RU2835105C1 - Containing derivative with three condensed rings, salt or crystalline form and pharmaceutical composition based thereon - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to acid addition salts of formula (II-B)

where R₁ is methyl; R₂ is hydrogen; R₃ is hydrogen; M is an inorganic acid or an organic acid, where said inorganic acid is sulfuric acid; and said organic acid is selected from the group consisting of ethanesulphonic acid and methanesulphonic acid; x is integer from 0 to 3; and y is integer 1, as well as to their crystalline forms, a method of producing a pharmaceutical composition and the use of an acid addition salt, a crystalline form or a pharmaceutical composition for producing a PI3K (phosphatidyl inositol-3-kinase)-inhibiting drug preparation.

EFFECT: obtaining novel acid addition salts of formula (II-B), which can be used to obtain a PI3K (phosphatidyl inositol-3-kinase)-inhibiting drug preparation.

25 cl, 16 tbl, 62 ex, 11 dwg

Description

AREA OF TECHNOLOGY

The present invention relates to the field of drug synthesis and, in particular, relates to a salt of a derivative of a salt with three condensed rings and its crystalline form, a method for their preparation and their use.

PRIOR ART

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

PI3Kα is activating mutant and amplified in various tumors and is a driver of tumorigenesis. PI3Kα is a heterodimer consisting of a catalytic subunit p110 and a regulatory subunit p85. PI3Kα is activated by receptor tyrosine kinases (RTKs) and G protein-coupled receptors (GPCRs). Once activated, it catalyzes the production of phosphatidylinositol-3-phosphate (PIP3) from phosphatidylinositol-2-phosphate (PIP2), and this PIP3 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 activate PI3Kα, thereby activating downstream proliferation signaling pathways in cells. Abnormal activation of PI3Kα can lead to rapid cell proliferation, thereby inducing tumorigenesis.

PI3Kα is an important target for anticancer drug research and development, but most of the compounds are broad-spectrum PI3K inhibitors, resulting in serious side effects in clinical trials, which seriously limits the development of PI3K inhibitors. Current studies have shown that most of the side effects of broad-spectrum PI3K inhibitors are caused by the inhibition of PI3Kβ, PI3Kδ and PI3Kγ subtypes. Among them, PI3Kβ plays an important role in the mechanism of the side effects of thrombocytopenia and thrombosis. Inhibition of PI3Kδ may lead to immune system disorders. Autoimmune and infectious toxic effects 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 main target that causes the side effect of hypertension. Therefore, the development of highly active and selective PDKα inhibitors can further improve the antitumor effect of PI3Kα inhibitors and reduce or eliminate various serious side effects such as inflammation, thrombocytopenia, hypertension and the like, which are caused by inhibition of other subtypes.

The selective PI3Kα inhibitor BYL-719, developed by Novartis, is currently in a phase III clinical trial, the selective PI3Kα inhibitor MLN1117, developed by Takeda, has entered a phase II clinical trial, and the selective inhibitor GDC-0077, developed by Genentech, is also in a phase I clinical trial.

International applications WO 2010029082 A1 and WO 2011022439 A1 reported compounds related to selective P13Kα inhibitors, but later studies showed that none of the compounds had high cellular activity, which affected their clinical antitumor effects. Therefore, there is an urgent need to develop selective PI3Kα inhibitors with high activity and high selectivity. Selective PI3Kα inhibitors can be used to treat various multiple tumors with PI3Kα activating mutations or amplifications and have great value for clinical application.

In the PCT patent applications (Application Numbers: PCT/CN2019/088788 and PCT/CN2019/104558) of Jiangsu Hansoh Pharmaceutical Group Co., Ltd., a series of structures of inhibitors based on three fused ring derivatives are disclosed. In the subsequent research and development, in order to make the products easy to handle, filter and dry and improve the solubility of the products, and to seek suitable characteristics for easy storage, long-term stability of the product, high bioavailability and the like, the present invention comprehensively studied the salts of the above substances and disclosed the preparation of the most suitable salts and crystal forms.

BRIEF DESCRIPTION OF THE INVENTION

The present invention may incorporate the entire contents of patent applications PCT/CN 2019/088788 and PCT/CN 2019/104558.

The aim of the present invention is to obtain an acid addition salt of formula (I) having the following structure:

Where:

W is selected from the group consisting of -O-, -S- and -NR _aa -;

G is selected from the group consisting of -O-, -S-, -CR _aa R _bb ,- and -NR _aa -;

each of R ₁ and R ₁ ' is selected from the group consisting of 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, -(CH ₂ ) _n R _cc , -(CH ₂ ) _n OR _cc and -CR _aa R _bb OR _cc ;

or R ₁ and R ₁ ' are joined together to form a C _3-8 cycloalkyl or a 3-8 membered heterocyclyl, wherein said C _3-8 cycloalkyl or 3-8 membered heterocyclyl is optionally further substituted with one or more substituents selected from the group consisting of 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 and 5-10 membered heteroaryl;

R ₂ is selected from the group consisting of 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, 5-10-membered heteroaryl and -(CH ₂ ) _n OR _cc ;

or any two R ₂ are joined together to form a C _3-8 cycloalkyl or a 3-8 membered heterocyclyl, wherein said C _3-8 cycloalkyl or 3-8 membered heterocyclyl is optionally further substituted with one or more substituents selected from the group consisting of 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 and 5-10 membered heteroaryl;

each of _R3 and _R3 ' is selected from the group consisting of hydrogen, deuterium, cyano, halogen, nitro, amino, _C1-6 alkyl, _C1-6 haloalkyl, _C1-6 alkoxy, _C1-6 hydroxyalkyl, _C3-8 cycloalkyl, 3-8-membered heterocyclyl, _C6-10 aryl, and 5-10-membered heteroaryl;

or _R3 and _R3 ' are joined together to form oxo, _C3-8 cycloalkyl or 3-8 membered heterocyclyl, wherein said _C3-8 cycloalkyl or 3-8 membered heterocyclyl is optionally further substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, cyano, halogen, nitro, amino, _C1-6 alkyl, _C1-6 haloalkyl, _C1-6 alkoxy, _C1-6 hydroxyalkyl, _C3-8 cycloalkyl, 3-8 membered heterocyclyl, _C6-10 aryl and 5-10 membered heteroaryl;

R ₄ is selected from the group consisting of 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 and 5-10-membered heteroaryl;

R ₅ is selected from the group consisting of hydrogen, deuterium, C _1-6 alkyl and C _1-6 haloalkyl;

or R ₁ or R ₁ ' are joined with R ₅ to form a 3-8 membered heterocyclyl, wherein said 3-8 membered heterocyclyl is optionally further substituted with one or more substituents selected from the group consisting of 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 and 5-10 membered heteroaryl;

each of R _aa , R _bb and R _cc is independently selected from the group consisting of 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 and 5-10-membered heteroaryl;

M is an inorganic acid or an organic acid, wherein said 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 said 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, 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 acids, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid and L-malic acid;

n is an integer between 0 and 3;

x is an integer between 0 and 3; and

y is an integer from 1 to 5, preferably an integer from 1 to 3, and more preferably 1.

In preferred embodiments of the present invention, in the acid addition salt of formula (I)

each of R ₁ and R ₁ ' is selected from the group consisting of hydrogen, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _1-6 haloalkyl, C _1-6 alkoxy, 3- to 8-membered heterocyclyl, -(CH ₂ ) _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- to 6-membered heterocyclyl, -(CH ₂ ) _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, fluorinated methyl, hydroxymethyl, _{oxacyclobutyl, -CH2OCH3 and} -CH( _CH3 ) _OCH3 .

In more preferred embodiments of the present invention, in the acid addition salt of formula (I)

R ₂ is selected from the group consisting of hydrogen, C _1-6 alkyl, halogen, cyano and -(CH ₂ ) _n OR _cc , preferably hydrogen, C _1-3 alkyl, halogen, cyano and -(CH ₂ ) _n OR _cc , more preferably hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, fluorine, chlorine, bromine and cyano, and even more preferably hydrogen, fluorine, methyl, methoxy and cyano;

or any two R ₂ are joined together to form a substituted or unsubstituted C _3-6 cycloalkyl or a substituted or unsubstituted 3-6 membered heterocyclyl, preferably a substituted or unsubstituted C _3-6 cycloalkyl or a substituted or unsubstituted 3-6 membered heterocyclyl containing from 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, and even more preferably cyclobutyl, cyclopentyl, 1,3-dioxocyclopentyl or 1,3-dioxocyclohexyl.

In further preferred embodiments of the present invention, in the acid addition salt of formula (I)

each of R ₃ and R ₃ ' is selected from the group consisting of 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 hydrogen, methyl, ethyl, propyl, fluoro, chlorine, bromine, cyano, methoxy, ethoxy and propoxy and more preferably hydrogen, fluoro, methyl, methoxy and cyano;

or R ₃ and R ₃ ' are joined together to form oxo, C _3-6 cycloalkyl or 3-6-membered heterocyclyl, preferably oxo, C _3-6 cycloalkyl or 3-6-membered heterocyclyl containing from 1 to 3 N, O or S atoms, more preferably oxo, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclopropyl, oxacyclobutyl, oxacyclopentyl, oxacyclohexyl, azacyclopropyl, azacyclobutyl, azacyclopentyl or azacyclohexyl, and even more preferably oxo, cyclopropyl or oxacyclobutyl.

In even more preferred embodiments of the present invention, in the acid addition salt of formula (I)

R ₄ is selected from the group consisting of 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, fluoro, chlorine, bromine, cyano, fluoromethyl, fluoroethyl, chloromethyl, chloroethyl, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, and even more preferably hydrogen, fluoro, chlorine, methyl, trifluoromethyl, cyano and cyclopropyl.

In preferred embodiments of the present invention, in the acid addition salt of formula (I)

R ₅ is selected from the group consisting of hydrogen, C _1-6 alkyl and C _1-6 haloalkyl, preferably hydrogen, C _1-3 alkyl and C _1-3 haloalkyl, more preferably hydrogen, methyl, ethyl, propyl, fluorinated methyl, fluorinated ethyl, fluorinated propyl, chlorinated methyl, chlorinated ethyl and chlorinated propyl, and even more preferably hydrogen and methyl;

or R ₁ or R ₁ ' are joined with R ₅ to form a 3- to 6-membered heterocyclyl optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, bromo, methyl, ethyl and propyl, preferably azacyclopropyl, azacyclobutyl, azacyclopentyl, azacyclohexyl, fluoro-substituted azacyclopropyl, fluoro-substituted azacyclobutyl, fluoro-substituted azacyclopentyl, fluoro-substituted azacyclohexyl, methyl-substituted azacyclopropyl, methyl-substituted azacyclobutyl, methylpyrrolidinyl or methyl-substituted azacyclohexyl, and even more preferably azacyclobutyl, azacyclopentyl or methylpyrrolidinyl.

In preferred embodiments of the present invention, in the acid addition salt of formula (I)

each of R _aa , R _bb and R _cc is independently selected from the group consisting of 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- to 6-membered heterocyclyl containing from 1 to 3 N, O or S atoms, more preferably hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclopropyl, oxacyclobutyl, oxacyclopentyl and oxacyclobutyl, and even more preferably hydrogen, methyl, ethyl, isopropyl, methoxy, cyclopropyl and oxacyclobutyl.

In preferred embodiments 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.

In further preferred embodiments of the present invention, in the acid addition salt of formula (I), W is O.

In further preferred embodiments of the present invention, in the acid addition salt of formula (I), G is O or S.

In further preferred embodiments of the present invention, in the acid addition salt of formula (I), R ₅ is hydrogen.

In further preferred embodiments of the present invention, in the acid addition salt of formula (I), R ₁ ' and R ₃ ' are hydrogen.

In further preferred embodiments of the present invention, in the acid addition salt of formula (I)

W is selected from the group consisting of -O-, -S- and -NR _aa -;

G is selected from the group consisting of -O- and -S-;

each of R ₁ and R ₁ ' is selected from the group consisting of hydrogen, methyl, methoxy, isopropyl, fluorine-containing methyl, hydroxymethyl, oxacyclobutyl, -CH ₂ OCH ₃ and -CH(CH ₃ )OCH ₃ ;

R ₂ is selected from the group consisting of hydrogen, fluoro, methyl, methoxy and cyano; each of R ₃ and R ₃ ' is selected from the group consisting of hydrogen, fluoro, methyl, methoxy and cyano;

R ₄ is selected from the group consisting of hydrogen, fluorine, chlorine, methyl, trifluoromethyl, cyano and cyclopropyl;

R ₅ is selected from the group consisting of hydrogen and methyl;

each of R _aa , R _bb and R _cc is independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, methoxy, cyclopropyl and oxacyclobutyl.

In further preferred embodiments of the present invention, when W is -O-, R ₅ is hydrogen, R ₁ is methyl, R ₁ ' is hydrogen, R ₂ is hydrogen, R ₃ and R ₃ ' are hydrogen, and R ₄ is hydrogen, G is not -O-.

In further preferred embodiments of the present invention, the structure of the acid addition salt of formula (I) is as shown in formula (II-A) or (II-B):

In further preferred embodiments of the present invention, the acid addition salt of formula (I) is in crystalline form or amorphous form.

In further preferred embodiments of the present invention, the acid addition salt of formula (I) includes both a crystalline form and an amorphous form, wherein said acid addition salt of formula (I) is a hydrate or an anhydrate, preferably an anhydrate.

The present invention further provides a process for producing an acid addition salt of formula (I), in particular comprising the following steps:

1) preparation of the mother liquor: weighing the free base of the compound and adding an organic solvent to obtain a clear or suspended mother liquor;

2) preparation of an acidic solution of the counterion: adding an acid with counterions M to an organic solvent or water to obtain a transparent acidic solution of the counterion;

3) obtaining a salt of the compound: adding an acidic solution of the counterion to the mother liquor to obtain a clear salt solution, stirring the salt solution to precipitate a solid, and drying the said solid;

Where:

the organic solvent is one or more solvents selected from the group consisting of alcohols, esters, hydrocarbons, ketones, ethers, benzenes, 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, and even more preferably one or more of methanol, ethanol, isopropanol, acetone and acetonitrile;

the acid with counterions is selected from the group consisting of 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, camphorsulfonic 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, dodecyl sulfuric 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, 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.

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

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

More preferably, the amount of acid with counterions in step 3) is from 0.4 to 2.0 equivalents, preferably from 0.5 to 1.5 equivalents, and more preferably from 0.6 to 1.2 equivalents.

The present invention further provides a process for preparing a compound of formula (I) and its crystalline form, in particular comprising the following steps:

1) weighing the appropriate amount of free base and suspending it in a weak solvent;

2) it is not necessary to weigh the appropriate amount of acid with counterions M and dissolve it in an organic solvent;

3) optionally adding the solution from step 2) to the suspension from step 1) and stirring the resulting mixture to precipitate the solid;

4) optionally adding an organic solvent to the solid obtained in step 3) and stirring the resulting mixture to precipitate the crystal;

5) mixing and cooling the mixture, followed by precipitation of the crystal to obtain the target product;

Where:

the weak solvent is one or more solvents from the group consisting of alcohols, esters, ketones, ethers, benzenes, 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, and 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 solvents selected from the group consisting of alcohols, esters, hydrocarbons, ketones, ethers, benzenes, 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, and more preferably one or more of methanol, ethanol, isopropyl alcohol, acetone and acetonitrile;

The above mentioned good solvents and organic solutions should be miscible when used;

the acid with counterions is selected from the group consisting of 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, 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, 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, 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.

The organic solvent in step 4) is one or more solvents 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, and even more preferably one or more of methanol, ethanol, isopropanol, ethyl acetate and methyl tert-butyl ether.

The present invention further provides a process for preparing a compound of formula (I) and its crystalline form, in particular comprising the following steps:

1) weighing the appropriate amount of the compound salt and suspending it in a weak solvent;

2) shaking the suspension obtained above;

3) centrifugation of the above suspension, removal of the supernatant and vacuum drying of the remaining solid substance to obtain the target product;

Where:

the weak solvent is one or more solvents selected from the group consisting of alcohols, ketones, esters, ethers, benzenes, 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, and even more preferably one or more of methanol, ethanol, n-propanol, isopropanol, 88% acetone and acetonitrile.

The density of the suspension in step 1) is from 20 to 200 mg/ml, preferably from 30 to 150 mg/ml, and more preferably from 50 to 100 mg/ml;

preferably the temperature in step 2) is from 20 to 80°C, preferably from 25 to 60°C, and more preferably from 25 to 40°C; the time is from 1 to 15 days, and preferably from 1 to 10 days;

more preferably, the vacuum drying temperature is from 20 to 60°C, preferably from 20 to 50°C, and more preferably 40°C.

The present invention further provides a method for preparing a compound of formula (I) and a crystalline form thereof, in particular comprising the following steps: 1) weighing out an appropriate amount of a salt of the compound and exposing the salt of the compound to a certain level of humidity for a certain period of time,

Where:

said humidity is a relative humidity (RH) of 70 to 95%, preferably RH of 75 to 95%, more preferably RH of 80 to 95%, and even more preferably RH of 92.5%; and said time is from 1 hour to 3 days, preferably from 1 hour to 2 days, more preferably from 1 hour to 1 day, and even more preferably 3 hours.

The present invention further provides a process for preparing a compound of formula (I) and its crystalline form, in particular comprising the following steps:

1) weighing the appropriate amount of free base and suspending it in a weak solvent;

2) weighing the appropriate amount of acid with counterions M and dissolving it in an organic solvent;

3) adding the solution from step 2) to the suspension from step 1) and heating the reaction;

4) it is not necessary to add an organic solvent to the solution from step 3);

5) optionally adding a salt of the compound to the solution from step 4);

6) cooling the mixture for crystal precipitation;

preferably the weak solvent is one or more solvents selected from the group consisting of alcohols, ketones, esters, ethers, benzenes, 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, and more preferably one or more of methanol, ethanol, n-propanol, isopropanol, acetone and acetonitrile;

preferably the acid with counterions is selected from the group consisting of 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, 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, 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, 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 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, and preferably one or more of methanol, ethanol, isopropanol and tert-butanol;

preferably, the heating temperature in step 3) is from 30 to 80°C, preferably from 40 to 60°C, and more preferably 50°C;

preferably the organic solvent in step 4) is one or more solvents 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, and even more preferably one or more of methanol, ethanol, isopropanol, ethyl acetate and methyl tert-butyl ether.

The present invention further provides a process for preparing a compound of formula (I) and its crystalline form, in particular comprising the following steps:

1) weighing the appropriate amount of free base and suspending it in a weak solvent;

2) weighing the appropriate amount of acid with counterions M and dissolving it in an organic solvent;

3) adding the solution from step 2) to the suspension from step 1) and adding an organic solvent after dissolution;

4) optionally adding an appropriate amount of a salt of the compound to the solution from step 3) and stirring the resulting mixture to precipitate the crystal;

preferably the weak solvent is one or more solvents selected from the group consisting of alcohols, ketones, esters, ethers, benzenes, 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, and more preferably one or more of methanol, ethanol, n-propanol, isopropanol, acetone and acetonitrile;

preferably the acid with counterions is selected from the group consisting of 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, 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, 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, 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 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, and preferably one or more of methanol, ethanol, isopropanol and tert-butanol;

preferably the organic solvent in step 3) is one or more solvents 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, and even more preferably one or more of methanol, ethanol, isopropanol, ethyl acetate and methyl tert-butyl ether.

In preferred embodiments of the present 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.

In further preferred embodiments 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:

wherein the powder X-ray diffraction pattern of which comprises one or more diffraction peaks at 2θ equal to 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°; and preferably includes optional 2, 4, 6, 8 or 10 of the above diffraction peaks;

or an X-ray powder diffraction pattern of which comprises two or three diffraction peaks at 2θ equal to 6.8±0.2°, 13.4±0.2°, 14.7±0.2° and 19.5±0.2°, optionally further comprising one or more diffraction peaks at 2θ equal to 20.1±0.2°, 23.9±0.2°, 24.4±0.2°, 25.0±0.2°, 23±0.2° and 23.6±0.2°; and preferably comprising 2, 3, 4, 5 or 6 of the above diffraction peaks;

for example, the X-ray powder diffraction pattern of which 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;

the X-ray powder diffraction pattern of which 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°;

the X-ray powder diffraction pattern of which has characteristic peaks at 6.8±0.2°, 13.4±0.2°, 14.7±0.2°, 19.5±0.2°, 29.1±0.2°, 23.9±0.2°, 24.4±0.2° and 25.0±0.2;

the X-ray powder diffraction pattern of which 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°, 23±0.2° and 23.6±0.2°.

In preferred embodiments of the present invention, the X-ray powder diffraction pattern has diffraction peaks at 2θ equal to 6.8±0.2°, 9.3±0.2°, 13.4±0.2° and 14.7±0.2°; further has diffraction peaks at 2θ equal to 17.3±0.2°, 19.5±0.2°, 20.8±0.2°, 23.9±0.2° and 25.0±0.2°; additionally has diffraction peaks at 2θ equal to 9.8±0.2°, 18.4±0.2°, 19.1±0.2°, 29.1±0.2°, 23.0±9.2°, 23.6±0.2°, 24.4±0.2°, 27.3±0.2° and 30.7±0.2°; and additionally has diffraction peaks at 2θ equal to 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°;

or the X-ray powder diffraction pattern has diffraction peaks at 2θ of 6.8±0.2° and 13.4±0.2°; preferably also has diffraction peaks at 2θ of 14.7±0.2° and 19.5±0.2°; more preferably also has diffraction peaks at 2θ (±0.2°) of 20.1±0.2°, 23.9±0.2°, 24.4±0.2° and 25.0±0.2°; more preferably also has diffraction peaks at 23±0.2° and 23.6±0.2°; more preferably also has diffraction peaks at 9.3±0.2° and 17.3±0.2°; even more preferably also has diffraction peaks at 2θ equal to 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°; and even more preferably also has diffraction peaks at 2θ equal to 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°.

The characteristic X-ray diffraction peaks obtained using Cu-Kα radiation, represented by the value of the angle 2θ and the interplanar distance d, are shown in Table 1.

The compound of formula (I) according to the present invention is crystalline form A of the ethanesulfonate salt

(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 thermogravimetric analysis (TGA) profile of which is substantially as shown in Figure 2; and the differential scanning calorimetry (DSC) profile of which is substantially as shown in Figure 3.

In further preferred embodiments 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:

wherein the X-ray powder diffraction pattern of which comprises one or more diffraction peaks at 2θ equal to 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°; and preferably includes optional 2, 4, 6, 8 or 10 of the above diffraction peaks;

or the X-ray powder diffraction pattern of which comprises two or three diffraction peaks at 2θ equal to 6.1±0.2°, 7.5±0.2° and 8.0±0.2°, optionally further comprises one or more diffraction peaks at 2θ equal to 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°; and preferably comprises 2, 3, 4, 5 or 6 of the above diffraction peaks;

for example, the X-ray powder diffraction pattern of which 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°.

Or the X-ray powder diffraction pattern of which has diffraction peaks at 2θ equal to 6.1±0.2°, 7.5±0.2°, 8.0±0.2°, 14.9±0.2° and 23.8±0.2°; additionally has diffraction peaks at 2θ equal to 8.4±0.2°, 18.8±0.2°, 20.7±0.2°, 22.3±0.2° and 22.8±0.2°; and additionally has diffraction peaks at 2θ equal to 13.5±0.2° and 25.2±0.2°.

The characteristic X-ray diffraction peaks obtained using Cu-Kα radiation, represented by the value of the angle 2θ and the interplanar distance d, are shown in Table 2.

The compound of formula (I) according to the present invention is the crystalline form A of the mesylate salt

(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 the X-ray powder diffraction pattern of which is substantially as shown in Figure 4.

In further preferred embodiments 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:

wherein the X-ray powder diffraction pattern of which comprises one or more diffraction peaks at 2θ equal to 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°; and preferably includes optional 2, 4, 6, 8 or 10 of the above diffraction peaks;

or the X-ray powder diffraction pattern of which comprises two or three diffraction peaks at 24.4±0.2°, 13.3±0.2° and 23.8±0.2°, optionally further comprises one or more diffraction peaks at 2θ equal to 9.9±0.2°, 9.9±0.2°, 26.7±0.2°, 17.2±0.2° and 23.1±0.2°; and preferably comprises 2, 3, 4 or 5 of the above diffraction peaks;

for example, the X-ray powder diffraction pattern of which has characteristic peaks at 24.4±0.2°, 13.3±0.2°, 23.8±0.2°, 9.9±0.2°, 9.9±0.2°, 26.7±0.2°, 17.2±0.2° and 23.1±0.2°.

Or the X-ray powder diffraction pattern of which has diffraction peaks at 2θ equal to 9.9±0.2°, 13.3±0.2°, 19.7±0.2° and 23.1±0.2°; additionally has diffraction peaks at 2θ equal to 9.9±0.2°, 17.2±0.2°, 20.3±0.2° and 26.7±0.2°; still additionally has diffraction peaks at 2θ equal to 14.3±0.2°, 21.6±0.2°, 23.8±0.2° and 28.4±0.2°; and additionally includes diffraction peaks at 2θ equal to 24.4±0.2°, 30.5±0.2° and 32.6±0.2°.

The characteristic X-ray diffraction peaks obtained using Cu-Kα radiation, represented by the value of the angle 2θ and the interplanar distance d, are shown in Table 3.

The compound of formula (Ia) according to the present invention is a 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 salt, and the X-ray powder diffraction pattern of which is essentially as shown in Figure 5.

In further preferred embodiments 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., a crystalline form C of the mesylate salt, having the following structure:

wherein the X-ray powder diffraction pattern of which comprises one or more diffraction peaks at 2θ equal to 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°; and preferably comprises optionally 2, 4, 6, 8 or 10 of the above diffraction peaks;

or the X-ray powder diffraction pattern of which comprises two or three diffraction peaks at 2θ equal to 22.5±0.2°, 8.5±0.2° and 7.2±0.2°, optionally further comprises one or more diffraction peaks at 2θ equal to 14.4±0.2°, 26.7±0.2°, 12.8±0.2°, 16.7±0.2° and 6.1±0.2°; and preferably comprises 2, 3, 4 or 5 of the above diffraction peaks;

for example, the X-ray powder diffraction pattern of which has characteristic peaks at 2θ equal to 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°.

Or the X-ray powder diffraction pattern of which has diffraction peaks at 2θ equal to 7.2±0.2°, 14.4±0.2°, 22.5±9.2° and 26.7±9.2°; additionally has diffraction peaks at 2θ equal to 6.1±0.2°, 12.8±0.2°, 16.7±0.2° and 20.8±0.2°; still additionally has diffraction peaks at 2θ equal to 8.5±0.2°, 15.2±0.2°, 22.0±0.2° and 25.3±0.2°; and additionally has diffraction peaks at 2θ equal to 12.1±0.2°, 19.1±0.2° and 23.8±0.2°.

The characteristic X-ray diffraction peaks obtained using Cu-Kα radiation, represented by the value of the angle 2θ and the interplanar distance d, are shown in Table 4.

The compound of formula (Ia) according to the present invention is a crystalline form C of the mesylate salt

(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 the X-ray powder diffraction pattern of which is substantially as shown in Figure 6.

In further preferred embodiments 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:

wherein the X-ray powder diffraction pattern of which comprises one or more diffraction peaks at 2θ equal to 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°; and preferably includes optional 2, 4, 6, 8 or 10 of the above diffraction peaks;

or the X-ray powder diffraction pattern of which comprises two or three diffraction peaks at 2θ equal to 8.4±0.2°, 7.2±0.2° and 20.1±0.2°, optionally further comprises one or more diffraction peaks at 2θ equal to 22.7±0.2°, 24.5±0.2°, 25.7±0.2°, 18.9±0.2° and 16.4±0.2°; and preferably comprises 2, 3, 4 or 5 of the above diffraction peaks;

for example, the X-ray powder diffraction pattern of which has diffraction peaks at 2θ equal to 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°.

Or the X-ray powder diffraction pattern of which has diffraction peaks at 2θ equal to 7.2±0.2°, 8.4±0.2°, 20.1±0.2° and 22.7±0.2°; additionally has diffraction peaks at 2θ equal to 5.8±0.2°, 16.4±0.2°, 18.9±0.2° and 26.7±0.2°; and still additionally has diffraction peaks at 2θ equal to 12.6±0.2°, 14.7±0.2°, 17.2±0.2° and 25.1±0.2°; and additionally has diffraction peaks at 2θ equal to 14.4±0.2°, 18.2±0.2°, 24.5±0.2° and 25.7±0.2°.

The characteristic X-ray diffraction peaks obtained using Cu-Kα radiation, represented by the value of the angle 2θ and the interplanar distance d, are shown in Table 5.

The compound of formula (Ia) according to the present invention is a 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 salt, and the X-ray powder diffraction pattern of which is essentially as shown in Figure 7.

In further preferred embodiments 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:

wherein the X-ray powder diffraction pattern of which comprises one or more diffraction peaks at 2θ equal to 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°; and preferably includes optional 2, 4, 6 or 8 of the above diffraction peaks;

for example, the X-ray powder diffraction pattern of which has diffraction peaks at 2θ equal to 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°.

Or the X-ray powder diffraction pattern of which has diffraction peaks at 2θ equal to 4.8±0.2° and 7.6±0.2°; and additionally has diffraction peaks at 2θ equal to 12.2±0.2°, 14.0±0.2°, 18.5±0.2°, 22.9±0.2° and 23.8±0.2°.

The characteristic X-ray diffraction peaks obtained using Cu-Kα radiation, represented by the value of the angle 2θ and the interplanar distance d, are shown in Table 6.

The compound of formula (I) according to the present invention is the 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 salt, and the X-ray powder diffraction pattern of which is essentially as shown in Figure 8.

In further preferred embodiments 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., a crystalline form C of the sulfate salt, having the following structure:

wherein the X-ray powder diffraction pattern of which comprises one or more diffraction peaks at 2θ equal to 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°; and preferably includes optional 2, 4, 6, 8 or 10 of the above diffraction peaks;

or the X-ray powder diffraction pattern of which comprises two or three diffraction peaks at 2θ equal to 24.5±0.2°, 13.3±0.2° and 23.9±0.2°, optionally further comprises one or more diffraction peaks at 2θ equal to 9.0±0.2°, 17.3±0.2°, 19.4±0.2°, 17.7±0.2° and 9.9±0.2°; and preferably comprises 2, 3, 4 or 5 of the above diffraction peaks;

for example, the X-ray powder diffraction pattern of which has diffraction peaks at 2θ equal to 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°.

Or the X-ray powder diffraction pattern of which has diffraction peaks at 2θ equal to 9.0±0.2°, 13.3±0.2°, 17.3±0.2° and 24.5±0.2°; additionally has diffraction peaks at 2θ equal to 9.9±0.2°, 17.7±0.2°, 19.4±0.2° and 26.9±0.2°; and still additionally has diffraction peaks at 2θ equal to 14.3±0.2°, 18.6±0.2°, 28.3±0.2° and 37.5±0.2°; and additionally has diffraction peaks at 2θ equal to 16.7±0.2°, 20.0±0.2°, 20.4±0.2°, 24.0±0.2° and 30.4±0.2°.

The characteristic X-ray diffraction peaks obtained using Cu-Kα radiation, represented by the value of the angle 2θ and the interplanar distance d, are shown in Table 7.

The compound of formula (Ia) according to the present invention is a 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 salt, and the X-ray powder diffraction pattern of which is essentially as shown in Figure 9.

In further preferred embodiments 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, having the following structure:

wherein the X-ray powder diffraction pattern of which comprises one or more diffraction peaks at 2θ equal to 7.6±0.2°, 22.5±0.2°, 8.9±0.2°, 15.0±0.2°, 23.9±9.2°, 26.6±0.2°, 24.6±9.2°, 5.8±9.2°, 12.9±9.2°, 19.9±0.2°, 29.7±9.2° and 11.6±0.2°; and preferably includes optional 2, 4, 6, 8 or 10 of the above diffraction peaks;

or the X-ray powder diffraction pattern of which comprises two or three diffraction peaks at 2θ equal to 7.6±0.2°, 22.5±0.2° and 8.9±0.2°, optionally further comprises one or more diffraction peaks at 2θ equal to 15.9±9.2°, 26.6±9.2°, 5.8±9.2°, 12.9±9.2° and 11.6±9.2°; and preferably comprises 2, 3, 4 or 5 of the above diffraction peaks;

For example, the X-ray powder diffraction pattern has diffraction peaks at 2θ equal to 7.6±9.2°, 22.5±9.2°, 8.9±9.2°, 15.9±9.2°, 26.6±9.2°, 5.8±9.2°, 12.9±9.2°, and 11.6±9.2°.

Or the X-ray powder diffraction pattern of which has diffraction peaks at 2θ equal to 7.6±9.2°, 15.9±9.2°, 22.5±9.2° and 23.9±9.2°; additionally has diffraction peaks at 2θ equal to 5.8±9.2°, 12.9±9.2°, 19.9±9.2° and 26.6±9.2°; additionally has diffraction peaks at 2θ equal to 8.9±0.2°, 16.8±9.2°, 29.7±9.2° and 24.6±9.2°; and additionally has diffraction peaks at 2θ equal to 19.1±9.2°, 11.6±9.2°, 17.4±0.2°, 18.2±0.2°, 19.1±9.2°, 21.9±0.2°, 25.4±0.2° and 27.7±9.2°.

The characteristic X-ray diffraction peaks obtained using Cu-Kα radiation, represented by the value of the angle 2θ and the interplanar distance d, are shown in Table 8.

The compound of formula (Ia) according to the present invention is a 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 salt, and the X-ray powder diffraction pattern of which is essentially as shown in Figure 10.

In further preferred embodiments 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 E of the sulfate salt, having the following structure:

wherein the X-ray powder diffraction pattern of which comprises one or more diffraction peaks at 2θ equal to 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°; and preferably includes optional 2, 4, 6, 8 or 10 of the above diffraction peaks;

or the X-ray powder diffraction pattern of which comprises two or three diffraction peaks at 2θ equal to 17.7±0.2°, 23.5±0.2° and 24.8±0.2°, optionally further comprises one or more diffraction peaks at 2θ equal to 9.9±0.2°, 22.6±0.2°, 21.2±0.2°, 19.1±0.2° and 29.4±0.2°; and preferably comprises 2, 3, 4 or 5 of the above diffraction peaks;

for example, the X-ray powder diffraction pattern of which has diffraction peaks at 2θ equal to 17.7±0.2°, 23.5±0.2°, 24.8±0.2°, 9.9±0.2°, 22.6±0.2°, 21.2±9.2°, 19.1±9.2° and 29.4±9.2°.

Or the X-ray powder diffraction pattern of which has diffraction peaks at 2θ equal to 9.9±0.2°, 17.7±0.2°, 22.6±9.2° and 24.8±9.2°; additionally has diffraction peaks at 2θ equal to 16.9±9.2°, 21.2±9.2°, 23.5±9.2° and 29.4±9.2°; and still additionally has diffraction peaks at 2θ equal to 17.3±9.2°, 19.1±9.2°, 28.4±9.2° and 39.5±9.2°; and additionally has diffraction peaks at 2θ equal to 14.1±9.2°, 16.2±9.2°, 19.6±9.2°, 29.7±9.2°, 24.5±9.2° and 26.5±9.2°.

The characteristic X-ray diffraction peaks obtained using Cu-Kα radiation, represented by the value of the angle 2θ and the interplanar distance d, are shown in Table 9.

The compound of formula (Ia) according to the present invention is a 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 salt, and the X-ray powder diffraction pattern of which is essentially as shown in Figure 11.

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

Where:

W is selected from the group consisting of -O-, -S- H-NR _aa -;

G is selected from the group consisting of -O-, -S-, -CR _aa R _bb - H-NR _aa -;

each of R ₁ and R ₁ ' is selected from the group consisting of 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, -(CH ₂ ) _n R _cc , -(CH ₂ ) _n OR _cc and -CR _aa R _bb OR _cc ;

or R ₁ and R ₁ ' are joined together to form a C _3-8 cycloalkyl or a 3-8 membered heterocyclyl, wherein said C _3-8 cycloalkyl or 3-8 membered heterocyclyl is optionally further substituted with one or more substituents selected from the group consisting of 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 and 5-10 membered heteroaryl;

R ₂ is selected from the group consisting of 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, 5-10-membered heteroaryl and -(CH ₂ ) _n OR _cc ;

or any two R ₂ are joined together to form a C _3-8 cycloalkyl or a 3-8 membered heterocyclyl, wherein said C _3-8 cycloalkyl or 3-8 membered heterocyclyl is optionally further substituted with one or more substituents selected from the group consisting of 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 and 5-10 membered heteroaryl;

each of _R3 and _R3 ' is selected from the group consisting of hydrogen, deuterium, cyano, halogen, nitro, amino, _C1-6 alkyl, _C1-6 haloalkyl, _C1-6 alkoxy, _C1-6 hydroxyalkyl, _C3-8 cycloalkyl, 3-8-membered heterocyclyl, _C6-10 aryl and 5-10-membered heteroaryl;

or _R3 and _R3 ' are joined together to form oxo, _C3-8 cycloalkyl or 3-8 membered heterocyclyl, wherein said _C3-8 cycloalkyl or 3-8 membered heterocyclyl is optionally further substituted with one or more substituents selected from the group consisting of deuterium, cyano, halogen, nitro, amino, _C1-6 alkyl, _C1-6 haloalkyl, _C1-6 alkoxy, _C1-6 hydroxyalkyl, C3-8 cycloalkyl, _3-8 membered heterocyclyl, _C6-10 aryl and 5-10 membered heteroaryl;

R ₄ is selected from the group consisting of 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 and 5-10-membered heteroaryl;

R ₅ is selected from the group consisting of hydrogen, deuterium, C _1-6 alkyl and C _1-6 haloalkyl;

or R ₁ or R ₁ ' are joined with R ₅ to form a 3-8 membered heterocyclyl, wherein said 3-8 membered heterocyclyl is optionally further substituted with one or more substituents selected from the group consisting of 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 and 5-10 membered heteroaryl;

each of R _aa , R _bb and R _cc is independently selected from the group consisting of 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 and 5-10-membered heteroaryl;

M is an inorganic acid or an organic acid, wherein said 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 said 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, cycloamic 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, 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 acids, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid and L-malic acid;

n is an integer between 0 and 3;

x is an integer between 0 and 3; and

y is an integer from 1 to 5, preferably an integer from 1 to 3, more preferably 1.

In preferred embodiments of the present invention, in the acid addition salt of formula (I)

each of R ₁ and R ₁ ' is selected from the group consisting of hydrogen, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _1-6 haloalkyl, C _1-6 alkoxy, 3- to 8-membered heterocyclyl, -(CH ₂ ) _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- to 6-membered heterocyclyl, -(CH ₂ ) _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, _-CH2OCH3 , -( _CH2 ) _2OCH3 , _-CH ( _CH3 ) _OCH3 and -C( _CH3 ) _2OCH3 , more preferably hydrogen, methyl, methoxy, isopropyl _, fluorinated methyl, hydroxymethyl, oxacyclobutyl, _-CH2OCH3 and -CH( _{CH3 ) OCH3} .

In preferred embodiments of the present invention, in the acid addition salt of formula (I)

R ₂ is selected from the group consisting of hydrogen, C _1-6 alkyl, halogen, cyano and -(CH ₂ ) _n OR _cc , preferably hydrogen, C _1-3 alkyl, halogen, cyano and -(CH ₂ ) _n OR _cc , more preferably hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, fluorine, chlorine, bromine and cyano, and even more preferably hydrogen, fluorine, methyl, methoxy and cyano;

or any two R ₂ are joined together to form a substituted or unsubstituted C _3-6 cycloalkyl or a substituted or unsubstituted 3-6 membered heterocyclyl, preferably a substituted or unsubstituted C _3-6 cycloalkyl or a substituted or unsubstituted 3-6 membered heterocyclyl containing from 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, and even more preferably cyclobutyl, cyclopentyl, 1,3-dioxocyclopentyl or 1,3-dioxocyclohexyl.

In preferred embodiments of the present invention, in the acid addition salt of formula (I)

each of R ₃ and R ₃ ' is selected from the group consisting of 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 hydrogen, methyl, ethyl, propyl, fluorine, chlorine, bromine, cyano, methoxy, ethoxy and propoxy, more preferably hydrogen, fluorine, methyl, methoxy and cyano;

or R ₃ and R ₃ ' are joined together to form oxo, C _3-6 cycloalkyl or 3-6-membered heterocyclyl, preferably oxo, C _3-6 cycloalkyl or 3-6-membered heterocyclyl containing from 1 to 3 N, O or S atoms, more preferably oxo, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclopropyl, oxacyclobutyl, oxacyclopentyl, oxacyclohexyl, azacyclopropyl, azacyclobutyl, azacyclopentyl or azacyclohexyl, and even more preferably oxo, cyclopropyl or oxacyclobutyl.

In preferred embodiments of the present invention, in the acid addition salt of formula (I)

R ₄ is selected from the group consisting of 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, fluoro, chlorine, bromine, cyano, fluoromethyl, fluoroethyl, chloromethyl, chloroethyl, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, and even more preferably hydrogen, fluoro, chlorine, methyl, trifluoromethyl, cyano and cyclopropyl.

In preferred embodiments of the present invention, in the acid addition salt of formula (I)

R ₅ is selected from the group consisting of hydrogen, C _1-6 alkyl and C _1-6 haloalkyl, preferably hydrogen, C _1-3 alkyl and C _1-3 haloalkyl, more preferably hydrogen, methyl, ethyl, propyl, fluorinated methyl, fluorinated ethyl, fluorinated propyl, chlorinated methyl, chlorinated ethyl and chlorinated propyl, and even more preferably hydrogen and methyl;

or R ₁ or R ₁ ' are joined with R ₅ to form a 3- to 6-membered heterocyclyl optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, bromo, methyl, ethyl and propyl, preferably azacyclopropyl, azacyclobutyl, azacyclopentyl, azacyclohexyl, fluoro-substituted azacyclopropyl, fluoro-substituted azacyclobutyl, fluoro-substituted azacyclopentyl, fluoro-substituted azacyclohexyl, methyl-substituted azacyclopropyl, methyl-substituted azacyclobutyl, methylpyrrolidinyl or methyl-substituted azacyclohexyl, and even more preferably azacyclobutyl, azacyclopentyl or methylpyrrolidinyl.

In preferred embodiments of the present invention, in the acid addition salt of formula (I)

each of R _aa , R _bb and R _cc is independently selected from the group consisting of 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- to 6-membered heterocyclyl containing from 1 to 3 N, O or S atoms, more preferably hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclopropyl, oxacyclobutyl, oxacyclopentyl and oxacyclobutyl, and even more preferably hydrogen, methyl, ethyl, isopropyl, methoxy, cyclopropyl and oxacyclobutyl.

In preferred embodiments 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.

In preferred embodiments of the present invention, in the acid addition salt of formula (I), W is -O-.

In preferred embodiments of the present invention, in the acid addition salt of formula (I), G is -O- or -S-.

In preferred embodiments of the present invention, in the acid addition salt of formula (I), R ₅ is hydrogen.

In preferred embodiments of the present invention, in the acid addition salt of formula (I), R ₁ ' and R ₃ ' are hydrogen.

In preferred embodiments of the present invention, the acid addition salt of formula (I) is further as shown in formula (II-A) or (II-B):

In preferred embodiments of the present invention, the specific structure of the acid addition salt of formula (I) is as follows:

Another object of the present invention is to provide the use of a compound of formula (I) and its crystalline form, as well as a pharmaceutical composition containing them, for the preparation of a PI3K-inhibiting drug and preferably a PI3Kα-inhibiting drug.

Another object of the present invention is to provide a compound of formula (I), a salt

(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 their crystalline form and one or more pharmaceutically acceptable carriers, diluents or excipients.

Another object of the present invention is to provide the use of a compound of formula (I), a 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 and a crystalline form thereof, and a pharmaceutical composition containing them for the preparation of a PI3K-inhibiting drug and preferably a PI3Kα-inhibiting drug.

The use is a use for the preparation of a medicinal product for the treatment of cancer, bone disease, inflammatory disease, immune disease, nervous system disease, metabolic disease, respiratory disease and cardiac disease; wherein the cancer is a cancer selected from the group consisting of breast cancer, pancreatic cancer, non-small cell lung cancer (NSCLC), thyroid cancer, seminoma, melanoma, bladder cancer, liver cancer, kidney cancer, myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) and colorectal cancer.

DESCRIPTION OF GRAPHIC MATERIALS

Figure 1 is an X-ray powder diffraction (XRPD) pattern 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 ethanesulfonate salt.

Figure 2 is a thermogravimetric analysis (TGA) profile 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 ethanesulfonate salt.

Figure 3 is a differential scanning calorimetry (DSC) profile 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 ethanesulfonate salt.

Figure 4 is an X-ray powder diffraction (XRPD) pattern 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.

Figure 5 is an X-ray powder diffraction (XRPD) pattern of the 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 is an X-ray powder diffraction (XRPD) pattern of the 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.

Figure 7 is an X-ray powder diffraction (XRPD) pattern 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 salt crystalline Form A.

Figure 8 is an X-ray powder diffraction (XRPD) pattern of the 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 salt.

Figure 9 is an X-ray powder diffraction (XRPD) pattern of the 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 salt.

Figure 10 is an X-ray powder diffraction (XRPD) pattern 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 salt.

Figure 11 is an X-ray powder diffraction (XRPD) pattern 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 salt.

DETAILED DESCRIPTION OF THE INVENTION

Unless otherwise specified, the terms used in the description and claims have the meanings given below.

The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched group containing from 1 to 20 carbon atoms, preferably alkyl containing from 1 to 8 carbon atoms, more preferably alkyl containing from 1 to 6 carbon atoms, and most preferably alkyl containing from 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-methyl pentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-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 isomers thereof. The alkyl may be substituted or unsubstituted. When substituted, the substituent group(s) may be inserted into any available substitution site. The substituent group(s) preferably represent 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.

The term "alkylene" refers to an alkyl in which one hydrogen atom is further substituted, for example, "methylene" refers to _-CH2- , "ethylene" refers to -( _CH2 ) _2- , "propylene" refers to -( _CH2 ) _3- , "butylene" refers to -( _CH2 ) _4- and the like. The above substituent groups may be bonded to different carbon atoms to form a carbon chain or may be bonded to a single carbon atom to form a cycloalkyl. The term "alkenyl" refers to alkyl, as defined above, which consists of at least two carbon atoms and at least one carbon-carbon double bond, for example, ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl and the like. Alkenyl may be substituted or unsubstituted. When substituted, the substituent group(s) preferably represents 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.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent group having from 3 to 20 carbon atoms, preferably from 3 to 8 carbon atoms, more preferably from 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl and the like. Polycyclic cycloalkyl includes cycloalkyl having a spiro ring, a fused ring or a bridged ring. Cycloalkyl is preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl.

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

The term "alkoxy" refers to the group -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above. Alkoxy is preferably alkoxy having from 1 to 8 carbon atoms, more preferably alkoxy having from 1 to 6 carbon atoms, and most preferably alkoxy having from 1 to 3 carbon atoms. Non-limiting examples of alkoxy include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy and cyclohexyloxy. Alkoxy may be optionally substituted or unsubstituted. When substituted, the substituent group(s) preferably represents 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.

The term "haloalkyl" refers to alkyl substituted with one or more halogens, wherein alkyl is as defined above.

The term "haloalkoxy" refers to an alkoxy substituted with one or more halogens, wherein alkoxy is as defined above.

The term "hydroxyalkyl" refers to alkyl substituted with hydroxy, wherein alkyl is as defined above.

The term "hydroxy" refers to the -OH group.

The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

The term "amino" refers to the -NH ₂ group.

The term "cyano" refers to the -CN group.

The term "nitro" refers to the -NO ₂ group.

The term "THF" refers to tetrahydrofuran.

The term "EtOAc" refers to ethyl acetate.

The term "DMSO" refers to dimethyl sulfoxide.

The term "LDA" refers to lithium diisopropylamide.

The term "DMAP" refers to 4-dimethylaminopyridine.

The term "EtMgBr" refers to ethyl magnesium bromide.

The term "HOSu" refers to N-hydroxysuccinimide.

The term "EDCl" refers to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.

The term "IPA" refers to isopropanol.

The term "MeOH" refers to methanol.

The term "EtOH" refers to ethanol.

The term "DMF" refers to N,N-dimethylformamide.

The term "DIPEA" refers to N,N-diisopropylethylamine.

The term "HEPES" refers to 4-hydroxyethylpiperazineethanesulfonic acid.

Various 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" and the like have the same meaning, namely that X may be any one or more of A, B and C.

"Optional" or "optional" means that the event or circumstance subsequently described may, but does not necessarily, occur, and the description includes a situation in which the event or circumstance does or does not occur.

"Substituted" refers to one or more hydrogen atoms in a group, preferably up to 5 and more preferably 1 to 3 hydrogen atoms, independently replaced by an appropriate number of substituent groups. It goes without saying that the substituent groups are only in their possible chemical positions. One skilled in the art can determine whether a substitution is possible or not by experimentation or based on theoretical knowledge without undue effort. For example, a combination of amino or hydroxy groups having free hydrogen atoms and carbon atoms having unsaturated bonds (such as olefinic) may be unstable.

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

All hydrogen atoms in the present invention may be replaced by a deuterium isotope, and any hydrogen atom in the compounds involved in the examples of the present invention may also be replaced by a deuterium atom.

"Pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, with other chemical components and other components, such as a physiologically/pharmaceutically acceptable carrier and excipient. The purpose of the pharmaceutical composition is to facilitate the administration of the drug into the body and to improve the absorption of the active ingredient in order to exert biological activity.

"Pharmaceutically acceptable salt" refers to a salt of a compound of the present invention that is safe and effective for use in mammals and possesses the desired biological activity.

As described in this document, new crystalline forms can be identified using X-ray powder diffraction patterns. However, those skilled in the art know that the peak intensities and/or peak conditions of X-ray powder diffraction may vary depending on different experimental conditions, such as different diffraction test conditions and/or preferred orientations. Meanwhile, due to the different accuracy of different instruments, the measured 2θ value will have an error of about ±0.2, and individual peaks may have an error of about ±0.3 or ±0.4. However, it is known that the relative peak intensity values depend more on certain properties of the measured sample, such as the size of the crystals in the sample, the orientation of the crystals and the purity of the analyzed material, than the position of the peaks. Therefore, the peak intensity shown may have a deviation in the range of about ±20% or more.

The term "TGA" refers to a thermogravimetric analysis (TGA) experiment.

The term "DSC" refers to a differential scanning calorimetry (DSC) experiment.

The term "XRPD" refers to an X-ray powder diffraction (XRPD) experiment.

The term "HPLC" refers to a high performance liquid chromatography (HPLC) experiment.

The term "PK" refers to a pharmacokinetic (PK) experiment.

The present invention will be further described with reference to the following examples, which should not be construed as limiting the scope of the present invention.

I. Obtaining compounds

Examples: The structures of the compounds of the present invention were determined by nuclear magnetic resonance (NMR) and/or liquid chromatography-mass spectrometry (LC-MS). The chemical shift in NMR (δ) is indicated in parts per million (ppm). NMR was measured using a Bruker AVANCE-400 nuclear magnetic spectrometer. The solvents for the measurement were deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated methanol (CD ₃ OD) and deuterated chloroform (CDCl ₃ ). The internal standard was tetramethylsilane (TMS).

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 column 150×4.6 mm) and a Waters 2695-2996 high-pressure liquid chromatograph (Gimini C18 column 150×4.6 mm).

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

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

Unless otherwise stated, all reactions of the present invention are carried out under continuous magnetic stirring under a dry nitrogen or argon atmosphere, the solvent is a dry solvent, and the reaction temperature is given in units of degrees Celsius.

Intermediate connection 1

(S)-4-(difluoromethyl)oxazolidin-2-one

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

(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 heated to 45 °C under 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] ⁺ .

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

(R)-3-benzyl-4-(hydroxymethyl)oxazolidin-2-one (4.14 g, 20.0 mmol) and IBX (2-iodoxybenzoic acid, 16.8 g, 60.0 mmol) were mixed in ethyl acetate (100 mL), and the reaction solution was stirred under nitrogen atmosphere at 85°C for 3 hours. After cooling, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain 4.46 g of crude product (S)-3-benzyl-4-(dihydroxymethyl)oxazolidin-2-one, which was directly used in the next step.

MS m/z (ESI): 224.2 [M+H] ⁺ .

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

(S)-3-benzyl-4-(dihydroxymethyl)oxazolidin-2-one (4.46 g, 20.0 mmol) was dissolved in dichloromethane (100 mL). DAST (4-dimethylamino-N-methyl-4-stilbazolium tosylate, 6.45 g, 40.0 mmol) was added dropwise under nitrogen atmosphere in an ice bath, and the reaction solution was naturally warmed to room temperature and reacted for 3 hours. The reaction solution was slowly added dropwise to 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 give the title compound (S)-3-benzyl-4-(difluoromethyl)oxazolidin-2-one (1.82 g, two-step yield: 40%).

MS m/z (ESI): 228.2 [M+H] ⁺ .

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

(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 under hydrogen atmosphere at 70 °C overnight. 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, CDCl ₃ ) 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);

MCm/z (ESI): 138.1 [M+H] ⁺ .

Intermediate connection 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

To a methanol solution (250 mL) of 4-bromo-2-hydroxybenzaldehyde (24.0 g, 119 mmol) was added an aqueous solution of glyoxal (40 wt %, 87 g, 597 mmol). Then, aqueous ammonia (28 wt %, 121 g, 860 mmol) was slowly added dropwise to the reaction solution on a water bath under stirring. The dropwise addition process was continued for 30 minutes, and the temperature of the reaction solution was controlled to be no higher than 40 °C. Then, the mixture was stirred at 35 °C for two days, cooled, and concentrated under reduced pressure to remove the organic solvent and obtain the crude product of 5-bromo-2-(1H-imidazol-2-yl)phenol, which was directly used in the next step.

MS m/z (ESI): 239.0 [M+H] ⁺ .

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

The crude product 5-bromo-2-(1H-imidazol-2-yl)phenol (about 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 give the title compound 9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (12.5 g, two-step yield: 38%).

MS m/z (ESI): 265.0 [M+H] ⁺ .

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

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 (N-iodosuccinimide, 29.8 g, 132 mmol) in batches at room temperature. The reaction solution was stirred at 60 °C overnight and cooled, then water was added to precipitate a solid. After filtration, the solid was dissolved in ethyl acetate, washed successively with 1 M aqueous NaOH solution 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, yield: 98.7%).

MS m/z (ESI): 516.7 [M+H] ⁺ .

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

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 slowly added dropwise EtMgBr (1.0 M solution in THF, 60.9 mL, 60.9 mmol) at −20 °C. After completion of the dropwise addition, the reaction solution was stirred at −15 °C for 3 h. The reaction solution was slowly warmed to room temperature, then saturated aqueous ammonium chloride solution was added dropwise. The reaction solution was stirred for 15 min and extracted with ethyl acetate several times. 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] ⁺ .

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

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 -dimethylcyclohexane-1,2-diamine (43 mg, 0.30 mmol), copper acetate (27 mg, 0.15 mmol) and cesium carbonate (489 mg, 1.5 mmol) were 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 min and extracted with EtOAc three times. The organic phases were combined and then washed with a saturated aqueous sodium chloride solution. The filtrate was dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the organic solvent, and then subjected to separation by 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)oxazolidin-2-one (186 mg, 61%).

^1H NMR (400 MHz, CDCl ₃ ) 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] ⁺ .

Example 1

Receiving

(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

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

To a solution of LDA (1.28 mL, 2.56 mmol) in tetrahydrofuran (10 mL) was added dropwise 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) at −78 °C. After completion of the dropwise addition, the reaction solution was stirred at −78 °C for 30 min. A solution of N-fluorobenzenesulfonamide (806 mg, 2.56 mmol) in tetrahydrofuran (9 mL) was added dropwise, and the reaction solution was stirred at the same temperature for 30 min. 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%).

¹ H NMR (400 MHz, DMSO-d ₆ ) 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] ⁺ .

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

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 -dimethylcyclohexane-1,2-diamine (35 mg, 0.24 mmol), copper 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 min and extracted with EtOAc three times. 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 give 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%).

¹ H NMR (400 MHz, CDCl ₃ ) 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=8.4 Hz, 1H);

MS m/z (ESI): 417.9 [M+H] ⁺ .

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

((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), copper iodide (4.8 mg, 0.025 mmol) and potassium phosphate (21 mg, 0.1 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 5 hours. The reaction solution was cooled to room temperature and directly used in the next step without treatment.

MS m/z (ESI): 427.1 [M+H] ⁺ .

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

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 were added ammonium chloride (16 mg, 0.29 mmol) and triethylamine (76 mg, 0.75 mmol). After stirring for 5 min, 0-(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 h and filtered. A saturated aqueous sodium bicarbonate solution was added to the filtrate, followed by extraction with ethyl acetate three times. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the organic solvent, and then separated by column chromatography to give 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, CDCl ₃ ) 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] ⁺ .

Example 2

Receiving

(S)-1-(2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-3-fluoro-5,6-dihydrobenzo[Pimidazo[1,2-d][1,4]oxazepin-9-yl)pyrrolidin-2-carboxamide

(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 the method described in Example 1.

MS m/z (ESI): 452.1 [M+H] ⁺ .

Example 3

Receiving

(S)-2-((3-chloro-2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[Pimidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide

(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 the method described in Example 1.

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 4

Receiving

(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

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

To a solution of 4-bromo-2-hydroxybenzaldehyde (5 g, 119 mmol) in methanol (100 mL) was added an aqueous solution of methylglyoxal (40 wt %, 80 mL). Then, aqueous ammonia (28 wt %, 40 g) was slowly added dropwise in a water bath with stirring. The dropwise addition process was continued for 30 minutes, and the temperature of the solution was controlled to be no higher than 40 °C. Then, the reaction solution was 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] ⁺ .

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

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 DMFA (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 anhydrous sodium sulfate, concentrated and subjected to column chromatography to give 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, CDCl ₃ ) 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] ⁺ .

Stage 3: Receiving

9-bromo-2-iodo-3-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d] [1,4]oxazepine

9-bromo-2-iodo-3-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine was prepared by the method described in Example 1.

MS m/z (ESI): 404.9 [M+H] ⁺ .

Stage 4: Receiving

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

(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 the method described in Example 1.

MS m/z (ESI): 414.0 [M+H] ⁺ .

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

(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 the method described in Example 1.

MS m/z (ESI): 423.1 [M+H] ⁺ .

Stage 6: Synthesis

(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

(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 the method described in Example 1.

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 5

Receiving

(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)pyrrolidin-2-carboxamide

(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 the method described in Example 4.

MS m/z (ESI): 448.2 [M+H] ⁺ .

Example 6

Receiving

(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

(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 the method described in Example 4.

MS m/z (ESI): 476.1 [M+H] ⁺ .

Example 7

Receiving

(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

(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 the method described in Example 4.

MS m/z (ESI): 433.1 [M+H] ⁺ .

Example 8

Receiving

(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)pyrrolidin-2-carboxamide

(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 the method described in Example 4.

MS m/z (ESI): 459.2 [M+H] ⁺ .

Example 9

Receiving

(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

(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 the method described in Example 4.

MS m/z (ESI): 448.2 [M+H] ⁺ .

Example 10

Receiving

(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

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

_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 under _N2 atmosphere in an ice bath. The reaction solution was naturally warmed to room temperature and reacted overnight. The reaction solution was added to 200 mL 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]oct-1(6),2,4-trien-3-yl)ethan-1-one (800 mg, 27%).

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

1-(Bicyclo[4.2.0]oct-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 N ₂ atmosphere, and the reaction was carried out at room temperature for 3 h. The reaction solution was concentrated, DCM (dichloromethane) 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 give the title compound

1-(5-bromobicyclo[4.2.0]oct-1(6),2,4-trien-3-yl)ethan-1-one (900 mg, 80%).

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

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

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

5-Bromobicyclo[4.2.0]oct-1(6),2,4-trien-3-yl acetate (723 mg, 3 mmol) was dissolved in methanol (20 mL). 5 N aqueous sodium hydroxide solution (3 mL) was added and the reaction was carried out at room temperature overnight. 50 mL water was added and the reaction solution was adjusted to pH 5 with 1 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-bromobicyclo[4.2.0]oct-1(6),2,4-trien-3-ol (567 mg, 95%).

Stage 5: Receiving

5-bromo-3-hydroxybicyclo[4.2.0]octa-1(6),2,4-triene-2-carbaldehyde

5-Bromobicyclo[4.2.0]oct-1(6),2,4-trien-3-ol (567.2 mg, 2.85 mmol), magnesium chloride (407 mg, 4.28 mmol) and TEA (triethylamide, 1.15 g, 11.4 mmol) were added to acetonitrile (5 mL). The reaction solution was heated to 40 °C and reacted for 30 min. 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 reaction solution was adjusted to pH 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%).

Stage 6: Receiving

(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

(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 the method described in Example 1.

MS m/z (ESI): 434.2 [M+H] ⁺ .

Example 11

Receiving

(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

(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 the method described in Example 10.

MS m/z (ESI): 450.1 [M+H] ⁺ .

Example 12

Receiving

(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

(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 the method described in Example 10.

MS m/z (ESI): 448.1 [M+H] ⁺ .

Example 13

Receiving

(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

(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 the method described in Example 10.

MS m/z (ESI): 452.1 [M+H] ⁺ .

Example 14

Receiving

(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

(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 the method described in Example 1.

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 15

Receiving

(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

(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 the method described in Example 1.

MS m/z (ESI): 424.1 [M+H] ⁺ .

Example 16

Receiving

(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

(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 the method described in Example 1.

MS m/z (ESI): 426.1 [M+H] ⁺ .

Example 17

Receiving

(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

(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 the method described in Example 1.

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 18

Receiving

(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

(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 the method described in Example 1.

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 19

Receiving

(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

(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 the method described in Example 1.

¹ H NMR (400 MHz, CD ₃ OD): 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); MC m/z (ESI): 422.1 [M+H] ⁺ .

Example 20

Receiving

(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

(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 the method described in Example 1.

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 21

Receiving

(S)-1-(2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)azetidin-2-carboxamide

(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 the method described in Example 1.

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 22

Receiving

(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

Stage 1: Receiving

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

To the solution

(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) was added Lawesson's reagent (1.01 g, 2.5 mmol), and the reaction solution was microwaved at 140 °C and reacted for three 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%).

¹ H NMR (400 MHz, DMSO-d ₆ ) 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);

MC m/z (ESI): 416.1 [M+H] ⁺ .

Stage 2: Receiving

(R)-3-(9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-4-(difluoromethyl)thiazide

olidin-2-one

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) were added dichloro(p-methylisopropylphenyl)ruthenium(II) dimer (14.7 mg, 0.024 mmol) and 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl (9.7 mg, 0.024 mmol), and the reaction was carried out under air atmosphere at 110 °C for 12 h. 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, CDCl ₃ ) 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);

MCm/z (ESI): 416.1 [M+H] ⁺ .

Stage 3: Receiving

(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

(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), copper 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. A saturated aqueous sodium bicarbonate solution was added, and the reaction solution was extracted with ethyl acetate three times. 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, CD ₃ OD) 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] ⁺ .

Example 23

Receiving

(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

(S)-2-((2-((S)-5-(difluoromethyl)-2-oxooxazolidin-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was prepared by the method described in Example 22.

MS m/z (ESI): 407.2 [M+H] ⁺ .

Example 24

Receiving

(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

(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 corresponds to Example 22.

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 25

Receiving

(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

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

Methyl L-threoninate 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 and a solution of ethylamine (895 mg, 8.84 mmol) in dichloromethane (2 mL) was added dropwise. After complete addition, the reaction was carried out at 0 °C for 1 h. Water was added and the reaction solution was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the organic solvent, and then the crude product was purified by column chromatography to give the title compound methyl (4S,5R)-5-methyl-2-oxooxazolidine-4-carboxylate (251 mg, 53%).

MCm/z (ESI): 160.1 [M+H] ⁺ .

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

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 one 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, concentrated under reduced pressure to remove the organic solvent, and then the crude product was 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] ⁺ .

Stage 3: Receiving

(4S,5R)-3-benzyl-4-(hydroxymethyl)-5-methyloxazolidin-2-one

(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 portions. The reaction solution was gradually warmed to room temperature and reacted for 2 hours. The reaction solution was concentrated, and then 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] ⁺ .

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

(4S,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 reacted under nitrogen atmosphere at 85°C for 3 hours. After cooling, the reaction solution was filtered and concentrated under reduced pressure to obtain 178 mg of crude product (4S,5R)-3-benzyl-5-methyl-2-oxooxazolidine-4-carbaldehyde, which was directly used in the next step.

MS m/z (ESI): 220.2 [M+H] ⁺ .

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

(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 under nitrogen atmosphere in an ice-water bath. DAST (262 mg, 1.62 mmol) was added dropwise, and the reaction solution was naturally warmed to room temperature and reacted for 3 h. 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 separated by column chromatography to give the title compound (4S,5R)-3-benzyl-4-(difluoromethyl)-5-methyloxazolidin-2-one (110 mg, two-step yield: 56%).

¹ H NMR (400 MHz, CDCl ₃ ) 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] ⁺ .

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

(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 reacted for 5 h. The reaction solution was cooled to room temperature, 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 separated by column chromatography to give 68 mg of the crude title compound (4S,5R)-4-(difluoromethyl)-5-methyloxazolidin-2-one, which was directly used in the next step.

MCm/z (ESI): 152.1 [M+H] ⁺ .

Stage 7: Receiving

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

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 -dimethylcyclohexane-1,2-diamine (22 mg, 0.15 mmol), copper 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 with ethyl acetate three times. The organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the organic solvent, and then subjected to column chromatography to give 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] ⁺ .

Stage 8: Receiving

(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

(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), copper 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 hours. 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 min, 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 h and filtered. Saturated aqueous sodium bicarbonate was added, and the reaction solution was extracted with ethyl acetate three times. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the organic solvent, and then separated by column chromatography to give 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, CD ₃ OD) 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] ⁺ .

Example 26

Receiving

(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

(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 the method described in Example 25.

MS m/z (ESI): 422.2 [M+H] ⁺ .

Example 27

Receiving

(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

(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 the method described in Example 25.

MS m/z (ESI): 436.2 [M+H] ⁺ .

Example 28

Receiving

(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

(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 the method described in Example 25.

MS m/z (ESI): 434.2 [M+H] ⁺ .

Example 29

Receiving

(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

(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 the method described in Example 25.

MS m/z (ESI): 450.2 [M+H] ⁺ .

Example 30

Receiving

(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

(S)-2-((2-((S)-5-(difluoromethyl)-3-methyl-2,4-dioxooxazolidin-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide was prepared by the method described in Example 1.

MS m/z (ESI): 435.2 [M+H] ⁺ .

Example 31

Receiving

(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

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

To a solution of 4-bromo-2,3-difluorobenzaldehyde (2.0 g, 9.05 mmol) in methanol (25 mL) was added sodium methoxide (733 mg, 13.56 mmol) 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] ⁺ .

Step 2: Preparation of 4-bromo-3-fluoro-2-hydroxybenzaldehyde

To a solution of 4-bromo-3-fluoro-2-methoxybenzaldehyde (1.78 g, 7.67 mmol) in acetic acid (15 mL) was added hydrobromic acid (8.7 mL, 48%) 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. Then, water and ethyl acetate were added to the reaction flask, and then the two phases were separated. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the organic solvent, and then purified by separation by column chromatography to give 4-bromo-3-fluoro-2-hydroxybenzaldehyde (1.12 g, 67%).

MS m/z (ESI): 219.0 [M+H] ⁺ .

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

To a methanol solution (12 mL) of 4-bromo-3-fluoro-2-hydroxybenzaldehyde (1.12 g, 5.14 mmol) was added an aqueous solution of glyoxal (40 wt %, 3.73 g, 25.7 mmol). Then, aqueous ammonia (28 wt %, 5.14 g, 51.4 mmol) was slowly added dropwise in a water bath with stirring. The dropwise addition process was continued for 30 minutes and the temperature of the reaction solution was controlled to be no higher than 40 °C. Then, the mixture was stirred at 35 °C for two 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] ⁺ .

Stage 4: Receiving

9-bromo-8-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine

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] ⁺ .

Stage 5: Receiving

9-bromo-8-fluoro-2,3-diiodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]okeazepine

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 solution 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] ⁺ .

Stage 6: Receiving

9-bromo-8-fluoro-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine

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 completion of the dropwise addition, the reaction solution was stirred at −15 °C for 3 h and slowly warmed to room temperature. Then, saturated aqueous ammonium chloride solution was added dropwise. The reaction solution was stirred for 15 min and extracted with ethyl acetate several times. The organic phases were combined and then washed with saturated brine. The organic phase was separated and dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the organic solvent, and subjected to separation by 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] ⁺ .

Stage 7: Receiving

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

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 -dimethylcyclohexane-1,2-diamine (42 mg, 0.30 mmol), copper 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 min and extracted with EtOAc three times. The organic phases were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to give 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] ⁺ .

(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 subsequently prepared by the method described in Example 1.

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 32

Receiving

(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

(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 the method described in Example 31.

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 33

Receiving

(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

(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 the method described in Example 31.

¹ H NMR (400 MHz, CD ₃ OD): 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] ⁺ .

Example 34

Receiving

(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

(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 the method described in Example 31.

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 35

Receiving

(S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-11-methyl-5,6-dihydrobenzo[f]imidazo

dazo[1,2-d][1,4]oxazepin-9-yl)amino)propionamide

(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 the method described in Example 31.

MS m/z (ESI): 422.1 [M+H] ⁺ .

Example 36

Receiving

(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

(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 the method described in Example 31.

¹ H NMR (400 MHz, CD ₃ OD): 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).

MC m/z (ESI): 422.1 [M+H] ⁺ .

Example 37

Receiving

(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

(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 the method described in Example 31.

MS m/z (ESI): 438.1 [M+H] ⁺ .

Example 38

Receiving

(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

(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 the method described in Example 31.

MS m/z (ESI): 438.1 [M+H] ⁺ .

Example 39

Receiving

(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

(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 the method described in Example 31.

MS m/z (ESI): 438.1 [M+H] ⁺ .

Example 40

Receiving

(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

(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 the method described in Example 31.

MS m/z (ESI): 433.1 [M+H] ⁺ .

Example 41

Receiving

(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

(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 the method described in Example 31.

MS m/z (ESI): 433.1 [M+H] ⁺ .

Example 42

Receiving

(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

(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 the method described in Example 31.

MS m/z (ESI): 433.1 [M+H] ⁺ .

Example 43

Receiving

(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

(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 the method described in Example 1.

¹ H NMR (400 MHz, CD ₃ OD) 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);

MC m/z (ESI): 438.2 [M+H] ⁺ .

Example 44

Receiving

(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

(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 the method described in Example 1.

¹ H NMR (400 MHz, CD ₃ OD): 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);

MC m/z (ESI): 452.2 [M+H] ⁺ .

Example 45

Receiving

(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

(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 the method described in Example 1.

MS m/z (ESI): 452.2 [M+H] ⁺ .

Example 46

Receiving

(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

(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 the method described in Example 1.

¹ H NMR (400 MHz, DMSO-d ₆ ) 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);

MC m/z (ESI): 406.2 [M+H] ⁺ .

Example 47

Receiving

(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

(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 the method described in Example 1.

¹ H NMR (400 MHz, CD ₃ OD) 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);

MC m/z (ESI): 436.2 [M+H] ⁺ .

Example 48

Receiving

(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

(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 the method described in Example 1.

MS m/z (ESI): 436.2 [M+H] ⁺ .

Example 49

Receiving

(S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-(1][1,4]oxazepin-9-yl)amino)-3-hydroxypropionamide

(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 the method described in Example 1.

¹ H NMR (400 MHz, CD ₃ OD) 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);

MC m/z (ESI): 424.1 [M+H] ⁺ .

Example 50

Receiving

(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

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

To a solution of 4-bromo-2,3-difluorobenzaldehyde (2.0 g, 9.05 mmol) in methanol (25 mL) was added sodium methoxide (733 mg, 13.56 mmol) 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 give 4-bromo-3-fluoro-2-methoxybenzaldehyde (1.78 g, 85%).

MS m/z (ESI): 233.0 [M+H] ⁺ .

Step 2: Preparation of 4-bromo-3-fluoro-2-hydroxybenzaldehyde

To a solution of 4-bromo-3-fluoro-2-methoxybenzaldehyde (1.78 g, 7.67 mmol) in acetic acid (15 mL) was added hydrobromic acid (8.7 mL, 48%) at room temperature. The reaction solution was heated to 120 °C and allowed to react for 16 hours. The reaction solution was cooled and then concentrated under reduced pressure. Then, water and ethyl acetate were added to the reaction flask, and then the two phases were separated. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the organic solvent, and then purified by separation by column chromatography to give 4-bromo-3-fluoro-2-hydroxybenzaldehyde (1.12 g, 67%).

MS m/z (ESI): 219.0 [M+H] ⁺ .

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

To a solution of 4-bromo-3-fluoro-2-hydroxybenzaldehyde (1.12 g, 5.14 mmol) in methanol (12 mL) was added an aqueous solution of glyoxal (40 wt %, 3.73 g, 25.7 mmol). Then, aqueous ammonia (28 wt %, 5.14 g, 51.4 mmol) was slowly added dropwise in a water bath with stirring. The dropwise addition process was continued for 30 minutes and the temperature of the reaction solution was controlled to be no higher than 40 °C. Then, the mixture was stirred at 35 °C for two days, cooled and purified by column chromatography after removing the organic solvent under reduced pressure to give 3-bromo-2-fluoro-6-(1H-imidazol-2-yl)phenol (1.31 g, 100%).

MS m/z (ESI): 257.0 [M+H] ⁺ .

Stage 4: Receiving

9-bromo-8-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine

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 with saturated brine several times, 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[1]imidazo[1,2-d][1,4]oxazepine (995 mg, 69%).

MS m/z (ESI): 283.0 [M+H] ⁺ .

Stage 5: Receiving

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

To a solution of 9-bromo-8-φτop-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 the solid. After filtration, the solid was dissolved in ethyl acetate, washed successively with 1 M aqueous NaOH solution 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] ⁺ .

Stage 6: Receiving

9-bromo-8-fluoro-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine

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 complete dropwise addition, the mixture was stirred at −15 °C for 3 h and slowly warmed to room temperature. Then, saturated aqueous ammonium chloride solution was 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 and 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] ⁺ .

Stage 7: Receiving

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

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 -dimethylcyclohexane-1,2-diamine (42 mg, 0.30 mmol), copper 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 min and extracted with EtOAc three times. The organic phases were combined, 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 (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] ⁺ .

Stage 8: Receiving

(S)-4-(difluoromethyl)-3-(8-fluoro-9-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)oxazolidin-2-thione

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 reacted for 6 h. 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] ⁺ .

Stage 9: Receiving

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

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) were 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 atmosphere at 115 °C for 16 h. 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] ⁺ .

Stage 10: Receiving

(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

(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), copper iodide (6.3 mg, 0.033 mmol) and potassium phosphate (53 mg, 0.25 mmol) were mixed in dimethyl sulfoxide (3 mL). The reaction system was purged with nitrogen three times and the reaction was carried out 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 thereto. The reaction solution was stirred at room temperature for 2 hours and filtered. A saturated aqueous sodium bicarbonate solution was added thereto, and the reaction solution was extracted with ethyl acetate three times. 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-((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, CD ₃ OD) 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);

MC m/z (ESI): 442.1 [M+H] ⁺ .

Example 51 Receipt

(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

(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 the method described in Example 50.

¹ H NMR (400 MHz, CD ₃ OD) 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);

MC m/z (ESI): 472.1 [M+H] ⁺ .

Example 52

Receiving

(S)-2-((2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[a]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)-3-methoxypropionamide

Stage 1: Receiving

(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

(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), copper 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 hours. 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 min, 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 h and filtered. Saturated aqueous sodium bicarbonate was added, and the reaction solution was extracted with ethyl acetate three times. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the organic solvent, and separated by column chromatography to give 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%).

¹ H NMR (400 MHz, CD ₃ OD) 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);

MC m/z (ESI): 454.1 [M+H] ⁺ .

Example 53

Receiving

(S)-1-(2-((R)-4-(difluoromethyl)-2-oxothiazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)pyrrolidin-2-carboxamide

(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 the method described in Example 22.

^1H 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);

MC m/z (ESI): 450.1 [M+H] ⁺ .

Example 54

Receiving

(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

(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 the method described in Example 22.

¹ H NMR (400 MHz, CD ₃ OD) 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);

MC m/z (ESI): 438.1 [M+H] ⁺ .

Example 55

Receiving

(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

(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 the method described in Example 1.

MC m/z (ESI): 448.1 [M+H] ⁺ .

Example 56

Receiving

(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

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

To a solution of 2-amino-4-bromobenzaldehyde (4.9 g, 24.6 mmol) in methanol (50 mL) was added an aqueous solution of glyoxal (40 wt %, 18 g, 124 mmol). Then, aqueous ammonia (28 wt %, 24 g, 172 mmol) was slowly added dropwise in a water bath under stirring. The dropwise addition process was continued for 30 minutes, and the temperature of the reaction solution was controlled to be no higher than 40 °C. Then, the mixture was stirred at 35 °C overnight, cooled, concentrated under reduced pressure, and subjected to column chromatography to give the title compound 5-bromo-2-(1H-imidazol-2-yl)aniline (3.5 g, yield: 60%).

MS m/z (ESI): 238.0 [M+H] ⁺ .

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

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 with EtOAc three times. 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 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] ⁺ .

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

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) portionwise at room temperature, followed by stirring at 60 °C overnight. After cooling, water was added to precipitate the solid. After filtration, the solid was dissolved in ethyl acetate, washed successively with 1 M aqueous NaOH solution 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%).

MC m/z (ESI): 515.8 [M+H] ⁺ .

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

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 slowly added dropwise EtMgBr (1.0 M solution in THF, 10 mL, 10 mmol) at −20 °C. After completion of the dropwise addition, the reaction solution was stirred at −15 °C for 3 h and slowly warmed to room temperature. Then, saturated aqueous ammonium chloride solution was added dropwise. The reaction solution was stirred for 15 min and extracted with ethyl acetate three times. 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] ⁺ .

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

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 -dimethylcyclohexane-1,2-diamine (28.4 mg, 0.2 mmol), copper 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 min and extracted with EtOAc three times. The organic phases were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to give the title compound (S)-3-(9-bromo-6,7-dihydro-5H-benzo[f]imidazo[1,2-d][1,4]diazoheptin-2-yl)-4-(difluoromethyl)oxazolidin-2-one (111 mg, yield: 60%).

MS m/z (ESI): 399.1 [M+H] ⁺ .

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

(S)-3-(9-bromo-6,7-dihydro-5H-benzo[f]imidazo[1,2-d][1,4]diazoheptin-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) were added, and the reaction solution was stirred at room temperature for 30 min. Sodium cyanoborohydride (39 mg, 0.62 mmol) was added. The reaction was carried out at room temperature for 3 h and quenched with saturated aqueous ammonium chloride solution. The reaction solution was extracted with EtOAc three times. The organic phases were combined, washed with a saturated aqueous solution of 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-7-methyl-6,7-dihydro-5H-benzo[f]imidazo[1,2-d][1,4]diazoheptin-2-yl)-4-(difluoromethyl)oxazolidin-2-one (81 mg, yield: 70%).

MC m/z (ESI): 413.1 [M+H] ⁺ .

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]diazoheptin-9-yl)amino)propionamide

(S)-3-(9-bromo-7-methyl-6,7-dihydro-5H-benzo[f]imidazo[1,2-d][1,4]diazoheptin-2-yl)-4-(difluoromethyl)oxazolidin-2-one (49.4 mg, 0.12 mmol), L-alanine (21.4 mg, 0.24 mmol), copper iodide (4.6 mg, 0.024 mmol) and potassium phosphate (51.5 mg, 0.24 mmol) were mixed in dimethyl sulfoxide (2 mL) and reacted at 100 °C for 5 hours. The reaction solution was cooled to room temperature, 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. A saturated aqueous sodium bicarbonate solution was added, and the reaction solution was extracted with ethyl acetate three times. 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]diazoheptin-9-yl)amino)propionamide (20 mg, yield: 40%).

¹ H NMR (400 MHz, CD ₃ OD) 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, 1.1 Hz, 1H), 6.35-6.68 (m, 1H), 7.16 (s, 1H), 7.84 (d, J=8.7 Hz, 1H);

MC m/z (ESI): 421.1 [M+H] ⁺ .

Example 57

Receiving

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

(S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-6,7-dihydro-5H-benzo[f]imidazo[1,2-d][1,4]diazoheptin-9-yl)amino)propionamide was prepared by the method described in Example 56.

¹ H NMR (400 MHz, CD ₃ OD) 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] ⁺ .

Example 58

Receiving

(S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-7-ethyl-6,7-dihydro-5H-benzo[f]imidazo[1,2-d][1,4]diazoheptin-9-yl)amino)propionamide

(S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-7-ethyl-6,7-dihydro-5H-benzo[f]imidazo[1,2-d][1,4]diazoheptin-9-yl)amino)propionamide was prepared by the method described in Example 56.

MS m/z (ESI): 435.1 [M+H] ⁺ .

Example 59

Receiving

(S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-7-isopropyl-6,7-dihydro-5H-benzo[f]imidazo[1,2-d][1,4]diazoheptin-9-yl)amino)propionamide

(S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-7-isopropyl-6,7-dihydro-5H-benzo[f]imidazo[1,2-d][1,4]diazoheptin-9-yl)amino)propionamide was prepared by the method described in Example 56.

MS m/z (ESI): 449.1 [M+H] ⁺ .

Example 60

Receiving

(S)-2-((7-cyclopropyl-2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-6,7-dihydro-5H-benzo[f]imidazo[1,2-d][1,4]diazoheptin-9-yl)amino)propionamide

(S)-2-((7-cyclopropyl-2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-6,7-dihydro-5H-benzo[f]imidazo[1,2-d][1,4]diazoheptin-9-yl)amino)propionamide was prepared by the method described in Example 56.

MS m/z (ESI): 447.1 [M+H] ⁺ .

Example 61

Receiving

(S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-7-(oxbutan-3-yl)-6,7-dihydro-5H-benzo[f]imidazo[1,2-d][1,4]diazoheptin-9-yl)amino)propionamide

(S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-7-(oxbutan-3-yl)-6,7-dihydro-5H-benzo[f]imidazo[1,2-d][1,4]diazoheptin-9-yl)amino)propionamide was prepared by the method described in Example 56.

MS m/z (ESI): 463.1 [M+H] ⁺ .

Example 62

Receiving

(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

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

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) and the dropwise addition of glyoxal (4.5 ml, 221.7 mmol), 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, and then dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography to give the title compound 2-(5-bromo-2-fluorophenyl)-1H-imidazole (3.3 g, yield: 56%).

¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

MC m/z (ESI): 241.0 [M+H] ⁺ .

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

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 with dichloromethane three times. The organic phases were combined, then dried over anhydrous sodium sulfate, concentrated under reduced pressure and subjected to column chromatography to give the title compound 9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]thiazepine (1.0 g, yield: 43%).

MC m/z (ESI): 281.0 [M+H] ⁺ .

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

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) portionwise at room temperature, followed by stirring at 60 °C overnight. After cooling, water was added to precipitate the solid. After filtration, the solid was dissolved in ethyl acetate, washed successively with 1 M aqueous NaOH solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound 9-bromo-2,3-diiodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]thiazepine (1.6 g, yield: 86%).

MC m/z (ESI): 532.8 [M+H] ⁺ .

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

To a solution of 9-bromo-2,3-diiodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]tizepine (1.6 g, 3.0 mmol) in THF (10 mL) was slowly added dropwise EtMgBr (1.0 M solution in THF, 3.3 mL, 3.3 mmol) at −20 °C. After completion of the dropwise addition, the reaction solution was stirred at −15 °C for 3 h and slowly warmed to room temperature. Then, saturated aqueous ammonium chloride solution was added dropwise. The reaction solution was stirred for 15 min and extracted with ethyl acetate three times. 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]thiazepine (1.03 g, yield: 85%).

MS m/z (ESI): 406.9 [M+H] ⁺ .

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

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 -dimethylcyclohexane-1,2-diamine (28.4 mg, 0.2 mmol), copper iodide (19.0 mg, 0.1 mmol) and potassium carbonate (138 mg, 1.0 mmol) were mixed in 1,4-dioxane (4 ml) and reacted at 100°C for 5 hours. The reaction solution was cooled to room temperature and 14% aqueous ammonia was added. The reaction solution was stirred for 5 min and extracted with EtOAc three times. The organic phases were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to give the title compound (S)-3-(9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]thiazepin-2-yl)-4-(difluoromethyl)oxazolidin-2-one (124 mg, yield: 65%).

MS m/z (ESI): 416.0 [M+H] ⁺ .

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

(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), copper iodide (4.6 mg, 0.024 mmol) and potassium phosphate (51.5 mg, 0.24 mmol) were mixed in dimethyl sulfoxide (2 mL) and reacted 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 thereto. The reaction solution was stirred at room temperature for 2 hours and filtered. A saturated aqueous sodium bicarbonate solution was added thereto, and the reaction solution was extracted with ethyl acetate three times. 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, CDCl ₃ ) 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] ⁺ .

II. Bioassay and evaluation of compounds

The present invention will be further described with reference to the following test examples, but these examples do not limit the scope of the present invention.

1. Determination of the inhibitory effect of the compounds according to the examples of the present invention on PI3Kα/β/γ/δ kinase activity

1.1 Purpose of the experiment:

The purpose of this test example was to test the inhibitory activity of the compounds according to the examples against PI3Kα/β/γ/δ kinase activity.

1.2 Experimental equipment:

The centrifuge (5810R) was purchased from Eppendorf. The pipettes were purchased from Eppendorf or Rainin.

The microplate reader was purchased from BioTek, USA, model: SynergyH1 Hybrid Multi-Mode Microplate Reader.

1.3 Experimental method:

ADP-Glo Lipid Kinase Assay (Promega #V9102) from Promega was used in this experiment. PI3Kα/β/γ/δ lipid kinases catalyze the reaction of ATP (adenosine triphosphate) to ADP (adenosine diphosphate) in the presence of PIP2:3PS substrate and ATP. Lipid kinase activity was characterized by measuring the ADP content of the reaction and the half-maximal inhibitory concentrations ( _IC50) of the compounds on PI3Kα/β/γ/δ kinase activity were obtained.

The specific experimental process was as follows:

Kinase reactions were performed in white 384-well plates (Perkin Elmer #6007299). 2 μl of various concentrations of compound diluted in _ddH2O containing 1% DMSO were added to each well, and 2 μl of _ddH2O containing 1% DMSO were added to the positive control wells. Then 2 μl of 0.1-2 nM PI3K kinase solution diluted in 5× kinase buffer (HEPES 250 mM, MgCl2 ₁₅ mM, NaCl 250 mM, BSA (bovine serum albumin) 0.05%) were added to each well, and 2 μl of 5× kinase buffer were added to the negative control wells. To all wells, 4 μl of 50 μM PIP2:3PS substrate (Promega#V1701) prepared with 10× dilution buffer and _ddH2O were added. Finally, 2 μl of 50-100 μM ATP solution diluted with water were added to start the reaction. After the reaction was carried out at room temperature for 90-120 minutes, 10 μl of ADP-Glo reagent (containing 10 mM _MgCl2 ) 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. After the reaction was allowed to proceed for 20 min at room temperature in the dark, chemiluminescence was measured using a BioTek Synergy H1 microplate reader.

Experimental method of data processing:

The percent inhibition data of the compound-treated well was calculated based on 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) × 100}. _IC50 values were calculated using GraphPad prism and a four-parameter nonlinear logistic formula to fit the data of different concentrations and the corresponding percent inhibition.

1.4 Experimental conclusion:

According to the above scheme, the compounds according to the examples of the present invention showed biological activity in the PI3Kα/β/γ/δ kinase activity test, as shown in Table 7 below.

The above data show that the compounds according to the examples of the present invention have good activity and selectivity with respect to PI3Kα/β/γ/δ kinase activity.

2. Determination of the proliferation inhibitory effect of the compounds according to the examples of the present invention on PI3Kα-mutant cancer cells

2.1 Objective of the experiment:

The objective of this test example was to test the proliferation inhibitory activity of the compounds according to the examples against PI3Kα-mutant cancer cells HCC1954 (H1047R), HGC-27 (E542K) and MKN1 (E545K).

2.2 Experimental devices:

The centrifuge (5702R) was purchased from Eppendorf.

The carbon dioxide incubator was purchased from Thermo.

The biological safety cabinet was purchased from Shanghai Boxun.

Pipettes were purchased from Eppendorf or Rainin.

The microplate reader was purchased from BioTek, USA, model: SynergyH1 Hybrid Multi-Mode Microplate Reader.

2.3 Experimental method:

The proliferation inhibitory activity of the compounds according to the examples against PI3Kα mutant cancer cell lines (HCC1954, HGC-27 and MKN1) was detected by the Cell Titer-Glo assay. The cell lines were cultured in RPMI 1640 medium (Gibco #22400089) containing 10% FBS (fetal bovine serum, Gibco #10091148) and 1% P/S (Hyclone #SV30010) at 37°C and 5% CO ₂ . The cells were harvested before the experiment and the cell density was adjusted after cell counting. The cells were seeded in a white 96-well plate (Corning #3610) at a density of 1000 to 10000 cells/well and incubated in an incubator at 37°C and 5% CO ₂ overnight. The resulting solutions of compounds of various concentrations and the corresponding solvent controls were added to the plate. The plate was again incubated in an incubator at 37°C and 5% _CO2 for 48-96 hours. The cell plate and its contents were then conditioned to room temperature. 20 to 100 µl of Cell Titer-Glo solution (Promega #G7573) were added to each well, the plate was shaken and mixed well, then incubated at room temperature for 5-30 minutes in the dark. Chemiluminescence was measured using a SynergyH1 microplate reader from BioTek.

2.4 Experimental method of data processing:

Percent inhibition data for the compound-treated well were calculated based on the solvent control wells on the plate {% inhibition = 100 - (test compound value - solvent control value) × 100}. _IC50 values were calculated using GraphPad prism and a four-parameter nonlinear logistic formula to fit the different concentration data and the corresponding percent inhibition.

2.5 Experimental conclusion of the experiment:

According to the above scheme, the compounds according to the examples of the present invention showed biological activity in the proliferation inhibitory activity test against PI3Kα-mutant cancer cells HCC1954 (H1047R), HGC-27 (E542K) and MKN1 (E545K), as shown in Table 8 below.

The above data demonstrate that the compounds according to the examples of the present invention have good activity in terms of proliferation inhibitory activity against PI3Kα-mutant cancer cells HCC1954 (H1047R), HGC-27 (E542K) and MKN1 (E545K).

3. 7-day repeated intragastric administration toxicity test in SD rats (Sprague-Dawley)

3.1 Purpose of the experiment

The aim 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 7-day repeated intragastric administration and to compare the differences in toxicity of GDC-0077, the compounds of Example 22 and Example 62.

3.2 Experimental materials and equipment

3.2.1 Test connections

Test Compound 1: GDC-0077

Test compound 2: compounds according to example 22 and example 62

3.2.2 Carrier

Name: 20% aqueous solution of SBE-β-CD (Captisol)

3.2.3 Information about animals

Species and strains: Sprague-Dawley (SD) rat

Animal class: SPF (Specific Pathogen Free) class

Number and sex of animals: 160 rats, half male and half female.

3.2.4 Devices

The ADVIA® 2120 Series Hematology System with Autoslide was used to count blood cells;

To detect indicators of blood coagulation function, the SYSMEX CA-500 coagulation analyzer was used;

To determine biochemical parameters of blood, an automatic biochemical analyzer TBA-120FR was used;

An Easylyte electrolyte analyzer was used to detect electrolytes;

API4000 Liquid Mass Spectrometry Detector;

Electron spray ionization (ESI) in positive ion mode and an Agilent ZORBAX XDB-C18 column (3.5 μm, 2.1×50 mm) were used for bioanalytical analysis of plasma samples.

3.3 Experimental method

1) In the experiment, 160 rats (80 rats/sex) were divided into 20 groups according to their sex and body weight, with 100 rats used for toxicological study (groups 1-10, 5 rats/sex/group) and 60 rats used for toxicokinetic study (groups 11-20, 3 rats/sex/group);

2) As a control group, animals in groups 1 and 11 were intragastrically administered a 20% aqueous solution of SBE-β-CD (Captisol);

3) Animals in groups 2 and 12, groups 3 and 13, and groups 4 and 14 were administered 10, 30, and 60 mg/kg GDC-0077 intragastrically, respectively;

4) Animals in groups 5 and 15, groups 6 and 16, and groups 7 and 17 were administered intragastrically 10, 30, and 60 mg/kg of the compound according to Example 22, respectively;

5) Animals in groups 8 and 18, groups 9 and 19, groups 10 and 20 were administered intragastrically 10, 30 and 60 mg/kg of the compound according to Example 62, respectively;

5) Animals were administered once daily for 7 consecutive days (animals in groups 7, 17, 10 and 20 were administered for 6 consecutive days).

6) The injection volume was 10 ml/kg.

7) During the experiment, such characteristics as clinical observation, body weight, food consumption, clinical and pathological indicators (blood cell count, blood clotting function, blood biochemistry), toxicokinetics, etc. were studied.

8) All animals were sacrificed on day 8 (animals in groups 7, 10, 17 and 20 were sacrificed after administration on day 6).

9) During the experiment, macroscopic anatomical observation was performed on the animals in Groups 1-10, animals in Groups 17 and 20, and dead animals (including animals in the toxicology study). Histopathological examination was performed on abnormal tissues, gastrointestinal tract tissues (such as colon, cecum), and immune tissues (such as thymus).

3.4 Experimental conclusion

At a dose of 30 mg, the mean AUC (area under the concentration-time curve) of systemic exposure of the compound according to Example 22 after the last administration (male: 11,400 h×ng/mL, female: 15,900 h×ng/mL) was approximately 2.4-3.8 times higher than that of GDC-0077 at the same dose (male: 3,000 h×ng/mL, female: 6,510 h×ng/mL), and was similar to that of GDC-0077 at a dose of 60 mg/kg after the first administration (male: 15,400 h×ng/mL, female: 22,800 h×ng/mL).

At a dose of 10 mg, the mean systemic exposure AUC of the compound according to Example 22 after the last administration (male: 2110 h×ng/mL, female: 3170 h×ng/mL) was approximately 1.4-2.5 times higher than that of GDC-0077 (male: 845 h×ng/mL, female: 2250 h×ng/mL).

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

In this experiment, the test compounds GDC-0077 and Example 22 were administered intragastrically to SD rats repeatedly for 7 days at doses of 10, 30, and 60 mg/kg (once daily). The lethal dose of GDC-0077 and the compound of Example 22 was 60 mg/kg, and the maximum tolerated dose (MTD) was 30 mg/kg. At the dose of 30 mg/kg, the C _max and AUC _{(0-24 h)} of the compound of Example 22 were significantly higher than those of GDC-0077. The tolerance to the compound of Example 22 was better than that of GDC-0077.

Under the conditions of this experiment, the test compounds GDC-0077, Example 22 and Example 62 were administered intragastrically to SD rats repeatedly for 7 days at doses of 10, 30 and 60 mg/kg (once daily). The C _max and AUC _{(0-24 h)} of the compounds according to Example 22 and Example 62 were significantly higher than those of GDC-0077. The tolerance to the compound according to Example 22 and Example 62 was better than that of GDC-0077.

4. In vivo efficacy testing of compounds according to the examples of the present invention

4.1 Purpose of the experiment

The aim was to screen compounds with greater potency and less toxicity and side effects using in vivo efficacy experiments.

4.2 Basic experimental equipment and materials

4.2.1 Devices:

1. Biological safety cabinet (BSC-1300II A2, Shanghai Boxun Medical Biological Instrument Corp.)

2. Ultra-clean workspace (CJ-2F, Suzhou Fengshi Laboratory Animal Equipment Co., Ltd.)

3. CO ₂ incubator (Thermo-311)

4. Centrifuge (Centrifuge 5702R, Eppendorf)

5. Automatic cell counter (Countess II, Life)

6. Pipettes (10-20 µl, Eppendorf)

7. Microscope (TS2, Nikon)

8. Vernier caliper (CD-6''AX, Mitutoyo, Japan)

9. Cell culture flasks (T75/T225, Corning)

10. Electronic scales (CPA2202S, Sartorius)

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-action antibiotics (15140-122, Gibco)

5. Phosphate buffered saline (PBS) (10010-023, Gibco)

6. Matrigel (Matrigel Matrix, 356234, Corning)

4.2.3 Animals:

Nude BALB/c mice (6 to 8 weeks old, ) were purchased from Shanghai Xipuer-Bikai Laboratory Animal Co., Ltd.

4.3 Experimental process

4.3.1 Cell culture and preparation of cell suspension

a. The HCC1954 cell strain was collected from the cell bank, reconstituted with RPMI-1640 medium (RPMI-1640 + 10% FBS + 1% SP), seeded into a cell culture flask (cell type, date, experimenter's name, etc. were noted on the wall of the flask), and cultured in a _CO2 incubator (the temperature was 37°C and the _CO2 concentration was 5% in the incubator).

b. The cells were subcultured when they covered 80 to 90% of the bottom of the culture flask. After subculture, the cells were further cultured in a CO ₂ incubator. This process was repeated until the number of cells was sufficient to conduct the in vivo efficacy assay.

c. The cultured cells were collected and counted using an automatic cell counter, and then resuspended with PBS and Matrigel Matrix according to the counting results to obtain a cell suspension (density 5× ¹⁰⁷ /mL), which was placed in a refrigerator for use.

4.3.2 Inoculation of cells

a. Nude mice were tagged with disposable universal rat and mouse ear tags prior to inoculation.

b. During inoculation, the cell suspension was mixed well. 0.1 to 1 ml of the cell suspension was withdrawn using a 1 ml syringe, air bubbles were removed, and then the syringe was placed on an ice pack for use.

c. The athymic mouse was restrained on the left arm. The area on the right side of the back near the right shoulder of the athymic mouse (inoculation site) was disinfected with 75% alcohol. Inoculation was started after 30 seconds.

d. Nude test mice were sequentially inoculated (each mouse was inoculated with 0.1 ml of cell suspension).

4.3.3 Tumor measurement, grouping and administration for tumor-bearing mice

a. According to tumor growth, tumors were measured at 14-18 days after inoculation and tumor size was calculated.

Tumor volume calculation: tumor volume ( ^mm3 ) = length (mm) x width (mm) x width (mm)/2

b. Tumor-bearing mice were grouped according to their body weight and tumor size by random grouping.

c. The test compounds were administered according to the grouping results (administration route: oral administration; administration dose: 10 mg/kg; administration volume: 10 ml/kg; administration frequency: once a day; administration cycle: 21 days; vehicle: 0.5% CMC/1% Tween 80).

d. Tumors were measured and weighed twice weekly after the start of test compound administration.

e. Animals were sacrificed at the end of the experiment.

f. The data were processed by software such as Excel. Calculation of tumor growth inhibition rate TGI (%) of the compound: when the tumor does not regress, TGI (%) = [(1 - (average tumor volume of the treatment group at the end of administration - average tumor volume of the treatment group at the start of administration)) / (average tumor volume of the vehicle control group at the end of treatment - average tumor volume of the vehicle control group at the start of treatment)] × 100%. When the tumor regresses, TGI (%) = [1 - (average tumor volume of the treatment group at the end of administration - average tumor volume of the treatment group at the start of administration) / average tumor volume of the treatment group at the start of administration] × 100%.

4.5 Experimental results:

From the above results, it is evident that the above compounds of the present invention have good tumor growth inhibition rates.

5. Pharmacokinetic (PK) analysis of compounds according to the examples of the present invention in mice

Pharmacokinetic analysis of the preferred compounds according to the examples of the present invention in mice was performed in male Balb/c mice (Shanghai Jiesijie Laboratory Animal Co., Ltd.).

5.1 Route of administration: single intragastric administration.

5.2 Dose of administration: 5 mg/10 ml/kg (body weight).

5.3 Composition: The compound was dissolved in 0.5% CMC-Na using ultrasound to obtain a clear solution or homogeneous suspension.

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

5.5 Sample processing:

1) 0.1 ml of orbital blood was collected and placed in a tube with _K2 -EDTA, centrifuged at 1000-3000×g at room temperature for 5-20 minutes to separate the plasma, which was then stored at minus 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 μl of the supernatant after treatment was collected and analyzed by LC/MS/MS analysis to determine the compound concentrations according to the example.

5.6 LC-MS/MS analysis:

Liquid Chromatography Condition: Shimadzu LC-20AD Pump

Mass spectrometry condition: mass spectrometer AB Sciex API 4000

Chromatographic column: phenomenex Gemiu 5 µm C18 50×4.6 mm

Mobile phase: Solution A was 0.1% aqueous formic acid and solution B was acetonitrile

Flow rate 0.8 ml/min

Elution time: 0 to 4 minutes, gradient elution

5.7 Pharmacokinetics:

The main parameters were calculated using WinNonlin 6.1, and the experimental results of the pharmacokinetic analysis in mice are shown in Table 10 below:

From the results of the pharmacokinetic analysis in mice shown in the table, it can be seen that the compounds according to the examples of the present invention showed good metabolic properties, and both the AUC for plasma exposure and the maximum plasma concentration C _max were good.

III. Study 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 salts and crystalline forms of the compound

1.1 Screening of compound salts

1.1.1 Objective of the experiment:

The goal is to identify acids with counterions that can form salts with the compound by selecting different acids with counterions and suitable crystallization methods.

1.1.2 Experimental stages:

1) Tools and equipment

2) Procedure for performing operations

(1) THF was used as a solvent in the liquid-liquid reaction for crystallization

Weighed out 300 mg of free base, added 15 ml of THF and heated the mixture to 50°C to completely dissolve. The solution of free base in THF was divided into 8 equal parts and a certain amount of acid was added to each part (the molar ratio in the reaction base:acid is 1:1.2), as described in detail below:

(2) Acetone was used as a solvent in the solid-liquid reaction for crystallization

20 mg of free base was weighed, 0.2 ml of acetone was added, the mixture was stirred and suspended at room temperature. Acid (the molar ratio of base:acid in the reaction was 1:1.2) was added to the suspension system for the reaction, as detailed below:

(3) Acetone was used as a solvent in the crystallization reaction

About 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:

(4) DMF was used as a solvent for crystallization

About 20 mg of the free base was weighed and dissolved in 200 µl of DMF to give a clear solution at room temperature. The following acids were added for the reaction:

(5) Methanol was used as a solvent for crystallization

20 mg of free base was weighed, 0.2 ml of methanol was added and the mixture was stirred and suspended at 50°C. Acid (the molar ratio of base:acid in the reaction was 1:1.2) was added to the suspension system for the reaction, as detailed below:

(6) The method of natural evaporation was used to obtain salts

THF was used as the solvent in #1-10, and the free base was dissolved in THF to form a clear solution, and then the acid was added. Ethanol was used as the solvent in #11-14, the free base was suspended in ethanol, and a clear solution was formed after the acid was added. The clear solution formed in #1-14 was left at room temperature without sealing the container to evaporate the solvent.

1.1.3 Experimental results

In the screening experiment with salt forms, the salt forms obtained with the crystalline forms were ethanesulfonate, methanesulfonate and sulfate salts.

2 Screening of crystalline forms of salts of the compound

Based on the results of the salt form screening, suitable crystallization methods were selected for screening various crystalline forms of ethanesulfonate, methanesulfonate and sulfate salts.

2.1 Experimental instruments

2.1.1 Some parameters of physical and chemical testing devices

2.2 Instruments and conditions for liquid phase analysis 2.2.1 Instruments and devices

2.2.2 Chromatographic conditions

Chromatographic column: ZORBAX (SB-C8, 3.5 µm, 4.6×75 mm)

Flow rate: 1 ml/min

Column temperature: 40°C

Detection wavelength: 220/328 nm

Injection volume: 5.0 µl

Working time: 12 min

Diluent: ACN (acetonitrile)-water (v/v, 1:1)

Mobile phase: A: water (0.05% trifluoroacetic acid); B: acetonitrile (0.05% trifluoroacetic acid)

2.3 Procedure for performing operations

(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

Weighed 60 mg

(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, 1.2 ml of acetone was added, and the mixture was stirred at 50 °C to obtain 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 ethanesulfonate salt crystal form A

(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, it had the XRPD diffraction pattern as shown in Figure 1, the TGA profile as shown in Figure 2, and the DSC profile as shown in Figure 3.

(2) Preparation 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

Weighed 60 mg

(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, 3 ml of ethanol were added and the mixture was stirred at 50°C to obtain 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. 0.6 ml of ethanol was added, the reaction solution was stirred and reacted at 50°C for 2 hours, then cooled, filtered and dried to finally obtain (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 crystalline form A. After detection and analysis, it had an XRPD pattern as shown in Figure 4.

(3) Preparation of crystalline form B 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

30 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 mesylate salt crystalline form A was weighed, 200 μL of methanol was added, and the mixture was suspended at room temperature for 10 days. Finally, the solid was centrifuged and the supernatant was removed. Then, the solid was dried in a vacuum drying oven at 40 °C to a constant weight to obtain mesylate salt crystalline form B

(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, it had an XRPD diffraction pattern as shown in Figure 5.

(4) Preparation of crystalline form C 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

30 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 mesylate salt crystalline form A was weighed and left to stand at room temperature at 92.5% relative humidity for 3 h to obtain mesylate salt crystalline form C

(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, it had an XRPD diffraction pattern as shown in Figure 6.

(5) Preparation 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

Weighed 14 mg

(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, 280 μl of isopropanol were added, and the mixture was suspended at 40°C. 39 μl _of 1 M _H2SO4 in ethanol was added, and an oil was formed and adhered to the wall. Then, the reaction system was stirred to precipitate a large amount of solid, which was characterized as amorphous after centrifugation. To the resulting amorphous solid, 200 μl of ethyl acetate was added, and after the mixture was suspended at room temperature, no crystal was still observed. Then 100 μL of ethanol was added and the system was completely dissolved to form a clear solution. A small amount of methyl tert-butyl ether was added at room temperature and the solution became cloudy. After stirring, the finally precipitated solid was (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 salt crystalline form A. After detection and analysis, it had an XRPD pattern as shown in Figure 7.

(6) Preparation 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

Weighed 15 mg

(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, 300 μL of isopropanol were added and the mixture was suspended at room temperature. 42 μL of 1 M H ₂ SO ₄ in ethanol were added, no reaction was observed and the free base remained. After the mixture was heated to 50 °C, stirred for 1 h and left to stand at room temperature overnight, no crystals were still observed. 100 μL of methanol was added, a small amount of oil was formed and adhered to the wall. The mixture was stirred at 50 °C to obtain a clear solution. A small amount of methyl tert-butyl ether was added and the solution became cloudy, it was stirred at room temperature for 48 hours and then at 50 °C. 200 μL of methanol and 400 μL of methyl tert-butyl ether were added and eventually the mixture became cloudy with the precipitation of a large amount of solid, which was the 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 salt. After detection and analysis, it had the XRPD pattern as shown in Figure 8.

(7) Preparation 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

Weighed 23.5 mg

(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, 235 μL of methanol were added, and the mixture was suspended at 50°C. 66 μL of 1 M H ₂ SO ₄ in ethanol was added, and the reaction solution became clear. 300 μL of methyl tert-butyl ether was added, and the reaction solution became cloudy. Then, a small amount of the sulfate salt crystal form A was added

(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 a large amount of solid precipitated. Finally, 400 μL of methanol was added, and the solid did not dissolve. After 1 h of reaction, 400 μL of methyl tert-butyl ether was added. Finally, the solid was centrifuged and dried to obtain the crystalline form C of the sulfate salt

(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, it had an XRPD diffraction pattern as shown in Figure 9.

(8) Obtaining the crystalline form D of the sulfate salt

(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

Weighed 60 mg

(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, 1.2 ml _of acetone 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 obtain 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 (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 salt crystal form C was added as a crystal nucleus. A large amount of solid precipitated after stirring. Finally, the reaction solution was stirred and reacted at 50°C for 2 hours, then cooled, filtered and dried to finally obtain (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 salt crystal form D. After detection and analysis, it had an XRPD diffraction pattern as shown in Figure 10.

(9) Preparation 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

30 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 sulfate salt crystalline form D was weighed, 200 μL of acetone was added, and the mixture was suspended at room temperature for 10 days. Finally, the solid was centrifuged and the supernatant was removed. Then, the solid was dried in a vacuum drying oven at 40 °C to a constant weight to obtain sulfate salt crystalline form E

(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, it had an XRPD diffraction pattern as shown in Figure 11.

3. Experiment on the stability of solids 3.1 Objective of the experiment

The aim was to study 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.

(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 conditions of accelerated degradation or influencing factors and providing a basis for screening salt forms and storage of salts of the compound.

3.2 Experimental scheme:

About 2 mg of mesylate salt crystalline Form A, sulfate salt crystalline Form C and ethanesulfonate salt 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 were placed in a sealed oven at 60°C, in a non-sealed container at room temperature at RH 95% (saturated aqueous _KNO3 solution) and in a light box (5000 lx ±500 lx) and observed for 5 days and 10 days. The salt content was determined by HPLC using the external standard method. The changes in the congener of the salt in the salt-related substances were calculated by normalizing the chromatographic peak area.

3.3 Experimental results:

When comparing the liquid chromatograms, it was found that for the mesylate salt crystalline form A, 1 new impurity appeared with an increase of 0.523% under light conditions for 10 days compared to 0 days, and the impurity increase was less than 0.05% at both 60°C and room temperature at 95% RH for 10 days compared to 0 days; for the sulfate salt crystalline form C, 1 new impurity appeared with an increase of 0.172% under light conditions for 10 days compared to 0 days, and the impurity increase was less than 0.05% at both 60°C and room temperature at 95% RH for 10 days compared to 0 days; For the ethanesulfonate salt crystalline form A, 1 new impurity appeared with an increase of 0.134% under light conditions for 10 days compared with 0 days, and the impurity increase was less than 0.05% at both 60°C and room temperature at RH 95% for 10 days compared with 0 days.

3.4 Experimental conclusion

Crystalline forms of the compound salts are unstable under light conditions and should be protected from light during subsequent storage. However, relatively speaking, the compound salts and their crystal forms are relatively stable under light conditions. In addition, the compound salts and their crystal forms are more stable at 60°C and at room temperature at RH 95%.

4. Experiment on hygroscopicity

4.1 Purpose of the experiment

The aim was to study 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.

(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 conditions of varying relative humidity and providing a basis for screening and storage of salts of the compound.

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 with different relative humidities so that the compound and the water vapor reached dynamic equilibrium, and the percentage of hygroscopic mass gain of the compound after equilibrium was calculated.

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

(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 had a hygroscopic mass gain of 3.6% at RH 80% and was hygroscopic. After 1 cycle of wetting and drying at a relative humidity of 0 to 95%, the XRPD diffraction pattern of 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 changed, i.e. the crystalline form changed, and the changed crystalline form was the crystalline form C of the mesylate salt.

2) Crystalline form D of sulfate salt

(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 1.256% at 80% RH and was hygroscopic.

3) Crystalline form A of ethanesulfonate salt

(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 weight gain of 0.207% at 80% RH, had a slight hygroscopicity, and had no obvious change in hygroscopicity. After 1 cycle of wetting and drying at a relative humidity of 0 to 95%, the XRPD diffraction pattern of crystalline form A of the ethanesulfonate salt of the compound

(S)-2-((2-(((R)-4-(difluoromethyl)methyl))-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.

5. Experiment on solubility in different media

5.1 Purpose of the experiment

The objective is to compare the solubility of crystalline form A of the ethanesulfonate salt

(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 with different pH values, water, simulated gastric juice (SGF), fasted simulated intestinal juice (FaSSIF) and fed simulated intestinal juice (FeSSIF), and to provide a basis for evaluating the medicinal potency of the salts.

5.2 Experimental scheme:

About 2 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 ethanesulfonate salt crystalline form A were suspended in various media for 24 hours. The thermodynamic solubility of the compound at 37°C was determined by HPLC using the external standard method.

5.3 Experimental results: As shown in Table 15.

5.4 Experimental conclusion

From the results of solubility of crystalline form A of 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 the above-mentioned various media, it is evident 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 after salt formation had slightly lower solubility in buffer media with pH from 4 to 8, but salt formation increased the solubility

(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 in water.

6. Polymorph screening experiment

6.1 Objective of the experiment:

The goal is to find more stable crystalline forms by screening polymorphs.

6.2 Experimental scheme:

Organic solvents and water with certain solubility were selected to suspend the compound in the solvent system, and the mixture was stirred and suspended at room temperature for 1 week, and then centrifuged. The supernatant was discarded, and the solid was dried in vacuum (-0.1 MPa) at 40°C overnight. Then, the XRPD of the solid was measured and compared with the XRPD of the salt of the compound.

6.3 Experimental results:

Through the process of suspension, replacement of the crystallization solvent, crystallization model, etc., only 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 crystalline form A was obtained.

7. PK studies on animals

7.1 Objective of the experiment:

7.1.1 The objective was to compare the differences in the effects of crystalline form A of the mesylate salt, crystalline form D of the sulfate salt and crystalline form A of the ethanesulfonate salt

(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 animals in vivo using animal PK studies.

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 uniformly 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 amount of the compound was completely converted into 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.

7.3 Experimental results:

7.3.1 Experimental results of the FC experiment of the crystalline form A of the mesylate salt, the crystalline form D of the sulfate salt and the crystalline form A of the ethanesulfonate salt

(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 presented in Table 16 below:

The 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

(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 higher effects. 7.4 Experimental conclusion

The effect of the drug on rats may be increased by salt formation.

Claims (128)

1. An addition salt of an acid of formula (II-B) having the following structure: Where: R ₁ is methyl; R ₂ is hydrogen; R ₃ is hydrogen; M is an inorganic acid or an organic acid, wherein said inorganic acid is sulfuric acid; and said organic acid is selected from the group consisting of ethanesulfonic acid and methanesulfonic acid; x is an integer between 0 and 3; and y represents the integer 1. 2. An addition salt of an acid, characterized in that its specific structure is as follows: M is an inorganic acid or an organic acid, wherein said inorganic acid is sulfuric acid; said organic acid is selected from the group consisting of ethanesulfonic acid and methanesulfonic acid; and y is equal to 1. 3. An acid addition salt of formula (II-B) according to claim 1, characterized in that said acid addition salt is an ethanesulfonate or 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. 4. An acid addition salt of formula (II-B) according to claim 3, characterized in that said acid addition salt is 5. A method for producing an acid addition salt according to any one of paragraphs 1-4, in particular comprising the following steps: 1) weighing the free base of the compound and adding an organic solvent to obtain a clear or suspended mother liquor; 2) adding acid M to an organic solvent or water to obtain an acidic solution of the counterion; 3) adding an acidic solution of the counterion to the mother liquor to obtain a salt solution, stirring the salt solution to precipitate a solid, and drying the said solid; the organic solvent in step 1) or 2) is one or more solvents selected from the group consisting of methanol, ethanol, isopropanol, ethyl acetate, acetone, dichloromethane and acetonitrile. 6. An acid addition salt according to any one of paragraphs 1-4, characterized in that the acid addition salt is in crystalline form or amorphous form. 7. An acid addition salt according to any one of paragraphs 1-4, characterized in that the acid addition salt is a hydrate or an anhydrate. 8. A crystalline form of an acid addition salt according to claim 6, characterized in that the crystalline form is 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, the X-ray powder diffraction pattern of which includes 4, 6, 8 or 10 diffraction peaks at 2θ equal to 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°, 23.6±0.2°, 9.3±0.2° and 17.3±0.2°; the crystalline form is 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, the X-ray powder diffraction pattern of which includes 4, 6, 8 or 10 diffraction peaks at 2θ equal to 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°; the crystalline form is 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, the X-ray powder diffraction pattern of which includes 4, 6, 8 or 10 diffraction peaks at 2θ equal to 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°; the crystalline form is 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, the X-ray powder diffraction pattern of which includes 4, 6, 8 or 10 diffraction peaks at 2θ equal to 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°; the crystalline form is 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, the X-ray powder diffraction pattern of which includes 4, 6, 8 or 10 diffraction peaks at 2θ equal to 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°; the crystalline form is 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, the X-ray powder diffraction pattern of which includes 4, 6, 8 or 10 diffraction peaks at 2θ equal to 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°; the crystalline form is 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, the X-ray powder diffraction pattern of which includes 4, 6, 8 or 10 diffraction peaks at 2θ equal to 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°; the crystalline form is the 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, the X-ray powder diffraction pattern of which includes 4, 6, 8 or 10 diffraction peaks at 2θ equal to 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°; the crystalline form is 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, the X-ray powder diffraction pattern of which includes 4, 6, 8 or 10 diffraction peaks at 2θ equal to 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°. 9. A crystalline form of an acid addition salt according to claim 8, characterized in that the crystalline form is 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, the X-ray powder diffraction pattern of which includes diffraction peaks at 2θ equal to 6.8±0.2°, 13.4±0.2°, 14.7±0.2°, and 19.5±0.2°, optionally further including 2, 3, 4, 5 or 6 diffraction peaks at 2θ equal to 20.1±0.2°, 23.9±0.2°, 24.4±0.2°, 25.0±0.2°, 23±0.2°, 23.6±0.2°; the crystalline form is 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, the X-ray powder diffraction pattern of which includes diffraction peaks at 2θ equal to 6.1±0.2°, 7.5±0.2° and 8.0±0.2°, optionally further includes 2, 3, 4, 5 or 6 diffraction peaks at 2θ equal to 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°; the crystalline form is 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, the X-ray powder diffraction pattern of which includes diffraction peaks at 24.4±0.2°, 13.3±0.2° and 23.8±0.2°, optionally further includes 2, 3, 4 or 5 diffraction peaks at 2θ equal to 9.0±0.2°, 9.9±0.2°, 26.7±0.2°, 17.2±0.2° and 23.1±0.2°; the crystalline form is 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, the X-ray powder diffraction pattern of which comprises diffraction peaks at 2θ equal to 22.5±0.2°, 8.5±0.2° and 7.2±0.2°, optionally further comprises 2, 3, 4 or 5 diffraction peaks at 2θ equal to 14.4±0.2°, 26.7±0.2°, 12.8±0.2°, 16.7±0.2° and 6.1±0.2°; the crystalline form is 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, the X-ray powder diffraction pattern of which comprises diffraction peaks at 2θ equal to 8.4±0.2°, 7.2±0.2° and 20.1±0.2°, optionally further comprises 2, 3, 4 or 5 diffraction peaks at 2θ equal to 22.7±0.2°, 24.5±0.2°, 25.7±0.2°, 18.9±0.2° and 16.4±0.2°; the crystalline form is 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, the X-ray powder diffraction pattern of which comprises diffraction peaks at 2θ equal to 24.5±0.2°, 13.3±0.2° and 23.9±0.2°, optionally further comprises 2, 3, 4 or 5 diffraction peaks at 2θ equal to 9.0±0.2°, 17.3±0.2°, 19.4±0.2°, 17.7±0.2° and 9.9±0.2°; the crystalline form is the 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, the X-ray powder diffraction pattern of which comprises diffraction peaks at 2θ equal to 7.6±0.2°, 22.5±0.2° and 8.9±0.2°, optionally further comprises 2, 3, 4 or 5 diffraction peaks at 2θ equal to 15.0±0.2°, 26.6±0.2°, 5.8±0.2°, 12.9±0.2° and 11.6±0.2°; the crystalline form is 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, the X-ray powder diffraction pattern of which comprises diffraction peaks at 2θ equal to 17.7±0.2°, 23.5±0.2° and 24.8±0.2°, optionally further comprises 2, 3, 4 or 5 diffraction peaks at 2θ equal to 9.9±0.2°, 22.6±0.2°, 21.2±0.2°, 19.1±0.2° and 29.4±0.2°. 10. A crystalline form of an acid addition salt according to claim 8, characterized in that the crystalline form is 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, the X-ray powder diffraction pattern of which 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°; or the X-ray powder diffraction pattern of which 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°; or the X-ray powder diffraction pattern of which 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°; or the X-ray powder diffraction pattern of which 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°; the crystalline form is 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, the X-ray powder diffraction pattern of which 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°; the crystalline form is 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, the X-ray powder diffraction pattern of which 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°; the crystalline form is 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, the X-ray powder diffraction pattern of which has characteristic peaks at 2θ equal to 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°; the crystalline form is 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, the X-ray powder diffraction pattern of which has diffraction peaks at 2θ equal to 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°; the crystalline form is 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, the X-ray powder diffraction pattern of which has diffraction peaks at 2θ equal to 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°; the crystalline form is 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, the X-ray powder diffraction pattern of which has diffraction peaks at 2θ equal to 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°; the crystalline form is the 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, the X-ray powder diffraction pattern of which has diffraction peaks at 2θ equal to 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°; the crystalline form is 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, the X-ray powder diffraction pattern of which has diffraction peaks at 2θ equal to 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°. 11. A crystalline form of an acid addition salt according to claim 6, characterized in that the crystalline form is 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, the X-ray powder diffraction pattern of which has diffraction peaks at 2θ equal to 6.8±0.2°, 9.3±0.2°, 13.4±0.2° and 14.7±0.2°; or the X-ray powder diffraction pattern of which has diffraction peaks at 2θ equal to 6.8±0.2°, 13.4±0.2°, 14.7±0.2° and 19.5±0.2°; the crystalline form is 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, the X-ray powder diffraction pattern of which has diffraction peaks at 2θ equal to 6.1±0.2°, 7.5±0.2°, 8.0±0.2°, 14.9±0.2° and 23.8±0.2°; the crystalline form is 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, the X-ray powder diffraction pattern of which has diffraction peaks at 2θ equal to 9.0±0.2°, 13.3±0.2°, 19.7±0.2° and 23.1±0.2°; the crystalline form is 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, the X-ray powder diffraction pattern of which has diffraction peaks at 2θ equal to 7.2±0.2°, 14.4±0.2°, 22.5±0.2° and 26.7±0.2°; the crystalline form is 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, the X-ray powder diffraction pattern of which has diffraction peaks at 2θ equal to 7.2±0.2°, 8.4±0.2°, 20.1±0.2° and 22.7±0.2°; the crystalline form is 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, the X-ray powder diffraction pattern of which has diffraction peaks at 2θ equal to 4.8±0.2° and 7.6±0.2°; the crystalline form is 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, the X-ray powder diffraction pattern of which has diffraction peaks at 2θ equal to 9.0±0.2°, 13.3±0.2°, 17.3±0.2° and 24.5±0.2°; the crystalline form is the 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, the X-ray powder diffraction pattern of which has diffraction peaks at 2θ equal to 7.6±0.2°, 15.0±0.2°, 22.5±0.2° and 23.9±0.2°; the crystalline form is 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, the X-ray powder diffraction pattern of which has diffraction peaks at 2θ equal to 9.9±0.2°, 17.7±0.2°, 22.6±0.2° and 24.8±0.2°. 12. A crystalline form of an acid addition salt according to claim 11, characterized in that the crystalline form is 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, the X-ray powder diffraction pattern of which also has diffraction peaks at 2θ equal to 17.3±0.2°, 19.5±0.2°, 20.8±0.2°, 23.9±0.2° and 25.0±0.2°; or the X-ray powder diffraction pattern of which also has one or two diffraction peaks at 2θ equal to 14.7±0.2° and 19.5±0.2°; the crystalline form is 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, the X-ray powder diffraction pattern of which also has diffraction peaks at 2θ equal to 8.4±0.2°, 18.8±0.2°, 20.7±0.2°, 22.3±0.2° and 22.8±0.2°; the crystalline form is 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, the X-ray powder diffraction pattern of which also has diffraction peaks at 2θ equal to 9.9±0.2°, 17.2±0.2°, 20.3±0.2° and 26.7±0.2°; the crystalline form is 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, the X-ray powder diffraction pattern of which also has diffraction peaks at 2θ equal to 6.1±0.2°, 12.8±0.2°, 16.7±0.2° and 20.8±0.2°; the crystalline form is 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, the X-ray powder diffraction pattern of which also has diffraction peaks at 2θ equal to 5.8±0.2°, 16.4±0.2°, 18.9±0.2° and 26.7±0.2°; the crystalline form is 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, the X-ray powder diffraction pattern of which also has diffraction peaks at 2θ equal to 9.9±0.2°, 17.7±0.2°, 19.4±0.2° and 26.9±0.2°; the crystalline form is the 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, the X-ray powder diffraction pattern of which also has diffraction peaks at 2θ equal to 5.8±0.2°, 12.9±0.2°, 19.9±0.2° and 26.6±0.2°; the crystalline form is 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, the X-ray powder diffraction pattern of which also has diffraction peaks at 2θ equal to 16.9±0.2°, 21.2±0.2°, 23.5±0.2° and 29.4±0.2°. 13. A crystalline form of an acid addition salt according to claim 12, characterized in that the crystalline form is 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, the X-ray powder diffraction pattern of which also has diffraction peaks at 2θ equal to 9.8±0.2°, 18.4±0.2°, 19.1±0.2°, 20.1±0.2°, 23.0±0.2°, 23.6±0.2°, 24.4±0.2°, 27.3±0.2° and 30.7±0.2°; or the X-ray powder diffraction pattern of which also has one or more diffraction peaks at 2θ (±0.2°) equal to 20.1±0.2°, 23.9±0.2°, 24.4±0.2° and 25.0±0.2°; the crystalline form is 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, the X-ray powder diffraction pattern of which also has diffraction peaks at 2θ equal to 13.5±0.2° and 25.2±0.2°; the crystalline form is 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, the X-ray powder diffraction pattern of which also has diffraction peaks at 2θ equal to 14.3±0.2°, 21.6±0.2°, 23.8±0.2° and 28.4±0.2°; the crystalline form is 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, the X-ray powder diffraction pattern of which also has diffraction peaks at 2θ equal to 8.5±0.2°, 15.2±0.2°, 22.0±0.2° and 25.3±0.2°; the crystalline form is 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, the X-ray powder diffraction pattern of which also has diffraction peaks at 2θ equal to 12.6±0.2°, 14.7±0.2°, 17.2±0.2° and 25.1±0.2°; the crystalline form is 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, the X-ray powder diffraction pattern of which also has diffraction peaks at 2θ equal to 14.3±0.2°, 18.6±0.2°, 28.3±0.2° and 37.5±0.2°; the crystalline form is the 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, the X-ray powder diffraction pattern of which also has diffraction peaks at 2θ equal to 8.9±0.2°, 16.8±0.2°, 20.7±0.2° and 24.6±0.2°; the crystalline form is 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, the X-ray powder diffraction pattern of which also has diffraction peaks at 2θ equal to 17.3±0.2°, 19.1±0.2°, 28.4±0.2° and 30.5±0.2°. 14. A crystalline form of an acid addition salt according to claim 13, characterized in that the crystalline form is 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, the X-ray powder diffraction pattern of which also has diffraction peaks at 2θ equal to 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°; or the X-ray powder diffraction pattern of which also has diffraction peaks at 2θ (±0.2°) equal to 23±0.2° and 23.6±0.2°; the crystalline form is 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, the X-ray powder diffraction pattern of which also has diffraction peaks at 2θ equal to 24.4±0.2°, 30.5±0.2° and 32.6±0.2°; the crystalline form is 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, the X-ray powder diffraction pattern of which also has diffraction peaks at 2θ equal to 12.1±0.2°, 19.1±0.2° and 23.8±0.2°; the crystalline form is 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, the X-ray powder diffraction pattern of which also has diffraction peaks at 2θ 14.4±0.2°, 18.2±0.2°, 24.5±0.2° and 25.7±0.2°; the crystalline form is 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, the X-ray powder diffraction pattern of which also has diffraction peaks at 2θ equal to 16.7±0.2°, 20.0±0.2°, 20.4±0.2°, 24.0±0.2° and 30.4±0.2°; the crystalline form is the 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, the X-ray powder diffraction pattern of which also has diffraction peaks at 2θ equal to 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°; the crystalline form is 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, the X-ray powder diffraction pattern of which also has diffraction peaks at 2θ equal to 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°. 15. A crystalline form of an acid addition salt according to claim 14, characterized in that the crystalline form is 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, the X-ray powder diffraction pattern of which also has diffraction peaks at 2θ equal to 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°; or the X-ray powder diffraction pattern of which also has one or two diffraction peaks at 9.3±0.2° and 17.3±0.2°. 16. A crystalline form of an acid addition salt according to claim 15, characterized in that the crystalline form is 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, the X-ray powder diffraction pattern of which also has diffraction peaks at 2θ equal to 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°; or the X-ray powder diffraction pattern of which also has one or two diffraction peaks at 2θ equal to 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°. 17. A crystalline form of an acid addition salt according to claim 16, characterized in that the crystalline form is 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, the X-ray powder diffraction pattern of which also has diffraction peaks at 2θ equal to 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°; or the X-ray powder diffraction pattern of which also has one or two diffraction peaks at 2θ equal to 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°. 18. A crystalline form of an acid addition salt according to claim 17, characterized in that the crystalline form is 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, the X-ray powder diffraction pattern of which is essentially as shown in Figure 1; the crystalline form is 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, the X-ray powder diffraction pattern of which is essentially as shown in Figure 4; the crystalline form is 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, the X-ray powder diffraction pattern of which is essentially as shown in Figure 5; the crystalline form is 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, the X-ray powder diffraction pattern of which is essentially as shown in Figure 6; the crystalline form is 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, the X-ray powder diffraction pattern of which is essentially as shown in Figure 7; the crystalline form is 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, the X-ray powder diffraction pattern of which is essentially as shown in Figure 8; the crystalline form is 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, the X-ray powder diffraction pattern of which is essentially as shown in Figure 9; the crystalline form is the 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, the X-ray powder diffraction pattern of which is essentially as shown in Figure 10; the crystalline form is 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, the X-ray powder diffraction pattern of which is essentially as shown in Figure 11. 19. A crystalline form of an acid addition salt according to claim 18, characterized in that the crystalline form is 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, the thermogravimetric analysis (TGA) profile of which is essentially as shown in Figure 2. 20. A crystalline form of an acid addition salt according to claim 19, characterized in that the crystalline form is 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, the differential scanning calorimetry (DSC) profile of which is essentially as shown in Figure 3. 21. A method for producing crystalline form A of the ethanesulfonate salt according to any one of claims 8 to 20, in particular comprising the following steps: 1) weighing the free base and suspending it in a weak solvent; 2) weighing ethanesulfonic acid and dissolving it in an organic solvent; 3) adding the solution from step 2) to the suspension from step 1) and stirring the resulting mixture to precipitate the solid; 4) mixing and cooling the mixture, followed by precipitation of the crystal to obtain the target product; the weak solvent is one or more solvents selected from the group consisting of methanol, ethanol, isopropanol, tetrahydrofuran, ethyl acetate, acetonitrile and acetone; the organic solvent in step 2) is one or more solvents selected from the group consisting of methanol, ethanol, isopropanol, tert-butanol, acetone, tetrahydrofuran, toluene, N,N-dimethylformamide and acetonitrile. 22. A pharmaceutical composition having an inhibitory effect on PI3Kα, containing a therapeutically effective amount of an acid addition salt according to any of claims 1-4 and 6-7 or a crystalline form according to any of claims 8-20 and one or more pharmaceutically acceptable carriers or excipients. 23. The pharmaceutical composition according to claim 22, characterized in that the acid addition salt is where M is selected from the group consisting of sulfuric acid, ethanesulfonic acid and methanesulfonic acid. 24. Use of an acid addition salt according to any one of claims 1-4 and 6-7, a crystalline form according to any one of claims 8-20 or a pharmaceutical composition according to claim 23 for producing a PI3K (phosphatidylinositol 3-kinase)-inhibiting drug, wherein the drug is intended for the treatment of cancer, a bone disease, an inflammatory disease, an immune disease, a nervous system disease, a metabolic disease, a respiratory disease and a heart disease; wherein said 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, kidney cancer, myelodysplastic syndrome, acute myeloid leukemia and colorectal cancer. 25. The use according to claim 24, wherein PI3K is PI3Kα.

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