Stereoselective synthesis of intermediate for preparation of heterocyclic compound

Abstract

Provided is a stereoselective synthesis of an intermediate for the preparation of the heterocyclic derivative as a Cap-dependent endonuclease inhibitor. The synthesis process has the advantages of simple operation, higher yield and relatively controllable steroselectivity, such that it is suitable for large-scale production.

Description

TECHNICAL FIELD 5           The present disclosure relates to a stereoselective process for producing a substituted heterocyclic compound. In addition, the present disclosure also relates to an intermediate for preparation of the substituted heterocyclic compound. BACKGROUND 10          Cap-dependent endonuclease is an enzyme involved in the inhibition of mRNA synthesis of influenza viruses. Inhibitors of Cap-dependent endonuclease are found to be effective against influenza virus A and B. Several compounds exhibited potent antiviral activity against influenza virus by inhibiting Cap-dependent endonuclease. In PCT published application, WO2019 / 144089, novel heterocyclic compounds as potent Cap- 15 dependent endonuclease inhibitors were first disclosed. Also described in WO2019 / 144089 is a process for preparation of the heterocyclic compounds, comprising using a racemic polycyclic compound containing a sulfur atom as an intermediate. However, synthetic control over the chirality of the heterocyclic compounds is lacking in this prior art. 20          Therefore, there is a need to address the above, and / or at least provide a useful alternative. SUMMARY The present disclosure provides an intermediate and a synthetic route for 25 preparation of heterocyclic compounds with simple chemical unit operation, higher yield, controllable chirality, and being suitable for industrial production. In some embodiments, the present disclosure also provides a process for preparing heterocyclic compounds by using a stereoselective intermediate. According to one aspect of the invention, there is provided a compound by 30 formula (I) below, or a salt thereof: 2021280928   25 Aug 2026 wherein R1 is halogen; R1’ is halogen; “*” stands for the R-enantiomer or the S-enantiomer. According to one embodiment, there is provided an intermediate represented by 35 formula (II) below, or a salt thereof: wherein R1 is halogen; R1’ is halogen; R2 is hydrogen, deuterium, halogen, or C1-C6 alkyl; R3 is hydrogen, NO, or NH2; m is 0, 1, 2, or 3; P is a protecting group; “*” stands for the R-enantiomer, the S-enantiomer, or the racemate. 40                  According to a further aspect of the invention, there is provided a process of preparing a compound of formula (Ia) below: or a salt thereof, wherein R1 is halogen, and R1’ is halogen, the process comprising conducting a condensation reaction by contacting a 45 compound of formula (I-1) below: 2021280928   25 Aug 2026 with (S)-C1-6 alkylsulfinamide or (S)-(-)-methylbenzylamine unsubstituted or substituted with one or more groups comprising halogen or C1-3 alkyl to form the compound of formula (Ia) or the salt thereof. 50           In at least one embodiment of the present disclosure, a process for preparing the intermediate of formula (I) is provided. In at least one embodiment of the present disclosure, a process for preparing the intermediate of formula (II) is provided. According to another aspect of the invention, there is provided a process of 55 preparing a compound of formula (IIa-1) below: or a salt thereof, wherein R1 is halogen; R1’ is halogen; R2 is hydrogen, deuterium, 60 halogen, or C1-C6 alkyl; m is an integer of 0, 1, 2, or 3; and P is a protecting group, the process comprising: reacting a compound of formula (I-2) below with a compound of formula (Ia) below: OP OH O               (R2)m to form the compound of formula (IIa-1) or the salt thereof. 65 DETAILED DESCRIPTION To facilitate understanding of the disclosure set forth herein, a number of terms are defined below. Generally, the nomenclature used herein and the laboratory procedures in organic 2021280928   25 Aug 2026 70 chemistry, medicinal chemistry, and pharmacology described herein are those well-known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The term “about” will be understood by a person of ordinary skill in the art and 75 will vary to some extent on the context in which it is used. As used herein, when referring to a measurable value such as an amount, a temporal duration, and the like, the term “about” is meant to encompass variations of ±20% or ±10%, including ±5%, ±1%, and ±0.1% from the specified value, as such variations are appropriate to perform the disclosed processes. 80           The term “halogen” used herein refers to fluorine, chlorine, bromine, or iodine. The term “C1-6 alkyl” used herein refers to a straight- or branched-chain saturated hydrocarbyl substituent containing 1 to 6 (e.g., 1 to 3, 1 to 4 and 1 to 5) carbon atoms. Examples of C1-6 alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secbutyl, tert-butyl, n-pentyl, and the like. 85           The term “one or more” used herein refers to either one or a number above one (e.g., 2, 3, 4, 5, 6, 7 or above). The term “protecting group” used herein refers to a moiety that is formed to render a functional moiety unreactive. The protecting group can be removed so as to restore the functional moiety to its original state. Various protecting groups and 90 protecting reagents, including hydroxy protecting groups, are well known to one of ordinary skill in the art and include compounds that are disclosed in Protective Groups in Organic Synthesis, 4th edition, T. W. Greene and P. G. M. Wuts, John Wiley & Sons, New York, 2006. The term “salt” used herein refers to an acid or base addition salt of a compound 95 of this disclosure. The “salt” includes, for example, a “pharmaceutically acceptable salt.” The term “pharmaceutically acceptable salt” used herein refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid, including an inorganic or organic base and an inorganic or organic acid. The examples of salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, 100 magnesium, manganese, potassium, sodium, zinc, and the like. The examples of salts 2021280928   25 Aug 2026 derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, naturally occurring substituted amines, cyclic amines, arginine, betaine, caffeine, choline, N,N'-dibenzylethylene-diamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, 105 ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. When the compound employed in the disclosure is basic, salts may be prepared from pharmaceutically acceptable inorganic and 110 organic acids. The examples of such inorganic acids include, but are not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and the like. The examples of such organic acids include, but are not limited to formic acid, acetic acid, phenylacetic acid, propionic acid, stearic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric 115 acid, fumaric acid, malonic acid, picric acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, malic acid, mandelic acid, citric acid, tartaric acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an amino acid, such as aspartic acid, glutaric acid or glutamic acid, an aromatic acid, such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid, or cinnamic acid, and the like. It 120 will be understood that, as used herein, references to the compounds of this disclosure are meant to also include the pharmaceutically acceptable salts thereof. Disclosed first in detail herein is an intermediate of formula (I), represented below, or a salt thereof: 125 wherein R1 is halogen; R1’ is halogen; “*” stands for the R-enantiomer or the S-enantiomer. In at least one embodiment, R1 is fluorine, and R1’ is fluorine. In at least one embodiment, the intermediate of formula (I) may be represented by formula (Ia) or formula (Ib): 2021280928   25 Aug 2026 130 In some embodiments, the intermediate of formula (I) is NH2 F F NH2 The present disclosure also provides an intermediate represented by formula (II): wherein R1 is halogen; R1’ is halogen; R2 is hydrogen, deuterium, halogen, or C1-C6 135 alkyl; R3 is hydrogen, NO or NH2; m is 0, 1, 2, or 3; P is a protecting group; “*” stands for the R-enantiomer, the S-enantiomer or the racemate. In at least one embodiment, R1 is fluorine, and R1’ is fluorine. In some embodiments, R2 is hydrogen, deuterium, or methyl. In some embodiments, R2 is hydrogen. In some embodiments, R3 is hydrogen or NO. In some embodiments, m is 0. In some embodiments, the examples of the protecting group 140 include, but are not limited to, benzyl (Bn), tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), acetyl (Ac), benzoyl (Bz), trityl and the like. In at least one embodiment, the intermediate of formula (II) may be represented by formula (IIa) or formula (IIb): 2021280928   25 Aug 2026 145 (IIa), wherein R1, R1’, R2, R3, m, and P are as defined above. (IIb), In some embodiments, the intermediate of formula (IIa) may be represented by formula (IIa-1) or formula (IIa-2): (IIa-2), 150 wherein R1, R1’, R2, m, and P are as defined above. In at least one embodiment, the intermediate of formula (IIb) may be represented by formula (IIb-1) or formula (IIb-2): (IIb-1), (IIb-2), wherein R1, R1’, R2, m, and P are as defined above. 2021280928   25 Aug 2026 155 In some embodiments, the intermediate of formula (II) is In one aspect of the present disclosure, a process of preparing the compound of formula (II) from the compound of formula (I) is provided. 160 In at least one embodiment, the present disclosure provides a process of preparing a compound of formula (IIa-1), comprising reacting the compound of formula (I-2) with the compound of formula (Ia) as below: OP OH (I-2)                              (Ia) (IIa-1) 165 to form the compound of formula (IIa-1), or a salt thereof, in the presence of an inert solvent, a suitable acid and a reducing agent at a temperature between about -20C and about 30OC, such as -15OC to 25OC, -10OC to 20C, -5OC to 15OC, 0OC to 10OC, 0OC to 5°C, and 5°C to 10C; wherein Ri, Ri’, R2, m, and P are as defined above. In at least one embodiment, the examples of the inert solvent include, but are not limited to, toluene, tetrahydrofuran (THF), methyl tert-butyl ether (MTBE), 2021280928   25 Aug 2026 170 dichloromethane (DCM), diethyl ether, acetonitrile, dimethylcarbonate, ethylacetate, isopropylacetate, tertbutylacetate, H2O, methanol, isopropanol, ethylene glycol, ethanol, propanol, hexane, heptane and the like, or mixtures thereof. In at least one embodiment, the inert solvent is toluene, THF, MTBE, DCM, diethyl ether, acetonitrile, ethylacetate, isopropylacetate, terbutylacetate, H2O, hexane, heptane or the like, or mixtures thereof. 175            In at least one embodiment, the examples of the suitable acid include, but are not limited to, acetic acid, sulfuric acid, nitric acid, phosphoric acid, trifluoroacetic acid, maleic acid, fumaric acid, citric acid, oxalic acid, succinic acid, tartaric acid, malic acid, benzoic acid and the like, or mixtures thereof. In at least one embodiment, the suitable acid is acetic acid, citric acid, fumaric acid, maleic acid, malic acid, tartaric acid, benzoic 180 acid, oxalic acid, succinic acid, or the like, or mixtures thereof. In at least one embodiment, the examples of the reducing agent include, but are not limited to, sodium borohydride (NaBH4), sodium triacetoxyborohydride (NaBH(OAc)3), sodium cyanoborohydride (NaBH3CN), lithium borohydride (LiBH4), potassium borohydride (KBH4) and the like, or mixtures thereof. 185           In at least one embodiment, the process of preparing a compound of formula (IIa-1) further comprises subjecting the compound of formula (IIa-1) to nitrosation reaction to form the compound of formula (IIa-2): OP OH ONN R1 R1 (IIa-2), or a salt thereof, in the presence of an inert solvent, a suitable acid and a nitrite at a 190 temperature between about -20°C and about 30oC, such as -15°C to 25°C, -10°C to 20C, -5OC to 15C, 0C to 10C, 0OC to 5OC, and 5OC to 10C; wherein Ri, Ri’, R2, m, and P are as defined above. In at least one embodiment, the examples of the inert solvent include, but are not limited to, toluene, THF, MTBE, DCM, diethyl ether, acetonitrile, acetone, 2021280928   25 Aug 2026 195 dimethylcarbonate, ethylacetate, isopropylacetate, tertbutylacetate, H2O, methanol, isopropanol, ethylene glycol, ethanol, propanol, hexane, heptane and the like, or mixtures thereof. In at least one embodiment, the inert solvent is toluene, THF, MTBE, DCM, diethyl ether, acetonitrile, ethylacetate, isopropylacetate, terbutylacetate, H2O, methanol, isopropanol, ethylene glycol, hexane, heptane or the like, or mixtures thereof. 200           In at least one embodiment, the examples of the suitable acid include, but are not limited to, acetic acid, sulfuric acid, hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, maleic acid, fumaric acid, citric acid, oxalic acid, succinic acid, tartaric acid, malic acid, benzoic acid and the like, or mixtures thereof. In at least one embodiment, the examples of the nitrite include, but are not 205 limited to, sodium nitrite, potassium nitrite, calcium nitrite, amyl nitrite, isoamyl nitrite, butyl nitrite, and isobutyl nitrite. In some embodiments, the above process of preparing a compound of formula (IIa-2) further comprises conducting cyclization reaction of the compound of formula (IIa-2) to form the compound of formula (III): 210 OP OH (III), or a salt thereof, in the presence of an inert solvent, a suitable acid and a catalyst at a temperature between about 30OC and about 80OC, such as 35°C to 75°C, 40°C to 70°C, 45 °C to 65C, 50OC to 60C, 55OC to 60C, and 50OC to 55C; wherein Ri, Ri’, R2, m, and P are as defined above. 2i5            In some embodiments, the examples of the inert solvent include, but are not limited to, toluene, THF, MTBE, diethyl ether, acetonitrile, acetone, dimethylcarbonate, ethylacetate, isopropylacetate, tertbutylacetate, H2O, methanol, isopropanol, ethylene glycol, ethanol, propanol, hexane, heptane and the like, or mixtures thereof. In at least one embodiment, the examples of the suitable acid include, but are not 220 limited to, acetic acid, sulfuric acid, hydrochloric acid, hydrobromic acid, nitric acid, 2021280928   25 Aug 2026 phosphoric acid, trifluoroacetic acid, maleic acid, fumaric acid, citric acid, oxalic acid, succinic acid, tartaric acid, malic acid, benzoic acid and the like, or mixtures thereof. In at least one embodiment, the examples of the catalyst include, but are not limited to, zinc, iron, manganese, copper, nickel, cobalt and the like, or mixtures thereof. 225          In some embodiments, the above process of preparing a compound of formula (III) further comprises conducting oxidation and deprotection of the compound of formula (III) to form the compound of formula (IV): OH O (IV), or a salt thereof; wherein R1, R1’, R2, and m are as defined above; wherein the oxidation 230 reaction is carried out in the presence of a first solvent and a oxidizing agent at a temperature between about 20C and about 60OC, such as 25°C to 55°C, 30°C to 50°C, 35OC to 45C, 40C to 45C, 40C to 50C, and 45C to 50C; and wherein the deprotection is carried out in the presence of a second solvent, a catalyst, and a suitable acid at a temperature between about 60C and about 100C, such as 65C to 95C, 70C 235 to 90C, 75C to 85C, 75C to 80C, or 80C to 85C. In at least one embodiment, the examples of the first solvent include, but are not limited to, toluene, THF, MTBE, DCM, diethyl ether, acetonitrile, acetone, dimethylcarbonate, ethylacetate, isopropylacetate, tertbutylacetate, H2O, hexane, heptane and the like, or mixtures thereof. 240           In at least one embodiment, the examples of the oxidizing agent include, but are not limited to, Dess-Martin periodinane, manganese dioxide, 2-iodoxybenzoic acid, tetrapropylammonium perruthenate / N-methylmorpholine N-oxide (TPAP / NMO), pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), sodium periodate, dimethylsulfoxide, sodium hypochlorite, Swern oxidation reagent and the like. 245            In at least one embodiment, the examples of the second solvent include, but are not limited to, toluene, THF, MTBE, DCM, diethyl ether, acetonitrile, acetone, 2021280928   25 Aug 2026 dimethylcarbonate, dimethylacetamide, ethylacetate, isopropylacetate, tertbutylacetate, H2O, hexane, heptane and the like, or mixtures thereof. In at least one embodiment, the examples of the suitable acid include, but are not 250 limited to, acetic acid, sulfuric acid, hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, trifluoroacetic acid, maleic acid, fumaric acid, citric acid, oxalic acid, succinic acid, tartaric acid, malic acid, benzoic acid and the like, or mixtures thereof. In at least one embodiment, the examples of the catalyst include, but are not limited to, lithium chloride, lithium bromide, lithium iodide, magnesium bromide, 255 magnesium chloride, magnesium iodide, zinc chloride, tetra-n-butylammonium bromide, tetra-n-butylammonium chloride and the like, or mixtures thereof. In some embodiments, the process of preparing a compound of formula (III) further comprises: (1) conducting oxidation of the compound of formula (III) to form the compound 260 of formula (III-a): OP O (III-a), or a salt thereof in the presence of a first solvent and an oxidizing agent at a temperature between about 20OC and about 60oC, such as 25OC to 55OC, 30oC to 50oC, 35OC to 45 °C, 40OC to 50C, 40OC to 45 °C, and 45OC to 50OC; and 265          (2) deprotecting the compound of formula (III-a) to form the compound of formula (IV): OH O (IV), 2021280928   25 Aug 2026 or a salt thereof in the presence of a second solvent, a catalyst, and a suitable acid at a temperature between about 60OC and about 100OC, such as 65°C to 95°C, 70°C to 90°C, 270   75°C to 85°C, 80oC to 85°C, and 75°C to 80oC; wherein Ri, Ri’, R2, and m are as defined above. In at least one embodiment, the examples of the first solvent include, but are not limited to, toluene, THF, MTBE, DCM, diethyl ether, acetonitrile, acetone, dimethylcarbonate, ethylacetate, isopropylacetate, tertbutylacetate, H2O, hexane, heptane 275 and the like, or mixtures thereof. In at least one embodiment, the examples of the oxidizing agent include, but are not limited to, Dess-Martin periodinane, manganese dioxide, 2-iodoxybenzoic acid, tetrapropylammonium perruthenate / N-methylmorpholine N-oxide (TPAP / NMO), pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), sodium periodate, 280 dimethylsulfoxide, sodium hypochlorite, Swern oxidation reagent and the like. In at least one embodiment, the examples of the second solvent include, but are not limited to, toluene, THF, MTBE, DCM, diethyl ether, acetonitrile, acetone, dimethylcarbonate, dimethylacetamide, ethylacetate, isopropylacetate, tertbutylacetate, H2O, hexane, heptane and the like, or mixtures thereof. 285            In at least one embodiment, the examples of the suitable acid include, but are not limited to, acetic acid, sulfuric acid, hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, trifluoroacetic acid, maleic acid, fumaric acid, citric acid, oxalic acid, succinic acid, tartaric acid, malic acid, benzoic acid and the like, or mixtures thereof. In at least one embodiment, the examples of the catalyst include, but are not 290 limited to, lithium chloride, lithium bromide, lithium iodide, magnesium bromide, magnesium chloride, magnesium iodide, zinc chloride, tetra-n-butylammonium bromide, tetra-n-butylammonium chloride and the like, or mixtures thereof. In some embodiments, the compound of the present disclosure may be converted into a prodrug by any known methods. For example, the above process of preparing a 295 compound of formula (IV) further comprises converting the compound of formula (IV) into a prodrug thereof having the following formula (V): 2021280928   25 Aug 2026 300 305 310 315 OG O m (V), or a pharmaceutically acceptable salt thereof in the presence of an inert solvent, a suitable base and a catalyst at a temperature between about 30OC and about 80OC, such as 35°C to 75OC, 40C to 70C, 45C to 65C, 50OC to 60C, 50OC to 55C, and 55OC to 60OC; wherein R1, R1’, R2, and m are as defined above; wherein G is any suitable prodrug group. In at least one embodiment, the examples of the prodrug group include, but are not limited to, O / , J OP O y, and ? In at least one embodiment, the examples of the inert solvent include, but are not limited to, toluene, THF, MTBE, DMA, diethyl ether, acetonitrile, acetone, dimethylcarbonate, ethylacetate, isopropylacetate, tertbutylacetate, H2O, methanol, isopropanol, ethylene glycol, ethanol, propanol, hexane, heptane and the like, or mixtures thereof. In at least one embodiment, the examples of the suitable base include, but are not limited to, an inorganic base, such as alkali metal hydroxides (e.g., sodium hydroxide, potassium hydroxide), alkali metal carbonates (e.g., sodium carbonate, potassium carbonate, Cs2CO3), alkali metal bicarbonates (e.g., sodium bicarbonate, potassium bicarbonate), alkali metal alkoxides (e.g., sodium methoxide, potassium methoxide) or an organic base and the like, or mixtures thereof. In at least one embodiment, the examples of the catalyst include, but are not 2021280928   25 Aug 2026 limited to, lithium iodide, sodium iodide, potassium iodide, lithium bromide, sodium bromide, potassium bromide, tetrabutyl ammonium bromide (TBAB) and the like, or 320 mixtures thereof. In another aspect of the present disclosure, a process of preparing the R-enantiomer or the S-enantiomer of the compound of formula (I) or a salt thereof is provided: 325 the process comprising: conducting a condensation of the compound of formula (I-1): by contacting with a (R)-form or (S)-form chiral resolving agent, such as C1-6 alkylsulfinamide and methylbenzylamine unsubstituted or substituted with one or more groups comprising halogen or C1-3 alkyl, in the presence of a transition metal catalyst and 330 an inert solvent; reducing with a suitable reducing agent, such as a borane reagent, in the presence of the inert solvent; and removing a protecting moiety, such as sulfinyl moiety and the ethylbenzene moiety, by treating with a mineral acid. In at least one embodiment, the process of preparing a compound of formula (Ia): 335 or a salt thereof comprises: conducting a condensation reaction of the compound of formula (I-1): 2021280928   25 Aug 2026 by contacting with a (S)-C1-6 alkylsulfinamide or (S)-(-)-methylbenzylamine unsubstituted or substituted with one or more groups comprising halogen or C1-3 alkyl in 340 the presence of a transition metal catalyst and an inert solvent; reducing with a suitable reducing agent, such as a borane reagent, in the presence of the inert solvent at a temperature between about -30°C and about 30OC, such as -25°C to 25°C, -20°C to 20C, -15OC to 15C, -10C to 10C, -10C to 5OC, -5OC to 5C, -5OC to 0C, and 0C to 5C; and removing the sulfinyl moiety or the ethylbenzene moiety by treating with a mineral 345 acid; wherein R1 is halogen, and R1’ is halogen. In at least one embodiment, the examples of the transition metal catalyst include, but are not limited to, titanium ethoxide, titanium methoxide, titanium isopropoxide, titanium tert-butoxide and the like. In at least one embodiment, the examples of the borane reagent include, but are 350 not limited to, BH3DMS, BH3-THF, BMS, BH3-Et2NPH and the like. In at least one embodiment, the examples of the inert solvent include, but are not limited to, toluene, THF, MTBE, DCM, diethyl ether, acetonitrile, ethylacetate, isopropylacetate, tertbutylacetate, H2O, methanol, isopropanol, ethylene glycol, ethanol, propanol, hexane, heptane and the like, or mixtures thereof. 355            In at least one embodiment, the examples of the mineral acid include, but are not limited to, hydrochloric acid, orthophosphoric acid, trifluoracetic acid, acetic acid, trifluoromethane sulfonic acid, p-toluenesulfonic acid, methane sulfonic acid, nitric acid, sulfuric acid and the like, or mixtures thereof. In some embodiments, the process of preparing a compound of formula (Ia): 360 or a salt thereof comprises: (1) conducting a condensation reaction by contacting the compound of formula (I-1): 2021280928   25 Aug 2026 365 with a resolving agent, such as (S)-C1-6 alkylsulfinamide or (S)-(-)-methylbenzylamine unsubstituted or substituted with one or more groups comprising halogen or C1-3 alkyl, to form the compound of formula (I-1a) or (I-1b): (I-1b), or a salt thereof in the presence of a transition metal catalyst and a first solvent; wherein 370   R1 is halogen; R1’ is halogen; R4 is C1-6 alkyl; and R5 is halogen or C1-3 alkyl; wherein the transition metal catalyst may be titanium ethoxide, titanium methoxide, titanium isopropoxide, titanium tert-butoxide and the like; wherein the first solvent may be toluene, THF, MTBE, DCM, diethyl ether, acetonitrile, ethylacetate, isopropylacetate, tertbutylacetate, H2O, methanol, isopropanol, ethylene glycol, ethanol, propanol, hexane, 375 heptane and the like, or mixtures thereof; (2) reducing the compound of formula (I-1a) or (I-1b) with a suitable reducing reagent, such as a borane reagent, to form the compound of formula (I-1a-1) or (I-1b-1): 380 (I-1b-1), or a salt thereof in the presence of a second solvent at a temperature between about -30°C and about 30C, such as -25C to 25C, -20C to 20C, -15C to 15C, -10C to 10C, -10C to 5C, -5C to 5C, -5C to 0C, and 0C to 5C; wherein the reducing reagent may be BH3DMS, BH3-THF, BMS, BH3-Et2NPH and the like; wherein the second solvent may be toluene, THF, MTBE, DCM, diethyl ether, acetonitrile, ethylacetate, 2021280928   25 Aug 2026 isopropylacetate, tertbutylacetate, H2O, methanol, isopropanol, ethylene glycol, ethanol, 385 propanol, hexane, heptane and the like, or mixtures thereof; and (3) removing the sulfinyl moiety of the compound of formula (I-1a-1) by treating with a mineral acid; wherein the mineral acid may be hydrochloric acid, orthophosphoric acid, trifluoracetic acid, acetic acid, trifluoromethane sulfonic acid, p-toluenesulfonic acid, methane sulfonic acid, nitric acid, sulfuric acid and the like, or mixtures thereof; or 390 removing the ethylbenzene moiety of the compound of formula (I-1b-1) by treating with a suitable reagent, such as a hydrogenating reagent. In at least one embodiment, the process of preparing the compound of formula (IIa-1) further comprises the process of: preparing the compound of formula (Ia) by reacting the compound of formula (I-1) with a (S)-C1-6 alkylsulfinamide, e.g., (S)-(-)-2-395 propanesulfinamide, in the presence of a transition metal catalyst and an inert solvent; reducing with a suitable reducing agent in the presence of an inert solvent; and removing the sulfinyl moiety by treating with a mineral acid. Without further elaboration, it is believed that one skilled in the art may, based on the above descriptions, utilize the present disclosure to its fullest extent. The following 400 examples are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever. The publications cited herein are incorporated by reference in their entirety. EXAMPLE 405 EXAMPLE 1: Preparation of 2-methyl-propane-2-sulfinic acid (1,2-difluoro-11H-10-thia-dibenzo[a,d]cyclohepten-5-ylidene)-amide O H2N Ti(OEt)4 Toluene 410           To a solution of 1,2-difluoro-11H-10-thia-dibenzo[a,d]cyclohepten-5-one (21 g, 2021280928   25 Aug 2026 80 mmole) and (S)-(-)-2-propanesulfinamide (11.6 g) in toluene was added Ti(OEt)4 (titanium ethoxide, 65 g). The reaction mixture was stirred and heated to 55°C for 5 hours under negative pressure. The reaction mixture was cooled down to room temperature, and ethyl acetate (EA, 80 mL) was added, followed by adding 1 N HCl(aq) (hydrochloric acid, 415   250 mL), stirring for 10 minutes, then adding more EA (200 mL), and stirring for 3 minutes. The phases were separated, and the separated water phase was removed to give the organic phase. MgSO4 (magnesium sulfate, 15 g) was added, followed by stirring for five minutes, filtered and concentrated. Next, EA (20 mL) was added and stirred. Then, heptane (200 mL) was added slowly, and solid was precipitated out. The mixture was 420 stirred at room temperature for 4 hours and washed with heptane (50 mL) and dried to afford yellow solid product (25.5 g, 87.3% yield, >99% purity). EXAMPLE 2: Preparation of 2-methyl-propane-2-sulfinic acid (1,2-difluoro-5,11-dihydro-10-thia-dibenzo[a,d]cyclohepten-5-yl)-amide 425 BH3DMS THF To a solution of 2-methyl-propane-2-sulfinic acid (1,2-difluoro-11H-10-thia-dibenzo[a,d]cyclohepten-5-ylidene)-amide (3.65 g, 10 mmole) was added anhydrate THF 430 (tetrahydrofuran, 70 mL) and stirred. The reaction mixture was cooled down to -10 C. BH3DMS (2 M) was added dropwise to the above THF solution, stirred for 2 hours at a temperature of -5C to 0C. The end of the reaction was checked by HPLC. Methanol was added slowly, stirred for 30 minutes, followed by adding ice-saturated brine (250 mL, 0C to 5C) and EA (30 mL), stirred for 10 minutes, then subjected to separate and 435 extract the organic phase. Further, more EA (20 mL) was added to the water phase, stirred for 5 minutes, then subjected to separate and extract the organic phase again. The extracted organic phases were combined. MgSO4 (15 g) was added to remove water, and 2021280928   25 Aug 2026 then filtered and concentrated, such that salt was formed. EA (50 mL) was added with stirring. The solution was filtered through a plate filter containing celite (15 g), and then 440 concentrated. IPA (isopropyl alcohol, 7 mL) was added and heated until the solid was completely dissolved. Next, the solution was cooled down to room temperature, such that a solid was precipitated out. Hexane (50 mL) was added slowly, stirred at room temperature for 2 hours, filtered and washed with hexane (30 mL), dried to afford white solid product (2.3 g, 63% yield, >99% purity, e.e. value (S:R) >96%). 445 EXAMPLE 3: Preparation of 1,2-difluoro-5,11-dihydro-10-thia-dibenzo[a,d]cyclohepten-5-ylamine HCl THF 450 To a solution of 2-methyl-propane-2-sulfinic acid (1,2-difluoro-5,11-dihyro-10-thia-dibenzo[a,d]cyclohepten-5-yl)-amide (1.08 g, 2.94 mmole) in THF (5 mL) was added 4 N HCl in dioxane (3.5 mL) slowly. The ice bath was removed after the reagent was added completely. The reaction mixture was stirred at room temperature for 2 hours. 455 The end of the reaction was checked by HPLC. The reaction mixture was cooled down to 0°C to 5 C, and then 4 N sodium hydroxide (NaOH) was added slowly until the pH value become 11 to 12. EA (20 mL) was added, stirred for 5 minutes, and then subjected to separate and extract the organic phase. EA (10 mL) was further added to the water phase, stirred for 5 minutes, and subjected to separate and extract the organic phase 460 again. The extracted organic phases were combined. MgSO4 (3 g) was added, stirred to remove water, and then filtered, washed with EA (10 mL) and concentrated to dryness. EA (3 mL) was added, followed by adding heptane (30 mL) slowly, stirring for 1 hour, filtering, and drying to afford white solid product (0.658 g, 85% yield, >99% purity, e.e. value (S:R) >97%). 2021280928   25 Aug 2026 465 EXAMPLE 4: Preparation of Compound (IIa-1-1) NaBH(OAc)3, AcOH THF Compound (IIa-1-1) 470 1-((3-benxyloxy-4-oxo-4H-pyran-2-yl)-hydroxy-methyl)- cyclopropanecarbaldehyde (360 g, 1.2 mole), 1,2-difluoro-5,11-dihydro-10-thia-dibenzo[a,d]cyclohepten-5-ylamine (263 g, 1 mole), THF (5 L) and acetic acid (90 mL) were added in a 10 L three-neck bottle. The reaction mixture was cooled down to 5±5°C 475 and stirred for 10 minutes. NaBH(OAc)3 (sodium triacetoxyborohydride, 165 g / per 30 minutes, three times) was added, stirred for 2 hours at 5±5C. After reaction completed, MeOH (methanol, 500 mL) was added, stirred for 10 minutes, followed by adding saturated brine (5 L) and EA (2 L), stirring for 10 minutes, and then subjecting to collect the EA layer. EA (1 L) was further added to the water phase, stirred for 5 minutes, and 480 subjected to separate and remove the water phase. The collected phases were combined. MgSO4 (150 g) was added, stirred for 10 minutes to remove water, and then filtered and concentrated to afford Compound (IIa-1-1), which was used for the next step without purification. 485 EXAMPLE 5: Preparation of Compound (IIa-2-1) 2021280928   25 Aug 2026 490 495 500 505 Compound (IIa-1-1) NaNO2 Compound (IIa-2-1) The crude residue of the above step was stirred for 10 minutes in acetic acid (3.6 L) and H2O (1 L) at 5±5°C, followed by adding NaNO2 (sodium nitrite, 69 g / per 30 minutes, three times), stirring for 2 hours at 5C to 10C. Ice H2O was added, stirred for 30 minutes, filtered, and then washed with H2O (1.5 L). EA (3 L) was added to dissolve the solid, followed by adding saturated brine (1.5 L), stirring for 10 minutes, and then subjecting to separate and remove the water phase. MgSO4 (150 g) was added, stirred for 10 minutes to remove water, filtered, and then concentrated. IPA (500 mL) was added and heated to 50C, and stirred for 10 minutes. Next, the reaction mixture was cooled down to 40C, followed by adding hexane (3 L) slowly. After the reagent was added completely, the reaction mixture was stirred for 2 hours at room temperature, and then filtered, and dried to afford the Compound (IIa-2-1) (540 g, 93.7% yield, 99.28% purity). EXAMPLE 6: Preparation of Compound (III-1) Compound (IIa-2-1) OBn OH Compound (III-1) 2021280928   25 Aug 2026 A solution of Zn (80 g) in THF (1.2 L), H2O (800 mL) and AcOH (acetic acid, 100 mL) was stirred and heated to 60OC. Compound (IIa-2-1) (115 g) was dissolved in THF (300 mL), then added dropwise slowly to the above solution, and stirred for 2 hours 510 at 60C. The reaction mixture was cooled down to room temperature, filtered and adjusted for the pH to be between about 7 and 8 with 2 N NaOH, and then subjected to separate and collect the organic phase. EA (500 mL) was further added to the water phase, stirred for 5 minutes, and then subjected to separate and collect the organic phase again. The collected organic phases were combined. MgSO4 (40 g) was added, stirred for 515   10 minutes at room temperature, filtered, washed with EA (100 mL), and then concentrated. EA (200 mL) was added, stirred, and heated to 50C, and then solid was precipitated out. The reaction mixture was cooled down to room temperature after stirring 10 minutes, and then MTBE (methyl tert-butyl ether, 200 mL) was added, stirred for 30 minutes, followed by adding heptane (300 mL) slowly. After the reagent was added 520 completely, the reaction mixture was stirred for 2 hours at room temperature, and then filtered, washed with MTBE / heptane (1:1, 100 mL, 0 C to 5 C), and vacuum dried (45C to 50C) to afford Compound (III-1) (52 g, 48% yield, 94% purity). EXAMPLE 7: Preparation of Compound (IV-1) 525 OBn OH                      OBn O                       OH O Compound (III-1)             Compound (III-1-a)              Compound (IV-1) To a solution of Compound (III-1) (172 g, 320 mmole) in DCM 530 (dichloromethane, 3.6 L) was added DMP (2,2-dimethoxypropane, 58 g). The reaction mixture was stirred and heated to about 40C for 1 hour, and then cooled down to 25C to 30C. DMP (58 g) was added, heated to about 40C, stirred for 1 hour, and then cooled down to 25C to 30C again. DMP (30 g) was added, heated to about 40C, and stirred 2021280928   25 Aug 2026 for 2 hours. The reaction mixture was cooled down to room temperature, filtered, washed 535 with DCM (400 mL), and then added to H2O (4 L) under stirring. NaHCO3 (sodium bicarbonate, 174 g) was added slowly, followed by adding Na2S2O3.5H2O (sodium thiosulfate, 296 g), and stirring for 3 hours. Water phase was removed, and MgSO4 was added, stirred for 10 minutes to remove water, and then filtered and concentrated to afford Compound (III-1-a), which was used for the next step without purification. 540           Compound (III-1-a) (133 g), LiCl (lithium chloride, 66.3 g), andDMA (dimethylacetamide, 520 mL) were added in a 3 L three-neck bottle, and stirred at 80OC for 1 hour, then cooled down to 0C to 10C, added with THF (700 mL), 0.5 N HCl (1.4 L), and stirred for 1 hour. DCM (1.4 L) was added, stirred for 5 minutes, extracted, and then washed with H2O (1.4 L) twice. MgSO4 (80 g) and activated carbon (80 g) were 545 added, stirred for 30 minutes, filtered, and concentrated to remove DCM and THF, and then solid was precipitated out. THF (200 mL) was added and stirred for 10 minutes, followed by adding MTBE (1.4 L), stirring for 2 hours at room temperature, filtering, washing with MTBE (230 mL), and then vacuum drying (40 C to 45C) to afford Compound (IV-1) (115.8 g, 80% yield, 99% purity). 550 OTHER EMBODIMENTS All of the features disclosed in this disclosure may be combined in any combination. Each feature disclosed in this disclosure may be replaced by an alternative feature serving the same, equivalent or similar purpose. Thus, unless expressly stated 555 otherwise, each feature disclosed is only an example of a series of equivalent or similar features. From the above descriptions, one skilled in the art can easily ascertain the characteristics of the present disclosure, and without departing from the scope thereof, can make various changes and modifications of the disclosure to adapt it to various usage 560 and conditions. Thus, other embodiments are also within the scope of the following claims. Throughout this specification and the claims which follow, unless the context requires otherwise, the word “comprise”, and variations such as “comprises” and “comprising”, will be understood to imply the inclusion of a stated integer or step or 2021280928   25 Aug 2026 565 group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or 570 information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.

Claims

1. A compound represented by formula (I) below or a salt thereof,575wherein R1 is halogen; R1’ is halogen; and “*” stands for an R-enantiomer or an S-enantiomer.

2. The compound or the salt thereof according to claim 1, wherein the compound is580 represented by formula (Ia) or formula (Ib) below:

3. The compound or the salt thereof according to claim 2, which isNH2For5854. A compound represented by the formula (II) below or a salt thereof,wherein R1 is halogen; R1’ is halogen; R2 is hydrogen, deuterium, halogen, or C1-C6alkyl; R3 is hydrogen, NO, or NH2; m is 0, 1, 2, or 3; P is a protecting group; and “*”590 stands for an R-enantiomer, an S-enantiomer or a racemate.2021280928   25 Aug 20265. The compound or the salt thereof according to claim 4, wherein the compound is represented by formula (IIa) or formula (IIb) below:(IIb).5956. The compound or the salt thereof according to claim 5, wherein the compound isrepresented by formula (IIa-1), formula (IIa-2), formula (IIb-1), or formula (IIb-2) below:2021280928   25 Aug 20266007. The compound or the salt thereof according to claim 6, which isFOF                   , or8. A process of preparing a compound of formula (Ia) below:605or a salt thereof, wherein R1 is halogen, and R1’ is halogen,the process comprising conducting a condensation reaction by contacting a compound of formula (I-1) below:610with (S)-C1-6 alkylsulfinamide or (S)-(-)-methylbenzylamine unsubstituted or substituted with one or more groups comprising halogen or C1-3 alkyl to form the compound of formula (Ia) or the salt thereof.

9. The process according to claim 8, further comprising a reduction step.2021280928   25 Aug 202661510. A process of preparing a compound of formula (IIa-1) below:620or a salt thereof, wherein R1 is halogen; R1’ is halogen; R2 is hydrogen, deuterium, halogen, or C1-C6 alkyl; m is an integer of 0, 1, 2, or 3; and P is a protecting group, the process comprising:reacting a compound of formula (I-2) below with a compound of formula (Ia) below:OP OHO               (R2)mto form the compound of formula (IIa-1) or the salt thereof.62511. The process according to claim 10, further comprising conducting a condensation reaction by contacting a compound of formula (I-1) below:630with (S)-C1-6 alkylsulfinamide or (S)-(-)-methylbenzylamine unsubstituted or substituted with one or more groups comprising halogen or C1-3 alkyl to form the compound of formula (Ia) or the salt thereof.

12. The process according to claim 10, further comprising subjecting the compound of formula (IIa-1) to nitrosation reaction to form a compound of formula (IIa-2) below:2021280928   25 Aug 2026635or a salt thereof.

13. The process according to claim 12, further comprising conducting a cyclization reaction of the compound of formula (IIa-2) to form a compound of formula (III) below:640or a salt thereof.OP OH(III),14. The process according to claim 13, further comprising conducting oxidation and deprotection of the compound of formula (III) to form a compound of formula (IV)645 below:OH Om(IV),or a salt thereof.

15. The process according to claim 14, further comprising converting the compound of650 formula (IV) into a prodrug, or a pharmaceutically acceptable salt thereof, represented by formula (V) below:2021280928   25 Aug 2026655OG Owherein G is a prodrug group.(V),