Benzo ring-containing compound as protein tyrosine phosphatase inhibitor, and use thereof

Abstract

The present invention relates to a benzo ring-containing compound as a PTPN1 and / or PTPN2 inhibitor and use thereof, and particularly relates to a compound of formula (I), a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, a method for preparing same, and use thereof in the preparation of a medicament for treating a PTPN1 and / or PTPN2-related disease.

Description

Benzocyclic compounds as inhibitors of protein tyrosine phosphatase and their uses

[0001] This invention claims the following:

[0002] Priority is claimed for the earlier application filed with the China National Intellectual Property Administration on November 20, 2024, with patent application number 202411667985.3 and title "Benzocyclic compounds as protein tyrosine phosphatase inhibitors and their uses therein".

[0003] Priority is claimed to the earlier application filed with the China National Intellectual Property Administration on January 22, 2025, with patent application number 202510104293.6 and title "Benzocyclic compounds as protein tyrosine phosphatase inhibitors and their uses therein".

[0004] Priority is claimed to the earlier application filed with the China National Intellectual Property Administration on April 21, 2025, with patent application number 202510503121.6 and title "Benzocyclic compounds as protein tyrosine phosphatase inhibitors and their uses therein".

[0005] The full text of the aforementioned prior application is incorporated herein by reference. Technical Field

[0006] This invention relates to the pharmaceutical field, and more specifically, to a class of benzo[a]cyclic compounds as inhibitors of PTPN1 and / or PTPN2 and their uses. Background Technology

[0007] 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.

[0008] 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.

[0009] 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 confirmed 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 mouse observations, 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-specific PTP1B deficiency does not promote systemic inflammation or autoimmunity. Nevertheless, PTP1B or PTPN2 deficiency in T cells significantly enhances anti-tumor immunity. PTPN2 deficiency 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 deficiency of PTP1B in T cells or CAR T cells significantly enhances anti-tumor immunity and promotes STAT-5 signaling. These studies identify PTP1B and PTPN2 as T cell checkpoints, with functions similar to those mediated by the inhibitory receptor PD-1 on the T cell surface.

[0010] 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

[0011] 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.

[0012] in,

[0013] R1 is H, NH2, CN, or -CR 11 =CR12 R 13 3-8 membered heterocyclic alkyl groups, C 6-10 Aryl or 5-10-membered heteroaryl, wherein the 3-8-membered heterocyclic alkyl, C 6-10 The aryl and 5-10 heteroaryl groups are independently and optionally bounded by 1, 2, 3 or 4 R groups. a replace;

[0014] R 11 R 12 and R 13 Each is independently H, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 3-8 cycloalkyl;

[0015] R 1’ H, halogen, OH, NH2, CN, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-8 cycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy and C 3-8 The cycloalkyl groups are each independently and optionally marked with 1, 2, 3 or 4 R's. a’ replace;

[0016] R2 and R 2’ They are, independently, H, halogen, OH, NH2, CN, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl or 3-8 membered heterocycloalkyl, wherein C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl and 3-8 membered heterocycloalkyl groups are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. b replace;

[0017] R3 and R 3’ They are, independently, H, halogen, OH, NH2, CN, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-8 Cycloalkyl or 3-8 membered heterocycloalkyl, wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-8 Cycloalkyl and 3-8 membered heterocycloalkyl groups are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. c replace;

[0018] R4 represents H, halogen, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy or C 3-8 cycloalkyl, the C 1-6 Alkyl, C 2-6 alkenyl, C 2- 6-acetylinyl, C 1-6 Alkoxy and C 3-8 The cycloalkyl groups are each independently and optionally marked with 1, 2, 3 or 4 R's. d replace;

[0019] R5 is H or halogen;

[0020] X is CR x1 R x1’ or NR x2 ;

[0021] R x1 For H, halogens, OH, CN, NH2, -NR x11 -C 1-10 Alkyl, -NR x11 -C 0-6 Alkylene-C 3-8 cycloalkyl, -NR x11 -C 0-6 alkylene-5-10 heteroaryl, -NR x11 -C 0-6 Alkylene-S(R) x12 ) w C 1-8 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-8 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl or 5-10 heteroaryl, the -NR x11 -C 1-10 Alkyl, -NR x11 -C 0-6 Alkylene-C 3-8 cycloalkyl, -NR x11 -C 0- 6-alkylene-5-10-membered heteroaryl, -NR x11 -C 0-6 Alkylene-S(R) x12 ) w C 1-8 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-8 Alkoxy, C3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 The aryl and 5-10 heteroaryl groups are independently and optionally bounded by 1, 2, 3 or 4 R groups. e replace;

[0022] R x11 For H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0023] Each R x12 Each is independently H, halogen, and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0024] Each R e 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 or C 3- 8-cycloalkyl, the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy and C 3-8 The cycloalkyl groups are each independently and optionally marked with 1, 2, 3 or 4 R's. f Replace; or, two Rs connected to the same C e form Among them, R e1 R e2 They are independently H, halogen, OH, CN, COOH, and C, respectively. 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0025] R x1’ H, -NR x11 -C 0-6 Alkylene-S(R) x12 ) w -S (=O) m -NR x11 -C 1-6 Alkyl, -NR x11 -C(R x13 )2-NR x11 -C 1-6 Alkyl, -NR x11 -C 0- 6-alkylene-C 7-10 cycloalkyl, -NR x11 -C 0-6 Alkylene-C 7-10Cycloalkenyl, -NR x11 -C 0-6 Alkylene (with 1, 2, 3 or 4 Rs) ee Replacement C 3- 6-cycloalkyl), -NR x11 -C 0-6 Alkylene-7-12-membered heterocyclic alkyl, -OC 3-8 cycloalkyl, -NR x11 -C 3-6 cycloalkyl-C 6-12 Aryl, -NR x11 -4-6 membered heterocyclic alkyl-C 6-12 Aryl, -NR x11 -C 6-12 Aryl, -NR x11 -5-12 heteroaryl groups, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-8 cycloalkyl, (with 1, 2, 3 or 4 Rs) ee Substituted 3-6-membered heterocyclic alkyl groups or 7-12-membered heterocyclic alkyl groups, wherein -NR x11 -C 0-6 Alkylene-S(R) x12 ) w -S (=O) m -NR x11 -C 1-6 Alkyl, -NR x11 -C(R x13 )2-NR x11 -C 1-6 Alkyl, -NR x11 -C 0-6 Alkylene-C 7-10 cycloalkyl, -NR x11 -C 0-6 Alkylene-C 7-10 Cycloalkenyl, -NR x11 -C 0-6 Alkylene (with 1, 2, 3 or 4 Rs) ee Replacement C 3-6 cycloalkyl), -NR x11 -C 0- 6-alkylene-7-12-membered heterocyclic alkyl, -OC 3-8 cycloalkyl, -NR x11 -C 3-6 cycloalkyl-C 6-12 Aryl, -NR x11 -4-6 membered heterocyclic alkyl-C 6-12 Aryl, -NR x11 -C6-12 Aryl, -NR x11 -5-12 heteroaryl groups, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-8 cycloalkyl, (with 1, 2, 3 or 4 Rs) ee The substituted 3-6-membered heterocyclic alkyl groups and 7-12-membered heterocyclic alkyl groups are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. e’ replace;

[0026] Each R x13 Each is independently H, halogen, and C. 1-6 Alkyl or C 1-6 Halogenated alkyl, or, two Rs x13 Formation = O;

[0027] R x2 -C 0-6 Alkylene-S(R) x12 ) w The -C 0-6 Alkylene-S(R) x12 ) w Independently and optionally by 1, 2, 3 or 4 R g replace;

[0028] Each R a R a’ R b R c R d R f R g Each can be independently H, halogen, OH, NH2, CN, COOH, or C. 1-6 alkyl;

[0029] Each R e’ The independent components are H, halogen, OH, NH2, CN, COOH, and C, respectively. 1-6 Alkyl, C 1-6 Halogenated alkyl or C 3-6 cycloalkyl; or, two R groups attached to the same C. e’ form

[0030] Each R ee Each independently

[0031] Each R e3 R e4 They are independently H, halogen, OH, CN, COOH, and C, respectively. 1-6 Alkyl or C 1-6Halogenated alkyl groups;

[0032] w is 1, 3, or 5;

[0033] m is 0, 1, or 2;

[0034] The equation (I) is not In addition, the R x1’ R x1 R1, R2, R 2’ One of the following conditions must be met:

[0035] a)R x1’ C 1-6 Alkyl, C 2-6 alkenyl, C 1-6 Alkoxy or C 3-8 When cycloalkyl, R x1 Not H; or,

[0036] b)R x1’ When H is true, R1 is not true; or,

[0037] c)R x1’ When H is , R2 and R 2’ Not both H;

[0038] The heteroatoms in the "heterocyclic alkyl" and "heteroaryl" include N, O, and S. The S heteroatoms can be optionally oxidized to S(=O) or S(=O)2. The number of heteroatoms is 1, 2, 3, or 4. When there are multiple heteroatoms, the heteroatoms may be the same or different.

[0039] According to embodiments of the present invention, compounds of formula (I), their tautomers, stereoisomers, or pharmaceutically acceptable salts are provided.

[0040] in,

[0041] R1 is H, NH2, CN, or -CR 11 =CR 12 R 13 3-8 membered heterocyclic alkyl groups, C 6-10 Aryl or 5-10-membered heteroaryl, wherein the 3-8-membered heterocyclic alkyl, C 6-10 The aryl and 5-10 heteroaryl groups are independently and optionally bounded by 1, 2, 3 or 4 R groups. a replace;

[0042] R 11 R 12 and R 13 Each is independently H, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C1-6 Alkoxy or C 3-8 cycloalkyl;

[0043] R 1’ H, halogen, OH, NH2, CN, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-8 cycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy and C 3-8 The cycloalkyl groups are each independently and optionally marked with 1, 2, 3 or 4 R's. a’ replace;

[0044] R2 and R 2’ They are, independently, H, halogen, OH, NH2, CN, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl or 3-8 membered heterocycloalkyl, wherein C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl and 3-8 membered heterocycloalkyl groups are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. b replace;

[0045] R3 and R 3’ They are, independently, H, halogen, OH, NH2, CN, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-8 Cycloalkyl or 3-8 membered heterocycloalkyl, wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-8 Cycloalkyl and 3-8 membered heterocycloalkyl groups are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. c replace;

[0046] R4 represents H, halogen, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy or C 3-8 cycloalkyl, the C 1-6 Alkyl, C 2-6 alkenyl, C 2- 6-acetylinyl, C 1-6 Alkoxy and C 3-8 The cycloalkyl groups are each independently and optionally marked with 1, 2, 3 or 4 R's. d replace;

[0047] R5 is H or halogen;

[0048] X is CR x1 R x1’ or NR x2 ;

[0049] R x1 For H, halogens, OH, CN, NH2, -NR x11 -C 1-10 Alkyl, -NR x11 -C 0-6 Alkylene-C 3-8 cycloalkyl, -NR x11 -C 0-6 alkylene-5-10 heteroaryl, -NR x11 -C 0-6 Alkylene-S(R) x12 ) w C 1-8 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-8 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl or 5-10 heteroaryl, the -NR x11 -C 1-10 Alkyl, -NR x11 -C 0-6 Alkylene-C 3-8 cycloalkyl, -NR x11 -C 0- 6-alkylene-5-10-membered heteroaryl, -NR x11 -C 0-6 Alkylene-S(R) x12 ) w C 1-8 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-8 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 The aryl and 5-10 heteroaryl groups are independently and optionally bounded by 1, 2, 3 or 4 R groups. e replace;

[0050] R x11 For H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0051] Each R x12 Each is independently H, halogen, and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0052] Each R e 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 or C 3- 8-cycloalkyl, the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy and C 3-8 The cycloalkyl groups are each independently and optionally marked with 1, 2, 3 or 4 R's. f replace;

[0053] R x1’ H, -NR x11 -C 0-6 Alkylene-S(R) x12 ) w -S (=O) m -NR x11 -C 1-6 Alkyl, -NR x11 -C(R x13 )2-NR x11 -C 1-6 Alkyl, -NR x11 -C 0- 6-alkylene-C 7-10 cycloalkyl, -NR x11 -C 0-6 Alkylene-7-12-membered heterocyclic alkyl, -OC 3-8 cycloalkyl, -NR x11 -C 3-6 cycloalkyl-C 6-12 Aryl, -NR x11 -4-6 membered heterocyclic alkyl-C 6-12 Aryl, -NR x11 -C 6-12 Aryl, -NR x11 -5-12 heteroaryl groups, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy or C 3-8 cycloalkyl, the -NR x11 -C 0-6 Alkylene-S(R) x12 ) w -S (=O) m -NR x11 -C 1-6 Alkyl, -NR x11 -C(Rx13 )2-NR x11 -C 1-6 Alkyl, -NR x11 -C 0-6 Alkylene-C 7-10 cycloalkyl, -NR x11 -C 0-6 Alkylene-7-12-membered heterocyclic alkyl, -OC 3-8 cycloalkyl, -NR x11 -C 3-6 cycloalkyl-C 6-12 Aryl, -NR x11 -4-6 membered heterocyclic alkyl-C 6-12 Aryl, -NR x11 -C 6-12 Aryl, -NR x11 -5-12 heteroaryl groups, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy and C 3-8 The cycloalkyl groups are each independently and optionally marked with 1, 2, 3 or 4 R's. e’ replace;

[0054] R x13 H, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl, or, two Rs x13 Formation = O;

[0055] R x2 -C 0-6 Alkylene-S(R) x12 ) w The -C 0-6 Alkylene-S(R) x12 ) w Independently and optionally by 1, 2, 3 or 4 R g replace;

[0056] Each R a R a’ R b R c R d R f R g Each can be independently H, halogen, OH, NH2, CN, COOH, or C. 1-6 alkyl;

[0057] Each R e’ The independent components are H, halogen, OH, NH2, CN, COOH, and C, respectively. 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0058] w is 1, 3, or 5;

[0059] m is 0, 1, or 2;

[0060] In addition, the R x1’ R x1 R1, R2, R 2’ One of the following conditions must be met:

[0061] a)R x1’ C 1-6 Alkyl, C 2-6 alkenyl, C 1-6 Alkoxy or C 3-8 When cycloalkyl, R x1 Not H; or,

[0062] b)R x1’ When H is true, R1 is not true; or,

[0063] c)R x1’ When H is , R2 and R 2’ Not both H;

[0064] The heteroatoms in the "heterocyclic alkyl" and "heteroaryl" include N, O, and S. The S heteroatoms can be optionally oxidized to S(=O) or S(=O)2. The number of heteroatoms is 1, 2, 3, or 4. When there are multiple heteroatoms, the heteroatoms may be the same or different.

[0065] According to embodiments of the present invention, compounds of formula (I), their tautomers, stereoisomers, or pharmaceutically acceptable salts are provided.

[0066] in,

[0067] R1 is H, NH2, CN, or -CR 11 =CR 12 R 13 3-8 membered heterocyclic alkyl groups, C 6-10 Aryl or 5-10-membered heteroaryl, wherein the 3-8-membered heterocyclic alkyl, C 6-10 The aryl and 5-10 heteroaryl groups are independently and optionally bounded by 1, 2, 3 or 4 R groups. a replace;

[0068] R 11 R 12 and R 13 Each is independently H, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 3-8cycloalkyl;

[0069] R 1’ H, halogen, OH, NH2, CN, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-8 cycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy and C 3-8 The cycloalkyl groups are each independently and optionally marked with 1, 2, 3 or 4 R's. a’ replace;

[0070] R2 and R 2’ They are, independently, H, halogen, OH, NH2, CN, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl or 3-8 membered heterocycloalkyl, wherein C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl and 3-8 membered heterocycloalkyl groups are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. b replace;

[0071] R3 and R 3’ They are, independently, H, halogen, OH, NH2, CN, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-8 Cycloalkyl or 3-8 membered heterocycloalkyl, wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-8 Cycloalkyl and 3-8 membered heterocycloalkyl groups are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. c replace;

[0072] R4 represents H, halogen, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy or C 3-8 cycloalkyl, the C 1-6 Alkyl, C 2-6 alkenyl, C 2- 6-acetylinyl, C 1-6 Alkoxy and C 3-8 The cycloalkyl groups are each independently and optionally marked with 1, 2, 3 or 4 R's. d replace;

[0073] R5 is H or halogen;

[0074] X is CR x1 R x1’ or NR x2 ;

[0075] R x1 For H, halogens, OH, CN, NH2, -NR x11 -C 1-10 Alkyl, -NR x11 -C 0-6 Alkylene-C 3-8 cycloalkyl, -NR x11 -C 0-6 alkylene-5-10 heteroaryl, -NR x11 -C 0-6 Alkylene-S(R) x12 ) w C 1-8 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-8 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl or 5-10 heteroaryl, the -NR x11 -C 1-10 Alkyl, -NR x11 -C 0-6 Alkylene-C 3-8 cycloalkyl, -NR x11 -C 0- 6-alkylene-5-10-membered heteroaryl, -NR x11 -C 0-6 Alkylene-S(R) x12 ) w C 1-8 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-8 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 The aryl and 5-10 heteroaryl groups are independently and optionally bounded by 1, 2, 3 or 4 R groups. e replace;

[0076] R x11 For H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0077] Each R x12 Each is independently H, halogen, and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0078] Each Re 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 or C 3- 8-cycloalkyl, the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy and C 3-8 The cycloalkyl groups are each independently and optionally marked with 1, 2, 3 or 4 R's. f replace;

[0079] R x1’ H, -NR x11 -C 0-6 Alkylene-S(R) x12 ) w -S (=O) m -NR x11 -C 1-6 Alkyl, -NR x11 -C(R x13 )2-NR x11 -C 1-6 Alkyl, -NR x11 -C 0- 6-alkylene-C 7-10 cycloalkyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy or C 3-8 cycloalkyl, the -NR x11 -C 0-6 Alkylene-S(R) x12 ) w -S (=O) m -NR x11 -C 1-6 Alkyl, -NR x11 -C(R x13 )2-NR x11 -C 1-6 Alkyl, -NR x11 -C 0-6 Alkylene-C 7-10 cycloalkyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy and C 3-8 The cycloalkyl groups are each independently and optionally marked with 1, 2, 3 or 4 R's. e’ replace;

[0080] R x13 H, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl, or, two Rs x13 Formation = O;

[0081] R x2 -C 0-6 Alkylene-S(R) x12 ) w The -C 0-6 Alkylene-S(R) x12 ) w Independently and optionally by 1, 2, 3 or 4 R g replace;

[0082] Each R a R a’ R b R c R d R e’ R f R g Each can be independently H, halogen, OH, NH2, CN, COOH, or C. 1-6 alkyl;

[0083] w is 1, 3, or 5;

[0084] m is 0, 1, or 2;

[0085] In addition, the R x1’ R x1 R1, R2, R 2’ One of the following conditions must be met:

[0086] a)R x1’ C 1-6 Alkyl, C 2-6 alkenyl, C 1-6 Alkoxy or C 3-8 When cycloalkyl, R x1 Not H; or,

[0087] b)R x1’ When H is true, R1 is not true; or,

[0088] c)R x1’ When H is , R2 and R 2’ They are not both H.

[0089] According to embodiments of the present invention, a compound of formula (I), its tautomers, stereoisomers, or pharmaceutically acceptable salts are provided.

[0090] in,

[0091] R1 is H, NH2, CN, or -CR 11 =CR 12 R 13 3-8 membered heterocyclic alkyl groups, C 6-10 Aryl or 5-10-membered heteroaryl, wherein the 3-8-membered heterocyclic alkyl, C 6-10 The aryl and 5-10 heteroaryl groups are independently and optionally bounded by 1, 2, 3 or 4 R groups. a replace;

[0092] R 11 R 12 and R 13 Each is independently H, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 3-8 cycloalkyl;

[0093] R 1’ H, halogen, OH, NH2, CN, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-8 cycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy and C 3-8 The cycloalkyl groups are each independently and optionally marked with 1, 2, 3 or 4 R's. a’ replace;

[0094] R2 and R 2’ They are, independently, H, halogen, OH, NH2, CN, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl or 3-8 membered heterocycloalkyl, wherein C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl and 3-8 membered heterocycloalkyl groups are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. b replace;

[0095] R3 and R 3’ They are, independently, H, halogen, OH, NH2, CN, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-8 Cycloalkyl or 3-8 membered heterocycloalkyl, wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-8Cycloalkyl and 3-8 membered heterocycloalkyl groups are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. c replace;

[0096] R4 represents H, halogen, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy or C 3-8 cycloalkyl, the C 1-6 Alkyl, C 2-6 alkenyl, C 2- 6-acetylinyl, C 1-6 Alkoxy and C 3-8 The cycloalkyl groups are each independently and optionally marked with 1, 2, 3 or 4 R's. d replace;

[0097] R5 is H or halogen;

[0098] X is CR x1 R x1’ or NR x2 ;

[0099] R x1 For H, halogens, OH, CN, NH2, -NR x11 -C 1-10 Alkyl, -NR x11 -C 0-6 Alkylene-C 3-8 cycloalkyl, -NR x11 -C 0-6 alkylene-5-10 heteroaryl, -NR x11 -C 0-6 Alkylene-S(R) x12 ) w C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl or 5-10 heteroaryl, the -NR x11 -C 1-10 Alkyl, -NR x11 -C 0-6 Alkylene-C 3-8 cycloalkyl, -NR x11 -C 0- 6-alkylene-5.10-membered heteroaryl, -NR x11 -C 0-6 Alkylene-S(R) x12 ) w C 1-6 Alkyl, C2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 The aryl and 5-10 heteroaryl groups are independently and optionally bounded by 1, 2, 3 or 4 R groups. e replace;

[0100] R x11 For H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0101] Each R x12 Each is independently H, halogen, and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0102] Each R e 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 or C 3- 8-cycloalkyl, the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy and C 3-8 The cycloalkyl groups are each independently and optionally marked with 1, 2, 3 or 4 R's. f replace;

[0103] R x1’ H, -NR x11 -C 0-6 Alkylene-S(R) x12 ) w C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy or C 3-8 cycloalkyl, the -NR x11 -C 0-6 Alkylene-S(R) x12 ) w C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy and C 3-8 The cycloalkyl groups are each independently and optionally marked with 1, 2, 3 or 4 R's. e’ replace;

[0104] R x2-C 0-6 Alkylene-S(R) x12 ) w The -C 0-6 Alkylene-S(R) x12 ) w Independently and optionally by 1, 2, 3 or 4 R g replace;

[0105] Each R a P a’ R b R c R d R e’ R f R g Each can be independently H, halogen, OH, NH2, CN, COOH, or C. 1-6 alkyl;

[0106] w is 1, 3, or 5;

[0107] In addition, the R x1’ R1, R2, R 2’ One of the following conditions must be met:

[0108] a)R x1’ Not H; or,

[0109] b)R x1’ When H is true, R1 is not true; or,

[0110] c)R x1’ When H is , R2 and R 2’ They are not both H.

[0111] According to embodiments of the present invention, the above-described compound may further include at least one of the following technical features:

[0112] In an optional embodiment of the present invention, R x1 For H, halogens, OH, CN, NH2, -NR x11 -C 1-8 Alkyl, -NR x11 -C 1-3 Alkylene-C 3-6 cycloalkyl, -NR x11 -C 1-3 alkylene-5-6-membered heteroaryl, -NR x11 -C 1-4 Alkylene-S(R) x12 ) w C 1-6 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, wherein -NR x11 -C 1-8 Alkyl, -NR x11 -C 1-3 Alkylene-C 3- 6-cycloalkyl, -NR x11 -C 1-3 alkylene-5-6-membered heteroaryl, -NR x11 -C 1-4 Alkylene-S(R) x12 ) w C 1-6 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6-membered heterocycloalkyl, phenyl, and 5-6-membered heteroaryl groups are each independently and optionally surrounded by 1, 2, 3, or 4 R groups. e replace.

[0113] In an optional embodiment of the present invention, R x1 For H, halogens, OH, CN, NH2, -NR x11 -C 1-8 Alkyl, -NR x11 -C 1-3 Alkylene-C 3-6 cycloalkyl, -NR x11 -C 1-3 alkylene-5-6-membered heteroaryl, -NR x11 -C 1-4 Alkylene-S(R) x12 ) w C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, wherein -NR x11 -C 1-8 Alkyl, -NR x11 -C 1-3 Alkylene-C 3- 6-cycloalkyl, -NR x11 -C 1-3 alkylene-5-6-membered heteroaryl, -NR x11 -C 1-4 Alkylene-S(R) x12 ) w C 1-3 Alkyl, C 2-4 alkenyl, C 2-4alkynyl group, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 3-6-membered heterocycloalkyl, phenyl, and 5-6-membered heteroaryl groups are each independently and optionally surrounded by 1, 2, 3, or 4 R groups. e replace.

[0114] In an optional embodiment of the present invention, R x11 For H, C 1-3 Alkyl or C 1-3 Halogenated alkyl groups.

[0115] In an optional embodiment of the present invention, R x11 For H.

[0116] In an optional embodiment of the present invention, each R x12 Each is independently H, halogen, and C. 1-3 Alkyl or C 1-3 Halogenated alkyl groups.

[0117] In an optional embodiment of the present invention, each R x12 They are H or F, respectively, independently.

[0118] In an optional embodiment of the present invention, each R e The independent components are H, halogen, OH, NH2, CN, COOH, and C, respectively. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy or C 3-6 cycloalkyl, the C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy and C 3-6 The cycloalkyl groups are each independently and optionally marked with 1, 2, 3 or 4 R's. f replace.

[0119] In an optional embodiment of the present invention, each R e Each of the following is independently H, halogen, OH, NH2, CN, COOH, methyl, or ethyl, wherein the methyl and ethyl groups are each optionally independently separated by 1, 2, 3, or 4 R groups. f replace.

[0120] In an optional embodiment of the present invention, each R f Each can be independently H, halogen, OH, NH2, CN, COOH, or methyl.

[0121] In an optional embodiment of the present invention, each R e Each can be independently H, halogen, OH, NH2, CN, COOH, methyl, ethyl, or -CH2OH.

[0122] In an optional embodiment of the present invention, two Rs connected to the same C e form Among them, R e1 R e2 Each can be independently H, halogen, OH, CN, COOH, methyl, ethyl, or propyl.

[0123] In an optional embodiment of the present invention, two Rs connected to the same C e form

[0124] In an optional embodiment of the present invention, R x1 The derivatives are H, -O-(CH2)2CH(CH3)2, -(CH2)3CH(CH3)2, -NH-(CH2)2CH(CH3)2, -NH-(CH2)2CH(CH2CH3)2, -NH-(CH2)2-cyclobutyl, -NH-(CH2)2-cyclopentyl, -NH-(CH2)2-pyrazolyl, -NH-(CH2)2-pyrroleyl, -NH-(CH2)2-imidazolyl, -NH-(CH2)2-pyridyl, -NH-(CH2)2-pyrimidinyl, -NH-(CH2)2-pyridazinyl, -NH-(CH2)2-pyrazinyl, or -NH-(CH2)3-SF5, wherein -O-(CH 2) 2CH(CH3)2, -(CH2)3CH(CH3)2, -NH-(CH2)2CH(CH3)2, -NH-(CH2)2CH(CH2CH3)2, -NH-(CH2)2-cyclobutyl, -NH-(CH2)2-cyclopentyl, -NH-(CH2)2-pyrazolyl, -NH-(CH2)2-pyrroleyl, -NH-(CH2)2-imidazolyl, -NH-(CH2)2-pyridyl, -NH-(CH2)2-pyrimidinyl, -NH-(CH2)2-pyridazinyl, -NH-(CH2)2-pyrazinyl or -NH-(CH2)3-SF5 are each independently and optionally separated by 1, 2, 3 or 4 R e replace.

[0125] In an optional embodiment of the present invention, Rx1 is H, -NH-(CH2)2CH(CH3)2, -NH-(CH2)2CH(CH2CH3)2, -NH-(CH2)2-cyclobutyl, -NH-(CH2)2-cyclopentyl, -NH-(CH2)2-pyrazolyl, -NH-(CH2)2-pyrroloyl, -NH-(CH2)2-imidazolyl, -NH-(CH2)2-pyridyl, -NH-(CH2)2-pyrimidinyl, -NH-(CH2)2-pyridazinyl, -NH-(CH2)2-pyrazinyl, or -NH-(CH2)3-SF5. The -NH-(CH2)2CH(CH3)2, -NH-(CH2)2CH(CH2CH3)2, -NH-(CH2)2-cyclobutyl, -NH-(CH2)2-cyclopentyl, -NH-(CH2)2-pyrazolyl, -NH-(CH2)2-pyrroloyl, -NH-(CH2)2-imidazolyl, -NH-(CH2)2-pyridyl, -NH-(CH2)2-pyrimidinyl, -NH-(CH2)2-pyridazinyl, -NH-(CH2)2-pyrazinyl or -NH-(CH2)3-SF5 are each independently and optionally separated by 1, 2, 3 or 4 R e replace.

[0126] In an optional embodiment of the present invention, R x1 The following are possible values: H, -O-(CH2)2CH(CH3)2, -(CH2)3CH(CH3)2, -NH-(CH2)2CH(CH3)2, -NH-(CH2)2CH(CH2CH3)2, -NH-(CH2)2-cyclobutyl, -NH-(CH2)2-cyclopentyl, -NH-(CH2)3-SF5.

[0127] In an optional embodiment of the present invention, R x1 The following are possible values: H, -NH-(CH2)2CH(CH3)2, -NH-(CH2)2CH(CH2CH3)2, -NH-(CH2)2-cyclobutyl, -NH-(CH2)2-cyclopentyl, -NH-(CH2)3-SF5.

[0128] In an optional embodiment of the present invention, R x1’ H, -NR x11 -C 1-4 Alkylene-S(R) x12 ) w -S(=O)2-NR x11 -C 1-4 Alkyl, -NR x11 -C(R x13 )2-NRx11 -C 1-4 Alkyl, -NR x11 -C 0-4 Alkylene-C 7-10 Monocyclic cycloalkyl, -NR x11 -C 0-4 Alkylene-C 7-10 Bicyclic cycloalkyl, NR x11 -C 0-4 Alkylene-C 7-10 Monocyclic cycloalkenyl, -NR x11 -C 0-4 Alkylene-C 7-10 Bicyclic cycloalkenyl, -NR x11 -C 0-4 Alkylene (with 1, 2, 3 or 4 Rs) ee Replacement C 3-6 cycloalkyl), -NR x11 -C 0-4 Alkylene-7-10-membered monocyclic heterocyclic alkyl, -NR x11 -C 0-4 Alkylene-7-10-membered bicyclic heterocyclic alkyl, -OC 6- 8. Bicyclic cycloalkyl, -NR x11 -C 3-6 Cycloalkyl-phenyl, -NR x11 -4-6 membered heterocyclic alkyl-phenyl, -NR x11 -C 8-10 Bicyclic aryl, -NR x11 -5-6 cyclic heteroaryl groups, -NR x11 -8-10 quinone bicyclic heteroaryl, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy, C 3-6 cycloalkyl, (with 1, 2, 3 or 4 Rs) ee Substituted 3-6-membered heterocyclic alkyl groups or 7-10-membered heterocyclic alkyl groups, wherein -NR x11 -C 1-4 Alkylene-S(R) x12 ) w -S(=O)2-NR x11 -C 1-4 Alkyl, -NR x11 -C(R x13 )2-NR x11 -C 1-4 Alkyl, -NR x11 -C 0-4 Alkylene-C 7-10 Monocyclic cycloalkyl, -NR x11 -C 0-4Alkylene-C 7-10 Bicyclic cycloalkyl, NR x11 -C 0-4 Alkylene-C 7-10 Monocyclic cycloalkenyl, -NR x11 -C 0-4 Alkylene-C 7-10 Bicyclic cycloalkenyl, -NR x11 -C 0-4 Alkylene (with 1, 2, 3 or 4 Rs) ee Replacement C 3-6 cycloalkyl), -NR x11 -C 0-4 Alkylene-7-10-membered monocyclic heterocyclic alkyl, -NR x11 -C 0-4 Alkylene-7-10-membered bicyclic heterocyclic alkyl, -OC 6-8 Bicyclic cycloalkyl, -NR x11 -C 3-6 Cycloalkyl-phenyl, -NR x11 -4-6 membered heterocyclic alkyl-phenyl, -NR x11 -C 8-10 Bicyclic aryl, -NR x11 -5-6 cyclic heteroaryl groups, -NR x11 -8-10 quinone bicyclic heteroaryl, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy, C 3-6 cycloalkyl, (with 1, 2, 3 or 4 Rs) ee The substituted 3-6-membered heterocyclic alkyl groups and 7-10-membered heterocyclic alkyl groups are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. e’ replace;

[0129] In an optional embodiment of the present invention, R x1’ H, -NR x11 -C 1-4 Alkylene-S(R) x12 ) w -S(=O)2-NR x11 -C 1-4 Alkyl, -NR x11 -C(R x13 )2-NR x11 -C 1-4 Alkyl, -NR x11 -C 0-4 Alkylene-C 7-10 Bicyclic cycloalkyl, -NR x11 -C 0-4 Alkylene-7-10-membered bicyclic heterocyclic alkyl, -OC6-8 Bicyclic cycloalkyl, -NR x11 -C 3-6 Cycloalkyl-phenyl, -NR x11 -4-6 membered heterocyclic alkyl-phenyl, -NR x11 -C 8-10 Bicyclic aryl, -NR x11 -8-10 quinone bicyclic heteroaryl, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy or C 3-6 cycloalkyl, the -NR x11 -C 1-4 Alkylene-S(R) x12 ) w -S(=O)2-NR x11 -C 1-4 Alkyl, -NR x11 -C(R x13 )2-NR x11 -C 1-4 Alkyl, -NR x11 -C 0-4 Alkylene-C 7-10 Bicyclic cycloalkyl, -NR x11 -C 0-4 Alkylene-7-10-membered bicyclic heterocyclic alkyl, -OC 6-8 Bicyclic cycloalkyl, -NR x11 -C 3-6 Cycloalkyl-phenyl, -NR x11 -4-6 membered heterocyclic alkyl-phenyl, -NR x11 -C 8-10 Bicyclic aryl, -NR x11 -8-10 quinone bicyclic heteroaryl, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy or C 3-6 The cycloalkyl groups are each independently and optionally marked with 1, 2, 3 or 4 R's. e’ replace.

[0130] In an optional embodiment of the present invention, R x1’ H, -NR x11 -C 1-4 Alkylene-S(R) x12 ) w -S(=O)2-NR x11 -C 1-4 Alkyl, -NR x11 -C(R x13 )2-NR x11-C 1-4 Alkyl, -NR x11 -C 0-4 Alkylene-C7 monocyclic cycloalkyl, -NR x11 -C 0-4 Alkylene-C 7-10 Spirocycloalkyl, -NR x11 -C 0-4 Alkylene-C 7-10 Spirocyclic cycloalkenyl, -NR x11 -C 0-4 Alkylene-C7 fused cycloalkyl, -NR x11 -C 0-4 Alkylene-C7 bridged cycloalkyl, -NR x11 -C 0-4 Alkylene (with 1, 2, 3 or 4 Rs) ee Replacement C 5-6 cycloalkyl), -NR x11 -C 0-4 Alkylene-7-membered monocyclic heterocyclic alkyl, -NR x11 -C 0-4 Alkylene-7-8 membered spirocyclic heterocyclic alkyl, -NR x11 -C 0-4 Alkylene-7-8-membered bridged heterocyclic alkyl, -O-C7 spirocyclic alkyl, -NR x11 -C 3-6 Cycloalkyl-phenyl, -NR x11 -4-6 membered heterocyclic alkyl-phenyl, -NR x11 -C9 fused aryl, -NR x11 -5-6 cyclic heteroaryl groups, -NR x11 -8-9 fused heteroaryl groups, C 1- 3-alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy or C 3-6 cycloalkyl, (with 1, 2, 3 or 4 Rs) ee The -NR is a substituted 5-6 member monocyclic heterocyclic alkyl group or a 7-10 member bicyclic heterocyclic alkyl group. x11 -C 1-4 Alkylene-S(R) x12 ) w -S(=O)2-NR x11 -C 1-4 Alkyl, -NR x11 -C(R x13 )2-NR x11 -C 1-4 Alkyl, -NR x11 -C 0-4 Alkylene-C7 monocyclic cycloalkyl, -NRx11 -C 0-4 Alkylene-C 7-10 Spirocycloalkyl, -NR x11 -C 0-4 Alkylene-C 7-10 Spirocyclic cycloalkenyl, -NR x11 -C 0-4 Alkylene-C7 fused cycloalkyl, -NR x11 -C 0-4 Alkylene-C7 bridged cycloalkyl, -NR x11 -C 0-4 Alkylene (with 1, 2, 3 or 4 Rs) ee Replacement C 5-6 cycloalkyl), -NR x11 -C 0-4 Alkylene-7-membered monocyclic heterocyclic alkyl, -NR x11 -C 0-4 Alkylene-7-8 membered spirocyclic heterocyclic alkyl, -NR x11 -C 0-4 Alkylene-7-8-membered bridged heterocyclic alkyl, -O-C7 spirocyclic alkyl, -NR x11 -C 3-6 Cycloalkyl-phenyl, -NR x11 -4-6 membered heterocyclic alkyl-phenyl, -NR x11 -C9 fused aryl, -NR x11 -5-6 cyclic heteroaryl groups, -NR x11 -8-9 fused heteroaryl groups, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy, C 3-6 cycloalkyl, (with 1, 2, 3 or 4 Rs) ee The substituted 5-6 membered monocyclic heterocyclic alkyl groups and 7-10 membered bicyclic heterocyclic alkyl groups are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. e’ replace.

[0131] In an optional embodiment of the present invention, R x1’ H, -NR x11 -C 1-4 Alkylene-S(R) x12 ) w -S(=O)2-NR x11 -C 1-4 Alkyl, -NR x11 -C(R x13 )2-NR x11 -C 1-4 Alkyl, -NR x11 -C 0-4 Alkylene-C7-10 Spirocycloalkyl, -NR x11 -C 0-4 Alkylene-C7 fused cycloalkyl, -NR x11 -C 0-4 Alkylene-C7 bridged cycloalkyl, -NR x11 -C 0-4 Alkylene, -7-8 membered spirocyclic heterocyclic alkyl, -O-C7 spirocyclic cycloalkyl, -NR x11 -C 3-6 Cycloalkyl-phenyl, -NR x11 -4-6 membered heterocyclic alkyl-phenyl, -NR x11 -C9 fused aryl, -NR x11 -8-9 fused heteroaryl groups, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy or C 3-6 cycloalkyl, the -NR x11 -C 1-4 Alkylene-S(R) x12 ) w -S(=O)2-NR x11 -C 1-4 Alkyl, -NR x11 -C(R x13 )2-NR x11 -C 1-4 Alkyl, -NR x11 -C 0-4 Alkylene-C 7-10 Spirocycloalkyl, -NR x11 -C 0-4 Alkylene-C7 fused cycloalkyl, -NR x11 -C 0-4 Alkylene-C7 bridged cycloalkyl, -NR x11 -C 0-4 Alkylene, -7-8 membered spirocyclic heterocyclic alkyl, -O-C7 spirocyclic cycloalkyl, -NR x11 -C 3-6 Cycloalkyl-phenyl, -NR x11 -4-6 membered heterocyclic alkyl-phenyl, -NR x11 -C9 fused aryl, -NR x11 -8-9 fused heteroaryl groups, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy and C 3-6 The cycloalkyl groups are each independently and optionally marked with 1, 2, 3 or 4 R's. e’ replace.

[0132] In an optional embodiment of the present invention, R x1’ H, -NR x11 -C 1-4 Alkylene-S(R) x12 ) w -S(=O)2-NR x11 -C 1-4 Alkyl, -NR x11 -C(R x13 )2-NR x11 -C 1-4 Alkyl, -NR x11 -C 0-4 Alkylene-C 7-10 Bicyclic cycloalkyl, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy or C 3-6 cycloalkyl, the -NR x11 -C 1-4 Alkylene-S(R) x12 ) w -S(=O)2-NR x11 -C 1-4 Alkyl, -NR x11 -C(R x13 )2-NR x11 -C 1-4 Alkyl, -NR x11 -C 0- 4-alkylene-C 7-10 Bicyclic cycloalkyl, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy or C 3-6 The cycloalkyl groups are each independently and optionally marked with 1, 2, 3 or 4 R's. e’ replace.

[0133] In an optional embodiment of the present invention, -NR x11 -C 0-4 Alkylene-C 7-10 C in bicyclic cycloalkyl 7-10 The bicyclic cycloalkyl group is C 7-10 Spirocyclic cycloalkyl.

[0134] In an optional embodiment of the present invention, the C 7-10 The spirocycloalkyl group is a C7 spirocycloalkyl group.

[0135] In an optional embodiment of the present invention, R x13 H, halogen, C 1-3 Alkyl or C 1-3 Halogenated alkyl groups.

[0136] In an optional embodiment of the invention, the two R x13 Formation = O.

[0137] In an optional embodiment of the present invention, R x1’ H, -NR x11 -C 1-4 Alkylene-S(R) x12 ) w C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy or C 3-6 cycloalkyl, the -NR x11 -C 1-4 Alkylene-S(R) x12 ) w C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy or C 3- The 6-cycloalkyl group is independently and optionally surrounded by 1, 2, 3 or 4 R groups. e’ replace.

[0138] In an optional embodiment of the present invention, R x1’ It is H, -NH-(CH2)3-SF5, -S(=O)2-NH-CH2CH(CH3)2, -NH-C(=O)-NH-CH(CH3)2, Methyl, ethyl, or cyclopropyl, wherein the -NH-(CH2)3-SF5, -S(=O)2-NH-CH2CH(CH3)2, -NH-C(=O)-NH-CH(CH3)2, ... The methyl, ethyl, or cyclopropyl groups are each independently and optionally surrounded by 1, 2, 3, or 4 R groups. e’ Replace; the Each can be independently and arbitrarily assigned to 1, 2, 3, or 4 R's. ee replace;

[0139] In an optional embodiment of the present invention, R x1’ It is H, -NH-(CH2)3-SF5, -S(=O)2-NH-CH2CH(CH3)2, -NH-C(=O)-NH-CH(CH3)2, Methyl, ethyl, or cyclopropyl, wherein -NH-(CH2)3-SF5, -S(=O)2-NH-CH2CH(CH3)2, -NH-C(=O)-NH-CH(CH3)2, The methyl, ethyl, and cyclopropyl groups are each independently and optionally marked with 1, 2, 3, or 4 R groups. e’ replace.

[0140] In an optional embodiment of the present invention, R x1’ It is H, -NH-(CH2)3-SF5, -S(=O)2-NH-CH2CH(CH3)2, -NH-C(=O)-NH-CH(CH3)2, Methyl, ethyl, or cyclopropyl, wherein -NH-(CH2)3-SF5, -S(=O)2-NH-CH2CH(CH3)2, -NH-C(=O)-NH-CH(CH3)2, The methyl, ethyl, and cyclopropyl groups are each independently and optionally marked with 1, 2, 3, or 4 R groups. e’ replace.

[0141] In an optional embodiment of the present invention, R x1’ The radical is H, -NH-(CH2)3-SF5, methyl, ethyl, or cyclopropyl, wherein the -NH-(CH2)3-SF5, methyl, ethyl, and cyclopropyl groups are each independently and optionally surrounded by 1, 2, 3, or 4 R groups. e’ replace.

[0142] In an optional embodiment of the present invention, each R e’ They are H, halogen, OH, and C, respectively. 1-3 Alkyl, C 1-3 Halogenated alkyl or C 3-4 cycloalkyl;

[0143] In an optional embodiment of the present invention, each R e’ They are H, halogen, OH, and C, respectively. 1-3 Alkyl or C 1-3 Halogenated alkyl groups.

[0144] In an optional embodiment of the present invention, each R e’ Each can be independently H, F, OH, methyl, CF3, -CH2CF3 or cyclopropyl;

[0145] In an optional embodiment of the present invention, each R e’ Each can be independently H, F, OH, methyl, or -CH2CF3.

[0146] In an optional embodiment of the present invention, each R e’ Each can be independently H, F, OH or methyl.

[0147] In an optional embodiment of the present invention, two Rs connected to the same C e’ form Among them, R e3 R e4 Each can be independently H, F, OH, CN, COOH, methyl, ethyl, or propyl.

[0148] In an optional embodiment of the present invention, two Rs connected to the same C e’ form

[0149] In an optional embodiment of the present invention, each R ee Each independently

[0150] In an optional embodiment of the present invention, R x1’ The following are possible combinations of compounds: H, -NH-(CH2)3-SF5, methyl, -CH2CH2OH, -CH2CH2F, cyclopropyl, -S(=O)2-NH-CH2CH(CH3)2, -NH-C(=O)-NH-CH(CH3)2.

[0151] In an optional embodiment of the present invention, R x1’ The following are possible combinations of compounds: H, -NH-(CH2)3-SF5, methyl, -CH2CH2OH, -CH2CH2F, cyclopropyl, -S(=O)2-NH-CH2CH(CH3)2, -NH-C(=O)-NH-CH(CH3)2.

[0152] In an optional embodiment of the present invention, R x1’ The following are possible combinations of compounds: H, -NH-(CH2)3-SF5, methyl, -CH2CH2OH, -CH2CH2F, cyclopropyl, -S(=O)2-NH-CH2CH(CH3)2, -NH-C(=O)-NH-CH(CH3)2.

[0153] In an optional embodiment of the present invention, R x1’ It can be H, -NH-(CH2)3-SF5, methyl, -CH2CH2OH, -CH2CH2F or cyclopropyl.

[0154] In an optional embodiment of the present invention, R x2 -C 1-4 Alkylene-S(R) x12 ) w The -C 1-4 Alkylene-S(R) x12 ) w Independently and optionally by 1, 2, 3 or 4 R g replace.

[0155] In an optional embodiment of the present invention, each R g They are H or F, respectively, independently.

[0156] In an optional embodiment of the present invention, R x2 It is -(CH2)3-SF5.

[0157] In an optional embodiment of the present invention, R1 is H, NH2, CN, or -CR. 11 =CR 12 R 13 5-6-membered heterocyclic alkyl, phenyl, or 5-6-membered heteroaryl, wherein the 5-6-membered heterocyclic alkyl, phenyl, and 5-6-membered heteroaryl are each optionally and independently bound by 1, 2, 3, or 4 R's. a replace.

[0158] In an optional embodiment of the present invention, R 11 R 12 and R 13 Each is independently H, halogen, and C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 3-6 Cycloalkyl.

[0159] In an optional embodiment of the present invention, R 11 R 12 and R 13 They are H or F, respectively, independently.

[0160] In an optional embodiment of the present invention, R1 is H or -CH=CF2.

[0161] In an optional embodiment of the present invention, R 1’ H, halogen, OH, NH2, CN, C 1-3 Alkyl, C 1-3 Alkoxy or C 3-6 cycloalkyl, the C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 The cycloalkyl groups are each independently and optionally marked with 1, 2, 3 or 4 R's. a’ replace.

[0162] In an optional embodiment of the present invention, R 1’ For H.

[0163] In an optional embodiment of the invention, R2 and R 2’ They are, independently, H, halogen, OH, NH2, CN, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, wherein C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl groups are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. b replace.

[0164] In an optional embodiment of the invention, R2 and R 2’ Each of the following groups is independently H, methyl, cyclopropyl, or azircyclopentyl, wherein the methyl, cyclopropyl, and azircyclopentyl groups are each optionally independently surrounded by 1, 2, 3, or 4 R groups. b replace.

[0165] In an optional embodiment of the present invention, each R b Each can be independently H, F, OH, NH2, CN, COOH, or methyl.

[0166] In an optional embodiment of the invention, R2 and R 2’ Each is independently H, methyl, cyclopropyl,

[0167] In an optional embodiment of the invention, R2 and R 2’ Each can be H, methyl, or cyclopropyl, independently.

[0168] In an optional embodiment of the invention, R3 and R 3’ They are, independently, H, halogen, OH, NH2, CN, and C. 1-3 Alkyl, C 2-4 alkenyl, C 2- 4-Alynyl group, C 1-3 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, wherein C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy, C 3- The 6-membered cycloalkyl group and the 3-6-membered heterocycloalkyl group are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. c replace.

[0169] In an optional embodiment of the invention, R3 and R 3’Each is independently represented by H.

[0170] In an optional embodiment of the present invention, R4 is H, halogen, or C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy or C 3-6 cycloalkyl, the C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy and C 3-6 The cycloalkyl groups are each independently and optionally marked with 1, 2, 3 or 4 R's. d replace.

[0171] In an optional embodiment of the present invention, R4 is H or F.

[0172] In an optional embodiment of the present invention, R5 is F.

[0173] In an optional embodiment of the present invention, R x1’ For -NR x11 -C 0-6 Alkylene-S(R) x12 ) w The -NR x11 -C 0-6 Alkylene-S(R) x12 ) w Independently and optionally by 1, 2, 3 or 4 R e’ replace.

[0174] In an optional embodiment of the present invention, R x1’ It is -NH-(CH2)3-SF5.

[0175] In an optional embodiment of the present invention, R x2 -C 0-6 Alkylene-S(R) x12 ) w The -C 0-6 Alkylene-S(R) x12 ) w Independently and optionally by 1, 2, 3 or 4 R g replace.

[0176] In an optional embodiment of the present invention, the compound shown in formula (I) has the structural formula (I-1):

[0177] in,

[0178] R1, R x1 R x1’ R2, R2’ R4 and R5 are as defined in this invention.

[0179] In an optional embodiment of the present invention, the compound represented by formula (I) has the structural formula (I-1A):

[0180] in,

[0181] R x1 For -NR x11 -C 1-10 Alkyl, -NR x11 -C 0-6 Alkylene-C 3-8 cycloalkyl, -NR x11 -C 0-6 alkylene-5-10 heteroaryl or -NR x11 -C 0-6 Alkylene-S(R) x12 ) w The -NR x11 -C 1-10 Alkyl, -NR x11 -C 0-6 Alkylene-C 3-8 cycloalkyl, -NR x11 -C 0-6 alkylene-5-10 heteroaryl and -NR x11 -C 0-6 Alkylene-S(R) x12 ) w Each can be independently and arbitrarily assigned to 1, 2, 3, or 4 R's. e replace;

[0182] R x1’ C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy or C 3-8 cycloalkyl, the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1- 6-alkoxy and C 3-8 The cycloalkyl groups are each independently and optionally marked with 1, 2, 3 or 4 R's. e’ replace;

[0183] R x11 R x12 R e R e’ w is as defined in this invention.

[0184] In an optional embodiment of the present invention, R x1 For -NRx11 -C 1-8 Alkyl, -NR x11 -C 1-3 Alkylene-C 3-6 cycloalkyl, -NR x11 -C 1-3 alkylene-5-6-membered heteroaryl or -NR x11 -C 1-4 Alkylene-S(R) x12 ) w The -NR x11 -C 1-8 Alkyl, -NR x11 -C 1-3 Alkylene-C 3-6 cycloalkyl, -NR x11 -C 1- 3-alkylene-5-6-membered heteroaryl and -NR x11 -C 1-4 Alkylene-S(R) x12 ) w Each can be independently and arbitrarily assigned to 1, 2, 3, or 4 R's. e replace.

[0185] In an optional embodiment of the present invention, R x1 The derivatives are -NH-(CH2)2CH(CH3)2, -NH-(CH2)2-cyclobutyl, -NH-(CH2)2-cyclopentyl, and -NH-(CH2)3-SF5.

[0186] In an optional embodiment of the present invention, R x1’ C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy or C 3-6 cycloalkyl, the C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy and C 3-6 The cycloalkyl groups are each independently and optionally marked with 1, 2, 3 or 4 R's. e’ replace.

[0187] In an optional embodiment of the present invention, R x1’ It can be methyl, -CH2CH2OH, -CH2CH2F or cyclopropyl.

[0188] In an optional embodiment of the invention, the compound represented by formula (I) has the structural formula (I-1B):

[0189] in,

[0190] R x1’ For -NR x11 -C 0-6 Alkylene-S(R) x12 ) w -S (=O) m -NR x11 -C 1-6 Alkyl, -NR x11 -C(R x13 )2-NR x11 -C 1-6 Alkyl or -NR x11 -C 0-6 Alkylene-C 7-10 cycloalkyl, -NR x11 -C 0-6 Alkylene-C 7-10 Cycloalkenyl, -NR x11 -C 0-6 Alkylene (with 1, 2, 3 or 4 Rs) ee Replacement C 3-6 cycloalkyl), -NR x11 -C 0-6 Alkylene-7-12-membered heterocyclic alkyl, -OC 3-8 cycloalkyl, -NR x11 -C 3-6 cycloalkyl-C 6-12 Aryl, -NR x11 -4-6 membered heterocyclic alkyl-C 6-12 Aryl, -NR x11 -C 6-12 Aryl, -NR x11 -5-12 heteroaryl groups, (with 1, 2, 3 or 4 R groups) ee Substituted 3-6-membered heterocyclic alkyl groups or 7-12-membered heterocyclic alkyl groups, wherein -NR x11 -C 0-6 Alkylene-S(R) x12 ) w 、、-S(=O) m -NR x11 -C 1-6 Alkyl, -NR x11 -C(R x13 )2-NR x11 -C 1-6 Alkyl, -NR x11 -C 0-6 Alkylene-C 7-10 cycloalkyl, -NR x11 -C 0-6 Alkylene-C 7-10 Cycloalkenyl, -NR x11 -C0-6 Alkylene (with 1, 2, 3 or 4 Rs) ee Replacement C 3-6 cycloalkyl), -NR x11 -C 0-6 Alkylene-7-12-membered heterocyclic alkyl, -OC 3-8 cycloalkyl, -NR x11 -C 3-6 cycloalkyl-C 6-12 Aryl, -NR x11 -4-6 membered heterocyclic alkyl-C 6-12 Aryl, -NR x11 -C 6-12 Aryl, NR x11 -5-12 heteroaryl groups, (with 1, 2, 3 or 4 R groups) ee The substituted 3-6-membered heterocyclic alkyl groups and 7-12-membered heterocyclic alkyl groups are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. e’ replace;

[0191] R x11 R x12 R x13 R e’ w and m are as defined in claim 1;

[0192] In an optional embodiment of the present invention, R x1’ For -NR x11 -C 1-4 Alkylene-S(R) x12 ) w -S(=O)2-NR x11 -C 1-4 Alkyl, -NR x11 -C(R x13 )2-NR x11 -C 1-4 Alkyl, -NR x11 -C 0-4 Alkylene-C 7-10 Monocyclic cycloalkyl, -NR x11 -C 0-4 Alkylene-C 7-10 Bicyclic cycloalkyl, NR x11 -C 0-4 Alkylene-C 7-10 Monocyclic cycloalkenyl, -NR x11 -C 0-4 Alkylene-C 7-10 Bicyclic cycloalkenyl, -NR x11 -C 0-4 Alkylene (with 1, 2, 3 or 4 Rs) ee Replacement C 3-6 cycloalkyl), -NRx11 -C 0-4 Alkylene-7-10-membered monocyclic heterocyclic alkyl, -NR x11 -C 0-4 Alkylene-7-10-membered bicyclic heterocyclic alkyl, -OC 6- 8. Bicyclic cycloalkyl, -NR x11 -C 3-6 Cycloalkyl-phenyl, -NR x11 -4-6 membered heterocyclic alkyl-phenyl, -NR x11 -C 8-10 Bicyclic aryl, -NR x11 -5-6 cyclic heteroaryl groups, -NR x11 -8-10 nucleotides, bicyclic heteroaryl groups (with 1, 2, 3 or 4 R groups) ee Substituted 3-6-membered heterocyclic alkyl groups or 7-10-membered heterocyclic alkyl groups, wherein -NR x11 -C 1-4 Alkylene-S(R) x12 ) w -S(=O)2-NR x11 -C 1-4 Alkyl, -NR x11 -C(R x13 )2-NR x11 -C 1-4 Alkyl, -NR x11 -C 0- 4-alkylene-C 7-10 Monocyclic cycloalkyl, -NR x11 -C 0-4 Alkylene-C 7-10 Bicyclic cycloalkyl, NR x11 -C 0-4 Alkylene-C 7-10 Monocyclic cycloalkenyl, -NR x11 -C 0-4 Alkylene-C 7-10 Bicyclic cycloalkenyl, -NR x11 -C 0-4 Alkylene (with 1, 2, 3 or 4 Rs) ee Replacement C 3-6 cycloalkyl), -NR x11 -C 0-4 Alkylene-7-10-membered monocyclic heterocyclic alkyl, -NR x11 -C 0-4 Alkylene-7-10-membered bicyclic heterocyclic alkyl, -OC 6-8 Bicyclic cycloalkyl, -NR x11 -C 3-6 Cycloalkyl-phenyl, -NR x11 -4-6 membered heterocyclic alkyl-phenyl, -NR x11 -C8-10 Bicyclic aryl, -NR x11 -5-6 cyclic heteroaryl groups, -NR x11 -8-10 nucleotides, bicyclic heteroaryl groups (with 1, 2, 3 or 4 R groups) ee The substituted 3-6-membered heterocyclic alkyl groups and 7-10-membered heterocyclic alkyl groups are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. e’ replace;

[0193] In an optional embodiment of the present invention, R x1’ For -NR x11 -C 1-4 Alkylene-S(R) x12 ) w -S(=O)2-NR x11 -C 1-4 Alkyl, -NR x11 -C(R x13 )2-NR x11 -C 1-4 Alkyl, -NR x11 -C 0-4 Alkylene-C7 monocyclic cycloalkyl, -NR x11 -C 0-4 Alkylene-C 7-10 Spirocycloalkyl, -NR x11 -C 0-4 Alkylene-C 7-10 Spirocyclic cycloalkenyl, -NR x11 -C 0-4 Alkylene-C7 fused cycloalkyl, -NR x11 -C 0-4 Alkylene-C7 bridged cycloalkyl, -NR x11 -C 0-4 Alkylene (with 1, 2, 3 or 4 Rs) ee Replacement C 5-6 cycloalkyl), -NR x11 -C 0-4 Alkylene-7-membered monocyclic heterocyclic alkyl, -NR x11 -C 0-4 Alkylene-7-8 membered spirocyclic heterocyclic alkyl, -NR x11 -C 0-4 Alkylene-7-8-membered bridged heterocyclic alkyl, -O-C7 spirocyclic alkyl, -NR x11 -C 3-6 Cycloalkyl-phenyl, -NR x11 -4-6 membered heterocyclic alkyl-phenyl, -NR x11 -C9 fused aryl, -NR x11 -5-6 cyclic heteroaryl groups, -NR x11-8-9 fused heteroaryl groups (with 1, 2, 3 or 4 R groups) ee The -NR is a substituted 5-6 member monocyclic heterocyclic alkyl group or a 7-10 member bicyclic heterocyclic alkyl group. x11 -C 1-4 Alkylene-S(R) x12 ) w -S(=O)2-NR x11 -C 1-4 Alkyl, -NR x11 -C(R x13 )2-NR x11 -C 1-4 Alkyl, -NR x11 -C 0-4 Alkylene-C7 monocyclic cycloalkyl, -NR x11 -C 0-4 Alkylene-C 7-10 Spirocycloalkyl, -NR x11 -C 0-4 Alkylene-C 7-10 Spirocyclic cycloalkenyl, -NR x11 -C 0-4 Alkylene-C7 fused cycloalkyl, -NR x11 -C 0- 4-alkylene-C7 bridged cycloalkyl, -NR x11 -C 0-4 Alkylene (with 1, 2, 3 or 4 Rs) ee Replacement C 5-6 cycloalkyl), -NR x11 -C 0-4 Alkylene-7-membered monocyclic heterocyclic alkyl, -NR x11 -C 0-4 Alkylene-7-8 membered spirocyclic heterocyclic alkyl, -NR x11 -C 0-4 Alkylene-7-8-membered bridged heterocyclic alkyl, -O-C7 spirocyclic cycloalkyl, NR x11 -C 3-6 Cycloalkyl-phenyl, -NR x11 -4-6 membered heterocyclic alkyl-phenyl, -NR x11 -C9 fused aryl, -NR x11 -5-6 cyclic heteroaryl groups, -NR x11 -8-9 fused heteroaryl groups (with 1, 2, 3 or 4 R groups) ee The substituted 5-6 membered monocyclic heterocyclic alkyl group or 7-10 membered bicyclic heterocyclic alkyl group is independently and optionally surrounded by 1, 2, 3 or 4 R groups. e 'replace;

[0194] In an optional embodiment of the present invention, R x1’is -NH-(CH2)3-SF5, -S(=O)2-NH-CH2CH(CH3)2, -NH-C(=O)-NH-CH(CH3)2,

[0195] In an optional embodiment of the invention, the compound represented by formula (I) has the structural formula (I-1B):

[0196] in,

[0197] R x1’ For -NR x11 -C 0-6 Alkylene-S(R) x12 ) w -S (=O) m -NR x11 -C 1-6 Alkyl, -NR x11 -C(R x13 )2-NR x11 -C 1-6 Alkyl or -NR x11 -C 0-6 Alkylene-C 7-10 cycloalkyl, -NR x11 -C 0-6 Alkylene-7-12-membered heterocyclic alkyl, -OC 3-8 cycloalkyl, -NR x11 -C 3-6 cycloalkyl-C 6-12 Aryl, -NR x11 -4-6 membered heterocyclic alkyl-C 6-12 Aryl, -NR x11 -C 6-12 Aryl or -NR x11 -5-12 heteroaryl groups, the -NR x11 -C 0-6 Alkylene-S(R) x12 ) w -S (=O) m -NR x11 -C 1-6 Alkyl, -NR x11 -C(R x13 )2-NR x11 -C 1-6 Alkyl, -NR x11 -C 0-6 Alkylene-C 7-10 cycloalkyl, -NR x11 -C 0-6 Alkylene-7-12-membered heterocyclic alkyl, -OC 3-8cycloalkyl, -NR x11 -C 3-6 cycloalkyl-C 6-12 Aryl, -NR x11 -4-6 membered heterocyclic alkyl-C 6-12 Aryl, -NR x11 -C 6-12 Aryl and NR x11 -5-12 heteroaryl groups are independently and optionally coated with 1, 2, 3 or 4 R groups. e’ replace;

[0198] R x11 R x12 R x13 R e’ w and m are as defined in this invention.

[0199] In an optional embodiment of the present invention, R x1’ For -NR x11 -C 1-4 Alkylene-S(R) x12 ) w -S(=O)2-NR x11 -C 1-4 Alkyl, -NR x11 -C(R x13 )2-NR x11 -C 1-4 Alkyl or -NR x11 -C 0-4 Alkylene-C 7-10 Bicyclic cycloalkyl, -NR x11 -C 0-4 Alkylene-7-10-membered bicyclic heterocyclic alkyl, -OC 6-8 Bicyclic cycloalkyl, -NR x11 -C 3-6 Cycloalkyl-phenyl, -NR x11 -4-6 membered heterocyclic alkyl-phenyl, -NR x11 -C 8-10 Bicyclic aryl or -NR x11 -8-10 nucleotide bicyclic heteroaryl group, the -NR x11 -C 1-4 Alkylene-S(R) x12 ) w -S(=O)2-NR x11 -C 1-4 Alkyl, -NR x11 -C(R x13 )2-NR x11 -C 1-4 Alkyl, -NR x11 -C 0-4 Alkylene-C 7-10Bicyclic cycloalkyl, -NR x11 -C 0-4 Alkylene-7-10-membered bicyclic heterocyclic alkyl, -OC 6-8 Bicyclic cycloalkyl, -NR x11 -C 3-6 Cycloalkyl-phenyl, -NR x11 -4-6 membered heterocyclic alkyl-phenyl, -NR x11 -C 8-10 Bicyclic aryl and -NR x11 -8-10 nucleotide bicyclic heteroaryl groups are independently and selectively bound by 1, 2, 3 or 4 R groups. e’ replace.

[0200] In an optional embodiment of the present invention, R x1’ For -NR x11 -C 1-4 Alkylene-S(R) x12 ) w -S(=O)2-NR x11 -C 1-4 Alkyl, -NR x11 -C(R x13 )2-NR x11 -C 1-4 Alkyl, -NR x11 -C 0-4 Alkylene-C 7-10 Spirocycloalkyl, -NR x11 -C 0-4 Alkylene-C7 fused cycloalkyl, -NR x11 -C 0-4 Alkylene-C7 bridged cycloalkyl, -NR x11 -C 0-4 Alkylene, -7-8 membered spirocyclic heterocyclic alkyl, -O-C7 spirocyclic cycloalkyl, -NR x11 -C 3-6 Cycloalkyl-phenyl, -NR x11 -4-6 membered heterocyclic alkyl-phenyl, -NR x11 -C9 fused aryl or -NR x11 -8-9 fused heteroaryl groups, the -NR x11 -C 1-4 Alkylene-S(R) x12 ) w -S(=O)2-NR x11 -C 1-4 Alkyl, -NR x11 -C(R x13 )2-NR x11 -C 1-4 Alkyl, -NR x11 -C 0-4 Alkylene-C7-10 Spirocycloalkyl, -NR x11 -C 0-4 Alkylene-C7 fused cycloalkyl, -NR x11 -C 0-4 Alkylene-C7 bridged cycloalkyl, -NR x11 -C 0-4 Alkylene-7-8 membered spirocyclic heterocyclic alkyl, -O-C7 spirocyclic cycloalkyl, NR x11 -C 3-6 Cycloalkyl-phenyl, -NR x11 -4-6 membered heterocyclic alkyl-phenyl, -NR x11 -C9 fused aryl and -NR x11 -8-9 fused heteroaryl groups are independently and optionally coated with 1, 2, 3 or 4 R groups. e’ replace.

[0201] In an optional embodiment of the present invention, R x1’ is -NH-(CH2)3-SF5, -S(=O)2-NH-CH2CH(CH3)2, -NH-C(=O)-NH-CH(CH3)2,

[0202] In an optional embodiment of the invention, the compound represented by formula (I) has the structural formula (I-1B):

[0203] in,

[0204] R x1’ For -NR x11 -C 0-6 Alkylene-S(R) x12 ) w -S (=O) m -NR x11 -C 1-6 Alkyl, -NR x11 -C(R x13 )2-NR x11 -C 1-6 Alkyl or -NR x11 -C 0-6 Alkylene-C 7-10 cycloalkyl, the -NR x11 -C 0-6 Alkylene-S(R) x12 ) w -S (=O) m -NR x11 -C 1-6 Alkyl, -NR x11 -C(R x13 )2-NR x11 -C1-6 Alkyl and -NR x11 -C 0-6 Alkylene-C 7-10 The cycloalkyl groups are each independently and optionally marked with 1, 2, 3 or 4 R's. e’ replace;

[0205] R x11 R x12 R x13 R e’ w and m are as defined in this invention.

[0206] In an optional embodiment of the present invention, R x1’ For -NR x11 -C 1-4 Alkylene-S(R) x12 ) w -S(=O)2-NR x11 -C 1-4 Alkyl, -NR x11 -C(R x13 )2-NR x11 -C 1-4 Alkyl or -NR x11 -C 0-4 Alkylene-C 7-10 Bicyclic cycloalkyl, the -NR x11 -C 1-4 Alkylene-S(R) x12 ) w -S(=O)2-NR x11 -C 1-4 Alkyl, -NR x11 -C(R x13 )2-NR x11 -C 1-4 Alkyl and -NR x11 -C 0-4 Alkylene-C 7-10 The bicyclic cycloalkyl group is independently and optionally marked with 1, 2, 3 or 4 R's. e’ replace.

[0207] In an optional embodiment of the present invention, R x1’ is -NH-(CH2)3-SF5, -S(=O)2-NH-CH2CH(CH3)2, -NH-C(=O)-NH-CH(CH3)2,

[0208] In an optional embodiment of the invention, the compound represented by formula (I) has a structural formula (I-1C) or (I-1D):

[0209] In equation (1-IC),

[0210] L1 is the key, -C 0-6 Alkylene-NR x11 -C 0-6 alkylene-, where R x11 It has the definition as described in claim 1;

[0211] L2, L3, L4, and L5 may be the same or different, and are independently: keys or optional keys controlled by one, two, three, or four Rs. L The following groups are substituted: methylene, ethylene, propylene, -CH2=CH2-, -O-, -N-; R L For H, OH, CN, NH2, oxo (=O), halogen, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkyl groups;

[0212] L6 is selected from C(R) e’ (R) e’ ), N(R) e’ ), O, S(O)2; L7 is selected from CR L Or N;

[0213] R1, R 1’ R2, R 2’ R3, R 3’ R4, R5, R e’ It has the definition as described in claim 1;

[0214] The condition is that, in equation (1-IC), L2 and L3 are not simultaneously bonds;

[0215] In an optional embodiment of the present invention, L1 is a key, -C 0-6 Alkylene-NR x11 -or-NR x11 -C 0-6 alkylene-, where R x11 It has the definition as described in claim 1;

[0216] In an optional embodiment of the present invention, each R e’ They are independently H, OH, halogen, and C, respectively. 1-6 Alkyl, C 1-6 Haloalkyl; or, two R groups attached to the same C. e’ form Each R e3 R e4 They are independently H, halogen, OH, CN, COOH, and C, respectively. 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0217] In an optional embodiment of the present invention, each R e3 R e4 Each can be independently H, F, OH, CN, COOH, methyl, ethyl, or propyl;

[0218] In an optional embodiment of the present invention, two Rs connected to the same C e’ form

[0219] In an optional embodiment of the present invention, each R e’ They are independently H, OH, F, CH3, CF3, and CH2CF3, respectively;

[0220] In an optional embodiment of the present invention, each R L They are independently H, OH, halogen, and C, respectively. 1-6 Alkyl, C 1-6 Halogenated alkyl groups;

[0221] In an optional embodiment of the present invention, each R L They are independently H, OH, F, CH3, CF3, and CH2CF3, respectively;

[0222] In an optional embodiment of the present invention, L2 and L3 are not simultaneously keys, and L4 and L5 are simultaneously keys;

[0223] In an optional embodiment of the present invention, L2 and L3 are not simultaneously keys, and L4 and L5 are keys;

[0224] In an optional embodiment of the present invention, when L4 and L5 are keys, L2 is optionally bounded by one, two, or three Rs. L The following groups are substituted: methylene, ethylene, propylene, butylene, and L3 is optionally replaced by one, two, or three R groups. L The following groups are substituted: methylene, ethylene, propylene, and butylene.

[0225] In equation (1-ID),

[0226] L1 is the key, -C 0-6 Alkylene-NR x11 -C 0-6 alkylene-, where R x11 It has the definition as described in claim 1;

[0227] L2, L3, L4, and L5 may be the same or different, and are independently: keys or optional keys controlled by one, two, three, or four Rs. L The following groups are substituted: methylene, ethylene, propylene, -CH2=CH2-, -O-, -N-; R LFor H, OH, CN, NH2, oxo (=O), halogen, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkyl groups;

[0228] L6 is selected from C(R) e’ (R) e’ ), N(R) e’ ), O, S(O)2; L7 is selected from CR L Or N;

[0229] R1, R 1’ R2, R 2’ R3, R 3’ R4, R5, R e’ It has the definition as described in claim 1;

[0230] In an optional embodiment of the present invention, L1 is a key, -C 0-6 Alkylene-NR x11 -or-NR x11 -C 0-6 alkylene-, where R x11 It has the definition as described in claim 1;

[0231] In an optional embodiment of the present invention, each R e’ They are independently H, OH, halogen, and C, respectively. 1-6 Alkyl, C 1-6 Haloalkyl; or, two R groups attached to the same C. e’ form Each R e3 R e4 They are independently H, halogen, OH, CN, COOH, and C, respectively. 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0232] In an optional embodiment of the present invention, each R e3 R e4 Each can be independently H, F, OH, CN, COOH, methyl, ethyl, or propyl;

[0233] In an optional embodiment of the present invention, two Rs connected to the same C e’ form

[0234] In an optional embodiment of the present invention, each R e’ Each of the following is independently H, OH, F, CH3, CF3, and CH2CF3; in an optional embodiment of the present invention, each R... L They are independently H, OH, halogen, and C, respectively. 1-6Alkyl, C 1-6 Halogenated alkyl groups;

[0235] In an optional embodiment of the present invention, each R L They are independently H, OH, F, CH3, CF3, and CH2CF3, respectively;

[0236] In an optional embodiment of the present invention, when L2 and L3 are keys, L4 is optionally bounded by one, two, or three Rs. L The following groups are substituted: methylene, ethylene, propylene, butylene, and L5 is optionally replaced by one, two, or three R groups. L The following groups are substituted: methylene, ethylene, propylene, and butylene.

[0237] In an optional embodiment of the present invention, when L4 and L5 are keys, L2 is optionally bounded by one, two, or three Rs. L The following groups are substituted: methylene, ethylene, propylene, butylene, and L3 is optionally replaced by one, two, or three R groups. L The following groups are substituted: methylene, ethylene, propylene, and butylene.

[0238] In an optional embodiment of the present invention, the compound shown in formula (I) has the structural formula (I-1):

[0239] in,

[0240] R x1’ C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy or C 3-8 cycloalkyl, the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1- 6-alkoxy and C 3-8 The cycloalkyl groups are each independently and optionally marked with 1, 2, 3 or 4 R's. e’ Replace; R1, R x1 R2, R 2’ R4, R5 and R e’ As defined in this invention.

[0241] In an optional embodiment of the present invention, the compound shown in formula (I) has structural formula (I-2):

[0242] in,

[0243] R1 is NH2, CN, or -CR 11 =CR 12 R13 3-8 membered heterocyclic alkyl groups, C 6-10 Aryl or 5-10-membered heteroaryl, wherein the 3-8-membered heterocyclic alkyl, C 6- 10 The aryl and 5-10 heteroaryl groups are independently and optionally bounded by 1, 2, 3 or 4 R groups. a replace;

[0244] R 11 R 12 R 13 R x1 and R a As defined in this invention.

[0245] In an optional embodiment of the present invention, R1 is -CR 11 =CR 12 R 13 The -CR 11 =CR 12 R 13 Independently and optionally by 1, 2, 3 or 4 R a replace.

[0246] In an optional embodiment of the present invention, R1 is -CH = CF2.

[0247] In an optional embodiment of the present invention, the compound shown in formula (I) has the structural formula (I-3):

[0248] in,

[0249] R2 can be a halogen, OH, NH2, CN, or C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl or 3-8 membered heterocycloalkyl, wherein C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl and 3-8 membered heterocycloalkyl groups are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. b replace;

[0250] R 2’ R x1 and R b As defined in this invention.

[0251] In an optional embodiment of the present invention, R2 is C. 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, wherein C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6Cycloalkyl and 3-6 membered heterocycloalkyl groups are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. b replace;

[0252] In an optional embodiment of the present invention, R2 is methyl, cyclopropyl,

[0253] 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:

[0254] 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:

[0255] 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.

[0256] In an optional embodiment of the invention, the pharmaceutical composition comprises a therapeutically effective amount of the above-described compound or its tautomers, stereoisomers, or pharmaceutically acceptable salts.

[0257] In an optional embodiment of the present invention, the above-described pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient.

[0258] 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:

[0259] Inhibit the expression of PTPN1 and / or PTPN2; and / or,

[0260] Prepare medicines for the treatment of PTPN1 and / or PTPN2-related diseases; and / or,

[0261] Preparation of PTPN1 and / or PTPN2 inhibitors; and / or,

[0262] Used to treat PTPN1 and / or PTPN2 related diseases.

[0263] In an optional embodiment of the invention, the disease includes a solid tumor.

[0264] 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.

[0265] In an optional embodiment of the present invention, the solid tumor includes head and neck cancer, melanoma, non-small cell lung cancer, and clear cell renal cell carcinoma.

[0266] Terms and Definitions

[0267] Unless otherwise stated, the terms and definitions used in this application, including those set forth in the specification and claims, are as follows.

[0268] 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.

[0269] 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.

[0270] 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.

[0271] 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.

[0272] 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.

[0273] 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.

[0274] Unless otherwise specified, the term "prodrug" refers to a compound of the present invention that can be converted into a biologically active form under physiological conditions or by solvation. The prodrugs of the present invention are prepared by modifying functional groups in the compound; such modification can be performed by conventional methods or removed in vivo to obtain the parent compound. Prodrugs comprise compounds formed by attaching a hydroxyl or amino group to any group within the compound of the present invention. When a prodrug of the compound of the present invention is administered to a mammalian individual, the prodrug is cleaved to form free hydroxyl and free amino groups, respectively.

[0275] 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.

[0276] 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.

[0277] When the bonds of the chiral carbons in the formulas of this invention are drawn in a straight line, it should be understood that both the (R) and (S) configurations of the chiral carbons 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 herein is derived from Maehr, J. Chem. Ed. 1985, 62: 114-120. Unless otherwise stated, wedge-shaped and dashed bonds denote the absolute configuration of a stereocenter. Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral formulations, or resolved using conventional techniques. Compounds of this invention containing asymmetrically substituted carbon atoms can be separated in their optically active or racemic forms. Resolution of racemic mixtures of compounds can be performed by any of the 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 include 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 suitable resolving agents for fractional crystallization methods include stereoisomerically pure forms of α-methylbenzylamine (e.g., S and R forms or diastereoisomerically pure forms), 2-phenylglycine, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, etc. Resolution of racemic mixtures can also be performed by elution on 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 diastereomer of the compound described in this invention can be obtained by stereoorganic synthesis using optically pure starting materials or reagents of known configuration.

[0278] 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.

[0279] 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:

[0280] 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 The relative configuration of the center of a solid.

[0281] 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.

[0282] For pharmaceuticals or pharmacologically active agents, the term "effective amount" or "therapeutic effective amount" refers to a sufficient quantity of a drug or agent that is non-toxic but achieves the desired effect. For the oral dosage forms of this invention, the "effective amount" of one active substance in the composition refers to the quantity 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 recipient's age and general condition, as well as the specific active substance. A suitable effective amount in any given case can be determined by a person skilled in the art through routine testing.

[0283] 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.

[0284] 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.

[0285] 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.

[0286] 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.

[0287] 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.

[0288] Unless otherwise specified, the term "alkyl" refers to a saturated straight-chain or branched monovalent hydrocarbon group containing 1 to 20 carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20), 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 8 carbon atoms (C). 1-8 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). 1-3 Examples 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.

[0289] 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 p carbon atoms in a branched, linear, or any combination of these three relationships, where α and p represent integers. It can also be represented by "C". α -C β The form "alkyl" is used. C0 alkyl indicates a straight bond.

[0290] 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 1-12 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. Those skilled in the art will understand that the term C... 0-m Alkylenes include C0 alkylenes (representing a straight bond) and C... 1-m Alkylene, for example, the term C 0-6 The alkylene group is selected from C0 alkylene (representing a straight bond) and C... 1-6 Alkylenes (C1 alkylene, C2 alkylene, C3 alkylene, C4 alkylene, C5 alkylene, C6 alkylene). Unless otherwise specified, the term "alkenyl" 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. 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.

[0291] 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). 2-4 Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propynyl (-CH2C≡CH), 1-propynyl (-C≡C-CH3), and so on.

[0292] 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.

[0293] 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 1-6In 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.

[0294] 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.

[0295] Unless otherwise specified, the term "cycloalkyl" refers to a monovalent or polyvalent saturated monocyclic, bicyclic, or tricyclic system containing 3 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, wherein the bicyclic or tricyclic system includes spirocyclic, fused, and bridged rings. In some embodiments, the cycloalkyl group comprises 3 to 12 carbon atoms (C... 3-12 In some embodiments, the cycloalkyl group contains 7-10 carbon atoms (C60-C90). 7-10 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.

[0296] Unless otherwise specified, the term "cycloalkenyl" refers to an unsaturated monocyclic, bicyclic, or tricyclic system containing 3 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms and having at least one double bond, wherein the bicyclic or tricyclic system includes spirocyclic, fused, and bridged rings. In some embodiments, the cycloalkenyl group comprises 3 to 12 carbon atoms (C... 3-12 In some embodiments, the cycloalkenyl group comprises 7-10 carbon atoms (C60-C90). 7- 10 In some implementations, the cycloalkenyl group comprises 3-8 carbon atoms (C6H ...7H6H6H6H6H6H7H6H6H6H6H7H6H 3-8 In some implementations, the cycloalkenyl group comprises 3-6 carbon atoms (C6H ...7H6H6H6H6H6H6H 3-6). The 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, cyclohexenyl, cycloheptenyl, etc.

[0297] Unless otherwise specified, the term "aryl" refers to a monocyclic, bicyclic, or tricyclic carbocyclic system containing 6-14 (e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14) ring atoms, or 6-12 ring atoms, 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.

[0298] 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.

[0299] Unless otherwise specified, the terms "heteroaryl," "heteroary ring," or "heteroarycycloyl" are used interchangeably to refer to a monocyclic, bicyclic, or polycyclic cyclic system containing 5 to 12 (e.g., 5, 6, 7, 8, 9, 10, 11, 12; "a" or "unit") ring atoms, at least one ring system being aromatic, preferably 5 to 10 ring atoms, 5 to 8 ring atoms, more preferably 5 to 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, the number of heteroatoms preferably being 1, 2, or 3, wherein the N heteroatoms or S heteroatoms on the ring may optionally be oxidized to form N-oxides (e.g., NO) or S-oxides (e.g., S(O)). p (where p is 1 or 2), and the N heteroatom on the ring may optionally be quaternized. 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 “heteroarylcycloyl” include, but are not limited to, 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isooxazolyl, 4-isooxazolyl, 5-isooxazolyl, 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.

[0300] 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 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 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, wherein the N or S heteroatom on the ring may optionally be oxidized to form an N-oxide (such as NO) or an S-oxide (such as S(O)). p (where p is 1 or 2), and the N heteroatom on the ring may optionally be quaternized. The heterocyclic 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 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.

[0301] Unless otherwise specified, the term "heterocyclic alkyl" means a saturated "heterocyclic group" as defined above, comprising 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 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, wherein the N or S heteroatom on the ring may optionally be oxidized to form an N-oxide (e.g., NO) or an S-oxide (e.g., S(O)). p(p is 1 or 2), and the N heteroatom on the ring may optionally be quaternized. The heterocyclic alkyl group is optionally substituted with 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 3-6 ring atoms (3-7-membered heterocyclic alkyl), or 7-12 ring atoms (7-12-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 heteroatoms are 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.

[0302] Unless otherwise specified, the term "heterocyclic alkenyl" refers to a partially unsaturated "heterocyclic group" as defined above, comprising 3 to 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, wherein the N or S heteroatom on the ring may optionally be oxidized to form an N-oxide (such as NO) or an S-oxide (such as S(O)). p (where p is 1 or 2), and the N heteroatom on the ring may optionally be quaternized. The heterocyclic alkenyl group is optionally substituted with 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).

[0303] Unless otherwise specified, the terms "halogen" or "halogen" refer to fluorine, chlorine, bromine, and iodine.

[0304] 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).

[0305] 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:

[0306] It also includes spirocyclic alkyl groups that share a spiro atom with a heterocyclic alkyl group, and non-limiting examples include:

[0307] (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:

[0308] (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:

[0309] 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.

[0310] 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.

[0311] 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.

[0312] Unless otherwise specified, the term “therapeutic effective amount” means the amount of an active compound or drug that researchers, veterinarians, physicians or other clinicians are looking for in a tissue, system, animal, individual or human to elicit a biological or medical response, including one or more of the following: (1) prevention of disease: for example, prevention of disease, disorder or condition in an individual who is susceptible to disease, disorder or condition but has not yet experienced or developed the pathology or symptoms of the disease. (2) suppression of disease: for example, suppression of disease, disorder or condition in an individual who is experiencing or developing the pathology or symptoms of the disease (i.e., preventing the further development of the pathology and / or symptoms). (3) relief of disease: for example, relief of disease, disorder or condition in an individual who is experiencing or developing the pathology or symptoms of the disease (i.e., reversal of the pathology and / or symptoms).

[0313] The term "treatment" and other similar synonyms used in this article include the following meanings:

[0314] (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;

[0315] (ii) To suppress a disease or symptom, that is, to curb its development;

[0316] (iii) To alleviate the disease or symptom, that is, to cause the condition of the disease or symptom to subside; or,

[0317] (iv) To alleviate the symptoms caused by the disease or condition.

[0318] 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; MEM represents 2-methoxyethoxymethyl; TsOH represents p-toluenesulfonic acid; DIEA represents N,N-diisopropylethylamine; t-Bu represents tert-butyl; Me represents methyl; TEA represents triethylamine; DCM represents dichloromethane; DAST represents diethylaminosulfonium trifluoride; PE represents petroleum ether; EA represents ethyl acetate; Boc represents tert-butyloxycarbonyl; Tf represents trifluoromethanesulfonyl; Ms represents methanesulfonyl; Bn represents benzyl; m-CPBA represents... m-chloroperoxybenzoic acid; DPPA represents diphenyl azidophosphate; HCl represents hydrochloric acid; EtOAc represents ethyl acetate; BBr3 represents boron tribromide; HTIB represents hydroxytoluenesulfonyl iodobenzene; tbubrettphosPdG3 represents 2-(di-tert-butylphosphino)-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl(2-amino-1,1′-biphenyl-2-yl)palladium(II); NaH represents sodium hydride; MEMCl represents 2-methoxyethoxymethyl chloride; TM P represents 2,2,6,6-tetramethylpiperidine; n-BuLi represents n-butyllithium; FA represents formic acid; Cbz represents benzyl formate; PPh3 represents triphenylphosphine; HCl represents hydrochloric acid; TMSCHN2 represents trimethylsilyldiazomethane; N2H4·H2O represents hydrazine hydrate; CuCl represents cuprous chloride; CBr4 represents carbon tetrabromide; MeB(OH)2 represents methylboronic acid; Pd(dppf)Cl2 represents 1,1′-bis(diphenylphosphine)ferrocene palladium(II) dichloride; TFA represents trifluoroacetic acid. Beneficial effects

[0319] According to embodiments of the present invention, the present invention has at least one of the following technical effects:

[0320] 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

[0321] 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.

[0322] Intermediate i-9: Preparation of target compound i-9

[0323] 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-oxo-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 Synthesis of 2,5-thiadiazolidine-1,1,3-trione (i-9)

[0324] The synthetic route for the target compound i-9 is shown below:

[0325] Step 1: Synthesis of 6-bromo-8-fluoro-3,4-dihydro-1H-spiro[naphthalene-2,2'-[1,3]dioxolane](i-1)

[0326] 90.0 g (370 mmol) of 6-bromo-8-fluoro-3,4-dihydronaphthyl-2(1H)-one was dissolved in toluene (900 mL), and ethylene glycol (138 g, 2.22 mol) and p-toluenesulfonic acid (14.1 g, 74.0 mmol) were added. The reaction was stirred at 145 °C for 1 hour under a water separator. After the reaction was complete, the reaction solution was poured into an aqueous sodium bicarbonate solution (500 mL) at 0 °C and extracted with ethyl acetate (300 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 6-bromo-8-fluoro-3,4-dihydro-1H-spiro[naphthyl-2,2'-[1,3]dioxolane](i-1) (112 g, crude product).

[0327] 1 H NMR (400MHz, DMSO-d6) δ7.21-7.30 (m, 2H), 3.92-4.01 (m, 4H), 2.90 (t, 2H, J=6.7Hz), 2.75 (s, 2H), 1.84 (t, 2H, J=6.7Hz)

[0328] Step 2: Synthesis of 2-(8-fluoro-3,4-dihydro-1H-spiro[naphthyl-2,2'-[1,3]dioxacyclopentane]-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (i-2)

[0329] 6-Bromo-8-fluoro-3,4-dihydro-1H-spiro[naphthalene-2,2'-[1,3]dioxolane](i-1) (110 g, 383 mmol) was dissolved in dioxane (1.1 L), and bis(diphenylphosphine)ferrocene palladium chloride (107 g, 421 mmol), 1,1-bis(diphenylphosphine)ferrocene palladium chloride (28.0 g, 38.3 mmol), and potassium acetate (113 g, 1.15 mol) were added. The reaction was purged with nitrogen three times and stirred at 100 °C for 12 hours. After the reaction was complete, the reaction solution was filtered and concentrated under reduced pressure to give compound 2-(8-fluoro-3,4-dihydro-1H-spiro[naphthalene-2,2'-[1,3]dioxolane]-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (i-2) (96.5 g, crude product). Step 3: Synthesis of 8-fluoro-3,4-dihydro-1H-spiro[naphthalene-2,2'-[1,3]dioxacyclopentane]-6-ol (i-3)

[0330] 2-(8-fluoro-3,4-dihydro-1H-spironaphth-2,2'-[1,3]dioxacyclopentane]-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (i-2) (96.5 g, 383 mmol) was dissolved in glacial acetic acid (600 mL), and hydrogen peroxide (65.2 g, 575 mmol) was added at 0 °C. The reaction was stirred at 25 °C for 2 hours. After the reaction was complete, the reaction solution was poured into an aqueous sodium sulfite solution (500 mL) under a nitrogen atmosphere at 0 °C, and extracted with ethyl acetate (300 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 5:1, R...). f The compound 8-fluoro-3,4-dihydro-1H-spiro[naphthalene-2,2'-[1,3]dioxacyclopentane]-6-ol (i-3) was obtained (76.0 g, 88% yield) with a yield of 0.17 g.

[0331] Step 4: Synthesis of 8-fluoro-6-((2-methoxyethoxy)methoxy)-3,4-dihydro-1H-spiro[naphthalene-2,2'-[1,3]dioxolane](i-4)

[0332] 8-Fluoro-3,4-dihydro-1H-spiro[naphthyl-2,2'-[1,3]dioxane]-6-ol (i-3) (76.0 g, 339 mmol) was dissolved in dichloromethane (800 mL), and methoxyethoxychloromethane (127 g, 1.02 mol) and N,N-diisopropylethylamine (175 g, 1.36 mol) were added. The reaction was stirred at 50 °C for 12 hours. After the reaction was complete, the product was concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 5:1, R...). f The compound 8-fluoro-6-((2-methoxyethoxy)methoxy)-3,4-dihydro-1H-spiro[naphthalene-2,2'-[1,3]dioxolane](i-4) (123 g, crude product) was obtained from 0.26 g of the compound.

[0333] 1 H NMR (400MHz, CDCl3) δ6.61-6.70 (m, 2H), 5.20 (s, 2H), 4.01-4.12 (m, 4H), 3.79 (dd, 2H, J=3.8, 5.5Hz), 3.55 (br s, 2H), 3.39 (s, 3H), 2.96 (t, 2H, J=6.7Hz), 2.85 (s, 2H), 1.92 (t, 2H, J=6.7Hz)

[0334] Step 5: Synthesis of 8-fluoro-6-((2-methoxyethoxy)methoxy)-3,4-dihydro-1H-spiro[naphthalene-2,2'-[1,3]dioxolane](i-5)

[0335] 2,2,6,6-Tetramethylpiperidine (81.0 g, 574 mmol) was dissolved in tetrahydrofuran (600 mL). The reaction was purged with nitrogen three times. Butyllithium (2.5 M, 215 mL) was added at -68 °C, and the reaction was stirred at 0 °C for 0.5 h. The temperature was then lowered to -68 °C, and 8-fluoro-6-((2-methoxyethoxy)methoxy)-3,4-dihydro-1H-spiro[naphthalene-2,2'-[1,3]dioxolane](i-4) (112 g, 358 mmol) and tetramethylethylenediamine (62.5 g, 538 mmol) dissolved in tetrahydrofuran (200 mL) were added. The reaction was stirred at -68 °C for 1 h. Iodine (182 g, 717 mmol) dissolved in tetrahydrofuran (200 mL) was added at -68 °C, and the reaction was slowly heated to 0 °C and stirred for 0.5 h. After the reaction was complete, the reaction solution was poured into an aqueous solution of ammonium chloride (1000 mL) and sodium thiosulfate (1000 mL) under a nitrogen atmosphere at 0 °C. Extraction was performed with ethyl acetate (500 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Purification was then performed by column chromatography (mobile phase: petroleum ether / ethyl acetate = 3:1, R...).f The compound 8-fluoro-6-((2-methoxyethoxy)methoxy)-3,4-dihydro-1H-spiro[naphthalene-2,2'-[1,3]dioxolane](i-5) (82.0 g, yield 52%) was obtained from 0.29 g of the compound 8-fluoro-6-((2-methoxyethoxy)methoxy)-3,4-dihydro-1H-spiro[naphthalene-2,2'-[1,3]dioxolane](i-5).

[0336] 1 H NMR (400MHz, CDCl3) δ6.74 (s, 1H), 5.31 (s, 2H), 4.00-4.11 (m, 4H), 3.85 (dd, 2H, J=3.8, 5.5Hz), 3.61-3.62 (m, 2H), 3.39 (s, 3H), 2.97 (br t, 2H, J=6.6Hz), 2.89 (s, 2H), 1.93 (t, 2H, J=6.7Hz)

[0337] Step 6: Synthesis of tert-butyl(8-fluoro-6-((2-methoxyethoxy)methoxy)-3,4-dihydro-1H-spiro[naphthyl-2,2'-[1,3]dioxacyclopentane]-7-yl)glycine ester (i-6)

[0338] 8-Fluoro-6-((2-methoxyethoxy)methoxy)-3,4-dihydro-1H-spiro[naphthyl-2,2'-[1,3]dioxolane](i-5) (40.0 g, 91.3 mmol) was dissolved in dioxane (400 mL), and glycine tert-butyl ester (21.5 g, 164 mmol) and 2-(dicyclohexylphosphino)-3,6-dimethoxy-2-4-6-triisocyanate were added. Propyl-1,1-biphenyl (1.22 g, 2.28 mmol), methanesulfonic acid (2-dicyclohexylphosphine-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl), palladium (2.07 g, 2.28 mmol), and cesium carbonate (89.2 g, 274 mmol) were reacted. The reaction mixture was purged with nitrogen three times and then stirred at 95 °C for 12 hours. After the reaction was complete, the reaction solution was directly concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 4:1, R...). f The compound tert-butyl(8-fluoro-6-((2-methoxyethoxy)methoxy)-3,4-dihydro-1H-spiro[naphthyl-2,2'-[1,3]dioxane]-7-yl)glycine ester (i-6) (34.0 g, 84% yield) was obtained from 0.26 g.

[0339] 1H NMR (400MHz, CDCl3) δ6.70 (s, 1H), 5.26 (s, 2H), 4.38 (br d, 1H, J=7.5Hz), 4.01-4.11 (m, 4H), 3.93 (d, 2H, J=1.8Hz), 3.80-3.91 (m, 2H), 3.56 (dd, 2H, J=3.7, 5.4Hz), 3.39 (s, 3H), 2.88 (br t, 2H, J=6.6Hz), 2.83 (s, 2H), 1.89 (t, 2H, J=6.6Hz), 1.45 (s, 9H).

[0340] LC-MS, M / Z (ESI): 442.3 [M+H] + .

[0341] Step 7: Synthesis of tert-butyl N-(8-fluoro-6-((2-methoxyethoxy)methoxy)-3,4-dihydro-1H-spiro[naphthyl-2,2'-[1,3]dioxacyclopentane]-7-yl)-N-aminosulfonylglycine ester (i-7)

[0342] 40.4 g (91.5 mmol) of tert-butyl(8-fluoro-6-((2-methoxyethoxy)methoxy)-3,4-dihydro-1H-spiro[naphthyl-2,2'-[1,3]dioxane]-7-yl)glycine ester (i-6) was dissolved in dichloromethane (650 mL), triethylamine (37.0 g, 366 mmol) was added, the mixture was slowly cooled to 0 °C, and aminosulfonyl chloride (52.8 g, 457 mmol) dissolved in dichloromethane (120 mL) was added. The reaction was stirred at 0 °C for 1 hour. After the reaction was complete, the reaction solution was poured into water (300 mL) under a nitrogen atmosphere at 0 °C and extracted with dichloromethane (300 mL × 3). The organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the compound tert-butyl N-(8-fluoro-6-((2-methoxyethoxy)methoxy)-3,4-dihydro-1H-spiro[naphthyl-2,2'-[1,3]dioxane]-7-yl)-N-aminosulfonylglycine ester (i-7) (49.6 g, yield 86%).

[0343] Step 8: Synthesis of 5-(8-fluoro-6-((2-methoxyethoxy)methoxy)-3,4-dihydro-1H-spiro[naphthyl-2,2'-[1,3]dioxane]-7-yl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (i-8)

[0344] Tert-butyl N-(8-fluoro-6-((2-methoxyethoxy)methoxy)-3,4-dihydro-1H-spiro[naphthyl-2,2'-[1,3]dioxacyclopentane]-7-yl)-N-aminosulfonylglycine ester (i-7) (48.6 g, 93.4 mmol) was dissolved in methanol (500 mL), and sodium methoxide (60.5 g, 280 mmol) was added at 0 °C. The reaction was stirred at 40 °C for 12 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure and purified by HPLC to obtain compound 5-(8-fluoro-6-((2-methoxyethoxy)methoxy)-3,4-dihydro-1H-spiro[naphthyl-2,2'-[1,3]dioxacyclopentane]-7-yl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (i-8) (22.1 g, yield 53%).

[0345] 1 H NMR (400MHz, DMSO-d6) δ 6.90-7.31 (m, 2H), 6.76 (s, 1H), 5.19 (s, 2H), 3.97 (br s, 6H), 3.72-3.81 (m, 2H), 3.42-3.51 (m, 2H), 3.22 (s, 3H), 2.86 (br t, 2H, J=6.4Hz), 2.72 (s, 2H), 1.83 (br t, 2H, J=6.5Hz).

[0346] LC-MS, M / Z (ESI): 445.1 [MH] - .

[0347] Step 9: 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-oxo-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 Synthesis of 2,5-thiadiazolidine-1,1,3-trione (i-9)

[0348] 5-(8-fluoro-6-((2-methoxyethoxy)methoxy)-3,4-dihydro-1H-spiro[naphthyl-2,2'-[1,3]dioxane]-7-yl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (i-8) (20.0 g, 44.8 mmol) was dissolved in formic acid (80 mL) and water (20 mL), and the reaction was stirred at 25 °C for 2 hours. After the reaction was complete, the reaction solution was poured into a sodium chloride aqueous solution (400 mL) at 0 °C, and extracted with acetonitrile and ethyl acetate (1:2, 200 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and then triethylamine (20 mL) was added. The mixture was concentrated under reduced pressure to obtain the crude product, which was then purified by HPLC (0.1% formic acid) to give the product 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-oxo-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (i-9) (12.0 g, yield 67%).

[0349] 1 H NMR (400MHz, DMSO-d6) δ6.98 (s, 1H), 5.27 (s, 2H), 4.19 (s, 1H), 3.7-3.8 (m, 2H), 3.4-3.5 (m, 3H), 3.23 (s, 3H), 3.00-3.11 (m, 6H), 2.07 (s, 1H)

[0350] LC-MS, M / Z(ESI): 420.1[M+18] + .

[0351] Example 1: Preparation of target compound 1

[0352] N-[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ] 6 [2,5-Thiadiazolidine-2-yl]-1,2,3,4-tetrahydronaphthyl-2-yl]-N'-(propion-2-yl)urea

[0353] The synthetic route for compound 1 is as follows:

[0354] Step 1: 5-{7-amino-1-fluoro-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 Synthesis of 2,5-thiadiazolidine-1,1,3-trione (1a)

[0355] At room temperature, 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-oxo-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ6 2,5-Thiadiazolidine-1,1,3-trione (i-9) (200 mg, 0.50 mmol) was dissolved in anhydrous methanol (10 mL), followed by the addition of ammonium acetate (1.14 g, 15.0 mmol) and sodium cyanoborohydride (62.0 mg, 1.00 mmol). After the addition was complete, the mixture was purged with nitrogen three times and reacted at 25 °C for 12 hours. After the reaction was complete, the reaction solution was slowly added to water (20 mL), and then extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (DCM:MeOH = 10:1-5:1) to obtain 5-{7-amino-1-fluoro-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (1a) (150 mg, yield 75%). Step 2: N-{8-fluoro-6-[(2-methoxyethoxy)methoxy]-7-(1,1,4-trioxo-1λ} 6 Synthesis of 2,5-thiadiazolidine-2-yl)-1,2,3,4-tetrahydronaphth-2-yl}-N′-(prop-2-yl)urea (1b)

[0356] At room temperature, 5-{7-amino-1-fluoro-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (1a) (150 mg, 0.37 mmol) was dissolved in anhydrous N,N-dimethylformamide (2 mL), and then triethylamine (75.1 mg, 0.74 mmol) and isopropyl isocyanate (63.2 mg, 0.74 mmol) were added at 0 °C. After the addition was complete, the reaction mixture was returned to 25 °C and reacted for 12 hours. After the reaction was complete, the reaction solution was slowly added to water (20 mL), and then extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by HPLC to obtain N-{8-fluoro-6-[(2-methoxyethoxy)methoxy]-7-(1,1,4-trioxo-1λ 6 ,2,5-Thiadiazolidine-2-yl)-1,2,3,4-tetrahydronaphthyl-2-yl}-N'-(prop-2-yl)urea (1b) (100 mg, yield 55%). Step 3: N-[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ] 6 Synthesis of 2,5-thiadiazolidine-2-yl)-1,2,3,4-tetrahydronaphth-2-yl]-N'-(prop-2-yl)urea (1)

[0357] At room temperature, N-{8-fluoro-6-[(2-methoxyethoxy)methoxy]-7-(1,1,4-trioxo-1λ 6 2,5-Thiadiazolidine-2-yl)-1,2,3,4-tetrahydronaphthyl-2-yl}-N'-(propan-2-yl)urea (1b) (100 mg, 0.21 mmol) was dissolved in dioxane hydrochloride (4 M, 5 mL) and then reacted at 25 °C for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain N-[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ] 6 ,2,5-Thiadiazolidine-2-yl)-1,2,3,4-tetrahydronaphthyl-2-yl]-N'-(propion-2-yl)urea (1) (29.4 mg, yield 36%).

[0358] 1 H NMR (600MHz, DMSO-d6) δ9.94 (s, 1H), 6.45 (s, 1H), 5.80 (s, 1H), 5.60 (s, 1H), 4.27 (s, 2H), 3.75 (s, 1H), 3.63 (s, 1H), 2.78 (dd, J=1 6.0, 5.2Hz, 1H), 2.69 (t, J=6.0Hz, 2H), 2.29 (dd, J=16.0, 7.9Hz, 1H), 1.82-1.78 (m, 1H), 1.58-1.52 (m, 1H), 0.99 (d, J=6.4Hz, 6H).

[0359] LC / MS (ESI) (m / z): 401.0 [M+H] + .

[0360] Example 2: Preparation of target compound 2

[0361] 5-{7-[(6,6-difluorospiro[3.3]hept-2-yl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione(2)

[0362] The synthetic route for compound 2 is as follows:

[0363] Step 1: 5-{7-[(6,6-difluorospiro[3.3]hept-2-yl)amino]-1-fluoro-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6Synthesis of 2,5-thiadiazolidine-1,1,3-trione (2a)

[0364] At room temperature, 6,6-difluorospiro[3.3]hept-2-amine hydrochloride (46.0 mg, 0.25 mmol) was dissolved in anhydrous methanol (2 mL), followed by the addition of sodium acetate (41.0 mg, 0.50 mmol), 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-oxo-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (i-9) (100 mg, 0.25 mmol) and sodium cyanoborohydride (31.0 mg, 0.50 mmol). After addition, nitrogen was purged three times and the reaction was carried out at 25 °C for 12 hours. After the reaction was completed, the reaction solution was slowly added to water (10 mL), and then extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (DCM:MeOH = 10:1-5:1) to obtain 5-{7-[(6,6-difluorospiro[3.3]hept-2-yl)amino]-1-fluoro-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (2a) (70.0 mg, yield 53%).

[0365] Step 2: 5-{7-[(6,6-difluorospiro[3.3]hept-2-yl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 Synthesis of 2,5-thiadiazolidine-1,1,3-trione (2)

[0366] At room temperature, 5-{7-[(6,6-difluorospiro[3.3]hept-2-yl)amino]-1-fluoro-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (2a) (70.0 mg, 0.13 mmol) was dissolved in dioxane hydrochloride (4 M, 2 mL) and reacted at 25 °C for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by HPLC to obtain 5-{7-[(6,6-difluorospiro[3.3]hept-2-yl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (2) (41.9 mg, yield 72%).

[0367] 1 H NMR (400MHz, DMSO-d6) δ9.29 (s, 1H), 8.78 (s, 2H), 6.43 (s, 1H), 3.91 (s, 2H) , 3.883.80 (m, 1H), 3.31-3.26 (m, 1H), 2.99 (dd, J=16.0, 5.2Hz, 1H), 2.73 (dd d, J=37.6, 18.8, 8.4Hz, 4H), 2.60 (t, J=12.4Hz, 2H), 2.47-2.38 (m, 3H), 2.3 4-2.27 (m, 2H), 2.04 (d, J=12.4Hz, 1H), 1.62 (ddd, J=16.4, 11.2, 5.6Hz, 1H).

[0368] LC / MS (ESI) (m / z): 446.0 [M+H] + .

[0369] Example 3: Preparation of target compound 3

[0370] 5-(7-{[(6,6-difluorospiro[3.3]hept-2-yl)methyl]amino}-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphth-2-yl)-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (3)

[0371] The synthetic route for compound 3 is as follows:

[0372] Step 1: Synthesis of methyl 6,6-difluorospiro[3.3]heptane-2-carboxylate (3a)

[0373] Methyl 6-oxospiro[3.3]heptane-2-carboxylate (2.00 g, 11.8 mmol) was dissolved in anhydrous 1,2-dichloroethane (20 mL) at room temperature, and then bis(2-methoxyethyl)aminosulfur trifluoride (5.21 g, 23.6 mmol) was added at 0 °C. After the addition was complete, the reaction was carried out at 25 °C for 12 hours. After the reaction was completed, the reaction solution was slowly poured into a saturated sodium bicarbonate aqueous solution (50 mL), and then extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (PE:EA = 1:0-1:1) to give methyl 6,6-difluorospiro[3.3]heptane-2-carboxylate (3a) (800 mg, yield 36%).

[0374] 1H NMR (600MHz, CDCl3) δ3.67 (d, J=1.2Hz, 3H), 3.10-3.01 (m, 1H), 2.60 (t, J=12.0Hz, 2H ), 2.54 (t, J=12.0Hz, 2H), 2.42 (dd, J=11.6, 9.2Hz, 2H), 2.32 (dd, J=11.6, 9.2Hz, 2H).

[0375] Step 2: Synthesis of 6,6-difluorospiro[3.3]heptane-2-carboxamide (3b)

[0376] Methyl 6,6-difluorospiro[3.3]heptane-2-carboxylic acid (3a) (800 mg, 4.21 mmol) was dissolved in anhydrous methanol (8 mL) at room temperature. Then, formamide (4.55 g, 101 mmol) and sodium methoxide methanol solution (5.4 M, 1.50 mL, 7.99 mmol) were added at 0 °C. The reaction was allowed to proceed at 0 °C for 1 hour. After the reaction was complete, the mixture was quenched with saturated ammonium chloride solution (1.5 mL) and slowly added to water (10 mL). The mixture was then extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (PE:EA = 0:1-1:1) to obtain 6,6-difluorospiro[3.3]heptane-2-carboxamide (3b) (700 mg, 95% yield).

[0377] 1 H NMR (600MHz, DMSO-d6) δ7.16 (s, 1H), 6.72 (s, 1H), 2.85 (dd, J=16.8, 8.4Hz, 1H), 2.59 ( t, J=12.4Hz, 2H), 2.48-2.43 (m, 2H), 2.23-2.17 (m, 2H), 2.12 (dd, J=15.2, 5.6Hz, 2H).

[0378] Step 3: Synthesis of 1-(6,6-difluorospiro[3.3]hept-2-yl)methylamine (3c)

[0379] At room temperature, 6,6-difluorospiro[3.3]heptane-2-carboxamide (3b) (100 mg, 0.57 mmol) was dissolved in anhydrous tetrahydrofuran (1 mL), and then lithium aluminum hydride (33.0 mg, 0.86 mmol) was added at 0 °C. After the addition was complete, the reaction was carried out at 75 °C for 2 hours. After the reaction was completed, the reaction solution was cooled to 0 °C and then quenched by adding water (0.05 mL), 15% sodium hydroxide solution (0.05 mL), and water (0.15 mL) dropwise. The solution was then diluted with ethyl acetate (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 1-(6,6-difluorospiro[3.3]heptane-2-yl)methylamine (3c) (90.0 mg, crude product).

[0380] Step 4: Synthesis of 5-(7-{[(6,6-difluorospiro[3.3]hept-2-yl)methyl]amino}-1-fluoro-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphthyl-2-yl)-1λ6,2,5-thiadiazolidine-1,1,3-trione (3d)

[0381] At room temperature, 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-oxo-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (i-9) (210 mg, 0.52 mmol) was dissolved in anhydrous methanol (2 mL), and then 1-(6,6-difluorospiro[3.3]hept-2-yl)methylamine (3c) (90.0 mg, 0.56 mmol) was added. Sodium cyanoborohydride (70.0 mg, 1.12 mmol) was then added. After the addition was complete, the reaction was carried out at 25 °C for 12 hours. After the reaction was complete, water (5 mL) was slowly added to quench the reaction mixture, and then the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (DCM:MeOH = 10:1-5:1) to obtain 5-(7-{[(6,6-difluorospiro[3.3]hept-2-yl)methyl]amino}-1-fluoro-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphthyl-2-yl)-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (3d) (100mg, yield 35%).

[0382] Step 5: 5-(7-{[(6,6-difluorospiro[3.3]hept-2-yl)methyl]amino}-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphth-2-yl)-1λ 6 Synthesis of 2,5-thiadiazolidine-1,1,3-trione (3)

[0383] At room temperature, 5-(7-{[(6,6-difluorospiro[3.3]hept-2-yl)methyl]amino}-1-fluoro-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphthyl-2-yl)-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (3d) (100 mg, 0.183 mmol) was dissolved in dioxane hydrochloride (4 M, 2 mL) and reacted at 25 °C for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by HPLC to obtain 5-(7-{[(6,6-difluorospiro[3.3]hept-2-yl)methyl]amino}-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthyl-2-yl)-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione(3) (71.4 mg, yield 85%).

[0384] 1H NMR (400MHz, DMSO-d6) δ9.33 (s, 1H), 8.56 (s, 2H), 6.44 (s, 1H), 3.92 (t, J = 7.6Hz, 2H), 3.06 (t, J = 8.8Hz, 3H), 2.80-2.69 (m, 2H ), 2.62 (t, J = 12.4Hz, 2H), 2.55-2.44 (m, 5H), 2.24-2.19 (m, 2H), 2.14 (d, J = 10.4Hz, 1H), 1.99-1.93 (m, 2H), 1.68-1.61 (m, 1H).

[0385] LC / MS (ESI) (m / z): 460.2 [M+H] + .

[0386] Example 4: Preparation of target compound 4

[0387] 5-{1-fluoro-3-hydroxy-7-[(spiro[2,4]hept-4-yl)amino]-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (4)

[0388] The synthetic route for compound 4 is as follows:

[0389] Step 1: 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-[(spiro[2,4]hept-4-yl)amino]-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 Synthesis of 2,5-thiadiazolidine-1,1,3-trione (4a)

[0390] At room temperature, 5-{7-amino-1-fluoro-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (1a) (150 mg, 0.37 mmol) was dissolved in anhydrous methanol (2 mL), and then spiro[2,4]heptane-4-one (61.4 mg, 0.56 mmol) and sodium cyanoborohydride (46.7 mg, 0.74 mmol) were added. After the addition was complete, the reaction mixture was reacted at 25 °C for 12 hours. After the reaction was complete, the reaction mixture was slowly added to water (10 mL), and then extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (DCM:MeOH = 10:1-5:1) to obtain 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-[(spiro[2,4]hept-4-yl)amino]-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (4a) (100 mg, yield 54%). Step 2: 5-{1-fluoro-3-hydroxy-7-[(spiro[2,4]hept-4-yl)amino]-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 Synthesis of 2,5-thiadiazolidine-1,1,3-trione (4)

[0391] At room temperature, 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-[(spiro[2,4]hept-4-yl)amino]-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (4a) (100 mg, 0.20 mmol) was dissolved in dioxane hydrochloride (4 M, 2 mL) and reacted at 25 °C for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by HPLC to obtain 5-{1-fluoro-3-hydroxy-7-[(spiro[2,4]hept-4-yl)amino]-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione(4) (6.1 mg, yield 8%).

[0392] 1H NMR (600MHz, DMSO-d6) δ9.25 (s, 1H), 6.43 (s, 1H), 3.91 (d, J = 4.4Hz, 2H), 3.06 (d, J = 12.4Hz , 1H), 2.78-2.70 (m, 2H), 2.51 (s, 1H), 2.14 (dd, J=16.0, 8.0Hz, 2H), 1.96 (dd, J=12.8, 5.6H z, 1H), 1.82 (d, J=7.6Hz, 2H), 1.69 (dd, J=8.4, 4.8Hz, 1H), 1.55 (dd, J=12.0, 5.2Hz, 1H), 1. 28 (dd, J=37.6, 28.0Hz, 3H), 0.96 (s, 1H), 0.65-0.59 (m, 2H), 0.49 (dd, J=10.0, 4.4Hz, 1H).

[0393] LC / MS (ESI) (m / z): 410.0 [M+H] + .

[0394] Example 5: Preparation of target compound 5

[0395] 5-{1-fluoro-3-hydroxy-7-[(spiro[3.3]hept-2-yl)amino]-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (5)

[0396] The synthetic route for compound 5 is as follows:

[0397] Step 1: 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-[(spiro[3.3]hept-2-yl)amino]-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 Synthesis of 2,5-thiadiazolidine-1,1,3-trione (5a)

[0398] At room temperature, spiro[3.3]heptane-2-amine hydrochloride (46.0 mg, 0.31 mmol) was dissolved in anhydrous methanol (2 mL), followed by the addition of sodium acetate (51.0 mg, 0.62 mmol), 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-oxo-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 62,5-Thiadiazolidine-1,1,3-trione (i-9) (125 mg, 0.31 mmol) and sodium cyanoborohydride (39.0 mg, 0.62 mmol). After addition, nitrogen was purged three times and the reaction was carried out at 25 °C for 12 hours. After the reaction was completed, the reaction solution was slowly added to water (10 mL), and then extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (DCM:MeOH = 10:1-5:1) to obtain 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-[(spiro[3.3]hept-2-yl)amino]-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (5a) (100 mg, yield 65%).

[0399] Step 2: 5-{1-fluoro-3-hydroxy-7-[(spiro[3.3]hept-2-yl)amino]-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 Synthesis of 2,5-thiadiazolidine-1,1,3-trione (5)

[0400] At room temperature, 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-[(spiro[3.3]hept-2-yl)amino]-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (5a) (100 mg, 0.20 mmol) was dissolved in dioxane hydrochloride (4 M, 2 mL) and reacted at 25 °C for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by HPLC to obtain 5-{1-fluoro-3-hydroxy-7-[(spiro[3.3]hept-2-yl)amino]-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (5) (39.7 mg, yield 48%).

[0401] 1H NMR (600MHz, DMSO-d6) δ9.31 (s, 1H), 8.74 (s, 2H), 6.43 (s, 1H), 3.91 (s, 2H), 3.80-3.7 3 (m, 1H), 2.99 (dd, J=15.6, 4.4Hz, 1H), 2.72 (qd, J=17.6, 8.0Hz, 2H), 2.47 (d, J=9.2Hz, 2H), 2.34 (dd, J=11.2, 7.6Hz, 2H), 2.07 (ddd, J=24.8, 17.6, 8.0Hz, 5H), 1.92 (t, J=7.6H z, 2H), 1.80-1.73 (m, 2H), 1.63 (dd, J=11.2, 5.2Hz, 1H). LC / MS (ESI) (m / z): 410.0 [M+H] + .

[0402] Example 6: Preparation of target compound 6

[0403] 5-{1-fluoro-3-hydroxy-7-[(6-hydroxyspiro[3.3]hept-2-yl)amino]-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (6)

[0404] The synthetic route for compound 6 is as follows:

[0405] Step 1: 5-{1-fluoro-7-[(6-hydroxyspiro[3.3]hept-2-yl)amino]-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 Synthesis of 2,5-thiadiazolidine-1,1,3-trione (6a)

[0406] At room temperature, 6-aminospiro[3.3]hepta-2-ol hydrochloride (51.0 mg, 0.31 mmol) was dissolved in anhydrous methanol (2 mL), followed by the addition of sodium acetate (51.0 mg, 0.62 mmol), 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-oxo-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 62,5-Thiadiazolidine-1,1,3-trione (i-9) (125 mg, 0.31 mmol) and sodium cyanoborohydride (39.0 mg, 0.62 mmol). After addition, nitrogen was purged three times and the reaction was carried out at 25 °C for 12 hours. After the reaction was completed, the reaction solution was slowly added to water (10 mL), and then extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (DCM:MeOH = 10:1-5:1) to obtain 5-{1-fluoro-7-[(6-hydroxyspiro[3.3]hept-2-yl)amino]-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (6a) (100 mg, yield 63%).

[0407] Step 2: 5-{1-fluoro-3-hydroxy-7-[(6-hydroxyspiro[3.3]hept-2-yl)amino]-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 Synthesis of 2,5-thiadiazolidine-1,1,3-trione (6)

[0408] At room temperature, 5-{1-fluoro-7-[(6-hydroxyspiro[3.3]hept-2-yl)amino]-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (6a) (100 mg, 0.19 mmol) was dissolved in dioxane hydrochloride (4 M, 2 mL) and reacted at 25 °C for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by HPLC to obtain 5-{1-fluoro-3-hydroxy-7-[(6-hydroxyspiro[3.3]hept-2-yl)amino]-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (6) (45.8 mg, yield 56%).

[0409] 1H NMR (600MHz, DMSO-d6) δ9.29 (s, 1H), 8.73 (s, 2H), 6.43 (s, 1H), 4.96 (d, J=6.0Hz, 1H), 3. 97-3.89 (m, 3H), 3.79 (dd, J=16.0, 8.0Hz, 1H), 3.31 (s, 1H), 2.98 (dd, J=15.6, 4.8Hz, 1H), 2.76-2.67(m, 2H), 2.47-2.41(m, 1H), 2.38-2.34(m, 1H), 2.31(dt, J=11.6, 4.8Hz, 1H), 2 .23-2.11(m, 4H), 2.05(d, J=9.2Hz, 1H), 1.81(dd, J=15.6, 8.4Hz, 2H), 1.65-1.58(m, 1H).

[0410] LC / MS (ESI) (m / z): 426.0 [M+H] + .

[0411] Example 7: Preparation of target compound 7

[0412] 5-{1-fluoro-3-hydroxy-7-[(spiro[2.5]oct-6-yl)amino]-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione(7)

[0413] The synthetic route for compound 7 is as follows:

[0414] Step 1: 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-[(spiro[2.5]oct-6-yl)amino]-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 Synthesis of 2,5-thiadiazolidine-1,1,3-trione (7a)

[0415] At room temperature, spiro[2.5]octyl-6-amine hydrochloride (50.0 mg, 0.31 mmol) was dissolved in anhydrous methanol (2 mL), followed by the addition of sodium acetate (51.0 mg, 0.62 mmol), 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-oxo-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 62,5-Thiadiazolidine-1,1,3-trione (i-9) (125 mg, 0.31 mmol) and sodium cyanoborohydride (39.0 mg, 0.62 mmol). After addition, nitrogen was purged three times and the reaction was carried out at 25 °C for 12 hours. After the reaction was completed, the reaction solution was slowly added to water (10 mL), and then extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (DCM:MeOH = 10:1-5:1) to obtain 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-[(spiro[2.5]oct-6-yl)amino]-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (7a) (80.0 mg, yield 51%).

[0416] Step 2: Synthesis of 5-{1-fluoro-3-hydroxy-7-[(spiro[2.5]oct-6-yl)amino]-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ6,2,5-thiadiazolidine-1,1,3-trione (7)

[0417] At room temperature, 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-[(spiro[2.5]oct-6-yl)amino]-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (7a) (80.0 mg, 0.16 mmol) was dissolved in dioxane hydrochloride (4 M, 2 mL) and reacted at 25 °C for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by HPLC to obtain 5-{1-fluoro-3-hydroxy-7-[(spiro[2.5]oct-6-yl)amino]-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (7) (28.9 mg, yield 56%).

[0418] 1H NMR (600MHz, DMSO-d6) δ9.29 (s, 1H), 8.46 (s, 2H), 6.44 (s, 1H), 3.91 (s, 2H), 3.57 (s , 1H), 3.09 (dd, J=15.6, 4.4Hz, 1H), 2.78 (s, 2H), 2.48 (s, 2H), 2.14 (d, J=10.8Hz, 1H ), 2.03 (dd, J=21.6, 9.6Hz, 2H), 1.79 (t, J=12.4Hz, 2H), 1.65 (dd, J=11.2, 6.8Hz, 1H ), 1.46-1.39 (m, 2H), 0.92 (d, J=13.2Hz, 2H), 0.34-0.29 (m, 2H), 0.22-0.17 (m, 2H).

[0419] LC / MS (ESI) (m / z): 424.0 [M+H] + .

[0420] Example 8: Preparation of target compound 8

[0421] 5-{1-fluoro-3-hydroxy-7-[(spiro[3.5]non-2-yl)amino]-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (8)

[0422] The synthetic route for compound 8 is as follows:

[0423] Step 1: 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-[(spiro[3.5]non-2-yl)amino]-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 Synthesis of 2,5-thiadiazolidine-1,1,3-trione (8a)

[0424] At room temperature, spiro[3.5]nonane-2-one (34.0 mg, 0.25 mmol) was dissolved in anhydrous methanol (2 mL), and then 5-{7-amino-1-fluoro-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ was added. 62,5-Thiadiazolidine-1,1,3-trione (1a) (100 mg, 0.25 mmol) and sodium cyanoborohydride (31.0 mg, 0.50 mmol). After addition, nitrogen was purged three times and the reaction was carried out at 25 °C for 12 hours. After the reaction was completed, the reaction solution was slowly added to water (10 mL), and then extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (DCM:MeOH = 10:1-5:1) to obtain 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-[(spiro[3.5]non-2-yl)amino]-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (8a) (60.0 mg, yield 46%).

[0425] Step 2: 5-{1-fluoro-3-hydroxy-7-[(spiro[3.5]non-2-yl)amino]-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 Synthesis of 2,5-thiadiazolidine-1,1,3-trione (8)

[0426] At room temperature, 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-[(spiro[3.5]non-2-yl)amino]-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (8a) (60.0 mg, 0.11 mmol) was dissolved in dioxane hydrochloride (4 M, 2 mL) and reacted at 25 °C for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by HPLC to obtain 5-{1-fluoro-3-hydroxy-7-[(spiro[3,5]non-2-yl)amino]-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (8) (18.0 mg, yield 52%).

[0427] 1H NMR (600MHz, DMSO-d6) δ9.28 (s, 1H), 8.74 (s, 2H), 6.43 (s, 1H), 3.92-3.87 (m, 3H), 3.03-2.98 (m, 1H), 2.77-2.69 (m, 2H), 2.48-2. 48 (m, 2H), 2.14-2.06 (m, 3H), 1.84-1.79 (m, 2H), 1.64 (dd, J=11.6, 5.6Hz, 1H), 1.47 (s, 2H), 1.40 (d, J=24.8Hz, 4H), 1.30 (s, 4H).

[0428] LC / MS (ESI) (m / z): 438.1 [M+H] + .

[0429] Example 9: Preparation of target compound 9

[0430] 5-{7-[(bicyclo[4.1.0]hept-7-yl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (9)

[0431] The synthetic route for compound 9 is as follows:

[0432] Step 1: 5-{7-[(bicyclo[4.1.0]hept-7-yl)amino]-1-fluoro-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 Synthesis of 2,5-thiadiazolidine-1,1,3-trione (9a)

[0433] At room temperature, bicyclo[4.1.0]heptamethamine hydrochloride (44.0 mg, 0.30 mmol) was dissolved in anhydrous methanol (2 mL), followed by the addition of sodium acetate (49.0 mg, 0.60 mmol), 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-oxo-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 62,5-Thiadiazolidine-1,1,3-trione (i-9) (120 mg, 0.30 mmol) and sodium cyanoborohydride (37.0 mg, 0.60 mmol) were added. After the addition was complete, the mixture was purged with nitrogen three times and reacted at 25 °C for 12 hours. After the reaction was complete, the reaction solution was slowly added to water (10 mL), and then extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (DCM:MeOH = 10:1-5:1) to obtain 5-{7-[(bicyclo[4.1.0]hept-7-yl)amino]-1-fluoro-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (9a) (100 mg, yield 67%).

[0434] Step 2: 5-{7-[(bicyclo[4.1.0]hept-7-yl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 Synthesis of 2,5-thiadiazolidine-1,1,3-trione (9)

[0435] At room temperature, 5-{7-[(bicyclo[4.1.0]hept-7-yl)amino]-1-fluoro-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (9a) (100 mg, 0.20 mmol) was dissolved in dioxane hydrochloride (4 M, 2 mL) and reacted at 25 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure and purified by HPLC to obtain 5-{7-[(bicyclo[4.1.0]hept-7-yl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (9) (42.8 mg, yield 52%).

[0436] 1H NMR (600MHz, DMSO-d6) δ9.28 (s, 1H), 8.64 (s, 2H), 6.44 (s, 1H), 3.91 (s, 2H), 3.48 (s, 1H), 3.06 (dd, J=15.6, 4.8Hz, 1H), 2.80-2. 70 (m, 2H), 2.54-2.49 (m, 2H), 2.13 (d, J=10.4Hz, 1H), 1.82 (d, J=4.0Hz, 2H), 1.68-1.60 (m, 3H), 1.29 (s, 2H), 1.20-1.12 (m, 4H).

[0437] LC / MS (ESI) (m / z): 410.0 [M+H] + .

[0438] Example 10: Preparation of target compound 10

[0439] 5-{1-fluoro-3-hydroxy-7-[(6-oxaspiro[3.4]oct-2-yl)amino]-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (10)

[0440] The synthetic route for compound 10 is as follows:

[0441] Step 1: 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-[(6-oxaspiro[3.4]oct-2-yl)amino]-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 Synthesis of 2,5-thiadiazolidine-1,1,3-trione (10a)

[0442] At room temperature, 6-oxaspiro[3.4]oct-2-one (31.0 mg, 0.25 mmol) was dissolved in anhydrous methanol (2 mL), and then 5-{7-amino-1-fluoro-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ was added. 62,5-Thiadiazolidine-1,1,3-trione (1a) (60.0 mg, 0.15 mmol) and sodium cyanoborohydride (31.0 mg, 0.50 mmol). After addition, nitrogen was purged three times and the reaction was carried out at 25 °C for 12 hours. After the reaction was completed, the reaction solution was slowly added to water (10 mL), and then extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (DCM:MeOH = 10:1-5:1) to obtain 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-[(6-oxaspiro[3.4]oct-2-yl)amino]-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (10a) (40.0 mg, yield 53%).

[0443] Step 2: 5-{1-fluoro-3-hydroxy-7-[(6-oxaspiro[3.4]oct-2-yl)amino]-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 Synthesis of 2,5-thiadiazolidine-1,1,3-trione (10)

[0444] At room temperature, 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-[(6-oxaspiro[3.4]oct-2-yl)amino]-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (10a) (40.0 mg, 0.08 mmol) was dissolved in dioxane hydrochloride (4 M, 2 mL) and reacted at 25 °C for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by HPLC to obtain 5-{1-fluoro-3-hydroxy-7-[(6-oxaspiro[3.4]oct-2-yl)amino]-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (10) (10.4 mg, yield 52%).

[0445] 1H NMR (600MHz, DMSO-d6) δ9.26 (d, J=24.4Hz, 1H), 8.80 (s, 2H), 6.44 (s, 1H), 4.0 0-3.89 (m, 3H), 3.68-3.61 (m, 3H), 3.54 (s, 1H), 3.35 (s, 1H), 3.02 (d, J=15.6Hz , 1H), 2.75 (t, J=19.2Hz, 2H), 2.50 (s, 1H), 2.31-2.19 (m, 4H), 2.08 (d, J=11.2H z, 1H), 1.95 (t, J=6.8Hz, 1H), 1.88 (dd, J=13.6, 6.4Hz, 1H), 1.68-1.61 (m, 1H).

[0446] LC / MS (ESI) (m / z): 426.3 [M+H] + .

[0447] Example 11: Preparation of target compound 11

[0448] 5-(1-Fluoro-3-hydroxy-7-{[2-(2,2,2-trifluoroethyl)-2-azaspiro[3.3]hept-6-yl]amino}-5,6,7,8-tetrahydronaphth-2-yl)-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione(11)

[0449] The synthetic route for compound 11 is as follows:

[0450] Step 1: Synthesis of tert-butyl[2-(2,2,2-trifluoroethyl)-2-azaspiro[3.3]hept-6-yl]carbamate (11a)

[0451] At room temperature, tert-butyl 2-azaspiro[3.3]hept-6-ylcarbamate (200 mg, 0.94 mmol) was dissolved in anhydrous tetrahydrofuran (2 mL), followed by the addition of diisopropylethylamine (244 mg, 1.88 mmol) and trifluoroethyl trifluoromethanesulfonate (262 mg, 1.13 mmol) at 0 °C. The reaction mixture was then reacted at 25 °C for 12 hours. After the reaction was complete, the reaction solution was slowly poured into a saturated sodium bicarbonate aqueous solution (5 mL), and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with a saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (DCM:MeOH = 10:1-5:1) to obtain tert-butyl[2-(2,2,2-trifluoroethyl)-2-azaspiro[3.3]hept-6-yl]carbamate (11a) (250 mg, yield 90%).

[0452] Step 2: Synthesis of 2-(2,2,2-trifluoroethyl)-2-azaspiro[3.3]hept-6-aminomethanesulfonate (11b)

[0453] At room temperature, tert-butyl[2-(2,2,2-trifluoroethyl)-2-azaspiro[3.3]hept-6-yl]carbamate (11a) (250 mg, 0.85 mmol) was dissolved in anhydrous dichloromethane (2 mL), and then trifluoroacetic acid (2 mL) and methanesulfonic acid (81.6 mg, 0.85 mmol) were added at 0 °C. After the addition was complete, the reaction was carried out at 25 °C for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and then slurried with tert-butyl methyl ether to obtain 2-(2,2,2-trifluoroethyl)-2-azaspiro[3.3]hept-6-amine methanesulfonate (11b) (200 mg, yield 81%).

[0454] Step 3: 5-(1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-{[2-(2,2,2-trifluoroethyl)-2-azaspiro[3.3]hept-6-yl]amino}-5,6,7,8-tetrahydronaphth-2-yl)-1λ 6 Synthesis of 2,5-thiadiazolidine-1,1,3-trione (11c)

[0455] At room temperature, 2-(2,2,2-trifluoroethyl)-2-azaspiro[3.3]hept-6-amine methanesulfonate (11b) (72.1 mg, 0.25 mmol) was dissolved in anhydrous methanol (2 mL), followed by the addition of sodium acetate (81.3 mg, 0.99 mmol) and 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-oxo-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (i-9) (100 mg, 0.25 mmol). Then sodium cyanoborohydride (31.1 mg, 0.50 mmol) was added. After addition, the reaction was carried out at 25 °C for 12 hours. After the reaction was complete, water (0.1 mL) was slowly added to quench the reaction mixture, followed by dilution with methanol (20 mL), filtration, and concentration under reduced pressure. The crude product was purified by thin-plate chromatography (DCM: MeOH = 10:1) to obtain 5-(1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-{[2-(2,2,2-trifluoroethyl)-2-azaspiro[3.3]hept-6-yl]amino}-5,6,7,8-tetrahydronaphth-2-yl)-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (11c) (100 mg, 70% yield).

[0456] Step 4: 5-(1-fluoro-3-hydroxy-7-{[2-(2,2,2-trifluoroethyl)-2-azaspiro[3.3]hept-6-yl]amino}-5,6,7,8-tetrahydronaphth-2-yl)-1λ 6 Synthesis of 2,5-thiadiazolidine-1,1,3-trione (11)

[0457] At room temperature, 5-(1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-{[2-(2,2,2-trifluoroethyl)-2-azaspiro[3,3]hept-6-yl]amino}-5,6,7,8-tetrahydronaphth-2-yl)-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (11c) (100 mg, 0.17 mmol) was dissolved in dioxane hydrochloride (4 M, 2 mL) and reacted at 25 °C for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by HPLC to obtain 5-(1-fluoro-3-hydroxy-7-{[2-(2,2,2-trifluoroethyl)-2-azaspiro[3.3]hept-6-yl]amino}-5,6,7,8-tetrahydronaphth-2-yl)-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (11) (2.3 mg, yield 3%).

[0458] 1 H NMR (600MHz, DMSO-d6) δ9.26 (s, 1H), 8.73 (s, 2H), 6.43 (s, 1H), 3.90 (s, 2H), 3.84-3.79 (m, 1H), 3.37 (s, 1H), 3.27 (s, 1H), 3.11 (dd, J=20.4, 10. 0Hz, 2H), 2.99 (dd, J=16.0, 5.2Hz, 2H), 2.78-2.70 (m, 2H), 2.45 (d, J=4.0Hz, 5H), 2.28-2.20 (m, 2H), 2.03 (s, 1H), 1.62 (dd, J=11.6, 5.6Hz, 1H).

[0459] LC / MS (ESI) (m / z): 493.0 [M+H] + .

[0460] Example 12: Preparation of target compound 12

[0461] 5-{7-[(1,1-difluorospiro[2,5]oct-6-yl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (12)

[0462] The synthetic route for compound 12 is as follows:

[0463] Step 1: 5-{7-[(1,1-difluorospiro[2,5]oct-6-yl)amino]-1-fluoro-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 Synthesis of 2,5-thiadiazolidine-1,1,3-trione (12a)

[0464] At room temperature, 1,1-difluorospiro[2.5]octane-6-amine hydrochloride (9.83 mg, 0.05 mmol) was dissolved in anhydrous methanol (1 mL), followed by the addition of sodium acetate (8.16 mg, 0.10 mmol), 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-oxo-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (i-9) (20.0 mg, 0.05 mmol) and sodium cyanoborohydride (6.26 mg, 0.10 mmol) were added. After the addition was complete, the mixture was purged with nitrogen three times and reacted at 25 °C for 12 hours. After the reaction was complete, the reaction solution was slowly added to water (5 mL), and then extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (DCM:MeOH = 10:1-5:1) to obtain 5-{7-[(1,1-difluorospiro[2.5]oct-6-yl)amino]-1-fluoro-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (12a) (20.0 mg, yield 74%).

[0465] Step 2: 5-{7-[(1,1-difluorospiro[2,5]oct-6-yl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 Synthesis of 2,5-thiadiazolidine-1,1,3-trione (12)

[0466] At room temperature, 5-{7-[(1,1-difluorospiro[2,5]oct-6-yl)amino]-1-fluoro-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 62,5-Thiadiazolidine-1,1,3-trione (12a) (20.0 mg, 0.04 mmol) was dissolved in dioxane hydrochloride (4 M, 2 mL) and reacted at 25 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure and purified by HPLC to obtain 5-{7-[(1,1-difluorospiro[2.5]oct-6-yl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (12) (6.7 mg, yield 40%).

[0467] 1 H NMR (600MHz, DMSO-d6) δ9.28 (s, 1H), 8.49 (s, 2H), 6.44 (s, 1H), 3.91 (s, 2H), 3.58 (d, J = 20.8Hz, 1H), 3.09 (d, J = 11.2Hz, 1H), 2.78 (s, 2H), 2.47-2.4 0 (m, 2H), 2.10 (d, J=16.4Hz, 3H), 1.76 (dd, J=29.6, 14.8Hz, 2H), 1.64 (s, 1 H), 1.52 (d, J=13.6Hz, 1H), 1.39 (d, J=11.6Hz, 3H), 1.25 (t, J=8.0Hz, 2H).

[0468] LC / MS (ESI) (m / z): 460.3 [M+H] + .

[0469] Example 13: Preparation of target compound 13

[0470] 5-{7-[(bicyclo[2.2.1]hept-2-yl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (13)

[0471] The synthetic route for compound 13 is as follows:

[0472] Step 1: 5-{7-[(bicyclo[2.2.1]hept-2-yl)amino]-1-fluoro-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 Synthesis of 2,5-thiadiazolidine-1,1,3-trione (13a)

[0473] At room temperature, bicyclo[2.2.1]hept-2-amine hydrochloride (8.15 mg, 0.05 mmol) was dissolved in anhydrous methanol (1 mL), followed by the addition of sodium acetate (8.16 mg, 0.10 mmol), 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-oxo-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (i-9) (20.0 mg, 0.05 mmol) and sodium cyanoborohydride (6.26 mg, 0.10 mmol) were added. After the addition was complete, the mixture was purged with nitrogen three times and reacted at 25 °C for 12 hours. After the reaction was complete, the reaction solution was slowly added to water (5 mL), and then extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (DCM:MeOH = 10:1-5:1) to obtain 5-{7-[(bicyclo[2.2.1]hept-2-yl)amino]-1-fluoro-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (13a) (20.0 mg, yield 81%).

[0474] Step 2: 5-{7-[(bicyclo[2.2.1]hept-2-yl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 Synthesis of 2,5-thiadiazolidine-1,1,3-trione (13)

[0475] At room temperature, 5-{7-[(bicyclo[2.2.1]hept-2-yl)amino]-1-fluoro-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (13a) (20.0 mg, 0.04 mmol) was dissolved in dioxane hydrochloride (4 M, 2 mL) and reacted at 25 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure and purified by HPLC to obtain 5-{7-[(bicyclo[2.2.1]hept-2-yl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (13) (8.5 mg, yield 52%).

[0476] 1H NMR (600MHz, DMSO-d6) δ9.25 (s, 1H), 8.51 (s, 2H), 6.43 (s, 1H), 3.94-3.88 ( m, 2H), 3.61 (d, J=12.4Hz, 1H), 3.08 (d, J=15.6Hz, 1H), 2.77 (dd, J=24.4, 11. 6Hz, 2H), 2.53 (s, 3H), 2.19 (d, J=27.6Hz, 2H), 1.95 (s, 1H), 1.67-1.61 (m, 1H ), 1.57-1.50 (m, 2H), 1.48-1.40 (m, 2H), 1.32 (t, J=9.6Hz, 2H), 1.04 (s, 1H).

[0477] LC / MS (ESI) (m / z): 410.3 [M+H] + .

[0478] Example 14: Preparation of target compound 14

[0479] 5-{7-[(2,2-dioxo-2λ 6 -thiaspiro[3.3]heptane-6-yl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 ,2,5-Thiadiazole-1,1,3-trione (14)

[0480] The synthetic route for compound 14 is as follows:

[0481] Step 1: 5-{7-[(2,2-dioxo-2λ 6 -thiaspiro[3.3]heptane-6-yl)amino]-1-fluoro-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 Synthesis of 2,5-thiadiazole-1,1,3-trione (14a)

[0482] At room temperature, 6-amino-2λ 6 Thiavispiro[3.3]heptane-2,2-dione (40.1 mg, 0.25 mmol) was dissolved in anhydrous methanol (1 mL), and then sodium acetate (40.8 mg, 0.50 mmol) was added. 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-oxo-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 62,5-Thiadiazolidine-1,1,3-trione (i-9) (100.0 mg, 0.25 mmol) and sodium cyanoborohydride (6.26 mg, 0.10 mmol) were added. After the addition was complete, the mixture was purged with nitrogen three times and reacted at 25 °C for 12 hours. After the reaction was complete, the reaction solution was slowly added to water (5 mL), and then extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (DCM:MeOH = 10:1-5:1) to obtain 5-{7-[(2,2-dioxo-2λ 6 -thiaspiro[3.3]heptane-6-yl)amino]-1-fluoro-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 2,5-Thiadiazole-1,1,3-trione (14a) (54.4 mg, yield 40%).

[0483] Step 2: 5-{7-[(2,2-dioxo-2λ] 6 -thiaspiro[3.3]heptane-6-yl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 Synthesis of 2,5-thiadiazole-1,1,3-trione (14)

[0484] At room temperature, 5-{7-[(2,2-dioxo-2λ 6 -thiaspiro[3.3]heptane-6-yl)amino]-1-fluoro-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 2,5-Thiadiazole-1,1,3-trione (14a) (54.4 mg, 0.10 mmol) was dissolved in dioxane hydrochloride (4 M, 2 mL) and reacted at 25 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure and purified by HPLC to obtain 5-{7-[(2,2-dioxo-2λ 6 -thiaspiro[3.3]heptane-6-yl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 ,2,5-thiadiazole-1,1,3-trione (14) (14.6 mg, yield 32%).

[0485] 1H NMR (600MHz, DMSO-d6) δ9.26 (s, 1H), 6.48 (d, J = 58.9Hz, 1H), 4.29 (s, 2H), 4.24 (s, 2H), 3.95 (d, J = 56.4Hz, 3H), 2.99 (dd, J=15.7, 4.8Hz, 1H), 2.78-2.55 (m, 2H), 2.46-2.29 (m, 4H), 2.02 (s, 1H), 1.63 (dd, J=11.6, 5.3Hz, 1H).

[0486] LC / MS (ESI) (m / z): 460.1 [M+H] + .

[0487] Example 15: Preparation of target compound 15

[0488] 5-{7-[(5,5-difluoro-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 ,2,5-Thiadiazole-1,1,3-trione (15)

[0489] The synthetic route for compound 15 is as follows:

[0490] Step 1: 5-{7-[(5,5-difluoro-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)amino]-1-fluoro-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 Synthesis of 2,5-thiadiazole-1,1,3-trione (15a)

[0491] At room temperature, 5,5-difluoro-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-amine (39.6 mg, 0.25 mmol) was dissolved in anhydrous methanol (1 mL), followed by the addition of sodium acetate (40.8 mg, 0.50 mmol), 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-oxo-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 62,5-Thiadiazolidine-1,1,3-trione (i-9) (100.0 mg, 0.25 mmol) and sodium cyanoborohydride (6.26 mg, 0.10 mmol) were added. After the addition was complete, the mixture was purged with nitrogen three times and reacted at 25 °C for 12 hours. After the reaction was complete, the reaction solution was slowly added to water (5 mL), and then extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (DCM:MeOH = 10:1-5:1) to obtain 5-{7-[(5,5-difluoro-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)amino]-1-fluoro-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 2,5-Thiadiazole-1,1,3-trione (15a) (35.3 mg, yield 26%).

[0492] Step 2: 5-{7-[(5,5-difluoro-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 Synthesis of 2,5-thiadiazole-1,1,3-trione (15)

[0493] At room temperature, 5-{7-[(5,5-difluoro-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)amino]-1-fluoro-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 2,5-Thiadiazole-1,1,3-trione (15a) (35.3 mg, 0.08 mmol) was dissolved in dioxane hydrochloride (4 M, 2 mL) and reacted at 25 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure and purified by HPLC to obtain 5-{7-[(5,5-difluoro-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 2,5-Thiadiazole-1,1,3-trione (15) (0.89 mg, yield 3%).

[0494] 1H NMR (400MHz, MeOD) δ6.51 (s, 1H), 5.57 (s, 1H), 4.38 (t, 2H), 4.28 (s, 2H), 3.61-3.71 (m, 1H), 3.43 (t, 2H), 3.24-3.12(m, 1H), 2.90-2.82(m, 1H), 2.53-2.43(m, 1H), 2.05-2.15(m, 1H), 1.75-1.66(m, 1H).

[0495] LC / MS (ESI) (m / z): 458.0 [M+H] + .

[0496] Example 16: Preparation of target compound 16

[0497] 5-[3-[(7,7-difluorospiro[3.3]hept-2-yl)amino]-5-fluoro-7-hydroxy-tetrahydronaphth-6-yl]-1,1-dioxo-1,2,5-thiadiazolidine-3-one (16)

[0498] The synthetic route for target compound 16 is shown below:

[0499] Step 1: Synthesis of 3-cyclopropylcyclobutanecarboxylate (16b)

[0500] The starting material, cyclopropyltriphenylphosphine bromide (90.0 g, 234 mmol), was dissolved in toluene (400 mL). Potassium tert-butoxide (43.8 g, 390 mmol) was slowly added under nitrogen protection, and the mixture was stirred at 55 °C for 2 hours. Then, benzyl 3-oxocyclobutane-1-carboxylate (16a) (40.0 g, 195 mmol) was added to the reaction mixture, and the mixture was stirred at 70 °C for 2 hours. After the reaction was complete, ammonium chloride solution (250 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (200 mL * 3), washed with saturated brine (200 mL * 3), and the combined organic phases were dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (mobile phase: petroleum ether / ethyl acetate = 20:1, R...). fp1 (0.65), yielding benzyl 3-cyclopropylcyclobutanecarboxylate (16b) (11.0 g, crude product).

[0501] Step 2: Synthesis of 8-oxabispiro[2.0.34.13]octane-6-carboxylic acid benzyl ester (16c)

[0502] The raw material, benzyl 3-cyclopropylcyclobutanecarboxylate (16b) (10.0 g, 43.8 mmol), was dissolved in anhydrous dichloromethane (100 mL). The reaction system was purged with nitrogen three times. At 0 °C, m-chloroperoxybenzoic acid (9.78 g, 48.2 mmol) was slowly added to the reaction solution, and the mixture was stirred at 0 °C for 0.5 hours. After the reaction was completed, sodium sulfite solution (50 mL) was added to quench the reaction. The mixture was extracted with dichloromethane (40 mL * 3), washed with saturated brine (50 mL * 3), and the combined organic phases were dried with anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure to obtain crude 8-oxadispiro[2.0.34.13]octane-6-carboxylic acid benzyl ester (16c) (10.0 g, crude product).

[0503] Step 3: Synthesis of 7-oxospiro[3.3]heptane-2-carboxylic acid benzyl ester (16d)

[0504] The starting material 8-oxadispiro[2.0.34.13]octane-6-carboxylic acid benzyl ester (16c) (10.0 g, 40.9 mmol) was dissolved in dichloromethane (100 mL). Then, under nitrogen protection, boron trifluoride diethyl ether (1.25 g, 4.09 mmol) was added to the reaction solution at 0 °C, and the mixture was stirred at 0 °C for 0.5 hours. After the reaction was complete, sodium bicarbonate (50.0 mL) was added to quench the reaction, followed by extraction with dichloromethane (50 mL * 3), washing with saturated brine (50 mL * 3), 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 (mobile phase: petroleum ether / ethyl acetate = 4:1, R...). fp1 For 0.51 and R fp2 (0.42), yielding 3.60 g of compound 7-oxospiro[3.3]heptane-2-carboxylic acid benzyl ester (16d), 36% yield).

[0505] Step 4: Synthesis of benzyl 7,7-difluorospiro[3.3]heptane-2-carboxylate (16e)

[0506] 7-oxospiro[3.3]heptane-2-carboxylic acid benzyl ester (16d) (3.40 g, 13.9 mmol) was dissolved in dichloromethane (70 mL). Then, under nitrogen protection, DAST (11.2 g, 69.6 mmol) and anhydrous ethanol (64.1 mg, 1.39 mmol) were added to the reaction solution at 0 °C, and the mixture was stirred at 25 °C for 8 hours. After the reaction was complete, sodium bicarbonate (100 mL) was added at 0 °C to quench the reaction. The mixture was extracted with dichloromethane (50 mL * 3), washed with saturated brine (50 mL * 3), and the combined organic phases were dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (mobile phase: petroleum ether / ethyl acetate = 3:1, R...).fp1 The concentration was 0.52), and the compound 7,7-difluorospiro[3.3]heptane-2-carboxylic acid benzyl ester (16e) (2.60 g, crude product) was obtained.

[0507] Step 5: Synthesis of 7,7-difluorospiro[3.3]heptane-2-carboxylic acid (16f)

[0508] The starting material 7,7-difluorospiro[3.3]heptane-2-carboxylic acid benzyl ester (16e) (2.20 g, 8.26 mmol) was dissolved in anhydrous tetrahydrofuran (22 mL). Then, 2M lithium hydroxide aqueous solution (41.3 mL, 82.6 mmol) was added to the reaction solution at 0 °C, and the mixture was stirred at 25 °C for 2 hours. After the reaction was completed, the reaction solution was diluted with water (15 mL), extracted with ethyl acetate (20 mL * 3), and then the aqueous phase was adjusted to pH 3 with 1M hydrochloric acid, extracted with dichloromethane (20 mL * 3), washed with saturated brine (50 mL * 3), and the combined organic phases were dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 7,7-difluorospiro[3.3]heptane-2-carboxylic acid (16f) (1.40 g, 96% yield).

[0509] Step 6: Synthesis of N-(7,7-difluorospiro[3.3]hept-2-yl)carbamate tert-butyl ester (16 g)

[0510] The starting materials 7,7-difluorospiro[3.3]heptane-2-carboxylic acid (16f) (1.20 g, 6.81 mmol) and N,N-diisopropylethylamine (1.06 mg, 8.17 mmol) were dissolved in anhydrous toluene (20 mL), followed by the addition of diphenyl azidophosphate (2.06 g, 7.49 mmol). The mixture was stirred at 100 °C for 0.5 h, and then tert-butanol (5.05 g, 68.1 mmol) was added to the reaction solution. The mixture was stirred at 100 °C for 8 h. After the reaction was complete, sodium bicarbonate solution (20 mL) was added to quench the reaction, followed by extraction with dichloromethane (20 mL * 3), washing with saturated brine (10 mL * 3), 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 (mobile phase: petroleum ether / ethyl acetate = 3:1, R...). fp1 The concentration was 0.64), and the compound N-(7,7-difluorospiro[3.3]hept-2-yl)carbamate tert-butyl ester (16 g) (800 mg, crude product) was obtained.

[0511] Step 7: Synthesis of 7,7-difluorospiro[3.3]hept-2-amine (16h)

[0512] The raw material N-(7,7-difluorospiro[3.3]hepta-2-yl)carbamate tert-butyl ester (16 g) (800 mg, 3.24 mmol) was dissolved in 2M methanol hydrochloride (15 mL), and then stirred at 25 °C for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a crude product, and then ethyl acetate (5 mL) was added. The mixture was stirred at 25 °C for 10 minutes and filtered to obtain 7,7-difluorospiro[3.3]hepta-2-amine (16 h) (150 mg, 25% yield).

[0513] Step 8: Synthesis of 5-[3-[(7,7-difluorospiro[3.3]hept-2-yl)amino]-5-fluoro-7-(2-methoxyethoxymethoxy)tetrahydronaphthyl-6-yl]-1,1-dioxo-1,2,5-thiadiazolidine-3-one (16i)

[0514] The starting material 7,7-difluorospiro[3.3]hepta-2-amine (16h) (140 mg, 762 μmol) and sodium acetate (156 mg, 1.51 mmol) were dissolved in methanol (5 mL) and stirred at 25 °C for 0.5 h. Then, 5-(1-fluoro-3-((2-methoxyethoxy)methoxy)-7-oxo-5,6,7,8-tetrahydronaphthyl-2-yl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (i-9) (153 mg, 381 μmol) was added to the reaction solution and stirred at 25 °C for 0.5 h. Then, sodium cyanoborohydride (71.8 mg, 1.14 mmol) was added to the reaction solution and stirred at 25 °C for 0.5 h. After the reaction was completed, the mixture was filtered and concentrated under reduced pressure to obtain the crude product. The residue was separated and purified by HPLC to give compound 5-[3-[(7,7-difluorospiro[3.3]hept-2-yl)amino]-5-fluoro-7-(2-methoxyethoxymethoxy)tetrahydronaphth-6-yl]-1,1-dioxo-1,2,5-thiadiazolidine-3-one (16i) (40.0 mg, 20% yield).

[0515] LC-MS, M / Z (ESI): 534.1 [M+H] +

[0516] Step 9: 5-[3-[(7,7-difluorospiro[3.3]hept-2-yl)amino]-5-fluoro-7-hydroxy-tetrahydronaphth-6-yl]-1,1-dioxo-1,2,5-thiadiazolidine-3-one (16)

[0517] The starting material 5-[3-[(7,7-difluorospiro[3.3]hept-2-yl)amino]-5-fluoro-7-(2-methoxyethoxymethoxy)tetrahydronaphthyl-6-yl]-1,1-dioxo-1,2,5-thiadiazolidine-3-one (16i) (30.0 mg, 56.2 μmol) dissolved in acetonitrile (0.5 mL) was added to the reaction solution. Then, dioxane hydrochloride (2 M, 0.5 mL) was slowly added to the reaction solution, and the mixture was stirred at 25 °C for 1 hour. After the reaction was completed, the solution was concentrated under reduced pressure to obtain the crude product. The residue was separated and purified by HPLC to obtain compound 5-[3-[(7,7-difluorospiro[3.3]hept-2-yl)amino]-5-fluoro-7-hydroxy-tetrahydronaphthyl-6-yl]-1,1-dioxo-1,2,5-thiadiazolidine-3-one (16).

[0518] 1 H NMR (400Hz, CD3OD) δ 6.53 (s, 1H), 4.23 (s, 2H), 3.75-4.11 (m, 1H), 3.42-3.56 (m, 1H), 3.09-3.22 (m, 1H), 2.89 (br d, J=5.3Hz, 3H), 2.34-2.77(m, 5H), 2.15-2.29(m, 2H), 1.96-2.09(m, 1H), 1.84-1.94(m, 1H), 1.70-1.84(m, 1H).

[0519] LC-MS, M / Z (ESI): 446.1 [M+H] +

[0520] Example 17: Preparation of target compound 17

[0521] Synthesis of 5-(1-fluoro-3-hydroxy-7-((6-methylpyridin-2-yl)amino)-5,6,7,8-tetrahydronaphthyl-2-yl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (17)

[0522] The synthetic route for target compound 17 is shown below:

[0523] Step 1: Synthesis of 5-(3-benzyloxy)-1-fluoro-7-((6-methylpyridin-2-yl)amino)-5,6,7,8-tetrahydronaphthyl-2-yl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide (17a)

[0524] At room temperature, 6-methylpyridin-2-amine (60.0 mg, 556 μmol) was added to tetrahydrofuran (3 mL) containing 5-(3-benzyloxy)-1-fluoro-7-oxo-5,6,7,8-tetrahydronaphthyl-2-yl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (150 mg, 371 μmol) (synthesis reference WO2022056281A1), tetraethoxytitanium (127 mg, 556 μmol), and the mixture was stirred at 70 °C for 3 hours. Sodium cyanoborohydride (93.0 mg, 1.48 mmol) was added at 25 °C, and the mixture was stirred at 25 °C for 1 hour. After the reaction was complete, dichloromethane (2 mL), methanol (2 mL), and water (1 mL) were added. The mixture was filtered through diatomaceous earth and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 7:1) to give 5-(3-benzyloxy)-1-fluoro-7-((6-methylpyridin-2-yl)amino)-5,6,7,8-tetrahydronaphthyl-2-yl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide (17a) (40.0 mg, crude product).

[0525] LC-MS, M / Z (ESI): 497.1 [M+H] +

[0526] Step 2: Synthesis of 5-(1-fluoro-3-hydroxy-7-((6-methylpyridin-2-yl)amino)-5,6,7,8-tetrahydronaphthyl-2-yl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (17)

[0527] At -70°C, boron tribromide (1M, 181 μL) was added dropwise to dichloromethane (1 mL) containing 30.0 mg (60.4 μmol) of 5-(3-benzyloxy)-1-fluoro-7-((6-methylpyridin-2-yl)amino)-5,6,7,8-tetrahydronaphthyl-2-yl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide (17a). The reaction mixture was stirred at -70°C for 1 hour. After the reaction was completed, methanol was slowly added dropwise at -60°C to quench the reaction. The crude product was concentrated under reduced pressure at low temperature. The crude product was purified by HPLC to obtain 5-(1-fluoro-3-hydroxy-7-((6-methylpyridin-2-yl)amino)-5,6,7,8-tetrahydronaphthyl-2-yl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide (17a).

[0528] 1H NMR(400MHz, DMSO-d6)δ9.24(br s, 1H), 7.77-7.71 (m, 1H), 6.84-6.82 (m, 1H), 6.68-6.60 (m, 1H), 6.49 (s, 1H), 4.13-4.16 (m, 1H), 3.97 (s, 2H) , 3.09-3.02(m, 1H), 2.86-2.80(m, 2H), 2.48-2.44(m, 2H), 2.42(s, 3H), 2.05-1.99(m, 1H), 1.82-1.75(m, 1H).

[0529] LC-MS, M / Z (ESI): 407.1 [M+H] +

[0530] Example 18: Preparation of target compound 18

[0531] 5-(6-(3,3-dimethylpyrrolidin-1-yl)-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthyl-2-yl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide (18)

[0532] The synthetic route for target compound 18 is shown below:

[0533] Step 1: Synthesis of 6-bromo-4-fluoro-1-methylene-2,3-dihydro-1H-indene (18b)

[0534] At 0 °C, potassium tert-butoxide (58.8 g, 524 mmol) was added to a tetrahydrofuran (2.20 L) solution of methyltriphenylphosphine bromide (187 g, 524 mmol). After 1 hour, a tetrahydrofuran (400 mL) solution of 6-bromo-4-fluoro-2,3-dihydro-1H-indene-1-one (18a) (48.0 g, 209 mmol) was added dropwise. The resulting mixture was reacted at 20 °C for 2 hours. The reaction was confirmed by TLC. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was subjected to silica gel column chromatography (petroleum ether:ethyl acetate = 100:0-90:10, gradient elution) to give 6-bromo-4-fluoro-1-methylene-2,3-dihydro-1H-indene (18b) (36.0 g, 76% yield).

[0535] 1 H NMR (400MHz, CDCl3): δ7.39 (s, 1H), 7.06 (d, J=8.0Hz, 1H), 5.48-5.08 (m, 2H), 2.95-2.83 (m, 4H).

[0536] Step 2: Synthesis of 7-bromo-5-fluoro-3,4-dihydronaphthyl-2(1H)-one (18c)

[0537] Hydroxytosyl iodobenzene (7.81 g, 19.8 mmol) was added to a methanol (90 mL) solution of 6-bromo-4-fluoro-1-methylene-2,3-dihydro-1H-indene (18b) (4.50 g, 19.8 mmol). The resulting mixture was stirred at 25 °C for 18 hours. The reaction was detected by TLC. The reaction solution was concentrated under reduced pressure, diluted with water (100 mL), extracted with dichloromethane (50 mL × 3), and the combined organic phases were concentrated under reduced pressure to obtain a crude product. The crude product was subjected to silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 100:0-85:15, gradient elution) to give 7-bromo-5-fluoro-3,4-dihydronaphthyl-2(1H)-one (18c) (2.40 g, 32% yield).

[0538] LC-MS, M / Z (ESI): 243 [M+H] + .

[0539] Step 3: Synthesis of 7-bromo-5-fluoro-3,4-dihydro-1H-spiro(naphthalene-2,2'-(1,3)dioxolane)(18d)

[0540] To a solution of 7-bromo-5-fluoro-3,4-dihydronaphthyl-2(1H)-one (18c) (27.0 g, 72.2 mmol) and ethylene glycol (4.85 mL, 86.6 mmol) in toluene (270 mL), p-toluenesulfonic acid (2.49 g, 14.4 mmol) was added. The resulting mixture was stirred at 110 °C for 16 hours using a water separator. The reaction was confirmed by LC-MS. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was then subjected to silica gel column chromatography (petroleum ether: acetate (V / V) = 100:0-75:25, gradient elution) to give 7-bromo-5-fluoro-3,4-dihydro-1H-spiro(naphthyl-2,2'-(1,3)dioxolane) (18d) (14.7 g, 71% yield).

[0541] 1 HNMR (400MHz, CDCl3): 67.05-6.95 (m, 2H), 4.03 (s, 4H), 2.94 (s, 2H), 2.88 (tJ=6.8Hz 2H), 1.93 (tJ=6.8Hz 2H).

[0542] Step 4: Synthesis of 5′-fluoro-3′,4′-dihydro-1′H-spiro((1,3)dioxolane-2,2′-naphthalene)-7′-ol (18e)

[0543] 7-Bromo-5-fluoro-3,4-dihydro-1H-spiro(naphthalene-2,2'-(1,3)dioxolane) (18d) (10.0 g, 34.8 mmol) was dissolved in a mixed solvent of N,N-dimethylformamide (100 mL) and water (1 mL). Then, 2-(di-tert-butylphosphino)-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl(2-amino-1,1′-biphenyl-2-yl)palladium(II) (0.740 g, 0.871 mmol) and cesium carbonate (22.7 g, 69.7 mmol) were added. The reaction mixture was reacted at 80 °C for 14 hours. The reaction was confirmed by LC-MS. Water (100 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (150 mL × 3). The organic layers were combined, washed with saturated brine (100 mL), dried with anhydrous sodium sulfate, 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) = 100:0-70:30, gradient elution) to obtain 5′-fluoro-3′,4′-dihydro-1′H-spiro((1,3)dioxolane-2,2′-naphthalene)-7′-ol (18e) (5.50 g, yield 70%).

[0544] LC-MS, M / Z (ESI): 225.0 [M+H] + .

[0545] Step 5: Synthesis of 5′-fluoro-7′-((2-methoxyethoxy)methoxy)-3′,4′-dihydro-1′H-spiro((1,3)dioxolane-2,2′-naphthalene)(18f)

[0546] 5′-fluoro-3′,4′-dihydro-1′H-spiro((1,3)dioxolane-2,2′-naphthalene)-7′-ol (18e) (6.70 g, 29.9 mmol) was dissolved in tetrahydrofuran (70 mL); the mixture was cooled to 0 °C, and sodium hydrogen (1.79 g, 44.8 mmol, 60% wt) was added. After reacting the mixture at 0 °C for 0.5 hours, 2-methoxyethoxymethyl chloride (5.58 g, 44.8 mmol) was added, and the resulting mixture was reacted at 25 °C for 14 hours. The reaction was confirmed by LC-MS. Water (100 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic layers were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, 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) = 100:0-75:25, gradient elution) to obtain 5′-fluoro-7′-((2-methoxyethoxy)methoxy)-3′,4′-dihydro-1'H-spiro((1,3)dioxolane-2,2'-naphthalene)(18f) (7.20 g, yield 77%).

[0547] Step 6: Synthesis of 5′-fluoro-6′-iodo-7′-((2-methoxyethoxy)methoxy)-3′,4′-dihydro-1′H-spiro((1,3)dioxolane-2,2′-naphthalene) (18g)

[0548] 2,2,6,6-Tetramethylpiperidine (299 mg, 2.11 mmol) was dissolved in tetrahydrofuran (3 mL) and cooled to -78 °C. Butyllithium (0.768 mL, 1.92 mmol, 2.5 M tetrahydrofuran solution) was added to the reaction solution. The reaction was carried out at -78 °C for 1 hour. Then, 5′-fluoro-7′-((2-methoxyethoxy)methoxy)-3′,4′-dihydro-1'H-spiro((1,3)dioxolane-2,2'-naphthalene)(18f) (300 mg, 0.960 mmol) in tetrahydrofuran (3 mL) was added to the reaction solution, and the reaction was carried out at -78 °C for 1 hour. Finally, iodine (390 mg, 1.54 mmol) in tetrahydrofuran (3 mL) was added to the reaction solution. The reaction was then heated to 25 °C and stirred for 14 hours. The reaction was confirmed to be complete by LC-MS. Add saturated sodium thiosulfate solution (50 mL) to the reaction system, extract with ethyl acetate (30 mL × 3), combine the organic layers, wash with saturated brine (50 mL), dry with anhydrous sodium sulfate, concentrate under reduced pressure to obtain crude product, and purify the crude product by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 100:0-75:25, gradient elution) to obtain 5′-fluoro-6′-iodo-7′-((2-methoxyethoxy)methoxy)-3′,4′-dihydro-1′H-spiro((1,3)dioxolane-2,2′-naphthalene) (18 g) (230 mg, yield 55%).

[0549] LC-MS, M / Z(ESI): 461.2[M+Na] + .

[0550] Step 7: Synthesis of tert-butyl 2-((5′-fluoro-7′-((2-methoxyethoxy)methoxy)-3′,4′-dihydro-1′H-spiro((1,3)dioxolane-2,2′-naphthalene)-6′-yl)amino)acetate (18h)

[0551] 5′-Fluoro-6′-iodo-7′-((2-methoxyethoxy)methoxy)-3′,4′-dihydro-1′H-spiro((1,3)dioxolane-2,2′-naphthalene) (230 mg, 0.525 mmol) was dissolved in N,N-dimethylformamide (5 mL); glycine tert-butyl ester (138 mg, 1.05 mmol) and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dioxolane were added to the reaction solution. Methoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (47.6 mg, 0.0520 mmol), 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4′-6'-tri-1-propyl-11′-biphenyl (56.3 mg, 0.105 mmol), and cesium carbonate (342 mg, 1.05 mmol) were added. The reaction mixture was reacted at 90 °C for 14 hours. The reaction was confirmed by LC-MS. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, 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) = 100:0-50:50, gradient elution) to give 120 mg of 2-((5′-fluoro-7′-((2-methoxyethoxy)methoxy)-3′,4′-dihydro-1′H-spiro((1,3)dioxolane-2,2′-naphthyl)-6′-yl)amino)tert-butyl acetate (18 h, yield 52%).

[0552] LC-MS, M / Z (ESI): 442.4 [M+H] + .

[0553] Step 8: Synthesis of 2-((5′-fluoro-7′-((2-methoxyethoxy)methoxy)-3′,4′-dihydro-1′H-spiro((1,3)dioxolane-2,2′-naphthalene)-6′-yl)(aminosulfonyl)amino)tert-butyl acetate (18i)

[0554] 2-((5′-fluoro-7′-((2-methoxyethoxy)methoxy)-3′,4′-dihydro-1′H-spiro((1,3)dioxolane-2,2′-naphthalene)-6′-yl)amino)tert-butyl acetate (18h) (120 mg, 0.272 mmol) was dissolved in dichloromethane (3 mL); pyridine (215 mg, 2.72 mmol) and aminosulfonyl chloride (157 mg, 1.36 mmol) were added to the reaction solution. The reaction solution was reacted at 25 °C for 3 hours. The reaction was detected by LC-MS to indicate completion. Water (20 mL) was added to the reaction system and extracted with ethyl acetate (30 mL × 3). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure with an organic solvent to obtain crude 2-((5′-fluoro-7′-((2-methoxyethoxy)methoxy)-3′,4′-dihydro-1′H-spiro((1,3)dioxolane-2,2′-naphthalene)-6′-yl)(aminosulfonyl)amino)tert-butyl acetate (18i) (100 mg, crude product). This crude product can be used directly in the next step without purification.

[0555] Step 9: Synthesis of 5-(5′-fluoro-7′-((2-methoxyethoxy)methoxy)-3′,4′-dihydro-1′H-spiro((1,3)dioxolane-2,2′-naphthalene)-6′-yl)-1,2,5-thiadiazol-3-one-1,1-dioxide (18j)

[0556] 2-((5′-fluoro-7′-((2-methoxyethoxy)methoxy)-3′,4′-dihydro-1′H-spiro((1,3)dioxolane-2,2′-naphthalene)-6′-yl)(aminosulfonyl)amino)tert-butyl acetate (18i) (100 mg, 0.115 mmol, 60% purity) was dissolved in methanol (3 mL); sodium methoxide methanol solution (1 mL, 5.4 mmol, 5.4 M) was added to the reaction solution. The reaction was carried out at 25 °C for 14 hours. The reaction was detected by LC-MS to indicate completion. The reaction solution was purified directly through a C18 column in reverse column chromatography (water:acetonitrile (V / V) = 100:0-70:30, gradient elution) to obtain 5-(5′-fluoro-7′-((2-methoxyethoxy)methoxy)-3′,4′-dihydro-1′H-spiro((1,3)dioxolane-2,2′-naphthyl)-6′-yl)-1,2,5-thiadiazol-3-one-1,1-dioxide (18j) (30.0 mg, yield 58%).

[0557] Step 10: Synthesis of 5-(1-fluoro-3-((2-methoxyethoxy)methoxy)-6-oxo-5,6,7,8-tetrahydronaphthyl-2-yl)-1,2,5-thiadiazolecyclo-3-one-1,1-dioxide (18k)

[0558] 5-(5′-fluoro-7′-((2-methoxyethoxy)methoxy)-3′,4′-dihydro-1′H-spiro[[1,3]dioxolane-2,2′-naphthyl]-6′-yl)-1,2,5-thiadiazol-3-one-1,1-dioxide (18k) (15.0 mg, 0.340 mmol) was dissolved in methanol (3 mL), and formic acid (1 mL) was added to the reaction solution. The reaction solution was reacted at 25 °C for 3 hours. The reaction was confirmed by LC-MS. The reaction solution was directly concentrated under reduced pressure to obtain crude 5-(1-fluoro-3-((2-methoxyethoxy)methoxy)-6-oxo-5,6,7,8-tetrahydronaphthyl-2-yl)-1,2,5-thiadiazolne-3-one-1,1-dioxide (18k) (15.0 mg, crude), which was used directly in the next step without purification.

[0559] LC-MS, M / Z(ESI): 425.2[M+Na] + .

[0560] Step 11: Synthesis of 5-(6-(3,3-dimethylpyrrolidin-1-yl)-1-fluoro-3-((2-methoxyethoxy)methoxy)-5,6,7,8-tetrahydronaphthyl-2-yl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide (18l)

[0561] 5-(1-fluoro-3-((2-methoxyethoxy)methoxy)-6-oxo-5,6,7,8-tetrahydronaphthyl-2-yl)-1,2,5-thiadiazolylcyclo-3-one-1,1-dioxide (18k) (15.0 mg, 0.03 mmol, 80% purity) and 3,3-dimethylpyrrole (8.87 mg, 0.089 mmol) were dissolved in methanol (2 mL), and triethylamine (6.04 mg, 0.060 mmol) was added. The reaction mixture was reacted at 25 °C for 10 min. Acetic acid (16.7 mg, 0.0890 mmol) was added to the reaction mixture, and the reaction mixture was reacted at 25 °C for 1 h. Sodium cyanoborohydride (7.50 mg, 0.119 mmol) was added to the reaction mixture, and the reaction mixture was reacted at 25 °C for 14 h. The reaction was confirmed by LC-MS. Water (10 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (10 mL × 3). The organic layers were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 5-(6-(3,3-dimethylpyrrolidone-1-yl)-1-fluoro-3-((2-methoxyethoxy)methoxy)-5,6,7,8-tetrahydronaphthyl-2-yl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide (18 l) (15.0 mg, crude product). This crude product can be used directly in the next step without purification.

[0562] LC-MS, M / Z (ESI): 486.2 [M+H] + .

[0563] Step 12: 5-(6-(3,3-dimethylpyrrolidone-1-yl)-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthyl-2-yl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide (18)

[0564] 5-(6-(3,3-dimethylpyrrolidin-1-yl)-1-fluoro-3-((2-methoxyethoxy)methoxy)-5,6,7,8-tetrahydronaphthyl-2-yl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide (18 l) (15 mg, 0.015 mmol, purity 60%) was dissolved in dioxane hydrochloride (3 mL, 4 mmol / L). The reaction solution was reacted at 25 °C for 5 hours. The reaction was confirmed by LC-MS. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was then purified by HPLC to obtain 5-(6-(3,3-dimethylpyrrolidin-1-yl)-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthyl-2-yl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide (18).

[0565] 1 H NMR (400MHz, CD3OD): δ6.54 (s, 1H), 4.23 (s, 2H), 3.82-3.74 (m, 1H), 3.57-3.42 (m, 4H), 3.13-3.08 (m, 1H), 3.00-2.84 (m, 2H) ), 2.72-2.62(m, 1H), 2.43-2.32(m, 1H), 2.03-1.95(m, 1H), 1.94-1.85(m, 1H), 1.83-1.70(m, 1H), 1.26(s, 3H), 1.22(s, 3H).

[0566] LC-MS, M / Z (ESI): 788.5 [M+H] + .

[0567] Example 19: Preparation of target compound 19

[0568] 5-{7-[(4,4-difluorocycloheptyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (19)

[0569] The synthetic route for target compound 19 is shown below:

[0570] Step 1: 5-{7-[(4,4-difluorocycloheptyl)amino]-1-fluoro-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 Synthesis of 2,5-thiadiazolidine-1,1,3-trione (19a)

[0571] At room temperature, 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-oxo-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (i-9) (200 mg, 0.5 mmol) was dissolved in anhydrous methanol (10 mL), followed by the addition of 4,4-difluorocycloheptanamine (89 mg, 0.6 mmol) and sodium cyanoborohydride (63 mg, 0.99 mmol). After the addition was complete, the mixture was purged with nitrogen three times and reacted at 25 °C for 12 hours. After the reaction was complete, the reaction solution was slowly added to water (20 mL), and then extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol (V / V) = 10:1-5:1) to obtain 5-{7-[(4,4-difluorocycloheptyl)amino]-1-fluoro-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (19a) (130 mg, yield 49%).

[0572] LC-MS, M / Z (ESI): 536.2 [M+H] +

[0573] Step 2: 5-{7-[(4,4-difluorocycloheptyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 Synthesis of 2,5-thiadiazolidine-1,1,3-trione (19)

[0574] At room temperature, 5-{7-[(4,4-difluorocycloheptyl)amino]-1-fluoro-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 62,5-Thiadiazolidine-1,1,3-trione (19a) (100 mg, 19 mmol) was dissolved in dioxane hydrochloride (4 M, 4 mL) and reacted at 25 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was then purified by HPLC to obtain 5-{7-[(4,4-difluorocycloheptyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (19).

[0575] 1 H NMR (600MHz, DMSO-d6) δ9.26 (s, 1H), 8.45 (s, 2H), 6.45 (s, 1H), 3.92 (s, 2H), 3.56 -3.49 (m, 2H), 3.08 (dt, J=16.0, 4.8Hz, 1H), 2.77 (dt, J=11.6, 4.8Hz, 2H), 2.45 (d , J=10.4Hz, 1H), 2.20 (dt, J=13.6, 6.8Hz, 1H), 2.12 (dq, J=15.6, 8.8Hz, 3H), 2.08 -1.93 (m, 3H), 1.74-1.69 (m, 1H), 1.69-1.61 (m, 2H), 1.53 (q, J=12.8, 12.4Hz, 2H).

[0576] LC-MS, M / Z (ESI): 448.1 [M+H] +

[0577] Example 20: Preparation of target compound 20

[0578] 5-{1-fluoro-3-hydroxy-7-[(oxepane-4-yl)amino]-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (20)

[0579] The synthetic route for target compound 20 is shown below:

[0580] Step 1: 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-[(oxepane-4-yl)amino]-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 Synthesis of 2,5-thiadiazolidine-1,1,3-trione (20a)

[0581] At room temperature, oxepane-4-amine hydrochloride (45.0 mg, 0.30 mmol) was dissolved in anhydrous methanol (1 mL), followed by the sequential addition of sodium acetate (51.0 mg, 0.62 mmol), 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-oxo-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ. 6 2,5-Thiadiazolidine-1,1,3-trione (i-9) (100 mg, 0.250 mmol) and sodium cyanoborohydride (31.0 mg, 0.500 mmol) were added. After the addition was complete, the mixture was purged with nitrogen three times and reacted at 25 °C for 12 hours. After the reaction was complete, saturated sodium chloride solution (5 mL) was slowly added to the reaction solution, and then extracted with a mixed solvent (ethyl acetate:acetonitrile (V / V) = 2:1, 3 × 10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH (V / V) = 10:1-5:1) to obtain 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-[(oxepane-4-yl)amino]-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (20a) (90.0 mg, yield 72%).

[0582] LC-MS, M / Z (ESI): 502.0 [M+H] +

[0583] Step 2: 5-{1-fluoro-3-hydroxy-7-[(oxepane-4-yl)amino]-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 Synthesis of 2,5-thiadiazolidine-1,1,3-trione (20)

[0584] At room temperature, 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-[(oxepane-4-yl)amino]-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (20a) (90.0 mg, 0.180 mmol) was dissolved in dioxane hydrochloride (4 M, 2 mL) and reacted at 25 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated to obtain a crude product, which was purified by HPLC to obtain 5-{1-fluoro-3-hydroxy-7-[(oxepane-4-yl)amino]-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (20).

[0585] 1H NMR (600MHz, DMSO-d6) δ9.26 (s, 1H), 8.47 (s, 2H), 6.45 (s, 1H), 3.92 (s, 2H) , 3.70 (dd, J=8.4, 4.4Hz, 1H), 3.67-3.64 (m, 1H), 3.55 (d, J=11.2Hz, 2H), 3. 48 (s, 1H), 3.08 (d, J = 9.2Hz, 1H), 2.77 (d, J = 11.6Hz, 2H), 2.50 (d, J = 7.2Hz, 1H), 2.46(s, 1H), 2.14(s, 2H), 2.06(s, 1H), 1.77(s, 1H), 1.71-1.64(m, 4H).

[0586] LC-MS, M / Z (ESI): 414.1 [M+H] +

[0587] Example 21: Preparation of target compound 21

[0588] {1-Fluoro-3-hydroxy-7-[(8-oxabicyclo[3.2.1]oct-3-yl)amino]-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (21)

[0589] The synthetic route for target compound 21 is shown below:

[0590] Step 1: 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-[(8-oxabicyclo[3.2.1]oct-3-yl)amino]-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 Synthesis of 2,5-thiadiazolidine-1,1,3-trione (21a)

[0591] At room temperature, 8-oxabicyclo[3.2.1]octyl-3-amine hydrochloride (45.0 mg, 0.270 mmol) was dissolved in anhydrous methanol (1 mL), followed by the addition of sodium acetate (45.0 mg, 0.550 mmol), 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-oxo-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 62,5-Thiadiazolidine-1,1,3-trione (i-9) (100 mg, 0.250 mmol) and sodium cyanoborohydride (31.0 mg, 0.500 mmol) were added. After the addition was complete, the mixture was purged with nitrogen three times and reacted at 25 °C for 12 hours. After the reaction was complete, saturated sodium chloride solution (5 mL) was slowly added to the reaction solution, and then extracted with a mixed solvent (ethyl acetate:acetonitrile (V / V) = 2:1, 3 × 10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH (V / V) = 10:1-5:1) to obtain 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-[(8-oxabicyclo[3.2.1]oct-3-yl)amino]-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (21a) (90.0 mg, 70% yield).

[0592] LC-MS, M / Z (ESI): 514.0 [M+H] +

[0593] Step 2: 5-{1-fluoro-3-hydroxy-7-[(8-oxabicyclo[3.2.1]oct-3-yl)amino]-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 Synthesis of 2,5-thiadiazolidine-1,1,3-trione (21)

[0594] At room temperature, 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-[(8-oxabicyclo[3.2.1]oct-3-yl)amino]-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (21a) (90.0 mg, 0.175 mmol) was dissolved in dioxane hydrochloride (4 M, 2 mL) and reacted at 25 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was then purified by HPLC to obtain 5-{1-fluoro-3-hydroxy-7-[(8-oxabicyclo[3.2.1]oct-3-yl)amino]-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (21).

[0595] 1H NMR (600MHz, DMSO-d6) δ9.39 (s, 1H), 8.43 (d, J=15.6Hz, 2H), 6.45 (s, 1H), 4.40 (s, 2H), 3.97 (s, 2H), 3.48 (s, 1H), 3.08-3.05 (m, 1H), 3.00-2 ...

[0596] LC-MS, M / Z (ESI): 426.3 [M+H] +

[0597] Example 22: Preparation of target compound 22

[0598] 5-{1-fluoro-3-hydroxy-7-[(4,5,6,7-tetrahydro-1,2-benzoxazol-5-yl)amino]-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ6,2,5-thiadiazolidine-1,1,3-trione (22)

[0599] The synthetic route for target compound 22 is as follows:

[0600] Step 1: 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-[(4,5,6,7-tetrahydro-1,2-benzoxazol-5-yl)amino]-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 Synthesis of 2,5-thiadiazolidine-1,1,3-trione (22a)

[0601] At room temperature, 4,5,6,7-tetrahydrobenzo[D]isoxazole-5-amine hydrochloride (43.0 mg, 0.250 mmol) was dissolved in anhydrous methanol (2 mL), followed by the addition of sodium acetate (41.0 mg, 0.490 mmol), 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-oxo-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 62,5-Thiadiazolidine-1,1,3-trione (i-9) (100 mg, 0.250 mmol) and sodium cyanoborohydride (31.0 mg, 0.490 mmol) were added. After the addition was complete, the mixture was purged with nitrogen three times and reacted at 25 °C for 12 hours. After the reaction was complete, saturated sodium chloride solution (5 mL) was slowly added to the reaction solution, and then extracted with a mixed solvent (ethyl acetate: acetonitrile = 2:1, 3 × 10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM: MeOH = 10:1 to 5:1) to obtain 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-[(4,5,6,7-tetrahydro-1,2-benzoxazol-5-yl)amino]-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (22a) (50.0 mg, yield 38%).

[0602] LC / MS (ESI) (m / z): 525.0 [M+H] + .

[0603] Step 2: 5-{1-fluoro-3-hydroxy-7-[(4,5,6,7-tetrahydro-1,2-benzoxazol-5-yl)amino]-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 Synthesis of 2,5-thiadiazolidine-1,1,3-trione (22)

[0604] At room temperature, 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-[(4,5,6,7-tetrahydro-1,2-benzoxazol-5-yl)amino]-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (22a) (50.0 mg, 0.095 mmol) was dissolved in dioxane hydrochloride (4 M, 2 mL) and reacted at 25 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by HPLC to obtain 5-{1-fluoro-3-hydroxy-7-[(4,5,6,7-tetrahydro-1,2-benzoxazol-5-yl)amino]-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (22).

[0605] 1H NMR (600MHz, DMSO-d6) δ9.21 (s, 1H), 8.66 (s, 2H), 8.41 (d, J=12.4Hz, 1H), 6.5 2 (s, 1H), 3.953.86 (m, 2H), 3.66 (s, 1H), 3.54 (s, 1H), 3.10 (d, J=8.4Hz, 1H), 2 .94 (d, J=12.0Hz, 1H), 2.84 (dd, J=30.4, 10.8Hz, 2H), 2.75 (dd, J=23.6, 11.2H z, 2H), 2.47-2.43 (m, 2H), 2.25 (s, 1H), 2.14 (s, 1H), 1.88 (s, 1H), 1.64 (s, 1H).

[0606] LC / MS (ESI) (m / z): 437.0 [M+H] +

[0607] Example 23: Preparation of target compound 23

[0608] {1-Fluoro-3-hydroxy-7-[(2-oxaspiro[3.3]hept-6-yl)amino]-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (23)

[0609] The synthetic route for target compound 23 is as follows:

[0610] Step 1: 5-(1-Fluoro-3-hydroxy-7-oxo-5,6,7,8-tetrahydronaphth-2-yl)-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (23a)

[0611] At room temperature, 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-oxo-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (i-9) (100 mg, 0.248 mmol) was dissolved in dioxane hydrochloride (2 mL). The reaction was then carried out at 25 °C for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure, slurried with dichloromethane, and filtered to obtain 5-(1-fluoro-3-hydroxy-7-oxo-5,6,7,8-tetrahydronaphthyl-2-yl)-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (23a) (50.0 mg, yield 64%).

[0612] Step 2: 5-{1-fluoro-3-hydroxy-7-[(2-oxaspiro[3.3]hept-6-yl)amino]-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 2,5-Thiadiazolidine-1,1,3-trione

[0613] At room temperature, 2-oxaspiro[3.3]heptane-6-amine hydrochloride (20.0 mg, 0.133 mmol) was dissolved in anhydrous methanol (1 mL), followed by the slow addition of sodium acetate (21.8 mg, 0.266 mmol) and 5-(1-fluoro-3-hydroxy-7-oxo-5,6,7,8-tetrahydronaphthyl-2-yl)-1λ. 6 2,5-Thiadiazolidine-1,1,3-trione (23a) (41.7 mg, 0.133 mmol) and sodium cyanoborohydride (16.7 mg, 0.266 mmol). The reaction was then carried out at 25 °C for 12 hours. After the reaction was complete, a small amount of water was added to quench the reaction, followed by filtration. The filtrate was concentrated to obtain a crude product, which was then purified by HPLC to obtain 5-{1-fluoro-3-hydroxy-7-[(2-oxaspiro[3.3]hept-6-yl)amino]-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (23).

[0614] 1 H NMR (600MHz, DMSO-d6) δ9.27 (s, 1H), 8.70 (s, 2H), 6.43 (s, 1H), 4.59 (s, 2H), 4.50-4.47 (m, 2H), 3.91 (s, 2H), 3.79-3.75 (m, 1H), 2.99-2.96 (m, 1H ), 2.77-2.70(m, 2H), 2.61-2.57(m, 2H), 2.49(s, 1H), 2.46-2.41(m, 1H) , 2.29 (dd, J=12.8, 6.8Hz, 2H), 2.03 (d, J=10.4Hz, 1H), 1.64-1.60 (m, 1H)

[0615] LC / MS (ESI) (m / z): 412.0 [M+H] +

[0616] Example 24: Preparation of target compound 24

[0617] [7-(cycloheptaylamino)-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphth-2-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (24)

[0618] The synthetic route for target compound 24 is as follows:

[0619] Step 1: 5-{7-(cycloheptaylamino)-1-fluoro-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 Synthesis of 2,5-thiadiazolidine-1,1,3-trione (24a)

[0620] At room temperature, 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-oxo-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (i-9) (100 mg, 0.250 mmol) was dissolved in anhydrous methanol (1 mL), followed by the addition of catalytic amounts of acetic acid, cycloheptanamine (42.0 mg, 0.370 mmol), and sodium cyanoborohydride (31.0 mg, 0.500 mmol). After the addition was complete, the mixture was purged with nitrogen three times and reacted at 25 °C for 12 hours. After the reaction was complete, a saturated sodium chloride solution (5 mL) was slowly added to the reaction solution, followed by extraction with a mixed solvent (ethyl acetate:acetonitrile = 2:1, 3 × 10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel (DCM:MeOH (V / V) = 10:1-5:1) to obtain 5-{7-(cycloheptylamino)-1-fluoro-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (24a) (90.0 mg, yield 72%).

[0621] LC / MS (ESI) (m / z): 500.0 [M+H] +

[0622] Step 2: 5-[7-(cycloheptaylamino)-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthyl-2-yl]-1λ 6 Synthesis of 2,5-thiadiazolidine-1,1,3-trione (24)

[0623] At room temperature, 5-{7-(cycloheptaylamino)-1-fluoro-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphth-2-yl}-1λ 62,5-Thiadiazolidine-1,1,3-trione (24a) (60.0 mg, 0.120 mmol) was dissolved in dioxane hydrochloride (4 M, 2 mL) and reacted at 25 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated and purified by HPLC to obtain 5-[7-(cycloheptylamino)-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthyl-2-yl]-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (24).

[0624] 1 H NMR (600MHz, DMSO-d6) δ9.28 (s, 1H), 8.33 (s, 2H), 6.44 (s, 1H), 3.91 (s, 2H), 3.51 (s, 1H), 3.39 (s, 1H), 3.07 (dd, J=15.6, 5.2Hz, 1H ), 2.79-2.73 (m, 2H), 2.46 (d, J=10.8Hz, 1H), 2.13 (d, J=10.8Hz, 1H), 2.03 (d, J=7.2Hz, 2H), 1.70-1.62 (m, 3H), 1.57-1.42 (m, 8H).

[0625] LC / MS (ESI) (m / z): 412.3 [M+H] +

[0626] Example 25: Preparation of target compound 25

[0627] 5-{7-[(3,3-difluorocycloheptyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (25)

[0628] The synthetic route for target compound 25 is as follows:

[0629] Step 1: 5-{7-[(3,3-difluorocycloheptyl)amino]-1-fluoro-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 Synthesis of 2,5-thiadiazolidine-1,1,3-trione (25a)

[0630] At room temperature, 3,3-difluorocyclohepta-1-amine (40.2 mg, 0.27 mmol) was dissolved in anhydrous methanol (1 mL), and then 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-oxo-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ was added sequentially.6 2,5-Thiadiazolidine-1,1,3-trione (i-9) (100 mg, 0.250 mmol) and sodium cyanoborohydride (31.0 mg, 0.50 mmol) were added. After the addition was complete, the mixture was purged with nitrogen three times and reacted at 25 °C for 12 hours. After the reaction was complete, saturated sodium chloride solution (5 mL) was slowly added to the reaction solution, and then extracted with a mixed solvent (ethyl acetate: acetonitrile = 2:1, 3 × 10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM: MeOH = 10:1 to 5:1) to obtain 5-{7-[(3,3-difluorocycloheptyl)amino]-1-fluoro-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (25a) (100 mg, 75% yield).

[0631] LC / MS (ESI) (m / z): 536.0 [M+H] + .

[0632] Step 2: Synthesis of 5-{7-[(3,3-difluorocycloheptyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ6,2,5-thiadiazolidine-1,1,3-trione (25)

[0633] At room temperature, 5-{7-[(3,3-difluorocycloheptyl)amino]-1-fluoro-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (25a) (100 mg, 0.186 mmol) was dissolved in dioxane hydrochloride (4 M, 2 mL) and reacted at 25 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated and purified by HPLC to obtain 5-{7-[(3,3-difluorocycloheptyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (25).

[0634] 1H NMR (600MHz, DMSO-d6) δ9.25 (s, 1H), 8.64 (s, 2H), 6.45 (s, 1H), 3.92 (s, 2H), 3.60-3.53 (m, 2H), 3.12-3.05 (m, 1H), 2.79 (d, J=3.6Hz, 2H), 2.62 -2.56 (m, 1H), 2.51 (s, 1H), 2.32-2.25 (m, 1H), 2.12 (dd, J=16.8, 11.2Hz, 4H), 1.77 (d, J=7.2Hz, 1H), 1.66-1.57 (m, 4H), 1.51 (d, J=9.6Hz, 1H).

[0635] LC / MS (ESI) (m / z): 448.0 [M+H] +

[0636] Example 26: Preparation of target compound 26

[0637] 5-{1-fluoro-3-hydroxy-7-[(3-hydroxy-3-methylcycloheptyl)amino]-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (26)

[0638] The synthetic route for target compound 26 is as follows:

[0639] Step 1: Synthesis of benzyl (3-oxocycloheptyl)carbamate (26b)

[0640] 2-Cyclohepten-1-one (26a) (5.00 g, 7.65 mmol) was dissolved in dichloromethane (50 mL), and bis(acetonitrile)palladium(II) chloride (1.18 g, 4.54 mmol) and benzyl carbamate (9.61 g, 63.5 mmol) were added. The reaction mixture was reacted at 25 °C for 14 hours. The reaction mixture was added to water (100 mL), extracted with ethyl acetate (100 mL × 3), the organic layers were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, 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) = 100:0-65:35, gradient elution) to give benzyl (3-oxocycloheptenyl)carbamate (26b) (14.3 g, 90% yield, 70% purity).

[0641] Step 2: Synthesis of (3-hydroxy-3-methylcycloheptyl)carbamate (26c)

[0642] (3-O-cycloheptyl)carbamate (26b) (2.00 g, 7.65 mmol) was dissolved in tetrahydrofuran (100 mL), cooled to -78 °C, and a methyllithium-lithium bromide complex (19.1 mL, 19.1 mmol, 1 M diethyl ether solution) was added. The reaction mixture was reacted at -78 °C for 1.5 h. The reaction mixture was added to water (100 mL), extracted with ethyl acetate (100 mL × 3), the organic layers were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, 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) = 100:0-55:45, gradient elution) to give (3-hydroxy-3-methylcycloheptyl)carbamate (26c) (1.80 g, 85% yield).

[0643] 1 H NMR (400MHz, DMSO-d6) δ7.42-7.26 (m, 5H), 7.20-7.09 (m, 1H), 5.09-4.93 (m, 2H), 4.21 (d, J=30.6Hz, 1H), 3.76-3.28 (m, 1H), 1.87-1.21 (m, 10H), 1.18-1.06 (m, 3H).

[0644] LC-MS, M / Z (ESI): 260.4 [M+H] + .

[0645] Step 3: Synthesis of 3-amino-1-methylcyclohepta-1-ol (26d)

[0646] At room temperature, benzyl (3-hydroxy-3-methylcycloheptayl)carbamate (26c) (300 mg, 1.08 mmol) was dissolved in anhydrous methanol (3 mL), and then wet palladium on carbon (10%, 30.0 mg) was added. After the addition was complete, the mixture was purged three times with hydrogen and reacted at 25 °C for 12 hours. After the reaction was complete, the reaction solution was filtered and concentrated under reduced pressure to give 3-amino-1-methylcycloheptayl-1-ol (26d) (150 mg, 96% yield).

[0647] LC / MS (ESI) (m / z): 144.0 [M+H] + .

[0648] Step 4: 5-{1-fluoro-7-[(3-hydroxy-3-methylcycloheptyl)amino]-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 Synthesis of 2,5-thiadiazolidine-1,1,3-trione (26e)

[0649] At room temperature, 3-amino-1-methylcyclohepta-1-ol (26d) (71.5 mg, 0.500 mmol) was dissolved in anhydrous methanol (2 mL), and then 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-oxo-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ was added sequentially. 6 2,5-Thiadiazolidine-1,1,3-trione (i-9) (200 mg, 0.500 mmol) and sodium cyanoborohydride (62.0 mg, 1.00 mmol) were added. After the addition was complete, the mixture was purged with nitrogen three times and reacted at 25 °C for 12 hours. After the reaction was complete, saturated sodium chloride solution (5 mL) was slowly added to the reaction solution, and then extracted with a mixed solvent (ethyl acetate: acetonitrile = 2:1, 3 × 10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM: MeOH = 10:1-5:1) to obtain 5-{1-fluoro-7-[(3-hydroxy-3-methylcycloheptyl)amino]-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (26e) (200 mg, 75% yield).

[0650] LC / MS (ESI) (m / z): 530.0 [M+H] + .

[0651] Step 5: Synthesis of 5-{1-fluoro-3-hydroxy-7-[(3-hydroxy-3-methylcycloheptyl)amino]-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ6,2,5-thiadiazolidine-1,1,3-trione (26)

[0652] At room temperature, 5-{1-fluoro-7-[(3-hydroxy-3-methylcycloheptyl)amino]-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (26e) (200 mg, 0.378 mmol) was dissolved in dioxane hydrochloride (4 M, 2 mL) and reacted at 25 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure and purified by HPLC to obtain 5-{1-fluoro-3-hydroxy-7-[(3-hydroxy-3-methylcycloheptyl)amino]-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (26).

[0653] 1H NMR (600MHz, DMSO-d6) δ9.24 (s, 1H), 8.34 (s, 2H), 6.45 (s, 1H), 4.56 (d, J=23.6Hz, 1H), 3.92 (s, 2H), 3.54 (s, 2H), 3.07 (d, J=10.8Hz, 1H), 3.00-2.92 (m, 1H), 2.80-2.74 (m, 2H), 2.15 (s, 1H), 2.0 7(d, J=12.0Hz, 1H), 1.92 (d, J=9.2Hz, 1H), 1.84 (d, J=14.4Hz, 1H), 1.75-1.71 (m, 1H), 1.68-1.6 3 (m, 2H), 1.56 (s, 2H), 1.46 (d, J = 10.4Hz, 1H), 1.40 (s, 1H), 1.28 (s, 1H), 1.17 (d, J = 18.0Hz, 3H).

[0654] LC / MS (ESI) (m / z): 442.0 [M+H] +

[0655] Example 27: Preparation of target compound 27

[0656] 5-{7-[(7,7-difluorobicyclo[4.1.0]hept-3-yl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (27)

[0657] The synthetic route for target compound 27 is as follows:

[0658] Step 1: 5-{7-[(7,7-difluorobicyclo[4.1.0]hept-3-yl)amino]-1-fluoro-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 Synthesis of 2,5-thiadiazolidine-1,1,3-trione (27a)

[0659] At room temperature, 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-oxo-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 62,5-Thiadiazolidine-1,1,3-trione (i-9) (200 mg, 0.5 mmol) was dissolved in anhydrous methanol (10 mL), followed by the addition of 7,7-difluoronorcarbazide-3-amine hydrochloride (130 mg, 0.99 mmol), sodium acetate (82 mg, 0.99 mmol), and sodium cyanoborohydride (63 mg, 0.99 mmol). After the addition was complete, the mixture was purged with nitrogen three times and reacted at 25 °C for 12 hours. After the reaction was complete, the reaction solution was slowly added to water (20 mL), and then extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH = 10:1-5:1) to obtain 5-{7-[(7,7-difluorobicyclo[4.1.0]hept-3-yl)amino]-1-fluoro-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (27a) (100 mg, yield 38%).

[0660] LC / MS (ESI) (m / z): 534.2 [M+H] + .

[0661] Step 2: 5-{7-[(7,7-difluorobicyclo[4.1.0]hept-3-yl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 Synthesis of 2,5-thiadiazolidine-1,1,3-trione (27)

[0662] At room temperature, 5-{7-[(7,7-difluorobicyclo[4.1.0]hept-3-yl)amino]-1-fluoro-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (27a) (100 mg, 19 mmol) was dissolved in dioxane hydrochloride (4 M, 4 mL) and reacted at 25 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure and purified by HPLC to obtain 5-{7-[(7,7-difluorobicyclo[4.1.0]hept-3-yl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (27).

[0663] 1H NMR (400MHz, DMSO-d6) δ9.26 (s, 1H), 8.57 (s, 1H), 6.49 (s, 1H), 3.94 (s, 2H), 3.62-3.64 (m, 1H), 3.09-3.1 3(m, 1H), 2.80-2.81(m, 2H), 1.95-2.14(m, 3H), 1.77-1.88(m, 7H), 1.24-1.26(m, 1H), 1.20-1.23(m, 1H).

[0664] LC / MS (ESI) (m / z): 446.1 [M+H] + .

[0665] Example 28: Preparation of target compound 28

[0666] 5-(7-{[4-(difluoromethylene)cyclohexyl]amino}-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphth-2-yl)-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (28)

[0667] The synthetic route for target compound 28 is as follows:

[0668] Step 1: Synthesis of benzyl (4-(difluoromethylene)cyclohexyl)carbamate (28b)

[0669] At -40°C, potassium tert-butoxide (4.08 g, 36.3 mmol) was added to a solution of 4-N-benzyloxycarbonylaminocyclohexanone (28a) (7.30 g, 27.9 mmol) and difluoromethyl (2-pyridyl) sulfone (5.40 g, 27.9 mmol) in N,N-dimethylformamide (50 mL). The resulting mixture was stirred at 25°C for 18 hours. The reaction was detected by LCMS. The reaction solution was diluted with water (200 mL) and ethyl acetate (50 mL). × 3) Extraction, combined organic phases, and concentrated under reduced pressure to obtain crude product. The crude product was purified by HPLC to obtain benzyl (4-(difluoromethylene)cyclohexyl)carbamate (28b) (1.00 g, yield 12%).

[0670] 1 H NMR (400MHz, CDCl3): δ7.44-7.27(m, 5H), 5.09(s, 2H), 4.68(s, 1H), 3.75-3.46(m, 1H), 2.52-2.31(m, 2H), 2.13-1.77(m, 4H), 1.33-1.08(m, 2H).

[0671] LC-MS, M / Z (ESI): 282.2 [M+H] +

[0672] Step 2: Synthesis of 3-(propyl-2-ylidene)cycloheptylamino (28c)

[0673] Benzyl (4-(difluoromethylene)cyclohexyl)carbamate (28b) (0.2 g, 0.70 mmol) was dissolved in trifluoroacetic acid (2 mL) and stirred at 70 °C for 3 hours. The reaction was confirmed by LCMS. The reaction solution was concentrated under reduced pressure to obtain crude 4-(difluoromethylene)cyclohexane-1-amine (28c) (0.16 g, crude product), which was then directly proceeded to the next step without purification.

[0674] LC-MS, M / Z (ESI): 148.1 [M+H] +

[0675] Step 3: 5-(7-{[4-(difluoromethylene)cyclohexyl]amino}-1-fluoro-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphth-2-yl)-1λ 6 Synthesis of 2,5-thiadiazole-1,1,3-trione (28d)

[0676] At room temperature, 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-oxo-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (i-9) (100 mg, 0.250 mmol) was dissolved in anhydrous methanol (1 mL), followed by the addition of catalytic amounts of acetic acid, 4-(difluoromethylene)cyclohexane-1-amine (28c) (55.2 mg, 0.370 mmol), and sodium cyanoborohydride (31.0 mg, 0.500 mmol). After the addition was complete, the mixture was purged with nitrogen three times and reacted at 25 °C for 12 hours. After the reaction was complete, a saturated sodium chloride solution (5 mL) was slowly added to the reaction solution, followed by extraction with a mixed solvent (ethyl acetate:acetonitrile = 2:1, 3 × 10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH (V / V) = 10:1-5:1) to obtain 5-(7-{[4-(difluoromethylene)cyclohexyl]amino}-1-fluoro-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphth-2-yl)-1λ 6 2,5-Thiadiazole-1,1,3-trione (28d) (61mg, yield 46%).

[0677] LC / MS (ESI) (m / z): 534.1 [M+H] +

[0678] Step 4: 5-(7-{[4-(difluoromethylene)cyclohexyl]amino}-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphth-2-yl)-1λ 6 Synthesis of 2,5-thiadiazolidine-1,1,3-trione (28)

[0679] At room temperature, 5-(7-{[4-(difluoromethylene)cyclohexyl]amino}-1-fluoro-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphthyl-2-yl)-1λ 6 2,5-Thiadiazole-1,1,3-trione (28d) (43.0 mg, 0.11 mmol) was dissolved in dioxane hydrochloride (4 M, 2 mL) and reacted at 25 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure and purified by HPLC to obtain 5-(7-{[4-(difluoromethylene)cyclohexyl]amino}-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthyl-2-yl)-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (28).

[0680] 1 H NMR (600MHz, DMSO-d6) δ9.59 (s, 1H), 8.63 (d, J = 19.9Hz, 2H), 6.49 (s, 1H), 4.07 (s, 2H), 3.50-3.30 (m, 2H), 3.13 (dd, J = 15.7, 4.9Hz, 1H), 2.80 (d, J=11.1Hz, 2H), 2.54-2.37 (m, 3H), 2.18 (t, J=12.1Hz, 3H), 1.99 (td, J=13.8, 4.3Hz, 2H), 1.69 (dt, J=11.4, 4.9Hz, 1H), 1.46-1.20 (m, 2H).

[0681] LC / MS (ESI) (m / z): 446.1 [M+H] +

[0682] Example 29: Preparation of target compound 29

[0683] 5-(7-((6,7-dihydro-5H-cyclopentadiazol-6-yl)amino)-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphth-2-yl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (29)

[0684] The synthetic route for target compound 29 is shown below:

[0685] Step 1: Synthesis of 6-azido-6,7-dihydro-5H-cyclopentan[b]pyridine (29b)

[0686] 6,7-Dihydro-5H-cyclopenta[b]pyridine-6-ol (29a) (200 mg, 1.48 mmol) and triphenylphosphine (504 mg, 1.92 mmol) were dissolved in tetrahydrofuran (3 mL), and then di-tert-butyl azodicarbonate (511 mg, 2.22 mmol) was added dropwise at 0 °C under nitrogen protection. The reaction was stirred at 0 °C for 0.25 h. Then, diphenyl azidophosphate (488 mg, 1.78 mmol) was added to the reaction mixture, and the reaction was carried out at 25 °C for 3 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain 6-azido-6,7-dihydro-5H-cyclopenta[b]pyridine (29b) (237 mg, crude product).

[0687] LC-MS, M / Z (ESI): 161.0 [M+H] +

[0688] Step 2: Synthesis of 6,7-dihydro-5H-cyclopentan[b]pyridine-6-amine (29c)

[0689] 6-Azide-6,7-dihydro-5H-cyclopentyl[b]pyridine (29b) (237 mg, 1.48 mmol) was dissolved in tetrahydrofuran (6 mL) and water (133 mg, 7.40 mmol), and then a mixture of triphenylphosphine (970 mg, 3.70 mmol) and tetrahydrofuran (2.5 mL) was added. The reaction was stirred at 50 °C for 12 hours. After the reaction was complete, the reaction solution was poured into 2 M hydrochloric acid (2 mL), and then back-extracted with ethyl acetate (3 mL * 3). The aqueous phase was purified by HPLC to obtain 6,7-dihydro-5H-cyclopentyl[b]pyridine-6-amine (29c) (110 mg, 55% yield).

[0690] LC-MS, M / Z (ESI): 135.1 [M+H] +

[0691] Step 3: Synthesis of 5-(3-benzyloxy)-7-((6,7-dihydro-5H-cyclopenta[b]pyridin-6-yl)amino)-1-fluoro-5,6,7,8-tetrahydronaphthyl-2-yl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (29d)

[0692] 6,7-Dihydro-5H-cyclopentan[b]pyridine-6-amine (29c) (59.7 mg, 445 μmol) was dissolved in N,N-dimethylformamide (2 mL), and then sodium acetate (109 mg, 1.34 mmol) was added. The reaction was stirred at 25 °C for 30 minutes, then 5-(7-benzyloxy-5-fluoro-3-oxo-tetrahydronaphthyl-6-yl)-1,1-dioxo-1,2,5-thiadiazolidine-3-one (180 mg, 445 μmol) was added, and the reaction was stirred at 25 °C for 1 hour. Finally, sodium triacetoxyborohydride (188 mg, 890 μmol) was added, and the reaction was stirred at 25 °C for 1 hour. After the reaction was completed, the reaction solution was purified by HPLC to obtain compound 5-(3-benzyloxy)-7-((6,7-dihydro-5H-cyclopenta[b]pyridin-6-yl)amino)-1-fluoro-5,6,7,8-tetrahydronaphth-2-yl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (29d) (40.0 mg, 17% yield).

[0693] LC-MS, M / Z (ESI): 523.2 [M+H] +

[0694] Step 4: 5-(7-((6,7-dihydro-5H-cyclopentan[b]pyridin-6-yl)amino)-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphth-2-yl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (29)

[0695] 5-(3-benzyloxy)-7-((6,7-dihydro-5H-cyclopentan[b]pyridin-6-yl)amino)-1-fluoro-5,6,7,8-tetrahydronaphthyl-2-yl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (29d) (30.0 mg, 57.4 μmol) was dissolved in dichloromethane (20 mL), and then boron tribromide (2.0 M, 71.9 mg) was added dropwise at -60 °C under nitrogen protection. The reaction was stirred at 25 °C for 1 hour. After the reaction was complete, the reaction solution was quenched with methanol (5 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 to obtain compound 5-(7-((6,7-dihydro-5H-cyclopenta[b]pyridin-6-yl)amino)-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphth-2-yl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (29).

[0696] 1H NMR (400MHz, DMSO-d6) δ9.29 (s, 1H), 8.35-8.37 (m, 1H), 7.67-7.69 (m, 1H), 7.19-7.22 (m, 1H), 6.47 (s, 1H), 4.29-4.3 2(m, 1H), 3.94(s, 2H), 3.52-3.54(m, 1H), 3.09-3.13(m, 4H), 2.80-2.81(m, 3H), 2.17-2.19(m, 2H), 1.67-1.72(m, 2H).

[0697] LC-MS, M / Z (ESI): 433.1 [M+H] +

[0698] Example 30: Preparation of target compound 30

[0699] 5-(1-fluoro-3-hydroxy-7-(3-(prop-2-methylene)pyrrolidine-1-yl)-5,6,7,8-tetrahydronaphthyl-2-yl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (30)

[0700] The synthetic route for target compound 30 is shown below:

[0701] Step 1: Synthesis of 5-(3-benzyloxy)-1-fluoro-7-oxo-5,6,7,8-tetrahydronaphthyl-2-yl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (30a)

[0702] 5-(6-benzyloxy)-8-fluoro-3,4-dihydro-1H-spiro[naphthyl-2,2'-[1,3]dioxane]-7-yl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (960 mg, 2.14 mmol) (synthetic reference WO2022056281 A1) was dissolved in formic acid (6 mL) and water (1.5 mL) at 0 °C, and then stirred at 25 °C for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to give compound 5-(3-benzyloxy)-1-fluoro-7-oxo-5,6,7,8-tetrahydronaphthyl-2-yl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (30a) (900 mg, crude product).

[0703] Step 2: Synthesis of 5-(3-benzyloxy)-1-fluoro-7-(3-prop-2-methylenepyrrolidine-1-yl)-5,6,7,8-tetrahydronaphthyl-2-yl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (30b)

[0704] 3-(propane-2-yl)pyrrolidine (110 mg, 989 μmol) and sodium acetate (203 mg, 2.47 mmol) were dissolved in dichloromethane (2 mL) and anhydrous methanol (0.2 mL) and stirred at 25 °C for 0.5 h. Then, 5-(3-benzyloxy)-1-fluoro-7-oxo-5,6,7,8-tetrahydronaphthyl-2-yl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (30a) 100 mg, 247 μmol) was added to the reaction solution and stirred at 25 °C for 0.5 h. Then, sodium cyanoborohydride (31.1 mg, 494 μmol) was added to the reaction solution and stirred at 25 °C for 2 h. After the reaction was completed, water (1 mL) was added to quench the reaction, and the solution was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by HPLC to obtain compound 5-(3-benzyloxy)-1-fluoro-7-(3-prop-2-methylenepyrrolidone-1-yl)-5,6,7,8-tetrahydronaphthyl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (30b) (70.0 mg, 19% yield).

[0705] Step 3: 5-(1-fluoro-3-hydroxy-7-(3-(prop-2-methylene)pyrrolidine-1-yl)-5,6,7,8-tetrahydronaphthyl-2-yl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (30)

[0706] 5-(3-benzyloxy)-1-fluoro-7-(3-prop-2-methylenepyrrolidine-1-yl)-5,6,7,8-tetrahydronaphthyl-2-yl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (30b) (55.0 mg, 110 μmol) was dissolved in dichloromethane (6 mL), and boron tribromide (552 mg, 2.20 mmol) was added under a nitrogen atmosphere at -68 °C. The reaction was stirred at -68 °C for 1 hour. After the reaction was complete, the reaction solution was quenched at -68℃ with methanol (10 mL), and the pH was adjusted to weakly alkaline by adding ammonia (257 mg, 2.20 mmol). The solution was dried and concentrated to obtain the crude product, which was then purified by HPLC to obtain 5-(1-fluoro-3-hydroxy-7-(3-(prop-2-methylene)pyrrolidine-1-yl)-5,6,7,8-tetrahydronaphthyl-2-yl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (30).

[0707] 1H NMR (DMSO-d6) δ9.60-10.2 (m, 1H), 9.28 (s, 1H), 6.47 (s, 1H), 4.21-4.41 (m, 1H), 3.93 (s, 2H), 3.72 -3.91(m, 2H), 3.52-3.63(m, 2H), 3.11-3.22(m, 2H), 2.63-2.81(m, 4H), 2.22-2.42(m, 2H), 1.67(br d, 6H, J=6H) LC-MS, M / Z (ESI): 410.1 [M+H] +

[0708] Example 31: Preparation of target compound 31

[0709] 5-[7-(6-azaspiro[3.4]octane-6-yl)-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthyl-2-yl]-1λ6,2,5-thiodiazine-1,1,3-trione (31)

[0710] The synthetic route for target compound 31 is as follows:

[0711] Step 1: 5-{7-[6-azaspiro[3,4]octane-6-yl]-1-fluoro-3-[[(2-methoxyethoxy)methoxy]methyl]-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 Synthesis of 2,5-thiodiazine-1,1,3-trione (31a)

[0712] At room temperature, 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-oxo-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 62,5-Thiadiazolidine-1,1,3-trione (i-9) (100 mg, 0.250 mmol) was dissolved in anhydrous methanol (1 mL), and then catalytic amounts of acetic acid, 6-azaspiro[3,4]octane (41.4 mg, 0.370 mmol), and sodium cyanoborohydride (31.0 mg, 0.500 mmol) were added. After the addition was complete, the mixture was purged with nitrogen three times and reacted at 25 °C for 12 hours. After the reaction was complete, saturated sodium chloride solution (5 mL) was slowly added to the reaction solution, and then the mixture was extracted with a mixed solvent (ethyl acetate:acetonitrile = 2:1, 3 × 10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (DCM:MeOH (V / V) = 10:1-5:1) to obtain 5-{7-[6-azaspiro[3,4]octane-6-yl]-1-fluoro-3-[[(2-methoxyethoxy)methoxy]methyl]-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 2,5-Thiodiazine-1,1,3-trione (31a) (68 mg, yield 55%).

[0713] LC / MS (ESI) (m / z): 498.0 [M+H] +

[0714] Step 2: 5-[7-(6-azaspiro[3.4]octane-6-yl)-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphth-2-yl]-1λ 6 Synthesis of 2,5-thiodiazine-1,1,3-trione (31)

[0715] At room temperature, 5-{7-[6-azaspiro[3,4]octane-6-yl]-1-fluoro-3-[[(2-methoxyethoxy)methoxy]methyl]-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 2,5-Thiodiazine-1,1,3-trione (31a) (68.0 mg, 0.14 mmol) was dissolved in dioxane hydrochloride (4 M, 2 mL) and reacted at 25 °C for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by HPLC to obtain 5-[7-(6-azaspiro[3.4]octane-6-yl)-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthyl-2-yl]-1λ 6 2,5-Thiodiazine-1,1,3-trione (31) (11 mg, yield 20%).

[0716] 1H NMR (600MHz, CD3OD) δ8.52 (s, 1H), 6.53 (d, J = 4.7Hz, 1H), 3.81 (t, J = 6.5Hz, 1H), 3.52 (t, J = 6.4Hz, 1H), 3.39 (dd, J = 8.0, 5.7 Hz, 3H), 3.28-3.14(m, 1H), 3.03-2.78(m, 3H), 2.67-2.57(m, 1H), 2.35-2.25(m, 4H), 2.26-2.13(m, 2H), 2.11-1.72(m, 3H).

[0717] LC / MS (ESI) (m / z): 410.1 [M+H] +

[0718] Example 32: Preparation of target compound 32

[0719] 5-{7-[(1-cyclopropyl-1H-pyrazol-4-yl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 ,2,5-Thiadiazole-1,1,3-trione (32)

[0720] The synthetic route for target compound 32 is as follows:

[0721] Step 1: 5-{7-[(1-cyclopropyl-1H-pyrazol-4-yl)amino]-1-fluoro-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 Synthesis of 2,5-thiadiazole-1,1,3-trione (32a)

[0722] At room temperature, 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-oxo-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 62,5-Thiadiazolidine-1,1,3-trione (i-9) (100 mg, 0.250 mmol) was dissolved in anhydrous methanol (1 mL), followed by the addition of catalytic amounts of acetic acid, 1-cyclopropyl-1H-pyrazole-4-amine (45.8 mg, 0.370 mmol), and sodium cyanoborohydride (31.0 mg, 0.500 mmol). After the addition was complete, the mixture was purged with nitrogen three times and reacted at 25 °C for 12 hours. After the reaction was complete, a saturated sodium chloride solution (5 mL) was slowly added to the reaction solution, followed by extraction with a mixed solvent (ethyl acetate:acetonitrile = 2:1, 3 × 10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (DCM:MeOH (V / V) = 10:1-5:1) to obtain 5-{7-[(1-cyclopropyl-1H-pyrazol-4-yl)amino]-1-fluoro-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 2,5-Thiadiazole-1,1,3-trione (32a) (63 mg, 50% yield).

[0723] LC / MS (ESI) (m / z): 510.1 [M+H] +

[0724] Step 2: 5-{7-[(1-cyclopropyl-1H-pyrazole-4-yl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 Synthesis of 2,5-thiadiazole-1,1,3-trione (32)

[0725] At room temperature, 5-{7-[(1-cyclopropyl-1H-pyrazol-4-yl)amino]-1-fluoro-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 2,5-Thiadiazole-1,1,3-trione (32a) (63.0 mg, 0.12 mmol) was dissolved in dioxane hydrochloride (4 M, 2 mL) and reacted at 25 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure and purified by HPLC to obtain 5-{7-[(1-cyclopropyl-1H-pyrazol-4-yl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 ,2,5-thiadiazole-1,1,3-trione (32).

[0726] 1H NMR (600MHz, CD3OD) δ7.30 (s, 1H), 7.18 (s, 1H), 6.50 (s, 1H), 4.24 (s, 2H), 3.59-3.49 (m, 1H), 3.05 (dd, J=16.4, 5.2 Hz, 1H), 2.93-2.74 (m, 3H), 2.40 (dd, J=16.5, 8.9Hz, 1H), 2.19-2.03 (m, 1H), 1.65-1.57 (m, 1H), 1.13-0.92 (m, 4H).

[0727] LC / MS (ESI) (m / z): 422.1 [M+H] +

[0728] Example 33: Preparation of target compound 33

[0729] 5-(7-{[4-(difluoromethylene)cycloheptyl]amino}-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthyl-2-yl)-1λ6,2,5-thiadiazole-1,1,3-trione (33)

[0730] The synthetic route for target compound 33 is as follows:

[0731] Step 1: Synthesis of benzyl (4-oxocycloheptyl)carbamate (33b)

[0732] At -78°C, 40.8 mL of 2.5 M butyllithium was added dropwise to a tetrahydrofuran solution of trimethylsilyl diazomethane (47.3 mL, 2 M tetrahydrofuran solution). After stirring at 25°C for 1 hour, the mixture was cooled to -78°C and benzyl (4-oxocyclohexyl) carbamate (33a) (18.0 g, 72.8 mmol) was added dropwise. The resulting mixture was stirred at 25°C for 1 hour, followed by the addition of methanol (5.90 mL, 146 mmol). The mixture was then stirred at 25°C for 18 hours. The reaction was confirmed by LC-MS. The reaction solution was quenched with water (300 mL), extracted with ethyl acetate (100 mL × 3), and the combined organic phases were concentrated under reduced pressure to obtain a crude product. The crude product was subjected to silica gel column chromatography (dichloromethane:methanol = 100:0-90:10, gradient elution) to obtain benzyl (4-oxocycloheptanyl) carbamate (33b) (8.00 g, 34% yield).

[0733] Step 2: Synthesis of benzyl (4-(difluoromethylene)cycloheptyl)carbamate (33c)

[0734] At -40°C, potassium tert-butoxide (4.08 g, 36.3 mmol) was added to a solution of benzyl (4-oxocycloheptyl)carbamate (33b) (7.30 g, 27.9 mmol) and difluoromethyl (2-pyridyl) sulfone (5.40 g, 27.9 mmol) in N,N-dimethylformamide (50 mL). The resulting mixture was stirred at 25°C for 18 hours. The reaction was confirmed by LCMS. The reaction solution was diluted with water (100 mL), extracted with ethyl acetate (50 mL × 3), and the combined organic phases were concentrated under reduced pressure to obtain a crude product. The crude product was purified by HPLC to obtain benzyl (4-(difluoromethylene)cycloheptyl)carbamate (33c) (1.00 g, 12% yield). 1 H NMR (400MHz, CDCl3): δ7.44-7.28(m, 5H), 5.08(s, 2H), 4.68(s, 1H), 3.81-3.42(m , 1H), 2.43-2.20(m, 2H), 2.20-1.87(m, 4H), 1.87-1.68(m, 1H), 1.56-1.13(m, 3H).

[0735] LC-MS, M / Z (ESI): 296.4 [M+H] +

[0736] Step 3: Synthesis of 4-difluoromethylenecycloheptylamino (33d)

[0737] Benzyl (4-(difluoromethylene)cycloheptyl)carbamate (33c) (0.2 g, 0.67 mmol) was dissolved in trifluoroacetic acid (2 mL) and stirred at 70 °C for 3 hours. The reaction was confirmed by LCMS. The reaction solution was concentrated under reduced pressure to obtain crude 4-difluoromethylenecycloheptylamino (33d) (0.17 g, crude product), which was then directly proceeded to the next step without purification.

[0738] LC-MS, M / Z (ESI): 162.2 [M+H] +

[0739] Step 4: 5-(7-{[4-(difluoromethylene)cycloheptyl]amino}-1-fluoro-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphth-2-yl)-1λ 6 Synthesis of 2,5-thiadiazole-1,1,3-trione (33e)

[0740] At room temperature, 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-oxo-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 62,5-Thiadiazolidine-1,1,3-trione (i-9) (100 mg, 0.250 mmol) was dissolved in anhydrous methanol (1 mL), followed by the addition of catalytic amounts of acetic acid, 4-difluoromethylenecycloheptenylamino (33d) (60.4 mg, 0.370 mmol), and sodium cyanoborohydride (31.0 mg, 0.500 mmol). After the addition was complete, the mixture was purged with nitrogen three times and reacted at 25 °C for 12 hours. After the reaction was complete, a saturated sodium chloride solution (5 mL) was slowly added to the reaction solution, followed by extraction with a mixed solvent (ethyl acetate:acetonitrile = 2:1, 3 × 10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH (V / V) = 10:1-5:1) to obtain 5-(7-{[4-(difluoromethylene)cycloheptyl]amino}-1-fluoro-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphth-2-yl)-1λ 6 2,5-Thiadiazole-1,1,3-trione (33e) (61 mg, yield 45%).

[0741] LC / MS (ESI) (m / z): 548.1 [M+H] +

[0742] Step 5: 5-(7-{[4-(difluoromethylene)cycloheptyl]amino}-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphth-2-yl)-1λ 6 Synthesis of 2,5-thiadiazole-1,1,3-trione (33)

[0743] At room temperature, 5-(7-{[4-(difluoromethylene)cycloheptyl]amino}-1-fluoro-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphth-2-yl)-1λ 6 2,5-Thiadiazole-1,1,3-trione (33e) (61.0 mg, 0.11 mmol) was dissolved in dioxane hydrochloride (4 M, 2 mL) and reacted at 25 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure and purified by HPLC to obtain 5-(7-{[4-(difluoromethylene)cycloheptyl]amino}-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthyl-2-yl)-1λ 6 ,2,5-thiadiazole-1,1,3-trione (33).

[0744] 1H NMR (600MHz, DMSO-d6) δ9.52 (s, 1H), 8.48 (s, 2H), 6.48 (s, 1H), 4.04 (s, 2H), 3.58 (d, J = 5.6Hz, 2H), 3.14-3.02 (m, 3H), 2. 80 (t, J=12.8Hz, 2H), 2.42-2.25 (m, 2H), 2.16-2.08 (m, 4H), 1.88 (d, J=7.3Hz, 1H), 1.78-1.60 (m, 1H), 1.62-1.34 (m, 3H).

[0745] LC / MS (ESI) (m / z): 460.1 [M+H] +

[0746] Example 34: Preparation of target compound 34

[0747] 55-(1-Fluoro-3-hydroxy-7-{[3-(propyl-2-ylidene)cycloheptyl]amino}-5,6,7,8-tetrahydronaphth-2-yl)-1λ 6 ,2,5-Thiadiazole-1,1,3-trione (34)

[0748] The synthetic route for target compound 34 is as follows:

[0749] Step 1: Synthesis of benzyl (3-(propion-2-ylidene)cycloheptyl)carbamate (34b)

[0750] A solution of benzyl (3-oxocycloheptyl)carbamate (34a) (5.00 g, 19.1 mmol) in dimethyl sulfoxide (25 mL) was added to a solution of hydrazine hydrate (1.20 g, 19.1 mmol) in dimethyl sulfoxide (25 mL). After stirring at room temperature for 1 hour, cuprous chloride (0.190 g, 1.91 mmol), ammonia (3.02 mL), and carbon tetrabromide (12.7 g, 38.3 mmol) were added. The resulting mixture was stirred at 25 °C for 18 hours. The reaction was detected by LCMS to indicate completion. The reaction solution was quenched with hydrochloric acid solution (1000 mL, 5% wt), extracted with dichloromethane (1000 mL × 3), and the combined organic phases were concentrated under reduced pressure to obtain a crude product. The crude product was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 100:0-70:30, gradient elution) to obtain benzyl (3-(dibromomethylene)cycloheptyl)carbamate (34b) (3.10 g, yield 39%).

[0751] LC-MS, M / Z (ESI): 418.0 [M+H] +

[0752] Step 2: Synthesis of benzyl (3-(propyl-2-ylidene)cycloheptyl)carbamate (34c)

[0753] Cesium carbonate (2.34 g, 7.19 mmol) and Pd(dppf)Cl2 (0.26 g, 0.360 mmol) were added to a solution of benzyl (3-(dibromomethylene)cycloheptyl)carbamate (34b) (1.50 g, 3.59 mmol) and methylboronic acid (0.86 g, 14.4 mmol) in dioxane (20 mL). The mixture was stirred at 100 °C for 18 hours, and the reaction was confirmed by LCMS. The reaction solution was filtered, and the filtrate was purified by HPLC to obtain benzyl (3-(propane-2-ylidene)cycloheptyl)carbamate (34c) (220 mg, yield 21%).

[0754] 1 H NMR (400MHz, DMSO-d6): δ7.46-7.25 (m, 5H), 7.19 (d, J=7.6Hz, 1H), 5.00 (s, 2H), 3.48-3.35 (m, 1H), 2.64-2.53 (m, 1H) ), 2.42-2.21(m, 1H), 2.12-1.85(m, 2H), 1.76-1.65(m, 4H), 1.64-1.50(m, 5H), 1.51-1.32(m, 2H), 1.26-1.08(m, 1H).

[0755] LC-MS, M / Z (ESI): 288.2 [M+H] +

[0756] Step 3: Synthesis of 3-(propane-2-yl)cycloheptane-1-amine (34d)

[0757] Benzyl (3-(propyl-2-ylidene)cycloheptyl)carbamate (34c) (0.2 g, 0.69 mmol) was dissolved in trifluoroacetic acid (2 mL) and stirred at 70 °C for 3 hours. The reaction was confirmed by LCMS. The reaction solution was concentrated under reduced pressure to obtain 3-(propyl-2-ylidene)cycloheptane-1-amine (34d) (0.16 g, crude product), which was then directly proceeded to the next step without purification.

[0758] LC-MS, M / Z (ESI): 154.2 [M+H] +

[0759] Step 4: 5-(1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-{[3-(propyl-2-ylidene)cycloheptyl]amino}-5,6,7,8-tetrahydronaphth-2-yl)-1λ 6Synthesis of 2,5-thiadiazole-1,1,3-trione (34e)

[0760] At room temperature, 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-oxo-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (i-9) (100 mg, 0.250 mmol) was dissolved in anhydrous methanol (1 mL), followed by the addition of catalytic amounts of acetic acid and 3-(propane-2-yl)cycloheptane-1-amine (34d) (57.5 mg, 0.370 mmol) and sodium cyanoborohydride (31.0 mg, 0.500 mmol). After the addition was complete, the mixture was purged with nitrogen three times and reacted at 25 °C for 12 hours. After the reaction was complete, a saturated sodium chloride solution (5 mL) was slowly added to the reaction solution, followed by extraction with a mixed solvent (ethyl acetate:acetonitrile (V / V) = 2:1, 3 × 10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH (V / V) = 10:1-5:1) to obtain 5-(1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-{[3-(propyl-2-ylidene)cycloheptyl]amino}-5,6,7,8-tetrahydronaphth-2-yl)-1λ 6 ,2,5-Thiadiazole-1,1,3-trione (34e) (43 mg, yield 32%).

[0761] LC / MS (ESI) (m / z): 540.1 [M+H] +

[0762] Step 5: 55-(1-fluoro-3-hydroxy-7-{[3-(propyl-2-ylidene)cycloheptyl]amino}-5,6,7,8-tetrahydronaphth-2-yl)-1λ 6 Synthesis of 2,5-thiadiazole-1,1,3-trione (34)

[0763] At room temperature, 5-(1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-{[3-(propyl-2-ylidene)cycloheptyl]amino}-5,6,7,8-tetrahydronaphth-2-yl)-1λ 6 2,5-Thiadiazole-1,1,3-trione (34e) (43.0 mg, 0.08 mmol) was dissolved in dioxane hydrochloride (4 M, 2 mL) and reacted at 25 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure and purified by HPLC to obtain 5-(1-fluoro-3-hydroxy-7-{[3-(propyl-2-ylidene)cycloheptyl]amino}-5,6,7,8-tetrahydronaphthyl-2-yl)-1λ 6,2,5-thiadiazole-1,1,3-trione (34).

[0764] 1 H NMR (600MHz, DMSO-d6) δ9.27 (s, 1H), 8.51 (d, J=37.5Hz, 2H), 6.47 (s, 1H), 4.31-3.73 (m, 3H), 3 .74-3.54(m, 1H), 3.20-2.67(m, 5H), 2.43-1.89(m, 6H), 1.81-1.54(m, 7H), 1.53-0.89(m, 5H).

[0765] LC / MS (ESI) (m / z): 452.2 [M+H] +

[0766] Example 35: Preparation of target compound 35

[0767] 5-(1-Fluoro-3-hydroxy-7-{[3-(propyl-2-ylidene)cycloheptyl]amino}-5,6,7,8-tetrahydronaphth-2-yl)-1λ 6 ,2,5-Thiadiazole-1,1,3-trione (35)

[0768] The synthetic route for target compound 35 is as follows:

[0769] Step 1: 5-(7-{[3-(difluoromethylene)cycloheptyl]amino}-1-fluoro-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphth-2-yl)-1λ 6 Synthesis of 2,5-thiadiazole-1,1,3-trione (35a)

[0770] At room temperature, 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-oxo-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 62,5-Thiadiazolidine-1,1,3-trione (i-9) (100 mg, 0.250 mmol) was dissolved in anhydrous methanol (1 mL), followed by the addition of catalytic amounts of acetic acid, 3-(difluoromethylene)cycloheptane-1-amine (57.5 mg, 0.370 mmol), and sodium cyanoborohydride (31.0 mg, 0.500 mmol). After the addition was complete, the mixture was purged with nitrogen three times and reacted at 25 °C for 12 hours. After the reaction was complete, a saturated sodium chloride solution (5 mL) was slowly added to the reaction solution, followed by extraction with a mixed solvent (ethyl acetate:acetonitrile (V / V) = 2:1, 3 × 10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH (V / V) = 10:1-5:1) to obtain 5-(7-{[3-(difluoromethylene)cycloheptyl]amino}-1-fluoro-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphthyl-2-yl)-1λ 6 2,5-Thiadiazole-1,1,3-trione (35a) (43 mg, yield 32%).

[0771] LC / MS (ESI) (m / z): 548.1 [M+H] +

[0772] Step 5: 5-(7-{[3-(difluoromethylene)cycloheptyl]amino}-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphth-2-yl)-1λ 6 Synthesis of 2,5-thiadiazole-1,1,3-trione (35)

[0773] At room temperature, 5-(7-{[3-(difluoromethylene)cycloheptyl]amino}-1-fluoro-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphth-2-yl)-1λ 6 2,5-Thiadiazole-1,1,3-trione (35a) (43.0 mg, 0.08 mmol) was dissolved in dioxane hydrochloride (4 M, 2 mL) and reacted at 25 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated and purified by HPLC to obtain 5-(7-{[3-(difluoromethylene)cycloheptyl]amino}-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthyl-2-yl)-1λ 6 ,2,5-thiadiazole-1,1,3-trione (35).

[0774] 1H NMR (600MHz, DMSO-d6) δ9.27 (s, 1H), 6.47 (s, 1H), 3.93 (s, 2H), 3.67-3.41 (m, 2H), 3.11 (d, J=13.3Hz, 1H), 2.92-2.65 (m, 3H), 2.18 (ddd, J=41.8, 32.8, 15.4Hz, 6H), 1.80 (d, J=7.2Hz, 2H), 1.68 (dt, J=17.6, 8.8Hz, 1H), 1.53-1.30 (m, 3H).

[0775] LC / MS (ESI) (m / z): 460.1 [M+H] +

[0776] Example 36: Preparation of target compound 36

[0777] Synthesis of 5-(1-fluoro-3-hydroxy-7-((3-methylenecyclopentyl)amino)-5,6,7,8-tetrahydronaphthyl-2-yl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide (36)

[0778] The synthetic route for target compound 36 is shown below.

[0779] Step 1: Synthesis of tert-butyl(3-methylcyclopentyl)carbamate (36b)

[0780] Potassium tert-butoxide (1 M, 20.2 mL) was dissolved in tetrahydrofuran (20 mL), and methyltriphenylphosphine bromide (7.17 g, 20.1 mmol) was added at 0 °C. The reaction was stirred at 25 °C for 0.5 h. Then, tert-butyl-N-(3-oxoylidenecyclopentyl)aminomethyl ester (36a) (2 g, 10.0 mmol) was added, and the reaction was stirred at 25 °C for 16 h. After the reaction was complete, the reaction solution was diluted with water, and then extracted with ethyl acetate (20 mL * 3). The organic layer was 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 (mobile phase: petroleum ether / ethyl acetate = 10:1, R...). fp1 (0.5) yielded tert-butyl(3-methylcyclopentyl)carbamate (36b) (500 mg, crude).

[0781] Step 2: Synthesis of 3-methylenecyclopentane-1-amine (36c)

[0782] 100 mg of tert-butyl(3-methylcyclopentyl)carbamate (36b) was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (0.5 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 obtain 3-methylenecyclopentane-1-aminetrifluoroacetate (36c) (40.0 mg, crude product).

[0783] Step 3: Synthesis of 5-(1-fluoro-3-((2-methoxyethoxy)methoxy)-7-((3-methylenecyclopentyl)amino)-5,6,7,8-tetrahydronaphthyl-2-yl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (36d)

[0784] 3-Methylenecyclopentane-1-amine trifluoroacetate (36c) (28.9 mg, 298 μmol) was dissolved in methanol (1 mL), and sodium acetate (163 mg, 1.99 mmol) was added. The reaction was stirred at 25 °C for 0.5 h. Then 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-oxo-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ was added. 6 2,5-Thiadiazolidine-1,1,3-trione (i-9) (100 mg, 248 μmol) was reacted with the mixture at 25 °C with stirring for 0.5 h. After the reaction was complete, the mixture was directly filtered, and the filtrate was purified by HPLC to obtain compound 5-(1-fluoro-3-((2-methoxyethoxy)methoxy)-7-((3-methylenecyclopentyl)amino)-5,6,7,8-tetrahydronaphthyl-2-yl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (36 d) (25 mg, crude product).

[0785] LC-MS, M / Z (ESI): 484.2 [M+H] +

[0786] Step 4: Synthesis of 5-(1-fluoro-3-hydroxy-7-((3-methylenecyclopentyl)amino)-5,6,7,8-tetrahydronaphthyl-2-yl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide (36)

[0787] 5-(1-fluoro-3-((2-methoxyethoxy)methoxy)-7-((3-methylenecyclopentyl)amino)-5,6,7,8-tetrahydronaphthyl-2-yl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (36d) (20.0 mg, 41.3 μmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (0.5 mL) was added at 0 °C. The reaction was stirred at 40 °C for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain compound 5-(1-fluoro-3-hydroxy-7-((3-methylenecyclopentyl)amino)-5,6,7,8-tetrahydronaphthyl-2-yl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide (36d).

[0788] 1 H NMR (400Hz, CD3OD) δ6.54 (s, 1H), 5.00 (br d, J=7.1Hz, 3H), 4.24 (s, 2H), 3.89 (br t, J=7.4Hz, 1H), 3.63-3.41 (m, 2H), 3.29-3.07 (m, 1H), 2.98-2.81 (m, 3H), 2 .68-2.52(m, 2H), 2.50-2.36(m, 2H), 2.34-2.21(m, 2H), 1.87-1.70(m, 2H).

[0789] LC-MS, M / Z (ESI): 396.1 [M+H] +

[0790] Example 37: Preparation of target compound 37

[0791] Synthesis of 5-(1-fluoro-3-hydroxy-7-((3-methylenecyclohexyl)amino)-5,6,7,8-tetrahydronaphthyl-2-yl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide (37)

[0792] The synthetic route for target compound 37 is shown below:

[0793] Step 1: Synthesis of tert-butyl(3-methylenecyclohexyl)carbamate (37b)

[0794] Potassium tert-butoxide (1 M, 9.38 mL) was dissolved in tetrahydrofuran (20 mL), and methyltriphenylphosphine bromide (3.35 g, 9.38 mmol) was added at 0 °C. The reaction was stirred at 25 °C for 0.5 h. Then, tert-butyl-N-(3-oxoylidenecyclohexyl)aminomethyl ester (37a) (1 g, 4.69 mmol) was added, and the reaction was stirred at 25 °C for 16 h. After the reaction was complete, the reaction solution was diluted with water, and then extracted with ethyl acetate (20 mL * 3). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (mobile phase: petroleum ether / ethyl acetate = 10:1, R...). fp1 (0.5), to obtain tert-butyl(3-methylenecyclohexyl)carbamate (37b) (200 mg, crude product).

[0795] Step 2: Synthesis of 3-methylenecyclohexane-1-amine (37c)

[0796] 100 mg (473 μmol) of tert-butyl(3-methylenecyclohexyl)carbamate (37b) was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (0.5 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 obtain 3-methylenecyclohexane-1-aminetrifluoroacetate (37c) (50 mg, crude product).

[0797] Step 3: Synthesis of 5-(1-fluoro-3-((2-methoxyethoxy)methoxy)-7-((3-methylenecyclohexyl)amino)-5,6,7,8-tetrahydronaphthyl-2-yl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (37d)

[0798] 3-Methylenecyclohexane-1-amine trifluoroacetate (37c) (33.1 mg, 298 μmol) was dissolved in methanol (1 mL), and sodium acetate (163 mg, 1.99 mmol) was added. The reaction was stirred at 25 °C for 0.5 h. Then 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-oxo-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ was added. 6 2,5-Thiadiazolidine-1,1,3-trione (i-9) (100 mg, 248 μmol) was reacted with the mixture at 25 °C with stirring for 0.5 h. After the reaction was complete, the reaction solution was filtered, and the filtrate was directly purified by HPLC to obtain compound 5-(1-fluoro-3-((2-methoxyethoxy)methoxy)-7-((3-methylenecyclohexyl)amino)-5,6,7,8-tetrahydronaphthyl-2-yl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (37 d) (40 mg, crude product).

[0799] LC-MS, M / Z (ESI): 498.4 [M+H] +

[0800] Step 4: Synthesis of 5-(1-fluoro-3-hydroxy-7-((3-methylenecyclohexyl)amino)-5,6,7,8-tetrahydronaphthyl-2-yl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide (37)

[0801] 5-(1-fluoro-3-((2-methoxyethoxy)methoxy)-7-((3-methylenecyclohexyl)amino)-5,6,7,8-tetrahydronaphthyl-2-yl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (37d) (35.0 mg, 70.3 μmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (0.5 mL) was added at 0 °C. The reaction was stirred at 40 °C for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by HPLC to obtain compound 5-(1-fluoro-3-hydroxy-7-((3-methylenecyclohexyl)amino)-5,6,7,8-tetrahydronaphthyl-2-yl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide (37d).

[0802] 1 H NMR (400Hz, CD3OD) δ 6.56 (s, 1H), 4.89 (br s, 3H), 4.26 (s, 2H), 3.76-3.63 (m, 1H), 3.21-3.24 (m, 1H), 3.00-2.88 (m, 2H), 2.85-2.75 (m, 1H), 2.60 (dd, J=9. 6, 16.0Hz, 1H), 2.43-2.34(m, 1H), 2.32-2.13(m, 3H), 2.11-1.96(m, 2H), 1.87-1.72(m, 1H), 1.65-1.41(m, 2H).

[0803] LC-MS, M / Z (ESI): 410.2 [M+H] +

[0804] Example 38: Preparation of target compound 38

[0805] 5-(7-((3-(difluoromethylene)cyclohexyl)amino)-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphth-2-yl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (38)

[0806] The synthetic route for target compound 38 is shown below:

[0807] Step 1: Synthesis of tert-butyl (3-(difluoromethylene)cyclohexyl)carbamate (38b)

[0808] Potassium tert-butoxide (474 ​​mg, 4.22 mmol) was dissolved in N,N-dimethylformamide (5 mL). Then, at -40 °C, 2-(difluoromethanesulfonyl)pyridine (38a) (543 mg, 2.81 mmol) and tert-butyl(3-oxocyclohexyl)carbamate (500 mg, 2.34 mmol) were dissolved in N,N-dimethylformamide (5 mL) and slowly added to the reaction mixture. The mixture was then stirred at 25 °C for 12 hours. After the reaction was complete, water (50 mL) was added to quench the reaction, followed by extraction with ethyl acetate (30 mL x 3), washing with saturated brine (20 mL), drying the combined organic phases with anhydrous sodium sulfate, filtering, and concentrating the filtrate 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 tert-butyl(3-(difluoromethylene)cyclohexyl)carbamate (38b) (360 mg, 62% yield).

[0809] Step 2: Synthesis of 3-(difluoromethylene)cyclohexane-1-amine hydrochloride (38c)

[0810] The starting material, tert-butyl (3-(difluoromethylene)cyclohexyl)carbamate (38b) (360 mg, 1.46 mmol), was dissolved in 2 M dioxane hydrochloride solution (7 mL), and then stirred at 25 °C for 12 hours. After the reaction was complete, the mixture was directly concentrated under reduced pressure to obtain compound 3-(difluoromethylene)cyclohexane-1-amine hydrochloride (38c) (250 mg, crude product). This was used directly in the next reaction step.

[0811] Step 3: Synthesis of 5-(7-((3-(difluoromethylene)cyclohexyl)amino)-1-fluoro-3-((2-methoxyethoxy)methoxy)-5,6,7,8-tetrahydronaphthyl-2-yl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (38d)

[0812] The raw materials 3-(difluoromethylene)cyclohexane-1-amine hydrochloride (38c) (219 mg, 1.19 mmol) and potassium acetate (585 mg, 5.96 mmol) were dissolved in methanol (5 mL) and stirred at 25 °C for 0.5 hours. Then, 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-oxo-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 62,5-Thiadiazolidine-1,1,3-trione (i-9) (240 mg, 596 μmol) was added to the reaction solution and stirred at 25 °C for 0.5 h. Then, sodium cyanoborohydride (112 mg, 1.79 mmol) was added to the reaction solution and stirred at 25 °C for 1 h. After the reaction was complete, water (2 mL) was added to quench the reaction, and the reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by HPLC to obtain compound 5-(7-((3-(difluoromethylene)cyclohexyl)amino)-1-fluoro-3-((2-methoxyethoxy)methoxy)-5,6,7,8-tetrahydronaphthyl-2-yl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (38 d) (105 mg, 33% yield).

[0813] LC-MS, M / Z (ESI): 534.2 [M+H] +

[0814] Step 4: 5-(7-((3-(difluoromethylene)cyclohexyl)amino)-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphth-2-yl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (38)

[0815] The starting material 5-(7-((3-(difluoromethylene)cyclohexyl)amino)-1-fluoro-3-((2-methoxyethoxy)methoxy)-5,6,7,8-tetrahydronaphthyl-2-yl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (38d) (90.0 mg, 169 μmol) was dissolved in dichloromethane (5 mL). Then, trifluoroacetic acid (192 mg, 1.69 mmol) was slowly added to the reaction solution, and the mixture was stirred at 40 °C for 4 hours. After the reaction was completed, the pH was adjusted to 8 with triethylamine, and the solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by HPLC to obtain compound 5-(7-((3-(difluoromethylene)cyclohexyl)amino)-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthyl-2-yl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (38d).

[0816] 1H NMR (400Hz, DMSO-d6) δ9.24 (s, 1H), 8.59 (s, 1H), 6.47 (s, 1H), 3.93 (s, 2H), 3.51-3.64 (m, 1H), 3.41-3.45 (m, 2H), 3.05-3.10 (m, 1H), 2.67-2.80(m, 4H), 2.25-2.33(m, 1H), 2.10-2.12(m, 2H), 1.82-1.83(m, 1H), 1.80-1.81(m, 2H), 1.62-1.67(m, 1H), 1.37-1.42(m, 2H).

[0817] LC-MS, M / Z (ESI): 446.1 [M+H] + ]

[0818] Example 39: Preparation of target compound 39

[0819] 5-(7-{[3-(difluoromethylene)cyclopentyl]amino}-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphth-2-yl)-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (39)

[0820] The synthetic route for target compound 39 is shown below:

[0821] Step 1: Synthesis of tert-butyl[3-(difluoromethylene)cyclopentyl]carbamate (39b)

[0822] Potassium tert-butoxide (1.01 g, 9.03 mmol) was dissolved in DMF (20 mL), cooled to -50 °C, and a mixture of 2-(difluoromethanesulfonyl)pyridine (872 mg, 4.52 mmol) and tert-butyl(3-oxocyclopentyl)carbamate (39a) (1 g, 5.02 mmol) in DMF (10 mL) was added dropwise under a nitrogen atmosphere. The mixture was stirred at this temperature for 0.5 h. The reaction mixture was then heated to 0 °C, and a saturated ammonium chloride solution (20 mL) and hydrochloric acid (5 mL, 6 M) were added. The mixture was stirred at room temperature for 3 h. After the reaction was complete, the mixture was extracted with ethyl acetate (3 × 40 mL). The combined organic phases were washed with a saturated sodium chloride solution (80 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA(V / V)=10:1-1:1) to obtain tert-butyl[3-(difluoromethylene)cyclopentyl]carbamate (39b) (450 mg, yield 38%).

[0823] LC-MS, M / Z (ESI): 234.1 [M+H]+

[0824] Step 2: Synthesis of 3-(difluoromethylene)cyclopentane-1-amine (39c)

[0825] At room temperature, tert-butyl[3-(difluoromethylene)cyclopentyl]carbamate (39b) (450 mg, 1.93 mmol) was dissolved in a mixed solution of dichloromethane and trifluoroacetic acid (V / V) = 3:1, 8 mL, and reacted at 25 °C for 4 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain crude 3-(difluoromethylene)cyclopentane-1-amine (39c) (250 mg, yield 97%).

[0826] LC-MS, M / Z (ESI): 134.0 [M+H] +

[0827] Step 3: 5-(7-{[3-(difluoromethylene)cyclopentyl]amino}-1-fluoro-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphth-2-yl)-1λ 6 Synthesis of 2,5-thiadiazolidine-1,1,3-trione (39d)

[0828] At room temperature, 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-oxo-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (i-9) (150 mg, 0.37 mmol) was dissolved in anhydrous methanol (10 mL), followed by the addition of 3-(difluoromethylene)cyclopentane-1-amine (39c) (100 mg, 0.74 mmol) and sodium cyanoborohydride (60 mg, 0.93 mmol). After the addition was complete, the mixture was purged with nitrogen three times and reacted at 25 °C for 12 hours. After the reaction was complete, the reaction solution was slowly added to water (20 mL), and then extracted with ethyl acetate (3 × 20 mL). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH (V / V) = 10:1-5:1) to obtain 5-(7-{[3-(difluoromethylene)cyclopentyl]amino}-1-fluoro-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphth-2-yl)-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (39d) (150mg, yield 77%).

[0829] LC-MS, M / Z (ESI): 520.1 [M+H] +

[0830] Step 4: 5-(7-{[3-(difluoromethylene)cyclopentyl]amino}-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphth-2-yl)-1λ 6 Synthesis of 2,5-thiadiazolidine-1,1,3-trione (39)

[0831] At room temperature, 5-(7-{[3-(difluoromethylene)cyclopentyl]amino}-1-fluoro-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphth-2-yl)-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (39d) (150 mg, 0.29 mmol) was dissolved in dioxane hydrochloride (4 M, 4 mL) and reacted at 25 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain 5-(7-{[3-(difluoromethylene)cyclopentyl]amino}-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthyl-2-yl)-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (39).

[0832] 1 H NMR (600MHz, DMSO-d6) δ9.12 (s, 1H), 6.44 (s, 1H), 3.93 (s, 2H), 3.62 (s, 1H), 3.01 (d, J=16.4Hz, 1H), 2.8 0-2.62 (m, 3H), 2.45-2.29 (m, 3H), 2.26 (d, J = 15.2Hz, 2H), 2.05 (d, J = 12.4Hz, 2H), 1.61 (d, J = 27.6Hz, 2H)

[0833] LC-MS, M / Z (ESI): 462.1 [M+H] +

[0834] Example 40: Synthesis of target compound 40

[0835] 5-(7-{[6-(difluoromethylene)spiro[3.3]heptane-2-yl]amino}-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphth-2-yl)-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (40)

[0836] The synthetic route for target compound 40 is as follows:

[0837] Step 1: Synthesis of 6-(difluoromethylene)spiro[3.3]heptane-2-amine trifluoroacetate (40b)

[0838] At room temperature, tert-butyl[6-(difluoromethylene)spiro[3.3]heptane-2-yl]carbamate (40a) (200 mg, 0.772 mmol) was dissolved in anhydrous dichloromethane (2 mL), and then trifluoroacetic acid (1 mL) was added. After the addition was complete, the mixture was purged with hydrogen three times and reacted at 25 °C for 2 hours. After the reaction was complete, the reaction solution was filtered and concentrated under reduced pressure to obtain 6-(difluoromethylene)spiro[3.3]heptane-2-amine trifluoroacetate (40b) (80.0 mg, yield 66%).

[0839] Step 2: 5-(7-{[6-(difluoromethylene)spiro[3,3]heptane-2-yl]amino}-1-fluoro-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphthyl-2-yl)-1λ 6 Synthesis of 2,5-thiadiazolidine-1,1,3-trione (40c)

[0840] At room temperature, 6-(difluoromethylene)spiro[3.3]heptane-2-amine trifluoroacetate (40b) (80.0 mg, 0.503 mmol) was dissolved in anhydrous methanol (2 mL), followed by the addition of sodium acetate (82.4 mg, 1.00 mmol), 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-oxo-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (i-9) (202 mg, 0.503 mmol) and sodium cyanoborohydride (62.0 mg, 1.00 mmol). After addition, the mixture was purged with nitrogen three times and reacted at 25 °C for 12 hours. After the reaction was complete, saturated sodium chloride solution (5 mL) was slowly added to the reaction solution, and then extracted with a mixed solvent (ethyl acetate: acetonitrile = 2:1, 3 × 10 mL). The organic phases were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM: MeOH = 10:1 to 5:1) to obtain 5-(7-{[6-(difluoromethylene)spiro[3.3]heptane-2-yl]amino}-1-fluoro-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphthyl-2-yl)-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (40c) (100 mg, yield 37%).

[0841] LC / MS (ESI) (m / z): 546.0 [M+H]+ .

[0842] Step 3: 5-(7-{[6-(difluoromethylene)spiro[3.3]heptane-2-yl]amino}-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphth-2-yl)-1λ 6 Synthesis of 2,5-thiadiazolidine-1,1,3-trione (40)

[0843] At room temperature, 5-(7-{[6-(difluoromethylene)spiro[3,3]heptane-2-yl]amino}-1-fluoro-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphthyl-2-yl)-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (40c) (100 mg, 0.183 mmol) was dissolved in dioxane hydrochloride (4 M, 2 mL) and reacted at 25 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain 5-(7-{[6-(difluoromethylene)spiro[3.3]heptane-2-yl]amino}-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthyl-2-yl)-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (40).

[0844] 1 H NMR (600MHz, DMSO-d6) δ9.25 (s, 1H), 8.74 (s, 2H), 6.43 (s, 1H), 3.91 (s, 2H), 3.84 -3.79 (m, 1H), 3.67 (d, J=23.2Hz, 1H), 3.43 (dd, J=5.6, 4.0Hz, 1H), 2.99 (dd, J=15 .6, 4.8Hz, 1H), 2.78(s, 2H), 2.76-2.69(m, 2H), 2.68(s, 2H), 2.45-2.41(m, 2H), 2 .22 (dd, J=20.4, 8.4Hz, 2H), 2.05 (d, J=9.6Hz, 1H), 1.63 (dt, J=17.2, 5.2Hz, 1H).

[0845] LC / MS (ESI) (m / z): 458.0 [M+H] + ;

[0846] Example 41: Synthesis of target compound 41

[0847] 5-{7-[(7,7-difluorospiro[3,5]nonane-2-yl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (41)

[0848] The synthetic route for target compound 41 is as follows:

[0849] Step 1: Synthesis of tert-butyl(7,7-difluorospiro[3.5]nonane-2-yl)carbamate (41b) and tert-butyl(7-fluorospiro[3.5]non-6-en-2-yl)carbamate (41e)

[0850] At room temperature, tert-butyl(7-oxospiro[3.5]nonane-2-yl)carbamate (41a) (150 mg, 0.593 mmol) was dissolved in anhydrous dichloromethane (3 mL), and then bis(2-methoxyethyl)aminosulfur trifluoride (0.3 mL, 1.63 mmol) was slowly added dropwise under nitrogen protection at 0 °C. After the addition was complete, the reaction was carried out at 25 °C for 12 hours. After the reaction was complete, the reaction was quenched with saturated ammonium chloride solution at 0 °C, diluted with water, and extracted with dichloromethane (3 × 10 mL). The organic phases were combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100:1 to 10:1) to give tert-butyl(7,7-difluorospiro[3.5]nonane-2-yl)carbamate (41b) (60.0 mg, 37% yield) and tert-butyl(7-fluorospiro[3.5]non-6-en-2-yl)carbamate (41e) (60.0 mg, 37% yield).

[0851] Step 2: Synthesis of 7,7-difluorospiro[3.5]nonane-2-amine trifluoroacetate (41c)

[0852] At room temperature, tert-butyl(7,7-difluorospiro[3.5]nonane-2-yl)carbamate (41b) (60.0 mg, 0.218 mmol) was dissolved in anhydrous dichloromethane (2 mL), and then trifluoroacetic acid (1 mL) was slowly added at 0 °C. After the addition was complete, the reaction was carried out at 25 °C for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain 7,7-difluorospiro[3.5]nonane-2-amine trifluoroacetate (41c) (50.0 mg, yield 79%).

[0853] LC / MS (ESI) (m / z): 176.0 [M+H] + .

[0854] Step 3: 5-{7-[(7,7-difluorospiro[3,5]nonane-2-yl)amino]-1-fluoro-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 Synthesis of 2,5-thiadiazolidine-1,1,3-trione (41d)

[0855] At room temperature, 7,7-difluorospiro[3.5]nonane-2-amine trifluoroacetate (41c) (50.0 mg, 0.173 mmol) was dissolved in anhydrous methanol (1 mL), followed by the sequential addition of sodium acetate (28.3 mg, 0.346 mmol), 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-oxo-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ6,2,5-thiadiazolidine-1,1,3-trione (i-9) (70.0 mg, 0.173 mmol), and sodium cyanoborohydride (21.7 mg, 0.346 mmol). After the additions, the mixture was purged with nitrogen three times and reacted at 25 °C for 12 hours. After the reaction was complete, a saturated sodium chloride solution (5 mL) was slowly added to the reaction solution, followed by extraction with a mixed solvent (ethyl acetate: acetonitrile = 2:1, 3 × 10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM: MeOH = 10:1 to 5:1) to obtain 5-{7-[(7,7-difluorospiro[3,5]nonane-2-yl)amino]-1-fluoro-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (41d) (90.0 mg, yield 93%). LC / MS (ESI) (m / z): 562.0 [M+H] + .

[0856] Step 4: 5-{7-[(7,7-difluorospiro[3.5]nonane-2-yl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 Synthesis of 2,5-thiadiazolidine-1,1,3-trione (41)

[0857] At room temperature, 5-{7-[(7,7-difluorospiro[3,5]nonane-2-yl)amino]-1-fluoro-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (41d) (90.0 mg, 0.160 mmol) was dissolved in dioxane hydrochloride (4 M, 2 mL) and reacted at 25 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain 5-{7-[(7,7-difluorospiro[3,5]nonane-2-yl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (41).

[0858] 1 H NMR (600MHz, DMSO-d6) δ9.28 (s, 1H), 9.05 (s, 1H), 6.46 (s, 1H), 3.99-3.91 ( m, 3H), 3.46 (d, J=5.6Hz, 1H), 3.25 (s, 1H), 3.05 (dd, J=15.6, 4.8Hz, 1H), 2. 81-2.71 (m, 2H), 2.54 (s, 1H), 2.49-2.44 (m, 1H), 2.24 (dd, J=12.0, 7.6Hz, 2 H), 2.10 (d, J=10.4Hz, 1H), 1.96-1.80 (m, 5H), 1.67 (dd, J=28.0, 6.0Hz, 4H).

[0859] LC / MS (ESI) (m / z): 474.0 [M+H] +

[0860] Example 42: Synthesis of target compound 42

[0861] 5-{1-fluoro-7-[(7-fluorospiro[3.5]non-6-en-2-yl)amino]-3-hydroxy-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (42)

[0862] The synthetic route for target compound 42 is as follows:

[0863] Step 1: Synthesis of 7-fluorospiro[3.5]non-6-ene-2-amine trifluoroacetate (42a)

[0864] At room temperature, tert-butyl(7-fluorospiro[3.5]non-6-en-2-yl)carbamate (41e) (60.0 mg, 0.234 mmol) was dissolved in anhydrous dichloromethane (2 mL), and then trifluoroacetic acid (1 mL) was slowly added at 0 °C. After the addition was complete, the reaction was carried out at 25 °C for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain 7-fluorospiro[3.5]non-6-en-2-amine trifluoroacetate (42a) (50.0 mg, yield 79%).

[0865] LC / MS (ESI) (m / z): 156.0 [M+H] + .

[0866] Step 2: 5-{1-fluoro-7-[(7-fluorospiro[3.5]non-6-en-2-yl)amino]-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 Synthesis of 2,5-thiadiazolidine-1,1,3-trione (42b)

[0867] At room temperature, 7-fluorospiro[3.5]non-6-en-2-amine trifluoroacetate (42a) (50.0 mg, 0.185 mmol) was dissolved in anhydrous methanol (1 mL), followed by the addition of sodium acetate (30.3 mg, 0.370 mmol), 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-oxo-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (74.3 mg, 0.185 mmol) and sodium cyanoborohydride (23.2 mg, 0.370 mmol) were added. After the addition was complete, the mixture was purged with nitrogen three times and reacted at 25 °C for 12 hours. After the reaction was complete, saturated sodium chloride solution (5 mL) was slowly added to the reaction solution, and then extracted with a mixed solvent (ethyl acetate:acetonitrile = 2:1, 3 × 10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH = 10:1-5:1) to obtain 5-{1-fluoro-7-[(7-fluorospiro[3.5]non-6-en-2-yl)amino]-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (42b) (70.0 mg, 70% yield).

[0868] LC / MS (ESI) (m / z): 542.0 [M+H] + .

[0869] Step 3: 5-{1-fluoro-7-[(7-fluorospiro[3.5]non-6-en-2-yl)amino]-3-hydroxy-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 Synthesis of 2,5-thiadiazolidine-1,1,3-trione (42) At room temperature, 5-{1-fluoro-7-[(7-fluorospiro[3.5]non-6-en-2-yl)amino]-3-[(2-methoxyethoxy)methoxy]-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 62,5-Thiadiazolidine-1,1,3-trione (42b) (70.0 mg, 0.129 mmol) was dissolved in dioxane hydrochloride (4 M, 2 mL) and reacted at 25 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain 5-{1-fluoro-7-[(7-fluorospiro[3.5]non-6-en-2-yl)amino]-3-hydroxy-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 ,2,5-Thiadiazolidine-1,1,3-trione (42).

[0870] 1 H NMR (600MHz, DMSO-d6) δ9.24 (s, 1H), 8.34 (s, 2H), 6.45 (s, 1H), 4.56 (d, J=23.6Hz, 1H), 3.92 (s, 2H), 3.54 (s, 2H), 3.07 (d, J=10.8Hz, 1H), 3.00-2.92 (m, 1H), 2.80-2.74 (m, 2H), 2.15 (s, 1H), 2.0 7(d, J=12.0Hz, 1H), 1.92 (d, J=9.2Hz, 1H), 1.84 (d, J=14.4Hz, 1H), 1.75-1.71 (m, 1H), 1.68-1.6 3 (m, 2H), 1.56 (s, 2H), 1.46 (d, J = 10.4Hz, 1H), 1.40 (s, 1H), 1.28 (s, 1H), 1.17 (d, J = 18.0Hz, 3H).

[0871] LC / MS (ESI) (m / z): 454.0 [M+H] +

[0872] Example 43: Preparation of target compound 43

[0873] 5-{1-fluoro-3-hydroxy-7-[(4-methyl-ylidenecyclohexyl)amino]-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 ,2,5-Thiodiazine-1,1,3-trione (43)

[0874] The synthetic route for target compound 43 is shown below:

[0875] Step 1: 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-[(4-methylcyclohexylene)amino]-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 Synthesis of 2,5-thiodiazine-1,1,3-trione (43a)

[0876] At room temperature, 4-methylenecyclohexane-1-amine (33.0 mg, 0.30 mmol) was dissolved in anhydrous methanol (1 mL), followed by the addition of sodium acetate (51.0 mg, 0.62 mmol) and 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-oxo-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ. 6 2,5-Thiadiazolidine-1,1,3-trione (i-9) (100 mg, 0.250 mmol) and sodium cyanoborohydride (31.0 mg, 0.500 mmol) were added. After the addition was complete, the mixture was purged with nitrogen three times and reacted at 25 °C for 12 hours. After the reaction was complete, saturated sodium chloride solution (5 mL) was slowly added to the reaction solution, and then extracted with a mixed solvent (ethyl acetate:acetonitrile (V / V) = 2:1, 10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH (V / V) = 10:1-5:1) to obtain 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-[(4-methylmethylenecyclohexyl)amino]-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 2,5-Thiodiazine-1,1,3-trione (43a) (33.4 mg, yield 27%).

[0877] LC-MS, M / Z (ESI): 498.1 [M+H] +

[0878] Step 2: 5-{1-fluoro-3-hydroxy-7-[(4-methyl-ylidenecyclohexyl)amino]-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 Synthesis of 2,5-thiodiazine-1,1,3-trione (43)

[0879] At room temperature, 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-[(4-methylylidenecyclohexyl)amino]-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 2,5-Thiodiazine-1,1,3-trione (43a) (33.4 mg, 0.07 mmol) was dissolved in dioxane hydrochloride (4 M, 2 mL) and reacted at 25 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated to obtain a crude product, which was purified by HPLC to obtain 5-{1-fluoro-3-hydroxy-7-[(4-methylmethylenecyclohexyl)amino]-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 ,2,5-Thiodiazine-1,1,3-trione (43).

[0880] 1H NMR (600MHz, DMSO-d6) δ9.46 (s, 1H), 8.58 (s, 2H), 6.48 (s, 1H), 5.32 (s, 2H), 4.01 (s, 2H), 3.6 1 (qd, J=8.1, 4.2Hz, 2H), 3.12 (dd, J=15.8, 5.6Hz, 1H), 2.92-2.56 (m, 5H), 2.28-1.56 (m, 8H).

[0881] LC-MS, M / Z (ESI): 410.1 [M+H] +

[0882] Example 44: Preparation of target compound 44

[0883] 5-{1-fluoro-3-hydroxy-7-[(3-methylenecyclobutyl)amino]-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 ,2,5-Thiadiazole-1,1,3-trione (44)

[0884] The synthetic route for target compound 44 is shown below:

[0885] Step 1: 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-[(3-methylenecyclobutyl)amino]-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 Synthesis of 2,5-thiadiazole-1,1,3-trione (44a)

[0886] At room temperature, 3-methylenecyclobutane-1-amine (25.0 mg, 0.30 mmol) was dissolved in anhydrous methanol (1 mL), followed by the addition of sodium acetate (51.0 mg, 0.62 mmol) and 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-oxo-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ. 62,5-Thiadiazolidine-1,1,3-trione (i-9) (100 mg, 0.250 mmol) and sodium cyanoborohydride (31.0 mg, 0.500 mmol) were added. After the addition was complete, the mixture was purged with nitrogen three times and reacted at 25 °C for 12 hours. After the reaction was complete, saturated sodium chloride solution (5 mL) was slowly added to the reaction solution, and then extracted with a mixed solvent (ethyl acetate:acetonitrile (V / V) = 2:1, 10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH (V / V) = 10:1-5:1) to obtain 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-[(3-methylenecyclobutyl)amino]-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 2,5-Thiadiazole-1,1,3-trione (44a) (72.3 mg, yield 62%).

[0887] LC-MS, M / Z (ESI): 470.1 [M+H] +

[0888] Step 2: 5-{1-fluoro-3-hydroxy-7-[(3-methylenecyclobutyl)amino]-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 Synthesis of 2,5-thiadiazole-1,1,3-trione (44)

[0889] At room temperature, 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-[(3-methylenecyclobutyl)amino]-5,6,7,8-tetrahydronaphth-2-yl}-1λ 6 2,5-Thiadiazole-1,1,3-trione (44a) (33.4 mg, 0.15 mmol) was dissolved in dioxane hydrochloride (4 M, 2 mL) and reacted at 25 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated to obtain a crude product, which was purified by HPLC to obtain 5-{1-fluoro-3-hydroxy-7-[(3-methylenecyclobutyl)amino]-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 ,2,5-Thiadiazole-1,1,3-trione (44).

[0890] 1H NMR (400MHz, DMSO-d6) δ9.42 (s, 1H), 9.00 (s, 2H), 6.47 (s, 1H), 4.93 (s, 2H), 4.18-3.92 (m, 3H), 3.15-2 .86 (m, 6H), 2.84-2.67 (m, 2H), 2.61-2.52 (m, 1H), 2.12 (d, J=9.9Hz, 1H), 1.69 (qd, J=10.9, 6.0Hz, 1H).

[0891] LC-MS, M / Z (ESI): 382.1 [M+H] +

[0892] Example 45: Preparation of target compound 45

[0893] 5-(1-Fluoro-3-hydroxy-7-((3-(prop-2-methylene)cyclohexyl)amino)-5,6,7,8-tetrahydronaphthyl-2-yl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (45)

[0894] The synthetic route for target compound 45 is shown below:

[0895] Step 1: Synthesis of tert-butyl (3-(prop-2-methylene)cyclohexyl)carbamate (45b)

[0896] Potassium tert-butoxide (9.47 g, 84.4 mmol) was dissolved in N,N-dimethylformamide (100 mL). Then, at -40 °C, 2-(isopropylsulfonyl)pyridine (4.34 g, 23.4 mmol) and tert-butyl(3-oxocyclohexyl)carbamate (45a) (10.0 g, 46.9 mmol) were dissolved in N,N-dimethylformamide (50 mL) and slowly added to the reaction solution. The mixture was then stirred at 25 °C for 12 hours. After the reaction was complete, water (500 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (100 mL * 3), washed with saturated brine (100 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) to give the compound tert-butyl (3-(prop-2-methylene)cyclohexyl)carbamate (45b) (70.0 mg, 1% yield).

[0897] Step 2: Synthesis of 3-(prop-2-methylene)cyclohexane-1-amine (45c)

[0898] tert-butyl (3-(prop-2-methylene)cyclohexyl)carbamate (45b) (60.0 mg, 250 μmol) was dissolved in dichloromethane (6 mL), and then trifluoroacetic acid (2 mL) was added at 0 °C. The mixture was stirred at 0 °C for 2 hours. After the reaction was complete, the mixture was directly concentrated under reduced pressure to obtain compound 3-(prop-2-methylene)cyclohexane-1-amine (45c) (34.0 mg, crude product).

[0899] LC-MS, M / Z (ESI): 140.2 [M+H] +

[0900] Step 3: Synthesis of 5-(1-fluoro-3-((2-methoxyethoxy)methoxy)-7-((3-(propyl-2-methylene)cyclohexyl)amino)-5,6,7,8-tetrahydronaphthyl-2-yl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (45d)

[0901] The raw material 3-(prop-2-methylene)cyclohexane-1-amine (45c) (33.2 mg, 239 μmol) and potassium acetate (195 mg, 1.99 mmol) were dissolved in dioxane (5 mL) and stirred at 25 °C for 0.5 hours. Then, 5-{1-fluoro-3-[(2-methoxyethoxy)methoxy]-7-oxo-5,6,7,8-tetrahydronaphthyl-2-yl}-1λ 6 2,5-Thiadiazolidine-1,1,3-trione (i-9) (80.0 mg, 199 μmol) was added to the reaction solution and stirred at 25 °C for 0.5 h. Then, sodium cyanoborohydride (37.5 mg, 596 μmol) was added to the reaction solution and stirred at 25 °C for 1 h. After the reaction was complete, water (2 mL) was added to quench the reaction, and the reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by HPLC to obtain compound 5-(1-fluoro-3-((2-methoxyethoxy)methoxy)-7-((3-(propyl-2-methylene)cyclohexyl)amino)-5,6,7,8-tetrahydronaphth-2-yl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (45 d) (20.0 mg, 19% yield).

[0902] LC-MS, M / Z (ESI): 526.4 [M+H] +

[0903] Step 4: 5-(1-fluoro-3-hydroxy-7-((3-(propyl-2-methylene)cyclohexyl)amino)-5,6,7,8-tetrahydronaphthyl-2-yl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (45)

[0904] The starting material 5-(1-fluoro-3-((2-methoxyethoxy)methoxy)-7-((3-(propyl-2-methylene)cyclohexyl)amino)-5,6,7,8-tetrahydronaphthyl-2-yl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (45d) (17.0 mg, 32.3 μmol) was dissolved in dichloromethane (3 mL). Then, trifluoroacetic acid (111 mg, 970 μmol) was slowly added to the reaction solution, and the mixture was stirred at 40 °C for 5 hours. After the reaction was completed, the pH was adjusted to 8 with triethylamine, and the reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by HPLC to obtain compound 5-(1-fluoro-3-hydroxy-7-((3-(prop-2-methylene)cyclohexyl)amino)-5,6,7,8-tetrahydronaphth-2-yl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (45).

[0905] 1 H NMR (400MHz, MeOD) δ6.54 (s, 1H), 4.24 (s, 2H), 3.71-3.74 (m, 1H), 3.22-3.25 (m, 2H), 3.13-3.17 (m, 1H), 2.91-2.92 (m, 2H), 2.73 (br d, 1H, J=12.5Hz), 2.59-2.64(m, 1H), 2.23-2.24(m, 2H), 1.89-1.92(m, 2H), 1.78-1.79(m, 2H), 1.75(br d, 3H, J=3.0Hz), 1.73 (s, 3H), 1.38-1.54 (m, 2H)

[0906] LC-MS, M / Z (ESI): 438.2 [M+H] +

[0907] The preparation methods for the following compounds are the same as those in Examples 1-45 above:

[0908] Biological testing

[0909] Experimental Example 1: Determination of the inhibitory effect of compounds on PTPN1 / PTPN2 enzyme activity

[0910] Experimental methods

[0911] 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.

[0912] 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.

[0913] 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.

[0914] 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.

[0915] 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.

[0916] 6) Use instruments from BMG (Germany) to read fluorescence signals with an excitation wavelength of 360 nm and an emission wavelength of 460 nm.

[0917] 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 by a nonlinear regression equation using XLfit 5.5.0 software, Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC50 - X) * HillSlope)).

[0918] Experimental conclusion: The compounds of this invention have excellent inhibitory effects on PTPN1 / PTPN2 enzyme activity in a dose-dependent manner.

[0919] Experimental Example 2: Determination of the effect of the compound on the proliferation of B16F10 cells

[0920] Experimental methods

[0921] 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.

[0922] 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.

[0923] 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.

[0924] 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.

[0925] 5) IFNγ treatment. After about 10 minutes, add IFNγ to bring the final concentration to 10 ng / mL.

[0926] 6) Activity assay. Cell viability was assessed 96 hours after drug treatment, using the method described above. 2.0 (Promega, #G9243) Instruction Manual.

[0927] 7) IC 50 Calculate the relative viability (%) as follows: (LumninenceDMSO - Lumininence experiment) / (LumninenceDMSO - Lumininence blank) * 100%. Calculate this using GraphPad Prism software based on log(inhibitor) vs. response -- Variable slope (four parameters).

[0928] Table 2 shows the inhibitory activity of the tested compounds on the proliferation of B16F10 cells.

[0929] Experimental conclusion: The compound of this invention can significantly inhibit the proliferation of B16F10 cells.

Claims

1. The compound represented by formula (I), its tautomers, stereoisomers, or pharmaceutically acceptable salts, in, R1 is H, NH2, CN, or -CR 11 =CR 12 R 13 3-8 membered heterocyclic alkyl groups, C 6-10 Aryl or 5-10-membered heteroaryl, wherein the 3-8-membered heterocyclic alkyl, C 6-10 The aryl and 5-10 heteroaryl groups are independently and optionally bounded by 1, 2, 3 or 4 R groups. a replace; R 11 R 12 and R 13 Each is independently H, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 3-8 cycloalkyl; R 1’ H, halogen, OH, NH2, CN, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-8 cycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy and C 3-8 The cycloalkyl groups are each independently and optionally marked with 1, 2, 3 or 4 R's. a’ replace; R2 and R 2’ They are, independently, H, halogen, OH, NH2, CN, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl or 3-8 membered heterocycloalkyl, wherein C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl and 3-8 membered heterocycloalkyl groups are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. b Replacement; R3 and R 3’ They are, independently, H, halogen, OH, NH2, CN, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-8 Cycloalkyl or 3-8 membered heterocycloalkyl, wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-8 Cycloalkyl and 3-8 membered heterocycloalkyl groups are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. c replace; R4 represents H, halogen, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy or C 3-8 cycloalkyl, the C 1-6 Alkyl, C 2-6 alkenyl, C 2- 6-acetylinyl, C 1-6 Alkoxy and C 3-8 The cycloalkyl groups are each independently and optionally substituted by 1, 2, 3 or 4 Rds; R5 is H or halogen; X is CR x1 R x1’ or NR x2 ; R x1 For H, halogens, OH, CN, NH2, -NR x11 -C 1-10 Alkyl, -NR x11 -C 0-6 Alkylene-C 3-8 cycloalkyl, -NR x11 -C 0-6 alkylene-5-10 heteroaryl, -NR x11 -C 0-6 Alkylene-S(R) x12 ) w C 1-8 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-8 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl or 5-10 heteroaryl, the -NR x11 -C 1-10 Alkyl, -NR x11 -C 0-6 Alkylene-C 3-8 cycloalkyl, -NR x11 -C 0- 6-alkylene-5-10-membered heteroaryl, -NR x11 -C 0-6 Alkylene-S(R) x12 ) w C 1-8 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-8 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 The aryl and 5-10 heteroaryl groups are independently and optionally bounded by 1, 2, 3 or 4 R groups. e replace; R x11 For H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Each R x12 Each is independently H, halogen, and C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Each R e 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 or C 3- 8-cycloalkyl, the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy and C 3-8 The cycloalkyl groups are each independently and optionally marked with 1, 2, 3 or 4 R's. f Replace; or, two Rs connected to the same C e form Among them, R e1 R e2 They are independently H, halogen, OH, CN, COOH, and C, respectively. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R x1’ H, -NR x11 -C 0-6 Alkylene-S(R) x12 ) w -S (=O) m -NR x11 -C 1-6 Alkyl, -NR x11 -C(R x13 )2-NR x11 -C 1-6 Alkyl, -NR x11 -C 0- 6-alkylene-C 7-10 cycloalkyl, -NR x11 -C 0-6 Alkylene-C 7-10 Cycloalkenyl, -NR x11 -C 0-6 Alkylene (with 1, 2, 3 or 4 Rs) ee Replacement C 3- 6-cycloalkyl), -NR x11 -C 0-6 Alkylene-7-12-membered heterocyclic alkyl, -OC 3-8 cycloalkyl, -NR x11 -C 3-6 cycloalkyl-C 6-12 Aryl, -NR x11 -4-6 membered heterocyclic alkyl-C 6-12 Aryl, -NR x11 -C 6-12 Aryl, -NR x11 -5-12 heteroaryl groups, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-8 cycloalkyl, (with 1, 2, 3 or 4 Rs) ee Substituted 3-6-membered heterocyclic alkyl groups or 7-12-membered heterocyclic alkyl groups, wherein -NR x11 -C 0-6 Alkylene-S(R) x12 ) w -S (=O) m -NR x11 -C 1-6 Alkyl, -NR x11 -C(R x13 )2-NR x11 -C 1-6 Alkyl, -NR x11 -C 0-6 Alkylene-C 7-10 cycloalkyl, -NR x11 -C 0-6 Alkylene-C 7-10 Cycloalkenyl, -NR x11 -C 0-6 Alkylene (with 1, 2, 3 or 4 Rs) ee Replacement C 3-6 cycloalkyl), -NR x11 -C 0- 6-alkylene-7-12-membered heterocyclic alkyl, -OC 3-8 cycloalkyl, -NR x11 -C 3-6 cycloalkyl-C 6-12 Aryl, -NR x11 -4-6 membered heterocyclic alkyl-C 6-12 Aryl, -NR x11 -C 6-12 Aryl, -NR x11 -5-12 heteroaryl groups, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-8 cycloalkyl, (with 1, 2, 3 or 4 Rs) ee The substituted 3-6-membered heterocyclic alkyl groups and 7-12-membered heterocyclic alkyl groups are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. e’ replace; Each R x13 Each is independently H, halogen, and C. 1-6 Alkyl or C 1-6 Halogenated alkyl, or, two Rs x13 Formation = O; R x2 -C 0-6 Alkylene-S(R) x12 ) w The -C 0-6 Alkylene-S(R) x12 ) w Independently and optionally by 1, 2, 3 or 4 R g replace; Each R a R a’ R b R c R d R f R g Each can be independently H, halogen, OH, NH2, CN, COOH, or C. 1-6 alkyl; Each R e’ The independent components are H, halogen, OH, NH2, CN, COOH, and C, respectively. 1-6 Alkyl, C 1-6 Halogenated alkyl or C 3-6 cycloalkyl; or, two R groups attached to the same C. e’ form Each R ee Each independently Each R e3 R e4 They are independently H, halogen, OH, CN, COOH, and C, respectively. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; w is 1, 3, or 5; m is 0, 1, or 2; The equation (I) is not In addition, the R x1’ R x1 R1, R2, R 2’ One of the following conditions must be met: a)R x1’ C 1-6 Alkyl, C 2-6 alkenyl, C 1-6 Alkoxy or C 3-8 When cycloalkyl, R x1 Not H; or, b)R x1’ When H is true, R1 is not true; or, c)R x1’ When H is , R2 and R 2’ Not both H; The heteroatoms in the "heterocyclic alkyl" and "heteroaryl" groups include N, O, and S, and the S heteroatoms may optionally be oxidized to S(=O) or S(=O)2. The number of heteroatoms is 1, 2, 3 or 4; when the number of heteroatoms is multiple, the heteroatoms may be the same or different.

2. The compound according to claim 1, its tautomers, stereoisomers, or pharmaceutically acceptable salts, characterized in that, R x1 For H, halogens, OH, CN, NH2, -NR x11 -C 1-8 Alkyl, -NR x11 -C 1-3 Alkylene-C 3-6 cycloalkyl, -NR x11 -C 1-3 alkylene-5-6-membered heteroaryl, -NR x11 -C 1-4 Alkylene-S(R) x12 ) w C 1-6 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, wherein -NR x11 -C 1-8 Alkyl, -NR x11 -C 1-3 Alkylene-C 3-6 cycloalkyl, -NR x11 -C 1-3 alkylene-5-6-membered heteroaryl, -NR x11 -C 1-4 Alkylene-S(R) x12 ) w C 1-6 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6-membered heterocycloalkyl, phenyl, and 5-6-membered heteroaryl groups are each independently and optionally surrounded by 1, 2, 3, or 4 R groups. e replace; Or, R x11 For H, C 1-3 Alkyl or C 1-3 Halogenated alkyl groups; Or, R x11 For H; Or, each R x12 Each is independently H, halogen, and C. 1-3 Alkyl or C 1-3 Halogenated alkyl groups; Or, each R x12 Each can be H or F independently; Or, each R e The independent components are H, halogen, OH, NH2, CN, COOH, and C, respectively. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy or C 3-6 cycloalkyl, the C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy and C 3-6 The cycloalkyl groups are each independently and optionally marked with 1, 2, 3 or 4 R's. f replace; Or, two Rs connected to the same C e form Among them, R e1 R e2 Each can be independently H, halogen, OH, CN, COOH, methyl, ethyl, or propyl; Or, two Rs connected to the same C e form Or, each R e Each of the following is independently H, halogen, OH, NH2, CN, COOH, methyl, or ethyl, wherein the methyl and ethyl groups are each optionally independently separated by 1, 2, 3, or 4 R groups. f replace; Or, each R f Each can be independently H, halogen, OH, NH2, CN, COOH, or methyl; Or, each R e Each can be independently H, halogen, OH, NH2, CN, COOH, methyl, ethyl, or -CH2OH; Or, R x1 The derivatives are H, -O-(CH2)2CH(CH3)2, -(CH2)3CH(CH3)2, -NH-(CH2)2CH(CH3)2, -NH-(CH2)2CH(CH2CH3)2, -NH-(CH2)2-cyclobutyl, -NH-(CH2)2-cyclopentyl, -NH-(CH2)2-pyrazolyl, -NH-(CH2)2-pyrroleyl, -NH-(CH2)2-imidazolyl, -NH-(CH2)2-pyridyl, -NH-(CH2)2-pyrimidinyl, -NH-(CH2)2-pyridazinyl, -NH-(CH2)2-pyrazinyl, or -NH-(CH2)3-SF5, wherein -O-(CH 2) 2CH(CH3)2, -(CH2)3CH(CH3)2, -NH-(CH2)2CH(CH3)2, -NH-(CH2)2CH(CH2CH3)2, -NH-(CH2)2-cyclobutyl, -NH-(CH2)2-cyclopentyl, -NH-(CH2)2-pyrazolyl, -NH-(CH2)2-pyrroleyl, -NH-(CH2)2-imidazolyl, -NH-(CH2)2-pyridyl, -NH-(CH2)2-pyrimidinyl, -NH-(CH2)2-pyridazinyl, -NH-(CH2)2-pyrazinyl or -NH-(CH2)3-SF5 are each independently and optionally separated by 1, 2, 3 or 4 R e replace; Or, R x1 The following are possible values: H, -O-(CH2)2CH(CH3)2, -(CH2)3CH(CH3)2, -NH-(CH2)2CH(CH3)2, -NH-(CH2)2CH(CH2CH3)2, -NH-(CH2)2-cyclobutyl, -NH-(CH2)2-cyclopentyl, -NH-(CH2)3-SF5. Or, R x1’ H, -NR x11 -C 1-4 Alkylene-S(R) x12 ) w -S(=O)2-NR x11 -C 1-4 Alkyl, -NR x11 -C(R x13 )2-NR x11 -C 1-4 Alkyl, -NR x11 -C 0-4 Alkylene-C 7-10 Monocyclic cycloalkyl, -NR x11 -C 0-4 Alkylene-C 7-10 Bicyclic cycloalkyl, NR x11 -C 0-4 Alkylene-C 7-10 Monocyclic cycloalkenyl, -NR x11 -C 0-4 Alkylene-C 7-10 Bicyclic cycloalkenyl, -NR x11 -C 0-4 Alkylene (with 1, 2, 3 or 4 Rs) ee Replacement C 3-6 cycloalkyl), -NR x11 -C 0-4 Alkylene-7-10-membered monocyclic heterocyclic alkyl, -NR x11 -C 0-4 Alkylene-7-10-membered bicyclic heterocyclic alkyl, -OC 6-8 Bicyclic cycloalkyl, -NR x11 -C 3-6 Cycloalkyl-phenyl, -NR x11 -4-6 membered heterocyclic alkyl-phenyl, -NR x11 -C 8-10 Bicyclic aryl, -NR x11 -5-6 cyclic heteroaryl groups, -NR x11 -8-10 quinone bicyclic heteroaryl, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy, C 3-6 cycloalkyl, (with 1, 2, 3 or 4 Rs) ee Substituted 3-6-membered heterocyclic alkyl groups or 7-10-membered heterocyclic alkyl groups, wherein -NR x11 -C 1-4 Alkylene-S(R) x12 ) w -S(=O)2-NR x11 -C 1-4 Alkyl, -NR x11 -C(R x13 )2-NR x11 -C 1-4 Alkyl, -NR x11 -C 0-4 Alkylene-C 7-10 Monocyclic cycloalkyl, -NR x11 -C 0-4 Alkylene-C 7-10 Bicyclic cycloalkyl, NR x11 -C 0-4 Alkylene-C 7-10 Monocyclic cycloalkenyl, -NR x11 -C 0-4 Alkylene-C 7-10 Bicyclic cycloalkenyl, -NR x11 -C 0-4 Alkylene (with 1, 2, 3 or 4 Rs) ee Replacement C 3-6 cycloalkyl), -NR x11 -C 0-4 Alkylene-7-10-membered monocyclic heterocyclic alkyl, -NR x11 -C 0-4 Alkylene-7-10-membered bicyclic heterocyclic alkyl, -OC 6-8 Bicyclic cycloalkyl, -NR x11 -C 3-6 Cycloalkyl-phenyl, -NR x11 -4-6 membered heterocyclic alkyl-phenyl, -NR x11 -C 8-10 Bicyclic aryl, -NR x11 -5-6 cyclic heteroaryl groups, -NR x11 -8-10 quinone bicyclic heteroaryl, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy, C 3-6 cycloalkyl, (with 1, 2, 3 or 4 Rs) ee The substituted 3-6-membered heterocyclic alkyl groups and 7-10-membered heterocyclic alkyl groups are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. e’ replace; Or, R x1’ H, -NR x11 -C 1-4 Alkylene-S(R) x12 ) w -S(=O)2-NR x11 -C 1-4 Alkyl, -NR x11 -C(R x13 )2-NR x11 -C 1-4 Alkyl, -NR x11 -C 0-4 Alkylene-C7 monocyclic cycloalkyl, -NR x11 -C 0-4 Alkylene-C 7-10 Spirocycloalkyl, -NR x11 -C 0-4 Alkylene-C 7-10 Spirocyclic cycloalkenyl, -NR x11 -C 0-4 Alkylene-C7 fused cycloalkyl, -NR x11 -C 0-4 Alkylene-C7 bridged cycloalkyl, -NR x11 -C 0-4 Alkylene (with 1, 2, 3 or 4 Rs) ee Replacement C 5-6 cycloalkyl), -NR x11 -C 0-4 Alkylene-7-membered monocyclic heterocyclic alkyl, -NR x11 -C 0-4 Alkylene-7-8 membered spirocyclic heterocyclic alkyl, -NR x11 -C 0-4 Alkylene-7-8-membered bridged heterocyclic alkyl, -O-C7 spirocyclic alkyl, -NR x11 -C 3-6 Cycloalkyl-phenyl, -NR x11 -4-6 membered heterocyclic alkyl-phenyl, -NR x11 -C9 fused aryl, -NR x11 -5-6 cyclic heteroaryl groups, -NR x11 -8-9 fused heteroaryl groups, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy, C 3-6 cycloalkyl, (with 1, 2, 3 or 4 Rs) ee The -NR is a substituted 5-6 member monocyclic heterocyclic alkyl group or a 7-10 member bicyclic heterocyclic alkyl group. x11 -C 1-4 Alkylene-S(R) x12 ) w -S(=O)2-NR x11 -C 1-4 Alkyl, -NR x11 -C(R x13 )2-NR x11 -C 1-4 Alkyl, -NR x11 -C 0-4 Alkylene-C7 monocyclic cycloalkyl, -NR x11 -C 0-4 Alkylene-C 7-10 Spirocycloalkyl, -NR x11 -C 0-4 Alkylene-C 7-10 Spirocyclic cycloalkenyl, -NR x11 -C 0-4 Alkylene-C7 fused cycloalkyl, -NR x11 -C 0-4 Alkylene-C7 bridged cycloalkyl, -NR x11 -C 0-4 Alkylene (with 1, 2, 3 or 4 Rs) ee Replacement C 5-6 cycloalkyl), -NR x11 -C 0-4 Alkylene-7-membered monocyclic heterocyclic alkyl, -NR x11 -C 0-4 Alkylene-7-8 membered spirocyclic heterocyclic alkyl, -NR x11 -C 0-4 Alkylene-7-8-membered bridged heterocyclic alkyl, -O-C7 spirocyclic alkyl, -NR x11 -C 3-6 Cycloalkyl-phenyl, -NR x11 -4-6 membered heterocyclic alkyl-phenyl, -NR x11 -C9 fused aryl, -NR x11 -5-6 cyclic heteroaryl groups, -NR x11 -8-9 fused heteroaryl groups, C 1-3 Alkyl, C 2-4 alkenyl, C 2- 4-Alynyl group, C 1-3 Alkoxy, C 3-6 cycloalkyl, (with 1, 2, 3 or 4 Rs) ee The substituted 5-6 membered monocyclic heterocyclic alkyl groups and 7-10 membered bicyclic heterocyclic alkyl groups are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. e’ replace; Or, R x13 H, halogen, C 1-3 Alkyl or C 1-3 Halogenated alkyl, or, two Rs x13 Formation = O; Or, R x1’ It is H, -NH-(CH2)3-SF5, -S(=O)2-NH-CH2CH(CH3)2, -NH-C(=O)-NH-CH(CH3)2, Methyl, ethyl, or cyclopropyl, wherein the -NH-(CH2)3-SF5, -S(=O)2-NH-CH2CH(CH3)2, -NH-C(=O)-NH-CH(CH3)2, ... The methyl, ethyl, or cyclopropyl groups are each independently and optionally surrounded by 1, 2, 3, or 4 R groups. e’ Replace; the Each can be independently and arbitrarily assigned to 1, 2, 3, or 4 R's. ee replace; Or, each R e’ They are H, halogen, OH, and C, respectively. 1-3 Alkyl, C 1-3 Halogenated alkyl or C 3-4 cycloalkyl; Or, each R e’ Each can be independently H, F, OH, methyl, CF3, -CH2CF3 or cyclopropyl; Or, two Rs connected to the same C e’ form Among them, R e3 R e4 Each can be independently H, F, OH, CN, COOH, methyl, ethyl, or propyl; Or, two Rs connected to the same C e’ form Or, each R ee Each independently Or, R x1’ The following are possible combinations of compounds: H, -NH-(CH2)3-SF5, methyl, -CH2CH2OH, -CH2CH2F, cyclopropyl, -S(=O)2-NH-CH2CH(CH3)2, -NH-C(=O)-NH-CH(CH3)2. Or, R x2 -C 1-4 Alkylene-S(R) x12 ) w The -C 1-4 Alkylene-S(R) x12 ) w Independently and optionally by 1, 2, 3 or 4 R g replace; Or, each R g Each can be H or F independently; Or, R x2 It is -(CH2)3-SF5.

3. The compound according to claim 1, its tautomers, stereoisomers, or pharmaceutically acceptable salts, characterized in that, R1 is H, NH2, CN, or -CR 11 =CR 12 R 13 5-6-membered heterocyclic alkyl, phenyl, or 5-6-membered heteroaryl, wherein the 5-6-membered heterocyclic alkyl, phenyl, and 5-6-membered heteroaryl are each optionally and independently bound by 1, 2, 3, or 4 R's. a replace; Or, R 11 R 12 and R 13 Each is independently H, halogen, and C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 3-6 cycloalkyl; Or, R 11 R 12 and R 13 Each can be H or F independently; Alternatively, R1 can be H or -CH = CF2; Or, R 1’ H, halogen, OH, NH2, CN, C 1-3 Alkyl, C 1-3 Alkoxy or C 3-6 cycloalkyl, the C 1-3 Alkyl, C 1-3 Alkoxy and C 3-6 The cycloalkyl groups are each independently and optionally marked with 1, 2, 3 or 4 R's. a’ replace; Or, R 1’ For H; Or, R2 and R 2’ They are, independently, H, halogen, OH, NH2, CN, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, wherein C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl groups are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. b replace; Or, R2 and R 2’ Each of the following groups is independently H, methyl, cyclopropyl, or azircyclopentyl, wherein the methyl, cyclopropyl, and azircyclopentyl groups are each optionally independently surrounded by 1, 2, 3, or 4 R groups. b replace; Or, each R b Each can be independently H, F, OH, NH2, CN, COOH, or methyl; Or, R2 and R 2’ Each is independently H, methyl, cyclopropyl, Or, R3 and R 3’ They are, independently, H, halogen, OH, NH2, CN, and C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy, C 3- 6-membered cycloalkyl or 3-6-membered heterocycloalkyl, wherein C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl groups are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. c replace; Or, R3 and R 3’ Each is independently represented by H; Alternatively, R4 can be H, halogen, or C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy or C 3-6 cycloalkyl, the C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy and C 3-6 The cycloalkyl groups are each independently and optionally marked with 1, 2, 3 or 4 R's. d replace; Alternatively, R4 can be H or F; Alternatively, R5 is F.

4. The compound according to claim 1, its tautomers, stereoisomers, or pharmaceutically acceptable salts, characterized in that, R x1’ For -NR x11 -C 0-6 Alkylene-S(R) x12 ) w The -NR x11 -C 0-6 Alkylene-S(R) x12 ) w Independently and optionally by 1, 2, 3 or 4 R e’ Replace; or, R x1’ It is -NH-(CH2)3-SF5; Or, R x2 -C 0-6 Alkylene-S(R) x12 ) w The -C 0-6 Alkylene-S(R) x12 ) w Independently and optionally by 1, 2, 3 or 4 R g Replace; or, R x2 It is -(CH2)3-SF5.

5. The compound according to claim 1, its tautomers, stereoisomers, or pharmaceutically acceptable salts, characterized in that, The compound shown in formula (I) has the structural formula (I-1): in, R1, R x1 R x1’ R2, R 2’ R4 and R5 are as defined in claim 1; Alternatively, the compound shown in formula (I) has the structural formula (I-1A): in, R x1 For -NR x11 -C 1-10 Alkyl, -NR x11 -C 0-6 Alkylene-C 3-8 cycloalkyl, -NR x11 -C 0-6 alkylene-5-10 heteroaryl or -NR x11 -C 0-6 Alkylene-S(R) x12 ) w The -NR x11 -C 1-10 Alkyl, -NR x11 -C 0-6 Alkylene-C 3-8 cycloalkyl, -NR x11 -C 0-6 alkylene-5-10 heteroaryl and -NR x11 -C 0-6 Alkylene-S(R) x12 ) w Each can be independently and arbitrarily assigned to 1, 2, 3, or 4 R's. e replace; R x1’ C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy or C 3-8 cycloalkyl, the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1- 6-alkoxy and C 3-8 The cycloalkyl groups are each independently and optionally marked with 1, 2, 3 or 4 R's. e’ replace; R x11 R x12 R e R e’ and w As defined in claim 1; Or, R x1 For -NR x11 -C 1-8 Alkyl, -NR x11 -C 1-3 Alkylene-C 3-6 cycloalkyl, -NR x11 -C 1-3 alkylene-5-6-membered heteroaryl or -NR x11 -C 1- 4-alkylene-S(R) x12 ) w The -NR x11 -C 1-8 Alkyl, -NR x11 -C 1-3 Alkylene-C 3-6 cycloalkyl, -NR x11 -C 1-3 alkylene-5-6-membered heteroaryl and -NR x11 -C 1-4 Alkylene-S(R) x12 ) w Each can be independently and arbitrarily assigned to 1, 2, 3, or 4 R's. e replace; Or, R x1 The derivatives are -NH-(CH2)2CH(CH3)2, -NH-(CH2)2-cyclobutyl, -NH-(CH2)2-cyclopentyl, and -NH-(CH2)3-SF5. Or, R x1’ C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy or C 3-6 cycloalkyl, the C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy and C 3-6 The cycloalkyl groups are each independently and optionally marked with 1, 2, 3 or 4 R's. e’ replace; Or, R x1’ It can be methyl, -CH2CH2OH, -CH2CH2F or cyclopropyl; Alternatively, the compound shown in formula (I) has the structural formula (I-1B): in, R x1’ For -NR x11 -C 0-6 Alkylene-S(R) x12 ) w -S (=O) m -NR x11 -C 1-6 Alkyl, -NR x11 -C(R x13 )2-NR x11 -C 1-6 Alkyl, -NR x11 -C 0-6 Alkylene-C 7-10 cycloalkyl, -NR x11 -C 0-6 Alkylene-C 7-10 Cycloalkenyl, -NR x11 -C0-6 alkylene- (with 1, 2, 3 or 4 R's) ee Replacement C 3-6 cycloalkyl), -NR x11 -C 0-6 Alkylene-7-12-membered heterocyclic alkyl, -OC 3-8 cycloalkyl, -NR x11 -C 3-6 cycloalkyl-C 6-12 Aryl, -NR x11 -4-6 membered heterocyclic alkyl-C 6-12 Aryl, -NR x11 -C 6-12 Aryl, -NR x11 -5-12 heteroaryl groups, (with 1, 2, 3 or 4 R groups) ee Substituted 3-6-membered heterocyclic alkyl groups or 7-12-membered heterocyclic alkyl groups, wherein -NR x11 -C 0-6 Alkylene-S(R) x12 ) w 、、-S(=O) m -NR x11 -C 1-6 Alkyl, -NR x11 -C(R x13 )2-NR x11 -C 1-6 Alkyl, -NR x11 -C 0-6 Alkylene-C 7-10 cycloalkyl, -NR x11 -C 0-6 Alkylene-C 7-10 Cycloalkenyl, -NR x11 -C 0-6 Alkylene (with 1, 2, 3 or 4 Rs) ee Replacement C 3-6 cycloalkyl), -NR x11 -C 0-6 Alkylene-7-12-membered heterocyclic alkyl, -OC 3-8 cycloalkyl, -NR x11 -C 3-6 cycloalkyl-C 6-12 Aryl, -NR x11 -4-6 membered heterocyclic alkyl-C 6-12 Aryl, -NR x11 -C 6-12 Aryl, NR x11 -5-12 heteroaryl groups, (with 1, 2, 3 or 4 R groups) ee The substituted 3-6-membered heterocyclic alkyl groups and 7-12-membered heterocyclic alkyl groups are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. e’ Replace; R x11 R x12 R x13 R e’ w and m are as defined in claim 1; Or, R x1’ For -NR x11 -C 1-4 Alkylene-S(R) x12 ) w -S(=O)2-NR x11 -C 1-4 Alkyl, -NR x11 -C(R x13 )2-NR x11 -C 1-4 Alkyl, -NR x11 -C 0-4 Alkylene-C 7-10 Monocyclic cycloalkyl, -NR x11 -C 0-4 Alkylene-C 7-10 Bicyclic cycloalkyl, NR x11 -C 0-4 Alkylene-C 7-10 Monocyclic cycloalkenyl, -NR x11 -C 0-4 Alkylene-C 7-10 Bicyclic cycloalkenyl, -NR x11 -C 0-4 Alkylene (with 1, 2, 3 or 4 Rs) ee Replacement C 3-6 cycloalkyl), -NR x11 -C 0-4 Alkylene-7-10-membered monocyclic heterocyclic alkyl, -NR x11 -C 0-4 Alkylene-7-10-membered bicyclic heterocyclic alkyl, -OC 6-8 Bicyclic cycloalkyl, -NR x11 -C 3-6 Cycloalkyl-phenyl, -NR x11 -4-6 membered heterocyclic alkyl-phenyl, -NR x11 -C 8-10 Bicyclic aryl, -NR x11 -5-6 cyclic heteroaryl groups, -NR x11 -8-10 nucleotides, bicyclic heteroaryl groups (with 1, 2, 3 or 4 R groups) ee Substituted 3-6-membered heterocyclic alkyl groups or 7-10-membered heterocyclic alkyl groups, wherein -NR x11 -C 1-4 Alkylene-S(R) x12 ) w -S(=O)2-NR x11 -C 1-4 Alkyl, -NR x11 -C(R x13 )2-NR x11 -C 1-4 Alkyl, -NR x11 -C 0-4 Alkylene-C 7-10 Monocyclic cycloalkyl, -NR x11 -C 0-4 Alkylene-C 7-10 Bicyclic cycloalkyl, NR x11 -C 0-4 Alkylene-C 7-10 Monocyclic cycloalkenyl, -NR x11 -C 0-4 Alkylene-C 7-10 Bicyclic cycloalkenyl, -NR x11 -C 0-4 Alkylene (with 1, 2, 3 or 4 Rs) ee Replacement C 3-6 cycloalkyl), -NR x11 -C 0-4 Alkylene-7-10-membered monocyclic heterocyclic alkyl, -NR x11 -C 0-4 Alkylene-7-10-membered bicyclic heterocyclic alkyl, -oC 6-8 Bicyclic cycloalkyl, -NR x11 -C 3-6 Cycloalkyl-phenyl, -NR x11 -4-6 membered heterocyclic alkyl-phenyl, -NR x11 -C 8-10 Bicyclic aryl, -NR x11 -5-6 cyclic heteroaryl groups, -NR x11 -8-10 nucleotides, bicyclic heteroaryl groups (with 1, 2, 3 or 4 R groups) ee The substituted 3-6-membered heterocyclic alkyl groups and 7-10-membered heterocyclic alkyl groups are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. e’ Replace; or, R x1’ For -NR x11 -C 1-4 Alkylene-S(R) x12 ) w -S(=O)2-NR x11 -C 1-4 Alkyl, -NR x11 -C(R x13 )2-NR x11 -C 1-4 Alkyl, -NR x11 -C 0-4 Alkylene-C7 monocyclic cycloalkyl, -NR x11 -C 0-4 Alkylene-C 7-10 Spirocycloalkyl, -NR x11 -C 0-4 Alkylene-C 7-10 Spirocyclic cycloalkenyl, -NR x11 -C 0-4 Alkylene-C7 fused cycloalkyl, -NR x11 -C 0-4 Alkylene-C7 bridged cycloalkyl, -NR x11 -C 0-4 Alkylene (with 1, 2, 3 or 4 Rs) ee Replacement C 5-6 cycloalkyl), -NR x11 -C 0-4 Alkylene-7-membered monocyclic heterocyclic alkyl, -NR x11 -C 0-4 Alkylene-7-8 membered spirocyclic heterocyclic alkyl, -NR x11 -C 0-4 Alkylene-7-8-membered bridged heterocyclic alkyl, -O-C7 spirocyclic alkyl, -NR x11 -C 3-6 Cycloalkyl-phenyl, -NR x11 -4-6 membered heterocyclic alkyl-phenyl, -NR x11 -C9 fused aryl, -NR x11 -5-6 cyclic heteroaryl groups, -NR x11 -8-9 fused heteroaryl groups (with 1, 2, 3 or 4 R groups) ee The -NR is a substituted 5-6 member monocyclic heterocyclic alkyl group or a 7-10 member bicyclic heterocyclic alkyl group. x11 -C 1-4 Alkylene-S(R) x12 ) w -S(=O)2-NR x11 -C 1-4 Alkyl, -NR x11 -C(R x13 )2-NR x11 -C 1-4 Alkyl, -NR x11 -C 0-4 Alkylene-C7 monocyclic cycloalkyl, -NR x11 -C 0-4 Alkylene-C 7-10 Spirocycloalkyl, -NR x11 -C 0-4 Alkylene-C 7-10 Spirocyclic cycloalkenyl, -NR x11 -C 0-4 Alkylene-C7 fused cycloalkyl, -NR x11 -C 0-4 Alkylene-C7 bridged cycloalkyl, -NR x11 -C 0-4 Alkylene (with 1, 2, 3 or 4 Rs) ee Replacement C 5-6 cycloalkyl), -NR x11 -C 0-4 Alkylene-7-membered monocyclic heterocyclic alkyl, -NR x11 -C 0-4 Alkylene-7-8 membered spirocyclic heterocyclic alkyl, -NR x11 -C 0-4 Alkylene-7-8-membered bridged heterocyclic alkyl, -O-C7 spirocyclic alkyl, -NR x11 -C 3-6 Cycloalkyl-phenyl, -NR x11 -4-6 membered heterocyclic alkyl-phenyl, -NR x11 -C9 fused aryl, -NR x11 -5-6 cyclic heteroaryl groups, -NR x11 -8-9 fused heteroaryl groups (with 1, 2, 3 or 4 R groups) ee The substituted 5-6 membered monocyclic heterocyclic alkyl group or 7-10 membered bicyclic heterocyclic alkyl group is independently and optionally surrounded by 1, 2, 3 or 4 R groups. e’ replace; Or, R x1’ is -NH-(CH2)3-SF5, S(=O)2-NH-CH2CH(CH3)2, -NH-C(=O)-NH-CH(CH3)2, Alternatively, the compound shown in formula (I) has the structural formula (I-1C) or (I-ID): In equation (1-IC), L1 is the key, -C 0-6 Alkylene-NR x11 -C 0-6 alkylene-, where R x11 It has the definition as described in claim 1; L2, L3, L4, and L5 may be the same or different, and are independently: keys or optional keys controlled by one, two, three, or four Rs. L The following groups are substituted: methylene, ethylene, propylene, -CH2=CH2-, -O-, -N-; R L For H, OH, CN, NH2, oxo (=O), halogen, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkyl groups; L6 is selected from C(R) e’ (R) e’ ), N(R) e’ ), O, S(O)2; L7 is selected from CR L Or N; R1, R 1’ R2, R 2’ R3, R 3’ R4, R5, R e’ It has the definition as described in claim 1; The condition is that, in equation (1-IC), L2 and L3 are not simultaneously bonds; Alternatively, L1 is the key, -C 0-6 Alkylene-NR x11 -or-NR x11 -C 0-6 alkylene-, where R x11 It has the definition as described in claim 1; Or, each R e’ They are independently H, OH, halogen, and C, respectively. 1-6 Alkyl, C 1-6 Haloalkyl; or, two R groups attached to the same C. e’ form Each R e3 R e4 They are independently H, halogen, OH, CN, COOH, and C, respectively. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Or, each R e3 R e4 Each can be independently H, F, OH, CN, COOH, methyl, ethyl, or propyl; Or, two Rs connected to the same C e’ form Or, each R e’ They are independently H, OH, F, CH3, CF3, and CH2CF3, respectively; Or, each R L They are independently H, OH, halogen, and C, respectively. 1-6 Alkyl, C 1-6 Halogenated alkyl groups; Or, each R L They are independently H, OH, F, CH3, CF3, and CH2CF3, respectively; Alternatively, L2 and L3 may not be keys at the same time, and L4 and L5 may not be keys at the same time; Alternatively, L2 and L3 may not be keys simultaneously, while L4 and L5 may be keys; Alternatively, when L4 and L5 are keys, L2 can be arbitrarily assigned to one, two, or three R keys. L The following groups are substituted: methylene, ethylene, propylene, butylene, and L3 is optionally replaced by one, two, or three R groups. L The following groups are substituted: methylene, ethylene, propylene, and butylene; In equation (1-ID), L1 is the key, -C 0-6 Alkylene-NR x11 -C 0-6 alkylene-, where R x11 It has the definition as described in claim 1; L2, L3, L4, and L5 may be the same or different, and are independently: keys or optional keys controlled by one, two, three, or four Rs. L The following groups are substituted: methylene, ethylene, propylene, -CH2=CH2-, -O-, -N-; R L For H, OH, CN, NH2, oxo (=O), halogen, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkyl groups; L6 is selected from C(R) e’ (R) e’ ), N(R) e’ ), O, S(O)2; L7 is selected from CR L Or N; R1, R 1’ R2, R 2’ R3, R 3’ R4, R5, R e’ It has the definition as described in claim 1; Alternatively, L1 is the key, -C 0-6 Alkylene-NR x11 -or-NR x11 -C 0-6 alkylene-, where R x11 It has the definition as described in claim 1; Or, each R e’ They are independently H, OH, halogen, and C, respectively. 1-6 Alkyl, C 1-6 Haloalkyl; or, two R groups attached to the same C. e’ form Each R e3 R e4 They are independently H, halogen, OH, CN, COOH, and C, respectively. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Or, each R e3 R e4 Each can be independently H, F, OH, CN, COOH, methyl, ethyl, or propyl; Or, two Rs connected to the same C e’ form Or, each R e’ Each of the following can be independently H, OH, F, CH3, CF3, CH2CF3; or, each of the following R... L They are independently H, OH, halogen, and C, respectively. 1-6 Alkyl, C 1-6 Halogenated alkyl groups; Or, each R L They are independently H, OH, F, CH3, CF3, and CH2CF3, respectively; Alternatively, when L2 and L3 are keys, L4 can be arbitrarily assigned to one, two, or three R keys. L The following groups are substituted: methylene, ethylene, propylene, butylene, and L5 is optionally replaced by one, two, or three R groups. L The following groups are substituted: methylene, ethylene, propylene, and butylene; Alternatively, when L4 and L5 are keys, L2 can be arbitrarily assigned to one, two, or three R keys. L The following groups are substituted: methylene, ethylene, propylene, butylene, and L3 is optionally replaced by one, two, or three R groups. L The following groups are substituted: methylene, ethylene, propylene, and butylene.

6. The compound according to claim 1, its tautomers, stereoisomers, or pharmaceutically acceptable salts, characterized in that, The compound shown in formula (I) has the structural formula (I-2): in, R1 is NH2, CN, or -CR 11 =CR 12 R 13 3-8 membered heterocyclic alkyl groups, C 6-10 Aryl or 5-10-membered heteroaryl, wherein the 3-8-membered heterocyclic alkyl, C 6- 10 The aryl and 5-10 heteroaryl groups are independently and optionally bounded by 1, 2, 3 or 4 R groups. a replace; R 11 R 12 R 13 R x1 and R a As defined in claim 1; Alternatively, R1 is -CR 11 =CR 12 R 13 The -CR 11 =CR 12 R 13 Independently and optionally by 1, 2, 3 or 4 R a replace; Alternatively, R1 is -CH=CF2.

7. The compound according to claim 1, its tautomers, stereoisomers, or pharmaceutically acceptable salts, characterized in that, The compound shown in formula (I) has the structural formula (I-3): in, R2 can be a halogen, OH, NH2, CN, or C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl or 3-8 membered heterocycloalkyl, wherein C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 The cycloalkyl and 3-8 membered heterocycloalkyl groups are each optionally and independently substituted with 1, 2, 3 or 4 Rb groups; R 2’ R x1 and R b As defined in claim 1; Alternatively, R2 is C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, wherein C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl groups are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. b replace; Alternatively, R2 can be methyl, cyclopropyl, 8. The compound according to claim 1, its tautomers, stereoisomers, or pharmaceutically acceptable salts, characterized in that, Selected from any of the following compounds or their tautomers, stereoisomers or pharmaceutically acceptable salts:

9. The compound according to claim 1, or its tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that, Selected from any of the following compounds or their tautomers, stereoisomers or pharmaceutically acceptable salts:

10. A pharmaceutical composition, characterized in that, It comprises the compound of any one of claims 1-9 or its tautomer, stereoisomer or pharmaceutically acceptable salt; and / or, a pharmaceutically acceptable carrier.

11. Use of the compound according to any one of claims 1-9, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or of the pharmaceutical composition of claim 10, 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.

12. The use according to claim 11, characterized in that, The diseases include solid tumors; and / or, the solid tumors include head and neck cancer, melanoma, non-small cell lung cancer, and clear cell renal cell carcinoma.

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