PTPN2 / PTPN1 inhibitor, preparation method therefor and medical use thereof

Abstract

The present invention belongs to the technical field of medicine, and specifically relates to a PTPN2 / PTPN1 inhibitor, a preparation method therefor, and the medical use thereof. Provided are a compound represented by formula (I), a composition thereof and the use thereof. The compound can be used for treating or preventing PTPN2 / PTPN1-mediated diseases or disorders.

Description

PTPN2 / PTPN1 inhibitors, their preparation methods, and pharmaceutical uses Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to the compound shown in formula (I) or its stereoisomers, tautomers, deuterated derivatives or pharmaceutical salts, as well as their preparation methods and applications in medicine. Background Technology

[0002] Protein tyrosine phosphorylation (pTyr) is a common post-translational modification that creates novel recognition motifs for protein-protein interactions and cellular localization, affects protein stability, and regulates enzyme activity. Therefore, maintaining appropriate levels of protein tyrosine phosphorylation is crucial for many cellular functions. Tyrosine-specific protein phosphatases (PTPases) catalyze the removal of phosphate groups linked to tyrosine residues using cysteyl phosphatase intermediates. These enzymes are key regulators of signal transduction pathways (such as the MAP kinase pathway) and the cell cycle, and play important roles in the control of cell growth, proliferation, differentiation, transformation, and synaptic plasticity.

[0003] Genome sequencing has revealed at least four classes of proteins with potential PTP activity, totaling more than 100. Non-receptor protein tyrosine phosphatases type 2 (PTPN2, TC-PTP) and type 1 (PTPN1, PTP1B) are two widely expressed classic PTPs, belonging to the non-receptor phosphatase family, and their catalytic domains share more than 74% identity.

[0004] In tumor cells, inhibition of PTPN2 / N1 (a negative regulator) can promote IFN inflammatory signaling through the JAK / STAT pathway, leading to growth retardation, increased tumor antigen presentation, and increased release of pro-inflammatory chemokines. In immune cells, inhibition of PTPN2 / N1 can promote the activation of various immune cell subsets and their pro-inflammatory and anti-tumor functions. For example, in T cells, PTPN2, as a negative regulator of TCR signaling, can increase T cell activation, proliferation, and immune effector function upon inhibition, thus producing a tumor-suppressive effect. Simultaneously, studies have shown that PTPN2 inhibition can increase PD-L1 expression, producing a synergistic effect when combined with anti-PD-1 (L1) monoclonal antibodies.

[0005] Patents WO2020186199 and WO2022056281 disclose a PTPN2 / N1 inhibitor developed by Calico (see structural formulas I / II). The structural feature of its parent core is the use of a benzo[6] saturated carbon ring or a benzo[6] saturated heterocyclic ring. The representative compound, ABBV-CLS-484, is currently in Phase I clinical trials. Calico plans to conduct studies on advanced solid tumors such as recurrent or refractory head and neck squamous cell carcinoma, recurrent or refractory non-small cell lung cancer, and advanced clear cell renal cell carcinoma, combining it with anti-PD-1 or PD-L1 monoclonal antibodies to combat PD-1 or PD-L1 monoclonal antibody resistance, or combining it with VEGFR kinase inhibitors for the treatment of locally advanced or metastatic recurrent or refractory head and neck squamous cell carcinoma, recurrent or refractory non-small cell lung cancer, and highly microsatellite unstable tumors. Preclinical studies have shown that ABBV-CLS-484 can enhance the sensitivity of tumor cells to IFN-γ and enhance T cell function, demonstrating excellent single-drug or combination anti-tumor activity in various tumor models.

[0006] However, there are currently no PTPN2 / PTPN1 inhibitors on the market, and the pharmacokinetics of ABBV-CLS-484 are poor, which may limit its clinical application. Therefore, it is necessary to develop new PTPN2 / PTPN1 inhibitors to meet clinical needs. Summary of the Invention

[0007] The technical problem to be solved by the present invention is to provide a novel tetrahydronaphthalene compound that can be used as a PTPN2 / PTPN1 inhibitor for the preparation of drugs for treating PTPN2 / PTPN1-mediated diseases or symptoms.

[0008] To solve the above-mentioned technical problems, the technical solution provided by the present invention is as follows:

[0009] On the one hand, the present invention provides a compound of formula (I), or a stereoisomer, tautomer, deuterated product, or pharmaceutical salt thereof:

[0010] in,

[0011] R 1 R 2 Each is independently selected from hydrogen, -R 1a -C(O)-R 1b -R 1a -C(O)OR 1b -R 1a -C(O)NR 1b R 1c -R 1a -C(O)OR 1b -OR1c -R 1a -C(O)OR 1b -OC(O)-R 1c -R 1a -OC(O)-R 1b -R 1a -OC(O)OR 1b -R 1a -OC(O)NR 1b R 1c -R 1a -SR 1b -R 1a -SR 1b -OR 1c -R 1a -SC(O)-R 1b -R 1a -SC(O)OR 1b -R 1a -SC(O)NR 1b R 1c -R 1a -P(O)(OR 1b (OR) 1c )-、-R 1a -P(O)(OR 1b SR 1c (OR) 1d SR 1e )-、-R 1a -P(O)(OR 1b OR 1c (OR) 1d OR 1e - or -R 1a -P(O)(OR 1b SR 1c (OR) 1d OR 1e )-;

[0012] And R 1 and R 2 They are not both hydrogen;

[0013] R 3 Selected from C 1-6 Alkyl, the C 1-6 Alkyl groups may optionally be further subjected to one or more R a replace;

[0014] R 1a R 1b R 1c R 1d R 1eEach is independently selected from non-existent, hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1- 6-alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-12 Aryl or 5-14 heteroaryl, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-12 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-12 aryl or 5-14 heteroaryl groups may be further substituted with one or more R groups. a replace;

[0015] R a Independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkyl sulfone group, C 1-6 alkylamine group, C 3-12 Cycloalkyl, 3-14 membered heterocyclic, 5-14 membered heteroaryl or C 6-12 Aryl, the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkyl sulfone group, C 1-6 alkylamine group, C 3-12 Cycloalkyl, 3-14 membered heterocyclic, 5-14 membered heteroaryl or C 6-12 The aryl group may be further selected by one or more groups chosen from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl or C 1-6 The substituents of the haloalkoxy group are replaced.

[0016] In some implementations, the R 3 Selected from C 1-6 Alkyl, the C 1-6 Alkyl groups may optionally be further divided by one or more groups selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, or C. 3-12 Substituents of cycloalkyl groups.

[0017] In some implementations, the R 3 Selected from

[0018] In some embodiments, the compound has a structure as shown in formulas (IIa), (IIb), (IIc), (IId), (IIe), or (IIIf):

[0019] Among them, R 1 R 2 The definition is as stated in general formula (I).

[0020] In some embodiments, the compound has a structure as shown in formula (IIIa), (IIIb), or (IIIc):

[0021] Among them, R 1 R 2 The definition is as stated in general formula (I).

[0022] In some implementations, the R 1 Selected from hydrogen, -C(O)-R 1b -C(O)NR 1b R 1c or -R 1a -OC(O)-R 1b ;

[0023] The R 1a Selected from C 1-6 alkyl;

[0024] The R 1b R 1c Each is independently selected from C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-12 Aryl or 5-14 heteroaryl, wherein C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-12 aryl or 5-14 heteroaryl groups optionally further selected from one or more groups selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, 3-14 membered heterocyclic groups, C 6-12 Substituents of aryl or 5-14 heteroaryl groups.

[0025] In some implementations, the R 1 Selected from hydrogen,

[0026] In some implementations, the R 2 Selected from hydrogen, -C(O)OR 1b or -C(O)OR 1b -OC(O)-R 1c ;

[0027] The R 1b R 1c Each is independently selected from C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-12 Aryl or 5-14 heteroaryl, wherein C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-12 aryl or 5-14 heteroaryl groups optionally further selected from one or more groups selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, 3-14 membered heterocyclic groups, C 6-12 Substituents of aryl or 5-14 heteroaryl groups.

[0028] In some implementations, the R 2 Selected from hydrogen,

[0029] In some embodiments, the compound is selected from...

[0030] On the other hand, the present invention provides a pharmaceutical composition comprising a compound represented by formula (I), (IIa), (IIb), (IIc), (IId), (IIe), (IIIf), (IIIa), (IIIb) or (IIIc), or a stereoisomer, tautomer, deuterated product or pharmaceutical salt thereof.

[0031] In another aspect, the present invention provides the use of compounds, stereoisomers, tautomers, deuterated derivatives or pharmaceutical salts thereof, as shown in formulas (I), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIIa), (IIIb) or (IIIc) above, in the preparation of medicaments for the prevention or treatment of PTPN2 / PTPN1 mediated diseases or conditions.

[0032] In another aspect, the present invention provides the use of compounds, stereoisomers, tautomers, deuterated derivatives or pharmaceutical salts thereof, as shown in formulas (I), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIIa), (IIIb) or (IIIc) above, in the prevention or treatment of diseases or conditions mediated by PTPN2 / PTPN1.

[0033] In another aspect, the present invention provides a method for treating and / or preventing a disease, comprising administering to a therapeutically effective amount of a compound represented by formula (I), (IIa), (IIb), (IIc), (IId), (IIe), (IIIf), (IIIa), (IIIb), or (IIIc) above, or a stereoisomer, tautomer, deuterated product, or pharmaceutical salt thereof, or a pharmaceutical composition thereof, to a therapeutic subject; wherein the disease treated and / or prevented is a PTPN2 / PTPN1 mediated disease or condition.

[0034] In some implementations, the PTPN2 / PTPN1-mediated disease or condition is a tumor or cancer.

[0035] In some embodiments, the tumor or cancer is selected from head and neck squamous cell carcinoma, clear cell renal cell carcinoma, high microsatellite instability tumor, glioma (glioblastoma), acute myeloid leukemia, acute myeloid leukemia, myelodysplastic / myeloproliferative neoplasm, sarcoma, chronic myelomonocytic leukemia, non-Hodgkin lymphoma, astrocytoma, melanoma, non-small cell lung cancer, small cell lung cancer, cholangiocarcinoma, chondrosarcoma, colon cancer, colorectal cancer, rectal cancer, or pancreatic cancer.

[0036] Unless otherwise stated, the general chemical terms used in the structural formulas have their usual meanings.

[0037] For example, unless otherwise stated, the term "halogen" as used in this invention refers to fluorine, chlorine, bromine, or iodine.

[0038] In this invention, unless otherwise stated, "alkyl" includes straight-chain or branched monovalent saturated hydrocarbon groups. For example, alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl, etc. Similarly, "C 1-6 "alkyl" 1-6 "" refers to a group consisting of 1, 2, 3, 4, 5 or 6 carbon atoms arranged in a straight or branched form.

[0039] The term "cyano" refers to the -CN group; "hydroxyl" refers to the -OH group; "amino" refers to the -NH2 group; and "mercapto" refers to the -SH group.

[0040] The term "alkoxy" refers to the oxygen ether form of the aforementioned straight-chain or branched alkyl group, i.e., -O-alkyl.

[0041] The term "halogenated alkyl" refers to an alkyl group in which one or more H atoms have been replaced by halogen atoms.

[0042] The term "haloalkoxy" refers to a group consisting of -O-haloalkyl groups.

[0043] The term "oxo" or "oxo group" refers to an oxygen atom in the form of a divalent substituent, which forms a carbonyl group when attached to a carbon atom, and a sulfoxide group, sulfone group, or N-oxide group when attached to a heteroatom.

[0044] The term "alkenyl" refers to an alkyl group having one or more carbon-carbon double bonds, such as vinyl, propenyl, 1,3-butadiene, cis-butenyl, trans-butenyl, etc.

[0045] The term "alkynyl" refers to an alkyl group having one or more carbon-carbon triple bonds, such as ethynyl, propynyl, etc.

[0046] The term "cycloalkyl" refers to a cyclic system having at least one cycloalkyl group. Preferably, C 3-12 Cycloalkyl, more preferably C 3-6 Yuan, of which "C" 3- 12 The term "cycloalkyl" refers to the fact that a cycloalkyl group can have 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 cyclic atoms. The cycloalkyl group can include monocyclic and polycyclic rings (e.g., having 2, 3, or 4 fused rings, spirocyclic, bridged rings, etc.). In some embodiments, the cycloalkyl group includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, etc.; the cycloalkyl group can also be fused to an aryl, heterocyclic, or heteroaryl ring, wherein the ring connected to the parent structure is a cycloalkyl group.

[0047] The term "aryl," in this invention, unless otherwise stated, refers to an unsubstituted or substituted monocyclic or fused-ring aromatic group comprising a carbide ring atom. Preferably C 6-12 aryl, more preferably aryl is C 6-10 Aromatic ring groups, either monocyclic or bicyclic. Preferably phenyl or naphthyl. The aryl ring may be fused to a heteroaryl, heterocyclic, or cycloalkyl group, wherein the ring attached to the parent structure is an aryl ring; non-limiting examples include, but are not limited to, benzocyclopentyl.

[0048] The term "heteroaryl" in this invention, unless otherwise stated, refers to a monocyclic or polycyclic (e.g., fused bicyclic) aromatic heterocycle having at least one heteroatom selected from N, O, and / or S, wherein the nitrogen or sulfur heteroatom is selectively oxidized, and the nitrogen heteroatom is selectively quaternized. Preferably, it is a 5-14 membered heteroaryl, wherein "5-14" in 5-14 membered heteroaryl refers to a heteroaryl containing 5-14 cyclic atoms of C, N, O, or S. More preferably, it is a 5-10 membered heteroaryl, and even more preferably, it is a 5-6 membered heteroaryl. Examples of heteroaryl groups include, but are not limited to, thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrroloyl, thiazolyl, thiadiazolyl, triazolyl, pyridinyl, pyridazinyl, indolyl, azaindolyl, indolyl, benzimidazolyl, benzofuranyl, benzothiophene, benzoisoxazolyl, benzothiazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyladenine, quinolinyl, or isoquinolinyl. The heteroaryl group may be fused to an aryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring.

[0049] The term "heterocyclic group" refers to a ring system having at least one cyclic alkyl or cyclic alkenyl group containing a heterocycle, wherein the heteroatom is selected from N, O, and / or S. The heterocyclic group can include monocyclic or polycyclic groups (e.g., having 2, 3, or 4 fused rings, spirocyclic, bridged rings, etc.). The heterocyclic group can be connected to other parts of the compound via cyclic carbon atoms or cyclic heteroatoms. Preferably, it is a 3-14 membered heterocyclic group, where "3-14" refers to a heterocyclic group consisting of 3-14 cyclic atoms of C, N, O, or S; more preferably, it is a 3-6 membered heterocyclic group, and even more preferably, a 5-6 membered heterocyclic group; wherein the nitrogen or sulfur heteroatom can be selectively oxidized, and the nitrogen heteroatom can be selectively quaternized. Examples of these heterocyclic groups include, but are not limited to, aza-butyl, pyrrolidinyl, piperidinyl, piperazinyl, oxoperazinyl, oxoperridinyl, tetrahydrofuranyl, dioxopentyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, and tetrahydrooxadiazolyl. Spiroheterocycles can be 6- to 12-membered spiroheterocycles, including, but not limited to, 4-azaspiro[2,4]heptane and 4-azaspiro[2,4]heptane. The heterocyclic group can be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group.

[0050] The term "alkylamine" refers to an open-chain alkyl group containing a nitrogen atom, such as C... 1-6 Alkylamine groups, including but not limited to methylamino, ethylamino, isopropylamino, dimethylamino, methylethylamino, diethylamino, etc.

[0051] The term "alkathioyl" refers to a straight-chain or branched alkyl group linked by sulfur atoms, i.e., -S-alkyl, such as C1-6 Alkylthio groups include, but are not limited to, methylthio, ethylthio, propylthio (including n-propylthio and isopropylthio), butylthio (including n-butylthio, isobutylthio, sec-butylthio, and tert-butylthio), pentylthio (including n-pentylthio, isopentylthio, and neopentylthio), and hexylthio (n-hexylthio, 2-methylpentylthio, 3-methylpentylthio, 2,3-dimethylbutylthio, and 2,2-dimethylbutylthio).

[0052] The term "alkylsulfonyl" refers to a straight-chain or branched alkyl group linked by a sulfone group, i.e., -SO2-alkyl, such as C 1-6 Alkyl sulfone groups, including but not limited to methyl sulfone, ethyl sulfone, propane sulfone (including n-propane sulfone and isopropane sulfone), butyl sulfone (including n-butyl sulfone, isobutyl sulfone, sec-butyl sulfone, and tert-butyl sulfone), pentyl sulfone (including n-pentyl sulfone, isopentyl sulfone, and neopentyl sulfone), and hexyl sulfone (n-hexyl sulfone, 2-methylpentyl sulfone, 3-methylpentyl sulfone, 2,3-dimethylbutyl sulfone, and 2,2-dimethylbutyl sulfone), etc.

[0053] The term "medicinal salt" refers to salt prepared from a pharmaceutically acceptable, non-toxic alkali or acid.

[0054] The "compound" described in this invention includes, but is not limited to, compounds in the following forms: free base, stereoisomer, geometric isomer, tautomer, isotope, pharmaceutically acceptable salt, solvate, hydrate, prodrug (ester), etc.

[0055] The "compound" described in this invention can be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers include, for example, enantiomers and diastereomers. Compounds containing asymmetric carbon atoms in this invention can be isolated in optically active pure form or in racemic form. Optically active pure form can be obtained by resolution of racemic mixtures, synthesis using chiral starting materials or chiral reagents.

[0056] The term “pharmaceutically acceptable” as used herein refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0057] The term "pharmaceutically acceptable salt" refers to a salt of the compounds of this invention, prepared by reacting a compound having specific substituents discovered in this invention with a relatively non-toxic acid or base. When the compounds of this invention contain relatively acidic functional groups, a base addition salt can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts or similar salts. When the compounds of this invention contain relatively basic functional groups, an acid addition salt can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. Certain specific compounds of this invention contain both basic and acidic functional groups, and thus can be converted into either a base or an acid addition salt.

[0058] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture thereof.

[0059] When the compounds provided by this invention are acids, their corresponding salts can be conveniently prepared from pharmaceutically acceptable, non-toxic bases, including inorganic and organic bases. Salts derived from inorganic bases include salts of aluminum, ammonium, calcium, copper (high and low valence), ferric iron, ferrous iron, lithium, magnesium, manganese (high and low valence), potassium, sodium, zinc, etc. Salts of ammonium, calcium, magnesium, potassium, and sodium are particularly preferred. Non-toxic organic bases capable of being derived into pharmaceutically acceptable salts include primary, secondary, and tertiary amines, as well as cyclic amines and amines containing substituents, such as naturally occurring and synthetic amines containing substituents. Other pharmaceutically acceptable non-toxic organic bases that can form salts include ion exchange resins, as well as arginine, betaine, caffeine, choline, N',N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucosamine, glucosamine, histidine, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resins, procaine, chloroprocaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.

[0060] When the compounds provided by this invention are bases, pharmaceutically acceptable non-toxic acids, including inorganic and organic acids, can be used to conveniently prepare their corresponding salts. Such acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucilage, nitric acid, pyric acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, oxalic acid, propionic acid, glycolic acid, hydroiodic acid, perchloric acid, cyclohexanesulfonic acid, salicylic acid, 2-naphthalenesulfonic acid, saccharinic acid, trifluoroacetic acid, tartaric acid, and p-toluenesulfonic acid, etc.

[0061] Unless otherwise stated, the term "isomer" is intended to include geometric isomers, cis-trans isomers, stereoisomers, enantiomers, optical isomers, diastereomers and tautomers.

[0062] The compounds described in this invention may contain one or more asymmetric centers, and may thereby produce diastereomers and optical isomers. This invention includes all possible diastereomers and their racemic mixtures, their substantially pure enantiomers, all possible geometric isomers, and their pharmaceutical salts.

[0063] Unless otherwise stated, this invention includes any possible tautomers and their pharmaceutical salts, and mixtures thereof, when the compounds represented by formulas (I), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIIa), (IIIb), or (IIIc) are present.

[0064] The compounds of this invention may contain atomic isotopes in non-natural proportions on one or more atoms constituting the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium. 3 H), Iodine-125 125 I) or C-14 14 C). For example, deuterium can be used to replace hydrogen to form deuterated drugs. The bond between deuterium and carbon is stronger than that between ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged drug biological half-life. All isotopic variations of the compounds of this invention, regardless of radioactivity, are included within the scope of this invention.

[0065] This invention also includes atoms of all isotopes, whether in intermediates or final compounds. Isotopic atoms include those having the same number of atoms but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

[0066] The term "pharmaceutical composition" refers to a mixture of one or more compounds of this application or their pharmaceutical salts with pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate the administration of the compounds of this application to an organism.

[0067] In this invention, the terms "a," "an," "the," "at least one," and "one or more" are used interchangeably. Thus, for example, a mixture comprising "a" pharmaceutically acceptable excipient can be interpreted as indicating that the pharmaceutical composition includes "one or more" pharmaceutically acceptable excipients.

[0068] The term "pharmaceuticalally acceptable excipient" refers to excipients that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

[0069] The pharmaceutical compositions of the present invention can be prepared by combining the compounds of this application with suitable pharmaceutically acceptable excipients, for example, in solid, semi-solid, liquid or gaseous formulations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalers, gels, microspheres and aerosols.

[0070] Typical routes of administration for the compounds of the present invention or their pharmaceutical salts or pharmaceutical compositions include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, nasal, ocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0071] The term "treatment" generally refers to achieving the desired pharmacological and / or physiological effect. This effect can be therapeutic, depending on whether it partially or completely stabilizes or cures the disease and / or causes side effects due to the disease. As used herein, "treatment" encompasses any treatment of a patient's disease, including: (a) suppressing the symptoms of the disease, i.e., preventing its progression; or (b) alleviating the symptoms of the disease, i.e., causing the disease or symptoms to regress.

[0072] The term "effective amount" means (i) the amount of the compound of this application used to treat or prevent a particular disease, condition, or disorder; (ii) to reduce, improve, or eliminate one or more symptoms of a particular disease, condition, or disorder; or (iii) to prevent or delay the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of the compound of this application constituting a "therapeutic effective amount" varies depending on the compound, the disease state and its severity, the route of administration, and the age of the mammal to be treated, but may routinely be determined by a person skilled in the art based on their own knowledge and the present disclosure.

[0073] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0074] This invention, based on target design, develops a novel PTPN2 / PTPN1 inhibitor. Related biological experiments have shown that the compound of this invention exhibits significant PTPN2 enzyme inhibitory activity. Compared to the positive control drug ABBV-CLS-484, the compound of this invention is effectively converted into the corresponding active metabolite in mice, and exhibits higher concentrations of the active metabolite in plasma and various tissues and organs. In mouse tumor models, the compound of this invention shows higher concentrations of the active metabolite in tumor tissues, demonstrating superior pharmacokinetic properties. In mouse colon cancer allogeneic xenograft models, the compound of this invention achieves complete tumor regression and tumor immunotherapy, with significantly better in vivo tumor suppression than the positive control drug ABBV-CLS-484, showing great promise for clinical application. Furthermore, the synthetic route provided by this invention is novel, safe, environmentally friendly, and has good feasibility for production. Attached Figure Description

[0075] Figure 1: Tumor volume in MC38 model mice after administration of compound 18 and ABBV-CLS-48 in Example 4.

[0076] Figure 2: Tumor volume in MC38 model mice after administration of compound 41 and ABBV-CLS-484 in Example 4. Detailed Implementation

[0077] To make the above content clearer and more explicit, the technical solution of the present invention will be further illustrated by the following embodiments. The following embodiments are only used to illustrate specific implementation methods of the present invention so that those skilled in the art can understand the present invention, but are not intended to limit the scope of protection of the present invention. In the specific implementation methods of the present invention, the technical means or methods, etc., not specifically described, are conventional technical means or methods in the art.

[0078] Unless otherwise stated, all temperatures in this invention refer to degrees Celsius.

[0079] This invention uses the following abbreviations:

[0080] DIPEA: N,N-diisopropylethylamine; MeCN: acetonitrile; Et3N: triethylamine; THF: tetrahydrofuran; H2: hydrogen; Pd / C: palladium / carbon; EtOH: ethanol; DMAP: 4-dimethylaminopyridine; H2O: water; DMF: N,N-dimethylformamide; LC-MS: liquid chromatography-mass spectrometry; HPLC: high performance liquid chromatography; Compound 484: compound ABBV-CLS-484; Ag2O: silver oxide; NaH: sodium hydride; KOH: potassium hydroxide; Pd2(dba)3: tris(dibenzylideneacetone)dipalladium; tBuXphos: 2-di-tert-butylphosphino-2',4',6' -Triisopropylbiphenyl; nBuLi: n-Butyllithium; I2: Iodine; BrettPhos-Pd-G3: (2-Dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium; BrettPhos: 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-11'-biphenyl; Cs2CO3: Cesium carbonate; Dioxane: Dioxane; Pyridine: Pyridine; MeONa: Sodium methoxide; HCl: Hydrogen chloride; EA: Ethyl acetate; MeCN: Acetonitrile.

[0081] Furthermore, all operations involving easily oxidized or hydrolyzed raw materials are performed under nitrogen protection. Unless otherwise stated, the raw materials used in this invention are commercially available and can be used directly without further purification.

[0082] All reaction raw materials and common intermediates involved in the embodiments of the present invention can be obtained commercially or by self-production. The preparation process of raw materials and common intermediates that need to be self-produced is described in detail below.

[0083] Example 1: Synthesis of (R)-3-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidine-2-yl)-4-fluoro-6-(isopentylamino)-5,6,7,8-tetrahydronaphthyl-2-ylneopentate (1)

[0084] Step 1: Synthesis of (R)-(7-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidine-2-yl)-8-fluoro-6-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)(isopentyl)carbamate (1-1)

[0085] Compound ABBV-CLS-484 (140 mg, 0.364 mmol) was dissolved in anhydrous acetonitrile (10 mL), followed by the sequential addition of triethylamine (73.0 mg, 0.723 mmol) and benzooxycarbonyl succinimide (100 mg, 0.402 mmol). The reaction mixture was incubated at 25 °C for 2 hours. After the reaction was confirmed to be complete by LCMS, the reaction mixture was concentrated under reduced pressure and purified by preparative chromatography (using dichloromethane:methanol = 95:15 as the eluent) to obtain compound 1-1 (300 mg), which was the crude product.

[0086] LC-MS (m / z): 518.0 [MH] - .

[0087] Step 2: Synthesis of (R)-6-(((benzyloxy)carbonyl)(isopentyl)amino)-3-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidine-2-yl)-4-fluoro-5,6,7,8-tetrahydronaphthalene-2-yl neopentanoate (1-2)

[0088] The crude product of compound 1-1 (150 mg) was dissolved in anhydrous THF (5 mL), and triethylamine (54.0 mg, 0.534 mmol) and tert-valeryl chloride (54.0 mg, 0.360 mmol) were added sequentially. The reaction solution was placed at 25 °C for 2 hours. After the reaction was complete as monitored by LCMS, the reaction solution was concentrated under reduced pressure, and purified by preparative plate separation (dichloromethane:methanol = 95:15 as eluent) to obtain compound 1-2 (200 mg), which was the crude product.

[0089] LC-MS (m / z): 602.0 [MH] - .

[0090] Step 3: Synthesis of (R)-3-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidine-2-yl)-4-fluoro-6-(isopentylamino)-5,6,7,8-tetrahydronaphthyl-2-ylneopentate (1)

[0091] The crude products of compounds 1-2 (200 mg) were dissolved in a mixed solution of ethanol (6 mL) and tetrahydrofuran (3 mL), and palladium on carbon (10%, 38.0 mg, 35.8 μmol) was added. The mixture was reacted at 25 °C for 16 hours under a hydrogen atmosphere. After the reaction was confirmed to be complete by LCMS, the reaction solution was filtered, concentrated under reduced pressure, and purified by HPLC to obtain compound 1 (2.2 mg), with a three-step yield of 2.6%.

[0092] LC-MS (m / z): 470.0 [M+H] + .

[0093] 1H NMR(600MHz,DMSO-d6)δ8.44(brs,1H),6.83(s,1H),3.76(s,2H),3.58-3.44(m,1H),3.24-3.14(m,1H),3.04(s,2H),2.95-2.87(m,1H ),2.87-2.75(m,1H),2.67-2.58(m,1H),2.27-2.15(m,1H),1.79-1.62(m,2H),1.53-1.46(m,2H),1.26(s,9H),0.92(d,J=6.7Hz,6H).

[0094] Example 2: Synthesis of (R)-3-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidine-2-yl)-4-fluoro-6-(isopentylamino)-5,6,7,8-tetrahydronaphthalene-2-yl dimethylcarbamate (2)

[0095] Step 1: Synthesis of (R)-(6-((dimethylcarbamoyl)oxy)-7-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidine-2-yl)-8-fluoro-1,2,3,4-tetrahydronaphth-2-yl)(isopentyl)carbamate (2-1)

[0096] Compound 1-1 (94.5 mg, 0.182 mmol) was dissolved in anhydrous THF (5 mL), and triethylamine (73.0 mg, 0.723 mmol), 4-dimethylaminopyridine (2.1 mg, 17.2 μmol), and dimethylcarbamoyl chloride (58.0 mg, 0.537 mmol) were added sequentially. The reaction solution was placed at 60 °C for 1 hour. After the reaction was monitored by LCMS until complete, the reaction solution was concentrated under reduced pressure, and purified by preparative plate separation (dichloromethane:methanol = 95:5 as eluent) to obtain compound 2-1 (150 mg), which was the crude product.

[0097] LC-MS (m / z): 589.0 [MH] - .

[0098] Step 2: Synthesis of (R)-3-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidine-2-yl)-4-fluoro-6-(isopentylamino)-5,6,7,8-tetrahydronaphthalene-2-yl dimethylcarbamate (2)

[0099] The crude product of compound 2-1 (150 mg) was dissolved in a mixed solution of ethanol (3 mL) and tetrahydrofuran (3 mL), and palladium on carbon (10%, 38.0 mg, 35.8 μmol) was added. The mixture was reacted at 25 °C for 16 hours under a hydrogen atmosphere. After the reaction was confirmed to be complete by LCMS, the reaction solution was filtered, concentrated under reduced pressure, and purified by HPLC to obtain compound 2 (29.0 mg), with a two-step yield of 34.9%.

[0100] LC-MS (m / z): 457.0 [M+H] + .

[0101] 1 H NMR(600MHz,DMSO-d6)δ8.42(brs,1H),6.85(s,1H),3.80(s,2H),3.49(d,J=13.7Hz,1H) ,3.18(dd,J=16.5,5.5Hz,1H),3.07-3.02(m,2H),3.01(s,3H),2.92-2.87(m,1H),2.86(s ,3H),2.84-2.79(m,1H),2.61(dd,J=16.4,9.9Hz,1H),2.23-2.16(m,1H),1.73(tt,J=11. 1,5.6Hz,1H),1.67(dt,J=13.3,6.7Hz,1H),1.50(q,J=7.0Hz,2H),0.92(d,J=6.6Hz,6H).

[0102] Example 18: Synthesis of ethyl 1-(((R)-7-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidine-2-yl)-8-fluoro-6-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)(isopentyl)carbamoyl)oxy)isobutyrate (18) and its ammonium salt

[0103] Step 1: Synthesis of ethyl isobutyrate (18) of 1-(((R)-7-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidine-2-yl)-8-fluoro-6-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)(isopentyl)carbamoyl)oxy)oxy)isobutyrate

[0104] Compound ABBV-CLS-484 (45.8 mg, 0.119 mmol) was dissolved in DMF (2 mL), and ethyl 1-(((4-nitrophenoxy)carbonyl)oxy)isobutyrate (35.6 mg, 0.120 mmol) and triethylamine (24.0 mg, 0.238 mmol) were added. The reaction mixture was placed at 40 °C for 16 hours. After the reaction was confirmed to be complete by LCMS, the reaction mixture was concentrated under reduced pressure and purified by HPLC to obtain compound 18 (24.7 mg), with a yield of 38.2%.

[0105] LC-MS (m / z): 542.0 [MH] - .

[0106] Step 2: Synthesis of ammonium ethyl isobutyrate salt of 1-(((R)-7-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidine-2-yl)-8-fluoro-6-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)(isopentyl)carbamoyl)oxy)isobutyrate

[0107] Compound 18 was purified by preparative HPLC to obtain its ammonium salt (24.7 mg), with a yield of 37.1%.

[0108] LC-MS (m / z): 542.0 [MH] - .

[0109] 1 H NMR(600MHz,DMSO-d6)δ9.06(brs,1H),7.08(s,4H),6.72-6.63(m,1H),6.44(s,1H),4.04-3.78(m,3H),3.26-3.08(m,2H),2.84-2.74(m,2H ),2.73-2.59(m,2H),2.56-2.51(m,1H),2.00-1.73(m,2H),1.58-1.48(m,1H),1.46-1.33(m,5H),1.15-0.99(m,6H),0.88(d,J=6.6Hz,6H).

[0110] Example 19: Synthesis of ethyl 1-(((R)-7-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidine-2-yl)-8-fluoro-6-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)(isopentyl)carbamoyl)oxy)cyclopentanecarboxylate (compound 19) and its ammonium salt

[0111] Step 1: Synthesis of ethyl 1-(((4-nitrophenoxy)carbonyl)oxy)cyclopentanecarboxylate (19-1)

[0112] Ethyl 1-chlorocarboxylate 4-nitrophenyl ester (2.00 g, 8.14 mmol) was dissolved in cyclopentanoic acid (8 mL), and silver oxide (1.89 g, 8.14 mmol) was added. The reaction mixture was placed at 100 °C for 2 hours. After the reaction was complete as monitored by LCMS, water (30 mL) was added to quench the reaction. The mixture was filtered through diatomaceous earth, washed with ethyl acetate, and the filtrate was diluted with water (30 mL). The aqueous phase was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 75:25 as eluent) to give 19-1 (2.10 g), yield 79.9%.

[0113] Step 2: Synthesis of 1-(((R)-7-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidine-2-yl)-8-fluoro-6-hydroxy-1,2,3,4-tetrahydronaphthyl-2-yl)(isopentyl)carbamoyl)oxy)cyclopentanecarboxylic acid ethyl ester (19)

[0114] ABBV-CLS-484 (60.0 mg, 0.16 mmol) and 19-1 (68.0 mg, 0.16 mmol) were dissolved in N,N-dimethylformamide (12 mL), and triethylamine (47.0 mg, 0.46 mmol) was added. The reaction mixture was placed at 40 °C for 16 hours. After the reaction was complete as monitored by LCMS, the reaction mixture was concentrated under reduced pressure, and the residue was purified by HPLC to obtain 19-1 (30.1 mg), with a yield of 33.1%.

[0115] LC-MS (m / z): 568.0 [M–H] – .

[0116] Step 3: Synthesis of 1-(((R)-7-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidine-2-yl)-8-fluoro-6-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)(isopentyl)carbamoyl)oxy)cyclopentanecarboxylic acid ethyl ester ammonium salt

[0117] Compound 19 was purified by preparative HPLC to obtain the ammonium salt (30.1 mg) of compound BP2303-287.

[0118] LC-MS (m / z): 568.0 [M–H] – .

[0119] 1H NMR (600MHz, DMSO-d6) δ9.07(s,1H),7.08(s,4H),6.72–6.62(m,1H),6.43(s,1H),4.05–3.72(m,3H),3.25–3.05(m,2H),2.85–2. 62(m,5H),1.99–1.88(m,1H),1.87–1.74(m,3H),1.74–1.64(m,1H),1.62–1.45(m,6H),1.46–1.32(m,5H),0.88(d,J=6.5Hz,6H).

[0120] Example 41: Synthesis of ethyl 1-(((R)-7-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidine-2-yl)-8-fluoro-6-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)(isopentyl)carbamoyl)oxy)cyclopropanecarboxylate (compound 41) and its ammonium salt

[0121] Step 1: Synthesis of ethyl 1-(((4-nitrophenoxy)carbonyl)oxy)cyclopropanecarboxylate (41-1)

[0122] Ethyl 1-chlorocarboxylate 4-nitrophenyl ester (1.00 g, 4.07 mmol) was dissolved in cyclopropionic acid (5 mL), and silver oxide (0.94 g, 4.07 mmol) was added. The reaction mixture was placed at 100 °C for 2 hours. After the reaction was complete as monitored by LCMS, water (30 mL) was added to quench the reaction. The mixture was filtered through diatomaceous earth, washed with ethyl acetate, and the filtrate was diluted with water (30 mL). The aqueous phase was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 75:25 as eluent) to give 41-1 (0.75 g), yield 62.5%.

[0123] Step 2: Synthesis of ethyl 1-(((R)-7-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidine-2-yl)-8-fluoro-6-hydroxy-1,2,3,4-tetrahydronaphthyl-2-yl)(isopentyl)carbamoyl)oxy)cyclopropanecarboxylate (41)

[0124] ABBV-CLS-484 (60.0 mg, 0.16 mmol) and 41-1 (59.0 mg, 0.16 mmol) were dissolved in N,N-dimethylformamide (12 mL), and triethylamine (47.0 mg, 0.46 mmol) was added. The reaction mixture was placed at 40 °C for 16 hours. After the reaction was complete as monitored by LCMS, the reaction mixture was concentrated under reduced pressure, and the residue was purified by HPLC to obtain 41 (32.1 mg), with a yield of 37.1%.

[0125] LC-MS (m / z): 540.0 [M–H] – .

[0126] Step 3: Synthesis of 1-(((R)-7-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidine-2-yl)-8-fluoro-6-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)(isopentyl)carbamoyl)oxy)cyclopropanecarboxylic acid ethyl ester ammonium salt

[0127] The ammonium salt of compound 41 was obtained by preparative HPLC separation and purification of compound BP2303-288.

[0128] LC-MS (m / z): 540.0 [M–H] – .

[0129] 1 H NMR(600MHz,DMSO-d6)δ9.11(s,1H),7.08(t,J=51.0Hz,4H),6.73–6.62(m,1H),6.44(s,1H),4.05–3.82(m,3H),3.24–3.06(m,3H),2 .84–2.75(m,2H),2.72–2.60(m,2H),1.99–1.76(m,2H),1.69–1.59(m,1H),1.58–1.47(m,1H),1.48–1.27(m,4H),0.96–0.81(m,10H).

[0130] Example 42: Synthesis of 1-(((2-cyclopropylethyl)((R)-7-(1,1-dioxo-4-oxo-1,2,5-thiodiazinid-2-yl)-8-fluoro-6-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)carbamoyloxy)ethyl)cyclopropane carbamate (compound 42)

[0131] Step 1: Synthesis of (R)-N-((R)-6-bromo-8-fluoro-1,2,3,4-tetrahydronaphthyl-2-yl)-N-(2-cyclopropylethyl)-2-methylpropane-2-sulfonamide (42-1)

[0132] 42-SM (1.50 g, 4.3 mmol) was dissolved in anhydrous N,N-dimethylformamide (20 mL), and NaH (60%, 0.26 g, 6.46 mmol) was added at 0 °C. The reaction mixture was stirred at 0 °C for 30 min, followed by the addition of (2-iodoethyl)cyclopropane (2.11 g, 10.77 mmol). The reaction mixture was stirred at 25 °C for 16 h. After the reaction was confirmed to be complete by LC-MS, water (50 mL) was added to quench the reaction. The aqueous phase was extracted with ethyl acetate (50 mL × 3), and the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 70:30 as eluent) to give compound 42-1 (0.37 g), yield 20.6%.

[0133] LC-MS (m / z): 416.0 / 418.0 [M+H] + .

[0134] Step 2: Synthesis of (R)-N-((R)-8-fluoro-6-hydroxy-1,2,3,4-tetrahydronaphthyl-2-yl)-N-(2-cyclopropylethyl)-2-methylpropane-2-sulfonamide (42-2)

[0135] 42-1 (0.72 g, 1.73 mmol), tris(dibenzylacetone)palladium (80.0 mg, 0.09 mmol), 2-di-tert-butylphospho-2',4',6'-triisopropylbiphenyl (147.0 mg, 0.35 mmol), and potassium hydroxide (0.19 g, 3.46 mmol) were dissolved in a mixed solvent of dioxane (5 mL) and water (5 mL). The reaction mixture was placed at 100 °C for 3 hours under nitrogen protection. After the reaction was confirmed to be complete by LC-MS, 1.0 M citric acid aqueous solution (5 mL) was added dropwise to adjust the pH of the aqueous phase to acidic. The aqueous phase was extracted with ethyl acetate (10 mL × 3), and the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 42-2 (350 mg), the crude product.

[0136] LC-MS (m / z): 354.0 [M+H] + .

[0137] Step 3: Synthesis of (R)-N-((R)-8-fluoro-6-((2-methoxyethoxy)methoxy)-1,2,3,4-tetrahydronaphthyl-2-yl)-N-(2-cyclopropylethyl)-2-methylpropane-2-sulfonamide (42-3)

[0138] The crude product of compound 42-2 (350 mg) was dissolved in anhydrous tetrahydrofuran (10 mL), and sodium hydride (59.0 mg, 1.49 mmol) was added at 0 °C. The reaction mixture was stirred at 0 °C for 30 minutes, followed by the addition of anhydrous tetrahydrofuran solution (5 mL) of 1-(chloromethoxy)-2-methoxyethane (148.0 mg, 1.19 mmol). The reaction mixture was then reacted at 25 °C for 2.5 hours. After the reaction was confirmed to be complete by LCMS, the reaction was quenched with saturated ammonium chloride aqueous solution (15 mL). The aqueous phase was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 50:50 as eluent) to give 42-3 (390.0 mg), with a two-step yield of 50.8%.

[0139] LC-MS (m / z): 442.0 [M+H] + .

[0140] Step 4: Synthesis of (R)-N-((R)-8-fluoro-7-iodo-6-((2-methoxyethoxy)methoxy)-1,2,3,4-tetrahydronaphthyl-2-yl)-N-(2-cyclopropylethyl)-2-methylpropane-2-sulfonamide (42-4)

[0141] 42-3 (0.39 g, 0.88 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL). A hexane solution of n-butyllithium (2.5 M, 1.4 mL, 3.50 mmol) was added dropwise at –78 °C. The reaction mixture was stirred at –78 °C for 30 minutes. Then, an anhydrous tetrahydrofuran solution of iodine (0.56 g, 2.21 mmol) (5 mL) was added dropwise. The reaction mixture was stirred at 25 °C for 2 hours. After the reaction was complete as monitored by LC-MS, the reaction was quenched by adding saturated ammonium chloride aqueous solution (10 mL) and saturated sodium thiosulfate aqueous solution (10 mL). The aqueous phase was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 50:50 as eluent) to give 42-4 (0.43 g), yield 85.8%.

[0142] LC-MS (m / z): 568.0 [M+H] + .

[0143] Step 5: Synthesis of tert-butyl((R)-7-(((R)-tert-butylsulfinyl)((2-cyclopropylethyl))amino)-1-fluoro-3-((2-methoxyethoxy)methoxy)-5,6,7,8-tetrahydronaphth-2-yl)glycine ester (42-5)

[0144] 42-4 (0.43 g, 0.75 mmol), glycine tert-butyl ester (198.0 mg, 1.51 mmol), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium (137.0 mg, 0.15 mmol), 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-11'-biphenyl (81.0 mg, 0.15 mmol) and cesium carbonate (0.74 g, 2.27 mmol) were dissolved in dioxane (8 mL). The reaction mixture was placed at 100 °C for 16 hours under nitrogen protection. After the reaction was monitored by LCMS until it was complete, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain 42-5 (0.51g), which was the crude product.

[0145] LC-MS (m / z): 571.0 [M+H] + .

[0146] Step 6: Synthesis of (R)-N-((R)-7-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidine-2-yl)-8-fluoro-6-((2-methoxyethoxy)methoxy)-1,2,3,4-tetrahydronaphthyl-2-yl)-N-(2-cyclopropylethyl)-2-methylpropane-2-sulfonamide (42-6)

[0147] The crude product of compound 42-5 (0.51 g) was dissolved in anhydrous tetrahydrofuran (10 mL), pyridine (178.0 mg, 2.26 mmol) was added, and chlorosulfonamide (174.0 mg, 1.51 mmol) was added at 0 °C. The reaction mixture was then incubated at 25 °C for 30 min. After the reaction was confirmed to be complete by LCMS, the reaction mixture was cooled to 0 °C, and a methanol solution of sodium methoxide (5.0 M, 0.6 mL, 3.00 mmol) was added dropwise at 0 °C. The reaction mixture was then incubated at 25 °C for 30 min. After the reaction was confirmed to be complete by LCMS, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 85:15 as eluent) to give 42-6 (0.21 g), with a two-step yield of 49.3%.

[0148] LC-MS (m / z): 574.0 [MH] - .

[0149] Step 7: Synthesis of (R)-5-(1-fluoro-3-hydroxy-7-((2-cyclopropylethyl)amino)-5,6,7,8-tetrahydronaphthyl-2-yl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide (42-7)

[0150] 42-6 (214.0 mg, 0.31 mmol) was dissolved in acetonitrile (2.0 mL), and an ethyl acetate solution of hydrogen chloride (4.0 M, 2.0 mL, 8.00 mmol) was added. The reaction mixture was placed at 25 °C and reacted for 30 minutes. After the reaction was confirmed to be complete by LCMS, the reaction mixture was concentrated under reduced pressure to obtain 42-7 (168.0 mg), which was the crude product.

[0151] LC-MS (m / z): 382.0 [MH] - .

[0152] Step 8: Synthesis of 1-(((2-cyclopropylethyl)((R)-7-(1,1-dioxo-4-oxo-1,2,5-thiodiazinid-2-yl)-8-fluoro-6-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)carbamoyloxy)ethyl)cyclopropane carbamate (42)

[0153] The crude product of compound 42-7 (141.0 mg) and 41-1 (119.0 mg, 0.40 mmol) were dissolved in N,N-dimethylformamide (10 mL), and triethylamine (186.0 mg, 1.84 mmol) was added. The reaction mixture was placed at 40 °C for 16 hours. After the reaction was complete as monitored by LCMS, the reaction mixture was concentrated under reduced pressure, and the residue was purified by HPLC to obtain 42 (12.1 mg), with a two-step yield of 8.6%.

[0154] LC-MS (m / z): 538.0 [MH] - .

[0155] 1 ¹H NMR (600MHz, DMSO-d⁶) δ 8.14–8.06 (m, 1H), 6.91–6.84 (m, 1H), 6.68–6.62 (m, 1H), 6.44 (s, 1H), 4.04–3.84 (m, 3H), 3.26–3.18 (m, 2H), 2.82–2.75 (m, 2H), 2.72–2.58 (m, 2H), 2.00–1.76 (m, 2H), 1.62 (s, 1H), 1.49–1.33 (m, 5H), 0.97–0.80 (m, 4H), 0.69–0.60 (m, 1H), 0.41 (d, J = 9.3Hz, 2H), 0.05 (d, J = 4.7Hz, 2H). Bioactivity assays

[0156] Example 1: In vitro enzymatic experiment of PTPN2

[0157] The purpose of this experiment is to test the ability of the compound to bind to and inhibit PTPN2 activity in vitro. The specific operating steps are as follows:

[0158] 1. Preparation of Assay Buffer: Prepare using sterile deionized ultrapure water (see table below).

[0159] 2. PTPN2 enzyme preparation: The enzyme stock solution concentration is 0.15 mg / mL, and the working solution is prepared to a concentration of 4 μg / mL, i.e., the final concentration is 2 μg / mL.

[0160] 3. pNPP substrate preparation: Weigh out powdered pNPP to prepare a 2mM working solution, i.e., the final concentration is 1mM.

[0161] 4. Compound solution preparation: First, dissolve the compound in DMSO to prepare a stock solution. Dilute the stock solution to 1 mM and then perform 4-fold serial dilutions with DMSO, resulting in 8 concentration gradients. Then, take 2 μL of each serially diluted compound in DMSO and add it to 17.8 μL of ddH2O to prepare the working solution of the compound to be tested (the final concentration of DMSO in the reaction system is 0.1%). Add 1 μL of each gradient concentration of the working solution to a 96-well plate and mix with 50 μL of PTPN2. Incubate the reaction system at room temperature for 10 minutes as a pre-incubation of the compound.

[0162] 5. After the pre-incubation of the compound, add 50 μL of substrate working solution to each well and incubate at 37 °C for 90 minutes. At this time, the final concentration gradient of the compound is 1 μM to 0.0610 nM.

[0163] 6. After the reaction is complete, add 50 μL of 3M NaOH to each well to stop the reaction, read the value at 405 nm using a microplate reader, and calculate the inhibition rate of each compound.

[0164] 7. Data Analysis: Convert raw data into inhibition rate and IC50. 50 The values ​​were fitted using the log(agonist) vs. response-variable slope four-parameter method in GraphPad software, and the results are shown in Table 1.

[0165] Table 1. Inhibitory activity of compounds against PTPN2 enzyme

[0166] The results showed that compounds 1, 2, 18, 19, 41, and 42 could significantly inhibit the activity of PTPN2 enzyme.

[0167] Example 2: Mouse Tissue Distribution Experiment

[0168] SPF-grade female C57BL / 6J mice (6 mice per compound) were administered a single oral gavage dose of 10 mg / kg of the compound. After euthanasia, blood was collected via orbital sampling at specified time points. Cardiac perfusion was performed, and brain, heart, liver, spleen, lung, kidney, stomach, large intestine, and thymus were collected. Approximately 0.1 mL of blood was collected from each animal via orbital sampling. The blood was anticoagulated with ETDA-2K and placed in an ice bath. Plasma was separated by centrifugation within 1 hour (centrifugation conditions: 2000 g / min, 10 min, 4℃). Plasma samples were stored at -20℃ before analysis. After washing the tissue with physiological saline, the tissue was blotted dry with filter paper, and a 1g:4mL methanol-physiological saline solution (1:1, v:v) was added. A small steel ball was then added, and the mixture was homogenized in a homogenizer to obtain a tissue homogenate. The homogenate was centrifuged within 1 hour (centrifugation conditions: 1500g / min, 5min, 4℃) to obtain the tissue supernatant. The tissue supernatant sample was stored at -80℃ before analysis. The concentrations of compound 1 and ABBV-CLS-484 in plasma and tissue were measured at different time points (the content of the metabolite ABBV-CLS-484 was also measured for compound 1). The experimental results are shown in the table below.

[0169] Table 2. Concentrations of Compound 1 and ABBV-CLS-484 in plasma and tissues after gavage administration of Compound 1

[0170] Table 3. Concentrations of ABBV-CLS-484 in plasma and tissues after gavage.

[0171] Table 4. Ratios of ABBV-CLS-484 concentrations in plasma and tissues after gavage administration of compound 1 and ABBV-CLS-484, respectively.

[0172] The results showed that after oral administration of compound 1 to mice, high concentrations of the metabolite ABBV-CLS-484 were found in relevant tissues and organs, with a significantly increased content compared to direct oral administration of ABBV-CLS-484. Therefore, compound 1 has greater advantages in the treatment of colorectal cancer, liver cancer, and lung cancer. Furthermore, compound 1 also has high exposure levels in the large intestine, and can exert antitumor effects in combination with its metabolites.

[0173] Example 3: MC38 model pharmacodynamic test and tumor-bearing mouse tissue distribution test

[0174] SPF-grade female steroid mice were administered a single dose of 1 mg / kg compound via gavage. Plasma was collected at 0.25 h, 0.5 h, and 1 h after the initial gavage administration; tumor samples were collected 1 h after gavage. Plasma was also collected at 2 h, 4 h, 8 h, and 24 h after gavage; tumor samples were collected 24 h after gavage. Blood was collected via the orbital cavity, approximately 0.06 mL per animal, anticoagulated with ETDA-2K, and placed in an ice bath. Plasma was separated by centrifugation within 1 hour (centrifugation conditions: 2000 g / min, 10 min, 4 °C). Plasma samples were stored at -20 °C before analysis. After each blood collection point, anesthesia was administered, the abdominal cavity was opened, cardiac perfusion was performed, tumor tissue was collected, and a 1g:4mL methanol-physiological saline solution (1:1, v:v) was added. Small steel balls were added, and the mixture was homogenized in a homogenizer to obtain a tissue homogenate. The homogenate was centrifuged within 1 hour (centrifugation conditions: 1500g / min, 5min, 4℃) to obtain the tissue supernatant. The tissue supernatant sample was stored at -80℃ before analysis. The concentrations of compound 41 and ABBV-CLS-484 in plasma and tissue were measured at different time points (the content of the metabolite ABBV-CLS-484 was also measured for compound 41). The experimental results are shown in the table below.

[0175] Table 5. Concentrations of ABBV-CLS-484 in plasma and tumor tissue after gavage administration of compound 41

[0176] The results showed that after oral administration of compound 41 to mice, the tumor tissue contained a higher concentration of the metabolite ABBV-CLS-484 compared to direct oral administration of ABBV-CLS-484. Furthermore, the plasma concentration was lower, further reducing the risk of systemic exposure. Therefore, compound 41 exhibits superior pharmacokinetic properties.

[0177] Example 4, MC38 efficacy test

[0178] To evaluate the antitumor activity of the compound of the present invention (hereinafter referred to as "test product"), we established a C57BL / 6 mouse MC38 colon cancer allogeneic xenograft model.

[0179] Main reagents:

[0180] Main instruments:

[0181] Cell culture: MC38 cells frozen in liquid nitrogen were revived in 1640 medium (containing 10% FBS + 1% penicillin and antibiotics) and cultured in a cell culture incubator at 37°C with 5% CO2. Cells were digested with trypsin solution and passaged to the desired cell number. Cell count and viability were assessed using an automated cell counter and trypan blue assay to ensure that cell viability was not less than 95% before seeding.

[0182] Methods and Model: Female C57BL / 6J mice aged 6-8 weeks were acclimatized for 6 days. Ectopic tumor modeling was established using the ectopic xenograft method. MC38 cells cultured to the logarithmic growth phase were harvested, filtered through a 70 μM filter, and the cell density was adjusted to 2 × 10⁻⁶ cells / mL with PBS. 5 Or 2×10 6 Cells were injected subcutaneously into the right axilla of mice at a rate of 0.1 mL / mL, with a total of 36 mice inoculated.

[0183] Experimental Design: The experiment included a solvent control group, a positive control group (ABBV-CLS-484), and different dose groups of the test product, with 6 mice in each group. The test product was administered via gavage twice daily for several consecutive days. The growth of the mice was observed, and tumor volume was measured.

[0184] Monitoring indicators: Weigh twice a week, measure tumor volume twice a week. Tumor volume calculation formula: V (mm²) 3 = (a×b×b) / 2. After the test termination condition is met, the mice are subjected to endpoint treatment, dissected, all tumor tissues are obtained, weighed, photographed, and the TGI (%) is calculated. Tumor weight inhibition rate TGI (%) = (W1-W2) / W1×100%.

[0185] Conclusions: As shown in Figure 1, after 27 days of continuous administration, all tumors in the mice treated with compound 18 completely regressed, achieving a tumor-free effect. Furthermore, after drug withdrawal, re-inoculation of tumor cells into the left side of the mice resulted in tumor immunity in all mice, preventing tumor formation, while all mice in the control group developed tumors. Additionally, compound 18 showed significantly better in vivo tumor-suppressing effects than the positive control drug ABBV-CLS-484. As shown in Figure 2, compound 41, at the same dose, significantly outperformed the positive control drug in the MC38 pharmacodynamic model, consistent with the previous drug tissue distribution results.

Claims

1. A compound having the following general structural formula (I), or a stereoisomer, tautomer, deuterated product, or pharmaceutical salt thereof: in, R 1 , R 2 are each independently selected from hydrogen, -R 1a -C(O)-R 1b , -R 1a -C(O)O-R 1b , -R 1a -C(O)NR 1b R 1c , -R 1a -C(O)O-R 1b -O-R 1c , -R 1a -C(O)O-R 1b -OC(O)-R 1c , -R 1a -OC(O)-R 1b , -R 1a -OC(O)O-R 1b , -R 1a -OC(O)NR 1b R 1c , -R 1a -S-R 1b , -R 1a -S-R 1b -O-R 1c , -R 1a -SC(O)-R 1b , -R 1a -SC(O)O-R 1b , -R 1a -SC(O)NR 1b R 1c , -R 1a -P(O)(OR 1b )(OR 1c )-, -R 1a -P(O)(OR 1b SR 1c )(OR 1d SR 1e )-, -R 1a -P(O)(OR 1b OR 1c )(OR 1d OR 1e )- or -R 1a -P(O)(OR 1b SR 1c )(OR 1d OR 1e )-; and R 1 and R 2 are not simultaneously hydrogen; R 3 selected from C 1-6 alkyl, said C 1-6 alkyl is optionally further substituted by one or more R a substituents; R 1a , R 1b , R 1c , R 1d , R 1e are each independently selected from absent, hydrogen, deuterium, halogen, cyano, hydroxyl, amino, thiol, oxo, C 1- 6alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-14 membered heterocyclyl, C 6-12 aryl, or 5-14 membered heteroaryl, said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-14 membered heterocyclyl, C 6-12 aryl, or 5-14 membered heteroaryl are optionally further substituted by one or more R a ; R a is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, thiol, oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylsulfone, C 1-6 alkylamino, C 3-12 cycloalkyl, 3-14 membered heterocyclyl, 5-14 membered heteroaryl, or C 6-12 aryl, said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylsulfone, C 1-6 alkylamino, C 3-12 cycloalkyl, 3-14 membered heterocyclyl, 5-14 membered heteroaryl, or C 6-12 aryl is optionally further substituted by one or more substituents selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, or C 1-6 haloalkoxy.

2. The compound as claimed in claim 1, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutical salts, characterized in that, The R 3 Selected from C 1-6 Alkyl, the C 1-6 Alkyl groups may optionally be further divided by one or more groups selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, or C. 3-12 Substituents of cycloalkyl groups.

3. The compound as described in claim 1 or 2, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutical salts, characterized in that, The R 3 Selected from 4. The compound according to any one of claims 1 to 3, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutical salts, characterized in that, The compound has a structure as shown in formulas (IIa), (IIb), (IIc), (IId), (IIe), or (IIIf): Among them, R 1 R 2 The definition is as described in claim 1.

5. The compound according to any one of claims 1 to 4, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutical salts, characterized in that, The compound has a structure as shown in formula (IIIa), (IIIb), or (IIIc): Among them, R 1 R 2 The definition is as described in claim 1.

6. The compound according to any one of claims 1 to 5, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutical salts, characterized in that, The R 1 Selected from hydrogen, -C(O)-R 1b -C(O)NR 1b R 1c or -R 1a -OC(O)-R 1b ; The R 1a Selected from C 1-6 alkyl; The R 1b R 1c Each is independently selected from C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-12 Aryl or 5-14 heteroaryl, wherein C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-12 aryl or 5-14 heteroaryl groups optionally further selected from one or more groups selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, 3-14 membered heterocyclic groups, C 6-12 Substituents of aryl or 5-14 heteroaryl groups.

7. The compound according to any one of claims 1 to 6, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutical salts, characterized in that, The R 1 Selected from hydrogen, 8. The compound according to any one of claims 1 to 7, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutical salts, characterized in that, The R 2 Selected from hydrogen, -C(O)OR 1b or -C(O)OR 1b -OC(O)-R 1c ; The R 1b R 1c Each is independently selected from C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-12 Aryl or 5-14 heteroaryl, wherein C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-12 aryl or 5-14 heteroaryl groups optionally further selected from one or more groups selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, 3-14 membered heterocyclic groups, C 6-12 Substituents of aryl or 5-14 heteroaryl groups.

9. The compound according to any one of claims 1 to 8, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutical salts, characterized in that, The R 2 Selected from hydrogen, 10. The compound according to any one of claims 1 to 9, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutical salts, characterized in that, The compound is selected from 11. A pharmaceutical composition comprising the compound as claimed in any one of claims 1 to 10, or a stereoisomer, tautomer, deuterated compound, or pharmaceutical salt thereof.

12. The use of the compound of any one of claims 1 to 10, or a stereoisomer, tautomer, deuterated form or pharmaceutical salt thereof, or the pharmaceutical composition of claim 10, in the preparation of a medicament for the prevention or treatment of PTPN2 / PTPN1 mediated diseases or conditions.

13. The use of the compound of any one of claims 1 to 10, or a stereoisomer, tautomer, deuterated form or pharmaceutical salt thereof, or the pharmaceutical composition of claim 11, in the prevention or treatment of PTPN2 / PTPN1 mediated diseases or conditions.

14. A method of treating and / or preventing a disease, comprising administering to a subject a therapeutically effective amount of the compound of any one of claims 1 to 10, or a stereoisomer, tautomer, deuterated compound, or pharmaceutical salt thereof, or the pharmaceutical composition of claim 11, wherein the disease being treated and / or prevented is a PTPN2 / PTPN1 mediated disease or condition.

15. The application as described in claim 12 or 13, and the method as described in claim 14, characterized in that, The PTPN2 / PTPN1-mediated diseases or conditions are tumors or cancers.

16. The application or method as described in claim 15, characterized in that, The tumor or cancer is selected from head and neck squamous cell carcinoma, clear cell renal cell carcinoma, high microsatellite instability tumor, glioma (glioblastoma), acute myeloid leukemia, acute myeloid leukemia, myelodysplastic / myeloproliferative neoplasm, sarcoma, chronic myelomonocytic leukemia, non-Hodgkin's lymphoma, astrocytoma, melanoma, non-small cell lung cancer, small cell lung cancer, cholangiocarcinoma, chondrosarcoma, colon cancer, colorectal cancer, rectal cancer, or pancreatic cancer.

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