Heterocyclic Compounds and Their Uses

Abstract

The SHP2 inhibitor represented by formula (I-1), or a pharmaceutically acceptable salt, stereoisomer, pharmaceutical composition thereof, and their use in the treatment and / or prevention of diseases, disorders, and conditions mediated by SHP2 activity.

Description

[0001] Cross - reference to related applications

[0002] This application claims the benefit and priority of Chinese Patent Application No. 202010534482.4, filed with the State Intellectual Property Office of the People's Republic of China on June 12, 2020, the entire content of which is hereby incorporated herein by reference in its entirety. Technical field

[0003] This application relates to the field of pharmaceutical technology. Specifically, it relates 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 art

[0004] SHP2 (Src homology domain, The Src homology - 2 domain) is encoded by protein tyrosine phosphatase non - receptor type 11 (PTP nonreceptor 11, PTPN11) and catalyzes the protein tyrosine dephosphorylation reaction. Generally, it is considered that the N - terminal of SHP2 contains two SH2 domains including N - src homology 2 domain (SH2) and C - SH2, and the C - terminal contains one catalytically active PTP domain. In the unactivated state, SHP2 is in a self - inhibitory state, and the binding of N - SH2 and C - PTP inhibits the phosphatase activity. In the presence of extracellular stimuli, they bind to related receptors and activate multiple downstream signaling pathways, such as multiple signal transduction pathways including Ras / MAPK, PI3K / AKT, etc., regulating cell proliferation, differentiation, apoptosis and survival.

[0005] Literature disclosures (Eur J Med Genet. 2015.58: 509; WO2018013597) have determined that germline mutations in PTPN11 and SHP2 are associated with a variety of human diseases, such as various malignancies (juvenile myelomonocytic leukemia, leukemia, lung cancer, etc.). The research of Revolution Medicines has also shown that SHP2 plays an important role in the oncogenic growth and survival signals of up to 45% of non - small cell lung cancers and some other common cancers.

[0006] In addition, studies have shown (Sci Adv. 2020.6(5): eaay4458) 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. After stimulation, PD-1 is phosphorylated at its immunoreceptor tyrosine-based inhibitory motif (ITIM) and immunoreceptor tyrosine-based switch motif (ITSM), and then binds to SHP2, initiating T cell inactivation. Therefore, SHP2 inhibitors can stimulate adaptive and innate immune activities in the tumor microenvironment and have the potential to restore anti-tumor immune responses that have been silenced by cancer cells. Therefore, there is an urgent need for compounds that act as SHP2 inhibitors to treat and prevent diseases, disorders, and conditions mediated by SHP2 activity. Summary of the Invention

[0008] On the one hand, the present application provides a compound represented by formula (I-1) or its prodrug, tautomer, stereoisomer, solvate, isotope derivative, or pharmaceutically acceptable salt thereof,

[0009]

[0010] X is selected from a bond or -S-;

[0011] X1 and X2 are each independently selected from N and CR8; wherein each R8 is independently selected from -H, halogen, -NH2, -NHR 8b 、-NR 8b R 8c 、-NHCOR 8a 、-CN、-OH、-NO2、-COOH、-CONH2、-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 monospiroalkyl, substituted or unsubstituted heteromonospiroalkyl, substituted or unsubstituted C 6～14 aryl, and substituted or unsubstituted 5-14 membered heteroaryl, wherein the substituted C 1～6 alkyl, substituted C 1～6 alkoxy, substituted C 3～6 cycloalkyl, substituted 3-6 membered heterocycloalkyl, substituted monospiroalkyl, substituted heteromonospiroalkyl, substituted C 6～14 aryl, and substituted 5-14 membered heteroaryl are each independently substituted independently selected from -OH, halogen, unsubstituted C 1-6alkyl, -NH2, -NO2, unsubstituted -COC 1-6 substituted with one or more substituents selected from alkyl, -CN, and =O groups;

[0012] R 8a selected from:

[0013]

[0014] R 8b and R 8c each independently selected from unsubstituted C 1～6 alkyl;

[0015] R1 and R3 are each independently selected from -H, halogen, -NH2, -CN, -OH, -NO2, -COOH, substituted or unsubstituted C 1～6 alkyl and substituted or unsubstituted C 1～6 alkoxy, wherein the substituted C 1～6 alkyl and substituted C 1～6 alkoxy are each independently substituted with one or more substituents independently selected from -OH, halogen, unsubstituted C 1-6 alkyl, -NH2, -NO2, unsubstituted -COC 1-6 alkyl, -CN, and =O groups;

[0016] R2 is selected from -H, halogen, -NH2, -CN, -OH, -NO2, carboxyl, -NHR 2a , -NR 2a R 2b , -CONH2, -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 monospiroalkyl, substituted or unsubstituted heteromonospiroalkyl, substituted or unsubstituted C 4～8 bridged cycloalkyl and substituted or unsubstituted 4- to 8-membered heterobridged cycloalkyl, wherein the substituted C 1～6 alkyl, substituted C 1～6 alkoxy, substituted C 3～6 cycloalkyl, substituted 3- to 6-membered heterocycloalkyl, substituted monospiroalkyl, substituted heteromonospiroalkyl, substituted C4～8 The bridged cycloalkyl and substituted 4- to 8-membered hetero-bridged cycloalkyl are each independently substituted by one or more substituents independently selected from -OH, halogen, unsubstituted C 1-6 alkyl, -NH2, -NO2, unsubstituted -COC 1-6 alkyl, -CN, and =O groups;

[0017] Alternatively, R2 and the adjacent R3 are cyclized to form a substituted or unsubstituted C6 or C 10 aryl, substituted or unsubstituted 5- to 8-membered heteroaryl, or substituted or unsubstituted non-aromatic 5- to 8-membered heterocyclic group, wherein the substituted C6 or C 10 aryl, substituted 5- to 8-membered heteroaryl, or substituted non-aromatic 5- to 8-membered heterocyclic group are each independently substituted by one or more substituents independently selected from -OH, halogen, unsubstituted C 1-6 alkyl, -NH2, -NO2, unsubstituted -COC 1-6 alkyl, -CN, and =O groups;

[0018] R 2a and R 2b are each independently selected from unsubstituted C 1～6 alkyl;

[0019] R7 is selected from -H, halogen, -CN, -COOR 7a , -COR 7b , substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, -CONH2, -C(O)-COOR 7a , substituted or unsubstituted C 3～6 cycloalkyl, substituted or unsubstituted C 2～6 heterocycloalkyl, substituted or unsubstituted monospirocycloalkyl, and substituted or unsubstituted heteromonospirocycloalkyl; R 7a is -H, substituted or unsubstituted C 1-6 alkyl, or substituted or unsubstituted C 3-6 cycloalkyl; R 7b is 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 the substituted C 2-6 alkenyl, substituted C 2-6 alkynyl, substituted C 3～6 cycloalkyl, substituted C 2～6 heterocycloalkyl, substituted monospirocycloalkyl, substituted heteromonospirocycloalkyl, substituted C 1-6An alkyl group, a substituted 3- to 6-membered heteroalkyl group, a substituted C 6～14 aryl group, and a substituted 5- to 10-membered heteroaryl group are each independently substituted by one or more substituents independently selected from -OH, halogen, -NH2, -NO2, unsubstituted C 1～6 alkyl group, unsubstituted C 1～6 alkoxy group, unsubstituted C 3～6 cycloalkyl group, unsubstituted -NH-C 1～6 alkyl group, unsubstituted -N(C 1～6 alkyl)(C 1～6 alkyl), unsubstituted -NH-C 3～6 cycloalkyl group, unsubstituted -N(C 3～6 cycloalkyl)(C 3～6 cycloalkyl), unsubstituted 3- to 6-membered heteroalkyl group, unsubstituted C 6～14 aryl group, or unsubstituted 5- to 10-membered heteroaryl group;

[0020] indicates the presence or absence of a bond;

[0021] i) When the bond is absent, X3 is also absent, and R4 and R5 are each independently selected from hydrogen, hydroxy, halogen, =O, substituted or unsubstituted C 1～6 alkyl group, and substituted or unsubstituted C 1～6 alkoxy group, where the case where R4 and R5 are each independently selected from "=O" means that another hydrogen atom at the same substitution position is simultaneously replaced by the oxygen atom, and the substituted C 1～6 alkyl group and substituted C 1～6 alkoxy group are each independently substituted by one or more substituents independently selected from -OH, halogen, unsubstituted C 1-6 alkyl group, -NH2, -NO2, unsubstituted -COC 1-6 alkyl group, -CN, and =O group;

[0022] ii) When the bond is present, X3 is CH2, and R4 and R5 are both hydrogen;

[0023] indicates a single bond or a double bond;

[0024] i) When the single bond is indicated, ring A and -(R6) m are absent, and Y1 and Y2 are each independently CR9R 10 , O, or NR 10 ;

[0025] Each R9 and R 10 is independently selected from -H, halogen, -OH, substituted or unsubstituted C1～6 Alkyl and substituted or unsubstituted C 1～6 alkoxy, wherein the substituted C 1～6 alkyl and substituted C 1～6 alkoxy are each independently substituted by one or more substituents independently selected from OH, halogen, unsubstituted C 1-6 alkyl, -NH2, -NO2, unsubstituted -COC 1-6 alkyl, -CN, and =O groups;

[0026] ii) When represents a double bond, Y1 and Y2 are both C, ring A is present, and ring A is selected from naphthyl, phenyl, or a 5- to 6-membered heteroaryl;

[0027] R6 is selected from halogen, -NH2, -NHR 6a , -NR 6a R 6b , -CN, -CONH2, -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, wherein R 6a and R 6b are each independently unsubstituted C 1～6 alkyl; n is selected from 0, 1, or 2, wherein the substituted -SO n C 1-6 alkyl, substituted C 1-6 alkyl, and substituted C 1～6 alkoxy are each independently substituted by one or more substituents independently selected from -OH, halogen, unsubstituted C 1-6 alkyl, -NH2, -NO2, unsubstituted -COC 1-6 alkyl, -CN, and =O groups;

[0028] m is selected from 0, 1, 2, 3, or 4;

[0029] wherein the number of ring atoms of the monospiroalkyl and heteromonospiroalkyl is independently selected from 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, and the count of each ring includes the spiro atom; and

[0030] the substituent "=O" means that two hydrogen atoms at the same substitution position are replaced by an oxygen atom.

[0031] In some embodiments of the present application, the compounds represented by formula (I) do not include the following compounds:

[0032]

[0033] On the other hand, 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 a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0034] 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 to an individual in need 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.

[0035] In still another aspect, the present application provides the use of 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, in the preparation of a drug for treating and / or preventing diseases, disorders, and conditions mediated by SHP2 activity.

[0036] In still 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 treating and / or preventing diseases, disorders, and conditions mediated by SHP2 activity.

[0037] In still another aspect, the present application provides the use of 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, in treating and / or preventing diseases, disorders, and conditions mediated by SHP2 activity. DETAILED DESCRIPTION OF THE INVENTION

[0039] In the following description, certain specific details are included to provide a thorough understanding of the various disclosed embodiments. However, those skilled in the relevant art will recognize that the embodiments can be practiced without one or more of these specific details, or with other methods, components, materials, etc.

[0040] Unless otherwise required in the present application, throughout the specification and the claims that follow, the word "comprise" and its English variants such as "comprises" and "comprising" shall be interpreted in an open, inclusive sense, i.e., "including but not limited to".

[0041] As used throughout this specification, the phrases "an embodiment", "some embodiments", "the embodiment", "in another embodiment", or "in certain embodiments" mean that at least one embodiment includes specific reference elements, structures, or features related to those described in that embodiment. Thus, the phrases "in an embodiment", "in the embodiment", "in another embodiment", or "in certain embodiments" that appear in different places throughout the specification do not necessarily all refer to the same embodiment. In addition, the specific elements, structures, or features may be combined in any suitable manner in one or more embodiments.

[0042] It should be understood that the singular forms of the articles "a", "an", and "the" (corresponding to the English "a", "an", and "the") used in the specification of this application and the appended claims include plural objects, unless otherwise expressly specified in the text. Thus, for example, a reaction that includes "a catalyst" includes one catalyst, or two or more catalysts. It should also be understood that the term "or" is generally used in its inclusive sense of "and / or", unless otherwise expressly specified in the text.

[0043] The object of the present application is to provide a class of novel heterocyclic compounds or their prodrugs, tautomers, stereoisomers, solvates, isotope derivatives, or pharmaceutically acceptable salts thereof that are used as SHP2 inhibitors, and at the same time provide the use of such compounds or their prodrugs, tautomers, stereoisomers, solvates, isotope derivatives, or pharmaceutically acceptable salts thereof in the treatment and prevention of diseases, disorders, and conditions mediated by SHP2 activity.

[0044] On the one hand, the present application provides a compound represented by formula (I-1) or its prodrug, tautomer, optical isomer, solvate, isotope derivative, or pharmaceutically acceptable salt thereof,

[0045]

[0046] X is selected from a bond or -S-;

[0047] X1 and X2 are each independently selected from N and CR8; where each R8 is independently selected from -H, halogen, -NH2, -NHR 8b 、-NR 8b R 8c 、-NHCOR 8a 、-CN、-OH、-NO2、-COOH、-CONH2、-CONHR 8b 、-CONR 8b R 8c 、-COOR 8b 、substituted or unsubstituted C 1～6alkyl, 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 monospiroalkyl, substituted or unsubstituted heteromonospiroalkyl, substituted or unsubstituted C 6～14 aryl, and substituted or unsubstituted 5- to 14-membered heteroaryl, wherein the substituted C 1～6 alkyl, substituted C 1～6 alkoxy, substituted C 3～6 cycloalkyl, substituted 3- to 6-membered heterocycloalkyl, substituted monospiroalkyl, substituted heteromonospiroalkyl, substituted C 6～14 aryl, and substituted 5- to 14-membered heteroaryl are each independently substituted by one or more substituents independently selected from -OH, halogen, unsubstituted C 1-6 alkyl, -NH2, -NO2, unsubstituted -COC 1-6 alkyl, -CN, and =O groups;

[0048] R 8a is selected from:

[0049]

[0050] R 8b and R 8c are each independently selected from unsubstituted C 1～6 alkyl;

[0051] R1 and R3 are each independently selected from -H, halogen, -NH2, -CN, -OH, -NO2, -COOH, substituted or unsubstituted C 1～6 alkyl, and substituted or unsubstituted C 1～6 alkoxy, wherein the substituted C 1～6 alkyl and substituted C 1～6 alkoxy are each independently substituted by one or more substituents independently selected from -OH, halogen, unsubstituted C 1-6 alkyl, -NH2, -NO2, unsubstituted -COC 1-6 alkyl, -CN, and =O groups;

[0052] R2 is selected from -H, halogen, -NH2, -CN, -OH, -NO2, carboxyl, -NHR 2a , -NR 2a R 2b , -CONH2, -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 monospiroalkyl, substituted or unsubstituted heteromonospiroalkyl, substituted or unsubstituted C 4～8 bridged cycloalkyl and substituted 4- to 8-membered heterobridged cycloalkyl, wherein the substituted C 1～6 alkyl, substituted C 1～6 alkoxy, substituted C 3～6 cycloalkyl, substituted 3- to 6-membered heterocycloalkyl, substituted monospiroalkyl, substituted heteromonospiroalkyl, substituted C 4～8 bridged cycloalkyl and substituted 4- to 8-membered heterobridged cycloalkyl are each independently substituted by one or more substituents independently selected from -OH, halogen, unsubstituted C 1-6 alkyl, -NH2, -NO2, unsubstituted -COC 1-6 alkyl, -CN and =O groups;

[0053] Or R2 and adjacent R3 cyclize to form a substituted or unsubstituted C6 or C 10 aryl, substituted or unsubstituted 5- to 8-membered heteroaryl or substituted or unsubstituted non-aromatic 5- to 8-membered heterocyclic group, wherein the substituted C6 or C 10 aryl, substituted 5- to 8-membered heteroaryl or substituted non-aromatic 5- to 8-membered heterocyclic group are each independently substituted by one or more substituents independently selected from -OH, halogen, unsubstituted C 1-6 alkyl, -NH2, -NO2, unsubstituted -COC 1-6 alkyl, -CN and =O groups;

[0054] R 2a and R 2b are each independently selected from unsubstituted C 1～6 alkyl;

[0055] R7 is selected from -H, halogen, -CN, -COOR 7a , -COR 7b , substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, -CONH2, -C(O)-COOR 7a , substituted or unsubstituted C 3～6 cycloalkyl, substituted or unsubstituted C 2～6 heterocycloalkyl, substituted or unsubstituted monospiroalkyl and substituted or unsubstituted heteromonospiroalkyl; R 7ais -H, substituted or unsubstituted C 1-6 alkyl or substituted or unsubstituted C 3-6 cycloalkyl; R 7b is selected from -H, substituted or unsubstituted C 1～6 alkyl, substituted or unsubstituted C 3～6 cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C 6～14 aryl and substituted or unsubstituted 5-10 membered heteroaryl; wherein the substituted C 2-6 alkenyl, substituted C 2-6 alkynyl, substituted C 3～6 cycloalkyl, substituted C 2～6 heterocycloalkyl, substituted monospiroalkyl, substituted heteromonospiroalkyl, substituted C 1-6 alkyl, substituted 3-6 membered heterocycloalkyl, substituted C 6～14 aryl and substituted 5-10 membered heteroaryl are each independently substituted by one or more substituents independently selected from -OH, halogen, -NH2, -NO2, 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 3-6 membered heterocycloalkyl, unsubstituted C 6～14 aryl or unsubstituted 5-10 membered heteroaryl;

[0056] indicates the presence or absence of a bond;

[0057] i) when indicating the absence of a bond, X3 is also absent, and R4 and R5 are each independently selected from hydrogen, hydroxy, halogen, =O, substituted or unsubstituted C 1～6 alkyl and substituted or unsubstituted C 1～6 alkoxy, where the case where R4 and R5 are each independently selected from "=O" means that another hydrogen atom at the same substitution position is simultaneously replaced by the oxygen atom, wherein the substituted C 1～6 alkyl and substituted C 1～6 alkoxy are each independently substituted by one or more substituents independently selected from -OH, halogen, unsubstituted C 1-6 alkyl, -NH2, -NO2, unsubstituted -COC 1-6substituted by one or more substituents selected from alkyl, -CN and =O groups;

[0058] ii) When representing the presence of a bond, X3 is CH2, and both R4 and R5 are hydrogen;

[0059] represents a single bond or a double bond;

[0060] i) When represents a single bond, ring A and -(R6) m do not exist, and Y1 and Y2 are each independently CR9R 10 , O or NR 10 ;

[0061] Each R9 and R 10 is independently selected from -H, halogen, -OH, substituted or unsubstituted C 1～6 alkyl and substituted or unsubstituted C 1～6 alkoxy, wherein the substituted C 1～6 alkyl and substituted C 1～6 alkoxy are each independently substituted by one or more substituents independently selected from OH, halogen, unsubstituted C 1-6 alkyl, -NH2, -NO2, unsubstituted -COC 1-6 alkyl, -CN and =O groups;

[0062] ii) When represents a double bond, both Y1 and Y2 are C, ring A exists, and ring A is selected from naphthyl, phenyl or 5-6 membered heteroaryl;

[0063] R6 is selected from halogen, -NH2, -NHR 6a , -NR 6a R 6b , -CN, -CONH2, -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, wherein R 6a and R 6b are each independently unsubstituted C 1～6 alkyl; n is selected from 0, 1 or 2, wherein the substituted -SO n C 1-6 alkyl, substituted C 1-6 alkyl and substituted C 1～6The alkoxy groups are each independently substituted by one or more substituents independently selected from -OH, halogen, unsubstituted C 1-6 alkyl, -NH2, -NO2, unsubstituted -COC 1-6 alkyl, -CN and =O groups;

[0064] m is selected from 0, 1, 2, 3 or 4;

[0065] wherein the number of ring atoms of the monospiroalkyl and heteromonospiroalkyl groups is independently selected from 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, and the count of each ring includes the spiro atom; and

[0066] The substituent "=O" means that two hydrogen atoms at the same substitution position are replaced by an oxygen atom.

[0067] In some embodiments of the present application, the compounds represented by formula (I) do not include the following compounds:

[0068]

[0069]

[0070] In some embodiments of the present application, the present application provides the compounds represented by formula (I) and their pharmaceutically acceptable salts,

[0071]

[0072] X is selected from a bond or S;

[0073] X1 and X2 are each independently selected from N or CR8; wherein R8 is selected from -H, halogen, -NH2, -NHR 8b , -NR 8b R 8c , -NHCOR 8a , -CN, -OH, -NO2, -COOH, -CONH2, -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 heteromonospiroalkyl; the "substituted" means that the substituent is independently selected from one or more -OH, halogen, C 1-6 alkyl, -NH2, -NO2, -COCH3 and, -CN and =O groups, and when the substituent is "=O", it means that two hydrogen atoms at the same substitution position are replaced by an oxygen atom;

[0074] Among them, R 8a is selected from:

[0075]

[0076] R 8b and R 8c each independently is selected from C 1～6 alkyl;

[0077] R1 and R3 each independently are selected from -H, halogen, -NH2, -CN, -OH, -NO2, -COOH, substituted or unsubstituted C 1～6 alkyl, substituted or unsubstituted C 1～6 alkoxy; the "substitution" means that the substituent is independently selected from one or more groups of -OH, halogen, C 1-6 alkyl, -NH2, -NO2, -COCH3, and, -CN and =O. When the substituent is "=O", it means that two hydrogen atoms at the same substitution position are replaced by an oxygen atom;

[0078] R2 is selected from -H, halogen, -NH2, -CN, -OH, -NO2, carboxyl, -NHR 2a 、-NR 2a R 2b 、-CONH2, -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 monospiroalkyl, substituted or unsubstituted heteromonospiroalkyl, substituted or unsubstituted C 4～8 bridged cycloalkyl and substituted or unsubstituted 4- to 8-membered heterobridged cycloalkyl; wherein, the number of ring atoms of the monospiroalkyl and heteromonospiroalkyl is selected from 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, and the count of each ring includes the spiro atom; the "substitution" means that the substituent is independently selected from one or more groups of -OH, halogen, C 1-6 alkyl, -NH2, -NO2, -COCH3, and, -CN and =O. When the substituent is "=O", it means that two hydrogen atoms at the same substitution position are replaced by an oxygen atom;

[0079] Or R2 cyclizes with adjacent R3 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 "substituted" means that the substituents are independently selected from one or more -OH, halogen, C 1-6 alkyl, -NH2, -NO2, -COCH3, and, -CN and =O groups, and the case where the substituent is "=O" means that two hydrogen atoms at the same substitution position are replaced by an oxygen atom;

[0080] R 2a and R 2b are each independently selected from C 1～6 alkyl;

[0081] R7 is selected from -H, halogen, -CN, -COOR 7a , -COR 7b , C 2-6 alkenyl, -CONH2, substituted or unsubstituted C 3～6 cycloalkyl, substituted or unsubstituted C 3～6 heterocycloalkyl and substituted or unsubstituted heteromonospiroalkyl containing 1 or 2 heteroatoms, wherein the number of ring atoms of the heteromonospiroalkyl is selected from 3-membered / 5-membered, 4-membered / 4-membered, 4-membered / 5-membered, and the count of each ring includes the spiro atom; R 7a is -H or substituted or unsubstituted C 1-6 alkyl; R 7b is 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 heteroaryl ring group; the "substituted" means that the substituents are independently selected from one or more -OH, halogen, -NH2, -NO2, C 1～6 alkyl, C 1～6 alkoxy, 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 heteroaryl ring group;

[0082] indicates the presence or absence of a bond;

[0083] i) When the bond does not exist, X3 does not exist either, and R4 and R5 are each independently selected from hydrogen, hydroxyl, halogen, =O, substituted or unsubstituted C 1～6 alkyl and substituted or unsubstituted C 1～6 alkoxy; when R4 and R5 are each independently selected from "=O", it means that another hydrogen atom at the same substitution position is simultaneously replaced by this oxygen atom; the "substitution" means that the substituents are independently selected from one or more -OH, halogen, C 1-6 alkyl, -NH2, -NO2, -COCH3, and, -CN and =O groups. When the substituent is "=O", it means that two hydrogen atoms at the same substitution position are replaced by an oxygen atom;

[0084] ii) When the bond exists, X3 is CH2, and both R4 and R5 are hydrogen;

[0085] represents a single bond or a double bond;

[0086] 1) When represents a single bond, ring A and -(R6) m do not exist, and Y1 and Y2 are each independently CR9R 10 , O or NR 10 ;

[0087] Each R9 and R 10 is independently selected from -H, halogen, -OH, substituted or unsubstituted C 1～6 alkyl, substituted or unsubstituted C 1～6 alkoxy; the "substitution" means that the substituents are independently selected from one or more -OH, halogen, C 1-6 alkyl, -NH2, -NO2, -COCH3, and, -CN and =O groups. When the substituent is "=O", it means that two hydrogen atoms at the same substitution position are replaced by an oxygen atom;

[0088] ii) When represents a double bond, Y1 and Y2 are both C, ring A exists, and ring A is selected from phenyl or a 5- to 6-membered heteroaryl;

[0089] R6 is selected from halogen, -NH2, -NHR 6a , -NR 6a R 6b , -CN, -CONH2, -CONHR 6a , -CONR 6a R 6b , -COR 6a , -COOH, -OH, -SO n C 1-6 alkyl, substituted or unsubstituted C 1-6Alkyl, substituted or unsubstituted C 1～6 alkoxy; wherein, R 6a and R 6b are each independently C 1～6 alkyl; n is selected from 0, 1 or 2; the "substitution" means that the substituents are independently selected from one or more -OH, halogen, C 1-6 alkyl, -NH2, -NO2, -COCH3, and, -CN and =O groups. When the substituent is "=O", it means that two hydrogen atoms at the same substitution position are replaced by an oxygen atom;

[0090] m is selected from 0, 1, 2, 3 or 4;

[0091] Unless otherwise specified, the heteroatoms in the above-mentioned heterocycloalkyl, heteroaryl, heterocyclic, heteromonospirocyclic, and heterobicyclic groups are independently selected from O, N or S, and the number of heteroatoms is 1, 2 or 3.

[0092] In some embodiments of the present application, the present application provides the compounds of formula (I) and their pharmaceutically acceptable salts,

[0093]

[0094] X is selected from a bond or S;

[0095] X1 and X2 are each independently selected from N or CR8; wherein R8 is selected from -H, halogen, -NH2, -NHR 8b , -NR 8b R 8c , -NHCOR 8a , -CN, -OH, -NO2, -COOH, -CONH2, -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;

[0096] wherein, R 8a is selected from:

[0097]

[0098] R 8b and R 8c are each independently selected from C 1～6 alkyl;

[0099] R1 and R3 are each independently selected from -H, halogen, -NH2, -CN, -OH, -NO2, -COOH, substituted or unsubstituted C 1～6 alkyl, substituted or unsubstituted C 1～6 alkoxy;

[0100] R2 is selected from -H, halogen, -NH2, -CN, -OH, -NO2, carboxyl, -NHR 2a , -NR 2a R 2b , -CONH2, -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 heteroalkyl, substituted or unsubstituted monospiroalkyl, substituted or unsubstituted heteromonospiroalkyl, substituted or unsubstituted C 4～8 bridged cycloalkyl and substituted or unsubstituted 4- to 8-membered heterobridged cycloalkyl; wherein the ring atoms of the monospiroalkyl and heteromonospiroalkyl are selected from 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, and the count of each ring includes the spiro atom;

[0101] or R2 cyclizes with the adjacent R3 to form a substituted or unsubstituted 5- to 8-membered heteroaryl or a substituted or unsubstituted non-aromatic 5- to 8-membered heterocyclic group;

[0102] R 2a and R 2b are each independently selected from C 1～6 alkyl;

[0103] R7 is selected from halogen, -CN, -COOR 7a , C 2-6 alkenyl, -CONH2, substituted or unsubstituted C 3～6 cycloalkyl, substituted or unsubstituted C 3～6 heteroalkyl and substituted or unsubstituted heteromonospiroalkyl containing 1 or 2 heteroatoms, wherein the ring atoms of the heteromonospiroalkyl are selected from 3-membered / 5-membered, 4-membered / 4-membered, 4-membered / 5-membered, and the count of each ring includes the spiro atom; R 7a is H or C 1-6 alkyl;

[0104] Indicates the presence or absence of a bond;

[0105] i) When indicating the absence of a bond, X3 is also absent, and R4 and R5 are each independently selected from hydrogen, hydroxyl, halogen, =O, substituted or unsubstituted C 1～6 alkyl and substituted or unsubstituted C 1～6 alkoxy; the case where R4 and R5 are each independently selected from "=O" means that another hydrogen atom at the same substitution position is simultaneously substituted by this oxygen atom;

[0106] ii) When indicating the presence of a bond, X3 is CH2, and both R4 and R5 are hydrogen;

[0107] Indicates a single bond or a double bond;

[0108] 1) When indicating a single bond, ring A and -(R6) m are absent, and Y1 and Y2 are each independently CR9R 10 , O or NR 10 ;

[0109] Each R9 and R 10 is independently selected from -H, halogen, -OH, substituted or unsubstituted C 1～6 alkyl, substituted or unsubstituted C 1～6 alkoxy;

[0110] ii) When indicating a double bond, both Y1 and Y2 are C, ring A is present, and ring A is selected from phenyl or a 5- to 6-membered heteroaryl;

[0111] R6 is selected from halogen, -NH2, -NHR 6a , -NR 6a R 6b , -CN, -CONH2, -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 alkoxy; wherein, R 6a and R 6b are each independently C 1～6 alkyl; n is selected from 0, 1 or 2;

[0112] m is selected from 0, 1, 2, 3 or 4;

[0113] The term "substituted" means that the substituents are independently selected from one or more of -OH, halogen, C 1-6 alkyl, -NH2, -NO2, -COCH3, and, -CN and =O groups. When the substituent is "=O", it means that two hydrogen atoms at the same substitution position are replaced by an oxygen atom;

[0114] Unless otherwise specified, the heteroatoms in the above-mentioned heterocycloalkyl, heteroaryl, heterocyclic, heteromonospirocyclic, and heterobicyclic groups are independently selected from O, N, or S, and the number of heteroatoms is 1, 2, or 3.

[0115] In some embodiments of the present application, the compounds provided by the present application or their prodrugs, tautomers, stereoisomers, solvates, isotope derivatives, or pharmaceutically acceptable salts thereof have the structure shown in formula (I-a):

[0116]

[0117] Wherein, R1, R2, R3, R4, R5, R6, R7, X1, X2, X3, Y1, Y2, ring A, and m are defined according to the compound of formula (I-1) of the present application.

[0118] In some embodiments of the present application, the compounds provided by the present application or their prodrugs, tautomers, stereoisomers, solvates, isotope derivatives, or pharmaceutically acceptable salts thereof have the structure shown in formula (I-b):

[0119]

[0120] Wherein, R1, R2, R3, R4, R5, R6, R7, X1, X2, X3, Y1, Y2, ring A, and m are defined according to the compound of formula (I-1) of the present application.

[0121] In some embodiments of the present application, the compounds of formula (I-1), formula (I), formula (I-a), and formula (I-b) or their prodrugs, tautomers, stereoisomers, solvates, isotope derivatives, or pharmaceutically acceptable salts thereof are provided, wherein the heteroatoms in the heterocycloalkyl, heteroaryl, heterocyclic, heteromonospiroalkyl, and heterobicyclic groups are independently selected from O, N, or S, and the number of heteroatoms is 1, 2, or 3.

[0122] In some embodiments of the present application, the present application provides compounds of formula (I-1), formula (I), formula (I-a) and formula (I-b), or prodrugs, tautomers, stereoisomers, solvates, isotopic derivatives or pharmaceutically acceptable salts thereof, wherein R1 and R3 are each independently selected from -H, halogen, -NH2, -CN, -OH, -NO2, -COOH, substituted or unsubstituted C 1～6 alkyl and substituted or unsubstituted C 1～6 alkoxy, wherein the substituted C 1～6 alkyl and the substituted C 1～6 alkoxy are each independently substituted by one or more substituents independently selected from -OH, halogen, -NH2, -NO2, -COC 1-6 alkyl and -CN groups; or,

[0123] R1 and R3 are each independently selected from -H, halogen, -NH2, -CN, -OH, substituted or unsubstituted C 1～6 alkyl and substituted or unsubstituted C 1～6 alkoxy, wherein the substituted C 1～6 alkyl and the substituted C 1～6 alkoxy are each independently substituted by one or more substituents independently selected from halogen, -NO2, -COC 1-6 alkyl (e.g., -COCH3) and -CN groups; or,

[0124] R1 and R3 are each independently selected from -H, halogen, -NH2, -CN, -OH, -NO2, -COOH, halogen-substituted or unsubstituted C 1～6 alkyl and halogen-substituted or unsubstituted C 1～6 alkoxy; or

[0125] R1 and R3 are each independently selected from -H, halogen and halogen-substituted C 1～6 alkyl; or

[0126] R1 and R3 are each independently selected from -H, -F, -Cl and fluorinated methyl (e.g., CF3); or

[0127] One of R1 and R3 is selected from -H, and the other is selected from -F, -Cl and fluorinated methyl (e.g., CF3); or

[0128] One of R1 and R3 is selected from -H, and the other is selected from -Cl.

[0129] In some embodiments of the present application, the compounds provided by the present application and their pharmaceutically acceptable salts, wherein R1 and R3 are each independently selected from -H, -F, -Cl, -Br, -NH2, -OH, halogenated or unsubstituted C1～6 alkyl, halogenated or unsubstituted C 1～6 alkoxy group.

[0130] In some embodiments of the present application, the compounds and their pharmaceutically acceptable salts provided by the present application, wherein R1 and R3 are each independently selected from -H, -F, -Cl, -NH2, -OH, fluorinated or unsubstituted C 1～6 alkyl, fluorinated or unsubstituted C 1～6 alkoxy group.

[0131] In some embodiments of the present application, the compounds and their pharmaceutically acceptable salts provided by the present application, wherein R1 and R3 are each independently selected from -H, -F, -Cl, -NH2, fluorinated or unsubstituted methyl.

[0132] In some embodiments of the present application, the present application provides compounds of formula (I-1), formula (I), formula (I-a) and formula (I-b) or their prodrugs, tautomers, stereoisomers, solvates, isotope derivatives or their pharmaceutically acceptable salts, wherein R2 is selected from -H, halogen, -NH2, -OH, -NHR 2a , -NR 2a R 2b , -CONH2, -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 monospirocycloalkyl and substituted or unsubstituted heteromonospirocycloalkyl, wherein R 2a and R 2b are each independently selected from unsubstituted C 1～6 alkyl, the number of ring atoms of the monospirocycloalkyl and heteromonospirocycloalkyl is independently selected from 3-membered / 5-membered, 4-membered / 4-membered or 4-membered / 5-membered rings, wherein the count of each ring includes the spiro atom, and the substituted C 1～6 alkyl, substituted C 1～6 alkoxy, substituted C 3～6 cycloalkyl, substituted 3- to 6-membered heterocycloalkyl, substituted monospirocycloalkyl and substituted heteromonospirocycloalkyl are each independently substituted by independently selected from -OH, halogen, C 1-6 alkyl, -NH2, -COC 1-6substituted by one or more substituents selected from an alkyl group (e.g., -COCH3), and -CN group; or R2 and adjacent R3 are cyclized to form a substituted or unsubstituted C6 aryl group, a substituted or unsubstituted 5- to 6-membered heteroaryl group, or a substituted or unsubstituted non-aromatic 5- to 6-membered heterocyclic group, wherein the substituted C6 aryl group, the substituted 5- to 6-membered heteroaryl group, or the substituted non-aromatic 5- to 6-membered heterocyclic group is independently substituted by independently selected from halogen, -NO2, -COC 1-6 substituted by one or more substituents selected from an alkyl group (e.g., -COCH3) and -CN group; or

[0133] R2 is selected from -H, halogen, -NH2, -OH, -NHR 2a , -NR 2a R 2b , -CONH2, -NHCOR 2a , -N(R 2a )-COR 2b , a substituted or unsubstituted C 1～6 alkyl group, a substituted or unsubstituted C 1～6 alkoxy group, a substituted or unsubstituted C 3～6 cycloalkyl group, a substituted or unsubstituted 3- to 6-membered heterocycloalkyl group, a substituted or unsubstituted monospiroalkyl group, and a substituted or unsubstituted heteromonospiroalkyl group, wherein R 2a and R 2b are each independently selected from unsubstituted C 1～3 alkyl groups, the monospiroalkyl group and the heteromonospiroalkyl group have a ring atom number of 4-membered / 4-membered ring, wherein the count of each ring includes the spiro atom, and the substituted C 1～6 alkyl group, the substituted C 1～6 alkoxy group, the substituted C 3～6 cycloalkyl group, the substituted 3- to 6-membered heterocycloalkyl group, the substituted monospiroalkyl group, and the substituted heteromonospiroalkyl group are each independently substituted by one or more substituents selected from -OH, halogen, C 1-3 alkyl group, and -NH2 group, or R2 and adjacent R3 are cyclized to form a substituted or unsubstituted 5- to 6-membered heteroaryl group or a substituted or unsubstituted non-aromatic 5- to 6-membered heterocyclic group, wherein the substituted 5- to 6-membered heteroaryl group or the substituted non-aromatic 5- to 6-membered heterocyclic group is independently substituted by independently selected from halogen (e.g., -F and -Cl), -COC 1-6 alkyl group (e.g., -COCH3), and -CN group; or,

[0134] R2 is selected from -H, halogen (e.g., -F, -Cl, and -Br), -NH2, -OH, -NHR 2a , -NR 2a R 2b , a substituted or unsubstituted C1～6 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 heteromonospiroalkyl, wherein R 2a and R 2b are each independently selected from unsubstituted C 1～3 alkyl (e.g., methyl), the heteromonospiroalkyl having a ring atom count of 4-membered / 4-membered rings (e.g., a 4-membered / 4-membered spiro ring containing 1 O atom and 1 N atom), where the count of each ring includes the spiro atom, and the substituted C 1～6 alkyl, substituted C 1～6 alkoxy, substituted C 3～6 cycloalkyl, substituted 3- to 6-membered heterocycloalkyl, and substituted heteromonospiroalkyl are each independently substituted by one or more substituents independently selected from -OH, halogen, C 1-3 alkyl, and -NH2 groups; or R2 and adjacent R3 cyclize to form a substituted or unsubstituted 5- to 6-membered heteroaryl or a substituted or unsubstituted non-aromatic 5- to 6-membered heterocyclic group, wherein the substituted 5- to 6-membered heteroaryl or the substituted non-aromatic 5- to 6-membered heterocyclic group are each independently substituted by one or more substituents independently selected from halogen (e.g., F and Cl), -COC 1-6 alkyl (e.g., -COCH3), and -CN groups; or,

[0135] R2 is selected from -H, -F, -Cl, -NH2, -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 heteromonospiroalkyl, wherein the heteromonospiroalkyl has a ring atom count of 4-membered / 4-membered rings (e.g., a 4-membered / 4-membered spiro ring containing 1 O atom and 1 N atom), where the count of each ring includes the spiro atom, and the substituted C 1～6 alkyl, substituted C 3～6 cycloalkyl, substituted 3- to 6-membered heterocycloalkyl, and substituted heteromonospiroalkyl are each independently substituted by one or more substituents independently selected from -OH, halogen, C 1-3 alkyl, and -NH2 groups; or R2 is selected from -H, -F, -Cl, or -NH2; or R2 is selected from -H or -NH2; or,

[0136] R2 and the adjacent R3 cyclize to form a substituted or unsubstituted non-aromatic 5- to 6-membered heterocyclic group, wherein the substituted non-aromatic 5- to 6-membered heterocyclic group is independently substituted by one or more substituents independently selected from halogen (e.g., F and Cl), -COC 1-6 alkyl (e.g., -COCH3) and -CN groups; or,

[0137] R2 and the adjacent R3 cyclize to form a substituted or unsubstituted non-aromatic 5-membered heterocyclic group with a heteroatom of N and one heteroatom, wherein the substituted non-aromatic 5-membered heterocyclic group is independently substituted by one or more substituents independently selected from -F, -COCH3 and -CN groups; or,

[0138] R2 and the adjacent R3 cyclize to form

[0139] In some embodiments of the present application, the compounds and their pharmaceutically acceptable salts provided by the present application, wherein R2 is selected from -H, -F, -Cl, -Br, -NH2, -OH, -NHR 2a , -NR 2a R 2b , -CONH2, -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 heteroalkyl; wherein, R 2a and R 2b each independently selected from C 1～6 alkyl; or R2 and the adjacent R3 cyclize to form a substituted or unsubstituted 5- to 6-membered heteroaryl or a substituted or unsubstituted non-aromatic 5- to 6-membered heterocyclic group; wherein, the heteroatom in R2 or the cyclized structure of R2 and R3 is N, O or S, and the number of heteroatoms is selected from 1 and 2; "substituted" in the structure of R2 or the cyclized structure of R2 and R3 means that the substituents are independently selected from one or more groups of OH, -F, -Cl, -CH3, -COCH3 and -CN.

[0140] In some embodiments of the present application, the compounds and their pharmaceutically acceptable salts provided by the present application, wherein R2 is selected from -H, -F, -Cl, -Br, -NH2, -OH, -NHCH3, -N(CH3)2, and -CONH2; or R2 and adjacent R3 cyclize to form a substituted or unsubstituted 5-membered heteroaryl or a substituted or unsubstituted non-aromatic 5-membered heterocyclic group, the heteroatom in the R2 and R3 cyclized structure is N, and the number of heteroatoms is 1, wherein the "substituted" means that the substituents are independently selected from one or more groups of -F, -COCH3, and -CN.

[0141] In some embodiments of the present application, the compounds and their pharmaceutically acceptable salts provided by the present application, wherein R2 and adjacent R3 cyclize to form a substituted or unsubstituted 5-membered heteroaryl or a substituted or unsubstituted non-aromatic 5-membered heterocyclic group, wherein the heteroatom is N, and the number of heteroatoms is 1, wherein the "substituted" means that the substituents are independently selected from one or more groups of -F, -COCH3, and -CN.

[0142] In some embodiments of the present application, the compounds and their pharmaceutically acceptable salts provided by the present application, wherein R2 and adjacent R3 cyclize to form the following groups:

[0143]

[0144] In some embodiments of the present application, the compounds and their pharmaceutically acceptable salts provided by the present application, wherein R2 and adjacent R3 cyclize to form the following groups:

[0145] In some embodiments of the present application, the compounds and their pharmaceutically acceptable salts provided by the present application, wherein R2 and adjacent R3 cyclize to form the following groups:

[0146] In some embodiments of the present application, the present application provides compounds of formula (I-1), formula (I), formula (I-a), and formula (I-b) or their prodrugs, tautomers, stereoisomers, solvates, isotope derivatives, or their pharmaceutically acceptable salts, wherein R7 is selected from halogen, -CN, -COOR 7a , -COR 7b , -C(O)-COOR 7a , unsubstituted C 2-4 alkenyl, unsubstituted C 2-4 alkynyl, -CONH2, -C(O)-COOR 7a , substituted or unsubstituted C 3～6Cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted monospiroalkyl, and substituted or unsubstituted heteromonospiroalkyl containing one or two heteroatoms, wherein the ring atoms of the monospiroalkyl and heteromonospiroalkyl are independently selected from 3-membered / 5-membered, 4-membered / 4-membered, or 4-membered / 5-membered rings, where the count of each ring includes the spiro atom, wherein R 7a is -H, unsubstituted C 1-6 alkyl or unsubstituted C 3-6 cycloalkyl; R 7b is 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 the substituted C 3～6 cycloalkyl, substituted 3- to 6-membered heterocycloalkyl, substituted monospiroalkyl, substituted heteromonospiroalkyl, substituted C 1-6 alkyl, substituted C 6～14 aryl, and substituted 5- to 10-membered heteroaryl are each independently substituted by one or more substituents independently selected from -OH, halogen, -NH2, C 1～6 alkyl, 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,

[0147] R7 is selected from -F, -Cl, -Br, -CN, -COOR 7a , -COR 7b , -C(O)-COOR 7a , unsubstituted C2 alkenyl, unsubstituted C2 alkynyl, -CONH2, -C(O)-COOR 7a , substituted or unsubstituted 3- to 6-membered heterocycloalkyl, and substituted or unsubstituted heteromonospiroalkyl containing one or two heteroatoms independently selected from N and O, wherein the ring atoms of the heteromonospiroalkyl are independently 4-membered / 4-membered rings, where the count of each ring includes the spiro atom, wherein R 7a is -H, unsubstituted C 1-3 alkyl or unsubstituted C 3-4 cycloalkyl; R 7b is selected from -H, substituted or unsubstituted C 1～3 alkyl, substituted or unsubstituted C 3～6 cycloalkyl, substituted or unsubstituted C6 or C 10Aryl and substituted or unsubstituted 5- to 6-membered heteroaryl; wherein the substituted 3- to 6-membered heterocycloalkyl, substituted heteromonospiroalkyl, substituted C 1-3 alkyl, substituted C 3～6 cycloalkyl, substituted C6 or C 10 aryl and substituted 5- to 6-membered heteroaryl are each independently substituted by one or more substituents independently selected from -OH, halogen, -NH2, C 1～6 alkyl, 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,

[0148] R7 is selected from -F, -Cl, -Br, -CN, -COOR 7a , -COR 7b , unsubstituted C2 alkenyl, unsubstituted C2 alkynyl, -CONH2, -C(O)-COOR 7a , unsubstituted 3- to 6-membered heterocycloalkyl (such as oxetane or azetidine) and unsubstituted heteromonospiroalkyl containing 1 or 2 heteroatoms independently selected from N and O, wherein the ring atoms of the heteromonospiroalkyl are independently 4-membered / 4-membered rings, wherein each ring count includes the spiro atom, wherein R 7a is -H, unsubstituted C 1-3 alkyl (such as methyl) or unsubstituted C 3-4 cycloalkyl (such as cyclopropyl); R 7b is selected from -H or unsubstituted C 1～3 alkyl (such as methyl); or

[0149] R7 is selected from -Cl, -COOR 7a , -COR 7b , unsubstituted C2 alkenyl, unsubstituted C2 alkynyl, -C(O)-COOR 7a , unsubstituted 3- to 6-membered heterocycloalkyl (such as oxetane or azetidine) and unsubstituted heteromonospiroalkyl containing 1 or 2 heteroatoms independently selected from N and O, wherein the ring atoms of the heteromonospiroalkyl are independently 4-membered / 4-membered rings, wherein each ring count includes the spiro atom, wherein R 7a is -H, unsubstituted C 1-3 alkyl (such as methyl) or unsubstituted C 3-4 cycloalkyl (such as cyclopropyl); R 7b is selected from -H or unsubstituted C 1～3 alkyl (such as methyl); or

[0150] R7 is selected from -CN, -COOR7a , -COR 7b , unsubstituted C2 alkenyl, unsubstituted C2 alkynyl, -C(O)-COOR 7a , and unsubstituted 3- to 6-membered heterocycloalkyl (such as oxetane or azetidine), where R 7a is -H, unsubstituted C 1-3 alkyl (such as methyl) or unsubstituted C 3-4 cycloalkyl (such as cyclopropyl); R 7b is selected from -H or unsubstituted C 1～3 alkyl (such as methyl); or

[0151] R7 is selected from -CN, -COOR 7a , -COR 7b , unsubstituted C2 alkenyl and unsubstituted C2 alkynyl, where R 7a is -H, unsubstituted C 1-3 alkyl (such as methyl) or unsubstituted C 3-4 cycloalkyl (such as cyclopropyl); R 7b is selected from -H or unsubstituted C 1～3 alkyl (such as methyl); or

[0152] R7 is selected from -F, -Cl, -CN, -COOR 7a , -COR 7b , unsubstituted C2 alkenyl and unsubstituted 4-membered heterocycloalkyl (such as oxetane or azetidine), where R 7a is -H, unsubstituted C 1-3 alkyl (such as methyl) or unsubstituted C 3-4 cycloalkyl (such as cyclopropyl); R 7b is selected from -H or unsubstituted C 1～3 alkyl (such as methyl); or

[0153] R7 is selected from -F, -Cl,, -COOR 7a , -COR 7b , unsubstituted C2 alkenyl and unsubstituted 4-membered heterocycloalkyl (such as oxetane or azetidine), where R 7a and R 7b are both methyl; or

[0154] R7 is selected from -COOR 7a or -COR 7b , where R 7a is -H, unsubstituted C 1-2 alkyl (such as methyl) or unsubstituted C 3-4 cycloalkyl (such as cyclopropyl); R 7b is selected from -H or unsubstituted C 1～2an alkyl group (such as methyl); or

[0155] R7 is selected from -COOR 7a or -COR 7b , where R 7a and R 7b are both unsubstituted methyl groups; or

[0156] R7 is selected from -H, -Cl, -F, -CN, -CHO, -COOH, -COOCH3, -COCH3, -CONH2, -CH=CH2, or

[0157] R7 is selected from -Cl, -F, -CN, -CHO, -COOH, -COOCH3, -COCH3, -CONH2, -CH=CH2, or

[0158] R7 is selected from -F, -COOCH3, -COCH3, -CH=CH2.

[0159] In some embodiments of the present application, the compounds and their pharmaceutically acceptable salts provided by the present application, wherein R7 is selected from -H, -F, -Cl, -Br, -I, -CN, -COOR 7a , -COR 7b , -CH=CH2, substituted or unsubstituted C 3～6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted spiro[3.3]heptyl containing 1 or 2 heteroatoms independently selected from N and O; wherein, R 7a is -H or C 1-6 alkyl, R 7b is selected from -H, substituted or unsubstituted C 1～6 alkyl, substituted or unsubstituted C 3～6 cycloalkyl, substituted or unsubstituted C 6～14 aryl, and the "substitution" means that the substituents are independently selected from one or more of -OH, -F, -Cl, -NH2, -CH3, C 1～6 alkoxy, -NH-C 1～6 alkyl, -N(C 1～6 alkyl)-C 1～6 alkyl, 3- to 6-membered heterocycloalkyl groups.

[0160] In some embodiments of the present application, the compounds and their pharmaceutically acceptable salts provided by the present application, wherein R7 is selected from -H, -Cl, -Br, -I, -CN, -COOR 7a , -COR 7b , -CH=CH2, substituted or unsubstituted C 3～6 cycloalkyl, substituted or unsubstituted C3～6 Heterocycloalkyl and substituted or unsubstituted spiro[3.3]heptyl containing 1 or 2 heteroatoms independently selected from N and O; wherein, R 7a is -H or C 1-3 alkyl, and R 7b is selected from -H, substituted or unsubstituted C 1～3 alkyl, C 3～6 cycloalkyl, C 6～10 aryl, and the "substituted" means that the substituents are independently selected from one or more groups of -OH, -F, -Cl, -NH2, -CH3, -OCH3, -N(CH3)CH3, 3- to 6-membered heterocycloalkyl.

[0161] In some embodiments of the present application, the compounds and their pharmaceutically acceptable salts provided by the present application, wherein, R7 is selected from -H, -Cl, -Br, -I, -CN, -COOR 7a , -COR 7b , -CH=CH2, substituted or unsubstituted cyclopropyl, substituted or unsubstituted oxetanyl and substituted or unsubstituted spiro[3.3]heptyl containing 1 or 2 heteroatoms independently selected from N and O; wherein, R 7a is -H or C 1-3 alkyl, and R 7b is selected from -H, substituted or unsubstituted methyl, C 3～4 cycloalkyl, C 6～10 aryl, and the "substituted" means that the substituents are independently selected from one or more groups of -OH, -F, -Cl, -NH2, -OCH3, -N(CH3)CH3, 3- to 6-membered heterocycloalkyl.

[0162] In some embodiments of the present application, the compounds and their pharmaceutically acceptable salts provided by the present application, wherein, R7 is selected from -H, -Cl, -Br, -CN, -CHO, -COOH, -COOCH3, -COCH3, -CONH2, -COCH2F, -COCH2OH, -COCH2OCH3, -COCH2NH2, -COCH2N(CH3)CH3, -CH=CH2, cyclopropyl,

[0163] In some embodiments of the present application, the compounds and their pharmaceutically acceptable salts provided by the present invention, wherein, R7 is selected from -F, -Cl, -Br, -I, -CN, -COOR 7a , -CH=CH2, substituted or unsubstituted C 3～6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted spiro[3.3]heptyl containing 1 or 2 heteroatoms independently selected from N and O; wherein, R 7a is C1-6 alkyl group, and the "substituted" means that the substituents are independently selected from one or more groups of -OH, -F, -Cl, -CH3.

[0164] In some embodiments of the present application, the compounds and their pharmaceutically acceptable salts provided by the present invention, wherein R7 is selected from -Cl, -Br, -I, -CN, -COOR 7a , -CH=CH2, substituted or unsubstituted C 3～6 cycloalkyl group, substituted or unsubstituted C 3～6 heterocycloalkyl group and substituted or unsubstituted spiro[3.3]heptyl group containing 1 or 2 heteroatoms independently selected from N and O; wherein R 7a is C 1-3 alkyl group, and the "substituted" means that the substituents are independently selected from one or more groups of -OH, -F, -Cl, -CH3.

[0165] In some embodiments of the present application, the compounds and their pharmaceutically acceptable salts provided by the present invention, wherein R7 is selected from -Cl, -Br, -I, -CN, -COOR 7a , -CH=CH2, substituted or unsubstituted cyclopropyl group, substituted or unsubstituted oxetanyl group and substituted or unsubstituted spiro[3.3]heptyl group containing 1 or 2 heteroatoms independently selected from N and O; wherein R 7a is C 1-3 alkyl group, and the "substituted" means that the substituents are independently selected from one or more groups of -OH, -F, -Cl.

[0166] In some embodiments of the present application, the compounds and their pharmaceutically acceptable salts provided by the present invention, wherein R7 is selected from -Cl, -Br, -CN, -COOCH3, -CH=CH2, cyclopropyl group,

[0167] In some embodiments of the present application, the present application provides compounds of formula (I-1), formula (I), formula (I-a) and formula (I-b) or their prodrugs, tautomers, stereoisomers, solvates, isotopic derivatives or their pharmaceutically acceptable salts, wherein X1 and X2 are each independently selected from N and CR8; wherein each R8 is independently selected from -H, halogen, -NH2, -NHR 8b , -NR 8b R 8c , -NHCOR 8a , -OH, substituted or unsubstituted C 1～6 alkyl group, substituted or unsubstituted C 1～6 alkoxy group, substituted or unsubstituted C 3～6Cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted monospiroalkyl, substituted or unsubstituted heteromonospiroalkyl, substituted or unsubstituted C 6～14 Aryl, substituted or unsubstituted 5- to 14-membered heteroaryl, wherein the ring atoms of the monospiroalkyl and heteromonospiroalkyl are independently selected from 3-membered / 5-membered, 4-membered / 4-membered or 4-membered / 5-membered rings, and the count of each ring includes the spiro atom, wherein the substituted C 1～6 Alkyl, substituted C 1～6 Alkoxy, substituted C 3～6 Cycloalkyl, substituted 3- to 6-membered heterocycloalkyl, substituted monospiroalkyl, substituted heteromonospiroalkyl, substituted C 6～14 Aryl, substituted 5- to 14-membered heteroaryl are each independently substituted by one or more substituents independently selected from -OH, halogen, C 1-6 Alkyl and -NH2 groups;

[0168] R 8a Selected from:

[0169]

[0170] R 8b And R 8c Are each independently selected from unsubstituted C 1～6 Alkyl; or

[0171] X1 and X2 are each independently selected from N and CR8; wherein each R8 is independently selected from -H, halogen, -NH2, -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- to 6-membered heterocycloalkyl (e.g., oxetanyl and azetidinyl), substituted or unsubstituted heteromonospiroalkyl, substituted or unsubstituted C 6～10 Aryl or substituted or unsubstituted 5- to 6-membered heteroaryl, wherein the heteromonospiroalkyl has a 4-membered / 4-membered ring (e.g., a 4-membered / 4-membered spiro ring containing 1 O atom and 1 N atom), and the count of each ring includes the spiro atom, wherein the substituted C 1～6 Alkyl, substituted C 1～6 Alkoxy, substituted C 3～6 Cycloalkyl, substituted 3- to 6-membered heterocycloalkyl, substituted heteromonospiroalkyl, substituted C 6～10 Aryl, substituted 5- to 6-membered heteroaryl are each independently substituted by one or more substituents independently selected from -OH, halogen, C1-6 substituted by one or more substituents selected from alkyl groups and -NH2 groups;

[0172] R 8a selected from:

[0173]

[0174] R 8b and R 8c are each independently selected from unsubstituted C 1～3 alkyl; or

[0175] X1 and X2 are each independently selected from N and CR8; wherein each R8 is independently selected from -H, -F, -Cl, -NH2, -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- to 6-membered heterocycloalkyl (e.g., oxetanyl and azetidinyl), unsubstituted heteromonospiroalkyl, unsubstituted C 6～10 aryl or unsubstituted 5- to 6-membered heteroaryl, wherein the heteromonospiroalkyl has a ring atom count of 4 atoms / 4-membered ring (e.g., a 4 / 4 spiro ring containing 1 O atom and 1 N atom), and the count of each ring includes the spiro atom, and wherein the substituted 3- to 6-membered heterocycloalkyl is substituted by one or more substituents independently selected from -OH, halogen, C 1-6 alkyl and -NH2 groups;

[0176] R 8a selected from:

[0177]

[0178] R 8b and R 8c are each independently selected from unsubstituted C 1～3 alkyl; or

[0179] X1 and X2 are each independently selected from N and CR8; wherein each R8 is independently selected from -H, -NH2, -NHCOR 8a , unsubstituted C 6～10 aryl or unsubstituted 5- to 6-membered heteroaryl, wherein R 8a is selected from:

[0180] or

[0181] X1 and X2 are each independently selected from N and CR8; wherein R8 is selected from -H, -NH2, -NHCOR 8a , wherein R 8a is selected from: or

[0182] X1 and X2 are each independently selected from N and CR8; wherein, R8 is selected from -H, or

[0183] one of X1 and X2 is N and the other is CR8, wherein R8 is independently selected from H, -Cl, -NH2, -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 is selected from: or R8 is independently selected from H, -NH2, 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

[0184] both X1 and X2 are CR8; one of R8 is -H and the other R8 is selected from, -Cl, -NH2, -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 is selected from: or R8 is selected from -NH2, 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.

[0185] In some embodiments of the present application, the structural unit is not and is preferably selected from

[0186] In some embodiments of the present application, the present application provides compounds of formula (I-1), formula (I), formula (I-a) and formula (I-b) or their prodrugs, tautomers, stereoisomers, solvates, isotopic derivatives or pharmaceutically acceptable salts thereof, wherein one of X1 and X2 is N and the other is CR8, wherein R8 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 both X1 and X2 are CR8; one of R8 is -H and the other R8 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 R7 is selected from -H, -F, -Cl, -CN, -COOR7a , -COR 7b , unsubstituted C2 alkenyl and unsubstituted 4-membered heterocycloalkyl (such as oxetane or azetidine), wherein R 7a is -H, unsubstituted C 1-3 alkyl (such as methyl) or unsubstituted C 3-4 cycloalkyl (such as cyclopropyl); R 7b is selected from -H or unsubstituted C 1～3 alkyl (such as methyl); or R7 is selected from -F, -Cl, -COOR 7a , -COR 7b , unsubstituted C2 alkenyl and unsubstituted 4-membered heterocycloalkyl (such as oxetane or azetidine), wherein R 7a and R 7b are both methyl.

[0187] In some embodiments of the present application, the present application provides compounds of formula (I-1), formula (I), formula (I-a) and formula (I-b) or their prodrugs, tautomers, stereoisomers, solvates, isotopic derivatives or pharmaceutically acceptable salts thereof, wherein one of X1 and X2 is N and the other is CR8, wherein R8 is an unsubstituted 5-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, or X1 and X2 are both CR8; one R8 is -H and the other R8 is an unsubstituted 5-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, and R7 is selected from -H, -F, -Cl, -CN, -COOR 7a , -COR 7b , unsubstituted C2 alkenyl and unsubstituted 4-membered heterocycloalkyl (such as oxetane or azetidine), wherein R 7a is -H, unsubstituted C 1-3 alkyl (such as methyl) or unsubstituted C 3-4 cycloalkyl (such as cyclopropyl); R 7b is selected from -H or unsubstituted C 1～3 alkyl (such as methyl); or R7 is selected from -F, -Cl, -COOR 7a , -COR 7b , unsubstituted C2 alkenyl and unsubstituted 4-membered heterocycloalkyl (such as oxetane or azetidine), wherein R 7a and R 7b are both methyl.

[0188] In some embodiments of the present application, the compounds provided by the present application and their pharmaceutically acceptable salts, wherein X1 and X2 are each independently selected from N or CR8; wherein R8 is selected from -H, -F, -Cl, -Br, -NH2, -NHCOR 8a, substituted or unsubstituted C 1～6 alkyl, substituted or unsubstituted C 1～6 alkoxy, substituted or unsubstituted C 3～6 cycloalkyl; and X1 and X2 are not simultaneously selected from N; wherein, R 8a is selected from:

[0189]

[0190] In some embodiments of the present application, the compounds and their pharmaceutically acceptable salts provided by the present application, wherein, R8 is selected from -H, -NH2, methyl, methoxy, cyclopropyl, -NHCOR 8a , wherein, R 8a is selected from:

[0191]

[0192] In some embodiments of the present application, the compounds and their pharmaceutically acceptable salts provided by the present application, wherein, R 8a is selected from:

[0193]

[0194] In some embodiments of the present application, the compounds and their pharmaceutically acceptable salts provided by the present invention, wherein, R8 is selected from -H, -Cl, -NH2, phenyl,

[0195] In some embodiments of the present application, the compounds and their pharmaceutically acceptable salts provided by the present invention, wherein, R8 is selected from -H,

[0196] In some embodiments of the present application, the compounds and their pharmaceutically acceptable salts provided by the present application, wherein, represents the absence of a bond, X3 is also absent, and R4 and R5 are each independently selected from hydrogen, F, hydroxy, =O, substituted or unsubstituted C 1～6 alkyl, substituted or unsubstituted C 1～6 alkoxy.

[0197] In some embodiments of the present application, the present application provides compounds of formula (I-1), formula (I), formula (I-a) and formula (I-b) or their prodrugs, tautomers, stereoisomers, solvates, isotope derivatives or their pharmaceutically acceptable salts, wherein represents the absence of a bond, X3 is also absent, and R4 and R5 are each independently selected from hydrogen, hydroxy, halogen (e.g., -F, -Cl, -Br), =O, unsubstituted C 1～3 alkyl and unsubstituted C 1～3 alkoxy; or Indicates that the bond does not exist, X3 does not exist, one of R4 and R5 is hydrogen, and the other is selected from hydrogen, hydroxyl, halogen (e.g., -F, -Cl), =O, unsubstituted C 1～3 alkyl (e.g., methyl) and unsubstituted C 1～3 alkoxy (e.g., methoxy); or Indicates that the bond does not exist, X3 does not exist, and both R4 and R5 are hydrogen.

[0198] In some embodiments of the present application, the compounds and their pharmaceutically acceptable salts provided by the present application, wherein, Indicates a double bond, Y1 and Y2 are both C, and ring A is selected from phenyl or a 5- to 6-membered heteroaryl containing 1 or 2 heteroatoms.

[0199] In some embodiments of the present application, the present application provides compounds of formula (I-1), formula (I), formula (I-a) and formula (I-b) or their prodrugs, tautomers, stereoisomers, solvates, isotope derivatives or their pharmaceutically acceptable salts, wherein Indicates a double bond, Y1 and Y2 are both C, ring A is selected from phenyl, a 6-membered heteroaryl containing 1 N atom and a 5-membered heteroaryl containing 1 S atom and 1 N atom, or ring A is selected from phenyl and a 6-membered heteroaryl containing 1 N atom, or ring A is phenyl.

[0200] In some embodiments of the present application, the present application provides compounds of formula (I-1), formula (I), formula (I-a) and formula (I-b) or their prodrugs, tautomers, stereoisomers, solvates, isotope derivatives or their pharmaceutically acceptable salts, wherein R6 is selected from halogen, -NH2, -NHR 6a 、-NR 6a R 6b 、-CN、-CONH2、-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, wherein R 6a and R 6b are each independently unsubstituted C 1～6 alkyl; n is selected from 0, 1 or 2, wherein the substituted -SO n C 1-6 alkyl, substituted C 1-6 alkyl and substituted C 1～6 alkoxy are each independently independently selected from -OH, halogen, C 1-6substituted by one or more substituents in the alkyl group and the -NH2 group; or

[0201] R6 is selected from halogen (e.g., -F, -Cl, -Br), -NH2, -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), where n is selected from 0, 1 or 2, and the substituted C 1-3 alkyl and substituted C 1～3 alkoxy are each independently substituted by one or more substituents independently selected from -OH, halogen, C 1-3 alkyl and the -NH2 group.

[0202] In some embodiments of the present application, the compounds and their pharmaceutically acceptable salts provided by the present application, wherein R6 is selected from halogen, -NH2, -CN, -OH, -OCH3, -OCH2CH3, -SCH3, -SO2CH3.

[0203] In some embodiments of the present application, the compounds and their pharmaceutically acceptable salts provided by the present application, wherein R6 is selected from halogen, -NH2, -CN, -OH, -OCH3, -SCH3, -SO2CH3.

[0204] In some embodiments of the present application, the present application provides compounds of formula (I-1), formula (I), formula (I-a) and formula (I-b) or their prodrugs, tautomers, stereoisomers, solvates, isotope derivatives or their pharmaceutically acceptable salts, wherein represents that the bond does not exist, X3 does not exist either, and both R4 and R5 are hydrogen; represents a double bond, both Y1 and Y2 are C, and ring A is selected from phenyl and a 6-membered heteroaryl containing 1 N atom (preferably phenyl); R6 is selected from halogen (e.g., -F, -Cl, -Br), -NH2, -CN, -OH, unsubstituted -SO n C 1-3 alkyl, unsubstituted C 1-3 alkyl and unsubstituted C 1～3 alkoxy, where n is selected from 0, 1 or 2, and m is 0, 1 or 2.

[0205] In some embodiments of the present application, the present application provides compounds of formula (I-1), formula (I), formula (I-a) and formula (I-b) or their prodrugs, tautomers, stereoisomers, solvates, isotope derivatives or their pharmaceutically acceptable salts, wherein represents that the bond does not exist, X3 does not exist either, and both R4 and R5 are hydrogen; represents a double bond, Y1 and Y2 are both C, ring A is a 5-membered heteroaryl containing 1 S atom and 1 N atom; R6 is selected from -NH2, -CN, -OH, unsubstituted -SO n C 1-3 alkyl, unsubstituted C 1-3 alkyl and unsubstituted C 1～3 alkoxy, where n is selected from 0, 1 or 2, and m is 1 or 2.

[0206] In some embodiments of the present application, in the compounds of formula (I-1), formula (I), formula (I-a) and formula (I-b) provided by the present application, or their prodrugs, tautomers, stereoisomers, solvates, isotope derivatives or pharmaceutically acceptable salts thereof, when representing a single bond, ring A and -(R6) m do not exist, Y1 and Y2 are each independently CR9R 10 , O or NR 10 ; each R9 and R 10 is independently selected from -H or unsubstituted C 1～6 alkyl; or, when representing a single bond, ring A and -(R6) m do not exist, one of Y1 and Y2 is CR9R 10 and the other is O; each R9 and R 10 is independently selected from -H or unsubstituted C 1～3 alkyl (e.g., methyl); or, the structural unit is preferably

[0207] In some embodiments of the present application, the present application provides compounds of formula (I-1), formula (I), formula (I-a) and formula (I-b) or their prodrugs, tautomers, stereoisomers, solvates, isotope derivatives or pharmaceutically acceptable salts thereof, wherein one of X1 and X2 is N and the other is CR8, where R8 is independently selected from -H, -NH2, -NHCOR 8a , substituted or unsubstituted C 6～14 aryl or substituted or unsubstituted 5- to 14-membered heteroaryl, where R 8a is selected from: Or X1 and X2 are both CR8; one of the R8s is -H and the other R8 is selected from -NH2, -NHCOR 8a , substituted or unsubstituted C 6～14 aryl or substituted or unsubstituted 5- to 14-membered heteroaryl, where R 8a is selected from:

[0208] R1 and R3 are each independently selected from -H, halogen (e.g., -Cl) or halogen-substituted C 1～6 alkyl (e.g., fluoro-substituted C 1～6 alkyl, such as -CF3);

[0209] R2 is selected from -H or -NH2;

[0210] R7 is selected from -F, -CN, -COOR 7a , -COR 7b , unsubstituted C2 alkenyl, unsubstituted C2 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);

[0211] represents that the bond does not exist, X3 does not exist, and both R4 and R5 are hydrogen;

[0212] represents a single bond or a double bond;

[0213] i) When represents a single bond, ring A and -(R6) m do not exist, one of Y1 and Y2 is CR9R 10 and the other is O; each R9 and R 10 is independently selected from -H or unsubstituted C 1～3 alkyl (e.g., methyl);

[0214] ii) represents a double bond, Y1 and Y2 are both C, and ring A is selected from phenyl or a 5- to 6-membered heteroaryl containing 1 or 2 heteroatoms;

[0215] R6 is selected from halogen or unsubstituted C 1-3 alkyl (e.g., methyl); and

[0216] m is selected from 0 or 1.

[0217] In some embodiments of the present application, the present application provides compounds of formula (I-1), formula (I), formula (I-a) and formula (I-b) or their prodrugs, tautomers, stereoisomers, solvates, isotope derivatives or their pharmaceutically acceptable salts, wherein

[0218] X is selected from a bond or -S-;

[0219] X1 and X2 are each independently selected from N and CR8; where each R8 is independently selected from -H, halogen, -NH2, -NHR8b 、 -NR 8b R 8c 、 -NHCOR 8a 、 -CN, -OH, -NO2, -COOH, -CONH2, -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 monospiroalkyl, substituted or unsubstituted heteromonospiroalkyl, substituted or unsubstituted C 6～14 aryl and substituted or unsubstituted 5 - 14 - membered heteroaryl, wherein the substituted C 1～6 alkyl, substituted C 1～6 alkoxy, substituted C 3～6 cycloalkyl, substituted 3 - 6 - membered heterocycloalkyl, substituted monospiroalkyl, substituted heteromonospiroalkyl, substituted C 6～14 aryl and substituted 5 - 14 - membered heteroaryl are each independently substituted by one or more substituents independently selected from -OH, halogen, unsubstituted C 1-6 alkyl, -NH2, -NO2, unsubstituted -COC 1-6 alkyl, -CN and =O groups;

[0220] R 8a Selected from:

[0221]

[0222] R 8b and R 8c are each independently selected from unsubstituted C 1～6 alkyl;

[0223] R1 and R3 are each independently selected from -H, halogen, -NH2, -CN, -OH, -NO2, -COOH, substituted or unsubstituted C 1～6 alkyl and substituted or unsubstituted C 1～6 alkoxy, wherein the substituted C 1～6 alkyl and substituted C 1～6 alkoxy are each independently substituted by one or more substituents independently selected from -OH, halogen, unsubstituted C 1-6 alkyl, -NH2, -NO2, unsubstituted -COC 1-6 alkyl, -CN and =O groups;

[0224] R2 is selected from -H, halogen, -NH2, -CN, -OH, -NO2, carboxyl, -NHR 2a , -NR 2a R 2b , -CONH2, -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 monospiroalkyl, substituted or unsubstituted heteromonospiroalkyl, substituted or unsubstituted C 4～8 bridged cycloalkyl and substituted or unsubstituted 4- to 8-membered heterobridged cycloalkyl, wherein the substituted C 1～6 alkyl, substituted C 1～6 alkoxy, substituted C 3～6 cycloalkyl, substituted 3- to 6-membered heterocycloalkyl, substituted monospiroalkyl, substituted heteromonospiroalkyl, substituted C 4～8 bridged cycloalkyl and substituted 4- to 8-membered heterobridged cycloalkyl are each independently substituted by one or more substituents independently selected from -OH, halogen, unsubstituted C 1-6 alkyl, -NH2, -NO2, unsubstituted -COC 1-6 alkyl, -CN and =O groups;

[0225] Or R2 cyclizes with adjacent R3 to form a substituted or unsubstituted C6 or C 10 aryl, substituted or unsubstituted 5- to 8-membered heteroaryl or substituted or unsubstituted non-aromatic 5- to 8-membered heterocyclic group, wherein the substituted C6 or C 10 aryl, substituted 5- to 8-membered heteroaryl or substituted non-aromatic 5- to 8-membered heterocyclic group are each independently substituted by one or more substituents independently selected from -OH, halogen, unsubstituted C 1-6 alkyl, -NH2, -NO2, unsubstituted -COC 1-6 alkyl, -CN and =O groups;

[0226] R 2a and R 2b are each independently selected from unsubstituted C 1～6 alkyl;

[0227] R7 is selected from -H;

[0228] Indicates the presence or absence of a bond;

[0229] i) When indicating the absence of a bond, X3 is also absent, and R4 and R5 are each independently selected from hydrogen, hydroxy, halogen, ═O, substituted or unsubstituted C 1～6 alkyl and substituted or unsubstituted C 1～6 alkoxy, where the case where R4 and R5 are each independently selected from "═O" means that another hydrogen atom at the same substitution position is simultaneously replaced by the oxygen atom, and the substituted C 1～6 alkyl and substituted C 1～6 alkoxy are each independently substituted by one or more substituents independently selected from -OH, halogen, unsubstituted C 1-6 alkyl, -NH2, -NO2, unsubstituted -COC 1-6 alkyl, -CN and ═O groups, provided that R4 and R5 cannot both be hydrogen;

[0230] ii) When indicating the presence of a bond, X3 is CH2, and both R4 and R5 are hydrogen;

[0231] Indicates a single bond or a double bond;

[0232] i) When indicating a single bond, ring A and -(R6) m are absent, and Y1 and Y2 are each independently CR9R 10 , O or NR 10 ;

[0233] Each R9 and R 10 is independently selected from -H, halogen, -OH, substituted or unsubstituted C 1～6 alkyl and substituted or unsubstituted C 1～6 alkoxy, where the substituted C 1～6 alkyl and substituted C 1～6 alkoxy are each independently substituted by one or more substituents independently selected from OH, halogen, unsubstituted C 1-6 alkyl, -NH2, -NO2, unsubstituted -COC 1-6 alkyl, -CN and ═O groups;

[0234] ii) When indicating a double bond, both Y1 and Y2 are C, ring A is present, and ring A is selected from naphthyl, phenyl or 5-6 membered heteroaryl;

[0235] R6 is selected from halogen, -NH2, -NHR 6a , -NR 6a R6b , -CN, -CONH2, -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, wherein R 6a and R 6b are each independently unsubstituted C 1～6 alkyl; n is selected from 0, 1 or 2, wherein the substituted -SO n C 1-6 alkyl, substituted C 1-6 alkyl and substituted C 1～6 alkoxy are each independently substituted by one or more substituents independently selected from -OH, halogen, unsubstituted C 1-6 alkyl, -NH2, -NO2, unsubstituted -COC 1-6 alkyl, -CN and =O group;

[0236] m is selected from 0, 1, 2, 3 or 4;

[0237] wherein the number of ring atoms of the monospiroalkyl and heteromonospiroalkyl is independently selected from 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, and the count of each ring includes the spiro atom; and

[0238] the substituent "=O" means that two hydrogen atoms at the same substitution position are replaced by an oxygen atom.

[0239] In some embodiments of the present application, the compound or its pharmaceutically acceptable salt provided by the present application, wherein the compound has the following structure:

[0240]

[0241]

[0242]

[0243]

[0244]

[0245]

[0246]

[0247]

[0248] The compounds of the present application may be asymmetric, for example, having one or more stereoisomers. Unless otherwise specified, all stereoisomers are included, such as enantiomers and diastereomers. Compounds of the present application containing asymmetric carbon atoms may be isolated in optically pure form or in racemic form. The optically pure form can be resolved from the racemic mixture or synthesized by using chiral starting materials or chiral reagents.

[0249] The compounds of the present application may have one or more atropisomers, and unless otherwise specified, the atropisomers refer to photoactive isomers generated due to the hindered free rotation between single bonds. Compounds of the present application containing a chiral axis may be isolated in optically pure form or in racemic form. The optically pure form can be resolved from the racemic mixture or synthesized by using chiral starting materials or chiral reagents.

[0250] 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 known as proton transfer tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations. Specific examples of proton tautomers are imidazole moieties, where the proton can migrate between two ring nitrogens. Valence tautomers include interconversions through the reorganization of some bonding electrons.

[0251] On the other hand, the present application also provides a pharmaceutical composition, which comprises the compound of the present application or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. In some embodiments, the present application also provides a pharmaceutical composition, which comprises a therapeutically effective amount of the compound represented by formula (I-1), formula (I), formula (Ia) or formula (Ib), or a prodrug, tautomer, stereoisomer, solvate, isotope derivative thereof, or a pharmaceutically acceptable salt thereof. In some embodiments, the present application also provides a pharmaceutical composition, which comprises a therapeutically effective amount of the compound represented by formula (I-1), formula (I), formula (Ia) or formula (Ib), or a prodrug, tautomer, stereoisomer, solvate, isotope derivative thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0252] Pharmaceutical composition

[0253] The compounds of the present application, or their prodrugs, tautomers, stereoisomers, solvates, isotope derivatives, or pharmaceutically acceptable salts thereof, can be administered alone as an active substance, preferably in the form of a pharmaceutical composition thereof.

[0254] On the other hand, the present application provides a pharmaceutical composition containing the compounds represented by formula (I-1), formula (I), formula (Ia), or formula (Ib), and their prodrugs, tautomers, stereoisomers, solvates, isotope derivatives, or pharmaceutically acceptable salts thereof as active ingredients.

[0255] The present application provides a pharmaceutical composition containing the compounds represented by formula (I-1), formula (I), formula (Ia), or formula (Ib), and their prodrugs, tautomers, stereoisomers, solvates, isotope derivatives, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable excipients.

[0256] The administration of the compounds of the present application, and their prodrugs, tautomers, stereoisomers, solvates, isotope 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 route of administration for drugs providing similar uses. The pharmaceutical composition of the present application can be prepared by combining the compounds represented by 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, and aerosols, etc. Generally, the above pharmaceutical compositions can be prepared by conventional preparation methods using conventional excipients in the field of pharmaceutical formulations.

[0257] The pharmaceutical composition of the present application can have the effect of treating and preventing diseases, disorders, and conditions mediated by SHP2 activity, such as cancer, cancer metastasis, cardiovascular diseases, immune disorders, or visual disorders.

[0258] On the other hand, the present application also provides the use of the compounds described in the present application, their pharmaceutically acceptable salts, or the pharmaceutical compositions of the present application in the preparation of drugs for treating, preventing, and / or treating diseases mediated by SHP2 activity.

[0259] In some embodiments, the present application also provides the use of the compounds represented by formula (I-1), formula (I), formula (Ia), or formula (Ib) of the present application, or their prodrugs, tautomers, stereoisomers, solvates, isotope derivatives, or pharmaceutically acceptable salts, or the pharmaceutical compositions of the present application in the preparation of drugs for treating, preventing, and / or treating diseases, disorders, and conditions mediated by SHP2 activity.

[0260] In 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 to an individual 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.

[0261] In yet another aspect, the present application provides 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 for treating and / or preventing diseases, disorders and conditions mediated by SHP2 activity.

[0262] 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.

[0263] In some embodiments of the present application, the diseases, disorders and conditions are tumors, cardiovascular diseases, immune disorders or visual disorders.

[0264] In some embodiments of the present application, the tumors include solid tumors and hematological tumors.

[0265] In some embodiments of the present application, the solid tumors include pancreatic cancer, lung cancer, preferably non-small cell lung cancer; the hematological tumors include leukemia, preferably juvenile myelomonocytic leukemia, acute myeloid leukemia.

[0266] In yet another aspect, the present application provides a method for preventing and / or treating diseases, disorders and conditions mediated by SHP2 activity, which comprises administering to an individual in need thereof a compound of formula (I-1), formula (I), formula (Ia) or formula (Ib) and its prodrug, tautomer, stereoisomer, solvate, isotopic derivative 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 visual disorders; more preferably, the tumors include solid tumors and hematological tumors; more preferably, the solid tumors include pancreatic cancer, lung cancer, preferably non-small cell lung cancer; the hematological tumors include leukemia, preferably juvenile myelomonocytic leukemia, acute myeloid leukemia.

[0267] On the other hand, the present application provides compounds represented by formula (I-1), formula (I), formula (Ia) or formula (Ib), their prodrugs, tautomers, stereoisomers, solvates, isotope derivatives or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for preventing and / or treating 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 tumors include solid tumors and hematological tumors; more preferably, the solid tumors include pancreatic cancer and lung cancer, and the lung cancer is preferably non-small cell lung cancer; the hematological tumors include leukemia, and the leukemia is preferably juvenile myelomonocytic leukemia and acute myeloid leukemia.

[0268] Furthermore, for the use or method provided by the present application, in which the compounds, their prodrugs, tautomers, stereoisomers, solvates, isotope derivatives or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof described in the present application are used in combination with another, two or more compounds having anti-tumor activity.

[0269] Furthermore, for the use provided by the present application, in which the compounds, their pharmaceutically acceptable salts or pharmaceutical compositions of the present application are used in combination with another, two or more compounds having anti-tumor activity.

[0270] Definitions

[0271] Unless otherwise specified, the following terms used in the present application have the following meanings. A particular term should not be considered indeterminate or unclear without a specific definition, but should be understood according to the ordinary meaning in the art. When a trade name appears in this text, it is intended to refer to the corresponding commodity or its active ingredient.

[0272] The term "compound" used herein includes all stereoisomeric forms, geometric isomeric forms, tautomeric forms and isotope forms of the compound.

[0273] The term "substituted" or "substitution" means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, as long as the valence state of the specific 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 an oxygen atom. Those skilled in the art can understand that for any group containing one or more substituents, no substitution or substitution pattern that is spatially impossible to exist and / or cannot be synthesized will be introduced.

[0274] When any variable (such as R) appears more than once in the composition or structure of a compound, its definition in each case is independent. Therefore, for example, if a group is substituted by 2 Rs, each R has independent options.

[0275] The "C" in this text m-n , means that this part has an integer number of carbon atoms within a given range. For example, "C 1-6 " means that the group can have 1, 2, 3, 4, 5, or 6 carbon atoms. For example, "C 3-6 " means that the group can have 3, 4, 5, or 6 carbon atoms.

[0276] The term "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group, including straight-chain or branched-chain groups containing 1 - 20 carbon atoms, preferably containing 1 - 10 carbon atoms (i.e., C 1-10 alkyl), more preferably containing 1 - 8 carbon atoms (C 1-8 alkyl), even more preferably containing 1 - 6 carbon atoms (i.e., C 1-6 alkyl). For example, "C 1-6 alkyl" means that the group is an alkyl group and the number of carbon atoms in the carbon chain is between 1 - 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, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, n-octyl, etc.

[0277] The term "alkenyl" refers to a straight-chain or branched-chain unsaturated aliphatic hydrocarbon group composed of carbon atoms and hydrogen atoms and having at least one double bond. The alkenyl can contain 2 - 20 carbon atoms, preferably containing 2 - 10 carbon atoms (i.e., C 2-10 alkenyl), more preferably containing 2 - 8 carbon atoms (C 2-8 alkenyl), even more preferably containing 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., C2 alkenyl). For example, "C 2-6 alkenyl" means that the group is an alkenyl group and the number of carbon atoms in the carbon chain is between 2 - 6 (specifically 2, 3, 4, 5, or 6). Non-limiting examples of alkenyl include but are not limited to vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, and 1,3-butadienyl, etc.

[0278] The term "alkynyl" refers to a straight-chain or branched-chain unsaturated aliphatic hydrocarbon group composed of carbon atoms and hydrogen atoms and having at least one triple bond. The alkynyl can contain 2 - 20 carbon atoms, preferably containing 2 - 10 carbon atoms (i.e., C2-10 alkynyl), more preferably containing 2 - 8 carbon atoms (C 2-8 alkynyl), even more preferably containing 2 - 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., C2 alkynyl), for example, "C 2-6 alkynyl" means that the group is an 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 include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, and 1-butynyl, etc.

[0279] The term "cycloalkyl" refers to a monocyclic saturated aliphatic hydrocarbon group having a specific number of carbon atoms, preferably containing 3 - 12 carbon atoms (i.e., C 3-12 cycloalkyl), more preferably containing 3 - 10 carbon atoms (C 3-10 cycloalkyl), further preferably 3 - 6 carbon atoms (C 3-6 cycloalkyl), 4 - 6 carbon atoms (C 4-6 cycloalkyl), 5 - 6 carbon atoms (C 5-6 cycloalkyl). Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, 2-ethyl-cyclopentyl, dimethylcyclobutyl, etc. In some embodiments of the present application, "cycloalkyl" refers to a monocyclic saturated aliphatic hydrocarbon group composed of carbon atoms and hydrogen atoms having a specific number of carbon atoms. In some embodiments of the present application, cycloalkyl also preferably contains 3 - 4 carbon atoms (C 3-4 cycloalkyl), 3 - 5 carbon atoms (C 3-5 cycloalkyl) or 4 - 5 carbon atoms (C 4-5 cycloalkyl).

[0280] The term "alkoxy" refers to -O-alkyl, where the alkyl is as defined above, i.e., containing 1 - 20 carbon atoms, preferably containing 1 - 10 carbon atoms, more preferably 1 - 8 carbon atoms, even more preferably 1 - 6 carbon atoms (specifically 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, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, etc.

[0281] The term "carboxyl" refers to the -COOH group. The term "halogen" or "halo" means F, Cl, Br, or I. The term "haloalkyl" means that one, two, or more hydrogen atoms or all hydrogen atoms in the alkyl group as defined above are replaced by halogen. Representative examples of haloalkyl include CCl3, CF3, CHCl2, CH2Cl, CH2Br, CH2I, CH2CF3, CF2CF3, etc.

[0282] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic, bicyclic, or polycyclic cyclic hydrocarbon substituent having a non-aromatic structure, containing 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, it contains 3 to 12 ring atoms (C 3-12 heterocyclic group), more preferably 3 to 10 ring atoms (C 3-10 heterocyclic group), or 3 to 8 ring atoms (C 3-8 heterocyclic group), or 3 to 6 ring atoms (C 3-6 heterocyclic group), or 4 to 6 ring atoms (C 4-6 heterocyclic group), or 5 to 6 ring atoms (C 5-6 heterocyclic group). The heteroatoms are preferably 1 to 4, more preferably 1 to 3 (i.e., 1, 2, or 3). Examples of monocyclic heterocyclic groups include oxiranyl, pyrrolidinyl, N-methylpyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuryl, dihydrofuryl, dihydropyrrolyl, piperidinyl, piperazinyl, pyranyl, morpholinyl, thiomorpholinyl, and tetrahydrothienyl, etc. Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups. In some embodiments of the present application, the heterocyclic group preferably contains 3 to 12 ring atoms (3- to 12-membered heterocyclic group), more preferably 3 to 10 ring atoms (3- to 10-membered heterocyclic group), or 3 to 8 ring atoms (3- to 8-membered heterocyclic group), or 3 to 6 ring atoms (3- to 6-membered heterocyclic group), or 4 to 6 ring atoms (4- to 6-membered heterocyclic group), 5 to 6 ring atoms (5- to 6-membered heterocyclic group), or 5 to 8 ring atoms (5- to 8-membered heterocyclic group, e.g., 5-, 6-, 7-, or 8-membered heterocyclic group).

[0283] The term "heterocycloalkyl" means a saturated "heterocyclic group" as defined above, containing 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, it contains 3 to 12 ring atoms (C 3-12 heterocycloalkyl), more preferably 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 4-6heterocycloalkyl), or 5 to 6 ring atoms (C 5-6 heterocycloalkyl). The heteroatoms are preferably 1 to 4, more preferably 1 to 3 (i.e., 1, 2, or 3). Examples include aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, oxane, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxolanyl, dithiane, oxazolidinyl, thiazolidinyl, pyrazolidinyl, imidazolidine, etc. In some embodiments of the present application, the heterocycloalkyl preferably contains 3 to 12 ring atoms (3- to 12-membered heterocycloalkyl), more preferably contains 3 to 10 ring atoms (3- to 10-membered heterocycloalkyl), or 3 to 8 ring atoms (3- to 8-membered heterocycloalkyl), or 3 to 7 ring atoms (3- to 7-membered heterocycloalkyl), or 3 to 6 ring atoms (3- to 6-membered heterocycloalkyl, such as 3, 4, 5, or 6-membered heterocycloalkyl), or 4 to 6 ring atoms (4- to 6-membered heterocycloalkyl), or 5 to 6 ring atoms (5- to 6-membered heterocycloalkyl).

[0284] The term "monospiroalkyl" refers to a saturated aliphatic hydrocarbon group in the form of a spiro ring composed of carbon atoms and hydrogen atoms that shares only one carbon atom and has a specific number of carbon atoms. It is preferably 6 to 14 members, more preferably 7 to 10 members. Non-limiting examples of monospiroalkyl are monospiroalkyls of 3 / 5, 4 / 4, 4 / 5, 4 / 6, 5 / 5, and 5 / 6 rings, where the count of each ring includes the spiro atom. Non-limiting examples of monospiroalkyl include: etc.

[0285] The term "heteromonospiroalkyl" refers to a saturated aliphatic hydrocarbon group in the form of a spiro ring that shares only one carbon atom and has a specific number of carbon atoms and heteroatoms. The heteroatoms in the heteromonospiroalkyl are preferably 1 to 4, more preferably 1 to 3 (i.e., 1, 2, or 3), and the heteroatoms are independently selected from N, O, and S. It is preferably 6 to 14 members, more preferably 7 to 10 members. Non-limiting examples of heteromonospiroalkyl are heteromonospiroalkyls of 3 / 5, 4 / 4, 4 / 5, 4 / 6, 5 / 5, and 5 / 6 rings, where the count of each ring includes the spiro atom. Non-limiting examples of heteromonospiroalkyl include:

[0286] etc.

[0287] "Bridged cycloalkyl" refers to a fully carbon polycyclic group having 5 to 20 ring atoms, in which any two rings share two non-adjacent carbon atoms, which may contain one or more double bonds, but no ring has a fully conjugated π electron system. It is preferably 6 to 14 ring atoms, more preferably 7 to 10 ring atoms. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyls, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyls include:

[0288] "Hetero-bridged cycloalkyl" refers to a polycyclic heterocyclic group having 5 to 14 ring atoms, in which any two rings share two non-adjacent atoms, which may contain one or more double bonds, but no ring has a fully conjugated π electron system, and one or more of the ring atoms are heteroatoms selected from nitrogen, oxygen or S(O)m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 ring atoms, more preferably 7 to 10 ring atoms. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic hetero-bridged cycloalkyls, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of hetero-bridged cycloalkyls include:

[0289] The term "aryl" means a monocyclic, bicyclic and tricyclic aromatic carbocyclic system containing 6 - 16 carbon atoms, or 6 - 14 carbon atoms, or 6 - 12 carbon atoms, or 6 - 10 carbon atoms, preferably 6 - 10 carbon atoms, and the term "aryl" can be used interchangeably with the term "aromatic ring". Examples of aryl groups can include but are not limited to phenyl, naphthyl, anthracenyl, phenanthryl or pyrenyl, etc.

[0290] The term "heteroaryl" refers to an aromatic monocyclic or polycyclic ring system having a 5- to 12-membered structure, or preferably a 5- to 10-membered structure, a 5- to 8-membered structure, more preferably a 5- to 6-membered structure, in which one, two, three or more ring atoms are heteroatoms and the remaining atoms are carbon, and the heteroatoms are independently selected from O, N or S, and the number of heteroatoms is preferably one, two or three. Examples of heteroaryl include, but are not limited to, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiodiazolyl, triazinyl, phthalazinyl, quinolinyl, isoquinolinyl, pteridinyl, purinyl, indolyl, isoindolyl, indazolyl, benzofuryl, benzothienyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, benzimidazolyl, benzophthalazinyl, pyrrolo[2,3-b]pyridyl, imidazo[1,2-a]pyridyl, pyrazolo[1,5-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, etc.

[0291] The term "pharmaceutically acceptable salt" or "medicinally acceptable salt" refers to a salt that is suitable for contact with mammalian tissues, particularly human tissues, within the scope of reasonable medical judgment, without excessive toxicity, irritation, allergic reaction, etc., and is commensurate with a reasonable benefit / risk ratio. For example, pharmaceutically acceptable salts of amines, carboxylic acids and other types of compounds are well known in the art.

[0292] The term "salt" or "pharmaceutically acceptable salt" includes salts prepared from inorganic acids, organic acids, etc. If the compound of the present application is acidic, pharmaceutically acceptable non-toxic bases include salts prepared from inorganic bases and organic bases. The inorganic acids, organic acids, inorganic bases and organic bases are well known to those skilled in the art.

[0293] Prodrugs are derivatives of designed active drugs that can improve some defined, undesirable physical or biological properties. Physical properties are usually related to solubility (excessive or insufficient lipid or water solubility) or stability, while problematic biological characteristics include too rapid metabolism or poor bioavailability, which may itself be related to physicochemical properties. Prodrugs are generally prepared as follows: a) forming esters, semi-esters, carbonates, nitrates, amides, hydroxamic acids, carbamates, imines, Mannich bases, phosphates, phosphonates, and enamines of the active drug, b) functionalizing the drug with azo, glycoside, peptide, and ether functional groups, c) using acetalamine, hemiacetalamine, 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. A typical reaction of these compounds is substitution of one heteroatom with another atom. Amides can be prepared in a similar manner from substrates containing amino or carboxyl groups. Esters can also react with amines or ammonia to form amides. Another way to prepare amides is to heat carboxylic acids and amines together.

[0294] "Isotope derivatives" means that the compounds of the present invention can exist in isotopically labeled or enriched forms, containing one or more atoms whose atomic weights or mass numbers are different from those of the atoms found in the greatest amounts in nature. Isotopes can be radioactive or non-radioactive isotopes. 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 these and / or other isotopes of other atoms are within the scope of the present invention. In another embodiment, the isotope-labeled compound contains deuterium (2H), tritium (3H), or 14C isotope. The isotope-labeled compounds of the present invention can be prepared using general methods well known to those of ordinary skill in the art. Additionally, drugs containing non-radioactive active isotopes, such as deuterated drugs known as "heavy drugs", can be used to treat related diseases and disorders. The amount of isotope present in the above compounds increased above its natural abundance is referred to as enrichment. Examples of amounts of enrichment include from 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 100 mol%. Any possible site in the molecular structure can be substituted with an isotope to obtain an isotope derivative. For example, any possible site in the molecule can be substituted with deuterium (2H) to obtain a deuterated form of the derivative. Drugs labeled with stable isotopes can alter the physicochemical properties of the drug, such as pKa and lipid solubility. If the isotope substitution affects the region involved in ligand-receptor interaction, then these effects and changes can affect the pharmacodynamic response of the drug molecule. Although some physical properties of the stable isotope-labeled molecule are different from those of the unlabeled molecule, the chemical and biological characteristics are the same. An important difference is that due to the increased mass of the heavy isotope, any bond involving the heavy isotope and another atom is stronger than the same bond between the light isotope and that atom. Accordingly, incorporating an isotope at the site of metabolic or enzymatic conversion can potentially slow down the reaction and, relative to the non-isotope compound, can alter the pharmacokinetic properties or effects.

[0295] The term "treatment" generally refers to administering the compounds or formulations described in the present application to obtain the desired pharmacological and / or physiological effects. The effect can be therapeutic, depending on partially or completely stabilizing or curing the disease and / or the side effects resulting from the disease. "Treatment" as used herein encompasses any treatment of a patient's disease, including: (a) inhibiting the symptoms of the disease, disorder, and condition, i.e., preventing its progression; or (b) alleviating the symptoms of the disease, disorder, and condition, i.e., causing the disease or symptoms to subside; or (c) improving or eliminating the disease, disorder, and condition or one or more symptoms associated with the disease.

[0296] The term "therapeutically effective amount" means an amount of a compound of the present application that (i) treats a specific disease, disorder or condition, (ii) alleviates, ameliorates or eliminates one or more symptoms of a specific disease, disorder or condition, or (iii) delays the onset of one or more symptoms of a specific disease, disorder or condition described herein. The amount of the 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 based on their own knowledge and the present disclosure.

[0297] The term "pharmaceutical composition" refers to a mixture comprising one or more compounds of the present application, or salts or stereoisomers thereof, and a pharmaceutically acceptable excipient. The purpose of the pharmaceutical composition is to facilitate the administration of the compounds of the present application to an organism.

[0298] The term "pharmaceutically acceptable excipient" refers to those excipients that do not cause significant irritation to an organism (such as a human) and do not impair the biological activity and properties of the active compound. Suitable excipients 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, etc. "Pharmaceutically acceptable excipients" may also refer to inert substances that are co-administered with the active ingredient and facilitate the administration of the active ingredient, including but not limited to any glidants, sweeteners, diluents, preservatives, dyes / colorants, flavoring agents, surfactants, wetting agents, dispersants, disintegrants, suspending agents, stabilizers, isotonic agents, solvents or emulsifying agents, etc. that are approved by the US Food and Drug Administration as acceptable for use in humans or animals (such as livestock). Non-limiting examples of such excipients include calcium carbonate, calcium phosphate, various sugars and starches, cellulose derivatives, gelatin, vegetable oils and polyethylene glycol.

[0299] The beneficial effects of the present application are:

[0300] The present application designs a novel class of compounds, providing a new direction for the treatment of cancer, cancer metastasis, cardiovascular diseases, immune disorders or visual disorders. In vitro inhibition studies of cell proliferation show that these compounds have strong inhibitory effects on pancreatic cancer cells MIA-PACA-2 cells, and the results of enzymatic assays indicate that the compounds of the present application have good target selectivity. The development of the compounds of the present application expands the selection of drugs for the treatment of the above diseases. In addition, the present application studies a specific synthesis method, which has a simple process, convenient operation, and is conducive to large-scale industrial production and application. The compounds of formula (I-1), formula (I), formula (Ia) or formula (Ib) of the present application, or their prodrugs, tautomers, stereoisomers, solvates, isotope derivatives or pharmaceutically acceptable salts thereof not only have good inhibitory effects on SHP2 activity, pancreatic cancer, acute myeloid leukemia and / or non-small cell lung cancer, but also have good pharmacokinetic properties, bioavailability and / or safety in vivo. Detailed implementation mode

[0301] The following further elaborates the present invention in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental methods without specific conditions noted in the following embodiments are usually carried out according to conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those familiar to professionals in the field. In addition, any methods and materials similar or equivalent to the described content can be applied to the methods of the present invention. The preferred implementation methods and materials shown in the text are only for demonstration purposes.

[0302] Intermediate preparation example 1: 5-Amino-3-chloro-6-[(2-(trifluoromethyl)pyridin-3-yl)thio]pyrazine-2-carbonitrile (Intermediate A1)

[0303]

[0304] Step a: Under nitrogen protection, a solution of 3-bromo-2-(trifluoromethyl)pyridine (9.00 g, 39.824 mmol, 1.00 equiv), 2-ethylhexyl 3-mercaptopropionate (17.39 g, 79.647 mmol, 2.00 equiv), DIEA (15.44 g, 119.471 mmol, 3.00 equiv), Pd2(dba)3·CHCl3 (1.03 g, 0.996 mmol, 0.02 equiv) and XantPhos (1.15 g, 1.991 mmol, 0.05 equiv) in 1,4-dioxane (135 ml) was stirred at 95 °C overnight; cooled to room temperature, the reaction solution was filtered through diatomaceous earth by suction, and the filtrate was concentrated under reduced pressure; the residue was purified by column chromatography (n-hexane∶EA = 10∶1) to obtain 2-ethylhexyl 3-[[[2-(trifluoromethyl)pyridin-3-yl]sulfanyl]propionate as a yellow oil (14.1 g, 97.42%), (ES, m / z): 364 [M + H] + .

[0305] Step b: Under nitrogen protection, at -78 °C, a solution of 2-ethylhexyl 3-[[[2-(trifluoromethyl)pyridin-3-yl]sulfanyl]propionate (14.10 g, 38.796 mmol, 1.00 equiv) in THF (141 mL) was added dropwise with a 1 mol / L solution of t-BuOK (116.60 mL, 116.388 mmol, 3.00 equiv) in THF, and the reaction was kept warm for 1.5 h; 300 ml of 2 mol / L aqueous K2CO3 solution was added to the reaction solution, and liquid separation was carried out; the aqueous phase was washed with MTBE (2 × 200 mL); the pH of the aqueous phase was adjusted to 4 with 6 mol / L hydrochloric acid; the aqueous phase was extracted with CHCl3 / i-PrOH = 9 / 1 (3 × 200 mL), and the organic phases were combined; the combined organic phases were washed with saturated NaCl (200 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure; to obtain 2-(trifluoromethyl)pyridine-3-thiol as a pale yellow solid (6.1 g, 87.76%), (ES, m / z): 180 [M + H] + .

[0306] 1 1H NMR (400 MHz, DMSO-d6) δ 8.51 - 8.45 (m, 1H), 8.12 (d, J = 8.1 Hz, 1H), 7.61 - 7.54 (m, 1H), 6.31 (s, 1H).

[0307] Step c: Under nitrogen protection, a solution of 3-bromo-6-chloro-pyrazin-2-amine (5.00 g, 23.988 mmol, 1.00 equiv), 2-(trifluoromethyl)pyridine-3-thiol (3.44 g, 19.190 mmol, 0.8 equiv), DIEA (9.30 g, 71.963 mmol, 3.0 equiv), Pd2(dba)3·CHCl3 (0.62 g, 0.600 mmol, 0.025 equiv) and XantPhos (0.69 g, 1.199 mmol, 0.05 equiv) in 1,4-dioxane (100 mL) was reacted overnight at 95 °C. After cooling to room temperature, the reaction solution was filtered through diatomaceous earth by suction filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (n-hexane∶EA = 2∶1) to obtain the solid 6-chloro-3-[[[2-(trifluoromethyl)pyridin-3-yl]sulfanyl]pyrazin-2-amine (1.7 g, 23.11%).

[0308] Step d: Under nitrogen protection and at 0 °C, a solution of ICl (1.27 g, 7.825 mmol, 1.50 equiv) in DCM (32 mL) was added dropwise to a solution of 6-chloro-3-[[[2-(trifluoromethyl)pyridin-3-yl]sulfanyl]pyrazin-2-amine (1.60 g, 5.217 mmol, 1.00 equiv) and K2CO3 (1.44 g, 10.434 mmol, 2.00 equiv) in MeOH (32 ml), and the reaction was controlled for 2 h. Then the reaction was carried out overnight at room temperature. 100 mL of 10% aqueous Na2SO3 solution was added to the reaction solution to quench the reaction. The layers were separated, and the aqueous phase was extracted with DCM (3×50 mL). The organic phases were combined. The combined organic phases were washed with 50 ml of saturated NaCl, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the brown solid 6-chloro-5-iodo-3-[[2-(trifluoromethyl)pyridin-3-yl]sulfanyl]pyrazin-2-amine (Intermediate A1-I) (1.7 g, 75.33%), (ES, m / z): 433 [M+H] + 。

[0309] Step e: Under nitrogen protection, a solution of 6-chloro-5-iodo-3-[[2-(trifluoromethyl)pyridin-3-yl]sulfanyl]pyrazine-2-amine (1.5 g, 3.467 mmol, 1.00 equiv), Pd(PPh3)4 (400 mg, 0.347 mmol, 0.10 equiv) and Zn(CN)2 (407 mg, 3.467 mmol, 1.00 equiv) in NMP (15.00 mL) was stirred at 100 °C for 2 h; the temperature was lowered to room temperature, EA (150 ml) and 25% aqueous ammonia (100 ml) were successively added to the reaction solution and stirred, and the layers were separated; the aqueous phase was extracted with EA (3 × 30 mL), and the organic phases were combined; the organic phase was washed with saturated NaCl, dried over anhydrous sodium sulfate and concentrated under reduced pressure; the residue was purified by column chromatography (n-hexane∶EA = 20∶1 to 5∶1) to obtain a light yellow solid 5-amino-3-chloro-6-[(2-(trifluoromethyl)pyridin-3-yl)sulfanyl]pyrazine-2-carbonitrile (Intermediate A1) (820 mg, 71%). (ES, m / z): 331.95 [M+H] + 。

[0310] Intermediate Preparation Example 2: 5-Amino-6-[(2-amino-3-chloropyridin-4-yl)sulfanyl]-3-chloropyrazine-2-carbonitrile (Intermediate A2) (Method 1 for preparing Intermediate A2)

[0311]

[0312] Step a: Under nitrogen protection, a solution of 2-amino-3-bromo-6-chloropyrazine (5 g, 23.99 mmol, 1 eq), methyl 3-mercaptopropionate (2.88 g, 23.99 mmol, 2.60 mL, 1 eq), DIEA (6.20 g, 47.97 mmol, 2 eq), Pd(OAc)2 (538.53 mg, 2.40 mmol, 0.1 eq) and Xantphos (2.08 g, 3.60 mmol, 0.15 eq) in 1,4-dioxane (80 ml) was stirred at 95 °C for 10 h; the temperature was lowered to room temperature, the reaction solution was filtered through diatomaceous earth by suction, and the filtrate was concentrated under reduced pressure; the residue was purified by column chromatography (n-hexane∶EA = 100∶1 to 20∶1) to obtain a yellow solid methyl 3-((3-amino-5-chloropyrazin-2-yl)sulfanyl)propionate (5 g, 84.1%).

[0313] 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.81 (s, 1H), 4.88 (br s, 2H), 3.72 (s, 3H), 3.46 (t, J = 6.8 Hz, 2H), 2.77 (t, J = 6.8 Hz, 2H).

[0314] Step b: Under nitrogen protection and at -30 °C, sodium methoxide (5 M, 6.30 mL, 1.3 eq) was added dropwise to a solution of methyl 3-((3-amino-5-chloropyrazin-2-yl)thio)propionate (6 g, 24.22 mmol, 1 eq) in methanol (50 mL). After the addition was complete, the mixture was stirred at the same temperature for 0.5 h and then reacted at room temperature for 10 h. The reaction solution was concentrated under reduced pressure, H2O (30 mL) was added, and the aqueous phase was extracted with CH2Cl2 (15 mL × 3). The aqueous phase was freeze-dried to obtain crude sodium 3-amino-5-chloropyrazine-2-thiol (5.5 g), which was used directly in the next step without purification.

[0315] Step c: Under nitrogen protection, a solution of sodium 3-amino-5-chloropyrazine-2-thiol (2.16 g, 11.79 mmol, 1.2 eq), 3-chloro-4-iodopyridin-2-amine (2.5 g, 9.82 mmol, 1 eq), DIEA (2.54 g, 19.65 mmol, 3.42 mL, 2 eq), Pd2(dba)3 (899.68 mg, 982.49 μmol, 0.1 eq) and Xantphos (852.73 mg, 1.47 mmol, 0.15 eq) in 1,4-dioxane (20 mL) was reacted at 75 °C for 2 h. The temperature was lowered to room temperature, EA (50 mL) and H2O (30 mL) were added, and the layers were separated. The aqueous phase was extracted with EA (20 mL × 2), and the organic phases were combined. The combined organic phase was washed with saturated NaCl (30 mL × 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∶1) to obtain yellow solid 3-((2-amino-3-chloropyridin-4-yl)thio)-6-chloropyrazin-2-amine (1.5 g, 52.9%).

[0316] 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.01 (s, 1H), 7.78 (d, J = 5.4 Hz, 1H), 6.11 (d, J = 5.4 Hz, 1H), 5.23 (br s, 2H), 4.95 (br s, 2H).

[0317] Steps (d - e): Using the product of the above step as the starting material, Intermediate A2-I was prepared according to Step d of Intermediate Preparation Example 1. Using Intermediate A2-I as the starting material, 5-amino-6-[(2-amino-3-chloropyridin-4-yl)thio]-3-chloropyrazine-2-carbonitrile (Intermediate A2) was prepared according to Step e of Intermediate Preparation Example 1. (ES, m / z): 312.79 [M + H] + 。

[0318] Intermediate Preparation Example 3: 5-Amino-6-[(2-amino-3-chloropyridin-4-yl)thio]-3-chloropyrazine-2-carbonitrile (Intermediate A2) (Second Preparation Method of Intermediate A2)

[0319]

[0320] Step a: Under nitrogen protection and at 0 °C, to a solution of 2-amino-6-chloropyrazine (40.00 g, 308.761 mmol, 1.00 equiv) and K2CO3 (85.34 g, 617.522 mmol, 2.00 equiv) in MeOH (200 ml), a solution of ICl (90.23 g, 555.770 mmol, 1.80 equiv) in DCM (200.00 mL) was added dropwise. The temperature was controlled for reaction for 2 h, and then the reaction was carried out overnight at room temperature. 800 mL of 10% aqueous Na2SO3 solution was added to the reaction solution to quench the reaction. The layers were separated, and the aqueous phase was extracted with DCM (3 × 300 mL). The organic phases were combined. The combined organic phase was washed with saturated NaCl, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was recrystallized from PE / EA (1∶1) to obtain 6-chloro-5-iodopyrazin-2-amine as a brown solid (34 g, 43.11%) (ES, m / z): 256 [M+H] + .

[0321] Step b: Under nitrogen protection, a solution of 6-chloro-5-iodopyrazin-2-amine (34.00 g, 133.104 mmol, 1.00 equiv) and CuCN (13.11 g, 146.414 mmol, 1.10 equiv) in DMF (340.00 mL) was reacted at 150 °C for 2 h. The temperature was cooled to room temperature, and EA (500 ml) and 25% aqueous ammonia (200 ml) were successively added to the reaction solution and stirred. The layers were separated. The aqueous phase was extracted with EA (3 × 300 mL). The organic phases were combined. The combined organic phase was washed with saturated NaCl, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was recrystallized from PE / EA (2∶1) to obtain 5-amino-3-chloropyrazine-2-carbonitrile as a pale yellow solid (7.5 g, 36.46%) (ES, m / z): 153 [M-H] - ; 1 HNMR (400 MHz, DMSO-d6) δ 8.13 (s, 2H), 7.88 (s, 1H).

[0322] Step c: At room temperature, NBS (3.47 g, 19.48 mmol, 1.50 equiv) was added to a solution of 5-amino-3-chloropyrazine-2-carbonitrile (2.00 g, 12.99 mmol, 1.00 equiv) in DCM (20.00 mL), and the mixture was stirred for 1 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (n-hexane∶EA = 10∶1 to 5∶1) to give a off-white solid, 5-amino-6-bromo-3-chloropyrazine-2-carbonitrile (2.38 g, 79.02%). (ES, m / z): 230.89 [M-H] - .

[0323] Step d: Under nitrogen protection, a solution of sodium 2-amino-3-chloropyridine-4-thiolate (2.00 g, 12.31 mmol, 1.2 eq), 5-amino-6-bromo-3-chloropyrazine-2-carbonitrile (2.38 g, 10.26 mmol, 1 eq), DIEA (3.98 g, 30.78 mmol, 3 eq), Pd2(dba)3 (900 mg, 1.026 mmol, 0.1 eq) and Xantphos (870 mg, 1.539 mmol, 0.15 eq) in 1,4-dioxane (40 mL) was heated at 100 °C for 3 h. After cooling to room temperature, EA (100 mL) and H2O (100 mL) were added, and the layers were separated. The aqueous layer was extracted with EA (2 × 20 mL). The combined organic layers were washed with saturated NaCl (2 × 30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (n-hexane∶EA = 20∶1 to 2∶1) to give an orange solid, 5-amino-6-[(2-amino-3-chloropyridin-4-yl)thio]-3-chloropyrazine-2-carbonitrile (Intermediate A2) (1.5 g, 38.07%). (ES, m / z): 312.90 [M+H] + .

[0324] Preparation Examples of Intermediates 4 - 11: Intermediates A3 - A10

[0325] Intermediates A3 - A10 were synthesized using the procedure of Preparation Example 2 of the intermediate and the following corresponding starting materials:

[0326]

[0327]

[0328] Preparation Example of Intermediate 12: N-(3-((3-Amino-5-chloro-6-cyanopyrazin-2-yl)thio)-2-chlorophenyl)-2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxamide (Intermediate A11)

[0329]

[0330] Step a: A xylene (50 mL) solution of 2-aminopyridine (5.00 g, 52.063 mmol) and triethyl methanetricarboxylate (10.89 g, 57.270 mmol) was reacted at 150 °C for 5 h; the reaction solution was concentrated under reduced pressure to obtain white solid ethyl 2-hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylate (10 g, 85.49%). (ES, m / z): 235 [M+H] + 。

[0331] Step b: A mixture of ethyl 2-hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylate (10.00 g, 41.843 mmol), Pd / C (0.98 g, 9.205 mmol) and EA (100 mL) was reacted at room temperature for 8 h under a hydrogen atmosphere; filtered, the filtrate was concentrated under reduced pressure to obtain white solid ethyl 2-hydroxy-4-oxo-6H,7H,8H,9H-pyrido[1,2-a]pyrimidine-3-carboxylate (10 g, 95.30%). (ES, m / z): 239 [M+H] + 。

[0332] Step c: A mixture of ethyl 2-hydroxy-4-oxo-6H,7H,8H,9H-pyrido[1,2-a]pyrimidine-3-carboxylate (10.00 g, 41.134 mmol), THF (100 mL) and NaOH (2 M) (103.00 mL, 205.670 mmol) was reacted overnight at room temperature; THF was removed by concentration under reduced pressure, the aqueous phase was adjusted to pH 3 with HCl (2 M), extracted with DCM (4 × 500 mL), the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain white solid 2-hydroxy-4-oxo-6H,7H,8H,9H-pyrido[1,2-a]pyrimidine-3-carboxylic acid (5.6 g, 63.47%). (ES, m / z): 211 [M+H] + 。

[0333] Step d: A solution of 2-chloro-3-fluoroaniline (5.00 g, 33.663 mmol), tert-butyl mercaptan (3.64 g, 40.396 mmol), and Cs2CO3 (32.90 g, 100.989 mmol) in DMF (50 mL) was reacted at 100 °C for 8 h; the temperature was lowered to room temperature, the reaction solution was poured into water (300 ml), extracted with CH2Cl2 (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 = 5∶1 to 1∶1) to obtain 3-(tert-butylthio)-2-chloroaniline as a colorless oil (7 g, 94.46%). (ES, m / z): 216 [M+H] + 。

[0334] Step e: 3-(tert-Butylthio)-2-chloroaniline (1.00 g, 4.543 mmol) and concentrated HCl (10 mL) were stirred overnight at 50 °C; the temperature was lowered to 0 °C, filtered, and the filter cake was washed by pulping with concentrated HCl (10 mL) and n-hexane (20 ml) in sequence, and dried; 3-amino-2-chlorobenzenethiol as a white solid (520 mg, 70.28%) was obtained. (ES, m / z): 160 [M+H] + 。

[0335] Steps (f - h): Using the product of the above step as the starting material, 5-amino-6-((3-amino-2-chlorophenyl)thio)3-chloropyrazine-2-carbonitrile was synthesized by the preparation steps (c - e) of Intermediate Preparation Example 1, wherein the product of step g was Intermediate A11-I.

[0336] Step j: Under nitrogen protection, 2-hydroxy-4-oxo-6H,7H,8H,9H-pyrido[1,2-a]pyrimidine-3-carboxylic acid (45 mg, 0.210 mmol, 1 eqv), 5-amino-6-((3-amino-2-chlorophenyl)thio)3-chloropyrazine-2-carbonitrile (79 mg, 0.252 mmol, 1.2 eqv), HATU (96 mg, 0.252 mmol, 1.2 eqv), and DIEA (68 mg, 0.525 mmol, 2.5 eqv) in DMF (2 mL) were reacted at room temperature for 1 h; then purified by reverse flash chromatography (gradient elution with 50 - 80% aqueous acetonitrile solution, modified with 10 mmol / L NH4HCO3) to obtain N-(3-((3-amino-5-chloro-6-cyanopyrazin-2-yl)thio)-2-chlorophenyl)-2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxamide (Intermediate A11) as a yellow solid (25.4 mg, 35%). (ES, m / z): 504.05 [M+H] +。

[0337] Intermediate Preparation Example 13: Methyl 3-chloro-5-((2,4-dimethoxybenzyl)amino)pyrazine-2-carboxylate (Intermediate A12)

[0338]

[0339] Under nitrogen protection, cesium fluoride (8.36 g, 55.07 mmol, 3 eq) was added to a DMSO (40 mL) solution of methyl 3,5-dichloropyrazine-2-carboxylate (3.8 g, 18.36 mmol, 1 eq) and 2,4-dimethoxybenzylamine (3.07 g, 18.36 mmol, 1 eq). Then the temperature was raised to 75 °C and the reaction was carried out for 3 h. After cooling to room temperature, the reaction solution was poured into water (200 mL) and EA (100 mL), and the layers were separated. The aqueous phase was extracted with EA (2 × 50 mL), and the organic phases were combined. The combined organic phases were 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 to 1∶1) to obtain methyl 3-chloro-5-((2,4-dimethoxybenzyl)amino)pyrazine-2-carboxylate (Intermediate A12) as a yellow solid (4 g, 54.06%). (ES, m / z): 338.1 [M+H] + ; 1 1H NMR (400 MHz, CDCl3): δ ppm 7.82 (s, 1H) 7.23 (d, J = 8.4 Hz, 1H) 6.41 - 6.51 (m, 2H) 5.66 (br s, 1H) 4.55 (d, J = 5.6 Hz, 2H) 3.94 (s, 3H) 3.85 (s, 3H) 3.81 (s, 3H).

[0340] Intermediate Preparation Example 14: 3-[(2-Amino-3-chloropyridin-4-yl)thio]-6-chloro-5-(oxetan-3-yl)pyrazin-2-amine (Intermediate A13)

[0341]

[0342] The dtbpy (32.41 mg, 0.121 mmol, 0.10 equiv) and DMA (20.00 mL) were purged with argon, NiBr2·DME (42.59 mg, 0.121 mmol, 0.10 equiv) was added, and the mixture was stirred at room temperature for 0.5 h; then 3-[(2-amino-3-chloropyridin-4-yl)thio]-6-chloro-5-iodopyrazin-2-amine (500.00 mg, 1.208 mmol, 1.00 equiv), 3-bromoxetane (330.82 mg, 2.415 mmol, 2.00 equiv), TBAI (44.60 mg, 0.121 mmol, 0.10 equiv), and Zn (157.97 mg, 2.415 mmol, 2.00 equiv) were added. The reaction was stirred overnight at 70 °C under argon protection; filtered, the filtrate was poured into water (60 ml), extracted with EA (2 × 50 ml), and the organic phases were combined; the organic phase was washed with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by Prep-HPLC (gradient elution with 20 - 50% aqueous acetonitrile solution, modified with 0.1% NH4HCO3) to obtain the yellow solid 3-[(2-amino-3-chloropyridin-4-yl)thio]-6-chloro-5-(oxetan-3-yl)pyrazin-2-amine (Intermediate A13) (101.8 mg, 24.5%). (ES, m / z): 344 [M + H] + 。

[0343] Intermediate Preparation Example 15: 1-(3,3-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indol-1-yl)ethanone (Intermediate B1)

[0344]

[0345] Under nitrogen protection, a solution of 1-(3,3-difluoro-4-iodoindol-1-yl)ethanone (3 g, 9.2 mmol, 1 eqv), Pin2B2 (3.54 g, 13.9 mmol, 1.5 eqv), Pd(dppf)Cl2 (1.36 g, 1.8 mmol, 0.2 eqv), and KOAc (3.19 g, 32.50 mmol, 3.5 eqv) in DMF (25 mL) was reacted at 60 °C for 12 h; cooled, the reaction solution was filtered through diatomaceous earth under reduced pressure, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (n-hexane∶EA = 50∶1 - 10∶1) to obtain the white solid 1-(3,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indol-1-yl)ethanone (Intermediate B1) (1.18 g, 33.82%). (ES, m / z): 324.1 [M + H] + ; 11H NMR (400 MHz, CHLOROFORM-d): δ = 8.47 (br d, J = 8.6 Hz, 1H), 7.63 - 7.55 (m, 1H), 7.51 (d, J = 8.2 Hz, 1H), 4.29 (brt, J = 15.6 Hz, 2H), 2.27 (s, 3H), 2.08 - 2.03 (m, 1H), 1.38 (s, 12H).

[0346] Intermediate Preparation Example 16: (R)-N-((S)-1,3-Dihydrospiro[indene-2,4'-piperidine]-1-yl)-2-methylpropan-2-sulfinamide (Intermediate C1)

[0347]

[0348] Step a: Under nitrogen protection, at 0 °C, to a solution of 1-indanone (10.00 g, 75.67 mmol, 1.00 equiv) in DMF (250 mL), 60% NaH (4.54 g, 189.17 mmol, 2.5 equiv) was added and the reaction was carried out for 1 h; then bis(2-chloroethyl) tert-butylcarbamate (20.15 g, 83.23 mmol, 1.1 eqv) was added dropwise and the reaction was carried out overnight at 60 °C; the reaction mixture was cooled to room temperature, poured into ice water (1 L), and extracted with EA (2 × 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 obtain tert-butyl 3-oxo-1H-spiro[indene-2,4-piperidine]-1-carboxylate (3.6 g, 15.79%). (ES, m / z): 302 [M + H] + 。

[0349] Step b: Under nitrogen protection, to a solution of tert-butyl 3-oxo-1H-spiro[indene-2,4'-piperidine]-1'-carboxylate (16.00 g, 0.053 mmol, 1.00 equiv) and (R)-2-methylpropane-2-sulfinamide (19.30 g, 0.159 mmol, 3 equiv) in THF (160.00 mL), add Ti(OEt)4 (121.10 g, 0.531 mmol, 10 equiv), and react overnight at 85 °C; then cool to 0 °C, add NaBH4 (3.00 g, 0.08 mmol, 1.5 equiv), and allow to warm to room temperature and react for 2 h; pour the reaction mixture into brine (100 ml) and EA (100 ml), filter, and separate the filtrate; wash the organic phase with brine (100 ml), dry over anhydrous sodium sulfate, and concentrate under reduced pressure; purify the residue by column chromatography (n-hexane∶EA = 10∶1) to obtain the yellow solid (S)-tert-butyl 1-((R)-1,1-dimethylethylsulfinylamino)-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate (16 g, 74.13%). (ES, m / z): 407 [M+H] + .

[0350] Step c: React a solution of (S)-tert-butyl 1-((R)-1,1-dimethylethylsulfinylamino)-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate (16.00 g, 0.039 mmol, 1.00 equiv) and TFA (40.00 mL) in DCM (160.00 mL) at room temperature for 2 h; concentrate under reduced pressure, and purify the residue by reverse-phase silica gel column chromatography (gradient elution with 10-50% aqueous acetonitrile solution) to obtain the white solid (R)-N-((S)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (Intermediate C1) (3.5 g, 29.02%). (ES, m / z): 307 [M+H] + ; 1 1H NMR (400 MHz, Methanol-d4) δ 7.36 - 7.29 (m, 1H), 7.29 - 7.21 (m, 3H), 5.92 (d, J = 10.4 Hz, 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 = 15.8 Hz, 1H), 2.29 (td, J = 13.5, 4.3 Hz, 1H), 1.97 (td, J = 13.6, 4.5 Hz, 1H), 1.88 (d, J = 14.4, 3.0 Hz, 1H), 1.58 - 1.48 (m, 1H), 1.38 (s, 9H).

[0351] Intermediate Preparation Example 17: (R)-N-((S)-5,7-Dihydrospiro[cyclopent[b]pyridine-6,4'-piperidine]-5-yl)-2-methylpropane-2-sulfinamide (Intermediate C2)

[0352]

[0353] Step a: Under nitrogen protection, at room temperature, to a toluene (80 ml) solution of 6,7-dihydro-5H-cyclopenta[b]pyridin-5-one (5.30 g, 39.805 mmol, 1.00 equiv) and N-benzyl-2-bromo-N-(2-bromoethyl)ethan-1-amine (15.34 g, 47.766 mmol, 1.2 equiv), potassium tert-butoxide (10.72 g, 95.531 mmol, 2.4 equiv) was added in three portions, and then the temperature was raised to 90 °C and reacted for 2 h; cooled to room temperature, water (100 ml) was added to quench the reaction, and the layers were separated; the aqueous phase was extracted with EA (3 × 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 - 50∶1) to obtain 1'-benzylspiro[cyclopent[b]pyridine-6,4'-piperidine]-5(7H)-1-one (7.2 g, 61.87%). (ES, m / z): 293 [M+H] + 。

[0354] Step b: Under nitrogen protection, to a MeOH (100.00 mL) solution of 1'-benzylspiro[cyclopent[b]pyridine-6,4'-piperidine]-5(7H)-1-one (7.23 g, 24.728 mmol, 1.00 equiv) and HCOONH4 (3.12 g, 49.456 mmol, 2.00 equiv), Pd / C (5.26 g, 49.427 mmol, 2.00 equiv) was added, and then the mixture was refluxed for 4 h; cooled to room temperature, filtered, and the filter cake was washed with MeOH (3x100 mL); the filtrate was concentrated under reduced pressure to obtain the crude product 3,4,5,7-tetrahydrospiro[cyclopent[b]pyridine-6,4-piperidine]-5-ol (2.8 g, 54.89%), which was used directly in the next step without purification. (ES, m / z): 207 [M+H] + 。

[0355] Step c: At room temperature, to a solution of 3,4,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,4'-piperidin]-5-ol (2.80 g, 13.573 mmol, 1.00 equiv) and (Boc)2O (3.26 g, 14.931 mmol, 1.10 equiv) in THF (15.00 mL) and H2O (15.00 mL), add NaHCO3 (2.28 g, 27.146 mmol, 2.00 equiv), and react for 2 h; concentrate under reduced pressure, extract the residual aqueous phase with EA (3 × 40 mL), and combine the organic phases; wash the organic phase with brine (1 × 50 mL), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product tert-butyl 5-hydroxy-3,4,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,4'-piperidine]-1'-carboxylate (3.52 g, 84.64%), which is used directly in the next step without purification. (ES, m / z): 307 [M+H] + 。

[0356] Step d: A solution of tert-butyl 5-hydroxy-3,4,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,4'-piperidine]-1'-carboxylate (4.32 g, 14.099 mmol, 1.00 equiv) and MnO2 (12.26 g, 0.141 mmol, 10.00 equiv) in DCE (50.00 mL) was stirred overnight at 85 °C; filtered, the filter cake was rinsed with DCM (3 x 20 mL), and the filtrate was concentrated under reduced pressure; the residue was purified by reverse-phase silica gel column (gradient elution with 20 - 70% aqueous acetonitrile solution) to obtain the light yellow solid tert-butyl 5-oxo-7H-spiro[cyclopenta[b]pyridine-6,4'-piperidine]-1'-carboxylate (630 mg, 11.97%). (ES, m / z): 303 [M+H] + 。

[0357] Step e: Under nitrogen protection, to a solution of tert-butyl 5-oxo-7H-spiro[cyclopent[b]pyridine-6,4'-piperidine]-1'-carboxylate (112.00 mg, 0.370 mmol, 1.00 equiv) and (R)-2-methylpropane-2-sulfinamide (359.14 mg, 2.963 mmol, 8.00 equiv) in THF (5.00 mL), add Ti(OEt)4 (844.92 mg, 3.704 mmol, 10.00 equiv), and react overnight at 85 °C; then cool to 0 °C, add NaBH4 (0.70 g, 18.581 mmol, 1 equiv), and allow to warm to room temperature and react for 2 h; pour the reaction mixture into brine (10 ml) and EA (10 ml), filter, and separate the filtrate; wash the organic phase with brine (10 ml), dry over anhydrous sodium sulfate, and concentrate under reduced pressure; purify the residue by column chromatography (n-hexane∶EA = 10∶1) to obtain a light yellow solid, (S)-tert-butyl 5-((R)-1,1-dimethylethylsulfinylamino)-5,7-dihydrospiro[cyclopent[b]pyridine-6,4'-piperidine]-1'-carboxylate (61 mg, 40.41%). (ES, m / z): 408 [M+H] + 。

[0358] Step f: To a solution of (S)-tert-butyl 5-((R)-1,1-dimethylethylsulfinylamino)-5,7-dihydrospiro[cyclopent[b]pyridine-6,4'-piperidine]-1'-carboxylate (60.00 mg, 0.147 mmol, 1.00 equiv) in DCM (7.00 mL), add TFA (1.00 mL), and react at room temperature for 2 h; concentrate under reduced pressure, and purify the residue by Prep-HPLC (gradient elution with 5-55% aqueous acetonitrile modified with 10 mmol / L NH4HCO3) to obtain a white solid, (R)-N-((S)-5,7-dihydrospiro[cyclopent[b]pyridine-6,4'-piperidine]-5-yl)-2-methylpropane-2-sulfinamide (Intermediate C2) (21 mg, 46.4%). (ES, m / z): 308 [M+H] + 。

[0359] Intermediate Preparation Example 18: (R)-N-((S)-5-methoxy-1,3-dihydrospiro[indene-2,4'-piperidine]-3-yl)-2-methylpropane-2-sulfinamide (Intermediate C3)

[0360]

[0361] Step a: Under nitrogen protection and at -70 °C, to a solution of ethyl N-Boc-4-piperidinecarboxylate (3.09 g, 12.00 mmol, 1 eqv) in dry THF (30 ml), dropwise add LDA (2M THF / Hex solution, 9 ml, 18 mmol, 1.5 eqv), react at this temperature for 1 h; then dropwise add 4-methoxybenzyl chloride (1.88 g, 12 mmol, 1 eqv), continue to keep warm for 2 h; then quench with saturated ammonium chloride solution (25 ml), separate the layers; extract the aqueous phase with EA (2×30 ml), combine the organic phases; dry with anhydrous sodium sulfate, concentrate under reduced pressure to obtain a pale yellow oily substance, ethyl 4-(4-methoxybenzyl)piperidine-1,4-dicarboxylate-1-tert-butyl (4.32 g). Without purification, it is directly used for the next reaction. (ES, m / z): 277.96 [M+H-100]

[0362] Step b: Reflux a mixture of ethyl 4-(4-methoxybenzyl)piperidine-1,4-dicarboxylate-1-tert-butyl (4.32 g, 11.44 mmol, 1 eqv), NaOH (2.29 g, 57.22 mmol, 5 eqv), EtOH (30 ml) and water (30 ml) overnight; cool to room temperature, concentrate under reduced pressure, adjust the pH of the remaining aqueous phase to 2 with 2M hydrochloric acid, extract with EA (3×30 ml), combine the organic phases; dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure; purify the residue by column chromatography (n-hexane∶EA = 4∶1 to 1∶1) to obtain a white solid, 1-(tert-butoxycarbonyl)-4-(4-methoxybenzyl)piperidine-4-carboxylic acid (2.43 g, 85.31%). (ES, m / z): 249.98 [M+H-100] +

[0363] Step c: React a mixture of 1-(tert-butoxycarbonyl)-4-(4-methoxybenzyl)piperidine-4-carboxylic acid (2.43 g, 6.95 mmol) and PPA (10 ml) at 120 °C for 2 h; cool down, pour the reaction solution into ice water (60 ml), adjust the pH to 10 with NaOH; then add (Boc)2O (2.27 g, 10.42 mmol), react overnight at room temperature; extract the reaction solution with EA (3×50 ml), combine the organic phases; wash the organic phase with brine (50 ml), dry with anhydrous sodium sulfate, concentrate under reduced pressure, purify the residue by column chromatography (n-hexane∶EA = 20∶1) to obtain a yellow solid, tert-butyl 6-methoxy-1-oxo-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate (1.49 g, 65%). (ES, m / z): 332 [M+H] +

[0364] Steps (d - e): Operate according to the preparation steps (e - f) of intermediate C2 to obtain a white solid, (R)-N-((S)-5-methoxy-1,3-dihydrospiro[indene-2,4'-piperidine]-3-yl)-2-methylpropane-2-sulfinamide (intermediate C3) (720 mg). (ES, m / z): 337.03 [M + H] + 。

[0365] Intermediate Preparation Examples 19 - 25: Intermediates C4 - C10

[0366] Referring to the process steps of Intermediate Preparation Example 18, synthesize Intermediates C4 - C10 using the following corresponding starting materials:

[0367]

[0368] Intermediate Preparation Example 26: (R)-N-((S)-2-chloro-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4'-piperidine]-6-yl)-2-methylpropane-2-sulfinamide (Intermediate C11)

[0369]

[0370] Step a: Under nitrogen protection, at -30 °C, add NaBH4 (20.32 g, 537.097 mmol) to a solution of ethyl 2-chloro-1,3-thiazole-4-carboxylate (30.00 g, 153.421 mmol) in MeOH (300 mL), then allow the temperature to rise to room temperature naturally and react for 1 h; pour the reaction solution into ice water (300 mL) and concentrate under reduced pressure; extract the residual aqueous phase with EA (2 × 300 mL), combine the organic phases; dry the organic phases with anhydrous sodium sulfate and concentrate under reduced pressure to obtain a colorless oil, (2-chloro-1,3-thiazol-4-yl)methanol (20 g, 85.40%). (ES, m / z): 150 [M + H] +

[0371] Step b: At 0 °C, add MsCl (16.51 g, 144.127 mmol) dropwise to a solution of (2-chloro-1,3-thiazol-4-yl)methanol (20.00 g, 131.025 mmol) and TEA (26.52 g, 262.050 mmol) in DCM (200 mL). After the addition is complete, react at room temperature for 0.5 h; add water (200 ml), separate the layers; extract the aqueous phase with CH2Cl2 (2 × 200 mL), combine the organic phases; dry the organic phases with anhydrous sodium sulfate and concentrate under reduced pressure; purify the residue by column chromatography (n-hexane∶EA = 1∶1) to obtain methyl (2-chloro-1,3-thiazol-4-yl)methanesulfonate (17 g, 55.85%). (ES, m / z): 228 [M + H] +

[0372] Step c: Under nitrogen protection and at -78 °C, slowly add dropwise LDA (2 M n-hexane solution) (140.00 mL, 280.239 mmol) to a solution of ethyl N-Boc-4-piperidinecarboxylate (34.34 g, 133.447 mmol) in THF (250.00 mL). After the addition is complete, keep the reaction mixture at the same temperature for 1 h. Then, slowly add dropwise a solution of methyl (2-chloro-1,3-thiazol-4-yl)methanesulfonate (31.00 g, 133.433 mmol) in THF (50 mL) to the reaction mixture. After the addition is complete, keep the reaction mixture at the same temperature for 4 h. Pour the reaction mixture into ice water (400 mL), and separate the layers. Extract the aqueous phase with EA (3 × 500 mL), and combine the organic phases. Dry the organic phases over anhydrous sodium sulfate and concentrate under reduced pressure. Purify the residue by column chromatography (n-hexane∶EA = 5∶1) to obtain 4-((2-chlorothiazol-4-yl)methyl)piperidine-1,4-dicarboxylic acid 1-tert-butyl 4-ethyl ester (20 g, 37.77%) as a yellow oil. (ES, m / z): 389 [M+H] +

[0373] Step d: Under nitrogen protection and at -78 °C, add dropwise LDA (66 mL, 0.132 mol, 2.00 eq) to a solution of 4-((2-chlorothiazol-4-yl)methyl)piperidine-1,4-dicarboxylic acid 1-tert-butyl 4-ethyl ester (22.3 g, 0.066 mol, 1.00 eq) in THF (200 mL). After stirring at the same temperature for 1 h, add water (250 mL) to quench the reaction at 0 °C. Wash and extract with EA (3 × 150 mL), combine the organic phases, dry over anhydrous Na2SO4, and concentrate under reduced pressure. Purify the residue by column chromatography (n-hexane∶EA = 15∶1 - 4∶1) to obtain tert-butyl 2-chloro-6-oxo-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate (7.62 g, 34%) as a yellow oil. (ES, m / z): 286.82 [M-56+H] + 。

[0374] Step e: At room temperature, to tert-butyl 2-chloro-6-oxo-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate (800 mg, 2.339 mmol, 1.00 eq) was added 33 - 35% Ti(OEt)4 (17.784 g, 23.386 mmol, 10.00 eq) and (R)-(+)-2-methyl-2-propanesulfinamide (850 mg, 7.016 mmol, 3.00 eq). The reaction was carried out at 70 °C for 8 h. After cooling to room temperature, the reaction was quenched by adding water (200 mL). A large amount of solid precipitated out upon stirring. The mixture was filtered under reduced pressure. The filter cake was washed with EA and discarded. The filtrate was extracted with EA, and the organic phases were combined. After drying over anhydrous Na2SO4, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (n-hexane∶EA = 15∶1 - 4∶1) to obtain a pale yellow solid, tert-butyl (R,E)-6-(tert-butylsulfinimino)-2-chloro-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate (310 mg, 30%). (ES, m / z): 345.94 [M - 100 + H] + 。

[0375] Step f: Under nitrogen protection, at -78 °C, to a solution of tert-butyl (R,E)-6-(tert-butylsulfinimino)-2-chloro-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate (3.16 g, 7.099 mmol, 1.00 eq) in dry THF (120 mL) was slowly added dropwise DIBAl-H (35.5 mL, 35.495 mmol, 5.00 eq). The reaction mixture was kept at the same temperature for 1 h. At 0 °C, the reaction was quenched by adding 15% aqueous NaOH solution (50 mL). Then water (100 mL) was added, and the mixture was extracted with EA (3 × 120 mL). The organic phases were combined. After drying over anhydrous Na2SO4, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (n-hexane∶EA = 3∶1 - 1∶3) to obtain a yellow solid, tert-butyl (S)-2-chloro-6-((R)-1,1-dimethylethanesulfinylamino)-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate (1.56 g, 49%). (ES, m / z): 347.95 [M - 100 + H] + 。

[0376] Step g: A solution of (S)-tert-butyl 2-chloro-6-((R)-1,1-dimethylethylsulfinylamino)-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate (1.56 g, 3.489 mmol, 1.00 eq), CF3COOH (6 mL) and DCM (18 mL) was reacted at room temperature for 1 h; the reaction solution was concentrated under reduced pressure to obtain (R)-N-((S)-2-chloro-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4'-piperidin]-6-yl)-2-methylpropane-2-sulfinamide (Intermediate C11) (1.1 g), (ES, m / z): 348 [M+H] + .

[0377] 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)

[0378]

[0379] Step a: Under nitrogen protection and at 0 °C, EtONa (0.60 g, 8.817 mmol) was added to a solution of (S)-tert-butyl 2-chloro-6-((R)-1,1-dimethylethylsulfinylamino)-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate (2.00 g, 4.375 mmol) in EtOH (20 mL); then the temperature was raised to 60 °C and reacted for 4 h; the temperature was lowered to room temperature and concentrated under reduced pressure; the residue was purified by column chromatography (n-hexane∶EA = 5∶1 to 1∶1) to obtain a yellow solid, (S)-tert-butyl 6-((R)-1,1-dimethylethylsulfinylamino)-2-ethoxy-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate (1.5 g, 73.43%). (ES, m / z): 458 [M+H] +

[0380] Step b: A solution of (S)-tert-butyl 6-((R)-1,1-dimethylethylsulfinylamino)-2-ethoxy-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate (1.50 g, 3.212 mmol) and TFA (4 mL) in DCM (12 mL) was reacted at room temperature for 1 h; concentrated under reduced pressure to obtain a yellow solid, (R)-N-((S)-2-ethoxy-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4'-piperidin]-6-yl)-2-methylpropane-2-sulfinamide (Intermediate C12) (1.1 g, 93.87%). (ES, m / z): 358 [M+H] + .

[0381] Intermediate Preparation Example 28: (R)-N-((S)-4,6-Dihydrospiro[cyclopentane[d]thiazole-5,4'-piperidine]-6-yl)-2-methylpropane-2-sulfinamide (Intermediate C13)

[0382]

[0383] Step a: A solution of (S)-2-chloro-6-((R)-1,1-dimethylethanesulfinylamino)-4,6-dihydrospiro[cyclopentane[d]thiazole-5,4'-piperidine]-1'-carboxylic acid tert-butyl ester (3.00 g, 6.563 mmol), TEA (2.00 mL, 19.775 mmol), and 10% Pd / C (1.035 g) in MeOH (60 ml) was reacted overnight at 50 °C under a H2 atmosphere; filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (n-hexane∶EA = 5∶1 to 2∶1) to obtain a pale gray solid, (S)-tert-butyl 6-((R)-1,1-dimethylethanesulfinylamino)-4,6-dihydrospiro[cyclopentane[d]thiazole-5,4'-piperidine]-1'-carboxylate (2.5 g, 90%). (ES, m / z): 414.06 [M+H] + 。

[0384] Step b: A solution of (S)-tert-butyl 6-(((R)-1,1-dimethylethanesulfinylamino)-4,6-dihydrospiro[cyclopentane[d]thiazole-5,4'-piperidine]-1'-carboxylate (2.50 g, 6.05 mmol) and TFA (4 mL) in DCM (12 mL) was reacted at room temperature for 1 h; concentrated under reduced pressure to obtain a yellow solid, (R)-N-((S)-4,6-dihydrospiro[cyclopentane[d]thiazole-5,4'-piperidine]-6-yl)-2-methylpropane-2-sulfinamide (Intermediate C13) (1.1 g, 87%). (ES, m / z): 314 [M+H] + 。

[0385] Intermediate Preparation Examples 29 - 32: Intermediates C14 - C17

[0386] Referring to the operating steps of Intermediate Preparation Example 26, Intermediates C14 - C17 were prepared using the following corresponding starting materials and preparation methods.

[0387]

[0388] Intermediate Preparation Example 33: Intermediate C18

[0389] Referring to the operating steps of Intermediate Preparation Example 27, Intermediate C18 was prepared using the following corresponding starting materials and preparation methods.

[0390]

[0391] Intermediate Preparation Example 34: Intermediate C19

[0392] Refer to the operation steps of Intermediate Preparation Example 28, and prepare Intermediate C19 using the following corresponding starting materials and preparation methods.

[0393]

[0394]

[0395] Intermediate Preparation Example 35: Preparation of (R)-N-((1S)-3'-Methoxy-1,3-dihydrospiro[indene-2,4'-piperidine]-1-yl)-2-methylpropan-2-sulfinamide (Intermediate C20)

[0396]

[0397] Step a: At room temperature, add potassium tert-butoxide (3.8 g, 34.1 mmol, 2.03 eqv) to a solution of THF (50 ml), cool the temperature to 0 °C, and slowly add ethyl 1-benzyl-3-oxa-4-piperidinecarboxylate hydrochloride (5.0 g, 16.8 mmol, 1.0 eqv). Raise the temperature to room temperature and react for 1 h; then cool the temperature to 0 °C, slowly add benzyl bromide (3.02 g, 17.6 mmol, 1.05 eqv), raise the temperature to room temperature and react overnight. Quench the reaction with saturated ammonium chloride solution (50 ml), and separate the layers; extract the aqueous phase with EA (3 × 30 ml), combine the organic phases; dry with anhydrous sodium sulfate, concentrate under reduced pressure, and purify the residue by column chromatography (n-hexane∶ethyl acetate = 10∶1) to obtain yellow oil ethyl 1,4-dibenzyl-3-oxa-4-piperidinecarboxylate (2.5 g, 42.32%). (ES, m / z): 352.09 [M+H] + .

[0398] Step b: Dissolve ethyl 1,4-dibenzyl-3-oxa-4-piperidinecarboxylate (2.5 g, 7.11 mmol) in methanol (50 ml), slowly add NaBH4 (809 mg, 21.3 mmol) to the reaction solution, react at room temperature for 6 h, quench with saturated ammonium chloride solution (20 ml), concentrate the solvent, extract the aqueous phase with EA (3 × 20 ml), combine the organic phases; dry with anhydrous sodium sulfate, concentrate under reduced pressure, and purify the residue by column chromatography (n-hexane∶ethyl acetate = 4∶1) to obtain yellow oil ethyl 1,4-dibenzyl-3-hydroxy-4-piperidinecarboxylate (1.2 g, 47.68%). (ES, m / z): 354.08 [M+H] + .

[0399] Step c: Dissolve ethyl 1,4-dibenzyl-3-hydroxy-4-piperidinecarboxylate (1.2 g, 3.39 mmol) in DMF (20 ml), cool to 0 °C, slowly add NaH (407 mg, 10.17 mmol) and react for 30 min. Then dropwise add methyl iodide (1.44 g, 10.17 mmol), warm to room temperature and react overnight. Quench with saturated ammonium chloride solution (30 ml) and separate the layers. Extract the aqueous phase with EA (3 × 30 ml), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography (n-hexane∶ethyl acetate = 6∶1) to obtain ethyl 1,4-dibenzyl-3-methoxy-4-piperidinecarboxylate as a yellow oil (600 mg, 48.08%). (ES, m / z): 368.10 [M+H] + .

[0400] Step d: Reflux ethyl 1,4-dibenzyl-3-methoxy-4-piperidinecarboxylate (600 mg, 1.63 mmol), NaOH (1.3 g, 32.6 mmol, 20 eqv), EtOH (15 ml) and water (15 ml) overnight. Cool to room temperature, concentrate under reduced pressure, adjust the pH of the remaining aqueous phase to 2 with 2M hydrochloric acid, extract with EA (3 × 30 ml), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Purify the residue by column chromatography (n-hexane∶ethyl acetate = 1∶1) to obtain 1,4-dibenzyl-3-methoxy-4-piperidinecarboxylic acid as a yellow oil (302 mg, 53.99%). (ES, m / z): 340.08 [M+H] + .

[0401] Step e: Heat 1,4-dibenzyl-3-methoxy-4-piperidinecarboxylic acid (302 mg, 0.88 mmol) and PPA (10 ml) to 120 °C and react for 6 h. Cool to room temperature and neutralize the reaction solution with 2M NaOH. Extract the aqueous phase with EA (3 × 30 ml), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product of 1′-benzyl-3′-methoxyspiro[indene-2,4′-piperidin]-1(3H)-one as a yellow oil (180 mg), which is used directly in the next step without purification. (ES, m / z): 322.04 [M+H] + .

[0402] Step f: 1'-Benzyl-3'-methoxyspiro[indene-2,4'-piperidin]-1(3H)-one (180 mg, 0.56 mmol), (R)-tert-butanesulfinamide (203.6 mg, 1.68 mmol) and titanium ethoxide (5 ml) were heated to 100 °C and reacted overnight. The reaction was quenched by adding water (20 ml), and the layers were separated. The aqueous phase was extracted with EA (3 × 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) to obtain (R,E)-N-(1'-benzyl-3'-methoxyspiro[indene-2,4'-piperidin]-1(3H)-alkylidene)-2-methylpropane-2-sulfinamide (123.6 mg, 52%). (ES, m / z): 425.13 [M+H] + 。

[0403] Step g: (R,E)-N-(1'-benzyl-3'-methoxyspiro[indene-2,4'-piperidin]-1(3H)-alkylidene)-2-methylpropane-2-sulfinamide (123.6 mg, 0.29 mmol), 10% Pt / C (50 mg) and EtOH (10 ml) were reacted overnight in a hydrogen atmosphere at 50 °C. The temperature was lowered to room temperature, and the mixture was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure, and the residue was purified by reverse-phase silica gel column chromatography (gradient elution with 10 - 50% aqueous acetonitrile solution) to obtain (R)-N-((1S)-3'-methoxy-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (Intermediate C20) (63.6 mg, 65%). 337.13 [M+H] + 。

[0404] Intermediate Preparation Example 36: 1-(5-Amino-3-chloropyrazin-2-yl)ethanone (Intermediate D1)

[0405]

[0406] To a solution of 2-amino-5-bromo-6-chloropyrazine (2.0 g, 9.666 mmol, 1.0 eq) in 1,4-dioxane (80 mL), tributyl(1-ethoxyvinyl)tin (5.236 g, 14.498 mmol, 1.5 eq), CuI (184 mg, 0.966 mmol, 0.1 eq), and Pd(Ph3P)2Cl2 (678 mg, 0.966 mmol, 0.1 eq) were added. Under nitrogen protection, the reaction flask was placed in an oil bath at 100 °C and stirred at a constant temperature for 7 h. Then the reaction solution was concentrated to dryness. Water (100 mL) was added to the concentrate, and the mixture was washed and extracted with EA (3 × 80 mL). The combined organic phases were washed with H2O (150 mL) and brine (150 mL), dried over anhydrous Na2SO4, filtered under reduced pressure, and the filtrate was concentrated to dryness. The product was purified by silica gel column chromatography (n-hexane∶EA = 10∶1 to 5∶1), and the product spot was collected and concentrated to dryness to obtain 1-(5-amino-3-chloropyrazin-2-yl)ethanone (1.02 g, 62%). (ES, m / z): 171.97 [M+H] + ;

[0407] Intermediate Preparation Example 37: 2-Chloro-3-(oxazol-2-yl)benzenethiol (Intermediate D2)

[0408]

[0409] Step a: A solution of 2-chloro-3-fluoroaniline (5.00 g, 33.663 mmol), tert-butyl mercaptan (3.64 g, 40.396 mmol), and Cs2CO3 (32.90 g, 100.989 mmol) in DMF (50 mL) was reacted at 130 °C for 24 h. After cooling to room temperature, the reaction solution was poured into water (300 ml), extracted with EA (2 × 300 mL), 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 = 100∶1 to 20∶1) to obtain a colorless oil, 3-(tert-butylthio)-2-chloroaniline (7.0 g, 94.46%). (ES, m / z): 216 [M+H] + 。

[0410] Step b: Cool the concentrated hydrochloric acid (15 ml) solution of 3-(tert-butylthio)-2-chloroaniline (7.0 g, 32.55 mmol, 1 eqv) to -10 to -5 °C, and dropwise add an aqueous solution of sodium nitrite (3.369 g, 48.83 mmol, 1.5 eqv) in water (105 ml). After the addition is complete, keep the reaction mixture at the same temperature for 30 min. At the same temperature, dropwise add an aqueous solution of potassium iodide (6.484 g, 39.06 mmol, 1.2 eqv) in water (65 ml). After the addition is complete, keep the reaction mixture at the same temperature for 20 min. Add ethyl acetate (100 ml) and saturated sodium thiosulfate solution (100 ml) to the reaction solution, stir for 10 min, separate the layers, extract the aqueous phase with EA (2 × 50 ml), and combine the organic phases. Wash the organic phase with brine (100 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the residue by column chromatography (n-hexane) to obtain tert-butyl(2-chloro-3-iodophenyl)sulfane (6.52 g, 61.45%). 1 H NMR(600MHz, DMSO-d6)δ7.975 - 7.990(m, 1H), 7.081 - 7.107(m, 1H), 1.287(s, 9H).

[0411] Step c: Add tert-butyl(2-chloro-3-iodophenyl)sulfane (6.5 g, 19.94 mmol, 1 eqv), oxazole (2.75 g, 39.88 mmol, 2 eqv), lithium tert-butoxide (1.92 g, 23.93 mmol, 1.2 eqv), and CuI (380 mg, 1.994 mmol, 0.1 eqv) to a solution of DMF (50 ml). Under nitrogen protection, react at 140 °C for 2 h. Monitor the reaction by TLC until it is complete. Cool the reaction mixture to room temperature, pour it into water (300 ml), extract with EA (2 × 150 mL), combine the organic phases, wash the organic phase with brine (2 × 100 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the residue by column chromatography (n-hexane∶EA = 25∶1 to 10∶1) to obtain 2-(3-(tert-butylthio)-2-chlorophenyl)oxazole (3.12 g, 58.58%). (ES, m / z): 267.93[M + H] + 。

[0412] Step d: At 0 °C, aluminum trichloride (6.23 g, 46.72 mmol, 4 eqv) was added to a toluene (60 ml) solution of 2-(3-(tert-butylthio)-2-chlorophenyl)oxazole (3.12 g, 11.68 mmol, 1 eqv), and the reaction was carried out overnight at room temperature; the temperature was lowered to 0 °C, water (60 ml) was added dropwise, and the mixture was stirred for 30 min, and then separated; the aqueous phase was extracted with toluene (30 ml), and the organic phases were combined; concentrated under reduced pressure, and the residue was purified by column chromatography (n-hexane∶EA = 20∶1 to 5∶1) to obtain 2-chloro-3-(oxazol-2-yl)benzenethiol (1.726 g, 70%). (ES, m / z): 211.89 [M+H] + 。

[0413] Intermediate Preparation Example 38: 2-Chloro-3-(pyrazin-2-yl)benzenethiol (Intermediate D3)

[0414]

[0415] Using tert-butyl(2-chloro-3-iodophenyl)sulfane (D2-2) and 2-(tributylstannyl)pyrazine as starting materials, it was prepared according to the method for preparing 6d in CN111647000A.

[0416] 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)

[0417]

[0418] Step a: To a solution of (3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine dihydrochloride (485 mg, 1.994 mmol, 1.05 eq) in DMSO (15 mL), DIEA (1.227 g, 9.498 mmol, 5.0 eq) was added dropwise. Methyl 3-chloro-5-((2,4-dimethoxybenzyl)amino)pyrazine-2-carboxylate (640 mg, 1.900 mmol, 1.0 eq) was added. The reaction was carried out at 105 °C for 5 h. Then the reaction flask was cooled to room temperature. Water (80 mL) was added to the reaction solution and mixed. The mixture was extracted with EA (60 mL × 3), and the combined organic phases were washed with H2O (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, filtered under reduced pressure, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with the eluent DCM∶MeOH = 100∶1, gradually increasing to 40∶1. The product-containing fractions were collected and concentrated to obtain the solid of methyl 3-methyl((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-5-((2,4-dimethoxybenzyl)amino)pyrazine-2-carboxylate (780 mg, 83%). (ES, m / z): 472.22 [M+H] + .

[0419] Step b: To a reaction flask containing methyl 3-methyl((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-5-((2,4-dimethoxybenzyl)amino)pyrazine-2-carboxylate (780 mg, 1.655 mmol, 1.0 eq), CF3COOH (5 mL) was added. After stirring the reaction at room temperature for 2 h, the reaction solution was rotary evaporated to dryness to obtain the crude product of methyl 5-amino-3-(((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazine-2-carboxylate. (ES, m / z): 322.21 [M+H] + .

[0420] Step c: At room temperature, TEA (502 mg, 4.965 mmol, 3.0 eq) was added to a solution of crude methyl 5-amino-3-(((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazine-2-carboxylate) (532 mg, 1.655 mmol, 1.0 eq) in DCM (15 mL). The pH was basic, and then Boc anhydride (542 mg, 2.482 mmol, 1.5 eq) was added. The reaction was stirred at room temperature for 2 h. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with EA (10 mL × 3). The combined organic phases were washed with H2O (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, filtered under reduced pressure, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with an eluent of DCM∶MeOH = 100∶1, gradually increasing to 60∶1. The product-containing fractions were collected and concentrated to obtain methyl 5-amino-3-((3S,4S)-4-((tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazine-2-carboxylate as a transparent solid (700 mg, 100%), (ES, m / z): 422.11 [M+H] + .

[0421] Step d: At -15 °C, NBS (311 mg, 1.745 mmol, 1.05 eq) was added to a solution of methyl 5-amino-3-((3S,4S)-4-((tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazine-2-carboxylate (700 mg, 1.662 mmol, 1.0 eq) in DCM (20 mL). The reaction was stirred at a constant temperature for 10 min. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (20 mL) and extracted with DCM (20 mL × 2). The combined organic phases were washed with H2O (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, filtered under reduced pressure, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with an eluent of n-hexane∶EA = 3∶1, gradually increasing to 1∶3, to obtain methyl 5-amino-6-bromo-3-((3S,4S)-4-((tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazine-2-carboxylate (450 mg, 54%), (ES, m / z): 500.07 [M+H] + .

[0422] Intermediate Preparation Example 40: (S)-Methyl 5-amino-6-bromo-3-(1-((tert-butoxycarbonyl)amino)-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)pyrazine-2-carboxylate (Intermediate E2)

[0423]

[0424] Step a: To a solution of (S)-N-((S)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-yl)-2-methylpropane-2-sulfinamide (200 mg, 0.653 mmol, 1.1 eq) in DMSO (5 mL) was added dropwise DIEA (230 mg, 1.779 mmol, 3.0 eq). The mixture was stirred at room temperature for 10 min, and then methyl 3-chloro-5-((2,4-dimethoxybenzyl)amino)pyrazine-2-carboxylate (200 mg, 0.593 mmol, 1.0 eq) was added. The reaction was carried out at 105 °C for 10 h. After cooling to room temperature, water (50 mL) was added, and the mixture was extracted with EA (3 × 30 mL). The combined organic phases were washed with H2O (100 mL) and brine (100 mL), dried over anhydrous Na2SO4, filtered under reduced pressure, and the filtrate was concentrated to dryness. Purification was carried out by silica gel column chromatography using an eluent of EA∶MeOH = 80∶1 to 50∶1, to obtain methyl 5-((2,4-dimethoxybenzyl)amino)-3-((S)-1-((R)-1,1-dimethylethylsulfinyl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)pyrazine-2-carboxylate (305 mg, 77%). (ES, m / z): 608.16 [M+H] + 。

[0425] Step b: To a reaction flask were added methyl 5-((2,4-dimethoxybenzyl)amino)-3-((S)-1-((R)-1,1-dimethylethylsulfinyl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)pyrazine-2-carboxylate (305 mg, 0.502 mmol, 1.0 eq) and CF3COOH (5 mL). The mixture was stirred at room temperature for 2 h, and then concentrated under reduced pressure to obtain the crude product of methyl 5-amino-3-((S)-1-((R)-1,1-dimethylethylsulfinyl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)pyrazine-2-carboxylate, which was used directly in the next step without purification (229 mg, 100%). (ES, m / z): 458.19 [M+H] + 。

[0426] Step c: To the reaction flask containing methyl 5-amino-3-((S)-1-((R)-1,1-dimethylethylsulfinylamino)-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)pyrazine-2-carboxylate (229 mg, 0.502 mmol), add MeOH / HCl solution (5 mL). After stirring the reaction at room temperature for 2 h, rotary evaporate the reaction solution to obtain crude (S)-methyl 5-amino-3-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)pyrazine-2-carboxylate as an oily substance (177 mg, 100%), (ES, m / z): 354.10 [M+H] + .

[0427] Step d: At room temperature, add TEA (152 mg, 1.503 mmol, 3.0 eq) to a solution of (S)-methyl 5-amino-3-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)pyrazine-2-carboxylate (177 mg, 0.501 mmol, 1.0 eq) in DCM (10 mL). Then add Boc anhydride (142 mg, 0.651 mmol, 1.3 eq) and stir the reaction at room temperature for 3 h. Add water (15 mL) to the reaction solution and mix. Extract with DCM (10 mL×2), wash the combined organic phases with H2O (20 mL) and brine (20 mL), dry over anhydrous sodium sulfate, filter under reduced pressure, concentrate the filtrate under reduced pressure, purify the residue by silica gel column chromatography, with the eluent being DCM∶MeOH = 100∶1, gradually increasing to 70∶1. Collect the product-containing fractions and concentrate to obtain (S)-methyl 5-amino-3-(1-(((tert-butoxycarbonyl)amino)-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)pyrazine-2-carboxylate as a transparent solid (133 mg, 61%), (ES, m / z): 438.15 [M+H] + .

[0428] Step e: Under the condition of -15 °C, NBS (57 mg, 0.319 mmol, 1.05 eq) was added to a solution of (S)-methyl 5-amino-3-(1-(((tert-butoxycarbonyl)amino)-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)pyrazine-2-carboxylate (133 mg, 0.304 mmol, 1.0 eq) in DCM (10 mL), and the reaction was stirred at a constant temperature for 10 min. The reaction solution was quenched with saturated aqueous sodium bicarbonate (10 mL), extracted with DCM (10 mL × 2), and the combined organic phases were washed with H2O (20 mL) and 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 silica gel column chromatography. The eluent was n-hexane∶EA = 5∶1, gradually increased to 3∶1, to obtain (S)-methyl 5-amino-6-bromo-3-(1-((tert-butoxycarbonyl)amino)-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)pyrazine-2-carboxylate as a transparent solid (100 mg, 62%), (ES, m / z): 532.09 [M+H] + 。

[0429] Intermediate Preparation Example 41: (S)-tert-butyl (1'-(3-acetyl-6-amino-5-bromopyrazin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-yl)carbamate (Intermediate E3)

[0430]

[0431] Step a: A solution of 1-(5-amino-3-chloropyrazin-2-yl)ethanone (266 mg, 1.555 mmol, 1.0 eq), (S)-N-((S)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-yl)-2-methylpropane-2-sulfinamide (571 mg, 1.866 mmol, 1.2 eq), and DIPEA (1.005 g, 7.775 mmol, 5.0 eq) in DMSO (10 ml) was reacted at 105 °C for 2.5 h; cooled to room temperature, water (50 mL) was added, and the mixture was extracted with EA (3 × 30 mL), and the organic phases were combined; the organic phases were washed with H2O (100 mL) and brine (100 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by silica gel column chromatography (the eluent was DCM∶MeOH = 80∶1 to 50∶1) to obtain (S)-N-((S)-1'-(3-acetyl-6-aminopyrazin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-yl)-2-methylpropane-2-sulfinamide (320 mg, 46%). (ES, m / z): 442.09 [M+H] + 。

[0432] Step b: Add MeOH / HCl solution (5 mL) to a reaction flask containing (S)-N-((S)-1′-(3-acetyl-6-aminopyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)-2-methylpropan-2-sulfinamide (320 mg, 0.725 mmol, 1.0 eq). After stirring the reaction at room temperature for 2 h, rotary evaporate the reaction solution to obtain the crude product (S)-1-(5-amino-3-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)pyrazin-2-yl)ethanone solid, (ES, m / z): 338.06 [M+H] + .

[0433] Step c: At room temperature, add TEA (220 mg, 2.175 mmol, 3.0 eq) to a solution of (S)-1-(5-amino-3-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)pyrazin-2-yl)ethanone (244 mg, 0.725 mmol, 1.0 eq) in DCM (10 mL), then add Boc anhydride (316 mg, 1.45 mmol, 2.0 eq), and stir the reaction at room temperature for 2 h. Add water (15 mL) to the reaction solution and mix. Extract with DCM (10 mL×2), and wash the combined organic phases with H2O (20 mL) and brine (20 mL). Dry over anhydrous sodium sulfate, filter under reduced pressure, concentrate the filtrate under reduced pressure, purify the residue by silica gel column chromatography, with the eluent being n-hexane∶EA = 5∶1, gradually increasing to 2∶1. Collect the product-containing spots and concentrate to obtain (S)-tert-butyl (1′-(3-acetyl-6-aminopyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate transparent solid (220 mg, 69%), (ES, m / z): 438.15 [M+H] + .

[0434] Step d: Under the condition of -15 °C, NBS (94 mg, 0.528 mmol, 1.05 eq) was added to a solution of (S)-tert-butyl (1′-(3-acetyl-6-aminopyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidine]-1-yl)carbamate (220 mg, 0.503 mmol, 1.0 eq) in DCM (10 mL), and the reaction was stirred at a constant temperature for 10 min. The reaction solution was quenched with saturated aqueous sodium bicarbonate (10 mL), extracted with DCM (10 mL×2), and the combined organic phases were washed with H2O (20 mL) and 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 silica gel column chromatography with the eluent of n-hexane∶EA = 5∶1, gradually increasing to 3∶1, to obtain (S)-tert-butyl (1′-(3-acetyl-6-amino-5-bromopyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidine]-1-yl)carbamate transparent solid (132 mg, 51%), (ES, m / z): 516.03 [M+H] + 。

[0435] According to the preparation process routes and operations of Intermediate Preparation Example 40 and Intermediate Preparation Example 41 respectively, using the following intermediates as starting materials, the following intermediates were prepared:

[0436]

[0437] Intermediate Preparation Example 49: (S)-Methyl 5-amino-3-(1-(((tert-butoxycarbonyl)amino)-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-yl)-6-mercaptopyrazine-2-carboxylate (Intermediate E6)

[0438]

[0439] Step a: To a reaction solution of (S)-methyl 5-amino-6-bromo-3-(1-((tert-butoxycarbonyl)amino)-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)pyrazine-2-carboxylate (1000 mg, 1.88 mmol, 1.0 eq) in 1,4-dioxane (10 mL), methyl 3-mercaptopropionate (340 mg, 2.82 mmol, 1.5 eq), Pd(OAc)2 (80 mg, 0.38 mmol, 0.2 eq), Xantphos (440 mg, 0.75 mmol, 0.4 eq), and DIEA (850 mg, 6.58 mmol, 3.5 eq) were added. Under nitrogen protection, the mixture was stirred at 97 °C for 8 h. The reaction solution was concentrated, mixed with water (100 mL), extracted with EA (50 mL × 2), and the combined organic phases were washed with H2O (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with the eluent of n-hexane∶EA = 5∶1, gradually increasing to 2∶1, to obtain (S)-methyl 5-amino-3-(1-((tert-butoxycarbonyl)amino)-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-((3-methoxy-3-oxopropyl)thio)pyrazine-2-carboxylate solid (1050 mg, 98%), (ES, m / z): 572.20 [M+H] + .

[0440] Step b: To a solution of (S)-methyl 5-amino-3-(1-((tert-butoxycarbonyl)amino)-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-((3-methoxy-3-oxopropyl)thio)pyrazine-2-carboxylate (1050 mg, 1.84 mmol, 1.0 eq) in MeOH (50 mL) in a reaction flask, NaOH (80 mg, 2.02 mmol, 1.1 eq) was added. After stirring at 50 °C for 3 h, the solution was rotary evaporated to dryness. Water (100 mL) was added to the concentrate and mixed, and the mixture was adjusted to acidic with 1N HCl. A large amount of yellow solid precipitated out. It was filtered under reduced pressure and dried to obtain (S)-methyl 5-amino-3-(1-(((tert-butoxycarbonyl)amino)-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-mercaptopyrazine-2-carboxylate solid (880 mg, 95%) (ES, m / z): 486.16 [M+H] + .

[0441] According to the preparation process route and operation of Intermediate Preparation Example 49, using the following intermediate as the starting material, the following intermediate was prepared:

[0442]

[0443] Intermediate Preparation Example 54: 3-Chloro-2-(pyrazin-2-yl)pyridine-4-thiol (Intermediate E11)

[0444]

[0445] Step a: Under nitrogen protection, a solution of 2,3-dichloro-4-iodopyridine (2.00 g, 7.33 mmol, 1.00 eqv), 2-ethylhexyl 3-mercaptopropionate (2.07 g, 9.51 mmol, 1.3 eqv), DIEA (2.862 g, 21.99 mmol, 3.00 eqv), Pd2(dba)3 (1.342 g, 1.466 mmol, 0.2 eqv) and XantPhos (1.696 g, 2.932 mmol, 0.4 eqv) in 1,4-dioxane (50 ml) was stirred at 96 °C for 8 h; the temperature was lowered to room temperature, the reaction solution was filtered through diatomaceous earth by suction, and the filtrate was concentrated under reduced pressure; the residue was purified by column chromatography (n-hexane:EA = 20:1) to obtain 2-ethylhexyl 3-[[(2,3-dichloropyridin-4-yl)thio]propionate (2.076 g, 78%), (ES, m / z): 364.06 [M+H] + 。

[0446] Step b: Under nitrogen protection, a solution of 2-ethylhexyl 3-[[(2,3-dichloropyridin-4-yl)thio]propionate (666 mg, 1.834 mmol, 1.0 eqv), pyrazin-2-boronic acid (250 mg, 2.02 mmol, 1.1 eqv), Pd(dppf)Cl2 (134 mg, 0.183 mmol, 0.1 eqv) and potassium carbonate (760 mg, 5.503 mmol, 3 eqv) in 1,4-dioxane (30 mL) and water (5 ml) was reacted at 96 °C for 4 h; the temperature was lowered, the reaction solution was poured into water (200 ml) and EA (100 ml), the phases were separated, the aqueous phase was extracted with EA (2 × 50 ml), and the organic phases were combined; 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 = 30:1 to 10:1) to obtain 2-ethylhexyl 3-((3-chloro-2-(pyrazin-2-yl)pyridin-4-yl)thio)propionate (637 mg, 85.3%). (ES, m / z): 408.15 [M+H] + 。

[0447] Step c: Under nitrogen protection, a solution of 2-ethylhexyl 3-((3-chloro-2-(pyrazin-2-yl)pyridin-4-yl)thio)propionate (637 g, 1.565 mmol, 1.0 eqv), NaOH (66 mg, 1.643 mmol, 1.05 eqv) in methanol (60 ml) was reacted at 50 °C for 3 h; the temperature was cooled to about 0 °C, and 4M HCl / MeOH solution was added dropwise to adjust the pH to 3-4; silica gel was added and column chromatography purification was carried out (n-hexane∶EA = 10∶1 - 5∶1) to obtain 3-chloro-2-(pyrazin-2-yl)pyridine-4-thiol (320 mg, 91.7%); (ES, m / z): 223.92 [M+H] + 。

[0448] The following are the preparation examples of the exemplary compounds of the present application.

[0449] Preparation Example 1: 5-Amino-6-[(2-amino-3-chloropyridin-4-yl)thio]-3-[(3S)-3-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl]pyrazine-2-carbonitrile (Compound 1)

[0450]

[0451] Step a: A solution of 5-amino-3-chloropyrazine-2-carbonitrile (400.00 mg, 2.588 mmol, 1.00 equiv), N-[(3S)-1,3-dihydrospiro[indene-2,4-piperidine]-3-yl]-2-methylpropane-2-sulfinamide (793.14 mg, 2.588 mmol, 1.00 equiv), and DIEA (1003.44 mg, 7.764 mmol, 3.00 equiv) in DMSO (4.00 mL) was reacted overnight at 80 °C; the temperature was cooled to room temperature, water (20 ml) was added, and extraction was carried out with EA (2×10 ml), and the organic phases were combined; the organic phase was washed with brine (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure; to obtain a 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 [M+H] + 。

[0452] Step b: At room temperature, NBS (280.87 mg, 1.578 mmol, 1.00 equiv) was added to a solution of (S)-N-[(3R)-1′-(6-amino-3-cyanopyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidine]-3-yl]-2-methylpropane-2-sulfinamide (670.00 mg, 1.578 mmol, 1.00 equiv) in DCM (10.00 mL), and the reaction was carried out at room temperature for 1 h; the reaction mixture was washed with water (2×5 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the yellow solid 5-amino-3-[(3R)-3-amino-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-yl]-6-bromopyrazine-2-carbonitrile (600 mg, 95.22%). (ES, m / z): 399 [M+H] + 。

[0453] Step c: To a solution of 5-amino-3-[(3R)-3-amino-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-yl]-6-bromopyrazine-2-carbonitrile (600.00 mg, 1.503 mmol, 1.00 equiv) and (Boc)2O (327.95 mg, 1.503 mmol, 1 equiv) in DCM (10 ml), TEA (152.05 mg, 1.503 mmol, 1.00 equiv) was added, and the reaction was carried out overnight at room temperature; the reaction mixture was washed with water (3×5 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure; the residue was purified by column chromatography (n-hexane∶EtOAC = 10∶1) to obtain tert-butyl N-[(3R)-1′-(6-amino-5-bromo-3-cyanopyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidine]-3-yl]carbamate (240 mg, 31.98%). (ES, m / z): 499 [M+H] + 。

[0454] Step d: Under nitrogen protection, a solution of tert-butyl N-[(3R)-1′-(6-amino-5-bromo-3-cyanopyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidine]-3-yl]carbamate (195.00 mg, 0.390 mmol, 1.00 equiv), 2-amino-3-chloropyridine-4-thiol (62.72 mg, 0.390 mmol, 1.00 equiv), DIEA (151.39 mg, 1.171 mmol, 3.00 equiv), Pd(dba)3 (18.32 mg, 0.020 mmol, 0.05 equiv) and Xantphos (11.58 mg, 0.020 mmol, 0.05 equiv) in 1,4-dioxane (2.00 mL) was reacted at 90 °C for 8 h; the temperature was lowered to room temperature, water (10 ml) was added, and the mixture was extracted with EA (3 × 5 mL), and the organic phases were combined; the organic phase was washed with water (3 × 5 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure; a white solid, tert-butyl N-[(3S)-1′-[6-amino-5-[(2-amino-3-chloropyridin-4-yl)thio]-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] + 。

[0455] Step e: tert-Butyl N-[(3S)-1′-[6-amino-5-[(2-amino-3-chloropyridin-4-yl)thio]-3-cyanopyrazin-2-yl]-1,3-dihydrospiro[indene-2,4′-piperidine]-3-yl]carbamate (194.00 mg, 0.336 mmol, 1.00 equiv) and 2M HCl / EA (4.00 ml) solution were reacted at room temperature for 2 h; the reaction solution was concentrated under reduced pressure; water (10 ml) was added to the residue, the pH was adjusted to 10 with 25% ammonia water, and the mixture was extracted with EA (2 × 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 (gradient elution with 5-25% aqueous acetonitrile solution, modified with 0.05% NH4HCO3) to obtain 5-amino-6-[(2-amino-3-chloropyridin-4-yl)thio]-3-[(3S)-3-amino-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-yl]pyrazine-2-carbonitrile (Compound 1) (150 mg). (ES, m / z): 479 [M+H] + 。

[0456] 1H NMR (400 MHz, Methanol-d4) δ 7.69 (d, J = 6.9 Hz, 1H), 7.53 (d, J = 7.5 Hz, 1H), 7.48 - 7.38 (m, 2H), 7.37 (td, J = 7.0, 6.5, 2.3 Hz, 1H), 6.41 (d, J = 6.9 Hz, 1H), 4.64 - 4.56 (m, 1H), 4.47 (d, J = 6.7 Hz, 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 = 13.5 Hz, 1H), 1.33 (d, J = 17.5 Hz, 1H).

[0457] Preparation Example 2: (S)-6-((1-Acetyl-3,3-difluoroindol-4-yl)thio)-5-amino-3-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)pyrazine-2-carbonitrile (Compound 2)

[0458]

[0459] Step a: A solution of 6-(((1-acetyl-3,3-difluoroindol-4-yl)thio)-5-amino-3-chloropyrazine-2-carbonitrile (100 mg, 0.262 mmol, 1 eqv), (R)-N-((S)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropan-2-sulfinamide (80 mg, 0.262 mmol, 1 eqv), and DIPEA (102 mg, 0.786 mmol, 3 eqv) in DMSO (5 ml) was reacted at 80 °C for 8 h; the temperature was lowered to room temperature, water (50 ml) was added, and the mixture was extracted with EA (2 × 20 ml). The organic phases were combined; the organic phase was washed with brine (20 ml) and concentrated under reduced pressure; the residue was purified by column chromatography (CH2Cl2∶CH3OH = 200∶1) to obtain a brown oil, (R)-N-((S)-1'-(5-((1-acetyl-3,3-difluoroindol-4-yl)thio)-6-amino-3-cyanopyrazin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropan-2-sulfinamide (140 mg). (ES, m / z): 652.15 [M+H] + 。

[0460] Step b: Add (R)-N-((S)-1′-(5-((1-acetyl-3,3-difluoroindol-4-yl)thio)-6-amino-3-cyanopyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidine]-1-yl)-2-methylpropane-2-sulfinamide (140 mg) to HCl / CH3OH (10 ml), and react at room temperature for 1 h; concentrate under reduced pressure, add water (20 ml) to the residue, adjust the pH to 10 with 25% ammonia water, extract with EA (2 × 20 ml), and combine the organic phases; wash the organic phase with brine (10 ml), and concentrate under reduced pressure; purify the residue by column chromatography (CH2Cl2∶CH3OH = 80∶1) to obtain (S)-6-((1-acetyl-3,3-difluoroindol-4-yl)thio)-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] + 。

[0461] Preparation Examples 3-8:

[0462] According to the preparation process route and operation of Preparation Example 2, use the following intermediates as starting materials to prepare Compounds 3-8.

[0463]

[0464]

[0465]

[0466] Preparation Example 9: 5-amino-3-[(3S)-3-amino-1,3-dihydrospiro[indene-2,4-piperidine]-1-yl]-6-[[2-(trifluoromethyl)pyridin-3-yl]thio]pyrazine-2-carbonitrile (Compound 9)

[0467]

[0468] Step a: A solution of 6-chloro-5-iodo-3-[[[2-(trifluoromethyl)pyridin-3-yl]sulfanyl]pyrazin-2-amine (320.00 mg, 0.740 mmol, 1.00 equiv), N-[(3S)-1,3-dihydrospiro[indene-2,4-piperidin]-3-yl]-2-methylpropane-2-sulfinamide (226.79 mg, 0.740 mmol, 1.00 equiv), and DIEA (286.82 mg, 2.219 mmol, 3.00 equiv) in DMSO (5.00 mL) was reacted at 100 °C for 3 h; cooled to room temperature, water (20 mL) was added, and the mixture was extracted with EA (2 × 50 mL), and the organic phases were combined; the organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure; the crude product of N-[(3S)-1-(6-amino-3-iodo-5-[[2-(trifluoromethyl)pyridin-3-yl]sulfanyl]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4-piperidin]-3-yl]-2-methylpropane-2-sulfinamide (300 mg) was obtained and used directly in the next step without purification.

[0469] Step b: Under nitrogen protection, a solution of N-[(3S)-1-(6-amino-3-iodo-5-[[2-(trifluoromethyl)pyridin-3-yl]sulfanyl]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4-piperidin]-3-yl]-2-methylpropane-2-sulfinamide (300.00 mg, 0.427 mmol, 1.00 equiv), Pd(PPh3)4 (49.34 mg, 0.043 mmol, 0.10 equiv), and Zn(CN)2 (50.15 mg, 0.427 mmol, 1.00 equiv) in NMP (5.00 mL) was reacted at 100 °C for 1 h; cooled to room temperature, EA (20 mL) was added, and the mixture was washed with brine (3 × 15 mL), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure; the residue was purified by column chromatography (n-hexane∶EA = 10∶1) to obtain a pale yellow solid, N-[(3S)-1-(6-amino-3-cyano-5-[[2-(trifluoromethyl)pyridin-3-yl]sulfanyl]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4-piperidin]-3-yl]-2-methylpropane-2-sulfinamide (120 mg, 46.71%). (ES, m / z): 602 [M+H] + 。

[0470] Step c: To a solution of N-[(3S)-1-(6-amino-3-cyano-5-[[2-(trifluoromethyl)pyridin-3-yl]sulfanyl]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4-piperidine]-3-yl]-2-methylpropane-2-sulfinamide (120.00 mg, 0.199 mmol, 1.00 equiv) in DCM (1.50 mL) was added a 1,4-dioxane solution of HCl (1.50 mL, 49.368 mmol). The reaction was carried out at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by Prep-HPLC (gradient elution with 30 - 70% aqueous acetonitrile solution modified with 10 mmol / L NH4HCO3) to obtain 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) (36 mg, 36.28%), (ES, m / z): 498 [M + H] + .

[0471] 1 1H NMR (400 MHz, Methanol-d4) δ 8.51 (d, 1H), 7.67 (d, J = 8.2 Hz, 1H), 7.54 (dd, J = 8.2, 4.6 Hz, 1H), 7.44 - 7.35 (m, 1H), 7.29 - 7.19 (m, 3H), 4.46 (dt, J = 13.4, 4.0 Hz, 2H), 3.98 (s, 1H), 3.51 - 3.35 (m, 2H), 3.17 (d, J = 15.7 Hz, 1H), 2.83 (d, J = 15.7 Hz, 1H), 2.05 (s, 1H, MeCN), 1.97 - 1.78 (m, 2H), 1.62 (d, J = 13.4 Hz, 1H), 1.46 (d, J = 13.4 Hz, 1H).

[0472] Preparation Examples 10 - 12: Compounds 10 - 12

[0473] With reference to the preparation process and operation of Preparation Example 9, Compounds 10 - 12 were synthesized using the following intermediates as starting materials:

[0474]

[0475]

[0476] Preparation Example 13: (3S)-1′-[6-amino-5-[(2-amino-3-chloropyridin-4-yl)thio]-3-(oxetan-3-yl)pyrazin-2-yl]-1,3-dihydrospiro[indene-2,4′-piperidine]-3-amine (Compound 13)

[0477]

[0478] A solution of 3-[(2-amino-3-chloropyridin-4-yl)thio]-6-chloro-5-(oxetan-3-yl)pyrazin-2-amine (50.00 mg, 0.145 mmol, 1.00 equiv), (S)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine dihydrochloride (47.97 mg, 0.174 mmol, 1.20 equiv), and DIEA (93.87 mg, 0.726 mmol, 5.00 equiv) in DMSO (2.00 mL) was reacted overnight at 80 °C; the reaction solution was purified by rapid Prep-HPLC (gradient elution with 10 - 50% aqueous acetonitrile solution, modified with 0.1% NH4HCO3) to obtain (3S)-1'-[6-amino-5-[(2-amino-3-chloropyridin-4-yl)thio]-3-(oxetan-3-yl)pyrazin-2-yl]-1,3-dihydrospiro[indene-2,4'-piperidine]-3-amine (Compound 13) (3.3 mg, 4.45%). (ES, m / z): 510 [M+H] + 。

[0479] 1 H NMR (400 MHz, Methanol-d4) δ 7.61 (d, J = 5.7 Hz, 1H), 7.43 (t, J = 8.8 Hz, 2H), 7.28 - 7.22 (m, 5H), 5.97 (d, J = 5.6 Hz, 1H), 4.05 (s, 1H), 4.00 (s, 1H), 3.43 (d, J = 13.4 Hz, 3H), 3.14 (s, 0H), 3.10 (s, 2H), 2.83 (dd, J = 24.0, 15.8 Hz, 2H), 1.93 (s, 3H), 1.82 (d, J = 13.0 Hz, 1H), 1.71 - 1.59 (m, 1H), 1.57 (s, 1H), 1.51 (d, J = 15.0 Hz, 1H), 1.31 (s, 2H), 0.90 (s, 1H).

[0480] Preparation Examples 14 - 15:

[0481] Referring to the preparation process route and operation of Preparation Example 13, the following intermediates were used as starting materials to synthesize Compounds 14 and 15:

[0482]

[0483] Preparation Example 16: (S)-1′-(6-Amino-5-((2-amino-3-chloropyridin-4-yl)thio)-3-ethenylpyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidine]-1-amine (Compound 16)

[0484]

[0485] Under nitrogen protection, (S)-1′-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)-3-iodopyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidine]-1-amine (50 mg, 0.085 mmol), potassium vinyltrifluoroborate (23 mg, 0.169 mmol), Pd(PPh3)4 (10 mg, 0.00847 mmol), and potassium carbonate (35 mg, 0.254 mmol) were added to toluene (6 ml), ethanol (3 ml), and water (1.5 ml), and the mixture was reacted at 80 °C for 2.5 h; concentrated under reduced pressure, water (20 ml) was added to the residue, and the mixture was extracted with EA (2 × 15 ml), and the organic phases were combined; 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 (CH2Cl2∶CH3OH = 30∶1) to obtain (S)-1′-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)-3-ethenylpyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidine]-1-amine (Compound 16) (17 mg, 42.5%) (ES, m / z): 480.02 [M+H] + 。

[0486] 1 1H NMR (600 MHz, CDCl3): δ 7.73 - 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).

[0487] 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)thio)pyrazine-2-carboxamide (Compound 17)

[0488]

[0489] 5-Amino-3-[(3S)-3-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl]-6-[(2-amino-3-chloropyridin-4-yl)thio]pyrazine-2-carbonitrile (170.00 mg, 0.355 mmol, 1.00 equiv) and NaOH (70.98 mg, 1.775 mmol, 5.00 equiv) were added to a mixture of H2O (2.00 mL) and MeOH (2.00 mL), and the reaction was carried out at 80 °C for 1.5 h; the reaction solution was concentrated under reduced pressure, and the residue was purified by Prep-TLC (gradient elution with 40 - 80% aqueous acetonitrile solution, modified with 10 mmol / L NH4HCO3) to obtain (S)-5-amino-3-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-((2-amino-3-chloropyridin-4-yl)thio)pyrazine-2-carboxamide (Compound 17) (7.6 mg, 4.31%). (ES, m / z): 497 [M+H] + 。

[0490] 1 1H NMR (400 MHz, Methanol-d4) δ 7.64 (d, J = 5.5 Hz, 1H), 7.42 - 7.35 (m, 1H), 7.28 - 7.17 (m, 3H), 6.02 (d, J = 5.5 Hz, 1H), 4.86 (s, 2H), 4.03 - 3.94 (m, 3H), 3.33 - 3.22 (m, 1H), 3.15 (d, J = 15.7 Hz, 1H), 2.83 (d, J = 15.7 Hz, 1H), 1.98 - 1.80 (m, 2H), 1.56 (d, J = 13.3 Hz, 1H), 1.43 (d, J = 13.4 Hz, 1H).

[0491] Preparation Example 18:

[0492] Referring to the preparation process route and operation of Preparation Example 17, using the final product of Preparation Example 9 as the starting material, Compound 18 was prepared:

[0493]

[0494] 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)thio)pyrazine-2-carboxylate (Compound 19)

[0495]

[0496] Step a: Under nitrogen protection, carbon monoxide was introduced into a solution of (R)-N-((S)-1′-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)-3-iodopyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidine]-1-yl)-2-methylpropane-2-sulfinamide (1.00 g, 1.462 mmol, 1.00 equiv), Pd(dppf)Cl2 (1.07 g, 0.146 mmol, 0.1 equiv), and Et3N (295.85 mg, 2.924 mmol, 2 equiv) in MeOH (15.00 mL). The reaction was carried out at 50 °C for 48 h. After cooling to room temperature, the mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (n-hexane∶EA = 2∶1) to obtain a crude product, which was further purified by Prep-HPLC (gradient elution with 10 - 50% aqueous acetonitrile solution, modified with 10 mmol / L NH4HCO3) to obtain 300 mg of methyl 5-amino-6-(((2-amino-3-chloropyridin-4-yl)thio)-3-((S)-1-((R)-1,1-dimethylethylsulfinylamino)-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-yl)pyrazine-2-carboxylate (33.30%). (ES, m / z): 616 [M + H] + 。

[0497] Step b: To a solution of methyl 5-amino-6-(((2-amino-3-chloropyridin-4-yl)thio)-3-((S)-1-((R)-1,1-dimethylethylsulfinylamino)-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-yl)pyrazine-2-carboxylate (230.00 mg) in DCM (2 mL) was added a 1,4-dioxane solution of HCl (1 mL). The reaction was carried out at room temperature for 1 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by Prep-HPLC (gradient elution with 10 - 50% aqueous acetonitrile solution, modified with 10 mmol / L NH4HCO3) to obtain 53.3 mg of methyl (S)-5-amino-3-(1-amino-1,3-dihydrospiro[indene-2,4-piperidine]-1′-yl)-6-((2-amino-3-chloropyridin-4-yl)thio)pyrazine-2-carboxylate (Compound 19). (ES, m / z): 512 [M + H] + 。

[0498] 11H NMR (400 MHz, Methanol-d4) δ 7.65 (d, J = 5.5 Hz, 1H), 7.38 - 7.32 (m, 1H), 7.25 (m, 3H), 6.01 (d, J = 5.5 Hz, 1H), 4.00 (d, J = 6.7 Hz, 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 = 13.1 Hz, 1H), 1.46 (m, 1H).

[0499] Preparation Example 20: Methyl (R)-5-amino-3-(1-amino-8-azaspiro[4.5]dec-8-yl)-6-((2,3-dichlorophenyl)thio)pyrazine-2-carboxylate (Compound 20)

[0500]

[0501] Step a: A solution of (R)-2-methyl-N-((R)-8-azaspiro[4.5]dec-1-yl)propane-2-sulfinamide (400 mg, 1.550 mmol), methyl 3-chloro-5-((2,4-dimethoxybenzyl)amino)pyrazine-2-carboxylate (522 mg, 1.550 mmol), and DIPEA (1.00 g, 7.75 mmol) in DMSO (10 ml) was stirred at 100 °C for 6 h; the temperature was lowered to room temperature, water (80 ml) was added to the reaction solution, and the mixture was extracted with EA (60 ml × 2), and the organic phases were combined; the organic phase was washed with H2O (20 ml) and brine (20 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (CH2Cl2∶CH3OH = 100∶1 - 50∶1) to obtain an oil, methyl 5-((2,4-dimethoxybenzyl)amino)-3-((R)-1-((R)-1,1-dimethylethylsulfinylamino)-8-azaspiro[4.5]dec-8-yl)pyrazine-2-carboxylate (106 mg, 12.2%), (ES, m / z): 560.21 [M+H] +

[0502] Step b: React methyl 5-((2,4-dimethoxybenzyl)amino)-3-((R)-1-((R)-1,1-dimethylethylsulfinylamino)-8-azaspiro[4.5]dec-8-yl)pyrazine-2-carboxylate (106 mg, 0.190 mmol) with CF3COOH (2 ml) at room temperature overnight; concentrate under reduced pressure, add water (20 ml) to the residue, adjust to pH = 9 - 10 with ammonia water, extract with EA (15 ml × 2), and combine the organic phases; wash the organic phases with H2O (20 ml) and brine (20 ml), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the residue by silica gel column chromatography (CH2Cl2∶CH3OH = 60∶1 - 30∶1) to obtain 5-amino-3-((R)-1-((R)-1,1-dimethylethylsulfinylamino)-8-azaspiro[4.5]dec-8-yl)pyrazine-2-carboxylic acid methyl ester as a pale yellow solid (70 mg, 90.0%) (ES, m / z): 410.07 [M+H] +

[0503] Step c: React 5-amino-3-((R)-1-((R)-1,1-dimethylethylsulfinylamino)-8-azaspiro[4.5]dec-8-yl)pyrazine-2-carboxylic acid methyl ester (70 mg, 0.171 mmol) with MeOH / HCl solution (1 ml) at room temperature overnight; concentrate under reduced pressure, add water (20 ml) to the residue, extract with EA (15 ml × 2), and combine the organic phases; wash the organic phases with H2O (10 ml) and brine (10 ml), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and obtain 5-amino-3-(1-amino-8-azaspiro[4.5]dec-8-yl)pyrazine-2-carboxylic acid (R)-methyl ester as a pale yellow solid (35 mg, 67.0%) (ES, m / z): 306.22 [M+H] +

[0504] Step d: To a solution of (R)-methyl 5-amino-3-(1-amino-8-azaspiro[4.5]dec-8-yl)pyrazine-2-carboxylate (35 mg, 0.115 mmol) and (Boc)2O (30 mg, 0.138 mmol) in DCM (3 ml), TEA (35 mg, 0.345 mmol) was added dropwise, and the reaction was stirred at room temperature for 1 h; water (10 ml) was added to the reaction solution, and liquid separation was performed; the aqueous phase was extracted with DCM (10 ml × 2), and the organic phases were combined; the organic phase was washed with H2O (20 ml) and brine (20 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (CH2Cl2∶CH3OH = 90∶1 to 30∶1) to obtain a pale yellow solid (R)-methyl 5-amino-3-(1-(((tert-butoxycarbonyl)amino)-8-azaspiro[4.5]dec-8-yl)pyrazine-2-carboxylate (34 mg, 73%), (ES, m / z): 406.19 [M+H] +

[0505] Step e: Under nitrogen protection, a solution of (R)-methyl 5-amino-3-(1-(((tert-butoxycarbonyl)amino)-8-azaspiro[4.5]dec-8-yl)pyrazine-2-carboxylate (34 mg, 0.084 mmol) and NBS (16 mg, 0.084 mmol) in DCM (5 ml) was reacted at 0 °C for 30 min; saturated aqueous sodium bicarbonate solution (10 ml) was added to the reaction solution, and liquid separation was performed; the aqueous phase was extracted with DCM (10 ml × 2), and the organic phases were combined; the organic phase was washed with H2O (20 ml) and brine (20 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain a transparent solid (R)-methyl-5-amino-6-bromo-3-(1-(((tert-butoxycarbonyl)amino)-8-azaspiro[4.5]dec-8-yl)pyrazine-2-carboxylate (28 mg, 69%), (ES, m / z): 483.97 [M+H] +

[0506] Step f: Under nitrogen protection, a solution of (R)-methyl 5-amino-6-bromo-3-(1-(((tert-butoxycarbonyl)amino)-8-azaspiro[4.5]dec-8-yl)pyrazine-2-carboxylate (28 mg, 0.058 mmol, 1.00 eqv), 2,3-dichlorobenzenethiol (10.38 mg, 0.058 mmol, 1.00 equiv), DIEA (22.49 mg, 0.174 mmol, 3.00 equiv), Pd2(dba)3 (5.5 mg, 0.006 mmol, 0.1 equiv) and Xantphos (5.21 mg, 0.009 mmol, 0.15 eq) in 1,4-dioxane (2.00 mL) was reacted at 90 °C for 8 h; filtered through diatomaceous earth, water (10 ml) was added to the filtrate, and extracted with EA (3 × 5 mL), and the organic phases were combined; the organic phase was washed with water (3 × 5 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure; (R)-methyl 5-amino-3-(1-((tert-butoxycarbonyl)amino)-8-azaspiro[4.5]dec-8-yl)-6-(((2,3-dichlorophenyl)thio)pyrazine-2-carboxylate (22 mg, 65.1%) was obtained. (ES, m / z): 582.04 [M+H] + 。

[0507] Step g: To a solution of (R)-methyl 5-amino-3-(1-((tert-butoxycarbonyl)amino)-8-azaspiro[4.5]dec-8-yl)-6-(((2,3-dichlorophenyl)thio)pyrazine-2-carboxylate (22 mg) in DCM (2 mL) was added a 1,4-dioxane solution of HCl (1 mL), and reacted at room temperature for 2 h; the reaction solution was concentrated under reduced pressure, and the residue was purified by Prep-HPLC (gradient elution with 20-50% aqueous acetonitrile solution, modified with 10 mmol / L NH4HCO3), and (R)-5-amino-3-(1-amino-8-azaspiro[4.5]dec-8-yl)-6-((2,3-dichlorophenyl)thio)pyrazine-2-carboxylate methyl ester (Compound 20) (5.2 mg) was obtained. (ES, m / z): 481.99 [M+H] + 。

[0508] 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)

[0509]

[0510] Step a: A solution of (R)-N-((S)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (1.00 g, 3.263 mmol, 1.00 equiv), 5-amino-3-chloropyrazine-2-carbonitrile (0.50 g, 3.235 mmol, 0.99 equiv) and DIEA (0.84 g, 6.526 mmol, 2 equiv) in DMSO (12.00 mL) was reacted at 80 °C for 3 h; the temperature was cooled to room temperature, water (60 ml) was added, and the mixture was extracted with EA (2 × 20 ml), and the organic phases were combined; the organic phase was washed with brine (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure; the crude product (R)-N-((S)-1'-(6-amino-3-cyanopyrazin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (1.21 g, 87.34%) was obtained. (ES, m / z): 425 [M+H] + . It was directly used in the next reaction without purification.

[0511] Step b: At room temperature, NBS (0.72 g, 4.063 mmol, 1.50 equiv) was added to (R)-N-((S)-1'-(6-amino-3-cyanopyrazin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (1.15 g, 2.709 mmol, 1.00 equiv) in DCM (15.00 mL), and the reaction was carried out for 1 h; the reaction solution was concentrated under reduced pressure, and the residue was purified by reverse flash column chromatography (gradient elution with 10 - 50% aqueous acetonitrile solution) to obtain the yellow solid 5-amino-3-[(3S)-3-amino-1,3-dihydrospiro[indene-2,4-piperidin]-1-yl]-6-bromopyrazine-2-carbonitrile (660 mg, 61.02%). (ES, m / z): 399 [M+H] + .

[0512] Step c: Under nitrogen protection, a solution of 5-amino-3-[(3S)-3-amino-1,3-dihydrospiro[indene-2,4-piperidine]-1-yl]-6-bromopyrazine-2-carbonitrile (200.00 mg, 0.501 mmol, 1.00 equiv), 1-(3,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indol-1-yl)ethanone (194.23 mg, 0.601 mmol, 1.2 equiv), K3PO4 (318.96 mg, 1.503 mmol, 3 equiv) and Pd(dppf)Cl2 (36.65 mg, 0.050 mmol, 0.1 equiv) in 1,4-dioxane (4.00 mL) and water (1.00 mL) was reacted at 100 °C for 1 h; the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (CH2Cl2∶MeOH = 12∶1), and then purified by Prep-HPLC (gradient elution with 30 - 60% aqueous acetonitrile solution, modified with 10 mmol / L NH4HCO3) 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) (23 mg, 8.91%). (ES, m / z): 516 [M+H] + .

[0513] 1 1H NMR (400 MHz, DMSO-d6) δ 8.31 (d, J = 8.3 Hz, 1H), 7.63 (t, J = 7.9 Hz, 1H), 7.33 (d, 1H), 7.24 - 7.12 (m, 3H), 7.11 (d, J = 7.5 Hz, 1H), 6.74 (s, 2H), 4.55 (t, J = 16.8 Hz, 2H), 4.35 - 4.25 (m, 2H), 3.88 (s, 1H), 3.31 - 3.21 (m, 4H), 3.08 (d, J = 15.7 Hz, 1H), 2.64 (d, 1H), 2.26 (s, 3H), 1.86 (td, J = 12.6, 4.0 Hz, 1H), 1.75 (td, J = 12.5, 4.2 Hz, 1H), 1.57 (d, J = 13.2 Hz, 1H), 1.16 (d, J = 13.3 Hz, 1H).

[0514] 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)thio)pyrazine-2-carbonitrile (Compound 22)

[0515]

[0516] Step a: A solution of 5-amino-6-(((2-amino-3-chloropyridin-4-yl)thio)-3-chloropyrazine-2-carbonitrile (82 mg, 0.262 mmol, 1 eqv), (R)-N-(((1S)-3'-methoxy-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropan-2-sulfinamide (88.2 mg, 0.262 mmol, 1 eqv), and DIPEA (102 mg, 0.786 mmol, 3 eqv) in DMSO (6 ml) was reacted at 120 °C for 10 h; cooled to room temperature, water (50 ml) was added, and the mixture was extracted with EA (2 × 20 ml), and the organic phases were combined; the organic phase was washed with brine (20 ml) and concentrated under reduced pressure; the residue was purified by column chromatography (CH2Cl2∶CH3OH = 150∶1) to obtain (R)-N-((1S)-1'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)-3-cyanopyrazin-2-yl)-3'-methoxy-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropan-2-sulfinamide (69 mg, 43%). (ES, m / z): 613.15 [M+H] + 。

[0517] Step b: (R)-N-((1S)-1'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)-3-cyanopyrazin-2-yl)-3'-methoxy-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropan-2-sulfinamide (69 mg) was added to HCl / CH3OH (15 ml), and the mixture was reacted at room temperature for 2 h; concentrated under reduced pressure, water (20 ml) was added to the residue, the pH was adjusted to 10 with 25% ammonia water, and the mixture was extracted with EA (2 × 20 ml), and the organic phases were combined; the organic phase was washed with brine (10 ml) and concentrated under reduced pressure; the residue was purified by column chromatography (CH2Cl2∶CH3OH = 60∶1) to obtain 5-amino-3-((1S)-1-amino-3'-methoxy-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-6-((2-amino-3-chloropyridin-4-yl)thio)pyrazine-2-carbonitrile (Compound 22) (21 mg). (ES, m / z): 509.09 [M+H] + 。

[0518] Preparation Example 23: Methyl 5-amino-3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-6-((2,3-dichlorophenyl)thio)pyrazine-2-carboxylate (Compound 23)

[0519]

[0520] Step a: A solution of (R)-2-methyl-N-((3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl)propane-2-sulfinamide (400 mg, 1.458 mmol), methyl 3-chloro-5-((2,4-dimethoxybenzyl)amino)pyrazine-2-carboxylate (492 mg, 1.458 mmol), and DIPEA (942 g, 7.29 mmol) in DMSO (10 ml) was stirred at 100 °C for 5 h. The temperature was lowered to room temperature, water (80 ml) was added to the reaction solution, and the mixture was extracted with EA (60 ml × 2). The organic phases were combined. The organic phase was washed with H2O (20 ml) and brine (20 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (CH2Cl2∶CH3OH = 100∶1 to 50∶1) to obtain methyl 5-(((2,4-dimethoxybenzyl)amino)-3-((3S,4S)-4-((R)-1,1-dimethylethylsulfinylamino)-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazine-2-carboxylate (590 mg), (ES, m / z): 576.24 [M+H] + 。

[0521] Step b: Methyl 5-(((2,4-dimethoxybenzyl)amino)-3-((3S,4S)-4-((R)-1,1-dimethylethylsulfinylamino)-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazine-2-carboxylate (590 mg) and CF3COOH (5 ml) were reacted overnight at room temperature. The mixture was concentrated under reduced pressure, water (20 ml) was added to the residue, the pH was adjusted to 10 with ammonia water, and the mixture was extracted with EA (15 ml × 2). The organic phases were combined. The organic phase was washed with H2O (20 ml) and brine (20 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (CH2Cl2∶CH3OH = 50∶1 to 30∶1) to obtain methyl 5-amino-3-((3S,4S)-4-((R)-1,1-dimethylethylsulfinylamino)-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazine-2-carboxylate (280 mg) (ES, m / z): 426.19 [M+H] + 。

[0522] Step c: React methyl 5-amino-3-((3S,4S)-4-((R)-1,1-dimethylethylsulfinylamino)-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazine-2-carboxylate (280 mg) with MeOH / HCl solution (5 ml) at room temperature overnight; concentrate under reduced pressure to obtain the crude product of methyl 5-amino-3-(((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazine-2-carboxylate, which is directly used in the next step without purification. (ES, m / z): 322.18 [M+H] + 。

[0523] Step d: Dropwise add TEA (200 mg, 1.976 mmol) to a solution of the crude product of methyl 5-amino-3-(((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazine-2-carboxylate and (Boc)2O (215 mg, 0.988 mmol) in DCM (30 ml), stir and react at room temperature for 2 h; add water (30 ml) to the reaction solution, separate the layers; extract the aqueous phase with DCM (10 ml × 2), combine the organic phases; wash the organic phase with H2O (20 ml) and brine (20 ml), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the residue by silica gel column chromatography (CH2Cl2∶CH3OH = 80∶1 - 30∶1) to obtain methyl 5-amino-3-((3S,4S)-4-((tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazine-2-carboxylate (110 mg), (ES, m / z): 422.11 [M+H] + 。

[0524] Step e: Under nitrogen protection, react a solution of methyl 5-amino-3-((3S,4S)-4-((tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazine-2-carboxylate (110 mg, 0.263 mmol) and NBS (56.2 mg, 0.316 mmol) in DCM (10 ml) at 0 °C for 30 min; add saturated aqueous sodium bicarbonate solution (10 ml) to the reaction solution, separate the layers; extract the aqueous phase with DCM (10 ml × 2), combine the organic phases; wash the organic phase with H2O (20 ml) and brine (20 ml), dry over anhydrous sodium sulfate, concentrate under reduced pressure to obtain 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 (65.7 mg), (ES, m / z): 499.98, 501.96 [M+H] + 。

[0525] Step f: Under nitrogen protection, a solution of 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 (65.7 mg, 0.132 mmol), 2,3-dichlorobenzenethiol (23.6 mg, 0.132 mmol), DIEA (51 mg, 0.396 mmol), Pd2(dba)3 (24.2 mg, 0.026 mmol) and Xantphos (11.5 mg, 0.020 mmol) in 1,4-dioxane (5.00 mL) was reacted at 90 °C for 8 h; filtered through diatomaceous earth, water (30 ml) was added to the filtrate, extracted with EA (3×10 mL), and the organic phases were combined; the organic phase was washed with water (2×10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure; the residue was purified by silica gel column chromatography (CH2Cl2∶CH3OH = 100∶1 to 60∶1) to obtain methyl 5-amino-3-((3S,4S)-4-((tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-6-(((2,3-dichlorophenyl)thio)pyrazine-2-carboxylate (53 mg). (ES, m / z): 598.10 [M+H] + 。

[0526] Step g: Trifluoroacetic acid (1 ml) was added to a solution of methyl 5-amino-3-((3S,4S)-4-((tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-6-(((2,3-dichlorophenyl)thio)pyrazine-2-carboxylate (53 mg) in dichloromethane (5 ml), and the reaction was carried out overnight at room temperature; the reaction solution was concentrated under reduced pressure, EA (10 ml) and water (10 ml) were added to the residue, the pH was adjusted to 10 with 25% ammonia water, and liquid separation was carried out; the aqueous phase was extracted with EA (5 ml), and the organic phases were combined; the organic phase was washed with water (10 ml) and brine (10 ml), dried over anhydrous sodium sulfate, and concentrated; the residue was purified by column chromatography (CH2Cl2∶CH3OH = 50∶1 to 20∶1) to obtain methyl 5-amino-3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-6-((2,3-dichlorophenyl)thio)pyrazine-2-carboxylate (23 mg). (ES, m / z): 498.09 [M+H] + 。

[0527] Preparation Example 24:

[0528] Referring to the preparation process route and operation of Preparation Example 23, the following existing compound starting materials were used to prepare Compound 24:

[0529]

[0530] Preparation Example 25: (R)-1-(5-Amino-6-((2-amino-3-chloropyridin-4-yl)thio)-3-(1-amino-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)ethanone (Compound 25)

[0531]

[0532] Step a: Cool a solution of (R)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-8-azaspiro[4.5]dec-1-amine (150 mg, 0.370 mmol) in dichloromethane (30 ml) to 0 °C, add triethylamine (75 mg, 0.740 mmol) and (Boc)2O (121 mg, 0.555 mmol), and allow to warm to room temperature and react for 3 h. After detecting the completion of the reaction by TLC, add water (15 ml) to the reaction solution, let it stand and separate the layers. Extract the aqueous phase with dichloromethane (2 × 5 ml), combine the organic phases. Wash the organic phase with brine (20 ml), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product of (R)-tert-butyl (8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-8-azaspiro[4.5]decyl-1-carbamate, which is directly used in the next step reaction. (ES, m / z): 506.16 [M+H] + 。

[0533] Step b: Under nitrogen protection, cool a solution of the crude product of (R)-tert-butyl (8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-8-azaspiro[4.5]decyl-1-carbamate in dichloromethane (50 ml) to -10 °C, add NBS (72.4 mg, 0.407 mmol), keep the temperature and react for 30 min. After detecting the completion of the reaction by TLC, add saturated aqueous sodium bicarbonate solution (20 ml) to the reaction solution, let it stand and separate the layers. Extract the aqueous phase with dichloromethane (2 × 5 ml), combine the organic phases. Wash the organic phase with brine (20 ml), dry over anhydrous sodium sulfate, and concentrate. Purify the residue by column chromatography (CH2Cl2∶CH3OH = 80∶1) to obtain (R)-tert-butyl (8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)-3-bromopyrazin-2-yl)-8-azaspiro[4.5]dec-1-ylcarbamate (34 mg). (ES, m / z): 583.99 [M+H] + 。

[0534] Step c: Under nitrogen protection, (R)-tert-butyl (8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)-3-bromopyrazin-2-yl)-8-azaspiro[4.5]dec-1-yl)carbamate (34 mg, 0.058 mmol), tributyl(1-ethoxyvinyl)tin (32 mg, 0.087 mmol), sodium carbonate (12 mg, 0.116 mmol), Pd(dppf)Cl2 (8 mg, 0.0116 mmol), 1,4-dioxane (6 ml) and water (2 ml) were reacted at 100 °C for 8 h. TLC detection showed that the reaction was basically complete. After cooling, ethyl acetate (EA) (50 ml) and water (50 ml) were added to the reaction solution, and the mixture was allowed to stand for liquid separation. The aqueous phase was extracted with EA (2×10 ml), and the organic phases were combined. The combined organic phase was washed with water (20 ml) and brine (20 ml), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography (CH2Cl2∶CH3OH = 100∶1 to 80∶1) to obtain (R)-tert-butyl (8-(3-acetyl-6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-8-azaspiro[4.5]dec-1-yl)carbamate (20 mg). (ES, m / z): 548.07 [M+H] + 。

[0535] Step d: To a solution of (R)-tert-butyl (8-(3-acetyl-6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-8-azaspiro[4.5]dec-1-yl)carbamate (20 mg) in dichloromethane (5 ml) was added trifluoroacetic acid (1 ml), and the mixture was stirred at room temperature for 3 h. The reaction solution was concentrated under reduced pressure. Ethyl acetate (EA) (10 ml) and water (10 ml) were added to the residue, and the pH was adjusted to 10 with 25% aqueous ammonia, followed by liquid separation. The aqueous phase was extracted with EA (5 ml), and the organic phases were combined. The combined organic phase was washed with water (10 ml) and brine (10 ml), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography (CH2Cl2∶CH3OH = 150∶1) to obtain (R)-1-(5-amino-6-((2-amino-3-chloropyridin-4-yl)thio)-3-(1-amino-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)ethanone (8 mg). (ES, m / z): 448.01 [M+H] + 。

[0536] Preparation Examples 26 and 27:

[0537] Referring to the preparation process route and operation of Preparation Example 25, the following existing compounds were used as starting materials to prepare Compound 26 and Compound 27:

[0538]

[0539] 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)thio)pyrazin-2-yl)ethanone

[0540]

[0541] Step a: Cool a solution of (S)-1'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine (92 mg, 0.203 mmol) in dichloromethane (10 ml) to 0 °C, add triethylamine (82 mg, 0.812 mmol) and (Boc)2O (87 mg, 0.406 mmol), and allow to warm to room temperature and react for 4 h. After detecting the completion of the reaction by TLC, add water (10 ml) to the reaction solution, let it stand and separate the layers. Extract the aqueous phase with dichloromethane (2 × 5 ml), combine the organic phases. Wash the organic phase with brine (10 ml), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain crude (S)-tert-butyl (1'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-yl)carbamate, which is used directly in the next step without purification. (ES, m / z): 554.13 [M+H] + 。

[0542] Step b: Under nitrogen protection, cool a solution of crude (S)-tert-butyl (1'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-yl)carbamate in dichloromethane (10 ml) to -10 °C, add NBS (43.4 mg, 0.244 mmol), keep the temperature and react for 30 min. After detecting the completion of the reaction by TLC, add saturated aqueous sodium bicarbonate solution (10 ml) to the reaction solution, let it stand and separate the layers. Extract the aqueous phase with dichloromethane (2 × 5 ml), combine the organic phases. Wash the organic phase with brine (10 ml), dry over anhydrous sodium sulfate, and concentrate. Purify the residue by column chromatography (CH2Cl2∶CH3OH = 100∶1) to obtain (S)-tert-butyl (1'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)-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] + 。

[0543] Step c: Under nitrogen protection, (S)-tert-butyl (1′-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)-3-bromopyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidine]-1-yl)carbamate (53 mg, 0.085 mmol), tributyl(1-ethoxyvinyl)tin (46 mg, 0.128 mmol), sodium carbonate (18 mg, 0.17 mmol), Pd(dppf)Cl2 (12 mg, 0.017 mmol), 1,4-dioxane (10 ml) and water (2 ml) were reacted at 100 °C for 6 h. TLC detection showed that the reaction was basically complete; the temperature was lowered, and EA (50 ml) and water (50 ml) were added to the reaction solution, and the mixture was allowed to stand and separated; the aqueous phase was extracted with EA (2×10 ml), and the organic phases were combined; the organic phase was washed with water (20 ml) and brine (20 ml), dried over anhydrous sodium sulfate, and concentrated; the residue was purified by column chromatography (CH2Cl2∶CH3OH = 100∶1 - 80∶1) to obtain (S)-tert-butyl (1′-(3-acetyl-6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidine]-1-yl)carbamate (12 mg). (ES, m / z): 596.07 [M+H] + 。

[0544] Step d: To a dichloromethane (5 ml) solution of (S)-tert-butyl (1′-(3-acetyl-6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidine]-1-yl)carbamate (12 mg), trifluoroacetic acid (1 ml) was added, and the mixture was stirred at room temperature for 2 h; the reaction solution was concentrated under reduced pressure, EA (20 ml) and water (10 ml) were added to the residue, and the pH was adjusted to 10 with 25% ammonia water, and the layers were separated; the aqueous phase was extracted with EA (5 ml), and the organic phases were combined; the organic phase was washed with water (10 ml) and brine (10 ml), dried over anhydrous sodium sulfate, and concentrated; the residue was purified by column chromatography (CH2Cl2∶CH3OH = 200∶1) to obtain (S)-1-(5-amino-3-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-yl)-6-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)ethanone (6.5 mg). (ES, m / z): 495.97 [M+H] + 。

[0545] 11H NMR (600 MHz, DMSO-d6) δ 7.697 (d, J = 4.8 Hz, 1H), 7.327 (d, J = 4.8 Hz, 1H), 7.208 - 7.174 (m, 3H), 7.026 (br, s, 2H), 6.322 (s, 3H), 5.882 (d, J = 4.2 Hz, 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).

[0546] 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)thio)pyrazine-2-carbaldehyde (Compound 29)

[0547]

[0548] Step a: Under nitrogen protection, cool a solution of methyl 5-amino-3-[(3S)-3-amino-1,3-dihydrospiro[indene-2,4-piperidine]-1-yl]-6-[(2-amino-3-chloropyridin-4-yl)thio]pyrazine-2-carboxylate (50 mg, 0.098 mmol) in THF (10 ml) to 0 °C, add LiBH4 (4.3 mg, 0.196 mmol), allow to warm to room temperature and react overnight. Monitor the reaction by TLC until completion. Cool the reaction mixture to below 5 °C and quench with saturated ammonium chloride solution (1 ml). Concentrate under reduced pressure and purify the residue by column chromatography (CH2Cl2∶CH3OH = 50∶1) to obtain (S)-(5-amino-3-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)methanol (32 mg). (ES, m / z): 483.97 [M+H] + 。

[0549] Step b: A solution of (S)-(5-amino-3-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)methanol (32 mg, 0.066 mmol) in dichloromethane (5 ml) was cooled to 0 °C, Dess-Martin periodinane (56.2 mg, 0.132 mmol) was added, and the mixture was allowed to warm to room temperature and stirred overnight. The reaction was monitored by TLC and was found to be complete. Saturated sodium bicarbonate solution (1 ml) was added to the reaction mixture, and the mixture was stirred for 30 min. Water (5 ml) was added, and the layers were separated. The organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography (CH2Cl2∶CH3OH = 100∶1 - 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)thio)pyrazine-2-carbaldehyde (12 mg). (ES, m / z): 482.07 [M+H] + 。

[0550] Preparation Example 30: Methyl 5-amino-3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-6-((2-chloro-3-(oxazol-2-yl)phenyl)thio)pyrazine-2-carboxylate (Compound 30)

[0551]

[0552] Step a: Under nitrogen protection, a solution of 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 (272.00 mg, 0.545 mmol, 1.0 eqv), 2-chloro-3-(oxazol-2-yl)benzenethiol (138 mg, 0.654 mmol, 1.2 eqv), DIPEA (246 mg, 1.908 mmol, 3.5 eqv), Pd2(dba)3 (100 mg, 0.109 mmol, 0.2 eqv) and Xantphos (126 mg, 0.218 mmol, 0.4 eqv) in 1,4-dioxane (20 mL) was heated at 96 °C for 5 h. The reaction mixture was cooled to room temperature, silica gel was added, and the mixture was purified by silica gel column chromatography (eluent: n-hexane∶EA = 5∶1) to give methyl 5-amino-3-((3S,4S)-4-((tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-6-(((2-chloro-3-(oxazol-2-yl)phenyl)thio)pyrazine-2-carboxylate (258 mg, 75.1%); (ES, m / z): 631.25 [M+H]+ 。

[0553] Step b: To a solution of methyl 5-amino-3-((3S,4S)-4-((tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-6-(((2-chloro-3-(oxazol-2-yl)phenyl)sulfanyl)pyrazine-2-carboxylate (258 mg) in dichloromethane (10 ml), trifluoroacetic acid (5 ml) was added, and the mixture was stirred at room temperature for 2 h; the reaction solution was concentrated under reduced pressure, ethyl acetate (20 ml) and water (10 ml) were added to the residue, the pH was adjusted to 10 with 25% ammonia water, and liquid separation was carried out; the aqueous phase was extracted with ethyl acetate (5 ml), and the organic phases were combined; the combined organic phase was washed with water (10 ml) and brine (10 ml), dried over anhydrous sodium sulfate, and concentrated; the residue was purified by column chromatography (CH2Cl2∶CH3OH = 20∶1) to obtain methyl 5-amino-3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-6-((2-chloro-3-(oxazol-2-yl)phenyl)sulfanyl)pyrazine-2-carboxylate (170 mg, 78.34%). (ES, m / z): 531.12 [M+H] + 。

[0554] 1 H NMR (600 MHz, DMSO-d6) δ 8.336 (s, 1H), 7.705 (d, J = 7.8 Hz, 1H), 7.477 (s, 1H), 7.389 - 7.363 (m, 1H), 6.924 (s, 2H), 6.805 (d, J = 7.8 Hz, 1H), 4.068 - 4.049 (m, 1H), 3.742 (s, 3H), 3.659 (d, J = 8.4 Hz, 1H), 3.588 - 3.539 (m, 3H), 3.490 - 3.476 (d, J = 8.4 Hz, 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 = 6.6 Hz, 3H).

[0555] Referring to the preparation process route and operation of Preparation Example 30, the following intermediates were used as starting materials to synthesize Compounds 31 - 33:

[0556]

[0557]

[0558] Preparation Example 34: (S)-Methyl 5-amino-3-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-((2,3-dichlorophenyl)thio)pyrazine-2-carboxylate (Compound 34)

[0559]

[0560] Step a: Under nitrogen protection, a solution of (S)-methyl 5-amino-6-bromo-3-(1-((tert-butoxycarbonyl)amino)-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)pyrazine-2-carboxylate (100 mg, 0.188 mmol, 1.00 eq), 2,3-dichlorobenzenethiol (51 mg, 0.282 mmol, 1.5 eq), DIEA (85 mg, 0.658 mmol, 3.50 eq), Pd2(dba)3 (14 mg, 0.015 mmol, 0.08 eq) and Xantphos (17 mg, 0.030 mmol, 0.16 eq) in 1,4-dioxane (4.00 mL) was reacted at 90 °C for 8 h; concentrated under reduced pressure, water (10 ml) was added to the residue, and the mixture was extracted with EA (3 × 5 mL), and the organic phases were combined; the organic phase was washed with water (3 × 5 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure; elution purification was carried out by silica gel column chromatography, and the eluent was n-hexane:EA = 5:1, gradually increased to 3:1, and the product spot was collected and concentrated to dryness to obtain (S)-methyl 5-amino-3-(1-(((tert-butoxycarbonyl)amino)-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(((2,3-dichlorophenyl)thio)pyrazine-2-carboxylate (76 mg, 64%). (ES, m / z): 630.15 [M+H] + 。

[0561] Step b: To a solution of (S)-methyl 5-amino-3-(1-(((tert-butoxycarbonyl)amino)-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-6-(((2,3-dichlorophenyl)thio)pyrazine-2-carboxylate (76 mg, 0.121 mmol, 1.00 eq) in DCM (5 mL) was added CF3COOH (2 mL), and the reaction was carried out at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure. Water (10 mL) was added to the concentrate and mixed. The pH was adjusted to 9 - 10 with ammonia water. The mixture was extracted with EA (20 mL × 2), and the combined organic phases were washed with H2O (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with an eluent of DCM∶MeOH = 50∶1, gradually increasing to 15∶1, to obtain (S)-methyl 5-amino-3-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-6-((2,3-dichlorophenyl)thio)pyrazine-2-carboxylate (44 mg, 69%). (ES, m / z): 530.10 [M+H] + 。

[0562] Referring to the preparation process route and operation of Preparation Example 34, the following intermediates were used as starting materials to synthesize Compounds 35 - 38:

[0563]

[0564] Preparation Example 39: (S)-methyl 6-((1-acetyl-3,3-difluoroindol-4-yl)thio)-5-amino-3-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)pyrazine-2-carboxylate (Compound 39)

[0565]

[0566] Step a: To a reaction solution of (S)-methyl 5-amino-3-(1-(((tert-butoxycarbonyl)amino)-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-mercaptopyrazine-2-carboxylate (88 mg, 0.181 mmol, 1.0 eq) in 1,4-dioxane (8 mL), 1-(3,3-difluoro-4-iodoindol-1-yl)ethanone (66 mg, 0.200 mmol, 1.1 eq), Pd2(dba)3 (33 mg, 0.036 mmol, 0.2 eq), Xantphos (42 mg, 0.072 mmol, 0.4 eq), and DIEA (82 mg, 0.634 mmol, 3.5 eq) were added. Under nitrogen protection, the mixture was stirred at 97 °C for 5 h. The reaction solution was concentrated to dryness, water (30 mL) was added to the concentrate and mixed, and the mixture was extracted with EA (20 mL × 2). The combined organic phases were washed with H2O (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with the eluent of n-hexane∶EA = 5∶1, gradually increasing to 2∶1, to obtain (S)-methyl 6-(((1-acetyl-3,3-difluoroindol-4-yl)thio)-5-amino-3-(1-(((tert-butoxycarbonyl)amino)-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)pyrazine-2-carboxylate as a foamy solid (100 mg, 81%), (ES, m / z): 681.21 [M+H] + 。

[0567] Step b: To a solution of (S)-methyl 6-(((1-acetyl-3,3-difluoroindol-4-yl)thio)-5-amino-3-(1-(((tert-butoxycarbonyl)amino)-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)pyrazine-2-carboxylate (100 mg, 0.147 mmol, 1.0 eq) in DCM (5 mL), CF3COOH (5 mL) was added. After stirring at room temperature for 2 h, the reaction solution was rotary evaporated to dryness. Water (30 mL) was added to the concentrate and mixed, and the pH was adjusted to 9 - 10 with ammonia water. The mixture was extracted with EA (20 mL × 2). The combined organic phases were washed with H2O (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with the eluent of DCM∶MeOH = 100∶1, gradually increasing to 50∶1, to obtain (S)-methyl 6-((1-acetyl-3,3-difluoroindol-4-yl)thio)-5-amino-3-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)pyrazine-2-carboxylate (50 mg, 59%) (ES, m / z): 581.22 [M+H] + 。

[0568] With reference to the preparation process route and operation of Preparation Example 39, the following intermediates were used as starting materials to synthesize Compounds 40-43:

[0569]

[0570]

[0571] 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)thio)pyrazin-2-yl)ethanone (Compound 44)

[0572]

[0573] Step a: Under nitrogen protection, a solution of (S)-tert-butyl (1'-(3-acetyl-6-amino-5-bromopyrazin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-yl)carbamate (520 mg, 1.009 mmol, 1.0 eqv), 2-chloro-3-(oxazol-2-yl)benzenethiol (256 mg, 1.211 mmol, 1.2 eqv), DIPEA (456 mg, 3.532 mmol, 3.5 eqv), Pd2(dba)3 (185 mg, 0.202 mmol, 0.2 eqv) and Xantphos (234 mg, 0.404 mmol, 0.4 eqv) in 1,4-dioxane (20 mL) was reacted at 96 °C for 5 h; after cooling to room temperature, silica gel was added to the reaction solution, and purification was carried out by silica gel column chromatography (eluent: n-hexane∶EA = 20∶1 to 2∶1) to obtain (S)-tert-butyl (1'-(3-acetyl-6-amino-5-((2-chloro-3-(oxazol-2-yl)phenyl)thio]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-yl)carbamate (565 mg, 87%); (ES, m / z): 647.26 [M+H] + 。

[0574] Step b: To a solution of (S)-tert-butyl (1′-(3-acetyl-6-amino-5-((2-chloro-3-(oxazol-2-yl)phenyl)thio]pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidin]-1-yl)carbamate (565 mg) in dichloromethane (20 ml) was added trifluoroacetic acid (5 ml), and the mixture was stirred at room temperature for 3 h; the reaction solution was concentrated under reduced pressure. To the residue was added EA (100 ml) and water (50 ml), and the pH was adjusted to 10 with 25% aqueous ammonia, and then liquid separation was carried out; the aqueous phase was extracted with EA (20 ml), and the organic phases were combined; the combined organic phase was washed with water (50 ml) and brine (50 ml), dried over anhydrous sodium sulfate, and concentrated; the residue was purified by column chromatography (CH2Cl2∶CH3OH = 20∶1) to obtain (S)-1-(5-amino-3-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidin]-1′-yl)-6-((2-chloro-3-(oxazol-2-yl)phenyl)thio)pyrazin-2-yl)ethanone (446 mg, 93.4%). (ES, m / z): 547.14 [M+H] + 。

[0575] 1 1H NMR (600 MHz, DMSO-d6) δ 8.333 (s, 1H), 7.740 (d, J = 7.2 Hz, 1H), 7.475 (s, 1H), 7.426 - 7.400 (m, 1H), 7.305 (d, J = 6.6 Hz, 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).

[0576] 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)thio)pyrazin-2-yl)ethanone (Compound 45)

[0577]

[0578] Step a: Under nitrogen protection, a solution of (S)-tert-butyl (1′-(3-acetyl-6-amino-5-bromopyrazin-2-yl)-5,7-dihydrospiro[cyclopent[b]pyridine-6,4′-piperidine]-5-yl)carbamate (140 mg, 0.27 mmol, 1.0 eqv), 2-chloro-3-(oxazol-2-yl)benzenethiol (69 mg, 0.325 mmol, 1.2 eqv), DIPEA (123 mg, 0.954 mmol, 3.5 eqv), Pd2(dba)3 (50 mg, 0.054 mmol, 0.2 eqv) and Xantphos (63 mg, 0.109 mmol, 0.4 eqv) in 1,4-dioxane (10 mL) was reacted at 96 °C for 4 h; the temperature was cooled to room temperature, silica gel was added to the reaction solution, and purification was carried out by silica gel column chromatography (eluent: n-hexane∶EA = 20∶1 to 2∶1) to obtain (S)-tert-butyl (1′-(3-acetyl-6-amino-5-((2-chloro-3-(oxazol-2-yl)phenyl)thio)pyrazin-2-yl)-5,7-dihydrospiro[cyclopent[b]pyridine-6,4′-piperidine]-5-yl)carbamate (152 mg, 87%); (ES, m / z): 648.14 [M+H] + .

[0579] Step b: To a solution of (S)-tert-butyl (1′-(3-acetyl-6-amino-5-((2-chloro-3-(oxazol-2-yl)phenyl)thio)pyrazin-2-yl)-5,7-dihydrospiro[cyclopent[b]pyridine-6,4′-piperidine]-5-yl)carbamate (152 mg) in dichloromethane (20 ml), trifluoroacetic acid (5 ml) was added, and the mixture was stirred at room temperature for 3 h; the reaction solution was concentrated under reduced pressure, EA (100 ml) and water (50 ml) were added to the residue, the pH was adjusted to 10 with 25% ammonia water, and liquid separation was carried out; the aqueous phase was extracted with EA (20 ml), and the organic phases were combined; the combined organic phase was washed with water (50 ml) and brine (50 ml), dried over anhydrous sodium sulfate, and concentrated; the residue was purified by column chromatography (CH2Cl2∶CH3OH = 20∶1) to obtain (S)-1-(5-amino-3-(5-amino-5,7-dihydrospiro[cyclopent[b]pyridine-6,4′-piperidine]-1′-yl)-6-((2-chloro-3-(oxazol-2-yl)phenyl)thio)pyrazin-2-yl)ethanone (120 mg, 93.4%). (ES, m / z): 548.14 [M+H] + .

[0580] 1H NMR (600 MHz, DMSO-d6) δ 8.332 - 8.310 (m, 2H), 7.747 (d, J = 7.8 Hz, 1H), 7.662 (d, J = 7.2 Hz, 1H), 7.477 (s, 1H), 7.433 - 7.407 (m, 1H), 7.176 - 7.156 (m, 1H), 7.050 (d, J = 7.8 Hz, 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).

[0581] Referring to the preparation process route and operation of Preparation Example 45, the following intermediates were used as starting materials to synthesize Compounds 46 - 48:

[0582]

[0583] Preparation Example 49: (3S,4S)-8-(6-Amino-5-((2-chloro-3-(oxazol-2-yl)phenyl)thio)-3-fluoropyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-amine (Compound 49)

[0584]

[0585] Step a: Under nitrogen protection, a solution of 3-bromo-6-chloropyrazin-2-amine (500 mg, 2.399 mmol, 1.00 eqv), 2-chloro-3-(oxazol-2-yl)benzenethiol (607 mg, 2.878 mmol, 1.2 eqv), DIEA (930 mg, 7.196 mmol, 3.0 eqv), Pd2(dba)3 (439 mg, 0.48 mmol, 0.2 eqv) and XantPhos (555 mg, 0.96 mmol, 0.4 eqv) in 1,4-dioxane (20 mL) was reacted at 96 °C for 8 h. After cooling to room temperature, the reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure; the residue was purified by column chromatography (n-hexane∶EA = 20∶1 - 2∶1) to obtain 6-chloro-3-((2-chloro-3-(oxazol-2-yl)phenyl)thio)pyrazin-2-amine (639 mg, 78.9%). (ES, m / z): 338.91 [M+H] + 。

[0586] Step b: Under nitrogen protection, a solution of 6-chloro-3-((2-chloro-3-(oxazol-2-yl)phenyl)thio)pyrazin-2-amine (639 mg, 1.89 mmol, 1 eqv), (3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine dihydrochloride (506 mg, 2.08 mmol, 1.1 eqv), and DIPEA (977 mg, 7.56 mmol, 4 eqv) in DMSO (9 ml) was reacted at 120 °C for 48 h. After cooling to room temperature, (Boc)2O (454 mg, 2.08 mmol, 1.1 eqv) and Et3N (765 mg, 7.56 mmol, 4 eqv) were added to the reaction solution and reacted overnight at room temperature. EA (100 ml) and brine (50 ml) were added to the reaction solution, and liquid separation was carried out. 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 (CH2Cl2∶CH3OH = 20∶1 to 15∶1) to obtain tert-butyl ((3S,4S)-8-(6-amino-5-((2-chloro-3-(oxazol-2-yl)phenyl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamate (865 mg, 80%).

[0587] Step c: Under nitrogen protection, a solution of tert-butyl ((3S,4S)-8-(6-amino-5-((2-chloro-3-(oxazol-2-yl)phenyl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamate (865 mg, 1.512 mmol, 1.0 eq), a selective fluorination reagent (643 mg, 1.81 mmol, 1.2 eq), and silver carbonate (42 mg, 0.151 mmol, 0.1 eq) in acetonitrile (20 mL) was refluxed overnight, and the reaction was monitored by LC-MS until completion. The reaction solution was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (CH2Cl2∶CH3OH = 80∶1 to 30∶1) to obtain tert-butyl ((3S,4S)-8-(6-amino-5-((2-chloro-3-(oxazol-2-yl)phenyl)thio)-3-fluoropyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamate (501 mg, 56.2%), (ES, m / z): 591.09 [M+H] + 。

[0588] Step d: To a solution of 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]dec-4-yl)carbamate (501 mg) in dichloromethane (10 ml) was added trifluoroacetic acid (5 ml), and the mixture was stirred at room temperature for 2 h; the reaction solution was concentrated under reduced pressure. To the residue were added EA (20 ml) and water (10 ml), and the pH was adjusted to 10 with 25% aqueous ammonia, and then the layers were separated; the aqueous phase was extracted with EA (5 ml), and the organic phases were combined; the combined organic phase was washed with water (10 ml) and brine (10 ml), dried over anhydrous sodium sulfate, and concentrated; the residue was purified by Prep-HPLC (gradient elution with 5-25% aqueous acetonitrile solution, modified with 0.05% NH4HCO3) to obtain (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 (198 mg, 47.6%), (ES, m / z): 491.09 [M+H] + 。

[0589] With reference to the preparation process route and operation of Preparation Example 49, the following intermediate was used as the starting material to synthesize Compound 50:

[0590]

[0591] 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]dec-4-amine (Compound 51)

[0592]

[0593] Steps a - b: The method was the same as Steps a - b in Preparation Example 49.

[0594] Step c: Under nitrogen protection, cool a solution of tert-butyl ((3S,4S)-8-(6-amino-5-((2-chloro-3-(oxazol-2-yl)phenyl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl)carbamate (300 mg, 0.524 mmol, 1.0 eq) in CH2Cl2 (20 mL) to -15 °C, add NCS (77 mg, 0.577 mmol, 1.1 eqv), react at 0 °C for 1 h, and monitor the reaction completion by LC-MS; add NaHCO3 solution (10 ml) to the reaction solution, stir for 20 min, let stand overnight, and separate the layers; concentrate the organic phase under reduced pressure, and purify the residue by column chromatography (CH2Cl2∶CH3OH = 50∶1 to 30∶1) to obtain tert-butyl ((3S,4S)-8-(6-amino-3-chloro-5-((2-chloro-3-(oxazol-2-yl)phenyl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl)carbamate (135 mg, 47.8%), (ES, m / z): 607.09 [M+H] + 。

[0595] Step d: Add trifluoroacetic acid (5 ml) to a solution of tert-butyl ((3S,4S)-8-(6-amino-3-chloro-5-((2-chloro-3-(oxazol-2-yl)phenyl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl)carbamate (135 mg) in dichloromethane (20 ml), stir at room temperature for 2.5 h; concentrate the reaction solution under reduced pressure, add EA (20 ml) and water (10 ml) to the residue, adjust the pH to 10 with 25% aqueous ammonia, and separate the layers; extract the aqueous phase with EA (5 ml), and combine the organic phases; wash the combined organic phases with water (10 ml) and brine (10 ml), dry over anhydrous sodium sulfate, and concentrate; purify the residue by Prep-HPLC (gradient elution with 10-30% aqueous acetonitrile solution modified with 0.05% NH4HCO3) to obtain (3S,4S)-8-(6-amino-3-chloro-5-((2-chloro-3-(oxazol-2-yl)phenyl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-amine (70 mg, 62%), (ES, m / z): 507.10 [M+H] + 。

[0596] Preparation Example 52: N-(3-((3-Amino-5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-6-cyanopyrazin-2-yl)thio)-2-chlorophenyl)-2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxamide (Compound 52)

[0597]

[0598] (3S,4S)-3-Methyl-2-oxa-8-azaspiro[4.5]dec-4-amine dihydrochloride (122 mg, 0.716 mmol, 1.2 eq), N-(3-((3-amino-5-chloro-6-cyanopyrazin-2-yl)thio)-2-chlorophenyl)-2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxamide (300 mg, 0.596 mmol, 1.0 eq), and DIEA (463 mg, 3.58 mmol, 5 eqv) in DMSO (5 ml) were reacted under nitrogen protection at 100 °C for 48 h. The reaction solution was cooled to room temperature, EA (50 ml) and water (50 ml) were added, and the mixture was stirred. The layers were separated, and the aqueous phase was extracted with EA (30 mL×2). The combined organic phases were washed with brine (30 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (gradient elution with 15 - 30% aqueous acetonitrile solution, modified with 0.1% CF3COOH) to obtain N-(3-((3-amino-5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-6-cyanopyrazin-2-yl)thio)-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 [M+H] + 。

[0599] With reference to the preparation process route and operation of Preparation Example 52, the following intermediate was used as the starting material to synthesize Compound 53:

[0600]

[0601] Preparation Example 54: (S)-1-(5-Amino-3-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(2,3-dichlorophenyl)pyrazin-2-yl)ethanone (Compound 54)

[0602]

[0603] Step a: Referring to the method in Step c of Preparation Example 21, (S)-tert-butyl (1′-(3-acetyl-6-amino-5-(2,3-dichlorophenyl)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidine]-1-yl)carbamate was prepared, (ES, m / z): 582.10 [M+H] + .

[0604] Step b: To a solution of (S)-tert-butyl (1′-(3-acetyl-6-amino-5-(2,3-dichlorophenyl)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4′-piperidine]-1-yl)carbamate (50 mg) in dichloromethane (5 ml), trifluoroacetic acid (2 ml) was added, and the mixture was stirred at room temperature for 1 h; the reaction solution was concentrated under reduced pressure, ethyl acetate (20 ml) and water (10 ml) were added to the residue, and the pH was adjusted to 10 with 25% aqueous ammonia, and the layers were separated; the aqueous phase was extracted with ethyl acetate (10 ml), and the organic phases were combined; the combined organic phases were washed with water (10 ml) and brine (5 ml), dried over anhydrous sodium sulfate, and concentrated; the residue was purified by column chromatography (CH2Cl2∶CH3OH = 30∶1) to obtain (S)-1-(5-amino-3-(1-amino-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-yl)-6-(2,3-dichlorophenyl)pyrazin-2-yl)ethanone (30 mg, 72.4%). (ES, m / z): 482.07 [M+H] + .

[0605] Referring to the preparation process route and operation of Preparation Example 54, the following intermediates were used as starting materials to synthesize Compounds 55-60:

[0606]

[0607]

[0608] Preparation Examples 61-63

[0609] Referring to the preparation process route, operation and other applicable process routes of Preparation Example 45, and using the corresponding intermediates as starting materials, Compounds 61-63 were prepared.

[0610]

[0611]

[0612] Preparation Examples 64-99

[0613] Referring to the preparation process routes, operations and other applicable process routes of Preparation Examples 1-63, and using the corresponding intermediates as starting materials, Compounds 64-99 were prepared.

[0614]

[0615]

[0616]

[0617]

[0618]

[0619]

[0620]

[0621] Experimental Example 1: Test on the inhibitory effect of the compound of the present application on SHP2 enzyme

[0622] 1. Preparation of working buffer and compounds

[0623] Prepare the working buffer 1x kinase buffer. Dilute the reference compound and the test compound to a storage concentration of 10 mM with DMSO solvent. First, dilute the test compound to an intermediate concentration of 1000 μM, and then perform a 3-fold serial dilution with DMSO. Therefore, the intermediate serial dilution concentrations of the test compound are: 1000 μM, 3-fold dilution, 11 gradients; similarly, the intermediate serial dilution concentrations of the reference compound RMC-4550 are: 500 μM, 3-fold dilution, 11 gradients; Transfer 8 μl of each of these intermediate serial dilution concentrations to a 384 LDV echo plate; Centrifuge this 384 LDV echo plate at 2000 rpm for 1 min. Using an Echo550 instrument, transfer 100 nl of each concentration of the compound in the 384 LDV echo plate to a new 384-well assay plate (Corning, Cat#4514), ensuring that the final concentration of the test compound is 10 μM, 3-fold dilution, 11 gradients, and 2 replicates after adding 10 μl of the reaction reagent. The final concentration of the reference compound RMC-4550 is 5 μM, 3-fold dilution, 11 gradients, and 2 replicates. The final DMSO concentration is 1%. For the negative control wells and positive control wells, 100 nl of DMSO will be transferred to each of them.

[0624] 2. SHP2 enzymatic reaction steps

[0625] Prepare a mixture with 1X enzyme buffer: 2X working SHP2 reagent (0.4 nM) and 0.5 μM SHP-2 activating peptide (BPSbioscience #79319-2). After incubating the above mixture at 25 °C for 60 minutes, transfer 5 μl of the activated SHP2 kinase solution to the compound wells and Max control wells (Corning, #4514) of the compound plate using a pipette. Then transfer 5 μl of 1x kinase buffer to the Min control well. Centrifuge at 1000 rpm for 30 seconds. Seal the plate and incubate the plate in an incubator at 25 °C for 30 minutes. Prepare a substrate solution of DiFMUP (#D6567, Invitrogen TM ) using 1x kinase reaction buffer, and its concentration should be 2 times the final experimental concentration (final concentration of DiFMUP: 10 μM). Use an electric pipette to transfer 5 μl of the prepared substrate solution to each well of the ELISA plate to initiate the reaction. Centrifuge at 1000 rpm for 30 seconds. Seal the plate and incubate the plate in an incubator at 25 °C for 60 minutes. Place the ELISA plate on the Spark machine and read the data at an excitation / emission wavelength of 358 / 455 nm.

[0626] 3. Calculation method and test results:

[0627] Copy the RLU values from Spark, calculate the inhibition rate using the RLU values. Inhibition rate = (maximum - sample RLU) / (maximum - minimum) * 100, where "minimum" refers to the RLU of the enzyme-free control and "maximum" refers to the RLU of the DMSO control. Fit the data in the XLFit excel add-in version 5.4.0.8 to obtain the IC50 value, and the results are shown in Table 1.

[0628] Table 1 Enzymatic effect test of the compounds of the present application and positive control drugs on SHP2

[0629]

[0630]

[0631] Note: The positive control drug RMC4550 is compound A-228 (Example 228) in WO2018013597A1; the positive control drug 123 is the compound obtained in Example 2 of TW201840553A.

[0632] Test Example 2: In vitro inhibitory effect of the compounds of the present application on the proliferation of human pancreatic cancer cell line MIA-PACA-2

[0633] 1. Test materials:

[0634] The experimental human pancreatic cancer cell line MIA-PACA-2 was purchased from Nanjing Kebai Biotechnology Co., Ltd. The complete culture medium required for cell culture was DMEM (GIBCO), supplemented with 10% fetal bovine serum (Lanzhou Minhai) and additionally 2.5% horse serum (Hyclone). The cells were cultured in an incubator at 37°C with 5% CO2. The reagents used in the experiment included dimethyl sulfoxide (purchased from Tianjin Kemiou Chemical Reagent Co., Ltd.) and MTT (THIAZOLYL BLUE TETRAZOLIUM BROMIDE, CAS.NO.298-93-1, AMRESCO). The test control RMC4550 was obtained by self-preparation or commercial purchase. The test substance was sealed and stored at 4°C.

[0635] 2. Test methods and results:

[0636] Using dimethyl sulfoxide as the solvent, the test substance was fully dissolved to prepare a stock solution with a concentration of 5×10 -2 mol / L, and the stock solution was stored at -20°C. Using the complete culture medium as the diluent, the test substance was serially diluted to different concentrations for use. In a 96-well culture plate, 100 μL / well (3×10 3 cells / well) of the MIA-PACA-2 cell complete medium suspension was added and cultured overnight. After the cells adhered for 24 hours, 100 μL / well of the corresponding different concentrations of the test substance were added respectively. Eight concentrations were set for each test substance, and three replicates were set for each concentration. The cells were cultured in an incubator at 37°C with 5% CO2. After the test substance acted for 72 h, 20 μL / well of MTT was added, and the cells were cultured in an incubator at 37°C with 5% CO2 for 4 hours. The supernatant was discarded, 150 μL / well of dimethyl sulfoxide was added, and the mixture was shaken and mixed evenly. The OD value was measured using an enzyme-linked immunosorbent assay (ELISA) reader at a wavelength of 550 nm. The wells containing only the cell suspension without the test substance were used as the control wells, and the wells containing only the complete culture medium were used as the blank wells. The inhibition rate of cell growth was calculated using the following formula:

[0637] Inhibition rate = (OD of control well - OD of test well) / (OD of control well - OD of blank well) * 100%. According to the inhibition rates at each concentration, the half-maximal inhibitory concentration IC 50 value was calculated using SPSS software, and the results are shown in Table 2.

[0638] Table 2 Cell proliferation inhibition effect test of the compounds of the present application and the positive control drug

[0639]

[0640] Note: The positive control drug RMC4550 is compound A-228 (Example 228) in WO2018013597A1.

[0641] The above data indicate that the compounds of the present invention all showed good inhibitory activity in the pancreatic cancer MIA-PACA-2 cell proliferation inhibition test, being superior to or comparable to the positive compound.

[0642] Test Example 3: In vitro inhibitory effect of the compounds of the present invention on the proliferation of human acute myeloid leukemia cells MV-4-11

[0643] 1. Test materials:

[0644] The experimental human acute myeloid leukemia cells MV-4-11 were purchased from the Shanghai Institute of Life Sciences, Chinese Academy of Sciences. The complete culture medium required for cell culture was IMDM (GIBCO), supplemented with 10% fetal bovine serum (GIBCO). The cells were cultured in an incubator at 37 °C and 5% CO2. The reagents used in the experiment included dimethyl sulfoxide (purchased from Tianjin Kemiou Chemical Reagent Co., Ltd.), MTT (Shanghai Tebor Chemical Technology Co., Ltd., CAS.NO.298-93-1). The test control TNO155 was obtained by self-preparation or commercial purchase. The test substances were sealed and stored at 4 °C.

[0645] 2. Test methods and results:

[0646] Using dimethyl sulfoxide as a solvent, the test substances were fully dissolved to prepare a stock solution with a concentration of 5×10 -2 mol / L, and the stock solution was stored at -20 °C. Using the complete culture medium as a diluent, the test substances were serially diluted to different concentrations for standby. In a 96-well culture plate, 100 μL / well (2×10 4 cells / well) of the MV-4-11 cell complete culture medium suspension was added, and 100 μL / well of the corresponding different concentrations of the test substances was added respectively. Each test substance was set at 8 concentrations, and each concentration was set with 3 replicates. The cells were cultured in an incubator at 37 °C and 5% CO2. After the test substances acted for 72 h, 20 μL / well of MTT was added, and the cells were cultured in an incubator at 37 °C and 5% CO2 for 4 hours. The supernatant was discarded, 150 μL / well of dimethyl sulfoxide was added, and the mixture was shaken well. The OD value was measured using an enzyme-linked immunosorbent assay (ELISA) reader at a wavelength of 550 nm. The wells containing only the cell suspension without the test substance were used as control wells, and the wells containing only the complete culture medium were used as blank wells. The inhibition rate of cell growth was calculated using the following formula:

[0647] Inhibition rate = (OD value of control well - OD value of test well) / (OD value of control well - OD value of blank well) * 100%. According to the inhibition rates at each concentration, the half-maximal inhibitory concentration IC 50 value was calculated using SPSS software, and the results are shown in Table 2.

[0648] Table 3 Test on the cell proliferation inhibition effect of the compounds of the present invention and the positive control drug

[0649]

[0650]

[0651] Note: The positive control drug TNO155 is the compound in WO2015107495A1 (Example 69); the positive control drug 123 is the compound prepared in Example 2 of TW201840553A.

[0652] The above data indicate that the compounds of the present invention all show good inhibitory activity in the human acute myeloid leukemia cell proliferation inhibition test, and the compounds of the present invention are all superior to or equivalent to the positive drugs.

[0653] Test Example 4: Pharmacokinetics Test in SD Rats

[0654] 1. Test method:

[0655] SD rats were intragastrically administered 20 mg / kg of the compound. At different time points after administration (0.25, 0.5, 1, 2, 4, 8, 24 h), blood was collected from the rat orbital cavity. The collected whole blood was anticoagulated with sodium heparin, and the rat plasma samples were obtained by centrifugation at 3000 g. Methanol protein precipitation was used, and the drug concentration in the rat plasma after administration was determined by HPLC-MS / MS method. The drug-time curve was plotted and the pharmacokinetic parameters were calculated. The pharmacokinetic behavior of the compound in the rats after administration was described by non-compartmental model statistical moment parameters.

[0656] 2. Test results:

[0657] The above-mentioned pharmacokinetics test was carried out on the compounds of the present invention. The test results show that the compounds of the present invention are all well absorbed in rats, as shown in Table 4.

[0658] Table 4 Pharmacokinetics Test of the Compounds of the Present Invention and Positive Control Drugs in SD Rats

[0659]

[0660]

[0661] The above data indicate that the compounds of the present invention all have a relatively high exposure in rats, superior to or equivalent to the positive drugs.

[0662] Test Example 5: Pharmacokinetics Test in Mice

[0663] 1. Test method:

[0664] ICR mice were intragastrically administered the compound at 10 mg / kg or 20 mg / kg. At different time points after administration (0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, 24 h), blood was collected from the mouse orbital cavity. The collected whole blood was anticoagulated with sodium heparin and centrifuged at 3000 g to separate the mouse plasma samples. Methanol protein precipitation was used, and the drug concentration in the mouse plasma after administration was determined by HPLC-MS / MS. The drug-time curve was plotted and the pharmacokinetic parameters were calculated. The pharmacokinetic behavior of the compound in mice after administration was described by non-compartmental model statistical moment parameters.

[0665] 2. Test results:

[0666] The above-mentioned pharmacokinetic tests were carried out on the compound of the present invention. The test results showed that the compound of the present invention was well absorbed in mice, as shown in Table 5.

[0667] Table 5 Pharmacokinetic tests of the compound of the present invention and the positive control drug in mice

[0668]

[0669] The above data indicate that at 20 mg / kg, the compound of the present invention has a high exposure in mice, which is superior to the positive control drug.

[0670] Test Example 6: In vivo efficacy test on NCI-H358

[0671] In vivo efficacy test:

[0672] In vivo efficacy test: SPF-grade 4-5-week-old female NU / NU mice were used in the test and purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. Human non-small cell lung cancer cell line NCI-H358 (1X10 6 cells / 0.1 ml / rat) was subcutaneously inoculated into the axilla of the forelimb of the mice to establish a subcutaneous xenograft tumor model. When the tumor volume grew to about 200 mm 3 (on the 5th day after inoculation), the mice were evenly grouped according to the tumor volume, with 6 mice in each group, which were the vehicle control group and the test drug group respectively. The dosing dose of the test drug group was set at 7.5 - 20 mg / kg, the dosing volume was 10 mL / kg, and the administration was by intragastric gavage once a day. The tumor diameter was measured 2 times a week and the data were recorded. The test ended after 21 consecutive days of administration, and the tumor was dissected and weighed.

[0673] The body weight growth rate, tumor volume and tumor weight inhibition rate were calculated according to the formula, where W i represents the body weight of a certain mouse in each experimental group on the nth day, and W0 is the body weight of a certain mouse in each experimental group at the start of dosing; the tumor volume (V) = 1 / 2 * a * b 2, where a and b respectively represent the major and minor axes of the tumor; the tumor growth inhibition rate TGI (%) = [1 - (Ti - T0) / (Vi - V0)] × 100, where Ti represents the average tumor volume of a certain dosing group on a certain day; T0 is the average tumor volume of this dosing group at the start of dosing; Vi is the average tumor volume of the vehicle control group on a certain day (the same day as Ti); V0 is the average tumor volume of the vehicle control group at the start of dosing.

[0674] Table 6 In vivo test data of the compounds of the present invention and the positive control drug on NCI-H358

[0675]

[0676] Compared with the vehicle control group, *P < 0.05, **P < 0.01, ***P < 0.001

[0677] Test conclusion: The compounds of the present invention can significantly inhibit tumor growth at the dosing doses of 7.5 - 20 mg / kg, and have good tolerance and good safety. The control compound 123 has low safety and poor tolerance at 20 mg / kg, and all the mice died at the end of the test. Therefore, the compounds of the present invention are superior to the control compound in terms of both safety and tolerance.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, which has the following structure:

2. A compound or a pharmaceutically acceptable salt thereof, which has the following structure:

3. A compound or a pharmaceutically acceptable salt thereof, which has the following structure:

4. A compound or a pharmaceutically acceptable salt thereof, which has the following structure:

5. A compound or a pharmaceutically acceptable salt thereof, which is selected from the following structures:

6. A compound or a pharmaceutically acceptable salt thereof, which is selected from the following structures:

7. A pharmaceutical composition, which comprises the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6 and a pharmaceutically acceptable excipient.

8. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6 or the pharmaceutical composition according to claim 7 in the preparation of a medicament for preventing and / or treating diseases, disorders and conditions mediated by SHP2 activity, wherein the diseases, disorders and conditions are selected from pancreatic cancer, acute myeloid lymphocytic leukemia and non-small cell lung cancer.

9. The use according to claim 8, wherein the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6 or the pharmaceutical composition according to claim 7 is used in combination with another, two or more compounds having antitumor activity.

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