Protein tyrosine phosphatase inhibitors and use thereof

Abstract

The application discloses a protein tyrosine phosphatase inhibitor and application thereof, and particularly discloses a compound shown in formula I or a pharmaceutically acceptable salt thereof, which can be used in the treatment of cancer and the like.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of medicine, and particularly relates to protein tyrosine phosphatase inhibitors and application thereof. BACKGROUND

[0002] Cancer immunotherapy regimens targeting immune evasion mechanisms, including checkpoint blockade (e.g., PD-1 / PD-L1 and CTLA-4 blocking antibodies), have proven effective in treating a variety of cancers, significantly improving outcomes in some populations that are refractory to conventional therapies. However, incomplete clinical responses and the development of intrinsic or acquired resistance will continue to limit the patient population that can benefit from checkpoint blockade.

[0003] Non-receptor protein tyrosine phosphatase type 2 (PTPN2), also known as T-cell protein tyrosine phosphatase (TC-PTP), is an intracellular member of the class 1 subfamily of phosphotyrosine-specific phosphatases that control multiple cellular regulatory processes by removing phosphate groups from tyrosine substrates. PTPN2 is widely expressed, but is expressed highest in hematopoietic and placental cells. In humans, post-transcriptional control of PTPN2 expression is mediated by the presence of two splice variants: a 45 kDa form with a nuclear localization signal in the C-terminus upstream of the splice junction and a 48 kDa canonical form with a C-terminal ER retention motif. The 45 kDa isoform can be passively translocated into the cytosol under certain cellular stress conditions. Both isoforms have an N-terminal phosphotyrosine phosphatase catalytic domain. PTPN2 negatively regulates signaling of non-receptor tyrosine kinases (e.g., JAK1, JAK3), receptor tyrosine kinases (e.g., INSR, EGFR, CSF1R, PDGFR), transcription factors (e.g., STAT1, STAT3, STAT5a / b), and Src family kinases (e.g., Fyn, Lck). As an important negative regulator of the JAK-STAT pathway, PTPN2 function is directly modulated by cytokine receptor (including IFNy) signaling. The PTPN2 catalytic domain has 74% sequence homology with PTPN1 (also known as PTP1B) and has similar enzymatic kinetics.

[0004] Data using CRISPR / Cas9 genome editing for loss-of-function in vivo genetic screening in a mouse B16F10 transplantable tumor model showed that loss of PTPN2 gene in tumor cells improved the response to an immunotherapy regimen of GM-CSF secreting vaccine (GVAX) plus PD-1 checkpoint blockade. PTPN2 loss sensitized tumors to immunotherapy by enhancing IFNy-mediated effects on antigen presentation and growth inhibition. The same screening also showed that genes known to be involved in immune evasion, including PD-L1 and CD47, were also depleted under the selective pressure of immunotherapy, while genes involved in the IFNy signaling pathway, including IFNGR, JAK1 and STAT1, were enriched. These observations point to a putative role of therapeutic strategies to enhance IFNy sensing and signaling in enhancing the efficacy of cancer immunotherapy regimens. SUMMARY

[0005] In one aspect of the present application, the present application provides a compound of Formula I,

[0006]

[0007] wherein ring A is selected from 8-membered heterocyclyl or cyclooctyl;

[0008] R 1 selected from -C 1-6 alkyl, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, -C 1-6 haloalkyl, -C 1-6 hydroxyalkyl, -C 1-6 aminoalkyl, -C 1-6 alkyl-C 3-6 cycloalkyl, or -C 1-6 alkyl-5-6 membered heterocyclyl;

[0009] n is selected from 0 or 1.

[0010] In some embodiments of the present application, the compound of Formula I is a compound of Formula II,

[0011]

[0012] R 1a selected from H or R 1 and the remaining variables are as defined in the present application.

[0013] In some embodiments of the present application, R 1 selected from -C 1-3 alkyl, C 3-6 cycloalkyl, or -C 1-3 alkyl-C 3-6 cycloalkyl, and the remaining variables are as defined in the present application.

[0014] In some embodiments of the present application, R 1 selected from -C 1-3 alkyl, cyclopropyl or -C 1-3 alkyl-cyclopropyl, and the remaining variables are as defined in the present application.

[0015] In some embodiments of the present application, the compound has a structure as shown in one of the following:

[0016]

[0017] In some embodiments of the present application, the compound has a structure as shown in one of the following:

[0018]

[0019] In some embodiments of the present application, the compound has a structure as shown in one of the following:

[0020]

[0021] In another aspect of the present application, the present application also provides a use of the aforementioned compound or a pharmaceutically acceptable salt thereof or the aforementioned pharmaceutical composition in the preparation of a medicament for treating a PTPN2-mediated disease.

[0022] In another aspect of the present application, the present application also provides a use of the aforementioned compound or a pharmaceutically acceptable salt thereof or the aforementioned pharmaceutical composition in the preparation of a medicament for treating a PTPN2-mediated disease.

[0023] In some embodiments of the present application, the PTPN2-mediated disease is selected from a cancer.

[0024] The present application has one of the following advantages:

[0025] 1) The compound of the present application has a novel structure;

[0026] 2) The compound of the present application has a strong level of PTPN2 inhibition;

[0027] 3) The compound of the present application has a high level of oral in vivo exposure.

[0028] As used herein, the term "pharmaceutically acceptable salt" refers to salts of the compounds of the present application which are pharmaceutically acceptable, as well as the pharmacologically active compounds. Such salts include acid addition salts with inorganic acids such as nitric, phosphoric, carbonic, and the like; or with organic acids such as propionic, hexanoic, cyclopentanepropionic, glycolic, pyruvic, malonic, alginic, lactic, succinic, malic, tartaric, citric, methane sulfonic, ethanesulfonic, toluenesulfonic and the like; or salts of metal ions such as alkali metal or alkaline earth metal ions which have replaced the acidic protons of the parent compound; or coordination compounds with organic bases such as ethanolamine, diethanolamine, triethanolamine, N-methylglucosamine and the like. The pharmaceutically acceptable salts of the present application can be synthesized from the parent compound that contains an acidic or basic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent or in a mixture of the two. Generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, among others, are preferred. In addition to salt forms, the compounds provided herein can also take the form of prodrugs. Prodrugs of the compounds described herein are readily converted by chemical or physiological action, or both, into the compounds of the present application. In addition, the prodrugs can be converted to the compounds of the present application in the body by chemical or biochemical methods.

[0029] Unless otherwise specified, the term "C 1-6 "alkyl" is used to denote a straight or branched chain, saturated carbon hydride group consisting of one to six carbon atoms. The C 1-6 alkyl group includes C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C6and C5alkyl, and the like; which can be monovalent (e.g., methyl), divalent (e.g., methylene), or multivalent (e.g., methine). Examples of C 1-6 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl, and t-butyl), pentyl (including n-pentyl, isopentyl, and neopentyl), hexyl, and the like.

[0030] Unless otherwise specified, the term "haloalkyl" refers to an alkyl group having up to the full valence of halo atom substituents, which can be the same or different. Non-limiting examples of haloalkyl groups include -CF3, -C2F5, -CHF2, -CC13, -CHC12, -C2C15, and the like. "C 1-6 haloalkyl" refers to an alkyl group having up to the full valence of halo atom substituents, which can be the same or different. Non-limiting examples of haloalkyl groups include -CF3, -C2F5, -CHF2, -CC13, -CHC12, -C2C15, and the like. "C

[0031] Unless otherwise specified, the term "C 1-6 Hydroxyalkyl" means -C 1-6 alkyl-hydroxy (OH). Preferably C 1-3 hydroxyalkyl (i.e., -C 1-3 alkyl-hydroxy) or C 1-4 hydroxyalkyl (i.e., -C 1-4 alkyl-hydroxy). Where the alkyl moiety is defined above.

[0032] Unless otherwise specified, the term "C 1-6 Aminoalkyl" means -C 1-6 alkyl-amino (NH2). Preferably C 1-3 aminoalkyl (i.e., -C 1-3 alkyl-amino) or C 1-4 aminoalkyl (i.e., -C 1-4 alkyl-amino). Where the alkyl moiety is defined above.

[0033] Unless otherwise specified, the number of atoms in a ring is generally defined as the number of members of the ring, e.g., "3-6 membered ring" means a "ring" that has 3-6 atoms arranged in a ring.

[0034] Unless otherwise specified, the term "5-6 membered heterocyclyl" by itself or in combination with other terms, means a saturated ring-like group consisting of 5 to 6 ring atoms, 1, 2, 3, or 4 of which are heteroatoms independently selected from O, S, and N, with the remainder being carbon atoms, wherein the nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p , respectively, and p is 1 or 2). It includes both monocyclic and bicyclic ring systems, where the bicyclic ring systems include spiro, fused, and bridged rings. Further, with respect to the "5-6 membered heterocyclyl", a heteroatom can occupy the position of attachment of the heterocycloalkyl group to the rest of the molecule. The 5-6 membered heterocyclyl group includes 5-membered and 6-membered heterocycloalkyl groups. Examples of 5-6 membered heterocyclyl groups include, but are not limited to, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl, and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, or homopiperidinyl, etc.

[0035] Unless otherwise specified, "C 3-6 Cycloalkyl" means a saturated ring-like carbon hydride group consisting of 3 to 6 carbon atoms, which is a monocyclic and bicyclic ring system, the C 3-6 cycloalkyl group includes C 3-5 , C4-5 and C 5-6 cycloalkyl, etc.; which can be monovalent, divalent or multivalent.C 3-6 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0036] The compounds of the present application represented by Formula I can be prepared using synthetic methods known in the art or using methods known in the art in combination with the methods described herein. The solvents, temperatures, and other reaction conditions given in the present application are exemplary and can be varied according to methods well known in the art. The compounds of the examples described herein can be synthesized according to the methods described in the examples using appropriate starting materials according to the specific structure of the compound, or can be synthesized using methods analogous to those described in the examples. The starting materials used to synthesize the compounds of the examples of the present application can be prepared by known synthetic methods or by analogous methods described in the literature, or obtained from commercial sources. The compounds can be further resolved into their stereoisomers, if desired, by methods well known in the art, such as crystallization, chromatography, and the like, the resolution conditions of which are readily obtained by one skilled in the art by routine means or limited experimentation. By way of further illustration, the compounds of Formula I of the present application can be synthesized using the following methods, wherein the solvent, temperature, and other reaction conditions in each step can be the same as or analogous to those described in the examples below, or using reaction conditions known in the art. DETAILED DESCRIPTION

[0037] The compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, embodiments formed using a combination of the other chemical synthetic methods well known to those skilled in the art, and equivalents thereof. Preferred embodiments include, but are not limited to, the examples of the present application.

[0038] The present application is described in detail below by way of examples, but is not meant to be limited by any of the examples. The present application has been described in detail by specific reference to embodiments herein, some of which embodiments have been published previously. This detailed description is indeed intended to be illustrative only and not limiting of the scope of the application as set forth in the appended claims. Various modifications and changes can be made thereto by those skilled in the art which fall within the scope and spirit of the application as described. Where no specific conditions are mentioned in the examples, the conditions are those conventional or recommended by the manufacturer. Where the manufacturer of the reagent or instrument is not mentioned, conventional or otherwise commercially available products were used.

[0039] Example 1

[0040]

[0041] Step 1 : To a solution of imidazole (116.6 g, 1.71 mol) in dichloromethane (1.17 L) was added a solution of thionyl chloride (37.3 mL, 514.0 mmol) in DCM (370 mL) dropwise at ice bath temperature. The reaction mixture was stirred at room temperature for 1 h, then the reaction was cooled to -10 °C. To the resulting suspension was added a solution of tert-butyl N-(3-hydroxypropyl)carbamate (50.0 g, 285.7 mmol) in dichloromethane (500 mL) dropwise at -10 °C. After the addition was complete, the reaction mixture was stirred at room temperature for 2 h. TLC showed that the desired spot was detected. After the reaction was complete, the reaction was concentrated, and the residue was purified by column chromatography on silica gel to give compound 1-2 (45.0 g, 71.3% yield). 1 H NMR (400 MHz, CDC13) δ 4.92-4.73 (m, 1H), 3.96-3.71 (m, 3H), 2.29-2.12 (m, 1H), 1.82-1.66 (m, 1H), 1.50 (s, 9H).

[0042] Step 2: To a solution of compound 1-2 (45.0 g, 203.6 mmol) in acetonitrile (500 mL) / water (250 mL) was added ruthenium chloride trihydrate (53.0 mg, 0.20 mmol) and sodium metaperiodate (47.8 g, 223.4 mmol) at ice bath temperature. The reaction mixture was stirred at room temperature for 2 h. Water (500 mL) was added to quench the reaction, and the reaction was extracted with ethyl acetate. The organic phase was combined, washed with water, dried, and concentrated. The resulting crude product was purified by column chromatography on silica gel to give compound 1-3 (40.0 g, 82.9% yield). 1 H NMR (400 MHz, CDC13) δ 4.92-4.73 (m, 1H), 3.96-3.71 (m, 3H), 2.29-2.12 (m, 1H), 1.82-1.66 (m, 1H), 1.50 (s, 9H).

[0043] Step 3: Under nitrogen, 1-(benzyloxy)-5-bromo-3-fluoro-2-nitrobenzene (20.0 g, 61.3 mmol) was dissolved in tetrahydrofuran (400 mL), and the reaction was cooled to -70 °C. Then lithium diisopropylamide (46.0 mL, 2.0 M) was added dropwise slowly. The reaction was stirred at -70 °C for half an hour. Then compound 1-3 (18.9 g, 79.7 mmol) in tetrahydrofuran (100 mL) was added dropwise slowly at -70 °C. The reaction was stirred at -70 °C for 3 h. After the reaction was complete, the reaction was poured into a solution of dilute hydrochloric acid (200 mL, 1.0 M) in an ice water bath to quench the reaction. The mixture was extracted with ethyl acetate, and the organic phase was combined, washed with water, dried, and concentrated. The resulting crude product was purified by column chromatography on silica gel to give compound 1-4 (21.0 g, 70.9% yield). 1HNMR (400 MHz, CDC13) δ 7.51-7.34 (m, 5H), 7.12 (d, J = 2.0 Hz, 1H), 5.16 (s, 2H), 4.61 (br s, 1H), 3.29-3.12 (m, 2H), 2.89-2.71 (m, 2H), 1.83-1.69 (m, 2H), 1.45 (s, 9H).

[0044] Step 4: Intermediate 1-4 (11.0 g, 22.7 mmol) was dissolved in dioxane / water (120 mL, 5 / 1 v / v), E-2-ethoxyvinyl-boronic acid pinacol ester (13.5 g, 68.2 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (1.66 g, 2.27 mmol) and cesium carbonate (22.2 g, 68.2 mmol) were added successively. The reaction mixture was stirred at 90 °C for 3 h under nitrogen atmosphere. The reaction mixture was cooled to room temperature, and the reaction was quenched by the addition of ice water. The mixture was extracted with ethyl acetate, and the organic phase was combined, washed with water, dried and concentrated. The resulting crude product was purified by column chromatography on silica gel to give compound 1-5 (10.0 g, yield 92.6%). 1 H NMR (400 MHz, CDC13) δ 7.45-7.31 (m, 5H), 6.79 (d, J = 12.4 Hz, 1H), 6.72 (d, J = 1.2 Hz, 1H), 5.89 (d, J = 12.4 Hz, 1H), 5.18 (s, 2H), 4.59 (br s, 1H), 3.95 (q, J = 7.2 Hz, 2H), 3.15 (d, J = 5.6 Hz, 2H), 2.64 (t, J = 6.8 Hz, 2H), 1.75-1.64 (m, 2H), 1.45 (s, 9H), 1.38 (t, J = 7.2 Hz, 3H).

[0045] Step 5: Intermediate 1-5 (10.0 g, 21.1 mmol) was dissolved in dioxane (100 mL), and hydrochloric acid dioxane solution (33.0 mL, 4 M) was added. The reaction was stirred at room temperature for 1 h. After the reaction was completed, the reaction was neutralized with aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate (200 mL x 3), and the organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a crude product. The crude product was separated and purified by column chromatography on silica gel to give intermediate 1-6 (5.5 g, yield 60.9%). LCMS (ESI) [M+Na] + : 451.2.

[0046] Step 6: Intermediate 1-6 (5.5 g, 12.8 mmol) was dissolved in methanol (60 mL) at room temperature, and an aqueous solution of ammonium chloride (6.9, 128.3 mmol) and zinc powder (4.2 g, 64.1 mmol) were added. The reaction was stirred at room temperature for 2 hours. After the reaction was completed, the reaction was filtered, and the filtrate was concentrated under reduced pressure to remove most of the methanol, and then diluted with ethyl acetate, and the organic phase was washed with water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain crude intermediate 1-7 (4.4 g, yield 86.0%). LCMS (ESI) [M+H] + : 399.2.

[0047] Step 7: Intermediate 1-7 (4.2 g, 10.5 mmol) was dissolved in dichloromethane (45 mL) at room temperature, and pyridine (2.6 mL, 31.6 mmol) and trifluoroacetic anhydride (2.9 g, 13.7 mmol) were added. The reaction was stirred at room temperature for half an hour. After the reaction was completed, it was poured into ice water, and then extracted with dichloromethane (50 mL x 3), and the organic phase was washed with water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by silica gel column chromatography to obtain intermediate 1-8 (4.8 g, yield 92.1%). LCMS (ESI) [M+Na] + : 517.2.

[0048] Step 8: Intermediate 1-8 (4.7 g, 9.5 mmol) was dissolved in N,N-dimethylformamide (50 mL) under a nitrogen atmosphere, and potassium carbonate (3.94 g, 28.5 mmol) and ethyl bromoacetate (2.18 g, 14.2 mmol) were sequentially added. The reaction mixture was stirred at 60°C for 1 hour. The mixture was cooled to room temperature, and the reaction was poured into ice water, and then extracted with ethyl acetate (50 mL x 3), and the organic phase was washed with water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by silica gel column chromatography to obtain intermediate 1-9 (5.0 g, yield 92.9%). LCMS (ESI) [M+Na] + : 589.2.

[0049] Step 9: Intermediate 1-9 (4.95 g, 8.73 mmol) was dissolved in methanol (55 mL) at room temperature, and a solution of sodium methoxide (9.0 mL, 5.4 M) in methanol was added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction was poured into ice water, and then extracted with dichloromethane (100 mL x 3), and the organic phase was washed with water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain crude intermediate 1-10 (4.0 g, yield 97.3%). LCMS (ESI) [M+Na] + : 471.2.

[0050] Step 10: At room temperature, dissolve intermediate 1-10 (3.90 g, 8.29 mmol) in dichloromethane (50 mL), add N,N-diisopropylethylamine (4.1 mL, 24.87 mmol), and slowly add N-(benzyloxycarbonyl)sulfonyl chloride dropwise while stirring.

[0051] (3.10 g, 12.43 mmol). The mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with ice water. The aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phase was washed with saturated brine (20 mL). The mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography to give intermediate 1-11 (5.0 g, yield 88.2%). LCMS(ESI)[M+Na] + :706.2.

[0052] Step 11: Intermediate 1-11 (2.0 g, 2.92 mmol) was dissolved in methanol (20 mL) at room temperature, and wetted palladium on carbon (400 mg, 3.76 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere (15 psi). The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain intermediate 1-12 (1.20 g, yield 89.7%). LCMS (ESI) [M+Na] + :482.0.

[0053] Step 12: At room temperature, intermediate 1-12 (1.20 g, 2.61 mmol) was dissolved in methanol (30 mL), and a methanol solution of sodium methoxide (5.0 mL, 5.4 M) was added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was poured into ice water and ammonium chloride solution, and then extracted with dichloromethane (100 mL × 3). The organic phase was washed with water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain crude intermediate 1-13 (1.1 g, crude product). LCMS(ESI)[M+Na] + :450.2.

[0054] Step 13: At room temperature, intermediate 1-13 (1.17 g, 2.73 mmol) was dissolved in methanol (20 mL), and wet palladium on carbon (500 mg) was added. The reaction mixture was stirred at 50 °C for 5 hours under a hydrogen atmosphere (15 psi). The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain crude intermediate 1-14 (1.20 g, crude product). LCMS(ESI)[M+Na] + :452.2.

[0055] Step 14: Intermediate 1-14 (200 mg, 0.47 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (3.0 mL) was added. The reaction was stirred at room temperature for 1 h, the solvent was removed under reduced pressure to give the crude product. The crude product was purified by preparative reverse phase HPLC to give 5-(7-fluoro-9-hydroxy-1,2,3,4,5,6-hexahydrobenzo[d]azocin-8-yl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Compound 1) (36.7 mg, yield 23.9 %). LCMS (ESI) [M+H] + : 330.1. 1 H NMR (400 MHz, DMSO-d6) δ 9.44-9.20 (m, 1H), 8.46 (brs, 2H), 6.63 (s, 1H), 3.95 (s, 2H), 3.18-3.10 (m, 2H), 2.98-2.87 (m, 4H), 2.81-2.72 (m, 2H), 1.88-1.76 (m, 2H).

[0056] Example 2

[0057]

[0058] Step 1: Compound 1 (90 mg, 0.27 mmol) was dissolved in methanol (10 mL) under nitrogen atmosphere, paraformaldehyde (82.1 mg, 2.73 mmol) and two drops of glacial acetic acid were added. The reaction mixture was stirred at 40 °C for 1 h. Sodium cyanoborohydride (85.8 mg, 1.37 mmol) was added in portions, the reaction was continued to stir at 40 °C for 12 h. The mixture was cooled to room temperature, the reaction was quenched by the addition of ice water (10 mL), the reaction was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative reverse phase HPLC to give 5-(7-fluoro-9-hydroxy-3-methyl-1,2,3,4,5,6-hexahydrobenzo[d]azocin-8-yl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Compound 2) (12.3 mg, yield 13.1 %). LCMS (ESI) [M+H] + : 344.1. 1 H NMR (400 MHz, DMSO-d6) δ 9.77 (brs, 1H), 8.89 (brs, 1H), 6.66 (s, 1H), 4.14 (s, 2H), 3.26-3.01 (m, 5H), 2.96-2.88 (m, 1H), 2.85-2.72 (m, 5H), 1.99-1.74 (m, 2H).

[0059] Example 3

[0060]

[0061] The compound of this example can be prepared using a similar synthetic method to that described in Example 2. LCMS (ESI)

[0062] [M+H] + :358.2. 1 H NMR (400 MHz, DMSO-d6) δ 9.54 (s, 1H), 8.66 (s, 1H), 6.66 (s, 1H), 4.04 (s, 2H), 3.26-2.86 (m, 8H), 2.83-2.75 (m, 2H), 1.95-1.79 (m, 2H), 1.20 (t, J = 7.2 Hz, 3H).

[0063] Example 4

[0064]

[0065] The compound of this example can be prepared using a similar synthetic method to that described in Example 2. LCMS (ESI)

[0066] [M+H] + :370.2. 1 H NMR (400 MHz, D2O) δ 6.64 (s, 1H), 4.28 (s, 2H), 3.23-3.17 (m, 1H), 3.14-3.08 (m, 1H), 3.02-2.94 (m, 2H), 2.92-2.86 (m, 1H), 2.77-2.72 (m, 1H), 2.51-2.42 (m, 1H), 1.82 (s, 2H), 1.24-1.14 (m, 3H), 0.68-0.59 (m, 3H).

[0067] Example 5

[0068]

[0069] The compound of this example can be prepared using a similar synthetic method to that described in Example 2. LCMS (ESI)

[0070] [M+H] + :384.2. 1 H NMR (400 MHz, DMSO-d6) δ 6.48 (s, 1H), 6.08 (s, 1H), 3.96 (s, 2H), 2.78-2.73 (m, 2H), 2.65-2.60 (m, 4H), 2.38-2.31 (m, 4H), 1.52 (s, 2H), 0.76 (s, 1H), 0.45-0.36 (m, 2H), 0.07-0.00 (m, 2H).

[0071] Example 6

[0072]

[0073] Step 1: Under nitrogen atmosphere, 1-(benzyloxy)-5-bromo-3-fluoro-2-nitrobenzene (30.0 g, 92.0 mmol) was dissolved in tetrahydrofuran (300 mL). The reaction solution was cooled to -70 °C, and then diisopropylaminolithium (92.0 mL, 2.0 M) was slowly added dropwise. The reaction solution was stirred at -70 °C for half an hour. Then, 3-Boc-1,2,3-oxathiazoline 2,2-dioxide (24.6 g, 110.3 mmol) in tetrahydrofuran (100 mL) was slowly added dropwise to the reaction solution at -70 °C, and the reaction solution was stirred at -70 °C for 3 hours. After the reaction was complete, the reaction solution was quenched in a saturated ammonium chloride solution in an ice-water bath. The mixed solution was extracted with ethyl acetate, the organic phases were combined, washed with water, dried, and concentrated. The crude product was purified by silica gel column chromatography to give compound 6-2 (35.0 g, yield 81.1%). LCMS(ESI)[M+Na] + :491.0.

[0074] Step 2: Intermediate 6-2 (25.0 g, 53.2 mmol) was dissolved in dioxane / water (120 mL, 5 / 1 v / v), followed by the addition of E-2-ethoxyvinyl-1-boronic acid pinacol ester (52.8 g, 266.3 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (1.9 g, 2.66 mmol), and cesium carbonate (52.1 g, 159.8 mmol). The reaction mixture was stirred at 90 °C for 3 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and quenched with ice water. The mixture was extracted with ethyl acetate, and the organic phases were combined, washed with water, dried, and concentrated. The crude product was purified by silica gel column chromatography to give compound 6-3 (17.5 g, 71.3% yield). LCMS (ESI) [M+Na] + :483.4.

[0075] Step 3: Intermediate 6-3 (17.0 g, 36.9 mmol) was dissolved in dioxane (150 mL), and dioxane hydrochloride solution (50 mL, 4 M) was added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was neutralized with sodium bicarbonate aqueous solution. The mixture was extracted with ethyl acetate (300 mL × 3), and the organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain intermediate 6-4 (8.5 g, yield 55.6%). LCMS (ESI) [M + Na] + :437.4.

[0076] Step 4: Intermediate 6-4 (17.1 g, 41.2 mmol) was dissolved in a mixture solvent of tetrahydrofuran (100 mL) and methanol (100 mL) at room temperature, and saturated ammonium chloride solution (50 mL) and zinc powder (13.5 g, 206.3 mmol) were added. The reaction was stirred at room temperature for 3 hours. After the reaction was completed, the reaction was filtered, and the filtrate was concentrated under reduced pressure to remove most of the methanol, and then diluted with dichloromethane, and the organic phase was washed with water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain crude intermediate 6-5 (12.5 g, yield 78.8%). LCMS (ESI) [M+H] + : 385.0.

[0077] Step 5: Intermediate 6-5 (12.5 g, 32.5 mmol) was dissolved in dichloromethane (150 mL) at room temperature, and pyridine (6.56 mL, 81.2 mmol) and trifluoroacetic anhydride (13.7 g, 65.0 mmol) were added. The reaction was stirred at room temperature for 2 hours. After the reaction was completed, it was poured into ice water, and then extracted with ethyl acetate (300 mL x 3), and the organic phase was washed with water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by silica gel column chromatography to obtain intermediate 6-6 (15.0 g, yield 96.0%). LCMS (ESI) [M+Na] + : 503.0.

[0078] Step 6: Intermediate 6-6 (13.0 g, 27.0 mmol) was dissolved in N,N-dimethylformamide (130 mL) under a nitrogen atmosphere, and potassium carbonate (11.2 g, 81.2 mmol) and methyl bromoacetate (5.0 g, 32.4 mmol) were sequentially added. The reaction mixture was stirred at 60°C for 14 hours. The mixture was cooled to room temperature, and the reaction was poured into ice water, and then extracted with ethyl acetate (300 mL x 3), and the organic phase was washed with water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by silica gel column chromatography to obtain intermediate 6-7 (13.8 g, yield 92.3%). LCMS (ESI) [M+Na] + : 575.0.

[0079] Step 7: Intermediate 6-7 (13.8 g, 25.0 mmol) was dissolved in methanol (120 mL) at room temperature, and a solution of sodium methoxide (9.0 mL, 5.4 M) in methanol was added. The reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction was poured into ice water, neutralized with saturated ammonium chloride, and then extracted with dichloromethane (100 mL x 3), and the organic phase was washed with water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain crude intermediate 6-8 (10.4 g, yield 91.6%). LCMS (ESI) [M+H]+ : 457.2.

[0080] Step 8: Intermediate 6-8 (5.0 g, 10.9 mmol) was dissolved in dichloromethane (50 mL) at room temperature, N,N-diisopropylethylamine (5.4 mL, 32.8 mmol) was added, and N-(benzyloxy carbonyl)sulfuryl chloride (4.1 g, 16.4 mmol) was added dropwise slowly with stirring. The mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with ice water. The aqueous phase was extracted with dichloromethane (100 mL x 3). The organic phase was washed with saturated brine. It was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a crude product, which was separated and purified by column chromatography on silica gel to give intermediate 6-9 (6.1 g, yield 83.2%). LCMS (ESI) [M-Boc+H] + : 570.2.

[0081] Step 9: Intermediate 6-9 (8.1 g, 12.1 mmol) was dissolved in isopropanol (100 mL) at room temperature, and wet palladium on carbon (810 mg, 7.61 mmol) was added. The reaction was stirred at 40 °C under hydrogen (15 psi) for 3 hours. The reaction was filtered, and the filtrate was concentrated under reduced pressure to give a crude product, intermediate 6-10 (4.7 g, yield 86.8%). LCMS (ESI)

[0082] [M+Na] + : 470.4.

[0083] Step 10: Intermediate 6-10 (4.1 g, 9.16 mmol) was dissolved in methanol (40 mL) at room temperature, and a solution of sodium methoxide (10.0 mL, 5.4 M) in methanol was added. The reaction was stirred at 40 °C for 1 hour. After the reaction was completed, the reaction was poured into ice water and an ammonium chloride solution, and then extracted with ethyl acetate (200 mL x 3). The organic phase was washed with water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a crude product, which was separated and purified by column chromatography on silica gel to give intermediate 6-11 (3.2 g, yield 84.1%). LCMS (ESI) [M+Na] + : 438.0.

[0084] Step 11: Intermediate 6-11 (5.4 g, 13.1 mmol) was dissolved in dichloromethane (45 mL) at ice bath, and trifluoroacetic acid (15 mL) was added. The reaction was slowly returned to room temperature, stirred for 2 hours, and the solvent was evaporated to give a crude product. The crude product was separated and purified by C18 reverse phase chromatography to give 5-(6-fluoro-8-hydroxy-2,3,4,5-tetrahydro-1H- benzo[d]azepin-7-yl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Compound 6) (2.1 g, yield 51.2%). LCMS (ESI)

[0085] [M+H] + : 316.0. 1 H NMR (400 MHz, DMSO-d6) δ 9.40 (br s, 1H), 7.26 (br s, 2H), 6.59 (s, 1H), 3.93 (s, 2H), 3.23-3.12 (m, 4H), 3.03-2.91 (m, 4H).

[0086] Example 7

[0087]

[0088] Step 1: Compound 6 (1.1 g, 3.49 mmol) was dissolved in isopropanol (20 mL) under nitrogen atmosphere, acetaldehyde (3.5 mL, 17.44 mmol) and glacial acetic acid (0.1 mL) were added. The reaction mixture was stirred at 40 °C for 1 h. Sodium cyanoborohydride (2.4 g, 34.88 mmol) was added portionwise and the reaction was continued to stir at 40 °C for 12 h. The mixture was cooled to room temperature, the reaction was quenched by the addition of ice water (10 mL) and the reaction was concentrated under reduced pressure to give the crude product. The crude product was purified by C18 reverse phase chromatography to give 5-(3-ethyl-6-fluoro-8-hydroxy-2,3,4,5-tetrahydro-1H- benzo[d]azepin-7-yl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (compound 7) (800 mg, yield 66.8 %). LCMS (ESI) [M+H] + : 344.1. 1 H NMR (400 MHz, DMSO-d6) δ 9.64-9.09 (m, 2H), 6.59 (s, 1H), 3.92 (s, 2H), 3.70-3.45 (m, 1H), 3.26-2.64 (m, 9H), 1.21 (t, J = 6.9 Hz, 3H).

[0089] Test Example 1: PTPN2 enzymatic inhibition assay

[0090] Using 6,8-difluoro-4-methyl umbelliferyl phosphate (DiFMUP) as substrate, 5 μL of PTPN2 solution (reaction buffer PTPN2 diluted to 0.2 nM: 50 mM Tris-HCl, pH 7.2, 50 mM NaCl, 0.01% Tween-20, 0.01% Brij-35, 0.01% BSA, 0.01% DTT) was added to the 384-well plate. The reaction was initiated by the addition of 5 μL of test compound (diluted in reaction buffer) and the plate was incubated at room temperature for 1 h. The reaction was stopped by the addition of 5 μL of stop solution (0.1 M NaOH, 0.1 M Na2CO3) and the plate was incubated at room temperature for 30 min. The fluorescence was measured at Ex 340 nm and Em 460 nm.

[0091] Triton X-100, 1 mM DTT) with compound or DMSO (0.5% v / v) for 10 min at room temperature. The reaction was initiated by adding 5 μL DiFMUP (10 μM) and incubated for 30 min at room temperature. The fluorescence of the final reaction solution was measured on a CLARIO Star Plus acu microplate reader (BMG) (excitation wavelength 360 nm, emission wavelength 460 nm). The experiment was performed in duplicate. The low control (DMSO and blank reaction buffer) was set as 100% inhibition, and the high control (DMSO and PTPN2 enzyme reaction solution) was set as 0% inhibition. The inhibition rate was calculated as 100*(average high control - compound well) / (average high control - average low control). The IC 50 values were determined by XLfit fitting a non-linear regression equation.

[0092] Table 1: PTPN2 enzymatic activity (IC 50 )

[0093] Compound No. IC 50 (nM) Compound 1 14.9 Compound 2 6.7 Compound 3 6.5 Compound 4 4.5 Compound 5 7.2 Compound 6 21.6

[0094] Test Example 2: Hela p-STAT1 activation detection

[0095] Hela cells were seeded in clear 96-well cell culture plates and placed in a carbon dioxide incubator for overnight incubation at 37 degrees. After the incubation, the cell plate was discarded supernatant, and 80 μL of basal medium was added. The compound to be tested was gradient diluted and added to the cell culture medium, and after mixing, the cell plate was placed back in the carbon dioxide incubator for continued incubation for 24 hours. Then 10 μL of 50 ng / mL IFNy was added, and the incubation was continued for 30 minutes. After the incubation was completed, the p-STAT1 was detected by using the Cisbio kit (63ADK026PEG). The cell supernatant was discarded, and 50 μL of cell lysis solution was added to each well, and the plate was incubated at room temperature for 60 minutes. 16 μL of cell lysate supernatant was taken from each well to a new 384 white microplate, and 2 μL of Phospho-STAT1 Eu Cryptate antibody dilution and 2 μL of Phospho-STAT1 d2 antibody dilution were added. The plate was incubated at room temperature overnight. After the incubation was completed, the fluorescence signal (excitation: 320 nm, emission: 615 nm, 665 nm) was read by using a multi-label analyzer.

[0096] Table 2: Hela p-STAT1 activation activity (EC 50 )

[0097] Compound No. EC 50 (μM) Compound 2 0.76 Compound 7 8.75

[0098] Although the specific embodiments of the present application have been described in detail, those skilled in the art can make various modifications and substitutions to the details of the technical solutions of the present application according to all the teachings contained in the disclosure, and these changes are within the scope of protection of the present application. The entire scope of the present application is given by the appended claims and any equivalents thereof.

Claims

1. A compound of formula II or a pharmaceutically acceptable salt thereof, ； R 1a -C 1-6 Alkyl, C 3-6 cycloalkyl or -C 1-6 Alkyl-C 3-6 Cycloalkyl.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, R 1a -C 1-3 Alkyl, C 3-6 cycloalkyl or -C 1-3 Alkyl-C 3-6 Cycloalkyl.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, R 1a -C 1-3 Alkyl, cyclopropyl or -C 1-3 Alkyl-cyclopropyl.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, The structure of the compound is shown in one of the following: or .

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, The structure of the compound is shown in one of the following: or .

6. A pharmaceutical composition, wherein, The pharmaceutical composition comprises the compound of any one of claims 1-5 or a pharmaceutically acceptable salt thereof. And, pharmaceutically acceptable carriers.

7. The use of the compound of any one of claims 1-5 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 6 in the preparation of a medicament for treating PTPN2-mediated diseases.

8. The application according to claim 7, wherein, The diseases mediated by PTPN2 are selected from cancer.

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