PTPN inhibitors

Abstract

The invention belongs to the field of medical chemistry, and particularly discloses a protein tyrosine phosphatase (PTPN) inhibitor as shown in a formula 1, a pharmaceutical composition and application of the PTPN inhibitor. The invention discloses a method for treating related diseases such as cancers and metabolic diseases by using the protein tyrosine phosphatase inhibitor. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry, and particularly relates to a protein tyrosine phosphatase inhibitor or a pharmaceutically acceptable salt thereof, a pharmaceutical composition, and uses 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 the 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 used 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 a subclass of phospho-tyrosine specific phosphatases. The PTPN2 controls multiple cellular regulatory processes by removing phosphate groups from tyrosine substrates in the cytoplasm or nucleus. PTPN2 is ubiquitously expressed in cells, with the highest expression in hematopoietic stem cells and placental cells. In humans, PTPN2 expression is controlled post-transcriptionally by the presence of two splice variants: a 45 kDa form containing 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. The two isoforms share an N-terminal phospho-tyrosine phosphatase catalytic domain, and the 45 kDa isoform can be passively imported into the cytosol under certain cellular stress conditions.

[0003] The catalytic domain of PTPN2 shares 74% sequence homology with PTPN1 and has similar enzyme kinetics. Protein tyrosine phosphatase PTPN2, as well as PTPN1, are both negative regulators of multiple cytokine signaling pathways and T cell receptor (TCR) signaling pathways, and are key checkpoints of the inflammatory response. PTPN2 and PTPN1 (PTPN2 / N1) inhibit inflammation by removing the phosphorylation of JAK and STAT family members. PTPN2 is also a phosphatase of LCK and FYN downstream of TCR signaling, thereby reducing the sensitivity of T cells to antigen recognition. 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 inflammation regulation. Genetic ablation of PTPN2 or PTPN1 in tumor cells enhances the signal transduction of type I and type II IFNγ3, increasing downstream effects, including cell growth arrest, production of immunocyte chemotactic agents, and increased antigen presentation. In addition, the deletion of PTPN2 or PTPN1 enhances the expansion of T cells, the response to IL-2, and the ability to control tumors. Therefore, different from current treatment methods, PTPN2 / PTPN1 targeted therapy can achieve a dual anti-cancer mechanism by directly acting on tumor cells and increasing the anti-tumor activity of immune cells, showing its potential as an anti-cancer drug target.

[0004] Data from in vivo loss-of-function gene screening using CRISPR / Cas9 genome editing in a murine B16F10 transplantable tumor model showed that deletion of the PTPN2 gene in tumor cells improved the response to an immunotherapy regimen of the GM-CSF-secreting vaccine (GVAX) plus PD-1 checkpoint blockade. Deletion of the PTPN2 gene sensitized tumors to immunotherapy by enhancing the IFNγ-mediated effects on antigen presentation and growth inhibition. The same screening data also revealed that genes known to be involved in immune evasion (including PD-L1 and CD47 blocking antibodies) were also depleted under the selective action of immunotherapy, while genes involved in the IFNγ signaling pathway (including IFNGR, JAK1, and STAT1) were enriched. These observations suggest that therapeutic strategies that 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, making it difficult to develop inhibitors targeting a single phosphatase and prone to causing serious adverse reactions. On the other hand, the active sites of phosphatases have a special polar and charged environment, resulting in the need for highly polar active site inhibitors. However, such inhibitors have low potency and poor pharmacokinetic properties. Due to the importance of PTPN2 / PTPN1 in tumors and immune cells and the high homology of their active sites, researchers have attempted to discover 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. ABBV-CLS-484 is the first known active site phosphatase inhibitor to enter cancer immunotherapy clinical trials and is currently being evaluated in patients with advanced solid tumors. ABBV-CLS-484 is a dual PTPN2 / N1 inhibitor that can increase the sensitivity of cancer cells to INF-γ, enhance the activation and effector functions of T cells and NK cells, thereby inhibiting cell proliferation.

[0007] However, so far, there have been few reports on PTPN2 inhibitors. Developing PTPN2 inhibitors with high activity, high selectivity, and better druggability has good value prospects and is worthy of development. Summary of the Invention General Overview of the Invention

[0009] Aiming at the deficiencies of the prior art, the purpose of the present invention is to provide a PTPN2 inhibitor, a pharmaceutical composition, and their uses with high activity, high selectivity, and better druggability, so as to improve the activity of anti-tumor immune cells. The compounds provided by the present invention have good inhibitory effects and druggable properties on protein tyrosine phosphatase inhibitors against PTPN2 / 1.

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

[0011] On the one hand, the present invention provides a compound, isomer, or a pharmaceutically acceptable salt thereof of the following formula (I):

[0012]

[0013] Wherein,

[0014] A is selected from a carbocyclic ring having 7 or more carbon atoms optionally substituted by one or more substituents R3, a heterocyclic ring having 7 or more atoms containing 1 to 3 heteroatoms selected from N, O or S, and a heteroaromatic ring having 7 or more atoms containing 1 to 3 heteroatoms selected from N, O or S;

[0015] R3 is selected from oxo, -C1-C6 alkyl, -C1-C6 haloalkyl;

[0016] X is selected from O, NR;

[0017] R is selected from H, -C1-C6 alkyl, -C1-C6 haloalkyl, -C3-C6 cycloalkyl;

[0018] L is selected from a chemical bond, -(CH2)n-;

[0019] n is 1, 2 or 3;

[0020] R1 and R2 are each independently selected from H, halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -CN, -ORa1, -NRa2Ra3;

[0021] Ra1, Ra2 and Ra3 are each independently selected from H, -C1-C6 alkyl, -C3-C6 cycloalkyl.

[0022] As a preferred technical solution, the compound is selected from:

[0023]

[0024] The present invention also provides a compound selected from the following formulae, its isomers, or a pharmaceutically acceptable salt thereof:

[0025]

[0026] The present invention also provides a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof according to any one of the above, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0027] The present invention also provides the use of the compound or a pharmaceutically acceptable salt thereof according to any one of the above, or the pharmaceutical composition in the preparation of a drug for treating a disease or disorder by inhibiting PTPN1 / PTPN2.

[0028] As a preferred technical solution, the disease or disorder 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, gastric cardia cancer, cervical cancer, colon cancer, colorectal cancer, esophageal cancer, fibrosarcoma, gastric cancer, gastrointestinal cancer, head, spine and cervical cancer, leukemia, liver cancer, lymphoma, melanoma, penile cancer, testicular germ cell cancer, thymoma cancer, thymic carcinoma, 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 fatty liver hepatitis (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 disease; the infectious disease is preferably selected from glandular plague; the genetic disease is preferably selected from Noonan syndrome, retinopathy.

[0029] Compared with the prior art, the present invention has the following beneficial effects:

[0030] The present invention modifies (ABBV-CLS-484 analogs) through computer-aided design. Through computer simulation, molecular docking analysis, and drug structure-activity relationship research, a variety of novel-structured compounds are screened. This series of compounds can specifically bind to protein tyrosine phosphatase and inhibit the function of PTPN2, and have extremely strong PTPN2 inhibitory activity. In vitro and in vivo experiments further show that this series of compounds can prevent and / or treat diseases such as pancreatic cancer, breast cancer, multiple myeloma, melanoma, secretory cell carcinoma, non-alcoholic fatty liver hepatitis (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 disease. Detailed Description of the Invention

[0032] The following further describes each aspect and feature of the present invention.

[0033] As used in the specification and the appended claims, unless otherwise indicated, the following terms have the meanings indicated below.

[0034] The abbreviations used herein have their conventional meanings in the fields of chemistry and biology. The chemical structures and chemical formulas shown herein are constructed according to the standard rules of chemical valence known in the chemical field.

[0035] The compounds of the present invention have asymmetric centers, and compounds containing asymmetrically substituted atoms in the present invention can be separated into optically active or racemic forms. Those skilled in the art know how to prepare optically active forms, such as by resolution of racemates or synthesis from optically active starting materials. Unless specifically indicating a particular stereochemistry or isomeric form, the present invention includes all chiral, diastereomers, and racemates. The methods for preparing the compounds of the present invention and their intermediates are part of the present invention. All tautomers of the compounds of the present invention also belong to the present invention.

[0036] "Alkyl" refers to a group of straight-chain or branched-chain saturated hydrocarbon groups having 1 to 10 carbon atoms ("C1-C10 alkyl"). In some embodiments, the alkyl has 1 to 8 carbon atoms ("C1-C8 alkyl"). In some embodiments, the alkyl has 1 to 6 carbon atoms ("C1-C6 alkyl"), the alkyl has 1 to 5 carbon atoms ("C1-C5 alkyl"), the alkyl has 1 to 4 carbon atoms ("C1-C4 alkyl"), the alkyl has 1 to 3 carbon atoms ("C1-C3 alkyl"), the alkyl has 1 to 2 carbon atoms ("C1-C2 alkyl"), and the alkyl has 1 carbon atom ("C1 alkyl"). In some embodiments, the alkyl has 2 to 6 carbon atoms ("C2-C6 alkyl"). Examples of C1-C6 alkyl 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-butanyl (C5), tert-pentyl (C5), and n-hexyl (C6). Additional examples of alkyl include n-heptyl (C7), n-octyl (C8), etc. Each instance of alkyl can be independently optionally substituted, i.e., unsubstituted ("unsubstituted alkyl") or substituted by one or more substituents; for example, substituted by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkyl"). In certain embodiments, the alkyl is unsubstituted C1-C10 alkyl (e.g., -CH3). In certain embodiments, the alkyl is substituted C1-C6 alkyl. Common alkyl abbreviations include Me (-CH3), Et (-CH2CH3), iPr (-CH(CH3)2), nPr (-CH2CH2CH3), n-Bu (-CH2CH2CH2CH3), or i-Bu (-CH2CH(CH3)2).

[0037] As described herein, the terms "halogen", "halo", "halo group", etc. represent fluorine, chlorine, bromine, or iodine, particularly represent fluorine, chlorine, bromine, and are particularly preferably fluorine, chlorine.

[0038] "Halogenated alkyl" 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., mono-halogenated alkyl, di-halogenated alkyl, and tri-halogenated alkyl). Such groups include, but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloro-fluoroalkyl, chloro-difluoroalkyl, and 2-fluoroisobutyl.

[0039] "Alkoxy" refers to an alkyl group as described herein (e.g., C1-C6 alkyl) which is attached to the molecule through an oxygen atom. This includes moieties in which the alkyl portion may be straight-chain or branched, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, and n-hexyloxy.

[0040] 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, the cycloalkyl has 3 to 8 ring carbon atoms ("C3-8 cycloalkyl" or "C3-C8 cycloalkyl"). In some embodiments, the cycloalkyl has 3 to 6 ring carbon atoms ("C3-6 cycloalkyl" or "C3-C6 cycloalkyl"). In some embodiments, the cycloalkyl has 5 to 6 ring carbon atoms ("C5-6 cycloalkyl" or "C5-C6 cycloalkyl"). In some embodiments, the 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 (C6). 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 instance of cycloalkyl is independently unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In certain embodiments, the cycloalkyl is an unsubstituted C3-C10 cycloalkyl. In certain embodiments, the cycloalkyl is a substituted C3-C10 cycloalkyl.

[0041] "Carbocyclic group", "carbocyclic", "carbocycle" and "carbocyclic" alone or when used as a composite group, refer to a mono-, bi- or tricyclic carbocycle having 3 to 14 carbon atoms, such as 3 to 7 carbon atoms, which may be saturated, unsaturated, partially unsaturated, aromatic (aryl) or non-aromatic having the specified number of atoms, usually 5 to about 14 ring atoms. Specific saturated carbocyclic groups of more than 7 members are cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, etc. Specific unsaturated carbocycles are aromatic such as naphthalene ring, anthracene ring. Specific partially unsaturated carbocyclic groups are cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclononene, cyclodecene, etc.

[0042] The terms "heterocyclic" and "heterocyclic group" are used interchangeably and refer to substituted and unsubstituted 3- to 7-membered monocyclic groups, 7- to 11-membered bicyclic groups, and 10- to 15-membered tricyclic groups that have at least one heteroatom (O, S, or N) in at least one ring, and the ring containing the heteroatom preferably has 1, 2, or 3 heteroatoms selected from O, S, and N. Each ring of such a heteroatom-containing group can contain one or two oxygen or sulfur atoms or one to four nitrogen atoms, provided that the total number of heteroatoms in each ring is four or less, and further provided that the ring contains at least one carbon atom. The nitrogen and sulfur atoms can be optionally oxidized, and the nitrogen atoms can be optionally quaternized. The fused rings that complete the bicyclic and tricyclic groups can contain only carbon atoms and can be saturated, partially saturated, or fully unsaturated. The heterocyclic group can be attached to any available nitrogen or carbon atom.

[0043] Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrol-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, dihydropyridyl, and thianyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and 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, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclic groups containing one heteroatom include, but are not limited to, azocanyl, oxocanyl, and thioctanyl. Exemplary 5-membered heterocyclic groups fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocycles) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinone, etc. Exemplary 6-membered heterocyclic groups fused to an aryl ring (also referred to herein as 6,6-bicyclic heterocycles) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

[0044] Exemplary monocyclic heterocyclic groups include azetidinyl, pyrrolidinyl, oxetanyl, imidazolinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, 1-pyridonyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholine sulfoxide, thiomorpholine sulfone, 1,3-dioxolane, and tetrahydro-1,1-dioxothienyl, etc., in addition to the heteroaryl groups described below. Exemplary bicyclic heterocyclic groups include quinolinyl rings.

[0045] The term "heteroaryl" refers to substituted and unsubstituted aromatic 5- or 6-membered monocyclic groups, 9- or 10-membered bicyclic groups, and 11- to 14-membered tricyclic groups, which have at least one heteroatom (O, S, or N) in at least one ring, and the ring containing the heteroatom preferably has 1, 2, or 3 heteroatoms selected from O, S, and N. Each ring of the heteroaryl containing heteroatoms can contain one or two oxygen or sulfur atoms or one to four nitrogen atoms, provided that the total number of heteroatoms in each ring is four or less and each ring has at least one carbon atom. The fused rings that complete the bicyclic and tricyclic groups can contain only carbon atoms and can be saturated, partially saturated, or unsaturated. The nitrogen and sulfur atoms can be optionally oxidized, and the nitrogen atoms can be optionally quaternized. As a bicyclic or tricyclic heteroaryl must include at least one fully aromatic ring, but one or more of the other fused rings can be aromatic or non-aromatic. The heteroaryl can be attached to any available nitrogen or carbon atom of any ring. Where valence permits, if the other ring is a cycloalkyl or heterocycle, it is additionally optionally substituted with =O (oxo).

[0046] Unless otherwise specified, when referring to a specifically named aryl (e.g., phenyl), heterocyclic group (e.g., pyrrolidinyl, piperidinyl, and morpholinyl), or heteroaryl (e.g., tetrazolyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl, and furyl), the reference is intended to include rings having 0 to 3, preferably 0 to 2 substituents, which are selected from the substituents listed above for aryl heterocyclic groups and / or heteroaryl groups, as appropriate.

[0047] As used 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 a use value in pharmacy, such as a salt formed as an intermediate during chiral resolution. Although such an intermediate salt cannot be directly administered to the subject, the salt can play a role in obtaining the end product of the present invention.

[0048] The term "excipient" refers to a non-toxic carrier, adjuvant, diluent or vehicle that does not destroy the pharmacological activity of the compound formulated with it. Pharmaceutically acceptable excipients that can be used in the manufacture of the pharmaceutical compositions of the present invention are any of those excipients well known in the art of pharmaceutical formulation and include inert diluents, dispersing and / or granulating agents, surfactants and / or emulsifying agents, disintegrants, binders, preservatives, buffering agents, lubricants and / or oils. Pharmaceutically acceptable excipients that can be used in the manufacture of the pharmaceutical compositions of the present invention include, but are not limited to, ion exchange agents, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffering substances such as phosphates, glycine, sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon dioxide, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polypropylene block polymers, polyethylene glycol and lanolin.

[0049] The compositions of the present invention can be administered orally, parenterally (including subcutaneously, intramuscularly, intravenously and intradermally), by inhalation spray, topically, rectally, nasally, orally, vaginally or by an implantable reservoir. In some embodiments, the provided compound or composition is administered intravenously or orally.

[0050] As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intraocular, intravitreal, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intraperitoneal, intralesional and intracranial injection or infusion techniques. Preferably, the composition is administered orally, subcutaneously, intraperitoneally or intravenously. The sterile injectable form of the compositions of the present invention can be an aqueous or oily suspension. These suspensions can be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, in the form of a 1,3-butanediol solution. Acceptable media and solvents that can be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are commonly used as a solvent or suspending medium.

[0051] The pharmaceutically acceptable compositions of the present invention can be administered orally in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, common carriers include lactose and corn starch. Lubricants, such as magnesium stearate, are typically also added. For oral administration in the form of capsules, diluents that can be used include lactose and dry corn starch. When an aqueous suspension for oral use is required, the active ingredient is combined with emulsifying and suspending agents. Certain sweetening, flavoring or coloring agents can also be added as needed. In some embodiments, the oral formulations provided are formulated for immediate release or sustained / delayed release. In some embodiments, the compositions are adapted for buccal or sublingual administration, including tablets, lozenges and troches. The compounds disclosed herein can also be in microencapsulated form.

[0052] The compositions of the present invention can be delivered by percutaneous, by topical route, and formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders and aerosols. Oral formulations include tablets, pills, powders, lozenges, capsules, liquids, lozenges, cachets, gels, syrups, slurries, suspensions, etc. suitable for ingestion by a patient. Solid form formulations include powders, tablets, pills, capsules, cachets, suppositories and dispersible granules. Liquid form formulations include solutions, suspensions and emulsions, such as aqueous or water / propylene glycol solutions

[0053] The cancers of the present invention include those resistant to standard treatments such as surgery, radiotherapy, chemotherapy and hormone therapy, etc.

[0054] "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, spinal and neck cancer, leukemia, liver cancer, lymphoma, melanoma, penile cancer, testicular germ cell cancer, thymoma cancer, thymic carcinoma, 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.

[0055] The "metabolic diseases" include 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 disease, etc.

[0056] The term "PTPN2" refers to non-receptor protein tyrosine phosphatase type 2. The term "PTPN1" refers to non-receptor protein tyrosine phosphatase type 1 (PTPN1), also known as protein tyrosine phosphatase-1B (PTP1B).

[0057] For the purpose of achieving the therapeutic effect and enhancing the treatment efficacy, the drugs or pharmaceutical compositions of the present invention can be administered by any known administration method.

[0058] The compounds or compositions of the present invention can be taken alone or in combination with other therapeutic drugs or symptomatic drugs. When there is a synergistic effect between the compounds of the present invention and other therapeutic drugs, the dosage should be adjusted according to the actual situation.

[0059] Beneficial technical effects

[0060] The inventors of the present invention found that the compounds in the present invention have good protein tyrosine phosphatase inhibitory activity, and the IC 50 or EC 50 is less than that of the positive control drug AC484. The present invention provides a class of protein tyrosine phosphatase inhibitor compounds with novel structures and strong activities, and these compounds have good application prospects in the prevention and / or treatment of indications related to the inhibition of protein tyrosine phosphatase PTPN2 / 1, such as cancer, metabolic diseases, etc. Specific embodiments

[0061] The following examples are helpful for those skilled in the art to better understand the technical solutions of the present invention, but do not limit the present invention in any way.

[0062] For all the following examples, standard operations and methods known to those skilled in the art can be used. Unless otherwise specified, all temperatures are expressed in °C (degrees Celsius). The structures of the compounds are determined by nuclear magnetic resonance spectroscopy (NMR) and / or mass spectrometry (MS).

[0063] The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) or / and liquid chromatography-mass spectrometry (LC-MS). The NMR chemical shift (δ) is in parts per million (ppm). Nuclear magnetic resonance was measured using a Bruker avance-400 nuclear magnetic resonance instrument, and the solvents were deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3), with tetramethylsilane (TMS) as the internal standard.

[0064] For the liquid chromatography-mass spectrometry LC-MS measurement, the liquid phase part uses an ACQUITY UPLC ultra-high pressure liquid chromatography, and the mass spectrometry part uses an Xevo G2-S Qtof mass spectrometer.

[0065] The starting materials in the examples of the present invention are known and can be purchased on the market, or can also be used or synthesized according to methods known in the art.

[0066] Example 1: Synthesis method of 5-(7-(adamantan-1-ylmethyl)amino)-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Compound PTP-1)

[0067]

[0068] Step 1: Synthesis of compound 6-bromo-8-fluoro-3,4-dihydro-1H-spiro[naphthalene-2,2'-[1,3]dioxolane]

[0069] 6-Bromo-8-fluoro-3,4-dihydronaphthalen-2(1H)-one (30 g, 124.0 mmol, 1.0 eq.) and ethylene glycol (10.4 g, 743.9 mmol, 6.0 eq.) were added to toluene (300 mL). At room temperature, 4-toluenesulfonic acid hydrate (4.7 g, 24.8 mmol, 0.2 eq.) was added to the reaction system, and the reaction was carried out at 100 °C for 2 hours. After the reaction was completed, the reactants were cooled to room temperature, and the reaction solution was directly concentrated to remove toluene. It was extracted and separated with ethyl acetate. The organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by silica gel column chromatography (75% petroleum ether, 25% ethyl acetate) to obtain the white solid product 6-bromo-8-fluoro-3,4-dihydro-1H-spiro[naphthalene-2,2'-[1,3]dioxolane] (19.2 g, yield 54.14%). LCMS (ESI) [M+H]+: 287.0. 1H NMR (400 MHz, CDCl3) δ 7.08 (t, J = 1.6 Hz, 1H), 7.02 (dd, J = 8.9, 1.9 Hz, 1H), 4.05–4.00 (m, 4H), 2.97 (t, J = 6.7 Hz, 2H), 2.85 (s, 2H), 1.92 (t, J = 6.7 Hz, 2H). 19F NMR (376 MHz, CDCl3) δ -116.12 (d, J = 8.8 Hz).

[0070] Step 2: Synthesis of compound 6-(benzyloxy)-8-fluoro-3,4-dihydro-1H-spiro[naphthalene-2,2'-[1,3]dioxolane]

[0071] 6-Bromo-8-fluoro-3,4-dihydro-1H-spiro[naphthalene-2,2'-[1,3]dioxolane] (19.2 g, 67.1 mmol, 1.0 eq.), benzyl alcohol (10.2 g, 93.99 mmol, 1.4 eq.), copper(I) iodide (1.27 g, 6.71 mmol, 0.1 eq.), sodium tert-butoxide (7.73 g, 80.52 mmol, 1.2 eq.), N,N'-bis(2-phenylethyl)oxamide (1.99 g, 6.71 mmol, 0.1 eq.) were added to a 1,4-dioxane solution (200 mL). After displacing nitrogen, the reaction was carried out at 100 °C for 16 hours. After the reaction was completed, silica gel was directly added for flash column chromatography purification (75% petroleum ether, 25% ethyl acetate) to obtain the white solid product 6-(benzyloxy)-8-fluoro-3,4-dihydro-1H-spiro[naphthalene-2,2'-[1,3]dioxolane] (12.1 g, yield 57.25%). LCMS (ESI) [M+H]+: 356.0. 1H NMR (400 MHz, DMSO-d6) δ 6.63–6.45 (m, 5H), 5.91–5.81 (m, 2H), 4.24 (s, 2H), 3.14–3.05 (m, 4H), 2.02 (t, J = 6.7 Hz, 2H), 1.88 (s, 2H), 1.00 (t, J = 6.7 Hz, 2H).

[0072] Step 3: Synthesis of compound 6-(benzyloxy)-7-bromo-8-fluoro-3,4-dihydro-1H-spiro[naphthalene-2,2'-[1,3]dioxolane]

[0073] Dissolve 2,2,6,6 - tetramethylpiperidine (8.16 g, 57.78 mmol, 1.5 eq.) in a solution of tetrahydrofuran (500 mL), and displace the system with nitrogen three times. At 0 °C, slowly add n - butyllithium (21.6 mL, 2.5 M, 53.93 mmol, 1.4 eq.) to the system, controlling the addition time to be 40 minutes. After the addition, stir at 0 °C for 30 minutes, dilute the reaction mixture with tetrahydrofuran (500 mL), and cool to - 78 °C. Subsequently, dissolve 6 - (benzyloxy) - 8 - fluoro - 3,4 - dihydro - 1H - spiro[naphthalene - 2,2'-[1,3]dioxolane] (12.1 g, 38.52 mmol, 1.0 eq.) in tetrahydrofuran (500 mL), and slowly add it to the reaction system, controlling the addition time within 30 minutes while maintaining the internal temperature of the reaction system below - 70 °C. Stir for 2 hours, and finally slowly add 1,2 - dibromo - 1,1,2,2 - tetrafluoroethane (12.0 g, 46.22 mmol, 1.2 eq.) while keeping the internal temperature below - 60 °C. After complete addition, warm the reaction mixture to - 10 °C, then quench it with saturated aqueous ammonium chloride solution and dilute with water and ethyl acetate. Separate the layers, wash the organic layer with 1 M hydrochloric acid, saturated aqueous sodium bicarbonate solution, and brine respectively, then dry over anhydrous sodium sulfate, filter, and concentrate in vacuo. Dilute the resulting residue with isopropanol, then heat to 50 °C and slowly cool to ambient temperature, filter to collect the solid, and obtain 6 - (benzyloxy) - 7 - bromo - 8 - fluoro - 3,4 - dihydro - 1H - spiro[naphthalene - 2,2'-[1,3]dioxolane] as a yellow solid (7.95 g, yield 52.51%). LC - MS [M + H]+: 393.0. 1H NMR (400 MHz, DMSO - d6) δ 7.47–7.25 (m, 5H), 6.38 (d, J = 0.9 Hz, 1H), 5.11 (t, J = 0.8 Hz, 2H), 3.97–3.86 (m, 2H), 3.86–3.76 (m, 2H), 3.13 (s, 2H), 2.81–2.73 (m, 2H), 2.11–2.03 (m, 2H).

[0074] Step 4: Synthesis of methyl [6 - (benzyloxy) - 8 - fluoro - 3,4 - dihydro - 1H - spiro[naphthalene - 2,2'-[1,3]dioxolane] - 7 - yl]glycinate

[0075] 6-(Benzyloxy)-7-bromo-8-fluoro-3,4-dihydro-1H-spiro[naphthalene-2,2'-[1,3]dioxolane] (7.95 g, 20.2 mmol, 1.0 eq.), glycine methyl ester hydrochloride (3.29 g, 26.3 mmol, 1.3 eq.), (2'-amino-1,1'-biphenyl-2-yl)palladium(II) bis(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl) (1.83 g, 2.02 mmol, 0.1 eq.), 2-dicyclohexylphosphino-3,6-dimethoxy-2'-4'-6'-tri-I-propyl-11'-biphenyl (2.17 g, 4.04 mmol, 0.2 eq.) and cesium carbonate (13.16 g, 40.4 mmol, 2.0 eq.) were added to a solution of 1,4-dioxane (100 mL). After purging with nitrogen, the reaction was carried out at 100 °C for 16 h. After completion of the reaction, silica gel was directly added and triturated, and normal-phase purification (50% petroleum ether, 50% ethyl acetate) gave the yellow solid product methyl [6-(benzyloxy)-8-fluoro-3,4-dihydro-1H-spiro[naphthalene-2,2'-[1,3]dioxolane]-7-yl]glycinate (6.55 g, yield 62.14%). LCMS (ESI) [M+H]+: 402.2. 1H NMR (400 MHz, DMSO-d6) δ 7.88 (m, J = 5.9, 4.8 Hz, 1H), 7.51–7.20 (m, 5H), 6.34 (t, J = 0.8 Hz, 1H), 5.14 (t, J = 0.8 Hz, 2H), 4.07 (d, J = 5.9 Hz, 2H), 3.97–3.89 (m, 2H), 3.85–3.77 (m, 2H), 3.08 (d, J = 5.0 Hz, 2H), 2.80–2.65 (m, 2H), 2.11–2.02 (m, 2H).

[0076] Step 5: Synthesis of methyl N-[6-(benzyloxy)-8-fluoro-3,4-dihydro-1H-spiro[naphthalene-2,2'-[1,3]dioxolane]-7-yl]-N-[(tert-butoxycarbonyl)sulfamoyl]glycinate

[0077] Under an ice bath, sulfonyl chloride isocyanate (4.26 mL, 48.95 mmol, 3.0 eq.) was mixed with dichloromethane (100 mL), and tert-butanol (4.68 mL, 48.95 mmol, 3.0 eq.) was added dropwise. After reacting for 30 minutes, a mixed solution of methyl [6-(benzyloxy)-8-fluoro-3,4-dihydro-1H-spiro[naphthalene-2,2'-[1,3]dioxolane]-7-yl]glycinate (6.55 g, 16.32 mmol, 1.0 eq.), triethylamine (9.07 mL, 65.27 mmol, 4.0 eq.) and dichloromethane (100 mL) was added dropwise to the reaction solution. After the addition was completed, the temperature was allowed to rise to room temperature naturally, and the reaction was continued for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure, extracted with ethyl acetate and water, washed three times with saturated brine, separated and dried, and concentrated to obtain the crude brown solid methyl N-[6-(benzyloxy)-8-fluoro-3,4-dihydro-1H-spiro[naphthalene-2,2'-[1,3]dioxolane]-7-yl]-N-[(tert-butoxycarbonyl)sulfamoyl]glycinate (7.27 g, crude). LCMS (ESI) [M+H]+: 581.2.

[0078] Step 6: Synthesis of methyl N-[6-(benzyloxy)-8-fluoro-3,4-dihydro-1H-spiro[naphthalene-2,2'-[1,3]dioxolane]-7-yl]-N-sulfamoylglycinate

[0079] Methyl N-[6-(benzyloxy)-8-fluoro-3,4-dihydro-1H-spiro[naphthalene-2,2'-[1,3]dioxolane]-7-yl]-N-[(tert-butoxycarbonyl)aminosulfonyl]glycinate (7.27 g) was added to a solution of dichloromethane (70.0 mL). At 0 °C, trifluoroacetic acid (35 mL) was slowly added. After the addition, the reaction mixture was stirred at room temperature for 2 h. After the reaction was completed, saturated sodium bicarbonate was added to neutralize the mixture to weak alkalinity. The mixture was extracted with dichloromethane three times, dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure, washed with a small amount of acetonitrile, filtered, and the filtrate was purified by normal-phase silica gel column chromatography (40% petroleum ether, 60% ethyl acetate) to obtain the brown solid product methyl N-[6-(benzyloxy)-8-fluoro-3,4-dihydro-1H-spiro[naphthalene-2,2'-[1,3]dioxolane]-7-yl]-N-aminosulfonylglycinate (1.56 g, 25.91%). LCMS (ESI) [M+H]+: 481.2. 1H NMR (400 MHz, Chloroform-d) δ 7.45–7.26 (m, 5H), 6.39 (t, J = 0.9 Hz, 1H), 5.14 (t, J = 0.8 Hz, 2H), 4.70 (s, 2H), 3.97–3.86 (m, 2H), 3.88–3.78 (m, 2H), 3.72 (s, 3H), 3.08 (d, J = 5.0 Hz, 2H), 2.92 (m, J = 14.3, 6.6, 0.9 Hz, 1H), 2.80 (m, J = 14.5, 6.7, 0.9 Hz, 1H), 2.07 (d, J = 13.4 Hz, 2H).

[0080] Step 7: Synthesis of 5-{6-(benzyloxy)-8-fluoro-3,4-dihydro-1H-spiro[naphthalene-2,2'-[1,3]dioxolane]-7-yl}-1,2,5-thiadiazolidine-3-one 1,1-dioxide

[0081] To a solution of methyl N-[6-(benzyloxy)-8-fluoro-3,4-dihydro-1H-spiro[naphthalene-2,2'-[1,3]dioxolane]-7-yl]-N-sulfamoylglycinate (1.56 g, 3.24 mmol, 1.0 eq.) in tetrahydrofuran (20 mL) was added a solution of sodium methoxide (1.2 mL, 5.4 M in MeOH, 6.48 mmol, 2.0 eq.). The reaction was carried out at room temperature for 1 hour. After completion of the reaction, the solid was filtered off, and the product was purified by reverse phase (0.1% formic acid in water and acetonitrile system). When the acetonitrile was 55%, 5-{6-(benzyloxy)-8-fluoro-3,4-dihydro-1H-spiro[naphthalene-2,2'-[1,3]dioxolane]-7-yl}-1,2,5-thiadiazolidine-3-one 1,1-dioxide (0.42 g, yield 28.80%) was obtained. LCMS (ESI) [M+H]+: 449.1. 1H NMR (400 MHz, DMSO-d6) δ 7.58 (s, 1H), 7.46–7.23 (m, 5H), 6.37 (t, J = 0.9 Hz, 1H), 5.15 (t, J = 0.9 Hz, 2H), 4.83 (s, 2H), 3.99–3.87 (m, 2H), 3.89–3.71 (m, 2H), 3.04 (s, 2H), 2.85–2.71 (m, 2H), 2.15–2.02 (m, 2H).

[0082] Step 8: Synthesis of compound 5-[3-(benzyloxy)-1-fluoro-7-oxo-5,6,7,8-tetrahydronaphthalen-2-yl]-1,2,5-thiadiazolidine-3-one-1,1-dioxide

[0083] 5-{6-(Benzyloxy)-8-fluoro-3,4-dihydro-1H-spiro[naphthalene-2,2'-[1,3]dioxolane]-7-yl}-1,2,5-thiadiazolidin-3-one 1,1-dioxide (420 mg, 0.94 mmol, 1.0 eq.) was added to formic acid solution (2 mL), and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, brine was added to dilute the reaction system, and the mixture was allowed to stand to precipitate a solid. The solid was filtered, washed with water, and dried to obtain the product 5-[3-(benzyloxy)-1-fluoro-7-oxo-5,6,7,8-tetrahydronaphthalen-2-yl]-1,2,5-thiadiazolidin-3-one-1,1-dioxide (0.36 g, yield 95.85%). LCMS (ESI) [M-H]+: 402.1. 1H NMR (400 MHz, DMSO-d6) δ 7.43 (d, J = 7.4 Hz, 2H), 7.41 - 7.25 (m, 3H), 7.00 (s, 1H), 5.16 (s, 2H), 4.38 (s, 2H), 3.44 (s, 2H), 3.08–3.01 (m, 2H), 2.51–2.48 (m, 2H).

[0084] Step 9: Synthesis of Compound 5-{7-[(Adamantan-1-ylmethyl)amino]-3-(benzyloxy)-1-fluoronaphthalen-2-yl}-1,2,5-thiadiazolidin-3-one 1,1-dioxide

[0085] The compound 5-[3-(benzyloxy)-1-fluoro-7-oxo-5,6,7,8-tetrahydronaphthalen-2-yl]-1,2,5-thiadiazolidine-3-one 1,1-dioxide (360 mg, 0.89 mmol, 1.0 eq.), 1-(aminomethyl)adamantane (221 mg, 1.34 mmol, 1.5 eq.), triethylamine (270 mg, 2.68 mmol, 3.0 eq.) were mixed with ethanol (5 mL). After stirring for 15 minutes, sodium cyanoborohydride (67 mg, 1.07 mmol, 1.2 eq.) was added. The mixture was stirred for 16 hours, then quenched with a small amount of dilute hydrochloric acid, filtered after adding N,N-dimethylformamide to assist dissolution, most of the solvent was removed by rotary evaporation, and then purified by reverse phase (0.1% formic acid in water and acetonitrile system) to obtain the product 5-{7-[(adamantan-1-ylmethyl)amino]-3-(benzyloxy)-1-fluoronaphthalen-2-yl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (222 mg, yield 45.12%). LCMS (ESI) [M-H]+: 552.2. 1H NMR (400 MHz, DMSO-d6) δ 7.58–7.26 (m, 5H), 6.36 (t, J = 0.8 Hz, 1H), 5.15 (t, J = 0.9 Hz, 2H), 4.83 (s, 2H), 3.92 (m, J = 6.7, 5.6 Hz, 1H), 3.14–3.04 (m, 1H), 2.99–2.84 (m, 2H), 2.81–2.65 (m, 4H), 2.07–1.89 (m, 4H), 1.70 (m, J = 13.5, 8.5, 5.9, 4.4 Hz, 1H), 1.63 (t, J = 5.7 Hz, 6H), 1.52 (d, J = 5.1 Hz, 6H).

[0086] Step 10: Synthesis of compound 5-[7-(adamantan-1-ylmethyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide

[0087] 5-{7-[(Adamantan-1-ylmethyl)amino]-3-(benzyloxy)-1-fluoronaphthalen-2-yl}-1,2,5-thiadiazolidine-3-one 1,1-dioxide (222 mg, 0.402 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (3.0 mL), 5% palladium on carbon (55% water) (200 mg) was added, and the gas was displaced with hydrogen three times. The reaction was carried out at room temperature for 2 hours under a hydrogen atmosphere. After completion of the reaction, the solid was removed by filtration, and purification was performed by HPLC to obtain the white solid 5-[7-(adamantan-1-ylmethyl)amino]-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (15.6 mg, yield 8.40%). LCMS (ESI) [M+H] - : 464.2. 1H NMR (400 MHz, DMSO-d6) δ 8.99 (s, 1H), 7.60 (s, 1H), 6.32 (t, J = 0.9 Hz, 1H), 4.83 (s, 2H), 3.92 (dt, J = 6.7, 5.6 Hz, 1H), 3.14–3.06 (m, 1H), 2.99–2.82 (m, 2H), 2.81–2.73 (m, 1H), 2.72–2.64 (m, 3H), 2.06–1.98 (m, 3H), 1.98–1.91 (m, 1H), 1.70 (m, J = 13.5, 8.5, 5.9, 4.4 Hz, 1H), 1.63 (t, J = 5.7 Hz, 6H), 1.52 (d, J = 5.1 Hz, 6H).

[0088] Example 2: Synthesis method of compound 5-(7-((7-ethyl-7-azaspiro[3.5]nonan-2-yl)methoxy)-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (Compound PTP-2)

[0089]

[0090] Step 1: Synthesis of compound (7-azaspiro[3.5]nonan-2-yl)methanol

[0091] tert-Butyl 2-(hydroxymethyl)-7-azaspiro[3.5]nonane-7-carboxylate (10.0 g, 39.16 mmol, 1.00 eq) was dissolved in dichloromethane (100 mL), cooled to 0 °C, and trifluoroacetic acid (11.16 g, 97.90 mmol, 2.50 eq) was added dropwise. After the addition, the temperature was allowed to rise to 25 °C naturally and the reaction was carried out for 3 hours. After completion of the reaction, the reaction solution was directly evaporated to dryness to obtain (7-azaspiro[3.5]nonan-2-yl)methanol (6.5 g, crude product) LCMS (ESI) [M+H]+: 156.15

[0092] Step 2: Synthesis of compound (7-ethyl-7-azaspiro[3.5]nonan-2-yl)methanol

[0093] Dissolve (7-azaspiro[3.5]nonan-2-yl)methanol (3.00 g, 19.32 mmol, 1.00 eq) in ethanol (20 mL), add acetaldehyde (5.80 mL, 5 mol / L solution in tetrahydrofuran, 1.50 eq), sodium triacetoxyborohydride (12.29 g, 57.97 mmol, 3.00 eq), displace with nitrogen, react at 25 °C for 12 h. After the reaction is completed, most of the ethanol in the reaction solution is removed by rotary evaporation, add saturated aqueous sodium bicarbonate solution, extract with dichloromethane, combine and dry the organic phases, concentrate, and purify by column chromatography to obtain (7-ethyl-7-azaspiro[3.5]nonan-2-yl)methanol (2.6 g, yield 73.4%). LCMS (ESI) [M+H]+: 184.18. 1H NMR (400 MHz, Chloroform-d) δ 3.45 (m, 1H), 2.60–2.50 (m, 1H), 2.45 (s, 1H), 2.55–2.26 (m, 2H), 1.89 (m, 1H), 1.69–1.56 (m, 2H), 1.40–1.27 (m, 2H), 1.04 (t, J = 8.0 Hz, 2H).

[0094] Step 3: Synthesis of compound (7-ethyl-7-azaspiro[3.5]nonan-2-yl)methyl 4-methylbenzenesulfonate

[0095] Dissolve (7-ethyl-7-azaspiro[3.5]nonan-2-yl)methanol (1.00 g, 5.46 mmol, 1.00 eq) in dichloromethane (15 mL), add 4-dimethylaminopyridine (1.00 g, 8.18 mmol, 1.50 eq), p-toluenesulfonyl chloride (1.25 g, 6.55 mmol, 1.20 eq), stir evenly, react at 30 °C for 12 h. After the reaction is completed, directly purify the reaction solution by column chromatography to obtain (7-ethyl-7-azaspiro[3.5]nonan-2-yl)methyl 4-methylbenzenesulfonate (1.32 g, yield 71.7%). 1H NMR (400 MHz, DMSO-d6) δ 7.76–7.70 (m, 1H), 7.48–7.40 (m, 1H), 3.47 (d, J = 7.3 Hz, 1H), 2.77-2.70 (m, 1H), 2.50–2.37 (m, 4H), 1.91-1.86 (m, 1H), 1.67-1.51 (m, 2H), 1.25-1.18 (m, 1H), 1.06 (t, J = 8.0 Hz, 2H).

[0096] Step 4: Synthesis of 5-(3-(Benzyloxy)-1-fluoro-7-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide

[0097] Dissolve 5-[3-(Benzyloxy)-1-fluoro-7-oxo-5,6,7,8-tetrahydronaphthalen-2-yl]-1,2,5-thiadiazolidin-3-one-1,1-dioxide (200 mg, 495 μmol, 1.00 eq) in tetrahydrofuran (5 mL), displace with nitrogen, cool to -70 °C, and add lithium tri-sec-butylborohydride dropwise (594 mmol, 1 mol / L tetrahydrofuran solution, 593 μmol). React at -70 °C for 1 hour. After the reaction is completed, quench the reaction with saturated ammonium chloride aqueous solution, extract with dichloromethane, concentrate the organic phase, and purify by column chromatography to obtain 5-(3-(Benzyloxy)-1-fluoro-7-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (164 mg, yield 81%). LCMS (ESI) [M+H]-: 405.08. 1H NMR (400 MHz, DMSO-d6) δ 7.51–7.43 (m, 2H), 7.43–7.27 (m, 3H), 7.23 (s, 1H), 6.48 (d, J = 1.2 Hz, 1H), 5.32–5.20 (m, 2H), 5.20 (s, 1H), 4.95 (d, J = 18.4 Hz, 1H), 4.74 (d, J = 4.8 Hz, 1H), 3.85 - 3.77 (m, 1H), 3.11 - 3.05 (m, 1H), 2.83–2.73 (m, 3H), 1.97 - 1.89 (m, 1H), 1.75–1.59 (m, 1H).

[0098] Step 5: Synthesis of 5-(3-(Benzyloxy)-7-((7-ethyl-7-azaspiro[3.5]nonan-2-yl)methoxy)-1-fluoro-5,6,7,8-tetrahydronaphthalen-2-yl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide

[0099] 5-(3-(Benzyloxy)-1-fluoro-7-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (150 mg, 369 μmol, 1.00 eq), (7-ethyl-7-azaspiro[3.5]nonan-2-yl)methyl 4-methylbenzenesulfonate (187 mg, 553 μmol, 1.50 eq) were dissolved in dioxane (5 mL). Potassium hydroxide (42 mg, 738 μmol, 2.00 eq) was dissolved in water (1 mL) and added to the above reaction solution. The reaction was carried out at 50 °C for 12 hours. After the reaction was completed, the reaction solution was cooled, extracted with dichloromethane, and the organic phases were combined and purified by reverse phase to obtain 5-(3-(benzyloxy)-7-((7-ethyl-7-azaspiro[3.5]nonan-2-yl)methoxy)-1-fluoro-5,6,7,8-tetrahydronaphthalen-2-yl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (62 mg, yield 29.3%). LCMS (ESI) [M+H]-: 570.23. 1H NMR (400 MHz, DMSO-d6) δ 7.54–7.43 (m, 2H), 7.45–7.26 (m, 3H), 6.48 (d, J = 1.4 Hz, 1H), 5.34–5.14 (m, 3H), 3.74 - 3.67 (m, 1H), 3.29 (d, J = 6.9 Hz, 2H), 3.14 - 3.08 (m, 1H), 2.87–2.70 (m, 5H), 2.56–2.40 (m, 5H), 2.03–1.83 (m, 3H), 1.76–1.50 (m, 5H), 1.36 - 1.30 (m, 1H), 1.24 - 1.18 (m, 1H), 1.06 (t, J = 8.0 Hz, 3H).

[0100] Step 6: Synthesis of 5-(7-((7-ethyl-7-azaspiro[3.5]nonan-2-yl)methoxy)-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide

[0101] 5-(3-(Benzyloxy)-7-((7-ethyl-7-azaspiro[3.5]nonan-2-yl)methoxy)-1-fluoro-5,6,7,8-tetrahydronaphthalen-2-yl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (60 mg, 105 μmol, 1.00 eq) was dissolved in tetrahydrofuran (3.0 mL), 5% palladium on carbon (55% water) (60 mg) was added, and the gas was displaced with hydrogen three times. The reaction was carried out at room temperature for 2 hours under a hydrogen atmosphere. After completion of the reaction, the solid was removed by filtration and purified by HPLC preparation to obtain the white solid 5-(7-((7-ethyl-7-azaspiro[3.5]nonan-2-yl)methoxy)-1-fluoro-3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide (3.5 mg, yield 6.9%). LCMS (ESI) [M+H]-: 480.18. 1H NMR (400 MHz, DMSO-d6) 7.57 (s, 1H), 6.25 (s, 1H), 5.54 (d, J = 18.5 Hz, 1H), 4.50 (d, J = 18.4 Hz, 1H), 3.71 - 3.64 (m, 1H), 3.29 (d, J = 8.0 Hz, 2H), 3.13 - 3.06 (m, 1H), 2.86–2.70 (m, 6H), 2.56–2.40 (m, 5H), 1.98 - 1.80 (m, 3H), 1.70–1.55 (m, 6H), 1.32–1.23 (m, 2H), 1.06 (t, J = 8.0 Hz, 3H).

[0102] Intermediates 1-8 and 2-4 were prepared by methods similar to those described in Examples 1 and 2, and the compounds listed in Table 1 below were prepared respectively, with appropriate changes in the amounts of reactants, reagents, protection and deprotection, solvents and reaction conditions. The characterization data of the compounds are summarized in Table 1 below.

[0103] Table 1: Structures and Characterizations of Some Compounds

[0104]

[0105]

[0106] Experimental Example 1: Activity Test of the Compounds of the Present Invention on PTPN2 / 1 Protease

[0107] Experimental Purpose: The purpose of this test example is to test the effect of the compounds on the function of PTPN2 / 1 enzyme

[0108] Background 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. The phosphatase 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 for inflammatory responses. p-Nitrophenyl phosphate (pNPP) is one of the most commonly used substrates for phosphatases. After adding the substrate to the microplate well, under the action of the phosphatase, PNPP generates a yellow water-soluble reaction product, and the solution turns yellow with p-nitrophenol. This reaction product has a large light absorption at 405 nm.

[0109] Experimental procedure:

[0110] Expression of PTPN2 / 1 protein: The PTPN2 sequence (residues 1 - 314) was cloned into the pET28A vector with a (His)6x tag; the PTPN1 sequence (residues 1 - 321) was cloned into the pET15B vector with a (His)6x tag. The constructed vectors were transformed into Escherichia coli BL21(DE3). When the OD reached 0.6 during shaking culture, 1 mM IPTG was added and cultured at 12 °C for 16 h. The bacterial cells were collected, lysed by sonication, and the supernatant was obtained by centrifugation. The protein was purified by Ni-NTA, and the protein concentration and purity were determined after dialysis. Then it was aliquoted and stored at -80 °C.

[0111] Enzyme activity assay of PTPN2 / 1: In the experimental buffer containing 25 mM Tris HCl (pH 7.4), 50 mM NaCl, and 1 mM DTT, the phosphatase activity of PTPN2 (or 1) was measured by monitoring the hydrolysis of p-nitrophenyl phosphate (pNPP) to p-nitrophenol. In the reaction system, the enzyme concentration was fixed at 50 nM, the pNPP concentration was 50 μM, and the total reaction volume was 100 μL. 1. Mix the enzyme and the compound and incubate at 30 °C for 10 minutes; 2. Add pNPP to the enzyme and compound mixture and incubate at 30 °C for 30 minutes; 3. Add 100 μL of 1 M NaOH to stop the reaction, and then measure the absorbance at 405 nm using a microplate reader. The IC50 was calculated by processing with GraphPad software, and compounds were screened by comparing with the positive drug ABBV-CLS-484 (abbreviated as AC484).

[0112] IC50 (half maximal inhibitory concentration) refers to the half inhibitory concentration of the antagonist being measured. It can indicate the half amount of a certain drug or substance (inhibitor) in inhibiting certain biological processes (or certain substances included in this process, such as enzymes, cell receptors, or microorganisms). Using AC484 as a positive reference compound, its synthesis method refers to patent CN114025844B. The structure of ABBV-CLS-484 is as follows:

[0113]

[0114] Determine the IC 50 value obtained for the protease functions of PTPN2 and PTPN1 by each compound. The results show that compounds 1-13 have good inhibitory effects on PTPN2 and PTPN1 enzymes.

[0115] Experimental Example 2: Determination of the effect of the compounds of the present invention on the proliferation of B16F10 cells

[0116] Experimental purpose: The purpose of this test example is to test the determination of the effect of the compounds on the proliferation of B16F10 cells

[0117] Background principle: IFNγ is a cytokine produced by immune system cells such as T cells or NK cells, which can inhibit the growth of certain cancer types, including melanoma. Inhibiting IFNγ signaling can promote tumor growth. On the contrary, enhancing IFNγ signaling can enhance tumor growth inhibition. Since PTPN2 and PTPN1 are negative regulators of cytokine signaling, including IFNγ signaling, through the dephosphorylation of JAK and STAT proteins, in the presence of IFNγ, an effective compound can inhibit the growth of tumor cells.

[0118] Experimental procedure:

[0119] B16F10 cells were cultured in DMEM + 10% FBS + 1% P / S growth medium. B16F10 cells in the logarithmic growth phase were inoculated into a 96-well plate, 100 μl per well, 500 cells / well, and left standing overnight in a 37°C incubator. On the second day, 50 μl of mouse IFN-γ (final concentration 0.5 ng / ml) was added; 50 μl of compounds at different concentrations (final concentration of DMSO 1%) was added, and incubated in a 37°C incubator for 5 days. On the sixth day, the old medium was aspirated, and 110 ul of medium (the ratio of medium to CCK8 is 100:10) was added, and incubated at 37°C for 1-4 h. The absorbance value was detected at 450 nM, and the IC 50 was calculated by processing with GraphPad software, and compounds were screened by comparing with the positive drug AC484.

[0120] The results showed that compounds 1-13 had good inhibitory effects on the proliferation of B16F10 cells.

[0121] Experimental Example 3: Determination of the effect of the compounds of the present invention on the phosphorylation of STAT1 in cells

[0122] Experimental purpose: The purpose of this test example is to test the determination of the effect of the compounds on the phosphorylation of STAT1 in cells

[0123] Background principle: PTPN2 / N1 inhibits inflammation by removing the phosphorylation of JAK and STAT family members. PTPN2 also targets proximal TCR signaling molecules, thereby inhibiting the antigen sensitivity of T cells. Therefore, after incubation with the compounds, the phosphorylation level of STAT in B16F10 cells can be detected by WB for the screening of inhibitors.

[0124] Experimental procedure:

[0125] B16F10 cells were cultured in DMEM + 10% FBS + 1% P / S growth medium. B16F10 cells in the logarithmic growth phase were seeded in 24-well plates, 450 μl per well, 200,000 cells per well, and left standing overnight in a 37 °C incubator. On the second day, 50 μl of compounds with different concentrations (the final concentration of DMSO was 1%) were added and incubated at 37 °C for 3 h; then stimulated with 100 ng / ml mouse IFN-γ for 10 min, and the cells were collected for WB. Protein electrophoresis: The voltage of the stacking gel was set at 60 v, and the voltage of the separating gel was set at 120 v; after electrophoresis, electrotransfer was started. The conditions for electrotransfer were set at 250 mA for 2 h; blocked with 5% BSA for 1 h; added with specific primary antibody and incubated overnight on a shaker at 4 °C; washed 4 times with TBST, 2.5 min each time; incubated with secondary antibody on a shaker at room temperature for 1 h; washed 4 times with TBST, 2.5 min each time; developed using ECL. The western blot bands were processed by image J and GraphPad software to calculate IC 50 , and the compounds were screened by comparing with the positive drug AC484.

Claims

1. A compound of formula (I), its isomers, or a pharmaceutically acceptable salt thereof: Wherein, A is selected from a carbocyclic ring having 7 or more carbon atoms, a heterocyclic ring having 7 or more atoms and containing 1 to 3 heteroatoms selected from N, O or S, or a heteroaromatic ring having 7 or more atoms and containing 1 to 3 heteroatoms selected from N, O or S, which is optionally substituted with one or more substituents R3; R3 is selected from oxo, -C1-C6 alkyl, -C1-C6 haloalkyl; X is selected from O, NR; R is selected from H, -C1-C6 alkyl, -C1-C6 haloalkyl, -C3-C6 cycloalkyl; L is selected from a chemical bond, -(CH2)n-; n is 1, 2 or 3; R1 and R2 are each independently selected from H, halogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -CN, -ORa1, -NRa2Ra3; Ra1, Ra2 and Ra3 are each independently selected from H, -C1-C6 alkyl, -C3-C6 cycloalkyl.

2. The compound according to claim 1, its isomers, or its pharmaceutically acceptable salts, characterized in that, The compound is selected from:

3. A compound selected from the following formula, its isomers, or a pharmaceutically acceptable salt thereof:

4. A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, and one or more pharmaceutically acceptable carriers, diluents or excipients.

5. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-3 or the pharmaceutical composition according to claim 4 in the preparation of a drug for treating a disease or disorder by inhibiting PTPN1 / PTPN2.

6. The pharmaceutical use according to claim 5, wherein the disease or disorder is cancer, a rheumatic disease, an inflammatory disease, an immune disease, a metabolic disease, an infectious disease, a neurodegenerative disease, a genetic disease, a 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, spinal and neck cancer, leukemia, liver cancer, lymphoma, melanoma, penile cancer, testicular germ cell cancer, thymoma cancer, thymic carcinoma, 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 disease; the infectious disease is preferably selected from bubonic plague; the genetic disease is preferably selected from Noonan syndrome, retinopathy.

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