Double bond substituent containing compound serving as protein tyrosine phosphatase inhibitor, and use thereof

Abstract

The present invention relates to a double bond substituent containing compound serving as a PTPN1 and / or PTPN2 inhibitor, and a use thereof, and in particular to a compound represented by formula (I), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, and a preparation method therefor, and a use in the preparation of a drug for treating diseases related to PTPN1 and / or PTPN2.

Description

Double-bond substituted compounds as protein tyrosine phosphatase inhibitors and uses thereof

[0001] This application claims priority to:

[0002] The priority of the prior application with the patent application number 202411162384.7, entitled "Double-bond substituted compounds as protein tyrosine phosphatase inhibitors and uses thereof", filed on August 22, 2024 with the China National Intellectual Property Office;

[0003] The priority of the prior application with the patent application number 202510087977.X, entitled "Double-bond substituted compounds as protein tyrosine phosphatase inhibitors and uses thereof", filed on January 20, 2025 with the China National Intellectual Property Office;

[0004] The priority of the prior application with the patent application number 202510645560.0, entitled "Double-bond substituted compounds as protein tyrosine phosphatase inhibitors and uses thereof", filed on May 19, 2025 with the China National Intellectual Property Office;

[0005] The priority of the prior application with the patent application number 202511142013.7, entitled "Double-bond substituted compounds as protein tyrosine phosphatase inhibitors and uses thereof", filed on August 14, 2025 with the China National Intellectual Property Office;

[0006] The above prior applications are incorporated herein by reference in their entirety. TECHNICAL FIELD

[0007] The present application relates to the field of medicine, in particular, to a class of double-bond substituted compounds as PTPN1 and / or PTPN2 inhibitors and uses thereof. BACKGROUND

[0008] The advent of immunotherapy has revolutionized the treatment of hematological and solid tumors. In particular, antibodies against immune checkpoints are able to reduce the inhibition of T cells by tumors, changing the therapeutic strategy for cancer. Immune checkpoint blockade (ICB) as a new immunotherapy approach, by targeting immune escape mechanisms, to improve the clinical response in cancer patients. However, the response rate to this therapy remains low for many tumors. Such tumors are usually characterized by a reduced immune infiltration, particularly a lack or scarcity of T cells. This scarcity can be attributed to a variety of factors, including low tumor mutation burden, poor T cell homing and infiltration, and downregulation of antigen presentation, resulting in the inability of the immune system to discover the tumor. However, resistance to immunotherapy is also common, and even some tumors dominated by tumor infiltrating lymphocytes (TILs) do not necessarily respond, while others initially respond but subsequently relapse. Incomplete clinical response and the emergence of sex resistance limit the application of immune checkpoint blockade therapy.

[0009] In the past few years, tyrosine-specific phosphatases PTP1B (encoded by PTPN1) and PTPN2 (also known as TCPTP, encoded by PTPN2) have gradually become exciting immunotherapy targets in cancer treatment. PTP1B and PTPN2 are the two most closely related members of the PTP superfamily, with high sequence and structural similarity in the catalytic domain, but differences in the non-catalytic fragments at the N- and C-termini. PTP1B is targeted to the cytosolic face of the endoplasmic reticulum (ER) by a hydrophobic sequence at the C-terminus, but can contact substrates at the plasma membrane and after receptor endocytosis. In addition, PTPN2 exists in two variants: one is a 48 kDa variant, which, like PTP1B, is targeted to the ER by a hydrophobic C-terminus; the other is a 45 kDa variant, which lacks a hydrophobic C-terminus, is targeted to the nucleus and transported between the nucleus and the cytoplasm. The two PTPs can co-regulate a variety of biological processes, such as the control of energy expenditure and glucose metabolism by the hypothalamus, and the biology and function of T cells, by dephosphorylating different or the same substrates. Both PTPs are key negative regulators of the JAK / STAT signaling pathway, PTP1B has high selectivity for JAK-2 and Tyk2, while PTPN2 has high selectivity for JAK-1 and JAK-3 in the cytoplasm, and in some cases also acts on STAT-1, STAT-3 and STAT-5 in the nucleus.

[0010] In T cells, PTPN2 antagonizes T cell receptor (TCR) signaling pathway by dephosphorylating and inactivating Src family kinases (SFKs) LCK and FYN, and attenuates cytokine signals, especially interleukin (IL)-2-induced STAT-5 signals and interferon (IFN)-induced STAT-1 signals, to regulate T cell responses and prevent misreaction to self during T cell homeostasis and antigen presentation. The importance of PTPN2 in T cell tolerance is demonstrated in PTPN2 knockout mice. Studies show that conditional deletion of Ptpn2 in T cells can cause apparent autoimmune diseases in aged C57BL / 6 mice and accelerate the development of type 1 diabetes and other co-morbidities in autoimmune-prone NOD mice. While systemic deletion of PTPN2 or inducible deletion in hematopoietic cells can cause apparent systemic inflammation and autoimmunity. These phenotypes are similar to mice lacking immune checkpoint receptors PD-1 or CTLA-4. Consistent with observations in mice, human single nucleotide polymorphisms (SNPs) of PTPN2 loss of function are also associated with autoimmune and inflammatory diseases. In contrast, PTP1B affects the development and function of T cells by attenuating IL-2 / -5 / -15-induced STAT-5 signals, and does not regulate TCR signals, and systemic or only T cell deletion of PTP1B does not promote systemic inflammation or autoimmunity. Nevertheless, deletion of PTP1B or PTPN2 in T cells can significantly enhance anti-tumor immunity. Deletion of PTPN2 enhances T cell-mediated immune surveillance, preventing the occurrence of blood and solid tumors in p53 heterozygous aged mice, while enhancing the anti-tumor activity of CAR-T cells. In addition, studies have found that the expression of PTP1B is elevated in intratumoral CD8+ effector T cells isolated from human melanoma or mouse homologous tumors, and inhibition or deletion of PTP1B in T cells or CAR T cells can significantly enhance anti-tumor immunity and promote STAT-5 signals. These studies identify PTP1B and PTPN2 as T cell checkpoints, whose functions are similar to those mediated by inhibitory receptors PD-1 on the surface of T cells.

[0011] In summary, inhibition of PTPN1 / PTPN2 is expected to be useful for cancer treatment, and PTPN1 / PTPN2 inhibitors can be a potential therapeutic strategy for ICB-resistant cancers. SUMMARY

[0012] In a first aspect of the present application, the present application provides a compound, which is a compound represented by formula (I), a tautomer thereof, a stereoisomer thereof or a pharmaceutically acceptable salt thereof,

[0013] wherein,

[0014] R1and R2are each independently H, halogen, C 1-6 alkyl, C2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, C 6-10 aryl, 3-8 membered heterocyclic alkyl, 4-8 membered heterocyclic alkenyl or 5-10 membered heteroaryl, wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, C 6-10 Aryl, 3-8 membered heterocyclic alkyl, 4-8 membered heterocyclic alkenyl and 5-10 membered heteroaryl are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. a replace;

[0015] Alternatively, R1, R2, and the carbon atoms they are bonded to form C. 3-8 Cycloalkyl or 3-8 membered heterocycloalkyl, wherein C 3-8 Cycloalkyl and 3-8 membered heterocycloalkyl groups are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. a replace;

[0016] Each R a They can be independently H, halogen, OH, NH2, CN, =O, COOH, or optionally by 1, 2, 3, or 4 Rs. a1 Replacement C 1-6 alkyl;

[0017] Each R a1 They are H and halogens, respectively, and can be distinguished independently.

[0018] Ring A is C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, C 6-10 aryl, 3-12-membered heterocyclic alkyl, 4-12-membered heterocyclic alkenyl, or 5-12-membered heteroaryl; wherein ring A is optionally surrounded by 1, 2, 3, or 4 Rs. A replace;

[0019] Each R A The independent components are H, halogen, OH, NH2, CN, =O, COOH, and C, respectively. 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0020] L is -O-, -S-, -C(=O)-, -S(=O)-, -S(=O)2-, -NR L1 -、-C(O)NRL1 -NR L1 C(O)-, -[C(R L2 )2] m -, -C(O)[C(R L2 )2] m - or -[C(R L2 )2] m C(O)-;

[0021] R L1 is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, or 3-8 membered heterocycloalkenyl, each of which C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl, C 3- 8cycloalkenyl, 3-8 membered heterocycloalkyl, and 3-8 membered heterocycloalkenyl is independently optionally substituted with 1, 2, 3, or 4 R b ;

[0022] each R b is independently H, halogen, OH, NH2, CN, =0, or COOH;

[0023] R L2 is H, halogen, OH, NH2, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, or 3-8 membered heterocycloalkenyl, each of which C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, and 3-8 membered heterocycloalkenyl is independently optionally substituted with 1, 2, 3, or 4 R c ;

[0024] each R ceach independently H, halogen, OH, NH2, CN, =O or COOH;

[0025] m is 1, 2, 3 or 4;

[0026] X1is N or CR x1 ;

[0027] X2is N or CR x2 ;

[0028] X3is N or CR x3 ;

[0029] X4is N or CR x4 ;

[0030] R x1 , R x2 , R x3 and R x4 each independently H, halogen, OH, NH2, CN, COOH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1- 6alkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, 3-8 membered heterocycloalkyl or 3-8 membered heterocycloalkenyl, each of which is optionally substituted with 1, 2, 3 or 4 R 1-6 ; 2- ; 2-6 ; 1-6 ; 1-6 ; 3-8 ; 3-8 ; d each independently H, halogen, OH, NH2, CN, =O or COOH;

[0031] each R d is independently H, halogen, OH, NH2, CN, =O or COOH;

[0032] the heteroatom groups in the "heterocycloalkyl", "heterocycloalkenyl" and "heteroaryl" groups comprise N, O or S, the number of the heteroatom groups being 1, 2, 3 or 4; when the number of the heteroatom groups is plural, the heteroatom groups are the same or different.

[0033] In a first aspect of the present application, the present application provides a compound, which is a compound represented by formula (I), a tautomer, a stereoisomer or a pharmaceutically acceptable salt thereof,

[0034] wherein,

[0035] R1and R2are each independently H, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, C 6-10 aryl, 3-8 membered heterocycloalkyl, 4-8 membered heterocycloalkenyl, or 5-10 membered heteroaryl, each of which C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, C 6-10 aryl, 3-8 membered heterocycloalkyl, 4-8 membered heterocycloalkenyl, and 5-10 membered heteroaryl, are each independently optionally substituted with 1, 2, 3, or 4 R a substituents;

[0036] Alternatively, R1, R2, and the carbon atom to which they are attached, form a C 3-8 cycloalkyl or 3-8 membered heterocycloalkyl, each of which C 3-8 cycloalkyl and 3-8 membered heterocycloalkyl, are each independently optionally substituted with 1, 2, 3, or 4 R a substituents;

[0037] each R a is each independently H, halogen, OH, NH2, CN, =O, or COOH;

[0038] Ring A is C 3-8 cycloalkyl, C 3-8 cycloalkenyl, C 6-10 aryl, 3-12 membered heterocycloalkyl, 4-12 membered heterocycloalkenyl, or 5-12 membered heteroaryl;

[0039] L is -O-, -S-, -C(=O)-, -S(=O)-, -S(=O)2-, -NR L1 -, -C(O)NR L1 -, -NR L1 C(O)-, -[C(R L2 )2] m -, -C(O)[C(R L2 )2] m -, or -[C(R L2 )2] m C(O)-;

[0040] RL1 H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, or 3-8 membered heterocycloalkenyl, each of which C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl, C 3- 8cycloalkenyl, 3-8 membered heterocycloalkyl, and 3-8 membered heterocycloalkenyl are each independently optionally substituted with 1, 2, 3, or 4 R b substituents;

[0041] each R b is independently H, halogen, OH, NH2, CN, =0, or COOH;

[0042] R L2 is H, halogen, OH, NH2, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, or 3-8 membered heterocycloalkenyl, each of which C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, and 3-8 membered heterocycloalkenyl are each independently optionally substituted with 1, 2, 3, or 4 R c substituents;

[0043] each R c is independently H, halogen, OH, NH2, CN, =0, or COOH;

[0044] m is 1, 2, 3, or 4;

[0045] X1is N or CR x1 ;

[0046] X2is N or CR x2 ;

[0047] X3 is N or CR x3 ;

[0048] X4 is N or CR x4 ;

[0049] R x1 R x2 R x3 and R x4 The independent components are H, halogen, OH, NH2, CN, COOH, and C, respectively. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1- 6-alkoxy, C 1-6 Alkylamino, C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, 3-8 membered heterocyclic alkyl, or 3-8 membered heterocyclic alkenyl, wherein C 1-6 Alkyl, C 2- 6-alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-8 cycloalkyl, C 3-8 The cycloalkenyl, 3-8 membered heterocyclic alkyl, and 3-8 membered heterocyclic alkenyl groups are each independently and optionally surrounded by 1, 2, 3, or 4 R groups. d replace;

[0050] Each R d They can be independently H, halogen, OH, NH2, CN, =O or COOH;

[0051] The heteroatom groups in the "heterocyclic alkyl", "heterocyclic alkenyl" and "heteroaryl" include N, O or S, and the number of the heteroatom groups is 1, 2, 3 or 4; when the number of the heteroatom groups is multiple, the heteroatom groups may be the same or different.

[0052] In a first aspect, the present invention provides a compound, which is a compound of formula (I), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof.

[0053] in,

[0054] R1 and R2 are independently H, halogen, and C, respectively. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, C 6-10aryl, 3-8 membered heterocycloalkyl, 4-8 membered heterocycloalkenyl, or 5-10 membered heteroaryl, each independently optionally substituted with 1, 2, 3, or 4 R 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, C 6-10 aryl, 3-8 membered heterocycloalkyl, 4-8 membered heterocycloalkenyl, and 5-10 membered heteroaryl, each independently optionally substituted with 1, 2, 3, or 4 R a substituents;

[0055] each R a is independently H, halogen, OH, NH2, CN, =O, or COOH;

[0056] ring A is C 3-8 cycloalkyl, C 3-8 cycloalkenyl, C 6-10 aryl, 3-12 membered heterocycloalkyl, 4-12 membered heterocycloalkenyl, or 5-12 membered heteroaryl;

[0057] L is -O-, -S-, -C(=O)-, -S(=O)-, -S(=O)2-, -NR L1 -, -C(O)NR L1 -, -NR L1 C(O)-, -[C(R L2 )2] m -, -C(O)[C(R L2 )2] m -, or -[C(R L2 )2] m C(O)-;

[0058] R L1 is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, or 3-8 membered heterocycloalkenyl, each independently optionally substituted with 1, 2, 3, or 4 R 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl, C 3- 8cycloalkenyl, 3-8 membered heterocycloalkyl, and 3-8 membered heterocycloalkenyl, each independently optionally substituted with 1, 2, 3, or 4 Rb substituted;

[0059] each R b is independently H, halogen, OH, NH2, CN, =0, or COOH;

[0060] R L2 is H, halogen, OH, NH2, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, or 3-8 membered heterocycloalkenyl, each of which is independently optionally substituted with 1, 2, 3, or 4 R 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, and 3-8 membered heterocycloalkenyl are each independently optionally substituted with 1, 2, 3, or 4 R c substituted;

[0061] each R c is independently H, halogen, OH, NH2, CN, =0, or COOH;

[0062] m is 1, 2, 3, or 4;

[0063] X1is N or CR x1 ;

[0064] X2is N or CR x2 ;

[0065] X3is N or CR x3 ;

[0066] X4is N or CR x4 ;

[0067] R x1 , R x2 , R x3 , and R x4 are each independently H, halogen, OH, NH2, CN, COOH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1- 6alkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl, C 3-8cycloalkenyl, 3-8 membered heterocycloalkyl, or 3-8 membered heterocycloalkenyl, each independently optionally substituted with 1, 2, 3, or 4 R 1-6 alkyl, C 2- 6alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, and 3-8 membered heterocycloalkenyl, each independently optionally substituted with 1, 2, 3, or 4 R d substituents;

[0068] each R d is independently H, halogen, OH, NH2, CN, =O, or COOH;

[0069] the heteroatom groups in the “heterocycloalkyl”, “heterocycloalkenyl”, and “heteroaryl” comprise N, O, or S, the number of the heteroatom groups is 1, 2, 3, or 4; when the number of the heteroatom groups is more than one, the heteroatom groups are the same or different.

[0070] In a first aspect, the present application provides a compound, which is a compound represented by formula (I), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof,

[0071] wherein,

[0072] R1and R2are each independently H, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, C 6-10 aryl, 3-8 membered heterocycloalkyl, 4-8 membered heterocycloalkenyl, or 5-10 membered heteroaryl, each independently optionally substituted with 1, 2, 3, or 4 R 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, C 6-10 aryl, 3-8 membered heterocycloalkyl, 4-8 membered heterocycloalkenyl, and 5-10 membered heteroaryl, each independently optionally substituted with 1, 2, 3, or 4 R a substituents;

[0073] each R a is independently H, halogen, OH, NH2, CN, =O, or COOH;

[0074] Ring A is C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, C 6-10 Aryl, 3-12 membered heterocycloalkyl, 4-12 membered heterocycloalkenyl, or 5-12 membered heteroaryl;

[0075] L is -0-, -S-, -C(=0)-, -S(=0)-, -S(=0)2-, -NR L1 -, -C(O)NR L1 -, -NR L1 C(O)-, or -[C(R L2 )2] m -;

[0076] R L1 is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, or 3-8 membered heterocycloalkenyl, said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl, C 3- 8cycloalkyl, 3-8 membered heterocycloalkyl, and 3-8 membered heterocycloalkenyl are each independently optionally substituted with 1, 2, 3, or 4 R b groups;

[0077] each R b is independently H, halogen, OH, NH2, CN, =0, or COOH;

[0078] R L2 is H, halogen, OH, NH2, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, or 3-8 membered heterocycloalkenyl, said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-8C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C1-6alkylamino, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C1-6alkylamino, C3-8cycloalkyl, C3-8cycloalkenyl, 3-8 membered heterocycloalkyl, or 3-8 membered heterocycloalkenyl, each independently optionally substituted with 1, 2, 3, or 4 R 3-8 C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C1-6alkylamino, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C1-6alkylamino, C3-8cycloalkyl, C3-8cycloalkenyl, 3-8 membered heterocycloalkyl, or 3-8 membered heterocycloalkenyl, each independently optionally substituted with 1, 2, 3, or 4 R c substituted;

[0079] each R c is independently H, halogen, OH, NH2, CN, =O, or COOH;

[0080] m is 1, 2, 3, or 4;

[0081] X1is N or CR x1 ;

[0082] X2is N or CR x2 ;

[0083] X3is N or CR x3 ;

[0084] X4is N or CR x4 ;

[0085] R x1 , R x2 , R x3 , and R x4 are each independently H, halogen, OH, NH2, CN, COOH, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C1-6alkylamino, C3-8cycloalkyl, C3-8cycloalkenyl, 3-8 membered heterocycloalkyl, or 3-8 membered heterocycloalkenyl, each independently optionally substituted with 1, 2, 3, or 4 R 1-6 ; 2-6 ; 2-6 ; 1- ; 1-6 ; 3-8 ; 3-8 ; 1-6 ; 2- ; 2-6 ; 1-6 ; 1-6 ; 3-8 ; 3-8 C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C1-6alkylamino, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C1-6alkylamino, C3-8cycloalkyl, C3-8cycloalkenyl, 3-8 membered heterocycloalkyl, or 3-8 membered heterocycloalkenyl, each independently optionally substituted with 1, 2, 3, or 4 R d substituted;

[0086] each R d is independently H, halogen, OH, NH2, CN, =O, or COOH;

[0087] The heteroatom groups in the “heterocycloalkyl”, “heterocycloalkenyl”, and “heteroaryl” groups comprise N, O, or S, the number of which is 1, 2, 3, or 4; when the number of the heteroatom groups is plural, the heteroatom groups are the same or different.

[0088] According to embodiments of the present invention, the above-described compound may further include at least one of the following technical features:

[0089] In an optional embodiment of the present invention, ring A is C. 3-6 cycloalkyl, C 3-6 Cycloalkenyl, C 6-10 Aryl, 3-10 heterocyclic alkyl, 4-10 heterocyclic alkenyl or 5-10 heteroaryl.

[0090] In an optional embodiment of the present invention, ring A is C. 3-6 Cycloalkyl, 3-8 member monocyclic heterocyclic alkyl or 6-10 member bicyclic heterocyclic alkyl, wherein the bicyclic includes fused ring, spiro ring and bridged ring.

[0091] In an optional embodiment of the present invention, the 6-10 nucleotide bicyclic heterocyclic alkyl group is a 4-6 nucleotide 4-6 nucleotide heterocyclic alkyl group.

[0092] In an optional embodiment of the present invention, ring A is cyclobutyl, cyclopentyl, cyclohexyl, azircyclobutyl, azircyclopentyl, azircyclohexyl, azircyclopentyl, and azircyclopentyl.

[0093] In one optional embodiment of the present invention for

[0094] In an optional embodiment of the invention, ring A is optionally surrounded by 1, 2, 3 or 4 R's. A Replace; each R A The independent components are H, halogen, OH, NH2, CN, =O, COOH, and C, respectively. 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

[0095] In an optional embodiment of the present invention, ring A is C. 3-6 cycloalkyl, C 3-6 Cycloalkenyl, C 6-10 aryl, 3-10-membered heterocyclic alkyl, 4-10-membered heterocyclic alkenyl, or 5-10-membered heteroaryl, wherein ring A is optionally surrounded by 1, 2, 3, or 4 Rs. A replace;

[0096] In an optional embodiment of the present invention, each R A Each is independently H, halogen, and C. 1-3 Alkyl or C 1-3 Halogenated alkyl groups;

[0097] In an optional embodiment of the present invention, each R A Each is independently represented by H;

[0098] In an optional embodiment of the present application, ring A is C 3-6 cycloalkyl, 3-8 membered monocyclic heterocycloalkyl, or 6-10 membered bicyclic heterocycloalkyl, wherein bicyclic includes fused, spiro, and bridged, said ring A is optionally substituted with 1, 2, 3, or 4 R A substituents;

[0099] In an optional embodiment of the present application, ring A is 5-6 membered monocyclic heterocycloalkyl, said ring A is optionally substituted with 1, 2, 3, or 4 R A substituents;

[0100] In an optional embodiment of the present application, ring A is azolidinyl;

[0101] In an optional embodiment of the present application,

[0102] In an optional embodiment of the present application, R1and R2are each independently H, F, Cl, Br, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 alkoxy, C 1-3 alkylamino, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, phenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, or 5-6 membered heteroaryl, said C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 alkoxy, C 1-3 alkylamino, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, phenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, and 5-6 membered heteroaryl are each independently optionally substituted with 1, 2, 3, or 4 R a substituents.

[0103] In an optional embodiment of the present application, each R a is each independently H, F, Cl, Br, OH, NH2, CN, =0, or COOH.

[0104] In an optional embodiment of the present application, each R a is each independently H or F.

[0105] In an optional embodiment of the present application, R1and R2are each independently H or F.

[0106] In an optional embodiment of the present application, R1and R2are each independently H, F, CF3, or methyl.

[0107] ​In an alternative embodiment of the application, R1and R2are each independently H, F, CF3, methyl or ethyl.

[0108] In an alternative embodiment of the application, R1and R2together with the carbon atom to which they are attached form a C 3-6 heterocycloalkyl group, said C 3-6 heterocycloalkyl group is each independently optionally substituted with 1, 2, 3 or 4 R a substituents;

[0109] In an alternative embodiment of the application, each R a is each independently H;

[0110] In an alternative embodiment of the application, the C 3-6 heterocycloalkyl group is selected from C 5-6 heterocycloalkyl group, said C 5-6 heterocycloalkyl group is each independently optionally substituted with 1, 2, 3 or 4 R a substituents;

[0111] In an alternative embodiment of the application, R1and R2together with the carbon atom to which they are attached form a tetrahydrofuranyl group;

[0112] In an alternative embodiment of the application, R1and R2together with the carbon atom to which they are attached form a C 3-6 cycloalkyl group, said C 3-6 cycloalkyl group is each independently optionally substituted with 1, 2, 3 or 4 R a substituents.

[0113] In an alternative embodiment of the application, each R a is each independently H, halogen or C a1 alkyl optionally substituted with 1, 2, 3 or 4 R 1-3 substituents;

[0114] In an alternative embodiment of the application, R1and R2together with the carbon atom to which they are attached form a C 3-6 cycloalkyl group, said C 3-6 cycloalkyl group is each independently optionally substituted with 1, 2, 3 or 4 R a substituents; wherein each R a is each independently H, F or methyl.

[0115] In an alternative embodiment of the application, R1and R2together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl or cyclopentyl group, said cyclopropyl, cyclobutyl and cyclopentyl group is each independently optionally substituted with 1, 2, 3 or 4 R a substituents.

[0116] In an alternative embodiment of the application, R1, R2, and the carbon atom to which they are attached together form a cyclopropyl, cyclobutyl, or cyclopentyl group, each of which is independently optionally substituted with 1, 2, 3, or 4 R a , each Ra is independently H, F, or methyl.

[0117] In an alternative embodiment of the application, ,

[0118] In an alternative embodiment of the application, ,

[0119] In an alternative embodiment of the application, ,

[0120] In an alternative embodiment of the application, ,

[0121] In an alternative embodiment of the application, ,

[0122] In an alternative embodiment of the application, ,

[0123] In an alternative embodiment of the application, ,

[0124] In an alternative embodiment of the application, L is -O-, -S-, -C(=O)-, -S(=O)-, -S(=O)2-, -NR L1 -, L1 -, L1 C(O)-, or -[C(R L2 )2] m -.

[0125] In an alternative embodiment of the application, L is -C(O)NR L1 -, L1 C(O)-, -[C(R L2 )2] m -, L2 m ​-OR L2 )2] m C(O)-.

[0126] In an alternative embodiment of the application, R L1 is H, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 alkoxy, C 1-3 alkylamino, C 3- cycloalkyl, C 3-6 cycloalkenyl, 3- to 6-membered heterocycloalkyl, or 3- to 6-membered heterocycloalkenyl, each of which C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 alkoxy, C 1-3 alkylamino, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, 3- to 6-membered heterocycloalkyl, and 3- to 6-membered heterocycloalkenyl is independently optionally substituted with 1, 2, 3, or 4 R b groups.

[0127] In an alternative embodiment of the application, each R b is independently H, F, Cl, Br, OH, NH2, CN, =O, or COOH.

[0128] In an alternative embodiment of the application, R L1 is H.

[0129] In an alternative embodiment of the application, R L2 is H, F, Cl, Br, OH, NH2, CN, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 alkoxy, C 1-3 alkylamino, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, 3- to 6-membered heterocycloalkyl, or 3- to 6-membered heterocycloalkenyl, each of which C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 alkoxy, C 1-3 alkylamino, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, 3- to 6-membered heterocycloalkyl, and 3- to 6-membered heterocycloalkenyl is independently optionally substituted with 1, 2, 3, or 4 R c groups.

[0130] In an alternative embodiment of the application, each Rc each independently H, F, Cl, Br, OH, NH2, CN, =0, or COOH.

[0131] In an alternative embodiment of the application, R L2 is H.

[0132] In an alternative embodiment of the application, L is -C(O)NH-, -NHC(O)-, or -(CH2)2-.

[0133] In an alternative embodiment of the application, L is -(CH2)2-.

[0134] In an alternative embodiment of the application, L is -C(O)NH-, -NHC(O)-, -(CH2)2-, -C(O)CH2-, or -CH2C(O)-.

[0135] In an alternative embodiment of the application, X1is CR x1 .

[0136] In an alternative embodiment of the application, R x1 is H, F, Cl, Br, OH, NH2, CN, COOH, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 alkoxy, C 1-3 alkylamino, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, 3-6 membered heterocycloalkyl, or 3-6 membered heterocycloalkenyl, each of which is independently optionally substituted with 1, 2, 3, or 4 R 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 alkoxy, C 1-3 alkylamino, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, 3-6 membered heterocycloalkyl, and 3-6 membered heterocycloalkenyl, each independently optionally substituted with 1, 2, 3, or 4 R d .

[0137] In an alternative embodiment of the application, R x1 is H, F, or methyl.

[0138] In an alternative embodiment of the application, R x1 is F.

[0139] In an alternative embodiment of the application, X2is N or CR x2 .

[0140] In an alternative embodiment of the application, R x2H, F, Cl, Br, OH, NH2, CN, COOH, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 alkoxy, C 1-3 alkylamino, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, 3- to 6-membered heterocycloalkyl or 3- to 6-membered heterocycloalkenyl, which C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 alkoxy, C 1-3 alkylamino, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, 3- to 6-membered heterocycloalkyl and 3- to 6-membered heterocycloalkenyl are each independently optionally substituted with 1, 2, 3 or 4 R d substituents.

[0141] In an optional embodiment of the present application, R x2 is H, F, Cl, CN, C 1-3 alkyl or C 2-4 alkynyl, which C 1-3 alkyl and C 2-4 alkynyl are each independently optionally substituted with 1, 2, 3 or 4 R d substituents.

[0142] In an optional embodiment of the present application, R x2 is H, F, Cl, CN, methyl, CF3or ethynyl (-C≡CH).

[0143] In an optional embodiment of the present application, R x2 is H, F, C 1-3 alkyl, which C 1-3 alkyl is optionally substituted with 1, 2, 3 or 4 R d substituents.

[0144] In an optional embodiment of the present application, R x2 is H, F or methyl.

[0145] In an optional embodiment of the present application, R x2 is H or methyl, which methyl is optionally substituted with 1, 2, 3 or 4 R d substituents.

[0146] In an optional embodiment of the present application, each R d is independently H, F, Cl, Br, OH, NH2, CN, =0 or COOH.

[0147] In an optional embodiment of the present application, Rx2 It can be H or CF3.

[0148] In an optional embodiment of the present invention, X3 is N or CR. x3 .

[0149] In an optional embodiment of the present invention, R x3 For H.

[0150] In an optional embodiment of the present invention, R x3 It can be H or F.

[0151] In an optional embodiment of the present invention, X4 is CR x4 .

[0152] In an optional embodiment of the present invention, R x4 It can be OH or NH2.

[0153] In an optional embodiment of the present invention, R x4 It is OH.

[0154] In an optional embodiment of the invention, the compound represented by formula (I) has structural formula (I-1) or (I-2):

[0155] R1, R2, L, R x1 X2 and ring A are as defined in this invention.

[0156] In an optional embodiment of the present invention, the above-mentioned compound is selected from any of the following compounds or their tautomers, stereoisomers or pharmaceutically acceptable salts:

[0157] In a second aspect, the present invention provides a pharmaceutical composition characterized in that it comprises the above-described compound or its tautomers, stereoisomers or pharmaceutically acceptable salts thereof.

[0158] In an optional embodiment of the invention, the pharmaceutical composition comprises a therapeutically effective amount of the compound of formula (I) or its tautomer, stereoisomer, or pharmaceutically acceptable salt.

[0159] In an optional embodiment of the present invention, the above-described pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient.

[0160] In a third aspect, the present invention provides for the use of the compounds described in the first aspect above, or their tautomers, stereoisomers, or pharmaceutically acceptable salts, or the pharmaceutical compositions described in the second aspect of the present invention, the uses including:

[0161] inhibiting the expression of PTPN1 and / or PTPN2; and / or,

[0162] manufacturing a medicament for treating a PTPN1 and / or PTPN2 related disease; and / or,

[0163] manufacturing a PTPN1 and / or PTPN2 inhibitor; and / or,

[0164] for use in treating a PTPN1 and / or PTPN2 related disease.

[0165] In an optional embodiment of the present application, the disease comprises a solid tumor.

[0166] In an optional embodiment of the present application, the solid tumor comprises head and neck cancer, non-small cell lung cancer, clear cell renal cell carcinoma, and melanoma.

[0167] In an optional embodiment of the present application, the solid tumor comprises head and neck cancer, non-small cell lung cancer, and clear cell renal cell carcinoma.

[0168] In an optional embodiment of the present application, the disease comprises a solid tumor, the solid tumor comprising head and neck cancer, non-small cell lung cancer, and clear cell renal cell carcinoma.

[0169] Terms and Definitions

[0170] Unless otherwise indicated, the terms and definitions recited in the present application, including the specification and claims of the present application, are as follows.

[0171] As will be understood by those skilled in the art, according to the conventions used in the art, are used to depict chemical bonds, the point at which a moiety or substituent is attached to a core or skeletal structure. As used herein, the meanings of "R1", "R1", and "R 1 " are the same and are interchangeable. Similar definitions apply to R2 and other other symbols.

[0172] The term "pharmaceutically acceptable", unless otherwise indicated, refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0173] The term "pharmaceutically acceptable salt", unless otherwise indicated, refers to a non-toxic acid or base salt of a pharmaceutically acceptable salt, including salts of inorganic acids and bases, salts of organic acids and bases.

[0174] In addition to pharmaceutically acceptable salts, other salts are also contemplated. These can be used, for example, in the preparation of the compound, in the purification of the compound, or in the identification, characterization, or purification of the compounds of the application, as intermediates, or for use in the preparation of other pharmaceutically acceptable salts.

[0175] The term "pharmaceutical composition" means, unless otherwise noted, a mixture of one or more of the compounds described herein, or a physiologically / pharmaceutically acceptable salt or prodrug thereof, with other chemical components, such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compound to the body.

[0176] The term "excipient" refers to a pharmaceutically acceptable inert ingredient, unless otherwise noted. Examples of classes of excipients include, but are not limited to, binders, disintegrants, lubricants, glidants, stabilizers, fillers, and diluents. Excipients can enhance the handling properties of a pharmaceutical formulation, i.e., make the formulation more amenable to direct compression by increasing flow and / or cohesion.

[0177] The term "stereoisomer" means, unless otherwise noted, isomers that have the same molecular formula but different structures resulting from the spatial arrangement of atoms. Stereoisomers include enantiomers (mirror image isomers), diastereomers (isomers that are not mirror image isomers), and conformational isomers.

[0178] Unless otherwise defined, the skilled artisan will understand that when a double bond is represented in a chemical reaction scheme by the symbol

[0179] Depending on the choice of starting materials and methods, the compounds of the application can be present in the form of one of the possible isomers or as a mixture of them, for example, as a mixture of racemic or diastereoisomers, depending on the number of asymmetric carbon atoms. When describing compounds having optical activity, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule with respect to a single chiral center (or multiple chiral centers) in the molecule. The prefixes D and L or (+) and (-) are used to designate the plane polarized light of a compound, wherein (-) or L indicates that the compound is levorotatory. Compounds with the prefix (+) or D are dextrorotatory. The stereochemical relationships are identical except that these stereoisomers are mirror images of one another. Specific stereoisomers are also referred to as enantiomers, and mixtures of such isomers are often identified as mixtures of enantiomers. A 50:50 mixture of enantiomers is referred to as a racemic mixture or racemate, and such mixtures can occur where there has been no stereocontrol or stereo selectivity in a chemical reaction or process. Many geometric isomers of olefins, C=N double bonds, and the like can also exist in the compounds described herein, and all such stable isomers are contemplated in the present application. When the compounds described herein contain olefinic double bonds, unless otherwise specified, both E and Z geometric isomers are encompassed. If the compounds contain a di-substituted cycloalkyl ring, the substituents can be in the cis- or trans- (or, alternatively, the Z- or E-) configuration.

[0180] When bonds to a chiral carbon in the formulas of the application are depicted as straight lines, it is understood that both the (R) and (S) configurations of the chiral carbon and the enantiomerically pure compounds and mixtures resulting therefrom are included within the scope of the general formula. The graphical representation of racemates or enantiomerically pure compounds herein is from Maehr, J. Chem. Ed. 1985, 62:114-120. Unless otherwise indicated, a wedge and a dashed line represent the absolute configuration of one stereogenic center.

[0181] Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. Compounds of the application containing asymmetrically substituted carbon atoms can exist in optically active form or as racemic mixtures. Resolution of racemic mixtures into their individual components can be achieved by any of a number of methods known in the art. Exemplary methods include fractional recrystallization using chiral resolving acids, which are optically active, salt-forming organic acids. Suitable resolving agents for fractional recrystallization procedures are, for example, optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as β- camphorsulfonic acid. Other resolving agents suitable for fractional crystallization procedures include the stereoisomerically pure forms of α-methyl- benzylamine (e.g., the S and R forms or diastereomeric pure forms), 2- phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like. Resolution of racemic mixtures can also be achieved by elution of chromatography columns packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). High performance liquid chromatography (HPLC) can be employed as can supercritical fluid chromatography (SFC). The choice of the particular method and elution conditions, chromatography column, etc. can be selected by one skilled in the art based upon the structure of the compound and test results. Further, optically pure starting materials or reagents of known configuration can be used to obtain any enantiomer or diastereomer of a compound described herein by stereo-organic synthesis.

[0182] The term "tautomer" refers to isomers of a molecule that differ only in the position of a proton, unless otherwise specified. Compounds of the application can exhibit tautomerism. Tautomeric compounds can exist in two or more interconvertible forms. Proton- shifting tautomers result from the migration of a hydrogen atom covalently bonded between two atoms. Tautomers generally exist in equilibrium and attempts to isolate a single tautomer usually result in a mixture whose physical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical environment within the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form predominates; in phenols, the enol form predominates. The present application includes all tautomeric forms of the compounds.

[0183] In examples of the present application, a proton can occupy two or more positions in a ring system of a heterocyclic ring system, for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H- isoindole, tetrazole, and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or spatially fixed in one form by appropriate substitution. For example:

[0184] Unless otherwise indicated, the following conventions are used in the Schemes and Examples herein: and a wedge-dashed bond represents the absolute configuration of a stereocenter, a straight solid bond and a straight-dashed bond represents the relative configuration of a stereocenter.

[0185] Unless otherwise specified, the term "solvate" means a compound of the present application or a salt thereof, including stoichiometric or non-stoichiometric amounts of solvent, when the solvent is water, then a hydrate.

[0186] 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 deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C). All isotopic variations of the compounds of the present application, whether radioactive or not, are encompassed within the scope of the present application.

[0187] The term "effective amount" or "therapeutically effective amount" with respect to a pharmaceutical or pharmacological agent refers to a nontoxic but sufficient amount of the agent to provide the desired effect, including one or more of the following: (1) preventing the disease: e.g., preventing a disease, disorder or condition from occurring in an individual that is predisposed or susceptible to the disease, but has not yet experienced or displayed any symptom of the pathology or disorder; (2) inhibiting the disease: e.g., arresting the development of a disease, disorder or condition (i.e., retarding the further development of a pathology and / or symptoms) in an individual that is experiencing or displaying the pathology or symptoms of the disease, disorder or condition; (3) relieving the disease: e.g., causing the regression of a disease, disorder or condition (i.e., reversing a pathology and / or symptoms) in an individual that is experiencing or displaying the pathology or symptoms of the disease, disorder or condition. For oral dosage forms in the present application, an "effective amount" of one active agent in a composition refers to the amount needed to achieve the desired effect in conjunction with another active agent in the composition. The determination of an effective amount is dependent on the age and general condition of the recipient, as well as the particular active agent, and an appropriate effective amount for a given case can be determined by one of ordinary skill in the art using routine trials.

[0188] Unless otherwise specified, the term "active ingredient," "therapeutic agent," "active agent" or "active agent" refers to a chemical entity that is effective in treating a disorder, disease or condition of interest.

[0189] The term "substituted," unless otherwise specified, means that any one or more hydrogen atoms on the particular atom is / are replaced with a substituent group, including heavy isotopes and variations of hydrogen, as long as the valency of the particular atom is not normally exceeded and the substituted compound is stable. When the substituent is a keto group (i.e., =0), it means that two hydrogen atoms are replaced. Keto substitution does not occur on aromatic groups.

[0190] The term "optionally" or "optional," unless otherwise specified, means that the subsequently described event or circumstance can or can not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0191] The term "optionally substituted," "optionally substituted with," or "optionally substituted by," unless otherwise specified, means that the group can or can not be substituted and that the type and number of substituents, unless otherwise specified, can be any chemically possible groups and number.

[0192] When any variable (e.g., R) occurs more than one time in a compound or substituent, its definition in each instance is independent of the definition of the other. Thus, for example, if a group is substituted with 0-2 R groups, then the group can optionally be substituted with up to two R groups, and each R group is selected independently of the other. Also, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. In addition, where multiple rings are substituted with substituents, it is intended that any of the rings can be substituted with the hydrogen atoms.

[0193] The term "alkyl," unless otherwise specified, represents a straight or branched chain monovalent hydrocarbon group containing from 1 to 20 carbon atoms, wherein the alkyl group can optionally be substituted with one or more substituents described herein. In some embodiments, the alkyl group contains 1-20 carbon atoms (C 1-20 ). In some embodiments, the alkyl group contains 1-12 carbon atoms (C 1-12 ). In some embodiments, the alkyl group contains 1-10 carbon atoms (C 1-10 ). In some embodiments, the alkyl group contains 1-6 carbon atoms (C 1-6 ). In some embodiments, the alkyl group contains 1-3 carbon atoms (C 1-3Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, t-butyl, isopentyl, 2-methylbutyl, 1- methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4- methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1- ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3- dimethylbutyl, 1,2-dimethylbutyl, and the like.

[0194] In the present application, the term "C α-β alkyl" means an alkyl group containing a minimum of alpha carbon atoms and a maximum of beta carbon atoms, where alpha and beta represent an integer, which can also be indicated in the form "C α -C β alkyl" means. Co alkyl represents a direct bond.

[0195] Unless otherwise specified, the term "alkenyl" means a straight or branched chain monovalent hydrocarbon group of from 2 to 12 carbon atoms containing at least one site of 2 double bond, wherein the alkenyl group can be optionally substituted with one or more substituents described herein, including "cis" and "trans" positioning, or "E" and "Z" positioning. In some embodiments, the alkenyl group contains from 2 to 12 carbon atoms (C 2-12 ). In some embodiments, the alkenyl group contains from 2 to 8 carbon atoms (C 2-8 ). In some embodiments, the alkenyl group contains from 2 to 6 carbon atoms (C 2- 6). In some embodiments, the alkenyl group contains from 2 to 4 carbon atoms (C 2-4 Examples of alkenyl groups include, but are not limited to, ethenyl (-CH=CH2), allyl (-CH2CH=CH2), and the like.

[0196] Unless otherwise specified, the term "alkynyl" means a straight or branched chain monovalent hydrocarbon group of from 2 to 12 carbon atoms containing at least one site of 2-12 double bond, wherein the alkenyl group can be optionally substituted with one or more substituents described herein, including "cis" and "trans" positioning, or "E" and "Z" positioning. In some embodiments, the alkenyl group contains from 2 to 12 carbon atoms (C 2-8 ). In some embodiments, the alkynyl group contains from 2 to 8 carbon atoms (C 2-6 ). In some embodiments, the alkynyl group contains from 2 to 6 carbon atoms (C 2-4 . In some embodiments, the alkynyl group contains from 2 to 4 carbon atoms (CExamples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propynyl (-CH2C≡CH), 1 -propynyl (-C≡C-CH3), and the like.

[0197] Unless otherwise specified, the term "alkylene" denotes a saturated, divalent hydrocarbon radical resulting from the removal of two hydrogen atoms from a saturated, straight- chain or branched-chain hydrocarbon group, wherein the alkylene group can be optionally substituted with one or more substituents described herein. In some embodiments, the alkylene group contains 1-12 carbon atoms (C 1-12 ) In some embodiments, the alkylene group contains 1-10 carbon atoms (C 1-10 ) In some embodiments, the alkylene group contains 1-6 carbon atoms (C 1-6 ) In some embodiments, the alkylene group contains 1-4 carbon atoms (C 1-4 ) In some embodiments, the alkylene group contains 1-3 carbon atoms (C 1-3 ) In some embodiments, the alkylene group contains 1-2 carbon atoms (C 1-2 ) Examples of alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), isopropylene (-CH(CH3)CH2-), and the like.

[0198] Unless otherwise specified, the term "alkoxy" denotes an alkyl group attached to the remainder of the molecule through an oxygen atom, or denotes an alkyl-O-alkyl group, the oxygen atom can be attached to any one of the carbon atoms of the alkyl group in either straight or branched chain, wherein alkyl has the meaning as described herein. In some embodiments, the alkoxy group contains 1-12 carbon atoms (C 1-12 ) In some embodiments, the alkoxy group contains 1-6 carbon atoms (C 1-6 ) In some embodiments, the alkoxy group contains 1-4 carbon atoms (C 1-4 ) In some embodiments, the alkoxy group contains 1-3 carbon atoms (C 1-3 ) The alkoxy group can be optionally substituted with one or more substituents described herein. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, 1 -propoxy, 2-propoxy, 1 -butoxy, 2-methyl- 1 -propoxy, 2-butoxy, 2-methyl-2-propoxy, 1 -pentoxy, 2-pentoxy, 3-pentoxy, 2-methyl-2-butoxy, 3-methyl-2-butoxy, 3-methyl- 1 -butoxy, 2-methyl- 1 -butoxy, CH3-O-CH2-, and the like.

[0199] Unless otherwise specified, the term "alkylamino" means an alkyl group attached to the remainder of the molecule through an amino group, wherein alkyl has the meaning as described herein. In some embodiments, the alkylamino group contains 1 to 12 carbon atoms (C 1-12 ). In some embodiments, the alkylamino group contains 1 to 6 carbon atoms (C 1-6 ). In some embodiments, the alkylamino group contains 1 to 4 carbon atoms (C 1-4 ). In some embodiments, the alkylamino group contains 1 to 3 carbon atoms (C 1-3 ). The alkylamino group can optionally be substituted with one or more substituents described herein. Examples of alkylamino groups include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -NHCH2CH2CH3, -NHCH(CH3)2, -NHCH2CH(CH3)2, and the like.

[0200] Unless otherwise specified, the term "haloalkyl", "haloalkenyl", or "haloalkoxy" means an alkyl, alkenyl, or alkoxy group substituted with one or more halogen atoms, examples of which include, but are not limited to, trifluoromethyl, trifluoromethoxy, and the like.

[0201] Unless otherwise specified, the term "cycloalkyl" means a monovalent or multivalent saturated monocyclic, bicyclic, or tricyclic ring system containing 3 to 12 carbon atoms, wherein the bicyclic or tricyclic ring system includes spiro, fused, and bridged rings. In some embodiments, the cycloalkyl group contains 3 to 12 carbon atoms (C 3-12 ). In some embodiments, the cycloalkyl group contains 3 to 8 carbon atoms (C 3-8 ). In some embodiments, the cycloalkyl group contains 3 to 6 carbon atoms (C 3-6 ). The cycloalkyl group can be independently unsubstituted or substituted with one or more substituents described herein. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, [2.2.2]bicyclooctane, and the like.

[0202] Unless otherwise specified, the term "cycloalkenyl" means a monovalent or multivalent non-aromatic unsaturated monocyclic, bicyclic, or tricyclic ring system containing 3 to 12 carbon atoms, wherein the bicyclic or tricyclic ring system includes spiro, fused, and bridged rings. In some embodiments, the cycloalkenyl group contains 3 to 12 carbon atoms (C 3-12 ). In some embodiments, the cycloalkenyl group contains 3 to 8 carbon atoms (C 3-8 ). In some embodiments, the cycloalkenyl group contains 3 to 6 carbon atoms (C 3-6). The cycloalkenyl groups can be independently unsubstituted or substituted with one or more substituents described herein. Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, cyclooctenyl, cyclopentadienyl, and the like.

[0203] Unless otherwise specified, the term "aryl" means a monocyclic, bicyclic and tricyclic carbocyclic ring system containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring system is aromatic, wherein each ring system contains 3-7 atoms in a ring, and has one or more points of attachment to the rest of the molecule. In some embodiments, aryl contains 6-14 carbon atoms (C 6-14 In some embodiments, aryl contains 6-12 carbon atoms (C 6-12 In some embodiments, aryl contains 6-10 carbon atoms (C 6-10 The aryl groups can be independently unsubstituted or substituted with one or more substituents described herein. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthryl, and the like.

[0204] Unless otherwise specified, Cn-n+m or Cn-Cn+m includes any one particular case of n to n+m carbons, for example, C 1-12 includes C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , and C 12 also includes any one range of n to n+m, for example, C 1-12 includes C 1- 3, C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12 and the like; by analogy, n-member to n+m-member means the number of atoms in a ring is n to n+m, for example, 3-12 membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring, 10-membered ring, 11-membered ring, and 12-membered ring, also includes any one range of n to n+m, for example, 3-12 membered ring includes 3-6 membered ring, 3-9 membered ring, 5-6 membered ring, 5-7 membered ring, 6-7 membered ring, 6-8 membered ring, and 6-10 membered ring, and the like.

[0205] Unless otherwise specified, the terms "heteroaryl," "heteroaromatic," or "heteroaromatic ring" are used interchangeably and mean a monocyclic, bicyclic or polycyclic ring system containing 5 to 12 ring atoms, at least one ring system having aromaticity, preferably 5 to 10 ring atoms, more preferably 5 to 6 ring atoms, wherein 1, 2, 3 or more ring atoms are heteroatoms and the remainder are carbon, the heteroatoms being independently selected from O, N or S, preferably 1, 2 or 3 in number. The "heteroaryl," "heteroaromatic," or "heteroaromatic ring" is optionally substituted with one or more substituents as described herein. Examples of "heteroaryl," "heteroaromatic," and "heteroaromatic ring" include, but are not limited to, 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thiophenyl, 3-thiophenyl, pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, pyrazinyl, 1,3,5-triazinyl; and also bicyclic rings, but not limited to these, such as benzimidazolyl, benzofuranyl, benzothiophenyl, indolyl (e.g., 2-indolyl), purinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl), imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridinyl, and the like.

[0206] Unless otherwise specified, the term "heterocyclyl" denotes a saturated or partially unsaturated monocyclic, bicyclic, or polycyclic ringed hydrocarbon substituent, which is a non-aromatic structure, containing 3 to 20 ring atoms, of which 1, 2, 3, or more ring atoms are selected from N, O, or S, with the remainder of the ring atoms being C. The heterocyclyl group is optionally substituted with one or more substituents described herein. Preferably, 3 to 12 ring atoms are contained (3-12 membered heterocyclyl), further preferably 3 to 10 ring atoms are contained (3-10 membered heterocyclyl), or 3 to 8 ring atoms are contained (3-8 membered heterocyclyl), or 3 to 6 ring atoms are contained (3-6 membered heterocyclyl), or 4 to 6 ring atoms are contained (4-6 membered heterocyclyl), or 5 to 6 ring atoms are contained (5-6 membered heterocyclyl). Preferably, 1 to 4, more preferably 1 to 3 (i.e., 1, 2, or 3) heteroatoms are contained. Examples of monocyclic heterocyclyl groups include, but are not limited to, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyranyl, and the like. Bicyclic or polycyclic heterocyclyl groups include spirocyclic, fused, and bridged ring heterocyclyl groups.

[0207] Unless otherwise specified, the term "heterocycloalkyl" denotes a saturated heterocyclyl group as defined above, containing 3 to 20 ring atoms, of which 1, 2, 3, or more ring atoms are selected from N, O, or S, with the remainder of the ring atoms being C. The heterocycloalkyl group is optionally substituted with one or more substituents described herein. Preferably, 3 to 12 ring atoms are contained (3-12 membered heterocycloalkyl), further preferably 3 to 8 ring atoms are contained (3-8 membered heterocycloalkyl), or 5 to 10 ring atoms are contained (5-10 membered heterocycloalkyl), or 5 to 7 ring atoms are contained (5-7 membered heterocycloalkyl), or 4 to 6 ring atoms are contained (4-6 membered heterocycloalkyl), or 5 to 6 ring atoms are contained (5-6 membered heterocycloalkyl). Preferably, 1 to 4, more preferably 1 to 3 (i.e., 1, 2, or 3) heteroatoms are contained. Examples of heterocycloalkyl groups include, but are not limited to, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, and the like), tetrahydrofuranyl (including tetrahydrofuran-2-yl, and the like), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl, and 3-piperidinyl, and the like), piperazinyl (including 1-piperazinyl and 2-piperazinyl, and the like), morpholinyl (including 3-morpholinyl and 4-morpholinyl, and the like), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, and the like.

[0208] Unless otherwise specified, the term "heteroaryloxy" means a heteroaryl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. The heteroaryloxy group is optionally substituted by one or more substituents described herein. Preferred are heteroaryloxy groups containing 4 to 20 ring atoms (4 to 20 membered heteroaryloxy), further preferred are 5 to 10 ring atoms (5 to 10 membered heteroaryloxy), or 5 to 8 ring atoms (5 to 8 membered heteroaryloxy), 4 to 8 ring atoms (4 to 8 membered heteroaryloxy), or 5 to 6 ring atoms (5 to 6 membered heteroaryloxy), or 7 ring atoms (7 membered heteroaryloxy). The heteroatoms are preferably 1 to 4, more preferably 1 to 3 (i.e. 1, 2 or 3).

[0209] Unless otherwise specified, the term "halo" or "halogen" is fluorine, chlorine, bromine and iodine.

[0210] Unless otherwise specified, the term "monocyclic" means a group having only one ring which can be saturated, unsaturated or partially saturated, and which can be carbocyclic (all ring atoms are carbon atoms) or heterocyclic (in addition to carbon atoms, ring atoms include, for example, 1, 2 or 3 heteroatoms, for example N, O or S).

[0211] Unless otherwise specified, the term "bicyclic" means a group having two linked rings. The bicyclic ring can be carbocyclic (all ring atoms are carbon atoms) or heterocyclic (in addition to carbon atoms, ring atoms include, for example, 1, 2 or 3 heteroatoms, for example N, O or S). Both rings can be aliphatic (e.g. decalin and norbornane), or aromatic (e.g. naphthalene), or a combination of aliphatic and aromatic (e.g. tetrahydronaphthalene). Bicyclic rings include (a) spiro compounds, in which the two rings share only one single atom (spiro atom, which is often a quaternary carbon). Examples of spiro compounds include, but are not limited to:

[0212] Also included are spirocycloalkyl groups sharing a spiro atom with a heterocycloalkyl group, non-limiting examples include:

[0213] (b) fused bicyclic compounds, in which the two rings share two adjacent atoms. In other words, the rings share one covalent bond, i.e. the bridgehead atoms are directly connected (e.g. α-thujene and decalin). Examples of fused bicyclic rings include, but are not limited to:

[0214] and (c) bridged bicyclic compounds, in which two rings share three or more atoms and the two bridgehead atoms are separated by a bridge comprising at least one atom. For example, norbornane, also known as bicyclo[2.2.1]heptane, can be considered as a pair of cyclopentane rings, each sharing three of their five carbon atoms. Examples of bridged bicyclics include, but are not limited to:

[0215] Further, it is to be understood that the description "independently" as employed herein in the specification in the context of describing various groups is to be interpreted in a broad sense, i.e. that each individual group described is independent of the other, and can be the same or different specific group. More specifically, the description "independently" can mean that the specific options expressed by the same symbol in different groups are independent of each other, and can also mean that the specific options expressed by the same symbol in the same group are independent of each other.

[0216] The term "patient" means any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine; cattle, sheep, horses, or primates, and most preferably humans, unless otherwise indicated.

[0217] The terms "comprising" or "comprise" or "including" or "include" or "containing" or "contain" are open-ended terms, i.e. they include but are not limited to the content of the immediately following clauses.

[0218] The terms "treatment" and other similar terms as used herein include the following meanings:

[0219] (i) preventing the disease or condition from occurring in a mammal, in particular, when such mammal is predisposed or at risk to developing the disease or condition but has not yet been diagnosed as having it;

[0220] (ii) inhibiting the disease or condition, i.e., arresting its development;

[0221] (iii) relieving the disease or condition, i.e., causing the condition state to regress; or,

[0222] (iv) relieving the symptoms of the disease or condition.

[0223] Definitions of abbreviations used in the present application are as follows: PTPN1 represents protein tyrosine phosphatase non-receptor type 1; PTP1B represents protein tyrosine phosphatase-1B; PTPN2 represents protein tyrosine phosphatase non-receptor type 2; TCPTP represents T cell protein tyrosine phosphatase; Tris-HCl represents hydroxymethyl aminomethane hydrochloride; NaCl represents sodium chloride; Triton X-100 represents polyethylene glycol octylphenyl ether; DTT represents dithiothreitol; DMSO represents dimethyl sulfoxide; DiFMUP represents 6,8-difluoro-4-methylumbelliferone phosphate; IFNγ represents gamma interferon; NBS represents N-bromosuccinimide; Me represents methyl; Et represents ethyl; Pd(dppf)Cl2 represents 1,1-bis(diphenylphosphino) ferrocene palladium chloride; Boc represents tert-butoxycarbonyl; EtOAc represents ethyl acetate; MEM represents 2-methoxyethoxymethyl; DIEA represents N,N-diisopropylethylamine; DCM represents dichloromethane; Ph represents phenyl; HCl represents hydrochloric acid; Bn represents benzyl; LiAlH4 represents lithium aluminum hydride; Ms represents methylsulfonyl; Ns represents 2-nitrobenzenesulfonyl; BBr3 represents boron tribromide; H2O2 represents hydrogen peroxide; PyHBr3 represents pyridinium tribromide; HCOOH represents formic acid; TEA represents triethylamine; DPPA represents diphenyl phosphorazide; t-BuOH represents tert-butanol; DMF represents N,N-dimethylformamide; DMA represents N,N-dimethylacetamide. Advantages

[0224] According to the embodiments of the present application, the present application has at least one of the following technical effects:

[0225] The present application provides a compound with novel structure, a tautomer, a stereoisomer or a pharmaceutically acceptable salt thereof, which has excellent pharmacokinetic properties, good drug efficacy and drugability, and can effectively treat PTPN1 and / or PTPN2 related diseases. The compound of the present application has strong inhibitory effect on PTPN1 and / or PTPN2, and can significantly inhibit the proliferation of B16F10 cells. DETAILED DESCRIPTION

[0226] The present application will be further described below in conjunction with specific examples. It should be understood that the following description is only the most preferred embodiment of the present application, and should not be considered as a limitation on the scope of protection of the present application. Based on a full understanding of the present application, the experimental methods not specified in the following examples are generally carried out under conventional conditions, or under the conditions recommended by the manufacturer, and the skilled person in the art can make non-essential modifications to the technical solutions of the present application. Such modifications should be considered to be within the scope of protection of the present application.

[0227] Example 1: Preparation of target compound 1

[0228] 5-(4-{2-[3-(difluoromethyl)azetidin-1-yl]ethyl}-2-fluoro-6-hydroxyphenyl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (1)

[0229] The synthetic route of the target compound 1 is shown as follows:

[0230] First step: synthesis of 4-bromo-2-fluoro-6-methoxyaniline (1a)

[0231] The starting material 2-fluoro-6-methoxyaniline (25.0 g, 177 mmol) was dissolved in N,N-dimethylformamide (250 mL), N-bromosuccinimide (34.7 g, 195 mmol) was slowly added, and then stirred at 25 °C for 2 hours. After the reaction was completed, water (300 mL) was added to quench, extracted with ethyl acetate (250 mL*3), washed with saturated brine (250 mL), the combined organic phase was dried over anhydrous sodium sulfate and filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column separation (petroleum ether: ethyl acetate = 5:1, R f = 0.4) to obtain compound 4-bromo-2-fluoro-6-methoxyaniline (1a) (35.0 g, yield 90%).

[0232] Second step: synthesis of ethyl 2-[(4-bromo-2-fluoro-6-methoxyphenyl)amino]acetate (1b)

[0233] The starting material 4-bromo-2-fluoro-6-methoxyaniline (1a) (34.0 g, 154 mmol) and ethyl glyoxylate toluene solution 50% (63.1 g, 309 mmol) were dissolved in N,N-dimethylformamide (350 mL), the reaction system was replaced with nitrogen three times, at 0 °C, trimethylsilyl chloride (23.5 g, 216 mmol) was dissolved in N,N-dimethylformamide (50 mL) and added to the reaction solution, and then stirred at 25 °C for 1 hour. At 0 °C, sodium cyanoborohydride (14.5 g, 231 mmol) was then added to the reaction solution, and then stirred at 25 °C for 1 hour. After the reaction was completed, water (300 mL) was added to quench, extracted with ethyl acetate (250 mL*3), washed with saturated brine (250 mL), the combined organic phase was dried over anhydrous sodium sulfate and filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column separation (petroleum ether: ethyl acetate = 5:1, R f= 0.35), to give compound ethyl 2-[(4-bromo-2-fluoro-6-methoxyphenyl)amino]acetate (1b) (35.0 g, yield 74%).

[0234] Third step: synthesis of ethyl 2-[(4-bromo-2-fluoro-6-methoxyphenyl)(sulfamoyl)amino]acetate (1c)

[0235] The starting material ethyl 2-[(4-bromo-2-fluoro-6-methoxyphenyl)amino]acetate (1b) (11.0 g, 35.9 mmol) was dissolved in N,N-dimethylacetamide (120 mL), then amino sulfuryl chloride (24.9 g, 215 mmol) was slowly added to the reaction solution at 0 °C, then stirred at 25 °C for 1 hour. After the reaction was completed, water (150 mL) was added to quench, extracted with ethyl acetate (250 mL*3), washed with saturated brine (250 mL), the combined organic phase was dried over anhydrous sodium sulfate and filtered, concentrated under reduced pressure to give compound ethyl 2-[(4-bromo-2-fluoro-6-methoxyphenyl)(sulfamoyl)amino]acetate (1c) 12.0 g, yield 87%).

[0236] Fourth step: synthesis of 5-(4-bromo-2-fluoro-6-methoxyphenyl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (1d)

[0237] The starting material ethyl 2-[(4-bromo-2-fluoro-6-methoxyphenyl)(sulfamoyl)amino]acetate (1c) (8.00 g, 20.7 mmol) was dissolved in anhydrous methanol (80.0 mL), 30% sodium methoxide methanol solution (22.4 g, 124 mmol) was slowly added at 0 °C, then stirred at 0 °C for 0.5 hour. After the reaction was completed, concentrated under reduced pressure to give the crude product. The crude product was separated and purified by HPLC to give compound 5-(4-bromo-2-fluoro-6-methoxyphenyl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (1d) (6.00 g, yield 85%).

[0238] 1 H NMR (DMSO-d6) δ 7.16 (dd, J = 9.3, 1.9 Hz, 1H), 7.11 (s, 1H), 3.91 (s, 2H), 3.80 (s, 3H).

[0239] LC-MS, M / Z (ESI): 338.9 [M-H] - .

[0240] Fifth step: synthesis of 5-(4-bromo-2-fluoro-6-hydroxyphenyl)-1λ6 Synthesis of 2,5-thiadiazolidine-1,1,3-trione (1e)

[0241] The raw material 5-(4-bromo-2-fluoro-6-methoxyphenyl)-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (1d) (2.00 g, 5.90 mmol) was dissolved in dichloromethane (40 mL). The reaction system was purged with nitrogen three times. Then, 2M boron tribromide (20.6 mL, 41.3 mmol) was slowly added to the reaction solution at -70 °C, and the temperature was slowly raised to 25 °C and stirred for 8 hours. After the reaction was completed, methanol (50 mL) was slowly added under nitrogen protection at -70 °C to quench the reaction. The pH was adjusted to 9 with ammonia, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 5:1, R... f =0.2), yielding compound 5-(4-bromo-2-fluoro-6-hydroxyphenyl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (1e) (1.80g, crude product).

[0242] Step 6: 5-{4-[(1E)-2-ethoxyvinyl]-2-fluoro-6-hydroxyphenyl}-1λ 6 Synthesis of 2,5-thiadiazolidine-1,1,3-trione (1f)

[0243] The raw material 5-(4-bromo-2-fluoro-6-hydroxyphenyl)-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (1e) (1.80 g, 5.54 mmol) and (E)-1-ethoxyvinyl-2-boronic acid linalool ester (2.19 g, 11.1 mmol) were dissolved in dioxane (20 mL) and water (10 mL), followed by the addition of sodium carbonate (1.76 g, 16.6 mmol) and 1,1-bis(diphenylphosphine)ferrocene palladium chloride (405 mg, 0.55 mmol). The reaction mixture was purged three times with nitrogen, and then the temperature was slowly increased to 100 °C and stirred for 8 hours. After the reaction was complete, the pH was adjusted to 3 with 1 M formic acid solution, and the mixture was extracted with ethyl acetate (25 mL * 3). The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 5:1, R... f =0.2), yielding compound 5-{4-[(1E)-2-ethoxyvinyl]-2-fluoro-6-hydroxyphenyl}-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (1f) (850 mg, yield 49%).

[0244] Step 7: Synthesis of 2-[3-fluoro-5-hydroxy-4-(1,1,4-trioxo-1 λ 6 Step 1 : Synthesis of 5-{4-[(1 E)-2-ethoxyvinyl]-2-fluoro-6-hydroxyphenyl}-1 λ

[0245] The starting material 5-{4-[(1 E)-2-ethoxyvinyl]-2-fluoro-6-hydroxyphenyl}-1 λ 6 Step 1 : Synthesis of 5-{4-[(1 E)-2-ethoxyvinyl]-2-fluoro-6-hydroxyphenyl}-1 λ 6 Step 1 : Synthesis of 5-{4-[(1 E)-2-ethoxyvinyl]-2-fluoro-6-hydroxyphenyl}-1 λ

[0246] Step 8: Synthesis of 3-(difluoromethyl)azetidine-1 -carboxylic acid tert-butyl ester (1 h)

[0247] The starting material 3-oxoazetidine-1 -carboxylic acid tert-butyl ester (5.00 g, 29.2 mmol) was dissolved in N,N-dimethylformamide (50.0 mL), the reaction system was replaced with nitrogen three times, then triphenylphosphine (11.5 mL, 43.8 mmol) and sodium difluorochloroacetate (5.34 g, 35.1 mmol) were slowly added to the reaction solution, then slowly warmed to 105 °C and stirred for 1 h. After the reaction was completed, water (50 mL) was added to quench the reaction, extracted with ethyl acetate (50 mL*3), washed with saturated brine (50 mL), the combined organic phase was dried over anhydrous sodium sulfate and filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column separation (petroleum ether: ethyl acetate = 5: 1) to obtain compound 3-(difluoromethyl)azetidine-1 -carboxylic acid tert-butyl ester (1 h) (1.20 g, yield 20%).

[0248] Step 9: Synthesis of 3-(difluoromethyl)azetidine hydrochloride (1 i)

[0249] The starting material 3-(difluoromethyl)azetidine-1 -carboxylic acid tert-butyl ester (1 h) 500 mg, 2.44 mmol) was dissolved in 2M hydrochloric acid ethyl acetate solution (5.00 mL), then stirred at 25 °C for 8 h. After the reaction was completed, the compound 3-(difluoromethyl)azetidine hydrochloride (1 i) (360 mg, crude) was directly concentrated under reduced pressure.

[0250] Step 10: 5-(4-{2-[3-(difluoromethylene)azacyclobutane-1-yl]ethyl}-2-fluoro-6-hydroxyphenyl)-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione(1)

[0251] The starting materials 3-(difluoromethylene)azacyclobutane hydrochloride (1i) (294 mg, 2.08 mmol) and sodium acetate (170 mg, 2.08 mmol) were dissolved in anhydrous methanol (5 mL) and anhydrous dichloromethane (5 mL) and stirred at 25 °C for 1 hour. Then, 2-[3-fluoro-5-hydroxy-4-(1,1,4-trioxo-1λ] 6 [2,5-Thiadiazolidine-2-yl)phenyl]acetaldehyde (1 g) (300 mg, 1.04 mmol) was added to the reaction solution and stirred at 25 °C for 1 hour. Then, sodium triacetoxyborohydride (330 mg, 1.56 mmol) was added to the reaction solution and stirred at 25 °C for 2 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The residue was separated and purified by HPLC using the following method (column: Welch Xtimate C18 150*25 mm*5 μm; solvent: A = water + 0.05 v / v hydrochloric acid (99%), B = acetonitrile; gradient: 1%-25%, 10 min), yielding compound 5-(4-{2-[3-(difluoromethylene)azacyclobutane-1-yl]ethyl}-2-fluoro-6-hydroxyphenyl)-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (1).

[0252] 1 H NMR (DMSO-d6) δ10.94-11.35 (s, 1H), 10.20-10.54 (s, 1H), 6.69-6.74 (m, 1H), 6.64-6.68 (m, 1 H), 4.73-4.84 (s, 2H), 4.77 (s, 2H), 4.31 (s, 2H), 3.48 (t, J=7.6Hz, 2H), 2.79 (m, J=7.6Hz, 2H).

[0253] LC-MS, M / Z (ESI): 378.1 [M+H] + .

[0254] Example 2: Preparation of target compound 2

[0255] (Z)-5-(2-fluoro-6-hydroxy-4-(2-(3-(2,2,2-trifluoroethylene)pyrrolidine-1-yl)ethyl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (2)

[0256] A synthetic route of the target compound 2 is shown below:

[0257] First Step: Synthesis of 5-(4-(2-ethoxyvinyl)-2-fluoro-6-methoxyphenyl)-1,2,5- thiadiazolidine-3-one 1,1-dioxide (2a)

[0258] Under nitrogen protection, 5-(4-bromo-2-fluoro-6-methoxyphenyl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (1d) (2.00 g, 5.90 mmol) was dissolved in 1,4-dioxane (20 mL) and water (5 mL), then (E)-1-ethoxyvinyl-2-boronic pinacol ester ((2.34 g, 11.8 mmol), sodium carbonate (1.88 g, 17.7 mmol) and 1,1-bis(diphenylphosphino)ferrocene palladium chloride (432 mg, 590 μmol) were added, and the reaction was stirred at 95 °C for 10 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column separation (ethyl acetate:methanol (V / V) = 1:0-10:1) to obtain compound 5-(4-(2-ethoxyvinyl)-2-fluoro-6-methoxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (2a) (1.60 g, yield 82%).

[0259] Second Step: Synthesis of 2-(4-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5- methoxyphenyl)acetaldehyde (2b)

[0260] 5-(4-(2-ethoxyvinyl)-2-fluoro-6-methoxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (2a) (600 mg, 1.82 mmol) was dissolved in formic acid (1 mL) and water (50 μL), and the reaction was stirred at 25 °C for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 2-(4-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5-methoxyphenyl)acetaldehyde (2b) (550 mg, crude), which was directly used in the next step.

[0261] Third Step: Synthesis of (Z)-5-(2-fluoro-6-methoxy-4-(2-(3-(2,2,2-trifluoroethylidene)pyrrolidin-1-yl)ethyl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (2c)

[0262] (Z)-3-(2,2,2-trifluoroethylidene)pyrrolidine hydrochloride (2e-01) (310 mg, 1.65 mmol) was dissolved in dichloromethane (10 mL) and methanol (1 mL), then sodium acetate (136 mg, 1.65 mmol) was added, the reaction was stirred at 25 °C for 15 min, then 2-(4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5- methoxyphenyl)acetaldehyde (2b) (250 mg, 827 pmol) was added, the reaction was stirred at 25 °C for 15 min, finally sodium cyanoborohydride (78.0 mg, 1.24 mmol) was added, the reaction was stirred at 25 °C for 2 h. After the reaction was completed, the reaction was quenched with water (3.00 mL), then concentrated under reduced pressure, the crude product was separated and purified by HPLC, the separation method was (column: Welch Ultimate XB-SiOH 150*40mm*10um; solvent: A = n-hexane, B = ethanol; gradient: 15%-45%, 12 min), to obtain compound (Z)-5-(2-fluoro-6-methoxy-4-(2-(3-(2,2,2-trifluoroethylidene)pyrrolidin-1- yl)ethyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (2c) (80.0 mg, yield 22%).

[0263] Fourth step: synthesis of (Z)-5-(2-fluoro-6-hydroxy-4-(2-(3-(2,2,2-trifluoroethylidene)pyrrolidin-1-yl)ethyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (2)

[0264] (Z)-5-(2-fluoro-6-methoxy-4-(2-(3-(2,2,2-trifluoroethylidene)pyrrolidin-1-yl)ethyl)phenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide (2c) (70.0 mg, 160 pmol) was dissolved in dichloromethane (5 mL), then boron tribromide (2.00 M, 500 uL) was added dropwise under nitrogen protection at -70 °C, the reaction was stirred at 25 °C for 3 h. After the reaction was completed, the reaction was quenched with methanol (10 mL) at -70 °C, then adjusted to pH = 7-8 with ammonia water, the reaction was concentrated under reduced pressure, the crude product was separated and purified by HPLC, the separation method was (column: Waters xbridge 150*25mm 10um; solvent: A = water, B = acetonitrile; gradient: 17%-47%, 15 min), then dried to obtain compound (Z)-5-(2-fluoro-6-hydroxy-4-(2-(3-(2,2,2-trifluoroethylidene)pyrrolidin-1-yl)ethyl)phenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide (2).

[0265] 1 H NMR (400 MHz, MeOD) δ 6.61-6.74 (m, 2H), 5.96 (br d, J = 8.40 Hz, 1H), 4.25 (s, 4H), 3.48 (br s, 2H), 3.38-3.44 (m, 2H), 2.85-3.04 (m, 4H).

[0266] LC-MS, M / Z (ESI): 424.0 [M+H] + .

[0267] Fifth step: Synthesis of (Z)-tert-butyl 3-(2,2,2-trifluoroethylidene)pyrrolidine-1- carboxylate (2d-01) and (E)-tert-butyl 3-(2,2,2-trifluoroethylidene)pyrrolidine-1- carboxylate (2d-02)

[0268] Under nitrogen protection, tert-butyl 3-methylene pyrrolidine-1-carboxylate (2.00 g, 10.9 mmol) was dissolved in 1,4-dioxane (20 mL), then 1-trifluoromethyl-1,2-benzoiodolyl-3(H)-one (6.90 g, 21.8 mmol) and tetrabutylammonium iodide (2.02 g, 5.46 mmol) were added, and the reaction was stirred at 80 °C for 10 hours. After the reaction was completed, the reaction solution was diluted with water (20 mL), then extracted with ethyl acetate (20 mL), the organic phases were combined, dried over sodium sulfate and filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column separation (petroleum ether: ethyl acetate (V / V) = 50:1-10:1) to obtain compound (Z)-tert-butyl 3-(2,2,2-trifluoroethylidene)pyrrolidine-1-carboxylate (2d-01) (1.00 g, yield 37%) and compound (E)-tert-butyl 3-(2,2,2-trifluoroethylidene)pyrrolidine-1-carboxylate (2d-02) (1.00 g, yield 37%).

[0269] 2d-01: 1 H NMR (DMSO-d6) δ 5.92-5.97 (m, 1H), 4.06 (s, 2H), 3.36-3.40 (m, 2H), 2.74 (m, 2H), 1.41 (s, 9H).

[0270] 2d-02: 1 H NMR (DMSO-d6) δ 5.96-5.99 (m, 1H), 4.04 (s, 2H), 3.43-3.47 (m, 2H), 2.77 (m, 2H), 1.41 (s, 9H).

[0271] Step 6: Synthesis of (Z)-3-(2,2,2-trifluoroethylidene)pyrrolidine hydrochloride (2e-01)

[0272] (Z)-3-(2,2,2-trifluoroethylidene)pyrrolidine-1-carboxylic acid tert-butyl ester (2d-01) (400 mg, 1.59 mmol) was dissolved in hydrochloric acid dioxane (5 mL), the reaction was stirred at 25 °C for 10 hours. After the reaction was completed, the reaction was concentrated to obtain compound (Z)-3-(2,2,2-trifluoroethylidene)pyrrolidine hydrochloride (2e-01) (300 mg, crude), which was used directly in the next step.

[0273] Example 3: Preparation of target compound 3

[0274] (E)-5-(2-fluoro-6-hydroxy-4-(2-(3-(2,2,2-trifluoroethylidene)pyrrolidin-1- yl)ethyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (3)

[0275] The synthetic route of target compound 3 is shown below:

[0276] Step 6: Synthesis of (Z)-3-(2,2,2-trifluoroethylidene)pyrrolidine hydrochloride (2e-01)

[0277] (E)-3-(2,2,2-trifluoroethylidene)pyrrolidine-1-carboxylic acid tert-butyl ester (2d-02) (500 mg, 1.99 mmol) was dissolved in hydrochloric acid dioxane (10.0 mL), the reaction was stirred at 25 °C for 10 hours. After the reaction was completed, the reaction was concentrated to obtain compound (E)-3-(2,2,2-trifluoroethylidene)pyrrolidine hydrochloride (2e-02) (350 mg, crude), which was used directly in the next step.

[0278] Step 6: Synthesis of (Z)-3-(2,2,2-trifluoroethylidene)pyrrolidine hydrochloride (2e-01)

[0279] (E)-3-(2,2,2-trifluoroethylidene)pyrrolidine hydrochloride (2e-02) (310 mg, 1.65 mmol) was dissolved in dichloromethane (10.0 mL) and methanol (1 mL), then sodium acetate (136 mg, 1.65 mmol) was added, the reaction was stirred at 25 °C for 15 min, then 2-(4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-5- methoxyphenyl)acetaldehyde (2b) (250 mg, 827 μmol) was added, the reaction was stirred at 25 °C for 15 min, finally sodium cyanoborohydride (78.0 mg, 1.24 mmol) was added, the reaction was stirred at 25 °C for 2 h. After the reaction was completed, the reaction was quenched with water (3 mL), then concentrated under reduced pressure, the crude product was separated and purified by HPLC, the separation method was (column: Welch Ultimate XB-SiOH 150*40mm*10um; solvent: A = n-hexane, B = ethanol; gradient: 15%-45%, 12 min), to obtain compound (E)-5-(2-fluoro-6-methoxy-4-(2-(3-(2,2,2-trifluoroethylidene)pyrrolidin-1-yl)ethyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (3a) (80.0 mg, yield 22%).

[0280] Third step: synthesis of (E)-5-(2-fluoro-6-hydroxy-4-(2-(3-(2,2,2-trifluoroethylidene)pyrrolidin-1-yl)ethyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (3b)

[0281] (E)-5-(2-fluoro-6-methoxy-4-(2-(3-(2,2,2-trifluoroethylidene)pyrrolidin-1-yl)ethyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (3b) (70.0 mg, 160 μmol) was dissolved in dichloromethane (5 mL), then boron tribromide (2.00 M, 500 uL) was added dropwise under nitrogen protection at -70 °C, the reaction was stirred at 25 °C for 3 h. After the reaction was completed, the reaction was quenched with methanol (10 mL) at -70 °C, then adjusted to pH = 7-8 with ammonia water, the reaction was concentrated, the crude product was separated and purified by HPLC, the separation method was (column: Waters xbridge 150*25mm 10um; solvent: A = water, B = acetonitrile; gradient: 17%-47%, 15 min), then dried to obtain compound (E)-5-(2-fluoro-6-hydroxy-4-(2-(3-(2,2,2-trifluoroethylidene)pyrrolidin-1-yl)ethyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (3).

[0282] 1 H NMR (400 MHz, MeOD) δ 6.60-6.78 (m, 2H), 5.91-6.08 (m, 1H), 4.21-4.28 (m, 2H), 3.99-4.20 (m, 2H), 3.46-3.58 (m, 2H), 3.38-3.43 (m, 2H), 2.89-3.03 (m, 4H).

[0283] LC-MS, M / Z (ESI): 424.0 [M+H] + .

[0284] Example 4: Preparation of target compound 4

[0285] 5-(4-(2-(3-(difluoromethyl)pyrrolidin-1-yl)ethyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (4)

[0286] The synthetic route of target compound 4 is shown as follows:

[0287] First step: synthesis of tert-butyl 3-(difluoromethyl)pyrrolidine-1-carboxylate (4a)

[0288] Tert-butyl 3-oxopyrrolidine-1-carboxylate (5.00 g, 26.9 mmol) and 2- (difluoromethylsulfonyl)pyridine (3.48 g, 18.0 mmol) were dissolved in N,N- dimethylformamide (50 mL), and then added to potassium tert-butoxide (4.04 g, 35.9 mmol) at -40 °C under a nitrogen atmosphere. The reaction was stirred at -40 °C under a nitrogen atmosphere for 1 hour. After the reaction was completed, the reaction mixture was added to an aqueous solution (100 mL), and extracted with ethyl acetate (50 mL*3). The organic layer was dried with anhydrous sodium sulfate, filtered, and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 5:1, Rf of 3-(difluoromethyl)pyrrolidine-1-carboxylate tert-butyl ester (4a) = 0.43) to obtain the product 3-(difluoromethyl)pyrrolidine-1-carboxylate tert-butyl ester (4a) (2.70 g, yield 68%). f

[0289] Second step: synthesis of 3-(difluoromethyl)pyrrolidine hydrochloride (4b)

[0290] ​tert-Butyl 3-(difluoromethyl)pyrrolidine-1 -carboxylate (4a) (2.70 g, 12.3 mmol) was dissolved in hydrochloric acid / ethyl acetate (2 M, 50 mL) and the reaction stirred at 25 °C for 12 h. After the reaction was complete, the reaction was concentrated in vacuo to give the product 3-(difluoromethyl)pyrrolidine hydrochloride (4b) (1.90 g, 99% yield).

[0291] 1 H NMR (400 MHz, CDC13) δ 10.10 (br s, 2H), 3.99 (br s, 2H), 3.49 (br t, 2H, J = 6.1 Hz), 2.76 (br s, 2H).

[0292] Third Step: Synthesis of 5-(4-(2-(3-(difluoromethyl)pyrrolidin-1 -yl)ethyl)-2-fluoro-6- methoxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1 -dioxide (4c)

[0293] tert-Butyl 3-(difluoromethyl)pyrrolidine-1 -carboxylate (4a) (2.70 g, 12.3 mmol) was dissolved in hydrochloric acid / ethyl acetate (2 M, 50 mL) and the reaction stirred at 25 °C for 12 h. After the reaction was complete, the reaction was concentrated in vacuo to give the product 3-(difluoromethyl)pyrrolidine hydrochloride (4b) (1.90 g, 99% yield).

[0294] Fourth Step: Synthesis of 5-(4-(2-(3-(difluoromethyl)pyrrolidin-1 -yl)ethyl)-2-fluoro-6- hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1 -dioxide (4)

[0295] Dissolve 5-(4-(2-(3-(difluoromethyl)pyrrolidin-1-yl)ethyl)-2-fluoro-6- methoxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1 -dioxide (4c) (90.0 mg, 222 pmol) in dichloromethane (9 mL), add boron tribromide (2 M, 610 pL) under nitrogen atmosphere at -75 °C, stir the reaction at 25 °C for 5 h. After completion of the reaction, quench the reaction with sodium bicarbonate (10 mL) at 0 °C, dry the organic phase and concentrate under reduced pressure to get the crude which was purified by HPLC prep (column: Waters xbridge 150*25mm*10um; mobile phase: solvent A = water + 10 mM ammonium bicarbonate, B = acetonitrile; gradient: 9% - 39%, 10.0 min) to get 5-(4-(2-(3-(difluoromethyl)pyrrolidin-1-yl)ethyl)-2-fluoro-6- hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1 -dioxide (4).

[0296] 1 H NMR (400 MHz, MeOD) d 6.58-6.74 (m, 2H), 4.60 (br s, 2H), 4.24 (s, 2H), 3.73-3.98 (m, 2H), 3.18-3.28 (m, 2H), 2.86-3.00 (m, 2H), 2.59-2.77 (m, 2H).

[0297] LC-MS, M / Z (ESI): 390.1 [M-H] - .

[0298] Example 5: Preparation of the target compound 5

[0299] 5-(2-Fluoro-6-hydroxy-4-{2-[3-(propan-2-ylidenyl)pyrrolidin-1-yl]ethyl}phenyl)-1 6 ,2,5-thiadiazolidine-1,1,3-trione (5)

[0300] The synthetic route of the target compound 5 is shown below:

[0301] First step: synthesis of 5-(4-bromo-2-fluoro-6-((2-methoxyethoxy)methoxy)phenyl)- 2-((2-methoxyethoxy)methyl)-1,2,5-thiadiazolidin-3-one 1,1 -dioxide (5a)

[0302] Dissolve 5-(4-bromo-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (1e) (5.50 g, 16.9 mmol) in dichloromethane (50 mL) at 0 °C, then add N,N-diisopropylethylamine (6.56 g, 50.8 mmol) and 2-methoxyethoxymethyl chloride (6.32 g, 50.8 mmol), stir the reaction at 20 °C for 10 hours. After the reaction is completed, dilute the reaction with water (50 mL), then extract with ethyl acetate (50 mL*3), combine the organic phases, dry over sodium sulfate and filter, concentrate under reduced pressure to obtain the crude product, purify the crude product by silica gel column separation (petroleum ether: ethyl acetate (V / V) = 10:1-3:1) to obtain compound 5-(4-bromo-2-fluoro-6-((2-methoxyethoxy)methoxy)phenyl)-2-((2-methoxyethoxy)methyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (5a) (5.30 g, yield 63%).

[0303] LC-MS, M / Z (ESI): 518.0 [M+H2O] + .

[0304] Second step: synthesis of 2-[3-fluoro-5-(2-methoxyethoxymethoxy)-4-[5-(2-methoxyethoxymethyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]phenyl]acetaldehyde (5b)

[0305] Dissolve the starting material bis(triphenylphosphine)palladium (168 mg, 329 umol) and anhydrous zinc fluoride (340 mg, 3.29 mmol) in dioxane (2 mL) under nitrogen protection, replace the reaction system with nitrogen three times, stir for 10 minutes at 25 °C, then dissolve 5-(4-bromo-2-fluoro-6-((2-methoxyethoxy)methoxy)phenyl)-2-((2-methoxyethoxy)methyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (5a) (330 mg, 658 umol) in dioxane (2 mL), then add to the reaction, finally add vinyltrimethylsilane (1.53 g, 13.2 mmol) to the reaction, stir at 75 °C for 0.5 hours. After the reaction is completed, filter, then dilute with petroleum ether (10 mL), concentrate the petroleum ether to obtain compound 2-[3-fluoro-5-(2-methoxyethoxymethoxy)-4-[5-(2-methoxyethoxymethyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]phenyl]acetaldehyde (5b) (300 mg, crude), which is directly used in the next step.

[0306] Step 3: 5-{2-fluoro-6-[(2-methoxyethoxy)methoxy]-4-{2-[3-(propan-2-ylidenyl)pyrrolidin-1- yl]ethyl}phenyl}-2-[(2-methoxyethoxy)methyl]-1 λ 6 Synthesis of 2,5-thiadiazolidine-1,1,3-trione (5c)

[0307] The starting material 3-(propan-2-ylidenyl)pyrrolidine hydrochloride (5g) (190 mg, 1.29 mmol) and sodium acetate (212 mg, 2.58 mmol) were dissolved in dioxane (5 mL) and stirred at 25 °C for 0.5 h. Then 2-[3-fluoro-5-(2-methoxyethoxymethoxy)-4-[5-(2-methoxyethoxymethyl)-1,1,4- trioxo-1,2,5-thiadiazolidin-2-yl]phenyl]acetaldehyde (5b) (300 mg, 646 umol) was added to the reaction solution and stirred at 25 °C for 0.5 h. Then sodium cyanoborohydride (81.2 mg, 1.29 mmol) was added to the reaction solution and stirred at 25 °C for 1 h. After the reaction was completed, sodium bicarbonate solution (10 mL) was added to quench, extracted with dichloromethane (10 mL*3), washed with saturated brine (10 mL), the combined organic phase was dried over anhydrous sodium sulfate and filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by HPLC, and the separation method was (column: Welch Ultimate XB-CN 250*50mm*10um; mobile phase: [Hexane-EtOH]; gradient: 5%-45%B over 15.0 min) to obtain compound 5-{2-fluoro-6-[(2-methoxyethoxy)methoxy]-4-{2-[3-(propan-2-ylidenyl)pyrrolidin-1- yl]ethyl}phenyl}-2-[(2-methoxyethoxy)methyl]-1 λ 6 2,5-thiadiazolidine-1,1,3-trione (5c) (40.0 mg, yield 11 %).

[0308] Step 4: 5-(2-fluoro-6-hydroxy-4-{2-[3-(propan-2-ylidenyl)pyrrolidin-1-yl]ethyl}phenyl)-1 λ 6 Synthesis of 2,5-thiadiazolidine-1,1,3-trione (5)

[0309] The starting material 5-{2-fluoro-6-[(2-methoxyethoxy)methoxy]-4-{2-[3-(propan-2-ylidenyl)pyrrolidin-1- yl]ethyl}phenyl}-2-[(2-methoxyethoxy)methyl]-1 λ 6,2,5-thiadiazolidine-l, 1,3-trione (5c) (40.0 mg, 71.5 umol) was dissolved in dichloromethane (2.00 mL), then the reaction system was replaced with nitrogen for three times, then 2M boron tribromide (98.5 mg, 393 umol) was slowly added to the reaction solution at -70 °C, then stirred at -40 °C for 0.5 hours. After the reaction was completed, the pH was adjusted to 8 with sodium bicarbonate solution, and the filtrate was concentrated under reduced pressure to obtain the crude product. The residue was separated and purified by HPLC, and the separation method was (column: Waters xbridge 150*25mm 10um; mobile phase: [H2O (10mM NH4HCO3)-ACN]; gradient: 10%-40% B over 10.0 min) to obtain compound 5-(2-fluoro-6-hydroxy-4-{2-[3-(propan-2-ylidenyl)pyrrolidin-l- yl]ethyl}phenyl)-llambda 6 ,2,5-thiadiazolidine-l, 1,3-trione (5).

[0310] 1 H NMR (MeOD) δ 9.77 (br s, 1H), 9.46 (s, 1H), 6.60-6.67 (m, 2H), 3.93 (s, 4H), 3.47-3.51 (m, 2H), 3.44-3.47 (m, 2H), 2.88-3.91 (m, 2H), 1.71 (br s, 6H).

[0311] LC-MS, M / Z (ESI): 384.1 [M+H] + .

[0312] Fifth step: synthesis of 2-(propan-2-ylsulfanyl)pyridine (5d)

[0313] The raw material 2-chloropyridine (4.00 g, 35.2 mmol) was dissolved in N,N-dimethylformamide (40 mL), sodium isopropyl mercaptide (34.7 g, 195 mmol) was slowly added, and then stirred at 140 °C for 6 hours. After the reaction was completed, water (50 mL) was added to quench, extracted with ethyl acetate (50 mL*3), washed with saturated brine (50 mL), the combined organic phase was dried with anhydrous sodium sulfate and filtered, and the crude product was concentrated under reduced pressure. The crude product was separated and purified by silica gel column (petroleum ether: ethyl acetate = 5: 1) to obtain compound 2-(propan-2-ylsulfanyl)pyridine (5d) (4.40 g, yield 82%).

[0314] Sixth step: synthesis of 2-(propane-2-sulfonyl)pyridine (5e)

[0315] The starting material 2-(propan-2-ylsulfanyl)pyridine (5d) (3.40 g, 22.2 mmol) and ammonium heptamolybdate (2.58 g, 2.22 mmol) were dissolved in anhydrous ethanol (40.0 mL), the reaction system was replaced with nitrogen three times, 30% hydrogen peroxide (17.6 g, 155 mmol) was slowly added dropwise into the reaction solution at 0°C, and then stirred at 25°C for 1 hour. After the reaction was completed, sodium sulfite solution (50 mL) was added for quenching, extracted with ethyl acetate (40 mL*3), washed with saturated brine (50 mL), the combined organic phase was dried with anhydrous sodium sulfate and filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column (petroleum ether: ethyl acetate = 5: 1, Rf= 0.25), to obtain compound 2-(propane-2-sulfonyl)pyridine (5e) (3.50 g, yield 85%). f

[0316] Seventh step: synthesis of tert-butyl 3-(propan-2-ylidenemethyl)pyrrolidine-1-carboxylate (5f)

[0317] The starting material potassium tert-butoxide (3.18 g, 28.3 mmol) was dissolved in N,N-dimethylformamide (50.0 mL), and then 2-(propane-2-sulfonyl)pyridine (5e) (3.50 g, 18.9 mmol) and tert-butyl 3-oxopyrrolidine-1-carboxylate (2c) (2.92 g, 15.7 mmol) were slowly added into the reaction solution at -40°C, and then stirred at 25°C for 1 hour. After the reaction was completed, water (50 mL) was added for quenching, extracted with ethyl acetate (50 mL*3), washed with saturated brine (50 mL), the combined organic phase was dried with anhydrous sodium sulfate and filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column (petroleum ether: ethyl acetate = 5: 1, Rf= 0.55), to obtain compound tert-butyl 3-(propan-2-ylidenemethyl)pyrrolidine-1-carboxylate (5f) (420 mg, yield 13%). f

[0318] Eighth step: synthesis of 3-(propan-2-ylidenemethyl)pyrrolidine hydrochloride (5g)

[0319] The starting material tert-butyl 3-(propan-2-ylidenemethyl)pyrrolidine-1-carboxylate (5f) (400 mg, 1.89 mmol) was dissolved in 2M hydrochloric acid ethyl acetate solution (5 mL), and then stirred at 25°C for 8 hours. After the reaction was completed, the compound 3-(propan-2-ylidenemethyl)pyrrolidine hydrochloride (5g) (275 mg, crude product) was directly concentrated under reduced pressure.

[0320] Example 6: preparation of target compound 6​​

[0321] 5-(2-Fluoro-4-(2-(3-(fluoromethyl)pyrrolidin-1-yl)ethyl)-6-hydroxyphenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide (6) was synthesized according to the following scheme:

[0322] The synthesis route of the target compound 6 is shown below:

[0323] First step: synthesis of tert-butyl 3-(fluoromethyl)pyrrolidine-1-carboxylate (6a)

[0324] Dissolve 2-((fluoromethyl)sulfonyl)pyridine (2.87 g, 16.3 mmol) in tetrahydrofuran (30 mL), then add potassium bis(trimethylsilyl)amide tetrahydrofuran solution (1 M, 19.4 mL) under nitrogen atmosphere at -78 °C. Stir the reaction under nitrogen atmosphere at -78 °C for 0.5 h. Then add tert-butyl 3-oxopyrrolidine-1-carboxylate (3.00 g, 16.2 mmol) dissolved in tetrahydrofuran (10 mL), stir the reaction under nitrogen protection at -78 °C for 3 h, then slowly warm to 25 °C and stir for 1 h. After the reaction is complete, add the reaction mixture to an aqueous ammonium chloride solution (100 mL), extract with ethyl acetate (50 mL*3). Dry the organic layer with anhydrous sodium sulfate, filter, wash the filter cake with ethyl acetate, and concentrate the filtrate under reduced pressure to obtain a crude product, which is purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 5:1, Rf of 3-(fluoromethyl)pyrrolidine-1-carboxylate tert-butyl ester (6a) = 0.63) to obtain the product tert-butyl 3-(fluoromethyl)pyrrolidine-1-carboxylate (6a) (900 mg, yield 28%). f

[0325] Second step: synthesis of 3-(fluoromethyl)pyrrolidine (6b)

[0326] Dissolve tert-butyl 3-(fluoromethyl)pyrrolidine-1-carboxylate (6a) (900 mg, 4.47 mmol) in hydrochloric acid / dioxane (2 M, 9 mL), and stir the reaction at 25 °C for 12 h. After the reaction is complete, concentrate the reaction under reduced pressure to obtain the product 3-(fluoromethyl)pyrrolidine 6b) (500 mg, 4.94 mmol).

[0327] 1 H NMR (400 MHz, CDCl3) δ 10.06 (br s, 2H), 6.54-6.75 (m, 1H), 4.07 (br s, 2H), 3.46 (t, J = 6.5 Hz 2H), 2.70 (br t, J = 6.5 Hz, 2H)

[0328] ​Step 3: Synthesis of 5-(2-fluoro-4-(2-(3-(fluoromethyl)pyrrolidin-1-yl)ethyl)-6- ((2-methoxyethoxy)methoxy)phenyl)-2-((2-methoxyethoxy)methyl)-1,2,5-thiadiazolidin- 3-one 1,1-dioxide (6c)

[0329] Dissolve 2-(3-fluoro-5-((2-methoxyethoxy)methoxy)-4-(5-((2- methoxyethoxy)methyl)-1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)phenyl)acetaldehyde (5b) (250 mg, 538 pmol) and 3-(fluoromethyl)pyrrolidine (6b) (272 mg, 2.69 mmol) in dioxane (5 mL), then add potassium acetate (264 mg, 2.69 mmol), stir the reaction at 25 °C for 1 h. Then add sodium cyanoborohydride (50.7 mg, 807 pmol), stir the reaction at 25 °C for 1 h. After the reaction is complete, add 10 mL of an aqueous solution to the reaction mixture, concentrate under reduced pressure to obtain the crude product. Purify the crude product by HPLC prep (column: Waters xbridge 150*25mm*10um; mobile phase: solvent A = water + 10 mM ammonium bicarbonate, B = acetonitrile; gradient: 35%-65%, 10.0 min) to obtain the product 5-(2-fluoro-4-(2-(3-(fluoromethyl)pyrrolidin-1-yl)ethyl)-6-((2- methoxyethoxy)methoxy)phenyl)-2-((2-methoxyethoxy)methyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (6c) (30.0 mg, 10% yield).

[0330] LC-MS, M / Z (ESI): 550.2 [M+H] + .

[0331] Step 4: Synthesis of 5-(2-fluoro-4-(2-(3-(fluoromethyl)pyrrolidin-1-yl)ethyl)-6- hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (6)

[0332] 5-(2-fluoro-4-(2-(3-(fluoromethylene)pyrrolidine-1-yl)ethyl)-6-((2-methoxyethoxy)methoxy)phenyl)-2-((2-methoxyethoxy)methyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (6c) (6c) (20.0 mg, 36.3 μmol) was dissolved in dichloromethane (1 mL), and boron tribromide (2 M, 100 μL) was added under a nitrogen atmosphere at -75°C. The reaction was stirred at -75°C for 0.5 hours. After the reaction was complete, sodium bicarbonate (10 mL) was added to the reaction solution at 0 degrees Celsius. The organic phase was dried and concentrated under reduced pressure to obtain the crude product. The crude product was purified by HPLC (column: Waters xbridge 150*25mm*10um; mobile phase: solvent A = water + 10mM ammonium bicarbonate, B = acetonitrile; gradient: 5%-35%, 10.0 min) to obtain 5-(2-fluoro-4-(2-(3-(fluoromethylene)pyrrolidone-1-yl)ethyl)-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (6).

[0333] 1 H NMR (400MHz, MeOD) δ6.52-6.91(m, 3H), 4.57(br s, 2H), 4.24(s, 2H), 3.43-3.45(m, 1H), 3.21-3.34(m, 1H), 2.80-2.85(m, 4H), 2.43-2.61(m, 2H)

[0334] LC-MS, M / Z (ESI): 374.0 [M+H] + .

[0335] Example 7: Preparation of target compound 7

[0336] 5-(4-(2-(4-(difluoromethylene)piperidin-1-yl)ethyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (7)

[0337] The synthetic route for target compound 7 is shown in the figure below:

[0338] Step 1: Synthesis of (E)-N-(2-benzyloxy-4-(2-ethoxyvinyl)-6-fluorophenyl)-N-(N-(benzyloxycarbonyl)aminosulfonyl)glycine methyl ester (7b)

[0339] To chlorosulfonyl isocyanate (567 mg, 4.0 mmol) in anhydrous dichloromethane (10 mL) was added benzyl alcohol (432 mg, 4 mmol) at 0 °C under nitrogen protection and reacted for 30 min at 0 °C. A solution of (E)-(2-benzyloxy)-4-(2-ethoxyvinyl)-6-fluorophenyl) glycine methyl ester (7a) (method synthesis refer to WO2021127499A1) (720 mg, 2 mmol) in anhydrous dichloromethane was added dropwise to the reaction solution, then the reaction temperature was raised to room temperature and stirred overnight. The reaction was quenched with water, extracted with ethyl acetate (10 mL*3), and the organic phase was concentrated under reduced pressure to give a crude product, which was purified by silica gel column separation (eluent: petroleum ether: ethyl acetate = 5: 1) to give (E)-N-(2-benzyloxy-4-(2-ethoxyvinyl)-6-fluorophenyl)-N-(N-(benzyloxy carbonyl) sulfamoyl) glycine methyl ester (7b) (900 mg, yield: 79%).

[0340] LC-MS, M / Z (ESI): 573.16 [M+H] +

[0341] Second step: synthesis of N-(2-benzyloxy-6-fluoro-4-(2-oxoethyl)phenyl)-N-(N-(benzyloxy) carbonyl) sulfamoyl) glycine methyl ester (7c)

[0342] To a solution of (E)-N-(2-benzyloxy-4-(2-ethoxyvinyl)-6-fluorophenyl)-N-(N-(benzyloxy carbonyl) sulfamoyl) glycine methyl ester (7b) (600 mg, 1.05 mmol) in anhydrous dichloromethane (5 mL) was added a solution of hydrochloric acid in 1,4-dioxane (4 M, 0.5 mL) dropwise at 0 °C, and reacted for 2 h at 0 °C. The reaction was complete by LCMS detection, and the reaction was concentrated under reduced pressure to give a crude product of N-(2-benzyloxy-6-fluoro-4-(2-oxoethyl)phenyl)-N-(N-(benzyloxy) carbonyl) sulfamoyl) glycine methyl ester (7c), which was directly subjected to the next step reaction.

[0343] Third step: synthesis of N-(4-(2-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)ethyl)-2-benzyloxy-6-fluorophenyl)-N-(N-((benzyloxy) carbonyl) sulfamoyl) glycine methyl ester (7d)

[0344] To a solution of N-(2-benzyloxy-6-fluoro-4-(2-oxoethyl)phenyl)-N-(N- (benzyloxy)carbonyl)sulfamoyl)glycine methyl ester (7c) (570 mg, 1.0 mmol) in anhydrous dichloromethane (5 mL) was added 4-piperidone glycol (270 mg, 2.0 mmol) and triethylamine (0.42 mL, 3.0 mmol) under nitrogen at 0 °C. After 30 min at 0 °C, sodium cyanoborohydride (190 mg, 3 mmol) was added, and then the reaction was stirred at room temperature for 3 h. The reaction was quenched with water and extracted with ethyl acetate (50 mL*3). The organic phase was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (eluent: dichloromethane:methanol = 10:1) to give N-(4-(2-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)ethyl)-2-benzyloxy-6-fluorophenyl)-N-(N-((benzyloxy)carbonyl)sulfamoyl)glycine methyl ester (7d) (300 mg, yield: 44%).

[0345] LC-MS, M / Z (ESI): 672.23 [M+H] + .

[0346] Fourth step: synthesis of N-(4-(2-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)ethyl)-2-fluoro-6- hydroxyphenyl)-N-sulfamoylglycine methyl ester (7e)

[0347] To a solution of N-(4-(2-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)ethyl)-2-benzyloxy-6- fluorophenyl)-N-(N-((benzyloxy)carbonyl)sulfamoyl)glycine methyl ester (7d) (300 mg, 0.44 mmol) in methanol (4 mL) was added palladium dichloride (78 mg, 0.44 mmol). The reaction system was first replaced with nitrogen and then replaced with hydrogen. The reaction was stirred at room temperature for 2 h. The reaction was detected by LCMS. After the reaction solution was filtered and concentrated under reduced pressure, the crude product was purified by silica gel column chromatography (eluent: dichloromethane:methanol = 10:1) to give N-(4-(2-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)ethyl)-2-fluoro-6-hydroxyphenyl)-N-sulfamoylglycine methyl ester (7e) (130 mg, yield: 66%).

[0348] LC-MS, M / Z (ESI): 448.15 [M+H] + .

[0349] Fifth step: synthesis of N-(2-fluoro-6-hydroxy-4-(2-(4-oxopiperidin-1-yl)ethyl)phenyl)-N- sulfamoylglycine methyl ester (7f)

[0350] A solution of N-(4-(2-(l,4-dioxa-8-azaspiro[4.5]dec-8-yl)ethyl)-2-fluoro-6- hydroxyphenyl)-N-sulfamoylglycine methyl ester (7e) (130 mg, 0.3 mmol) in formic acid (2 mL) was heated to 80 °C for 2 h under nitrogen atmosphere. The reaction was monitored by LCMS and found to be complete. The reaction mixture was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography (eluent: dichloromethane:methanol = 10:1) to give N-(2-fluoro-6-hydroxy-4-(2-(4-oxopiperidin-l- yl)ethyl)phenyl)-N-sulfamoylglycine methyl ester (7f) (80 mg, yield: 66%).

[0351] LC-MS, M / Z (ESI): 404.12 [M+H] +

[0352] Sixth Step: Synthesis of 5-(4-(2-(4-(difluoromethyl)piperidin-l-yl)ethyl)-2-fluoro-6- hydroxyphenyl)-l,2,5-thiadiazolidin-3-one 1,1-dioxide (7)

[0353] To a solution of N-(2-fluoro-6-hydroxy-4-(2-(4-oxopiperidin-l-yl)ethyl)phenyl)-N- sulfamoylglycine methyl ester (7f) (40 mg, 0.1 mmol) in DMF was added difluoromethyl(2- pyridyl)sulfone (39 mg, 0.2 mmol), potassium tert-butoxide in tetrahydrofuran (1.0 M, 0.22 mL) sequentially at -78 °C under nitrogen atmosphere. The reaction mixture was then allowed to warm to room temperature and stirred until the reaction was complete as monitored by LCMS. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was concentrated under reduced pressure and the residue was purified by HPLC to give 5-(4-(2-(4-(difluoromethyl)piperidin-l-yl)ethyl)-2-fluoro-6- hydroxyphenyl)-l,2,5-thiadiazolidin-3-one 1,1-dioxide (7).

[0354] 1 H NMR (400 MHz, DMSO-d6) δ 9.36 - 9.21 (s, 1H), 6.61 - 6.52 (m, 2H), 3.90 (s, 2H), 2.80 - 2.62 (m, 4H), 2.53 - 2.50 (m, 2H), 2.33 - 2.12 (m, 4H), 1.24 - 1.18 (m, 2H)

[0355] LC-MS, M / Z (ESI): 406.10 [M+H] + .

[0356] Example 8: Preparation of target compound 8

[0357] 5-(4-(2-(3-cyclobutylidenepyrrolidin-1-yl)ethyl)-2-fluoro-6-hydroxyphenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide (8)

[0358] The synthetic route of target compound 8 is shown as follows:

[0359] First step: synthesis of tert-butyl 3-cyclobutylylidene pyrrolidine-1-carboxylate (8b)

[0360] Tert-butyl 3-oxopyrrolidine-1-carboxylate (8a) (15.0 g, 81.0 mmol) was dissolved in tetrahydrofuran (150 mL) under nitrogen protection at 0 °C, then potassium tert-butoxide (21.8 g, 194 mmol) was added, the reaction was stirred at 0 °C for 0.5 h, then a solution of (4-bromobutyl)triphenylphosphonium bromide (46.5 g, 97.2 mmol) in tetrahydrofuran (150 mL) was slowly added dropwise, the reaction was stirred at 25 °C for 10 h. After the reaction was completed, the reaction liquid was diluted with water (200 mL), then extracted with ethyl acetate (200 mL*3), the organic phase was combined, dried over sodium sulfate and filtered, concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column separation (petroleum ether: ethyl acetate (V / V) = 5:1, Rf of 8b = 0.8, coloration of potassium permanganate), to obtain compound tert-butyl 3-cyclobutylylidene pyrrolidine-1-carboxylate (8b) (900 mg, yield 5%). fp1 Tert-butyl 3-cyclobutylylidene pyrrolidine-1-carboxylate (8b) (700 mg, 3.13 mmol) was dissolved in hydrochloric acid dioxane (4M, 10.0 mL), the reaction was stirred at 25 °C for 1 h. After the reaction was completed, the reaction liquid was concentrated to obtain compound 3-cyclobutylylidene pyrrolidine hydrochloride (8c) (500 mg, crude), which was directly used in the next step.

[0361] Second step: synthesis of 3-cyclobutylylidene pyrrolidine hydrochloride (8c)

[0362] Tert-butyl 3-cyclobutylylidene pyrrolidine-1-carboxylate (8b) (700 mg, 3.13 mmol) was dissolved in hydrochloric acid dioxane (4M, 10.0 mL), the reaction was stirred at 25 °C for 1 h. After the reaction was completed, the reaction liquid was concentrated to obtain compound 3-cyclobutylylidene pyrrolidine hydrochloride (8c) (500 mg, crude), which was directly used in the next step.

[0363] Third step: synthesis of 5-(2-benzyloxy)-4-(2-(3-cyclobutylidenepyrrolidin-1-yl)ethyl)-6- fluoro phenyl)-1,2,5-thiadiazo lidin-3-one 1,1-dioxide (8e)

[0364] Dissolve 3-cyclobutylidenepyrrolidine hydrochloride (8c) (310 mg, 1.65 mmol) in dichloromethane (5.00 mL) and methanol (3.00 mL), then add sodium acetate (225 mg, 2.74 mmol), stir the reaction at 25 °C for 15 minutes, then add 2-(3-benzyloxy)-4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-5-fluorophenyl)acetaldehyde (8d, synthesis reference WO2023200964A1) (450 mg, 1.19 mmol), stir the reaction at 25 °C for 15 minutes, finally add sodium triacetoxyborohydride (378 mg, 1.78 mmol), stir the reaction at 25 °C for 8 hours. After the reaction is completed, dilute the reaction with water (20.0 mL), then extract with dichloromethane / methanol (10 / 1, 20.0 mL*5), combine the organic phases, dry over sodium sulfate and filter, concentrate under reduced pressure to obtain the crude product. Purify the crude product by HPLC separation to obtain compound 5-(2-benzyloxy)-4-(2-(3-cyclobutylidenepyrrolidin-1-yl)ethyl)-6-fluorophenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (8e) (300 mg, crude).

[0365] LC-MS, M / Z (ESI): 486.1 [M+H + ]

[0366] Fourth step: synthesis of 5-(4-(2-(3-cyclobutylidenepyrrolidin-1-yl)ethyl)-2-fluoro-6- hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (8)

[0367] Dissolve 5-(2-benzyloxy)-4-(2-(3-cylobutylidene pyrrolidin-1-yl)ethyl)-6- fluorophenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (8e) (200 mg, 412 μmol) in dichloromethane (10 mL), then add boron tribromide (2.00 M, 1.3 mL) dropwise at -70 °C under nitrogen protection, stir the reaction at -70 °C for 1 hour. After the reaction is completed, quench the reaction with methanol (10.0 mL) at -70 °C, then adjust to pH = 7-8 with ammonia water, concentrate the reaction, purify the crude product by HPLC twice, separation methods are (column: Waters xbridge 150*25 mm 10 um; solvent: A = water + 0.05% ammonia water (30%), B = acetonitrile; gradient: 1%-20%, 10 minutes) and (column: Waters xbridge 150*25 mm 10 um; solvent: A = water + 10 mM ammonium bicarbonate, B = acetonitrile; gradient: 15%-45%, 10 minutes) respectively, dry to obtain compound 5-(4-(2-(3-cylobutylidene pyrrolidin-1-yl)ethyl)-2-fluoro-6- hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (8).

[0368] 1 H NMR (400 MHz, MeOD) δ 6.62-6.73 (m, 2H), 4.24 (s, 2H), 3.70-3.94 (m, 2H), 3.37-3.51 (m, 4H), 2.92-3.04 (m, 2H), 2.65-2.74 (m, 4H), 2.50-2.62 (m, 2H), 2.07 (q, J = 8.00 Hz, 2H).

[0369] LC-MS, M / Z (ESI): 396.0 [M+H + ]

[0370] Example 9: Preparation of target compound 9

[0371] 5-(2-Fluoro-6-hydroxy-4-(2-(3-methylene pyrrolidin-1-yl)ethyl)phenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide (9)

[0372] The synthetic route of target compound 9 is shown as follows:

[0373] First step: synthesis of 5-(2-benzyloxy)-6-fluoro-4-(2-(3-methylene pyrrolidin-1- yl)ethyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (9a)

[0374] The starting material 3-methylpyrrolidine hydrochloride (316 mg, 2.64 mmol) and sodium acetate (650 mg, 7.93 mmol) were dissolved in methanol (5 mL) and stirred at 25 °C for 0.5 h, then 2-(3-benzyloxy)-4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-5-fluorophenyl)acetaldehyde (8d) (500 mg, 1.32 mmol) was added to the reaction solution, which was stirred at 25 °C for 0.5 h. Then sodium cyanoborohydride (207 mg, 3.30 mmol) was added to the reaction solution, which was stirred at 25 °C for 1 h. After the reaction was completed, an aqueous solution (3 mL) was added to quench, and the crude product was obtained by concentration under reduced pressure. The crude product was separated and purified by HPLC to obtain 5-(2-benzyloxy)-6-fluoro-4-(2-(3-methylpyrrolidin-1-yl)ethyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (9a) (200 mg, yield 34%).

[0375] LC-MS, M / Z (ESI): 446.1 [M+H + ].

[0376] Second Step: Synthesis of 5-(2-fluoro-6-hydroxy-4-(2-(3-methylpyrrolidin-1-yl)ethyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (9)

[0377] The starting material 5-(2-benzyloxy)-6-fluoro-4-(2-(3-methylpyrrolidin-1-yl)ethyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (9a) (50 mg, 112 μmol) was dissolved in dichloromethane (5 mL), then the reaction system was replaced with nitrogen three times, then 2M boron tribromide (281 mg, 1.12 mmol) was slowly added to the reaction solution at -70 °C, and then stirred at -40 °C for 0.5 h. After the reaction was completed, the pH was adjusted to 8 with a sodium bicarbonate solution, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by HPLC (column: Waters xbridge 150*25mm 10um; mobile phase: [H2O (10mm NH4HCO3)-ACN]; gradient: 1%-20% B over 10.0 min) to obtain compound 5-(2-fluoro-6-hydroxy-4-(2-(3-methylpyrrolidin-1-yl)ethyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (9) (20.5 mg, yield 52%).

[0378] 1H NMR (400 MHz, DMSO-d6) δ 9.71-9.99 (m, 1H) 9.47 (s, 1H) 6.64-6.71 (m, 1H) 6.62 (s, 1H) 5.14 (br d, J=10.52 Hz, 2H) 3.99-4.37 (m, 1H) 3.94 (s, 2H) 3.57-3.89 (m, 2H) 3.44-3.54 (m, 1H) 3.20-3.33 (m, 2H) 2.87 (br t, J=7.94 Hz, 2H) 2.57-2.74 (m, 2H)

[0379] LC-MS, M / Z (ESI): 356.0 [M+H + ]

[0380] Example 10: Preparation of target compound 10

[0381] 5-(4-(2-(3-(butan-2-ylidenyl)pyrrolidin-1-yl)ethyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (10)

[0382] The synthetic route of target compound 10 is shown as follows:

[0383] First step: synthesis of dimethyl 2-(butan-2-ylidenyl)succinate (10b)

[0384] Dimethyl succinate (10a) (35 g, 239 mmol, 31.3 mL) and butan-2-one (17.2 g, 239 mmol) were dissolved in tert-butanol (300 mL), the reaction was reduced to 0°C under nitrogen protection, then potassium tert-butoxide (26.8 g, 239 mmol) was quickly added to the reaction, and stirred at 25°C for 0.5 hours. After the reaction was completed, the reaction was poured into ice dilute hydrochloric acid (2M, 100 mL), then extracted with ethyl acetate (200 mL*3), the organic phase was combined, dried over sodium sulfate and filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was dissolved in methanol (100 mL) and cooled to 0°C, and concentrated sulfuric acid (5 mL) was added, and stirred for 2 hours. After the reaction was completed, the reaction was poured into ice water (100 mL), then extracted with ethyl acetate (100 mL*3), the organic phase was combined, dried over sodium sulfate and filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column (petroleum ether: ethyl acetate (V / V)=3:1, Rfp1 was 0.4, potassium permanganate coloration), to obtain compound dimethyl 2-(butan-2-ylidenyl)succinate (10b) (20.1 g, yield 42%).

[0385] Step 2: Synthesis of 2-(but-2-ylmethyl)butane-1,4-diol (10c)

[0386] Dissolve 2-(but-2-ylmethyl)succinic acid dimethyl ester (10b) (20.0 g, 99.8 mmol) in tetrahydrofuran (100 mL) under nitrogen protection, slowly drop lithium aluminum hydride (2.5 M, 79.9 mL) at 0 °C, stir for 1 h. After the reaction is completed, add water (7.6 mL), 15% sodium hydroxide aqueous solution (7.6 g) and water (22.8 g) to the reaction solution in turn, stir at room temperature for 1 h. Then filter, wash the filter cake with ethyl acetate (100 mL), dry the filtrate and concentrate under reduced pressure to obtain compound 2-(but-2-ylmethyl)butane-1,4-diol (10c) (9.00 g, crude product), which is directly used in the next step.

[0387] Step 3: Synthesis of 2-(but-2-ylmethyl)butane-1,4-diyl dimethanesulfonate (10d)

[0388] Dissolve 2-(but-2-ylmethyl)butane-1,4-diol (10c) (9.00 g, 62.4 mmol) and triethylamine (25.2 g, 249 mmol) in dichloromethane (120 mL), add methanesulfonic anhydride (32.6 g, 187 mmol) at 0 °C under nitrogen protection, stir for 12 h. After the reaction is completed, dilute the reaction solution with water (200 mL), then extract with ethyl acetate (200 mL*3), combine the organic phases, dry with sodium sulfate and filter, concentrate under reduced pressure to obtain the crude product. Purify the crude product by silica gel column separation (petroleum ether: ethyl acetate (V / V) = 2:1, Rfp1 is 0.35, potassium permanganate coloration) to obtain compound 2-(but-2-ylmethyl)butane-1,4-diyl dimethanesulfonate (10d) (3.20 g, yield 17%).

[0389] Step 4: Synthesis of 3-(2-butylidene)-1-((4-nitrophenyl)sulfonyl)pyrrolidine (10e)

[0390] Dissolve 2-nitrobenzenesulfonamide (2.58 g, 12.7 mmol) in N,N-dimethylformamide (30 mL), then add anhydrous potassium carbonate (3.53 g, 25.5 mmol) to the reaction, stir at 25 °C for 1 h. Then add 2-(but-2-ylidenemethyl)butane-1,4-diyl dimethanesulfonate (10d) (3.20 g, 10.6 mmol), stir at 50 °C for 1 h. After the reaction is completed, dilute the reaction with water (150 mL), then extract with ethyl acetate (90 mL*3), combine the organic phases, dry over sodium sulfate and filter, concentrate under reduced pressure to obtain compound 3-(2-butylidenemethyl)-1-((4-nitrophenyl)sulfonyl)pyrrolidine (10e) (2.10 g, crude), which is directly subjected to the next step.

[0391] Fifth step: synthesis of 3-(but-2-ylidenemethyl)pyrrolidine (10f)

[0392] Dissolve 3-(2-butylidenemethyl)-1-((4-nitrophenyl)sulfonyl)pyrrolidine (10e) (2.10 g, 6.77 mmol), dodecan-1-thiol (2.05 g, 10.1 mmol) and anhydrous potassium carbonate (2.81 g, 20.3 mmol) in N,N-dimethylformamide (10 mL), stir the reaction at 120 °C for 1 h. After the reaction is completed, filter the reaction directly, concentrate under reduced pressure to obtain the crude product. Purify the crude product by HPLC separation to obtain compound 3-(but-2-ylidenemethyl)pyrrolidine (10f) (210 mg, 25% yield)

[0393] Sixth step: synthesis of 5-(2-benzyloxy)-4-(2-(3-(but-2-ylidenemethyl)pyrrolidin-1-yl)ethyl)-6-fluorophenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (10g)

[0394] Dissolve 3-(butan-2-ylidenemethyl)pyrrolidine (10f) (248 mg, 1.98 mmol) in dichloromethane (10 mL), then add sodium acetate (162 mg, 1.98 mmol), stir the reaction at 25 °C for 15 min, then add 2-(3-benzyloxy)-4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-5-fluorophenyl)acetaldehyde (8d) (500 mg, 1.32 mmol), stir the reaction at 25 °C for 1 h, then add sodium triacetoxyborohydride (560 mg, 2.64 mmol), stir the reaction at 25 °C for 1 h. After completion of the reaction, dilute the reaction with water (3 mL), then extract with dichloromethane / methanol (10 / 1, 20 mL*5), combine the organic phases, dry over sodium sulfate and filter, concentrate under reduced pressure to give the crude product. Purify the crude product by HPLC to give compound 5-(2-benzyloxy)-4-(2-(3-(butan-2-ylidenemethyl)pyrrolidin-1-yl)ethyl)-6-fluorophenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (10g) (57.0 mg, 9% yield).

[0395] LC-MS, M / Z (ESI): 488.2 [M+H + ].

[0396] Seventh step: 5-(4-(2-(3-(butan-2-ylidenemethyl)pyrrolidin-1-yl)ethyl)-2-fluoro-6- hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (10)

[0397] Dissolve 5-(2-benzyloxy)-4-(2-(3-(butan-2-ylidenemethyl)pyrrolidin-1-yl)ethyl)-6- fluorophenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (10g) (57.0 mg, 116 μmol) in dichloromethane (5 mL), then add boron tribromide (2 M, 292 μL) dropwise under nitrogen protection at -70 °C, stir the reaction at -70 °C for 1 h. After completion of the reaction, quench the reaction with methanol (5 mL) at -70 °C, then adjust to pH = 7-8 with ammonia water, concentrate the reaction under reduced pressure, purify the crude product by HPLC (column: Waters xbridge 150*25 mm 10 um; solvent: A = water + 10 mM ammonium bicarbonate, B = acetonitrile; gradient: 1%-30%, 12 min) to give compound 5-(4-(2-(3-(butan-2-ylidenemethyl)pyrrolidin-1-yl)ethyl)-2-fluoro-6- hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (10).

[0398] 1H NMR (400 MHz, DMSO-d6) δ 9.21 - 9.67 (m, 2H), 6.64 - 6.72 (m, 1H), 6.63 (br s, 1H), 3.93 (s, 2H), 3.66 - 3.88 (m, 1H), 3.37 - 3.54 (m, 2H), 3.16 - 3.27 (m, 2H), 2.83 - 3.06 (m, 2H), 2.30 - 2.47 (m, 2H), 2.02 - 2.26 (m, 1H), 1.66 (br s, 3H), 1.62 (br s, 2H), 1.22 - 1.49 (m, 3H)

[0399] LC-MS, M / Z (ESI): 398.1 [M+H + ]

[0400] Example 11: Preparation of the target compound 11

[0401] Synthesis of 5-(4-(2-(3-cyclopentylidene pyrrolidin-1-yl)ethyl)-2-fluoro-6- hydroxyphenyl)-1,2,5-thiazolidin-3-one 1,1-dioxide (11)

[0402] The synthetic route of the target compound 11 is shown below:

[0403] First step: Synthesis of 2-(cyclopentylthio)pyridine (11b)

[0404] To pyridine-2-thiol (11a) (6.00 g, 53.9 mmol), bromocyclopentane (10.1 g, 67.5 mmol) in acetone (80 mL) was added anhydrous potassium carbonate (11.2 g, 81.0 mmol) at room temperature. The reaction solution was stirred at 25 °C for 2 hours. After the reaction was completed, the crude product was concentrated under reduced pressure, then diluted with water (80 mL) and extracted with methyl tert-butyl ether (30 mL*3). The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 2-(cyclopentylthio)pyridine (11b) (9.60 g, yield 99%).

[0405] Second step: Synthesis of 2-(cyclopentylsulfonyl)pyridine (11c)

[0406] To a solution of 2-(cyclopentylsulfonyl)pyridine (11c) (4.11 g, 19.5 mmol) in tetrahydrofuran (30 mL) was added lithium bis(trimethylsilyl)amide (1 M, 19.5 mL) dropwise at -60 °C under nitrogen and stirred for 0.5 h at -60 °C. To the reaction mixture was added a solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (3 g, 16.2 mmol) in tetrahydrofuran (10 mL) dropwise at -60 °C and stirred for 12 h at 25 °C. The reaction mixture was quenched with ammonium chloride (100 mL) and extracted with ethyl acetate (30 mL*2). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate (1 / 0 to 10 / 1)) to give tert-butyl 3-cyclopentylidenepyrrolidine-1-carboxylate (11d) (282 mg, yield 8%).

[0407] Third Step: Synthesis of tert-butyl 3-cyclopentylidenepyrrolidine-1-carboxylate (11d)

[0408] To a solution of 2-(cyclopentylsulfonyl)pyridine (11c) (4.11 g, 19.5 mmol) in tetrahydrofuran (30 mL) was added lithium bis(trimethylsilyl)amide (1 M, 19.5 mL) dropwise at -60 °C under nitrogen and stirred for 0.5 h at -60 °C. To the reaction mixture was added a solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (3 g, 16.2 mmol) in tetrahydrofuran (10 mL) dropwise at -60 °C and stirred for 12 h at 25 °C. The reaction mixture was quenched with ammonium chloride (100 mL) and extracted with ethyl acetate (30 mL*2). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate (1 / 0 to 10 / 1)) to give tert-butyl 3-cyclopentylidenepyrrolidine-1-carboxylate (11d) (282 mg, yield 8%).

[0409] Fourth Step: Synthesis of 3-cyclopentylidenepyrrolidine hydrochloride (11e)

[0410] To a solution of tert-butyl 3-cyclopentylidenepyrrolidine-1-carboxylate (11d) (280 mg, 1.18 mmol) in dioxane (1 mL) was added hydrochloric acid in dioxane (2 M, 5 mL) at room temperature and stirred for 2 h at 25 °C. The reaction mixture was directly concentrated under reduced pressure to give 3-cyclopentylidenepyrrolidine hydrochloride (11e) (230 mg, crude).

[0411] LC-MS, M / Z (ESI): 174.1 [M+H + ]

[0412] Step 5: Synthesis of 5-(2-(benzyloxy)-4-(2-(3-cyclopentylidenepyrrolidin-l- yl)ethyl)-6-fluorophenyl)-l,2,5-thiadiazolidin-3-one 1,1-dioxide (11f)

[0413] To a mixture of 5-(2-(benzyloxy)-4-(2-(3-cyclopentylidenepyrrolidin-l- yl)ethyl)-6-fluorophenyl)-l,2,5-thiadiazolidin-3-one 1,1-dioxide (11f) (25.0 mg, 50.0 μmol) in dichloromethane (3 mL) and methanol (2 mL) was added sodium cyanoborohydride (66.4 mg, 1.06 mmol) at room temperature. The reaction mixture was stirred at 25 °C for 0.5 h. After the reaction was completed, the mixture was filtered directly to give the crude product. The crude product was purified by HPLC to give 5-(2-(benzyloxy)-4-(2-(3-cyclopentylidenepyrrolidin-l- yl)ethyl)-6-fluorophenyl)-l,2,5-thiadiazolidin-3-one 1,1-dioxide (11f) (30.0 mg, 11% yield).

[0414] LC-MS, M / Z (ESI): 500.1 [M+H + ]

[0415] Step 6: Synthesis of 5-(4-(2-(3-cyclopentylidenepyrrolidin-l-yl)ethyl)-2-fluoro-6- hydroxyphenyl)-l,2,5-thiadiazolidin-3-one 1,1-dioxide (11)

[0416] To a mixture of 5-(2-(benzyloxy)-4-(2-(3-cyclopentylidenepyrrolidin-l- yl)ethyl)-6-fluorophenyl)-l,2,5-thiadiazolidin-3-one 1,1-dioxide (11f) (25.0 mg, 50.0 μmol) in dichloromethane (3 mL) and methanol (2 mL) was added sodium cyanoborohydride (66.4 mg, 1.06 mmol) at room temperature. The reaction mixture was stirred at 25 °C for 0.5 h. After the reaction was completed, the mixture was filtered directly to give the crude product. The crude product was purified by HPLC to give 5-(2-(benzyloxy)-4-(2-(3-cyclopentylidenepyrrolidin-l- yl)ethyl)-6-fluorophenyl)-l,2,5-thiadiazolidin-3-one 1,1-dioxide (11f) (30.0 mg, 11% yield).

[0417] 1 H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1H), 6.68-6.61 (m, 2H), 3.94 (s, 2H), 3.48-3.37 (m, 2H), 2.92-2.81 (m, 2H), 2.63-2.54 (m, 2H), 2.49-2.22 (m, 4H), 2.27-2.14 (m, 4H), 1.71-1.59 (m, 4H)

[0418] LC-MS, M / Z (ESI): 410.1 [M+H + ]

[0419] Example 12: Preparation of target compound 12

[0420] Synthesis of 5-(3,6-difluoro-2-hydroxy-4-(2-(3-(propan-2-ylidene)pyrrolidin-1- yl)ethyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (12)

[0421] The synthetic route of target compound 12 is shown below:

[0422] First step: Synthesis of 4-bromo-3,6-difluoro-2-methoxyaniline (12b)

[0423] To a mixture of 3,6-difluoro-2-methoxyaniline (12a) (1.40 g, 8.80 mmol) in dichloromethane (20 mL) was added slowly 3-bromopyridinium (3.10 g, 9.68 mmol) at 0 °C under nitrogen atmosphere. The reaction was stirred at 25 °C for 0.5 h. After the reaction was completed, the reaction was poured into saturated sodium bicarbonate (60 mL). The mixture was extracted with dichloromethane (30 mL*3). The organic phase was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound 4-bromo-3,6-difluoro-2-methoxyaniline (12b) (2.24 g, crude).

[0424] Second step: Synthesis of ethyl 4-bromo-3,6-difluoro-2-methoxyphenyl)glycinate (12c)

[0425] A mixture of 4-bromo-3,6-difluoro-2-methoxyaniline (12b) (2.00 g, 8.40 mmol) and ethyl glyoxylate in toluene (3.43 g, 16.8 mmol) was dissolved in N,N-dimethylformamide (20 mL) at 0 °C. Trimethylsilyl chloride (1.37 g, 12.6 mmol) was added slowly dropwise and the reaction was stirred at 25 °C for 2 h. Sodium cyanoborohydride (792 mg, 12.6 mmol) was added slowly to the reaction at 0 °C and then stirred at 25 °C for 1 h. After the reaction was completed, water (200 mL) was added for dilution and ethyl acetate (40 mL*2) was used for extraction. The organic phase was dried over anhydrous sodium sulfate and filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (petroleum ether: ethyl acetate (1 / 0 to 5 / 1)) to obtain compound ethyl 4-bromo-3,6-difluoro-2-methoxyphenyl)glycinate (12c) (1.78 g, yield 65%).

[0426] Third step: Synthesis of N-(4-bromo-3,6-difluoro-2-methoxyphenyl)-N- sulfamoyl glycine ethyl ester (12d)

[0427] To a mixture of ethyl 4-bromo-3,6-difluoro-2-methoxyphenyl)glycinate (12c) (1.52 g, 4.63 mmol) and triethylamine (2.34 g, 23.1 mmol) in dichloromethane (30 mL) at 0 °C, sulfamoyl chloride (1.60 g, 13.9 mmol) was added portionwise slowly and the reaction was stirred at 0 °C for 2 h. After the reaction was completed, water (50 mL) was added for dilution and dichloromethane (30 mL*2) was used for extraction. The organic phase was washed with water (40 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound N-(4-bromo-3,6-difluoro-2-methoxyphenyl)-N-sulfamoyl glycine ethyl ester (12d) (1.50 g, crude).

[0428] Fourth step: Synthesis of 5-(4-bromo-3,6-difluoro-2-methoxyphenyl)-1,2,5- thiazolidin-3-one 1,1-dioxide (12e)

[0429] To a solution of N-(4-bromo-3,6-difluoro-2-methoxyphenyl)-N- sulfamoylglycine ethyl ester (12d) (1.50 g, 3.72 mmol) in methanol (15 mL) was added dropwise a solution of sodium methoxide (2.01 g, 11.2 mmol, 33% content) at 0°C and the reaction was stirred at 0°C for 1 hour. After the reaction was completed, acetic acid (1.00 g) was added slowly dropwise to the reaction and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (dichloromethane:methanol = 1 / 0 to 7 / 1) to give compound 5-(4-bromo-3,6-difluoro-2-methoxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (12e) (1.02 g, crude).

[0430] Fifth step: Synthesis of 5-(4-(2-ethoxyvinyl)-3,6-difluoro-2- methoxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (12f)

[0431] To a solution of 5-(4-bromo-3,6-difluoro-2-methoxyphenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide (12e) (1.00 g, 2.80 mmol), 2-[(E)-2- ethoxyvinyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (721 mg, 3.64 mmol) and anhydrous potassium carbonate (774 mg, 5.60 mmol) in dioxane (10 mL) and water (1 mL) was added 1,1'-bis(diphenylphosphino)ferrocene palladium chloride (81.9 mg, 112 μmol) at room temperature and the reaction was stirred at 95°C for 3 hours. After the reaction was completed, acetic acid (200 mg) was added slowly dropwise at 0°C and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (dichloromethane:methanol = 1 / 0 to 7 / 1) to give compound 5-(4-(2-ethoxyvinyl)-3,6-difluoro-2-methoxyphenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide (12f) (485 mg, yield 50%).

[0432] Sixth step: Synthesis of 2-(4-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)- 2,5-difluoro-3-methoxyphenyl)acetaldehyde (12g)

[0433] To a solution of 5-(4-(2-ethoxyvinyl)-3,6-difluoro-2-methoxyphenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide (12g) (250 mg, 574 μmol) in formic acid (3.50 mL) was added water (0.50 mL) at room temperature and the reaction was stirred at 25 °C for 3 hours. After the reaction was completed, the reaction was concentrated under reduced pressure at 30 °C to give compound 2-(4-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-2,5-difluoro-3- methoxyphenyl)acetaldehyde (12g) (203 mg, crude).

[0434] Step 7: Synthesis of 5-(3,6-difluoro-2-hydroxy-4-(2-(3-(propan-2-ylidene)pyrrolidin-1- yl)ethyl)phenyl)-1,2,5-thiadiazolidin-3-one-1,1-dioxide (12)

[0435] To a solution of 2-(4-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-2,5-difluoro-3- methoxyphenyl)acetaldehyde (12g) (195 mg, 609 μmol) and 3-(propan-2-ylidene)pyrrolidine hydrochloride (108 mg, 731 μmol) in methanol (4 mL) was added sodium acetate (250 mg, 3.04 mmol) at room temperature and the reaction was stirred at 25 °C for 0.5 hours. Sodium cyanoborohydride (76.5 mg, 1.22 mmol) was added slowly to the reaction and stirred at 25 °C for 0.5 hours. After the reaction was completed, the reaction was filtered to give crude product. The crude product was purified by HPLC to give compound 5-(3,6-difluoro-2-hydroxy-4-(2-(3-(propan-2-ylidene)pyrrolidin-1- yl)ethyl)phenyl)-1,2,5-thiadiazolidin-3-one-1,1-dioxide (12) (55.0 mg, yield 22%).

[0436] LC-MS, M / Z (ESI): 416.0 [M+H + ]

[0437] Step 8: Synthesis of 5-(3,6-difluoro-2-hydroxy-4-(2-(3-(propan-2-ylidene)pyrrolidin-1- yl)ethyl)phenyl)-1,2,5-thiadiazolidin-3-one-1,1-dioxide (12)

[0438] To 5-(3,6-difluoro-2-methoxy-4-(2-(3-(propan-2-ylidenyl)pyrrolidin-1- yl)ethyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (12h) (45.0 mg, 108 pmol) in N,N dimethylformamide (3.0 mL) was added ethanethiol sodium (91.0 mg, 1.08 mmol) at room temperature and the reaction was stirred at 85 °C for 0.5 h. The reaction was filtered directly for preparation. The crude was purified by HPLC preparation (column: Waters xbridge 150*25mm 10um; mobile phase: solvent A = water +10 nM ammonium bicarbonate, B = acetonitrile; gradient: 1%-30%, 12 min) to give compound 5-(3,6-difluoro-2-hydroxy-4-(2-(3-(propan-2- ylidenyl)pyrrolidin-1-yl)ethyl)phenyl)-1,2,5-thiadiazolidin-3-one-1,1-dioxide (12).

[0439] 1 H NMR (400 MHz, DMSO-d6) d 10.06-9.64 (m, 2H), 6.75 (dd, J = 10.4, 6.40 Hz 1H), 3.95 (s, 2H), 3.81-3.41 (m, 4H), 3.30-3.14 (m, 2H), 3.94 (t, J = 8.0 Hz 2H), 2.54-2.51 (m, 2H), 1.64 (s, 6H)

[0440] LC-MS, M / Z (ESI): 402.1 [M+H + ]

[0441] Example 13: Preparation of target compound 13

[0442] 5-(4-(2-(3-(Dihydrofuran-3(2H)-ylidenyl)pyrrolidin-1-yl)ethyl)-2-fluoro-6- hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (13)

[0443] The synthetic route of target compound 13 is shown below:

[0444] First step: synthesis of 2-((tetrahydrofuran-3-yl)thio)pyridine (13b)

[0445] Dissolve 2-mercaptopyridine (13a) (5.00 g, 45.0 mmol) in acetonitrile (50 mL), then add anhydrous potassium carbonate (9.32 g, 67.5 mmol) and 3-bromotetrahydrofuran (8.15 g, 54.0 mmol), and stir the reaction at 30°C for 10 hours. After the reaction is completed, dilute the reaction with water (200 mL), then extract with ethyl acetate (200 mL*3), combine the organic phases, wash with water (200 mL*3), dry over sodium sulfate, filter, and concentrate under reduced pressure to obtain compound 2-((tetrahydrofuran-3-yl)thio)pyridine (13b) (8.00 g, yield 98%).

[0446] Second step: synthesis of 2-((tetrahydrofuran-3-yl)sulfonyl)pyridine (13c)

[0447] Dissolve 2-mercaptopyridine (13a) (5.00 g, 45.0 mmol) in acetonitrile (50 mL), then add anhydrous potassium carbonate (9.32 g, 67.5 mmol) and 3-bromotetrahydrofuran (8.15 g, 54.0 mmol), and stir the reaction at 30°C for 10 hours. After the reaction is completed, dilute the reaction with water (200 mL), then extract with ethyl acetate (200 mL*3), combine the organic phases, wash with water (200 mL*3), dry over sodium sulfate, filter, and concentrate under reduced pressure to obtain compound 2-((tetrahydrofuran-3-yl)thio)pyridine (13b) (8.00 g, yield 98%).

[0448] Third step: synthesis of tert-butyl 3-(dihydrofuran-3(2H)-ylidenemethyl)pyrrolidine-1-carboxylate (13d)

[0449] Dissolve 2-mercaptopyridine (13a) (5.00 g, 45.0 mmol) in acetonitrile (50 mL), then add anhydrous potassium carbonate (9.32 g, 67.5 mmol) and 3-bromotetrahydrofuran (8.15 g, 54.0 mmol), and stir the reaction at 30°C for 10 hours. After the reaction is completed, dilute the reaction with water (200 mL), then extract with ethyl acetate (200 mL*3), combine the organic phases, wash with water (200 mL*3), dry over sodium sulfate, filter, and concentrate under reduced pressure to obtain compound 2-((tetrahydrofuran-3-yl)thio)pyridine (13b) (8.00 g, yield 98%). fp1was 0.6, potassium permanganate coloration), to obtain tert-butyl 3-(dihydrofuran-3(2H)- ylmethyl)pyrrolidine-1-carboxylate (13d) (1.00 g, yield 19%).

[0450] Fourth step: synthesis of 3-(dihydrofuran-3(2H)-ylmethyl)pyrrolidine hydrochloride (13e)

[0451] Tert-butyl 3-(dihydrofuran-3(2H)-ylmethyl)pyrrolidine-1-carboxylate (13d) (1.00 g, 4.18 mmol) was dissolved in hydrochloric acid dioxane (10 mL) under nitrogen protection, and the reaction was stirred at 25 °C for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain 3-(dihydrofuran-3(2H)-ylmethyl)pyrrolidine hydrochloride (13e) (700 mg, yield 95%).

[0452] Fifth step: synthesis of 5-(2-(benzyloxy)-4-(2-(3-(dihydrofuran-3(2H)-ylmethyl)pyrrolidin-1- yl)ethyl)-6-fluorophenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (13f)

[0453] Tert-butyl 3-(dihydrofuran-3(2H)-ylmethyl)pyrrolidine-1-carboxylate (13d) (1.00 g, 4.18 mmol) was dissolved in hydrochloric acid dioxane (10 mL) under nitrogen protection, and the reaction was stirred at 25 °C for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain 3-(dihydrofuran-3(2H)-ylmethyl)pyrrolidine hydrochloride (13e) (700 mg, yield 95%).

[0454] LC-MS, M / Z (ESI): 502.1 [M+H + ]

[0455] Step 6: Synthesis of 5-(4-(2-(3-(dihydrofuran-3(2H)-ylmethyl)pyrrolidin-1-yl)ethyl)-2- fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (13)

[0456] Step 6: Synthesis of 5-(4-(2-(3-(dihydrofuran-3(2H)-ylmethyl)pyrrolidin-1-yl)ethyl)-2- fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (13)

[0457] 1 H NMR (400 MHz, DMSO-d6) δ 9.34 (s, 1H), 6.55-6.73 (m, 2H), 4.08-4.18 (m, 2H), 3.94 (s, 2H), 3.79-3.84 (m, 2H), 3.15-3.28 (m, 4H), 2.80-2.89 (m, 2H), 2.55-2.66 (m, 2H), 2.34-2.48 (m, 4H).

[0458] LC-MS, M / Z (ESI): 412.0 [M+H + ]

[0459] Example 14: Preparation of target compound 14

[0460] 5-(2,3-difluoro-6-hydroxy-4-(2-(3-(propan-2-ylmethyl)pyrrolidin-1-yl)ethyl)phenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide (14)

[0461] The synthetic route of target compound 14 is shown below:

[0462] First step: synthesis of tert-butyl (2,3-difluoro-6-methoxyphenyl)carbamate (14b)

[0463] Dissolve 2,3-difluoro-6-methoxybenzoic acid (14a) (18.7 g, 99.4 mmol) in tert-butyl alcohol (190 mL), add triethylamine (11.1 g, 109 mmol) and diphenyl phosphorazide (30.1 g, 109 mmol) to the reaction solution, then replace three times with nitrogen, slowly warm to 80 °C and stir for 12 hours. After the reaction is complete, the reaction solution is concentrated under reduced pressure, dissolved in ethyl acetate (500 mL), extracted with water (500 mL*3), the organic phase is washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain tert-butyl (2,3-difluoro-6-methoxyphenyl)carbamate (14b) (21.0 g, yield 81%).

[0464] Second step: synthesis of 2,3-difluoro-6-methoxyaniline (14c)

[0465] Dissolve tert-butyl (2,3-difluoro-6-methoxyphenyl)carbamate (14b) (21.0 g, 81.0 mmol) in methanol (210 mL), add hydrochloric acid (12 M, 33 mL) to the reaction solution, then stir at 60 °C for 2 hours. After the reaction is complete, the reaction solution is concentrated under reduced pressure, dissolved in ethyl acetate (200 mL), add aqueous sodium hydroxide solution (1 M, 300 mL), extract with ethyl acetate (300 mL*3), wash the combined organic phase with saturated brine (200 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product. Purify the crude product by column chromatography (mobile phase: petroleum ether / ethyl acetate = 5:1, Rf of 2,3-difluoro-6-methoxyaniline (14c) = 0.47) to obtain 2,3-difluoro-6-methoxyaniline (14c) (7.87 g, yield 61%). f

[0466] Third step: synthesis of 4-bromo-2,3-difluoro-6-methoxyaniline (14d)

[0467] ​A solution of 2,3-difluoro-6-methoxyaniline (14c) (7.80 g, 49.0 mmol) in N,N- dimethylformamide (75 mL) was slowly added with a solution of N-bromosuccinimide (9.60 g, 53.9 mmol) in N,N-dimethylformamide (20 mL) at 0 °C, then stirred at 0 °C for 2 h. After the reaction was completed, water (300 mL) was added to quench, extracted with ethyl acetate (250 mL*3), washed with saturated brine (250 mL), the combined organic phase was dried over anhydrous sodium sulfate and filtered, concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 5:1, Rfwas 0.50) to give compound 4-bromo-2,3-difluoro-6-methoxyaniline (14d) (8.00 g, yield 69%). f A solution of 2,3-difluoro-6-methoxyaniline (14c) (7.80 g, 49.0 mmol) in N,N- dimethylformamide (75 mL) was slowly added with a solution of N-bromosuccinimide (9.60 g, 53.9 mmol) in N,N-dimethylformamide (20 mL) at 0 °C, then stirred at 0 °C for 2 h. After the reaction was completed, water (300 mL) was added to quench, extracted with ethyl acetate (250 mL*3), washed with saturated brine (250 mL), the combined organic phase was dried over anhydrous sodium sulfate and filtered, concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 5:1, Rfwas 0.50) to give compound 4-bromo-2,3-difluoro-6-methoxyaniline (14d) (8.00 g, yield 69%).

[0468] Fourth step: synthesis of (4-bromo-2,3-difluoro-6-methoxyphenyl) glycine ethyl ester (14e)

[0469] A solution of 2,3-difluoro-6-methoxyaniline (14c) (7.80 g, 49.0 mmol) in N,N- dimethylformamide (75 mL) was slowly added with a solution of N-bromosuccinimide (9.60 g, 53.9 mmol) in N,N-dimethylformamide (20 mL) at 0 °C, then stirred at 0 °C for 2 h. After the reaction was completed, water (300 mL) was added to quench, extracted with ethyl acetate (250 mL*3), washed with saturated brine (250 mL), the combined organic phase was dried over anhydrous sodium sulfate and filtered, concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 5:1, Rfwas 0.50) to give compound 4-bromo-2,3-difluoro-6-methoxyaniline (14d) (8.00 g, yield 69%).

[0470] Fifth step: synthesis of N-(4-bromo-2,3-difluoro-6-methoxyphenyl)-N- sulfamoylglycine ethyl ester (14f)

[0471] N,N-dimethylacetamide (60 mL) and then slowly added aminosulfonyl chloride (12.8 g, 111 mmol) at 0 °C, and then stirred at 25 °C for 12 hours. After the reaction was completed, water (200 mL) was added to quench, extracted with ethyl acetate (50 mL*3), washed with saturated brine (50 mL), the combined organic phase was dried over anhydrous sodium sulfate and filtered, and concentrated under reduced pressure to obtain compound N-(4-bromo-2,3-difluoro-6-methoxyphenyl)-N- sulfamoylglycine ethyl ester (14f) (2.40 g, crude).

[0472] Step 6: Synthesis of N-(4-bromo-2,3-difluoro-6-methoxyphenyl)-N- sulfamoylglycine ethyl ester (14g)

[0473] N-(4-bromo-2,3-difluoro-6-methoxyphenyl)-N-sulfamoylglycine ethyl ester (14f) (2.40 g, 5.95 mmol) was dissolved in anhydrous methanol (20 mL), and then 30% sodium methoxide methanol solution (6.43 g, 35.7 mmol) was slowly added at 0 °C, and then stirred at 0 °C for 2 hours. After the reaction was completed, it was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (mobile phase: dichloromethane / methanol = 5:1, Rf 0.28) to obtain compound N-(4-bromo-2,3-difluoro-6-methoxyphenyl)-N-sulfamoylglycine ethyl ester (14g) (1.40 g, yield 66%) as a yellow solid.

[0474] Step 7: Synthesis of 5-(4-(2-ethoxyvinyl)-2,3-difluoro-6-methoxyphenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide (14h)

[0475] N-(4-bromo-2,3-difluoro-6-methoxyphenyl)-N-sulfamoylglycine ethyl ester (14g) (600 mg, 1.68 mmol) and (E)-1-ethoxyvinyl-2-boronic pinacol ester (665 mg, 3.36 mmol) were dissolved in dioxane (6 mL) and water (3 mL), and then sodium carbonate (534 mg, 5.04 mmol) and 1,1-bis(diphenylphosphino)ferrocene palladium chloride (122 mg, 168 μmol) were added, the reaction system was replaced with nitrogen three times, and then slowly warmed to 100 °C and stirred for 8 hours. After the reaction was completed, it was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (mobile phase: dichloromethane / methanol = 5:1, Rf 0.28) to obtain compound 5-(4-(2-ethoxyvinyl)-2,3-difluoro-6-methoxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (14h) (400 mg, yield 62%) as a yellow solid. fTo give compound 5-(4-(2-ethoxyvinyl)-2,3-difluoro-6-methoxyphenyl)- 1,2,5-thiadiazolidin-3-one 1,1 -dioxide (14h) (400 mg, yield 68%).

[0476] Eighth step: synthesis of 2-(4-(1,1 -dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)- 2,3-difluoro-5-methoxyphenyl)acetaldehyde (14i)

[0477] To give compound 5-(4-(2-ethoxyvinyl)-2,3-difluoro-6-methoxyphenyl)- 1,2,5-thiadiazolidin-3-one 1,1 -dioxide (14h) (400 mg, yield 68%).

[0478] Ninth step: synthesis of 5-(2,3-difluoro-6-methoxy-4-(2-(3-(propan-2- ylmethyl)pyrrolidin-1 -yl)ethyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1 -dioxide (14j)

[0479] To give compound 5-(4-(2-ethoxyvinyl)-2,3-difluoro-6-methoxyphenyl)- 1,2,5-thiadiazolidin-3-one 1,1 -dioxide (14h) (400 mg, yield 68%).

[0480] Step 10: 5-(2,3-difluoro-6-hydroxy-4-(2-(3-(prop-2-enyl)pyrrolidin-l- yl)ethyl)phenyl)-l,2,5-thiadiazolidin-3-one 1,1-dioxide (14)

[0481] To a solution of 5-(2,3-difluoro-6-methoxy-4-(2-(3-(prop-2-enyl)pyrrolidin-l- yl)ethyl)phenyl)-l,2,5-thiadiazolidin-3-one 1,1-dioxide (14j) (20.0 mg, 48.1 μmol) in N,N-dimethylformamide (2 mL) was added sodium ethanethiol (20 mg, 240 μmol) and the reaction was stirred at 140 °C for 10 min. The reaction mixture was filtered and concentrated under reduced pressure to give a crude product. The crude product was purified by HPLC (column: Waters xbridge 150*25mm*10um; solvent: A = water + 0.1% ammonium bicarbonate, B = acetonitrile; gradient: 7% - 37%, 12 min) to give 5-(2,3-difluoro-6-hydroxy-4-(2-(3-(prop-2-enyl)pyrrolidin-l- yl)ethyl)phenyl)-l,2,5-thiadiazolidin-3-one 1,1-dioxide (14).

[0482] LC-MS, M / Z (ESI): 400.0 [M-H] - .

[0483] Example 15: Preparation of target compound 15

[0484] Synthesis of 5-(4-(2-(3-(3,3-difluorocyclobutylidene)pyrrolidin-l- yl)ethyl)-2-fluoro-6-hydroxyphenyl)-l,2,5-thiadiazolidin-3-one 1,1-dioxide (15)

[0485] The synthetic route of target compound 15 is shown below:

[0486] Step 1: Synthesis of 2-((3,3-difluorocyclobutyl)thio)pyridine (15b)

[0487] To a solution of pyridine-2-thiol (15a) (2.20 g, 19.8 mmol), 3-bromo-1,1-difluoro-cyclobutane (4.06 g, 23.7 mmol) in N,N-dimethylformamide (1.05 mL) was added anhydrous potassium carbonate (4.10 g, 29.7 mmol) at room temperature and the reaction was stirred at 70 °C for 3 hours. After the reaction was completed, the reaction was diluted with water (120 mL) and extracted with ethyl acetate (30 mL*3). The organic phase was washed with water (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound 2-((3,3-difluorocyclobutyl)thio)pyridine (15b) (3.61 g, yield 90%).

[0488] Second step: synthesis of 2-((3,3-difluorocyclobutyl)sulfonyl)pyridine (15c)

[0489] To a solution of 2-((3,3-difluorocyclobutyl)thio)pyridine (15b) (3.61 g, 17.9 mmol), sodium tungstate dihydrate (590 mg, 1.79 mmol) in methanol (40 mL) was added hydrogen peroxide (7.10 g, 62.6 mmol, 30% content) at 0 °C and the reaction was stirred at 25 °C for 12 hours. After the reaction was completed, the reaction was quenched with an aqueous sodium sulfite solution (300 mL), concentrated to remove methanol, extracted with ethyl acetate (50 mL*3), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound 2-((3,3-difluorocyclobutyl)sulfonyl)pyridine (15c) (3.53 g, yield 84%).

[0490] Third step: synthesis of tert-butyl 3-(3,3-difluorocyclobutylmethylidene)pyrrolidine-1-carboxylate (15d)

[0491] To a solution of potassium tert-butoxide (2.69 g, 24.0 mmol) in N,N-dimethylformamide (35 mL) was slowly added a mixed solution of 2-((3,3-difluorocyclobutyl)sulfonyl)pyridine (15c) (3.51 g, 12.0 mmol) and tert-butyl 3-oxopyrrolidine-1-carboxylate (2.89 g, 15.6 mmol) in N,N-dimethylformamide (15 mL) at -20 °C under nitrogen atmosphere. The reaction was stirred at 25 °C for 12 hours. After the reaction was completed, the reaction was poured into a saturated aqueous ammonium chloride solution (600 mL) and extracted with ethyl acetate (50 mL*3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate (1 / 0 to 10 / 1)) to obtain compound tert-butyl 3-(3,3-difluorocyclobutylmethylidene)pyrrolidine-1-carboxylate (15d) (178 mg, yield 6%).

[0492] Step 4: Synthesis of 3-(3,3-difluorocyclobutylidene)pyrrolidine hydrochloride (15e)

[0493] To tert-butyl 3-(3,3-difluorocyclobutylmethylidene)pyrrolidine-1-carboxylate (15d) (178 mg, 687 μmol) in dioxane (1.00 mL) was added hydrochloric acid in dioxane (2 M, 6 mL) at room temperature. The reaction was stirred at 25 °C for 3 h. After the reaction was completed, the reaction was directly concentrated to give compound 3-(3,3-difluorocyclobutylidene)pyrrolidine hydrochloride (15e) (121 mg, 90% yield).

[0494] Step 5: Synthesis of 5-(2-(benzyloxy)-4-(2-(3-(3,3-difluorocyclobutylidene)pyrrolidin-1- yl)ethyl)-6-fluorophenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (15f)

[0495] To 2-(3-benzyloxy)-4-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-5-fluorophenyl)acetaldehyde (8d) (240 mg, 634 μmol) and sodium acetate (260 mg, 3.17 mmol) in methanol (5.00 mL) was added 3-(3,3-difluorocyclobutylidene)pyrrolidine hydrochloride (15e) (99.0 mg, 507 μmol) at room temperature. The reaction was stirred at 25 °C for 0.5 h. Then sodium cyanoborohydride (120 mg, 1.90 mmol) was added to the reaction, which was then stirred at 25 °C for another 0.5 h. After the reaction was completed, the reaction was directly filtered to give the crude product. The crude product was purified by HPLC prep to give compound 5-(2-(benzyloxy)-4-(2-(3-(3,3-difluorocyclobutylidene)pyrrolidin-1-yl)ethyl)-6-fluorophenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (15f) (35.0 mg, 10% yield).

[0496] LC-MS, M / Z (ESI): 522.2 [M+H + ]

[0497] Step 6: Synthesis of 5-(4-(2-(3-(3,3-difluorocyclobutylidene)pyrrolidin-1-yl)ethyl)-2-fluoro-6- hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (15)

[0498] To 5-(2-(benzyloxy)-4-(2-(3-(3,3-difluorocyclobutylmethyl)pyrrolidin-l- yl)ethyl)-6-fluorophenyl)-l,2,5-thiadiazolidin-3-one 1,1-dioxide (15f) (35.0 mg, 50.0 μmol) in dichloromethane (5 mL) was added boron tribromide (1 M, 150 μL) slowly at -70 °C under nitrogen protection. The reaction was stirred at -70 °C for 1 h. After the reaction was completed, methanol (2 mL) was added at -40 °C. The mixture was concentrated under reduced pressure. The residue was purified by HPLC (column: Phenomenex luna C18 150*25mm*10μm; mobile phase: solvent A = water + 0.225% formic acid, B = acetonitrile; gradient: 5% to 35%, 12 min) to give 5-(4-(2-(3-(3,3-difluorocyclobutylmethyl)pyrrolidin-l-yl)ethyl)-2- fluoro-6-hydroxyphenyl)-l,2,5-thiadiazolidin-3-one 1,1-dioxide (15).

[0499] LC-MS, M / Z (ESI): 432.1 [M+H+]

[0500] Example 16: Preparation of the target compound 16

[0501] 5-(2-Fluoro-6-hydroxy-3-methyl-4-(2-(3-(propan-2-ylmethyl)pyrrolidin-l- yl)ethyl)phenyl)-l,2,5-thiadiazolidin-3-one 1,1-dioxide (16)

[0502] The synthetic route of the target compound 16 is shown below:

[0503] First Step: Synthesis of l-(benzyloxy)-4-bromo-3-fluoro-2-nitrobenzene (16b)

[0504] l-Bromo-2,4-difluoro-3-nitrobenzene (16a) (23.7 g, 0.10 mol) was dissolved in N,N-dimethylformamide (250.0 mL), anhydrous potassium carbonate (27.6 g, 0.20 mol) was added, and benzyl alcohol (10.8 g, 0.10 mol) was added. After mixing, the reaction was heated at 90 °C for 16 h. The reaction was monitored by LC-MS. After the reaction was completed, ethyl acetate (500.0 mL) was added after the reaction was cooled to room temperature. The mixture was washed with water (500.0 mL x 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate (1 / 0 to 10 / 1)) to give l-(benzyloxy)-4-bromo-3-fluoro-2-nitrobenzene (16b) (15.5 g, yield 48%).

[0505] Second Step: Synthesis of 6-(benzyloxy)-3-bromo-2-fluoroaniline (16c)

[0506] Dissolve 1-(benzyloxy)-4-bromo-3-fluoro-2-nitrobenzene (16b) (30.0 g, 92.0 mmol) in a mixture of methanol: tetrahydrofuran (100 mL: 100 mL), add iron powder (20.7 g, 368 mmol), dissolve ammonium chloride (39.2 g, 736 mmol) in water (200 mL), mix and react at room temperature for 10 hours, monitor the reaction end by LC-MS, filter after recovering the room temperature, concentrate the filtrate under reduced pressure, add ethyl acetate (500.0 mL), wash with water (500.0 mL), dry the organic phase over anhydrous sodium sulfate, concentrate under reduced pressure, purify the crude by column chromatography (petroleum ether: ethyl acetate (1 / 0 to 7 / 3)) to obtain compound 6-(benzyloxy)-3-bromo-2-fluoroaniline (16c) (26.3 g, yield 96%).

[0507] Third Step: Synthesis of (6-(benzyloxy)-3-bromo-2-fluorophenyl) glycine tert-butyl ester (16d)

[0508] Dissolve 6-(benzyloxy)-3-bromo-2-fluoroaniline (16c) (3.00 g, 10.0 mmol) in N,N-dimethylformamide (30.0 mL), add anhydrous potassium carbonate (3.90 g, 20.0 mmol), add tert-butyl bromoacetate (4.14 g, 30.0 mmol), mix and heat the reaction at 90 °C for 16 hours, monitor the reaction end by LC-MS, add ethyl acetate (100.0 mL) after recovering the room temperature, wash with water (100.0 mL x 3), dry the organic phase over anhydrous sodium sulfate, concentrate under reduced pressure, purify the crude by column chromatography (petroleum ether: ethyl acetate (1 / 0 to 8 / 2)) to obtain compound (6-(benzyloxy)-3-bromo-2-fluorophenyl) glycine tert-butyl ester (16d) (3.56 g, yield 87%).

[0509] Fourth Step: Synthesis of (6-(benzyloxy)-2-fluoro-3-methylphenyl) glycine tert-butyl ester (16e)

[0510] (6-(benzyloxy)-3-bromo-2-fluorophenyl) glycine tert-butyl ester (16d) (409 mg, 1.0 mmol) was dissolved in 1,4-dioxane (10.0 mL), cesium carbonate (980 mg, 3.0 mmol) was added, water (1.0 mL) was added, pinacol methylboronate (284 mg, 2.0 mmol) was added, Pd(dppf)Cl2(74 mg, 0.1 mmol) was added, after mixing, the reaction was exchanged with nitrogen, heated at 100 °C for 16 hours, the reaction was monitored by LC-MS, after recovering the room temperature, filtered, ethyl acetate (50.0 mL) was added to the filtrate, washed with water (100.0 mL), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, the crude product was separated and purified by column chromatography (petroleum ether: ethyl acetate (1 / 0 to 8 / 2)) to obtain (6-(benzyloxy)-2-fluoro-3-methylphenyl) glycine tert-butyl ester (16e) (250 mg, yield 72%).

[0511] Fifth step: synthesis of (6-(benzyloxy)-4-bromo-2-fluoro-3-methylphenyl) glycine tert-butyl ester (16f)

[0512] (6-(benzyloxy)-2-fluoro-3-methylphenyl) glycine tert-butyl ester (16e) (500 mg, 1.45 mmol) was dissolved in N,N-dimethylformamide (10.0 mL), NBS (254 mg, 1.50 mmol) was added, after reacting at room temperature for 2 hours, the reaction was monitored by LC-MS, after recovering the room temperature, ethyl acetate (50.0 mL) was added, washed with water (50.0 mL x 3), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, the crude product was separated and purified by column chromatography (petroleum ether: ethyl acetate (1 / 0 to 8 / 2)) to obtain compound (6-(benzyloxy)-4-bromo-2-fluoro-3-methylphenyl) glycine tert-butyl ester (16f) (520 mg, yield 80%).

[0513] Sixth step: synthesis of N-(6-(benzyloxy)-4-bromo-2-fluoro-3-methylphenyl)-N- sulfamoyl glycine tert-butyl ester (16g)

[0514] N-(6-(benzyloxy)-4-bromo-2-fluoro-3-methylphenyl)-N-sulfamoylglycine tert-butyl ester (16g) (500 mg, 1.0 mmol) was dissolved in anhydrous methanol (10.0 mL), sodium methoxide in methanol (2.0 mL, 1.00 mol / L) was added at 0 °C, the reaction was monitored by LC-MS after 3 hours, the reaction was completed, the solution was adjusted to be slightly acidic, concentrated under reduced pressure, the white mixture was washed with anhydrous acetone, filtered and concentrated under reduced pressure to obtain compound 5-(6-(benzyloxy)-4-bromo-2-fluoro-3-methylphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (16h) (352 mg, yield 82%).

[0515] Step 7: Synthesis of 5-(6-(benzyloxy)-4-bromo-2-fluoro-3-methylphenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide (16h)

[0516] N-(6-(benzyloxy)-4-bromo-2-fluoro-3-methylphenyl)-N-sulfamoylglycine tert-butyl ester (16g) (500 mg, 1.0 mmol) was dissolved in anhydrous methanol (10.0 mL), sodium methoxide in methanol (2.0 mL, 1.00 mol / L) was added at 0 °C, the reaction was monitored by LC-MS after 3 hours, the reaction was completed, the solution was adjusted to be slightly acidic, concentrated under reduced pressure, the white mixture was washed with anhydrous acetone, filtered and concentrated under reduced pressure to obtain compound 5-(6-(benzyloxy)-4-bromo-2-fluoro-3-methylphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (16h) (352 mg, yield 82%).

[0517] Step 8: Synthesis of 5-(6-benzyloxy)-4-(2-ethoxyvinyl)-2-fluoro-3-methylphenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide (16i)

[0518] The starting material 5-(6-benzyloxy-4-bromo-2-fluoro-3-methylphenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide (16h) (1.70 g, 3.96 mmol) and (E)-1-ethoxyvinyl-2- boronic pinacol ester (1.57 g, 7.92 mmol) were dissolved in dioxane (20 mL) and water, sodium carbonate (1.26 g, 11.8 mmol) and 1,1-bis(diphenylphosphino)ferrocene palladium chloride (289 mg, 396 μmol) were added slowly, and then stirred at 95 °C for 8 hours. After the reaction was completed, the reaction solution was filtered, washed with ethyl acetate (50 mL*3), and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (dichloromethane:methanol = 5:1) to obtain compound 5-(6-benzyloxy)-4-(2-ethoxyvinyl)-2-fluoro-3-methylphenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide (16i) (700 mg, yield 42%).

[0519] Ninth step: Synthesis of 2-(5-benzyloxy)-4-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-3- fluoro-2-methylphenyl)acetaldehyde (16j)

[0520] 5-(6-benzyloxy)-4-(2-ethoxyvinyl)-2-fluoro-3-methylphenyl)-1,2,5-thiadiazolidin-3-one 1,1- dioxide (16i) was dissolved in formic acid (5 mL) and water (0.2 mL) under nitrogen protection, the reaction system was replaced with nitrogen three times, and stirred at 25 °C for 1.5 hours. After the reaction was completed, formic acid and water were removed by concentration under reduced pressure at room temperature to obtain compound 2-(5-benzyloxy)-4-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-2- methylphenyl)acetaldehyde (16j) (370 mg, crude product), which was directly used in the next step.

[0521] Tenth step: Synthesis of 5-(6-benzyloxy)-2-fluoro-3-methyl-4-(2-(3-(propan-2-ylidene)pyrrolidin-1- yl)ethyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (16k)

[0522] The starting material 3-(propan-2-ylidenemethyl)pyrrolidine hydrochloride (278 mg, 1.89 mmol) and sodium acetate (464 mg, 5.66 mmol) were dissolved in methanol (5 mL) and stirred at 25 °C for 0.5 h, then 2-(5-benzyloxy)-4-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-3-fluoro-2-methylphenyl)acetaldehyde (16j) (370 mg, 942 μmol) was added to the reaction solution, and stirred at 25 °C for 0.5 h. Then sodium cyanoborohydride (148 mg, 2.36 mmol) was added to the reaction solution, and stirred at 25 °C for 1 h. After the reaction was completed, sodium bicarbonate solution (10 mL) was added to quench, extracted with dichloromethane (20 mL*3), washed with saturated brine (20 mL*3), the combined organic phase was dried over anhydrous sodium sulfate and filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by HPLC to obtain compound 5-(6-benzyloxy)-2-fluoro-3-methyl-4-(2-(3-(propan-2-ylidenemethyl)pyrrolidin-1-yl)ethyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (16k) (140 mg, yield 30%).

[0523] LC-MS, M / Z (ESI): 486.2 [M+H + ]

[0524] Tenth step: synthesis of 5-(2-fluoro-6-hydroxy-3-methyl-4-(2-(3-(propan-2-ylidenemethyl)pyrrolidin-1-yl)ethyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (16)

[0525] The starting material 5-(6-benzyloxy)-2-fluoro-3-methyl-4-(2-(3-(propan-2- ylmethyl)pyrrolidin-1-yl)ethyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (16k) (140 mg, 287 μmol) was dissolved in dichloromethane (3 mL), then the reaction system was replaced with nitrogen for three times, then 2M boron tribromide (1.44 ml) was slowly added to the reaction solution at -70 °C, then stirred at -70 °C for 1 hour. After the reaction was completed, methanol (3 mL) was added at -70 °C to quench the reaction, and the pH was adjusted to 8 with an ammonia solution, filtered and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by HPLC, and the separation method was (column: Waters Atlantis T3 100*30mm*5μm; solvent: A = water + 10 mM ammonium bicarbonate, B = acetonitrile; gradient: 5%-35%, 10 minutes) to obtain compound 5-(2-fluoro-6-hydroxy-3-methyl-4-(2-(3-(propan-2-ylmethyl)pyrrolidin-1-yl)ethyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (16).

[0526] 1 H NMR (400 MHz, DMSO-d6) δ 9.68-9.94 (m, 1H) 9.12 (s, 1H) 6.59 (s, 1H) 4.11-4.39 (m, 1H) 3.93 (s, 2H) 3.54-3.86 (m, 2H) 3.12-3.31 (m, 3H) 2.84-3.02 (m, 2H) 2.59-2.76 (m, 1H) 2.10 (d, J = 1.75 Hz, 3H) 1.66 (s, 6H)

[0527] LC-MS, M / Z (ESI): 398.2 [M+H + ]

[0528] The following compounds were prepared according to the above Examples 1-16:

[0529] Biological test

[0530] Experimental Example 1: Determination of the inhibition of PTPN1 / PTPN2 enzyme activity by the compound

[0531] Experimental method

[0532] 1) Protein preparation. PTPN1 protein (#1366-PT) was purchased from R&D Systems, and PTPN2 protein (#E2302T-H28H) was from Sino Biological. PTPN1 and PTPN2 proteins were diluted with diluent (50 mM Tris-HCl, pH 7.2, 50 mM NaCl, 0.01% Triton X-100, 1 mM DTT) to make enzyme working solution with final concentration of 0.2 nM and 0.5 nM, respectively.

[0533] 2) Dilute the compounds in 384-well plates. The compounds were dissolved in DMSO as 10 mM stock solution, and the compounds were diluted by 3-fold gradient to make the concentrations of 100 μM, 33.3 μM, 11.1 μM, 3.7 μM, 1.23 μM, 0.41 μM, 0.14 μM, 0.046 μM and 0.015 μM, respectively.

[0534] 3) Transfer 0.1 μL of the diluted compound solution in each row to the 384-well assay plate using Echo liquid handling system, and each column contains 2 replicates.

[0535] 4) Add 5 μL of enzyme working solution to the 384-well assay plate, and centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 10 minutes.

[0536] 5) Add 5 μL of substrate (DiFMUP, Thermo Fisher, D6567) working solution with a final concentration of 10 μM, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 30 minutes.

[0537] 6) Read the fluorescence signal at excitation wavelength 360 nm and emission wavelength 460 nm using the instrument from BMG, Germany.

[0538] 7) Data analysis: The percentage (%) of inhibition of the compound well = 100 x (average high control value - compound well value) / (average high control value - average low control value), wherein the high control: dimethyl sulfoxide (DMSO) and enzyme, and the low control: dimethyl sulfoxide (DMSO) and assay buffer; the half maximal inhibitory concentration (IC50) of the compound was fitted by a nonlinear regression equation using XLfit 5.5.0 software, Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC50-X)*HillSlope)).

[0539] Experimental conclusion: The compounds of the present application have excellent inhibitory effect on PTPN2 enzyme, and the IC 50 are all less than 500 nM, and the exemplary compounds are shown in Table 1.

[0540] Table 1 Inhibitory activity of test compounds on PTPN2 enzyme

[0541] Experimental Example 2: Determination of the effect of the compound on the proliferation of B16F10 cells

[0542] Experimental method

[0543] 1) Cell culture. B16F10 mouse melanoma cells (purchased from Wuhan Pons Life Science Co., Ltd.) were cultured in 1640 medium containing 10% (v / v) inactivated fetal bovine serum, 100 U / mL penicillin and 100 μg / mL streptomycin in a 37°C, 5% CO2 incubator, and the cells were subcultured when the confluence rate reached 80-90%.

[0544] 2) Cell plating. Cells in the logarithmic growth phase were used for plating, and B16F10 mouse melanoma cells were plated in a 96-well plate at 100 μL of medium per well, about 500 cells per well, and incubated overnight.

[0545] 3) Compound dilution. The compound was dissolved in DMSO to a concentration of 10 mM. Then the compound was gradiently diluted with DMSO to concentrations of 10 mM, 3.33 mM, 1.11 mM, 0.37 mM, 0.12 mM, 0.041 mM, 0.014 mM, 0.0046 mM and 0.0015 mM, respectively.

[0546] 4) Change of liquid treatment. 1 μL of the diluted compound was added to 1 mL of complete medium and mixed, the culture solution in the 96-well plate was removed, and 100 μL of the drug solution was added to the 96-well plate, with working concentrations of 10 μM, 3.33 μM, 1.11 μM, 0.37 μM, 0.12 μM, 0.041 μM, 0.014 μM, 0.0046 μM and 0.0015 μM, respectively.

[0547] 5) IFNγ treatment. About 10 minutes later, IFNγ was added to a final concentration of 10 ng / mL.

[0548] 6) Activity detection. Cell viability was detected 96 hours after drug treatment, and the detection method was referred to the instructions of CellTiter 2.0 (Promega, #G9243). 2.0 (Promega, #G9243) instructions.

[0549] 7) IC 50Calculation. Relative viability (%) = (LumninenceDMSO - Lumninence experiment) / (LumninenceDMSO - Lumninence blank) * 100%, calculated by fitting according to log(inhibitor) vs. response - Variable slope (four parameters) using GraphPad Prism software.

[0550] Experimental conclusion: The compound of the present application can significantly inhibit the proliferation of B16F10 cells, IC 50 are less than 5 μM, and exemplary compounds are shown in Table 2.

[0551] Table 2 Inhibitory activity of test compounds on the proliferation of B16F10 cells

[0552] The positive control drug in the following experimental examples 3-5 is selected from compound 118 disclosed in WO2022056281A1, the structure of which is as follows:

[0553] Experimental example 3: mouse pharmacokinetic test

[0554] The mouse pharmacokinetic test uses male ICR mice, 20-25 g, fasted overnight. 3 mice are taken, and 10 mg / kg is administered orally by gavage. Blood is collected before administration and at 15, 30 minutes, and 1, 2, 4, 8, 24 hours after administration. Another 3 ICR mice are taken, and 1 mg / kg is administered intravenously, and blood is collected before administration and at 15, 30 minutes, and 1, 2, 4, 8, 24 hours after administration. The blood samples are centrifuged at 6800 g at 2-8°C for 6 minutes, and the plasma is collected and stored at -80°C. The plasma at each time point is mixed with 3-5 times the amount of internal standard-containing acetonitrile solution, vortexed for 1 minute, centrifuged at 13000 rpm for 10 minutes at 4°C, and the supernatant is mixed with 3 times the amount of water, and an appropriate amount of the mixture is subjected to LC-MS / MS analysis. The main pharmacokinetic parameters are analyzed by non-compartment model using WinNonlin 7.0 software.

[0555] Table 3 Results of mouse pharmacokinetic test

[0556] The results of the mouse pharmacokinetic test show that the compound of the present application exhibits excellent mouse pharmacokinetic properties, with low clearance, high systemic exposure and bioavailability, and good drug properties.

[0557] Experimental example 4: rat pharmacokinetic test

[0558] Rat pharmacokinetic test, male SD rats, 180-240 g, fasted overnight. Take 3 rats, oral gavage administration of 10 mg / kg. Blood samples were taken before administration and at 15, 30 minutes and 1, 2, 4, 8, 24 hours after administration. Blood samples were centrifuged at 6800 g, 2-8℃ for 6 minutes, and the plasma was collected and stored at -80℃. Take the plasma at each time point, add 3-5 times the amount of internal standard acetonitrile solution, mix, vortex mix for 1 minute, centrifuge at 13000 rpm for 10 minutes at 4℃, take the supernatant and add 3 times the amount of water, take an appropriate amount of mixture for LC-MS / MS analysis. The main pharmacokinetic parameters were analyzed by WinNonlin 7.0 software non-compartment model.

[0559] Table 4 Rat pharmacokinetic test results

[0560] The results of the rat pharmacokinetic test show that the compounds of the present application exhibit excellent rat pharmacokinetic properties and good drug development potential.

[0561] Experimental Example 5: Dog pharmacokinetic test

[0562] Dog pharmacokinetic test, male Beagle dogs, 8-10 kg, fasted overnight. Take 3 Beagle dogs, oral gavage administration of 5 mg / kg, blood samples were taken before administration and at 15, 30 minutes and 1, 2, 4, 8, 24 hours after administration. Take another 3 Beagle dogs, intravenous injection administration of 1 mg / kg, blood samples were taken before administration and at 15, 30 minutes and 1, 2, 4, 8, 24 hours after administration. Blood samples were centrifuged at 6800 g, 2-8℃ for 6 minutes, and the plasma was collected and stored at -80℃. Take the plasma at each time point, add 3-5 times the amount of internal standard acetonitrile solution, mix, vortex mix for 1 minute, centrifuge at 13000 rpm for 10 minutes at 4℃, take the supernatant and add 3 times the amount of water, take an appropriate amount of mixture for LC-MS / MS analysis. The main pharmacokinetic parameters were analyzed by WinNonlin 7.0 software non-compartment model.

[0563] Table 5 Dog pharmacokinetic test results

[0564] The results of the dog pharmacokinetic test show that the compounds of the present application exhibit excellent dog pharmacokinetic properties, with low clearance, high systemic exposure and bioavailability, and good drug development potential.

Claims

1. A compound represented by Formula (I), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein, R1and R2are each independently H, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, C 6-10 aryl, 3-8 membered heterocycloalkyl, 4-8 membered heterocycloalkenyl, or 5-10 membered heteroaryl, each of which is independently optionally substituted with 1, 2, 3, or 4 R 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, C 6-10 aryl, 3-8 membered heterocycloalkyl, 4-8 membered heterocycloalkenyl, and 5-10 membered heteroaryl, each of which is independently optionally substituted with 1, 2, 3, or 4 R a substituents; or R1, R2, together with the carbon atom to which they are attached, form C 3-8 cycloalkyl or 3-8 membered heterocycloalkyl, said C 3-8 cycloalkyl and 3-8 membered heterocycloalkyl are each independently optionally substituted with 1, 2, 3, or 4 R a substituents; each R a are each independently H, halogen, OH, NH2, CN, =0, COOH, or optionally substituted C a1 alkyl; each R 1-6 alkyl; each R Each R a1 They are H and halogens, respectively, and can be distinguished independently. Cycloalkyl, C 3-8 Cycloalkenyl, C 3-8 Cycloalkenyl, C 6-10 Aryl, 3-12 membered heterocycloalkyl, 4-12 membered heterocycloalkenyl, or 5-12 membered heteroaryl; said ring A is optionally substituted with 1, 2, 3, or 4 R A substituents; Each R A The independent components are H, halogen, OH, NH2, CN, =O, COOH, and C, respectively. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; L is -0-, -S-, -C(=0)-, -S(=0)-, -S(=0)2-, -NR L1 -, -C(O)NR L1 -, -NR L1 C(O)-, -[C(R L2 )2] m -, -C(O)[C(R L2 )2] m - or -[C(R L2 )2] m C(O)-; R L1 is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, or 3-8 membered heterocycloalkenyl, each of which is independently optionally substituted with 1, 2, 3, or 4 R 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl, C 3- 8cycloalkenyl, 3-8 membered heterocycloalkyl, and 3-8 membered heterocycloalkenyl, each of which is independently optionally substituted with 1, 2, 3, or 4 R b substituents; Each R b They can be independently H, halogen, OH, NH2, CN, =O or COOH; R L2 H, halogen, OH, NH2, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, or 3-8 membered heterocycloalkenyl, each of which C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, 3-8 membered heterocycloalkyl, and 3-8 membered heterocycloalkenyl, are each independently optionally substituted with 1, 2, 3, or 4 R c substituents; Each R c They can be independently H, halogen, OH, NH2, CN, =O or COOH; m is 1, 2, 3 or 4; X1is N or CR x1 ; X2is N or CR x2 ; X3is N or CR x3 ; X4is N or CR x4 ; R x1 R x2 R x3 and R x4 The independent components are H, halogen, OH, NH2, CN, COOH, and C, respectively. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1- 6-alkoxy, C 1-6 Alkylamino, C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, 3-8 membered heterocyclic alkyl, or 3-8 membered heterocyclic alkenyl, wherein C 1-6 Alkyl, C 2- 6-alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-8 cycloalkyl, C 3-8 The cycloalkenyl, 3-8 membered heterocyclic alkyl and 3-8 membered heterocyclic alkenyl groups are each independently and optionally substituted by 1, 2, 3 or 4 Rd groups; Each R d They can be independently H, halogen, OH, NH2, CN, =O or COOH; the heteroatom groups in the "heterocycloalkyl", "heterocycloalkenyl" and "heteroaryl" comprise N, O or S, the number of the heteroatom groups is 1, 2, 3 or 4; when the number of the heteroatom groups is plural, the heteroatom groups are the same or different.

2. The compound, tautomer, stereoisomer, or pharmaceutically acceptable salt thereof of claim 1, wherein Cycloalkyl, C 3-6 Cycloalkenyl, C 3-6 Cycloalkenyl, C 6-10 Aryl, 3-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, or 5-10 membered heteroaryl, said ring A is optionally substituted with 1, 2, 3, or 4 R A substituents; and / or, each R is independently H, halogen, C A each R is independently H, halogen, C 1-3 alkyl or C 1-3 haloalkyl; And / or, each R A Each is independently represented by H; and / or, ring A is C 3-6 cycloalkyl, 3-8 membered monocyclic heterocycloalkyl, or 6-10 membered bicyclic heterocycloalkyl, wherein bicyclic includes fused, spiro, and bridged, said ring A is optionally substituted with 1, 2, 3, or 4 R A substituents; and / or, the 6-10 membered bicyclic heterocycloalkyl is 4-6 membered and 4-6 membered heterocycloalkyl; and / or, ring A is cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetidinyl, azetidinyl, azetidinyl and azetidinyl; and / or, For and / or, ring A is a 5-6 membered monocyclic heterocycloalkyl, said ring A is optionally substituted with 1, 2, 3, or 4 R A substituents; and / or, ring A is azetidinyl; and / or, For and / or, R1and R2are each independently H, F, Cl, Br, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 alkoxy, C 1-3 alkylamino, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, phenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, or 5-6 membered heteroaryl, each of which C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 alkoxy, C 1-3 alkylamino, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, phenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, and 5-6 membered heteroaryl, each of which C a is independently optionally substituted with 1, 2, 3, or 4 R And / or, each R a They can be independently H, F, Cl, Br, OH, NH2, CN, =O, or COOH; and / or, each R is independently H or F; and a are each independently H or F; and / or, R1 and R2 are each independently H, F, CF3, methyl or ethyl; and / or, R1, R2together with the carbon atom to which they are attached form C 3-6 heterocycloalkyl, said C 3-6 heterocycloalkyl are each independently optionally substituted with 1, 2, 3, or 4 R a substituents; And / or, each R a Each is independently represented by H; and / or, the C 3-6 heterocycloalkyl is selected from C 5-6 heterocycloalkyl, the C 5-6 heterocycloalkyl is independently optionally substituted by 1, 2, 3 or 4 R a substituents; and / or, R1, R2 and the carbon atom to which they are attached form tetrahydrofuranyl; and / or, R1, R2together with the carbon atom to which they are attached form C 3-6 cycloalkyl, said C 3-6 cycloalkyl is each independently optionally substituted with 1, 2, 3, or 4 R a substituents; and / or, each R a is independently H, halogen, or optionally substituted C a1 alkyl; and / or, each R 1-3 alkyl; and / or, each R and / or, R1, R2together with the carbon atom to which they are attached form a C 3-6 cycloalkyl, said C 3-6 cycloalkyl is independently optionally substituted by 1, 2, 3 or 4 R a substituents; wherein each R a is independently H, F or methyl; and / or, R1, R2, together with the carbon atom to which they are attached, form a cyclopropyl, cyclobutyl, or cyclopentyl, each independently optionally substituted with 1, 2, 3, or 4 R a substituted; and / or, R1, R2, together with the carbon atom to which they are attached, form a cyclopropyl, cyclobutyl, or cyclopentyl, each independently optionally substituted with 1, 2, 3, or 4 R a substituents; wherein each R a is independently H, F, or methyl; and / or, For and / or, For and / or, For 3. The compound, tautomer, stereoisomer, or pharmaceutically acceptable salt thereof of claim 1, wherein L is -C(O)NR L1 -, -NR L1 C(O)-, -[C(R L2 )2] m -, -C(O)[C(R L2 )2] m - or -[C(R L2 )2] m C(O)-; and / or, R L1 is H, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 alkoxy, C 1-3 alkylamino, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, 3-6 membered heterocycloalkyl, or 3-6 membered heterocycloalkenyl, each of which is independently optionally substituted with 1, 2, 3, or 4 R 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 alkoxy, C 1-3 alkylamino, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, 3-6 membered heterocycloalkyl, and 3-6 membered heterocycloalkenyl are each independently optionally substituted with 1, 2, 3, or 4 R b substituents; And / or, each R b They can be independently H, F, Cl, Br, OH, NH2, CN, =O, or COOH; and / or, R L1 is H; and / or, R L2 is H, F, CI, Br, OH, NH2, CN, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 alkoxy, C 1-3 alkylamino, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, 3-6 membered heterocycloalkyl or 3-6 membered heterocycloalkenyl, said C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 alkoxy, C 1-3 alkylamino, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, 3-6 membered heterocycloalkyl and 3-6 membered heterocycloalkenyl are each independently optionally substituted with 1, 2, 3 or 4 R c substituents; And / or, each R c They can be independently H, F, Cl, Br, OH, NH2, CN, =O, or COOH; and / or, R L2 is H; and / or, L is -C(O)NH-, -NHC(O)-, -(CH2)2-, -C(O)CH2- or -CH2C(O)-; and / or L is -(CH2)2-.

4. The compound, tautomer, stereoisomer, or pharmaceutically acceptable salt thereof of claim 1, wherein X1is CR x1 ; and / or, R x1 is H, F, CI, Br, OH, NH2, CN, COOH, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 alkoxy, C 1-3 alkylamino, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, 3- to 6-membered heterocycloalkyl, or 3- to 6-membered heterocycloalkenyl, each of which C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 alkoxy, C 1-3 alkylamino, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, 3- to 6-membered heterocycloalkyl, and 3- to 6-membered heterocycloalkenyl, each of which is independently optionally substituted with 1, 2, 3, or 4 R d substituents; and / or, R x1 is H, F or methyl; and / or, R x1 is F; and / or X2is N or CR x2 ; and / or, R x2 is H, F, Cl, B r , OH, NH2, CN, COOH, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 alkoxy, C 1-3 alkylamino, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, 3-6 membered heterocycloalkyl or 3-6 membered heterocycloalkenyl, said C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 alkoxy, C 1-3 alkylamino, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, 3-6 membered heterocycloalkyl and 3-6 membered heterocycloalkenyl are each independently optionally substituted with 1, 2, 3 or 4 R d substituents; and / or, R x2 is H, F, CI, CN, C 1-3 alkyl or C 2-4 alkynyl, said C 1-3 alkyl and C 2-4 alkynyl are each independently optionally substituted with 1, 2, 3, or 4 R d substituents; and / or, R x2 is H, F, CI, CN, methyl, CF3or ethynyl (-C≡CH); and / or, R x2 is H, F, C 1-3 alkyl, said C 1-3 alkyl is optionally substituted with 1, 2, 3, or 4 R d substituents; and / or, R x2 is H, F or methyl; and / or, each R is independently H, F, Cl, B d is independently H, F, Cl, B r , OH, NH2, CN, =0 or COOH; and / or, X3 is N or CR x3 ; and / or, R x3 is H or F; and / or X4is CR x4 ; and / or, R x4 is OH or NH2; and / or, R x4 is OH.

5. The compound, tautomer, stereoisomer, or pharmaceutically acceptable salt thereof of claim 1, wherein The compound of formula (I) has the structural formula (I-1) or (I-2): R1, R2, L, R x1 , X2and ring A are as defined in claim 1.

6. The compound, tautomer, stereoisomer, or pharmaceutically acceptable salt thereof of claim 1, wherein The compound is selected from the following structures:

7. A pharmaceutical composition, characterized by, comprising a therapeutically effective amount of the compound of any one of claims 1-6 or a tautomer, stereoisomer or pharmaceutically acceptable salt thereof; and / or a pharmaceutically acceptable carrier.

8. Use of the compound of any one of claims 1-6 or a tautomer, stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 7, comprising: inhibiting the expression of PTPN1 and / or PTPN2; and / or, preparing a medicament for treating a PTPN1 and / or PTPN2 related disease; and / or, preparing a PTPN1 and / or PTPN2 inhibitor; and / or, for treating a PTPN1 and / or PTPN2 related disease.

9. Use according to claim 8, characterized in that, The disease includes a solid tumor.

10. Use according to claim 8, characterized in that, The solid tumor includes head and neck cancer, non-small cell lung cancer, clear cell renal cell carcinoma and melanoma.

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