Indoline compounds and use thereof

Abstract

The present invention relates to a class of indoline compounds, and particularly relates to use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof in treating a related disease. Further disclosed are a preparation method for the indoline compounds and pharmaceutical use thereof. The indoline compounds can be used as a PTPN2 / PTPN1 inhibitor for treating diseases related to PTPN2 / PTPN1 signal pathway-mediated abnormal expression (including but not limited to tumors).

Description

Indolines and uses thereof TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine, and relates to a kind of indoline compounds, and specifically relates to the application of a compound shown in formula (I) or a pharmaceutically acceptable salt thereof in the preparation of related diseases. BACKGROUND

[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 an appropriate level 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 a cysteine phosphatase intermediate. 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 work has revealed at least four types of more than 100 proteins with potential PTP activity. Protein tyrosine phosphatase non-receptor type 2 (PTPN2, TC-PTP) and type 1 (PTPN1, PTP1B) belong to non-receptor type phosphatases and are two commonly expressed classic PTPs, with a catalytic domain having more than 74% identity.

[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 and pro-inflammatory anti-tumor functions of various immune cell subsets. For example, in T cells, PTPN2 acts as a negative regulator of TCR signaling, and its inhibition can increase T cell activation, proliferation, and immune effector function, resulting in tumor suppression. Studies have also shown that PTPN2 inhibition can increase PD-L1 expression, and combined use of anti-PD-1 (L1) monoclonal antibodies produces a synergistic effect.

[0005] Patents WO2020186199 and WO2022056281 disclose PTPN2 / N1 inhibitors developed by Calico (see structural general formula I / II), the structural characteristics of the parent nucleus of which are that a benzohexa-saturated carbocyclic ring or a benzohexa-saturated heterocyclic ring structure is adopted. The representative compound ABBV-CLS-484 is in clinical phase I study. Information shows that Calico plans to carry out studies on advanced solid tumors such as relapsed or refractory head and neck squamous cell carcinoma, relapsed or refractory non-small cell lung cancer, advanced clear cell renal cell carcinoma, and the like, and the combination of anti-PD-1 or PD-L1 monoclonal antibodies, anti-PD-1 or PD-L1 monoclonal antibodies resistant, or the combination of VEGFR kinase inhibitors for the treatment of locally advanced or metastatic relapsed or refractory head and neck squamous cell carcinoma, relapsed or refractory non-small cell lung cancer, and highly microsatellite unstable tumors. The preclinical related study of ABBV-CLS-484 published in Nature (https: / / doi.org / 10.1038 / s41586-023-06575-7) shows that ABBV-CLS-484 can enhance the sensitivity of tumor cells to IFN-γ, enhance T cell function, and exhibit excellent single-agent or combination anti-tumor activity in various tumor models.

[0006] At present, there is no PTPN2 / PTPN1 inhibitor on the market, so it is necessary to develop new PTPN2 / PTPN1 inhibitors to meet the clinical needs. SUMMARY

[0007] The technical problem to be solved by the present application is to provide a structurally novel indoline compound which can be used as a PTPN2 / PTPN1 inhibitor for preparing a drug for treating PTPN2 / PTPN1-mediated diseases or disorders and related diseases or disorders. To solve the above technical problem, the technical solution provided by the present application is as follows:

[0008] In one aspect, the present application provides a compound represented by formula (I) or a pharmaceutically acceptable salt, isotope derivative, solvate thereof, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof:

[0009] wherein W is selected from C, CH or N;

[0010] is a double bond or a single bond;

[0011] R 1 and R 2 are each independently selected from hydrogen, deuterium, halogen, hydroxyl, oxo or cyano;

[0012] R 3Selected from one or more R a Substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C8 cycloalkyl, C2-C9 heterocyclic, C6-C 10 Aryl, C1-C9 heteroaryl, C1-C6 alkylene C3-C8 cycloalkyl, C1-C6 alkylene C2-C9 heterocyclic, C1-C6 alkylene C6-C 10 Aryl, C1-C6 alkylene, C1-C9 heteroaryl, -C(O)OR 4 -COR 4 , -C(O)NR 4 R 5 -S(O)2NR 4 R 5 -S(O)2R 4 -SOR 4 -S(=O)(=NH)NR 4 R 5 -S(=O)(=NH)R 4 ,

[0013] R 4 and R 5 Each element is independently selected from hydrogen, deuterium, hydroxyl, halogen, oxo, cyano, or by one or more R groups. a Substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C8 cycloalkyl, C2-C9 heterocyclic, C6-C 10 Aryl, C1-C9 heteroaryl, C1-C6 alkylene C3-C8 cycloalkyl, C1-C6 alkylene C2-C9 heterocyclic, C1-C6 alkylene C6-C 10 Aryl, C1-C6 alkylene, C1-C9 heteroaryl;

[0014] Or, R 4 and R 5 The atoms in the middle and the atoms they connect together form a structure consisting of one or more R atoms. a Substituted 3-12 membered heterocyclic groups or C3-C8 cycloalkyl groups;

[0015] R 6 and R 7 Each element is independently selected from hydrogen, deuterium, hydroxyl, halogen, oxo, cyano, or by one or more R groups. a Substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C8 cycloalkyl, C2-C9 heterocyclic, C6-C 10 Aryl, C1-C9 heteroaryl;

[0016] Or, R 6 and R 7Together with the atoms they are connected to, they form a structure formed by one or more R a Substituted 3-7 membered heterocyclic groups or C3-C7 cycloalkyl groups;

[0017] R a Each is independently selected from hydrogen, deuterium, hydroxyl, halogen, oxo, cyano, or by one or more R groups. f Substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C8 cycloalkyl, C2-C9 heterocyclic, C6-C 10 Aryl, C1-C9 heteroaryl, C1-C6 alkylene C3-C8 cycloalkyl, C1-C6 alkylene C2-C9 heterocyclic, C1-C6 alkylene C6-C 10 Aryl, C1-C6 alkylene, C1-C9 heteroaryl, -OR b -SR b -NR b R c -C(O)OR b , -OC(O)NR b R c -NR e C(O)NR b R c -NR e C(O)OR b -S(O)2NR b R c -S(O)2R b -NR e S(O)2R b -COR b -SOR b -OCOR b -NR e COR b -NR e SOR b -S(=O)(=NH)NR b R c -NR e S(=O)(=NH)R b -S(=O)(=NH)R b , R b R c and R e Each is independently selected from hydrogen, deuterium, hydroxyl, halogen, oxo, cyano, or by one or more R groups. f Substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C8 cycloalkyl, C2-C9 heterocyclic, C6-C 10Aryl, C1-C9 heteroaryl, C1-C6 alkylene C3-C8 cycloalkyl, C1-C6 alkylene C2-C9 heterocyclic, C1-C6 alkylene C6-C 10 Aryl, C1-C6 alkylene, C1-C9 heteroaryl;

[0018] or R b R c and R e Any two groups and the atoms they are attached to together form a compound formed by one or more R groups. f Substituted 3-12 membered heterocyclic groups or C3-C8 cycloalkyl groups;

[0019] R f The components are independently selected from hydrogen, deuterium, hydroxyl, halogen, oxo, cyano, sulfone, sulfoxide, phosphooxy, C1-C6 alkyl, C1-C6 alkoxy, or C3-C8 cycloalkyl, wherein the C1-C6 alkyl, C1-C6 alkoxy, or C3-C8 cycloalkyl may optionally be substituted by one or more hydrogen, deuterium, hydroxyl, halogen, oxo, or cyano groups.

[0020] In some implementations, the R f The group is independently selected from hydrogen, deuterium, hydroxyl, halogen, oxo, cyano, sulfone, sulfoxide, phosphooxy, C1-C6 alkyl, or C3-C8 cycloalkyl, wherein the C1-C6 alkyl or C3-C8 cycloalkyl may optionally be substituted by one or more hydrogen, deuterium, hydroxyl, halogen, oxo, or cyano groups.

[0021] In some embodiments, the compound has the structure shown in formula (II):

[0022] Among them, R 1 R 2 R 3 R 6 and R 7 The definition is as described in compound (I).

[0023] In some implementations, the R 3 Selected from one or more R a Replacement C6-C 10 Aryl, C1-C9 heteroaryl, -C(O)OR 4 -COR 4 , -C(O)NR 4 R 5 -S(O)2NR 4 R 5 or -S(=O)(=NH)NR 4 R 5 .

[0024] In some embodiments, the compound has the structure of Formula (IIA):

[0025] wherein R 1 , R 2 , R 4 , R 6 , and R 7 are as described for compounds of Formula (I).

[0026] In some embodiments, the compound has the structure of Formula (IIB):

[0027] wherein Z1, Z2, or Z3 is each independently selected from N, NH, CH, or CR a ;

[0028] R a , R 1 , R 2 , R 6 , and R 7 are as described for compounds of Formula (I).

[0029] In some embodiments, the compound has the structure of Formula (IIC):

[0030] wherein X1, X2, or X3 is each independently selected from N, NH, CH, or CR a ;

[0031] R a , R 1 , R 2 , R 6 , and R 7 are as described for compounds of Formula (I).

[0032] In some embodiments, R 1 is selected from hydrogen.

[0033] In some embodiments, R 2 is selected from hydrogen.

[0034] In some embodiments, R 6 and R 7 are each independently selected from hydrogen, deuterium, hydroxyl, halogen, oxo, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, C2-C9heterocyclyl, C6-C10aryl, or C1-C9heteroaryl, said C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, C2-C9heterocyclyl, C6-C10aryl, or C1-C9heteroaryl being optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, oxo, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, C2-C9heterocyclyl, C6-C10aryl, and C1-C9heteroaryl. 10 In some embodiments, R 10 is selected from hydrogen, deuterium, hydroxyl, halogen, oxo, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, C2-C9heterocyclyl, C6-C10aryl, or C1-C9heteroaryl, said C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, C2-C9heterocyclyl, C6-C10aryl, or C1-C9heteroaryl being optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, oxo, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, C2-C9heterocyclyl, C6-C10aryl, and C1-C9heteroaryl.The aryl or C1-C9 heteroaryl group may optionally be substituted by one or more hydrogens, deuteriums, hydroxyl groups, halogens, oxo groups, or cyano groups;

[0035] Or, R 6 and R 7 Together with the atoms they are attached to, they form a 3-7 membered heterocyclic group or a C3-C7 cycloalkyl group, which may optionally be substituted by one or more hydrogens, deuteriums, hydroxyl groups, halogens, oxo groups, or cyano groups.

[0036] In some embodiments, the compound has the structure shown in formula (III):

[0037] Among them, R 3 R 6 and R 7 The definition is as described in compound (I).

[0038] In some embodiments, the compound has the structures shown in formulas (IIIA), (IIIB), and (IIIC):

[0039] Among them, X1, X2, or X3 are each independently selected from N, NH, CH, or CR. a ;

[0040] Z1, Z2, or Z3 are each independently selected from N, NH, CH, or CR. a ;

[0041] R a R 4 R 6 R 7 The definition is as described in compound (I).

[0042] In some embodiments, the compound has the structures shown in formulas (IIIA-1), (IIIA-2), (IIIB-1), (IIIB-2), (IIIC-1), and (IIIC-2):

[0043] Among them, X1, X2, or X3 are each independently selected from N, NH, CH, or CR. a ;

[0044] Z1, Z2, or Z3 are each independently selected from N, NH, CH, or CR. a ;

[0045] R a R 4 The definition is as described in compound (I);

[0046] m, n and q are each independently selected from 0, 1, 2, 3, 4 or 5;

[0047] Q is selected from CH2, NH, O or S.

[0048] In some embodiments, the compound has the structure shown in formula (IVA), (IVB) and (IVC) below:

[0049] wherein each of X1, X2, X3or X4is independently selected from N, NR a , CR a or C(R a )2;

[0050] each of Z1, Z2, Z3, Z4or Z5is independently selected from N, NR a , CR a or C(R a )2;

[0051] R a , R 4 are as defined for the compound of formula (I).

[0052] In some embodiments, the R 4 is selected from hydrogen, deuterium, or C1-C6alkyl, C3-C8cycloalkyl, 3-10 membered heterocyclyl, 5-14 membered heteroaryl, C1-C6alkyleneC3-C8cycloalkyl, C1-C6alkylene3-10 membered heterocyclyl, C1-C6alkyleneC6-C a aryl, or C1-C6alkylene5-14 membered heteroaryl, substituted with one or more R 10 ;

[0053] the R a is selected from hydrogen, deuterium, hydroxyl, halogen, cyano, or C1-C6alkyl, C1-C6alkoxy, C1-C6alkylamino, C3-C8cycloalkyl, or C2-C9heterocyclyl, substituted with one or more R f ;

[0054] the R f is selected from hydrogen, deuterium, hydroxyl, halogen, C1-C6alkyl, or C1-C6alkoxy.

[0055] In some embodiments, the R 4 is selected from H, CH3, the R is selected from the R is selected from

[0056] On the other hand, the present invention provides compounds having the following general structural formula (I') or pharmaceutically acceptable salts thereof:

[0057] Among them, W' is selected from C, CH or N; It can be a double bond or a single bond;

[0058] R 1 '、R 2 Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, oxo group, or cyano group;

[0059] R 3 Selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic groups, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted 5-14 heteroaryl, -C(O)OR 4 '、-COR 4 '、-C(O)NR 4 'R 5 '、-S(O)2NR 4 'R 5 '、-S(O)2R 4 '、-SOR 4 '、-S(=O)(=NH)NR 4 'R 5 '、-S(=O)(=NH)R 4 '、 When R 3 The C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-10 membered heterocyclic groups, and C6-C 14 When an aryl or 5-14 membered heteroaryl group has substituents, it may be substituted by at least one of the following groups: deuterium, hydroxyl, halogen, oxo, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 ynyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic group, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted 5-14 heteroaryl, -OR b '、-SR b '、-NR b 'R c '、-C(O)OR b '、-OC(O)NR b 'Rc 'NR e 'C(O)NR b 'R c 'NR e 'C(O)OR b 'S(O)2NR b 'R c 'S(O)2R b 'NR e 'S(O)2R b 'COR b 'SOR b 'OCOR b 'NR e 'COR b 'NR e 'SOR b 'S(=O)(=NH)NR b 'R c 'NR e 'S(=O)(=NH)R b 'S(=O)(=NH)R b ', wherein when a substituent is present on C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, 3-10 membered heterocyclyl, C6-C10aryl, or 5-14 membered heteroaryl, it can be substituted with at least one deuterium, hydroxyl, halogen, oxo, cyano, sulfone, sulfoxide, phosphine oxide, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C3-C8cycloalkyl, further when a substituent is present on C1-C6alkyl or C3-C8cycloalkyl, it can be substituted with at least one deuterium, hydroxyl, halogen, oxo, or cyano; 14 C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, 3-10 membered heterocyclyl, C6-C10aryl, or 5-14 membered heteroaryl, it can be substituted with at least one deuterium, hydroxyl, halogen, oxo, cyano, sulfone, sulfoxide, phosphine oxide, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C3-C8cycloalkyl, further when a substituent is present on C1-C6alkyl or C3-C8cycloalkyl, it can be substituted with at least one deuterium, hydroxyl, halogen, oxo, or cyano;

[0060] R 4 'R 5 each independently selected from hydrogen, deuterium, hydroxyl, halogen, oxo, cyano, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C2-C6alkynyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclyl, substituted or unsubstituted C6-C10aryl, substituted or unsubstituted 5-14 membered heteroaryl, when R 14 ' is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, 3-10 membered heterocyclyl, C6-C10aryl, or 5-14 membered heteroaryl, it can be substituted with at least one deuterium, hydroxyl, halogen, oxo, cyano, sulfone, sulfoxide, phosphine oxide, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C3-C8cycloalkyl, further when a substituent is present on C1-C6alkyl or C3-C8cycloalkyl, it can be substituted with at least one deuterium, hydroxyl, halogen, oxo, or cyano; 4 'R 5 each independently selected from hydrogen, deuterium, hydroxyl, halogen, oxo, cyano, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C2-C6alkynyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclyl, substituted or unsubstituted C6-C10aryl, substituted or unsubstituted 5-14 membered heteroaryl, when R 14When an aryl or 5-14 membered heteroaryl group has substituents, it may be substituted by at least one of the following groups: deuterium, hydroxyl, halogen, oxo, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 ynyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic group, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted 5-14 heteroaryl, -OR b '、-SR b '、-NR b 'R c '、-C(O)OR b '、-OC(O)NR b 'R c '、-NR e 'C(O)NR b 'R c '、-NR e 'C(O)OR b '、-S(O)2NR b 'R c '、-S(O)2R b '、-NR e 'S(O)2R b '、-COR b '、-SOR b '、-OCOR b '、-NR e 'COR b '、-NR e 'SOR b '、-S(=O)(=NH)NR b 'R c '、-NR e 'S(=O)(=NH)R b '、-S(=O)(=NH)R b '、 Among them, when C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-10 membered heterocyclic, C6-C 14 When aryl or 5-14-membered heteroaryl groups are substituents, they may be substituted by at least one of the following groups: deuterium, hydroxyl, halogen, oxo, cyano, sulfone, sulfoxide, phosphooxy, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl. Furthermore, when C1-C6 alkyl or C3-C8 cycloalkyl groups are substituents, they may be substituted by at least one of the following groups: deuterium, hydroxyl, halogen, oxo or cyano.

[0061] Or, R 4R 5 ' are optionally connected to each other to form a substituted or unsubstituted 3-10 membered heterocyclyl, a substituted or unsubstituted C3-C8 cycloalkyl; when R 4 ' are optionally connected to each other to form a substituted or unsubstituted 3-10 membered heterocyclyl, a substituted or unsubstituted C3-C8 cycloalkyl; when R 5 ' are optionally connected to each other to form a substituted or unsubstituted 3-10 membered heterocyclyl, a substituted or unsubstituted C3-C8 cycloalkyl; when R 14 ' are optionally connected to each other to form a substituted or unsubstituted 3-10 membered heterocyclyl, a substituted or unsubstituted C3-C8 cycloalkyl; when R b ' are optionally connected to each other to form a substituted or unsubstituted 3-10 membered heterocyclyl, a substituted or unsubstituted C3-C8 cycloalkyl; when R b ' are optionally connected to each other to form a substituted or unsubstituted 3-10 membered heterocyclyl, a substituted or unsubstituted C3-C8 cycloalkyl; when R b ' are optionally connected to each other to form a substituted or unsubstituted 3-10 membered heterocyclyl, a substituted or unsubstituted C3-C8 cycloalkyl; when R c ' are optionally connected to each other to form a substituted or unsubstituted 3-10 membered heterocyclyl, a substituted or unsubstituted C3-C8 cycloalkyl; when R b ' are optionally connected to each other to form a substituted or unsubstituted 3-10 membered heterocyclyl, a substituted or unsubstituted C3-C8 cycloalkyl; when R b ' are optionally connected to each other to form a substituted or unsubstituted 3-10 membered heterocyclyl, a substituted or unsubstituted C3-C8 cycloalkyl; when R c ' are optionally connected to each other to form a substituted or unsubstituted 3-10 membered heterocyclyl, a substituted or unsubstituted C3-C8 cycloalkyl; when R e ' are optionally connected to each other to form a substituted or unsubstituted 3-10 membered heterocyclyl, a substituted or unsubstituted C3-C8 cycloalkyl; when R b ' are optionally connected to each other to form a substituted or unsubstituted 3-10 membered heterocyclyl, a substituted or unsubstituted C3-C8 cycloalkyl; when R c ' are optionally connected to each other to form a substituted or unsubstituted 3-10 membered heterocyclyl, a substituted or unsubstituted C3-C8 cycloalkyl; when R e ' are optionally connected to each other to form a substituted or unsubstituted 3-10 membered heterocyclyl, a substituted or unsubstituted C3-C8 cycloalkyl; when R b ' are optionally connected to each other to form a substituted or unsubstituted 3-10 membered heterocyclyl, a substituted or unsubstituted C3-C8 cycloalkyl; when R b ' are optionally connected to each other to form a substituted or unsubstituted 3-10 membered heterocyclyl, a substituted or unsubstituted C3-C8 cycloalkyl; when R c ' are optionally connected to each other to form a substituted or unsubstituted 3-10 membered heterocyclyl, a substituted or unsubstituted C3-C8 cycloalkyl; when R b ' are optionally connected to each other to form a substituted or unsubstituted 3-10 membered heterocyclyl, a substituted or unsubstituted C3-C8 cycloalkyl; when R e ' are optionally connected to each other to form a substituted or unsubstituted 3-10 membered heterocyclyl, a substituted or unsubstituted C3-C8 cycloalkyl; when R b ' are optionally connected to each other to form a substituted or unsubstituted 3-10 membered heterocyclyl, a substituted or unsubstituted C3-C8 cycloalkyl; when R b ' are optionally connected to each other to form a substituted or unsubstituted 3-10 membered heterocyclyl, a substituted or unsubstituted C3-C8 cycloalkyl; when R b ' are optionally connected to each other to form a substituted or unsubstituted 3-10 membered heterocyclyl, a substituted or unsubstituted C3-C8 cycloalkyl; when R b ' are optionally connected to each other to form a substituted or unsubstituted 3-10 membered heterocyclyl, a substituted or unsubstituted C3-C8 cycloalkyl; when R e ' are optionally connected to each other to form a substituted or unsubstituted 3-10 membered heterocyclyl, a substituted or unsubstituted C3-C8 cycloalkyl; when R b ' are optionally connected to each other to form a substituted or unsubstituted 3-10 membered heterocyclyl, a substituted or unsubstituted C3-C8 cycloalkyl; when R e ' are optionally connected to each other to form a substituted or unsubstituted 3-10 membered heterocyclyl, a substituted or unsubstituted C3-C8 cycloalkyl; when R b ' are optionally connected to each other to form a substituted or unsubstituted 3-10 membered heterocyclyl, a substituted or unsubstituted C3-C8 cycloalkyl; when R b ' are optionally connected to each other to form a substituted or unsubstituted 3-10 membered heterocyclyl, a substituted or unsubstituted C3-C8 cycloalkyl; when R c ' are optionally connected to each other to form a substituted or unsubstituted 3-10 membered heterocyclyl, a substituted or unsubstituted C3-C8 cycloalkyl; when R e ' are optionally connected to each other to form a substituted or unsubstituted 3-10 membered heterocyclyl, a substituted or unsubstituted C3-C8 cycloalkyl; when R b ' are optionally connected to each other to form a substituted or unsubstituted 3-10 membered heterocyclyl, a substituted or unsubstituted C3-C8 cycloalkyl; when R b ' are optionally connected to each other to form a substituted or unsubstituted 3-10 membered heterocyclyl, a substituted or unsubstituted C3-C8 cycloalkyl; when R ' are optionally connected to each other to form a substituted or unsubstituted 3-10 membered heterocyclyl, a substituted or unsubstituted C3-C8 cycloalkyl; when R 14when substituted, by at least one deuterium, hydroxy, halogen, oxo, cyano, sulfone, sulfoxide, phosphorine, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C3-C8cycloalkyl, further when C1-C6alkyl or C3-C8cycloalkyl is present, substituted by at least one deuterium, hydroxy, halogen, oxo or cyano;

[0062] R 6 R 7 each independently selected from the group consisting of hydrogen, deuterium, hydroxy, halogen, oxo, cyano, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C2-C6alkynyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted 5-14 membered heteroaryl; when R 6 R 7 each independently selected from the group consisting of hydrogen, deuterium, hydroxy, halogen, oxo, cyano, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C2-C6alkynyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclyl, substituted or unsubstituted C6-C 14 when substituted, by at least one deuterium, hydroxy, halogen, oxo, cyano, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C2-C6alkynyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted 5-14 membered heteroaryl, -OR b R b R b R c R b R b R c R e R b R c R e R b R b R c R b R e R b R b R b R b R e Rb '、-NR e 'SOR b '、-S(=O)(=NH)NR b 'R c '、-NR e 'S(=O)(=NH)R b '、-S(=O)(=NH)R b '、 Among them, when C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-10 membered heterocyclic, C6-C 14 When aryl or 5-14-membered heteroaryl groups are substituents, they may be substituted by at least one of the following groups: deuterium, hydroxyl, halogen, oxo, cyano, sulfone, sulfoxide, phosphooxy, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl. Furthermore, when C1-C6 alkyl or C3-C8 cycloalkyl groups are substituents, they may be substituted by at least one of the following groups: deuterium, hydroxyl, halogen, oxo or cyano.

[0063] Or, R 6 '、R 7 'Any two groups may be linked together to form a substituted or unsubstituted 3-10 membered heterocyclic group, or a substituted or unsubstituted C3-C8 cycloalkyl group; when R 6 '、R 7 When the 3-10 membered heterocyclic group or C3-C8 cycloalkyl group in ' has a substituent, it may be substituted by at least one of the following groups: deuterium, hydroxyl, halogen, oxo, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 ynyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic group, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted 5-14 heteroaryl, -OR b '、-SR b '、-NR b 'R c '、-C(O)OR b '、-OC(O)NR b 'R c '、-NR e 'C(O)NR b 'R c '、-NR e 'C(O)OR b '、-S(O)2NR b 'R c '、-S(O)2R b '、-NR e'S(O)2R b ', -COR b ', -SOR b ', -OCOR b ', -NR e 'COR b ', -NR e 'SOR b ', -S(=O)(=NH)NR b 'R c ', -NR e 'S(=O)(=NH)R b ', -S(=O)(=NH)R b ', wherein when a substituent is present on the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, 3-10 membered heterocyclyl, C6-C 14 aryl, or 5-14 membered heteroaryl, it can be substituted with at least one deuterium, hydroxy, halogen, oxo, cyano, sulfone, sulfoxide, phosphine oxide, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C3-C8cycloalkyl, further when a substituent is present on the C1-C6alkyl or C3-C8cycloalkyl, it can be substituted with at least one deuterium, hydroxy, halogen, oxo, or cyano;

[0064] R b ', R c ', R e each independently is selected from hydrogen, deuterium, hydroxy, halogen, oxo, cyano, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C2-C6alkynyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted 5-14 membered heteroaryl; when R b ', R c ', R e each independently is selected from hydrogen, deuterium, hydroxy, halogen, oxo, cyano, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C2-C6alkynyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclyl, substituted or unsubstituted C6-C 14 aryl, or 5-14 membered heteroaryl, it can be substituted with at least one deuterium, hydroxy, halogen, oxo, cyano, sulfone, sulfoxide, phosphine oxide, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C3-C8cycloalkyl; further when a substituent is present on the C1-C6alkyl or C3-C8cycloalkyl, it can be substituted with at least one deuterium, hydroxy, halogen, oxo, or cyano;

[0065] or, R b ', Rc two of R e two of R b two of R c two of R e three of R 1 two of R 2 two of R 5 two of R 6 two of R 7 two of R

[0066] The heterocyclyl, heteroaryl contains at least one heteroatom selected from N, O, or S.

[0067] In some embodiments, the compound is a compound of Formula (IIA’), having the following general structure:

[0068] R 1 two of R 2 two of R 5 two of R 6 two of R 7 two of R

[0069] In some embodiments, the compound is a compound of Formula (IIB’), having the following structure:

[0070] wherein each of Z1’, Z2’, Z3’, and Z4’ is independently selected from N, CH, or CR a ’;

[0071] two of Z1’, Z2’, Z3’, and Z4’ are optionally connected to each other to form a substituted or unsubstituted 3-10 membered heterocyclyl, or a substituted or unsubstituted C3-C8 cycloalkyl; and when the 3-10 membered heterocyclyl, C3-C8 cycloalkyl of Z1’, Z2’, Z3’, and Z4’ is substituted, it is substituted with at least one of deuterium, hydroxyl, halogen, oxo, cyano, sulfone, sulfoxide, phosphine oxide, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclyl, substituted or unsubstituted C6-C 14 substituted or unsubstituted C6-C b substituted or unsubstituted C6-C b substituted or unsubstituted C6-C b substituted or unsubstituted C6-Cc ', -C(O)OR b ', -OC(O)NR b ' R c ', -NR e ' C(O)NR b ' R c ', -NR e ' C(O)OR b ', -S(O)2NR b ' R c ', -S(O)2R b ', -NR e ' S(O)2R b ', -COR b ', -SOR b ', -OCOR b ', -NR e ' COR b ', -NR e ' SOR b ', -S(=O)(=NH)NR b ' R c ', -NR e ' S(=O)(=NH)R b ', -S(=O)(=NH)R b ', wherein when a substituent is present on C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, 3-10 membered heterocyclyl, C6-C 14 aryl, or 5-14 membered heteroaryl, it can be substituted with at least one deuterium, hydroxy, halo, oxo, cyano, sulfone, sulfoxide, phosphooxy, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C3-C8cycloalkyl, further when a substituent is present on C1-C6alkyl, C3-C8cycloalkyl, it can be substituted with at least one deuterium, hydroxy, halo, oxo, or cyano;

[0072] R a ' is selected from deuterium, hydroxy, halo, oxo, cyano, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C2-C6alkynyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted 5-14 membered heteroaryl, -OR b ', -SR b ', -NR b ' R c ', -C(O)OR b'、-OC(O)NR b 'R c '、-NR e 'C(O)NR b 'R c '、-NR e 'C(O)OR b '、-S(O)2NR b 'R c '、-S(O)2R b '、-NR e 'S(O)2R b '、-COR b '、-SOR b '、-OCOR b '、-NR e 'COR b '、-NR e 'SOR b '、-S(=O)(=NH)NR b 'R c '、-NR e 'S(=O)(=NH)R b '、-S(=O)(=NH)R b '、 When R a The C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-10 membered heterocyclic groups, and C6-C 14 When aryl or 5-14-membered heteroaryl groups are substituents, they may be substituted by at least one of the following groups: deuterium, hydroxyl, halogen, oxo, cyano, sulfone, sulfoxide, phosphooxy, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl. Furthermore, when C1-C6 alkyl or C3-C8 cycloalkyl groups are substituents, they may be substituted by at least one of the following groups: deuterium, hydroxyl, halogen, oxo or cyano.

[0073] R 1 '、R 2 '、R 6 '、R 7 '、R b '、R c '、R e The definition of ' is as described in compound (I').

[0074] In some embodiments, the compound has the structure shown in formula (IIC'):

[0075] Among them, X1', X2', X3', and X4' are each independently selected from N, NH, CH, or CR.a ’;

[0076] R a ’ is as defined for a compound of Formula (IIB’); R 1 ’ is as defined for a compound of Formula (IIB’); R 2 ’ is as defined for a compound of Formula (IIB’); R 6 ’ is as defined for a compound of Formula (IIB’); R 7 ’ is as defined for a compound of Formula (I’).

[0077] In some embodiments, R 1 ’ is hydrogen;

[0078] In some embodiments, R 2 ’ is hydrogen;

[0079] In some embodiments, R 6 ’ is as defined for a compound of Formula (IIB’); R 7 ’ are each independently selected from hydrogen, deuterium, hydroxyl, halogen, oxo, cyano, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C2-C6alkynyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclyl, substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted 5-14 membered heteroaryl; when R 6 ’ is as defined for a compound of Formula (IIB’); R 7 ’ is as defined for a compound of Formula (IIB’); R 14 when a substituent is present on the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, 3-10 membered heterocyclyl, C6-C

[0080] or, optionally, two of R 6 ’ are joined to form substituted or unsubstituted 3-10 membered heterocyclyl, substituted or unsubstituted C3-C8cycloalkyl, when R 7 ’ is as defined for a compound of Formula (IIB’); R 6 ’ is as defined for a compound of Formula (IIB’); R 7 when a substituent is present on the 3-10 membered heterocyclyl or C3-C8cycloalkyl in R

[0081] The heterocyclyl, heteroaryl contains at least one heteroatom selected from N, O, or S.

[0082] In some embodiments, the compound of the present application is selected from the following structures:

[0083] In another aspect, the present application provides a pharmaceutical composition comprising a compound of formula (I), (II), (IIA), (IIB), (IIC), (III), (IIIA), (IIIB), (IIIC), (IIIA-1), (IIIA-2), (IIIB-1), (IIIB-2), (IIIC-1), (IIIC-2), (IVA), (IVB), (IVC), (I’), (IIA’), (IIB’), and (IIC’), or a pharmaceutically acceptable salt, isotopic derivative, solvate, or stereoisomer, geometric isomer, tautomer, or prodrug molecule, metabolite thereof, or a pharmaceutical composition as described above.

[0084] In another aspect, the present application provides a pharmaceutical composition comprising a compound of formula (I), (II), (IIA), (IIB), (IIC), (III), (IIIA), (IIIB), (IIIC), (IIIA-1), (IIIA-2), (IIIB-1), (IIIB-2), (IIIC-1), (IIIC-2), (IVA), (IVB), (IVC), (I’), (IIA’), (IIB’), and (IIC’), or a pharmaceutically acceptable salt, isotopic derivative, solvate, or stereoisomer, geometric isomer, tautomer, or prodrug molecule, metabolite thereof, or a pharmaceutical composition as described above.

[0085] In another aspect, the present application provides a pharmaceutical composition comprising a compound of formula (I), (II), (IIA), (IIB), (IIC), (III), (IIIA), (IIIB), (IIIC), (IIIA-1), (IIIA-2), (IIIB-1), (IIIB-2), (IIIC-1), (IIIC-2), (IVA), (IVB), (IVC), (I’), (IIA’), (IIB’), and (IIC’), or a pharmaceutically acceptable salt, isotopic derivative, solvate, or stereoisomer, geometric isomer, tautomer, or prodrug molecule, metabolite thereof, or a pharmaceutical composition as described above.

[0086] In some embodiments, the disease treated and / or prevented is a PTPN2 / PTPN1 mediated disease, which is a tumor or cancer selected from the group consisting of head and neck squamous cell carcinoma, clear cell renal cell carcinoma, microsatellite instability-high tumor, glioma (glioblastoma), acute myeloid leukemia, acute myelocytic leukemia, myelodysplastic / myeloproliferative neoplasm, sarcoma, chronic myelomonocytic leukemia, non-Hodgkin lymphoma, astrocytoma, melanoma, non-small cell lung cancer, small cell lung cancer, cholangiocarcinoma, chondrosarcoma, colon cancer, colorectal cancer, rectal cancer, or pancreatic cancer.

[0087] Unless otherwise indicated, the general chemical terms used in the structural formulae have the usual meanings.

[0088] For example, the term "halogen" as used herein, means fluorine, chlorine, bromine, or iodine, unless otherwise indicated.

[0089] In the present application, unless otherwise indicated, "alkyl" includes straight-chain or branched-chain monovalent saturated hydrocarbon groups. For example, alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl, and the like. Similarly, "C 1-6 " in "alkyl" means a straight-chain or branched-chain group containing 1, 2, 3, 4, 5, or 6 carbon atoms. 1-6

[0090] The term "alkylene" refers to the group obtained after removal of one hydrogen from the aforementioned "alkyl". For example, methylene, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH(CH3)-, -CH2CH(CH3)CH2-, and the like.

[0091] The term "alkoxy" refers to the oxygen ether form of the aforementioned straight-chain or branched-chain alkyl, i.e., -O-alkyl.

[0092] The term "haloalkyl" refers to an alkyl group in which one or more H has been replaced by a halogen atom.

[0093] The term "haloalkoxy" refers to the group -O-haloalkyl.

[0094] The term "oxo" or "oxo group" refers to an oxygen atom in its bivalent substituent form, which forms a carbonyl group when attached to a C, or a sulfoxide or sulfone group or N-oxide group when attached to a heteroatom.

[0095] The term "cycloalkyl" refers to a ring system having at least one ring of cyclized alkyl groups. Preferably, the cycloalkyl is a C 3-12 C 3-6 ​"n" is a number from 1 to 12, inclusive. "C 3- 12 "n" is a number from 1 to 12, inclusive. "C

[0096] The term "alkenyl" refers to an alkyl group having one or more carbon-carbon double bonds, such as ethenyl, propenyl, 1,3-butadienyl, cis-but-2-enyl, trans-but-2-enyl, and the like.

[0097] The term "alkynyl" refers to an alkyl group having one or more carbon-carbon triple bonds, such as ethynyl, propynyl, and the like.

[0098] The term "alkylamino" refers to an open chain alkyl group containing a nitrogen atom, such as C 1-6 Alkylamino groups include, but are not limited to, methylamino, ethylamino, isopropylamino, dimethylamino, methylethylamino, diethylamino, and the like.

[0099] The term "aryl", unless otherwise indicated, is intended to mean a monocyclic or fused ring aromatic group, including carbocyclic ring atoms, which is unsubstituted or substituted. Preferably, the aryl group is a C 6-12 More preferably, the aryl group is a C 6-10 monocyclic or bicyclic aromatic ring group. Preferably, the aryl group is phenyl, naphthyl. The aryl ring can be fused to a heteroaryl, heterocyclyl, or cycloalkyl ring, wherein the ring that is attached to the parent structure is the aryl ring, non-limiting examples of which include, but are not limited to, benzocyclopentyl.

[0100] The term "heteroaryl," as used herein, unless otherwise indicated, means a monocyclic or polycyclic (e.g., fused bicyclic) aromatic heterocycle having at least one heteroatom selected from N, O, and / or S, and wherein the nitrogen or sulfur heteroatoms can optionally be oxidized, and the nitrogen heteroatoms can optionally be quaternized. Preferred are 5-14 membered heteroaryl groups, wherein "5-14 membered" in 5-14 membered heteroaryl refers to a heteroaryl group consisting of 5-14 C, N, O, or S ring-forming atoms. More preferred are 5-10 membered heteroaryl groups, and even more preferred are 5-6 membered heteroaryl groups. Examples of heteroaryl groups include, but are not limited to, thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzothiazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl adenine, quinolinyl, or isoquinolinyl. The heteroaryl group can be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring that is attached to the parent structure is a heteroaryl ring.

[0101] The term "heterocyclyl" means a ring system having at least one ring alkyl or ring alkenyl ring containing a heteroatom selected from N, O, and / or S. The heterocyclyl group can include a single ring or multiple rings (e.g., having 2, 3, or 4 fused rings, spiro rings, bridged rings, etc.). The heterocyclyl group can be attached to the remainder of the compound via a ring-forming carbon atom or a ring-forming heteroatom. Preferred are 3-14 membered heterocyclyl groups, wherein "3-14 membered" in 3-14 membered heterocyclyl refers to a heterocyclyl group consisting of 3-14 C, N, O, or S ring-forming atoms; more preferred are 3-6 membered heterocyclyl groups, and even more preferred are 5-6 membered heterocyclyl groups; wherein the nitrogen or sulfur heteroatoms can optionally be oxidized, and the nitrogen heteroatoms can optionally be quaternized. Examples of these heterocyclyl groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, and tetrahydrooxadiazolyl. The spiro heterocycle can be a 6-12 membered spiro heterocycle, including but not limited to: 4-azaspiro[2.4]heptane, 4-azaspiro[2.4]heptane. The heterocyclyl group can be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring that is attached to the parent structure is a heterocyclyl ring.

[0102] The term "compound," as used herein, includes, but is not limited to, the following forms of the compound: free base, stereoisomers, geometric isomers, tautomers, isotopologues, pharmaceutically acceptable salts, solvates, hydrates, prodrugs (esters), and the like.

[0103] The term "pharmaceutically acceptable" as used herein pertains to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0104] The term "pharmaceutically acceptable salts" means salts of the compounds of the present application that are prepared from a compound of the present application having a particular substituent by conventional chemical methods. Generally, such salts are prepared from the free acid or base forms of the compounds by reaction with the appropriate base or acid in a solvent or mixture of solvents.

[0105] When the compounds provided herein contain relatively acidic functionalities, base salts can be formed with pharmaceutically acceptable, non-toxic bases. These salts include those derived from inorganic bases such as ammonium, calcium, copper (ic and ous), ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic bases, including primary, secondary, and tertiary amines, as well as cyclic amines, and the like, are also contemplated. Other pharmaceutically acceptable non-toxic organic bases from which salts can be derived include isopropylamine, trimethylamine, 2-ethylamino ethanol, 2-dimethylaminoethanol, ethanolamine, diethylamine, N-ethyl-morpholine, N-ethylpiperidine, lysine, arginine, cadaverine, putrescine, histidine, isopropylamine, caffeine, procaine, quinine, theobromine, triethylamine, pyridine, picoline, and the like.

[0106] When the compounds provided herein contain relatively acidic functionalities, base salts can be formed with pharmaceutically acceptable, non-toxic bases. These salts include those derived from inorganic bases such as ammonium, calcium, copper (ic and ous), ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic bases, including primary, secondary, and tertiary amines, as well as cyclic amines, and the like, are also contemplated. Other pharmaceutically acceptable non-toxic organic bases from which salts can be derived include isopropylamine, trimethylamine, 2-ethylamino ethanol, 2-dimethylaminoethanol, ethanolamine, diethylamine, N-ethyl-morpholine, N-ethylpiperidine, lysine, arginine, cadaverine, putrescine, histidine, isopropylamine, caffeine, procaine, quinine, theobromine, triethylamine, pyridine, picoline, and the like.

[0107] The compounds of the present application can contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds can be radiolabeled with radioactive isotopes, such as for example tritium (3H), carbon-14 (14C), and the like.3 H), iodine-125 125 I) or C-14 14 C). For example, deuterium substituted drugs can be used in which some or all of the hydrogens have been replaced by deuterium. Deuterium substituted drugs have advantages over non-deuterium substituted drugs including, but not limited to, increased stability, increased half-life, increased efficacy, and reduced toxicity. All isotopic variations of the compounds of the present application, whether radioactive or not, are encompassed within the scope of the present application.

[0108] Prodrugs of the compounds of the present application are included within the scope of the present application. In general, such prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the desired compound. Thus, for example, any pharmaceutically acceptable salt, ester, salt of an ester, or other derivative of a compound of the present application, which upon in vivo administration is capable of providing (directly or indirectly) the compound of the present application or a pharmaceutically active metabolite or residue thereof, is within the scope of this application.

[0109] The compounds described herein can contain one or more asymmetric centers and can thus give rise to diastereomers and optical isomers. The present application includes all possible diastereomers, the racemic mixtures, the substantially pure resolved enantiomers, all possible geometric isomers, and the pharmaceutically acceptable salts thereof.

[0110] When the compounds of formula (I), (II), (IIA), (IIB), (IIC), (III), (IIIA), (IIIB), (IIIC), (IIIA-1), (IIIA-2), (IIIB-1), (IIIB-2), (IIIC-1), (IIIC-2), (IVA), (IVB), (IVC), (I’), (IIA’), (IIB’), and (IIC’) exist in tautomeric forms, the present application includes any and all tautomers and the pharmaceutically acceptable salts thereof, and mixtures thereof, unless otherwise specified.

[0111] The term "pharmaceutical composition" means a mixture of one or more of the compounds of the present application or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable excipient. The purpose of a pharmaceutical composition is to facilitate administration of a compound of the present application to an organism.

[0112] In the present application, "a," "an," "the," "at least one," and "one or more" are used interchangeably. Thus, for example, a mixture comprising "a" pharmaceutically acceptable excipient can be interpreted to mean that the pharmaceutical composition includes "one or more" pharmaceutically acceptable excipients.

[0113] The term "pharmaceutically acceptable excipient" means an excipient that is not biologically or otherwise undesirable, i.e., the excipient can be administered to an organism without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. Suitable excipients are well known to those skilled in the art, e.g., carbohydrates, waxes, water soluble and / or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.

[0114] The pharmaceutical composition of the present application can be prepared by combining a compound of the present application with a suitable pharmaceutically acceptable excipient, and can be formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalers, gels, microspheres, aerosols and the like.

[0115] Typical routes of administering the compounds of the present application, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.

[0116] The term "treatment" generally means obtaining a desired pharmacologic and / or physiologic effect. The effect can be therapeutic in terms of partially or completely arresting or reversing the symptoms of a disease and / or side effects caused by the disease. As used herein, "treatment" covers any treatment of a patient, including: (a) inhibiting the symptoms, i.e., arresting their development; or (b) relieving the symptoms, i.e., causing regression of diseases or symptoms.

[0117] The term "effective amount" means the amount of a compound of the present application which (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein. The amount of a compound of the present application which constitutes an "effective amount" will vary depending on the compound, the disease state and its severity, the route of administration, and the age of the mammal to be treated, but can be determined routinely by the skilled practitioner without undue experimentation.

[0118] The beneficial effects of the present application compared to the prior art are as follows:

[0119] Based on the target of PTPN2 / PTPN1 inhibitors, the present application develops a series of structurally novel indoline compounds, which can significantly inhibit the enzyme activity of PTPN2 / PTPN1, have low hERG toxicity, in-vitro liver microsomal metabolic stability, small species difference, good pharmacokinetic properties, high plasma and tissue site drug exposure after oral administration, and have extremely high oral administration potential. The compounds of the present application have potential in preventing or treating diseases related to abnormal PTPN2 / PTPN1 receptors, and have good clinical application prospects. DETAILED DESCRIPTION

[0120] In order to make the above content more clear and explicit, the technical solutions of the present application will be further explained by the following examples. The following examples are only used to illustrate the specific embodiments of the present application, so that those skilled in the art can understand the present application, but not used to limit the protection scope of the present application. In the specific embodiments of the present application, the technical means or methods not specifically described are the conventional technical means or methods in the art.

[0121] Unless otherwise specified, all temperatures of the present application refer to degrees Celsius.

[0122] The following abbreviations are used in the present application:

[0123] DMF-DMA: N,N-dimethylformamide dimethyl acetal; Et3N: triethylamine; Fe: iron powder; AcOH: acetic acid; SiHEt3: triethylsilane; TFA: trifluoroacetic acid; DCM: dichloromethane; Boc2O: di-tert-butyl dicarbonate; DMAP: 4-dimethylaminopyridine; THF: tetrahydrofuran; Pd2(dba)3: tris(dibenzylideneacetone)dipalladium; tBuXPhos: 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl; KOH: potassium hydroxide; Dioxane: 1,4-dioxane; H2O: water; BnBr: benzyl bromide; K2CO3: potassium carbonate; DMF: N,N-dimethylformamide; NBS: N-bromosuccinimide; MeCN: acetonitrile; PhNH2: aniline; DIPEA: N,N-diisopropylethylamine; Triphosgene: triphosgene; (tBuPh)-Pd-G3: 2'-(amino-N)[1,1'-biphenyl]-2-methyl-C][2'-[(1,1-dimethylethyl)phenylphosphino]-N2,N2,N6,N6-tetramethyl[1,1'-biphenyl]-2,6-diamine](methylsulfonyl-O)palladium; tBuONa: sodium tert-butoxide; MeONa: sodium methoxide; H2: hydrogen; Pd / C: palladium on carbon; MeOH: methanol; LC-MS: liquid chromatography-mass spectrometry; TLC: thin layer chromatography; HPLC: high performance liquid chromatography; BrettPhos: 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-I-propyl-11'-biphenyl; Cs2CO3: cesium carbonate; Pyridine: pyridine; HCl: hydrochloric acid; EA: ethyl acetate; t tBuOH: tert-butyl alcohol; tBuBrettPhos-Pd-G3: methylsulfonic acid-2-(di-tert-butylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl(2-amino-1,1'-biphenyl-2-yl)palladium; TBAF: tetrabutylammonium fluoride; ZnBr2: zinc bromide.

[0124] In the embodiments of the present application, x mL x y: indicates repeating y times, each time x mL, for example, extraction with ethyl acetate (50 mL x 3) indicates using 50 mL of ethyl acetate each time, and repeating 3 times; in the embodiments of the present application, the amount of eluent is by volume ratio, for example, petroleum ether: ethyl acetate = 50:50 indicates that the volume ratio of the amount of petroleum ether and ethyl acetate is 50:50.

[0125] In addition, all operations involving easily oxidizable or easily hydrolyzable raw materials are carried out under nitrogen protection. Unless otherwise specified, the raw materials used in the present application are commercially available raw materials, which can be directly used without further purification.

[0126] The raw materials and common intermediates involved in the embodiments of the present application can be obtained by purchase or self-preparation, wherein the raw materials and common intermediates that need to be obtained by self-preparation are prepared as follows.

[0127] Example 1, synthesis of 5-(1,1-dioxide-4-oxo-1,2,5-thiadiazolin-2-yl)-4-fluoro-6- hydroxy-N-phenylindoline-1-carboxamide (1)

[0128] Step 1: synthesis of compound 6-bromo-4-fluoro-1H-indole (1-1)

[0129] Compound 1-SM (3.00 g, 12.88 mmol) was dissolved in N,N-dimethylformamide (30 mL), triethylamine (2.86 g, 28.34 mmol) and N,N-dimethylformamide dimethyl acetal (3.37 g, 28.34 mmol) were added, and the reaction system was placed at 110°C for 2 hours. After the reaction was completed by LC-MS monitoring, water (50 mL) was added, and the aqueous phase was extracted with ethyl acetate (50 mL x 3), the combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. A mixture of acetic acid (40 mL) and toluene (60 mL) was added, and reduced iron powder (14.56 g, 0.26 mol) was added, and the reaction system was placed at 100°C for 3 hours. After the reaction was completed by LC-MS monitoring, diatomite was filtered, water (50 mL) was added to the filtrate, the aqueous phase was extracted with ethyl acetate (50 mL x 3), the combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (petroleum ether: ethyl acetate = 50:50 as eluent) gave compound 1-1 (2.68 g) in 97.8% yield.

[0130] MS-ESI calculated value [M-H] + 212.0 / 214.0, found 212.0 / 214.0.

[0131] 1 H NMR (400 MHz, DMSO-d6) δ 11.56 (s, 1H), 7.46 (t, J = 1.2 Hz, 1H), 7.43 (t, J = 2.8 Hz, 1H), 7.01 (dd, J = 10.0, 1.5 Hz, 1H), 6.51 (ddd, J = 3.0, 2.0, 0.9 Hz, 1H).

[0132] Step 2: Synthesis of compound 6-bromo-4-fluoroindoline (1-2)

[0133] Compound 1-1 (2.48 g, 11.64 mmol) was dissolved in dichloromethane (20 mL), triethylsilane (3.38 g, 29.10 mmol) and trifluoroacetic acid (5 mL) were added, and the reaction system was placed at 25 °C for 16 hours. After the reaction was completed by LC-MS monitoring, ammonia water was slowly added to the reaction system, and the aqueous phase was adjusted to basicity, the aqueous phase was extracted with dichloromethane (20 mL x 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 (petroleum ether: ethyl acetate = 75:25 as eluent) to obtain compound 1-2 (2.30 g) as a yellow liquid, with a yield of 92.0%.

[0134] MS-ESI calculated [M+H] + 216.0 / 218.0, found 216.0 / 218.0.

[0135] 1 H NMR (600 MHz, Chloroform-d) δ 6.55 (dd, J = 8.2, 1.5 Hz, 1H), 6.52 (d, J = 1.5 Hz, 1H), 3.62 (t, J = 8.5 Hz, 2H), 3.01 (t, J = 8.5 Hz, 2H).

[0136] Step 3: Synthesis of compound tert-butyl 6-bromo-4-fluoroindoline-1-carboxylate (1-3)

[0137] Compound 1-2 (1.28 g, 5.95 mmol) was dissolved in THF (10 mL), triethylamine (1.20 g, 11.90 mmol), 4-dimethylaminopyridine (725.90 mg, 5.95 mmol) and di-tert-butyl dicarbonate (5.16 g, 23.67 mmol) were added, and the reaction system was placed at 60 °C for 16 hours. After the reaction was completed by LC-MS monitoring, it was concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 95:5 as eluent) to obtain compound 1-3 (1.80 g) with a yield of 96.1%.

[0138] 1 H NMR (600 MHz, DMSO-d6) δ 7.79-7.53 (br s, 1H), 7.09 (dd, J = 8.3, 1.6 Hz, 1H), 3.98 (t, J = 8.7 Hz, 2H), 3.04 (t, J = 8.7 Hz, 2H), 1.50 (s, 9H).

[0139] Step 4: Synthesis of compound tert-butyl 4-fluoro-6-hydroxyindoline-1-carboxylate (1-4)

[0140] Compound 1-3 (1.80 g, 5.71 mmol), tris(dibenzylideneacetone)dipalladium (261.20 mg, 0.29 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (485.40 mg, 1.14 mmol) and potassium hydroxide (639.5 mg, 11.42 mmol) were added into a mixed solvent of 1,4-dioxane (10 mL) and water (10 mL), and the reaction was carried out at 100 °C for 6 hours under nitrogen protection. After the reaction was completed by LC-MS monitoring, 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 be acidic. The aqueous phase was extracted with dichloromethane (30 mL x 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 (petroleum ether: ethyl acetate = 65:35 as eluent) to obtain compound 1-4 (1.35 g) with a yield of 93.8%.

[0141] MS-ESI calculated value [M+H] + 254.1, found 254.0.

[0142] 1 H NMR (600 MHz, DMSO-d6) δ 9.68 (s, 1H), 7.07 (br s, 1H), 6.13 (dd, J = 10.7, 2.0 Hz, 1H), 3.91 (t, J = 8.6 Hz, 2H), 2.93 (t, J = 8.6 Hz, 2H), 1.49 (s, 9H).

[0143] Step 5: Synthesis of compound tert-butyl 6-(benzyloxy)-4-fluoroindoline-1-carboxylate (1-5)

[0144] Compound 1-4 (1.44 g, 5.69 mmol) was dissolved in N,N-dimethylformamide (20 mL), benzyl bromide (1.95 g, 11.38 mmol) and potassium carbonate (2.36 g, 17.07 mmol) were added and the reaction was allowed to proceed at 25 °C for 16 h. Upon completion of the reaction as monitored by TLC, water (30 mL) was added and the product was extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using petroleum ether: ethyl acetate (90: 10) as the eluent to obtain compound 1-5 (960.00 mg) in 49.2% yield.

[0145] MS-ESI calculated [M+H] + 344.2, found 344.0.

[0146] 1 H NMR (400 MHz, Chloroform-d) δ 7.58 - 7.46 (m, 2H), 7.43 - 7.29 (m, 4H), 5.15 (s, 2H), 4.02 (t, J = 8.7 Hz, 2H), 3.08 (t, J = 8.7 Hz, 2H), 1.55 (s, 9H).

[0147] Step 6: Synthesis of compound tert-butyl 6-(benzyloxy)-5-bromo-4-fluoroindoline-1- carboxylate (1-6)

[0148] Compound 1-5 (0.96 g, 2.80 mmol) was dissolved in acetonitrile (10 mL) and N- bromosuccinimide (498.40 mg, 2.80 mmol) was added and the reaction was allowed to proceed at 25 °C for 1 h. Upon completion of the reaction as monitored by LC-MS, water (30 mL) was added and the product was extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with water (30 mL), saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using petroleum ether: ethyl acetate (90: 10) as the eluent to obtain compound 1-6 (1.05 g) in 89.1% yield.

[0149] 1 H NMR (400 MHz, Chloroform-d) δ 7.58 - 7.46 (m, 2H), 7.43 - 7.29 (m, 4H), 5.15 (s, 2H), 4.02 (t, J = 8.7 Hz, 2H), 3.08 (t, J = 8.7 Hz, 2H), 1.55 (s, 9H).

[0150] Step 7: Synthesis of compound 6-(benzyloxy)-5-bromo-4-fluoroindoline (1-7)

[0151] Compound 1-6 (1.05 g, 2.49 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (5 mL) was added, and the reaction system was placed at 25 °C for 3 hours. After the reaction was completed by LC-MS monitoring, it was concentrated under reduced pressure, water (20 mL) was added, the aqueous phase was adjusted to basicity by saturated sodium bicarbonate aqueous solution, the aqueous phase was extracted with ethyl acetate (20 mL x 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 (petroleum ether: ethyl acetate = 75:25 as eluent) to obtain compound 1-7 (500 mg) with a yield of 62.6%.

[0152] MS-ESI calculated value [M+H] + 322.0 / 324.0, found 322.0 / 324.0.

[0153] 1 H NMR (600 MHz, Chloroform-d) δ 7.45 (d, J = 7.4 Hz, 2H), 7.41-7.35 (m, 2H), 7.34-7.29 (m, 1H), 6.10 (s, 1H), 5.09 (s, 2H), 3.61 (t, J = 8.4 Hz, 2H), 3.05 (t, J = 8.4 Hz, 2H).

[0154] Step 8: Synthesis of compound 6-(benzyloxy)-5-bromo-4-fluoro-N-phenylindole-1- carboxamide (1-8)

[0155] Aniline (131.1 mg, 1.41 mmol) and N,N-diisopropylethylamine (363.8 mg, 2.82 mmol) were dissolved in anhydrous dichloromethane (5 mL), a dichloromethane solution (3 mL) of triphosgene (139.6 mg, 0.47 mmol) was added dropwise at 0 °C, and then the reaction system was placed at 25 °C for 1 hour. After the reaction was completed by LC-MS monitoring, a dichloromethane solution (6 mL) of compound 1-7 (150.00 mg, 0.47 mmol) was added to the reaction system, and the reaction system was placed at 25 °C for 3 hours. After the reaction was completed by LC-MS monitoring, water (20 mL) was added, extracted with dichloromethane (20 mL x 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 (petroleum ether: ethyl acetate = 65:35 as eluent) to obtain compound 1-8 (167.00 mg) with a yield of 80.9%.

[0156] MS-ESI calculated value [M+H] + 441.1 / 443.1, found 441.0 / 443.0.

[0157] Step 9: Synthesis of compound tert-butyl (6-benzyloxy-4-fluoro-l- (phenylcarbamoyl)indol-5-yl)glycinate (1-9)

[0158] Compound 1-8 (167.00 mg, 0.38 mmol), tert-butyl glycinate (149.30 mg, 1.14 mmol), 2'-[(amino-N)[l,l'-biphenyl]-2-methyl-C][2'-[(l,l-dimethylethyl) phenylphosphino]-N2,N2,N6,N6-tetramethyl[l,l'-biphenyl]-2,6-diamine] (methylsulfonyl-0)palladium (31.00 mg, 0.04 mmol) and sodium tert-butoxide (109.40 mg, 1.14 mmol) were dissolved in dioxane (10 mL) and reacted at 100 °C for 16 hours under nitrogen protection. After the reaction was completed by LC-MS monitoring, the reaction solution was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 85: 15 as eluent) to obtain compound 1-9 (147.00 mg) with a yield of 78.8%.

[0159] MS-ESI calculated value [M+H] + 492.2, found 492.0.

[0160] Step 10: Synthesis of compound 6-benzyloxy-5-(l,l-dioxido-4-oxo-l,2,5- thiazolidin-2-yl)-4-fluoro-N-phenylindole-l-carboxamide (1-10)

[0161] Compound 1-9 (147.00 mg, 0.30 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), triethylamine (151.50 mg, 1.50 mmol) was added, the reaction solution was cooled to 0 °C, and a solution of chlorosulfonamide (173.30 mg, 1.50 mmol) in tetrahydrofuran (3 mL) was added dropwise. The reaction solution was stirred at room temperature for 1 hour. After the reaction was completed by LC-MS monitoring, the reaction solution was cooled to 0 °C, a solution of sodium methoxide in methanol (5.0 M, 0.6 mL) was added dropwise, and the reaction solution was stirred at room temperature for 30 minutes. After the reaction was completed by LC-MS monitoring, the reaction solution was diluted with ethyl acetate (10 mL), the methanol was removed by rotary evaporation under reduced pressure, the remaining reaction solution was adjusted to acidic pH with 1.0 M dilute hydrochloric acid, the aqueous phase was extracted with ethyl acetate (20 mL x 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 thin layer chromatography (dichloromethane:methanol = 85: 15 as eluent) to obtain compound 1-10 (40.00 mg) with a yield of 26.9%.

[0162] MS-ESI calculated value [M+H] +497.1, found 497.0.

[0163] Step 11: Synthesis of compound 5-(1,1 -dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-4- fluoro-6-hydroxy-N-phenylindoline-1 -carboxamide (1)

[0164] Compound 1-10 (40.00 mg, 0.08 mmol) was dissolved in methanol (5 mL), palladium on carbon (8.50 mg, 0.008 mmol) was added, and the reaction was stirred at 25 °C for 16 h under hydrogen atmosphere. When the reaction was completed by LC-MS monitoring, the reaction was filtered, concentrated under reduced pressure, and purified by HPLC to give compound 1 (2.1 mg) in 6.5% yield.

[0165] MS-ESI calculated [M+H] + 407.1, found 407.0.

[0166] 1 H NMR (600 MHz, DMSO-d6) δ 8.88 (s, 1H), 8.55 (s, 1H), 7.54 (d, J = 8.0 Hz, 2H), 7.32 - 7.26 (m, 3H), 7.02 (t, J = 7.3 Hz, 1H), 4.15 (t, J = 8.5 Hz, 2H), 3.91 (s, 2H), 3.08 (t, J = 8.5 Hz, 2H).

[0167] Example 2, Synthesis of 5-(4-fluoro-6-hydroxy-1-(4-hydroxy-6-methoxy pyrimidin-2-yl)indol-5-yl)-1,2,5-thiadiazolin-3-one 1,1 -dioxide (2)

[0168] Step 1: Synthesis of tert-butyl 6-(benzyloxy)-5-((2-(tert-butoxy)-2-oxoethyl)amino)- 4-fluoroindoline-1-carboxylate (2-1)

[0169] Compound 1-6 (2.00 g, 4.75 mmol), glycine tert-butyl ester (2.00 g, 15.3 mmol), tris(dibenzylideneacetone)dipalladium (0.920 g, 1.01 mmol), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-I- propyl-11'-biphenyl (0.540 g, 1.01 mmol) and cesium carbonate (4.90 g, 15.0 mmol) were dissolved in dioxane (60 mL) and stirred at 100 °C for 16 hours under nitrogen atmosphere. After the reaction was completed by LCMS monitoring, the reaction solution was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 90:10 as eluent) to obtain compound 2-1 (2.12 g) with a yield of 94.6%.

[0170] MS-ESI calculated value [M+H] + 473.3, found 473.0.

[0171] Step 2: Synthesis of 6-(benzyloxy)-5-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-4- fluoroinodo line-1 -carboxylic acid tert-butyl ester (2-2)

[0172] Compound 2-1 (2.12 g, 4.49 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), and pyridine (1.78 g, 22.5 mmol) was added. The reaction solution was cooled to 0 °C, and chlorosulfonamide (2.60 g, 22.4 mmol) was added dropwise. The reaction solution was stirred at room temperature for 1 hour. After the reaction was completed by LCMS monitoring, the reaction solution was cooled to 0 °C, and a sodium methoxide solution in methanol (5.0 M, 5.0 mL) was added dropwise. The reaction solution was stirred at room temperature for 30 minutes. After the reaction was completed by LCMS monitoring, the reaction solution was diluted with ethyl acetate (10 mL), and methanol was distilled off under reduced pressure. The remaining reaction solution was adjusted to an acidic pH with 1.0 M aqueous citric acid solution, and the aqueous phase was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (dichloromethane:methanol = 90:10 as eluent) yielded compound 2-2 (1.70 g) with a yield of 79.4%.

[0173] MS-ESI calculated value [M-H] – 476.1, found 476.0.

[0174] Step 3: Synthesis of 5-(6-(benzyloxy)-4-fluoroindolin-5-yl)-1,2,5-thiadiazolin-3-one 1,1- dioxide hydrochloride (2-3)

[0175] Compound 2-2 (2.50 g, 5.24 mmol) was dissolved in ethyl acetate (10 mL), hydrochloric acid ethyl acetate solution (4.0 M, 10 mL) was added, and the reaction liquid was placed at 25 °C for 2 hours. After the reaction was completed by LCMS monitoring, the reaction liquid was filtered, the filter cake was washed with ethyl acetate (5 mL x 3), and the filter cake was collected to obtain compound 2-3 (1.30 g, 3.15 mmol) with a yield of 60.1%.

[0176] MS-ESI calculated value [M-H] – 376.1, found 376.0.

[0177] 1 H NMR (600 MHz, DMSO-d6) δ 7.46-7.41 (m, 2H), 7.36 (dd, J = 8.4, 6.7 Hz, 2H), 7.32-7.28 (m, 1H), 6.13 (s, 1H), 5.08 (s, 2H), 4.33 (s, 2H), 3.51 (t, J = 8.6 Hz, 2H), 2.92 (t, J = 8.6 Hz, 2H).

[0178] Step 4: Synthesis of 5-(6-(benzyloxy)-1-(4-(benzyloxy-6-methoxy pyrimidin-2-yl)-4- fluoroindolin-5-yl)-1,2,5-thiadiazin-3-one 1,1-dioxide (2-4)

[0179] Compound 2-3 (0.200 g, 0.484 mmol), 4-(benzyloxy)-2-chloro-6-methoxypyrimidine (0.300 g, 1.20 mmol), tris(dibenzylideneacetone)dipalladium (0.100 g, 0.109 mmol), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-I-propyl-11'-biphenyl (70.0 mg, 0.130 mmol), and cesium carbonate (0.700 g, 2.15 mmol) were dissolved in tert-butanol (10 mL), and the reaction liquid was placed at 100 °C for 4 hours under nitrogen protection. After the reaction was completed by LCMS monitoring, the reaction liquid was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane:methanol = 90:10 as eluent) to obtain compound 2-4 (0.156 g) with a yield of 54.5%.

[0180] MS-ESI calculated value [M+H] + 592.2, found 592.0.

[0181] Step 5: Synthesis of 5-(4-fluoro-6-hydroxy-1-(4-hydroxy-6-methoxypyrimidin-2-yl)indolin-5- yl)-1,2,5-thiadiazin-3-one 1,1-dioxide (2)

[0182] Compound 2-4 (0.110 g, 0.186 mmol) was dissolved in a mixture solution of methanol (10 mL) and N,N-dimethylformamide (5 mL), palladium on carbon (10%, 40.0 mg, 0.0377 mol) was added, and the reaction was carried out at 25 °C for 16 hours under hydrogen atmosphere. After the reaction was completed by LCMS monitoring, the reaction solution was filtered, concentrated under reduced pressure, and purified by HPLC to obtain compound 2 (8.0 mg) with a yield of 10.5%.

[0183] MS-ESI calculated value [M-H] – 410.1, found 410.0.

[0184] 1 H NMR (600 MHz, DMSO-d6) δ 10.02 (s, 1H), 7.88 (s, 1H), 5.59 (s, 1H), 4.28 (s, 2H), 4.06 (t, J = 8.5, Hz, 2H), 3.88 (s, 3H), 3.12 - 3.04 (m, 2H).

[0185] Example 3, Synthesis of N-cyclohexyl-5-(1,1-dioxido-4-oxo-1,2,5-thiadiazol-2-yl)-4- fluoro-6-hydroxyindoline-1-carboxamide (3)

[0186] Step 1: Synthesis of 6-(benzyloxy)-N-cyclohexyl-5-(1,1-dioxido-4-oxo-1,2,5- thiadiazol-2-yl)-4-fluoroindoline-1-carboxamide (3-1)

[0187] Compound 2-3 (0.200 g, 0.484 mmol) and N,N-diisopropyl ethylamine (0.212 g, 1.64 mmol) were dissolved in acetonitrile (5 mL), cyclohexyl isocyanate (0.121 g, 0.968 mmol) was added, and the reaction was carried out at 25 °C for 4 hours. After the reaction was completed by LCMS monitoring, the reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane:methanol = 90:10 as eluent) to obtain compound 3-1 (0.166 g) with a yield of 68.3%.

[0188] MS-ESI calculated value [M-H] – 501.2, found 501.0.

[0189] Step 2: Synthesis of N-cyclohexyl-5-(1,1-dioxido-4-oxo-1,2,5-thiadiazol-2-yl)-4- fluoro-6-hydroxyindoline-1-carboxamide (3)

[0190] Compound 3-1 (0.166 g, 0.331 mmol) was dissolved in methanol (5 mL), palladium on carbon (10%, 35.0 mg, 0.0330 mol) was added, and the reaction was stirred at 25 °C for 16 hours under hydrogen atmosphere. When the reaction was completed by LCMS monitoring, the reaction was filtered, concentrated under reduced pressure, and purified by HPLC to obtain compound 3 (86.0 mg) with a yield of 63.2%.

[0191] MS-ESI calculated [M-H] – 411.1, found 411.0.

[0192] 1 H NMR (600 MHz, DMSO-d6) δ 9.05 (s, 1H), 7.24 (s, 1H), 6.30 (d, J = 7.8 Hz, 1H), 3.90 (s, 2H), 3.90 - 3.86 (m, 2H), 3.53 - 3.45 (m, 1H), 2.99 (t, J = 8.6 Hz, 2H), 1.82 - 1.75 (m, 2H), 1.75 - 1.66 (m, 2H), 1.59 (d, J = 13.0 Hz, 1H), 1.31 - 1.21 (m, 4H), 1.14 - 1.05 (m, 1H).

[0193] Example 4, Synthesis of 5-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-4-fluoro-6- hydroxyindoline-1-carboxamide (compound 4)

[0194] Step 1: Synthesis of 6-(benzyloxy)-5-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-4- fluoroindoline-1-carboxamide (4-1)

[0195] Compound 2-3 (100.0 mg, 0.24 mmol) was suspended in a mixed solvent of acetic acid (1 mL) and water (1 mL), potassium cyanate (60.0 mg, 0.72 mmol) was added, and the reaction was stirred at 25 °C for 1 hour. When the reaction was completed by LCMS monitoring, the reaction was concentrated under reduced pressure to obtain compound 4-1 (150.0 mg) as a crude product.

[0196] LC-MS (m / z): 421.0 [M+H] + .

[0197] Step 2: Synthesis of 5-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-4-fluoro-6- hydroxyindoline-1-carboxamide (4)

[0198] The crude product of compound 4-1 (150.0 mg) was dissolved in a mixed solvent of methanol (5 mL) and N,N-dimethylformamide (2 mL), palladium on carbon (10%, 51.0 mg, 48.1 μmol) was added, and the reaction solution was allowed to react at 25°C for 16 hours under a hydrogen atmosphere. After the reaction was completed as monitored by LCMS, the reaction solution was filtered, concentrated under reduced pressure, and purified by HPLC separation to obtain compound 4 (2.5 mg) in a two-step yield of 3.2%

[0199] LC-MS (m / z): 329.0 [M-H] – .

[0200] 1 H NMR (600 MHz, DMSO-d6) δ 7.27 (s, 1H), 7.09 (brs, 1H), 6.34 (s, 2H), 3.94-3.79 (m, 4H), 3.02-2.96 (m, 2H).

[0201] Example 5, Synthesis of 5-(1,1-dioxide-4-oxo-1,2,5-thiadiazolin-2-yl)-4-fluoro-6- hydroxy-N-methylindoline-1-carboxamide (5)

[0202] Step 1: Synthesis of 6-(benzyloxy)-5-(1,1-dioxide-4-oxo-1,2,5-thiadiazolin-2-yl)-4- fluoro-N-methylindoline-1-carboxamide

[0203] Compound 2-3 (0.200 g, 0.484 mmol) and N,N-diisopropylethylamine (0.263 g, 2.04 mmol) were dissolved in acetonitrile (5 mL), N-methyl-1-imidazolecarboxamide (0.121 g, 0.968 mmol) was added, and the reaction solution was allowed to react at 80°C for 16 hours. After the reaction was completed as monitored by LCMS, the reaction solution was concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane:methanol = 90:10 as eluent) to obtain compound 5-1 (0.167 g) in a yield of 79.5%.

[0204] MS-ESI calc [M-H] – 433.1, found 433.0.

[0205] Step 2: Synthesis of 5-(1,1-dioxide-4-oxo-1,2,5-thiadiazolin-2-yl)-4-fluoro-6-hydroxy-N- methylindoline-1-carboxamide

[0206] Compound 5-1 (0.167 g, 0.385 mmol) was dissolved in methanol (5 mL), palladium on carbon (10%, 40.0 mg, 0.0387 mol) was added, and the mixture was stirred at 25 °C for 6 h under hydrogen atmosphere. When the reaction was completed by LCMS monitoring, the reaction solution was filtered, concentrated under reduced pressure, and purified by HPLC to give compound 5 (5.2 mg) with a yield of 3.9%.

[0207] MS-ESI calculated value [M-H] – 343.1, found 343.0.

[0208] 1 H NMR (600 MHz, DMSO-d6) δ 9.57 (s, 1H), 7.32 (s, 1H), 6.70-6.61 (m, 1H), 4.10 (s, 2H), 3.88 (t, J = 8.6 Hz, 2H), 3.01 (t, J = 8.5 Hz, 2H), 2.65 (d, J = 4.2 Hz, 3H).

[0209] Example 6, Synthesis of 5-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-N-ethyl-4- fluoro-6-hydroxyindoline-1-carboxamide (6)

[0210] Step 1: Synthesis of 6-(benzyloxy)-5-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-N- ethyl-4-fluoroindoline-1-carboxamide (6-1)

[0211] Compound 2-3 (0.150 g, 0.363 mmol) and N,N-diisopropylethylamine (0.234 g, 1.81 mmol) were dissolved in acetonitrile (5 mL), ethyl isocyanate (77.3 mg, 1.09 mmol) was added, and the mixture was stirred at 25 °C for 16 h. When the reaction was completed by LCMS monitoring, the reaction solution was quenched with water (10 mL), the pH of the aqueous phase was adjusted to 2 with 2.0 M aqueous hydrochloric acid solution, and the filter cake was obtained by filtration. The filtrate was extracted with ethyl acetate (10 mL x 3), the organic phases were combined, and concentrated under reduced pressure. The product obtained by concentration under reduced pressure was combined with the filter cake to give compound 6-1 (0.150 g, crude).

[0212] MS-ESI calculated value [M+H] + 449.1, found 449.0.

[0213] Step 2: Synthesis of 5-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-N-ethyl-4-fluoro-6- hydroxyindoline-1-carboxamide

[0214] Compound 6-1 (0.150 g, 0.335 mmol) was dissolved in methanol (10 mL), palladium on carbon (10%, 15.0 mg) was added, and the reaction was stirred at 25 °C for 16 hours under hydrogen atmosphere. When the reaction was completed by LCMS monitoring, the reaction was filtered, concentrated under reduced pressure, and purified by HPLC to give compound 6 (63.0 mg) with a yield of 52.6%.

[0215] MS-ESI calculated [M+H] + 359.1, found 359.0.

[0216] 1 H NMR (600 MHz, DMSO-d6) δ 9.08 (s, 1H), 7.27 (s, 1H), 6.68 (t, J = 5.4 Hz, 1H), 3.91 (s, 2H), 3.87 (t, J = 8.4 Hz, 2H), 3.16 - 3.10 (m, 2H), 3.00 (t, J = 8.4 Hz, 2H), 1.07 (t, J = 7.2 Hz, 3H).

[0217] Example 7, Synthesis of 5-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-4-fluoro-6- hydroxy-N-isopropylindoline-1-carboxamide (Compound 7)

[0218] Step 1: Synthesis of 6-(benzyloxy)-5-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-4- fluoro-N-isopropylindoline-1-carboxamide (7-1)

[0219] Compound 2-3 (100.0 mg, 0.24 mmol) and triethylamine (73.0 mg, 0.72 mmol) were dissolved in acetonitrile (5 mL), isopropyl isocyanate (41.0 mg, 0.48 mmol) was added, and the reaction was stirred at 25 °C for 3 hours. When the reaction was completed by LCMS monitoring, the reaction was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 90:10 as eluent) to give compound 7-1 (100.0 mg) with a yield of 90.2%.

[0220] LC-MS (m / z): 461.0 [M-H] – .

[0221] Step 2: Synthesis of 5-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-4-fluoro-6-hydroxy-N- isopropylindoline-1-carboxamide (7)

[0222] Compound 7-1 (100.0 mg, 0.22 mmol) was dissolved in methanol (5 mL), and palladium on carbon (10%, 44.0 mg, 41.5 μmol) was added. The reaction mixture was placed at 25 °C for 16 hours under a hydrogen atmosphere. After the reaction was confirmed to be complete by LCMS, the reaction mixture was filtered, concentrated under reduced pressure, and purified by HPLC to obtain the ammonium salt of compound 7 (15.0 mg), with a yield of 18.3%.

[0223] LC-MS (m / z): 373.0 [M+H] + .

[0224] 1 H NMR (600MHz, DMSO-d6) δ9.03(s,1H),7.25(s,1H),7.10(t,J=46.5Hz,4H),6.33(d,J=7.8H z,1H),3.91–3.87(m,4H),3.87–3.84(m,1H),2.99(t,J=8.4Hz,2H),1.12(d,J=6.6Hz,6H).

[0225] Example 8: Synthesis of N-cyclopropyl-5-(1,1-dioxo-4-oxo-1,2,5-thiadiazolin-2-yl)-4-fluoro-6-hydroxyindoline-1-carboxamide (8)

[0226] Step 1: Synthesis of 6-(benzyloxy)-N-cyclopropyl-5-(1,1-dioxo-4-oxo-1,2,5-thiadiazolin-2-yl)-4-fluoroindoline-1-carboxamide

[0227] Compounds 2-3 (0.100 g, 0.242 mmol) and N,N-diisopropylethylamine (0.160 g, 1.24 mmol) were dissolved in acetonitrile (3 mL), and cyclopropyl isocyanate (60.0 mg, 0.723 mmol) was added. The mixture was reacted at 25 °C for 16 hours. After the reaction was complete as monitored by LCMS, water (10 mL) was added to quench the reaction. The pH of the aqueous phase was adjusted to 2 with 2.0 M hydrochloric acid solution, and the mixture was filtered to obtain a filter cake. The filtrate was extracted with ethyl acetate (10 mL × 3), and the organic phases were combined and concentrated under reduced pressure. The product obtained from the reduced pressure concentration was combined with the filter cake to obtain compound 8-1 (0.106 g, crude product).

[0228] MS-ESI calculated value [M+H] + 461.1, measured value 461.0.

[0229] Step 2: Synthesis of N-cyclopropyl-5-(1,1-dioxo-4-oxo-1,2,5-thiadiazolin-2-yl)-4-fluoro-6-hydroxyindole-1-carboxamide

[0230] Compound 8-1 (106.0 mg, 0.230 mmol) was dissolved in methanol (10 mL), palladium on carbon (10%, 10.0 mg) was added, and the reaction was stirred at 25 °C for 16 hours under hydrogen atmosphere. When the reaction was completed by LCMS monitoring, the reaction was filtered, concentrated under reduced pressure, and purified by HPLC to obtain compound 8 (7.3 mg) with a yield of 8.6%.

[0231] MS-ESI calculated value [M+H] + 371.1, found 371.0.

[0232] 1 H NMR (600 MHz, DMSO-d6) δ 9.05 (s, 1H), 7.26 (s, 1H), 6.75 (d, J = 3.0 Hz, 1H), 3.90 (s, 2H), 3.84 (t, J = 8.4 Hz, 2H), 2.98 (t, J = 8.4 Hz, 2H), 2.63-2.55 (m, 1H), 0.63-0.59 (m, 2H), 0.51-0.46 (m, 2H).

[0233] Synthesis of 5-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-4-fluoro-6-hydroxy-N- isopentylindoline-1-carboxamide (10)

[0234] Step 1: Synthesis of 4-nitrophenyl 6-(benzyloxy)-5-(1,1-dioxide-4-oxo-1,2,5- thiazolidin-2-yl)-4-fluoroindoline-1-carboxylate (10-1)

[0235] Compound 2-3 (0.100 g, 0.242 mmol) and pyridine (63.0 mg, 0.797 mmol) were dissolved in dichloromethane (5 mL), and p-nitrophenyl chloroformate (58.6 mg, 0.290 mmol) was added. The reaction was stirred at 25 °C for 1 hour. When the reaction was completed by LCMS monitoring, the aqueous phase was adjusted to be acidic by using 1.0 M aqueous citric acid solution, and the aqueous phase was extracted with dichloromethane (10 mL x 3). The combined organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (dichloromethane:methanol = 90:10 as eluent) gave compound 10-1 (45.0 mg) with a yield of 34.3%.

[0236] MS-ESI calculated value [M-H] – 541.1, found 541.0.

[0237] Step 2: Synthesis of 6-(benzyloxy)-5-(1,1 -dioxide-4-oxo-1,2,5-thiadiazol-2-yl)-4- fluoro-N-isopentenylindoline-1 -carboxamide (10-2)

[0238] Compound 10-1 (45.0 mg, 0.0830 mmol), isopentylamine (35.0 mg, 0.402 mmol) and N,N-diisopropyl ethylamine (52.0 mg, 0.403 mmol) were dissolved in tetrahydrofuran (2 mL) and stirred at 70 °C for 16 hours in a sealed tube. When the reaction was completed by LCMS monitoring, the reaction solution was concentrated under reduced pressure, and separated and purified by thin layer chromatography (dichloromethane:methanol = 98:2 as eluent) to obtain compound 10-2 (40.0 mg) with a yield of 97.6%.

[0239] MS-ESI calculated value [M-H] – 489.2, found 489.0.

[0240] Step 3: Synthesis of 5-(1,1 -dioxide-4-oxo-1,2,5-thiadiazol-2-yl)-4-fluoro-6- hydroxy-N-isopentylindoline-1 -carboxamide (10)

[0241] Compound 10-2 (40.0 mg, 0.0816 mmol) was dissolved in methanol (5 mL), and palladium-carbon (10%, 10.0 mg, 0.00943 mol) was added, and stirred at 25 °C for 6 hours under hydrogen atmosphere. When the reaction was completed by LCMS monitoring, the reaction solution was filtered, concentrated under reduced pressure, and purified by HPLC preparation to obtain compound 10 (6.6 mg) with a yield of 20.2%

[0242] MS-ESI calculated value [M-H] – 399.1, found 399.0.

[0243] 1 H NMR (600 MHz, DMSO-d6) δ 7.25 (s, 1 H), 6.63 (t, J = 5.5 Hz, 1 H), 3.88 (s, 2H), 3.87 (t, J = 8.6 Hz, 2H), 3.16 - 3.09 (m, 2H), 3.06 - 2.94 (m, 2H), 1.37 (q, J = 7.1 Hz, 2H), 1.30 - 1.21 (m, 1 H), 0.89 (d, J = 6.6 Hz, 6H).

[0244] Example 11, Synthesis of N-cyclopentyl-5-(1,1 -dioxide-4-oxo-1,2,5-thiadiazol-2-yl)- 4-fluoro-6-hydroxyindoline-1 -carboxamide (11 ) MS-ESI calculated value [M-H] 1 H NMR (600 MHz, DMSO-d6) δ 7.25 (s, 1 H), 6.63 (t, J = 5.5 Hz, 1 H), 3.88 (s, 2H), 3.87 (t, J = 8.6 Hz, 2H), 3.16 - 3.09 (m, 2H), 3.06 - 2.94 (m, 2H), 1.37 (q, J = 7.1 Hz, 2H), 1.30 - 1.21 (m, 1 H), 0.89 (d, J = 6.6 Hz, 6H).

[0245] Step 1: Synthesis of 6-(benzyloxy)-N-cyclopentyl-5-(l,l-dioxido-4-oxo-l,2,5- thiadiazolidin-2-yl)-4-fluoroindoline-l-carboxamide (11-1)

[0246] Compound 2-3 (0.100 g, 0.265 mmol) and triethylamine (53.5 mg, 0.530 mmol) were dissolved in acetonitrile (3 mL), and cyclopentyl isocyanate (88.2 mg, 0.795 mmol) was added. The reaction solution was allowed to react at 25 °C for 2 hours. After the reaction was completed by LCMS monitoring, the reaction solution was diluted with water, and 1.0 M dilute hydrochloric acid (2 mL) was added. The mixture was extracted with dichloromethane (10 mL x 3), and the combined organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by thin layer chromatography (dichloromethane:methanol = 90:10 as eluent) gave compound 11-1 (0.102 g) in a yield of 78.8%.

[0247] MS-ESI calculated value [M-H] – 487.2, found 487.0.

[0248] Step 2: Synthesis of N-cyclopentyl-5-(l,l-dioxido-4-oxo-l,2,5-thiadiazolidin-2-yl)-4- fluoro-6-hydroxyindoline-l-carboxamide (11)

[0249] Compound 11-1 (0.102 g, 0.209 mmol) was dissolved in methanol (5 mL), and palladium-carbon (10%, 43.0 mg, 0.0405 mmol) was added. The reaction solution was allowed to react at 25 °C for 16 hours under a hydrogen atmosphere. After the reaction was completed by LCMS monitoring, the reaction solution was filtered, concentrated under reduced pressure, and purified by thin layer chromatography (dichloromethane:methanol = 75:25 as eluent) to obtain compound 11 (56.3 mg) in a yield of 67.7%

[0250] MS-ESI calculated value [M-H] – 397.1, found 397.0.

[0251] 1 H NMR (600 MHz, DMSO-d6) δ 8.81 (s, 1H), 7.24 (s, 1H), 6.38 (d, J = 7.1 Hz, 1H), 4.00 (p, J = 7.1 Hz, 1H), 3.94 - 3.85 (m, 4H), 2.99 (t, J = 8.6 Hz, 2H), 1.90 - 1.79 (m, 2H), 1.71 - 1.61 (m, 2H), 1.48 (qd, J = 11.2, 5.2 Hz, 4H).

[0252] Example 15, Synthesis of 5-(l,l-dioxide-4-oxo-l,2,5-thiadiazolidin-2-yl)-4-fluoro-6- hydroxy-N-(l-methylcyclopropyl)indoline-l-carboxamide (15)

[0253] Step 1: Synthesis of 6-(benzyloxy)-5-(l,l-dioxide-4-oxo-l,2,5-thiadiazolidin-2-yl)-4- fluoro-N-(l-methylcyclopropyl)indoline-l-carboxamide (15)

[0254] To a solution of l-methylcyclopropanamine hydrochloride (78.0 mg, 0.72 mmol) and N,N- diisopropylethylamine (187.0 mg, 1.45 mmol) in anhydrous dichloromethane (5 mL) was added dropwise a solution of triphosgene (72.0 mg, 0.24 mmol) in anhydrous dichloromethane (1 mL) at -50 °C. The reaction was stirred at -50 °C for 20 min, then compound 2-3 (100.0 mg, 0.24 mmol) was added at -50 °C. The reaction was stirred at 25 °C for 2 h. When the reaction was completed by LCMS, the reaction was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 90: 10 as eluent) to give compound 15-1 (100.0 mg) in 87.9% yield.

[0255] LC-MS (m / z): 473.0 [M - H] – .

[0256] Step 2: Synthesis of 5-(l,l-dioxide-4-oxo-l,2,5-thiadiazolidin-2-yl)-4-fluoro-6-hydroxy-N- (l-methylcyclopropyl)indoline-l-carboxamide (15)

[0257] To a solution of compound 15-1 (100.0 mg, 0.21 mmol) in methanol (5 mL) was added palladium on carbon (10%, 20.0 mg, 18.9 μmol). The reaction was stirred at 25 °C for 16 h under hydrogen atmosphere. When the reaction was completed by LCMS, the reaction was filtered and concentrated under reduced pressure. Compound 15 (17.0 mg) was obtained by HPLC purification in 21.1% yield.

[0258] LC-MS (m / z): 385.0 [M + H] + .

[0259] 1H NMR (600 MHz, DMSO-d6) δ 7.63 (br s, 1H), 7.25 (s, 1H), 6.94 (s, 1H), 3.88 (s, 2H), 3.81 (t, J = 8.6 Hz, 2H), 2.96 (t, J = 8.6 Hz, 2H), 1.32 (s, 3H), 0.70 - 0.65 (m, 2H), 0.57 - 0.51 (m, 2H).

[0260] Example 21. Synthesis of N-(tetrahydro-2H-pyran-4-yl)-5-(1,1-dioxido-4-oxo- 1,2,5-thiadiazol-2-yl)-4-fluoro-6-hydroxyindoline-1 -carboxamide (21)

[0261] Step 1. Synthesis of 6-(benzyloxy)-N-(tetrahydro-2H-pyran-4-yl)-5-(1,1-dioxido-4- oxo-1,2,5-thiadiazol-2-yl)-4-fluoroindoline-1 -carboxamide (21-1)

[0262] Compound 2-3 (0.100 g, 0.265 mmol) and triethylamine (80.3 mg, 0.795 mmol) were dissolved in acetonitrile (3 mL), and at 0 °C, triphosgene (35.3 mg, 0.119 mmol) was added, and it was allowed to react at 25 °C for 30 minutes. When the reaction was completed by LC-MS monitoring, 4- aminotetrahydropyran (53.5 mg, 0.530 mmol) was added at 0 °C, and it was allowed to react at 25 °C for 1.5 hours. When the reaction was completed by LCMS monitoring, the reaction solution was concentrated under reduced pressure, and thin layer chromatography plate was purified (dichloromethane:methanol = 90:10 as eluent) to obtain compound 21-1 (0.115 g) at a yield of 86.2%.

[0263] MS-ESI calculated [M-H] – 503.1, found 503.0.

[0264] Step 2. Synthesis of N-(tetrahydro-2H-pyran-4-yl)-5-(1,1-dioxido-4-oxo-1,2,5- thiadiazol-2-yl)-4-fluoro-6-hydroxyindoline-1 -carboxamide

[0265] Compound 21-1 (0.115 g, 0.227 mmol) was dissolved in methanol (3 mL), and palladium-carbon (10%, 43.0 mg, 0.0403 mmol) was added, and it was allowed to react at 25 °C for 16 hours under a hydrogen atmosphere. When the reaction was completed by LCMS monitoring, the reaction solution was filtered, concentrated under reduced pressure, and purified by HPLC preparation to obtain compound 21 (8.9 mg) at a yield of 9.4%.

[0266] MS-ESI calculated [M-H] – 413.1, found 413.0.

[0267] 1 H NMR (600 MHz, DMSO-d6) δ 9.05 (s, 1H), 7.24 (s, 1H), 6.44 (d, J = 7.7 Hz, 1H), 3.96 - 3.82 (m, 7H), 3.81 - 3.67 (m, 2H), 3.00 (t, J = 8.6 Hz, 2H), 1.76 - 1.66 (m, 2H), 1.53 (dd, J = 12.1, 4.3 Hz, 1H), 1.28 - 1.23 (m, 1H).

[0268] Example 30, Synthesis of N-benzyl-5-(1,1-dioxido-4-oxo-1,2,5-thiadiazolin-2-yl)-4- fluoro-6-hydroxyindoline-1-carboxamide (30)

[0269] Step 1 : Synthesis of 6-(benzyloxy)-N-benzyl-5-(1,1-dioxido-4-oxo-1,2,5-thiadiazolin-2- yl)-4-fluoroindoline-1-carboxamide (30-1 )

[0270] Compound 2-3 (0.100 g, 0.265 mmol) and triethylamine (53.5 mg, 0.530 mmol) were dissolved in acetonitrile (3 mL), benzyl isocyanate (0.106 g, 0.795 mmol) was added, and the reaction solution was allowed to react at 25 °C for 2 hours. After the reaction was completed as monitored by LCMS, the reaction solution was diluted with water, 1.0 M dilute hydrochloric acid (2 mL) was added, and dichloromethane (10 mL x 3) was extracted. The combined organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification was performed by thin layer chromatography (dichloromethane:methanol = 90:10 as eluent) to obtain compound 30-1 (0.105 g) in a yield of 85.0%.

[0271] MS-ESI calculated [M-H] – 509.1, found 509.0.

[0272] Step 2: Synthesis of N-benzyl-5-(1,1-dioxido-4-oxo-1,2,5-thiadiazolin-2-yl)-4-fluoro-6- hydroxyindoline-1-carboxamide

[0273] Compound 30-1 (0.107 g, 0.207 mmol) was dissolved in tetrahydrofuran (3 mL), and palladium on carbon (10%, 42.0 mg, 0.0404 mmol) was added. The mixture was reacted at 25 °C for 16 hours under a hydrogen atmosphere. After the reaction was confirmed to be complete by LCMS, the reaction solution was filtered, concentrated under reduced pressure, and purified by HPLC to obtain compound 30 (18.2 mg), with a yield of 19.2%.

[0274] MS-ESI calculated value [MH] – 419.1, measured value 419.0.

[0275] 1 H NMR(600MHz,DMSO-d6)δ9.08(s,1H),7.31(d,J=4.5Hz,5H),7.27(s,1H),7.23(h,J=4.4H z,1H),4.32(d,J=5.8Hz,2H),3.96(t,J=8.5Hz,2H),3.91(s,2H),3.03(t,J=8.5Hz,2H).

[0276] Example 52: Synthesis of 5-(4-fluoro-6-hydroxy-1-(1H-1,2,4-triazol-3-ylindoline-5-yl)-1,2,5-thiadiazolin-3-one 1,1-dioxide (52)

[0277] Step 1: Synthesis of 5-(6-(benzyloxy)-4-fluoro-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)indololin-5-yl)-1,2,5-thiadiazolin-3-one 1,1-dioxide (52-1)

[0278] Compounds 2-3 (0.290 g, 0.702 mmol), 3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole (0.580 g, 2.09 mmol), 2-(di-tert-butylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl(2-amino-1,1'-biphenyl-2-yl)palladium (67.0 mg, 0.0705 mg), and cesium carbonate (0.687 g, 2.11 mmol) were dissolved in tert-butanol (15 mL) and reacted at 90 °C for 16 hours under nitrogen protection. After the reaction was monitored by LCMS to be complete, the reaction solution was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane:methanol = 80:20 as eluent) to obtain compound 52-1 (0.200 g), with a yield of 49.6%.

[0279] MS-ESI calculated value [MH]– 573.2, found 573.0.

[0280] Step 2: Synthesis of 5-(6-(benzyloxy)-4-fluoro-l-(lH-l,2,4-triazol-3-yl)indolin-5-yl)- 1,2,5-thiadiazolidin-3-one 1,1-dioxide (52-2)

[0281] Compound 52-1 (0.160 g, 0.279 mmol) was dissolved in tetrahydrofuran (15 mL), tetrabutylammonium fluoride (0.330 g, 1.26 mmol) was added, and the reaction solution was reacted at 70 °C for 16 hours. After the reaction was completed by LCMS monitoring, the reaction solution was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane:methanol = 80:20 as eluent) to obtain compound 52-2 (0.100 g) with a yield of 80.6%.

[0282] MS-ESI calculated [M+H] + 445.1, found 445.0.

[0283] Step 3: Synthesis of 5-(4-fluoro-6-hydroxy-l-(lH-l,2,4-triazol-3-ylindolin-5-yl)- 1,2,5-thiadiazolidin-3-one 1,1-dioxide (52)

[0284] Compound 52-2 (0.100 g, 0.225 mmol) was dissolved in methanol (5 mL), palladium-carbon (10%, 24.0 mg, 0.0226 mol) was added, and the reaction solution was reacted at 25 °C for 6 hours under a hydrogen atmosphere. After the reaction was completed by LCMS monitoring, the reaction solution was filtered, concentrated under reduced pressure, and purified by HPLC preparation to obtain compound 52 (7.0 mg) with a yield of 8.8%

[0285] MS-ESI calculated [M+H] + 355.1, found 355.0.

[0286] 1 H NMR (600 MHz, DMSO-d6) δ 13.48 (s, 1H), 9.03 (s, 1H), 8.35 (s, 1H), 7.28 (s, 1H), 4.04 (t, J = 8.6 Hz, 2H), 3.89 (s, 2H), 3.07 (t, J = 8.7 Hz, 2H).

[0287] Example 54, Synthesis of 5-(4-fluoro-6-hydroxy-l-(2H-l,2,3-triazol-4-yl)indolin-5-yl)- 1,2,5-thiadiazolidin-3-one-l,l-dioxide (54) MS-ESI calculated [M+H]

[0288] Step 1: Synthesis of 5-(6-(benzyloxy)-4-fluoro-l-(2-((2- (trimethylsilyl)ethoxy)methyl)-2H-l,2,3-triazol-4-yl)indolin-5-yl)-l,2,5-thiadiazol-3- one- 1,1 -dioxide (54-1)

[0289] Compound 2-3 (0.250 g, 0.605 mmol), 4-bromo-2-((2- (trimethylsilyl)ethoxy)methyl)-2H-l,2,3-triazole (0.350 g, 1.26 mmol), 2-(di-tert- butylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl- 1,1 '-biphenyl-2-amine palladium (0.125 g, 0.132 mmol) and cesium carbonate (0.625 g, 1.92 mmol) were dissolved in tert-butanol (15 mL) and stirred at 100 °C for 9 h under nitrogen. When the reaction was completed by LCMS, the reaction was filtered and concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane:methanol = 80:20 as eluent) to give compound 54-1 (0.339 g) in 97.6% yield.

[0290] MS-ESI calculated [M-H] – 573.2, found 573.0.

[0291] Step 2: Synthesis of 5-(6-(benzyloxy)-4-fluoro-l-(2H-l,2,3-triazol-4- yl)indolin-5-yl)-l,2,5-thiadiazolidin-3-one- 1,1 -dioxide (54-2)

[0292] Compound 54-1 (0.339 g, 0.591 mmol) was dissolved in tetrahydrofuran (10 mL), and tetrabutylammonium fluoride hydrate (0.230 g, 0.881 mmol) was added. The reaction was stirred at 70 °C for 16 h. When the reaction was completed by LCMS, the reaction was filtered and concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane:methanol = 90:10 as eluent) to give compound 54-2 (86.0 mg) in 32.8% yield.

[0293] MS-ESI calculated [M+H] + 445.1, found 445.0.

[0294] Step 3: Synthesis of 5-(4-fluoro-6-hydroxy-l-(2H-l,2,3-triazol-4- yl)indolin-5-yl)-l,2,5-thiadiazolidin-3-one- 1,1 -dioxide (54)

[0295] Compound 54-2 (86.0 mg, 0.194 mmol) was dissolved in methanol (6 mL), palladium on carbon (10%, 21.0 mg, 19.8 μmol) was added, and the reaction was stirred at 25 °C for 16 h under hydrogen atmosphere. When the reaction was completed by LCMS, the reaction was filtered, concentrated under reduced pressure, and purified by HPLC to give compound 54 (10.1 mg) in 14.7% yield.

[0296] MS-ESI calculated [M+H] + 355.1, found 355.0.

[0297] 1 H NMR (600 MHz, DMSO-d6) δ 9.03 (s, 1H), 7.55 (s, 1H), 7.07 (s, 1H), 6.93 (s, 1H), 3.95 (t, J = 8.5 Hz, 2H), 3.89 (s, 2H), 3.09 (t, J = 8.6 Hz, 2H).

[0298] Example 57, Synthesis of N-cyclopentyl-5'-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-4'-fluoro-6'-hydroxyspiro[cyclopropane-1,3'-indolin]-1'-formamide (57)

[0299] Step 1: Synthesis of 2-(4-bromo-2-fluoro-6-nitrophenyl)acetic acid (57-1)

[0300] Compound 57-1 (8.70 g) was dissolved in acetic acid (15 mL) and concentrated hydrochloric acid (15 mL), and the reaction was stirred at 110 °C for 6 h. When the reaction was completed by TLC, the reaction was slowly poured into water (100 mL), and a solid was precipitated and filtered. The filter cake was washed with water (50 mL x 2) to give compound 57-1 (8.70 g) as a crude product.

[0301] Step 2: Synthesis of 6-bromo-4-fluoroindolin-2-one (57-2)

[0302] The crude product of compound 57-1 (8.70 g) was dissolved in acetic acid (80 mL), and iron powder (4.72 g, 84.49 mmol) was added. The reaction was placed at 100 °C for 4 h. After the reaction was completed by LCMS monitoring, the reaction was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (100 mL) and filtered through diatomite. The filtrate was added to water (100 mL), and the aqueous phase was extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with saturated sodium chloride solution (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 70:30 as eluent) to give compound 57-2 (5.50 g) in a two-step yield of 76.41%.

[0303] LC-MS (m / z): 228.0 [M-H] – .

[0304] Step 3: Synthesis of 6'-bromo-4'-fluorospiro[cyclopropane-l,3'-indol]-2'-one (57-3)

[0305] Compound 57-2 (4.10 g, 17.82 mmol) was dissolved in N,N-dimethylformamide (100 mL), and (2-bromoethyl)diphenylsulfonium trifluoromethanesulfonate (9.48 g, 21.39 mmol) and zinc trifluoromethanesulfonate (12.96 g, 35.65 mmol) were added sequentially. The reaction was stirred at 25 °C for 30 min, and then triethylamine (5.41 g, 53.47 mmol) was added. The reaction was placed at 25 °C for 4 h. After the reaction was completed by TLC monitoring, the reaction was poured into saturated aqueous ammonium chloride solution (150 mL), and the aqueous phase was extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with water (100 mL x 2) and saturated sodium chloride solution (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: ethyl acetate = 60:40 as eluent) to give compound 57-3 (3.90 g) in a yield of 76.16%.

[0306] LC-MS (m / z): 256.0 / 258.0 [M+H] + .

[0307] 1 H NMR (600 MHz, DMSO-d6) δ 10.92 (s, 1H), 7.08 (d, J = 9.6 Hz, 1H), 6.93 (d, J = 1.2 Hz, 1H), 1.78 (q, J = 4.2 Hz, 2H), 1.47 (q, J = 4.2 Hz, 2H).

[0308] Step 4: Synthesis of 6'-bromo-4'-fluorospiro[cyclopropane-l,3'-indole] (57-4)

[0309] Compound 57-3 (3.90 g, 15.23 mmol) was dissolved in anhydrous tetrahydrofuran (45 mL), and borane dimethyl sulfide (2.0 M, 38.07 mL, 76.15 mmol) was added dropwise at 0 °C. The reaction was placed at 60 °C for 3 hours under nitrogen protection. After the reaction was completed by LCMS monitoring, the reaction was cooled to 0 °C, and 1.0 M dilute hydrochloric acid (80 mL) was added slowly dropwise. The reaction was placed at 60 °C for 30 minutes, and then the aqueous phase was adjusted to basic with saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate (100 mL x 3), washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: ethyl acetate = 95:5 as eluent) to give compound 57-4 (4.00 g) in 98.04% yield.

[0310] LC-MS (m / z): 242.0 / 244.0 [M+H] + .

[0311] 1 H NMR (600 MHz, DMSO-d6) δ 6.44 (dd, J = 9.6, 1.2 Hz, 1H), 6.42 (d, J = 1.2 Hz, 1H), 6.22 (s, 1H), 3.49 (s, 2H), 1.20 (q, J = 4.2 Hz, 2H), 0.88 (q, J = 4.2 Hz, 2H).

[0312] Step 5: Synthesis of tert-butyl 6'-bromo-4'-fluorospiro[cyclopropane-l,3'-indole]-l'- carboxylate (57-5)

[0313] Compound 57-4 (4.00 g, 16.52 mmol) and 4-dimethylaminopyridine (4.04 g, 33.05 mmol) were dissolved in tetrahydrofuran (80 mL), and di-tert-butyl dicarbonate (16.23 g, 74.35 mmol) was added. The reaction was placed at 50 °C for 1 hour. After the reaction was completed by LCMS monitoring, the reaction was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 95:5 as eluent) to give compound 57-5 (6.00 g) as a crude product.

[0314] 1H NMR (600 MHz, DMSO-d6) δ 7.72 (s, 1H), 7.02 (dd, J = 9.6, 1.8 Hz, 1H), 3.92 (s, 2H), 1.50 (s, 9H), 1.34 - 1.30 (m, 2H), 1.09 - 1.05 (m, 2H).

[0315] Step 6: Synthesis of tert-butyl 4'-fluoro-6'-hydroxyspiro[cyclopropane-l,3'-indol]-l'- carboxylate (57-6)

[0316] The crude product of compound 57-5 (6.00 g) was dissolved in a mixture solvent of anhydrous dioxane (50 mL) and water (50 mL), and then tris(dibenzylideneacetone)dipalladium (0.80 g, 0.88 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (1.49 g, 3.51 mmol) and potassium hydroxide (1.97 g, 35.07 mmol) were added successively. The reaction solution was placed at 100 °C for 5 hours under nitrogen protection. After the reaction was completed by LCMS monitoring, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residual aqueous solution was added dropwise with 1.0 M aqueous citric acid solution, and the aqueous phase was adjusted to be acidic. The aqueous phase was extracted with dichloromethane (50 mL x 3), and the combined organic phase was washed with saturated sodium chloride solution (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: ethyl acetate = 90: 10 as eluent) to give compound 57-6 (3.30 g) with a two-step yield of 58.41%.

[0317] LC-MS (m / z): 280.0 [M+H] + .

[0318] 1 H NMR (600 MHz, DMSO-d6) δ 9.68 (s, 1H), 7.37 - 6.65 (m, 1H), 6.07 (d, J = 12.0 Hz, 1H), 3.85 (s, 2H), 1.49 (s, 9H), 1.22 - 1.16 (m, 2H), 0.98 - 0.92 (m, 2H).

[0319] Step 7: Synthesis of tert-butyl 6'-(benzyloxy)-4'-fluorospiro[cyclopropane-l,3'-indol]-l'- carboxylate (57-7)

[0320] Compound 57-6 (3.30 g, 11.81 mmol) and potassium carbonate (4.90 g, 35.44 mmol) were dissolved in N,N-dimethylformamide (100 mL), and benzyl bromide (4.04 g, 23.63 mmol) was added, and the reaction solution was allowed to react at 25°C for 16 hours. After completion of the reaction was confirmed by LCMS, the reaction solution was poured into water (300 mL), and the aqueous phase was extracted with ethyl acetate (100 mL x 3), and the combined organic phase was washed with saturated sodium chloride solution (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: ethyl acetate = 90:10 as eluent) to obtain compound 57-7 (4.20 g) at a yield of 96.22%.

[0321] LC-MS (m / z): 370.0 [M+H] + .

[0322] 1 H NMR (600 MHz, DMSO-d6) δ 7.47-7.21 (m, 6H), 6.43 (d, J = 12.0 Hz, 1H), 5.07 (s, 2H), 3.89 (s, 2H), 1.49 (s, 9H), 1.25-1.21 (m, 2H), 1.02-0.95 (m, 2H).

[0323] Step 8: Synthesis of tert-butyl 6'-(benzyloxy)-5'-bromo-4'-fluorospiro[cyclopropane-1,3'-indole]-1'-carboxylate (57-8)

[0324] Compound 57-7 (3.70 g, 10.02 mmol) was dissolved in acetonitrile (50 mL), and N-bromosuccinimide (1.78 g, 10.02 mmol) was added, and the reaction solution was allowed to react at 25°C for 1 hour. After completion of the reaction was confirmed by TLC, the reaction solution was concentrated under reduced pressure, the filter cake was collected by filtration, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: ethyl acetate = 95:5 as eluent) to obtain compound 57-8 (4.50 g) at a yield of 88.29%.

[0325] 1 H NMR (600 MHz, DMSO-d6) δ 7.47-7.21 (m, 6H), 6.43 (d, J = 12.0 Hz, 1H), 5.07 (s, 2H), 3.89 (s, 2H), 1.49 (s, 9H), 1.25-1.21 (m, 2H), 1.02-0.95 (m, 2H).

[0326] Step 9: Synthesis of tert-butyl 6'-(benzyloxy)-5'-((2-(tert-butoxy)-2-oxoethyl)amino)-4'-fluorospiro[cyclopropane-1,3'-indoline]-1'-carboxylate (57-9)

[0327] Compound 57-8 (1.00 g, 2.23 mmol) was dissolved in anhydrous dioxane (15 mL), and then glycine tert-butyl ester (0.88 g, 6.69 mmol), cesium carbonate (2.18 g, 6.69 mmol), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-I-propyl-11'-biphenyl (0.24 g, 0.45 mmol) and tris(dibenzylideneacetone)dipalladium (0.41 g, 0.45 mmol) were added successively. The reaction was carried out at 100 °C for 16 h under nitrogen protection. After the reaction was completed by LCMS monitoring, the reaction was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 95:5 as eluent) to give compound 57-9 (0.61 g) with a yield of 54.85%.

[0328] LC-MS (m / z): 499.0 [M+H] + .

[0329] Step 10: Synthesis of tert-butyl 6'-(benzyloxy)-5'-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-4'-fluorospiro[cyclopropane-1,3'-indolin]-1'-carboxylate (57-10)

[0330] Compound 57-9 (0.61 g, 1.22 mmol) and pyridine (0.29 g, 3.67 mmol) were dissolved in anhydrous tetrahydrofuran (10 mL), and then a solution of sulfamoyl chloride (0.42 g, 3.67 mmol) in anhydrous tetrahydrofuran (2 mL) was added at 0 °C. The reaction was carried out at 25 °C for 1 h under nitrogen protection. After the reaction was completed by LCMS monitoring, the reaction was cooled to 0 °C, and then a solution of sodium methoxide in methanol (5.0 M, 0.85 mL, 4.28 mmol) was slowly added. After the reaction was completed by LCMS monitoring, the reaction was poured into a citric acid solution (1.0 M, 100 mL), and the aqueous phase was extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with saturated sodium chloride solution (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 80:20 as eluent) to give compound 57-10 (0.50 g) with a yield of 81.16%.

[0331] LC-MS (m / z): 502.0 [M-H] – .

[0332] Step 11: Synthesis of 5-(6'-(benzyloxy)-4'-fluorospiro[cyclopropane-1,3'-indol]-5'-yl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (57-11)

[0333] Compound 57-10 (0.50 g, 0.99 mmol) was dissolved in hydrogen chloride ethyl acetate solution (4.0 M, 5 mL), the reaction was placed at 25 °C for 1 hour. After LCMS monitoring reaction complete, the reaction was filtered, the filter cake was dried to give compound 57-11 (0.34 g) as a crude product.

[0334] LC-MS (m / z): 402.0 [M-H] – .

[0335] Step 12: Synthesis of 6'-(benzyloxy)-N-cyclopentyl-5'-(1,1-dioxide-4-oxo-1,2,5- thiadiazolidin-2-yl)-4'-fluorospiro[cyclopropane-1,3'-indolin]-1'-formamide (57-12)

[0336] The above compound 57-11 crude product (0.10 g) was dissolved in anhydrous acetonitrile (2 mL), N,N-diisopropyl ethylamine (0.15 g, 1.14 mmol) and cyclopentyl isocyanate (0.08 g, 0.68 mmol) were added successively, the reaction was placed at 25 °C for 1 hour. After LCMS monitoring reaction complete, the reaction was concentrated under reduced pressure, the residue was purified by TLC (dichloromethane:methanol = 90:10 as eluent) to give compound 57-12 (0.14 g) as a crude product.

[0337] LC-MS (m / z): 515.0 [M+H] + .

[0338] Step 13: Synthesis of N-cyclopentyl-5'-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-4'-fluoro-6'-hydroxyspiro[cyclopropane-1,3'-indolin]-1'-formamide (57)

[0339] The above compound 57-12 crude product (0.14 g) was dissolved in methanol (5 mL), palladium on carbon (10%, 0.02 g, 18.9 μmol) was added, the reaction was placed at 25 °C for 16 hours under hydrogen atmosphere. After LCMS monitoring reaction complete, the reaction was concentrated under reduced pressure, the residue was purified by HPLC to give ammonium salt of compound 57 (45.4 mg) with 11.33% three-step yield.

[0340] LC-MS (m / z): 425.0 [M+H] + .

[0341] 1H NMR (600 MHz, DMSO-d6) δ 9.07 (s, 1H), 7.29 (s, 1H), 7.08 (t, J = 51.0 Hz, 4H), 6.30 (d, J = 7.2 Hz, 1H), 4.03 - 3.96 (m, 1H), 3.94 - 3.77 (m, 4H), 1.89 - 1.77 (m, 2H), 1.71 - 1.60 (m, 2H), 1.56 - 1.40 (m, 4H), 1.29 - 1.16 (m, 2H), 0.97 - 0.84 (m, 2H).

[0342] Example 85, Synthesis of 5-(1,1 -dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-4-fluoro-6- hydroxy-N-propylindoline-1 -carboxamide (85)

[0343] Step 1 : Synthesis of 6-(benzyloxy)-5-(1,1 -dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-4- fluoro-N-propylindoline-1 -carboxamide (85-1 )

[0344] Compound 2-3 (0.100 g, 0.242 mmol) and N,N-diisopropylethylamine (0.156 g, 1.21 mmol) were dissolved in acetonitrile (3 mL), propyl isocyanate (61.7 mg, 0.726 mmol) was added, and the mixture was reacted at 25 °C for 16 hours. After the reaction was completed as monitored by LCMS, the reaction solution was quenched with water (10 mL), the aqueous phase was adjusted to pH 2 with 2.0 M aqueous hydrochloric acid solution, and the filter cake was obtained by filtration. The filtrate was extracted with ethyl acetate (10 mL x 3), the organic phases were combined, and concentrated under reduced pressure. The product obtained by concentration under reduced pressure was combined with the filter cake to obtain compound 85-1 (0.177 g, crude).

[0345] MS-ESI calculated value [M+H] + 463.1, found 463.0.

[0346] Step 2: Synthesis of 5-(1,1 -dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-4-fluoro-6-hydroxy-N- propylindoline-1 -carboxamide (85)

[0347] Compound 85-1 (0.177 g, 0.383 mmol) was dissolved in methanol (10 mL), palladium on carbon (10%, 20.0 mg) was added, and the mixture was reacted at 25 °C for 16 hours under a hydrogen atmosphere. After the reaction was completed as monitored by LCMS, the reaction solution was filtered, concentrated under reduced pressure, and purified by HPLC to obtain compound 85 (9.6 mg) with a yield of 6.7%

[0348] MS-ESI calculated for [M+H] + 373.1, found 373.0.

[0349] 1 H NMR (600 MHz, DMSO-d6) δ 9.05 (s, 1H), 7.26 (s, 1H), 6.68 (t, J = 5.4 Hz, 1H), 3.92 - 3.86 (m, 4H), 3.06 (q, J = 6.6 Hz, 2H), 3.00 (t, J = 8.4 Hz, 2H), 1.52 - 1.44 (m, 2H), 0.86 (t, J = 7.2 Hz, 3H).

[0350] Example 86, Synthesis of 5-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-4-fluoro-6- hydroxy-N-(2,2,2-trifluoroethyl)indoline-1-carboxamide (86)

[0351] Step 1: Synthesis of 6-(benzyloxy)-5-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-4- fluoro-N-(2,2,2-trifluoroethyl)indoline-1-carboxamide (86-1)

[0352] Compound 2-3 (0.100 g, 0.242 mmol) and N,N-diisopropyl ethylamine (93.0 mg, 0.721 mmol) were dissolved in anhydrous acetonitrile (3 mL), a solution of triphosgene (36.0 mg, 0.121 mmol) in acetonitrile (2 mL) was added dropwise at 0 °C, and then the reaction system was placed at 25 °C for 30 minutes. After the reaction was completed by LC-MS monitoring, a solution of 2,2,2-trifluoroethylamine (48.0 mg, 0.485 mmol) in acetonitrile (1 mL) was added to the reaction system, and the reaction system was placed at 25 °C for 1 hour. After the reaction was completed by LC-MS monitoring, the reaction was quenched with a 1.0 M aqueous hydrochloric acid solution (10 mL), and the aqueous phase was extracted with ethyl acetate (20 mL x 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 (dichloromethane:methanol = 90:10 as eluent) to obtain compound 86-1 (60.0 mg) with a yield of 49.4%.

[0353] MS-ESI calculated for [M-H] – 501.1, found 501.0.

[0354] Step 2: Synthesis of 5-(1,1 -dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-4-fluoro-6- hydroxy-N-(2,2,2-trifluoroethyl)indoline-1 -carboxamide (86)

[0355] Compound 86-1 (60.0 mg, 0.120 mmol) was dissolved in a mixed solution of methanol (6 mL) and N,N-dimethylformamide (2 mL), palladium on carbon (10%, 20.0 mg, 0.0189 mol) was added, and the reaction was carried out at 25 °C for 16 hours under a hydrogen atmosphere. After the reaction was completed as monitored by LCMS, the reaction solution was filtered, concentrated under reduced pressure, and purified by HPLC to obtain compound 86 (5.1 mg) at a yield of 10.3%.

[0356] MS-ESI calculated value [M-H] – 411.0, found 411.0.

[0357] 1 H NMR (600 MHz, DMSO-d6) δ 9.15 (s, 1H), 7.36 (t, J = 6.2 Hz, 1H), 7.26 (s, 1H), 4.01 - 3.79 (m, 6H), 3.04 (t, J = 8.5 Hz, 2H).

[0358] Example 87, Synthesis of N-(4-fluorophenyl)-5-(1,1 -dioxide-4-oxo-1,2,5- thiadiazolidin-2-yl)-4-fluoro-6-hydroxyindoline-1 -carboxamide (87)

[0359] Step 1 : Synthesis of 6-(benzyloxy)-N-(4-fluorophenyl)-5-(1,1 -dioxide-4-oxo-1,2,5- thiadiazolidin-2-yl)-4-fluoroindoline-1 -carboxamide (87-1 )

[0360] Compound 2-3 (0.100 g, 0.265 mmol) and triethylamine (53.5 mg, 0.530 mmol) were dissolved in acetonitrile (3 mL), 4-fluorophenyl isocyanate (0.109 g, 0.795 mmol) was added, and the reaction was carried out at 25 °C for 2 hours. After the reaction was completed as monitored by LCMS, the reaction solution was diluted with water, 1.0 M dilute hydrochloric acid (2 mL) was added, and dichloromethane (10 mL x 3) was extracted. The combined organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by thin layer chromatography (dichloromethane:methanol = 95:5 as eluent) to obtain compound 87-1 (0.113 g) at a yield of 82.3%.

[0361] MS-ESI calculated value [M-H]– 513.1, found 513.0.

[0362] Step 2: Synthesis of N-(4-fluorophenyl)-5-(1,1-dioxido-4-oxo-1,2,5-thiadiazol-2-yl)- 4-fluoro-6-hydroxyindoline-1-carboxamide (87)

[0363] Compound 87-1 (0.113 g, 0.219 mmol) was dissolved in tetrahydrofuran (3 mL), palladium on carbon (10%, 46.0 mg, 0.0406 mmol) was added, and the reaction was stirred at 25 °C for 16 h under hydrogen atmosphere. When the reaction was completed by LCMS monitoring, the reaction was filtered, concentrated under reduced pressure, and separated and purified by thin layer chromatography (dichloromethane:methanol = 85:15 as eluent) to give compound 87 (24.9 mg) with a yield of 26.7%.

[0364] MS-ESI calculated [M-H] – 423.1, found 423.0.

[0365] 1 H NMR (600 MHz, DMSO-d6) δ 9.15 (s, 1H), 8.61 (s, 1H), 7.58 - 7.52 (m, 2H), 7.28 (s, 1H), 7.13 (t, J = 8.9 Hz, 2H), 4.13 (t, J = 8.5 Hz, 2H), 3.90 (s, 2H), 3.08 (t, J = 8.5 Hz, 2H).

[0366] Example 88, Synthesis of N-(3-fluorophenyl)-5-(1,1-dioxido-4-oxo-1,2,5-thiadiazol-2- yl)-4-fluoro-6-hydroxyindoline-1-carboxamide (88)

[0367] Step 1 : Synthesis of 6-(benzyloxy)-N-(3-fluorophenyl)-5-(1,1-dioxido-4-oxo-1,2,5- thiadiazol-2-yl)-4-fluoroindoline-1-carboxamide (88-1 )

[0368] Compound 2-3 (0.100 g, 0.265 mmol) and triethylamine (53.4 mg, 0.530 mmol) were dissolved in acetonitrile (3 mL), and 3-fluorophenyl isocyanate (0.109 g, 0.795 mmol) was added. The reaction solution was allowed to react at 25°C for 2 hours. After the completion of the reaction was confirmed by LCMS, the reaction solution was diluted with water, and 1.0 M diluted hydrochloric acid (2 mL) was added. The mixture was extracted with dichloromethane (10 mL x 3), and the combined organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by thin layer chromatography (dichloromethane:methanol = 95:5 as eluent) gave compound 88-1 (0.107 g) in a yield of 78.5%.

[0369] MS-ESI calculated value [M-H] – 513.1, observed value 513.0.

[0370] Step 2: Synthesis of N-(3-fluorophenyl)-5-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-4-fluoro-6-hydroxyindoline-1-carboxamide (88)

[0371] Compound 88-1 (0.107 g, 0.207 mmol) was dissolved in tetrahydrofuran (3 mL), and palladium-carbon (10%, 42.0 mg, 0.0404 mmol) was added. The reaction solution was allowed to react at 25°C for 16 hours under a hydrogen atmosphere. After the completion of the reaction was confirmed by LCMS, the reaction solution was filtered, concentrated under reduced pressure, and purified by thin layer chromatography (dichloromethane:methanol = 85:15 as eluent) to obtain compound 88 (15.1 mg) in a yield of 16.2%.

[0372] MS-ESI calculated value [M-H] – 423.1, observed value 423.0.

[0373] 1 H NMR (600 MHz, DMSO-d6) δ 9.19 (s, 1H), 8.74 (s, 1H), 7.52 (dt, J = 12.0, 2.3 Hz, 1H), 7.37 (dt, J = 8.2, 1.3 Hz, 1H), 7.35 - 7.27 (m, 2H), 6.83 (td, J = 8.4, 2.6 Hz, 1H), 4.15 (t, J = 8.4 Hz, 2H), 3.91 (s, 2H), 3.08 (t, J = 8.5 Hz, 2H).

[0374] Example 89, Synthesis of N-(3,4-difluorophenyl)-5-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-4-fluoro-6-hydroxyindoline-1-carboxamide (89)

[0375] Step 1: Synthesis of 6-(benzyloxy)-N-(3,4-difluorophenyl)-5-(1,1-dioxide-4-oxo- 1,2,5-thiadiazolidin-2-yl)-4-fluoroindoline-1-carboxamide (89-1)

[0376] Compound 2-3 (0.100 g, 0.242 mmol) and triethylamine (0.107 g, 1.06 mmol) were dissolved in acetonitrile (3 mL), 3,4-difluorophenyl isothiocyanate (82.0 mg, 0.529 mmol) was added, and the reaction was allowed to react at 25 °C for 3 hours. After the reaction was completed by LCMS monitoring, the reaction was diluted with water, 1.0 M dilute hydrochloric acid (2 mL) was added, and dichloromethane (10 mL x 3) was extracted. The combined organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification was performed by thin layer chromatography (dichloromethane:methanol = 95:5 as eluent) to obtain compound 89-1 (86.0 mg) with a yield of 66.8%.

[0377] MS-ESI calculated value [M-H] – 531.1, found 531.0.

[0378] Step 2: Synthesis of N-(3,4-difluorophenyl)-5-(1,1-dioxide-4-oxo-1,2,5- thiadiazolidin-2-yl)-4-fluoro-6-hydroxyindole-1-carboxamide (89)

[0379] Compound 89-1 (86.0 mg, 0.162 mmol) was dissolved in tetrahydrofuran (3 mL), and palladium-carbon (10%, 42.0 mg, 39.6 μmol) was added. The reaction was allowed to react at 25 °C for 16 hours under a hydrogen atmosphere. After the reaction was completed by LCMS monitoring, the reaction was filtered, concentrated under reduced pressure, and purified by thin layer chromatography (dichloromethane:methanol = 85:15 as eluent) to obtain compound 89 (19.7 mg) with a yield of 29.5%.

[0380] MS-ESI calculated value [M-H] – 441.1, found 441.0.

[0381] 1 H NMR (600 MHz, DMSO-d6) δ 9.20 (s, 1H), 8.76 (s, 1H), 7.75-7.64 (m, 1H), 7.44-7.32 (m, 2H), 7.28 (s, 1H), 4.14 (t, J = 8.5 Hz, 2H), 3.91 (s, 2H), 3.08 (t, J = 8.4 Hz, 2H).

[0382] Example 90, Synthesis of N-(3,5-difluorophenyl)-5-(1,1-dioxido-4-oxo-1,2,5- thiadiazolidin-2-yl)-4-fluoro-6-hydroxyindole-1-carboxamide (90)

[0383] Step 1: Synthesis of 6-(benzyloxy)-N-(3,5-difluorophenyl)-5-(1,1-dioxido-4-oxo-1,2,5- thiadiazolidin-2-yl)-4-fluoroindoline-1-carboxamide (90-1)

[0384] Compound 2-3 (0.100 g, 0.242 mmol) and triethylamine (0.107 g, 1.06 mmol) were dissolved in acetonitrile (3 mL), 3,5-difluorophenyl isothiocyanate (82.0 mg, 0.529 mmol) was added, and the reaction solution was allowed to react at 25°C for 3 hours. After the reaction was completed as monitored by LCMS, the reaction solution was diluted with water, 1.0 M dilute hydrochloric acid (2 mL) was added, and dichloromethane (10 mL x 3) was extracted. The combined organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification was performed by thin layer chromatography (dichloromethane:methanol = 95:5 as eluent) to obtain compound 90-1 (0.126 g) at a yield of 97.7%.

[0385] MS-ESI calculated value [M-H] – 531.1, found 531.0.

[0386] Step 2: Synthesis of N-(3,5-difluorophenyl)-5-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-4- fluoro-6-hydroxyindole-1-carboxamide (90)

[0387] Compound 90-1 (0.126 g, 0.237 mmol) was dissolved in tetrahydrofuran (3 mL), and palladium-carbon (10%, 43.0 mg, 40.6 μmol) was added. The reaction was allowed to react at 25°C for 16 hours under a hydrogen atmosphere. After the reaction was completed as monitored by LCMS, the reaction solution was filtered, concentrated under reduced pressure, and purified by thin layer chromatography (dichloromethane:methanol = 85:15 as eluent) to obtain compound 90 (24.0 mg) at a yield of 22.9%.

[0388] MS-ESI calculated value [M-H] – 441.1, found 441.0.

[0389] 1H NMR (600 MHz, DMSO-d6) δ 9.25 (s, 1H), 8.90 (s, 1H), 7.43 - 7.32 (m, 2H), 7.29 (s, 1H), 6.84 (tt, J = 9.2, 2.4 Hz, 1H), 4.15 (t, J = 8.4 Hz, 2H), 3.91 (s, 2H), 3.09 (t, J = 8.4 Hz, 2H).

[0390] Example 91, Synthesis of 5-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-4-fluoro-6- hydroxy-N-(4-(trifluoromethyl)phenyl)indole-1-carboxamide (91)

[0391] Step 1: Synthesis of 6-(benzyloxy)-5-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-4- fluoro-N-(4-(trifluoromethyl)phenyl)indoline-1-carboxamide (91-1)

[0392] Compound 2-3 (0.100 g, 0.265 mmol) and triethylamine (80.0 mg, 0.792 mmol) were dissolved in acetonitrile (3 mL), 4-trifluoromethylphenyl isocyanate (0.149 g, 0.795 mmol) was added, and the reaction solution was allowed to react at 25 °C for 2 hours. After the reaction was completed as monitored by LCMS, the reaction solution was diluted with water, 1.0 M dilute hydrochloric acid (2 mL) was added, and dichloromethane (10 mL x 3) was added. The combined organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification was performed by thin layer chromatography (dichloromethane:methanol = 95:5 as eluent) to obtain compound 91-1 (0.116 g) in a yield of 77.5%.

[0393] MS-ESI calculated [M-H] – 563.1, found 563.0.

[0394] Step 2: Synthesis of 5-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-4-fluoro-6-hydroxy-N- (4-(trifluoromethyl)phenyl)indole-1-carboxamide (91)

[0395] Compound 91-1 (0.116 g, 0.205 mmol) was dissolved in tetrahydrofuran (3 mL), and palladium-carbon (10%, 48.0 mg, 40.6 μmol) was added. The reaction was allowed to react at 25 °C for 16 hours under a hydrogen atmosphere. After the reaction was completed as monitored by LCMS, the reaction solution was filtered, concentrated under reduced pressure, and purified by thin layer chromatography (dichloromethane:methanol = 85:15 as eluent) to obtain compound 91 (19.6 mg) in a yield of 20.1%.

[0396] MS-ESI calculated [M-H] – 473.1, found 473.0.

[0397] 1 H NMR (600 MHz, DMSO-d6) δ 9.07 (s, 1H), 8.92 (s, 1H), 7.80 (d, J = 8.5 Hz, 2H), 7.65 (d, J = 8.5 Hz, 2H), 7.30 (s, 1H), 4.18 (t, J = 8.5 Hz, 2H), 3.91 (s, 2H), 3.09 (t, J = 8.5 Hz, 2H).

[0398] Example 92, Synthesis of 5-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-4-fluoro-6- hydroxy-N-(3-(trifluoromethyl)phenyl)indoline-1-carboxamide (92)

[0399] Step 1: Synthesis of 6-(benzyloxy)-5-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-4- fluoro-N-(3-(trifluoromethyl)phenyl)indoline-1-carboxamide (92-1)

[0400] Compound 2-3 (0.100 g, 0.242 mmol) and triethylamine (0.107 g, 1.06 mmol) were dissolved in acetonitrile (3 mL), and 3-(trifluoromethyl)phenyl isocyanate (99.0 mg, 0.529 mmol) was added. The reaction solution was placed at 25 °C for 3 hours. When the reaction was completed by LCMS monitoring, the reaction solution was diluted with water, 1.0 M dilute hydrochloric acid (2 mL) was added, and dichloromethane (10 mL x 3) was extracted. The combined organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification was performed on a thin layer chromatography plate (dichloromethane:methanol = 90:10 as eluent) to obtain compound 92-1 (0.132 g) with a yield of 96.7%.

[0401] MS-ESI calculated [M-H] – 563.1, found 563.0.

[0402] Step 2: Synthesis of 5-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-4-fluoro-6-hydroxy-N- (3-(trifluoromethyl)phenyl)indoline-1-carboxamide (92)

[0403] Compound 92-1 (0.132 g, 0.234 mmol) was dissolved in tetrahydrofuran (3 mL), palladium on carbon (10%, 56.0 mg, 52.8 μmol) was added, and the reaction was stirred at 25 °C for 16 hours under hydrogen atmosphere. When the reaction was completed by LCMS monitoring, the reaction was filtered, concentrated under reduced pressure, and purified by thin layer chromatography (dichloromethane:methanol = 85:15 as eluent) to give compound 92 (39.2 mg) with a yield of 35.3%.

[0404] MS-ESI calculated [M-H] – 473.1, found 473.0.

[0405] 1 H NMR (600 MHz, DMSO-d6) δ 9.01 (s, 1H), 8.88 (s, 1H), 8.01 (d, J = 2.0 Hz, 1H), 7.87 (dd, J = 8.2, 2.2 Hz, 1H), 7.53 (t, J = 8.0 Hz, 1H), 7.36 (d, J = 7.7 Hz, 1H), 7.32 (s, 1H), 4.18 (t, J = 8.4 Hz, 2H), 3.91 (s, 2H), 3.09 (t, J = 8.4 Hz, 2H).

[0406] Example 93, Synthesis of N-(3-chlorophenyl)-5-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-4-fluoro-6-hydroxyindole-1-carboxamide (93)

[0407] Step 1: Synthesis of 6-(benzyloxy)-N-(3-chlorophenyl)-5-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-4-fluoroindole-1-carboxamide (93-1)

[0408] Compound 2-3 (0.100 g, 0.242 mmol) and triethylamine (0.107 g, 1.06 mmol) were dissolved in acetonitrile (3 mL), m-chlorobenzenesulfonyl isocyanate (81.0 mg, 0.529 mmol) was added, and the reaction was stirred at 25 °C for 3 hours. When the reaction was completed by LCMS monitoring, the reaction was diluted with water, 1.0 M dilute hydrochloric acid (2 mL) was added, and dichloromethane (10 mL x 3) was used for extraction. The combined organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by thin layer chromatography (dichloromethane:methanol = 90:10 as eluent) to give compound 93-1 (0.128 g) with a yield of 99.8%.

[0409] MS-ESI calculated [M-H] –529.1, found 529.0.

[0410] Step 2: Synthesis of N-(3-chlorophenyl)-5-(1,1 -dioxide-4-oxo- 1,2,5-thiadiazolidin-2-yl)-4-fluoro-6-hydroxyindoline-1 -carboxamide (93)

[0411] Compound 93-1 (0.128 g, 0.241 mmol) was dissolved in a mixture solution of tetrahydrofuran (3 mL) and ethyl acetate (3 mL), palladium on carbon (10%, 56.0 mg, 52.8 μmol) and zinc bromide (14.0 mg, 0.0622 mmol) were added, and the reaction was stirred at 25 °C for 58 h under hydrogen atmosphere. When the reaction was completed by LCMS monitoring, the reaction was filtered, concentrated under reduced pressure, and purified by HPLC to give compound 93 (6.6 mg) in 6.2% yield.

[0412] MS-ESI calculated [M-H] – 439.0, found 439.0.

[0413] 1 H NMR (600 MHz, DMSO-d6) δ 8.72 (s, 1H), 7.73 (t, J = 2.2 Hz, 1H), 7.56 - 7.50 (m, 1H), 7.36 - 7.28 (m, 2H), 7.07 (dd, J = 8.0, 2.2 Hz, 2H), 4.15 (t, J = 8.5 Hz, 2H), 3.91 (s, 2H), 3.08 (t, J = 8.4 Hz, 2H).

[0414] Example 94, Synthesis of N-(3,3-difluorocyclobutyl)-5-(1,1 -dioxide-4-oxo- 1,2,5-thiadiazolidin-2-yl)-4-fluoro-6-hydroxyindoline-1 -carboxamide (94)

[0415] Step 1 : Synthesis of 6-(benzyloxy)-N-(3,3-difluorocyclobutyl)-5-(1,1 -dioxide-4- oxo-1,2,5-thiadiazolidin-2-yl)-4-fluoroindoline-1 -carboxamide (94-1 )

[0416] Compound 3,3-difluorocyclobutylamine hydrochloride (0.103 g, 0.720 mmol) and N,N-diisopropylethylamine (0.185 g, 1.43 mmol) were dissolved in anhydrous acetonitrile (5 mL), and a solution of triphosgene (71.0 mg, 0.239 mmol) in anhydrous acetonitrile (2 mL) was added at 0 °C. The reaction was stirred at 0 °C for 10 min. Then compound 2-3 (0.100 g, 0.242 mmol) was added at 0 °C, and the reaction was stirred at 25 °C for 2 h. When the reaction was completed by LCMS, the reaction was concentrated under reduced pressure, and purified by thin layer chromatography (dichloromethane:methanol = 90:10 as eluent) to give compound 94-1 (0.100 g) in 81.0% yield.

[0417] MS-ESI calculated [M+H] + 511.1, found 511.0.

[0418] Step 2: Synthesis of N-(3,3-difluorocyclobutyl)-5-(1.1-dioxido-4-oxo-1.2.5- thiadiazolidin-2-yl)-4-fluoro-6-hydroxyindoline-1-carboxamide (94)

[0419] Compound 94-1 (0.100 g, 0.196 mmol) was dissolved in methanol (10 mL), and palladium hydroxide on carbon (20%, 40.0 mg, 57.1 μmol) was added. The reaction was stirred at 25 °C for 16 h under hydrogen atmosphere. When the reaction was completed by LCMS, the reaction was filtered, concentrated under reduced pressure, and purified by HPLC prep to give compound 94 (10.2 mg) in 12.4% yield.

[0420] MS-ESI calculated [M-H] – 419.1, found 419.0.

[0421] 1 H NMR (600 MHz, DMSO-d6) δ 9.10 (s, 1H), 7.25 (s, 1H), 7.03 (d, J = 6.8 Hz, 1H), 4.07 (p, J = 7.5 Hz, 1H), 3.97 - 3.85 (m, 4H), 3.02 (t, J = 8.5 Hz, 2H), 2.92 - 2.81 (m, 2H), 2.76 - 2.65 (m, 2H).

[0422] Example 95, Synthesis of N-(3,3-difluorocyclopentyl)-5-(1.1-dioxido-4-oxo-1.2.5- thiadiazolidin-2-yl)-4-fluoro-6-hydroxyindoline-1-carboxamide (95)

[0423] Step 1 : Synthesis of 6-(benzyloxy)-N-(3,3-difluorocyclopentyl)-5-(1,1-dioxide-4- oxo-1,2,5-thiadiazolidin-2-yl)-4-fluoroindoline-1 -carboxamide (95-1 )

[0424] Compound 2-3 (0.100 g, 0.242 mmol) and N,N-diisopropyl ethylamine (0.156 g, 1.21 mmol) were dissolved in anhydrous dichloromethane (5 mL), and a solution of triphosgene (42.0 mg, 0.141 mmol) in anhydrous dichloromethane (2 mL) was added at -50 °C. The reaction was allowed to react at 25 °C for 30 minutes. Then a solution of compound 3,3-difluorocyclopentylamine hydrochloride (76.0 mg, 0.484 mmol) in anhydrous dichloromethane (2 mL) was added, and the reaction was allowed to react at 25 °C for 1 hour. When the reaction was completed by LCMS, the reaction was concentrated under reduced pressure, and preparative plate separation and purification (dichloromethane:methanol = 90:10 as eluent) gave compound 95-1 (0.100 g) with a yield of 78.9%.

[0425] MS-ESI calculated [M+H] + 525.1, found 525.0.

[0426] Step 2: Synthesis of N-(3,3-difluorocyclopentyl)-5-(1,1-dioxide-4-oxo-1,2,5- thiadiazolidin-2-yl)-4-fluoro-6-hydroxyindoline-1 -carboxamide (95)

[0427] Compound 95-1 (0.100 g, 0.191 mmol) was dissolved in methanol (6 mL), and palladium on carbon (10%, 56.0 mg, 52.8 μmol) was added. The reaction was allowed to react at 25 °C for 32 hours under a hydrogen atmosphere. When the reaction was completed by LCMS, the reaction was filtered, concentrated under reduced pressure, and purified by HPLC preparation to give compound 95 (26.6 mg) with a yield of 32.1 %

[0428] MS-ESI calculated [M-H] – 433.1, found 433.0.

[0429] 1H NMR (600 MHz, DMSO-d6) δ 9.13 (s, 1H), 7.25 (s, 1H), 6.72 (d, J = 7.2 Hz, 1H), 4.21 (h, J = 8.0 Hz, 1H), 3.95 - 3.86 (m, 4H), 3.01 (t, J = 8.5 Hz, 2H), 2.44 (tt, J = 15.5, 8.1 Hz, 1H), 2.22 (td, J = 17.5, 14.0, 10.1 Hz, 1H), 2.18 - 2.10 (m, 1H), 2.04 (tdd, J = 14.1, 8.1, 4.2 Hz, 2H), 1.78 (pd, J = 8.2, 7.6, 3.6 Hz, 1H).

[0430] Example 97, Synthesis of 5-(4-fluoro-6-hydroxy-l-(l,4,5,6-tetrahydropyrimidin-2- yl)indolin-5-yl)-l,2,5-thiadiazolidine-3-one-l,l-dioxide (97)

[0431] Step 1: Synthesis of 5-(6-(benzyloxy)-4-fluoro-l-(pyrimidin-2-yl)indolin-5-yl)-l,2,5- thiadiazole-3-one-l,l-dioxide (97-1)

[0432] Compound 2-3 (0.100 g, 0.242 mmol), 2-chloropyrimidine (84.0 mg, 0.730 mmol), methanesulfonic acid-2-(di-tert-butylphosphino)-3,6-dimethoxy-2',4',6'- triisopropyl-l,l'-biphenyl-2-yl)palladium (23.0 mg, 24.2 μmol) and cesium carbonate (0.234 g, 0.718 mmol) were dissolved in t-butanol (10 mL) and stirred at 100 °C for 2 hours under nitrogen. After the reaction was completed by LCMS monitoring, it was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane:methanol = 90:10 as eluent) to obtain compound 97-1 (0.100 g) with a yield of 90.6%.

[0433] MS-ESI calculated [M+H] + 456.1, found 456.0.

[0434] Step 2: Synthesis of 5-(4-fluoro-6-hydroxy-l-(l,4,5,6-tetrahydropyrimidin-2- yl)indolin-5-yl)-l,2,5-thiadiazolidine-3-one-l,l-dioxide (97)

[0435] Compound 97-1 (0.100 g, 0.220 mmol) was dissolved in methanol (15 mL), concentrated hydrochloric acid (40 μL) was added, palladium on carbon (10%, 23.0 mg, 21.7 μmol) was added, and the reaction was stirred at 25 °C for 16 hours under hydrogen atmosphere. When the reaction was completed by LCMS monitoring, the reaction was filtered, concentrated under reduced pressure, and purified by HPLC to give compound 97 (6.6 mg) in 8.1% yield.

[0436] MS-ESI calculated [M-H] – 368.1, found 368.0.

[0437] 1 H NMR (600 MHz, DMSO-d6) δ 8.30 - 7.91 (m, 2H), 6.67 (s, 1H), 4.00 (t, J = 8.1 Hz, 2H), 3.91 (s, 2H), 3.37 (t, J = 5.8 Hz, 4H), 3.03 (t, J = 8.2 Hz, 2H), 1.88 (p, J = 5.8 Hz, 2H).

[0438] Example 98, Synthesis of N-(3,5-difluorophenyl)-5'-(1,1-dioxide-4-oxo-1,2,5- thiazolidin-2-yl)-4'-fluoro-6'-hydroxyspiro[cyclopropane-1,3'-indolin]-1'-carboxamide (98)

[0439] Step 1: Synthesis of 6'-(benzyloxy)-N-(3,5-difluorophenyl)-5'-(1,1-dioxide-4-oxo-1,2,5- thiazolidin-2-yl)-4'-fluorospiro[cyclopropane-1,3'-indolin]-1'-carboxamide (98-1)

[0440] Compound 57-11 (100.0 mg, 0.23 mmol) and triethylamine (69.0 mg, 0.68 mmol) were dissolved in acetonitrile (5 mL), 3,5-difluoro phenylhydrazine carboxylate (71.0 mg, 0.46 mmol) was added, and the reaction was stirred at 25 °C for 1 hour. When the reaction was completed by LCMS monitoring, the reaction was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 90:10 as eluent) to give compound 98-1 (100.0 mg) in 77.9% yield.

[0441] LC-MS (m / z): 557.0 [M-H] – .

[0442] Step 2: Synthesis of N-(3,5-difluorophenyl)-5'-(1,1-dioxide-4-oxo-1,2,5- thiadiazolidin-2-yl)-4'-fluoro-6'-hydroxyspiro[cyclopropane-1,3'-indolin]-1'- carboxamide (98)

[0443] Compound 98-1 (100.0 mg, 0.18 mmol) was dissolved in methanol (5 mL), palladium on carbon (10%, 40.0 mg, 37.7 μmol) was added, and the reaction was stirred at 25 °C for 16 h under hydrogen atmosphere. When the reaction was completed by LCMS monitoring, the reaction was filtered, concentrated under reduced pressure, and purified by HPLC to give the ammonium salt of compound 98 (24.0 mg) in 28.5% yield.

[0444] LC-MS (m / z): 469.0 [M+H] + .

[0445] 1 H NMR (600 MHz, DMSO-d6) δ 9.39 (s, 1H), 8.85 (s, 1H), 7.37 - 7.32 (m, 3H), 7.09 (t, J = 51.0 Hz, 4H), 6.86 - 6.81 (m, 1H), 4.11 (s, 2H), 3.92 (s, 2H), 1.33 - 1.28 (m, 2H), 1.01 - 0.96 (m, 2H).

[0446] Example 101, Synthesis of 5'-(1,1-dioxide-4-oxo-1,2,5-thiadiazo lidin-2-yl)-4'-fluoro-6'- hydroxy-N-methylspiro[cyclopropane-1,3'-indolin]-1'-carboxamide (101)

[0447] Step 1: Synthesis of 6'-(benzyloxy)-5'-(1,1-dioxide-4-oxo-1,2,5-thiadiazo lidin-2-yl)-4'-fluoro-N-methylspiro[cyclopropane-1,3'-indolin]-1'-carboxamide (101-1)

[0448] Compound 57-11 (100.0 mg, 0.23 mmol) was dissolved in anhydrous acetonitrile (5 mL), N,N-diisopropylethylamine (150.0 mg, 1.14 mmol) and N-methyl-1- imidazolecarboxamide (56.9 mg, 0.45 mmol) were added, and the reaction was stirred at 80 °C for 16 h. When the reaction was completed by LCMS monitoring, the reaction was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 90:10 as eluent) to give compound 101-1 (60.0 mg) in 56.7 yield.

[0449] LC-MS (m / z): 459.0 [M-H] – .

[0450] Step 2: Synthesis of 5'-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-4'-fluoro-6'- hydroxy-N-methylspiro[cyclopropane-1,3'-indolin]-1'-carboxamide (101)

[0451] Compound 101-1 (100.0 mg, 0.13 mmol) was dissolved in methanol (5 mL), palladium on carbon (10%, 42.0 mg, 39.6 μmol) was added, the reaction was placed in 25 °C for 16 hours under hydrogen atmosphere. When the reaction was completed by LCMS monitoring, the reaction was filtered, concentrated under reduced pressure, and compound 101 (36.0 mg) was obtained by HPLC separation and purification with a yield of 74.8%.

[0452] LC-MS (m / z): 371.0 [M+H] + .

[0453] 1 H NMR (600 MHz, DMSO-d6) δ 7.31 (s, 1H), 7.17 (brs, 1H), 6.56 (q, J = 4.4 Hz, 1H), 3.86 (s, 2H), 3.82 (s, 2H), 2.64 (d, J = 4.2 Hz, 3H), 1.25 (q, J = 4.8 Hz, 2H), 0.90 (q, J = 4.8 Hz, 2H).

[0454] Example 111, Synthesis of 5-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-4-fluoro-6- hydroxy-N,3,3-trimethylindolin-1-carboxamide (111)

[0455] Step 1: Synthesis of tert-butyl 6-bromo-4-fluoro-2-oxoindoline-1-carboxylate (111-1)

[0456] Compound 57-2 (6.00 g, 26.09 mmol) and sodium bicarbonate (7.67 g, 91.31 mmol) were dissolved in tetrahydrofuran (60 mL), di-tert-butyl dicarbonate (6.30 g, 28.90 mmol) was added, and the reaction was stirred at 50 °C for 18 hours. When the reaction was completed by LCMS monitoring, the reaction was filtered, the filtrate was concentrated under reduced pressure, and compound 111-1 (6.30 g) was obtained by silica gel column chromatography (petroleum ether: ethyl acetate = 90:10 as eluent) with a yield of 73.4%.

[0457] LC-MS (m / z): 328.0 / 330.0 [M-H]– .

[0458] Step 2: Synthesis of tert-butyl 6-bromo-4-fluoro-3,3-dimethyl-2-oxoindoline-1- carboxylate (111-2)

[0459] Compound 111-1 (5.20 g, 15.81 mmol) and potassium carbonate (8.70 g, 63.04 mmol) were dissolved in N,N-dimethylformamide (80 mL), and iodomethane (6.70 g, 47.18 mmol) was added. The reaction was stirred at 25 °C for 1 h. After the reaction was completed by LCMS monitoring, water (100 mL) was added, and the aqueous phase was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 85: 15 as eluent) to give compound 111-2 (3.60 g) with a yield of 63.8%.

[0460] Step 3: Synthesis of 6-bromo-4-fluoro-3,3-dimethylindolin-2-one (111-3)

[0461] Compound 111-2 (3.60 g, 10.08 mmol) was dissolved in hydrogen chloride ethyl acetate solution (4.0 M, 30 mL), and the reaction was stirred at 25 °C for 3 h. After the reaction was completed by LCMS monitoring, the reaction was concentrated under reduced pressure to give compound 111-3 (2.45 g) as a crude product.

[0462] LC-MS (m / z): 256.0 / 258.0 [M-H] – .

[0463] Step 4: Synthesis of 6-bromo-4-fluoro-3,3-dimethylindoline (111-4)

[0464] The crude product of compound 111-3 (2.25 g) was dissolved in anhydrous tetrahydrofuran (20 mL), and borane dimethyl sulfide complex (10.0 M, 4.4 mL, 44.00 mmol) was added dropwise at 0 °C. The reaction was stirred at 60 °C for 4 h. After the reaction was completed by LCMS monitoring, the reaction was cooled to 0 °C, and 1.0 M dilute hydrochloric acid (30 mL) was added dropwise slowly. The reaction was stirred at 60 °C for 30 min, and then the pH of the aqueous phase was adjusted to basic with saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate (50 mL x 3), and the combined organic phase was washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 111-4 (2.00 g) as a crude product.

[0465] LC-MS (m / z): 244.0 / 246.0 [M+H]+ .

[0466] Step 5: Synthesis of tert-butyl 6-bromo-4-fluoro-3,3-dimethylindoline-1-carboxylate (111-5)

[0467] The crude product of compound 111-4 (2.00 g) was dissolved in anhydrous tetrahydrofuran (20 mL), 4-dimethylaminopyridine (2.00 g, 16.39 mmol) and di-tert-butyl dicarbonate (3.61 g, 16.56 mmol) were added, and the reaction solution was stirred at 50 °C for 17 hours. After the reaction was completed by LCMS monitoring, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 95:5 as eluent) to obtain compound 111-5 (2.60 g), with a three-step yield of 75.2%.

[0468] Step 6: Synthesis of tert-butyl 4-fluoro-6-hydroxy-3,3-dimethylindoline-1-carboxylate (111-6)

[0469] Compound 111-5 (2.60 g, 7.58 mmol), tris(dibenzylideneacetone)dipalladium (345.0 mg, 0.38 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (641.0 mg, 1.51 mmol) and potassium hydroxide (847.0 mg, 15.13 mmol) were dissolved in a mixed solvent of dioxane (15 mL) and water (15 mL), and the reaction solution was reacted at 100 °C for 3 hours under nitrogen protection. After the reaction was completed by LCMS monitoring, the reaction solution was concentrated, and a 1.0 M aqueous solution of citric acid was added dropwise to the residual aqueous solution, and the aqueous phase was adjusted to be acidic. The aqueous phase was extracted with dichloromethane (50 mL x 3), the combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 80:20 as eluent) to obtain compound 111-6 (1.60 g), with a yield of 75.1%.

[0470] LC-MS (m / z): 280.0 [M-H] – .

[0471] Step 7: Synthesis of tert-butyl 6-(benzyloxy)-4-fluoro-3,3-dimethylindoline-1-carboxylate (111-7)

[0472] Compound 111-6 (1.60 g, 5.69 mmol) was dissolved in N,N-dimethylformamide (20 mL), benzyl bromide (1.95 g, 11.40 mmol) and potassium carbonate (2.36 g, 17.10 mmol) were added, and the reaction liquid was placed at 25 °C for 17 hours. After the reaction was completed by LCMS monitoring, water (30 mL) was added, the aqueous phase was extracted with ethyl acetate (30 mL x 3), the combined organic phase was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 111-7 (2.10 g) as a crude product.

[0473] LC-MS (m / z): 370.0 [M-H] – .

[0474] Step 8: Synthesis of tert-butyl 6-(benzyloxy)-5-bromo-4-fluoro-3,3-dimethylindoline-1-carboxylate (111-8)

[0475] The crude product of compound 111-7 (2.10 g) was dissolved in acetonitrile (20 mL), N-bromosuccinimide (1.09 g, 6.12 mmol) was added, and the reaction liquid was placed at 25 °C for 1 hour. After the reaction was completed by LCMS monitoring, the reaction liquid was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 90:10 as eluent) to obtain compound 111-8 (1.70 g) with a two-step yield of 66.5%.

[0476] Step 9: Synthesis of tert-butyl 6-(benzyloxy)-5-((2-(tert-butoxy)-2-oxoethyl)amino)-4-fluoro-3,3-dimethylindoline-1-carboxylate (111-9)

[0477] Compound 111-8 (1.70 g, 3.79 mmol), tert-butyl glycinate (1.49 g, 11.37 mmol), tris(dibenzylideneacetone)dipalladium (518.0 mg, 0.57 mmol), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-I-propyl-11'-biphenyl (303.0 mg, 0.57 mmol), and cesium carbonate (3.69 g, 11.25 mmol) were dissolved in dioxane (20 mL), and the reaction liquid was placed at 100 °C for 18 hours under nitrogen protection. After the reaction was completed by LCMS monitoring, the reaction liquid was filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 90:10 as eluent) to obtain compound 111-9 (2.30 g) as a crude product.

[0478] LC-MS (m / z): 501.0 [M+H] + .

[0479] Step 10: Synthesis of tert-butyl 6-(benzyloxy)-5-(1,1-dioxido-4-oxo-1,2,5- thiadiazolidin-2-yl)-4-fluoro-3,3-dimethylindolin-1 -carboxylate (111-10)

[0480] The crude product of compound 111-9 (2.30 g) was dissolved in anhydrous tetrahydrofuran (20 mL), pyridine (1.08 g, 13.67 mmol) was added, and chlorosulfonic amide (1.59 g, 13.83 mmol) was added at 0 °C. The reaction solution was placed at 25 °C for 2.5 hours. After the reaction was completed by LCMS monitoring, the reaction solution was cooled to 0 °C, and a sodium methoxide solution in methanol (5.0 M, 3.3 mL) was added dropwise. The reaction solution was placed at 25 °C for 440 minutes. After the reaction was completed by LCMS monitoring, ethyl acetate (10 mL) was added for dilution, and the aqueous phase was adjusted to acidic pH with a 1.0 M aqueous citric acid solution. The aqueous phase was extracted with ethyl acetate (20 mL x 3), and the combined organic phase was washed with saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 90:10 as eluent) to obtain compound 111-10 (1.05 g) with a two-step yield of 54.9%.

[0481] LC-MS (m / z): 504.0 [M-H] – .

[0482] Step 11 : Synthesis of 5-(6-benzyloxy-4-fluoro-3,3-dimethylindol-5-yl)-1,2,5- thiadiazolidin-3-one 1,1 -dioxide (111-11)

[0483] Compound 111-10 (1.05 g, 2.08 mmol) was dissolved in a hydrogen chloride solution in ethyl acetate (4.0 M, 5 mL), and the reaction solution was placed at 25 °C for 1 hour. After the reaction was completed by LCMS monitoring, the reaction solution was filtered, the filter cake was washed with ethyl acetate (10 mL x 2), and the filter cake was dried to obtain compound 111-11 (500.0 mg) with a yield of 59.4%.

[0484] LC-MS (m / z): 404.0 [M-H] – .

[0485] Step 12: Synthesis of 6-(benzyloxy)-5-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-4- fluoro-N,3,3-trimethylindolin-1 -carboxamide (111-12)

[0486] Compound 111-11 (150.0 mg, 0.34 mmol) was dissolved in anhydrous acetonitrile (5 mL), N,N-diisopropyl ethylamine (237.0 mg, 1.84 mmol) and N-methyl-1- imidazolecarboxamide (138.0 mg, 1.10 mmol) were added, and the reaction was placed at 80 °C for 17 hours. After the reaction was completed by LCMS monitoring, water (1 mL) was added, 1.0 M dilute hydrochloric acid (2 mL) was added, and the reaction was filtered, and the filter cake was dried to obtain compound 111-12 (142.0 mg) as a crude product.

[0487] LC-MS (m / z): 371.0 [M-H] – .

[0488] Step 13: Synthesis of 5-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-4-fluoro-6- hydroxy-N,3,3-trimethylindoline-1-carboxamide (111)

[0489] The crude product of compound 111-12 (142.0 mg) was dissolved in methanol (2 mL) and N,N-dimethylformamide (1 mL), palladium on carbon (10%, 70.0 mg, 66.0 μmol) was added, and the reaction was placed at 25 °C for 17 hours under a hydrogen atmosphere. After the reaction was completed by LCMS monitoring, the reaction was filtered, concentrated under reduced pressure, and separated and purified by HPLC to obtain the ammonium salt of compound 111 (32.7 mg) with a two-step yield of 25.9%.

[0490] LC-MS (m / z): 371.0 [M-H] – .

[0491] 1 H NMR (600 MHz, DMSO-d6) δ 9.11 (s, 1H), 7.27 (s, 1H), 7.09 (br s, 4H), 6.62 (q, J = 4.4 Hz, 1H), 3.89 (s, 2H), 3.60 (s, 2H), 2.64 (d, J = 4.3 Hz, 3H), 1.33 (s, 6H).

[0492] Example 115, Synthesis of 5'-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-4'-fluoro-6'- hydroxy-N-methylspiro[cyclohexane-1,3'-indoline]-1'-carboxamide (115)

[0493] Step 1: Synthesis of 6'-bromo-4'-fluorospiro[cyclohexane-1,3'-indoline]-2'-one (115-1)

[0494] Compound 57-2 (4.58 g, 20.00 mmol) was dissolved in anhydrous tetrahydrofuran (70 mL), and a tetrahydrofuran solution (1.0 M, 40 mL) of LHMDS was added dropwise at -78 °C. The reaction was stirred at -40 °C for 30 min, and then cooled to -78 °C. A solution of 1,5-dibromopentane (4.60 g, 20.00 mmol) in anhydrous tetrahydrofuran (30 mL) was added, and the reaction was stirred at 70 °C for 3 h. After the reaction was completed by LCMS monitoring, the reaction was quenched by adding saturated aqueous ammonium chloride solution (40 mL) and water (40 mL) at 0 °C. The aqueous phase was extracted with ethyl acetate (60 mL x 3), and the combined organic phase was washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 90:10 as eluent) to give compound 115-1 (5.00 g) in 84.2% yield.

[0495] LC-MS (m / z): 296.0 / 298.0 [M-H] – .

[0496] 1 H NMR (600 MHz, DMSO-d6) δ 10.61 (s, 1H), 7.06 (dd, J = 9.4, 1.7 Hz, 1H), 6.82 (d, J = 1.7 Hz, 1H), 2.02-1.90 (m, 2H), 1.86-1.76 (m, 2H), 1.76-1.62 (m, 3H), 1.61-1.51 (m, 2H), 1.42-1.33 (m, 1H).

[0497] Step 2: Synthesis of 6'-bromo-4'-fluorospiro[cyclohexane-1,3'-indole] (115-2)

[0498] Compound 115-1 (5.00 g, 16.84 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL), and borane dimethyl sulfide complex (10.0 M, 8 mL, 80.00 mmol) was added dropwise at 0 °C. The reaction was stirred at 60 °C for 1.5 h. After the reaction was completed by LCMS monitoring, the reaction was quenched by slowly adding 2.0 M dilute hydrochloric acid (40 mL) at 0 °C. The reaction was stirred at 60 °C for another 30 min, and then the aqueous phase was adjusted to basic with saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate (60 mL x 3), and the combined organic phase was washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 90:10 as eluent) to give compound 115-2 (2.50 g) in 52.5% yield.

[0499] LC-MS (m / z): 284.0 / 286.0 [M+H] + .

[0500] Step 3: Synthesis of tert-butyl 6'-bromo-4'-fluorospiro[cyclohexane-l,3'-indole]-l'- carboxylate (115-3)

[0501] Compound 115-2 (2.50 g, 8.83 mmol) was dissolved in anhydrous tetrahydrofuran (40 mL), 4-dimethylaminopyridine (2.15 g, 17.62 mmol) and di-tert-butyl dicarbonate (5.78 g, 26.51 mmol) were added, and the reaction was stirred at 50 °C for 3 hours. After the reaction was completed by LCMS monitoring, the reaction was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 95:5 as eluent) to obtain compound 115-3 (4.20 g) as a crude product.

[0502] Step 4: Synthesis of tert-butyl 4'-fluoro-6'-hydroxyspiro[cyclohexane-l,3'-indole]-l'- carboxylate (115-4)

[0503] The above crude product of compound 115-3 (4.20 g), tris(dibenzylideneacetone)dipalladium (504.0 mg, 0.55 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (924.0 mg, 2.18 mmol) and potassium hydroxide (1.22 g, 21.79 mmol) were dissolved in a mixed solvent of dioxane (25 mL) and water (25 mL), and the reaction was carried out at 100 °C for 3 hours under nitrogen protection. After the reaction was completed by LCMS monitoring, the reaction was concentrated, and a 1.0 M aqueous citric acid solution was added dropwise to the residual aqueous solution, and the aqueous phase was adjusted to be acidic. The aqueous phase was extracted with dichloromethane (50 mL x 3), the combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 80:20 as eluent) to obtain compound 115-4 (2.80 g) with a two-step yield of 98.8%.

[0504] LC-MS (m / z): 320.0 [M-H] – .

[0505] Step 5: Synthesis of tert-butyl 6'-(benzyloxy)-4'-fluorospiro[cyclohexane-l,3'-indole]-l'- carboxylate (115-5)

[0506] Compound 115-4 (2.80 g, 8.72 mmol) was dissolved in N,N-dimethylformamide (25 mL), benzyl bromide (2.20 g, 13.10 mmol) and potassium carbonate (3.60 g, 26.20 mmol) were added, and the reaction was placed at 25 °C for 3 hours. After the reaction was completed by LCMS monitoring, water (30 mL) was added, the aqueous phase was extracted with ethyl acetate (30 mL x 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 the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 90:10 as eluent) to obtain compound 115-5 (1.80 g) with a yield of 50.2%.

[0507] LC-MS (m / z): 410.0 [M-H] – .

[0508] 1 H NMR (600 MHz, DMSO-d6) δ 7.67-7.06 (m, 6H), 6.45 (dd, J = 12.2, 2.2 Hz, 1H), 5.07 (s, 2H), 3.77 (s, 2H), 1.85-1.74 (m, 2H), 1.70-1.58 (m, 5H), 1.50 (s, 9H), 1.35-1.15 (m, 3H).

[0509] Step 6: Synthesis of tert-butyl 6'-(benzyloxy)-5'-bromo-4'-fluorospiro[cyclohexane-1,3'-indole]-1'- carboxylate (115-6)

[0510] Compound 115-5 (1.80 g, 4.38 mmol) was dissolved in acetonitrile (20 mL), N-bromosuccinimide (940.0 mg, 5.28 mmol) was added, and the reaction was placed at 25 °C for 1 hour. After the reaction was completed by LCMS monitoring, saturated aqueous sodium thiosulfate solution (30 mL) was added to quench the reaction, the aqueous phase was extracted with ethyl acetate (30 mL x 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 the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 80:20 as eluent) to obtain compound 115-6 (1.85 g) with a yield of 86.4%.

[0511] 1 H NMR (600 MHz, DMSO-d6) δ 7.62-7.18 (m, 6H), 5.18 (s, 2H), 3.81 (s, 2H), 1.87-1.72 (m, 2H), 1.72-1.60 (m, 5H), 1.52 (s, 9H), 1.38-1.27 (m, 2H), 1.27-1.15 (m, 1H).

[0512] Step 7: Synthesis of tert-butyl 6'-(benzyloxy)-5'-(1,1-dioxido-4-oxo-1,2,5- thiadiazolidin-2-yl)-4'-fluorospiro[cyclohexane-1,3'-indolin]-1'-carboxylate (115-8)

[0513] Compound 115-6 (220.0 mg, 0.41 mmol), tert-butyl glycinate (161.0 mg, 1.23 mmol), tris(dibenzylideneacetone)dipalladium (75.0 mg, 0.082 mmol), 2- (dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-I-propyl-11'-biphenyl (44.0 mg, 0.082 mmol) and cesium carbonate (400.0 mg, 1.23 mmol) were dissolved in dioxane (8 mL), the reaction was placed in 100 °C for 16 hours under nitrogen protection. When the reaction was completed by LCMS monitoring, the reaction was filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 90:10 as eluent) to give compound 115-7 (200.0 mg) with a yield of 90.3%.

[0514] LC-MS (m / z): 541.0 [M+H] + .

[0515] Step 8: Synthesis of tert-butyl 6'-(benzyloxy)-5'-(1,1-dioxido-4-oxo-1,2,5- thiadiazolidin-2-yl)-4'-fluorospiro[cyclohexane-1,3'-indolin]-1'-carboxylate (115-8)

[0516] Compound 115-7 (200.0 mg, 0.37 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), pyridine (146.0 mg, 1.85 mmol) was added, and chlorosulfonamide (215.0 mg, 1.85 mmol) was added at 0 °C. The reaction was placed at 25 °C for 30 minutes. When the reaction was completed by LCMS monitoring, the reaction was cooled to 0 °C, and a sodium methoxide solution in methanol (5.0 M, 0.4 mL) was added dropwise. The reaction was placed at 25 °C for 30 minutes. When the reaction was completed by LCMS monitoring, ethyl acetate (10 mL) was added to dilute the reaction, and the aqueous phase was adjusted to acidic pH with a 1.0 M aqueous citric acid solution. The aqueous phase was extracted with ethyl acetate (20 mL x 3), the combined organic phase was washed with saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 90:10 as eluent) to give compound 115-8 (100.0 mg) with a yield of 49.6%.

[0517] LC-MS (m / z): 544.0 [M-H] –.

[0518] Step 9: Synthesis of 5-(6'-(benzyloxy)-4'-fluorospiro[cyclohexane-1,3'-indol]-5'-yl)- 1,2,5-thiadiazolidin-3-one 1,1-dioxide (115-9)

[0519] Compound 115-8 (100.0 mg, 0.18 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (2 mL) was added, and the reaction was placed at 25 °C for 1 hour. After the reaction was completed by LCMS monitoring, the reaction was concentrated under reduced pressure to obtain compound 115-9 (100.0 mg) as a crude product.

[0520] LC-MS (m / z): 444.0 [M-H] – .

[0521] Step 10: Synthesis of 6'-(benzyloxy)-5'-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-4'- fluoro-N-methylspiro[cyclohexane-1,3'-indoline]-1'-carboxamide (115-10)

[0522] The crude product of compound 115-9 (100.0 mg) was dissolved in anhydrous acetonitrile (6 mL), N,N-diisopropylethylamine (116.0 mg, 0.90 mmol) and N-methyl-1- imidazolecarboxamide (45.0 mg, 0.36 mmol) were added, and the reaction was placed at 80 °C for 24 hours. After the reaction was completed by LCMS monitoring, the reaction was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 90:10 as eluent) to obtain compound 115-10 (100.0 mg) as a crude product.

[0523] LC-MS (m / z): 501.0 [M-H] – .

[0524] Step 11: Synthesis of 5'-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-4'-fluoro-6'-hydroxy-N- methylspiro[cyclohexane-1,3'-indoline]-1'-carboxamide (115)

[0525] The crude product of compound 115-10 (100.0 mg) was dissolved in methanol (6 mL), palladium on carbon (10%, 42.0 mg, 39.6 μmol) was added, and the reaction was placed at 25 °C for 16 hours under a hydrogen atmosphere. After the reaction was completed by LCMS monitoring, the reaction was filtered and concentrated under reduced pressure, and the product was purified by HPLC to obtain ammonium salt of compound 115 (18.3 mg) with a three-step yield of 24.7%

[0526] LC-MS (m / z): 411.0 [M-H] – .

[0527] 1 H NMR (600 MHz, DMSO-d6) δ 9.07 (s, 1H), 7.29 (s, 1H), 7.08 (t, J = 51.0 Hz, 4H), 6.69 (q, J = 4.4 Hz, 1H), 3.88 (s, 2H), 3.71 (s, 2H), 2.66 (d, J = 4.3 Hz, 3H), 1.86 - 1.74 (m, 2H), 1.70 - 1.55 (m, 5H), 1.39 - 1.27 (m, 2H), 1.26 - 1.15 (m, 1H).

[0528] Example 117, Synthesis of 5-(4-fluoro-6-hydroxy-l-(3-methyl-lH-l,2,4-triazol-5-yl)indolin-5-yl)- 1,2,5-thiadiazolidin-3-one 1,1-dioxide (117)

[0529] Step 1: Synthesis of 5-(6-(benzyloxy)-4-fluoro-l-(3-methyl-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-l,2,4-triazol-5-yl)indolin-5-yl)-l,2,5-thiadiazolidin-3-one 1,1- dioxide (117-1)

[0530] Compound 2-3 (0.210 g, 0.508 mmol), 117-SM (0.290 g, 1.00 mmol), 2-(di-tert- butylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl-2-amine-palladium(0) (0.100 g, 0.105 mmol) and cesium carbonate (0.500 g, 1.53 mmol) were dissolved in tert-butanol (15 mL) and reacted at 100 °C for 3 hours under nitrogen protection. After the reaction was completed by LCMS monitoring, it was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane:methanol = 90:10 as eluent) to obtain compound 117-1 (0.230 g) with a yield of 77.0%.

[0531] MS-ESI calculated [M+H] + 589.2, found 589.0.

[0532] Step 2: Synthesis of 5-(6-(benzyloxy)-4-fluoro-l-(3-methyl-lH-l,2,4-triazol-5-yl)indolin-5-yl)- 1,2,5-thiadiazolidin-3-one 1,1-dioxide (117-2)

[0533] Compound 117-1 (0.230 g, 0.391 mmol) was dissolved in tetrahydrofuran (3 mL), tetrabutylammonium fluoride (0.380 g, 1.46 mmol) was added, and the reaction solution was allowed to react at 70°C for 16 hours. After confirming completion of the reaction by LCMS, the reaction solution was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane:methanol = 90:10 as an eluent) to obtain compound 117-2 (0.136 g) at a yield of 76.0%.

[0534] MS-ESI calculated value [M+H] + 459.1, observed value 459.0.

[0535] Step 3: Synthesis of 5-(4-fluoro-6-hydroxy-1-(3-methyl-1H-1,2,4-triazol-5-yl)indolin-5-yl)- 1,2,5-thiadiazolidin-3-one-1,1-dioxide (117)

[0536] Compound 117-2 (0.136 g, 0.297 mmol) was dissolved in methanol (3 mL), palladium-carbon (10%, 63.0 mg, 59.4 µmol) was added, and the reaction solution was allowed to react at 25°C for 16 hours under a hydrogen atmosphere. After confirming completion of the reaction by LCMS, the reaction solution was filtered, concentrated under reduced pressure, and purified by HPLC preparation to obtain compound 117 (5.5 mg) at a yield of 5.0%

[0537] MS-ESI calculated value [M+H] + 369.1, observed value 369.0.

[0538] 1 H NMR (600 MHz, DMSO-d6) δ 13.08 (s, 1H), 9.00 (s, 1H), 7.23 (s, 1H), 4.00 (t, J = 8.7 Hz, 2H), 3.90 (s, 2H), 3.04 (t, J = 8.6 Hz, 2H), 2.33 (s, 3H).

[0539] Example 118, Synthesis of 5-(4-fluoro-6-hydroxy-1-(1-methyl-1H-1,2,3-triazol-4-yl)indolin-5-yl)- 1,2,5-thiadiazolidin-3-one-1,1-dioxide (118)

[0540] Step 1: Synthesis of 5-(6-(benzyloxy)-4-fluoro-1-(1-methyl-1H-1,2,3-triazol-4-yl)indolin-5-yl)- 1,2,5-thiadiazolidin-3-one-1,1-dioxide (118-1)

[0541] Compound 2-3 (0.100 g, 0.242 mmol), 4-bromo-1-methyl-1H-1,2,3-triazole (58.7 mg, 0.362 mmol), methanesulfonic acid-2-(di-tert-butylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'- biphenyl-2-yl)palladium (68.8 mg, 72.4 μmol) and cesium carbonate (0.236 g, 0.724 mmol) were dissolved in tert-butanol (5 mL) and stirred at 100 °C for 8 h under nitrogen atmosphere. After the reaction was completed by LCMS monitoring, the reaction solution was filtered, concentrated under reduced pressure, and separated and purified by thin layer chromatography (dichloromethane:methanol = 85:15 as eluent) to obtain compound 118-1 (40.0 mg) with a yield of 36.1%.

[0542] MS-ESI calculated value [M-H] – 457.1, found 457.0.

[0543] Step 2: Synthesis of 5-(4-fluoro-6-hydroxy-1-(1-methyl-1H-1,2,3-triazol-4-yl)indolin-5-yl)- 1,2,5-thiadiazolidin-3-one-1,1-dioxide

[0544] Compound 118-1 (40.0 mg, 87.3 μmol) was dissolved in methanol (5 mL) and palladium on carbon (10%, 10.0 mg, 9.43 μmol) was added. The reaction was stirred at 25 °C for 16 h under hydrogen atmosphere. After the reaction was completed by LCMS monitoring, the reaction solution was filtered, concentrated under reduced pressure, and purified by HPLC prep to obtain compound 118 (10.5 mg) with a yield of 32.7%

[0545] MS-ESI calculated value [M+H] + 369.1, found 369.0.

[0546] 1 H NMR (600 MHz, DMSO-d6) δ 8.97 (s, 1H), 7.82 (s, 1H), 6.89 (s, 1H), 4.03 (s, 3H), 3.92-3.88 (m, 4H), 3.08 (t, J = 9.0 Hz, 2H).

[0547] Example 120, Synthesis of 5-(4-fluoro-6-hydroxy-1-(1-methyl-1H-1,2,4-triazol-3-yl)indolin-5-yl)- 1,2,5-thiadiazolidin-3-one-1,1-dioxide (120)

[0548] Step 1: Synthesis of 5-(6-(benzyloxy)-4-fluoro-1-(1-methyl-1H-1,2,4-triazol-3-yl)indolin-5-yl)- 1,2,5-thiadiazolidin-3-one-1,1-dioxide (120-1)

[0549] Compound 2-3 (0.100 g, 0.242 mmol), 3-bromo-1-methyl-1H-1,2,4-triazole (58.7 mg, 0.362 mmol), methanesulfonic acid-2-(di-tert-butylphosphino)-3,6-dimethoxy-2',4',6'- triisopropyl-1,1'-biphenyl-2-yl)palladium (45.9 mg, 48.3 μmol) and cesium carbonate (0.236 g, 0.724 mmol) were dissolved in tert-butanol (5 mL) and stirred at 100 °C for 7 h under nitrogen. When the reaction was completed by LCMS, the reaction was filtered, concentrated under reduced pressure, and separated by thin layer chromatography (dichloromethane:methanol = 85:15 as eluent) to give compound 120-1 (40.0 mg) in 36.1% yield.

[0550] MS-ESI calculated [M-H] – 457.1, found 457.0.

[0551] Step 2: Synthesis of 5-(4-fluoro-6-hydroxy-1-(1-methyl-1H-1,2,4-triazol-3-yl)indolin-5-yl)- 1,2,5-thiadiazolidin-3-one-1,1-dioxide

[0552] Compound 120-1 (40.0 mg, 87.3 μmol) was dissolved in methanol (5 mL) and palladium on carbon (10%, 10.0 mg, 9.43 μmol) was added. The reaction was stirred at 25 °C for 20 h under hydrogen atmosphere. When the reaction was completed by LCMS, the reaction was filtered, concentrated under reduced pressure, and purified by HPLC prep to give compound 120 (10.0 mg) in 31.1% yield.

[0553] MS-ESI calculated [M+H] + 369.1, found 369.0.

[0554] 1 H NMR (600 MHz, DMSO-d6) δ 8.99 (s, 1H), 8.29 (s, 1H), 7.24 (s, 1H), 4.02 (t, J = 8.4 Hz, 2H), 3.89 (s, 2H), 3.80 (s, 3H), 3.06 (t, J = 8.4 Hz, 2H).

[0555] Example 121. Synthesis of N-(2,5-difluorophenyl)-5-(1,1-dioxide-4-oxo-1,2,5- thiadiazolidin-2-yl)-4-fluoro-6-hydroxyindoline-1-carboxamide (121)

[0556] Step 1: Synthesis of 6-(benzyloxy)-N-(2,5-difluorophenyl)-5-(1,1-dioxide-4-oxo-1,2,5- thiadiazolidin-2-yl)-4-fluoroindoline-1-carboxamide (121-1)

[0557] Compound 2-3 (0.100 g, 0.242 mmol) and triethylamine (73.3 mg, 0.726 mmol) were dissolved in acetonitrile (3 mL), and 2,5-difluorophenyl isocyanate (75.0 mg, 0.484 mmol) was added. The reaction solution was allowed to react at 25°C for 1 hour. After the reaction was confirmed to be complete by LCMS, the reaction solution was diluted with water, and 1.0 M dilute hydrochloric acid (2 mL) was added. The mixture was extracted with dichloromethane (10 mL x 3), and the combined organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by preparative plate separation (dichloromethane:methanol = 90:10 as eluent) gave compound 121-1 (80.0 mg) at a yield of 62.2%.

[0558] MS-ESI calculated value [M-H] – 531.1, found 531.0.

[0559] Step 2: Synthesis of N-(2,5-difluorophenyl)-5-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-4- fluoro-6-hydroxyindoline-1-carboxamide (121)

[0560] Compound 121-1 (80.0 mg, 0.150 mmol) was dissolved in tetrahydrofuran (5 mL), and palladium-carbon (10%, 40.0 mg, 37.7 μmol) was added. The reaction solution was allowed to react at 25°C for 16 hours under a hydrogen atmosphere. After the reaction was confirmed to be complete by LCMS, the reaction solution was filtered, concentrated under reduced pressure, and purified by HPLC preparative purification to give compound 121 (41.0 mg) at a yield of 61.8%.

[0561] MS-ESI calculated value [M-H] – 441.1, found 441.0.

[0562] 1H NMR (600 MHz, DMSO-d6) δ 9.23 (s, 1H), 8.50 (s, 1H), 7.48 (ddd, J = 9.7, 6.2, 3.2 Hz, 1H), 7.31 (td, J = 9.6, 5.1 Hz, 1H), 7.25 (s, 1H), 7.02 (tt, J = 8.9, 7.3, 3.4 Hz, 1H), 4.16 (t, J = 8.5 Hz, 2H), 3.92 (s, 2H), 3.09 (t, J = 8.4 Hz, 2H).

[0563] Example 122, Synthesis of N-(2,4-difluorophenyl)-5-(1,1-dioxide-4-oxo-1,2,5- thiazolidin-2-yl)-4-fluoro-6-hydroxyindoline-1-carboxamide (122)

[0564] Step 1: Synthesis of 6-(benzyloxy)-N-(2,4-difluorophenyl)-5-(1,1-dioxide-4-oxo-1,2,5- thiazolidin-2-yl)-4-fluoroindoline-1-carboxamide (122-1)

[0565] Compound 2-3 (0.100 g, 0.242 mmol) and triethylamine (0.176 g, 1.74 mmol) were dissolved in acetonitrile (3 mL), 2,4-difluorophenyl isocyanate (0.162 g, 1.05 mmol) was added, and the reaction solution was allowed to react at 25°C for 1 hour. After the reaction was completed as monitored by LCMS, the reaction solution was diluted with water, 1.0 M dilute hydrochloric acid (2 mL) was added, and dichloromethane (10 mL x 3) was extracted. The combined organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by preparative plate separation (dichloromethane:methanol = 90:10 as eluent) gave compound 122-1 (80.0 mg) with a yield of 62.2%.

[0566] MS-ESI calculated value [M-H] – 531.1, found 531.0.

[0567] Step 2: Synthesis of N-(2,4-difluorophenyl)-5-(1,1-dioxide-4-oxo-1,2,5-thiazolidin-2-yl)-4- fluoro-6-hydroxyindoline-1-carboxamide (122)

[0568] Compound 122-1 (80.0 mg, 0.150 mmol) was dissolved in tetrahydrofuran (3 mL), palladium on carbon (10%, 40.0 mg, 37.7 μmol) was added, and the reaction was stirred at 25 °C for 16 hours under hydrogen atmosphere. When the reaction was completed by LCMS monitoring, the reaction was filtered, concentrated under reduced pressure, and purified by preparative plate (dichloromethane:methanol = 85:15 as eluent) to give compound 122 (31.3 mg) in 47.2% yield.

[0569] MS-ESI calculated [M-H] – 441.1, found 441.0.

[0570] 1 H NMR (600 MHz, DMSO-d6) δ 9.14 (s, 1H), 8.47 (s, 1H), 7.48 (td, J = 8.9, 6.1 Hz, 1H), 7.35 - 7.26 (m, 1H), 7.23 (s, 1H), 7.07 (td, J = 8.6, 2.9 Hz, 1H), 4.13 (t, J = 8.4 Hz, 2H), 3.90 (s, 2H), 3.09 (t, J = 8.4 Hz, 2H).

[0571] Example 123, Synthesis of N-(2,3-difluorophenyl)-5-(1,1-dioxide-4-oxo-1,2,5- thiazolidin-2-yl)-4-fluoro-6-hydroxyindole-1-carboxamide (123)

[0572] Step 1: Synthesis of 6-(benzyloxy)-N-(2,3-difluorophenyl)-5-(1,1-dioxide-4-oxo-1,2,5- thiazolidin-2-yl)-4-fluoroindoline-1-carboxamide (123-1)

[0573] Step 1: Synthesis of 6-(benzyloxy)-N-(2,3-difluorophenyl)-5-(1,1-dioxide-4-oxo-1,2,5- thiazolidin-2-yl)-4-fluoroindoline-1-carboxamide (123-1)

[0574] MS-ESI calculated [M-H] –531.1, found 531.0.

[0575] Step 2: Synthesis of N-(2,3-difluorophenyl)-5-(1,1-dioxide-4-oxo-1,2,5- thiadiazolidin-2-yl)-4-fluoro-6-hydroxyindole-1-carboxamide (123)

[0576] Compound 123-1 (0.158 g, 0.297 mmol) was dissolved in tetrahydrofuran (3 mL), palladium on carbon (10%, 62.0 mg, 58.5 μmol) was added, and the reaction was stirred at 25 °C for 16 h under hydrogen atmosphere. When the reaction was completed by LCMS monitoring, the reaction was filtered, concentrated under reduced pressure, and purified by HPLC to give compound 123 (52.7 mg) in 40.1% yield.

[0577] MS-ESI calculated [M-H] – 441.1, found 441.0.

[0578] 1 H NMR (600 MHz, DMSO-d6) δ 9.20 (s, 1H), 8.65 (s, 1H), 7.31 (t, J = 7.3 Hz, 1H), 7.26 - 7.21 (m, 2H), 7.21 - 7.15 (m, 1H), 4.15 (t, J = 8.4 Hz, 2H), 3.91 (s, 2H), 3.09 (t, J = 8.4 Hz, 2H).

[0579] Example 124, Synthesis of 5-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-4-fluoro-6- hydroxy-N-(3,4,5-trifluorophenyl)indoline-1-carboxamide (124)

[0580] Step 1: Synthesis of 6-(benzyloxy)-5-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-4- fluoro-N-(3,4,5-trifluorophenyl)indoline-1-carboxamide (124-1)

[0581] To a solution of compound 2-1 (0.100 g, 0.230 mmol) in anhydrous acetonitrile (3 mL) was added 3,4,5-trifluoroaniline (0.345 g, 2.35 mmol) and N,N- diisopropylethylamine (0.337 g, 2.61 mmol) in anhydrous acetonitrile (5 mL) at 0 °C. The reaction was stirred at 25 °C for 30 min. Then a solution of compound 2-2 (0.150 g, 0.363 mmol) in anhydrous acetonitrile (3 mL) was added. The reaction was stirred at 25 °C for 1 h. The reaction was monitored by LCMS. When the reaction was completed, the reaction was concentrated under reduced pressure. The residue was purified by preparative plate (dichloromethane:methanol = 90:10 as eluent) to give compound 124-1 (0.128 g) in 64.1% yield.

[0582] MS-ESI calculated [M-H] – 549.1, found 549.0.

[0583] Step 2: Synthesis of 5-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-4-fluoro-6- hydroxy-N-(3,4,5-trifluorophenyl)indoline-1-carboxamide (124)

[0584] To a solution of compound 124-1 (0.128 g, 0.233 mmol) in tetrahydrofuran (3 mL) was added palladium on carbon (10%, 54.0 mg, 50.9 μmol) at 25 °C under hydrogen atmosphere. The reaction was stirred at 25 °C for 16 h. The reaction was monitored by LCMS. When the reaction was completed, the reaction was filtered and concentrated under reduced pressure. The residue was purified by HPLC preparative to give compound 124 (12.8 mg) in 11.9% yield.

[0585] MS-ESI calculated [M-H] – 459.0, found 459.0.

[0586] Example 125, Synthesis of 5-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-4-fluoro-N- ((1R,2S)-2-fluorocyclopropyl)-6-hydroxyindoline-1-carboxamide (125)

[0587] Step 1: Synthesis of 6-(benzyloxy)-5-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-4- fluoro-N-[(1R,2S)-2-fluorocyclopropyl]indoline-1-carboxamide (125-1)

[0588] Compound 125-1 (100.0 mg, 0.21 mmol) was dissolved in methanol (10 mL), palladium on carbon (10%, 44.0 mg, 41.5 μmol) was added, and the reaction was stirred at 25 °C for 18 h under hydrogen atmosphere. When the reaction was completed by LCMS, the reaction was filtered, concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (dichloromethane:methanol = 80:20 as eluent) to give compound 125 (12.9 mg) in 15.8% yield.

[0589] LC-MS (m / z): 387.0 [M-H] – .

[0590] Step 2: Synthesis of 5-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-4-fluoro-N-((1R,2S)-2- fluorocyclopropyl)-6-hydroxyindoline-1-carboxamide (125)

[0591] Compound 125-1 (100.0 mg, 0.21 mmol) was dissolved in methanol (10 mL), palladium on carbon (10%, 44.0 mg, 41.5 μmol) was added, and the reaction was stirred at 25 °C for 18 h under hydrogen atmosphere. When the reaction was completed by LCMS, the reaction was filtered, concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (dichloromethane:methanol = 80:20 as eluent) to give compound 125 (12.9 mg) in 15.8% yield.

[0592] LC-MS (m / z): 387.0 [M-H] – .

[0593] 1 H NMR (600 MHz, DMSO-d6) δ 9.05 (s, 1H), 7.25 (s, 1H), 6.84 (d, J = 2.9 Hz, 1H), 4.76 - 4.49 (m, 1H), 3.98 - 3.76 (m, 4H), 3.01 (t, J = 8.6 Hz, 2H), 2.62 - 2.57 (m, 1H), 1.12 - 0.96 (m, 2H).

[0594] Example 126, Synthesis of N-(2,2-difluoroethyl)-5-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-4- fluoro-6-hydroxyindoline-1-carboxamide (126)

[0595] Step 1: Synthesis of 6-(benzyloxy)-N-(2,2-difluoroethyl)-5-(1,1-dioxido-4-oxo-1,2,5- thiadiazolidin-2-yl)-4-fluoroindoline-1-carboxamide (126-1)

[0596] Difluoroethylamine hydrochloride (93.4 mg, 0.79 mmol) and N,N-diisopropylethylamine (205.0 mg, 1.59 mmol) were dissolved in anhydrous dichloromethane (5 mL), and a solution of triphosgene (78.6 mg, 0.26 mmol) in anhydrous dichloromethane (1 mL) was added dropwise at -78 °C. The reaction was stirred at -78 °C for 20 minutes, and then 2-3 (100.0 mg, 0.24 mmol) was added at -78 °C. The reaction was stirred at -78 °C for 2 hours. After the reaction was completed by LCMS monitoring, the reaction was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 90:10 as eluent) to obtain compound 126-1 (60.0 mg) with a yield of 51.7%.

[0597] LC-MS (m / z): 483.0 [M-H] – .

[0598] Step 2: Synthesis of N-(2,2-difluoroethyl)-5-(1,1-dioxido-4-oxo-1,2,5-thiadiazo lidin-2-yl)-4-fluoro-6-hydroxyindoline-1-carboxamide (126)

[0599] Compound 126-1 (60.0 mg, 0.12 mmol) was dissolved in methanol (5 mL), and palladium on carbon (10%, 20.0 mg, 18.9 μmol) was added. The reaction was stirred at 25 °C for 16 hours under a hydrogen atmosphere. After the reaction was completed by LCMS monitoring, the reaction was filtered and concentrated under reduced pressure, and the ammonium salt of compound 126 was obtained by HPLC separation and purification (25.0 mg) with a yield of 52.9%.

[0600] LC-MS (m / z): 395.0 [M+H] + .

[0601] 1 H NMR (600 MHz, DMSO-d6) δ 9.11 (s, 1H), 7.26 (s, 1H), 7.09 (t, J = 51.0 Hz, 4H), 7.12 (t, J = 6.0 Hz, 1H), 6.15 - 5.94 (m, 1H) 3.92 (t, J = 8.4 Hz, 2H), 3.90 (s, 2H), 3.55 - 3.45 (m, 2H), 3.03 (t, J = 8.4 Hz, 2H).

[0602] Example 127, Synthesis of 5-(l,l-dioxide-4-oxo-l,2,5-thiadiazolidin-2-yl)-4- fluoro-N-(3-fluorocyclobutyl)-6-hydroxyindole-l-carboxamide (127)

[0603] Step 1: Synthesis of 6-(benzyloxy)-5-(l,l-dioxide-4-oxo-l,2,5-thiadiazolidin-2-yl)-4- fluoro-N-(3-fluorocyclobutyl)indoline-l-carboxamide (127-1)

[0604] To a solution of 3-fluorocyclobutylamine hydrochloride (99.8 mg, 0.79 mmol) and N,N-diisopropylethylamine (205.0 mg, 1.59 mmol) in anhydrous dichloromethane (3 mL) was added dropwise a solution of triphosgene (78.6 mg, 0.26 mmol) in anhydrous dichloromethane (1 mL) at -50 °C. The reaction mixture was stirred at -50 °C for 20 min, then compound 2-3 (100.0 mg, 0.24 mmol) was added at -50 °C. The reaction mixture was stirred at 25 °C for 2 h. When the reaction was completed by LCMS, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane:methanol = 90: 10 as eluent) to give compound 127-1 (50.0 mg) in 42.3% yield.

[0605] LC-MS (m / z): 491.0 [M - H] – .

[0606] Step 2: Synthesis of 5-(l,l-dioxide-4-oxo-l,2,5-thiadiazolidin-2-yl)-4-fluoro-N-(3- fluorocyclobutyl)-6-hydroxyindole-l-carboxamide (127)

[0607] To a solution of compound 127-1 (50.0 mg, 0.10 mmol) in methanol (5 mL) was added palladium on carbon (10%, 20.0 mg, 18.9 μmol). The reaction mixture was stirred at 25 °C for 16 h under hydrogen atmosphere. When the reaction was completed by LCMS, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane:methanol = 85: 15 as eluent) to give compound 127 (10.0 mg) in 24.9% yield.

[0608] LC-MS (m / z): 403.0 [M + H] + .

[0609] 1H NMR (600 MHz, DMSO-d6) δ 9.03 (s, 1H), 7.23 (s, 1H), 6.88 (t, J = 6.6 Hz, 1H), 5.32 - 5.16 (m, 0.5H), 4.89 - 4.73 (m, 0.5H), 4.37 (q, J = 7.2 Hz, 0.5H), 3.91 (t, J = 8.6 Hz, 2H), 3.88 (s, 2H), 3.80 - 3.72 (m, 0.5H), 3.01 (t, J = 8.4 Hz, 2H), 2.72 - 2.63 (m, 1H), 2.47 - 2.35 (m, 2H), 2.31 - 2.18 (m, 1H).

[0610] Synthesis of Example 128, 5-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-4-fluoro-6- hydroxy-N-(3-(methoxymethyl)cyclobutyl)indoline-1-carboxamide (128)

[0611] Step 1: Synthesis of 6-(benzyloxy)-5-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-4- fluoro-N-(3-(methoxymethyl)cyclobutyl)indoline-1-carboxamide (128-1)

[0612] Compound 2-3 (200.0 mg, 0.48 mmol) and N,N-diisopropylethylamine (342.0 mg, 2.65 mmol) were dissolved in a mixed solvent of anhydrous dichloromethane (5 mL) and anhydrous tetrahydrofuran (2 mL), and a solution of triphosgene (70.0 mg, 0.24 mmol) in anhydrous dichloromethane (1 mL) was added dropwise at -50°C. The reaction solution was stirred at 25°C for 2 hours, and then 3-methoxymethyl-cyclobutylamine (122.0 mg, 1.06 mmol) was added. The reaction solution was stirred at 25°C for 3 hours. After the completion of the reaction was confirmed by LCMS, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 90:10 as eluent) to obtain compound 128-1 (226.0 mg) at a yield of 90.9%.

[0613] LC-MS (m / z): 517.0 [M-H] – .

[0614] Step 2: Synthesis of 5-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-4-fluoro-6-hydroxy-N- (3-(methoxymethyl)cyclobutyl)indoline-1-carboxamide (128)

[0615] Compound 128-1 (226.0 mg, 0.44 mmol) was dissolved in methanol (3 mL), palladium on carbon (10%, 112.0 mg, 0.11 mmol) was added, and the reaction was stirred at 25 °C for 18 h under hydrogen atmosphere. When the reaction was completed by LCMS, the reaction was filtered, concentrated under reduced pressure, and purified by HPLC to give the ammonium salt of compound 128 (33.1 mg) in 17.6% yield.

[0616] LC-MS (m / z): 427.0 [M-H] – .

[0617] 1 H NMR (600 MHz, DMSO-d6) δ 9.03 (s, 1H), 7.23 (s, 1H), 7.09 (brs, 4H), 6.75 (d, J = 7.7 Hz, 1H), 4.13-4.03 (m, 1H), 3.94-3.87 (m, 4H), 3.29 (d, J = 6.2 Hz, 2H), 3.23 (s, 3H), 2.99 (t, J = 8.5 Hz, 2H), 2.29-2.21 (m, 2H), 2.16-2.09 (m, 1H), 1.80-1.72 (m, 2H).

[0618] Example 129, Synthesis of N-(2,6-difluorophenyl)-5-(1,1-dioxido-4-oxo-1,2,5- thiadiazolidin-2-yl)-4-fluoro-6-hydroxyindole-1-carboxamide (129)

[0619] Step 1: Synthesis of 6-(benzyloxy)-N-(2,6-difluorophenyl)-5-(1,1-dioxido-4-oxo-1,2,5- thiadiazolidin-2-yl)-4-fluoroindoline-1-carboxamide (129-1)

[0620] Compound 2-3 (100.0 mg, 0.24 mmol) and triethylamine (73.0 mg, 0.72 mmol) were dissolved in acetonitrile (5 mL), and 2,6-difluorophenyl isocyanate (56.0 mg, 0.36 mmol) was added. The reaction was stirred at 25 °C for 1 h. When the reaction was completed by LCMS, the reaction was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 90:10 as eluent) to give compound 129-1 (40.0 mg) in 31.3% yield.

[0621] LC-MS (m / z): 531.0 [M-H] – .

[0622] Step 2: Synthesis of N-(2,6-difluorophenyl)-5-(1,1-dioxide-4-oxo-1,2,5- thiadiazolidin-2-yl)-4-fluoro-6-hydroxyindole-1-carboxamide (129)

[0623] Compound 129-1 (40.0 mg, 0.075 mmol) was dissolved in methanol (5 mL), palladium on carbon (10%, 40.0 mg, 37.7 μmol) was added, and the reaction was stirred at 25 °C for 16 h under hydrogen atmosphere. When the reaction was completed by LCMS monitoring, the reaction was filtered, concentrated under reduced pressure, and purified by HPLC to give the ammonium salt of compound 129 (2.8 mg) in 8.4% yield.

[0624] LC-MS (m / z): 443.0 [M+H] + .

[0625] 1 H NMR (600 MHz, DMSO-d6) δ 8.47 (s, 1H), 7.39 - 7.26 (m, 2H), 7.22 (s, 1H), 7.20 - 7.14 (m, 2H), 7.04 (brs, 4H), 4.12 (t, J = 8.5 Hz, 2H), 3.90 (s, 1H), 3.11 (t, J = 8.5 Hz, 2H).

[0626] Example 130, Synthesis of 5'-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-N- ethyl-4'-fluoro-6'-hydroxyspiro[cyclohexane-1,3'-indolin]-1'-carboxamide (130)

[0627] Step 1: Synthesis of 6'-(benzyloxy)-5'-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)- N-ethyl-4'-fluorospiro[cyclohexane-1,3'-indolin]-1'-carboxamide (130-1)

[0628] Compound 115-9 (100.0 mg, 0.22 mmol) and triethylamine (68.1 mg, 0.67 mmol) were dissolved in acetonitrile (5 mL), ethyl isocyanate (31.9 mg, 0.45 mmol) was added, and the reaction was stirred at 25 °C for 16 h. When the reaction was completed by LCMS monitoring, the reaction was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 90:10 as eluent) to give compound 130-1 (100.0 mg) in 88.1% yield.

[0629] LC-MS (m / z): 515.0 [M-H] – .

[0630] Step 2: Synthesis of 5'-(l,l-dioxide-4-oxo-l,2,5-thiadiazolidin-2-yl)-N-ethyl-4'-fluoro-6'- hydroxyspiro[cyclohexane-l,3'-indolin]-l'-carboxamide (130)

[0631] Compound 130-1 (100.0 mg, 0.19 mmol) was dissolved in methanol (5 mL), palladium on carbon (10%, 20.0 mg, 18.9 μmol) was added, and the reaction was stirred at 25 °C for 16 hours under hydrogen atmosphere. When the reaction was completed by LCMS monitoring, the reaction was filtered, concentrated under reduced pressure, and purified by HPLC to give ammonium salt of compound 130 (15.2 mg) in 18.8% yield.

[0632] LC-MS (m / z): 427.0 [M+H] + .

[0633] 1 H NMR (600 MHz, DMSO-d6) δ 9.18 (s, 1H), 7.30 (s, 1H), 7.09 (t, J = 51.0 Hz, 4H), 6.73 (t, J = 5.4 Hz, 1H), 3.92 (s, 2H), 3.72 (s, 2H), 3.21 - 3.04 (m, 2H), 1.84 - 1.75 (m, 2H), 1.70 - 1.64 (m, 3H), 1.64 - 1.56 (m, 2H), 1.41 - 1.28 (m, 2H), 1.27 - 1.13 (m, 1H), 1.09 (t, J = 7.1 Hz, 3H).

[0634] Example 131, Synthesis of 5'-(l,l-dioxide-4-oxo-l,2,5-thiadiazolidin-2-yl)-4'-fluoro-6'- hydroxyspiro[cyclohexane-l,3'-indolin]-l'-carboxamide (131)

[0635] Step 1: Synthesis of 6'-(benzyloxy)-5'-(l,l-dioxide-4-oxo-l,2,5-thiadiazolidin-2-yl)-4'-fluoro- spiro[cyclohexane-l,3'-indolin]-l'-carboxamide (131-1)

[0636] Compound 115-9 (100.0 mg, 0.22 mmol) was suspended in a mixture solvent of acetic acid (2 mL) and water (2 mL), potassium cyanate (50.0 mg, 0.62 mmol) was added, and the reaction was stirred at 25 °C for 1 hour. When the reaction was completed by LCMS monitoring, the reaction was concentrated under reduced pressure to give compound 131-1 (180.0 mg) as a crude product.

[0637] LC-MS (m / z): 489.0 [M+H] + .

[0638] Step 2: Synthesis of 5'-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-4'-fluoro-6'- hydroxyspiro[cyclohexane-1,3'-indolin]-1'-formamide (131)

[0639] The crude product of compound 131-1 (180.0 mg) was dissolved in methanol (5 mL), and palladium on carbon (10%, 44.0 mg, 41.5 μmol) was added. The reaction was stirred at 25 °C for 16 h under hydrogen atmosphere. When the reaction was completed by LCMS monitoring, the reaction was filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 85:15 as eluent) to give compound 131 (35.0 mg) in 40.0% yield over two steps.

[0640] LC-MS (m / z): 399.0 [M+H] + .

[0641] 1 H NMR (600 MHz, DMSO-d6) δ 9.13 (s, 1H), 7.30 (s, 1H), 6.38 (s, 2H), 3.88 (s, 2H), 3.73 (s, 2H), 1.85 - 1.73 (m, 2H), 1.70 - 1.57 (m, 5H), 1.38 - 1.27 (m, 2H), 1.26 - 1.14 (m, 1H).

[0642] Biological activity

[0643] Example 1, in vitro enzymatic experiment of PTPN2

[0644] The purpose of this experiment is to test the ability of the compound to bind and inhibit the activity of PTPN2 in vitro. The specific operation steps are as follows:

[0645] 1. Preparation of Assay Buffer: Prepared using sterile deionized ultrapure water (see table below).

[0646] 2. PTPN2 enzyme preparation: The enzyme stock solution concentration is 0.15 mg / mL, and the working solution is prepared to be 4 μg / mL, i.e. the final concentration is 2 μg / mL.

[0647] 3. pNPP substrate preparation: Weigh the powdered pNPP to prepare a working solution of 2 mM, i.e. the final concentration is 1 mM.

[0648] 4. Compound solution preparation: first dissolve the compound into DMSO as a stock solution, dilute the compound stock solution to 1 mM, then perform 4 times serial dilution with DMSO, totally 8 concentration gradients; then take 2 μL of the DMSO gradient-diluted compound and add to 17.8 μL of ddH2O to obtain the working solution of the compound to be tested (the final concentration of DMSO in the reaction system is 0.1%). Add 1 μL of the working solution of the compound at each gradient concentration to 50 μL of PTPN2 in a 96-well plate, and incubate the reaction system at room temperature for 10 minutes for compound pre-incubation.

[0649] 5. After the completion of the compound pre-incubation, add 50 μL of the substrate working solution to each well, and incubate at 37°C for 90 minutes, at which time the final concentration gradient of the compound is 1 μM to 0.0610 nM.

[0650] 6. After the completion of the reaction, add 50 μL of 3M NaOH to each well to stop the reaction, and read the 405 nm of the microplate reader, convert the original data into inhibition rate, and fit the IC 50 value by the four-parameter method of log(agonist) vs. response-Variable slope of GraphPad software, and the results are shown in Table 1.

[0651] Table 1 Inhibition activity of compounds on PTPN2 enzyme Note: 0 nM < “+++” < 15 nM; 15 nM ≤ “++” < 50 nM; “+” ≥ 50 nM.

[0652] As can be seen from the data in Table 1, the compound provided by the present application has excellent in-vitro inhibition activity on PTPN2.

[0653] Example 2 Investigation of mouse pharmacokinetic characteristics

[0654] SPF female Balb / c mice, 3 in each group, single gavage administration, blood sampling at the specified time points, plasma separation, and storage in a-80°C refrigerator for standby. Take the plasma sample to be tested, thaw at room temperature, vortex (2500 rpm, 1 min), take 30.0 μL of the plasma sample into a 1.5 mL centrifuge tube, add 6.00 μL of the internal standard (ramelteon, 500.0 ng / mL), add 1000 μL of methanol, vortex (2500 rpm, 1 min), centrifuge (17000 g, 4°C) for 10 min, take 180 μL of the supernatant into a 96-well plate, seal the film, and perform LC-MS / MS analysis, and the sample injection amount is 1.00 μL. The experimental data are shown in Table 2.

[0655] Table 2 In-vivo pharmacokinetic parameters of the compound (p.o.)

[0656] As can be seen from the data in Table 2, the compound of the application has good plasma exposure after oral administration, showing excellent potential for oral administration.

[0657] Example 3 hERG toxicity

[0658] The inhibitory effect of the compound on human hERG ion channel stably expressed in HEK293 cells was tested by traditional patch clamp. The compound was prepared at a concentration of 10 μM. Each cell was used as a control. The compound was perfused using a perfusion system utilizing the force of gravity. After the current was stable, the size of the hERG current before and after the addition of the compound was compared, and the blocking effect of the compound on the hERG current was calculated, and the results are shown in Table 3.

[0659] Table 3 Blocking effect of the compound on hERG current (10 μM)

[0660] Example 5 in vitro metabolic stability

[0661] Main reagent materials:

[0662] Incubation system: Note: The liver microsomes in the incubation system are selected from one of human (mixed) liver microsomes, SD rat (mixed) liver microsomes, and CD mouse (mixed) liver microsomes.

[0663] Experimental method:

[0664] 1 μM of the test substance and the positive control testosterone were incubated with microsomes in the presence of NADPH for 120 min, and a negative control group (the test substance was incubated with microsomes in the absence of any coenzyme for 120 min) was set; samples were taken at 0 min and 120 min, 300 μL of pre-cooled methanol solution containing the internal standard (ramelteon: 1.000 ng / mL) was added, vortexed (2500 rpm, 1 min), centrifuged (4700 rpm, 4°C) for 10 min, 50.0 μL of supernatant + 200 μL of pure water was taken to a 96-well plate, vortexed (1000 rpm, 10 min), sealed, and subjected to LC-MS / MS analysis. The remaining amount of the parent substance of the test substance or probe substrate was detected by LC-MS / MS, and the metabolic stability of the test substance was represented by the percentage of the remaining amount of the test substance at each time point relative to the parent amount before incubation (0 min), and the data was calculated according to the following formula: Parent remaining (%) = T x parent amount / T0 parent amount x 100; T x : any incubation time point; T0: 0 min incubation time point. The results are shown in Table 4.

[0665] Table 4 In vitro metabolic stability results of compounds

[0666] From the data in Table 4, it can be seen that the compounds of the present application have good in vitro metabolic stability, and the species difference is small.

Claims

1. A compound of general formula (I), or a pharmaceutically acceptable salt, isotope derivative, solvate thereof, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule or metabolite thereof: wherein W is selected from C, CH or N; is a double bond or a single bond; R 1 and R 2 each independently is selected from hydrogen, deuterium, halogen, hydroxyl, oxo, or cyano; R 3 selected from C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, C2-C9heterocyclyl, C6-C10aryl, C1-C9heteroaryl, C1-C6alkyleneC3-C8cycloalkyl, C1-C6alkyleneC2-C9heterocyclyl, C1-C6alkyleneC6-C10aryl, C1-C6alkyleneC1-C9heteroaryl, -C(O)OR a 10 10 4 4 4 R 5 4 R 5 4 4 4 R 5 4 , ​​​​​​​​​​ R 4 and R 5 each independently is selected from hydrogen, deuterium, hydroxyl, halogen, oxo, cyano, or substituted with one or more R a substituted C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, C2-C9heterocyclyl, C6-C 10 aryl, C1-C9heteroaryl, C1-C6alkyleneC3-C8cycloalkyl, C1-C6alkyleneC2-C9heterocyclyl, C1-C6alkyleneC6-C 10 aryl, C1-C6alkyleneC1-C9heteroaryl; or R 4 and the atom to which they are attached together with the atom to which they are attached form a 3-12 membered heterocyclyl or C3-C8cycloalkyl substituted with one or more R 5 and the atom to which they are attached together with the atom to which they are attached form a 3-12 membered heterocyclyl or C3-C8cycloalkyl substituted with one or more R a substituents; R 6 and R 7 each independently is selected from hydrogen, deuterium, hydroxyl, halogen, oxo, cyano, or substituted with one or more R a substituted C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, C2-C9heterocyclyl, C6-C 10 aryl, C1-C9heteroaryl; or R 6 and the atom to which they are attached together form a 3-7 membered heterocyclyl or C3-C7cycloalkyl substituted with one or more R 7 and the atom to which they are attached together form a 3-7 membered heterocyclyl or C3-C7cycloalkyl substituted with one or more R a substituents; R a each independently is selected from hydrogen, deuterium, hydroxyl, halogen, oxo, cyano, or substituted with one or more R f substituted Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, C2-C9heterocyclyl, C6-C 10 aryl, Ci-C9heteroaryl, Ci-C6alkyleneC3-C8cycloalkyl, Ci-C6alkyleneC2-C9heterocyclyl, Ci-C6alkyleneC6-C 10 aryl, Ci-C6alkyleneCi-C9heteroaryl, -OR b , -SR b , -NR b R c , -C(O)OR b , -OC(O)NR b R c , -NR e C(O)NR b R c , -NR e C(O)OR b , -S(O)2NR b R c , -S(O)2R b , -NR e S(O)2R b , -COR b , -SOR b , -OCOR b , -NR e COR b , -NR e SOR b , -S(=O)(=NH)NR b R c , -NR e S(=O)(=NH)R b , -S(=O)(=NH)R b , R b R c and R e Each is independently selected from hydrogen, deuterium, hydroxyl, halogen, oxo, cyano, or by one or more R groups. f Substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C8 cycloalkyl, C2-C9 heterocyclic, C6-C 10 Aryl, C1-C9 heteroaryl, C1-C6 alkylene C3-C8 cycloalkyl, C1-C6 alkylene C2-C9 heterocyclic, C1-C6 alkylene C6-C 10 Aryl, C1-C6 alkylene, C1-C9 heteroaryl; or R b , R c , and R e are optionally taken together to form a 3-12 membered heterocyclyl or C3-C8cycloalkyl substituted with one or more R f groups; R f independently selected from hydrogen, deuterium, hydroxyl, halogen, oxo, cyano, sulfone, sulfoxide, phosphorooxy, C1-C6alkyl, C1-C6alkoxy or C3-C8cycloalkyl, said C1-C6alkyl, C1-C6alkoxy or C3-C8cycloalkyl can be optionally substituted with one or more hydrogen, deuterium, hydroxyl, halogen, oxo or cyano.

2. The compound of claim 1, or a pharmaceutically acceptable salt, isotopic derivative, solvate, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, wherein, R is independently selected from hydrogen, deuterium, hydroxyl, halogen, oxo, cyano, sulfone, sulfoxide, phosphine oxide, C1-C6alkyl, or C3-C8cycloalkyl, said C1-C6alkyl, C3-C8cycloalkyl can be optionally substituted with one or more hydrogen, deuterium, hydroxyl, halogen, oxo, or cyano. f R is independently selected from hydrogen, deuterium, hydroxyl, halogen, oxo, cyano, sulfone, sulfoxide, phosphine oxide, C1-C6alkyl, or C3-C8cycloalkyl, said C1-C6alkyl, C3-C8cycloalkyl can be optionally substituted with one or more hydrogen, deuterium, hydroxyl, halogen, oxo, or cyano.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, isotopic derivative, solvate, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, characterized in that, The compound has the following formula (II): wherein R 1 , R 2 , R 3 , R 6 and R 7 are as defined in claim 1 or 2.

4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt, isotopic derivative, solvate, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, wherein, R 3 selected from one or more R a substituted C6-C 10 aryl, C1-C9 heteroaryl, -C(O)OR 4 , -COR 4 , -C(O)NR 4 R 5 , -S(O)2NR 4 R 5 or -S(=O)(=NH)NR 4 R 5 .

5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt, isotopic derivative, solvate, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, characterized in that, The compound has the following formula (IIA): wherein R 1 , R 2 , R 4 , R 6 and R 7 are as defined in claim 1 or 2.

6. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt, isotopic derivative, solvate, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, wherein, The compound has the following formula (IIB): wherein each of Z1, Z2or Z3is independently selected from N, NH, CH or CR a ; R a , R 1 , R 2 , R 6 and R 7 are as defined in claim 1 or 2.

7. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt, isotopic derivative, solvate, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, wherein, The compound has the following formula (IIC): wherein each of X1, X2or X3is independently selected from N, NH, CH or CR a ; R a , R 1 , R 2 , R 6 and R 7 are as defined in claim 1 or 2.

8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt, isotopic derivative, solvate, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, wherein, said R 1 selected from hydrogen.

9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt, isotopic derivative, solvate, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, wherein, said R 2 selected from hydrogen.

10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt, isotopic derivative, solvate, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, wherein, R 6 and R 7 each independently is selected from the group consisting of hydrogen, deuterium, hydroxyl, halogen, oxo, cyano, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, C2-C9heterocyclyl, C6-C 10 aryl or C1-C9heteroaryl, said C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, C2-C9heterocyclyl, C6-C 10 aryl or C1-C9heteroaryl can be optionally substituted with one or more hydrogen, deuterium, hydroxyl, halogen, oxo, cyano; or R 6 and R 7 and the atom to which they are attached together form a 3-7 membered heterocyclyl or C3-C7 cycloalkyl, which can be optionally substituted with one or more hydrogen, deuterium, hydroxyl, halogen, oxo, cyano.

11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt, isotopic derivative, solvate, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, wherein, The compound has the following formula (III): wherein R 3 , R 6 and R 7 are as defined in claim 1 or 2.

12. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt, isotopic derivative, solvate, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, wherein, The compounds have the following formula (IIIA), (IIIB) and (IIIC): wherein each of X1, X2or X3is independently selected from N, NH, CH or CR a ; Z1, Z2or Z3are each independently selected from N, NH, CH or CR a ; R a , R 4 , R 6 , R 7 are as defined in claim 1 or 2.

13. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt, isotopic derivative, solvate, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, wherein, The compounds have the following structures of formula (IIIA-1), (IIIA-2), (IIIB-1), (IIIB-2), (IIIC-1), and (IIIC-2): wherein each of X1, X2or X3is independently selected from N, NH, CH or CR a ; Z1, Z2or Z3are each independently selected from N, NH, CH or CR a ; R a , R 4 are as defined in claim 1 or 2; m, n and q are each independently selected from 0, 1, 2, 3, 4 or 5; Q is selected from CH2, NH, O or S.

14. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt, isotopic derivative, solvate, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, wherein, The compounds have the following structures shown in formulae (IVA), (IVB) and (IVC): wherein each of X1, X2, X3or X4is independently selected from N, NR a , CR a or C(R a )2; Z1, Z2, Z3, Z4or Z5are each independently selected from N, NR a , CR a or C(R a )2; R a , R 4 The definitions are as in claim 1.

15. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt, isotopic derivative, solvate, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, wherein, The R 4 Selected from hydrogen, deuterium, or by one or more R a Substituted C1-C6 alkyl, C3-C8 cycloalkyl, 3-10 heterocyclic, 5-14 heteroaryl, C1-C6 alkylene C3-C8 cycloalkyl, C1-C6 alkylene 3-10 heterocyclic, C1-C6 alkylene C6-C 10 Aryl or C1-C6 alkylene 5-14 heteroaryl; said R a selected from hydrogen, deuterium, hydroxyl, halogen, cyano, or substituted with one or more R f substituted Ci-C6alkyl, Ci-C6alkoxy, Ci-C6alkylamino, C3-C8cycloalkyl, or C2-C9heterocyclyl; said R f selected from hydrogen, deuterium, hydroxyl, halogen, C1-C6alkyl or C1-C6alkoxy.

16. The compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt, isotopic derivative, solvate, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, wherein, said R 4 selected from H, CH3, said selected from said selected from 17. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt, isotopic derivative, solvate, or a stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, wherein, The compound is selected from the following structural compounds:

18. A pharmaceutical composition, characterized by, The pharmaceutical composition contains a therapeutically effective amount of the compound of any one of claims 1 to 17 or a pharmaceutically acceptable salt, isotopic derivative, solvate, or stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof.

19. Use of the compound of any one of claims 1 to 17 or a pharmaceutically acceptable salt, isotopic derivative, solvate, or stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, or the pharmaceutical composition of claim 18 in the manufacture of a medicament for treating a PTPN2 / PTPN1 mediated disease or disorder and related diseases or disorders.

20. Use of the compound of any one of claims 1 to 17 or a pharmaceutically acceptable salt, isotopic derivative, solvate, or stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, or the pharmaceutical composition of claim 18 in the treatment of a PTPN2 / PTPN1 mediated disease or disorder and related diseases or disorders.

21. A method of treating and / or preventing a disease, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of any one of claims 1 to 17 or a pharmaceutically acceptable salt, isotopic derivative, solvate, or stereoisomer, geometric isomer, tautomer thereof, or a prodrug molecule, metabolite thereof, or the pharmaceutical composition of claim 18, the disease being a PTPN2 / PTPN1 mediated disease or disorder and related diseases or disorders.

22. Use according to claim 19 or 20, or method according to claim 21, characterised in that, The PTPN2 / PTPN1 mediated disease or disorder and related diseases or disorders is a tumor or cancer selected from the group consisting of head and neck squamous cell carcinoma, clear cell renal cell carcinoma, microsatellite instability-high tumor, glioma (glioblastoma), acute myeloid leukemia, acute myelocytic leukemia, myelodysplastic / myeloproliferative neoplasm, sarcoma, chronic myelomonocytic leukemia, non-Hodgkin lymphoma, astrocytoma, melanoma, non-small cell lung cancer, small cell lung cancer, cholangiocarcinoma, chondrosarcoma, colon cancer, colorectal cancer, rectal cancer or pancreatic cancer.

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