Double-bond substituted compound as protein tyrosine phosphatase inhibitor and application thereof

Abstract

The invention relates to a compound containing double bond substitution as a PTPN1 and / or PTPN2 inhibitor and application thereof, in particular to a compound shown in a formula (I), a tautomer, a stereoisomer or pharmaceutically acceptable salt of the compound, a preparation method of the tautomer, the stereoisomer or the pharmaceutically acceptable salt of the compound, and application of the tautomer, the stereoisomer or the pharmaceutically acceptable salt in preparation of drugs for treating PTPN1 and / or PTPN2 related diseases.

Description

[0001] This invention claims the following:

[0002] Priority is claimed to the earlier application filed with the China National Intellectual Property Administration on August 22, 2024, with patent application number 202411162384.7 and title "Compounds containing double bonds as inhibitors of protein tyrosine phosphatase and their applications therein".

[0003] Priority is claimed for the earlier application filed with the China National Intellectual Property Administration on January 20, 2025, with patent application number 202510087977.X and title "Compounds with double bond substitution as protein tyrosine phosphatase inhibitors and their applications thereto".

[0004] Priority is claimed for the earlier application filed with the China National Intellectual Property Administration on May 19, 2025, with patent application number 202510645560.0 and title "Compounds containing double bonds as inhibitors of protein tyrosine phosphatase and their applications therein".

[0005] Priority is claimed to the earlier application filed with the China National Intellectual Property Administration on August 14, 2025, with patent application number 202511142013.7 and title "Compounds containing double bonds as inhibitors of protein tyrosine phosphatase and their applications therein".

[0006] The full text of the aforementioned prior application is incorporated herein by reference. Technical Field

[0007] This invention relates to the pharmaceutical field, and more specifically, to a class of compounds containing double-bond substitutions as inhibitors of PTPN1 and / or PTPN2, and their applications. Background Technology

[0008] The advent of immunotherapy has revolutionized the treatment of hematologic malignancies and solid tumors. In particular, antibodies targeting immune checkpoints can alleviate tumor suppression of T cells, altering cancer treatment strategies. Immune checkpoint blockade (ICB), as a novel immunotherapy approach, aims to improve clinical responses in cancer patients by targeting immune escape mechanisms. However, response rates to this therapy remain low for many tumors. These tumors typically exhibit reduced immune infiltration, particularly a lack or scarcity of T cells. This scarcity can be attributed to a variety of factors, including low tumor mutational burden, poor T cell homing and infiltration, and downregulation of antigen presentation, preventing the tumor from being detected by the immune system. Furthermore, resistance to immunotherapy is common; even some tumors predominantly composed of tumor-infiltrating lymphocytes (TILs) may not respond, while other tumors may initially respond but subsequently relapse. Incomplete clinical responses and the emergence of resistance limit the application of immune checkpoint blockade therapy.

[0009] In recent years, tyrosine-specific phosphatases PTP1B (encoded by PTPN1) and PTPN2 (also known as TCPTP, encoded by PTPN2) have become exciting immunotherapeutic targets in cancer treatment. PTP1B and PTPN2 are two of the most closely related members of the PTP superfamily, sharing high similarity in the sequence and structure of their catalytic domains, but differing in their non-catalytic segments at the N-terminus and C-terminus. PTP1B is targeted to the cytoplasmic surface of the endoplasmic reticulum (ER) via a hydrophobic C-terminus, but can access substrates after endocytosis at the plasma membrane and receptors. Furthermore, PTPN2 exists in two variants: a 48 kDa variant, like PTP1B, is targeted to the ER via a hydrophobic C-terminus; the other is a 45 kDa variant lacking the hydrophobic C-terminus, which is targeted to the nucleus and transported between the nucleus and cytoplasm. These two PTPs can co-regulate a variety of biological processes by dephosphorylating different or the same substrates, such as the hypothalamus's control of energy expenditure and glucose metabolism, and the biology and function of T cells. Both PTPs are key negative regulators of the JAK / STAT signaling pathway. PTP1B is highly selective for JAK-2 and Tyk2, while PTPPN2 is highly selective 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 the T cell receptor (TCR) signaling pathway by dephosphorylating and inactivating Src family kinases (SFKs) LCK and FYN, and attenuates cytokine signaling, particularly interleukin (IL)-2-induced STAT-5 signaling and interferon (IFN)-induced STAT-1 signaling, to regulate T cell responses and prevent erroneous responses to itself during T cell homeostasis and antigen presentation. The importance of PTPN2 in T cell tolerance has been demonstrated in PTPN2 knockout mice. Studies have shown that conditional deletion of Ptpn2 in T cells may lead to significant autoimmune diseases in aged C57BL / 6 mice and accelerate the development of type 1 diabetes and other comorbidities in autoimmune-prone NOD mice. Systemic deletion of PTPN2 or inducible deletion in hematopoietic cells leads to significant systemic inflammation and autoimmunity. These phenotypes are similar to those in mice lacking immune checkpoint receptors PD-1 or CTLA-4. Consistent with observations in mice, loss-of-function single nucleotide polymorphisms (SNPs) of human PTPN2 are also associated with autoimmune and inflammatory diseases. In contrast, PTP1B affects T cell development and function by attenuating IL-2 / -5 / -15-induced STAT-5 signaling, but does not regulate TCR signaling; systemic or T cell-only loss of PTP1B does not promote systemic inflammation or autoimmunity. Nevertheless, loss of PTP1B or PTPN2 in T cells significantly enhances anti-tumor immunity. PTPN2 loss enhances T cell-mediated immune surveillance, prevents the development of hematologic and solid tumors in p53-hybrid aged mice, and enhances the anti-tumor activity of CAR-T cells. Furthermore, studies have found increased PTP1B expression in tumor-associated CD8+ effector T cells isolated from human melanoma or mouse homologous tumors, and inhibition or loss of PTP1B in T cells or CAR T cells significantly enhances anti-tumor immunity and promotes STAT-5 signaling. These studies identified PTP1B and PTPN2 as T cell checkpoints, whose functions are similar to those mediated by the inhibitory receptor PD-1 on the surface of T cells.

[0011] In summary, inhibiting PTPN1 / PTPN2 holds promise for cancer treatment, and PTPN1 / PTPN2 inhibitors may become a potential therapeutic strategy for ICBs to combat cancer. Summary of the Invention

[0012] 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.

[0013]

[0014] in,

[0015] 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 6-10 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;

[0016] 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;

[0017] 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;

[0018] Each R a1 They are H and halogens, respectively, and can be distinguished independently.

[0019] 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;

[0020] 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;

[0021] 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)-;

[0022] R L1 For H, 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, 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. b replace;

[0023] Each R b They can be independently H, halogen, OH, NH2, CN, =O or COOH;

[0024] R L2 H, halogen, OH, NH2, CN, 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, 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 3-8The 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. c replace;

[0025] Each R c They can be independently H, halogen, OH, NH2, CN, =O or COOH;

[0026] m can be 1, 2, 3, or 4;

[0027] X1 is N or CR x1 ;

[0028] X2 is N or CR x2 ;

[0029] X3 is N or CR x3 ;

[0030] X4 is N or CR x4 ;

[0031] 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;

[0032] Each R d They can be independently H, halogen, OH, NH2, CN, =O or COOH;

[0033] 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.

[0034] 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.

[0035]

[0036] in,

[0037] 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 6-10 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;

[0038] 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;

[0039] Each R a They can be independently H, halogen, OH, NH2, CN, =O or COOH;

[0040] 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; 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(RL2 )2] m -or-[C(R)] L2 )2] m C(O)-;

[0041] R L1 For H, 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, 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. b replace;

[0042] Each R b They can be independently H, halogen, OH, NH2, CN, =O or COOH;

[0043] R L2 H, halogen, OH, NH2, CN, 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, 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. c replace;

[0044] Each R c They can be independently H, halogen, OH, NH2, CN, =O or COOH;

[0045] m can be 1, 2, 3, or 4;

[0046] X1 is N or CR x1 ;

[0047] X2 is N or CR x2 ;

[0048] X3 is N or CR x3 ;

[0049] X4 is N or CR x4 ;

[0050] 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;

[0051] Each R d They can be independently H, halogen, OH, NH2, CN, =O or COOH;

[0052] 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.

[0053] 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.

[0054]

[0055] in,

[0056] R1 and R2 are independently H, halogen, and C, respectively. 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;

[0057] Each R a They can be independently H, halogen, OH, NH2, CN, =O or COOH;

[0058] 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; 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)-;

[0059] R L1 For H, 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, 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 1-6Alkoxy, 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. b replace;

[0060] Each R b They can be independently H, halogen, OH, NH2, CN, =O or COOH;

[0061] R L2 H, halogen, OH, NH2, CN, 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, 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. c replace;

[0062] Each R c They can be independently H, halogen, OH, NH2, CN, =O or COOH;

[0063] m can be 1, 2, 3, or 4;

[0064] X1 is N or CR x1 ;

[0065] X2 is N or CR x2 ;

[0066] X3 is N or CR x3 ;

[0067] X4 is N or CR x4 ;

[0068] 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, C2-6 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;

[0069] Each R d They can be independently H, halogen, OH, NH2, CN, =O or COOH;

[0070] 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.

[0071] 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.

[0072]

[0073] in,

[0074] 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 6-10 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 6-10Aryl, 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;

[0075] Each R a They can be independently H, halogen, OH, NH2, CN, =O or COOH;

[0076] 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; L is -O-, -S-, -C(=O)-, -S(=O)-, -S(=O)2-, -NR L1 -、-C(O)NR L1 -、-NR L1 C(O)- or -[C(R) L2 )2] m -;

[0077] R L1 For H, 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, 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. b replace;

[0078] Each R b They can be independently H, halogen, OH, NH2, CN, =O or COOH;

[0079] R L2 H, halogen, OH, NH2, CN, 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 3-8Cycloalkenyl, 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. c replace;

[0080] Each R c They can be independently H, halogen, OH, NH2, CN, =O or COOH;

[0081] m can be 1, 2, 3, or 4;

[0082] X1 is N or CR x1 ;

[0083] X2 is N or CR x2 ;

[0084] X3 is N or CR x3 ;

[0085] X4 is N or CR x4 ;

[0086] 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;

[0087] Each R d They can be independently H, halogen, OH, NH2, CN, =O or COOH;

[0088] 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.

[0089] According to embodiments of the present invention, the above-described compound may further include at least one of the following technical features:

[0090] 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.

[0091] 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.

[0092] 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.

[0093] In an optional embodiment of the present invention, ring A is cyclobutyl, cyclopentyl, cyclohexyl, azircyclobutyl, azircyclopentyl, azircyclohexyl, azircyclopentyl, and azircyclopentyl.

[0094] In one optional embodiment of the present invention for

[0095] 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.

[0096] 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;

[0097] In an optional embodiment of the present invention, each R AEach is independently H, halogen, and C. 1-3 Alkyl or C 1-3 Halogenated alkyl groups;

[0098] In an optional embodiment of the present invention, each R A Each is independently represented by H;

[0099] In an optional embodiment of the present invention, ring A is C. 3-6 Cycloalkyl, 3-8 membered monocyclic heterocyclic alkyl, or 6-10 membered bicyclic heterocyclic alkyl, wherein the bicyclic includes fused rings, spirocyclic rings, and bridged rings, and the ring A is optionally surrounded by 1, 2, 3, or 4 R's. A replace;

[0100] In an optional embodiment of the invention, ring A is a 5-6 membered monocyclic heterocyclic alkyl group, wherein ring A is optionally surrounded by 1, 2, 3 or 4 R groups. A replace;

[0101] In an optional embodiment of the present invention, ring A is an azacyclopentyl group;

[0102] In one optional embodiment of the present invention for

[0103] In an optional embodiment of the present invention, R1 and R2 are independently H, F, Cl, Br, and C, respectively. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy, C 1-3 Alkylamino, C 3-6 cycloalkyl, C 3-6 Cycloalkenyl, phenyl, 3-6 membered heterocyclic alkyl, 3-6 membered heterocyclic alkenyl or 5-6 membered heteroaryl, wherein C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy, C 1-3 Alkylamino, C 3-6 cycloalkyl, C 3-6 Cycloalkenyl, phenyl, 3-6-membered heterocyclic alkyl, 3-6-membered heterocyclic alkenyl, and 5-6-membered heteroaryl are each independently and optionally surrounded by 1, 2, 3, or 4 R groups. a replace.

[0104] In an optional embodiment of the present invention, each R a They can be H, F, Cl, Br, OH, NH2, CN, =O or COOH, respectively.

[0105] In an optional embodiment of the present invention, each R a They are H or F, respectively, independently.

[0106] In an optional embodiment of the invention, R1 and R2 are independently H or F, respectively.

[0107] In an optional embodiment of the invention, R1 and R2 are independently H, F, CF3 or methyl.

[0108] In an optional embodiment of the invention, R1 and R2 are independently H, F, CF3, methyl, or ethyl.

[0109] In an optional embodiment of the invention, R1, R2, together with the carbon atoms they are attached to, form C. 3-6 Heterocyclic alkyl, the C 3-6 Heterocyclic alkyl groups are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. a replace;

[0110] In an optional embodiment of the present invention, each R a Each is independently represented by H;

[0111] In an optional embodiment of the present invention, the C 3-6 Heterocyclic alkyl groups are selected from C 5-6 Heterocyclic alkyl, the C 5-6 Heterocyclic alkyl groups are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. a replace;

[0112] In an optional embodiment of the invention, R1, R2, together with the carbon atoms to which they are attached, form a tetrahydrofuran group;

[0113] In an optional embodiment of the invention, R1, R2, together with the carbon atoms they are attached to, form C. 3-6 cycloalkyl, the C 3-6 The cycloalkyl groups are each independently and optionally marked with 1, 2, 3 or 4 R's. a replace.

[0114] In an optional embodiment of the present invention, each R a Each is independently H, halogen, or optionally surrounded by 1, 2, 3, or 4 Rs. a1 Replacement C 1-3 alkyl;

[0115] In an optional embodiment of the invention, R1, R2, together with the carbon atoms they are attached to, form C. 3-6 cycloalkyl, the C 3-6 The cycloalkyl groups are each independently and optionally marked with 1, 2, 3 or 4 R's. a Replace; where each R a Each can be H, F, or methyl, independently.

[0116] In an optional embodiment of the invention, R1, R2, together with the carbon atoms they are attached to, form a cyclopropyl, cyclobutyl, or cyclopentyl group, wherein the cyclopropyl, cyclobutyl, and cyclopentyl groups are each independently and optionally converted by 1, 2, 3, or 4 R atoms. a replace.

[0117] In an optional embodiment of the invention, R1, R2, together with the carbon atoms they are attached to, form a cyclopropyl, cyclobutyl, or cyclopentyl group, wherein the cyclopropyl, cyclobutyl, and cyclopentyl groups are each independently and optionally converted by 1, 2, 3, or 4 R atoms. a Substitution; wherein each Ra is independently H, F or methyl.

[0118] In one optional embodiment of the present invention for

[0119] In one optional embodiment of the present invention for

[0120] In one optional embodiment of the present invention for

[0121] In one optional embodiment of the present invention for In one optional embodiment of the present invention for In one optional embodiment of the present invention for

[0122] In one optional embodiment of the present invention for

[0123] In an optional embodiment of the present invention, L is -O-, -S-, -C(=O)-, -S(=O)-, -S(=O)2-, -NR L1 -、-C(O)NR L1 -、-NR L1 C(O)- or -[C(R) L2 )2] m -

[0124] In an optional embodiment of the present invention, 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)-.

[0125] In an optional embodiment of the present invention, R L1 For H, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy, C 1-3 Alkylamino, C 3-6 cycloalkyl, C 3-6 Cycloalkenyl, 3-6 membered heterocyclic alkyl, or 3-6 membered heterocyclic alkenyl, wherein C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy, C 1-3 Alkylamino, C 3-6 cycloalkyl, C 3-6 The cycloalkenyl, 3-6 membered heterocyclic alkyl, and 3-6 membered heterocyclic alkenyl groups are each independently and optionally surrounded by 1, 2, 3, or 4 R groups. b replace.

[0126] In an optional embodiment of the present invention, each R b They can be H, F, Cl, Br, OH, NH2, CN, =O or COOH, respectively.

[0127] In an optional embodiment of the present invention, R L1 For H.

[0128] In an optional embodiment of the present invention, R L2 For H, F, Cl, Br, OH, NH2, CN, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy, C 1-3 Alkylamino, C 3-6 cycloalkyl, C 3-6 Cycloalkenyl, 3-6 membered heterocyclic alkyl, or 3-6 membered heterocyclic alkenyl, wherein C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy, C 1-3 Alkylamino, C 3-6 cycloalkyl, C 3-6 The cycloalkenyl, 3-6 membered heterocyclic alkyl, and 3-6 membered heterocyclic alkenyl groups are each independently and optionally surrounded by 1, 2, 3, or 4 R groups. creplace.

[0129] In an optional embodiment of the present invention, each R c They can be H, F, Cl, Br, OH, NH2, CN, =O or COOH, respectively.

[0130] In an optional embodiment of the present invention, R L2 For H.

[0131] In an optional embodiment of the present invention, L is -C(O)NH-, -NHC(O)-, or -(CH2)2-.

[0132] In an optional embodiment of the present invention, L is -(CH2)2-.

[0133] In an optional embodiment of the present invention, L is -C(O)NH-, -NHC(O)-, -(CH2)2-, -C(O)CH2-, or -CH2C(O)-.

[0134] In an optional embodiment of the present invention, X1 is CR x1 .

[0135] In an optional embodiment of the present invention, R x1 For H, F, Cl, Br, OH, NH2, CN, COOH, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy, C 1-3 Alkylamino, C 3-6 cycloalkyl, C 3-6 Cycloalkenyl, 3-6 membered heterocyclic alkyl, or 3-6 membered heterocyclic alkenyl, wherein C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy, C 1-3 Alkylamino, C 3-6 cycloalkyl, C 3-6 The cycloalkenyl, 3-6 membered heterocyclic alkyl, and 3-6 membered heterocyclic alkenyl groups are each independently and optionally surrounded by 1, 2, 3, or 4 R groups. d replace.

[0136] In an optional embodiment of the present invention, R x1 It can be H, F, or methyl.

[0137] In an optional embodiment of the present invention, R x1 It is F.

[0138] In an optional embodiment of the present invention, X2 is N or CR. x2 .

[0139] In an optional embodiment of the present invention, R x2 For H, F, Cl, Br, OH, NH2, CN, COOH, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy, C 1-3 Alkylamino, C 3-6 cycloalkyl, C 3-6 Cycloalkenyl, 3-6 membered heterocyclic alkyl, or 3-6 membered heterocyclic alkenyl, wherein C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy, C 1-3 Alkylamino, C 3-6 cycloalkyl, C 3-6 The cycloalkenyl, 3-6 membered heterocyclic alkyl, and 3-6 membered heterocyclic alkenyl groups are each independently and optionally surrounded by 1, 2, 3, or 4 R groups. d replace.

[0140] In an optional embodiment of the present invention, R x2 For H, F, Cl, CN, C 1-3 Alkyl or C 2-4 alkynyl group, the C 1-3 Alkyl and C 2-4 The alkynyl group is independently and optionally surrounded by 1, 2, 3 or 4 R groups. d replace.

[0141] In an optional embodiment of the present invention, R x2 It can be H, F, Cl, CN, methyl, CF3, or ethynyl (-C≡CH).

[0142] In an optional embodiment of the present invention, R x2 For H, F, C 1-3 Alkyl, the C 1-3 Alkyl groups are optionally surrounded by 1, 2, 3 or 4 R's. d replace.

[0143] In an optional embodiment of the present invention, R x2 It can be H, F, or methyl.

[0144] In an optional embodiment of the present invention, R x2 It is H or methyl, wherein the methyl group is optionally surrounded by 1, 2, 3 or 4 R. d replace.

[0145] In an optional embodiment of the present invention, each R d They can be H, F, Cl, Br, OH, NH2, CN, =O or COOH, respectively.

[0146] In an optional embodiment of the present invention, R x2 It can be H or CF3.

[0147] In an optional embodiment of the present invention, X3 is N or CR. x3 .

[0148] In an optional embodiment of the present invention, R x3 For H.

[0149] In an optional embodiment of the present invention, R x3 It can be H or F.

[0150] In an optional embodiment of the present invention, X4 is CR x4 .

[0151] In an optional embodiment of the present invention, R x4 It can be OH or NH2.

[0152] In an optional embodiment of the present invention, R x4 It is OH.

[0153] In an optional embodiment of the present invention, the compound represented by formula (I) has structural formula (I-1) or (I-2):

[0154]

[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]

[0158]

[0159]

[0160] 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.

[0161] In an optional embodiment of the invention, the pharmaceutical composition comprises a therapeutically effective amount of the compound represented by formula (I) or its tautomers, stereoisomers or pharmaceutically acceptable salts.

[0162] In an optional embodiment of the invention, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient.

[0163] 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:

[0164] Inhibit the expression of PTPN1 and / or PTPN2; and / or,

[0165] Prepare medicines for the treatment of PTPN1 and / or PTPN2-related diseases; and / or,

[0166] Preparation of PTPN1 and / or PTPN2 inhibitors; and / or,

[0167] Used to treat PTPN1 and / or PTPN2 related diseases.

[0168] In an optional embodiment of the invention, the disease includes a solid tumor.

[0169] In an optional embodiment of the present invention, the solid tumor includes head and neck cancer, non-small cell lung cancer, clear cell renal cell carcinoma, and melanoma.

[0170] In an optional embodiment of the present invention, the solid tumor includes head and neck cancer, non-small cell lung cancer, and clear cell renal cell carcinoma.

[0171] In an optional embodiment of the present invention, the disease includes solid tumors, including head and neck cancer, non-small cell lung cancer, and clear cell renal cell carcinoma.

[0172] Terms and Definitions

[0173] Unless otherwise stated, the terms and definitions used in this application, including those set forth in the specification and claims, are as follows.

[0174] Those skilled in the art will understand that, according to the conventions used in the art, in the structural formula of this application, Used to describe chemical bonds, which are points where a portion or a substituent is connected to a core or skeletal structure. As used herein, “R1”, “R1”, and “R” are used to describe chemical bonds. 1 The meanings of "" are the same and they can be used interchangeably. The same definition applies to other symbols such as R2.

[0175] Unless otherwise specified, the term "pharmaceutical acceptable" refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0176] Unless otherwise specified, the term "pharmaceutically acceptable salt" means a pharmaceutically acceptable non-toxic salt of an acid or base, including salts of inorganic acids and bases, and salts of organic acids and bases.

[0177] In addition to pharmaceutically acceptable salts, the present invention also contemplates other salts. These may serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts, or may be used for the identification, characterization, or purification of the compounds of the present invention.

[0178] Unless otherwise specified, the term "pharmaceutical composition" means a mixture of one or more compounds described in this text or their physiologically / pharmaceutical acceptable salts or prodrugs with other chemical components, such as physiologically / pharmaceutical acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate the administration of the compound to a living organism.

[0179] Unless otherwise specified, the term "excipient" refers to a pharmaceutically acceptable inert ingredient. Examples of the term "excipient" include, without limitation, binders, disintegrants, lubricants, flow aids, stabilizers, fillers, and diluents. Excipients enhance the handling properties of pharmaceutical formulations, i.e., by increasing flowability and / or adhesion, making the formulation more suitable for direct compression.

[0180] Unless otherwise specified, the term "stereoisomer" refers to isomers that are produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, non-corresponding isomers, and conformational isomers.

[0181] Unless otherwise defined, those skilled in the art will understand that when a chemical reaction formula contains... When representing a double bond, it implies that the cis-trans isomerism of the double bond is undetermined.

[0182] Depending on the choice of raw materials and methods, the compounds of the present invention may exist as one or a mixture of possible isomers, for example as purely optical isomers, or as mixtures of isomers, such as racemic and diastereomeric mixtures, depending on the number of asymmetric carbon atoms. When describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to the chiral center (or multiple chiral centers) in the molecule. The prefixes D and L or (+) and (–) are symbols used to specify the plane-polarized rotation of light induced by the compound, where (–) or L indicates that the compound is levorotatory. Compounds with the prefix (+) or D are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers may also be called enantiomers, and mixtures of said isomers are generally referred to as mixtures of enantiomers. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or method. Many geometric isomers of alkenes, C=N double bonds, etc., can also exist in the compounds described herein, and all such stable isomers are considered in this invention. When the compounds described herein contain an alkene double bond, unless otherwise stated, such double bond includes E and Z geometric isomers. If the compound contains a disubstituted cycloalkyl group, the substituent of the cycloalkyl group may be in cis or trans (cis- or trans-) configuration.

[0183] When the bonds of the chiral carbon in the formulas of this invention are depicted as straight lines, it should be understood that both the (R) and (S) configurations of the chiral carbon and the resulting enantiomerically pure compounds and mixtures thereof are included within the scope of the general formula. The illustration of racemic or enantiomerically pure compounds in this document is derived from Maehr, J. Chem. Ed. 1985, 62:114-120. Unless otherwise stated, wedge-shaped and dashed bonds represent the absolute configuration of a stereocenter.

[0184] Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral formulations, or resolved using conventional techniques. Compounds of the present invention containing asymmetrically substituted carbon atoms can be separated in either an optically active or racemic form. Resolution of racemic mixtures of compounds can be performed by any of many methods known in the art. Exemplary methods include fractional recrystallization using a chiral resolving acid, which is an optically active salt-forming organic acid. Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, or various optically active camphorsulfonic acids such as the D and L forms of β-camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include stereoisomerically pure α-methylbenzylamine (e.g., S and R forms or diastereoisomeric forms), 2-phenylglycine, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, etc. Resolution of racemic mixtures can also be achieved by elution onto a chromatographic column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). High-performance liquid chromatography (HPLC) or supercritical fluid chromatography (SFC) can be used. The specific method, elution conditions, and column selection can be chosen by those skilled in the art based on the structure of the compound and experimental results. Furthermore, any enantiomer or diastereomeric form of the compound described in this invention can be obtained through stereoorganic synthesis using optically pure starting materials or reagents with known configurations.

[0185] Unless otherwise specified, the term "tautomer" refers to a functional group isomer resulting from the rapid movement of an atom between two positions in a molecule. The compounds of this invention can exhibit tautomerism. Tautomeric compounds can exist in two or more interconvertible forms. Proton-transfer tautomers arise from the migration of covalently bonded hydrogen atoms between two atoms. Tautomers generally exist in equilibrium form, and attempts to isolate a single tautomer usually produce a mixture whose physicochemical properties are consistent with those of the mixture of compounds. The equilibrium position depends on the intramolecular chemical characteristics. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the ketone form is dominant; while in phenols, the enol form is dominant. This invention encompasses all tautomeric forms of the compounds.

[0186] In examples of the present invention, the proton can occupy two or more positions in the cyclic form of the heterocyclic system, for example, 1H- and 3H-imidazolium, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, tetrazolium, and 1H- and 2H-pyrazole. The tautomer form can be in equilibrium or spatially fixed in one form through appropriate substitution. For example:

[0187]

[0188] Unless otherwise specified, use wedge-shaped solid line keys. and wedge-shaped dashed key The absolute configuration of the center of a solid is represented by a straight solid line key. and straight dashed key Represents the relative configuration of the center of a solid.

[0189] Unless otherwise specified, the term "solvent" means that the compound of the present invention or its salts include a stoichiometric or non-stoichiometric solvent bound by intermolecular noncovalent forces, and when the solvent is water, it is a hydrate.

[0190] The compounds of this invention may contain atomic isotopes in non-natural proportions on one or more atoms constituting the compound. For example, the compounds may be labeled 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 invention, regardless of radioactivity, are included within the scope of the present invention.

[0191] For the purposes of this invention, the term "effective amount" or "therapeutic effective amount" refers to a sufficient amount of a drug or agent that is non-toxic but achieves the desired effect, including one or more of the following: (1) prevention of disease: for example, prevention of disease, disorder, or condition in individuals who are susceptible to disease, disorder, or symptom but have not yet experienced or developed the pathology or symptoms of the disease; (2) inhibition of disease: for example, inhibition of disease, disorder, or symptom in individuals who are experiencing or developing the pathology or symptoms of the disease (i.e., preventing further development of the pathology and / or symptoms); (3) relief of disease: for example, relief of disease, disorder, or symptom in individuals who are experiencing or developing the pathology or symptoms of the disease (i.e., reversal of the pathology and / or symptoms). For oral dosage forms of this invention, the "effective amount" of one active substance in the composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, as well as on the specific active substance. The appropriate effective amount in a case can be determined by a person skilled in the art based on routine testing.

[0192] Unless otherwise specified, the terms “active ingredient,” “therapeutic agent,” “active substance,” or “active agent” refer to a chemical entity that can effectively treat a target disorder, disease, or condition.

[0193] Unless otherwise specified, the term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, including deuterium and hydrogen variants, provided that the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is a ketone group (i.e., =O), it means that two hydrogen atoms are replaced. Ketone substitution does not occur on aromatic groups.

[0194] Unless otherwise specified, the terms “optional” or “optionally” refer to events or conditions described below that may but are not required to occur, and the description includes both cases where said events or conditions occur and cases where said events or conditions do not occur.

[0195] Unless otherwise specified, the terms “optionally substituted,” “optionally substituted with…” or “optionally substituted with…” mean that something may or may not be substituted, and unless otherwise specified, the type and number of substituents may be arbitrary on the basis that is chemically feasible.

[0196] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Therefore, for example, if a group is substituted by 0-2 Rs, the group can optionally be substituted by at most two Rs, and R has independent options in each case. Furthermore, combinations of substituents and / or their variants are only permitted if such combinations produce stable compounds. Additionally, when polycyclic (fused, spirocyclic, or bridged) rings are substituted, it means that the hydrogen atoms on each ring can potentially be substituted.

[0197] Unless otherwise specified, the term "alkyl" refers to a saturated straight-chain or branched monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may optionally be substituted by one or more substituents described in this invention. In some embodiments, the alkyl group contains 1-20 carbon atoms (C... 1-20 In some embodiments, the alkyl group comprises 1 to 12 carbon atoms (C1 to C2). 1-12 In some embodiments, the alkyl group comprises 1 to 10 carbon atoms (C). 1-10 In some embodiments, the alkyl group comprises 1 to 6 carbon atoms (C6H ...7H6H6H6H6H6H6 1-6 In some embodiments, the alkyl group contains 1 to 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, tert-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, etc.

[0198] In this application, the term "C" is used either alone or as part of other substituents. α-β "Alkyl" refers to an alkyl group containing a minimum of α and a maximum of β carbon atoms in a branched, linear, or any combination of these three relationships, where α and β represent integers. It can also be represented by "C". α -C β The form "alkyl" is used. C0 alkyl indicates a straight bond.

[0199] Unless otherwise specified, the term "alkenyl" refers to a straight-chain or branched monovalent hydrocarbon group containing 2 to 12 carbon atoms, wherein there is at least one unsaturated site, i.e., one carbon-carbon sp. 2 The double bond, wherein the alkenyl group may optionally be substituted by one or more substituents described in this invention, including the orientation of "cis" and "tans", or the orientation of "E" and "Z". In some embodiments, the alkenyl group comprises 2-12 carbon atoms (C... 2-12 In some embodiments, the alkenyl group comprises 2-8 carbon atoms (C). 2-8 In some embodiments, the alkenyl group comprises 2-6 carbon atoms (C6H ...7H6H6H6H6H6H6H7H6H6H6H6H6H7 2-6 In some embodiments, the alkenyl group comprises 2-4 carbon atoms (C). 2-4 Examples of alkenyl groups include, but are not limited to, vinyl (-CH=CH2), allyl (-CH2CH=CH2), etc.

[0200] Unless otherwise specified, the term "alkynyl" refers to a straight-chain or branched monovalent hydrocarbon group containing 2-12 carbon atoms, wherein there is at least one unsaturated site, i.e., one carbon-carbon sp triple bond, wherein the alkynyl group may optionally be substituted by one or more substituents described in this invention. In some embodiments, the alkynyl group comprises 2-12 carbon atoms (C... 2-12 In some implementations, the alkynyl group contains 2-8 carbon atoms (C). 2-8 In some implementations, the alkynyl group contains 2-6 carbon atoms (C). 2-6 In some implementations, the alkynyl group contains 2-4 carbon atoms (C). 2-4Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propynyl (-CH2C≡CH), 1-propynyl (-C≡C-CH3), and so on.

[0201] Unless otherwise specified, the term "alkylene" refers to a saturated divalent hydrocarbon group obtained by removing two hydrogen atoms from a saturated straight-chain or branched hydrocarbon group, wherein the alkylene group may optionally be substituted by one or more substituents described in this invention. 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 (C6H ...7H6H6H6H6H6H6H7H6H6H6H6H6H7 1-6 In some embodiments, the alkylene group contains 1-4 carbon atoms (C4). 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-), etc.

[0202] Unless otherwise specified, the term "alkoxy" means an alkyl group attached to the remainder of the molecule by an oxygen atom, or is represented as alkyl-O-alkyl, wherein the oxygen atom may be attached to either a carbon atom of the straight chain of the alkyl group or to any carbon atom of the straight chain, wherein the alkyl group has the meaning as described herein. In some embodiments, the alkoxy group contains 1-12 carbon atoms (C... 1-12 In some implementations, the alkoxy group contains 1-6 carbon atoms (C). 1-6 In some implementations, the alkoxy group contains 1-4 carbon atoms (C). 1-4 In some implementations, the alkoxy group contains 1-3 carbon atoms (C). 1-3 The alkoxy group may optionally be replaced by one or more substituents described in this invention. 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-, etc.

[0203] Unless otherwise specified, the term "alkylamino" means that an alkyl group is attached to the remainder of the molecule by an amino group, wherein the alkyl group has the meaning as described in this invention. In some embodiments, the alkylamino contains 1-12 carbon atoms (C1-C2). 1-12 In some implementations, the alkylamino group contains 1-6 carbon atoms (C6H ...7H6H6H6H6H6H6H 1-6 In some implementations, the alkylamino group contains 1-4 carbon atoms (C4). 1-4 In some implementations, the alkylamino group contains 1-3 carbon atoms (C). 1-3 The alkylamino group may optionally be replaced by one or more substituents described in this invention. 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, etc.

[0204] Unless otherwise specified, the terms “haloalkyl”, “haloalkenyl” or “haloalkoxy” mean alkyl, alkenyl or alkoxy groups that are replaced by one or more halogen atoms, examples of which include, but are not limited to, trifluoromethyl, trifluoromethoxy, etc.

[0205] Unless otherwise specified, the term "cycloalkyl" refers to a monovalent or polyvalent saturated monocyclic, bicyclic, or tricyclic system containing 3-12 carbon atoms, wherein bicyclic or tricyclic systems include spirocyclic, fused, and bridged rings. In some embodiments, the cycloalkyl group comprises 3-12 carbon atoms (C... 3-12 In some embodiments, the cycloalkyl group contains 3-8 carbon atoms (C60-C82). 3-8 In some embodiments, the cycloalkyl group contains 3-6 carbon atoms (C64-C64). 3-6 The cycloalkyl group may be independently unsubstituted or substituted by one or more substituents described in this invention. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, [2.2.2]bicyclooctane, etc.

[0206] Unless otherwise specified, the term "cycloalkenyl" refers to a monovalent or polyvalent, non-aromatic, unsaturated monocyclic, bicyclic, or tricyclic system containing 3-12 carbon atoms, wherein the bicyclic or tricyclic system includes spirocyclic, fused, and bridged rings. In some embodiments, the cycloalkenyl group comprises 3-12 carbon atoms (C... 3-12 In some implementations, the cycloalkenyl group comprises 3-8 carbon atoms (C64-C82). 3-8 In some implementations, the cycloalkenyl group contains 3-6 carbon atoms (C64-C64). 3-6The cycloalkenyl group may be independently unsubstituted or substituted by one or more substituents described in this invention. Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, cyclooctenyl, cyclopentadienyl, etc.

[0207] Unless otherwise specified, the term "aryl" refers to a monocyclic, bicyclic, or tricyclic carbocyclic system containing 6-14, 6-12, or 6-10 ring atoms, wherein at least one ring system is aromatic, and each ring system comprises a ring of 3-7 atoms and has one or more bonding sites attached to the remainder of the molecule. In some embodiments, the aryl group comprises 6-14 carbon atoms (C... 6-14 In some embodiments, the aryl group comprises 6-12 carbon atoms (C6H ...7H6H6H6H6H6H 6-12 In some embodiments, the aryl group comprises 6-10 carbon atoms (C6H ...7H6H6H6H6H6H6H 6-10 The aryl group may be independently unsubstituted or substituted by one or more substituents described in this invention. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracene, etc.

[0208] Unless otherwise specified, Cn-n+m or Cn-Cn+m includes any specific case of n to n+m carbons, such as C 1-12 Including C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 C 11 and C 12 It also includes any range from n to n+m, such as C 1-12 Including 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 Similarly, n-membered to n+m-membered rings represent the number of atoms in the ring from n to n+m. For example, 3-12-membered rings include 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, and 12-membered rings, and also any range from n to n+m. For example, 3-12-membered rings include 3-6-membered, 3-9-membered, 5-6-membered, 5-7-membered, 6-7-membered, 6-8-membered, and 6-10-membered rings, etc.

[0209] Unless otherwise specified, the terms "heteroaryl," "heteroary ring," or "heteroarylcycloyl" are used interchangeably to refer to a monocyclic, bicyclic, or polycyclic cyclic system containing 5-12 ring atoms, at least one ring system being aromatic, preferably 5-10 ring atoms, 5-8 ring atoms, more preferably 5-6 ring atoms, wherein one, two, three, or more ring atoms are heteroatoms and the remaining atoms are carbon, the heteroatoms being independently selected from O, N, or S, and the number of heteroatoms is preferably one, two, or three. The "heteroaryl," "heteroary ring," or "heteroarylcycloyl" may optionally be substituted by one or more substituents described in this invention. Examples of "heteroaryl", "heteroary ring", and "heteroary cyclic group" 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-pyrroleyl, 2-pyrroleyl, 3-pyrroleyl, 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-thienyl, 3-thienyl, 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-Thiodiazolyl, 1,3,4-Thiodiazolyl, 1,2,5-Thiodiazolyl, pyrazinyl, 1,3,5-triazinyl; also including, but not limited to, the following bicyclic compounds: benzimidazolyl, benzofuranyl, benzothiopheneyl, indoleyl (e.g., 2-indoleyl), purinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), isoquinolinyl (e.g., 1- Isoquinolinyl, 3-isoquinolinyl or 4-isoquinolinyl), imidazo[1,2-a]pyridyl, pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridyl, etc.

[0210] Unless otherwise specified, the term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic, bicyclic, or polycyclic cyclic hydrocarbon substituent, which is a non-aromatic structure containing 3-20 ring atoms, wherein one, two, three, or more ring atoms are selected from N, O, or S, and the remaining ring atoms are C. The heterocyclic group is optionally substituted by one or more substituents described in this invention. Preferably, it contains 3-12 ring atoms (3-12-membered heterocyclic group), more preferably 3-10 ring atoms (3-10-membered heterocyclic group), or 3-8 ring atoms (3-8-membered heterocyclic group), or 3-6 ring atoms (3-6-membered heterocyclic group), or 4-6 ring atoms (4-6-membered heterocyclic group), or 5-6 ring atoms (5-6-membered heterocyclic group). The number of heteroatoms is preferably 1-4, more preferably 1-3 (i.e., 1, 2, or 3). Examples of monocyclic heterocyclic groups include, but are not limited to, pyrrolidinyl, imidazoalkyl, tetrahydrofuranyl, dihydropyrrolidinyl, piperidinyl, piperazinyl, pyranyl, etc. Bicyclic or polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups.

[0211] Unless otherwise specified, the term "heterocyclic alkyl" refers to a saturated "heterocyclic group" as defined above, comprising 3-20 ring atoms, wherein one, two, three or more ring atoms are selected from N, O or S, and the remaining ring atoms are C. The heterocyclic alkyl group may optionally be substituted by one or more substituents described in this invention. Preferably, it comprises 3-12 ring atoms (3-12-membered heterocyclic alkyl), more preferably 3-8 ring atoms (3-8-membered heterocyclic alkyl), or 5-10 ring atoms (5-10-membered heterocyclic alkyl), or 5-7 ring atoms (5-7-membered heterocyclic alkyl), or 4-6 ring atoms (4-6-membered heterocyclic alkyl), or 5-6 ring atoms (5-6-membered heterocyclic alkyl). The number of heteroatoms is preferably 1-4, more preferably 1-3 (i.e., 1, 2 or 3). Examples of heterocyclic alkyl groups include, but are not limited to, oxetyl, aziridine, oxetyl, thioheterobutyl, pyrrolidinyl, pyrazolyl, imidazoalkyl, tetrahydrothiopheneyl (including tetrahydrothiophene-2-yl and tetrahydrothiophene-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxyl, dithiaalkyl, isoxazolyl, isothiazolyl, 1,2-oxazinyl, 1,2-thiaazinyl, hexahydropyridazinyl, etc.

[0212] Unless otherwise specified, the term "heterocyclic alkenyl" refers to a partially unsaturated "heterocyclic group" as defined above, comprising 3-20 ring atoms, wherein one, two, three or more ring atoms are selected from N, O or S, and the remaining ring atoms are C. The heterocyclic alkenyl group may optionally be substituted by one or more substituents described in this invention. Preferably, it comprises 4-12 ring atoms (4-12-membered heterocyclic alkenyl), more preferably 5-10 ring atoms (5-10-membered heterocyclic alkenyl), or 5-8 ring atoms (5-8-membered heterocyclic alkenyl), 4-8 ring atoms (4-8-membered heterocyclic alkenyl), or 5-6 ring atoms (5-6-membered heterocyclic alkenyl), or 7 ring atoms (7-membered heterocyclic alkenyl). The number of heteroatoms is preferably 1-4, more preferably 1-3 (i.e., 1, 2 or 3).

[0213] Unless otherwise specified, the terms "halogen" or "halogen" refer to fluorine, chlorine, bromine, and iodine.

[0214] Unless otherwise specified, the term "monocyclic" means a group that can be saturated, unsaturated or partially saturated and has only one ring, which can be a carbocyclic (all ring atoms are carbon atoms) or a heterocyclic (in addition to carbon atoms, the ring atoms include, for example, 1, 2 or 3 heteroatoms, such as N, O or S).

[0215] Unless otherwise specified, the term "bicyclic" means a group having two connecting rings. A bicyclic ring can be a carbocyclic ring (all ring atoms are carbon atoms) or a heterocyclic ring (in addition to carbon atoms, the ring atoms include, for example, one, two, or three heteroatoms, such as N, O, or S). Both rings can be aliphatic (e.g., naphthane and norbornane), or aromatic (e.g., naphthalene), or a combination of aliphatic and aromatic (e.g., tetrahydronaphthalene). Bicyclic rings include (a) spirocyclic compounds in which the two rings share only one single atom (the spiro atom, which is usually a quaternary carbon). Examples of spirocyclic compounds include, but are not limited to:

[0216]

[0217] It also includes spirocyclic alkyl groups that share a spiro atom with a heterocyclic alkyl group, and non-limiting examples include:

[0218]

[0219] (b) Fused bicyclic compounds in which the two rings share two adjacent atoms. In other words, the rings share a single covalent bond, i.e., the bridgehead atoms are directly connected (e.g., α-thuenene and naphthane). Examples of fused bicyclic compounds include, but are not limited to:

[0220]

[0221] (c) Bridged bicyclic compounds, wherein the two rings share three or more atoms and are separated by a bridge containing at least one atom. For example, norbornane, also known as bicyclic [2.2.1]heptane, can be considered as a pair of cyclopentane rings, each ring sharing three of its five carbon atoms. Examples of bridged bicyclic compounds include, but are not limited to:

[0222]

[0223] Furthermore, it should be noted that, unless otherwise explicitly stated, the descriptive phrase "...independently" used in this invention should be interpreted broadly, meaning that the described individuals are independent of each other and can independently be the same or different specific groups. More specifically, the descriptive phrase "...independently" can mean either that the specific options expressed by the same symbols in different groups do not affect each other, or that the specific options expressed by the same symbols in the same group do not affect each other.

[0224] Unless otherwise specified, the term "patient" means any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, with human being being the most preferred.

[0225] Unless otherwise specified, the terms "comprising" or "including" are open-ended expressions, meaning they include the contents specified in this invention but do not exclude other aspects.

[0226] The term "treatment" and other similar synonyms used in this article include the following meanings:

[0227] (i) To prevent the occurrence of disease or condition in mammals, especially when such mammals are susceptible to the disease or condition but have not yet been diagnosed with it;

[0228] (ii) To suppress a disease or symptom, that is, to curb its development;

[0229] (iii) To alleviate the disease or symptom, that is, to cause the condition of the disease or symptom to subside; or,

[0230] (iv) To alleviate the symptoms caused by the disease or condition.

[0231] The abbreviations in this invention are defined 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 hydroxymethylaminomethane 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-methylumbelliferyl ketone phosphate; IFNγ represents gamma interferon; NBS represents N-bromosuccinimide; Me represents methyl; Et represents ethyl; Pd(dppf)Cl2 represents 1,1-bis(diphenylphosphine)ferrocene palladium chloride; Boc represents tert-butyloxycarbonyl; EtOAc represents ethyl acetate; MEM represents 2-methoxyethoxymethyl; DIEA represents N,N-di... Isopropylethylamine; DCM represents dichloromethane; Ph represents phenyl; HCl represents hydrochloric acid; Bn represents benzyl; LiAlH4 represents lithium aluminum hydride; Ms represents methanesulfonyl; 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 azidophosphate; t-BuOH represents tert-butanol; DMF represents N,N-dimethylformamide; DMA represents N,N-dimethylacetamide.

[0232] Beneficial effects

[0233] According to embodiments of the present invention, the present invention has at least one of the following technical effects:

[0234] This invention provides novel compounds, their tautomers, stereoisomers, or pharmaceutically acceptable salts, which exhibit excellent pharmacokinetic properties, good efficacy and drug-likeness, and can effectively treat PTPN1 and / or PTPN2-related diseases. The compounds of this invention have strong inhibitory effects on PTPN1 and / or PTPN2 and can significantly inhibit the proliferation of B16F10 cells. Detailed Implementation

[0235] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that the following description is merely the most preferred embodiment of the present invention and should not be considered as a limitation on the scope of protection of the present invention. Based on a full understanding of the present invention, experimental methods in the following embodiments that do not specify specific conditions are generally performed under conventional conditions or as recommended by the manufacturer. Those skilled in the art can make non-essential modifications to the technical solutions of the present invention, and such modifications should be considered to be included within the scope of protection of the present invention.

[0236] Example 1: Preparation of target compound 1

[0237] 5-(4-{2-[3-(difluoromethylene)azacyclobutane-1-yl]ethyl}-2-fluoro-6-hydroxyphenyl)-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione(1)

[0238]

[0239] The synthetic route for target compound 1 is shown below:

[0240]

[0241]

[0242] Step 1: Synthesis of 4-bromo-2-fluoro-6-methoxyaniline (1a)

[0243]

[0244] The starting material 2-fluoro-6-methoxyaniline (25.0 g, 177 mmol) was dissolved in N,N-dimethylformamide (250 mL), and N-bromosuccinimide (34.7 g, 195 mmol) was slowly added. The mixture was then stirred at 25 °C for 2 hours. After the reaction was complete, water (300 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (250 mL * 3), washed with saturated brine (250 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1, R... f =0.4), to give compound 4-bromo-2-fluoro-6-methoxyaniline (1a) (35.0 g, 90% yield).

[0245] Step 2: Synthesis of ethyl 2-[(4-bromo-2-fluoro-6-methoxyphenyl)amino] (1b)

[0246]

[0247] The starting material 4-bromo-2-fluoro-6-methoxyaniline (1a) (34.0 g, 154 mmol) and 50% (63.1 g, 309 mmol) ethyl glyoxylate toluene solution were dissolved in N,N-dimethylformamide (350 mL). The reaction system was purged with nitrogen three times. At 0 °C, trimethylchlorosilane (23.5 g, 216 mmol) dissolved in N,N-dimethylformamide (50 mL) was added to the reaction solution, and the mixture was stirred at 25 °C for 1 hour. Sodium cyanoborohydride (14.5 g, 231 mmol) was then added to the reaction solution at 0 °C, and the mixture was stirred at 25 °C for 1 hour. After the reaction was complete, water (300 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (250 mL * 3), washed with saturated brine (250 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1, R). f =0.35), to give compound 2-[(4-bromo-2-fluoro-6-methoxyphenyl)amino]ethyl acetate (1b) (35.0 g, yield 74%).

[0248] Step 3: Synthesis of ethyl acetate 2-[(4-bromo-2-fluoro-6-methoxyphenyl)(aminosulfonyl)amino] (1c)

[0249]

[0250] 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, aminosulfonyl chloride (24.9 g, 215 mmol) was slowly added to the reaction solution at 0 °C, and the mixture was stirred at 25 °C for 1 hour. After the reaction was completed, water (150 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (250 mL * 3). The mixture was washed with saturated brine (250 mL), and the combined organic phases were dried over anhydrous sodium sulfate and filtered. The mixture was concentrated under reduced pressure to give 12.0 g of compound 2-[(4-bromo-2-fluoro-6-methoxyphenyl)(aminosulfonyl)amino]acetate (1c), yield 87%.

[0251] Step 4: 5-(4-bromo-2-fluoro-6-methoxyphenyl)-1λ 6 Synthesis of 2,5-thiadiazolidine-1,1,3-trione (1d)

[0252]

[0253] Ethyl 2-[(4-bromo-2-fluoro-6-methoxyphenyl)(aminosulfonyl)amino]ethyl acetate (1c) (8.00 g, 20.7 mmol) was dissolved in anhydrous methanol (80.0 mL). A 30% sodium methoxide methanol solution (22.4 g, 124 mmol) was slowly added at 0 °C, followed by stirring at 0 °C for 0.5 hours. After the reaction was complete, the solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by HPLC to give compound 5-(4-bromo-2-fluoro-6-methoxyphenyl)-1λ. 6 2,5-Thiadiazolidine-1,1,3-trione (1d) (6.00g, yield 85%).

[0254] 1 H NMR (DMSO-d6) δ7.16 (dd, J = 9.3, 1.9 Hz, 1H), 7.11 (s, 1H), 3.91 (s, 2H), 3.80 (s, 3H).

[0255] LC-MS, M / Z (ESI): 338.9 [MH] - .

[0256] Step 5: 5-(4-bromo-2-fluoro-6-hydroxyphenyl)-1λ 6 Synthesis of 2,5-thiadiazolidine-1,1,3-trione (1e)

[0257]

[0258] 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 with stirring 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).

[0259] Step 6: 5-{4-[(1E)-2-ethoxyvinyl]-2-fluoro-6-hydroxyphenyl}-1λ 6 Synthesis of 2,5-thiadiazolidine-1,1,3-trione (1f)

[0260]

[0261] 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%).

[0262] Step 7: 2-[3-fluoro-5-hydroxy-4-(1,1,4-trioxo-1λ] 6 Synthesis of 2,5-thiadiazolidine-2-yl)phenyl]acetaldehyde (1 g)

[0263]

[0264] The raw material 5-{4-[(1E)-2-ethoxyvinyl]-2-fluoro-6-hydroxyphenyl}-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (1f) (250 mg, 790 μmol) was dissolved in formic acid (4.00 mL) and water (0.10 mL), and then stirred at 25 °C for 1 hour. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure to give compound 2-[3-fluoro-5-hydroxy-4-(1,1,4-trioxo-1λ] 6 [2,5-Thiadiazolidine-2-yl)phenyl]acetaldehyde (1g) (320mg, crude product).

[0265] Step 8: Synthesis of 3-(difluoromethylene)azacyclobutane-1-carboxylic acid tert-butyl ester (1 h)

[0266]

[0267] The starting material, tert-butyl 3-oxoazacyclobutane-1-carboxylic acid (5.00 g, 29.2 mmol), was dissolved in N,N-dimethylformamide (50.0 mL). The reaction system was purged with nitrogen three times. Then, under nitrogen protection, triphenylphosphine (11.5 mL, 43.8 mmol) and sodium difluorochloroacetate (5.34 g, 35.1 mmol) were slowly added to the reaction solution, and the mixture was slowly heated to 105 °C and stirred for 1 hour. After the reaction was complete, water (50 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL * 3). The mixture was washed with saturated brine (50 mL), and the combined organic phases were dried over anhydrous sodium sulfate and filtered. The crude product was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain compound 3-(difluoromethylene)azacyclobutane-1-carboxylic acid tert-butyl ester (1 h) (1.20 g, yield 20%).

[0268] Step 9: Synthesis of 3-(difluoromethylene)azacyclobutane hydrochloride (1i)

[0269]

[0270] 500 mg (2.44 mmol) of 3-(difluoromethylene)azacyclobutane-1-carboxylic acid tert-butyl ester (1h) was dissolved in 5.00 mL of 2M ethyl acetate hydrochloride solution, and then stirred at 25 °C for 8 hours. After the reaction was completed, the mixture was directly concentrated under reduced pressure to obtain compound 3-(difluoromethylene)azacyclobutane hydrochloride (1i) (360 mg, crude product).

[0271] 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)

[0272]

[0273] 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).

[0274] 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).

[0275] LC-MS, M / Z (ESI): 378.1 [M+H] + .

[0276] Example 2: Preparation of target compound 2

[0277] (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)

[0278]

[0279] The synthetic route for target compound 2 is shown below:

[0280]

[0281] Step 1: Synthesis of 5-(4-(2-ethoxyvinyl)-2-fluoro-6-methoxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (2a)

[0282]

[0283] 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-boronate linalool ester (2.34 g, 11.8 mmol), sodium carbonate (1.88 g, 17.7 mmol) and 1,1-bis(diphenylphosphine)ferrocene palladium chloride (432 mL) were added. The reaction was carried out at 95 °C for 10 hours with stirring (590 μmol g). After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (ethyl acetate:methanol (V / V) = 1:0-10:1) to give compound 5-(4-(2-ethoxyvinyl)-2-fluoro-6-methoxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (2a) (1.60 g, yield 82%).

[0284] Step 2: Synthesis of 2-(4-(1,1-dioxo-4-oxo-1,2,5-thiadiazolidine-2-yl)-3-fluoro-5-methoxyphenyl)acetaldehyde (2b)

[0285]

[0286] 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 complete, the reaction solution was concentrated under reduced pressure to give compound 2-(4-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidine-2-yl)-3-fluoro-5-methoxyphenyl)acetaldehyde (2b) (550 mg, crude product), which was used directly in the next step.

[0287] Step 3: Synthesis of (Z)-5-(2-fluoro-6-methoxy-4-(2-(3-(2,2,2-trifluoroethylene)pyrrolidine-1-yl)ethyl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (2c)

[0288]

[0289] (Z)-3-(2,2,2-trifluoroethylene)pyrrolidine hydrochloride (2e-01) (310 mg, 1.65 mmol) was dissolved in dichloromethane (10 mL) and methanol (1 mL), and then sodium acetate (136 mg, 1.65 mmol) was added. The reaction was stirred at 25 °C for 15 minutes, then 2-(4-(1,1-dioxo-4-oxo-1,2,5-thiadiazolidine-2-yl)-3-fluoro-5-methoxyphenyl)acetaldehyde (2b) (250 mg, 827 μmol) was added, and the reaction was stirred at 25 °C for 15 minutes. Finally, sodium cyanoborohydride (78.0 mg, 1.24 mmol) was added, and the reaction was stirred at 25 °C for 2 hours. After the reaction was completed, the reaction solution was quenched with water (3.00 mL), then concentrated under reduced pressure. The crude product was purified by HPLC using the following method (column: Welch Ultimate XB-SiOH 150*40mm*10um; solvent: A = n-hexane, B = ethanol; gradient: 15%-45%, 12 min), yielding compound (Z)-5-(2-fluoro-6-methoxy-4-(2-(3-(2,2,2-trifluoroethylene)pyrrolidine-1-yl)ethyl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (2c) (80.0 mg, yield 22%).

[0290] Step 4: Synthesis of (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)

[0291]

[0292] (Z)-5-(2-fluoro-6-methoxy-4-(2-(3-(2,2,2-trifluoroethylene)pyrrolidine-1-yl)ethyl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (2c) (70.0 mg, 160 μmol) was dissolved in dichloromethane (5 mL), and then boron tribromide (2.00 M, 500 μL) was added dropwise at -70 °C under nitrogen protection. The reaction was stirred at 25 °C for 3 hours. After the reaction was completed, the reaction solution was quenched with methanol (10 mL) at -70 °C, and then the pH was adjusted to 7-8 with ammonia. The reaction solution was concentrated under reduced pressure, and the crude product was purified by HPLC. The separation method was (column: Waters xbridge 150*25mm 10um; solvent: A=water, B=acetonitrile; gradient: 17%-47%, 15 min). The product was then dried to obtain compound (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).

[0293] 1 H NMR (400MHz, MeOD) δ6.61-6.74(m,2H),5.96(br d,J=8.40Hz,1H),4.25(s,4H),3.48(br s,2H),3.38-3.44(m,2H),2.85-3.04(m,4H).

[0294] LC-MS, M / Z (ESI): 424.0 [M+H] + .

[0295] Step 5: Synthesis of (Z)-3-(2,2,2-trifluoroethylene)pyrrolidine-1-carboxylic acid tert-butyl ester (2d-01) and (E)-3-(2,2,2-trifluoroethylene)pyrrolidine-1-carboxylic acid tert-butyl ester (2d-02)

[0296]

[0297] Under nitrogen protection, tert-butyl 3-methylenepyrrolidine-1-carboxylate (2.00 g, 10.9 mmol) was dissolved in 1,4-dioxane (20 mL), followed by the addition of 1-trifluoromethyl-1,2-benzyl-3(H)-one (6.90 g, 21.8 mmol) and tetrabutylammonium iodide (2.02 g, 5.46 mmol). The reaction was stirred at 80 °C for 10 hours. After the reaction was complete, 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 chromatography (petroleum ether: ethyl acetate (V / V) = 50:1-10:1) to give compound (Z)-3-(2,2,2-trifluoroethylene)pyrrolidine-1-carboxylic acid tert-butyl ester (2d-01) (1.00 g, yield 37%) and compound (E)-3-(2,2,2-trifluoroethylene)pyrrolidine-1-carboxylic acid tert-butyl ester (2d-02) (1.00 g, yield 37%).

[0298] 2d-01: 1 H NMR(DMSO-d6)δ5.92-5.97(m,1H),4.06(s,2H),3.36-3.40(m,2H),2.74(m,2H),1.41(s,9H).

[0299] 2d-02: 1 H NMR(DMSO-d6)δ5.96-5.99(m,1H),4.04(s,2H),3.43-3.47(m,2H),2.77(m,2H),1.41(s,9H).

[0300] Step 6: Synthesis of (Z)-3-(2,2,2-trifluoroethylene)pyrrolidine hydrochloride (2e-01)

[0301]

[0302] (Z)-3-(2,2,2-trifluoroethylene)pyrrolidine-1-carboxylic acid tert-butyl ester (2d-01) (400 mg, 1.59 mmol) was dissolved in dioxane hydrochloride (5 mL), and the reaction was stirred at 25 °C for 10 hours. After the reaction was completed, the reaction solution was concentrated to obtain compound (Z)-3-(2,2,2-trifluoroethylene)pyrrolidine hydrochloride (2e-01) (300 mg, crude product), which was directly used in the next step.

[0303] Example 3: Preparation of target compound 3

[0304] (E)-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 (3)

[0305]

[0306] The synthetic route for target compound 3 is shown below:

[0307]

[0308] Step 1: Synthesis of (E)-3-(2,2,2-trifluoroethylene)pyrrolidine hydrochloride (2e-02)

[0309]

[0310] (E)-3-(2,2,2-trifluoroethylene)pyrrolidine-1-carboxylic acid tert-butyl ester (2d-02) (500 mg, 1.99 mmol) was dissolved in dioxane hydrochloride (10.0 mL), and the reaction was stirred at 25 °C for 10 hours. After the reaction was complete, the reaction solution was concentrated to obtain compound (E)-3-(2,2,2-trifluoroethylene)pyrrolidine hydrochloride (2e-02) (350 mg, crude product), which was directly used in the next step.

[0311] Step 2: Synthesis of (E)-5-(2-fluoro-6-methoxy-4-(2-(3-(2,2,2-trifluoroethylene)pyrrolidine-1-yl)ethyl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (3a)

[0312]

[0313] (E)-3-(2,2,2-trifluoroethylene)pyrrolidine hydrochloride (2e-02) (310 mg, 1.65 mmol) was dissolved in dichloromethane (10.0 mL) and methanol (1 mL), and then sodium acetate (136 mg, 1.65 mmol) was added. The reaction was stirred at 25 °C for 15 minutes, then 2-(4-(1,1-dioxo-4-oxo-1,2,5-thiadiazolidine-2-yl)-3-fluoro-5-methoxyphenyl)acetaldehyde (2b) (250 mg, 827 μmol) was added, and the reaction was stirred at 25 °C for 15 minutes. Finally, sodium cyanoborohydride (78.0 mg, 1.24 mmol) was added, and the reaction was stirred at 25 °C for 2 hours. After the reaction was completed, the reaction solution was quenched with water (3 mL), then concentrated under reduced pressure. The crude product was purified by HPLC using the following method (column: Welch Ultimate XB-SiOH 150*40mm*10um; solvent: A = n-hexane, B = ethanol; gradient: 15%-45%, 12 min), yielding compound (E)-5-(2-fluoro-6-methoxy-4-(2-(3-(2,2,2-trifluoroethylene)pyrrolidine-1-yl)ethyl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (3a) (80.0 mg, yield 22%).

[0314] Step 3: Synthesis of (E)-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 (3b)

[0315]

[0316] (E)-5-(2-fluoro-6-methoxy-4-(2-(3-(2,2,2-trifluoroethylene)pyrrolidine-1-yl)ethyl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (3b) (70.0 mg, 160 μmol) was dissolved in dichloromethane (5 mL), and then boron tribromide (2.00 M, 500 μL) was added dropwise at -70 °C under nitrogen protection. The reaction was stirred at 25 °C for 3 hours. After the reaction was completed, the reaction solution was quenched with methanol (10 mL) at -70 °C, and then the pH was adjusted to 7-8 with ammonia. The reaction solution was concentrated, and the crude product was purified by HPLC. The separation method was (column: Waters xbridge 150*25mm 10um; solvent: A=water, B=acetonitrile; gradient: 17%-47%, 15 min). The product was then dried to obtain compound (E)-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 (3).

[0317] 1 H NMR(400MHz,MeOD)δ6.60-6.78(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).

[0318] LC-MS, M / Z (ESI): 424.0 [M+H] + .

[0319] Example 4: Preparation of target compound 4

[0320] 5-(4-(2-(3-(difluoromethylene)pyrrolidine-1-yl)ethyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (4)

[0321]

[0322] The synthetic route for target compound 4 is shown below:

[0323]

[0324] Step 1: Synthesis of tert-butyl 3-(difluoromethylene)pyrrolidine-1-carboxylate (4a)

[0325]

[0326] 3-O-pyrrolidine-1-carboxylic acid tert-butyl ester (5.00 g, 26.9 mmol) and 2-(difluoromethanesulfonyl)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) under a nitrogen atmosphere at -40 °C. The reaction mixture was stirred at -40 °C for 1 hour under a nitrogen atmosphere. After the reaction was complete, the reaction mixture was added to an aqueous solution (100 mL) and extracted with ethyl acetate (50 mL * 3). The organic layer was dried over anhydrous sodium sulfate and filtered. The filter cake was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was then subjected to column chromatography (mobile phase: petroleum ether / ethyl acetate = 5:1, R...). f The product tert-butyl 3-(difluoromethylene)pyrrolidine-1-carboxylate (4a) was obtained (2.70 g, yield 68%).

[0327] Step 2: Synthesis of 3-(difluoromethylene)pyrrolidine hydrochloride (4b)

[0328]

[0329] 3-(difluoromethylene)pyrrolidine-1-carboxylic acid tert-butyl ester (4a) (2.70 g, 12.3 mmol) was dissolved in hydrochloric acid / ethyl acetate (2 M, 50 mL), and the reaction was stirred at 25 °C for 12 hours. After the reaction was complete, the reaction solution was evaporated to dryness to give the product 3-(difluoromethylene)pyrrolidine hydrochloride (4b) (1.90 g, 99% yield).

[0330] 1 H NMR (400MHz, CDCl3) δ10.10 (br s, 2H), 3.99 (br s, 2H), 3.49 (br t, 2H, J = 6.1Hz), 2.76 (br s, 2H).

[0331] Step 3: Synthesis of 5-(4-(2-(3-(difluoromethylene)pyrrolidone-1-yl)ethyl)-2-fluoro-6-methoxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (4c)

[0332]

[0333] 3-(difluoromethylene)pyrrolidine hydrochloride (4b) (267 mg, 1.72 mmol) was dissolved in dichloromethane (5 mL) and methanol (0.5 mL), followed by the addition of sodium acetate (141 mg, 1.72 mmol). The reaction mixture was stirred at 25 °C for 0.5 h. Then, 2-(4-(1,1-dioxo-4-oxo-1,2,5-thiadiazolidine-2-yl)-3-fluoro-5-methoxyphenyl)acetaldehyde (8) (260 mg, 860 μmol) was added, and the reaction mixture was stirred at 25 °C for 0.5 h. Sodium cyanoborohydride (108 mg, 1.72 mmol) was then added, and the reaction mixture was stirred at 25 °C for 1 h. After the reaction was complete, 10 mL of aqueous solution was added to the reaction mixture, and the mixture was concentrated under reduced pressure to obtain the crude product. The product 5-(4-(2-(3-(difluoromethylene)pyrrolidine-1-yl)ethyl)-2-fluoro-6-methoxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (4c) (90.0 mg, yield 26%) was prepared and purified by HPLC (column: Welch Ultimate XB-SiOH 250*50mm*10um; mobile phase: n-hexane-ethanol; gradient: 10%-50%, 15.0 min).

[0334] Step 4: Synthesis of 5-(4-(2-(3-(difluoromethylene)pyrrolidine-1-yl)ethyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (4)

[0335]

[0336] 5-(4-(2-(3-(difluoromethylene)pyrrolidine-1-yl)ethyl)-2-fluoro-6-methoxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (4c) (90.0 mg, 222 μmol) was dissolved in dichloromethane (9 mL), and boron tribromide (2 M, 610 μL) was added under a nitrogen atmosphere at -75°C. The reaction was stirred at 25°C for 5 hours. After the reaction was complete, the reaction solution was quenched at 0 degrees by adding sodium bicarbonate (10 mL). The organic phase was dried and concentrated under reduced pressure to obtain the crude product, which was purified by HPLC (column: Waters xbridge 150*25mm*10um; mobile phase: solvent A = water + 10mM ammonium bicarbonate, B = acetonitrile; gradient: 9%-39%, 10.0 min) to obtain 5-(4-(2-(3-(difluoromethylene)pyrrolidine-1-yl)ethyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (4).

[0337] 1H NMR (400MHz, MeOD) δ6.58-6.74(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).

[0338] LC-MS, M / Z (ESI): 390.1 [MH] - .

[0339] Example 5: Preparation of target compound 5

[0340] 5-(2-fluoro-6-hydroxy-4-{2-[3-(prop-2-methylene)pyrrolidone-1-yl]ethyl}phenyl)-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione(5)

[0341]

[0342] The synthetic route for target compound 5 is shown below:

[0343]

[0344] Step 1: Synthesis of 5-(4-bromo-2-fluoro-6-((2-methoxyethoxy)methoxy)phenyl)-2-((2-methoxyethoxy)methyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (5a)

[0345]

[0346] At 0 °C, 5-(4-bromo-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (1e) (5.50 g, 16.9 mmol) was dissolved in dichloromethane (50 mL), and then N,N-diisopropylethylamine (6.56 g, 50.8 mmol) and 2-methoxyethoxymethyl chloride (6.32 g, 50.8 mmol) were added. The reaction was stirred at 20 °C for 10 hours. After the reaction was completed, the reaction solution was diluted with water (50 mL), then extracted with ethyl acetate (50 mL * 3), the organic phases were combined, dried over sodium sulfate and filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 10:1-3:1) to give compound 5-(4-bromo-2-fluoro-6-((2-methoxyethoxy)methoxy)phenyl)-2-((2-methoxyethoxy)methyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (5a) (5.30 g, yield 63%).

[0347] LC-MS, M / Z (ESI): 518.0 [M+H2O] + .

[0348] Step 2: Synthesis of 2-[3-fluoro-5-(2-methoxyethoxymethoxy)-4-[5-(2-methoxyethoxymethyl)-1,1,4-trioxo-1,2,5-thiadiazolidine-2-yl]phenyl]acetaldehyde (5b)

[0349]

[0350] Under nitrogen protection, the starting materials bis(tert-tert-butylphosphine)palladium (168 mg, 329 μmol) and anhydrous zinc fluoride (340 mg, 3.29 mmol) were dissolved in dioxane (2 mL). The reaction system was purged with nitrogen three times and stirred at 25 °C for 10 minutes. Then, 5-(4-bromo-2-fluoro-6-((2-methoxyethoxy)methoxy)phenyl)-2-((2-methoxyethoxy)methyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (5a) (330 mg, 658 μmol) was dissolved in dioxane (2 mL) and added to the reaction solution. Finally, ethyleneoxytrimethylsilane (1.53 g, 13.2 mmol) was added to the reaction solution and stirred at 75 °C for 0.5 hours. After the reaction was complete, the mixture was filtered, then diluted with petroleum ether (10 mL), and concentrated to remove the petroleum ether to obtain compound 2-[3-fluoro-5-(2-methoxyethoxymethoxy)-4-[5-(2-methoxyethoxymethyl)-1,1,4-trioxo-1,2,5-thiadiazolidine-2-yl]phenyl]acetaldehyde (5b) (300 mg, crude product). This crude product was used directly in the next step.

[0351] Step 3: 5-{2-fluoro-6-[(2-methoxyethoxy)methoxy]-4-{2-[3-(propyl-2-methylene)pyrrolidin-1-yl]ethyl}phenyl}-2-[(2-methoxyethoxy)methyl]-1λ 6 Synthesis of 2,5-thiadiazolidine-1,1,3-trione (5c)

[0352]

[0353] The starting materials 3-(propane-2-methylene)pyrrolidine hydrochloride (5 g) (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 hours. Then, 2-[3-fluoro-5-(2-methoxyethoxymethoxy)-4-[5-(2-methoxyethoxymethyl)-1,1,4-trioxo-1,2,5-thiadiazolidine-2-yl]phenyl]acetaldehyde (5b) (300 mg, 646 μmol) was added to the reaction solution and stirred at 25 °C for 0.5 hours. Then, sodium cyanoborohydride (81.2 mg, 1.29 mmol) was added to the reaction solution and stirred at 25 °C for 1 hour. After the reaction was complete, sodium bicarbonate solution (10 mL) was added to quench the reaction, followed by extraction with dichloromethane (10 mL * 3), washing with saturated brine (10 mL), drying the combined organic phases with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain the crude product. The crude product was purified by HPLC using the following method (column: Welch Ultimate XB-CN 250 * 50 mm * 10 μm; mobile phase: [Hexane-EtOH]; gradient: 5% - 45% B over 15.0 min), yielding compound 5-{2-fluoro-6-[(2-methoxyethoxy)methoxy]-4-{2-[3-(propyl-2-methylene)pyrrolidine-1-yl]ethyl}phenyl}-2-[(2-methoxyethoxy)methyl]-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (5c) (40.0 mg, yield 11%).

[0354] Step 4: 5-(2-fluoro-6-hydroxy-4-{2-[3-(prop-2-methylene)pyrrolidone-1-yl]ethyl}phenyl)-1λ 6 Synthesis of 2,5-thiadiazolidine-1,1,3-trione (5)

[0355]

[0356] The raw material 5-{2-fluoro-6-[(2-methoxyethoxy)methoxy]-4-{2-[3-(prop-2-methylene)pyrrolid-1-yl]ethyl}phenyl}-2-[(2-methoxyethoxy)methyl]-1λ 62,5-Thiadiazolidine-1,1,3-trione (5c) (40.0 mg, 71.5 μmol) was dissolved in dichloromethane (2.00 mL). The reaction system was then purged with nitrogen three times. 2M boron tribromide (98.5 mg, 393 μmol) was then slowly added to the reaction solution at -70 °C, and the mixture was stirred at -40 °C for 0.5 hours. After the reaction was complete, 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 using the following method: (column: Waters xbridge 150*25mm 10µm; mobile phase: [H2O(10mM NH4HCO3)-ACN]; gradient: 10%-40% B over 10.0 min), yielding compound 5-(2-fluoro-6-hydroxy-4-{2-[3-(prop-2-methylene)pyrrolidone-1-yl]ethyl}phenyl)-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (5).

[0357] 1 H NMR(MeOD)δ9.77(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).

[0358] LC-MS, M / Z (ESI): 384.1 [M+H] + .

[0359] Step 5: Synthesis of 2-(propyl-2-ylthioalkyl)pyridine (5d)

[0360]

[0361] The starting material, 2-chloropyridine (4.00 g, 35.2 mmol), was dissolved in N,N-dimethylformamide (40 mL), and sodium isopropyl mercaptan (34.7 g, 195 mmol) was slowly added. The mixture was then stirred at 140 °C for 6 hours. After the reaction was complete, water (50 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL x 3). The extract was washed with saturated brine (50 mL), and the combined organic phases were dried over anhydrous sodium sulfate and filtered. The mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to give compound 2-(propyl-2-ylthioalkyl)pyridine (5 d) (4.40 g, yield 82%).

[0362] Step 6: Synthesis of 2-(propane-2-sulfonyl)pyridine (5e)

[0363]

[0364] The starting materials 2-(propyl-2-ylthioalkyl)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 purged with nitrogen three times. At 0 °C, 30% hydrogen peroxide (17.6 g, 155 mmol) was slowly added dropwise to the reaction solution, and then stirred at 25 °C for 1 hour. After the reaction was completed, sodium sulfite solution (50 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (40 mL * 3). The mixture was washed with saturated brine (50 mL), and the combined organic phases were dried over anhydrous sodium sulfate and filtered. The crude product was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1, R... f =0.25), to give compound 2-(propane-2-sulfonyl)pyridine (5e) (3.50 g, yield 85%).

[0365] Step 7: Synthesis of tert-butyl 3-(propane-2-methylene)pyrrolidine-1-carboxylate (5f)

[0366]

[0367] Potassium tert-butoxide (3.18 g, 28.3 mmol) was dissolved in N,N-dimethylformamide (50.0 mL). Then, 2-(propane-2-sulfonyl)pyridine (5e) (3.50 g, 18.9 mmol) and tert-butyl 3-oxopyrrolidine-1-carboxylic acid (2c) (2.92 g, 15.7 mmol) were dissolved in N,N-dimethylformamide (20 mL) at -40 °C and slowly added to the reaction solution. The mixture was stirred at 25 °C for 1 hour. After the reaction was complete, water (50 mL) was added to quench the reaction, followed by extraction with ethyl acetate (50 mL x 3), washing with saturated brine (50 mL), drying the combined organic phases with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1, R... f =0.55), to give compound tert-butyl 3-(prop-2-methylene)pyrrolidine-1-carboxylate (5f) (420 mg, yield 13%).

[0368] Step 8: Synthesis of 3-(propane-2-methylene)pyrrolidine hydrochloride (5g)

[0369]

[0370] The starting material, tert-butyl 3-(propan-2-methylene)pyrrolidine-1-carboxylate (5f) (400 mg, 1.89 mmol), was dissolved in 2M ethyl acetate hydrochloride solution (5 mL), and then stirred at 25 °C for 8 hours. After the reaction was completed, the mixture was directly concentrated under reduced pressure to obtain compound 3-(propan-2-methylene)pyrrolidine hydrochloride (5 g) (275 mg, crude product).

[0371] Example 6: Preparation of target compound 6

[0372] Synthesis of 5-(2-fluoro-4-(2-(3-(fluoromethylene)pyrrolidone-1-yl)ethyl)-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (6)

[0373]

[0374] The synthetic route for target compound 6 is shown below:

[0375]

[0376] Step 1: Synthesis of tert-butyl 3-(fluoromethylene)pyrrolidine-1-carboxylate (6a)

[0377]

[0378] 2-((fluoromethyl)sulfonyl)pyridine (2.87 g, 16.3 mmol) was dissolved in tetrahydrofuran (30 mL), and then 19.4 mL of 1 M potassium di(trimethylsilyl)aminotetrahydrofuran solution was added under a nitrogen atmosphere at -78 °C. The reaction was stirred at -78 °C for 0.5 h under a nitrogen atmosphere. Then, 3-oxopyrrolidine-1-carboxylic acid tert-butyl ester (3.00 g, 16.2 mmol) dissolved in tetrahydrofuran (10 mL) was added, and the reaction was stirred at -78 °C for 3 h under nitrogen protection, and then slowly heated to 25 °C and stirred for 1 h. After the reaction was complete, the reaction mixture was extracted with ammonium chloride aqueous solution (100 mL) and ethyl acetate (50 mL * 3). The organic layer was dried over anhydrous sodium sulfate and filtered. The filter cake was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was then subjected to column chromatography (mobile phase: petroleum ether / ethyl acetate = 5:1, R...). f The product tert-butyl 3-(fluoromethylene)pyrrolidine-1-carboxylate (6a) was obtained (900 mg, yield 28%).

[0379] Step 2: Synthesis of 3-(fluoromethylene)pyrrolidine (6b)

[0380]

[0381] 3-(fluoromethylene)pyrrolidine-1-carboxylic acid tert-butyl ester (6a) (900 mg, 4.47 mmol) was dissolved in hydrochloric acid / dioxane (2 M, 9 mL), and the reaction was stirred at 25 °C for 12 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to give product 3-(fluoromethylene)pyrrolidine 6b (500 mg, 4.94 mmol).

[0382] 1 H NMR (400MHz, CDCl3) δ10.06 (br s, 2H), 6.54-6.75 (m, 1H), 4.07 (br s, 2H), 3.46 (t, J = 6.5Hz 2H), 2.70 (br t, J = 6.5Hz, 2H)

[0383] Step 3: Synthesis of 5-(2-fluoro-4-(2-(3-(fluoromethylene)pyrrolidone-1-yl)ethyl)-6-((2-methoxyethoxy)methoxy)phenyl)-2-((2-methoxyethoxy)methyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (6c)

[0384]

[0385] 2-(3-fluoro-5-((2-methoxyethoxy)methoxy)-4-(5-((2-methoxyethoxy)methyl)-1,1-dioxo-4-oxo-1,2,5-thiadiazolidine-2-yl)phenyl)acetaldehyde (5b) (250 mg, 538 μmol) and 3-(fluoromethylene)pyrrolidine (6b) (272 mg, 2.69 mmol) were dissolved in dioxane (5 mL), followed by the addition of potassium acetate (264 mg, 2.69 mmol), and the reaction mixture was stirred at 25 °C for 1 hour. Then, sodium cyanoborohydride (50.7 mg, 807 μmol) was added, and the reaction mixture was stirred at 25 °C for 1 hour. After the reaction was complete, 10 mL of aqueous solution was added to the reaction mixture, and the mixture was concentrated under reduced pressure to obtain the crude product. The product 5-(2-fluoro-4-(2-(3-(fluoromethylene)pyrrolidone-1-yl)ethyl)-6-((2-methoxyethoxy)methoxy)phenyl)-2-((2-methoxyethoxy)methyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (6c) (30.0 mg, yield 10%) was prepared and purified by HPLC (column: Waters xbridge 150*25mm*10um; mobile phase: solvent A = water + 10mM ammonium bicarbonate, B = acetonitrile; gradient: 35%-65%, 10.0 min).

[0386] LC-MS, M / Z (ESI): 550.2 [M+H] + .

[0387] Step 4: Synthesis of 5-(2-fluoro-4-(2-(3-(fluoromethylene)pyrrolidone-1-yl)ethyl)-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (6)

[0388]

[0389] 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).

[0390] 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)

[0391] LC-MS, M / Z (ESI): 374.0 [M+H] + .

[0392] Example 7: Preparation of target compound 7

[0393] 5-(4-(2-(4-(difluoromethylene)piperidin-1-yl)ethyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (7)

[0394]

[0395] The synthetic route for target compound 7 is shown in the figure below:

[0396]

[0397] Step 1: Synthesis of (E)-N-(2-benzyloxy-4-(2-ethoxyvinyl)-6-fluorophenyl)-N-(N-(benzyloxycarbonyl)aminosulfonyl)glycine methyl ester (7b)

[0398]

[0399] Under nitrogen protection and at 0°C, benzyl alcohol (432 mg, 4 mmol) was added to 10 mL of anhydrous dichloromethane containing chlorosulfonyl isocyanate (567 mg, 4.0 mmol), and the reaction was carried out at 0°C for 30 minutes. An anhydrous dichloromethane solution of (E)-(2-benzyloxy)-4-(2-ethoxyvinyl)-6-fluorophenyl)glycine methyl ester (7a) (method synthesis reference WO2021127499 A1) (720 mg, 2 mmol) was added dropwise to the reaction mixture, and the reaction temperature was then 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 obtain the crude product. The crude product was then purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 5:1) to give (E)-N-(2-benzyloxy-4-(2-ethoxyvinyl)-6-fluorophenyl)-N-(N-(benzyloxycarbonyl)aminosulfonyl)glycine methyl ester (7b) (900 mg, yield: 79%).

[0400] LC-MS, M / Z (ESI): 573.16 [M+H] +

[0401] Step 2: Synthesis of N-(2-benzyloxy-6-fluoro-4-(2-oxoethyl)phenyl)-N-(N-(benzyloxy)carbonyl)aminosulfonyl)glycine methyl ester (7c)

[0402]

[0403] Under nitrogen protection and at 0°C, a solution of 1,4-dioxane hydrochloric acid (4M, 0.5mL) was added dropwise to an anhydrous dichloromethane (5mL) solution of (E)-N-(2-benzyloxy-4-(2-ethoxyvinyl)-6-fluorophenyl)-N-(N-(benzyloxycarbonyl)aminosulfonyl)glycine methyl ester (7b) (600mg, 1.05mmol). The reaction was carried out at 0°C for 2 hours. The reaction was confirmed to be complete by LCMS. The reaction solution was concentrated under reduced pressure to obtain crude N-(2-benzyloxy-6-fluoro-4-(2-oxoethyl)phenyl)-N-(N-(benzyloxy)carbonyl)aminosulfonyl)glycine methyl ester (7c), which was then directly used for the next reaction.

[0404] Step 3: Synthesis of N-(4-(2-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)ethyl)-2-benzyloxy-6-fluorophenyl)-N-(N-((benzyloxy)carbonyl)aminosulfonyl)glycine methyl ester (7d)

[0405]

[0406] Under nitrogen protection and at 0°C, crude N-(2-benzyloxy-6-fluoro-4-(2-oxoethyl)phenyl)-N-(N-(benzyloxy)carbonyl)aminosulfonyl)glycine methyl ester (7c) (570 mg, 1.0 mmol) in anhydrous dichloromethane (5 mL) was reacted with 4-piperidine ketal ethylene glycol (270 mg, 2.0 mmol) and triethylamine (0.42 mL, 3.0 mmol). After reacting at 0°C for 30 minutes, sodium cyanoborohydride (190 mg, 3...) was added. mmol), then reacted at room temperature for 3 hours, the reaction was quenched with water, extracted with ethyl acetate (50 mL * 3), the organic phase was concentrated under reduced pressure to obtain crude product, and purified by silica gel column separation (eluent: dichloromethane: methanol = 10: 1) to obtain N-(4-(2-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)ethyl)-2-benzyloxy-6-fluorophenyl)-N-(N-((benzyloxy)carbonyl)aminosulfonyl)glycine methyl ester (7d) (300 mg, yield: 44%).

[0407] LC-MS, M / Z (ESI): 672.23 [M+H] + .

[0408] Step 4: Synthesis of N-(4-(2-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)ethyl)-2-fluoro-6-hydroxyphenyl)-N-aminosulfonylglycine methyl ester (7e)

[0409]

[0410] Palladium dichloride (78 mg, 0.44 mmol) was added to a methanol (4 mL) solution of N-(4-(2-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)ethyl)-2-benzyloxy-6-fluorophenyl)-N-(N-((benzyloxy)carbonyl)aminosulfonyl)glycine methyl ester (7d) (300 mg, 0.44 mmol). The reaction system was first replaced with nitrogen gas, and then with hydrogen gas. The reaction was carried out at room temperature for 2 hours, and the reaction was confirmed to be complete by LCMS. The reaction solution was filtered and concentrated under reduced pressure to obtain crude product, which was purified by silica gel column chromatography (eluent: dichloromethane: methanol = 10:1) to obtain N-(4-(2-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)ethyl)-2-fluoro-6-hydroxyphenyl)-N-aminosulfonylglycine methyl ester (7e) (130 mg, yield: 66%).

[0411] LC-MS, M / Z (ESI): 448.15 [M+H] + .

[0412] Step 5: Synthesis of N-(2-fluoro-6-hydroxy-4-(2-(4-oxopiperidin-1-yl)ethyl)phenyl)-N-aminosulfonylglycine methyl ester (7f)

[0413]

[0414] Under nitrogen protection, a formic acid solution (2 mL) of N-(4-(2-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)ethyl)-2-fluoro-6-hydroxyphenyl)-N-aminosulfonylglycine methyl ester (7e) (130 mg, 0.3 mmol) was heated to 80 °C and reacted for 2 hours. The reaction was confirmed to be complete by LCMS. The crude product obtained by concentration of the reaction solution under reduced pressure was purified by silica gel column chromatography (eluent: dichloromethane: methanol = 10:1) to obtain N-(2-fluoro-6-hydroxy-4-(2-(4-oxopiperidin-1-yl)ethyl)phenyl)-N-aminosulfonylglycine methyl ester (7f) (80 mg, yield: 66%).

[0415] LC-MS, M / Z (ESI): 404.12 [M+H] +

[0416] Step 6: Synthesis of 5-(4-(2-(4-(difluoromethylene)piperidin-1-yl)ethyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (7)

[0417]

[0418] Under nitrogen protection and at -78°C, difluoromethyl (2-pyridine) sulfone (39 mg, 0.2 mmol) and a tetrahydrofuran solution of potassium tert-butoxide (1.0 M, 0.22 mL) were added sequentially to a DMF solution of N-(2-fluoro-6-hydroxy-4-(2-(4-oxopiridin-1-yl)ethyl)phenyl)-N-aminosulfonylglycine methyl ester (7f) (40 mg, 0.1 mmol) were added sequentially. The reaction solution was then slowly heated to room temperature. The reaction was confirmed to be complete by LCMS. The reaction was quenched with water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure and dried before being purified by HPLC to obtain 5-(4-(2-(4-(difluoromethylene)piperidin-1-yl)ethyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (7).

[0419] 1 H NMR(400MHz,DMSO-d6)δ9.36–9.21(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)

[0420] LC-MS, M / Z (ESI): 406.10 [M+H] + .

[0421] Example 8: Preparation of target compound 8

[0422] 5-(4-(2-(3-cyclomethoxypyrrolidone-1-yl)ethyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (8)

[0423]

[0424] The synthetic route for target compound 8 is shown below:

[0425]

[0426] Step 1: Synthesis of tert-butyl 3-cyclobutide-1-carboxylate (8b)

[0427]

[0428] Under nitrogen protection, tert-butyl 3-oxopyrrolidine-1-carboxylate (8a) (15.0 g, 81.0 mmol) was dissolved in tetrahydrofuran (150 mL) at 0 °C, followed by the addition of potassium tert-butoxide (21.8 g, 194 mmol). The reaction was stirred at 0 °C for 0.5 h, followed by the slow dropwise addition of a tetrahydrofuran (150 mL) solution of (4-bromobutyl)triphenylphosphine bromide (46.5 g, 97.2 mmol). The reaction was stirred at 25 °C for 10 h. After the reaction was complete, the reaction solution was diluted with water (200 mL), then extracted with ethyl acetate (200 mL * 3). The organic phases were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 5:1, R... fp1 The concentration was 0.8, and the color was developed with potassium permanganate to obtain compound tert-butyl 3-cyclobutyride-1-carboxylate (8b) (900 mg, yield 5%).

[0429] Step 2: Synthesis of 3-cyclobutyrylpyrrolidine hydrochloride (8c)

[0430]

[0431] 3-Cyclobutylidene-1-carboxylic acid tert-butyl ester (8b) (700 mg, 3.13 mmol) was dissolved in dioxane hydrochloride (4 M, 10.0 mL), and the reaction was stirred at 25 °C for 1 hour. After the reaction was complete, the reaction solution was concentrated to obtain compound 3-cyclobutylidene pyrrolidine hydrochloride (8c) (500 mg, crude product), which was used directly in the next step.

[0432] Step 3: Synthesis of 5-(2-benzyloxy)-4-(2-(3-cyclomethoxypyrrolidone-1-yl)ethyl)-6-fluorophenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (8e)

[0433]

[0434] 3-Cyclobutyrylpyrrolidine hydrochloride (8c) (310 mg, 1.65 mmol) was dissolved in dichloromethane (5.00 mL) and methanol (3.00 mL), followed by the addition of sodium acetate (225 mg, 2.74 mmol). The reaction was stirred at 25 °C for 15 minutes. Then, 2-(3-benzyloxy)-4-(1,1-dioxo-4-oxo-1,2,5-thiadiazolidine-2-yl)-5-fluorophenyl)acetaldehyde (8d, synthesis reference WO2023200964 A1) (450 mg, 1.19 mmol) was added, and the reaction was stirred at 25 °C for 15 minutes. Finally, sodium triacetoxyborohydride (378 mg, 1.78 mmol) was added, and the reaction was stirred at 25 °C for 8 hours. After the reaction was complete, the reaction solution was diluted with water (20.0 mL), then extracted with dichloromethane / methanol (10 / 1, 20.0 mL * 5), the organic phases were combined, dried over sodium sulfate and filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by HPLC to obtain compound 5-(2-benzyloxy)-4-(2-(3-cyclomethoxypyrrolidone-1-yl)ethyl)-6-fluorophenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (8e) (300 mg, crude product).

[0435] LC-MS, M / Z (ESI): 486.1 [M+H] + ]

[0436] Step 4: Synthesis of 5-(4-(2-(3-cyclomethoxypyrrolidone-1-yl)ethyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (8)

[0437]

[0438] 5-(2-benzyloxy)-4-(2-(3-cyclomethoxypyrrolidone-1-yl)ethyl)-6-fluorophenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (8e) (200 mg, 412 μmol) was dissolved in dichloromethane (10 mL), and then boron tribromide (2.00 M, 1.3 mL) was added dropwise at -70 °C under nitrogen protection. The reaction was stirred at -70 °C for 1 hour. After the reaction was completed, the reaction solution was quenched with methanol (10.0 mL) at -70℃, and then the pH was adjusted to 7-8 with ammonia. The reaction solution was concentrated, and the crude product was purified twice by HPLC. The separation methods were (column: Waters xbridge 150*25mm 10um; solvent: A = water + 0.05% ammonia (30%), B = acetonitrile; gradient: 1%-20%, 10 min) and (column: Waters xbridge 150*25mm 10um; solvent: A = water + 10mM ammonium bicarbonate, B = acetonitrile; gradient: 15%-45%, 10 min). After drying, compound 5-(4-(2-(3-cyclomethoxypyrrolidone-1-yl)ethyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (8) was obtained.

[0439] 1 H NMR(400MHz,MeOD)δ6.62-6.73(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=8.00Hz,2H).

[0440] LC-MS, M / Z (ESI): 396.0 [M+H] + ]

[0441] Example 9: Preparation of target compound 9

[0442] 5-(2-fluoro-6-hydroxy-4-(2-(3-methylenepyrrolidone-1-yl)ethyl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (9)

[0443]

[0444] The synthetic route for target compound 9 is shown below:

[0445]

[0446] Step 1: Synthesis of 5-(2-benzyloxy)-6-fluoro-4-(2-(3-methylenepyrrolidone-1-yl)ethyl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (9a)

[0447]

[0448] The starting materials 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 hours. Then, 2-(3-benzyloxy)-4-(1,1-dioxo-4-oxo-1,2,5-thiadiazolidine-2-yl)-5-fluorophenyl)acetaldehyde (8d) (500 mg, 1.32 mmol) was added to the reaction solution and stirred at 25 °C for 0.5 hours. Then, sodium cyanoborohydride (207 mg, 3.30 mmol) was added to the reaction solution and stirred at 25 °C for 1 hour. After the reaction was complete, an aqueous solution (3 mL) was added to quench the reaction, and the mixture was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by HPLC to obtain 5-(2-benzyloxy)-6-fluoro-4-(2-(3-methylenepyrrolidone-1-yl)ethyl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (9a) (200 mg, yield 34%).

[0449] LC-MS, M / Z (ESI): 446.1 [M+H] + ].

[0450] Step 2: Synthesis of 5-(2-fluoro-6-hydroxy-4-(2-(3-methylenepyrrolidone-1-yl)ethyl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (9)

[0451]

[0452] The starting material 5-(2-benzyloxy)-6-fluoro-4-(2-(3-methylenepyrrolidone-1-yl)ethyl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (9a) (50 mg, 112 μmol) was dissolved in dichloromethane (5 mL). The reaction system was then purged with nitrogen three times. 2M boron tribromide (281 mg, 1.12 mmol) was slowly added to the reaction solution at -70 °C, and the mixture was stirred at -40 °C for 0.5 hours. After the reaction was complete, the pH was adjusted to 8 with 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 10.0min) to obtain compound 5-(2-fluoro-6-hydroxy-4-(2-(3-methylenepyrrolidone-1-yl)ethyl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (9) (20.5mg, yield 52%).

[0453] 1 H NMR(400MHz,DMSO-d6)δ9.71-9.99(m,1H)9.47(s,1H)6.64-6.71(m,1H)6.62(s,1H)5.14(br d,J=10.52Hz,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=7.94Hz,2H)2.57-2.74(m,2H)

[0454] LC-MS, M / Z (ESI): 356.0 [M+H] + ]

[0455] Example 10: Preparation of target compound 10

[0456] 5-(4-(2-(3-(but-2-methylene)pyrrolidine-1-yl)ethyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (10)

[0457]

[0458] The synthetic route for target compound 10 is shown below:

[0459]

[0460] Step 1: Synthesis of dimethyl 2-(butane-2-methylene)succinate (10b)

[0461]

[0462] Dimethyl succinate (10a) (35 g, 239 mmol, 31.3 mL) and butanone (17.2 g, 239 mmol) were dissolved in tert-butanol (300 mL). Under nitrogen protection, the reaction mixture was cooled to 0 °C, and then potassium tert-butoxide (26.8 g, 239 mmol) was rapidly added to the reaction solution. The mixture was stirred at 25 °C for 0.5 hours. After the reaction was complete, the reaction solution was poured into ice-cold dilute hydrochloric acid (2 M, 100 mL), and then extracted with ethyl acetate (200 mL * 3). The organic phases were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was dissolved in methanol (100 mL), cooled to 0 °C, and concentrated with concentrated sulfuric acid (5 mL) for 2 hours. After the reaction was complete, the reaction solution was poured into ice water (100 mL), and then extracted with ethyl acetate (100 mL * 3). The organic phases were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 3:1, Rfp1 = 0.4, potassium permanganate for color development) to give compound 2-(but-2-methylene)succinate dimethyl ester (10b) (20.1 g, yield 42%).

[0463] Step 2: Synthesis of 2-(butan-2-methylene)butan-1,4-diol (10c)

[0464]

[0465] Dimethyl 2-(butane-2-methylene)succinate (10b) (20.0 g, 99.8 mmol) was dissolved in tetrahydrofuran (100 mL). Under nitrogen protection, lithium aluminum hydride (2.5 M, 79.9 mL) was slowly added dropwise at 0 °C, and the mixture was stirred for 1 hour. After the reaction was complete, water (7.6 mL), 15% sodium hydroxide aqueous solution (7.6 g), and water (22.8 g) were slowly added dropwise to the reaction solution in sequence, and the mixture was stirred at room temperature for 1 hour. The mixture was then filtered, and the filter cake was washed with ethyl acetate (100 mL). The filtrate was dried and concentrated under reduced pressure to give compound 2-(butane-2-methylene)butane-1,4-diol (10c) (9.00 g, crude product), which was used directly in the next step.

[0466] Step 3: Synthesis of 2-(but-2-methylene)butane-1,4-dimethyldimethylsulfonate (10d)

[0467]

[0468] 2-(butan-2-methylene)butan-1,4-diol (10c) (9.00 g, 62.4 mmol) and triethylamine (25.2 g, 249 mmol) were dissolved in dichloromethane (120 mL). Methanesulfonic anhydride (32.6 g, 187 mmol) was added under nitrogen protection at 0 °C, and the mixture was stirred for 12 hours. After the reaction was complete, the reaction solution was diluted with water (200 mL), then extracted with ethyl acetate (200 mL * 3). The organic phases were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 2:1, Rfp1 = 0.35, potassium permanganate for color development) to give compound 2-(butan-2-methylene)butane-1,4-dimethyl dimethanesulfonate (10d) (3.20 g, yield 17%).

[0469] Step 4: Synthesis of 3-(2-Butylemethylene)-1-((4-nitrophenyl)sulfonyl)pyrrolidine (10e)

[0470]

[0471] 2-Nitrobenzenesulfonamide (2.58 g, 12.7 mmol) was dissolved in N,N-dimethylformamide (30 mL), and anhydrous potassium carbonate (3.53 g, 25.5 mmol) was added to the reaction mixture, which was stirred at 25 °C for 1 hour. Then, 2-(butane-2-methylene)butane-1,4-dimethyl dimethylsulfonate (10d) (3.20 g, 10.6 mmol) was added, and the mixture was stirred at 50 °C for 1 hour. After the reaction was complete, the reaction solution was diluted with water (150 mL), then extracted with ethyl acetate (90 mL * 3), the organic phases were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give compound 3-(2-butane-methylene)-1-((4-nitrophenyl)sulfonyl)pyrrolidine (10e) (2.10 g, crude product), which was directly proceeded to the next step.

[0472] Step 5: Synthesis of 3-(but-2-methylene)pyrrolidine (10f)

[0473]

[0474] 3-(2-Butylemethylene)-1-((4-nitrophenyl)sulfonyl)pyrrolidine (10e) (2.10 g, 6.77 mmol), dodecane-1-thiol (2.05 g, 10.1 mmol), and anhydrous potassium carbonate (2.81 g, 20.3 mmol) were dissolved in N,N-dimethylformamide (10 mL), and the reaction was stirred at 120 °C for 1 hour. After the reaction was complete, the reaction solution was directly filtered and concentrated under reduced pressure to obtain the crude product. The crude product was purified by HPLC to obtain compound 3-(butyr-2-methylene)pyrrolidine (10f) (210 mg, 25% yield).

[0475] Step 6: Synthesis of 5-(2-benzyloxy)-4-(2-(3-(but-2-methylene)pyrrolidine-1-yl)ethyl)-6-fluorophenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (10g)

[0476]

[0477] 3-(butan-2-methylene)pyrrolidine (10f) (248 mg, 1.98 mmol) was dissolved in dichloromethane (10 mL), followed by the addition of sodium acetate (162 mg, 1.98 mmol). The reaction was stirred at 25 °C for 15 minutes. Then, 2-(3-benzyloxy)-4-(1,1-dioxo-4-oxo-1,2,5-thiadiazol-2-yl)-5-fluorophenyl)acetaldehyde (8d) (500 mg, 1.32 mmol) was added, and the reaction was stirred at 25 °C for 1 hour. Finally, sodium triacetoxyborohydride (560 mg, 2.64 mmol) was added, and the reaction was stirred at 25 °C for 1 hour. After the reaction was complete, the reaction solution was diluted with water (3 mL), then extracted with dichloromethane / methanol (10 / 1, 20 mL * 5). The organic phases were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by HPLC to obtain compound 5-(2-benzyloxy)-4-(2-(3-(but-2-methylene)pyrrolidine-1-yl)ethyl)-6-fluorophenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (10 g) (57.0 mg, yield 9%).

[0478] LC-MS, M / Z (ESI): 488.2 [M+H] + ].

[0479] Step 7: 5-(4-(2-(3-(but-2-methylene)pyrrolidine-1-yl)ethyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (10)

[0480]

[0481] 5-(2-benzyloxy)-4-(2-(3-(but-2-methylene)pyrrolidine-1-yl)ethyl)-6-fluorophenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (10 g) (57.0 mg, 116 μmol) was dissolved in dichloromethane (5 mL), and then boron tribromide (2 M, 292 μL) was added dropwise at -70 °C under nitrogen protection. The reaction was stirred at -70 °C for 1 hour. After the reaction was completed, the reaction solution was quenched with methanol (5 mL) at -70℃, and then the pH was adjusted to 7-8 with ammonia. The reaction solution was concentrated under reduced pressure, and the crude product was purified by HPLC separation (column: Waters xbridge 150*25mm 10um; solvent: A = water + 10mM ammonium bicarbonate, B = acetonitrile; gradient: 1%-30%, 12 min) to obtain compound 5-(4-(2-(3-(but-2-methylene)pyrrolidine-1-yl)ethyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (10).

[0482] 1 H NMR(400MHz,DMSO-d6)δ9.21-9.67(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)

[0483] LC-MS, M / Z (ESI): 398.1 [M+H] + ]

[0484] Example 11: Preparation of target compound 11

[0485] Synthesis of 5-(4-(2-(3-cyclopentylpyrrolidone-1-yl)ethyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazopentidin-3-one 1,1-dioxide (11)

[0486]

[0487] The synthetic route for target compound 11 is shown below:

[0488]

[0489] Step 1: Synthesis of 2-(cyclopentylthio)pyridine (11b)

[0490]

[0491] At room temperature, anhydrous potassium carbonate (11.2 g, 81.0 mmol) was added to acetone (80 mL) containing pyridine-2-thiol (11a) (6.00 g, 53.9 mmol), bromocyclopentane (10.1 g, 67.5 mmol), and pyridine-2-thiol (11a) (6.00 g, 53.9 mmol). The reaction mixture was stirred at 25 °C for 2 hours. After the reaction was complete, the crude product was concentrated under reduced pressure, diluted with water (80 mL), extracted with methyl tert-butyl ether (30 mL x 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give compound 2-(cyclopentylthio)pyridine (11b) (9.60 g, 99% yield).

[0492] Step 2: Synthesis of 2-(cyclopentylsulfonyl)pyridine (11c)

[0493]

[0494] At 0°C, hydrogen peroxide (19.2 g, 169 mmol) was added dropwise to a methanol solution (100 mL) of 2-(cyclopentylthio)pyridine (11b) (9.50 g, 53.0 mmol) and sodium tungstate dihydrate (1.75 g, 5.30 mmol). After the addition was complete, the reaction mixture was stirred at 25°C for 12 hours. After the reaction was complete, the mixture 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 give compound 2-(cyclopentylsulfonyl)pyridine (11c) (8.91 g, yield 80%).

[0495] Step 3: Synthesis of tert-butyl 3-cyclopentamethylenepyrrolidine-1-carboxylate (11d)

[0496]

[0497] Under nitrogen protection at -60°C, lithium di(trimethylsilyl)amino (1M, 19.5mL) was slowly added dropwise to a tetrahydrofuran solution (30mL) of 2-(cyclopentylsulfonyl)pyridine (11c) (4.11g, 19.5mmol), and the mixture was stirred at -60°C for 0.5 hours. After the reaction was complete, a tetrahydrofuran solution (10mL) of 3-oxopyrrolidine-1-carboxylic acid tert-butyl ester (3g, 16.2mmol) was added dropwise at -60°C, and the reaction mixture was stirred at 25°C for 12 hours. The reaction mixture was quenched with ammonium chloride (100mL), extracted with ethyl acetate (30mL*2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography (petroleum ether: ethyl acetate (1 / 0 to 10 / 1) to give compound 3-cyclopentamethylenepyrrolidine-1-carboxylic acid tert-butyl ester (11d) (282 mg, yield 8%).

[0498] Step 4: Synthesis of 3-cyclopentamethylenepyrrolidine hydrochloride (11e)

[0499]

[0500] At room temperature, dioxane hydrochloride (2M, 5mL) was added to 1mL of dioxane (1mL) of 3-cyclopentamethylenepyrrolidine-1-carboxylic acid tert-butyl ester (11d) (280mg, 1.18mmol), and the reaction solution was stirred at 25°C for 2 hours. After the reaction was completed, the solution was directly concentrated under reduced pressure to obtain compound 3-cyclopentamethylenepyrrolidine hydrochloride (11e) (230mg, crude product).

[0501] LC-MS, M / Z (ESI): 174.1 [M+H] + ]

[0502] Step 5: Synthesis of 5-(2-(benzyloxy)-4-(2-(3-cyclopentylpyrrolidone-1-yl)ethyl)-6-fluorophenyl)-1,2,5-thiadiazopentidin-3-one 1,1-dioxide (11f)

[0503]

[0504] At room temperature, 3-cyclopentanemethylpyrrolidine hydrochloride (11e) (108 mg, 626 μmol) was added to a mixed solution of 2-(3-benzyloxy)-4-(1,1-dioxo-4-oxo-1,2,5-thiadiazolidine-2-yl)-5-fluorophenyl)acetaldehyde (8d) (200 mg, 528 μmol) and sodium acetate (216 mg, 2.64 mmol) in dichloromethane (3 mL) and methanol (2 mL). The reaction solution was stirred at 25 °C for 0.5 hours. Sodium cyanoborohydride (66.4 mg, 1.06 mmol) was then added to the reaction solution, and the mixture was stirred at 25 °C for another 0.5 hours. After the reaction was complete, the crude product was obtained by direct filtration. The crude product was purified by HPLC to obtain compound 5-(2-benzyloxy)-4-(2-(3-cyclopentamethylenepyrrolidone-1-yl)ethyl)-6-fluorophenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (11f) (30.0 mg, yield 11%).

[0505] LC-MS, M / Z (ESI): 500.1 [M+H + ]

[0506] Step 6: Synthesis of 5-(4-(2-(3-cyclopentamethylenepyrrolidone-1-yl)ethyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (11)

[0507]

[0508] At -70°C, boron tribromide (1M, 150μL) was slowly added dropwise to 5-(2-benzyloxy)-4-(2-(3-cyclopentamethylenepyrrolidone-1-yl)ethyl)-6-fluorophenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (11f) (25.0 mg, 50.0 μmol), and the reaction mixture was stirred at -70°C for 1 hour. After the reaction was completed, methanol (2 mL) was added dropwise at -40°C, and the mixture was concentrated under reduced pressure at low temperature to obtain the crude product. The crude product was purified by HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: solvent A = water + 0.225% formic acid, B = acetonitrile; gradient: 5%-35%, 12min) to obtain compound 5-(4-(2-(3-cyclopentamethylenepyrrolidin-1-yl)ethyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (11).

[0509] 1H NMR(400MHz,DMSO-d6)δ9.39(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)

[0510] LC-MS, M / Z (ESI): 410.1 [M+H + ]

[0511] Example 12: Preparation of target compound 12

[0512] Synthesis of 5-(3,6-difluoro-2-hydroxy-4-(2-(3-(prop-2-methylene)pyrrolidine-1-yl)ethyl)phenyl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide (12)

[0513]

[0514] The synthetic route for target compound 12 is shown below:

[0515]

[0516] Step 1: Synthesis of 4-bromo-3,6-difluoro-2-methoxyaniline (12b)

[0517]

[0518] At 0°C, tribromopyridinium (3.10 g, 9.68 mmol) was slowly added to a mixture of 3,6-difluoro-2-methoxyaniline (12a) (1.40 g, 8.80 mmol) and dichloromethane (20 mL) under a nitrogen atmosphere. The reaction mixture was stirred at 25°C for 0.5 hours. After the reaction was complete, the reaction mixture was poured into saturated sodium bicarbonate (60 mL). The mixture was extracted with dichloromethane (30 mL x 3), the organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure to give compound 4-bromo-3,6-difluoro-2-methoxyaniline (12b) (2.24 g, crude product).

[0519] Step 2: Synthesis of ethyl 4-bromo-3,6-difluoro-2-methoxyphenyl)glycine (12c)

[0520]

[0521] At 0 °C, a toluene solution of 4-bromo-3,6-difluoro-2-methoxyaniline (12b) (2.00 g, 8.40 mmol) and ethyl glyoxylate (3.43 g, 16.8 mmol) was dissolved in N,N-dimethylformamide (20 mL). Trimethylchlorosilane (1.37 g, 12.6 mmol) was then slowly added dropwise, and the reaction mixture was stirred at 25 °C for 2 hours. Sodium cyanoborohydride (792 mg, 12.6 mmol) was slowly added to the reaction mixture at 0 °C, and the mixture was stirred at 25 °C for 1 hour. After the reaction was complete, the mixture was diluted with water (200 mL) and extracted with ethyl acetate (40 mL * 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate (1 / 0 to 5 / 1) to give compound 4-bromo-3,6-difluoro-2-methoxyphenyl)glycine ethyl ester (12c) (1.78 g, yield 65%).

[0522] Step 3: Synthesis of N-(4-bromo-3,6-difluoro-2-methoxyphenyl)-N-aminosulfonylglycine ethyl ester (12d)

[0523]

[0524] At 0 °C, aminosulfonyl chloride (1.60 g, 13.9 mmol) was slowly added in portions to a mixed solution of 4-bromo-3,6-difluoro-2-methoxyphenyl)-N-aminosulfonylglycine ethyl ester (12c) (1.52 g, 4.63 mmol) and triethylamine (2.34 g, 23.1 mmol) in dichloromethane (30 mL). The reaction mixture was stirred at 0 °C for 2 hours. After the reaction was complete, the mixture was diluted with water (50 mL) and extracted with dichloromethane (30 mL * 2). The organic phase was washed with water (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound N-(4-bromo-3,6-difluoro-2-methoxyphenyl)-N-aminosulfonylglycine ethyl ester (12d) (1.50 g, crude product).

[0525] Step 4: Synthesis of 5-(4-bromo-3,6-difluoro-2-methoxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (12e)

[0526]

[0527] At 0°C, sodium methoxide (2.01 g, 11.2 mmol, 33% purity) solution was added dropwise to a methanol (15 mL) solution of N-(4-bromo-3,6-difluoro-2-methoxyphenyl)-N-aminosulfonylglycine ethyl ester (12d) (1.50 g, 3.72 mmol), and the reaction solution was stirred at 0°C for 1 hour. After the reaction was completed, acetic acid (1.00 g) was slowly added dropwise to the reaction solution, and the solution was concentrated under reduced pressure to obtain the 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-thiadiazolidine-3-one 1,1-dioxide (12e) (1.02 g, crude product).

[0528] Step 5: Synthesis of 5-(4-(2-ethoxyvinyl)-3,6-difluoro-2-methoxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (12f)

[0529]

[0530] At room temperature, 1,1-bis(diphenylphosphine)ferrocene palladium chloride (81.9 mg, 112 μmol) was added to 5-(4-bromo-3,6-difluoro-2-methoxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (12e) (1.00 g, 2.80 mmol), 2-[(E)-2-ethoxyvinyl]-4,4,5,5-tetramethyl-1,3,2-dioxoboropentan (721 mg, 3.64 mmol), anhydrous potassium carbonate (774 mg, 5.60 mmol), dioxane (10 mL), and water (1 mL). The reaction mixture was stirred at 95 °C for 3 hours. After the reaction was completed, acetic acid (200 mg) was slowly added dropwise at 0 °C, and the mixture was concentrated under reduced pressure to obtain the 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-thiadiazolidine-3-one 1,1-dioxide (12f) (485 mg, yield 50%).

[0531] Step 6: Synthesis of 2-(4-(1,1-dioxo-4-oxo-1,2,5-thiadiazolidine-2-yl)-2,5-difluoro-3-methoxyphenyl)acetaldehyde (12g)

[0532]

[0533] At room temperature, 0.50 mL of water was added to a solution of 5-(4-(2-ethoxyvinyl)-3,6-difluoro-2-methoxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (12 g) (250 mg, 574 μmol) in formic acid (3.50 mL), and the reaction mixture was stirred at 25 °C for 3 hours. After the reaction was completed, the solution was concentrated under reduced pressure at 30 °C to give compound 2-(4-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidine-2-yl)-2,5-difluoro-3-methoxyphenyl)acetaldehyde (12 g) (203 mg, crude product).

[0534] Step 7: Synthesis of 5-(3,6-difluoro-2-methoxy-4-(2-(3-(prop-2-methylene)pyrrolidine-1-yl)ethyl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (12h)

[0535]

[0536] Sodium acetate (250 mg, 3.04 mmol) was added to a methanol (4 mL) solution of 2-(4-(1,1-dioxo-4-oxo-1,2,5-thiadiazol-2-yl)-2,5-difluoro-3-methoxyphenyl)acetaldehyde (12 g) (195 mg, 609 μmol) and 3-(propane-2-methylene)pyrrolidine hydrochloride (108 mg, 731 μmol). The reaction solution was stirred at 25 °C for 0.5 h. Sodium cyanoborohydride (76.5 mg, 1.22 mmol) was slowly added to the reaction solution, and the mixture was stirred at 25 °C for 0.5 h. After the reaction was complete, the reaction solution was filtered to obtain the crude product. The crude product was purified by HPLC to obtain compound 5-(3,6-difluoro-2-methoxy-4-(2-(3-(prop-2-methylene)pyrrolidone-1-yl)ethyl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (12h) (55.0 mg, yield 22%).

[0537] LC-MS, M / Z (ESI): 416.0 [M+H] + ]

[0538] Step 8: Synthesis of 5-(3,6-difluoro-2-hydroxy-4-(2-(3-(prop-2-methylene)pyrrolidine-1-yl)ethyl)phenyl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide (12)

[0539]

[0540] At room temperature, sodium ethanethiol (91.0 mg, 1.08 mmol) was added to 5-(3,6-difluoro-2-methoxy-4-(2-(3-(prop-2-methylene)pyrrolidine-1-yl)ethyl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (12 h) (45.0 mg, 108 μmol) in 3.0 mL of N,N-dimethylformamide. The reaction mixture was stirred at 85 °C for 0.5 h. The reaction mixture was then directly filtered for use in the preparation. The crude product was purified by HPLC (column: Waters xbridge 150*25mm 10um; mobile phase: solvent A = water + 10nM ammonium bicarbonate, B = acetonitrile; gradient: 1%-30%, 12min) to obtain compound 5-(3,6-difluoro-2-hydroxy-4-(2-(3-(prop-2-methylene)pyrrolidone-1-yl)ethyl)phenyl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide (12).

[0541] 1 H NMR (400MHz, DMSO-d6) δ10.06-9.64(m,2H),6.75(dd,J=10.4,6.40Hz 1H),3.95(s,2H),3.81-3.41(m,4H),3.30-3.14(m,2H),3.94(t,J=8.0Hz 2H),2.54-2.51(m,2H),1.64(s,6H)

[0542] LC-MS, M / Z (ESI): 402.1 [M+H] + ]

[0543] Example 13: Preparation of target compound 13

[0544] 5-(4-(2-(3-(dihydrofuran-3(2H)-methylene)pyrrolidine-1-yl)ethyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (13)

[0545]

[0546] The synthetic route for target compound 13 is shown below:

[0547]

[0548] Step 1: Synthesis of 2-((tetrahydrofuran-3-yl)thio)pyridine (13b)

[0549]

[0550] 2-Mercaptopyridine (13a) (5.00 g, 45.0 mmol) was dissolved in acetonitrile (50 mL), and then anhydrous potassium carbonate (9.32 g, 67.5 mmol) and 3-bromotetrahydrofuran (8.15 g, 54.0 mmol) were added. The reaction mixture was stirred at 30 °C for 10 hours. After the reaction was complete, the reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (200 mL x 3). The organic phases were combined, washed with water (200 mL x 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give compound 2-((tetrahydrofuran-3-yl)thio)pyridine (13b) (8.00 g, 98% yield).

[0551] Step 2: Synthesis of 2-((tetrahydrofuran-3-yl)sulfonyl)pyridine (13c)

[0552]

[0553] Under nitrogen protection, 2-((tetrahydrofuran-3-yl)thio)pyridine (13b) (6.00 g, 33.1 mmol) and sodium tungstate dihydrate (1.09 g, 3.31 mmol) were dissolved in methanol (60.0 mL) at 0 °C, followed by the slow addition of hydrogen peroxide (12.3 g, 109 mmol, 10.5 mL, 30.0% purity). The reaction was stirred at 25 °C for 10 hours. After the reaction was complete, the reaction solution was quenched with a saturated sodium sulfite aqueous solution (100 mL), then extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with a saturated sodium sulfite aqueous solution (100 mL x 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 2-((tetrahydrofuran-3-yl)sulfonyl)pyridine (13c) (8.00 g, crude). This was used directly in the next step.

[0554] Step 3: Synthesis of tert-butyl 3-(dihydrofuran-3(2H)-methylene)pyrrolidine-1-carboxylate (13d)

[0555]

[0556] Under nitrogen protection, 2-((tetrahydrofuran-3-yl)sulfonyl)pyridine (13c) (5.99 g, 28.1 mmol) and N-Boc-3-pyrrolidone (4.00 g, 21.6 mmol) were slowly added to a solution of potassium tert-butoxide (21.8 g, 194 mmol) in N,N-dimethylformamide (40.0 mL) at -40 °C. The reaction was stirred at 25 °C for 10 hours. After the reaction was complete, the reaction solution was diluted with water (200 mL) and extracted with ethyl acetate (100 mL * 3). The organic phases were combined, washed with water (100 mL * 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 5:1, R... fp1 The concentration was 0.6, and the color was developed with potassium permanganate to obtain compound 3-(dihydrofuran-3(2H)-methylene)pyrrolidine-1-carboxylic acid tert-butyl ester (13d) (1.00 g, yield 19%).

[0557] Step 4: Synthesis of 3-(dihydrofuran-3(2H)-methylene)pyrrolidine hydrochloride (13e)

[0558]

[0559] Under nitrogen protection, tert-butyl 3-(dihydrofuran-3(2H)-methylene)pyrrolidine-1-carboxylate (13d) (1.00 g, 4.18 mmol) was dissolved in dioxane hydrochloride (10 mL), and the reaction was stirred at 25 °C for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure to give compound 3-(dihydrofuran-3(2H)-methylene)pyrrolidine hydrochloride (13e) (700 mg, 95% yield).

[0560] Step 5: Synthesis of 5-(2-(benzyloxy)-4-(2-(3-(dihydrofuran-3(2H)-methylene)pyrrolidine-1-yl)ethyl)-6-fluorophenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (13f)

[0561]

[0562] 3-(dihydrofuran-3(2H)-methylene)pyrrolidine hydrochloride (13e) (348 mg, 1.98 mmol) was dissolved in dichloromethane (5 mL), and then sodium acetate (300 mg, 3.66 mmol) was added. The reaction was stirred at 25 °C for 30 minutes. Then, a solution of 2-(3-benzyloxy)-4-(1,1-dioxo-4-oxo-1,2,5-thiadiazolidine-2-yl)-5-fluorophenyl)acetaldehyde (8d) (500 mg, 1.32 mmol) in dichloromethane (5 mL) and methanol (5 mL) was added. The reaction was stirred at 25 °C for 1 hour. Finally, sodium triacetoxyborohydride (420 mg, 1.98 mmol) was added, and the reaction was stirred at 25 °C for 1 hour. After the reaction was completed, the reaction solution was diluted with water (10 mL) and then concentrated under reduced pressure. The crude product was purified by HPLC to obtain compound 5-(2-(benzyloxy)-4-(2-(3-(dihydrofuran-3(2H)-methylene)pyrrolidine-1-yl)ethyl)-6-fluorophenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (13f) (230 mg, yield 35%).

[0563] LC-MS, M / Z (ESI): 502.1 [M+H] + ]

[0564] Step 6: Synthesis of 5-(4-(2-(3-(dihydrofuran-3(2H)-methylene)pyrrolidine-1-yl)ethyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (13)

[0565]

[0566] 5-(2-(benzyloxy)-4-(2-(3-(dihydrofuran-3(2H)-methylene)pyrrolidine-1-yl)ethyl)-6-fluorophenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (13f) (200 mg, 399 μmol) was dissolved in dichloromethane (5 mL), and then boron tribromide (2.00 M, 1.3 mL) was added dropwise at -70 °C under nitrogen protection. The reaction was stirred at -70 °C for 2 hours. After the reaction was complete, the reaction solution was quenched with methanol (20 mL) at -70 °C, and then the pH was adjusted to 7-8 with ammonia. The reaction solution was concentrated under reduced pressure, and the crude product was purified by HPLC (column: Waters Atlantis T3 100*30mm*5um; solvent: A = water + 10mM ammonium bicarbonate, B = acetonitrile; gradient: 1%-30%, 10 minutes) to obtain compound 5-(4-(2-(3-(dihydrofuran-3(2H)-methylene)pyrrolidine-1-yl)ethyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (13).

[0567] 1 H NMR(400MHz,DMSO-d6)δ9.34(s,1H),6.55-6.73(m,2H),4.08-4.18(m,2H),3.94(s,2H),3.7 9-3.84(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).

[0568] LC-MS, M / Z (ESI): 412.0 [M+H + ]

[0569] Example 14: Preparation of target compound 14

[0570] 5-(2,3-difluoro-6-hydroxy-4-(2-(3-(prop-2-methylene)pyrrolidine-1-yl)ethyl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (14)

[0571]

[0572] The synthetic route for target compound 14 is shown below:

[0573]

[0574] Step 1: Synthesis of tert-butyl (2,3-difluoro-6-methoxyphenyl)carbamate (14b)

[0575]

[0576] 2,3-Difluoro-6-methoxybenzoic acid (14a) (18.7 g, 99.4 mmol) was dissolved in tert-butanol (190 mL). Triethylamine (11.1 g, 109 mmol) and diphenyl azidophosphate (30.1 g, 109 mmol) were added to the reaction solution. The mixture was then purged with nitrogen three times, and the temperature was slowly raised to 80 °C and stirred for 12 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, dissolved in ethyl acetate (500 mL), and extracted with water (500 mL * 3). The organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound (2,3-difluoro-6-methoxyphenyl) tert-butyl carbamate (14b) (21.0 g, yield 81%).

[0577] Step 2: Synthesis of 2,3-difluoro-6-methoxyaniline (14c)

[0578]

[0579] (2,3-Difluoro-6-methoxyphenyl)tert-butyl carbamate (14b) (21.0 g, 81.0 mmol) was dissolved in methanol (210 mL), and hydrochloric acid (12 M, 33 mL) was added to the reaction solution. The mixture was then stirred at 60 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, dissolved in ethyl acetate (200 mL), and extracted with ethyl acetate (300 mL x 3) after adding sodium hydroxide aqueous solution (1 M, 300 mL). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 5:1, R...). f The compound 2,3-difluoro-6-methoxyaniline (14c) (7.87 g, yield 61%) was obtained by reducing the concentration of 0.47 g.

[0580] Step 3: Synthesis of 4-bromo-2,3-difluoro-6-methoxyaniline (14d)

[0581]

[0582] 2,3-Difluoro-6-methoxyaniline (14c) (7.80 g, 49.0 mmol) was dissolved in N,N-dimethylformamide (75 mL). A solution of N-bromo-succinimide (9.60 g, 53.9 mmol) dissolved in N,N-dimethylformamide (20 mL) was slowly added at 0 °C, followed by stirring at 0 °C for 2 hours. After the reaction was complete, water (300 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (250 mL x 3), washed with saturated brine (250 mL), and the combined organic phases were dried over anhydrous sodium sulfate and filtered. The crude product was concentrated under reduced pressure. The crude product was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 5:1, R...). f The compound 4-bromo-2,3-difluoro-6-methoxyaniline (14d) was obtained (8.00 g, yield 69%) by reacting 0.50 g of the compound with 0.50 g of the compound.

[0583] Step 4: Synthesis of (4-bromo-2,3-difluoro-6-methoxyphenyl)glycine ethyl ester (14e)

[0584]

[0585] 4-Bromo-2,3-difluoro-6-methoxyaniline (14d) (8.00 g, 33.6 mmol) and 50% (13.7 g, 67.2 mmol) ethyl glyoxylate toluene solution were dissolved in N,N-dimethylformamide (80 mL). The reaction system was purged with nitrogen three times. At 0 °C, trimethylchlorosilane (5.11 g, 47.0 mmol) dissolved in N,N-dimethylformamide (10 mL) was added to the reaction solution, and the mixture was stirred at 25 °C for 1 hour. Sodium cyanoborohydride (3.17 g, 50.4 mmol) was then added to the reaction solution at 0 °C, and the mixture was stirred at 25 °C for 1 hour. After the reaction was complete, water (500 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (300 mL x 3), washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 5:1, Rf = 0.49) to give compound (4-bromo-2,3-difluoro-6-methoxyphenyl)glycine ethyl ester (14e) (5.80 g, yield 53%).

[0586] Step 5: Synthesis of N-(4-bromo-2,3-difluoro-6-methoxyphenyl)-N-aminosulfonylglycine ethyl ester (14f)

[0587]

[0588] (4-bromo-2,3-difluoro-6-methoxyphenyl)glycine ethyl ester (14e) (2.00 g, 6.17 mmol) and triethylamine (9.37 g, 92.5 mmol) were dissolved in N,N-dimethylacetamide (60 mL). Then, aminosulfonyl chloride (12.8 g, 111 mmol) was slowly added to the reaction solution at 0 °C, and the mixture was stirred at 25 °C for 12 hours. After the reaction was complete, water (200 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL x 3). The extract was washed with saturated brine (50 mL), and the combined organic phases were dried over anhydrous sodium sulfate and filtered. The mixture was concentrated under reduced pressure to give compound N-(4-bromo-2,3-difluoro-6-methoxyphenyl)-N-aminosulfonylglycine ethyl ester (14f) (2.40 g, crude product).

[0589] Step 6: Synthesis of N-(4-bromo-2,3-difluoro-6-methoxyphenyl)-N-aminosulfonylglycine ethyl ester (14g)

[0590]

[0591] N-(4-bromo-2,3-difluoro-6-methoxyphenyl)-N-aminosulfonylglycine ethyl ester (14f) (2.40 g, 5.95 mmol) was dissolved in anhydrous methanol (20 mL). A 30% sodium methoxide methanol solution (6.43 g, 35.7 mmol) was slowly added at 0 °C, followed by stirring at 0 °C for 2 hours. After the reaction was complete, the solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (mobile phase: dichloromethane / methanol = 5:1, Rf = 0.28) to give the yellow solid compound N-(4-bromo-2,3-difluoro-6-methoxyphenyl)-N-aminosulfonylglycine ethyl ester (14 g) (1.40 g, yield 66%).

[0592] Step 7: Synthesis of 5-(4-(2-ethoxyvinyl)-2,3-difluoro-6-methoxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (14h)

[0593]

[0594] N-(4-bromo-2,3-difluoro-6-methoxyphenyl)-N-aminosulfonylglycine ethyl ester (14 g) (600 mg, 1.68 mmol) and (E)-1-ethoxyvinyl-2-boronate phenanol ester (665 mg, 3.36 mmol) were dissolved in dioxane (6 mL) and water (3 mL). Then, sodium carbonate (534 mg, 5.04 mmol) and 1,1-bis(diphenylphosphine)ferrocene palladium chloride (122 mg, 168 μmol) were added. The reaction system was purged three times with nitrogen, and then the temperature was slowly raised to 100 °C and stirred for 8 hours. After the reaction was complete, the mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (mobile phase: dichloromethane / methanol = 5:1, R...). f The compound 5-(4-(2-ethoxyvinyl)-2,3-difluoro-6-methoxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (14h) (400mg, yield 68%) was obtained (0.22).

[0595] Step 8: Synthesis of 2-(4-(1,1-dioxo-4-oxo-1,2,5-thiadiazolidine-2-yl)-2,3-difluoro-5-methoxyphenyl)acetaldehyde (14i)

[0596]

[0597] 5-(4-(2-ethoxyvinyl)-2,3-difluoro-6-methoxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (14h) (400 mg, 1.15 mmol) was dissolved in formic acid (4 mL) and water (0.5 mL), and then stirred at 25 °C for 12 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to give compound 2-(4-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidine-2-yl)-2,3-difluoro-5-methoxyphenyl)acetaldehyde (14i) (360 mg, crude product).

[0598] Step 9: Synthesis of 5-(2,3-difluoro-6-methoxy-4-(2-(3-(prop-2-methylene)pyrrolidine-1-yl)ethyl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (14j)

[0599]

[0600] 3-(propane-2-methylene)pyrrolidine hydrochloride (249 mg, 1.69 mmol) and sodium acetate (553 mg, 6.74 mmol) were dissolved in anhydrous methanol (5 mL) and stirred at 25 °C for 1 hour. Then, 2-(4-(1,1-dioxo-4-oxo-1,2,5-thiadiazolidine-2-yl)-2,3-difluoro-5-methoxyphenyl)acetaldehyde (14i) (360 mg, 1.12 mmol) was added to the reaction solution and stirred at 25 °C for 1 hour. Then, sodium cyanoborohydride (106 mg, 1.69 mmol) was added to the reaction solution and stirred at 25 °C for 2 hours. After the reaction was completed, water (10 mL) was added to quench the reaction, and the solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified twice by HPLC to obtain compound 5-(2,3-difluoro-6-methoxy-4-(2-(3-(prop-2-methylene)pyrrolidine-1-yl)ethyl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (14j) (80.0 mg, yield 17%).

[0601] Step 10: 5-(2,3-difluoro-6-hydroxy-4-(2-(3-(prop-2-methylene)pyrrolidine-1-yl)ethyl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (14)

[0602]

[0603] 5-(2,3-difluoro-6-methoxy-4-(2-(3-(prop-2-methylene)pyrrolidine-1-yl)ethyl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (14j) (20.0 mg, 48.1 μmol) was dissolved in N,N-dimethylformamide (2 mL), and then sodium ethanethiol (20 mg, 240 μmol) was added. The reaction was purged with nitrogen three times and stirred at 140 °C for 10 minutes. After the reaction was completed, the filtrate was 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; solvent: A=water + 0.1% ammonium bicarbonate, B=acetonitrile; gradient: 7%-37%, 12 min) to obtain compound 5-(2,3-difluoro-6-hydroxy-4-(2-(3-(prop-2-methylene)pyrrolidone-1-yl)ethyl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (14).

[0604] LC-MS, M / Z (ESI): 400.0 [MH] - .

[0605] Example 15: Preparation of target compound 15

[0606] Synthesis of 5-(4-(2-(3-(3,3-difluorocyclobutylidene)pyrrolidine-1-yl)ethyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (15)

[0607]

[0608] The synthetic route for target compound 15 is shown below:

[0609]

[0610] Step 1: Synthesis of 2-((3,3-difluorocyclobutyl)thio)pyridine (15b)

[0611]

[0612] At room temperature, anhydrous potassium carbonate (4.10 g, 29.7 mmol) was added to pyridine-2-thiol (15a) (2.20 g, 19.8 mmol), 3-bromo-1,1-difluoro-cyclobutane (4.06 g, 23.7 mmol), and N,N-dimethylformamide (1.05 mL). The reaction mixture was stirred at 70 °C for 3 hours. After the reaction was complete, the mixture was diluted with water (120 mL), extracted with ethyl acetate (30 mL x 3), washed with water (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 2-((3,3-difluorocyclobutyl)thio)pyridine (15b) (3.61 g, 90% yield).

[0613] Step 2: Synthesis of 2-((3,3-difluorocyclobutyl)sulfonyl)pyridine (15c)

[0614]

[0615] At 0°C, hydrogen peroxide (7.10 g, 62.6 mmol, 30% purity) was added dropwise to a methanol solution (40 mL) of 2-((3,3-difluorocyclobutyl)thio)pyridine (15b) (3.61 g, 17.9 mmol) and sodium tungstate dihydrate (590 mg, 1.79 mmol). After the addition was complete, the reaction mixture was stirred at 25°C for 12 hours. After the reaction was completed, the mixture 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 give compound 2-((3,3-difluorocyclobutyl)sulfonyl)pyridine (15c) (3.53 g, yield 84%).

[0616] Step 3: Synthesis of tert-butyl 3-(3,3-difluorocyclobutylmethylene)pyrrolidine-1-carboxylate (15d)

[0617]

[0618] Under nitrogen protection at -20°C, a mixture 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) was slowly added dropwise to a solution of potassium tert-butoxide (2.69 g, 24.0 mmol) in N,N-dimethylformamide (15 mL). The reaction mixture was stirred at 25°C for 12 hours. After the reaction was completed, the reaction mixture was poured into a saturated ammonium chloride aqueous solution (600 mL), extracted with ethyl acetate (50 mL * 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate (1 / 0 to 10 / 1) to give compound 3-(3,3-difluorocyclobutylmethylene)pyrrolidine-1-carboxylic acid tert-butyl ester (15d) (178mg, yield 6%).

[0619] Step 4: Synthesis of 3-(3,3-difluorocyclobutanediyl)pyrrolidine hydrochloride (15e)

[0620]

[0621] At room temperature, dioxane hydrochloride (2M, 6 mL) was added to 1.00 mL of dioxane (15d) containing 178 mg, 687 μmol of 3-(3,3-difluorocyclobutylmethylene)pyrrolidine-1-carboxylic acid tert-butyl ester (15d). The reaction mixture was stirred at 25 °C for 3 hours. After the reaction was completed, the solution was directly concentrated to give compound 3-(3,3-difluorocyclobutylmethylene)pyrrolidine hydrochloride (15e) (121 mg, 90% yield).

[0622] Step 5: Synthesis of 5-(2-(benzyloxy)-4-(2-(3-(3,3-difluorocyclobutylidene)pyrrolidine-1-yl)ethyl)-6-fluorophenyl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide (15f)

[0623]

[0624] At room temperature, 240 mg (634 μmol) of 2-(3-benzyloxy)-4-(1,1-dioxo-4-oxo-1,2,5-thiadiazol-2-yl)-5-fluorophenyl)acetaldehyde (8d) and sodium acetate (260 mg, 3.17 mmol) in methanol (5.00 mL) were mixed with 3-(3,3-difluorocyclobutanediyl)pyrrolidine hydrochloride (15e) (99.0 mg, 507 μmol). The reaction mixture was stirred at 25 °C for 0.5 h. Then, sodium cyanoborohydride (120 mg, 1.90 mmol) was added to the reaction mixture, and the mixture was stirred gently at 25 °C for 0.5 h. After the reaction was complete, the crude product was obtained by direct filtration. The crude product was purified by HPLC to obtain compound 5-(2-(benzyloxy)-4-(2-(3-(3,3-difluorocyclobutylidene)pyrrolidine-1-yl)ethyl)-6-fluorophenyl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide (15f) (35.0 mg, yield 10%).

[0625] LC-MS, M / Z (ESI): 522.2 [M+H] + ]

[0626] Step 6: Synthesis of 5-(4-(2-(3-(3,3-difluorocyclobutylidene)pyrrolidine-1-yl)ethyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (15)

[0627]

[0628] Under nitrogen protection at -70°C, boron tribromide (1M, 150μL) was slowly added dropwise to 5-(2-(benzyloxy)-4-(2-(3-(3,3-difluorocyclobutylidene)pyrrolidine-1-yl)ethyl)-6-fluorophenyl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide (15f) (35.0 mg, 50.0 μmol) in dichloromethane (5 mL). The reaction mixture was stirred at -70°C for 1 hour. After the reaction was completed, methanol (2 mL) was added dropwise at -40°C, and the mixture was concentrated under reduced pressure at low temperature to obtain the crude product. The crude product was purified by HPLC (column: Phenomenex luna C18 150*25mm*10μm; mobile phase: solvent A = water + 0.225% formic acid, B = acetonitrile; gradient: 5%-35%, 12min) to obtain compound 5-(4-(2-(3-(3,3-difluorocyclobutylidene)pyrrolidine-1-yl)ethyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (15).

[0629] LC-MS, M / Z (ESI): 432.1 [M+H + ]

[0630] Example 16: Preparation of target compound 16

[0631] 5-(2-fluoro-6-hydroxy-3-methyl-4-(2-(3-(prop-2-methylene)pyrrolidine-1-yl)ethyl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (16)

[0632]

[0633] The synthetic route for target compound 16 is shown below:

[0634]

[0635] Step 1: Synthesis of 1-(benzyloxy)-4-bromo-3-fluoro-2-nitrobenzene (16b)

[0636]

[0637] 1-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. The mixture was heated at 90 °C for 16 hours. The reaction was monitored by LC-MS until it ended. After returning to room temperature, ethyl acetate (500.0 mL) was added, and the mixture was washed with water (500.0 mL × 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate (1 / 0 to 10 / 1) to give compound 1-(benzyloxy)-4-bromo-3-fluoro-2-nitrobenzene (16b) (15.5 g, yield 48%).

[0638] Step 2: Synthesis of 6-(benzyloxy)-3-bromo-2-fluoroaniline (16c)

[0639]

[0640] 1-(benzyloxy)-4-bromo-3-fluoro-2-nitrobenzene (16b) (30.0 g, 92.0 mmol) was dissolved in a mixture of methanol and tetrahydrofuran (100 mL: 100 mL), iron powder (20.7 g, 368 mmol) was added, and ammonium chloride (39.2 g, 736 mmol) was dissolved in water (200 mL). The mixture was reacted at room temperature for 10 hours. The reaction was monitored by LC-MS until it ended. After returning to room temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. Ethyl acetate (500.0 mL) was added, and the mixture was washed with water (500.0 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate (1 / 0 to 7 / 3) to give compound 6-(benzyloxy)-3-bromo-2-fluoroaniline (16c) (26.3 g, 96% yield).

[0641] Step 3: Synthesis of (6-(benzyloxy)-3-bromo-2-fluorophenyl)glycine tert-butyl ester (16d)

[0642]

[0643] 6-(benzyloxy)-3-bromo-2-fluoroaniline (16c) (3.00 g, 10.0 mmol) was dissolved in N,N-dimethylformamide (30.0 mL), anhydrous potassium carbonate (3.90 g, 20.0 mmol) was added, and tert-butyl bromoacetate (4.14 g, 30.0 mmol) was added. The mixture was heated at 90 °C for 16 hours. The reaction was monitored by LC-MS until it ended. After returning to room temperature, ethyl acetate (100.0 mL) was added, and the mixture was washed with water (100.0 mL × 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate (1 / 0 to 8 / 2) to give compound (6-(benzyloxy)-3-bromo-2-fluorophenyl)glycine tert-butyl ester (16d) (3.56 g, yield 87%).

[0644] Step 4: Synthesis of (6-(benzyloxy)-2-fluoro-3-methylphenyl)glycine tert-butyl ester (16e)

[0645]

[0646] Dissolve (6-(benzyloxy)-3-bromo-2-fluorophenyl)glycine tert-butyl ester (16d) (409 mg, 1.0 mmol) in 1,4-dioxane (10.0 mL), add cesium carbonate (980 mg, 3.0 mmol), add water (1.0 mL), add pinacol methylborate (284 mg, 2.0 mmol), add Pd(dppf)Cl2 (74 mg, 0.1 mmol), mix, and then purge with nitrogen. The reaction was heated at 100℃ for 16 hours. The reaction was monitored by LC-MS until it ended. After returning to room temperature, the mixture was filtered. Ethyl acetate (50.0 mL) was added to the filtrate, and the mixture was washed with water (100.0 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate (1 / 0 to 8 / 2) to give (6-(benzyloxy)-2-fluoro-3-methylphenyl)glycine tert-butyl ester (16e) (250 mg, yield 72%).

[0647] Step 5: Synthesis of (6-(benzyloxy)-4-bromo-2-fluoro-3-methylphenyl)glycine tert-butyl ester (16f)

[0648]

[0649] (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), and NBS (254 mg, 1.50 mmol) was added. After reacting at room temperature for 2 hours, the reaction was monitored by LC-MS until it ended. After returning to room temperature, ethyl acetate (50.0 mL) was added, and the mixture was washed with water (50.0 mL × 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate (1 / 0 to 8 / 2)) to give compound (6-(benzyloxy)-4-bromo-2-fluoro-3-methylphenyl)glycine tert-butyl ester (16f) (520 mg, yield 80%).

[0650] Step 6: Synthesis of N-(6-(benzyloxy)-4-bromo-2-fluoro-3-methylphenyl)-N-aminosulfonylglycine tert-butyl ester (16g)

[0651]

[0652] (6-(benzyloxy)-4-bromo-2-fluoro-3-methylphenyl)glycine tert-butyl ester (16f) (423 mg, 1.0 mmol) was dissolved in N,N-dimethylacetamide (10.0 mL), and aminosulfonyl chloride (460 mg, 4.00 mol) was added at 0 °C. After reacting for 5 hours, the reaction was monitored by LC-MS to indicate the end of the reaction. Ethyl acetate (50.0 mL) was added, and the mixture was washed with water (50.0 mL × 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate (1 / 0 to 5 / 5)) to give compound N-(6-(benzyloxy)-4-bromo-2-fluoro-3-methylphenyl)-N-aminosulfonylglycine tert-butyl ester (16 g) (430 mg, yield 86%).

[0653] Step 7: Synthesis of 5-(6-(benzyloxy)-4-bromo-2-fluoro-3-methylphenyl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide (16h)

[0654]

[0655] N-(6-(benzyloxy)-4-bromo-2-fluoro-3-methylphenyl)-N-aminosulfonylglycine tert-butyl ester (16 g) (500 mg, 1.0 mmol) was dissolved in anhydrous methanol (10.0 mL), and a methanol solution of sodium methoxide (2.0 mL, 1.00 mol / L) was added at 0 °C. After reacting for 3 hours, the reaction was monitored by LC-MS until it was slightly acidic. The solution was then concentrated under reduced pressure, and the white mixture was washed with anhydrous acetone. After filtration, the mixture was concentrated under reduced pressure to give compound 5-(6-(benzyloxy)-4-bromo-2-fluoro-3-methylphenyl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide (16 h) (352 mg, yield 82%).

[0656] Step 8: Synthesis of 5-(6-benzyloxy)-4-(2-ethoxyvinyl)-2-fluoro-3-methylphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (16i)

[0657]

[0658] The starting materials 5-(6-benzyloxy-4-bromo-2-fluoro-3-methylphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (16h) (1.70 g, 3.96 mmol) and (E)-1-ethoxyvinyl-2-boronate linalool 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(diphenylphosphine)ferrocene palladium chloride (289 mg, 396 μmol) were slowly added, and the mixture was stirred at 95 °C for 8 hours. After the reaction was complete, the reaction solution was filtered, washed with ethyl acetate (50 mL * 3), and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:methanol = 5:1) to give compound 5-(6-benzyloxy)-4-(2-ethoxyvinyl)-2-fluoro-3-methylphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (16i) (700 mg, yield 42%).

[0659] Step 9: Synthesis of 2-(5-benzyloxy)-4-(1,1-dioxo-4-oxo-1,2,5-thiadiazolidine-2-yl)-3-fluoro-2-methylphenyl)acetaldehyde (16j)

[0660]

[0661] Under nitrogen protection, 5-(6-benzyloxy)-4-(2-ethoxyvinyl)-2-fluoro-3-methylphenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (16i) was dissolved in formic acid (5 mL) and water (0.2 mL). The reaction system was purged with nitrogen three times and stirred at 25 °C for 1.5 hours. After the reaction was complete, the 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-thiadiazolidine-2-yl)-3-fluoro-2-methylphenyl)acetaldehyde (16j) (370 mg, crude product), which was directly used in the next step.

[0662] Step 10: Synthesis of 5-(6-benzyloxy)-2-fluoro-3-methyl-4-(2-(3-(prop-2-methylene)pyrrolidone-1-yl)ethyl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (16k)

[0663]

[0664] The starting materials 3-(propane-2-methylene)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-dioxo-4-oxo-1,2,5-thiadiazolidine-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 the reaction, and the mixture was extracted with dichloromethane (20 mL * 3), washed with saturated brine (20 mL * 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by HPLC to obtain compound 5-(6-benzyloxy)-2-fluoro-3-methyl-4-(2-(3-(prop-2-methylene)pyrrolidine-1-yl)ethyl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (16k) (140mg, yield 30%).

[0665] LC-MS, M / Z (ESI): 486.2 [M+H] + ]

[0666] Step 11: Synthesis of 5-(2-fluoro-6-hydroxy-3-methyl-4-(2-(3-(prop-2-methylene)pyrrolidine-1-yl)ethyl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (16)

[0667]

[0668] The starting material 5-(6-benzyloxy)-2-fluoro-3-methyl-4-(2-(3-(prop-2-methylene)pyrrolidine-1-yl)ethyl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (16k) (140mg, 287μmol) was dissolved in dichloromethane (3mL). The reaction system was then purged with nitrogen three times. 2M boron tribromide (1.44mL) was slowly added to the reaction solution at -70°C, and the mixture was stirred at -70°C for 1 hour. After the reaction was complete, methanol (3mL) was added at -70°C to quench the reaction. The pH was adjusted to 8 with ammonia solution, and the mixture was filtered and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by HPLC using the following method (column: Waters Atlantis T3 100*30mm*5μm; solvent: A = water + 10mM ammonium bicarbonate, B = acetonitrile; gradient: 5%-35%, 10 minutes) to obtain compound 5-(2-fluoro-6-hydroxy-3-methyl-4-(2-(3-(prop-2-methylene)pyrrolidone-1-yl)ethyl)phenyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (16).

[0669] 1 H NMR(400MHz,DMSO-d6)δ9.68-9.94(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=1.75Hz,3H)1.66(s,6H)

[0670] LC-MS, M / Z (ESI): 398.2 [M+H] + ]

[0671] The preparation methods for the following compounds are the same as those in Examples 1-16 above:

[0672]

[0673]

[0674]

[0675] Biological testing

[0676] Experimental Example 1: Determination of the inhibitory effect of compounds on PTPN1 / PTPN2 enzyme activity

[0677] Experimental methods

[0678] 1) Protein preparation. PTPN1 protein (#1366-PT) was purchased from R&D Company, and PTPN2 protein (#E2302T-H28H) was from Aisipu Company. PTPN1 and PTPN2 proteins were diluted with diluent (50mM Tris-HCl, pH 7.2, 50mM NaCl, 0.01% Triton X-100, 1mM DTT) to obtain final enzyme working solutions of 0.2nM and 0.5nM, respectively.

[0679] 2) Dilute the compound in 384-well plates. Dissolve the compound in DMSO to prepare a 10 mM stock solution, and then perform a 3-fold serial dilution to obtain 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.

[0680] 3) Use the Echo pipetting system to transfer 0.1 μL of the diluted compound solution in each row to a 384-well detection plate, with each column containing 2 replicates.

[0681] 4) Add 5 μL of enzyme working solution to the 384-well plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 10 minutes.

[0682] 5) Add 5 μL of substrate (DiFMUP, Thermo Fisher, D6567) working solution to a final concentration of 10 μM, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 30 minutes.

[0683] 6) Use instruments from BMG (Germany) to read fluorescence signals with an excitation wavelength of 360 nm and an emission wavelength of 460 nm.

[0684] 7) Data Analysis: Inhibition percentage (%) of compound wells = 100 × (mean high control value - compound well value) / (mean high control value - mean low control value), where high control: dimethyl sulfoxide (DMSO) and enzyme, low control: dimethyl sulfoxide (DMSO) and assay buffer; the half-maximal inhibitory concentration (IC50) of the compound was fitted using XLfit 5.5.0 software via a nonlinear regression equation, Y = Bottom +

[0685] (Top-Bottom) / (1+10^((LogIC50-X)*HillSlope)).

[0686] Experimental conclusion: The compound of this invention has excellent inhibitory effect on PTPN2 enzyme, IC50... 50 All are less than 500 nM. Exemplary compounds are shown in Table 1 below.

[0687] Table 1. Inhibitory activity of the tested compounds against PTPN2 enzyme.

[0688] Test compounds <![CDATA[IC 50 (nM)]]> Compound 4 10.3 Compound 5 11.9 Compound 6 21.3

[0689] Experimental Example 2: Determination of the effect of the compound on the proliferation of B16F10 cells

[0690] Experimental methods

[0691] 1) Cell culture. The culture medium was 1640 medium containing 10% (v / v) inactivated fetal bovine serum, 100 U / mL penicillin and 100 μg / mL streptomycin. B16F10 mouse melanoma cells (purchased from Wuhan Pronosai Life Science Technology Co., Ltd.) were cultured in an incubator at 37℃ and 5% CO2. After the cell confluence reached 80-90%, the cells were passaged separately in separate bottles.

[0692] 2) Cell plating. Cells in the logarithmic growth phase were used for plating. B16F10 mouse melanoma cells were plated in 96-well plates with 100 μL of culture medium, approximately 500 cells per well, and cultured overnight.

[0693] 3) Compound dilution. The compound was dissolved in DMSO to a concentration of 10 mM. Subsequently, the compound was serially 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.

[0694] 4) Medium replacement treatment. Take 1 μL of the diluted compound and add it to 1 mL of complete culture medium. Mix well. Take out the culture medium from the 96-well plate and add 100 μL of the drug solution to the 96-well plate. The working concentrations are 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.

[0695] 5) IFNγ treatment. After about 10 minutes, add IFNγ to bring the final concentration to 10 ng / mL.

[0696] 6) Activity assay. Cell viability was assessed 96 hours after drug treatment, using the method described above. 2.0 (Promega, #G9243)

[0697] manual.

[0698] 7) IC 50calculate. Relative viability(%)=(LumninenceDMSO-Lumninence experiment) / (LumninenceDMSO-

[0699] The slope was calculated using GraphPad Prism software with a margin of 100% (no data) and a log (inhibitor) vs. response--Variable slope (four parameters).

[0700] Experimental conclusion: The compound of this invention can significantly inhibit the proliferation of B16F10 cells, IC50... 50 All are less than 5 μM, and exemplary compounds are shown in Table 2.

[0701] Table 2 shows the inhibitory activity of the tested compounds on the proliferation of B16F10 cells.

[0702]

[0703]

[0704] The positive control drugs in Experiments 3-5 below are selected from compound 118 disclosed in WO2022056281A1, with the following structure:

[0705]

[0706] Experimental Example 3: Mouse Pharmacokinetic Study

[0707] Pharmacokinetic studies were conducted in mice using male ICR mice (20-25g, fasted overnight). Three mice were administered 10 mg / kg orally via gavage. Blood samples were collected before administration and at 15, 30 minutes, and 1, 2, 4, 8, and 24 hours post-administration. Three other ICR mice were administered 1 mg / kg intravenously, with blood samples collected before administration and at 15, 30 minutes, and 1, 2, 4, 8, and 24 hours post-administration. Blood samples were centrifuged at 6800g and 2-8℃ for 6 minutes, and plasma was collected and stored at -80℃. Plasma samples from each time point were mixed with 3-5 times the volume of acetonitrile solution containing an internal standard, vortexed for 1 minute, centrifuged at 13000 rpm at 4℃ for 10 minutes, and the supernatant was mixed with 3 times the volume of water. An appropriate amount of the mixture was analyzed by LC-MS / MS. Key pharmacokinetic parameters were analyzed using a non-compartmental model with WinNonlin 7.0 software.

[0708] Table 3 Results of mouse pharmacokinetics test

[0709]

[0710] The results of the pharmacokinetic studies in mice showed that the compounds of the present invention exhibited excellent pharmacokinetic properties in mice, with low clearance, high systemic exposure and bioavailability, and good drug-likeness.

[0711] Experimental Example 4: Rat Pharmacokinetic Study

[0712] Pharmacokinetic studies were conducted on male SD rats (180-240g) that had been fasted overnight. Three rats were administered the drug 10 mg / kg orally via gavage. Blood samples were collected before administration and at 15, 30 minutes, 1, 2, 4, 8, and 24 hours after administration. Blood samples were centrifuged at 6800g and 2-8℃ for 6 minutes, and plasma was collected and stored at -80℃. Plasma samples at each time point were mixed with 3-5 times the volume of acetonitrile solution containing an internal standard, vortexed for 1 minute, centrifuged at 13000 rpm at 4℃ for 10 minutes, and the supernatant was mixed with 3 times the volume of water. An appropriate amount of the mixture was analyzed by LC-MS / MS. The main pharmacokinetic parameters were analyzed using a non-compartmental model with WinNonlin 7.0 software.

[0713] Table 4 Results of Rat Pharmacokinetic Test

[0714]

[0715] The results of the pharmacokinetic studies in rats showed that the compound of the present invention exhibited excellent pharmacokinetic properties in rats and good drug-likeness.

[0716] Experimental Example 5: Canine Pharmacokinetic Study

[0717] Canine pharmacokinetic studies were conducted using male Beagle dogs, weighing 8-10 kg, which were fasted overnight. Three Beagle dogs were administered 5 mg / kg orally via gavage, and blood samples were collected before administration and at 15, 30 minutes, and 1, 2, 4, 8, and 24 hours post-administration. Another three Beagle dogs were administered 1 mg / kg intravenously, and blood samples were collected before administration and at 15, 30 minutes, and 1, 2, 4, 8, and 24 hours post-administration. Blood samples were centrifuged at 6800g and 2-8℃ for 6 minutes, and plasma was collected and stored at -80℃. Plasma samples from each time point were mixed with 3-5 times the volume of acetonitrile solution containing an internal standard, vortexed for 1 minute, centrifuged at 13000 rpm at 4℃ for 10 minutes, and the supernatant was mixed with 3 times the volume of water. An appropriate amount of the mixture was analyzed by LC-MS / MS. Key pharmacokinetic parameters were analyzed using a non-compartmental model with WinNonlin 7.0 software.

[0718] Table 5 Results of canine pharmacokinetics studies

[0719]

[0720] The results of canine pharmacokinetic studies show that the compounds of this invention exhibit excellent canine pharmacokinetic properties, with low clearance, high systemic exposure and bioavailability, and good drug-likeness.

Claims

1. The compound represented by formula (Ⅰ), its tautomers, stereoisomers, or pharmaceutically acceptable salts, in, 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 6-10 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; 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; 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; Each R a1 They are H and halogens, respectively, and can be distinguished independently. 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; 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 -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)-; R L1 For H, 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, 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. b replace; 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 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. c replace; Each R c They can be independently H, halogen, OH, NH2, CN, =O or COOH; m can be 1, 2, 3, or 4; X1 is N or CR x1 ; X2 is N or CR x2 ; X3 is N or CR x3 ; X4 is 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 surrounded by 1, 2, 3, or 4 R groups. d replace; Each R d They can be independently H, halogen, OH, NH2, CN, =O or COOH; The heteroatom groups in the "heterocyclic alkyl", "heterocyclic alkenyl" and "heteroaryl" include N, O or S, and the number of heteroatom groups is 1, 2, 3 or 4; when the number of heteroatom groups is multiple, the heteroatom groups may be the same or different.

2. The compound according to claim 1, its tautomers, stereoisomers, or pharmaceutically acceptable salts, characterized in that, 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; And / or, each R A Each is independently H, halogen, and C. 1-3 Alkyl or C 1-3 Halogenated alkyl groups; And / or, each R A Each is independently represented by H; And / or, ring A is C 3-6 Cycloalkyl, 3-8 membered monocyclic heterocyclic alkyl, or 6-10 membered bicyclic heterocyclic alkyl, wherein the bicyclic includes fused rings, spirocyclic rings, and bridged rings, and the ring A is optionally surrounded by 1, 2, 3, or 4 R's. A replace; And / or, the 6-10 quinone bicyclic heterocyclic alkyl group is a 4-6 quinone 4-6 quinone heterocyclic alkyl group; And / or, ring A is cyclobutyl, cyclopentyl, cyclohexyl, azircyclobutyl, azircyclopentyl, azircyclohexyl, azircyclopentyl, and azircyclopentyl; And / or, for And / or, ring A is a 5-6 membered monocyclic heterocyclic alkyl group, wherein ring A is optionally surrounded by 1, 2, 3 or 4 R groups. A replace; And / or, ring A is an azacyclopentyl group; And / or, for And / or, R1 and R2 are independently H, F, Cl, Br, C, respectively. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy, C 1-3 Alkylamino, C 3-6 cycloalkyl, C 3-6 Cycloalkenyl, phenyl, 3-6 membered heterocyclic alkyl, 3-6 membered heterocyclic alkenyl or 5-6 membered heteroaryl, wherein C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy, C 1-3 Alkylamino, C 3-6 cycloalkyl, C 3-6 Cycloalkenyl, phenyl, 3-6-membered heterocyclic alkyl, 3-6-membered heterocyclic alkenyl, and 5-6-membered heteroaryl are each independently and optionally surrounded by 1, 2, 3, or 4 R groups. a replace; And / or, each R a They can be independently H, F, Cl, Br, OH, NH2, CN, =O, or COOH; And / or, each R a Each can be H or F independently; And / or, R1 and R2 are independently H, F, CF3, methyl or ethyl; And / or, R1, R2, together with the carbon atoms they are bonded to, form C 3-6 Heterocyclic alkyl, the C 3-6 Heterocyclic alkyl groups are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. a replace; And / or, each R a Each is independently represented by H; And / or, the C 3-6 Heterocyclic alkyl groups are selected from C 5-6 Heterocyclic alkyl, the C 5-6 Heterocyclic alkyl groups are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. a replace; And / or, R1, R2 together with the carbon atoms they are attached to form a tetrahydrofuranyl group; And / or, R1, R2, together with the carbon atoms they are bonded to, form C 3-6 cycloalkyl, the C 3-6 The cycloalkyl groups are each independently and optionally marked with 1, 2, 3 or 4 R's. a replace; And / or, each R a Each is independently H, halogen, or optionally surrounded by 1, 2, 3, or 4 Rs. a1 Replacement C 1-3 alkyl; And / or, R1, R2, together with the carbon atoms they are bonded to, form C 3-6 cycloalkyl, the C 3-6 The cycloalkyl groups are each independently and optionally marked with 1, 2, 3 or 4 R's. a Replace; where each R a Each can be independently H, F, or methyl; And / or, R1, R2, together with the carbon atoms they are attached to, form cyclopropyl, cyclobutyl, or cyclopentyl groups, wherein the cyclopropyl, cyclobutyl, and cyclopentyl groups are each independently and optionally converted by 1, 2, 3, or 4 R atoms. a replace; And / or, R1, R2, together with the carbon atoms they are attached to, form cyclopropyl, cyclobutyl, or cyclopentyl groups, wherein the cyclopropyl, cyclobutyl, and cyclopentyl groups are each independently and optionally converted by 1, 2, 3, or 4 R atoms. a Replace; where each R a Each can be independently H, F, or methyl; And / or, for And / or, for And / or, for 3. The compound according to claim 1, its tautomers, stereoisomers, or pharmaceutically acceptable salts, characterized in that, 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 For H, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy, C 1-3 Alkylamino, C 3-6 cycloalkyl, C 3-6 Cycloalkenyl, 3-6 membered heterocyclic alkyl, or 3-6 membered heterocyclic alkenyl, wherein C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy, C 1-3 Alkylamino, C 3-6 cycloalkyl, C 3-6 The cycloalkenyl, 3-6 membered heterocyclic alkyl, and 3-6 membered heterocyclic alkenyl groups are each independently and optionally surrounded by 1, 2, 3, or 4 R groups. b replace; And / or, each R b They can be independently H, F, Cl, Br, OH, NH2, CN, =O, or COOH; And / or, R L1 For H; And / or, R L2 For H, F, Cl, Br, OH, NH2, CN, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy, C 1-3 Alkylamino, C 3-6 cycloalkyl, C 3-6 Cycloalkenyl, 3-6 membered heterocyclic alkyl, or 3-6 membered heterocyclic alkenyl, wherein C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy, C 1-3 Alkylamino, C 3-6 cycloalkyl, C 3-6 The cycloalkenyl, 3-6 membered heterocyclic alkyl, and 3-6 membered heterocyclic alkenyl groups are each independently and optionally surrounded by 1, 2, 3, or 4 R groups. c replace; And / or, each R c They can be independently H, F, Cl, Br, OH, NH2, CN, =O, or COOH; And / or, R L2 For 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 according to claim 1, its tautomers, stereoisomers, or pharmaceutically acceptable salts, characterized in that, X1 is CR x1 ; And / or, R x1 For H, F, Cl, Br, OH, NH2, CN, COOH, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy, C 1-3 Alkylamino, C 3-6 cycloalkyl, C 3-6 Cycloalkenyl, 3-6 membered heterocyclic alkyl, or 3-6 membered heterocyclic alkenyl, wherein C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy, C 1-3 Alkylamino, C 3-6 cycloalkyl, C 3-6 The cycloalkenyl, 3-6 membered heterocyclic alkyl, and 3-6 membered heterocyclic alkenyl groups are each independently and optionally surrounded by 1, 2, 3, or 4 R groups. d replace; And / or, R x1 It can be H, F, or methyl; And / or, R x1 For F; And / or, X2 is N or CR x2 ; And / or, R x2 For H, F, Cl, Br, OH, NH2, CN, COOH, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy, C 1-3 Alkylamino, C 3-6 cycloalkyl, C 3-6 Cycloalkenyl, 3-6 membered heterocyclic alkyl, or 3-6 membered heterocyclic alkenyl, wherein C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy, C 1-3 Alkylamino, C 3-6 cycloalkyl, C 3-6 The cycloalkenyl, 3-6 membered heterocyclic alkyl, and 3-6 membered heterocyclic alkenyl groups are each independently and optionally surrounded by 1, 2, 3, or 4 R groups. d replace; And / or, R x2 For H, F, Cl, CN, C 1-3 Alkyl or C 2-4 alkynyl group, the C 1-3 Alkyl and C 2-4 The alkynyl group is independently and optionally surrounded by 1, 2, 3 or 4 R groups. d replace; And / or, R x2 It can be H, F, Cl, CN, methyl, CF3, or ethynyl (-C≡CH); And / or, R x2 For H, F, C 1-3 Alkyl, the C 1-3 Alkyl groups are optionally surrounded by 1, 2, 3 or 4 R's. d replace; And / or, R x2 It can be H, F, or methyl; And / or, each R d They can be independently H, F, Cl, Br, OH, NH2, CN, =O, or COOH; And / or, X3 is N or CR x3 ; And / or, R x3 For H or F; And / or, X4 is CR x4 ; And / or, R x4 It is OH or NH2; And / or, R x4 It is OH.

5. The compound according to claim 1, its tautomers, stereoisomers, or pharmaceutically acceptable salts, characterized in that, The compound shown in formula (Ⅰ) has structural formula (Ⅰ-1) or (Ⅰ-2): R1, R2, L, R x1 X2 and ring A are as defined in claim 1.

6. The compound according to claim 1, its tautomers, stereoisomers, or pharmaceutically acceptable salts, characterized in that, The compound is selected from the following structures:

7. A pharmaceutical composition, characterized in that, It comprises a therapeutically effective amount 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 according to any one of claims 1-6, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or of the pharmaceutical composition of claim 7, wherein the use comprises: Inhibit the expression of PTPN1 and / or PTPN2; And / or, Prepare medicines for the treatment of PTPN1 and / or PTPN2-related diseases; and / or, Preparation of PTPN1 and / or PTPN2 inhibitors; and / or, Used to treat PTPN1 and / or PTPN2 related diseases.

9. The use according to claim 8, characterized in that, The diseases mentioned include solid tumors.

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

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