Three types of fused ring derivative-containing salts or crystalline forms and pharmaceutical compositions thereof

Abstract

Three fused ring derivative-containing salts and crystalline forms thereof. In particular, the present invention relates to a compound having general formula (I), its crystalline forms, preparation methods therefor, pharmaceutical compositions containing a therapeutically effective amount of the compound and its crystalline forms, and its use in preparing medicaments for treating PI3K-mediated related diseases. TIFF2023503010000180.tif65157

Description

[Technical Field]

[0001] The present invention relates to the field of drug synthesis, and specifically to the salts of three ring-fused derivatives and their crystalline forms, preparation methods and uses thereof. [Background technology]

[0002] The phosphatidylinositol 3-kinase (PI3K) protein family is classified into four major classes: I, II, III, and IV, and is involved in regulating various cellular functions, such as cell growth, proliferation, differentiation, survival, and glucose metabolism. The four PI3K proteins have distinct structures and functions, with class I PI3K being the most widely studied, which is further divided into four subtypes: PI3Kα, PI3Kβ, PI3Kδ, and PI3Kγ. Among these, PI3Kα is activated, mutated, and amplified in various tumors and is closely associated with tumor development and progression. It has been reported that PI3Kβ can activate platelets and plays an important role in the development and progression of thrombosis and other diseases. PI3Kδ and PI3Kγ are primarily expressed in the blood system and are closely associated with the immune system and inflammation. In addition, PI3Kγ is closely associated with blood pressure stability and smooth muscle contraction.

[0003] PI3Kα is activated, mutated, and amplified in various tumors and is a driving factor in tumorigenesis. PI3Kα is a heterodimer consisting of a p110 catalytic subunit and a p85 regulatory subunit. PI3Kα is activated by receptor tyrosine kinases (RTKs) and G protein-coupled receptors (GPCRs). After activation, it catalyzes the production of phosphatidylinositol triphosphate (PIP3) from phosphatidylinositol diphosphate (PIP2), which can further activate protein kinase B (PKB, also known as AKT) and its downstream signaling pathways. Various cell growth factors, such as epidermal growth factor (EGF), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), and insulin, can all activate PI3Kα, thereby activating downstream cell proliferation signaling pathways. Abnormal activation of PI3Kα can lead to rapid cell proliferation, potentially leading to tumorigenesis.

[0004] PI3Kα has become an important target for tumor drug research and development. However, many compounds are broad-spectrum inhibitors of PI3K, which have been shown to cause severe side effects in clinical studies, significantly limiting the development of PI3K inhibitors. Current research has shown that many of the side effects of broad-spectrum PI3K inhibitors are caused by the inhibition of PI3Kβ, PI3Kδ, and PI3Kγ subtypes. Among these, PI3Kβ plays an important role in the mechanism of thrombocytopenia and thrombosis side effects. PI3Kδ inhibition can lead to immune system abnormalities. Autoimmune and infectious toxicities such as pneumonia, hepatitis, and diarrhea / enteritis are closely related to the inhibition of PI3Kδ targets. PI3Kγ is closely related to blood pressure stability and smooth muscle contraction and is the primary target responsible for hypertension side effects. Therefore, the development of highly active and selective PI3Kα inhibitors can further improve the antitumor effects of PI3Kα inhibitors and reduce or eliminate various serious side effects such as inflammation, thrombocytopenia, hypertension, etc., which are caused by the inhibition of other subtypes.

[0005] BYL-719, a selective PI3Kα inhibitor developed by Novartis, is currently in Phase III clinical trials, MLN1117, a selective PI3Kα inhibitor developed by Takeda, has entered Phase II clinical trials, and GDC-0077, a selective inhibitor developed by Genentech, is also in Phase I clinical trials.

[0006] Although international applications WO2010029082A1 and WO2011022439A1 report compounds related to PI3K α selective inhibitors, the latter test showed that none of the compounds had high cellular activity, which affected their clinical antitumor effects.Therefore, there is an urgent need to develop a PI3K α selective inhibitor with high activity and high selectivity.A PI3K α selective inhibitor can be used to treat a variety of tumors with PI3K α activating mutations or amplifications, and has great value for clinical application.

[0007] Jiangsu Hansoh Pharmaceutical Group Co., Ltd.'s PCT patent applications (application numbers: PCT / CN2019 / 088788 and PCT / CN2019 / 104558) disclose a series of structures for three ring-fused derivative inhibitors. In subsequent research and development, the present invention is committed to conducting comprehensive research on salts of the above substances to find the most suitable salts and crystalline forms, in order to create products that are easy to handle, filter, and dry, improve the solubility of the products, and explore favorable characteristics such as easy storage, long-term product stability, and high bioavailability.

[0008] The entire contents of patent applications PCT / CN2019 / 088788 and PCT / CN2019 / 104558 may be incorporated by reference into the present invention. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] WO2010029082A1 No. [Patent Document 2] WO2011022439A1 No. [Patent Document 3] PCT / CN2019 / 088788 issue [Patent Document 4] PCT / CN2019 / 104558 issue Summary of the Invention [Means for solving the problem]

[0010] An object of the present invention is to provide an acid addition salt of formula (I) having the following structure:

[0011] [ka]

[0012] [In the formula, W is -O-, -S-, and -NR aa - selected from the group consisting of; G is -O-, -S-, -CR aa R bb - and -NR aa - selected from the group consisting of; R1 and R1' are each hydrogen, deuterium, cyano, halogen, nitro, amino, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, cyano-substituted C 1~6 Alkyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~10 Aryl, 5-10 membered heteroaryl, -(CH2) n R cc , -(CH2) n OR cc , and -CR aa R bb OR cc or selected from the group consisting of; Or, R1 and R1' are bonded to each other to form C 3~8Forming a cycloalkyl or 3- to 8-membered heterocyclyl, C 3~8 The cycloalkyl or 3- to 8-membered heterocyclyl may optionally be substituted with hydrogen, deuterium, cyano, halogen, nitro, amino, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~10 further substituted with one or more substituents selected from the group consisting of aryl, and 5- to 10-membered heteroaryl; R2 is hydrogen, deuterium, cyano, halogen, nitro, amino, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~10 Aryl, 5- to 10-membered heteroaryl, and -(CH2) n OR cc or selected from the group consisting of; Or, any two R2 are bonded to each other to form C 3~8 Forming a cycloalkyl or 3- to 8-membered heterocyclyl, C 3~8 The cycloalkyl or 3- to 8-membered heterocyclyl may optionally be substituted with hydrogen, deuterium, cyano, halogen, nitro, amino, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~10 further substituted with one or more substituents selected from the group consisting of aryl, and 5- to 10-membered heteroaryl; R3 and R3' are each hydrogen, deuterium, cyano, halogen, nitro, amino, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 3~8Cycloalkyl, 3-8 membered heterocyclyl, C 6~10 selected from the group consisting of aryl, and 5- to 10-membered heteroaryl; Or, R3 and R3' are bonded to each other to form oxo, C 3~8 Forming a cycloalkyl or 3- to 8-membered heterocyclyl, C 3~8 The cycloalkyl or 3- to 8-membered heterocyclyl may optionally be substituted with hydrogen, deuterium, cyano, halogen, nitro, amino, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~10 further substituted with one or more substituents selected from the group consisting of aryl, and 5- to 10-membered heteroaryl; R4 is hydrogen, deuterium, cyano, halogen, nitro, amino, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~10 selected from the group consisting of aryl, and 5- to 10-membered heteroaryl; R5 is hydrogen, deuterium, C 1~6 Alkyl, and C 1~6 haloalkyl; Or, R1 or R1' is joined to R5 to form a 3-8 membered heterocyclyl, which is optionally hydrogen, deuterium, cyano, halogen, nitro, amino, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~10 further substituted with one or more substituents selected from the group consisting of aryl, and 5- to 10-membered heteroaryl; R aa , R bb , and Rcc are each independently hydrogen, deuterium, cyano, halogen, nitro, amino, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~10 selected from the group consisting of aryl, and 5- to 10-membered heteroaryl; M is an inorganic acid or an organic acid, and the inorganic acid is selected from the group consisting of hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, and phosphoric acid; and the organic acid is selected from the group consisting of 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4-aminobenzoic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, isoascorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, dodecyl sulfuric acid, dibenzoic acid, ... ethanolic acid, ... n is an integer from 0 to 3; x is an integer from 0 to 3; y is an integer of 1 to 5, preferably an integer of 1 to 3, and more preferably 1.

[0013] In a preferred embodiment of the present invention, in the acid addition salt of formula (I), R1 and R1' are each hydrogen, C 1~6 Alkyl, C 1~6 Hydroxyalkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, 3-8 membered heterocyclyl, -(CH2) n OR cc , and -CR aa R bb OR cc , preferably hydrogen, C 1~3 Alkyl, C 1~3 Hydroxyalkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy, 3-6 membered heterocyclyl, -(CH2) n OR cc , and -CR aa R bb OR cc , more preferably hydrogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, fluoromethyl, fluoroethyl, fluoropropyl, chloromethyl, chloroethyl, chloropropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, oxacyclopropyl, oxacyclobutyl, oxacyclopentyl, oxacyclohexyl, azacyclopropyl, azacyclobutyl, azacyclopentyl, azacyclohexyl, -(CH2)OCH3, -(CH2)2OCH3, -CH(CH3)OCH3 and -C(CH3)2OCH3, and even more preferably hydrogen, methyl, methoxy, isopropyl, fluorine-containing methyl, hydroxymethyl, oxacyclobutyl, -(CH2)OCH3 and -CH(CH3)OCH3.

[0014] In a more preferred embodiment of the present invention, in the acid addition salt of formula (I), R2 is hydrogen, C 1~6 Alkyl, halogen, cyano, and -(CH2) n OR cc , preferably hydrogen, C 1~3 Alkyl, halogen, cyano, and -(CH2) n OR cc, more preferably selected from the group consisting of hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, fluorine, chlorine, bromine, and cyano, even more preferably hydrogen, fluorine, methyl, methoxy, and cyano; Or, any two R2 are bonded to each other to form a substituted or unsubstituted C 3~6 Cycloalkyl or substituted or unsubstituted 3- to 6-membered heterocyclyl, preferably substituted or unsubstituted C 3~6 It forms a cycloalkyl or a substituted or unsubstituted 3- to 6-membered heterocyclyl containing 1 to 3 atoms selected from the group consisting of N, O, and S, more preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclopropyl, oxacyclobutyl, oxacyclopentyl, oxacyclohexyl, azacyclopropyl, azacyclobutyl, azacyclopentyl, or azacyclohexyl, even more preferably cyclobutyl, cyclopentyl, 1,3-dioxocyclopentyl, or 1,3-dioxocyclohexyl.

[0015] In a further preferred embodiment of the present invention, in the acid addition salt of formula (I), R3 and R3' are each hydrogen, C 1~6 Alkyl, halogen, cyano, and C 1~6 Alkoxy, preferably hydrogen, C 1~3 Alkyl, halogen, cyano, and C 1~3 alkoxy, more preferably selected from the group consisting of hydrogen, methyl, ethyl, propyl, fluorine, chlorine, bromine, cyano, methoxy, ethoxy, and propoxy, more preferably hydrogen, fluorine, methyl, methoxy, and cyano; Or, R3 and R3' are bonded to each other to form oxo, C 3~6 Cycloalkyl or 3- to 6-membered heterocyclyl, preferably oxo, C 3~6It forms a cycloalkyl or a 3- to 6-membered heterocyclyl containing 1 to 3 N, O, or S atoms, more preferably oxo, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclopropyl, oxacyclobutyl, oxacyclopentyl, oxacyclohexyl, azacyclopropyl, azacyclobutyl, azacyclopentyl, or azacyclohexyl, even more preferably oxo, cyclopropyl, or oxacyclobutyl.

[0016] In an even more preferred embodiment of the present invention, in the acid addition salt of formula (I), R4 is hydrogen, C 1~6 Alkyl, halogen, cyano, C 1~6 Haloalkyl, and C 3~8 Cycloalkyl, preferably hydrogen, C 1~3 Alkyl, halogen, cyano, C 1~3 Haloalkyl, and C 3~6 Cycloalkyl, more preferably hydrogen, methyl, ethyl, propyl, fluorine, chlorine, bromine, cyano, fluoromethyl, fluoroethyl, chloromethyl, chloroethyl, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, and even more preferably hydrogen, fluorine, chlorine, methyl, trifluoromethyl, cyano, and cyclopropyl.

[0017] In a preferred embodiment of the present invention, in the acid addition salt of formula (I), R5 is hydrogen, C 1~6 Alkyl, and C 1~6 Haloalkyl, preferably hydrogen, C 1~3 Alkyl, and C 1~3 haloalkyl, more preferably selected from the group consisting of hydrogen, methyl, ethyl, propyl, fluorine-containing methyl, fluorine-containing ethyl, fluorine-containing propyl, chlorine-containing methyl, chlorine-containing ethyl, and chlorine-containing propyl, even more preferably hydrogen and methyl; Alternatively, R1 or R1' is bonded to R5 to form a 3- to 6-membered heterocyclyl optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, and propyl, preferably azacyclopropyl, azacyclobutyl, azacyclopentyl, azacyclohexyl, fluorine-substituted azacyclopropyl, fluorine-substituted azacyclobutyl, fluorine-substituted azacyclopentyl, fluorine-substituted azacyclohexyl, methyl-substituted azacyclopropyl, methyl-substituted azacyclobutyl, methylpyrrolidinyl, or methyl-substituted azacyclohexyl, more preferably azacyclobutyl, azacyclopentyl, or methylpyrrolidinyl.

[0018] In a preferred embodiment of the present invention, in the acid addition salt of formula (I), R aa , R bb , and R cc are each independently hydrogen, C 1~6 Alkyl, C 1~6 Alkoxy, C 3~8 Cycloalkyl and 3- to 8-membered heterocyclyl, preferably hydrogen, C 1~3 Alkyl, C 1~3 Alkoxy, C 3~6 Cycloalkyl or 3-6 membered heterocyclyl containing 1-3 N, O or S atoms, more preferably hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclopropyl, oxacyclobutyl, oxacyclopentyl and oxacyclobutyl, even more preferably hydrogen, methyl, ethyl, isopropyl, methoxy, cyclopropyl and oxacyclobutyl.

[0019] In a preferred embodiment of the present invention, in the acid addition salt of formula (I), M is selected from the group consisting of sulfuric acid, phosphoric acid, benzenesulfonic acid, cinnamic acid, tartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, fumaric acid, and methanesulfonic acid, preferably sulfuric acid, tartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, fumaric acid, and methanesulfonic acid, more preferably sulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, and methanesulfonic acid, and even more preferably ethanesulfonic acid.

[0020] In a further preferred embodiment of the invention, W is O in the acid addition salts of formula (I).

[0021] In a further preferred embodiment of the invention, G is O or S in the acid addition salt of formula (I).

[0022] In a further preferred embodiment of the invention, in the acid addition salt of formula (I), R5 is hydrogen.

[0023] In a further preferred embodiment of the invention, in the acid addition salt of formula (I), R1' and R3' are hydrogen.

[0024] In a further preferred embodiment of the present invention, in the acid addition salt of formula (I), W is -O-, -S-, and -NR aa - selected from the group consisting of; G is selected from the group consisting of -O- and -S-; R1 and R1' are each selected from the group consisting of hydrogen, methyl, methoxy, isopropyl, fluorine-containing methyl, hydroxymethyl, oxacyclobutyl, -CH2OCH3, and -CH(CH3)OCH3; R2 is selected from the group consisting of hydrogen, fluorine, methyl, methoxy, and cyano; R3 and R3' are each selected from the group consisting of hydrogen, fluorine, methyl, methoxy, and cyano; R4 is selected from the group consisting of hydrogen, fluorine, chlorine, methyl, trifluoromethyl, cyano, and cyclopropyl; R5 is selected from the group consisting of hydrogen and methyl; R aa , R bb , and R cc are each independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, methoxy, cyclopropyl, and oxacyclobutyl.

[0025] In a further preferred embodiment of the invention, when W is -O-, R5 is hydrogen, R1 is methyl, R1' is hydrogen, R2 is hydrogen, R3 and R3' are hydrogen, and R4 is hydrogen, then G is not -O-.

[0026] In a further preferred embodiment of the present invention, the structure of the acid addition salt of formula (I) is shown in formula (II-A) or (II-B).

[0027] [ka]

[0028] In a further preferred embodiment of the invention, the acid addition salt of formula (I) is in crystalline or amorphous form.

[0029] In a further preferred embodiment of the invention, the acid addition salts of formula (I), including both crystalline and amorphous forms, are hydrated or anhydrous, preferably anhydrous.

[0030] The present invention provides a process for preparing an acid addition salt of formula (I), comprising the steps of: 1) preparing a stock solution: weighing out the free base of the compound and adding an organic solvent to obtain a clear or suspended stock solution; 2) preparing a counterion acid solution: adding the counterion acid M to an organic solvent or water to obtain a clear counterion acid solution; 3) Preparing a salt of the compound: adding a counterion acid solution to the stock solution to obtain a clear salt solution, stirring the salt solution to precipitate a solid, and drying the solid. Specifically including, the organic solvent is one or more selected from the group consisting of alcohols, esters, hydrocarbons, ketones, ethers, benzene, amides, and nitriles, preferably one or more of methanol, ethanol, isopropanol, tert-butanol, ethyl acetate, n-hexane, heptane, dichloromethane, chloroform, carbon tetrachloride, dichloroethane, acetone, 2-butanone, 3-pentanone, isopropyl ether, petroleum ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, benzene, toluene, N,N-dimethylformamide, and acetonitrile, more preferably one or more of methanol, ethanol, isopropanol, ethyl acetate, acetone, dichloromethane, and acetonitrile, even more preferably one or more of methanol, ethanol, isopropanol, acetone, and acetonitrile; Counter ionic acids include hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, phosphoric acid, 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4-aminobenzoic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, and camphor. Sulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, isoascorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, D-tartaric acid, pamoic acid, dodecylsulfuric acid, dibenzoyltartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactonic acid, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, asparagine acetic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methanesulfonic acid, 1,5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, embonic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanic acid, undecylenic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, and L-malic acid, Preferably, the acid is selected from the group consisting of sulfuric acid, phosphoric acid, benzenesulfonic acid, cinnamic acid, tartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, fumaric acid, and methanesulfonic acid, more preferably sulfuric acid, tartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, fumaric acid, and methanesulfonic acid, even more preferably sulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, and methanesulfonic acid, and even more preferably ethanesulfonic acid; A method is further provided.

[0031] The concentration of the organic solvent in step 2) is 0.8 to 3.0 mol / L, preferably 1.0 to 2.5 mol / L, and more preferably 1.2 to 2.2 mol / L.

[0032] Preferably, the vacuum temperature in step 3) is 30 to 60°C, preferably 35 to 50°C, and more preferably 40°C.

[0033] More preferably, the amount of the counter ion acid in step 3) is 0.4 to 2.0 equivalents, preferably 0.5 to 1.5 equivalents, more preferably 0.6 to 1.2 equivalents.

[0034] The present invention provides a process for preparing the compound of formula (I) and its crystalline forms, comprising the steps of: 1) weighing out an appropriate amount of free base and suspending it in an anti-solvent; 2) optionally, weighing out an appropriate amount of counterion acid M and dissolving it in an organic solvent; 3) optionally adding the solution of step 2) to the suspension of step 1) and stirring the resulting mixture to allow the solid to precipitate; 4) optionally adding an organic solvent to the solid obtained in step 3) and stirring the resulting mixture to precipitate crystals; 5) Stirring and cooling the mixture, followed by precipitating the crystals to obtain the target product. Specifically including, the anti-solvent is one or more selected from the group consisting of alcohols, esters, ketones, ethers, benzene, amides, and nitriles, preferably one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, ethyl acetate, acetone, 2-butanone, tetrahydrofuran, 1,4-dioxane, benzene, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, and acetonitrile, more preferably one or more of methanol, ethanol, isopropanol, tetrahydrofuran, ethyl acetate, acetonitrile, and acetone, even more preferably one or more of methanol, ethanol, isopropanol, tetrahydrofuran, ethyl acetate, acetonitrile, or 88% acetone; the organic solvent in step 2) is one or more selected from the group consisting of alcohols, esters, hydrocarbons, ketones, ethers, benzene, amides, and nitriles, preferably one or more of methanol, ethanol, isopropanol, tert-butanol, ethyl acetate, dichloromethane, chloroform, carbon tetrachloride, dichloroethane, n-hexane, heptane, acetone, 2-butanone, 3-pentanone, petroleum ether, tetrahydrofuran, methyl tert-butyl ether, isopropyl ether, 1,4-dioxane, benzene, toluene, N,N-dimethylformamide, and acetonitrile, more preferably one or more of methanol, ethanol, isopropanol, tert-butanol, acetone, tetrahydrofuran, toluene, N,N-dimethylformamide, and acetonitrile, more preferably one or more of methanol, ethanol, isopropanol, acetone, and acetonitrile; The above-mentioned good solvents and organic solutions must be miscible when used; Counter ionic acids include hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, phosphoric acid, 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4-aminobenzoic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, and camphor. -sulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, isoascorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, dodecyl sulfate, dibenzoyltartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactonic acid, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, asparagine acid, lauric acid, camphoric acid, maleic acid, malonic acid, methanesulfonic acid, 1,5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, embonic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanic acid, undecylenic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, and L-malic acid, Preferably selected from the group consisting of sulfuric acid, phosphoric acid, benzenesulfonic acid, cinnamic acid, tartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, fumaric acid, and methanesulfonic acid, more preferably sulfuric acid, tartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, fumaric acid, and methanesulfonic acid, even more preferably sulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, and methanesulfonic acid, even more preferably ethanesulfonic acid; the organic solvent in step 4) is one or more selected from the group consisting of alcohols, esters, and ethers, preferably one or more of methanol, ethanol, n-propanol, isopropanol, ethyl acetate, petroleum ether, methyl tert-butyl ether, tetrahydrofuran, and 1,4-dioxane, more preferably one or more of methanol, ethanol, n-propanol, isopropanol, ethyl acetate, methyl tert-butyl ether, and tetrahydrofuran, even more preferably one or more of methanol, ethanol, isopropanol, ethyl acetate, and methyl tert-butyl ether; A method is further provided.

[0035] The present invention provides a process for preparing the compound of formula (I) and its crystalline forms, comprising the steps of: 1) weighing an appropriate amount of a salt of a compound and suspending it in a poor solvent; 2) shaking the suspension obtained above; 3) centrifuging the suspension, removing the supernatant, and vacuum-drying the remaining solid to obtain the target product. Specifically including, the anti-solvent is one or more selected from the group consisting of alcohols, ketones, esters, ethers, benzene, amides, and nitriles, preferably one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, acetone, 2-butanone, ethyl acetate, tetrahydrofuran, 1,4-dioxane, benzene, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, and acetonitrile, more preferably one or more of methanol, ethanol, n-propanol, isopropanol, 88% acetone, and acetonitrile; A method is further provided.

[0036] The concentration of the suspension in step 1) is 20 to 200 mg / mL, preferably 30 to 150 mg / mL, and more preferably 50 to 100 mg / mL; Preferably, the temperature in step 2) is 20 to 80°C, preferably 25 to 60°C, more preferably 25 to 40°C; the time is 1 to 15 days, preferably 1 to 10 days; More preferably, the temperature for vacuum drying is 20 to 60°C, preferably 20 to 50°C, and more preferably 40°C.

[0037] The present invention provides a process for preparing the compound of formula (I) and its crystalline forms, comprising the steps of: 1) weighing out an appropriate amount of a salt of the compound and exposing the salt of the compound to a certain humidity for a predetermined period of time. Specifically including, The humidity is RH=70% to 95%, preferably RH=75% to 95%, more preferably RH=80% to 95%, and even more preferably RH=92.5%; the time is 1 hour to 3 days, preferably 1 hour to 2 days, more preferably 1 hour to 1 day, and even more preferably 3 hours. A method is further provided.

[0038] The present invention provides a process for preparing the compound of formula (I) and its crystalline forms, comprising the steps of: 1) weighing out an appropriate amount of free base and suspending it in an anti-solvent; 2) weighing out an appropriate amount of counter ion acid M and dissolving it in an organic solvent; 3) adding the solution of step 2) to the suspension of step 1) and heating the reaction; 4) optionally adding an organic solvent to the solution of step 3); 5) optionally adding a salt of the compound to the solution of step 4); 6) Cooling the mixture to precipitate crystals Specifically including, Preferably, the anti-solvent is one or more selected from the group consisting of alcohols, ketones, esters, ethers, benzene, amides, and acetonitrile, preferably one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, acetone, 2-butanone, ethyl acetate, tetrahydrofuran, 1,4-dioxane, benzene, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, and acetonitrile, more preferably one or more of methanol, ethanol, n-propanol, isopropanol, acetone, and acetonitrile; Preferably, the counter ion acid is hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, phosphoric acid, 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4-aminobenzoic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, camphor acid, citric acid, cyclohexane ... Phosulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, isoascorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, dodecylsulfuric acid, dibenzoyltartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactonic acid, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, Lauric acid, camphoric acid, maleic acid, malonic acid, methanesulfonic acid, 1,5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, embonic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanic acid, undecylenic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, and L-malic acid, preferably sulfuric acid. acid, phosphoric acid, benzenesulfonic acid, cinnamic acid, tartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, fumaric acid, and methanesulfonic acid, more preferably sulfuric acid, tartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, fumaric acid, and methanesulfonic acid, even more preferably sulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, and methanesulfonic acid, even more preferably ethanesulfonic acid and methanesulfonic acid; Preferably, the organic solvent in step 2) is selected from alcoholic solvents, preferably one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, and tert-butanol, preferably one or more of methanol, ethanol, isopropanol, and tert-butanol; Preferably, the heating temperature in step 3) is 30 to 80°C, preferably 40 to 60°C, more preferably 50°C; Preferably, the organic solvent in step 4) is one or more selected from the group consisting of alcohols, esters, and ethers, preferably one or more of methanol, ethanol, n-propanol, isopropanol, ethyl acetate, petroleum ether, methyl tert-butyl ether, tetrahydrofuran, and 1,4-dioxane, more preferably one or more of methanol, ethanol, n-propanol, isopropanol, ethyl acetate, methyl tert-butyl ether, and tetrahydrofuran, even more preferably one or more of methanol, ethanol, isopropanol, ethyl acetate, and methyl tert-butyl ether, A method is still further provided.

[0039] The present invention provides a process for preparing the compound of formula (I) and its crystalline forms, comprising the steps of: 1) weighing out an appropriate amount of free base and suspending it in an anti-solvent; 2) weighing out an appropriate amount of counter ion acid M and dissolving it in an organic solvent; 3) adding the solution of step 2) to the suspension of step 1) and adding an organic solvent after dissolution; 4) optionally adding an appropriate amount of a salt of the compound to the solution of step 3) and stirring the resulting mixture to precipitate crystals; Specifically including, Preferably, the anti-solvent is one or more selected from the group consisting of alcohols, ketones, esters, ethers, benzene, amides, and acetonitrile, preferably one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, acetone, 2-butanone, ethyl acetate, tetrahydrofuran, 1,4-dioxane, benzene, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, and acetonitrile, more preferably one or more of methanol, ethanol, n-propanol, isopropanol, acetone, and acetonitrile; Preferably, the counter ion acid is hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, phosphoric acid, 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4-aminobenzoic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, camphor acid, citric acid, cyclohexane ... Phosulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, isoascorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, dodecylsulfuric acid, dibenzoyltartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactonic acid, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, Lauric acid, camphoric acid, maleic acid, malonic acid, methanesulfonic acid, 1,5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, embonic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanic acid, undecylenic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, and L-malic acid, preferably sulfuric acid. acid, phosphoric acid, benzenesulfonic acid, cinnamic acid, tartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, fumaric acid, and methanesulfonic acid, more preferably sulfuric acid, tartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, fumaric acid, and methanesulfonic acid, even more preferably sulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, and methanesulfonic acid, even more preferably ethanesulfonic acid and methanesulfonic acid; Preferably, the organic solvent in step 2) is selected from alcoholic solvents, preferably one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, and tert-butanol, preferably one or more of methanol, ethanol, isopropanol, and tert-butanol; Preferably, the organic solvent in step 3) is one or more selected from the group consisting of alcohols, esters, and ethers, preferably one or more of methanol, ethanol, n-propanol, isopropanol, ethyl acetate, petroleum ether, methyl tert-butyl ether, tetrahydrofuran, and 1,4-dioxane, more preferably one or more of methanol, ethanol, n-propanol, isopropanol, ethyl acetate, methyl tert-butyl ether, and tetrahydrofuran, even more preferably one or more of methanol, ethanol, isopropanol, ethyl acetate, and methyl tert-butyl ether; A method is further provided.

[0040] In a preferred embodiment of the invention, the compound of formula (I) is the ethanesulfonate, mesylate, or sulfate salt of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide.

[0041] In a further preferred embodiment of the present invention, the compound of formula (I) is a crystalline form of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, wherein M is ethanesulfonic acid and y is 1, i.e., crystalline form A of the ethanesulfonate salt, having the following structure:

[0042] [ka]

[0043] its X-ray powder diffraction pattern comprises one or more diffraction peaks at 2θ of 6.8±0.2°, and 13.4±0.2°, 14.7±0.2°, and 19.5±0.2°, 20.1±0.2°, 23.9±0.2°, 24.4±0.2°, 25.0±0.2°, 23±0.2°, 23.6±0.2°, 9.3±0.2°, and 17.3±0.2°; preferably any 2, 4, 6, 8, or 10 of the above diffraction peaks; or its X-ray powder diffraction pattern comprises two or three diffraction peaks at 6.8±0.2°, 13.4±0.2°, 14.7±0.2°, and 19.5±0.2° 2θ, and optionally further comprises one or more diffraction peaks at 20.1±0.2°, 23.9±0.2°, 24.4±0.2°, 25.0±0.2°, 23±0.2°, and 23.6±0.2° 2θ; preferably comprises any 2, 3, 4, 5, or 6 of the above diffraction peaks; For example, its X-ray powder diffraction pattern has characteristic peaks at 13.4±0.2°, 14.7±0.2°, 19.5±0.2°, 20.1±0.2°, 23±0.2°, 23.9±0.2°, 24.4±0.2°, and 25.0±0.2°; Its X-ray powder diffraction pattern has characteristic peaks at 6.8±0.2°, 13.4±0.2°, 14.7±0.2°, 19.5±0.2°, 20.1±0.2°, 23.9±0.2°, 23±0.2°, and 23.6±0.2°; Its X-ray powder diffraction pattern has characteristic peaks at 6.8±0.2°, 13.4±0.2°, 14.7±0.2°, 19.5±0.2°, 20.1±0.2°, 23.9±0.2°, 24.4±0.2°, and 25.0±0.2°; Its X-ray powder diffraction pattern has characteristic peaks at 6.8±0.2°, 13.4±0.2°, 14.7±0.2°, 19.5±0.2°, 20.1±0.2°, 23.9±0.2°, 24.4±0.2°, 25.0±0.2°, 23±0.2°, and 23.6±0.2°.

[0044] In a preferred embodiment of the invention, the X-ray powder diffraction pattern has diffraction peaks at 6.8±0.2°, 9.3±0.2°, 13.4±0.2°, and 14.7±0.2° 2θ; further diffraction peaks at 17.3±0.2°, 19.5±0.2°, 20.8±0.2°, 23.9±0.2°, and 25.0±0.2° 2θ; still further having diffraction peaks at 2θ of 0.1±0.2°, 23.0±0.2°, 23.6±0.2°, 24.4±0.2°, 27.3±0.2°, and 30.7±0.2°; or still further having diffraction peaks at 2θ of 10.5±0.2°, 17.5±0.2°, 26.9±0.2°, 27.7±0.2°, 28.6±0.2°, 29.6±0.2°, 35.7±0.2°, and 37.6±0.2°; Alternatively, the X-ray powder diffraction pattern has diffraction peaks at 2θ of 6.8±0.2° and 13.4±0.2°; preferably also at 2θ of 14.7±0.2° and 19.5±0.2°; more preferably also at 2θ (±0.2°) of 20.1±0.2°, 23.9±0.2°, 24.4±0.2°, and 25.0±0.2°; even more preferably also at 2θ (±0.2°) of 23±0.2° and 23.6±0.2°; even more preferably also at 2θ (±0.2°) of 9.3±0.2° and and more preferably, also has diffraction peaks at 17.3±0.2°; even more preferably, also has diffraction peaks at 9.8±0.2°, 18.4±0.2°, 19.1±0.2°, 23.6±0.2°, 27.3±0.2°, and 30.7±0.2° 2θ; and even more preferably, also has diffraction peaks at 10.5±0.2°, 17.5±0.2°, 26.9±0.2°, 27.7±0.2°, 28.6±0.2°, 29.6±0.2°, 35.7±0.2°, and 37.6±0.2° 2θ.

[0045] Using Cu-Kα radiation, the characteristic X-ray diffraction peaks expressed in 2θ angles and d-spacing values ​​are shown in Table 1.

[0046] [Table 1]

[0047] The compound of formula (I) according to the present invention is crystalline form A of the ethanesulfonic acid salt of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern of which is substantially as shown in Figure 1; the TGA spectrum of which is substantially as shown in Figure 2; and the DSC spectrum of which is substantially as shown in Figure 3.

[0048] In a further preferred embodiment of the present invention, the compound of formula (I) is a crystalline form of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, wherein M is the mesylate salt and y is 1, i.e., crystalline form A of the mesylate salt, having the following structure:

[0049] [ka]

[0050] its X-ray powder diffraction pattern comprises one or more diffraction peaks at 2θ of 6.1±0.2°, 7.5±0.2°, 8.0±0.2°, 14.9±0.2°, 23.8±0.2°, 8.4±0.2°, 18.8±0.2°, 20.7±0.2°, 22.3±0.2°, and 22.8±0.2°; preferably any 2, 4, 6, 8, or 10 of the above diffraction peaks; or its X-ray powder diffraction pattern comprises two or three diffraction peaks at 6.1±0.2°, 7.5±0.2°, and 8.0±0.2° 2θ, and optionally further comprises one or more diffraction peaks at 14.9±0.2°, 18.8±0.2°, 20.7±0.2°, 22.3±0.2°, 22.8±0.2°, and 23.8±0.2° 2θ; preferably comprises any 2, 3, 4, 5, or 6 of the above diffraction peaks; For example, its X-ray powder diffraction pattern has characteristic peaks at 6.1±0.2°, 7.5±0.2°, 8.0±0.2°, 14.9±0.2°, 18.8±0.2°, 22.3±0.2°, 22.8±0.2°, and 23.8±0.2°.

[0051] or its X-ray powder diffraction pattern has diffraction peaks at 6.1±0.2°, 7.5±0.2°, 8.0±0.2°, 14.9±0.2°, and 23.8±0.2° 2θ; further has diffraction peaks at 8.4±0.2°, 18.8±0.2°, 20.7±0.2°, 22.3±0.2°, and 22.8±0.2° 2θ; and still further has diffraction peaks at 13.5±0.2° and 25.2±0.2° 2θ.

[0052] Characteristic X-ray diffraction peaks and d-spacing values ​​expressed in 2θ angles using Cu-Kα radiation are shown in Table 2.

[0053] [Table 2]

[0054] The compound of formula (I) according to the present invention is crystalline form A of the mesylate salt of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern of which is substantially as shown in Figure 4.

[0055] In a further preferred embodiment of the present invention, the compound of formula (I) is a crystalline form of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, wherein M is the mesylate salt and y is 1, i.e., crystalline form B of the mesylate salt, having the following structure:

[0056] [ka]

[0057] its X-ray powder diffraction pattern comprises one or more diffraction peaks at 24.4±0.2°, 13.3±0.2°, 23.8±0.2°, 20.3±0.2°, 19.7±0.2°, 17.2±0.2°, 26.7±0.2°, 9.0±0.2°, 23.1±0.2°, 9.9±0.2°, 14.3±0.2°, and 21.6±0.2° 2θ; preferably comprises any 2, 4, 6, 8, or 10 of the above diffraction peaks; or its X-ray powder diffraction pattern comprises two or three diffraction peaks at 24.4±0.2°, 13.3±0.2°, and 23.8±0.2°, and optionally further comprises one or more diffraction peaks at 9.0±0.2°, 9.9±0.2°, 26.7±0.2°, 17.2±0.2°, and 23.1±0.2° 2θ; preferably comprises any two, three, four, or five of the above diffraction peaks; For example, its X-ray powder diffraction pattern has characteristic peaks at 24.4±0.2°, 13.3±0.2°, 23.8±0.2°, 9.0±0.2°, 9.9±0.2°, 26.7±0.2°, 17.2±0.2°, and 23.1±0.2°.

[0058] or its X-ray powder diffraction pattern has diffraction peaks at 9.0±0.2°, 13.3±0.2°, 19.7±0.2°, and 23.1±0.2° 2θ; further has diffraction peaks at 9.9±0.2°, 17.2±0.2°, 20.3±0.2°, and 26.7±0.2° 2θ; still further has diffraction peaks at 14.3±0.2°, 21.6±0.2°, 23.8±0.2°, and 28.4±0.2° 2θ; and still further includes diffraction peaks at 24.4±0.2°, 30.5±0.2°, and 32.6±0.2° 2θ.

[0059] Characteristic X-ray diffraction peaks and d-spacing values ​​expressed in 2θ angles using Cu-Kα radiation are shown in Table 3.

[0060] [Table 3]

[0061] The compound of formula (Ia) according to the present invention is crystalline form B of the mesylate salt of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern of which is substantially as shown in Figure 5.

[0062] In a further preferred embodiment of the present invention, the compound of formula (I) is in the crystalline form (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, wherein M is the mesylate salt and y is 1, i.e., crystalline form C of the mesylate salt, having the following structure:

[0063] [ka]

[0064] its X-ray powder diffraction pattern comprises one or more diffraction peaks at 22.5±0.2°, 8.5±0.2°, 7.2±0.2°, 14.4±0.2°, 26.7±0.2°, 25.3±0.2°, 12.8±0.2°, 16.7±0.2°, 6.1±0.2°, 12.1±0.2°, 15.2±0.2°, and 22.0±0.2° 2θ; preferably, any 2, 4, 6, 8, or 10 of the above diffraction peaks; or its X-ray powder diffraction pattern comprises two or three diffraction peaks at 22.5±0.2°, 8.5±0.2°, and 7.2±0.2° 2θ, and optionally further comprises one or more diffraction peaks at 14.4±0.2°, 26.7±0.2°, 12.8±0.2°, 16.7±0.2°, and 6.1±0.2° 2θ; preferably comprises any two, three, four, or five of the above diffraction peaks; For example, its X-ray powder diffraction pattern has characteristic peaks at 22.5±0.2°, 8.5±0.2°, 7.2±0.2°, 14.4±0.2°, 26.7±0.2°, 12.8±0.2°, 16.7±0.2°, and 6.1±0.2° 2θ.

[0065] or its X-ray powder diffraction pattern has diffraction peaks at 7.2±0.2°, 14.4±0.2°, 22.5±0.2°, and 26.7±0.2° 2θ; further has diffraction peaks at 6.1±0.2°, 12.8±0.2°, 16.7±0.2°, and 20.8±0.2° 2θ; still further has diffraction peaks at 8.5±0.2°, 15.2±0.2°, 22.0±0.2°, and 25.3±0.2° 2θ; and still further has diffraction peaks at 12.1±0.2°, 19.1±0.2°, and 23.8±0.2° 2θ.

[0066] Characteristic X-ray diffraction peaks and d-spacing values ​​expressed in 2θ angles using Cu-Kα radiation are shown in Table 4.

[0067] [Table 4]

[0068] The compound of formula (Ia) according to the present invention is crystalline form C of the mesylate salt of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern of which is substantially as shown in Figure 6.

[0069] In a further preferred embodiment of the present invention, the compound of formula (I) is a crystalline form of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, wherein M is the sulfate salt and y is 1, i.e., crystalline form A of the sulfate salt, having the following structure:

[0070] [ka]

[0071] its X-ray powder diffraction pattern comprises one or more diffraction peaks at 2θ of 8.4±0.2°, 7.2±0.2°, 20.1±0.2°, 22.7±0.2°, 24.5±0.2°, 25.7±0.2°, 18.9±0.2°, 26.7±0.2°, 16.4±0.2°, 18.2±0.2°, 22.0±0.2°, and 12.6±0.2°; preferably any 2, 4, 6, 8, or 10 of the above diffraction peaks; or its X-ray powder diffraction pattern comprises two or three diffraction peaks at 8.4±0.2°, 7.2±0.2°, and 20.1±0.2° 2θ, and optionally further comprises one or more diffraction peaks at 22.7±0.2°, 24.5±0.2°, 25.7±0.2°, 18.9±0.2°, and 16.4±0.2° 2θ; preferably comprises any two, three, four, or five of the above diffraction peaks; For example, its X-ray powder diffraction pattern has diffraction peaks at 8.4±0.2°, 7.2±0.2°, 20.1±0.2°, 22.7±0.2°, 24.5±0.2°, 25.7±0.2°, 18.9±0.2°, and 16.4±0.2° 2θ.

[0072] or its X-ray powder diffraction pattern has diffraction peaks at 7.2±0.2°, 8.4±0.2°, 20.1±0.2°, and 22.7±0.2° 2θ; further has diffraction peaks at 5.8±0.2°, 16.4±0.2°, 18.9±0.2°, and 26.7±0.2° 2θ; still further has diffraction peaks at 12.6±0.2°, 14.7±0.2°, 17.2±0.2°, and 25.1±0.2° 2θ; and still further has diffraction peaks at 14.4±0.2°, 18.2±0.2°, 24.5±0.2°, and 25.7±0.2° 2θ.

[0073] Characteristic X-ray diffraction peaks and d-spacing values ​​expressed in 2θ angles using Cu-Kα radiation are shown in Table 5.

[0074] [Table 5]

[0075] The compound of formula (Ia) according to the present invention is crystalline form A of the sulfate salt of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern of which is substantially as shown in Figure 7.

[0076] In a further preferred embodiment of the present invention, the compound of formula (I) is a crystalline form of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, wherein M is the sulfate salt and y is 1, i.e., crystalline form B of the sulfate salt, having the following structure:

[0077] [ka]

[0078] its X-ray powder diffraction pattern comprises one or more diffraction peaks at 2θ of 4.8±0.2°, 7.6±0.2°, 12.2±0.2°, 14.0±0.2°, 18.5±0.2°, 22.9±0.2°, 23.8±0.2°, and 24.9±0.2°; preferably any 2, 4, 6, or 8 of the above diffraction peaks; For example, its X-ray powder diffraction pattern has diffraction peaks at 2θ of 4.8±0.2°, 7.6±0.2°, 12.2±0.2°, 14.0±0.2°, 18.5±0.2°, 22.9±0.2°, 23.8±0.2°, and 24.9±0.2°.

[0079] Alternatively, its X-ray powder diffraction pattern has diffraction peaks at 4.8±0.2° and 7.6±0.2° 2θ; and further has diffraction peaks at 12.2±0.2°, 14.0±0.2°, 18.5±0.2°, 22.9±0.2°, and 23.8±0.2° 2θ.

[0080] Characteristic X-ray diffraction peaks and d-spacing values ​​expressed in 2θ angles using Cu-Kα radiation are shown in Table 6.

[0081] [Table 6]

[0082] The compound of formula (I) according to the present invention is crystalline form B of the sulfate salt of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern of which is substantially as shown in Figure 8.

[0083] In a further preferred embodiment of the present invention, the compound of formula (I) is a crystalline form of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, wherein M is the sulfate salt and y is 1, i.e., crystalline form C of the sulfate salt, having the following structure:

[0084] [ka]

[0085] its X-ray powder diffraction pattern comprises one or more diffraction peaks at 2θ of 24.5±0.2°, 13.3±0.2°, 23.9±0.2°, 9.0±0.2°, 17.3±0.2°, 19.4±0.2°, 26.9±0.2°, 20.4±0.2°, 17.7±0.2°, 9.9±0.2°, 20.0±0.2°, and 28.3±0.2°; preferably any 2, 4, 6, 8, or 10 of the above diffraction peaks; or its X-ray powder diffraction pattern comprises two or three diffraction peaks at 24.5±0.2°, 13.3±0.2°, and 23.9±0.2° 2θ, and optionally further comprises one or more diffraction peaks at 9.0±0.2°, 17.3±0.2°, 19.4±0.2°, 17.7±0.2°, and 9.9±0.2° 2θ; preferably comprises any two, three, four, or five of the above diffraction peaks; For example, its X-ray powder diffraction pattern has diffraction peaks at 24.5±0.2°, 13.3±0.2°, 23.9±0.2°, 9.0±0.2°, 17.3±0.2°, 19.4±0.2°, 17.7±0.2°, and 9.9±0.2° 2θ.

[0086] or its X-ray powder diffraction pattern has diffraction peaks at 9.0±0.2°, 13.3±0.2°, 17.3±0.2°, and 24.5±0.2° 2θ; further has diffraction peaks at 9.9±0.2°, 17.7±0.2°, 19.4±0.2°, and 26.9±0.2° 2θ; still further has diffraction peaks at 14.3±0.2°, 18.6±0.2°, 28.3±0.2°, and 37.5±0.2° 2θ; and still further has diffraction peaks at 16.7±0.2°, 20.0±0.2°, 20.4±0.2°, 24.0±0.2°, and 30.4±0.2° 2θ.

[0087] Characteristic X-ray diffraction peaks and d-spacing values ​​expressed in 2θ angles using Cu-Kα radiation are shown in Table 7.

[0088] [Table 7]

[0089] The compound of formula (Ia) according to the present invention is crystalline form C of the sulfate salt of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern of which is substantially as shown in Figure 9.

[0090] In a further preferred embodiment of the present invention, the compound of formula (I) is a crystalline form of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, wherein M is the sulfate salt and y is 1, i.e., crystalline form D of the sulfate salt, and has the following structure:

[0091] [ka]

[0092] its X-ray powder diffraction pattern comprises one or more diffraction peaks at 2θ of 7.6±0.2°, 22.5±0.2°, 8.9±0.2°, 15.0±0.2°, 23.9±0.2°, 26.6±0.2°, 24.6±0.2°, 5.8±0.2°, 12.9±0.2°, 19.9±0.2°, 20.7±0.2°, and 11.6±0.2°; preferably any 2, 4, 6, 8, or 10 of the above diffraction peaks; or its X-ray powder diffraction pattern comprises two or three diffraction peaks at 7.6±0.2°, 22.5±0.2°, and 8.9±0.2° 2θ, and optionally further comprises one or more diffraction peaks at 15.0±0.2°, 26.6±0.2°, 5.8±0.2°, 12.9±0.2°, and 11.6±0.2° 2θ; preferably comprises any two, three, four, or five of the above diffraction peaks; For example, its X-ray powder diffraction pattern has diffraction peaks at 2θ of 7.6±0.2°, 22.5±0.2°, 8.9±0.2°, 15.0±0.2°, 26.6±0.2°, 5.8±0.2°, 12.9±0.2°, and 11.6±0.2°.

[0093] or its X-ray powder diffraction pattern has diffraction peaks at 2θ of 7.6±0.2°, 15.0±0.2°, 22.5±0.2°, and 23.9±0.2°; and further diffraction peaks at 2θ of 5.8±0.2°, 12.9±0.2°, 19.9±0.2°, and 26.6±0.2°; and still further diffraction peaks at 10.1±0.2°, 11.6±0.2°, 17.4±0.2°, 18.2±0.2°, 19.1±0.2°, 21.9±0.2°, 25.4±0.2°, and 27.7±0.2° 2θ.

[0094] Characteristic X-ray diffraction peaks and d-spacing values ​​expressed in 2θ angles using Cu-Kα radiation are shown in Table 8.

[0095] [Table 8]

[0096] The compound of formula (Ia) according to the present invention is crystalline form D of the sulfate salt of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern of which is substantially as shown in Figure 10.

[0097] In a further preferred embodiment of the present invention, the compound of formula (I) is the crystalline form of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, wherein M is the sulfate salt and y is 1, i.e., crystalline form E of the sulfate salt, and has the following structure:

[0098] [ka]

[0099] its X-ray powder diffraction pattern comprises one or more diffraction peaks at 2θ of 17.7±0.2°, 23.5±0.2°, 24.8±0.2°, 9.9±0.2°, 22.6±0.2°, 21.2±0.2°, 19.1±0.2°, 29.4±0.2°, 16.9±0.2°, 28.4±0.2°, 17.3±0.2°, and 24.5±0.2°; preferably any 2, 4, 6, 8, or 10 of the above diffraction peaks; or its X-ray powder diffraction pattern comprises two or three diffraction peaks at 17.7±0.2°, 23.5±0.2°, and 24.8±0.2° 2θ, and optionally further comprises one or more diffraction peaks at 9.9±0.2°, 22.6±0.2°, 21.2±0.2°, 19.1±0.2°, and 29.4±0.2° 2θ; preferably comprises any two, three, four, or five of the above diffraction peaks; For example, its X-ray powder diffraction pattern has diffraction peaks at 2θ of 17.7±0.2°, 23.5±0.2°, 24.8±0.2°, 9.9±0.2°, 22.6±0.2°, 21.2±0.2°, 19.1±0.2°, and 29.4±0.2°.

[0100] or its X-ray powder diffraction pattern has diffraction peaks at 9.9±0.2°, 17.7±0.2°, 22.6±0.2°, and 24.8±0.2° 2θ; further has diffraction peaks at 16.9±0.2°, 21.2±0.2°, 23.5±0.2°, and 29.4±0.2° 2θ; still further has diffraction peaks at 17.3±0.2°, 19.1±0.2°, 28.4±0.2°, and 30.5±0.2° 2θ; and still further has diffraction peaks at 14.1±0.2°, 16.2±0.2°, 19.6±0.2°, 20.7±0.2°, 24.5±0.2°, and 26.5±0.2° 2θ.

[0101] Characteristic X-ray diffraction peaks and d-spacing values ​​expressed in 2θ angles using Cu-Kα radiation are shown in Table 9.

[0102] [Table 9]

[0103] The compound of formula (Ia) according to the present invention is crystalline form E of the sulfate salt of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, the X-ray powder diffraction pattern of which is substantially as shown in Figure 11.

[0104] Another object of the present invention is to provide pharmaceutical compositions comprising a therapeutically effective amount of the compound of formula (I) and its crystalline forms, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0105] [ka]

[0106] [In the formula, W is -O-, -S-, and -NR aa - selected from the group consisting of; G is -O-, -S-, -CRaa R bb - and -NR aa - selected from the group consisting of; R1 and R1' are each hydrogen, deuterium, cyano, halogen, nitro, amino, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, cyano-substituted C 1~6 Alkyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~10 Aryl, 5-10 membered heteroaryl, -(CH2) n R cc , -(CH2) n OR cc , and -CR aa R bb OR cc or selected from the group consisting of; Or, R1 and R1' are bonded to each other to form C 3~8 Forming a cycloalkyl or 3- to 8-membered heterocyclyl, C 3~8 The cycloalkyl or 3- to 8-membered heterocyclyl may optionally be substituted with deuterium, cyano, halogen, nitro, amino, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~10 further substituted with one or more substituents selected from the group consisting of aryl, and 5- to 10-membered heteroaryl; R2 is hydrogen, deuterium, cyano, halogen, nitro, amino, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~10 Aryl, 5- to 10-membered heteroaryl, and -(CH2) n OR cc or selected from the group consisting of; Or, any two R2 are bonded to each other to form C 3~8 Forming a cycloalkyl or 3- to 8-membered heterocyclyl, C 3~8 The cycloalkyl or 3- to 8-membered heterocyclyl may optionally be substituted with deuterium, cyano, halogen, nitro, amino, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~10 further substituted with one or more substituents selected from the group consisting of aryl, and 5- to 10-membered heteroaryl; R3 and R3' are each hydrogen, deuterium, cyano, halogen, nitro, amino, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~10 selected from the group consisting of aryl, and 5- to 10-membered heteroaryl; Or, R3 and R3' are bonded to each other to form oxo, C 3~8 Forming a cycloalkyl or 3- to 8-membered heterocyclyl, C 3~8 The cycloalkyl or 3- to 8-membered heterocyclyl may optionally be substituted with deuterium, cyano, halogen, nitro, amino, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~10 further substituted with one or more substituents selected from the group consisting of aryl, and 5- to 10-membered heteroaryl; R4 is hydrogen, deuterium, cyano, halogen, nitro, amino, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 3~8Cycloalkyl, 3-8 membered heterocyclyl, C 6~10 selected from the group consisting of aryl, and 5- to 10-membered heteroaryl; R5 is hydrogen, deuterium, C 1~6 Alkyl, and C 1~6 haloalkyl; Or, R1 or R1′ and R5 are bonded to each other to form a 3- to 8-membered heterocyclyl, which is optionally substituted with deuterium, cyano, halogen, nitro, amino, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~10 further substituted with one or more substituents selected from the group consisting of aryl, and 5- to 10-membered heteroaryl; R aa , R bb , and R cc are each independently hydrogen, deuterium, cyano, halogen, nitro, amino, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~10 selected from the group consisting of aryl, and 5- to 10-membered heteroaryl; M is an inorganic acid or an organic acid, and the inorganic acid is selected from the group consisting of hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, and phosphoric acid; and the organic acid is selected from the group consisting of 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4-aminobenzoic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, isoascorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, dodecyl sulfuric acid, dibenzoic acid, ... ethanolic acid, ... n is an integer from 0 to 3; x is an integer from 0 to 3; y is an integer of 1 to 5, preferably an integer of 1 to 3, and more preferably 1.

[0107] In a preferred embodiment of the present invention, in the acid addition salt of formula (I), R1 and R1' are each hydrogen, C 1~6 Alkyl, C 1~6 Hydroxyalkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, 3-8 membered heterocyclyl, -(CH2) n OR cc , and -CR aa R bb ORcc , preferably hydrogen, C 1~3 Alkyl, C 1~3 Hydroxyalkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy, 3-6 membered heterocyclyl, -(CH2) n OR cc , and -CR aa R bb OR cc , more preferably selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, fluoromethyl, fluoroethyl, fluoropropyl, chloromethyl, chloroethyl, chloropropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, oxacyclopropyl, oxacyclobutyl, oxacyclopentyl, oxacyclohexyl, azacyclopropyl, azacyclobutyl, azacyclopentyl, azacyclohexyl, -CHOCH, -(CH)OCH, -CH(CH)OCH and -C(CH)OCH, more preferably selected from the group consisting of hydrogen, methyl, methoxy, isopropyl, fluorine-containing methyl, hydroxymethyl, oxacyclobutyl, -CHOCH and -CH(CH)OCH.

[0108] In a preferred embodiment of the present invention, in the acid addition salt of formula (I), R2 is hydrogen, C 1~6 Alkyl, halogen, cyano, and -(CH2) n OR cc , preferably hydrogen, C 1~3 Alkyl, halogen, cyano, and -(CH2) n OR cc , more preferably selected from the group consisting of hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, fluorine, chlorine, bromine, and cyano, even more preferably hydrogen, fluorine, methyl, methoxy, and cyano; Or, any two R2 are bonded to each other to form a substituted or unsubstituted C 3~6 Cycloalkyl or substituted or unsubstituted 3- to 6-membered heterocyclyl, preferably substituted or unsubstituted C 3~6It forms a cycloalkyl or a substituted or unsubstituted 3- to 6-membered heterocyclyl containing 1 to 3 atoms selected from the group consisting of N, O, and S, more preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclopropyl, oxacyclobutyl, oxacyclopentyl, oxacyclohexyl, azacyclopropyl, azacyclobutyl, azacyclopentyl, or azacyclohexyl, even more preferably cyclobutyl, cyclopentyl, 1,3-dioxocyclopentyl, or 1,3-dioxocyclohexyl.

[0109] In a preferred embodiment of the present invention, in the acid addition salt of formula (I), R3 and R3' are each hydrogen, C 1~6 Alkyl, halogen, cyano, and C 1~6 Alkoxy, preferably hydrogen, C 1~3 Alkyl, halogen, cyano, and C 1~3 alkoxy, more preferably selected from the group consisting of hydrogen, methyl, ethyl, propyl, fluorine, chlorine, bromine, cyano, methoxy, ethoxy, and propoxy, more preferably hydrogen, fluorine, methyl, methoxy, and cyano; Or, R3 and R3' are bonded to each other to form oxo, C 3~6 Cycloalkyl or 3- to 6-membered heterocyclyl, preferably oxo, C 3~6 It forms a cycloalkyl or a 3- to 6-membered heterocyclyl containing 1 to 3 N, O, or S atoms, more preferably oxo, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclopropyl, oxacyclobutyl, oxacyclopentyl, oxacyclohexyl, azacyclopropyl, azacyclobutyl, azacyclopentyl, or azacyclohexyl, even more preferably oxo, cyclopropyl, or oxacyclobutyl.

[0110] In a preferred embodiment of the present invention, in the acid addition salt of formula (I), R4 is hydrogen, C 1~6 Alkyl, halogen, cyano, C 1~6 Haloalkyl, and C3~8 Cycloalkyl, preferably hydrogen, C 1~3 Alkyl, halogen, cyano, C 1~3 Haloalkyl, and C 3~6 Cycloalkyl, more preferably hydrogen, methyl, ethyl, propyl, fluorine, chlorine, bromine, cyano, fluoromethyl, fluoroethyl, chloromethyl, chloroethyl, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, and even more preferably hydrogen, fluorine, chlorine, methyl, trifluoromethyl, cyano, and cyclopropyl.

[0111] In a preferred embodiment of the present invention, in the acid addition salt of formula (I), R5 is hydrogen, C 1~6 Alkyl, and C 1~6 Haloalkyl, preferably hydrogen, C 1~3 Alkyl, and C 1~3 haloalkyl, more preferably selected from the group consisting of hydrogen, methyl, ethyl, propyl, fluorine-containing methyl, fluorine-containing ethyl, fluorine-containing propyl, chlorine-containing methyl, chlorine-containing ethyl, and chlorine-containing propyl, even more preferably hydrogen and methyl; Alternatively, R1 or R1' is bonded to R5 to form a 3- to 6-membered heterocyclyl optionally substituted with one or more substituents selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, and propyl, preferably azacyclopropyl, azacyclobutyl, azacyclopentyl, azacyclohexyl, fluorine-substituted azacyclopropyl, fluorine-substituted azacyclobutyl, fluorine-substituted azacyclopentyl, fluorine-substituted azacyclohexyl, methyl-substituted azacyclopropyl, methyl-substituted azacyclobutyl, methylpyrrolidinyl, or methyl-substituted azacyclohexyl, more preferably azacyclobutyl, azacyclopentyl, or methylpyrrolidinyl.

[0112] In a preferred embodiment of the present invention, in the acid addition salt of formula (I), R aa , R bb , and Rcc are each independently hydrogen, C 1~6 Alkyl, C 1~6 Alkoxy, C 3~8 Cycloalkyl or 3- to 8-membered heterocyclyl, preferably hydrogen, C 1~3 Alkyl, C 1~3 Alkoxy, C 3~6 Cycloalkyl or 3-6 membered heterocyclyl containing 1-3 N, O or S atoms, more preferably hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclopropyl, oxacyclobutyl, oxacyclopentyl and oxacyclobutyl, even more preferably hydrogen, methyl, ethyl, isopropyl, methoxy, cyclopropyl and oxacyclobutyl.

[0113] In a preferred embodiment of the present invention, in the acid addition salt of formula (I), M is selected from the group consisting of sulfuric acid, phosphoric acid, benzenesulfonic acid, cinnamic acid, tartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, fumaric acid, and methanesulfonic acid, preferably sulfuric acid, tartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, fumaric acid, and methanesulfonic acid, more preferably sulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, and methanesulfonic acid, and even more preferably ethanesulfonic acid.

[0114] In a preferred embodiment of the invention, in the acid addition salt of formula (I), W is —O—.

[0115] In a preferred embodiment of the invention, in the acid addition salt of formula (I), G is —O— or —S—.

[0116] In a preferred embodiment of the invention, in the acid addition salt of formula (I), R5 is hydrogen.

[0117] In a preferred embodiment of the present invention, in the acid addition salt of formula (I), R1' and R3' are hydrogen.

[0118] In a preferred embodiment of the present invention, the acid addition salt of formula (I) is further represented by formula (II-A) or (II-B):

[0119] [ka]

[0120] In a preferred embodiment of the present invention, the specific structure of the acid addition salt of formula (I) is as follows:

[0121] [ka]

[0122] [ka]

[0123] Another object of the present invention is to provide the use of the compound of formula (I) and its crystalline forms, and pharmaceutical compositions comprising them, in the preparation of a medicament for inhibiting PI3K, preferably a medicament for inhibiting PI3K alpha.

[0124] Another object of the present invention is to provide salts of the compound of formula (I), (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, and crystalline forms thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0125] Another object of the present invention is to provide use of the compound of formula (I), (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide salt, and crystalline forms thereof, and pharmaceutical compositions containing them, in the preparation of a PI3K inhibitor medicament, preferably a PI3K alpha inhibitor medicament.

[0126] The use is in the preparation of a medicament for treating cancer, bone disease, inflammatory disease, immune disease, nervous system disease, metabolic disease, respiratory disease, and cardiac disease; the cancer is selected from the group consisting of breast cancer, pancreatic cancer, non-small cell lung cancer (NSCLC), thyroid cancer, seminoma, melanoma, bladder cancer, liver cancer, renal cancer, myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), and colorectal cancer. [Brief explanation of the drawings]

[0127] [Figure 1] FIG. 1 is an XRPD pattern of crystalline form A of the ethanesulfonate salt of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide. [Figure 2] FIG. 1 is a TGA spectrum of crystalline form A of the ethanesulfonate salt of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide. [Figure 3] FIG. 1 is a DSC spectrum of crystalline form A of the ethanesulfonate salt of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide. [Figure 4] FIG. 1 is an XRPD pattern of crystalline form A of the mesylate salt of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide. [Figure 5]FIG. 1 is an XRPD pattern of crystalline form B of the mesylate salt of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide. [Figure 6] FIG. 1 is an XRPD pattern of crystalline form C of the mesylate salt of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide. [Figure 7] FIG. 1 is an XRPD pattern of crystalline form A of the sulfate salt of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide. [Figure 8] FIG. 1 is an XRPD pattern of crystalline form B of the sulfate salt of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide. [Figure 9] FIG. 1 is an XRPD pattern of crystalline form C of the sulfate salt of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide. [Figure 10] FIG. 1 is an XRPD pattern of crystalline form D of the sulfate salt of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide. [Figure 11]FIG. 1 is an XRPD pattern of crystalline form E of the sulfate salt of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide. DETAILED DESCRIPTION OF THE INVENTION

[0128] Unless otherwise stated, terms used in the specification and claims have the following meanings:

[0129] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, straight or branched chain, containing 1 to 20 carbon atoms, preferably alkyl containing 1 to 8 carbon atoms, more preferably alkyl with 1 to 6 carbon atoms, and most preferably alkyl with 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, Examples of alkyl include 3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-decyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof. Alkyl may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available attachment point.The substituents are preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, oxo, carboxy, and alkoxycarbonyl. The alkyl of the present invention is preferably selected from the group consisting of methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl, hydroxy-substituted alkyl, and cyano-substituted alkyl.

[0130] The term "alkylene" refers to an alkyl with one hydrogen atom further substituted, e.g., "methylene" refers to -CH-, "ethylene" refers to -(CH)-, "propylene" refers to -(CH)-, "butylene" refers to -(CH)-, etc. The above substituents can be attached to different carbon atoms to form a carbon chain or to a single carbon atom to form a cycloalkyl. The term "alkenyl" refers to an alkyl, as defined above, consisting of at least two carbon atoms and at least one carbon-carbon double bond, e.g., ethenyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, etc. Alkenyl can be substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocyclylthio.

[0131] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent having 3 to 20 carbon atoms, preferably 3 to 8 carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptanetrienyl, cyclooctyl, and the like. Polycyclic cycloalkyls include cycloalkyls having spirocyclic, fused, or bridged rings. Cycloalkyls are preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, and cycloheptyl.

[0132] The term "heterocyclyl" refers to a 3- to 20-membered saturated or partially unsaturated monocyclic or polycyclic hydrocarbon group in which one or more ring atoms are selected from nitrogen, oxygen, and S(O) m (m is an integer of 0 to 2), except that, except for the -OO-, -OS-, or -SS- ring portion, the remaining ring atoms are carbon atoms. Preferably, the heterocyclyl has 3 to 12 ring atoms, of which 1 to 4 atoms are heteroatoms; more preferably, 3 to 8 ring atoms; and most preferably, 3 to 8 ring atoms. Non-limiting examples of monocyclic heterocyclyls include oxacyclobutyl, pyrrolidinyl, pyrrolidonyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, and the like, preferably oxacyclobutyl, pyrrolidonyl, tetrahydrofuranyl, pyrazolidinyl, morpholinyl, piperazinyl, and pyranyl. Polycyclic heterocyclyls include heterocyclyls having spiro, fused, or bridged rings, which are optionally bonded to other groups through a single bond or further fused to other cycloalkyls, heterocyclyls, aryls, and heteroaryls through any two or more atoms in the ring.

[0133] The term "alkoxy" refers to the -O-(alkyl) and -O-(unsubstituted cycloalkyl) groups, where alkyl is defined above. Alkoxy is preferably an alkoxy having 1 to 8 carbon atoms, more preferably an alkoxy having 1 to 6 carbon atoms, and most preferably an alkoxy having 1 to 3 carbon atoms. Non-limiting examples of alkoxy include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, and cyclohexyloxy. Alkoxy can be optionally substituted or unsubstituted. If substituted, the substituents are preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, carboxy, and alkoxycarbonyl.

[0134] "Haloalkyl" refers to alkyl substituted with one or more halogens, where alkyl is defined above.

[0135] "Haloalkoxy" refers to an alkoxy substituted with one or more halogens, where alkoxy is defined above.

[0136] "Hydroxyalkyl" refers to alkyl substituted with hydroxy, where alkyl is defined above.

[0137] "Hydroxy" refers to the group --OH.

[0138] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0139] "Amino" refers to the group -NH2.

[0140] "Cyano" refers to the radical -CN.

[0141] "Nitro" refers to the -NO2 group.

[0142] "THF" refers to tetrahydrofuran.

[0143] "EtOAc" refers to ethyl acetate.

[0144] "DMSO" refers to dimethyl sulfoxide.

[0145] "LDA" refers to lithium diisopropylamide.

[0146] "DMAP" refers to 4-dimethylaminopyridine.

[0147] "EtMgBr" refers to ethylmagnesium bromide.

[0148] "HOSu" refers to N-hydroxysuccinimide.

[0149] "EDCl" refers to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.

[0150] "IPA" refers to isopropanol.

[0151] "MeOH" refers to methanol.

[0152] "EtOH" refers to ethanol.

[0153] "DMF" refers to N,N-dimethylformamide.

[0154] "DIPEA" refers to N,N-diisopropylethylamine.

[0155] "HEPES" refers to 4-hydroxyethylpiperazineethanesulfonic acid.

[0156] Different expressions such as "X is selected from the group consisting of A, B, or C," "X is selected from the group consisting of A, B, and C," "X is A, B, or C," "X is A, B, and C," etc., represent the same meaning, i.e., X can be any one or more of A, B, and C.

[0157] "Optional" or "optionally" means that the subsequently described event or circumstance may occur, but need not occur, and the description includes circumstances in which the event or circumstance occurs or does not occur.

[0158] "Substituted" refers to one or more hydrogen atoms of a group, preferably up to 5 hydrogen atoms, more preferably 1 to 3 hydrogen atoms, independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only present in their possible chemical positions. Those skilled in the art can determine whether a substitution is possible or impossible by experiment or theory without undue effort. For example, the combination of an amino or hydroxyl group having free hydrogen with a carbon atom having an unsaturated bond (e.g., an olefin) may be unstable.

[0159] "Stereoisomerism" includes geometric isomerism (cis-trans isomerism), optical isomerism, and conformational isomerism.

[0160] All hydrogen atoms of the present invention can be replaced with deuterium, which is an isotope, and any hydrogen atom of the compounds included in the examples of the present invention can also be replaced with a deuterium atom.

[0161] A "pharmaceutical composition" refers to a mixture containing one or more of the compounds described herein, or physiologically / pharmaceutically acceptable salts or prodrugs thereof with other chemical components, and other components, such as physiologically / pharmaceutically acceptable carriers and additives. The purpose of a pharmaceutical composition is to facilitate drug administration to an organism and benefit the absorption of the active ingredient to exert its biological activity.

[0162] "Pharmaceutically acceptable salt" refers to salts of compounds of the present invention that are safe and effective for use in mammals and possess the desired biological activity.

[0163] As described herein, novel crystalline forms can be identified by powder X-ray diffraction patterns. However, those skilled in the art are aware that peak intensities and / or peak states in powder X-ray diffraction may vary depending on different experimental conditions, such as different diffraction test conditions and / or preferred orientations. Due to the different precision of different instruments, measured 2θ values ​​may have an error of approximately ±0.2, and individual peaks may have an error of approximately ±0.3 or ±0.4. However, it is known that the relative intensity values ​​of peaks depend more on certain characteristics of the measured sample, such as the size and orientation of the crystals in the sample, and the purity of the analyzed material, than on the peak position. Therefore, the peak intensities shown may have a deviation of approximately ±20% or more.

[0164] "TGA" refers to thermogravimetric analysis (TGA) testing.

[0165] "DSC" refers to differential scanning calorimetry (DSC) testing.

[0166] "XRPD" refers to X-ray powder diffraction (XRPD) testing.

[0167] "HPLC" refers to high performance liquid chromatography (HPLC) testing.

[0168] "PK" refers to pharmacokinetic (PK) studies.

[0169] The present disclosure is further illustrated by the following examples, which should not be construed as limiting the scope of the disclosure.

[0170] I. Compound Preparation [Example]

[0171] The structures of the compounds of the present invention were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are expressed in parts per million (ppm). NMR was determined using a Bruker AVANCE-400 nuclear magnetic spectrometer. The solvents used for the measurements were deuterated dimethyl sulfoxide (DMSO-d), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3). The internal standard was tetramethylsilane (TMS).

[0172] Liquid chromatography-mass spectrometry (LC-MS) was performed on an Agilent 1200 Infinity Series mass spectrometer. High-performance liquid chromatography (HPLC) was performed on an Agilent 1200DAD high-pressure liquid chromatograph (Sunfire C18 150 × 4.6 mm column) and a Waters 2695-2996 high-pressure liquid chromatograph (Gimini C18 150 × 4.6 mm column).

[0173] Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates were used as silica gel plates for thin-layer chromatography (TLC). The size of the silica gel plates used in TLC was 0.15 mm to 0.2 mm, and the size of the silica gel plates used in product purification was 0.4 mm to 0.5 mm. Yantai Huanghai 200-300 mesh silica gel was generally used as the support for column chromatography.

[0174] The starting materials in the examples of the present invention are known, commercially available, or can be synthesized using methods known in the art.

[0175] Unless otherwise specified, all reactions of the present invention are carried out under a dry nitrogen or argon atmosphere with continuous magnetic stirring, solvents are dry solvents, and reaction temperatures are given in degrees Celsius.

[0176] Intermediate 1 (S)-4-(Difluoromethyl)oxazolidin-2-one

[0177] [ka]

[0178] Step 1: Preparation of (R)-3-benzyl-4-(hydroxymethyl)oxazolidin-2-one

[0179] [ka]

[0180] (R)-Oxapropan-2-ylmethanol (3.7 g, 50.0 mmol) and (isocyanatomethyl)benzene (6.66 g, 50.0 mmol) were mixed in dichloromethane (50 mL). The reaction solution was warmed to 45° C. under a nitrogen atmosphere and stirred overnight. After cooling, 100 mL of saturated aqueous sodium bicarbonate solution was added, and the reaction solution was extracted with dichloromethane (100 mL × 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography to give the title compound, (R)-3-benzyl-4-(hydroxymethyl)oxazolidin-2-one (4.14 g, 40%). MS m / z(ESI):208.2[M+H] + .

[0181] Step 2: Preparation of (S)-3-benzyl-4-(dihydroxymethyl)oxazolidin-2-one

[0182] [ka]

[0183] (R)-3-benzyl-4-(hydroxymethyl)oxazolidin-2-one (4.14 g, 20.0 mmol) and IBX (16.8 g, 60.0 mmol) were mixed in ethyl acetate (100 mL), and the reaction solution was stirred at 85° C. under a nitrogen atmosphere for 3 hours. After cooling, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give 4.46 g of crude product, (S)-3-benzyl-4-(dihydroxymethyl)oxazolidin-2-one, which was used directly in the next step. MS m / z(ESI):224.2[M+H] + .

[0184] Step 3: Preparation of (S)-3-benzyl-4-(difluoromethyl)oxazolidin-2-one

[0185] [ka]

[0186] (S)-3-benzyl-4-(dihydroxymethyl)oxazolidin-2-one (4.46 g, 20.0 mmol) was dissolved in dichloromethane (100 mL). DAST (6.45 g, 40.0 mmol) was added dropwise in an ice bath under a nitrogen atmosphere, and the reaction solution was allowed to warm to room temperature and react for 3 hours. The reaction solution was slowly added dropwise to a pre-cooled saturated aqueous sodium bicarbonate solution and extracted with dichloromethane (200 mL × 2). The organic phases were combined, concentrated under reduced pressure, and subjected to column chromatography to obtain the title compound, (S)-3-benzyl-4-(difluoromethyl)oxazolidin-2-one (1.82 g, 40% yield over two steps). MS m / z(ESI):228.2[M+H] + .

[0187] Step 4: Preparation of (S)-4-(difluoromethyl)oxazolidin-2-one

[0188] [ka]

[0189] (S)-3-Benzyl-4-(difluoromethyl)oxazolidin-2-one (1.82 g, 8 mmol) was dissolved in ethanol (100 mL). Pd(OH)2 / C (300 mg) was added, and the reaction solution was stirred overnight at 70 °C under a hydrogen atmosphere. The reaction solution was cooled and filtered. The filtrate was concentrated under reduced pressure to give the title compound, (S)-4-(difluoromethyl)oxazolidin-2-one (0.88 g, 80%). 1 H NMR (400 MHz, CDCl3) δ 4.05-4.18 (m, 1H), 4.39-4.45 (m, 1H), 4.54 (t, J = 9.3 Hz, 1H), 5.78 (td, J = 55.3, 4.7 Hz, 1H), 6.07 (s, 1H); MS m / z (ESI): 138.1 [M+H] + .

[0190] Intermediate 2 9-Bromo-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine Step 1: Preparation of 5-bromo-2-(1H-imidazol-2-yl)phenol

[0191] [ka]

[0192] To a solution of 4-bromo-2-hydroxybenzaldehyde (24.0 g, 119 mmol) in methanol (250 mL) was added an aqueous solution of glyoxal (40% by weight, 87 g, 597 mmol). Then, an aqueous solution of ammonia (28% by weight, 121 g, 860 mmol) was slowly added dropwise to the reaction solution in a water bath under stirring. The dropwise addition process continued for 30 minutes, and the temperature of the reaction solution was controlled so as not to exceed 40°C. The mixture was then stirred at 35°C for 2 days, cooled, and concentrated under reduced pressure to remove the organic solvent, yielding the crude product, 5-bromo-2-(1H-imidazol-2-yl)phenol, which was used directly in the next step. MS m / z (ESI): 239.0 [M + H] + .

[0193] Step 2: Preparation of 9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine

[0194] [ka]

[0195] The crude product, 5-bromo-2-(1H-imidazol-2-yl)phenol (approximately 29 g, 119 mmol), cesium carbonate (158 g, 485 mmol), and 1,2-dibromoethane (42 mL, 485 mmol) were mixed in DMF (250 mL). The reaction solution was stirred at 85 °C overnight, cooled, and diluted with a large amount of ethyl acetate. The organic phase was washed several times with saturated brine, then dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography to obtain the title compound, 9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (12.5 g, 38% yield over two steps). MS m / z (ESI): 265.0 [M + H] + .

[0196] Step 3: Preparation of 9-bromo-2,3-diiodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine

[0197] [ka]

[0198] To a solution of 9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (11.7 g, 44.1 mmol) in DMF (150 mL) was added NIS (29.8 g, 132 mmol) in a batchwise manner at room temperature. The reaction solution was stirred at 60 °C overnight, cooled, and then water was added to precipitate a solid. After filtration, the solid was dissolved in ethyl acetate, washed successively with 1 M aqueous NaOH and saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound, 9-bromo-2,3-diiodo-5,6-dihydrobenzene[f]imidazo[1,2-d][1,4]oxazepine (22.5 g, 98.7% yield). MS m / z(ESI):516.7[M+H] + .

[0199] Step 4: Preparation of 9-bromo-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine

[0200] [ka]

[0201] To a solution of 9-bromo-2,3-diiodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (21.0 g, 40.6 mmol) in THF (140 mL) was added EtMgBr (1.0 M solution in THF, 60.9 mL, 60.9 mmol) slowly dropwise at −20° C. After the dropwise addition was complete, the reaction solution was stirred at −15° C. for 3 hours. The reaction solution was allowed to warm slowly to room temperature, and then saturated aqueous ammonium chloride solution was added dropwise. The reaction solution was stirred for 15 minutes and extracted several times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and subjected to column chromatography to give the title compound 9-bromo-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (12.5 g, yield: 79%). MS m / z(ESI):390.9[M+H] + .

[0202] Step 5: Preparation of (S)-3-(9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-4-(difluoromethyl)oxazolidin-2-one

[0203] [ka]

[0204] 9-Bromo-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (300 mg, 0.77 mmol), (S)-4-(difluoromethyl)oxazolidin-2-one (105 mg, 0.77 mmol), (1R,2R)-N 1 ,N 2 A mixture of 1,2-dimethylcyclohexane-1,2-diamine (43 mg, 0.30 mmol), copper acetate (27 mg, 0.15 mmol), and cesium carbonate (489 mg, 1.5 mmol) was mixed in 2-methyltetrahydrofuran (6 mL). The reaction system was purged with nitrogen three times and the reaction was carried out at 78 °C for 22 hours. The reaction solution was cooled to room temperature, and 15% aqueous ammonia was added. The reaction solution was stirred for 5 minutes and extracted three times with EtOAc. The organic phases were combined and then washed with saturated aqueous sodium chloride. The filtrate was dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the organic solvent, and then subjected to column chromatography to obtain the title compound, (S)-3-(9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-4-(difluoromethyl)oxazolidin-2-one (186 mg, 61%). 1 H NMR (400 MHz, CDCl3) δ 4.35-4.41 (m, 2H), 4.44-4.52 (m, 2H), 4.53-4.55 (m, 1H), 4.73-4.76 (m, 1H), 4.89-4.91 (m, 1H), 6.62-6.71 (m, 1H), 7.19-7.28 (m, 2H), 7.30 (s, 1H), 8.21 (d, J = 8.6 Hz, 1H); MS m / z (ESI): 400.1 [M+H] + .

[0205] Example 1 Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-3-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide

[0206] [ka]

[0207] Step 1: Preparation of 9-bromo-3-fluoro-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine

[0208] [ka]

[0209] To a solution of LDA (1.28 mL, 2.56 mmol) in tetrahydrofuran (10 mL), a solution of 9-bromo-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (500 mg, 1.28 mmol) in tetrahydrofuran (10 mL) was added dropwise at −78° C. After completion of the dropwise addition, the reaction solution was stirred at −78° C. for 30 minutes. A solution of N-fluorobenzenesulfonamide (806 mg, 2.56 mmol) in tetrahydrofuran (9 mL) was added dropwise, and the reaction solution was stirred at this temperature for 30 minutes. The reaction was quenched with saturated aqueous ammonium chloride solution. The reaction solution was extracted with dichloromethane (100 mL × 2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and subjected to column chromatography to give the title compound 9-bromo-3-fluoro-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (150 mg, 29%). 1H NMR (400 MHz, DMSO-d6) δ 4.31-4.34 (m, 2H), 4.43-4.48 (m, 2H), 7.19-7.34 (m, 2H), 8.17 (d, J = 8.6 Hz, 1H); MS m / z (ESI): 408.9 [M+H] + .

[0210] Step 2: Preparation of (S)-3-(9-bromo-3-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-4-(difluoromethyl)oxazolidin-2-one

[0211] [ka]

[0212] 9-Bromo-3-fluoro-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (100 mg, 0.24 mmol), (S)-4-(difluoromethyl)oxazolidin-2-one (33.5 mg, 0.24 mmol), (1R,2R)-N 1 ,N 2

[0043] 1,2-Dimethylcyclohexane-1,2-diamine (35 mg, 0.24 mmol), cuprous iodide (46 mg, 0.24 mmol), and potassium phosphate (155 mg, 0.73 mmol) were mixed in dimethyl sulfoxide (10 mL), and the reaction was carried out at 130 °C for 3 hours. The reaction solution was cooled to room temperature, and 15% aqueous ammonia was added. The reaction solution was stirred for 5 minutes and extracted three times with EtOAc. The organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography to obtain the title compound, (S)-3-(9-bromo-3-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-4-(difluoromethyl)oxazolidin-2-one (21 mg, 20%). 1H NMR (400 MHz, CDCl3) δ 4.25-4.29 (m, 1H), 4.42-4.50 (m, 2H), 4.56-4.69 (m, 4H), 6.16-6.35 (m, 1H), 7.20-7.25 (m, 2H), 8.15 (d, J = 8.4Hz, 1H); MS m / z (ESI): 417.9 [M+H] + .

[0213] Step 3: Preparation of (2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-3-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-L-alanine

[0214] [ka]

[0215] ((S)-3-(9-Bromo-3-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-4-(difluoromethyl)oxazolidin-2-one (21 mg, 0.05 mmol), L-alanine (13.5 mg, 0.15 mmol), cuprous iodide (4.8 mg, 0.025 mmol), and potassium phosphate (21 mg, 0.1 mmol) were mixed in dimethyl sulfoxide (3 mL). The reaction was purged with nitrogen three times and the reaction was carried out at 100°C for 5 hours. The reaction solution was cooled to room temperature and used directly in the next step without further treatment. MS m / z(ESI):427.1[M+H] + .

[0216] Step 4: Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-3-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide

[0217] [ka]

[0218] To the crude reaction solution of (2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-3-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-L-alanine from the previous step, ammonium chloride (16 mg, 0.29 mmol) and triethylamine (76 mg, 0.75 mmol) were added. After stirring for 5 minutes, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (166 mg, 0.44 mmol) was added. The reaction solution was stirred at room temperature for 2 hours and filtered. Saturated aqueous sodium bicarbonate solution was added to the filtrate, followed by extraction three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the organic solvent, and then subjected to column chromatography separation to obtain the title compound (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-3-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide (8.5 mg, 39%). 1 H NMR (400 MHz, CDCl3) δ 1.55 (d, J = 7.0 Hz, 3H), 3.70-3.87 (m, 1H), 4.21 (d, J = 3.6 Hz, 2H), 4.43 (d, J = 5.2 Hz, 2H), 4.57-4.66 (m, 2H), 5.35 (s, 1H), 6.10-6.27 (m, 2H), 6.37-6.50 (m, 2H), 8.07 (d, J = 8.6 Hz, 1H). MS m / z (ESI): 426.1 [M+H] + .

[0219] Example 2 Preparation of (S)-1-(2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-3-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide

[0220] [ka]

[0221] (S)-1-(2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-3-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide was prepared by referring to the method of Example 1. MS m / z(ESI):452.1[M+H] + .

[0222] Example 3 Preparation of (S)-2-((3-chloro-2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide

[0223] [ka]

[0224] (S)-2-((3-chloro-2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was prepared by referring to the method of Example 1. 1H NMR (400 MHz, CD3OD) δ 1.46 (d, J = 7.0 Hz, 3H), 3.80-3.86 (m, 1H), 4.29-4.32 (m, 2H), 4.43-4.46 (m, 2H), 4.57-4.67 (m, 3H), 6.07-6.31 (m, 2H), 6.43-6.46 (m, 1H), 7.98 (d, J = 8.8 Hz, 1H); MS m / z (ESI): 442.1 [M+H] + .

[0225] Example 4 Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-3-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide

[0226] [ka]

[0227] Step 1: Preparation of 5-bromo-2-(5-methyl-1H-imidazol-2-yl)phenol

[0228] [ka]

[0229] To a solution of 4-bromo-2-hydroxybenzaldehyde (5 g, 119 mmol) in methanol (100 mL) was added an aqueous solution of methylglyoxal (40% by weight, 80 mL). Then, an aqueous ammonia solution (28% by weight, 40 g) was slowly added dropwise under stirring in a water bath. The dropwise addition process continued for 30 minutes, and the temperature of the solution was controlled not to exceed 40°C. The reaction solution was then stirred at 75°C for 2 hours, and then cooled to room temperature to precipitate a solid, which was filtered to give the title compound, 5-bromo-2-(5-methyl-1H-imidazol-2-yl)phenol (3.6 g, 57%). MS m / z (ESI): 253.0 [M + H] + .

[0230] Step 2: Preparation of 9-bromo-3-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine

[0231] [ka]

[0232] 5-Bromo-2-(5-methyl-1H-imidazol-2-yl)phenol (2.5 g, 9.8 mmol), cesium carbonate (12.2 g, 37.5 mmol), and 1,2-dibromoethane (42.0 mL, 37.5 mmol) were mixed in DMF (30 mL), and the reaction solution was stirred at 85 °C overnight. The reaction solution was cooled to room temperature and diluted with a large amount of ethyl acetate. The organic phase was washed several times with saturated brine, then dried over sodium sulfate, concentrated, and subjected to column chromatography to obtain the title compound, 9-bromo-3-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (0.92 g, 33%). 1 H NMR (400 MHz, CDCl3) δ 2.25 (s, 3H), 4.12-4.29 (m, 2H), 4.40-4.53 (m, 2H), 6.94 (s, 1H), 7.14-7.18 (m, 1H), 7.20-7.22 (m, 1H), 8.37 (d, J = 8.6 Hz, 1H); MS m / z (ESI): 279.1 [M+H] + .

[0233] Step 3: Preparation of 9-bromo-2-iodo-3-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine

[0234] [ka]

[0235] 9-Bromo-2-iodo-3-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine was prepared by referring to the method of Example 1. MS m / z(ESI):404.9[M+H] + .

[0236] Step 4: Preparation of (S)-3-(9-bromo-3-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-4-(difluoromethyl)oxazolidin-2-one

[0237] [ka]

[0238] (S)-3-(9-bromo-3-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-4-(difluoromethyl)oxazolidin-2-one was prepared by referring to the method of Example 1. MS m / z(ESI):414.0[M+H] + .

[0239] Step 5: Preparation of (2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-3-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-L-alanine

[0240] [ka]

[0241] (2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-3-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-L-alanine was prepared by referring to the method of Example 1. MS m / z(ESI):423.1[M+H] +.

[0242] Step 6: Synthesis of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-3-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide

[0243] [ka]

[0244] (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-3-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was prepared by referring to the method of Example 1. 1 H NMR (400 MHz, CD3OD) δ 1.37 (d, J = 7.0 Hz, 3H), 2.08 (s, 3H), 3.68-3.75 (m, 1H), 4.18-4.24 (m, 2H), 4.32-4.35 (m, 2H), 4.45-4.61 (m, 3H), 6.10 (m, 2H), 6.34 (d, J = 8.8 Hz, 1H), 7.83 (d, J = 8.8 Hz, 1H). MS m / z (ESI): 422.2 [M+H] + .

[0245] Example 5 Preparation of (S)-1-(2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-3-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide

[0246] [ka]

[0247] (S)-1-(2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-3-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide was prepared by referring to the method of Example 4. MS m / z(ESI):448.2[M+H] + .

[0248] Example 6 Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-3-(trifluoromethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide

[0249] [ka]

[0250] (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-3-(trifluoromethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was prepared by referring to the method of Example 4. MS m / z(ESI):476.1[M+H] + .

[0251] Example 7 Preparation of (S)-2-((3-cyano-2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide

[0252] [ka]

[0253] (S)-2-((3-cyano-2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was prepared by referring to the method of Example 4. MS m / z(ESI):433.1[M+H] + .

[0254] Example 8 Preparation of (S)-1-(3-cyano-2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide

[0255] [ka]

[0256] (S)-1-(3-cyano-2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide was prepared by referring to the method of Example 4. MS m / z(ESI):459.2[M+H] + .

[0257] Example 9 Preparation of (S)-2-((3-cyclopropyl-2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide

[0258] [ka]

[0259] (S)-2-((3-cyclopropyl-2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was prepared by referring to the method of Example 4. MS m / z(ESI):448.2[M+H] + .

[0260] Example 10 Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6,10,11-tetrahydrocyclobuta[5,6]benzo[1,2-f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide

[0261] [ka]

[0262] Step 1: Preparation of 1-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)ethan-1-one

[0263] [ka]

[0264] AlCl3 (3.33 g, 25 mmol) was suspended in nitromethane (25 mL). A solution of bicyclo[4.2.0]octa-1(6),2,4-triene (2.08 g, 20 mmol) and acetyl chloride (1.73 g, 22 mmol) in nitromethane (25 mL) was added dropwise in an ice bath under a N2 atmosphere. The reaction solution was allowed to warm to room temperature and the reaction was carried out overnight. The reaction solution was added to 200 mL of ice water and extracted with DCM (200 mL × 2). The organic phases were combined, concentrated under reduced pressure, and subjected to column chromatography to give the title compound, 1-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)ethan-1-one (800 mg, 27%).

[0265] Step 2: Preparation of 1-(5-bromobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)ethan-1-one

[0266] [ka]

[0267] 1-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)ethan-1-one (731 mg, 5 mmol) was dissolved in acetic acid (20 mL). Bromine (878.9 mg, 5.5 mmol) was added dropwise under a N2 atmosphere, and the reaction was carried out at room temperature for 3 hours. The reaction solution was concentrated, and DCM and saturated aqueous sodium bicarbonate solution were added to the concentrate, and the two phases were separated. The organic phase was concentrated under reduced pressure and then subjected to column chromatography to obtain the title compound, 1-(5-bromobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)ethan-1-one (900 mg, 80%).

[0268] Step 3: Preparation of 5-bromobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl acetate

[0269] [ka]

[0270] 1-(5-Bromobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)ethan-1-one (900 mg, 4 mmol) and m-CPBA (75%, 2.30 g, 10 mmol) were mixed in DCM (20 mL). The reaction solution was refluxed and reacted overnight under a N atmosphere. After cooling to room temperature, the reaction solution was filtered to remove insoluble matter and washed with saturated aqueous sodium bicarbonate. The organic phase was concentrated under reduced pressure and then subjected to column chromatography to obtain the title compound, 5-bromobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl acetate (723 mg, 75%).

[0271] Step 4: Preparation of 5-bromobicyclo[4.2.0]octa-1(6),2,4-trien-3-ol

[0272] [ka]

[0273] 5-Bromobicyclo[4.2.0]octa-1(6),2,4-trien-3-yl acetate (723 mg, 3 mmol) was dissolved in methanol (20 mL). 5N aqueous sodium hydroxide solution (3 mL) was added, and the reaction was carried out at room temperature overnight. 50 mL of water was added, and the pH of the reaction solution was adjusted to 5 with 1N hydrochloric acid. The reaction solution was extracted with DCM (50 mL × 2). The organic phases were combined, concentrated under reduced pressure, and subjected to column chromatography to obtain the title compound, 5-bromobicyclo[4.2.0]octa-1(6),2,4-trien-3-ol (567 mg, 95%).

[0274] Step 5: Preparation of 5-bromo-3-hydroxybicyclo[4.2.0]octa-1(6),2,4-triene-2-carbaldehyde

[0275] [ka]

[0276] 5-Bromobicyclo[4.2.0]octa-1(6),2,4-trien-3-ol (567.2 mg, 2.85 mmol), magnesium chloride (407 mg, 4.28 mmol), and triethanolamine (1.15 g, 11.4 mmol) were added to acetonitrile (5 mL). The reaction solution was heated to 40 °C and reacted for 30 minutes. Paraformaldehyde (770 mg, 8.55 mmol) was added, and the reaction was carried out at 80 °C overnight. After cooling to room temperature, 50 mL of water was added, and the pH of the reaction solution was adjusted to 5 with 4 N hydrochloric acid. The reaction solution was extracted with DCM (50 mL × 2). The organic phases were combined, concentrated under reduced pressure, and subjected to column chromatography to give the title compound 5-bromo-3-hydroxybicycle[4.2.0]octa-1(6),2,4-triene-2-carbaldehyde (517.6 mg, 80%).

[0277] Step 6: Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6,10,11-tetrahydrocyclobuta[5,6]benzo[1,2-f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide

[0278] [ka]

[0279] (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6,10,11-tetrahydrocyclobuta[5,6]benzo[1,2-f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was prepared by referring to the method of Example 1. MS m / z(ESI):434.2[M+H] + .

[0280] Example 11 Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6,10,11-tetrahydrocyclobuta[5,6]benzo[1,2-f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-2-methoxyacetamide

[0281] [ka]

[0282] (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6,10,11-tetrahydrocyclobuta[5,6]benzo[1,2-f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-2-methoxyacetamide was prepared by referring to the method of Example 10. MS m / z(ESI):450.1[M+H] + .

[0283] Example 12 Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6,11,12-tetrahydro-10H-imidazo[1,2-d]indeno[4,5-f][1,4]oxazepin-9-yl)amino)propionamide

[0284] [ka]

[0285] (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6,11,12-tetrahydro-10H-imidazo[1,2-d]indeno[4,5-f][1,4]oxazepin-9-yl)amino)propionamide was prepared by referring to the method of Example 10. MS m / z(ESI):448.1[M+H] + .

[0286] Example 13 Preparation of (S)-2-((11-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-7,8-dihydro-[1,3]dioxazolo[4',5':5,6]benzo[1,2-f]imidazo[1,2-d][1,4]oxazepin-4-yl)amino)propionamide

[0287] [ka]

[0288] (S)-2-((11-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-7,8-dihydro-[1,3]dioxazolo[4',5':5,6]benzo[1,2-f]imidazo[1,2-d][1,4]oxazepin-4-yl)amino)propionamide was prepared by referring to the method of Example 10. MS m / z(ESI):452.1[M+H] + .

[0289] Example 14 Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-3-methylbutanamide

[0290] [ka]

[0291] (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-3-methylbutanamide was prepared by referring to the method of Example 1. 1H NMR (400 MHz, CD3OD) δ 1.09 (t, J = 6.1 Hz, 6H), 2.13 (d, J = 7.0 Hz, 1H), 3.60 (d, J = 6.4 Hz, 1H), 4.38 (d, J = 19.3 Hz, 4H), 4.68-4.60 (m, 3H), 6.27 (s, 1H), 6.43-6.78 (m, 2H), 7.17 (s, 1H), 8.06 (d, J = 8.7 Hz, 1H); MS m / z (ESI): 436.1 [M+H] + .

[0292] Example 15 Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-2-methoxyacetamide

[0293] [ka]

[0294] (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-2-methoxyacetamide was prepared by referring to the method of Example 1. MS m / z(ESI):424.1[M+H] + .

[0295] Example 16 Preparation of (R)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-3-fluoropropionamide

[0296] [ka]

[0297] (R)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-3-fluoropropionamide was prepared by referring to the method of Example 1. MS m / z(ESI):426.1[M+H] + .

[0298] Example 17 Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-2-(oxetan-3-yl)acetamide

[0299] [ka]

[0300] (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-2-(oxetan-3-yl)acetamide was prepared by referring to the method of Example 1. 1 H NMR (400 MHz, CD3OD) δ 3.26-3.33 (m, 2H), 4.08 (d, J = 9.6 Hz, 1H), 4.22-4.25 (m, 2H), 4.29-4.31 (m, 2H), 4.40-4.50 (m, 5H), 4.61-4.69 (m, 1H), 6.18 (d, J = 2.2 Hz, 1H), 6.44-6.50 (m, 2H), 7.06 (s, 1H), 7.97 (d, J = 8.8 Hz, 1H); MS m / z (ESI): 450.1 [M+H] + .

[0301] Example 18 Preparation of (S)-2-((2-(4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-2-methylpropionamide

[0302] [ka]

[0303] (S)-2-((2-(4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-2-methylpropionamide was prepared by referring to the method of Example 1. 1 H NMR (400 MHz, CD3OD) δ 1.50 (s, 6H), 4.31-4.36 (m, 2H), 4.38-4.43 (m, 2H), 4.61-4.65 (m, 2H), 4.95 (d, J = 10.6 Hz, 1H), 6.19 (d, J = 2.2 Hz, 1H), 6.64-6.81 (m, 2H), 7.17 (s, 1H), 8.05 (d, J = 8.8 Hz, 1H); MS m / z (ESI): 422.1 [M+H] + .

[0304] Example 19 Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)(methyl)amino)propionamide

[0305] [ka]

[0306] (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)(methyl)amino)propionamide was prepared by referring to the method of Example 1. 1 H NMR (400 MHz, CD3OD): δ 1.40 (d, J = 6.8 Hz, 3H), 2.90 (s, 3H), 4.37-4.64 (m, 7H), 4.96 (m, 1H), 6.41 (s, 1H), 6.46-6.74 (m, 2H), 7.16 (s, 1H), 8.13 (d, J = 9.2 Hz, 1H); MS m / z (ESI): 422.1 [M+H] + .

[0307] Example 20 Preparation of (S)-3-((2-(4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)oxetane-3-carboxamide

[0308] [ka]

[0309] (S)-3-((2-(4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)oxetane-3-carboxamide was prepared by referring to the method of Example 1. 1H NMR (400 MHz, CD3OD) δ 4.35 (m, 4H), 4.63 (m, 4H), 4.90 (m, 1H), 5.10 (d, J = 8.0 Hz, 2H), 5.90 (s, 1H), 6.29 (d, J = 8.0 Hz, 1H), 6.59 (t, J = 56 Hz, 1H), 7.16 (s, 1H), 8.10 (d, J = 8.0 Hz, 1H); MS m / z (ESI): 436.1 [M+H] + .

[0310] Example 21 Preparation of (S)-1-(2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)azetidine-2-carboxamide

[0311] [ka]

[0312] (S)-1-(2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)azetidine-2-carboxamide was prepared by referring to the method of Example 1. 1 H NMR (400 MHz, CD3OD) δ 2.30-2.40 (m, 1H), 2.52-2.58 (m, 1H), 3.66-3.72 (m, 1H), 3.91-3.96 (m, 1H), 4.22-4.27 (m, 2H), 4.28-4.34 (m, 2H), 4.48-4.59 (m, 2H), 4.79-4.85 (m, 2H), 6.00 (d, J = 2.2 Hz, 1H), 6.20-6.22 (m, 1H), 6.37-6.65 (m, 1H), 7.08 (s, 1H), 8.06 (d, J = 8.7 Hz, 1H). MS m / z (ESI): 420.1 [M+H] + .

[0313] Example 22 Preparation of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide

[0314] [ka]

[0315] Step 1: Preparation of (S)-3-(9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-4-(difluoromethyl)oxazolidine-2-thione

[0316] [ka]

[0317] To a solution of (S)-3-(10-bromo-6,7-dihydro-5H-benzo[b]imidazo[2,1-d][1,5]oxazin-2-yl)-4-(difluoromethyl)oxazolidin-2-one (100 mg, 0.25 mmol) in toluene (10 mL), Lawesson's reagent (1.01 g, 2.5 mmol) was added, and the reaction solution was microwaved at 140 °C for 3 hours. After cooling to room temperature, the reaction solution was filtered. The filter cake was washed with EtOAc (20 mL). The filtrate was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography to give the title compound, (S)-3-(9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-4-(difluoromethyl)oxazolidine-2-thione (42 mg, 40%). 1H NMR (400 MHz, DMSO-d6) δ 4.43-4.52 (m, 4H), 4.79-4.86 (m, 2H), 5.24-5.35 (m, 1H), 6.57-6.85 (m, 1H), 7.23-7.38 (m, 2H), 8.10 (s, 1H), 8.26 (d, J = 8.6 Hz, 1H); MS m / z (ESI): 416.1 [M+H] + .

[0318] Step 2: Preparation of (R)-3-(9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-4-(difluoromethyl)thiazolidin-2-one

[0319] [ka]

[0320] To a solution of (S)-3-(10-bromo-6,7-dihydro-5H-benzo[b]imidazo[2,1-d][1,5]oxazin-2-yl)-4-(difluoromethyl)oxazolidine-2-thione (33 mg, 0.079 mmol) in toluene (1 mL), dichloro(p-methylisopropylphenyl)ruthenium(II) dimer (14.7 mg, 0.024 mmol) and 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl (9.7 mg, 0.024 mmol) were added, and the reaction was carried out under air at 110°C for 12 hours. The reaction solution was cooled to room temperature and diluted with EtOAc. The organic phase was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure and subjected to column chromatography to give the title compound, (R)-3-(9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-4-(difluoromethyl)thiazolidin-2-one (26 mg, 79%). 1H NMR (400 MHz, CDCl3) δ 3.57-3.72 (m, 2H), 4.28-4.41 (m, 2H),4.44-4.47 (m, 2H) 5.14-5.24 (m, 1H), 6.29-6.67 (m, 1H), 7.14-7.25 (m, 2H), 7.42 (s, 1H), 8.21 (d, J = 8.8 Hz, 1H); MS m / z (ESI): 416.1 [M+H] + .

[0321] Step 3: Preparation of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide

[0322] [ka]

[0323] (R)-3-(9-Bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-4-(difluoromethyl)thiazolidin-2-one (26 mg, 0.062 mmol), L-alanine (19.5 mg, 0.22 mmol), cuprous iodide (6 mg, 0.03 mmol), and potassium phosphate (40 mg, 0.19 mmol) were mixed in dimethyl sulfoxide (3 mL). The reaction system was purged with nitrogen three times and the reaction was carried out at 100 °C for 12 h. The reaction solution was cooled to room temperature, and then ammonium chloride (20 mg, 0.37 mmol) and triethylamine (95 mg, 0.94 mmol) were added. The reaction solution was stirred for 5 minutes, and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (212 mg, 0.56 mmol) was added. The reaction solution was stirred at room temperature for 2 hours and filtered. Saturated aqueous sodium bicarbonate solution was added, and the reaction solution was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography to obtain the title compound, (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide (15 mg, 56%). 1 H NMR (400 MHz, CD3OD) δ 1.37 (d, J = 7.2 Hz, 3H), 3.57-3.61 (m, 1H), 3.83-3.87 (m, 2H), 4.33-4.41 (m, 4H), 5.12-5.19 (m, 1H), 6.15-6.17 (m, 1H), 6.47-6.52 (m, 2H), 7.28 (s, 1H), 8.10 (d, J = 8.8 Hz, 1H); MS m / z (ESI): 424.1 [M+H] + .

[0324] Example 23 Preparation of (S)-2-((2-((S)-5-(difluoromethyl)-2-oxoimidazolidin-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide

[0325] [ka]

[0326] (S)-2-((2-((S)-5-(difluoromethyl)-2-oxoimidazolidin-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was prepared by referring to the method of Example 22. MS m / z(ESI):407.2[M+H] + .

[0327] Example 24 Preparation of (S)-2-((2-((S)-5-(difluoromethyl)-3-methyl-2-oxoimidazolidin-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide

[0328] [ka]

[0329] (S)-2-((2-((S)-5-(difluoromethyl)-3-methyl-2-oxoimidazolidin-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was prepared according to Example 22. 1H NMR (400 MHz, CD3OD) δ 1.46 (d, J = 7.0 Hz, 3H), 2.85 (s, 3H), 3.62-3.68 (m, 2H), 3.79-3.85 (m, 1H), 4.27-4.30 (m, 2H), 4.35-4.37 (m, 2H), 4.63-4.69 (m, 1H), 6.17 (d, J = 2.0 Hz, 1H), 6.34-6.62 (m, 2H), 7.05 (s, 1H), 8.01 (d, J = 8.8 Hz, 1H); MS m / z (ESI): 421.2 [M+H] + .

[0330] Example 25 Preparation of (S)-2-((2-((4S,5R)-4-(difluoromethyl)-5-methyl-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide

[0331] [ka]

[0332] Step 1: Preparation of methyl (4S,5R)-5-methyl-2-oxooxazolidine-4-carboxylate

[0333] [ka]

[0334] Methyl L-threonine hydrochloride (500 mg, 2.95 mmol) was dissolved in dichloromethane (15 mL), and the resulting solution was cooled to 0 °C in an ice-water bath. Triphosgene (289 mg, 0.97 mmol) was added, followed by the dropwise addition of a solution of ethylamine (895 mg, 8.84 mmol) in dichloromethane (2 mL). After the addition was complete, the reaction was carried out at 0 °C for 1 hour. Water was added, and the reaction solution was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the organic solvent. The crude product was then purified by column chromatography to give the title compound, methyl (4S,5R)-5-methyl-2-oxooxazolidine-4-carboxylate (251 mg, 53%). MS m / z(ESI):160.1[M+H] + .

[0335] Step 2: Preparation of methyl (4S,5R)-3-benzyl-5-methyl-2-oxooxazolidine-4-carboxylate

[0336] [ka]

[0337] Methyl (4S,5R)-5-methyl-2-oxooxazolidine-4-carboxylate (200 mg, 1.26 mmol) was dissolved in DMF (5 mL), and the resulting solution was cooled to −15° C. NaH (60% in kerosene, 50 mg, 1.26 mmol) was added, and the reaction solution was stirred at this temperature for 1 hour. Benzyl bromide (322 mg, 1.89 mmol) was added, and the reaction solution was stirred for 2 hours. The reaction was quenched by adding water, and the reaction solution was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the organic solvent. The crude product was then purified by column chromatography to give the title compound, methyl (4S,5R)-3-benzyl-5-methyl-2-oxooxazolidine-4-carboxylate (260 mg, 83%). MS m / z(ESI):250.1[M+H] + .

[0338] Step 3: Preparation of (4R,5R)-3-benzyl-4-(hydroxymethyl)-5-methyloxazolidin-2-one

[0339] [ka]

[0340] (4S,5R)-3-benzyl-5-methyl-2-oxooxazolidine-4-carboxylate (260 mg, 1.0 mmol) was dissolved in methanol (5 mL), and the resulting solution was cooled to 0 °C in an ice-water bath. Sodium borohydride (11 mg, 3.1 mmol) was added in batches. The reaction solution was gradually warmed to room temperature, and the reaction was carried out for 2 hours. The reaction solution was concentrated, and the crude product was purified by column chromatography to give the title compound, (4R,5R)-3-benzyl-4-(hydroxymethyl)-5-methyloxazolidin-2-one (180 mg, 78%). MS m / z(ESI):222.1[M+H] + .

[0341] Step 4: Preparation of (4S,5R)-3-benzyl-5-methyl-2-oxooxazolidine-4-carbaldehyde

[0342] [ka]

[0343] (4R,5R)-3-benzyl-4-(hydroxymethyl)-5-methyloxazolidin-2-one (180 mg, 0.81 mmol) and IBX (683 mg, 2.44 mmol) were mixed in ethyl acetate (10 mL), and the reaction was carried out under a nitrogen atmosphere at 85° C. for 3 hours. After cooling, the reaction solution was filtered and concentrated under reduced pressure to give 178 mg of crude product, (4S,5R)-3-benzyl-5-methyl-2-oxooxazolidine-4-carbaldehyde, which was used directly in the next step. MS m / z(ESI):220.2[M+H]+ .

[0344] Step 5: Preparation of (4S,5R)-3-benzyl-4-(difluoromethyl)-5-methyloxazolidin-2-one

[0345] [ka]

[0346] (4S,5R)-3-benzyl-5-methyl-2-oxooxazolidine-4-carbaldehyde (178 mg, 0.81 mmol) was dissolved in dichloromethane (10 mL), and the resulting solution was cooled to 0 °C in an ice-water bath under a nitrogen atmosphere. DAST (262 mg, 1.62 mmol) was added dropwise, and the reaction solution was allowed to warm to room temperature and react for 3 hours. The reaction solution was slowly added dropwise to pre-cooled saturated aqueous sodium bicarbonate solution and extracted with dichloromethane (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the organic solvent, and then subjected to column chromatography to obtain the title compound, (4S,5R)-3-benzyl-4-(difluoromethyl)-5-methyloxazolidin-2-one (110 mg, 56% yield over two steps). 1 H NMR (400 MHz, CDCl3) δ 1.33 (d, J = 6.4 Hz, 3H), 3.27-3.33 (m, 1H), 4.16-4.20 (m, 1H), 4.41-4.64 (m, 1H), 4.91 (d, J = 15.0 Hz, 1H), 5.56-5.88 (m, 1H), 7.27-7.44 (m, 5H); MS m / z (ESI): 242.1 [M+H] + .

[0347] Step 6: Preparation of (4S,5R)-4-(difluoromethyl)-5-methyloxazolidin-2-one

[0348] [ka]

[0349] (4S,5R)-3-benzyl-4-(difluoromethyl)-5-methyloxazolidin-2-one (110 mg, 0.46 mmol) was dissolved in mesitylene (2 mL), followed by the addition of methanesulfonic acid (438 mg, 4.56 mmol). The reaction solution was heated to 135 °C and the reaction was carried out for 5 hours. The reaction solution was cooled to room temperature and slowly added dropwise to pre-cooled saturated aqueous sodium bicarbonate solution, followed by extraction with dichloromethane (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the organic solvent, and subjected to column chromatography separation to obtain 68 mg of crude title compound (4S,5R)-4-(difluoromethyl)-5-methyloxazolidin-2-one, which was used directly in the next step. MS m / z(ESI):152.1[M+H] + .

[0350] Step 7: Preparation of (4S,5R)-3-(9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-4-(difluoromethyl)-5-methyloxazolidin-2-one

[0351] [ka]

[0352] 9-Bromo-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (100 mg, 0.25 mmol), (4S,5R)-4-(difluoromethyl)-5-methyloxazolidin-2-one (38.5 mg, 0.25 mmol), (1R,2R)-N 1 ,N 2

[0044] 1,2-Dimethylcyclohexane-1,2-diamine (22 mg, 0.15 mmol), cuprous iodide (14 mg, 0.08 mmol), and potassium phosphate (108 mg, 0.51 mmol) were mixed in dimethyl sulfoxide (3 mL) and the reaction was carried out at 130 °C for 3 hours. The reaction solution was cooled to room temperature, and 15% aqueous ammonia (5 mL) was added. The reaction solution was stirred for 5 minutes and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the organic solvent. The resulting mixture was then subjected to column chromatography to obtain the title compound, (S)-3-(9-bromo-3-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-4-(difluoromethyl)oxazolidin-2-one (61 mg, 57%). MS m / z(ESI):414.2[M+H] + .

[0353] Step 8: Preparation of (S)-2-((2-((4S,5R)-4-(difluoromethyl)-5-methyl-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide

[0354] [ka]

[0355] (4S,5R)-3-(9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-4-(difluoromethyl)-5-methyloxazolidin-2-one (61 mg, 0.15 mmol), L-alanine (39 mg, 0.44 mmol), cuprous iodide (14 mg, 0.07 mmol), and potassium phosphate (94 mg, 0.44 mmol) were mixed in dimethyl sulfoxide (5 mL). The reaction system was purged with nitrogen three times and the reaction was carried out at 100 °C for 5 h. The reaction solution was cooled to room temperature, and then ammonium chloride (47 mg, 0.88 mmol) and triethylamine (223 mg, 2.21 mmol) were added. The reaction solution was stirred for 5 minutes, and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (505 mg, 1.33 mmol) was added. The reaction solution was stirred at room temperature for 2 hours and filtered. Saturated aqueous sodium bicarbonate solution was added, and the reaction solution was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the organic solvent. The organic phases were then subjected to column chromatography separation to obtain the title compound, (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-6,7-dihydro-5H-benzo[b]imidazo[2,1-d][1,5]oxazin-10-yl)amino)propionamide (33 mg, 53%). 1 H NMR (400 MHz, CD3OD) δ 1.46 (d, J = 6.8 Hz, 3H), 1.53 (d, J = 6.2 Hz, 3H), 3.79-3.85 (m, 1H), 4.32-4.39 (m, 4H), 4.46-4.55 (m, 1H), 4.93-4.95 (m, 1H), 6.17 (s, 1H), 6.39-6.72 (m, 2H), 7.14 (s, 1H), 8.03 (d, J = 8.6 Hz, 1H); MS m / z (ESI): 422.1 [M+H] + .

[0356] Example 26 Preparation of (R)-2-((2-((4S,5R)-4-(difluoromethyl)-5-methyl-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide

[0357] [ka]

[0358] (R)-2-((2-((4S,5R)-4-(difluoromethyl)-5-methyl-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was prepared by referring to the method of Example 25. MS m / z(ESI):422.2[M+H] + .

[0359] Example 27 Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-5,5-dimethyl-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide

[0360] [ka]

[0361] (S)-2-((2-((S)-4-(difluoromethyl)-5,5-dimethyl-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was prepared by referring to the method of Example 25. MS m / z(ESI):436.2[M+H] + .

[0362] Example 28 Preparation of (S)-2-((2-((S)-7-(difluoromethyl)-5-oxo-4-oxa-6-azaspiro[2.4]heptan-6-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide

[0363] [ka]

[0364] (S)-2-((2-((S)-7-(difluoromethyl)-5-oxo-4-oxa-6-azaspiro[2.4]heptan-6-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was prepared by referring to the method of Example 25. MS m / z(ESI):434.2[M+H] + .

[0365] Example 29 Preparation of (S)-2-((2-((S)-8-(difluoromethyl)-6-oxo-2,5-dioxa-7-azaspiro[3.4]octan-7-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide

[0366] [ka]

[0367] (S)-2-((2-((S)-8-(difluoromethyl)-6-oxo-2,5-dioxa-7-azaspiro[3.4]octan-7-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was prepared by referring to the method of Example 25. MS m / z(ESI): 450.2 [M+H]+.

[0368] Example 30 Preparation of (S)-2-((2-((S)-5-(difluoromethyl)-3-methyl-2,4-dioxoimidazolidin-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide

[0369] [ka]

[0370] (S)-2-((2-((S)-5-(difluoromethyl)-3-methyl-2,4-dioxoimidazolidin-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was prepared by referring to the method of Example 1. MS m / z(ESI):435.2[M+H] + .

[0371] Example 31 Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-8-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide

[0372] [ka]

[0373] Step 1: Preparation of 4-bromo-3-fluoro-2-methoxybenzaldehyde

[0374] [ka]

[0375] To a solution of 4-bromo-2,3-difluorobenzaldehyde (2.0 g, 9.05 mmol) in methanol (25 mL), sodium methoxide (733 mg, 13.56 mmol) was added at room temperature, and the reaction was carried out at 65° C. for 2 hours. The reaction solution was concentrated and purified by column chromatography to give 4-bromo-3-fluoro-2-methoxybenzaldehyde (1.78 g, 85%). MS m / z (ESI): 233.0 [M + H] + .

[0376] Step 2: Preparation of 4-bromo-3-fluoro-2-hydroxybenzaldehyde

[0377] [ka]

[0378] To a solution of 4-bromo-3-fluoro-2-methoxybenzaldehyde (1.78 g, 7.67 mmol) in acetic acid (15 mL), hydrobromic acid (8.7 mL, 48%) was added at room temperature, and the reaction was carried out at 120° C. for 16 hours. The reaction solution was cooled and concentrated under reduced pressure. Water and ethyl acetate were then added to the reaction flask, and the two phases were then separated. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the organic solvent, and then purified by column chromatography separation to obtain 4-bromo-3-fluoro-2-hydroxybenzaldehyde (1.12 g, 67%). MS m / z (ESI): 219.0 [M + H] + .

[0379] Step 3: Preparation of 3-bromo-2-fluoro-6-(1H-imidazol-2-yl)phenol

[0380] [ka]

[0381] To a solution (12 mL) of 4-bromo-3-fluoro-2-hydroxybenzaldehyde (1.12 g, 5.14 mmol) in methanol, an aqueous solution of glyoxal (40% by weight, 3.73 g, 25.7 mmol) was added. Then, an aqueous solution of ammonia (28% by weight, 5.14 g, 51.4 mmol) was slowly added dropwise in a water bath under stirring. The dropwise addition process continued for 30 minutes, and the temperature of the reaction solution was controlled so as not to exceed 40°C. The mixture was then stirred at 35°C for 2 days, cooled, concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography to give 3-bromo-2-fluoro-6-(1H-imidazol-2-yl)phenol (1.31 g, 100%). MS m / z (ESI): 257.0 [M + H] + .

[0382] Step 4: Preparation of 9-bromo-8-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine

[0383] [ka]

[0384] 3-Bromo-2-fluoro-6-(1H-imidazol-2-yl)phenol (1.31 g, 5.14 mmol), cesium carbonate (6.3 g, 19.53 mmol), and 1,2-dibromoethane (3.6 g, 19.12 mmol) were mixed in DMF (12 mL), and the reaction solution was stirred at 85 °C overnight. The reaction solution was cooled and diluted with ethyl acetate. The organic phase was washed several times with saturated brine, then dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography to give the title compound, 9-bromo-8-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (995 mg, 69%). MS m / z (ESI): 283.0 [M + H] + .

[0385] Step 5: Preparation of 9-bromo-8-fluoro-2,3-diiodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine

[0386] [ka]

[0387] To a solution of 9-bromo-8-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (995 mg, 3.53 mmol) in DMF (8 mL) was added NIS (2.23 g, 9.88 mmol) at room temperature, and the reaction solution was stirred at 60 °C overnight. The reaction solution was cooled, and water was added to precipitate a solid. After filtration, the solid was dissolved in ethyl acetate, washed successively with 1 M aqueous NaOH and saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound, 9-bromo-8-fluoro-2,3-diiodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (1.79 g, 94%). MS m / z(ESI):534.7[M+H] + .

[0388] Step 6: Preparation of 9-bromo-8-fluoro-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine

[0389] [ka]

[0390] To a solution of 9-bromo-8-fluoro-2,3-diiodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (1.79 g, 3.35 mmol) in THF (10 mL) was slowly added dropwise EtMgBr (1.0 M solution in THF, 1.23 mL, 3.69 mmol) at -20 °C. After the dropwise addition was complete, the reaction solution was stirred at -15 °C for 3 h and slowly warmed to room temperature. Saturated aqueous ammonium chloride solution was then added dropwise. The reaction solution was stirred for 15 min and extracted several times with ethyl acetate. The organic phases were combined and then washed with saturated brine. The organic phase was separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the organic solvent, and subjected to column chromatography separation to give the title compound 9-bromo-8-fluoro-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (610 mg, 45%). MS m / z(ESI):408.9[M+H] + .

[0391] Step 7: Preparation of (S)-4-(difluoromethyl)-3-(8-fluoro-9-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)oxazolidin-2-one

[0392] [ka]

[0393] 9-Bromo-8-fluoro-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (300 mg, 0.74 mmol), (S)-4-(difluoromethyl)oxazolidin-2-one (102 mg, 0.74 mmol), (1R,2R)-N 1 ,N 2

[0047] 1,4-Dimethylcyclohexane-1,2-diamine (42 mg, 0.30 mmol), cuprous iodide (28 mg, 0.15 mmol), and potassium carbonate (205 mg, 1.5 mmol) were mixed in 1,4-dioxane (6 mL). The reaction system was purged with nitrogen three times and the reaction was carried out at 105 °C for 5 hours. The reaction solution was cooled to room temperature, and 15% aqueous ammonia was added. The reaction solution was stirred for 5 minutes and extracted three times with EtOAc. The organic phases were combined, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to obtain the title compound, (S)-4-(difluoromethyl)-3-(8-fluoro)-9-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)oxazolidin-2-one (225 mg, 65%). MS m / z (ESI): 466.0 [M + H] + .

[0394] Then, (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-8-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was prepared by referring to the method of Example 1.

[0395] [ka]

[0396] 1 H NMR (400 MHz, CD3OD) δ 1.50 (d, J = 7.0 Hz, 3H), 3.95-4.01 (m, 1H), 4.36 -4.41 (m, 2H), 4.47-4.53 (m, 2H), 4.57-4.67 (m, 2H), 4.93-4.98 (m, 1H), 6.37-6.42 (m, 1H), 6.44-6.73 (m, 1H), 7.20 (s, 1H),7.87-7.91 (m, 1H); MS m / z (ESI): 426.1 [M+H] +.

[0397] Example 32 Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-11-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide

[0398] [ka]

[0399] (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-11-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was prepared by referring to the method of Example 31. 1 H NMR (400 MHz, CD3OD) δ 1.46 (d, J = 4.0 Hz, 3H), 3.84 (m, 1H), 4.24 (m, 2H), 4.49 (m, 2H), 4.60 (m, 3H), 6.19 (s, 1H), 6.28 (d, J = 8.0 Hz, 1H), 6.49 (t, J = 56 Hz, 1H), 7.30 (s, 1H); MS m / z (ESI): 426.1 [M+H] + .

[0400] Example 33 Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-10-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide

[0401] [ka]

[0402] (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-10-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was prepared by referring to the method of Example 31. 1 H NMR (400 MHz, CD3OD): δ 1.52 (d, J = 6.8 Hz, 3H), 3.86-3.96 (m, 1H), 4.30-4.42 (m, 4H), 4.60-4.69 (m, 3H), 4.91-5.00 (m, 1H), 6.19-6.25 (m, 1H), 6.46-6.76 (m, 1H), 7.18 (s, 1H), 8.04 (d, J = 13.4 Hz, 1H). MS m / z (ESI): 426.1 [M+H] + .

[0403] Example 34 Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-8-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide

[0404] [ka]

[0405] (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-8-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was prepared by referring to the method of Example 31. 1H NMR (400 MHz, CD3OD) δ 1.51 (d, J = 6.9 Hz, 3H), 2.15 (s, 3H), 3.99-4.02 (m, 1H), 4.33-4.37 (m, 2H), 4.43-4.47 (m, 2H), 4.55-4.68 (m, 2H), 4.93-4.97 (m, 1H), 6.36 (d, J = 8.9 Hz, 1H), 6.43-6.71 (m, 1H), 7.19 (s, 1H),7.94 (d, J = 8.8 Hz, 1H); MS m / z (ESI): 422.1 [M+H] + .

[0406] Example 35 Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-11-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide

[0407] [ka]

[0408] (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-11-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was prepared by referring to the method of Example 31. MS m / z(ESI):422.1[M+H] + .

[0409] Example 36 Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-10-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide

[0410] [ka]

[0411] (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-10-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was prepared by referring to the method of Example 31. 1 H NMR (400 MHz, CD3OD): δ 1.52 (d, J = 6.9 Hz, 3H), 2.19 (s, 3H), 3.85-3.93 (m, 1H), 4.25-4.36 (m, 4H), 4.55-4.67 (m, 2H), 4.92-4.96 (m, 1H), 6.09 (s, 1H), 6.43-6.71 (m, 1H), 7.12 (s, 1H), 7.90 (s, 1H). MS m / z (ESI): 422.1 [M+H] + .

[0412] Example 37 Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-8-methoxy-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide

[0413] [ka]

[0414] (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-8-methoxy-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was prepared by referring to the method of Example 31. MS m / z(ESI):438.1[M+H] + .

[0415] Example 38 Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-11-methoxy-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide

[0416] [ka]

[0417] (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-11-methoxy-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was prepared by referring to the method of Example 31. MS m / z(ESI):438.1[M+H] + .

[0418] Example 39 Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-10-methoxy-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide

[0419] [ka]

[0420] (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-10-methoxy-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was prepared by referring to the method of Example 31. MS m / z(ESI):438.1[M+H] + .

[0421] Example 40 Preparation of (S)-2-((8-cyano-2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide

[0422] [ka]

[0423] (S)-2-((8-cyano-2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was prepared by referring to the method of Example 31. MS m / z(ESI):433.1[M+H] + .

[0424] Example 41 Preparation of (S)-2-((11-cyano-2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide

[0425] [ka]

[0426] (S)-2-((11-cyano-2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was prepared by referring to the method of Example 31. MS m / z(ESI):433.1[M+H] + .

[0427] Example 42 Preparation of (S)-2-((10-cyano-2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide

[0428] [ka]

[0429] (S)-2-((10-cyano-2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was prepared by referring to the method of Example 31. MS m / z(ESI):433.1[M+H] + .

[0430] Example 43 Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-3-methoxypropionamide

[0431] [ka]

[0432] (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-3-methoxypropionamide was prepared by referring to the method of Example 1. 1H NMR (400 MHz, CD3OD) δ 3.39 (s, 3H), 3.67-3.76 (m, 2H), 3.94-3.98 (m, 1H), 4.30-4.34 (m, 2H), 4.37-4.41 (m, 2H), 4.57-4.66 (m, 2H), 4.91-4.96 (m, 1H), 6.21-6.25 (m, 1H), 6.43-6.46 (m, 1H), 6.48-6.73 (m, 1H), 7.15 (s, 1H), 8.06 (d, J = 8.8 Hz, 1H); MS m / z (ESI): 438.2 [M+H] + .

[0433] Example 44 Preparation of (2S,3R)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-3-methoxybutanamide

[0434] [ka]

[0435] (2S,3R)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-3-methoxybutanamide was prepared by referring to the method of Example 1. 1H NMR (400 MHz, CD3OD): δ 1.23-1.27 (d, J = 6.9 Hz, 3H), 3.39 (s, 3H), 3.75-3.80 (m, 1H), 3.88-3.93 (m, 1H), 4.29-4.43 (m, 4H), 4.56-4.68 (m, 2H), 4.89-4.98 (m, 1H), 6.22-6.25 (m, 1H), 6.43-6.74 (m, 2H), 7.15 (s, 1H), 8.03-8.08 (d, J = 8.8 Hz, 1H); MS m / z (ESI): 452.2 [M+H] + .

[0436] Example 45 Preparation of (2S,3S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-3-methoxybutanamide

[0437] [ka]

[0438] (2S,3S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-3-methoxybutanamide was prepared by referring to the method of Example 1. MS m / z(ESI):452.2[M+H] + .

[0439] Example 46 Preparation of (S)-2-((2-((S)-2-(difluoromethyl)-5-oxopyrrolidin-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide

[0440] [ka]

[0441] (S)-2-((2-((S)-2-(difluoromethyl)-5-oxopyrrolidin-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was prepared by referring to the method of Example 1. 1 H NMR (400 MHz, DMSO-d6) δ 1.30 (d, J = 8.0 Hz, 3H), 2.20-2.45 (m, 3H), 3.31 (d, J = 8.0 Hz, 1H), 3.76 (t, J = 7.6 Hz, 1H), 4.32-4.36 (m, 4H), 4.69-4.78 (m, 1H), 6.08 (s, 1H), 6.15 (d, J = 8.0 Hz, 1H), 6.41 (d, J = 8.0 Hz, 1H), 6.66 (t, J = 56 Hz, 1H), 7.00 (s, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.40 (s, 1H), 8.00 (d, J = 8.0 Hz, 1H); MS m / z (ESI): 406.2 [M+H] + .

[0442] Example 47 Preparation of (S)-2-((2-((3S,5S)-5-(difluoromethyl)-3-methoxy-2-oxopyrrolidin-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide

[0443] [ka]

[0444] (S)-2-((2-((3S,5S)-5-(difluoromethyl)-3-methoxy-2-oxopyrrolidin-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was prepared by referring to the method of Example 1. 1 H NMR (400 MHz, CD3OD) δ 1.46 (d, J = 7.0 Hz, 3H), 2.10-2.20 (m, 1H), 2.74-2.84 (m, 1H), 3.57 (s, 3H), 3.81 (q, J = 7.0 Hz, 1H), 4.25-4.40 (m, 5H), 4.71-4.84 (m, 1H), 6.13-6.18 (m, 1H), 6.37-6.70 (m, 2H), 7.38 (s, 1H), 8.04 (d, J = 8.8 Hz, 1H); MS m / z (ESI): 436.2 [M+H] + .

[0445] Example 48 Preparation of (S)-2-((2-((3R,5S)-5-(difluoromethyl)-3-methoxy-2-oxopyrrolidin-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide

[0446] [ka]

[0447] (S)-2-((2-((3R,5S)-5-(difluoromethyl)-3-methoxy-2-oxopyrrolidin-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was prepared by referring to the method of Example 1. MS m / z(ESI):436.2[M+H] + .

[0448] Example 49 Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-3-hydroxypropionamide

[0449] [ka]

[0450] (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-3-hydroxypropionamide was prepared by referring to the method of Example 1. 1 H NMR (400 MHz, CD3OD) δ 3.87 (s, 2H), 4.34 (d, J = 4.3 Hz, 2H), 4.37-4.43 (m, 2H), 4.62 (m, 4H), 6.23 (d, J = 2.6 Hz, 1H), 6.41-6.62 (m, 2H), 7.16 (s, 1H), 8.06 (d, J = 8.8 Hz, 1H); MS m / z (ESI): 424.1[M+H] + .

[0451] Example 50 Preparation of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-8-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide

[0452] [ka]

[0453] Step 1: Preparation of 4-bromo-3-fluoro-2-methoxybenzaldehyde

[0454] [ka]

[0455] To a solution of 4-bromo-2,3-difluorobenzaldehyde (2.0 g, 9.05 mmol) in methanol (25 mL), sodium methoxide (733 mg, 13.56 mmol) was added at room temperature. The reaction solution was heated to 65° C. and reacted for 2 hours. The reaction solution was concentrated and purified by column chromatography to obtain 4-bromo-3-fluoro-2-methoxybenzaldehyde (1.78 g, 85%). MS m / z (ESI): 233.0 [M + H] + .

[0456] Step 2: Preparation of 4-bromo-3-fluoro-2-hydroxybenzaldehyde

[0457] [ka]

[0458] To a solution of 4-bromo-3-fluoro-2-methoxybenzaldehyde (1.78 g, 7.67 mmol) in acetic acid (15 mL), hydrobromic acid (8.7 mL, 48%) was added at room temperature. The reaction solution was heated to 120° C. and reacted for 16 hours. The reaction solution was cooled and then concentrated under reduced pressure. Water and ethyl acetate were then added to the reaction flask, and the two phases were then separated. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the organic solvent, and purified by column chromatography separation to obtain 4-bromo-3-fluoro-2-hydroxybenzaldehyde (1.12 g, 67%). MS m / z (ESI): 219.0 [M + H] + .

[0459] Step 3: Preparation of 3-bromo-2-fluoro-6-(1H-imidazol-2-yl)phenol

[0460] [ka]

[0461] To a solution of 4-bromo-3-fluoro-2-hydroxybenzaldehyde (1.12 g, 5.14 mmol) in methanol (12 mL) was added an aqueous glyoxal solution (40% by weight, 3.73 g, 25.7 mmol). Then, an aqueous ammonia solution (28% by weight, 5.14 g, 51.4 mmol) was slowly added dropwise in a water bath under stirring. The dropwise addition process continued for 30 minutes, and the temperature of the reaction solution was controlled not to exceed 40°C. The mixture was then stirred at 35°C for 2 days, cooled, and the organic solvent was removed under reduced pressure. After that, the mixture was purified by column chromatography to obtain 3-bromo-2-fluoro-6-(1H-imidazol-2-yl)phenol (1.31 g, 100%). MS m / z (ESI): 257.0 [M + H] + .

[0462] Step 4: Preparation of 9-bromo-8-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine

[0463] [ka]

[0464] 3-Bromo-2-fluoro-6-(1H-imidazol-2-yl)phenol (1.31 g, 5.14 mmol), cesium carbonate (6.3 g, 19.53 mmol), and 1,2-dibromoethane (3.6 g, 19.12 mmol) were mixed in DMF (12 mL) and stirred at 85 °C overnight. The reaction solution was cooled and diluted with ethyl acetate. The organic phase was washed several times with saturated brine, then dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the organic solvent, and then purified by column chromatography to give the title compound, 9-bromo-8-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (995 mg, 69%). MS m / z (ESI): 283.0 [M + H]+ .

[0465] Step 5: Preparation of 9-bromo-8-fluoro-2,3-diiodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine

[0466] [ka]

[0467] To a solution of 9-bromo-8-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (995 mg, 3.53 mmol) in DMF (8 mL) was added NIS (2.23 g, 9.88 mmol) at room temperature, followed by stirring at 60 °C overnight. After cooling, water was added to precipitate a solid. After filtration, the solid was dissolved in ethyl acetate, washed successively with 1 M aqueous NaOH and saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound, 9-bromo-8-fluoro-2,3-diiodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (1.79 g, 94%). MS m / z(ESI):534.7[M+H] + .

[0468] Step 6: Preparation of 9-bromo-8-fluoro-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine

[0469] [ka]

[0470] To a solution of 9-bromo-8-fluoro-2,3-diiodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (1.79 g, 3.35 mmol) in THF (10 mL) was slowly added dropwise at −20° C. EtMgBr (1.0 M solution in THF, 1.23 mL, 3.69 mmol) was added dropwise. After the dropwise addition was complete, the mixture was stirred at −15° C. for 3 hours and allowed to warm slowly to room temperature. Saturated aqueous ammonium chloride solution was then added dropwise. The reaction solution was stirred for 15 minutes and extracted several times with ethyl acetate. The organic phases were combined and then washed with saturated brine. The organic phase was separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the organic solvent, and subjected to column chromatography to give the title compound 9-bromo-8-fluoro-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (610 mg, 45%). MS m / z(ESI):408.9[M+H] + .

[0471] Step 7: Preparation of (S)-4-(difluoromethyl)-3-(8-fluoro-9-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)oxazolidin-2-one

[0472] [ka]

[0473] 9-Bromo-8-fluoro-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (300 mg, 0.74 mmol), (S)-4-(difluoromethyl)oxazolidin-2-one (102 mg, 0.74 mmol), (1R,2R)-N 1 ,N 2A mixture of 1,2-dimethylcyclohexane-1,2-diamine (42 mg, 0.30 mmol), cuprous iodide (28 mg, 0.15 mmol), and potassium carbonate (205 mg, 1.5 mmol) was mixed in 1,4-dioxane (6 mL). The reaction system was purged with nitrogen three times and the reaction was carried out at 105 °C for 5 hours. The reaction solution was cooled to room temperature, and 15% aqueous ammonia was added. The reaction solution was stirred for 5 minutes and extracted three times with EtOAc. The organic phases were combined, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography to obtain the title compound, (S)-4-(difluoromethyl)-3-(8-fluoro)-9-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)oxazolidin-2-one (225 mg, 65%). MS m / z (ESI): 466.0 [M + H] + .

[0474] Step 8: Preparation of (S)-4-(difluoromethyl)-3-(8-fluoro-9-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)oxazolidine-2-thione

[0475] [ka]

[0476] To a solution of (S)-4-(difluoromethyl)-3-(8-fluoro-9-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazin-2-yl)oxazolidin-2-one (220 mg, 0.47 mmol) in toluene (20 mL) was added Lawesson's reagent (1.92 g, 4.73 mmol). The reaction solution was heated to 145 °C and the reaction was carried out for 6 hours. After cooling to room temperature, the reaction solution was filtered. The filter cake was washed with EtOAc (20 mL). The filtrate was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography to give the title compound (S)-3-(9-bromo-8-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-4-(difluoromethyl)oxazolidine-2-thione (105 mg, 46%). MS m / z(ESI):482.1[M+H] + .

[0477] Step 9: Preparation of (R)-4-(difluoromethyl)-3-(8-fluoro-9-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)thiazolidin-2-one

[0478] [ka]

[0479] To a solution of (S)-3-(9-bromo-8-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-4-(difluoromethyl)oxazolidine-2-thione (105 mg, 0.22 mmol) in toluene (3 mL) was added dichloro(p-methylisopropylphenyl)ruthenium(II) dipolymer (27 mg, 0.045 mmol) and 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl (27 mg, 0.065 mmol). The reaction was carried out under air at 115 °C for 16 hours. The reaction solution was cooled to room temperature and diluted with EtOAc. The organic phase was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography to give the title compound, (R)-4-(difluoromethyl)-3-(8-fluoro-9-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)thiazolidin-2-one (55 mg, 52%). MS m / z(ESI): 482.1 [M+H]+.

[0480] Step 10: Preparation of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-8-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide

[0481] [ka]

[0482] (R)-4-(Difluoromethyl)-3-(8-fluoro-9-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)thiazolidin-2-one (40 mg, 0.083 mmol), L-alanine (15 mg, 0.17 mmol), cuprous iodide (6.3 mg, 0.033 mmol), and potassium phosphate (53 mg, 0.25 mmol) were mixed in dimethyl sulfoxide (3 mL). The reaction was purged with nitrogen three times and heated at 125 °C for 1.5 h. The reaction solution was cooled to room temperature, and then ammonium chloride (27 mg, 0.5 mmol) and DMAP (161 mg, 1.25 mmol) were added. The reaction solution was stirred for 5 minutes, and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (284 mg, 0.75 mmol) was added. The reaction solution was stirred at room temperature for 2 hours and filtered. Saturated aqueous sodium bicarbonate solution was added, and the reaction solution was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to give the title compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-8-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide (7.9 mg, 22%). 1 H NMR (400 MHz, CD3OD) δ 1.49 (d, J = 7.0 Hz, 3H), 3.54-3.60 (m, 1H), 3.76-3.93 (m, 1H), 3.95-4.00 (m, 1H), 4.36-4.40 (m, 2H), 4.47-4.52 (m, 2H), 5.10-5.20 (m, 1H), 6.32-6.62 (m, 2H), 7.32 (s, 1H), 7.85-7.91 (m, 1H); MS m / z (ESI): 442.1 [M+H] + .

[0483] Example 51 Preparation of (S)-2-((2-((R)-4(difluoromethyl)-2-oxothiazolidin-3-yl)-8-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-3-methoxypropionamide

[0484] [ka]

[0485] (S)-2-((2-((R)-4(difluoromethyl)-2-oxothiazolidin-3-yl)-8-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-3-methoxypropionamide was prepared by referring to the method of Example 50. 1 H NMR (400 MHz, CD3OD) δ 3.40 (s, 3H), 3.53-3.60 (m, 1H), 3.69-3.83 (m, 3H), 4.06-4.13 (m, 1H), 4.35-4.41 (m, 2H), 4.47-4.52 (m, 2H), 5.10-5.21 (m, 1H), 6.30-6.60 (m, 2H), 7.32 (s, 1H), 7.89 (d, J = 8.5 Hz, 1H); MS m / z (ESI): 472.1 [M+H] + .

[0486] Example 52 Preparation of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-3-methoxypropionamide

[0487] [ka]

[0488] Step 1: Preparation of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-3-methoxypropionamide

[0489] [ka]

[0490] (R)-3-(9-Bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-4-(difluoromethyl)thiazolidin-2-one (26 mg, 0.062 mmol), O-methyl-L-serine (22 mg, 0.18 mmol), cuprous iodide (6.0 mg, 0.03 mmol), and potassium phosphate (40 mg, 0.19 mmol) were mixed in dimethyl sulfoxide (3 mL). The reaction system was purged with nitrogen three times and the reaction was carried out at 100 °C for 12 h. The reaction solution was cooled to room temperature, and then ammonium chloride (20 mg, 0.37 mmol) and triethylamine (95 mg, 0.94 mmol) were added. The reaction solution was stirred for 5 minutes, and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (212 mg, 0.56 mmol) was added. The reaction solution was stirred at room temperature for 2 hours and filtered. A saturated aqueous solution of sodium bicarbonate was added, and the reaction solution was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the organic solvent, and subjected to column chromatography separation to obtain the title compound, (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-3-methoxypropionamide (13 mg, 46%). 1H NMR (400 MHz, CD3OD) δ 3.39 (s, 3H), 3.53-3.57 (m, 1H), 3.62-3.76 (m, 3H), 3.93-3.98 (m, 1H), 4.16-4.30 (m, 4H), 5.06-5.16 (m, 1H), 6.21-6.23 (m, 1H), 6.28-6.52 (m, 2H), 7.23 (s, 1H), 8.02 (d, J = 8.8 Hz, 1H); MS m / z (ESI): 454.1 [M+H] + .

[0491] Example 53 Preparation of (S)-1-(2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide

[0492] [ka]

[0493] (S)-1-(2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide was prepared by referring to the method of Example 22. 1 H NMR (400 MHz, DMSO-d6) δ 1.83-1.92 (m, 2H), 2.09-2.15 (m, 1H), 3.72-3.81 (m, 4H), 4.25-4.32 (m, 4H), 5.07-5.15 (m, 1H), 5.93-5.97 (m, 1H), 6.22-6.28 (m, 1H), 6.35-6.65 (s, 1H), 7.00 (s, 1H), 7.26 (s, 1H), 7.35 (s, 1H), 7.99 (d, J = 8.6 Hz, 1H); MS m / z (ESI): 450.1 [M+H]+ .

[0494] Example 54 Preparation of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)(methyl)amino)propionamide

[0495] [ka]

[0496] (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)(methyl)amino)propionamide was prepared by referring to the method of Example 22. 1 H NMR (400 MHz, CD3OD) δ 1.40 (d, J = 7.0 Hz, 3H), 2.90 (s, 3H), 3.53-3.58 (m, 1H), 3.75-3.80 (m, 1H), 4.30-4.44 (m, 4H), 4.46-4.51 (m, 1H), 5.08-5.18 (m, 1H), 6.22-6.41 (m, 2H), 6.51-6.73 (m, 1H),7.28 (s, 1H), 8.11 (d, J = 9.0 Hz, 1H); MS m / z (ESI): 438.1[M+H] + .

[0497] Example 55 Preparation of (2S,3R)-1-(2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-3-methylpyrrolidine-2-carboxamide

[0498] [ka]

[0499] (2S,3R)-1-(2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-3-methylpyrrolidine-2-carboxamide was prepared by referring to the method of Example 1. MS m / z(ESI):448.1[M+H] + .

[0500] Example 56 Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-7-methyl-6,7-dihydro-5H-benzo[f]imidazo[1,2-d][1,4]diazoheptin-9-yl)amino)propionamide

[0501] [ka]

[0502] Step 1: Preparation of 5-bromo-2-(1H-imidazol-2-yl)aniline

[0503] [ka]

[0504] To a solution of 2-amino-4-bromobenzaldehyde (4.9 g, 24.6 mmol) in methanol (50 mL) was added aqueous glyoxal solution (40% by weight, 18 g, 124 mmol). Then, aqueous ammonia solution (28% by weight, 24 g, 172 mmol) was slowly added dropwise under stirring in a water bath. The dropwise addition process continued for 30 minutes, and the temperature of the reaction solution was controlled not to exceed 40°C. The mixture was then stirred at 35°C overnight, cooled, concentrated under reduced pressure, and subjected to column chromatography to obtain the title compound, 5-bromo-2-(1H-imidazol-2-yl)aniline (3.5 g, yield: 60%). MS m / z (ESI): 238.0 [M + H] + .

[0505] Step 2: Preparation of 10-bromo-5,6,7,8-tetrahydrobenzo[c]imidazo[1,2-a][1,5]diazine

[0506] [ka]

[0507] 5-Bromo-2-(1H-imidazol-2-yl)aniline (3.3 g, 14 mmol), 1,2-dibromoethane (1.38 mL, 15.9 mmol), and cesium carbonate (10.4 g, 31.8 mmol) were mixed in N,N-dimethylformamide (50 mL), and the reaction solution was stirred at room temperature for 1.5 hours. Water was added, and the reaction solution was stirred for 5 minutes and extracted three times with EtOAc. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to obtain the title compound, 10-bromo-5,6,7,8-tetrahydrobenzo[c]imidazo[1,2-a][1,5]diazine (1.55 g, yield: 40%). MS m / z (ESI): 278.0 [M + H] + .

[0508] Step 3: Preparation of 9-bromo-2,3-diiodo-6,7-dihydro-5H-benzo[f]imidazo[1,2-d][1,4]diazepine

[0509] [ka]

[0510] To a solution of 10-bromo-5,6,7,8-tetrahydrobenzo[c]imidazo[1,2-a][1,5]diazepine (1.55 g, 5.6 mmol) in DMF (30 mL) was added NIS (3.8 g, 16.8 mmol) in a batchwise manner at room temperature, followed by stirring at 60 °C overnight. After cooling, water was added to precipitate a solid. After filtration, the solid was dissolved in ethyl acetate, washed successively with 1 M aqueous NaOH and saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound, 9-bromo-2,3-diiodo-6,7-dihydro-5H-benzo[f]imidazo[1,2-d][1,4]diazepine (2.6 g, yield: 90.2%). MS m / z(ESI):515.8[M+H] + .

[0511] Step 4: Preparation of 9-bromo-2-iodo-6,7-dihydro-5H-benzo[f]imidazo[1,2-d][1,4]diazepine

[0512] [ka]

[0513] To a solution of 9-bromo-2,3-diiodo-6,7-dihydro-5H-benzo[f]imidazo[1,2-d][1,4]diazepine (2.52 g, 4.9 mmol) in THF (20 mL) was added EtMgBr (1.0 M solution in THF, 10 mL, 10 mmol) slowly dropwise at −20° C. After the dropwise addition was complete, the reaction solution was stirred at −15° C. for 3 h and then allowed to warm slowly to room temperature. Saturated aqueous ammonium chloride solution was added dropwise. The reaction solution was stirred for 15 min and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and then subjected to column chromatography to give the title compound 9-bromo-2-iodo-6,7-dihydro-5H-benzo[f]imidazo[1,2-d][1,4]diazepine (1.52 g, yield: 80%). MS m / z(ESI):389.9[M+H] + .

[0514] Step 5: Preparation of (S)-3-(9-bromo-6,7-dihydro-5H-benzo[f]imidazo[1,2-d][1,4]diazoheptyn-2-yl)-4-(difluoromethyl)oxazolidin-2-one

[0515] [ka]

[0516] 9-Bromo-2-iodo-6,7-dihydro-5H-benzo[f]imidazo[1,2-d][1,4]diazepine (179 mg, 0.46 mmol), (S)-4-(difluoromethyl)oxazolidin-2-one (63 mg, 0.46 mmol), (1R,2R)-N 1 ,N 2

[0044] Dimethylcyclohexane-1,2-diamine (28.4 mg, 0.2 mmol), cuprous iodide (19.0 mg, 0.1 mmol), and potassium carbonate (138 mg, 1.0 mmol) were mixed in 1,4-dioxane (4 mL). The reaction solution was heated to 100 °C and reacted for 5 hours. The reaction solution was cooled to room temperature, and 14% aqueous ammonia was added. The reaction solution was stirred for 5 minutes and extracted three times with EtOAc. The organic phases were combined, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to obtain the title compound, (S)-3-(9-bromo-6,7-dihydro-5H-benzo[f]imidazo[1,2-d][1,4]diazoheptyn-2-yl)-4-(difluoromethyl)oxazolidin-2-one (111 mg, yield: 60%). MS m / z (ESI): 399.1 [M + H] + .

[0517] Step 6: Preparation of (S)-3-(9-bromo-7-methyl-6,7-dihydro-5H-benzo[f]imidazo[1,2-d][1,4]diazoheptyn-2-yl)-4-(difluoromethyl)oxazolidin-2-one

[0518] [ka]

[0519] (S)-3-(9-Bromo-6,7-dihydro-5H-benzo[f]imidazo[1,2-d][1,4]diazoheptyn-2-yl)-4-(difluoromethyl)oxazolidin-2-one (111 mg, 0.28 mmol) was dissolved in methanol (5 mL). A catalytic amount of acetic acid and aqueous formaldehyde (37% aqueous solution, 50 mg, 0.62 mmol) was added, and the reaction solution was stirred at room temperature for 30 minutes. Sodium cyanoborohydride (39 mg, 0.62 mmol) was added. The reaction was carried out at room temperature for 3 hours and then quenched with saturated aqueous ammonium chloride solution. The reaction solution was extracted three times with EtOAc. The organic phases were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to obtain the title compound (S)-3-(9-bromo-7-methyl-6,7-dihydro-5H-benzo[f]imidazo[1,2-d][1,4]diazoheptyn-2-yl)-4-(difluoromethyl)oxazolidin-2-one (81 mg, yield: 70%). MS m / z(ESI):413.1[M+H] + .

[0520] Step 7: Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-7-methyl-6,7-dihydro-5H-benzo[f]imidazo[1,2-d][1,4]diazoheptyn-9-yl)amino)propionamide

[0521] [ka]

[0522] (S)-3-(9-Bromo-7-methyl-6,7-dihydro-5H-benzo[f]imidazo[1,2-d][1,4]diazoheptyn-2-yl)-4-(difluoromethyl)oxazolidin-2-one (49.4 mg, 0.12 mmol), L-alanine (21.4 mg, 0.24 mmol), cuprous iodide (4.6 mg, 0.024 mmol), and potassium phosphate (51.5 mg, 0.24 mmol) were mixed in dimethyl sulfoxide (2 mL) and the reaction was carried out at 100 °C for 5 hours. The reaction solution was cooled to room temperature, and then ammonium chloride (39 mg, 0.72 mmol) and triethylamine (184 mg, 1.8 mmol) were added. The reaction solution was stirred for 5 minutes, and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (418 mg, 1.1 mmol) was added. The reaction solution was stirred at room temperature for 2 hours and filtered. Saturated aqueous sodium bicarbonate solution was added, and the reaction solution was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography to obtain the title compound, (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-7-methyl-6,7-dihydro-5H-benzo[f]imidazo[1,2-d][1,4]diazoheptyn-9-yl)amino)propionamide (20 mg, yield: 40%). 1 H NMR (400 MHz, CD3OD) δ 1.47 (d, J = 7.0 Hz, 3H), 2.95 (s, 3H), 3.43-3.50 (m, 2H), 3.86 (q, J = 7.0 Hz, 1H), 4.15 (t, J = 5.2 Hz, 2H), 4.54-4.67 (m, 2H), 4.90-4.95 (m, 1H), 6.18 (d, J = 2.2 Hz, 1H), 6.27 (dd, J = 8.7, 2.2 Hz, 1H), 6.35-6.68 (m, 1H), 7.16 (s, 1H), 7.84 (d, J = 8.7 Hz, 1H); MS m / z (ESI): 421.1 [M+H] + .

[0523] Example 57 Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-6,7-dihydro-5H-benzo[f]imidazo[1,2-d][1,4]diazoheptyn-9-yl)amino)propionamide

[0524] [ka]

[0525] (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-6,7-dihydro-5H-benzo[f]imidazo[1,2-d][1,4]diazoheptyn-9-yl)amino)propionamide was prepared by referring to the method of Example 56. 1 H NMR (400 MHz, CD3OD) δ 1.45 (d, J = 7.0 Hz, 3H), 3.42-3.49 (m, 2H), 3.78 (q, J = 7.0 Hz, 1H), 4.12-4.18 (m, 2H), 4.54-4.67 (m, 2H), 4.90-4.96 (m, 1H), 5.86 (d, J = 2.3 Hz, 1H), 6.17 (dd, J = 8.8, 2.3 Hz, 1H), 6.32-6.62 (m, 1H), 7.05 (s, 1H), 7.91 (d, J = 8.8 Hz, 1H); MS m / z (ESI): 407.1 [M+H] + .

[0526] Example 58 Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-7-ethyl-6,7-dihydro-5H-benzo[f]imidazo[1,2-d][1,4]diazoheptyn-9-yl)amino)propionamide

[0527] [ka]

[0528] (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-7-ethyl-6,7-dihydro-5H-benzo[f]imidazo[1,2-d][1,4]diazoheptyn-9-yl)amino)propionamide was prepared by referring to the method of Example 56. MS m / z(ESI):435.1[M+H] + .

[0529] Example 59 Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-7-isopropyl-6,7-dihydro-5H-benzo[f]imidazo[1,2-d][1,4]diazoheptyn-9-yl)amino)propionamide

[0530] [ka]

[0531] (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-7-isopropyl-6,7-dihydro-5H-benzo[f]imidazo[1,2-d][1,4]diazoheptyn-9-yl)amino)propionamide was prepared by referring to the method of Example 56. MS m / z(ESI):449.1[M+H] + .

[0532] Example 60 Preparation of (S)-2-((7-cyclopropyl-2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-6,7-dihydro-5H-benzo[f]imidazo[1,2-d][1,4]diazoheptyn-9-yl)amino)propionamide

[0533] [ka]

[0534] (S)-2-((7-cyclopropyl-2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-6,7-dihydro-5H-benzo[f]imidazo[1,2-d][1,4]diazoheptyn-9-yl)amino)propionamide was prepared by referring to the method of Example 56. MS m / z(ESI):447.1[M+H] + .

[0535] Example 61 Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-7-(oxobutan-3-yl)-6,7-dihydro-5H-benzo[f]imidazo[1,2-d][1,4]diazoheptyn-9-yl)amino)propionamide

[0536] [ka]

[0537] (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-7-(oxobutan-3-yl)-6,7-dihydro-5H-benzo[f]imidazo[1,2-d][1,4]diazoheptyn-9-yl)amino)propionamide was prepared by referring to the method of Example 56. MS m / z(ESI):463.1[M+H] + .

[0538] Example 62 Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]thiazepin-9-yl)amino)propionamide

[0539] [ka]

[0540] Step 1: Preparation of 2-(5-bromo-2-fluorophenyl)-1H-imidazole

[0541] [ka]

[0542] 5-Bromo-2-fluorobenzaldehyde (5.0 g, 24.6 mmol) was dissolved in isopropanol / water (25 mL / 25 mL) at room temperature, followed by the addition of ammonium acetate (17.6 g, 221.7 mmol). Glyoxal (4.5 mL, 221.7 mmol) was added dropwise, and the reaction solution was stirred overnight. The reaction solution was diluted with isopropanol, filtered, and then concentrated under reduced pressure. Dichloromethane and water were added to the concentrate, and the two phases were separated. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography to obtain the title compound, 2-(5-bromo-2-fluorophenyl)-1H-imidazole (3.3 g, yield: 56%). 1 H NMR (400 MHz, DMSO-d6) δ 8.16-8.10 (m, 1H), 7.60-7.56 (m, 1H), 7.38-7.33 (m, 1H), 7.27-7.18 (m, 2H). MS m / z (ESI): 241.0[M+H] + .

[0543] Step 2: Preparation of 9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]thiazepine

[0544] [ka]

[0545] 2-(5-Bromo-2-fluorophenyl)-1H-imidazole (2.0 g, 8.4 mmol) was dissolved in N,N-dimethylformamide (10 mL), followed by the addition of sodium hydride (442 mg, 9.2 mmol) in an ice-water bath, and the reaction solution was stirred for 10 minutes. Ethylene sulfide (612 mg, 10.2 mmol) was added. The reaction solution was heated to 95°C and stirred for 6 hours. After cooling to room temperature, saturated aqueous ammonium chloride solution was added to the reaction flask. The reaction solution was extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography to obtain the title compound, 9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]thiazepine (1.0 g, yield: 43%). MS m / z (ESI): 281.0 [M + H] + .

[0546] Step 3: Preparation of 9-bromo-2,3-diiodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]thiazepine

[0547] [ka]

[0548] To a solution of 9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]thiazepine (980 mg, 3.5 mmol) in DMF (20 mL) was added NIS (2.4 g, 10.5 mmol) in a batchwise manner at room temperature, followed by stirring at 60 °C overnight. After cooling, water was added to precipitate a solid. After filtration, the solid was dissolved in ethyl acetate, washed successively with 1 M aqueous NaOH and saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound, 9-bromo-2,3-diiodo-5,6-dihydrobenzene[f]imidazo[1,2-d][1,4]thiazepine (1.6 g, yield: 86%). MS m / z (ESI): 532.8 [M + H] + .

[0549] Step 4: Preparation of 9-bromo-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]thiazepine

[0550] [ka]

[0551] To a solution of 9-bromo-2,3-diiodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]thiazepine (1.6 g, 3.0 mmol) in THF (10 mL) was slowly added dropwise at −20° C. EtMgBr (1.0 M solution in THF, 3.3 mL, 3.3 mmol) was added dropwise. After the dropwise addition was complete, the reaction solution was stirred at −15° C. for 3 hours and then slowly warmed to room temperature. Saturated aqueous ammonium chloride solution was added dropwise. The reaction solution was stirred for 15 minutes and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and then subjected to column chromatography to give the title compound, 9-bromo-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]thiazepine (1.03 g, 85% yield). MS m / z(ESI):406.9[M+H] + .

[0552] Step 5: Preparation of (S)-3-(9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]thiazepin-2-yl)-4-(difluoromethyl)oxazolidin-2-one

[0553] [ka]

[0554] 9-Bromo-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]thiazepine (186.7 mg, 0.46 mmol), (S)-4-(difluoromethyl)oxazolidin-2-one (63 mg, 0.46 mmol), (1R,2R)-N 1 ,N 2

[0044]

[0045]

[0046]

[0047]

[0048] [0049 ... MS m / z(ESI):416.0[M+H] + .

[0555] Step 6: Preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]thiazepin-9-yl)amino)propionamide

[0556] [ka]

[0557] (S)-3-(9-Bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]thiazepin-2-yl)-4-(difluoromethyl)oxazolidin-2-one (49.8 mg, 0.12 mmol), L-alanine (21.4 mg, 0.24 mmol), cuprous iodide (4.6 mg, 0.024 mmol), and potassium phosphate (51.5 mg, 0.24 mmol) were mixed in dimethyl sulfoxide (2 mL) and the reaction was carried out at 100 °C for 5 hours. The reaction solution was cooled to room temperature, and then ammonium chloride (39 mg, 0.72 mmol) and triethylamine (184 mg, 1.8 mmol) were added. The reaction solution was stirred for 5 minutes, and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (418 mg, 1.1 mmol) was added. The reaction solution was stirred at room temperature for 2 hours and filtered. Saturated aqueous sodium bicarbonate solution was added, and the reaction solution was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to obtain the title compound, (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]thiazepin-9-yl)amino)propanamide (18 mg, yield: 35%). 1 H NMR (400 MHz, CDCl3) δ 1.56 (d, J = 7.0 Hz, 3H), 3.44-3.52 (m, 2H), 3.84-3.92 (m, 1H), 4.12-4.21 (m, 2H), 4.48-4.56 (m, 1H), 4.68-4.74 (m, 1H), 4.88-5.02 (m, 1H), 5.36 (s, 1H), 6.40 (s, 1H), 6.45-6.77 (m, 2H), 6.83-6.88 (m, 1H), 7.33 (s, 1H), 7.61 (d, J = 8.4 Hz, 1H); MS m / z (ESI): 424.1 [M+H] + .

[0558] II. Biological Assays and Evaluation of Compounds The present invention will now be further described with reference to the following test examples, which should not be construed as limiting the scope of the invention.

[0559] 1. Determination of the inhibitory effect of compounds according to the present invention on PI3K α / β / γ / δ kinase activity 1.1 Experimental Objectives: The purpose of this example was to test the inhibitory activity of example compounds on PI3K α / β / γ / δ kinase activity.

[0560] 1.2 Experimental equipment: The centrifuge (5810R) was purchased from Eppendorf.

[0561] Pipettes were purchased from Eppendorf or Rainin.

[0562] The microplate reader was purchased from BioTek (USA). Model: SynergyH1 Hybrid Multi-Mode Microplate Reader.

[0563] 1.3 Experimental Method: In this experiment, the ADP-Glo ​​Lipid Kinase Assay (Promega #V9102) manufactured by Promega was used. Lipid kinase PI3Kα / β / γ / δ catalyzed the reaction from ATP to ADP in the presence of substrates PIP2:3PS and ATP. Lipid kinase activity was characterized by measuring the ADP content in the reaction, and the 50% inhibitory concentration (IC) of compounds on PI3Kα / β / γ / δ kinase activity was calculated. 50 obtained.

[0564] The specific experimental process is as follows:

[0565] Kinase reactions were performed in a white 384-well plate (Perkin Elmer #6007299). 2 μL of various concentrations of compound diluted in ddH2O containing 1% DMSO was added to each well, and 2 μL of ddH2O containing 1% DMSO was added to the positive control wells. Next, 2 μL of 0.1-2 nM PI3K kinase solution diluted in 5x kinase buffer (250 mM HEPES, 15 mM MgCl2, 250 mM NaCl, 0.05% BSA) was added to each well, and 2 μL of 5x kinase buffer was added to the negative control wells. 4 μL of 50 μM substrate PIP2:3PS (Promega #V1701) prepared in 10x dilution buffer and ddH2O was added to all wells. Finally, 2 μL of 50-100 μM ATP solution diluted in water was added to initiate the reaction. After the reaction was carried out at room temperature for 90-120 minutes, 10 μL of ADP-Glo ​​reagent (containing 10 mM MgCl) was added to each well and the reaction was carried out at room temperature for 60 minutes to eliminate excess adenosine triphosphate (ATP) in the reaction. Then, 20 μL of kinase detection reagent was added to each well. The reaction was carried out at room temperature in the dark for 20 minutes, after which chemiluminescence was measured using a BioTek Synergy H1 microplate reader.

[0566] [Table 10]

[0567] Experimental data processing method: Percent inhibition data for compound-treated wells was calculated from the positive control wells (DMSO control wells) and negative control wells (no kinase added) on the plate {% inhibition = 100 - [(test compound value - negative control value)] / (positive control value - negative control value) x 100}. IC 50 Values ​​were calculated using GraphPad Prism using a four-parameter nonlinear logistic equation to fit the data for different concentrations and the corresponding % inhibition.

[0568] 1.4 Experimental conclusions: According to the above scheme, the compounds of the examples of the present invention exhibited biological activity in the PI3K α / β / γ / δ kinase activity assay, as shown in Table 7 below.

[0569] [Table 11]

[0570] The above data demonstrate that the compounds of the examples of the present invention have good activity and selectivity in PI3K α / β / γ / δ kinase activity.

[0571] 2. Determination of the growth inhibitory effect of compounds according to the present invention on PI3Kα mutant cancer cells 2.1 Experimental Objectives: The purpose of this example was to test the growth inhibitory activity of the example compounds in PI3Kα mutant cancer cells HCC1954 (H1047R), HGC-27 (E542K), and MKN1 (E545K).

[0572] 2.2 Experimental equipment: The centrifuge (5702R) was purchased from Eppendorf.

[0573] A carbon dioxide incubator was purchased from Thermo.

[0574] The biological safety cabinet was purchased from Shanghai Boxun Company.

[0575] Pipettes were purchased from Eppendorf or Rainin.

[0576] The microplate reader was purchased from BioTek (USA). Model: SynergyH1 Hybrid Multi-Mode Microplate Reader.

[0577] 2.3 Experimental Method: The growth inhibitory effects of example compounds on PI3Kα mutant cancer cell lines (HCC1954, HGC-27, and MKN1) were detected using the Cell Titer-Glo method. Cell lines were cultured in RPMI 1640 medium (Gibco #22400089) containing 10% FBS (Gibco #10091148) and 1% P / S (Hyclone #SV30010) at 37°C and 5% CO2. Cells were harvested before the experiment, and cell density was adjusted after cell counting. Cells were seeded into white 96-well plates (Corning #3610) at a density of 1,000–10,000 cells / well and incubated overnight in an incubator at 37°C and 5% CO2. Different concentrations of prepared compound solutions and corresponding solvent controls were added to the plates. The plate was again incubated in an incubator at 37°C, 5% CO for 48–96 hours. The cell plate and its contents were then equilibrated to room temperature. 20–100 μL of Cell Titer-Glo solution (Promega #G7573) was added to each well, the plate was shaken to mix thoroughly, and then incubated in the dark at room temperature for 5–30 minutes. Chemiluminescence was measured using a BioTek Synergy H1 microplate reader.

[0578] 2.4 Experimental data processing method: Percent inhibition data for compound-treated wells was calculated from the solvent control wells on the plate {% inhibition = 100 - (test compound value - solvent control value) x 100}. IC 50 Values ​​were calculated using GraphPad Prism using a four-parameter nonlinear logistic equation to fit the data for different concentrations and the corresponding % inhibition.

[0579] 2.5 Experimental Conclusions: According to the above scheme, the compounds of the examples of the present invention showed biological activity in the growth inhibitory activity test in PI3Kα mutant cancer cells HCC1954 (H1047R), HGC-27 (E542K), and MKN1 (E545K), as shown in Table 8 below.

[0580] [Table 12]

[0581] The above data show that the compounds of the examples of the present invention have good activity in the growth inhibitory activity test in PI3Kα mutant cancer cells HCC1954 (H1047R), HGC-27 (E542K), and MKN1 (E545K).

[0582] 3. Toxicity study of repeated intragastric administration for 7 days in SD rats 3.1 Purpose of the experiment The purpose of this study was to investigate the possible toxic reactions of GDC-0077, the compounds of Example 22 and Example 62 in SD rats after repeated intragastric administration for 7 days, and to compare the differences in toxicity of GDC-0077, the compounds of Example 22 and Example 62.

[0583] 3.2 Experimental materials and equipment 3.2.1 Test Compounds Test compound 1: GDC-0077 Test compound 2: Compounds of Example 22 and Example 62

[0584] 3.2.2 Vehicle Name: 20% SBE-β-CD (Captisol) aqueous solution

[0585] 3.2.3 Animal Information Species & strain: Sprague-Dawley (SD) rats Animal Grade: SPF Grade Number and sex of animals: 160 rats, half male, half female

[0586] 3.2.4 Equipment An ADVIA® 2120 series hematology system equipped with Autoslide was used for blood cell counting; A SYSMEX CA-500 coagulation analyzer was used to detect indicators of coagulation function; The TBA-120FR automatic biochemical analyzer was used to detect blood biochemical indicators; An Easylyte electrolyte analyzer was used for the detection of electrolytes; Liquid mass spectrometry detector model API4000; Electrospray ionization (ESI) positive ion mode and column type Agilent ZORBAX XDB-C18 (3.5 μm, 2.1×50 mm) were used for bioanalytical detection of plasma samples.

[0587] 3.3 Experimental method 1) In the experiment, 160 rats (80 rats / sex) were divided into 20 groups according to their sex and weight, 100 rats were used for toxicology tests (groups 1-10, 5 rats / sex / group), and 60 rats were used for toxicokinetic tests (groups 11-20, 3 rats / sex / group); 2) As a vehicle control group, animals in groups 1 and 11 were intragastrically administered with 20% aqueous SBE-β-CD (Captisol); 3) Animals in groups 2 and 12, groups 3 and 13, and groups 4 and 14 were intragastrically administered 10, 30, and 60 mg / kg of GDC-0077, respectively; 4) Animals in groups 5 and 15, groups 6 and 16, and groups 7 and 17 were intragastrically administered 10, 30, and 60 mg / kg of the compound of Example 22, respectively; 5) Animals in groups 8 and 18, 9 and 19, and 10 and 20 were intragastrically administered 10, 30, and 60 mg / kg of the compound of Example 62, respectively; 5) Animals were dosed once daily for 7 consecutive days (animals in groups 7, 17, 10, and 20 were dosed for 6 consecutive days). 6) The administration volume was 10 mL / kg. 7) During the experiment, items such as clinical observation, body weight, food intake, clinical pathological index (red blood cell count, coagulation function, blood biochemistry), toxicokinetics, etc. were examined. 8) All animals were euthanized on day 8 (animals in groups 7, 10, 17, and 20 were euthanized after dosing on day 6). 9) During the experiment, gross anatomical observations were performed on animals in groups 1 to 10, animals in groups 17 and 20, and animals that died (including animals in toxicology studies). Histopathological examinations were performed on abnormal tissues, gastrointestinal tissues (e.g., colon, cecum), and immune tissues (e.g., thymus).

[0588] 3.4 Experimental Conclusions At a dose of 30 mg, the mean systemic exposure AUC of the compound of Example 22 after the final dose (male: 11,400 h*ng / mL, female: 15,900 h*ng / mL) was approximately 2.4 to 3.8 times that of GDC-0077 at the same dose (male: 3,000 h*ng / mL, female: 6,510 h*ng / mL) and similar to that of GDC-0077 at 60 mg / kg after the first dose (male: 15,400 h*ng / mL, female: 22,800 h*ng / mL).

[0589] At the 10 mg dose, the mean systemic exposure AUC of the compound of Example 22 after the final administration (male: 2110 h*ng / mL, female: 3170 h*ng / mL) was approximately 1.4 to 2.5 times that of GDC-0077 (male: 845 h*ng / mL, female: 2250 h*ng / mL).

[0590] Thus, the systemic exposure of the compound of Example 22 was significantly higher than that of GDC-0077 at the same dose.

[0591] Under the conditions of this experiment, the test compounds GDC-0077 and Example 22 were repeatedly intragastrically administered to SD rats at doses of 10, 30, and 60 mg / kg for 7 days (once / day). The lethal dose of GDC-0077 and Example 22 was 60 mg / kg, and the maximum tolerated dose (MTD) was 30 mg / kg. At a dose of 30 mg / kg, the C of Example 22 compound was max and AUC (0-24h) The tolerability of the compound of Example 22 was better than that of GDC-0077.

[0592] Under the conditions of this experiment, the test compounds GDC-0077, Example 22, and Example 62 were repeatedly intragastrically administered to SD rats at doses of 10, 30, and 60 mg / kg for 7 days (once / day). max and AUC (0-24h) was significantly higher than that of GDC-0077. The compounds of Example 22 and Example 62 were better tolerated than that of GDC-0077.

[0593] 4. In vivo efficacy test of compounds according to the present invention 4.1 Purpose of the experiment The aim is to screen for compounds with more significant efficacy and lower toxicity and side effects through in vivo efficacy experiments.

[0594] 4.2 Main experimental equipment and materials 4.2.1 Equipment: 1. Biological safety cabinet (BSC-1300II A2, Shanghai Boxun Medical Biological Instrument Corp.) 2. Ultra-clean workbench (CJ-2F, Suzhou Fengshi Laboratory Animal Equipment Co., Ltd.) 3. CO2 incubator (Thermo-311) 4. Centrifuge (Centrifuge 5702R, Eppendorf) 5. Automatic cell counter (Countess II, Life) 6. Pipette (10-20 μL, Eppendorf) 7. Microscope (TS2, Nikon) 8. Vernier caliper with vernier scale (CD-6"AX, Mitutoyo, Japan) 9. Cell culture flasks (T75 / T225, Corning) 10. Electronic balance (CPA2202S, Sartorius)

[0595] 4.2.2 Reagents: 1. RPMI-1640 medium (22400-089, Gibco) 2. Fetal bovine serum (FBS) (10091-148, Gibco) 3. 0.25% trypsin (25200-056, Gibco) 4. Penicillin-streptomycin dual antibiotic (15140-122, Gibco) 5. Phosphate-buffered saline (PBS) (10010-023, Gibco) 6. Matrigel Matrix (356234, Corning)

[0596] 4.2.3 Animals: BALB / c nude mice (6-8 weeks old, female) were purchased from Shanghai Xipuer-Bikai Laboratory Animal Co., Ltd.

[0597] 4.3 Experimental process 4.3.1 Cell culture and cell suspension preparation a. HCC1954 cell line was obtained from a cell bank, recovered using RPMI-1640 medium (RPMI-1640 + 10% FBS + 1% SP), plated in a cell culture flask (the cell type, date, experiment name, etc. were labeled on the flask wall), and cultured in a CO2 incubator (the temperature inside the incubator was 37°C, and the CO2 concentration was 5%). b. When 80-90% of the bottom surface of the culture flask was covered, the cells were passaged. After passage, the cells continued to be cultured in a CO2 incubator. This process was repeated until the number of cells was sufficient for in vivo efficacy testing. c. The cultured cells were collected and counted using an automated cell counter, and then resuspended in PBS and Matrigel matrix according to the counting results to obtain a cell suspension (density 5 × 10 7 / mL) was prepared and placed in an icebox for use.

[0598] 4.3.2 Cell inoculation a. Nude mice were tagged with disposable common ear tags for rats and mice before inoculation. b. During inoculation, the cell suspension was mixed thoroughly. 0.1–1 mL of the cell suspension was drawn into a 1 mL syringe, air bubbles were removed, and the syringe was then placed on an ice pack for use. c) The nude mouse's left hand was tied. The right side of the back near the right shoulder (the inoculation site) was disinfected with 75% alcohol. Inoculation began 30 seconds later. d. Test nude mice were inoculated sequentially (each mouse was inoculated with 0.1 mL of cell suspension).

[0599] 4.3.3 Tumor Measurement, Classification, and Dosing of Tumor-Bearing Mice a. Tumor growth: Tumors were measured 14-18 days after inoculation and tumor size was calculated. Tumor volume calculation: Tumor volume (mm 3 ) = length (mm) x width (mm) x width (mm) / 2 b. Tumor-bearing mice were sorted according to their weight and tumor size in random order. c. The test compound was administered according to the classification results (administration route: oral administration; administration dose: 10 mg / kg; administration volume: 10 mL / kg; administration frequency: once / day; administration cycle: 21 days; vehicle: 0.5% CMC / 1% Tween 80). d. Tumors were measured and weighed twice a week after test compound administration began. e. Animals were euthanized at the end of the experiment. f. Data is processed by using software such as Excel. Calculation of compound tumor growth inhibition rate TGI (%): if tumor does not regress, TGI (%) = [(1-(mean tumor volume of treatment group at the end of administration - mean tumor volume of treatment group at the beginning of administration)) / (mean tumor volume of vehicle control group at the end of treatment - mean tumor volume of vehicle control group at the beginning of treatment)] × 100%. If tumor regresses, TGI (%) = [1-(mean tumor volume of treatment group at the end of administration - mean tumor volume of treatment group at the beginning of administration) / mean tumor volume of treatment group at the beginning of administration] × 100%.

[0600] 4.4 The test data is shown in Table 9 below.

[0601] [Table 13]

[0602] 4.5 Experimental results It can be seen from the above results that the compounds of the present invention have good tumor growth inhibition rates.

[0603] 5. Pharmacokinetic (PK) Assay of Compounds of the Present Invention Examples in Mice Pharmacokinetic assays of preferred compounds of the present invention examples in mice were carried out in male Balb / c mice (Shanghai Jiesijie Laboratory Animal Co., Ltd.).

[0604] 5.1 Route of administration: Single intragastric administration.

[0605] 5.2 Dosage: 5mg / 10ml / kg (body weight).

[0606] 5.3 Formulation: Compounds were dissolved in 0.5% CMC-Na by sonication to obtain a clear solution or homogeneous suspension.

[0607] 5.4 Sampling points: 0.5, 1, 2, 4, 6, 8, and 24 hours after administration

[0608] 5.5 Sampling process: 1) 0.1 mL of orbital blood was collected, placed in a K2-EDTA test tube, and centrifuged at 1000-3000 xg for 5-20 minutes at room temperature to separate the plasma, which was then stored at -80°C. 2) 160 μL of acetonitrile was added to 40 μL of plasma sample for precipitation. After mixing, the sample was centrifuged at 500–2000 × g for 5–20 minutes. 3) 100 uL of the supernatant after treatment was collected and analyzed by LC / MS / MS assay to determine the concentration of the example compound.

[0609] 5.6 LC-MS / MS Assay: Liquid chromatography conditions: Shimadzu LC-20AD pump Mass spectrometry conditions: AB Sciex API 4000 mass spectrometer Chromatography column: phenomenex Gemiu 5μm C18 50×4.6mm Mobile phase: Solution A was 0.1% formic acid in water, and solution B was acetonitrile Flow rate: 0.8mL / min Elution time: 0-4 minutes, gradient elution

[0610] 5.7 Pharmacokinetics The main parameters were calculated using WinNonlin 6.1, and the experimental results of the mouse pharmacokinetic assay are shown in Table 10 below.

[0611] [Table 14]

[0612] The compounds of the examples of the present invention exhibit good metabolic properties, and have plasma exposure AUC and maximum plasma concentration C max The results of the pharmacokinetic assay in mice shown in the table show that both of the above were favorable.

[0613] III. Examination of Salts and Crystalline Forms of (S)-2-((2-((R)-4-(Difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide 1. Screening of salt and crystalline forms of compounds 1.1 Screening of compound salts 1.1.1 Experimental Objective: The goal is to select different counter ionic acids and identify those that can form salts with the compound by a suitable method of crystallization.

[0614] 1.1.2 Experimental steps: 1) Instruments and equipment

[0615] [Table 15]

[0616] 2) The operation procedure (1) THF was used as the solvent in the liquid-liquid reaction for crystallization. 300 mg of the free base was weighed out, 15 mL of THF was added, and the mixture was heated to 50° C. to completely dissolve. The solution of the free base in THF was divided into 8 equal portions, and a specific amount of acid was added to each portion (reaction molar ratio of base:acid=1:1.2), as detailed below.

[0617] [Table 16]

[0618] (2) Acetone was used as the solvent for the solid-liquid reaction for crystallization. 20 mg of the free base was weighed out, 0.2 mL of acetone was added, and the mixture was stirred and suspended at room temperature. Acid (reaction molar ratio of base:acid=1:1.2) was added to the suspension for reaction as detailed below.

[0619] [Table 17]

[0620] (3) Acetone was used as the reaction solvent for crystallization. Approximately 20 mg of the free base was weighed and suspended in 400 μl of acetone at room temperature. The following acids were added for the reaction:

[0621] [Table 18]

[0622] (4) DMF was used as the solvent for crystallization. Approximately 20 mg of the free base was weighed and dissolved in 200 μl of DMF at room temperature to form a clear solution. The following acids were added for the reaction:

[0623] [Table 19]

[0624] (5) Methanol was used as the solvent for crystallization. 20 mg of the free base was weighed out, 0.2 mL of methanol was added, and the mixture was stirred and suspended at 50° C. Acid (reaction molar ratio of base:acid=1:1.2) was added to the suspension for reaction as detailed below.

[0625] [Table 20]

[0626] (6) The salt was prepared using the natural evaporation method. THF was used as the solvent for numbers 1-10, where the free base was dissolved in THF to form a clear solution, followed by the addition of the acid. Ethanol was used as the solvent for numbers 11-14, where the free base was suspended in ethanol, followed by the addition of the acid to form a clear solution. The clear solutions formed in numbers 1-14 were left unsealed at room temperature to allow the solvent to evaporate.

[0627] [Table 21]

[0628] 1.1.3 Experimental results: Through salt form screening experiments, the salt forms obtained in crystalline form were the ethanesulfonate, methanesulfonate, and sulfate salts.

[0629] Screening of crystalline forms of salts of two compounds According to the results of salt formation screening, the preferred crystallization method was selected to screen different crystalline forms of ethanesulfonate, methanesulfonate, and sulfate salts.

[0630] 2.1 Experimental equipment 2.1.1 Some parameters of physical and chemical test equipment

[0631] [Table 22]

[0632] 2.2 Apparatus and conditions for liquid phase analysis 2.2.1 Instruments and Devices

[0633] [Table 23]

[0634] 2.2.2 Chromatography conditions Chromatography column: ZORBAX (SB-C8, 3.5 μm, 4.6*75 mm) Flow rate: 1mL / min Column temperature: 40℃ Detection wavelength: 220 / 328nm Injection volume: 5.0 μL Runtime: 12 minutes Diluent: ACN-water (v / v, 1:1) Mobile phase: A: Water (0.05% trifluoroacetic acid); B: Acetonitrile (0.05% trifluoroacetic acid)

[0635] [Table 24]

[0636] 2.3 Operation procedure (1) Preparation of Crystalline Form A of the Ethanesulfonate Salt of (S)-2-((2-((R)-4-(Difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide 60 mg of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was weighed, 1.2 mL of acetone was added, and the mixture was stirred at 50° C. to form a suspension. 0.18 mL of 1 M ethanesulfonic acid in methanol was added to the system to form a clear solution, which was stirred to precipitate a large amount of solid. Finally, the reaction solution was stirred and reacted at 50°C for 2 hours, then cooled, filtered and dried to finally obtain crystalline form A of the ethanesulfonate salt of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide. After detection and analysis, the XRPD pattern is as shown in Figure 1, the TGA spectrum is as shown in Figure 2, and the DSC spectrum is as shown in Figure 3.

[0637] (2) Preparation of Crystalline Form A of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide Mesylate 60 mg of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was weighed, 3 mL of ethanol was added, and the mixture was stirred at 50° C. to form a suspension. 0.18 mL of 1 M methanesulfonic acid in methanol was added to the system to form a clear solution, and a large amount of solid was rapidly precipitated. Then, 0.6 mL of ethanol was added, and the reaction solution was stirred and reacted at 50° C. for 2 hours, then cooled, filtered, and dried to finally obtain crystalline form A of mesylate salt of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide. After detection and analysis, the XRPD pattern is as shown in FIG. 4.

[0638] (3) Preparation of Crystalline Form B of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide Mesylate 30 mg of crystalline form A of the mesylate salt of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was weighed, and 200 μL of methanol was added. The mixture was slurried at room temperature for 10 days. Finally, the solid was centrifuged and the supernatant was removed. The solid was then dried in a vacuum drying oven at 40° C. to a constant weight to obtain crystalline form B of the mesylate salt of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide. After detection and analysis, the XRPD pattern was as shown in FIG. 5.

[0639] (4) Preparation of Crystalline Form C of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide Mesylate 30 mg of crystalline form A of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide mesylate salt was weighed and allowed to stand at room temperature and 92.5% relative humidity for 3 hours to obtain crystalline form C of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide mesylate salt. After detection and analysis, the XRPD pattern was as shown in FIG. 6.

[0640] (5) Preparation of Crystalline Form A of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide Sulfate 14 mg of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was weighed, and 280 μL of isopropanol was added. The mixture was suspended at 40 °C. 39 μL of 1 M H2SO4 in ethanol was added, resulting in the formation of an oily substance that adhered to the wall. The reaction system was then stirred to precipitate a large amount of solid, which was characterized as amorphous after centrifugation. 200 μL of ethyl acetate was added to the resulting amorphous solid, but no obvious crystals remained even after the mixture was slurried at room temperature. 100 μL of ethanol was then added, completely dissolving the system to form a clear solution. A small amount of methyl tert-butyl ether was added at room temperature, turning the solution cloudy. After stirring, the solid that finally precipitated was crystalline Form A of the sulfate salt of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide. After detection and analysis, the XRPD pattern was as shown in FIG. 7.

[0641] (6) Preparation of Crystalline Form B of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide Sulfate 15 mg of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was weighed out, and 300 μL of isopropanol was added, and the mixture was suspended at room temperature. 42 μL of 1 M H2SO4 in ethanol was added, but no reaction occurred and the free base remained. The mixture was warmed to 50 °C and stirred for 1 hour. After standing at room temperature overnight, no obvious crystals remained. 100 μL of methanol was added, and a small amount of oil formed and adhered to the wall. The mixture was stirred at 50 °C to form a clear solution. A small amount of methyl tert-butyl ether was added, and the solution turned cloudy and was stirred at room temperature for 48 hours, then at 50 °C. After adding 200 μL of methanol and 400 μL of methyl tert-butyl ether, the mixture eventually turned cloudy and a large amount of solid precipitated, which was crystalline form B of the sulfate salt of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide. After detection and analysis, the XRPD pattern was as shown in FIG. 8.

[0642] (7) Preparation of Crystalline Form C of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide Sulfate 23.5 mg of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was weighed, 235 μL of methanol was added, and the mixture was suspended at 50 °C. 66 μL of 1 M H2SO4 in ethanol was added, and the reaction solution turned transparent. 300 μL of methyl tert-butyl ether was added, and the reaction solution turned cloudy. Then, a small amount of crystalline form A of the sulfate salt of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was added to precipitate a large amount of solid. Finally, 400 μL of methanol was added, but the solid did not dissolve. After 1 hour of reaction, 400 μL of methyl tert-butyl ether was added. Finally, the solid was centrifuged and dried to obtain crystalline form C of the sulfate salt of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide. After detection and analysis, the XRPD pattern is as shown in FIG. 9.

[0643] (8) Preparation of Crystalline Form D of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide Sulfate 60 mg of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was weighed, 1.2 mL of methanol was added, and the mixture was stirred at 50 °C to form a suspension. 0.18 mL of 1 M H2SO4 in ethanol was added to the system to form a clear solution. Then, 2.4 mL of methyl tert-butyl ether was added, and the solution became slightly cloudy. Then, a small amount of crystalline form C of the sulfate salt of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was added as a crystal seed. After stirring, a large amount of solid precipitated. Finally, the reaction solution was stirred and reacted at 50°C for 2 hours, then cooled, filtered and dried to finally obtain crystalline form D of the sulfate salt of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide. After detection and analysis, the XRPD pattern is as shown in Figure 10.

[0644] (9) Preparation of Crystalline Form E of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide Sulfate 30 mg of crystalline form D of the sulfate salt of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was weighed, and 200 μL of acetone was added. The mixture was slurried at room temperature for 10 days. Finally, the solid was centrifuged and the supernatant was removed. The solid was then dried in a vacuum drying oven at 40° C. to a constant weight to obtain crystalline form E of the sulfate salt of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide. After detection and analysis, the XRPD pattern was as shown in FIG. 11.

[0645] 3. Solid Stability Experiments 3.1 Experimental Objectives: The objective is to investigate the physicochemical stability of crystalline Form A of the mesylate salt, crystalline Form C of the sulfate salt, and crystalline Form A of the ethanesulfonate salt of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide under accelerated conditions or influencing factors, and to provide a basis for screening salt forms and storage of the compound salts.

[0646] 3.2 Experimental scheme: Approximately 2 mg of crystalline Form A of the mesylate salt, Form C of the sulfate salt, and Form A of the ethanesulfonate salt of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide were placed in a sealed oven at 60°C, in an open container at room temperature under RH 95% (saturated aqueous KNO3 solution), and in a light box (5000 lx ± 500 lx) and observed for 5 and 10 days. The salt content was determined by HPLC using the external standard method. The change in salt-related substances was calculated by normalizing the chromatographic peak areas.

[0647] 3.3 Experimental results: By comparing the liquid chromatograms, it was found that in crystalline form A of the mesylate salt, one new impurity appeared under light conditions for 10 days compared to day 0, with an increase of 0.523%, and the increase in the impurity was less than 0.05% at both 60°C and room temperature under 95% RH for 10 days compared to day 0; in crystalline form C of the sulfate salt, one new impurity appeared under light conditions for 10 days compared to day 0, with an increase of 0.172%, and the increase in the impurity was less than 0.05% at both 60°C and room temperature under 95% RH for 10 days compared to day 0; and in crystalline form A of the ethanesulfonate salt, one new impurity appeared under light conditions for 10 days compared to day 0, with an increase of 0.134%, and the increase in the impurity was less than 0.05% at both 60°C and room temperature under 95% RH for 10 days compared to day 0.

[0648] 3.4 Experimental Conclusions The crystalline form of the salt of the compound is unstable under light conditions and needs to be protected from light during subsequent storage.However, relatively speaking, the salt of the compound and its crystalline form are relatively stable under light conditions.Furthermore, the salt of the compound and its crystalline form are more stable at 60°C and room temperature under RH 95%.

[0649] 4. Hygroscopicity Experiment 4.1 Purpose of the experiment The objective is to investigate and provide a basis for screening the hygroscopicity of crystalline Form A of the mesylate salt, crystalline Form D of the sulfate salt, and crystalline Form A of the ethanesulfonate salt of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide under different relative humidity conditions and storage of the compound salts.

[0650] 4.2 Experimental scheme: Crystalline Form A of the mesylate salt, Crystalline Form D of the sulfate salt, and Crystalline Form A of the ethanesulfonate salt of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide were placed in saturated water vapor at different relative humidities so that the compound and water vapor reached dynamic equilibrium, and the percentage of hygroscopic mass increase of the compound after equilibrium was calculated.

[0651] 4.3 Experimental results: 4.3.1 Hygroscopicity of Crystalline Form A of the Mesylate Salt, Crystalline Form D of the Sulfate Salt, and Crystalline Form A of the Ethanesulfonate Salt of (S)-2-((2-((R)-4-(Difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide 1) Crystalline Form A of the mesylate salt of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide is hygroscopic, with a hygroscopic mass gain of 3.6% at 80% RH. After one cycle of humidification and dehumidification under a relative humidity of 0 to 95%, the XRPD pattern of crystalline form A of the mesylate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide changed, i.e., the crystalline form changed, and the changed crystalline form was crystalline form C of the mesylate salt. 2) Crystalline form D of the sulfate salt of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide is hygroscopic, with a hygroscopic mass gain of 1.256% at 80% RH. 3) Crystalline Form A of the ethanesulfonate salt of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide had a hygroscopic mass gain of 0.207% at 80% RH, exhibiting slight hygroscopicity and no obvious change in hygroscopicity. After one cycle of humidification and dehumidification under a relative humidity of 0 to 95%, the XRPD pattern of crystalline form A of the ethanesulfonate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide did not change, i.e., the crystalline form did not change.

[0652] 5. Solubility Experiment in Different Media 5.1 Purpose of the experiment The objective was to compare the solubility of crystalline form A of the ethanesulfonate salt of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide in media at different pH values: water, simulated gastric fluid (SGF), fasted simulated intestinal fluid (FaSSIF), and fed simulated intestinal fluid (FeSSIF), providing a basis for evaluating the druggability of the salt.

[0653] 5.2 Experimental scheme: Approximately 2 mg of crystalline Form A of the ethanesulfonate salt of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was suspended in different media for 24 hours. The thermodynamic solubility of the compound at 37°C was determined by HPLC using the external standard method.

[0654] 5.3 Experimental results: As shown in Table 15.

[0655] [Table 25]

[0656] 5.4 Experimental Conclusions From the above results of solubility of crystalline form A of the ethanesulfonate salt of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide in different media, it is clear that after salt formation, (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2 It can be seen that (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide had slightly lower solubility in buffered media at pH 4-8, but salt formation increased the solubility of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide in other media, most obviously water.

[0657] 6. Polymorphism screening experiment 6.1 Experimental Objectives: The goal is to find a more stable crystalline form by polymorph screening.

[0658] 6.2 Experimental scheme: The compound was suspended in a solvent system selected from an organic solvent and water having a specific solubility, and the mixture was stirred and slurried at room temperature for one week, followed by centrifugation. The supernatant was discarded, and the solid was dried under vacuum (-0.1 MPa) at 40°C overnight. The XRPD of the solid was then measured and compared with the XRPD of the salt of the compound.

[0659] 6.3 Experimental results: During the course of slurrying, solvent changes for crystallization, crystallization modeling, etc., only crystalline form A of the ethanesulfonic acid salt of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was obtained.

[0660] 7. Animal PK studies 7.1 Experimental Objectives: 7.1.1 The objective is to compare the exposure differences in animals between crystalline Form A of the mesylate salt, crystalline Form D of the sulfate salt, and crystalline Form A of the ethanesulfonate salt of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide in vivo through animal PK studies.

[0661] 7.2 Experimental scheme: 7.2.1 Crystalline Form A of the mesylate salt, Crystalline Form D of the sulfate salt, and Crystalline Form A of the ethanesulfonate salt of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide were homogeneously suspended in an aqueous solution containing 0.5% HPMC (hydroxypropyl methylcellulose) K4M and then intragastrically administered to rats in duplicate at a dose of 30 mg / kg. The amounts of all compounds were converted to the amount of the same compound, (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide.

[0662] 7.3 Experimental results: 7.3.1 The experimental results of PK studies of crystalline Form A of the mesylate salt, crystalline Form D of the sulfate salt, and crystalline Form A of the ethanesulfonate salt of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide are shown below in Table 16.

[0663] [Table 26]

[0664] PK results in rats showed that crystalline form A of the mesylate salt, crystalline form D of the sulfate salt, and crystalline form A of the ethanesulfonate salt of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide all had higher exposure.

[0665] 7.4 Experimental Conclusions Drug exposure in rats can be increased with a salt formulation.

Claims

1. An acid addition salt of formula (II-B) having the structure: 【Chemistry 1】 [In the formula, R1 is C 1～6 Alkyl and -(CH 2 ) n ORcc; R 2 is hydrogen, halogen, and C 1～6 selected from the group consisting of alkyl; R3 is hydrogen and C 1～6 selected from the group consisting of alkyl; R cc is hydrogen and C 1～6 selected from the group consisting of alkyl; M is an inorganic acid or an organic acid, the inorganic acid being selected from the group consisting of hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, and phosphoric acid; the organic acid being selected from the group consisting of 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4-aminobenzoic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, isoascorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, dodecylsulfuric acid, dibenzoic acid, ... zoyltartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactonic acid, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methanesulfonic acid, 1,5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, embonic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanic acid, undecylenic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, and L-malic acid; n is an integer from 0 to 3; x is an integer from 0 to 3; y is an integer from 1 to 5.

2. R1 is methyl, ethyl, propyl, isopropyl, -CH 2 OCH 3 , -(CH 2 ) 2 OCH 3 , -CH(CH 3 )OCH 3 and -C(CH 3 ) 2 OCH3; R2 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, fluorine, chlorine, and bromine; R 3 is selected from the group consisting of hydrogen, methyl, ethyl, and propyl.

2. The acid addition salt of formula (II-B) according to claim 1,

3. R1 is selected from the group consisting of methyl and -CH2OCH3; R 2 is selected from the group consisting of hydrogen and fluorine; R 3 is hydrogen 2. The acid addition salt of formula (II-B) according to claim 1, 4. The acid addition salt of formula (II-B) according to claim 1, wherein y is an integer from 1 to 3.

5. The acid addition salt of formula (II-B) according to claim 1, wherein y is 1.

6. 2. The acid addition salt of formula (II-B) according to claim 1, characterized in that M is selected from the group consisting of sulfuric acid, phosphoric acid, benzenesulfonic acid, cinnamic acid, tartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, fumaric acid, and methanesulfonic acid.

7. The acid addition salt of formula (II-B) according to claim 1, wherein M is selected from the group consisting of sulfuric acid, tartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, fumaric acid, and methanesulfonic acid.

8. The acid addition salt of formula (II-B) according to claim 1, wherein M is selected from the group consisting of sulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, and methanesulfonic acid.

9. The acid addition salt of formula (II-B) according to claim 1, wherein M is ethanesulfonic acid.

10. 2. The acid addition salt of formula (II-B) according to claim 1, characterized in that its specific structure is: 【Chemistry 2】

11. 2. The acid addition salt of formula (II-B) according to claim 1, characterized in that it is the ethanesulfonate, mesylate or sulfate salt of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide.

12. 【Chemical 3】 12. The acid addition salt of formula (II-B) according to claim 11, characterized in that

13. A process for preparing an acid addition salt according to any one of claims 1 to 12, comprising the steps of: 1) weighing out the free base of the compound and adding an organic solvent to obtain a clear or suspended stock solution; 2) adding an acid M to an organic solvent or water to obtain a counterion acid solution; 3) adding a counterion acid solution to the stock solution to obtain a salt solution, stirring the salt solution to precipitate a solid, and drying the solid. The method specifically includes:

14. 13. An acid addition salt of formula (II-B) according to any one of claims 1 to 12, characterized in that it is in crystalline or amorphous form.

15. 13. An acid addition salt of formula (II-B) according to any one of claims 1 to 12, characterized in that it is a hydrate or anhydrous.

16. a crystalline form A of the ethanesulfonate salt of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, having an X-ray powder diffraction pattern having diffraction peaks at 6.8±0.2°, 13.4±0.2°, 14.7±0.2°, and 19.5±0.2° 2θ; or a crystalline form A of the mesylate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, having an X-ray powder diffraction pattern having diffraction peaks at 6.1±0.2°, 7.5±0.2°, 8.0±0.2°, and 14.9±0.2° 2θ; or a crystalline form B of the mesylate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, having an X-ray powder diffraction pattern having diffraction peaks at 2θ of 24.4±0.2°, 13.3±0.2°, 23.8±0.2°, and 20.3±0.2°; or a crystalline form C of the mesylate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, having an X-ray powder diffraction pattern having diffraction peaks at 2θ of 22.5±0.2°, 8.5±0.2°, 7.2±0.2°, and 14.4±0.2°; or a crystalline form A of the sulfate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, having an X-ray powder diffraction pattern having diffraction peaks at 8.4±0.2°, 7.2±0.2°, 20.1±0.2°, and 22.7±0.2° 2θ; or a crystalline form B of the sulfate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, having an X-ray powder diffraction pattern having diffraction peaks at 4.8±0.2°, 7.6±0.2°, 12.2±0.2°, and 14.0±0.2° 2θ; or a crystalline form C of the sulfate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, having an X-ray powder diffraction pattern having diffraction peaks at 2θ of 24.5±0.2°, 13.3±0.2°, 23.9±0.2°, and 9.0±0.2°; or a crystalline form D of the sulfate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, having an X-ray powder diffraction pattern having diffraction peaks at 7.6±0.2°, 22.5±0.2°, 8.9±0.2°, and 15.0±0.2° 2θ; or crystalline form E of the sulfate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, having an X-ray powder diffraction pattern having diffraction peaks at 2θ of 17.7±0.2°, 23.5±0.2°, 24.8±0.2°, and 9.9±0.2°; A crystal of the acid addition salt of formula (II-B) according to claim 14.

17. The crystalline form A of the ethanesulfonate salt of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, having diffraction peaks at 2θ of 20.1±0.2° and 23.9±0.2°; the crystalline form A of the mesylate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, also having diffraction peaks at 2θ of 23.8±0.2° and 8.4±0.2°; the crystalline form B of the mesylate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, also having diffraction peaks at 2θ of 19.7±0.2° and 17.2±0.2°; the crystalline form C of the mesylate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, also having diffraction peaks at 2θ of 26.7±0.2° and 25.3±0.2°; the crystalline form A of the sulfate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, also having diffraction peaks at 2θ of 24.5±0.2° and 25.7±0.2°; the crystalline form B of the sulfate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, also having diffraction peaks at 2θ of 18.5±0.2° and 22.9±0.2°; the crystalline form C of the sulfate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, also having diffraction peaks at 2θ of 17.3±0.2° and 19.4±0.2°; a crystalline form D of the sulfate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, also having diffraction peaks at 2θ of 23.9±0.2° and 26.6±0.2°; or The crystalline form E of the sulfate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, which also has diffraction peaks at 2θ of 22.6±0.2° and 21.2±0.2°. A crystal of the acid addition salt of formula (II-B) according to claim 16.

18. The crystalline form A of the ethanesulfonate salt of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, having diffraction peaks at 2θ of 24.4±0.2° and 25.0±0.2°; the crystalline form A of the mesylate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, also having diffraction peaks at 2θ of 18.8±0.2° and 20.7±0.2°; the crystalline form B of the mesylate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, also having diffraction peaks at 2θ of 26.7±0.2° and 9.0±0.2°; the crystalline form C of the mesylate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, also having diffraction peaks at 2θ of 12.8±0.2° and 16.7±0.2°; the crystalline form A of the sulfate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, also having diffraction peaks at 2θ of 18.9±0.2° and 26.7±0.2°; the crystalline form B of the sulfate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, also having diffraction peaks at 2θ of 23.8±0.2° and 24.9±0.2°; the crystalline form C of the sulfate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, also having diffraction peaks at 2θ of 26.9±0.2° and 20.4±0.2°; a crystalline form D of the sulfate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, also having diffraction peaks at 2θ of 24.6±0.2° and 5.8±0.2°; or The crystalline form E of the sulfate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, which also has diffraction peaks at 2θ of 19.1±0.2° and 29.4±0.2°.

18. A crystal of the acid addition salt of formula (II-B) according to claim 17.

19. The crystalline form A of the ethanesulfonate salt of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, having diffraction peaks at 2θ of 23±0.2° and 23.6±0.2°; the crystalline form A of the mesylate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, also having diffraction peaks at 2θ of 22.3±0.2° and 22.8±0.2°; the crystalline form B of the mesylate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, also having diffraction peaks at 2θ of 23.1±0.2° and 9.9±0.2°; the crystalline form C of the mesylate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, also having diffraction peaks at 2θ of 6.1±0.2° and 12.1±0.2°; the crystalline form A of the sulfate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, also having diffraction peaks at 2θ of 16.4±0.2° and 18.2±0.2°; the crystalline form B of the sulfate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, also having diffraction peaks at 2θ of 9.6±0.2° and 20.4±0.2°; the crystalline form C of the sulfate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, also having diffraction peaks at 2θ of 17.7±0.2° and 9.9±0.2°; a crystalline form D of the sulfate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, also having diffraction peaks at 12.9±0.2 degrees and 19.9±0.2 degrees 2θ; or The crystalline form E of the sulfate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, which also has diffraction peaks at 2θ of 16.9±0.2° and 28.4±0.2°.

19. A crystalline form of the acid addition salt of formula (II-B) according to claim 18, characterized in that 20. The crystalline form A of the ethanesulfonate salt of (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, having diffraction peaks at 2θ of 9.3±0.2° and 17.3±0.2°; the crystalline form A of the mesylate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, also having diffraction peaks at 2θ of 13.5±0.2° and 25.2±0.2; the crystalline form B of the mesylate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, also having diffraction peaks at 2θ of 14.3±0.2° and 21.6±0.2°; the crystalline form C of the mesylate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, also having diffraction peaks at 2θ of 15.2±0.2° and 22.0±0.2°; the crystalline form A of the sulfate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, also having diffraction peaks at 2θ of 22.0±0.2° and 12.6±0.2°; the crystalline form B of the sulfate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, also having diffraction peaks at 2θ of 20.7±0.2° and 26.9±0.2°; the crystalline form C of the sulfate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, also having diffraction peaks at 2θ of 20.0±0.2° and 28.3±0.2°; a crystalline form D of the sulfate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, also having diffraction peaks at 20.7±0.2° and 11.6±0.2° 2θ; or The crystalline form E of the sulfate salt of the compound (S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide, which also has diffraction peaks at 2θ of 17.3±0.2° and 24.5±0.2°.

20. A crystal of the acid addition salt of formula (II-B) according to claim 19.

21. A method for preparing a crystal as defined in any one of claims 14 and 16 to 20, comprising: 1) weighing out an appropriate amount of free base and suspending it in a poor solvent; 2) weighing out an appropriate amount of acid M and dissolving it in an organic solvent; 3) adding the solution of step 2) to the suspension of step 1) and stirring the resulting mixture to allow the solid to precipitate; 4) optionally adding an organic solvent to the solid obtained in step 3) and stirring the resulting mixture to precipitate crystals; 5) Stirring and cooling the mixture, followed by precipitating the crystals to obtain the target product. The method specifically includes:

22. The method of claim 21, wherein the anti-solvent is one or more selected from the group consisting of alcohols, ketones, esters, ethers, benzene, amides, and nitriles; The organic solvent in step 2) is one or more selected from the group consisting of alcohols, esters, hydrocarbons, ketones, ethers, benzene, amides, and nitriles; 22. The method for preparing the crystal according to claim 21, wherein the organic solvent in step 4) is one or more selected from the group consisting of alcohols, esters, and ethers.

23. A method for preparing a crystal as defined in any one of claims 14 and 16 to 20, comprising: 1) weighing out an appropriate amount of a salt of a compound and suspending it in a poor solvent; 2) shaking the suspension obtained above; 3) centrifuging the above suspension, removing the supernatant and vacuum drying the remaining solid to obtain the target product.

24. A method for preparing a crystal as defined in any one of claims 14 and 16 to 20, comprising: Weighing out an appropriate amount of a salt of the compound and exposing the salt of the compound to humidity for a predetermined period of time. The method specifically includes:

25. A method for preparing a crystal as defined in any one of claims 14 and 16 to 20, comprising: 1) weighing out an appropriate amount of free base and suspending it in a poor solvent; 2) weighing out an appropriate amount of acid M and dissolving it in an organic solvent; 3) adding the solution of step 2) to the suspension of step 1) and heating the reaction; 4) optionally adding an organic solvent to the solution of step 3); 5) optionally adding a salt of the compound to the solution of step 4); 6) Cooling the mixture to precipitate crystals The method specifically includes:

26. 21. A pharmaceutical composition comprising a therapeutically effective amount of an acid addition salt according to any one of claims 1 to 12, or a crystal as defined in any one of claims 14 and 16 to 20, and one or more pharma- ceutically acceptable carriers or excipients.

27. The acid addition salt is 【Chemistry 4】 and M is selected from the group consisting of sulfuric acid, tartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, fumaric acid, and methanesulfone.

27. The pharmaceutical composition according to claim 26.

28. The pharmaceutical composition of claim 27, wherein M is ethanesulfonic acid.

29. Use of an acid addition salt as defined in any one of claims 1 to 12, a crystal as defined in any one of claims 14 and 16 to 20, and a pharmaceutical composition as defined in any one of claims 26 to 28 in the preparation of a PI3K inhibitor medicament.

30. The use described in claim 29, wherein the PI3K inhibitor drug is a PI3K alpha inhibitor drug.

31. 30. The use of claim 29 in the preparation of a medicament for treating cancer, bone disease, inflammatory disease, immune disease, nervous system disease, metabolic disease, respiratory disease, and cardiac disease; wherein the cancer is selected from the group consisting of breast cancer, pancreatic cancer, non-small cell lung cancer, thyroid cancer, seminoma, melanoma, bladder cancer, liver cancer, renal cancer, myelodysplastic syndrome, acute myeloid leukemia, and colorectal cancer.

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