Protein tyrosine phosphatase inhibitor, pharmaceutical composition and application thereof

Abstract

The invention belongs to the field of medical chemistry, and particularly discloses a protein tyrosine phosphatase inhibitor, a pharmaceutical composition and application of the protein tyrosine phosphatase inhibitor, and the protein tyrosine phosphatase inhibitor is a compound shown in a general formula (I) or pharmaceutically acceptable salt of the compound. The invention also discloses a method for using the protein tyrosine phosphatase inhibitor to treat cancers, metabolic diseases and other related diseases. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry, and in particular relates to a protein tyrosine phosphatase inhibitor or a pharmaceutically acceptable salt thereof, a pharmaceutical composition and use thereof. Background Art

[0002] Protein tyrosine phosphatase non-receptor type 1 (PTPN1), also known as protein tyrosine phosphatase 1B (PTP1B), has been shown to play a key role in insulin and leptin signaling and is the main mechanism for downregulating insulin and leptin receptor signaling pathways. Studies have found that animals lacking PTP1B have improved glucose regulation and lipid profiles and are resistant to weight gain when treated with a high-fat diet. Therefore, PTP1B inhibitors are expected to be useful in the treatment of type 2 diabetes, obesity, and metabolic syndrome. Protein tyrosine phosphatase non-receptor type 2 (PTPN2), also known as T-cell protein tyrosine phosphatase (TCPTP), is an intracellular member of the class 1 subfamily of phospho-tyrosine-specific phosphatases that control multiple cellular regulatory processes in the cytoplasm or nucleus by removing phosphate groups from tyrosine substrates. PTPN2 is ubiquitously expressed in cells, with the highest expression in hematopoietic stem cells and placental cells. In humans, PTPN2 expression is posttranscriptionally controlled by the presence of two splice variants: a 45 kDa form that contains a nuclear localization signal at the C-terminus upstream of the splice junction, and a 48 kDa canonical form with a C-terminal ER retention motif. Both isoforms share an N-terminal phospho-tyrosine phosphatase catalytic domain, and the 45 kDa isoform can be passively imported into the cytosol under certain conditions of cellular stress.

[0003] The PTPN2 catalytic domain shares 74% sequence homology with PTPN1 and has similar enzyme kinetics. Protein tyrosine phosphatases PTPN2 and PTPN1 are negative regulators of multiple cytokine signaling pathways and T cell receptor (TCR) signaling pathways and are key checkpoints in inflammatory responses. PTPN2 and PTPN1 (PTPN2 / N1) inhibit inflammation by removing phosphorylation of JAK and STAT family members. PTPN2 is also a phosphatase for LCK and FYN downstream of TCR signaling, thereby reducing the sensitivity of T cell recognition of antigens. Loss-of-function (LOF) single nucleotide polymorphisms at the PTPN2 locus are associated with several autoimmune diseases, which may be due to the central role of PTPN2 in the regulation of inflammation. Genetic ablation of PTPN2 or PTPN1 in tumor cells enhances the signaling of type I and type II IFNγ3 and increases downstream effects, including cell growth arrest, production of immune cell chemoattractants, and increased antigen presentation. In addition, loss of PTPN2 or PTPN1 enhances T cell expansion, IL-2 response, and the ability to control tumors. Therefore, unlike current treatments, PTPN2 / PTPN1 targeted therapy can achieve a dual anti-cancer mechanism by acting directly on tumor cells and increasing the anti-tumor activity of immune cells, showing its potential as an anti-cancer drug target.

[0004] Data from an in vivo loss-of-function genetic screen using CRISPR / Cas9 genome editing in a mouse B16F10 transplantable tumor model showed that PTPN2 gene deletion in tumor cells improved the response to an immunotherapy regimen of a secreted GM-CSF vaccine (GVAX) plus PD-1 checkpoint blockade. PTPN2 gene deletion sensitized tumors to immunotherapy by enhancing IFNγ-mediated effects on antigen presentation and growth inhibition. The same screen data also revealed that genes known to be involved in immune evasion (including PD-L1 and CD47 blocking antibodies) were also selectively depleted by immunotherapy, while genes involved in the IFNγ signaling pathway (including IFNGR, JAK1, and STAT1) were enriched. These observations suggest that therapeutic strategies to enhance IFNy sensing and signaling have a significant role in enhancing cancer immunotherapy.

[0005] However, in drug discovery, phosphatases are considered undruggable due to their highly polar active sites. The challenges of identifying candidate drugs for phosphatase targets are well known. On the one hand, the catalytic subunits of phosphatases are highly similar, and it is difficult to develop inhibitors targeting a single phosphatase, which can easily cause serious adverse reactions. On the other hand, the active sites of phosphatases have special polarity and charged environments, which means that their active site inhibitors also need to be highly polar, but such inhibitors have low potency and poor pharmacokinetic properties. However, due to the importance of PTPN2 / PTPN1 in tumors and immune cells and the high homology of their active sites, researchers are trying to find a small molecule inhibitor targeting these two phosphatases.

[0006] On October 4, 2023, AbbVie published a preclinical study of the PTPN2 / PTPN1 inhibitor ABBV-CLS-484 in the journal Nature. AC484 is the first known active site phosphatase inhibitor to enter clinical trials for cancer immunotherapy and is currently being evaluated in patients with advanced solid tumors. AC484 is a dual PTPN2 / N1 inhibitor that increases the sensitivity of cancer cells to INF-γ, enhances the activation and effector function of T cells and NK cells, and thus inhibits cell proliferation.

[0007] However, to date, there are few reports on PTPN2 inhibitors based on a naphthalene ring core. WO200706761 first disclosed compounds based on a naphthalene ring core for inhibiting protein tyrosine phosphatase, but the activity was poor. PTPN2 high-activity and high-selectivity inhibitors based on a naphthalene ring core are very promising and worth developing. Summary of the invention SUMMARY OF THE INVENTION

[0009] In view of the shortcomings of the prior art, the purpose of the present invention is to provide a protein tyrosine phosphatase inhibitor based on a naphthalene ring core structure with high activity, low side effects and high selectivity, a pharmaceutical composition and its use, to improve the activity of anti-tumor immune cells. The compound provided by the present invention has a good inhibitory effect on the protein tyrosine phosphatase inhibitor PTPN2 / 1.

[0010] The present invention solves the above technical problems through the following technical solutions.

[0011] In one aspect, the present invention provides a compound as shown in Formula I or a pharmaceutically acceptable salt thereof:

[0012]

[0013] in,

[0014] R 1 Selected from hydrogen, halogen, cyano, C 1 -C6 Alkoxy, -O(CH 2 ) n CN;

[0015] R 2 is selected from -NH-C(O)-NH-C 1 -C 6 Alkyl, -NH-C(O)-NH-6-10-membered aryl, -NH-C(S)-NH-6-10-membered aryl, -NH-C(O)-NH-(CH 2 ) n -3-10 membered heterocycloalkyl, -NH-C(O)-(CH 2 ) n -C 1 -C 6 Alkyl, -NH-C(O)-(CH 2 ) n -C 3 -C 10 Cycloalkyl, -NH-C(O)-(CH 2 ) n -6-10 membered aryl, -NH-(CH 2 ) n -C 3 -C 10 Cycloalkyl, -NH-(CH 2 ) n -C 3 -C 10 Heterocycloalkyl, -NHS(O) 2 -(CH 2 ) n -6-10 membered aryl, -S(O) 2 -(CH 2 ) n -6-10 membered aryl, -C(O)-NH-(CH 2 ) n -C 1 -C 6 Alkyl, -C(O)-NH-(CH 2 ) n -C 3 -C 10 Cycloalkyl, -C(O)-NH-(CH 2 ) n -C 3 -C 10 Heterocycloalkyl, -C(O)-NH-(CH 2 ) n -5-10 membered heteroaryl, -C(O)-NH-(CH 2 ) n-6-10 membered aryl, -C(O)-(CH 2 ) n -C 2 -C 6 Alkenyl, -O-(CH 2 ) n -C 1 -C 6 Alkyl, -O-(CH 2 ) n -C 2 -C 6 Alkenyl, -O-(CH 2 ) n -6-10 membered aryl, -O-(CH 2 ) n -Cyano, -O-(CH 2 ) n -S(O) 2 -NH 2 、-O-(CH 2 ) n -C 3 -C 10 Cycloalkyl, -O-(CH 2 ) n -C 3 -C 10 Heterocycloalkyl, -O-(CH 2 ) n -3-10 membered heterocyclic group, -O-(CH 2 ) n -5-10 membered heteroaryl, -O-(CH 2 ) n -C(O)OC 1 -C 6 Alkyl, -OC(O)-6-10 membered aryl, -OC(O)-(CH 2 ) n -C 1 -C 6 Alkyl, -C 3 -C 10 Heterocycloalkyl-C(O)-C 1 -C 6 The group consisting of alkyl groups,

[0016] R 2 It may be optionally substituted by one or more of the following substituents: halogen, hydroxy, cyano, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, acetylene, C 2 -C 6 Alkenyl, -S(O) 2 -C1 -C 6 Alkyl, -S(O)-C 1 -C 6 Alkyl, NR a R b ;

[0017] R a , R b are each independently selected from hydrogen, C 1 -C 3 alkyl;

[0018] n=0-6.

[0019] As a preferred technical solution, the R 2 Selected from the group consisting of:

[0020]

[0021] As a preferred technical solution, the R 2 It may be optionally substituted with one or more of the following substituents: chloro, fluoro, hydroxy, cyano, methyl, trifluoromethane, acetylene, ethylene, -S(O) 2 -methyl, -S(O)-methyl, amino, ethyl, -N(CH 3 )CH 3 .

[0022] The present invention also provides a compound as shown in Formula II or a pharmaceutically acceptable salt thereof:

[0023]

[0024] X is selected from a bond, -O-, -NH-, -NHC(O)-, -C(O)NH-, -NHC(O)NH-, -NHS(O) 2 -, -OC(O)-, -NHC(S)NH-, -S(O) 2 -, -C(O)-;

[0025] L is a bond or optionally replaced by one or more C 1 -C 6 Alkyl substituted C 1 -C 6 Alkylene;

[0026] R 1 Selected from hydrogen, halogen, cyano, C 1 -C 6 Alkoxy, -O(CH 2 ) n CN;

[0027] R 2a Selected from hydrogen, cyano, C1 -C 6 Alkyl, 6-10 membered aryl, C 3 -C 10 Heterocycloalkyl, C 3 -C 10 Cycloalkyl, 5-10 membered heteroaryl, C 2 -C 6 Alkenyl, -S(O) 2 NH 2 、3-10 membered heterocyclic group、-C(O)OC 1 -C 6 Alkyl, -OC(O)-C 1 -C 6 Alkyl, -C 3 -C 10 Heterocycloalkyl-C(O)-C 1 -C 6 alkyl;

[0028] R 2a It may be optionally substituted by one or more of the following substituents: halogen, hydroxy, cyano, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, acetylene, C 2 -C 6 Alkenyl, -S(O) 2 -C 1 -C 6 Alkyl, -S(O)-C 1 -C 6 Alkyl, NR a R b ;

[0029] R a , R b are each independently selected from hydrogen, C 1 -C 3 alkyl;

[0030] n=0-6.

[0031] As a preferred technical solution, wherein L is selected from the group consisting of:

[0032] key, Where * and # represent R 2a Point of covalent attachment to X.

[0033] As a preferred technical solution, the R 1 Selected from hydrogen, chlorine, fluorine, cyano, methoxy, -OCH 2 CH 3 、-OCH 2 CN、-OCH2 CH 2 CN.

[0034] The present invention also provides a compound as shown in Formula III or a pharmaceutically acceptable salt thereof:

[0035]

[0036] X is selected from a bond, -O-, -NH-, -NHC(O)-, -C(O)NH-, -NHC(O)NH-, -NHS(O) 2 -, -OC(O)-, -NHC(S)NH-, -S(O) 2 -, -C(O)-;

[0037] L is a bond or optionally replaced by one or more C 1 -C 6 Alkyl substituted C 1 -C 6 Alkylene;

[0038] R 2a Selected from hydrogen, cyano, C 1 -C 6 Alkyl, 6-10 membered aryl, C 3 -C 10 Heterocycloalkyl, C 3 -C 10 Cycloalkyl, 5-10 membered heteroaryl, C 2 -C 6 Alkenyl, -S(O) 2 NH 2 、3-10 membered heterocyclic group、-C(O)OC 1 -C 6 Alkyl, -OC(O)-C 1 -C 6 Alkyl, -C 3 -C 10 Heterocycloalkyl-C(O)-C 1 -C 6 alkyl;

[0039] R 2a It may be optionally substituted by one or more of the following substituents: halogen, hydroxy, cyano, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, acetylene, C 2 -C 6 Alkenyl, -S(O) 2 -C 1 -C 6 Alkyl, -S(O)-C 1 -C6 Alkyl, NR a R b ;

[0040] R a , R b are each independently selected from hydrogen, C 1 -C 3 alkyl;

[0041] n=0-6.

[0042] As a preferred technical solution, R 2a is selected from hydrogen, cyano, C 1 -C 6 alkyl,

[0043]

[0044]

[0045] Composed of groups.

[0046] The present invention also provides the following compounds or pharmaceutically acceptable salts thereof, wherein the compound is selected from:

[0047]

[0048]

[0049] The present invention also provides a pharmaceutical composition, comprising any of the above compounds or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0050] The present invention also provides use of any of the above compounds or pharmaceutically acceptable salts thereof or the pharmaceutical composition in the preparation of a drug for treating a disease or condition by inhibiting PTPN1 / PTPN2.

[0051] As a preferred technical solution, the disease or condition is cancer, rheumatic disease, inflammatory disease, immune disease, metabolic disease, infectious disease, neurodegenerative disease, genetic disease, heart disease; the cancer is preferably selected from T-cell acute lymphoblastic leukemia, ovarian cancer, primary mediastinal B-cell lymphoma, bladder cancer, bone cancer, brain cancer, cardia cancer, cervical cancer, colon cancer, colorectal cancer, esophageal cancer, fibrosarcoma, gastric cancer, gastrointestinal cancer, head, spine and neck cancer, leukemia, liver cancer, lymphoma, melanoma, penile cancer, testicular germ cell cancer, thymoma cancer, thymic cancer, lung cancer, ovarian ... Ovarian cancer, prostate cancer, pancreatic cancer, breast cancer, multiple myeloma, melanoma, secretory cell carcinoma, head and neck squamous cell carcinoma, non-small cell lung cancer, renal cell carcinoma; the metabolic disease is preferably selected from non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), liver fibrosis, obesity, type 2 diabetes, heart disease, atherosclerosis, arthritis, cystinosis, phenylketonuria, proliferative retinopathy, metabolic syndrome or Kearns-Sayre's disease; the infectious disease is preferably selected from bubonic plague; the genetic disease is preferably selected from Noonan syndrome, retinopathy.

[0052] Compared with the prior art, the present invention has the following beneficial effects:

[0053] The present invention modifies (ABBV-CLS-484 analogues) by computer-aided design, and screens a variety of novel compounds through computer simulation, molecular docking analysis, and drug structure-activity relationship research. This series of compounds can specifically bind to protein tyrosine phosphatases and inhibit PTPN2 function, and has extremely strong PTPN2 inhibitory activity. In vitro and in vivo experiments further show that this series of compounds can prevent and / or treat pancreatic cancer, breast cancer, multiple myeloma, melanoma, secretory cell carcinoma, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), liver fibrosis, obesity, type 2 diabetes, heart disease, atherosclerosis, arthritis, cystinosis, phenylketonuria, proliferative retinopathy, metabolic syndrome or Kearns-Sell's disease and other diseases. DETAILED DESCRIPTION OF THE INVENTION

[0055] Various aspects and features of the present invention are further described below.

[0056] As used in the specification and the appended claims, the following terms have the following indicated meanings unless indicated to the contrary.

[0057] Abbreviations used herein have their conventional meanings within the fields of chemistry and biology.Chemical structures and formulae shown herein are constructed according to standard rules of chemical valency known in the chemical arts.

[0058] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes examples when the event or circumstance occurs and examples when it does not occur. For example, "optionally substituted aryl" means that the aryl may or may not be substituted, and the description includes substituted aryl and aryl without substitution. "Optionally substituted" and "substituted or unsubstituted" and "unsubstituted or substituted" are used interchangeably herein.

[0059] "Alkyl" refers to a group of straight or branched saturated hydrocarbon groups having 1 to 10 carbon atoms ("C1-C10 alkyl"). In some embodiments, the alkyl group has 1 to 8 carbon atoms ("C1-C8 alkyl"). In some embodiments, the alkyl group has 1 to 6 carbon atoms ("C1-C6 alkyl"), the alkyl group has 1 to 5 carbon atoms ("C1-C5 alkyl"), the alkyl group has 1 to 4 carbon atoms ("C1-C4 alkyl"), the alkyl group has 1 to 3 carbon atoms ("C1-C3 alkyl"), the alkyl group has 1 to 2 carbon atoms ("C1-C2 alkyl"), and the alkyl group has 1 carbon atom ("C1 alkyl"). In some embodiments, the alkyl group has 2 to 6 carbon atoms ("C2-C6 alkyl"). Examples of C1-C6 alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), and n-hexyl (C6). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Each instance of alkyl may independently be optionally substituted, i.e., unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents; such as, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkyl"). In certain embodiments, alkyl groups are unsubstituted C1-C10 alkyl groups (e.g., -CH3). In certain embodiments, alkyl groups are substituted C1-C6 alkyl groups. Common alkyl abbreviations include Me(–CH3), Et(–CH2CH3), iPr(–CH(CH3)2), nPr(–CH2CH2CH3), n–Bu(–CH2CH2CH2CH3), or i–Bu(–CH2CH(CH3)2).

[0060] In some embodiments, "cycloalkyl" is a monocyclic saturated cycloalkyl having 3 to 10 ring carbon atoms ("C3-10 cycloalkyl" or "C3-C10 cycloalkyl"). In some embodiments, cycloalkyl has 3 to 8 ring carbon atoms ("C3-8 cycloalkyl" or "C3-C8 cycloalkyl"). In some embodiments, cycloalkyl has 3 to 6 ring carbon atoms ("C3-6 cycloalkyl" or "C3-C6 cycloalkyl"). In some embodiments, cycloalkyl has 5 to 6 ring carbon atoms ("C5-6 cycloalkyl" or "C5-C6 cycloalkyl"). In some embodiments, cycloalkyl has 5 to 10 ring carbon atoms ("C5-10 cycloalkyl" or "C5-C10 cycloalkyl"). Examples of C5-C6 cycloalkyl include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-C6 cycloalkyl include the aforementioned C5-C6 cycloalkyl as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-C8 cycloalkyl include the aforementioned C3-C6 cycloalkyl as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each example of cycloalkyl is independently unsubstituted ("unsubstituted cycloalkyl") or substituted ("substituted cycloalkyl") with one or more substituents. In certain embodiments, cycloalkyl is an unsubstituted C3-C10 cycloalkyl. In certain embodiments, cycloalkyl is a substituted C3-C10 cycloalkyl.

[0061] "Heterocycloalkyl" refers to a saturated or partially unsaturated ring radical containing two to twenty carbon atoms and at least one heteroatom. In certain embodiments, heteroatoms are independently selected from N, O, Si, P, B and S atoms. Heterocycloalkyl can be selected from a monocyclic or bicyclic ring (fused when fused to an aryl or heteroaryl ring, the heterocycloalkyl is bonded by a non-aromatic ring atom) or a bridged ring system. The heteroatoms in the heterocycloalkyl radical are optionally oxidized. One or more nitrogen atoms (if present) are optionally quaternized. The heterocycloalkyl is connected to the rest of the molecule through any atom of the heterocycloalkyl (valence permitting), such as any carbon atom or nitrogen atom of the heterocycloalkyl. In certain embodiments, the heterocycloalkyl contains 5 to 20 carbon atoms. In certain embodiments, the heterocycloalkyl contains 5 to 10 carbon atoms. In other embodiments, the heterocycloalkyl contains 5 to 7 carbon atoms. In some embodiments, the heterocycloalkyl is fully saturated. Examples of fully saturated heterocycloalkyl radicals include, but are not limited to, 1,4-dioxanyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopiperidinyl, Pyrrolidinyl, oxazolidinyl, oxiranyl, piperidinyl, piperazinyl, 4-piperidinyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1,1-oxo-thiomorpholinyl and 1,1-dioxo-thiomorpholinyl. In some embodiments, the heterocycloalkyl moiety is unsaturated or is also referred to as "heterocycloalkenyl". Examples of heterocycloalkenyl groups include 1,2,3,4-tetrahydropyridinyl, 1,2-dihydropyridinyl, 2-oxo-1,3-dioxolyl, etc.In certain embodiments, the heterocycloalkyl is optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thio, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb- -Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa (t is 1 or 2), -Rb-S(O)tORa (t is 1 or 2), -Rb-S(O)tRa (t is 1 or 2) and -Rb-S(O)tN(Ra)2 (t is 1 or 2), wherein each Ra is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, each Rb is independently a straight bond or a straight or branched alkylene or alkenylene chain, and Rc is a straight or branched alkylene or alkenylene chain, wherein each of the above substituents is unsubstituted unless otherwise specified.

[0062] "Heterocyclyl" or "heterocycle" refers to a 3- to 10-membered non-aromatic ring system radical having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon ("3- to 10-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, when valence permits. A heterocyclyl group may be monocyclic ("monocyclic heterocyclyl") or a fused, bridged or spiro ring system, such as a bicyclic ring system ("bicyclic heterocyclyl"), and may be saturated or may be partially unsaturated. Heterocyclyl bicyclic ring systems may include one or more heteroatoms in one or both rings. "Heterocyclyl" also includes a ring system in which the heterocyclyl ring as defined above is fused to one or more cycloalkyls, wherein the point of attachment is on the cycloalkyl or heterocyclyl ring, or a ring system in which the heterocyclyl ring as defined above is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such cases, the number of ring members continues to represent the number of ring members in the heterocyclyl ring system. Heterocyclyl can be described as, for example, 3- to 7-membered heterocyclyls, wherein the term "member" refers to non-hydrogen ring atoms within the moiety, i.e., carbon, nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. Each example of a heterocyclyl can be independently optionally substituted, for example, unsubstituted ("unsubstituted heterocyclyl") or substituted ("substituted heterocyclyl") by one or more substituents. In certain embodiments, a heterocyclyl is an unsubstituted 3- to 10-membered heterocyclyl. In certain embodiments, a heterocyclyl is a substituted 3- to 10-membered heterocyclyl.

[0063] Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to, aziridine, oxirane, and thiirane. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to, azetidinyl, oxirane, and thiirane. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxathiolanyl, dithiolanyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thiacyclohexyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, triazinyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azepanyl, oxepane and thiepanyl. Exemplary 8-membered heterocyclic groups containing one heteroatom include, but are not limited to, azocyclooctanyl, oxoctanyl and thiecyclooctanyl. Exemplary 5-membered heterocyclic groups fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclic rings) include, but are not limited to, indolyl, isoindolyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinone, etc. Exemplary 6-membered heterocyclic groups fused to an aryl ring (also referred to herein as 6,6-bicyclic heterocyclic rings) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

[0064] Unless otherwise stated, the term "alkylene" by itself or as part of another substituent means a divalent radical derived from an alkyl radical, such as -CH 2 CH 2 CH 2 CH 2 - is exemplified, but not limited thereto. Typically, an alkyl (or alkylene) group will have from 1 to 10 carbon atoms, with those groups having 6 or fewer carbon atoms being preferred in the present disclosure. Unless otherwise stated, the term "alkenylene" alone or as part of another substituent means a divalent group derived from an alkene. The alkylene group may be straight or branched. The alkylene group may be described, for example, as C1-C6 alkylene, which describes an alkylene moiety having between one and six carbon atoms.

[0065] "Haloalkyl" refers to an alkyl group as described herein (e.g., C1-C6 alkyl) in which one or more hydrogen atoms are replaced by halogen (e.g., monohaloalkyl, dihaloalkyl, and trihaloalkyl). Such groups include, but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloro-fluoroalkyl, chloro-difluoroalkyl, and 2-fluoroisobutyl.

[0066] "Alkoxy" refers to an alkyl group as described herein (e.g., C1-C6 alkyl) attached to the molecule through an oxygen atom. This includes groups in which the alkyl portion can be straight or branched, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, and n-hexoxy.

[0067] "Haloalkoxy" refers to an alkoxy group as described herein (e.g., C1-C6 alkoxy) in which one or more hydrogen atoms are replaced by halogen (e.g., monohaloalkoxy, dihaloalkoxy, and trihaloalkoxy). Such groups include, but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloro-fluoroalkoxy, chloro-difluoroalkoxy, and 2-fluoroisobutoxy.

[0068] As used herein, the terms "halogen", "halo" and the like represent fluorine, chlorine, bromine or iodine, and particularly represent fluorine, chlorine and bromine, with fluorine and chlorine being particularly preferred.

[0069] "Amino" refers to the group -NH 2 ; “Cyano” refers to the group -CN; “Hydroxyl” refers to the group –OH.

[0070] "Alkenyl" refers to a group of straight or branched hydrocarbon groups having 2 to 10 carbon atoms, one or more carbon-carbon double bonds, and no triple bonds ("C2-C10 alkenyl"). In some embodiments, alkenyl has 2 to 8 carbon atoms ("C2-C8 alkenyl"). In some embodiments, alkenyl has 2 to 6 carbon atoms ("C2-C6 alkenyl"). In some embodiments, alkenyl has 2 to 5 carbon atoms ("C2-C5 alkenyl"). In some embodiments, alkenyl has 2 to 4 carbon atoms ("C2-C4 alkenyl"). In some embodiments, alkenyl has 2 to 3 carbon atoms ("C2-C3 alkenyl"). In some embodiments, alkenyl has 2 carbon atoms ("C2 alkenyl"). One or more carbon-carbon double bonds may be internal (such as in 2-butenyl) or at the terminal (such as in 1-butenyl). Examples of C2-C4 alkenyl include vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), etc. Examples of C2-C6 alkenyl include the C2-4 alkenyl mentioned above as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), etc. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), etc. Each instance of alkenyl may be independently optionally substituted, for example, unsubstituted ("unsubstituted alkenyl") or substituted ("substituted alkenyl") with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, alkenyl is an unsubstituted C2-C10 alkenyl. In certain embodiments, alkenyl is a substituted C2-C6 alkenyl.

[0071] "Aryl" refers to a group having a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) with 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system ("C6-C14 aryl"). In some embodiments, the aryl has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, the aryl has ten ring carbon atoms ("C10 aryl"; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl has fourteen ring carbon atoms ("C14 aryl"; e.g., anthracenyl). Aryl may be described, for example, as C6-C10 aryl. Aryl includes, but is not limited to, phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Each instance of aryl may be independently optionally substituted, e.g., unsubstituted ("unsubstituted aryl") or substituted ("substituted aryl") with one or more substituents. In certain embodiments, aryl is an unsubstituted C6-C14 aryl. In certain embodiments, aryl is a substituted C6-C14 aryl.

[0072] Representative examples of aryl groups include, but are not limited to:

[0073]

[0074] "Heteroaryl" refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom when valence permits. Heteroaryl bicyclic ring systems may include one or more heteroatoms in one or both rings. "Heteroaryl" also includes ring systems in which a heteroaryl ring as defined above is fused to one or more aryl groups, wherein the point of attachment is on the aryl or heteroaryl ring, and in such cases, the number of ring members refers to the number of ring members in the fused (aryl / heteroaryl) ring system. For bicyclic heteroaryls in which one ring does not contain heteroatoms (e.g., indolyl, quinolyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., the ring carrying the heteroatom (e.g., 2-indolyl), or the ring containing no heteroatoms (e.g., 5-indolyl). Heteroaryls can be described, for example, as 6-10 membered heteroaryls, where the term "membered" refers to non-hydrogen ring atoms within the moiety.

[0075] Exemplary 5-membered heteroaryls containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thienyl. Exemplary 5-membered heteroaryls containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryls containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryls containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryls containing one heteroatom include, but are not limited to, pyridyl and pyridone. Exemplary 6-membered heteroaryls containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryls containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryls containing one heteroatom include, but are not limited to, azacycloheptatrienyl, oxacycloheptenyl, and thiacycloheptenyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolyl, isoquinolyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0076] Unless otherwise indicated, when referring to a specifically named aryl (e.g., phenyl, indane, indenyl, naphthyl ring, etc.), heterocyclyl (e.g., pyrrolidinyl, piperidinyl and morpholinyl), or heteroaryl (e.g., tetrazolyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl and furanyl) group, the reference is intended to include the ring optionally having 0 to 3, preferably 0 to 2, substituents selected from the substituents listed above for the arylheterocyclyl and / or heteroaryl groups.

[0077] As described herein, the term "pharmaceutically acceptable salt" means that the salt is not only physiologically acceptable to the subject, but also refers to a synthetic substance that has pharmaceutical use value, such as a salt formed as an intermediate when performing chiral separation. Although the salt of this intermediate cannot be directly administered to the subject, the salt can play a role in obtaining the final product of the present invention.

[0078] The cancer treatments of the present invention include standard treatments such as surgery, radiation therapy, chemotherapy and hormone therapy.

[0079] "Cancer" includes T-cell acute lymphoblastic leukemia, ovarian cancer, primary mediastinal B-cell lymphoma, bladder cancer, bone cancer, brain cancer, cardia cancer, cervical cancer, colon cancer, colorectal cancer, esophageal cancer, fibrosarcoma, gastric cancer, gastrointestinal cancer, head, spine and neck cancer, leukemia, liver cancer, lymphoma, melanoma, penile cancer, testicular germ cell cancer, thymoma cancer, thymic cancer, lung cancer, ovarian cancer, prostate cancer, pancreatic cancer, breast cancer, multiple myeloma, melanoma, secretory cell carcinoma, head and neck squamous cell carcinoma, non-small cell lung cancer, renal cell carcinoma, etc. The "metabolic disease" includes non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), liver fibrosis, obesity, type 2 diabetes, heart disease, atherosclerosis, arthritis, cystinosis, phenylketonuria, proliferative retinopathy, metabolic syndrome or Kearns-Sayre's disease.

[0080] The compounds of the present invention or pharmaceutical compositions containing the same can be administered in unit dosage form, and the administration route can be enteral or parenteral, such as oral, intravenous, intramuscular, intravenous drip, subcutaneous injection, nasal cavity, oral mucosa, eyes, lungs and respiratory tract, skin, vagina, rectum, etc.

[0081] The term "PTPN2" refers to type 2 non-receptor protein tyrosine phosphatase. The term "PTPN1" refers to type 1 non-receptor protein tyrosine phosphatase (PTPN1), also known as protein tyrosine phosphatase-1B (PTP1B).

[0082] In order to achieve the purpose of medication and enhance the therapeutic effect, the drug or pharmaceutical composition of the present invention can be administered by any known administration method.

[0083] The compound or composition of the present invention can be taken alone or in combination with other therapeutic drugs or symptomatic drugs. When the compound of the present invention has a synergistic effect with other therapeutic drugs, its dosage should be adjusted according to the actual situation.

[0084] Beneficial technical effects

[0085] The inventors have found that the compounds of the present invention have good protein tyrosine phosphatase inhibitory activity, IC 50 or EC 50 The present invention provides a class of protein tyrosine phosphatase inhibitor compounds with novel structure and strong activity, which have good application prospects in preventing and / or treating indications related to protein tyrosine phosphatase PTPN2 / 1 inhibition, such as cancer, metabolic diseases, etc. DETAILED DESCRIPTION

[0086] The following embodiments are intended to help those skilled in the art better understand the technical solutions of the present invention, but are not intended to limit the present invention in any way.

[0087] For all the following examples, standard procedures and methods known to those skilled in the art can be used. Unless otherwise indicated, all temperatures are expressed in ° C (Celsius). The structures of the compounds are determined by nuclear magnetic resonance spectroscopy (NMR) and / or mass spectroscopy (MS).

[0088] The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). The NMR chemical shift (δ) is in parts per million (ppm). The NMR was measured using a Bruker avance-400 NMR spectrometer, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ), and the internal standard was tetramethylsilane (TMS).

[0089] Liquid phase mass spectrometry LC-MS measurement The liquid phase part uses ACQUITY UPLC ultra-high pressure liquid chromatography, and the mass spectrometry part uses Xevo G2-S Qtof mass spectrometer.

[0090] The starting materials in the examples of the present invention are known and can be purchased commercially, or can be synthesized using or according to methods known in the art.

[0091] Example 011: Synthesis of 5-[3-hydroxy-7-(3-hydroxy-3-methylbutyloxy)-1-methoxynaphthalen-2-yl]-1,2,5-thiadiazoline-3-one 1,1-dioxide

[0092] Intermediate: 5-[3-(Benzyloxy)-7-bromo-1-fluoronaphthalen-2-yl]-1,2,5-thiadiazolin-3-one-1,1-dioxide Synthesis of

[0093]

[0094] Step 1: Synthesis of 3-(Benzyloxy)-7-bromo-2-naphthoic acid benzyl ester

[0095] 7-Bromo-3-hydroxy-2-naphthoic acid (100.0 g, 374.4 mmol, 1.0 eq.), cesium carbonate (366.0 g, 1120.0 mmol, 3.0 eq.) and benzyl bromide (128.08 g, 748.8 mmol, 2.0 eq.) were added to N,N-dimethylformamide (500 mL) in sequence, and the temperature was raised to 50°C for 2.5 hours. After the reaction was completed, 1 liter of water was added for dilution, and then extracted with ethyl acetate three times. The organic phases were combined, washed three times with saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, and the filtrate was dried to obtain a white solid product, 3-(benzyloxy)-7-bromo-2-naphthoic acid benzyl ester (95.6 g, yield 57.62%). LCMS (ESI) [M+H] + :446.1. 1 H NMR (400 MHz, DMSO-d 6 )δ8.28(s,1H),8.24(d,J=2.0Hz,1H),7.81(d,J=8.8Hz,1H),7.66(dd,J=8.8,2.1Hz, 1H),7.62(s,1H),7.46(d,J=6.4Hz,2H),7.44–7.28(m,8H),5.33(s,2H),5.25(s,2H).

[0096] Step 2: Synthesis of 3-(benzyloxy)-7-bromo-2-naphthoic acid

[0097] Dissolve 3-(Benzyloxy)-7-bromo-2-naphthoic acid benzyl ester (95.0 g, 212.4 mmol, 1.0 eq.) in a mixed solution of (300 mL) water and methanol (600 mL), add lithium hydroxide, heat to 70°C, react for 2 hours, dilute with 1.8 L of water, adjust pH to 3 with dilute hydrochloric acid (2 M), and filter to obtain a white solid product 3-(benzyloxy)-7-bromo-2-naphthoic acid (72.0 g, yield 94.91%). LCMS (ESI) [M+H] + :356.0. 1 H NMR (400 MHz, DMSO-d 6)δ8.03(d,J=2.0Hz,1H),7.74(s,1H),7.69(d,J=8.8Hz,1H),7.53(d,J=7.1Hz,2H), 7.49(dd,J=8.8,2.1Hz,1H),7.40–7.33(m,3H),7.29(t,J=7.3Hz,1H),5.20(s,2H).

[0098] Step 3: Synthesis of tert-butyl [3-(benzyloxy)-7-bromonaphthalen-2-yl]carbamate

[0099] 3-(Benzyloxy)-7-bromo-2-naphthoic acid (30.0 g, 84.0 mol, 1.0 eq.), triethylamine (9.35 g, 92.4 mmol, 1.1 eq.), 4A molecular sieve (30 g) were mixed with toluene (300 mL) and tert-butyl alcohol (300 mL), nitrogen was introduced to replace the gas for 5 minutes, and the mixture was reacted at 80°C for 1 hour. After cooling to room temperature, diphenylphosphoryl azide (16.0 ml, 92.4 mmol, 1.1 eq) was slowly added dropwise under nitrogen protection, and the temperature was raised to 80°C for 12 hours. After the reaction is completed, water is added to dilute and filtered, the filter cake is washed with ethyl acetate, the filtrate is extracted three times with ethyl acetate, the organic phases are combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and spin-dried to obtain a white solid product [3-(benzyloxy)-7-bromonaphthalen-2-yl]carbamic acid tert-butyl ester (26.00 g, yield 76.62%). [M+H] + :427.1. 1 H NMR(400MHz,Chloroform-d)δ8.46(s,1H),7.88(d,J=2.0Hz,1H),7.50–7.43( m,5H),7.43–7.39(m,2H),7.35(s,1H),7.13(s,1H),5.23(s,2H),1.55(s,9H).

[0100] Step 4: Synthesis of N-[3-(benzyloxy)-7-bromonaphthalen-2-yl]-N-(tert-butoxycarbonyl)glycine methyl ester

[0101] Under ice bath, tert-butyl (3-(benzyloxy)-7-bromonaphthalene-2-yl)carbamate (50.0g, 116.7mmol, 1.0eq.) and N,N-dimethylformamide (500mL) were mixed, and then 60% sodium hydride (5.14g, 128.4mmol, 1.1eq.) was added, and the reaction was continued for 20 minutes, and then methyl bromoacetate (24.4g, 140.1mmol, 1.2eq.) was added, and the reaction was continued for 1 hour under ice bath. After the reaction was completed, 1 liter of water was added to dilute, and then extracted with ethyl acetate three times, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a white solid product N-[3-(benzyloxy)-7-bromonaphthalene-2-yl]-N-(tert-butoxycarbonyl)glycine methyl ester (47.8g, yield 83.27%). LCMS (ESI) [M+H] + :500.1. 1 H NMR (400 MHz, DMSO-d 6 )δ8.16(s,1H),7.85(s,1H),7.78(d,J=8.8Hz,1H),7.60–7.55(m,2H),7.50(d,J=7.5Hz,2H),7.41(t,J=7 .4Hz, 2H), 7.34 (t, J = 7.3Hz, 1H), 5.24 (d, J = 18.4Hz, 2H), 3.67 (d, J = 11.6Hz, 3H), 1.30 (d, J = 69.9Hz, 9H).

[0102] Step 5: Synthesis of [3-(benzyloxy)-7-bromonaphthalen-2-yl]glycine methyl ester

[0103] Add N-[3-(Benzyloxy)-7-bromonaphthalene-2-yl]-N-(tert-butoxycarbonyl)glycine methyl ester (47.5g, 94.9mmol, 1.0eq.) to dichloromethane (300mL), slowly add trifluoroacetic acid (150mL) at 0℃, and after the addition is complete, naturally warm to room temperature and react for 1 hour. After the reaction is completed, add saturated sodium bicarbonate until the reaction solution is neutral, extract with ethyl acetate three times, combine the organic phases, and wash with saturated brine. Dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a white solid product [3-(Benzyloxy)-7-bromonaphthalene-2-yl]glycine methyl ester (34.5g, 90.79%). LCMS (ESI) [M+H] + :400.1. 1 H NMR (400 MHz, DMSO-d 6)δ7.76(d,J=2.0Hz,1H),7.59–7.51(m,3H),7.42(t,J=7.3Hz,2H),7.38–7.31(m,2H),7.22(dd,J=8 .5,2.0Hz,1H),6.67(s,1H),5.81(t,J=6.2Hz,1H),5.27(s,2H),4.07(d,J=6.1Hz,2H),3.66(s,3H).

[0104] Step 6: Synthesis of [3-(benzyloxy)-7-bromo-1-fluoronaphthalen-2-yl]glycine methyl ester

[0105] Dissolve the selective fluorine reagent (48.85 g, 137.9 mmol, 1.6 eq.) in N,N-dimethylformamide (400 mL), add a solution of [3-(benzyloxy)-7-bromonaphthalene-2-yl]glycine methyl ester (34.5 g, 86.19 mmol, 1.0 eq.) in N,N-dimethylformamide (300 mL) dropwise at 0°C, and react for 10 minutes at 0°C. After the reaction is completed, add 10% ethanol solution, solid precipitates, filter under reduced pressure, and dry to obtain a yellow solid product [3-(benzyloxy)-7-bromo-1-fluoronaphthalene-2-yl]glycine methyl ester crude product (27.8 g, crude, 50% purity). LCMS (ESI) [M+H] + :420.0.

[0106] Step 7: Synthesis of N-[3-(benzyloxy)-7-bromo-1-fluoronaphthalen-2-yl]-N-[N-(tert-butoxycarbonyl)sulfamoyl]glycine methyl ester

[0107] Under ice bath, sulfonyl chloride isocyanate (16.9 ml, 193.6 mmol, 3.0 eq.) was mixed with dichloromethane (300 mL), tert-butanol (24.7 ml, 193.6 mmol, 3.0 eq.) was added dropwise, and the mixture was reacted for 30 minutes. A mixed solution of [3-(benzyloxy)-7-bromo-1-fluoronaphthalen-2-yl]glycine methyl ester (27.0 g, 64.6 mmol, 1.0 eq.), triethylamine (24.7 ml, 258.2 mmol, 4.0 eq.) and dichloromethane (300 mL) was added dropwise to the reaction solution. After the addition was completed, the mixture was naturally heated to room temperature and the reaction was continued for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain brown solid N-[3-(benzyloxy)-7-bromo-1-fluoronaphthalen-2-yl]-N-[N-(tert-butyloxycarbonyl)sulfamoyl]glycine methyl ester, which was directly used in the next reaction (30 g, crude product). LCMS (ESI) [M+H] + :597.0.

[0108] Step 8: Synthesis of N-[3-(benzyloxy)-7-bromo-1-fluoronaphthalen-2-yl]-N-aminosulfonylglycine methyl ester

[0109] Trifluoroacetic acid (100 mL) was slowly added to a dichloromethane (300.0 mL) solution of the compound N-[3-(benzyloxy)-7-bromo-1-fluoronaphthalene-2-yl]-N-[N-(tert-butoxycarbonyl)aminosulfonyl]glycine methyl ester (30.0 g, crude product) at 0°C, and then the mixture was reacted at room temperature for 1 hour. After the reaction was completed, saturated sodium bicarbonate was added to neutralize the mixture until it was weakly alkaline, and the mixture was extracted with ethyl acetate three times, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then slurried with a small amount of acetonitrile, filtered, and the filtrate was separated with a normal phase column, ethyl acetate and petroleum ether system, and when the ethyl acetate was 60%, a brown solid product N-[3-(benzyloxy)-7-bromo-1-fluoronaphthalene-2-yl]-N-aminosulfonylglycine methyl ester (5.2 g, 17.3%) was obtained. LCMS (ESI) [M+H] + :499.0. 1 HNMR (400 MHz, DMSO-d 6 )δ8.13(d,J=1.9Hz,1H),7.84(dd,J=8.9,1.2Hz,1H),7.69(dd,J=8.8,2.0Hz,1H),7.58(d,J=7.0Hz,2H),7.47–7.39( m,3H),7.36(d,J=7.3Hz,1H),7.11(s,2H),5.28(s,2H),4.50(d,J=17.8Hz,1H),4.34(d,J=17.8Hz,1H),3.57(s,3H).

[0110] Step 9: Synthesis of 5-[3-(benzyloxy)-7-bromo-1-fluoronaphthalen-2-yl]-1,2,5-thiadiazolin-3-one-1,1-dioxide

[0111] To a solution of compound N-(3-(benzyloxy)-7-bromo-1-fluoronaphthalen-2-yl)-N-aminosulfonylglycine methyl ester (5.2 g, 10.4 mmol, 1.0 eq.) in tetrahydrofuran (40.0 mL), sodium methoxide solution (4.65 mL, 20.9 mmol, 2.0 eq.) was added and reacted at room temperature for 1 hour. After the reaction was completed, the solid was filtered out and purified by reverse phase column, 0.1% trifluoroacetic acid and acetonitrile system, when acetonitrile was 55%, the product 5-[3-(benzyloxy)-7-bromo-1-fluoronaphthalen-2-yl]-1,2,5-thiadiazoline-3-one-1,1-dioxide (1.5 g, yield 28.8%) was obtained. LCMS (ESI) [MH] - :464.9. 1H NMR (400 MHz, DMSO-d 6 )δ8.10(d,J=1.9Hz,1H),7.84–7.79(m,1H),7.66(dd,J=8.8,2.0Hz,1H),7.58–7.53(m,2H),7.47–7.27(m,5H),5.26(s,2H),4.09(s,2H).

[0112] 5-[3-Hydroxy-7-(3-hydroxy-3-methylbutyloxy)-1-methoxynaphthalen-2-yl]-1,2,5-thiadiazoline-3- Synthesis of Ketone 1,1-Dioxide

[0113]

[0114] Step 1: Synthesis of 5-[3-(benzyloxy)-7-bromo-1-methoxynaphthalen-2-yl]-1,2,5-thiadiazolin-3-one 1,1-dioxide

[0115] Compound N-[3-(benzyloxy)-7-bromo-1-fluoronaphthalen-2-yl]-N-sulfamoylglycine methyl ester (5.2 g, 10.21 mmol, 1.0 eq.), sodium methoxide (2.2 g, 40.84 mmol, 4.0 eq.) and tetrahydrofuran (70 mL) were mixed and reacted at room temperature for 2 hours. After the reaction was completed, vacuum concentration was performed and then the mixture was separated and purified by reverse phase column. A 1% trifluoroacetic acid aqueous solution and acetonitrile system was used. When the acetonitrile was 45%, a yellow solid product 5-[3-(benzyloxy)-7-bromo-1-methoxynaphthalen-2-yl]-1,2,5-thiadiazoline-3-one 1,1-dioxide (1.1 g, yield 22.6%) was obtained. LCMS (ESI) [M+H]+: 479.0. 1 H NMR (400 MHz, DMSO-d 6 )δ8.13(d,J=2.0Hz,1H),7.72(d,J=8.9Hz,1H),7.57(m,J=8.0,4.0,1.6Hz, 3H),7.40-7.26(m,3H),7.21(s,1H),5.20(s,2H),4.11(s,3H),4.08(s,2H).

[0116] Step 2: Synthesis of 5-[3-(benzyloxy)-7-(3-hydroxy-3-methylbutyloxy)-1-methoxynaphthalen-2-yl]-1,2,5-thiadiazolin-3-one 1,1-dioxide

[0117] 5-[3-(Benzyloxy)-7-bromo-1-methoxynaphthalen-2-yl]-1,2,5-thiadiazoline-3-one 1,1-dioxide (350.0 mg, 0.73 mmol, 1.0 eq.) and cesium carbonate (477.8 mg, 1.46 mmol, 2.0 eq.) were added to N,N-dimethylformamide (2 mL), followed by the addition of [(2-di-tert-butylphosphino-3-methoxy-6-methyl-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2-aminobiphenyl)]methanesulfonate palladium (II) (63.5 mg, 0.07 mmol, 0.1 eq.), nitrogen replacement, heating to 100°C, and reaction for 12 hours. After the reaction, the mixture was filtered and the filtrate was prepared, separated and purified to obtain a yellow solid product 5-[3-(benzyloxy)-7-(3-hydroxy-3-methylbutyloxy)-1-methoxynaphthalen-2-yl]-1,2,5-thiadiazoline-3-one 1,1-dioxide (39 mg, yield 10.99%). LCMS (ESI) [M+H] + :501.2. 1 H NMR (400 MHz, DMSO-d 6 )δ7.71(d,J=8.9Hz,1H),7.55-7.50(m,2H),7.39-7.31(m,4H),7.24(s,1H),7.16(dd,J=8.9,2.6Hz,1 H), 5.18 (s, 2H), 4.37 (s, 2H), 4.19 (t, J = 7.2Hz, 2H), 4.06 (s, 3H), 1.90 (t, J = 7.1Hz, 2H), 1.20 (s, 6H).

[0118] Step 3: Synthesis of 5-[3-hydroxy-7-(3-hydroxy-3-methylbutyloxy)-1-methoxynaphthalen-2-yl]-1,2,5-thiadiazolin-3-one 1,1-dioxide

[0119] The compound 5-[3-(benzyloxy)-7-(3-hydroxy-3-methylbutyloxy)-1-methoxynaphthalene-2-yl]-1,2,5-thiadiazoline-3-one 1,1-dioxide (50 mg, 0.10 mmol, 1.0 eq) was dissolved in THF (1 mL), 5% palladium carbon (21.4 mg, 0.20 mmol, 2.0 eq.) was added, hydrogen was replaced, and the reaction was carried out at room temperature for 12 hours. After the reaction was completed, the mixture was filtered, and the filtrate was prepared, separated and purified to obtain a yellow solid product 5-[3-hydroxy-7-(3-hydroxy-3-methylbutyloxy)-1-methoxynaphthalene-2-yl]-1,2,5-thiadiazoline-3-one 1,1-dioxide (22 mg, yield 53.6%). LCMS (ESI) [M+H] + :411.1. 1H NMR (400 MHz, Methanol-d 4 )δ7.56(d,J=9.0Hz,1H),7.35(s,1H),7.08(dd,J=8.8,2.4Hz,1H),6.99(s,1H),4. 44(s,2H),4.23(t,J=6.8Hz,2H),4.11(s,3H),2.03(t,J=6.8Hz,2H),1.32(s,6H).

[0120] Example 014: Synthesis of 5-{7-[(2-oxaspiro[3.3]heptane-6-yl)oxy]-3-(benzyloxy)-1-fluoronaphthalen-2-yl}-1,2,5-thiadiazoline-3-one-1,1-dioxide

[0121]

[0122] Step 1: Synthesis of 2-oxaspiro[3.3]heptane-6-yl 4-methylbenzenesulfonate

[0123] 2-Oxaspiro[3.3]heptane-6-ol (500 mg, 4.4 mmol, 1.0 eq.), triethylamine (1.1 g, 10.9 mmol, 2.5 eq.), 4-dimethylaminopyridine (53.7 mg, 0.44 mmol, 0.1 eq.) were dissolved in dichloromethane (10 mL), p-toluenesulfonyl chloride (912 mg, 4.8 mmol, 1.1 eq.) was added under stirring, and the mixture was reacted at room temperature for 3 hours. After the reaction was complete, the sample was mixed with silica gel, and purified by normal phase column separation (ethyl acetate content was 30%) to obtain colorless liquid 2-oxaspiro[3.3]heptane-6-yl 4-methylbenzenesulfonate (870 mg, yield 73.8%). 1H NMR (400MHz, DMSO) δ7.80–7.72(m,2H),7.47(d,J=8.1Hz,2H),4.67(p,J=7.2Hz,1H),4.45( d,J=16.6Hz,4H),2.47(m,J=7.1,3.1Hz,2H),2.42(s,3H),2.21(m,J=10.3,7.3,3.2Hz,2H).

[0124] Step 2: Synthesis of 5-[3-(benzyloxy)-1-fluoro-7-hydroxynaphthalen-2-yl]-1,2,5-thiadiazolin-3-one-1,1-dioxide

[0125] 5-[3-(Benzyloxy)-7-bromo-1-fluoronaphthalen-2-yl]-1,2,5-thiadiazolin-3-one-1,1-dioxide (200 mg, 0.43 mmol, 1.0 eq.), cesium carbonate (421 mg, 1.29 mmol, 3.0 eq.), methanesulfonyl[2-(di-tert-butylphosphino)-3-methoxy-6-methyl-2',4',6'-triisopropyl-1,1'-biphenyl](2'-amino-1,1'-biphenyl-2-yl)palladium(II) (36.1 mg, 0.04 mmol, 0.1 eq.) and water (23.0 mg, 1.29 mmol, 3.0 eq.) were dissolved in N,N-dimethylformamide (3 mL), replaced with nitrogen, and reacted at 100°C for 16 hours. After the reaction is complete, the mixture is filtered and the filtrate is subjected to formic acid / water inversion to obtain a brown solid 5-[3-(benzyloxy)-1-fluoro-7-hydroxynaphthalen-2-yl]-1,2,5-thiadiazoline-3-one-1,1-dioxide (160 mg, yield 93.0%). LCMS (ESI) [MH]-: 401.04. 1H NMR (400 MHz, DMSO) δ 8.45 (s, 1H), 7.95 (s, 1H), 7.67 (d, J = 8.8 Hz, 1H), 7.56-7.53 (m, 2H), 7.38-7.29 (m, 3H), 7.22 (s, 1H), 7.15-7.10 (m, 2H), 5.19 (s, 2H), 4.07 (s, 2H).

[0126] Step 3: Synthesis of 5-{7-[(2-oxaspiro[3.3]heptane-6-yl)oxy]-3-(benzyloxy)-1-fluoronaphthalen-2-yl}-1,2,5-thiadiazolin-3-one-1,1-dioxide

[0127] 5-[3-(Benzyloxy)-1-fluoro-7-hydroxynaphthalen-2-yl]-1,2,5-thiadiazolin-3-one-1,1-dioxide (160 mg, 0.4 mmol, 1.0 eq.), 2-oxaspiro[3.3]heptane-6-yl 4-methylbenzenesulfonate (106.7 mg, 0.4 mmol, 1.0 eq.) and cesium carbonate (651.6 mg, 2.0 mmol, 5.0 eq.) were dissolved in N,N-dimethylformamide (1.5 mL) and reacted at 80°C for 1 hour. After the reaction is complete, the mixture is filtered and the filtrate is subjected to formic acid / water inversion to obtain a white solid 5-{7-[(2-oxaspiro[3.3]heptane-6-yl)oxy]-3-(benzyloxy)-1-fluoronaphthalen-2-yl}-1,2,5-thiadiazoline-3-one-1,1-dioxide (14 mg, yield 7.0%). LCMS (ESI) [MH]-: 497.11. 1H NMR (400MHz, DMSO) δ7.74 (d, J = 8.9 Hz, 1H), 7.55 (d, J = 7.3 Hz, 2H), 7.34-7.26 (m, 2H), 7.22 (d, J = 2.2 Hz, 1H), 7.13 (m, J = 8.9, 2.4 Hz, 1H), 7.11-7.06 (m, 2H), 6.97 (d, J = 2. 2Hz,1H),5.21(d,J=2.2Hz,2H),4.79–4.69(m,1H),4.66(d,J=2.2Hz,2H),4.54(d,J =2.2Hz, 2H), 4.09 (d, J = 2.2Hz, 2H), 2.88–2.81 (m, 2H), 2.27 (m, J = 13.1, 3.3Hz, 2H).

[0128] Step 4: Synthesis of 5-{7-[(2-oxaspiro[3.3]heptane-6-yl)oxy]-3-(benzyloxy)-1-fluoronaphthalen-2-yl}-1,2,5-thiadiazolin-3-one-1,1-dioxide

[0129] 5-{7-[(2-oxaspiro[3.3]heptane-6-yl)oxy]-3-(benzyloxy)-1-fluoronaphthalene-2-yl}-1,2,5-thiadiazoline-3-one-1,1-dioxide (14 mg, 0.03 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (0.5 mL), and palladium carbon catalyst (Pd / C) (14 mg) was added. After replacing hydrogen, the mixture was reacted at room temperature for 2 hours. After the reaction was complete, N,N-dimethylformamide (2 ml) was added to assist in dissolution. After filtering, tetrahydrofuran was removed under reduced pressure. The filtrate was reversed with acetonitrile / ammonium bicarbonate water to obtain a white solid 5-{7-[(2-oxaspiro[3.3]heptane-6-yl)oxy]-3-(benzyloxy)-1-fluoronaphthalene-2-yl}-1,2,5-thiadiazoline-3-one-1,1-dioxide (4.8 mg, yield 42%). LCMS(ESI)[MH]-:407.06.1HNMR(400MHz,CD3OD)δ7.59(d,J=8.8Hz,1H),7.12–7.04(m,2H),7.02(s,1H),4.94(s ,1H),4.80(s,2H),4.70(s,2H),4.40(s,2H),2.89(m,J=10.0,6.7,3.2Hz,2H),2.36(m,J=10.2,6.5,3.1Hz,2H).

[0130] Example 018: Synthesis of N-[7-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-8-fluoro-6-hydroxynaphthalen-2-yl]-3-hydroxy-3-methylbutanamide

[0131]

[0132] Step 1: Synthesis of tert-butyl [6-(benzyloxy)-7-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-8-fluoronaphthalen-2-yl]carbamate

[0133] To a solution of the compound 5-[3-(benzyloxy)-7-bromo-1-fluoronaphthalen-2-yl]-1,2,5-thiadiazoline-3-one-1,1-dioxide (1.5 g, 3.22 mmol, 1.0 eq.) in toluene (30.0 mL) were added potassium carbonate (1.34 g, 9.67 mmol, 3.0 eq.), tert-butyl carbamate (1.51 g, 12.90 mmol, 4.0 eq.), N,N'-dimethylethylenediamine (284.2 mg, 3.22 mmol, 1.0 eq.) and cuprous iodide (614.0 mg, 3.22 mmol, 1.0 eq.), the gas was replaced with nitrogen for 5 minutes, and the mixture was refluxed at 100°C with stirring for 16 hours. After the reaction was completed, the solid was removed by filtration and concentrated under reduced pressure to obtain a brown solid [6-(benzyloxy)-7-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-8-fluoronaphthalen-2-yl]carbamic acid tert-butyl ester (1.0 g, yield 66.7%). LCMS (ESI) [MH] - :500.1.

[0134] Step 2: Synthesis of 5-[7-amino-3-(benzyloxy)-1-fluoronaphthalen-2-yl]-1,2,5-thiadiazolin-3-one-1,1-dioxide

[0135] Dissolve tert-butyl [6-(benzyloxy)-7-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-8-fluoronaphthalen-2-yl]carbamate (1.0 g, 1.0 eq.) in dichloromethane (20.0 mL), add trifluoroacetic acid (10.0 mL), and react at room temperature for 1 hour. After the reaction is completed, adjust the pH to neutral with saturated sodium bicarbonate solution, add dichloromethane, extract three times, combine the organic phases, concentrate under reduced pressure, and purify by reverse phase column, water (0.1% formic acid) and acetonitrile system, the product flows out when the acetonitrile content is 35%, and obtain white solid 5-[7-amino-3-(benzyloxy)-1-fluoronaphthalen-2-yl]-1,2,5-thiadiazolin-3-one 1,1-dioxide (230 mg, yield 23.0%). LCMS (ESI) [MH] - :400.1. 1 H NMR (400 MHz, DMSO-d 6 )δ8.31(s,2H),7.55–7.49(m,3H),7.35(dd,J=8.1,6.3Hz,2H),7.32–7.28(m,1H),7.0 9(s,1H),6.96(dd,J=8.7,2.2Hz,1H),6.88(d,J=2.2Hz,1H),5.15(s,2H),4.06(s,2H).

[0136] Step 3: Synthesis of N-(6-(benzyloxy)-7-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-8-fluoronaphthalen-2-yl)-3-hydroxy-3-methylbutanamide

[0137] 5-[7-Amino-3-(benzyloxy)-1-fluoronaphthalen-2-yl]-1,2,5-thiadiazoline-3-one-1,1-dioxide (100.0 mg, 0.25 mmol, 1.0 eq.) was dissolved in N,N-dimethylformamide (2.0 mL) solution, followed by the addition of N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (243.8 mg, 0.29 mmol, 1.2 eq.), β-hydroxyisovaleric acid (58.8 mg, 0.49 mmol, 2.0 eq.) and N,N-diisopropylethylamine (130.5 mmL, 0.74 mmol, 3.0 eq.), nitrogen was introduced into the mixture for 5 minutes, and the mixture was reacted at 60° C. for 3 hours. After the reaction, the solid was removed by filtration and then purified by reverse phase column. When the acetonitrile content was 40%, the product flowed out and was concentrated to obtain a white solid N-(6-(benzyloxy)-7-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-8-fluoronaphthalene-2-yl)-3-hydroxy-3-methylbutanamide (70.0 mg, yield 70.0%). LCMS (ESI) [M+H] + :502.1.

[0138] Step 4: Synthesis of N-[7-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-8-fluoro-6-hydroxynaphthalen-2-yl]-3-hydroxy-3-methylbutanamide

[0139] N-(6-(Benzyloxy)-7-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-8-fluoronaphthalene-2-yl)-3-hydroxy-3-methylbutanamide (70.0 mg) was dissolved in tetrahydrofuran (2.0 mL), and 5% palladium carbon (55% water) (70 mg) was introduced into hydrogen to replace the gas for 5 minutes, and the mixture was reacted at room temperature for 1 hour. After the reaction was completed, the solid was filtered off and purified by HPLC to obtain a white solid N-[7-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-8-fluoro-6-hydroxynaphthalene-2-yl]-3-hydroxy-3-methylbutanamide (4.5 mg, yield 6.4%). LCMS (ESI) [M+H] + :412.1. 1 H NMR (400 MHz, Methanol-d 4)δ8.28(d,J=2.0Hz,1H),7.70–7.55(m,2H),7.05(s,1H),4.51(s,2H),2.56(s,2H),1.36(s,6H),0.00(s,2H).19F NMR(376MHz,MeOD)δ-127.65.

[0140] Example 019: Synthesis of 7-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-8-fluoro-6-hydroxy-N-(2-hydroxy-2-methylpropyl)-2-naphthamide

[0141]

[0142] Step 1: Synthesis of 6-(benzyloxy)-7-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-8-fluoro-2-naphthalenecarbonitrile

[0143] To N,N-dimethylformamide (5 mL), 5-[3-(benzyloxy)-7-bromo-1-fluoronaphthalen-2-yl]-1,2,5-thiadiazoline-3-one 1,1-dioxide (400.0 mg, 0.89 mmol, 1.0 eq.), cesium carbonate (840.2 mg, 2.58 mmol, 3.0 eq.), zinc cyanide (151.4 mg, 1.29 mmol, 1.5 eq.) and tetrakistriphenylphosphine palladium (99.03 mg, 0.859 mmol, 0.1 eq.) were added in sequence, and nitrogen was introduced to replace the gas for 5 minutes. The reaction was carried out at 110°C for 16 hours. After the reaction was completed, a saturated sodium bicarbonate solution was added to dilute the solution and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was dried to obtain a yellow liquid product, 6-(benzyloxy)-7-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-8-fluoro-2-naphthalenecarbonitrile (300.0 mg, 75%). LCMS (ESI) [MH] - :410.0.

[0144] Step 2: Synthesis of 6-(benzyloxy)-7-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-8-fluoro-2-naphthoic acid

[0145] 6-(Benzyloxy)-7-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-8-fluoro-2-naphthoic acid (300.0 mg, 1.0 eq.) was dissolved in water (4 mL) and sodium hydroxide solution (2 mL, 3 mol / L) and reacted at 80°C for 16 hours. After the reaction was completed, it was acidified to pH=3 with dilute hydrochloric acid (1 mol / L) and filtered to obtain a white solid product 6-(benzyloxy)-7-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-8-fluoro-2-naphthoic acid (230.0 mg, 82.1% yield). LCMS (ESI) [MH] - :429.1.

[0146] Step 3: Synthesis of 6-(benzyloxy)-7-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-8-fluoro-N-(2-hydroxy-2-methylpropyl)-2-naphthamide

[0147] To a solution of 6-(benzyloxy)-7-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-8-fluoro-2-naphthoic acid in N,N-dimethylformamide (5.0 ml) were added N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (243.8 mg, 0.64 mmol, 1.2 eq.), 1-amino-2-methylpropan-2-ol (95.2 mg, 1.07 mmol, 2.0 eq.) and triethylamine (222.8 mml, 1.6 mmol, 3.0 eq.), the atmosphere was replaced with nitrogen for 5 minutes, and the reaction was carried out at 60°C for 12 hours. After the reaction, the solid was filtered out and purified by HPLC to obtain a white solid 6-(benzyloxy)-7-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-8-fluoro-N-(2-hydroxy-2-methylpropyl)-2-naphthamide (28.0 mg, yield 12.2%). LCMS (ESI) [MH] - :500.1.

[0148] Step 4: Synthesis of 7-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-8-fluoro-6-hydroxy-N-(2-hydroxy-2-methylpropyl)-2-naphthoyl

[0149] 6-(Benzyloxy)-7-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-8-fluoro-N-(2-hydroxy-2-methylpropyl)-2-naphthamide (28.0 mg, 0.020 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (1.0 mL), palladium carbon (55% water, 5 wt%) (43.0 mg, 0.01 mmol, 0.5 eq.) was added, hydrogen was introduced to replace the gas for 5 minutes, and the reaction was carried out at room temperature for 2 hours. After the reaction was completed, the solid was filtered out and purified by HPLC to obtain a white solid 7-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-8-fluoro-6-hydroxy-N-(2-hydroxy-2-methylpropyl)-2-naphthamide (12 mg, yield 42.8%). LCMS (ESI) [M+H] + :412.1. 1 H NMR (400 MHz, Methanol-d 4 )δ8.53(d,J=1.8Hz,1H),7.91(dd,J=8.7,1.8Hz,1H),7.77(d,J=8.7Hz,1H),7.14(s,1H),4.43(s,2H),3.46(s,2H),1.26(s,6H).

[0150] Example 033: Synthesis of 1-(4-chlorophenyl)-3-[7-(1,1-dioxido-4-oxo-1,2,5-thiadiazolin-2-yl)-8-fluoro-6-hydroxynaphthalene-2-yl]urea

[0151]

[0152] Step 1: Synthesis of 1-[6-(benzyloxy)-7-(1,1-dioxido-4-oxo-1,2,5-thiadiazolin-2-yl)-8-fluoronaphthalen-2-yl]-3-(4-chlorophenyl)urea

[0153] 5-[7-amino-3-(benzyloxy)-1-fluoronaphthalene-2-yl]-1,2,5-thiadiazoline-3-one-1,1-dioxide (100 mg, 0.25 mmol, 1.0 eq.) was dissolved in dichloromethane (2 mL), 1-chloro-4-isocyanobenzene (57.4 mg, 0.27 mmol, 1.5 eq.) and triethylamine (50.6 mg, 0.5 mmol, 2.0 eq.) were added, and the mixture was reacted at room temperature for 2 hours. After the reaction was complete, the reaction solution was separated and purified by C-18 reverse phase column to obtain brown solid 1-[6-(benzyloxy)-7-(1,1-dioxido-4-oxo-1,2,5-thiadiazoline-2-yl)-8-fluoronaphthalene-2-yl]-3-(4-chlorophenyl)urea (219.7 mg). LCMS (ESI) [MH]-: 553.1 H NMR (400 MHz, DMSO-d 6 )δ9.66(s,1H),9.57(s,1H),8.18(d,J=2.1Hz,1H),7.75(d,J=8.8Hz,1H),7.5 7-7.53(m,5H),7.33(ddd,J=12.3,7.5,3.6Hz,7H),5.22(s,2H),4.09(s,2H).

[0154] Step 2: Synthesis of 1-(4-chlorophenyl)-3-[7-(1,1-dioxido-4-oxo-1,2,5-thiadiazolin-2-yl)-8-fluoro-6-hydroxynaphthalen-2-yl]urea

[0155] 1-[6-(Benzyloxy)-7-(1,1-dioxido-4-oxo-1,2,5-thiadiazolin-2-yl)-8-fluoronaphthalene-2-yl)-3-(4-chlorophenyl)urea (200 mg, 0.36 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (2 mL), and palladium carbon catalyst (Pd / C) (200 mg) was added. After replacing the hydrogen, the mixture was reacted at room temperature for 2 hours. After the reaction was complete, N,N-dimethylformamide (2 ml) was added to assist in dissolution. After filtering, tetrahydrofuran was removed under reduced pressure. The filtrate was used to prepare a white solid 1-(4-chlorophenyl)-3-[7-(1,1-dioxido-4-oxo-1,2,5-thiadiazolin-2-yl)-8-fluoro-6-hydroxynaphthalene-2-yl]urea (4.4 mg, yield 2.6%). LCMS (ESI) [M+H] + :465.04. 1 H NMR (400MHz, MeOD) δ 8.01 (s, 1H), 7.63 (d, J = 9.0Hz, 1H), 7.53 (d, J = 8.9Hz, 1H), 7.46 (d, J = 8.4Hz, 2H), 7.28 (d, J = 8.4Hz, 2H), 7.03 (s, 1H), 4.41 (s, 2H).

[0156] Example 034: Synthesis of 1-[7-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-8-fluoro-6-hydroxynaphthalene-2-yl]-3-isopropylurea

[0157]

[0158] Step 1: Synthesis of 1-[6-(benzyloxy)-7-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-8-fluoronaphthalen-2-yl]-3-isopropylurea

[0159] Compound 5-[3-(benzyloxy)-7-bromo-1-fluoronaphthalen-2-yl]-1,2,5-thiadiazoline-3-one 1,1-dioxide (300.0 mg, 0.644 mmol, 1.0 eq.) was added to a mixed solution of 1,4-dioxane (5.0 mL) and water (1.0 mL), followed by cesium carbonate (630.2 mg, 1.93 mmol, 3.0 eq.), isopropyl urea ( 72.4mg, 0.709mmol, 1.1eq.), palladium acetate (14.4mg, 0.064mmol, 0.1eq.) and 2-(di-tert-butylphosphine)-3,6-dimethoxy-2'-4'-6'tri-1-propyl-1,1'-biphenyl (74.6mg, 0.128mmol, 0.2eq.), nitrogen was introduced into the gas for 5 minutes, and refluxed and stirred at 90°C for 3 hours. After the reaction was completed, the solid was filtered out and purified by HPLC to obtain a white solid 1-[6-(benzyloxy)-7-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-8-fluoronaphthalene-2-yl]-3-isopropylurea (40.0mg, yield 13.3%). LCMS (ESI) [MH]-: 485.1. 1 H NMR (400 MHz, DMSO-d 6 )δ8.58(s,1H),8.04(d,J=2.1Hz,1H),7.69(dd,J=9.0,1.5Hz,1H),7.58–7.52(m,2H),7.47(dd,J=8.9,2.2Hz,1H),7.36(dd,J=8.1,6.4Hz ,2H),7.32–7.28(m,1H),7.23(s,2H),6.06(d,J=7.6Hz,1H),5.21(s,2H),4.08(s,2H),3.79(m,J=13.3,6.6Hz,1H),1.12(d,J=6.5Hz,6H).

[0160] Step 2: Synthesis of 1-[6-(benzyloxy)-7-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-8-fluoronaphthalen-2-yl]-3-isopropylurea

[0161] 1-[6-(Benzyloxy)-7-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-8-fluoronaphthalene-2-yl]-3-isopropylurea (40.0 mg, 1.0 eq.) was dissolved in tetrahydrofuran (1.0 mL), and palladium carbon (55% water, 5 wt.%, 80.0 mg) was added. Hydrogen was introduced to replace the gas for 5 minutes, and the reaction was allowed to proceed at room temperature for 2 hours. After the reaction was completed, the solid was filtered out and purified by HPLC to obtain a white solid 1-[7-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-8-fluoro-6-hydroxynaphthalene-2-yl]-3-isopropylurea (2.3 mg, yield 8.7%). LCMS (ESI) [MH] - :395.1. 1 H NMR (400MHz, CD 3 OD)δ7.96(d,J=2.3Hz,1H),7.63–7.56(m,1H),7.47(dd,J=9.0,2.2Hz,1H),7.01(s,1H),4.45(s,2H),3.91(m,J=6.5Hz,1H),1.20(d,J=6.5Hz,6H).

[0162] Example 035: Synthesis of N-[7-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-8-fluoro-6-hydroxynaphthalene-2-]-4-methylbenzenesulfonamide

[0163]

[0164] Step 1: Synthesis of N-[6-(benzyloxy)-7-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-8-fluoronaphthalen-2-yl]-4-methylbenzenesulfonamide

[0165] To a mixed solution of the compound 5-[3-(benzyloxy)-7-bromo-1-fluoronaphthalen-2-yl]-1,2,5-thiadiazoline-3-1,1-dioxide (300 mg, 0.65 mmol, 1.0 eq.) in 1,4-dioxane (3.0 mL) and water (0.3 mL) were added cesium carbonate (635 mg, 1.95 mmol, 3.0 eq.), palladium acetate (30 mg, 0.13 mmol, 0.2 eq.), 2-(di-tert-butylphosphine)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-1,1'-biphenyl (126 mg, 0.26 mmol, 0.4 eq.), the gas was replaced with nitrogen three times, and the mixture was refluxed with stirring at 100°C for 16 hours. After the reaction was completed, the solid was filtered off and purified by HPLC to obtain a yellow solid N-[6-(benzyloxy)-7-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-8-fluoronaphthalen-2-yl]-4-methylbenzenesulfonamide (41 mg, yield 11.4%). LCMS (ESI) [MH]-: 554.1.

[0166] Step 2: Synthesis of N-[7-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-8-fluoro-6-hydroxynaphthalene-2-]-4-methylbenzenesulfonamide

[0167] N-[6-(Benzyloxy)-7-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-8-fluoronaphthalene-2-yl]-4-methylbenzenesulfonamide (41 mg, 0.074 mmol, 1.0 eq.) and 5% palladium on carbon (55% water, 40 mg) were added to tetrahydrofuran (1.0 mL), and hydrogen was introduced to replace the gas for 5 minutes. The reaction was allowed to proceed at room temperature for 1 hour. After the reaction was completed, the solid was removed by filtration and purified by HPLC to obtain a white solid N-[7-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-8-fluoro-6-hydroxynaphthalene-2-]-4-methylbenzenesulfonamide (5.3 mg, yield 15.4%). LCMS (ESI) [MH] - :464.06. 1 H NMR (400 MHz, DMSO-d 6)δ10.35(s,1H),9.76(s,1H),7.63(dd,J=10.6,8.5Hz,3H),7.48(d,J=2.2Hz,1H),7.32(d,J= 8.1Hz, 2H), 7.25 (dd, J = 8.9, 2.2Hz, 1H), 6.96 (s, 1H), 6.52 (s, 1H), 4.05 (s, 2H), 2.30 (s, 3H). 19F NMR (376MHz, DMSO-d6) δ-126.25.

[0168] The compounds listed in Table 1 below were prepared by methods similar to those described in the Examples, wherein the reactants, amounts of reagents, protection and deprotection, solvents and reaction conditions were appropriately varied. Characterization data of the compounds are summarized in Table 1 below.

[0169] Table 1: Structure and characterization of some compounds

[0170]

[0171]

[0172]

[0173]

[0174]

[0175] Experimental Example 1: Activity test of the compounds of the present invention on PTPN2 / 1 protease

[0176] Experimental purpose: The purpose of this test case is to test the effect of the compound on the PTPN2 / 1 enzyme function

[0177] Background and Principle: Through in vivo CRISPR screening, it was found that PTPN2 and its closely related PTPN1 can be used as new targets for cancer immunotherapy. Knocking out PTPN2 can improve the effect of tumor immunotherapy by enhancing interferon-γ-mediated antigen presentation and growth inhibition. Phosphatases PTPN2 (also known as TC-PTP) and PTPN1 (also known as PTP-1B) are negative regulators of multiple cytokine signaling pathways and T cell receptor (TCR) signaling pathways, and are key checkpoints in inflammatory responses. p-Nitrophenyl phosphate (pNPP) is one of the most commonly used substrates for phosphatases. After adding the substrate to the microwell, under the action of phosphatases, PNPP generates a yellow water-soluble reaction product, and the solution turns into the yellow color of p-nitrophenol. The reaction product has a large light absorption at 405nm.

[0178] Experimental process:

[0179] PTPN2 / 1 protein expression: The PTPN2 sequence (residues 1-314) was cloned into the pET28A vector containing the (His)6x tag; the PTPN1 sequence (residues 1-321) was cloned into the pET15B vector containing the (His)6x tag. The constructed vector was transformed into E. coli BL21 (DE3), and the cells were shaken to OD 0.6, and 1mM IPTG was added, and cultured at 12℃ for 16h. The cells were collected, ultrasonically disrupted, and the supernatant was taken by centrifugation. The protein was purified by Ni-NTA, and the protein concentration and purity were determined after dialysis, and the cells were stored in aliquots at -80℃.

[0180] PTPN2 / 1 enzyme activity assay: The PTPN2 (or 1) phosphatase activity was measured by monitoring the hydrolysis of p-nitrophenyl phosphate (pNPP) to p-nitrophenol in an experimental buffer containing 25mM Tris HCl (pH 7.4), 50mM NaCl, and 1mM DTT. In the reaction system, the enzyme concentration was fixed at 50nM, the pNPP concentration was 50μM, and the total reaction volume was 100μL. 1. Mix the enzyme and compound and incubate at 30℃ for 10 minutes; 2. Add pNPP to the enzyme and compound mixture and incubate at 30℃ for 30 minutes; 3. Add 100uL 1M NaOH to stop the reaction, and then measure the absorbance at 405nm using a microplate reader. IC50 was calculated by GraphPad software, and the compounds were screened by comparing with the positive drug ABBV-CLS-484 (abbreviated as AC484).

[0181] IC50 (half maximal inhibitory concentration) refers to the half inhibitory concentration of the measured antagonist. It can indicate the half amount of a drug or substance (inhibitor) in inhibiting certain biological processes (or certain substances contained in this process, such as enzymes, cell receptors or microorganisms). AC484 is used as a positive reference compound, and its synthesis method refers to patent CN114025844B.

[0182] The structure of ABBV-CLS-484 is as follows:

[0183]

[0184] The IC values ​​of each compound against PTPN2 and PTPN1 protease functions were determined. 50 The values ​​are shown in Table 2 below. The compound numbers correspond to the compound numbers shown in Table 1, and "A" represents IC 50 Less than 1nM, "B" indicates IC 50 The range is 1nM to 10nM; "C" indicates IC 50 Range is 10nM to 100nM; "D" indicates IC50 The range is greater than 100nM.

[0185] Table 2: IC values ​​of exemplary compounds of the present invention for PTPN2 / 1 protease activity assay 50 value

[0186]

[0187]

[0188] The results showed that the compounds of the present invention had a very strong inhibitory effect on PTPN2 / 1 protease, IC 50 The values ​​all reached nM level, which is equivalent to or less than the positive control drug AC484, indicating that the compounds of the present invention have good selectivity for PTPN2 / 1 protease. This strong inhibitory effect or selectivity has important therapeutic significance for the treatment of symptoms or diseases related to PTPN2 / 1 inhibition.

[0189] Experimental Example 2: Determination of the effect of the compounds of the present invention on the proliferation of B16F10 cells

[0190] Experimental purpose: The purpose of this test case is to test the effect of the compound on the proliferation of B16F10 cells

[0191] Background: IFNγ is a cytokine produced by immune system cells such as T cells or NK cells that can inhibit the growth of certain cancer types, including melanoma. Inhibition of IFNγ signaling can promote tumor growth, and conversely, enhancement of IFNγ signaling can enhance tumor growth inhibition. Because PTPN2 and PTPN1 are negative regulators of cytokine signaling, including IFNγ signaling, a potent compound can inhibit tumor cell growth in the presence of IFNγ through dephosphorylation of JAK and STAT proteins.

[0192] Experimental process:

[0193] B16F10 cells were cultured in DMEM+10% FBS+1% P / S growth medium. B16F10 cells in the logarithmic growth phase were inoculated in 96-well plates, 100μl per well, 500 cells / well, and incubated overnight at 37°C incubator. On the second day, 50μl of mouse IFN-γ (final concentration of 0.5ng / ml) was added; 50μl of compounds of different concentrations (DMSO final concentration of 1%) were added, and incubated at 37°C incubator for 5 days. On the sixth day, the old culture medium was aspirated, 110ul of culture medium was added (the ratio of culture medium to CCK8 was 100:10), and incubated at 37°C for 1-4h. The absorbance was detected at 450nM, and the IC was calculated by GraphPad software. 50 , and screen compounds by comparing with the positive drug AC484.

[0194] The following table summarizes the IC values ​​of B16F10 IFNγ-induced cell growth inhibition of exemplary compounds of the present invention: 50 The compound numbers correspond to those shown in Table 1, where “A” represents IC 50 Less than 10nM, "B" indicates IC 50 Range is 10nM to 100nM; "C" indicates IC 50 Range is 100nM to 1μM; "D" indicates IC 50 The range is greater than 1 μM.

[0195] Table 3: IC of exemplary compounds of the invention in the B16F10 IFNγ-induced cell growth inhibition assay 50 value

[0196]

[0197]

[0198] The results showed that the compounds of the present invention can significantly enhance the inhibitory effect of INF-γ on the growth of tumor cells after treating B16F10 cells, and the IC50 values ​​all reached nM level, which is equivalent to or less than the positive control drug AC484. This strong inhibitory effect has important therapeutic significance for the treatment of symptoms or diseases related to the inhibition of protein tyrosine phosphatase PTPN2 / 1.

[0199] Experimental Example 3: Determination of the effect of the compounds of the present invention on cell STAT1 phosphorylation

[0200] Experimental purpose: The purpose of this test case is to test the effect of compounds on cell STAT1 phosphorylation

[0201] Background Principle: PTPN2 / N1 inhibits inflammation by removing phosphorylation of JAK and STAT family members. PTPN2 also targets proximal TCR signaling molecules, thereby inhibiting the antigen sensitivity of T cells. Therefore, after compound incubation, the phosphorylation level of STAT in B16F10 cells was detected by WB, which can be used for inhibitor screening.

[0202] Experimental process:

[0203] B16F10 cells were cultured in DMEM+10% FBS+1% P / S growth medium. B16F10 cells in the logarithmic growth phase were inoculated in 24-well plates, 450μl per well, 200,000 / well, and left to stand overnight in a 37°C incubator. On the second day, 50μl of different concentrations of compounds (DMSO final concentration was 1%) were added and incubated at 37°C for 3h; then stimulated with 100ng / ml mouse IFN-γ for 10min, and the cells were collected for WB. Protein electrophoresis: The voltage of the concentrated gel was set to 60v, and the voltage of the separation gel was set to 120v; after the electrophoresis, electrotransfer was started. The conditions for electrotransfer were set to 250mA, 2h; 5% BSA was blocked for 1h; specific primary antibodies were added and incubated overnight on a shaker at 4°C; TBST was washed 4 times, 2.5min each time; secondary antibodies were incubated on a shaker at room temperature for 1h; TBST was washed 4 times, 2.5min each time; ECL was used for development. Western blot bands were transformed and processed using Image J and GraphPad software to calculate IC 50 , and screen compounds by comparing with the positive drug AC484.

[0204] The following table summarizes the IC values ​​of exemplary compounds of the present invention for cellular STAT1 phosphorylation assays: 50 The compound numbers correspond to those shown in Table 1, where “A” represents IC 50 Less than 10nM, "B" indicates IC 50 Range is 10nM to 100nM; "C" indicates IC 50 Range is 100nM to 1μM; "D" indicates IC 50 The range is greater than 1 μM.

[0205] Table 4: IC values ​​of exemplary compounds of the present invention on cellular STAT1 phosphorylation assay 50 value

[0206]

[0207]

[0208] The results showed that the compounds of the present invention could significantly inhibit the phosphorylation of STAT1 protein in B16F10 cells and had strong cell activity. 50 The values ​​all reached nM level, which is equivalent to or less than the positive control drug AC484. This strong inhibitory effect has important therapeutic significance for the treatment of symptoms or diseases related to the inhibition of protein tyrosine phosphatases PTPN2 and PTPN1.

Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof: in, R1 is selected from hydrogen, halogen, cyano, C1-C6 alkoxy, -O(CH2) n CN; R2 is selected from -NH-C(O)-NH-C1-C6 alkyl, -NH-C(O)-NH-6-10 membered aryl, -NH-C(S)-NH-6-10 membered aryl, -NH-C(O)-NH-(CH2) n -3-10 membered heterocycloalkyl, -NH-C(O)-(CH2) n -C1-C6 alkyl, -NH-C(O)-(CH2) n -C3-C 10 Cycloalkyl, -NH-C(O)-(CH2) n -6-10 membered aryl, -NH-(CH2) n -C3-C 10 Cycloalkyl, -NH-(CH2) n -C3-C 10 Heterocycloalkyl, -NHS(O)2-(CH2) n -6-10 membered aryl, -S(O)2-(CH2) n -6-10 membered aryl, -C(O)-NH-(CH2) n -C1-C6 alkyl, -C(O)-NH-(CH2) n -C3-C 10 Cycloalkyl, -C(O)-NH-(CH2) n -C3-C 10 Heterocycloalkyl, -C(O)-NH-(CH2) n -5-10 membered heteroaryl, -C(O)-NH-(CH2) n -6-10 membered aryl, -C(O)-(CH2) n -C2-C6 alkenyl, -O-(CH2) n -C1-C6 alkyl, -O-(CH2) n -C2-C6 alkenyl, -O-(CH2) n -6-10 membered aryl, -O-(CH2) n -Cyano, -O-(CH2) n -S(O)2-NH2, -O-(CH2) n -C3-C 10 Cycloalkyl, -O-(CH2) n -C3-C 10 Heterocycloalkyl, -O-(CH2) n -3-10 membered heterocyclic group, -O-(CH2) n -5-10 membered heteroaryl, -O- (CH2) n -C(O)O-C1-C6 alkyl, -OC(O)-6-10 membered aryl, -OC(O)-(CH2) n -C1-C6 alkyl, -C3-C 10 The group consisting of heterocycloalkyl-C(O)-C1-C6 alkyl, R2 may be optionally substituted with one or more of the following substituents: halogen, hydroxy, cyano, C1-C6 alkyl, C1-C6 haloalkyl, acetylene, C2-C6 alkenyl, -S(O)2-C1-C6 alkyl, -S(O)-C1-C6 alkyl, NR a R b ; R a , R b Each is independently selected from hydrogen, C1-C3 alkyl; n=0 to 6.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: The R2 is selected from the group consisting of:

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: The R2 may be optionally substituted by one or more of the following substituents: chlorine, fluorine, hydroxyl, cyano, methyl, trifluoromethane, acetylene, ethylene, -S(O)2-methyl, -S(O)-methyl, amino, ethyl, -N(CH3)CH3.

4. A compound represented by formula (II) or a pharmaceutically acceptable salt thereof: X is selected from a bond, -O-, -NH-, -NHC(O)-, -C(O)NH-, -NHC(O)NH-, -NHS(O)2-, -OC(O)-, - NHC(S)NH-, -S(O)2-, -C(O)-; L is a bond or a C1-C6 alkylene group optionally substituted with one or more C1-C6 alkyl groups; R1 is selected from hydrogen, halogen, cyano, C1-C6 alkoxy, -O(CH2) n CN; R 2a Selected from hydrogen, cyano, C1-C6 alkyl, 6-10 membered aryl, C3-C 10 Heterocycloalkyl, C3-C 10 Cycloalkyl, 5-10 membered heteroaryl, C2-C6 alkenyl, -S(O)2NH2, 3-10 membered heterocyclyl, -C(O)O-C1-C6 alkyl, -OC(O)-C1-C6 alkyl, -C3-C 10 Heterocycloalkyl-C(O)-C1-C6alkyl; R 2a It may be optionally substituted by one or more of the following substituents: halogen, hydroxy, cyano, C1-C6 alkyl, C1-C6 haloalkyl, acetylene, C2-C6 alkenyl, -S(O)2-C1-C6 alkyl, -S(O)-C1-C6 alkyl, NR a R b ; R a , R b Each is independently selected from hydrogen, C1-C3 alkyl; n=0 to 6.

5. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein L is selected from the group consisting of: a bond, Where * and # represent R 2a Point of covalent attachment to X.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: The R1 is selected from hydrogen, chlorine, fluorine, cyano, methoxy, -OCH2CH3, -OCH2CN, -OCH2CH2CN.

7. A compound represented by formula (III) or a pharmaceutically acceptable salt thereof: X is selected from a bond, -O-, -NH-, -NHC(O)-, -C(O)NH-, -NHC(O)NH-, -NHS(O)2-, -OC(O)-, -NHC(S)NH-, -S(O)2-, -C(O)-; L is a bond or a C1-C6 alkylene group optionally substituted with one or more C1-C6 alkyl groups; R 2a Selected from hydrogen, cyano, C1-C6 alkyl, 6-10 membered aryl, C3-C 10 Heterocycloalkyl, C3-C 10 Cycloalkyl, 5-10 membered heteroaryl, C2-C6 alkenyl, -S(O)2NH2, 3-10 membered heterocyclyl, -C(O)O-C1-C6 alkyl, -OC(O)-C1-C6 alkyl, -C3-C 10 Heterocycloalkyl-C(O)-C1-C6alkyl; R 2a It may be optionally substituted by one or more of the following substituents: halogen, hydroxy, cyano, C1-C6 alkyl, C1-C6 haloalkyl, acetylene, C2-C6 alkenyl, -S(O)2-C1-C6 alkyl, -S(O)-C1-C6 alkyl, NR a R b ; R a , R b Each is independently selected from hydrogen, C1-C3 alkyl; n＝0-6。 8. A compound according to any one of claims 4 to 7 or a pharmaceutically acceptable salt thereof, wherein R 2a is selected from hydrogen, cyano, C1-C6 alkyl, The group composed of.

9. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

11. Use of the compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 10 in the preparation of a medicament for treating a disease or disorder by inhibiting PTPN1 / PTPN2.

12. The pharmaceutical use according to claim 11, wherein the disease or condition is cancer, rheumatic disease, inflammatory disease, immune disease, metabolic disease, infectious disease, neurodegenerative disease, genetic disease, heart disease; the cancer is preferably selected from T-cell acute lymphoblastic leukemia, ovarian cancer, primary mediastinal B-cell lymphoma, bladder cancer, bone cancer, brain cancer, cardia cancer, cervical cancer, colon cancer, colorectal cancer, esophageal cancer, fibrosarcoma, gastric cancer, gastrointestinal cancer, head, spine and neck cancer, leukemia, liver cancer, lymphoma, melanoma, penile cancer, testicular germ cell cancer, thymoma cancer, thymic cancer, Lung cancer, ovarian cancer, prostate cancer, pancreatic cancer, breast cancer, multiple myeloma, melanoma, secretory cell carcinoma, head and neck squamous cell carcinoma, non-small cell lung cancer, renal cell carcinoma; the metabolic disease is preferably selected from non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), liver fibrosis, obesity, type 2 diabetes, heart disease, atherosclerosis, arthritis, cystinosis, phenylketonuria, proliferative retinopathy, metabolic syndrome or Kearns-Sayre's disease; the infectious disease is preferably selected from bubonic plague; the genetic disease is preferably selected from Noonan syndrome, retinopathy.

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