyl containing 1 or 2 heteroatoms independently selected from N and O, wherein the number of ring atoms of the heteromonospirocycloalkyl is independently 4-to 4-membered rings, wherein each ring count includes spiro atoms, wherein R _7a is-H, unsubstituted C _1-3 Alkyl or unsubstituted C _3-4 A cycloalkyl group; r _7b Selected from-H, substituted or unsubstituted C _1～3 Alkyl, substituted or unsubstituted C _3～6 Cycloalkyl, substituted or unsubstituted C ₆ Or C ₁₀ Aryl and substituted or unsubstituted 5-to 6-membered heteroaryl; wherein, the substituted 3-to 6-membered heterocycloalkyl group, the substituted heteromonospirocycloalkyl group, the substituted C _1-3 Alkyl, substituted C _3～6 Cycloalkyl, substituted C ₆ Or C ₁₀ Aryl and substituted 5-to 6-membered heteroaryl are each independently selected from-OH, halogen, -NH ₂ 、C _1～6 Alkyl radical, C _1～6 Alkoxy, -NH-C _1～6 Alkyl, -N (C) _1～6 Alkyl) (C) _1～6 Alkyl) and unsubstituted 3-to 6-membered heterocycloalkyl; or,

R ₇ selected from-F, -Cl, -Br, -CN, -COOR _7a 、-COR _7b Unsubstituted C ₂ Alkenyl, unsubstituted C ₂ Alkynyl, -CONH ₂ 、-C(O)-COOR _7a Unsubstituted 3-to 6-membered heterocycloalkyl (e.g. oxetane or azetidine) and unsubstituted heteromonospirocycloalkyl containing 1 or 2 heteroatoms independently selected from N and O, wherein the number of ring atoms of said heteromonospirocycloalkyl is independently 4-to 4-membered rings, wherein each ring count includes spiro atoms, wherein R is _7a is-H, unsubstituted C _1-3 Alkyl (e.g. methyl) or unsubstituted C _3-4 Cycloalkyl (e.g., cyclopropyl); r is _7b Is selected from-H orUnsubstituted C _1～3 Alkyl (e.g., methyl); or

R ₇ Selected from-Cl, -COOR _7a 、-COR _7b Unsubstituted C ₂ Alkenyl, unsubstituted C ₂ Alkynyl, -C (O) -COOR _7a Unsubstituted 3-to 6-membered heterocycloalkyl (e.g. oxetane or azetidine) and unsubstituted heteromonospirocycloalkyl containing 1 or 2 heteroatoms independently selected from N and O, wherein the number of ring atoms of said heteromonospirocycloalkyl is independently 4-membered/4-membered rings, wherein the count for each ring includes spiro atoms, wherein R is _7a is-H, unsubstituted C _1-3 Alkyl (e.g. methyl) or unsubstituted C _3-4 Cycloalkyl (e.g., cyclopropyl); r _7b Is selected from-H or unsubstituted C _1～3 Alkyl (e.g., methyl); or

R ₇ Selected from-CN, -COOR _7a 、-COR _7b Unsubstituted C ₂ Alkenyl, unsubstituted C ₂ Alkynyl, -C (O) -COOR _7a And unsubstituted 3-to 6-membered heterocycloalkyl (e.g., oxetane or azetidine), wherein R _7a is-H, unsubstituted C _1-3 Alkyl (e.g. methyl) or unsubstituted C _3-4 Cycloalkyl (e.g., cyclopropyl); r _7b Is selected from-H or unsubstituted C _1～3 Alkyl (e.g., methyl); or alternatively

R ₇ Selected from-CN, -COOR _7a 、-COR _7b Unsubstituted C ₂ Alkenyl and unsubstituted C ₂ Alkynyl, wherein R _7a is-H, unsubstituted C _1-3 Alkyl (e.g. methyl) or unsubstituted C _3-4 Cycloalkyl (e.g., cyclopropyl); r _7b Is selected from-H or unsubstituted C _1～3 Alkyl (e.g., methyl); or

R ₇ Selected from-F, -Cl, -CN, -COOR _7a 、-COR _7b Unsubstituted C ₂ Alkenyl and unsubstituted 4-membered heterocycloalkyl (e.g. phenyl)Oxetane or azetidine) in which R _7a is-H, unsubstituted C _1-3 Alkyl (e.g. methyl) or unsubstituted C _3-4 Cycloalkyl (e.g., cyclopropyl); r _7b Is selected from-H or unsubstituted C _1～3 Alkyl (e.g., methyl); or alternatively

R ₇ Selected from-F, -Cl, -COOR _7a 、-COR _7b Unsubstituted C ₂ Alkenyl and unsubstituted 4-membered heterocycloalkyl (e.g., oxetane or azetidine), wherein R _7a And R _7b Are all methyl; or

R ₇ Is selected from-COOR _7a or-COR _7b Wherein R is _7a is-H, unsubstituted C _1-2 Alkyl (e.g. methyl) or unsubstituted C _3-4 Cycloalkyl (e.g., cyclopropyl); r _7b Is selected from-H or unsubstituted C _1～2 Alkyl (e.g., methyl); or

R ₇ Is selected from-COOR _7a or-COR _7b Wherein R is _7a And R _7b Are all unsubstituted methyl groups; or alternatively

R ₇ Selected from-H, -Cl, -F, -CN, -CHO, -COOH and-COOCH ₃ 、-COCH ₃ 、-CONH ₂ 、-CH＝CH ₂ 、

Or alternatively

R ₇ Selected from-Cl, -F, -CN, -CHO, -COOH and-COOCH ₃ 、-COCH ₃ 、-CONH ₂ 、-CH＝CH ₂ 、

Or

R ₇ Is selected from-F, -COOCH ₃ 、-COCH ₃ 、-CH＝CH ₂ 。

In some embodiments of the present application, provided herein are compounds and pharmaceutically acceptable salts thereof, wherein R is ₇ Selected from-H, -F, -Cl, -Br, -I, -CN, -COOR _7a 、-COR _7b 、-CH＝CH ₂ Substituted or unsubstituted C _3～6 Cycloalkyl, substituted or unsubstituted 3-to 6-membered heterocycloalkyl, substituted or unsubstituted spiro [3.3 ] containing 1 or 2 heteroatoms independently selected from N and O ]A heptalkyl group; wherein R is _7a is-H or C _1-6 Alkyl radical, R _7b Selected from-H, substituted or unsubstituted C _1～6 Alkyl, substituted or unsubstituted C _3～6 Cycloalkyl, substituted or unsubstituted C _6～14 Aryl, said "substituted" meaning that the substituents are independently selected from one or more of-OH, -F, -Cl, -NH ₂ 、-CH ₃ 、C _1～6 Alkoxy, -NH-C _1～6 Alkyl, -N (C) _1～6 Alkyl) -C _1～6 Alkyl, 3-to 6-membered heterocycloalkyl group.

In some embodiments of the present application, provided herein are compounds and pharmaceutically acceptable salts thereof, wherein R is ₇ Selected from-H, -Cl, -Br, -I, -CN and-COOR _7a 、-COR _7b 、-CH＝CH ₂ Substituted or unsubstituted C _3～6 Cycloalkyl, substituted or unsubstituted C _3～6 Heterocycloalkyl and substituted or unsubstituted spiro [3.3 ] containing 1 or 2 heteroatoms independently selected from N and O]A heptalkyl group; wherein R is _7a is-H or C _1-3 Alkyl radical, R _7b Selected from-H, substituted or unsubstituted C _1～3 Alkyl radical, C _3～6 Cycloalkyl, C _6～10 Aryl, said "substituted" meaning that the substituents are independently selected from one or more of-OH, -F, -Cl, -NH ₂ 、-CH ₃ 、-OCH ₃ 、-N(CH ₃ )CH ₃ And a 3-to 6-membered heterocycloalkyl group.

In the bookIn some embodiments of the application, provided herein are compounds and pharmaceutically acceptable salts thereof, wherein, R ₇ Selected from-H, -Cl, -Br, -I, -CN, -COOR _7a 、-COR _7b 、-CH＝CH ₂ Substituted or unsubstituted cyclopropane, substituted or unsubstituted oxetanyl and substituted or unsubstituted spiro [3.3 ] containing 1 or 2 heteroatoms independently selected from N and O ]A heptalkyl group; wherein R is _7a is-H or C _1-3 Alkyl radical, R _7b Selected from-H, substituted or unsubstituted methyl, C _3～4 Cycloalkyl radical, C _6～10 Aryl, said "substituted" meaning that the substituents are independently selected from one or more of-OH, -F, -Cl, -NH ₂ 、-OCH ₃ 、-N(CH ₃ )CH ₃ And a 3-to 6-membered heterocycloalkyl group.

In some embodiments of the present application, provided herein are compounds and pharmaceutically acceptable salts thereof, wherein R is ₇ Selected from-H, -Cl, -Br, -CN, -CHO, -COOH and-COOCH ₃ 、-COCH ₃ 、-CONH ₂ 、-COCH ₂ F、-COCH ₂ OH、-COCH ₂ OCH ₃ 、-COCH ₂ NH ₂ 、-COCH ₂ N(CH ₃ )CH ₃ 、-CH＝CH ₂ A cyclopropane group,

In some embodiments of the present application, the present invention provides compounds and pharmaceutically acceptable salts thereof, wherein R is ₇ Selected from-F, -Cl, -Br, -I, -CN, -COOR _7a 、-CH＝CH ₂ Substituted or unsubstituted C _3～6 Cycloalkyl, substituted or unsubstituted 3-to 6-membered heterocycloalkyl, containing 1 or 2 atoms of alkylSubstituted or unsubstituted spiro [3.3 ] rings selected immediately from N and O heteroatoms]A heptalkyl group; wherein R is _7a Is C _1-6 Alkyl, said "substituted" meaning that the substituents are independently selected from one or more of-OH, -F, -Cl, -CH ₃ A group of (1).

In some embodiments of the present application, the present invention provides compounds and pharmaceutically acceptable salts thereof, wherein R is ₇ Selected from-Cl, -Br, -I, -CN, -COOR _7a 、-CH＝CH ₂ Substituted or unsubstituted C _3～6 Cycloalkyl, substituted or unsubstituted C _3～6 Heterocycloalkyl and substituted or unsubstituted spiro [3.3 ] containing 1 or 2 heteroatoms independently selected from N and O ]A heptalkyl group; wherein R is _7a Is C _1-3 Alkyl, said "substituted" meaning that the substituents are independently selected from one or more of-OH, -F, -Cl, -CH ₃ A group of (1).

In some embodiments of the present application, the present invention provides compounds and pharmaceutically acceptable salts thereof, wherein R is ₇ Selected from-Cl, -Br, -I, -CN, -COOR _7a 、-CH＝CH ₂ Substituted or unsubstituted cyclopropane, substituted or unsubstituted oxetanyl and substituted or unsubstituted spiro [3.3 ] containing 1 or 2 heteroatoms independently selected from N and O]A heptalkyl group; wherein R is _7a Is C _1-3 Alkyl, said "substituted" means that the substituents are independently selected from one or more groups-OH, -F, -Cl.

In some embodiments of the present application, the present invention provides compounds and pharmaceutically acceptable salts thereof, wherein R is ₇ Selected from-Cl, -Br, -CN, -COOCH ₃ 、-CH＝CH ₂ A cyclopropane group,

In some embodiments of the present application, the present application provides compounds of formula (I-1), formula (I-a), and formula (I-b) or prodrugs, tautomers, stereoisomers, solutions thereofA solvate, isotopic derivative or pharmaceutically acceptable salt thereof, wherein X ₁ And X ₂ Each independently selected from N and CR ₈ (ii) a Wherein each R ₈ Independently selected from-H, halogen, -NH ₂ 、-NHR _8b 、-NR _8b R _8c 、-NHCOR _8a OH, substituted or unsubstituted C _1～6 Alkyl, substituted or unsubstituted C _1～6 Alkoxy, substituted or unsubstituted C _3～6 Cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted mono spirocycloalkyl, substituted or unsubstituted hetero mono spirocycloalkyl, substituted or unsubstituted C _6～14 Aryl, substituted or unsubstituted 5-14 membered heteroaryl, wherein the number of ring atoms of the mono-spirocycloalkyl and the hetero-spirocycloalkyl are independently selected from 3-membered/5-membered, 4-membered/4-membered or 4-membered/5-membered rings, the number of each ring counting including the spiro atom, wherein said substituted C is _1～6 Alkyl, substituted C _1～6 Alkoxy, substituted C _3～6 Cycloalkyl, substituted 3-6 membered heterocycloalkyl, substituted mono spirocycloalkyl, substituted hetero mono spirocycloalkyl, substituted C _6～14 Aryl, substituted 5-to 14-membered heteroaryl are each independently selected from-OH, halogen, C _1-6 Alkyl and-NH ₂ Substituted in one or more substituents in the group;

R _8a selected from the group consisting of:

R _8b and R _8c Each independently selected from unsubstituted C _1～6 An alkyl group; or

X ₁ And X ₂ Each independently selected from N and CR ₈ (ii) a Wherein each R ₈ Independently selected from-H, halogen, -NH ₂ 、-NHR _8b 、-NR _8b R _8c 、-NHCOR _8a OH, substituted or unsubstituted C _1～6 Alkyl, substituted or unsubstituted C _1～6 Alkoxy, substituted or unsubstituted C _3～6 Cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted 3-6 membered heterocycloalkyl (e.g., oxetanyl and azetidinyl), substituted or unsubstituted heteromonospirocycloalkyl, substituted or unsubstituted C _6～10 Aryl or substituted or unsubstituted 5-to 6-membered heteroaryl, wherein the number of ring atoms of the heteromonospirocycloalkyl group is 4-membered/4-membered ring (e.g., a 4-membered/4-membered spirocyclic ring containing 1O atom and 1N atom), each ring including a spiro atom in the number of rings, wherein the substituted C is _1～6 Alkyl, substituted C _1～6 Alkoxy, substituted C _3～6 Cycloalkyl, substituted 3-6 membered heterocycloalkyl, substituted heteromonospirocycloalkyl, substituted C _6～10 Aryl, substituted 5-to 6-membered heteroaryl are each independently selected from-OH, halogen, C _1-6 Alkyl and-NH ₂ Substituted in one or more substituents in the group;

R _8a selected from:

R _8b and R _8c Each independently selected from unsubstituted C _1～3 An alkyl group; or alternatively

X ₁ And X ₂ Each independently selected from N and CR ₈ (ii) a Wherein each R ₈ Independently selected from-H, -F, -Cl, -NH ₂ 、-NHCOR _8a -OH, unsubstituted C _1～3 Alkyl, unsubstituted C _1～3 Alkoxy, unsubstituted C _3～6 Cycloalkyl (e.g., cyclopropyl), substituted or unsubstituted 3-6 membered heterocycloalkyl (e.g., oxetanyl and azetidinyl), unsubstituted heteromonospirocycloalkyl, unsubstituted C _6～10 Aryl orUnsubstituted 5-6 membered heteroaryl, wherein the number of ring atoms of the heteromonospirocycloalkyl is 4-membered/4-membered ring (e.g., a 4-membered/4-membered spirocyclic ring containing 1O atom and 1N atom), each ring numbered inclusive of spiro atoms, wherein the substituted 3-6 membered heterocycloalkyl group is independently selected from-OH, halo, C _1-6 Alkyl and-NH ₂ Substituted in one or more substituents in the group;

R _8a selected from:

R _8b and R _8c Each independently selected from unsubstituted C _1～3 An alkyl group; or

X ₁ And X ₂ Each independently selected from N and CR ₈ (ii) a Wherein each R ₈ Independently selected from-H, -F, -Cl, -NH ₂ 、-NHCOR _8a Unsubstituted C _6～10 Aryl or unsubstituted 5-to 6-membered heteroaryl, wherein R _8a Selected from:

or

X ₁ And X ₂ Each independently selected from N and CR ₈ (ii) a Wherein R is ₈ Selected from-H, -NH ₂ 、-NHCOR _8a 、

Wherein R is _8a Selected from:

or

X ₁ And X ₂ Each independently selected from N and CR ₈ (ii) a Wherein R is ₈ Selected from the group consisting of-H,

Or

X ₁ And X ₂ One of them is N and the other is CR ₈ Wherein R is ₈ Independently selected from H, -Cl, -NH ₂ 、-NHCOR _8a Unsubstituted C _6～10 Aryl or unsubstituted 5-to 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein R is _8a Selected from:

or R ₈ Independently selected from H, -NH ₂ Unsubstituted C _6～10 Aryl or unsubstituted 5-to 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S; or alternatively

X ₁ And X ₂ Are all CR ₈ (ii) a Wherein one R ₈ is-H, another R ₈ Selected from the group consisting of-Cl, -NH ₂ 、-NHCOR _8a Unsubstituted C _6～10 Aryl or unsubstituted 5-to 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein R _8a Selected from:

or R ₈ Is selected from-NH ₂ Unsubstituted C _6～10 Aryl or unsubstituted 5-to 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S.

In some embodiments of the present application, a building block

Is not that

And is preferably selected from

In some embodiments of the present application, provided herein are compounds of formula (I-1), formula (I-a), and formula (I-b) or prodrugs, tautomers, stereoisomers, solvates, isotopic derivatives, or pharmaceutically acceptable salts thereof, wherein X ₁ And X ₂ One of them is N and the other is CR ₈ Wherein R is ₈ Is unsubstituted C _6～10 Aryl or unsubstituted 5-to 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, or X ₁ And X ₂ Are all CR ₈ (ii) a Wherein one R is ₈ is-H, another R ₈ Is unsubstituted C _6～10 Aryl or unsubstituted 5-to 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, and R ₇ Selected from-H, -F, -Cl, -CN, -COOR _7a 、-COR _7b Unsubstituted C ₂ Alkenyl and unsubstituted 4-membered heterocycloalkyl (e.g., oxetane or azetidine), wherein R _7a is-H, unsubstituted C _1-3 Alkyl (e.g. methyl) or unsubstituted C _3-4 Cycloalkyl (e.g., cyclopropyl); r _7b Is selected from-H or unsubstituted C _1～3 Alkyl (e.g., methyl); or R ₇ Selected from-F, -Cl, -COOR _7a 、-COR _7b Unsubstituted C ₂ Alkenyl and unsubstituted 4-membered heterocycloalkyl (e.g., oxetane or azetidine), wherein R _7a And R _7b Are all methyl.

In the bookIn some embodiments of the application, the present application provides compounds of formula (I-1), formula (I-a), and formula (I-b) or prodrugs, tautomers, stereoisomers, solvates, isotopic derivatives, or pharmaceutically acceptable salts thereof, wherein X ₁ And X ₂ One of them is N and the other is CR ₈ Wherein R is ₈ Is an unsubstituted 5-membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N, O and S, or X ₁ And X ₂ Are all CR ₈ (ii) a Wherein one R is ₈ is-H, another R ₈ Is unsubstituted 5-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, and R ₇ Selected from-H, -F, -Cl, -CN, -COOR _7a 、-COR _7b Unsubstituted C ₂ Alkenyl and unsubstituted 4-membered heterocycloalkyl (e.g., oxetane or azetidine), where R _7a is-H, unsubstituted C _1-3 Alkyl (e.g. methyl) or unsubstituted C _3-4 Cycloalkyl (e.g., cyclopropyl); r is _7b Is selected from-H or unsubstituted C _1～3 Alkyl (e.g., methyl); or R ₇ Selected from-F, -Cl, -COOR _7a 、-COR _7b Unsubstituted C ₂ Alkenyl and unsubstituted 4-membered heterocycloalkyl (e.g., oxetane or azetidine), wherein R _7a And R _7b Are all methyl.

In some embodiments of the present application, provided herein are compounds and pharmaceutically acceptable salts thereof, wherein X is ₁ And X ₂ Each independently selected from N or CR ₈ (ii) a Wherein R is ₈ Selected from-H, -F, -Cl, -Br, -NH ₂ 、-NHCOR _8a Substituted or unsubstituted C _1～6 Alkyl, substituted or unsubstituted C _1～6 Alkoxy, substituted or unsubstituted C _3～6 A cycloalkyl group; and X ₁ And X ₂ Not simultaneously selected from N; wherein R is _8a Selected from the group consisting of:

in some embodiments of the present application, provided herein are compounds and pharmaceutically acceptable salts thereof, wherein R is ₈ Selected from-H, -NH ₂ Methyl, methoxy, cyclopropyl, -NHCOR _8a Wherein R is _8a Selected from:

in some embodiments of the present application, provided herein are compounds and pharmaceutically acceptable salts thereof, wherein R is _8a Selected from the group consisting of:

in some embodiments of the present application, the present invention provides compounds and pharmaceutically acceptable salts thereof, wherein R is ₈ Selected from-H, -Cl, -NH ₂ A phenyl group,

In some embodiments of the present application, the present invention provides compounds and pharmaceutically acceptable salts thereof, wherein R is ₈ Selected from the group consisting of-H,

In some embodiments herein, provided are compounds, and pharmaceutically acceptable salts thereof, wherein,

denotes the absence of a bond, X ₃ Nor is present, R ₄ And R ₅ Each independently selected from hydrogen, F, hydroxy, = O, substituted or unsubstituted C _1～6 Alkyl, substituted or unsubstituted C _1～6 An alkoxy group.

In some embodiments of the present application, the present application provides compounds of formula (I-1), formula (I-a), and formula (I-b) or prodrugs, tautomers, stereoisomers, solvates, isotopic derivatives, or pharmaceutically acceptable salts thereof, wherein

Denotes the absence of a bond, X ₃ Nor is present, R ₄ And R ₅ Each independently selected from hydrogen, hydroxy, halogen (e.g., -F, -Cl, -Br), = O, unsubstituted C _1～3 Alkyl and unsubstituted C _1～3 An alkoxy group; or

Denotes the absence of a bond, X ₃ Nor is present, R ₄ And R ₅ One of which is hydrogen and the other is selected from hydrogen, hydroxy, halogen (e.g., -F, -Cl), = O, unsubstituted C _1～3 Alkyl (e.g. methyl) and unsubstituted C _1～3 Alkoxy (e.g., methoxy); or

Denotes the absence of a bond, X ₃ Nor is present, R ₄ And R ₅ Are all hydrogen.

represents a double bond, Y ₁ And Y ₂ Both are C, and ring A is selected from phenyl or 5-6 membered heteroaryl containing 1 or 2 heteroatoms.

Represents a double bond, Y ₁ And Y ₂ Both are C, ring a is selected from phenyl, 6-membered heteroaryl having 1N atom and 5-membered heteroaryl having 1S atom and 1N atom, or ring a is selected from phenyl and 6-membered heteroaryl having 1N atom, or ring a is phenyl.

In some embodiments of the present application, the present application provides compounds of formula (I-1), formula (I-a), and formula (I-b) or prodrugs, tautomers, stereoisomers, solvates, isotopic derivatives, or pharmaceutically acceptable salts thereof, wherein R is ₆ Selected from halogen, -NH ₂ 、-NHR _6a 、-NR _6a R _6b 、-CN、-CONH ₂ 、-CONHR _6a 、-CONR _6a R _6b 、-COR _6a -COOH, -OH, substituted or unsubstituted-SO _n C _1-6 Alkyl, substituted or unsubstituted C _1-6 Alkyl and substituted or unsubstituted C _1～6 Alkoxy radical, wherein R _6a And R _6b Each independently of the other being unsubstituted C _1～6 An alkyl group; n is selected from 0, 1 or 2, wherein said substituted-SO _n C _1-6 Alkyl, substituted C _1-6 Alkyl and substituted C _1～6 Alkoxy is independently selected from-OH, halogen, C _1-6 Alkyl and-NH ₂ One or more substituents in the group; or

R ₆ Selected from halogens (e.g., -F, -Cl, -Br), -NH ₂ -CN, -OH, unsubstituted-SO _n C _1-3 Alkyl, substituted or unsubstituted C _1-3 Alkyl (e.g. methyl) and substituted or unsubstituted C _1～3 Alkoxy (e.g., methoxy), wherein n is selected from 0, 1 or 2, wherein said substituted C _1-3 Alkyl and substituted C _1～3 Alkoxy is independently selected from-OH, halogen, C _1-3 Alkyl and-NH ₂ One or more substituents in the group.

In some embodiments of the present application, provided herein are compounds and pharmaceutically acceptable salts thereof, wherein R is ₆ Selected from halogen, -NH ₂ 、-CN、-OH、-OCH ₃ 、-OCH ₂ CH ₃ 、-SCH ₃ 、-SO ₂ CH ₃ 。

In some embodiments of the present application, provided herein are compounds and pharmaceutically acceptable salts thereof, wherein R is ₆ Selected from halogen, -NH ₂ 、-CN、-OH、-OCH ₃ 、-SCH ₃ 、-SO ₂ CH ₃ 。

Denotes the absence of a bond, X ₃ Nor is present, R ₄ And R ₅ Are all hydrogen;

represents a double bond, Y ₁ And Y ₂ Are both C, ring A is selected from phenylAnd 6-membered heteroaryl containing 1N atom (preferably phenyl); r is ₆ Selected from halogens (e.g., -F, -Cl, -Br), -NH ₂ -CN, -OH, unsubstituted-SO _n C _1-3 Alkyl, unsubstituted C _1-3 Alkyl and unsubstituted C _1～3 Alkoxy, wherein n is selected from 0, 1 or 2, and m is 0, 1 or 2.

represents a double bond, Y ₁ And Y ₂ Both are C, ring A is a 5-membered heteroaryl group containing 1S atom and 1N atom; r is ₆ Is selected from-NH ₂ -CN, -OH, unsubstituted-SO _n C _1-3 Alkyl, unsubstituted C _1-3 Alkyl and unsubstituted C _1～3 Alkoxy, wherein n is selected from 0, 1 or 2, and m is 1 or 2.

In some embodiments of the present application, the compounds of formula (I-1), formula (I-a), and formula (I-b) provided herein, or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative, or pharmaceutically acceptable salt thereof,

when represents a single bond, ring A and- (R) ₆ ) _m Is absent, Y ₁ And Y ₂ Each independently is CR ₉ R ₁₀ O or NR ₁₀ (ii) a Each R ₉ And R ₁₀ Independently selected from-H or unsubstituted C _1～6 An alkyl group; or,

when represents a single bond, ring A and- (R) ₆ ) _m Is absent, Y ₁ And Y ₂ One of them is CR ₉ R ₁₀ And the other is O; each R ₉ And R ₁₀ Independently selected from-H or unsubstituted C _1～3 Alkyl (e.g., methyl); or, a structural unit

Is composed of

Preference is given to

In some embodiments of the present application, the present application provides compounds of formula (I-1), formula (I-a), and formula (I-b) or prodrugs, tautomers, stereoisomers, solvates, isotopic derivatives, or pharmaceutically acceptable salts thereof, wherein X is ₁ And X ₂ One of them is N and the other is CR ₈ Wherein R is ₈ Independently selected from-H, -NH ₂ 、-NHCOR _8a Substituted or unsubstituted C _6～14 Aryl or substituted or unsubstituted 5-to 14-membered heteroaryl, wherein R _8a Selected from the group consisting of:

or X ₁ And X ₂ Are all CR ₈ (ii) a Wherein one R ₈ is-H, another R ₈ Is selected from-NH ₂ 、-NHCOR _8a Substituted or unsubstituted C _6～14 Aryl or substituted or unsubstituted 5-to 14-membered heteroaryl, wherein R is _8a Selected from the group consisting of:

R ₁ and R ₃ Each independently selected from-H, halogen (e.g. -Cl), or halogen substituted C _1～6 Alkyl (e.g. fluoro substituted C) _1～6 Alkyl radicals, e.g. CF ₃ )；

R ₂ Is selected from-H or-NH ₂ ；

R ₇ Selected from-F, -CN, -COOR _7a 、-COR _7b Unsubstituted C ₂ Alkenyl, unsubstituted C ₂ Alkynyl and unsubstituted 3-to 6-membered heterocycloalkyl (e.g., oxetanyl), where R _7a is-H or unsubstituted C _1-3 Alkyl (e.g. methyl), R _7b Is selected from-H or unsubstituted C _1～3 Alkyl (e.g., methyl);

represents a single or double bond;

i) When the temperature is higher than the set temperature

When represents a single bond, ring A and- (R) ₆ ) _m Is absent, Y ₁ And Y ₂ Is CR ₉ R ₁₀ And the other is O; each R ₉ And R ₁₀ Independently selected from-H or unsubstituted C _1～3 Alkyl (e.g., methyl);

ii)

represents a double bond, Y ₁ And Y ₂ Both are C, ring A is selected from phenyl or 5-to 6-membered heteroaryl containing 1 or 2 heteroatoms;

R ₆ Selected from halogen or unsubstituted C _1-3 Alkyl (e.g., methyl); and

m is selected from 0 or 1.

X is selected from a bond or-S-;

R _8a Selected from:

R ₁ and R ₃ Each independently selected from-H, halogen, -NH ₂ 、-CN、-OH、-NO ₂ -COOH, substituted or unsubstituted C _1～6 Alkyl and substituted or unsubstituted C _1～6 Alkoxy, wherein said substituted C _1～6 Alkyl and substituted C _1～6 Alkoxy is independently selected from-OH, halogen, unsubstituted C _1-6 Alkyl, -NH ₂ 、-NO ₂ unsubstituted-COC _1-6 Alkyl, -CN and = O;

R ₂ selected from-H, halogen, -NH ₂ 、-CN、-OH、-NO ₂ Carboxy, -NHR _2a 、-NR _2a R _2b 、-CONH ₂ 、-CONHR _2a 、-CONR _2a R _2b 、-COR _2a 、-COOR _2a 、-NHCOR _2a 、-N(R _2a )-COR _2b Substituted or unsubstituted C _1～6 Alkyl, substituted or unsubstituted C _1～6 Alkoxy, substituted or unsubstituted C _3～6 Cycloalkyl, substituted or unsubstituted 3-to 6-membered heterocycloalkyl, substituted or unsubstituted mono-spirocycloalkyl, substituted or unsubstituted hetero-mono-spirocycloalkyl, substituted or unsubstituted C _4～8 Bridged cycloalkyl and substituted or unsubstituted 4-8 membered heterobridged cycloalkyl, wherein said substituted C _1～6 Alkyl, substituted C _1～6 Alkoxy, substituted C _3～6 Cycloalkyl, substituted 3-to 6-membered heterocycloalkyl, substituted mono-spirocycloalkyl, substituted hetero mono-spirocycloalkyl, substituted C _4～8 The bridged cycloalkyl group and the substituted 4-8 membered heterobridged cycloalkyl group are each independently selected from-OH, halogen, unsubstituted C _1-6 Alkyl, -NH ₂ 、-NO ₂ unsubstituted-COC _1-6 Alkyl, -CN, and = O;

or R ₂ To adjacent R ₃ By cyclization to form substituted or unsubstituted C ₆ Or C ₁₀ Aryl, substituted or unsubstituted 5-to 8-membered heteroaryl or substituted or unsubstituted non-aromatic 5-to 8-membered heterocyclyl, wherein C is substituted ₆ Or C ₁₀ Aryl, substituted 5-to 8-membered heteroaryl or substituted non-aromatic 5-to 8-membered heterocyclyl are each independently selected from-OH, halogen, unsubstituted C _1-6 Alkyl, -NH ₂ 、-NO ₂ unsubstituted-COC _1-6 Alkyl, -CN and = O;

R ₇ is selected from-H;

indicates the presence or absence of a bond;

i)

when it indicates that a bond is absent, X ₃ Nor is present, R ₄ And R ₅ Each independently selected from hydrogen, hydroxy, halogen, = O, substituted or unsubstituted C _1～6 Alkyl and substituted or unsubstituted C _1～6 Alkoxy radical, wherein R ₄ And R ₅ Each independently selected from "= O" means that another hydrogen atom at the same substitution position is simultaneously substituted by the oxygen atom, wherein the substituted C is _1～6 Alkyl and substituted C _1～6 Alkoxy is independently selected from-OH, halogen, unsubstituted C _1-6 Alkyl, -NH ₂ 、-NO ₂ unsubstituted-COC _1-6 Alkyl, -CN and = O, with the proviso that R is ₄ And R ₅ Cannot be simultaneously hydrogen;

ii)

when a bond is present, X ₃ Is CH ₂ ，R ₄ And R ₅ Are all hydrogen;

represents a single or double bond;

i) When the temperature is higher than the set temperature

Each R ₉ And R ₁₀ Independently selected from-H, halogen, -OH, substituted or unsubstituted C _1～6 Alkyl and substituted or unsubstituted C _1～6 Alkoxy, wherein said substituted C _1～6 Alkyl and substituted C _1～6 Alkoxy is independently selected from OH, halogen, unsubstituted C _1-6 Alkyl, -NH ₂ 、-NO ₂ unsubstituted-COC _1-6 Alkyl, -CN and = O;

ii) when

When represents a double bond, Y ₁ And Y ₂ Both C, ring A is present and is selected from naphthyl, phenyl or 5-to 6-membered heteroaryl;

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

In some embodiments of the present application, there is provided a compound, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure:

the compounds of the present application may be asymmetric, e.g., having one or more stereoisomers. Unless otherwise indicated, all stereoisomers are included, such as enantiomers and diastereomers. The compounds of the present application containing asymmetric carbon atoms can be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from a racemic mixture or synthesized by using chiral starting materials or chiral reagents.

The compounds of the present application may have one or more atropisomers, which unless otherwise indicated, refers to the optically active isomer resulting from the hindrance of free rotation between single bonds. The compounds containing the chiral axis of the present application can be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from a racemic mixture or synthesized by using chiral starting materials or chiral reagents.

The compounds and intermediates of the present application may also exist in different tautomeric forms, and all such forms are included within the scope of the present application. 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 isomerizations. A specific example of a proton tautomer is an imidazole moiety, wherein the proton can migrate between two ring nitrogens. Valence tautomers include interconversion by recombination of some of the bonding electrons.

In another aspect, the present application provides a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. In some embodiments, the present application also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I-1), formula (I), formula (Ia), or formula (Ib), or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof. In some embodiments, the present application also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I-1), formula (I), formula (Ia), or formula (Ib), or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative, or pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

Pharmaceutical composition

The compounds of the present application or their prodrugs, tautomers, stereoisomers, solvates, isotopic derivatives or pharmaceutically acceptable salts thereof can be administered as the active substance alone, preferably in the form of a pharmaceutical composition thereof.

In another aspect, the present application provides a pharmaceutical composition containing a compound represented by formula (I-1), formula (I), formula (Ia) or formula (Ib), and a prodrug, tautomer, stereoisomer, solvate, isotopic derivative or pharmaceutically acceptable salt thereof, as an active ingredient.

The application provides a pharmaceutical composition which contains a compound shown as a formula (I-1), a formula (I), a formula (Ia) or a formula (Ib) and a prodrug, a tautomer, a stereoisomer, a solvate, an isotopic derivative or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable auxiliary materials.

Administration of the compounds of the present application and their prodrugs, tautomers, stereoisomers, solvates, isotopic derivatives, or pharmaceutically acceptable salts thereof, can be carried out in pure form or in the form of a suitable pharmaceutical composition by any acceptable mode of administration which provides a drug of similar utility. The pharmaceutical compositions of the present application may be prepared by combining a compound of formula (I-1), formula (I), formula (Ia) or formula (Ib) of the present application with suitable pharmaceutically acceptable excipients. The pharmaceutical composition of the present application can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, solutions, suppositories, injections, inhalants, gels, microspheres, aerosols, and the like. Generally, the above pharmaceutical composition can be prepared by a conventional preparation method using excipients which are conventional in the field of formulation.

The pharmaceutical compositions of the present application may have effects in the treatment and prevention of diseases, disorders and conditions mediated by SHP2 activity, such as cancer, cancer metastasis, cardiovascular disease, immune disorders or visual disorders.

In another aspect, the present application provides the use of a compound described herein, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present application for the manufacture of a medicament for the treatment, prevention and/or treatment of a disease mediated by SHP2 activity.

In some embodiments, the present application also provides the use of a compound of formula (I-1), formula (I), formula (Ia), or formula (Ib), or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present application, in the manufacture of a medicament for the treatment prevention and/or treatment of diseases, disorders, and conditions mediated by SHP2 activity.

In yet another aspect, the present application provides methods for treating and/or preventing diseases, disorders, and conditions mediated by SHP2 activity, comprising administering to a subject in need thereof a compound of formula (I-1), formula (I), formula (Ia), or formula (Ib), or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

In yet another aspect, the present application provides a compound represented by formula (I-1), formula (I), formula (Ia), or formula (Ib), or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the treatment and/or prevention of diseases, disorders, and conditions mediated by SHP2 activity.

In yet another aspect, the present application provides the use of a compound of formula (I-1), formula (I), formula (Ia) or formula (Ib), or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the treatment and/or prevention of diseases, disorders, and conditions mediated by SHP2 activity.

In some embodiments of the present application, the diseases, disorders, and conditions are tumors, cardiovascular diseases, immune disorders, or vision disorders.

In some embodiments of the present application the tumor includes a solid tumor and a hematological tumor.

In some embodiments of the present application the solid tumor comprises pancreatic cancer, lung cancer, preferably non-small cell lung cancer; the blood tumor comprises leukemia, preferably juvenile myelomonocytic leukemia and acute myelogenous leukemia.

In yet another aspect, the present application provides methods for preventing and/or treating diseases, disorders, and conditions mediated by SHP2 activity, comprising administering to a subject in need thereof a compound represented by formula (I-1), formula (I), formula (Ia), or formula (Ib), and prodrugs, tautomers, stereoisomers, solvates, isotopic derivatives thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof; preferably, the diseases, disorders and conditions are tumors, cardiovascular diseases, immune disorders or vision disorders; more preferably, the tumor includes solid tumors and hematological tumors; more preferably, the solid tumor comprises pancreatic cancer, lung cancer, preferably non-small cell lung cancer; the blood tumor comprises leukemia, preferably juvenile myelomonocytic leukemia and acute myelogenous leukemia.

In yet another aspect, the present application provides compounds represented by formula (I-1), formula (I), formula (Ia), or formula (Ib), and prodrugs, tautomers, stereoisomers, solvates, isotopic derivatives thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for use in the prevention and/or treatment of diseases, disorders, and conditions mediated by SHP2 activity; preferably, the diseases, disorders and conditions are tumors, cardiovascular diseases, immune disorders or vision disorders; more preferably, the tumor includes solid tumors and hematological tumors; more preferably, the solid tumor comprises pancreatic cancer, lung cancer, preferably non-small cell lung cancer; the blood tumor comprises leukemia, preferably juvenile myelomonocytic leukemia and acute myelogenous leukemia.

Further, the use or method provided herein, wherein the compound described herein and its prodrug, tautomer, stereoisomer, solvate, isotopic derivative or pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof is used in combination with another, two or more compounds having tumor-inhibiting activity.

Further, the use as provided herein, wherein the compound described herein, a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present invention is used in combination with another compound, two or more compounds having tumor inhibiting activity.

Definition of

The following terms used in the present application have the following meanings, unless otherwise specified. A particular term should not be considered as indefinite or unclear unless it is specifically defined, but rather construed according to ordinary meaning in the art. When a trade name appears herein, it is intended to refer to its corresponding commodity or its active ingredient.

The term "compound" as used herein includes all stereoisomeric, geometric isomeric, tautomeric and isotopic forms of the compounds.

The term "substituted" or "substituted" means that any one or more hydrogen atoms on a particular atom is replaced with a substituent, provided that the valency of the particular atom is normal and the substituted compound is stable. When the substituent is oxo (i.e = O), it means that two hydrogen atoms on the same carbon atom are replaced by oxygen atoms. It will be appreciated by those skilled in the art that any group containing one or more substituents will not incorporate any substitution or substitution pattern which is sterically impossible and/or cannot be synthesized.

When any variable (e.g., R) occurs more than one time in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 2R, then each R has separate options.

Herein C _m-n It is the moiety that has an integer number of carbon atoms in the given range. E.g. "C _1-6 By "is meant that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms. For example, "C _3-6 By "is meant that the group may have 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.

The term "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group, a straight or branched chain group containing 1-20 carbon atoms, preferably 1-10 carbon atoms (i.e., C) _1-10 Alkyl), further preferably containing 1 to 8 carbon atoms (C) _1-8 Alkyl), more preferably containing 1 to 6 carbon atoms (i.e., C) _1-6 Alkyl) such as "C _1-6 By alkyl is meant that the group is alkyl and the number of carbon atoms in the carbon chain is between 1 and 6 (specifically 1,2, 3, 4, 5 or 6). Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, n-octyl and the like.

The term "alkenyl" refers to a straight or branched chain unsaturated aliphatic hydrocarbon group having at least one double bond, consisting of carbon atoms and hydrogen atoms. The alkenyl group may contain 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms (i.e. C) _2-10 Alkenyl), further preferably containing 2 to 8 carbon atoms (C) _2-8 Alkenyl), more preferablyContaining 2-6 carbon atoms (i.e. C) _2-6 Alkenyl), 2-5 carbon atoms (i.e., C) _2-5 Alkenyl), 2-4 carbon atoms (i.e., C) _2-4 Alkenyl), 2-3 carbon atoms (i.e., C) _2-3 Alkenyl), 2 carbon atoms (i.e., C) ₂ Alkenyl) such as "C _2-6 By alkenyl "is meant that the group is alkenyl and the number of carbon atoms in the carbon chain is between 2 and 6 (specifically 2, 3, 4, 5 or 6). Non-limiting examples of alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, and 1, 3-butadienyl, and the like.

The term "alkynyl" refers to a straight or branched chain unsaturated aliphatic hydrocarbon group having at least one triple bond consisting of carbon atoms and hydrogen atoms. Alkynyl groups can contain 2-20 carbon atoms, preferably 2-10 carbon atoms (i.e., C) _2-10 Alkynyl) and further preferably contains 2 to 8 carbon atoms (C) _2-8 Alkynyl) and more preferably contains 2 to 6 carbon atoms (i.e., C) _2-6 Alkynyl), 2-5 carbon atoms (i.e., C) _2-5 Alkynyl), 2-4 carbon atoms (i.e., C) _2-4 Alkynyl), 2-3 carbon atoms (i.e., C) _2-3 Alkynyl), 2 carbon atoms (i.e., C) ₂ Alkynyl) such as "C _2-6 Alkynyl "means that the group is alkynyl and the number of carbon atoms in the carbon chain is between 2 and 6 (specifically 2, 3, 4, 5 or 6). Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, and 1-butynyl, and the like.

The term "cycloalkyl" refers to a monocyclic saturated aliphatic radical having the specified number of carbon atoms, preferably comprising 3 to 12 carbon atoms (i.e., C) _3-12 Cycloalkyl), more preferably containing 3 to 10 carbon atoms (C) _3-10 Cycloalkyl group), further preferably 3 to 6 carbon atoms (C) _3-6 Cycloalkyl), 4 to 6 carbon atoms (C) _4-6 Cycloalkyl), 5 to 6 carbon atoms (C) _5-6 Cycloalkyl groups). Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, 2-ethyl-cyclopentyl, dimethylcyclobutyl, and the like. In some embodiments herein, "cycloalkyl" refers to a group consisting of carbon atoms and hydrogenA monocyclic saturated aliphatic hydrocarbon group having a specific carbon number in terms of atoms. In some embodiments herein, cycloalkyl groups also preferably contain 3 to 4 carbon atoms (C) _3-4 Cycloalkyl), 3 to 5 carbon atoms (C) _3-5 Cycloalkyl) or 4 to 5 carbon atoms (C) _4-5 Cycloalkyl).

The term "alkoxy" refers to an-O-alkyl group, as defined above, i.e. containing 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms (in particular 1,2, 3, 4, 5 or 6). Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, tert-butoxy, pentyloxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1-dimethylpropoxy, 1, 2-dimethylpropoxy, 2-dimethylpropoxy, 1-ethylpropoxy, and the like.

The term "carboxy" refers to the-COOH group. The term "halogen" or "halo" refers to F, cl, br, I. The term "haloalkyl" means an alkyl group as defined above wherein one, two or more hydrogen atoms or all hydrogen atoms are replaced by halogen. Representative examples of haloalkyl groups include CCl ₃ 、CF ₃ 、CHCl ₂ 、CH ₂ Cl、CH ₂ Br、CH ₂ I、CH ₂ CF ₃ 、CF ₂ CF ₃ And the like.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic, bicyclic, or polycyclic cyclic hydrocarbon substituent, non-aromatic in structure, containing from 3 to 20 ring atoms, wherein 1,2, 3, or more ring atoms are selected from N, O, or S, and the remaining ring atoms are C. Preferably containing 3 to 12 ring atoms (C) _3-12 Heterocyclyl) and further preferably contains 3 to 10 ring atoms (C) _3-10 Heterocyclic group), or 3 to 8 ring atoms (C) _3-8 Heterocyclyl), or 3 to 6 ring atoms (C) _3-6 Heterocyclyl), or 4 to 6 ring atoms (C) _4-6 Heterocyclyl), or 5 to 6 ring atoms (C) _5-6 A heterocyclic group). Hetero atomThe number of subgroups is preferably 1-4, more preferably 1-3 (i.e. 1, 2 or 3). Examples of monocyclic heterocyclic groups include oxiranyl, pyrrolidinyl, N-methylpyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl, and the like. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups. In some embodiments herein, heterocyclyl preferably comprises 3 to 12 ring atoms (3-12 membered heterocyclyl), further preferably 3 to 10 ring atoms (3-10 membered heterocyclyl), or 3 to 8 ring atoms (3-8 membered heterocyclyl), or 3 to 6 ring atoms (3-6 membered heterocyclyl), or 4 to 6 ring atoms (4-6 membered heterocyclyl), 5 to 6 ring atoms (5-6 membered heterocyclyl), or 5 to 8 ring atoms (5-8 membered heterocyclyl, e.g., 5, 6, 7, or 8 membered heterocyclyl).

The term "heterocycloalkyl" refers to a saturated "heterocyclyl" as defined above, containing 3 to 20 ring atoms, of which 1, 2, 3 or more ring atoms are selected from N, O or S, the remaining ring atoms being C. Preferably containing 3 to 12 ring atoms (C) _3-12 Heterocycloalkyl group), further preferably contains 3 to 10 ring atoms (C) _3-10 Heterocycloalkyl), or 3 to 8 ring atoms (C) _3-8 Heterocycloalkyl), or 3 to 7 ring atoms (C) _3-7 Heterocycloalkyl), or 3 to 6 ring atoms (C) _3-6 Heterocycloalkyl), or 4 to 6 ring atoms (C) _4-6 Heterocycloalkyl), or 5 to 6 ring atoms (C) _5-6 Heterocycloalkyl). The number of heteroatoms is preferably 1-4, more preferably 1-3 (i.e. 1, 2 or 3). Examples include aziridinyl, oxacyclopropaneyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, oxacyclohexane, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithiacyclohexyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, imidazolinidinyl, and the like. In some embodiments herein, heterocycloalkyl preferably comprises 3-12 ring atoms (3-12 membered heterocycloalkyl), further preferably 3-10 ring atoms (3-10 membered heterocycloalkyl), or 3-8 ring atoms (3-8 membered heterocycloalkyl), or 3-7 ring atoms (3-7 membered heterocycloalkyl)Heterocycloalkyl), or 3 to 6 ring atoms (3-6 membered heterocycloalkyl, e.g., 3, 4, 5, or 6 membered heterocycloalkyl), or 4 to 6 ring atoms (4-6 membered heterocycloalkyl), or 5 to 6 ring atoms (5-6 membered heterocycloalkyl).

The term "mono spirocycloalkyl" is a saturated aliphatic hydrocarbon group having a specific number of carbon atoms in total consisting of carbon atoms and hydrogen atoms in the form of a spiro ring. Preferably 6 to 14, more preferably 7 to 10. Non-limiting examples of mono spirocycloalkyl groups are 3-membered/5-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, and 5-membered/6-membered rings, wherein the count for each ring includes spiro atoms. Non-limiting examples of mono spirocycloalkyl groups include:

and the like.

The term "heteromonospirocycloalkyl" is a saturated aliphatic hydrocarbon group having a specific number of carbon atoms and heteroatoms, which has only one carbon atom in total, in the form of a spiro ring. The heteroatoms in the heteromonospirocycloalkyl group are preferably 1-4, more preferably 1-3 (i.e. 1, 2 or 3), and are independently selected from N, O and S. Preferably 6 to 14, more preferably 7 to 10. Non-limiting examples of heteromonospirocycloalkyl groups are 3-membered/5-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered and 5-membered/6-membered rings, where the count for each ring includes the spiro atom. Non-limiting examples of heteromonospirocycloalkyl groups include:

and so on.

"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, but none of the rings have a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. According to the number of constituent rings, they may be bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl radicals, preferably bicyclic, tricyclic or tetracyclic And a ring, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

"Heterobridged cycloalkyl" refers to a 5 to 14 membered polycyclic heterocyclic group in which any two rings share two atoms not directly attached, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system, where one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen, or S (O) m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

the term "aryl" denotes monocyclic, bicyclic and tricyclic aromatic carbocyclic ring systems containing from 6 to 16 carbon atoms, or from 6 to 14 carbon atoms, or from 6 to 12 carbon atoms, or from 6 to 10 carbon atoms, preferably from 6 to 10 carbon atoms, the term "aryl" being used interchangeably with the term "aromatic ring". Examples of the aryl group may include, but are not limited to, phenyl, naphthyl, anthryl, phenanthryl, pyrenyl, or the like.

The term "heteroaryl" denotes an aromatic monocyclic or polycyclic ring system containing a 5-12 membered structure, or preferably a 5-10 membered structure, a 5-8 membered structure, more preferably a 5-6 membered structure, wherein 1,2, 3 or more ring atoms are heteroatoms and the remaining atoms are carbon, the heteroatoms are independently selected from O, N or S, the number of heteroatoms is preferably 1,2 or 3. Examples of heteroaryl groups include, but are not limited to, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiadiazolyl, triazinyl, phthalazinyl, quinolyl, isoquinolyl, pteridinyl, purinyl, indolyl, isoindolyl, indazolyl, benzofuranyl, benzothienyl, benzopyridyl, benzopyrimidinyl, benzimidazolyl, phthalizinyl, pyrrolo [2,3-b ] pyridyl, imidazo [1,2-a ] pyridyl, pyrazolo [1,5-a ] pyrimidinyl, imidazo [1,2-b ] pyridazinyl, [1,2,4] triazolo [4,3-b ] pyridazinyl, [1,2,4] triazolo [1,5-a ] pyrimidinyl, [1,2,4] triazolo [1,5-a ] pyridyl, and the like.

The term "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt" refers to salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of mammals, especially humans, without excessive toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, such as the medically acceptable salts of amines, carboxylic acids, and other types of compounds, are well known in the art.

The term "salt" or "pharmaceutically acceptable salt" encompasses salts prepared from inorganic acids, organic acids, and the like. Pharmaceutically acceptable non-toxic bases include salts prepared with inorganic and organic bases if the compounds of the present application are acidic. Such inorganic acids, organic acids, inorganic bases and organic bases are well known to those skilled in the art.

Prodrugs are derivatives of the active drug of design that may improve some defined, undesirable physical or biological property. Physical properties are often associated solubility (too high or insufficient lipid or water solubility) or stability, while problematic biological properties include too rapid metabolism or poor bioavailability, which may itself be associated with physicochemical properties. Prodrugs are generally prepared as follows: a) forming esters, half-esters, carbonates, nitrates, amides, hydroxamic acids, carbamates, imines, mannich bases, phosphates and enamines of the active drug, b) functionalizing the drug with azo, glycoside, peptide and ether functionalities, c) using the aminal, hemiaminal, polymer, salt, complex, phosphoramide, acetal, hemiacetal and ketal forms of the drug. Esters can be prepared from substrates containing hydroxyl or carboxyl groups using general methods known to those skilled in the art. Typical reactions for these compounds are substitutions in which one heteroatom is replaced by another atom. Amides can be prepared in a similar manner from substrates containing amino or carboxyl groups. Esters may also react with amines or ammonia to form amides. Another way to prepare the amide is to heat the carboxylic acid and the amine together.

By "isotopically-derived" is meant that the compounds of the present invention can exist in isotopically-labelled or enriched forms, containing one or more atoms whose atomic mass or mass number is different from the atomic mass or mass number of the largest amount of atoms found in nature. The isotope may be a radioactive or non-radioactive isotope. Isotopes of atoms such as hydrogen, carbon, phosphorus, sulfur, fluorine, chlorine, and iodine include, but are not limited to: 2H,3H,13C,14C,15N,18O,32P,35S,18F,36Cl and 125I. Compounds containing other isotopes of these and/or other atoms are within the scope of the present invention. In another embodiment, isotopically labeled compounds contain deuterium (2H), tritium (3H), or 14C isotopes. Isotopically-labeled compounds of the present invention can be prepared by conventional methods well known to those of ordinary skill in the art. In addition, drugs containing non-radioactive isotopes, such as deuterated drugs known as "heavy drugs," can be used to treat related diseases and conditions. An increase in the amount of isotope present in the above compound above its natural abundance is referred to as enrichment. Examples of amounts of enrichment include about 0.5,1,2,3,4,5,6,7,8,9, 10, 12, 16, 21, 25, 29, 33, 37, 42, 46, 50, 54, 58, 63, 67, 71, 75, 79, 84, 88, 92, 96 to about 100mol%. Any possible site in the molecular structure can be substituted by an isotope to obtain an isotope derivative. For example, any possible site in the molecule may be substituted with deuterium (2H) to give the derivative in a deuterated form. With stable isotopically labeled drugs, the physicochemical properties of the drug, such as pKa and lipid solubility, can be altered. If isotopic substitution affects the regions involved in ligand-receptor interactions, then these effects and changes can affect the pharmacodynamic response of the drug molecule. Although some of the physical properties of the stably isotopically labeled molecules differ from those of the unlabeled molecules, the chemical and biological properties are the same, an important difference being: any bond involving the heavy isotope and another atom is stronger than the same bond between the light isotope and that atom due to the increased mass of the heavy isotope. Accordingly, the incorporation of isotopes at the site of metabolic or enzymatic conversion may potentially slow the reaction, and may alter the pharmacokinetic properties or effects relative to non-isotopic compounds.

The term "treatment" generally refers to the administration of a compound or formulation described herein to achieve a desired pharmacological and/or physiological effect. The effect may be therapeutic in terms of partially or completely stabilizing or curing the disease and/or side effects due to the disease. As used herein, "treatment" encompasses any treatment of a disease in a patient, including: (a) Inhibiting the symptoms of, i.e., arresting the development of, diseases, disorders, and conditions; or (b) alleviating the symptoms of the disease, disorder, and condition, i.e., causing regression of the disease or symptoms; or (c) ameliorating or eliminating a disease, disorder, and condition or one or more symptoms associated with the disease.

The term "therapeutically effective amount" means an amount of a compound of the present application that (i) treats a particular disease, disorder, or condition, (ii) alleviates, ameliorates, or eliminates one or more symptoms of the particular disease, disorder, or condition, or (iii) delays the onset of one or more symptoms of the particular disease, disorder, or condition described herein. The amount of a compound of the present application that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art with their own knowledge and this disclosure.

The term "pharmaceutical composition" refers to a mixture comprising one or more compounds of the present application or salts thereof or stereoisomers thereof and pharmaceutically acceptable excipients. The purpose of the pharmaceutical composition is to facilitate administration of the compounds of the present application to an organism.

The term "pharmaceutically acceptable adjuvants" refers to those adjuvants which do not have a significant irritating effect on the organism (e.g., human) and which do not impair the biological activity and performance of the active compound. Suitable adjuvants are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like. "pharmaceutically acceptable adjuvants" may also refer to inert substances which are administered with the active ingredient to facilitate its administration, including, but not limited to, any glidant, sweetener, diluent, preservative, dye/colorant, flavoring, surfactant, wetting agent, dispersant, disintegrant, suspending agent, stabilizer, isotonicity agent, solvent, or emulsifier which is approved by the U.S. food and drug administration for use in humans or animals (e.g., livestock). Non-limiting examples of such excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

The beneficial effect of this application does:

the application designs a compound with novel structure, and provides a new direction for treating cancer, cancer metastasis, cardiovascular diseases, immune disorders or visual disorders. In-vitro inhibition research of cell proliferation shows that the compounds have stronger inhibition effect on pancreatic cancer cell MIA-PACA-2 cells, and enzymatic test results show that the compounds have good selectivity on targets. The development of the compound expands the selection of the medicines for treating the diseases. In addition, a specific synthesis method is researched, and the synthesis method is simple in process, convenient to operate and beneficial to large-scale industrial production and application. The compound shown in the formula (I-1), the formula (I), the formula (Ia) or the formula (Ib) or a prodrug, a tautomer, a stereoisomer, a solvate, an isotope derivative or a pharmaceutically acceptable salt thereof has a good inhibiting effect on SHP2 activity, pancreatic cancer, acute myelogenous leukemia and/or non-small cell lung cancer, and also has good pharmacokinetic properties, bioavailability and/or safety in vivo.

Detailed Description

The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Experimental procedures without specific conditions noted in the following examples are generally performed under conventional conditions or conditions recommended by the manufacturers. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials are described herein for illustrative purposes only.

Intermediate preparation example 1: 5-amino-3-chloro-6- [ (2- (trifluoromethyl) pyridin-3-yl) sulfanyl ] pyrazine-2-carbonitrile (intermediate A1)

Step a: under the protection of nitrogen, 3-bromo-2-trifluoromethylpyridine (9.00g, 39.824mmol, 1.00equiv), 2-ethylhexyl 3-mercaptopropionate (17.39g, 79.647mmol, 2.00equiv), DIEA (15.44g, 119.471mmol, 3.00equiv), pd ₂ (dba) ₃ .CHCl ₃ (1.03g, 0.996mmol, 0.02equiv) and XantPhos (1.15g, 1.991mmol, 0.05equiv) in 1, 4-dioxane (135 ml) were stirred at 95 ℃ overnight; cooling to room temperature, filtering the reaction solution with diatomite, and concentrating the filtrate under reduced pressure; the residue was purified by column chromatography (n-hexane: EA =10: 1) to give 3- [ [ [2- (trifluoromethyl) pyridin-3-yl ] yellow oil]Sulfanyl radical]2-ethylhexyl propionate (14.1g, 97.42%), (ES, m/z): 364[ deg. ] M + H] ⁺ 。

Step b: under the protection of nitrogen, under the condition of-78 ℃,3- [ [ [2- (trifluoromethyl) pyridine-3-yl ] is reacted]Sulfanyl radical]Adding 1mol/L t-BuOK (116.60mL, 116.388mmol, 3.00equiv) THF solution of 2-ethylhexyl propionate (14.10g, 38.796mmol, 1.00equiv) into THF (141 mL), and reacting for 1.5h under heat preservation; 300ml of 2mol/L K is added to the reaction mixture ₂ CO ₃ Aqueous solution and liquid separation; the aqueous phase was washed with MTBE (2X 200 mL) by extraction; adjusting the pH value of the water phase to 4 by using 6mol/L hydrochloric acid; aqueous phase with CHCl ₃ extraction/i-PrOH =9/1 (3 × 200 mL), combined organic phases; the organic phase was washed with saturated NaCl (200 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure; obtaining light yellow solid 2- (trifluoromethyl)) Pyridine-3-thiol (6.1g, 87.76%), (ES, m/z): 180[ 2 ] M + H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ )δ8.51–8.45(m,1H),8.12(d,J＝8.1Hz,1H),7.61–7.54(m,1H),6.31(s,1H).

Step c: under the protection of nitrogen, 3-bromo-6-chloro-pyrazin-2-amine (5.00g, 23.988mmol, 1.00equiv), 2- (trifluoromethyl) pyridine-3-thiol (3.44g, 19.190mmol, 0.8equiv), DIEA (9.30g, 71.963mmol, 3.0equiv), pd ₂ (dba) ₃ .CHCl ₃ Reacting (0.62g, 0.600mmol, 0.025equiv) and a 1, 4-dioxane (100 mL) solution of XantPhos (0.69g, 1.199mmol, 0.05equiv) at 95 ℃ overnight, cooling to room temperature, filtering the reaction solution with diatomite, and concentrating the filtrate under reduced pressure; the residue was purified by column chromatography (n-hexane: EA =2 1) to give 6-chloro-3- [ [ [2- (trifluoromethyl) pyridin-3-yl ] solid]Sulfanyl radical]Pyrazine-2-amine (1.7g, 23.11%).

Step d: under the protection of nitrogen and at the temperature of 0 ℃, 6-chloro-3- [ [ [2- (trifluoromethyl) pyridine-3-yl ] is reacted]Sulfanyl radical]Pyrazin-2-amine (1.60g, 5.217mmol, 1.00equiv), K ₂ CO ₃ To a solution of (1.44g, 10.434mmol, 2.00equiv) in MeOH (32 mL) was added dropwise a solution of ICl (1.27g, 7.825mmol, 1.50equiv) in DCM (32 mL) and the reaction was carried out for 2h at controlled temperature. Then reacting at room temperature overnight; adding 100mL of 10% Na to the reaction solution ₂ SO ₃ The aqueous solution was quenched, separated, the aqueous phase extracted with DCM (3 × 50 mL), and the organic phases combined; the organic phase was washed with saturated NaCl 50ml, dried over anhydrous sodium sulfate and concentrated under reduced pressure; to obtain brown solid 6-chloro-5-iodo-3- [ [2- (trifluoromethyl) pyridin-3-yl]Sulfanyl radical]Pyrazine-2-amine (intermediate A1-I) (1.7g, 75.33%), (ES, m/z): 433[ m ] +H] ⁺ 。

Step e: under the protection of nitrogen, 6-chloro-5-iodo-3- [ [2- (trifluoromethyl) pyridin-3-yl ] is reacted]Sulfanyl radical]Pyrazine-2-amine (1.5 g,3.467mmol, 1.00equiv), pd (PPh) ₃ ) ₄ (400mg, 0.347mmol, 0.10equiv) and Zn (CN) ₂ (407mg, 3.467mmol, 1.00equiv) in NMP (15.00 mL) at 100 ℃ for 2h with stirring; cooling to room temperature, sequentially adding EA (150 ml) and 25% ammonia water (100 ml) into the reaction solution, stirring, and separating; EA (3) for the aqueous phaseX 30 mL), and combining organic phases; washing the organic phase with saturated NaCl, drying over anhydrous sodium sulfate and concentrating under reduced pressure; the residue was purified by column chromatography (n-hexane: EA =20:1 to 5) to obtain 5-amino-3-chloro-6- [ (2- (trifluoromethyl) pyridin-3-yl) sulfanyl) as a pale yellow solid]Pyrazine-2-carbonitrile (intermediate A1) (820 mg, 71%) (ES, m/z): 331.95[ 2 [ M ] +H ]] ⁺ 。

Intermediate preparation example 2: 5-amino-6- [ (2-amino-3-chloropyridin-4-yl) sulfanyl ] -3-chloropyrazine-2-carbonitrile (intermediate A2) (preparation of intermediate A2I)

Step a: under the protection of nitrogen, 2-amino-3-bromo-6-chloropyrazine (5g, 23.99mmol, 1eq), methyl 3-mercaptopropionate (2.88g, 23.99mmol,2.60mL, 1eq), DIEA (6.20g, 47.97mmol, 2eq), pd (OAc) ₂ (538.53mg, 2.40mmol, 0.1eq) and Xantphos (2.08g, 3.60mmol, 0.15eq) in 1, 4-dioxane (80 ml) were stirred at 95 ℃ for 10h; cooling to room temperature, filtering the reaction solution with diatomite, and concentrating the filtrate under reduced pressure; the residue was purified by column chromatography (n-hexane: EA =100:1 to 20) to obtain methyl 3- ((3-amino-5-chloropyrazin-2-yl) sulfanyl) propionate (5g, 84.1%) as a yellow solid.

¹ H NMR(400MHz,CHLOROFORM-d)δ7.81(s,1H),4.88(br s,2H),3.72(s,3H),3.46(t,J＝6.8Hz,2H),2.77(t,J＝6.8Hz,2H).

Step b: under the protection of nitrogen and at the temperature of-30 ℃, dropwise adding sodium methoxide (5M, 6.30mL, 1.3eq) into a methanol (50 ml) solution of methyl 3- ((3-amino-5-chloropyrazin-2-yl) sulfanyl) propionate (6 g,24.22mmol, 1eq), preserving heat and stirring for 0.5h after the dropwise adding is finished, and then reacting at room temperature for 10h; the reaction solution is concentrated under reduced pressure and H is added ₂ O (30 ml), with CH ₂ Cl ₂ (15ml × 3) extract wash aqueous phase; the aqueous phase was lyophilized to give a yellow solid crude 3-amino-5-chloropyrazine-2-thiol sodium salt (5.5 g) which was used in the next reaction without purification.

Step c: under the protection of nitrogen, 3-amino-5-chloropyrazine-2-thiolSodium (2.16g, 11.79mmol, 1.2eq), 3-chloro-4-iodopyridin-2-amine (2.5g, 9.82mmol, 1eq), DIEA (2.54g, 19.65mmol,3.42mL, 2eq), pd ₂ (dba) ₃ (899.68mg, 982.49umol, 0.1eq) and Xantphos (852.73mg, 1.47mmol, 0.15eq) in 1, 4-dioxane (20 mL) were reacted at 75 ℃ for 2H, cooled to room temperature, EA (50 mL) and H were added ₂ O (30 mL), the layers were separated, the aqueous layer was extracted with EA (20 mL. Times.2), and the organic layers were combined. The organic phase was washed with saturated NaCl (30 mL. Times.2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (n-hexane: EA =100:1 to 2) to obtain 3- ((2-amino-3-chloropyridin-4-yl) sulfanyl) -6-chloropyrazin-2-amine (1.5g, 52.9%) as a yellow solid.

¹ H NMR(400MHz,CHLOROFORM-d)δ8.01(s,1H),7.78(d,J＝5.4Hz,1H),6.11(d,J＝5.4Hz,1H),5.23(br s,2H),4.95(br s,2H).

Step (d) to step (e): preparation of intermediate A2-I Using the product of the above procedure as starting Material with reference to step d of intermediate preparation example 1, and preparation of 5-amino-6- [ (2-amino-3-chloropyridin-4-yl) sulfanyl with reference to step e of intermediate preparation example 1 with reference to intermediate A2-I]-3-chloropyrazine-2-carbonitrile (intermediate A2) (ES, m/z): 312.79[ M ] +H] ⁺ 。

Intermediate preparation example 3: 5-amino-6- [ (2-amino-3-chloropyridin-4-yl) sulfanyl ] -3-chloropyrazine-2-carbonitrile (intermediate A2) (preparation of intermediate A2 II)

A, step a: under the protection of nitrogen and at the temperature of 0 ℃, 2-amino-6-chloropyrazine (40.00g, 308.761mmol, 1.00equiv), K ₂ CO ₃ (85.34g, 617.522mmol, 2.00equiv) in MeOH (200 mL), and ICl (90.23g, 555.770mmol, 1.80equiv) in DCM (200.00 mL) were added dropwise, the temperature was controlled for reaction for 2h, and then the reaction was carried out overnight at room temperature; adding 800mL of 10% Na to the reaction solution ₂ SO ₃ The reaction was quenched with aqueous solution, separated, the aqueous phase extracted with DCM (3 × 300 mL), and the organic phases combined; organic phase is saturatedAnd NaCl washing, drying by anhydrous sodium sulfate and concentrating under reduced pressure; the crude product is recrystallized by PE/EA (1)] ⁺ 。

Step b: a solution of 6-chloro-5-iodopyrazin-2-amine (34.00g, 133.104mmol, 1.00equiv), cuCN (13.11g, 146.414mmol, 1.10equiv) in DMF (340.00 mL) was reacted at 150 ℃ for 2h under nitrogen protection; cooling to room temperature, sequentially adding EA (500 ml) and 25% ammonia water (200 ml) into the reaction solution, stirring, and separating; the aqueous phase was extracted with EA (3X 300 mL) and the organic phases were combined; washing the organic phase with saturated NaCl, drying over anhydrous sodium sulfate and concentrating under reduced pressure; the crude product was recrystallized from PE/EA (2)] ^- ； ¹ H NMR(400MHz,DMSO-d ₆ )δ8.13(s,2H),7.88(s,1H)。

Step c: NBS (3.47g, 19.48mmol, 1.50equiv) was added to DCM (20.00 mL) of 5-amino-3-chloropyrazine-2-carbonitrile (2.00g, 12.99mmol, 1.00equiv) at room temperature, and reacted for 1h; the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (n-hexane: EA =10, 1 to 5 ] ^- 。

Step d, under the protection of nitrogen, adding 2-amino-3-chloropyridine-4-sodium mercaptide (2.00g, 12.31mmol, 1.2eq), 5-amino-6-bromo-3-chloropyrazine-2-carbonitrile (2.38g, 10.26mmol, 1eq), DIEA (3.98g, 30.78mmol, 3eq), pd ₂ (dba) ₃ (900mg, 1.026mmol, 0.1eq) and Xantphos (870mg, 1.539mmol, 0.15eq) in 1, 4-dioxane (40 mL) at 100 deg.C for 3H, cooling to room temperature, adding EA (100 mL) and H ₂ O (100 mL), separation, extraction of the aqueous phase with EA (2 × 20 mL), combination of the organic phases, washing of the organic phase with saturated NaCl (2 × 30 mL), drying over anhydrous sodium sulfate, concentration under reduced pressure, purification of the residue by column chromatography (n-hexane: EA =20:1 to 1)]-3-chloropyrazine-2-carbonitrile (intermediate A2) (1.5 g, 38.07%) (ES, m/z): 312.90[ 2 [ M + H ]] ⁺ 。

Intermediate preparation examples 4 to 11: intermediates A3 to A10

The intermediates A3 to a10 were synthesized using the procedure of intermediate preparation example 2 and the following corresponding starting materials:

intermediate preparation example 12: n- (3- ((3-amino-5-chloro-6-cyanopyrazin-2-yl) sulfanyl) -2-chlorophenyl) -2-hydroxy-4-oxo-6, 7,8, 9-tetrahydro-4H-pyrido [1,2-a ] pyrimidine-3-carboxamide (intermediate A11)

A, step a: 2-aminopyridine (5.00g, 52.063mmol), triethyl methanetricarboxylate (10.89g, 57.270mmol) in xylene (50 mL) was reacted at 150 ℃ for 5h; concentrating the reaction solution under reduced pressure to obtain white solid 2-hydroxy-4-oxo-4H-pyrido [1,2-a ] ]Pyrimidine-3-carboxylic acid ethyl ester (10g, 85.49%) (ES, m/z): 235[ m + H ], (S, m/z) ]] ⁺ 。

Step b: 2-hydroxy-4-oxo-4H-pyrido [1,2-a ]]The mixture of pyrimidine-3-carboxylic acid ethyl ester (10.00g, 41.843 mmol), pd/C (0.98g, 9.205mmol) and EA (100 mL) reacts for 8h at room temperature under hydrogen atmosphere; filtering, concentrating the filtrate under reduced pressure to obtain white solid 2-hydroxy-4-oxo-6H, 7H,8H, 9H-pyridine [1,2-a]Pyrimidine-3-carboxylic acid ethyl ester (10g, 95.30%) (ES, m/z): 239[ M ] +H] ⁺ 。

Step c: 2-hydroxy-4-oxo-6H, 7H,8H, 9H-pyridine [1,2-a ]]Ethyl pyrimidine-3-carboxylate (10.00g, 41.134mmol), THF (100 mL) and NaOH (2M) (103.00mL, 205.670mmol) were mixed and reacted at room temperature overnight; THF was removed by concentration under reduced pressure, the aqueous phase was adjusted to pH 3 with HCl (2M), extracted with DCM (4X 500 mL) and the organic phase with anhydrous sulfurDrying sodium, concentrating under reduced pressure to obtain white solid 2-hydroxy-4-oxo-6H, 7H,8H, 9H-pyridine [1,2-a]Pyrimidine-3-carboxylic acid (5.6 g, 63.47%) (ES, m/z): 211[ deg. ] M + H] ⁺ 。

Step d: 2-chloro-3-fluoroaniline (5.00g, 33.663mmol), tert-butylmercaptan (3.64g, 40.396mmol), cs ₂ CO ₃ (32.90g, 100.989 mmol) in DMF (50 mL) at 100 ℃ for 8h; the temperature was reduced to room temperature, and the reaction mixture was poured into water (300 ml) and washed with CH ₂ Cl ₂ (2 × 300 mL) and the organic phases were combined, washed with brine (3 × 500 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (n-hexane: EA =5 ] ⁺ 。

Step e: 3- (tert-Butylsulfanyl) -2-chloroaniline (1.00g, 4.543mmol) and concentrated HCl (10 mL) were reacted at 50 ℃ overnight with stirring; cooling to 0 ℃, filtering, sequentially pulping and washing a filter cake by using concentrated HCl (10 mL) and n-hexane (20 mL), and drying; white solid 3-amino-2-chlorobenzenethiol (520mg, 70.28%) (ES, m/z): 160[ 2 [ M ] +H ]] ⁺ 。

Step (f-h): the product obtained in the step (g) is an intermediate A11-I, and 5-amino-6- ((3-amino-2-chlorophenyl) sulfanyl) 3-chloropyrazine-2-carbonitrile is synthesized by using the product obtained in the step (g) as an initiator and the preparation steps (c) to (e) in the intermediate preparation example 1.

Step j: under the protection of nitrogen, 2-hydroxy-4-oxo-6H, 7H,8H, 9H-pyridine [1,2-a ]]Pyrimidine-3-carboxylic acid (45mg, 0.210mmol, 1eqv), 5-amino-6- ((3-amino-2-chlorophenyl) sulfanyl) 3-chloropyrazine-2-carbonitrile (79mg, 0.252mmol, 1.2eqv), HATU (96mg, 0.252mmol, 1.2eqv), DIEA (68mg, 0.525mmol, 2.5eqv) in DMF (2 mL) was reacted at room temperature for 1h; then purified by reverse flash chromatography (gradient elution with 50-80% acetonitrile in water, 10mmol/L NH) ₄ HCO ₃ Modification) to obtain yellow solid N- (3- ((3-amino-5-chloro-6-cyanopyrazin-2-yl) sulfanyl) -2-chlorophenyl) -2-hydroxy-4-oxo-6, 7,8, 9-tetrahydro-4H-pyrido [1,2-a ] of]Pyrimidine-3-carboxamide (intermediate a 11) (25.4 mg, 35%). (ES, m/z): 504.05[ m ] +H ] ⁺ 。

Intermediate preparation example 13: 3-chloro-5- ((2, 4-dimethoxybenzyl) amino) pyrazine-2-carboxylic acid methyl ester (intermediate A12)

Adding CsF (8.36g, 55.07mmol and 3eq) into DMSO (40 mL) of 3, 5-dichloropyrazine-2-carboxylic acid methyl ester (3.8g, 18.36mmol and 1eq) and 2, 4-dimethoxybenzylamine (3.07g, 18.36mmol and 1eq) under the protection of nitrogen, then heating to 75 ℃ and reacting for 3h; cooling to room temperature, pouring the reaction solution into water (200 ml) and EA (100 ml), separating the solution, extracting the water phase with EA (2X 50 ml), and combining the organic phases; the organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (n-hexane: EA =10, 1-1] ⁺ ； ¹ H NMR(400MHz,CDCl ₃ )：δppm 7.82(s,1H)7.23(d,J＝8.4Hz,1H)6.41-6.51(m,2H)5.66(br s,1H)4.55(d,J＝5.6Hz,2H)3.94(s,3H)3.85(s,3H)3.81(s,3H)。

Intermediate preparation example 14:3- [ (2-amino-3-chloropyridin-4-yl) sulfanyl ] -6-chloro-5- (oxetan-3-yl) pyrazin-2-amine (intermediate A13)

Replacement of argon with dtbpy (32.41mg, 0.121mmol,0.10 equiv) and DMA (20.00 mL), and addition of NiBr ₂ DME (42.59mg, 0.121mmol, 0.10equiv), stirred at room temperature for 0.5h; then adding 3- [ (2-amino-3-chloropyridin-4-yl) sulfanyl]6-chloro-5-iodopyrazin-2-amine (500.00mg, 1.208mmol, 1.00equiv), 3-bromooxetane (330.82mg, 2.415mmol, 2.00equiv), TBAI (44.60mg, 0.121mmol, 0.10equiv), zn (157.97mg, 2.415mmol, 2.00equiv), under the protection of argon, stirring at 70 ℃ overnight for reaction; filtering, pouring the filtrate into water (60 ml) Extracting with EA (2 × 50 ml), and mixing organic phases; the organic phase is washed with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue is purified by Prep-HPLC (gradient elution from 20 to 50% acetonitrile in water, 0.1% NH% ₄ HCO ₃ Modified) to obtain yellow solid 3- [ (2-amino-3-chloropyridin-4-yl) sulfanyl]-6-chloro-5- (oxetan-3-yl) pyrazin-2-amine (intermediate A13) (101.8mg, 24.5%) (ES, m/z): 344[ 2 ], [ M + H ])] ⁺ 。

Intermediate preparation example 15:1- (3, 3-difluoro-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) indol-1-yl) ethanone (intermediate B1)

Under the protection of nitrogen, 1- (3, 3-difluoro-4-iodoindol-1-yl) ethanone (3 g,9.2mmol, 1eqv), pin ₂ B ₂ (3.54g,13.9mmol,1.5eqv),Pd(dppf)Cl ₂ (1.36g, 1.8mmol, 0.2eqv) and KOAc (3.19g, 32.50 mmol, 3.5eqv) in DMF (25 mL) at 60 ℃ for 12h; the temperature was reduced, the reaction solution was suction-filtered through celite, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (n-hexane: EA =50] ⁺ ； ¹ H NMR(400MHz,CHLOROFORM-d)：δ＝8.47(br d,J＝8.6Hz,1H),7.63-7.55(m,1H),7.51(d,J＝8.2Hz,1H),4.29(br t,J＝15.6Hz,2H),2.27(s,3H),2.08-2.03(m,1H),1.38(s,12H)。

Intermediate preparation example 16: (R) -N- ((S) -1, 3-dihydrospiro [ indene-2, 4' -piperidine ] -1-yl) -2-methylpropane-2-sulfinamide (intermediate C1)

Step a: to 1-indanone (10.00g, 75.67mmol) at 0 ℃ under the protection of nitrogen1.00 equiv) in DMF (250 mL), 60% NaH (4.54g, 189.17mmol,2.5 equiv) was added and reacted for 1h; tert-butyl bis (2-chloroethyl) carbamate (20.15g, 83.23mmol, 1.1eqv) was then added dropwise and reacted overnight at 60 ℃; cooling to room temperature, pouring the reaction solution into ice water (1L), and extracting with EA (2X 200 ml); the organic phase was washed with brine (100 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure; the residue was purified by column chromatography (n-hexane: EA =10 = 1) to give 3-oxo-1H-spiro [ indene-2, 4-piperidine as a yellow solid]Tert-butyl-1-carboxylate (3.6 g, 15.79%) (ES, m/z): 302[ 2 ], [ M + H ]] ⁺ 。

Step b: under the protection of nitrogen, 3-oxo-1H-spiro [ indene-2, 4-piperidine is added]1-Carboxylic acid tert-butyl ester (16.00g, 0.053mmol, 1.00equiv), (R) -2-methylpropane-2-sulfinamide (19.30g, 0.159mmol, 3equiv) in THF (160.00 mL), ti (OEt) was added ₄ (121.10g, 0.531mmol, 10equiv), and reacting at 85 ℃ overnight; then cooling to 0 ℃, adding NaBH ₄ (3.00g, 0.08mmol and 1.5 equiv), and naturally heating to room temperature for reacting for 2 hours; pouring the reaction solution into brine (100 ml) and EA (100 ml), filtering, and separating filtrate; the organic phase was washed with brine (100 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure; the residue was purified by column chromatography (n-hexane: EA =10 1) to give (S) -tert-butyl 1- ((R) -1, 1-dimethylethylsulphideneamino) -1, 3-dihydrospiro [ indene-2, 4' -piperidine as a yellow solid ]-1' -carboxylate (1lg, 74.13%) (ES, m/z): 407[ M + H ], [ C ], [ M + ]] ⁺ .

Step c: reacting (S) -tert-butyl 1- ((R) -1, 1-dimethylethylenesulfonamido) -1, 3-dihydrospiro [ indene-2, 4' -piperidine]A solution of-1' -carboxylic acid ester (16.00g, 0.039mmol, 1.00equiv), TFA (40.00 mL) in DCM (160.00 mL) was reacted for 2h at RT; concentrating under reduced pressure, purifying the residue with reverse phase silica gel column (gradient elution with 10-50% acetonitrile in water) to obtain white solid (R) -N- ((S) -1, 3-dihydrospiro [ indene-2, 4' -piperidine)]-1-yl) -2-methylpropane-2-sulfinamide (intermediate C1) (3.5g, 29.02%) (ES, m/z): 307[ M + H ], (M + H)] ⁺ ； ¹ H NMR(400MHz,Methanol-d ₄ )δ7.36–7.29(m,1H),7.29–7.21(m,3H),5.92(d,J＝10.4Hz,1H),4.66–4.59(m,1H),3.48–3.36(m,1H),3.39–3.34(m,1H),3.28–3.10(m,3H),2.82(d,J＝15.8Hz,1H),2.29(td,J＝13.5,4.3Hz,1H),1.97(td,J＝13.6,4.5Hz,1H),1.88(d,J＝14.4,3.0Hz,1H),1.58–1.48(m,1H),1.38(s,9H)。

Intermediate preparation example 17: (R) -N- ((S) -5, 7-dihydrospiro [ cyclopenta [ b ] pyridine-6, 4' -piperidin ] -5-yl) -2-methylpropane-2-sulfinamide (intermediate C2)

A, step a: under the protection of nitrogen and at room temperature, 6, 7-dihydro-5H-cyclopenta [ B ] is reacted]To a solution of pyridin-5-one (5.30g, 39.805mmol, 1.00equiv) and N-benzyl-2-bromo-N- (2-bromoethyl) ethan-1-amine (15.34g, 47.766mmol, 1.2equiv) in toluene (80 ml) was added potassium tert-butoxide (10.72g, 95.531mmol, 2.4equiv) in three portions, followed by heating to 90 ℃ for 2h; cooling to room temperature, adding water (100 ml) to quench the reaction, and separating liquid; the aqueous phase was extracted with EA (3X 60 ml) and the organic phases were combined; the organic phase was washed with brine (100 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure; the residue was purified by column chromatography (EA: n-hexane =10, 1 to 50 ]Pyridine-6, 4' -piperidines]-5 (7H) -1-one (7.2g, 61.87%) (ES, m/z): 293[ 2 ], [ M + H ]] ⁺ 。

Step b: under the protection of nitrogen, to 1' -benzyl spiro [ cyclopentyl [ b ]]Pyridine-6, 4' -piperidines]-5 (7H) -1-one (7.23g, 24.728mmol, 1.00equiv) and HCOONH ₄ (3.12g, 49.456mmol, 2.00equiv) in MeOH (100.00 mL), pd/C (5.26g, 49.427mmol, 2.00equiv) was added, and then the reaction was refluxed for 4h; cooling to room temperature, filtering, and leaching a filter cake with MeOH (3X 100mL); concentrating the filtrate under reduced pressure to obtain crude product 3,4,5, 7-tetrahydrospiro [ cyclopenta [ b ]]Pyridine-6, 4-piperidines]-5-ol (2.8g, 54.89%), which is used directly in the next reaction without purification (ES, m/z): 207[ M ] +H] ⁺ 。

Step c: to 3,4,5, 7-tetrahydrospiro [ cyclopenta [ b ] s at room temperature]Pyridine-6, 4-piperidines]-5-ol (2.80g, 13.573mmol, 1.00 equiv) and (Boc) ₂ O (3.26g, 14.931mmol, 1.10equiv) in THF (15.00 mL) and H ₂ O (15.00 mL) solution, naHCO was added ₃ (2.28g, 27.146mmol, 2.00equiv), and reacting for 2 hours; concentrating under reduced pressure, and collecting residual water phase with EA (3 extract40 mL), and combining organic phases; the organic phase was washed with brine (1X 50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude 5-hydroxy-3, 4,5, 7-tetrahydrospiro [ cyclopenta [ b ] b]Pyridine-6, 4' -piperidines]Tert-butyl (3.52g, 84.64%) 1' -carboxylate, which is used without purification in the next reaction (ES, m/z): 307[ 2 ], [ M ] +H ] ⁺ 。

Step d: reacting 5-hydroxy-3, 4,5, 7-tetrahydrospiro [ cyclopenta [ b ] b]Pyridine-6, 4' -piperidines]-1' -Carboxylic acid tert-butyl ester (4.32g, 14.099mmol, 1.00equiv) and MnO ₂ (12.26g, 0.141mmol, 10.00equiv) in DCE (50.00 mL) and stirred overnight at 85 deg.C; filtering, leaching a filter cake with DCM (3 x 20mL), and concentrating a filtrate under reduced pressure; the residue was purified by reverse phase silica gel column (gradient elution with 20-70% acetonitrile in water) to give 5-oxo-7H-spiro [ cyclopenta [ b ] as a pale yellow solid]Pyridine-6, 4' -piperidines]Tert-butyl-1' -carboxylate (630 mg, 11.97%) (ES, m/z): 303[ M + H ]] ⁺ 。

Step e, under the protection of nitrogen, 5-oxo-7H-spiro [ cyclopentyl [ b ] is added]Pyridine-6, 4' -piperidines]To a solution of tert-butyl (112.00mg, 0.370mmol, 1.00equiv), (R) -2-methylpropane-2-sulfinamide (359.14mg, 2.963mmol, 8.00equiv) in THF (5.00 mL) was added Ti (OEt) ₄ (844.92mg, 3.704mmol, 10.00equiv), at 85 ℃ overnight; then cooling to 0 ℃, adding NaBH ₄ (0.70g, 18.581mmol, 1equiv), naturally heating to room temperature, and reacting for 2h; pouring the reaction solution into saline (10 ml) and EA (10 ml), filtering, and separating filtrate; the organic phase was washed with brine (10 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure; the residue was purified by column chromatography (n-hexane: EA =10: 1) to give (S) -tert-butyl 5- ((R) -1, 1-dimethylethylenesulfonamido) -5, 7-dihydrospiro [ cyclopenta [ b ] amine ]Pyridine-6, 4' -piperidines]-1' -carboxylate (61mg, 40.41%) (ES, m/z): 408[ 2 ], [ M + H ]] ⁺ 。

Step f preparation of (S) -tert-butyl 5- ((R) -1, 1-dimethylethylenesulfonamido) -5, 7-dihydrospiro [ cyclopenta [ b ] amine]Pyridine-6, 4' -piperidines]A solution of 1' -carboxylate (60.00mg, 0.147mmol, 1.00equiv), TFA (1.00 mL) in DCM (7.00 mL) was reacted at room temperature for 2h; concentrated under reduced pressure and the residue purified by Prep-HPLC (gradient elution from 5 to 55% acetonitrile in water, 10mmol/L NH) ₄ HCO ₃ Modification) to obtain a white solid(R) -N- ((S) -5, 7-dihydrospiro [ cyclopenta [ b ] b]Pyridine-6, 4' -piperidines]-5-yl) -2-methylpropane-2-sulfinamide (intermediate C2) (21mg, 46.4%) (ES, m/z): 308[ deg. ] M + H] ⁺ 。

Intermediate preparation example 18: (R) -N- ((S) -5-methoxy-1, 3-dihydrospiro [ indene-2, 4' -piperidin ] -3-yl) -2-methylpropane-2-sulfinamide (intermediate C3)

A, step a: LDA (2M THF/Hex solution, 9ml,18mmol, 1.5eqv) was added dropwise to a solution of ethyl N-Boc-4-piperidinecarboxylate (3.09g, 12.00mmol, 1eqv) in ultra-dry THF (30 ml) at-70 ℃ under nitrogen protection, and the reaction was carried out at that temperature for 1 hour; then, dropwise adding p-methoxybenzyl chloride (1.88g, 12mmol and 1eqv), and continuously preserving heat for 2 hours; then quenching with saturated ammonium chloride solution (25 ml), and separating liquid; the aqueous phase was extracted with EA (2X 30 ml) and the organic phases were combined; dried over anhydrous sodium sulfate, concentrated under reduced pressure to give 4- (4-methoxybenzyl) piperidine-1-tert-butyl 4-ethyl-1, 4-dicarboxylate (4.32 g) as a brown yellow oil, which was used in the next reaction without purification. (ES, m/z): 277.96[ 2 ] M + H-100]

Step b: 1-tert-butyl-4-ethyl 4- (4-methoxybenzyl) piperidine-1, 4-dicarboxylate (4.32g, 11.44mmol, 1eqv), naOH (2.29g, 57.22mmol, 5eqv), etOH (30 ml) and water (30 ml) were refluxed overnight to react; cooling to room temperature, concentrating under reduced pressure, adjusting pH of residual water phase to 2 with 2M hydrochloric acid, extracting with EA (3 × 30 ml), and mixing organic phases; drying the organic phase with anhydrous sodium sulfate, and concentrating under reduced pressure; the residue was purified by column chromatography (n-hexane: EA =4:1 to 1) to give 1- (tert-butoxycarbonyl) -4- (4-methoxybenzyl) piperidine-4-carboxylic acid (2.43g, 85.31%) as a white solid. (ES, m/z): 249.98[ M ] +H-100] ⁺

Step c: reacting a mixture of 1- (tert-butoxycarbonyl) -4- (4-methoxybenzyl) piperidine-4-carboxylic acid (2.43g, 6.95mmol) and PPA (10 ml) at 120 ℃ for 2h; cooling, pouring the reaction solution into ice water (60 ml), and adjusting the pH value to 10 by using NaOH; then add (Boc) ₂ O (2.27g, 10.42mmol), reacting at room temperature overnight; EA (3) for reaction solutionX 50 ml) and combining the organic phases; the organic phase was washed with brine (50 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (n-hexane: EA = 20) to give tert-butyl 6-methoxy-1-oxo-1, 3-dihydrospiro [ indene-2, 4' -piperidine as a yellow solid ]-1' -carboxylic acid ester (1.49g, 65%) (ES, m/z): 332[ M ] +H] ⁺

Step (d) to step (e): the operation is carried out according to the preparation steps (e-f) of the intermediate C2 to obtain the white solid (R) -N- ((S) -5-methoxyl-1, 3-dihydrospiro [ indene-2, 4' -piperidine)]-3-yl) -2-methylpropane-2-sulfinamide (intermediate C3) (720 mg). (ES, m/z): 337.03[ 2 ] M + H] ⁺ 。

Intermediate preparation examples 19 to 25: intermediates C4 to C10

Referring to the process steps of intermediate preparation 18, intermediates C4 to C10 were synthesized using the corresponding starting materials:

intermediate preparation 26: (R) -N- ((S) -2-chloro-4, 6-dihydrospiro [ cyclopenta [ d ] thiazole-5, 4' -piperidin ] -6-yl) -2-methylpropane-2-sulfinamide (intermediate C11)

Step a: to a solution of ethyl 2-chloro-1, 3-thiazole-4-carboxylate (30.00g, 153.421mmol) in MeOH (300 mL) at-30 deg.C under nitrogen was added NaBH ₄ (20.32g, 537.097mmol), then naturally warmed to room temperature and reacted for 1h; the reaction mixture was poured into ice water (300 mL) and concentrated under reduced pressure; the residual aqueous phase was extracted with EA (2X 300 mL) and the organic phases were combined; the organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain colorless oily substance (2-chloro-1, 3-thiazol-4-yl) methanol (20g, 85.40%) (ES, m/z): 150[ m ] +H +] ⁺

Step b: to (2-chloro-1, 3-thiazol-4-yl) methanol (20.00g, 131.025mmol), TEA (26.5) at 0 deg.C 2g, 262.050mmol) in DCM (200 mL), adding MsCl (16.51g, 144.127mmol) dropwise, and reacting at room temperature for 0.5h after dropwise addition; adding water (200 ml), separating; using CH as the aqueous phase ₂ Cl ₂ Extracting (2 x 200mL), and combining organic phases; drying the organic phase with anhydrous sodium sulfate, and concentrating under reduced pressure; the residue was purified by column chromatography (n-hexane: EA = 1) to obtain methyl (2-chloro-1, 3-thiazol-4-yl) methanesulfonate (17g, 55.85%) (ES, m/z): 228[ m ] +H ]] ⁺

Step c: under the protection of nitrogen and at-78 ℃, LDA (2M N-hexane solution) (140.00mL, 280.239mmol) is slowly added dropwise into a THF (250.00 mL) solution of N-Boc-4-piperidinecarboxylic acid ethyl ester (34.34g, 133.447mmol), and the temperature is kept for 1h after the LDA solution is completely added dropwise; then slowly dropwise adding a THF (50 mL) solution of (2-chloro-1, 3-thiazole-4-yl) methyl methanesulfonate (31.00g, 133.433mmol), and reacting for 4h after dropwise adding; the reaction solution was poured into ice water (400 mL) and separated; the aqueous phase was extracted with EA (3X 500 mL) and the organic phases were combined; drying the organic phase with anhydrous sodium sulfate, and concentrating under reduced pressure; the residue was purified by column chromatography (n-hexane: EA =5: 1) to give 4- ((2-chlorothiazol-4-yl) methyl) piperidine-1, 4-dicarboxylic acid 1-tert-butyl 4-ethyl ester (20g, 37.77%) as a yellow oil (ES, m/z): 389[ m ] +H ]] ⁺

Step d: under the protection of nitrogen, LDA (66mL, 0.132mol, 2.00eq) is dropwise added into a THF (200 mL) solution of 4- ((2-chlorothiazol-4-yl) methyl) piperidine-1, 4-dicarboxylic acid 1-tert-butyl 4-ethyl ester (22.3g, 0.066mol, 1.00eq) at the temperature of-78 ℃, water (250 mL) is added into the reaction solution to quench the reaction under the condition of temperature-controlled stirring for 1h, EA (3X 150 mL) is added for washing and extraction, organic phases are combined, and anhydrous Na ₂ SO ₄ Drying, and concentrating under reduced pressure; the residue was purified by column chromatography (n-hexane: EA =15:1 to 4]Thiazole-5, 4' -piperidines]-tert-butyl 1' -carboxylate (7.62g, 34%) (ES, m/z): 286.82[ M-56 ] H] ⁺ 。

Step e: to 2-chloro-6-oxo-4, 6-dihydrospiro [ cyclopentyl [ d ] at room temperature]Thiazole-5, 4' -piperidines]Tert-butyl (800mg, 2.339mmol, 1.00eq) of-1' -carboxylate added with 33-35% of Ti (OEt) ₄ (17.784g, 23.386mmol, 10.00eq) and(R) - (+) -2-methyl-2-propanesulfinamide (850mg, 7.016mmol, 3.00eq) at 70 ℃ for 8h; cooling to room temperature, adding water (200 mL) to quench the reaction, stirring to separate out a large amount of solid, carrying out vacuum filtration, leaching a filter cake with EA, discarding, extracting the filtrate with EA, and combining organic phases; anhydrous Na ₂ SO ₄ Drying, and concentrating under reduced pressure; the residue was purified by column chromatography (n-hexane: EA =15:1 to 4]Thiazole-5, 4' -piperidines]-1' -carboxylic acid ester (310mg, 30%) (ES, m/z): 345.94[ 2 ] M-100+ H] ⁺ 。

Step f: under the protection of nitrogen and at-78 ℃, to (R, E) 6- (tert-butylsulfinylimino) tert-butyl-2-chloro-4, 6-dihydrospiro [ cyclopentyl [ d ] ]Thiazole-5, 4' -piperidines]DIBAL-H (35.5mL, 35.495mol, 5.00eq) is added dropwise into a solution of-1' -carboxylic ester (3.16g, 7.099mol, 1.00eq) in ultra-dry THF (120 mL), and the reaction is kept for 1H; quenching the reaction mixture at 0 deg.C with 15% (v/v) NaOH aqueous solution (50 mL), adding water (100 mL), extracting with EA (3X 120 mL), and mixing the organic phases; organic phase anhydrous Na ₂ SO ₄ Drying, and concentrating under reduced pressure; the residue was purified by column chromatography (n-hexane: EA =3:1 to 1]Thiazole-5, 4' -piperidines]-1' -Carboxylic acid tert-butyl ester (1.56g, 49%). (ES, m/z): 347.95[ 2 ] M-100+H] ⁺ 。

Step g: reacting (S) 2-chloro-6- ((R) -1, 1-dimethylethylenesulfonamido) -4, 6-dihydrospiro [ cyclopenta [ d ]]Thiazole-5, 4' -piperidines]-1' -Carboxylic acid tert-butyl ester (1.56g, 3.489mmol, 1.00eq), CF ₃ COOH (6 mL) and DCM (18 mL) solution, and reacting for 1h at room temperature; concentrating the reaction solution under reduced pressure to obtain (R) -N- ((S) -2-chloro-4, 6-dihydrospiro [ cyclopentyl [ d ]]Thiazole-5, 4' -piperidines]-6-yl) -2-methylpropane-2-sulfinamide (intermediate C11) (1.1 g), (ES, m/z): 348[ 2 ] M + H] ⁺ 。

Intermediate preparation example 27: (R) -N- ((S) -2-ethoxy-4, 6-dihydrospiro [ cyclopenta [ d ] thiazole-5, 4' -piperidin ] -6-yl) -2-methylpropane-2-sulfinamide (intermediate C12)

Step a: to (S) -2-chloro-6- ((R) -1, 1-dimethylethylsulphideneamino) -4, 6-dihydrospiro [ cyclopentyl [ d ] at 0 ℃ under the protection of nitrogen]Thiazole-5, 4' -piperidines]-1' -Carboxylic acid tert-butyl ester (2.00g, 4.375mmol) in EtOH (20 mL) and EtONa (0.60g, 8.817mmol) were added; then heating to 60 ℃ for reaction for 4h; cooling to room temperature, and concentrating under reduced pressure; the residue was purified by column chromatography (n-hexane: EA =5, 1 to 1) to give (S) -tert-butyl 6- ((R) -1, 1-dimethylethylenesulfonamido) -2-ethoxy-4, 6-dihydrospiro [ cyclopenta [ d]Thiazole-5, 4' -piperidines]-1' -carboxylic acid ester (1.5g, 73.43%) (ES, m/z): 458[ n ], [ M ] +H] ⁺

Step b: reacting (S) -tert-butyl 6- ((R) -1, 1-dimethylethylenesulfonamido) -2-ethoxy-4, 6-dihydrospiro [ cyclopenta [ d ]]Thiazole-5, 4' -piperidines]-1' -carboxylate (1.50g, 3.212mmol), TFA (4 mL) in DCM (12 mL) reacted at room temperature for 1h; concentrating under reduced pressure to obtain yellow solid (R) -N- ((S) -2-ethoxy-4, 6-dihydrospiro [ cyclopentyl [ d ]]Thiazole-5, 4' -piperidines]-6-yl) -2-methylpropane-2-sulfinamide (intermediate C12) (1.1g, 93.87%) (ES, m/z): 358[ 2 ], [ M ] +H] ⁺ 。

Intermediate preparation example 28: (R) -N- ((S) -4, 6-dihydrospiro [ cyclopenta [ d ] thiazole-5, 4' -piperidin ] -6-yl) -2-methylpropane-2-sulfinamide (intermediate C13)

Step a: (S) -2-chloro-6- ((R) -1, 1-dimethylethylenesulfonamido) -4, 6-dihydrospiro [ cyclopenta [ d ] e]Thiazole-5, 4' -piperidines]-1' -Carboxylic acid tert-butyl ester (3.00g, 6.5631 mmol), TEA (2.00mL, 19.775mmol), 10% Pd/C (1.035 g) in MeOH (60 ml) ₂ Reacting at 50 ℃ overnight under the atmosphere; filtration, concentration of the filtrate under reduced pressure, and column chromatography purification of the residue (n-hexane: EA =5:1 to 2Penta [ d ]]Thiazole-5, 4' -piperidines]-1' -Carboxylic acid ester (2.5g, 90%). (ES, m/z): 414.06[ M ] +H] ⁺ 。

Step b: reacting (S) -tert-butyl 6- (((R) -1, 1-dimethylethylsulphonimido) -4, 6-dihydrospiro [ cyclopenta [ d ]]Thiazole-5, 4' -piperidines]1' -Carboxylic acid ester (2.50g, 6.05mmol), TFA (4 mL) in DCM (12 mL) and reacted at room temperature for 1h; concentrating under reduced pressure to obtain yellow solid (R) -N- ((S) -4, 6-dihydrospiro [ cyclopentyl [ d ]]Thiazole-5, 4' -piperidines]-6-yl) -2-methylpropane-2-sulfinamide (intermediate C13) (1.1g, 87%) (ES, m/z): 314[ m ] +H ]] ⁺ 。

Intermediate preparation examples 29 to 32: intermediates C14 to C17

Referring to the procedure of intermediate preparation example 26, intermediates C14 to C17 were prepared using the following corresponding starting materials and preparation methods.

Intermediate preparation 33: intermediate C18

Intermediate C18 was prepared using the corresponding starting materials and preparation methods described below with reference to the procedure of intermediate preparation 27.

Intermediate preparation example 34: intermediate C19

Intermediate C19 was prepared using the corresponding starting materials and preparation methods described below with reference to the procedure of intermediate preparation example 28.

Intermediate preparation example 35: preparation of (R) -N- ((1S) -3 '-methoxy-1, 3-dihydrospiro [ indene-2, 4' -piperidin ] -1-yl) -2-methylpropane-2-sulfinamide (intermediate C20)

Step a: at room temperature, potassium tert-butoxide (3.8g, 34.1mmol, 2.03eqv) was added to a THF (50 ml) solution, cooled to 0 ℃ and 1-benzyl-3-oxa-4-piperidinecarboxylic acid ethyl ester hydrochloride (5.0 g,16.8mmol, 1.0eqv) was slowly added to warm to room temperature for 1h; then cooling to 0 ℃, slowly dropwise adding benzyl bromide (3.02g, 17.6mmol, 1.05eqv), heating to room temperature for reacting overnight, quenching the reaction with saturated ammonium chloride solution (50 ml), and separating liquid; the aqueous phase was extracted with EA (3X 30 ml) and the organic phases were combined; dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (n-hexane: ethyl acetate = 10). (ES, m/z): 352.09[ 2 ] M + H] ⁺ 。

Step b: ethyl 1, 4-dibenzyl-3-oxa-4-piperidinecarboxylate (2.5g, 7.11mmol) was dissolved in methanol (50 ml), and NaBH was slowly added to the reaction solution ₄ (809mg, 21.3mmol), reacting at room temperature for 6h, adding saturated ammonium chloride solution (20 ml), quenching, concentrating the solvent, extracting the aqueous phase with EA (3X 20 ml), and combining the organic phases; dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (n-hexane: ethyl acetate =4: 1) to give ethyl 1, 4-dibenzyl-3-hydroxy-4-piperidinecarboxylate as a yellow oil (1.2g, 47.68%). (ES, m/z): 354.08[ 2 ] M + H] ⁺ 。

Step c: dissolving 1, 4-dibenzyl-3-hydroxy-4-piperidinecarboxylic acid ethyl ester (1.2g, 3.39mmol) in DMF (20 ml), cooling to 0 ℃, slowly adding NaH (407mg, 10, 17mmol) and reacting for 30min, dropwise adding methyl iodide (1.44g, 10.17mmol), heating to room temperature for reacting overnight, quenching with saturated ammonium chloride solution (30 ml), and separating; the aqueous phase was extracted with EA (3X 30 ml) and the organic phases were combined; the mixture is dried by using anhydrous sodium sulfate,concentrated under reduced pressure and purified by column chromatography (n-hexane: ethyl acetate = 6) to give ethyl 1, 4-dibenzyl-3-methoxy-4-piperidinecarboxylate as a yellow oil (600mg, 48.08%). (ES, m/z): 368.10[ M ] +H] ⁺ 。

Step d: refluxing 1, 4-dibenzyl-3-methoxy-4-piperidinecarboxylic acid ethyl ester (600mg, 1.63mmol), naOH (1.3g, 32.6mmol, 20eqv), etOH (15 ml) and water (15 ml) overnight; cooling to room temperature, concentrating under reduced pressure, adjusting pH of residual water phase to 2 with 2M hydrochloric acid, extracting with EA (3 × 30 ml), and mixing organic phases; drying the organic phase with anhydrous sodium sulfate, and concentrating under reduced pressure; the residue was purified by column chromatography (n-hexane: ethyl acetate = 1) to give 1, 4-dibenzyl-3-methoxy-4-piperidinecarboxylic acid (302mg, 53.99%) as a yellow oil. (ES, m/z): 340.08[ 2 ] M + H ] ⁺ 。

Step e: heating 1, 4-dibenzyl-3-methoxy-4-piperidinecarboxylic acid (302mg, 0.88mmol) and PPA (10 ml) to react at 120 deg.C for 6h, cooling to room temperature, and neutralizing the reaction solution with 2M NaOH; the aqueous phase was extracted with EA (3X 30 ml) and the organic phases were combined; drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain crude 1' -benzyl-3 ' -methoxyspiro [ indene-2, 4' -piperidine as yellow oily product]-1 (3H) -one (180 mg), used directly in the next step without purification. (ES, m/z): 322.04[ mu ] M + H] ⁺ 。

Step f: 1' -benzyl-3 ' -methoxyspiro [ indene-2, 4' -piperidine]-1 (3H) -one (180mg, 0.56mmol), (R) -tert-butylsulfinamide (203.6mg, 1.68mmol) and ethyl titanate (5 ml) were heated to 100 ℃ for overnight reaction, quenched with water (20 ml) and separated; the aqueous phase was extracted with EA (3X 20 ml) and the organic phases were combined; dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (N-hexane: ethyl acetate = 6)]-1 (3H) -alkylene) -2-methylpropane-2-sulfinamide (123.6mg, 52%). (ES, m/z): 425.13[ M ] +H] ⁺ 。

Step g: mixing (R, E) -N- (1 ' -benzyl-3 ' -methoxyspiro [ indene-2, 4' -piperidine)]-1 (3H) -alkylene) -2-methylpropane-2-sulfinamide (123.6 mg, 0.29mmol), 10% Pt/C (50 mg) and EtOH (10 ml) were reacted overnight at 50 ℃ in a hydrogen atmosphere; cooling to room temperature, filtering with diatomaceous earth, and filtering Concentrating the solution under reduced pressure, purifying the residue with reverse phase silica gel column (gradient elution with 10-50% acetonitrile in water) to obtain (R) -N- ((1S) -3 '-methoxy-1, 3-dihydrospiro [ indene-2, 4' -piperidine)]-1-yl) -2-methylpropane-2-sulfinamide (intermediate C20) (63.6 mg, 65%). 337.13 [ M + H] ⁺ 。

Intermediate preparation 36:1- (5-amino-3-chloropyrazin-2-yl) ethanone (intermediate D1)

To a solution of 2-amino-5-bromo-6-chloropyrazine (2.0g, 9.666mmol, 1.0eq) in 1, 4-dioxane (80 mL) was added tributyl (1-ethoxyvinyl) tin (5.236g, 14.498mmol, 1.5eq), cuI (184mg, 0.966mmol, 0.1eq), pd (Ph, ph) ₃ P) ₂ Cl ₂ (678mg, 0.966mmol, 0.1eq) under nitrogen protection, placing the reaction flask in an oil bath kettle at 100 deg.C, stirring at constant temperature for reaction for 7H, concentrating the reaction solution to dryness, adding water (100 mL) to the concentrate, adding EA (3X 80 mL) for washing and extraction, and extracting with H ₂ O (150 mL), brine wash (150 mL) of the combined organic phases, anhydrous Na ₂ SO ₄ The extract was dried, vacuum filtered, and the filtrate was concentrated to dryness, and eluted and purified by silica gel column chromatography (n-hexane: EA =10:1 to 5. (ES, m/z): 171.97[ m ] +H] ⁺ ；

Intermediate preparation example 37: 2-chloro-3- (oxazol-2-yl) benzenethiol (intermediate D2)

A, step a: 2-chloro-3-fluoroaniline (5.00g, 33.663mmol), tert-butylmercaptan (3.64g, 40.396mmol), cs ₂ CO ₃ (32.90g, 100.989 mmol) in DMF (50 mL) at 130 ℃ for 24h; cooling to room temperature, and pouring the reaction solutionWater (300 mL) was added, extraction was performed with EA (2 × 300 mL), the organic phases were combined, the organic phase was washed with brine (3 × 500 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (n-hexane: EA =100, 1 to 20] ⁺ 。

Step b: reducing the temperature of concentrated hydrochloric acid (15 ml) liquid of 3- (tert-butylsulfanyl) -2-chloroaniline (7.0 g,32.55mmol, 1eqv) to-10 to-5 ℃, dropwise adding a water (105 ml) solution of sodium nitrite (3.369g, 48.83mmol, 1.5eqv), and preserving the temperature for 30min after dropwise adding; at the same temperature, dropwise adding a water (65 ml) solution of potassium iodide (6.484g, 39.06mmol, 1.2eqv), and after dropwise adding, preserving heat and reacting for 20min; adding ethyl acetate (100 ml) and saturated sodium thiosulfate solution (100 ml) into the reaction solution, stirring for 10min, separating, extracting the aqueous phase with EA (2X 50 ml), and combining the organic phases; the organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (n-hexane) to give tert-butyl (2-chloro-3-iodophenyl) sulfane (6.52g, 61.45%). ¹ H NMR(600MHz,DMSO-d ₆ )δ7.975–7.990(m,1H),7.081–7.107(m,1H),1.287(s,9H)。

Step c, reacting tertiary butyl (2-chloro-3-iodophenyl) sulfane (6.5g, 19.94mmol, 1eqv), oxazole (2.75g, 39.88mmol, 2eqv), lithium tert-butoxide (1.92g, 23.93mmol, 1.2eqv), cuI (380mg, 1.994mmol, 0.1eqv) in DMF (50 ml) at 140 ℃ for 2h under the protection of nitrogen, and detecting the reaction completion by TLC; the reaction solution was cooled to room temperature, poured into water (300 mL), extracted with EA (2 × 150 mL), the organic phases were combined, the organic phase was washed with brine (2 × 100 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (n-hexane: EA =25:1 to 10] ⁺ 。

Step d, adding aluminum trichloride (6.23g, 46.72mmol,4 eq) to a solution of 2- (3- (tert-butylthio) -2-chlorophenyl) oxazole (3.12g, 11.68mmol, 1eq) in toluene (60 ml) at 0 ℃ and reacting overnight at room temperature; cooling to 0 deg.C, adding water (60 ml), stirring for 30min, and separating; the aqueous phase was extracted with toluene (30 ml) and the organic phases were combined; concentrating under reduced pressure to obtain residuePurifying by column chromatography (n-hexane: EA =20: 1-5) to obtain 2-chloro-3- (oxazole-2-yl) benzenethiol (1.726 g, 70%) (ES, m/z): 211.89[ 2 ], [ M ] +H ]] ⁺ 。

Intermediate preparation example 38: 2-chloro-3- (pyrazin-2-yl) benzenethiol (intermediate D3)

Prepared by the method of preparation 6D in CN111647000A by taking tert-butyl (2-chloro-3-iodophenyl) sulfane (D2-2) and 2- (tri-n-butyltin) pyrazine as starting materials.

Intermediate preparation example 39: methyl 5-amino-6-bromo-3- ((3S, 4S) -4- ((tert-butoxycarbonyl) amino) -3-methyl-2-oxa-8-azaspiro [4.5] dec-8-yl) pyrazine-2-carboxylate (intermediate E1)

Step a: to (3S, 4S) -3-methyl-2-oxa-8-azaspiro [4.5]Deca-4-amine dihydrochloride (485mg, 1.994mmol, 1.05eq) in DMSO (15 mL), DIEA (1.227g, 9.498mmol, 5.0eq) was added dropwise, methyl 3-chloro-5- ((2, 4-dimethoxybenzyl) amino) pyrazine-2-carboxylate (640mg, 1.900mmol, 1.0eq) was added thereto, the reaction was carried out at 105 ℃ for 5 hours, then the reaction flask was cooled to room temperature, water (80 mL) was added to the reaction solution, mixed, extracted with EA (60 mL. Times.3), and the mixture was extracted with H ₂ The combined organic phases were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered under reduced pressure, the filtrate was concentrated under reduced pressure, the residue was purified by column chromatography on silica gel with DCM: meOH =100, gradually increasing to 40, the product-containing spots were collected and concentrated to give 3-methyl ((3s, 4 s) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Dec-8-yl) -5- ((2, 4-dimethoxybenzyl) amino) pyrazine-2-carboxylate solid (780mg, 83%),. (ES, m/z): 472.22[ M ] +H ] ⁺ 。

Step b: to the flask was charged with 3-methyl ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5 ]]Deca-8-yl) -5- ((2, 4-dimethoxybenzyl) amino) pyrazine-2-carboxylic acid ester (780mg, 1.655mmol, 1.0eq) was added into a reaction bottle ₃ COOH (5 mL) is stirred at room temperature for 2 hours of reaction, and then the reaction liquid is dried by spinning to obtain crude 5-amino-3- (((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5 ]]Decan-8-yl) pyrazine-2-carboxylic acid methyl ester. (ES, m/z): 322.21[ M ] +H] ⁺ 。

Step c: TEA (502mg, 4.965mmol, 3.0eq) was added to the crude product containing 5-amino-3- (((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5 ] at room temperature]Decyl-8-yl) pyrazine-2-carboxylic acid methyl ester (532mg, 1.655mmol, 1.0eq) in DCM (15 mL) at a basic pH, boc anhydride (542mg, 2.482mmol, 1.5eq) was added and the reaction was stirred at room temperature for 2h. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with EA (10 mL. Times.3) and then with H ₂ The combined organic phases were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered under reduced pressure, the filtrate was concentrated under reduced pressure, the residue was purified by column chromatography over silica gel with DCM: meOH =100, eluent gradually increasing to 60, the product-containing spots were collected and concentrated to give 5-amino-3- ((3s, 4s) -4- ((tert-butoxycarbonyl) amino) -3-methyl-2-oxa-8-azaspiro [4.5 ]Decyl-8-yl) pyrazine-2-carboxylic acid methyl ester transparent solid (700mg, 100%), (ES, m/z): 422.11, M + H] ⁺ 。

Step d: NBS (311mg, 1.745mmol, 1.05eq) was added to a solution containing 5-amino-3- ((3S, 4S) -4- ((tert-butoxycarbonyl) amino) -3-methyl-2-oxa-8-azaspiro [4.5 ] at-15 deg.C]Decyl-8-yl) pyrazine-2-carboxylic acid methyl ester (700mg, 1.662mmol,1.0 eq) in DCM (20 mL) and stirred at constant temperature for 10min. The reaction was quenched by addition of saturated aqueous sodium bicarbonate (20 mL), extracted with DCM (20 mL. Times.2), and quenched with H ₂ The combined organic phases were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered under reduced pressure, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel with eluent n-hexane: EA =3, gradually increasing to 1, to give methyl 5-amino-6-bromo-3- ((3s, 4s) -4- ((tert-butoxycarbonyl) amino) -3-methyl-2-oxa-8-azaspiro [4.5]Decyl-8-yl) pyrazine-2-carboxylate (450mg, 54%), (ES, m/z): 500.07[ 2 ], [ M + H ]] ⁺ 。

Intermediate preparation example 40: (S) -methyl-5-amino-6-bromo-3- (1- ((tert-butoxycarbonyl) amino) -1, 3-dihydrospiro [ indene-2, 4 '-piperidin ] -1' -yl) pyrazine-2-carboxylate (intermediate E2)

Step a: to (S) -N- ((S) -1, 3-dihydrospiro [ indene-2, 4' -piperidine)]-1-yl) -2-methylpropane-2-sulfinamide (200mg, 0.653mmol, 1.1eq) in DMSO (5 mL), DIEA (230mg, 1.779mmol, 3.0eq) was added dropwise, stirring was carried out at room temperature for 10min, then methyl 3-chloro-5- ((2, 4-dimethoxybenzyl) amino) pyrazine-2-carboxylate (200mg, 0.593mmol, 1.0eq) was added, and reaction was carried out at 105 ℃ for 10h; cooled to room temperature, water (50 mL) was added, extraction was performed with EA (3X 30 mL), the combined organic phases were washed with H ₂ O (100 mL), brine wash (100 mL), anhydrous Na ₂ SO ₄ Drying, suction filtration under reduced pressure, concentration of the filtrate to dryness, and purification by elution with silica gel column chromatography, eluent EA: meOH =80, 1 to 1, to give 5- ((2, 4-dimethoxybenzyl) amino) -3- ((S) -1- ((R) -1, 1-dimethylethylenesulfonamido) -1, 3-dihydrospiro [ indene-2, 4' -piperidine ]]-1' -yl) pyrazine-2-carboxylic acid methyl ester (305mg, 77%). (ES, m/z): 608.16[ m ] +H] ⁺ 。

Step b: to the reaction flask was added 5- ((2, 4-dimethoxybenzyl) amino) -3- ((S) -1- ((R) -1, 1-dimethylethylenesulfonamido) -1, 3-dihydrospiro [ indene-2, 4' -piperidine]-1' -yl) pyrazine-2-carboxylic acid methyl ester (305mg, 0.502mmol, 1.0eq) and CF ₃ COOH (5 mL) was stirred at room temperature for 2 hours, and then concentrated under reduced pressure to give methyl 5-amino-3- ((S) -1- ((R) -1, 1-dimethylethylsulphonimido) -1, 3-dihydrospiro [ indene-2, 4' -piperidine]The crude (E) -1' -yl) pyrazine-2-carboxylic acid ester was used in the next reaction without purification (229mg, 100%). (ES, m/z): 458.19[ M ] +H] ⁺ 。

Step c: to a reaction vessel charged with methyl 5-amino-3- ((S) -1- ((R) -1, 1-dimethylethylsulphideneamino) -1, 3-dihydrospiro [ indene-2, 4' -piperidine]-1' -yl) pyrazine-2-carboxylic acid ester (229mg, 0.502mmol) the above reactionAdding MeOH/HCl solution (5 mL) into a bottle, stirring at room temperature for reaction for 2h, and then spin-drying the reaction liquid to obtain crude 5-amino-3- (1-amino-1, 3-dihydrospiro [ indene-2, 4' -piperidine) ]-1' -yl) pyrazine-2-carboxylic acid (S) -methyl ester oil (177mg, 100%), (ES, m/z): 354.10[ m ] +H] ⁺ 。

Step d: TEA (152mg, 1.503mmol, 3.0eq) was added to a solution containing 5-amino-3- (1-amino-1, 3-dihydrospiro [ indene-2, 4' -piperidine) at room temperature]-1' -yl) pyrazine-2-carboxylic acid (S) -methyl ester (177mg, 0.501mmol, 1.0eq) in DCM (10 mL) followed by Boc anhydride (142mg, 0.651mmol, 1.3eq) and stirring reaction at room temperature for 3h. Water (15 mL) was added to the reaction mixture, which was mixed, extracted with DCM (10 mL. Times.2), and washed with H ₂ The combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered under reduced pressure, the filtrate was concentrated under reduced pressure, the residue was purified by column chromatography on silica gel with DCM: meOH =100, 1, gradually increasing to 70, the product-containing spots were collected and concentrated to give (S) -methyl 5-amino-3- (1- (((tert-butoxycarbonyl) amino) -1, 3-dihydrospiro [ indene-2, 4' -piperidine)]-1' -yl) pyrazine-2-carboxylate transparent solid (133mg, 61%), (ES, m/z): 438.15[ 2 ] M + H] ⁺ 。

Step e: NBS (57mg, 0.319mmol, 1.05eq) was added to a solution containing (S) -methyl 5-amino-3- (1- (((tert-butoxycarbonyl) amino) -1, 3-dihydrospiro [ indene-2, 4' -piperidine) at-15 deg.C]The reaction mixture was stirred at constant temperature for 10min in a solution of (1' -yl) pyrazine-2-carboxylate (133mg, 0.304mmol,1.0 eq) in DCM (10 mL). The reaction was quenched with saturated aqueous sodium bicarbonate (10 mL), extracted with DCM (10 mL. Times.2), and quenched with H ₂ The combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered under reduced pressure, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel with eluent n-hexane: EA =5, 1, gradually increasing to 3 to give (S) -methyl 5-amino-6-bromo-3- (1- ((tert-butoxycarbonyl) amino) -1, 3-dihydrospiro [ indene-2, 4' -piperidine]-1' -yl) pyrazine-2-carboxylate transparent solid (100mg, 62%), (ES, m/z): 532.09[ m ] +H] ⁺ 。

Intermediate preparation example 41: (S) -tert-butyl (1 '- (3-acetyl-6-amino-5-bromopyrazin-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidin ] -1-yl) carbamate (intermediate E3)

Step a: 1- (5-amino-3-chloropyrazin-2-yl) ethanone (266mg, 1.555mmol, 1.0eq), (S) -N- ((S) -1, 3-dihydrospiro [ indene-2, 4' -piperidine)]-1-yl) -2-methylpropane-2-sulfinamide (571mg, 1.866mmol, 1.2eq), DIPEA (1.005g, 7.775mmol, 5.0eq) in DMSO (10 ml) at 105 ℃ for 2.5h; cooling to room temperature, adding water (50 mL), extracting with EA (3X 30 mL), and combining the organic phases; h for organic phase ₂ O (100 mL), brine (100 mL), anhydrous Na ₂ SO ₄ Dried, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent DCM: meOH =80:1 to 50) ]-1-yl) -2-methylpropane-2-sulfinamide (320mg, 46%). (ES, m/z) 442.09[ M ] +H] ⁺ 。

Step b: to a flask containing (S) -N- ((S) -1'- (3-acetyl-6-aminopyrazin-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine)]Adding MeOH/HCl solution (5 mL) into a reaction bottle of (E) -1-methyl propane-2-sulfinamide (320mg, 0.725mmol, 1.0eq), stirring at room temperature for 2h, and then carrying out spin drying on the reaction liquid to obtain crude product of (S) -1- (5-amino-3- (1-amino-1, 3-dihydrospiro [ indene-2, 4' -piperidine)]-1' -yl) pyrazin-2-yl) ethanone solid, (ES, m/z) 338.06[ 2 ] M + H] ⁺ 。

Step c: TEA (220mg, 2.175mmol, 3.0eq) was added to a solution containing (S) -1- (5-amino-3- (1-amino-1, 3-dihydrospiro [ indene-2, 4' -piperidine) at room temperature]-1' -yl) pyrazin-2-yl) ethanone (244mg, 0.725mmol, 1.0eq) in DCM (10 mL) and then Boc anhydride (316mg, 1.45mmol, 2.0eq) were added and the reaction stirred at room temperature for 2h. Water (15 mL) was added to the reaction mixture, which was mixed, extracted with DCM (10 mL. Times.2), and extracted with H ₂ The combined organic phases were washed with O (20 mL), brine (20 mL), dried over anhydrous sodium sulfate, filtered under reduced pressure, the filtrate was concentrated under reduced pressure, the residue was purified by column chromatography on silica gel, eluent n-hexane: EA =5, increasing gradually to 2Collecting the product, concentrating to obtain (S) -tert-butyl (1 '- (3-acetyl-6-aminopyrazin-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine ]-1-yl) carbamate transparent solid (220mg, 69%), (ES, m/z): 438.15, (M + H] ⁺ 。

Step d: NBS (94mg, 0.528mmol, 1.05eq) was added to a solution containing (S) -tert-butyl (1 '- (3-acetyl-6-aminopyrazin-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine) at-15 deg.C]A solution of (E) -1-yl) carbamate (220 mg, 0.503mmol,1.0 eq) in DCM (10 mL) was stirred at constant temperature for 10min. The reaction was quenched with saturated aqueous sodium bicarbonate (10 mL), extracted with DCM (10 mL. Times.2), and quenched with H ₂ The combined organic phases were washed with O (20 mL), brine (20 mL), dried over anhydrous sodium sulfate, filtered under reduced pressure, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel with n-hexane: EA =5, 1, gradually increasing to 3 to give (S) -tert-butyl (1 '- (3-acetyl-6-amino-5-bromopyrazin-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine]-1-yl) carbamate clear solid (132mg, 51%), (ES, m/z): 516.03[ 2 ] M + H] ⁺ 。

The following intermediates were prepared according to the preparative route and procedure of intermediate preparation 40 and intermediate preparation 41, respectively, using the following intermediates as starting materials:

intermediate preparation example 49: (S) -methyl-5-amino-3- (1- (((tert-butoxycarbonyl) amino) -1, 3-dihydrospiro [ indene-2, 4 '-piperidin ] -1' -yl) -6-mercaptopyrazine-2-carboxylate (intermediate E6)

A, step a: to (S) -methyl 5-amino-6-bromo-3- (1- ((tert-butoxycarbonyl) amino) -1, 3-dihydrospiro [ indene-2, 4' -piperidine]To a reaction solution of (E) -1' -yl) pyrazine-2-carboxylic acid ester (1000mg, 1.88mmol, 1.0eq) in 1, 4-dioxane (10 mL) was added methyl 3-mercaptopropionate (340mg, 2.82mmol, 1.5eq), pd (OAc) ₂ (80mg, 0.38mmol, 0.2eq), xantphos (440mg, 0.75mmol, 0.4eq), DIEA (850mg, 6.58mmol, 3.5eq), under nitrogen protection, and stirring at 97 ℃ for reaction for 8h. The reaction mixture was concentrated, mixed with water (100 mL), extracted with EA (50 mL. Times.2), and then extracted with H ₂ The combined organic phases were washed with O (20 mL), brine (20 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with n-hexane EA =5 to 1, gradually increasing to 2 to give (S) -methyl 5-amino-3- (1- ((tert-butoxycarbonyl) amino) -1, 3-dihydrospiro [ indene-2, 4' -piperidine ] 1]-1' -yl) -6- ((3-methoxy-3-oxopropyl) thio) pyrazine-2-carboxylate solid (1050 mg, 98%), (ES, m/z): 572.20[ m + h ], (] ⁺ 。

Step b: to (S) -methyl 5-amino-3- (1- ((tert-butoxycarbonyl) amino) -1, 3-dihydrospiro [ indene-2, 4' -piperidine](ii) 1 '-yl) -6- ((3-methoxy-3-oxopropyl) thio) pyrazine-2-carboxylic acid ester (1050mg, 1.84mmol, 1.0eq) in MeOH (50 mL), naOH (80mg, 2.02mmol, 1.1eq) was added to a reaction flask, after stirring at 50 ℃ for reaction for 3h, the solution was dried by spinning, water (100 mL) was added to the concentrate, the concentrate was made acidic with 1N HCl, a large amount of yellow solid precipitated, and the mixture was filtered under reduced pressure and dried to give (S) -methyl 5-amino-3- (1- (((tert-butoxycarbonyl) amino) -1, 3-dihydrospiro [ indene-2, 4' -piperidine ] in the form of a yellow solid ]-1' -yl) -6-mercaptopyrazine-2-carboxylate solid (880mg, 95%) (ES, m/z): 486.16[ deg. [ M ] +H ]] ⁺ 。

According to the preparation process route and operation of intermediate preparation example 49, the following intermediates were prepared using the following intermediates as starting materials:

intermediate preparation example 54: 3-chloro-2- (pyrazin-2-yl) pyridine-4-thiol (intermediate E11)

A, step a: under the protection of nitrogen, 2, 3-dichloro-4-iodopyridine (2.00g, 7.33mmol,1.00eq v), 2-ethylhexyl 3-mercaptopropionate (2.07g, 9.51mmol,1.3eq v), DIEA (2.862g, 21.99mmol,3.00eq v), pd ₂ (dba) ₃ (1.342g, 1.466mmol, 0.2eqv) and XantPhos (1.696g, 2.932mmol, 0.4eqv) in 1, 4-dioxane (50 ml) was stirred at 96 ℃ for 8h; cooling to room temperature, suction-filtering the reaction solution with diatomite, and concentrating the filtrate under reduced pressure; the residue was purified by column chromatography (n-hexane: EA =20: 1) to give 3- [ [ [2, 3-dichloropyridin-4-yl ]]Sulfanyl radical]2-ethylhexyl propionate (2.076 g, 78%), (ES, m/z): 364.06 2 [2 ], [ M ] +H] ⁺ 。

Step b: under the protection of nitrogen, 3- [ [ [2, 3-dichloropyridin-4-yl ] is reacted]Sulfanyl radical]2-ethylhexyl propionate (666mg, 1.834mmol, 1.0eqv), pyrazine-2-boronic acid (250mg, 2.02mmol, 1.1eqv), pd (dppf) Cl ₂ (134mg, 0.183mmol, 0.1eqv) and potassium carbonate (760mg, 5.503mmol, 3eqv) in 1, 4-dioxane (30 mL) and water (5 mL) at 96 ℃ for 4h; cooling, pouring the reaction solution into water (200 ml) and EA (100 ml), separating the solution, extracting the water phase with EA (2X 50 ml), and combining the organic phases; the organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (n-hexane: EA =30 ] ⁺ 。

Step c: under the protection of nitrogen, a mixture of 2-ethylhexyl 3- ((3-chloro-2- (pyrazin-2-yl) pyridin-4-yl) sulfanyl) propionate (637g, 1.565mmol, 1.0eqv), naOH (66mg, 1.643mmol, 1.05eqv)Reacting with methanol (60 ml) solution at 50 ℃ for 3h; cooling to about 0 ℃, dropwise adding 4M HCl/MeOH solution, and adjusting the pH to 3-4; silica gel is added for column chromatography purification (normal hexane: EA =10: 1-5), and 3-chloro-2- (pyrazin-2-yl) pyridine-4-thiol (320 mg, 91.7%) is obtained; (ES, m/z): 223.92[ M ] +H] ⁺ 。

The following are examples of the preparation of exemplary compounds of the present application.

Preparation example 1: 5-amino-6- [ (2-amino-3-chloropyridin-4-yl) sulfanyl ] -3- [ (3S) -3-amino-1, 3-dihydrospiro [ indene-2, 4 '-piperidine ] -1' -yl ] pyrazine-2-carbonitrile (Compound 1)

Step a: 5-amino-3-chloropyrazine-2-carbonitrile (400.00mg, 2.588mmol, 1.00equiv), N- [ (3S) -1, 3-dihydrospiro [ indene-2, 4-piperidine]-3-yl]A solution of 2-methylpropane-2-sulfinamide (793.14mg, 2.588mmol, 1.00equiv), and DIEA (1003.44mg, 7.764mmol, 3.00equiv) in DMSO (4.00 mL) was reacted overnight at 80 ℃; cooling to room temperature, adding water (20 ml), extracting with EA (2 × 10 ml), and mixing organic phases; the organic phase was washed with brine (20 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure; to obtain white solid (S) -N- [ (3R) -1'- (6-amino-3-cyanopyrazin-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine ]-3-yl]-2-methylpropane-2-sulfinamide (670 mg, 60.98%) (ES, m/z): 415[ 2 [ M ] +H ]] ⁺ 。

Step b: to (S) -N- [ (3R) -1'- (6-amino-3-cyanopyrazin-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine at room temperature]-3-yl]NBS (280.87mg, 1.578mmol, 1.00equiv) was added to DCM (10.00 mL) of 2-methylpropane-2-sulfinamide (670.00mg, 1.578mmol, 1.00equiv) and reacted at room temperature for 1 hour; the reaction mixture was washed with water (2X 5 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 5-amino-3- [ (3R) -3-amino-1, 3-dihydrospiro [ indene-2, 4' -piperidine as a yellow solid]-1' -yl]6-bromopyrazine-2-carbonitrile (600mg, 95.22%) (ES, m/z): 399[ M ] +H] ⁺ 。

Step c: to 5-amino-3- [ (3R) -3-amino-1, 3-dihydrospiro [ indene-2, 4' -piperidine]-1'-radical]-6-bromopyrazine-2-carbonitrile (600.00mg, 1.503mmol, 1.00equiv), (Boc) ₂ To a solution of O (327.95mg, 1.503mmol, 1equiv) in DCM (10 ml) was added TEA (152.05mg, 1.503mmol, 1.00equiv) and reacted at room temperature overnight; the reaction mixture was washed with water (3X 5 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure; the residue was purified by column chromatography (N-hexane: etOAC =10: 1) to give tert-butyl N- [ (3R) -1'- (6-amino-5-bromo-3-cyanopyrazin-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine]-3-ylcarbamate (240mg, 31.98%) (ES, m/z): 499[ deg. ] M + H ] ⁺ 。

Step d: under the protection of nitrogen, tert-butyl N- [ (3R) -1'- (6-amino-5-bromo-3-cyanopyrazin-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine]-3-ylcarbamate (195.00mg, 0.390mmol, 1.00equiv), 2-amino-3-chloropyridine-4-thiol (62.72mg, 0.390mmol, 1.00equiv), DIEA (151.39mg, 1.171mmol, 3.00equiv), pd (dba) ₃ (18.32mg, 0.020mmol, 0.05equiv) and Xantphos (11.58mg, 0.020mmol, 0.05equiv) in 1, 4-dioxane (2.00 mL) at 90 ℃ for 8h; cooling to room temperature, adding water (10 mL), extracting with EA (3X 5 mL), and combining organic phases; the organic phase was washed with water (3X 5 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure; to obtain white solid tert-butyl N- [ (3S) -1' - [ 6-amino-5- [ (2-amino-3-chloropyridin-4-yl) sulfanyl]-3-cyanopyrazin-2-yl]-1, 3-dihydrospiro [ indene-2, 4' -piperidine]-3-yl]Carbamate (194.4 mg, 86.21%) (ES, m/z): 579[ M ] +H] ⁺ 。

Step e: tert-butyl N- [ (3S) -1' - [ 6-amino-5- [ (2-amino-3-chloropyridin-4-yl) sulfanyl]-3-cyanopyrazin-2-yl]-1, 3-dihydrospiro [ indene-2, 4' -piperidine]-3-yl]Carbamate (194.00mg, 0.336mmol, 1.00equiv) and 2M HCl/EA (4.00 ml) solution, and the reaction is carried out for 2h at room temperature; concentrating the reaction solution under reduced pressure; to the residue was added water (10 ml), the pH was adjusted to 10 with 25% ammonia, extracted with EA (2X 5 ml), and the organic phases were combined; the organic phase was washed with brine (10 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure; the residue was purified by Prep-HPLC (5-25% acetonitrile in water gradient elution, 0.05% NH.) ₄ HCO ₃ Modification) to obtain 5-amino-6- [ (2-amino-3-chloropyridin-4-yl) sulfanyl]-3- [ (3S) -3-amino-1, 3-dihydrospiro [ indene-2, 4' -piperidine]-1' -yl]Pyrazine-2-carbonitriles(Compound 1) (150 mg) (ES, m/z): 479[ M + H ]] ⁺ 。

1H NMR(400MHz,Methanol-d4)δ7.69(d,J＝6.9Hz,1H),7.53(d,J＝7.5Hz,1H),7.48–7.38(m,2H),7.37(td,J＝7.0,6.5,2.3Hz,1H),6.41(d,J＝6.9Hz,1H),4.64–4.56(m,1H),4.47(d,J＝6.7Hz,2H),3.55–3.43(m,2H),3.30(s,2H),3.22(s,2H),2.06–1.94(m,1H),1.94–1.77(m,2H),1.68(d,J＝13.5Hz,1H),1.33(d,J＝17.5Hz,1H)。

Preparation example 2: (S) -6- ((1-acetyl-3, 3-difluoroindol-4-yl) sulfanyl) -5-amino-3- (1-amino-1, 3-dihydrospiro [ indene-2, 4 '-piperidine ] ] -1' -yl) pyrazine-2-carbonitrile (Compound 2)

Step a: 6- (((1-acetyl-3, 3-difluoroindol-4-yl) sulfanyl) -5-amino-3-chloropyrazine-2-carbonitrile (100mg, 0.262mmol, 1eqv), (R) -N- ((S) -1, 3-dihydrospiro [ indene-2, 4' -piperidine)]-1-yl) -2-methylpropane-2-sulfinamide (80mg, 0.262mmol, 1eqv), DIPEA (102mg, 0.786mmol, 3eqv) in DMSO (5 ml) at 80 ℃ for 8h; cooling to room temperature, adding water (50 ml), extracting with EA (2 × 20 ml), and mixing organic phases; the organic phase was washed with brine (20 ml) and concentrated under reduced pressure; the residue was purified by column Chromatography (CH) ₂ Cl ₂ :CH ₃ OH = 200) to give a brown oil (R) -N- ((S) -1'- (5- ((1-acetyl-3, 3-difluoroindol-4-yl) sulfanyl) -6-amino-3-cyanopyrazin-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine)]-1-yl) -2-methylpropane-2-sulfinamide (140 mg) (ES, m/z): 652.15[ m + H ], [] ⁺ 。

Step b: (R) -N- ((S) -1'- (5- ((1-acetyl-3, 3-difluoroindol-4-yl) sulfanyl) -6-amino-3-cyanopyrazin-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine ]-1-yl) -2-methylpropane-2-sulfinamide (140 mg) was added to HCl/CH ₃ In OH (10 ml), the reaction is carried out for 1h at room temperature; concentrating under reduced pressure, adding water (20 ml) to the residue, adjusting pH to 10 with 25% ammonia water, extracting with EA (2X 20 ml), and combining the organic phases; the organic phase was washed with brine (10 ml) and concentrated under reduced pressure; disabled personThe residue was purified by column Chromatography (CH) ₂ Cl ₂ :CH ₃ OH = 80) to give (S) -6- ((1-acetyl-3, 3-difluoroindol-4-yl) sulfanyl) -5-amino-3- (1-amino-1, 3-dihydrospiro [ indene-2, 4' -piperidine)]]-1' -yl) pyrazine-2-carbonitrile (compound 2) (60 mg). (ES, m/z): 548.09[ m ] +H] ⁺ 。

Preparation examples 3 to 8:

compounds 3 to 8 were prepared according to the preparative route and operation of preparation example 2, using the following intermediates as starting materials.

Preparation example 9: 5-amino-3- [ (3S) -3-amino-1, 3-dihydrospiro [ indene-2, 4-piperidine ] -1-yl ] -6- [ [2- (trifluoromethyl) pyridin-3-yl ] sulfanyl ] pyrazine-2-carbonitrile (Compound 9)

Step a: a solution of 6-chloro-5-iodo-3- [ [ [2- (trifluoromethyl) pyridin-3-yl ] sulfanyl ] pyrazin-2-amine (320.00mg, 0.740mmol, 1.00equiv), N- [ (3S) -1, 3-dihydrospiro [ indene-2, 4-piperidine ] -3-yl ] -2-methylpropane-2-sulfinamide (226.79mg, 0.074mmol, 1.00equiv), DIEA (286.82mg, 2.21mmol, 3.00equiv) in DMSO (5.00 mL) was reacted at 100 ℃ for 3h; cooling to room temperature, adding water (20 ml), extracting with EA (2 × 50 ml), and mixing organic phases; the organic phase was washed with brine (20 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure; to obtain a crude product (300 mg) of N- [ (3S) -1- (6-amino-3-iodo-5- [ [2- (trifluoromethyl) pyridin-3-yl ] sulfanyl ] pyrazin-2-yl) -1, 3-dihydrospiro [ indene-2, 4-piperidine ] -3-yl ] -2-methylpropane-2-sulfinamide, which is directly used for the next reaction without purification.

Step b: under the protection of nitrogen, N- [ (3S) -1- (6-amino-3-iodo-5- [ [2- (trifluoromethyl) pyridin-3-yl)]Sulfanyl radical]Pyrazin-2-yl) -1, 3-dihydrospiro [ indene-2, 4-piperidine]-3-yl]2-methylpropane-2-sulfinamide (300.00mg, 0.427mmol, 1.00equiv), pd (PPh) ₃ ) ₄ (49.34mg, 0.043mmol, 0.10equiv) and Zn (CN) ₂ Reacting (50.15mg, 0.427mmol, 1.00equiv) NMP (5.00 mL) solution at 100 deg.C for 1h; cooling to room temperature, adding EA (20 mL), washing with brine (3X 15 mL), drying the organic phase with anhydrous sodium sulfate, and concentrating under reduced pressure; the residue was purified by column chromatography (N-hexane: EA =10 1) to give N- [ (3S) -1- (6-amino-3-cyano-5- [ [2- (trifluoromethyl) pyridin-3-yl ] brown yellow solid]Sulfanyl radical]Pyrazin-2-yl) -1, 3-dihydrospiro [ indene-2, 4-piperidine]-3-yl]-2-methylpropane-2-sulfinamide (120mg, 46.71%) (ES, m/z): 602[ 2[ M + H ])] ⁺ 。

Step c: to N- [ (3S) -1- (6-amino-3-cyano-5- [ [2- (trifluoromethyl) pyridin-3-yl group]Sulfanyl radical]Pyrazin-2-yl) -1, 3-dihydrospiro [ indene-2, 4-piperidine]-3-yl]-2-methylpropane-2-sulfinamide (120.00mg, 0.199mmol, 1.00equiv) in DCM (1.50 mL) was added HCl in 1, 4-dioxane (1.50mL, 49.368mmol) and reacted at room temperature for 1h; the reaction was concentrated under reduced pressure and the residue was purified by Prep-HPLC (gradient elution from 30 to 70% acetonitrile in water, using 10mmol/L NH) ₄ HCO ₃ Modification) to obtain 5-amino-3- [ (3S) -3-amino-1, 3-dihydrospiro [ indene-2, 4-piperidine]-1-yl]-6- [ [2- (trifluoromethyl) pyridin-3-yl ] amino acid]Sulfanyl radical]Pyrazine-2-carbonitrile (compound 9) (36mg, 36.28%), (ES, m/z): 498[ 2 ], [ M + H ]] ⁺ 。

¹ H NMR(400MHz,Methanol-d4)δ8.51(d,1H),7.67(d,J＝8.2Hz,1H),7.54(dd,J＝8.2,4.6Hz,1H),7.44–7.35(m,1H),7.29–7.19(m,3H),4.46(dt,J＝13.4,4.0Hz,2H),3.98(s,1H),3.51–3.35(m,2H),3.17(d,J＝15.7Hz,1H),2.83(d,J＝15.7Hz,1H),2.05(s,1H,MeCN),1.97–1.78(m,2H),1.62(d,J＝13.4Hz,1H),1.46(d,J＝13.4Hz,1H)。

Preparation examples 10 to 12: 10 to 12 Compounds

Referring to the preparation route and operation of preparation example 9, compounds 10 to 12 were synthesized using the following intermediates as starting materials:

preparation example 13: (3S) -1'- [ 6-amino-5- [ (2-amino-3-chloropyridin-4-yl) sulfanyl ] -3- (oxetan-3-yl) pyrazin-2-yl ] -1, 3-dihydrospiro [ indene-2, 4' -piperidine ] -3-amine (Compound 13)

Reacting a 3- [ (2-amino-3-chloropyridin-4-yl) sulfanyl group]-6-chloro-5- (oxetan-3-yl) pyrazin-2-amine (50.00mg, 0.145mmol, 1.00equiv), (S) -1, 3-dihydrospiro [ indene-2, 4' -piperidine]1-amine dihydrochloride (47.97mg, 0.174mmol, 1.20equiv), DIEA (93.87mg, 0.726mmol, 5.00equiv) in DMSO (2.00 mL) was reacted at 80 ℃ overnight; the reaction solution was purified by rapid Prep-HPLC (gradient elution of 10-50% acetonitrile in water, 0.1% NH.) ₄ HCO ₃ Modification) to obtain (3S) -1' - [ 6-amino-5- [ (2-amino-3-chloropyridin-4-yl) sulfanyl]-3- (oxetan-3-yl) pyrazin-2-yl]-1, 3-dihydrospiro [ indene-2, 4' -piperidine]-3-amine (Compound 13) (3.3mg, 4.45%) (ES, m/z): 510[ 2 [ M ] +H ] ] ⁺ 。

¹ H NMR(400MHz,Methanol-d ₄ )δ7.61(d,J＝5.7Hz,1H),7.43(t,J＝8.8Hz,2H),7.28–7.22(m,5H),5.97(d,J＝5.6Hz,1H),4.05(s,1H),4.00(s,1H),3.43(d,J＝13.4Hz,3H),3.14(s,0H),3.10(s,2H),2.83(dd,J＝24.0,15.8Hz,2H),1.93(s,3H),1.82(d,J＝13.0Hz,1H),1.71–1.59(m,1H),1.57(s,1H),1.51(d,J＝15.0Hz,1H),1.31(s,2H),0.90(s,1H)。

Preparation examples 14 to 15:

referring to the preparation process route and operation of preparation example 13, compounds 14 and 15 were synthesized using the following intermediates as starting materials:

preparation example 16: (S) -1'- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) sulfanyl) -3-vinylpyrazin-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine ] -1-amine (Compound 16)

Under the protection of nitrogen, (S) -1'- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) sulfanyl) -3-iodopyrazin-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine]-1-amine (50mg, 0.085mmol), potassium vinyltrifluoroborate (23mg, 0.1699 mmol), pd (PPh) ₃ ) ₄ (10mg, 0.00847mmol), potassium carbonate (35mg, 0.254mmol) were added to toluene (6 ml), ethanol (3 ml) and water (1.5 ml) and reacted at 80 ℃ for 2.5 hours; concentrating under reduced pressure, adding water (20 ml) to the residue, extracting with EA (2X 15 ml), and combining the organic phases; the organic phase was washed with brine (10 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column Chromatography (CH) ₂ Cl ₂ :CH ₃ OH = 30) to give (S) -1'- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) sulfanyl) -3-vinylpyrazin-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine)]-1-amine (Compound 16) (17mg, 42.5%) (ES, m/z): 480.02[ deg. ], M + H] ⁺ 。

¹ H NMR(600MHz,CDCl3):δ7.73-7.71(m,1H),7.43(s,2H),7.26-7.21(m,4H),6.73-6.69(m,1H),6.11-6.06(m,2H),5.33-5.31(m,1H),4.91(s,4H),4.1(s,1H),3.69(s,2H),3.14-3.08(m,2.5H),2.8-2.76(m,1.5H),1.59-1.49(m,4H)。

Preparation example 17: (S) -5-amino-3- (1-amino-1, 3-dihydrospiro [ indene-2, 4 '-piperidine ] -1' -yl) -6- ((2-amino-3-chloropyridin-4-yl) sulfanyl) pyrazine-2-carboxamide (Compound 17)

Reacting 5-amino-3- [ (3S) -3-amino-1, 3-dihydrospiro [ indene-2, 4' -piperidine]-1' -yl]-6- [ (2-amino-3-chloropyridin-4-yl) sulfanyl]Pyrazine-2-carbonitrile (170.00mg, 0.355mmol, 1.00equiv) and NaOH (70.98mg, 1.775mmol, 5.00equiv) were added to H ₂ O (2.00 mL) and MeOH (2.00 mL) at 80 ℃ for 1.5h; the reaction was concentrated under reduced pressure and the residue was purified by Prep-TLC (40-80% acetonitrile in water gradient elution with 10mmol/L NH) ₄ HCO ₃ Modification) to obtain (S) -5-amino-3- (1-amino-1, 3-dihydrospiro [ indene-2, 4' -piperidine)]-1' -yl) -6- ((2-amino-3-chloropyridin-4-yl) sulfanyl) pyrazine-2-carboxamide (Compound 17) (7.6 mg, 4.31%) (ES, m/z): 497[ m ] +H] ⁺ 。

¹ H NMR(400MHz,Methanol-d4)δ7.64(d,J＝5.5Hz,1H),7.42–7.35(m,1H),7.28–7.17(m,3H),6.02(d,J＝5.5Hz,1H),4.86(s,2H),4.03–3.94(m,3H),3.33–3.22(m,1H),3.15(d,J＝15.7Hz,1H),2.83(d,J＝15.7Hz,1H),1.98–1.80(m,2H),1.56(d,J＝13.3Hz,1H),1.43(d,J＝13.4Hz,1H).

Preparation example 18:

referring to the preparative route and procedure of preparation example 17, starting from the final product of preparation example 9, compound 18 was prepared:

preparation example 19: methyl- (S) -5-amino-3- (1-amino-1, 3-dihydrospiro [ indene-2, 4-piperidine ] -1' -yl) -6- ((2-amino-3-chloropyridin-4-yl) sulfanyl) pyrazine-2-carboxylic acid ester (Compound 19)

A, step a: to (R) -N- ((S) -1'- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) sulfanyl) -3-iodopyrazin-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine) under nitrogen protection]-1-yl) -2-methylpropane-2-sulfinamide (1.00g, 1.462mmol, 1.00equiv), pd (dppf) Cl ₂ (1.07g,0.146mmol,0.1equiv)，Et ₃ Introducing CO into a solution of N (295.85mg, 2.924mmol, 2equiv) in MeOH (15.00 mL), and reacting for 48h at 50 ℃; cooling to room temperature, suction-filtering with diatomite, and concentrating the filtrate under reduced pressure; the residue was purified by column chromatography (n-hexane: EA =2: 1) to give crude product, which was further purified by Prep-HPLC (gradient elution of 10-50% acetonitrile in water, 10mmol/L NH ₄ HCO ₃ Modification) to obtain off-white solid methyl 5-amino-6- (((2-amino-3-chloropyridin-4-yl) sulfanyl) -3- ((S) -1- ((R) -1, 1-dimethylethylsulphinylidene) -1, 3-dihydrospiro [ indene-2, 4' -piperidine]-1' -yl) pyrazine-2-carboxylate (300mg, 33.30%) (ES, m/z): 616[ 2 ], [ M + H ]] ⁺ 。

Step b: to methyl 5-amino-6- (((2-amino-3-chloropyridin-4-yl) sulfanyl) -3- ((S) -1- ((R) -1, 1-dimethylethylsulphideneamino) -1, 3-dihydrospiro [ indene-2, 4' -piperidine]-1' -yl) pyrazine-2-carboxylate (230.00 mg) in DCM (2 mL) was added HCl in 1, 4-dioxane (1 mL) and reacted at room temperature for 1h; the reaction was concentrated under reduced pressure and the residue was purified by Prep-HPLC (gradient elution of 10-50% acetonitrile in water, 10mmol/L NH) ₄ HCO ₃ Modification) to obtain methyl- (S) -5-amino-3- (1-amino-1, 3-dihydrospiro [ indene-2, 4-piperidine)]-1' -yl) -6- ((2-amino-3-chloropyridin-4-yl) sulfanyl) pyrazine-2-carboxylate (Compound 19) (53.3 mg) ((ES, m/z): 512[ M + H ]) ] ⁺ 。

¹ H NMR(400MHz,Methanol-d4)δ7.65(d,J＝5.5Hz,1H),7.38–7.32(m,1H),7.25(m,3H),6.01(d,J＝5.5Hz,1H),4.00(d,J＝6.7Hz,1H),3.99-3.87(m,2H),3.87(s,3H),3.33–3.26(m,2H),3.16(m,1H),2.83(m,1H),1.93-1.84(m,2H),1.59(m,J＝13.1Hz,1H),1.46(m,1H)。

Preparation example 20: (R) -5-amino-3- (1-amino-8-azaspiro [4.5] decan-8-yl) -6- ((2, 3-dichlorophenyl) sulfanyl) pyrazine-2-carboxylic acid methyl ester (Compound 20)

Step a: reacting (R) -2-methyl-N- ((R) -8-azaspiro [4.5]]Decan-1-yl) propane-2-sulfinamide (400mg, 1.550mmol), methyl 3-chloro-5- ((2, 4-dimethoxybenzyl) amino) pyrazine-2-carboxylate (522mg, 1.550mmol), DIPEA (1.00g, 7.75mmol) in DMSO (10 ml) and stirred at 100 ℃ for 6h; cooling to room temperature, adding water (80 ml) into the reaction solution, extracting with EA (60 ml × 2), and combining the organic phases; h for organic phase ₂ O (20 ml), brine (20 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue purified by silica gel column Chromatography (CH) ₂ Cl ₂ :CH ₃ OH =100, 1 to 50)]Decyl-8-yl) pyrazine-2-carboxylate (106mg, 12.2%), (ES, m/z): 560.21, M + H] ⁺

Step b: methyl 5- ((2, 4-dimethoxybenzyl) amino) -3- ((R) -1, 1-dimethylethylenesulfonamido) -8-azaspiro [4.5]Decyl-8-yl) pyrazine-2-carboxylate (106mg, 0.190mmol) and CF ₃ COOH (2 ml) was reacted at room temperature overnight; concentrating under reduced pressure, adding water (20 ml) to the residue, adjusting to pH = 9-10 with ammonia water, extracting with EA (15 ml × 2), and combining the organic phases; h for organic phase ₂ O (20 ml), brine (20 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue purified by silica gel column Chromatography (CH) ₂ Cl ₂ :CH ₃ OH =60, 1-30) to give 5-amino-3- ((R) -1, 1-dimethylethylenesulfonamido) -8-azaspiro [ 4.5) as a pale yellow solid]Decyl-8-yl) pyrazine-2-carboxylic acid methyl ester (70mg, 90.0%) (ES, m/z): 410.07[ 2 ] M + H] ⁺

Step c, adding 5-ammoniaRadical-3- ((R) -1, 1-dimethylethylsulphonidino) -8-azaspiro [4.5]Decyl-8-yl) pyrazine-2-carboxylic acid methyl ester (70mg, 0.171mmol) and MeOH/HCl solution (1 ml) were reacted at room temperature overnight; concentrating under reduced pressure, adding water (20 ml) into residue, extracting with EA (15 ml × 2), and combining organic phases; h for organic phase ₂ Washed with O (10 ml) and brine (10 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 5-amino-3- (1-amino-8-azaspiro [4.5 ] as a pale yellow solid]Decyl-8 yl) pyrazine-2-carboxylic acid (R) -methyl ester (35mg, 67.0%) (ES, m/z): 306.22[ m ] +H] ⁺

Step d: to 5-amino-3- (1-amino-8-azaspiro [4.5 ]]Decyl-8-yl) pyrazine-2-carboxylic acid (R) -methyl ester (35mg, 0.115mmol), (Boc) ₂ Adding TEA (35mg, 0.345mmol) dropwise into a DCM (3 ml) solution of O (30mg, 0.138mmol), and stirring at room temperature for reaction for 1h; water (10 ml) was added to the reaction solution, followed by liquid separation; the aqueous phase was extracted with DCM (10 ml. Times.2) and the organic phases were combined; h for organic phase ₂ O (20 ml), brine (20 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue purified by silica gel column Chromatography (CH) ₂ Cl ₂ :CH ₃ OH =90, 1 to 30) to give (R) -methyl 5-amino-3- (1- (((tert-butoxycarbonyl) amino) -8-azaspiro [ 4.5) -azaspiro [4.5 ] as a pale yellow solid]Dec-8-yl) pyrazine-2-carboxylate (34mg, 73%), (ES, m/z): 406.19[ m ] +H] ⁺

Step e reaction of (R) -methyl-5-amino-3- (1- (((tert-butoxycarbonyl) amino) -8-azaspiro [4.5 ] under nitrogen protection]Decyl-8-yl) pyrazine-2-carboxylic acid ester (34mg, 0.084 mmol) and NBS (16954 mmol) in DCM (5 ml) were reacted at 0 deg.C for 30min; a saturated aqueous sodium bicarbonate solution (10 ml) was added to the reaction solution, followed by liquid separation; the aqueous phase was extracted with DCM (10 ml. Times.2) and the organic phases were combined; h for organic phase ₂ O (20 ml), brine (20 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give (R) -methyl-5-amino-6-bromo-3- (1- (((tert-butoxycarbonyl) amino) -8-azaspiro [4.5 ] as a clear solid]Decyl-8-yl) pyrazine-2-carboxylate (28mg, 69%), (ES, m/z): 483.97[ mu ] M + H] ⁺

Step f preparation of (R) -methyl-5-amino-6-bromo-3- (1- (((tert-butoxycarbonyl) amino) -8-azaspiro [4.5 ] under nitrogen]Decyl-8-yl) pyrazine-2-carboxylic acid esters(28mg, 0.058mmol, 1.00equiv), 2, 3-dichlorobenzenethiol (10.38mg, 0.058mmol, 1.00equiv), DIEA (22.49mg, 0.174mmol, 3.00equiv), pd ₂ (dba) ₃ (5.5mg, 0.006mmol, 0.1equiv) and Xantphos (5.21mg, 0.009mmol, 0.15eq) in 1, 4-dioxane (2.00 mL) at 90 ℃ for 8h; filtering through celite, adding water (10 mL) to the filtrate, extracting with EA (3 × 5 mL), and combining the organic phases; the organic phase was washed with water (3X 5 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure; to obtain (R) -methyl-5-amino-3- (1- ((tert-butoxycarbonyl) amino) -8-azaspiro [4.5]Decyl-8-yl) -6- (((2, 3-dichlorophenyl) sulfanyl) pyrazine-2-carboxylate (22mg, 65.1%) (ES, m/z): 582.04[ m ] +H ]] ⁺ 。

Step g Synthesis of (R) -methyl-5-amino-3- (1- ((tert-butoxycarbonyl) amino) -8-azaspiro [4.5 ]]Adding a 1, 4-dioxane solution (1 mL) of HCl into DCM (2 mL) of decyl-8-yl) -6- (((2, 3-dichlorophenyl) sulfanyl) pyrazine-2-carboxylic acid ester (22 mg), and reacting at room temperature for 2h; the reaction was concentrated under reduced pressure and the residue was purified by Prep-HPLC (gradient elution from 20-50% acetonitrile in water, using 10mmol/L NH) ₄ HCO ₃ Modified to obtain (R) -5-amino-3- (1-amino-8-azaspiro [4.5 ]]Decyl-8-yl) -6- ((2, 3-dichlorophenyl) sulfanyl) pyrazine-2-carboxylic acid methyl ester (compound 20) (5.2 mg) ((ES, m/z): 481.99[ 2 [ M + H ]] ⁺ 。

Preparation example 21:6- (1-acetyl-3, 3-difluoro-2H-indol-4-yl) -5-amino-3- [ (3S) -3-amino-1, 3-dihydrospiro [ indene-2, 4-piperidine ] -1-yl ] pyrazine-2-carbonitrile (Compound 21)

Step a: mixing (R) -N- ((S) -1, 3-dihydrospiro [ indene-2, 4' -piperidine)]-1-yl) -2-methylpropane-2-sulfinamide (1.00g, 3.263mmol, 1.00equiv), 5-amino-3-chloropyrazine-2-carbonitrile (0.50g, 3.235mmol, 0.99equiv) and DIEA (0.84g, 6.526mmol, 2equiv) in DMSO (12.00 mL) were reacted at 80 ℃ for 3h; cooling to room temperature, adding water (60 ml), extracting with EA (2 × 20 ml), and mixing organic phases; the organic phase was washed with brine (20 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressurePerforming pressure concentration; to obtain crude product of (R) -N- ((S) -1'- (6-amino-3-cyanopyrazin-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine)]-1-yl) -2-methylpropane-2-sulfinamide (1.21g, 87.34%) (ES, m/z): 425[ m + H ], [ 2] ⁺ . The reaction mixture was used in the next step without purification.

Step b: to (R) -N- ((S) -1'- (6-amino-3-cyanopyrazin-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine) at room temperature]-1-yl) -2-methylpropane-2-sulfinamide (1.15g, 2.709mmol, 1.00equiv) in DCM (15.00 mL) was added NBS (0.72g, 4.063mmol, 1.50equiv) and reacted for 1h; the reaction was concentrated under reduced pressure and the residue was purified by reverse flash column chromatography (gradient elution with 10-50% acetonitrile in water) to give 5-amino-3- [ (3S) -3-amino-1, 3-dihydrospiro [ indene-2, 4-piperidine ] as a yellow solid]-1-yl]-6-bromopyrazine-2-carbonitrile (660 mg, 61.02%) (ES, m/z): 399[ 2 [ M + H ] ] ⁺ .

Step c: under the protection of nitrogen, 5-amino-3- [ (3S) -3-amino-1, 3-dihydrospiro [ indene-2, 4-piperidine]-1-yl]6-bromopyrazine-2-carbonitrile (200.00mg, 0.501mmol, 1.00equiv), 1- (3, 3-difluoro-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) indol-1-yl) ethanone (194.23mg, 0.601mmol, 1.2equiv), K ₃ PO ₄ (318.96mg, 1.503mmol, 3equiv) and Pd (dppf) Cl ₂ (36.65mg, 0.050mmol, 0.1equiv) of a solution of 1, 4-dioxane (4.00 mL) and water (1.00 mL) at 100 ℃ for 1h; concentrating the reaction solution under reduced pressure, and purifying the residue by column Chromatography (CH) ₂ Cl ₂ : meOH = 12) ₄ HCO ₃ Modification) to obtain 6- (1-acetyl-3, 3-difluoro-2H-indol-4-yl) -5-amino-3- [ (3S) -3-amino-1, 3-dihydrospiro [ indene-2, 4-piperidine]-1-yl]Pyrazine-2-carbonitrile (compound 21) (23mg, 8.91%) (ES, m/z): 516, [ M + H ], [] ⁺ 。

¹ H NMR(400MHz,DMSO-d6)δ8.31(d,J＝8.3Hz,1H),7.63(t,J＝7.9Hz,1H),7.33(d,1H),7.24–7.12(m,3H),7.11(d,J＝7.5Hz,1H),6.74(s,2H),4.55(t,J＝16.8Hz,2H),4.35–4.25(m,2H),3.88(s,1H),3.31–3.21(m,4H),3.08(d,J＝15.7Hz,1H),2.64(d,1H),2.26(s,3H),1.86(td,J＝12.6,4.0Hz,1H),1.75(td,J＝12.5,4.2Hz,1H),1.57(d,J＝13.2Hz,1H),1.16(d,J＝13.3Hz,1H)。

Preparation example 22: 5-amino-3- ((1S) -1-amino-3 ' -methoxy-1, 3-dihydrospiro [ indene-2, 4' -piperidine ] -1' -yl) -6- ((2-amino-3-chloropyridin-4-yl) sulfanyl) pyrazine-2-carbonitrile (Compound 22)

Step a: 5-amino-6- (((2-amino-3-chloropyridin-4-yl) sulfanyl) -3-chloropyrazine-2-carbonitrile (82mg, 0.262mmol, 1eqv), (R) -N- (((1S) -3 '-methoxy-1, 3-dihydrospiro [ indene-2, 4' -piperidine) ]-1-yl) -2-methylpropane-2-sulfinamide (88.2mg, 0.262mmol, 1eqv), DIPEA (102mg, 0.786mmol, 3eqv) in DMSO (6 ml) at 120 ℃ for 10h; cooling to room temperature, adding water (50 ml), extracting with EA (2 × 20 ml), and mixing organic phases; the organic phase was washed with brine (20 ml) and concentrated under reduced pressure; the residue was purified by column Chromatography (CH) ₂ Cl ₂ :CH ₃ OH = 150) to give (R) -N- ((1S) -1' - (6-amino-5- ((2-amino-3-chloropyridin-4-yl) sulfanyl) -3-cyanopyrazin-2-yl) -3' -methoxy-1, 3-dihydrospiro [ indene-2, 4' -piperidine]-1-yl) -2-methylpropane-2-sulfinamide (69mg, 43%) (ES, m/z): 613.15[ M + H ]] ⁺ 。

Step b: (R) -N- ((1S) -1' - (6-amino-5- ((2-amino-3-chloropyridin-4-yl) sulfanyl) -3-cyanopyrazin-2-yl) -3' -methoxy-1, 3-dihydrospiro [ indene-2, 4' -piperidine]-1-yl) -2-methylpropane-2-sulfinamide (69 mg) was added to HCl/CH ₃ Reacting for 2 hours at room temperature in OH (15 ml); concentrating under reduced pressure, adding water (20 ml) to the residue, adjusting pH to 10 with 25% ammonia water, extracting with EA (2X 20 ml), and combining the organic phases; the organic phase was washed with brine (10 ml) and concentrated under reduced pressure; the residue was purified by column Chromatography (CH) ₂ Cl ₂ :CH ₃ OH = 60) to give 5-amino-3- ((1S) -1-amino-3 '-methoxy-1, 3-dihydrospiro [ indene-2, 4' -piperidine) ]-1' -yl) -6- ((2-amino-3-chloropyridin-4-yl) sulfanyl) pyrazine-2-carbonitrile (Compound 22) (21 mg) ((ES, m/z): 509.09[ M ] +H ]] ⁺ 。

Preparation example 23: methyl-5-amino-3- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -6- ((2, 3-dichlorophenyl) sulfanyl) pyrazine-2-carboxylate (Compound 23)

A, step a: reacting (R) -2-methyl-N- ((3S, 4S) -3-methyl-2-oxa-8-azaspiro [ 4.5%]Decan-4-yl) propane-2-sulfinamide (400mg, 1.458mmol), methyl 3-chloro-5- ((2, 4-dimethoxybenzyl) amino) pyrazine-2-carboxylate (492mg, 1.458mmol), DIPEA (942g, 7.29mmol) in DMSO (10 ml) was stirred at 100 ℃ for 5h; cooling to room temperature, adding water (80 ml) into the reaction solution, extracting with EA (60 ml × 2), and combining the organic phases; h for organic phase ₂ O (20 ml), brine (20 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue purified by silica gel column Chromatography (CH) ₂ Cl ₂ :CH ₃ OH =100, 1-50) to obtain methyl-5- (((2, 4-dimethoxybenzyl) amino) -3- ((3s, 4 s) -4- ((R) -1, 1-dimethylethylenesulfonamido) -3-methyl-2-oxa-8-azaspiro [4.5]Decyl-8-yl) pyrazine-2-carboxylate (590 mg), (ES, m/z): 576.24[ M ] +H] ⁺ 。

Step b: methyl-5- (((2, 4-dimethoxybenzyl) amino) -3- ((3S, 4S) -4- ((R) -1, 1-dimethylethylenesulfonamido) -3-methyl-2-oxa-8-azaspiro [ 4.5% ]Decyl-8-yl) pyrazine-2-carboxylate (590 mg) and CF ₃ COOH (5 ml) was reacted at room temperature overnight; concentrated under reduced pressure, water (20 ml) was added to the residue, adjusted to pH =10 with aqueous ammonia, extracted with EA (15 ml × 2), and the organic phases were combined; h for organic phase ₂ O (20 ml), brine (20 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue purified by silica gel column Chromatography (CH) ₂ Cl ₂ :CH ₃ OH =50]Decyl-8-yl) pyrazine-2-carboxylate (280 mg) (ES, m/z) 426.19[ m + H ], [ solution of C] ⁺ 。

Step c methyl 5-amino-3- ((3S, 4S) -4- ((R) -1, 1-dimethylethylenesulfonamido) -3-methyl-2-oxa-8-azaspiro [4.5 ]]Decyl-8-yl) pyrazine-2-carboxylate (280 mg) and MeOH/HCl solution (5 ml) were reacted at room temperature overnight; concentrating under reduced pressure to obtain 5-amino-3- (((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]The crude methyl decan-8-yl pyrazine-2-carboxylate, which is used in the next reaction without purification (ES, m/z): 322.18[ M + H ]] ⁺ 。

Step d: to 5-amino-3- (((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5 ]]Decyl-8-yl) pyrazine-2-carboxylic acid methyl ester crude product, (Boc) ₂ Adding TEA (200mg, 1.976 mmol) dropwise into a DCM (30 ml) solution of O (215mg, 0.988mmol), and stirring at room temperature for reacting for 2h; water (30 ml) was added to the reaction solution, followed by liquid separation; the aqueous phase was extracted with DCM (10 ml. Times.2) and the organic phases were combined; h for organic phase ₂ O (20 ml), brine (20 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue purified by silica gel column Chromatography (CH) ₂ Cl ₂ :CH ₃ OH =80, 1 to 30)]Decyl-8-yl) pyrazine-2-carboxylic acid methyl ester (110 mg), (ES, m/z): 422.11[ 2 ] M + H] ⁺ 。

Step e 5-amino-3- ((3S, 4S) -4- ((tert-butoxycarbonyl) amino) -3-methyl-2-oxa-8-azaspiro [4.5 ] under nitrogen protection]Decyl-8-yl) pyrazine-2-carboxylic acid methyl ester (110mg, 0.263mmol) NBS (56.2mg, 0.316mmol) in DCM (10 ml) was reacted at 0 ℃ for 30min; a saturated aqueous sodium bicarbonate solution (10 ml) was added to the reaction solution, followed by liquid separation; the aqueous phase was extracted with DCM (10 ml. Times.2) and the organic phases were combined; h for organic phase ₂ Washed with O (20 ml), brine (20 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give methyl 5-amino-6-bromo-3- ((3S, 4S) -4- ((tert-butoxycarbonyl) amino) -3-methyl-2-oxa-8-azaspiro [4.5]Decyl-8-yl) pyrazine-2-carboxylate (65.7 mg), (ES, m/z) 499.98,501.96, M + H] ⁺ 。

Step f, under the protection of nitrogen, methyl 5-amino-6-bromo-3- ((3S, 4S) -4- ((tert-butoxycarbonyl) amino) -3-methyl-2-oxa-8-azaspiro [4.5 ]]Decyl-8-yl) pyrazine-2-carboxylic acid ester (65) 7mg, 0.132mmol), 2, 3-dichlorobenzenethiol (23.6 mg, 0.132mmol), DIEA (51mg, 0.396mmol), pd ₂ (dba) ₃ (24.2mg, 0.026mmol) and Xantphos (11.5mg, 0.020mmol) in 1, 4-dioxane (5.00 mL) at 90 ℃ for 8h; filtering through diatomite, adding water (30 mL) into the filtrate, extracting with EA (3X 10 mL), and combining the organic phases; the organic phase was washed with water (2X 10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure; the residue was purified by silica gel column Chromatography (CH) ₂ Cl ₂ :CH ₃ OH =100, 1) to give methyl 5-amino-3- ((3s, 4s) -4- ((tert-butoxycarbonyl) amino) -3-methyl-2-oxa-8-azaspiro [ 4.5)]Decyl-8-yl) -6- (((2, 3-dichlorophenyl) sulfanyl) pyrazine-2-carboxylate (53 mg. (ES, m/z): 598.10[ M ] +H] ⁺ 。

Step g Synthesis of 5-amino-3- ((3S, 4S) -4- ((tert-butoxycarbonyl) amino) -3-methyl-2-oxa-8-azaspiro [4.5 ] methyl]To a solution of dec-8-yl) -6- (((2, 3-dichlorophenyl) sulfanyl) pyrazine-2-carboxylate (53 mg) in dichloromethane (5 ml) was added trifluoroacetic acid (1 ml) and reacted overnight at room temperature; concentrating the reaction solution under reduced pressure, adding EA (10 ml) and water (10 ml) into the residue, adjusting pH to 10 with 25% ammonia water, and separating; the aqueous phase was extracted with EA (5 ml) and the organic phases were combined; the organic phase was washed with water (10 ml), brine (10 ml), dried over anhydrous sodium sulfate and concentrated; the residue was purified by column Chromatography (CH) ₂ Cl ₂ ：CH ₃ OH =50]Decyl-8-yl) -6- ((2, 3-dichlorophenyl) sulfanyl) pyrazine-2-carboxylate (23 mg). (ES, m/z): 498.09[ 2M + H ]] ⁺ 。

Preparation example 24:

compound 24 was prepared using the following existing compound starting materials, with reference to the preparative route and procedure of preparation example 23:

preparation example 25: (R) -1- (5-amino-6- ((2-amino-3-chloropyridin-4-yl) sulfanyl) -3- (1-amino-8-azaspiro [4.5] decan-8-yl) pyrazin-2-yl) ethanone (Compound 25)

Step a) Synthesis of (R) -8- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) sulfanyl) pyrazin-2-yl) -8-azaspiro [4.5]Decan-1-amine (150mg, 0.370mmol) in dichloromethane (30 ml) was cooled to 0 deg.C and triethylamine (75mg, 0.740mmol) and (Boc) were added ₂ O (121mg, 0.555mmol), naturally raising the temperature to room temperature for reaction for 3h; after the TLC detection reaction is finished, adding water (15 ml) into the reaction solution, and standing for liquid separation; the aqueous phase was extracted with dichloromethane (2X 5 ml) and the organic phases combined; the organic phase was washed with brine (20 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure; to obtain (R) -tert-butyl (8- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) sulfanyl) pyrazin-2-yl) -8-azaspiro [4.5]The crude product of-decyl-1-carbamate is used directly in the next reaction (ES, m/z): 506.16[ M + H ], [ ] ⁺ 。

Step b: under the protection of nitrogen, (R) -tert-butyl (8- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) sulfanyl) pyrazin-2-yl) -8-azaspiro [4.5]Dichloromethane solution (50 ml) of crude-decyl-1-carbamate, cooling to-10 deg.C, adding NBS (72.4mg, 0.407mmol), keeping temperature for reaction for 30min, and detecting by TLC to complete the reaction; adding saturated aqueous sodium bicarbonate (20 ml) into the reaction solution, standing, and separating; the aqueous phase was extracted with dichloromethane (2X 5 ml) and the organic phases were combined; the organic phase was washed with brine (20 ml), dried over anhydrous sodium sulfate and concentrated; the residue was purified by column Chromatography (CH) ₂ Cl ₂ ：CH ₃ OH = 80) to give (R) -tert-butyl (8- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) sulfanyl) -3-bromopyrazin-2-yl) -8-azaspiro [4.5]Decyl-1-ylcarbamate (34 mg) ((ES, m/z): 583.99[ M + H ])] ⁺ 。

Step c: under the protection of nitrogen, (R) -tert-butyl (8- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) sulfanyl) -3-bromopyrazin-2-yl) -8-azaspiro [4.5]Decan-1-ylcarbamate (34mg, 0.058 mmol), tributyl (1-ethoxy)Vinyl) tin (32mg, 0.087mmol), sodium carbonate (12mg, 0.116mmol), pd (dppf) Cl ₂ (8mg, 0.0116mmol), 1, 4-dioxane (6 ml) and water (2 ml) react at 100 ℃ for 8h, and the TLC detection shows that the reaction is basically complete; cooling, adding EA (50 ml) and water (50 ml) into the reaction solution, and standing for liquid separation; the aqueous phase was extracted with EA (2X 10 ml) and the organic phases were combined; washing the organic phase with water (20 ml), brine (20 ml), drying with anhydrous sodium sulfate, and concentrating; the residue was purified by column Chromatography (CH) ₂ Cl ₂ ：CH ₃ OH =100, 1 to 80) to give (R) -tert-butyl (8- (3-acetyl-6-amino-5- ((2-amino-3-chloropyridin-4-yl) sulfanyl) pyrazin-2-yl) -8-azaspiro [4.5]Decyl-1-ylcarbamate (20 mg) (ES, m/z): 548.07[ m ] +H] ⁺ 。

Step d Synthesis of (R) -tert-butyl (8- (3-acetyl-6-amino-5- ((2-amino-3-chloropyridin-4-yl) sulfanyl) pyrazin-2-yl) -8-azaspiro [4.5]To a dichloromethane (5 ml) solution of dec-1-ylcarbamate (20 mg) was added trifluoroacetic acid (1 ml), and the mixture was stirred at room temperature for 3 hours; the reaction solution was concentrated under reduced pressure, EA (10 ml) and water (10 ml) were added to the residue, pH was adjusted to 10 with 25% aqueous ammonia, and liquid separation was performed; the aqueous phase was extracted with EA (5 ml) and the organic phases were combined; the organic phase was washed with water (10 ml), brine (10 ml), dried over anhydrous sodium sulfate and concentrated; the residue was purified by column Chromatography (CH) ₂ Cl ₂ ：CH ₃ OH = 150)]Decyl-8-yl) pyrazin-2-yl) ethanone (8 mg) (ES, m/z): 448.01[ 2M + H ]] ⁺ 。

Preparation examples 26 and 27:

compound 26 and compound 27 were prepared using the following existing compound starting materials, according to the preparative route and procedure of preparation example 25:

preparation example 28: (S) -1- (5-amino-3- (1-amino-1, 3-dihydrospiro [ indene-2, 4 '-piperidine ] -1' -yl) -6- ((2-amino-3-chloropyridin-4-yl) sulfanyl) pyrazin-2-yl) ethanone

Step a: mixing (S) -1'- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) sulfanyl) pyrazin-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine]A solution of-1-amine (92mg, 0.203mmol) in dichloromethane (10 ml) was cooled to 0 ℃ and triethylamine (82mg, 0.812mmol) and (Boc) were added ₂ O (87mg, 0.406mmol) and naturally raised to room temperature for reaction for 4h; after TLC detection reaction, adding water (10 ml) into the reaction solution, standing and separating; the aqueous phase was extracted with dichloromethane (2X 5 ml) and the organic phases were combined; the organic phase was washed with brine (10 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure; to obtain (S) -tert-butyl (1 '- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) sulfanyl) pyrazin-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine)]Crude-1-yl) carbamate, which is used without purification in the next reaction (ES, m/z): 554.13[ 2 [ M ] +H] ⁺ 。

Step b: under the protection of nitrogen, (S) -tert-butyl (1 '- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) sulfanyl) pyrazin-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine)]Cooling dichloromethane solution (10 ml) of the crude-1-yl) carbamate to-10 ℃, adding NBS (43.4mg, 0.244mmol), preserving heat for reaction for 30min, and detecting the reaction by TLC; adding saturated aqueous sodium bicarbonate (10 ml) into the reaction solution, standing and separating; the aqueous phase was extracted with dichloromethane (2X 5 ml) and the organic phases combined; the organic phase was washed with brine (10 ml), dried over anhydrous sodium sulfate and concentrated; the residue was purified by column Chromatography (CH) ₂ Cl ₂ ：CH ₃ OH = 100) to give (S) -tert-butyl (1 '- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) sulfanyl) -3-bromopyrazin-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine)]-1-yl) carbamate (53 mg., (ES, m/z): 632.02,633.99, M + H] ⁺ 。

Step c: under the protection of nitrogen, (S) -tert-butyl (1 '- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) sulfanyl) -3-bromopyrazin-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine)]-1-yl) carbamate (53 m)g,0.085 mmol), tributyl (1-ethoxyvinyl) tin (46mg, 0.128mmol), sodium carbonate (18mg, 0.17mmol), pd (dppf) Cl ₂ (12mg, 0.017mmol), 1, 4-dioxane (10 ml) and water (2 ml) were reacted at 100 ℃ for 6h, and the reaction was detected by TLC to be essentially complete; cooling, adding EA (50 ml) and water (50 ml) into the reaction solution, and standing for liquid separation; the aqueous phase was extracted with EA (2X 10 ml) and the organic phases were combined; the organic phase was washed with water (20 ml), brine (20 ml), dried over anhydrous sodium sulfate and concentrated; the residue was purified by column Chromatography (CH) ₂ Cl ₂ ：CH ₃ OH =100, 1) to give (S) -tert-butyl (1 '- (3-acetyl-6-amino-5- ((2-amino-3-chloropyridin-4-yl) sulfanyl) pyrazin-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine)]-1-yl) carbamate (12 mg) ((ES, m/z): 596.07[ 2 ] M + H] ⁺ 。

Step d Synthesis of (S) -tert-butyl (1 '- (3-acetyl-6-amino-5- ((2-amino-3-chloropyridin-4-yl) sulfanyl) pyrazin-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine ]To a solution of the (12 mg) -1-yl) carbamate in dichloromethane (5 ml) was added trifluoroacetic acid (1 ml), and the mixture was stirred at room temperature for 2 hours; the reaction solution was concentrated under reduced pressure, EA (20 ml) and water (10 ml) were added to the residue, pH was adjusted to 10 with 25% aqueous ammonia, and liquid separation was performed; the aqueous phase was extracted with EA (5 ml) and the organic phases were combined; the organic phase was washed with water (10 ml), brine (10 ml), dried over anhydrous sodium sulfate and concentrated; the residue was purified by column Chromatography (CH) ₂ Cl ₂ ：CH ₃ OH = 200) to give (S) -1- (5-amino-3- (1-amino-1, 3-dihydrospiro [ indene-2, 4' -piperidine)]-1' -yl) -6- ((2-amino-3-chloropyridin-4-yl) sulfanyl) pyrazin-2-yl) ethanone (6.5 mg) ((ES, m/z): 495.97[ M ] +H +] ⁺ 。

¹ H NMR(600MHz,DMSO-d6)δ7.697(d,J＝4.8Hz,1H),7.327(d,J＝4.8Hz,1H),7.208-7.174(m,3H),7.026(br,s,2H),6.322(s,3H),5.882(d,J＝4.2Hz,1H),3.871-3.785(m,3H),3.199-3.126(m,3H),3.082-3.056(m,2H),2.664-2.638(m,1H),2.380(s,3H),1.856-1.820(m,1H),1.760-1.725(m,1H),1.509-1.488(m,1H),1.148-1.125(m,1H)。

Preparation example 29: (S) -5-amino-3- (1-amino-1, 3-dihydrospiro [ indene-2, 4 '-piperidine ] -1' -yl) -6- ((2-amino-3-chloropyridin-4-yl) sulfanyl) pyrazine-2-carbaldehyde (Compound 29)

Step a: under the protection of nitrogen, methyl 5-amino-3- [ (3S) -3-amino-1, 3-dihydrospiro [ indene-2, 4-piperidine]-1-yl]-6- [ (2-amino-3-chloropyridin-4-yl)]Sulfanyl radical]The solution of pyrazine-2-carboxylate (50mg, 0.098mmol) in THF (10 ml) was cooled to 0 ℃ and LiBH was added ₄ (4.3mg, 0.196mmol), naturally heating, reacting at room temperature overnight, and detecting by TLC to complete the reaction; cooling to below 5 deg.C, quenching with saturated ammonium chloride solution (1 ml), concentrating under reduced pressure, and purifying the residue by column Chromatography (CH) ₂ Cl ₂ ：CH ₃ OH =50, 1) to give (S) - (5-amino-3- (1-amino-1, 3-dihydrospiro [ indene-2, 4' -piperidine)]-1' -yl) -6- (((2-amino-3-chloropyridin-4-yl) sulfanyl) pyrazin-2-yl) methanol (32 mg) ((ES, m/z): 483.97[ M ] +H +] ⁺ 。

Step b: mixing (S) - (5-amino-3- (1-amino-1, 3-dihydrospiro [ indene-2, 4' -piperidine)]A dichloromethane (5 ml) solution of (1' -yl) -6- (((2-amino-3-chloropyridin-4-yl) sulfanyl) pyrazin-2-yl) methanol (32mg, 0.066 mmol) is cooled to 0 ℃, dess-martin oxidant (56.2mg, 0.132mmol) is added, the temperature is naturally raised, the reaction is carried out overnight at room temperature, and the TLC detection reaction is complete; adding saturated sodium bicarbonate solution (1 ml) into the reaction solution, and stirring for 30min; adding water (5 ml), separating; concentrating the organic phase under reduced pressure, and purifying the residue by column Chromatography (CH) ₂ Cl ₂ ：CH ₃ OH =100, 1) to give (S) -5-amino-3- (1-amino-1, 3-dihydrospiro [ indene-2, 4' -piperidine]-1' -yl) -6- ((2-amino-3-chloropyridin-4-yl) sulfanyl) pyrazine-2-carbaldehyde (12 mg) ((ES, m/z): 482.07[ 2 ], [ M + H ])] ⁺ 。

Preparation example 30: methyl 5-amino-3- ((3s, 4s) -4-amino-3-methyl-2-oxa-8-aza-spiro [4.5] decan-8-yl) -6- ((2-chloro-3- (oxazol-2-yl) phenyl) sulfanyl) pyrazine-2-carboxylate (compound 30)

Step a: methyl 5-amino-6-bromo-3- ((3S, 4S) -4- ((tert-butoxycarbonyl) amino) -3-methyl-2-oxa-8-azaspiro [4.5] under nitrogen protection ]Dec-8-yl) pyrazine-2-carboxylic acid ester (272.00mg, 0.545mmol, 1.0eqv), 2-chloro-3- (oxazol-2-yl) benzenethiol (138mg, 0.654mmol, 1.2eqv), DIPEA (246mg, 1.908mmol, 3.5eqv), pd ₂ (dba) ₃ (100mg, 0.109mmol, 0.2eqv) and Xantphos (126mg, 0.218mmol, 0.4eqv) in 1, 4-dioxane (20 mL) at 96 ℃ for 5h; the reaction mixture was cooled to room temperature, silica gel was added to the reaction mixture, and the mixture was purified by silica gel column chromatography (eluent: n-hexane: EA =5: 1) to obtain methyl 5-amino-3- ((3s, 4s) -4- ((tert-butoxycarbonyl) amino) -3-methyl-2-oxa-8-azaspiro [4.5]Decan-8-yl) -6- (((2-chloro-3- (oxazol-2-yl) phenyl) thio) pyrazine-2-carboxylate (258mg, 75.1%); (ES, m/z): 631.25[ m ] +H] ⁺ 。

Step b Synthesis of 5-amino-3- ((3S, 4S) -4- ((tert-butoxycarbonyl) amino) -3-methyl-2-oxa-8-azaspiro [4.5 ] methyl]Adding trifluoroacetic acid (5 ml) into dichloromethane (10 ml) solution of decyl-8-yl) -6- (((2-chloro-3- (oxazol-2-yl) phenyl) thio) pyrazine-2-carboxylate (258 mg), and stirring at room temperature for 2h; the reaction solution was concentrated under reduced pressure, EA (20 ml) and water (10 ml) were added to the residue, pH was adjusted to 10 with 25% aqueous ammonia, and liquid separation was performed; the aqueous phase was extracted with EA (5 ml) and the organic phases were combined; the organic phase was washed with water (10 ml), brine (10 ml), dried over anhydrous sodium sulfate and concentrated; the residue was purified by column Chromatography (CH) ₂ Cl ₂ ：CH ₃ OH =20, 1) to give methyl 5-amino-3- ((3s, 4s) -4-amino-3-methyl-2-oxa-8-aza-spiro [4.5]Decyl-8-yl) -6- ((2-chloro-3- (oxazol-2-yl) phenyl) sulfanyl) pyrazine-2-carboxylate (170mg, 78.34%) (ES, m/z): 531.12[ M ] +H] ⁺ 。

¹ H NMR(600MHz,DMSO-d6)δ8.336(s,1H),7.705(d,J＝7.8Hz,1H),7.477(s,1H),7.389–7.363(m,1H),6.924(s,2H),6.805(d,J＝7.8Hz,1H),4.068-4.049(m,1H),3.742(s,3H),3.659(d,J＝8.4Hz,1H),3.588-3.539(m,3H),3.490-3.476(d,J＝8.4Hz,1H),3.318-3.269(m,1H),3.210-3.194(m,1H),2.914-2.907(m,1H),1.807-1.775(m,1H),1.684-1.652(m,1H),1.553-1.533(m,1H),1.488-1.467(m,1H),1.413(brs,1H),1.087-1.076(d,J＝6.6Hz,3H)。

Referring to the preparative route and procedure of preparation example 30, compounds 31-33 were synthesized using the following intermediates as starting materials:

preparation example 34: (S) -methyl 5-amino-3- (1-amino-1, 3-dihydrospiro [ indene-2, 4 '-piperidine ] -1' -yl) -6- ((2, 3-dichlorophenyl) sulfanyl) pyrazine-2-carboxylic acid ester (Compound 34)

Step a, under the protection of nitrogen, adding (S) -methyl 5-amino-6-bromo-3- (1- ((tert-butyloxycarbonyl) amino) -1, 3-dihydrospiro [ indene-2, 4' -piperidine]-1' -yl) pyrazine-2-carboxylic acid ester (100mg, 0.188mmol, 1.00eq), 2, 3-dichlorobenzenethiol (51mg, 0.282mmol, 1.5eq), DIEA (85mg, 0.658mmol, 3.50eq), pd ₂ (dba) ₃ (14mg, 0.015mmol, 0.08eq) and Xantphos (17mg, 0.030mmol, 0.16eq) in 1, 4-dioxane (4.00 mL) at 90 ℃ for 8h; concentrating under reduced pressure, adding water (10 mL) into the residue, extracting with EA (3X 5 mL), and combining the organic phases; the organic phase was washed with water (3X 5 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure; purification by elution was performed by silica gel column chromatography using n-hexane as eluent, EA =5, 1, gradually increased to 3, 1, and the product was collected and concentrated to dryness to give (S) -methyl 5-amino-3- (1- (((tert-butoxycarbonyl) amino) -1, 3-dihydrospiro [ indene-2, 4' -piperidine) ]-1' -yl) -6- (((2, 3-dichlorophenyl) sulfanyl) pyrazine-2-carboxylic acid ester (76mg, 64%). (ES, m/z): 630.15[ M ] +H] ⁺ 。

Step b to (S) -methyl-5-amino-3- (1- (((tert-butoxycarbonyl) amino) -1, 3-dihydrospiro [ indene-2, 4' -piperidine)](2, 3-dichlorophenyl) sulfanyl) pyrazine-2-carboxylate (76mg, 0.121mmol, 1.00eq) in DCM (5 mL) was added CF ₃ COOH (2 mL) and reacting at room temperature for 1h; concentrating under reduced pressure, adding water (10 mL) into the concentrate, mixing, adjusting pH to 9-10 with ammonia water, extracting with EA (20 mL × 2), and extracting with H ₂ O (20 mL), brine wash (20 mL) combined organic phases, dry over anhydrous sodium sulfate, filter, concentrate filtrate under reduced pressure, purify the residue by silica gel column chromatography with DCM: meOH =50, 1, gradually increasing to 15 to give (S) -methyl 5-amino-3- (1-amino-1, 3-dihydrospiro [ indene-2, 4' -piperidine]-1' -yl) -6- ((2, 3-dichlorophenyl) sulfanyl) pyrazine-2-carboxylic acid ester (44mg, 69%). (ES, m/z): 530.10[ M ] +H] ⁺ 。

Referring to the preparative route and procedure of preparation example 34, compounds 35-38 were synthesized using the following intermediates as starting materials:

preparation example 39: (S) -methyl 6- ((1-acetyl-3, 3-difluoroindol-4-yl) sulfanyl) -5-amino-3- (1-amino-1, 3-dihydrospiro [ indene-2, 4 '-piperidine ] -1' -yl) pyrazine-2-carboxylic acid ester (Compound 39)

Step a: to (S) -methyl-5-amino-3- (1- (((tert-butoxycarbonyl) amino) -1, 3-dihydrospiro [ indene-2, 4' -piperidine)]To a reaction solution of (e) -1' -yl) -6-mercaptopyrazine-2-carboxylate (88mg, 0.181mmol, 1.0eq) in 1, 4-dioxane (8 mL) was added 1- (3, 3-difluoro-4-iodoindol-1-yl) ethanone (66mg, 0.200mmol, 1.1eq) and Pd ₂ (dba) ₃ (33mg，0.036mmol，0.2eq)、Xantphos(42mg，0.072mmol，0.4eq)、DIEA(82mg,0.634mmol, 3.5eq), nitrogen protection, and stirring reaction at 97 ℃ for 5h. The reaction mixture was concentrated to dryness, water (30 mL) was added to the concentrate, and the mixture was extracted with EA (20 mL. Times.2), and H ₂ The combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with n-hexane EA =5 to 1, gradually increasing to 2 to give (S) -methyl 6- (((1-acetyl-3, 3-difluoroindol-4-yl) sulfanyl) -5-amino-3- (1- (((tert-butoxycarbonyl) amino) -1, 3-dihydrospiro [ indene-2, 4' -piperidine)]-1' -yl) pyrazine-2-carboxylate as a foamy solid (100mg, 81%), (ES, m/z): 681.21[ M + H ]] ⁺ 。

Step b: to the reaction mixture containing (S) -methyl 6- (((1-acetyl-3, 3-difluoroindol-4-yl) sulfanyl) -5-amino-3- (1- (((tert-butoxycarbonyl) amino) -1, 3-dihydrospiro [ indene-2, 4' -piperidine)]To a solution of (100mg, 0.147mmol,1.0 eq) of (1001' -yl) pyrazine-2-carboxylic acid ester in DCM (5 mL) was added CF ₃ COOH (5 mL), after stirring at room temperature for 2H, the reaction was spin-dried, water (30 mL) was added to the concentrate, the pH was adjusted to 9-10 with ammonia, EA (20 mL. Times.2) was used for extraction, and H was added ₂ The combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel with DCM: meOH =100, eluent gradually increasing to 50 to give (S) -methyl 6- ((1-acetyl-3, 3-difluoroindol-4-yl) sulfanyl) -5-amino-3- (1-amino-1, 3-dihydrospiro [ indene-2, 4' -piperidine]-1' -yl) pyrazine-2-carboxylate (50mg, 59%) (ES, m/z) 581.22[ m + H ],] ⁺ 。

referring to the preparative route and procedure of preparation example 39, compounds 40-43 were synthesized using the following intermediates as starting materials:

preparation example 44: (S) -1- (5-amino-3- (1-amino-1, 3-dihydrospiro [ indene-2, 4 '-piperidine ] -1' -yl) -6- ((2-chloro-3- (oxazol-2-yl) phenyl) sulfanyl) pyrazin-2-yl) ethanone (Compound 44)

Step a: under the protection of nitrogen, (S) -tert-butyl (1 '- (3-acetyl-6-amino-5-bromopyrazin-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine)]-1-yl) carbamate (520mg, 1.009mmol, 1.0eqv), 2-chloro-3- (oxazol-2-yl) benzenethiol (256mg, 1.211mmol, 1.2eqv), DIPEA (456mg, 3.532mmol, 3.5eqv), pd ₂ (dba) ₃ (185mg, 0.202mmol, 0.2eqv) and Xantphos (234mg, 0.404mmol, 0.4eqv) in 1, 4-dioxane (20 mL) at 96 ℃ for 5h; cooling to room temperature, adding silica gel to the reaction solution, and purifying by silica gel column chromatography (eluent: n-hexane: EA =20:1 to 2]Pyrazin-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine]-1-yl) carbamate (565mg, 87%); (ES, m/z): 647.26[ m ] +H] ⁺ 。

Step b Synthesis of (S) -tert-butyl (1' - (3-acetyl-6-amino-5- ((2-chloro-3- (oxazol-2-yl) phenyl) sulfanyl)]Pyrazin-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine]-1-yl) carbamate (565 mg) in dichloromethane (20 ml), trifluoroacetic acid (5 ml) was added and stirred at room temperature for 3 hours; the reaction solution was concentrated under reduced pressure, EA (100 ml) and water (50 ml) were added to the residue, pH was adjusted to 10 with 25% aqueous ammonia, and liquid separation was performed; the aqueous phase was extracted with EA (20 ml) and the organic phases were combined; the organic phase was washed with water (50 ml), brine (50 ml), dried over anhydrous sodium sulfate and concentrated; the residue was purified by column Chromatography (CH) ₂ Cl ₂ ：CH ₃ OH =20, 1) to give (S) -1- (5-amino-3- (1-amino-1, 3-dihydrospiro [ indene-2, 4' -piperidine)]-1' -yl) -6- ((2-chloro-3- (oxazol-2-yl) phenyl) sulfanyl) pyrazin-2-yl) ethanone (446 mg, 93.4%) (ES, m/z): 547.14[ m ] +H ] ⁺ 。

¹ H NMR(600MHz,DMSO-d6)δ8.333(s,1H),7.740(d,J＝7.2Hz,1H),7.475(s,1H),7.426–7.400(m,1H),7.305(d,J＝6.6Hz,1H),7.189-7.131(m,3H),7.039-7.025(m，3H)，3.844-3.767(m,3H),3.181-3.108(m,2H),3.064-3.038(m,1H),2.638-2.612(m,1H),2.313(s,3H),1.849-1.814(m,3H),1.755-1.713(m,2H),1.494-1.473(m,1H),1.122-1.100(m,1H)。

Preparation example 45: (S) -1- (5-amino-3- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ] pyridine-6, 4 '-piperidin ] -1' -yl) -6- ((2-chloro-3- (oxazol-2-yl) phenyl) sulfanyl) pyrazin-2-yl) ethanone (Compound 45)

Step a: under the protection of nitrogen, (S) -tert-butyl (1' - (3-acetyl-6-amino-5-bromopyrazin-2-yl) -5, 7-dihydrospiro [ cyclopentyl [ b ]]Pyridine-6, 4' -piperidines]-5-yl) carbamate (140mg, 0.27mmol, 1.0eqv), 2-chloro-3- (oxazol-2-yl) benzenethiol (69mg, 0.325mmol, 1.2eqv), DIPEA (123mg, 0.954mmol, 3.5eqv), pd ₂ (dba) ₃ (50mg, 0.054mmol, 0.2eqv) and Xantphos (63mg, 0.109mmol, 0.4eqv) in 1, 4-dioxane (10 mL) at 96 ℃ for 4h; cooling to room temperature, adding silica gel to the reaction solution, and purifying by silica gel column chromatography (eluent is n-hexane: EA =20:1 to 2)]Pyrazin-2-yl) -5, 7-dihydrospiro [ cyclopenta [ b ] s]Pyridine-6, 4' -piperidines]-5-yl) carbamate (152mg, 87%); (ES, m/z): 648.14[ M ] +H] ⁺ 。

Step b to (S) -tert-butyl (1' - (3-acetyl-6-amino-5- ((2-chloro-3- (oxazol-2-yl) phenyl) sulfanyl)]Pyrazin-2-yl) -5, 7-dihydrospiro [ cyclopenta [ b ] s]Pyridine-6, 4' -piperidines]-5-yl) carbamate (152 mg) in dichloromethane (20 ml), trifluoroacetic acid (5 ml) was added and stirred at room temperature for 3h; concentrating the reaction solution under reduced pressure, adding EA (100 ml) and water (50 ml) to the residue, adjusting pH to 10 with 25% ammonia water, and separating; the aqueous phase was extracted with EA (20 ml) and the organic phases were combined; is provided with The organic phase was washed with water (50 ml), brine (50 ml), dried over anhydrous sodium sulfate and concentrated; the residue was purified by column Chromatography (CH) ₂ Cl ₂ ：CH ₃ OH =20, 1) to give (S) -1- (5-amino-3- (5-amino-5, 7-dihydrospiro [ cyclopenta [ b ]]Pyridine-6, 4' -piperidines]-1' -yl) -6- ((2-chloro-3- (oxazol-2-yl) phenyl) sulfanyl) pyrazin-2-yl) ethanone (120mg, 93.4%) (ES, m/z): 548.14[ M + H ], (M + H)] ⁺ 。

1H NMR(600MHz,DMSO-d6)δ8.332-8.310(m,2H),7.747(d,J＝7.8Hz,1H),7.662(d,J＝7.2Hz,1H),7.477(s,1H),7.433–7.407(m,1H),7.176–7.156(m,1H),7.050(d,J＝7.8Hz,3H),3.909(s,1H),3.854-3.779(m,2H),3.198-3.134(m,2H),3.098-3.071(m,1H),2.761-2.734(m,1H),2.320(s,3H),2.042(br s,2H),1.866-1.764(m,2H),1.526-1.504(m,1H),1.165-1.143(m,1H)。

Referring to the preparative route and procedure of preparation example 45, compounds 46-48 were synthesized using the following intermediates as starting materials:

preparation example 49: (3S, 4S) -8- (6-amino-5- ((2-chloro-3- (oxazol-2-yl) phenyl) sulfanyl) -3-fluoropyrazin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] dec-4-amine (Compound 49)

Step a: under the protection of nitrogen, 3-bromo-6-chloro-pyrazin-2-amine (500mg, 2.399mmol,1.00eq v), 2-chloro-3- (oxazol-2-yl) benzenethiol (607mg, 2.878mmol,1.2eq v), DIEA (930mg, 7.196mmol,3.0eq v), pd ₂ (dba) ₃ (4399mg, 0.48mmol and 0.4eqv) and XantPhos (555mg, 0.96mmol and 0.4eqv) in a 1, 4-dioxane (20 mL) solution, reacting at 96 ℃ for 8 hours, cooling to room temperature, filtering the reaction solution by suction through kieselguhr, and concentrating the filtrate under reduced pressure; the residue was purified by column chromatography (n-hexane: EA =20:1 to 2)(oxazol-2-yl) phenyl) sulfanyl ]Pyrazin-2-amine (639mg, 78.9%). (ES, m/z): 338.91[ m ] +H] ⁺ 。

Step b: under the protection of nitrogen, 6-chloro-3- ((2-chloro-3- (oxazole-2-yl) phenyl) sulfanyl]Pyrazin-2-amine (639mg, 1.89mmol, 1eqv), (3S, 4S) -3-methyl-2-oxa-8-azaspiro [4.5 ]]Deca-4-amine dihydrochloride (506mg, 2.08mmol,1.1eq v), DIPEA (977mg, 7.56mmol,4eq v) in DMSO (9 ml) was reacted at 120 ℃ for 48h; cooled to room temperature and added (Boc) ₂ O(454mg，2.08mmol，1.1eqv)、Et ₃ N (765mg, 7.56mmol, 4eqv) and reacted at room temperature overnight; EA (100 ml) and brine (50 ml) were added to the reaction solution, and the mixture was separated; the aqueous phase was extracted with EA (20 ml) and the organic phases were combined; the organic phase was washed with brine (20 ml), dried over anhydrous sodium sulfate and concentrated; the residue was purified by column Chromatography (CH) ₂ Cl ₂ ：CH ₃ OH =20, 1 to 15), to give tert-butyl ((3s, 4s) -8- (6-amino-5- ((2-chloro-3- (oxazol-2-yl) phenyl) sulfanyl)]Pyrazin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5]Decyl-4-yl) carbamate (865mg, 80%)

Step c: under nitrogen protection, tert-butyl ((3S, 4S) -8- (6-amino-5- ((2-chloro-3- (oxazol-2-yl) phenyl) sulfanyl)]Pyrazin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5]Decyl-4-yl) carbamate (865 mg, 1.512mmol,1.0 eq), selective fluorine reagent (643mg, 1.81mmol,1.2 eq), silver carbonate (42mg, 0.151mmol,0.1 eq) in acetonitrile (20 mL), refluxing overnight reaction, LC-MS detecting reaction completion; filtering the reaction solution, concentrating under reduced pressure, and purifying the residue by column Chromatography (CH) ₂ Cl ₂ ：CH ₃ OH =80, 1 to 30)]Decyl-4-yl) carbamate (501mg, 56.2%), (ES, m/z): 591.09[ deg. ], M + H] ⁺ 。

Step d to tert-butyl ((3S, 4S) -8- (6-amino-5- ((2-chloro-3- (oxazol-2-yl) phenyl) sulfanyl) -3-fluoropyrazin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5]To a solution of decan-4-yl) carbamate (501 mg) in dichloromethane (10 ml) was added trifluoroethyl etherAcid (5 ml), stir at room temperature for 2h; the reaction solution was concentrated under reduced pressure, EA (20 ml) and water (10 ml) were added to the residue, pH was adjusted to 10 with 25% aqueous ammonia, and liquid separation was performed; the aqueous phase was extracted with EA (5 ml) and the organic phases were combined; the organic phase was washed with water (10 ml), brine (10 ml), dried over anhydrous sodium sulfate and concentrated; the residue was purified by Prep-HPLC (gradient elution of 5-25% acetonitrile in water, 0.05% ₄ HCO ₃ Modification) to obtain (3S, 4S) -8- (6-amino-5- ((2-chloro-3- (oxazole-2-yl) phenyl) sulfanyl) -3-fluoropyrazine-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5]Decyl-4-amine (198mg, 47.6%), (ES, m/z): 491.09[ m ] +H] ⁺ 。

Referring to the preparative route and procedure of preparation 49, compound 50 was synthesized using the following intermediate as starting material:

Preparation example 51: (3S, 4S) -8- (6-amino-3-chloro-5- ((2-chloro-3- (oxazol-2-yl) phenyl) sulfanyl) pyrazin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine (Compound 51)

Step a to step b: the procedure was as in Steps a-b of preparation 49.

Step c tert-butyl ((3S, 4S) -8- (6-amino-5- ((2-chloro-3- (oxazol-2-yl) phenyl) sulfanyl) under nitrogen protection]Pyrazin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5]Dec-4-yl) carbamate (300mg, 0.524mmol, 1.0eq) in CH ₂ Cl ₂ Cooling to-15 deg.C (20 mL), adding NCS (77mg, 0.577mmol, 1.1eqv), reacting at 0 deg.C for 1h, and detecting by LC-MS to complete reaction; adding NaHCO into the reaction liquid ₃ Stirring the solution (10 ml) for 20min, standing overnight, and separating; concentrating the organic phase under reduced pressure, and purifying the residue by column Chromatography (CH) ₂ Cl ₂ ：CH ₃ OH =50]Decyl-4-yl) carbamate (135mg, 47.8%), (ES, m/z): 607.09[ m + H ], (] ⁺ 。

Step d to tert-butyl ((3S, 4S) -8- (6-amino-3-chloro-5- ((2-chloro-3- (oxazol-2-yl) phenyl) sulfanyl) pyrazin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5 ]To a solution of decan-4-yl) carbamate (135 mg) in dichloromethane (20 ml) was added trifluoroacetic acid (5 ml), and the mixture was stirred at room temperature for 2.5 hours; the reaction solution was concentrated under reduced pressure, EA (20 ml) and water (10 ml) were added to the residue, pH was adjusted to 10 with 25% aqueous ammonia, and liquid separation was performed; the aqueous phase was extracted with EA (5 ml) and the organic phases were combined; the organic phase was washed with water (10 ml), brine (10 ml), dried over anhydrous sodium sulfate and concentrated; the residue was purified by Prep-HPLC (gradient elution from 10-30% acetonitrile in water, 0.05% ₄ HCO ₃ Modification) to obtain (3S, 4S) -8- (6-amino-3-chloro-5- ((2-chloro-3- (oxazole-2-yl) phenyl) sulfanyl) pyrazine-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5]Decyl-4-amine (70mg, 62%), (ES, m/z): 507.10[ 2 ] M + H] ⁺ 。

Preparation example 52: n- (3- ((3-amino-5- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -6-cyanopyrazin-2-yl) sulfanyl) -2-chlorophenyl) -2-hydroxy-4-oxo-6, 7,8, 9-tetrahydro-4H-pyrido [1,2-a ] pyrimidine-3-carboxamide (Compound 52)

(3S, 4S) -3-methyl-2-oxa-8-azaspiro [4.5]]Decyl-4-amine dihydrochloride (122mg, 0.716mmol, 1.2eq) and N- (3- ((3-amino-5-chloro-6-cyanopyrazin-2-yl) sulfanyl) -2-chlorophenyl) -2-hydroxy-4-oxo-6, 7,8, 9-tetrahydro-4H-pyrido [1,2-a ] ]Pyrimidine-3-carboxamide (300mg, 0.596mmol, 1.0eq), DIEA (463mg, 3.58mmol, 5eq) in DMSO (5 ml) was reacted at 100 ℃ for 48 hours under nitrogen protection. Cooling the reaction solution to room temperature, adding EA (50 ml) and water (50 ml), mixing and stirring, separating liquid, and adding waterThe phases were extracted with EA (30 mL. Times.2) and the combined organic phases were washed with brine (30 mL. Times.3), dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the residue purified by Prep-HPLC (gradient elution of 15-30% acetonitrile in water, 0.1% CF ₃ COOH) to obtain N- (3- ((3-amino-5- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Decan-8-yl) -6-cyanopyrazin-2-yl) sulfanyl) -2-chlorophenyl) -2-hydroxy-4-oxo-6,7, 8,9-tetrahydro-4H-pyrido [1,2-a ]]Pyrimidine-3-carboxamide (87 mg), (ES, m/z) 637.19[ 2 ], [ M + H ]] ⁺ 。

Compound 53 was synthesized following the preparative route and procedure of preparative example 52, using the following intermediates as starting materials:

preparation example 54: (S) -1- (5-amino-3- (1-amino-1, 3-dihydrospiro [ indene-2, 4 '-piperidin ] -1' -yl) -6- (2, 3-dichlorophenyl) pyrazin-2-yl) ethanone (Compound 54)

A, step a: with reference to the procedure of preparation 21, step c, (S) -tert-butyl (1 '- (3-acetyl-6-amino-5- (2, 3-dichlorophenyl) pyrazin-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine) was obtained ]-1-yl) carbamate, (ES, m/z): 582.10[ M ] +H] ⁺ 。

To (S) -tert-butyl (1 '- (3-acetyl-6-amino-5- (2, 3-dichlorophenyl) pyrazin-2-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine)]To a solution of the (E) -1-yl) carbamate (50 mg) in dichloromethane (5 ml) was added trifluoroacetic acid (2 ml), and the mixture was stirred at room temperature for 1 hour; concentrating the reaction solution under reduced pressure, adding EA (20 ml) and water (10 ml) to the residue, adjusting pH to 10 with 25% ammonia water, and separating; the aqueous phase was extracted with EA (10 ml) and the organic phases were combined; the organic phase was washed with water (10 ml), brine (5 ml), dried over anhydrous sodium sulfate and concentrated; the residue was purified by column Chromatography (CH) ₂ Cl ₂ ：CH ₃ OH =30, 1) to give (S) -1- (5-amino-3- (1-amino-1, 3-dihydrospiro [ indene-2, 4' -piperidine)]-1' -yl) -6- (2, 3-dichlorophenyl) pyrazin-2-yl) ethanone (30mg, 72.4%) (ES, m/z): 482.07[ 2 [ M + H ])] ⁺ 。

Referring to the preparative route and procedure of preparation 54, compounds 55-60 were synthesized using the following intermediates as starting materials:

preparation examples 61 to 63

Compounds 61-63 were prepared according to the preparative route, procedure and other applicable routes of preparation example 45, using the corresponding intermediates as starting materials.

Preparation examples 64 to 99

Compounds 64-99 were prepared by reference to the preparative route, procedures and other applicable routes of preparation examples 1-63, using the corresponding intermediates as starting materials.

Test example 1: test for the inhibitory Effect of the Compounds of the present application on SHP2 enzyme

1. Preparation of working buffer and preparation of Compound

Working buffer 1x kinase buffer was prepared. The reference compound and test compound were diluted with DMSO solvent to 10mM stock concentration. Test compounds were first diluted to an intermediate concentration of 1000. Mu.M and then diluted in DMSO in 3-fold steps. Thus, the intermediate gradient dilution concentrations of the test compound are: 1000 μ M, 3-fold dilution, 11 gradients; similarly, the intermediate gradient dilution concentrations for reference compound RMC-4550 were: 500 μ M,3 fold dilution, 11 gradients; these intermediate gradient dilution concentrations were transferred to 384 LDV echo plates each in 8. Mu.l; this 384 LDV echo plate was centrifuged at 2000rpm for 1min. Using an Echo550 instrument, 100nl of each concentration of compound in a 384 LDV Echo plate was transferred to a new 384 enzyme-linked plate (corning, cat # 4514) to ensure that the final concentration of test compound was 10. Mu.M, 3-fold dilution, 11 gradients, 2 replicate wells after 10. Mu.l of reagent was added. The final concentration of reference compound RMC-4550 was 5. Mu.M, 3-fold dilution, 11 gradients, 2 replicate wells. The final DMSO concentration was 1%. For both negative and positive control wells, 100nl of DMSO will be transferred.

Step of enzymatic reaction of SHP2

Configuration with 1X enzyme buffer: 2X working SHP2 reagent (0.4 nM) and 0.5. Mu.M SHP-2 activating peptide (BPS bioscience # 79319-2) in a mixed solution. After incubating the above mixture at 25 ℃ for 60 minutes, 5. Mu.l of the activated SHP2 kinase solution was transferred by pipette to the compound wells of the compound plate and Max control wells (Corning, # 4514). Then 5. Mu.l of 1 Xkinase buffer was transferred to Min control wells. Centrifuge at 1000rpm for 30 seconds. Plates were closed and incubated in a 25 ℃ incubator for 30 minutes. DiFMUP (# D6567, invitrogen) was prepared with 1 Xkinase reaction buffer ^TM ) The concentration of the substrate solution of (2 times the experimental final concentration) (final concentration of difmuup: 10 μ M). By means of electric movementThe liquid gun transferred 5. Mu.l of the prepared substrate solution to each well of the enzyme-linked plate to initiate the reaction. Centrifuge at 1000rpm for 30 seconds. Plates were closed and incubated in a 25 ℃ incubator for 60 minutes. The enzyme-linked plate was placed on a Spark machine and data were read at 358/455nm excitation/emission wavelength.

3. The calculation method and the detection result are as follows:

RLU values were replicated from Spark and used to calculate the inhibition = (max-sample RLU)/(max-min) × 100, "min" refers to RLU without enzyme control and "max" refers to RLU with DMSO control. Fitting the data in XLFit excel plug-in version 5.4.0.8 to obtain IC ₅₀ The values, results are shown in Table 1.

TABLE 1 test of the enzymatic Effect of the Compounds of the present application and Positive controls on SHP2

Preparation example No	Enzymology (IC 50 nM)	Preparation example No	Enzymology (IC 50 nM)
RMC4550	4.21	31	4.4
123	2.13	32	7.7

1	7.29	34	4.4
13	6.04	35	10
16	3.55	38	14
17	1.51	40	7.7
19	2.58	44	6.6
23	19	45	13
27	3.5	49	5.2
28	8.4	52	11
30	9	57	16

Note: the positive control drug RMC4550 was compound A-228 (example 228) of WO2018013597A 1; the positive control 123 was TW201840553A the compound prepared in example 2.

Test example 2: in vitro inhibition of human pancreatic cancer cell MIA-PACA-2 proliferation by the compounds of the present application

1. Test materials:

human pancreatic cancer cells MIA-PACA-2 were purchased from Bai Biotech, inc. of Nanjing Ke, and the complete medium for cell culture was DMEM (GIBCO Co.), supplemented with 10% fetal bovine serum (Minhai, lanzhou), and further supplemented with 2.5% horse serum (Hyclone Co.). Subjecting the cells to 5% CO at 37% ₂ Culturing in an incubator. The reagents used in the experiment include dimethyl sulfoxide (available from Mimeou Chemicals, inc., of Tianjin), MTT (Thiazol BLUE Tetrazollium Bromide, CAS. No.298-93-1, AMRESCO). The experimental control, RMC4550, was obtained either by-house or commercially. The test articles were stored sealed at 4 ℃.

2. Test methods and results:

using dimethyl sulfoxide as solvent to fully dissolve the tested substance to prepare the product with the concentration of 5 multiplied by 10 ^-2 Storing the solution at-20 ℃ in mol/L. Taking complete culture medium as diluent, and diluting the test substance in gradient to different concentrations for later use. In a 96-well plate, 100. Mu.L/well (3X 10) ³ Cell number/well) MIA-PACA-2 cells were cultured overnight in complete media suspension. Adding 100 μ L/well of test substances with different concentrations 24 hr after cell adherence, 8 concentrations per test substance, 3 duplicate wells per concentration, at 37 deg.C, 5% ₂ Culturing in an incubator. After the test substance had been exposed for 72 hours, 20. Mu.L/well of MTT was added, and the content of CO was 5% at 37 ℃ ₂ Culturing for 4 hours in an incubator, discarding supernatant, adding dimethyl sulfoxide 150 mu L/hole, shaking and mixing uniformly, and detecting OD value by using an enzyme-labeling instrument at the wavelength of 550 nm. Wells containing no test substance added with cell suspension alone are control wells, and wells containing complete medium only are blank wells. The inhibition rate of cell growth was calculated by the following formula:

inhibition rate = (control hole OD-test hole OD)/(control hole OD-blank hole OD) × 100%, and according to each concentration inhibition rate, the half inhibition concentration IC is calculated by SPSS software ₅₀ The values, results are shown in Table 2.

TABLE 2 test of cell growth inhibitory Effect of the Compounds of the present application and Positive control drugs

Note: the positive control drug RMC4550 was compound A-228 of WO2018013597A1 (example 228).

The data show that the compound of the invention shows good inhibitory activity in the pancreatic cancer MIA-PACA-2 cell proliferation inhibition test, which is superior to or equivalent to that of the positive compound.

Test example 3: in vitro inhibition of human acute myeloid leukemia cell MV-4-11 proliferation by the compounds of the present invention

1. Test materials:

the experimental human acute myelogenous leukemia cell MV-4-11 was purchased from Shanghai Life sciences research institute of Chinese academy of sciences, and the complete culture medium for cell culture was IMDM (GIBCO Co.), and was supplemented with 10% fetal bovine serum (GIBCO Co.). Cells at 37 ℃ C. 5% CO ₂ IncubatorAnd (5) culturing. Reagents used for the experiments included dimethylsulfoxide (available from Kemi Euro Chemicals, inc., tianjin), MTT (Shanghai Teber Chemicals, inc., CAS. No. 298-93-1). The test control TNO155 was obtained by either home-made or commercial purchase. The test articles were stored sealed at 4 ℃.

2. Test methods and results:

using dimethyl sulfoxide as solvent to fully dissolve the tested substance to prepare the compound with the concentration of 5 multiplied by 10 ^-2 Storing the storage solution at-20 ℃ by mol/L. The complete culture medium is used as a diluent, and the test substance is diluted in a gradient way to different concentrations for standby. In a 96-well plate, 100. Mu.L/well (2X 10) ⁴ Cell number/well) MV-4-11 cell complete medium suspension, adding 100. Mu.L/well of test substance at respective different concentrations, 8 concentrations per test substance, 3 duplicate wells per concentration, at 37 deg.C, 5% ₂ Culturing in an incubator. After the test substance has acted for 72 hours, adding MTT 20. Mu.L/well, at 37 ℃,5% ₂ Culturing for 4 hours in an incubator, removing supernatant, adding 150 mu L/hole of dimethyl sulfoxide, shaking and mixing uniformly, and detecting OD value by using an enzyme-labeling instrument at the wavelength of 550 nm. Wells containing no test substance added with cell suspension alone are control wells, and wells containing complete medium only are blank wells. The inhibition rate of cell growth was calculated by the following formula:

inhibition rate = (control well OD-test well OD)/(control well OD-blank well OD) × 100%, and half inhibition concentration IC was calculated according to each concentration inhibition rate by using SPSS software ₅₀ The values and results are shown in Table 2.

TABLE 3 test of cell proliferation inhibitory Effect of the Compound of the present invention and Positive control

Note: the positive control drug TNO155 is the compound in WO2015107495A1 (example 69); the positive control 123 was TW201840553A, a compound prepared in example 2.

The data show that the compounds of the invention all show good inhibitory activity in the cell proliferation inhibition test of human acute myeloid leukemia, and the compounds of the invention are superior to or equivalent to positive drugs.

Test example 4: pharmacokinetic testing of SD rats

1. The test method comprises the following steps:

SD rats are gavaged with 20mg/kg of compound, at different time points (0.25, 0.5, 1, 2, 4, 8, 24 h) after administration, blood is collected from the orbit of the rat, collected whole blood is anticoagulated by heparin sodium, 3000g of the collected whole blood is centrifuged to obtain a rat plasma sample, methanol protein is adopted for precipitation, the drug concentration in the plasma of the rat after administration is measured by an HPLC-MS/MS method, a drug-time curve is drawn, pharmacokinetic parameters are calculated, and the pharmacokinetic behavior of the compound in the body of the rat after administration is described by non-atrioventricular model statistical moment parameters.

2. And (3) test results:

the pharmacokinetic experiments on the compound of the invention show that the compound of the invention can be absorbed well in rats, and the results are shown in table 4.

TABLE 4 pharmacokinetic testing of SD rats with inventive Compounds and Positive control

The data show that the compound of the invention has higher exposure in rats, which is superior to or equivalent to the positive drug.

Test example 5: mouse pharmacokinetic testing

1. The test method comprises the following steps:

ICR mice are gavaged with 10mg/kg or 20mg/kg of compound, blood is collected from orbital wells of the mice at different time points (0.25 h, 0.5h, 1h, 2h, 4h, 8h and 24 h) after administration, the collected whole blood is anticoagulated by heparin sodium, 3000g of the blood is centrifugally separated to obtain mouse plasma samples, methanol protein is adopted for precipitation, the drug concentration in the plasma of the mice after administration is measured by an HPLC-MS/MS method, a drug-time curve is drawn, pharmacokinetic parameters are calculated, and pharmacokinetic behaviors in the mice after administration of the compound are described by non-compartmental model statistical moment parameters.

2. And (3) test results:

the pharmacokinetic experiments on the compound of the invention show that the compound of the invention is well absorbed in mice, as shown in table 5.

TABLE 5 mouse pharmacokinetic testing of Compounds of the invention and Positive controls

The data show that the compound has higher exposure in mice at 20mg/kg, and is superior to the positive control drug.

Test example 6: NCI-H358 in vivo efficacy assay

In vivo efficacy test:

in vivo efficacy test: SPF-grade 4-5 week-old, female NU/NU mice were tested and purchased from Peking Witongliwa laboratory animal technologies, inc. Mouse forelimb axilla subcutaneous inoculation of human non-small cell lung carcinoma cell NCI-H358 (1X 10) ⁶ One/0.1 ml/one), a subcutaneous transplantation tumor model was established. The tumor volume is up to about 200mm ³ At (day 5 after inoculation), mice were divided into groups of 6 mice each with a balanced tumor volume, vehicle control group and test drug group. The administration dose of the tested drug group is set to be 7.5-20mg/kg, the administration volume is 10mL/kg, the drug is administrated by intragastric administration once a day, the tumor diameter is measured for 2 times every week, and data are recorded. After 21 days of continuous administration, the test was terminated, and the tumor was removed and weighed.

Calculating the weight growth rate, the tumor volume and the tumor weight inhibition rate according to a formula,

Wherein W _i The weight, W, of a particular mouse in each experimental group on the nth day is shown ₀ Body weight at the time of starting administration for a certain mouse in each experimental group; tumor volume (V) =1/2 a b ² Wherein a and b represent the length and the length of the tumor respectively; tumor growth inhibition ratio TGI (%) = [1- (Ti-T0)/(Vi-V0)]X 100, where Ti represents the mean tumor volume of a given group on a given day; t0 is the mean tumor volume of the administration group at the beginning of administration; vi is the mean tumor volume of the vehicle control group on one day (same day as Ti); v0 is the mean tumor volume at the start of dosing in the vehicle control group.

TABLE 6 NCI-H358 in vivo test data for the compounds of the invention and positive controls

P <0.05, P <0.01, P <0.001, compared to vehicle control group

And (4) test conclusion: the compound can obviously inhibit the growth of tumors under the administration dosage of 7.5-20mg/kg, and has good tolerance and safety. Control compound 123 was poorly safe at 20mg/kg, poorly tolerated and all mice died at the end of the experiment. The compounds of the invention are therefore superior to the control compounds in both safety and tolerability.

Claims

A compound represented by formula (I) or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative or pharmaceutically acceptable salt thereof,

X is selected from a bond or-S-;

X ₁ and X ₂ Each independently selected from N and CR ₈ (ii) a Wherein each R ₈ Independently selected from-H, halogen, -NH ₂ 、-NHR _8b 、-NR _8b R _8c 、-NHCOR _8a 、-CN、-OH、-NO ₂ 、-COOH、-CONH ₂ 、-CONHR _8b 、-CONR _8b R _8c 、-COOR _8b Substituted or unsubstituted C _1～6 Alkyl, substituted or unsubstituted C _1～6 Alkoxy, substituted or unsubstituted C _3～6 Cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted mono spirocycloalkyl, substituted or unsubstituted hetero mono spirocycloalkyl, substituted or unsubstituted C _6～14 Aryl and substituted or unsubstituted 5-to 14-membered heteroaryl, wherein said substituted C _1～6 Alkyl, substituted C _1～6 Alkoxy, substituted C _3～6 Cycloalkyl, substituted 3-6 membered heterocycloalkyl, substituted mono spirocycloalkyl, substituted hetero mono spirocycloalkyl, substituted C _6～14 Aryl and substituted 5-to 14-membered heteroaryl are each independently selected from-OH, halogen, unsubstituted C _1-6 Alkyl, -NH ₂ 、-NO ₂ unsubstituted-COC _1-6 Alkyl, -CN and = O;

R _8a selected from the group consisting of:

R _8b and R _8c Each independently selected from unsubstituted C _1～6 An alkyl group;

R ₁ and R ₃ Each independently selected from-H, haloElement, -NH ₂ 、-CN、-OH、-NO ₂ -COOH, substituted or unsubstituted C _1～6 Alkyl and substituted or unsubstituted C _1～6 Alkoxy, wherein said substituted C _1～6 Alkyl and substituted C _1～6 Alkoxy is independently selected from-OH, halogen, unsubstituted C _1-6 Alkyl, -NH ₂ 、-NO ₂ unsubstituted-COC _1-6 Alkyl, -CN and = O;

R ₂ selected from-H, halogen, -NH ₂ 、-CN、-OH、-NO ₂ Carboxy, -NHR _2a 、-NR _2a R _2b 、-CONH ₂ 、-CONHR _2a 、-CONR _2a R _2b 、-COR _2a 、-COOR _2a 、-NHCOR _2a 、-N(R _2a )-COR _2b Substituted or unsubstituted C _1～6 Alkyl, substituted or unsubstituted C _1～6 Alkoxy, substituted or unsubstituted C _3～6 Cycloalkyl, substituted or unsubstituted 3-to 6-membered heterocycloalkyl, substituted or unsubstituted mono-spirocycloalkyl, substituted or unsubstituted hetero-mono-spirocycloalkyl, substituted or unsubstituted C _4～8 Bridged cycloalkyl and substituted or unsubstituted 4-8 membered heterobridged cycloalkyl, wherein said substituted C _1～6 Alkyl, substituted C _1～6 Alkoxy, substituted C _3～6 Cycloalkyl, substituted 3-to 6-membered heterocycloalkyl, substituted mono-spirocycloalkyl, substituted hetero-mono-spirocycloalkyl, substituted C _4～8 The bridged cycloalkyl group and the substituted 4-8 membered heterobridged cycloalkyl group are each independently selected from-OH, halogen, unsubstituted C _1-6 Alkyl, -NH ₂ 、-NO ₂ unsubstituted-COC _1-6 Alkyl, -CN and = O;

or R ₂ To adjacent R ₃ By ring closure to form substituted or unsubstituted C ₆ Or C ₁₀ Aryl, substituted or unsubstituted 5-to 8-membered heteroaryl or substituted or unsubstituted non-aromatic 5-to 8-membered heterocyclyl, wherein C is substituted ₆ Or C ₁₀ Aryl, substituted 5-to 8-membered heteroaryl or substituted non-aromatic 5-to 8-membered heterocyclyl are each independently selected from-OH, halogen, unsubstituted C _1-6 Alkyl, -NH ₂ 、-NO ₂ unsubstituted-COC _1-6 Alkyl, -CN, and = O;

R _2a and R _2b Each independently selected from unsubstituted C _1～6 An alkyl group;

R ₇ selected from halogen, -CN, -COOR _7a 、-COR _7b Substituted or unsubstituted C _2-6 Alkenyl, substituted or unsubstituted C _2-6 Alkynyl, -CONH ₂ 、-C(O)-COOR _7a Substituted or unsubstituted C _3～6 Cycloalkyl, substituted or unsubstituted C _2～6 Heterocycloalkyl, substituted or unsubstituted mono-spirocycloalkyl and substituted or unsubstituted hetero-mono-spirocycloalkyl; r is _7a is-H, substituted or unsubstituted C _1-6 Alkyl or substituted or unsubstituted C _3-6 A cycloalkyl group; r is _7b Selected from-H, substituted or unsubstituted C _1～6 Alkyl, substituted or unsubstituted C _3～6 Cycloalkyl, substituted or unsubstituted 3-to 6-membered heterocycloalkyl, substituted or unsubstituted C _6～14 Aryl and substituted or unsubstituted 5-to 10-membered heteroaryl; wherein, said substituted C _2-6 Alkenyl, substituted C _2-6 Alkynyl, substituted C _3～6 Cycloalkyl, substituted C _2～6 Heterocycloalkyl, substituted mono-spirocycloalkyl, substituted hetero-mono-spirocycloalkyl, substituted C _1-6 Alkyl, substituted 3-to 6-membered heterocycloalkyl, substituted C _6～14 Aryl radicalAnd substituted 5-to 10-membered heteroaryl are each independently selected from-OH, halogen, -NH ₂ 、-NO ₂ Unsubstituted C _1～6 Alkyl, unsubstituted C _1～6 Alkoxy, unsubstituted C _3～6 Cycloalkyl, unsubstituted-NH-C _1～6 Alkyl, unsubstituted-N (C) _1～6 Alkyl) (C _1～6 Alkyl), unsubstituted-NH-C _3～6 Cycloalkyl, unsubstituted-N (C) _3～6 Cycloalkyl) (C) _3～6 Cycloalkyl), unsubstituted 3-to 6-membered heterocycloalkyl, unsubstituted C _6～14 Aryl or unsubstituted 5-to 10-membered heteroaryl;

indicates the presence or absence of a bond;

i)
when no bond is present, X ₃ Nor is present, R ₄ And R ₅ Each independently selected from hydrogen, hydroxy, halogen, = O, substituted or unsubstituted C _1～6 Alkyl and substituted or unsubstituted C _1～6 Alkoxy radical, wherein R ₄ And R ₅ Each independently selected from "= O" means that another hydrogen atom at the same substitution position is simultaneously substituted by the oxygen atom, wherein the substituted C _1～6 Alkyl and substituted C _1～6 Alkoxy is independently selected from-OH, halogen, unsubstituted C _1-6 Alkyl, -NH ₂ 、-NO ₂ unsubstituted-COC _1-6 Alkyl, -CN, and = O;

ii)
when a bond is present, X ₃ Is CH ₂ ，R ₄ And R ₅ Are all hydrogen;

represents a single bond or a double bond;

i) When the temperature is higher than the set temperature
When represents a single bond, ring A and- (R) ₆ ) _m Absence, Y ₁ And Y ₂ Each independently is CR ₉ R ₁₀ O or NR ₁₀ ；

Each R ₉ And R ₁₀ Independently selected from-H, halogen, -OH, substituted or unsubstituted C _1～6 Alkyl and substituted or unsubstituted C _1～6 Alkoxy, wherein said substituted C _1～6 Alkyl and substituted C _1～6 Alkoxy is independently selected from OH, halogen, unsubstituted C _1-6 Alkyl, -NH ₂ 、-NO ₂ unsubstituted-COC _1-6 Alkyl, -CN, and = O;

ii) when
When representing a double bond, Y ₁ And Y ₂ Are both C, ring A is present, ring A is selected from naphthyl, phenyl or 5-to 6-membered heteroaryl;

R ₆ selected from halogen, -NH ₂ 、-NHR _6a 、-NR _6a R _6b 、-CN、-CONH ₂ 、-CONHR _6a 、-CONR _6a R _6b 、-COR _6a -COOH, -OH, substituted or unsubstituted-SO _n C _1-6 Alkyl, substituted or unsubstituted C _1-6 Alkyl and substituted or unsubstituted C _1～6 Alkoxy radical, wherein R _6a And R _6b Each independently of the other being unsubstituted C _1～6 An alkyl group; n is selected from 0, 1 or 2, wherein said substituted-SO _n C _1-6 Alkyl, substituted C _1-6 Alkyl and substituted C _1～6 Alkoxy is independently selected from-OH, halogen, unsubstituted C _1-6 Alkyl, -NH ₂ 、-NO ₂ unsubstituted-COC _1-6 Alkyl, -CN, and = O;

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

wherein the number of ring atoms of the mono-and hetero-spirocycloalkyl groups are independently selected from the group consisting of 3-membered/5-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, and 5-membered/6-membered rings, wherein the count for each ring includes a spiro atom; and

Substituent "= O" means that two hydrogen atoms at the same substitution position are substituted by oxygen atoms,

with the proviso that the compounds of formula (I) do not include the following compounds:
a compound of formula (I) or a pharmaceutically acceptable salt thereof,

x is selected from a bond or S;

X ₁ and X ₂ Each independently selected from N or CR ₈ (ii) a Wherein R is ₈ Selected from-H, halogen, -NH ₂ 、-NHR _8b 、-NR _8b R _8c 、-NHCOR _8a 、-CN、-OH、-NO ₂ 、-COOH、-CONH ₂ 、-CONHR _8b 、-CONR _8b R _8c 、-COOR _8b Substituted or unsubstituted C _1～6 Alkyl, substituted or unsubstituted C _1～6 Alkoxy, substituted or unsubstituted C _3～6 Cycloalkyl, substituted or unsubstituted heteromonospirocycloalkyl; the term "substituted" means that the substituents are independently selected from one or more of-OH, halogen, C _1-6 Alkyl, -NH ₂ 、-NO ₂ 、-COCH ₃ And, -CN and = O, the case where the substituent is "= O" means that two hydrogen atoms at the same substitution position are substituted by oxygen atoms;

wherein R is _8a Selected from:

R _8b and R _8c Each independently selected from C _1～6 An alkyl group;

R ₁ and R ₃ Each independently selected from-H, halogen, -NH ₂ 、-CN、-OH、-NO ₂ -COOH, substituted or unsubstituted C _1～6 Alkyl, substituted or unsubstituted C _1～6 An alkoxy group; the term "substituted" means that the substituents are independently selected from one or more of-OH, halogen, C _1-6 Alkyl, -NH ₂ 、-NO ₂ 、-COCH ₃ And, -CN and = O, substitutedThe case where the group is "= O" means that two hydrogen atoms at the same substitution position are substituted with an oxygen atom;

R ₂ Selected from-H, halogen, -NH ₂ 、-CN、-OH、-NO ₂ Carboxy, -NHR _2a 、-NR _2a R _2b 、-CONH ₂ 、-CONHR _2a 、-CONR _2a R _2b 、-COR _2a 、-COOR _2a 、-NHCOR _2a 、-N(R _2a )-COR _2b Substituted or unsubstituted C _1～6 Alkyl, substituted or unsubstituted C _1～6 Alkoxy, substituted or unsubstituted C _3～6 Cycloalkyl, substituted or unsubstituted 3-to 6-membered heterocycloalkyl, substituted or unsubstituted mono-spirocycloalkyl, substituted or unsubstituted hetero mono-spirocycloalkyl, substituted or unsubstituted C _4～8 Bridged cycloalkyl and substituted or unsubstituted 4-8 membered heterobridged cycloalkyl; wherein the number of ring atoms of the mono-and heteromonospirocycloalkyl groups is selected from the group consisting of 3-membered/5-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, and 5-membered/6-membered rings, wherein the count for each ring includes a spiro atom; the term "substituted" means that the substituents are independently selected from one or more of-OH, halogen, C _1-6 Alkyl, -NH ₂ 、-NO ₂ 、-COCH ₃ And, -CN and = O, the case where the substituent is "= O" means that two hydrogen atoms at the same substitution position are substituted by oxygen atoms;

or R ₂ To adjacent R ₃ Cyclizing to form a substituted or unsubstituted 5-to 8-membered heteroaryl or a substituted or unsubstituted non-aromatic 5-to 8-membered heterocyclic group; the term "substituted" means that the substituents are independently selected from one or more of-OH, halogen, C _1-6 Alkyl, -NH ₂ 、-NO ₂ 、-COCH ₃ And, -CN and = O, the case where the substituent is "= O" means that two hydrogen atoms at the same substitution position are substituted by oxygen atoms;

R _2a And R _2b Each independently selected from C _1～6 An alkyl group;

R ₇ selected from halogen, -CN, -COOR _7a 、-COR _7b 、C _2-6 Alkenyl, -CONH ₂ Substituted or unsubstituted C _3～6 Cycloalkyl, substituted or unsubstituted C _3～6 Heterocycloalkyl and substituted or unsubstituted heteromonospirocycloalkyl containing 1 or 2 heteroatoms, wherein the number of ring atoms of said heteromonospirocycloalkyl is selected from 3-membered/5-membered, 4-membered/4-membered, 4-membered/5-membered, the number of each ring counted including spiro atoms; r _7a is-H or substituted or unsubstituted C _1-6 An alkyl group; r _7b Selected from-H, substituted or unsubstituted C _1～6 Alkyl, substituted or unsubstituted C _3～6 Cycloalkyl, substituted or unsubstituted 3-to 6-membered heterocycloalkyl, substituted or unsubstituted C _6～14 Aryl or substituted or unsubstituted 5-to 10-membered heteroaromatic ring; the term "substituted" means that the substituents are independently selected from one or more of-OH, halogen, -NH ₂ 、-NO ₂ 、C _1～6 Alkyl radical, C _1～6 Alkoxy radical, C _3～6 Cycloalkyl, -NH-C _1～6 Alkyl, -N (C) _1～6 Alkyl) -C _1～6 Alkyl, -NH-C _3～6 Cycloalkyl, -N (C) _3～6 Cycloalkyl) -C _3～6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C _6～14 Aryl or 5-to 10-membered heteroaromatic ring;

indicates the presence or absence of a bond;

i)
when it indicates that a bond is absent, X ₃ Nor is it used forExist, R ₄ And R ₅ Each independently selected from hydrogen, hydroxy, halogen, = O, substituted or unsubstituted C _1～6 Alkyl and substituted or unsubstituted C _1～6 An alkoxy group; r ₄ And R ₅ Each independently selected from "= O" means that another hydrogen atom at the same substitution position is simultaneously substituted by the oxygen atom; the term "substituted" means that the substituents are independently selected from one or more of-OH, halogen, C _1-6 Alkyl, -NH ₂ 、-NO ₂ 、-COCH ₃ And, -CN and = O, the case where the substituent is "= O" means that two hydrogen atoms at the same substitution position are substituted by oxygen atoms;

ii)
when a bond is present, X ₃ Is CH ₂ ，R ₄ And R ₅ Are all hydrogen;

represents a single bond or a double bond;

1) When in use
When represents a single bond, ring A and- (R) ₆ ) _m Absence, Y ₁ And Y ₂ Each independently is CR ₉ R ₁₀ O or NR ₁₀ ；

Each R ₉ And R ₁₀ Independently selected from-H, halogen, -OH, substituted or unsubstituted C _1～6 Alkyl, substituted or unsubstituted C _1～6 An alkoxy group; the term "substituted" means that the substituents are independently selected from one or moreA group of-OH, halogen, C _1-6 Alkyl, -NH ₂ 、-NO ₂ 、-COCH ₃ And, -CN and = O, the case where the substituent is "= O" means that two hydrogen atoms at the same substitution position are substituted with an oxygen atom;

ii) when
When representing a double bond, Y ₁ And Y ₂ Both are C, ring A is present, ring A is selected from phenyl or 5-to 6-membered heteroaryl;

R ₆ selected from halogen, -NH ₂ 、-NHR _6a 、-NR _6a R _6b 、-CN、-CONH ₂ 、-CONHR _6a 、-CONR _6a R _6b 、-COR _6a 、-COOH、-OH、-SO _n C _1-6 Alkyl, substituted or unsubstituted C _1-6 Alkyl, substituted or unsubstituted C _1～6 An alkoxy group; wherein R is _6a And R _6b Each independently is C _1～6 An alkyl group; n is selected from 0, 1 or 2; the term "substituted" means that the substituents are independently selected from one or more of-OH, halogen, C _1-6 Alkyl, -NH ₂ 、-NO ₂ 、-COCH ₃ And, -CN and = O, the case where the substituent is "= O" means that two hydrogen atoms at the same substitution position are substituted with an oxygen atom;

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

unless otherwise specified, the heteroatoms in the above heterocycloalkyl, heteroaryl ring, heterocyclyl, heteromonospirocyclic, heterobridged ring are independently selected from O, N or S, the number of heteroatoms being 1, 2 or 3,

provided that the compounds of formula (I) do not include:
a compound represented by formula (I) or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative or pharmaceutically acceptable salt thereof,

x is selected from a bond or-S-;

X ₁ and X ₂ Each independently selected from N and CR ₈ (ii) a Wherein each R ₈ Independently selected from-H, halogen, -NH ₂ 、-NHR _8b 、-NR _8b R _8c 、-NHCOR _8a 、-CN、-OH、-NO ₂ 、-COOH、-CONH ₂ 、-CONHR _8b 、-CONR _8b R _8c 、-COOR _8b Substituted or unsubstituted C _1～6 Alkyl, substituted or unsubstituted C _1～6 Alkoxy, substituted or unsubstituted C _3～6 Cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted mono spirocycloalkyl, substituted or unsubstituted hetero mono spirocycloalkyl, substituted or unsubstituted C _6～14 Aryl and substituted or unsubstituted 5-to 14-membered heteroaryl, wherein said substituted C _1～6 Alkyl, substituted C _1～6 Alkoxy, substituted C _3～6 Cycloalkyl, substituted 3-6 membered heterocycloalkyl, substituted mono spirocycloalkyl, substituted hetero mono spirocycloalkyl, substituted C _6～14 Aryl and substituted 5-to 14-membered heteroaryl are each independently selected from-OH, halogen, unsubstituted C _1-6 Alkyl, -NH ₂ 、-NO ₂ unsubstituted-COC _1-6 One or more substituents of alkyl, -CN and = O groupSubstitution;

R _8a selected from:

R _8b and R _8c Each independently selected from unsubstituted C _1～6 An alkyl group;

R ₁ and R ₃ Each independently selected from-H, halogen, -NH ₂ 、-CN、-OH、-NO ₂ -COOH, substituted or unsubstituted C _1～6 Alkyl and substituted or unsubstituted C _1～6 Alkoxy, wherein said substituted C _1～6 Alkyl and substituted C _1～6 Alkoxy is independently selected from-OH, halogen, unsubstituted C _1-6 Alkyl, -NH ₂ 、-NO ₂ unsubstituted-COC _1-6 Alkyl, -CN and = O;

R ₂ selected from-H, halogen, -NH ₂ 、-CN、-OH、-NO ₂ Carboxy, -NHR _2a 、-NR _2a R _2b 、-CONH ₂ 、-CONHR _2a 、-CONR _2a R _2b 、-COR _2a 、-COOR _2a 、-NHCOR _2a 、-N(R _2a )-COR _2b Substituted or unsubstituted C _1～6 Alkyl, substituted or unsubstituted C _1～6 Alkoxy, substituted or unsubstituted C _3～6 Cycloalkyl, substituted or unsubstituted 3-to 6-membered heterocycloalkyl, substituted or unsubstituted mono-spirocycloalkyl, substituted or unsubstituted hetero-mono-spirocycloalkyl, substituted or unsubstituted C _4～8 Bridged cycloalkyl and substituted or unsubstituted 4-8 membered heterobridged cycloalkyl, wherein said substituted C _1～6 Alkyl, aryl, heteroaryl, and heteroaryl,Substituted C _1～6 Alkoxy, substituted C _3～6 Cycloalkyl, substituted 3-to 6-membered heterocycloalkyl, substituted mono-spirocycloalkyl, substituted hetero mono-spirocycloalkyl, substituted C _4～8 The bridged cycloalkyl group and the substituted 4-8 membered heterobridged cycloalkyl group are each independently selected from-OH, halogen, unsubstituted C _1-6 Alkyl, -NH ₂ 、-NO ₂ unsubstituted-COC _1-6 Alkyl, -CN, and = O;

or R ₂ To adjacent R ₃ By cyclization to form substituted or unsubstituted C ₆ Or C ₁₀ Aryl, substituted or unsubstituted 5-to 8-membered heteroaryl or substituted or unsubstituted non-aromatic 5-to 8-membered heterocyclyl, wherein C is substituted ₆ Or C ₁₀ Aryl, substituted 5-to 8-membered heteroaryl or substituted non-aromatic 5-to 8-membered heterocyclyl are each independently selected from-OH, halogen, unsubstituted C _1-6 Alkyl, -NH ₂ 、-NO ₂ unsubstituted-COC _1-6 Alkyl, -CN and = O;

R _2a and R _2b Each independently selected from unsubstituted C _1～6 An alkyl group;

R ₇ is selected from-H;

indicates the presence or absence of a bond;

i)
when it indicates that a bond is absent, X ₃ Nor is present, R ₄ And R ₅ Each independently selected from hydrogen, hydroxy, halogen, = O, substituted or unsubstituted Substituted C _1～6 Alkyl and substituted or unsubstituted C _1～6 Alkoxy radical, wherein R ₄ And R ₅ Each independently selected from "= O" means that another hydrogen atom at the same substitution position is simultaneously substituted by the oxygen atom, wherein the substituted C _1～6 Alkyl and substituted C _1～6 Alkoxy is independently selected from-OH, halogen, unsubstituted C _1-6 Alkyl, -NH ₂ 、-NO ₂ unsubstituted-COC _1-6 Alkyl, -CN and = O, with the proviso that R is ₄ And R ₅ Cannot be simultaneously hydrogen;

ii)
when a bond is present, X ₃ Is CH ₂ ，R ₄ And R ₅ Are all hydrogen;

represents a single bond or a double bond;

i) When the temperature is higher than the set temperature
When represents a single bond, ring A and- (R) ₆ ) _m Is absent, Y ₁ And Y ₂ Each independently is CR ₉ R ₁₀ O or NR ₁₀ ；

Each R ₉ And R ₁₀ Independently selected from-H, halogen, -OH, substituted or unsubstituted C _1～6 Alkyl and substituted or unsubstituted C _1～6 Alkoxy, wherein said substituted C _1～6 Alkyl and alkyl radicalsGeneration C _1～6 Alkoxy is independently selected from OH, halogen, unsubstituted C _1-6 Alkyl, -NH ₂ 、-NO ₂ unsubstituted-COC _1-6 Alkyl, -CN and = O;

ii) when
When representing a double bond, Y ₁ And Y ₂ Are both C, ring A is present, ring A is selected from naphthyl, phenyl or 5-to 6-membered heteroaryl;

R ₆ Selected from halogen, -NH ₂ 、-NHR _6a 、-NR _6a R _6b 、-CN、-CONH ₂ 、-CONHR _6a 、-CONR _6a R _6b 、-COR _6a -COOH, -OH, substituted or unsubstituted-SO _n C _1-6 Alkyl, substituted or unsubstituted C _1-6 Alkyl and substituted or unsubstituted C _1～6 Alkoxy radical, wherein R _6a And R _6b Each independently of the other being unsubstituted C _1～6 An alkyl group; n is selected from 0, 1 or 2, wherein said substituted-SO _n C _1-6 Alkyl, substituted C _1-6 Alkyl and substituted C _1～6 Alkoxy is independently selected from-OH, halogen, unsubstituted C _1-6 Alkyl, -NH ₂ 、-NO ₂ unsubstituted-COC _1-6 Alkyl, -CN and = O;

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

wherein the number of ring atoms of the mono-and hetero-spirocycloalkyl groups are independently selected from the group consisting of 3-membered/5-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, and 5-membered/6-membered rings, wherein the count for each ring includes a spiro atom; and

the substituent "= O" means that two hydrogen atoms at the same substitution position are substituted with an oxygen atom.
A compound according to any one of claims 1 to 3, having the structure shown in formula (I-a):

wherein R is ₁ ，R ₂ ，R ₃ ，R ₄ ，R ₅ ，R ₆ ，R ₇ ，X ₁ ，X ₂ ，X ₃ ，Y ₁ ，Y ₂ Ring a and m are as defined for the compound according to any one of claims 1-3.
A compound according to any one of claims 1 to 3, having the structure shown in formula (I-b):

Wherein R is ₁ ，R ₂ ，R ₃ ，R ₄ ，R ₅ ，R ₆ ，R ₇ ，X ₁ ，X ₂ ，X ₃ ，Y ₁ ，Y ₂ Ring a and m are as defined for the compound according to any one of claims 1-3.
The compound of any one of claims 1-5, or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R ₁ And R ₃ Each independently selected from-H, halogen、-NH ₂ 、-CN、-OH、-NO ₂ -COOH, substituted or unsubstituted C _1～6 Alkyl and substituted or unsubstituted C _1～6 Alkoxy, wherein said substituted C _1～6 Alkyl and substituted C _1～6 Alkoxy is independently selected from-OH, halogen, -NH ₂ 、-NO ₂ 、-COC _1-6 Alkyl and one or more substituents of the-CN group; or,

R ₁ and R ₃ Each independently selected from-H, halogen, -NH ₂ CN, -OH, substituted or unsubstituted C _1～6 Alkyl and substituted or unsubstituted C _1～6 Alkoxy, wherein said substituted C _1～6 Alkyl and substituted C _1～6 Alkoxy is independently selected from halogen, -NO ₂ 、-COC _1-6 Alkyl (e.g., -COCH) ₃ ) And one or more substituents in the-CN group; or,

R ₁ and R ₃ Each independently selected from-H, halogen, -NH ₂ 、-CN、-OH、-NO ₂ COOH, halogen substituted or unsubstituted C _1～6 Alkyl and halogen substituted or unsubstituted C _1～6 An alkoxy group; or alternatively

R ₁ And R ₃ Each independently selected from-H, halogen and halogen substituted C _1～6 An alkyl group; or

R ₁ And R ₃ Each independently selected from-H, -F, -Cl, and fluoro-methyl; or

R ₁ And R ₃ One of which is selected from-H and the other is selected from-F, -Cl and CF ₃ (ii) a Or

R ₁ And R ₃ Each independently selected from-H, -F, -Cl, -Br and-NH ₂ OH, -OH, halo or unsubstituted C _1～6 Alkyl, halo or unsubstituted C _1～6 An alkoxy group; or

R ₁ And R ₃ Each independently selected from-H, -F, -Cl, -NH ₂ OH, fluoro or unsubstituted C _1～6 Alkyl, fluoro or unsubstituted C _1～6 An alkoxy group; or

R ₁ And R ₃ Each independently selected from-H, -F, -Cl, -NH ₂ Fluoro or unsubstituted methyl.
The compound of any one of claims 1-6, or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R is ₂ Selected from-H, halogen, -NH ₂ 、-OH、-NHR _2a 、-NR _2a R _2b 、-CONH ₂ 、-NHCOR _2a 、-N(R _2a )-COR _2b Substituted or unsubstituted C _1～6 Alkyl, substituted or unsubstituted C _1～6 Alkoxy, substituted or unsubstituted C _3～6 Cycloalkyl, substituted or unsubstituted 3-to 6-membered heterocycloalkyl, substituted or unsubstituted mono-spirocycloalkyl and substituted or unsubstituted hetero-mono-spirocycloalkyl, wherein R _2a And R _2b Each independently selected from unsubstituted C _1～3 Alkyl, said mono-and hetero-spirocycloalkyl having a ring atom number of 4-to 4-membered rings, wherein each ring count includes the spiro atom, and said substituted C _1～6 Alkyl, substituted C _1～6 Alkoxy, substituted C _3～6 Cycloalkyl, substituted 3-to 6-membered heterocycloalkyl, substituted mono-spirocycloalkyl and substituted hetero-mono-spirocycloalkyl each independently selected from-OH, halogen, C _1-3 Alkyl and-NH ₂ Substituted by one or more substituents in the radical, or R ₂ To adjacent R ₃ Ring-closure to form a substituted or unsubstituted 5-to 6-membered heteroaryl or a substituted or unsubstituted non-aromatic 5-to 6-membered heterocyclyl, wherein said substituted 5-to 6-membered heteroaryl or substituted non-aromatic 5-to 6-membered heterocyclyl are each independently selected from halo (e.g., -F and-Cl), -COC _1-6 Alkyl (e.g., -COCH) ₃ ) And one or more substituents in the-CN group; or,

R ₂ selected from-H, halogen, -NH ₂ 、-OH、-NHR _2a 、-NR _2a R _2b Substituted or unsubstituted C _1～6 Alkyl, substituted or unsubstituted C _1～6 Alkoxy, substituted or unsubstituted C _3～6 Cycloalkyl, substituted or unsubstituted 3-to 6-membered heterocycloalkyl, and substituted or unsubstituted heteromonospirocycloalkyl, wherein R _2a And R _2b Each independently selected from unsubstituted C _1～3 Alkyl, the number of ring atoms of said heteromonospirocycloalkyl group being 4-membered/4-membered ring, wherein each ring count includes spiro atoms, and said substituted C _1～6 Alkyl, substituted C _1～6 Alkoxy, substituted C _3～6 Cycloalkyl, substituted 3-to 6-membered heterocycloalkyl and substituted heteromonospirocycloalkyl are each independently selected from-OH, halogen, C _1-3 Alkyl and-NH ₂ One or more substituents in the group; or R ₂ To adjacent R ₃ Ring-closure to form a substituted or unsubstituted 5-to 6-membered heteroaryl or a substituted or unsubstituted non-aromatic 5-to 6-membered heterocyclyl, wherein said substituted 5-to 6-membered heteroaryl or substituted non-aromatic 5-to 6-membered heterocyclyl are each independently selected from halogen, -COC _1-6 Alkyl and one or more substituents in the-CN group; or,

R ₂ selected from-H, -F, -Cl, -NH ₂ OH, substituted or unsubstituted C _1～6 Alkyl, substituted or unsubstituted C _3～6 Cycloalkyl, substituted or unsubstituted 3-to 6-membered heterocycloalkyl and substitutedOr unsubstituted heteromonospirocycloalkyl, wherein heteromonospirocycloalkyl is a 4-membered/4-membered spirocycloalkyl containing 1O atom and 1N atom, wherein the number of each ring includes spiro atoms, and said substituted C _1～6 Alkyl, substituted C _3～6 Cycloalkyl, substituted 3-to 6-membered heterocycloalkyl and substituted heteromonospirocycloalkyl are each independently selected from-OH, halogen, C _1-3 Alkyl and-NH ₂ One or more substituents in the group; or R ₂ Selected from-H, -F, -Cl or-NH ₂ (ii) a Or R ₂ Is selected from-H or-NH ₂ (ii) a Or alternatively

R ₂ Selected from-H, -F, -Cl, -Br, -NH ₂ 、-OH、-NHR _2a 、-NR _2a R _2b 、-CONH ₂ 、-CONHR _2a 、-CONR _2a R _2b 、-COR _2a 、-COOR _2a 、-NHCOR _2a 、-N(R _2a )-COR _2b Substituted or unsubstituted C _1～6 Alkyl, substituted or unsubstituted C _1～6 Alkoxy, substituted or unsubstituted C _3～6 Cycloalkyl, substituted or unsubstituted 3-to 6-membered heterocycloalkyl; wherein R is _2a And R _2b Each independently selected from C _1～6 An alkyl group; or R ₂ To the adjacent R ₃ Cyclizing to form a substituted or unsubstituted 5-6 membered heteroaryl or a substituted or unsubstituted non-aromatic 5-6 membered heterocyclic group; wherein R is ₂ Or R ₂ And R ₃ The hetero atom in the ring-closing structure is N, O or S, and the number of the hetero atoms is selected from 1 and 2; r is ₂ Structure or R ₂ And R ₃ By "substituted" in the ring-closing structure is meant that the substituents are independently selected from one or more of OH, -F, -Cl, -CH ₃ 、-COCH ₃ and-CN; or alternatively

R ₂ Selected from-H, -F, -Cl, -Br and-NH ₂ 、-OH、-NHCH ₃ 、-N(CH ₃ ) ₂ and-CONH ₂ (ii) a Or R ₂ To the adjacent R ₃ Cyclized to form a substituted or unsubstituted 5-membered heteroaryl or a substituted or unsubstituted non-aromatic 5-membered heterocyclyl, R ₂ And R ₃ The heteroatom in the ring-closing structure is N, the number of the heteroatom is 1, wherein the substituent is selected from one or more of-F and-COCH ₃ and-CN; or

R ₂ To adjacent R ₃ Ring closure to form a substituted or unsubstituted 5-membered heteroaryl or a substituted or unsubstituted non-aromatic 5-membered heterocyclyl, wherein the heteroatom is N and the number of heteroatoms is 1, wherein "substituted" means that the substituents are independently selected from one or more of-F, -COCH ₃ and-CN; or

R ₂ To adjacent R ₃ Ring closure to form the following groups:
the compound of any one of claims 1-7, or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein X ₁ And X ₂ Each independently selected from N and CR ₈ (ii) a Wherein each R ₈ Independently selected from-H, halogen, -NH ₂ 、-NHR _8b 、-NR _8b R _8c 、-NHCOR _8a OH, substituted or unsubstituted C _1～6 Alkyl, substituted or unsubstituted C _1～6 Alkoxy, substituted or unsubstituted C _3～6 Cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted heteromonospirocycloalkyl, substituted or unsubstituted C _6～10 Aryl or substituted or unsubstituted 5-to 6-membered heteroaryl, wherein the number of ring atoms of the heteromonospirocycloalkyl group is 4-membered/4-membered ring, each ring count including a spiro atom, wherein said substituted C _1～6 Alkyl, substituted C _1～6 Alkoxy, substituted C _3～6 Cycloalkyl, substituted 3-6 membered heterocycloalkyl, substituted heteromonospirocycloalkyl, substituted C _6～10 Aryl, substituted 5-to 6-membered heteroaryl are each independently selected from-OH, halogen, C _1-6 Alkyl and-NH ₂ Substituted in one or more substituents in the group;

R _8a selected from the group consisting of:

R _8b and R _8c Each independently selected from unsubstituted C _1～3 An alkyl group; or

X ₁ And X ₂ Each independently selected from N and CR ₈ (ii) a Wherein each R ₈ Independently selected from-H, -F, -Cl, -NH ₂ 、-NHCOR _8a -OH, unsubstituted C _1～3 Alkyl, unsubstituted C _1～3 Alkoxy, unsubstituted C _3～6 Cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, unsubstituted heteromonospirocycloalkyl, unsubstituted C _6～10 Aryl or unsubstituted 5-6 membered heteroaryl, wherein the heteromonospirocycloalkyl is a 4-membered/4-membered spirocycloalkyl containing 1O atom and 1N atom, each ring count including a spiro atom, wherein said substituted 3-6 membered heterocycloalkyl is independently selected from-OH, halo, C _1-6 Alkyl and-NH ₂ Substituted in one or more substituents in the group;

R _8a selected from:

R _8b and R _8c Each independently selected from unsubstituted C _1～3 An alkyl group; or

X ₁ And X ₂ Each independently selected from N and CR ₈ (ii) a Wherein each R ₈ Independently selected from-H, -F, -Cl, -NH ₂ 、-NHCOR _8a Unsubstituted C _6～10 Aryl or unsubstituted 5-to 6-membered heteroaryl, wherein R _8a Selected from:
or

X ₁ And X ₂ Each independently selected from N and CR ₈ (ii) a Wherein R is ₈ Selected from-H, -NH ₂ 、-NHCOR _8a 、
Wherein R is _8a Selected from:
or

X ₁ And X ₂ One of them is N and the other is CR ₈ Wherein R is ₈ Independently selected from H, -Cl, -NH ₂ 、-NHCOR _8a Unsubstituted C _6～10 Aryl or unsubstituted 5-to 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein R _8a Selected from:
or R ₈ Independently selected from H, -NH ₂ Unsubstituted C _6～10 Aryl or unsubstituted 5-to 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, preferably from unsubstituted C _6～10 Aryl or unsubstituted 5-to 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, more preferably unsubstituted 5-to 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S; or

X ₁ And X ₂ Are all CR ₈ (ii) a Wherein one R ₈ is-H, another R ₈ Selected from-Cl, -NH ₂ 、-NHCOR _8a Unsubstituted C _6～10 Aryl or unsubstituted 5-to 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein R is _8a Selected from:
or R ₈ Is selected from-NH ₂ Unsubstituted C _6～10 Aryl or unsubstituted 5-to 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, preferably from unsubstituted C _6～10 Aryl or unsubstituted 5-to 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, more preferably unsubstituted 5-to 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S; or

X ₁ And X ₂ Each independently selected from N or CR ₈ (ii) a Wherein R is ₈ Selected from-H, -F, -Cl, -Br, -NH ₂ 、-NHCOR _8a Substituted or unsubstituted C _1～6 Alkyl, substituted or unsubstituted C _1～6 Alkoxy, substituted or unsubstituted C _3～6 A cycloalkyl group; and X ₁ And X ₂ Not simultaneously selected from N; wherein R is _8a Selected from:

or

R ₈ Selected from-H, -NH ₂ Methyl, methoxy, cyclopropyl, -NHCOR _8a Wherein R is _8a Selected from:

or

R _8a Selected from the group consisting of:
the compound of any one of claims 1-8, or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein
Represents a double bond, Y ₁ And Y ₂ Are both C, ring A is selected from phenyl or 5-to 6-membered heteroaryl containing 1 or 2 heteroatoms; or

Represents a double bond, Y ₁ And Y ₂ Are both C, ring A is selected from phenyl, 6-membered heteroaryl having 1N atom, and 5-membered heteroaryl having 1S atom and 1N atom, or

Represents a double bond, Y ₁ And Y ₂ Both C, ring a is selected from phenyl and 6-membered heteroaryl containing 1N atom, preferably phenyl.
The compound of any one of claims 1-9, or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R is ₆ Selected from halogen, -NH ₂ 、-NHR _6a 、-NR _6a R _6b 、-CN、-CONH ₂ 、-CONHR _6a 、-CONR _6a R _6b 、-COR _6a -COOH, -OH, substituted or unsubstituted-SO _n C _1-6 Alkyl, substituted or unsubstituted C _1-6 Alkyl and substituted or unsubstituted C _1～6 Alkoxy radical, wherein R _6a And R _6b Each independently of the other being unsubstituted C _1～6 An alkyl group; n is selected from 0, 1 or 2, wherein said substituted-SO _n C _1-6 Alkyl, substituted C _1-6 Alkyl and substituted C _1～6 Alkoxy is independently selected from-OH, halogen, C _1-6 Alkyl and-NH ₂ One or more substituents in the group; or alternatively

R ₆ Selected from-F, -Cl, -Br, -NH ₂ -CN, -OH, unsubstituted-SO _n C _1-3 Alkyl, substituted or unsubstituted C _1-3 Alkyl and substituted or unsubstituted C _1～3 Alkoxy, wherein n is selected from 0, 1 or 2, wherein said substituted C _1-3 Alkyl and substituted C _1～3 Alkoxy is independently selected from-OH, halogen, C _1-3 Alkyl and-NH ₂ One or more substituents in the group; or alternatively

R ₆ Selected from halogen, -NH ₂ 、-CN、-OH、-OCH ₃ 、-SCH ₃ 、-SO ₂ CH ₃ 。
The compound of any one of claims 1-10, or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein
When represents a single bond, ring A and- (R) ₆ ) _m Absence, Y ₁ And Y ₂ Each independently is CR ₉ R ₁₀ O or NR ₁₀ (ii) a Each R ₉ And R ₁₀ Independently selected from-H or unsubstituted C _1～6 An alkyl group; or alternatively

When represents a single bond, ring A and- (R) ₆ ) _m Is absent, Y ₁ And Y ₂ One of them is CR ₉ R ₁₀ And the other is O; each R ₉ And R ₁₀ Independently selected from-H or unsubstituted C _1～3 Alkyl, preferably methyl.
A compound according to any one of claims 1-2 or 4-11, or a prodrug, tautomer thereofA body, a stereoisomer, a solvate, an isotopic derivative or a pharmaceutically acceptable salt thereof, wherein
Denotes the absence of a bond, X ₃ Nor is present, R ₄ And R ₅ Each independently selected from hydrogen, hydroxy, -F, -Cl, -Br, = O, unsubstituted C _1～3 Alkyl and unsubstituted C _1～3 An alkoxy group; or alternatively
Denotes the absence of a bond, X ₃ Nor is present, R ₄ And R ₅ Are all hydrogen.
The compound of any one of claims 1-12, or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein
Denotes the absence of a bond, X ₃ Nor is present, R ₄ And R ₅ One of which is hydrogen and the other is selected from hydrogen, hydroxy, -F, -Cl, = O, unsubstituted C _1～3 Alkyl and unsubstituted C _1～3 An alkoxy group.
The compound of any one of claims 1-2 or 4-13, or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein R is ₇ Selected from halogen, -CN, -COOR _7a 、-COR _7b Unsubstituted C _2-4 Alkenyl, unsubstituted C _2-4 Alkynyl, -CONH ₂ 、-C(O)-COOR _7a Substituted or unsubstituted C _3～6 Cycloalkyl, substituted or unsubstituted C _2～6 Heterocycloalkyl, substituted or unsubstituted mono-spirocycloalkyl and substituted or unsubstituted hetero-spirocycloalkyl containing 1 or 2 heteroatoms, wherein the number of ring atoms of said mono-spirocycloalkyl and hetero-spirocycloalkyl is independently selected from 3-membered/5-membered, 4-membered/4-membered or 4-membered/5-membered rings, wherein the count for each ring includes a spiro atom, wherein R is _7a is-H, unsubstituted C _1-6 Alkyl or unsubstituted C _3-6 A cycloalkyl group; r is _7b Selected from-H, substituted or unsubstituted C _1～6 Alkyl, substituted or unsubstituted C _3～6 Cycloalkyl, substituted or unsubstituted 3-to 6-membered heterocycloalkyl, substituted or unsubstituted C _6～14 Aryl and substituted or unsubstituted 5-to 10-membered heteroaryl; wherein said substituted C _3～6 Cycloalkyl, substituted C _2～6 Heterocycloalkyl, substituted mono-spirocycloalkyl, substituted hetero-mono-spirocycloalkyl, substituted C _1-6 Alkyl, substituted 3-to 6-membered heterocycloalkyl, substituted C _6～14 Aryl and substituted 5-to 10-membered heteroaryl are each independently selected from-OH, halogen, -NH ₂ 、C _1～6 Alkyl radical, C _1～6 Alkoxy, -NH-C _1～6 Alkyl, -N (C) _1～6 Alkyl) (C _1～6 Alkyl) and unsubstituted 3-to 6-membered heterocycloalkyl; or,

R ₇ Selected from-F, -Cl, -Br, -CN, -COOR _7a 、-COR _7b 、-C(O)-COOR _7a Unsubstituted C ₂ Alkenyl, unsubstituted C ₂ Alkynyl, -CONH ₂ 、-C(O)-COOR _7a Substituted or unsubstituted C _2～6 Heterocycloalkyl and substituted or unsubstituted heteromonospirocycloalkyl containing 1 or 2 heteroatoms independently selected from N and O, wherein the number of ring atoms of said heteromonospirocycloalkyl is independently 4-membered/4-membered ring, wherein each ring isEach number including spiro atoms, wherein R _7a is-H, unsubstituted C _1-3 Alkyl or unsubstituted C _3-4 A cycloalkyl group; r _7b Selected from-H, substituted or unsubstituted C _1～3 Alkyl, substituted or unsubstituted C _3～6 Cycloalkyl, substituted or unsubstituted C ₆ Or C ₁₀ Aryl and substituted or unsubstituted 5-to 6-membered heteroaryl; wherein, said substituted C _2～6 Heterocycloalkyl, substituted heteromonospirocycloalkyl, substituted C _1-3 Alkyl, substituted C _3～6 Cycloalkyl, substituted C ₆ Or C ₁₀ Aryl and substituted 5-to 6-membered heteroaryl are each independently selected from-OH, halogen, -NH ₂ 、C _1～6 Alkyl radical, C _1～6 Alkoxy, -NH-C _1～6 Alkyl, -N (C) _1～6 Alkyl) (C _1～6 Alkyl) and unsubstituted 3-to 6-membered heterocycloalkyl; or,

R ₇ selected from-F, -Cl, -Br, -CN, -COOR _7a 、-COR _7b Unsubstituted C ₂ Alkenyl, unsubstituted C ₂ Alkynyl, -CONH ₂ 、-C(O)-COOR _7a Unsubstituted C _2～6 Heterocycloalkyl and unsubstituted heteromonospirocycloalkyl containing 1 or 2 heteroatoms independently selected from N and O, wherein said heteromonospirocycloalkyl has a ring atom number of independently 4-membered/4-membered ring, wherein the count for each ring includes spiro atoms, wherein R _7a is-H, unsubstituted C _1-3 Alkyl or unsubstituted C _3-4 A cycloalkyl group; r is _7b Is selected from-H or unsubstituted C _1～3 An alkyl group; or alternatively

R ₇ Selected from-CN, -COOR _7a 、-COR _7b Unsubstituted C ₂ Alkenyl, unsubstituted C ₂ Alkynyl, -C (O) -COOR _7a And unsubstituted C _2～6 Heterocycloalkyl, wherein R is _7a is-H, unsubstituted C _1-3 Alkyl or unsubstituted C _3-4 A cycloalkyl group; r is _7b Is selected from-H or unsubstituted C _1～3 An alkyl group; or

R ₇ Selected from-CN, -COOR _7a 、-COR _7b Unsubstituted C ₂ Alkenyl and unsubstituted C ₂ Alkynyl, wherein R _7a is-H, unsubstituted C _1-3 Alkyl or unsubstituted C _3-4 A cycloalkyl group; r _7b Is selected from-H or unsubstituted C _1～3 An alkyl group; or

R ₇ Selected from-F, -Cl, -CN, -COOR _7a 、-COR _7b Unsubstituted C ₂ Alkenyl and unsubstituted 4-membered heterocycloalkyl, wherein R _7a is-H, unsubstituted C _1-3 Alkyl or unsubstituted C _3-4 A cycloalkyl group; r _7b Is selected from-H or unsubstituted C _1～3 An alkyl group; or alternatively

R ₇ Selected from-F, -Cl, -COOR _7a 、-COR _7b Unsubstituted C ₂ Alkenyl and unsubstituted 4-membered heterocycloalkyl, wherein R _7a And R _7b Are all methyl; or

R ₇ Is selected from-COOR _7a or-COR _7b Wherein R is _7a And R _7b Are all unsubstituted methyl groups; or alternatively

R ₇ Selected from-Cl, -F, -CN, -CHO, -COOH and-COOCH ₃ 、-COCH ₃ 、-CONH ₂ 、-CH＝CH ₂ 、
Or

R ₇ Selected from-F and-COOCH ₃ 、-COCH ₃ 、-CH＝CH ₂ ；

R ₇ Selected from-F, -Cl, -Br, -I, -CN, -COOR _7a 、-COR _7b -C = CH, substituted or unsubstituted C _3～6 Cycloalkyl, substituted or unsubstituted 3-to 6-membered heterocycloalkyl, substituted or unsubstituted spiro [3.3 ] containing 1 or 2 heteroatoms independently selected from N and O]A heptanyl group; wherein R is _7a is-H or C _1-6 Alkyl radical, R _7b Selected from-H, substituted or unsubstituted C _1～6 Alkyl, substituted or unsubstituted C _3～6 Cycloalkyl, substituted or unsubstituted C _6～14 Aryl, said "substituted" meaning that the substituents are independently selected from one or more of-OH, -F, -Cl, -NH ₂ 、-CH ₃ 、C _1～6 Alkoxy, -NH-C _1～6 Alkyl, -N (C) _1～6 Alkyl) -C _1～6 Alkyl, 3-to 6-membered heterocycloalkyl group; or

R ₇ Selected from-Cl, -Br, -I, -CN, -COOR _7a 、-COR _7b -C = CH, substituted or unsubstituted C _3～6 Cycloalkyl, substituted or unsubstituted C _3～6 Heterocycloalkyl and substituted or unsubstituted spiro [3.3 ] containing 1 or 2 heteroatoms independently selected from N and O]A heptalkyl group; wherein R is _7a is-H or C _1-3 Alkyl radical, R _7b Selected from-H, substituted or unsubstituted C _1～3 Alkyl radical, C _3～6 Cycloalkyl radical, C _6～10 Aryl, said "substituted" meaning that the substituents are independently selected from one or more of-OH, -F, -Cl, -NH ₂ 、-CH ₃ 、-OCH ₃ 、-N(CH ₃ )CH ₃ 3-6 membered heterocycloalkyl group; or alternatively

R ₇ Selected from-Cl, -Br, -I, -CN, -COOR _7a 、-COR _7b 、-C＝CHSubstituted or unsubstituted cyclopropane, substituted or unsubstituted oxetanyl and substituted or unsubstituted spiro [3.3 ] containing 1 or 2 heteroatoms independently selected from N and O]A heptalkyl group; wherein R is _7a is-H or C _1-3 Alkyl radical, R _7b Selected from-H, substituted or unsubstituted methyl, C _3～4 Cycloalkyl radical, C _6～10 Aryl, said "substituted" meaning that the substituents are independently selected from one or more of-OH, -F, -Cl, -NH ₂ 、-OCH ₃ 、-N(CH ₃ )CH ₃ A 3-to 6-membered heterocycloalkyl group; or

R ₇ Selected from-Cl, -Br, -CN, -CHO, -COOH and-COOCH ₃ 、-COCH ₃ 、-CONH ₂ 、-COCH ₂ F、-COCH ₂ OH、-COCH ₂ OCH ₃ 、-COCH ₂ NH ₂ 、-COCH ₂ N(CH ₃ )CH ₃ -C = CH, cyclopropylalkyl, cyclopropyl,
A compound, or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, selected from the following structures:
a pharmaceutical composition comprising a compound of any one of claims 1-15, or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof; preferably, it comprises a compound of any one of claims 1 to 15, or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
Use of a compound of any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, or a pharmaceutical composition of claim 16, in the manufacture of a medicament for the prevention and/or treatment of diseases, disorders, and conditions mediated by SHP2 activity; preferably, the diseases, disorders and conditions are tumors, cardiovascular diseases, immune disorders or visual disorders; more preferably, the tumor includes solid tumors and hematological tumors; more preferably, the solid tumor comprises pancreatic cancer, lung cancer, preferably non-small cell lung cancer; the blood tumor comprises leukemia, preferably juvenile myelomonocytic leukemia and acute myelogenous leukemia.
The use according to claim 17, wherein the compound according to any one of claims 1 to 15 or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 16 is used in combination with another, two or more compounds having tumor-inhibiting activity.