Aza-tricyclic compound and application thereof

Abstract

The invention discloses an aza-tricyclic compound, and particularly relates to structural forms such as free alkali, isomeride and pharmaceutically acceptable salt of the compound. Furthermore, the invention also discloses a preparation method and pharmaceutical application of the aza-tricyclic compound, and the aza-tricyclic compound can be used as a PTPN2 and / or PTPN1 inhibitor for treating diseases related to abnormal expression of mediated PTPN2 and PTPN1 signal pathways. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the technical field of small molecule chemical drugs, and relates to a class of azatricyclic compounds, and specifically to free bases, isomers and pharmaceutically acceptable salts of the compounds; further, the present invention also discloses a preparation method of the azatricyclic compounds and their pharmaceutical uses, which can be used as PTPN2 / PTPN1 inhibitors for treating diseases (including but not limited to tumors) related to abnormal expression of PTPN2 / PTPN1 signaling pathways. Background Art

[0002] Protein tyrosine phosphorylation (pTyr) is a common post-translational modification that can create new recognition motifs for protein interactions and cellular localization, affect protein stability, and regulate enzyme activity. Therefore, maintaining appropriate levels of protein tyrosine phosphorylation is essential for many cellular functions. Tyrosine-specific protein phosphatases (PTPases) catalyze the removal of phosphate groups attached to tyrosine residues using cysteinyl phosphatase intermediates. These enzymes are key regulatory components of signal transduction pathways (such as the MAP kinase pathway) and cell cycle control, and play an important role in the control of cell growth, proliferation, differentiation, transformation, and synaptic plasticity.

[0003] Genome sequencing has revealed at least four classes of more than 100 proteins with potential PTP activity. Protein tyrosine phosphatase non-receptor type 2 (PTPN2, TC-PTP) and type 1 (PTPN1, PTP1B) are non-receptor phosphatases and are two ubiquitously expressed classical PTPs, with a catalytic domain identity of more than 74%.

[0004] Inhibition of PTPN2 / N1 (negative regulator) in tumor cells can promote IFN inflammatory signaling through the JAK / STAT pathway, leading to growth retardation, increased tumor antigen presentation, and increased release of pro-inflammatory chemokines. In immune cells, inhibition of PTPN2 / 1 can promote the activation of multiple immune cell subsets and pro-inflammatory anti-tumor functions. For example, in T cells, PTPN2 acts as a negative regulator of TCR signaling. Inhibition can increase T cell activation, proliferation, and immune effector function, resulting in an anti-tumor effect. At the same time, studies have shown that PTPN2 inhibition can increase PD-L1 expression, and combined with anti-PD-1 (L1) monoclonal antibodies to produce a synergistic effect.

[0005] Patents WO2020186199 and WO2022056281 disclose PTPN2 / N1 inhibitors (see general structural formula I / II), the structural characteristics of which are: the use of a benzo six-membered saturated carbon ring, or a benzo six-membered saturated heterocyclic structure. The representative compound ABBV-CLS-484 is in Phase I clinical research. Information shows that Calico intends to conduct trials on subjects with advanced solid tumors such as recurrent or refractory head and neck squamous cell carcinoma, recurrent or refractory non-small cell lung cancer, and advanced clear cell renal cell carcinoma, as well as combined with anti-PD-1 or PD-L1 monoclonal antibodies, anti-PD-1 or PD-L1 monoclonal antibody resistance or combined with VEGFR kinase inhibitors for the treatment of locally advanced or metastatic recurrent or refractory head and neck squamous cell carcinoma, recurrent or refractory non-small cell lung cancer, and highly microsatellite unstable tumors. ABBV-CLS-484 preclinical study published in Nature (https: / / doi.org / 10.1038 / s41586-023-06575-7) showed that ABBV-CLS-484 can enhance the sensitivity of tumor cells to IFN-γ, enhance T cell function, and show excellent single-drug or combined anti-tumor activity in multiple tumor models. However, no related drugs are currently on the market.

[0006]

[0007] Therefore, the development of PTPN2 / 1 inhibitors can drive dual anti-cancer mechanisms related to tumor cells and immune cells respectively, and is a very attractive target in the field of tumor immunotherapy. Summary of the invention

[0008] The technical problem to be solved by the present invention is to provide an azatricyclic compound with a novel structure and excellent activity, which can be used as a PTPN2 / 1 inhibitor for the treatment of cancer.

[0009] In order to solve the above technical problems, the technical solutions provided by the present invention are as follows:

[0010] An azatricyclic compound is a compound having the following structural formula (I) or a pharmaceutically acceptable salt thereof:

[0011]

[0012] in: is a double bond or a single bond; n is 1, 2 or 3;

[0013] W is selected from C, CH or N;

[0014] X and Y are each independently selected from N(R3) j or C(R3) k ;

[0015] j is 0 or 1, k is 1 or 2;

[0016] Z is selected from O, S, Se, OR4, SR4, SeR4, NR4 or NR4R 4A ;

[0017] P is selected from CH or N;

[0018] Q is selected from hydrogen, deuterium, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 1-6 alkoxy, hydroxy, cyano, amino, amide, sulfone or sulfoxide; when the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 When there is a substituent for the alkoxy group, it may be substituted by at least one of the following groups: halogen, hydroxyl, amino, amide, sulfone, sulfoxide, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl;

[0019] R1, R4, R 4A are each independently selected from hydrogen, deuterium, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, hydroxyl, cyano; when the C 1-6 Alkyl, C 1-6 When there is a substituent for the alkoxy group, it may be substituted by at least one of the following groups: halogen, hydroxyl, amino, amide, sulfone, sulfoxide, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl;

[0020] R2 is absent, or R2 is selected from hydrogen, deuterium, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, hydroxyl, cyano; when the C 1-6 Alkyl, C 1-6 When there is a substituent for the alkoxy group, it may be substituted by at least one of the following groups: halogen, hydroxyl, amino, amide, sulfone, sulfoxide, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl;

[0021] Each R3 is independently selected from hydrogen, deuterium, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 3-10 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic group, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, cyano, -OR5, -SR5, -SOR5, -S(O)2R5, -COR5, -C(O)OR5, -C(O)NR5R 5A or -NR5R 5A ; When the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 When aryl and 5-10 membered heteroaryl have substituents, they may be substituted by at least one of the following groups: halogen, hydroxyl, amino, amide, sulfone, sulfoxide, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -OR6, -SR6, -SOR6, -S(O)2R6, -COR6, -C(O)OR6, -C(O)NR6R 6A 、-NR6R 6A ;

[0022] Each R5, R 5A , R6, R 6A are each independently selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 1-6 Alkoxy, -OR7, -SR7, -S(O)2R7, -COR7, -C(O)OR7, -C(O)NR7R 7A 、-NR7R 7A ; When the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 When there is a substituent for the alkoxy group, it may be substituted by at least one of the following groups: halogen, hydroxyl, cyano, amino, amide, sulfone, sulfoxide, substituted or unsubstituted C 3-10 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic group, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, -OR8, -NR8S(O)2R 8A; Further, when the C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 When aryl and 5-10 membered heteroaryl have substituents, they may be substituted by at least one of the following groups: halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy;

[0023] Each R7, R 7A , R8, R 8A are each independently selected from hydrogen, halogen, C 1-6 Alkyl, substituted or unsubstituted C 3-10 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic group, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl; when the C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 When aryl and 5-10 membered heteroaryl have substituents, they may be substituted by at least one of the following groups: halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy;

[0024] The heterocyclic group and heteroaryl group contain at least one heteroatom, and the heteroatom is selected from N, O or S.

[0025] The present invention also provides an azatricyclic compound, which is a compound having the following structural formula (I) or a pharmaceutically acceptable salt thereof:

[0026]

[0027] in: is a double bond or a single bond; n is 1, 2 or 3;

[0028] W is selected from C, CH or N;

[0029] X and Y are each independently selected from NR3 or CR3;

[0030] Z is selected from O, S, Se, OR4, SR4, SeR4, NR4 or NR4R 4A ;

[0031] P is selected from C or N;

[0032] Q is selected from hydrogen, deuterium, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6Alkynyl, substituted or unsubstituted C 1-6 Alkoxy, hydroxy, cyano, amino, amide, sulfone or sulfoxide; when C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 When there is a substituent for the alkoxy group, it may be substituted by at least one of the following groups: halogen, hydroxyl, amino, amide, sulfone, sulfoxide, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl;

[0033] R1, R2, R4, R 4A are each independently selected from hydrogen, deuterium, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, hydroxyl, cyano; when C 1-6 Alkyl, C 1-6 When there is a substituent for the alkoxy group, it may be substituted by at least one of the following groups: halogen, hydroxyl, amino, amide, sulfone, sulfoxide, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl;

[0034] R3 is selected from hydrogen, deuterium, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 3-10 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic group, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, cyano, -OR5, -SR5, -SOR5, -S(O)2R5, -COR5, -C(O)OR5, -C(O)NR5R 5A or -NR5R 5A ; When C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 When aryl and 5-10 membered heteroaryl have substituents, they may be substituted by at least one of the following groups: halogen, hydroxyl, amino, amide, sulfone, sulfoxide, 3-10 membered cycloalkyl, 3-10 membered heterocyclic, C 6-10Aryl, 5-10 membered heteroaryl, -OR6, -SR6, -SOR6, -S(O)2R6, -COR6, -C(O)OR6, -C(O)NR6R 6A 、-NR6R 6A ;

[0035] R5, R 5A , R6, R 6A are each independently selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 1-6 Alkoxy, -OR7, -SR7, -S(O)2R7, -COR7, -C(O)OR7, -C(O)NR7R 7A 、-NR7R 7A ; When C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 When there is a substituent for the alkoxy group, it may be substituted by at least one of the following groups: halogen, hydroxyl, cyano, amino, amide, sulfone, sulfoxide, substituted or unsubstituted C 3-10 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic group, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, -OR8, -NR8S(O)2R 8A ; Further, when C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 When aryl and 5-10 membered heteroaryl have substituents, they may be substituted by at least one of the following groups: halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy;

[0036] R7, R 7A , R8, R 8A are each independently selected from hydrogen, halogen, C 1-6 Alkyl, substituted or unsubstituted C 3-10 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic group, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl; when C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 When aryl and 5-10 membered heteroaryl have substituents, they may be substituted by at least one of the following groups: halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C1-6 Alkyl, halogenated C 1-6 Alkoxy;

[0037] The heterocyclic group and the heteroaryl group contain at least one heteroatom, and the heteroatom is selected from N, O or S.

[0038] Preferably, in the aforementioned general structural formula (I), W is selected from C or N, X and Y are each independently selected from N or CR3, Z is selected from O, and P is selected from C or N.

[0039] More preferably, in the aforementioned general structural formula (I), when W is selected from C, P is N, X and Y are N and N respectively, or X and Y are N and CR3 respectively, or X and Y are CR3 and N respectively, or X and Y are CR3 and CR3 respectively; or, when W is selected from N, P is N, X and Y are N and N respectively, or X and Y are N and CR3 respectively, or X and Y are CR3 and N respectively, or X and Y are CR3 and CR3 respectively.

[0040] Furthermore, the present invention also provides an azatricyclic compound, which is a compound having the following structural formula (II) or a pharmaceutically acceptable salt thereof:

[0041]

[0042] Where: n is 1, 2 or 3;

[0043] Q is selected from hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 1-6 Alkoxy, hydroxy, cyano, amino, amide, sulfone or sulfoxide; when C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 When there is a substituent for the alkoxy group, it may be substituted by at least one of the following groups: halogen, hydroxyl, amino, amide, sulfone, sulfoxide, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl;

[0044] R1 and R2 are each independently selected from hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, hydroxyl, cyano; when C 1-6 Alkyl, C 1-6 When there is a substituent for the alkoxy group, it may be substituted by at least one of the following groups: halogen, hydroxyl, amino, amide, sulfone, sulfoxide, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C6-10 Aryl, 5-10 membered heteroaryl;

[0045] R3 is selected from hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 3-10 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic group, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, cyano, -OR5, -SR5, -SOR5, -S(O)2R5, -COR5, -C(O)OR5, -C(O)NR5R 5A or -NR5R 5A ; When C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 When aryl and 5-10 membered heteroaryl have substituents, they may be substituted by at least one of the following groups: halogen, hydroxyl, amino, amide, sulfone, sulfoxide, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -OR6, -SR6, -SOR6, -S(O)2R6, -COR6, -C(O)OR6, -C(O)NR6R 6A 、-NR6R 6A ;

[0046] R5, R 5A , R6, R 6A are each independently selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 1-6 Alkoxy, -OR7, -SR7, -S(O)2R7, -COR7, -C(O)OR7, -C(O)NR7R 7A 、-NR7R 7A ; When C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 When there is a substituent for the alkoxy group, it may be substituted by at least one of the following groups: halogen, hydroxyl, cyano, amino, amide, sulfone, sulfoxide, substituted or unsubstituted C 3-10Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic group, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, -OR8, -NR8S(O)2R 8A ; Further, when C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 When aryl and 5-10 membered heteroaryl have substituents, they may be substituted by at least one of the following groups: halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy;

[0047] R7, R 7A , R8, R 8A are each independently selected from hydrogen, halogen, C 1-6 Alkyl, substituted or unsubstituted C 3-10 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic group, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl; when C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 When aryl and 5-10 membered heteroaryl have substituents, they may be substituted by at least one of the following groups: halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy;

[0048] The heterocyclic group and the heteroaryl group contain at least one heteroatom, and the heteroatom is selected from N, O or S.

[0049] Furthermore, the present invention also provides an azatricyclic compound, which is a compound having the following structural formula (IIA) or a pharmaceutically acceptable salt thereof:

[0050]

[0051] Wherein: R1, R2 are each independently selected from hydrogen, C 1-6 alkyl;

[0052] R3 is selected from hydrogen, substituted or unsubstituted C 3-10 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic group, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, -OR5, -NR5R 5A ; When C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10When aryl and 5-10 membered heteroaryl have substituents, they may be substituted by at least one of the following groups: -S(O)2R6;

[0053] R5, R 5A , R6 are each independently selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl; when C 1-6 When an alkyl group has a substituent, it may be substituted by at least one of the following groups: halogen, hydroxyl, cyano, substituted or unsubstituted C 3-10 Cycloalkyl, -OR8, -NR8S(O)2R 8A ; Further, when C 3-10 When a cycloalkyl group has a substituent, it may be substituted by at least one of the following groups: halogen;

[0054] R7, R8, R 8A are each independently selected from hydrogen, C 1-6 Alkyl or 3-10 membered heterocyclic group;

[0055] The heterocyclic group and the heteroaryl group contain at least one heteroatom, and the heteroatom is selected from N, O or S.

[0056] Furthermore, the present invention also provides an azatricyclic compound, which is a compound having the following structural formula (II-1), (II-2) or (II-3) or a pharmaceutically acceptable salt thereof:

[0057]

[0058] R5 is selected from substituted or unsubstituted C 1-6 Alkyl; when the C 1-6 When an alkyl group has a substituent, it may be substituted by at least one of the following groups: halogen, hydroxyl, cyano, substituted or unsubstituted C 3-10 Cycloalkyl, -NHS(O)2R 8A ; Further, when the C 3-10 When a cycloalkyl group has a substituent, it may be substituted by at least one of the following groups: halogen;

[0059] R 5A is selected from substituted or unsubstituted C 1-6 Alkyl; when the C 1-6 When an alkyl group has a substituent, it may be substituted by at least one of the following groups: cyano, C 3-10 Cycloalkyl;

[0060] R6 is selected from substituted or unsubstituted C 1-6 Alkyl; when the C 1-6 When an alkyl group has a substituent, it may be substituted by at least one of the following groups: halogen, cyano, -OR8;

[0061] R8 is selected from C 1-6 alkyl;

[0062] R 8A is selected from 3-10 membered heterocyclic groups;

[0063] The heterocyclic group and heteroaryl group contain at least one heteroatom, and the heteroatom is selected from N, O or S.

[0064] Furthermore, the present invention also provides an azatricyclic compound, which is a compound having the following structural formula (III) or a pharmaceutically acceptable salt thereof:

[0065]

[0066] Where: n is 1, 2 or 3;

[0067] Q is selected from hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 1-6 Alkoxy, hydroxy, cyano, amino, amide, sulfone or sulfoxide; when C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 When there is a substituent for the alkoxy group, it may be substituted by at least one of the following groups: halogen, hydroxyl, amino, amide, sulfone, sulfoxide, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl;

[0068] R1 and R2 are each independently selected from hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, hydroxyl, cyano; when C 1-6 Alkyl, C 1-6 When there is a substituent for the alkoxy group, it may be substituted by at least one of the following groups: halogen, hydroxyl, amino, amide, sulfone, sulfoxide, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl;

[0069] R3 is selected from hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 3-10Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic group, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, cyano, -OR5, -SR5, -SOR5, -S(O)2R5, -COR5, -C(O)OR5, -C(O)NR5R 5A or -NR5R 5A ; When C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 When aryl and 5-10 membered heteroaryl have substituents, they may be substituted by at least one of the following groups: halogen, hydroxyl, amino, amide, sulfone, sulfoxide, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -OR6, -SR6, -SOR6, -S(O)2R6, -COR6, -C(O)OR6, -C(O)NR6R 6A 、-NR6R 6A ;

[0070] R5, R 5A , R6, R 6A are each independently selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 1-6 Alkoxy, -OR7, -SR7, -S(O)2R7, -COR7, -C(O)OR7, -C(O)NR7R 7A 、-NR7R 7A ; When C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 When there is a substituent for the alkoxy group, it may be substituted by at least one of the following groups: halogen, hydroxyl, cyano, amino, amide, sulfone, sulfoxide, substituted or unsubstituted C 3-10 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic group, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, -OR8, -NR8S(O)2R 8A ; Further, when C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 When aryl and 5-10 membered heteroaryl have substituents, they may be substituted by at least one of the following groups: halogen, C 1-6Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy;

[0071] R7, R 7A , R8, R 8A are each independently selected from hydrogen, halogen, C 1-6 Alkyl, substituted or unsubstituted C 3-10 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic group, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl; when C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 When aryl and 5-10 membered heteroaryl have substituents, they may be substituted by at least one of the following groups: halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy;

[0072] The heterocyclic group and the heteroaryl group contain at least one heteroatom, and the heteroatom is selected from N, O or S.

[0073] Furthermore, the present invention also provides an azatricyclic compound, which is a compound having the following structural formula (IVA) or (VA) or a pharmaceutically acceptable salt thereof:

[0074]

[0075] Wherein: R1 and R2 are each independently selected from hydrogen;

[0076] R3 is selected from -OR5, -NHR 5A ;

[0077] R5, R 5A are each independently selected from substituted or unsubstituted C 1-6 Alkyl; when the C 1-6 When an alkyl group has a substituent, it may be substituted by at least one of the following groups: halogen, C 3-10 Cycloalkyl.

[0078] The present invention also provides an azatricyclic compound, including but not limited to the following structural compounds numbered 1-23, isomers, or pharmaceutically acceptable salts thereof:

[0079]

[0080]

[0081]

Term Definition

[0082] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered to be uncertain or unclear in the absence of a special definition, but should be understood according to its ordinary meaning. When a trade name appears in this article, it is intended to refer to its corresponding commercial product or its active ingredient.

[0083] The "compound" described in the present invention includes but is not limited to the following forms of the compound: free base, stereoisomers, geometric isomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, prodrugs (esters) and the like.

[0084] In the above definition of "compound", its solvent compound is selected from hydrate, ethanolate, methanolate, acetoneate, etherate or isopropanolate.

[0085] In the above definition of "compound", "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0086] In the above definition of "compound", the prodrug is easily converted into the compound of the present invention by chemical changes under physiological conditions. Furthermore, the prodrug can be converted into the compound of the present invention by chemical or biochemical methods in an in vivo environment.

[0087] The "isomer" of the present invention refers to stereoisomers or tautomers unless otherwise specified. Unless otherwise specified, the term "stereoisomer" refers to compounds with the same chemical structure but different spatial arrangements of atoms or groups. Stereoisomers include, but are not limited to, enantiomers, diastereomers, conformers (rotational isomers), geometric isomers (cis / trans) isomers, and atropisomers. Any mixture of stereoisomers obtained can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on the differences in the physicochemical properties of the components, for example, by chromatography and / or fractional crystallization. For example, an optically pure form can be obtained by resolving a racemic mixture, using chiral raw materials or chiral reagents for synthesis. Unless otherwise specified, the term "tautomer" refers to structural isomers with different energies that can be mutually converted through a low energy barrier. If tautomerism is possible (such as in a solution), a chemical equilibrium of tautomers can be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions via reorganization of some of the bonding electrons.

[0088] The term "isotope" as used herein means that, unless otherwise specified, the compounds of the present invention may exist in an isotopically-tagged or enriched form, containing one or more atoms whose atomic mass or mass number is different from the atomic mass or mass number of the largest atom found in nature. Isotopes may be radioactive or non-radioactive isotopes. Isotopes commonly used as isotope labels are: hydrogen isotopes, including but not limited to 2 H and 3 H; Carbon isotopes: including but not limited to 13 C and 14 C; Chlorine isotopes: including but not limited to 35 Cl and 37 Cl; Fluorine isotopes: including but not limited to 18F; Iodine isotopes: including but not limited to 123 I and 125 I; Nitrogen isotopes: including but not limited to 13 N and 15 N; oxygen isotopes: including but not limited to 15 O. 17 O and 18 O; Sulfur isotopes: including but not limited to 35 S. These isotope-labeled compounds can be used to study the distribution of drug molecules in tissues, especially 3 H and 13 C, because they are easy to label and detect, they are more widely used. Some heavy isotopes, such as deuterium ( 2 H) substitution can enhance metabolic stability and prolong half-life, thereby achieving the purpose of reducing dosage and providing therapeutic advantages. Isotope-labeled compounds generally start from labeled starting materials and use known synthesis techniques to complete their synthesis like non-isotope-labeled compounds.

[0089] The "pharmaceutically acceptable salt" of the present invention refers to the salt of the compound of the present invention, which is obtained by reacting the compound with a specific substituent discovered by the present invention with 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, hydroiodide, hydroxynaphthalene, isethionic acid, lactic acid, lactose, dodecylsulfonic acid , maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, acetic acid, succinic acid, aminosulfonic acid, p-aminobenzenesulfonic acid, sulfuric acid, tannin, tartaric acid and p-toluenesulfonic acid; or when containing relatively acidic functional groups, a base addition salt can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, sodium, potassium, calcium, magnesium salts, ammonium or organic amines. For example: alkali metal salts, alkaline earth metal salts, other metal salts, inorganic base salts, organic base salts, inorganic acid salts, lower alkane sulfonates, aryl sulfonates, organic acid salts, amino acid salts.

[0090] For the compounds defined by the above general structural formula, the substituent terms expressing the structural forms have the following meanings:

[0091] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

[0092] The term "cyano" refers to -CN.

[0093] The term "amino" refers to -NH2.

[0094] The term "alkyl" refers to a straight-chain or branched saturated hydrocarbon group consisting of carbon atoms and hydrogen atoms. 1-6 Alkyl groups include, but are not limited to, methyl, ethyl, propyl (including: 1-propyl or n-propyl, 2-propyl or isopropyl), butyl (including: 1-butyl or n-butyl, 2-methyl-1-propyl or isobutyl, 2-methyl-1-propyl or isobutyl, 1-methylpropyl or sec-butyl, 1,1-dimethylethyl or tert-butyl), pentyl (1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl), hexyl (1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl and 3,3-dimethyl-2-butyl), etc.

[0095] The term "alkoxy" refers to a straight or branched chain alkyl group attached through an oxygen atom, such as C 1-6Alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, sec-butoxy and tert-butoxy), pentoxy (including n-pentoxy, isopentoxy and neopentoxy), hexoxy (n-hexyloxy, 2-methylpentoxy, 3-methylpentoxy, 2,3-dimethylbutoxy and 2,2-dimethylbutoxy), and the like.

[0096] The term "halogenated C 1-6 "Alkyl" refers to an alkyl group in which one or more H atoms are replaced by one or more halogen atoms (such as fluorine, chlorine, bromine or iodine), including but not limited to -CF3, -CH2Cl, -CH2CF3, -CCl2, -CF3, etc.

[0097] The term "halogenated C 1-6 "Alkoxy" refers to an alkoxy group in which one or more H is replaced by one or more halogen atoms (such as fluorine, chlorine, bromine or iodine), including but not limited to -OCF3, -OCH2Cl, -OCH2CF3, -OCCl2, -OCF3, etc.

[0098] The term "cycloalkyl" refers to a monocyclic alkyl group consisting of carbon atoms and hydrogen atoms, such as C 3-8 Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0099] The term "alkenyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one double bond. 2-6 "Alkenyl" includes, but is not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1,3-butadien-1-yl, 1,3-butadien-2-yl, and the like.

[0100] The term "alkynyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one triple bond. 2-6 "Alkynyl" includes, but is not limited to, ethynyl, 1-propynyl, 1-butynyl, 1,3-butadiynyl, 1-pentynyl, 3-methyl-1-butynyl, 1,3-pentadiynyl, 1,4-pentadiynyl, 1-hexynyl, 3-methyl-1-pentynyl, 4-methyl-1-pentynyl, 3,3-dimethyl-1-butynyl, 3-ethyl-1-butynyl, 1,3-hexadiynyl, 1,4-hexadiynyl, 3-methyl-1,4-pentadiynyl, 1,5-hexadiynyl, and the like.

[0101] The term "aromatic ring" refers to an all-carbon monocyclic ring or fused polycyclic ring of 6-16 carbon atoms, having a completely conjugated π-electron system, including but not limited to a benzene ring, a naphthalene ring, anthracene ring, etc., preferably a benzene ring.

[0102] The term "aryl" refers to an all-carbon monocyclic or condensed polycyclic group of 6 to 16 carbon atoms with a completely conjugated π-electron system, including but not limited to phenyl, naphthyl, anthracenyl, etc., preferably phenyl.

[0103] The term "heterocycle" refers to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic cyclic hydrocarbon, which is a non-aromatic structure and contains 3-20 ring atoms, wherein 1, 2, 3 or more ring atoms are selected from N, O or S, and the remaining ring atoms are C. Bicyclic or polycyclic heterocycles include spirocyclic, condensed and bridged heterocycles. Bicyclic or polycyclic "heterocycles" include those in which one ring is aromatic and the other rings are non-aromatic, including spirocyclic, condensed and bridged heterocycles. Bicyclic heterocycles may contain one or more heteroatoms in one or both rings. In some embodiments, heterocycle also includes a ring system in which a heterocycle as defined above is fused to one or more carbocyclic groups, wherein the point of attachment is on the ring of the carbocyclic or heterocyclic ring; or, in some embodiments, heterocycle also includes a ring system in which a heterocycle as defined above is fused to one or more aromatic / heteroaromatic rings, wherein the point of attachment is on the ring of the aromatic / heteroaromatic ring or heterocyclic ring; or, in some embodiments, a ring system in which a heterocycle as defined above is fused to one or more heterocycles as defined above, wherein the point of attachment is on the ring of either heterocycle. In the above cases, the number of ring members of the heterocycle ring system is the number of ring atoms in the ring system after fusion. In some embodiments, heterocycle is optionally substituted, for example, unsubstituted (unsubstituted heterocycle) or substituted by one or more substituents (substituted heterocycle). For example, a 3-membered heterocycle containing one heteroatom includes but is not limited to aziridine, oxirane and thiirane; a 4-membered heterocycle containing one heteroatom includes but is not limited to azetidine, oxetane and thiirane; a 5-membered heterocycle containing one heteroatom includes but is not limited to tetrahydrofuran, dihydrofuran, tetrahydrothiophene, dihydrothiophene, pyrrolidine, dihydropyrrole and 2,5-pyrrolidinedione; a 6-membered heterocycle containing one heteroatom includes but is not limited to piperidine, tetrahydropyran, dihydropyridine and tetrahydrothiopyran; a 5-membered heterocycle containing two heteroatoms includes but is not limited to dioxolane, oxathiolane, dithiolane and 2-oxoxazolidine; The 6-membered heterocycle with 2 heteroatoms includes but is not limited to piperazine, morpholine, thiomorpholine, etc.; the 5-membered heterocycle containing 3 heteroatoms includes but is not limited to triazole, oxadiazole and thiadiazole, etc.; the 6-membered heterocycle containing 3 heteroatoms includes but is not limited to triazine, oxadiazine, thiadiazine, oxathiazine and dioxazine, etc.; the 5-membered heterocycle fused to a C6 aromatic ring (also referred to as 5,6-bicyclic heterocycle) includes but is not limited to dihydroindole, isoindole, dihydrobenzofuran, dihydrobenzothiophene, benzoxazolinone, etc.; the 6-membered heterocycle fused to a C6 aromatic ring (also referred to as 6,6-bicyclic heterocycle) includes but is not limited to tetrahydroquinoline, tetrahydroisoquinoline, etc.

[0104] The term "heterocyclic group" refers to a substituent generated on the basis of the above-mentioned definition of heterocycle. Similarly, for example, a 3-membered heterocyclic group containing 1 heteroatom includes but is not limited to aziridine, oxirane and thiirane, etc.; a 4-membered heterocyclic group containing 1 heteroatom includes but is not limited to azetidinyl, oxetanyl and thiidine, etc.; a 5-membered heterocyclic group containing 1 heteroatom includes but is not limited to tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl and 2,5-dioxopyrrolidinyl, etc.; a 6-membered heterocyclic group containing 1 heteroatom includes but is not limited to piperidinyl, tetrahydropyranyl, dihydropyridinyl and tetrahydrothiopyranyl, etc.; a 5-membered heterocyclic group containing 2 heteroatoms includes but is not limited to dioxolane, oxathiolanyl, dithiolanyl, 2-oxoxazolidinyl, etc.; a 6-membered heterocyclic group containing 1 heteroatom includes but is not limited to piperidinyl, tetrahydropyranyl, dihydropyridinyl and tetrahydrothiopyranyl, etc.; a 5-membered heterocyclic group containing 2 heteroatoms includes but is not limited to dioxolane, oxathiolanyl, dithiolanyl, 2-oxoxazolidinyl, etc.; The 6-membered heterocyclic group with 2 heteroatoms includes, but is not limited to, piperazinyl, morpholinyl, dithianyl and dioxanyl; the 5-membered heterocyclic group containing 3 heteroatoms includes, but is not limited to, triazolinyl, oxadiazolinyl and thiadiazolinyl; the 6-membered heterocyclic group containing 3 heteroatoms includes, but is not limited to, triazinyl, oxadiazinyl, thiadiazinyl, oxathiazinyl and dioxazinyl; the 5-membered heterocyclic group fused to a C6 aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic group) includes, but is not limited to, dihydroindolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinone, etc.; the 6-membered heterocyclic group fused to a C6 aryl ring (also referred to herein as a 6,6-bicyclic heterocyclic group) includes, but is not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

[0105] The term "heteroaromatic ring" refers to an aromatic monocyclic, bicyclic or polycyclic ring system containing a 5-16-membered structure (preferably 5-14-membered, 5-12-membered, 5-10-membered, 5-8-membered, and more preferably 5-6-membered), wherein 1, 2, 3 or more ring atoms are heteroatoms and the remaining atoms are carbon, the heteroatoms are independently selected from O, N or S, and the number of heteroatoms is preferably 1, 2 or 3. Bicyclic or polycyclic heteroaromatic rings include fused-ring heteroaromatic rings. Examples of heteroaromatic rings include, but are not limited to, furan, thiophene, oxazole, thiazole, isoxazole, oxadiazole, thiadiazole, pyrrole, pyrazole, imidazole, triazole, tetrazole, pyridine, pyrimidine, pyrazine, pyridazine, thiodiazole, triazine, phthalazine, quinoline, isoquinoline, pteridine, purine, indole, isoindole, indazole, benzofuran, benzothiophene, benzopyridine, benzopyrimidine, benzopyrazine, benzimidazole, benzo Phthaloazine, pyrrolo[2,3-b]pyridine, imidazo[1,2-a]pyridine, pyrazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrimidine, imidazo[1,2-b]pyridazine, [1,2,4]triazolo[4,3-b]pyridazine, [1,2,4]triazolo[1,5-a]pyrimidine, [1,2,4]triazolo[1,5-a]pyridine, etc.

[0106] The term "heteroaryl" refers to a substituent derived from the above definition of heteroaromatic ring. Similarly, examples of heteroaryl include, but are not limited to, furanyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiodiazolyl, triazinyl, phthalazinyl, quinolyl, isoquinolyl, pteridinyl, purinyl, indolyl, isoindolyl, indazolyl, benzofuranyl, benzothiophenyl, benzopyridinyl, benzopyrimidinyl, benzo [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridinyl, and the like.

[0107] The term "amido" refers to a -NH-C(O)-alkyl group.

[0108] The term "sulfone group" refers to the functional group of sulfonic acid after losing the hydroxyl group, specifically refers to the -S(O)2- group.

[0109] The term "sulfoxide" refers to a -S(O)- group.

[0110] The present invention also provides a pharmaceutical composition comprising the aforementioned compound or a pharmaceutically acceptable salt thereof as an active ingredient, and at least one pharmaceutically acceptable carrier.

[0111] The "pharmaceutical composition" of the present invention refers to a preparation of one or more compounds of the present invention or their salts and a carrier generally accepted in the art for delivering biologically active compounds to an organism (e.g., human). The purpose of a pharmaceutical composition is to facilitate administration and delivery to an organism.

[0112] The present invention also provides routes of administration of the above-mentioned pharmaceutical composition, including but not limited to oral, rectal, transmucosal, enteral administration, or topical transdermal, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0113] The present invention also provides a use of the above-mentioned compound or pharmaceutical composition in the preparation of a drug for preventing or treating a disease associated with PTPN2 or PTPN1.

[0114] Preferably, the aforementioned medicine is used to prevent or treat tumors.

[0115] More preferably, the aforementioned tumor is selected from recurrent or refractory head and neck squamous cell carcinoma, recurrent or refractory non-small cell lung cancer, advanced clear cell renal cell carcinoma, or a high-microsatellite instability tumor.

[0116] Compared with the prior art, the present invention has the following beneficial effects:

[0117] The azatricyclic compounds developed by the present invention are designed based on target science and rational compound structure, and a series of compounds with novel structures are obtained through group substitution modification; and combined with the evaluation of in vivo and in vitro efficacy experiments, a series of compounds that can significantly inhibit the activity of PTPN2 or PTPN1 are optimized and screened out, which have great clinical application prospects and considerable potential for drug development. DETAILED DESCRIPTION

[0118] The following are specific embodiments of the present invention, which further describe the technical solution of the present invention, but the protection scope of the present invention is not limited to these embodiments. Any changes or equivalent substitutions that do not deviate from the concept of the present invention are included in the protection scope of the present invention.

[0119] In addition, all operations involving raw materials that are easily oxidized or hydrolyzed are carried out under nitrogen protection. Unless otherwise specified, the raw materials used in the present invention are commercially available raw materials and can be used directly without further purification.

[0120] The reaction starting materials and common intermediates involved in the embodiments of the present invention can be purchased commercially or prepared by themselves. The preparation process of the starting materials and common intermediates that need to be prepared by themselves is described in detail as follows:

[0121] The present invention uses the following abbreviations:

[0122] NBS: N-bromosuccinimide; AIBN: azobisisobutyronitrile; CCl4: carbon tetrachloride; TMSCN: trimethylsilyl cyanide; K2CO3: potassium carbonate; MeCN: acetonitrile; CsOAc: cesium acetate; DMSO: dimethyl sulfoxide; NMP: N-methylpyrrolidone; MOMBr: (bromomethyl) methyl ether; Brettphos: dicyclohexyl[3,6-dimethoxy-2',4',6'-triisopropyl[1,1'-biphenyl]-2-yl]phosphine; CyPF- t Bu: (R)-(–)-1-[(S)-2-(dicyclohexylphosphino)ferrocene]ethyl di-tert-butylphosphine; Brettphos-Pd-G3: methanesulfonic acid (2-dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium; Pd2(dba)3: tris(dibenzylideneacetone)dipalladium; tBuXPhos: 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl; Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; B2pin2: bipinacol boronate; BI-DIME: 3-(tert-butyl)-4-(2,6-dimethoxyphenyl)-2,3-dihydrobenzo[d][1,3]oxaphosphole; DCM: dichloromethane; THF: tetrahydrofuran; DMF: N,N-dimethylformamide; Pd(dppf)Cl2: 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride; BBr3: boron tribromide; Cs2CO3: cesium carbonate; K3PO4: potassium phosphate; KOAc: potassium acetate; HPLC: high performance liquid chromatography; LC-MS: HPLC with mass spectrometry detection; TLC: thin layer chromatography; pNPP: disodium p-nitrophenyl phosphate; HEPES: 4-hydroxyethylpiperazineethanesulfonic acid; EDTA: ethylenediaminetetraacetic acid; NaCl: sodium chloride; DTT: dithiothreitol; ddH2O: double distilled water; NaOH: sodium hydroxide; BSA: bovine serum albumin; BH3: borane; CuI: cuprous iodide; KOH: potassium hydroxide; DME: dimethyl sulfate; Pd(OAc)2: palladium acetate.

[0123] In the embodiments of the present invention, a ml*b means that a ml of solvent is used each time and repeated b times; for example, extraction with ethyl acetate (20 mL*3) means that 20 ml of ethyl acetate solvent is used each time and repeated 3 times.

[0124] The experimental instrument involved in the present invention is described in detail as follows:

[0125] name source model Medical low temperature refrigerator Thermo Fisher Scientific (Suzhou) Instrument Co., Ltd. 902-ULTS Low speed centrifuge Anhui Zhongke Zhongjia Scientific Instrument Co., Ltd. SC-3616 Biochemical incubator Shanghai Yiheng Scientific Instrument Co., Ltd. SHP-150 Multifunctional ELISA reader Thermo Tecan SPARK

[0126] The experimental materials involved in the present invention are as follows:

[0127] name source model PTPN2 enzyme Sino Biological 10570-HNCB pNPP meilunbio MB3188 NaOH Sinopharm Chemical Reagent Co., Ltd. 1310-73-2 Hepes Beyotime ST2425 EDTA Beyotime ST066 NaCl Sinopharm Chemical Reagent Co., Ltd. 7647-14-5 DTT Beyotime 060622220817 BSA Solebao H1130 Dimethyl sulfoxide Sinopharm Chemical Reagent Co., Ltd. 67-68-5 Dimethyl sulfoxide Sinopharm Chemical Reagent Co., Ltd. 67-68-5 96 flat plate NEST 0724238L01

[0128] 1. Preparation of Common Intermediate A

[0129]

[0130] Step 1: Synthesis of compound 1,3-dibromo-2-(bromomethyl)-5-fluorobenzene (A-2)

[0131] Compound A-1 (2.94 g, 11.10 mmol) was dissolved in carbon tetrachloride (80 mL), N-bromosuccinimide (2.17 g, 12.21 mmol) and azobisisobutyronitrile (182.00 mg, 1.11 mmol) were added, and the mixture was reacted at 80°C for 7 hours. After TLC monitoring, water (80 mL) was added, and the mixture was extracted with ethyl acetate (50 mL*3). The combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether as eluent) to obtain compound A-2 (3.15 g) as a white solid with a yield of 82.5%.

[0132] 1 H NMR (400MHz, CDCl3) δ7.37(s,1H),7.36(s,1H),4.82(s,2H).

[0133] Step 2: Synthesis of compound 2-(2,6-dibromo-4-fluorophenyl)acetonitrile (A-3)

[0134] Compound A-2 (3.15 g, 9.16 mmol) was dissolved in anhydrous acetonitrile (30 mL), potassium carbonate (2.02 g, 14.6 mmol) was added, the reaction solution was cooled to 0°C, trimethylsilyl cyanide (1.36 g, 13.7 mmol) was added, and the mixture was reacted at 25°C for 18 hours. When the reaction was complete as monitored by TLC, water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL*3). The combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 10:90 as eluent) to obtain compound A-3 (2.56 g) as a white solid with a yield of 96.1%.

[0135] Step 3: Synthesis of compound 2-(2,6-dibromo-4-fluorophenyl)ethan-1-amine (A-4)

[0136] Compound A-3 (2.56 g, 8.80 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL), the reaction solution was cooled to 0 ° C, borane tetrahydrofuran solution (1.0 M, 26 mL) was added dropwise, and the reaction solution was placed at 65 ° C for 1 hour. After TLC monitoring, the reaction solution was cooled to 0 ° C, dilute hydrochloric acid (1.0 M, 15 mL) was added dropwise, and the reaction solution was placed at 65 ° C for 1 hour. After the reaction was completed, the pH value of the aqueous phase was adjusted to about 11 with a 1.0 M sodium hydroxide aqueous solution, water (30 mL) was added, and ethyl acetate (30 mL*3) was extracted. The combined organic phase was washed with a saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (methanol: dichloromethane = 10:90 as eluent) to obtain compound A-4 (2.18 g) as a white solid with a yield of 83.8%.

[0137] MS-ESI calculated value [M+H] + 295.9 / 297.9 / 299 / 9, measured values ​​296.0 / 298.0 / 300.0.

[0138] Step 4: Synthesis of compound 4-bromo-6-fluoroindoline (A-5)

[0139] Compound A-4 (2.18 g, 7.39 mmol) was dissolved in anhydrous dimethyl sulfoxide (30 mL), and cuprous iodide (1.40 g, 7.37 mmol) and cesium acetate (4.25 g, 22.1 mmol) were added. The mixture was reacted at 25 °C for 1 hour under nitrogen protection. After the reaction was complete as monitored by LC-MS, water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL*3). The combined organic phase was washed with a saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 10:90 as eluent) to obtain compound A-5 (1.12 g) as a white solid with a yield of 70.9%.

[0140] MS-ESI calculated value [M+H] + 216.0 / 218.0, measured value 216.0 / 218.0.

[0141] 1 H NMR (400MHz, CDCl3) δ6.52(dd,J=9.0,2.1Hz,1H),6.22(dd,J=9.5,2.1Hz,1H),3.97(brs,1H),3.63(t,J=8.5Hz,2H),2.99(td,J=8.5,1.5Hz,2H).

[0142] Step 5: Synthesis of compound (E)-1-(4-bromo-6-fluoroindoline-1-yl)-3-ethoxyprop-2-en-1-one (A-6): Dissolve compound A-5 (500.00 mg, 2.33 mmol) in anhydrous tetrahydrofuran (20 mL), add pyridine (368.00 mg, 4.66 mmol), cool the reaction solution to -30 ° C, add 3-ethoxyacryloyl chloride (472.00 mg, 3.50 mmol) dropwise, and place the reaction solution at -30 ° C for 0.5 hours. After TLC monitoring showed that the reaction was complete, the reaction solution was quenched with water (20 mL), extracted with ethyl acetate (20 mL*3), the combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 10:90 as eluent) to obtain compound A-6 (700.00 mg) as a white solid with a yield of 96.0%.

[0143] MS-ESI calculated value [M+H] + 314.0 / 316.0, measured value 314.0 / 316.0.

[0144] Step 6: Synthesis of compound 9-bromo-7-fluoro-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (A-7)

[0145] Compound A-6 (700.00 mg, 2.24 mmol) was dissolved in concentrated sulfuric acid (5 mL) and allowed to react at 25°C for 1 hour. After the reaction was complete as monitored by LC-MS, the reaction solution was added dropwise into ice water (20 mL), the aqueous phase was extracted with ethyl acetate (20 mL*3), the combined organic phase was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 35:65 as eluent) to obtain compound A-7 (536.00 mg) as a white solid with a yield of 89.6%.

[0146] MS-ESI calculated value [M+H] + 268.0 / 270.0, measured value 268.0 / 270.0.

[0147] 1 H NMR (400MHz, DMSO-d6) δ7.92(d,J=9.5Hz,1H),7.28(d,J=10.1Hz,1H),6.63(d,J=9.5Hz,1H),4.31-4.40(m,2H),3.22-3.28(m,2H).

[0148] Step 7: Synthesis of compound 7-fluoro-9-hydroxy-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (A-8)

[0149] Compound A-7 (536.00 mg, 2.01 mmol), tris(dibenzylideneacetone)dipalladium (91.60 mg, 0.10 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (170.00 mg, 0.40 mmol) and potassium hydroxide (224.00 mg, 4.00 mmol) were added to a mixed solvent of dioxane (5 mL) and water (5 mL), and reacted at 100° C. for 6 hours under nitrogen protection. After the reaction was complete as monitored by LC-MS, the reaction solution was concentrated, and 1.0 M dilute hydrochloric acid was added dropwise to the residual aqueous solution to adjust the pH of the aqueous phase to acidic. The aqueous phase was extracted with dichloromethane (30 mL*3), and the combined organic phases were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (methanol: dichloromethane = 5:95 as eluent) to obtain compound A-8 (281.00 mg) as a yellow solid with a yield of 68.2%.

[0150] MS-ESI calculated value [M+H] + 206.1, measured value 206.0.

[0151] Step 8: Synthesis of compound 7-fluoro-9-(methoxymethoxy)-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (A-9)

[0152] Sodium hydride (60% wt, 180.00 mg, 4.50 mmol) was suspended in anhydrous tetrahydrofuran (20 mL) and cooled to 0°C. Compound A-8 (615.00 mg, 3.00 mmol) was dissolved in N-methylpyrrolidone (20 mL) and added dropwise to the above suspension of sodium hydride in tetrahydrofuran. The reaction system was heated to room temperature for 30 minutes. The reaction system was then cooled to 0°C, (bromomethyl) methyl ether (413.00 mg, 3.30 mmol) was added dropwise, and the reaction system was heated to room temperature for 13 hours. After the reaction was completed as monitored by TLC, a saturated aqueous solution of ammonium chloride (40 mL) was added, and the mixture was extracted with ethyl acetate (50 mL*3). The combined organic phase was washed with a saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 65:35 as eluent) to obtain compound A-9 (620 mg) as a yellow solid with a yield of 83.0%.

[0153] MS-ESI calculated value [M+H] + 250.1, measured value 250.0.

[0154] Step 9: Synthesis of compound 5,8-dibromo-7-fluoro-9-(methoxymethoxy)-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (A)

[0155] Compound A-9 (620.00 mg, 2.49 mmol) was dissolved in N,N-dimethylformamide (15 mL), N-bromosuccinimide (1.11 g, 6.24 mmol) was added, and the mixture was reacted at 40°C for 1 hour. After the reaction was complete as monitored by LC-MS, water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL*3). The combined organic phase was washed with water (30 mL), washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 65:35 as eluent) to obtain compound A (935.00 mg) as a yellow solid with a yield of 92.6%.

[0156] MS-ESI calculated value [M+H] + 405.9 / 407.9 / 409.9, measured values ​​406.0 / 408.0 / 410.0.

[0157] Example 1: Synthesis of 5-(7-fluoro-9-hydroxy-5-(isopentylamino)-4-oxo-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)isothiazol-3(2H)-one 1,1-dioxide (1)

[0158]

[0159] Step 1: Synthesis of compound 7-fluoro-9-methoxy-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (1-1) The synthesis of compound A-8 was prepared by referring to steps 1 to 7 in "Preparation of common intermediate A".

[0160] Compound A-8 (700.00 mg, 3.41 mmol) was dissolved in acetonitrile (20 mL), dimethyl sulfate (868.00 mg, 6.89 mmol) and potassium carbonate (1.40 g, 10.1 mmol) were added, and the mixture was reacted at 65°C for 2 hours. After the reaction was complete as monitored by TLC, water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL*3). The combined organic phase was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 50:50 as eluent) to obtain compound 1-1 (530.00 mg) as a yellow solid with a yield of 71.0%.

[0161] MS-ESI calculated value [M+H] +220.1, measured value 220.0.

[0162] Step 2: Synthesis of compound 5,8-dibromo-7-fluoro-9-methoxy-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (1-2)

[0163] Compound 1-1 (220.00 g, 1.00 mmol) was dissolved in N,N-dimethylformamide (10 mL), N-bromosuccinimide (356.00 mg, 2.00 mmol) was added, and the mixture was reacted at 50°C for 1 hour. After the reaction was complete as monitored by LC-MS, water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL*3). The combined organic phase was washed with water (30 mL), washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 25:75 as eluent) to obtain compound 1-2 (282.00 mg) as a yellow solid with a yield of 75.0%.

[0164] MS-ESI calculated value [M+H] + 375.9 / 377.9 / 379.9, measured values ​​376.0 / 378.0 / 380.0.

[0165] 1 H NMR (400MHz, DMSO-d6) δ8.37(s,1H),4.30-4.44(m,2H),4.11(s,3H),3.57-3.76(m,2H).

[0166] Step 3: Synthesis of compound 8-bromo-7-fluoro-5-(isopentylamino)-9-methoxy-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (1-3)

[0167] Compound 1-2 (680.00 mg, 1.81 mmol), isopentylamine (237.00 mg, 2.72 mmol), palladium acetate (82.40 mg, 0.36 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (205.30 mg, 0.35 mmol) and cesium carbonate (1.77 g, 5.43 mmol) were added to anhydrous dioxane (60 mL), and the mixture was placed in a sealed tube at 100° C. for 17 hours under nitrogen protection. After the reaction was complete as monitored by LC-MS, the reaction solution was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 35:65 as eluent) to obtain compound 1-3 (225.00 mg) as a yellow solid with a yield of 32.5%.

[0168] MS-ESI calculated value [M+H] +383.1 / 385.1, measured value 383.0 / 385.0.

[0169] 1 H NMR (400MHz, DMSO-d6) δ6.29 (s, 1H), 5.90 (t, J = 5.7Hz, 1H), 4.31-4.41 (m, 2H), 3.95 (s, 3H), 3.51 -3.60(m,2H),3.15(q,J=6.7Hz,2H),1.57-1.73(m,1H),1.46-1.55(m,2H),0.92(d,J=6.6Hz,6H).

[0170] Step 4: Synthesis of compound 7-fluoro-5-(isopentylamino)-9-methoxy-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (1-4)

[0171] Compound 1-3 (225.00 mg, 0.59 mmol), pinacol borate (457.00 mg, 1.80 mmol), palladium acetate (13.4 mg, 0.06 mmol), 3-(tert-butyl)-4-(2,6-dimethoxyphenyl)-2,3-dihydrobenzo[d][1,3]oxaphosphole (40.00 mg, 0.12 mmol) and potassium acetate (176.00 mg, 1.80 mmol) were added to anhydrous dioxane (20 mL) and reacted at 110° C. for 2 hours under nitrogen protection. After the reaction was complete as monitored by LC-MS, the reaction solution was filtered, concentrated under reduced pressure, and separated by preparative TLC (thin layer chromatography) plate (ethyl acetate: petroleum ether = 65:35 as eluent) to obtain compound 1-4 (216.00 mg) as a white solid with a yield of 85.1%.

[0172] MS-ESI calculated value [M+H] + 431.3, measured value 431.0.

[0173] Step 5: Synthesis of compound 2-(tert-butyl)-5-(7-fluoro-5-(isopentylamino)-9-methoxy-4-oxo-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)isothiazol-3(2H)-one 1,1-dioxide (1-6)

[0174] Compound 1-4 (216.00 mg, 0.50 mmol), compound 1-5 (112.00 mg, 0.50 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium (32.3 mg, 0.05 mmol), and potassium phosphate (318.00 mg, 1.50 mmol) were added to a mixed solution of dioxane (10 mL) and water (2 mL), and reacted at 100° C. for 3 hours under nitrogen protection. After the reaction was complete as monitored by LC-MS, the reaction solution was filtered, concentrated under reduced pressure, and separated by preparative TLC (thin layer chromatography) plate (ethyl acetate: petroleum ether = 50:50 as eluent) to obtain compound 1-6 (112.00 mg) as a yellow solid with a yield of 45.6%.

[0175] MS-ESI calculated value [M+H] + 492.2, measured value 492.0.

[0176] Step 6: Synthesis of compound 5-(7-fluoro-9-hydroxy-5-(isopentylamino)-4-oxo-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)isothiazol-3(2H)-one 1,1-dioxide formate (1)

[0177] Compound 1-6 (100.00 mg, 0.20 mmol) was dissolved in anhydrous dichloromethane (5 mL), the reaction solution was cooled to -78 ° C, and a dichloromethane solution of boron tribromide (2.0 M, 3 mL) was added dropwise under nitrogen protection, and the mixture was allowed to react at 25 ° C for 4 hours. After the reaction was completed as monitored by LC-MS, the reaction solution was cooled to -78 ° C, methanol (5 mL) was added dropwise to quench the reaction, and the mixture was concentrated under reduced pressure and purified by HPLC to obtain compound 1 (5.80 mg) formate as an orange-yellow solid with a yield of 6.87%.

[0178] MS-ESI calculated value [M+H] + 422.1, measured value 422.0.

[0179] 1 H NMR(400MHz,DMSO-d6)δ9.87(brs,1H),7.21(s,1H),7.09(s,1H),6.96(s,1H),6.55(s,1H),6.29(s,1H),5.67(brs,1H),4.2 3-4.42(m,2H),3.24(t,J=8.2Hz,2H),3.12(t,J=7.5Hz,2H),1.58-1.73(m,1H),1.50(q,J=7.1Hz,2H),0.92(d,J=6.6Hz,6H).

[0180] Example 2: Synthesis of 5-(7-fluoro-9-hydroxy-5-(isopentylamino)-4-oxo-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)-1,2,5-thiadiazolidin-3-one-1,1-dioxide (2)

[0181]

[0182] Step 1: Synthesis of compound 8-bromo-7-fluoro-5-(isopentylamino)-9-(methoxymethoxy)-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (2-1)

[0183] The synthesis of common intermediate A was prepared by referring to “Preparation of common intermediate A”.

[0184] Compound A (935.00 mg, 2.31 mmol), isopentylamine (301.00 mg, 3.46 mmol), palladium acetate (105.00 mg, 0.46 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (266.00 mg, 0.46 mmol) and cesium carbonate (2.26 g, 6.93 mmol) were dissolved in anhydrous dioxane (70 mL), and reacted at 100° C. in a sealed tube under nitrogen protection for 17 hours. After LC-MS monitoring of the reaction was complete, the reaction solution was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 50:50 as eluent) to obtain compound 2-1 (315.00 mg) as a yellow solid with a yield of 33.1%.

[0185] MS-ESI calculated value [M+H] + 413.1 / 415.1, measured value 413.0 / 415.0.

[0186] 1 H NMR (400MHz, DMSO-d6) δ6.30(s,1H),5.96(t,J=5.7Hz,1H),5.20(s,2H),4.30-4.43(m,2H),3.50(s,3H),3.45(t ,J=7.8Hz,2H),3.15(q,J=6.6Hz,2H),1.66(dt,J=13.2,6.7Hz,1H),1.50(q,J=6.9Hz,2H),0.92(d,J=6.6Hz,6H).

[0187] Step 2: Synthesis of compound tert-butyl (7-fluoro-5-(isopentylamino)-9-(methoxymethoxy)-4-oxo-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl) glycine ester (2-2)

[0188] Compound 2-1 (100.00 mg, 0.24 mmol), glycine tert-butyl ester (47.00 mg, 0.36 mmol), tris(dibenzylideneacetone)dipalladium (44.00 mg, 0.05 mmol), dicyclohexyl[3,6-dimethoxy-2',4',6'-triisopropyl[1,1'-biphenyl]-2-yl]phosphine (26.00 mg, 0.05 mmol) and cesium carbonate (235.00 mg, 0.72 mmol) were dissolved in toluene (5 mL) and reacted at 90° C. for 16 hours under nitrogen protection. After the reaction was complete as monitored by LC-MS, the reaction solution was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 50:50 as eluent) to obtain compound 2-2 (61.00 mg) as a yellow solid with a yield of 55.0%.

[0189] MS-ESI calculated value [M+H] + 464.3, measured value 464.0.

[0190] Step 3: Synthesis of compound 5-(7-fluoro-5-(isopentylamino)-9-(methoxymethoxy)-4-oxo-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)-1,2,5-thiadiazolin-3-one 1,1-dioxide (2-3)

[0191] Compound 2-2 (61.00 mg, 0.13 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), pyridine (75.40 mg, 0.65 mmol) was added, the reaction solution was cooled to 0 ° C, chlorosulfonylamide (51.40 mg, 0.65 mmol) was added dropwise, and the reaction solution was heated to room temperature and stirred for 1 hour. After LC-MS monitoring of the reaction was complete, the reaction solution was cooled to 0 ° C, and a methanol solution of sodium methoxide (5.0 M, 0.3 mL) was added dropwise, and the reaction solution was heated to room temperature and stirred for 30 minutes. After LC-MS monitoring of the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain a crude compound 2-3, which was directly used for the next step without further purification.

[0192] MS-ESI calculated value [M+H] + 469.2, measured value 469.0.

[0193] Step 4: Synthesis of 5-(7-fluoro-9-hydroxy-5-(isopentylamino)-4-oxo-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)-1,2,5-thiadiazolidin-3-one-1,1-dioxide (2)

[0194] The crude product of the above compound 2-3 was dissolved in ethyl acetate (2 mL), and a solution of hydrochloric acid in ethyl acetate (4.0 M, 5 mL) was added, and the reaction solution was stirred at room temperature for 30 minutes. After the reaction was completed as monitored by LC-MS, the reaction solution was concentrated under reduced pressure and purified by HPLC to obtain compound 2 (5.10 mg) as a white solid, with a two-step yield of 9.3%.

[0195] MS-ESI calculated value [M+H] + 425.1, measured value 425.0.

[0196] 1 H NMR (400MHz, DMSO-d6) δ7.20(brs,2H),6.26(s,1H),5.56(t,J=5.7Hz,1H),4.33(t,J=8.1Hz,2H),3.96(s,2H),3.20 (t,J=8.0Hz,2H),3.11(q,J=6.6Hz,2H),1.65(dq,J=13.2,6.5Hz,1H),1.50(q,J=7.1Hz,2H),0.92(d,J=6.6Hz,6H).

[0197] Example 3: Synthesis of 5-(5-((2-cyclobutylethyl)amino)-7-fluoro-9-hydroxy-4-oxo-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)-1,2,5-thiadiazolin-3-one 1,1-dioxide (3)

[0198]

[0199] Step 1: Synthesis of compound 8-bromo-5-((2-cyclobutylethyl)amino)-7-fluoro-9-(methoxymethoxy)-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (3-1)

[0200] The synthesis of common intermediate A was prepared by referring to “Preparation of common intermediate A”.

[0201] Compound A (400.00 mg, 0.98 mmol), 2-cyclobutylethylamine (146.00 mg, 1.47 mmol), palladium acetate (45.40 mg, 0.20 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (116.00 mg, 0.20 mmol) and cesium carbonate (958.00 mg, 2.94 mmol) were dissolved in anhydrous dioxane (20 mL), and reacted at 100° C. in a sealed tube under nitrogen protection for 17 hours. After the reaction was complete as monitored by LC-MS, the reaction solution was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 50:50 as eluent) to obtain compound 3-1 (120.00 mg) as a yellow solid with a yield of 28.8%.

[0202] MS-ESI calculated value [M+H] + 425.1 / 427.1, measured value 425.0 / 427.0.

[0203] Step 2: Synthesis of compound (5-((2-cyclobutylethyl)amino)-7-fluoro-9-(methoxymethoxy)-4-oxo-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)glycine tert-butyl ester (3-2)

[0204] Compound 3-1 (120.00 mg, 0.28 mmol), glycine tert-butyl ester (55.00 mg, 0.42 mmol), tris(dibenzylideneacetone)dipalladium (55.00 mg, 0.06 mmol), dicyclohexyl[3,6-dimethoxy-2',4',6'-triisopropyl[1,1'-biphenyl]-2-yl]phosphine (32.22 mg, 0.06 mmol) and cesium carbonate (274.00 mg, 0.84 mmol) were dissolved in toluene (8 mL) and reacted at 90° C. for 16 hours under nitrogen protection. After the reaction was complete as monitored by LC-MS, the reaction solution was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 50:50 as eluent) to obtain compound 3-2 (90.00 mg) as a yellow solid with a yield of 67.7%.

[0205] MS-ESI calculated value [M+H] + 476.3, measured value 476.0.

[0206] Step 3: Synthesis of 5-(5-((2-cyclobutylethyl)amino)-7-fluoro-9-(methoxymethoxy)-4-oxo-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)-1,2,5-thiadiazolin-3-one 1,1-dioxide (3-3)

[0207] Compound 3-2 (90.00 mg, 0.19 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), pyridine (75.14 mg, 0.95 mmol) was added, the reaction solution was cooled to 0°C, chlorosulfonylamide (109.75 mg, 0.95 mmol) was added dropwise, and the reaction solution was heated to room temperature and stirred for 1 hour. After LC-MS monitoring showed that the reaction was complete, the reaction solution was cooled to 0°C, and a methanol solution of sodium methoxide (5.0 M, 0.3 mL) was added dropwise, and the reaction solution was heated to room temperature and stirred for 30 minutes. After LC-MS monitoring showed that the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain a crude compound 3-3, which was directly used for the next step without further purification.

[0208] MS-ESI calculated value [M+H] + 481.2, measured value 481.0.

[0209] Step 4: Synthesis of compound 5-(5-((2-cyclobutylethyl)amino)-7-fluoro-9-hydroxy-4-oxo-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)-1,2,5-thiadiazolin-3-one 1,1-dioxide (3)

[0210] The crude product of the above compound 3-3 was dissolved in ethyl acetate (2 mL), and a solution of hydrochloric acid in ethyl acetate (4.0 M, 5 mL) was added, and the reaction solution was stirred at room temperature for 30 minutes. After the reaction was completed as monitored by LC-MS, the reaction solution was concentrated under reduced pressure and purified by HPLC to obtain compound 3 (7.70 mg) as a white solid, with a two-step yield of 9.3%.

[0211] MS-ESI calculated value [M+H] + 437.1, measured value 437.0.

[0212] 1 H NMR (400MHz, DMSO-d6) δ9.10(s,1H),6.24(s,1H),5.56(t,J=5.8Hz,1H),4.32(q,J=8.1Hz,2H),3.97(s,2H),3.20( t,J=8.1Hz,2H),3.02(q,J=6.5Hz,2H),2.27-2.39(m,1H),1.99-2.09(m,2H),1.69-1.90(m,2H),1.20-1.75(m,4H).

[0213] Example 4: Synthesis of 5-(7-fluoro-9-hydroxy-5-(isopentyloxy)-4-oxo-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)-1,2,5-thiadiazoline-3-one 1,1-dioxide (6)

[0214]

[0215] Step 1: Synthesis of compound 7-fluoro-5-(isopentyloxy)-9-(methoxymethoxy)-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (6-1)

[0216] The synthesis of common intermediate A was prepared by referring to “Preparation of common intermediate A”.

[0217] Compound A (644.00 mg, 1.59 mmol), isoamyl alcohol (280.00 mg, 3.18 mmol), tris(dibenzylideneacetone)dipalladium (147.00 mg, 0.16 mmol), (R)-(–)-1-[(S)-2-(dicyclohexylphosphino)ferrocene]ethyldi-tert-butylphosphine (178.00 mg, 0.32 mmol) and cesium carbonate (1.56 g, 4.80 mmol) were dissolved in anhydrous dioxane (30 mL), and reacted at 130° C. in a sealed tube under nitrogen protection for 18 hours. After the reaction was complete as monitored by LC-MS, the reaction solution was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 60:40 as eluent) to obtain compound 6-1 (201.00 mg) with a yield of 37.4% as a yellow solid.

[0218] MS-ESI calculated value [M+H] + 336.2, measured value 336.0.

[0219] Step 2: Synthesis of compound 8-bromo-7-fluoro-5-(isopentyloxy)-9-(methoxymethoxy)-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (6-2)

[0220] Compound 6-1 (201.00 mg, 0.60 mmol) was dissolved in N,N-dimethylformamide (7 mL), N-bromosuccinimide (214.00 mg, 1.20 mmol) was added, and the mixture was allowed to react at room temperature for 1 hour. After the reaction was complete as monitored by LC-MS, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL*3). The combined organic phase was washed with water (20 mL), washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 65:35 as eluent) to obtain compound 6-2 (243.00 mg) as a yellow solid with a yield of 98.0%.

[0221] MS-ESI calculated value [M+H] + 414.1 / 416.1, measured value 414.0 / 416.0.

[0222] 1 H NMR (400MHz, Methanol-d4) δ7.15 (s, 1H), 5.27 (s, 2H), 4.36-4.51 (m, 2H), 4.10 (t, J = 6.6Hz, 2H), 3.5 7-3.63(m,2H),3.56(s,3H),1.88(dt,J=13.2,6.8Hz,1H),1.69-1.80(m,2H),0.99(d,J=6.6Hz,6H).

[0223] Step 3: Synthesis of compound (7-fluoro-5-(isopentyloxy)-9-(methoxymethoxy)-4-oxo-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)glycine tert-butyl ester (6-3)

[0224] Compound 6-2 (80.00 mg, 0.19 mmol), glycine tert-butyl ester (50.00 mg, 0.38 mmol), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (35.00 mg, 0.04 mmol), dicyclohexyl [3,6-dimethoxy-2',4',6'-triisopropyl [1,1'-biphenyl] -2-yl] phosphine (20.00 mg, 0.04 mmol) and cesium carbonate (188.00 mg, 0.58 mmol) were dissolved in anhydrous dioxane (10 mL) and reacted at 100 ° C under nitrogen protection for 16 hours. After the reaction was completed as monitored by LC-MS, the reaction solution was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 65:35 as eluent) to obtain compound 6-3 (85.00 mg) as a white solid with a yield of 96.6%.

[0225] MS-ESI calculated value [M+H] + 465.2, measured value 465.0.

[0226] Step 4: Synthesis of compound 5-(7-fluoro-5-(isopentyloxy)-9-(methoxymethoxy)-4-oxo-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)-1,2,5-thiadiazolin-3-one 1,1-dioxide (6-4)

[0227] Compound 6-3 (85.00 mg, 0.18 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), pyridine (50.00 mg, 0.63 mmol) was added, the reaction solution was cooled to 0°C, chlorosulfonylamide (73.00 mg, 0.63 mmol) was added dropwise, and the reaction solution was warmed to room temperature and stirred for 1 hour. After LC-MS monitoring of the reaction was complete, the reaction solution was cooled to 0°C, and a methanol solution of sodium methoxide (5.0 M, 0.4 mL) was added dropwise, and the reaction solution was warmed to room temperature and stirred for 30 minutes. After LC-MS monitoring of the reaction was complete, the reaction solution was concentrated under reduced pressure and purified on a silica gel plate (methanol: dichloromethane = 5:95 as the eluent) to obtain compound 6-4 (34.00 mg) as a white solid with a yield of 40.3%.

[0228] MS-ESI calculated value [M+H] + 470.1, measured value 470.0.

[0229] Step 5: Synthesis of compound 5-(7-fluoro-9-hydroxy-5-(isopentyloxy)-4-oxo-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)-1,2,5-thiadiazolin-3-one 1,1-dioxide (6)

[0230] Compound 6-4 (34.00 mg, 0.07 mmol) was dissolved in ethyl acetate (2 mL), and a solution of hydrochloric acid in ethyl acetate (4.0 M, 5 mL) was added, and the reaction solution was stirred at room temperature for 30 minutes. After the reaction was completed as monitored by LC-MS, the reaction solution was concentrated under reduced pressure and purified on a silica gel plate (methanol: dichloromethane = 20:80 as the eluent) to obtain compound 6 (12.10 mg) as a white solid with a yield of 40.3%.

[0231] MS-ESI calculated value [M+H] + 426.1, measured value 426.0.

[0232] 1 H NMR(400MHz, DMSO-d6)δ7.01(s,1H),4.27(dd,J=11.3,5.2Hz,2H),3.99(t,J=6.8Hz,2H),3.96 (s,2H),3.18(t,J=8.2Hz,2H),1.73-1.83(m,1H),1.63(q,J=6.6Hz,2H),0.94(d,J=6.6Hz,6H).

[0233] Example 5: Synthesis of 5-(5-(2-cyclopropylethoxy)-7-fluoro-9-hydroxy-4-oxo-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)-1,2,5-thiadiazoline-3-one 1,1-dioxide (7)

[0234]

[0235] Step 1: Synthesis of compound 5-(2-cyclopropylethoxy)-7-fluoro-9-(methoxymethoxy)-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (7-1)

[0236] The synthesis of common intermediate A was prepared by referring to “Preparation of common intermediate A”.

[0237] Compound A (400.00 mg, 0.98 mmol), 2-cyclopropylethanol (169.80 mg, 1.97 mmol), tris(dibenzylideneacetone)dipalladium (90.40 mg, 0.098 mmol), (R)-(–)-1-[(S)-2-(dicyclohexylphosphino)ferrocene]ethyldi-tert-butylphosphine (109.60 mg, 0.19 mmol) and cesium carbonate (0.96 g, 2.96 mmol) were dissolved in anhydrous dioxane (15 mL), and reacted at 125° C. in a sealed tube under nitrogen protection for 18 hours. After the reaction was complete as monitored by LC-MS, the reaction solution was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 60:40 as eluent) to obtain compound 7-1 (200.00 mg) as a yellow solid with a yield of 61.3%.

[0238] MS-ESI calculated value [M+H] + 334.2, measured value 334.0.

[0239] Step 2: Synthesis of 8-bromo-5-(2-cyclopropylethoxy)-7-fluoro-9-(methoxymethoxy)-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (7-2)

[0240] Compound 7-1 (200.00 mg, 0.60 mmol) was dissolved in N,N-dimethylformamide (5 mL), N-bromosuccinimide (213.00 mg, 1.20 mmol) was added, and the mixture was allowed to react at room temperature for 1 hour. After the reaction was complete as monitored by LC-MS, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL*3). The combined organic phase was washed with water (20 mL), washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 65:35 as eluent) to obtain compound 7-2 (130.00 mg) as a yellow solid with a yield of 52.8%.

[0241] MS-ESI calculated value [M+H] + 412.1 / 414.1, measured value 412.0 / 414.0.

[0242] Step 3: Synthesis of compound (5-(2-cyclopropylethoxy)-7-fluoro-9-(methoxymethoxy)-4-oxo-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)glycine tert-butyl ester (7-3)

[0243] Compound 7-2 (130.00 mg, 0.31 mmol), glycine tert-butyl ester (82.87 mg, 0.63 mmol), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (57.37 mg, 0.06 mmol), dicyclohexyl [3,6-dimethoxy-2',4',6'-triisopropyl [1,1'-biphenyl] -2-yl] phosphine (33.97 mg, 0.06 mmol) and cesium carbonate (309.00 mg, 0.94 mmol) were dissolved in anhydrous dioxane (3 mL) and reacted at 100 ° C under nitrogen protection for 16 hours. After the reaction was completed as monitored by LC-MS, the reaction solution was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 65:35 as eluent) to obtain compound 7-3 (120.00 mg) as a white solid with a yield of 82.2%.

[0244] MS-ESI calculated value [M+H] + 463.2, measured value 463.0.

[0245] Step 4: Synthesis of compound 5-(5-(2-cyclopropylethoxy)-7-fluoro-9-(methoxymethoxy)-4-oxo-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)-1,2,5-thiadiazolin-3-one 1,1-dioxide (7-4)

[0246] Compound 7-3 (120.00 mg, 0.26 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), pyridine (61.00 mg, 0.78 mmol) was added, the reaction solution was cooled to 0 ° C, chlorosulfonylamide (90.00 mg, 0.78 mmol) was added dropwise, and the reaction solution was warmed to room temperature and stirred for 1 hour. After LC-MS monitoring of the reaction was complete, the reaction solution was cooled to 0 ° C, and a methanol solution of sodium methoxide (5.0 M, 0.5 mL) was added dropwise, and the reaction solution was warmed to room temperature and stirred for 30 minutes. After LC-MS monitoring of the reaction was complete, the reaction solution was concentrated under reduced pressure and purified on a silica gel plate (methanol: dichloromethane = 5:95 as the eluent) to obtain compound 7-4 (42.00 mg) as a white solid with a yield of 35.0%.

[0247] MS-ESI calculated value [M+H] + 468.1, measured value 468.0.

[0248] Step 5: Synthesis of compound 5-(5-(2-cyclopropylethoxy)-7-fluoro-9-hydroxy-4-oxo-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)-1,2,5-thiadiazolin-3-one 1,1-dioxide (7)

[0249] Compound 7-4 (42.00 mg, 0.08 mmol) was dissolved in ethyl acetate (2 mL), and a solution of hydrochloric acid in ethyl acetate (4.0 M, 3 mL) was added, and the reaction solution was stirred at room temperature for 30 minutes. After the reaction was complete as monitored by LC-MS, the reaction solution was concentrated under reduced pressure and purified on a silica gel plate (methanol: dichloromethane = 20:100 as the eluent) to obtain compound 7 (12.00 mg) as a white solid with a yield of 32.4%.

[0250] MS-ESI calculated value [M+H] + 424.1, measured value 424.0.

[0251] 1 H NMR (400MHz, DMSO-d6) δ7.50(s,2H),7.01(s,1H),4.30(dd,J=9.0,7.4Hz,2H),4.03(t,J=6.6Hz,2H),3.96(s ,2H),3.20(t,J=8.4Hz,2H),1.65(q,J=6.7Hz,2H),0.77-0.91(m,1H),0.35-0.51(m,2H),0.09-0.21(m,2H).

[0252] Example 6: Synthesis of 5-(5-(2-cyclopentylethoxy)-7-fluoro-9-hydroxy-4-oxo-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)-1,2,5-thiadiazolin-3-one 1,1-dioxide (8)

[0253]

[0254] Step 1: Synthesis of compound 8-bromo-5-(2-cyclopentylethoxy)-7-fluoro-9-(methoxymethoxy)-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (8-1)

[0255] The synthesis of common intermediate A was prepared by referring to “Preparation of common intermediate A”.

[0256] Compound A (400.00 mg, 0.98 mmol), 2-cyclopentaneethanol (224.00 mg, 1.96 mmol), tris(dibenzylideneacetone)dipalladium (92.00 mg, 0.10 mmol), (R)-(–)-1-[(S)-2-(dicyclohexylphosphino)ferrocene]ethyldi-tert-butylphosphine (111.00 mg, 0.20 mmol) and cesium carbonate (9.58 g, 2.94 mmol) were dissolved in anhydrous dioxane (20 mL), and reacted at 130° C. in a sealed tube under nitrogen protection for 18 hours. After the reaction was complete as monitored by LC-MS, the reaction solution was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 60:40 as eluent) to obtain compound 8-1 (140.00 mg) as a yellow solid with a yield of 32.3%.

[0257] MS-ESI calculated value [M+H] + 440.1 / 442.1, measured value 440.0 / 442.0.

[0258] Step 2: Synthesis of compound (5-(2-cyclopentylethoxy)-7-fluoro-9-(methoxymethoxy)-4-oxo-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)glycine tert-butyl ester (8-2)

[0259] Compound 8-1 (140.00 mg, 0.32 mmol), glycine tert-butyl ester (50.00 mg, 0.64 mmol), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (35.00 mg, 0.06 mmol), dicyclohexyl [3,6-dimethoxy-2',4',6'-triisopropyl [1,1'-biphenyl] -2-yl] phosphine (20.00 mg, 0.06 mmol) and cesium carbonate (188.00 mg, 0.96 mmol) were dissolved in anhydrous dioxane (15 mL) and reacted at 100 ° C under nitrogen protection for 16 hours. After the reaction was completed as monitored by LC-MS, the reaction solution was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 65:35 as eluent) to obtain compound 8-2 (87.00 mg) as a white solid with a yield of 55.8%.

[0260] MS-ESI calculated value [M+H] + 491.2, measured value 491.0.

[0261] Step 3: Synthesis of compound 5-(5-(2-cyclopentylethoxy)-7-fluoro-9-(methoxymethoxy)-4-oxo-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)-1,2,5-thiadiazolin-3-one 1,1-dioxide (8-3)

[0262] Compound 8-2 (87.00 mg, 0.18 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), pyridine (50.00 mg, 0.63 mmol) was added, the reaction solution was cooled to 0°C, chlorosulfonylamide (73.00 mg, 0.63 mmol) was added dropwise, and the reaction solution was warmed to room temperature and stirred for 1 hour. After LC-MS monitoring showed that the reaction was complete, the reaction solution was cooled to 0°C, and a methanol solution of sodium methoxide (5.0 M, 0.4 mL) was added dropwise, and the reaction solution was warmed to room temperature and stirred for 30 minutes. After LC-MS monitoring showed that the reaction was complete, the reaction solution was concentrated under reduced pressure and purified on a silica gel plate (methanol: dichloromethane = 5:95 as the eluent) to obtain compound 8-3 (50.00 mg) as a white solid with a yield of 56.1%.

[0263] MS-ESI calculated value [M+H] + 496.2, measured value 496.0.

[0264] Step 4: Synthesis of compound 5-(5-(2-cyclopentylethoxy)-7-fluoro-9-hydroxy-4-oxo-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)-1,2,5-thiadiazolin-3-one 1,1-dioxide (8)

[0265] Compound 8-3 (50.00 mg, 0.10 mmol) was dissolved in ethyl acetate (2 mL), and a solution of hydrochloric acid in ethyl acetate (4.0 M, 5 mL) was added, and the reaction solution was stirred at room temperature for 30 minutes. After the reaction was completed as monitored by LC-MS, the reaction solution was concentrated under reduced pressure, and compound 8 (4.0 mg) was obtained as a white solid by high-efficiency preparative liquid phase, with a yield of 8.9%.

[0266] MS-ESI calculated value [M+H] + 452.1, measured value 452.0.

[0267] 1 H NMR (400MHz, DMSO-d6) δ7.51(s,2H),7.01(s,1H),4.24-4.34(m,2H),4.00(t,J=6.7Hz,2H),3.96(s,2H),3.21(t,J=8.2Hz,2H ),1.94(h,J=7.7Hz,1H),1.79(dq,J=17.6,6.9Hz,4H),1.60(qd,J=9.3,7.9,2.9Hz,2H),1.42-1.53(m,2H),1.09-1.22(m,2H).

[0268] Example 7: Synthesis of 5-(7-fluoro-9-hydroxy-4-oxo-5-(4,4,4-trifluorobutoxy)-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)-1,2,5-thiadiazoline-3-one 1,1-dioxide (21)

[0269]

[0270] Step 1: Synthesis of compound 7-fluoro-9-(methoxymethoxy)-5-(4,4,4-trifluorobutoxy)-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (21-1)

[0271] The synthesis of common intermediate A was prepared by referring to “Preparation of common intermediate A”.

[0272] Compound A (1.00 g, 2.46 mmol), 4,4,4-trifluorobutanol (629.40 mg, 4.91 mmol), tris(dibenzylideneacetone)dipalladium (112.49 mg, 0.12 mmol), (R)-(–)-1-[(S)-2-(dicyclohexylphosphino)ferrocene]ethyldi-tert-butylphosphine (136.24 mg, 0.25 mmol) and cesium carbonate (1.60 g, 4.91 mmol) were dissolved in anhydrous dioxane (10 mL), and reacted at 120° C. in a sealed tube under nitrogen protection for 16 hours. After the reaction was complete as monitored by LC-MS, the reaction solution was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 50:50 as eluent) to obtain compound 21-1 (400.00 mg, yield 43.5%).

[0273] MS-ESI calculated value [M+H] + 376.1, measured value 376.0.

[0274] Step 2: Synthesis of compound 8-bromo-7-fluoro-9-(methoxymethoxy)-5-(4,4,4-trifluorobutoxy)-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (21-2)

[0275] Compound 21-1 (400.00 mg, 1.07 mmol) was dissolved in N,N-dimethylformamide (4 mL), N-bromosuccinimide (284.53 mg, 1.60 mmol) was added, and the mixture was reacted at 80°C for 1 hour. After the reaction was complete as monitored by LC-MS, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL*3). The combined organic phase was washed with water (20 mL), washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 50:50 as eluent) to obtain compound 21-2 (170.00 mg, yield 35.1%).

[0276] MS-ESI calculated value [M+H] + 454.0 / 456.0, measured value 454.0 / 456.0.

[0277] Step 3: Synthesis of compound (7-fluoro-9-(methoxymethoxy)-4-oxo-5-(4,4,4-trifluorobutoxy)-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)glycine tert-butyl ester (21-3)

[0278] Compound 21-2 (170.00 mg, 0.37 mmol), glycine tert-butyl ester (58.91 mg, 0.45 mmol), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (33.93 mg, 0.04 mmol), dicyclohexyl [3,6-dimethoxy-2',4',6'-triisopropyl [1,1'-biphenyl] -2-yl] phosphine (20.09 mg, 0.04 mmol) and cesium carbonate (243.89 mg, 0.75 mmol) were dissolved in anhydrous dioxane (10 mL) and reacted at 100 ° C under nitrogen protection for 16 hours. After the reaction was completed as monitored by LC-MS, the reaction solution was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 70:30 as eluent) to obtain compound 21-3 (100.00 mg, yield 53.2%).

[0279] MS-ESI calculated value [M+H] + 505.2, measured value 505.0.

[0280] Step 4: Synthesis of compound 5-(7-fluoro-9-(methoxymethoxy)-4-oxo-5-(4,4,4-trifluorobutoxy)-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)-1,2,5-thiadiazolin-3-one 1,1-dioxide (21-4)

[0281] Compound 21-3 (100.00 mg, 0.20 mmol) was dissolved in anhydrous tetrahydrofuran (3 mL), pyridine (47.04 mg, 0.59 mmol) was added, the reaction solution was cooled to 0°C, chlorosulfonylamide (68.70 mg, 0.59 mmol) was added dropwise, and the reaction solution was heated to room temperature and stirred for 1 hour. After LC-MS monitoring of the reaction was complete, the reaction solution was cooled to 0°C, and a methanol solution of sodium methoxide (5.0 M, 0.33 mL) was added dropwise, and the reaction solution was heated to room temperature and stirred for 30 minutes. After LC-MS monitoring of the reaction was complete, the reaction solution was concentrated under reduced pressure and purified on a silica gel plate (methanol: dichloromethane = 1:4 as the eluent) to obtain compound 21-4 (80.00 mg, yield 80.0%).

[0282] MS-ESI calculated value [M+H] + 510.1, measured value 510.0.

[0283] Step 5: Synthesis of compound 5-(7-fluoro-9-hydroxy-4-oxo-5-(4,4,4-trifluorobutoxy)-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)-1,2,5-thiadiazolin-3-one 1,1-dioxide (21)

[0284] Compound 21-4 (80.00 mg, 0.16 mmol) was dissolved in ethyl acetate (2 mL), and a solution of hydrochloric acid in ethyl acetate (4.0 M, 2 mL) was added, and the reaction solution was stirred at room temperature for 1 hour. After the reaction was complete as monitored by LC-MS, the reaction solution was concentrated under reduced pressure and purified to obtain compound 7 (40.00 mg, yield 54.7%).

[0285] MS-ESI calculated value [M+H] + 466.1, measured value 466.0.

[0286] 1 H NMR (400MHz, DMSO-d6) δ7.30 (s, 2H), 7.05 (s, 1H), 4.33-4.26 (m, 2H), 4.07 (t, J = 6. 4Hz,2H),3.97(s,2H),3.21(t,J=8.4Hz,2H),2.47-2.38(m,2H),2.01-1.92(m,2H).

[0287] Example 8: Synthesis of 5-(5-((2-cyclobutylethyl)amino)-7-fluoro-9-hydroxy-4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)-1,2,5-thiadiazol-3-one-1,1-dioxide (22)

[0288]

[0289] Compound 3 (150 mg, 0.34 mmol) was added to a 100 mL hydrogenation reactor, and then 10 mL of ethanol was added to dissolve it. Then 10% Pd(OH)2 / C (10 mg) was added, and two drops of ammonia water were added. The hydrogen was replaced three times, and the mixture was stirred at 80°C for 12 h in a 2.0 MPa hydrogen atmosphere. LC-MS monitoring showed that the target product accounted for 25%. After cooling, Pd(OH)2 / C was filtered out, and the ethanol was concentrated under reduced pressure. The mixture was prepared and purified by HPLC and freeze-dried to obtain compound 22 (0.4 mg, yield 0.3%).

[0290] MS-ESI calculated value [M+H] + 439.1, measured value 439.0.

[0291] Example 9: Synthesis of 5-(7-fluoro-9-hydroxy-4-oxo-5-(4,4,4-trifluorobutyryl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)-1,2,5-thiadiazole-3-one-1,1-dioxide (23)

[0292]

[0293] Compound 21 (25 mg, 0.054 mmol) was added to a 100 mL hydrogenation reactor, and then 5 mL of ethanol was added to dissolve it. Then 10% Pd(OH)2 / C (2 mg) was added, and a drop of ammonia water was added. The hydrogen was replaced three times, and the mixture was stirred at 80°C for two days under a 2.0 MPa hydrogen atmosphere. LCMS monitoring showed that the target product accounted for 53%. After cooling, Pd(OH)2 / C was filtered out, and the ethanol was concentrated under reduced pressure. The mixture was prepared and purified by HPLC and freeze-dried to obtain compound 23 (6.5 mg, yield 26%).

[0294] MS-ESI calculated value [M+H] - 466.1, measured value 465.9.

[0295] Example 10: PTPN2 in vitro enzymatic assay

[0296] The purpose of this experiment is to test the ability of the compound to bind to and inhibit PTPN2 activity in vitro. The specific steps are as follows: 1. Preparation of Assay Buffer: Use sterile deionized ultrapure water for preparation (see the table below).

[0297] Assay Buffer Stock Volume (2000 μL) Work Hepes 1000mM 250μL 25mM EDTA 500mM 20μL 1mM NaCl 1000mM 500μL 50mM DTT 1000mM 10μL 1mM <![CDATA[H2O]]> 9220μL

[0298] 2. PTPN2 enzyme preparation: The enzyme stock solution concentration is 0.15 mg / mL, and it is prepared into a 4 μg / mL working solution, that is, the final concentration is 2 μg / mL.

[0299] 3. Preparation of pNPP substrate: Weigh powdered pNPP to prepare a 2 mM working solution, i.e. the final concentration is 1 mM.

[0300] 4. Preparation of compound solution: First dissolve the compound in DMSO to form a stock solution, dilute the compound stock solution to 1mM, and then dilute it 4 times with DMSO, for a total of 8 concentration gradients; then take 2μL of the compound diluted in DMSO gradient and add it to 17.8μL ddH2O to prepare the working solution of the compound to be tested (the final DMSO concentration in the reaction system is 0.1%). Add 1μL of the compound working solution of each gradient concentration to the 96-well plate, mix with 50μL PTPN2, and incubate the reaction system at room temperature for 10 minutes for compound pre-incubation.

[0301] 5. After the compound pre-incubation, add 50 μL of substrate working solution to each well and incubate at 37°C for 90 minutes. At this time, the final compound concentration gradient is 1 μM to 0.0610 nM.

[0302] 6. After the reaction is completed, add 50 μL of 3M NaOH to each well to stop the reaction, read the plate reader at 405 nm and calculate the inhibition rate of each compound.

[0303] 7. Data analysis: Convert raw data into inhibition rate, IC 50 The values ​​were obtained by GraphPad software log(agonist) vs.response-

[0304] Variable slope four-parameter method fitting, the results are shown in Table 1.

[0305] Table 1. Inhibitory activity of compounds against PTPN2 enzyme

[0306] Compound <![CDATA[IC 50 (nΜ)]]> <![CDATA[IC 50 (nΜ)]]> 1 20 ++ 2 10.8 ++ 3 6.2 +++ 6 66.5 ++ 7 74.5 ++ 8 16.1 ++

[0307]

Note

[0308] It can be seen from the data in Table 1 that the compounds provided by the present invention have excellent in vitro inhibitory activity against PTPN2.

Claims

1. An azatricyclic compound, which is a compound having the following structural formula (I) or a pharmaceutically acceptable salt thereof: in: is a double bond or a single bond; n is 1, 2 or 3; W is selected from C, CH or N; X and Y are each independently selected from N(R3) j or C(R3) k ; j is 0 or 1, k is 1 or 2; Z is selected from O, S, Se, OR4, SR4, SeR4, NR4 or NR4R 4A ; P is selected from CH or N; Q is selected from hydrogen, deuterium, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 1-6 alkoxy, hydroxy, cyano, amino, amide, sulfone or sulfoxide; when the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 When there is a substituent for the alkoxy group, it may be substituted by at least one of the following groups: halogen, hydroxyl, amino, amide, sulfone, sulfoxide, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl; R1, R4, R 4A are each independently selected from hydrogen, deuterium, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, hydroxyl, cyano; when the C 1-6 Alkyl, C 1-6 When there is a substituent for the alkoxy group, it may be substituted by at least one of the following groups: halogen, hydroxyl, amino, amide, sulfone, sulfoxide, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl; R2 is absent, or R2 is selected from hydrogen, deuterium, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, hydroxyl, cyano; when the C 1-6 Alkyl, C 1-6 When there is a substituent for the alkoxy group, it may be substituted by at least one of the following groups: halogen, hydroxyl, amino, amide, sulfone, sulfoxide, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl; Each R3 is independently selected from hydrogen, deuterium, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 3-10 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic group, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, cyano, -OR5, -SR5, -SOR5, -S(O)2R5, -COR5, -C(O)OR5, -C(O)NR5R 5A or -NR5R 5A ; When the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 When aryl and 5-10 membered heteroaryl have substituents, they may be substituted by at least one of the following groups: halogen, hydroxyl, amino, amide, sulfone, sulfoxide, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -OR6, -SR6, -SOR6, -S(O)2R6, -COR6, -C(O)OR6, -C(O)NR6R 6A 、-NR6R 6A ; Each R5, R 5A , R6, R 6A are each independently selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 1-6 Alkoxy, -OR7, -SR7, -S(O)2R7, -COR7, -C(O)OR7, -C(O)NR7R 7A 、-NR7R 7A ; When the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 When there is a substituent for the alkoxy group, it may be substituted by at least one of the following groups: halogen, hydroxyl, cyano, amino, amide, sulfone, sulfoxide, substituted or unsubstituted C 3-10 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic group, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, -OR8, -NR8S(O)2R 8A ; Further, when the C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 When aryl and 5-10 membered heteroaryl have substituents, they may be substituted by at least one of the following groups: halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy; Each R7, R 7A , R8, R 8A are each independently selected from hydrogen, halogen, C 1-6 Alkyl, substituted or unsubstituted C 3-10 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic group, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl; when the C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 When aryl and 5-10 membered heteroaryl have substituents, they may be substituted by at least one of the following groups: halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy; The heterocyclic group and heteroaryl group contain at least one heteroatom, and the heteroatom is selected from N, O or S.

2. An azatricyclic compound, which is a compound having the following structural formula (I) or a pharmaceutically acceptable salt thereof: in: is a double bond or a single bond; n is 1, 2 or 3; When W is selected from C, P is N, X and Y are N and N respectively, or X and Y are N and CR3 respectively, or X and Y are CR3 and N respectively, or X and Y are CR3 and CR3 respectively; or, When W is selected from N, P is N, X and Y are N and N respectively, or X and Y are N and CR3 respectively, or X and Y are CR3 and N respectively, or X and Y are CR3 and CR3 respectively. Z is selected from O, S, Se, OR4, SR4, SeR4, NR4 or NR4R 4A ; Q is selected from hydrogen, deuterium, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 1-6 alkoxy, hydroxy, cyano, amino, amide, sulfone or sulfoxide; when the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 When there is a substituent for the alkoxy group, it may be substituted by at least one of the following groups: halogen, hydroxyl, amino, amide, sulfone, sulfoxide, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl; R1, R2, R4, R 4A are each independently selected from hydrogen, deuterium, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, hydroxyl, cyano; when the C 1-6 Alkyl, C 1-6 When there is a substituent for the alkoxy group, it may be substituted by at least one of the following groups: halogen, hydroxyl, amino, amide, sulfone, sulfoxide, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl; R3 is selected from hydrogen, deuterium, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 3-10 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic group, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, cyano, -OR5, -SR5, -SOR5, -S(O)2R5, -COR5, -C(O)OR5, -C(O)NR5R 5A or -NR5R 5A ; When the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 When aryl and 5-10 membered heteroaryl have substituents, they may be substituted by at least one of the following groups: halogen, hydroxyl, amino, amide, sulfone, sulfoxide, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -OR6, -SR6, -SOR6, -S(O)2R6, -COR6, -C(O)OR6, -C(O)NR6R 6A 、-NR6R 6A ; R5, R 5A , R6, R 6A are each independently selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 1-6 Alkoxy, -OR7, -SR7, -S(O)2R7, -COR7, -C(O)OR7, -C(O)NR7R 7A 、-NR7R 7A ; When the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 When there is a substituent for the alkoxy group, it may be substituted by at least one of the following groups: halogen, hydroxyl, cyano, amino, amide, sulfone, sulfoxide, substituted or unsubstituted C 3-10 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic group, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, -OR8, -NR8S(O)2R 8A ; Further, when the C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 When aryl and 5-10 membered heteroaryl have substituents, they may be substituted by at least one of the following groups: halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy; R7, R 7A , R8, R 8A are each independently selected from hydrogen, halogen, C 1-6 Alkyl, substituted or unsubstituted C 3-10 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic group, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl; when the C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 When aryl and 5-10 membered heteroaryl have substituents, they may be substituted by at least one of the following groups: halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy; The heterocyclic group and heteroaryl group contain at least one heteroatom, and the heteroatom is selected from N, O or S.

3. The azatricyclic compound according to claim 2, characterized in that: A compound having the following general structural formula (IIA) or a pharmaceutically acceptable salt thereof: Wherein: R1, R2 are each independently selected from hydrogen, C 1-6 alkyl; R3 is selected from hydrogen, substituted or unsubstituted C 3-10 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic group, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, -OR5, -NR5R 5A ; When the C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 When aryl and 5-10 membered heteroaryl have substituents, they may be substituted by at least one of the following groups: -S(O)2R6; R5, R 5A , R6 are each independently selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl; when the C 1-6 When an alkyl group has a substituent, it may be substituted by at least one of the following groups: halogen, hydroxyl, cyano, substituted or unsubstituted C 3-10 Cycloalkyl, -OR8, -NR8S(O)2R 8A ; Further, when the C 3-10 When a cycloalkyl group has a substituent, it may be substituted by at least one of the following groups: halogen; R7, R8, R 8A are each independently selected from hydrogen, C 1-6 Alkyl or 3-10 membered heterocyclic group; The heterocyclic group and heteroaryl group contain at least one heteroatom, and the heteroatom is selected from N, O or S.

4. The azatricyclic compound according to claim 3, characterized in that: A compound having the following general structural formula (II-1), (II-2) or (II-3) or a pharmaceutically acceptable salt thereof: R5 is selected from substituted or unsubstituted C 1-6 Alkyl; when the C 1-6 When an alkyl group has a substituent, it may be substituted by at least one of the following groups: halogen, hydroxyl, cyano, substituted or unsubstituted C 3-10 Cycloalkyl, -NHS(O)2R 8A ; Further, when the C 3-10 When a cycloalkyl group has a substituent, it may be substituted by at least one of the following groups: halogen; R 5A Selected from substituted or unsubstituted C 1-6 Alkyl; when the C 1-6 When an alkyl group has a substituent, it may be substituted by at least one of the following groups: cyano, C 3-10 Cycloalkyl; R6 is selected from substituted or unsubstituted C 1-6 Alkyl; when the C 1-6 When an alkyl group has a substituent, it may be substituted by at least one of the following groups: halogen, cyano, -OR8; R8 is selected from C 1-6 alkyl; R 8A is selected from 3-10 membered heterocyclic groups; The heterocyclic group and heteroaryl group contain at least one heteroatom, and the heteroatom is selected from N, O or S.

5. The azatricyclic compound according to claim 1, characterized in that: A compound having the following general structural formula (IVA) or (VA) or a pharmaceutically acceptable salt thereof: Wherein: R1 and R2 are each independently selected from hydrogen; R3 is selected from -OR5, -NHR 5A ; R5, R 5A are each independently selected from substituted or unsubstituted C 1-6 Alkyl; when the C 1-6 When an alkyl group has a substituent, it may be substituted by at least one of the following groups: halogen, C 3-10 Cycloalkyl.

6. An azatricyclic compound having the following structure or a pharmaceutically acceptable salt thereof:

7. A pharmaceutical composition comprising the compound according to any one of claims 1 to 6 as an active ingredient, and at least one pharmaceutically acceptable carrier.

8. Use of the compound 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 or treating a disease associated with PTPN1 / PTPN2 receptors.

9. The use according to claim 8, characterized in that: The medicine is used for preventing or treating cancer.

10. The use according to claim 9, characterized in that: The cancer is selected from relapsed or refractory head and neck squamous cell carcinoma, relapsed or refractory non-small cell lung cancer, advanced clear cell renal cell carcinoma, or microsatellite instability-high tumors.

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