Intermediate for preparing PTPN1 / n2 inhibitor, preparation method therefor, and use thereof

Abstract

The present invention relates to the field of pharmaceutical synthesis, and specifically relates to intermediates of a small-molecule PTPN1 / N2 inhibitor, a method for preparing the intermediates, and a method for preparing the PTPN1 / N2 inhibitor using these intermediates. The present invention provides novel intermediates, represented by formula (3), of the PTPN1 / N2 inhibitor, and a method for preparing these intermediates. The present invention also provides a method for preparing the PTPN1 / N2 inhibitor ABBV-CLS-484 and an enantiomer thereof using the compound represented by formula (3).

Description

An intermediate for the preparation of PTPN1 / N2 inhibitors, its preparation method and uses Technical Field

[0001] This invention relates to the field of drug synthesis, specifically to intermediates for small molecule ABBV-CLS-484 and its enantiomers, as well as methods for preparing these intermediates and methods for preparing ABBV-CLS-484 and its enantiomers, as well as other PTPN1 / 2 inhibitors. Background Technology

[0002] ABBV-CLS-484, developed by AbbVie and Calico Life Sciences, is a novel type I and type II non-receptor protein tyrosine phosphatase (PTPN1 / N2) inhibitor currently in Phase I clinical trials for the treatment of cancer, non-small cell lung cancer, advanced solid tumors, clear cell renal cell carcinoma, head and neck squamous cell carcinoma, and solid tumors. Preclinical studies have shown that ABBV-CLS-484 treatment amplifies the intrinsic tumor response to interferon and increases the activation and function of several immune cell subsets that promote cellular pathways, including JAK-STAT signaling in animal models. In a mouse cancer model resistant to PD-1 blockade, ABBV-CLS-484 monotherapy produced potent anti-tumor immunity. In vivo studies and single-cell transcriptional analysis of tumor-infiltrating lymphocytes from treated mice revealed that ABBV-CLS-484 stimulates the tumor microenvironment and promotes NK and CD8 expression. + T cell function. From a mechanistic perspective, ABBV-CLS-484 induces epigenetic and metabolic changes in T cells, resulting in a unique functional state that leads to increased cytotoxicity and reduced T cell exhaustion and dysfunction.

[0003] The chemical name of ABBV-CLS-484 is (R)-5-(1-fluoro-3-hydroxy-7-(isopentylamino)-5,6,7,8-tetrahydronaphthyl-2-yl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide, and its molecular formula is C2. 17 H 24 FN3O4S, CAS No.: 2489404-97-7, has the chemical structure shown in the following formula:

[0004] AbbVie disclosed the chemical structure and pharmaceutical uses of ABBV-CLS-484 in patent CN114025844A, along with a method for preparing the compound using preparative chiral supercritical fluid chromatography (SFC) for chiral separation. Chiral SFC separation is expensive and has low throughput, limiting its application in large-scale production. Therefore, it is essential to develop a preparation method that produces high-performance intermediates and meets the needs of practical production. Summary of the Invention

[0005] The purpose of this invention is to provide key intermediates in the synthesis of PTPN1 / 2 inhibitors such as ABBV-CLS-484 and its enantiomers, as well as methods for synthesizing these intermediates. Another purpose of this invention is to provide a method for preparing PTPN1 / 2 inhibitors such as ABBV-CLS-484 and its enantiomers using the aforementioned intermediates.

[0006] To achieve the above objectives, the present invention adopts the following technical solution:

[0007] On the one hand, the present invention provides a compound represented by formula (3), or a stereoisomer, tautomer, deuterated product, or pharmaceutical salt thereof, for the preparation of compound ABBV-CLS-484 and its enantiomers:

[0008] Where X is selected from chlorine, bromine or iodine.

[0009] In some embodiments, the compound has the structure shown in formula (3a), or a stereoisomer, tautomer, deuterated product, or pharmaceutical salt thereof:

[0010] On the other hand, the present invention provides a method for preparing compounds of formula (3) or (3a), the method comprising the following steps:

[0011] (a) The compound of formula (1) and (R)-tert-butylsulfinamide were dissolved in reaction solvent 1 and reacted under the action of catalyst 1 to obtain the compound shown in formula (2);

[0012] (b) The compound of formula (2) is dissolved in reaction solvent 2, and its carbon-nitrogen double bond is reduced by a reducing agent under the action of catalyst 2 to obtain the compounds shown in formula (R-3) and (S-3), respectively;

[0013] The definition of X is as described in general formula (3).

[0014] In some embodiments, in step (a), the amount of (R)-tert-butylsulfinamide is 1.0 to 2.0 times that of the compound of formula (1);

[0015] The amount of catalyst 1 is 1.0 to 2.0 times that of the compound of formula (1);

[0016] The catalyst 1 is selected from titanate esters, preferably tetraethyl titanate;

[0017] The reaction solvent 1 is selected from ether solvents, toluene, dichloromethane, N,N-dimethylformamide, and preferably tetrahydrofuran;

[0018] The reaction temperature in step (a) is from room temperature to the reflux temperature of reaction solvent 1.

[0019] In some embodiments, in step (b), the amount of reducing agent is 2.0 to 3.0 times that of the compound of formula (2);

[0020] The amount of catalyst 2 is 1.0 to 2.0 times that of the compound of formula (2);

[0021] The reducing agent is selected from alkali metal borohydrides or substituted alkali metal borohydrides, preferably sodium borohydride;

[0022] The catalyst 2 is selected from titanate, cobalt chloride, cerium chloride, and nickel chloride, and is preferably tetraethyl titanate;

[0023] The reaction solvent 2 is selected from ether solvents, toluene, dichloromethane, N,N-dimethylformamide, and preferably tetrahydrofuran;

[0024] The reaction temperature in step (b) is from room temperature to the reflux temperature of reaction solvent 2;

[0025] The reaction products were purified by column chromatography to obtain compounds of formula (R-3) and (S-3) with single configurations, respectively.

[0026] In another aspect, the present invention provides a method for preparing ABBV-CLS-484 and its enantiomer intermediates using compounds of formula (3) or (3a), the method comprising the following steps:

[0027] (a') The compound of formula (3) reacts with iodoisopentane to give the compound of formula (4);

[0028] (b') The compound of formula (4) undergoes a hydrolysis reaction to give the compound of formula (5);

[0029] (c') Protecting the hydroxyl group of the compound of formula (5) yields the compound shown in formula (6);

[0030] (d') The compound of formula (6) undergoes an iodination reaction on the benzene ring to give the compound shown in formula (7);

[0031] The compound of formula (7) is reacted with glycine tert-butyl ester to give the compound of formula (8);

[0032] (f') The compound of formula (8) reacts with chlorosulfonamide to give the compound of formula (9);

[0033] (g')Removing the hydroxyl protecting group from compound (9) yields compound ABBV-CLS-484 and its enantiomers;

[0034] Wherein, P is a hydroxyl protecting group; the definition of X is as described in general formula (3).

[0035] In some embodiments, the hydroxyl protecting group P is selected from methyl, benzyl, p-methoxybenzyl, allyl, methoxymethyl, tetrahydropyranyl, (trimethylsilyl)ethoxymethyl, 1-methoxy-2-methoxyethane, acetyl, benzoyl, preferably 1-methoxy-2-methoxyethane.

[0036] In some embodiments, the hydroxyl protecting group P is selected from methyl, benzyl, p-methoxybenzyl, allyl, methoxymethyl, tetrahydropyranyl, (trimethylsilyl)ethoxymethyl, 1-methoxy-2-methoxyethyl, acetyl, benzoyl, preferably benzyl.

[0037] In some embodiments, step (a') further includes adding an inorganic base to the reaction system, preferably sodium hydride.

[0038] In some embodiments, step (d') further includes adding n-butyllithium and iodine to the reaction system.

[0039] In some embodiments, step (e') further includes adding catalyst 3 and a base to the reaction system, wherein catalyst 3 is preferably methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) and / or 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-1,1'-biphenyl, and the base is preferably cesium carbonate.

[0040] In some embodiments, step (f') further includes adding a base to the reaction system, preferably pyridine and / or sodium methoxide.

[0041] In another aspect, the present invention provides compounds represented by formulas (3), (3a), (4), (5), (6), (7), (8) or (9), or their stereoisomers, tautomers, deuterated derivatives or pharmaceutical salts:

[0042] Where P is a hydroxyl protecting group; X is selected from chlorine, bromine or iodine.

[0043] This invention provides compounds represented by formulas (4), (5), (6), (7), (8) or (9), or their stereoisomers, tautomers, deuterated derivatives or pharmaceutical salts:

[0044] Where P is a hydroxyl protecting group; X is selected from chlorine, bromine or iodine.

[0045] In another aspect, the present invention provides the use of compounds of formula (3), (3a), (4), (5), (6), (7), (8) or (9) as described above, or their stereoisomers, tautomers, deuterated derivatives or pharmaceutical salts, in the preparation of PTPN1 / 2 inhibitors.

[0046] In some embodiments, the PTPN1 / 2 inhibitor is selected from compound ABBV-CLS-484 and its enantiomers.

[0047] Unless otherwise stated, the general chemical terms used in the structural formulas have their usual meanings.

[0048] The term "medicinal salt" refers to salt prepared from a pharmaceutically acceptable, non-toxic alkali or acid.

[0049] 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.

[0050] 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.

[0051] 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.

[0052] Unless otherwise stated, the present invention includes any possible tautomers and their pharmaceutical salts, and mixtures thereof, when the compounds shown in formulas (3), (3a), (4), (5), (6), (7), (8), or (9) are present.

[0053] 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.

[0054] In this invention, "room temperature" refers to ambient temperature, which is generally between 15°C and 25°C.

[0055] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0056] This invention introduces chiral amines via chiral induction, allowing for efficient separation of the chiral starting material using conventional silica gel column chromatography. This chiral starting material can then be used for the efficient synthesis of PTPN2 / 1 inhibitors, such as ABBV-CLS-484 and its enantiomers. AbbVie disclosed a method for preparing ABBV-CLS-484 in patent CN114025844A, which uses preparative chiral supercritical fluid chromatography (SFC) for chiral resolution. However, chiral SFC resolution is expensive and has low throughput, limiting its application in large-scale production. This invention employs a one-pot method for introducing the chiral group and reducing the enamine, resulting in high yield, simple operation, mild reaction conditions, environmental friendliness, and high purity of the final product, making it suitable for large-scale industrial production. Detailed Implementation

[0057] 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.

[0058] Unless otherwise stated, all temperatures in this invention refer to degrees Celsius.

[0059] The following abbreviations were used in the examples:

[0060] Ti(OEt)4: Tetraethyl titanate; THF: Tetrahydrofuran; NaBH4: Sodium borohydride; NaH: Sodium hydride; DMF: N,N-Dimethylformamide; Pd2(dba)3: Tris(dibenzylacetone)dipalladium; tBuXphos: 2-Di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl; KOH: Potassium hydroxide; nBuLi: n-Butyllithium; BrettPhos-Pd-G3: Methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2' ,4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II); BrettPhos: 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-1,1'-biphenyl; Cs2CO3: cesium carbonate; MeONa: sodium methoxide; HCl: hydrogen chloride; MeCN: acetonitrile; H2O: water; LC-MS: liquid chromatography-mass spectrometry; 20mL×3: 3 times, 20mL each time.

[0061] 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.

[0062] All reaction raw materials and common intermediates involved in the embodiments of the present invention can be purchased commercially or obtained in-house. The preparation process of raw materials and common intermediates that need to be obtained in-house is detailed below.

[0063] Example 1: Synthesis of N-((R)-6-bromo-8-fluoro-1,2,3,4-tetrahydronaphth-2-yl)-2-methylprop-2-sulfonamide (3)

[0064] Step 1: Synthesis of (R)-N-(6-bromo-8-fluoro-3,4-dihydronaphthyl-2(1H)-ylidene)-2-methylprop-2-sulfonamide (2)

[0065] Compound 6-bromo-8-fluoro-3,4-dihydronaphthyl-2(1H)-one (6.90 g, 28.5 mmol) was dissolved in anhydrous tetrahydrofuran (90 mL), followed by the addition of (R)-tert-butylsulfinamide (4.14 g, 34.2 mmol) and tetraethyl titanate (9.75 g, 42.8 mmol). The reaction was carried out at 45 °C for 3 hours under nitrogen protection. After the reaction was confirmed to be complete by LC-MS, the reaction was quenched by adding water (30 mL) in an ice-water bath. The mixture was filtered through diatomaceous earth, and the filtrate was diluted with water (30 mL). The filtrate was extracted with ethyl acetate (60 mL × 3), and the organic phases were combined. The organic phases were washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 2 (9.50 g), which was the crude product.

[0066] LC-MS (m / z): 344.0 / 346.0 [M–H] + .

[0067] Step 2: Synthesis of N-((R)-6-bromo-8-fluoro-1,2,3,4-tetrahydronaphth-2-yl)-2-methylprop-2-sulfonamide (3)

[0068] Compound 2 (9.50 g) was dissolved in tetrahydrofuran (90 mL), and tetraethyl titanate (6.50 g, 28.5 mmol) was added. Sodium borohydride (3.25 g, 85.5 mmol) was added at –50 °C, and the mixture was then reacted at 25 °C for 2 hours. After the reaction was complete as monitored by LC-MS, the reaction was quenched with water (30 mL) in an ice-water bath. The mixture was filtered through diatomaceous earth, and the filtrate was diluted with water (30 mL). The aqueous phase was extracted with ethyl acetate (60 mL × 3). The organic phases were combined, washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 50:50 as eluent) to give compound R-3 (3.66 g) and compound S-3 (2.00 g).

[0069] LC-MS (m / z): 348.0 / 350.0 [M+H] + .

[0070] R-3: 1H NMR (600MHz, DMSO-d6) δ7.27(dd,J=9.0,1.9Hz,1H),7.18(d,J=2.0Hz,1H),5.23(d,J=6.1Hz,1H),3.54–3.40(m,1H),3.01( dd,J=17.2,5.4Hz,1H),2.91–2.72(m,2H),2.60(dd,J=17.2,8.6Hz,1H),2.02–1.89(m,1H),1.79–1.65(m,1H),1.12(s,9H).

[0071] S-3: 1 H NMR (600MHz, DMSO-d6) δ7.27(dd,J=9.1,2.0Hz,1H),7.19(s,1H),5.28(d,J=6.0Hz,1H),3.48(tdd,J=8.9,5.7,3.1Hz,1H ),2.94–2.84(m,2H),2.85–2.75(m,1H),2.55(dd,J=17.2,8.9Hz,1H),2.12–2.01(m,1H),1.81–1.68(m,1H),1.10(s,9H).

[0072] Example 2: Synthesis of (R)-5-(1-fluoro-3-hydroxy-7-(isopentylamino)-5,6,7,8-tetrahydronaphthyl-2-yl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide (ABBV-CLS-484)

[0073] Step 1: Synthesis of (R)-N-((R)-6-bromo-8-fluoro-1,2,3,4-tetrahydronaphth-2-yl)-N-isopentyl-2-methylpropane-2-sulfonamide (R-4)

[0074] Compound R-3 (423.0 mg, 1.22 mmol) was dissolved in anhydrous N,N-dimethylformamide (8 mL). Sodium hydride (122.0 mg, 3.05 mmol) was added at 0 °C and stirred for 30 minutes while maintaining the temperature. Then, isopentane iodopentane (483.0 mg, 2.44 mmol) was added, and the mixture was reacted at 25 °C for 16 hours. After the reaction was confirmed to be complete by LC-MS, water (10 mL) was added to quench the reaction. The aqueous phase was extracted with ethyl acetate (10 mL × 3). The organic phases were combined and washed with saturated brine (10 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 75:25 as eluent) to give compound R-4 (389.0 mg).

[0075] LC-MS (m / z): 418.0 / 420.0 [M+H] + .

[0076] 1 H NMR(600MHz,DMSO-d6)δ7.29(dd,J=9.2,1.9Hz,1H),7.20(s,1H),3.48–3.34(m, 1H),3.22–3.13(m,1H),2.97–2.90(m,1H),2.88–2.77(m,2H),2.70–2.56(m,2H), 2.07(d,J=12.0Hz,1H),1.79(qd,J=12.2,5.1Hz,1H),1.55(ddp,J=19.4,12.9,6 .5,6.0Hz,2H),1.33(tt,J=10.5,5.6Hz,1H),1.13(s,9H),0.88(t,J=6.9Hz,6H).

[0077] Step 2: Synthesis of (R)-N-((R)-8-fluoro-6-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)-N-isopentyl-2-methylpropane-2-sulfonamide (R-5)

[0078] Compound R-4 (300.0 mg, 0.72 mmol), tris(dibenzylacetone)dipalladium (30.0 mg, 0.033 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (60.0 mg, 0.14 mmol), and potassium hydroxide (78.0 mg, 1.39 mmol) were dissolved in a mixed solvent of dioxane (5 mL) and water (5 mL). The mixture was reacted at 100 °C for 3 hours under nitrogen protection. After the reaction was confirmed to be complete by LC-MS, 10 mL of 1.0 M citric acid aqueous solution was added dropwise to adjust the pH of the aqueous phase to acidic. The aqueous phase was extracted with ethyl acetate (20 mL × 3), and the combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 50:50 as eluent) to give compound R-5 (289.0 mg), which was the crude product.

[0079] LC-MS (m / z): 356.0 [M+H] + .

[0080] Step 3: Synthesis of (R)-N-((R)-8-fluoro-6-((2-methoxyethoxy)methoxy)-1,2,3,4-tetrahydronaphth-2-yl)-N-isopentyl-2-methylpropane-2-sulfonamide (R-6)

[0081] Compound R-5 (289.0 mg) was dissolved in anhydrous tetrahydrofuran (8 mL). Sodium hydride (50.0 mg, 1.25 mmol) was added at 0 °C and stirred for 30 minutes. Then, 1-(chloromethoxy)-2-methoxyethane (121.0 mg, 0.97 mmol) was added, and the mixture was reacted at 25 °C for 2.5 hours. After the reaction was complete as monitored by LC-MS, the reaction was quenched with saturated ammonium chloride aqueous solution (10 mL). The aqueous phase was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 50:50 as eluent) to give compound R-6 (280.0 mg), with a two-step yield of 87.8%.

[0082] LC-MS (m / z): 444.0 [M+H] + .

[0083] 1 H NMR (600MHz, DMSO-d6) δ6.69 (dd, J=11.3, 2.4Hz, 1H), 6.63 (d, J=2.4Hz, 1H), 5.23–5 .18(m,2H),3.71–3.64(m,2H),3.47–3.43(m,2H),3.40–3.34(m,1H),3.22(s,3H),3 .21–3.14(m,1H),2.91–2.75(m,3H),2.69–2.56(m,2H),2.11–2.03(m,1H),1.85–1. 72(m,1H),1.63–1.46(m,2H),1.38–1.27(m,1H),1.13(s,9H),0.88(t,J=6.8Hz,6H).

[0084] Step 4: Synthesis of (R)-N-((R)-8-fluoro-7-iodo-6-((2-methoxyethoxy)methoxy)-1,2,3,4-tetrahydronaphthyl-2-yl)-N-isopentyl-2-methylpropane-2-sulfonamide (R-7)

[0085] Compound R-6 (280.0 mg, 0.63 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL). A hexane solution of n-butyllithium (0.5 mL, 1.25 mmol, 2.5 M) was added dropwise at –78 °C with stirring for 1 hour. Then, an anhydrous tetrahydrofuran solution of iodine (320.0 mg, 1.26 mmol) (2 mL) was added dropwise, and the mixture was reacted at 25 °C for 3 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 (20 mL × 3). The organic phases were combined, 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 column chromatography (petroleum ether:ethyl acetate = 50:50 as eluent) to give compound R-7 (185.0 mg).

[0086] LC-MS (m / z): 570.0 [M+H] + .

[0087] 1 H NMR(600MHz,DMSO-d6)δ6.75(s,1H),5.35–5.22(m,2H),3.80–3.67(m,2H) ,3.51–3.37(m,2H),3.42–3.34(m,1H),3.23(s,3H),3.22–3.12(m,1H),2. 92–2.75(m,3H),2.72–2.55(m,2H),2.11–2.03(m,1H),1.85–1.71(m,1H), 1.60–1.48(m,2H),1.39–1.29(m,1H),1.13(s,9H),0.88(t,J=6.6Hz,6H).

[0088] Step 5: Synthesis of tert-butyl((R)-7-(((R)-tert-butylsulfinyl)(isopentyl)amino)-1-fluoro-3-((2-methoxyethoxy)methoxy)-5,6,7,8-tetrahydronaphth-2-yl)glycine ester (R-8)

[0089] Compound R-7 (185.0 mg, 0.33 mmol), glycine tert-butyl ester (86.0 mg, 0.66 mmol), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (60.0 mg, 0.066 mmol), 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-1,1'-biphenyl (35.0 mg, 0.065 mmol), and cesium carbonate (326.0 mg, 1.00 mmol) were dissolved in dioxane (6 mL). The mixture was reacted at 100 °C for 16 hours under nitrogen protection. After the reaction was complete as monitored by LC-MS, the reaction solution was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 50:50 as eluent) to give compound R-8 (172.0 mg).

[0090] LC-MS (m / z): 573.0 [M+H] + .

[0091] 1 H NMR(600MHz,DMSO-d6)δ6.60(s,1H),5.22–5.14(m,2H),4.86–4.75(m,1H),3.87(dd,J=7 .0,2.4Hz,2H),3.79–3.71(m,2H),3.48–3.45(m,2H),3.39–3.32(m,1H),3.24(s,3H),3.2 1–3.11(m,1H),2.81–2.66(m,3H),2.65–2.55(m,2H),2.10–1.93(m,1H),1.80–1.69(m,1H ),1.61–1.47(m,2H),1.36(s,9H),1.35–1.29(m,1H),1.13(s,9H),0.88(t,J=6.4Hz,6H).

[0092] 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-isopentyl-2-methylpropane-2-sulfonamide (R-9)

[0093] Compound R-8 (172.00 mg, 0.30 mmol) was dissolved in anhydrous tetrahydrofuran (6 mL), pyridine (71.0 mg, 0.90 mmol) was added, and chlorosulfonamide (104.0 mg, 0.90 mmol) was added at 0 °C. The mixture was then reacted at 25 °C for 30 minutes. After the reaction was complete as monitored by LC-MS, the reaction solution was cooled to 0 °C, and a methanol solution of sodium methoxide (5.0 M, 0.4 mL) was added dropwise. The mixture was then reacted at 25 °C for 30 minutes. After the reaction was complete as monitored by LC-MS, the reaction solution was diluted with ethyl acetate (10 mL), and a 1.0 M citric acid aqueous solution (10 mL) was added dropwise to adjust the pH of the aqueous phase to acidic. The aqueous phase was extracted with ethyl acetate (20 mL × 3), and the combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 90:10 as eluent) to give compound R-9 (200.0 mg), which was the crude product.

[0094] LC-MS (m / z): 578.0 [M+H] + .

[0095] Step 7: Synthesis of (R)-5-(1-fluoro-3-hydroxy-7-(isopentylamino)-5,6,7,8-tetrahydronaphthyl-2-yl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide (ABBV-CLS-484)

[0096] Method 1: Compound R-9 (200.0 mg) was dissolved in acetonitrile (4 mL), and ethyl acetate solution of hydrogen chloride (0.4 mL, 4.0 M) was added. The mixture was reacted at 25 °C for 1 hour. After the reaction was complete as monitored by LC-MS, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain compound ABBV-CLS-484 (15.0 mg). Preparation method: A C18 column was used, and the mobile phase was 10 mmol / L ammonium bicarbonate aqueous solution (A) and acetonitrile (B). Gradient elution was performed at a flow rate of 15 mL / min, based on the volume content of phase B: 0 to 10 min (15% → 100%), 10.01 min to 15 min (100%), and 15.01 min to 20 min (100% → 15%).

[0097] Method 2: Compound R-9 (100.0 mg, 0.17 mmol) was dissolved in acetonitrile (4 mL), and a solution of ethyl acetate containing hydrogen chloride (0.4 mL, 4.0 M) was added. The mixture was reacted at 25 °C for 4 hours. After the reaction was confirmed to be complete by LC-MS, ammonia (1 mL) was added to quench the reaction, followed by the addition of water (0.5 mL). The mixture was then purified by C18 reversed-phase column chromatography (water as the mobile phase) to obtain compound ABBV-CLS-484 (47.4 mg), with a yield of 72.4%.

[0098] LC-MS (m / z): 386.0 [M+H] + .

[0099] 1 H NMR(600MHz,DMSO-d6)δ9.24(s,1H),8.39(brs,2H),6.46(s,1H),3.93(s,2H),3. 46–3.38(m,1H),3.09(dd,J=15.9,5.5Hz,1H),3.02(tt,J=8.1,4.1Hz,2H),2.81( dt,J=17.2,4.7Hz,1H),2.73(ddd,J=16.8,11.0,5.3Hz,1H),2.54–2.51(m,1H),2 .19–2.12(m,1H),1.71–1.61(m,2H),1.49(q,J=7.4Hz,2H),0.92(d,J=6.6Hz,6H).

[0100] Example 3: Synthesis of (S)-5-(1-fluoro-3-hydroxy-7-(isopentylamino)-5,6,7,8-tetrahydronaphthyl-2-yl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide (S-ABBV-CLS-484)

[0101] The target compound S-ABBV-CLS-484 was prepared using the same method as in Example 2, except that R-3 was replaced with S-3. All other intermediate materials and preparation methods were the same as in Example 2, yielding the target compound S-ABBV-CLS-484 (3.3 mg). Preparation method: A C18 column was used. The mobile phase consisted of 10 mmol / L ammonium bicarbonate aqueous solution (A) and acetonitrile (B). Gradient elution was performed at a flow rate of 15 mL / min, based on the volume percentage of phase B: 0 to 10 min (15% → 100%), 10.01 min to 15 min (100%), and 15.01 min to 20 min (100% → 15%).

[0102] LC-MS (m / z): 386.0 [M+H] + .

[0103] 1H NMR(600MHz,DMSO-d6)δ9.23(s,1H),8.34(brs,2H),6.46(s,1H),3.93(s,2H),3. 45–3.36(m,1H),3.08(dd,J=16.0,5.5Hz,1H),3.06–2.94(m,2H),2.80(dt,J=17.3 ,4.7Hz,1H),2.73(ddd,J=16.9,11.1,5.4Hz,1H),2.55–2.51(m,1H),2.20–2.07( m,1H),1.66(dp,J=13.2,6.3Hz,2H),1.49(q,J=7.4Hz,2H),0.92(d,J=6.6Hz,6H).

[0104] Example 4: Synthesis of (R)-5-(1-fluoro-3-hydroxy-7-(isopentylamino)-5,6,7,8-tetrahydronaphthyl-2-yl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide (ABBV-CLS-484)

[0105] Step 1: Synthesis of (R)-N-((R)-8-fluoro-6-benzyloxy-1,2,3,4-tetrahydronaphth-2-yl)-N-isopentyl-2-methylpropane-2-sulfonamide (R-6-1)

[0106] Compound R-5 (2.10 g, 5.91 mmol) was dissolved in N,N-dimethylformamide (20 mL), followed by the addition of cesium carbonate (3.85 g, 11.81 mmol), and then benzyl bromide (1.31 g, 7.68 mmol). The reaction mixture was incubated at 25 °C for 1 hour. After the reaction was confirmed to be complete by LC-MS, water (40 mL) was added to quench the reaction. The aqueous phase was extracted with ethyl acetate (40 mL × 3). The combined organic phases were washed with saturated brine (40 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 R-6-1 (2.40 g), with a yield of 91.2%.

[0107] LC-MS (m / z): 342.0 [M+H-104] + .

[0108] 1H NMR(600MHz,DMSO-d6)δ7.42(d,J=6.9Hz,2H),7.41–7.36(m,2H),7.34–7.32(m,1H),6.69( dd,J=11.5,2.4Hz,1H),6.63(d,J=2.5Hz,1H),5.07(s,2H),3.42–3.33(m,1H),3.22–3.14(m ,1H),2.90–2.84(m,1H),2.82–2.71(m,2H),2.61(dq,J=20.8,11.9Hz,2H),2.09–2.00(m,1H ),1.84–1.73(m,1H),1.61–1.50(m,2H),1.38–1.29(m,1H),1.13(s,9H),0.91–0.86(m,6H).

[0109] Step 2: Synthesis of (R)-N-((R)-8-fluoro-7-iodo-6-benzyloxy)-1,2,3,4-tetrahydronaphth-2-yl)-N-isopentyl-2-methylpropane-2-sulfonamide (R-7-1)

[0110] Compound R-6-1 (0.40 g, 0.90 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL). A hexane solution of n-butyllithium (1.6 M, 2.2 mL, 3.5 mmol) was added dropwise at –78 °C. The reaction mixture was stirred at –78 °C for 1 hour. Subsequently, an anhydrous tetrahydrofuran solution of iodine (0.57 g, 2.24 mmol) (5 mL) was added dropwise. The reaction mixture was then incubated at 25 °C for 2 hours. After the reaction was complete as monitored by LC-MS, the reaction was quenched sequentially with saturated ammonium chloride aqueous solution (20 mL) and saturated sodium thiosulfate aqueous solution (20 mL). The aqueous phase was extracted with ethyl acetate (40 mL × 3). The combined organic phases were washed with saturated brine (40 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 = 60:40 as eluent) to give compound R-7-1 (0.20 g), yield 39.0%.

[0111] LC-MS (m / z): 468.0 [M+H-104] + .

[0112] 1H NMR(600MHz,DMSO-d6)δ7.49(d,J=7.6Hz,2H),7.41(t,J=7.6Hz,2H),7.33(t,J=7 .4Hz,1H),6.74(s,1H),5.17(s,2H),3.47–3.33(m,1H),3.21–3.12(m,1H),2.92– 2.83(m,1H),2.84–2.77(m,2H),2.72–2.64(m,1H),2.09–2.04(m,1H),1.84–1.74 (m,1H),1.60–1.49(m,2H),1.41–1.28(m,2H),1.13(s,9H),0.88(t,J=6.7Hz,6H).

[0113] Step 3: Synthesis of tert-butyl((R)-7-(((R)-tert-butylsulfinyl)(isopentyl)amino)-1-fluoro-3-benzyloxy)-5,6,7,8-tetrahydronaphth-2-yl)glycine ester (R-8-1)

[0114] Compound R-7-1 (0.20 g, 0.35 mmol), glycine tert-butyl ester (92.0 mg, 0.70 mmol), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium (63.0 mg, 0.06 mmol), 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-11'-biphenyl (38.0 mg, 0.06 mmol), and cesium carbonate (0.35 g, 1.05 mmol) were dissolved in dioxane (5 mL). The reaction mixture was placed at 100 °C for 16 hours under nitrogen protection. After the reaction was complete as monitored by LCMS, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 50:50 as eluent) to give compound R-8-1 (0.20 g), yield 99.4%.

[0115] LC-MS (m / z): 575.0 [M+H] + .

[0116] 1H NMR(600MHz,DMSO-d6)δ7.46(d,J=7.2Hz,2H),7.43–7.37(m,2H),7.36–7.31(m,1H), 6.58(s,1H),5.08(s,2H),4.82–4.75(m,1H),3.88(dd,J=7.0,2.3Hz,2H),3.21–3.13( m,1H),2.91–2.82(m,1H),2.81–2.68(m,3H),2.66–2.55(m,2H),2.09–2.00(m,1H),1 .82–1.71(m,1H),1.60–1.51(m,3H),1.34(s,9H),1.13(s,9H),0.88(t,J=6.5Hz,6H).

[0117] Step 4: Synthesis of (R)-N-((R)-7-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidine-2-yl)-8-fluoro-6-benzyloxy)-1,2,3,4-tetrahydronaphthyl)-N-isopentyl-2-methylpropane-2-sulfonamide (R-9-1)

[0118] Compound R-8-1 (195.0 mg, 0.34 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), and pyridine (54.0 mg, 0.68 mmol) was added. Chlorosulfonamide (78.0 mg, 0.68 mmol) was added at 0 °C, and the reaction mixture was incubated at 25 °C for 30 minutes. The reaction mixture was then cooled to 0 °C, and a methanol solution of sodium methoxide (5.0 M, 0.3 mL, 1.50 mmol) was added dropwise. The reaction mixture was incubated at 25 °C for 30 minutes. After the reaction was complete as monitored by LC-MS, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 90:10 as eluent) to give compound R-9-1 (120.0 mg), in a yield of 61.0%.

[0119] LC-MS (m / z): 578.0 [MH] – .

[0120] 1H NMR(600MHz,DMSO-d6)δ7.49(d,J=7.5Hz,2H),7.41–7.32(m,2H),7.29(t,J =7.4Hz,1H),6.70(s,1H),5.10(s,2H),3.94(s,2H),3.18(t,J=13.2Hz,1H) ,2.87–2.72(m,4H),2.67–2.62(m,2H),2.09–2.00(m,1H),1.83–1.75(m,1H ),1.62–1.47(m,2H),1.37–1.33(m,1H),1.14(s,9H),0.88(t,J=6.7Hz,6H).

[0121] Step 5: Synthesis of (R)-5-(1-fluoro-3-hydroxy-7-(isopentylamino)-5,6,7,8-tetrahydronaphthyl-2-yl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide (R-10)

[0122] Compound R-9-1 (115.0 mg, 1.82 mmol) was dissolved in dichloromethane (3 mL), and an ethyl acetate solution of hydrogen chloride (4.0 M, 1 mL, 4.00 mmol) was added. The reaction mixture was placed at 25 °C for 5 minutes. After the reaction was monitored by LCMS until complete, the reaction mixture was concentrated under reduced pressure to give compound R-10 (94.0 mg), with a yield of 99.6%.

[0123] LC-MS (m / z): 474.0 [MH] – .

[0124] 1 H NMR (600MHz, DMSO-d6) δ8.84–8.77(m,1H),7.47(d,J=7.4Hz,2H),7.36(t,J=7.5Hz,2H),7.31(t,J=7 .4Hz,1H),6.83(s,1H),5.14(s,2H),4.26(s,2H),3.16(dd,J=16.1,5.5Hz,1H),3.03(dq,J=12.2,6. 4Hz,2H),2.91–2.85(m,1H),2.84–2.72(m,1H),2.68–2.62(m,1H),2.26–2.20(m,1H),1.75(qd,J=11 .7,5.3Hz,1H),1.66(dq,J=13.3,6.7Hz,1H),1.57–1.50(m,2H),1.24(s,1H),0.92(d,J=6.6Hz,6H).

[0125] Step 6: Synthesis of (R)-5-(1-fluoro-3-hydroxy-7-(isopentylamino)-5,6,7,8-tetrahydronaphthyl-2-yl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide (ABBV-CLS-484)

[0126] Compound R-10 was dissolved in methanol, and palladium on carbon (10%, 20.0 mg, 0.019 mmol) was added. The reaction solution was placed at 25°C for 5 hours under a hydrogen atmosphere. After the reaction was confirmed to be complete by LCMS, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain compound ABBV-CLS-484.

[0127] LC-MS (m / z): 386.0 [M+H] + .

[0128] 1 H NMR(600MHz,DMSO-d6)δ9.24(s,1H),8.39(brs,2H),6.46(s,1H),3.93(s,2H),3. 46–3.38(m,1H),3.09(dd,J=15.9,5.5Hz,1H),3.02(tt,J=8.1,4.1Hz,2H),2.81( dt,J=17.2,4.7Hz,1H),2.73(ddd,J=16.8,11.0,5.3Hz,1H),2.54–2.51(m,1H),2 .19–2.12(m,1H),1.71–1.61(m,2H),1.49(q,J=7.4Hz,2H),0.92(d,J=6.6Hz,6H).

[0129] While the invention has been fully described through its embodiments, it is worth noting that various changes and modifications will be apparent to those skilled in the art. Such changes and modifications should be included within the scope of the appended claims.

Claims

1. A compound of formula (3), or a stereoisomer, tautomer, deuterated derivative or pharmaceutical salt thereof, for the preparation of compound ABBV-CLS-484 and its enantiomers: in, X is selected from chlorine, bromine, or iodine.

2. The compound according to claim 1, or its stereoisomers, tautomers, deuterated derivatives, or pharmaceutical salts, characterized in that, The compound has the structure shown in formula (3a):

3. A method for preparing the compound according to any one of claims 1-2, characterized in that, The method includes the following steps: (a) The compound of formula (1) and (R)-tert-butylsulfinamide were dissolved in reaction solvent 1 and reacted under the action of catalyst 1 to obtain the compound shown in formula (2); (b) The compound of formula (2) is dissolved in reaction solvent 2, and its carbon-nitrogen double bond is reduced by a reducing agent under the action of catalyst 2 to obtain the compounds shown in formula (R-3) and (S-3), respectively; Wherein, the definition of X is as described in claim 1.

4. The method according to claim 3, characterized in that, In step (a), the amount of (R)-tert-butylsulfinamide is 1.0 to 2.0 times that of the compound of formula (1); The amount of catalyst 1 is 1.0 to 2.0 times that of the compound of formula (1); The catalyst 1 is selected from titanate esters, preferably tetraethyl titanate; The reaction solvent 1 is selected from ether solvents, toluene, dichloromethane, N,N-dimethylformamide, and preferably tetrahydrofuran; The reaction temperature in step (a) is from room temperature to the reflux temperature of reaction solvent 1.

5. The method according to claim 3, characterized in that, In step (b), the amount of the reducing agent is 2.0 to 3.0 times that of the compound of formula (2); The amount of catalyst 2 is 1.0 to 2.0 times that of the compound of formula (2); The reducing agent is selected from alkali metal borohydrides or substituted alkali metal borohydrides, preferably sodium borohydride; The catalyst 2 is selected from titanate, cobalt chloride, cerium chloride, and nickel chloride, and is preferably tetraethyl titanate; The reaction solvent 2 is selected from ether solvents, toluene, dichloromethane, N,N-dimethylformamide, and preferably tetrahydrofuran; The reaction temperature in step (b) is from room temperature to the reflux temperature of reaction solvent 2; The reaction products were purified by column chromatography to obtain compounds of formula (R-3) and (S-3) with single configurations, respectively.

6. A method for preparing intermediates of ABBV-CLS-484 and its enantiomers using the compound of claim 1 or 2, characterized in that, The method includes the following steps: (a') The compound of formula (3) reacts with iodoisopentane to give the compound of formula (4); (b') The compound of formula (4) undergoes a hydrolysis reaction to give the compound of formula (5); (c') Protecting the hydroxyl group of the compound of formula (5) yields the compound shown in formula (6); (d') The compound of formula (6) undergoes an iodination reaction on the benzene ring to give the compound shown in formula (7); The compound of formula (7) is reacted with glycine tert-butyl ester to give the compound of formula (8); (f') The compound of formula (8) reacts with chlorosulfonamide to give the compound of formula (9); (g')Removing the hydroxyl protecting group from compound (9) yields compound ABBV-CLS-484 and its enantiomers; Wherein, P is a hydroxyl protecting group; and X is defined as described in claim 1.

7. The method according to claim 6, characterized in that, The hydroxyl protecting group P is selected from methyl, benzyl, p-methoxybenzyl, allyl, methoxymethyl, tetrahydropyranyl, (trimethylsilyl)ethoxymethyl, 1-methoxy-2-methoxyethane, acetyl, benzoyl, and preferably 1-methoxy-2-methoxyethane.

8. The method according to claim 6, characterized in that, The hydroxyl protecting group P is selected from methyl, benzyl, p-methoxybenzyl, allyl, methoxymethyl, tetrahydropyranyl, (trimethylsilyl)ethoxymethyl, 1-methoxy-2-methoxyethyl, acetyl, benzoyl, preferably benzyl.

9. The method according to claim 6, characterized in that, Step (a') further includes adding an inorganic base to the reaction system, wherein the inorganic base is preferably sodium hydride.

10. The method according to claim 6, characterized in that, Step (d') further includes adding n-butyllithium and iodine to the reaction system.

11. The method according to claim 6, characterized in that, Step (e') further includes adding catalyst 3 and a base to the reaction system, wherein catalyst 3 is preferably methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) and / or 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-1,1'-biphenyl, and the base is preferably cesium carbonate.

12. The method according to claim 6, characterized in that, Step (f') further includes adding a base to the reaction system, preferably pyridine and / or sodium methoxide.

13. The compounds represented by formulas (3), (3a), (4), (5), (6), (7), (8), or (9), or their stereoisomers, tautomers, deuterated derivatives, or pharmaceutical salts: in, P is a hydroxyl protecting group; X is defined as described in claim 1.

14. The compounds represented by formulas (4), (5), (6), (7), (8) or (9), or their stereoisomers, tautomers, deuterated derivatives or pharmaceutical salts: in, P is a hydroxyl protecting group; X is defined as described in claim 1.

15. Use of the compound of claim 13 or 14 or its stereoisomers, tautomers, deuterated derivatives or pharmaceutical salts in the preparation of PTPN1 / 2 inhibitors.

16. The use according to claim 15, characterized in that, The PTPN1 / 2 inhibitor is selected from compound ABBV-CLS-484 and its enantiomers.

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